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IIN UN TORN AT THEORMA US 20180126000A1UNUI NO TAI TIKA ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0126000 A1 MCPHERSON et al. (43 ) Pub . Date : May 10 , 2018 (54 ) GLUCOCORTICOID RECEPTOR AGONIST (22 ) Filed : Jun . 1, 2017 AND IMMUNOCONJUGATES THEREOF Related U . S . Application Data (71 ) Applicant: AbbVie Inc ., North Chicago , IL (US ) (60 ) Provisional application No . 62 / 344 ,948 , filed on Jun . ( 72 ) Inventors : Michael J. MCPHERSON , Ashby, MA 2 , 2016 , provisional application No. 62 / 371, 134 , filed (US ) ; Adrian D . HOBSON , on Aug . 4 , 2016 . Shrewsbury , MA (US ) ; Martin E . HAYES , Pepperell , MA (US ) ; Publication Classification Christopher C . MARVIN , Grayslake , (51 ) Int. Cl. IL (US ) ; Diana SCHMIDT , Antioch , A61K 47/ 68 ( 2006 .01 ) IL (US ) ; Wendy WAEGELL , CO7K 16 /24 (2006 . 01) Brookfield , MA (US ) ; Christian ( 52) U . S . CI. GOESS , Sturbridge, MA (US ) ; Jason CPC ...... A61K 47/ 6845 (2017 .08 ) ; C07K 16 / 241 Z . OH , Worcester , MA (US ) ; Axel ( 2013 .01 ) ; CO7K 2317 / 92 ( 2013 .01 ) ; A61K HERNANDEZ , JR ., Charlton , MA 47 /6803 (2017 .08 ); A61K 47 /6889 (2017 . 08 ) (US ) ; John T . RANDOLPH , Libertyville , IL ( US) (57 ) ABSTRACT Provided herein are glucocorticoid receptor agonist immu (73 ) Assignee: AbbVie Inc ., North Chicago , IL (US ) noconjugates, glucocorticoid receptor agonists , and methods of using the same, e . g . , to treat autoimmune or inflammatory ( 21 ) Appl. No. : 15 /611 , 037 diseases . Patent Application Publication May 10 , 2018 Sheet 1 of 24 US 2018 / 0126000 A1

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GLUCOCORTICOID RECEPTOR AGONIST ticoid receptor agonist immunoconjugate represented by AND IMMUNOCONJUGATES THEREOF Formulae I -a and I- b , below . Glucocorticoid receptor agonist immunoconjugates having Formulae I - a and I - b are useful RELATED APPLICATIONS for treating autoimmune diseases such as, but not limited to , rheumatoid arthritis , juvenile idiopathic arthritis , psoriatic [0001 ] This application claims priority to U . S . Provisional arthritis, ankylosing spondylitis , adult Crohn ' s disease , pedi Application No . 62 /344 ,948 , filed Jun . 2 , 2016 , and U . S . atric Crohn ' s disease, ulcerative colitis , plaque psoriasis , Provisional Application No . 62 / 371, 134 , filed Aug . 4 , 2016 , hidradenitis suppurativa , uveitis , Behcets disease , a spon each of which is herein incorporated by reference in its dyloarthropathy, or psoriasis . In one aspect , glucocorticoid entirety . receptor agonist immunoconjugates having Formulae I -a and I - b are useful for treating rheumatoid arthritis . In one REFERENCE TO A SEQUENCE LISTING aspect, glucocorticoid receptor agonist immunoconjugates SUBMITTED ELECTRONICALLY VIA having Formulae I - a and I - b are useful for treating juvenile EFS -WEB idiopathic arthritis . In one aspect , glucocorticoid receptor [0002 ] The content of the electronically submitted agonist immunoconjugates having Formulae I - a and I - b are sequence listing (Name : 3685 .0100002 _ SeqListing_ ST25 . useful for treating psoriatic arthritis . In one aspect, gluco txt, Size : 95 , 162 bytes ; and Date of Creation : Jun . 1 , 2017 ) , corticoid receptor agonist immunoconjugates having For filed with the application is herein incorporated by reference mulae I -a and I - b are useful for treating ankylosing spon in its entirety . dylitis . In one aspect , glucocorticoid receptor agonist immunoconjugates having Formulae I - a and I - b are useful FIELD OF THE INVENTION for treating adult Crohn ' s disease . In one aspect, glucocor [0003 ] The field of the invention generally relates to ticoid receptor agonist immunoconjugates having Formulae glucocorticoid receptor agonist immunoconjugates, and I - a and I - b are useful for treating pediatric Crohn ' s disease . In one aspect , glucocorticoid receptor agonist immunocon methods ofmaking and using the same, e . g ., to treat auto jugates having Formulae I- a and I- b are useful for treating immune or inflammatory diseases . ulcerative colitis . In one aspect , glucocorticoid receptor agonist immunoconjugates having Formulae I- a and I- b are BACKGROUND OF THE INVENTION useful for treating plaque psoriasis . In one aspect , glucocor [ 0004 ] Tumor Necrosis Factor alpha ( TNFa ) plays a cen ticoid receptor agonist immunoconjugates having Formulae tral role in the pathophysiology of several human disorders, I - a and I -b are useful for treating hidradenitis suppurativa. In and anti - TNFa agents ( e . g ., adalimumab , etanercept, and one aspect , glucocorticoid receptor agonist immunoconju infliximab ) have clinically validated therapeutic utility in the gates having Formulae I -a and I - b are useful for treating treatment of autoimmune and inflammatory disorders , such uveitis . In one aspect, glucocorticoid receptor agonist immu as rheumatoid arthritis , psoriasis and inflammatory bowel noconjugates having Formulae I - a and I -b are useful for disease . Despite their success in the clinic , anti - TNFa bio treating Behcets disease . In one aspect, glucocorticoid logics are still limited in the maximal efficacy they can receptor agonist immunoconjugates having Formulae I - a achieve in patients , necessitating the identification and and I- b are useful for treating a spondyloarthropathy . In one development of more potent and effective therapeutics . aspect, glucocorticoid receptor agonist immunoconjugates Patients treated with anti - TNFa biologics may also develop having Formulae I - a and I - b are useful for treating psoriasis . an immunogenic response to the therapeutic thus limiting its effectiveness . Therefore anti - TNFa therapies with lower [0007 ] In another aspect, the present disclosure provides a immunogenicity and high efficacy would be useful for glucocorticoid receptor agonist represented by Formulae further controlling disease . VII , VII - A , VII - B , VIII , VIII- a , VIII- b , IX , IX - a , and IX - b , [0005 ] Synthetic glucocorticoid receptor agonists ( e .g ., or by Formulae VII' , VII - A ', VII - B ', VIII' , VIII - a' , VIII - b ', dexamethasone , prednisolone , and budesonide ) are a potent IX ' , IX - a ', IX - b ', VII" , VII - A " , VII - B " , VIII " , VIII - a " , VIII class of small molecules used in the treatment of inflamma b " , IX " , IX - a " , and IX - b " , below , (wherein R7 is hydrogen ) tory disorders, but their utility in the chronic treatment of and the pharmaceutically acceptable salts , solvates , or pro disease is limited due to severe side effects. Several drugs thereof. In another aspect, the present disclosure approaches to retain the anti- inflammatory efficacy of syn provides a glucocorticoid receptor agonist represented by thetic glucocorticoids while sparing the unwanted toxicities Formulae VII, VII - A , VII - B , VIII , VIII - a , VIII - b , IX , IX - a , have been described (Rosen , J and Miner, J N Endocrine and IX - b , or by Formulae VII' , VII- A ', VII- B ', VIII' , VIII - a ', Reviews 26 : 452 -64 (2005 )) . However these methodologies VIII -b ', IX ', IX -a ', IX - b ', VII " , VII - A " , VII- B " , VIII" , VIII have met with little success . There is a need in the field of a " , VIII - b " , IX " , IX - a " , and IX - b " , below , (wherein R7b is autoimmune and inflammatory disease therapeutics to hydrogen ). Compounds having Formulae VII, VII -A , VII - B , develop therapeutics with enhanced efficacy and longer VIII, VIII - a , VIII- b , IX , IX - a , and IX - b , or Formulae VII' , VII - A ', VII - B ' , VIII ', VIII- a ', VIII - b ', IX ', IX - a ', IX - b ', VII " , duration of action compared to anti - TNF antibodies and with VII -A " , VII - B " , VIII " , VIII -a " , VIII - b " , IX " , IX - a " , and minimal unwanted effects . IX - b " , are useful for treating autoimmune diseases such as , but not limited to , rheumatoid arthritis , juvenile idiopathic BRIEF SUMMARY OF THE INVENTION arthritis, psoriatic arthritis , ankylosing spondylitis , adult [0006 ] In one aspect , the present disclosure provides a Crohn ' s disease , pediatric Crohn ' s disease , ulcerative coli glucocorticoid receptor agonist immunoconjugate repre tis, plaque psoriasis , hidradenitis suppurativa , uveitis , Beh sented by Formulae I- a and I- b , below , and the pharmaceu cets disease , a spondyloarthropathy, or psoriasis . In one tically acceptable salts, solvates, or prodrugs thereof. In aspect , compounds having Formulae VII , VII - A , VII - B , another aspect , the present disclosure provides a glucocor- VIII, VIII- a , VIII - b , IX , IX - a , and IX -b , or Formulae VII' , US 2018 /0126000 A1 May 10 , 2018

VII - A ', VII - B ', VIII' , VIII - a ', VIII - b ', IX ', IX - a ', IX - b ', VII " , VIII , VIII - a , VIII - b , IX , IX - a , and IX - b , or by Formulae VII' , VII- A " , VII - B " , VIII " , VIII- a " , VIII - b " , IX " , IX - a " , and VII - A ' , VII - B ', VIII' , VIII - a ', VIII- b ', IX ', IX - a ', IX - b ', VII" , IX - b " , are useful for treating rheumatoid arthritis . In one VII - A " , VII - B " , VIII" , VIII - a " , VIII - b " , IX " , IX - a " , and aspect, compounds having Formulae VII, VII - A , VII - B , IX - b " , as synthetic intermediates that can be used to prepare VIII, VIII - a , VIII - b , IX , IX - a , and IX - b , or Formulae VII , glucocorticoid receptor agonist immunoconjugates having VII - A '. VII - B '. VIII' , VIII- a ' , VIII - b ' , IX ', IX - a ', IX - b ', VII " , Formulae I - a and I - b . VII - A " , VII - B " , VIII" , VIII - a " , VIII- b " , IX " , IX - a " , and [0009 ] In another aspect , the present disclosure provides a IX - b " , are useful for treating juvenile idiopathic arthritis . In pharmaceutical composition comprising a glucocorticoid one aspect , compounds having Formulae VII , VII - A , VII - B , receptor agonist immunoconjugate represented by Formulae VIII, VIII - a , VIII - b , IX , IX - a , and IX - b , or Formulae VII ', I - a and I - b , or a glucocorticoid receptor agonist represented VII - A ', VII - B ', VIII' , VIII - a ', VIII - b ', IX ', IX - a ', IX - b ', VII" , by Formulae VII, VII - A , VII - B , VIII, VIII- a , VIII - b , IX , VII- A " , VII- B " , VIII " , VIII - a " , VIII - b " , IX " , IX - a " , and IX - a, and IX - b , or by Formulae VII' , VII - A ', VII- B ', VIII' , IX - b " , are useful for treating psoriatic arthritis . In one VIII- a' , VIII- b ', IX ', IX - a ', IX - b ', VII" , VII - A " , VII - B " , aspect , compounds having Formulae VII , VII - A , VII - B , VIII" , VIII -a " , VIII -b " , IX " , IX - a " , and IX -b " , and an VIII, VIII- a , VIII - b , IX , IX - a , and IX - b , or Formulae VII , excipient and/ or a pharmaceutically acceptable carrier . VII - A ', VII - B ', VIII ', VIII - a ', VIII -b ', IX ', IX -a ' , IX - b ' , VII " , [0010 ] In another aspect, the present disclosure provides a VII - A " , VII- B " , VIII" , VIII -a " , VIII - b " , IX ", IX -a " , and glucocorticoid receptor agonist immunoconjugate repre IX - b " , are useful for treating ankylosing spondylitis . In one sented by Formulae I - a and I - b , or a glucocorticoid receptor aspect, compounds having Formulae VII, VII - A , VII - B , agonist represented by Formulae VII , VII- A , VII - B , VIII , VIII, VIII - a , VIII - b , IX , IX - a , and IX - b , or Formulae VII' , VIII- a , VIII - b , IX , IX - a , and IX - b or by Formulae VII' , VII - A ', VII - B ', VIII ', VIII - a ', VIII -b ', IX ', IX -a ' , IX - b ' , VII " , VII - A ', VII - B ', VIII' , VIII - a ', VIII - b ', IX ', IX - a ', IX - b ', VII " , VII- A " , VII- B " , VIII " , VIII - a " , VIII - b " , IX " , IX - a " , and VII - A " , VII - B " , VIII " , VIII - a " , VIII - b " , IX " , IX - a " , and IX - b " , are useful for treating adult Crohn ' s disease. In one IX - b " , for use in treatment of autoimmune diseases . aspect , compounds having Formulae VII, VII- A , VII - B , [0011 ] In another aspect , the present disclosure provides a VIII, VIII - a , VIII - b , IX , IX - a , and IX - b , or Formulae VII' , use of a glucocorticoid receptor agonist immunoconjugates VII - A ', VII - B ', VIII ', VIII - a ', VIII -b ', IX ', IX -a ' , IX - b ' , VII " , represented by Formulae I - a and l - b , or a glucocorticoid VII- A " , VII- B " , VIII " , VIII - a " , VIII - b " , IX " , IX - a " , and receptor agonist represented by Formulae VII, VII - A , VII - B , IX - b " , are useful for treating pediatric Crohn ' s disease . In VIII , VIII - a , VIII - b , IX , IX - a , and IX - b , or by Formulae VII' , one aspect, compounds having Formulae VII , VII- A , VII - B , VII - A ', VII - B ' , VIII ', VIII- a ', VIII - b ', IX ', IX - a ', IX - b ', VII " , VIII, VIII - a , VIII - b , IX , IX - a , and IX - b , or Formulae VII ', VII - A " , VII- B " , VIII" , VIII -a ", VIII - b " , IX " , IX - a " , and VII - A ', VII - B ', VIII' , VIII -a ' , VIII -b ', IX ', IX -a ' , IX -b ', VII" , IX - b " , for the manufacture of a medicament for treating VII- A " , VII - B " , VIII " , VIII - a " , VIII - b " , IX " , IX - a " , and autoimmune diseases . IX - b " , are useful for treating ulcerative colitis . In one aspect, [0012 ]. In another aspect , the present disclosure provides compounds having Formulae VII , VII - A , VII -B , VIII , VIII methods of preparing glucocorticoid receptor agonist immu a , VIII - b , IX , IX - a , and IX - b , or Formulae VII' , VII - A ' , noconjugates represented by Formulae I -a and I- b . VII -B ', VIII ', VIII -a ', VIII -b ', IX ', IX - a' , IX -b ', VII" , VII- A ", VII - B " , VIII " , VIII - a " , VIII - b " , IX " , IX - a " , and IX - b " , are BRIEF DESCRIPTION OF THE useful for treating plaque psoriasis . In one aspect, com DRAWINGS / FIGURES pounds having Formulae VII, VII - A , VII - B , VIII , VIII - a , [0013 ] FIG . 1 shows the proteolytic stability of an ADC VIII - b , IX , IX - a , and IX - b , or Formulae VII , VII - A ', VII - B ', containing a steroid and an ADC containing MMAE VIII' , VIII -a ', VIII -b ', IX ', IX -a ' , IX -b ', VII " , VII - A " , VII - B " , (monomethyl auristatin E ) . (See Example 76 . ) VIII " , VIII - a " , VIII- b " , IX " , IX - a " , and IX - b " , are useful for [0014 ] FIG . 2 shows the kinetics of drug linker loss of treating hidradenitis suppurativa . In one aspect, compounds steroid ADC in mice . (See Example 77 .) having Formulae VII, VII- A , VII - B , VIII, VIII - a, VIII -b , IX , [ 0015 ] FIG . 3 shows the activity of a single therapeutic IX -a , and IX -b , or Formulae VII , VII - A ', VII - B ' , VIII' , dose response of anti - m TNFa steroid ADC in a mouse VIII - a ', VIII- b ', IX ' , IX - a ' , IX - b ', VII " , VII - A " , VII - B " , model of arthritis . (See Example 85 . ) VIII ", VIII - a" , VIII - b " , IX " , IX -a " , and IX -b " , are useful for [0016 ] FIG . 4 shows the activity of anti -human TNFa treating uveitis . In one aspect , compounds having Formulae steroid in hu TNFa Tg CAIA mouse model of arthritis. (See VII, VII - A , VII - B , VIII , VIII - a , VIII - b , IX , IX - a , and IX - b , Example 87 . ) or Formulae VII' , VII - A ', VII - B ', VIII' , VIII - a ', VIII- b ', IX ' , [0017 ] FIG . 5 is a HIC chromatogram showing a heterog IX - a' , IX -b ', VII " , VII - A " , VII -B " , VIII" , VIII -a " , VIII -b " , enous mixture containing antibodies having zero SM - L - Q IX " , IX -a " , and IX -b " , are useful for treating Behcets molecules attached (“ EO ” peak ) , two SM - L - Q - molecules disease . In one aspect, compounds having Formulae VII, attached (“ E2 ” peak ) , four SM - L - Q - molecules attached VII - A , VII- B , VIII, VIII - a , VIII - b , IX , IX - a , and IX - b , or ( “ E4 " peak ) , SM - L - O - moieties attached ( " E6 " peak ) , and Formulae VII , VII - A ' , VII - B ', VIII' , VIII- a ', VIII- b ', IX ', eight SM -L - Q -molecules attached (“ E8 ” peak ), depending IX - a ', IX - b ', VII " , VII- A " , VII- B " , VIII" , VIII - a " , VIII - b " , upon the number of interchain disulfide bonds that have IX " , IX - a " , and IX - b " , are useful for treating a spondyloar been reduced . ( SM is a radical of a glucocorticosteroid ; L is thropathy. In one aspect , compounds having Formulae VII , a linker , and Q is a heterobifunctional group or heterotri VII - A , VII -B , VIII , VIII -a , VIII - b , IX , IX - a, and IX - b , or functional group ; or Q is absent. ) (See Example 74 . ) Formulae VII , VII - A ' , VII - B ' , VIII' , VIII- a ' , VIII- b ', IX ', [0018 ] FIG . 6 is a SEC chromatogram of adalimumab IX - a ', IX - b ', VII " , VII- A " , VII- B " , VIII" , VIII - a " , VIII - b " , conjugated with a glucocorticosteroid . ( See Example 74 . ) IX " , IX - a " , and IX - b " , are useful for treating psoriasis . [0019 ] FIG . 7 is a line graph showing raw MS data of [ 0008 ] In another aspect, the present disclosure provides adalimumab conjugated with a glucocorticosteroid . (See compounds represented by Formulae VII , VII - A , VII - B , Example 74 .) US 2018 /0126000 A1 May 10 , 2018

[0020 ] FIG . 8 is a line graph showing deconvoluted MS [0036 ] FIG . 24 shows the activity of an anti - TNF steroid data of adalimumab conjugated with a glucocorticosteroid . ADC and an anti - CD163 steroid ADC in mouse collagen Black square and circle represent the ADC with succinimide induced arthritis . (See Example 89 . ) hydrolyzed and unhydrolyzed , respectively . The relative abundance of hydrolyzed and unhydrolyzed ADC is used to DETAILED DESCRIPTION OF THE determine hydrolysis conversion . (See Example 74 . ) INVENTION [0021 ] FIG . 9 shows that an anti- TNF steroid ADC is significantly more effective in reducing ear inflammation in [0037 ] Provided herein are glucocorticoid receptor agonist mice than the concurrent combination of the anti - TNF immunoconjugates, glucocorticoid receptor agonists , and antibody and the steroid or than the anti - TNF antibody methods of making and using the same . alone. (See Example 84 . ) 10022 ]. FIG . 10 shows that a single dose of an anti - TNF I. Definitions steroid ADC is as effective in reducing paw swelling as 21 days of daily dosing of a steroid . (See Example 85. ) [0038 ] To facilitate an understanding of the present dis [0023 ] FIG . 11 shows the change in weights of animals closure , a number of terms and phrases are defined below . treated with steroid , an anti - TNF antibody , an anti - TNF [ 0039 ] The term “ anti - TNF alpha protein ” refers to pro ADC , or an isotype ADC . (See Example 85 . ) teins that are capable of ( i ) binding to TNF alpha and ( ii ) 10024 ] FIG . 12 shows that a single dose of an anti - TNF inhibiting binding of soluble TNF - alpha to cell surface TNF steroid ADC can reduce established paw swelling , whereas receptors ( p55 and /or p75 ) and /or lysing surface TNF alpha a single dose of an anti - TNF antibody had a minimal effect. or TNF alpha receptor expressing cells in vitro in the (See Example 88 .) presence of complement. Anti - TNF alpha proteins include , [0025 ] FIG . 13 shows the effect of treatment with an for example , anti- TNF antibodies or antigen - binding frag anti - TNF steroid ADC on tarsal bone loss as measured by ments thereof ( e .g ., adalimumab or infliximab ) as well as Micro - Computed Tomography ( CT) . ( The individual data soluble TNF receptors (e .g ., etanercept) . points (e .g ., circles , squares, or triangles ) represent indi [0040 ] As used herein , the terms " antibody ” and “ anti vidual animals . ) (See Example 88 . ) bodies ” are terms of art and can be used interchangeably [0026 ] FIG . 14 shows the effect of treatment with an herein and refer to a molecule with an antigen -binding site anti - TNF steroid ADC on inflammation . ( The individual that specifically binds an antigen . data points ( e . g ., circles , squares, or triangles ) represent [ 0041 ] The term “ antibody” means an immunoglobulin individual animals . ) (See Example 88 . ) molecule that recognizes and specifically binds to a target , [0027 ] FIG . 15 shows the effect of treatment with an such as a protein , polypeptide, peptide , carbohydrate , poly anti - TNF steroid ADC on pannus formation . ( The individual nucleotide , lipid , or combinations of the foregoing through data points ( e . g ., circles , squares , or triangles ) represent at least one antigen recognition site within the variable individual animals . ) (See Example 88 . ) region of the immunoglobulin molecule . As used herein , the [0028 ] FIG . 16 shows the effect of treatment with an term “ antibody " encompasses intact polyclonal antibodies , anti - TNF steroid ADC on bone erosion . ( The individual data intact monoclonal antibodies, chimeric antibodies , human points ( e . g . , circles , squares, or triangles ) represent indi ized antibodies, human antibodies , fusion proteins compris vidual animals .) (See Example 88 .) ing an antibody, and any other modified immunoglobulin [ 0029 ] FIG . 17 shows the effect of treatment with an molecule so long as the antibodies exhibit the desired anti - TNF steroid ADC on cartilage damage . ( The individual biological activity . An antibody can be of any the five major data points ( e . g ., circles , squares , or triangles ) represent classes of immunoglobulins : IgA , IgD , IgE , IgG , and IgM , individual animals . ) (See Example 88 . ) or subclasses ( isotypes ) thereof ( e . g . IgG1, IgG2, IgG3, ( 0030 ) FIG . 18 shows effect of treatment with an anti - TNF IgG4, IgAl and IgA2 ) , based on the identity of their steroid ADC on white blood cells in peripheral blood . ( The heavy - chain constant domains referred to as alpha , delta , individual data points (e . g. , circles, squares, or diamonds ) epsilon , gamma, and mu , respectively . The different classes represent individual animals . ) (See Example 88 . ) of immunoglobulins have different and well known subunit [0031 ] FIG . 19 shows effect of treatment with an anti - TNF structures and three - dimensional configurations . Antibodies steroid ADC on neutrophils in peripheral blood . ( The indi can be naked or conjugated to other molecules such as vidual data points ( e . g . , circles , squares, or diamonds) rep toxins, radioisotopes , etc . As used herein , the term “ anti resent individual animals . ) (See Example 88 . ) body " encompasses bispecific and multispecific antibodies. [0032 ] FIG . 20 shows effect of treatment with an anti - TNF [0042 ] The term “ antibody fragment” refers to a portion of steroid ADC on lymphocytes in peripheral blood . ( The an intact antibody. An “ antigen -binding fragment” refers to individual data points ( e . g . , circles, squares , or diamonds ) a portion of an intact antibody that binds to an antigen . An represent individual animals .) (See Example 88 .) antigen - binding fragment can contain the antigenic deter [0033 ] FIG . 21 shows effect of treatment with an anti - TNF mining variable regions of an intact antibody. Examples of steroid ADC on monocytes in peripheral blood . ( The indi antibody fragments include, but are not limited to Fab , Fab ', vidual data points ( e . g . , circles , squares , or diamonds ) rep F ( ab ' ) 2 , and Fv fragments , linear antibodies, and single resent individual animals . ) (See Example 88 . ) chain antibodies. An “ antigen - binding fragment" can be a [0034 ] FIG . 22 shows effect of treatment with an anti- TNF bispecific or multispecific antigen -binding fragment. steroid ADC on eosinophils in peripheral blood . (See [ 0043 ] A “ blocking” antibody or an “ antagonist antibody Example 88 . ) is one which inhibits or reduces biological activity of the 10035 ] FIG . 23 shows effect of treatment with an anti - TNF antigen it binds , such as TNF - alpha . In some embodiments , steroid ADC on basophils in peripheral blood . (See Example blocking antibodies or antagonist antibodies substantially or 88 . ) completely inhibit the biological activity of the antigen . The US 2018 /0126000 A1 May 10 , 2018 biological activity can be reduced by 10 % , 20 % , 30 % , 50 % , methods used to generate humanized antibodies are 70 % , 80 % , 90 % , 95 % , or even 100 % . described in U .S . Pat . No. 5 ,225 , 539 ; Roguska et al ., Proc . [ 0044 ] The term “ anti - TNF- alpha antibody” or “ an anti Natl. Acad . Sci. , USA , 91 ( 3 ) : 969 - 973 ( 1994 ) , and Roguska body that binds to TNF - alpha ” refers to an antibody that is et al. , Protein Eng. 9 ( 10 ) :895 - 904 ( 1996 ) . In some embodi capable of binding TNF -alpha with sufficient affinity such ments , a “ humanized antibody" is a resurfaced antibody. that the antibody is useful as a diagnostic and /or therapeutic agent in targeting TNF- alpha . The extent of binding of an [0047 ] A “ variable region ” of an antibody refers to the anti - TNF- alpha antibody to an unrelated , non - TNF -alpha variable region of the antibody light chain or the variable protein can be less than about 10 % of the binding of the region of the antibody heavy chain , either alone or in antibody to TNF - alpha as measured , e . g . , by a radioimmu combination . The variable regions of the heavy and light noassay (RIA ) . In certain embodiments, an antibody that chain each consist of four framework regions (FR ) con binds to TNF - alpha has a dissociation constant (Kd ) of sl nected by three complementarity determining regions UM , s100 nM , s10 nM , sl nM , or s0 . 1 nM . (CDRs ) also known as hypervariable regions. The CDRs in [0045 ] A “ monoclonal” antibody or antigen - binding frag each chain are held together in close proximity by the FRs ment thereof refers to a homogeneous antibody or antigen and , with the CDRs from the other chain , contribute to the binding fragment population involved in the highly specific formation of the antigen - binding site of antibodies . There recognition and binding of a single antigenic determinant, or are at least two techniques for determining CDRs: ( 1 ) an epitope . This is in contrast to polyclonal antibodies that approach based on cross - species sequence variability ( i . e . , typically include different antibodies directed against differ Kabat et al. Sequences of Proteins of Immunological Inter ent antigenic determinants . The term “monoclonal " antibody est , (5th ed . , 1991, National Institutes of Health , Bethesda or antigen -binding fragment thereof encompasses both Md. ) ) ; and ( 2 ) an approach based on crystallographic studies intact and full- length monoclonal antibodies as well as of antigen - antibody complexes (Al - lazikani et al ( 1997) J . antibody fragments (such as Fab , Fab ', F (ab ') 2 , Fv ) , single Molec . Biol. 273 :927 -948 )) . In addition , combinations of chain ( scFv ) mutants , fusion proteins comprising an anti body portion , and any other modified immunoglobulin mol these two approaches are sometimes used in the art to ecule comprising an antigen recognition site . Furthermore , determine CDRs. " monoclonal ” antibody or antigen -binding fragment thereof [ 0048 ] The Kabat numbering system is generally used refers to such antibodies and antigen -binding fragments when referring to a residue in the variable domain (approxi thereof made in any number of manners including but not mately residues 1 - 107 of the light chain and residues 1 - 113 limited to by hybridoma, phage selection , recombinant of the heavy chain ) ( e . g . , Kabat et al. , Sequences of Immu expression , and transgenic animals . nological Interest . 5th Ed . Public Health Service, National [0046 ] The term “ humanized ” antibody or antigen - binding Institutes of Health , Bethesda , Md . ( 1991 ) ) . Unless explic fragment thereof refers to forms of non - human ( e . g .murine ) itly indicated otherwise, the numbering system used herein antibodies or antigen - binding fragments that are specific is the Kabat numbering system . immunoglobulin chains , chimeric immunoglobulins, or fragments thereof that contain minimal non -human ( e . g . , [ 0049 ] The amino acid position numbering as in Kabat , murine ) sequences. Typically , humanized antibodies or anti refers to the numbering system used for heavy chain variable gen -binding fragments thereof are human immunoglobulins domains or light chain variable domains of the compilation in which residues from the complementary determining of antibodies in Kabat et al. , Sequences of Proteins of region ( CDR ) are replaced by residues from the CDR of a Immunological Interest, 5th Ed. Public Health Service , non -human species ( e . g . mouse , rat , rabbit , hamster ) that National Institutes of Health , Bethesda, Md. ( 1991 ) . Using have the desired specificity , affinity , and capability (“ CDR this numbering system , the actual linear amino acid grafted ” ) ( Jones et al. , Nature 321 : 522 -525 ( 1986 ); Riech sequence can contain fewer or additional amino acids cor mann et al. , Nature 332 :323 - 327 ( 1988 ) ; Verhoeyen et al. , responding to a shortening of, or insertion into , a FR or CDR Science 239: 1534 -1536 ( 1988 )) . In some instances, the Fv of the variable domain . For example, a heavy chain variable framework region ( FR ) residues of a human immunoglobu domain can include a single amino acid insert (residue 52a lin are replaced with the corresponding residues in an according to Kabat ) after residue 52 of H2 and inserted antibody or fragment from a non -human species that has the residues ( e . g . residues 82a , 82b , and 82c , etc . according to desired specificity , affinity , and capability . The humanized Kabat ) after heavy chain FR residue 82 . The Kabat num antibody or antigen -binding fragment thereof can be further bering of residues can be determined for a given antibody by modified by the substitution of additional residues either in alignment at regions of homology of the sequence of the the Fv framework region and/ or within the replaced non antibody with a " standard ” Kabat numbered sequence . human residues to refine and optimize antibody or antigen Chothia refers instead to the location of the structural loops binding fragment thereof specificity , affinity , and / or capa (Chothia and Lesk J . Mol. Biol. 196 : 901- 917 ( 1987 ) ) . The bility . In general, the humanized antibody or antigen - binding end of the Chothia CDR -H1 loop when numbered using the fragment thereof will comprise substantially all of at least Kabat numbering convention varies between H32 and H34 one, and typically two or three , variable domains containing depending on the length of the loop ( this is because the all or substantially all of the CDR regions that correspond to Kabat numbering scheme places the insertions at H35A and the non -human immunoglobulin whereas all or substantially H35B ; if neither 35A nor 35B is present, the loop ends at 32 ; all of the FR regions are those of a human immunoglobulin if only 35A is present, the loop ends at 33 ; if both 35A and consensus sequence . The humanized antibody or antigen 35B are present, the loop ends at 34 ) . The AbM hypervari binding fragment thereof can also comprise at least a portion able regions represent a compromise between the Kabat of an immunoglobulin constant region or domain (Fc ) , CDRs and Chothia structural loops , and are used by Oxford typically that of a human immunoglobulin . Examples of Molecular' s AbM antibody modeling software. US 2018 /0126000 A1 May 10 , 2018

human made using any technique known in the art. This Loop KabatKabat Ab?AbM Chothia definition of a human antibody includes intact or full -length L1 L24 - L34 L24 - L34 L24 - L34 antibodies , fragments thereof, and / or antibodies comprising L2 L50 - L56 L50 - L56 L50 - L56 at least one human heavy and/ or light chain polypeptide L3 L89 - L97 L89 - L97 L89 - L97 such as, for example , an antibody comprising murine light H1 H31 -H35B H26 - H35B H26 -H32 . . 34 chain and human heavy chain polypeptides . (Kabat Numbering ) 100551 The term “ chimeric ” antibodies refers to antibodies H1Hi H31 - H35 H26 -H35 H26 -H32 wherein the amino acid sequence of the immunoglobulin ( Chothia Numbering ) molecule is derived from two or more species . Typically , the variable region of both light and heavy chains corresponds H2 H50 - H65 H50 - H58 H52 - H56 H3 H95 -H102 to the variable region of antibodies derived from one species H95 -H102 H95 -H102 of mammals ( e . g . mouse , rat, rabbit , etc . ) with the desired specificity , affinity, and capability while the constant regions [ 0050 ] In certain aspects , the CDRs of an antibody or are homologous to the sequences in antibodies derived from antigen -binding fragment thereof can be determined accord another (usually human ) to avoid eliciting an immune ing to the Chothia numbering scheme, which refers to the response in that species . location of immunoglobulin structural loops ( see , e . g . , [0056 ] The term " epitope” or “ antigenic determinant” are Chothia C & Lesk A M , ( 1987 ), J Mol Biol 196 : 901 - 917 ; used interchangeably herein and refer to that portion of an Al- Lazikani B et al. , ( 1997) J Mol Biol 273 : 927- 948; antigen capable of being recognized and specifically bound Chothia C et al. , ( 1992 ) J Mol Biol 227 : 799 - 817 ; Tramon by a particular antibody . When the antigen is a polypeptide , tano A et al. , ( 1990 ) J Mol Biol 215 ( 1 ): 175 -82 ; and U . S . Pat . epitopes can be formed both from contiguous amino acids No. 7 , 709, 226 ) . Typically , when using the Kabat numbering and noncontiguous amino acids juxtaposed by tertiary fold convention , the Chothia CDR - H1 loop is present at heavy ing of a protein . Epitopes formed from contiguous amino chain amino acids 26 to 32 , 33 , or 34 , the Chothia CDR - H2 acids are typically retained upon protein denaturing , loop is present atheavy chain amino acids 52 to 56 , and the whereas epitopes formed by tertiary folding are typically Chothia CDR -H3 loop is present at heavy chain amino acids lost upon protein denaturing . An epitope typically includes 95 to 102 , while the Chothia CDR -L1 loop is present at light at least 3 , and more usually , at least 5 or 8 - 10 amino acids chain amino acids 24 to 34 , the Chothia CDR - L2 loop is in a unique spatial conformation . present at light chain amino acids 50 to 56 , and the Chothia [0057 ] “ Binding affinity ” generally refers to the strength CDR -L3 loop is present at light chain amino acids 89 to 97 . of the sum total of noncovalent interactions between a single The end of the Chothia CDR -H1 loop when numbered using binding site of a molecule ( e . g ., an antibody ) and its binding the Kabat numbering convention varies between H32 and partner (e . g ., an antigen ). Unless indicated otherwise , as H34 depending on the length of the loop ( this is because the used herein , “ binding affinity ” refers to intrinsic binding Kabat numbering scheme places the insertions at H35A and affinity which reflects a 1 : 1 interaction between members of H35B ; if neither 35A nor 35B is present, the loop ends at 32 ; a binding pair ( e . g . , antibody and antigen ) . The affinity of a if only 35A is present, the loop ends at 33 ; if both 35A and molecule X for its partner Y can generally be represented by 35B are present, the loop ends at 34 ). the dissociation constant (Kd ) . Affinity can be measured by [0051 ] In certain aspects , the CDRs of an antibody or common methods known in the art , including those antigen -binding fragment thereof can be determined accord described herein . Low - affinity antibodies generally bind ing to the IMGT numbering system as described in Lefranc antigen slowly and tend to dissociate readily , whereas high M - P , ( 1999 ) The Immunologist 7 : 132 - 136 and Lefranc M - P affinity antibodies generally bind antigen faster and tend to et al. , ( 1999 ) Nucleic Acids Res 27 : 209 -212 . According to remain bound longer. A variety of methods of measuring the IMGT numbering scheme, VH -CDR1 is at positions 26 binding affinity are known in the art , any of which can be to 35 , VH - CDR2 is at positions 51 to 57 , VH -CDR3 is at used for purposes of the present disclosure . Specific illus positions 93 to 102 , VL -CDR1 is at positions 27 to 32 , trative embodiments are described in the following . VL - CDR2 is at positions 50 to 52 , and VL -CDR3 is at 10058 ] " Or better” when used herein to refer to binding positions 89 to 97 . affinity refers to a stronger binding between a molecule and [0052 ] In certain aspects , the CDRs of an antibody or its binding partner. “ Or better” when used herein refers to a antigen - binding fragment thereof can be determined accord stronger binding , represented by a smaller numerical Kd ing to MacCallum R M et al. , ( 1996 ) J Mol Biol 262 : value . For example , an antibody which has an affinity for an 732 - 745 . See also , e . g ., Martin A . “ Protein Sequence and antigen of “ 0 . 6 nM or better ” , the antibody ' s affinity for the Structure Analysis of Antibody Variable Domains , " in Anti antigen is < 0 . 6 nM , i . e . 0 . 59 nM , 0 . 58 nM , 0 .57 nM etc . or body Engineering , Kontermann and Dübel, eds. , Chapter 31 , any value less than 0 .6 nM . pp . 422 -439 , Springer - Verlag , Berlin (2001 ) . [0059 ] By " specifically binds, " it is generally meant that [0053 ] In certain aspects , the CDRs of an antibody or an antibody binds to an epitope via its antigen binding antigen - binding fragment thereof can be determined accord domain , and that the binding entails some complementarity ing to the ABM numbering scheme, which refers AbM between the antigen binding domain and the epitope . hypervariable regions which representa compromise According to this definition , an antibody is said to “ specifi between the Kabat CDRs and Chothia structural loops, and cally bind ” to an epitope when it binds to that epitope, via are used by Oxford Molecular ’ s AbM antibody modeling its antigen binding domain more readily than it would bind software ( Oxford Molecular Group , Inc . ). to a random , unrelated epitope . The term “ specificity ” is [0054 ] The term “ human ” antibody means an antibody used herein to qualify the relative affinity by which a certain produced by a human or an antibody having an amino acid antibody binds to a certain epitope . For example , antibody sequence corresponding to an antibody produced by a “ A ” may be deemed to have a higher specificity for a given US 2018 /0126000 A1 May 10 , 2018

epitope than antibody “ B , " or antibody “ A ” may be said to bind to epitope “ C ” with a higher specificity than it has for related epitope “ D . ” hetrerobifunctional [ 0060 ] By " preferentially binds, ” it is meant that the dipeptide group antibody specifically binds to an epitope more readily than it would bind to a related , similar , homologous, or analogous Tuin epitope . Thus , an antibody which “ preferentially binds ” to a SM given epitope would more likely bind to that epitope than to NH N SA a related epitope , even though such an antibody may cross react with the related epitope . [0061 ] An antibody is said to " competitively inhibit ” binding of a reference antibody to a given epitope if the [0066 ] In the present disclosure , the term " linker” refers to antibody preferentially binds to that epitope or an overlap any chemical moiety capable of linking a protein , e . g ., ping epitope to the extent that it blocks , to some degree , antibody, antibody fragment ( e . g ., antigen binding frag binding of the reference antibody to the epitope. Competi ments) or functional equivalent to a glucocorticosteroid . tive inhibition may be determined by any method known in Linkers may be susceptible to cleavage ( a " cleavable the art, for example, competition ELISA assays . An antibody may be said to competitively inhibit binding of the reference linker ” ) thereby facilitating release of the glucocorticoster antibody to a given epitope by at least 90 % , at least 80 % , at oid . For example , such cleavable linkers may be susceptible least 70 % , at least 60 % , or at least 50 % . to acid - induced cleavage , photo - induced cleavage , pepti [ 0062 ] The phrase " substantially similar ,” or “ substan dase - induced cleavage , esterase - induced cleavage , and dis tially the same” , as used herein , denotes a sufficiently high ulfide bond cleavage , at conditions under which the gluco degree of similarity between two numeric values (generally corticosteroid and / or the antibody remains active . one associated with an antibody of the disclosure and the Alternatively , linkers may be substantially resistant to cleav other associated with a reference / comparator antibody ) such age ( a “ noncleavable linker” ) . that one of skill in the art would consider the difference [ 0067] In the present disclosure , non - cleavable linkers are between the two values to be of little or no biological and / or any chemical moiety capable of linking a glucocorticoster statistical significance within the context of the biological oid to an antibody in a stable , covalentmanner and does not characteristic measured by said values ( e . g . , Kd values ). The difference between said two values can be less than about fall off under the categories listed above for cleaveable 50 % , less than about 40 % , less than about 30 % , less than linkers. Thus , non - cleavable linkers are substantially resis about 20 % , or less than about 10 % as a function of the value tant to acid - induced cleavage, photo -induced cleavage , pep for the reference /comparator antibody. tidase - induced cleavage, esterase - induced cleavage and dis [0063 ] A polypeptide, antibody, polynucleotide, vector, ulfide bond cleavage . Furthermore , non - cleavable refers to cell, or composition which is “ isolated ” is a polypeptide , the ability of the chemical bond in the linker or adjoining to antibody , polynucleotide , vector, cell, or composition which the linker to withstand cleavage induced by an acid , photo is in a form not found in nature . Isolated polypeptides , labile - cleaving agent, a peptidase , an esterase , or a chemical antibodies , polynucleotides, vectors , cell or compositions or physiological compound that cleaves a disulfide bond , at include those which have been purified to a degree that they conditions under which a glucocorticosteroid and / or the are no longer in a form in which they are found in nature . In antibody does not lose its activity . some embodiments , an antibody, polynucleotide , vector , [ 0068 ] Some cleavable linkers are cleaved by peptidases cell, or composition which is isolated is substantially pure . ( peptidase cleavable linkers ” ) . Only certain peptides are [0064 ] As used herein , " substantially pure” refers to mate readily cleaved inside or outside cells , see e . g . Trout et al. , rial which is at least 50 % pure ( i. e ., free from contaminants ) , 79 Proc. Natl. Acad . Sci. USA , 626 - 629 ( 1982 ) and at least 90 % pure , at least 95 % pure , at least 98 % pure , or Umemoto et al. 43 Int. J . Cancer, 677 -684 ( 1989 ) . Further at least 99 % pure . more , peptides are composed of a -amino acid units and [ 0065 ] The term “ immunoconjugate , " " conjugate ,” “ anti peptidic bonds , which chemically are amide bonds between body -drug conjugate ,” or “ ADC ” as used herein refers to a the carboxylate of one amino acid and the amino group of a compound or a derivative thereof that is linked to protein second amino acid . Other amide bonds, such as the bond such as a cell binding agent ( e. g ., an anti - TNF -alpha anti between a carboxylate and the a -amino acid group of lysine , body or fragment thereof) and is defined by a generic are understood not to be peptidic bonds and are considered formula : (SM - L - Q . - A , wherein SM = radical derived from a non - cleavable . small- molecule glucocorticoid receptor agonist, e . g . , a glu [0069 ] Some linkers are cleaved by esterases (“ esterase cocorticosteroid , L = linker, Q = heterobifunctional group , a cleavable linkers ” ) . Only certain esters can be cleaved by heterotrifunctional group , or is absent, and A = a protein ( e .g ., esterases present inside or outside of cells . Esters are formed an antibody or antigen - binding fragment thereof , an anti by the condensation of a carboxylic acid and an alcohol. TNF protein , an anti - TNF - alpha antibody or fragment Simple esters are esters produced with simple alcohols , such thereof, a soluble receptor , or a soluble TNF receptor ), and as aliphatic alcohols, and small cyclic and small aromatic n = 1 - 10 . Immunoconjugates can also be defined by the alcohols . generic formula in reverse order : A - ( Q - L - SM )n . By way of [0070 ] In some embodiments , the cleavable linker com illustration , the following generic formula shows a immu ponent may comprise a peptide comprising one to ten amino noconjugate having a dipeptide ( Ala - Ala ) linker and suc acid residues . In these embodiments, the peptide allows for cinimide thioether -based heterobifunctional group : cleavage of the linker by a protease, thereby facilitating US 2018 /0126000 A1 May 10 , 2018 7 May10, 2018 release of the glucocorticosteroid upon exposure to intrac - continued ellular proteases , such as lysosomal enzymes (Doronina et OH al. ( 2003 ) Nat . Biotechnol. 21: 778 -784 ). Exemplary pep tides include , but are not limited to , dipeptides , tripeptides , tetrapeptides, and pentapeptides . Exemplary dipeptides include , but are not limited to , alanine -alanine ( ala -ala ), valine - citrulline (vc or val- cit ), alanine - phenylalanine (af or 11111) ala - phe ) ; phenylalanine - lysine ( fk or phe - lys ) ; phenylala nine -homolysine (phe -homolys ); and N -methyl - valine - cit | rulline (Me - val - cit ) . Exemplary tripeptides include , but are not limited to , glycine - valine- citrulline ( gly - val- cit ) and glycine - glycine- glycine (gly -gly - gly ). 1| [0071 ] A peptide may comprise naturally occurring and /or non -natural amino acid residues . The term “ naturally occur triamcinolone acetonide ring amino acid ” refer to Ala, Asp , Cys , Glu , Phe , Gly , His , He, Lys , Leu ,Met , Asn , Pro , Gin , Arg, Ser , Thr, Val , Trp , and Tyr. “ Non - natural amino acids ” ( i . e . , amino acids do not occur naturally ) include, by way of non -limiting example , homoserine , homoarginine , citrulline , phenylglycine , tau HO 1 rine, iodotyrosine , seleno -cysteine , norleucine (“ Nle ” ) , nor " 11111lll valine (“ Nva ” ) , beta - alanine , L - or D - naphthalanine , orni thine (“ Orn ” ) , and the like . Peptides can be designed and | optimized for enzymatic cleavage by a particular enzyme, for example , a tumor- associated protease , cathepsin B , C and D , or a plasmin protease . T| [0072 ] Amino acids also include the D - forms of natural and non - natural amino acids. “ D - ” designates an amino acid fluticasone propionate having the “ D ” (dextrorotary ) configuration , as opposed to the configuration in the naturally occurring ( “ L - ” ) amino acids . Natural and non - natural amino acids can be purchased commercially (Sigma Chemical Co . , Advanced Chemtech ) or synthesized using methods known in the art . [ 0073] In the present disclosure , the term " glucocorticos sun teroid ” refers to naturally -occurring or synthetic steroid hormones that interact with glucocorticoid receptors . Non limiting exemplary glucocorticosteroids include :

OH beclomethasone diproprionate 0 H HOR

A B HO SUI O budesonide ??

HO #sto ciclesonide **1111111 11lllll ) By way of example , the A -, B -, C - , and D - rings of the steroid skeleton are marked for budesonide . Glucocorticosteroids are described in WO 2009/ 069032 .

. [0074 ] A “ radical of a glucocorticosteroid ” is derived from the removal of one or more hydrogen atoms from a parent I glucocorticosteroid . The removal of hydrogen atom ( s ) flunisonide facilitates the attachment of the parent glucocorticosteroid to a linker. In one embodiment, the hydrogen atom is removed US 2018 /0126000 A1 May 10 , 2018 from any suitable - NH2 group of the parent glucocorticos - A non -limiting exemplary heterotrifunctional group is : teroid . In another embodiment, the hydrogen atom is removed from any suitable OH group of the parent glucocorticosteroid . In another embodiment , the hydrogen atom is removed from any suitable a — SH group of the parent glucocorticosteroid . In another embodiment, the hydrogen atom is removed from any suitable — N ( H ) group of the parent glucocorticosteroid . In another embodi ment, the hydrogen atom is removed from any suitable . _ CHZ, CH , — or CH = group of the parent glucocor ticosteroid . In one embodiment, the “ radical of a glucocor m ticosteroid ” is a monovalent radical derived from the ni removal of one hydrogen atom from a parent glucocorticos [0076 ] The term “ drug antibody ratio ” or “ DAR ” refers to teroid . the number of SMs ( i . e . , radical derived from a small [0075 ] In the present disclosure, the term “ heterobifunc molecule glucocorticoid receptor agonist , e . g . , a glucocor tional group ” or the term " heterotrifunctional group ” refers ticosteroid ) linked to A ( i. e ., a protein , e . g . , an antibody or to a chemical moiety that connects a linker and protein , e . g . , antigen -binding fragment thereof, an anti - TNF protein , an an antibody. Heterobi- and tri - functional groups are charac anti - TNF - alpha antibody or fragment thereof, a soluble terized as having different reactive groups at either end of receptor, or a soluble TNF receptor ). Thus , in the immuno the chemical moiety . Non - limiting exemplary heterobifunc conjugate having the generic formula (SM - L - Qn- A , the tional groups include : DAR is defined by the variable “ n .” [0077 ] When referring to a compound having formula ( SM - L - Q ) , - A representing an individual immunoconjugate , the DAR refers to the number of SMs linked to the indi vidual A ( e . g . , n is an integer of 1 to 10 ) . HO2S [0078 ]. When referring to a compound having formula ( SM - L - Q ) , - A representing a plurality of immunoconjugates , the DAR refers to the average number of SMs linked to the non As (e . g. , n is an integer or fraction of 1 to 10 ). Thus, by way mu of an example , a compound having formula ( SM - L - Q ) . - A w comprising a first immunoconjugate with 3 SM per A and a second immunoconjugate with 4 SM per A would have a DAR ( i. e ., an “ n ” ) of 3 . 5 . 100791. The term “ subject ” refers to any animal ( e . g ., a mammal) , including , but not limited to humans , non -human primates , rodents, and the like , which is to be the recipient of a particular treatment. Typically , the terms “ subject " and “ patient” are used interchangeably herein in reference to a human subject. ??! [0080 ] The term “ pharmaceutical formulation ” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective , and which contains no additional components which are unacceptably min toxic to a subject to which the formulation would be waw administered . The formulation can be sterile . [0081 ] An " effective amount” of an immunoconjugate or glucocorticoid receptor agonist as disclosed herein is an and amount sufficient to carry out a specifically stated purpose . An “ effective amount" can be determined in relation to the stated purpose . man [0082 ] The term “ therapeutically effective amount” refers to an amount of an immunoconjugate or glucocorticoid receptor agonist effective to " treat” a disease or disorder in mm a subject or mammal. A “ prophylactically effective amount” refers to an amount effective to achieve the desired prophy lactic result . [ 0083 ] Terms such as " treating " or " treatment” or “ to treat" or " alleviating ” or “ to alleviate ” refer to therapeutic measures that cure , slow down , lessen symptoms of , and / or halt progression of a diagnosed pathologic condition or disorder. Thus, those in need of treatment include those mu already diagnosed with or suspected of having the disorder. Prophylactic or preventative measures refer to measures that prevent and /or slow the development of a targeted patho US 2018 /0126000 A1 May 10 , 2018 logical condition or disorder. Thus , those in need of pro associated with cationic condensing agents , DNA or RNA phylactic or preventative measures include those prone to expression vectors encapsulated in liposomes , and certain have the disorder and those in whom the disorder is to be eukaryotic cells , such as producer cells . prevented . [0086 ] The terms “ polypeptide, " " peptide, ” and “ protein ” [0084 ] “ Polynucleotide, ” or “ nucleic acid , ” as used inter are used interchangeably herein to refer to polymers of changeably herein , refer to polymers of nucleotides of any amino acids of any length . The polymer can be linear or length , and include DNA and RNA . The nucleotides can be branched , it can comprise modified amino acids, and it can deoxyribonucleotides , ribonucleotides , modified nucleotides be interrupted by non - amino acids . The terms also encom or bases, and / or their analogs , or any substrate that can be pass an amino acid polymer that has been modified naturally incorporated into a polymer by DNA or RNA polymerase . A or by intervention ; for example , disulfide bond formation , polynucleotide can comprise modified nucleotides, such as glycosylation , lipidation , acetylation , phosphorylation , or methylated nucleotides and their analogs . If present, modi any other manipulation or modification , such as conjugation fication to the nucleotide structure can be imparted before or with a labeling component. Also included within the defi after assembly of the polymer . The sequence of nucleotides nition are , for example , polypeptides containing one ormore can be interrupted by non - nucleotide components . A poly analogs of an amino acid ( including, for example , unnatural nucleotide can be further modified after polymerization , amino acids, etc . ), as well as other modifications known in such as by conjugation with a labeling component. Other the art. It is understood that , because the polypeptides of this types of modifications include , for example , " caps ” , substi disclosure are based upon antibodies , in certain embodi tution of one or more of the naturally occurring nucleotides ments , the polypeptides can occur as single chains or asso with an analog , internucleotide modifications such as , for ciated chains . example , those with uncharged linkages ( e .g ., methyl phos [0087 ] The terms “ identical” or percent “ identity ” in the phonates, phosphotriesters , phosphoamidates, cabamates , context of two or more nucleic acids or polypeptides , refer etc . ) and with charged linkages ( e . g ., phosphorothioates , to two or more sequences or subsequences that are the same phosphorodithioates, etc . ) , those containing pendant moi or have a specified percentage of nucleotides or amino acid eties , such as, for example, proteins (e . g. , nucleases , toxins , residues that are the same, when compared and aligned antibodies , signal peptides, ply - L - lysine , etc . ) , those with ( introducing gaps , if necessary ) for maximum correspon intercalators ( e . g . , acridine , psoralen , etc . ) , those containing dence , not considering any conservative amino acid substi chelators ( e . g . , metals , radioactive metals , boron , oxidative tutions as part of the sequence identity . The percent identity metals , etc . ), those containing alkylators, those with modi can be measured using sequence comparison software or fied linkages ( e . g . , alpha anomeric nucleic acids , etc . ) , as algorithms or by visual inspection . Various algorithms and well as unmodified forms of the polynucleotide ( s ) . Further , software are known in the art that can be used to obtain any of the hydroxyl groups ordinarily present in the sugars alignments of amino acid or nucleotide sequences . One such can be replaced , for example , by phosphonate groups, phos non - limiting example of a sequence alignment algorithm is phate groups , protected by standard protecting groups, or the algorithm described in Karlin et al , Proc . Natl . Acad . activated to prepare additional linkages to additional nucleo Sci. , 87 :2264 - 2268 ( 1990 ), asmodified in Karlin et al ., Proc . tides , or can be conjugated to solid supports . The 5 ' and 3 Natl. Acad . Sci. , 90 :5873 - 5877 ( 1993 ) , and incorporated into terminal OH can be phosphorylated or substituted with the NBLAST and XBLAST programs (Altschul et al. , amines or organic capping group moieties of from 1 to 20 Nucleic Acids Res. , 25 : 3389 - 3402 ( 1991 ) ) . In certain carbon atoms. Other hydroxyls can also be derivatized to embodiments , Gapped BLAST can be used as described in standard protecting groups . Polynucleotides can also contain Altschul et al ., Nucleic Acids Res . 25 : 3389 - 3402 ( 1997 ) . analogous forms of ribose or deoxyribose sugars that are BLAST- 2 , WU -BLAST - 2 ( Altschul et al. , Methods in Enzy generally known in the art , including , for example , 2 - O mology , 266 : 460 - 480 ( 1996 ) ) , ALIGN , ALIGN - 2 (Genen methyl- , 2 - O -ally1 , 2 ' - fluoro - or 2 '- azido - ribose , carbocyclic tech , South San Francisco , Calif .) or Megalign (DNASTAR ) sugar analogs , alpha. - anomeric sugars , epimeric sugars are additional publicly available software programs that can such as arabinose , xyloses or lyxoses, pyranose sugars, be used to align sequences. In certain embodiments , the furanose sugars , sedoheptuloses , acyclic analogs and abasic percent identity between two nucleotide sequences is deter nucleoside analogs such as methyl riboside . One or more mined using the GAP program in GCG software ( e . g ., using phosphodiester linkages can be replaced by alternative link a NWSgapdna .CMP matrix and a gap weight of 40 , 50 , 60 , ing groups . These alternative linking groups include, but are 70 , or 90 and a length weight of 1 , 2 , 3 , 4 , 5 , or 6 ). In certain not limited to , embodiments wherein phosphate is replaced alternative embodiments , the GAP program in the GCG by P ( O ) S ( “ thioate ” ) , P ( S ) S (“ dithioate ” ) , “ ( O ) NR2 ( “ ami software package , which incorporates the algorithm of date” ) , P (O ) R , P (O )OR ', CO or CH , (“ formacetal” ), in Needleman and Wunsch ( J . Mol . Biol. ( 48 ) : 444 - 453 ( 1970 ) ) which each R or R ' is independently H or substituted or can be used to determine the percent identity between two unsubstituted alkyl ( 1 - 20 C ) optionally containing an ether amino acid sequences ( e . g . , using either a Blossum 62 ( 0 % ) linkage , aryl, alkenyl, cycloalkyl, cycloalkenyl or matrix or a PAM250 matrix , and a gap weight of 16 , 14 , 12 , araldyl. Not all linkages in a polynucleotide need be iden 10 , 8 , 6 , or 4 and a length weight of 1 , 2 , 3 , 4 , 5 ) . tical. The preceding description applies to all polynucle Alternatively , in certain embodiments , the percent identity otides referred to herein , including RNA and DNA . between nucleotide or amino acid sequences is determined [0085 ] The term " vector ” means a construct, which is using the algorithm of Myers and Miller (CABIOS , 4 : 11 - 17 capable of delivering , and optionally expressing , one or (1989 )) . For example , the percent identity can be determined more gene (s ) or sequence ( s ) of interest in a host cell. using the ALIGN program ( version 2 . 0 ) and using a Examples of vectors include , but are not limited to , viral PAM120 with residue table , a gap length penalty of 12 and vectors, naked DNA or RNA expression vectors , plasmid , a gap penalty of 4 . Appropriate parameters for maximal cosmid or phage vectors , DNA or RNA expression vectors alignment by particular alignment software can be deter US 2018 /0126000 A1 May 10 , 2018 mined by one skilled in the art. In certain embodiments , the abrogate the binding of the antibody containing the amino default parameters of the alignment software are used . In acid sequence , to the antigen ( s ) , e . g . , the TNF - alpha to certain embodiments , the percentage identity “ X ” of a first which the antibody binds .Methods of identifying nucleotide amino acid sequence to a second sequence amino acid is and amino acid conservative substitutions which do not calculated as 100x ( Y / Z ) , where Y is the number of amino eliminate antigen binding are well -known in the art (see , acid residues scored as identical matches in the alignment of e .g ., Brummell et al ., Biochem . 32 : 1180 -1 187 (1993 ); the first and second sequences ( as aligned by visual inspec Kobayashi et al ., Protein Eng . 12 ( 10 ) : 879 - 884 ( 1999 ) ; and tion or a particular sequence alignment program ) and Z is the Burks et al . , Proc. Natl. Acad . Sci . USA 94 :412 -417 ( 1997 ) ) . total number of residues in the second sequence . If the [0091 ] In the present disclosure , the term “ halo ” as used length of a first sequence is longer than the second sequence , by itself or as part of another group refers to C1, - F, - Br, the percent identity of the first sequence to the second or — I . In one embodiment, the halo is — Cl or — F . sequence will be longer than the percent identity of the [0092 ] In the present disclosure , the term “ hydroxy " as second sequence to the first sequence . used by itself or as part of another group refers to — OH . [0088 ] As a non - limiting example , whether any particular 10093 ] In the present disclosure , the term " thiol” or the polynucleotide has a certain percentage sequence identity term “ sulfhydryl” as used by itself or as part of another ( e . g . , is at least 80 % identical, at least 85 % identical, at least group refers to — SH . 90 % identical, and in some embodiments, at least 95 % , 10094 ] In the present disclosure , the term “ alkyl” as used 96 % , 97 % , 98 % , or 99 % identical) to a reference sequence by itself or as part of another group refers to unsubstituted can , in certain embodiments , be determined using the Bestfit straight - or branched - chain aliphatic hydrocarbons contain program (Wisconsin Sequence Analysis Package, Version 8 ing from one to twelve carbon atoms, i . e . , C1- 12 alkyl, or the for Unix , Genetics Computer Group , University Research number of carbon atoms designated , e . g ., a C , alkyl such as Park , 575 Science Drive , Madison , Wis . 53711 ) . Bestfit uses methyl , a C2 alkyl such as ethyl, a Cz alkyl such as propyl the local homology algorithm of Smith and Waterman or isopropyl, a C1- 3 alkyl such as methyl, ethyl, propyl, or (Advances in Applied Mathematics 2 : 482 489 (1981 ) ) to isopropyl, and so on . In one embodiment, the alkyl is a C1- 10 find the best segment ofhomology between two sequences. alkyl. In another embodiment, the alkyl is a C1- 6 alkyl. In When using Bestfit or any other sequence alignment pro another embodiment, the alkyl is a C , . 4 alkyl. In another gram to determine whether a particular sequence is , for embodiment, the alkyl is a straight chain C1- 10 alkyl . In instance , 95 % identical to a reference sequence according to another embodiment, the alkyl is a branched chain C3 - 10 the present disclosure, the parameters are set such that the alkyl. In another embodiment, the alkyl is a straight chain percentage of identity is calculated over the full length of the C1- 6 alkyl . In another embodiment, the alkyl is a branched reference nucleotide sequence and that gaps in homology of chain Cz , alkyl. In another embodiment, the alkyl is a up to 5 % of the total number of nucleotides in the reference straight chain C1- 4 alkyl. In another embodiment, the alkyl sequence are allowed . is a branched chain Cz - 4 alkyl. In another embodiment, the 10089 ] In some embodiments , two nucleic acids or poly alkyl is a straight or branched chain C3- 4 alkyl . Non - limiting peptides of the disclosure are substantially identical, mean exemplary C1- 10 alkyl groups include methyl , ethyl, propyl , ing they have at least 70 % , at least 75 % , at least 80 % , at least isopropyl, butyl, sec -butyl , tert- butyl , iso - butyl, 3 -pentyl , 85 % , at least 90 % , and in some embodiments at least 95 % , hexyl , heptyl, octyl, nonyl, and decyl . Non - limiting exem 96 % , 97 % , 98 % , 99 % nucleotide or amino acid residue plary C . 4 alkyl groups include methyl, ethyl, propyl, iso identity , when compared and aligned for maximum corre propyl, butyl, sec -butyl , tert -butyl , and iso -butyl . spondence , as measured using a sequence comparison algo [0095 ] In the present disclosure , the term " optionally rithm or by visual inspection . Identity can exist over a region substituted alkyl” as used by itself or as part of another of the sequences that is at least about 10 , about 20 , about group refers to an alkyl that is either unsubstituted or 40 -60 residues in length or any integral value there between , substituted with one , two , or three substituents indepen and can be over a longer region than 60 - 80 residues , for dently selected from the group consisting of nitro , hydroxy , example , at least about 90 - 100 residues , and in some cyano, haloalkoxy, aryloxy, alkylthio , sulfonamido , alkyl embodiments , the sequences are substantially identical over carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy , the full length of the sequences being compared , such as the carboxamido , alkoxycarbonyl, thiol , N ( H ) CEO )NH2 , coding region of a nucleotide sequence for example . and — N ( H ) C ( = NH ) NH2, optionally substituted aryl, and [ 0090 ] " conservative amino acid substitution ” is one in optionally substituted heteroaryl. In one embodiment, the which one amino acid residue is replaced with another optionally substituted alkyl is substituted with two substitu amino acid residue having a similar side chain . Families of ents . In another embodiment, the optionally substituted alkyl amino acid residues having similar side chains have been is substituted with one substituent. In another embodiment, defined in the art, including basic side chains ( e . g . , lysine , the optionally substituted alkyl is unsubstituted . Non -limit arginine, histidine ) , acidic side chains ( e . g . , aspartic acid , ing exemplary substituted alkyl groups include _ CH2OH , glutamic acid ) , uncharged polar side chains ( e . g . , glycine , CH SH , CH ,Ph , CH2( 4 -OH )Ph , CH ( imidazolyl) , asparagine , glutamine , serine , threonine , tyrosine, cysteine ) , - CH2CH2CO2H , CH2CH2SO2CH3, CH2CH _ COPh , nonpolar side chains ( e . g . , alanine , valine , leucine , isoleu and — CHOC (= O )CHZ . cine , proline , phenylalanine , methionine , tryptophan ), beta [ 0096 ] In the present disclosure, the term " cycloalkyl ” as branched side chains ( e . g ., threonine, valine , isoleucine ) and used by itself or as part of another group refers to unsub aromatic side chains ( e . g . , tyrosine , phenylalanine , trypto stituted saturated or partially unsaturated , e . g . , containing phan , histidine ) . For example , substitution of a phenylala one or two double bonds , cyclic aliphatic hydrocarbons nine for a tyrosine is a conservative substitution . In some containing one to three rings having from three to twelve embodiments , conservative substitutions in the sequences of carbon atoms, i . e . , C3. 12 cycloalkyl , or the number of car the polypeptides and antibodies of the disclosure do not bons designated . In one embodiment, the cycloalkyl has two US 2018 /0126000 A1 May 10 , 2018

rings . In another embodiment, the cycloalkyl has one ring . another embodiment, the optionally substituted phenyl has In another embodiment, the cycloalkyl is saturated . In three substituents . In another embodiment, the optionally another embodiment, the cycloalkyl is unsaturated . In substituted phenyl has two substituents . In another embodi another embodiment, the cycloalkyl is a C3- 8 cycloalkyl. In ment, the optionally substituted phenyl has one substituent . another embodiment, the cycloalkyl is a C3- 6 cycloalkyl . The In another embodiment, the optionally substituted phenyl is term “ cycloalkyl” is meant to include groups wherein a ring unsubstituted . Non - limiting exemplary substituted aryl - CH2 – is replaced with a C ( O ) - Non - limiting groups include 2 -methylphenyl , 2 - methoxyphenyl, 2 - fluo exemplary cycloalkyl groups include cyclopropyl, cyclobu rophenyl, 2 -chlorophenyl , 2 - bromophenyl , 3 -methylphenyl , tyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, nor 3 -methoxyphenyl , 3 - fluorophenyl, 3 -chlorophenyl , 4 -meth bornyl, decalin , adamantyl , cyclohexenyl, cyclopentenyl, ylphenyl , 4 -ethylphenyl , 4 -methoxyphenyl , 4 - fluorophenyl, and cyclopentanone . 4 - chlorophenyl, 2 , 6 -di - fluorophenyl, 2 , 6 - di- chlorophenyl, [ 0097 ] In the present disclosure , the term “ optionally 2 -methyl , 3 -methoxyphenyl , 2 - ethyl, 3 -methoxyphenyl , 3 , 4 substituted cycloalkyl” as used by itself or as part of another di- methoxyphenyl , 3 , 5 - di- fluorophenyl 3 , 5 - di- methylphe group refers to a cycloalkyl that is either unsubstituted or nyl, 3 , 5 -dimethoxy , 4 -methylphenyl , 2 - fluoro - 3 -chlorophe substituted with one , two , or three substituents indepen nyl , 3 - chloro - 4 - fluorophenyl, 4 - (pyridin - 4 -ylsulfonyl ) dently selected from the group consisting of halo , nitro , phenyl The term optionally substituted aryl includes phenyl cyano, hydroxy , alkylcarbonyloxy , cycloalkylcarbonyloxy , groups having a fused optionally substituted cycloalkyl or amino , haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, ary fused optionally substituted heterocyclo group . An option loxy, aralkyloxy, alkylthio , carboxamido , sulfonamido , alky ally substituted phenyl having a fused optionally substituted Icarbonyl, arylcarbonyl , alkylsulfonyl, arylsulfonyl, car cycloalkyl or fused optionally substituted heterocyclo group boxy, carboxyalkyl, optionally substituted alkyl , optionally may be attached to the remainder of the molecule at any substituted cycloalkyl , alkenyl, alkynyl , optionally substi available carbon atom on the phenyl ring . tuted aryl, optionally substituted heteroaryl, optionally sub [0101 ] In the present disclosure , the term “ alkeny?” as stituted heterocyclo , alkoxyalkyl, ( amino Jalkyl, (carboxami used by itself or as part of another group refers to an alkyl do Jalkyl, (heterocyclo Jalkyl, and OCTO ) - amino , The containing one , two or three carbon - to - carbon double bonds . term optionally substituted cycloalkyl includes cycloalkyl In one embodiment, the alkenyl has one carbon - to - carbon groups having a fused optionally substituted aryl , e . g ., double bond . In another embodiment, the alkenyl is a C2 -6 phenyl, or fused optionally substituted heteroaryl , e . g ., alkenyl. In another embodiment, the alkenyl is a C2- 4 pyridyl. An optionally substituted cycloalkyl having a fused alkenyl. Non - limiting exemplary alkenyl groups include optionally substituted aryl or fused optionally substituted ethenyl, propenyl, isopropenyl , butenyl, sec -butenyl , pente heteroaryl group may be attached to the remainder of the nyl, and hexenyl. molecule at any available carbon atom on the cycloalkyl [ 0102 ] In the present disclosure , the term " optionally ring. In one embodiment, the optionally substituted substituted alkenyl" as used herein by itself or as part of cycloalkyl is substituted with two substituents . In another another group refers to an alkenyl that is either unsubstituted embodiment, the optionally substituted cycloalkyl is substi or substituted with one, two or three substituents indepen tuted with one substituent. In another embodiment, the dently selected from the group consisting of halo , nitro , optionally substituted cycloalkyl is unsubstituted . cyano , hydroxy , amino , alkylamino , dialkylamino , [0098 ] In the present disclosure , the term “ aryl” as used by haloalkyl , hydroxyalkyl, alkoxy , haloalkoxy , aryloxy , itself or as part of another group refers to unsubstituted aralkyloxy , alkylthio , carboxamido , sulfonamido , alkylcar monocyclic or bicyclic aromatic ring systems having from bonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, six to fourteen carbon atoms , i. e. , a C6- 14 aryl. Non - limiting carboxyalkyl, optionally substituted alkyl, optionally sub exemplary aryl groups include phenyl ( abbreviated as “ Ph ” ) , stituted cycloalkyl, alkenyl, alkynyl, optionally substituted naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphe aryl, heteroaryl, and optionally substituted heterocyclo . nyl, biphenylenyl , and fluorenyl groups . In one embodiment , [0103 ] In the present disclosure , the term “ alkynyl” as the aryl group is phenyl or naphthyl. used by itself or as part of another group refers to an alkyl [0099 ] In the present disclosure, the term “ optionally containing one to three carbon - to -carbon triple bonds . In one substituted aryl ” as used herein by itself or as part of another embodiment , the alkynyl has one carbon - to - carbon triple group refers to an aryl that is either unsubstituted or sub bond . In another embodiment, the alkynyl is a C2- 6 alkynyl. stituted with one to five substituents independently selected In another embodiment, the alkynyl is a C2- 4 alkynyl . from the group consisting of halo , nitro , cyano , hydroxy , Non - limiting exemplary alkynyl groups include ethynyl, thiol, amino , alkylamino , dialkylamino , optionally substi propynyl, butynyl, 2 -butynyl , pentynyl , and hexynyl groups . tuted alkyl, haloalkyl, hydroxyalkyl , alkoxy , haloalkoxy , [0104 ]. In the present disclosure , the term " optionally aryloxy , aralkyloxy , alkylthio , carboxamido , sulfonamido , substituted alkynyl” as used herein by itself or as part refers alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfo to an alkynyl that is either unsubstituted or substituted with nyl cycloalkylsulfonyl, ( cycloalkyl) alkylsulfonyl, arylsulfo one , two or three substituents independently selected from nyl, heteroarylsulfonyl, heterocyclosulfonyl, carboxy , car the group consisting of halo , nitro , cyano , hydroxy , amino , boxyalkyl , optionally substituted cycloalkyl , alkenyl, alkylamino , dialkylamino , haloalkyl, hydroxyalkyl, alkoxy , alkynyl, optionally substituted aryl, optionally substituted haloalkoxy , aryloxy , aralkyloxy, alkylthio , carboxamido , heteroaryl, optionally substituted heterocyclo , alkoxycarbo sulfonamido , alkylcarbonyl, arylcarbonyl , alkylsulfonyl , nyl, alkoxyalkyl , ( amino ) alkyl, ( carboxamido ) alkyl, and arylsulfonyl, carboxy , carboxyalkyl, optionally substituted (heterocyclo )alkyl . alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted [0100 ] In one embodiment, the optionally substituted aryl aryl, optionally substituted heteroaryl, and heterocyclo . is an optionally substituted phenyl. In another embodiment, [0105 ] In the present disclosure , the term “ haloalkyl” as the optionally substituted phenyl has four substituents . In used by itself or as part of another group refers to an alkyl US 2018 /0126000 A1 May 10 , 2018

substituted by one or more fluorine, chlorine , bromine 1H -pyrrol - 3 - yl) , imidazolyl ( e . g ., 2H - imidazol- 2 - yl and and / or iodine atoms. In one embodiment, the alkyl group is 2H - imidazol- 4 - yl) , pyrazolyl ( e . g ., 1H - pyrazol - 3 - yl, substituted by one , two , or three fluorine and /or chlorine 1H -pyrazol - 4 - yl, and 1H - pyrazol - 5 - yl) , pyridyl ( e . g ., pyri atoms. In another embodiment, the haloalkyl group is a C . 4 . din -2 -yl , pyridin - 3 -yl , and pyridin -4 - yl ), pyrimidinyl (e .g ., haloalkyl group . Non - limiting exemplary haloalkyl groups pyrimidin - 2 - yl, pyrimidin - 4 -yl , and pyrimidin - 5 -yl ) , thiaz include fluoromethyl, 2 - fluoroethyl , difluoromethyl, trifluo olyl ( e. g ., thiazol- 2 -yl , thiazol- 4 -yl , and thiazol- 5 -yl ) , iso romethyl, pentafluoroethyl, 1, 1 -difluoroethyl , 2, 2 -difluoro thiazolyl ( e . g ., isothiazol- 3 - yl, isothiazol- 4 - yl, and isothi ethyl, 2, 2 , 2 - trifluoroethyl, 3 ,3 ,3 - trifluoropropyl, 4 ,4 ,4 - trif azol - 5 - yl) , oxazolyl ( e . g . , oxazol - 2 - yl, oxazol- 4 - yl, and luorobutyl, and trichloromethyl groups . oxazol- 5 -yl ) , isoxazolyl (e . g. , isoxazol- 3 -yl , isoxazol- 4 - yl, [0106 ] In the present disclosure , the term “ alkoxy ” as used and isoxazol- 5 - yl) , and indazolyl (e . g. , 1H -indazol - 3 -yl ) . by itself or as part of another group refers to an optionally The term " heteroaryl” is also meant to include possible substituted alkyl, optionally substituted cycloalkyl, option N -oxides . A non - limiting exemplary N -oxide is pyridyl ally substituted alkenyl, or optionally substituted alkynyl N -oxide . attached to a terminal oxygen atom . In one embodiment , the [0110 ] In one embodiment, the heteroaryl is a 5 - or alkoxy is an optionally substituted alkyl attached to a 6 -membered heteroaryl. In one embodiment, the heteroaryl terminal oxygen atom . In one embodiment, the alkoxy group is a 5 -membered heteroaryl, i. e . , the heteroaryl is a mono is a Cl- alkyl attached to a terminal oxygen atom . In another cyclic aromatic ring system having 5 ring atoms wherein at embodiment, the alkoxy group is a C1- 4 alkyl attached to a least one carbon atom of the ring is replaced with a het terminal oxygen atom . Non - limiting exemplary alkoxy eroatom independently selected from nitrogen , oxygen , and groups include methoxy, ethoxy , and tert -butoxy . sulfur. Non - limiting exemplary 5 -membered heteroaryl [0107 ] In the present disclosure , the term “ alkylthio ” as groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl , used by itself or as part of another group refers to an imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In optionally substituted alkyl attached to a terminal sulfur another embodiment, the heteroaryl is a 6 -membered het atom . In one embodiment, the alkylthio group is a C1- 4 eroaryl, e . g . , the heteroaryl is a monocyclic aromatic ring alkylthio group . Non - limiting exemplary alkylthio groups system having 6 ring atoms wherein at least one carbon atom include - SCH , and - SCH CHz. of the ring is replaced with a nitrogen atom . Non - limiting [0108 ] In the present disclosure , the term “ haloalkoxy ” as exemplary 6 -membered heteroaryl groups include pyridyl, used by itself or as part of another group refers to a haloalkyl pyrazinyl, pyrimidinyl , and pyridazinyl. attached to a terminal oxygen atom . Non - limiting exemplary [ 0111 ] In the present disclosure , the term " optionally sub haloalkoxy groups include fluoromethoxy, difluoromethoxy, stituted heteroaryl” as used by itself or as part of another trifluoromethoxy, and 2 , 2 , 2 - trifluoroethoxy. group refers to a heteroaryl that is either unsubstituted or [0109 ] In the present disclosure , the term “ heteroaryl” substituted with one two, three, or four substituents , inde refers to unsubstituted monocyclic and bicyclic aromatic pendently selected from the group consisting of halo , nitro , ring systems having 5 to 14 ring atoms, i. e . , a 5 - to cyano , hydroxy, amino, alkylamino , dialkylamino , 14 -membered heteroaryl, wherein at least one carbon atom haloalkyl, hydroxyalkyl, alkoxy , haloalkoxy, aryloxy , of one of the rings is replaced with a heteroatom indepen aralkyloxy , alkylthio , carboxamido , sulfonamido , alkylcar dently selected from the group consisting of oxygen , nitro bonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl gen and sulfur. In one embodiment, the heteroaryl contains cycloalkylsulfonyl, ( cycloalkyl) alkylsulfonyl, arylsulfonyl, 1 , 2 , 3 , or 4 heteroatoms independently selected from the heteroarylsulfonyl, carboxy, carboxyalkyl, optionally sub group consisting of oxygen , nitrogen and sulfur . In one stituted alkyl, optionally substituted cycloalkyl, alkenyl, embodiment, the heteroaryl has three heteroatoms. In alkynyl, optionally substituted aryl, optionally substituted another embodiment, the heteroaryl has two heteroatoms. In heteroaryl, optionally substituted heterocyclo , alkoxyalkyl, another embodiment, the heteroaryl has one heteroatom . In ( amino Jalkyl, ( carboxamido ) alkyl, and (heterocyclo Jalkyl. another embodiment, the heteroaryl is a 5 - to 10 -membered In one embodiment, the optionally substituted heteroaryl has heteroaryl. In another embodiment, the heteroaryl is a 5 - or one substituent. In another embodiment, the optionally sub 6 -membered heteroaryl. In another embodiment, the het stituted heteroaryl is unsubstituted . Any available carbon or eroaryl has 5 ring atoms, e . g . , thienyl, a 5 -membered het nitrogen atom can be substituted . The term optionally sub eroaryl having four carbon atoms and one sulfur atom . In stituted heteroaryl includes heteroaryl groups having a fused another embodiment, the heteroaryl has 6 ring atoms, e . g . , optionally substituted cycloalkyl or fused optionally substi pyridyl, a 6 -membered heteroaryl having five carbon atoms tuted heterocyclo group . An optionally substituted het and one nitrogen atom . Non - limiting exemplary heteroaryl eroaryl having a fused optionally substituted cycloalkyl or groups include thienyl, benzo [b ] thienyl, naphtho [ 2 ,3 -b ] thie fused optionally substituted heterocyclo group may be nyl, thianthrenyl, furyl, benzofuryl , pyranyl, isobenzofura attached to the remainder of the molecule at any available nyl, benzooxazonyl, chromenyl, xanthenyl, 2H - pyrrolyl , carbon atom on the heteroaryl ring . pyrrolyl , imidazolyl , pyrazolyl, pyridyl , pyrazinyl, pyrim [0112 ] In the present disclosure , the term " heterocyclo ” as idinyl, pyridazinyl, isoindolyl, 3H - indolyl, indolyl, inda used by itself or as part of another group refers to unsub zolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl , naphthy stituted saturated and partially unsaturated , e .g ., containing ridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH -carbazolyl , one or two double bonds, cyclic groups containing one , two, carbazolyl, ß -carbolinyl , phenanthridinyl, acridinyl, pyrim or three rings having from three to fourteen ring members , idinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, i . e . , a 3 - to 14 -membered heterocyclo , wherein at least one phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In carbon atom of one of the rings is replaced with a heteroa one embodiment , the heteroaryl is selected from the group tom . Each heteroatom is independently selected from the consisting of thienyl ( e . g ., thien - 2 - yl and thien - 3 - yl ) , furyl group consisting of oxygen , sulfur, including sulfoxide and ( e . g . , 2 - furyl and 3 - furyl) , pyrrolyl ( e . g . , 1H - pyrrol - 2 - yl and sulfone , and / or nitrogen atoms, which can be oxidized or US 2018 /0126000 A1 May 10 , 2018 13

quaternized . The term " heterocyclo ” includes groups [0117 ] In the present disclosure, the term “ carboxy ” as wherein a ring - CH2 - is replaced with a C ( O ) - , for used by itself or as part of another group refers to a radical example , cyclic ureido groups such as 2 - imidazolidinone of the formula — CO , H . and cyclic amide groups such as B - lactam , y - lactam , f0118 ] In the present disclosure , the term “ maleimide ” as d - lactam , ? - lactam , and piperazin -2 - one. The term “ hetero used by itself or as part of another group refers to : cyclo ” also includes groups having fused optionally substi tuted aryl groups, e .g . , indolinyl or chroman - 4 -yl . In one embodiment, the heterocyclo group is a C4 - 6 heterocyclo , i. e . , a 4 - , 5 - or 6 -membered cyclic group , containing one ring and one or two oxygen and / or nitrogen atoms. In one embodiment, the heterocyclo group is a C2 heterocyclo mama containing one ring and one nitrogen atom . The heterocyclo O = can be optionally linked to the rest of the molecule through any available carbon or nitrogen atom . Non - limiting exem plary heterocyclo groups include azetidinyl, dioxanyl, tet [0119 ] In the present disclosure , the term “ succinimide” as rahydropyranyl , 2 -oxopyrrolidin - 3 - yl, piperazin - 2 - one , pip used as part of a cleavable linker refers to : erazine - 2 ,6 - dione , 2 - imidazolidinone , piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl. [0113 ] In the present disclosure , the term " optionally substituted heterocyclo ” as used herein by itself or part of another group refers to a heterocyclo that is either unsub mm stituted or substituted with one , two , three , or four substitu ents independently selected from the group consisting of halo , nitro , cyano , hydroxy , amino , alkylamino , dialky lamino , haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, ary [0120 ] In the present disclosure , the term “ hydrolyzed loxy, aralkyloxy , alkylthio , carboxamido , sulfonamido , alky succinimide ” as used as part of a cleavable linker refers to : lcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl , CF2C GO) — , arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alk enyl, alkynyl , optionally substituted aryl , optionally substi tuted heteroaryl, optionally substituted heterocyclo , alkoxy mm alkyl, ( amino )alkyl , ( carboxamido Jalkyl, or (heterocyclo ) N alkyl. Substitution may occur on any available carbon or nitrogen atom , or both . [0114 ] In the present disclosure, the term “ amino ” as used CO2H by itself or as part of another group refers to a radical of the formula NR224R22b, wherein R22a and R22b are each [ 0121 ] In the present disclosure , the term " amide ” as used independently selected from the group consisting of hydro as part of a cleavable linker refers to : gen , optionally substituted alkyl, and aralkyl, or R22a and R225 are taken together to form a 3 - to 8 -membered option ally substituted heterocyclo . Non - limiting exemplary amino groups include — NH , and — N ( H ) (CH3 ) . [0115 ] In the present disclosure , the term " carboxamido ” i as used by itself or as part of another group refers to a radical ma of formula - C ( = O )NR234R236 , wherein R23a and R236 are each independently selected from the group consisting of hydrogen , optionally substituted alkyl, hydroxyalkyl, and [0122 ] In the present disclosure , the term “ thiourea ” as optionally substituted aryl, optionally substituted heterocy used as part of a cleavable linker refers to : clo , and optionally substituted heteroaryl , or R23a and R236 taken together with the nitrogen to which they are attached form a 3 - to 8 -membered optionally substituted heterocyclo group . In one embodiment, R230 and R236 are each indepen dently hydrogen or optionally substituted alkyl . In one embodiment, R23a and R236 are taken together to taken man N together with the nitrogen to which they are attached form a 3 - to 8 -membered optionally substituted heterocyclo [0123 ] In the present disclosure , the term “ thioether ” as group . Non - limiting exemplary carboxamido groups include used as part of a cleavable linker refers to : CONH2, CON ( H ) CH3, and CON (CH3 ) 2 . [ 0116 ] In the present disclosure , the term “ alkoxycarbo nyl” as used by itself or as part of another group refers to a carbonyl group , i. e ., — CEO ) — , substituted with an alkoxy. In one embodiment, the alkoxy is a C1- 4 alkoxy. han Non - limiting exemplary alkoxycarbonyl groups include - C ( O ) OMe, CEO ) OEt, and C ( O ) OtBu. US 2018 /0126000 A1 May 10 , 2018 14

[0124 ] In the present disclosure , the term “ oxime” as used pound of the present disclosure is about 2 : 1, about 1 :1 or as part of a cleavable linker refers to : about 1: 2 , respectively . This physical association involves varying degrees of ionic and covalent bonding , including hydrogen bonding . In certain instances, the solvate can be HO . isolated , such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid . Thus , “ solvate ” encompasses both solution - phase and iso mm latable solvates . Compounds disclosed herein can be present min as solvated forms with a pharmaceutically acceptable sol vent, such as water, methanol , ethanol, and the like , and it is intended that the disclosure includes both solvated and [ 0125 ] In the present disclosure , the term “ self - immolative unsolvated forms of compounds disclosed herein . One type group ” as used as part of a cleavable linker refers to of solvate is a hydrate . A “ hydrate ” relates to a particular bifunctional chemical moiety that is capable of covalently subgroup of solvates where the solvent molecule is water . linking two spaced chemical moieties into a normally stable Solvates typically can function as pharmacological equiva tripartite molecule , can release one of the spaced chemical lents . Preparation of solvates is known in the art. See , for moieties from the tripartite molecule by means of enzymatic example , M . Caira et al, J . Pharmaceut. Sci. , 93 ( 3 ) : 601 -611 cleavage ; and following enzymatic cleavage , can spontane ( 2004 ) , which describes the preparation of solvates of flu ously cleave from the remainder of the molecule to release conazole with ethyl acetate and with water. Similar prepa the other of the spaced chemical moieties, e . g ., a glucocor ration of solvates , hemisolvates , hydrates , and the like are ticosteroid . In some embodiments , a self - immolative group described by E . C . van Tonder et al ., AAPS Pharm . Sci. comprises a p - aminobenzyl unit . In some such embodi Tech . , 5 ( 1 ) : Article 12 ( 2004 ) , and A . L . Bingham et al. , ments , a p - aminobenzyl alcohol is attached to an amino acid Chem . Commun . 603 -604 (2001 ) . A typical , non - limiting, unit via an amide bond , and a carbamate , methylcarbamate , process of preparing a solvate would involve dissolving a or carbonate is made between the benzyl alcohol and the compound disclosed herein in a desired solvent (organic , drug (Hamann et al. (2005 ) Expert Opin . Ther . Patents water , or a mixture thereof ) at temperatures above 20° C . to ( 2005 ) 15 : 1087 - 1103 ) . In some embodiments , the self - im molative group is p -aminobenzyloxycarbonyl (PAB ) . about 25° C . , then cooling the solution at a rate sufficient to [ 0126 ] In the present disclosure, the term “ protecting form crystals , and isolating the crystals by known methods , group ” or “ PG ” refers to group that blocks, i. e . , protects , the e . g . , filtration . Analytical techniques such as infrared spec amine functionality while reactions are carried out on other troscopy can be used to confirm the presence of the solvent functional groups or parts of the molecule . Those skilled in in a crystal of the solvate . the art will be familiar with the selection , attachment, and [0129 ] The present disclosure encompasses the prepara cleavage of amine protecting groups, and will appreciate that tion and use of salts of the compounds disclosed herein , many different protective groups are known in the art, the including non - toxic pharmaceutically acceptable salts . suitability of one protective group or another being depen Examples of pharmaceutically acceptable addition salts dent on the particular the synthetic scheme planned . Trea include inorganic and organic acid addition salts and basic tises on the subject are available for consultation , such as salts . The pharmaceutically acceptable salts include , but are Wuts , P . G . M . ; Greene , T . W ., " Greene' s Protective Groups not limited to , metal salts such as sodium salt, potassium in Organic Synthesis ” , 4th Ed ., J. Wiley & Sons, N Y , 2007 . salt, cesium salt and the like ; alkaline earth metals such as Suitable protecting groups include the carbobenzyloxy calcium salt , magnesium salt and the like ; organic amine ( Cbz ), tert -butyloxycarbonyl (BOC ) , 9 - fluorenylmethyloxy salts such as triethylamine salt , pyridine salt, picoline salt , carbonyl ( FMOC ) , and benzyl ( Bn ) group . In one embodi ethanolamine salt, triethanolamine salt, dicyclohexylamine ment, the protecting group is the BOC group . salt, N , N -dibenzylethylenediamine salt and the like; inor [0127 ] The compounds disclosed herein contain asymmet ganic acid salts such as hydrochloride, hydrobromide, phos ric centers and thus give rise to enantiomers , diastereomers , phate , sulphate and the like; organic acid salts such as and other stereoisomeric forms. The present disclosure is citrate, lactate , tartrate , maleate , fumarate, mandelate , meant to encompass the use of all such possible forms, as acetate , dichloroacetate , trifluoroacetate , oxalate , formate well as their racemic and resolved forms and mixtures and the like ; sulfonates such as methanesulfonate , benzene thereof. The individual enantiomers can be separated sulfonate , p - toluenesulfonate and the like; and amino acid according to methods known in the art in view of the present salts such as arginate, asparginate , glutamate and the like . disclosure . When the compounds described herein contain [0130 ] Acid addition salts can be formed by mixing a olefinic double bonds or other centers of geometric asym solution of the particular compound disclosed with a solu metry , and unless specified otherwise , it is intended that they tion of a pharmaceutically acceptable non - toxic acid such as include both E and Z geometric isomers. All tautomers are hydrochloric acid , fumaric acid , maleic acid , succinic acid , also intended to be encompassed by the present disclosure . acetic acid , citric acid , tartaric acid , carbonic acid , phos [0128 ] The present disclosure encompasses the prepara phoric acid , oxalic acid , dichloroacetic acid , or the like. tion and use of solvates of the compounds disclosed herein . Basic salts can be formed by mixing a solution of the Solvates typically do not significantly alter the physiological compound of the present disclosure with a solution of a activity or toxicity of the compounds , and as such may pharmaceutically acceptable non - toxic base such as sodium function as pharmacological equivalents . The term “ solvate ” hydroxide , potassium hydroxide, choline hydroxide, sodium as used herein is a combination , physical association and /or carbonate and the like . solvation of a compound of the present disclosure with a [0131 ] As used in the present disclosure and claims, the solvent molecule such as, e . g . a disolvate , monosolvate or singular forms “ a ," " an ,” and “ the ” include plural forms hemisolvate , where the ratio of solvent molecule to com unless the context clearly dictates otherwise . US 2018 /0126000 A1 May 10 , 2018

[0132 ] It is understood that wherever embodiments are - continued described herein with the language “ comprising, ” otherwise analogous embodiments described in terms of " consisting VEEQLEWLSQRANALLANGMDLKDNQLVVPADGLYLVYSQVLFKGQGCPD of ” and / or " consisting essentially of " are also provided . [ 0133 ] The term “ and / or” as used in a phrase such as “ A YVLLTHTVSRFAISYQEKVNLLSAVKSPCPKDTPEGAEL KPWYEPIYLGG and / or B ” herein is intended to include both “ A and B , ” “ A VFQLEKGDQLSAEVNLPKYLDFAESGQVYFGVIAL . or B , ” “ A ” and “ B .” Likewise , the term “ and /or ” as used in a phrase such as “ A , B , and / or C ” is intended to encompass Soluble murine TNF alpha contains amino acids 80 - 235 of each of the following embodiments : A , B , and C ; A , B , or C ; SEQ ID NO : 2 . AorC ; A or B ; B or C ; A and C ; A and B ; B and C ; A (alone ) ; [0138 ] In some embodiments , the anti - TNF -alpha anti B ( alone ); and C ( alone ) . body or antigen -binding fragment thereof binds to human TNF -alpha . In some embodiments , the anti - TNF - alpha anti II . Proteins for Linkage to Glucocorticoid Receptor body or antigen - binding fragment thereof is human , human Agonists ized , or chimeric . 0134 ] The present disclosure provides agents immuno [0139 ] In some embodiments , the anti - TNF -alpha anti conjugates containing glucocorticoid receptor agonists body or antigen - binding fragment thereof binds to murine linked to proteins, for example, antibodies or antigen -bind TNF -alpha . In some embodiments , the anti - TNF - alpha anti ing fragments thereof and soluble receptor proteins. In some body or antigen - binding fragment thereof is murine . embodiments , the antibody or antigen -binding fragment [0140 ] In certain embodiments , the anti - TNF - alpha anti thereof is human , humanized , chimeric , or murine . In some body or antigen -binding fragment has one or more of the embodiments , the protein , e . g . , antibody , antigen - binding following effects : neutralizes human TNF - alpha cytotoxicity fragment thereof, or soluble receptor protein , can bind to a in a in vitro L929 assay with an IC50 of 1x10 - 7 M or less ; target on the surface of a cell and become internalized . 10135 ]. The present disclosure also provides immunocon blocks the interaction of TNF -alpha with p55 and p75 cell jugates containing glucocorticoid receptor agonists linked to surface receptors ; and /or lyses surface TNF expressing cells anti - TNF alpha proteins . In certain embodiments , the anti in vitro in the presence of complement. TNF alpha proteins are antibodies or antigen - binding frag [0141 ] In certain embodiments , the anti - TNF - alpha anti ments thereof. In certain embodiments, the anti - TNF alpha body or antigen -binding fragment does not bind to TNF proteins are antibodies or antigen -binding fragments thereof beta . that bind to TNF alpha ( e . g ., soluble TNF alpha and /or 10142 ] Anti - TNF -alpha antibodies and antigen - binding membrane bound TNF alpha ) . In certain embodiments, the fragments thereof include , for example , adalimumab , inflix anti - TNF alpha proteins are soluble TNF receptor proteins , imab , certolizumab pegol, afelimomab , nerelimomab , ozo e . g ., soluble TNF receptor proteins fused to a heavy chain ralizumab , placulumab , and golimumab . Additional anti constant domain or fragment thereof such as an Fc . In some TNF- alpha antibodies and antigen -binding fragments are embodiments , the anti - TNF alpha protein , e . g ., anti - TNF provided , for example , in WO 2013 /087912 , WO 2014 / antibody , antigen - binding fragment thereof, or soluble TNF 152247 and WO 2015 /073884 , each of which is herein receptor can bind to TNF alpha on the surface of a cell and incorporated by reference in its entirety . become internalized . For example , US 2014 /0294813 , [0143 ] Adalimumab is described in U . S . Pat . No . 6 ,258 , which is herein incorporated by reference in its entirety , 562 , which is herein incorporated by reference in its entirety . discloses anti - TNF proteins that exhibit cellular internaliza Infliximab is described in U . S . Pat. No. 5 ,656 ,272 , which is tion upon binding to cell surface human TNF. herein incorporated by reference in its entirety . Certoli [ 0136 ] In certain embodiments, the antibodies or antigen zumab is discussed in WO 01 / 94585 , which is herein binding fragments thereof bind to human and / or mouse incorporated by reference in its entirety . Afelimomab (also TNF - alpha. Antibodies and antigen -binding fragments that known as MAK195 ) is discussed in Vincent, Int. J . Clin . bind to TNF - alpha are known in the art . Pract . 54 : 190 - 193 ( 2000 ) , which is herein incorporated by 101371. The full -length amino acid sequence formembrane reference in its entirety . Ozoralizumab ( also known as bound human TNF alpha is : ATN - 103 ) is a nanobody . It contains three heavy chain variable regions fused by GlySer linkers . Variable regions 1 ( SEQ ID NO : 1 ) and 3 are identical, and ozoralizumab does not contain a MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCL heavy chain . Ozoralizumab is discussed in WO 2012 / 131053 , which is herein incorporated by reference in its LHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEG entirety . Placulumab ( also known as CEP - 37247 ) is a QLQWLNRRANALLANGVELRDNOLVVPSEGLYLIYSQVLFKGQGCPSTHV domain antibody consisting of a dimer of VL -PCH1 - CH2 CH3 or [ V - kappa ] 2 -Fc and is discussed in Gay et al. , Mabs LLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVF 2 : 625 -638 ( 2010 ) , which is herein incorporated by reference in its entirety . Golimumab (also known as CNTO 148 ) is QLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL . discussed in WO2013 / 087912 , and sequences are provided Soluble human TNF alpha contains amino acids 77 - 233 of in GenBank : D1496971 .1 and GenBank DI 496970 . 1, each SEO ID NO : 1 . The full - length amino acid sequence for of which is herein incorporated by reference in its entirety. membrane bound murine TNF - alpha is : [0144 ] Anti- TNF - alpha antibodies and antigen -binding fragments thereof also include antibodies and antigen -bind ( SEQ ID NO : 2 ) ing fragments thereof that competitively inhibit binding of MSTESMIRDVELAEEALPQKMGGFONSRRCLCLSLFSFLLVAGATTLFCL adalimumab , infliximab , certolizumab pegol, afelimomab , nerelimomab , ozoralizumab , placulumab , or golimumab to LNFGVIGPORDEKF PNGLPLISSMAOTLTLRSSSONSSDKPVAHVVANHO TNF - alpha . Anti - TNF - alpha antibodies and antigen -binding fragments thereof also include antibodies and antigen -bind US 2018 /0126000 A1 May 10 , 2018 16 ing fragments that bind to the same TNF- alpha epitope as ments , the anti - TNF- alpha antibody or antigen - binding frag adalimumab , infliximab , certolizumab pegol, afelimomab , ment thereof is adalimumab . nerelimomab , ozoralizumab , placulumab , or golimumab . 014 ] In certain embodiments , an anti - TNF -alpha anti [ 0145 ] In certain embodiments, the anti - TNF - alpha anti body or antigen - binding fragment thereof comprises body or antigen -binding fragment thereof competitively sequences of adalimumab , infliximab , certolizumab pegol, inhibits binding of adalimumab to TNF -alpha . In certain afelimomab , nerelimomab , ozoralizumab , placulumab , or embodiments , the anti - TNF - alpha antibody or antigen -bind golimumab , e . g ., the complementarity - determining regions ing fragment thereof binds to the same TNF - alpha epitope as (CDRs ) , the variable heavy domain (VH ) , and / or the vari adalimumab . In certain embodiments , the anti - TNF - alpha able light domain (VL ) . Sequences of exemplary anti- TNF antibody or antigen - binding fragment thereof is adalimumab alpha antibodies or antigen -binding fragments thereof are or an antigen - binding fragment thereof. In certain embodi provided in Tables 1 - 6 . TABLE 1 Variable heavy chain CDR amino acid sequences : Antibody VH - CDR1 VH - CDR2 VH - CDR3 adalimumab DYAMH ( SEQ ID AITWNSGHIDYADSVEG VSYLSTASS ( SEQ ID NO : 5 ) NO : 3 ) or ( SEO ID NO : 4 ) VSYLSTASSLDY ( SEQ ID GFTFDDYAMH ( SEQ NO : 94 ) ID NO : 6 ) infliximab GFIFSNHWMN ( SEQ EIRSKSINSATHYAESVKG NYYGSTYDY ( SEQ ID ID NO : 7 ) ( SEQ ID NO : 8 ) NO : 9 ) certolizumab DYGMN ( SEQ ID WINTYIGEPIYADSV KG GYRSYAMDY ( SEQ ID NO : 10 ) or ( SEQ ID NO : 11 ) NO : 12 ) GYVFTDYGMN ( SEQ ID NO : 13 ) afelimomab DYGVN ( SEQ ID MIWGDGSTDYDSTLKS EWHHGPVAY ( SEQ ID NO : 14 ) ( SEQ ID NO : 15 ) NO : 16 ) nerelimomab DYNVD ( SEO ID NINPNNGGTIYNOKFKG SAFYNNYEYFDV ( SEQ ID NO : 17 ) ( SEQ ID NO : 18 ) NO : 19 ) ozoralizumab V1 :DYWMY ( SEQ ID V1 : V1 : SPSGFNR ( SEQ ID NO : 20 ) EINTNGLITKYPDSVKG NO : 22 ) V2 : SFGMS ( SEQ ID ( SEQ ID NO : 21 ) V2 : GGSLSRSS ( SEQ ID NO : 23 ) V2 : NO : 25 ) V3 : DYWMY ( SEQ ID SISGSGSDTLYADSVKG V3 : SPSGFNR ( SEQ ID NO : 26 ) ( SEQ ID NO : 24 ) NO : 28 ) V3 : EINTNGLITKYPDSVKG ( SEQ ID NO : 27 ) golimumab GFIFSSYAMH ( SEQ FMSYDGSNKKYADSVKG DRGIAAGGNYYYYGMDV ID NO : 29 ) ( SEO ID NO : 30 ) ( SEO ID NO : 31 ) placulumab RASQAIDSYLH ( SEQ SASNLET QQVVWRPFT ( SEQ ID ID NO : 88 ) (SEQ ID NO : 89 ) NO : 90 )

TABLE 2 Variable light chain CDR amino acid sequences Antibody VL - CDR1 VL - CDR2 VL - CDR3 adalimumab RASQGIRNYLA ( SEQ ID AASTLOS ( SEQ ID QRYNRAPYT ( SEQ ID NO : 32 ) NO : 33 ) NO : 34 ) infliximab RASQFVGSSIH ( SEQ ID YASESMS ( SEQ ID QOSHSWPFT! ( SEO ID NO : 35 ) NO : 36 ) NO : 37 ) certolizumab KASONVGTNVA ( SEQ SASFLYS ( SEQ ID QOYNIYPLT ( SEO ID ID NO : 38 ) NO : 39 ) NO : 40 ) afelimomab KASQAVSSAVA ( SEQ ID WASTRHT ( SEQ ID QQHYSTPFT ( SEQ ID NO : 41 ) NO : 42 ) NO : 43 ) nerelimomab KSSOSLLYSNNOKNYLA WASTRES ( SEO ID QQYYDYPWT ( SEQ ID ( SEO ID NO : 44 ) NO : 45 ) NO : 46 ) US 2018 /0126000 A1 May 10 , 2018 17

TABLE 2 - continued Variable light chain CDR amino acid sequences Antibody VL - CDR1 VL - CDR2 VL - CDR3 ozoralizumab N / A N / A N / A golimumab RASOSVYSYLA ( SEO ID DASNRAT ( SEO ID OORSNWPPFT ( SEO ID NO : 47 ) NO : 48 ) NO : 49 )

TABLE 3 Variable heavy chain amino acid sequences Antibody VH Amino Acid Sequence ( SEQ ID NO ) adalimumab EVOLVESGGGLVOPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSA ITWNSGHIDYADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVSY LSTASSLDYWGQGTLVTVSS ( SEQ ID NO : 50 ) infliximab EVKLEESGGGLVOPGGSMKLSCVASGFIFSNHWMNWVROSPEKGLEWVAE IRSKSINSATHYAESVKGRFTISRDDSKSAVYLQMTDLRTEDTGVYYCSRNY YGSTYDYWGOGTTLTVSS ( SEO ID NO : 91 ) EVKLEESGGGLVOPGGSMKLSCVASGFIFSNHWMNWVROSPEKGLEWVAE IRSKSINSATHYAESVKGRFTISRDDSKSAVYLOMNSLRTEDTGVYYCSRNY YGSTYDYWGQGTTLTVS ( SEQ ID NO : 51 ) certolizumab EVOLVESGGGLVOPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMG WINTYIGEPIYADSVKGRFTFSLDTSKSTAYLOMNSLRAEDTAVYYCARGY RSYAMDYWGQGTLVTVSS ( SEQ ID NO : 52 ) afelimomab OVOLKESGPGLVAPSOSLSITCTVSGFSLTDYGVNWVROPPGKGLEWLGMI WGDGSTDYDSTLKSRLSISKDNSKSQIFLKNNSLQTDDTARYYCAREWHHG PVAYWGQGTLVTVSA ( SEQ ID NO : 53 ) nerelimomab OVOLVOSGAEVVKPGSSVKVSCKASGYTFTDYNVDWVKOAPGOGLOWIG NINPNNGGTIYNOKFKGKGTL TVDKSTSTAYMELSSLTSEDTAVYYCARSAF YNNYEYFDVWGQGTTVTVSS ( SEQ ID NO : 54 ) ozoralizumab V1 : EVOLVESGGGLVOPGGSLRLSCAASGFTFSDYWMYWVROAPGKGLEWVSE INTNGLITKYPDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCARSPSG FNRGOGTLVIVSS ( SEQ ID NO : 55 ) V2 : EVOLVESGGGLVOPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSI SGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RSSQGTLVTVSS ( SEQ ID NO : 56 ) V3 : EVOLVESGGGLVOPGGSLRLSCAASGFTFSDYWMYWVROAPGKGLEWVSE INTNGLITKYPDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCARSPSG FNRGQGTLVTVSS ( SEQ ID NO : 57 ) golimumab QVOLVESGGGVVQPGRSLRLSCAASGFIFSSYAMHWVRQAPGNGLEWVAF MSYDGSNKKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDR GIAAGGNYYYYGMDVWGQGTTVTVSS ( SEQ ID NO : 58 )

TABLE 4 Variable light chain amino acid sequences Antibody VL Amino Acid Sequence ( SEQ ID NO ) adalimumab DIQMTOSPSSLSASVGDRVTITCRASQGIRNYLAWYOQKPGKAPKLLIYAAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCORYNRAPYTFGQGTKV EIK ( SEO ID NO : 59 ) infliximab DILLTOSPAILSVSPGERVSFSCRASQFVGSSIHWYQQRTNGSPRLLIKYASES MSGIPSRFSGSGSGTDFTLSINTVESEDIADYYCOQSHSWPFTFGSGTNLEVK ( SEQ ID NO : 60 ) certolizumab DIQMTOSPSSLSASVGDRVTITCKASONVGTNVAWYOQKPGKAPKALIYSA SFLYSGVPYRFSGSGSGTDFTLTISSLOPEDFATYYCQQYNIYPLTFGQGTKV EIK ( SEO ID NO : 61 ) US 2018 /0126000 A1 May 10 , 2018

TABLE 4 - continued Variable light chain amino acid sequences Antibody VL Amino Acid Sequence (SEQ ID NO ) afelimomab DIVMTQSHKFMSTTVGDRVSITCKASQAVSSAVAWYOQKPGQSPKLLIYWA STRHTGVPDRFTGSGSVTDFTLTIHNLQAEDLALYYCQQHYSTPFTFGSGTK LEIK ( SEQ ID NO : 62 ) nerelimomab DIMMTQSPSTLSASVGDRVTITCKSSQSLLYSNNOKNYLAWYQQKPGQAPK LLISWASTRESGVPSRFIGSGSGTEFTLTISSLQPDDVATYYCQQYYDYPWTF GOGTKVEIK ( SEO ID NO : 92 ) DIMMTQSPSTLSASVGDRVTITCKSSQSLLYSNNQKNYLAWYQQKPGQAPK LLISWASTRESGVPSRFIGSGSGTEFTLTISSLQPDDVATYYCOQYYDYPWTF GQGTKVEIKR ( SEQ ID NO : 63 ) placulumab DIQMTOSPSSLSASVGDRVTITCRASQAIDSYLHWYOQKPGKAPKLLIYSAS NLETGVPSRFSGSGSGTDFTLTISSLLPEDFATYYCOOWWWRPFTFGOGTKV EIK ( SEQ ID NO : 64 ) golimumab EIVLTQSPATLSLSPGERATLSCRASQSVYSYLAWYQQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCOQRSNWPPFTFGPGTKV DIK ( SEQ ID NO : 65 )

TABLE 5 Full - length heavy chain amino acid sequences Antibody Full - Length Heavy Chain Amino Acid Sequence ( SEQ ID NO ) Adalimumab EVOLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSA ( D2E7 ) ITWNSGHIDYADSVEGRFTISRDNAKNSLYLOMNSLRAEDTAVYYCAKVSY LSTASSLDYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTOTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTOKSLSLSPGK ( SEQ ID NO : 66 ) infliximab EVKLEESGGGLVOPGGSMKLSCVASGFIFSNHWMNWVROSPEKGLEWVAE IRSKSINSATHYAESVKGRFTISRDDSKSAVYLOMTDLRTEDTGVYYCSRNY YGSTYDYWGOGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTOTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVL TVLHODWLNGKEYKCKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRDEL TKNOVSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTOKSLSLSPGK ( SEQ ID NO : 67 ) certolizumab EVOLVESGGGLVOPGGSLRLSCAASGYVFTDYGMNWVROAPGKGLEWMG WINTYIGEPIYADSVKGRFTFSLDTSKSTAYLOMNSLRAEDTAVYYCARGY RSYAMDYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTOTYICNV NHKPSNTKVDKKVEPKSCDKTHTCAA ( SEO ID NO : 68 ) a felimomab QVQLKESGPGLVAPSQSLSITCTVSGFSLTDYGVNWVROPPGKGLEWLGMI WGDGSTDYDSTLKSRLSISKDNSKSQIFLKNNSLQTDDTARYYCAREWHHG PVAYWGQGTLVTVSAATTTAPSVYPLVPGCSDTSGSSVTLGCLVKGYFPEP VTVKWNYGALSSGVRTVSSVLOSGFYSLSSLVTVPSSTWPSQTVICNVAHPA SKTELIKRIEPRIPKPSTPPGSSCPPGNILGGPSVFIFPPKPKDALMISLTPKVTC VVVDVSEDDPDVHVSWFVDNKEVHTAWTOPREAQYNSTFRVVSALPIQHQ DWMRGKEFKCKVNNKALPAPIERTISKPKGRAQTPQVYTIPPPREQMSKKK VSLTCLVTNFFSEAISVEWERNGELEQDYKNTPPILDSDGTYFLYSKLTVDT DSWLQGEIFTCSVVHEALHNHHTQKNLSRSPGK ( SEQ ID NO : 69 ) ozoralizumab EVOLVESGGGLVOPGGSLRLSCAASGFTFSDYWMYWVRQAPGKGLEWVSE INTNGLITKYPDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCARSPSG FNRGQGTLVTVSSggggsgggSEVOLVESGGGLVOPGNSLRLSCAASGFTFSSF GMSWVROAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLOM NSLRPEDTAVYYCTIGGSLSRSSOGTLVTVSSggggsgggs EVOLVESGGGLVOP GGSLRLSCAASGFTFSDYWMYWVROAPGKGLEWVSEINTNGLITKYPDSV KGRFTISRDNAKNTLYLOMNSLRPEDTAVYYCARSPSGFNRGOGTLVTVSS ( SEQ ID NO : 70 ) US 2018 /0126000 A1 May 10 , 2018

TABLE 5 - continued Full - length heavy chain amino acid sequences Antibody Full - Length Heavy Chain Amino Acid Sequence ( SEQ ID NO ) placulumab VEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTV LHODWLNGKEYKCKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDG SFFLYSKL TVDKSRWOOGNVFSCSVMHEALHNHYTOKSLSLSPGK ( SEO ID NO : 93 ) RVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPOVYTLPPS RDELTKNOVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTOKSLSLSPGK ( SEQ ID NO : 71 ) golimumab OVOLVESGGGVVOPGRSLRLSCAASGFIFSSYAMHWVROAPGNGLE WVAFMSYDGSNKKYADSVKGRFTISRDNSKNTLYLOMNSLRAEDTA VYYCARDRGIAAGGNYYYYGMDVWGOGTTVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLO SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPE VKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGK EYKCKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRDELTKNOVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWOQGNVFSCSVMHEALHNHYTOKSLSLSPGK ( SEQ ID NO : 72 )

TABLE 6 Full - length light chain amino acid sequences Antibody Full - length Light Chain Amino Acid Sequence ( SEQ ID NO ) Adalimumab DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAAS ( D2E7 ) TLOSGVPSRFSGSGSGTDFTLTISSLOPEDVATYYCORYNRAPYTFGOGTKV EIKRTVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC ( SEQ ID NO : 73 ) infliximab DILLTOSPAILSVSPGERVSFSCRASQFVGSSIHWYQQRTNGSPRLLIKYASES MSGIPSRFSGSGSGTDFTLSINTVESEDIADYYCOOSHSWPFTFGSGTNLEVK RTVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC ( SEQ ID NO : 74 ) certolizumab DIQMTOSPSSLSASVGDRVTITCKASONVGTNVAWYQQKPGKAPKALIYSA SFLYSGVPYRFSGSGSGTDFTLTISSLOPEDFATYYCQQYNIYPLTFGQGTKV EIKRTVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC ( SEQ ID NO : 75 ) a felimomab DIVMTQSHKFMSTTVGDRVSITCKASQAVSSAVAWYQQKPGQSPKLLIYWA STRHTGVPDRFTGSGSVTDFTLTIHNLQAEDLALYYCOQHYSTPFTFGSGTK LEIKRADAAPTVSIFPPSSEOLTSGGASWCFLNNFYPKDINVKWKIDGSERO NGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKS FNRNEC ( SEQ ID NO : 76 ) placulumab DIQMTQSPSSLSASVGDRVTITCRASQAIDSYLHWYOQKPGKAPKLLIYSAS NLETGVPSRFSGSGSGTDFTLTISSLLPEDFATYYCOQVVWRPFTFGQGTKV EIKR ( SEQ ID NO : 77 ) golimumab EIVLTOSPATLSLSPGERATLSCRASQSVYSYLAWYOQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCOORSNWPPFTFGPGTKV DIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALOS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC ( SEQ ID NO : 78 ) [ 0147 ] Also provided are antibodies or antigen -binding Also provided are antibodies or antigen -binding fragments fragments that comprise a VH and a VL having at least 80 % that comprise a VH and a VL having at least 85 % sequence sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 and 61 , and 61, 53 and 62 , 54 and 63 , or 58 and 65 , respectively . or 53 and 62 , 54 and 63 , or 58 and 65 , respectively . Also US 2018 /0126000 A1 May 10 , 2018 20 provided are antibodies or antigen -binding fragments that 14 - 16 , and 41- 43; 17 - 19 and 44 -46 ; or 29 - 31 and 47 -49 , comprise a VH and a VL having at least 85 % sequence respectively . Also provided are antibodies or antigen -bind identity to SEQ ID NOs: 91 and 60 , or 54 and 92, respec ing fragments that comprise a VH and a VL having at least tively . Also provided are antibodies or antigen -binding frag 85 % sequence identity to SEQ ID NOs: 50 and 59 , 91 and ments that comprise a VH and a VL having at least 90 % 60 , or 54 and 92 respectively , and contain the CDRs of SEQ sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 ID NOs: 3 or 6 , 4 , 94 , and 32 - 34 ; 7 - 9 and 35 - 37 ; or 17 - 19 and 61 , 53 and 62, 54 and 63, or 58 and 65 , respectively . and 44 -46 , respectively . Also provided are antibodies or Also provided are antibodies or antigen -binding fragments antigen - binding fragments that comprise a VH and a VL that comprise a VH and a VL having at least 90 % sequence having at least 90 % sequence identity to SEQ ID NOs: 50 identity to SEQ ID NOs: 91 and 60 , or 54 and 92 , respec and 59 , 51 and 60 , 52 and 61 , 53 and 62 , 54 and 63 , or 58 tively . Also provided are antibodies or antigen - binding frag ments that comprise a VH and a VL having at least 95 % and 65 , respectively and contain the CDRs of SEQ ID NOs : sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 3 or 6 , 4 , 5 , and 32 - 34 ; 7 - 9 and 35 - 37 ; 10 or 13 , 11 , 12 , and and 61, 53 and 62 , 54 and 63, or 58 and 65 , respectively . 38 - 40 ; 14 - 16 , and 41 -43 ; 17 - 19 and 44 - 46 ; or 29 - 31 and Also provided are antibodies or antigen -binding fragments 47 -49 , respectively . Also provided are antibodies or antigen that comprise a VH and a VL having at least 95 % sequence binding fragments that comprise a VH and a VL having at identity to SEQ ID NOs: 91 and 60 , or 54 and 92, respec least 90 % sequence identity to SEQ ID NOs: 50 and 59 , 91 tively . Also provided are antibodies or antigen -binding frag and 60 , or 54 and 92 respectively , and contain the CDRs of ments that comprise a VH and a VL having at least 96 % SEQ ID NOs : 3 or 6 , 4 , 94 , and 32 -34 ; 7 - 9 and 35 - 37 ; or sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 17 - 19 and 44 -46 , respectively . Also provided are antibodies and 61, 53 and 62 , 54 and 63 , or 58 and 65 , respectively. or antigen - binding fragments that comprise a VH and a VL Also provided are antibodies or antigen -binding fragments having at least 95 % sequence identity to SEQ ID NOs: 50 that comprise a VH and a VL having at least 96 % sequence and 59 , 51 and 60 , 52 and 61, 53 and 62 , 54 and 63 , or 58 identity to SEQ ID NOs: 91 and 60 , or 54 and 92 , respec and 65 , respectively and contain the CDRs of SEQ ID NOs: tively . Also provided are antibodies or antigen - binding frag 3 or 6 , 4 , 5 , and 32 - 34 ; 7 - 9 and 35 - 37 ; 10 or 13 , 11 , 12 , and ments that comprise a VH and a VL having at least 97 % 38 - 40 ; 14 - 16 , and 41- 43 ; 17 - 19 and 44 - 46 ; or 29 - 31 and sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 47 -49 , respectively . Also provided are antibodies or antigen and 61, 53 and 62 , 54 and 63, or 58 and 65 , respectively . binding fragments that comprise a VH and a VL having at Also provided are antibodies or antigen -binding fragments least 95 % sequence identity to SEQ ID NOs: 50 and 59 , 91 that comprise a VH and a VL having at least 97 % sequence and 60 , or 54 and 92 respectively , and contain the CDRs of identity to SEQ ID NOs : 91 and 60 , or 54 and 92, respec SEQ ID NOs: 3 or 6 , 4 , 94 , and 32 - 34 ; 7 - 9 and 35 - 37 ; or tively . Also provided are antibodies or antigen - binding frag 17 - 19 and 44 - 46 , respectively. Also provided are antibodies ments that comprise a VH and a VL having at least 98 % or antigen - binding fragments that comprise a VH and a VL sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 having at least 96 % sequence identity to SEQ ID NOs: 50 and 61, 53 and 62 , 54 and 63, or 58 and 65 , respectively . and 59 , 51 and 60 , 52 and 61, 53 and 62 , 54 and 63 , or 58 Also provided are antibodies or antigen - binding fragments and 65 , respectively and contain the CDRs of SEQ ID NOs: 3 or 6 , 4 , 5 , and 32 -34 ; 7 - 9 and 35 - 37 ; 10 or 13 , 11 , 12 , and that comprise a VH and a VL having at least 98 % sequence 38 -40 ; 14 - 16 , and 41 -43 ; 17 - 19 and 44 - 46 ; or 29 -31 and identity to SEQ ID NOs : 91 and 60 , or 54 and 92 , respec 47 -49 , respectively . Also provided are antibodies or antigen tively. Also provided are antibodies or antigen - binding frag binding fragments that comprise a VH and a VL having at ments that comprise a VH and a VL having at least 99 % least 96 % sequence identity to SEQ ID NOs : 50 and 59 , 91 sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 and 60 , or 54 and 92 respectively, and contain the CDRs of and 61 , 53 and 62 , 54 and 63 , or 58 and 65 , respectively. SEQ ID NOs: 3 or 6 , 4 , 94 , and 32 - 34 ; 7 - 9 and 35 - 37 ; or Also provided are antibodies or antigen -binding fragments 17 - 19 and 44 - 46 , respectively . Also provided are antibodies that comprise a VH and a VL having at least 99 % sequence or antigen - binding fragments that comprise a VH and a VL identity to SEQ ID NOs: 91 and 60 , or 54 and 92, respec having at least 97 % sequence identity to SEQ ID NOs: 50 tively . and 59 , 51 and 60 , 52 and 61 , 53 and 62 , 54 and 63 , or 58 [0148 ] Also provided are antibodies or antigen - binding and 65 , respectively and contain the CDRs of SEQ ID NOs : fragments that comprise a VH and a VL having at least 80 % 50 and 59, 51 and 60 , 52 and 61, 53 and 62, 54 and 63 , or sequence identity to SEQ ID NOs: 50 and 59 , 51 and 60 , 52 58 and 65 , respectively . Also provided are antibodies or and 61 , 53 and 62 , 54 and 63 , or 58 and 65 , respectively , and antigen -binding fragments that comprise a VH and a VL contain the CDRs of SEQ ID NOs: 3 or 6 , 4 , 5 , and 32 -34 ; having at least 97 % sequence identity to SEQ ID NOs: 50 7 - 9 and 35 - 37 ; 10 or 13 , 11 , 12 , and 38 - 40 ; 14 - 16 , and and 59 , 91 and 60 , or 54 and 92 respectively , and contain the 41 -43 ; 17 - 19 and 44 - 46 ; or 29 - 31 and 47 -49 , respectively. CDRs of SEQ ID NOs: 3 or 6 , 4 , 94 , and 32 - 34 ; 7 - 9 and Also provided are antibodies or antigen - binding fragments 35 - 37 ; or 17 - 19 and 44 - 46 , respectively . Also provided are that comprise a VH and a VL having at least 80 % sequence antibodies or antigen - binding fragments that comprise a VH identity to SEQ ID NOs: 50 and 59 , 91 and 60 , or 54 and 92 and a VL having at least 98 % sequence identity to SEQ ID respectively , and contain the CDRs of SEQ ID NOs : 3 or 6 , NOs: 50 and 59 , 51 and 60 , 52 and 61 , 53 and 62 , 54 and 63 , 4 , 94 , and 32 -34 ; 7 - 9 and 35 - 37 ; or 17 - 19 and 44 -46 , or 58 and 65 , respectively and contain the CDRs of SEQ ID respectively . Also provided are antibodies or antigen -bind NOs: 3 or 6 , 4 , 5 , and 32 -34 ; 7 - 9 and 35 - 37 ; 10 or 13 , 11 , ing fragments that comprise a VH and a VL having at least 12 , and 38 - 40 ; 14 - 16 , and 41 - 43 ; 17 - 19 and 44 - 46 ; or 29 - 31 85 % sequence identity to SEQ ID NOs: 50 and 59 , 51 and and 47 - 49 , respectively . Also provided are antibodies or 60 , 52 and 61 , 53 and 62 , 54 and 63 , or 58 and 65 , antigen - binding fragments that comprise a VH and a VL respectively and contain the CDRs of SEQ ID NOs: 3 or 6 , having at least 98 % sequence identity to SEQ ID NOs: 50 4 , 5 , and 32 -34 ; 7 - 9 and 35 -37 ; 10 or 13 , 11 , 12 , and 38 -40 ; and 59 , 91 and 60 , or 54 and 92 respectively , and contain the US 2018 /0126000 A1 May 10 , 2018

CDRs of SEQ ID NOs: 3 or 6 , 4 , 94, and 32 - 34 ; 7 - 9 and limomab , nerelimomab , ozoralizumab , placulumab , or goli 35 - 37 ; or 17 - 19 and 44 - 46 , respectively . Also provided are mumab as determined by the method in MacCallum R M et antibodies or antigen -binding fragments that comprise a VH al. and a VL having at least 99 % sequence identity to SEQ ID [0154 ] In a particular embodiment, provided herein are NOs: 50 and 59 , 51 and 60 , 52 and 61 , 53 and 62 , 54 and 63, antibodies or antigen -binding fragments thereof that specifi or 58 and 65 , respectively and contain the CDRs of SEQ ID cally bind to TNF - alpha and comprise CDRs of adalim NOs: 3 or 6 , 4 , 5 , and 32 - 34 ; 7 - 9 and 35 - 37 ; 10 or 13 , 11 , umab , infliximab , certolizumab pegol, afelimomab , nereli 12 , and 38 -40 ; 14 - 16 , and 41- 43 ; 17 - 19 and 44 -46 ; or 29 -31 momab , ozoralizumab , placulumab , or golimumab as and 47 -49 , respectively . Also provided are antibodies or determined by the AbM numbering scheme. antigen - binding fragments that comprise a VH and a VL [0155 ] In a particular embodiment, provided herein are having at least 99 % sequence identity to SEQ ID NOs: 50 antibodies or antigen - binding fragments thereof that specifi and 59 , 91 and 60 , or 54 and 92 respectively, and contain the cally bind to CD163 . CDRs of SEQ ID NOs: 3 or 6 , 4 , 94 , and 32 - 34 ; 7 - 9 and [0156 ] Monoclonal antibodies can be prepared using 35 - 37 ; or 17 - 19 and 44 - 46 , respectively . hybridomamethods , such as those described by Kohler and [0149 ] In certain embodiments , the anti - TNF alpha anti Milstein ( 1975 ) Nature 256 : 495 . Using the hybridoma body or antigen -binding fragment thereof comprises the method , a mouse , hamster, or other appropriate host animal, CDRs of SEQ ID NOs: 3 -5 and 32 -34 or of SEQ ID NOs: is immunized to elicit the production by lymphocytes of 6 , 4 , 5 , and 32 -34 . In certain embodiments , the anti - TNF antibodies that will specifically bind to an immunizing alpha antibody or antigen -binding fragment thereof com antigen . Lymphocytes can also be immunized in vitro . prises the CDRs of SEO ID NOs: 3 , 4 , 94 and 32 - 34 or of Following immunization , the lymphocytes are isolated and SEQ ID NOs: 6 , 4 , 94 , and 32 -34 . In certain embodiments , fused with a suitable myeloma cell line using, for example , the anti - TNF alpha antibody or antigen - binding fragment polyethylene glycol, to form hybridoma cells that can then thereof comprises the VH of SEQ ID NO : 50 and /or the VL be selected away from unfused lymphocytes and myeloma of SEQ ID NO : 59 . In certain embodiments , the anti - TNF cells . Hybridomas that produce monoclonal antibodies alpha antibody comprises the heavy chain of SEQ ID NO : 66 directed specifically against a chosen antigen as determined and / or the light chain of SEQ ID NO :75 . by immunoprecipitation , immunoblotting, or by an in vitro 10150 ] F alpha antibody comprises the heavy chain of binding assay ( e . g ., radioimmunoassay (RIA ) ; enzyme SEQ ID NO : 74 and / or the light chain of SEQ ID NO : 82 . linked immunosorbent assay ( ELISA ) ) can then be propa 0151] In certain aspects , provided herein are antibodies or gated either in vitro culture using standard methods (God antigen -binding fragments thereof that specifically bind to ing , Monoclonal Antibodies: Principles and Practice , TNF- alpha and comprise the Chothia VL CDRs of a VL of Academic Press , 1986 ) or in vivo as ascites tumors in an adalimumab , infliximab , certolizumab pegol , afelimomab , animal. The monoclonal antibodies can then be purified nerelimomab , ozoralizumab , placulumab , or golimumab . In from the culture medium or ascites fluid as described for certain aspects , provided herein are antibodies or antigen polyclonal antibodies. binding fragments thereof that specifically bind to TNF [0157 ] Alternatively monoclonal antibodies can also be alpha and comprise the Chothia VH CDRs of a VH of made using recombinant DNA methods as described in U . S . adalimumab , infliximab , certolizumab pegol, afelimomab , Pat . No . 4 ,816 , 567 . The polynucleotides encoding a mono nerelimomab , ozoralizumab , placulumab , or golimumab . In clonal antibody are isolated from mature B -cells or certain aspects , provided herein are antibodies or antigen hybridoma cells , such as by RT - PCR using oligonucleotide binding fragments thereof that specifically bind to TNF primers that specifically amplify the genes encoding the alpha and comprise the Chothia VL CDRs of a VL of heavy and light chains of the antibody , and their sequence is adalimumab , infliximab , certolizumab pegol, afelimomab , determined using conventional procedures . The isolated nerelimomab , ozoralizumab , placulumab , or golimumab and polynucleotides encoding the heavy and light chains are then comprise the Chothia VH CDRs of a VH of adalimumab , cloned into suitable expression vectors, which when trans infliximab , certolizumab pegol, afelimomab , nerelimomab , fected into host cells such as E . coli cells , simian COS cells , ozoralizumab , placulumab , or golimumab . In certain Chinese hamster ovary (CHO ) cells , or myeloma cells that embodiments , antibodies or antigen - binding fragments that do not otherwise produce immunoglobulin protein , mono specifically bind to TNF - alpha comprise one or more CDRs, clonal antibodies are generated by the host cells . Also , in which the Chothia and Kabat CDRs have the same amino recombinant monoclonal antibodies or fragments thereof of acid sequence . In certain embodiments , provided herein are the desired species can be isolated from phage display antibodies and antigen -binding fragments thereof that spe libraries expressing CDRs of the desired species as cifically bind to TNF - alpha and comprise combinations of described (McCafferty et al. , 1990 , Nature , 348 :552 -554 ; Kabat CDRs and Chothia CDRs . Clackson et al. , 1991 , Nature , 352 :624 -628 ; and Marks et [0152 ] In a particular embodiment, provided herein are al. , 1991, J . Mol. Biol. , 222 :581 - 597 ) . antibodies or antigen - binding fragments thereof that specifi [0158 ] The polynucleotide ( s ) encoding a monoclonal anti cally bind to TNF - alpha and comprise CDRs of adalim body can further be modified in a number of different umab , infliximab , certolizumab pegol, afelimomab , nereli manners using recombinant DNA technology to generate momab , ozoralizumab , placulumab , or golimumab as alternative antibodies . In some embodiments , the constant determined by the IMGT numbering system , for example, as domains of the light and heavy chains of, for example , a described in Lefranc M -P ( 1999 ) supra and Lefranc M - P et mouse monoclonal antibody can be substituted 1 ) for those al. , ( 1999) supra ). regions of, for example , a human antibody to generate a [0153 ] In a particular embodiment, provided herein are chimeric antibody or 2 ) for a non - immunoglobulin polypep antibodies that specifically bind to TNF - alpha and comprise tide to generate a fusion antibody . In some embodiments , the CDRs of adalimumab , infliximab , certolizumab pegol, afe constant regions are truncated or removed to generate the US 2018 /0126000 A1 May 10 , 2018 desired antibody fragment of a monoclonal antibody. Site 4 , 816 , 567 ; PCT/ : US98 / 16280 ; US96 / 18978 ; US91 /09630 ; directed or high - density mutagenesis of the variable region US91 / 05939 ; US94 /01234 ; GB89/ 01334 ; GB91 /01134 ; can be used to optimize specificity , affinity , etc . of a mono GB92 /01755 ; W090 / 14443 ; W090 / 14424 ; WO90 / 14430 ; clonal antibody . EP 229246 ; U . S . Pat. Nos . 7 ,557 , 189 ; 7 ,538 , 195 ; and 7 ,342 , [0159 ] In some embodiments , the monoclonal antibody 110 , each of which is entirely incorporated herein by refer against the TNF - alpha is a humanized antibody . In certain ence , including the references cited therein . embodiments , such antibodies are used therapeutically to [0164 ] In certain alternative embodiments , the antibody reduce antigenicity and HAMA (human anti -mouse anti ( e . g . , an anti - TNFalpha antibody ) is a human antibody . body ) responses when administered to a human subject . Human antibodies can be directly prepared using various [0160 ] Methods for engineering, humanizing or resurfac techniques known in the art. Immortalized human B lym ing non -human or human antibodies can also be used and are phocytes immunized in vitro or isolated from an immunized well known in the art . A humanized , resurfaced or similarly individual that produce an antibody directed against a target engineered antibody can have one or more amino acid antigen can be generated (See , e . g . , Cole et al. , Monoclonal residues from a source that is non -human , e . g . , but not Antibodies and Cancer Therapy , Alan R . Liss, p . 77 ( 1985 ) ; limited to , mouse , rat , rabbit , non -human primate or other Boemer et al . , 1991, J . Immunol. , 147 ( 1 ) : 86 - 95 ; and U . S . mammal. These non -human amino acid residues are Pat . No. 5 ,750 , 373 ) . Also , the human antibody can be replaced by residues that are often referred to as “ import ” selected from a phage library , where that phage library residues, which are typically taken from an “ import ” vari expresses human antibodies , as described , for example , in able, constant or other domain of a known human sequence . Vaughan et al. , 1996 , Nat . Biotech ., 14 : 309 -314 , Sheets et [0161 ] Such imported sequences can be used to reduce al. , 1998 , Proc . Nat' l . Acad . Sci. , 95 :6157 -6162 , Hoogen immunogenicity or reduce , enhance or modify binding , boom and Winter, 1991 , J . Mol. Biol. , 227 : 381 , and Marks affinity , on - rate , off - rate , avidity , specificity , half - life , or any et al. , 1991, J . Mol. Biol. , 222 : 581) . Techniques for the other suitable characteristic , as known in the art . In general, generation and use of antibody phage libraries are also the CDR residues are directly and most substantially described in U . S . Pat. Nos . 5 , 969 , 108 , 6 , 172 , 197 , 5 , 885 , 793 , involved in influencing TNF - alpha binding. Accordingly , 6 ,521 ,404 ; 6 , 544 , 731 ; 6 ,555 , 313 ; 6 ,582 , 915 ; 6 , 593 ,081 ; part or all of the non - human or human CDR sequences are 6 , 300 , 064 ; 6 ,653 , 068 ; 6 , 706 , 484 ; and 7 , 264 , 963 ; and Rothe maintained while the non - human sequences of the variable et al. , 2007 , J . Mol. Bio . , doi : 10 . 1016 / j. jmb . 2007 . 12 .018 and constant regions can be replaced with human or other ( each of which is incorporated by reference in its entirety ) . amino acids. Affinity maturation strategies and chain shuffling strategies [0162 ] Antibodies can also optionally be humanized , (Marks et al. , 1992 , Bio / Technology 10 :779 - 783 , incorpo resurfaced , engineered or human antibodies engineered with rated by reference in its entirety ) are known in the art and retention of high affinity for the antigen e . g . , TNF -alpha , and can be employed to generate high affinity human antibodies . other favorable biological properties . To achieve this goal, [0165 ] Humanized antibodies can also be made in trans humanized (or human ) or engineered antibodies and resur genic mice containing human immunoglobulin loci that are faced antibodies can be optionally prepared by a process of capable upon immunization of producing the full repertoire analysis of the parental sequences and various conceptual of human antibodies in the absence of endogenous immu humanized and engineered products using three -dimen noglobulin production . This approach is described in U . S . sional models of the parental, engineered , and humanized Pat. Nos. 5 ,545 ,807 ; 5 ,545 , 806 ; 5 , 569 ,825 ; 5 ,625 , 126 ; sequences . Three - dimensional immunoglobulin models are 5 ,633 ,425 ; and 5 , 661, 016 . commonly available and are familiar to those skilled in the [0166 ] In certain embodiments are provided an antibody art. Computer programs are available which illustrate and fragment to , for example , increase tumor penetration . Vari display probable three -dimensional conformational struc ous techniques are known for the production of antibody tures of selected candidate immunoglobulin sequences . fragments . Traditionally , these fragments are derived via Inspection of these displays permits analysis of the likely proteolytic digestion of intact antibodies ( for example role of the residues in the functioning of the candidate Morimoto et al. , 1993 , Journal of Biochemical and Bio immunoglobulin sequence , i . e . , the analysis of residues that physical Methods 24 : 107 - 117 ; Brennan et al ., 1985 , Sci influence the ability of the candidate immunoglobulin to ence, 229: 81 ) . In certain embodiments , antibody fragments bind its antigen , such as TNF -alpha . In this way , framework are produced recombinantly. Fab , Fv , and scFv antibody ( FR ) residues can be selected and combined from the fragments can all be expressed in and secreted from E . coli consensus and import sequences so that the desired antibody or other host cells , thus allowing the production of large characteristic , such as increased affinity for the target anti amounts of these fragments . Such antibody fragments can gen (s ), is achieved . also be isolated from antibody phage libraries . The antibody [ 0163] Humanization , resurfacing or engineering of anti fragment can also be linear antibodies as described in U . S . bodies of the present disclosure can be performed using any Pat . No . 5 ,641 , 870 . Other techniques for the production of known method , such as but not limited to those described in , antibody fragments will be apparent to the skilled practitio Winter ( Jones et al . , Nature 321: 522 ( 1986 ) ; Riechmann et ner. al ., Nature 332 : 323 ( 1988 ); Verhoeyen et al ., Science 239 : f0167] For the purposes of the present disclosure , it should 1534 (1988 ) ) , Sims et al. , J . Immunol. 151 : 2296 ( 1993 ) ; be appreciated that modified antibodies can comprise any Chothia and Lesk , J. Mol. Biol. 196 : 901 ( 1987) , Carter et al. , type of variable region that provides for the association of Proc . Natl. Acad . Sci. U . S . A . 89 : 4285 ( 1992 ) ; Presta et al. , the antibody with the antigen ( e. g ., TNF alpha ). In this J . Immunol. 151: 2623 ( 1993 ) , U . S . Pat . Nos . 5 ,639 , 641 , regard , the variable region can comprise or be derived from 5 ,723 , 323 ; 5 , 976 ,862 ; 5 ,824 , 514 ; 5 , 817 , 483 ; 5 ,814 ,476 ; any type ofmammal that can be induced to mount a humoral 5 , 763 , 192 ; 5 ,723 ,323 ; 5 ,766 ,886 ; 5 , 714 , 352 ; 6 , 204 , 023 ; response and generate immunoglobulins against the desired 6 , 180 ,370 ; 5 ,693 ,762 ; 5 ,530 , 101; 5 ,585 ,089 ; 5 ,225 ,539 ; tumor associated antigen . As such , the variable region of the US 2018 /0126000 A1 May 10 , 2018 23 modified antibodies can be , for example , of human , murine , [0175 ] Those skilled in the art will appreciate that the non - human primate (e . g. , cynomolgus monkeys, macaques, antibodies and antigen -binding fragments thereof of this etc . ) or lupine origin . In some embodiments both the vari disclosure and the anti - TNF proteins of this disclosure able and constant regions of the modified immunoglobulins include antibodies , antigen - binding fragments thereof, and are human . In other embodiments the variable regions of anti - TNF proteins (e .g ., full- length antibodies, antigen -bind compatible antibodies (usually derived from a non - human source ) can be engineered or specifically tailored to improve ing fragments of antibodies, or soluble TNF receptor pro the binding properties or reduce the immunogenicity of the teins ) comprising one or more of constant region domains , molecule . In this respect , variable regions useful in the including domains that have been altered so as to provide present disclosure can be humanized or otherwise altered desired biochemical characteristics such as reduced serum through the inclusion of imported amino acid sequences . half - life when compared with an antibody , antigen - binding [0168 ] In certain embodiments , the variable domains in fragment thereof, or anti - TNF protein of approximately the both the heavy and light chains are altered by at least partial same immunogenicity comprising a native or unaltered replacement of one or more CDRs and, if necessary, by constant region . In some embodiments , the constant region partial framework region replacement and sequence chang of the antibody, antigen -binding fragment thereof, or anti ing . Although the CDRs can be derived from an antibody of TNF protein ( e . g . , full - length antibodies, antigen -binding the same class or even subclass as the antibody from which fragments of antibodies, or soluble TNF receptor proteins ) the framework regions are derived , it is envisaged that the will comprise a human constant region . Modifications to the CDRs will be derived from an antibody of different class and constant region compatible with this disclosure comprise in certain embodiments from an antibody from a different additions , deletions , or substitutions of one or more amino species . It may not be necessary to replace all of the CDRs acids in one ormore domains. That is , the antibody, antigen with the complete CDRs from the donor variable region to binding fragment thereof, or anti - TNF proteins ( e . g . , full transfer the antigen -binding capacity of one variable domain length antibodies , antigen -binding fragments of antibodies , to another. Rather , it may only be necessary to transfer those or soluble TNF receptor proteins) disclosed herein can residues that are necessary to maintain the activity of the comprise alterations or modifications to one or more of the antigen -binding site . Given the explanations set forth in U . S . three heavy chain constant domains (CH1 , CH2 or CH3 ) Pat . Nos . 5 ,585 ,089 , 5 ,693 ,761 and 5 ,693 , 762 , it will be well and / or to the light chain constant domain ( CL ) . In some within the competence of those skilled in the art, either by embodiments , modified constant regions wherein one or carrying out routine experimentation or by trial and error more domains are partially or entirely deleted are contem testing to obtain a functional antibody with reduced immu plated . In some embodiments , the antibodies, antigen - bind nogenicity . ing fragments thereof, or anti - TNF proteins ( e . g ., full - length [0169 ] Anti - TNF alpha proteins include soluble TNF antibodies, antigen -binding fragments of antibodies, or receptor proteins . The anti- TNF alpha protein can be a soluble TNF receptor proteins ) will comprise domain soluble p75 TNF receptor. The anti - TNF alpha protein can deleted constructs or variants wherein the entire CH2 be a soluble p55 TNF receptor. domain has been removed ( ACH2 constructs ). In some [0170 ] The soluble TNF receptor can bind to both TNF embodiments , the omitted constant region domain will be alpha and TNF beta . The soluble TNF receptor can bind to replaced by a short amino acid spacer ( e . g . , 10 residues ) that TNF alpha, but not to TNF beta . provides some of the molecular flexibility typically imparted [0171 ] The soluble TNF receptor can inhibit binding of by the absent constant region . TNF alpha ( and optionally TNF beta ) to cell surface TNF [ 0176 ] It will be noted that in certain embodiments , the receptors . antibodies , antigen -binding fragments thereof, or anti - TNF [ 0172 ] The soluble TNF receptor can be etanercept. proteins ( e . g . , full - length antibodies , antigen - binding frag [0173 ] An anti - TNF alpha protein , e . g . , a soluble TNF ments of antibodies , or soluble TNF receptor proteins ) can receptor , can be fused to a heavy chain constant domain or be engineered to fuse the CH3 domain directly to the hinge fragment thereof or an Fc region or fragment thereof. The region of the respective antibodies, antigen - binding frag heavy chain constant domain fragment or Fc fragment can ments thereof, or anti - TNF proteins ( e . g. , full - length anti be a portion of the constant domain or Fc that is capable of bodies , antigen -binding fragments of antibodies, or soluble binding to Fc receptor. The heavy chain constant domain TNF receptor proteins) . In other constructs it can be desir fragment or Fc fragment can be a portion of the constant able to provide a peptide spacer between the hinge region domain or Fc that is capable of inducing cell lysis in vitro in and the modified CH2 and /or CH3 domains . For example , the presence of complement. The heavy chain constant compatible constructs could be expressed wherein the CH2 domain fragment or Fc fragment can be a portion of the domain has been deleted and the remaining CH3 domain constant domain or Fc that is capable of inducing ADCC . (modified or unmodified ) is joined to the hinge region with [ 0174 ] The heavy chain constant domain or fragment a 5 - 20 amino acid spacer . Such a spacer can be added , for thereof or Fc region or fragment thereof can be a human instance , to ensure that the regulatory elements of the heavy chain constant domain or fragment thereof or human constant domain remain free and accessible or that the hinge Fc region or fragment thereof . The heavy chain constant region remains flexible . However, it should be noted that domain or fragment thereof or Fc region or fragment thereof amino acid spacers can , in some cases , prove to be immu can be an IgG1 heavy chain constant domain or fragment nogenic and elicit an unwanted immune response against the thereof or an IgG1 Fc region or fragment thereof. The heavy construct. Accordingly , in certain embodiments , any spacer chain constant domain or fragment thereof or Fc region or added to the construct will be relatively non - immunogenic , fragment thereof can be a human IgG1 heavy chain constant or even omitted altogether, so as to maintain the desired domain or fragment thereof or human IgG1 Fc region or biochemical qualities of the antibodies, antigen - binding fragment thereof. fragments thereof, or anti- TNF proteins ( e . g ., full - length US 2018 /0126000 A1 May 10 , 2018 24.

antibodies , antigen -binding fragments of antibodies , or that some amino acid sequences of the disclosure can be soluble TNF receptor proteins) . varied without significant effect of the structure or function (0177 ] It will be appreciated that the antibodies, antigen of the protein . Thus , the disclosure further includes varia binding fragments thereof, and anti - TNF proteins ( e . g ., tions of the polypeptides which show substantial activity or full - length antibodies, antigen -binding fragments of anti which include regions of an antibody, antigen - binding frag bodies , or soluble TNF receptor proteins ) of the present ment thereof , or anti - TNF alpha protein . Such mutants disclosure can be provided by the partial deletion or substi include deletions, insertions, inversions, repeats , and type tution of a few or even a single amino acid . For example , the substitutions . mutation of a single amino acid in selected areas of the CH2 [0181 ] The polypeptides and analogs can be further modi domain can be enough to substantially reduce Fc binding fied to contain additional chemical moieties not normally and thereby increase tumor localization . Similarly , it may be part of the protein . Those derivatized moieties can improve desirable to simply delete that part of one or more constant the solubility, the biological half life or absorption of the region domains that control the effector function ( e . g . , protein . The moieties can also reduce or eliminate any complement CiQ binding) to be modulated . Such partial desirable side effects of the proteins and the like . An deletions of the constant regions can improve selected overview for those moieties can be found in REMING characteristics of the antibody ( serum half - life ) while leav TON ' S PHARMACEUTICAL SCIENCES , 20th ed . , Mack ing other desirable functions associated with the subject Publishing Co ., Easton , Pa. ( 2000 ). constant region domain intact. Moreover, as alluded to [0182 ] The isolated polypeptides described herein can be above , the constant regions of the disclosed antibodies, produced by any suitable method known in the art. Such antigen - binding fragments thereof, and anti- TNF proteins methods range from direct protein synthetic methods to ( e . g . , full - length antibodies, antigen - binding fragments of constructing a DNA sequence encoding isolated polypeptide antibodies , or soluble TNF receptor proteins ) can be modi sequences and expressing those sequences in a suitable fied through the mutation or substitution of one or more transformed host . In some embodiments , a DNA sequence is amino acids that enhances the profile of the resulting con constructed using recombinant technology by isolating or struct. In this respect it can be possible to disrupt the activity synthesizing a DNA sequence encoding a wild - type protein provided by a conserved binding site ( e . g ., Fc binding ) while of interest . Optionally , the sequence can be mutagenized by substantially maintaining the configuration and immuno site -specific mutagenesis to provide functional analogs genic profile of the antibodies, antigen -binding fragments thereof . See , e . g ., Zoeller et al. , Proc . Nat ' l . Acad . Sci . USA thereof, and anti - TNF proteins ( e . g . , full -length antibodies , 81: 5662- 5066 ( 1984 ) and U . S . Pat . No . 4 ,588 , 585 . antigen - binding fragments of antibodies, or soluble TNF [0183 ] In some embodiments a DNA sequence encoding a receptor proteins ) . Certain embodiments can comprise the polypeptide of interest would be constructed by chemical addition of one or more amino acids to the constant region synthesis using an oligonucleotide synthesizer. Such oligo to enhance desirable characteristics such as decreasing or nucleotides can be designed based on the amino acid increasing effector function or provide for more glucocor sequence of the desired polypeptide and selecting those ticoid receptor agonist attachment. In such embodiments it codons that are favored in the host cell in which the can be desirable to insert or replicate specific sequences recombinant polypeptide of interest will be produced . Stan derived from selected constant region domains. dard methods can be applied to synthesize an isolated [0178 ] It will be appreciated that the antibodies , antigen polynucleotide sequence encoding an isolated polypeptide binding fragments thereof, and anti - TNF proteins ( e . g . , of interest. For example , a complete amino acid sequence full - length antibodies , antigen -binding fragments of anti can be used to construct a back - translated gene. Further , a bodies , or soluble TNF receptor proteins) of the present DNA oligomer containing a nucleotide sequence coding for disclosure can bemodified to reduce immunogenicity , i. e ., to the particular isolated polypeptide can be synthesized . For reduce the anti -drug immune response (ADA ) . Methods of example , several small oligonucleotides coding for portions doing so are disclosed , for example , in WO 2015 /073884 , of the desired polypeptide can be synthesized and then which is herein incorporated by reference in its entirety . ligated . The individual oligonucleotides typically contain 5' [0179 ] The present disclosure further embraces variants or 3 ' overhangs for complementary assembly . and equivalents which are substantially homologous to [ 0184 ] Once assembled (by synthesis , site - directed muta antibodies , antigen - binding fragments thereof , and anti - TNF genesis or another method ), the polynucleotide sequences proteins ( e . g . , full -length antibodies, antigen -binding frag encoding a particular isolated polypeptide of interest will be ments of antibodies , or soluble TNF receptor proteins ) set inserted into an expression vector and operatively linked to forth herein . These can contain , for example , conservative an expression control sequence appropriate for expression of substitution mutations, i . e . , the substitution of one or more the protein in a desired host. Proper assembly can be amino acids by similar amino acids. For example , conser confirmed by nucleotide sequencing, restriction mapping , vative substitution refers to the substitution of an amino acid and expression of a biologically active polypeptide in a with another within the same general class such as, for suitable host. As is well known in the art , in order to obtain example , one acidic amino acid with another acidic amino high expression levels of a transfected gene in a host , the acid , one basic amino acid with another basic amino acid or gene must be operatively linked to transcriptional and trans one neutral amino acid by another neutral amino acid .What lational expression control sequences that are functional in is intended by a conservative amino acid substitution is well the chosen expression host. known in the art . [0185 ] In certain embodiments , recombinant expression [0180 ] The polypeptides of the present disclosure can be vectors are used to amplify and express DNA encoding recombinant polypeptides, natural polypeptides , or synthetic antibodies , antigen -binding fragments thereof, or anti- TNF polypeptides of an antibody, antigen - binding fragment proteins ( e . g . , full -length antibodies , antigen - binding frag thereof, or anti - TNF protein . It will be recognized in the art ments of antibodies, or soluble TNF receptor proteins ) . US 2018 /0126000 A1 May 10 , 2018 25

Recombinant expression vectors are replicable DNA con Patent Publication No. WO 04009823 , each of which is structs which have synthetic or cDNA -derived DNA frag hereby incorporated by reference herein in its entirety . ments encoding a polypeptide chain of an antibody , antigen [0188 ] Various mammalian or insect cell culture systems binding fragment thereof, or anti - TNF protein ( e . g . , full are also advantageously employed to express recombinant length antibodies , antigen - binding fragments of antibodies , protein . Expression of recombinant proteins in mammalian or soluble TNF receptor proteins ) , operatively linked to cells can be performed because such proteins are generally suitable transcriptional or translational regulatory elements correctly folded , appropriately modified and completely derived from mammalian , microbial, viral or insect genes . A functional. Examples of suitable mammalian host cell lines transcriptional unit generally comprises an assembly of ( 1 ) include HEK - 293 and HEK - 2937, the COS - 7 lines of mon a genetic element or elements having a regulatory role in key kidney cells , described by Gluzman ( Cell 23 : 175 , 1981 ) , gene expression , for example, transcriptional promoters or and other cell lines including, for example, L cells , C127 , enhancers , ( 2 ) a structural or coding sequence which is 3T3 , Chinese hamster ovary ( CHO ) , HeLa and BHK cell transcribed into mRNA and translated into protein , and ( 3 ) lines . Mammalian expression vectors can comprise nontran appropriate transcription and translation initiation and ter scribed elements such as an origin of replication , a suitable mination sequences. Such regulatory elements can include promoter and enhancer linked to the gene to be expressed , an operator sequence to control transcription . The ability to and other 5 ' or 3 ' flanking nontranscribed sequences , and 5 ' replicate in a host, usually conferred by an origin of repli or 3 ' nontranslated sequences, such as necessary ribosome cation , and a selection gene to facilitate recognition of binding sites, a polyadenylation site , splice donor and accep transformants can additionally be incorporated . DNA tor sites , and transcriptional termination sequences. Bacu regions are operatively linked when they are functionally lovirus systems for production of heterologous proteins in related to each other . For example , DNA for a signal peptide insect cells are reviewed by Luckow and Summers , Bio / (secretory leader ) is operatively linked to DNA for a poly Technology 6 : 47 ( 1988 ). peptide if it is expressed as a precursor which participates in [0189 ] The proteins produced by a transformed host can the secretion of the polypeptide ; a promoter is operatively be purified according to any suitable method . Such standard linked to a coding sequence if it controls the transcription of methods include chromatography ( e . g ., ion exchange , affin the sequence ; or a ribosome binding site is operatively ity and sizing column chromatography ) , centrifugation , dif linked to a coding sequence if it is positioned so as to permit ferential solubility , or by any other standard technique for translation . Structural elements intended for use in yeast protein purification . Affinity tags such as hexahistidine , expression systems include a leader sequence enabling maltose binding domain , influenza coat sequence and glu extracellular secretion of translated protein by a host cell . tathione - S - transferase can be attached to the protein to allow Alternatively, where recombinant protein is expressed with easy purification by passage over an appropriate affinity out a leader or transport sequence , it can include an N - ter column . Isolated proteins can also be physically character minal methionine residue . This residue can optionally be ized using such techniques as proteolysis, nuclear magnetic subsequently cleaved from the expressed recombinant pro resonance and x - ray crystallography. tein to provide a final product. [0190 ] For example , supernatants from systems which [0186 ] The choice of expression control sequence and secrete recombinant protein into culture media can be first expression vector will depend upon the choice of host . A concentrated using a commercially available protein con wide variety of expression host/ vector combinations can be centration filter, for example , an Amicon or Millipore Pel employed . Useful expression vectors for eukaryotic hosts , licon ultrafiltration unit . Following the concentration step , include , for example , vectors comprising expression control the concentrate can be applied to a suitable purification sequences from SV40 , bovine papilloma virus , adenovirus matrix . Alternatively , an anion exchange resin can be and cytomegalovirus . Useful expression vectors for bacterial employed , for example , a matrix or substrate having pendant hosts include known bacterial plasmids, such as plasmids diethylaminoethyl (DEAE ) groups . The matrices can be from Escherichia coli, including PCR 1 , PBR322 , PMB9 acrylamide , agarose, dextran , cellulose or other types com and their derivatives, wider host range plasmids, such as monly employed in protein purification . Alternatively , a M13 and filamentous single - stranded DNA phages. cation exchange step can be employed . Suitable cation [0187 ] Suitable host cells for expression of antibodies , exchangers include various insoluble matrices comprising antigen - binding fragments thereof, and anti- TNF proteins sulfopropyl or carboxymethyl groups. Finally, one or more ( e . g ., full -length antibodies, antigen -binding fragments of reversed - phase high performance liquid chromatography antibodies , or soluble TNF receptor proteins ) include pro (RP -HPLC ) steps employing hydrophobic RP -HPLC media , karyotes , yeast, insect or higher eukaryotic cells under the e . g . , silica gel having pendant methyl or other aliphatic control of appropriate promoters . Prokaryotes include gram groups , can be employed to further purify anti - TNF proteins negative or gram positive organisms, for example E . coli or ( e . g . , full- length antibodies , antigen -binding fragments of bacilli . Higher eukaryotic cells include established cell lines antibodies, or soluble TNF receptor proteins ) . Some or all of of mammalian origin . Cell - free translation systems could the foregoing purification steps , in various combinations, also be employed . Appropriate cloning and expression vec can also be employed to provide a homogeneous recombi tors for use with bacterial, fungal, yeast , and mammalian nant protein . cellular hosts are described by Pouwels et al. (Cloning [0191 ] Recombinant protein produced in bacterial culture Vectors : A Laboratory Manual, Elsevier, N . Y . , 1985 ) , the can be isolated , for example , by initial extraction from cell relevant disclosure of which is hereby incorporated by pellets , followed by one or more concentration , salting- out , reference . Additional information regarding methods of pro aqueous ion exchange or size exclusion chromatography tein production , including antibody production , can be steps . High performance liquid chromatography (HPLC ) can found , e. g. , in U . S . Patent Publication No . 2008 /0187954 , be employed for final purification steps. Microbial cells U . S . Pat. Nos. 6 ,413 ,746 and 6 , 660, 501 , and International employed in expression of a recombinant protein can be US 2018 /0126000 A1 May 10 , 2018 disrupted by any convenient method , including freeze - thaw cycling , sonication , mechanical disruption , or use of cell lysing agents . SM - S SMC - N [0192 ] Methods known in the art for purifying antibodies, antigen -binding fragments thereof, and anti - TNF alpha pro and teins also include , for example , those described in U . S . w Patent Publication Nos. 2008 /0312425 , 2008 /0177048 , and SM - N 2009 /0187005 , each of which is hereby incorporated by reference herein in its entirety . III . Immunoconjugates Containing Glucocorticoid [0210 ] wherein the sulfur, oxygen , or nitrogen atom is Receptor Agonists attached directly or indirectly to the C - or D -ring of the [ 0193] Immunoconjugates containing glucocorticoid glucocorticosteroid , and R is C - 4 alkyl . In another embodi receptor agonists are provided herein . In some embodi ment, the sulfur, oxygen , or nitrogen atom is attached ments , an immunoconjugate provided herein binds to Fc directly or indirectly to the D - ring of the glucocorticoster gamma receptor. In some embodiments , an immunoconju oid . gate provided herein is active in the GRE transmembrane 10211 ] In another embodiment, disclosed herein is a com TNF -alpha reporter assay (as used herein the “GRE trans pound having Formula I - a , or a pharmaceutically acceptable membrane TNF - alpha reporter assay ” refers to the assay salt thereof , wherein SM is a monovalent radical of a used in Example 79 below ) . In some embodiments , an glucocorticosteroid having Formula II -a : immunoconjugate provided herein is active in the L929 assay (as used herein , the “ L929 assay ” refers to the assay used in Example 82 below ) . In some embodiments , an II - a immunoconjugate provided herein shows reduced immuno mm genicity ( reduced anti - drug immune response (ADA ) ) as R90 compared to the protein in the immunoconjugate ( e . g ., the o antibody , antigen -binding fragment thereof, or soluble R96 receptor ) alone . [01941 In one embodiment, disclosed herein is a com = pound having Formula I - a : (SM -L -Q ) , -A1 I - a . or a pharmaceutically acceptable salt thereof, wherein : [0195 ] Al is an anti - tumor necrosis factor ( TNF ) alpha protein ; [0212 ] wherein : [0196 ] L is a linker; [0213 ] R ' is selected from the group consisting of hydro [0197 ] Q is a heterobifunctional group or heterotrifunc gen and halo ; tional group ; or [0214 ] R2 is selected from the group consisting of hydro [ 0198 ] Q is absent; gen , halo, and hydroxy ; [0199 ] n is 1 - 10 ; and [ 0215 ] R3 is selected from the group consisting of [ 0200 ] SM is a radical of a glucocorticosteroid . CH , OH , CH , SH , CH2C1, SCH , C1, - SCH , F , [ 0201 ] In one embodiment, disclosed herein is a com SCH ,CF3 , - OH ( or hydroxy ), - OCH CN , - OCH C1, pound having Formula 1 - a : - OCH F , OCH3, - OCH CH3, — SCH CN , ( SM -L - Q) , -A ' I - a or a pharmaceutically acceptable salt thereof, wherein : w [ 0202 ] Al is an anti - tumor necrosis factor ( TNF ) alpha antibody, an anti - TNF alpha monoclonal antibody , or adali ?? mumabmi ; [ 0203] L is a linker ; [0204 ] Q is a heterobifunctional group or heterotrifunc *" IMOLL" OH , tional group ; or COH [0205 ) Q is absent; w [ 0206 n is 1 - 10 ; and LOR3 30, andand [0207 ] SM is a radical of a glucocorticosteroid . mm 10208 ] In another embodiment, disclosed herein is a com R3a O pound having Formula I - a , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid . PO- R3d , [0209 ] In another embodiment, disclosed herein is a com ma pound having Formula I- a, or a pharmaceutically acceptable O - RER3e salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid selected from the group consisting of: US 2018 /0126000 A1 May 10 , 2018 27

[0216 ] R3a is selected from the group consisting of hydro - (0235 ] In another embodiment, disclosed herein is a com gen and C1- 4 alkyl; pound having Formula I- a , wherein SM is a monovalent [0217 ] R36 is selected from the group consisting of C1- 4 radical of a glucocorticosteroid having Formula II - a , alkyl and C1- 4 alkoxy ; wherein Rºa is : [0218 ] R3e is selected from the group consisting of hydro R6a gen , C1- 4 alkyl, — CH2OH , and C1- 4 alkoxy ; [ 0219 ] R3d and R3e are independently selected from hydro ROB gen and C1- 4 alkyl; [0220 ] R94 is selected from the group consisting of option ally substituted alkyl , optionally substituted cycloalkyl, Roe R?c . optionally substituted aryl, and optionally substituted het nahin eroaryl; Rød [0221 ] R® is selected from the group consisting of hydro [0236 ] In another embodiment, disclosed herein is a com gen and alkyl; or pound having Formula I - a , wherein SM is a monovalent [0222 ] Rºa is: radical of a glucocorticosteroid having Formula II - a' : II- a O P3 ROQ Rya ROBR66 R96, ma Roe CITIZ or

R60 R2 wherein R ' , R2, R3, R9 , Rb and - - - are as defined in connection with Formula II - a . Roe Y R6C . 102371 In another embodiment, disclosed herein is a com pound having Formula I - a , wherein SM is a monovalent mm Rød radical of a glucocorticosteroid having Formula II - b :

II - b and DR3 [0223 ] Rºb is hydrogen or methyl ; men [ 0224 ] X is selected from the group consisting of Illll - (CR4aR46 ) , 0 - , - S - , - S ( O ) - , - S ( O ) R96 - NR , CH , S — — CH , O — — N ( H ) C ( R $ ) H ( R8 ) , CR4C — CR4d , and — C = C — ; or [0225 ] X is absent ; INX [ 0226 ] tis 1 or 2 ;

[ 0227] Z is selected from the group consisting of = CH - , N = C (OH ) — , and = N — ; [0228 ] each R4a and R4h are independently selected from wherein R ' , R², R3, R9 , Rºb , and - - - are as defined in the group consisting of hydrogen and C1- 4 alkyl ; or connection with Formula II - a . [0229 ] R4a and R46 taken together with the carbon atom to [0238 ] In another embodiment, disclosed herein is a com which they are attached form a 3 - to 6 -membered pound having Formula I - a , wherein SM is a monovalent cycloalkyl; radical of a glucocorticosteroid having Formula II - b ': [0230 ] R4C and R4d are independently selected from the II- b . OR3 group consisting of hydrogen and C -4 alkyl ; non [0231 ] R * is selected from the group consisting of hydro Rya gen and C1- 4 alkyl; [0232 ] Ra, Rób , Róc, Ród , and R6e are each independently R 96 selected from the group consisting of hydrogen , halo , C1- 4 H alkyl, C1- 4 haloalkyl, cyano , hydroxy , thiol , amino , alkyl IT) thio , and alkoxy ; [0233 ] R8a and R86 are independently selected from the group consisting of hydrogen and C1- 4 alkyl; [0234 ] Ril is selected from the group consisting of hydro R2 gen , halo , C1- 4 alkyl, hydroxy, thiol, amino , alkylthio , and wherein R1, R2, R3, Rºa , Rºb , and - -- are as defined in alkoxy ; and - - - represents a single or double bond . connection with Formula II - a . US 2018 /0126000 A1 May 10 , 2018

[0239 ] In another embodiment, disclosed herein is a com [0244 ] wherein R ' , R ? , R9 , Rºb , W , and -- - are as defined pound having Formula I - a , or a pharmaceutically acceptable in connection with Formula Il - c . salt thereof, wherein SM is a monovalent radical of a [0245 ] In another embodiment, disclosed herein is a com glucocorticosteroid having Formula II - c : pound having Formula I - a , wherein SM is a monovalent IL- C radical of a glucocorticosteroid having Formula II - d ':

II - d '

HO wi Rºb, R90 . ?? , Kill R 96

[ 0240 ] wherein R ', R ? , R9 , Rºb , and - - - are as defined in connection with Formula II - a ; and (0241 ] W is selected from the group consisting of O and - S — . In another embodiment, W is 0 . In another embodiment , W is S — . wherein R ', R2, R9 , R? , W , and -- - are as defined in [ 0242 ] In another embodiment, disclosed herein is a com connection with Formula II - c . pound having Formula I -a , wherein SM is a monovalent [0246 ] In another embodiment, disclosed herein is a com radical of a glucocorticosteroid having Formula Il - c ': pound having Formula I - a , or a pharmaceutically acceptable II - c ' salt thereof , wherein SM is a monovalent radical of a glucocorticosteroid having Formula II - e :

nem II- e

HO RIC R96 mui

HO - ORS -Red

wherein R ', R2, Rºa , Rºb , W , and -- - are as defined in connection with Formula II - c . [0243 ] In another embodiment , disclosed herein is a com pound having Formula 1 - a , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having Formula II - d : [0247 ] wherein : [ 0248 ] R ', R2, W , and - - - are as defined in connection II - d with Formula II- c ; [0249 ] Rº is selected from the group consisting of hydro gen , C2- 4 alkyl, and - C ( = O ) R ; [0250 ] Rºd is selected from the group consisting of hydro gen , optionally substituted alkyl , optionally substituted HO RE cycloalkyl , optionally substituted aryl , and optionally sub | | stituted heteroaryl; and R 96 [0251 ] Rºe is selected from the group consisting of hydro 2. gen , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally sub stituted heteroaryl.

JM [0252 ] In another embodiment, disclosed herein is a com pound having Formula I - a , wherein SM is a monovalent radical of a glucocorticosteroid having Formula II - e ': US 2018 /0126000 A1 May 10 , 2018

[0257 ] In another embodiment, disclosed herein is a com Il - e ' pound having Formula I- b : ( SM -L - Q) , - A2 I- b or a pharmaceutically acceptable salt thereof, wherein : nun [0258 ] A² is a protein ; [0259 ] L is a linker ; [0260 ] Q is a heterobifunctional group or heterotrifunc HO -OR tional group ; or Red [0261 ] Q is absent; H [0262 ] n is 1 - 10 ; and [ 0263 ] SM is a monovalent radical of a glucocorticoster oid having any one of: ( 1 ) Formula II- 1 : [0264 ] wherein R ', R2, W , R " , Rºd , and - - - are as defined in connection with Formula Il - e . [ 0253] In another embodiment, disclosed herein is a com II - 1 pound having Formula I- a , or a pharmaceutically acceptable R ?? salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having Formula II- f : HO Roe II- f TV 10 R11b HO THIOR% ( 2 ) Formula II- m : TITR9d [0265 ] IR II - m Roa R3 [ 0254 ] wherein : R9F min [ 0255 ] R ' , R2 , R9 , Rºd , W , and -- - are as defined in R11B Roe Roc connection with Formula Il - e . H I mmo" V10 R116 powingR6d [ 0256 ] In another embodiment, disclosed herein is a com pound having Formula I - a , wherein SM is a monovalent radical of a glucocorticosteroid having Formula II - f' : HORR

II - f (3 ) Formula II -n : mi [0266 ] II - n 1111OR R ?? HUR 9d OR 2X mamda Rod ! wherein R1, R², R9 , Rºd , W , and -- - are as defined in at connection with Formula II- e . US 2018 /0126000 A1 May 10 , 2018 30

( 4 ) Formula Il - o : -continued [ 0267 ] R30, and II- o Roa - KyykyR3a OR3 RosR66 R9f my PO - R3d , Y Y2 ma R6d O - R3e [0274 ] R3a is selected from the group consisting of hydro gen and C1- 4 alkyl; [0275 ] R36 is selected from the group consisting of C1- 4 alkyl and C1- 4 alkoxy ; ( 5 ) Formula Il - p : [ 0276 ] R3° is selected from the group consisting ofhydro [ 0268 ] gen , C1- 4 alkyl, - CH2OH , and C1- 4 alkoxy; [0277 ] R3d and R3e are independently selected from hydro Il - p gen and C1- 4 alkyl; R?? [0278 ] RÓG ,R6b , RÓC ,Rød , and Roe are each independently selected from the group consisting of hydrogen , halo , C1- 4 OR3 alkyl, C - 4 haloalkyl, cyano , hydroxy, thiol, amino , alkyl HO 10 .My thio , and alkoxy ; wenn [0279 ] X is selected from the group consisting of Rod (CR4aR46 , , O - , - S - , - S ( O ) - , - S (= O ) 2 - , - NRG , CH S — , CH , O , N ( H ) C ( R $ ) [ TR ] (R8b ) , CR4C = CR42 — ( including both E and Z iso mers ), and — C = C — ; ( wherein when X is CH S — , CH , 0 — , or — N ( H ) C (R82 ) (R86 ) , the heteroatom of CH , S — , - CH20 — , or — N ( H ) C (R84 ) (R8b ) - can be ( 6 ) Formula Il - q : attached to either 6 -membered ring , i. e ., — CH , S — is [ 0269] equivalent to — SCH — , CH2O is equivalent to OCH , — , and — N (H ) C (R $ ) (R85 ) — is equivalent to II- q - C ( R8a ) (R8b ) N ( H ) ); or ROQ [0280 ] X is absent, i. e ., X represents a chemical bond ; R66 [0281 ] Y² is selected from the group consisting of 0 - , O R3 - S — , and — N (R74 ) — ; or HO [0282 ] Y2 is absent, i. e ., Y2 represents a chemical bond ; R mun [ 0283 ] t is 1 or 2 ; A li ) , ó Rílo R6d [ 0284 ] Z is selected from the group consisting of YRY = CR11a — and = N — ; [0285 ] each R4a and R46 are independently selected from the group consisting of hydrogen and C1- 4 alkyl; or [0286 ] R40 and R44 taken together with the carbon atom to [0270 ] wherein : which they are attached form a 3 - to 6 -membered [ 0271 ] Rl is selected from the group consisting of hydro cycloalkyl; gen and halo ; [0287 ] R4C and R4d are independently selected from the [0272 ] R ’ is selected from the group consisting of hydro group consisting of hydrogen and C1- 4 alkyl; gen , halo , and hydroxy ; [ 0288 ] R is selected from the group consisting of hydro [ 0273] R3 is selected from the group consisting of gen and C1- 4 alkyl; - CH , OH , CH ,SH , CH , C1, SCH , C1, — SCH , F, [0289 ] Ria is selected from the group consisting of hydro - SCH CF3, OH , OCH CN , OCH _ C1, OCH F , gen and C1- 4 alkyl; - OCHZ, OCH CH3, SCH ,CN , [0290 ] R8a and R86 are independently selected from the OH group consisting of hydrogen and C1- 4 alkyl; [0291 ] Rºis selected from the group consisting of hydro tan ?? gen and C1- 4 alkyl; [0292 ] Rila and Rllb are independently selected from the ** * group consisting of hydrogen , halo , C1- 4 alkyl, C1- 4 " OH , haloalkyl, cyano , hydroxy , thiol, amino , alkylthio , and CO2H alkoxy ; and [0293 ] - -- represents a single or double bond . US 2018 /0126000 A1 May 10 , 2018 31 ereen [ 0294 ] In another embodiment , disclosed herein is a com - ( 4) Formula II -o ': pound having Formula I- b : [0304 ] (SM -L - Q) n - A ? die I- b , wherein : van[ 0295 ] A2 is a protein ; II - o ' [0296 ] L is a linker: Roa [0297 ] Q is a heterobifunctional group or heterotrifunc tional group ; or OR 10298 ] Q is absent ; Per devan [0299 ] n is 1 - 10 ; and HO ..110 R6e R11 [ 0300 ] SM is a monovalent radical having any one of: R?? ( 1) Formula II- 1 ' : H [0301 ]

II- 1 ' ROQ .( 5 ) Formula II -p : -R3o Roxse [0305 ] HO Powin R116 RoeRoe A H ., Ríló ROM II- p ' Roa R3 Reze R60 HO J110 Roe R116 wulan ( 2 ) Formula Il -m ': Rod [0302 ]

Il- m ' R ?? ... (6 ) Formulamer Il - q' : [0306 ] R6d Ceny.com Il- q ' R?? OR ZX hundred

(11) on HO Roe ( 3 ) Formula II- n ': R118 R6d w [ 0303 ] CHI

II - n ' ROQ OR3 [0307 ] wherein R1, R2, R3, = , Rºa , Rºc, Rod , Rºe , R2 , R11b , Y ? , X , and Z are as defined in connection with Formula How I man II -1 . Pomo [0308 ] In another embodiment, disclosed herein is a com RIC R6e R?? pound having Formula I - b : A I| (SM -L - Q) , - A ? I- b , wherein : [ 0309 ] A² is a protein ; [0310 ] L is a linker; US 2018 /0126000 A1 May 10 , 2018 32 May10 ,2018

[0311 ] Q is a heterobifunctional group or heterotrifunc ( 4 ) Formula II -o " : tional group ; or [0318 ] [ 0312] Q is absent ; [0313 ] nis 1 -10 ; and II- o ! [0314 ] SM is a monovalent radical having any one of: Roa ( 1) Formula 11- 1 " : [0315 ] Vail . Ó R116 ReyR6d 111T IIIII- 1 " OR3 O. RON HOVO Roe (5 ) Formula Il -p " : Alibópony R16 RodRod [0319 ] letnie Rii * Il -p " Roa OR NAX R6 ( 2 ) Formula Il -m " : HootyHO 110 RON R11bR116 Roe mm e[os 0316 moments ] ' u10 Rod IIII- m "! 0 R6a de 0 R3 RerR9fNS or HO Outly Roe Powin R11B R6d ( 6 ) Formula Il- q " : IM [0320 ] * II- q " (3 ) Formula II- n" : OR3 mm RIBB Roe Y [ 0317] wiló Ríló Róé R6d

II- n " * ROQ OR3 R9 [ 0321] wherein R ', R2, R3 , = , Rºa, Rºc, Rºd , Rºe , R2 , HOHonly ROCman R11b , Y , and X are as defined in connection with Formula R?? II- 1 , and the carbon atom marked with an “ * ” is either the ! R - isomer or the S - isomer when R2 is halo or hydroxyl . In I| one embodiment, the carbon atom marked with an “ * ” is the * R -isomer . In another embodiment, the carbon atom marked with an “ * ” is the S - isomer . [0322 ] In another embodiment, disclosed herein is a com pound having Formula 1- a or I -b , or a pharmaceutically US 2018 /0126000 A1 May 10 , 2018 33 acceptable salt thereof, wherein SM is a monovalent radical [0336 ] R4a and R4h taken together with the carbon atom to of a glucocorticosteroid having Formula II - 1: which they are attached form a 3 - to 6 -membered cycloalkyl; II - 1 [0337 ] R4C and R4d are independently selected from the R ?? group consisting of hydrogen and C1- 4 alkyl; [ 0338 ] R is selected from the group consisting of hydro OR3 gen and C1- 4 alkyl ; mm [ 0339 ] RÓG, RÓ , Ród , and Røe are each independently HOL. RITY Rhe Y Roc selected from the group consisting of hydrogen , halo , C1- 4 110 R116 Rod alkyl, C1- 4 haloalkyl, cyano , hydroxy , thiol , amino , alkyl thio , and alkoxy ; [0340 ] Y2 is selected from the group consisting of O , - S — , and — N (R74 ) — ; or [0341 ] Y ? is absent; [0342 ] Ria is selected from the group consisting of hydro [ 0323 ] wherein : gen and C1- 4 alkyl ; [ 0324 ] Riis selected from the group consisting of hydro [0343 ] R & a and R $5 are independently selected from the gen and halo ; group consisting of hydrogen and C1- 4 alkyl; [0325 ] R² is selected from the group consisting of hydro [0344 ] R is selected from the group consisting of hydro gen , halo , and hydroxy ; gen and C1- 4 alkyl; [0326 ] R * is selected from the group consisting of [0345 ] Rlla and Rllb are independently selected from the - CH , OH , CH ,SH , — CH , C1, SCH , C1, — SCH F, group consisting of hydrogen , halo , C - 4 alkyl, C1 . 4 - SCH , CF3, OH , OCH CN , OCH C1, VOCH , F , haloalkyl, cyano , hydroxy, thiol, amino , alkylthio , and OCHZ, OCH CH3, - SCH , CN , alkoxy ; and LOH [0346 ] - - - represents a single or double bond . INI [0347 ] In another embodiment, disclosed herein is a com ma OH pound having Formula I - a or l - b , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical ** of a glucocorticosteroid having Formula II - m : " OH , II- m CO2H Roa R3b 1 Rºf ma ?? , Pere mi R3a 0 Rbe w I 1010 R11R Rød R3c , and YRJA

mm [0348 ] wherein R1, R², R3, -- , R60 , R6 , Ród , Røe , Rº , R11b , Y ? , X , and Z are as defined in connection with Formula - O - R3d , II- 1. O - R3e [ 0349 ] In another embodiment, disclosed herein is a com [0327 ] R3a is selected from the group consisting of hydro pound having Formula I- a or Ib , or a pharmaceutically gen and C1- 4 alkyl; acceptable salt thereof, wherein SM is a monovalent radical [ 0328] R3b is selected from the group consisting of C -4 of a glucocorticosteroid having Formula II - n : alkyl and C1- 4 alkoxy ; [0329 ] R3° is selected from the group consisting of hydro II - n gen , C1- 4 alkyl, CH2OH , and C1- 4 alkoxy ; P?? [ 0330 ] R3d and R3e are independently selected from hydro R3 2X gen and C1- 4 alkyl; [0331 ] X is selected from the group consisting of HO NO RAZ R60 R11b Rbe Y – (CR44R46 ) , 04 , S4 , S40 , - S ( O ) Rod 22, NR?, CH , S?, CHÚ0 , LN ( H ) C ( R84 ) II ( R8 ) , _ CR4C — CR4d , and C = C — ; or i [0332 ] X is absent; [ 0333] tis 1 or 2 ; [ 0334 ] Z is selected from the group consisting of = CRila — and = N — ; [0350 ] wherein R ', R ?, R }, - -- , R6a , Ró , Ród , Roe, Rº, [ 0335 ] each R4a and R4h are independently selected from R11b , Y ? , X , and Z are as defined in connection with Formula the group consisting of hydrogen and C1- 4 alkyl ; or II - 1 . US 2018 /0126000 A1 May 10 , 2018 34

[0351 ] In another embodiment, disclosed herein is a com [0357 ] In another embodiment, disclosed herein is a com pound having Formula I - a or I -b , or a pharmaceutically pound having Formula I - a or I -b , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having Formula II - o : of a glucocorticosteroid having any one of Formulae II - a , II -b , II - c , II- d , II- e , II - f , II - 1, Il - m , Il - n , II - o , II - p , or Il - q , or any one of Formulae II- a ', II - b ', II -c ', II - d ', II - e ', II - f , II- 1' , II - o II - m ', II - n ', II -o ' , Il - p ', Il -q ' , II- 1" , II -m " , II - n " , II - 0 " , Il - p " , or R?? II - q " , wherein - - - represents a double bond . RÓC [0358 ] In another embodiment, disclosed herein is a com Rex pound having Formula 1 - a or l - b , or a pharmaceutically HO . mm acceptable salt thereof, wherein SM is a monovalent radical True RoeR6e ? of a glucocorticosteroid having any one of Formulae II - a , vid R1 R6d II - b , II - c , II - d , Il - e , II- f , II - 1 , Il - m , Il - n , Il - o , Il - p , or Il - q , or any one of Formulae II - a' , II - b ', II - c' , II - d ', II - e' , II - f , II- l' , Il - m ', II - n ', II - o ', II - p ', Il - q ', II- 1 " , II - m " , II - n " , II - 0 " , Il - p " , or II -q " , wherein R ' is selected from the group consisting of II hydrogen and fluoro . [ 0352 ] wherein R ', R , R , – , R60 , R60 , R6 , Rºf, R116 , [0359 ] In another embodiment, disclosed herein is a com Y ? , X , and Z are as defined in connection with Formula II- 1 ; pound having Formula I- a or 1 -b , or a pharmaceutically and RÓh is selected from the group consisting of hydrogen , acceptable salt thereof, wherein SM is a monovalent radical halo , C1- 4 alkyl, C1- 4 haloalkyl, cyano , hydroxy, thiol, of a glucocorticosteroid having any one of Formulae II - a , amino , alkylthio , and alkoxy . II - b , II - c , II - d , Il - e , II - f , II - 1 , II - m , II - n , II - o , Il - p , or Il - q , or [ 0353] In another embodiment, disclosed herein is a com any one of Formulae II -a ', II- b' , II - c' , II - d ', II - e' , II - f , II - l' , pound having Formula 1- a or l -b , or a pharmaceutically II- m ', II - n ', II - o ', II- p ', II- q ', 11- 1" , II - m " , II- n " , II- 0 " , II- p " , or acceptable salt thereof, wherein SM is a monovalent radical Il - q " , wherein R ’ is selected from the group consisting of of a glucocorticosteroid having Formula II - p : hydrogen and fluoro . [0360 ] In another embodiment, disclosed herein is a com pound having Formula I - a or 1 - b , or a pharmaceutically Il- p acceptable salt thereof, wherein SM is a monovalent radical P?? of a glucocorticosteroid having any one of Formulae II- a , II -b , II - 1, Il- m , II - n , Il - o , Il - p , or II - q , or any one of Formulae OR3 Zyx II -a ', II- b ', 11 -1 ' , II -m ', II -n ', II -o ', Il -p ' , II - q' , 11 -1 ' , II -m " , II -n " , II - 0 " , II - p " , or II - q " , wherein R3 is selected from the group HOMOKIRbe Y min consisting of CH2OH , CH2C1, — SCH , C1, — SCHZF , allilH ' 10 R11Rio Roe RodY and — OH . i [0361 ] In another embodiment, disclosed herein is a com pound having Formula 1- a or I -b , or a pharmaceutically 1171 acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having any one of Formulae II- a , [0354 ] wherein R1, R², R } , - - , R60 , R60 , R60 , Ró , R ” , II -b , II -1 , II -m , II - n , II - o , Il -p , or Il - q, or any one of Formulae R11b , Y2, X , and Z are as defined in connection with Formula II - a ', II - b ', II - l' , II - m ', II - n ', II - o ', II- p ', Il - q ', 11 - 1' , II - m " , II - n " , Il - o . II -0 " , Il - p " , or Il - q " , wherein : [0355 ] In another embodiment, disclosed herein is a com pound having Formula I - a or I - b , or a pharmaceutically [0362 ] R3 is selected from the group consisting of: acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having Formula II - q : OH E. mm III. OH II- 2 Roa " OH , OR ZYXY TO2H HO Os= V é in mm I Ó Ríló Roe Rod 20 R35 , Rii R3a or 71 R3c, and [0356 ] wherein R ', R2, R }, -- , R6a , Rób , Ród , Roe, Rºf, mo R11b , Y2 , X , and Z are as defined in connection with Formula Il - o . US 2018 /0126000 A1 May 10 , 2018 35

- continued II - b , II - c , II - d , II - 1, II - m , II - n , Il - o , Il - p , or II - q , or any one of Formulae II - a ', II - b ', II- c ', II - d ' , II - 1' , Il - m ' , Il - n ', II- o ', II- p ', Il - q ' , II - l" , Il- m " , II - n " , II - 0 " , Il - p " , or Il - q " , wherein : [0373 ] X is selected from the group consisting of man 0 - R3d , - (CR44R46 ) — , - 04 , - S — , - S ( O ) - , - S (= O ) O - R3e 24 , CH S , and — N (H ) CH ( R $ ) — ; [0374 ] t is 1; [0363 ] R3a is selected from the group consisting of hydro [0375 ) R4a and R4h are independently selected from the gen and methyl; group consisting of hydrogen and methyl ; or [ 0364 ] R3h is selected from the group consisting of methyl, [0376 ] R40 and R44 taken together with the carbon atom to ethyl, isopropyl , isobutyl ,methoxy , ethoxy, isopropoxy , and which they are attached form a 3 -membered cycloalkyl; and isobutoxy ; [0377 ] R & a is selected from the group consisting of hydro [ 0365 ] R3e is selected from the group consisting of hydro gen and methyl. In another embodiment, X is _ CH _ — . In gen , methyl, ethyl, CH , OH , methoxy, ethoxy, and iso another embodiment, X is selected from the group consist propoxy ; ing of: [0366 ] R3d and R3e are independently selected from the group consisting of hydrogen , methyl, and ethyl. [ 0367 ] In another embodiment, disclosed herein is a com pound having Formula I- a or I- b , or a pharmaceutically mm acceptable salt thereof, wherein SM is a monovalent radical mm mm and more of a glucocorticosteroid having any one of Formulae II - a , II -b , II- C, II -d , II -1 , II -m , II -n , II - o, Il -p , or Il - q, or any one CH3 of Formulae II - a ', II - b ', Il - c ', II - d ' , II - l' , Il - m ', II - n ', II - o ', Il - p ' , Il- q ' , II - 1 " , II - m " , II - n " , II - 0 " , Il - p " , or Il - q " , wherein R and R & a are independently selected from the group consisting of [0378 ] In another embodiment, X is O — . In another hydrogen and methyl. embodiment, X is S — . In another embodiment, X is [0368 ] In another embodiment, disclosed herein is a com CH , S — . In another embodiment, X is N ( H )CH , — . In pound having Formula 1 - a or l - b , or a pharmaceutically another embodiment, X is selected from the group consist acceptable salt thereof, wherein SM is a monovalent radical ing of: of a glucocorticosteroid having any one of Formulae II - a , II- b , Il- c , II - d , II - 1, Il - m , Il- n , Il- o , Il- p , or II -q , or any one ofFormulae II - a ', II - b ', II - c ', II - d ', II - 1 ', II - m ', II - n ', II - o ', II - p ' , N Il- q ', II - 1" , II - m " , II - n " , II - 0 " , Il - p " , or Il - q " , wherein Z is mm and = CH mm mm mm [0369 ] In another embodiment, disclosed herein is a com CH3 pound having Formula I - a or 1 - b , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having any one of Formulae II - a , [0379 ] In another embodiment, disclosed herein is a com II- b , Il -c , II -d , II- 1 , II - m , Il - n , Il - o , Il -p , or Il - q , or any one pound having Formula I - a or I - b , or a pharmaceutically of Formulae II -a ' , II -b ', Il -c ' , II - d' , II -1 ' , Il -m ', II - n ', II - o' , Il - p ', acceptable salt thereof, wherein SM is a monovalent radical Il- q ', II - 1" , II - m " , II - n " , II - 0 " , II- p " , or Il - q " , wherein Z is of a glucocorticosteroid having any one of Formulae II - a , = N — II - b , II - c , II - d , II - 1 , II- m , or II - n , or any one of Formulae II - a ' , [0370 ] In another embodiment , disclosed herein is a com II -b ', II - c' , II -d ', II- 1 ' , Il -m ', II- n' , Il -1 " , Il -m " , or II -n " , pound having Formula 1 - a or I - b , or a pharmaceutically wherein R?C is selected from the group consisting of hydro acceptable salt thereof, wherein SM is a monovalent radical gen , — C1, — OMe ( or — OCHZ) , and — OH . of a glucocorticosteroid having any one of Formulae II - a , [0380 ] In another embodiment, disclosed herein is a com II - b , II - c , II - d , II- 1, II - m , II - n , II - o , II- p , or Il - q , or any one pound having Formula I- a or I -b , or a pharmaceutically of Formulae II -a ' , II -b ', II - c' , II - d' , II -1 ' , Il -m ', II - n ', II - o' , Il -p ', acceptable salt thereof, wherein SM is a monovalent radical Il -q ', II - 1" , II - m " , II -n " , II -0 ", II- p " , or Il -q " , wherein Roa, of a glucocorticosteroid having any one of Formulae II - a , Ród , and Róe are hydrogen . II - b , Il - c , II - d , Il - o , Il - p , or Il - q , or any one of Formulae II - a ', [ 0371 ] In another embodiment, disclosed herein is a com II - b ' , Il - c ', II - d ' , II- o ', Il - p ', Il - q ', II - 0 " , II - p " , or Il - q " wherein pound having Formula 1 - a or 1 - b , or a pharmaceutically R® is selected from the group consisting of hydrogen , — C1, acceptable salt thereof, wherein SM is a monovalent radical - OMe (or — OCHZ) , and — OH . of a glucocorticosteroid having any one of Formulae II - 1 , [0381 ] In another embodiment, disclosed herein is a com Il- m , II - n , II - o , Il - p , or Il - q , or any one of Formulae II - l' , pound having Formula 1 - a or 1 - b , or a pharmaceutically Il - m ', II - n ', II - o ', Il - p ', Il - q ', II - 1" , Il - m " , II - n " , II - 0 " , Il - p " , or acceptable salt thereof, wherein SM is a monovalent radical Il - q " , wherein Y ’ is — N ( R ) . In another embodiment , of a glucocorticosteroid having any one of Formulae II - 1 , R7a is selected from the group consisting of hydrogen and Il -m , II - n , II - o , Il -p , or Il -q , or any one of Formulae II - 1' , methyl. In another embodiment, R ' “ is hydrogen . In another II- m ', II -n ', II - o' , II - p' , Il - q' , 11 -1 ", Il - m ", II- n ", II- o ", Il - p" , or embodiment, R7a is methyl. Il - q " , wherein R is hydrogen . [0372 ] In another embodiment, disclosed herein is a com [0382 ] In another embodiment, disclosed herein is a com pound having Formula I - a or I - b , or a pharmaceutically pound having Formula I- a or I -b , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having any one of Formulae II - a , of a glucocorticosteroid having any one of Formulae II - 1, US 2018 /0126000 A1 May 10 , 2018 36

Il -m , II - n , II -o , Il -p , or Il - q , or any one of Formulae II - l' , Il - m ' , II - n ', II - o ' , II - p ', Il - q ', II - 1 " , II - m " , II - n " , II - o " , II - p " , or Q - 1 Il - q " , wherein R ” is methyl. [0383 ] In another embodiment, disclosed herein is a com pound having Formula I- a or I- b , or a pharmaceutically acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having any one of Formulae II - 1, Il - m , Il - n , II - o , Il - p , or Il - q , or any one of Formulae II - 1' , Il - m ', II - n ', II - o ', Il - p ', Il- q ', II - 1" , II - m " , II- n " , II - o " , Il - p " , or w Il - q " , wherein Rlla is selected from the group consisting of Q - 2 hydrogen and OH . HO2C . [ 0384 ] In another embodiment, disclosed herein is a com pound having Formula 1 - a or I - b , or a pharmaceutically w acceptable salt thereof, wherein SM is a monovalent radical of a glucocorticosteroid having any one of Formulae II- 1 , m Il - m , Il - n , Il - o , Il - p , or Il - q , or any one of Formulae II - l' , OS II -m ', II -n ', II -o ', Il -p ', 11 -q ', 11 -1 " , II -m " , II- n " , II -O " , II- p " , or Il- q " , wherein Rllb is hydrogen . [0385 ] In another embodiment, disclosed herein is a com pound having Formula I- a or I -b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula I - a or I -b wherein SM is a monovalent radical of a glucocorti costeroid having any one of Formulae II - a , II - b , Il - c , II - d , Il -e , II -f , II -1 , II -m , II -n , Il -o , Il -p , or Il - q, or any one of Formulae II - a ', II - b ' , II - c ' , II - d ', Il - e ', II - f , II- 1 ', II - m ' , II - n ' , www Q - 4 Il- o ', Il - p ', Il - q ', Il - 1 " , Il- m " , Il - n " , II - 0 " , Il - p " , or Il - q " , HO2C wherein L is a cleavable linker. In another embodiment, the HYw cleavable linker comprises a succinimide, amide, thiourea , thioether, oxime, or self - immolative group , or a combination thereof. In another embodiment , the cleavable linker com prises a peptide . In another embodiment, the cleavable linker Height comprises a tripeptide . In another embodiment , the cleav Q - 5 able linker comprises a dipeptide . In another embodiment, the cleavable linker comprises phosphate ester . In another embodiment, the cleavable linker comprises a pyrophos phate diester . [ 0386 In another embodiment, disclosed herein is a com mm pound having Formula I - a or I - b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula I - a or I - b wherein SM is a monovalent radical of a glucocorti and costeroid having any one of Formulae II - a , II -b , II - c , II - d , Q - 6 Il -e , II- f, II -1 , II - m , II- n , Il -o , Il -p , or Il -q , or any one of Formulae Il - a ' , II - b ', II - c ' , II - d ', Il - e ', II - f , Il - 1' , II - m ', Il - n ', II -o ', Il - p ', Il - q' , II- 1 " , II- m " , II - n " , II -0 " , II- p " , or Il -q " , mo wherein Q is absent . [0387 ] In another embodiment, disclosed herein is a com pound having Formula I - a or I - b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula I - a or I- b wherein SM is a monovalent radical of a glucocorti costeroid having any one of Formulae Il - a , II - b , Il - c , II - d , mi II - e , II - f, II - 1, Il - m , II -n , II -o , Il -p , or Il - q , or any one of Formulae II - a ', II - b ', II -c ', II- d ', Il - e ', II - f , II - 1 ', II - m ' , II - n ', wherein m is 1 , 2 , 3 , 4 , 5 , or 6 . In another embodiment, Q II -o ', II- p ', II - q ', II -1 " , II -m " , II - n " , II - 0 " , Il - p " , or II - q " , is selected from the group consisting of Q - 1 , Q - 2 , Q - 3 , and wherein Q is a heterobifunctional group . 0 - 4 . In another embodiment, Q is selected from the group [0388 ] In another embodiment, disclosed herein is a com consisting of Q - 3 and Q - 4 . In another embodiment, m is 2 . pound having Formula I - a or I- b , or a pharmaceutically [ 0389 ) In another embodiment, disclosed herein is a com acceptable salt thereof, e . g . a compound having Formula I - a pound having Formula I- a or I -b , or a pharmaceutically or I- b wherein SM is a monovalent radical of a glucocorti acceptable salt thereof, e . g . a compound having Formula I - a costeroid having any one of Formulae II - a , II - b , Il -c , II - d , or I -b wherein SM is a monovalent radical of a glucocorti Il- e , Il - f , II - 1 , II - m , II - n , II - o , Il- p , or II - q , or any one of costeroid having any one of Formulae II -a , II -b , II -c , II - d , Formulae II - a ', II - b ', Il - c ', II - d ', II - e ', II - f , II - 1' , II - m ', II - n ' , II - e , II- f , II - 1, II - m , Il - n , Il - o , Il - p , or Il - q , or any one of II- o ', Il - p ', Il - q ', II - 1 " , II- m " , II - n " , II - 0 " , Il - p " , or Il - q " , Formulae II - a ', II -b ', II - c ', II - d ' , Il - e ' , II- f' , II -1 ', II - m ', II- n ', wherein Q is a heterobifunctional group selected from the Il - o ', Il - p ', Il - q ', Il - 1 " , Il - m " , II- n " , II - o " , Il - p " , or Il - q " , group consisting of: wherein Q is a heterotrifunctional group . US 2018 /0126000 A1 May 10 , 2018 37

[0390 ] In another embodiment, disclosed herein is a com pound having Formula I- a or l- b , or a pharmaceutically In another embodiment, - L - Q - is : acceptable salt thereof, e . g . a compound having Formula I - a LO - 4 or 1 - b wherein SM is a monovalent radical of a glucocorti costeroid having any one of Formulae II - a , Il - b , Il- c , II - d , II - e , II - f, II - 1, IÌ - m , II -n , II -o , Il -p , or Il - q , or any one of Formulae II - a ' , II - b ' , II - c ', II - d ' , II - e ' , II - f , II - 1 ', II - m ', II- n ' , II -o ', Il - p ', Il - q' , II- 1 " , II- m " , Il - n " , II- o " , II- p " , or Il -q " , R 100 m wherein Q is a heterotrifunctional group that is : Q -7 wa N HiyotR10a 0 mm In another embodiment, -L - Q - is : LQ - 5 min ma w R100V 0 [0391 ] In another embodiment, disclosed herein is a com pound having Formula I - a or 1 - b , or a pharmaceutically ZI acceptable salt thereof, e . g . a compound having Formula I - a or I -b wherein SM is a monovalent radical of a glucocorti J NH costeroid having any one of Formulae II- a , II - b , Il -c , II - d , man R102D 10a 0 Il - e , II- f , II - 1 , II - m , II - n , II - o , Il - p , or Il - q , or any one of tylist Formulae II - a ', Il - b ', II - c ', II - d ', II- e ', Il - f' , II - 1' , II - m ', II - n ', [0394 ] In another embodiment, disclosed herein is a com II - o ', Il - p ', II - q ', II - 1" , II- m " , II- n " , II - o " , II - p " , or Il - q " , pound having Formula I- a or I -b , or a pharmaceutically wherein - L - Q - is : acceptable salt thereof, e . g . a compound having Formula I- a or I - b wherein SM is a monovalent radical of a glucocorti S LO - 1 costeroid having any one of Formulae II - a , II - b , II - c , Il - d , II -e , Il - f, II- 1, II- m , II- n , Il -o , II- p , or Il -q , or any one of Formulae Il - a ', Il - b ', Il - c ', Il - d ', Il - e ', II - f , II - l' , Il - m ', II - n ', II -o ', II- p ', Il - q ', II -1 " , II -m " , II - n " , II - 0 " , Il - p " , or Il - q " , R105 wherein - L - Q - is : LQ- 6 N HO2C ww R102 0 O R 1000 [0392 ] m is 2 or 3 ; and [ 0393] Rl0a and Riob are independently selected from the group consisting of hydrogen and optionally substituted C1- 6 HighestR 10a alkyl . In another embodiment, m is 2 . In another embodi ment, m is 1 . In another embodiment, - L - Q - is : [0395 ] m is 2 or 3 ; and [0396 ] R10a and R105 are independently selected from the LQ - 2 group consisting of hydrogen and optionally substitutedC6 alkyl. In another embodiment , m is 2 . In another embodi ment, - L - Q - is : R 106 0 LQ - 7 1111| HO2C R100 IZ R102 0 N In another embodiment, - L - Q - is : HortlightR10a 0 Histle LO - 3 In another embodiment, - L - Q - is : LQ - 8 HO2C . R100 0 R 100 en i ZE ni lllll N 111ll NH RT0a R100 m US 2018 /0126000 A1 May 10 , 2018 38

In another embodiment, -L - Q - is : Formulae II- a' , II- b ' , II -c ' , II- d ', II -e ', II- f', II- 1 ' , II -m ', II- n ', II -o ', Il - p ', Il - q' , II- 1 " , II- m " , Il - n " , II -0 " , II- p " , or Il -q " , wherein - L - Q - is : LQ - 9 R 1000 HO2C LQ - 12 N m NH O S R 10a100 ma???? CNH – COH; In another embodiment, - L - Q - is : w NH [0402 ] m is 2 or 3 ; and [0403 ] x is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , or LQ - 10 15 . In another embodiment, m is 2 . HO2C [0404 ] In another embodiment, disclosed herein is a com R 10b O pound having Formula I- a or 1 -b , or a pharmaceutically N ZIMIT acceptable salt thereof, e . g . a compound having Formula 1 - a > or I- b wherein SM is a monovalent radical of a glucocorti lll costeroid having any one of Formulae II - a , Il - b , Il - c , II - d , mm R 10a 0 II - e , II- f , II - 1, Il - m , II- n , II - o , Il - p , or Il - q , or any one of Formulae II - a ', II - b ', II - c ', II - d ', II - e ', II - f' , II- 1' , II- m ', II- n ', [ 0397 ] In another embodiment, disclosed herein is a com II - o ' , Il - p ', II - q ', 11 - 1" , Il - m " , II - n " , II - o " , II - p " , or Il - q " , pound having Formula 1 - a or I - b , or a pharmaceutically wherein - L - Q - is : acceptable salt thereof, e . g . a compound having Formula I - a or I -b wherein SM is a monovalent radical of a glucocorti costeroid having any one of Formulae II - a , II - b , Il - c , II - d , LQ - 13 Il - e , Il - f , II- 1, Il - m , II- n , II - o , Il - p , or Il - q , or any one of Formulae Il - a ' , II - b ', II - c ' , II - d ', Il - e ', II - f' , Il - 1' , II - m ', Il - n ', II - o ', II - p ', Il - q ', II - 1 " , II - m " , II - n " , II - 0 " , Il - p " , or Il - q " , wherein L is a noncleavable linker. In another embodiment , the linker comprises one or more polyethylene glycol units . . [0398 ] In another embodiment, disclosed herein is a com m pound having Formula 1 - a or 1 - b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula I - a and or I - b wherein SM is a monovalent radical of a glucocorti [0405 ] x is 0 , 1, 2, 3 , 4 , 5 , 6 , 7 , 8, 9, 10 , 11, 12, 13, 14, or costeroid having any one of Formulae II- a , II -b , II - c , II - d , 15 . Il - e , II- f , II- 1, Il - m , II- n , II - o , Il - p , or Il - q , or any one of [0406 ] The compound of any one of claims 1 - 47, or a Formulae Il - a ', II- b ', Il - c ', II - d ', Il - e ', II - f' , II - l' , Il - m ', Il - n ' , pharmaceutically acceptable salt or solvate thereof, wherein II- o ', Il - p ', Il - q ', II - 1" , II- m " , II- n " , II - 0 " , II- p " , or Il - q " , - L - Q - is : wherein - L - Q - is : LQ - 29 LQ - 11 mu NH winno nemhones CO2H w sotros and [0407 ] x is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7, 8 , 9 , 10 , 11, 12 , 13 , 14 , or 15 . [0399 ] m is 2 or 3 ; and [0408 ]. In another embodiment, disclosed herein is a com [0400 ] x is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, 12 , 13 , 14 , or pound having Formula I - a or 1 - b , or a pharmaceutically 15 . In another embodiment, m is 2 . acceptable salt thereof, e . g . a compound having Formula I - a 10401 ] In another embodiment, disclosed herein is a com or I -b wherein SM is a monovalent radical of a glucocorti pound having Formula I - a or I - b , or a pharmaceutically costeroid having any one of Formulae II -a , II -b , II -c , II - d , acceptable salt thereof, e . g . a compound having Formula I - a II -e , II - f, II - 1, II - m , II - n , II -o , Il- p , or Il - q , or any one of or 1 - b wherein SM is a monovalent radical of a glucocorti Formulae II- a ', II - b ', II -c ', II- d ', II - e ', II - f , II - 1 ', II - m ' , II - n ', costeroid having any one of Formulae II - a , II - b , Il - c , II - d , II- o ', II- p ', II - q ', II- 1" , II -m " , II - n " , II - o " , Il - p " , or II - q " , Il -e , II- f, II -1 , Il -m , II -n , Il -o , Il -p , or Il -q , or any one of wherein - L - Q - is : US 2018 /0126000 A1 May 10 , 2018 US2018 / 01 2600 A1 39 May 10, 2018

LQ - 14

R100 NH NH mw R 10a m is 1 or 2 ; x is 0 , 1 , 2, 3 , 4 , 5 , 6 , 7 , 8, 9 , 10 , 11 , 12 , 13 , 14 , or 15 ; and R10a and R106 are independently selected from the group consisting of hydrogen and optionally substituted C1- 6 alkyl. In another embodiment, - L - Q - is : LQ- 15 MMC 105 0 NH ma R 10a In another embodiment, - L - Q - is :

LQ - 16

R 1060 mu N HyfinansiostR 10a O " In another embodiment, -L - Q - is :

LQ - 17

R 1000 NH NH HyfinnsiftR10a " In another embodiment, - L - Q - is :

LQ - 18

R100

illll NH N HyshamiftR 10a US 2018 /0126000 A1 May 10 , 2018 40

[0409 ] In another embodiment, disclosed herein is a com pound having Formula 1 - a or I - b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula I - a or I - b wherein SM is a monovalent radical of a glucocorti costeroid having any one of Formulae II - a , II - b , II - c , II - d , Il - e , Il - f, Il - 1 , II - m , II - n , Il - o , Il - p , or Il - q , or any one of Formulae II- a ', II - b ', II- c , II - d ', Il- e ', II - f , II - 1' , II - m ', Il - n ' , Il- o ', Il - p ', Il - q ', Il - 1 " , Il - m " , Il - n " , II - 0 " , Il - p " , or Il - q " , wherein - L - Q - is :

LQ - 19

R 1000

NH maw N IZ CO2H ; HighnesiaR 100 m is 1 or 2 ; x is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13, 14 , or 15 ; and R10a and R106 are independently selected from the group consisting of hydrogen and optionally substituted C1- 6 alkyl. [ 0410 ] In another embodiment, - L - Q - is :

LQ - 20

R 1000

| ?? CO2H . mm N HishamedR10a O In another embodiment, - L - Q - is :

LQ -21

R 1050

NH CO H . N IZ ????R10 ???? In another embodiment, - L - Q - is :

LQ - 22

R 10b O NH N - C02H . Hyllitman R10a US 2018 /0126000 A1 May 10 , 2018

[0411 ] In another embodiment, - L - Q - is : LQ -23

VIR 1000 N CO H . manHylasext R10a [0412 ] In another embodiment, disclosed herein is a com Il -e , II- f, II -1 , Il -m , Il -n , Il -o , Il -p , or Il -q , or any one of pound having Formula 1 - a or I - b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula I - a Formulae II- a ' , II - b ', II- c ' , II - d ', II- e' , Il - f' , II -1 ', II - m ', II - n ', or 1- b wherein SM is a monovalent radical of a glucocorti II -o ', Il -p ', Il -q ', II- 1 " , II- m " , II -n " , II - o" , II -p " , or II -q " , costeroid having any one of Formulae II- a , II - b , II - c , II - d , wherein - L - Q - is :

R106 0 LQ- 24 man NH HisthantyR10a men [0413 ] x is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7, 8 , 9 , 10 , 11, 12 , 13 , 14 , or 15 ; and R10a and R106 are independently selected from the group consisting of hydrogen and optionally substituted C1- 6 alkyl. [ 0414 ] In another embodim ent, - L - Q - is :

LQ - 25 R1060 N HirilmeytyR10a Ö mm [0415 ] In another embodiment, -L - Q - is :

LQ - 26 R100 0

ma 11 N HyhmityR 10a10a 0 min [0416 ] In another embodiment, - L - Q - is :

LQ - 27 R 1000 N HythmetyR100 mm US 2018 /0126000 A1 May 10 , 2018 1242 May 10. 2018 [0417 ] In another embodiment , - L - Q - is :

LQ - 28 106 O mu N HylandD 10a ma [0418 ] In another embodiment, disclosed herein is a com II -e , Il - f, II- 1, II- m , II -n , Il -o , II- p , or Il -q , or any one of pound having Formula I - a or I - b , or a pharmaceutically acceptable salt thereof, e . g . a compound having Formula 1- a Formulae Il - a ', II -b ', II - c ', II -d ', Il - e ', II- f , II -I ', II- m ', II - n ', or I - b wherein SM is a monovalent radical of a glucocorti - Il -o ', Il - p ', Il - q ', Il- 1" , II - m " , II -n " , Il - o " , Il -p " , or Il - q " , 2a5costeroid having any one of Formulae II -a , II -b , II - c , II - d , wherein - L - Q - is : LQ - 30 R1060 H N N R 10a no CO2H [ 0419 ] x is 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, 12 , 13, 14, or 15 ; and R10a and R10b are independently selected from the group consisting of hydrogen and optionally substituted C1- 6 alkyl. [0420 ] In another embodiment, - L - Q - is : LQ -31 R 1000 w Mm. NH R 10a 0 nim CO2H

[0421 ] In another embodiment, - L - Q - is : LQ - 32 R100 N III NH HythwartyR 10a CO2H 1942[0422 ] Inin another embodiment embotinei,, -L L. -Quis Q - is : LQ - 33 R100 O

IZ NH din. HyR 100 OS heardy CO2H US 2018 /0126000 A1 May 10 , 2018 43

[0423 ] In another embodiment , - L - Q - is :

LQ -34 106 O N ma p 10a Hoshandynim . COH

[ 0424 ] In another embodiment, disclosed herein is a com II - e , II - f , II- 1, Il - m , II - n , II - o , Il -p , or Il - q , or any one of pound having Formula 1 - a or I - b , or a pharmaceutically Formulae II- a ', II -b ', II- c ', II - d ', II- e' , II -f , II - l' , II - m ', Il - n ', acceptable salt thereof , e . g . a compound having Formula I- a II - o ' , Il - p ', Il - q ', II - l" , II - m " , II - n " , Il - o " , Il - p " , or Il - q " , or I- b wherein SM is a monovalent radical of a glucocorti - wherein - L - Q - is any one of the chemical structures of Table costeroid having any one of Formulae II -a , II -b , II -c , II -d , I: TABLE I

| mm NH IZ HyllyHOC mw ma HisthytyHO2C HO

ma mm HihergyHO2C N HN

mm NH se puedeHO2C

HN mu H553525 HO , C y US 2018 /0126000 A1 May 10 , 2018 18 0126000A1 4 44 May 10, 2018 TABLE I- continued Pololevabinet HO2C mm en

HO2C . mafunnyggt mu HO2C Azzeriquemm HO2C mm

HO2C fuumemming ma HO2C men mo

min

HO , menn

fondymi US 2018 /0126000 A1 May 10 , 2018 45

TABLE I- continued mm HO2C

HOC mmfunnight N we quy?? , ? HO2C mm ZE ha

mi ArobyHO2C JTC HO2C . man IZ mm and HO . HO2C ma ZI

[0425 ] In another embodiment , disclosed herein is a com another embodiment, n is 2 . In another embodiment n is 3 . pound having Formula 1 - a or 1 - b , or a pharmaceutically In another embodiment, n is 4 . In another embodiment, n is acceptable salt thereof, e . g . a compound having Formula I - a 5 . In another embodiment, n is 6 . In another embodiment, n or 1- b wherein SM is a monovalent radical of a glucocorti is 7 . In another embodiment, n is 8 . costeroid having any one of Formulae II - a , II -b , Il - c , II- d , Il -e , Il - f, II- 1 , II - m , Il -n , Il -o , Il- p , or Il - q , or any one of [0426 ] In another embodiment, disclosed herein is a com Formulae II - a ' , II - b ', II - c ', II - d ', Il - e ', Il - f , II- 1 ', II - m ', II - n ', pound having Formula 1 - a or I -b , or a pharmaceutically II - o ' , Il - p ', Il - q ', II - 1" , II - m " , II - n " , II - 0 " , II - p " , or II - q " , acceptable salt thereof, wherein SM is a monovalent radical wherein n is 2 - 8 . In another embodiment, n is 1 - 5 . In another of a glucocorticosteroid which is any one of the chemical embodiment, n is 2 - 5 . In another embodiment, n is 1 . In s tructures of Table II . US 2018 /0126000 A1 May 10 , 2018 US 201801260 1 46 TABLE II O. II IN

?? (LIIT Mao = O H

NH HO

HO . Maattaaor Illll 111111 TRE

HO , ull Illit 111111 NH

1]|

HON

1|11 US 2018 / 0126000 A1 May 10 , 2018 47

TABLE II -continued H0

H0 S IIIIII

HN HTIIIIII( ??????

HO ( . il (

IIIIIIII IIIIIII) LIIIII HTIIIIII( ????HN

H ( . IIIIIIOr

???IIIII LIIIIII IIIIIII(

IIIIII } : IIIIII H HTIIIIII IIIIIII( US 2018 /0126000 A1 May 10 , 2018 4848

TABLE Il - continued OH opelHO , L illl ( ) coramHN OH watHO Illo ons> * *11111 HO mm optionsHO Juill ) HO

HO , 1 . 1ll10

1| M muna NH |

T ??

HO , 111lll

. 111ull ) TI) mi Tin US 2018 / 0126000 A1 May 10 , 2018 496t

TABLE II - continued

H (

IIIIII IIIIII) ???FIIIIIII( ?

HO . IIIII (

??IIIII) LZ ?????

HTIIIII(

H ( )

0 = H (

! ! ! IIIIIII ???? FIIIIIII

H0 ??

0 = HO ?? FIIIIIII) ??? FIIIIIII( US 2018 / 0126000 A1 May 10 , 2018 50

TABLE II- continued OH

HO ) IIIIIIII (

IIIIII)

w HTIIIIII( HN

0H MAN , ?? NH

HO , IIIIII (

. IIIIII )

???IIII

IIIIII(

HO iiill ( H FTIIIIII) LIIIIII: ?? ???FIIIIIII( ??

HO IIIII ( H IIIIII NH; HTIIIIII 2???? US 2018 /0126000 A1 May 10 , 2018 51

TABLE II -continued HO

HO 11

1] INDES

HN 11111L men

HO Jull

Dll

HN TIR men

- NH

HO Illllll

?? Ilut 111111 Im mer US 2018 /0126000 A1 May 10 , 2018 52

TABLE II - continued HO

HO H

T|IJIlli

IIIIII: mm

HO methingHO Hull mi

HO 111110 H

T Tri HN www US 2018 /0126000 A1 May 10 , 2018 53

TABLE II - continued HO

?? Inn H TIT) ?H

T HN ingum. IITTI

ul| | ZI

1)|

Gostosa N m

.HO

?? . 2 . 11lillo H

HO mosos2

HO 2 : 11

10 11

1)Ir

ni US 2018 / 0126000 A1 May 10 , 2018 54

TABLE II - continued OH

HO IIIII (

IIIIIII)

HTIIIIII(

HO IIIIII (

IIIIIII) H

IIIIIII( ?? ?? . HO0

HO IIIIIIII IIIIIII) /

IIIIII ( H IIIIIC ) IIIIII US 2018 / 0126000 A1 May 10 , 2018 us2018012 . 00 AM ? 55 ? TABLE II -continued

??????? .

H IIIIII (

i1IIIIEL:

H (

:IIIIII HN H0 110 ?? IIIIII LIIIII ??? IIIIIII(

HTIIIII)

.IIIIIII HM H ( H 1111111 IIIIII) ?? 0 IIIIIII( US 2018 /0126000 A1 May 10 , 2018 US 2020 56. TABLE II -continued na

HO torty** 1111110

HO , dul

7 mu

NH ; HO . .sto mm * 111111 T|1n. In

H NH ww "HILI US 2018 /0126000 A1 May 10 , 2018 57

TABLE II -continued

NH UNI Tin

11111|

HO mm

TUT webTIL tros

OB HO troy

HO NH nh HO 11111

u1|

1] US 2018 / 0126000 A1 May 10 , 2018 58

TABLE II - continued

HO(

.NH ?? { }{ } ( ?? IIIIII

IIIIIII(

II!TT

HO IIIII HO NH ) .( 41 ?????? IIIIIII HTIIIIII H0

IIIIII ( LZ ??

?? HO ?????? OH . .IIIIII ( ) FIIIIIII) ??? HO

H ( ?mln H ?? US 2018 / 0126000 A1 May 10 , 2018 59

TABLE II- continued

H0 ??????? ??: IIIIIII H0

0H lil IIIII ?????

IIIIIIII:

H ( 11III .

???IIIII

HTIIIIII:

IIII

H ; HN IIIIII ?? H0 ??

IIIII ( H ?? US 2018 /0126000 A1 May 10 , 2018 60

TABLE II - continued ??

omo HO illll

111111

HO mm

MotorOH ?? , OuY NH

motorHO HO Z muhaw O HO O111

HO lllll min H TIT

TI US 2018 /0126000 A1 May 10 , 2018

TABLE II - continued

IZ ?

HO !Ilin

HO 111llll .. $ NHmm 2 .; and 1111110 ull Tn

1111|

?? NH2 totHO ong OH

[0427 ] In another embodiment, disclosed herein is a com pound having Formula 1 - a or I - b , or a pharmaceutically -continued acceptable salt thereof, wherein SM is a monovalent radical OH of a glucocorticosteroid selected from the group consisting of: HO , (LIC H . M 11111) IIIII:{

; and

OH mu US 2018 /0126000 A1 May 10 , 2018 62

- continued Formulae II -1 ' , II - m ', II -n ', II -o ', II - p' , II - q' , II -1 " , II- m " , II -n " , OH II -0 " , Il - p " , or Il - q " , wherein Al is an anti - tumor necrosis factor ( TNF ) alpha protein that binds to soluble TNF alpha or wherein A² is protein that binds to soluble TNF alpha . HO [ 0431 ] In another embodiment, disclosed herein is a com INC pound having Formula I- a, or a pharmaceutically acceptable salt thereof, e . g ., a compound having Formula I - a , wherein SM is a monovalent radical of a glucocorticosteroid having 71 any one of Formulae II - a , II - b , II- c , II- d , II - e , II- f, II- 1, II - m , II - n , II - o , II - p , or Il - q , or any one of Formulae II - a ', II - b ', II - c ', II - d ', II - e ', II - f , II -I ' , II - m ', II - n ', II -o ', II - p ', Il - q ', II- 1 " , Il - m " , II - n " , II- 0 " , Il - p " , or Il- q " , or a compound having Tin Formula I- b , or a pharmaceutically acceptable salt thereof, e .g ., a compound having Formula I- b , wherein SM is a HN monovalent radical of a glucocorticosteroid having any one m of Formulae II - 1 , II - m , II - n , II - o , Il - p , or II - q , or any one of an Formulae II -1 ' , II -m ', II -n ', II -o ', II -p ', II -q ', 11 -1 " , II- m " , II -n " , II -0 " , Il - p " , or Il -q " , wherein Al is an anti -tumor necrosis factor ( TNF ) alpha protein that binds to membrane- bound [0428 ] In another embodiment, disclosed herein is a com TNF alpha or wherein A² is a protein that binds to mem pound having Formula I - a , or a pharmaceutically acceptable brane -bound TNF alpha . salt thereof, e . g . , a compound having Formula I - a , wherein [0432 ] In another embodiment, disclosed herein is a com SM is a monovalent radical of a glucocorticosteroid having pound having Formula I - a , or a pharmaceutically acceptable any one of Formulae II - a , II - b , II - c , II - d , II - e , II - f , II - 1 , II - m , salt thereof, e. g. , a compound having Formula I- a , wherein Il - n , Il- o , Il -p , or Il - q , or any one of Formulae II -a ', II -b ', SM is a monovalent radical of a glucocorticosteroid having Il - c ', II - d ', II - e ', II - f , II -' , II- m ', II- n ', II - o ', II - p ', II - q ', II - 1" , any one of Formulae II - a , II -b , II -c , II - d , II -e , Il -f , II -1 , II -m , II- m " , II -n " , II -0 " , II - p " , or Il - q " , or a compound having II- n , II - o , Il - p , or Il - q , or any one of Formulae II -a ', II- b ', Formula 1 - b , or a pharmaceutically acceptable salt thereof, II - C ', II - d ', II - e ', II- f' , II - I' , II - m ', II- n ', II - o ', II- p ', II - q ', II -1 " , e .g ., a compound having Formula I- b , wherein SM is a II -m " , II - n " , II - 0 " , Il -p " , or Il- q " , or a compound having monovalent radical of a glucocorticosteroid having any one Formula I - b , or a pharmaceutically acceptable salt thereof, of Formulae II -1 , II - m , II -n , II - o , Il - p , or Il -q , or any one of e . g ., a compound having Formula I -b , wherein SM is a Formulae II- 1 ', Il- m ', II - n ', II - o ', II- p ', II - q ' , II- 1 " , Il - m " , II - n " , monovalent radical of a glucocorticosteroid having any one Il- 0 " , Il - p " , or Il - q " , wherein A is an antibody or antigen of Formulae II - 1 , II - m , Il - n , II - o , Il- p , or Il - q , or any one of binding fragment thereof or wherein A² is an antibody or Formulae II - 1 ', II - m ', II - n '. II - o '. Il - p ', II - q ' , II - 1 " , II - m " , II - n " , antigen - binding fragment thereof . II - o " , Il - p " , or II - q " , wherein A is an anti -tumor necrosis [0429 ] In another embodiment, disclosed herein is a com factor ( TNF ) alpha protein comprising an anti - TNF antibody pound having Formula I- a , or a pharmaceutically acceptable or wherein A ’ is protein comprising an anti- TNF antibody . salt thereof, e . g ., a compound having Formula I - a , wherein [0433 ] In another embodiment, disclosed herein is a com SM is a monovalent radical of a glucocorticosteroid having pound having Formula I - a , or a pharmaceutically acceptable any one of Formulae II -a , II -b , Il - c , II - d , II - e , Il - f, II - 1 , II - m , salt thereof, e . g ., a compound having Formula I - a , wherein Il - n , Il- o , Il - p , or II - q , or any one of Formulae II - a ' , II - b ', SM is a monovalent radical of a glucocorticosteroid having II- c ' , II- d ', II - e ', II - f , II- 1' , II - m ', II - n ', II - o ' , Il - p ', II - q ', II - 1 " , any one of Formulae II - a , II - b , II - c , II -d , II - e , II - f, 11 -1 , II - m , Il - m " , II - n " , II - o " , Il - p " , or Il- q " , or a compound having II - n , Il - o , Il - p , or Il - q , or any one of Formulae Il - a ', II - b ', Formula I - b , or a pharmaceutically acceptable salt thereof, II -c ', II - d ', II - e ', II- f , II- ', II - m ', II - n ', II - o ', Il - p ', II - q ', II- 1 " , e .g ., a compound having Formula I- b , wherein SM is a II -m " , II- n " , II -0 " , II - p " , or Il - q " , or a compound having monovalent radical of a glucocorticosteroid having any one Formula 1 - b , or a pharmaceutically acceptable salt thereof, of Formulae II - 1, II - m , II - n , II - o , Il- p , or Il - q , or any one of e . g ., a compound having Formula I -b , wherein SM is a Formulae II -1 ' , II - m ', II -n ', II -o ', II- p ', Il - q' , II -1 " , II- m " , II -n " , monovalent radical of a glucocorticosteroid having any one II -0 " , Il - p " , or Il - q " , wherein Al is an anti - tumor necrosis of Formulae II -1 , II- m , II -n , II -o , Il -p , or Il -q , or any one of factor ( TNF ) alpha protein that binds to human TNF alpha Formulae II -1 ' , II- m ', II -n ', II -o ', Il - p ', II - q ', II -1 " , II- m " , II -n " , and / or murine TNF alpha or wherein A is protein that binds II -O " , II- p " , or II - q " , wherein Al is an anti- tumor necrosis to human TNF alpha and /or murine TNF alpha . factor ( TNF ) alpha protein comprising an anti - TNF receptor [0430 ] In another embodiment, disclosed herein is a com antibody or wherein A² is a protein comprising an anti - TNF pound having Formula I- a , or a pharmaceutically acceptable receptor antibody. salt thereof, e . g ., a compound having Formula I - a , wherein [0434 ] In another embodiment, disclosed herein is a com SM is a monovalent radical of a glucocorticosteroid having pound having Formula I - a , or a pharmaceutically acceptable any one of Formulae II - a , II - b , Il - c , II - d , II - e , Il- f, II - 1, II - m , salt thereof, e . g ., a compound having Formula I - a , wherein II - n , Il- o , Il - p , or Il - q , or any one of Formulae II - a ', II - b ', SM is a monovalent radical of a glucocorticosteroid having II - c ', II - d ', II - e ', II - f' , II - 1' , II - m ', II - n ', II - o ', II - p ', Il - q ', II - 1" , any one of Formulae II- a , II - b , II- c , II - d , II -e , II - f , II - 1 , Il - m , Il - m " , II - n " , II - 0 " , Il - p " , or II - q " , or a compound having II - n , II - o , Il - p , or Il - q , or any one of Formulae II - a ', II - b ', Formula I- b , or a pharmaceutically acceptable salt thereof, II -c ' , II - d ', II - e ', II- f , II -' , II - m ', II - n ' , II - o ', Il - p ', II - q ', II- 1 " , e .g ., a compound having Formula I- b , wherein SM is a Il -m " , II -n " , II -o " , II - p " , or Il - q " , or a compound having monovalent radical of a glucocorticosteroid having any one Formula I- b , or a pharmaceutically acceptable salt thereof, of Formulae II- 1, II - m , Il - n , Il - o , Il - p , or Il- q , or any one of e . g. , a compound having Formula I -b , wherein SM is a US 2018 /0126000 A1 May 10 , 2018 monovalent radical of a glucocorticosteroid having any one salt thereof, e. g ., a compound having Formula I -a , wherein of Formulae II - 1 , II - m , Il- n , Il - o , Il- p , or Il - q , or any one of SM is a monovalent radical of a glucocorticosteroid having Formulae II- 1 ' , Il - m ', II- n ', II -o ', Il -p ' , Il - q' , II -1 " , II -m " , II -n " , any one of Formulae II - a , II - b , II - c , II - d , Il - e , Il - f, II - 1, Il - m , II -O " , II -p " , or II - q " , wherein Al is an anti- tumor necrosis II - n , Il - o , Il - p , or Il - q , or any one of Formulae Il - a ', II - b ', factor ( TNF) alpha protein comprising an antigen -binding II -c ', II- d ', II - e ', II - f , II- 1' , Il - m ', II - n ', II- o ', II -p ', Il - q ', II- 1 " , fragment of an anti - TNF antibody or wherein A is a protein II - m " , II - n " , II - o " , II -p " , or Il - q " , or a compound having comprising an antigen - binding fragment of an anti - TNF Formula I- b , or a pharmaceutically acceptable salt thereof, antibody . e . g ., a compound having Formula I -b , wherein SM is a [0435 ] In another embodiment, disclosed herein is a com monovalent radical of a glucocorticosteroid having any one pound having Formula I - a , or a pharmaceutically acceptable of Formulae II - 1 , II - m , II - n , Il - o , Il - p , or II - q , or any one of salt thereof, e . g ., a compound having Formula I - a , wherein SM is a monovalent radical of a glucocorticosteroid having Formulae II - 1' , II - m ', II - n ', II - o ', Il - p ', II - q ', 11 - 1" , Il - m " , II - n " , any one of Formulae II -a , II -b , Il - c , II - d , Il - e , II - f, II - 1 , II - m , II - 0 " , II- p " , or Il - q " , wherein Al is an anti - tumor necrosis II- n , Il -o , Il -p , or Il - q , or any one of Formulae II- a ', II -b ', factor ( TNF ) alpha protein comprising a soluble TNF recep II -c ', II -d ', II - e' , II- f , II- ' , II -m ', II -n ', II -o ', Il -p ', II -q ', II -1 " , tor or wherein A ’ is a protein comprising a soluble TNF Il - m " , II - n " , II - o " , Il - p " , or Il- q " , or a compound having receptor. In another embodiment, the soluble TNF receptor Formula I - b , or a pharmaceutically acceptable salt thereof, is a soluble p75 TNF receptor. e . g . , a compound having Formula I - b , wherein SM is a [ 0439 ] In another embodiment, disclosed herein is a com monovalent radical of a glucocorticosteroid having any one pound having Formula I - a , or a pharmaceutically acceptable of Formulae II- 1 , II- m , II- n , II - o , Il - p , or Il- q , or any one of salt thereof, e . g. , a compound having Formula I- a , wherein Formulae II - 1 ', Il - m ', II - n ' , II - o ', II - p ', II - q ', 11- 1 " , II - m " , II - n " , SM is a monovalent radical of a glucocorticosteroid having Il -o " , II - p " , or Il - q " , wherein A ' is an anti -tumor necrosis any one of Formulae II - a , II - b , Il - c , II - d , II - e , II - f, II -1 , II - m , factor ( TNF ) alpha protein comprising an antigen -binding II - n , II- o , Il -p , or II -q , or any one of Formulae II - a ', II - b ', fragment of an anti- TNF receptor antibody or wherein A² is II -c ' , II- d ', II - e ', II - f , II -1 ' , Il - m ', II - n ', II- o ', II -p ', Il - q ', II- 1 " , an anti -tumor necrosis factor ( TNF ) alpha protein compris Il - m " , II - n " , II - 0 " , Il - p " , or Il - q" , or a compound having ing an antigen -binding fragment of an anti- TNF receptor Formula I - b , or a pharmaceutically acceptable salt thereof, antibody . e .g ., a compound having Formula I- b , wherein SM is a [ 0436 ] In another embodiment, disclosed herein is a com monovalent radical of a glucocorticosteroid having any one pound having Formula I - a , or a pharmaceutically acceptable of Formulae II - 1 , II - m , II - n , Il- o , Il- p , or II - q , or any one of salt thereof, e . g ., a compound having Formula I - a , wherein Formulae II - 1' , II - m ', II - n ', II - o ', Il - p ' , II - q ', II- 1" , Il - m " , II - n " , SM is a monovalent radical of a glucocorticosteroid having II - 0 " , II - p " , or Il - q " , wherein A comprises a heavy chain any one of Formulae II- a , II - b , Il - c , II - d , II - e , II - f, II - 1, II - m , constant domain or a fragment thereof or wherein or A ? Il- n , Il - o , Il - p , or Il- q , or any one of Formulae II - a ', II - b ', comprises a heavy chain constant domain or a fragment II - c ', II - d ', II - e ', II - f' , II - 1 ', II - m ' , II- n ', II - o ', Il - p ', II - q ', II - 1 " , thereof . In another embodiment, the heavy chain constant II -m " , II -n " , II -0 " , II- p" , or Il -q " , or a compound having domain or fragment thereof comprises a constant domain Formula I- b , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (a ) an IgA constant e . g ., a compound having Formula I -b , wherein SM is a domain ; (b ) an IgD constant domain ; (c ) an IgE constant monovalent radical of a glucocorticosteroid having any one domain ; ( d ) an IgG1 constant domain ; ( e ) an IgG2 constant of Formulae II - 1 , II - m , II- n , Il- o , Il - p , or Il - q , or any one of domain ; ( f ) an IgG3 constant domain ; ( g ) an IgG4 constant Formulae II -1 ' , II - m ', Il -n ', II -o ', II- p' , II - q' , II -1 " , II- m " , II -n " , domain ; and ( h ) an IgM constant domain or is a fragment II- 0 " , II- p " , or II - q " , wherein the antigen -binding fragment thereof . In another embodiment, the heavy chain constant is selected from the group consisting of Fab , Fab ', F (ab ') 2, domain comprises a human IgG1 heavy chain constant single chain Fv or scFv, disulfide linked Fv, V - NAR domain , domain or fragment thereof. In another embodiment, the IgNar, intrabody , IgGACH2, minibody , F ( ab ' ) 3 , tetrabody, heavy chain constant domain comprises a human IgG1 Fc triabody, diabody, single -domain antibody, DVD - Ig , Fcab , domain . mAb2 , ( scFv ) 2 , or scFv -Fc . [0440 ] In another embodiment, disclosed herein is a com [0437 ] In another embodiment, disclosed herein is a com pound having Formula I - a , or a pharmaceutically acceptable pound having Formula I - a , or a pharmaceutically acceptable salt thereof, e . g ., a compound having Formula I - a , wherein salt thereof, e . g ., a compound having Formula I - a , wherein SM is a monovalent radical of a glucocorticosteroid having SM is a monovalent radical of a glucocorticosteroid having any one of Formulae II - a , II -b , II -c , II - d , II -e , Il -f , II -1 , II -m , any one of Formulae II - a , II - b , II - c , II - d , II - e , Il - f , II - 1 , II - m , II - n , II - o , Il - p , or Il- q , or any one of Formulae II- a ', II - b ', Il- n , Il- o , Il- p , or Il - q , or any one of Formulae Il - a ', Il - b ', II - c ', II - d ', II - e ', II - f' , II - 1' , II - m ', II - n '. II - o '. Il - p ' , Il - q ', II - 1" . II -c ', II -d ', II -e ', II -f , II- I , II -m ', II -n ', II -o ', Il -p ', Il -q ', II -1 " , II- m " , II- n " , II - o " , II- p " , or Il - q " , or a compound having II- m " , II- n " , II - o " , II- p " , or Il - q " , or a compound having Formula I- b , or a pharmaceutically acceptable salt thereof, Formula I- b , or a pharmaceutically acceptable salt thereof, e . g ., a compound having Formula I - b , wherein SM is a e . g ., a compound having Formula 1 - b , wherein SM is a monovalent radical of a glucocorticosteroid having any one monovalent radical of a glucocorticosteroid having any one of Formulae II -1 , II - m , II - n , II - o , Il - p , or Il - q , wherein A of Formulae II - 1, II -m , II- n , II- o , Il - p , or Il- q , or any one of comprises a light chain constant domain or a fragment Formulae II -1 ' , Il - m ', II -n ', II -o ' , Il -p ', II -q ', II- 1" , Il - m " , II- n " , thereof or wherein A² comprises a light chain constant Il -o ", II- p " , or Il - q ", wherein the antibody or antigen domain or a fragment thereof. In another embodiment , the binding fragment thereof is murine , chimeric , humanized , or light chain constant domain or fragment thereof comprises a human . constant domain selected group consisting of ( a ) an Ig kappa [0438 ] In another embodiment , disclosed herein is a com constant domain and ( b ) an Ig lambda constant domain or is pound having Formula I- a , or a pharmaceutically acceptable a fragment thereof. US 2018 /0126000 A1 May 10 , 2018 64

[0441 ] In another embodiment, disclosed herein is a com II- C' , II- d ', Il -e ', II -f , II- l' , II -m ', II - n' , II- o ', Il -p ', Il- q' , II -1 ", pound having Formula I - a , or a pharmaceutically acceptable II -m " , II -n " , II -o " , Il - p " , or Il -q " , or a compound having salt thereof, e . g ., a compound having Formula I -a , wherein Formula I - b , or a pharmaceutically acceptable salt thereof, SM is a monovalent radical of a glucocorticosteroid having e . g . , a compound having Formula l - b , wherein SM is a any one of Formulae II - a , II - b , II - c , II- d , II - e , Il - f , II- 1 , II - m , monovalent radical of a glucocorticosteroid having any one Il - n , Il- o , Il - p , or Il - q , or any one of Formulae II - a ', II - b ' , of Formulae II - 1 , Il - m , II - n , Il - o , Il - p , or Il - q , or any one of Il - c ', II - d ', Il - e ', II - f , II - l' , Il - m ', Il - n ', II - o ', Il - p ', Il - q ', II - l" , Formulae II - l' , II - m ', Il - n ', II - o ', Il - p ', Il - q ', II - 1 " , II - m " , Il - n " , Il - m " , II - n " , II - o " , Il - p " , or II - q " , or a compound having II - o " , Il - p " , or Il - q " , wherein A ' comprises the variable Formula I - b , or a pharmaceutically acceptable salt thereof, heavy chain CDR1, CDR2 , and CDR3 sequences of SEQ ID e .g . , a compound having Formula I- b , wherein SM is a NO : 3 or 6 , SEO ID NO : 4 , and SEQ ID NO : 5 , respectively monovalent radical of a glucocorticosteroid having any one and the variable light chain CDR1, CDR2, and CDR3 of Formulae II - 1 , II - m , II - n , II- o , II - p , or Il - q , or any one of sequences of SEQ ID NO : 32 , SEQ ID NO : 33 , and SEQ ID Formulae II - 1' , II - m ', II - n ', II - o ', Il - p ', Il - q ', II - 1" , Il - m " , II - n " , NO :34 , respectively or wherein A² comprises the variable II- 0 " , Il - p " , or Il - q " , wherein Al competitively inhibits heavy chain CDR1, CDR2, and CDR3 sequences of SEQ ID binding of an antibody selected from the group consisting of NO : 3 or 6 , SEQ ID NO :4 , and SEQ ID NO : 5 respectively adalimumab , infliximab , certolizumab pegol, and golim and the variable light chain CDR1 , CDR2, and CDR3 umab to TNF - alpha or wherein A2 competitively inhibits sequences of SEQ ID NO : 32 , SEQ ID NO : 33 , and SEQ ID binding of an antibody selected from the group consisting of NO : 34 , respectively . adalimumab , infliximab , certolizumab pegol, and golim [0445 ] In another embodiment, disclosed herein is a com umab to TNF - alpha . pound having Formula I- a, or a pharmaceutically acceptable [0442 ] In another embodiment , disclosed herein is a com salt thereof, e. g. , a compound having Formula I- a , wherein pound having Formula I - a , or a pharmaceutically acceptable SM is a monovalent radical of a glucocorticosteroid having salt thereof, e . g ., a compound having Formula I - a , wherein any one of Formulae II -a , II -b , II -c , II - d , II -e , II- f, II -1 , II- m , SM is a monovalent radical of a glucocorticosteroid having II - n , II - o , Il - p , or Il - q , or any one of Formulae II - a ', II- b ', any one of Formulae II -a , II -b , II - c , II - d , II - e , Il - f, II - 1 , II - m , II - c' , II - d ', Il - e ', Il - f , II - 1 ', II - m ', II- n ', II - o ', Il - p ', Il - q ', II - 1 " , Il- n , Il- o , Il- p , or Il - q , or any one of Formulae II - a ', II - b ', Il - m " , II - n " , II - 0 " , II - p " , or Il - q " , or a compound having Il - c ', II - d ', II - e ', II- f' , II - I' , II - m ', II- n ', II - o ', II- p ', II - q ', II - 1" , Formula I - b , or a pharmaceutically acceptable salt thereof, Il - m " , II - n " , II - 0 " , II - p " , or Il - q " , or a compound having e. g ., a compound having Formula I- b , wherein SM is a Formula I - b , or a pharmaceutically acceptable salt thereof, monovalent radical of a glucocorticosteroid having any one e. g. , a compound having Formula I- b , wherein SM is a of Formulae II -1 , II -m , II -n , II -o , Il - p , or Il - q , or any one of monovalent radical of a glucocorticosteroid having any one Formulae II - l' , II - m ', Il- n ', II - o ', Il - p ', Il - q ', Il - 1" , Il - m " , Il - n " , of Formulae II -1 , II - m , II -n , II - o , Il - p , or Il -q , or any one of Il - 0 " , Il - p " , or Il - q " , wherein Al comprises the variable Formulae II - 1' , Il - m ', II - n ', II - o ', Il - p ', II - q ', II - 1" , Il - m " , II - n " , heavy chain sequence of SEQ ID NO :50 and the variable II - 0 " , II - p " , or II - q " , wherein Al binds to the same TNF light chain sequence of SEQ ID NO :59 or wherein A ? alpha epitope as an antibody selected from the group con comprises the variable heavy chain sequence of SEQ ID sisting of adalimumab , infliximab , certolizumab pegol, afe NO :50 and the variable light chain sequence of SEQ ID limomab , nerelimomab , Ozoralizumab , placulumab , and NO :59 . golimumab or wherein A² binds to the same TNF- alpha [ 0446 ] In another embodiment, disclosed herein is a com epitope as an antibody selected from the group consisting of pound having Formula I - a , or a pharmaceutically acceptable adalimumab , infliximab , certolizumab pegol, afelimomab , salt thereof, e . g . , a compound having Formula I - a , wherein nerelimomab , ozoralizumab , placulumab , and golimumab . SM is a monovalent radical of a glucocorticosteroid having [0443 ] In another embodiment, disclosed herein is a com any one of Formulae II - a , II - b , II - c , II - d , Il - e , II - f , II - 1 , Il - m , pound having Formula I - a , or a pharmaceutically acceptable II - n , II - o , Il - p , or Il - q , or any one of Formulae II - a ', II- b ', salt thereof, e . g ., a compound having Formula I - a , wherein II -c ', II -d ', II -e ', II -f ' , II- 1 ' , II -m ', II -n ', II -o ', II- p ', Il -q ', II -1 " , SM is a monovalent radical of a glucocorticosteroid having II -m " , II -n " , II -0 " , Il - p " , or Il -q " , or a compound having any one of Formulae II -a , II -b , II - c, II - d, Il -e , Il -f , II - 1, II -m , Formula 1 - b , or a pharmaceutically acceptable salt thereof, Il- n , II - o , Il - p , or Il - q , or any one of Formulae II - a ', II - b ', e .g . , a compound having Formula I- b , wherein SM is a Il -c ', II -d ', II - e' , II - f , II -I ' , II- m ', II- n ', II -o ', II -p ', Il - q' , II -1 " , monovalent radical of a glucocorticosteroid having any one II- m " , II- n " , II - o " , II- p " , or Il - q " , or a compound having of Formulae II - 1 , II - m , II - n , Il - o , Il - p , or Il - q , or any one of Formula 1 - b , or a pharmaceutically acceptable salt thereof, Formulae II - 1' , II - m ', Il - n ', II -o ', Il - p ', II - q ', II - 1" , II - m " , II - n " , e . g ., a compound having Formula I - b , wherein SM is a II - 0 " , Il - p " , or Il- q " , wherein Al does not bind to TNF beta monovalent radical of a glucocorticosteroid having any one or wherein A ? does not bind to TNF beta . of Formulae II - 1 , II - m , II - n , Il - o , Il - p , or Il - q , or any one of [ 0447 ] In another embodiment, disclosed herein is a com Formulae II -1 ' , II - m ', II -n ', II -o ', II- p ', Il - q' , II -1 " , II- m " , II -n " , pound having Formula I - a , or a pharmaceutically acceptable Il - 0 " , II -p " , or Il - q " , wherein the anti- TNF alpha protein is salt thereof, e . g . , a compound having Formula I - a , wherein selected from the group consisting of adalimumab , inflix SM is a monovalent radical of a glucocorticosteroid having imab , certolizumab pegol, afelimomab , nerelimomab , ozo any one of Formulae II - a , II - b , II - c , II - d , II - e , Il - f, II - 1 , II - m , ralizumab , placulumab , and golimumab . Il - n , II - o , Il - p , or Il - q , or any one of Formulae II - a ', Il - b ', [0444 ] In another embodiment, disclosed herein is a com II - c ', II - d ' , II - e ', II - f , II - 1' , Il - m ', II - n ', II - o ', II - p ' , II - q ', II - 1 " , pound having Formula I - a , or a pharmaceutically acceptable Il - m " , Il - n " , Il - o " , Il - p " , or Il - q " , or a compound having salt thereof, e . g . , a compound having Formula 1 - a , wherein Formula I - b , or a pharmaceutically acceptable salt thereof, SM is a monovalent radical of a glucocorticosteroid having e. g ., a compound having Formula I- b , wherein SM is a any one of Formulae II - a , Il - b , Il - c , II - d , Il - e , II - f , II - 1, Il - m , monovalent radical of a glucocorticosteroid having any one II - n , Il- o , Il - p , or Il - q , or any one of Formulae II- a ', II - b ', of Formulae II -1 , II -m , II - n , Il -o , Il - p, or Il - q , or any one of US 2018 /0126000 A1 May 10 , 2018 65

Formulae II -1 ' , II - m ', II -n ', II -o ', Il -p ', II -q ', II- 1" , II - m " , II -n " II- m " , II- n " , II - 0" , II- p " , or II - q" , or a compound having II - 0 " , II - p " , or Il - q " , wherein Albinds to TNF beta or Formula 1 - b , or a pharmaceutically acceptable salt thereof, wherein Al binds to TNF beta . e . g ., a compound having Formula I -b , wherein SM is a [0448 ] In another embodiment, disclosed herein is a com monovalent radical of a glucocorticosteroid having any one pound having Formula I - a , or a pharmaceutically acceptable of Formulae II- 1 , Il - m , II- n , II - o , Il - p , or Il - q , or any one of salt thereof, e. g. , a compound having Formula I- a , wherein Formulae II -1 ' , II- m ', II -n ', II -o ', Il - p ', II - q ', II -1 " , II- m " , II -n " , SM is a monovalent radical of a glucocorticosteroid having II -O " , II- p " , or II - q " , wherein Al lyses surface TNF express any one of Formulae II- a , Il - b , II - c , II - d , II - e , II - f, II - 1, Il - m , ing cells in vitro in the presence of complement or wherein II- n , Il - o , Il- p , or II - q , or any one of Formulae II - a ', II - b ', A² lyses surface TNF expressing cells in vitro in the pres Il - c ', II - d ', II - e ', II- f' , II - I' , II - m ', II- n ', II - o ', II- p ', II - q ', II - 1" , ence of complement . Il - m " , II - n " , II - 0 " , Il - p " , or Il - q " , or a compound having Formula I- b , or a pharmaceutically acceptable salt thereof, [ 0451 ] In another embodiment, disclosed herein is a com e. g. , a compound having Formula I- b , wherein SM is a pound having Formula I - a , or a pharmaceutically acceptable monovalent radical of a glucocorticosteroid having any one salt thereof, e . g . , a compound having Formula I- a , wherein of Formulae II - 1, II - m , II - n , II - o , Il- p , or Il - q , or any one of SM is a monovalent radical of a glucocorticosteroid having Formulae II -1 ' , II- m ', Il -n ', II -o ', Il -p ', Il -q ', Il - 1" , II - m " , II -n " , any one of Formulae II - a, II -b , II - c, II -d , Il -e , Il -f , II - 1, II -m , II - 0 " , Il - p " , or Il - q " , wherein Al neutralizes human TNF II- n , II - o , Il - p , or Il - q , or any one of Formulae II- a ', II -b ', alpha cytotoxicity in a in vitro L929 assay with an IC50 of II - c ', II - d ' , II - e ', II- f' , II - l' , II- m ', II- n ', II - o ', Il - p ', Il - q ', II - 1 " , 1x10 - 7 M or less or wherein A² neutralizes human TNF II- m " , II- n " , II - o " , II- p " , or Il - q " , or a compound having alpha cytotoxicity in a in vitro L929 assay with an IC50 of Formula I - b , or a pharmaceutically acceptable salt thereof, 1210 - 7 M or less . e. g. , a compound having Formula I- b , wherein SM is a [0449 ] In another embodiment, disclosed herein is a com monovalent radical of a glucocorticosteroid having any one pound having Formula I - a , or a pharmaceutically acceptable of Formulae II -1 , II - m , II -n , II -o , II - p , or Il -q , or any one of salt thereof, e . g ., a compound having Formula I - a , wherein Formulae II - 1' , II - m ', Il - n ', II - o ', II - p ', II - q ', 11 - 1" , II - m " , II - n " , SM is a monovalent radical of a glucocorticosteroid having II - 0 " , II- p " , or II - q " , wherein the soluble p75 TNF receptor any one of Formulae II- a , II -b , II - c , II - d , II - e , Il - f, II - 1 , II - m , is etanercept. II- n , II- o , Il - p, or Il -q , or any one of Formulae II- a ', II - b' , [ 0452 ] In another embodiment, disclosed herein is a com Il - c ', II - d ', II - e ', II - f , II -' , II- m ', II- n ', II - o ', II - p ', II - q ', II - 1" , pound having Formula I - a , or a pharmaceutically acceptable II- m " , II- n " , II - o " , II- p " , or Il - q " , or a compound having salt thereof, e. g ., a compound having Formula I- a , wherein Formula 1 - b , or a pharmaceutically acceptable salt thereof, SM is a monovalent radical of a glucocorticosteroid having e. g. , a compound having Formula I- b , wherein SM is a any one of Formulae II - a , II - b , II - c , II - d , II - e , II - f, II -1 , Il - m , monovalent radical of a glucocorticosteroid having any one II- n , II - o , II - p , or II - q , or any one of Formulae II - a ', II- b ' , of Formulae II - 1, II - m , II - n , II - o , Il- p , or Il - q , or any one of II -c ', II- d ', II - e ', II - f , II -1 ' , II - m ', II - n ', II- o ', II - p ', Il - q ', II- 1 " , Formulae II - 1' , II - m ', II - n ', II - o ', Il - p ', II - q ', II - 1" , Il - m " , II - n " , II -m " , II- n ", II- 0 " , II- p " , or II - q" , or a compound having II -0 " , II- p" , or Il -q " , wherein Al blocks the interaction of Formula I - b , or a pharmaceutically acceptable salt thereof , TNF -alpha with p55 and p75 cell surface receptors or e . g . , a compound having Formula I- b , wherein SM is a wherein A² blocks the interaction of TNF -alpha with p55 monovalent radical of a glucocorticosteroid having any one and p75 cell surface receptors. of Formulae II- 1 , II- m , II- n , Il - o , Il - p , or Il - q , or any one of [ 0450 ] In another embodiment, disclosed herein is a com Formulae II - 1' , II - m ', II -n ', II -o ', II -p ', Il - q ', II - 1" , II - m " , II - n " , pound having Formula I- a , or a pharmaceutically acceptable II -0 " , II - p " , or Il - q " , wherein the antibody is adalimumab . salt thereof, e. g ., a compound having Formula I- a , wherein [0453 ] In another embodiment, disclosed herein is a com SM is a monovalent radical of a glucocorticosteroid having pound having Formula I - a , or a pharmaceutically acceptable any one of Formulae II -a , II -b , II - c , II -d , II -e , II -f , II- 1, II -m , salt thereof, or a compound having Formula I -b , or a II -n , Il - o , Il - p , or Il - q , or any one of Formulae II- a ', II - b ', pharmaceutically acceptable salt thereof, which is any one of II -c ', II -d ', II -e ', II -f ' , II- 1 ' , II -m ', II -n ', II -o ', II- p ', Il -q ', Il -1 " , the chemical structures of Table III : TABLE III

HO ?? 111111 SM + A ; HN TUTTI HO2C US 2018 /0126000 A1 May 10 , 2018

TABLE III - continued

HO •*11111 + A ; HN NH whertinytHO , C

ZI 11|LI SA; ?? NH ?? , ? HO peIN proprietat ?F>

HN SA; HOC

HN HO N NYA S - A ;; HO2C comeTITI. caught

HO2C HA; O ZI HO

?? accorgetPYY US 2018 /0126000 A1 May 10 , 2018 67

TABLE III -continued HO2C

1111 - A ; N o

HO StockingHO HO2C 11111 " S - A ; NH HO

- A , HODI QeyriftIZ H02C?? , ? HO

SA- A ; NH HO IZ LoofHOM o HO20 1111 SA; HO NH HO f thingsHOC to

Last1 o US 2018 /0126000 A1 May 10 , 2018

TABLE III - continued

HO2C

11111 S6A ; NH LaHO

- A , HO o QihettHO2C

Tallinn

HO2C

S - A ; HN

Leonorogo>:11

HOC

S - A ;

0 HO O oomumungonte L . II. US 2018 /0126000 A1 May 10 , 2018 69

TABLE III -continued HO2C

TILL

111101 - A : NH IZ HO2C ?? bonbyghting

02 111111 NH IZ IZ HOC " HO

HO La| bona

HO , C

?? S - A ; NH mitologist?? TI US 2018/ 0126000 A1 May 10, 2018 saranorm. .70 . . ? TABLE III -continued HO, SA- ; ?? .. HO ?

HOHO0

A HO " { HO

HI H)?( 3, 5+

HOO

SA; HO , I H ( ???????????HO, C HO2C R Ez HO

III)

HUI US 2018 /0126000 A1 May 10 , 2018 71

TABLE III -continued HO2C 1111 SHA IZ LoitoolHO forget TIR

HO2C ill A NH HO moraHO bitingto

Ir 11

HO2C IZ

NH O HO

MoramiteTII HO2C

HO welcomingHON to

11 US 2018 /0126000 A1 May 10 , 2018 72

TABLE III -continued HO2C H NH Careeritud?? 111 HO2C HN N LaimdoborygghtHO TIK

HO2C

SA losHO?? C ojosoomargt

HOC

ZI SHA IZ HO boroviyyet TT11 US 2018 /0126000 A1 May 10 , 2018

TABLE III -continued HO20

S - A HO Cum augstHOC

4 ;

NH HO C HO _ Ally to

HOì ?? HO 11111 SA; HN N Cooperasi terseyHO2C

HO2C

0 Y S - A ; HO LorontoLundHO US 2018 /0126000 A1 May 10 , 2018 74

TABLE III- continued HO2C SHA NH HO HO Las111 corriget

HO2C OE LII - A ; IZ LentoonbangetHO

HO2C roovoovon A ; LolosoHO famamona 1

HOC “Ys A ;

HOP locosIH .10 US 2018 /0126000 A1 May 10 , 2018 75

TABLE III -continued HO2C

S - A ;

HOHOP LerntorgetHO

HO O NH HO unul SHA; IZ HO2C lambang111

HO . C

11111 SA;

HO O HO LaTO

111111 S A HOHOP HO , C

confolation1 that