OSMR-binding antibodies

Abstract

Provided and exemplified herein are antibodies and antibody fragments that bind OSMR.

Description

Attorney Docket Number: 67321-706.601OSMR-BINDING ANTIBODIES CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial Number 63 / 736,528 filed on December 19, 2024, the entirety of which is hereby incorporated by reference herein.1. BACKGROUND

[0002] Oncostatin M Receptor (OSMR) expression or overexpression is associated with a variety of diseases or conditions, including inflammatory bowel disease (IBD).2. SUMMARY

[0003] The current anti -OSMR antibody in clinical use or clinical trials has an undesirable half-life of as short as 7 days (See Howard Sofen et al., EClinicalMedicine 2023 Feb 3:57: 101826, indicating that subcutaneous administration of an anti-OSMR antibody slowly achieved peak blood concentrations in 125 hours, which then “declined with a half-life of 168 hours (7 days)”). Such undesirable short life necessitates clinical dosing of anti-OSMR antibodies once a week or once every two weeks. Such dosing frequency can have a negative impact on patients, especially for patients with chronic inflammatory diseases who require a maintenance dosing regimen for a prolonged period (e.g. half a year, a year, or even longer). Thus, there is a significant unmet need of anti-OSMR therapeutic antibody with extended serum half-life in patients.

[0004] Accordingly, provided herein are human or humanized antibodies that target OSMR or cells expressing OSMR. Also described herein are OSMR antibodies comprising one or more modifications in the human IgG constant region, which may increase the therapeutic benefit of the OSMR antibody, for instance, by increasing the half-life of the antibody and / or modulating the effector function of the antibody.

[0005] Provided and exemplified herein are various embodiments of anti-OSMR antibodies and antigen-binding fragments thereof.

[0006] Embodiment 1. An anti-OSMR antibody or antigen-binding fragment that binds to OSMR, comprising: (i) a heavy chain variable domain comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising CDR-H1 of heavy chain variable domain set forth in SEQ ID NO: 9; a heavy chain complementarity determining region 2 (CDR-H2) comprising CDR-H2 of heavy chain variable domain set forth in SEQ ID NO: 9; and a heavy chain complementarity determining region 3 (CDR-H3) comprising CDR-H3 of heavy chain variable domain set forth in SEQ ID NO: 9; (ii) a light chainAttorney Docket Number: 67321-706.601 variable domain comprising: a light chain complementarity determining region 1 (CDR-L1) comprising CDR-L1 of light chain variable domain set forth in SEQ ID NO: 8; a light chain complementarity determining region 2 (CDR-L2) comprising CDR-L2 of light chain variable domain set forth in SEQ ID NO: 8; and a light chain complementarity determining region 3 (CDR-L3) comprising CDR-L3 of light chain variable domain set forth in SEQ ID NO: 8; and (iii) a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39; an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; or an amino acid sequence (a) comprising a IgG4-IgGl heavy chain constant region chimera, and (b) having at least one half-life extension mutation , at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84.

[0007] Embodiment 2. The anti-OSMR antibody or antigen-binding fragment of embodiment 1, wherein the CDR-H1 comprises SEQ ID NO: 4, SEQ ID NO: 44, SEQ ID NO: 54, SEQ ID NO: 64, or SEQ ID NO: 74; the CDR-H2 comprises SEQ ID NO: 5; SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 75; or SEQ ID NO: 7; the CDR- H3 comprises SEQ ID NO: 6, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, or SEQ ID NO: 76; the CDR-L1 comprises SEQ ID NO: 1, SEQ ID NO: 41, SEQ ID NO: 51, SEQ ID NO: 61, or SEQ ID NO: 71; the CDR-L2 comprises SEQ ID NO: 2, SEQ ID NO: 42, SEQ ID NO: 52, SEQ ID NO: 62, or SEQ ID NO: 72; and the CDR-L3 comprises SEQ ID NO: 3, SEQ ID NO: 43, SEQ ID NO: 53, SEQ ID NO: 63, or SEQ ID NO: 73.

[0008] Embodiment 3. The anti-OSMR antibody or antigen-binding fragment of embodiment 2, wherein the CDR-H1 comprises: SEQ ID NO: 4, the CDR-H2 comprises SEQ ID NO: 5, the CDR-H3 comprises SEQ ID NO: 6, the CDR-L1 comprises: SEQ ID NO: 1, the CDR-L2 comprises SEQ ID NO: 2, and the CDR-L3 comprises SEQ ID NO: 3.

[0009] Embodiment 4. The anti-OSMR antibody or antigen-binding fragment of embodiment 2, wherein the CDR-H1 comprises: SEQ ID NO: 4, the CDR-H2 comprises SEQAttorney Docket Number: 67321-706.601ID NO: 7, the CDR-H3 comprises SEQ ID NO: 6, the CDR-L1 comprises: SEQ ID NO: 1, the CDR-L2 comprises SEQ ID NO: 2, and the CDR-L3 comprises SEQ ID NO: 3.

[0010] Embodiment 5. The anti-OSMR antibody or antigen-binding fragment of embodiment 2, wherein the CDR-H1 comprises: SEQ ID NO: 44, the CDR-H2 comprises SEQ ID NO: 45, the CDR-H3 comprises SEQ ID NO: 46, the CDR-L1 comprises: SEQ ID NO: 41, the CDR-L2 comprises SEQ ID NO: 42, and the CDR-L3 comprises SEQ ID NO: 43.

[0011] Embodiment 6. The anti-OSMR antibody or antigen-binding fragment of embodiment 2, wherein the CDR-H1 comprises: SEQ ID NO: 54, the CDR-H2 comprises SEQ ID NO: 55, the CDR-H3 comprises SEQ ID NO: 56, the CDR-L1 comprises: SEQ ID NO: 51, the CDR-L2 comprises SEQ ID NO: 52, and the CDR-L3 comprises SEQ ID NO: 53.

[0012] Embodiment 7. The anti-OSMR antibody or antigen-binding fragment of embodiment 2, wherein the CDR-H1 comprises: SEQ ID NO: 64, the CDR-H2 comprises SEQ ID NO: 65, the CDR-H3 comprises SEQ ID NO: 66, the CDR-L1 comprises: SEQ ID NO: 61, the CDR-L2 comprises SEQ ID NO: 62, and the CDR-L3 comprises SEQ ID NO: 63.

[0013] Embodiment 8. The anti-OSMR antibody or antigen-binding fragment of embodiment 2, wherein the CDR-H1 comprises: SEQ ID NO: 74, the CDR-H2 comprises SEQ ID NO: 75, the CDR-H3 comprises SEQ ID NO: 76, the CDR-L1 comprises: SEQ ID NO: 71, the CDR-L2 comprises SEQ ID NO: 72, and the CDR-L3 comprises SEQ ID NO: 73.

[0014] Embodiment 9. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-8, wherein the heavy chain variable domain comprises an amino acid sequence set forth in SEQ ID NO: 9.

[0015] Embodiment 10. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-9, wherein the light chain variable domain comprises an amino acid sequence set forth in SEQ ID NO: 8.

[0016] Embodiment 11. An anti-OSMR antibody or antigen-binding fragment that binds to OSMR, comprising (i) a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 9; (ii) a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 8; and (iii) a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at leastAttorney Docket Number: 67321-706.60192%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 15-30 and 32-39; an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; or an amino acid sequence (a) comprising an IgG4-IgGl heavy chain constant region chimera, and (b) having at least one half-life extension mutation , at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84.

[0017] Embodiment 12. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1 to 11, wherein the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5.

[0018] Embodiment 13. The anti-OSMR antibody or antigen-binding fragment of embodiment 12, wherein the at least one half-life extension mutation comprises YTE (M252Y, S254T, and T256E by EU numbering) or LS (M324L and N434S by EU numbering).

[0019] Embodiment 14. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1 to 13, wherein the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5.

[0020] Embodiment 15. The anti-OSMR antibody or antigen-binding fragment of embodiment 14, wherein the at least one effector function mutation comprises LALAGA (L234A, L235A and G237A by EU numbering), LALAPA (L234A, L235A and P329A by EU numbering), LALAPG (L234A, L235A and P329G by EU numbering), LALAKA (L234A, L235A and K322A by EU numbering), or STR (F234S, L235T, and G236R by EU numbering).

[0021] Embodiment 16. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 15.Attorney Docket Number: 67321-706.601

[0022] Embodiment 17. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 16.

[0023] Embodiment 18. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 17.

[0024] Embodiment 19. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 18.

[0025] Embodiment 20. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 19.

[0026] Embodiment 21. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 20.

[0027] Embodiment 22. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 21.

[0028] Embodiment 23. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 22.

[0029] Embodiment 24. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 23.

[0030] Embodiment 25. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 24.

[0031] Embodiment 26. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 25.

[0032] Embodiment 27. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 26.

[0033] Embodiment 28. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 27.

[0034] Embodiment 29. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 28.

[0035] Embodiment 30. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 29.

[0036] Embodiment 31. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 30.

[0037] Embodiment 32. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 32.Attorney Docket Number: 67321-706.601

[0038] Embodiment 33. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 33.

[0039] Embodiment 34. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 34.

[0040] Embodiment 35. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 35.

[0041] Embodiment 36. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 36.

[0042] Embodiment 37. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 37.

[0043] Embodiment 38. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 38.

[0044] Embodiment 39. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the heavy chain constant region comprises SEQ ID NO: 39.

[0045] Embodiment 40. The anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-39, further comprising a light chain constant region comprising an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 12 or SEQ ID NO: 13.

[0046] Embodiment 41. A polynucleotide comprising nucleotide sequences encoding a heavy chain (HC), a light chain (LC), or both a HC and a LC of the antibody of any one of embodiments 1-40.

[0047] Embodiment 42. The polynucleotide of embodiment 41, wherein the polynucleotide is operably linked to a promoter.

[0048] Embodiment 43. A vector comprising the polynucleotide of any one of embodiments 41-42.

[0049] Embodiment 44. A cell comprising the polynucleotide of any one of embodiments 41-42.

[0050] Embodiment 45. A cell comprising the vector of embodiment 44.

[0051] Embodiment 46. A cell comprising (i) a polynucleotide comprising a nucleotide sequence encoding a HC and a polynucleotide comprising a nucleotide sequence encoding a LC, wherein the HC and LC are a matching pair from the antibody of any one of embodiments 1-40; or (ii) a vector comprising a polynucleotide that comprises a nucleotideAttorney Docket Number: 67321-706.601 sequence encoding a HC and a vector comprising a polynucleotide that comprises a nucleotide sequence encoding a LC, wherein the HC and LC are a matching pair from the antibody of any one of embodiments 1-40.

[0052] Embodiment 47. An isolated cell producing the antibody or antigen-binding fragment thereof of any one of embodiments 1-40.

[0053] Embodiment 48. A kit comprising the antibody or antigen-binding fragment thereof of any one of embodiments 1-40.

[0054] Embodiment 49. A method of making an antibody or antigen-binding fragment thereof which specifically binds to OSMR, comprising culturing the cell of any one of embodiment 44-46 to express the antibody or antigen-binding fragment thereof.

[0055] Embodiment 50. A method of making an antibody or antigen-binding fragment thereof which specifically binds to OSMR, comprising expressing the polynucleotide of any one of embodiments 41-42.

[0056] Embodiment 51. A pharmaceutical composition comprising: the antibody and antibody fragment of any one of embodiments 1-40; and a pharmaceutically acceptable carrier.

[0057] Embodiment 52. A method of treating a disease or condition in a subject, the method comprising: administering to the subject the anti-OSMR antibody or antigen-binding fragment of any one of embodiments 1-40, or the pharmaceutical composition of embodiment 41.

[0058] Embodiment 53. The method of embodiment 42, wherein the disease or condition is inflammatory bowel disease (IBD).

[0059] Embodiment 54. The method of embodiment 42, wherein the disease or condition is Crohn’s disease (CD).

[0060] Embodiment 55. The method of embodiment 42, wherein the disease or condition is ulcerative colitis (UC).3. DETAILED DESCRIPTION

[0061] Provided and exemplified herein are antibodies that bind OSMR (anti-OSMR antibody or interchangeably OSMR antibody) and antigen-binding fragments of such antibodies (antigen-binding fragments thereof). Non-limiting example of antibodies and antigen-binding fragments are provided herein, e.g., as further described in this Section 3 and as illustrated in Tables 2-3. In some embodiments, the anti-OSMR antibody or antigenbinding fragment thereof comprises a constant region, where the constant region mayAttorney Docket Number: 67321-706.601 comprise one or more mutations relative to human IgGl (SEQ ID NO: 14) or IgG4 (SEQ ID NO: 31). Non-limiting example constant regions of an anti-OSMR antibody or antigenbinding fragment are provided in Tables 4-5. The positions of the mutations within the IgGl or IgG4 constant region are noted using the EU numbering system, e.g. in Tables 4-5.

[0062] In some embodiments, the anti-OSMR antibodies or antigen-binding fragments herein inhibit IL-31 induced activation of the IL-31 receptor (OSMR and IL31 receptor a (IL3 IRa) complex) and inhibit oncostatin M (OSM)-induced activation of the type II OSM receptor (OSMR and GP130 complex), through binding to OSMR, the subunit common to both receptors. In some embodiments, the anti-OSMR antibody or antigen-binding fragments bind to human and / or cynomolgus (cyno) OSMR, do not bind to rodent OSMR. In certain embodiments, the anti-OSMR antibody or antigen-binding fragments are antagonist against the binding of OSMR ligand and ligand-induced OSMR signaling, wherein the ligand is IL31, OSM, or both IL31 and OSM. In some embodiments, the anti-OSMR antibody or antigen-binding fragments provided herein (i) bind to human and / or cyno OSMR, (ii) compete for binding with OSMR ligand (e.g., OSM and / or IL31), and / or (iii) block OSMR signaling induced by OSM and / or IL31. In one embodiment, the anti-OSMR antibody or antigen-binding fragments bind to human OSMR. In one embodiment, the anti-OSMR antibody or antigen-binding fragments bind to cyno OSMR. In one embodiment, the anti- OSMR antibody or antigen-binding fragments bind to both human OSMR and cyno OSMR. In some embodiments, the anti-OSMR antibody or antigen-binding fragments compete with OSM for binding to type II OSM receptor (OSMR and GP130 complex). In some embodiments, the anti-OSMR antibody or antigen-binding fragments compete with IL31 for binding to IL31 receptor complex (OSMR and IL3 IRa). In other embodiments, the anti- OSMR antibody or antigen-binding fragments block OSMR signaling. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragments block OSMR signaling that is induced by OSM through type II OSM receptor (OSMR and GP130 complex). In yet another embodiment, the anti-OSMR antibody or antigen-binding fragments block OSMR signaling that is induced by IL31 through IL31 receptor complex (OSMR and IL3 IRa complex). In a further embodiment, the anti-OSMR antibody or antigen-binding fragments block OSMR signaling that is induced by OSM through type II OSM receptor and block OSMR signaling that is induced by IL31 through IL31 receptor complex.

[0063] In some embodiments, the antibodies or antibody fragments bind to an OSMR protein with an equilibrium dissociation constant (KD) of about 1 nM to about 10 pM. Binding canAttorney Docket Number: 67321-706.601 be determined by bio-layer interferometry, surface plasmon resonance (e.g., using Biacore), isothermal titration calorimetry, or ELISA. Affinity generally refers to or includes the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen such as OSMR). Unless indicated otherwise, binding affinity generally encompasses and refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of an antibody for an antigen (e.g., OSMR) can generally be represented by the dissociation constant (KD). Affinity can be measured and determined by bio-layer interferometry, surface plasmon resonance, isothermal titration calorimetry, and / or ELISA. For instance, as described in Example 2 herein.

[0064] In certain instances, OSMR comprises an amino acid sequence having at least 70, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 101. In certain instances, OSMR comprises an amino acid sequence having at least 70, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 102. In some embodiments, the anti-OSMR antibody or antigen-binding fragments described herein binds to OSMR. In some embodiments, the anti-OSMR antibody or antigen-binding fragments described herein binds to OSMR comprising the amino acid sequence that is at least 70, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity to SEQ ID NO: 101 or SEQ ID NO: 102.Table 1. Non-limiting examples of OSMR amino acid sequencesAttorney Docket Number: 67321-706.601

[0065] In some embodiments of the present disclosure, the anti-OSMR antibody or antigenbinding fragments may comprise immunoglobulin variable regions which comprise one or more CDRs as described in Table 2. In such anti-OSMR antibody or antigen-binding fragments, the CDRs may be joined with one or more scaffold regions or framework regions (FRs), which orient(s) the CDR(s) such that the proper antigen binding properties of the CDR(s) is achieved. Such anti-OSMR antibody or antigen-binding fragments can block or inhibit OSM binding to the type II OSM receptor (OSMR and GP130 complex) and thus block or inhibit OSM-induced OSMR signaling. Alternatively, such anti-OSMR antibody or antigen-binding fragments as described herein can block or inhibit IL31 binding to IL31 receptor complex (OSMR and IL3 IRa complex) and thus block or inhibit IL31 -induced OSMR signaling. Additionally, such anti-OSMR antibody or antigen-binding fragments as described herein can (i) block or inhibit can block or inhibit OSM binding to the type II OSM receptor (OSMR and GP130 complex) and thus block or inhibit OSM-induced OSMR signaling, and (ii) block or inhibit OSM binding to the type II OSM receptor (OSMR and GP130 complex) and thus block or inhibit OSM-induced OSMR signaling.

[0066] In certain embodiments, the antibodies or antibody fragments that bind OSMR comprise an Fc region. In certain embodiments, the Fc region is an IgG Fc region. In certain embodiments, the Fc region is an IgGl Fc region. In certain embodiments, the Fc region is an IgG4 Fc region. In some embodiments, the Fc region is an amino acid sequence comprising a combination of a human IgGl constant region and a human IgG4 constant region. ForAttorney Docket Number: 67321-706.601 example, the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. The constant region(s) and / or hinge may comprise one or more mutations. For instance, the hinge from human IgG4 can have a Ser to Pro mutation at position 228. The CH2 domain from human IgG may have an Asn to Gin mutation at position 297. The constant domain may have a substitution as shown in Table 5.3.1 Antibody and antibody fragment that bind OSMR

[0067] Provided herein are anti-OSMR antibody or antigen-binding fragments that bind OSMR. Antibody is used in the broadest sense and generally refers to and / or includes monoclonal antibodies, multi-valent antibodies, multi-specific, and antigen-binding fragments of antibodies that bind an OSMR protein. Antigen-binding fragments of antibodies (antigen-binding antibody fragments, or antigen-binding fragments) generally refer to and / or include antibody-derived proteins that comprise a functional set of CDRs (e.g., a CDR-H1-3 and CDR-L1-3) that bind an OSMR protein and have a molecule weight less than a full length IgG antibody (e.g., a molecular weight less than -150,000 Daltons). In certain embodiments, an antigen-binding antibody fragment (e.g., an OSMR-binding fragment) includes: fragment antigen binding (Fab) fragment, F(ab’)2 fragment, Fab’ fragment, Fv fragment, reduced IgG (rlgG, or half IgG) fragment, and single chain antibody fragment, including single chain variable fragment (sFv or scFv). Antibodies and antigen-binding fragments of antibodies generally encompass genetically engineered, and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, heteroconjugate antibodies, multi -specific antibodies, multi-valent antibodies, diabodies, triabodies, tetrabodies, tandem di-scFv, and tandem tri-scFv. A full-length antibody, intact antibody, and / or whole antibody are interchangeable, and generally include and / or refer to an antibody having a structure substantially similar to a native antibody structure having heavy chains that contain an Fc region and / or include antibodies of any class or sub-class, including IgG and sub-classes thereof (e.g., IgGl and IgG4), IgM, IgE, IgA, and IgD.

[0068] In certain embodiments, the antibodies and / or antibody fragments that bind OSMR comprise an Fc region. In certain embodiments, the Fc region is an IgG Fc region. In certain embodiments, the Fc region is a human IgGl Fc region. In certain embodiments, the Fc region is a human IgG4 Fc region. In some embodiments, the Fc region is an amino acid sequence comprising a combination of human IgGl constant region and human IgG4 constant region. For example, the CHI domain of human IgG4, the hinge from human IgG4,Attorney Docket Number: 67321-706.601 the CH2 domain of human IgG4, and the CH3 domain of human IgGl. The constant region(s) and / or hinge may comprise one or more mutations. For instance, the hinge from human IgG4 can have a Ser to Pro mutation at position 228. The CH2 domain from human IgG may have an Asn to Gin mutation at position 297. The constant domain may have a substitution as shown in Table 5.

[0069] Method of engineering or manufacturing the anti-OSMR antibody or antigen-binding fragment may be performed using methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3d ed. 2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Diibel eds., 2d ed. 2010).

[0070] Provided and exemplified herein are the anti-OSMR antibodies or antigen-binding fragments comprising at least one heavy chain variable domain or at least one light chain variable domain. In some embodiments, the antibody or the antibody fragment comprises at least one heavy chain variable domain and at least one light chain variable domain. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a heavy chain complementarity determining region 1 (CDR-H1); a heavy chain complementarity determining region 2 (CDR-H2); and a heavy chain complementarity determining region 3 (CDR-H3). In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain complementarity determining region 1 (CDR-L1); a light chain complementarity determining region 2 (CDR-L2); and a light chain complementarity determining region 3 (CDR-L3). In some embodiments, the anti-OSMR antibody or antigenbinding fragment comprises a heavy chain complementarity determining region 1 (CDR-H1); a heavy chain complementarity determining region 2 (CDR-H2); a heavy chain complementarity determining region 3 (CDR-H3); a light chain complementarity determining region 1 (CDR-L1); a light chain complementarity determining region 2 (CDR-L2); and a light chain complementarity determining region 3 (CDR-L3). In some embodiments, the CDR sequence of the anti-OSMR antibody or antigen-binding fragment can be selected from any one of the CDR sequences as shown in Table 2. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 44, SEQ ID NO: 54, SEQ ID NO: 64, or SEQ ID NO: 74. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 5; SEQ ID NO: 45,Attorney Docket Number: 67321-706.601SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 75; or SEQ ID NO: 7. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, or SEQ ID NO: 76. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 41, SEQ ID NO: 51, SEQ ID NO: 61, or SEQ ID NO: 71. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 42, SEQ ID NO: 52, SEQ ID NO: 62, or SEQ ID NO: 72. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 43, SEQ ID NO: 53, SEQ ID NO: 63, or SEQ ID NO: 73.Table 2. Non-limiting examples of CDR sequence of the anti-OSMR antibodies or antigen-binding fragmentsAttorney Docket Number: 67321-706.601

[0071] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain (e.g., comprising a light chain variable domain) or a heavy chain (e.g., comprising a heavy chain variable domain). In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain and a heavy chain. In some embodiments, the light chain or the heavy chain can be selected from any one of the amino acid sequences as shown in Table 3. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain having an amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a heavy chain having an amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain having an amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain having an amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the anti-OSMRAttorney Docket Number: 67321-706.601 antibody or antigen-binding fragment comprises a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 8; and a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 9.Table 3. Non-limiting examples of light chain sequences and heavy chain sequences of the anti-OSMR antibodies or antigen-binding fragments

[0072] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain constant region or a heavy chain constant region. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain constant region and a heavy chain constant region. In some embodiments, the light chain constant region can be selected from any one of the amino acid sequences as shown in Table 4 and / or the heavy chain constant region can be selected from any one of the amino acid sequence as shown in Table 4. In some embodiments, the anti-OSMR antibody or antigenbinding fragment comprises a light chain constant region that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain constant region that is SEQ ID NO: 12 or SEQ ID NO: 13. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises aAttorney Docket Number: 67321-706.601 heavy chain constant region that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 14-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a heavy chain constant region that is any one of SEQ ID NOs: 14-39. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain constant region that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13; and a heavy chain constant region that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 14-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a light chain constant region that is SEQ ID NO: 12 or SEQ ID NO: 13; and a heavy chain constant region that is any one of SEQ ID NOs: 14-39.Table 4. Non-limiting examples of light chain constant region sequences and heavy chain constant region sequences of the anti-OSMR antibodies or antigen-binding fragmentsAtorney Docket Number: 67321-706.601Atorney Docket Number: 67321-706.601Atorney Docket Number: 67321-706.601Atorney Docket Number: 67321-706.601Atorney Docket Number: 67321-706.601Atorney Docket Number: 67321-706.601Attorney Docket Number: 67321-706.601

[0073] In some embodiments, the anti-OSMR antibody or antigen-binding fragment thereof comprises at least one mutation as compared to wild type IgGl or IgG4 in the heavy chain constant region. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of IgGl constant region. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of the human IgGl constant region (SEQ ID NO: 14). In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgGl constant region having at least one half-life extension mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgGl constant region having at least one effector function mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgGl constant region having at least one half-life extension mutation as listed in Table 5 and at least one effector function mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereofAttorney Docket Number: 67321-706.601 comprises an amino acid sequence of IgG4 constant region. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgG4 constant region (SEQ ID NO: 41). In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgG4 constant region having at least one effector function mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation as listed in Table 5 and at least one effector function mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising an IgG4- IgGl heavy chain constant region chimera having at least one half-life extension mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising an IgG4-IgGl heavy chain constant region chimera having at least one effector function mutation as listed in Table 5. In some embodiments, the heavy chain constant region of the anti-OSMR antibody or antigen-binding fragment thereof comprises an amino acid sequence comprising an IgG4-IgGl heavy chain constant region chimera having at least one half-life extension mutation as listed in Table 5 and at least one effector function mutation as listed in Table 5. In some embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5, wherein each set comprises one or more half-life extension mutations as specified in each row indicated as half-life extension mutations in Table 5. In some embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5, wherein each set comprises one or more effector function mutations as specified in each row indicated as effector function mutations in Table 5. In some embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera comprisesAttorney Docket Number: 67321-706.601 the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.Table 5. Non-limiting examples of at least one mutation introduced into a heavy chain constant region sequence of an anti-OSMR antibody or antigen-binding fragment.Atorney Docket Number: 67321-706.601Attorney Docket Number: 67321-706.601(In Table 5, each set of half-life extension mutations comprises one or more half-life extension mutations as specified in the 2ndcolumn of each row that is indicated as half-life extension mutations in the 1stcolumn of the same row. Similarly, in Table 5, each set of effector function mutations comprises one or more effector function mutations as specified in the 2ndcolumn of each row that is indicated as effector function mutations in the 1stcolumn of the same row. All mutations in Table 5 are described according to EU numbering system. See Kabat EA, et al. Sequences of proteins of immunological interest, 5th.; Bethesda (MD): National Institutes of Health; 1991.)

[0074] Provided herein are antibodies and antibody fragments that bind to OSMR. In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a heavy chain variable domain comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising an amino acid sequence of CDR-H1 of heavy chain variable domain set forth in SEQ ID NO: 9; a heavy chain complementarity determining region 2 (CDR-H2) comprising an amino acid sequence of CDR-H2 of heavy chain variable domain set forth in SEQ ID NO: 9; and a heavy chain complementarity determining region 3 (CDR-H3) comprising an amino acid sequence of CDR-H3 of heavy chain variable domain set forth in SEQ ID NO: 9; and a light chain variable domain comprising: a light chain complementarity determining region 1 (CDR-L1) comprising an amino acid sequence of CDR-L1 of light chain variable domain set forth in SEQ ID NO: 8; a light chain complementarity determining region 2 (CDR-L2) comprising an amino acid sequence of CDR-L1 of light chain variable domain set forth in SEQ ID NO: 8; and a light chain complementarity determining region 3 (CDR-L3) comprising an amino acid sequence of CDR-L1 of light chain variable domain set forth in SEQ ID NO: 8. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at leastAttorney Docket Number: 67321-706.60185%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigenbinding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation atAttorney Docket Number: 67321-706.601 position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0075] In some embodiments, the antibody or antibody fragment that binds to OSMR comprises a heavy chain variable domain comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 44, SEQ ID NO: 54, SEQ ID NO: 64, or SEQ ID NO: 74; a heavy chain complementarity determining region 2 (CDR-H2) comprising an amino acid sequence of SEQ ID NO: 5; SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 75; or SEQ ID NO: 7; and a heavy chain complementarity determining region 3 (CDR-H3) comprising an amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, or SEQ ID NO: 76; a light chain variable domain comprising: a light chain complementarity determining region 1 (CDR-L1) comprising an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 41, SEQ ID NO: 51, SEQ ID NO: 61, or SEQ ID NO: 71; a light chain complementarity determining region 2 (CDR-L2) comprising an amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 42, SEQ ID NO: 52, SEQ ID NO: 62, or SEQ ID NO: 72; and a light chain complementarity determining region 3 (CDR-L3) comprising an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 43, SEQ ID NO: 53, SEQ ID NO: 63, or SEQ ID NO: 73. The anti -OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of thisAttorney Docket Number: 67321-706.601 paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigenbinding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0076] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises: a CDR-H1 comprising or consisting of SEQ ID NO: 4; a CDR-H2 comprising or consisting of SEQ ID NO: 5; a CDR-H3 comprising or consisting of SEQ ID NO: 6; a CDR- L1 comprising or consisting of SEQ ID NO: 1; a CDR-L2 comprising or consisting of SEQ ID NO: 2; and a CDR-L3 comprising or consisting of SEQ ID NO: 3. In other embodiments, the anti-OSMR antibody or antigen-binding fragment comprises: a CDR-H1 comprising or consisting of SEQ ID NO: 4; a CDR-H2 comprising or consisting of SEQ ID NO: 7; a CDR- H3 comprising or consisting of SEQ ID NO: 6; a CDR-L1 comprising or consisting of SEQAttorney Docket Number: 67321-706.601ID NO: 1; a CDR-L2 comprising or consisting of SEQ ID NO: 2; and a CDR-L3 comprising or consisting of SEQ ID NO: 3. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti- OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5Attorney Docket Number: 67321-706.601 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0077] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises: a CDR-H1 comprising or consisting of SEQ ID NO: 44; a CDR-H2 comprising or consisting of SEQ ID NO: 45; a CDR-H3 comprising or consisting of SEQ ID NO: 46; a CDR-L1 comprising or consisting of SEQ ID NO: 41; a CDR-L2 comprising or consisting of SEQ ID NO: 42; and a CDR-L3 comprising or consisting of SEQ ID NO: 43. The anti- OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a furtherAttorney Docket Number: 67321-706.601 embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl . In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0078] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises: a CDR-H1 comprising or consisting of SEQ ID NO: 54; a CDR-H2 comprising or consisting of SEQ ID NO: 55; a CDR-H3 comprising or consisting of SEQ ID NO: 56; a CDR-L1 comprising or consisting of SEQ ID NO: 51; a CDR-L2 comprising or consisting of SEQ ID NO: 52; and a CDR-L3 comprising or consisting of SEQ ID NO: 53. The anti- OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at leastAttorney Docket Number: 67321-706.60191%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl . In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.Attorney Docket Number: 67321-706.601

[0079] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises: a CDR-H1 comprising or consisting of SEQ ID NO: 64; a CDR-H2 comprising or consisting of SEQ ID NO: 65; a CDR-H3 comprising or consisting of SEQ ID NO: 66; a CDR-L1 comprising or consisting of SEQ ID NO: 61; a CDR-L2 comprising or consisting of SEQ ID NO: 62; and a CDR-L3 comprising or consisting of SEQ ID NO: 63. The anti- OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selectedAttorney Docket Number: 67321-706.601 from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl . In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0080] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises: a CDR-H1 comprising or consisting of SEQ ID NO: 74; a CDR-H2 comprising or consisting of SEQ ID NO: 75; a CDR-H3 comprising or consisting of SEQ ID NO: 76; a CDR-L1 comprising or consisting of SEQ ID NO: 71; a CDR-L2 comprising or consisting of SEQ ID NO: 72; and a CDR-L3 comprising or consisting of SEQ ID NO: 73. The anti- OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can additionally comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32- 39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigenbinding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one halflife extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph canAttorney Docket Number: 67321-706.601 comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of halflife extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0081] In some embodiments, the antibody or antibody fragment that binds to OSMR comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 9; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 8. The anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can further comprise a light chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or SEQ ID NO: 13. The anti-OSMR antibody orAttorney Docket Number: 67321-706.601 antigen-binding fragment of any clause of this paragraph can additionally comprise a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32-39, wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84. In other embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In yet another embodiment, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In a further embodiment, the anti-OSMR antibody or antigenbinding fragment of any clause of this paragraph can comprise a heavy chain constant region comprising an amino acid sequence comprising a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation. In some embodiments, the at least one half-life extension mutation of any applicable clause of this paragraph comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5. In some embodiments, the at least one effector function mutation of any applicable clause of this paragraph comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments of any applicable clause of this paragraph, the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. In some embodiments, the IgG4-IgGl heavy chain constant region chimera of any applicable clause of this paragraph comprises the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In some further embodiments of the anti-OSMR antibody or antigen-binding fragment provided in this paragraph, the IgG4-IgGl heavy chain constantAttorney Docket Number: 67321-706.601 region chimera of any applicable clause of this paragraph comprises a Ser to Pro mutation at position 228 of the IgG4 hinge and / or an Asn to Gin mutation at position 297 of IgG4 CH2 domain.

[0082] In some embodiments, the anti-OSMR antibody or antigen-binding fragment comprises a heavy chain variable region comprising or consisting of an amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising or consisting of an amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-OSMR antibody or antigenbinding fragment of any clause of this paragraph further comprises a light chain constant region consisting of an amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 13. In some embodiments, the anti-OSMR antibody or antigen-binding fragment of any clause of this paragraph additionally comprises a heavy chain constant region consisting of an amino acid sequence of any one of SEQ ID NOs: 15-30 and 32-39. In some embodiments, the anti- OSMR antibody or antigen-binding fragment comprises a heavy chain constant region consisting of IgGl, IgG4, or a IgG4-IgGl heavy chain constant region chimera, optionally having at least one half-life extension mutation and / or at least one effector function mutation, wherein the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5.3.2 Pharmaceutical compositions

[0083] In some embodiments, provided herein are pharmaceutical compositions and / or formulations comprising an anti-OSMR antibody or antigen-binding fragment described herein. An example of such anti-OSMR antibody or antigen-binding fragment is illustrated in Section 3.1 above. A pharmaceutical composition includes and / or refers to a preparation that is in such form as to permit biological activity of the anti-OSMR antibody or antigen-binding fragment (e.g., binding to OSMR and blocking OSMR signaling (induced by OSM or IL31)), and that contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier (e.g., an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to an individual). A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, and preservative.Attorney Docket Number: 67321-706.6013.3 Methods

[0084] The antibodies and antibody fragments that bind OSMR can be useful in methods that include and / or require specific recognition of OSMR. An example of such anti-OSMR antibody or antigen-binding fragment is illustrated in Section 3.1.

[0085] Accordingly, in some embodiments, provided herein are methods for contacting a cell expressing OSMR with the antibody or antibody fragment that binds OSMR (as those described herein, e.g., Section 3.1). In some embodiments, the cell expressing OSMR is a cell involved in inflammatory bowel disease. In one aspect, provided herein is a method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject an antibody or antibody fragment that binds to OSMR for instance, the anti-OSMR antibody or antigen-binding fragment of Section 3.1. In some embodiments, the disease or condition comprises inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC).

[0086] Anti-OSMR antibodies may be produced by culturing cells transformed or transfected with a vector containing anti-OSMR antibody-encoding nucleic acids. Polynucleotide sequences encoding polypeptide components of the antibody of the present disclosure can be obtained using standard recombinant techniques. Desired polynucleotide sequences may be isolated and sequenced from antibody producing cells such as hybridomas cells.Alternatively, polynucleotides can be synthesized using nucleotide synthesizer or PCR techniques. Once obtained, sequences encoding the polypeptides are inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in host cells. Many vectors that are available and known in the art can be used for the purpose of the present disclosure. Selection of an appropriate vector will depend mainly on the size of the nucleic acids to be inserted into the vector and the particular host cell to be transformed with the vector. Host cells suitable for expressing antibodies of the present disclosure include prokaryotes such as Archaebacteria and Eubacteria, including Gram-negative or Grampositive organisms, eukaryotic microbes such as filamentous fungi or yeast, invertebrate cells such as insect or plant cells, and vertebrate cells such as mammalian host cell lines. Host cells are transformed with the above-described expression vectors and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. Antibodies produced by the host cells are purified using standard protein purification methods as known in the art.Attorney Docket Number: 67321-706.601

[0087] Methods for antibody production including vector construction, expression, and purification are further described in Pliickthun et al., Antibody Engineering: Producing antibodies in Escherichia coli: From PCR to fermentation 203-52 (McCafferty et al. eds., 1996); Kwong and Rader, E. coli Expression and Purification of Fab Antibody Fragments, in Current Protocols in Protein Science (2009); Tachibana and Takekoshi, Production of Antibody Fab Fragments in Escherischia coli, in Antibody Expression and Production (Al- Rubeai ed., 2011); and Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed., 2009).

[0088] It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare anti-OSMR antibodies. For instance, the appropriate amino acid sequence, or portions thereof, may be produced by direct peptide synthesis using solidphase techniques (see, e.g., Stewart et al., Solid-Phase Peptide Synthesis (1969); and Merrifield, 1963, J. Am. Chem. Soc. 85:2149-54). In vitro protein synthesis may be performed using manual techniques or by automation. Various portions of the anti-OSMR antibody may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the desired anti-OSMR antibody. Alternatively, antibodies may be purified from cells or bodily fluids, such as milk, of a transgenic animal engineered to express the antibody, as disclosed, for example, in U.S. Pat. Nos. 5,545,807 and 5,827,690.4. Definitions

[0089] The terms “oncostatin M receptor,” “oncostatin-M-specific receptor subunit beta,” “OSMR,” “OSMRP,” “OSMR-P,” “OSMRbeta,” “OSMR-beta,” “OSMR beta,” (also known as IL-31 Receptor Subunit Beta, IL-31 receptor beta, IL-31R subunit beta, IL-3 IR-beta, IL- 31RB, IL-3 IRp, PLCA1, ) are used interchangeably and are intended to mean a polypeptide (“polypeptide” and “protein” are used interchangeably herein), that is a member of the type I cytokine receptor family and that in humans is encoded by the OSMR gene (in other species encoded by the corresponding OSMR genes for such other species). Such OSMR heterodimerizes with interleukin 6 signal transducer (also known as gpl30, glycoprotein 130, IL6ST, IL6R-beta or CD130) to form the type II oncostatin M receptor complex and with interleukin 31 receptor A to form the interleukin 31 receptor complex, and thus transduces oncostatin M and interleukin 31 induced signaling events. Accordingly, OSMR has two physiological ligands, IL31 (when OSMR pairs with IL31 receptor a, IL3 IRa, to form IL31 receptor complex) and OSM (when OSMR pairs with GP130 to form the type II OSM receptor). Examples of glycoprotein 130 encompasses any such native polypeptide from anyAttorney Docket Number: 67321-706.601 vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. In certain embodiments, the terms include “related OSMR polypeptides,” including SNP variants thereof. The term “OSMR” also encompasses “full-length,” unprocessed OSMR as well as any form of OSMR that results from processing in the cell. In some embodiments, the human OSMR has an amino acid sequence of SEQ ID NO: 101. In other embodiments, the OSMR has an amino acid sequence of SEQ ID NO: 102, which is cynomolgus monkey OSMR. NCBI Reference Sequences NP_001161827.1, NP_001310433.1 , NP_001310434.1 , NP_001310435.1, NP_001310436.1, NP_003990.1, and UniProtKB : Q99650 provides other exemplary amino acid sequences of OSMR, including the OSMR encoded by OSMR gene including one or more polymorphisms. GENBANK accession number 9180, NCBI Reference Sequences NM_003999.3, NM_001323507.2, NM_001323506.2, NM_001323505.2, NM_001323504.2, and NM_001168355.3 provide exemplary human OSMR nucleic acid sequence.

[0090] The term “OSM,” “Oncostatin-M,” or “Oncostatin M” is intended to mean a cytokine that is a member of the interleukin (IL)-6 cytokine family and that in humans is encoded by the OSM gene on human chromosome 22 (in other species encoded by the corresponding OSM genes for such other species). Examples of OSM encompasses any such native polypeptide from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynos), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. In certain embodiments, the term includes all natural variants of OSM, including allelic variants (e.g., SNP variants); splice variants; fragments; and derivatives. The term “OSM,” “Oncostatin-M,” or “Oncostatin M” also encompasses “full-length,” unprocessed OSM as well as any form of OSM that results from processing in the cell. NCBI Reference Sequences NP_065391.1, NP_001306037.1, XP_047297343.1, and Uniprot database P13725 provides exemplary amino acid sequences of OSM. GenBank™ ID number 5008, NM_020530.6, NM_001319108.2, and XM_047441387.1 provide exemplary human OSM nucleic acid sequence.

[0091] As described herein, the term “percent (%) sequence identity,” and terms related thereto, in the context of amino acid sequences or nucleic acid sequences, is the percentage of amino acid residues or nucleic acid residues in a candidate sequence that are identical with the amino acid residues or nucleic acid residues, respectively, in a selected sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percentAttorney Docket Number: 67321-706.601 sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity or percent nucleic acid identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as Clustal Omega, BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software, with BLAST being the alignment algorithm of preference. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared, although for simplicity it maybe preferred to use default parameters.

[0092] As used herein, the term “individual” is synonymous with patient and / or subject and includes and / or refers to a human and may be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein. However, examples are not limited to humans and include, chimpanzees, marmosets, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. The term individual includes vertebrates. The individual is typically a human and may be a human that has been diagnosed as needing to treat a disease or condition as disclosed herein.

[0093] “Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. “Oligonucleotide,” as used herein, refers to short, generally single-stranded, synthetic polynucleotides that are generally, but not necessarily, fewer than about 200 nucleotides in length. The terms “oligonucleotide” and “polynucleotide” are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides. A cell that produces an anti-OSMR antibody of the present disclosure may include a parent hybridoma cell, as well as bacterial and eukaryotic host cells into which nucleic acids encoding the antibodies have been introduced. Suitable host cells are disclosed below.

[0094] Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions onAttorney Docket Number: 67321-706.601 the DNA strand having the same sequence as the RNA transcript that are 5’ to the 5’ end of the RNA transcript are referred to as “upstream sequences”; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 3’ to the 3’ end of the RNA transcript are referred to as “downstream sequences.”

[0095] The term “vector” refers to a substance that is used to carry or include a nucleic acid sequence, including for example, a nucleic acid sequence encoding an anti-OSMR antibody as described herein, in order to introduce a nucleic acid sequence into a host cell. Vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, epi somes, and artificial chromosomes, which can include selection sequences or markers operable for stable integration into a host cell’s chromosome. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included, for example, provide resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not in the culture media. Expression control sequences can include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, which are well known in the art. When two or more nucleic acid molecules are to be co-expressed (e.g., both an antibody heavy and light chain or an antibody VH and VL), both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors. For single vector expression, the encoding nucleic acids can be operationally linked to one common expression control sequence or linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. The introduction of nucleic acid molecules into a host cell can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA, immunoblotting for expression of gene products, or other suitable analytical methods to test the expression of an introduced nucleic acid sequence or its corresponding gene product. It is understood by those skilled in the art that the nucleic acid molecules are expressed in a sufficient amount to produce a desired product (e.g., an anti-OSMR antibody as described herein), and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0096] The term “antibody,” “immunoglobulin,” or “Ig” is used interchangeably herein, and is used in the broadest sense and specifically covers, for example, individual anti-OSMR monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full length orAttorney Docket Number: 67321-706.601 intact monoclonal antibodies), anti-OSMR antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g, bispecific antibodies so long as they exhibit the desired biological activity), formed from at least two intact antibodies, single chain anti-OSMR antibodies, and fragments of anti-OSMR antibodies, as described below. An antibody can be human, humanized, chimeric and / or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc. The term “antibody” is intended to include a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy -terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). In specific embodiments, the specific molecular antigen can be bound by an antibody provided herein, including an OSMR polypeptide, an OSMR fragment, or an OSMR epitope. Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti -idiotypic (anti -Id) antibodies, and functional fragments (e.g, antigen-binding fragments such as OSMR-binding fragments) of any of the above, which refers to a portion of an antibody heavy or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments such as OSMR-binding fragments) include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab’) fragments, F(ab)2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen-binding site that binds to an OSMR antigen (e.g., one or more CDRs of an anti-OSMR antibody). Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22: 189-224; Pliickthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990). The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g.,Attorney Docket Number: 67321-706.601IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2) of immunoglobulin molecule. Anti-OSMR antibodies may be agonistic antibodies or antagonistic antibodies. Provided herein are antagonistic antibodies to OSMR, including antibodies that reduce or block OSMR signaling, block or reduce binding between IL31 and IL31 receptor complex (OSMR and IL3 IRa complex), and / or block or reduce binding between OSM and type II OSM receptor (OSMR and GP130 complex).

[0097] An “antigen” is a predetermined antigen to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide.

[0098] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” “antigen binding fragment,” “antigen binding domain,” “antigen binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., the CDRs).

[0099] The terms “binds” or “binding” refer to an interaction between molecules including, for example, to form a complex. Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. A complex can also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non- covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as OSMR, is the affinity of the antibody or functional fragment for that epitope. The ratio of dissociation rate (koff) to association rate (kon) of an antibody to a monovalent antigen (koff / kon) is the dissociation constant KD, which is inversely related to affinity. The lower the KD value, the higher the affinity of the antibody. The value of KD varies for different complexes of antibody and antigen and depends on both konand koff. The dissociation constant KD for an antibody provided herein can be determined using any method provided herein or any other method well known to those skilled in the art. The affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen. When complex antigens containing multiple, repeating antigenic determinants, such as a polyvalent OSMR, come in contact with antibodies containing multiple binding sites, the interaction of antibody with antigen at one site will increase the probability of a reaction at a second site. The strength of such multiple interactions betweenAttorney Docket Number: 67321-706.601 a multivalent antibody and antigen is called the avidity. The avidity of an antibody can be a better measure of its binding capacity than is the affinity of its individual binding sites. For example, high avidity can compensate for low affinity as is sometimes found for pentameric IgM antibodies, which can have a lower affinity than IgG, but the high avidity of IgM, resulting from its multivalence, enables it to bind antigen effectively.

[0100] The terms “antibodies that specifically bind to OSMR,” “antibodies that specifically bind to an OSMR epitope,” and similar terms refer to antibodies that specifically bind to an OSMR polypeptide, such as an OSMR antigen, or fragment, or epitope (e.g., human OSMR such as a human OSMR polypeptide, antigen, or epitope). The terms “specifically bind to,” “specific binding,” and analogous terms when used in the context of one molecule binding to the other, means that one molecule binds to the other molecule with significantly higher affinity than to any cross-reactive antigen or off-target antigen (together as non-target antigen) as determined using experimental techniques, such as Surface Plasmon Resonance (SPR), fluorescence activated cell sorting (FACS) analysis, Kinetic Exclusion Assay (KinExA), isothermal titration calorimetry (ITC), radioimmunoassays (RIA) and enzyme linked immunosorbent assays (ELISAs). An antibody that specifically binds to OSMR (e.g., human OSMR) may bind to the extracellular domain or peptide derived from the extracellular domain of OSMR. An antibody that specifically binds to an OSMR antigen (e.g., human OSMR) may be cross-reactive with related antigens (e.g., cyno OSMR). In certain embodiments, an antibody that specifically binds to an OSMR antigen does not cross-react with other antigens. An antibody that specifically binds to an OSMR antigen can be identified, for example, by immunoassays, Biacore®, or other techniques known to those of skill in the art. An antibody binds specifically to an OSMR antigen when it binds to an OSMR antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme linked immunosorbent assays (ELISAs). Typically a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding antibody specificity. An antibody which “binds an antigen of interest” (e.g., a target antigen such as OSMR) is one that binds the antigen with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody to a “non-target” protein will be less than about 10% of the binding of theAttorney Docket Number: 67321-706.601 antibody to its particular target protein, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIA. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term “anti-OSMR antibody” or “an antibody that binds to OSMR” includes an antibody that is capable of binding OSMR with sufficient affinity such that the antibody is useful, for example, as an agent in targeting OSMR. In certain embodiments, an antibody that binds to OSMR has a dissociation constant (KD) of less than or equal to 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. In certain embodiments, an anti-OSMR antibody binds to an epitope of OSMR that is conserved among OSMR from different species (e.g., between human and cyno OSMR). In some embodiments, an anti-OSMR antibody binds to an epitope of OSMR that is the region that contacts with OSM when OSM is bound to type II OSM receptor (OSMR and GP130 complex). In other embodiments, an anti-OSMR antibody binds to an epitope of OSMR that is the region that contacts with IL31 when IL31 is bound to IL31 receptor complex (complex of OSMR and IL3 IRa).

[0101] The term “variable region,” “variable domain,” “V region,” or “V domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the aminoterminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH ” The variable region of the light chain may be referred to as “VL ” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” that are each about 9-12 amino acids long. The variable regions of heavy and light chains eachAttorney Docket Number: 67321-706.601 comprise four FRs, largely adopting a P sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases form part of, the P sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al. , Sequences of Proteins of Immunological Interest (5th ed. 1991)). The constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). The variable regions differ extensively in sequence between different antibodies. In specific embodiments, the variable region is a human variable region.

[0102] An “intact” antibody is one comprising an antigen-binding site as well as a CL and at least heavy chain constant regions, CHI, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0103] “Antibody fragments” comprise a portion of an intact antibody, such as the antigenbinding or variable region of the intact antibody. Examples of antibody fragments include, without limitation, Fab, Fab’, F(ab’)2, and Fv fragments; diabodies and di-diabodies (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. 90:6444-48; Lu et al., 2005, J. Biol. Chem. 280: 19665-72; Hudson et al., 2003, Nat. Med. 9: 129-34; WO 93 / 11161; and U.S. Pat. Nos. 5,837,242 and 6,492,123); single-chain antibody molecules (see, e.g., U.S. Pat. Nos. 4,946,778; 5,260,203; 5,482,858; and 5,476,786); dual variable domain antibodies (see, e.g., U.S. Pat. No. 7,612,181); single variable domain antibodies (sdAbs) (see, e.g., Woolven et al., 1999, Immunogenetics 50: 98-101; and Streltsov et al., 2004, Proc Natl Acad Sci USA. 101 : 12444-49); and multispecific antibodies formed from antibody fragments.

[0104] A “functional fragment,” “binding fragment,” or “antigen-binding fragment” of a therapeutic antibody refer to an antibody fragments that will exhibit at least one if not some or all of the biological functions attributed to the intact antibody, the function comprising at least binding to the target antigen (e.g., an OSMR binding fragment or fragment that binds to OSMR).

[0105] The term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy -terminal portionAttorney Docket Number: 67321-706.601 includes a constant region. The constant region can be one of five distinct types, (e.g., isotypes) referred to as (a), delta (6), epsilon (a), gamma (y), and mu (p), based on the amino acid sequence of the heavy chain constant region. The distinct heavy chains differ in size: a, 8, and y contain approximately 450 amino acids, while p and a contain approximately 550 amino acids. When combined with a light chain, these distinct types of heavy chains give rise to five well known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, respectively, including four subclasses of IgG, namely IgGl, IgG2, IgG3, and IgG4. A heavy chain can be a human heavy chain.

[0106] The term “light chain” when used in reference to an antibody refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy -terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, referred to as kappa (K) or lambda (1) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. A light chain can be a human light chain.

[0107] The term “host” as used herein refers to an animal, such as a mammal (e.g., a human).

[0108] The term “host cell” as used herein refers to a particular subject cell that may be transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.

[0109] “Humanized” forms of nonhuman (e.g., murine) antibodies are chimeric antibodies that include human immunoglobulins (e.g., recipient antibody) in which the native CDR residues are replaced by residues from the corresponding CDR of a nonhuman species (e.g., donor antibody) such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, one or more FR region residues of the human immunoglobulin are replaced by corresponding nonhuman residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. A humanized antibody heavy or light chain can comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a nonhuman immunoglobulin and all or substantially all of the FRs are those of a humanAttorney Docket Number: 67321-706.601 immunoglobulin sequence. In certain embodiments, the humanized antibody will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, Jones et al., 1986, Nature 321 :522-25; Riechmann et al., 1988, Nature 332:323-29; Presta, 1992, Curr. Op. Struct. Biol. 2:593-96; Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; U.S. Pat. Nos: 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.

[0110] A “human antibody” is one that possesses an amino acid sequence which corresponds to that of an antibody produced by a human and / or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol. 227:381; Marks et al., 1991, J. Mol. Biol. 222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1 : 755-68). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985); Boerner et al., 1991, J. Immunol. 147(l):86-95; and van Dijk and van de Winkel, 2001, Curr. Opin. Pharmacol. 5: 368-74. Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., mice (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561 -66; Bruggemann and Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58; and U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al., 2006, Proc. Natl. Acad. Sci. USA 103:3557-62 regarding human antibodies generated via a human B-cell hybridoma technology.

[0111] A “complementarity determining region” or “CDR” refers to one of three hypervariable regions (Hl, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH P-sheet framework, or one of three hypervariable regions (LI, L2 or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. The three CDRs in the VH can be referred to as CDR-H1 or VH CDR1, CDR-H2 or VH CDR2, CDR-H3 or VH CDR3, respectively. The three CDRs in the VL can be referred to as CDR-L1 or VL CDR1, CDR-L2 or VL CDR2, CDR-L3 or VL CDR3, respectively. CDR regions are well known to those skilled in the art and have beenAttorney Docket Number: 67321-706.601 defined by, for example, Kabat as the regions of most hypervariability within the antibody variable (V) domains (Kabat et al., 1997, J. Biol. Chem. 252:6609-16; Kabat, 1978, Adv. Prot. Chem. 32: 1-75). CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved P-sheet framework, and thus are able to adapt different conformations (Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17). Both terminologies are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (Al-Lazikani etal., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra . Such nomenclature is similarly well known to those skilled in the art.

[0112] The term “hypervariable region,” “HVR,” or “HV,” when used herein refers to the regions of an antibody variable region that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six hypervariable regions, three in the VH (Hl, H2, H3) and three in the VL (LI, L2, L3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., supra). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35 A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Diibel eds., 2d ed. 2010)). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these hypervariable regions or CDRs are noted below.

[0113] Recently, a universal numbering system has been developed and widely adopted, ImMunoGeneTics (IMGT) Information System® (Lafranc et al., 2003, Dev. Comp. Immunol. 27(1): 55-77). IMGT is an integrated information system specializing in immunoglobulinsAttorney Docket Number: 67321-706.601(IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHo) has been developed by Honegger and Pluckthun, 2001, J. Mol. Biol. 309: 657-70. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra, Chothia and Lesk, supra, Martin, supra, Lefranc et al., supra). The various numbering schemes and the CDR boundaries according to each numbering schemes are summarized below in Table 6.Table 6: CDR boundaries according to various numbering schemes

[0114] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 or 26-35A (Hl), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in the VH. As used herein, the terms “HVR” and “CDR” are used interchangeably.

[0115] Accordingly, the term “variable region residue numbering as in Kabat” or “amino acid position numbering as in Kabat”, and variations thereof, refer to the numbering systemAttorney Docket Number: 67321-706.601 used for heavy chain variable regions or light chain variable regions of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, an FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 and three inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody. Other numbering systems have been described, for example, by AbM, Chothia, Contact, IMGT, and AHo.

[0116] The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The term refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site. The constant region may contain the CHI, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0117] The term “IgG4-IgGl heavy chain constant region chimera” refers to a heavy chain constant region with an amino acid sequence that have parts from IgG4 and parts from IgGl . A heavy chain constant region generally have 4 domains: a CHI domain, a hinge region connecting CHI and CH2 domain, CH2 domain, and a CH3 domain. A IgG4-IgGl heavy chain constant region chimera can thus have 1, 2, or 3 domains selected from CHI, hinge, CH2, and CH3 of the heavy chain constant region from IgG4 and the remaining domains from IgGl . In one embodiment, a IgG4-IgGl heavy chain constant region chimera can comprise the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgGl. In another embodiment, a IgG4-IgGl heavy chain constant region chimera can comprise the CHI domain of human IgG4, the hinge of human IgG4, the CH2 domain of human IgGl, and the CH3 domain of human IgGl.Attorney Docket Number: 67321-706.601In a further embodiment, a IgG4-IgGl heavy chain constant region chimera can comprise the CHI domain of human IgG4, the hinge of human IgGl, the CH2 domain of human IgGl, and the CH3 domain of human IgGl. In yet another embodiment, a IgG4-IgGl heavy chain constant region chimera can comprise the CHI domain of human IgGl, the hinge of human IgGl, the CH2 domain of human IgGl, and the CH3 domain of human IgG4. In one embodiment, a IgG4-IgGl heavy chain constant region chimera can comprise the CHI domain of human IgGl, the hinge of human IgGl, the CH2 domain of human IgG4, and the CH3 domain of human IgG4. In another embodiment, a IgG4-IgGl heavy chain constant region chimera can comprise the CHI domain of human IgGl, the hinge of human IgG4, the CH2 domain of human IgG4, and the CH3 domain of human IgG4.

[0118] The term “framework” or “FR” refers to those variable region residues flanking the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues.

[0119] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.

[0120] Antibody “effector functions” refer to those biological activities attributable to the Fc region (e.g., a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: Clq binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); and / or antibody -dependent cellular phagocytosis (ADCP).Attorney Docket Number: 67321-706.601

[0121] “Effector function mutations” refer to mutations in the Fc region that modulates effector functions of Fc. In some embodiments, the effector function mutations reduce or eliminate Clq binding. In some embodiments, the effector function mutations reduce or eliminate CDC. In some embodiments, the effector function mutations reduce or eliminate Fc receptor binding. In some embodiments, the effector function mutations reduce or eliminate ADCC. In some embodiments, the effector function mutations reduce or eliminate ADCP. In some embodiments, the effector function mutations reduce or eliminate any or any combination of Clq binding, CDC, Fc receptor binding, ADCC, and ADCP. Examples of effector function mutations are listed in Table 5. As further described in the legend to Table 5, the effector function mutations can be combined as a set of effector function mutations that work together to provide the desired modulation of effector functions. Such set of effector function mutations can comprise 1, 2, 3, 4, 5, 6, 7 or more mutations, for example, as specified in the 2ndcolumn of each row of Table 5 that is indicated as effector function mutations in the 1stcolumn of the same row.

[0122] The term “half-life extension mutation” or “half-life extension mutations” refer to mutations in the Fc region that extend the half-life of the protein containing such Fc in human as compared to the Fc-containing protein without such mutations. Such half-life extension mutations often increase the binding of Fc to Fc receptor at acidic pH (e.g. pH 6.0), e.g. by fold increase of 2 to 80 folds as measured by KD, SO that the Fc remains bound to the Fc receptor, and recycles back on to the cell membrane and out of the endosomal degradation pathways. Examples of half-life extension mutations are listed in Table 5. As further described in the legend to Table 5, the half-life extension mutations can be combined as a set of half-life extension mutations that work together to provide the desired extension of halflife. Such set of half-life extension mutations can comprise 1, 2, 3, 4, 5, 6, 7 or more mutations, for example, as specified in the 2ndcolumn of each row of Table 5 that is indicated as half-life extension mutations in the 1stcolumn of the same row.

[0123] As used herein, treating or treatment of includes and / or refers to ameliorating the disease or disorder or symptoms thereof (e.g., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In certain embodiments, treating or treatment also includes and / or refers to alleviating or ameliorating at least one physical and / or biological parameters including those which may not be discernible by the patient. In certain embodiments, treating or treatment includes and / or refers to modulating a disease, disorder, or biological process either physically, (e.g., stabilizationAttorney Docket Number: 67321-706.601 of a discernible symptom), physiologically, (e.g., stabilization of a physical and / or biological parameter), or both. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying the onset or development or progression of the disease or disorder. In certain embodiments, treating or treatment includes and / or refers to preventing or delaying or inhibiting the deterioration of (i) a healthy physiological state or (ii) a baseline physiological state e.g., the progression of a disease or disorder).

[0124] As used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of’ and / or “consisting of,” unless context clearly connotes otherwise. Similarly, as used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of’ and / or “consists of,” unless context clearly connotes otherwise.

[0125] As used herein, the term “about,” in the context of a given value or range, includes and / or refers to a value or range that is within 10% of the given value or range.

[0126] As used herein, the term “and / or” as used in a phrase with a list of members is intended to include all members individually and all combination of full or partial list of members. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A (alone), (ii) B (alone), (iii) A or B, and (iv) A and B, just as if each were set out individually herein. Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).5. EXAMPLESExample 1. OSMR blocking assay

[0127] The ability of OSMR antibodies to block signaling through OSMR is determined using assays with human oncostatin M (OSM) or human interleukin 31 (IL-31) as the ligand. In combination, the assays show that an antibody herein comprising the CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 8 and CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 9 can inhibit signaling of OSMR triggered through the binding of OSM or IL-31.

[0128] OSM assay: Stimulation of primary lung fibroblast cells with OSM induces phosphorylation of STATS and subsequent translocation to the nucleus. Cells are seeded in multi-well plates and allowed to adhere overnight. Cells were pre-treated with antibody for 20 minutes. The cells are then stimulated with 80 pM of human OSM for 30 minutes, fixed with formaldehyde, washed for 3 times, and permeabilized with a 0.5% Triton solution. Cells are stained with an anti-phosphoSTAT3 antibody for an hour, washed and stained with anAttorney Docket Number: 67321-706.601AlexaFluor conjugated antibody. Plates are read for a nuclear intensity value or a cytoplasmic intensity value. Results are reported as the difference between these two values and normalized to control data containing maximally stimulated cells and media-treated cells. The data indicates that an antibody having the CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 8 and CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 9 is able to block the signaling of OSM through OSMR.

[0129] IL-31 assay: Stable BaF3 cell lines overexpressing IL-31R (complex of OSMR and IL3 IRa) are plated in multi-well plates. In the absence of murine IL-3, this cell line is only able to proliferate in response to human IL-31 and, therefore, could be used to specifically evaluate the blocking ability of anti-OSMR antibodies. IL31 alone or the antibody and human IL31 is added to the wells, and the plates incubated for 72 hours. Following incubation, Alamar Blue is added to each well to quantify the viable cells at the end of the incubation, and plates are read on a plate reader (570-600 nm) at various timepoints postaddition of Alamar Blue. The data indicates that an antibody having the CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 8 and CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 9is able to inhibit proliferative signal of IL-31 through OSMR in a stable cell line overexpressing IL-31R (complex of OSMR and IL3 IRa).Example 2. Characterization of anti-OSMR antibodies

[0130] ELISA experiments are performed under various formats (Capture ELISA for avidity -less format; Sandwich ELISA for solution phase format; and Direct ELISA for solid state avidity format) with an OSMR antibody having a light chain sequence of SEQ ID NO: 10 and a heavy chain sequence of SEQ ID NO: 11.

[0131] The EC50 calculated for the OSMR antibody having a light chain sequence of SEQ ID NO: 10 and a heavy chain sequence of SEQ ID NO: 11 using the capture format is 1.61 nM, the sandwich format is 0.064 nM, and the direct format is 0.0558 nM.

[0132] Binding studies were performed using surface plasmon resonance (Biacore). The antibody having a light chain variable region sequence of SEQ ID NO: 8, a heavy chain variable region sequence of SEQ ID NO: 9, and a IgG2 constant region was immobilized on a CM4 chip (GE Lifesciences) as per manufacturer's protocols. Soluble OSMR was used as the analyte. The KD is calculated as 0.289 nM.

[0133] The stability of the antibody having a light chain variable region sequence of SEQ ID NO: 8, a heavy chain variable region sequence of SEQ ID NO: 9, and a IgG4-IgGl heavy chain constant region chimera (the CHI domain of human IgG4, the hinge of human IgG4,Attorney Docket Number: 67321-706.601 the CH2 domain of human IgG4, and the CH3 domain of human IgGl with S228P and N297Q mutations) is determined by assessing the thermal unfolding of the antibody. The Tm is 76.69 °C with a standard error of 0.018 °C.Example 3. Modification of OSMR antibody

[0134] Modified versions of the OSMR antibody having the CDR-L1, CDR-L2, and CDR- L3 of SEQ ID NO: 8 and CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 9 are generated. Examples of such modified OSMR antibodies comprise the CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NO: 8 and CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NO: 9, the light chain constant region of SEQ ID NO: 12 or 13, and the heavy chain constant region of (i) any one of SEQ ID NOS: 15-30 and 32-39, (ii) an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation, wherein the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5, (iii) an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation, wherein the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5, or (iv) an amino acid sequence of a IgG4-IgGl heavy chain constant region chimera having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation, wherein the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5 and the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5. Such exemplary modified OSMR antibodies can have the light chain variable region sequence of SEQ ID NO: 8, a heavy chain variable region sequence of SEQ ID NO: 9. Binding assays such as ELISA or SPR (e.g., Biacore) can be performed to determine the OSMR binding affinity of such modified anti-OSMR antibody as described in Example 2. The potency ofAttorney Docket Number: 67321-706.601 such modified OSMR antibody for blocking IL31 and OSM signaling can be determined as described in Example 1. The stability of such anti-OSMR antibody or antigen-binding fragment can be determined by assessing the thermal unfolding of antibody as described in Example 2. High melting temperature can correlate directly to increased stability. Such modified anti-OSMR antibody of this Example can have comparable binding affinity, IL-31 blocking potency, OSM-blocking potency, and / or melting temperature as described in Examples 1 and 2.

[0135] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the instant disclosure. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the embodiments disclosed herein, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

Attorney Docket Number: 67321-706.601CLAIMSWhat is claimed is:

1. An antibody or antigen-binding fragment thereof that binds to OSMR (anti-OSMR or antigen-binding fragment), comprising:(i) a heavy chain variable domain comprising: a heavy chain complementarity determining region 1 (CDR-H1) comprising CDR-H1 of heavy chain variable domain set forth in SEQ ID NO: 9; a heavy chain complementarity determining region 2 (CDR-H2) comprising CDR-H2 of heavy chain variable domain set forth in SEQ ID NO: 9; and a heavy chain complementarity determining region 3 (CDR-H3) comprising CDR-H3 of heavy chain variable domain set forth in SEQ ID NO: 9;(ii) a light chain variable domain comprising: a light chain complementarity determining region 1 (CDR-L1) comprising CDR-L1 of light chain variable domain set forth in SEQ ID NO: 8; a light chain complementarity determining region 2 (CDR-L2) comprising CDR-L2 of light chain variable domain set forth in SEQ ID NO: 8; and a light chain complementarity determining region 3 (CDR-L3) comprising CDR-L3 of light chain variable domain set forth in SEQ ID NO: 8; and(iii) a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-30 and 32- 39; an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; or an amino acid sequence (a) comprising a IgG4-IgGl heavy chain constant region chimera, and (b) having at least one half-life extension mutation , at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation;Attorney Docket Number: 67321-706.601 wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84.

2. The anti-OSMR antibody or antigen-binding fragment of claim 1, wherein the CDR-H1 comprises SEQ ID NO: 4, SEQ ID NO: 44, SEQ ID NO: 54, SEQ ID NO: 64, or SEQ ID NO: 74; the CDR-H2 comprises SEQ ID NO: 5; SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 75; or SEQ ID NO: 7; the CDR-H3 comprises SEQ ID NO: 6, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, or SEQ ID NO: 76; the CDR-L1 comprises SEQ ID NO: 1, SEQ ID NO: 41, SEQ ID NO: 51, SEQ ID NO: 61, or SEQ ID NO: 71; the CDR-L2 comprises SEQ ID NO: 2, SEQ ID NO: 42, SEQ ID NO: 52, SEQ ID NO: 62, or SEQ ID NO: 72; and the CDR-L3 comprises SEQ ID NO: 3, SEQ ID NO: 43, SEQ ID NO: 53, SEQ ID NO: 63, or SEQ ID NO: 73.

3. The antibody or antibody fragment of claim 2, wherein the CDR-H1 comprises: SEQ ID NO: 4, the CDR-H2 comprises SEQ ID NO: 5, the CDR-H3 comprises SEQ ID NO: 6, the CDR-L1 comprises: SEQ ID NO: 1, the CDR-L2 comprises SEQ ID NO: 2, and the CDR-L3 comprises SEQ ID NO: 3.

4. The anti-OSMR antibody or antigen-binding fragment of claim 2, wherein the CDR-H1 comprises: SEQ ID NO: 4, the CDR-H2 comprises SEQ ID NO: 7, the CDR-H3 comprises SEQ ID NO: 6, the CDR-L1 comprises: SEQ ID NO: 1, the CDR-L2 comprises SEQ ID NO: 2, and the CDR-L3 comprises SEQ ID NO: 3.

5. The anti-OSMR antibody or antigen-binding fragment of claim 2, wherein the CDR-H1 comprises: SEQ ID NO: 44, the CDR-H2 comprises SEQ ID NO: 45, the CDR-H3 comprises SEQ ID NO: 46, the CDR-L1 comprises: SEQ ID NO: 41, the CDR-L2 comprises SEQ ID NO: 42, and the CDR-L3 comprises SEQ ID NO: 43.

6. The anti-OSMR antibody or antigen-binding fragment of claim 2, wherein the CDR-H1 comprises: SEQ ID NO: 54, the CDR-H2 comprises SEQ ID NO: 55, the CDR-H3 comprises SEQ ID NO: 56, the CDR-L1 comprises: SEQ ID NO: 51, the CDR-L2 comprises SEQ ID NO: 52, and the CDR-L3 comprises SEQ ID NO: 53.Attorney Docket Number: 67321-706.6017. The anti-OSMR antibody or antigen-binding fragment of claim 2, wherein the CDR-H1 comprises: SEQ ID NO: 64, the CDR-H2 comprises SEQ ID NO: 65, the CDR-H3 comprises SEQ ID NO: 66, the CDR-L1 comprises: SEQ ID NO: 61, the CDR-L2 comprises SEQ ID NO: 62, and the CDR-L3 comprises SEQ ID NO: 63.

8. The anti-OSMR antibody or antigen-binding fragment of claim 2, wherein the CDR-H1 comprises: SEQ ID NO: 74, the CDR-H2 comprises SEQ ID NO: 75, the CDR-H3 comprises SEQ ID NO: 76, the CDR-L1 comprises: SEQ ID NO: 71, the CDR-L2 comprises SEQ ID NO: 72, and the CDR-L3 comprises SEQ ID NO: 73.

9. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1-8, wherein the heavy chain variable domain comprises an amino acid sequence set forth in SEQ ID NO: 9.

10. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1-9, wherein the light chain variable domain comprises an amino acid sequence set forth in SEQ ID NO: 8.

11. An anti-OSMR antibody or antigen-binding fragment that binds to OSMR, comprising(i) a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 9;(ii) a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 8; and(iii) a heavy chain constant region comprising: an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 15-30 and 32-39; an amino acid sequence of human IgGl constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; an amino acid sequence of human IgG4 constant region having at least one half-life extension mutation, at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; or an amino acid sequence (a) comprising an IgG4-IgGl heavy chain constantAttorney Docket Number: 67321-706.601 region chimera, and (b) having at least one half-life extension mutation , at least one effector function mutation, or at least one half-life extension mutation and at least one effector function mutation; wherein the heavy chain constant region does not comprise an amino acid sequence of SEQ ID Nos: 14, 31, or 84.

12. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1 to 11, wherein the at least one half-life extension mutation comprises any set of half-life extension mutations selected from the sets of half-life extension mutations listed in Table 5.

13. The anti-OSMR antibody or antigen-binding fragment of claim 12, wherein the at least one half-life extension mutation comprises YTE (M252Y, S254T, and T256E by EU numbering) or LS (M324L and N434S by EU numbering).

14. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1 to 13, wherein the at least one effector function mutation comprises any set of effector function mutations selected from the sets of effector function mutations listed in Table 5.

15. The anti-OSMR antibody or antigen-binding fragment of claim 14, wherein the at least one effector function mutation comprises LALAGA (L234A, L235A and G237A by EU numbering), LALAPA (L234A, L235A and P329A by EU numbering), LALAPG (L234A, L235A and P329G by EU numbering), LALAKA (L234A, L235A and K322A by EU numbering), or STR (F234S, L235T, and G236R by EU numbering).

16. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 15.

17. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 16.

18. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 17.

19. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 18.Attorney Docket Number: 67321-706.60120. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 19.

21. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 20.

22. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 21.

23. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 22.

24. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 23.

25. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 24.

26. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 25.

27. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 26.

28. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 27.

29. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 28.

30. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 29.

31. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 30.

32. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 32.Attorney Docket Number: 67321-706.60133. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 33.

34. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 34.

35. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 35.

36. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 36.

37. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 37.

38. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 38.

39. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 11, wherein the heavy chain constant region comprises SEQ ID NO: 39.

40. The anti-OSMR antibody or antigen-binding fragment of any one of claims 1- 39, further comprising a light chain constant region comprising an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 12 or SEQ ID NO: 13.

41. A polynucleotide comprising nucleotide sequences encoding a heavy chain (HC), a light chain (LC), or both a HC and a LC of the antibody of any one of claims 1-40.

42. The polynucleotide of claim 41, wherein the polynucleotide is operably linked to a promoter.

43. A vector comprising the polynucleotide of any one of claims 41-42.

44. A cell comprising the polynucleotide of any one of claims 41-42.

45. A cell comprising the vector of claim 44.Attorney Docket Number: 67321-706.60146. A cell comprising (i) a polynucleotide comprising a nucleotide sequence encoding a HC and a polynucleotide comprising a nucleotide sequence encoding a LC, wherein the HC and LC are a matching pair from the antibody of any one of claims 1-40; or (ii) a vector comprising a polynucleotide that comprises a nucleotide sequence encoding a HC and a vector comprising a polynucleotide that comprises a nucleotide sequence encoding a LC, wherein the HC and LC are a matching pair from the antibody of any one of claims 1- 40.

47. An isolated cell producing the antibody or antigen-binding fragment thereof of any one of claims 1-40.

48. A kit comprising the antibody or anti gen -binding fragment thereof of any one of claims 1-40.

49. A method of making an antibody or antigen-binding fragment thereof which specifically binds to OSMR, comprising culturing the cell of any one of claim 44-46 to express the antibody or antigen-binding fragment thereof.

50. A method of making an antibody or antigen-binding fragment thereof which specifically binds to OSMR, comprising expressing the polynucleotide of any one of claims 41-42.

51. A pharmaceutical composition comprising: the antibody and antibody fragment of any one of claims 1-40; and a pharmaceutically acceptable carrier.

52. A method of treating a disease or condition in a subject, the method comprising: administering to the subject the anti-OSMR antibody or antigen-binding fragment of any one of claims 1-40, or the pharmaceutical composition of claim 41.

53. The method of claim 42, wherein the disease or condition is inflammatory bowel disease (IBD).

54. The method of claim 42, wherein the disease or condition is Crohn’s disease (CD).

55. The method of claim 42, wherein the disease or condition is ulcerative colitis (UC).

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