US010363295B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 363, 295 B2 Schoor et al. ( 45 ) Date of Patent: Jul. 30 , 2019 ( 54 ) PEPTIDES AND COMBINATION OF ( 58 ) Field of Classification Search PEPTIDES FOR USE IN IMMUNOTHERAPY ??? . .. A61K 39 /00 AGAINST NHL AND OTHER CANCERS USPC . .. .. .. .. 424 / 1 . 41 See application file for complete search history . (71 ) Applicant: Immatics Biotechnologies GmbH , Tuebingen (DE ) (56 ) References Cited ( 72 ) Inventors : Oliver Schoor , Tuebingen ( DE ) ; Andrea Mahr , Tuebingen (DE ); Toni U . S . PATENT DOCUMENTS Weinschenk , Aichwald (DE ) ; Anita 9 ,023 , 803 B2 5 / 2015 Singh et al. Wiebe , Ruebgarten (DE ) ; Jens 9 , 056 , 069 B2 6 / 2015 Singh et al . Fritsche , Dusslingen (DE ) ; Harpreet 9 , 791, 443 B2 10 / 2017 Weinschenk et al. Singh , Muenchen Schwabing (DE ) 9 ,791 , 444 B2 10 / 2017 Weinschenk et al. 2008/ 0039413 A1 2 / 2008 Morris et al. 2011/ 0257890 A1 10 / 2011 Weinschenk et al. ( 73 ) Assignee: IMMATICS BIOTECHNOLOGIES 2012 /0027684 A12 / 2012 Singh et al. GMBH , Tuebingen (DE ) 2013 / 0096016 A1 4 /2013 Weinschenk et al . 2013/ 0164254 A1* 6 / 2013 Pieczykolan .. CO7K 14 /70575 ( * ) Notice : Subject to any disclaimer, the term of this 424 / 85 . 1 patent is extended or adjusted under 35 2013 /0177525 A1 7 /2013 Singh et al . U . S . C . 154 ( b ) by 0 days . FOREIGN PATENT DOCUMENTS ( 21 ) Appl. No .: 16 / 193 , 334 EP 1589100 Al 10 /2005 WO 0157273 A2 8 / 2001 ( 22 ) Filed : Nov . 16 , 2018 WO 2011037827 A2 3 / 2011 WO 2011 / 128448 A 10 / 2011 (65 ) Prior Publication Data WO 2011/ 151403 Al 12 / 2011 WO 2015 / 150327 A1 10 / 2015 US 2019 /0076514 A1 Mar . 14 , 2019 Wo 2015 / 193359 A2 12 / 2015 Related U . S . Application Data OTHER PUBLICATIONS (63 ) Continuation of application No . 15 / 436 , 385, filed on T . Weinschenk , et al. , “ Integrated Functional Genomics Approach Feb . 17 , 2017 , now Pat. No . 10 , 293 , 036 . for the Design of Patientindividual Antitumor Vaccines ” , Cancer Research , vol . 62 , Oct . 2002 , pp . 5818 - 5827 . Search Report dated Nov . 28 , 2016 . ( 60 ) Provisional application No . 62/ 297 ,495 , filed on Feb . International Search Report issued in counterpart application No. 19 , 2016 . PCT/ EP2017 / 053704 dated Jul. 17, 2017 . (30 ) Foreign Application Priority Data * cited by examiner Feb . 19 , 2016 (GB ) . .. .. .. 1602918 . 3 Primary Examiner — Sean E Aeder (51 ) Int. CI. ( 74 ) Attorney , Agent, or Firm — McBee Moore A61K 39 /00 ( 2006 .01 ) CO7K 14 /47 ( 2006 .01 ) Woodward & Vanik IP , LLC CO7K 14 /705 ( 2006 .01 ) CO7K 14 / 725 ( 2006 . 01 ) (57 ) ABSTRACT CO7K 14 / 74 ( 2006 .01 ) CO7K 16 / 30 ( 2006 .01 ) The present invention relates to peptides , proteins, nucleic C12N 5 /0783 ( 2010 .01 ) acids and cells for use in immunotherapeutic methods . In C12N 15 / 115 ( 2010 .01 ) particular, the present invention relates to the immuno C120 1 /6886 ( 2018 .01 ) therapy of cancer. The present invention furthermore relates GOIN 33 / 574 ( 2006 .01 ) to tumor -associated T -cell peptide epitopes, alone or in (52 ) U . S . CI. combination with other tumor - associated peptides that can CPC . .. .. A61K 39 /0011 ( 2013 .01 ) ; C07K 14 /4748 for example serve as active pharmaceutical ingredients of ( 2013 .01 ) ; CO7K 14 / 705 ( 2013 .01 ) ; COOK vaccine compositions that stimulate anti -tumor immune 14 / 7051 (2013 . 01 ) ; CO7K 14 / 70539 ( 2013 .01 ) ; responses, or to stimulate T cells ex vivo and transfer into CO7K 16 / 30 ( 2013 . 01 ) ; C12N 5 / 0638 patients . Peptides bound to molecules of the major histo ( 2013 .01 ) ; C12N 15 / 115 ( 2013 .01 ) ; C120 compatibility complex (MHC ) , or peptides as such , can also 1 / 6886 ( 2013 .01 ) ; GOIN 33 /57492 ( 2013 .01 ) ; be targets of antibodies, soluble T - cell receptors, and other A61K 2039 /5158 ( 2013 .01 ) ; COZK 2319 / 33 binding molecules. ( 2013 .01 ) ; C12N 2310 / 16 ( 2013 .01 ) ; C12N 2501 / 50 ( 2013 . 01 ) ; C120 2600 / 106 ( 2013 .01 ) ; C12Q 2600 / 156 (2013 . 01 ) ; C12Q 2600/ 158 16 Claims, 22 Drawing Sheets ( 2013 .01 ) Specification includes a Sequence Listing . U . S . Patent Jul. 30 , 2019 Sheet 1 of 22 US 10 , 363, 295 B2 . 18NHL samples . 3adiposetissues,adrenalglands15bloodcellsamplesy12vessels10bonemarrows7brainsen breasts,2cartilageseyes3gallbladders6hearts14kidneys19largeintestines20llvers45lungs&lymph 3pleuras,prostatessalivaryslands5skeletalmuscles11skinssmallintestines12spleensstomachs nades,7nerves3ovaries10pancreasesparathyroidglands1peritoneum5pituitary6placentas . 6testes,2thymithyroidglands9tracheas7ureters&urinarybladders5uteriesophagi . Peptide:LLSGOLPTI(A*02) 305normaltissues SeqIDNO:1 FIG.1A U . S . Patent Jul. 30 , 2019 Sheet 2 of 22 US 10 , 363 ,295 B2 . samples 3adiposetissues,adrenalglands15bloodcellsamples12vessels10bonemarrows7brains8 breasts,2cartilageseyes3gallbladders6hearts14kidneys19largeintestines20livers45lungs8lympha nodes,7nerves3ovaries10pancreasesparathyroidglands1peritoneumSpituitary6placentas ipleuras,3prostates7salivaryglands5skeletalmuscles11skinssmallintestines13spleensstarnacks 6testes,2thymithyroidglanda9tracheas7ureters&urinarybledders5utertesophagi Peptide:VLQGLTFTL(A*02) www 305normaltissues SeqIDNO:5 FIG.1B ) Units Arbitrary ( Presentation Relative U . S . Patent Jul. 30 , 2019 Sheet 3 of 22 US 10 , 363, 295 B2 . M. MMMMM MMMMMM ) LAS. LLLLLLLLLLLLSLLLLLLLLLLLLLL4449193 samples 3diposetissues,iadrenalglands15bloodcellsamples12vessels10bonemarrowsingbrains8 breasts,2cartilageseyes3gallbladders6hearts14kidneys19largeintestines20livers45lunes8lymph nodes,7nervesiovaries10pancreases3parathyroidglands1peritoneum5pituitary6placentas 3pleuras,prostates7salivaryglands5skeletalmuscles11skinsmallintestinesspleensSstomeche Stestes,2thymithyroidglands9tracheas7ureters8urinarybladders5uterte&esophagi Peptide:ILASIFETV(A*02) 305normaltissues SeqIDNO:41 FIG.1C U . S . Patent Jul. 30 , 2019 Sheet 4 of 22 US 10 , 363 ,295 B2 Cancertissues 4cancercelllines,6normaltissues(1lymphnode3spleensstomachIuterus)552braincancersbreast cancer,1cecum6coloncancers&leukocyticleukemia2liver10lung8lymphnodemyeloidcellcancer,3ovariancancersIprostaterectum4skin2stomachurinarybladder cancer,uteruscancers(fromlefttoright) Peptide:NLLEQFILL(A*02) issues . Peptidedetectedon SEQIDNO:248 lines FIG.1D ?????????????? U . S . Patent Jul. 30 , 2019 Sheet 5 of 22 US 10 , 363, 295 B2 "TT444444444 Peptide:LLSEETPSA(A*02) SEQIDNO:2 FIG.1E U . S . Patent Jul. 30 , 2019 Sheet 6 of 22 US 10 , 363, 295 B2 . .1. " 1999999999999999999* . -1. * * * * * Peptide:FLLVOTOIDL(A*02) * SEQIDNO:10 1F.FIG U . S . Patent Jul . 30 , 2019 Sheet 7 of 22 US 10, 363 , 295 B2 - ? . ?? .? FIG.1G ??????? U .S . Patentatent Jul. 30 , 2019 Sheet 8 of 22 US 10 , 363, 295 B2 100% . 02)*HLVPASWKL(APeptide: .ba SEQIDNO:13 FIG.1H U . S . Patent Jul . 30 , 2019 Sheet 9 of 22 US 10, 363 , 295 B2 ???????? Peptide:FLGSFIDHV(A*02) 26NO:IDSEQ FIG.11 U .S . Patentatent Jul. 30 , 2019 Sheet 10 of 22 US 10 , 363 ,295 B2 * * * * * * * 02)ILSTLDVEL*(APeptide: SEQIDNO:30 > FIG.1J IV U . S . Patent Jul. 30 , 2019 ????? ?? J0 zz US 10 , 363, 295 B2 11111111111111111111111111111 . ' , ' , ' ' , ' ' , ' ' . SEQIDNO:36 FIG.1K U . S . Patent JulJul. 3030, , 2019 2019 Sheet 12 of 22 US 10 ,363 ,295 B2 1. 1.2 * 1. 2. M 7 TITUT Peptide:ALLEGVKNV(A*02) SEQIDNO:43 FIG.1L U . S . Patent Jul . 3030 , , 20182019 Sheet 13 of 22 US 10 ,363 ,295 B2 . 02)A*SLDLRPLEV(Peptide: 1. FIG.1M U . S . Patent Jul. 30 , 2019 Sheet 14 of 22 US 10 , 363 ,295 B2 . FIG.1N U . S . Patent Jul. 30 , 2019 Sheet 15 of 22 US 10 ,363 ,295 B2 444444444444444444 SEQIDNO:257 FIG.10 U . S . Patent Jul 30 , 2019 Sheet 16 of 22 US 10 ,363 ,295 B2 ••• Peptide:TVLDGLEFKV(A*02) ? SEQIDNO:259 FIG.1P ?? U . S . Patent Jul. 30 , 2019 Sheet 17 of 22 US 10 ,363 ,295 B2 10NHLsamples min traintenimenterendentemente minimumco minnanhimminman un m melaminankunniambiniadminismamamahandanminumantemammametbeideomonmintenimentdelaminemineamministratieonvanderinwinterme tissue,1adrenalgland5bonemarrowscartilagecolonesophagus2eyes 6arteries,2bloodcellsamplesbralns1heartllvers3lungsveinsIadipose gallbladders,1kidney6lymphnodes4pancreases2peripheralnervespituitary glands,1rectum2salivaryskeletalmusclesskinsmallintestinespleen 1stomach,thyroidgland7tracheasurinarybladderIbreast;5ovariesplacentas wasle Normaltissuesamples(eachsamplerepresentsapoolofseveraldönorsk 1prostate,testisIthymusuterus(fromlefttoright) (Peptide:LLPPPSPAA,SEQIDNO160) domainemain entretenimientointernacionais mimic momento FIG.2A Gene:MIXL1 Expression Relative U . S . Patent Jul. 30 , 2019 Sheet 18 of 22 US 10 ,363 ,295 B2 10VAL*ølets 6arteries,2bloodcellsamplesbralns1heartlivers3lungsvelnsadipose tissue,1adrenalglandÍbonemarrowscartilagecolonesophagus2eyes glands,Irectum2salivarytkeletalmuscles1skinsmallintestinespleen 1stomach,thyroidgland7tracheosurinarybladderbreast5overiesplacentas Normaltissuesaipples(eachsamplerepresentsapoolofseveraldonors): gallbladders,Ikidney6lymphnodes4pancreases2peripheralnervespituitary iprostate,1testisIthymusuterus{fromlefttoright) 1991NO:SEQIDSLNSTTWKV,Peptide:( 2B.FIG Gene:CCR4 U . S . Patent Jul. 30 , 2019 Sheet 19 of 22 US 10 , 363, 295 B2 10NHLsamples Micaila M tissue,1adrenalglandSbonemarrowscartilagecolonesophagus2dyes 6arteries,2bloodcellsamplesbruins1heartlivers3lungsveinsadipose gallbladders,1kidney6lymphnodes4pancreases2peripheralnervespituitary glands,1rectum2salivaryskeletalmusclesskinsmallintestineIspleen 1stomach,Ithyroidgland7tracheasurinarybladderbreast5avariesplacentas Normaltissuesamples(eechsamplerepresentsapoolofseveraldonorsk.