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THETWO TONDITIONUS 20170306038A1 TO MARTIN ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017/ 0306038 A1 BROGDON et al. (43 ) Pub . Date : Oct. 26 , 2017 (54 ) COMPOSITIONS AND METHODS OF USE Publication Classification FOR AUGMENTED IMMUNE RESPONSE (51 ) Int. Cl. AND CANCER THERAPY CO7K 16 / 28 ( 2006 .01 ) (71 ) Applicants : Jennifer BROGDON , Sudbury, MA CO7K 16 / 28 ( 2006 . 01) (US ); Daniela CIPOLLETTA , A61K 45 /06 (2006 . 01) Arlington , MA (US ) ; Glenn A61K 39 /00 ( 2006 .01 ) DRANOFF , Lexington , MA ( US ) ; A61K 39 /00 (2006 .01 ) Deborah A . KNEE . Del Mar. CA (US ) : (52 ) U .S . Cl. CPC ...... CO7K 16 / 2878 ( 2013. 01 ) ; C07K 16 /2818 Fei WANG , San Diego , CA (US ) ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; CO7K ( 72 ) Inventors : Jennifer BROGDON , Sudbury , MA 2317 / 74 (2013 . 01 ) ; C07K 2317 / 732 ( 2013 .01 ); (US ) ; Daniela CIPOLLETTA , CO7K 2317 /567 (2013 . 01 ) ; COZK 2317 / 56 Arlington , MA (US ) ; Glenn (2013 . 01 ); CO7K 2317 /51 ( 2013 .01 ); CO7K DRANOFF , Lexington , MA (US ) ; 2317 /24 (2013 .01 ) ; A61K 2039 /507 (2013 . 01 ); Deborah A . KNEE , Del Mar, CA (US ) ; A61K 2039 /505 ( 2013 . 01 ) ; COZK 2317 / 75 ( 2013 .01 ) ; CO7K 2317/ 92 ( 2013 .01 ) ; CO7K Fei WANG , San Diego , CA (US ) 2317/ 515 (2013 . 01) ( 21 ) Appl. No. : 15 /517 ,872 (57 ) ABSTRACT (22 ) PCT Filed : Oct . 8 , 2015 The present invention provides antibody compositions , (86 ) PCT No. : PCT/ US2015 / 054770 including , e . g ., antibodies, engineered antibodies and anti body fragments that bind to a tumor necrosis factor receptor $ 371 ( c ) ( 1 ), superfamily member ( i. e . , 18 ) , and compositions comprising (2 ) Date : Apr. 7, 2017 one or more additional therapeutic agents. Provided com positions are useful in enhancing CD4 + and CD8 + T cell Related U . S. Application Data responses, and in the treatment, amelioration and prevention (60 ) Provisional application No. 62/ 061, 644 , filed on Oct . of diseases that can be counteracted with an augmented 8 , 2014 , provisional application No . 62 / 198 ,673 , filed immune response, e . g . , cancers. Also provided are methods on Jul. 29, 2015 , provisional application No . 62 / 220 , of use of combinations that find use in treatment or preven 764 , filed on Sep . 18 , 2015 . tion of cancerous or infectious conditions and disorders. Patent Application Publication Oct. 26 , 2017 Sheet 1 of 14 US 2017 /0306038 A1

120 120 120

100100 -100 _100I Bod

60 FIG.1A ? or L607 A40

- P

0+ 0+ 0.1 04 -0.17 0.2 0.1 -0.14 -0.1 27.0 -0.2 2.0- RPTGGPCCGPGRLLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVCPEFHCGDPCCTTCRHHPCPPGQGVQSGGKFSFGFQCDCASGTFSGGHEGHCKPWTDCTCFGFL 0.05 059.0- -0.15 Patent Application Publication Oct. 26 , 2017 Sheet 2 of 14 US 2017 /0306038 A1

CRD1 CRD2 CRD3 TM

hGITR ecd hGITR CRD1 - tail

- - hGITR CRD2 - tail

- - hGITR CRD - tail

- - hGITR ecd - tail - FIG . 1B

- OD650nm ????????????????? hGITR ecd CRD1 - tail CRD2 - tail CRD3 - tail tail MAB4 MAB5 Control MAB FIG . 1C Patent Application Publication Oct. 26 , 2017 Sheet 3 of 14 US 2017 /0306038 A1 PBS hGITRecdmFc R90A R59A R56A R51A R48A R38A R27A K147 K129A K105A FIG.1D E161A AlanineMutantConstructs E125A E78A E69A E65A E64A D133A JUDULLUQUQU D114A D83A D71A D60A ) D46 _ _ 650. D . 0 Patent Application Publication Oct. 26 , 2017 Sheet 4 of 14 US 2017 /0306038 A1

OD650 OD650 ?não

o GL OI MAB4 MAB4 1C MAB4 MAB5 Human GITR cyno GITR Human GITR Mouse GITR O Rat GITR ODFIG . 2A FIG . 2B Human GITR Ligand and MAB7 100007 Competition 9000 55h 80007000 6000 PE?hthumanMFI 5000 4000 2000 + 4nM MABZ AAAA OD650 1000 o 4nM Isotype Control hoNon 04 RmpimppiAni Amrit ? ? ö . . . Human Mouse Cyno Human GITR Ligand to MAB7 / Isotype GITR GITR GITR control Molar Ratio USFIG . 2C FIG . 2D Patent Application Publication Oct. 26 , 2017 Sheet 5 of 14 US 2017 /0306038 A1

OD590nm Ö62ö° WWWWH ??????????????????? BAFFRSBCMA Cova DR53 CD1373 HVEM DcR38NGFR TNFR3B 0X40 CD27 TNFR13 DR3S DR4 TACIO Cosa FAS GIINVTTTTTTT MAB4 MAB5 Control MAB FIG . 2E Patent Application Publication Oct . 26, 2017 Shet 6 of 14 US 2017 /0306038 A1

IIII?

111mm,III 0.1101000 [mAb]nM) -MAB4+XLMABSMAB5 FIG.3B [mAb]MM-MAB4+XLMABS FIG.3D [T]TWITTIT??0.001011i101001000 IIII

TIT ope > P?np 64208648? Activation Fold Activation Fold

??????????????????? Concentration(nM) i101001000 ?HumanGITR-L AMAB4+XL·MAB7•MAB8 [GITR-]nM FIG.3A "dan61i101001000 FIG.3C

? TITm??? 765452? ? ? ? ?? ? ? Activity Fold 1? Activation Fold Patent Application Publication Oct. 26 , 2017 Sheet 7 of 14 US 2017 /0306038 A1

Proliferation of CD4+ T cells Proliferation of CD8 + T cells •

Proliferatingcells/uLofsample ??©oto Proliferatingcells/plofsample

5 10 15 0 5 10 15 % GITR Ab Conjugated on Beads % GITR Ab Conjugated on Beads - IC - MAB7 + IC + MAB7 FIG . 4A FIG . 4B

Secretion of IFNY

[IFNy]ng/ml ?is

H o6de0 5 10 15 % GITR Ab Conjugated on Beads + IC + MAB7 FIG . 4C Patent Application Publication Oct. 26 , 2017 Sheet 8 of 14 US 2017 /0306038 A1

KH H

hGITR-Daudi#1F5(~5,700GITRmolecules) örg HGITR-Daudi#2011(~5,700GITRmolecules) [Ab]nM FIG.5B [Ab]nMFIG.5D

öso 35007+Control3000+ MAB7 . j 0001. 0 35007+Control3000+ +MAB7 500 2500+ 500 04 250020004 >1500 1000 01ATIRE 200015001 1000

04A+ hGITR-Daudi#203(~4,000GITRmolecules) HGITR-Daudi#1F7(~8,700GITRmolecules) .öz FIG.5C •[AB]NM FIG.5A [Ab]nM

35007+Control30004 +MABZ azez 35007+Control3000+ MAB7 ?? 2500 15004 1000500 2500 150041000 500 >2000 220004 O4KHEH Patent Application Publication Oct. 26 , 2017 Sheet 9 of 14 US 2017 /0306038 A1

H HH %HGITR+ofCD19-CD8cells %hfctofCD19-CD8+cells

2?? o untreated-toe IgG14to NoStimolanti Ö : g CD3/CD28 untreated MAB7 (nM ) FIG .6A FIG .OB

to+* %plkKtofCD19-CD8+cells KH %CD25+ofCD19-CD8cells loeto =o;$: met =o;$ 1961to 1961isto untreatedto ? Á S untreatedpeber MAB7 (nm ) MAB7 ( nM ) FIG . 6C FIG .OD Patent Application Publication Oct. 26 , 2017 Sheet 10 of 14 US 2017 /0306038 A1

MABI ZE.FIG? 90218 Vehicle doanh cells + CD8 + CD3 - CD19 of + hGITR %

16 HEH HA 14 *

ISIT FIG.ZD HHHH Vehicle og DO ou cells + FOXP3 + CD4 + CD3 - CD19 of + HGITR % .MAB715mg/kg Dose 24 1 # MABT Ò 1500€Vehicle 94 Vehicle FIG.7C? § § G SEM )mm3 ( Volume Tumor Mean cells + CD8 + CD3 - CD19 of + hGITR %

* 11 MAB7 FIG.7B - Vehicle 9 og 8 cells + FOXP3 + CD4 + CD3 - CD19 of + hGITR % Patent Application Publication Oct . 26, 2017 Shet 11 of14 US 2017 /0306038 A1

* * "*

Vehicle? AbsoluteCD19-CD3+ ·?4:* AbsoluteCD19-CD3+CD8CD25 cellsFOXP3+CD4CD3CD19-% cells/mmtumor cels/mmstumor ….MAP74M ?? ???99 vehiceH?? MAB7. MAB7] ed999 9MAB7\ Vehicle | FIG. 8A FIG. 8B FIG . 8C -* p = 0. 052 Teff/regRatio Spotspermillioncells gegg .

- ? VehicleVehicle )Me79 FIG .8E Patent Application Publication Oct. 26 , 2017 Sheet 12 of 14 US 2017 /0306038 A1

* 1 - DIA SpleenCD8PD1+ 1- ÖDTA FIG.9C 18 mlgg2a Ti ? ? 98 0 2 cells + CD8 + CD3 - CD19 of + 1 - PD %

* CD8PD1+ 14- 04 Mic20mlgg2a 4000 tumor mmº per cells + PD1 + CD8 + CD3 - CD19 of Number

* TumorCD8PD1+ N 14- SOTA FIG.9A -migc2a mlgG2a TiI 8 = = = p cells + CD8 + CD3 - CD19 of + PD1 % Patent Application Publication Oct. 26 , 2017 Sheet 13 of 14 US 2017 /0306038 A1

* * U co -

- -

- - TTTTT TTT B-antiRMP114+mlgg2a

71421283542 C-antiDTA–1+rlgg2aD—RMP114 FIG.10 - TTTTTTTTTTTTTTTTTTTTTTTTT Daysposttumorimplantation A—isotypecontrol

0 study on remaining Percent juajed uogjeddy and uopjes Po 97 ' LIOT J??US JODI DI SN LIOZ / 8E0908O IV

GITR – 0 + PD1 - a * $ GITR - a +PD1 - 0 Isotype + GITRGITR -- G0 ) Isotypet + GITRGITR - aO

* Isotype+ PD1– 0 : 1 Isotype+ PD1 - a Isotypes de Isotypes $ $ o pom Neu on )tumor ( CD8 / PD1 ) spleen( CD8/ PD1

* - - - GITR – a + PD1 - a - GITR - a + PD1 - a * -Isotype + GITR- Isotype + GITR - -

* . 1 Isotype + PD1 - a Isotype +PD1 - a FIG.11 Isotypes : : Isotypes $ ? o ?? ,) tumor( CD8 /TIM3 ) spleen ( CD8 / TIM3 ofe GITR - a + PD1 - a GITRI - a + PD1 - a : on Isotype + GITR - a Isotype + GITR - a * Isotype+ PD1 - 0 Isotype+ PD1 - a • Isotypes • : Isotypes 8 8 8 8 8 e 28? tumor CD8 / + LAG3 spleen CD8 / + LAG3 US 2017 /0306038 A1 Oct . 26 , 2017

COMPOSITIONS AND METHODS OF USE and human GITR , it is unknown whether findings seen with FOR AUGMENTED IMMUNE RESPONSE surrogate studies in mouse would translate to modification AND CANCER THERAPY of human GITR function . RELATED APPLICATIONS DESCRIPTION OF THE INVENTION [ 0001 ] This application claims priority to and the benefit [0006 ] We have identified antibodies that specifically bind of U . S . Provisional Application No. 62 / 061, 644 , filed Oct . 8 , to human glucocorticoid - induced tumor necrosis factor 2014 , U . S . Provisional Application No. 62/ 198 ,673 , filed receptor superfamily member 18 (“ GITR ” ) , wherein the Jul. 29, 2015 , and U . S . Provisional Application No . 62/ 220 , antibodies have in vitro hGITR agonist activity when cross 764 , filed Sep . 18 , 2015 , each of which is hereby incorpo linked in vitro , and wherein the antibodies confer hGITR rated by reference in its entirety . activity in vivo and induce an elevated Teff : Treg ratio at tumor sites , resulting in inhibition of tumor progression . FIELD OF THE INVENTION Thus , the present invention provides agonist antibodies , antibody fragments , and antigen binding molecules that [ 0002 ] The present invention relates to antibodies, anti specifically bind to and promote intracellular signaling and body fragments , and antigen binding molecules that bind to or modulate immune response through targeting cells tumor necrosis factor receptor superfamily member 18 / glu expressing human GITR . In one aspect , the invention pro cocorticoid induced TNFR -related protein (“ GITR ” ) , and vides isolated antibodies , antibody fragments , and antigen more specifically that are agonists , stimulate signaling binding molecules that specifically bind to human GITR , through the receptor and/ or modulate immune response . wherein the antibody, antibody fragment, or the antigen binding molecule binds to an epitope comprising the cyste BACKGROUND OF THE INVENTION ine - rich domain 1 ( “ CRD1" , SEQ ID NO : 4 : CGPGRLLL [0003 ] Glucocorticoid - induced TNFR -related protein GTGTDARCCRVHTTRCCRDYPGEECCSEWDC ) and (“ GITR ” ) is a member of the Tumor Necrosis Factor Super the cysteine- rich domain 2 (“ CRD2” , SEQ ID NO : 5 : family ( TNFRSF ) which includes more than 20 type I MCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQG transmembrane proteins, several splicing variants and sev KFSFGFQC ), and wherein the antibody , antibody fragment, eral viral proteins, all of which have a cysteine -rich domain or the antigen binding molecule is an agonist of GITR , and as a common structural feature . The extracellular domain wherein the antibody, antibody fragment, or the antigen (ECD ) ofGITR consists of 3 cysteine -rich domains (CRDs ) , binding molecule optionally has an intact or increased FcR followed by a transmembrane domain ( TM ) and an intrac effector function . ellular domain ( ICD ) . [ 0007 ] In some embodiments , the antibody, antibody frag [ 0004 ] GITR expression is detected constitutively on ment , or the antigen binding molecule binds to an epitope murine and human CD4 + CD25 + regulatory T cells which comprising SEQ ID NO : 88 ) of human GITR . In some can be further increased upon activation . In contrast, effector embodiments , the antibody, antibody fragment, or antigen CD4 +CD25 - T cells and CD8 + CD25 - T cells express low binding molecule competes with an antibody or antibody to undetectable levels of GITR , which is rapidly upregulated fragment that binds to an epitope comprising SEQ ID NO : 88 following T cell receptor activation . Expression of GITR has of human GITR . In some embodiments , the antibody, anti also been detected on activated NK cells , dendritic cells , and body fragment , or antigen binding molecule binds to at least macrophages . Signal transduction pathway downstream of one amino acid residue within SEQ ID NO : 88 of human GITR has been shown to involve MAPK and the canonical GITR , for example , the antibody , antibody fragment, or NFKB pathways . Various TRAF family members have been antigen binding molecule binds to an epitope that overlaps implicated as signaling intermediates downstream of GITR with SEQ ID NO :88 of human GITR . (Nocentini et al. ( 2005 ) Eur . J . Immunol. , 35 : 1016 - 1022 ) . [0008 ] In some embodiments, the antibody , antibody frag [ 0005 ] Cellular activation through GITR is believed to ment, or the antigen binding molecule binds to an epitope serve several functions depending on the cell type and comprising CRD1 ( residues 34 -72 , SEQ ID NO : 4 ) and microenvironment including , but not limited to , costimula residue 78 of human GITR . In some embodiments , the tion to augment proliferation and effector function , inhibi antibody, antibody fragment, or antigen binding molecule tion of suppression by regulatory T cells, and protection competes with an antibody or antibody fragment that binds from activation - induced cell death ( Shevach and Stephens to an epitope within CRDi ( residues 34 - 72 , SEO ID NO : 4 ) ( 2006 ) Nat . Rev. Immunol. , 6 :613 -618 ). Ko et al. (( 2005 ) J . and residue 78 of human GITR . In some embodiments , the Exp . Med . , 202 : 885 - 891 ) first demonstrated that an agonis antibody , antibody fragment, or antigen binding molecule tic monoclonal antibody against mouse GITR effectively binds to at least one amino acid residue within CRD1 induced tumor -specific immunity and eradicated established ( residues 34 -72 , SEQ ID NO : 4 ) and residue 78 of human tumors in a mouse syngeneic tumor model . Additionally GITR , for example , the antibody , antibody fragment, or and /or alternatively , an anti -mGITR which has functional Fc antigen binding molecule binds to an epitope that overlaps effector activity has been shown in some preclinical models with CRDI (residues 34 - 72 , SEQ ID NO : 4 ) and residue 78 to deplete regulatory T cells , as well as enhance T effector of human GITR . cell proliferation and cytokine secretion in select tumor [0009 ] In some embodiments , the antibody , antibody frag environment. These findings suggest that an agonistic anti ment, or antigen binding molecule binds to SEQ ID NO : 1 body to mGITR can disrupt immune tolerance balance , and comprises ( a ) a heavy chain variable region comprising which in turn will allow T cells to combat tumors and a human heavy chain wherein : i) the heavy chain CDR1 persistent viral infections. However, studies to date have comprises SEQ ID NO :22 , and ii ) the heavy chain CDR2 largely focused on use of surrogate antibodies in rodent comprises a sequence selected from any one of SEQ ID systems. Due to the divergence of structure among mouse NO : 23 , SEQ ID NO : 24 , SEQ ID NO : 25, SEQ ID NO : 26 , US 2017 /0306038 A1 Oct. 26 , 2017 and SEQ ID NO : 27 , and iii ) the heavy chain CDR3 com v ) the light chain CDR2 comprises SEQ ID NO :33 , and vi) prises SEO ID NO : 29 or SEO ID NO : 109 ; and ( b ) a light the light chain CDR3 comprises SEQ ID NO :34 . chain variable region , wherein i ) the light chain CDR1 [0017 ] In some embodiments , provided is an antibody, comprises SEQ ID NO : 30 or SEQ ID NO : 31 , and ii ) the antibody fragment or antigen binding molecule wherein : light chain CDR2 comprises SEQ ID NO : 33 , and iii ) the wherein : i ) the heavy chain CDR1 comprises SEQ ID light chain CDR3 comprises SEQ ID NO :34 . NO : 22 ; ii) the heavy chain CDR2 comprises SEQ ID [0010 ] In some embodiments , the antibody, antibody frag NO :25 ; iii ) the heavy chain CDR3 comprises SEQ ID ment, or antigen binding molecule binds to SEQ ID NO : 88 NO :29 ; iv ) the light chain CDR1 comprises SEQ ID NO : 30 ; and comprises (a ) a heavy chain variable region comprising v ) the light chain CDR2 comprises SEQ ID NO : 33 , and vi ) a human heavy chain wherein : i ) the heavy chain CDR1 the light chain CDR3 comprises SEQ ID NO : 34 . comprises SEQ ID NO : 22 , and ii ) the heavy chain CDR2 [0018 ] In some embodiments , provided is an antibody , comprises a sequence selected from any one of SEQ ID antibody fragment or antigen binding molecule wherein : NO : 23, SEQ ID NO : 24 , SEQ ID NO : 25 , SEQ ID NO : 26 , wherein : i ) the heavy chain CDR1 comprises SEQ ID and SEQ ID NO : 27 , and iii ) the heavy chain CDR3 com NO : 22 ; ii ) the heavy chain CDR2 comprises SEQ ID prises SEQ ID NO : 29 or SEQ ID NO : 109 ; and (b ) a light NO :26 ; iii ) the heavy chain CDR3 comprises SEQ ID chain variable region , wherein i) the light chain CDR1 NO : 29 ; iv ) the light chain CDR1 comprises SEQ ID NO : 30 ; comprises SEQ ID NO :30 or SEQ ID NO :31 , and ii ) the v ) the light chain CDR2 comprises SEQ ID NO : 33 , and vi ) light chain CDR2 comprises SEQ ID NO : 33 , and iii ) the the light chain CDR3 comprises SEQ ID NO : 34 . light chain CDR3 comprises SEQ ID NO : 34 . [0019 ] In some embodiments , provided is an antibody, [0011 ] With respect to further embodiments of the anti antibody fragment or antigen binding molecule wherein : bodies , antibody fragments , or antigen binding molecules , in wherein : i ) the heavy chain CDR1 comprises SEQ ID some embodiments the heavy chain variable region has at NO : 22 ; ii ) the heavy chain CDR2 comprises SEQ ID least 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid NO : 27 ; iii) the heavy chain CDR3 comprises SEQ ID sequence identity to the variable region of SEQ ID NO : 16 NO : 29 ; iv ) the light chain CDR1 comprises SEQ ID NO : 30 ; and the light chain variable region has at least 95 % , 96 % , v ) the light chain CDR2 comprises SEQ ID NO : 33 , and vi ) 97 % , 98 % , 99 % , or 100 % amino acid sequence identity to the light chain CDR3 comprises SEQ ID NO :34 . the variable region of SEQ ID NO : 17 . In particular embodi [0020 ] In some embodiments , provided is an antibody , ments , the antibody, antibody fragment, or antigen binding antibody fragment or antigen binding molecule wherein : molecule comprises a heavy chain comprising SEQ ID wherein : i ) the heavy chain CDR1 comprises SEQ ID NO : 16 and a light chain comprising SEQ ID NO : 17 . In some NO : 22 ; ii ) the heavy chain CDR2 comprises SEQ ID embodiments , the antibody, antibody fragment, or antigen NO : 25 ; iii ) the heavy chain CDR3 comprises SEQ ID binding molecule competes with an antibody that comprises NO : 109; iv ) the light chain CDR1 comprises SEQ ID a heavy chain comprising SEQ ID NO : 16 and a light chain NO : 30 ; v ) the light chain CDR2 comprises SEO ID NO : 33 , comprising SEQ ID NO : 17 . and vi) the light chain CDR3 comprises SEQ ID NO :34 . [0012 ] In some embodiments, the heavy chain FR4 is a [ 0021 ] In a further aspect, the invention provides antibod human germline FR4 . In particular embodiments , the heavy ies, antibody fragments, or antigen binding molecules that chain FR4 is SEQ ID NO :42 . specifically bind GITR , wherein the antibody or antibody [0013 ] In some embodiments , the light chain FR4 is a fragment comprises a heavy chain variable region and a light human germline FR4 . In particular embodiments, the light chain variable region wherein : i) the CDR1 of the heavy chain FR4 is SEQ ID NO : 50 . chain comprises an amino acid sequence selected from the [0014 ] In some embodiments , provided is an antibody, group consisting of SEQ ID NO : 22, SEQ ID NO : 79 , or SEQ antibody fragment or antigen binding molecule wherein : i) ID NO : 84 ; ii ) the CDR2 of the heavy chain comprises an the heavy chain CDR1 comprises SEQ ID NO :22 or SEQ ID amino acid sequence selected from the group consisting of NO : 84 ; ii ) the heavy chain CDR2 comprises SEQ ID NO :28 SEQ ID NO : 23 , SEQ ID NO : 24 , SEQ ID NO :25 , SEQ ID or SEQ ID NO :80 ; iii ) the heavy chain CDR3 comprises NO : 26 , SEQ ID NO : 27 , SEQ ID NO :62 , and SEQ ID SEQ ID NO : 29 or SEQ ID NO : 109 ; iv ) the light chain NO : 80 ; iii ) the CDR3 of the heavy chain comprises SEQ ID CDR1 comprises SEQ ID NO : 30 or SEQ ID NO : 85 ; v ) the NO : 29 or SEQ ID NO : 109; iv ) the CDR1 of the light chain light chain CDR2 comprises SEQ ID NO :33 or SEQ ID comprises an amino acid sequence selected from the group NO :82 , and vi) the light chain CDR3 comprises SEQ ID consisting of SEQ ID NO :30 , SEQ ID NO :31 , SEQ ID NO : 34 or SEQ ID NO :83 . NO :63 , SEQ ID NO :81 , SEQ ID NO :85 , and SEQ ID [0015 ] In some embodiments , provided is an antibody, NO : 86 ; v ) the CDR2 of the light chain comprises an amino antibody fragment or antigen binding molecule wherein : acid sequence selected from the group consisting of SEQ ID wherein : i ) the heavy chain CDR1 comprises SEQ ID NO : 33 , SEQ ID NO :64 , and SEQ ID NO : 82 ; and the CDR3 NO : 22 ; ii ) the heavy chain CDR2 comprises SEQ ID of the light chain comprises SEQ ID NO :34 or SEQ ID NO : 23 ; iii ) the heavy chain CDR3 comprises SEQ ID NO : 83 . NO : 29 ; iv ) the light chain CDR1 comprises SEQ ID NO : 30 ; [0022 ] In other embodiments of the antibodies, antibody v ) the light chain CDR2 comprises SEQ ID NO : 33 , and vi) fragments , or antigen binding molecules , the heavy chain the light chain CDR3 comprises SEQ ID NO : 34 . variable region has at least 90 % , 93 % , 95 % , 96 % , 97 % , 10016 ). In some embodiments, provided is an antibody, 98 % , 99 % , or 100 % amino acid sequence identity to the antibody fragment or antigen binding molecule wherein : variable region of a sequence selected from the group wherein : i ) the heavy chain CDR1 comprises SEQ ID consisting of SEQ ID NO : 6 , SEQ ID NO : 8 , SEQ ID NO : 12 , NO : 22 ; ii ) the heavy chain CDR2 comprises SEQ ID SEQ ID NO : 14 , SEQ ID NO : 99 and SEQ ID NO : 105 , and NO :24 ; iii ) the heavy chain CDR3 comprises SEQ ID the light chain variable region has at least 90 % , 93 % , 95 % , NO : 29 ; iv ) the light chain CDR1 comprises SEQ ID NO :31 ; 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence US 2017 /0306038 A1 Oct. 26 , 2017 identity to the variable region of a sequence selected from embodiments the antibody, antibody fragment, or antigen the group consisting of SEQ ID NO : 9 and SEQ ID NO : 7 . In binding molecule comprises an IgG isotype antibody Fc particular embodiments , the isolated antibody, antibody region . In particular embodiments the antibody, antibody fragment, or antigen binding molecule comprises a heavy fragment, or antigen binding molecule comprises an IgG1 or chain variable domain comprising a sequence selected from an IgG2 isotype antibody Fc region . In certain embodiments any of SEQ ID NO : 6 , SEQ ID NO :8 , SEQ ID NO : 10 , SEQ the antibody , antibody fragment, or antigen binding mol ID NO : 12 , SEQ ID NO : 14 , SEQ ID NO : 99 and SEQ ID ecule is an IgG1 or an IgG2 antibody . In some embodiments , NO : 105 ; and light chain variable domain comprising SEQ the antibody, antibody fragment, or antigen binding mol ID NO :7 or SEQ ID NO : 9 . In some embodiments , the ecule contains at least one mutation that modulates ( i. e ., isolated antibody, antibody fragment, or antigen binding increases or decreases ) binding of the antibody or antibody molecule comprises a heavy chain variable domain of SEQ fragment to an Fc receptor. In some embodiments , the ID NO : 6 and a light chain variable domain of SEQ ID NO : 7 . antibody , antibody fragment, or antigen binding molecule In some embodiments , the isolated antibody or antibody contains at least one mutation that modulates ( i . e . , increases fragment comprises a heavy chain variable domain com or decreases ) the antibody , antibody fragment, or antigen prising SEQ ID NO : 8 and a light chain variable domain binding molecule to activate an Fc receptor. In particular comprising SEQ ID NO : 9 . In other embodiments , the iso embodiments, the antibody, antibody fragment, or antigen lated antibody or antibody fragment comprises a heavy binding molecule contains at least one mutation that chain variable domain comprising SEQ ID NO : 10 and a increases binding of the antibody or antibody fragment to an light chain variable domain comprising SEQ ID NO : 7 . In Fc receptor. In certain embodiments , the antibody, antibody other embodiments , the isolated antibody or antibody frag fragment, or antigen binding molecule contains at least one ment comprises a heavy chain variable domain comprising mutation that increases the antibody, antibody fragment, or SEQ ID NO : 12 and a light chain variable domain compris antigen binding molecule to activate an Fc receptor. ing SEQ ID NO : 7 . In other embodiments , the isolated [0029 ] In some embodiments , the antibody , antibody frag antibody or antibody fragment comprises a heavy chain ment, or antigen binding molecule cross - reacts with human variable domain comprising SEQ ID NO : 14 and a light and non - human primate GITR . In some embodiments , the chain variable domain comprising SEQ ID NO : 7 . antibody, antibody fragment, or antigen binding molecule 10023 ] With respect to further embodiments of the anti does not cross -react with rodent GITR , e . g . , rat GITR or bodies, antibody fragments , or antigen bindingmolecules , in mouse GITR . some embodiments the heavy chain variable region has at least 90 % , 93 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % [0030 ] In a related aspect, the invention further provides amino acid sequence identity to the variable region of SEQ polynucleotides encoding an antibody , antibody fragment or ID NO : 99 and the light chain variable region has at least antigen binding molecule of the invention as described 90 % , 93 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid herein . In some embodiments , the polynucleotide encoding sequence identity to the variable region of SEQ ID NO : 7 . In the light chain variable region has at least 90 % , 93 % , 95 % , some embodiments , the isolated antibody or antibody frag 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid sequence ment comprises a heavy chain variable domain comprising identity to a nucleic acid sequence selected from SEQ ID the SEQ ID NO : 99 and a light chain variable domain NO :52 , SEQ ID NO : 54 and SEQ ID NO : 102 . In some comprising SEQ ID NO : 7 . embodiments , the polynucleotide encoding the heavy chain [ 0024 ] With respect to further embodiments of the anti variable region has at least 90 % , 93 % , 95 % , 96 % , 97 % , bodies , antibody fragments , or antigen binding molecules, in 98 % , 99 % , or 100 % nucleic acid sequence identity to a some embodiments the heavy chain variable region has at nucleic acid sequence selected from SEQ ID NO : 51 , SEO least 90 % , 93 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % ID NO :53 , SEQ ID NO :55 , SEQ ID NO : 56 , SEQ ID NO :57 , amino acid sequence identity to the variable region of SEQ SEQ ID NO : 101, and SEQ ID NO : 107 . In some embodi ID NO : 105 and the light chain variable region has at least ments , the polynucleotide encoding the light chain variable 90 % , 93 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid region has a nucleic acid sequence selected from SEQ ID sequence identity to the variable region of SEQ ID NO : 7 . In NO : 52 , SEQ ID NO :54 , and SEQ ID NO : 102 . In some some embodiments , the isolated antibody or antibody frag embodiments , the polynucleotide encoding the heavy chain ment comprises a heavy chain variable domain comprising variable region has a nucleic acid sequence selected from the SEQ ID NO : 105 and a light chain variable domain SEQ ID NO : 51 , SEQ ID NO :53 , SEQ ID NO :55 , SEQ ID comprising SEQ ID NO : 7 . NO : 56 , SEQ ID NO :57 SEQ ID NO : 101 and SEQ ID [ 0025 ]. In some embodiments , the antibody , antibody frag NO : 107 . ment, or antigen binding molecule that binds to GITR is [0031 ] In a related aspect, the invention further provides humanized . In certain embodiments , the antibody or anti compositions comprising an antibody, antibody fragment, or body fragment comprises a human constant region . antigen binding molecule of the invention , as described 10026 ] In some embodiments , the antibody fragment is a herein , and a pharmaceutically acceptable carrier. In some Fab ' fragment. In some embodiments , the antibody fragment embodiments , the invention provides pharmaceutical com is a single chain antibody ( scFv) . In some embodiments , the positions comprising an antibody, antibody fragment, or antibody fragment is a single - domain antibody or nanobody. antigen binding molecule of the invention for administering [0027 ] In some embodiments , the antibody or antibody to an individual. fragment is cross- linked to a second antibody or antibody [0032 ] In some embodiments , the composition further fragment. In some embodiments, the antibody is glycosy comprises a target antigen , for example , a cancer -associated lated . antigen or a tumor- associated antigen . In some embodi [0028 ] In some embodiments , the antibody, antibody frag ments, the target antigen is a viral antigen , a bacterial ment, or antigen binding molecule is an IgG . In certain antigen , a fungal antigen or a parasitic antigen . US 2017 /0306038 A1 Oct. 26 , 2017

[0033 ] In some embodiments , the composition further body or antibody fragment is co -administered with cancer comprises an antagonist of CTLA4 . In some embodiments , cells from the patient , i. e ., autologous cancer cells . the composition further comprises an antagonist of LAG3. [0041 ] In some embodiments , the anti -GITR agonist anti In some embodiments , the composition further comprises an body , antibody fragment, or antigen binding molecule is antagonist of TIM3. In some embodiments , the composition co - administered with an antagonist of CTLA4 . In some further comprises an inhibitor of PD - 1 / PD -L1 ( e . g . , B7 -H1 embodiments , the anti -GITR agonist antibody, antibody or analogue thereof, PD - 1 antibody ) interaction . In certain fragment, or antigen binding molecule is co -administered embodiments the composition further comprises an antago with an antagonist of LAGS . In some embodiments , the nist of PD - 1 . In certain embodiments the composition fur anti- GITR agonist antibody, antibody fragment, or antigen ther comprises an antagonist of PD - L1 . binding molecule is co - administered with an antagonist of [ 0034 ] In a further aspect, the invention further provides TIM3. In some embodiments , the anti -GITR agonist anti kits comprising an antibody or antibody fragment of the body or antibody fragment is co administered with an invention , as described herein . inhibitor of PD - 1 /PD -L1 ( e . g ., B7 -H1 ) interaction . In certain [ 0035 ] In some embodiments, kits further comprise a embodiments , the anti -GITR agonist antibody, antibody second agent for co - administration with the antibody . In fragment, or antigen binding molecule is co - administered some embodiments , the second agent is a target antigen , for with an antagonist of PD - 1 . In certain embodiments, the example , a cancer- associated antigen or a tumor - associated anti -GITR agonist antibody, antibody fragment, or antigen antigen . In some embodiments , the target antigen is a viral binding molecule is co -administered with an antagonist of antigen , a bacterial antigen , a fungal antigen or a parasitic PD -L1 . antigen . [0042 ] In some embodiments , the anti- GITR agonist anti [0036 ] In some embodiments , the second agent is an body, antibody fragment, or antigen binding molecule is antagonist of CTLA4 . In some embodiments , the second co - administered with a chemotherapeutic agent or a cyto agent is an antagonist of TIM3. In some embodiments , the toxin . second agent is an antagonist of LAG3. In some embodi [0043 ] In some embodiments , the T cell response is a ments , the second agent is an inhibitor of PD - 1/ PD -L1 ( e .g ., CD8 + cytotoxic T lymphocyte (CTL ) T cell response . In B7 -H1 or analogue thereof, PD - 1 antibody ) interaction . In some embodiments, the T cell response is a CD4 + helper T certain embodiments the second agent is an antagonist of cell ( Th ) response . PD - 1 . In certain embodiments the second agent is an antago [0044 ] In some embodiments provided compositions ( e. g. , nist of PD -L1 . anti -GITR agonist antibody , antibody fragment, or antigen [ 0037] Optionally , the antibody or antibody fragment and binding molecules and methods of using them ) can be used second agent are provided as a mixture . Optionally , the in combination with other agents or therapeutic modalities , antibody or antibody fragment and the second agent are e. g ., a second therapeutic agent chosen from one ormore of provided in separate formulations . the agents listed in Table 6 . In one embodiment , the methods [ 0038 ] In another aspect , the invention provides methods described herein include administering to the subject an of enhancing a T cell response in an individual in need anti -GITR agonist antibody, antibody fragment , or antigen thereof, comprising administering to the individual a thera binding molecule as described herein ( optionally in combi peutically effective amount of an anti- GITR agonist anti nation with one or more inhibitors of PD - 1 , PD -L1 , LAG - 3 , body or antibody fragment of the invention , as described TIM - 3 , CEACAM ( e . g ., CEACAM - 1 , CEACAM - 3 , and /or herein . In a further aspect , the invention provides an anti CEACAM - 5 ) , or CTLA - 4 ) ) , further include administration GITR agonist antibody or antibody fragment of the inven of a second therapeutic agent chosen from one or more of the tion for use in enhancing a T cell response in an individual . agents listed in Table 6 , in an amount effective to treat or In a further aspect, the invention provides a composition prevent a disorder, e . g ., a disorder as described herein , e . g . , comprising an antibody or antibody fragment of the inven a cancer . When administered in combination , the anti tion for use in enhancing a T cell response in an individual. GITR agonist antibody , antibody fragment, or antigen bind 0039 ] In a further aspect, the invention provides methods ing molecule , the additional agent ( e . g . , second or third of treating tumor growth of a cancer that expresses a tumor agent) , or all , can be administered in an amount or dose that associated antigen in an individual in need thereof, com is higher, lower or the same than the amount or dosage of prising administering to the individual a therapeutically each agent used individually , e . g . , as a monotherapy . In effective amount of an anti -GITR agonist antibody , antibody certain embodiments , the administered amount or dosage of fragment, or antigen binding molecule of the invention , as the anti -GITR agonist antibody, antibody fragment, or anti described herein . The invention further provides an anti gen binding molecule , the additional agent ( e . g . , second or GITR agonist antibody or antibody fragment of the inven third agent ) , or all, is lower ( e . g . , at least 20 % , at least 30 % , tion for use in treating tumor growth of a cancer in an at least 40 % , or at least 50 % ) than the amount or dosage of individual . The invention further provides a composition each agent used individually , e . g . , as a monotherapy. In other comprising an antibody or antibody fragment of the inven embodiments , the amount or dosage of the anti -GITR ago tion for use in reducing, inhibiting or preventing tumor nist antibody , antibody fragment, or antigen binding mol growth of a cancer that expresses a tumor associated antigen ecule , the additional agent ( e . g ., second or third agent ), or in an individual. all , that results in a desired effect ( e . g . , treatment of cancer ) 10040 ] With respect to embodiments of the methods and is lower ( e . g . , at least 20 % , at least 30 % , at least 40 % , or at medical uses , in some embodiments , the anti- GITR agonist least 50 % lower ). antibody , antibody fragment, or antigen binding molecule is 0045 ] In other embodiments , the second therapeutic agent co - administered with an antigen . In some embodiments , the is chosen from one or more of the agents listed in Table 6 In antigen is a cancer -associated antigen or a tumor- associated one embodiment, the cancer is chosen from a lung cancer antigen . In some embodiments , the anti- GITR agonist anti ( e . g . , a non - small cell lung cancer (NSCLC ) ( e . g ., a NSCLC US 2017 /0306038 A1 Oct. 26 , 2017 with squamous and / or non - squamous histology , or a NSCLC cell lung cancer (NSCLC ) and breast cancer. In one embodi adenocarcinoma ), or disclosed in a publication listed in ment, the type of cancer is selected from the group consist Table 6 . In some embodiments , the second therapeutic agent ing of: pancreatic cancer, melanomas , breast cancer , lung is chosen from one or more of: 1 ) a protein kinase C (PKC ) cancer, bronchial cancer, colorectal cancer, prostate cancer, inhibitor; 2 ) a heat shock protein 90 (HSP90 ) inhibitor; 3 ) an stomach cancer , ovarian cancer , urinary bladder cancer, inhibitor of a phosphoinositide 3 - kinase (PI3K ) and / or target brain or central nervous system cancer , peripheral nervous of rapamycin (mTOR ) ; 4 ) an inhibitor of cytochrome P450 system cancer, esophageal cancer, cervical cancer, uterine or ( e . g . , a CYP17 inhibitor or a 17alpha -Hydroxylase /C17 - 20 endometrial cancer, cancer of the oral cavity or pharynx , Lyase inhibitor ); 5 ) an iron chelating agent; 6 ) an aromatase head and neck squamous cell carcinoma (HNSCC ) , liver inhibitor; 7 ) an inhibitor of p53 , e .g . , an inhibitor of a cancer, kidney cancer , testicular cancer, biliary tract cancer, p53/ Mdm2 interaction ; 8 ) an apoptosis inducer ; 9 ) an angio small bowel or appendix cancer , salivary gland cancer, genesis inhibitor ; 10 ) an aldosterone synthase inhibitor; 11 ) thyroid gland cancer , adrenal gland cancer, osteosarcoma, a smoothened (SMO ) receptor inhibitor ; 12 ) a prolactin chondrosarcoma, and cancer of hematological tissues . receptor ( PRLR ) inhibitor ; 13 ) a Wnt signaling inhibitor; 14 ) [0048 ] In some embodiments , the patient has an infectious a CDK4 /6 inhibitor; 15 ) a fibroblast growth factor receptor disease , for example , a viral infection , a bacterial infection , 2 (FGFR2 ) / fibroblast growth factor receptor 4 (FGFR4 ) a fungal antigen or a parasitic antigen . In some embodi inhibitor ; 16 ) an inhibitor ofmacrophage colony - stimulating ments , the anti -GITR agonist antibody is co - administered factor ( M -CSF ) ; 17 ) an inhibitor of one or more of C -KIT , with a viral antigen ( e . g ., from HCV, HSV or HIV ). In some histamine release , Flt3 ( e . g . , FLK2/ STK1) or PKC ; 18 ) an embodiments , the anti -GITR agonist antibody is co -admin inhibitor of one or more of VEGFR - 2 (e . g ., FLK - 1 /KDR ) , PDGFRbeta , c -KIT or Raf kinase C ; 19 ) a somatostatin istered with a bacterial antigen . In some embodiments , the agonist and / or a growth hormone release inhibitor; 20 ) an anti -GITR agonist antibody is co - administered with a fungal anaplastic lymphoma kinase ( ALK ) inhibitor ; 21 ) an insulin antigen . In some embodiments , the anti -GITR agonist anti like growth factor 1 receptor ( IGF - 1R ) inhibitor; 22 ) a body is co - administered with a parasitic antigen ( e . g ., filari P -Glycoprotein 1 inhibitor ; 23 ) a vascular endothelial asis ) . growth factor receptor (VEGFR ) inhibitor; 24 ) a BCR -ABL [0049 ] In still other embodiments , provided is an isolated kinase inhibitor; 25 ) an FGFR inhibitor ; 26 ) an inhibitor of antibody, antibody fragment, or antigen binding molecule CYP11B2; 27 ) a HDM2 inhibitor, e . g ., an inhibitor of the for use in for use in therapy . In certain embodiments the HDM2- p53 interaction ; 28 ) an inhibitor of a tyrosine kinase ; antibody , antibody fragment or antigen binding molecule are 29 ) an inhibitor of c -MET ; 30 ) an inhibitor of JAK ; 31) an provided for use enhancing a T cell response in an individual inhibitor of DAC ; 32 ) an inhibitor of 113 - hydroxylase ; 33 ) in need thereof. In certain embodiments the antibody, anti an inhibitor of IAP ; 34 ) an inhibitor of PIM kinase ; 35 ) an body fragment or antigen binding molecule are provided for inhibitor of Porcupine ; 36 ) an inhibitor of BRAF, e . g ., use in the treatment of tumor growth in an individual in need BRAF V600E or wild - type BRAF ; 37 ) an inhibitor of thereof . HER3; 38 ) an inhibitor ofMEK ; or 39 ) an inhibitor of a lipid 0050 ] Provided combinations disclosed herein can result kinase , e .g ., as described herein and in Table 6 . in one or more of: an increase in antigen presentation , an [0046 ] Alternatively , or in combination with , the methods increase in effector cell function ( e . g ., one or more of T cell disclosed herein , the invention features a method of treating proliferation , IFN - y secretion or cytolytic function ) , inhibi ( e . g . , inhibiting , reducing , ameliorating, or preventing ) a tion of regulatory T cell function , an effect on the activity of disorder , e . g ., a hyperproliferative condition or disorder multiple cell types, such as regulatory T cell, effector T cells ( e . g . , a cancer ) in a subject . Methods include administering and NK cells ), an increase in tumor infiltrating lymphocytes, to the subject a combination of two , three or more thera an increase in T - cell receptor mediated proliferation , and a peutic agents chosen from one , two or all of the following decrease in immune evasion by cancerous cells . Thus , such categories ( i) - ( iii ) : ( i ) an agent that enhances antigen ( e . g ., combinations can be used to treat or prevent disorders where tumor antigen ) presentation ; ( ii ) an agent that enhances an enhancing an immune response in a subject is desired . effector cell response ( e . g . , B cell and /or T cell activation [0051 ] Accordingly , in another aspect , a method of modu and / or mobilization ) ; or ( iii) an agent that decreases tumor lating an immune response in a subject is provided . The immunosuppression , thereby treating the disorder , e . g . , the method comprises administering to the subject a combina hyperproliferative condition or disorder ( e . g . , the cancer ) . tion disclosed herein ( e . g . , a combination comprising a Exemplary therapeutic agents of categories ( i ) - ( iii ) are cho therapeutically effective amount of an anti -GITR antibody sen from one or more of the agents listed in Table 7 and molecule ) , alone or in combination with one or more agents further described herein . In some embodiments , the combi or procedures , such that the immune response in the subject nation includes at least a GITR modulator ( e . g . , an nti -GITR is modulated . In one embodiment, the antibody molecule agonist antibody , antibody fragment, or antigen binding enhances, stimulates or increases the immune response in molecule as described herein ) and one or more additional the subject. The subject can be a mammal, e . g . , a primate , therapeutic agents of categories ( i ) - ( iii ) . The cancer treated preferably a higher primate , e . g . , a human ( e . g . , a patient can be, e . g . , a cancer described herein , such as lung cancer having , or at risk of having , a disorder described herein ) . In ( squamous ) , lung cancer (adenocarcinoma ) , head and neck one embodiment , the subject is in need of enhancing an cancer , cervical cancer ( squamous ) , stomach cancer, thyroid immune response . In one embodiment , the subject has , or is cancer , melanoma, nasopharyngeal cancer, or breast cancer. at risk of, having a disorder described herein , e . g . , a cancer [0047 ] In some embodiments , the patient has a cancer that or an infectious disorder as described herein . In certain expresses a tumor associated antigen . In some embodiments, embodiments , the subject is , or is at risk of being, immu the cancer is selected from the group consisting of mela nocompromised . For example , the subject is undergoing or noma, ovarian cancer, colorectal cancer, prostate , non - small has undergone a chemotherapeutic treatment and /or radia US 2017 /0306038 A1 Oct. 26 , 2017 tion therapy. Alternatively , or in combination , the subject is , ies , or those synthesized de novo using recombinant DNA or is at risk of being , immunocompromised as a result of an methodologies, that retain binding specificity and agonist infection . activity for GITR . Examples of antibody fragments include Fv fragments , single chain antibodies ( ScFv ), Fab , Fab ', Fd Definitions (Vh and CH1 domains ) , dAb (Vh and an isolated CDR ) ; and [0052 ] An “ antibody ” refers to a polypeptide of the immu multimeric versions of these fragments ( e . g . , F ( ab ' ) ) with noglobulin family that is capable of noncovalently , revers the same binding specificity . Antibody fragments can also be ibly, and specifically binding a corresponding antigen . An incorporated into single domain antibodies, maxibodies , exemplary antibody structural unit comprises a tetramer. minibodies , diabodies , triabodies, tetrabodies , VNAR , bis Each tetramer is composed of two identical pairs of poly scFv, and other variations of antibody - like compounds to peptide chains, each pair having one “ light” chain (about 25 achieve the binding specificity and activity provided in the kD ) and one “ heavy ” chain ( about 50 -70 kD ) , connected present invention . through a disulfide bond . Recognized immunoglobulin [ 0054 ] A “ Fab ” domain as used in the context of the genes include the K , N , O , y , d , e , and u constant region genes , invention comprises a heavy chain variable domain , a con as well as the myriad immunoglobulin variable region stant region CH1 domain , a light chain variable domain , and genes. Light chains are classified as either K or 2 . Heavy a light chain constant region CL domain . The interaction of chains are classified as y, u , a , d , or e, which in turn define the domains is stabilized by a disulfide bond between the the immunoglobulin classes, IgG , IgM , IgA , IgD , and IgE , CH1 and CL domains . In some embodiments , the heavy respectively . Antibodies of the invention can be of any chain domains of the Fab are in the order , from N -terminus isotype /class ( e . g ., IgG , IgM , IgA , IgD , and IgE ) , or any to C - terminus, VH - CH and the light chain domains of a Fab subclass ( e . g . , IgG1, IgG2 , IgG3, IgG4 , IgA1, IgA2 ) . The are in the order , from N -terminus to C - terminus , VL -CL . In N - terminus of each chain defines a variable region of about some embodiments , the heavy chain domains of the Fab are 100 to 110 or more amino acids primarily responsible for in the order, from N - terminus to C - terminus, CH — VH and antigen recognition . The terms variable light chain (VL ) and the light chain domains of the Fab are in the order CL - VL . variable heavy chain (VH ) refer to these regions of light and Although Fabs were historically identified by papain diges heavy chains respectively . In addition to V regions, both tion of an intact immunoglobulin , in the context of this heavy chains and light chains contain a constant ( C ) region invention , a “ Fab ” is typically produced recombinantly by or domain . A secreted form of a immunoglobulin C region any method . Each Fab fragment is monovalent with respect is made up of three C domains , CH1, CH2 , CH3 , optionally to antigen binding , i. e . , it has a single antigen - binding site . CH4 (Cu ), and a hinge region . A membrane -bound form of [0055 ] The C -terminal portion of the immunoglobulin an immunglobulin C region also has membrane and intra heavy chains, comprising the CH2 and CH3 domains , is the cellular domains. Each light chain has a VL at the N - termi “ Fc ” domain . An “ Fc region " as used herein refers to the nus followed by a constant domain (C ) at its other end . The constant region of an antibody excluding the first constant VL is aligned with the VH and the CL is aligned with the first region immunoglobulin domain . Fc refers to the last two constant domain of the heavy chain . The pairing of a VH and constant region immunoglobulin domains of IgA , IgD , and VL together forms a single antigen -binding site . A “ conven IgG , and the last three constant region immunoglobulin tional antibody ” IgG immunoglobulin as used herein refers domains of IgE and IgM , and the flexible hinge N -terminal to an antibody in a configuration that occurs in nature . to these domains . For IgA and IgM Fc may include the J Typically , a conventional antibody IgG has four chains, two chain . For IgG , Fc comprises immunoglobulin domains Cy2 identical heavy chains and two identical light chains linked and Cy3 and the hinge between Cyl and Cy. It is understood together through disulfide bonds . As used herein , an " anti in the art that the boundaries of the Fc region may vary , body ” also encompasses variations of antibodies and con however, the human IgG heavy chain Fc region is usually ventional antibody structures that possess a particular bind defined to comprise residues C226 or P230 to its carboxyl ing specificity, i. e ., for GITR . Thus, within the scope of this terminus, using the numbering is according to the EU index concept are full length antibodies , chimeric antibodies , and as in Kabat et al . ( 1991 , NIH Publication 91 -3242 , National humanized antibodies , that possess a particular binding Technical Information Service , Springfield , Va . ) . “ Fc specificity for GITR . region " may refer to this region in isolation or this region in [0053 ] Antibodies exist as intact immunoglobulins or as a the context of an antibody or antibody fragment. “ Fc region ” number of well -characterized fragments produced by diges includes naturally occurring allelic variants of the Fc region , tion with various peptidases. Thus , for example , pepsin e . g ., in the CH2 and CH3 region , as well as modifications digests an antibody below the disulfide linkages in the hinge that modulate effector function . Fc regions also include region to produce F ( ab )' 2 , a dimer of Fab ' which itself is a variants that don ' t result in alterations to biological function . light chain joined to V -Cyl by a disulfide bond . The For example , one or more amino acids can be deleted from F (ab )' may be reduced under mild conditions to break the the N - terminus or C -terminus of the Fc region of an immu disulfide linkage in the hinge region , thereby converting the noglobulin without substantial loss of biological function . F (ab )' dimer into an Fab ' monomer. The Fab ' monomer is For example , in certain embodiments a C -terminal lysine essentially Fab with part of the hinge region . Paul, Funda may bemodified replaced or removed . In particular embodi mental Immunology 3d ed . ( 1993 ) . While various antibody ments one or more C - terminal residues in the Fc region is fragments are defined in terms of the digestion of an intact altered or removed . In certain embodiments one or more antibody , one of skill will appreciate that such fragments C - terminal residues in the Fc ( e . g . , the terminal lysine ) is may be synthesized de novo either chemically or by using deleted . In certain other embodiments one or more C - ter recombinant DNA methodology . As used herein , an “ anti minal residues in the Fc is substituted with an alternate body fragment” refers to one or more portions of an anti amino acid ( e . g . , the terminal lysine is replaced ) . Such body , either produced by the modification of whole antibod variants can be selected according to general rules known in US 2017 /0306038 A1 Oct. 26 , 2017

the art so as to have minimal effect on activity (see , e . g ., V , or Vy , respectively . The endogenous V , is encoded by Bowie , et al. , Science 247 : 306 - 1310 , 1990 ) . The Fc domain the gene segments V ( variable ) and J (junctional ) , and the is the portion of the Ig recognized by cell receptors , such as endogenous Vy by V , D ( diversity ) , and J . Each of V , or Vh the FcR , and to which the complement- activating protein , includes the CDRs as well as the framework regions . In this C1 q , binds. The lower hinge region , which is encoded in the application , antibody light chains and / or antibody heavy 5 ' portion of the CH2 exon , provides flexibility within the chains may , from time to time , be collectively referred to as antibody for binding to FcR receptors . " antibody chains. ” These terms encompass antibody chains [ 0056 ] “ Complementarity - determining domains" or containing mutations that do not disrupt the basic structure “ complementary - determining regions ( “ CDRs” ) inter of V? or Vu , as one skilled in the art will readily recognize . changeably refer to the hypervariable regions of V , and VH . [0061 ] The term “ valency ” as used herein refers to the CDRs are the target protein -binding site of the antibody number of potential target binding sites in a polypeptide . chains that harbors specificity for such target protein . There Each target binding site specifically binds one target mol are three CDRs ( CDR1- 3 , numbered sequentially from the ecule or specific site on a target molecule . When a polypep N - terminus ) in each human Vz or V . , constituting about tide comprises more than one target binding site , each target 15 - 20 % of the variable domains. CDRs are structurally binding site may specifically bind the same or different complementary to the epitope of the target protein and are molecules ( e. g ., may bind to different molecules , e .g ., dif thus directly responsible for the binding specificity . The ferent antigens , or different epitopes on the same molecule ) . remaining stretches of the V , or Vy , the so - called frame A conventional antibody , for example, has two binding sites work regions, exhibit less variation in amino acid sequence and is bivalent. The antibodies, antigen binding molecules, (Kuby , Immunology, 4th ed . , Chapter 4 . W . H . Freeman & and fragments thereof, can be monovalent ( i . e . , bind one Co ., New York , 2000 ) . target molecule ), bivalent, or multivalent ( i. e . , bind more [ 0057 ] Positions of the CDRs and framework regions can than one target molecule) . be determined using various well known definitions in the [0062 ] For preparation of monoclonal or polyclonal anti art , e . g ., Kabat, Chothia , international ImMunoGeneTics bodies, any technique known in the art can be used ( see , e . g . , database ( IMGT) (on the worldwide web at imgt. cines . fr /) , Kohler & Milstein , Nature 256 : 495 -497 ( 1975 ) ; Kozbor et and AbM ( see, e . g . , Johnson et al ., Nucleic Acids Res ., al. , Immunology Today 4 :72 ( 1983) ; Cole et al. ,Monoclonal 29 : 205 - 206 (2001 ); Chothia and Lesk , J. Mol. Biol. , 196 : Antibodies and Cancer Therapy , pp . 77 - 96 . Alan R . Liss , 901 - 917 ( 1987 ) ; Chothia et al . , Nature , 342 :877 - 883 ( 1989 ) ; Inc . 1985 ) . Techniques for the production of single chain Chothia et al. , J . Mol. Biol. , 227: 799 -817 (1992 ) ; Al antibodies ( U . S . Pat. No . 4 , 946 , 778 ) can be adapted to Lazikani et al. , J . Mol . Biol. , 273 : 927 - 748 ( 1997 )) . Defini produce antibodies to polypeptides of this invention . Also , tions of antigen combining sites are also described in the transgenic mice , or other organisms such as other mammals , following: Ruiz et al ., Nucleic Acids Res ., 28 :219 - 221 may be used to express primatized or humanized antibodies . ( 2000 ) ; and Lefranc, M . P . , Nucleic Acids Res . , 29 : 207 - 209 Alternatively , phage display technology can be used to ( 2001 ) ; MacCallum et al. , J. Mol . Biol. , 262 : 732 -745 identify antibodies and heteromeric Fab fragments that ( 1996 ) ; and Martin et al. , Proc . Natl. Acad . Sci . USA , specifically bind to selected antigens ( see , e . g . , McCafferty 86 : 9268 - 9272 ( 1989) ; Martin et al. , Methods Enzymol ., et al ., supra ; Marks et al ., Biotechnology , 10 :779 -783 , 203 : 121 - 153 ( 1991 ) ; and Rees et al. , In Sternberg M . J . E . ( 1992 )) . ( ed .) , Protein Structure Prediction , Oxford University Press, [ 0063 ] Methods for primatizing or humanizing non - hu Oxford , 141 - 172 ( 1996 ) . man antibodies are well known in the art . Generally, a 10058 ]. Under Kabat , CDR amino acid residues in the Vy primatized or humanized antibody has one or more amino are numbered 31- 35 (HCDR1 ) , 50 - 65 (HCDR2 ) , and 95 - 102 acid residues introduced into it from a source which is (HCDR3 ) ; and the CDR amino acid residues in the V , are non - primate or non -human . These non -primate or non numbered 24 - 34 (LCDR1 ) , 50 -56 (LCDR2 ) , and 89 - 97 human amino acid residues are often referred to as import ( LCDR3 ) . Under Chothia , CDR amino acids in the Vy are residues , which are typically taken from an import variable numbered 26 -32 (HCDR1 ) , 52 - 56 (HCDR2 ), and 95 - 102 domain . Humanization can be essentially performed follow (HCDR3 ) ; and the amino acid residues in V , are numbered ing the method of Winter and co - workers (see , e. g ., Jones et 26 -32 ( LCDR1) , 50 -52 (LCDR2 ) , and 91 - 96 (LCDR3 ) . By al. , Nature 321: 522 - 525 (1986 ) ; Riechmann et al. , Nature combining the CDR definitions of both Kabat and Chothia , 332 : 323 - 327 ( 1988 ) ; Verhoeyen et al. , Science 239 : 1534 the CDRs consist of amino acid residues 26 - 35 (HCDR1 ) , 1536 ( 1988 ) and Presta , Curr. Op . Struct . Biol. 2 :593 -596 50 -65 (HCDR2 ) , and 95 - 102 (HCDR3 ) in human VH and ( 1992 ) ) , by substituting rodent CDRs or CDR sequences for amino acid residues 24 - 34 (LCDR1 ) , 50 -56 (LCDR2 ) , and the corresponding sequences of a human antibody. Accord 89 - 97 (LCDR3 ) in human VL . ingly , such humanized antibodies are chimeric antibodies [0059 ] The term “ binding specificity determinant” or ( U . S . Pat . No. 4 , 816 , 567) , wherein substantially less than an “ BSD ” interchangeably refer to a minimum contiguous or intact human variable domain has been substituted by the non - contiguous amino acid sequence within a complemen corresponding sequence from a non -human species . In prac tary determining region necessary for determining the bind tice , primatized or humanized antibodies are typically pri ing specificity of an antibody . A minimum binding specific mate or human antibodies in which some complementary ity determinant can be within one or more CDR sequences . determining region (“ CDR " ) residues and possibly some In some embodiments , the minimum binding specificity framework (" FR " ) residues are substituted by residues from determinants reside within ( i. e . , are determined solely by ) a analogous sites in an originating species (e .g . , rodent anti portion or the full -length of the CDR3 sequences of the bodies ) to confer binding specificity . heavy and light chains of the antibody. [ 0064 ] A " chimeric antibody” is an antibody molecule in [ 0060] An “ antibody light chain ” or an “ antibody heavy which ( a ) the constant region , or a portion thereof, is altered , chain ” as used herein refers to a polypeptide comprising the replaced or exchanged so that the antigen binding site US 2017 /0306038 A1 Oct. 26 , 2017

(variable region ) is linked to a constant region of a different CDR regions and replacing the remaining parts of the or altered class, effector function and / or species , or an antibody with human counterparts . See , e. g. , Morrison et al. , entirely different molecule which confers new properties to Proc . Natl . Acad . Sci. USA , 81 :6851 - 6855 ( 1984 ) ; Morrison the chimeric antibody, e . g. , an enzyme , toxin , hormone , and Oi, Adv. Immunol. , 44: 65 - 92 ( 1988 ) ; Verhoeyen et al. , growth factor , and drug ; or ( b ) the variable region , or a Science , 239 : 1534 - 1536 ( 1988 ) ; Padlan , Molec. Immun ., portion thereof, is altered , replaced or exchanged with a 28 : 489 -498 ( 1991 ); Padlan , Molec. Immun ., 31( 3 ): 169 - 217 variable region having a different or altered antigen speci ( 1994 ). ficity . 10072 ] The term " corresponding human germline [0065 ] Antibodies or antigen -binding molecules of the sequence ” refers to the nucleic acid sequence encoding a invention further include one or more immunoglobulin human variable region amino acid sequence or subsequence chains that are chemically conjugated to , or expressed as, that shares the highest determined amino acid sequence fusion proteins with other proteins. It also includes bispe identity with a reference variable region amino acid cific antibody. A bispecific or bifunctional antibody is an sequence or subsequence in comparison to all other all other artificial hybrid antibody having two different heavy / light known variable region amino acid sequences encoded by chain pairs and two different binding sites . Other antigen human germline immunoglobulin variable region binding fragments or antibody portions of the invention sequences . The corresponding human germline sequence include bivalent scFv (diabody ) , bispecific scFv antibodies can also refer to the human variable region amino acid where the antibody molecule recognizes two different sequence or subsequence with the highest amino acid epitopes , single binding domains (dAbs ) , and minibodies. sequence identity with a reference variable region amino [0066 ] The various antibodies or antigen -binding frag acid sequence or subsequence in comparison to all other ments described herein can be produced by enzymatic or evaluated variable region amino acid sequences . The corre chemical modification of the intact antibodies, or synthe sponding human germline sequence can be framework sized de novo using recombinant DNA methodologies ( e . g ., regions only , complementary determining regions only , single chain Fv ), or identified using phage display libraries framework and complementary determining regions , a vari ( see , e . g . , McCafferty et al. , Nature 348 : 552 - 554 , 1990 ) . For able segment ( as defined above ) , or other combinations of example, minibodies can be generated using methods sequences or subsequences that comprise a variable region . described in the art , e . g . , Vaughan and Sollazzo , Comb Sequence identity can be determined using the methods Chem High Throughput Screen . 4 :417 - 30 2001 . Bispecific described herein , for example , aligning two sequences using antibodies can be produced by a variety of methods includ BLAST, ALIGN , or another alignment algorithm known in ing fusion of hybridomas or linking of Fab ' fragments . See , the art. The corresponding human germline nucleic acid or e . g ., Songsivilai & Lachmann , Clin . Exp . Immunol. 79 : 315 amino acid sequence can have at least about 90 % , 92 % , 321 ( 1990 ) ; Kostelny et al ., J . Immunol. 148 , 1547 - 1553 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % sequence ( 1992 ) . Single chain antibodies can be identified using identity with the reference variable region nucleic acid or phage display libraries or ribosome display libraries, gene amino acid sequence . Corresponding human germline shuffled libraries . Such libraries can be constructed from sequences can be determined , for example , through the synthetic , semi- synthetic or native and immunocompetent publicly available international ImMunoGeneTics database sources . (IMGT ) (on the worldwide web at imgt .cines . fr / ) and V - base [0067 ] The term “ antigen binding molecule ” or “ non (on the worldwide web at vbase .mrc - cpe. cam .ac . uk ) . antibody ligand ” refers to antibody mimics that use non [ 0073 ] The phrase " specifically binds ” or “ selectively immunoglobulin protein scaffolds, including but not limited binds , " when used in the context of describing the interac to , adnectins, avimers, single chain polypeptide binding tion between an antigen ( e . g . , a protein ) and an antibody, molecules, and antibody - like binding peptidomimetics. antibody fragment , or antibody -derived binding agent, refers [ 0068 ] The term “ variable region ” or “ V - region ” inter to a binding reaction that is determinative of the presence of changeably refer to a heavy or light chain comprising the antigen in a heterogeneous population of proteins and FR1- CDR1- FR2 - CDR2- FR3 - CDR3- FR4. An endogenous other biologics , e . g ., in a biological sample , e . g ., a blood , variable region is encoded by immunoglobulin heavy chain serum , plasma or tissue sample . Thus, under certain desig V - D - J genes or light chain V - J genes. A V -region can be nated immunoassay conditions, the antibodies or binding naturally occurring , recombinant or synthetic . agents with a particular binding specificity bind to a par [0069 ] As used herein , the term “ variable segment” or ticular antigen at least two times the background and do not “ V - segment” interchangeably refer to a subsequence of the substantially bind in a significant amount to other antigens variable region including FR1- CDR1 - FR2 -CDR2 - FR3. An present in the sample . In one embodiment, under designated endogenous V - segment is encoded by an immunoglobulin immunoassay conditions, the antibody or binding agents V - gene . A V - segment can be naturally occurring, recombi with a particular binding specificity bind to a particular nant or synthetic . antigen at least ten ( 10 ) times the background and do not [0070 ] As used herein , the term “ J- segment ” refers to a substantially bind in a significant amount to other antigens subsequence of the variable region encoded comprising a present in the sample . Specific binding to an antibody or C -terminal portion of a CDR3 and the FR4 . An endogenous binding agent under such conditions may require the anti J - segment is encoded by an immunoglobulin J - gene . A body or agent to have been selected for its specificity for a J - segment can be naturally occurring , recombinant or syn particular protein ( e . g ., human GITR ) . As used herein , thetic . specific binding includes antibodies fragments thereof and [0071 ] A “ humanized ” antibody is an antibody that retains binding molecules that selectively bind to human GITR and the reactivity ( e . g ., binding specificity , activity ) of a non do not include antibodies that cross - react with , e . g ., murine human antibody while being less immunogenic in humans. GITR molecules or other TNF receptor superfamily mem This can be achieved , for instance, by retaining non - human bers . In some embodiments , antibodies or antibody frag US 2017 /0306038 A1 Oct. 26 , 2017 ments are selected that cross -react with non -human primate binding molecule of this invention , and each of the antigen GITR (e .g . , cynomolgus GITR ). binding regions may be identical or different from the others . In some embodiments, at least one of the antigen -binding [ 0074 ] A variety of immunoassay formats may be used to regions of a GITR -binding molecule of this invention acts as select antibodies specifically immunoreactive with a par an agonist of GITR . ticular protein . For example , solid - phase ELISA immuno 10077 ] The term “ antibody agonist " or " agonist ” inter assays are routinely used to select antibodies specifically changeably refer to an antibody capable of activating a immunoreactive with a protein ( see , e . g . , Harlow & Lane , receptor to induce a full or partial receptor- mediated Using Antibodies, A Laboratory Manual (1998 ), for a response . For example , an agonist of GITR binds to GITR description of immunoassay formats and conditions that can and induces GITR -mediated intracellular signaling ( e . g . , be used to determine specific immunoreactivity ) . Typically increased NF -KB expression activation ) . The antibody ago a specific or selective binding reaction will produce a signal nist stimulates signaling through GITR similarly to the at least twice over the background signal and more typically native ligand , GITR -L . Binding ofGITR - L to GITR induces at least than 10 to 100 times over the background . NFKB activation due to degradation of IKB . In some [0075 ] The term “ equilibrium dissociation constant (KD , embodiments , a GITR antibody agonist can be identified by M ) ” refers to the dissociation rate constant (kd , time- 1 ) its ability to bind GITR and induce T cell ( e. g ., CD8 + CTLS divided by the association rate constant ( km , time- , M - ) . or CD4 + Th cells ) proliferation , survival, cytolytic activity Equilibrium dissociation constants can be measured using and /or cytokine production ( e .g ., IFNY, IL - 10 , IL - 13, TNFa ) any known method in the art . The antibodies of the present or as otherwise described herein . invention generally will have an equilibrium dissociation 10078 ] The term “ GITR ” or “ glucocorticoid - induced constant of less than about 10 - 7 or 10 - 8 M , for example , less tumor necrosis factor receptor receptor ” or “ tumor necrosis than about 10 - 9 M or 10 - 1° M , in some embodiments , less factor receptor superfamily , member 18” or “ TNFRSF18 ” than about 10 - 11 M , 10 - 12 M or 10 -13 M . In some embodi interchangeably refer to a type I transmembrane protein that ments , the isolated antibody or antibody fragment binds to is a member of the TNF -receptor superfamily . GITR is human GITR with an equilibrium dissociation constant ( K ) expressed at high levels on CD4 + CD25 + and on activated of about 1 nM or less. In some embodiments , the antibody effector CD4 + and CD8 + T cells . The nucleic acid and amino or antibody fragment binds to human GITR with a K , that acid sequences ofGITR are known , and have been published is less than 1 nM . In some embodiments , the antibody or in

GenBank Accession Nos . NM 004195 . 2 ? NP 004186 . 1 ( isoform 1 precursor ) , SEQ ID NO : 1 : 1 maqhgamgaf ralcglallc alslgqrptg gpgcgpgrli lgtgtdarcc rvhttrocrd 61 ypgeeccsew dcmcvqpefh cgdpccttcr hhpcppgagv qsqgkfsfgf qcidcasgtf 121 sggheghckp wtdctqfgfl tvfpgnkthn avcvpgsppa eplgwltvvl lavaacvili 181 tsaqlgihiw q?rsqcmwpr etqlllevpp stedarscqf peeergersa eekgrlgdlw 241 V ; NM 148901 . 1 ? NP 683699 . 1 ( isoform 2 precursor ) , SEQ ID NO : 2 : 1 maqhgamgaf ralcglallc alslgqrptg gpgcgpgrli Igtgtdarcc rvhttrocrd 61 ypgeeccsew dcmcvqpefh cgdpccttcr hhpcppgqgv qsqgkfsfgf qcidcasgt f 121 sggheghckp wtdccwrcrr rpktpeaass prksgasdrq rrrggwetcg cepgrppgpp 181 taaspspgap qaagalrsal grallpwaqk wvqeggsdqr pgpcssaaaa gpcrreretq 241 swppsslagp dgvgs ; and NM _ 148902 . 1 ? NP _ 683700 . 1 ( isoform 3 precursor ) , SEQ ID NO : 3 : 1 maqhgamgaf ralcglallc alslgqrptg gpgcgpgrll lgtgtdarcc rvhttrccrd 61 ypgeeccsew dcmcvqpefh cgdpccttcr hhpcppgqgv qsqgkfsfgf qcidcasgtf 121 sggheghckp wtdctqfgfl tvfpgnkthn avcvpgsppa epigwltvvl lavaacvlil 181 tsaqlglhiw qlrktqille vppstedars cqfpeeerge rsaeekgrlg dlwv . antibody fragment binds to human GITR with a Ky that is See also , GenBank Accession No. NM _ 005092 -> NP _ in the range of from about 0 . 5 nM to about 1 . 0 nM . 005083 . 2 . Structurally , a GITR amino acid sequence is a [ 0076 ] As used herein , the term “ antigen -binding region ” type I transmembrane protein that is a member of the refers to a domain of the GITR -binding molecule of this TNF -receptor superfamily having a signal peptide, an extra invention that is responsible for the specific binding between cellular domain (ECD ) comprising three cysteine - rich the molecule and GITR . An antigen -binding region includes domains (CRDs ) and has over its full length at least about at least one antibody heavy chain variable region and at least 90 % , 91 % 92 % 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or one antibody light chain variable region . There are at least 100 % sequence identity with the amino acid sequence of one such antigen -binding regions present in each GITR GenBank accession numbers NP _ 004186 . 1 ( SEQ ID NO : 1 ) , US 2017 /0306038 A1 Oct. 26 , 2017

NP _ 683699. 1 (SEQ ID NO : 2 ), NP _ 683700 . 1 (SEQ ID [0082 ] The terms “ polypeptide, " " peptide, ” and “ protein ” NO : 3 ) , or NP _ 005083 . 2 . Structurally , a GITR nucleic acid are used interchangeably herein to refer to a polymer of sequence has over its full length at least about 90 % , 91 % , amino acid residues . The terms apply to amino acid poly 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % mers in which one or more amino acid residue is an artificial sequence identity with the nucleic acid sequence of Gen chemical mimetic of a corresponding naturally occurring Bank accession numbers NM _ 004195 . 2 , NM _ 148901. 1 , amino acid , as well as to naturally occurring amino acid NM _ 148902. 1 , NM _ 005092 or SEQ ID NOs: 1 - 4 . Function polymers and non -naturally occurring amino acid polymer . ally , agonism of rodent GITR inhibits , at least transiently , 10083 ] The term “ amino acid ” refers to naturally occurring suppressor activity of CD25 + regulatory T cells ( Treg ) . and synthetic amino acids, as well as amino acid analogs and GITR agonism further enhances immunoactivity, e . g . , pro amino acid mimetics that function in a manner similar to the liferation , survival, cytokine production and cytolytic activ naturally occurring amino acids . Naturally occurring amino ity of activated effector CD4 + and CD8 + T cells . See , e . g . , acids are those encoded by the genetic code , as well as those Nocentini, et al. , Eur J Immunol ( 2007 ) 37 : 1165 - 1169 : amino acids that are later modified , e . g . , hydroxyproline , Expert Opin Ther Patents (2007 ) 17 ( 5 ): 567 -757 ; Shevach y - carboxyglutamate , and O - phosphoserine . Amino acid ana and Stephens, Nature Reviews Immunology ( 2006 ) 6 :613 logs refer to compounds that have the same basic chemical 618 . structure as a naturally occurring amino acid , i . e . , an a - car [0079 ] “ Activity ” of a polypeptide of the invention refers bon that is bound to a hydrogen , a carboxyl group , an amino to structural, regulatory , or biochemical functions of a group , and an R group , e . g ., homoserine , norleucine , polypeptide in its native cell or tissue. Examples of activity methionine sulfoxide , methionine methyl sulfonium . Such of a polypeptide include both direct activities and indirect analogs have modified R groups ( e . g . , norleucine ) or modi activities . Exemplary activities of GITR agonism include fied peptide backbones , but retain the same basic chemical intracellular signaling that results in increased activation of structure as a naturally occurring amino acid . Amino acid NF -KB , increased proliferation , survival, cytokine produc mimetics refers to chemical compounds that have a structure tion ( e . g . , IFNY, IL - 10 , IL - 13 , TNFa ) , and cytolytic activity that is different from the general chemical structure of an of activated effector CD4 + and CD8 + T cells . Therapeuti amino acid , but that functions in a manner similar to a cally , agonism of GITR augments antitumor and antiviral naturally occurring amino acid . T - cell responses in vivo . 100841 “ Conservatively modified variants ” applies to both amino acid and nucleic acid sequences . With respect to [ 0080 ] The term “ isolated , ” when applied to a nucleic acid particular nucleic acid sequences, conservatively modified or protein , denotes that the nucleic acid or protein is essen variants refers to those nucleic acids which encode identical tially free of other cellular components with which it is or essentially identical amino acid sequences , or where the associated in the natural state . It is preferably in a homoge nucleic acid does not encode an amino acid sequence , to neous state . It can be in either a dry or aqueous solution . essentially identical sequences . Because of the degeneracy Purity and homogeneity are typically determined using of the genetic code , a large number of functionally identical analytical chemistry techniques such as polyacrylamide gel nucleic acids encode any given protein . For instance , the electrophoresis or high performance liquid chromatography. codons GCA , GCC , GCG , and GCU all encode the amino A protein that is the predominant species present in a acid alanine . Thus, at every position where an alanine is preparation is substantially purified . In particular, an isolated specified by a codon , the codon can be altered to any of the gene is separated from open reading frames that flank the corresponding codons described without altering the gene and encode a protein other than the gene of interest. encoded polypeptide . Such nucleic acid variations are The term " purified ” denotes that a nucleic acid or protein " silent variations, ” which are one species of conservatively gives rise to essentially one band in an electrophoretic gel. modified variations. Every nucleic acid sequence herein Particularly , it means that the nucleic acid or protein is at which encodes a polypeptide also describes every possible least 85 % pure , more preferably at least 95 % pure , and most silent variation of the nucleic acid . One of skill will recog preferably at least 99 % pure . nize that each codon in a nucleic acid (except AUG , which [0081 ] The term “ nucleic acid ” or “ polynucleotide” refers is ordinarily the only codon for methionine , and TGG , which to deoxyribonucleic acids (DNA ) or ribonucleic acids is ordinarily the only codon for tryptophan ) can be modified (RNA ) and polymers thereof in either single - or double to yield a functionally identicalmolecule . Accordingly , each stranded form . Unless specifically limited , the term encom silent variation of a nucleic acid that encodes a polypeptide passes nucleic acids containing known analogues of natural is implicit in each described sequence . nucleotides that have similar binding properties as the [0085 ] As to amino acid sequences, one of skill will reference nucleic acid and are metabolized in a manner recognize that individual substitutions , deletions or addi similar to naturally occurring nucleotides . Unless otherwise tions to a nucleic acid , peptide , polypeptide , or protein indicated , a particular nucleic acid sequence also implicitly sequence which alters , adds or deletes a single amino acid or encompasses conservatively modified variants thereof ( e .g ., a small percentage of amino acids in the encoded sequence degenerate codon substitutions ) , alleles, orthologs, SNPs, is a “ conservatively modified variant ” where the alteration and complementary sequences as well as the sequence results in the substitution of an amino acid with a chemically explicitly indicated . Specifically , degenerate codon substi similar amino acid . Conservative substitution tables provid tutions may be achieved by generating sequences in which ing functionally similar amino acids are well known in the the third position of one or more selected ( or all ) codons is art. Such conservatively modified variants are in addition to substituted with mixed -base and / or deoxyinosine residues and do not exclude polymorphic variants , interspecies ( Batzer et al. , Nucleic Acid Res. 19 :5081 ( 1991 ) ; Ohtsuka et homologs , and alleles of the invention . al. , J. Biol. Chem . 260 :2605 - 2608 ( 1985 ); and Rossolini et [0086 ] The following eight groups each contain amino al ., Mol. Cell . Probes 8 : 91 - 98 ( 1994 )) . acids that are conservative substitutions for one another : 1 ) US 2017 /0306038 A1 Oct. 26 , 2017

Alanine ( A ), Glycine (G ); 2 ) Aspartic acid (D ), Glutamic algorithm then calculates the percent sequence identities for acid ( E ); 3 ) Asparagine (N ) ,Glutamine ( Q ) ; 4 ) Arginine (R ) the test sequences relative to the reference sequence , based Lysine ( K ) ; 5 ) Isoleucine ( I ), Leucine ( L ) , Methionine (M ) , on the program parameters. Valine ( V ) ; 6 ) Phenylalanine ( F ) , Tyrosine ( Y ) , Tryptophan 10090 ] A “ comparison window ” , as used herein , includes ( W ); 7 ) Serine (S ) , Threonine ( T ) ; and 8 ) Cysteine ( C ), reference to a segment of any one of the number of con Methionine ( M ) ( see , e. g ., Creighton , Proteins (1984 )) . tiguous positions selected from the group consisting of from [ 0087] “ Percentage of sequence identity ” is determined by 20 to 600 , usually about 50 to about 200 ,more usually about comparing two optimally aligned sequences over a compari 100 to about 150 in which a sequence may be compared to son window , wherein the portion of the polynucleotide a reference sequence of the same number of contiguous sequence in the comparison window may comprise additions positions after the two sequences are optimally aligned . or deletions ( i. e ., gaps ) as compared to the reference Methods of alignment of sequences for comparison are well sequence (e .g ., a polypeptide of the invention ) , which does known in the art. Optimal alignment of sequences for not comprise additions or deletions, for optimal alignment of comparison can be conducted , e . g ., by the local homology the two sequences . The percentage is calculated by deter algorithm of Smith and Waterman ( 1970 ) Adv . Appl. Math . mining the number of positions at which the identical 2 : 482c, by the homology alignment algorithm of Needleman nucleic acid base or amino acid residue occurs in both and Wunsch ( 1970 ) J . Mol . Biol. 48 :443 , by the search for sequences to yield the number of matched positions, divid similarity method of Pearson and Lipman ( 1988 ) Proc . ing the number of matched positions by the total number of Nat ' l. Acad . Sci. USA 85 : 2444 , by computerized implemen positions in the window of comparison and multiplying the tations of these algorithms (GAP , BESTFIT , FASTA , and result by 100 to yield the percentage of sequence identity . TFASTA in the Wisconsin Genetics Software Package , [0088 ] The terms “ identical ” or percent “ identity ,” in the Genetics Computer Group , 575 Science Dr. , Madison , Wis . ) , context of two or more nucleic acids or polypeptide or by manual alignment and visual inspection ( see , e . g ., sequences , refer to two or more sequences or subsequences Ausubel et al. , Current Protocols in Molecular Biology that are the same sequences . Two sequences are “ substan ( 1995 supplement) ) . tially identical” if two sequences have a specified percentage [0091 ] Two examples of algorithms that are suitable for of amino acid residues or nucleotides that are the same ( i . e . , determining percent sequence identity and sequence simi at least 75 % , 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % or 99 % larity are the BLAST and BLAST 2 .0 algorithms, which are sequence identity over a specified region , or, when not described in Altschul et al. ( 1977 ) Nuc . Acids Res . 25 : 3389 specified , over the entire sequence of a reference sequence) , 3402 , and Altschul et al. ( 1990 ) J . Mol . Biol. 215 : 403 -410 , when compared and aligned for maximum correspondence respectively. Software for performing BLAST analyses is over a comparison window , or designated region as mea publicly available through the National Center for Biotech sured using one of the following sequence comparison nology Information . This algorithm involves first identifying algorithms or by manual alignment and visual inspection . high scoring sequence pairs (HSPs ) by identifying short The invention provides polypeptides or polynucleotides that words of length W in the query sequence, which either are substantially identical to the polypeptides or polynucle match or satisfy some positive -valued threshold score T otides, respectively , exemplified herein ( e . g . , the variable when aligned with a word of the same length in a database regions exemplified in any one of SEOID NOS : 6 - 10 , 12 , 14 , sequence . T is referred to as the neighborhood word score 59 and 61 ; the variable segments exemplified in any one of threshold ( Altschul et al. , supra ) . These initial neighborhood SEQ ID NOS: 16 - 17 ; the CDRs exemplified in any one of word hits act as seeds for initiating searches to find longer SEQ ID NOS: 22 -34 ; the FRs exemplified in any one ofSEQ HSPs containing them . The word hits are extended in both ID NOS : 35 -50 ; and the nucleic acid sequences exemplified directions along each sequence for as far as the cumulative in any on of SEQ ID NOS: 51 - 58 and 60 ) . Optionally, the alignment score can be increased . Cumulative scores are identity exists over a region that is at least about 15 , 25 or calculated using , for nucleotide sequences, the parameters M 50 nucleotides in length , or more preferably over a region (reward score for a pair of matching residues; always > 0 ) that is 100 to 500 or 1000 or more nucleotides in length , or and N (penalty score for mismatching residues ; always < 0 ) . over the full length of the reference sequence . With respect For amino acid sequences , a scoring matrix is used to to amino acid sequences , identity or substantial identity can calculate the cumulative score . Extension of the word hits in exist over a region that is at least 5 , 10 , 15 or 20 amino acids each direction are halted when : the cumulative alignment in length , optionally at least about 25 , 30, 35, 40 , 50 , 75 or score falls off by the quantity X from its maximum achieved 100 amino acids in length , optionally at least about 150 , 200 value ; the cumulative score goes to zero or below , due to the or 250 amino acids in length , or over the full length of the accumulation of one or more negative - scoring residue align reference sequence . With respect to shorter amino acid ments; or the end of either sequence is reached . The BLAST sequences , e . g ., amino acid sequences of 20 or fewer amino algorithm parameters W , T , and X determine the sensitivity acids , substantial identity exists when one or two amino acid and speed of the alignment. The BLASTN program ( for residues are conservatively substituted , according to the nucleotide sequences ) uses as defaults a wordlength ( W ) of conservative substitutions defined herein . 11 , an expectation ( E ) or 10 , M = 5 , N = - 4 and a comparison [0089 ] For sequence comparison , typically one sequence of both strands. For amino acid sequences, the BLASTP acts as a reference sequence , to which test sequences are program uses as defaults a wordlength of 3 , and expectation compared . When using a sequence comparison algorithm , ( E ) of 10 , and the BLOSUM62 scoring matrix (see Henikoff test and reference sequences are entered into a computer, and Henikoff ( 1989 ) Proc . Natl . Acad . Sci. USA 89 : 10915 ) subsequence coordinates are designated , if necessary , and alignments ( B ) of 50 , expectation (E ) of 10 , M = 5 , N = - 4 , and sequence algorithm program parameters are designated . a comparison of both strands . Default program parameters can be used , or alternative [0092 ] The BLAST algorithm also performs a statistical parameters can be designated . The sequence comparison analysis of the similarity between two sequences ( see , e . g . , US 2017 /0306038 A1 Oct. 26 , 2017

Karlin and Altschul ( 1993 ) Proc . Natl . Acad . Sci. USA cally acceptable amount does not induce or cause undesir 90 :5873 - 5787 ) . One measure of similarity provided by the able side effects . A therapeutically acceptable amount can be BLAST algorithm is the smallest sum probability ( P ( N ) ) , determined by first administering a low dose , and then which provides an indication of the probability by which a incrementally increasing that dose until the desired effect is match between two nucleotide or amino acid sequences achieved . A “ prophylactically effective amount, ” and a would occur by chance . For example , a nucleic acid is " therapeutically effective amount, ” of a GITR agonizing considered similar to a reference sequence if the smallest antibody of the invention can prevent the onset of , or result sum probability in a comparison of the test nucleic acid to in a decrease in severity of, respectively, disease symptoms, the reference nucleic acid is less than about 0 . 2 , more including symptoms associated with cancer or infectious preferably less than about 0 .01 , and most preferably less disease . A " prophylactically effective amount ” refers to an than about 0 . 001. amount effective , at dosages and for periods of time neces [0093 ] An indication that two nucleic acid sequences or sary, to achieve the desired prophylactic result . Typically, polypeptides are substantially identical is that the polypep since a prophylactic dose is used in subjects prior to or at an tide encoded by the first nucleic acid is immunologically earlier stage of disease , the prophylactically effective cross reactive with the antibodies raised against the poly amount will be less than the therapeutically effective peptide encoded by the second nucleic acid , as described amount . A “ therapeutically effective amount ” refers to an below . Thus , a polypeptide is typically substantially identi amount effective, at dosages and for periods of time neces cal to a second polypeptide , for example , where the two sary , to achieve the desired therapeutic result. A therapeu peptides differ only by conservative substitutions . Another tically effective amount of the modified antibody or antibody indication that two nucleic acid sequences are substantially fragmentmay vary according to factors such as the disease identical is that the two molecules or their complements state , age , sex , and weight of the individual, and the ability hybridize to each other under stringent conditions , as of the antibody or antibody portion to elicit a desired described below . Yet another indication that two nucleic acid response in the individual. A therapeutically effective sequences are substantially identical is that the same primers amount is also one in which any toxic or detrimental effects can be used to amplify the sequence . of the modified antibody or antibody fragment is outweighed [0094 ] The term " link ," when used in the context of by the therapeutically beneficial effects . A “ therapeutically describing how the antigen -binding regions are connected effective dosage” preferably inhibits a measurable param within a GITR -binding molecule of this invention , encom eter, e. g . , tumor growth rate by at least about 20 % , more passes all possible means for physically joining the regions . preferably by at least about 40 % , even more preferably by The multitude of antigen -binding regions are frequently at least about 60 % , and stillmore preferably by at least about joined by chemical bonds such as a covalent bond ( e . g . , a 80 % relative to untreated subjects . The ability of a com peptide bond or a disulfide bond ) or a non - covalent bond , pound to inhibit a measurable parameter , e . g ., cancer, can be which can be either a direct bond ( i. e ., without a linker evaluated in an animal model system predictive of efficacy between two antigen - binding regions ) or indirect bond ( i. e ., in human tumors . Alternatively , this property of a compo with the aid of at least one linker molecule between two or sition can be evaluated by examining the ability of the more antigen - binding regions ). compound to inhibit , such inhibition in vitro by assays [0095 ] The terms “ subject, " " patient, ” and “ individual ” known to the skilled practitioner . interchangeably refer to a mammal, for example , a human or [ 0098 ] The term “ co - administer” refers to the simultane a non -human primate mammal. The mammal can also be a ous presence of two active agents in the blood of an laboratory mammal, e . g . , mouse , rat, rabbit , hamster. In individual. Active agents that are co - administered can be some embodiments , the mammal can be an agricultural concurrently or sequentially delivered . mammal ( e . g . , equine , ovine , bovine, porcine, camelid ) or [0099 ] As used herein , the phrase " consisting essentially domestic mammal ( e . g ., canine, feline ) . of” refers to the genera or species of active pharmaceutical [0096 ] As used herein , the terms “ treat ,” “ treating, " or agents included in a method or composition , as well as any " treatment” of any disease or disorder refer in one embodi inactive carrier or excipients for the intended purpose of the ment, to ameliorating the disease or disorder ( i . e . , slowing or methods or compositions. In some embodiments , the phrase arresting or reducing the development of the disease or at " consisting essentially of expressly excludes the inclusion least one of the clinical symptoms thereof) . In another of one or more additional active agents other than an agonist embodiment, " treat, " " treating, ” or “ treatment ” refers to anti -GITR antibody of the invention . In some embodiments , alleviating or ameliorating at least one physical parameter the phrase " consisting essentially of expressly excludes the including those which may not be discernible by the patient . inclusion of one or more additional active agents other than In yet another embodiment, " treat ," " treating, " or " treat an agonist anti -GITR antibody of the invention and a second ment ” refers to modulating the disease or disorder , either co - administered agent. physically , ( e . g ., stabilization of a discernible symptom ) , [0100 ] The term “ cancer” refers to a disease characterized physiologically , ( e . g . , stabilization of a physical parameter ), by the rapid and uncontrolled growth of aberrant cells . or both . In yet another embodiment, " treat, " " treating, ” or Cancer cells can spread locally or through the bloodstream " treatment” refers to preventing or delaying the onset or and lymphatic system to other parts of the body . Examples development or progression of the disease or disorder. of various cancers are described herein and include but are [0097 ]. The term “ therapeutically acceptable amount" or not limited to , breast cancer , prostate cancer, ovarian cancer , “ therapeutically effective dose ” interchangeably refer to an cervical cancer, skin cancer , pancreatic cancer, colorectal amount sufficient to effect the desired result (i . e . , a reduction cancer, renal cancer , liver cancer , brain cancer, lymphoma , in tumor size , inhibition of tumor growth , prevention of leukemia , lung cancer and the like . The terms “ tumor” and metastasis , inhibition or prevention of viral , bacterial, fungal " cancer” are used interchangeably herein , e . g ., both terms or parasitic infection ). In some embodiments , a therapeuti encompass solid and liquid , e . g ., diffuse or circulating , US 2017 /0306038 A1 Oct. 26 , 2017 tumors. As used herein , the term “ cancer” or “ tumor ” immune response , e . g . , in the promotion of an immune includes premalignant, as well as malignant cancers and effector response . Examples of immune effector cells tumors. include T cells , e . g . , alpha / beta T cells and gamma/ delta T [0101 ] The terms “ cancer- associated antigen ” or “ tumor cells , B cells , natural killer (NK ) cells , natural killer T associated antigen ” or “ tumor - specific marker ” or “ tumor (NKT ) cells , mast cells , and myeloid - derived phagocytes. marker” interchangeably refers to a molecule ( typically [0105 ] " Immune effector " or " effector" " function ” or protein , carbohydrate or lipid ) that is preferentially “ response , ” as that term is used herein , refers to function or expressed on the surface of a cancer cell in comparison to a response , e . g . , of an immune effector cell , that enhances or normal cell, and which is useful for the preferential targeting promotes an immune attack of a target cell . E . g ., an immune of a pharmacological agent to the cancer cell . Oftentimes, a effector function or response refers a property of a T or NK cancer -associated antigen is a cell surface molecule that is cell that promotes killing or the inhibition of growth or overexpressed in a cancer cell in comparison to a normal proliferation , of a target cell . In the case of a T cell , primary cell, for instance , 1 - fold over expression , 2 - fold overexpres stimulation and co -stimulation are examples of immune sion , 3 - fold overexpression or more in comparison to a effector function or response . normal cell . Oftentimes, a cancer -associated antigen is a cell f0106 ] The term " effector function ” refers to a specialized surface molecule that is inappropriately synthesized in the function of a cell . Effector function of a T cell , for example , cancer cell, for instance , a molecule that contains deletions, may be cytolytic activity or helper activity including the additions or mutations in comparison to the molecule secretion of cytokines . expressed on a normal cell . Oftentimes , a cancer - associated [0107 ] As used herein , the terms “ first” , “ second ”, “ third ” antigen will be expressed exclusively on the cell surface of and “ fourth ” , with respect to antigen binding moieties , e . g . , a cancer cell and not synthesized or expressed on the surface Fabs , are used for convenience of distinguishing when there of a normal cell . Exemplified cell surface tumor markers is more than one of each moiety . Use of these terms is not include the proteins c - erbB - 2 and human epidermal growth intended to confer a specific order or orientation of the factor receptor (HER ) for breast cancer, PSMA for prostate antibody unless otherwise stated . cancer, and carbohydrate mucins in numerous cancers , [0108 ] The terms “ a, " " an ,” and “ the ” include plural including breast, ovarian and colorectal . referents , unless the context clearly indicates otherwise [ 0102 ] The term “ antigen presenting cell ” or “ APC ” refers to an immune system cell such as an accessory cell ( e . g ., a Agonist Anti -GITR Antibodies B - cell , a dendritic cell , and the like ) that displays a foreign f0109 ] The present invention provides antibodies, anti antigen complexed with major histocompatibility complexes body fragments , and antigen binding molecules that bind to (MHC ' s ) on its surface . T -cells may recognize these com and stimulate signaling through GITR and /or induce a plexes using their T - cell receptors ( TCRs ) . APCs process potentiated immune response in vivo . The antibodies , anti antigens and present them to T -cells . body fragments , and antigen binding molecules find uses in [ 0103 ] The term “ costimulatory molecule ” refers to the enhancing CD4 + T helper ( Th ) and / or CD8 + cytolytic T cognate binding partner on a T cell that specifically binds lymphocyte (CTL ) responses against a target antigen . They with a costimulatory ligand , thereby mediating a costimu also find uses in treating disease conditions whose progres latory response by the T cell , such as, but not limited to , sion can be reversed or inhibited by an effective immune proliferation . Costimulatory molecules are cell surface mol response , including cancers and infectious diseases . ecules other than antigen receptors or their ligands that are [0110 ] The antibodies, antibody fragments and antigen required for an efficient immune response . Costimulatory binding molecules of the present invention show suitable molecules include , but are not limited to an MHC class I properties to be used in human patients , for example , they molecule, TNF receptor proteins , Immunoglobulin - like pro have low risk for immunogenicity issues for uses in human teins, cytokine receptors , integrins, signaling lymphocytic ( they are encoded by human germline nucleic acid activation molecules (SLAM proteins ), activating NK cell sequences , with the exception of the binding specificity receptors , BTLA , a Toll ligand receptor, OX40 , CD2, CD7, determining regions (BSD ) , in particular at least CDR3) ; CD27 , CD28 , CD30 , CD40 , CDS , ICAM - 1 , LFA - 1 (CD11a / have high affinity to GITR (e . g. , K , is at least less than 5 CD18 ) , 4 - 1BB (CD137 ) , B7 -H3 , CDS , ICAM - 1 , ICOS nM ) ; do not cross -react with other members of the TNFR ( CD278 ), GITR , BAFFR , LIGHT, HVEM ( LIGHTR ) , superfamily ; cross - react with human and non - human pri KIRDS2, SLAMF7 , NKp80 (KLRF1 ) , NKp44 , NKP30 , mate GITR ; and agonize GITR signaling at low doses ( e . g . , NKP46 , CD19 , CD4, CD8alpha , CD8beta , IL2R beta , IL2R in concentrations of less than 5 nM in in vitro assays ) . Other gamma, IL / R alpha , ITGA4, VLA1, CD49a , ITGA4, IA4, activities and characteristics are also demonstrated through CD49D , ITGA6 , VLA - 6 , CD49f , ITGAD , CD11d , ITGAE , out the specification . CD103 , ITGAL , CD11a , LFA - 1 , ITGAM , CD11b , ITGAX , [0111 ] Accordingly , the present invention provides anti CD11c , ITGB1, CD29 , ITGB2 , CD18 , LFA - 1 , ITGB7 , bodies , antibody fragments , and antigen -binding molecules NKG2D , NKG2C , TNFR2 , TRANCE /RANKL , DNAM1 that are agonists of GITR . Provided anti- GITR antibodies , (CD226 ), SLAMF4 (CD244 , 2B4 ) , CD84 , CD96 ( Tactile ) , antibody fragments, or antigen -binding molecules contain a CEACAMI, CRTAM , Ly9 (CD229 ) , CD160 (BY55 ) , minimum binding sequence determinant (BSD ) within the PSGL1, CD100 (SEMA4D ), CD69, SLAMF6 (NTB - A , CDR3 of the heavy and light chains derived from the Ly108 ), SLAM (SLAMF1 , CD150 , IPO - 3 ), BLAME originating or reference monoclonal antibody, for example , (SLAMF8 ) , SELPLG (CD162 ) , LTBR , LAT, GADS, SLP the antibodies described in Table 1 and Table 2 below . The 76 , PAG /Cbp , CD19a, and a ligand that specifically binds remaining sequences of the heavy chain and light chain with CD83. variable regions (CDR and FR ) , e . g . , V - segment and J - seg [ 0104 ] “ Immune effector cell, ” or “ effector cell” as that ment, are from corresponding human germline and affinity term is used herein , refers to a cell that is involved in an matured amino acid sequences . The V - segments can be US 2017 /0306038 A1 Oct . 26 , 2017 14

selected from a human V - segment library . Further sequence - continued refinement can be accomplished by affinity maturation or other methods known in the art to optimize binding activity TISRDNSKNTLYLOMNSLRAEDTAVYYCA (KR ) ( H / N ) AYGHDGGFAM or activity of the antibodies , antibody fragments or antigen DYWGQGTLVTVSS . binding molecules of the invention . [0116 ] In some embodiments , the light chain V -segment [ 0112] In another embodiment, heavy and light chains of has at least 95 % , 96 % , 97 % , 98 % , 99 % or 100 % sequence the anti- GITR antibodies or antibody fragments contain a identity to the amino acid sequence human V - segment from the corresponding human germline sequence (FR1 -CDR1 - FR2 -CDR2 - FR3) , e . g . , selected from a human V - segment library , and a CDR3 - FR4 sequence ( SEQ ID NO : 17 ) segment from the originating monoclonal antibody ( e . g . , the EIVMTQSPATLSVSPGERATLSCRAS ( E / Q ) SVSSN ( L / V ) AWYQQ antibodies as described in Table 1 and Table 2 ) . The CDR3 FR4 sequence segment can be further refined by replacing ( K / R ) PGQAPRLLIYGASNRATGIP ( D / A ) RFSGSGSGTDFTLTIS sequence segments with corresponding human germline RLEPEDFAVYYCGQSYSYPFTFGOGTKLEIK . sequences and/ or by affinity maturation . For example , the [0117 ] In some embodiments , i) the heavy chain CDR3 FR4 and / or the CDR3 sequence surrounding the BSD can be comprises the amino acid sequence HAYGHDGGFAMDY replaced with the corresponding human germline sequence , (SEQ ID NO : 29 ) or NAYGHDGGFAMDY ( SEQ ID while the BSD from the CDR3 of the originating monoclo NO : 109 ); and ii ) the light chain CDR3 variable region nal antibody is retained . comprises the amino acid sequence GQSYSYPFT (SEQ ID [ 0113] In some embodiments , the corresponding human NO :34 ) , or SYSYPF (SEQ ID NO :83 ) . germline sequence for the heavy chain V - segment is VH3 [0118 ] In some embodiments , the antibodies or antibody 3 - 13 /30 : EVOLVESGGGLVOPGGSLRLSCAASGFTF fragments of the invention comprise a heavy chain variable SSYGMHWVRQAPGKGLEWVAVIRYDGSN KYYADS region comprising a CDR1 comprising an amino acid VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK sequence SYGVD ( SEQ ID NO : 22 ) , or GFSLSSY (SEQ ID (SEQ ID NO : 89 ) . In one embodiment, the last amino acid in NO : 84 ) ; a CDR2 comprising an amino acid sequence SEQ ID NO :89 , lysine (“ K ” ), is substituted with arginine VIWGGGGTYY ( A / T ) (A / S )S ( L / V ) M ( A / G ) ( SEQ ID (“ R ” ) . In some embodiments , the corresponding human NO :28 ), or WGGGG (SEQ ID NO : 80 ); and a CDR3 com germline sequence for the heavy chain J- segment is JH4. In prising an amino acid sequence of HAYGHDGGFAMDY some embodiments , the heavy chain J - segment comprises (SEQ ID NO : 29 ) or NAYGHDGGFAMDY (SEQ ID the human germline JH4 partial sequence WGQGTLVTVSS NO : 109 ). ( SEQ ID NO : 90 ) . The full - length J - segment from human [0119 ] In some embodiments , the antibodies or antibody germline JH4 is YFDYWGQGTLVTVSS ( SEQ ID NO :91 ) . fragments of the invention comprise a light chain variable The variable region genes are referenced in accordance with region comprising a CDR1 comprising an amino acid the standard nomenclature for immunoglobulin variable sequence RAS (E / Q ) SVSSN (LN ) A (SEQ ID NO :32 ) or region genes . Current immunoglobulin gene information is S ( E / Q )SVSSN (SEQ ID NO : 87 ) ; a CDR2 comprising an available through the worldwide web , for example , on the amino acid sequence GASNRAT ( SEQ ID NO : 33 ) , or GAS ImMunoGene Tics (IMGT ) , V -base and PubMed databases . (SEQ ID NO :82 ) ; and a CDR3 comprising an amino acid See also , Lefranc , Exp Clin Immunogenet. 2001 ; 18 ( 2 ): 100 sequence of GQSYSYPFT (SEQ ID NO :34 ), or SYSYPF 16 ; Lefranc, Exp Clin Immunogenet. 2001; 18 ( 3 ) : 161- 74 ; ( SEQ ID NO :83 ) . Exp Clin Immunogenet. 2001 ; 18 ( 4 ) : 242 - 54 ; and Giudicelli , [0120 ] In some embodiments , the antibodies or antibody et al. , Nucleic Acids Res. 2005 Jan . 1 ; 33 (Database issue) : fragments of the invention comprise a heavy chain variable D256 -61 . region comprising a CDR1 comprising an amino acid [0114 ] In some embodiments , the corresponding human sequence SYGVD (SEQ ID NO : 22 ), or GFSLSSY (SEQ ID germline sequence for the light chain V - segment is VKIII NO :84 ) ; a CDR2 comprising an amino acid sequence L16 / A27 : EIVMTOSPATLSVSPGERATLSCRASOS VIWGGGGTYY ( A / T ) ( A / S ) S ( L / ) M ( A / G ) (SEQ ID VSSNLAWYOOKPGQAPRLLIYGASTRATGIPD NO :28 ) or WGGGG (SEQ ID NO : 80 ) ; and a CDR3 com RFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSP prising an amino acid sequence of HAYGHDGGFAMDY (SEQ ID NO :92 ). In some embodiments , the corresponding ( SEQ ID NO : 29 ) or NAYGHDGGFAMDY (SEQ ID human germline sequence for the light chain J - segment is NO : 109 ). Such antibodies or antibody fragments of the JK2. In some embodiments , the light chain J - segment com invention further comprise a light chain variable region prises the human germline Jk2 partial sequence FGQGT comprising a CDR1 comprising an amino acid sequence KLEIK (SEQ ID NO : 93 ) . The full - length J segment from RAS ( E / Q ) SVSSN ( LN ) A (SEQ ID NO : 32 ) , or S ( E / Q ) SVSSN (SEQ ID NO :87 ) ; a CDR2 comprising an amino human germline Jk2 is YTFGQGTKLEIK ( SEQ ID NO : 94 ) . acid sequence GASNRAT (SEQ ID NO :33 ) , or GAS (SEQ [ 0115 ]. In some embodiments , the heavy chain V - segment ID NO :82 ) ; and a CDR3 comprising an amino acid sequence has at least 95 % , 96 % , 97 % , 98 % , 99 % or 100 % sequence of GQSYSYPFT (SEQ ID NO : 34 ) , or SYSYPF (SEQ ID identity to the amino acid sequence NO : 83 ) . 10121 ] In some embodiments , the antibodies or antibody fragments of the invention comprise a heavy chain variable ( SEO ID NO : 16 ) region comprising a CDR1 comprising an amino acid ( E / Q )VQLVESGGGLVO (P / S ) GGSLRLSCAASGFSLSSYGVDWVRQA sequence SYGVD (SEQ ID NO : 22 ) , or GFSLRSY (SEQ ID PGKGLEW ( L / V )GVIWGGGGTYY ( A / T ) ( A / S ) S ( L / V ) M ( A / G ) RF NO :79 ) ; a CDR2 comprising an amino acid sequence VIWGGGGTNYNSALMA ( SEQ ID NO :62 ) , or WGGGG US 2017 /0306038 A1 Oct. 26 , 2017 15

( SEQ ID NO : 80 ) ; and a CDR3 comprising an amino acid substituted amino acids ( e . g . , from affinity maturation ) or sequence of HAYGHDGGFAMDY (SEQ ID NO : 29 ) or one or two conservatively substituted amino acids. NAYGHDGGFAMDY ( SEO ID NO : 109 ) . In some embodi- f0125 ] In some embodiments , the light chain variable ments , the antibodies or antibody fragments are humanized . region comprises a FR1 comprising an amino acid sequence of EIVMTOSPATLSVSPGERATLSC (SEO ID NO : 43 ) ; a [0122 ] In some embodiments , the antibodies or antibody FR2 comprising the amino acid sequence of WYQQ ( K / R ) fragments of the invention comprise a light chain variable PGQAPRLLIY (SEQ ID NO : 46 ) ; a FR3 comprising the region comprising a CDR1 comprising an amino acid amino acid sequence of GIP ( A /D )RFSGSGSGTD sequence KASENVDTFVS (SEQ ID NO :63 ), or SENVDTF FTLTISRLEPEDFAVYYC (SEQ ID NO :49 ); and a FR4 (SEQ ID NO : 81 ) ; a CDR2 comprising an amino acid comprising the amino acid sequence of SEQ ID NO : 50 . In sequence GASNRYT ( SEQ ID NO :64 ) , or GAS (SEQ ID some embodiments , the light chain variable region com NO : 82 ) ; and a CDR3 comprising an amino acid sequence of prises a FR1 comprising an amino acid sequence of SEQ ID GOSYSYPFT (SEO ID NO : 34 ) , or SYSYPF (SEO ID NO :43 ; a FR2 comprising the amino acid sequence selected NO : 83 ). In some embodiments , the antibodies or antibody from WYQQRPGQAPRLLIY (SEQ ID NO : 44 ) and fragments are humanized . WYQQKPGQAPRLLIY (SEQ ID NO :45 ); a FR3 compris ing the amino acid sequence selected from GIPARFSGSGS 10123] In some embodiments, the antibodies or antibody GTDFTLTISRLEPEDFAVYYC (SEQ ID NO :47 ) and GIP fragments of the invention comprise a heavy chain variable DRFSGSGSGTDFTLTISRLEPEDFAVYYC ( SEQ ID region comprising a CDR1 comprising an amino acid NO :48 ) ; and a FR4 comprising the amino acid sequence of sequence SYGVD (SEQ ID NO : 22 ) , or GFSLRSY (SEQ ID FGQGTKLEIK ( SEQ ID NO : 50 ) . The identified amino acid NO :79 ) ; a CDR2 comprising an amino acid sequence sequences may have one or more substituted amino acids VIWGGGGTNYNSALMA (SEQ ID NO :62 ) , or WGGGG ( e . g . , from affinity maturation ) or one or two conservatively (SEQ ID NO : 80 ) ; and a CDR3 comprising an amino acid substituted amino acids . sequence of HAYGHDGGFAMDY ( SEQ ID NO : 29 ) or [0126 ] Over their full length , the variable regions of the NAYGHDGGFAMDY (SEQ ID NO : 109 ) . Such antibodies anti -GITR antibodies of the present invention generally will or antibody fragments further comprise a lightchain variable have an overall variable region ( e . g ., FR1- CDR1- FR2 region comprising a CDR1 comprising an amino acid CDR2 - FR3 -CDR3 - FR4 ) amino acid sequence identity of at sequence KASENVDTFVS (SEQ ID NO :63 ) , or SENVDTF least about 85 % , for example , at least about 85 % , 89 % , 90 % , (SEQ ID NO :81 ) ; a CDR2 comprising an amino acid 91 % , 92 % , 93 % 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % sequence GASNRYT (SEQ ID NO :64 ), or GAS (SEQ ID to the corresponding human germline variable region amino NO : 82 ) ; and a CDR3 comprising an amino acid sequence of acid sequence . For example , the heavy chain of the anti GOSYSYPFT ( SEQ ID NO : 34 ) , or SYSYPF (SEQ ID GITR antibodies can have at least about 85 % , 89 % , 90 % , NO : 83 ) . In some embodiments, the antibodies or antibody 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % fragments are humanized . amino acid sequence identity to the human germline variable (0124 ] In some embodiments , the heavy chain variable region EVOLVESGGGLVOPGGSLRLSCAASGFTF region comprises a FR1 comprising the amino acid sequence SSYGMHWVRQAPGKGLEWVAVIRYDGSN KYYADS of ( E /QVQLVESGGGLVQ ( P / S )GGSLRLSCAASGFSLS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK ( SEQ ID NO : 37 ); a FR2 comprising the amino acid YFDYWGOGTLVTVSS (SEO ID NOS : 89 and 91 ) VH3 sequence of WVRQAPGKGLEW (LN ) G ( SEQ ID NO : 40 ) ; 3 - 13 / 30 + CDR3 + JH4 , the hyphen represents CDR3, which a FR3 comprising the amino acid sequence of RFTISRDN may be variable in length ). In one embodiment, the last SKNTLYLOMNSLRAEDTAVYYCA ( K / R ) (SEQ ID amino acid in SEQ ID NO : 89 , lysine ( K ) , is substituted with NO : 41 ) ; and a FR4 comprising the amino acid sequence of arginine ( R ) . The light chain of the anti -GITR antibodies can WGQGTLVTVSS ( SEQ ID NO :42 ) . In some embodiments, have at least about 85 % , 89 % , 90 % , 91 % 92 % , 93 % , 94 % , the heavy chain variable region comprises a FR1 comprising 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence the amino acid sequence selected from QVQLVES identity to the human germline variable region EIVMTOS GGGLVOPGGSLRLSCAASGFSLS (SEQ ID NO :35 ) and PATLSVSPGERATLSCRASOSVSSNLAWYOOK QVQLVESGGGLVQPGGSLRLSCAASGFSLS (SEQ ID PGQAPRLLIYGASTRATGIPD RFSGSGSGTDFTLTISR NO : 36 ) ; a FR2 comprising the amino acid sequence selected LEPEDFAVYYC -YTFGQGTKLEIK (SEQ ID NOS :98 and from WVRQAPGKGLEWVG ( SEQ ID NO : 38 ) and 94 ) (VKIII L16 / A27 +CDR3 + JK2; the hyphen represents WVRQAPGKGLEWLG (SEQ ID NO : 39 ) ; a FR3 compris CDR3 , which may be variable in length ) . In some embodi ing the amino acid sequence of SEQ ID NO : 41 ; and a FR4 ments , only amino acids within the framework regions are comprising the amino acid sequence of SEQ ID NO :42 . The added , deleted , or substituted . In some embodiments , the identified amino acid sequences may have one or more sequence identity comparison excludes the CDR3. TABLE 1 Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence 61 : VH , MAB1 QVQLKESGPGLVAPSQSLSITCTVSGFSLRSYGVDWVROPPGKGLEWLGVIWGG GGTNYNSALMAKLSISKDKSKSOVFLKMNSLOTDDTAMYYCAKHAYGHDGGFAM DYWGQGTSVTVSS US 2017 /0306038 A1 Oct. 26 , 2017 16

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence 59 : VL , MABI NIVMTQSPKSMSMSVGERVTLSCKASENVDTFVSWYOQKPDHSPKLLIYGASNR YTGVPDRFTGSGSATDFTLTISSVQAEDLADYHCGQSYSYPFTFGSGTKLEIK 60 : PN of VH , CAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTG MAB1 TCCATCACTTGCACTGTCTCTGGGTTTTCATTAAGGAGCTATGGTGTAGACTGG encoding GTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEO ID NO : 61 GGAGGCACAAATTATAATTCAGCTCTCATGGCCAAACTGAGTATCAGCAAAGAC ( VH ) AAGTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACA GCCATGTACTACTGTGCCAAACATGCCTATGGTCACGACGGCGGTTTTGCTATG GACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA 58 : PN of VL , AACATTGTAATGACCCAATCTCCCAAATCCATGTCCATGTCAGTAGGAGAGAGG MAB1 GTCACCTTGAGCTGCAAGGCCAGTGAGAATGTGGATACTTTTGTATCCTGGTAT encoding CAACAGAAACCAGACCACTCTCCTAAACTACTGATATACGGGGCATCCAACCGG SEQ ID NO : 59 TACACTGGGGTCCCCGATCGCTTCACAGGCAGTGGATCTGCAACAGATTTCACT ( VL ) CTGACCATCAGCAGTGTGCAGGCTGAAGACCTTGCAGATTATCACTGTGGACAG AGTTACAGCTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA 6 : VH , MAB 2 QVOLVESGGGLVOPGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG GGTYYASSVMARFTISRDNSKNTLYLOMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSS 7 : VL , MAB2 EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNR ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 65 : Heavy QVOLVESGGGLVQPGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG chain , MAB2 GGTYYASSVMARFTISRDNSKNTLYLOMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPOVYTLPPSREEMTKNOVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTOKSLSLSPGK 66 : Light chain , EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYQORPGQAPRLLIYGASNR MAB2 ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKR TVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGNSOES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 51 : PN of VH , CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTG MAB2 AGAc???ccTGTGCAGcc???GGATTc?cccTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGGTGGGAGTTATATGGGGTGGT SEQ ID NO : 6 GGAGGCACATATTATGCTTCTTCTGTCATGGCCAGATT CACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GccGTGTATTACTGCGCCAAACATaccTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCA 52 : PN of VL , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTTTCTCCAGGAGAAAGA MAB2 GccAccc??????GCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGccTGGTAC encoding CAGCAGAGACCTGGCCAGGCACCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEQ ID NO : 7 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAG 67 : PN of HC , CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTG MAB2 AGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGGTGGGAGTTATATGGGGTGGT SEQ ID NO : 65 GGAGGCACATATTATGCTTCTTCTGTCATGGCCAGATT CACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GCCGTGTATTACTGCGCCAAACATGCCTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCAGCTAGCACCAAGGGC CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCC ccccTGGGCTGccTGGTGAAGG???????ccccGAccccGTGAccGTGTccTGG AACAGCGGAGcccTG????ccGGCGTGCACAcc??cccccccGTGCTGCAGAGC AGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGC ACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGO AAGAGAGTGGAGC?CAAGAGCTGCGACAAGAccCACAccTGcccccccTGccCA GccccAGAccTGCTGGGCGGAccc?ccGTGTTccTGTTcccccccAAGcccAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG US 2017 /0306038 A1 Oct. 26 , 2017 17

TABLE 1 - continued Examples ofof artanti - GITRang TABLEagonist aantibodies continue of theone presentpersoane invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence AGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAG SCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAG GCCAAGGGccAcccAcGGGAcccccAGGTGTACAccc?ccccccc?ccccGGAG GAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCC AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG ACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTG ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATG CAcGAGGcccTGCACAAccACTACAcccAGAAGAGccTGAGccTGTcccccGGC AAG 68 : PN of LC , GAAATAGTGATGAcGCAGTc?ccAGCCAcccTGTCTGT ????ccAGGAGAAAGA MAB2 GCCACCCTCTCCTGCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGCCTGGTAC encoding CAGCAGAGACCTGGCCAGGCACCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEQ ID NO : 66 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGC???ccATTTAccTTTGGccAGGGCACCAAGCTTGAAATTAAGCGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAG AGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCC AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 8 : VH , MAB3 QVOLVESGGGLVQPGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWLGVIWGG GGTYYTASLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSS 9 : VL , MAB3 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYOQKPGQAPRLLIYGASNR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 69 : Heavy QVOLVESGGGLVOPGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWLGVIWGG chain , MAB3 GGTYYTASLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYK CKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSREEMTKNOVSLTCLVKGFYP SDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWOOGNVFSCSVM HEALHNHYTOKSLSLSPGK 70 : Light chain , EIVMTOSPATLSVSPGERATLSCRASOSVSSNLAWYOOKPGOAPRLLIYGASNR MAB3 ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCGOSYSYPFTFGOGTKLEIKR TVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGNSOES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC 53 : PN of VH , CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTG MAB3 AGAC??????GTGCAccc???GGATT??cccTCAGCAccTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEQ ID NO : 8 GGAGGCACATATTATACTGCTTCTCTCATGGGCAGATT CACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GCCGTGTATTACTGCGCCAAACATGCCTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCA 54 : PN of VL , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGA MAB3 GCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTAC encoding CAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEQ ID NO : 9 GCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTC TGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTTTACTACTGCGGCCAG AGCTATAGC???ccATTTAccTTTGGccAGGGCAccAAGCTTGAAATTAAA 71 : PN of HC , CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTG MAB3 AGAc???ccTGTGCAGcc???GGATTc?cccTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEQ ID NO : 69 GGAGGCACATATTATACTGCTTCTCTCATGGGCAGATT CACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GccGTGTATTACTGCGCCAAACATGccTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCAGCTAGCACCAAGGGC C?CAGCGTGTTcccccTGGcccccAGCAGCAAGAGCAccAGCGGCGGCACAGcc US 2017 /0306038 A1 Oct. 26 , 2017 18

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence GcccTGGGC?????GGTGAAGG???????ccccGAGcccGTGAccGTGTccTGG AACAGCGGAGCCCTGACCTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGC AGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGC ACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTGGAGC?CAAGAGCTGCGACAAGAcccACAccTGcccccccccccA GCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG AGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAG ?GCAAGGTCTccAACAAGGcccTGccAGcccccATCGAAAAGAccATCAGCAAG GCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAG GAGATGAccAAGAACCAGGTGTcccTGAccTGTCTGGTGAAGGGCTICTAcccc AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG ACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTG ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATG CACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGGC AAG 72 : PN of LC , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGA MAB3 GccAccc???ccTGCAGGGccAGTcAGAGTGTTAGCAGCAACTTAGCCTGGTAC encoding CAGCAGAAAccTGGCCAGGCTC?CAGGCTccTCATCTACGGGGCATCCAAccGG SEQ ID NO : 70 GCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTC TGGGACAGACTTCACT ???ACCATCAGCAGACTGGAGccTGAAGATTTTGCAGT TTACTACTGCGGccAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAACGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAG AGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCC AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 10 : VH , MAB4 EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG GGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGQGTLVTVSS 7 : VL , MAB4 EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQORPGQAPRLLIYGASNR ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 73 : Heavy EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG chain , MAB4 GGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSREEMTKNOVSLTCLVKGFYP SDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWOOGNVFSCSVM HEALHNHYTOKSLSLSPGK 66 : Light chain , EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYOQRPGQAPRLLIYGASNR MAB4 ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 55 : PN of VH , GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGTCTGGGGGGTCCCTG MAB4 AGAc???ccTGTGCAGcc???GGATTc?cccTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGGTGGGAGTTATATGGGGTGGT SEO ID NO : 10 GGAGGCACATATTATGCTTCTTCTCTCATGGGCAGATT CACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GccGTGTATTACTGcGcCAAACATaccTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCA 52 : PN of VL , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTTTCTCCAGGAGAAAGA MAB4 GCCAccc????c?aCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGccTGGTAC encoding CAGCAGAGACCTGGCCAGGCACCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEQ ID NO : 7 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAG US 2017 /0306038 A1 Oct. 26 , 2017 19

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence

74 : PN of HC , GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGTCTGGGGGGTCCCTG MAB4 AGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGGTGGGAGTTATATGGGGTGGT SEQ ID NO : 73 GGAGGCACATATTATGC?????c???CATGGGCAGATTCACCATCTccAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GCCGTGTATTACTGCGCCAAACATGCCTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCAGCTAGCACCAAGGGC CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCC GCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGG AACAGCGGAGcccTGAcc?ccGGCGTGCACAcc??cccccccGTGCGCAGAGC AGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGC ACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCA GCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG AGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAG TGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAG GCCAAGGGCCAGCCAcGGGAGccccAGGTGTACAcccTGcccccc?cccGGGAG GAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCC AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG ACCAcccccccAGTGCTGGACAdcGAcGGCAGC??c??ccTGTACAGCAAGC?? ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATG CACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGGC AAG 68 : PN of LC , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTTTCTCCAGGAGAAAGA MAB4 GCCACCCTCTCCTGCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGCCTGGTAC encoding CAGCAGAGACCTGGCCAGGCACCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEQ ID NO : 66 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAGCGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAG AGCGGCAccGccAGCGTGGTGTGccTGCTGAACAACTICTAcccccGGGAGGcc AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 12 : VH , MAB5 EVOLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWLGVIWGG GGTYYTSSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGQGTLVTVSS 7 : VL , MAB5 EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNR ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 75 : Heavy EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVROAPGKGLEWLGVIWGG chain , MAB5 GGTYYTSSLMGRFTISRDNSKNTLYLOMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHODWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVM HEALHNHYTOKSLSLSPGK

66 : Liqht chain , EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYOORPGOAPRLLIYGASNR MAB5 ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 56 : PN of VH , GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGTCTGGGGGGTCCCTG MAB5 AGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEQ ID NO : 12 GGAGGCACAT?TT??????c???????ATGGGCAGATT ????????ccAGAGAc AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GCCGTGTATTACTGCGCCAAACATGCCTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCA US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence

52 : PN of VL , GAAATAGTGATGAcccAGTCTccAGCCAcccTGTCTGTTTc?ccAGGAGAAAGA MAB5 GCCACCCTCTCCTGCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGCCTGGTAC encoding CAGCAGAGACCTGGCCAGGCACCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEQ ID NO : 7 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAG 76 : PN of HC , GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGTCTGGGGGGTCCCTG MAB5 AGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEQ ID NO : 75 GGAGGCACATATTATACTTCTTCTCTCATGGGCAGATTCACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GCCGTGTATTACTGCGCCAAACATGCCTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCAGCTAGCACCAAGGGC CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCC GCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGG AACAGCGGAGcccTG????ccGGCGTGCACAcc??cccccccGTGCTGCAGAGC AGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGC ACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCA GCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG AGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAG TGCAAGGTCTCCAACAAGGCCCTGCCAGCCCCCATCGAAAAGACCATCAGCAAG GCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCTCCCGGGAG GAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCC AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG ACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTG ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATG CACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGGC AAG 68 : PN of LC , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTTTCTCCAGGAGAAAGA MAB5 GCCAccc???ccTGCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGccTGGTAC encoding CAGCAGAGACCTGGCCAGGCACCCAGGCTCCTCATCTACGGGGCATCCAACCGG SEO ID NO : 66 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGC???ccATTTAccTTTGGccAGGGCAccAAGCTIGAAATTAAGCGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAG AGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCC AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 14 : VH , MAB6 EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWLGVIWGG GGTYYTSSLMARFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGQGTLVTVSS 7 : VL , MAB6 EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYOQRPGQAPRLLIYGASNR ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 77 : Heavy EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWLGVIWGG chain , MAB 6 GGTYYTSSLMARFTISRDNSKNTLYLOMNSLRAEDTAVYYCAKHAYGHDGGFAM DYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTOTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSREEMTKNOVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVM HEALHNHYTOKSLSLSPGK 66 : Light chain , EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYOQRPGQAPRLLIYGASNR MAB6 ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKR TVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSGES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC US 2017 /0306038 A1 Oct. 26 , 2017 21

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence 57 : PN of VH , GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGTCTGGGGGGTCCCTG MAB6 AGAc???ccTGTGCAGcc???GGATTc?cccTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEO ID NO : 14 GGAGGCACAT?TT??????c??????cATGGCCAGATT ????????ccAGAGAc AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GCCGTGTATTACTGCGCCAAACATGCCTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCA 52 : PN of VL , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTTTCTCCAGGAGAAAGA MAB6 GCCACCCTCTCCTGCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGCCTGGTAC encoding CAGCAGAGAccTGGCCAGGCAcccAGGCTccTCATCTACGGGGCATccAAccGG SEQ ID NO : 7 GCCACTGGCATC?CAGCCAGGTICAGTGGCAGTGGG???GGGACAGACTICACT ???ACCATCAGCAGACTGGAGccTGAAGATTTTGCAGT GTACTACTGCGGccAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAG 78 : PN of HC , GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGTCTGGGGGGTCCCTG MAB6 AGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGCAGCTATGGTGTGGACTGG encoding GTTCGCCAGGCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTTATATGGGGTGGT SEQ ID NO : 77 GGAGGCACATATTATACTTCTTCTCTCATGGCCAGATT CACCATCTCCAGAGAC AATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACG GccGTGTATTACTGCGCCAAACATGccTATGGCCATGATGGCGGCTTTGCTATG GATTATTGGGGCCAGGGTACCCTTGTGACCGTGAGCTCAGCTAGCACCAAGGGC CCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCC GcccTGGGCTGccTGGTGAAGG???????ccccGAGcccGTGAccGTGTccTGG AACAGCGGAGC?CTG????ccGGCGTGCACACC??cccccccGTGCTGCAGAGC AGCGGCCTGTACAGCCTGTCCAGCGTGGTGACAGTGCCCAGCAGCAGCCTGGGC ACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCA GCCCCAGAGCTGCTGGGCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG AGCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAG ?GCAAGGTCTccAACAAGGcccTGccAGcccccATCGAAAAGAccATCAGCAAG GCCAAGGGCCAGCCAcGGGAGccccAGGTGTACAC?CTGcccccc?cccGGGAG GAGATGAccAAGAAccAGGTGTcccTGAcc?GT??GGTGAAGGGCTICTAcccc AGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAAC ACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTG ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATG CACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCCCGGC AAG 68 : PN of LC , GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTTTCTCCAGGAGAAAGA MAB6 "GCAGGGCCAGTGAGAGTGTTAGCAGTAATGTAGCCTGGTAC encoding CAGCAGAGAccTGGccAGGCAcccAGGCTcc????cTACGGGGCATccAAccGG SEQ ID NO : 66 GCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACT CTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTACTACTGCGGCCAG AGCTATAGCTATCCATTTACCTTTGGCCAGGGCACCAAGCTTGAAATTAAGCGT ACGGTGGccGc?cccAGCGTGTTCATc??cccccccAGCGAcGAGCAGCTGAAG AGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCC AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACZ GTCAccGAGCAGGACAGCAAGG???ccAccTACAGccTGAGCAGCAcccTGAcc CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 99 : VH , MAB7 EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG GGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAM DYWGQGTLVTVSS 7 : VL , MAB7 EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNR ! ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK 100 : Heavy EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG chain , MAB7 GGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAM DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence CKVSNKALPAPIEKTISKAKGQPREPOVYTLPPSREEMTKNOVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTOKSLSLSPGK 66 : Light chain , EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNR MAB7 ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKR TVAAPSVFIFPPSDEOLKSGTASWCLLNNFYPREAKVQWKVDNALOSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 101 : PN of VH , GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGCGGCTCTCTG MAB7 AGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGG encoding GTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGA SEQ ID NO : 99 GGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCTCCCGGGAC AACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACC GCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATG GATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCC 102 : PN of VL , GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGA MAB7 GCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTAT encoding CAGCAGAGAccTGGTCAGGcccc?cGGCTGCTGATCTACGGcGccTCTAAccGG SEQ ID NO : 7 GccAccGGCATccc?accAGATT??ccGGCTccGGCAGcGGCAccGACTICAcc CTGACCATCTCCCGGCTGGAACCCGAGGACTTCGCCGTGTACTACTGCGGCCAG ?ccTACTCATAccccTTCACCTICGGCCAGGGCACCAAGCTGGAAATCAAG 103 : PN of HC , GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGCGGCTCTCTG MAB7 AGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGG encoding GTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGA SEQ ID NO : 100 GGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTT CACCATCTCCCGGGAC AACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACC GCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATG GATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGC ccAAGTGTGTTTccccTGGcccccAGCAGCAAGTC?????ccGGcGGAAC???? GCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGG AACTCTGGGGCTCTGAc??ccGGCGTGCACAcc??cccccccGTGCTGCAGAGC AGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGA AcccAGAccTATATCTGCAACGTGAAccACAAGcccAGCAACAccAAGGTGGAC AAGAGAGTGGAGC?CAAGAGCTGCGACAAGAccCACAccTGcccccccTGC?CA GCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG TCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAG TGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGACAATCAGCAAG GCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAG GAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCC AGCGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG ACCAcccccccAGTGCTGGAcAGCGAcGGCAGc??c??ccTGTACAGCAAGCTG ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATG CACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGC AAG 104 : PN of LC , GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGA MAB7 GCCAcccTGAGCTGCAGAccc?ccGAGTccGTGTcc??CAACGTGGccTGGTAT encoding CAccAGAGAccTGGTCAcccccc?????????GATC?AcccccccTCTAAcccc SEQ ID NO : 66 GCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACC ??GAccATCTcccGGCTGGAAcccGAGG????cccccTGTACTACTGccGcMAG ?cc????cATAccccTTCAcc??cGGccAGGGCAccAAG??GGAAATCAAdcGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAG AGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCC AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC 105 : VH , EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG MAB8 GGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNAYGHDGGFAM DYWGOGTLVTVSS 7 : VL , MAB8 EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYQORPGQAPRLLIYGASNR ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK US 2017 /0306038 A1 Oct. 26 , 2017 23

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence

106 : Heavy EVOLVESGGGLVOSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGG chain , MAB8 GGTYYASSLMGRFTISRDNSKNTLYLOMNSLRAEDTAVYYCARNAYGHDGGFAM DYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPOVYTLPPSREEMTKNOVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTOKSLSLSPGK 66 : Light chain , EIVMTOSPATLSVSPGERATLSCRASESVSSNVAWYOQRPGQAPRLLIYGASNR MABA ATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGOSYSYPFTFGOGTKLEIKR TVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGNSOES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC 107 : PN of VH , GAGGTGCAGCTGGTGGAATCAGGCGGCGGACTGGTGCAGTCAGGCGGTAGCCTG MAB8 AGACTGAGCTGcGccGcc?ccGGCTTTAGccTGTCTAGCTACGGCGTGG???GG encoding GTCCGACAGGCCCCTGGCAAAGGCCTGGAGTGGGTCGGAGTGATCTGGGGCGGA SEQ ID NO : 105 GGCGGAACCTACTACGCCTCTAGCCTGATGGGCCGGTTCACTATCTCTAGGGAC AACTCTAAGAACACCCTGTACCTGCAGATGAACTCACTGAGAGCCGAGGACACC GCCGTCTACTACTGCGCTAGAAACGCCTACGGTCACGACGGCGGCTTCGCTATG GACTACTGGGGTCAGGGCACCCTGGTCACCGTGAGTTCA 102 : PN of VL , GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGA MAB8 GCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTAT encoding CAGCAGAGAccTGGTAGGcccc?cGGCTGCTGATCTACGGcGccTCTAAccGG SEO ID NO : 7 GCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACC CTGACCATCTCCCGGCTGGAACCCGAGGACTTCGCCGTGTACTACTGCGGCCAG ?ccTACTCATAcccc????????cGGCCAGGGCACCAAGCTGGAAATCAAG 108 : PN of HC , GAGGTGCAGCTGGTGGAATCAGGCGGCGGACTGGTGCAGTCAGGCGGTAGCCTG MAB8 AGACTGAGCTGcGccccc?ccGGCTTTAGccTGTCTAGCTACGGcGTGGACTGG encoding GTCCGACAGGCCCCTGGCAAAGGCCTGGAGTGGGTCGGAGTGATCTGGGGCGGA SEQ ID NO : 106 GGCGGAACCTACTACGCCTCTAGCCTGATGGGCCGGTTCACTATCTCTAGGGAC AACTCTAAGAACAcccTGTAccTGCAGATGAACTCACTGAGAGccGAGGACAcc GCCGTCTACTACTGCGCTAGAAACGCCTACGGTCACGACGGCGGCTTCGCTATG GACTACTGGGGTCAGGGCACCCTGGTCACCGTGAGTTCAGCTAGCACTAAGGGC ccAAGTGTGTTTccccTGGcccccAGCAGCAAGTCTACTICCGGCGGAACTGCT GcccTGGGTTGccTGGTGAAGG???????ccccGAGcccGTGACAGTGTccTGG AACTCTGGGGCTCTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGC AGCGGccTGTACAGccTGAGCAGCGTGGTGACAGTGccc?ccAGC?????GGGA ACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGAC AAGAGAGTGGAGC?CAAGAGCTGCGACAAGAccCACAccTGcccccccTGccCA GCTccAGAACTGCTGGGAGGGcc??ccGTGTTccTGTTcccccccAAGcccAAG GACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTG TCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG CACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTG GTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAG TGCAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAGACAATCAGCAAG GCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAG GAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCC AGCGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAG AccAcccccccAGTGCTGGAcAGCGAcGGCAGC??c??ccTGTACAGCAAGCTG ACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTT CAGCTGCAGCGTGATG CACGAGGcccTGCACAACCACTACAC?CAGAAGTcccTGAGCCTGAGccccGGC AAG 104 : PN of LC , GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGA MAB8 GCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTAT encoding CAGCAGAGAccTGGTCAGGcccc?cGGCTGCTGATCTACGGCGcc??TAAccGG SEQ ID NO : 66 GCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACC ??GACCATCTccccccTGGAAcccGAGG????cGccGTGTACTACTGCGGccAG TCCTACTCATACCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAGCGT ACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAG AGCGGCAccGccAGCGTGGTGTGccTGCTGAACAACTICTAcccccGGGAGGcc AAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGC GTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC US 2017 /0306038 A1 Oct. 26 , 2017 24

TABLE 1 - continued Examples of anti - GITR agonist antibodies of the present invention . SEQ ID NO : Amino acid or polynucleotide ( PN ) description Sequence CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCAC CAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC

[0127 ] The CDRs of the antibodies listed in Table 1 can be Immunological Interest, ” 5th Ed . Public Health Service , determined by well known numbering systems known in the National Institutes of Health , Bethesda, Md . (“ Kabat” num bering scheme) , NIH Publication No . 91 - 3242 ; and ( 2 ) art, including those described herein . Table 2 listed the Chothia , see Al- Lazikani et al ., ( 1997 ) “ Standard conforma CDRs that are defined by ( 1 ) using the numbering system tions for the canonical structures of immunoglobulins, ” J . described in Kabat et al. ( 1991 ), “ Sequences of Proteins of Mol. Biol. 273: 927 - 948 . TABLE 2 Kabat and Chothia CDR Comparison SEQ ID NO : Kabat SEQ ID NO : Chothia CDR CDR ( Kabat et al . , 1991 ) CDR ( Al - Laikani et al . , 1997 ) MAB1 CDRH1 22 : SYGVD 79 : GFSLRSY MAB1 CDRH2 62 : VIWGGGGTNYNSALMA 80 : WGGGG MAB1 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHDGGFAMDY MAB1 CDRL1 63 : KASENVDTFVS 81 : SENVDTF MAB1 CDRL2 64 : GASNRYT 82 : GAS MAB1 CDRL3 34 : GQSYSYPFT 83 : SYSYPF MAB2 CDRH1 22 : SYGVD 84 : GFSLSSY MAB2 CDRH2 23 : VIWGGGGTYYASSVMA 80 : WGGGG MAB2 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHDGGFAMDY MAB2 CDRLI 30 : RASESVSSNVA 85 : SESVSSN MAB2 CDRL2 33 : GASNRAT 82 : GAS MAB2 CDRL3 34 : GQSYSYPFT 83 : SYSYPF MAB3 CDRH1 22 : SYGVD 84 : GFSLSSY MAB3 CDRH2 24 : VIWGGGGTYYTASLMG 80 : WGGGG MAB3 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHDGGFAMDY MAB3 CDRLI 31 : RASOSVSSNLA 86 : SQSVSSN MAB3 CDRL2 33 : GASNRAT 82 : GAS MAB3 CDRL3 34 : GOSYSYPFT 83 : SYSYPF MAB4 CDRH1 22 : SYGVD 84 : GFSLSSY MAB4 CDRH2 25 : VIWGGGGTYYASSLMG 80 : WGGGG MAB4 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHDGGFAMDY MAB4 CDRLI 30 : RASESVSSNVA 85 : SESVSSN MAB4 CDRL2 33 : GASNRAT 82 : GAS MAB4 CDRL3 34 : GOSYSYPFT 83 : SYSYPF MAB5 CDRH1 22 : SYGVD 84 : GFSLSSY US 2017 /0306038 A1 Oct. 26 , 2017 25

TABLE 2 - continued Kabat and Chothia CDR Comparison SEQ ID NO : Kabat SEQ ID NO : Chothia CDR CDR ( Kabat et al . , 1991 ) CDR ( Al - Laikani et al . , 1997 )

MAB5 CDRH2 26 : VIWGGGGTYYTSSLMG 8 0 : WGGGG MAB5 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHDGGFAMDY MAB5 CDRL1 30 : RASESVSSNVA 85 : SESVSSN MAB5 CDRL2 33 : GASNRAT 82 : GAS MAB5 CDRL3 34 : GQSYSYPFT 83 : SYSYPF MAB6 CDRH1 22 : SYGVD 84 : GFSLSSY MAB6 CDRH2 27 : VIWGGGGTYYTSSLMA 80 : WGGGG MAB6 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHDGGFAMDY MAB6 CDRLI 30 : RASESVSSNVA 85 : SESVSSN MAB6 CDRL2 33 : GASNRAT 82 : GAS MAB6 CDRL3 34 : GOSYSYPFT 83 : SYSYPF MAB7 CDRH1 22 : SYGVD 84 : GFSLSSY MAB7 CDRH2 25 : VIWGGGGTYYASSLMG 80 : WGGGG MAB7 CDRH3 29 : HAYGHDGGFAMDY 29 : HAYGHD GGFAMDY MAB7 CDRL1 30 : RASESVSSNVA 85 : SESVSSN MAB7 CDRL2 33 : GASNRAT 82 : GAS MAB7 CDRL3 34 : GOSYSYPFT 83 : SYSYPF MAB8 CDRH1 22 : SYGVD 84 : GFSLSSY MAB8 CDRH2 25 : VIWGGGGTYYASSLMG 80 : WGGGG MAB8 CDRH3 109 : NAYGHDGGFAMDY 109 : NAYGHDGGFAMDY MAB8 CDRLI 30 : RASESVSSNVA 85 : SESVSSN MAB8 CDRL2 33 : GASNRAT 82 : GAS MAB8 CDRL3 34 : GOSYSYPFT 83 : SYSYPF

[ 0128 ] In some embodiments , the anti -GITR antibodies or NO :25 , the heavy chain CDR3 comprises SEQ ID NO : 29 , antibody fragments of the invention that binds to GITR ( e . g ., the light chain CDR1 comprises SEQ ID NO : 30 , the light SEQ ID NO : 1 , cellular processed SEQ ID NO : 1 ) , is selected chain CDR2 comprises SEQ ID NO : 33 , and the light chain from any one of: i) an antibody, antibody fragment, or CDR3 comprises SEQ ID NO :34 ; iv ) an antibody, antibody antigen binding molecule wherein : the heavy chain CDR1 fragment, or antigen binding molecule wherein : the heavy comprises SEQ ID NO : 22 , the heavy chain CDR2 comprises chain CDR1 comprises SEQ ID NO :22 , the heavy chain SEQ ID NO : 23 , the heavy chain CDR3 comprises SEQ ID CDR2 comprises SEQ ID NO : 26 , the heavy chain CDR3 NO : 29 , the light chain CDR1 comprises SEQ ID NO :30 , the comprises SEQ ID NO :29 , the light chain CDR1 comprises light chain CDR2 comprises SEQ ID NO : 33 , and the light SEQ ID NO :30 , the light chain CDR2 comprises SEQ ID chain CDR3 comprises SEQ ID NO : 34 ; ii ) an antibody, NO : 33 , and the light chain CDR3 comprises SEQ ID NO :34 ; antibody fragment , or antigen binding molecule wherein : the v ) an antibody, antibody fragment, or antigen binding mol heavy chain CDR1 comprises SEQ ID NO : 22 , the heavy ecule wherein : the heavy chain CDR1 comprises SEQ ID chain CDR2 comprises SEQ ID NO : 24 , the heavy chain NO :22 , the heavy chain CDR2 comprises SEQ ID NO :27 , CDR3 comprises SEO ID NO : 29 , the light chain CDR1 the heavy chain CDR3 comprises SEO ID NO : 29 , the light comprises SEQ ID NO :31 , the light chain CDR2 comprises chain CDR1 comprises SEQ ID NO :30 , the light chain SEQ ID NO :33 , and the light chain CDR3 comprises SEQ CDR2 comprises SEO ID NO : 33 , and the light chain CDR3 ID NO : 34 ; iii) an antibody , antibody fragment, or antigen comprises SEQ ID NO :34 ; and vi) an antibody, antibody bindingmolecule wherein : the heavy chain CDR1 comprises fragment, or antigen binding molecule wherein : the heavy SEQ ID NO :22 , the heavy chain CDR2 comprises SEQ ID chain CDR1 comprises SEQ ID NO :22 , the heavy chain US 2017 /0306038 A1 Oct. 26 , 2017

CDR2 comprises SEQ ID NO :25 , the heavy chain CDR3 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or comprises SEQ ID NO : 109, the light chain CDR1 comprises 100 % amino acid sequence identity to a light chain variable SEQ ID NO : 30 , the light chain CDR2 comprises SEQ ID region of SEQ ID NO : 7 . NO : 33 , and the light chain CDR3 comprises SEQ ID NO :34 . [0134 ] In some embodiments , the anti -GITR antibodies or In some embodiments , the antibodies or antibody fragments antibody fragments of the invention comprise a heavy chain are humanized . In particular embodiments the antibodies or polypeptide having at least 90 % , 91 % , 92 % , 93 % , 94 % , antibody fragments comprise a human constant region . In 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence some embodiments the antibodies or antibody fragments identity to a heavy chain variable region of SEQ ID NO : 14 comprise an IgG Fc region . In certain embodiments the and comprise a light chain polypeptide having at least 90 % , antibody or antigen binding fragment is glycosylated . In 91 % 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % some embodiments the antibodies or antibody fragments are amino acid sequence identity to a light chain variable region modified or expressed in a modified cell , wherein such of SEQ ID NO :7 . modification results in increased FcR effector function of the [0135 ] In some embodiments , the anti -GITR antibodies or antibody or antibody fragment. In certain embodiments the antibody fragments of the invention comprise a heavy chain antibody or antigen fragment induces an elevated Teff: Treg variable region having at least 90 % , 91 % , 92 % , 93 % , 94 % , ratio in vivo . In some embodiments the antibody or antibody 95 % , 96 % , 97 % , 98 % , 99 % or 100 % amino acid sequence fragment induces a potentiated immune response in vivo . In identity to a heavy chain variable region of SEQ ID NO :99 some embodiments when the antibody or antibody fragment and comprise a light chain variable region having at least is cross linked to a second antibody or antibody fragment it 90 % , 91 % 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or is an agonist of SEQ ID NO : 1 , SEQ ID NO : 2 or SEQ ID 100 % amino acid sequence identity to a light chain variable NO3 . region of SEQ ID NO : 7 . 0129 ] In some embodiments , the anti -GITR antibodies or [0136 ] In some embodiments , the anti -GITR antibodies or antibody fragments of the invention comprise a heavy chain antibody fragments of the invention comprise a heavy chain variable region having at least 95 % , 96 % , 97 % , 98 % , 99 % , variable region having at least 90 % , 91 % , 92 % , 93 % , 94 % , or 100 % amino acid sequence identity to a heavy chain 95 % , 96 % , 97 % , 98 % , 99 % or 100 % amino acid sequence variable region of SEQ ID NO : 16 and comprise a light chain identity to a heavy chain variable region of SEQ ID NO : 105 variable region having at least 95 % , 96 % , 97 % , 98 % , 99 % , and comprise a light chain variable region having at least or 100 % amino acid sequence identity to a light chain 90 % , 91 % 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or 100 % amino acid sequence identity to a light chain variable variable region of SEQ ID NO : 17 . region of SEQ ID NO : 7 . [0130 ] In some embodiments , the anti -GITR antibodies or [0137 ] In some embodiments , the anti -GITR antibodies or antibody fragments of the invention comprise a heavy chain antibody fragments of the invention comprise a heavy chain variable region having at least 90 % , 91 % , 92 % , 93 % , 94 % , polypeptide having at least 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence identity to a heavy chain variable region of SEQ ID NO :6 identity to a heavy chain variable region of SEQ ID NO :61 and comprise a light chain variable region having at least and comprise a light chain polypeptide having at least 90 % , 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % 100 % amino acid sequence identity to a light chain variable amino acid sequence identity to a light chain variable region region of SEQ ID NO : 7 . of SEQ ID NO :59 . [ 0131] In some embodiments , the anti -GITR antibodies or [0138 ] Over their full length , the anti -GITR antibodies of antibody fragments of the invention comprise a heavy chain the present invention generally can have an overall constant variable region having at least 90 % , 91 % , 92 % , 93 % , 94 % , region ( e . g . , IgG1) amino acid sequence identity of at least 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence about 85 % , for example , at least about 85 % , 89 % , 90 % , identity to a heavy chain variable region of SEQ ID NO : 8 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % and comprise a light chain variable region having at least to human constant region , e . g . , IgG1/kappa constant region 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or amino acid sequences . For example, the heavy chain of the 100 % amino acid sequence identity to a light chain variable anti -GITR antibodies can have at least about 85 % , 89 % , region of SEQ ID NO : 9 . 90 % , 91 % 92 % 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence identity to the human IgG1 [0132 ] In some embodiments , the anti -GITR antibodies or constant region ASTKGPSVFPLAPSSKSTSGGTAALG antibody fragments of the invention comprise a heavy chain CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLOSS variable region having at least 90 % , 91 % , 92 % , 93 % , 94 % , GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD 95 % , 96 % , 97 % , 98 % , 99 % or 100 % amino acid sequence KRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKP identity to a heavy chain variable region of SEQ ID NO : 10 KDTLMISRTPEVTCVVVDVSHEDPEVKFN and comprise a light chain variable region having at least WYVDGVEVHNAKTKPREEQY 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % or NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA 100 % amino acid sequence identity to a light chain variable PIEKTISKAKGQPREPOVYTLPPSR EEMTKNQVSLT region of SEQ ID NO : 7 . CLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDS [ 0133 ] In some embodiments , the anti -GITR antibodies or DGSFFLYSKLTVDK antibody fragments of the invention comprise a heavy chain SRWQQGNVFSCSVMHEALHNHYTOKSLSLSPGK variable region having at least 90 % , 91 % , 92 % , 93 % , 94 % , (SEQ ID NO : 20 ) . In one embodiment , the last amino acid , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence lysine ( K ) , is substituted with arginine ( R ) . The light chain identity to a heavy chain variable region of SEQ ID NO : 12 of the anti -GITR antibodies can have at least about 85 % , and comprise a light chain variable region having at least 89 % , 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , US 2017 /0306038 A1 Oct. 26 , 2017 27

99 % , or 100 % amino acid sequence identity to the human constant (K ) ) of less than about 10 - 8M or 10 -9 M , for kappa light chain constant region example , or less than about 10 - 10 M or 10 - 11 M , and in some embodiments , less than about 10 - 12 M or 10 - 13 M . Antibodies that Bind to the Same Epitope ( SEO ID NO : 21 ) [0143 ] The present invention provides antibodies and anti RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALOS body fragments that bind to an epitope comprising the GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV cysteine - rich domain 1 (“ CRDI” , SEQ ID NO : 4 : CGPGRLLLGTGTDARCCRVHTTRCCRDYP TKSFNRGEC . GEECCSEWDC ) and the cysteine -rich domain 2 (“ CRD2” , In some embodiments , amino acids within the constant SEQ ID NO : 5 : MCVQPEFHCGDPCCTTCRHHPCP regions are added , deleted , or substituted . PGQGVQSQGKFSFGFQC ) of human GITR , and wherein [ 0139 ] In some embodiments , such antibody is a human or the antibody, antibody fragment, or the antigen binding humanized antibody . The VH , VL , full length light chain , molecule is an agonist of hGITR , and wherein the antibody , and full length heavy chain sequences ( amino acid antibody fragment, or the antigen binding molecule option sequences and the nucleotide sequences encoding the amino ally has an intact or increased FcR effector function . In some acid sequences ) can be “ mixed and matched ” to create other embodiments , an antibody , antibody fragment, or the anti GITR -binding antibodies of the invention . Such “ mixed and gen binding molecule binds to an epitope comprising SEQ matched ” GITR - binding antibodies can be tested using the ID NO :88 ) of human GITR . In some embodiments an binding assays known in the art ( e .g ., ELISAs, and other epitope comprises residues within SEQ ID NO : 88 . In some assays described in the Example section ) to confirm activity . embodiments an epitope comprises amino acid residues When chains are mixed and matched , a VH sequence from within residues 34 - 72 and 78 of human GITR , where such a particular VH / VL pairing should be replaced with a antibodies and antibody fragments are agonists of hGITR . structurally similar VH sequence. Likewise a full length 101441. The present invention also provides antibodies and heavy chain sequence from a particular full length heavy antibody fragments that bind to the same epitope as do the chain / full length light chain pairing should be replaced with GITR -binding antibodies described in Table 1 . Additional a structurally similar full length heavy chain sequence . antibodies and antibody fragments can therefore be identi Likewise, a VL sequence from a particular VH /VL pairing fied based on their ability to cross - compete ( e . g ., to com should be replaced with a structurally similar VL sequence . petitively inhibit the binding of, in a statistically significant Likewise a full length light chain sequence from a particular manner ) with other antibodies of the invention in GITR full length heavy chain / full length light chain pairing should binding assays . The ability of a test antibody to inhibit the be replaced with a structurally similar full length light chain binding of antibodies and antibody fragments of the present sequence . Accordingly , in one aspect, the invention provides invention to a GITR protein ( e. g . , human GITR ) demon an isolated monoclonal antibody or antibody fragment hav strates that the test antibody can compete with that antibody ing : a heavy chain variable region comprising an amino acid or antibody fragment for binding to hGITR ; such an anti sequence selected from the group consisting of SEQ ID body may , according to non - limiting theory , bind to the same NOS :6 , 8 , 10 , 12 , 14 , 99 and 105 ; and a light chain variable or a related ( e . g . , a structurally similar or spatially proximal) region comprising an amino acid sequence selected from the epitope on the GITR protein as the antibody or antibody group consisting of SEQ ID NOS : 7 and 9 ; wherein the fragment with which it competes . In a certain embodiment, antibody specifically binds to GITR . the antibody that binds to the same epitope on hGITR as the [0140 ] In some embodiments , the anti -GITR antibodies or antibodies or antibody fragments of the present invention is antibody fragments of the invention comprise a heavy chain a human or humanized monoclonal antibody . Such human or polypeptide having at least 90 % , 91 % , 92 % , 93 % , 94 % , humanized monoclonal antibodies can be prepared and 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % amino acid sequence isolated as described herein . identity to a heavy chain sequence selected from any of SEQ ID NO :65 , SEQ ID NO :69 , SEQ ID NO :73 , SEQ ID NO :75 , Engineered and Modified Antibodies SEQ ID NO :77 , SEQ ID NO : 100 and SEQ ID NO : 106 ; and [ 0145 ] An antibody or antibody fragment of the invention comprise a light chain polypeptide having at least 90 % , further can be prepared using an antibody having one or 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % more of the CDRs and / or VH and / or VL sequences shown amino acid sequence identity to a light chain of SEQ ID herein ( e . g ., Table 1 ) as starting material to engineer a NO : 66 or SEQ ID NO :70 . In certain embodiments , the modified antibody or antibody fragment, which modified anti- GITR antibodies or antibody fragments of the invention antibody may have altered properties from the starting comprise a heavy chain polypeptide selected from any of antibody . An antibody or antibody fragment can be engi SEQ ID NO :65 , SEQ ID NO :69 , SEQ ID NO :73 , SEQ ID neered by modifying one or more residues within one or NO :75 , SEQ ID NO :77 , SEQ ID NO : 100 and SEQ ID both variable regions ( i . e ., VH and /or VL ) , for example NO : 106 ; and comprise a light chain polypeptide of SEQ ID within one or more CDR regions and / or within one or more NO :66 or SEQ ID NO :70 . framework regions. Additionally or alternatively , an anti [0141 ] For identified amino acid sequences less than 20 body or antibody fragment can be engineered by modifying amino acids in length , one or two conservative amino acid residues within the constant region ( s ), for example to alter residue substitutions can be tolerated while still retaining the the effector function ( s ) of the antibody. desired specific binding and / or agonist activity . [0146 ] One type of variable region engineering that can be [ 0142 ] Anti -GITR antibodies and antibody fragments of performed is CDR grafting . Antibodies interact with target the present invention generally will bind GITR , including antigens predominantly through amino acid residues that are isoform 1 (SEQ ID NO : 1 ) , isoform 2 ( SEQ ID NO : 2 ) and located in the six heavy and light chain complementarity isoform 3 (SEQ ID NO :3 ) , with an equilibrium dissociation determining regions (CDRs ) . For this reason , the amino acid US 2017 /0306038 A1 Oct. 26 , 2017 sequences within CDRs are more diverse between individual enhance the antigen binding ability of the antibody (see e . g . , antibodies than sequences outside of CDRs. Because CDR U . S . Pat. Nos. 5 , 530 , 101; 5 , 585 , 089; 5 ,693 , 762 and 6 , 180 , sequences are responsible for most antibody - antigen inter 370 to Queen et al) . actions , it is possible to express recombinant antibodies that [0150 ] Another type of variable region modification is to mimic the properties of a specific antibody by constructing mutate amino acid residues within the VH and / or VL CDR1, expression vectors that include CDR sequences from the CDR2 , and / or CDR3 regions to thereby improve one or specific antibody grafted onto framework sequences from a more binding properties ( e . g ., affinity ) of the antibody of different antibody with different properties (see , e . g . , Riech interest , known as “ affinity maturation .” Site - directed muta mann , L . et al. , 1998 Nature 332 :323 - 327 ; Jones, P . et al. , genesis or PCR -mediated mutagenesis can be performed to 1986 Nature 321 : 522 -525 ; Queen , C . et al. , 1989 Proc . Natl . introduce the mutation (s ) and the effect on antibody binding , Acad ., U .S . A . 86 : 10029 - 10033 ; U . S . Pat . No . 5 ,225 ,539 to or other functional property of interest, can be evaluated in Winter , and U .S . Pat . Nos. 5 , 530 , 101 ; 5 ,585 ,089 ; 5, 693 , 762 in vitro or in vivo assays as described herein and provided and 6 , 180 ,370 to Queen et al. ). in the Examples and /or alternative or additional assays [0147 ] Accordingly, another embodiment of the invention known in the art. Conservative modifications can be intro pertains to an isolated monoclonal antibody, or an antigen duced . The mutations may be amino acid substitutions, binding fragment thereof, comprising a heavy chain variable additions or deletions . Moreover, typically no more than region comprising CDR1 sequence having an amino acid one , two, three , four or five residues within a CDR region are sequence selected from the group consisting of SEQ ID altered . NOS: 22 , 79 , and 84 ; CDR2 sequences having an amino acid [0151 ] Engineered antibodies or antibody fragments of the sequence selected from the group consisting of SEQ ID invention include those in which modifications have been NOS :23 , 24 , 25 , 26 , 27 , 62 , and 80 ; CDR3 sequences having made to framework residues within VH and / or VL , e . g . to an amino acid sequence selected from the group consisting improve the properties of the antibody. Typically such of SEQ ID NOS : 29 , 34 and 109 , respectively ; and a light framework modifications are made to decrease the immu chain variable region having CDR1 sequences having an nogenicity of the antibody. For example , one approach is to amino acid sequence selected from the group consisting of “ backmutate” one or more framework residues to the cor SEQ ID NOS : 30 , 31 , 63, 81, 85 , and 86 ; CDR2 sequences responding germline sequence . More specifically , an anti having an amino acid sequence selected from the group body that has undergone somatic mutation may contain consisting of SEQ ID NOS : 33 , 64 , and 82 ; and CDR3 framework residues that differ from the germline sequence sequences consisting of an amino acid sequence selected from which the antibody is derived . Such residues can be from the group consisting of SEQ ID NOS :34 and 83 ; identified by comparing the antibody framework sequences respectively . Thus, such antibodies contain the VH and VL to the germline sequences from which the antibody is CDR sequences of monoclonal antibodies , yet may contain derived . To return the framework region sequences to their different framework sequences from these antibodies . In germline configuration , the somatic mutations can be “ back certain embodiments , the isolated antibodies or antibody mutated ” to the germline sequence by , for example, site fragments comprise sequences that have amino acid directed mutagenesis . Such " backmutated ” antibodies are sequence identity of at least about 85 % , 89 % , 90 % , 91 % , also intended to be encompassed by the invention . 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % to [0152 ] Another type of framework modification involves the corresponding sequences in this paragraph . mutating one or more residues within the framework region , [ 0148 ] Such framework sequences can be obtained from or even within one or more CDR regions, to remove T cell public DNA databases or published references that include epitopes to thereby reduce the potential immunogenicity of germline antibody gene sequences . For example, germline the antibody. This approach is also referred to as “ deimmu DNA sequences for human heavy and light chain variable nization ” and is described in further detail in U . S . Patent region genes can be found in the “ VBase ” human germline Publication No. 20030153043 by Carr et al. sequence database (available on the Internet at www .mrc [0153 ] When present , the constant regions of the anti cpe .cam .ac . uk /vbase ), as well as in Kabat , E . A . , et al ., 1991 GITR antibodies or antibody fragments can be any type or Sequences of Proteins of Immunological Interest , Fifth subtype , as appropriate , and can be selected to be from the Edition , U . S . Department of Health and Human Services, species of the subject to be treated by the present methods NIH Publication No . 91 - 3242 ; Tomlinson , I . M . , et al ., 1992 ( e . g ., human , non -human primate or other mammal, for J . fol. Biol. 227 :776 -798 ; and Cox , J. P . L . et al. , 1994 Eur. example , agricultural mammal ( e . g . , equine , ovine , bovine , J Immunol. 24 : 827 -836 . porcine , camelid ) , domestic mammal ( e . g ., canine , feline) or [0149 ] An example of framework sequences for use in the rodent ( e . g . , rat, mouse , hamster, rabbit ) . In some embodi antibodies of the invention are those that are structurally ments the anti -GITR antibodies are engineered to generate similar to the framework sequences used by selected anti humanized or Humaneered® antibodies . In some embodi bodies of the invention , e . g ., consensus sequences and / or ments , the constant region isotype is IgG , for example , framework sequences used by monoclonal antibodies of the IgG1, IgG2 , IgG3 , IgG4. In certain embodiments the con invention . The VH CDR1, 2 and 3 sequences , and the VL stant region isotype is IgG . CDR1, 2 and 3 sequences , can be grafted onto framework 10154 ) In addition or alternative to modifications made regions that have the identical sequence as that found in the within the framework or CDR regions, antibodies or anti germline immunoglobulin gene from which the framework body fragments of the invention may be engineered to sequence derive , or the CDR sequences can be grafted onto include modifications within the Fc region , typically to alter framework regions that contain one or more mutations as one or more functional properties of the antibody , such as compared to the germline sequences . For example , it has serum half - life , complement fixation , Fc receptor binding , been found that in certain instances it is beneficial to mutate and /or antigen - dependent cellular cytotoxicity . Furthermore , residues within the framework regions to maintain or an antibody or antibody fragment of the invention may be US 2017 /0306038 A1 Oct. 26 , 2017

chemically modified ( e . g . , one or more chemical moieties increase the affinity of the antibody for an Fey receptor by can be attached to the antibody ) or be modified to alter its modifying one or more amino acids. This approach is glycosylation , again to alter one or more functional proper described further in PCT Publication WO 00 /42072 by ties of the antibody or antibody fragment. Presta . Moreover , the binding sites on human IgG1 for [0155 ] In one embodiment, the hinge region of CH1 is FcyR1, FcYRII , FcyRIII and FcRn have been mapped and modified such that the number of cysteine residues in the variants with improved binding have been described (see hinge region is altered , e . g ., increased or decreased . This Shields, R . L . et al. , 2001 J . Biol. Chen . 276 :6591 -6604 ). approach is described further in U . S . Pat. No. 5 ,677 , 425 by [0163 ] In still another embodiment, glycosylation of an Bodmer et al . The number of cysteine residues in the hinge antibody is modified . For example , an aglycoslated antibody region of CH1 is altered to , for example , facilitate assembly can be made ( i . e ., the antibody lacks glycosylation ) . Gly of the light and heavy chains or to increase or decrease the cosylation can be altered to , for example , increase the stability of the antibody or antibody fragment. affinity of the antibody for “ antigen ' . Such carbohydrate [0156 ] In another embodiment, the Fc hinge region of an modifications can be accomplished by, for example , altering antibody is mutated to alter the biological half - life of the one or more sites of glycosylation within the antibody antibody .More specifically , one or more amino acid muta sequence . For example , one or more amino acid substitu tions are introduced into the CH2 -CH3 domain interface tions can be made that result in elimination of one or more region of the Fc -hinge fragment such that the antibody has variable region framework glycosylation sites to thereby impaired Staphylococcyl protein A (SPA ) binding relative to eliminate glycosylation at that site . Such aglycosylation may native Fc - hinge domain SpA binding . This approach is increase the affinity of the antibody for antigen . Such an described in further detail in U . S . Pat . No . 6 , 165, 745 by approach is described in further detail in U . S . Pat . Nos . Ward et al . [0157 ] In another embodiment, the antibody is modified to 5 ,714 , 350 and 6 , 350 ,861 by Co et al. increase its biological half - life . Various approaches are [0164 ] Additionally or alternatively , an antibody can be possible . For example , one or more of the following muta made that has an altered type of glycosylation , such as a tions can be introduced : T252L , T254S , T256F , as described hypofucosylated antibody having reduced amounts of fuco in U . S . Pat . No . 6 ,277 , 375 to Ward . Alternatively , to increase syl residues or an antibody having increased bisecting the biological half life , the antibody can be altered within the GlcNac structures . Such altered glycosylation patterns have CH1 or CL region to contain a salvage receptor binding been demonstrated to increase the ADCC ability of antibod epitope taken from two loops of a CH2 domain of an Fc ies . Such carbohydrate modifications can be accomplished region of an IgG , as described in U . S . Pat. Nos. 5 , 869, 046 by, for example , expressing the antibody in a host cell with and 6 , 121, 022 by Presta et al. altered glycosylation machinery . Cells with altered glyco [0158 ] In yet other embodiments , the Fc region is altered sylation machinery have been described in the art and can be by replacing at least one amino acid residue with a different used as host cells in which to express recombinant antibod amino acid residue to alter the effector functions of the ies of the invention to thereby produce an antibody with antibody . For example , one or more amino acids can be altered glycosylation . For example , EP 1 , 176 , 195 by Hang replaced with a different amino acid residue such that the et al . describes a cell line with a functionally disrupted FUT8 antibody has an altered affinity for an effector ligand but gene , which encodes a fucosyl transferase , such that anti retains the antigen -binding ability of the parent antibody . bodies expressed in such a cell line exhibit hypofucosy The effector ligand to which affinity is altered can be , for lation . PCT Publication WO 03 / 035835 by Presta describes example , an Fc receptor (FcR ) or the C1 component of a variant CHO cell line , Lec13 cells , with reduced ability to complement. This approach is described in further detail in attach fucose to Asn ( 297 ) - linked carbohydrates, also result U . S . Pat . Nos. 5 ,624 ,821 and 5 ,648 , 260 , both by Winter et ing in hypofucosylation of antibodies expressed in that host cell (see also Shields , R . L . et al . , 2002 J . Biol. Chem . 10159 ] In another embodiment, one or more amino acids 277 :26733 - 26740 ). PCT Publication WO 99/ 54342 by selected from amino acid residues can be replaced with a Umana et al. describes cell lines engineered to express different amino acid residue such that the antibody has glycoprotein -modifying glycosyl transferases ( e . g ., beta ( 1 , altered Clq binding and /or reduced or abolished comple 4 ) - N acetylglucosaminyltransferase III (GnTIII ) ) such that ment dependent cytotoxicity (CDC ) . This approach is antibodies expressed in the engineered cell lines exhibit described in further detail in U . S . Pat . No. 6 , 194 ,551 by increased bisecting GlcNac structures which results in Idusogie et al . increased ADCC activity of the antibodies (see also Umana (0160 ] Antibodies containing such mutations mediate et al. , 1999 Nat . Biotech . 17 :176 -180 ) . reduced or no antibody -dependent cellular cytotoxicity [0165 ] Grafting Antigen - Binding Domains into Alterna ( ADCC ) or complement- dependent cytotoxicity (CDC ) . In tive Frameworks or Scaffolds some embodiments , amino acid residues L234 and L235 of [0166 ] A wide variety of antibody / immunoglobulin frame the IgGl constant region are substituted to Ala234 and works or scaffolds can be employed so long as the resulting Ala235 . In some embodiments , amino acid residue N267 of polypeptide includes at least one binding region which the IgGl constant region is substituted to Ala267. specifically binds to GITR . Such frameworks or scaffolds [0161 ] In another embodiment, one or more amino acid include the 5 main idiotypes of human immunoglobulins, or residues are altered to thereby alter the ability of the anti fragments thereof, and include immunoglobulins of other body to fix complement. This approach is described further animal species, preferably having humanized aspects . Single in PCT Publication WO 94 / 29351 by Bodmer et al. heavy - chain antibodies such as those identified in camelids [0162 ] In yet another embodiment, the Fc region is modi are of particular interest in this regard . Novel frameworks , fied to increase the ability of the antibody to mediate scaffolds and fragments continue to be discovered and antibody dependent cellular cytotoxicity (ADCC ) and / or to developed by those skilled in the art . US 2017 /0306038 A1 Oct. 26 , 2017 30

[0167 ] In one aspect , the invention pertains to generating which are randomized to generate affibody libraries with a non - immunoglobulin based antibodies using non - immuno large number of ligand variants ( See e . g ., U . S . Pat. No . globulin scaffolds onto which CDRs of the invention can be 5 ,831 ,012 ) . Affibody molecules mimic antibodies, they have grafted . Known or future non - immunoglobulin frameworks a molecular weight of 6 kDa, compared to the molecular and scaffolds may be employed , as long as they comprise a weight of antibodies, which is 150 kDa. In spite of its small binding region specific for the target GITR protein ( e . g ., size , the binding site of affibody molecules is similar to that human and /or cynomolgus GITR ). Known non - immuno of an antibody. globulin frameworks or scaffolds include , but are not limited [0172 ] Anticalins are products developed by the company to , fibronectin (Compound Therapeutics , Inc. , Waltham , Pieris ProteoLab AG . They are derived from lipocalins , a Mass .) , ankyrin (Molecular Partners AG , Zurich , Switzer widespread group of small and robust proteins that are land ) , domain antibodies (Domantis , Ltd . , Cambridge , usually involved in the physiological transport or storage of Mass. , and Ablynx nv , Zwijnaarde, Belgium ) , lipocalin chemically sensitive or insoluble compounds. Several natu (Pieris Proteolab AG , Freising , Germany ) , small modular ral lipocalins occur in human tissues or body liquids . The immuno -pharmaceuticals ( Trubion Pharmaceuticals Inc . , protein architecture is reminiscent of immunoglobulins, with Seattle , Wash . ), maxybodies ( Avidia , Inc ., Mountain View , hypervariable loops on top of a rigid framework . However, Calif. ) , Protein A (Affibody AG , Sweden ) , and affilin in contrast with antibodies or their recombinant fragments , (gamma - crystallin or ubiquitin ) ( Scil Proteins GmbH , Halle , lipocalins are composed of a single polypeptide chain with Germany ). 160 to 180 amino acid residues , being just marginally bigger [ 0168 ] The fibronectin scaffolds are based on fibronectin than a single immunoglobulin domain . The set of four loops , type III domain ( e . g . , the tenth module of the fibronectin which makes up the binding pocket, shows pronounced type III ( 10 Fn3 domain )) . The fibronectin type III domain structural plasticity and tolerates a variety of side chains. has 7 or 8 beta strands which are distributed between two The binding site can thus be reshaped in a proprietary beta sheets , which themselves pack against each other to process in order to recognize prescribed target molecules of form the core of the protein , and further containing loops different shape with high affinity and specificity . One protein ( analogous to CDRs) which connect the beta strands to each of lipocalin family , the bilin - binding protein (BBP ) of Pieris other and are solvent exposed . There are at least three such Bras sicae has been used to develop anticalins by mutagen loops at each edge of the beta sheet sandwich , where the izing the set of four loops . One example of a patent edge is the boundary of the protein perpendicular to the application describing anticalins is in PCT Publication No . direction of the beta strands ( see U . S . Pat. No. 6 ,818 ,418 ) . WO 199916873 . These fibronectin - based scaffolds are not an immunoglobu [0173 ] Affilin molecules are small non - immunoglobulin lin , although the overall fold is closely related to that of the proteins which are designed for specific affinities towards smallest functional antibody fragment, the variable region of proteins and small molecules. New affilin molecules can be the heavy chain , which comprises the entire antigen recog very quickly selected from two libraries , each of which is nition unit in camel and llama IgG . Because of this structure , based on a different human derived scaffold protein . Affilin the non - immunoglobulin antibody mimics antigen binding molecules do not show any structural homology to immu properties that are similar in nature and affinity to those of noglobulin proteins. Currently , two affilin scaffolds are antibodies . These scaffolds can be used in a loop random employed , one of which is gamma crystalline , a human ization and shuffling strategy in vitro that is similar to the structural eye lens protein and the other is " ubiquitin " process of affinity maturation of antibodies in vivo . These superfamily proteins . Both human scaffolds are very small , fibronectin -based molecules can be used as scaffolds where show high temperature stability and are almost resistant to the loop regions of the molecule can be replaced with CDRs pH changes and denaturing agents . This high stability is of the invention using standard cloning techniques . mainly due to the expanded beta sheet structure of the [0169 ] The ankyrin technology is based on using proteins proteins . Examples of gamma crystalline derived proteins with ankyrin derived repeat modules as scaffolds for bearing are described in WO200104144 and examples of “ ubiquitin variable regions which can be used for binding to different like” proteins are described in WO2004106368 . targets . The ankyrin repeat module is a 33 amino acid 101741 Protein epitope mimetics (PEM ) are medium polypeptide consisting of two anti -parallel a - helices and a sized , cyclic , peptide -like molecules (MW 1 - 2 kDa ) mim B - turn . Binding of the variable regions is mostly optimized icking beta - hairpin secondary structures of proteins , the by using ribosome display . major secondary structure involved in protein -protein inter 10170 ] Avimers are derived from natural A - domain con actions . taining protein such as LRP - 1 . These domains are used by [0175 ] Human or Humanized Antibodies nature for protein - protein interactions and in human over [0176 ] The present invention provides engineered human 250 proteins are structurally based on A - domains . Avimers antibodies that specifically bind to GITR protein ( e . g ., consist of a number of different “ A - domain ” monomers human GITR ) . Compared to the chimeric , primatized , or ( 2 - 10 ) linked via amino acid linkers . Avimers can be created humanized antibodies , the human GITR - binding antibodies that can bind to the target antigen using the methodology of the invention have further reduced antigenicity when described in , for example , U . S . Patent Application Publica administered to human subjects . tion Nos. 20040175756 ; 20050053973 ; 20050048512 ; and [0177 ] The human GITR -binding antibodies can be gen 20060008844 . erated using methods that are known in the art . For example, [0171 ] Affibody affinity ligands are small, simple proteins the Humaneered® technology platform (KaloBios , Sout San composed of a three -helix bundle based on the scaffold of Francisco , Calif . ) was used to convert non - human antibodies one of the IgG -binding domains of Protein A . Protein A is a into engineered human antibodies. U . S . Patent Publication surface protein from the bacterium Staphylococcus aureus. No. 20050008625 describes an in vivo method for replacing This scaffold domain consists of 58 amino acids, 13 of a nonhuman antibody variable region with a human variable US 2017 /0306038 A1 Oct. 26 , 2017 31 region in an antibody while maintaining the same or pro sequence from within the CDR3 regions and have human viding better binding characteristics relative to that of the germ - line framework 4 (FR4 ) regions. nonhuman antibody. The method relies on epitope guided replacement of variable regions of a non -human reference [0181 ] Camelid Antibodies antibody with a fully human antibody . The resulting human [0182 ] Antibody proteins obtained from members of the antibody is generally unrelated structurally to the reference camel and dromedary (Camelus bactrianus and Calelus nonhuman antibody , but binds to the same epitope on the dromaderius ) family including new world members such as same antigen as the reference antibody. llama species ( e . g . , Lama paccos , Lama glama , and Lama [0178 ] The anti- GITR antibodies of the invention are vicugna ) have been characterized with respect to size , struc based on engineered human antibodies with V - region tural complexity and antigenicity for human subjects . Cer sequences having substantial amino acid sequence identity tain IgG antibodies from this family of mammals as found to human germline V region sequences while retaining the in nature lack light chains, and are thus structurally distinct specificity and affinity of a reference antibody . See , U . S . from the typical four chain quaternary structure having two Patent Publication No. 2005 / 0255552 and U . S . Patent Pub heavy and two light chains, for antibodies from other lication No. 2006 /0134098 , both of which are hereby incor animals . See PCT/ EP93 / 02214 (WO 94 /04678 published 3 porated herein by reference . The process of improvement Mar. 1994 ). identifies minimal sequence information required to deter [0183 ] A region of the camelid antibody which is the small mine antigen -binding specificity from the variable region of single variable domain identified as VHH can be obtained by a reference antibody, and transfers that information to a genetic engineering to yield a small protein having high library of human partial V - region gene sequences to generate affinity for a target, resulting in a low molecular weight an epitope - focused library of human antibody V regions. A antibody -derived protein known as a " camelid nanobody ” . microbial - based secretion system can be used to express See U . S . Pat. No . 5 ,759 ,808 issued Jun . 2 , 1998 ; see also members of the library as antibody Fab fragments and the Stijlemans , B . et al. , 2004 J Biol Chem 279 : 1256 - 1261; library is screened for antigen -binding Fabs, for example , Dumoulin , M . et al. , 2003 Nature 424 : 783 -788 ; Plesch using a colony - lift binding assay . See, e . g . , U . S . Patent berger , M . et al. 2003 Bioconjugate Chem 14 : 440 - 448 ; Publication No . 2007 /0020685 . Positive clones can be fur Cortez -Retamozo , V . et al. 2002 Int J Cancer 89 : 456 -62 ; and ther characterized to identify those with the highest affinity . Lauwereys, M . et al. 1998 EMBO J 17 : 3512 - 3520 . Engi The resultant engineered human Fabs retain the binding neered libraries of camelid antibodies and antibody frag specificity of the parent, reference anti -GITR antibody, ments are commercially available , for example , from Abl typically have equivalent or higher affinity for antigen in ynx , Ghent, Belgium . As with other antibodies of non comparison to the parent antibody , and have V -regions with human origin , an amino acid sequence of a camelid antibody a high degree of sequence identity compared with human can be altered recombinantly to obtain a sequence that more germ - line antibody V -regions . closely resembles a human sequence , i . e . , the nanobody can [0179 ] The minimum binding specificity determinant be “ humanized " . Thus the natural low antigenicity of cam (BSD ) required to generate the epitope- focused library is elid antibodies to humans can be further reduced . typically represented by a sequence within the heavy chain [0184 ] The camelid nanobody has a molecular weight CDR3 ( “ CDRH3” ) and a sequence within the light chain of approximately one - tenth that of a human IgG molecule , and CDR3 ( “ CDRL3 ” ) . The BSD can comprise a portion or the the protein has a physical diameter of only a few nanome entire length of a CDR3 . The BSD can be comprised of ters . One consequence of the small size is the ability of contiguous or non - contiguous amino acid residues. In some camelid nanobodies to bind to antigenic sites that are cases, the epitope - focused library is constructed from human functionally invisible to larger antibody proteins, i. e ., cam V -segment sequences linked to the unique CDR3- FR4 elid nanobodies are useful as reagents detect antigens that region from the reference antibody containing the BSD and are otherwise cryptic using classical immunological tech human germ -line J segment sequences ( see , U . S . Patent niques, and as possible therapeutic agents. Thus yet another Publication No. 2005 /0255552 ) . Alternatively , the human V consequence of small size is that a camelid nanobody can segment libraries can be generated by sequential cassette inhibit as a result of binding to a specific site in a groove or replacement in which only part of the reference antibody V narrow cleft of a target protein , and hence can serve in a segment is initially replaced by a library of human capacity that more closely resembles the function of a sequences. The identified human " cassettes” supporting classical low molecular weight drug than that of a classical binding in the context of residual reference antibody amino antibody . acid sequences are then recombined in a second library [0185 ] The low molecular weight and compact size further screen to generate completely human V segments (see , U . S . result in camelid nanobodies being extremely thermostable , Patent Publication No. 2006 /0134098 ). stable to extreme pH and to proteolytic digestion , and poorly [0180 ] In each case, paired heavy and light chain CDR3 antigenic . Another consequence is that camelid nanobodies segments , CDR3 -FR4 segments, or J segments , containing readily move from the circulatory system into tissues , and specificity determinants from the reference antibody, are even cross the blood -brain barrier and can treat disorders used to constrain the binding specificity so that antigen that affect nervous tissue . Nanobodies can further facilitated binders obtained from the library retain the epitope- speci drug transport across the blood brain barrier. See U . S . patent ficity of the reference antibody . Additional maturational application 20040161738 published Aug . 19 , 2004 . These changes can be introduced in the CDR3 regions of each features combined with the low antigenicity to humans chain during the library construction in order to identify indicate great therapeutic potential. Further , these molecules antibodies with optimal binding kinetics . The resulting engi can be expressed in prokaryotic cells such as E . coli and are neered human antibodies have V - segment sequences derived expressed as fusion proteins with bacteriophage and are from the human germ - line libraries, retain the short BSD functional. US 2017 /0306038 A1 Oct. 26 , 2017 32

[ 0186 ] Accordingly , a feature of the present invention is a body molecule ) is covalently linked , e . g ., fused , to another camelid antibody or nanobody having high affinity for partner e . g . , a protein e . g . , one , two or more cytokines, e . g . , GITR . In certain embodiments herein , the camelid antibody as a fusion molecule for example a fusion protein . In other or nanobody is naturally produced in the camelid animal, embodiments , the fusion molecule comprises one or more i. e . , is produced by the camelid following immunization proteins, e . g ., one , two or more cytokines. In some embodi with GITR or a peptide fragment thereof, using techniques ments the antibody of the invention is derivatized or func described herein for other antibodies. Alternatively , the tionally linked ( e . g . , by chemical coupling , genetic fusion , GITR - binding camelid nanobody is engineered , i . e ., pro noncovalent association or otherwise ) to more than one duced by selection for example from a library of phage other functional molecule to generate multivalent molecules displaying appropriately mutagenized camelid nanobody that bind to two ormore different binding sites which are the proteins using panning procedures with GITR as a target as same or different binding sites on the same target molecule . described in the examples herein . Engineered nanobodies In certain embodiments , the multivalent binding sites are the can further be customized by genetic engineering to have a same. In some embodiments the antibody of the invention is half life in a recipient subject of from 45 minutes to two derivatized or linked to more than one other functional weeks. In a specific embodiment, the camelid antibody or molecule to generate multi -specific molecules that bind two nanobody is obtained by grafting the CDRs sequences of the or more different binding sites on at least two target mol heavy or light chain of the human antibodies of the invention ecules ; such multispecific molecules are also intended to be into nanobody or single domain antibody framework encompassed by the term “ bispecific molecule ” or “ multi sequences , as described for example in PCT/ EP93/ 02214 . In specific ” as used herein . To create a bispecific molecule of some embodiments , the present invention provides multi the invention , an antibody of the invention can be function valent camelid antibody or nanobody, according the meth ally linked ( e . g ., by chemical coupling , genetic fusion , ods described below . noncovalent association or otherwise ) to one or more other [0187 ] Multivalent Antibodies binding molecules , such as another antibody , antibody frag [ 0188 ] In another aspect , provided are multivalent mol ment, peptide or binding mimetic , such that a multivalent ecules (monospecific , bispecific , or multispecific ) compris molecule results . The present invention includes bispecific ing a GITR -binding antibody, or a fragment thereof, of the molecules comprising at least one first binding specificity invention . In an embodiment an antibody molecule is a for GITR and a second binding specificity for a second target multispecific antibody molecule , e . g . , it comprises a plural epitope . For example, the second target epitope is another ity of immunoglobulin variable domains sequences, wherein epitope of GITR different from the first target epitope . a first immunoglobulin variable domain sequence of the Additionally , for the invention in which the molecule is plurality has binding specificity for a first epitope and a multi -specific , in some embodiments the molecule further second immunoglobulin variable domain sequence of the includes a third binding specificity, in addition to the first plurality has binding specificity for a second epitope . In an and second target epitope . In an embodiment a multispecific embodiment the first and second epitopes are on the same antibody molecule comprises a third , fourth or fifth immu antigen , e . g ., the same protein (or subunit of a multimeric noglobulin variable domain . In an embodiment, a multispe protein ) . In an embodiment the first and second epitopes cific antibody molecule is a bispecific antibody molecule , a overlap . In an embodiment the first and second epitopes do trispecific antibody molecule, or tetraspecific antibody mol not overlap . In an embodiment the first and second epitopes ecule . are on different antigens, e . g ., the different proteins ( or [0190 ] In one embodiment, the bispecific molecules of the different subunits of a multimeric protein ). invention comprise as a binding specificity at least one [0189 ] An antibody of the invention , or antigen -binding antibody, or an antibody fragment thereof, including , e . g . , an regions thereof, can be derivatized or linked to another Fab , Fab ' , F ( ab ') 2 , Fv , or a single chain Fv. The antibody functional molecule , e . g ., another peptide or protein ( e . g ., may also be a light chain or heavy chain dimer , or any another antibody or ligand for a receptor ) to generate a minimal fragment thereof such as a Fv or a single chain multivalent molecule that binds to at least two different construct as described in Ladner et al. U . S . Pat. No. 4 , 946 , binding sites (which may be the same or different target sites 778 . or molecules ) . As used herein , a " derivatized ” antibody [0191 ] Diabodies are bivalent, bispecific molecules in molecule is one that has been modified . Methods of deriva which VH and VL domains are expressed on a single tization include but are not limited to the addition of a polypeptide chain , connected by a linker that is too short to fluorescent moiety , a radionucleotide , a toxin , an enzyme or allow for pairing between the two domains on the same an affinity ligand such as biotin . Accordingly , the antibody chain . The VH and VL domains pair with complementary molecules of the invention are intended to include deriva domains of another chain , thereby creating two antigen tized and otherwise modified forms of the antibodies binding sites ( see e . g . , Holliger et al. , 1993 Proc . Natl. Acad . described herein , including immunoadhesion molecules . For Sci. USA 90 :6444 -6448 ; Poljak et al ., 1994 Structure example , an antibody molecule can be functionally linked 2 : 1121- 1123 ) . Diabodies can be produced by expressing two (by chemical coupling, genetic fusion , noncovalent associa polypeptide chains with either the structure VHA -VLB and tion or otherwise ) to one or more other molecular entities , VHB - VLA (VH - VL configuration ) , or VLA - VHB and such as another antibody ( e . g ., a bispecific antibody or a VLB - VHA ( VL - VH configuration ) within the same cell . diabody ) , a detectable agent, a cytotoxic agent, a pharma Most of them can be expressed in soluble form in bacteria . ceutical agent, and / or a protein or peptide that can mediate Single chain diabodies ( scDb ) are produced by connecting association of the antibody or antibody portion with another the two diabody - forming polypeptide chains with linker of molecule ( such as a streptavidin core region or a polyhisti approximately 15 amino acid residues (see Holliger and dine tag ) . In other embodiments , an antibody of the inven Winter , 1997 Cancer Immunol. Immunother ., 45 ( 3 - 4 ) : 128 tion ( e . g ., a monospecific , bispecific , or multispecific anti 30 ; Wu et al ., 1996 Immunotechnology , 2 ( 1 ) :21 - 36 ) . scDb US 2017 /0306038 A1 Oct . 26 , 2017 33

can be expressed in bacteria in soluble , active monomeric [0197 ] Antibodies with Extended Half Life form ( see Holliger and Winter, 1997 Cancer Immunol. [0198 ] The present invention provides for antibodies and Immunother. , 45 (34 ) : 128 - 30 ; Wu et al. , 1996 Immunotech antibody fragments that specifically bind to GITR protein nology , 2 ( 1 ): 21 - 36 ; Pluckthun and Pack , 1997 Immunotech which have an extended half - life in vivo . nology , 3 ( 2 ) : 83 - 105 ; Ridgway et al ., 1996 Protein Eng. , [0199 ] Many factors may affect a protein 's half life in 9 (7 ): 617 -21 ). A diabody can be fused to Fc to generate a vivo . For examples, kidney filtration , metabolism in the " di- diabody ” (see Lu et al ., 2004 J . Biol. Chem ., 279 (4 ): liver , degradation by proteolytic enzymes ( proteases ), and 2856 -65 ). immunogenic responses ( e . g . , protein neutralization by anti [0192 ] Other antibodies which can be employed in the bodies and uptake by macrophages and dentritic cells ). A bispecific molecules of the invention are murine , chimeric variety of strategies can be used to extend the half life of the and humanized monoclonal antibodies. antibodies of the present invention . For example , by chemi [0193 ] The bispecific and /or multivalentmolecules of the cal linkage to polyethyleneglycol (PEG ), reCODE PEG , present invention can be prepared by conjugating the con antibody scaffold , polysialic acid (PSA ) , hydroxyethyl stituent binding specificities, using methods known in the starch (HES ) , albumin -binding ligands, and carbohydrate art . For example , each binding specificity of the bispecific shields ; by genetic fusion to proteins binding to serum and / or multivalentmolecule can be generated separately and proteins, such as albumin , IgG , FcRn , and transferring; by then conjugated to one another . When the binding specifici coupling ( genetically or chemically ) to other binding moi ties are proteins or peptides, a variety of coupling or eties that bind to serum proteins, such as nanobodies , Fabs , cross -linking agents can be used for covalent conjugation . DARPins , avimers , aflibodies , and anticalins; by genetic Examples of cross- linking agents include protein A , carbo fusion to rPEG , albumin , domain of albumin , albumin diimide , N - succinimidyl- S - acetyl- thioacetate (SATA ) , 5 , 5 binding proteins, and Fc ; or by incorporation into nancarri dithiobis ( 2 - nitrobenzoic acid ) (DTNB ), o - phenylenedima ers , slow release formulations , or medical devices. leimide (OPDM ) , N - succinimidyl- 3 -( 2 -pyridyldithio ) [0200 ] To prolong the serum circulation of antibodies in propionate (SPDP ) , and sulfosuccinimidyl 4 - ( N vivo , inert polymer molecules such as high molecular maleimidomethyl) cyclohaxane - 1- carboxylate (sulfo weight PEG can be attached to the antibodies or a fragment SMCC ) ( see e .g ., Karpovsky et al. , 1984 J. Exp . Med . thereof with or without a multifunctional linker either 160 : 1686 ; Liu , MA et al. , 1985 Proc . Natl . Acad . Sci. USA through site - specific conjugation of the PEG to the N - or 82 : 8648 ) . Other methods include those described in Paulus, C - terminus of the antibodies or via epsilon - amino groups 1985 Behring Ins . Mitt . No. 78 , 118 - 132 ; Brennan et al. , present on lysine residues . To pegylate an antibody, the 1985 Science 229 :81 - 83 ) , and Glennie et al . , 1987 J . Immu antibody, or fragment thereof, typically is reacted with nol. 139 : 2367 - 2375 ) . Conjugating agents are SATA and polyethylene glycol ( PEG ) , such as a reactive ester or sulfo -SMCC , both available from Pierce Chemical Co . aldehyde derivative of PEG , under conditions in which one or more PEG groups become attached to the antibody or (Rockford , Ill. ). antibody fragment. The pegylation can be carried out by an [0194 ] When binding specificities are antibodies , they can acylation reaction or an alkylation reaction with a reactive be conjugated by sulfhydryl bonding of the constant domain PEG molecule ( or an analogous reactive water - soluble poly hinge regions of the two heavy chains. In a particular mer) . As used herein , the term “ polyethylene glycol ” is embodiment, the hinge region is modified to contain an odd intended to encompass any of the forms of PEG that have number of sulfhydryl residues, for example one, prior to been used to derivatize other proteins , such as mono (C1 conjugation . C10 ) alkoxy - or aryloxy - polyethylene glycol or polyethyl [0195 ] Alternatively , binding specificities can be encoded ene glycol -maleimide . In certain embodiments , the antibody in the same vector and expressed and assembled in the same to be pegylated is an aglycosylated antibody. Linear or host cell . This method is particularly useful where the branched polymer derivatization that results in minimal loss bispecific and / or multivalent molecule is a mAbxmAb , of biological activity will be used . The degree of conjugation mAbxFab , FabxF (ab ' ) 2 or ligand x Fab fusion protein . A can be closely monitored by SDS - PAGE and mass spec bispecific and / or multivalent molecule of the invention can trometry to ensure proper conjugation of PEG molecules to be a single chain molecule comprising one single chain the antibodies . Unreacted PEG can be separated from anti antibody and a binding determinant , or a single chain body -PEG conjugates by size - exclusion or by ion - exchange bispecific molecule comprising two binding determinants . chromatography . PEG - derivatized antibodies can be tested Bispecific molecules may comprise at least two single chain for binding activity as well as for in vivo efficacy using molecules . Methods for preparing bispecific molecules are methods well - known to those of skill in the art , for example , described for example in U . S . Pat. No. 5 , 260 , 203; U . S . Pat . by immunoassays described herein . Methods for pegylating No . 5 , 455 , 030 ; U . S . Pat. No . 4 , 881 , 175 ; U . S . Pat. No . proteins are known in the art and can be applied to the 5 , 132 , 405 ; U . S . Pat . No . 5 , 091, 513 ; U . S . Pat . No . 5 , 476 , 786 ; antibodies of the invention . See for example , EP 0 154 316 U . S . Pat. No. 5 ,013 ,653 ; U . S . Pat. No. 5 ,258 ,498 ; and U . S . by Nishimura et al. and EP 0401 384 by Ishikawa et al. Pat . No . 5 ,482 ,858 . [0201 ) Other modified pegylation technologies include [01961 Binding of bispecific and / or multivalentmolecules reconstituting chemically orthogonal directed engineering to their specific targets can be confirmed by , for example , technology (ReCODE PEG ) , which incorporates chemically enzyme- linked immunosorbent assay ( ELISA ), radioimmu specified side chains into biosynthetic proteins via a recon noassay (REA ), FACS analysis , bioassay (e . g ., growth inhi stituted system that includes tRNA synthetase and tRNA . bition ) , or Western Blot assay. Each of these assays gener This technology enables incorporation ofmore than 30 new ally detects the presence of protein -antibody complexes of amino acids into biosynthetic proteins in E . coli , yeast , and particular interest by employing a labeled reagent ( e . g ., an mammalian cells . The tRNA incorporates a nonnative amino antibody ) specific for the complex of interest . acid any place an amber codon is positioned , converting the US 2017 /0306038 A1 Oct. 26 , 2017 34 amber from a stop codon to one that signals incorporation of recombinantly fused or chemically conjugated ( including the chemically specified amino acid . both covalent and non - covalent conjugations) to a heterolo [ 0202 ] Recombinant pegylation technology (rPEG ) can gous protein or polypeptide (or fragment thereof, preferably also be used for serum halflife extension . This technology to a polypeptide of at least 10 , at least 20 , at least 30 , at least involves genetically fusing a 300 -600 amino acid unstruc 40 , at least 50 , at least 60 , at least 70 , at least 80 , at least 90 , tured protein tail to an existing pharmaceutical protein . or at least 100 amino acids ) to generate fusion proteins . In Because the apparent molecular weight of such an unstruc particular , the invention provides fusion proteins comprising tured protein chain is about 15 - fold larger than its actual an antigen -binding fragment of an antibody described herein molecular weight, the serum halflife of the protein is greatly ( e . g . , a Fab fragment, Fd fragment, Fv fragment, F ( ab ) 2 increased . In contrast to traditional PEGylation , which fragment, a VH domain , a VH CDR , a VL domain , or a VL requires chemical conjugation and repurification , the manu CDR ) and a heterologous protein , polypeptide , or peptide . facturing process is greatly simplified and the product is Methods for fusing or conjugating proteins, polypeptides , or homogeneous . peptides to an antibody or an antibody fragment are known [ 0203 ] Polysialytion is another technology, which uses the in the art . See , e . g . , U . S . Pat. Nos. 5 ,336 ,603 , 5 ,622 , 929 , natural polymer polysialic acid (PSA ) to prolong the active 5 ,359 ,046 , 5 ,349 ,053 , 5 ,447 ,851 , and 5 , 112, 946 ; European life and improve the stability of therapeutic peptides and Patent Nos . EP 307 , 434 and EP 367 , 166 ; International proteins. PSA is a polymer of sialic acid ( a sugar ) . When Publication Nos . WO 96 / 04388 and WO 91 /06570 ; Ashke used for protein and therapeutic peptide drug delivery, nazi et al. , 1991 , Proc . Natl. Acad . Sci. USA 88 : 10535 polysialic acid provides a protective microenvironment on 10539; Zheng et al ., 1995 , J . Immunol. 154 :5590 -5600 ; and conjugation . This increases the active life of the therapeutic Vil et al ., 1992 , Proc. Natl . Acad. Sci . USA 89: 11337 - 11341 . protein in the circulation and prevents it from being recog [0210 ] Additional fusion proteins may be generated nized by the immune system . The PSA polymer is naturally through the techniques of gene - shuffling, motif- shuffling , found in the human body . It was adopted by certain bacteria exon - shuffling , and / or codon - shuffling ( collectively referred which evolved over millions of years to coat their walls with to as “ DNA shuffling " ) . DNA shuffling may be employed to it. These naturally polysialylated bacteria were then able, by alter the activities of antibodies of the invention or frag virtue of molecular mimicry , to foil the body ' s defence ments thereof ( e . g . , antibodies or fragments thereof with system . PSA , nature ' s ultimate stealth technology , can be higher affinities and lower dissociation rates ) . See , generally, easily produced from such bacteria in large quantities and U . S . Pat . Nos. 5 ,605 ,793 , 5 ,811 , 238 , 5 ,830 ,721 , 5 , 834 , 252 , with predetermined physical characteristics . Bacterial PSA and 5 , 837 , 458 ; Patten et al. , 1997 , Curr . Opinion Biotechnol. is completely non - immunogenic , even when coupled to 8 : 724 - 33 ; Harayama , 1998 , Trends Biotechnol . 16 ( 2 ) : 76 - 82 ; proteins , as it is chemically identical to PSA in the human Hansson , et al. , 1999 , J .Mol . Biol. 287 : 265 - 76 ; and Lorenzo body . and Blasco , 1998 , Biotechniques 24 ( 2 ) : 308 -313 (each of [ 0204 ] Another technology include the use of hydroxy these patents and publications are hereby incorporated by ethyl starch (“ HES ” ) derivatives linked to antibodies. HES reference in its entirety ) . Antibodies or fragments thereof, or is a modified natural polymer derived from waxy maize the encoded antibodies or fragments thereof, may be altered starch and can be metabolized by the body ' s enzymes. HES by being subjected to random mutagenesis by error- prone solutions are usually administered to substitute deficient PCR , random nucleotide insertion or other methods prior to blood volume and to improve the rheological properties of recombination . A polynucleotide encoding an antibody or the blood . Hesylation of an antibody enables the prolonga fragment thereof that specifically binds to a GITR protein tion of the circulation halflife by increasing the stability of may be recombined with one or more components , motifs , the molecule , as well as by reducing renal clearance , result sections, parts , domains , fragments, etc . of one or more ing in an increased biological activity . By varying different heterologous molecules . parameters, such as the molecular weight of HES , a wide [0211 ] Moreover , the antibodies or fragments thereof can range of HES antibody conjugates can be customized . be fused to marker sequences , such as a peptide to facilitate [0205 ] Antibodies having an increased half - life in vivo purification . In preferred embodiments , the marker amino can also be generated introducing one or more amino acid acid sequence is a hexa -histidine (HHHHHH SEQ ID modifications ( i. e ., substitutions , insertions or deletions) into NO : 11 ) peptide, such as the tag provided in a pQE vector an IgG constant domain , or FcRn binding fragment thereof ( QIAGEN , Inc . , 9259 Eton Avenue , Chatsworth , Calif ., (preferably a Fc or hinge Fc domain fragment) . See, e. g ., 91311 ) , among others , many of which are commercially International Publication No. WO 98 /23289 ; International available . As described in Gentz et al ., 1989, Proc. Natl . Publication No . WO 97 /34631 ; and U . S . Pat. No. 6 ,277 ,375 . Acad . Sci. USA 86 :821 - 824 , for instance, hexa -histidine 02061 Further , antibodies can be conjugated to albumin in (SEQ ID NO : 11 ) provides for convenient purification of the order to make the antibody or antibody fragment more stable fusion protein . Other peptide tags useful for purification in vivo or have a longer half life in vivo . The techniques are include, but are not limited to , the hemagglutinin (“ HA ” ) well -known in the art, see , e . g . , International Publication tag , which corresponds to an epitope derived from the Nos. WO 93 / 15199 , WO 93 / 15200 , and WO 01 /77137 ; and influenza hemagglutinin protein (Wilson et al. , 1984 , Cell European Patent No. EP 413 ,622 . 37: 767) , and the “ flag” tag. [0207 ] The strategies for increasing half life is especially [ 0212 ] An antibody molecules may be conjugated to useful in nanobodies, fibronectin - based binders , and other another molecular entity , typically a diagnostic, detectable , antibodies or proteins for which increased in vivo half life is or a therapeutic ( e . g . , a cytotoxic or cytostatic ) agent or desired . moiety . Radioactive isotopes can be used in diagnostic or [ 0208 ] Antibody Conjugates therapeutic applications . In other embodiments, antibodies [ 0209 ] The present invention provides antibodies or frag - of the present invention or fragments thereof conjugated to ments thereof that specifically bind to a GITR protein a diagnostic or detectable agent. Such antibodies can be US 2017 /0306038 A1 Oct. 26 , 2017 35 useful for monitoring or prognosing the onset , development, 26 ( 8 ): 943 -50 , each incorporated by reference in their entire progression and /or severity of a disease or disorder as part ties . Examples of other therapeutic agents include taxol, of a clinical testing procedure , such as determining the cytochalasin B , gramicidin D , ethidium bromide, emetine , efficacy of a particular therapy . Such diagnosis and detection mitomycin , etoposide , tenoposide, vincristine , vinblastine , can accomplished by coupling the antibody to detectable colchicine , doxorubicin , daunorubicin , dihydroxy anthracin substances including, but not limited to , various enzymes , dione , mitoxantrone , mithramycin , actinomycin D , 1 - dehy such as , but not limited to , horseradish peroxidase , alkaline drotestosterone , glucocorticoids, procaine, tetracaine, lido phosphatase , beta - galactosidase, or acetylcholinesterase ; caine , propranolol, puromycin , maytansinoids, e . g . , may prosthetic groups, such as, but not limited to , streptavidin tansinol ( see U . S . Pat . No. 5 , 208 , 020 ), CC - 1065 ( see U . S . lbiotin and avidin /biotin ; fluorescent materials , such as , but Pat. Nos . 5 , 475 ,092 , 5 ,585 , 499 , 5 , 846 , 545 ) and analogs or not limited to , umbelliferone , fluorescein , fluorescein isoth homologs thereof. Therapeutic agents include , but are not iocynate , rhodamine , dichlorotriazinylamine fluorescein , limited to , antimetabolites ( e .g . , methotrexate , 6 -mercap dansyl chloride or phycoerythrin ; luminescent materials , topurine, 6 - thioguanine, cytarabine , 5 - fluorouracil decarba such as, but not limited to , luminol; bioluminescent mate zine ), alkylating agents ( e . g ., mechlorethamine , thioepa rials , such as but not limited to , luciferase , luciferin , and chlorambucil , CC - 1065 , melphalan , carmustine (BSNU ) aequorin ; radioactive materials , such as, but not limited to , and lomustine ( CCNU ) , cyclothosphamide , busulfan , dibro iodine ( 1311 , 1251, 1231, and 1211 ,) , carbon ( 14C ), sulfur momannitol , streptozotocin , mitomycin C , and cis -dichlo ( 35S ) , tritium (3H ) , indium (1151n , 1131n , 1121n , and rodiamine platinum ( II ) (DDP ) cisplatin ) , anthracyclinies 1111n , ) , technetium ( 99Tc ) , thallium ( 201Ti) , gallium ( e . g ., daunorubicin ( formerly daunomycin ) and doxorubi (68Ga , 67Ga) , palladium ( 103Pd ) , molybdenum (99Mo ) , cin ) , antibiotics ( e . g ., dactinomycin ( formerly actinomycin ) , xenon (133Xe ) , fluorine ( 18F ), 153Sm , 177Lu , 159Gd , bleomycin , mithramycin , and anthramycin (AMC ) ) , and 149Pm , 140La , 175Yb , 166Ho , 90Y, 47Sc , 186Re, 188Re, anti- mitotic agents ( e . g . , vincristine , vinblastine , taxol and 142Pr, 105Rh , 97Ru , 68Ge, 57Co , 65Zn , 85Sr, 32P , 153Gd, maytansinoids) . 169Yb , 51Cr, 54Mn, 75Se, 113Sn , and 117Tin ; and positron [0215 ] Techniques for conjugating therapeutic moieties to emitting metals using various positron emission tomogra antibodies are well known, see , e . g. , Amon et al. , “Mono phies , and noradioactive paramagnetic metal ions . Radioac clonal Antibodies For Immunotargeting Of Drugs In Cancer tive isotopes can be used in diagnostic or therapeutic appli Therapy ” , in Monoclonal Antibodies And Cancer Therapy , cations . Reisfeld et al . ( eds . ) , pp . 243 - 56 ( Alan R . Liss, Inc . 1985 ) ; [ 0213] The present invention further encompasses an anti Hellstrom et al. , “ Antibodies For Drug Delivery ” , in Con body or fragment thereof conjugated to a therapeutic moiety trolled Drug Delivery ( 2nd Ed .) , Robinson et al. (eds . ), pp . or drug moiety that modifies a given biological effect or 623 - 53 (Marcel Dekker , Inc . 1987) ; Thorpe , “ Antibody response and uses of antibodies or fragments thereof con Carriers Of Cytotoxic Agents In Cancer Therapy : A jugated to a therapeutic moiety . Therapeutic moieties or drug Review ” , in Monoclonal Antibodies 84 : Biological And moieties are not to be construed as limited to classical Clinical Applications, Pinchera et al. ( eds. ), pp . 475 -506 chemical therapeutic agents . For example , the drug moiety ( 1985 ) ; " Analysis , Results , And Future Prospective Of The may be a protein , peptide , or polypeptide possessing a Therapeutic Use Of Radiolabeled Antibody In Cancer desired biological activity . Such proteins may include , for Therapy ” , in Monoclonal Antibodies For Cancer Detection example , a toxin such as abrin , ricin A , pseudomonas And Therapy , Baldwin et al. ( eds . ) , pp . 303 - 16 ( Academic exotoxin , cholera toxin , or diphtheria toxin ; a protein such as Press 1985 ) , and Thorpe et al. , 1982 , Immunol . Rev. 62 : 119 tumor necrosis factor , a - interferon , B - interferon , nerve 58 . growth factor, platelet derived growth factor, tissue plasmi 10216 ) Antibodies may also be attached to solid supports , nogen activator, an apoptotic agent, an anti - angiogenic which are particularly useful for immunoassays or purifica agent ; or, a biological response modifier such as, for tion of the target antigen . Such solid supports include , but example, a lymphokine . An antibody or fragment thereof are not limited to , glass , cellulose , polyacrylamide, nylon , may be conjugated to a therapeutic moiety such as a cyto polystyrene , polyvinyl chloride or polypropylene . toxin , e . g ., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion , e . g . , alpha - emitters . A Polynucleotides Encoding Agonist Anti- GITR Antibodies cytotoxin or cytotoxic agent includes any agent that is [0217 ] Anti -GITR antibodies , antigen binding molecules , detrimental to cells . and fragments thereof, can be produced by any means [0214 ] For example , an antibody can be conjugated to known in the art, including but not limited to , recombinant therapeutic moieties such as a radioactive metal ion , such as expression , chemical synthesis, and enzymatic digestion of alph -emiters such as 213Bi or macrocyclic chelators useful antibody tetramers , whereas full -length monoclonal anti for conjugating radiometal ions, including but not limited to , bodies can be obtained by, e . g ., hybridoma or recombinant 131In , 131LU , 131Y , 131Ho, 131Sm , to polypeptides . In production . Recombinant expression can be from any appro certain embodiments , the macrocyclic chelator is 1, 4 ,7 ,10 priate host cells known in the art , for example , mammalian tetraazacyclododecane- N , N ', N " ,N " " - tetraacetic acid host cells, bacterial host cells , yeast host cells , insect host (DOTA ) which can be attached to the antibody via a linker cells , etc . molecule . Such linker molecules include for example , gly [0218 ] The invention further provides polynucleotides cine linkers e . g . , GGGGS ( SEQ ID NO : 15 ) , which may encoding the antibodies described herein , e . g ., polynucle optionally be repeated , e . g ., GGGGSGGGGSGGGGS ( SEQ otides encoding heavy or light chain variable regions or ID NO : 18 ), or other linkers are commonly known in the art segments comprising the complementary determining and described in Denardo et al. , 1998 , Clin Cancer Res. regions as described herein . In some embodiments , the 4 ( 10 ) : 2483 - 90 ; Peterson et al. , 1999 , Bioconjug . Chem . polynucleotide encoding the heavy chain variable regions 10 ( 4 ): 553 -7 ; and Zimmerman et al. , 1999 , Nucl. Med . Biol. comprises a sequence having at least 85 % , 89 % , 90 % , 91 % , US 2017 /0306038 A1 Oct. 26 , 2017 36

92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % acid sequence identity with a polynucleotide of SEQ ID nucleic acid sequence identity with a polynucleotide NO : 108 . In some embodiments , the polynucleotide encod selected from the group consisting of SEQ ID NO :51 , SEQ ing the light chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , ID NO :53 , SEQ ID NO : 55 , SEQ ID NO : 56 , SEQ ID NO :57 , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic SEQ ID NO : 101 , and SEQ ID NO : 107 . In some embodi acid sequence identity with a polynucleotide of SEQ ID ments , the polynucleotide encoding the light chain variable NO : 104 . regions comprises a sequence having at least 85 % , 89 % , [0226 ] In some embodiments , the polynucleotide encod 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % 92 % , 100 % nucleic acid sequence identity with a polynucleotide 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic selected from the group consisting of SEQ ID NO : 52 , SEQ acid sequence identity with a polynucleotide of SEQ ID ID NO : 54 , and SEQ ID NO : 102 . NO :60 . In some embodiments , the polynucleotide encoding [0219 ] In some embodiments , the polynucleotide encod the light chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , 93 % , ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % 92 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic sequence identity with a polynucleotide of SEQ ID NO :58 . acid sequence identity with a polynucleotide of SEQ ID [0227 ] The polynucleotides of the invention can encode NO :67 . In some embodiments , the polynucleotide encoding only the variable region sequence of an anti -GITR antibody . the light chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , 93 % , They can also encode both a variable region and a constant 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid region of the antibody. Some of the polynucleotide sequence identity with a polynucleotide of SEQ ID NO :68 . sequences encode a polypeptide that comprises variable [0220 ] In some embodiments , the polynucleotide encod regions ofboth the heavy chain and the light chain of one of ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , the exemplified mouse anti- GITR antibody. Some other 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic polynucleotides encode two polypeptide segments that acid sequence identity with a polynucleotide of SEQ ID respectively are substantially identical to the variable NO : 72 . In some embodiments, the polynucleotide encoding regions of the heavy chain and the light chain of one of the the light chain has at least 85 % , 89 % , 90 % , 91 % 92 % 93 % , mouse antibodies. 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid [0228 ] The polynucleotide sequences can be produced by sequence identity with a polynucleotide selected of SEQ ID de novo solid - phase DNA synthesis or by PCR mutagenesis NO : 73 . of an existing sequence ( e . g . , sequences as described herein ) [ 0221 ] In some embodiments , the polynucleotide encod encoding an anti -GITR antibody or its binding fragment . ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , Direct chemical synthesis of nucleic acids can be accom 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic plished by methods known in the art, such as the phospho acid sequence identity with a polynucleotide of SEQ ID triester method of Narang et al. , Meth . Enzymol. 68 : 90 , NO : 74 . In some embodiments , the polynucleotide encoding 1979 ; the phosphodiester method of Brown et al. , Meth . the light chain has at least 85 % , 89 % , 90 % , 91 % 92 % , 93 % , Enzymol. 68 : 109 , 1979 ; the diethylphosphoramidite method 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid of Beaucage et al. , Tetra . Lett ., 22 : 1859 , 1981 ; and the solid sequence identity with a polynucleotide of SEQ ID NO :68 . support method of U .S . Pat . No . 4 ,458 ,066 . Introducing 0222 ] In some embodiments , the polynucleotide encod mutations to a polynucleotide sequence by PCR can be ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % 92 % , performed as described in , e . g . , PCR Technology : Principles 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic and Applications for DNA Amplification , H . A . Erlich (Ed . ) , acid sequence identity with a polynucleotide of SEQ ID Freeman Press , NY, N . Y . , 1992 ; PCR Protocols : A Guide to NO :76 . In some embodiments , the polynucleotide encoding Methods and Applications , Innis et al . ( Ed . ) , Academic the light chain has at least 85 % , 89 % , 90 % , 91 % 92 % , 93 % , Press , San Diego , Calif. , 1990 ; Mattila et al . , Nucleic Acids 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid Res . 19 : 967, 1991; and Eckert et al. , PCR Methods and sequence identity with a polynucleotide of SEQ ID NO :68 . Applications 1 : 17 , 1991. [0223 ] In some embodiments , the polynucleotide encod [0229 ] Also provided in the invention are expression vec ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , tors and host cells for producing the anti- GITR antibodies 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic described above . Various expression vectors can be acid sequence identity with a polynucleotide of SEQ ID employed to express polynucleotides encoding the anti NO :78 . In some embodiments, the polynucleotide encoding GITR antibody chains, fragments , or binding fragments . the light chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , 93 % , Both viral- based and nonviral expression vectors can be 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic acid used to produce the antibodies in a mammalian host cell. sequence identity with a polynucleotide of SEQ ID NO :68 . Nonviral vectors and systems include plasmids, episomal [0224 ] In some embodiments , the polynucleotide encod vectors , typically with an expression cassette for expressing ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % 92 % , a protein or RNA , and human artificial chromosomes (see , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic e. g ., Harrington et al. , Nat Genet 15 :345 , 1997) . For acid sequence identity with a polynucleotide selected from example , nonviral vectors useful for expression of the anti the group consisting of SEQ ID NO : 103 . In some embodi GITR polynucleotides and polypeptides in mammalian ( e . g . , ments , the polynucleotide encoding the light chain has at human ) cells include pThioHis A , B & C , pcDNA3. 1 /His , least 85 % , 89 % , 90 % , 91 % 92 % 93 % , 94 % , 95 % , 96 % , pEBVHis A , B & C ( Invitrogen , San Diego , Calif. ), MPSV 97 % , 98 % , 99 % , or 100 % nucleic acid sequence identity vectors , and numerous other vectors known in the art for with a polynucleotide of SEQ ID NO : 104 . expressing other proteins . Useful viral vectors include vec [0225 ] In some embodiments , the polynucleotide encod tors based on retroviruses , adenoviruses, adenoassociated ing the heavy chain has at least 85 % , 89 % , 90 % , 91 % , 92 % , viruses , herpes viruses , vectors based on SV40 , papilloma 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 100 % nucleic virus, HBP Epstein Barr virus, vaccinia virus vectors and US 2017 /0306038 A1 Oct. 26 , 2017 37

Semliki Forest virus (SFV ) . See , Brent et al. , supra ; Smith , noglobulin genes ( e . g . , the myeloma hybridoma clones as Annu . Rev . Microbiol. 49: 807, 1995 ; and Rosenfeld et al. , described in the Examples ) or a mammalian cell line har Cell 68 : 143 , 1992 . boring an exogenous expression vector ( e . g . , the SP2/ 0 [ 0230 ] The choice of expression vector depends on the myeloma cells exemplified below ) . These include any nor intended host cells in which the vector is to be expressed . mal mortal or normal or abnormal immortal animal or Typically , the expression vectors contain a promoter and human cell . For example , a number of suitable host cell lines other regulatory sequences ( e . g . , enhancers ) that are oper capable of secreting intact immunoglobulins have been ably linked to the polynucleotides encoding an anti -GITR developed , including the CHO cell lines , various Cos cell antibody chain or fragment. In some embodiments , an lines, HeLa cells , myeloma cell lines, transformed B -cells inducible promoter is employed to prevent expression of and hybridomas . The use ofmammalian tissue cell culture to inserted sequences except under inducing conditions . Induc express polypeptides is discussed generally in , e . g . , Win ible promoters include , e . g ., arabinose , lacZ , metallothion nacker , From Genes to Clones , VCH Publishers, N . Y ., N . Y . , ein promoter or a heat shock promoter. Cultures of trans 1987. Expression vectors for mammalian host cells can formed organisms can be expanded under noninducing include expression control sequences, such as an origin of conditions without biasing the population for coding replication , a promoter, and an enhancer ( see , e . g ., Queen et sequences whose expression products are better tolerated by al. , Immunol. Rev. 89 : 49 -68 , 1986 ) , and necessary process the host cells . In addition to promoters , other regulatory ing information sites, such as ribosome binding sites , RNA elements may also be required or desired for efficient splice sites , polyadenylation sites , and transcriptional termi expression of an anti -GITR antibody chain or fragment. nator sequences . These expression vectors usually contain These elements typically include an ATG initiation codon promoters derived from mammalian genes or from mam and adjacent ribosome binding site or other sequences . In malian viruses . Suitable promoters may be constitutive , cell addition , the efficiency of expression may be enhanced by type - specific , stage - specific , and / or modulatable or regulat the inclusion of enhancers appropriate to the cell system in able . Useful promoters include , but are not limited to , the use ( see , e . g. , Scharf et al ., Results Probl. Cell Differ. metallothionein promoter, the constitutive adenovirus major 20 : 125 , 1994 ; and Bittner et al. , Meth . Enzymol. , 153: 516 , late promoter, the dexamethasone - inducible MMTV pro 1987 ) . For example , the SV40 enhancer or CMV enhancer moter, the SV40 promoter , the MRP polIII promoter, the may be used to increase expression in mammalian host cells . constitutive MPSV promoter, the tetracycline - inducible [ 0231] Expression vectors may also provide a secretion CMV promoter (such as the human immediate -early CMV signal sequence position to form a fusion protein with promoter ), the constitutive CMV promoter, and promoter polypeptides encoded by inserted anti -GITR antibody enhancer combinations known in the art . sequences . More often , the inserted anti -GITR antibody [0234 ] Methods for introducing expression vectors con sequences are linked to a signal sequences before inclusion taining the polynucleotide sequences of interest vary in the vector. Vectors to be used to receive sequences depending on the type of cellular host. For example, calcium encoding anti- GITR antibody light and heavy chain variable chloride transfection is commonly utilized for prokaryotic domains sometimes also encode constant regions or parts cells , whereas calcium phosphate treatment or electropora thereof. Such vectors allow expression of the variable tion may be used for other cellular hosts ( see generally regions as fusion proteins with the constant regions thereby Sambrook et al ., supra ). Other methods include, e .g ., elec leading to production of intact antibodies or fragments troporation , calcium phosphate treatment, liposome- medi thereof. Typically , such constant regions are human . ated transformation , injection and microinjection , ballistic [ 0232 ] Host cells for harboring and expressing the anti methods , virosomes, immunoliposomes , polycation :nucleic GITR antibody chains can be either prokaryotic or eukary acid conjugates, naked DNA , artificial virions, fusion to the otic . E . coli is one prokaryotic host useful for cloning and herpes virus structural protein VP22 (Elliot and O ' Hare , Cell expressing the polynucleotides of the present invention . 88 : 223 , 1997 ) , agent- enhanced uptake of DNA , and ex vivo Other microbialhosts suitable for use include bacilli , such as transduction . For long -term , high - yield production of Bacillus subtilis, and other enterobacteriaceae , such as Sal recombinant proteins , stable expression will often be monella , Serratia , and various Pseudomonas species. In desired . For example , cell lines which stably express anti these prokaryotic hosts , one can also make expression GITR antibody chains or binding fragments can be prepared vectors , which typically contain expression control using expression vectors of the invention which contain viral sequences compatible with the host cell ( e . g ., an origin of origins of replication or endogenous expression elements replication ) . In addition , any number of a variety of well and a selectable marker gene . Following introduction of the known promoters will be present, such as the lactose pro vector , cells may be allowed to grow for 1 - 2 days in an moter system , a tryptophan (trp ) promoter system , a beta enriched media before they are switched to selective media . lactamase promoter system , or a promoter system from The purpose of the selectable marker is to confer resistance phage lambda . The promoters typically control expression , to selection , and its presence allows growth of cells which optionally with an operator sequence , and have ribosome successfully express the introduced sequences in selective binding site sequences and the like, for initiating and com media . Resistant, stably transfected cells can be proliferated pleting transcription and translation . Other microbes, such as using tissue culture techniques appropriate to the cell type . yeast, can also be employed to express anti -GITR polypep tides of the invention . Insect cells in combination with Assays for Identifying Agonist Anti -GITR Antibodies baculovirus vectors can also be used . 10233 ] In some preferred embodiments , mammalian host [0235 ] Assays for identifying agonist anti -GITR antibod cells are used to express and produce the anti- GITR poly ies are known in the art and described herein . Agonist peptides of the present invention . For example , they can be anti -GITR antibodies bind to GITR and promote , induce , either a hybridoma cell line expressing endogenous immu stimulate intracellular signaling through GITR . US 2017 /0306038 A1 Oct. 26 , 2017 38

[0236 ] Binding of the anti -GITR antibodies to GITR can ceutically acceptable carrier. Optionally , pharmaceutical be determined using any method known in the art. For compositions can additionally contain other therapeutic example , binding to GITR can be determined using known agents that are suitable for treating or preventing a given techniques, including without limitation ELISA , Western disorder . Pharmaceutically acceptable carriers enhance or blots , surface plasmon resonance (e . g. , BIAcore ), and flow stabilize the composition , or to facilitate preparation of the cytometry . composition . Pharmaceutically acceptable carriers include [ 0237 ] Intracellular signaling through GITR can be mea solvents , dispersion media , coatings, antibacterial and anti sured using any method known in the art. For example , fungal agents , isotonic and absorption delaying agents , and activation through GITR promotes NFKB and MAPK sig the like that are physiologically compatible . The carrier can naling .Methods for measuring NFkB and MAPK activation be suitable for intravenous , intramuscular, subcutaneous , are standard in the art ( e . g . , use of reporter gene assays, parenteral, rectal, spinal or epidermal administration ( e . g . by nuclear translocation of NFKB proteins, phosphorylation injection or infusion ) . In another aspect , the present inven status of MAPK proteins) . Activation through GITR is a tion provides compositions , e . g . , pharmaceutically accept co - stimulatory signal that promotes proliferation of acti able compositions, which include an antibody molecule vated CD4 + and CD8 + T cells in the presence of activation described herein , formulated together with a pharmaceuti through the T - cell receptor ( e . g . , in the presence of primary cally acceptable carrier . The compositions of this invention or target antigen ). Methods for measuring proliferation of may be in a variety of forms. These include, for example , cells are standard in the art ( e . g . , ' H - thymidine incorpora liquid , semi- solid and solid dosage forms, such as liquid tion assays, CFSE labeling ) . Signaling through GITR also solutions ( e . g . , injectable and infusible solutions ), disper co -stimulates activated CD4 + and CD8 + T cells in the sions or suspensions , liposomes and suppositories . The presence of activation through the T - cell receptor to produce preferred form depends on the intended mode of adminis cytokines . Signaling through GITR also co - stimulates acti tration and therapeutic application . Typical preferred com vated NK cells to produce cytokines . The cytokines can be positions are in the form of injectable or infusible solutions. either or both Th1 - type cytokines ( e . g ., interferon - y, IL - 2 The preferred mode of administration is parenteral ( e . g . , and TNF ) and Th2 - type cytokines ( e . g ., IL - 4 , IL - 5 , IL - 10 intravenous , subcutaneous, intraperitoneal, intramuscular) . and IL - 13 ) . Methods formeasuring cytokine production are In a preferred embodiment, the antibody is administered by well known in the art ( e . g . , ELISA assays , ELISpot assays ) . intravenous infusion or injection . In another preferred Activation through GITR may also induce apoptosis . Meth embodiment, the antibody is administered by intramuscular ods for measuring apoptosis of cells are standard in the art or subcutaneous injection . ( e . g . , Annexin V staining) . In performing in vitro assays , test [0240 ] A pharmaceutical composition of the present cells or culture supernatant from test cells contacted with the invention can be administered by a variety of methods agonist anti -GITR antibodies can be compared to control known in the art . The phrases " parenteral administration ” cells or culture supernatants from control cells that have not and “ administered parenterally ” as used herein means modes been contacted with the agonist anti- GITR antibodies . of administration other than enteral and topical administra [0238 ] The GITR agonist functionalities of the present tion , usually by injection , and includes , without limitation , antibodies can also be measured in vivo . Preferred agonist intravenous , intramuscular , intraarterial, intrathecal, intraca anti- GITR antibodies have the ability to activate and expand psular, intraorbital, intracardiac , intradermal, intraperito CD4 + and CD8 + T - cells . The in vivo activation and expan neal, transtracheal, subcutaneous, subcuticular, intraarticu sion of CD4 + and CD8 + T -cells can be measured using any lar, subcapsular , subarachnoid , intraspinal , epidural and method known in the art , e . g . , by flow cytometry . Preferred intrasternal injection and infusion . Route and /or mode of agonist anti -GITR antibodies can be therapeutically useful administration vary depending upon the desired results . It is in inhibiting tumor growth or promoting tumor retraction . preferred that administration be intravenous , intramuscular, Tumor growth , or inhibition thereof, can be measured using intraperitoneal, or subcutaneous, or administered proximal any method known in the art ( e. g. , visual inspection , cali to the site of the target . A pharmaceutically acceptable pers , weight, imaging techniques , including MRI) . Preferred carrier should be suitable for intravenous, intramuscular, agonist anti -GITR antibodies can be therapeutically useful subcutaneous , parenteral, intranasal, inhalational, spinal or in preventing , reducing , inhibiting or eliminating the caus epidermal administration ( e . g . , by injection or infusion ) . ative factor of an infectious disease , e . g ., a bacterial, fungal, Depending on the route of administration , active compound , viral or parasitic infection . The efficacy of the agonist e .g ., antibody or antigen binding fragment or multivalent anti -GITR antibodies in augmenting a T - cell response or molecule of the invention ( e . g . , monospecific , bispecific or reducing the severity of a disease can be determined by multispecific molecule ) , may be coated in a material to administering a therapeutically effective amount of the anti protect the compound from the action of acids and other body to a subject and comparing the subject before and after natural conditions that may inactivate the compound . administration of the antibody. Efficacy of the agonist anti [0241 ] An antibody or fragment thereof, alone or in com GITR antibodies in augmenting a T - cell response or reduc bination with other suitable components , can be made into ing the severity of a disease also can be determined by aerosol formulations ( i. e ., they can be “ nebulized ” ) to be administering a therapeutically effective amount of the anti administered via inhalation . Aerosol formulations can be body to a test subject and comparing the test subject to a placed into pressurized acceptable propellants, such as control subject who has not been administered the antibody . dichlorodifluoromethane , propane , nitrogen , and the like . [0242 ] In some embodiments , the composition is sterile Compositions Comprising Agonist Anti -GITR Antibodies and fluid . Proper fluidity can be maintained , for example , by [0239 ] The invention provides pharmaceutical composi use of coating such as lecithin , by maintenance of required tions comprising the present anti -GITR antibodies or anti particle size in the case of dispersion and by use of surfac gen -binding molecules formulated together with a pharma tants . In many cases , it is preferable to include isotonic US 2017 /0306038 A1 Oct. 26 , 2017 39 agents , for example , sugars , polyalcohols such as mannitol with the particular compositions employed , the age , sex , or sorbitol, and sodium chloride in the composition . Long weight, condition , general health and prior medical history term absorption of the injectable compositions can be of the patient being treated , and like factors. brought about by including in the composition an agent [ 0245 ] The antibody molecules can be administered by a which delays absorption , for example , aluminum monoste variety of methods known in the art, although for many arate or gelatin . In certain embodiments compositions can be therapeutic applications , the preferred route/ mode of admin prepared for storage in a lyophilized form using appropriate istration is intravenous injection or infusion . For example , excipients ( e. g. , sucrose ) the antibody molecules can be administered by intravenous [0243 ] Pharmaceutical compositions of the invention can infusion at a rate of more than 20 mg /min , e . g ., 20 - 40 be prepared in accordance with methods well known and mg/ min , and typically greater than or equal to 40 mg/ min to routinely practiced in the art . Pharmaceutically acceptable reach a dose of about 35 to 440 mg/ m² , typically about 70 carriers are determined in part by the particular composition to 310 mg /m² , and more typically , about 110 to 130 mg/ m² . being administered , as well as by the particular method used In embodiments , the antibody molecules can be adminis to administer the composition . Accordingly , there is a wide tered by intravenous infusion at a rate of less than 10 variety of suitable formulations of pharmaceutical compo mg/ min ; preferably less than or equal to 5 mg/min to reach sitions of the present invention . Applicable methods for a dose of about 1 to 100 mg/ m ” , preferably about 5 to 50 formulating the antibodies and determining appropriate dos mg/ m² , about 7 to 25 mg/ m² and more preferably, about 10 ing and scheduling can be found , for example , in Reming mg/ m2 . As will be appreciated by the skilled artisan , the ton : The Science and Practice of Pharmacy, 21st Ed. , Uni route and /or mode of administration will vary depending versity of the Sciences in Philadelphia , Eds. , Lippincott upon the desired results . In certain embodiments , the active Williams & Wilkins ( 2005 ) ; and in Martindale : The Com compound may be prepared with a carrier that will protect plete Drug Reference, Sweetman , 2005 , London : Pharma the compound against rapid release , such as a controlled ceutical Press ., and in Martindale , Martindale : The Extra release formulation , including implants, transdermal Pharmacopoeia , 31st Edition . , 1996 , Amer Pharmaceutical patches, and microencapsulated delivery systems. Biode Assn , and Sustained and Controlled Release Drug Delivery gradable , biocompatible polymers can be used , such as Systems, J . R . Robinson , ed . , Marcel Dekker, Inc ., New ethylene vinyl acetate , polyanhydrides, polyglycolic acid , York , 1978 , each of which are hereby incorporated herein by collagen , polyorthoesters, and polylactic acid . Many meth reference . Pharmaceutical compositions are preferably ods for the preparation of such formulations are patented or manufactured under GMP conditions. Typically , a therapeu generally known to those skilled in the art . See , e . g . , tically effective dose or efficacious dose of the anti -GITR Sustained and Controlled Release Drug Delivery Systems, J . antibody is employed in the pharmaceutical compositions of R . Robinson , ed. , Marcel Dekker, Inc. , New York , 1978 . the invention . The anti -GITR antibodies are formulated into [0246 ] Dosage regimens are adjusted to provide the opti pharmaceutically acceptable dosage forms by conventional mum desired response ( e . g ., a therapeutic response ) . For methods known to those of skill in the art . Dosage regimens example , a single bolus may be administered , several are adjusted to provide the desired response ( e . g ., a thera divided doses may be administered over time or the dose peutic response ) . In determining a therapeutically or pro may be proportionally reduced or increased as indicated by phylactically effective dose , a low dose can be administered the exigencies of the therapeutic situation . It is especially and then incrementally increased until a desired response is advantageous to formulate parenteral compositions in dos achieved with minimal or no undesired side effects . For age unit form for ease of administration and uniformity of example , a single bolus may be administered , several dosage . Dosage unit form as used herein refers to physically divided doses may be administered over time or the dose discrete units suited as unitary dosages for the subjects to be may be proportionally reduced or increased as indicated by treated ; each unit contains a predetermined quantity of the exigencies of the therapeutic situation . It is especially active compound calculated to produce the desired thera advantageous to formulate parenteral compositions in dos peutic effect in association with the required pharmaceutical age unit form for ease of administration and uniformity of carrier . The specification for the dosage unit forms of the dosage . Dosage unit form as used herein refers to physically invention are dictated by and directly dependent on ( a ) the discrete units suited as unitary dosages for the subjects to be unique characteristics of the active compound and the par treated ; each unit contains a predetermined quantity of ticular therapeutic effect to be achieved , and ( b ) the limita active compound calculated to produce the desired thera tions inherent in the art of compounding such an active peutic effect in association with the required pharmaceutical compound for the treatment of sensitivity in individuals . carrier. [ 0247 ] An exemplary , non -limiting range for a therapeu [0244 ) Actual dosage levels of active ingredients in the tically or prophylactically effective amount of an antibody pharmaceutical compositions of the present invention can be molecule is 0 . 1 -30 mg/ kg , more preferably 1 - 25 mg/ kg . varied so as to obtain an amount of the active ingredient Dosages and therapeutic regimens of the anti -GITR anti which is effective to achieve the desired therapeutic body molecule can be determined by a skilled artisan . In response for a particular patient, composition , and mode of certain embodiments , the anti -GITR antibody molecule is administration , without being toxic to the patient. The administered by injection ( e .g ., subcutaneously or intrave selected dosage level depends upon a variety of pharma nously ) at a dose of about 1 to 40 mg /kg , e .g ., 1 to 30 mg/ kg , cokinetic factors including the activity of the particular e . g ., about 5 to 25 mg/ kg , about 10 to 20 mg/ kg , about 1 to compositions of the present invention employed , or the ester, 5 mg/ kg , 1 to 10 mg/ kg , 5 to 15 mg/ kg , 10 to 20 mg/ kg , 15 salt or amide thereof, the route of administration , the time of to 25 mg/ kg , or about 3 mg/ kg . The dosing schedule can administration , the rate of excretion of the particular com - vary from e . g . , once a week to once every 2 , 3 , or 4 weeks. pound being employed , the duration of the treatment, other In one embodiment, the anti -GITR antibody molecule is drugs , compounds and /or materials used in combination administered at a dose from about 10 to 20 mg/ kg every US 2017 /0306038 A1 Oct. 26 , 2017 40 other week . The antibody molecule can be administered by spp ., Moraxella spp , Bordetella spp , Mycobacterium spp , intravenous infusion at a rate of more than 20 mg/min , e . g ., Legionella spp , Escherichia spp , Vibrio spp , Yersinia spp , 20 -40 mg/min , and typically greater than or equal to 40 Campylobacter spp , Salmonella spp , Listeria spp ., Helico mg/min to reach a dose of about 35 to 440 mg/m² , typically bacter spp , Pseudomonas spp , Staphylococcus spp ., Entero about 70 to 310 mg/ m² , and more typically , about 110 to 130 coccus spp , Clostridium spp . , Bacillus spp , Corynebacte mg/ m² . In embodiments , the infusion rate of about 110 to rium spp . , Borrelia spp ., Ehrlichia spp , Rickettsia spp , 130 mg/ m ? achieves a level of about 3 mg/ kg . In other Chlamydia spp ., Leptospira spp ., Treponema spp . embodiments , the antibody molecule can be administered by [ 0252 ] In some embodiments , the anti- GITR antibodies or intravenous infusion at a rate of less than 10 mg/ min , e . g . , antigen binding molecules are co - formulated in a mixture less than or equal to 5 mg/min to reach a dose of about 1 to with a tumor -associated antigen ( TAA ) . The TAA can be an 100 mg/ m² , e . g. , about 5 to 50 mg/ m² , about 7 to 25 mg /m² , isolated polypeptide or peptide, can be part of an intact cell or, about 10 mg/m2 . In some embodiments , the antibody is or part of a tumor cell lysate . The TAAs can be a polynucle infused over a period of about 30 min . It is to be noted that otide , for example a naked plasmid or a viral vector com dosage values may vary with the type and severity of the prising a polynucleotide encoding one or more TAAS . condition to be alleviated . It is to be further understood that Examples of known TAAs include without limitation , mela for any particular subject, specific dosage regimens should noma associated antigens (MAGE - 1 , MAGE - 3 , TRP- 2 , mel be adjusted over time according to the individual need and anosomal membrane glycoprotein gp100 , gp75 and MUC - 1 the professional judgment of the person administering or (mucin - 1 ) associated with melanoma) ; CEA (carcinoembry supervising the administration of the compositions, and that onic antigen ) which can be associated , e . g. , with ovarian , dosage ranges set forth herein are exemplary only and are melanoma or colon cancers ; folate receptor alpha expressed not intended to limit the scope or practice of the claimed by ovarian carcinoma ; free human chorionic gonadotropin composition . beta (hCGB ) subunit expressed by many different tumors, Co - Formulation with Second Agent including but not limited to myeloma; HER - 2 /neu associ [ 0248 ] In some embodiments , the pharmacological com ated with breast cancer; encephalomyelitis antigen HuD positions comprise a mixture of the anti -GITR antibody or associated with small -cell lung cancer ; tyrosine hydroxylase antigen binding molecule and a second pharmacological associated with neuroblastoma; prostate - specific antigen agent. Exemplary second agents for inclusion in mixtures (PSA ) associated with prostate cancer ; CA125 associated with the present anti- GITR agonist antibody or antigen with ovarian cancer ; and the idiotypic determinants of a B binding molecule include without limitation primary or cell lymphoma can generate tumor- specific immunity ( at target antigens , agents that increase the immunogenicity of tributed to idiotype - specific humoral immune response ) . a tumor cell , agents that inhibit or suppress co - inhibitory Moreover, antigens of human T cell leukemia virus type 1 signals . have been shown to induce specific CTL responses and [ 0249] The anti- GITR antibodies or antigen binding mol antitumor immunity against the virus - induced human adult ecules of the invention can be co - formulated ( i. e ., provided T cell leukemia (ATL ) . See , e .g ., Haupt, et al. , Experimental as a mixture or prepared in a mixture ) with a primary or Biology and Medicine ( 2002 ) 227 :227 - 237 ; Ohashi, et al. , target antigen . The target antigen , or vaccine , will depend on Journal of Virology ( 2000 ) 74 ( 20 ): 9610 - 9616 . Other TAAS the disease condition to be treated . For example , the target are known and find use for co - formulation with the anti antigen may be from a tumor cell , a bacterial cell, a fungus, GITR antibodies. a virus or a parasite . The target antigen can be in the form [0253 ] In some embodiments , the anti -GITR antibodies or of a peptide, a polypeptide , a cell or a polynucleotide , as antigen binding molecules are co - formulated with autolo appropriate. gous tumor cells from the patient , or allogeneic tumor cells [0250 ] In one embodiment, the target antigen is from a of the same tissue type from another patient . The tumor cells virus, e . g . , selected from the group consisting of: hepatitis can be in the form of intact cells , tumor cell lysate , apoptotic type A , hepatitis type B , hepatitis type C , influenza , vari tumor cells or total tumor mRNA. The tumor cells can be cella , adenovirus, herpes simplex type I (HSV I ) , herpes transfected to express a polypeptide that enhances or aug simplex type II (HSV II ) , rinderpest, rhinovirus, echovirus , ments the immunogenity of the tumor cell in the patient, e . g . , rotavirus, respiratory syncytial virus, papilloma virus , transfected to express granulocyte colony stimulating factor papova virus , cytomegalovirus, echinovirus, arbovirus, han (GM -CSF ) . The tumor cells can be from any cancerous tavirus , coxsackie virus, mumps virus , measles virus, rubella tissue, including without limitation , epithelial cancers or virus , polio virus , human immunodeficiency virus type I carcinomas, as well as sarcomas and lymphomas . In some (HIV I ) , and human immunodeficiency virus type II (HIV embodiments , the cancer is melanoma, ovarian cancer, renal II ), any picornaviridae , enteroviruses, caliciviridae , any of cancer, colorectal cancer, prostate , lung cancer including the Norwalk group of viruses, togaviruses, such as alphavi non - small cell lung cancer (NSCLC ) , breast cancer, glioma, ruses , flaviviruses, coronaviruses , rabies virus, Marburg fibrosarcoma, hematologic cancer, or a head and neck viruses , ebola viruses , parainfluenza virus , orthomyxovi squamous cell carcinoma (HNSCC ) . See , e . g ., Pardee , et al, ruses, bunyaviruses , arenaviruses , reoviruses, rotaviruses , Immunotherapy (2009 ) 1 ( 2 ) : 249 - 264 , and references dis orbiviruses , human T cell leukemia virus type I , human T cussed therein . In some embodiments , the tumor cell is from , cell leukemia virus type II, simian immunodeficiency virus, e . g ., pancreatic cancer , melanomas, breast cancer, lung can lentiviruses, polyomaviruses , parvoviruses , Epstein Barr cer, bronchial cancer , colorectal cancer, prostate cancer, virus, human herpesvirus 6 , cercopithecine herpes virus 1 ( B stomach cancer, ovarian cancer, urinary bladder cancer , virus) , and poxviruses . brain or central nervous system cancer, peripheral nervous [0251 ] In one embodiment, the target antigen is from a system cancer , esophageal cancer , cervical cancer, uterine or bacterium , e . g . , selected from the group consisting of: endometrial cancer, cancer of the oral cavity or pharynx , Neisseria spp , Streptococcus spp , S . mutans, Haemophilus liver cancer , kidney cancer , testicular cancer , biliary tract US 2017 /0306038 A1 Oct. 26 , 2017 cancer , small bowel or appendix cancer, salivary gland as TNFRSF9 , 4 - 1BB or CD137) . See, e. g . , Expert Opin Ther cancer , thyroid gland cancer, adrenal gland cancer , osteo Patents ( 2007) 17( 5 ): 567 -575 ; Pardee , et al, Immunotherapy sarcoma, chondrosarcoma, and cancer of hematological tis ( 2009 ) 1 (2 ) : 249 -264 ; and Melero , et al ., Clin Cancer Res sues . (2009 ) 15 ( 5 ): 1507 - 1509, and the references discussed [ 0254 ] In some embodiments , the anti -GITR antibodies or therein . antigen binding molecules are co - formulated with a cyto [ 0257 ] The anti -GITR antibodies or antigen binding mol toxic agent . For example , the anti -GITR antibodies or anti ecules can also be co - formulated with a chemotherapeutic gen binding molecules are co - formulated with an agonist agent. The selected agent will depend on the condition to be antibody or antigen binding molecule that binds to and treated , e. g ., a cancer or an infectious disease , such as a reduces or depletes CD4 +CD25 + regulatory T cells ( Treg ). bacterial infection , a fungal infection , a viral infection or a Exemplary Treg cell - depleting antibodies or antigen binding parasitic infection . The anti -GITR antibodies or antigen molecules bind to CD25 or CCR4 . See , Expert Opin Ther binding molecules can be co - formulated with a chemothera Patents ( 2007 ) 17 (5 ) :567 -575 , and the references discussed peutic known by those of skill to treat the disease condition therein . being treated . Chemotherapeutic agents , e. g ., for the treat [ 0255 ] In some embodiments , the anti -GITR antibodies or ment of cancers and infectious diseases are known in the art, antigen binding molecules are co - formulated with an inhibi and are described , e . g ., in Goodman and Gilman ' s The tor of a co - inhibitory signal. Exemplary inhibitors include Pharmacological Basis of Therapeutics, 11th Ed . , Brunton , inhibitors of CTLA - 4 and inhibitors of the PD - 1 /PD -L1 Lazo and Parker , Eds. , McGraw -Hill (2006 ); 2010 Physi ( e. g ., B7 -H1 ) interaction . In some embodiments , the anti cians ' Desk Reference (PDR ), 64th Edition , Thomson PDR . GITR antibodies are co - formulated with an antibody that binds to and inhibits CTLA - 4 . In some embodiments , the 0258 ] In some embodiments , the anti -GITR antibodies or anti -GITR antibodies are co - formulated with an antibody antigen binding molecules can be co - formulated with an that binds to and inhibits TIM3. In some embodiments , the antineoplastic agent. Exemplary antineoplastic agents that anti- GITR antibodies are co -formulated with an antibody find use for mixing in compositions with the anti -GITR that binds to and inhibits LAG3 . In some embodiments , the antibodies include alkylating agents (e . g ., nitrogen mus anti -GITR antibodies are co - formulated with an antibody tards , ethyleneimines and methylmelamines , methylhydra that binds to and inhibits PD - 1 . In some embodiments, the zine derivative , alkyl sulfonate , nitrosoureas , triazenes and anti- GITR antibodies are co - formulated with an antibody platinum coordination complexes ) ; antimetabolites ( e . g . , that binds to and inhibits B7 -H1 . See, e . g ., Expert Opin Ther folic acid analogs , pyrimidine analogs, purine analogs ; natu Patents ( 2007 ) 17 ( 5 ) : 567 -575 ; and Melero , et al. , Clin ral products (e .g ., vinca alkaloids, taxanes, epipodophyllo Cancer Res (2009 ) 15 ( 5 ) : 1507 - 1509 , and the references toxins, camptothecins, antibiotics , and anthracenedione ). In discussed therein . In certain embodiments , formulations some embodiments, the anti -GITR antibodies or antigen comprising a bispecific molecule including an anti -GITR binding molecules are co - formulated with an antimetabolite antibody or antigen binding molecule and inhibitor of a antineoplastic agent, e . g . , a folic acid analog ( e . g ., metho co - inhibitory signal. In some embodiments, formulations trexate , pemetrexed , trimetrexate ), a pyrimidine analog comprise a bispecific molecule including an anti -GITR ( e . g ., 5 - fluorouracil , capecitabine , cytarabine , gemcitabine ) , antibody or antigen binding molecule and an inhibitor of a purine analog ( e . g . , mercaptopurine , pentostatin , cladrib CTLA4 . In some embodiments , formulations comprise a ine fludarabine ) , or mixtures thereof. In some embodiments , bispecific molecule including an anti- GITR antibody or the anti -GITR antibodies or antigen binding molecules are antigen binding molecule and an inhibitor of TIM3. In some co - formulated with an alkylating agent antineoplastic agent, embodiments , formulations comprise a bispecific molecule e . g ., nitrogen mustards ( e . g ., mechlorethamine , cyclophos including an anti -GITR antibody or antigen binding mol phamide, ifosfamide, melphalan , chlorambucil) , ethyl ecule and an inhibitor of LAG3 . In some embodiments , eneimines ( e . g . , altretamine ) and methylmelamines ( e . g . , formulations comprise a bispecific molecule including an thiotepa ), methylhydrazine derivatives (e .g ., procarbazine ), anti -GITR antibody or antigen binding molecule and an alkyl sulfonate ( e . g . , busulfan ) , nitrosoureas ( e . g . , carmus inhibitor of PD - 1 / PD -L1 . In some embodiments , formula tine , streptozocin ) , triazenes ( e . g ., dacarbazine , temozolo tions comprise a bispecific molecule including an anti -GITR mide) and platinum coordination complexes ( e . g ., cisplatin , antibody or antigen binding molecule and an inhibitor carboplatin , oxaliplatin ). B7H1. [0259 ] In some embodiments , the anti -GITR antibodies or [ 0256 ] The anti- GITR antibodies or antigen binding mol antigen binding molecules can be co - formulated with an ecules can also be co - formulated with one or more immu antiviral agent . Exemplary antiviral agents include without nostimulatory agents . For example , in some embodiments , limitation anti - herpesvirus agents ( e . g . , acyclovir , cidofovir , the anti -GITR antibodies are co - formulated with an immu- famciclovir , foscarnet, thiovir , fomivirsen , ganciclovir , nostimulatory cytokine , for example , IL - 7 , IL - 12 or IL - 15 . idoxuridine , penciclovir , trifluridine , valacyclovir , valgenci Alternatively , the anti -GITR antibodies or antigen binding clovir , resiquimod ) ; anti - influenza agents ( e . g ., amantadine , molecules can be co - formulated with a second immunos oseltamivir , rimantadine , zanamivir , peramivir, E - 118958 ); timulatory antibody. For example , the anti -GITR antibodies anti- hepatitis agents ( e . g . , adeforvir dipivoxil, interferon or antigen binding molecules can also be co - formulated with alpha , lamivudine , entecavir , clevudine , emtricitabine , tel an agonist antibody or antigen binding molecule of another bivudine , tenofovir , viramidine , BILN 2061, NM283 ) and member of the tumor necrosis factor receptor superfamily . other antiviral agents ( e . g ., ribavirin , imiquimod , maribavir , Exemplary secondary immunostimulatory targets include SICAM - 1 , pleconaril ). The antiviral agent can be an antiret without limitation TNFRSF4 tumor necrosis factor receptor roviral agent. Exemplary antiretroviral agents include with superfamily, member 4 ( also known as OX40 ) or tumor o ut limitation zidovudine , didanosine , stavudine , zalcit necrosis factor receptor superfamily , member 9 ( also known abine, lamivudine , abacavir , tenofavir, emtricitabine , US 2017 /0306038 A1 Oct. 26 , 2017 nevirapine, efavirenz , delavirdine , saquinavir , indinavir , ing molecules can be provided in the kit with the second or ritonavir , nelfinavir , amprenavir , lopinavir , atazanavir , fos third agents in the same or separate formulations ( e. g ., as amprenavir and enfuvirtide . mixtures or in separate containers ) . The kits can contain [0260 ] In some embodiments , the anti- GITR antibodies or aliquots of the anti- GITR antibodies, antibody fragments , or antigen binding molecules can be co - formulated with an antigen binding molecules that provide for one or more antibacterial agent. Exemplary antibacterial agents include doses. If aliquots for multiple administrations are provided , without limitation sulfonamides ( e . g . , sulfanilamide , sulfa the doses can be uniform or varied . Varied dosing regimens diazine , sulfamethoxazole , sulfisoxazole , sulfacetamide ) , can be escalating or decreasing , as appropriate . The dosages trimethoprim , quinolones ( e . g ., nalidixic acid , cinoxacin , of the anti -GITR antibody , antibody fragment, or antigen norfloxacin , ciprofloxacin , ofloxacin , sparfloxacin , fleroxa binding molecule and the second agent can be independently cin , perloxacin , levofloxacin , garenoxacin and gemifloxa uniform or varying . The kit can include one or more other cin ), methenamine , nitrofurantoin , penicillins ( e .g ., penicil elements including: instructions for use ; other reagents , e . g . , lin G , penicillin V , methicilin oxacillin , cloxacillin , a label, a therapeutic agent, or an agent useful for chelating , dicloxacillin , nafcilin , ampicillin , amoxicillin , carbenicillin , or otherwise coupling, an antibody to a label or therapeutic ticarcillin , mezlocillin , and piperacillin ) , cephalosporins agent, or a radioprotective composition ; devices or other ( e . g . , cefazolin , cephalexin , cefadroxil , cefoxitin , cefaclor, materials for preparing the antibody for administration ; cefprozil, cefuroxime, cefuroxime acetil , loracarbef, cefo pharmaceutically acceptable carriers ; and devices or other tetan , ceforanide , cefotaxime, cefpodoxime proxetil , cefib materials for administration to a subject. uten , cefdinir , cefditoren pivorxil , ceftizoxime, ceftriaxone , [0264 ] In some embodiments , the kits further contain a cefoperazone, ceftazidime, and cefepine ) , carbapenems target antigen . The target antigen , or vaccine , will depend on ( e . g ., imipenem , aztreonam ), and aminoglycosides ( e . g . , the disease condition to be treated . For example , the target neomycin , kanamycin , streptomycin , gentamicin , toramy- antigen may be from a tumor cell , a bacterial cell, a fungus, cin , netilmicin , and amikacin ) . a parasite or a virus. The target antigen can be in the form [0261 ] In some embodiments , the anti -GITR antibodies or of a peptide , a polypeptide , a cell , a polynucleotide ( e . g . , antigen binding molecules can be co - formulated with an naked plasmid or viral vector ) as appropriate . In some anti -parasitic agent. Exemplary anti -parasitic agents include embodiments , the target antigen is a tumor associated anti without limitation anti- malarial agents ( e. g. , quinolines gen . Exemplary target antigens are discussed herein ; others including chloroquine , mefloquine , quinine, quinidine, and known in the art also find use . primaquine ; diaminopyrimidines including pyrimethamine , [0265 ] In some embodiments , the kits further contain a sulfadoxine , tetracyclines , atovaquone , and proguanil ) ; anti cytotoxic agent. For example , the kits can contain an agonist protozoal agents including amphotericin , chloroquine , eflo antibody or antigen binding molecule that binds to and rnithine , emetine , fumagillin , 8 -hydroxyquinolines , melar reduces or depletes CD4 + CD25 + regulatory T cells ( Treg ) . soprol, metronidazole , miltefosine , nifurtimox , Exemplary Treg cell - depleting antibodies or antigen binding nitazoxanide, paromomycin , pentamidine, sodium stiboglu molecules bind to CD25 or CCR4. See , Expert Opin Ther conate , and suramin . Patents (2007 ) 17 (5 ) : 567 -575 , and the references discussed [0262 ] In some embodiments , the anti -GITR antibodies or therein . antigen binding molecules can be co - formulated with an [0266 ] In some embodiments , the kits further contain an anti - fungal agent. Exemplary anti - fungal agents include inhibitor of a co - inhibitory signal. Exemplary inhibitors without limitation polyenes ( e . g ., natamycin , rimocidin , include inhibitors of CTLA - 4 , LAG3, TIM3, and / or inhibi filipin , nystatin , amphotericin B , candicin , and hamycin ) , tors of the PD - 1 /PD -L1 ( e . g . , B7- H1 ) interaction . In some imidazoles ( e . g ., miconazole , ketoconazole , clotrimazole , embodiments , the kits further contain an antibody that binds econazole , bifonazole , butoconazole , fenticonazole , isocon to and inhibits CTLA - 4 . In some embodiments , the kits azole , oxiconazole , sertaconazole, sulconazole , tiocon further contain an antibody that binds to and inhibits LAG3. azole ), triazoles ( e . g ., fluconazole, itraconazole , isavucon In some embodiments , the kits further contain an antibody azole , ravuconazole, posaconazole , voriconazole , that binds to and inhibits TIM3. In some embodiments , the terconazole ) , thiazoles ( e . g ., abafungin ), allylamines ( e . g ., kits further contain an antibody that binds to and inhibits terbinafine , amorolfine , naftifine, butenafine ) , echinocandins PD - 1 . In some embodiments , the kits further contain an ( e . g ., anidulafungin , caspofungin , micafungin ), benzoic antibody that binds to and inhibits B7- H1 . See , e . g ., Expert acid , ciclopirox , tolnaftate , undecylenic acid , flucytosine or Opin Ther Patents ( 2007 ) 17 ( 5 ) : 567 -575 ; and Melero , et al. , 5 - fluorocytosine , griseofulvin , and haloprogin . Clin Cancer Res (2009 ) 15 ( 5 ) : 1507 - 1509 , and the references discussed therein . Kits 10267] In some embodiments, the kits further contain one [0263 ] The anti -GITR compositions of the present inven or more immunostimulatory agents . For example , in some tion can be provided in a kit . The anti -GITR antibody, embodiments , the kits contain an immunostimulatory antibody fragment, or antigen binding molecule is generally cytokine , for example , IL - 7 , IL - 12 or IL - 15 . Alternatively, in a vial or a container . As appropriate , the antibody can be the kits can contain a second immunostimulatory antibody . in liquid or dried ( e . g ., lyophilized ) form . The kits can For example , the kits can contain an agonist antibody or comprise an anti -GITR antibody , antibody fragment, or antigen binding molecule of another member of the tumor antigen binding molecule of the invention , as described necrosis factor receptor superfamily . Exemplary secondary herein , and optionally also contain a second or third agent. immunostimulatory targets include without limitation In some embodiments , the kits contain anti -GITR antibody , TNFRSF4 tumor necrosis factor receptor superfamily , mem antibody fragment, or antigen binding molecule of the ber 4 (also known as OX40 ) or tumor necrosis factor invention and a pharmaceutically acceptable diluent. The receptor superfamily, member 9 (also known as TNFRSF9 , anti- GITR antibodies, antibody fragments , or antigen bind 4 - 1BB or CD137 ). See, e .g ., Expert Opin Ther Patents US 2017 /0306038 A1 Oct. 26 , 2017 43

(2007 ) 17 (5 ): 567 -575 ; Pardee, et al, Immunotherapy (2009 ) gland cancer , thyroid gland cancer, adrenal gland cancer, 1 ( 2 ) : 249 - 264; and Melero , et al. , Clin Cancer Res ( 2009 ) osteosarcoma, chondrosarcoma, cancer of hematological 15 (5 ) : 1507 - 1509 , and the references discussed therein . tissues and head and neck squamous cell carcinoma (HN [ 0268] In some embodiments , the kits further contain a SCC ). chemotherapeutic agent . The selected agent will depend on [0272 ] In one aspect, the invention provides methods of the condition to be treated , e . g . , a cancer or an infectious treating tumor growth of a cancer that expresses a tumor disease, such as a bacterial infection , a fungal infection , a associated antigen in an individual in need thereof, com viral infection or a parasitic infection . Exemplary chemo prising administering to the individual a therapeutically therapy agents include any antineoplastic , antiviral, antibac effective amount of an anti -GITR agonist antibody or anti terial, antiparasitic , and antifungal agents known in the art body fragment of the invention , as described herein . The and described herein . invention also provides an anti -GITR agonist antibody or antibody fragment of the invention for use in treating tumor Methods of Enhancing T Cell Responses growth of a cancer that expresses a tumor associated antigen in an individual. The invention further provides a compo Conditions Subject to Treatment or Prevention sition comprising an antibody or antibody fragment of the [ 0269 ] The anti -GITR agonist antibodies and antibody invention for use in reducing, inhibiting or preventing tumor fragments of the invention find use in augmenting CD4 + T growth of a cancer that expresses a tumor associated antigen helper and CD8 + cytolytic T cell responses in a patient in in an individual. need thereof. Therefore , the antibodies find use in enhancing [0273 ] In some embodiments , methods for facilitating the or augmenting a T cell response in a patient, e .g ., to effect diagnosis or prognosis of cancer in an individual, compris the reduction , reversal, inhibition or prevention of a disease ing using an anti -GITR agonist antibody or antibody frag that can be counteracted with an enhanced or augmented ment of the invention for the detection of expression of immune response . In one aspect, the invention provides GITR in or around a tumor in the individual . methods of enhancing a T cell response in an individual in [0274 ] In some embodiments , the patient has an infectious need thereof, comprising administering to the individual a disease , for example , a bacterial, viral, fungal or parasitic therapeutically effective amount of an anti -GITR agonist infection . The anti -GITR agonist antibodies find use in antibody or antibody fragment of the invention , as described reducing , inhibiting and / or preventing parasites in , e . g ., herein . The invention also provides in one aspect an anti filariasis and leishmaniasis . GITR agonist antibody or antibody fragment for use in [0275 ] In some embodiments , anti -GITR agonist antibod enhancing a T cell response in an individual. In a further ies find use in treatment of viral infections, including with aspect, the invention provides a composition comprising out limitation hepatitis virus infection , for example , chronic such an antibody or antibody fragment for use in enhancing hepatitis C (HCV ) infection , herpes simplex virus (HSV ) a T cell response in an individual. infection or human immunodeficiency virus (HIV ) infection . [ 0270 ] Conditions subject to treatment include cancers In some embodiments , anti -GITR agonist antibodies find and infectious disease . For therapeutic purposes, the patient use in treating a viral infection selected from the group may have a cancer or tumor or an infectious disease , e . g. , a consisting of: hepatitis type A , hepatitis type B , hepatitis bacterial, viral, fungal or parasitic infection . For preventa type C , influenza , varicella , adenovirus , herpes simplex type tive purposes, the patient may be in remission from a cancer I (HSV I) , herpes simplex type II (HSV II ) , rinderpest , or may anticipate being exposed to a bacterial, viral, fungal rhinovirus , echovirus , rotavirus , respiratory syncytial virus , or parasitic infection . The antibodies can also serve as an papilloma virus, papova virus , cytomegalovirus, echinovi adjuvant to enhance or promote or boost an immune rus , arbovirus, hantavirus, coxsackie virus , mumps virus , response against a primary antigen or a target antigen , e . g . , measles virus, rubella virus, polio virus, human immunode a vaccine . ficiency virus type I (HIVI ) , and human immunodeficiency [0271 ] In some embodiments , the patient has a cancer, is virus type II (HIV II ) , any picornaviridae , enteroviruses , suspected of having a cancer, or is in remission from a caliciviridae , any of the Norwalk group of viruses , togavi cancer. Cancers subject to treatment with the anti -GITR ruses , such as alphaviruses, flaviviruses , coronaviruses , antibodies usually express a tumor -associated antigen rabies virus, Marburg viruses, ebola viruses, parainfluenza ( TAA ) , as described herein . Cancers subject to treatment virus , orthomyxoviruses , bunyaviruses , arenaviruses , reovi include without limitation epithelial cancers or carcinomas, ruses , rotaviruses, orbiviruses , human T cell leukemia virus as well as sarcomas and lymphomas . In some embodiments , type I, human T cell leukemia virus type II , simian immu the cancer is melanoma , ovarian cancer, renal cancer, col nodeficiency virus , lentiviruses , polyomaviruses , parvovi orectal cancer, prostate , lung cancer including non - small cell ruses, Epstein Barr virus, human herpesvirus 6 , cercopith lung cancer (NSCLC ) , breast cancer, glioma, or fibrosar ecine herpes virus 1 (B virus ), and poxviruses . coma. See , e. g ., Pardee, et al , Immunotherapy (2009 ) 1( 2 ): [0276 ] In some embodiments , anti -GITR agonist antibod 249 - 264, and references discussed therein . In some embodi ies find use in treating bacterial infections, including without ments , the type of cancer is selected from the group limitation an infection of Neisseria spp, Streptococcus spp , consisting of : pancreatic cancer, melanomas , breast cancer , S . mutans, Haemophilus spp ., Moraxella spp , Bordetella lung cancer, bronchial cancer, colorectal cancer, prostate spp , Mycobacterium spp , Legionella spp , Escherichia spp , cancer , stomach cancer , ovarian cancer , urinary bladder Vibrio spp , Yersinia spp , Campylobacter spp , Salmonella cancer, brain or central nervous system cancer , peripheral spp , Listeria spp ., Helicobacter spp , Pseudomonas spp , nervous system cancer , esophageal cancer , cervical cancer, Staphylococcus spp . , Enterococcus spp , Clostridium spp ., uterine or endometrial cancer, cancer of the oral cavity or Bacillus spp , Corynebacterium spp ., Borrelia spp ., Ehrli pharynx , liver cancer , kidney cancer, testicular cancer , bil chia spp , Rickettsia spp, Chlamydia spp. , Leptospira spp. , iary tract cancer, small bowel or appendix cancer, salivary Treponema spp. US 2017 /0306038 A1 Oct. 26 , 2017 44

Administration of Anti- GITR Antibodies tered as a mixture or in separate formulations. The anti [0277 ] A physician or veterinarian can start doses of the GITR antibody, antibody fragment, or antigen binding mol antibodies or antibody fragments of the invention employed ecule and the second or agent can be administered in the pharmaceutical composition at levels lower than that concurrently or sequentially . The anti -GITR antibody, anti required to achieve the desired therapeutic effect and gradu body fragment, or antigen binding molecule and the second ally increase the dosage until the desired effect is achieved . or agent can be administered via the same route of admin In general , effective doses of the compositions of the present istration or via different routes of administration , as appro invention vary depending upon many different factors, priate . Exemplary second agents and third agents for co including the specific disease or condition to be treated , administration with the present anti -GITR agonist means of administration , target site , physiological state of antibodies, antibody fragments, or antigen binding mol the patient , whether the patient is human or an animal , other ecules include without limitation , primary or target antigens , medications administered , and whether treatment is prophy agents that increase the immunogenicity of a tumor cell, lactic or therapeutic . Treatment dosages need to be titrated agents that inhibit or suppress co - inhibitory signals . The to optimize safety and efficacy. For administration with an anti -GITR agonist antibodies, antibody fragments , or anti antibody , the dosage ranges from about 0 .0001 to 100 gen binding molecules can also be co - administered with mg/ kg , and more usually 0 .01 to 5 mg /kg , of the host body chemotherapeutic used to treat the disease condition being weight. For example dosages can be 1 mg/ kg body weight treated , e . g . , to enhance the efficacy of the chemotherapeutic or 10 mg /kg body weight or within the range of 1 - 10 mg/ kg . agent or to further enhance an immune response against a Dosing can be daily , weekly , bi- weekly , monthly , or more or target antigen . The anti- GITR agonist antibodies , antibody less often , as needed or desired . An exemplary treatment fragments , or antigen binding molecules also find use in regime entails administration once weekly , once per every combination therapies with established procedures for treat two weeks or once a month or once every 3 to 6 months. ing the designated disease condition , e . g . , radiation or sur 0278 ] In some embodiments, an polynucleotide encoding gery . an anti- GITR antibody , antibody fragment, or antigen bind [0281 ] By " a combination " or " in combination with ,” it is ing molecule of the invention is administered . In embodi not intended to imply that the therapy or the therapeutic mentsm where the agent is a nucleic acid , typical dosages can agents must be administered at the same time and / or for range from about 0 . 1 mg/ kg body weight up to and including mulated for delivery together, although these methods of about 100 mg/ kg body weight, e . g . , between about 1 mg/ kg delivery are within the scope described herein . The thera body weight to about 50 mg/ kg body weight. In some peutic agents in the combination can be administered con embodiments , about 1 , 2 , 3 , 4 , 5 , 10 , 15 , 20 , 30 , 40 or 50 currently with , prior to , or subsequent to , one or more other mg/ kg body weight. additional therapies or therapeutic agents . The therapeutic [0279 ] The antibody or antibody fragment can be admin agents or therapeutic protocol can be administered in any istered in single or divided doses . Antibody or antibody order. In general, each agent will be administered at a dose fragment is usually administered on multiple occasions. and /or on a time schedule determined for that agent. In will Intervals between single dosages can be weekly , bi -weekly , further be appreciated that the additional therapeutic agent monthly or yearly , as needed or desired . Intervals can also be utilized in this combination may be administered together in irregular as indicated by measuring blood levels of anti a single composition or administered separately in different GITR antibody or antibody fragment in the patient . In some compositions. In general, it is expected that additional methods , dosage is adjusted to achieve a plasma antibody or therapeutic agents utilized in combination be utilized at antibody fragment concentration of 1 - 1000 ug/ ml and in levels that do not exceed the levels atwhich they are utilized some methods 25 - 300 ug /ml . Alternatively, antibody or individually . In some embodiments , the levels utilized in antibody fragment can be administered as a sustained release combination will be lower than those utilized individually . formulation , in which case less frequent administration is [0282 ] In embodiments , the additional therapeutic agent is required . Dosage and frequency vary depending on the administered at a therapeutic or lower - than therapeutic dose . halflife of the antibody or antibody fragment in the patient. In certain embodiments , the concentration of the second In general, humanized antibodies show longer half life than therapeutic agent that is required to achieve inhibition , e . g . , that of chimeric antibodies and nonhuman antibodies. The growth inhibition , is lower when the second therapeutic dosage and frequency of administration can vary depending agent is administered in combination with the first thera on whether the treatment is prophylactic or therapeutic . In peutic agent, e . g ., the anti -GITR antibody molecule , than prophylactic applications, a relatively low dosage is admin when the second therapeutic agent is administered individu istered at relatively infrequent intervals over a long period of ally . In certain embodiments , the concentration of the first time. Some patients continue to receive treatment for the rest therapeutic agent that is required to achieve inhibition , e . g . , of their lives. In therapeutic applications, a relatively high growth inhibition , is lower when the first therapeutic agent dosage at relatively short intervals is sometimes required is administered in combination with the second therapeutic until progression of the disease is reduced or terminated , and agent than when the first therapeutic agent is administered preferably until the patient shows partial or complete ame individually . In certain embodiments , in a combination lioration of symptoms of disease . Thereafter , the patient can therapy , the concentration of the second therapeutic agent be administered a prophylactic regime. that is required to achieve inhibition , e . g ., growth inhibition , Co -Administration with Additional Agent( s ) is lower than the therapeutic dose of the second therapeutic [0280 ] In some embodiments , the anti -GITR antibody, agent as a monotherapy, e. g. , 10 -20 % , 20 -30 % , 30 -40 % , antibody fragment, or antigen binding molecule is co -ad 40 -50 % , 50 -60 % , 60 -70 % , 70 -80 % , or 80 - 90 % lower. In ministered with a second or third pharmacological agent. certain embodiments , in a combination therapy, the concen The anti- GITR antibody, antibody fragment, or antigen tration of the first therapeutic agent that is required to binding molecule and the second or agent can be adminis achieve inhibition , e . g ., growth inhibition , is lower than the US 2017 /0306038 A1 Oct. 26 , 2017 45 therapeutic dose of the first therapeutic agent as a mono [0288 ] In some embodiments , the anti -GITR antibodies , therapy , e .g ., 10 - 20 % , 20 - 30 % , 30 - 40 % , 40 - 50 % , 50 -60 % , antibody fragments, or antigen binding molecules are co 60 - 70 % , 70 - 80 % , or 80 - 90 % lower. administered with autologous tumor cells from the patient, [ 0283] The term “ inhibition , ” “ inhibitor, ” or “ antagonist ” or allogeneic tumor cells of the same tissue type from includes a reduction in a certain parameter , e .g ., an activity , another patient. The tumor cells can be in the form of intact of a given molecule , e . g ., an immune checkpoint inhibitor. cells , tumor cell lysate , apoptotic tumor cells or total tumor For example , inhibition of an activity , e . g . , a coinhibitory mRNA . The tumor cells can be transfected to express a activity , of at least 5 % , 10 % , 20 % , 30 % , 40 % or more is polypeptide that enhances or augments the immunogenity of included by this term . Thus, inhibition need not be 100 % . the tumor cell in the patient, e . g . , transfected to express granulocyte colony stimulating factor (GM -CSF ) . The The term “ activation ,” “ activator, ” or “ agonist” includes an tumor cells can be from any cancerous tissue , including increase in a certain parameter, e . g . , an activity , of a given without limitation , epithelial cancers or carcinomas, as well molecule , e . g ., a costimulatory molecule . For example , as sarcomas and lymphomas. In some embodiments, the increase of an activity , e . g . , a costimulatory activity , of at cancer is melanoma , ovarian cancer, renal cancer , colorectal least 5 % , 10 % , 25 % , 50 % , 75 % or more is included by this cancer , prostate , lung cancer including non - small cell lung term . cancer (NSCLC ) , breast cancer , glioma, or fibrosarcoma . [0284 ] The anti -GITR antibodies, antibody fragments , or See , e . g ., Pardee, et al, Immunotherapy ( 2009 ) 1 ( 2 ) : 249 -264 , antigen binding molecules of the invention can be co and references discussed therein . In one embodiment , the administered with a primary or target antigen . The target tumor cell is from , e . g . , pancreatic cancer, melanomas , antigen , or vaccine , will depend on the disease condition to breast cancer , lung cancer, bronchial cancer, colorectal can be treated . For example , the target antigen may be from a cer, prostate cancer , stomach cancer , ovarian cancer, urinary tumor cell , a bacterial cell , a fungus , a virus or a parasite . bladder cancer, brain or central nervous system cancer, The target antigen can be in the form of a peptide , a peripheral nervous system cancer, esophageal cancer, cer polypeptide , a cell or a polynucleotide , as appropriate . vical cancer, uterine or endometrial cancer, cancer of the oral [ 0285 ] In some embodiments , the anti- GITR antibodies , cavity or pharynx , liver cancer, kidney cancer, testicular antibody fragments , or antigen binding molecules are co cancer, biliary tract cancer, small bowel or appendix cancer, administered with a target antigen from a virus , e . g . , selected salivary gland cancer, thyroid gland cancer, adrenal gland from the group consisting of : hepatitis type A , hepatitis type cancer, osteosarcoma, chondrosarcoma, cancer of hemato B , hepatitis type C , influenza , varicella , adenovirus , herpes logical tissues and head and neck squamous cell carcinoma simplex type I (HSV I ) , herpes simplex type II (HSV II ) , (HNSCC ). rinderpest , rhinovirus , echovirus , rotavirus , respiratory syn Combinations with Immunomodulators cytial virus, papilloma virus , papova virus, cytomegalovirus, (0289 ] In certain embodiments, an immunomodulator echinovirus , arbovirus , hantavirus , coxsackie virus, mumps used in the combinations with an anti GITR antibody virus, measles virus , rubella virus, polio virus, human immu molecule of the invention ( e . g ., in combination with a nodeficiency virus type I (HIV I ) , and human immunodefi therapeutic agent chosen from an antigen - presentation com ciency virus type II (HIV II ) , any picornaviridae , enterovi bination ) is an inhibitor of an immune checkpoint molecule . ruses, caliciviridae , any of the Norwalk group of viruses, In one embodiment, the immunomodulator is an inhibitor of togaviruses , such as alphaviruses , flaviviruses , coronavi PD - 1 , PD - L1, PD - L2 , CTLA4, TIM - 3 , LAG - 3 , CEACAM ruses , rabies virus, Marburg viruses , ebola viruses , parain ( e . g . , CEACAM - 1 , - 3 and / or - 5 ) , VISTA , BTLA , TIGIT, fluenza virus , orthomyxoviruses , bunyaviruses, arenavi LAIR1, CD160 , 2B4 and/ or TGFR beta . In one embodi ruses , reoviruses , rotaviruses, orbiviruses , human T cell ment, the inhibitor of an immune checkpoint molecule leukemia virus type I, human T cell leukemia virus type II , inhibits PD - 1 , PD -L1 , LAG - 3 , TIM - 3 , CEACAM ( e . g . , simian immunodeficiency virus, lentiviruses , polyomavi CEACAM - 1 , - 3 and /or - 5 ) , CTLA - 4 , or any combination ruses , parvoviruses , Epstein Ban virus, human herpesvirus 6 , thereof. cercopithecine herpes virus 1 ( B virus ) , and poxviruses . [0290 ] Inhibition of an inhibitory molecule can be per [0286 ] In some embodiments, the anti -GITR antibodies , formed at the DNA , RNA or protein level . In embodiments , antibody fragments , or antigen binding molecules are co an inhibitory nucleic acid ( e . g . , a dsRNA , siRNA or administered with target antigen from a bacterium , e . g ., shRNA ) , can be used to inhibit expression of an inhibitory selected from the group consisting of: Neisseria spp , Strep molecule . In other embodiments , the inhibitor of an inhibi tococcus spp , S . mutans , Haemophilus spp . , Moraxella spp , tory signal is , a polypeptide e . g . , a soluble ligand ( e . g . , Bordetella spp , Mycobacterium spp , Legionella spp , PD - 1 -Ig or CTLA -4 Ig ), or an antibody or antigen -binding Escherichia spp , Vibrio spp , Yersinia spp , Campylobacter fragment thereof, that binds to the inhibitory molecule ; e . g . , spp , Salmonella spp , Listeria spp ., Helicobacter spp , an antibody or fragment thereof (also referred to herein as Pseudomonas spp , Staphylococcus spp . , Enterococcus spp , " an antibody molecule ” ) that binds to PD - 1, PD -L1 , PD -L2 , Clostridium spp ., Bacillus spp , Corynebacterium spp ., Bor CEACAM ( e . g . , CEACAM - 1 , - 3 and / or - 5 ) , CTLA - 4 , TIM relia spp ., Ehrlichia spp , Rickettsia spp , Chlamydia spp . , 3 , LAG - 3 , VISTA , BTLA , TIGIT , LAIR1, CD160 , 2B4 Leptospira spp ., Treponema spp . and / or TGFR beta , or a combination thereof. [ 0287 ] In some embodiments , the anti -GITR antibodies , [0291 ] The GITR agonist can be administered alone , or in antibody fragments , or antigen binding molecules are co combination with other immunomodulators , e . g . , in combi administered with a tumor- associated antigen ( TAA ) . The nation with an inhibitor of PD - 1 , PD - L1 , CTLA - 4 , TAA can be an isolated polypeptide or peptide , can be part CEACAM (e .g . , CEACAM - 1, -3 and /or -5 ), TIM - 3 or of an intact cell or part of a tumor cell lysate . Exemplary LAG - 3 . In one exemplary embodiment, the anti -GITR anti TAAs are discussed above ; others known in the art also find body molecule ( e . g ., as described herein ) is administered in use . combination with an anti - PD - 1 antibody molecule . The US 2017 /0306038 A1 Oct. 26 , 2017 46

GITR antibody molecule and the anti -PD - 1 antibody mol CEACAM - 1 , e . g ., human CEACAM - 1 . In another embodi ecule may be in the form of separate antibody composition , ment, the immunomodulator is an inhibitor of CEACAM - 3 , or as a bispecific antibody molecule . In other embodiments , e . g . , human CEACAM - 3 . In another embodiment, the a GITR agonist can be administered in combination with immunomodulator is an inhibitor of CEACAM - 5 , e . g ., other costimulatory molecule , e . g . , an agonist of OX40 , human CEACAM - 5 . In one embodiment, the inhibitor of CD2 , CD27 , CD28 , CDS , ICAM - 1, LFA - 1 ( CD11a/ CD18 ), CEACAM ( e . g ., CEACAM - 1 , - 3 and / or - 5 ) is an antibody ICOS (CD278 ), 4 - 1BB (CD137 ) , CD30 , CD40 , BAFFR , molecule to CEACAM ( e . g . , CEACAM - 1 , - 3 and /or - 5 ). HVEM , CD7, LIGHT, NKG2C , SLAMF7, NKp80 , CD160 , The CEACAM ( e . g . , CEACAM - 1 , - 3 and /or - 5 ) inhibitor B7 -H3 , or CD83 ligand . can be administered alone , or in combination with other [0292 ] In certain embodiments , the antibody molecule is immunomodulators , e . g . , in combination with an inhibitor of in the form of a bispecific or multispecific antibody mol LAG - 3 , TIM - 3 , PD - 1 , PD - L1 or CTLA - 4 . ecule . In some embodiments , the anti -GITR antibody mol 10295 ] In other embodiments , the immunomodulator is an ecule is a bispecific antibody that binds to GITR and PD - 1 , inhibitor of LAG - 3 , e . g . , human LAG - 3 . In one embodi PD - L1 , CTLA - 4 , CEACAM ( e . g . , CEACAM - 1 , - 3 and /or ment, the inhibitor of LAG - 3 is an antibody molecule to - 5 ) , TIM - 3 or LAG - 3 . In one embodiment, the bispecific LAG - 3 . The LAG - 3 inhibitor can be administered alone , or antibody molecule has a first binding specificity to GITR in combination with other immunomodulators , e. g . , in com and a second binding specifity , e . g ., a second binding bination with an inhibitor of CEACAM ( e .g ., CEACAM - 1, specificity to PD - 1 , PD -L1 TIM - 3 , CEACAM ( e . g ., - 3 and / or - 5 ) , TIM - 3 , PD - 1 , PD - L1 or CTLA - 4 . CEACAM - 1 , - 3 and /or - 5 ) , LAG - 3 , or PD -L2 . [0296 ] In other embodiments , the immunomodulator is an [ 0293 ] In certain embodiments , the immunomodulator is inhibitor of TIM - 3 , e . g . , human TIM - 3 . In one embodiment, an agonist of GITR , e .g ., human GITR ( e . g . , an antibody the inhibitor of TIM - 3 is an antibody molecule to TIM - 3 . molecule as described herein ). In another embodiment, the The TIM - 3 inhibitor can be administered alone , or in com immunomodulator is an antagonist , e . g . , human GITRL . In bination with other immunomodulators , e . g . , in combination one embodiment, the agonist of GITR and / or antagonist of with an inhibitor of CEACAM ( e . g ., CEACAM - 1 , - 3 and /or GITRL is an antibody molecule to GITR . The GITR anti - 5 ) , LAG - 3 , PD - 1 , PD -L1 or CTLA - 4 . body can be administered alone , or in combination with [0297 ] In certain embodiments , the immunomodulator other immunomodulators , e . g ., in combination with an used in the combinations disclosed herein (e . g ., in combi inhibitor of PD - 1 , PD -L1 , LAG - 3 , TIM -3 , CEACAM ( e . g ., nation with a therapeutic agent chosen from an antigen CEACAM - 1 , - 3 and /or -5 ) or CTLA -4 . In an exemplary presentation combination ) is an activator or agonist of a embodiment, the agonist of GITR , e . g . , the anti -GITR costimulatory molecule . In one embodiment, the agonist of antibody molecule , is administered in combination with a the costimulatory molecule is chosen from an agonist ( e . g ., PD - 1 or PD - L1 inhibitor. In another embodiment, the ago an agonistic antibody or antigen -binding fragment thereof, nist of GITR , e . g . , the anti -GITR antibody molecule , is or a soluble fusion ) of OX40 , CD2, CD27 , CD28 , CDS, administered in combination with a LAG - 3 inhibitor, e. g ., an ICAM - 1 , LFA - 1 (CD11a /CD18 ), ICOS (CD278 ) , 4 - 1BB anti -LAG - 3 antibody molecule. In another embodiment, the (CD137 ) , GITR , CD30 , CD40 , BAFFR , HVEM , CD7 , agonist of GITR , e . g . , the anti -GITR antibody molecule , is LIGHT, NKG2C , SLAMF7 , NKp80 , CD160 , B7- H3 , or administered in combination with a TIM - 3 inhibitor, e . g . , an CD83 ligand . anti - TIM - 3 antibody molecule . In another embodiment, the (0298 ] In other embodiments , the immunomodulator is an the agonist of GITR , e . g . , the anti -GITR antibody molecule , activator of a costimulatory molecule ( e . g . , an OX40 ago is administered in combination with a CEACAM inhibitor nist ). In one embodiment, the OX40 agonist is an antibody ( e . g . , CEACAM - 1 , - 3 and / or - 5 inhibitor ) , e . g ., an anti molecule to OX40 . The OX40 agonist can be administered CEACAM antibody molecule . In another embodiment, the alone , or in combination with other immunomodulators , the agonist of GITR , e . g . , the anti -GITR antibody molecule , e . g . , in combination with an inhibitor of PD - 1 , PD -L1 , is administered in combination with a CEACAM - 1 inhibitor , CTLA - 4 , CEACAM ( e .g . , CEACAM - 1 , - 3 and /or -5 ), e. g. , an anti- CEACAM -1 antibody molecule . In another TIM - 3 or LAG - 3 . In some embodiments , the anti- OX40 embodiment, the the agonist of GITR , e . g . , the anti -GITR antibody molecule is a bispecific antibody that binds to antibody molecule , is administered in combination with a GITR and PD - 1 , PD -L1 , CTLA - 4 , CEACAM ( e . g . , CEACAM - 5 inhibitor , e . g . , an anti -CEACAM - 5 antibody CEACAM - 1 , - 3 and /or - 5 ), TIM - 3 or LAG - 3 . In one exem molecule . In yet other embodiments , the agonist of GITR , plary embodiment, an OX40 antibody molecule is admin e . g ., the anti -GITR antibody molecule , is administered in istered in combination with an anti- GITR antibody molecule combination with a LAG - 3 inhibitor, e . g . , an anti -LAG - 3 ( e . g . , an anti- GITR molecule as described herein ) . The antibody molecule , and a TIM - 3 inhibitor, e . g . , an anti OX40 antibody molecule and the anti -GITR antibody mol TIM - 3 antibody molecule . Other combinations of immuno ecule may be in the form of separate antibody composition , modulators with a GITR modulator ( e . g . , one or more of or as a bispecific antibody molecule . In other embodiments , PD - L2 , CTLA - 4 , TIM - 3 , LAG - 3 , CEACAM ( e . g ., the OX40 agonist can be administered in combination with CEACAM - 1 , - 3 and /or - 5 ) , VISTA , BTLA , TIGIT , LAIR1, other costimulatory molecule , e . g . , an agonist of GITR , CD160 , 2B4 and /or TGFR ) are also within the present CD2, CD27 , CD28 , CDS , ICAM - 1 , LFA - 1 (CD11a /CD18 ) , invention . Any of the antibody molecules known in the art ICOS (CD278 ), 4 - 1BB (CD137 ) , CD30 , CD40 , BAFFR , or disclosed herein can be used in the aforesaid combina HVEM , CD7 , LIGHT, NKG2C , SLAMF7, NKp80 , CD160 , tions of inhibitors of checkpoint molecule . B7 -H3 , or CD83 ligand . [ 0294 ] In other embodiments , the immunomodulator is an [0299 ] In other embodiments , the immunomodulator is an inhibitor of CEACAM ( e . g . , CEACAM - 1 , - 3 and / or - 5 ) , activator of a costimulatory molecule ( e . g . , an 4 - 1BB ( CD e . g ., human CEACAM ( e . g ., CEACAM - 1 , - 3 and / or - 5 ) . In 137 ) agonist ). In one embodiment, the 4 - 1BB (CD - 137 ) one embodiment, the immunomodulator is an inhibitor of agonist is an antibody molecule to 4 - 1BB (CD - 137 ) . In some US 2017 /0306038 A1 Oct. 26 , 2017 47 embodiments , the combination disclosed herein , e . g . , a one or more immunostimulatory agents . For example , in combination comprising an anti- GITR antibody molecule , is some embodiments , the anti -GITR antibodies or antibody administered with a 4 - 1BB receptor targeting agent ( e . g . , an fragments are co - administered with an immunostimulatory antibody that stimulates signaling through 4 - 1BB (CD - 137 ) , cytokine , for example , IL - 7 , IL - 12 or IL - 15 . Alternatively, e . g ., PF - 2566 ). In one embodiment, the anti -GITR antibody the anti -GITR antibodies, antibody fragments, or antigen molecule is administered in combination with a tyrosine binding molecules can be co -administered with a second kinase inhibitor ( e . g . , axitinib ) and a 4 - 1BB receptor target immunostimulatory antibody . For example , the anti -GITR ing agent. antibodies, antibody fragments , or antigen binding mol [0300 ] The 4 -1BB agonist can be combined alone, or in ecules can also be co - administered with an agonist antibody, combination with other immunomodulators, e . g . , in combi antibody fragment, or antigen binding molecule of another nation with an inhibitor of PD - 1 , PD - L1 , CTLA - 4 , member of the tumor necrosis factor receptor superfamily . CEACAM ( e . g . , CEACAM - 1 , - 3 and / or - 5 ) , TIM - 3 or Exemplary secondary immunostimulatory targets include LAG - 3 . In some embodiments , the anti -4 - 1BB antibody without limitation TNFRSF4 tumor necrosis factor receptor molecule is a bispecific antibody that binds to GITR and superfamily , member 4 (also known as OX40 ) or tumor PD - 1 , PD -L1 , CTLA - 4 , CEACAM ( e . g ., CEACAM - 1, - 3 necrosis factor receptor superfamily, member 9 (also known and / or - 5 ) , TIM - 3 or LAG - 3 . In one exemplary embodiment, as TNFRSF9, 4 - 1 BB or CD137 ) . See , e . g . , Expert Opin Ther an 4 - 1BB antibody molecule is administered in combination Patents ( 2007 ) 17 ( 5 ) :567 -575 ; Pardee , et al, Immunotherapy with an anti -GITR antibody molecule ( e . g . , an anti -GITR ( 2009 ) 1 ( 2 ) : 249 - 264 ; and Melero , et al. , Clin Cancer Res molecule as described herein ) . The 4 - 1BB antibody mol ( 2009 ) 15 ( 5 ) : 1507 - 1509 , and the references discussed ecule and the anti -GITR antibody molecule may be in the therein . form of separate antibody composition , or as a bispecific [0305 ] The anti- GITR antibodies, antibody fragments , or antibody molecule . In other embodiments , the 4 - 1BB ago antigen binding molecules can also be co -administered with nist can be administered in combination with other costimu a chemotherapeutic agent. The selected agent will depend on latory molecule , e . g . , an agonist of GITR , CD2, CD27 , the condition to be treated , e . g . , a cancer or an infectious CD28 , CDS , ICAM - 1 , LFA - 1 (CD11a /CD18 ), ICOS disease , such as a bacterial infection , a fungal infection , a (CD278 ) , 4 - 1BB (CD137 ) , CD30 , CD40 , BAFFR , HVEM , viral infection or a parasitic infection . The anti -GITR anti CD7, LIGHT, NKG2C , SLAMF7 , NKp80 , CD160 , B7 -H3 , bodies , antibody fragments , or antigen binding molecules or CD83 ligand . can be co - administered with a chemotherapeutic known by [ 0301 ] It is noted that only exemplary combinations of those of skill to treat the disease condition being treated . inhibitors of checkpoint inhibitors or agonists of costimu Exemplary chemotherapeutic agents are discussed above ; latory molecules are provided herein . Additional combina others known in the art also find use . tions of these agents are within the scope of the present invention . Additional Combination Therapies [0302 ] In some embodiments , the anti -GITR antibodies , [0306 ] Combinations disclosed herein , e . g ., combination antibody fragments , or antigen binding molecules are co of PD - 1 antibody molecules , with one or more further administered with a cytotoxic agent. For example , the anti therapeutics are provided herein . Many of the combinations GITR antibodies or antigen binding molecules are co in this section are useful in treating cancer, but other administered with an agonist antibody or antigen binding indications are also described . This section focuses on molecule that binds to and reduces or depletes CD4 +CD25 + combinations of anti -GITR - 1 antibody molecules of the regulatory T cells ( Treg ) . Exemplary Treg cell - depleting invention , optionally in combination with one or more antibodies or antigen binding molecules bind to CD25 or immunomodulators ( e . g . , an anti -PD - 1 antibody molecule , CCR4 . See, Expert Opin Ther Patents ( 2007) 17 ( 5 ) : 567 an anti - TIM - 3 antibody molecule , an anti -LAG - 3 antibody 575 , and the references discussed therein . molecule , or an anti -PD -L1 antibody molecule ) , with one or [0303 ] In some embodiments , the anti- GITR antibodies , more of the agents described in Table 6 . In the combinations antibody fragments , or antigen binding molecules are co herein below , in one embodiment, the anti- GITR antibody administered with an inhibitor of a co - inhibitory signal. molecule includes : an antibody or an antibody fragment, or Exemplary inhibitors include inhibitors of CTLA - 4 , LAG3 , antigen binding molecule thereof that binds to SEQ ID TIM3 and / or inhibitors of the PD - 1 /PD -L1 ( e . g . , B7 -H1 ) NO : 1 , and wherein the antibody , antibody fragment, or interaction . In some embodiments, the anti -GITR antibodies antigen binding molecule comprises are co -administered with an antibody that binds to and inhibits CTLA - 4 . In some embodiments , the anti -GITR [0307 ] ( a ) a heavy chain variable region , wherein : antibodies are co - administered with an antibody that binds [0308 ] i) the heavy chain CDR1 comprises SEQ ID to and inhibits TIM3. In some embodiments , the anti -GITR NO :22 , and antibodies are co - administered with an antibody that binds [ 0309 ] ii) the heavy chain CDR2 comprises a to and inhibits LAG3 . In some embodiments , the anti -GITR sequence selected from any one of SEQ ID NO :23 , antibodies are co - administered with an antibody that binds SEQ ID NO : 24 , SEQ ID NO : 25 , SEQ ID NO : 26 , and to and inhibits PD - 1 . In some embodiments , the anti -GITR SEQ ID NO :27 , and antibodies are co -administered with an antibody that binds [0310 ] ii ) the heavy chain CDR3 comprises SEQ ID to and inhibits B7 -H1 . See , e . g ., Expert Opin Ther Patents NO : 29 or SEQ ID NO :109 ; and (2007 ) 17 ( 5 ) : 567 -575 ; and Melero , et al ., Clin Cancer Res [0311 ] (b ) a light chain variable region , wherein (2009 ) 15 ( 5 ) :1507 - 1509 , and the references discussed [0312 ] i ) the light chain CDR1 comprises SEQ ID therein . NO : 30 or SEQ ID NO :31 , and [0304 ] The anti -GITR antibodies, antibody fragments , or [0313 ] ii ) the light chain CDR2 comprises SEQ ID antigen binding molecules can also be co -administered with NO : 33 , and US 2017 /0306038 A1 Oct. 26 , 2017

[0314 ] iii ) the light chain CDR3 comprises SEQ ID 039549. In one embodiment, a GITR antibody molecule is NO : 34 . used in combination with Sotrastaurin (Compound A1) , or a compound as described in PCT Publication No . WO 2005/ Combination Therapies 039549 , to treat a disorder such as a cancer , a melanoma, a [0315 ] In certain embodiments , any of the combinations non -Hodgkin lymphoma, an inflammatory bowel disease , disclosed herein further includes one or more of the agents transplant rejection , an ophthalmic disorder , or psoriasis . described in Table 6 . [0321 ] In certain embodiments , Sotrastaurin (Compound [ 0316 ] In some embodiments , the additional therapeutic A1 ) is administered at a dose of about 20 to 600 mg, e . g . , agent is chosen from one or more of: 1 ) a protein kinase C about 200 to about 600 mg, about 50 mg to about 450 mg, ( PKC ) inhibitor; 2 ) a heat shock protein 90 (HSP90 ) inhibi about 100 mg to 400 mg, about 150 mg to 350 mg, or about tor; 3 ) an inhibitor of a phosphoinositide 3 -kinase (PI3K ) 200 mg to 300 mg, e . g . , about 50 mg, 100 mg, 150 mg, 200 and / or target of rapamycin (mTOR ) ; 4 ) an inhibitor of mg, 300 mg, 400 mg, 500 mg, or 600 mg. The dosing cytochrome P450 ( e . g . , a CYP17 inhibitor or a 17 alpha schedule can vary from e . g. , every other day to daily , twice Hydroxylase /C17 - 20 Lyase inhibitor ) ; 5 ) an iron chelating or three times a day . agent; 6 ) an aromatase inhibitor; 7 ) an inhibitor of p53 , e . g . , [ 0322 ] In one embodiment , the combination , e . g ., a com an inhibitor of a p53 /Mdm2 interaction ; 8 ) an apoptosis bination comprising an anti -GITR antibody molecule as inducer; 9 ) an angiogenesis inhibitor ; 10 ) an aldosterone provided herein , is used in combination with a BCR - ABL synthase inhibitor; 11 ) a smoothened (SMO ) receptor inhibi- inhibitor, TASIGNA ( Compound A2) , or a compound dis tor; 12 ) a prolactin receptor (PRLR ) inhibitor; 13 ) a Wnt closed in PCT Publication No . WO 2004 /005281 , to treat a signaling inhibitor; 14 ) a CDK4/ 6 inhibitor ; 15 ) a fibroblast disorder , e . g . , a disorder described herein . In one embodi growth factor receptor 2 (FGFR2 )/ fibroblast growth factor ment, the BCR - ABL inhibitor is TASIGNA , or a compound receptor 4 (FGFR4 ) inhibitor; 16 ) an inhibitor of macro disclosed in PCT Publication No. WO 2004 / 005281 . In one phage colony - stimulating factor ( M -CSF ) ; 17 ) an inhibitor embodiment, a GITR antibody molecule is used in combi of one or more of c -KIT , histamine release , Flt3 ( e . g . , nation with TASIGNA (Compound A2 ) , or a compound as FLK2/ STK1 ) or PKC ; 18 ) an inhibitor of one or more of described in PCT Publication No . WO 2004 /005281 , to treat VEGFR - 2 ( e. g ., FLK - 1 /KDR ) , PDGFRbeta , c -KIT or Raf a disorder such as a lymphocytic leukemia , Parkinson ' s kinase C ; 19 ) a somatostatin agonist and /or a growth hor Disease , a neurologic cancer , a melanoma , a digestive ! mone release inhibitor ; 20 ) an anaplastic lymphoma kinase gastrointestinal cancer , a colorectal cancer, a myeloid leu ( ALK ) inhibitor ; 21 ) an insulin - like growth factor 1 receptor kemia , a head and neck cancer, or pulmonary hypertension . ( IGF - 1R ) inhibitor; 22 ) a P -Glycoprotein 1 inhibitor; 23 ) a 10323 ] In one embodiment , the BCR - ABL inhibitor or vascular endothelial growth factor receptor (VEGFR ) TASIGNA is administered at a dose of about 300 mg ( e . g ., inhibitor ; 24 ) a BCR - ABL kinase inhibitor ; 25 ) an FGFR twice daily , e . g ., for newly diagnosed Ph + CML -CP ) , or inhibitor; 26 ) an inhibitor of CYP11B2 ; 27 ) a HDM2 about 400 mg, e . g . , twice daily , e . g . , for resistant or intol inhibitor, e . g . , an inhibitor of the HDM2- p53 interaction ; 28 ) erant Ph + CML -CP and CML - AP ) . BCR - ABL inhibitor or a an inhibitor of a tyrosine kinase ; 29 ) an inhibitor of c -MET ; Compound A2 is administered at a dose of about 300 - 400 30 ) an inhibitor of JAK ; 31 ) an inhibitor of DAC ; 32 ) an mg. inhibitor of 11B - hydroxylase ; 33 ) an inhibitor of IAP ; 34 ) an [0324 ] In another embodiment, the combination , e . g . , a inhibitor of PIM kinase ; 35 ) an inhibitor of Porcupine ; 36 ) combination comprising an anti- GITR antibody molecule as an inhibitor of BRAF , e . g . , BRAF V600E or wild - type provided herein , is used in combination with an HSP90 BRAF ; 37 ) an inhibitor of HER3 ; 38 ) an inhibitor of MEK ; inhibitor, such as 5 - ( 2 , 4 - dihydroxy - 5 - isopropylphenyl) - N or 39 ) an inhibitor of a lipid kinase , e . g ., as described herein ethyl- 4 - ( 4 - (morpholinomethyl )phenyl ) isoxazole - 3 - carbox and in Table 6 . amide ( Compound A3 ) , or a compound disclosed in PCT [ 0317 ] In one embodiment, the additional therapeutic Publication No. WO 2010 / 060937 or WO 2004 / 072051 , to agent is chosen from one or more of: Compound AS, treat a disorder, e . g. , a disorder described herein . In one Compound A17 , Compound A23 , Compound A24 , Com embodiment, the HSP90 inhibitor is 5 - ( 2 , 4 - dihydroxy - 5 pound A27 , Compound A29, Compound A33 , and Com isopropylphenyl) - N - ethyl- 4 - ( 4 - (morpholinomethyl ) phenyl) pound A13. isoxazole -3 - carboxamide (Compound A3) , or a compound [0318 ] In other embodiments , the additional therapeutic disclosed in PCT Publication No . WO 2010 / 060937 or WO agent is chosen from one or more of: Compound A5 , 2004 /072051 . In one embodiment , a GITR antibody mol Compound A8 , Compound A17 , Compound A23 , Com ecule is used in combination with 5 - (2 , 4 - dihydroxy - 5 - iso pound A24 , Compound A29 , and Compound A40 . propylphenyl) - N -ethyl -4 - (4 -(morpholinomethyl ) phenyl ) [0319 ] In other embodiments , the additional therapeutic isoxazole -3 - carboxamide (Compound A3) , or a compound agent is chosen from one or more of: Compound A9 , as described in PCT Publication No . WO 2010 /060937 or Compound A16 , Compound A17 , Compound A21 , Com WO 2004 /072051 , to treat a disorder such as a cancer, a pound A22 , Compound A25 , Compound A28 , Compound multiple myeloma, a non - small cell lung cancer, a lym A48, and Compound 49 . phoma, a gastric cancer , a breast cancer, a digestive /gastro [ 0320 ] In one embodiment, the combination , e . g . , a com intestinal cancer , a pancreatic cancer, a colorectal cancer, a bination comprising an anti -GITR antibody molecule as solid tumor, or a hematopoiesis disorder. described herein , is used in combination with a PKC inhibi 10325 ]. In another embodiment, the combination , e . g ., a tor, Sotrastaurin (Compound A1) , or a compound disclosed combination comprising an anti- GITR antibody molecule as in PCT Publication No . WO 2005 /039549 , to treat a disor described herein , is used in combination with an inhibitor of der, e . g ., a disorder described herein . In one embodiment, PI3K and /or mTOR , Dactolisib (Compound A4 ) or 8 -( 6 the PKC inhibitor is Sotrastaurin (Compound A1) or a Methoxy - pyridin - 3 - yl) - 3 -methyl - 1 - ( 4 - piperazin - 1 - yl - 3 - trif compound disclosed in PCT Publication No . WO 2005 / luoromethyl- phenyl ) - 1 , 3 -dihydro - imidazo [ 4 , 5 - c ] quinolin US 2017 /0306038 A1 Oct. 26 , 2017 49

2 -one (Compound A41 ) , or a compound disclosed in PCT boxamide (Compound A7 ) or a compound disclosed in PCT Publication No . WO 2006 / 122806 , to treat a disorder , e . g ., Publication No. WO 2009/ 141386 to treat a disorder, e . g ., a a disorder described herein . In one embodiment, the PI3K disorder described herein . In one embodiment , the FGFR and / ormTOR inhibitor is Dactolisib (Compound A4) , 8 - ( 6 inhibitor is 8 - ( 2 , 6 - difluoro - 3 , 5 - dimethoxyphenyl) - N - ( 4 Methoxy - pyridin - 3 - yl) - 3 -methyl - 1 - ( 4 -piperazin - 1 - yl- 3 - trif ( ( dimethylamino )methyl ) - 1H - imidazol- 2 - yl) quinoxaline - 5 luoromethyl- phenyl) - 1 , 3 - dihydro - imidazo [ 4 , 5 - c ] quinolin carboxamide (Compound A7 ) or a compound disclosed in a 2 - one (Compound A41) , or a compound disclosed in PCT PCT Publication No . WO 2009 / 141386 . In one embodiment, Publication No. WO 2006 / 122806 . In one embodiment, a the FGFR inhibitor is 8 - (2 , 6 -difluoro - 3, 5 -dimethoxyphe GITR antibody molecule is used in combination with Dac nyl) - N - ( 4 -( (dimethylamino )methyl ) - 1H -imidazol - 2 -yl ) qui tolisib ( Compound A4 ), 8 - ( 6 -Methoxy -pyridin - 3 - yl) - 3 noxaline - 5 - carboxamide ( Compound A7) . In one embodi methyl- 1 - ( 4 - piperazin - 1 - yl- 3 - trifluoromethyl- phenyl) - 1 , 3 ment, a GITR antibody molecule is used in combination dihydro - imidazo [ 4 , 5 - c ] quinolin - 2 - one (Compound A41 ) , or with 8 - ( 2 , 6 - difluoro - 3 , 5 -dimethoxyphenyl ) - N - ( 4 - ( ( dimeth a compound described in PCT Publication No. WO 2006 / ylamino )methyl ) - 1H - imidazol- 2 - yl) quinoxaline -5 - carbox 122806 , to treat a disorder such as a cancer, a prostate amide ( Compound A7) , or a compound disclosed in PCT cancer , a leukemia ( e . g ., lymphocytic leukemia ) , a breast Publication No . WO 2009/ 141386 , to treat a disorder such as cancer, a brain cancer, a bladder cancer, a pancreatic cancer, a cancer characterized by angiogenesis. a renal cancer, a solid tumor, or a liver cancer . [ 0331 ] In one embodiment , the FGFR inhibitor or 8 - ( 2 ,6 [0326 ] In another embodiment, the combination , e. g ., a difluoro - 3 , 5 - dimethoxyphenyl) - N - ( 4 - ( (dimethylamino ) combination comprising an anti -GITR antibody molecule as methyl ) - 1H - imidazol- 2 - yl) quinoxaline - 5 - carboxamide described herein , is used in combination with an FGFR (Compound A7) is administered at a dose of e . g . , from inhibitor, 3 - ( 2 , 6 - dichloro - 3 , 5 - dimethoxyphenyl ) - 1 - ( 6 - ( ( 4 approximately 3 mg to approximately 5 g , more preferably ( 4 - ethylpiperazin - 1 -yl ) phenyl) amino )pyrimidin - 4 - yl) - 1 from approximately 10 mg to approximately 1. 5 g per methylurea (Compound A5 ) or a compound disclosed in person per day, optionally divided into 1 to 3 single doses U . S . Pat. No. 8 , 552 , 002, to treat a disorder , e . g . , a disorder which may , for example, be of the same size . described herein . In one embodiment, the FGFR inhibitor is [0332 ] In another embodiment the combination , e .g ., a 3 - ( 2 ,6 - dichloro - 3 , 5 - dimethoxyphenyl) - 1 - ( 6 - ( ( 4 - ( 4 - ethylpip combination comprising an anti- GITR antibody molecule as erazin - 1 -yl ) phenyl) amino )pyrimidin - 4 -yl ) - 1 -methylurea described herein , is used in combination with a PI3K inhibi (Compound A5 ) or a compound disclosed in U . S . Pat. No. tor, ( S ) - N1- ( 4 -methyl - 5 - ( 2 - ( 1 , 1 , 1 - trifluoro - 2 - methylpro 8 , 552 ,002 . In one embodiment, a GITR antibody molecule pan - 2 - yl) pyridin - 4 -yl ) thiazol- 2 - yl) pyrrolidine - 1 , 2 - dicar is used in combination with Compound A5 , or a compound boxamide (Compound A8 ) or a compound disclosed PCT as described in U . S . Pat . No . 8 , 552 ,002 , to treat a disorder Publication No . WO 2010 /029082 to treat a disorder, e .g ., a such as a digestive/ gastrointestinal cancer, a hematological disorder described herein . In one embodiment, the PI3K cancer, or a solid tumor. inhibitor is ( S ) — N1- ( 4 -methyl - 5 - ( 2 - ( 1 , 1 , 1 - trifluoro - 2 [ 0327 ] In one embodiment, the FGFR inhibitor or 3 - ( 2 , 6 methylpropan - 2 - yl) pyridin - 4 - yl) thiazol- 2 - yl) pyrrolidine - 1 , dichloro -3 , 5 -dimethoxyphenyl ) - 1 -( 6 - ([ 4 -( 4 - ethylpiperazin 2 -dicarboxamide (Compound A8 ) or a compound disclosed 1 - yl) phenyl ) amino )pyrimidin - 4 -yl ) - 1 -methylurea (Com PCT Publication No . WO 2010 /029082 . In one embodiment, pound A5) is administered at a dose of about 100 - 125 mg a GITR antibody molecule is used in combination with ( e. g ., per day ) , e. g ., about 100 mg or about 125 mg. ( S ) - N1- ( 4 - methyl- 5 - ( 2 - ( 1 , 1 , 1 - trifluoro - 2 -methylpropan - 2 [ 0328 ] In another embodiment, the combination , e . g ., a yl) pyridin - 4 - yl) thiazol- 2 -yl ) pyrrolidine - 1 , 2 -dicarboxamide combination comprising an anti- GITR antibody molecule as (Compound A8 ) , or a compound disclosed PCT Publication described herein , is used in combination with a PI3K inhibi No. WO 2010 /029082 , to treat a disorder such as a gastric tor, Buparlisib (Compound A6 ), or a compound disclosed in cancer, a breast cancer, a pancreatic cancer, a digestive / PCT Publication No . WO 2007 /084786 , to treat a disorder , gastrointestinal cancer, a solid tumor, and a head and neck e . g ., a disorder described herein . In one embodiment, the cancer . PI3K inhibitor is Buparlisib (Compound A6 ) or a compound [0333 ] In one embodiment, the PI3K inhibitor or ( S ) disclosed in PCT Publication No. WO 2007 /084786 . In one N1- ( 4 -methyl - 5 - ( 2 - ( 1 , 1 , 1 - trifluoro - 2 -methylpropan - 2 - yl) embodiment, a GITR antibody molecule is used in combi pyridin - 4 - yl) thiazol- 2 - yl ) pyrrolidine - 1, 2 -dicarboxamide nation with Buparlisib (Compound A6 ) , or a compound (Compound A8 ) is administered at a dose of about 150 -300 , disclosed in PCT Publication No. WO 2007 /084786 , to treat 200 - 300 , 200 - 400 , or 300 - 400 mg ( e . g ., per day ) , e . g ., about a disorder such as , a prostate cancer , a non - small cell lung 200 , 300 , or 400 mg. cancer , an endocrine cancer, a leukemia , an ovarian cancer , [0334 ] In another embodiment, the combination , e . g . , a a melanoma, a bladder cancer , a breast cancer, a female combination comprising an anti -GITR antibody molecule as reproductive system cancer, a digestive / gastrointestinal can described herein , is used in combination with an inhibitor of cer, a colorectal cancer, a glioblastoma multiforme, a solid cytochrome P450 ( e . g . , a CYP17 inhibitor ) or a compound tumor, a non -Hodgkin lymphoma , a hematopoiesis disorder, disclosed in PCT Publication No . WO 2010 / 149755 , to treat or a head and neck cancer . a disorder , e . g . , a disorder described herein . In one embodi [ 0329 ] In one embodiment, the PI3K inhibitor or Bupar ment, the cytochrome P450 inhibitor ( e . g ., the CYP17 lisib ( Compound A6 ) is administered at a dose of about 100 inhibitor ) is a compound disclosed in PCT Publication No . mg ( e . g ., per day ) . WO 2010 / 149755. In one embodiment, a GITR antibody [ 0330 ] In another embodiment, the combination , e . g . , a molecule is used in combination with a compound disclosed combination comprising an anti -GITR antibody molecule as in PCT Publication No . WO 2010 / 149755 , to treat prostate described herein , is used in combination with an FGFR cancer. inhibitor, 8 - ( 2 , 6 - difluoro - 3 , 5 - dimethoxyphenyl) -N - ( 4 - ( (di - (0335 ] In another embodiment, the combination , e . g ., a methylamino )methyl ) - 1H - imidazol- 2 - yl) quinoxaline -5 - car combination comprising an anti -GITR antibody molecule as US 2017 /0306038 A1 Oct. 26 , 2017 50 described herein , is used in combination with an HDM2 In one embodiment, the PI3K inhibitor is (4S ,5R )- 3 -( 2 inhibitor, ( S ) - 1 - (4 - chlorophenyl) - 7 - isopropoxy -6 -methoxy amino - 2 -morpholino - 4 ' - ( trifluoromethyl) - [ 4 , 5 -bipyrimi 2 - ( 4 - (methyl ( ( ( 1r, 4S ) - 4 - ( 4 -methyl - 3 -oxopiperazin - 1 -yl ) cy din ) - 6 - yl) - 4 - ( hydroxymethyl) - 5 -methyloxazolidin - 2 -one clohexyl) methyl ) amino ) phenyl) - 1 , 2 - dihydroisoquinolin - 3 (Compound A13 ) or a compound disclosed in PCT Publi (4H ) -one ( Compound A10 ) or a compound disclosed in PCT cation No . WO2013 / 124826 . In one embodiment, a GITR Publication No . WO 2011/ 076786 to treat a disorder , e. g. , a antibody molecule is used in combination with (4S ,5R )- 3 disorder described herein ) . In one embodiment, the HDM2 ( 2 '- amino - 2 -morpholino - 4 '- ( trifluoromethyl) - [ 4 , 5 '- bipyrimi inhibitor is ( S ) - 1 - ( 4 - chlorophenyl) - 7 - isopropoxy - 6 din ) - 6 - yl) - 4 - hydroxymethyl) - 5 -methyloxazolidin - 2 - one methoxy - 2 - ( 4 -( methyl ( ( ( 1r , 4S ) - 4 - ( 4 -methyl - 3 -oxopiper (Compound A13 ), or a compound disclosed in PCT Publi azin - 1 -yl ) cyclohexyl ) methyl ) amino ) phenyl) - 1, 2 -dihy cation No. WO2013 / 124826 , to treat a disorder such as a droisoquinolin - 3 (4H ) -one (Compound A10 ) or a compound cancer or an advanced solid tumor. disclosed in PCT Publication No . WO 2011/ 076786 . In one [0340 ] In another embodiment, the combination , e. g ., a embodiment, a GITR antibody molecule is used in combi combination comprising an anti- GITR antibody molecule as nation with (S ) - 1 -( 4 -chlorophenyl ) - 7 - isopropoxy - 6 described herein , is used in combination with an inhibitor of methoxy - 2 - (4 -( methyl (( ( 1r ,4S ) - 4 - (4 -methyl - 3 - oxopiper p53 and / or a p53 /Mdm2 interaction , ( S ) - 5 - ( 5 - chloro - 1 azin - 1 - yl) cyclohexyl) methyl ) amino )phenyl ) - 1 , 2 methyl- 2 -oxo - 1 , 2 -dihydropyridin - 3 - yl) - 6 - ( 4 -chlorophenyl ) dihydroisoquinolin - 3 ( 4H ) -one (Compound A10 ), or a 2 - ( 2 , 4 - dimethoxypyrimidin - 5 - yl) - 1 - isopropyl- 5 , 6 -dihydro compound disclosed in PCTPublication No . WO 2011 / pyrrolo [ 3 , 4 - d ] imidazol- 4 ( 1H ) - one (Compound A14 ) , or a 076786 , to treat a disorder such as a solid tumor. compound disclosed in PCT Publication No . [0336 ] In one embodiment, the HDM2 inhibitor or (S ) - 1 [0341 ] WO2013 /111105 to treat a disorder , e .g ., a disorder ( 4 - chlorophenyl ) - 7 - isopropoxy - 6 -methoxy - 2 - ( 4 - (methyl described herein . In one embodiment , the p53 and / or a ( ( ( 1r ,4S ) - 4 - ( 4 - methyl- 3 - oxopiperazin - 1 - yl) cyclohexyl) p53 /Mdm2 interaction inhibitor is ( S ) - 5 - ( 5 -chloro - 1 methyl) amino ) phenyl ) - 1 , 2 - dihydroisoquinolin - 3 ( 4H ) - one methyl- 2 -oxo - 1 , 2 - dihydropyridin - 3 - yl) - 6 - ( 4 -chlorophenyl ) ( Compound A10 ) is administered at a dose of about 400 to 2 -( 2 , 4 - dimethoxypyrimidin - 5 - yl) - 1 - isopropyl- 5 , 6 -dihydro 700 mg, e .g ., administered three times weekly , 2 weeks on pyrrolo [ 3 , 4 - dJimidazol- 4 ( 1H ) -one (Compound A14 ) or a and one week off. In some embodiments , the dose is about compound disclosed in PCT Publication No . WO2013 / 400 , 500 , 600 , or 700 mg; about 400 -500 , 500 -600 , or 111105 . In one embodiment, a GITR antibody molecule is 600 - 700 mg, e . g ., administered three times weekly. used in combination with ( S ) -5 - (5 - chloro -1 -methyl -2 - oxo [ 0337 ] In another embodiment, the combination , e .g . , a 1 , 2 - dihydropyridin - 3 - yl ) - 6 - ( 4 -chlorophenyl ) - 2 - ( 2 , 4 -dime combination comprising an anti- GITR antibody molecule as thoxypyrimidin - 5 - yl ) - 1 - isopropyl- 5 ,6 - dihydropyrrolo [ 3 , 4 described herein , is used in combination with an iron chelat dJimidazol- 4 ( 1H ) -one (Compound A14 ) , or a compound ing agent, Deferasirox ( also known as EXJADE; Compound disclosed in PCT Publication No. WO2013 / 111105 , to treat A11 ) , or a compound disclosed in PCT Publication No . WO a disorder such as a cancer or a soft tissue sarcoma . 1997 /049395 to treat a disorder , e . g . , a disorder described [0342 ] In another embodiment, the combination , e . g . , a herein . In one embodiment , the iron chelating agent is combination comprising an anti- GITR antibody molecule as Deferasirox or a compound disclosed in PCT Publication described herein , is used in combination with a CSF - 1R No . WO 1997 / 049395 . In one embodiment, the iron chelat tyrosine kinase inhibitor, 4 - ( ( 2 - ( ( ( 1R , 2R ) - 2 -hydroxycyclo ing agent is Deferasirox (Compound A11 ) . In one embodi hexyl )amino )benzo [d ]thiazol - 6 -yl ) oxy )- N -methylpicolina ment, a GITR antibody molecule is used in combination mide (Compound A15 ) , or a compound disclosed in PCT with Deferasirox (Compound A11 ) , or a compound dis Publication No. WO 2005 / 073224 to treat a disorder , e . g . , a closed in PCT Publication No. WO 1997 /049395 , to treat disorder described herein . In one embodiment, the CSF - 1R iron overload , hemochromatosis , or myelodysplasia . tyrosine kinase inhibitor is 4 - (( 2 - ( ( (1R , 2R ) - 2 - hydroxycyclo [0338 ] In another embodiment, the combination , e. g. , a hexyl) amino )benzo [ d ] thiazol- 6 - yl) oxy ) - N -methylpicolina combination comprising an anti -GITR antibody molecule as mide (Compound A15 ) or a compound disclosed in PCT described herein , is used in combination with an aromatase Publication No. WO 2005 /073224 . In one embodiment, a inhibitor , Letrozole ( also known as FEMARA ; Compound GITR antibody molecule is used in combination with 4 - ( ( 2 A12 ), or a compound disclosed in U . S . Pat . No . 4 , 978 ,672 (( ( 1R 2R )- 2 -hydroxycyclohexyl ) amino )benzo [ d ]thiazol - 6 to treat a disorder, e .g . , a disorder described herein . In one yl) oxy ) - N -methylpicolinamide ( Compound A15 ) or a com embodiment, the aromatase inhibitor is Letrozole (Com pound disclosed in PCT Publication No. WO 2005 / 073224 , pound A12 ) or a compound disclosed in U . S . Pat. No. to treat a disorder such as cancer. 4 , 978 ,672 . In one embodiment, a GITR antibody molecule [ 0343 ] In another embodiment , the combination , e . g ., a is used in combination with Letrozole (Compound A12 ) , or combination comprising an anti -GITR antibody molecule as a compound disclosed in U . S . Pat . No. 4 , 978 ,672 , to treat a described herein , is used in combination with an apoptosis disorder such as a cancer, a leiomyosarcoma , an endome inducer and /or an angiogenesis inhibitor , such as Imatinib trium cancer, a breast cancer, a female reproductive system mesylate ( also known as GLEEVEC ; Compound A16 ) or a cancer, or a hormone deficiency . compound disclosed in PCT Publication No . wO1999 / [ 0339] In another embodiment, the combination , e . g . , a 003854 to treat a disorder, e . g . , a disorder described . In one combination comprising an anti- GITR antibody molecule as embodiment, the apoptosis inducer and /or an angiogenesis described herein , is used in combination with a PI3K inhibi inhibitor is Imatinib mesylate ( Compound A16 ) or a com tor, e . g ., a pan - PI3K inhibitor, (4S ,5R ) - 3 - ( 2 - amino - 2 -mor pound disclosed in PCT Publication No . WO1999 /003854 . pholino - 4 ' -( trifluoromethyl ) - [ 4 ,5 -bipyrimidin )- 6 - yl )- 4 -( hy In one embodiment , a GITR antibody molecule is used in droxymethyl) - 5 -methyloxazolidin - 2 -one (Compound A13 ) combination with Imatinib mesylate (Compound A16 ) , or a or a compound disclosed in PCT Publication No . WO2013 / compound disclosed in PCT Publication No. WO1999 / 124826 to treat a disorder , e .g . , a disorder described herein . 003854, to treat a disorder such as a cancer, a multiple US 2017 /0306038 A1 Oct. 26 , 2017 myeloma, a prostate cancer , a non -small cell lung cancer, a of about 15 - 25 mg, e. g ., twice daily. In some embodiments , lymphoma, a gastric cancer, a melanoma, a breast cancer, a the dose is about 15 , 20 , or 25 mg, or about 15 - 20 or 20 - 25 pancreatic cancer , a digestive / gastrointestinal cancer, a col mg. orectal cancer , a glioblastoma multiforme , a liver cancer , a [0349 ] In another embodiment , the combination , e . g ., a head and neck cancer, asthma, multiple sclerosis , allergy , combination comprising an anti- GITR antibody molecule as Alzheimer ' s dementia , amyotrophic lateral sclerosis , or described herein , is used in combination with a deacetylase rheumatoid arthritis . (DAC ) inhibitor , Panobinostat (Compound A19 ), or a com [0344 ] In certain embodiments , Imatinib mesylate (Com pound disclosed in PCT Publication No . WO 2014 /072493 pound A16 ) is administered at a dose of about 100 to 1000 to treat a disorder, e . g . , a disorder described herein . In one mg, e. g ., about 200 mg to 800 mg , about 300 mg to 700 mg, embodiment, the DAC inhibitor is Panobinostat (Compound or about 400 mg to 600 mg, e . g . , about 200 mg, 300 mg, 400 A19 ) or a compound disclosed in PCT Publication No . WO mg, 500 mg, 600 mg, or 700 mg. The dosing schedule can 2014 /072493 . In one embodiment, a GITR antibody mol vary from e . g ., every other day to daily, twice or three times ecule is used in combination with Panobinostat (Compound a day . In one embodiment, Imatinib mesylate is administered A19 ) , a compound disclosed in PCT Publication No . WO at an oral dose from about 100 mg to 600 mg daily , e .g ., 2014 / 072493, to treat a disorder such as a small cell lung about 100 mg, 200 mg, 260 mg, 300 mg, 400 mg, or 600 mg cancer, a respiratory / thoracic cancer , a prostate cancer , a daily . multiple myeloma, myelodysplastic syndrome, a bone can [ 0345 ] In another embodiment, the combination , e . g . , a cer, a non - small cell lung cancer, an endocrine cancer, a combination comprising an anti -GITR antibody molecule as lymphoma, a neurologic cancer , a leukemia , HIV /AIDS , an described herein , is used in combination with a JAK inhibi immune disorder, transplant rejection , a gastric cancer, a tor, 2 - fluoro - N -methyl - 4 - 07 - (quinolin - 6 -ylmethyl ) imidazo melanoma, a breast cancer , a pancreatic cancer , a colorectal [ 1 , 2 - b ] [ 1 , 2 , 4 ] triazin - 2 - yl) benzamide (Compound A17 ) , or a cancer, a glioblastoma multiforme, a myeloid leukemia , a dihydrochloric salt thereof, or a compound disclosed in PCT hematological cancer, a renal cancer , a non - Hodgkin lym Publication No . WO 2007/ 070514 , to treat a disorder, e .g ., phoma, a head and neck cancer, a hematopoiesis disorders , a disorder described herein . In one embodiment, the JAK inhibitor is 2 -fluoro - N -methyl - 4 -( 7 -( quinolin -6 -ylmethyl ) or a liver cancer . imidazo [ 1 , 2 - b ] [ 1 , 2 , 4 ] triazin - 2 - yl) benzamide ( Compound 50350 ] In one embodiment, the DAC inhibitor or Panobin A17 ) , or a dihydrochloric salt thereof, or a compound ostat (Compound A19 ) is administered at a dose of about 20 disclosed in PCT Publication No. WO 2007/ 070514 . In one mg (e . g . , per day ). embodiment, a GITR antibody molecule is used in combi [0351 ] In another embodiment, the combination , e .g ., a nation with 2 - fluoro - N -methyl - 4 - ( 7 - ( quinolin - 6 - ylmethyl) combination comprising an anti -GITR antibody molecule as imidazo [ 1, 2 -b ][ 1 ,2 , 4 ]triazin -2 -yl ) benzamide ( Compound described herein , is used in combination with an inhibitor of A17 ) , or a dihydrochloric salt thereof, or a compound one or more of cytochrome P450 ( e . g . , 11B2) , aldosterone or disclosed in PCT Publication No . WO 2007 /070514 , to treat angiogenesis , Osilodrostat (Compound A20 ) , or a com a disorder such as colorectal cancer , myeloid leukemia , pound disclosed in PCT Publication No. WO2007 / 024945 to hematological cancer , autoimmune disease , non - Hodgkin treat a disorder, e . g . , a disorder described herein . In one lymphoma, or thrombocythemia . embodiment, the inhibitor of one or more of cytochrome [ 0346 ] In one embodiment , the JAK inhibitor or a P450 ( e. g ., 11B2 ), aldosterone or angiogenesis is Osilo 2 - fluoro - N -methyl - 4 -( 7 -( quinolin -6 - ylmethyl) imidazo [1 , 2 drostat (Compound A20 ) or a compound disclosed in PCT b ] [ 1 , 2 , 4 ]triazin - 2 - yl) benzamide (Compound A17 ), or a Publication No. WO2007 / 024945 . In one embodiment, a dihydrochloric salt thereof is administered at a dose of about GITR antibody molecule is used in combination with Osi 400 -600 mg (e .g . , per day ), e. g ., about 400 , 500 , or 600 mg, lodrostat ( Compound A20 ), or a compound disclosed in PCT or about 400 - 500 or 500 - 600 mg. Publication No . WO2007 /024945 , to treat a disorder such as [ 0347] In another embodiment, the combination , e . g . , a Cushing 's syndrome, hypertension , or heart failure therapy . combination comprising an anti -GITR antibody molecule as [ 0352 ] In another embodiment , the combination , e . g ., a described herein , is used in combination with a JAK inhibi combination comprising an anti -GITR antibody molecule as tor , Ruxolitinib Phosphate ( also known as JAKAFI; Com described herein , is used in combination with a IAP inhibi pound A18 ) or a compound disclosed in PCT Publication tor, ( S ) — N — ( ( S ) - 1 - cyclohexyl - 2 - ( ( S ) - 2 - ( 4 - ( 4 - fluoroben No. WO 2007 / 070514 to treat a disorder , e . g ., a disorder zoyl) thiazol - 2 - yl) pyrrolidin - 1 - yl) - 2 - oxoethyl) - 2 - (methyl described herein . In one embodiment, the JAK inhibitor is amino )propanamide (Compound A21) or a compound Ruxolitinib Phosphate ( Compound A18 ) or a compound disclosed in U . S . Pat. No . 8 ,552 ,003 to treat a disorder, e . g . , disclosed in PCT Publication No. WO 2007 /070514 . In one a disorder described herein . In one embodiment, the IAP embodiment , a GITR antibody molecule is used in combi inhibitor is ( S ) — N — ( S ) - 1 - cyclohexyl- 2 - ( ( S ) - 2 - ( 4 - ( 4 - fluo nation with Ruxolitinib Phosphate ( Compound A18 ) , or a robenzoyl) thiazol - 2 - yl) pyrrolidin - 1 - yl) - 2 - oxoethyl) - 2 compound disclosed in PCT Publication No. WO 2007 / (methylamino )propanamide ( Compound A21) or a com 070514 , to treat a disorder such as a prostate cancer, a pound disclosed in U . S . Pat . No. 8 ,552 ,003 . In one lymphocytic leukemia , a multiple myeloma, a lymphoma, a embodiment, a GITR antibody molecule is used in combi lung cancer, a leukemia , cachexia , a breast cancer, a pan nation with ( S ) — N — ( S ) -1 -cyclohexyl - 2 -( ( S )- 2 - (4 - ( 4 - fluo creatic cancer, rheumatoid arthritis , psoriasis, a colorectal robenzoyl) thiazol- 2 - yl) pyrrolidin - 1 - yl) - 2 - oxoethyl) - 2 cancer, a myeloid leukemia , a hematological cancer, an (methylamino )propanamide (Compound A21 ) , or a autoimmune disease , a non -Hodgkin lymphoma, or throm compound disclosed in U .S . Pat. No . 8 ,552 , 003 , to treat a bocythemia . disorder such as a multiple myeloma , a breast cancer, an [0348 ] In one embodiment, the JAK inhibitor or Ruxoli ovarian cancer, a pancreatic cancer, or a hematopoiesis tinib Phosphate (Compound A18 ) is administered at a dose disorder . US 2017 /0306038 A1 Oct. 26 , 2017

[0353 ] In one embodiment, the IAP inhibitor or (S ) — N — a GITR antibody molecule is used in combination with ( ( S ) - 1 - cyclohexyl- 2 - ( ( S ) - 2 - ( 4 - ( 4 - fluorobenzoyl) thiazol- 2 7 - cyclopentyl- N , N -dimethyl - 2 - ( ( 5 - (piperazin - 1 -yl ) pyridin yl) pyrrolidin - 1 -yl ) - 2 - oxoethyl) - 2 - methylamino ) propana 2 - yl) amino ) - 7H -pyrrolo [ 2 , 3 - d ] pyrimidine -6 - carboxamide mide ( Compound A21 ) or a compound disclosed in U . S . Pat. ( Compound A24 ) , or a compound disclosed in U . S . Pat. No. No . 8 , 552 ,003 is administered at a dose of approximately 8 , 415 , 355 or U . S . Pat. No . 8 ,685 , 980, to treat a disorder such 1800 mg, e . g . , once weekly . as a lymphoma, a neurologic cancer , a melanoma , a breast [0354 ] In another embodiment, the combination , e. g ., a cancer, or a solid tumor. combination comprising an anti- GITR antibody molecule as [0359 ] In one embodiment, the JAK and /or CDK4 /6 described herein , is used in combination a Smoothened inhibitor or 7 -cyclopentyl - N , N -dimethyl - 2 -( (5 - (piperazin - 1 ( SMO ) inhibitor, Sonidegib phosphate ( Compound A22 ) , yl) pyridin - 2 - yl) amino ) -7H - pyrrolo [ 2 , 3 - d ] pyrimidine - 6 -car ( R ) - 2 - ( 5 - ( 4 - ( 6 -benzyl - 4 , 5 -dimethylpyridazin - 3 - yl) - 2 -meth boxamide (Compound A24 ) is administered at a dose of ylpiperazin - 1 - yl) pyrazin - 2 - yl ) propan - 2 - ol (Compound approximately 200 -600 mg, e . g . , per day . In one embodi A25 ), or a compound disclosed in PCT Publication No . WO ment, the compound is administered at a dose of about 200 , 2007 /131201 or WO 2010 /007120 to treat a disorder , e . g . , a 300 , 400 , 500 , or 600 mg, or about 200 - 300 , 300 - 400 , disorder described herein . In one embodiment, the SMO 400 - 500 , or 500 -600 mg . inhibitor is Sonidegib phosphate (Compound A22 ), ( R ) - 2 10360 ]. In another embodiment, the combination , e . g . , a ( 5 - ( 4 - (6 -benzyl - 4 ,5 -dimethylpyridazin - 3 -yl ) - 2 -methylpiper combination comprising an anti -GITR antibody molecule as azin - 1 - yl) pyrazin - 2 -yl ) propan - 2 - ol (Compound A25 ), or a described herein , is used in combination a prolactin receptor compound disclosed in PCT Publication No . WO 2007 / (PRLR ) inhibitor , a human monoclonal antibody molecule 131201 or WO 2010 /007120 . In one embodiment, a GITR (Compound A26 ) as disclosed in U . S . Pat . No . 7 , 867 ,493 ), antibody molecule is used in combination with Sonidegib to treat a disorder, e . g . , a disorder described herein . In one phosphate (Compound A22 ), (R )- 2 -( 5 -( 4 -( 6 -benzyl - 4, 5 -di embodiment , the PRLR inhibitor is a human monoclonal methylpyridazin - 3 -yl ) - 2 -methylpiperazin - 1 -yl ) pyrazin - 2 antibody (Compound A26 ) disclosed in U . S . Pat . No . 7 , 867 , yl) propan - 2 -ol ( Compound A25 ) , or a compound disclosed 493 . In one embodiment, a GITR antibody molecule is used in PCT Publication No . WO 2007 / 131201 or WO 2010 / in combination with human monoclonal antibody molecule 007120 to treat a disorder such as a cancer , a medulloblas (Compound A26 ) described in U . S . Pat . No . 7 , 867, 493 to toma, a small cell lung cancer, a prostate cancer, a basal cell treat a disorder such as, a cancer, a prostate cancer, or a carcinoma , a pancreatic cancer, or an inflammation . breast cancer. [ 0355 ] In certain embodiments, Sonidegib phosphate [0361 ] In another embodiment, the combination , e . g . , a ( Compound A22 ) is administered at a dose of about 20 to combination comprising an anti -GITR antibody molecule as 500 mg, e . g . , about 40 mg to 400 mg, about 50 mg to 300 described herein , is used in combination with a PIM Kinase mg, or about 100 mg to 200 mg, e . g . , about 50 mg, 100 mg, inhibitor, N - ( 4 - ( ( 1R , 35 ,5S ) - 3 -amino - 5 -methylcyclohexyl ) 150 mg, 200 mg, 250 mg, or 300 mg. The dosing schedule pyridin - 3 - yl) - 6 - ( 2 , 6 - difluorophenyl) - 5 - fluoropicolinamide can vary from e . g ., every other day to daily , twice or three (Compound A27 ) or a compound disclosed in PCT Publi times a day . cation No . WO 2010 /026124 to treat a disorder, e . g ., a [ 0356 ] In another embodiment, the combination , e . g . , a disorder described herein . In one embodiment, the PIM combination comprising an anti -GITR antibody molecule as Kinase inhibitor is N -( 4 - ( 1R ,35 , 5S ) - 3 - amino - 5 -methylcy described herein , is used in combination with an Alk inhibi clohexyl) pyridin - 3 - yl) - 6 - ( 2 , 6 - difluorophenyl) - 5 - fluoropico tor, ceritinib (also known as ZYKADIA ; Compound A23 ) or linamide (Compound A27 ) or a compound disclosed in PCT a compound disclosed in PCT Publication No. WO 2007 / Publication No. WO 2010 /026124 . In one embodiment, a 131201 to treat a disorder, e . g . , a disorder described herein . GITR antibody molecule is used in combination with N - ( 4 In one embodiment, the Alk inhibitor is ceritinib (Com ( ( 1R , 3S ,5S ) - 3 - amino - 5 -methylcyclohexyl ) pyridin - 3 - yl ) - 6 pound A23 ) or a compound disclosed in PCT Publication ( 2 , 6 - difluorophenyl ) - 5 - fluoropicolinamide (Compound No. WO 2007 / 131201. In one embodiment, a GITR anti A27 ) , or a compound disclosed in PCT Publication No . WO body molecule is used in combination with ceritinib (Com 2010 /026124 , to treat a disorder such as a multiple pound A23) , or a compound disclosed in PCT Publication myeloma, myelodysplastic syndrome, a myeloid leukemia , No. WO 2007 / 131201, to treat a disorder such as non - small or a non -Hodgkin lymphoma. cell lung cancer or solid tumors . [0362 ]. In another embodiment, the combination , e . g ., a [ 0357] In one embodiment , the Alk inhibitor or ceritinib combination comprising an anti- GITR antibody molecule as (Compound A23 ) is administered at a dose of approximately described herein , is used in combination a Wnt signaling 750 mg, e . g . , once daily . inhibitor , 2 - ( 2 , 3 - dimethyl- [ 2 , 4 ' - bipyridin ) - 5 - yl) - N -( 5 [ 0358 ] In another embodiment , the combination , e . g . , a (pyrazin -2 -yl ) pyridin - 2 -yl ) acetamide (Compound A28 ) or a combination comprising an anti- GITR antibody molecule as compound disclosed in PCT publication No . WO 2010 / described herein , is used in combination with a JAK and/ or 101849 to treat a disorder, e . g . , a disorder described herein . CDK4 /6 inhibitor, 7 -cyclopentyl - N ,N -dimethyl - 2 -( ( 5 - (pip In one embodiment , the Wnt signaling inhibitor is 2 - ( 2 , 3 erazin - 1 - yl) pyridin - 2 -yl ) amino ) -7H -pyrrolo [ 2 , 3 - d ] pyrimi dimethyl- [ 2 , 4 - bipyridin ) - 5 -yl ) - N - ( 5 - ( pyrazin - 2 - yl) pyridin dine - 6 - carboxamide (Compound A24 ) , or a compound dis 2 -yl ) acetamide (Compound A28 ) or a compound disclosed closed in U .S . Pat. No . 8 ,415 ,355 or U . S . Pat. No . 8 ,685 ,980 in PCT publication No . WO 2010 / 101849. In one embodi to treat a disorder, e . g ., a disorder described herein . In one ment , the Wnt signaling inhibitor is 2 -( 2 , 3 -dimethyl - [ 2 , 4 ' embodiment, the JAK and /or CDK4 /6 inhibitor is 7 - cyclo bipyridin )- 5 -yl ) - N -( 5 - (pyrazin - 2 -yl ) pyridin - 2 -yl ) acetamide pentyl - N , N - dimethyl- 2 - ( ( 5 - (piperazin - 1 - yl) pyridin - 2 - yl) (Compound A28 ). In one embodiment , a GITR antibody amino )- 7H -pyrrolo [ 2 ,3 - d] pyrimidine -6 - carboxamide (Com molecule is used in combination with 2 - ( 2 , 3 -dimethyl - [ 2 , pound A24 ) or a compound disclosed in U .S . Pat. No . 4 '- bipyridin ) -5 - yl) - N - ( 5 - (pyrazin - 2 - yl) pyridin - 2 - yl) acet 8 ,415 , 355 or U . S . Pat . No. 8 ,685 , 980 . In one embodiment, amide (Compound A28 ), or a compound disclosed in PCT US 2017 /0306038 A1 Oct. 26 , 2017 53 publication No . WO 2010 /101849 , to treat a disorder such as esophageal cancer , a head and neck cancer, a squamous cell a solid tumor ( e . g . , a head and neck cancer, a squamous cell carcinoma, a stomach cancer, a breast cancer (e .g ., meta carcinoma , a breast cancer , a pancreatic cancer, or a colon static breast cancer ) , or a digestive / gastrointestinal cancer. cancer ). [0368 ] In some embodiments , Compound A31 is a human [0363 ] In certain embodiments , 2 - ( 2 , 3 -dimethyl - [ 2 , 4 '- bi monoclonal antibody molecule . pyridin ) - 5 - yl) - N - ( 5 - (pyrazin - 2 - yl )pyridin - 2 - yl ) acetamide [0369 ] In one embodiment, the HER3 inhibitor or Com ( Compound A28 ) is administered at a dose of about 1 to 50 pound A31 is administered at a dose of about 3 , 10 , 20 , or mg, e . g . , about 2 mg to 45 mg, about 3 mg to 40 mg, about 40 mg/ kg , e . g . , once weekly (QW ) . In one embodiment, the 5 mg to 35 mg, 5 mg to 10 mg, or about 10 mg to 30 mg, compound is administered at a dose of about 3 - 10 , 10 - 20 , or e . g . , about 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg. The 20 - 40 mg/ kg . dosing schedule can vary from e. g ., every other day to daily , [ 0370 ] In another embodiment , the combination , e . g ., a twice or three times a day. combination comprising an anti- GITR antibody molecule as [ 0364 ] In another embodiment , the combination , e . g . , a described herein , is used in combination an FGFR2 and /or combination comprising an anti -GITR antibody molecule as FGFR4 inhibitor, Compound A32 , or a compound disclosed described herein , is used in combination with a BRAF in a publication PCT Publication No . WO 2014 / 160160 inhibitor, Encorafenib (Compound A29 ) , or a compound ( e . g . , an antibody molecule drug conjugate against an disclosed in PCT Publication No . WO 2011/ 025927 to treat FGFR2 and / or FGFR4 , e . g . ,mAb 12425 ) , to treat a disorder , a disorder , e. g ., a disorder described herein . In one embodi e . g ., a disorder described herein . In one embodiment, the ment, the BRAF inhibitor is Encorafenib (Compound A29 ) FGFR2 and /or FGFR4 inhibitor is Compound A32 or a or a compound disclosed in PCT Publication No . WO compound disclosed in a publication PCT Publication No . 2011/ 025927 . In one embodiment, a GITR antibody mol WO 2014 / 160160 . In one embodiment, a GITR antibody ecule is used in combination with Encorafenib ( Compound molecule is used in combination with Compound A32 , or a A29 ), or a compound disclosed in PCT Publication No . WO compound as described in Table 6 , to treat a disorder such 2011 /025927 , to treat a disorder such as a non - small cell as a cancer, a gastric cancer , a breast cancer, a rhabdomyo lung cancer, a melanoma , or a colorectal cancer. sarcoma , a liver cancer, an adrenal cancer, a lung cancer , an [0365 ] In one embodiment, the BRAF inhibitor or esophageal cancer , a colon cancer , or an endometrial cancer . Encorafenib (Compound A29 ) is administered at a dose of 0371 ] In some embodiments , Compound A32 is an anti about 200 - 300 , 200 - 400 , or 300 - 400 mg, e . g . , per day. In one body molecule drug conjugate against an FGFR2 and /or embodiment, the compound is administered at a dose of FGFR4, e . g ., mAb 12425 . about 200 , about 300 or about 400 mg . [0372 ] In another embodiment , the combination , e .g ., a [ 0366 ] In another embodiment, the combination , e . g . , a combination comprising an anti -GITR antibody molecule as combination comprising an anti -GITR antibody molecule as described herein , is used in combination an M -CSF inhibi described herein , is used in combination a CDK4/ 6 inhibitor, tor, Compound A33 , or a compound disclosed in PCT 7 - cyclopentyl- N , N -dimethyl - 2 - ( ( 5 - ( ( 1R ,6S ) - 9 -methyl - 4 Publication No . WO 2004 / 045532 ( e . g . , an antibody mol oxo - 3 , 9 - diazabicyclo [ 4 . 2 . 1 ] nonan - 3 - yl) pyridin - 2 -yl ) ecule or Fab fragment against M -CSF ) , to treat a disorder, amino ) - 7H - pyrrolo [ 2 , 3 - d ] pyrimidine - 6 - carboxamide (Com e . g . , a disorder described herein . pound A30 ), or a compound disclosed in PCT publication [0373 ] In one embodiment, the M - CSF inhibitor is Com No . WO 2011 / 101409 to treat a disorder, e . g . , a disorder pound A33 or a compound disclosed in PCT Publication No . described herein . In one embodiment, the CDK4 /6 inhibitor WO 2004 / 045532 . In one embodiment, a GITR antibody is 7 - cyclopentyl- N , N - dimethyl- 2 - ( (5 - ( ( 1R ,6S ) - 9 -methyl - 4 molecule is used in combination with Compound A33 , or a oxo - 3 , 9 -diazabicyclo [ 4 . 2 . 1 ]nonan - 3 -yl ) pyridin - 2 - yl) compound as described in PCT Publication No. WO 2004 / amino )- 7H - pyrrolo [ 2, 3 -d ]pyrimidine -6 -carboxamide (Com 045532 , to treat a disorder such as a cancer, a prostate pound A30 ) or a compound disclosed in PCT publication cancer, a breast cancer, or pigmented villonodular synovitis No. WO 2011 / 101409 . In one embodiment , a GITR anti (PVNS ). body molecule is used in combination with 7 -cyclopentyl [0374 ] In embodiments , Compound A33 is a monoclonal N ,N - dimethyl -2 - (( 5 -( ( 1R ,6S ) -9 -methyl - 4 - oxo -3 ,9 - diazabi antibody molecule against M - CSF or a fragment ( e . g . , Fab cyclo [ 4 . 2 . 1 ]nonan - 3 - yl) pyridin - 2 - yl) amino ) - 7H -pyrrolo [ 2 , fragment) thereof. In embodiments , the M - CSF inhibitor or 3 - d ]pyrimidine - 6 - carboxamide (Compound A30 ) , or a Compound A33 is administered at an average dose of about compound disclosed in PCT publication No . WO 2011 / 10 mg/kg . 101409 , to treat a disorder such as a cancer, a mantle cell [0375 ] In another embodiment, the combination , e . g . , a lymphoma, a liposarcoma, a non -small cell lung cancer, a combination comprising an anti- GITR antibody molecule as melanoma, a squamous cell esophageal cancer, or a breast described herein , is used in combination with a MEK cancer . inhibitor, Binimetinib ( Compound A34 ) , or a compound 103671. In another embodiment, the combination , e . g ., a disclosed in PCT Publication No . WO 2003 /077914 to treat combination comprising an anti -GITR antibody molecule as a disorder , e. g ., a disorder described herein . In one embodi described herein , is used in combination with a HER3 ment, the MEK inhibitor is Binimetinib (Compound A34 ) , inhibitor, Compound A31, or a compound disclosed in PCT or a compound disclosed in PCT Publication No . WO Publication No . WO 2012 /022814 , to treat a disorder, e . g ., 2003 /077914 . In one embodiment, a GITR antibody mol a disorder described herein . In one embodiment, the HER3 ecule is used in combination with Binimetinib (Compound inhibitor is Compound A31 or a compound disclosed in PCT A34 ) , or a compound disclosed in PCT Publication No . WO Publication WO 2012 /022814 . In one embodiment, a GITR 2003 /077914 , to treat a disorder such as a non - small cell antibody molecule is used in combination with Compound lung cancer , a multisystem genetic disorder, a melanoma, an A31 , or a compound disclosed in PCT Publication WO ovarian cancer, a digestive / gastrointestinal cancer , a rheu 2012 / 022814 , to treat a disorder such as a gastric cancer, an matoid arthritis , or a colorectal cancer . US 2017 /0306038 A1 Oct. 26 , 2017 54

[0376 ] In one embodiment, the MEK inhibitor or Binim 2 - amine (Compound A37 ) , or a compound disclosed in PCT etinib (Compound A34 ) is administered at a dose of about 45 Publication No . WO 2007 /030377 , to treat a disorder such as mg, e . g . , twice daily. a cancer, a melanoma, or a solid tumor. [0377 ] In another embodiment, the combination , e. g. , a [0381 ] In another embodiment, the combination , e .g ., a combination comprising an anti- GITR antibody molecule as combination comprising an anti- GITR antibody molecule as described herein , is used in combination an inhibitor of one described herein , is used in combination a somatostatin or more of C - KIT, histamine release , Fit3 ( e . g . , FLK2/ STK1 ) agonist and / or growth hormone release inhibitor, Pasireotide or PKC , Midostaurin (Compound A35 ) or a compound diaspartate ( also known as SIGNIFOR ; Compound A38 ) or disclosed in PCT Publication No . WO 2003 /037347 to treat a compound disclosed in PCT Publication No . WO2002/ a disorder , e . g. , a disorder described herein . In one embodi- 010192 or U . S . Pat. No. 7 , 473 , 761 to treat a disorder , e . g . , ment, the inhibitor is Midostaurin (Compound A35 ) or a disorder described herein . In one embodiment, the soma compound disclosed in PCT Publication No . WO 2003 / tostatin agonist and / or growth hormone release inhibitor is 037347 . In one embodiment, the inhibitor of one or more of Pasireotide diaspartate ( Compound A38 ) or a compound C -KIT , histamine release , Fit3 ( e . g ., FLK2/ STK1 ) or PKC is disclosed in PCT Publication No. WO2002 /010192 or U . S . Midostaurin . In one embodiment, a GITR antibody molecule Pat. No . 7 , 473 , 761 . In one embodiment , a GITR antibody is used in combination with Midostaurin (Compound A35 ) , molecule is used in combination with Pasireotide diaspartate or compound disclosed in PCT Publication No . WO 2003 / (Compound A38 ), or a compound disclosed in PCT Publi 037347 , to treat a disorder such as a cancer , a colorectal cation No . WO2002/ 010192 or U . S . Pat. No . 7 , 473 , 761, to cancer, a myeloid leukemia , myelodysplastic syndrome, an treat a disorder such as a prostate cancer , an endocrine age -related mascular degeration , a diabetic complication , or cancer, a nurologic cancer, a skin cancer ( e . g . , a melanoma ) , a dermatologic disorder . a pancreatic cancer, a liver cancer, Cushing' s syndrome, a [ 0378 ] In another embodiment, the combination , e . g . , a gastrointestinal disorder, acromegaly , a liver and biliary tract combination comprising an anti -GITR antibody molecule as disorder, or liver cirrhosis . described herein , is used in combination with a TOR inhibi [0382 ] In another embodiment , the combination , e .g ., a tor ( e . g ., mTOR inhibitor ), Everolimus (also known as combination comprising an anti -GITR antibody molecule as AFINITOR ; Compound A36 ) or a Compound disclosed in described herein , is used in combination a signal transduc PCT Publication No. WO 2014 /085318 to treat a disorder, tion modulator and / or angiogenesis inhibitor, Dovitinib e . g . , a disorder described herein ) . In one embodiment, the ( Compound A39 ) or a compound disclosed in PCT Publi TOR inhibitor is Everolimus ( Compound A36 ) or a Com cation No. WO 2009/ 115562 to treat a disorder , e . g . , a pound disclosed in PCT Publication No . WO 2014 /085318 . disorder described herein . In one embodiment , the signal In one embodiment, a GITR antibody molecule is used in transduction modulator and / or angiogenesis inhibitor is combination with Everolimus (Compound A36 ) to treat a Dovitinib (Compound A39 ) or a compound disclosed in disorder such as an interstitial lung disease , a small cell lung PCT Publication No . WO 2009 / 115562 . In one embodiment , cancer , a respiratory /thoracic cancer , a prostate cancer , a a GITR antibody molecule is used in combination with multiple myeloma, a sarcoma, an age -related macular Dovitinib ( Compound A39 ) , or a compound disclosed in degeneration , a bone cancer, tuberous sclerosis , a non -small PCT Publication No. WO 2009 / 115562 , to treat a disorder cell lung cancer , an endocrine cancer , a lymphoma, a neu such as a cancer , a respiratory / thoracic cancer, a multiple rologic disorders, an astrocytoma, a cervical cancer, a neu myeloma, a prostate cancer, a non - small cell lung cancer , an rologic cancer, a leukemia , an immune disorders, transplant endocrine cancer, or a neurological genetic disorder. rejection , a gastric cancer, a melanoma, epilepsy , a breast 10383 ]. In another embodiment, the combination , e . g ., a cancer , or a bladder cancer. combination comprising an anti -GITR antibody molecule as [0379 ] In one embodiment, the TOR inhibitor or Everoli described herein , is used in combination with an EGFR musis (Compound A36 ) administered at a dose of about inhibitor , ( R , E ) - N - ( 7 - chloro - 1 - ( 1 - ( 4 - ( dimethylamino )but - 2 2 .5 - 20 mg/ day . In one embodiment, the compound is admin enoyl) azepan - 3 -yl ) - 1H -benzo [ d ] imidazol- 2 - yl) - 2 -methyl istered at a dose of about 2 . 5 , 5 , 10 , or 20 mg/ day , e .g ., about isonicotinamide (Compound A40 ) or a compound disclosed 2 .5 -5 , 5 - 10 , or 10 -20 mg/ day . in PCT Publication No . WO 2013 / 184757 to treat a disorder, [ 0380 ] In another embodiment, the combination , e . g . , a e . g ., a disorder described herein . In one embodiment, the combination comprising an anti -GITR antibody molecule as EGFR inhibitor is ( R , E ) - N - ( 7 - chloro - 1 - ( 1 - ( 4 - ( dimethyl described herein , is used in combination an inhibitor of one amino ) but- 2 -enoyl ) azepan - 3 - yl) - 1H -benzo [ d ] imidazol- 2 or more of VEGFR - 2 , PDGFRbeta , KIT or Raf kinase C , yl) - 2 -methylisonicotinamide (Compound A40 ) or a com 1 -methyl - 5 - ( ( 2 - ( 5 - ( trifluoromethyl) - 1H - imidazol- 2 - yl) pyri pound disclosed in PCT Publication No . WO 2013 / 184757 . din - 4 - yl) oxy ) - N - ( 4 - ( trifluoromethyl) phenyl ) - 1H -benzo [ d ] In one embodiment, a GITR antibody molecule is used in imidazol- 2 - amine (Compound A37 ) or a compound dis combination with (R , E ) -N -( 7 -chloro - 1 -( 1- (4 - ( dimethyl closed in PCT Publication No. WO 2007 /030377 to treat a amino )but - 2 - enoyl) azepan - 3 - yl) - 1H - benzo [ d ] imidazol- 2 disorder, e . g ., a disorder described herein . In one embodi yl) - 2 -methylisonicotinamide (Compound A40 ) , or a com ment, the inhibitor of one or more of VEGFR - 2 , PDG pound disclosed in PCT Publication No . WO 2013 / 184757 , FRbeta , KIT or Raf kinase C is 1 -methyl - 5 - (( 2 - (5 - ( trifluo to treat a disorder such as a cancer , e. g. , a solid tumor . romethyl) - 1H - imidazol- 2 - yl) pyridin - 4 -yl ) oxy ) - N - ( 4 [0384 ] In one embodiment, the EGFR inhibitor or (R , E ) ( trifluoromethyl) phenyl) - 1H -benzo [djimidazol - 2 - amine N - ( 7 - chloro - 1 - ( 1 - ( 4 - ( dimethylamino )but - 2 - enoyl )azepan - 3 ( Compound A37 ) or a compound disclosed in PCT Publi yl) -1H -benzo [d ] imidazol- 2 -yl ) -2 -methylisonicotinamide cation No. WO 2007/ 030377 . In one embodiment, a GITR (Compound A40 ) is administered at a dose of 150 - 250 mg, antibody molecule is used in combination with 1 -methyl - 5 e .g . , per day. In one embodiment, the compound is admin ( ( 2 - ( 5 - ( trifluoromethyl ) - 1H - imidazol- 2 - yl) pyridin - 4 -yl ) istered at a dose of about 150 , 200 , or 250 mg, or about oxy )- N -( 4 - (trifluoromethyl ) phenyl ) - 1H -benzo [ d ]imidazol 150 - 200 or 200 - 250 mg. US 2017 /0306038 A1 Oct. 26 , 2017 55

[0385 ] In another embodiment, the combination , e . g . , a embodiment, a GITR antibody molecule is used in combi combination comprising an anti -GITR antibody molecule as nation with Valspodar (Compound A46 ) , or a compound described herein , is used in combination an ALK inhibitor, disclosed in EP 296122 , to treat a disorder such as a cancer N - ( 2 - isopropoxy - 5 -methyl - 4 - ( 1- methylpiperidin - 4 - yl) phe or a drug- resistant tumor. nyl) - N * - ( 2 - ( isopropylsulfonyl) phenyl) - 1H -pyrazolo [ 3 , 4 - d ] [0388 ] In another embodiment , the combination , e .g ., a pyrimidine- 4, 6 -diamine (Compound A42 ) or a compound combination comprising an anti -GITR antibody molecule as disclosed in PCT Publication No . WO 2008 / 073687 to treat described herein , is used in combination one or more of a a disorder, e . g . , a disorder described herein . In one embodi VEGFR inhibitor, Vatalanib succinate ( Compound A47 ) or ment, the ALK inhibitor is N -( 2 - isopropoxy - 5 -methyl - 4 a compound disclosed in EP 296122 to treat a disorder, e . g . , ( 1 -methylpiperidin - 4 - yl) phenyl) - N + - ( 2 - ( isopropylsulfonyl) a disorder described herein . In one embodiment, the VEGFR phenyl) - 1H - pyrazolo [ 3 , 4 - d ]pyrimidine - 4 , 6 - diamine inhibitor is Vatalanib succinate ( Compound A47 ) or a com ( Compound A42 ) or a compound disclosed in PCT Publi pound disclosed in EP 296122 . In one embodiment, a GITR cation No . WO 2008 /073687 . In one embodiment, a GITR antibody molecule is used in combination with Vatalanib antibody molecule is used in combination with Nº - ( 2 succinate (Compound A47 ) , or a compound disclosed in EP isopropoxy - 5 -methyl - 4 - ( 1 -methylpiperidin - 4 - yl) phenyl) 296122 , to treat cancer. N4 - (2 -( isopropylsulfonyl) phenyl) -1H -pyrazolo [3 , 4 - d ]py [ 0389 ] In another embodiment , the combination , e . g ., a rimidine -4 , 6 - diamine (Compound A42 ), or a compound combination comprising an anti -GITR antibody molecule as disclosed in PCT Publication No. WO 2008 /073687 , to treat described herein , is used in combination with an IDH a disorder such as a cancer, an anaplastic large - cell lym inhibitor or a compound disclosed in WO2014 / 141104 to phoma (ALCL ), a non - small cell lung carcinoma (NSCLC ), treat a disorder, e . g ., a disorder described herein . In one or a neuroblastoma. embodiment, the IDH inhibitor is a compound disclosed in [0386 ] In another embodiment, the combination , e .g ., a PCT Publication No. combination comprising an anti -GITR antibody molecule as described herein , is used in combination an IGF - 1R inhibi [0390 ] WO2014/ 141104. In one embodiment, a GITR tor, 3 - ( 4 - ( 4 - ( ( 5 - chloro - 4 -( (5 -methyl - 1H -pyrazol - 3 - yl) antibody molecule is used in combination with a compound amino )pyrimidin - 2 - yl) amino ) - 5 - fluoro - 2 -methylphenyl ) pi disclosed in WO2014 /141104 to treat a disorder such as a peridin - 1 - yl) thietane 1 , 1 - dioxide (Compound A43 ) , cancer. 5 - chloro -N2 - ( 2 - fluoro - 5 -methyl - 4 - ( 1 - ( tetrahydro - 2H -pyran [0391 ] In another embodiment, the combination , e . g ., a 4 -yl ) piperidin -4 -yl ) phenyl) - N4 -( 5 -methyl - 1H -pyrazol - 3 -yl ) combination comprising an anti -GITR antibody molecule as pyrimidine -2 , 4 -diamine (Compound A44 ), or 5 -chloro -N2 described herein , is used in combination with a BCL -ABL (4 -( 1 -ethylpiperidin - 4 -yl ) - 2 - fluoro - 5 -methylphenyl ) -N4 - ( 5 inhibitor or a compound disclosed in PCT Publication No . methyl- 1H - pyrazol- 3 - yl) pyrimidine -2 , 4 -diamine WO2013 / 171639 , WO2013 / 171640 , WO2013 / 171641 , or (Compound A45 ) or a compound disclosed in PCT Publi WO2013 / 171642 to treat a disorder , e . g ., a disorder cation No . WO 2010 / 002655 to treat a disorder , e . g ., a described herein . In one embodiment, the BCL -ABL inhibi disorder described . In one embodiment, the IGF - 1R inhibi tor is a compound disclosed in PCT Publication No . tor is 3 - ( 4 - ( 4 - ( ( 5 - chloro - 4 - ( ( 5 -methyl - 1H -pyrazol - 3 - yl) WO2013 / 171639 , WO2013 / 171640 , WO2013 / 171641, or amino ) pyrimidin - 2 - yl) amino ) - 5 - fluoro - 2 -methylphenyl ) pi WO2013 / 171642 . In one embodiment, a GITR antibody peridin -1 -yl ) thietane 1 ,1 -dioxide (Compound A43 ), molecule is used in combination with a compound disclosed 5 - chloro -N2 -( 2 - fluoro - 5 -methyl - 4 -( 1 -( tetrahydro - 2H -pyran in PCT Publication No. WO2013 / 171639 , WO2013 / 171640 , 4 -yl ) piperidin - 4 -yl ) phenyl ) - N4 - ( 5 -methyl - 1H -pyrazol - 3 -yl ) WO2013 / 171641, or WO2013 / 171642 to treat a disorder pyrimidine- 2 , 4 - diamine ( Compound A44 ) , 5 - chloro - N2- ( 4 such as a cancer. ( 1 - ethylpiperidin -4 -yl ) -2 - fluoro -5 -methylphenyl ) - N4- ( 5 [0392 ] In another embodiment, the combination , e .g . , a methyl- 1H -pyrazol - 3 -yl ) pyrimidine - 2 , 4 -diamine combination comprising an anti- GITR antibody molecule as ( Compound A45 ), or a compound disclosed in PCT Publi described herein , is used in combination with a c -RAF cation No . WO 2010 / 002655 . In one embodiment, a GITR inhibitor or a compound disclosed in PCT Publication No . antibody molecule is used in combination with 3 - ( 4 - ( 4 - ( ( 5 WO2014 / 151616 to treat a disorder , e . g ., a disorder chloro -4 -( (5 -methyl - 1H -pyrazol - 3 - yl) amino )pyrimidin - 2 described herein . In one embodiment, the c -RAF inhibitor is yl) amino ) - 5 - fluoro - 2 -methylphenyl )piperidin - 1 -yl ) thietane Compound A50 or a compound disclosed in PCT Publica 1 , 1 -dioxide ( Compound A43 ) , 5 - chloro -N² - ( 2 - fluoro - 5 tion No . WO2014 / 151616 . In one embodiment, a GITR methyl- 4 -( 1 -( tetrahydro - 2H -pyran - 4 -yl ) piperidin - 4 -yl ) phe antibody molecule is used in combination with a compound nyl ) -N4 - ( 5 -methyl - 1H - pyrazol- 3 - yl) pyrimidine - 2 , 4 - di disclosed in PCT Publication No . WO2014 / 151616 to treat amine ( Compound A44 ), 5 - chloro -N2 - (4 -( 1 - ethylpiperidin a disorder such as a cancer. 4 - yl) - 2 - fluoro - 5 -methylphenyl ) -N4 - ( 5 -methyl - 1H -pyrazol [0393 ] In another embodiment , the combination , e .g ., a 3 -yl ) pyrimidine - 2 , 4 - diamine (Compound A45 ) , or a combination comprising an anti -GITR antibody molecule as compound disclosed in PCT Publication No. WO 2010 / described herein , is used in combination with an ERK1/ 2 002655 , to treat a disorder such as a cancer or a sarcoma. ATP competitive inhibitor or a compound disclosed in [0387 ] In another embodiment, the combination , e . g . , a International Patent Application No . PCT/ US2014 / 062913 combination comprising an anti- GITR antibody molecule as to treat a disorder, e . g . , a disorder described herein . In one described herein , is used in combination a P -Glycoprotein 1 embodiment, the ERK1/ 2 ATP competitive inhibitor is a inhibitor, Valspodar (also known as AMDRAY ; Compound compound disclosed in PCT Publication No . WO2015/ A46 ) or a compound disclosed in EP 296122 to treat a 066188 . In one embodiment , a GITR antibody molecule is disorder, e . g ., a disorder described herein . In one embodi- used in combination with Compound A51 or a compound ment, the P -Glycoprotein 1 inhibitor is Valspodar (Com - disclosed in PCT Publication No . WO2015 /066188 to treat pound A46 ) or a compound disclosed in EP 296122 . In one a disorder such as a cancer. US 2017 /0306038 A1 Oct. 26 , 2017 56

[ 0394 ] In some embodiments , the combination , e . g ., a Compound A16 ( or compound related to Compound A16 ) is combination comprising an anti -GITR antibody molecule as administered at a dose of approximately 400 -600 mg PO described herein , is administerd in combination with one or qDay . In some embodiments , the Compound A29 (or com more agents selected from , Compound A8 , Compound A17 , pound related to Compound A29) is administered at a dose Compound A23 , Compound A24 , Compound A27 , Com of approximately 200 - 400 or 300 - 400 mg. In some embodi pound A29, and Compound A33 . ments, the Compound A24 (or compound related to Com [0395 ] In some embodiments , the combination , e. g. , a pound A24 ) is administered at a dose of approximately combination comprising an anti -GITR antibody molecule as 200 -600 mg. In some embodiments , the Compound A23 described herein , is administered in combination with an ( ceritinib ) ( or compound related to ceritinib ) is administered anti- cancer agent having a known activity in an immune cell at a dose of approximately 750 mg once daily. In some assay, e. g. , in one or more of a huMLR assay, a T cell embodiments , the Compound A8 ( or compound related to proliferation assay, and a B -cell proliferation assay. Exem Compound A8 ) is administered at a dose of approximately plary assays are described below . Based on the assay, an 200 -400 or 300 -400 mg. In some embodiments , the Com IC50 for can be calculated for each test agent. In embodi pound A5 (or compound related to Compound A5 ) is admin ments , the anti -cancer agent has an IC50 of, e .g ., 0 -1 uM , istered at a dose of approximately 100 - 125 mg . In some 1 - 4 uM , or greater than 4 uM , e . g ., 4 - 10 uM or 4 -20 uM . In embodiments , the Compound A6 ( or compound related to embodiments , the second therapeutic agent is chosen from Compound A6 ) is administered at a dose of about 100 mg. one or more of: Compound A9, Compound A16 , Compound In some embodiments , the Compound A1 ( or compound A17 , Compound A21, Compound A22 , Compound A25 , related to Compound Al) is administered at a dose of Compound A28, Compound A48 , and Compound 49 . approximately 200 - 300 or 200 -600 mg. In some embodi [ 0396 ] In some embodiments , the Compound A28 ( or a ments , the Compound A40 (or compound related to Com compound related to Compound A28 ) is administered at a pound A40 ) is administered at a dose of approximately dose of approximately 5 - 10 or 10 - 30 mg. In some embodi 150 -250 mg. In embodiments , the Compound A10 (or ments, the Compound A22 (or compound related to Com compound related to Compound A10 ) is administered at a pound A22 ) is administered at a dose of about 200 mg. In dose of approximately 400 to 700 mg, e . g ., administered some embodiments , the Compound A17 ( or compound three times weekly , 2 weeks on and one week off . In related to Compound A17 ) is administered at a dose of embodiments , the BCR - ABL inhibitor is administered at a approximately 400 -600 mg. In some embodiments , the dose of approximately 20 mg bid -80 mg bid .

TABLE 6 Selected therapeutic agents that can be administered in combination with the anti- GITR antibody molecules provided herein , e . g ., as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of : an activator of a costimulatory molecule and /or an inhibitor of an immune checkpoint molecule ) . Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein .

Patents / Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A1 Sotrastaurin EP 1682103 US 2007 / 142401 WO 2005 / 039549

CH3 US 2017 /0306038 A1 Oct. 26 , 2017 57

TABLE 6 - continued

Selected therapeutic agents that can be administered in combination with the anti- GITR antibody molecules provided herein , e . g . , as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and /or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein .

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A2 Nilotinib HCI CH3 WO 2004 / 005281 monohydrate U . S . Pat. No . TASIGNA? 7 , 169 , 791

N F H C

HCl•H20

A3 H3C WO 2010 /060937 LCH3 WO 2004 / 072051 ?? EP 1611112 U . S . Pat . No . 8 ,450 , 310

A4A4 Dactolisib WO 2006 / 122806 =

CH3 US 2017 /0306038 A1 Oct. 26 , 2017 58

TABLE 6 - continued

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A5 0 - CH3 U . S . Pat . No . 8 ,552 , 002 H?? c ” NHNHI ŽZZö N – CH

CH ;

A6 Buparlisib WO 2007 /084786

H2N N US 2017 /0306038 A1 Oct. 26 , 2017 59

TABLE 6 - continued

Patents/ Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A7 CH3 WO 2009 /141386 US 2010 /0105667

HzC - N CH3

A8 H2C . N WO 2010 /029082

0 NH2

CH3 HzC

A9 CYP17 inhibitor WO 2010 / 149755 U . S . Pat. No. 8 ,263 , 635 B2 EP 2445903 B1 US 2017 /0306038 A1 Oct. 26 , 2017 60

TABLE 6 - continued Selected therapeutic agents that can be administered in combination with the anti -GITR antibody molecules provided herein , e . g . , as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and / or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein . Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A10 WO 2011 /076786

1111117 CH3

H3C CH3 CH3

A11 Deferasirox WO 1997 /049395 EXJADE ® i HO

A12 Letrozole U . S . Pat. No . FEMARA ® 4 , 978 ,672

NE A13 WO 2013 / 124826 US 2013 /0225574

F FLF - OH

CH3 HN US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 6 - continued

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A14 CH3 WO 2013 /111105 CIACHN

H3C

H3C O - CH3

H3C

A15 CH3 WO 2005 /073224 HN

NH IH US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 6 - continued Selected therapeutic agents that can be administered in combination with the anti- GITR antibody molecules provided herein , e. g ., as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and /or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein .

Patents / Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A16 Imatinib WO 1999 / 003854 mesylate GLEEVEC ®

CH3

Mesylate

A17 H C EP 2099447 U . S . Pat . No . NH 7 ,767 , 675 U . S . Pat . No . 8 ,420 ,645

Dihydrochloric salt US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 6 - continued Selected therapeutic agents that can be administered in combination with the anti- GITR antibody molecules provided herein , e . g . , as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and/ or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein .

Patents / Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A18 Ruxolitinib WO 2007 /070514 Phosphate EP 2474545 JAKAFI? U . S . Pat. No . 7 ,598 ,257 WO 2014 /018632

N - N

H3PO4 A19 Panobinostat WO 2014 /072493 WO 2002 /022577 OH EP 1870399 NH

???HN CH3 P A20 Osilodrostat WO 2007 /024945

A21 WO 2008 /016893 EP 2051990 U . S . Pat. No . 8 , 546 ,336

- NH N111

HN - O US 2017 / 0306038 A1 Oct . 26, 2017 64

TABLE 6 -continued Selected therapeutic agents that can be administered in combination with the anti -GITR antibody molecules provided herein , e . g . , as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and / or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein .

Patents / Patent Compound Generic Name Application Designation Tradename Compound Structure Publications Sonidegib A22 | WO 2007/ 131201 phosphate EP 2021328 U . S . Pat. No.

| 8 , 178 , 563

CH : 0 H H3C H

A23 ceritinib WO 2008 /073687 7YKADIAR NH U . S . Pat. No . 8 ,039 ,479

0 = S = 0

A24 U . S . Pat . No. 8 ,415 ,355 8 , 685 ,980 HN N – CH , CH , US 2017 /0306038 A1 Oct. 26 , 2017 65

TABLE 6 - continued

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A25 CH3 WO 2010 /007120 H3COH

H3C

ZEZ

Human monoclonal antibody to PRLR U . S . Pat . No . 7 , 867, 493

WO 2010 /026124 EP 2344474 US 2010 / 0056576 HN CH3 WO2008 / 106692

I US 2017 /0306038 A1 Oct. 26 , 2017 66

TABLE 6 - continued Selected therapeutic agents that can be administered in combination with the anti- GITR antibody molecules provided herein, e. g ., as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and /or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein . Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A28 WO 2010 / 101849 H3C

A29 EncomfenibEncorafenib WO 2011 / 025927 HzC NH

CH3 IZ

0 CH

A30 H3C WO 2011 / 101409 N - CH3

Villlll

Hac US 2017 /0306038 A1 Oct. 26 , 2017 67

TABLE 6 - continued

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A31 Human monoclonal antibody to HER3 WO 2012 /022814 EP 2606070 U . S . Pat. No . 8 ,735 ,551 A32 Antibody Drug Conjugate (ADC ) WO 2014 / 160160 Ab : 12425 (see Table 1 , paragraph [00191 ]) Linker: SMCC (see paragraph [00117 ] Pay load : DM1 ( see paragraph [00111 ] See also Claim 29 A33 Monoclonal antibody or Fab to M -CSF WO 2004 /045532

A34 WO 2003 /077914 Binimetinib HO .

H3C - N Br

A35 midostaurin HN WO 2003 /037347 EP 1441737 US 2012 /252785

CH3 CH3 110110

CH3 US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 6 - continued Selected therapeutic agents that can be administered in combination with the anti -GITR antibody molecules provided herein , e . g. , as a single agent or in combination with other immunomodulators described herein ( e . g . , one ormore of : an activator of a costimulatory molecule and / or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety , including all structural formulae therein . Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A36 Everolimus - OH WO 2014 /085318 AFINITOR®

CH3

Hin- CH33 - CH3 CH HÓó H3C HO FC - CH3 -CH3

H3C H3C

A37 -3) WO 2007 / 030377 U . S . Pat. No . XT 7 ,482 . 367

HN ??????H3C

HN FF US 2017 /0306038 A1 Oct. 26 , 2017 69

HN H2N

HN . HN NH

?? NH2

A39 Divitinib WO 2009 / 115562 U . S . Pat. No . F 8 , 563. 556 - NH2

A40 WO 2013 / 184757

IZ Hzc HC US 2017 /0306038 A1 Oct. 26 , 2017 70

TABLE 6 - continued

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A41 HN FFF WO 2006 / 122806

HO N - CH3

A42 WO 2008 / 073687 U . S . Pat. No . 8 , 372 . 858

H3C CH3 NNHNH

H3C .

CH3 US 2017 /0306038 A1 Oct. 26 , 2017 71

TABLE 6 - continued

Patents/ Patent Compound Generic Name Application Designation Tradename Compound Structure Publications

A43 WO 2010 /002655 N CH3 8 ,519 . 129

- NH

F -CH3

A44 WO 2010 /002655 U . S . Pat. No . 8 , 519 , 129

H3C TF

Z HzC NH US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 6 - continued

Patents /Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A45 H3C2 WO 2010 / 002655

HzCH3C %

E-z

CH3

A46 Valspodar EP 296122 AMDRAY TM CH3 H3C CH3

INHNH HZC HC HN LCH3

0 NH?? H3C O / CCH3 H3C - NH HzC N 7 CH3 = 0 H?c | _ CH, H3C CH3

CH3 H3C CH3 US 2017 /0306038 A1 Oct. 26 , 2017

TABLE 6 - continued Selected therapeutic agents that can be administered in combination with the anti -GITR antibody molecules provided herein , e . g ., as a single agent or in combination with other immunomodulators described herein ( e . g . , one or more of: an activator of a costimulatory molecule and /or an inhibitor of an immune checkpoint molecule ). Each publication listed in this Table is herein incorporated by reference in its entirety, including all structural formulae therein . Patents / Patent Compound Generic Name Application Designation Tradename Compound Structure Publications A47 Vatalanib WO 98 / 35958 succinate

A48 IDH inhibitor WO2014 / 141104 A49 BCR - ABL inhibitor WO2013 / 171639 WO2013 / 171640 WO2013 / 171641 WO2013 / 171642 A50 CRAF inhibitor WO2014 / 151616 A51 ERK1/ 2 ATP competitive inhibitor WO2015066188 Table 6 provides from left to right the following: the Compound Designation of the second therapeutic agent, the Compound structure , and Patent publication ( s ) disclosing the Compound .

Combinations of Antigen -Presentation Combinations , antigen presentation , e. g ., increasing antigen presentation Effector Cell Combinations and Anti- Tumor ( e . g ., by enhancing one or more of dendritic cell activity or Immunosuppression Agents maturation , antigen uptake, or antigen processing ); ( ii ) effector cell response , e . g . , increasing effector cell response [0397 ] Provided herein , at least in part , are methods and ( e . g ., enhancing B cell and / or T cell activation and /or compositions comprising a combination of two , three or mobilization , e . g ., in the lymph node ) ; or ( iii ) tumor immu more therapeutic agents chosen from one , two , or all of the nosuppression , e . g . , decreasing tumor immunosuppression following categories ( i ) - ( iii ) : ( i ) an agent that enhances ( e . g ., increasing T cell infiltration and tumor cell killing ). antigen presentation (e . g. , tumor antigen presentation ) ; ( ii ) [0399 ] The combinations described herein can provide a an agent that enhances an effector cell response ( e . g ., B cell superior beneficial effect, e . g ., in the treatment of a disorder, and / or T cell activation and / or mobilization ) ; or (iii ) an agent such as an enhanced anti- cancer effect, reduced toxicity that decreases tumor immunosuppression , wherein at least and /or reduced side effects , compared to monotherapy one therapeutic agent is a GITR antibody , antibody fragment administration of the therapeutic agents in the combination . or antigen binding agent provided herein . For example , one or more of the therapeutic agents in the [0398 ] Without wishing to be bound by theory , it is combination can be administered at a lower dosage , or for a believed that therapeutic approaches that enhance anti shorter period of administration , than would be required to tumor immunity work more effectively when the immune achieve the same therapeutic effect compared to the mono response is optimized by targeting multiple components at therapy administration . Thus, compositions and methods for one or more stages of an immune response , e . g . , an anti treating cancer and other immune disorders using the afore tumor immune response . For example , approaches that said combination therapies are disclosed . enhance antigen presentation , e . g . , by activation and /or [ 0400 ] Accordingly , in one aspect, the invention features a maturation of dendritic cells , combined with approaches that method of treating ( e. g . , inhibiting , reducing , ameliorating , enhance cellular and humoral immune responses ( e . g ., by or preventing ) a disorder , e . g . , a hyperproliferative condition stimulating , e . g . , disinhibiting , phagocytes and / or tumor or disorder (e . g. , a cancer ) in a subject. The method includes infiltrating lymphocytes ( e . g . , NK cells and T cells ) ) , while administering to the subject a combination of two , three or blocking tumor immunosuppressive signaling ( e .g ., by more therapeutic agents chosen from one , two or all of the increasing macrophage polarization , increasing Treg deple following categories ( i ) - ( iii ) : ( i ) an agent that enhances tion and /or decreasing myeloid -derived suppressive cells antigen ( e . g . , tumor antigen ) presentation ; ( ii ) an agent that (MDSCs ) ) can result in a more effective and /or prolonged enhances an effector cell response ( e . g ., B cell and / or T cell therapeutic response . Accordingly , disclosed herein are activation and / or mobilization ) ; or ( iii ) an agent that combination therapies that optimize one, two , or all of: ( i) decreases tumor immunosuppression , thereby treating the US 2017 /0306038 A1 Oct. 26 , 2017 74 disorder, e . g . , the hyperproliferative condition or disorder CSF ( e . g . , CSF1 , or CSF2 ) . In some embodiments, the ( e . g . , the cancer ) . The combinations include a -GITR modu antigen - presenting combination includes a bi- or tri -specific lator ( e . g . , an anti- GITR antibody molecule as described cell engager, e . g . , a bi- or trispecific antibody molecule to herein ) . The cancer treated can be , e . g ., a cancer described CD47 and CD19 , with or without an Fc domain . In some herein , such as lung cancer ( squamous ), lung cancer (adeno embodiments , the antigen - presenting combination includes carcinoma ) , head and neck cancer, cervical cancer a TGFb inhibitor ( e . g ., an anti - TGFb antibody ) . In other (squamous ) , stomach cancer, thyroid cancer, melanoma, embodiments , the antigen - presenting combination includes nasopharyngeal cancer, or breast cancer . an IDO / TDO inhibitor. In yet other embodiments , the anti gen - presenting combination includes an A2AR antagonist . Antigen Presentation Combinations In yet other embodiments , the antigen - presenting combina [0401 ] In certain embodiments , the combination includes tion includes a vaccine ( e . g . , IL - 2 in combination with one, two , three, four or more therapeutic agents that enhance MUC1, or a dendritic cell based vaccine (e .g ., Provenge® )) . antigen ( e . g . , tumor antigen ) presentation ( referred to herein In yet other embodiments , the antigen - presenting combina as an “ antigen -presentation combination ” ) in addition to a tion includes a vaccine and a TLR agonist ( e . g . , a TLR GITR modulator ( e . g . , an anti -GITR antibody molecule as agonist as described herein ) . In certain embodiment, the described herein ) . In certain embodiments , the antigen pre antigen -presentation combination includes a vaccine and a sentation combination includes one or more of: an agent that STING agonist . In certain embodiment, the antigen - presen enhances antigen presentation ( e . g . , a vaccine , e . g ., a cell - or tation combination includes a vaccine , a STING agonist and antigen - based vaccine ); an agent that enhances lysis of a TLR agonist. tumor cells ( e . g . , an oncolytic virus ) ; an agent that stimulates ( e . g . , disinhibits ) a phagocyte , e . g . , a Type I interferon (IFN ) Effector Cell Combinations activator ( e . g . , a TLR agonist , a RIG - I - like receptor agonist [0403 ] In certain embodiments , the combination includes (RLRs ) ) , and /or an agent that activates and /or recruits a one , two, three , four, five or more therapeutic agents that dendritic cell or a macrophage ( e . g ., a macrophage I ) , e . g ., enhance an effector cell response (referred to herein as an a bi- or trispecific cell engager . " effector cell combination ” ) in addition to a GITR modula 10402] In some embodiments , the antigen - presentation tor ( e . g ., an anti -GITR antibody molecule as described combination includes one , two, three , four, five or more herein ) . In some embodiments , the effector cell combination therapeutic agents chosen from : (i ) an agonist of Stimulator includes a lymphocyte activator, e . g . , an NK cell activator of Interferon Genes (a STING agonist ), ( ii) an agonist of a and / or a T cell activator. In some embodiments , the effector Toll - like receptor ( TLR ) ( e . g . , an agonist of TLR - 3 , - 4 , - 5 , cell combination activates ( e . g . , disinhibits ) a tumor infil - 7 , -8 , or - 9 ), ( iii ) a TIM -3 modulator (e . g ., an anti - TIM - 3 trating lymphocyte ( TIL ) , e . g ., an NK cell or a T cell. In antibody molecule ) , ( iv ) a vascular endothelial growth factor some embodiments , the effector cell combination includes receptor (VEGFR ) inhibitor, ( v ) a c -Met inhibitor, ( vi) a an NK cell modulator chosen from a modulator ( e . g ., an TGFb inhibitor ( e. g ., an anti - TGFb antibody ), ( vii ) an IDO / antibody molecule ) of an NK receptor ( e . g . , a modulator of TDO inhibitor, ( viii ) an A2AR antagonist , ( ix ) an oncolytic one or more of NKG2A , KIR3DL , NKP46 , MICA or virus, ( x ) a vaccine ( e . g . , a scaffold vaccine ) , or ( xi) a bi- or CEACAM1) ; an interleukin or an interleukin variant ( e . g ., tri -specific cell engager . Any combination of the aforesaid IL - 2 , IL - 15 , IL -21 , IL - 13R or IL - 12 cytokine or variant agents ( i ) - (xi ) can be used in the antigen -presentation com thereof, or a combination thereof) ; a bi- or tri - specific cell bination . In one exemplary embodiment, the antigen -pre engager ( e . g ., a bispecific antibody molecule of NKG2A and sentation combination includes a STING agonist. In another CD138 , or a bispecific antibody molecule of CD3 and TCR ) ; exemplary embodiment, the antigen -presentation combina an NK cell therapy; or a vaccine that includes NK cells and tion includes a TLR agonist ( e . g ., a TLR7 agonist ) . In an antigen / immune stimulant . In some embodiments , the another exemplary embodiment, the antigen -presentation effector cell combination includes an immunomodulator combination includes a STING agonist and a TLR agonist ( e . g ., one or more of: an activator of a costimulatory ( e . g . , a TLR7 agonist ) . In some embodiments , the antigen molecule or an inhibitor of an immune checkpoint molecule presentation combination is chosen from a STING agonist, as described herein ). In some embodiments , the effector cell a TLR agonist, an A2AR antagonist , or an oncolytic virus or combination includes a T cell modulator chosen from an a combination thereof, and optionally , one or more of inhibitor of a checkpoint inhibitor ( e . g . , an inhibitor of one ( iii ) - ( vii ) or ( x ) - (xi ) . In some embodiments , the antigen or more of: PD - 1 , PD -L1 , TIM - 3 , LAG - 3 , VISTA , DKG - Q , presentation combination is chosen from a STING agonist or B7- H3 , B7 -H4 , TIGIT , CTLA4 , BTLA , CD160 , TIMI, IDO , a TLR agonist , or a combination of both , and optionally, one LAIR1, IL - 12 , or a combination thereof , e . g ., an inhibitor of or more of ( iii ) - ( xi) . In another embodiment, the antigen PD - 1 and TIM - 3 , or an inhibitor of PD - 1 and LAG - 3 ) . In one presentation combination includes a STING agonist , a TLR embodiment, the inhibitor of the checkpoint inhibitor is an agonist ( e . g . , a TLR7 agonist ) and a TIM - 3 modulator ( e . g . , antibody molecule ( e . g ., a mono - or bispecific antibody or an anti - TIM - 3 inhibitor) . In another embodiment, the anti fragment thereof as described herein ) . For example , the gen -presentation combination includes a STING agonist , a inhibitor of the checkpoint inhibitor is an antibody molecule TLR agonist ( e . g ., a TLR7 agonist ) and a VEGFR inhibitor. against PD - 1 , PD -L1 , TIM - 3 , LAG - 3 , VISTA , B7- H4 , In another embodiment, the antigen - presentation combina CTLA4 or TIGIT , or any combination thereof ( e . g . a com tion includes a STING agonist , a TLR agonist ( e . g . , a TLR7 bination as described herein ). In some embodiments , the agonist) and a c -MET inhibitor. In yet other embodiments , effector cell combination includes a T cell modulator chosen the antigen - presenting combination includes an oncolytic from an agonist or an activator of a costimulatory molecule . virus . In other embodiments, the antigen - presenting combi In one embodiment, the agonist of the costimulatory mol nation includes an oncolytic virus and a cytokine , e . g . , an ecule is chosen from an agonist ( e . g ., an agonistic antibody oncolytic virus expressing one or more of GM - CSF, or a or antigen - binding fragment thereof , or a soluble fusion ) of US 2017 /0306038 A1 Oct. 26 , 2017 75

GITR , OX40 , ICOS, SLAM (e .g . , SLAMF7 ), HVEM , Anti- Tumor Immunosuppression Combinations LIGHT, CD2, CD27 , CD28 , CDS, ICAM - 1 , LFA - 1 ( CD11a / [0405 ] In certain embodiments , the combination includes CD18 ), ICOS ( CD278 ), 4 - 1BB (CD137 ), CD30 , CD40 , one , two , three , four, five or more therapeutic agents that BAFFR , CD7, NKG2C , NKp80 , CD160 , B7 - H3 , or CD83 decrease tumor immunosuppression (referred to herein as an ligand . In other embodiments , the effector cell combination “ antitumor immunosuppression combination ” ) in addition includes a bispecific T cell engager (e .g . , a bispecific anti to a GITR modulator ( e . g . , an anti -GITR antibody molecule body molecule that binds to CD3 and a tumor antigen ( e. g ., as described herein ). In some embodiments, the combination EGFR , PSCA , PSMA , EpCAM , HER2 among others ) . modulates the activity or level of one or more of Tregg macrophage 2 or MDSCs. In some embodiments, the com [0404 ] In some embodiments , the effector cell combina bination increases one or more of M2 polarization , Treo tion includes one, two, three , four, five or more therapeutic depletion , or T cell recruitment. In some embodiments, the agents chosen from : ( i) a GITR modulator (e . g. , a GITR antitumor immunosuppression combination includes one , agonist ( e . g . , an anti -GITR antibody molecule as described two , three , four, five or more therapeutic agents chosen herein ) ) , ( ii) a PD - 1 inhibitor, ( iii ) a PD - L1 inhibitor, ( iv ) an from : ( i ) an immunomodulator ( e . g . , one or more of: an inhibitor of IAP (Inhibitor of Apoptosis Protein ), ( v ) an activator of a costimulatory molecule ( e . g ., a GITR agonist ) , inhibitor of EGFR (Epidermal Growth Factor Receptor ), (vi ) or an inhibitor of an immune checkpoint molecule ( e . g ., one an inhibitor of target of rapamycin (mTOR ) , (vii ) IL - 15 or or more of PD - 1 , PD -L1 , LAG - 3 , TIM - 3 or CTLA - 4 ) , as a variant thereof, ( viii ) a CTLA -4 inhibitor, ( ix ) a bispecific described herein ), ( ii ) a CSF - 1 / 1R inhibitor ( e . g ., an inhibi T cell engager ( e .g ., a bispecific antibody molecule that tor of macrophage colony - stimulating factor ( M -CSF ) ) , ( iii ) binds to CD3 and a tumor antigen ( e . g . , EGFR , PSCA , an IL - 17 inhibitor, ( iv ) an IL - 1B inhibitor, ( v ) a CXCR2 PSMA, EpCAM , HER2 among others ), ( x ) a CD40 agonist inhibitor , ( vi) an inhibitor of a phosphoinositide 3 -kinase ( e . g . , an anti - CD40 antibody molecule ) , ( xi) an OX40 ago (PI3K , e . g . , PI3Ky or PI3K8) , ( vii ) a BAFF - R inhibitor, nist ( e . g ., an anti -OX40 antibody molecule ), or ( xii ) a CD27 (viii ) a MALT- 1 /BTK inhibitor, ( ix ) a JAK inhibitor, ( x ) a agonist ( e. g ., an anti -CD27 antibody molecule ). Any com CRTH2 inhibitor, (xi ) a VEGFR inhibitor, ( xiii) an IL - 15 or bination of the aforesaid agents can be used in the effector a variant thereof, ( xiv ) a CTLA - 4 inhibitor, ( xv ) an IDO / cell combination . In one exemplary embodiment, the effec TDO inhibitor, (xvi ) an A2AR antagonist , ( xvii ) a TGFb tor cell combination includes a GITR agonist ( e . g . , an inhibitor, or ( xviii ) a PFKFB3 inhibitor . In certain embodi anti -GITR antibody molecule as described herein ) . In ments, the immunomodulator is an inhibitor of an immune another embodiment, the effector cell combination includes checkpoint molecule ( e . g . , an inhibitor of PD - 1 , PD - L1 , a PD - 1 inhibitor . In another embodiment, the effector cell LAG - 3 , TIM - 3, CEACAM ( e .g ., CEACAM - 1 , -3 and /or - 5 ), or CTLA - 4 , or any combination thereof) . Any combination combination includes a PD -L1 inhibitor. In other embodi of the aforesaid agents can be used in the tumor immuno ments, the effector cell combination includes a GITR agonist suppression combination . In one exemplary embodiment, ( e . g . , an anti- GITR antibody molecule as described herein ) the anti - tumor immunosuppression combination includes and a PD - 1 inhibitor. In other embodiments , the effector cell one , two , three , four , five or more therapeutic agents chosen combination includes a GITR agonist ( e . g . , an anti -GITR from a PD - 1 inhibitor, a PD -L1 inhibitor, a LAG - 3 inhibitor, antibody molecule as described herein ) and a PD -L1 inhibi a TIM - 3 modulator ( e . g . , an anti - TIM - 3 inhibitor ), a GITR tor. In other embodiments , the effector cell combination agonist ( e . g ., an anti -GITR antibody molecule as described includes a GITR agonist ( e . g ., an anti- GITR antibody mol herein ) , a CSF - 1 / 1R inhibitor ( e . g . , an M -CSF inhibitor ) , an ecule as described herein ) , a PD - 1 inhibitor, and a PD -L1 IL - 17 inhibitor , an IL - 1B inhibitor , or a CXCR2 inhibitor. In inhibitor. In other embodiments , the effector cell combina one embodiment, the anti - tumor immunosuppression com tion includes a PD - 1 inhibitor, and a PD - L1 inhibitor. In one bination includes one , two , or all of a GITR agonist (e .g ., an embodiment, the effector cell combination includes a GITR anti -GITR antibody molecule as described herein ) , CSF - 1 / agonist ( e . g . , an anti -GITR antibody molecule as described 1R inhibitor ( e . g . , an M - CSF inhibitor) , an IL - 17 inhibitor, herein ) and an inhibitor of IAP . In another embodiment , the an IL - 1ß inhibitor . In one embodiment, the anti -tumor effector cell combination includes a GITR agonist ( e . g . , an immunosuppression combination includes a a GITR agonist anti -GITR antibody molecule as described herein ) and an ( e . g ., an anti- GITR antibody molecule as described herein ) , inhibitor of an EGFR inhibitor . In yet another embodiment, an IL - 17 inhibitor, a CXCR2 inhibitor , a CRTH2 inhibitor , the effector cell combination includes a GITR agonist ( e . g . , an A2AR antagonist , or a PFKFB3 inhibitor , or a combina an anti -GITR antibody molecule as described herein ) and an t ion thereof. inhibitor of an mTOR inhibitor. In one embodiment, the [0406 ] In some embodiments , the combination includes effector cell combination includes IL - 15 or a variant thereof. one or more therapeutic agents of the antigen - presentation In one embodiment, the effector cell combination includes a combination . In other embodiments , the combination CTLA - 4 inhibitor. In one embodiment, the effector cell includes one or more therapeutic agents of the effector cell combination includes a bispecific T cell engager ( e . g . , a combination . In yet other embodiments, the combination bispecific antibody molecule that binds to CD3 and a tumor includes one or more therapeutic agents of the anti - tumor antigen ( e . g . , EGFR , PSCA , PSMA , EpCAM , HER2 among immunosuppression combination . In other embodiments , others ) . In one embodiment, the effector cell combination the combination includes one or more therapeutic agents of includes a CD40 agonist ( e . g ., an anti -CD40 antibody mol the antigen -presentation combination and one or more thera ecule ) . In one embodiment, the effector cell combination peutic agents of the effector cell combination . In other includes an OX40 agonist ( e . g . , an anti -OX40 antibody embodiments, the one or more therapeutic agents of the molecule ) . In one embodiment, the effector cell combination antigen - presentation combination and one or more therapeu includes a CD27 agonist ( e . g ., an anti -CD27 antibody mol tic agents of the anti - tumor immunosuppression combina ecule ) . tion . In other embodiments , the combination includes one or US 2017 /0306038 A1 Oct. 26 , 2017 76 more therapeutic agents of the antigen - presentation combi A8B10 , A8B11 , A8B12 , A9B1 , A9B2, A9B3 , A9B4 , A9B5 , nation , one or more therapeutic agents of the effector cell A9B6 , A9B7 , A9B8 , A9B9 , A9B10 , A9B11 , A9B12 , combination and one or more therapeutic agents of the A10B1, A10B2, A10B3, A10B4 , A10B5, A10B6 , A10B7, antitumor immunosuppression combination . In other A10B8 , A10B9 , A10B10 , A10B11, A10B12 , A11B1, embodiments , the combination includes one or more thera A11B2 , A11B3, A11B4 , A11B5 , A11B6 , A11B7 , A1108 , peutic agents of the antigen -presentation combination , one A11B9 , A11B10 , A11B11, A11B12 , A1C1, A1C2, A1C3 , or more therapeutic agents of the effector cell combination A1C4 , A1C5 , A1C6 , A1C7, A1C8 , A1C9, A1C10 , A1C11, and one or more therapeutic agents of the antitumor immu A1C12 , A1C13 , A1C14 , A1C15 , A1C16 , A1C17 , A1C18 , nosuppression combination . [0407 ) Provided herein are methods and compositions that A1C19 , A1C20 , A1C21, A2C1, A2C2 , A2C3 , A2C4 , A2C5 , include a combination of one or more of: ( i ) an agent that A2C6 , A2C7, A2C8 , A2C9, A2C10 , A2C11 , A2C12 , enhances antigen ( e . g ., tumor antigen ) presentation ; ( ii ) an A2C13 , A2C14 , A2C15 , A2C16 , A2C17 , A2C18 , A2C19 , agent that enhances an effector cell response ( e . g ., B cell A2C20 , A2C21 , A3C1, A3C2, A3C3, A3C4 , A3C5 , A3C6 , and /or T cell activation and /or mobilization ); or ( iii ) an agent A3C7, A3C8, A3C9, A3C10 , A3C11 , A3C12 , A3C13 , that decreases tumor immunosuppression , thereby treating A3C14 , A3C15 , A3C16 , A3C17 , A3C18 , A3C19 , A3C20 , the disorder , e . g . , the hyperproliferative condition or disor A3C21 , A4C1, A4C2, A4C3, A4C4 , A4C5 , A4C6 , A4C7, der ( e . g ., the cancer ). Provided combinations include a A4C8 , A4C9, A4C10 , A4C11 , A4C12 , A4C13 , A4C14 , GITR modulator ( e . g . , an anti -GITR antibody molecule as A4C15 , A4C16 , A4C17 , A4C18 , A4C19 , A4C20 , A4C21 , A5C1, A5C2, A5C3, A5C4 , A5C5 , A5C6 , A5C7, A5C8 , described herein ) . Exemplary combinations of therapeutic A5C9 , A5C10 , A5C11 , A5C12 , A5C13 , A5C14 , A5C15 , agents from two or more of Antigen - Presentation Combi A5C16 , A5C17 , A5C18 , A5C19 , A5C20 , A5C21 , A6C1, nations category ( A ), Effector Cell Combinations category A6C2, A6C3, A6C4 , A6C5 , A6C6 , A6C7, A6C8 , A6C9, (B ), and Anti- tumor Immunosuppression Combinations cat A6C10 , A6C11 , A6C12 , A6C13 , A6C14 , A6C15 , A6C16 , egory (C ) are provided in Table 7 : A6C17 , A6C18 , A6C19 , A6C20 , A6C21 , A7C1 , A7C2 , A7C3, A7C4 , A7C5 , A7C6 , A7C7 , A7C8, A7C9, A7C10 , TABLE 7 A7C11 , A7C12 , A7C13 , A7C14 , A7C15 , A7C16 , A7C17 , Listing of Therapeutic Agents in Categories ( A ) - ( C ) A7C18 , A7C19 , A7C20 , A7C21, A8C1 , A8C2 , A8C3 , A8C4, A8C5 , A8C6 , A8C7, A8C8 , A8C9, A8C10 , A8C11 , A = Antigen C = Anti -tumor A8C12 , A8C13 , A8C14 , A8C15 , A8C16 , A8C17 , A8C18 , Presentation B = Effector Cell Immunosuppression A8C19 , A8C20 , A8C21 , A9C1, A9C2, A9C3 , A9C4, A9C5 , 1 STING agonist GITR agonist PD - 1 inhibitor A9C6 , A9C7, A9C8, A9C9, A9C10 , A9C11 , A9C12 , 2 TLR agonist PD - 1 inhibitor PD - L1 inhibitor A9C13 , A9C14 , A9C15 , A9C16 , A9C17 , A9C18 , A9C19 , 3 TIM - 3 modulator PD - L1 inhibitor LAG - 3 inhibitor 4 VEGFR inhibitor IAP inhibitor TILTIM - 3 inhibitor A9C20 , A9C21 , A10C1, A10C2, A10C3 , A10C4, A1005 , 5 C -MET inhibitor EGFR inhibitor GITR inhibitor A1006 , A1007 , A1008 , A10C9, A10C10 , A10C11 , A10C12 , 6 TGFb inhibitor mTOR inhibitor CSF - 1 / 1R inhibitor A10C13 , A10C14 , A10C15 , A10C16 , A10C17 , A10C18 , 7 IDO / TDO inhibitor IL - 15 agonist IL - 17 inhibitor 8 A2AR antagonist CTLA - 4 inhibitor IL - 1B inhibitor A10019 , A10C20 , A10C21 , A11C1, A11C2, A11C3, 9 Oncolytic viruses Bispecific T - cell CXCR2 inhibitor A11C4, A1105 , A1106 , A11C7, A11C8, A11C9, A11C10 , engagers A11C11 , A11C12 , A11C13 , A11C14 , A11C15 , A11C16 , 10 Scaffold vaccines CD40 agonist PI3K - Y , - d inhibitor A11C17 , A11C18 , A11C19 , A11C20 , A11C21, B1C1, 11 Bispecific T - cell OX40 agonist BAFF - R inhibitor B1C2 , B1C3 , B1C4 , B1C5 , B1C6 , B1C7 , B1C8 , B1C9, engagers 12 CD27 agonist MALT - 1 /BTK inhibitor B1C10 , B1C11, B1C12 , B1C13 , B1C14 , B1C15 , B1C16 , JAK inhibitor B1C17 , B1C18 , B1C19 , B1C20 , B1C21 , B2C1, B2C2 , CRTH2 inhibitor B2C3 , B2C4 , B2C5, B2C6 , B2C7 , B2C8 , B2C9, B2C10 , VEGFR inhibitor B2C11, B2C12 , B2C13 , B2C14 , B2C15 , B2C16 , B2C17 , UAva IL - 15 agonist Anti - TGFb inhibitor B2C18 , B2C19 , B2C20 , B2C21, B3C1, B3C2, B3C3 , IDO / TDO inhibitor B3C4 , B3C5, B3C6 , B3C7, B3C8, B3C9 , B3C10 , B3C11 , 19 A2AR antagonist B3C12 , B3C13 , B3C14 , B3C15 , B3C16 , B3C17 , B3C18 , 20 CTLA - 4 inhibitor B3C19 , B3C20 , B3C21 , B4C1, B4C2, B4C3 , B4C4, B4C5 , 21 PFKFB3 inhibitor B4C6 , B4C7 , B4C8, B4C9, B4C10 , B4C11 , B4C12 , B4C13 , B4C14 , B4C15 , B4C16 , B4C17 , B4C18 , B4C19 , [ 0408 ] In some embodiments , the combinations of the B4C20 , B4C21, B5C1, B5C2, B5C3, B5C4 , B5C5 , B5C6 , present invention include one or more of the following B5C7, B5C8 , B5C9, B5C10 , B5C11 , B5C12 , B5C13 , ( designations indicate combinations of agents provided in B5C14 , B5C15 , B5C16 , B5C17 , B5C18 , B5C19 , B5C20 , the matrix in Table 7 ) : A1B1, A1B2, A1B3, A1B4 , A1B5 , B5C21 , B6C1 , B6C2 , B6C3, B6C4 , B6C5 , B6C6, B6C7, A1B6 , A1B7 , A1B8 , A1B9, A1B10 , A1B11 , A1B12 , A2B1, B6C8, B6C9, B6C10 , B6C11 , B6C12 , B6C13 , B6C14 , A2B2, A2B3 , A2B4, A2B5, A2B6 , A2B7, A2B8 , A2B9, B6C15 , B6C16, B6C17 , B6C18, B6C19, B6C20 , B6C21 , A2B10 , A2B11 , A2B12 , A3B1, A3B2, A3B3 , A3B4 , A3B5 , B7C1, B7C2 , B7C3, B7C4 , B7C5 , B7C6 , B7C7, B7C8 , A3B6 , A3B7 , A3B8 , A3B9, A3B10 , A3B11 , A3B12 , A4B1, B7C9, B7C10 , B7C11 , B7C12 , B7C13 , B7C14 , B7C15 , A4B2, A4B3 , A4B4, A4B5 , A4B6 , A4B7, A4B8 , A4B9, B7C16 , B7C17 , B7C18 , B7C19 , B7C20 , B7C21 , B8C1, A4B10 , A4B11 , A4B12 , A5B1, A5B2, A5B3 , A5B4, A5B5, B8C2 , B8C3 , B8C4, B8C5 , B8C6 , B8C7 , B8C8 , B8C9 , A5B6 , A5B7 , A5B8, A5B9, A5B10 , A5B11 , A5B12 , A6B1, B8C10 , B8C11, B8C12 , B8C13 , B8C14 , B8C15 , B8C16 , A6B2, A6B3 , A6B4, A6B5 , A6B6 , A6B7, A6B8 , A6B9 , B8C17 , B8C18 , B8C19 , B8C20 , B8C21, B9C1, B9C2, A6B10 , A6B11 , A6B12 , A7B1, A7B2, A7B3, A7B4, A7B5 , B9C3 , B9C4 , B9C5 , B9C6 , B9C7, B9C8, B9C9, B9C10 , A7B6 , A7B7 , A7B8 , A7B9, A7B10 , A7B11 , A7B12 , A8B1, B9C11, B9C12 , B9C13 , B9C14 , B9C15 , B9C16 , B9C17 , A8B2 , A8B3 , A8B4 , A8B5 , A8B6 , A8B7, A8B8 , A8B9, B9C18 , B9C19 , B9C20 , B9C21, B10C1 , B10C2 , B10C3, US 2017 /0306038 A1 Oct. 26 , 2017 77

B10C4 , B10C5 , B10C6 , B10C7 , B10C8, B10C9, B10C10 , A2B2C4 , A2B2C5 , A2B2C6 , A2B2C7 , A2B2C8 , A2B2C9 , B10C11 , B10C12 , B10C13 , B10C14 , B10C15 , B10C16 , A2B2C10 , A2B2C11, A2B2C12 , A2B2C13 , A2B2014 , B10C17 , B10C18 , B10C19 , B10C20 , B10C21 , B11C1, A2B2C15 , A2B2C16 , A2B2C17 , A2B2C18 , A2B2C19 , B11C2 , B11C3 , B11C4 , B11C5 , B11C6 , B11C7 , B11C8 , A2B2020 , A2B2C21 , A2B3C1, A2B3C2 , A2B3C3 , B11C9, B11C10 , B11C11 , B11C12 , B11C13 , B11C14 , A2B3C4 , A2B3C5 , A2B3C6 , A2B3C7 , A2B3C8 , A2B3C9 , B11C15 , B11C16 , B11C17 , B11C18 , B11C19 , B11C20 , A2B3C10 , A2B3C11 , A2B3C12 , A2B3C13 , A2B3C14 , B11C21, B12C1, B12C2, B12C3, B12C4, B12C5, B12C6 , A2B3C15 , A2B3C16 , A2B3C17 , A2B3C18 , A2B3C19 , B12C7 , B12C8, B12C9, B12C10 , B12C11 , B12C12 , A2B3C20 , A2B3C21 , A2B4C1, A2B4C2, A2B4C3 , B12C13 , B12C14 , B12C15 , B12C16 , B12C17 , B12C18 , A2B4C4, A2B4C5, A2B4C6 , A2B4C7, A2B4C8 , A2B4C9 , B12C19 , B12C20 , B12C21, A1B1C1, A1B1C2, A1B1C3, A2B4C10 , A2B4C11 , A2B4C12 , A2B4C13 , A2B4C14 , A1B1C4 , A1B1C5 , A1B1C6 , A1B1C7, A1B1C8, A1B1C9 , A2B4C15 , A2B4C16 , A2B4C17 , A2B4C18 , A2B4C19 , A1B1C10 , A1B1C11, A1B1C12 , A1B1C13 , A1B1C14 , A2B4C20 , A2B4C21 , A2B5C1 , A2B5C2, A2B5C3 , A1B1C15 , A1B1C16 , A1B1C17 , A1B1C18 , A1B1C19 , A2B5C4, A2B5C5 , A2B5C6 , A2B5C7 , A2B5C8, A2B5C9 , A1B1C20 , A1B1C21, A1B2C1, A1B2C2, A1B2C3 , A2B5C10 , A2B5C11 , A2B5C12 , A2B5C13 , A2B5C14 . A1B2C4 , A1B2C5 , A1B2C6 , A1B2C7 , A1B2C8 , A1B2C9 , A2B5C15 , A2B5C16 , A2B5C17 , A2B5C18 , A2B5C19 , A1B2C10 , A1B2C11 , A1B2C12 , A1B2C13 , A1B2C14 , A2B5C20 , A2B5C21 , A2B6C1, A2B6C2 , A2B6C3 , A1B2C15 , A1B2C16 , A1B2C17 , A1B2C18 , A1B2C19 , A2B6C4 , A2B6C5, A2B6C6 , A2B6C7 , A2B6C8 , A2B6C9, A1B2C20 , A1B2C21, A1B3C1, A1B3C2 , A1B3C3 , A2B6C10 , A2B6C11 , A2B6C12 , A2B6C13 , A2B6C14 , A1B3C4 , A1B3C5 , A1B3C6 , A1B3C7 , A1B3C8 , A1B3C9, A2B6C15 , A2B6C16 , A2B6C17 , A2B6C18 , A2B6C19 , A1B3C10 , A1B3C11 , A1B3C12 , A1B3C13 , A1B3C14 , A2B6C20 , A2B6C21 , A2B7C1, A2B7C2 , A2B7C3 , A1B3C15 , A1B3C16 , A1B3C17 , A1B3C18 , A1B3C19 , A2B7C4, A2B7C5, A2B7C6 , A2B7C7 , A2B7C8 , A2B7C9 , A1B3C20 , A1B3C21, A1B4C1, A1B4C2, A1B4C3, A2B7C10 , A2B7C11 , A2B7C12 , A2B7C13 , A2B7C14 , A1B4C4 , A1B4C5 , A1B4C6 , A1B4C7, A1B4C8 , A1B4C9, A2B7C15 , A2B7C16 , A2B7C17 , A2B7C18 , A2B7C19 , A1B4C10 , A1B4C11 , A1B4C12 , A1B4C13 , A1B4C14 , A2B7C20 , A2B7C21 , A2B8C1, A2B8C2, A2B8C3 , A1B4C15 , A1B4C16 , A1B4C17 , A1B4C18 , A1B4C19 , A2B8C4 , A2B8C5 , A2B8C6 , A2B8C7 , A2B8C8 , A2B8C9 , A1B4C20 , A1B4C21, A1B5C1, A1B5C2, A1B5C3, A2B8C10 , A2B8C11 , A2B8C12 , A2B8C13 , A2B8C14 , A1B5C4 , A1B5C5 , A1B5C6 , A1B5C7, A1B5C8 , A1B5C9, A2B8C15 , A2B8C16 , A2B8C17 , A2B8C18 , A2B8C19 , A1B5C10 , A1B5C11 , A1B5C12 , A1B5C13 , A1B5C14 , A2B8C20 , A2B8C21, A2B9C1, A2B9C2, A2B9C3 , A1B5C15 , A1B5C16 , A1B5C17 , A1B5C18 , A1B5C19 , A2B9C4, A2B9C5, A2B9C6 , A2B9C7, A2B9C8 , A2B9C9 , A1B5C20 , A1B5C21 , A1B6C1, A1B6C2, A1B6C3 , A2B9C10 , A2B9C11, A2B9C12 , A2B9C13 , A2B9C14 , A1B6C4 , A1B6C5 , A1B6C6 , A1B6C7, A1B6C8 , A1B6C9, A2B9C15 , A2B9C1 , A2B9C17 , A2B9C18 , A2B9C19 , A1B6C10 , A1B6C11 , A1B6C12 , A1B6C13 , A1B6C14 , A2B9C20 , A2B9C21 , A2B10C1, A2B10C2 , A2B10C3, A1B6C15 , A1B6C16 , A1B6C17 , A1B6C18 , A1B6C19 , A2B10C4 , A2B10C5, A2B10C6 , A2B10C7 , A2B10C8 , A1B6C20 , A1B6C21, A1B7C1, A1B7C2, A1B7C3 , A2B10C9, A2B10C10 , A2B10C11 , A2B10C12 , A1B7C4 , A1B7C5 , A1B7C6 , A1B7C7 , A1B7C8 , A1B7C9 , A2B10C13 , A2B10C14 , A2B10C15 , A2B10C16 , A1B7C10 , A1B7C11 , A1B7C12 , A1B7C13 , A1B7C14 , A2B10C17 , A2B10C18 , A2B10C19 , A2B10C20 , A1B7C15 , A1B7C16 , A1B7C17 , A1B7C18 , A1B7C19 , A2B10C21 , A2B11C1, A2B11C2 , A2B11C3 , A2B11C4 , A1B7C20 , A1B7C21 , A1B8C1, A1B8C2, A1B8C3 , A2B11C5, A2B11C6 , A2B11C7 , A2B11C8 , A2B11C9 , A1B8C4 , A1B8C5 , A1B8C6 , A1B8C7, A1B8C8 , A1B8C9, A2B11C10 , A2B11C11, A2B11C12 , A2B11C13 , A1B8C10 , A1B8C11, A1B8C12 , A1B8C13 , A1B8C14 , A2B11C14 , A2B11C15 , A2B11C16 , A2B11C17 , A1B8C15 , A1B8C16 , A1B8C17 , A1B8C18 , A1B8C19 , A2B11C18 , A2B11C19 , A2B11C20 , A2B11C21 , A2B12C1 . A1B8C20 , A1B8C21, A1B9C1, A1B9C2, A1B9C3, A2B12C2 , A2B12C3, A2B12C4 , A2B12C5 , A2B12C6 , A1B9C4, A1B9C5, A1B9C6 , A1B9C7, A1B9C8, A1B9C9, A2B12C7 , A2B12C8, A2B12C9, A2B12C10 , A2B12C11 , A1B9C10 , A1B9C11 , A1B9C12 , A1B9C13 , A1B9C14 , A2B12C12 , A2B12C13 , A2B12C14 , A2B12C15 , A1B9C15 , A1B9C16 , A1B9C17 , A1B9C18 , A1B9C19, A2B12C16 , A2B12C17 , A2B12C18 , A2B12C19 , A1B9C20 , A1B9C21 , A1B10C1, A1B10C2, A1B10C3 , A2B12C20 , A2B12C21 , A3B1C1, A3B1C2, A3B1C3 , A1B10C4, A1B10C5 , A1B10C6 , A1B10C7, A1B10C8, A3B1C4 , A3B1C5 , A3B1C6 , A3B1C7, A3B1C8 , A3B1C9 , A1B10C9 , A1B10C10 , A1B10C11 , A1B10C12 , A3B1C10 , A3B1C11 , A3B1C12 , A3B1C13 , A3B1C14 , A1B10C13 , A1B10C14 , A1B10C15 , A1B10C16 , A3B1C15 , A3B1C16 , A3B1C17 , A3B1C18 , A3B1C19 , A1B10C17 , A1B10C18 , A1B10C19 , A1B10C20 , A3B1C20 , A3B1C21 , A3B2C1, A3B2C2 , A3B2C3, A1B10C21 , A1B11C1, A1B11C2, A1B11C3 , A1B11C4 , A3B2C4, A3B2C5, A3B2C6 , A3B2C7 , A3B2C8 , A3B2C9 , A1B11C5 , A1B11C6 , A1B11C7, A1B11C8 , A1B11C9 , A3B2C10 , A3B2C11 , A3B2C12, A3B2C13 , A3B2C14 , A1B11C10 , A1B11C11 , A1B11C12 , A1B11C13 , A3B2C15, A3B2C16 , A3B2C17 , A3B2C18 , A3B2C19, A1B11C14 , A1B11C15 , A1B11C16 , A1B11C17 , A3B2C20 , A3B2C21 , A3B3C1, A3B3C2, A3B3C3 , A1B11C18 , A1B11C19 , A1B11C20 , A1B11C21 , A1B12C1, A3B3C4 , A3B3C5 , A3B3C6 , A3B3C7, A3B3C8 , A3B3C9, A1B12C2, A1B12C3 , A1B12C4, A1B12C5 , A1B12C6 , A3B3C10 , A3B3C11 , A3B3C12 , A3B3C13 , A3B3C14 , A1B12C7 , A1B12C8 , A1B12C9, A1B12C10 , A1B12C11 , A3B3C15 , A3B3C16 , A3B3C17 , A3B3C18 , A3B3C19 , A1B12C12 , A1B12C13 , A1B12C14 , A1B12C15 , A3B3C20 , A3B3C21, A3B4C1, A3B4C2 , A3B4C3 , A1B12C16 , A1B12C17 , A1B12C18 , A1B12C19 , A3B4C4, A3B4C5, A3B4C6 , A3B4C7, A3B4C8, A3B4C9, A1B12C20 , A1B12C21 , A2B1C1, A2B1C2 , A2B1C3, A3B4C10 , A3B4C11 , A3B4C12 , A3B4C13 , A3B4C14 , A2B1C4, A2B1C5, A2B1C6 , A2B1C7 , A2B1C8 , A2B1C9 , A3B4C15 , A3B4C16 , A3B4C17 , A3B4C18 , A3B4C19 , A2B1C10 , A2B1C11 , A2B1C12 , A2B1C13 , A2B1C14 , A3B4C20 , A3B4C21, A3B5C1, A3B5C2, A3B5C3 , A2B1C15 , A2B1C16 , A2B1C17 , A2B1C18 , A2B1C19 , A3B5C4, A3B5C5 , A3B5C6 , A3B5C7 , A3B5C8, A3B5C9, A2B1C20 , A2B1C21 , A2B2C1, A2B2C2 , A2B2C3 , A3B5C10 , A3B5C11 , A3B5C12 , A3B5C13 , A3B5C14 , US 2017 /0306038 A1 Oct. 26 , 2017 78

A3B5C15 , A3B5C16 , A3B5C17 , A3B5C18 , A3B5C19 , A4B9C4 , A4B9C5, A4B9C6 , A4B9C7, A4B9C8, A4B9C9, A3B5C20 , A3B5C21 , A3B6C1, A3B6C2, A3B6C3 , A4B9C10 , A4B9C11, A4B9C12 , A4B9C13 , A4B9C14 , A3B6C4, A3B6C5, A3B6C6 , A3B6C7, A3B6C8, A3B6C9, A4B9C15 , A4B9C16 , A4B9C17 , A4B9C18 , 4B9C19 , A3B6C10 , A3B6C11 , A3B6C12 , A3B6C13 , A3B6C14 , A4B9C20 , A4B9C21 , A4B10C1, A4B10C2 , A4B10C3, A3B6C15 , A3B6C16 , A3B6C17 , A3B6C18 , A3B6C19 , A4B10C4 , A4B10C5 , A4B10C6 , A4B10C7, A4B10C8 , A3B6C20 , A3B6C21, A3B7C1, A3B7C2, A3B7C3 , A4B10C9, A4B10C10 , A4B10C11 , A4B10C12 , A3B7C4 , A3B7C5 , A3B7C6 , A3B7C7, A3B7C8, A3B7C9 , A4B10C13 , A4B10C14 . A4B10C15 , A4B10C16 , A3B7C10 , A3B7C11, A3B7C12 , A3B7C13 , A3B7C14 , A4B10C17 , A4B10C18 , A4B10C19 , A4B10C20 , A3B7C15 , A3B7C16 , A3B7C17 , A3B7C18 , A3B7C19 , A4B10C21, A4B11C1 , A4B11C2, A4B11C3, A4B11C4 , A3B7C20 , A3B7C21 , A3B8C1 , A3B8C2, A3B8C3 , A4B11C5 , 4B11C6 , A4B11C7, A4B11C8 , 4B11C9 , A3B8C4 , A3B8C5 , A3B8C6 , A3B8C7, A3B8C8 , A3B8C9 , A4B11C10 , A4B11C11, A4B11C12 , A4B11C13 , A3B8C10 , A3B8C11 , A3B8C12 , A3B8C13 , A3B8C14 , A4B11C14 , A4B11C15 , A4B11C16 , A4B11C17 , A3B8C15 , A3B8C16 , A3B8C17 , A3B8C18 , A3B8C19 , A4B11C18 , A4B11C19 , A4B11C20 , A4B11C21 , A4B12C1, A3B8C20 , A3B8C21 , A3B9C1, A3B9C2, A3B9C3 , A4B12C2 , A4B12C3 , A4B12C4 , A4B12C5 , A4B12C6 , A3B9C4 , A3B9C5, A3B9C6 , A3B9C7, A3B9C8 , A3B9C9 , A4B12C7 , A4B12C8 , A4B12C9 , A4B12C10 , A4B12011 , A3B9C10 , A3B9C11 , A3B9C12 , A3B9C13 , A3B9C14 , A4B12C12, A4B12C13 , A4B12C14 , A4B12C15 , A3B9C15 , A3B9C16 , A3B9C17 , A3B9C18 , A3B9C19 , A4B12C16 , A4B12C17 , A4B12C18 , A4B12C19 , A3B9C20 , A3B9C21, A3B10C1, A3B10C2, A3B10C3 , A4B12C20 , A4B12C21, A5B1C1 , A5B1C2, A5B1C3 , A3B10C4, A3B10C5 , A3B10C6 , A3B10C7, A3B10C8, A5B1C4 , A5B1C5, A5B1C6 , A5B1C7, A5B1C8 , A5B1C9, A3B10C9, A3B10C10 , A3B10C11 , A3B10C12 , A5B1C10 , A5B1C11 , A5B1C12 , A5B1C13 , A5B1C14 , A3B10C13 , A3B10C14 , A3B10C15 , A3B10C16 , A5B1C15 , A5B1C16 , A5B1C17 , A5B1C18 , A5B1C19 , A3B10C17 , A3B10C18 , A3B10C19 , A3B10C20 , A5B1C20 , A5B1C21 , A5B2C1, A5B2C2 , A5B2C3 , A3B10C21 , A3B11C1 , A3B11C2, A3B11C3 , A3B11C4 , A5B2C4 , A5B2C5 , A5B2C6 , A5B2C7 , A5B2C8 , A5B2C9, A3B11C5 , A3B11C6 , A3B11C7, A3B11C8 , A3B11C9 , A5B2C10 , A5B2C11 , A5B2C12 , A5B2C13 , A5B2C14 . A3B11C10 , A3B11C11 , A3B11C12 , A3B11C13 , A5B2C15 , A5B2C16 , A5B2C17 , A5B2C18 , A5B2C19 , A3B11C14 , A3B11C15 , A3B11C16 , A3B11C17 , A5B2C20 , A5B2C21, A5B3C1, A5B3C2 , A5B3C3 , A3B11C18 , A3B11C19 , A3B11C20 , A3B11C21, A3B12C1, A5B3C4 , A5B3C5 , A5B3C6 , A5B3C7, A5B3C8 , A5B3C9 , A3B12C2, A3B12C3 , A3B12C4, A3B12C5 , A3B12C6 , A5B3C10 , A5B3C11 , A5B3C12 , A5B3C13 , A5B3C14 , A3B12C7 , A3B12C8, A3B12C9 , A3B12C10 , A3B12C11 , A5B3C15 , A5B3C16 , A5B3C17 , A5B3C18 , A5B3C19 , A3B12C12 , A3B12C13 , A3B12C14 , A3B12C15 , A5B3C20 , A5B3C21 , A5B4C1, A5B4C2 , A5B4C3 , A3B12C16 , A3B12C17 , A3B12C18 , A3B12C19 , A5B4C4 , A5B4C5 , A5B4C6 , A5B4C7, A5B4C8 , A5B4C9 , A3B12C20 , A3B12C21, A4B1C1 , A4B1C2, A4B1C3 , A5B4C10 , A5B4C11 , A5B4C12 , A5B4C13 , A5B4C14 , A4B1C4, A4B1C5, A4B1C6 , A4B1C7 , A4B1C8 , A4B1C9 , A5B4C15 , A5B4C16 , A5B4C17 , A5B4C18 , A5B4C19 , A4B1C10 , A4B1C11 , A4B1C12 , A4B1C13 , A4B1C14 . A5B4C20 , A5B4C21 , A5B5C1, A5B5C2, A5B5C3. A4B1C15 , A4B1C16 , A4B1C17 , A4B1C18 , A4B1C19 , A5B5C4, A5B5C5, A5B5C6 , A5B5C7, A5B5C8, A5B5C9, A4B1C20 , A4B1C21 , A4B2C1, A4B2C2 , A4B2C3 , A5B5C10 , A5B5C11 , A5B5C12 , A5B5C13 , A5B5C14 , A4B2C4, A4B2C5, A4B2C6 , A4B2C7, A4B2C8, A4B2C9, A5B5C15 , A5B5C16 , A5B5C17 , A5B5C18 , A5B5C19 , A4B2C10 , A4B2C11 , A4B2C12 , A4B2C13 , A4B2C14 , A5B5C20 , A5B5C21 , A5B6C1, A5B6C2, A5B6C3 , A4B2C15 , A4B2C16 , A4B2C17 , A4B2C18 , A4B2C19 , A5B6C4 , A5B6C5, A5B6C6 , A5B6C7 , A5B6C8 , A5B6C9, A4B2C20 , A4B2C21, A4B3C1, A4B3C2 , A4B3C3 , A5B6C10 , A5B6C11, A5B6C12 , A5B6C13 , A5B6C14 , A4B3C4 , A4B3C5 , A4B3C6 , A4B3C7 , A4B3C8 , A4B3C9 , A5B6C15 , A5B6C16 , A5B6C17 , A5B6C18 , A5B6C19 . A4B3C10 , A4B3C11, A4B3C12 , A4B3C13 , A4B3C14 , A5B6C20 , A5B6C21 , A5B7C1, A5B7C2 , A5B7C3 , A4B3C15 , A4B3C16 , A4B3C17 , A4B3C18 , A4B3C19 , A5B7C4, A5B7C5, A5B7C6 , A5B7C7 , A5B7C8 , A5B7C9 , A4B3C20 , A4B3C21, A4B4C1, A4B4C2, A4B4C3, A5B7C10 , A5B7C11 , A5B7C12 , A5B7C13 , A5B7C14 . A4B4C4, A4B4C5, A4B4C6 , A4B4C7, A4B4C8, A4B4C9 , A5B7C15 , A5B7C16 , A5B7C17 , A5B7C18 , A5B7C19 , A4B4C10 , A4B4C11 , A4B4C12 , A4B4C13 , A4B4C14 , A5B7C20 , A5B7C21, A5B8C1, A5B8C2, A5B8C3 , A4B4C15 , A4B4C16 , A4B4C17 , A4B4C18 , A4B4C19 , A5B8C4 , A5B8C5 , A5B8C6 , A5B8C7, A5B8C8 , A5B8C9 , A4B4C20 , 4B4C21 , A4B5C1 , A4B5C2, A4B5C3 , A5B8C10 , A5B8C11 , A5B8C12, A5B8C13 , A5B8C14 , A4B5C4, A4B5C5, A4B5C6 , A4B5C7, A4B5C8 , A4B5C9 , A5B8C15 , A5B8C16 , A5B8C17 , A5B8C18 , A5B8C19 , A4B5C10 , A4B5C11, A4B5C12 , A4B5C13 , A4B5C14 , A5B8C20 , A5B8C21 , A5B9C1, A5B9C2, A5B9C3 , A4B5C15 , A4B5C16 , A4B5C17 , A4B5C18 , 4B5C19 , A5B9C4, A5B9C5, A5B9C6 , A5B9C7, A5B9C8 , A5B9C9 , A4B5C20 , A4B5C21 , A4B6C1 , A4B6C2, A4B6C3 , A5B9C10 , A5B9C11 , A5B9C12, A5B9C13 , A5B9C14 , A4B6C4 , A4B6C5 , A4B6C6 , A4B6C7, A4B6C8 , A4B6C9 , A5B9C15 , A5B9C16 , A5B9C17 , A5B9C18 , A5B9C19 , A4B6C10 , A4B6C11, A4B6C12 , A4B6C13 , A4B6C14 , A5B9C20 , A5B9C21, A5B10C1, A5B10C2 , A5B10C3 , A4B6C15 , A4B6C16 , A4B6C17 , A4B6C18 , A4B6C19 , A5B10C4 , A5B10C5, A5B10C6 , A5B10C7 , A5B10C8 , A4B6C20 , A4B6C21 , A4B7C1 , A4B7C2, A4B7C3 , A5B10C9, A5B10C10 , A5B10C11 , A5B10C12 , A4B7C4, A4B7C5, A4B7C6 , A4B7C7 , A4B7C8 , A4B7C9 , A5B10C13 , A5B10C14 , A5B10C15 , A5B10C16 , A4B7C10 , A4B7C11 , A4B7C12 , A4B7C13 , A4B7C14 , A5B10C17 , A5B10C18 , A5B10C19 , A5B10C20 , A4B7C15 , A4B7C16 , A4B7C17 , A4B7C18 , A4B7C19 , A5B10C21 , A5B11C1, A5B11C2 , A5B11C3 , A5B11C4 , A4B7C20 , A4B7C21, A4B8C1, A4B8C2, A4B8C3, A5B11C5 , A5B11C6 , A5B11C7 , A5B11C8 , A5B11C9 , A4B8C4, A4B8C5, A4B8C6 , A4B8C7, A4B8C8 , A4B8C9 , A5B11C10 , A5B11C11 , A5B11C12, A5B11C13 , A4B8C10 , A4B8C11 , A4B8C12 , A4B8C13 , A4B8C14 , A5B11C14 , A5B11C15 , A5B11C16 , A5B11C17 , A4B8C15 , A4B8C16 , A4B8C17 , A4B8C18 , A4B8C19 , A5B11C18 , A5B11C19 , A5B11C20 , A5B11C21, A5B12C1, A4B8C20 , A4B8C21 , A4B9C1, A4B9C2, A4B9C3 , A5B12C2, A5B12C3, A5B12C4 , A5B12C5 , A5B12C6 , US 2017 /0306038 A1 Oct. 26 , 2017 79

A5B12C7 , A5B12C8, A5B12C9, A5B12C10 , A5B12C11 , A7B3C15 , A7B3C16 , A7B3C17 , A7B3C18 , A7B3C19 , A5B12C12 , A5B12C13 , A5B12C14 , A5B12C15 , A7B3C20 , A7B3C21, A7B4C1, A7B4C2, A7B4C3, A5B12C16 , A5B12017 , A5B12C18 , A5B12C19 , A7B4C4, A7B4C5 , A7B4C6 , A7B4C7 , A7B4C8 , A7B4C9, A5B12C20 , A5B12C21, A6B1C1 , A6B1C2, A6B1C3 , A7B4C10 , A7B4C11, A7B4C12 , A7B4C13 , A7B4C14 , A6B1C4, A6B1C5, A6B1C6 , A6B1C7, A6B1C8, A6B1C9, A7B4C15 , A7B4C16 , A7B4C17 , A7B4C18 , A7B4C19 , A6B1010 , A6B1C11 , A6B1C12 , A6B1C13 , A6B1C14 . A7B4C20 , A7B4C21 , A7B5C1 , A7B5C2 , A7B5C3 , A6B1C15 , A6B1C16 , A6B1C17 , A6B1C18 , A6B1C19 , A7B5C4, A7B5C5 , A7B5C6 , A7B5C7 , A7B5C8 , A7B5C9, A6B1C20 , A6B1C21, A6B2C1, A6B2C2, A6B2C3 , A7B5C10 , A7B5C11 , A7B5C12 , A7B5C13 , A7B5C14 , A6B2C4 , A6B2C5 , A6B2C6 , A6B2C7 , A6B2C8, A6B2C9 , A7B5C15 , A7B5C16 , A7B5C17, A7B5C18, A7B5C19 , A6B2C10 , A6B2C11 , A6B2C12 , A6B2C13 , A6B2C14 , A7B5C20 , A7B5C21 , A7B6C1, A7B6C2 , A7B6C3 , A6B2C15 , A6B2C16 , A6B2C17 , A6B2C18 , A6B2C19 , A7B6C4, A7B6C5, A7B6C6 , A7B6C7, A7B6C8 , A7B6C9 , A6B2C20 , A6B2C21 , A6B3C1 , A6B3C2, A6B3C3 , A7B6C10 , A7B6C11 , A7B6C12, A7B6C13 , A7B6C14 , A6B3C4, A6B3C5, A6B3C6 , A6B3C7, A6B3C8 , A6B3C9 , A7B6C15 , A7B6C16 , A7B6C17 , A7B6C18 , A7B6C19 , A6B3C10 , A6B3C11 , A6B3C12 , A6B3C13 , A6B3C14 , A7B6C20 , A7B6C21, A7B7C1, A7B7C2, A7B7C3, A6B3C15 , A6B3C16 , A6B3C17 , A6B3C18 , A6B3C19 , A7B7C4, A7B7C5, A7B7C6 , A7B7C7, A7B7C8 , A7B7C9 , A6B3C20 , A6B3C21, A6B4C1, A6B4C2, A6B4C3, A7B7C10 , A7B7C11 , A7B7C12 , A7B7C13 , A7B7C14 , A6B4C4 , A6B4C5 , A6B4C6 , A6B4C7, A6B4C8 , A6B4C9 , A7B7C15 , A7B7C16 , A7B7C17 , A7B7C18 , A7B7C19 , A6B4C10 , A6B4C11 , A6B4C12 , A6B4C13 , A6B4C14 , A7B7C20 , A7B7C21, A7B8C1, A7B8C2, A7B8C3 , A6B4C15 , A6B4C16 , A6B4C17 , A6B4C18 , A6B4C19 , A7B8C4 , A7B8C5 , A7B8C6 , A7B8C7 , A7B8C8 , A7B8C9 , A6B4C20 , A6B4C21, A6B5C1, A6B5C2, A6B5C3, A7B8C10 , A7B8C11 , A7B8C12 , A7B8C13 , A7B8C14 , A6B5C4, A6B5C5, A6B5C6 , A6B5C7, A6B5C8 , A6B5C9 , A7B8C15 , A7B8C16 , A7B8C17 , A7B8C18 , A7B8C19 . A6B5C10 , A6B5C11 , A6B5C12 , A6B5C13 , A6B5C14 , A7B8C20 , A7B8C21 , A7B9C1, A7B9C2, A7B9C3 , A6B5C15 , A6B5C16 , A6B5C17 , A6B5C18 , A6B5C19 , A7B9C4 , A7B9C5 , A7B9C6 , A7B9C7, A7B9C8, A7B9C9 , A6B5C20 , A6B5C21 , A6B6C1, A6B6C2, A6B6C3 , A7B9C10 , A7B9C11 , A7B9C12 , A7B9C13 , A7B9C14 . A6B6C4, A6B6C5, A6B6C6 , A6B6C7, A6B6C8, A6B6C9, A7B9C15 , A7B9C16 , A7B9C17 , A7B9C18 , A7B9C19 , A6B6C10 , A6B6C11 , A6B6C12 , A6B6C13 , A6B6C14 , A7B9C20 , A7B9C21, A7B10C1, A7B10C2 , A7B10C3 , A6B6C15 , A6B6C16 , A6B6C17 , A6B6C18 , A6B6C19 , A7B10C4 , A7B10C5 , A7B10C6 , A7B10C7, A7B10C8 , A6B6C20 , A6B6C21 , A6B7C1, A6B7C2, A6B7C3 , A7B10C9 , A7B10C10 , A7B10C11, A7B10C12 , A6B7C4 , A6B7C5 , A6B7C6 , A6B7C7, A6B7C8 , A6B7C9, A7B10C13 , A7B10C14 , A7B10C15 , A7B10C16 , A6B7C10 , A6B7C11, A6B7C12 , A6B7C13 , A6B7C14 , A7B10C17 , A7B10C18 , A7B10C19 , A7B10C20 , A6B7C15 , A6B7C16 , A6B7C17 , A6B7C18 , A6B7C19 , A7B10C21, A7B11C1, A7B11C2, A7B11C3 , A7B11C4 , A6B7C20 , A6B7C21 , A6B8C1, A6B8C2 , A6B8C3 , A7B11C5, A7B11C6 , A7B11C7, A7B11C8, A7B11C9 , A6B8C4, A6B8C5, A6B8C6 , A6B8C7, A6B8C8 , A6B8C9 , A7B11C10 , A7B11C11 , A7B11C12, A7B11C13 , A6B8C10 , A6B8C11 , A6B8C12 , A6B8C13 , A6B8C14 , A7B11C14 , A7B11C15 , A7B11C16 , A7B11C17 . A6B8C15 , A6B8C16 , A6B8C17 , A6B8C18 , A6B8C19 , A7B11C18 , A7B11C19 , A7B11C20 , A7B11C21, A7B12C1, A6B8C20 , A6B8C21, A6B9C1, A6B9C2, A6B9C3, A7B12C2 , A7B12C3, A7B12C4, A7B12C5, A7B12C6 , A6B9C4, A6B9C5, A6B9C6 , A6B9C7, A6B9C8, A6B9C9, A7B12C7 , A7B12C8 , A7B12C9 , A7B12C10 , A7B12C11 . A6B9C10 , A6B9C11 , A6B9C12 , A6B9C13 , A6B9C14 , A7B12C12 , A7B12C13 , A7B12C14 , A7B12C15 , A6B9C15 , A6B9C16 , A6B9C17 , A6B9C18 , A6B9C19 , A7B12C16 , A7B12C17 , A7B12C18 , A7B12C19 , A6B9C20 , A6B9C21, A6B10C1, A6B10C2, A6B10C3 , A7B12C20 , A7B12C21, A8B1C1, A8B1C2, A8B1C3 , A6B10C4 , A6B10C5 , A6B10C6 , A6B10C7 , A6B10C8 , A8B1C4 , A8B1C5 , A8B1C6 , A8B1C7 , A8B1C8 , A8B1C9 . A6B10C9, A6B10C10 , A6B10C11 , A6B10C12 , A8B1C10 , A8B1C11 , A8B1C12 , A8B1C13 , A8B1C14 , A6B10C13 , A6B10C14 , A6B10C15 , A6B10C16 , A8B1C15 , A8B1C16 , A8B1C17 , A8B1C18 , A8B1C19 , A6B10C17 , A6B10C18 , A6B10C19 , A6B10C20 , A8B1C20 , A8B1C21 , A8B2C1, A8B2C2 , A8B2C3 , A6B10C21, A6B11C1 , A6B11C2 , A6B11C3, A6B11C4 , A8B2C4 , A8B2C5 , A8B2C6 , A8B2C7, A8B2C8 , A8B2C9, A6B11C5 , A6B11C6 , A6B11C7, A6B11C8 , A6B11C9 , A8B2C10 , A8B2C11 , A8B2C12 , A8B2C13 , A8B2C14 , A6B11C10 , A6B11C11 , A6B11C12 , A6B11C13 , A8B2C15 , A8B2C16 , A8B2C17 , A8B2C18 , A8B2C19 , A6B11C14 , A6B11C15 , A6B11C16 , A6B11C17 , A8B2C20 , A8B2C21 , A8B3C1, A8B3C2, A8B3C3 , A6B11C18 , A6B11C19 , A6B11C20 , A6B11C21 , A6B12C1, A8B3C4 , A8B3C5, A8B3C6 , A8B3C7, A8B3C8, A8B3C9, A6B12C2 , A6B12C3 , A6B12C4, A6B12C5 , A6B12C6 , A8B3C10 , A8B3C11 , A8B3C12 , A8B3C13 , A8B3C14 , A6B12C7, A6B12C8 , A6B12C9, A6B12C10 , A6B12C11 , A8B3C15 , A8B3C16 , A8B3C17 , A8B3C18 , A8B3C19 , A6B12C12 , A6B12C13 , A6B12C14 , A6B12C15 , A8B3C20 , A8B3C21 , A8B4C1, A8B4C2, A8B4C3 , A6B12C16 , A6B12C17 , A6B12C18 , A6B12C19 , A8B4C4 , A8B4C5, A8B4C6 , A8B4C7, A8B4C8, A8B4C9, A6B12C20 , A6B12C21, A7B1C1, A7B1C2 , A7B1C3 , A8B4C10 , A8B4C11 , A8B4C12 , A8B4C13 , A8B4C14 . A7B1C4, A7B1C5, A7B1C6 , A7B1C7 , A7B1C8 , A7B1C9 , A8B4C15 , A8B4C16 , A8B4C17 , A8B4C18 , A8B4C19 , A7B1C10 , A7B1C11 , A7B1C12 , A7B1C13 , A7B1C14 , A8B4C20 , A8B4C21 , A8B5C1, A8B5C2, A8B5C3 , A7B1C15 , A7B1C16 , A7B1C17 , A7B1C18 , A7B1C19 , A8B5C4, A8B5C5 , A8B5C6 , A8B5C7 , A8B5C8 , A8B5C9, A7B1C20 , A7B1C21 , A7B2C1, A7B2C2 , A7B2C3 , A8B5C10 , A8B5C11 , A8B5C12 , A8B5C13 , A8B5C14 , A7B2C4 , A7B2C5 , A7B2C6 , A7B2C7, A7B2C8 , A7B2C9 , A8B5C15 , A8B5C16 , A8B5C17 , A8B5C18 , A8B5C19 , A7B2C10 , A7B2C11 , A7B2C12 , A7B2C13 , A7B2C14 , A8B5C20 , A8B5C21 , A8B6C1, A8B6C2, A8B6C3 , A7B2C15 , A7B2C16 , A7B2C17 , A7B2C18 , A7B2C19 , A8B6C4 , A8B6C5, A8B6C6 , A8B6C7, A8B6C8, A8B6C9, A7B2C20 , A7B2C21 , A7B3C1, A7B3C2, A7B3C3 , A8B6C10 , A8B6C11 , A8B6C12 , A8B6C13 , A8B6C14 , A7B3C4, A7B3C5, A7B3C6 , A7B3C7, A7B3C8 , A7B3C9 , A8B6C15 , A8B6C16 , A8B6C17 , A8B6C18 , A8B6C19 , A7B3C10 , A7B3C11, A7B3C12 , A7B3C13 , A7B3C14 , A8B6C20 , A8B6C21 , A8B7C1, A8B7C2, A8B7C3 , US 2017 /0306038 A1 Oct. 26 , 2017

A8B7C4 , A8B7C5 , A8B7C6 , A8B7C7, A8B7C8, A8B7C9 , A9B10C13, A9B10C14 , A9B10C15 , A9B10C16 , A8B7C10 , A8B7C11 , A8B7C12 , A8B7C13 , A8B7C14 , A9B10C17 , A9B10C18 , A9B10C19 , A9B10C20 , A8B7C15 , A8B7C16 , A8B7C17 , A8B7C18 , A8B7C19 , A9B10C21, A9B11C1 , A9B11C2 , A9B11C3, A9B11C4 , A8B7C20 , A8B7C21 , A8B8C1, A8B8C2 , A8B8C3, A9B11C5 , A9B11C6 , A9B11C7, A9B11C8 , A9B11C9 , A8B8C4, A8B8C5, A8B8C6 , A8B8C7, A8B8C8, A8B8C9, A9B11C10 , A9B11C11, A9B11C12 , A9B11C13 , A8B8C10 , A8B8C11 , A8B8C12 , A8B8C13 , A8B8C14 , A9B11C14 . A9B11C15 , A9B11C16 , A9B11C17 . A8B8C15 , A8B8C16 , A8B8C17 , A8B8C18 , A8B8C19 , A9B11C18 , A9B11C19 , A9B11C20 , A9B11C21 , A9B12C1, A8B8C20 , A8B8C21 , A8B9C1, A8B9C2, A8B9C3, A9B12C2 , A9B12C3, A9B12C4 , A9B12C5 , A9B12C6 , A8B9C4, A8B9C5, A8B9C6 , A8B9C7, A8B9C8 , A8B9C9 , A9B12C7 , A9B12C8, A9B12C9 , A9B12C10 , A9B12C11, A8B9C10 , A8B9C11 , A8B9C12 , A8B9C13 , A8B9C14 , A9B12C12 , A9B12C13 , A9B12C14 , A9B12C15 , A8B9C15 , A8B9C16 , A8B9C17 , A8B9C18 , A8B9C19 , A9B12C16 , A9B12C17 , A9B12C18 , A9B12C19 , A8B9C20 , A8B9C21, A8B10C1, A8B10C2, A8B10C3 , A9B12C20 , A9B12C21 , A10B1C1, A10B1C2, A10B1C3, A8B10C4 , A8B10C5 , A8B10C6 , A8B10C7 , A8B10C8, A10B1C4 , A10B1C5 , A10B1C6 , A10B1C7, A10B1C8 , A8B10C9 , A8B10C10 , A8B10C11 , A8B10C12 , A10B1C9 , A10B1C10 , A10B1C11 , A10B1C12 , A8B10C13 , A8B10C14 , A8B10C15 , A8B10C16 , A10B1C13 , A10B1C14 , A10B1C15 , A10B1C16 , A8B10C17 , A8B10C18 , A8B10C19 , A8B10C20 , A10B1C17 , A10B1C18 , A10B1C19 , A10B1C20 , A8B10C21, A8B11C1, A8B11C2 , A8B11C3 , A8B11C4 . A10B1C21 , A10B2C1, A10B2C2, A10B2C3 , A10B2C4 , A8B11C5, A8B11C6 , A8B11C7, A8B11C8 , A8B11C9 , A10B2C5, A10B2C6 , A10B2C7, A1OB2C8 , A10B2C9, A8B11C10 , A8B11C11 , A8B11C12 , A8B11C13 , A10B2C10 , A10B2C11 , A10B2C12 , A10B2C13 , A8B11C14 , A8B11C15 , A8B11C16 , A8B11C17 , A1OB2014 . A10B2C15 , A1OB2C16 , A1OB2017 , A8B11C18 , A8B11C19 , A8B11C20 , A8B11C21 , A8B12C1 , A10B2C18 , A10B2C19 , 10B2C20 , A10B2C21, A8B12C2 , A8B12C3 , A8B12C4 , A8B12C5 , A8B12C6 , A10B3C1, A10B3C2, A10B3C3 , A10B3C4 , A1OB3C5 , A8B12C7 , A8B12C8, A8B12C9, A8B12C10 , A8B12C11 , A10B3C6 , A10B3C7, A10B3C8, A10B3C9, A10B3C10 , A8B12C12 , A8B12C13 , A8B12C14 , A8B12C15 , A10B3C11 , A10B3C12 , A10B3C13 , A10B3C14 , A8B12C16 , A8B12C17 , A8B12C18 , A8B12C19 , A10B3C15 , A10B3C16 , A10B3C17 , A10B3C18 , A8B12C20 , A8B12C21, A9B1C1 , A9B1C2, A9B1C3 , A10B3C19, A10B3C20 , A10B3C21, A10B4C1, A10B4C2, A9B1C4 , A9B1C5 , A9B1C6 , A9B1C7, A9B1C8 , A9B1C9, A10B4C3 , A10B4C4 , A10B4C5, A10B4C6 , A10B4C7, A9B1C10 , A9B1C11 , A9B1C12 , A9B1C13 , A9B1C14 , A10B4C8 , A10B4C9, A10B4C10 , A10B4C11 , A10B4C12 , A9B1C15 , A9B1C16 , A9B1C17 , A9B1C18 , A9B1C19 , A10B4C13 , A10B4C14 , A10B4C15, A10B4C16 , A9B1C20 , A9B1C21 , A9B2C1, A9B2C2, A9B2C3 , A10B4C17 , A10B4C18 , A10B4C19 , A10B4C20 , A9B2C4 , A9B2C5 , A9B2C6 , A9B2C7, A9B2C8 , A9B2C9 , A10B4C21, A10B5C1, A10B5C2, A10B5C3, A10B5C4 , A9B2C10 , A9B2C11 , A9B2C12 , A9B2C13 , A9B2C14 , A10B5C5 , A10B5C6 , A10B5C7, A10B5C8 , A10B5C9 , A9B2C15 , A9B2C16 , A9B2C17 , A9B2C18 , A9B2C19 , A10B5C10 , A10B5C11 , A10B5C12 , A10B5C13 , A9B2C20 , A9B2C21, A9B3C1, A9B3C2 , A9B3C3 , A10B5C14 , A10B5C15 , A10B5C16 , A10B5C17 , A9B3C4, A9B3C5, A9B3C6 , A9B3C7, A9B3C8, A9B3C9, A10B5C18 , A10B5C19 , A10B5C20 , A10B5C21, A9B3C10 , A9B3C11 , A9B3C12 , A9B3C13 , A9B3C14 , A10B6C1, A10B6C2, A10B6C3 , A10B6C4, A10B6C5 , A9B3C15 , A9B3C16 , A9B3C17 , A9B3C18 , A9B3C19 , A10B6C6 , A10B6C7 , A10B6C8 , A10B6C9 , A10B6C10 , A9B3C20 , A9B3C21, A9B4C1 , A9B4C2, A9B4C3 , A10B6C11 , A10B6C12 , A10B6C13 , A10B6C14 , A9B4C4 , A9B4C5 , A9B4C6 , A9B4C7, A9B4C8 , A9B4C9 , A10B6C15 , A10B6C16 , A10B6C17 , A10B6C18 , A9B4C10 , A9B4C11, A9B4C12 , A9B4C13 , A9B4C14 , A10B6C19 , A10B6C20 , A10B6C21, A10B7C1, A10B7C2, A9B4C15 , A9B4C16 , A9B4C17 , A9B4C18 , A9B4C19 , A10B7C3 , A10B7C4 , A10B7C5 , A10B7C6 , A10B7C7 , A9B4C20 , A9B4C21 , A9B5C1, A9B5C2 , A9B5C3 , A10B7C8 , A10B7C9, A10B7C10 , A10B7C11, A10B7C12 , A9B5C4, A9B5C5, A9B5C6 , A9B5C7, A9B5C8 , A9B5C9 , A10B7C13 , A10B7C14 , A10B7C15, A10B7C16 , A9B5C10 , A9B5C11, A9B5C12 , A9B5C13 , A9B5C14 , A10B7C17 , A10B7C18 , A10B7C19 , A10B7C20 , A9B5C15 , A9B5C16 , A9B5C17 , A9B5C18 , A9B5C19 , A10B7C21, A10B8C1, A10B8C2 , A10B8C3, A10B8C4 , A9B5C20 , A9B5C21, A9B6C1, A9B6C2, A9B6C3 , A10B8C5, A10B8C6 , A10B8C7, A10B8C8 , A10B8C9, A9B6C4 , A9B6C5 , A9B6C6 , A9B6C7, A9B6C8 , A9B6C9, A10B8C10 , A10B8C11 , A10B8C12 , A10B8C13 , A9B6C10 , A9B6C11, A9B6C12 , A9B6C13 , A9B6C14 , A10B8C14 , A10B8C15 , A10B8C16 , A10B8C17 , A9B6C15 , A9B6C16 , A9B6C17 , A9B6C18 , A9B6C19 , A10B8C18 , A10B8C19 , A10B8C20, A10B8C21, A9B6C20 , A9B6C21 , A9B7C1, A9B7C2 , A9B7C3 , A10B9C1, A10B9C2, A10B9C3, A10B9C4, A10B9C5, A9B7C4, A9B7C5, A9B7C6 , A9B7C7 , A9B7C8 , A9B7C9 , A10B9C6 , A10B9C7, A10B9C8 , A10B9C9 , A10B9C10 , A9B7C10 , A9B7C11 , A9B7C12 , A9B7C13 , A9B7C14 , A10B9C11 , A10B9C12 , A10B9C13 , A10B9C14 , A9B7C15 , A9B7C16 , A9B7C17 , A9B7C18 , A9B7C19 , A10B9C15 , A10B9C16 , A10B9C17 , A10B9C18 , A9B7C20 , A9B7C21 , A9B8C1, A9B8C2 , A9B8C3 , A10B9C19 , A10B9C20 , A10B9C21, A10B10C1, A9B8C4, A9B8C5, A9B8C6 , A9B8C7, A9B8C8 , A9B8C9 , A10B10C2, A10B10C3 , A10B10C4, A10B10C5 , A9B8C10 , A9B8C11 , A9B8C12 , A9B8C13 , A9B8C14 , A10B10C6 , A10B10C7 , A10B10C8 , A10B10C9. A9B8C15 , A9B8C16 , A9B8C17 , A9B8C18 , A9B8C19 , A10B10C10 , A10B10C11 A10B10C12 , A10B10C13 , A9B8C20 , A9B8C21 , A9B9C1, A9B9C2, A9B9C3 , A10B10C14 , A10B10C15 , A10B10C16 , A10B10C17 , A9B9C4, A9B9C5, A9B9C6 , A9B9C7, A9B9C8 , A9B9C9 , A10B10C18 , A10B10019 , A10B10C20 , A10B10C21 . A9B9C10 , A9B9C11 , A9B9C12 , A9B9C13 , A9B9C14 , A10B11C1, A10B11C2, A10B11C3 , A10B11C4 , A9B9C15 , A9B9C16 , A9B9C17 , A9B9C18 , A9B9C19 , A10B11C5, A10B11C6 , A10B11C7, A10B11C8 , A9B9C20 , A9B9C21 , A9B10C1, A9B10C2 , A9B10C3 , A10B11C9, A10B11C10 , A10B11C11 , A10B11C12 , A9B10C4 , A9B10C5, A9B10C6 , A9B10C7 , A9B10C8 , A10B11C13 , A10B11C14 , A10B11C15 , A10B11C16 , A9B10C9 , A9B10C10 , A9B10C11 , A9B10C12 , A10B11C17 , A10B11C18 , A10B11C19 , A10B11C20 , US 2017 /0306038 A1 Oct. 26 , 2017

A10B11C21, A10B12C1, A10B12C2, A10B12C3, STING Agonists A10B12C4 , A10B12C5, A10B12C6 , A10B12C7 , A10B12C8, A10B12C9, A10B12C10 A10B12C11 , [0409 ] In an embodiment, the combination includes a A10B12C12 , A10B12C13 , A10B12C14 , A10B12C15 , STING agonist. In some embodiments , the combination is A10B12C16 , A10B12C17 , A10B12C18 , A10B12C19 , used to treat a cancer, e . g ., a cancer described herein e . g . , a A10B12C20 , A10B12C21, A11B1C1, A11B1C2, A11B1C3, solid tumor ( e . g . , a breast cancer, a squamous cell carci noma , a melanoma, an ovarian cancer, a fallopian tube A11B1C4 , A11B1C5 , A11B1C6 , A11B1C7 , A11B1C8 , carcinoma , a peritoneal carcinoma, a soft tissue sarcoma , a A11B1C9 , A11B1C10 , A11B1C11 , A11B1C12 , A11B1C13 , melanoma, a breast cancer , an esophageal cancer, a head and A11B1C14 , A11B1C15 , A11B1C16 , A11B1C17 , neck cancer, an endometrial cancer, a cervical cancer, or a A11B1C18 , A11B1C19 , A11B1C20 , A11B1C21 , A11B2C1, basal cell carcinoma ) , e . g ., a hematologic malignancy ( e . g . , A11B2C2 , A11B2C3 , A11B2C4 , A11B2C5 , A11B2C6 , a leukemia ( e . g ., a chronic lymphocytic leukemia ( CLL ) , or A11B2C7, A11B2C8 , A11B2C9, A11B2C10 , A11B2C11 , a lymphoma ( e. g. , a marginal zone B -cell lymphoma, a small A11B2C12 , A11B2C13 , A11B2C14 , A11B2C15 , lymphocytic lymphoma, a follicular lymphoma , Hodgkin A11B2C16 , A11B2C17 , A11B2C18 , A11B2C19 , lymphoma, non -Hodgkin lymphoma) ) . A11B2C20 , A11B2C21, A11B3C1, A11B3C2, A11B3C3, [0410 ] In some embodiments , the STING agonist is cyclic A11B3C4 , A11B3C5, A11B3C6 , A11B3C7 , A11B3C8 , dinucleotide , e . g ., a cyclic dinucleotide comprising purine or A11B3C9 , A11B3C10 , A11B3C11 , A11B3C12 , A11B3C13 , pyrimidine nucleobases ( e . g . , adenosine , guanine , uracil , A11B3C14 , A11B3C15 , A11B3C16 , A11B3C17 , thymine , or cytosine nucleobases ). In some embodiments , A11B3C18 , A11B3C19 , A11B3C20 , A11B3C21 , A11B4C1, the nucleobases of the cyclic dinucleotide comprise the same A11B4C2, A11B4C3, A11B4C4 , A11B4C5 , A11B4C6 , nucleobase or different nucleobases. A11B4C7, A11B4C8 , A11B4C9 , A11B4C10 , A11B4C11 , [0411 ] In some embodiments , the STING agonist com A11B4C12 , A11B4C13 , A11B4C14 , A11B4C15 , prises an adenosine or a guanosine nucleobase . In some A11B4C16 , A11B4C17 , A11B4C18 , A11B4C19 , embodiments , the STING agonist comprises one adenosine A11B4C20 , A11B4C21, A11B5C1, A11B5C2, A11B5C3 , nucleobase and one guanosine nucleobase . In some embodi A11B5C4 , A11B5C5 , A11B5C6 , A11B5C7, A11B5C8 , ments , the STING agonist comprises two adenosine nucle A11B5C9, A11B5C10 , A11B5C11 , A11B5C12 , A11B5C13 , obases or two guanosine nucleobases . A11B5C14 , A11B5C15 , A11B5C16 , A11B5C17 , [0412 ] In some embodiments , the STING agonist com A11B5C18 , A11B5C19 , A11B5C20 , A11B5C21 , A11B6C1, prises a modified cyclic dinucleotide , e . g ., comprising a A11B6C2, A11B6C3 , A11B6C4 , A11B6C5, A11B6C6 , modified nucleobase , a modified ribose , or a modified phos A11B6C7, A11B6C8, A11B6C9 , A11B6C10 , A11B6C11, phate linkage . In some embodiments , the modified cyclic A11B6C12 , A11B6C13 , A11B6C14 , A11B6C15 , dinucleotide comprises a modified phosphate linkage , e . g . , a A11B6C16 , A11B6C17 , A11B6C18 , A11B6C19 , thiophosphate . A11B6C20 , A11B6C21 , A11B7C1, A11B7C2, A11B7C3, [0413 ] In some embodiments , the STING agonist com A11B7C4 , A11B7C5 , A11B7C6 , A11B7C7 , A11B7C8 , prises a cyclic dinucleotide ( e . g ., a modified cyclic dinucle A11B7C9 , A11B7C10 , A11B7C11, A11B7C12 , A11B7C13 , otide ) with 2 , 5 ' or 3 ', 5 ' phosphate linkages. In some embodi A11B7C14 , A11B7C15 , A11B7C16 , A11B7C17 , ments , the STING agonist comprises a cyclic dinucleotide A11B7C18 , A11B7C19 , A11B7C20 , A11B7C21 , A11B8C1 , ( e . g ., a modified cyclic dinucleotide ) with Rp or Sp stereo A11B8C2, A11B8C3 , A11B8C4 , A11B8C5 , A11B8C6 , chemistry around the phosphate linkages . A11B8C7, A11B8C8, A11B8C9 , A11B8C10 , A11B8C11 , [0414 ] In some embodiments, the STING agonist is Rp ,Rp A11B8C12 , A11B8C13 , A11B8C14 , A11B8C15 , dithio 2 ', 3 ' c - di- AMP ( e . g ., Rp ,Rp - dithio c - [ A ( 2 , 5 ') pA ( 3 ' , A11B8C16 , A11B8C17 , A11B8C18 , A11B8C19 , 5 ') p ]) , or a cyclic dinucleotide analog thereof. In some A11B8C20 , A11B8C21 , A11B9C1, A11B9C2 , A11B9C3, embodiments , the STING agonist is a compound depicted in A11B9C4, A11B9C5, A11B9C6 , A11B9C7 , A11B9C8, U . S . Patent Publication No. US2015/ 0056224 ( e . g . , a com A11B9C9, A11B9C10 , A11B9C11, A11B9C12 , A11B9C13 , pound in FIG . 2c , e . g ., compound 21 or compound 22 ). In A11B9C14 , A11B9C15 , A11B9C16 , A11B9C17 , some embodiments , the STING agonist is c - [ G ( 2 ' , 5 ' ) pG ( 3 ', A11B9C18 , A11B9C19 , 11B9C20 , A11B9C21 , 5 ') p ] , a dithio ribose O - substituted derivative thereof , or a A11B10C1, A11B10C2, A11B10C3 , A11B10C4 , compound depicted in FIG . 4 of PCT Publication Nos . WO A11B10C5 , A11B10C6 , A11B10C7 , A11B10C8 , 2014 / 189805 and WO 2014 / 189806 . In some embodiments , A11B10C9 , A11B10C10 , A11B10C11 , A11B10C12 , the STING agonist is c - [ A ( 2 , 5 ' )pA ( 3 , 5 ') p ] or a dithio ribose A11B10C13 , A11B10C14 , A11B10C15 , A11B10C16 , 0 -substitued derivative thereof, or is a compound depicted in A11B10C17 , A11B10C18 , A11B10C19 , A11B10C20 , FIG . 5 of PCT Publication Nos. WO 2014 / 189805 and WO A11B10C21, A11B11C1, A11B11C2 , A11B11C3 , 2014 / 189806 . In some embodiments , the STING agonist is A11B11C4 , A11B11C5 , A11B11C6 , A11B11C7 , C - [G ( 2 ,5 ') pA ( 3 ,5 ') p ), or a dithio ribose 0 -substitued deriva A11B11C8 , A11B11C9, A11B11C10 , A11B11C11, tive thereof, or is a compound depicted in FIG . 5 of PCT A11B11C12 , A11B11C13 , A11B11C14 , A11B11C15 , Publication Nos. WO 2014 /189805 and WO 2014 / 189806 . A11B11C16 , A11B11C17 , A11B11C18 , A11B11C19 , In some embodiments , the STING agonist is 2' - O -propargyl A11B11C20 , A11B11C21 , A11B12C1, A11B12C2, cyclic - [ A ( 2 , 5 ') pA ( 3 , 5 ') p ] ( 2 - O - propargyl- ML -CDA ) or a A11B12C3, A11B12C4 , A11B12C5 , A11B12C6 , compound depicted in FIG . 7 of PCT Publication No . WO A11B12C7, A11B12C8, A11B12C9, A11B12C10 , 2014 / 189806 . A11B12C11 , A11B12C12 , A11B12C13 , A11B12C14 , [0415 ] Other exemplary STING agonists are disclosed , A11B12C15 , A11B12C16 , A11B12017 , A11B12C18 , e .g ., in PCT Publication Nos. WO 2014/ 189805 and WO A11B12C19 , A11B12C20 , or A11B12C21 . 2014 / 189806 , and U . S . Publication No . 2015 /0056225 . US 2017 /0306038 A1 Oct. 26 , 2017

TLR Agonists and activate TLR - 9 , e . g . , in monocytes/ macrophages , plas [ 0416 In an embodiment, a combination described herein macytoid dendritic cells (DCs ) and B cells , initiating includes a Toll - like receptor ( TLR ) agonist. In some immune signaling pathways and activating B cells and DCs embodiments , the combination is used to treat a cancer, e . g ., and inducing T -helper cell cytokine production . a cancer described herein , e . g ., a solid tumor ( e . g ., a breast [ 0424 ] Other exemplary TLR agonists that can be used in cancer, a squamous cell carcinoma, a melanoma, an ovarian the combination include , e . g . , TLR - 1 / 2 agonists ( e .g . , cancer , a fallopian tube carcinoma, a peritoneal carcinoma , Pam3Cys ) , TLR - 2 agonists ( e . g . , CFA , MALP2 , Pam2Cys , a soft tissue sarcoma, a melanoma, a breast cancer, an FSL - 1 , or Hib -OMPC ) , TLR - 3 agonists ( e . g ., polyribosinic : esophageal cancer , a head and neck cancer , an endometrial polyribocytidic acid (Poly I: C ) , polyadenosine -polyuridylic cancer, a cervical cancer, or a basal cell carcinoma ) , e . g . , a acid (poly AU ), polyinosinic -polycytidylic acid stabilized hematologic malignancy ( e . g ., a leukemia (e . g ., a chronic with poly - L - lysine and carboxymethylcellulose ( Hilto lymphocytic leukemia ( CLL ), or a lymphoma ( e . g ., a mar nol® ) ) , TLR - 4 agonists ( e . g . , monophosphoryl lipid A ginal zone B - cell lymphoma, a small lymphocytic lym (MPL ) , LPS , sialyl- Tn (STn ) ), TLR - 5 agonists ( e . g . , bacte phoma, a follicular lymphoma, Hodgkin lymphoma , non rial flagellin ), TLR - 7 agonists ( e . g ., imiquimod ) , TLR - 7 / 8 Hodgkin lymphoma) ) . agonists ( e . g ., resiquimod or loxoribine ) , and TLR - 9 ago 0417 ] TLRs are a family of pattern recognition receptors nists ( e . g . , unmethylated CpG dinucleotide (CpG -ODN )) . that were initially identified as sensors of the innate immune [0425 ] In another embodiment, the TLR agonist is used in system that recognize microbial pathogens . In humans, the combination with a GITR agonist, e . g . , as described in TLRs include TLR - 1 , TLR - 2 , TLR - 3 , TLR - 4 , TLR - 5 , TLR WO2004060319 , and International Publication No .: 6 , TLR - 7 , TLR - 8 , TLR - 9 , and TLR - 10 . TLR - 1 , - 2 , - 4 , - 5 , WO2014012479. and - 6 , are expressed on the surface of cells and TLR - 3 , - 7 / 8 , and - 9 are expressed with the ER compartment. Human VEGFR Inhibitors dendritic cell subsets can be identified on the basis of distinct [0426 ] In one embodiment, a combination described TLR expression patterns. The myeloid or " conventional” herein includes a vascular endothelial growth factor (VEGF ) subset of human dendritic cells express TLRs 1 - 8 and the receptor inhibitor ( e . g ., an inhibitor of one or more of plasmacytoid subset of dendritic cells express only TLR - 7 VEGFR ( e . g ., VEGFR - 1 , VEGFR - 2 , VEGFR -3 ) or VEGF ) . and TLR - 9 . Ligand binding to TLRs invokes a cascade of In some embodiments , the combination is used to treat a intra - cellular signaling pathways that induce the production cancer, e . g ., a cancer described herein , e .g ., a solid tumor of factors involved in inflammation and immunity . Upon ( e. g ., a melanoma, a breast cancer, a colon cancer, an stimulation , the myeloid subset and the plasmacytoid subset esophageal cancer, a gastrointestinal stromal tumor (GIST ) , of human dendritic cells result in antigen - specific CD4 + and a kidney cancer ( e. g ., a renal cell cancer) , a liver cancer, a CD8 + T cell priming and activation of NK cells and T - cells , non - small cell lung cancer (NSCLC ), an ovarian cancer , a respectively . pancreatic cancer , a prostate cancer, or a stomach cancer ) , [ 0418 ] In some embodiments , the TLR agonist is chosen e .g . , a hematologic malignancy ( e . g ., a lymphoma ). from one or more of a TLR - 1 agonist , a TLR - 2 agonist , a [0427 ) In some embodiments , the VEGFR inhibitor is TLR - 3 agonist, a TLR - 4 agonist , a TLR - 5 agonist, a TLR - 6 vatalanib succinate (Compound A47 ) or a compound dis agonist, a TLR - 7 agonist , a TLR - 8 agonist, a TLR - 9 agonist , closed in EP 296122 . a TLR - 10 agonist , a TLR - 1 / 2 agonist , a TLR - 2 / 6 agonist , or [0428 ] In some embodiment, the VEGFR inhibitor is an a TLR - 7 / 8 agonist. In one embodiment, the TLR agonist is inhibitor of one or more of VEGFR - 2 , PDGFRbeta , KIT or a TLR7 agonist. Raf kinase C , 1 -methyl - 5 - ( ( 2 - ( 5 - ( trifluoromethyl ) - 1H - imi [0419 ] In some embodiments , the TLR agonist is imiqui dazol- 2 - yl) pyridin - 4 - yl) oxy ) - N - ( 4 - ( trifluoromethyl) phe mod or 3 - ( 2 -Methylpropyl ) - 3 , 5 , 8 - triazatricyclo [ 7 . 4 . 0 . 02 ,6 ] nyl) - 1H - benzo [ djimidazol- 2 -amine (Compound A37 ) or a trideca - 1 ( 9 ) , 2 (6 ) , 4 , 7 ,10 , 12 -hexaen - 7 - amine . Imiquimod or compound disclosed in PCT Publication No . WO 2007 / 3 - ( 2 -Methylpropyl ) - 3 , 5 , 8 - triazatricyclo [ 7 . 4 . 0 .02 , 6 ] trideca - 1 030377 . ( 9 ) , 2 (6 ), 4 , 7 , 10 , 12 -hexaen - 7 - amine can bind to and activate [ 0429 ] Other exemplary VEGFR pathway inhibitors that TLR - 7 and /or TLR - 8 . can be used in the combinations disclosed herein include , [0420 ] In some embodiments, the TLR agonist is 852A . e . g . , bevacizumab (AVASTIN® ) , axitinib ( INLYTA? ) ; 852A is disclosed , e . g . , in Inglefield et al. J Interferon brivanib alaninate (BMS -582664 , (S ) - (( R ) - 1- (4 - (4 -Fluoro Cytokine Res . 2008 ; 28 ( 4 ) : 253 - 63 . 852A can bind to and 2 -methyl - 1H - indol- 5 - yloxy ) - 5 -methylpyrrolo [ 2 , 1 - f ][ 1 , 2 , 4 ] activate TLR - 7 and / or TLR - 8 . triazin - 6 -yloxy ) propan - 2 -yl ) 2 -aminopropanoate ); sorafenib [0421 ] In some embodiments , the TLR agonist is Bacille (NEXAVAR® ) ; pazopanib (VOTRIENT® ) ; sunitinib Calmette -Guérin (BCG ) . BCG can bind to and activate malate (SUTENT® ) ; cediranib (AZD2171 , CAS 288383 TLR - 9 . 20 - 1) ; vargatef (BIBF1120 , CAS 928326 -83 -4 ); Foretinib [0422 ] In some embodiments , the TLR agonist is EMD (GSK1363089 ); telatinib (BAY57 - 9352 , CAS 332012 -40 120108. EMD 120108 is a synthetic oligonucleotide con 5 ) ; apatinib ( YN968D1, CAS 811803 - 05 - 1 ) ; imatinib taining phosphorothioate oligodeoxynucleotide. EMD GLEEVEC®( ) ; ponatinib ( AP24534 , CAS 943319 -70 - 8 ) ; 1201081 can bind to and activate TLR - 9 , e . g , in monocytes/ tivozanib (AV951 , CAS 475108 - 18 - 0 ) ; regorafenib macrophages, plasmacytoid dendritic cells (DCs ) and B (BAY73 - 4506 , CAS 755037 -03 - 7 ) ; vatalanib dihydrochlo cells , initiating immune signaling pathways , activating B ride (PTK787 , CAS 212141 - 51 - 0 ) ; brivanib (BMS -540215 , cells and inducing T -helper cell cytokine production . CAS 649735 - 46 - 6 ); vandetanib (CAPRELSA? or [0423 ] In some embodiments , the TLR agonist is IMO AZD6474 ) ; motesanib diphosphate ( AMG706 , CAS 2055 . IMO - 2055 is a synthetic oligonucleotide containing 857876 -30 - 3 , N - ( 2 , 3 - dihydro - 3 , 3 -dimethyl - 1H - indol- 6 -yl ) unmethylated CpG dinucleotides . Mimicking unmethylated 2 - [ ( 4 - pyridinylmethyl ) amino ] - 3 -pyridinecarboxamide , CpG sequences in bacterial DNA , IMO - 2055 can bind to described in PCT Publication No . WO 02 / 066470 ) ; dovitinib US 2017 /0306038 A1 Oct. 26 , 2017

dilactic acid ( TK1258 , CAS 852433 - 84 - 2 ); linfanib [ 0433 ] In some embodiments, the c -MET inhibitor is ( ABT869, CAS 796967 - 16 - 3 ) ; cabozantinib (XL184 , CAS JNJ- 38877605 . JNJ- 38877605 is an orally available , small 849217 -68 - 1) ; lestaurtinib (CAS 111358 - 88 -4 ); N - [5 - [[ [ 5 molecule inhibitor of c -Met . JNJ- 38877605 selectively ( 1, 1 - dimethylethyl ) - 2 - oxazolyl ]methyl ]thio ] - 2 - thiazolyl] - 4 binds to c -MET , thereby inhibiting c -MET phosphorylation piperidinecarboxamide (BMS38703 , CAS 345627 - 80 - 7 ) ; and disrupting c -Met signal transduction pathways . ( 3R , 4R ) -4 - amino - 1 - ( [4 - (( 3 -methoxyphenyl )amino )pyrrolo [0434 ] In some embodiments , the c -Met inhibitor is AMG [ 2 , 1 - f ] [ 1 , 2 , 4 ]triazin - 5 - yl) methyl ) piperidin - 3 - ol 208 . AMG 208 is a selective small -molecule inhibitor of (BMS690514 ) ; N - ( 3 , 4 -Dichloro - 2 - fluorophenyl) - 6 C -MET . AMG 208 inhibits the ligand -dependent and ligand methoxy - 7 - [[ ( 3aa ,58 ,6aa )- octahydro - 2 -methylcyclopenta independent activation of c -MET , inhibiting its tyrosine [ c ] pyrrol- 5 - yl ]methoxy ] -4 - quinazolinamine (XL647 , CAS kinase activity , which may result in cell growth inhibition in 781613 - 23 - 8 ); 4 -methyl - 3 -[ [ 1- methyl - 6 - ( 3 -pyridinyl ) -1H tumors that overexpress c -Met . pyrazolo [ 3, 4 -d ]pyrimidin - 4 -yl ] amino ]- N - [3 - ( trifluorom 0435 ] In some embodiments , the c -Met inhibitor is AMG ethyl) phenyl ] - benzamide ( BHG712 , CAS 940310 -85 -0 ) ; 337 . AMG 337 is an orally bioavailable inhibitor of c -Met . aflibercept (EYLEA® ), and endostatin (ENDOSTAR® ). AMG 337 selectively binds to C -MET , thereby disrupting [0430 ] Exemplary anti - VEGF antibodies that can be used C -MET signal transduction pathways. in the combinations disclosed herein include , e . g. , a mono [0436 ] In some embodiments, the c -Met inhibitor is clonal antibody that binds to the same epitope as the LY2801653 . LY2801653 is an orally available , small mol monoclonal anti- VEGF antibody A4 . 6 . 1 produced by ecule inhibitor of c -Met . LY2801653 selectively binds to hybridoma ATCC HB 10709 ; a recombinant humanized C -MET , thereby inhibiting c -MET phosphorylation and dis anti -VEGF monoclonal antibody generated according to rupting c -Met signal transduction pathways . Presta et al. ( 1997) Cancer Res. 57 :4593 -4599 . In one [ 0437 ] In some embodiments , c -Met inhibitor is embodiment, the anti - VEGF antibody is Bevacizumab MSC2156119J. MSC2156119J is an orally bioavailable (BV ), also known as rhuMAL VEGF or AVASTIN® . It inhibitor of c- Met . MSC2156119J selectively binds to comprises mutated human IgG1 framework regions and C -MET , which inhibits c -MET phosphorylation and disrupts antigen - binding complementarity - determining regions from c -Met -mediated signal transduction pathways . the murine anti- hVEGF monoclonal antibody A . 4 .6 . 1 that [ 0438 ] In some embodiments , the c -MET inhibitor is blocks binding of human VEGF to its receptors. Bevaci capmatinib . Capmatinib is also known as INCB028060 . zumab and other humanized anti - VEGF antibodies are fur Capmatinib is an orally bioavailable inhibitor of c- MET . ther described in U . S . Pat . No . 6 ,884 ,879 issued Feb . 26 , Capmatinib selectively binds to c -Met , thereby inhibiting 2005 . Additional antibodies include the G6 or B20 series C -Met phosphorylation and disrupting c -Met signal trans antibodies ( e . g ., G6 - 31, B20 - 4 . 1 ) , as described in PCT duction pathways. Publication No . WO2005/ 012359 , PCT Publication No . [0439 ] In some embodiments , the c -MET inhibitor is WO2005 /044853 , the contents of these patent applications crizotinib . Crizotinib is also known as PF -02341066 . Crizo are expressly incorporated herein by reference . For addi tinib is an orally available aminopyridine -based inhibitor of tional antibodies see U .S . Pat . Nos . 7 , 060 , 269 , 6 ,582 ,959 , the receptor tyrosine kinase anaplastic lymphoma kinase 6 ,703 ,020 , 6 ,054 ,297 , WO98 /45332 , WO 96 /30046 , WO94 / ( ALK ) and the c -Met / hepatocyte growth factor receptor 10202 , EP 0666868B1, U . S . Patent Application Publication (HGFR ). Crizotinib , in an ATP - competitive manner , binds to Nos. 2006009360 , 20050186208 , 20030206899 , and inhibits ALK kinase and ALK fusion proteins. In 20030190317 , 20030203409, and 20050112126 ; and Pop addition , crizotinib inhibits c -Met kinase , and disrupts the kov et al, Journal of Immunological Methods 288 : 149- 164 c -Met signaling pathway . Altogether, this agent inhibits ( 2004 ) . Other antibodies include those that bind to a func tumor cell growth . tional epitope on human VEGF comprising of residues F17 , [0440 ] In some embodiments , the c -MET inhibitor is M18 , D19 , Y21 , Y25 , 289 , 191 , K1 01, E1 03 , and C104 or, golvatinib . Golvatinib is an orally bioavailable dual kinase alternatively , comprising residues F17 , Y21, Q22 , Y25 , D63 , inhibitor of c -MET and VEGFR - 2 with potential antine 183 and 289. oplastic activity . Golvatinib binds to and inhibits the activi C -MET Inhibitors ties of both c -MET and VEGFR - 2 , which may inhibit tumor [0431 ] In one embodiment , a combination described cell growth and survival of tumor cells that overexpress herein includes an inhibitor of c -MET . In some embodi these receptor tyrosine kinases . ments , the combination is used to treat a cancer, e . g . , a (0441 ] In some embodiments , the c -MET inhibitor is cancer described herein , e . g . , a solid tumor ( e . g . , a non -small tivantinib . Tivantinib is also known as ARQ 197 . Tivantinib cell lung cancer , a pancreatic cancer , a liver cancer, a thyroid is an orally bioavailable small molecule inhibitor of C -MET . cancer, a brain tumor (e . g ., a glioblastoma ), a kidney cancer Tivantinib binds to the c -MET protein and disrupts c -Met ( e . g ., a renal cell carcinoma ), a head and neck cancer ( e . g . , signal transduction pathways , which may induce cell death a head and neck squamous cell carcinoma ) . in tumor cells overexpressing C -MET protein or expressing [0432 ] In some embodiments , the c- MET inhibitor is consitutively activated c -Met protein . Compound A17 or a compound described in U .S . Pat. Nos. 7 ,767 ,675 and 8 ,420 ,645 ) . C -MET , a receptor tyrosine kinase TGFb Inhibitors overexpressed or mutated in many tumor cell types , plays (0442 ] In one embodiment, a combination described key roles in tumor cell proliferation , survival, invasion , herein includes a transforming growth factor beta ( TGF- B ) metastasis , and tumor angiogenesis . Inhibition of c -MET inhibitor . In some embodiments , the combination is used to may induce cell death in tumor cells overexpressing C -MET treat a cancer, e . g ., a cancer described herein , e . g ., a solid protein or expressing constitutively activated c -MET pro tumor ( e . g . , a brain cancer ( e . g . , a glioma ) , a melanoma, a tein . kidney cancer ( e . g ., a renal cell carcinoma ), a pleural malig US 2017 /0306038 A1 Oct. 26 , 2017 84 nant mesothelioma ( e . g ., a relapsed pleural malignant meso A2AR Antagonists thelioma ), or a breast cancer ( e . g ., a metastatic breast [0453 ] In one embodiment, a combination described cancer )) . herein includes an adenosine A2a receptor (A2aR ) antago [0443 ] In some embodiments , the TGF -B inhibitor is fre nist ( e . g . , an inhibitor of A2R pathway , e . g . , an adenosine solimumab (CAS Registry Number : 948564 - 73 - 6 ) . Fresoli inhibitor, e . g . , an inhibitor of A2aR or CD - 73 ) . In some mumab is also known as GC1008 . Fresolimumab is a human embodiments , the combination is used to treat a cancer, e . g . , monoclonal antibody that binds to and inhibits TGF - beta a cancer described herein . isoforms 1 , 2 and 3 . [0454 ] In some embodiments , the A2aR antagonist is [0444 ] Fresolimumab is disclosed , e . g ., in WO 2006 / istradefylline (CAS Registry Number : 155270 - 99 - 8 ) . 086469 , U . S . Pat . No . 8 , 383 ,780 , and U . S . Pat. No . 8 , 591 , Istradefylline is also known as KW -6002 or 8 -[ ( E ) -2 - ( 3, 4 901 . dimethoxyphenyl) vinyl] - 1, 3 -diethyl - 7 -methyl - 3 ,7 -dihydro [ 0445 ] In some embodiments , the TGF- B inhibitor is 1H -purine - 2 , 6 - dione. Istradefylline is disclosed , e . g . , in XOMA 089 . XOMA 089 is also known as XPA .42 .089 . LeWitt et al . ( 2008 ) Annals of Neurology 63 ( 3 ) : 295 - 302) . XOMA 089 is a fully human monoclonal antibody that [0455 ] In some embodiments , the A2aR antagonist is tozadenant (Biotie ). Tozadenant is also known as SYN115 or specifically binds and neutralizes TGF - beta 1 and 2 ligands. 4 - hydroxy - N - ( 4 -methoxy - 7 -morpholin - 4 - yl- 1 , 3 -benzothi [0446 ] The heavy chain variable region of XOMA 089 has azol- 2 - yl) - 4 -methylpiperidine - 1 -carboxamide . Tozadenant the amino acid sequence disclosed as SEQ ID NO : 6 in WO blocks the effect of endogenous adenosine at the A2a recep 2012 / 167143 . The light chain variable region of XOMA 089 tors, resulting in the potentiation of the effect of dopamine has the amino acid sequence disclosed as SEQ ID NO : 8 in at the D2 receptor and inhibition of the effect of glutamate WO 2012 / 167143 . at the mGluR5 receptor. e. g . , In some embodiments , the A2aR antagonist is preladenant (CAS Registry Number: IDO / TDO Inhibitors 377727 -87 - 2 ) . Preladenant is also known as SCH 420814 or 2 -( 2 -Furanyl ) - 7 -[ 2 - [ 4 -[ 4 - (2 -methoxyethoxy )phenyl ] - 1 -pip [0447 ] In one embodiment, a combination described erazinyl] ethyl] 7H - pyrazolo [ 4 , 3 - e ] [ 1 , 2 , 4 ] triazolo [ 1 , 5 - c ]py herein includes an inhibitor of indoleamine 2 , 3 - dioxygenase rimidine - 5 - amine . Preladenant was developed as a drug that ( IDO ) and / or tryptophan 2 , 3 - dioxygenase ( TDO ) . In some acted as a potent and selective antagonist at the adenosine embodiments , the combination is used to treat a cancer, e . g . , A2A receptor. a cancer described herein , e . g ., a solid tumor ( e . g . , mela [0456 ] In some embodiments , the A2R antagonist is noma, non -small cell lung cancer, colon cancer, squamous vipadenan . Vipadenan is also known as BIIB014 , V2006 , or cell head and neck cancer, ovarian cancer , peritoneal cancer, 3 - [ ( 4 - amino - 3 -methylphenyl ) methyl ] - 7 - furan - 2 - yl) triazolo fallopian tube cancer, breast cancer ( e . g . , metastatic or [ 4 , 5 - d ]pyrimidin - 5 -amine . e . g . , In some embodiments , the HER2 -negative breast cancer ) ) , e . g . , a hematologic malig A2aR antagonist is PBF - 509 ( Palobiofarma) . e . g ., In some nancy ( e. g . , a lymphoma, e . g ., a non -Hodgkin ' s lymphoma embodiments , the A2aR antagonist, e . g . , PBF -509 is admin or a Hodgkin ' s lymphoma ( e . g . , a diffuse large B - cell istered at a daily dose of about 80 mg, 160 mg, or 240 mg. lymphoma (DLBCL )) ) . 104571 Other exemplary A2aR antagonists include , e . g . , [0448 ] In some embodiments , the IDO / TDO inhibitor is ATL -444 , MSX - 3 , SCH - 58261, SCH - 412 , 348 , SCH -442 , chosen from (4E ) - 4 - [ ( 3 - chloro - 4 - fluoroanilino )- nitrosom 416 , VER -6623 , VER -6947 , VER - 7835 , CGS- 15943 , or ethylidene ] - 1 , 2 , 5 - oxadiazol- 3 - amine ( also known as ZM - 241 ,385 . INCB24360 ) , indoximod ( 1 -methyl - D - tryptophan ), or a - cy [0458 ). In some embodiments , the A2aR antagonist is an clohexyl -5H - Imidazo [ 5 , 1 - alisoindole - 5 - ethanol ( also A2aR pathway antagonist ( e . g ., a CD -73 inhibitor, e . g . , an known as NLG919 ) . anti- CD73 antibody ) is MEDI9447 . MEDI9447 is a mono clonal antibody specific for CD73 . Targeting the extracel [0449 ] In some embodiments , the IDO / TDO inhibitor is lular production of adenosine by CD73 may reduce the epacadostat (CAS Registry Number : 1204669- 58 - 8 ) . Epaca immunosuppressive effects of adenosine . MEDI9447 was dostat is also known as INCB24360 or INCB024360 (In reported to have a range of activities, e . g ., inhibition of cyte ). Epacadostat is a potent and selective indoleamine CD73 ectonucleotidase activity , relief from AMP- mediated 2 , 3 - dioxygenase ( IDO1) inhibitor with IC50 of 10 nM , lymphocyte suppression , and inhibition of syngeneic tumor highly selective over other related enzymes such as IDO2 or growth . MEDI9447 can drive changes in both myeloid and tryptophan 2 ,3 -dioxygenase (TDO ). lymphoid infiltrating leukocyte populations within the tumor [ 0450 ] In some embodiments , the IDO / TDO inhibitor is microenvironment. These changes include , e . g ., increases in indoximod (New Link Genetics ) . Indoximod , the D isomer CD8 effector cells and activated macrophages, as well as a of 1 -methyl - tryptophan , is an orally administered small reduction in the proportions of myeloid -derived suppressor molecule indoleamine 2 , 3 - dioxygenase ( IDO ) pathway cells (MDSC ) and regulatory T lymphocytes. inhibitor that disrupts the mechanisms by which tumors evade immune -mediated destruction . Oncolytic Viruses [0451 ] In some embodiments , the IDO / TDO inhibitor is [0459 ] In some embodiments , a combination as described NLG919 (New Link Genetics ) . NLG919 is a potent IDO herein includes an oncolytic virus . In embodiments , onco ( indoleamine- ( 2 , 3 ) - dioxygenase ) pathway inhibitor with lytic viruses are capable of selectively replicating in and Ki/ EC50 of 7 nM / 75 nM in cell - free assays . triggering the death of or slowing the growth of a cancer cell . [0452 ] In some embodiments , the IDO / TDO inhibitor is In some cases , oncolytic viruses have no effect or a minimal F001287 (Flexus / BMS) . F001287 is a small molecule effect on non -cancer cells. An oncolytic virus includes but is inhibitor of indoleamine 2 ,3 - dioxygenase 1 (IDO1 ) . not limited to an oncolytic adenovirus, oncolytic Herpes US 2017 /0306038 A1 Oct. 26 , 2017

Simplex Viruses, oncolytic retrovirus, oncolytic parvovirus, promoter drives expression of the essential Ela viral genes, oncolytic vaccinia virus, oncolytic Sinbis virus, oncolytic thereby restricting viral replication and cytotoxicity to Rb influenza virus , or oncolytic RNA virus ( e . g . , oncolytic pathway - defective tumor cells (Cold Genesys , Inc . ) ( see , reovirus, oncolytic Newcastle Disease Virus (NDV ), onco e . g ., Clinical Trial Identifier: NCT02143804 ) ; or lytic measles virus, or oncolytic vesicular stomatitis virus [0469 ] DNX - 2401 ( formerly named Delta -24 -RGD ), ( VSV ) ) . which is an adenovirus that has been engineered to replicate [ 0460 ] In some embodiments , the oncolytic virus is a selectively in retinoblastoma ( Rb ) -pathway deficient cells virus , e . g . , recombinant oncolytic virus , described in and to infect cells that express certain RGD - binding integ US2010 /0178684 A1 , which is incorporated herein by ref rins more efficiently ( Clinica Universidad de Navarra , Uni erence in its entirety. In some embodiments , a recombinant versidad de Navarra /DNAtrix , Inc .) ( see , e . g . , Clinical Trial oncolytic virus comprises a nucleic acid sequence ( e . g . , Identifier: NCT01956734 ). heterologous nucleic acid sequence ) encoding an inhibitor of [0470 ] In some embodiments , an oncolytic virus described an immune or inflammatory response , e . g ., as described in herein is administering by injection , e . g . , subcutaneous , US2010 /0178684 A1, incorporated herein by reference in its intra - arterial, intravenous, intramuscular, intrathecal, or entirety . In embodiments , the recombinant oncolytic virus , intraperitoneal injection . In embodiments , an oncolytic virus e . g ., oncolytic NDV, comprises a pro - apoptotic protein ( e . g . , described herein is administered intratumorally , transder apoptin ) , a cytokine ( e . g ., GM -CSF , CSF , interferon gamma, interleukin - 2 (IL - 2 ) , tumor necrosis factor- alpha ) , mally , transmuco sally , orally , intranasally , or via pulmonary an immunoglobulin ( e . g ., an antibody against ED - B fir administration . bonectin ) , tumor associated antigen , a bispecific adapter protein ( e . g . , bispecific antibody or antibody fragment Vaccines , e . g . , Scaffold Vaccines directed against NDV HN protein and a T cell co - stimula [0471 ] In one embodiment, a combination described tory receptor , such as CD3 or CD28 ; or fusion protein herein includes a vaccine , e . g . , a scaffold vaccine . In some between human IL - 2 and single chain antibody directed embodiments , the combination is used to treat a cancer , e . g . , against NDV HN protein ) . See, e . g . , Zamarin et al. Future a cancer described herein . Microbiol. 7 .3 (2012 ): 347 -67 , incorporated herein by refer [0472 ] Cancer vaccines are disclosed , e .g ., in PCT Publi ence in its entirety . In some embodiments , the oncolytic cation Nos . WO 2007 /070660 and WO 2012 / 167230 , EP virus is a chimeric oncolytic NDV described in U . S . Pat. No . 1960009 B1, U . S . Pat. No . 8, 067, 237 and U . S . Pat. No. 8 ,591 , 881 B2 , US 2012 /0122185 A1 , or US 2014 /0271677 8 , 932, 583 , and U . S . Publication No . US 2011 / 0020216 . The Al, each of which is incorporated herein by reference in components that can be used within cancer vaccines ( e . g ., their entireties . implantable scaffold materials ) are disclosed , e . g . , in PCT [0461 ] In some embodiments , the oncolytic virus com Publication Nos. WO 2009 / 102465 and WO 2013 / 106852 . prises a conditionally replicative adenovirus (CRAD ) , which Methods that can be used for administration of cancer is designed to replicate exclusively in cancer cells . See , e . g ., vaccines are disclosed , e .g ., in PCT Publication Nos. WO Alemany et al . Nature Biotechnol. 18 ( 2000 ): 723 -27 . In 2013 / 158673 , WO 2012 /048165 , and WO 2012/ 149358 . some embodiments, an oncolytic adenovirus comprises one [0473 ] In some embodiments , the cancer vaccine includes described in Table 1 on page 725 of Alemany et al. , a macroporous scaffold comprising ( i ) cells or a cell recruit incorporated herein by reference in its entirety . ment composition , and ( ii ) a deployment signal capable of [ 0462 ] Exemplary oncolytic viruses include but are not inducing or promoting migration of cells , and ( iii ) a bioac limited to the following : tive composition coated or seeded onto /into the scaffold , [0463 ] Group B Oncolytic Adenovirus (ColoAdl ) ( Psi which causes cells recruited into the scaffold be modified . Oxus Therapeutics Ltd .) (see , e . g . , Clinical Trial Identifier: Migration of the modified cells can be promoted by the NCT02053220 ) ; [ 0464 ] ONCOS - 102 (previously called CGTG - 102 ), open , interconnected macropores and the deployment signal. which is an adenovirus comprising granulocyte -macrophage [0474 ] In some embodiments , the cancer vaccine induces colony stimulating factor (GM - CSF ) (Oncos Therapeutics ) an endogenous immune response to a cancer target via ( see , e . g . , Clinical Trial Identifier : NCT01598129 ) ; administration of a porous scaffold bearing a recruitment [ 0465 ] VCN -01 , which is a genetically modified oncolytic composition and a target antigen composition , wherein an human adenovirus encoding human PH20 hyaluronidase endogenous antigen presenting cell is recruited into the (VCN Biosciences , S . L . ) ( see , e . g . , Clinical Trial Identifiers : scaffold to encounter antigen and where said cell resides NCT02045602 and NCT02045589 ) ; until a deployment signal induces egress to a lymph node [ 0466 ] Conditionally Replicative Adenovirus ICOVIR - 5 , tissue outside the scaffold , thereby stimulating an endog which is a virus derived from wild - type human adenovirus enous immune response to said cancer target. serotype 5 (Had5 ) that has been modified to selectively [ 0475 ] In some embodiments , the cancer vaccine is used replicate in cancer cells with a deregulated retinoblastoma/ to remove a target cell from a mammal using a scaffold E2F pathway ( Institut Catala d 'Oncologia ) ( see , e . g ., Clini composition . cal Trial Identifier: NCT01864759 ) ; [0476 ] In some embodiments , an in situ cancer vaccine is [0467 ] Celyvir , which comprises bone marrow -derived generated via recruitment of cancer cells to an implanted autologous mesenchymal stem cells (MSCs ) infected with scaffold and destruction of the cells using a cytotoxic agent. ICOVIR5, an oncolytic adenovirus (Hospital Infantil Uni [0477 ] In some embodiments , a cytosine - guanosine oligo versitario Niño Jesús , Madrid , Spain /Ramon Alemany ) (see , nucleotide (CpG -ODN ) is used as a componentof a scaffold , e . g ., Clinical Trial Identifier: NCT01844661) ; which can effectively reprogram and deploy dendritic cells [0468 ] CG0070 , which is a conditionally replicating onco recruited to the scaffold , and generate an effective antitumor lytic serotype 5 adenovirus ( Ad5 ) in which human E2F - 1 response .