Anti-TL1A antibodies and methods of use thereof

Abstract

The present invention discloses an isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), comprising CDR-H1, CDR-H2, and CDR-H3 sequences of a TL1A-VH sequence selected from the group consisting of: SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, SEQ And a CDR-L1 sequence, a CDR-L2 sequence and a CDR-L3 sequence of SEQ ID NO: 18.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 364,559, filed on May 11, 2022, U.S. Provisional Application No. 63 / 371,697, filed on August 17, 2022, and U.S. Provisional Application No. 63 / 495,762, filed on April 12, 2023, the entire contents of which are incorporated herein by reference.

[0003] field

[0004] The present invention relates to antibodies that specifically bind to TL1A. The present invention further relates to antibodies that bind to TL1A and p40. The present invention further relates to monovalent antibodies that specifically bind to TL1A. The present invention also relates to related molecules (e.g., nucleic acids encoding such antibodies), compositions and related methods (e.g., methods for producing and purifying such antibodies), and their use in diagnosis and treatment.

[0005] Incorporation by Reference into the Sequence Listing

[0006] A sequence listing named 42065_Sequence_Listing.xml in XML format was created on May 4, 2023, is 344KB in size, and was submitted to the United States Patent and Trademark Office through Patent Center, which is incorporated herein by reference.

[0007] background

[0008] Inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis (UC), is a chronic inflammatory disorder that affects approximately 1.6 million people in the United States and approximately 2.5-3 million people in Europe. To induce remission in patients with moderately to severely active UC, treatment recommendations include appropriate doses of oral corticosteroids, biologic therapies such as the tumor necrosis factor inhibitors (TNFi) infliximab (monotherapy or in combination with azathioprine), adalimumab, ustekinumab, golimumab; the integrin receptor antagonist vedolizumab); and the oral small molecule Janus kinase inhibitor tofacitinib. 17 However, non-response and loss of response to treatment have been observed in UC, and thus, the development of novel treatments for UC and IBD remains an unmet clinical need. 18 .

[0009] A range of mucosal immune system components (including epithelial cells, innate and adaptive immune cells, cytokines, and chemokines) contribute to the pathogenesis of IBD 19 One of the immune components involved in the pathogenesis of IBD is TNF-like ligand 1A (TL1A, or tissue necrosis factor superfamily member 15 (TNFSF15)).

[0010] Tumor necrosis factor (TNF)-like ligand 1A (TL1A) is a member of the TNF family of cytokines, also known as TNFSF15. TL1A is the only known ligand for its receptor, death receptor 3 (DR3), also known as TNFRSF25. TL1A expression on antigen presenting cells (monocytes, macrophages, dendritic cells) and DR3 expression on effector cells (T cells, NK and NKT cells) are highly dependent on pro-inflammatory conditions. 20-22 In vivo and in vitro evidence supports a costimulatory role for the TL1A / DR3 pathway for T cell and effector cell function, inflammatory cell expansion, and cytokine secretion. In addition, this pathway has been implicated in the regulation of pathogenic Th1, Th2, and Th17 T helper cell responses, as well as NK and NKT cell responses in immune-mediated diseases. 21,23-26 .

[0011] Studies in mice deficient in DR3 or TL1A genes or treated with anti-TL1A antibodies have demonstrated a role for this pathway in a variety of autoimmune disease models, such as IBD, asthma, multiple sclerosis, and arthritis. 25,27-28 .

[0012] Furthermore, a large body of literature from studies involving nonclinical species and humans implicates TL1A in the pathophysiology of inflammatory bowel diseases (IBD), most notably ulcerative colitis (UC) and Crohn's disease (CD). Namely, multiple genome-wide association studies have associated several polymorphisms of the TL1A gene with UC and CD in patient populations of Japanese, European, and Asian origin. 29-33 .

[0013] Additionally, human inflamed IBD tissues show high levels of TL1A and DR3 expression, and several independent laboratories have demonstrated that antibody blockade of TL1A prevents or attenuates established intestinal inflammation in multiple murine IBD models. 22,24,26,34-39 .

[0014] Although the exact etiology of IBD, such as CD and UC, remains unclear, inhibition of proinflammatory cytokines and adhesion molecules has been shown to provide some therapeutic benefit. However, despite current medical therapies, most CD patients may eventually require surgery, and repeated resections over time can lead to short bowel syndrome, ultimately resulting in patients being burdened with long-term parenteral nutrition and its associated complications. Therefore, there is a long-standing unmet need for more robust therapies for CD patients. In addition, there is a long-standing unmet need for novel therapies for treating or ameliorating IBD, including UC and CD, as well as for treating other TL1A-mediated diseases and conditions. The present invention meets these needs.

[0015] IL-12 and IL-23 are involved in type 1 and type 3 (Th17) responses, respectively (77). IL-12 drives T helper 1 (Th1) cell differentiation and interferon-γ (IFN-γ) production, while IL-23 promotes the maintenance of Th17 cells that produce IL-17 and other type 3 cytokines. Type 1 and type 3 responses have been implicated in a range of human inflammatory and autoimmune diseases. A causal role for IL-12p40-containing cytokines (IL-12p40 is hereinafter referred to as p40) has been established through multiple drug approvals (75). p40 neutralizers (ustekinumab; Janssen) neutralizes both IL-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. IL-23 selective anti-IL-23p19 blocker (guselkumab; Janssen), (risankizumab; Boehringer Ingelheim / AbbVie) and (tildrakizumab; Sun Pharmaceutical) is approved for a range of psoriatic conditions.

[0016] Despite the utility of current treatments, there remains an unmet need for safe and effective therapeutics that address a broad range of pathogenic mechanisms for a variety of diseases characterized by proinflammatory responses. Summary of the invention

[0017] Provided herein are antibodies (including antigen-binding fragments thereof) that specifically bind to TL1A, including, for example, but not limited to, bispecific TL1A-p40 antibodies, monovalent TL1A antibodies thereof, other related antibodies, related nucleic acids; uses thereof and related methods. The disclosure also provides methods for making, preparing and generating the antibodies disclosed herein, including antibodies that bind to one or both of TL1A and p40. The antibodies of the disclosure are useful for diagnosing, preventing or treating one or more of disorders or conditions mediated by or associated with one or more of TL1A and TL1A / p40 activity, including but not limited to, for the manufacture of medicaments for treating diseases, disorders or conditions mediated by TL1A. In some embodiments, the disease, disorder, or condition is at least one selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease, disease; GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonreactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjogren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urointestinal disorders, uveitis, and vasculitis.

[0018] The disclosure further encompasses the expression of antibodies, and the preparation and manufacture of compositions comprising the antibodies of the disclosure, such as medicaments using the antibodies.

[0019] Also provided are polynucleotides encoding antibodies that specifically bind to TL1A, as well as bispecific TL1A-p40 antibodies, monovalent TL1A antibodies thereof, and other related antibodies. Also provided are polynucleotides encoding antibody heavy chains or light chains or both. Host cells expressing antibodies are provided. Methods of treatment using the antibodies are provided. Such methods include, but are not limited to, one or more of the methods for treating or preventing diseases associated with or mediated by TL1A, and any one or both of TL1A and p40 expression, or one or more diseases selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, Eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary bowel disorders, uveitis, and vasculitis.

[0020] The present invention can be more easily understood by reference to the following detailed description of embodiments of the present invention and the examples included herein. It should be understood that the present invention is not limited to a specific manufacturing method, which of course can vary. It should also be understood that the terms used herein are only for the purpose of describing a specific embodiment and are not intended to be restrictive. Those skilled in the art will recognize that, or only use routine experiments to determine many equivalents of the specific embodiments of the present invention described herein. Such equivalents are intended to be covered by the following embodiment (E).

[0021] E1. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), comprising a CDR-H1, CDR-H2, and CDR-H3 sequence of a TL1A-VH sequence selected from the group consisting of: SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:57, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:110, SEQ ID NO:120; and SEQ ID NO:130; The CDR-L1, CDR-L2 and CDR-L3 sequences of NO:18.

[0022] E2. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), comprising CDR-H1, CDR-H2 and CDR-H3 sequences according to SEQ ID NO:42; and CDR-L1, CDR-L2 and CDR-L3 sequences according to SEQ ID NO:18.

[0023] E3. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), comprising a CDR-L1 sequence according to SEQ ID NO: 11; a CDR-L2 sequence according to SEQ ID NO: 12; and a CDR-L3 sequence according to SEQ ID NO: 13, and comprising a set of heavy chain CDRs selected from the following list:

[0024] (i) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0025] (ii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0026] (iii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:32;

[0027] (iv) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:35;

[0028] (v) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0029] (vi) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0030] (vii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0031] (viii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:35;

[0032] (ix) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0033] (x) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0034] (xi) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0035] (xii) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0036] (xiii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 31; a CDR-H3 sequence according to SEQ ID NO: 35;

[0037] (xiv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:38; a CDR-H3 sequence according to SEQ ID NO:35;

[0038] (xv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0039] (xvi) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0040] (xvii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 46; a CDR-H3 sequence according to SEQ ID NO: 35;

[0041] (xviii) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0042] (xix) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0043] (xx) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32;

[0044] (xxi) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 41; a CDR-H3 sequence according to SEQ ID NO: 35; or (xxii) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32.

[0045] E4. An isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), wherein the CDR-L1 sequence is according to SEQ ID NO:11, the CDR-L2 sequence is according to SEQ ID NO:12, and the CDR-L3 sequence is according to SEQ ID NO:13; and wherein the CDR-H1 sequence is according to SEQ ID NO:30, the CDR-H2 sequence is according to SEQ ID NO:41, and the CDR-H3 sequence is according to SEQ ID NO:32.

[0046] E5. The antibody of any one of E1 to E4, comprising a TL1A-VH framework sequence derived from a human germline VH sequence selected from the group consisting of IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02.

[0047] E6. The antibody of any one of E1 to E5, which comprises a TL1A-VH framework sequence derived from a human IGHV1-18*01 germline sequence.

[0048] E7. The antibody of any one of E1 to E6, which comprises a TL1A-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01.

[0049] E8. The antibody of any one of E1 to E7, which comprises a TL1A-VL framework sequence derived from a human germline IGKV1-39*01 sequence.

[0050] E9. An antibody as described in any one of E1 to E8, which comprises a TL1A-VL framework sequence and a TL1A-VH framework sequence, wherein one or both of the TL1A-VL framework sequence and the TL1A-VH framework sequence are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0051] E10. The antibody of any one of E1 to E9, comprising a TL1A-VL framework sequence and a TL1A-VH framework sequence, and wherein one or both of the TL1A-VL framework sequence or the TL1A-VH framework sequence are identical to the human germline sequence from which they are derived.

[0052] E11. An antibody as described in any one of E1 to E10, wherein the TL1A-VL comprises an amino acid sequence according to SEQ ID NO: 18, and wherein the TL1A-VH comprises an amino acid sequence according to a sequence selected from the group consisting of: SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:57, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:110 and SEQ ID NO:120.

[0053] E12. An antibody as described in any one of E1 to E1, which comprises a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:42, and comprises a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:18.

[0054] E13. The antibody of any one of E1 to E12, comprising the TL1A-VH sequence of SEQ ID NO:42 and the TL1A-VL sequence of SEQ ID NO:18.

[0055] E14. The antibody of any one of E1 to E13, which comprises a TL1A-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 228.

[0056] E15. The antibody of any one of E1 to E14, which comprises a TL1A-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 229.

[0057] E16. The antibody of any one of E1 to E15, which comprises a TL1A-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127347.

[0058] E17. The antibody of any one of E1 to E16, which comprises a TL1A-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127348.

[0059] E18. An antibody comprising a TL1A-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127347, and a TL1A-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127438.

[0060] E19. The antibody of E1 to E18, wherein in a competitive ELISA, the TL1A IC 50 Less than 20nM.

[0061] E20. The antibody of E1 to E19, wherein in a competitive ELISA, the TL1A IC 50 Less than 10nM.

[0062] E21. The antibody of E1 to E20, wherein in the TF-1 NFκB reporter cell bioassay, the TL1A IC 50 Less than 50nM.

[0063] E22. The antibody of E1 to E21, wherein in the TF-1 NFκB reporter cell bioassay, the TL1A IC 50 Less than 30nM.

[0064] E23. The antibody of E1 to E22, wherein in the whole blood IFNγ assay, the TL1A IC 50 Less than 1nM.

[0065] E24. The antibody of E1 to E23, wherein in the TF-1 NFκB reporter cell bioassay, the TL1A IC 50 Less than 30nM.

[0066] E25. The antibody of E1 to E24, further comprising a heavy chain constant domain (TL1A-CH1) and a light chain constant domain (TL1A-CL).

[0067] E26. The antibody of E25, wherein said TL1A-CH1 comprises a sequence selected from the group consisting of: SEQ ID NO:6, SEQ ID NO:195 and SEQ ID NO:199.

[0068] E27. The antibody of E25 to E26, wherein said TL1A-CH1 comprises the sequence according to SEQ ID NO:6.

[0069] E28. The antibody of E25 to E27, wherein the TL1A-CL comprises a sequence selected from the group consisting of: SEQ ID NO: 16 and SEQ ID NO: 201.

[0070] E29. The antibody of E25 to E28, wherein the TL1A-CL comprises the sequence according to SEQ ID NO:16.

[0071] E30. The antibody of E25 to E29, wherein the TL1A-CH1 is linked to the TL1A-VH, and the TL1A-CL is linked to the TL1A-VL, thereby forming a TL1A binding Fab domain (TL1A-Fab).

[0072] E31. The antibody of any one of E1 to E30, which comprises an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0073] E32. The antibody of E31, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0074] E33. The antibody of E32, wherein the Fc domain is the Fc domain of IgG1.

[0075] E34. The antibody of E31 to E34, wherein the first Fc chain comprises from N-terminus to C-terminus: a first hinge region, a first CH2 region and a first CH3 region, and the second Fc chain comprises from N-terminus to C-terminus: a second hinge region, a second CH2 region and a second CH3 region.

[0076] E35. The antibody of E33, which comprises at least a first TL1A-CH1 domain, wherein the N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CH1 domain.

[0077] E36. The antibody of E35 to E37, wherein the first CH2 region and the second CH2 region each comprise a sequence according to SEQ ID NO:8.

[0078] E37. An antibody as described in E35, wherein either or both of the first hinge regions comprise a sequence selected from the group consisting of: SEQ ID NO:7, SEQ ID NO:157, SEQ ID NO:179, SEQ ID NO:182, and SEQ ID NO:189, SEQ ID NO:191, SEQ ID NO:204, and SEQ ID NO:206.

[0079] E38. The antibody of E44, wherein the hinge region comprises the sequence according to SEQ ID NO:7.

[0080] E39. The antibody of E35 to E38, wherein the CH3 region on the first Fc chain and the CH3 region on the second Fc chain each comprise a sequence according to SEQ ID NO:9.

[0081] E40. An antibody as described in any one of E35 to E39, which comprises a light chain (TL1A-LC) comprising a sequence according to SEQ ID NO: 19, and a heavy chain (TL1A-HC) comprising a sequence according to the group consisting of SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:58, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:90, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:111 and SEQ ID NO:121.

[0082] E41. The antibody of any one of E35 to E40, which comprises a light chain (TL1A-LC) comprising the sequence according to SEQ ID NO: 19, and a heavy chain (TL1A-HC) comprising the sequence according to SEQ ID NO: 43.

[0083] E42. The antibody of any one of E34 to E41, which comprises two identical TL1A-Fab domains.

[0084] E43. The antibody of any one of E34 to E37, which comprises a single TL1A-Fab domain.

[0085] E44. The antibody of E43, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote binding of the first Fc chain to the second Fc chain.

[0086] E45. The antibody of E44, wherein the first Fc chain comprises a first CH3 region, and the second Fc chain comprises a second CH3 region, and the first CH3 region and the second CH3 region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0087] (i) SEQ ID NO:160 and SEQ ID NO:162;

[0088] (ii) SEQ ID NO:180 and SEQ ID NO:183;

[0089] (iii) SEQ ID NO: 155 and SEQ ID NO: 158; and

[0090] (iv) SEQ ID NO:185 and SEQ ID NO:SEQ ID NO:187.

[0091] E46. The antibody of E45, wherein the first CH3 region and the second CH3 region comprise SEQ ID NO:160 and SEQ ID NO:162.

[0092] E47. The antibody of E44 to E45, wherein the first hinge region and the second hinge region each contain one or more amino acid modifications that promote binding of the first hinge region to the second hinge region.

[0093] E48. The antibody of E47, wherein the first hinge region and the second hinge region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0094] (i) SEQ ID NO: 179 and SEQ ID NO: 182; and

[0095] (ii) SEQ ID NO:189 and SEQ ID NO:191.

[0096] E49. The antibody of any one of E1 to E48, characterized in that it has a score of less than 4 in affinity-capture self-interaction nanoparticle spectroscopy (AC SINS) analysis.

[0097] E50. The antibody of E43 to E49, wherein the TL1A-Fab domain is fused to the first Fc chain, and the second Fc chain is not fused to the Fab domain.

[0098] E51. An antibody as described in E43 to E50, comprising a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 161, SEQ ID NO: 164 and SEQ ID NO: 165, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0099] E52. An antibody as described in E43 to E51, comprising a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0100] E52. An antibody as described in E43 to E51, comprising a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 164, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0101] E54. An antibody as described in E43 to E51, comprising a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 165, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0102] E55. An antibody as described in E43 to E49, comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (TL1A-Fab) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (xTL1A-Fab) that contains a non-binding TL1A binding domain that does not specifically bind to a target, and wherein the first light chain and the second light chain are identical.

[0103] E56. The antibody of E55, wherein the second Fab domain comprises a non-binding TL1A heavy chain variable region (xTL1A-VH) and a non-binding TL1A light chain variable region (xTL1A-VL), wherein the CDR-L1 sequence is according to SEQ ID NO: 11, the CDR-L2 sequence is according to SEQ ID NO: 12, and the CDR-L3 sequence is according to SEQ ID NO: 13, and wherein (i) the CDR-H1 sequence is according to SEQ ID NO: 139; the CDR-H2 sequence is according to SEQ ID NO: 140; and the CDR-H3 sequence is according to SEQ ID NO: 133;

[0104] (ii) the CDR-H1 sequence is according to SEQ ID NO: 128; the CDR-H2 sequence is according to SEQ ID NO: 129; and the CDR-H3 sequence is according to SEQ ID NO: 130;

[0105] (iii) the CDR-H1 sequence is according to SEQ ID NO: 128; the CDR-H2 sequence is according to SEQ ID NO: 129; and the CDR-H3 sequence is according to SEQ ID NO: 133;

[0106] (iv) the CDR-H1 sequence is according to SEQ ID NO: 128; the CDR-H2 sequence is according to SEQ ID NO: 129; and the CDR-H3 sequence is according to SEQ ID NO: 136;

[0107] (v) CDR-H1 sequence is according to SEQ ID NO: 139; CDR-H2 sequence is according to SEQ ID NO: 140; CDR-H3 sequence is according to SEQ ID NO: 130;

[0108] (vi) CDR-H1 sequence is according to SEQ ID NO: 139; CDR-H2 sequence is according to SEQ ID NO: 140; CDR-H3 sequence is according to SEQ ID NO: 136;

[0109] (vii) CDR-H1 sequence is according to SEQ ID NO: 147; CDR-H2 sequence is according to SEQ ID NO: 148; CDR-H3 sequence is according to SEQ ID NO: 130;

[0110] (viii) the CDR-H1 sequence is according to SEQ ID NO:147; the CDR-H2 sequence is according to SEQ ID NO:148; and the CDR-H3 sequence is according to SEQ ID NO:133; or (ix) the CDR-H1 sequence is according to SEQ ID NO:147; the CDR-H2 sequence is according to SEQ ID NO:148; and the CDR-H3 sequence is according to SEQ ID NO:136.

[0111] E57. An antibody as described in E55 to E56, wherein the second Fab domain comprises a heavy chain variable region (xTL1A-VH) and a light chain variable region (xTL1A-VL), wherein the CDR-L1 sequence is according to SEQ ID NO: 11, the CDR-L2 sequence is according to SEQ ID NO: 12, and the CDR-L3 sequence is according to SEQ ID NO: 13; and wherein the CDR-H1 sequence is according to SEQ ID NO: 139, the CDR-H2 sequence is according to SEQ ID NO: 140, and the CDR-H3 sequence is according to SEQ ID NO: 133.

[0112] E58. An antibody as described in any one of E55 to E56, wherein the second Fab domain comprises a light chain variable region amino acid sequence according to SEQ ID NO: 18, and wherein the second Fab domain comprises a heavy chain variable region amino acid sequence according to a sequence selected from the group consisting of: SEQ ID NO: 143, SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 149, SEQ ID NO: 151 and SEQ ID NO: 153.

[0113] E59. The antibody of E58, wherein the second Fab domain comprises the light chain variable region amino acid sequence according to SEQ ID NO: 18, and wherein the second Fab domain comprises the heavy chain variable region amino acid sequence according to SEQ ID NO: 143.

[0114] E60. An antibody as described in E55 to E59, comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (TL1A-Fab) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (xTL1A-Fab) that contains a non-binding TL1A binding domain that does not specifically bind to a target, wherein the first antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 166.

[0115] E61. An antibody as described in E55 to E60, comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (TL1A-Fab) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (xTL1A-Fab) that contains a non-binding TL1A binding domain that does not specifically bind to a target, wherein the first antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 166.

[0116] E62. The antibody of any one of E1 to E61, wherein the terminal half-life of the antibody in cynomolgus monkeys is less than 7 days.

[0117] E63. The antibody of any one of E1 to E63, characterized in that the score of high molecular weight species is less than 2% when determined by analytical size exclusion chromatography (aSEC).

[0118] E64. The antibody of any one of E1 to E63, characterized in that the score is less than 7 in the affinity capture self-interaction nanoparticle spectroscopy (AC SINS) analysis.

[0119] E65. The antibody of any one of E1 to E64, characterized in that it has a score of less than 6 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) analysis.

[0120] E66. The antibody of any one of E1 to E65, characterized in that it has a score of less than 5 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) analysis.

[0121] E67. The antibody of any one of E1 to E66, characterized in that it has a score of less than 4 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) analysis.

[0122] E68. The antibody of any one of E1 to E67, characterized in that it has a score of less than 3 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) analysis.

[0123] E69. The antibody of any one of E1 to E68, wherein the IC50 is less than 2 nM in a NFκB TL1A neutralization bioassay.

[0124] E70. The antibody of any one of E1 to E69, characterized in that the KD is less than 500 pM as measured by SPR.

[0125] E71. The antibody of any one of E1 to E70, characterized in that the KD is less than 320 pM as measured by SPR.

[0126] E72. The antibody of any one of E1 to E71, characterized in that the KD is less than 300 pM as measured by SPR.

[0127] E73. The antibody of any one of E1 to E72, wherein the terminal half-life of the antibody in cynomolgus monkeys is at least 21 days.

[0128] E74. The antibody of any one of E1 to E73, wherein the terminal half-life of the antibody in cynomolgus monkeys is at least 25 days.

[0129] E75. The antibody of any one of E1 to E74, wherein the terminal half-life of the antibody in cynomolgus monkeys is at least 28 days.

[0130] E76. The antibody of any one of E1 to E75, wherein said antibody binds to cynomolgus monkey TL1A within an order of magnitude of human TL1A as measured by SPR.

[0131] E77. The antibody of any one of E1 to E76, characterized in that the binding affinity of the antibody for human TL1A is at least 500× higher than for mouse T1A as measured by SPR.

[0132] E78. The antibody of any one of E1 to E77, wherein the binding affinity of the antibody for human TL1A is at least 2000× higher than for mouse TL1A as measured by SPR.

[0133] E79. An antibody as described in E1 to E38, wherein the antibody specifically binds to p40 via a p40 binding domain, the antibody comprising a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), comprising CDR-H1, CDR-H2 and CDR-H3 sequences according to the p40-VH sequence of SEQ ID NO: 171, and CDR-L1, CDR-L2 and CDR-L3 sequences according to the p40-VL sequence of SEQ ID NO: 177.

[0134] E80. An antibody as described in E1 to E38, wherein the antibody specifically binds to p40 via a p40 binding domain, the antibody comprising a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), wherein the CDR-L1 sequence is according to SEQ ID NO: 173, the CDR-L2 sequence is according to SEQ ID NO: 174, and the CDR-L3 sequence is according to SEQ ID NO: 175; and wherein the CDR-H1 sequence is according to SEQ ID NO: 167, the CDR-H2 sequence is according to SEQ ID NO: 168, and the CDR-H3 sequence is according to SEQ ID NO: 169.

[0135] E81. An isolated antibody comprising a first antigen binding site that binds to TL1A and a second antigen binding site that binds to p40, wherein the first antigen binding site comprises a TL1A binding heavy chain variable region (TL1A-VH) and a TL1A binding light chain variable region (TL1A-VL), wherein the second antigen binding site comprises a p40 binding heavy chain variable region (p40-VH) and a p40 binding light chain variable region (p40-VL), and wherein the p40 binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 173, a CDR-L2 sequence according to SEQ ID NO: 174, and a CDR-L3 sequence according to SEQ ID NO: 175, a CDR-H1 sequence according to SEQ ID NO: 167, a CDR-H2 sequence according to SEQ ID NO: 168, and a CDR-H3 sequence according to SEQ ID NO: 169, and wherein the TL1A binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 11, a CDR-L2 sequence according to SEQ ID NO: 11, and a CDR-L3 sequence according to SEQ ID NO: 11 NO:12 and a CDR-L3 sequence according to SEQ ID NO:13, and further comprising a set of heavy chain CDRs selected from the following list:

[0136] (i) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0137] (ii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0138] (iii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:32;

[0139] (iv) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:35;

[0140] (v) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0141] (vi) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0142] (vii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0143] (viii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:35;

[0144] (ix) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0145] (x) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0146] (xi) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0147] (xii) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0148] (xiii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 31; a CDR-H3 sequence according to SEQ ID NO: 35;

[0149] (xiv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:38; a CDR-H3 sequence according to SEQ ID NO:35;

[0150] (xv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0151] (xvi) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0152] (xvii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 46; a CDR-H3 sequence according to SEQ ID NO: 35;

[0153] (xviii) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0154] (xix) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0155] (xx) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32;

[0156] (xxi) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 41; a CDR-H3 sequence according to SEQ ID NO: 35; and

[0157] (xxii) CDR-H1 sequence according to SEQ ID NO: 109; CDR-H2 sequence according to SEQ ID NO: 56; CDR-H3 sequence according to SEQ ID NO: 32.

[0158] E82. An isolated antibody comprising a first antigen binding site that binds to TL1A and a second antigen binding site that binds to p40, wherein the first antigen binding site comprises a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), wherein the second antigen binding site comprises a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), and wherein (i) the p40 binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 173; a CDR-L2 sequence according to SEQ ID NO: 174; and a CDR-L3 sequence according to SEQ ID NO: 175; a CDR-H1 sequence according to SEQ ID NO: 167; a CDR-H2 sequence according to SEQ ID NO: 168; and a CDR-H3 sequence according to SEQ ID NO: 169, and (ii) the TL1A binding domain comprises a CDR-L2 sequence according to SEQ ID NO: 174; and a CDR-L3 sequence according to SEQ ID NO: 175; a CDR-H1 sequence according to SEQ ID NO: 167; a CDR-H2 sequence according to SEQ ID NO: 168; and a CDR-H3 sequence according to SEQ ID NO: 169 according to the CDR-L1 sequence of SEQ ID NO:11; according to the CDR-L2 sequence of SEQ ID NO:12; and according to the CDR-L3 sequence of SEQ ID NO:13; according to the CDR-H1 sequence of SEQ ID NO:30; according to the CDR-H2 sequence of SEQ ID NO:41; and according to the CDR-H3 sequence of SEQ ID NO:32.

[0159] E83. An antibody as described in any one of E79 to E82, which comprises a TL1A-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: GHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02.

[0160] E84. The antibody of any one of E79 to E83, which comprises a TL1A-VH framework sequence derived from a human IGHV1-18*01 germline sequence.

[0161] E85. An antibody as described in any one of E79 to E84, which comprises a TL1A-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV1-39*01, IGKV1-39*01, IGKV1-39*01, IGKV3D-7*01, IGKV3D-7*01, IGKV3D-7*01.

[0162] E86. The antibody of any one of E79 to E85, which comprises a TL1A-VL framework sequence derived from a human germline IGKV1-39*01 sequence.

[0163] E87. An antibody as described in any one of E79 to E86, which comprises a TL1A-VL framework sequence and a TL1A-VH framework sequence, wherein one or both of the TL1A-VL framework sequence and the TL1A-VH framework sequence are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0164] E88. The antibody of any one of E79 to E87, which comprises a TL1A-VL framework sequence and a TL1A-VH framework sequence, and wherein one or both of the TL1A-VL framework sequence or the TL1A-VH framework sequence are identical to the human germline sequence from which they are derived.

[0165] E89. An antibody as described in any one of E79 to E88, wherein the TL1A-VL comprises the amino acid sequence according to SEQ ID NO: 18, and wherein the TL1A-VH comprises the amino acid sequence according to the sequence selected from the group consisting of: SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:57, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:89, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:110 and SEQ ID NO:120.

[0166] E90. An antibody as described in any one of E79 to E89, which comprises a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:42, and comprises a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:18.

[0167] E91. The antibody of any one of E79 to E90, which comprises the TL1A-VH sequence of SEQ ID NO:42, and the TL1A-VL of SEQ ID NO:18.

[0168] E92. The antibody of any one of E79 to E91, which comprises a TL1A-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 228.

[0169] E93. The antibody of any one of E79 to E92, comprising a TL1A-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 229.

[0170] E94. The antibody of any one of E1 to E15, which comprises a TL1A-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127347.

[0171] E95. The antibody of any one of E1 to E16, which comprises a TL1A-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127348.

[0172] E96. An antibody comprising a TL1A-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127347, and a TL1A-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127438.

[0173] E97. The antibody of any one of E79 to E96, which comprises a p40-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP3, DP7, DP73, DP75 and DP88.

[0174] E98. The antibody of any one of E79 to E97, which comprises a p40-VH framework sequence derived from a human DP73 germline sequence.

[0175] E99. The antibody of any one of E79 to E98, which comprises a p40-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK4, DPK5, DPK7, DPK8 and DPK9.

[0176] E100. The antibody of any one of E79 to E99, which comprises a p40-VL framework sequence derived from a human germline DPK9 sequence.

[0177] E101. An antibody as described in any one of E79 to E100, which comprises a p40-VL framework sequence and a p40-VH framework sequence, wherein one or both of the p40-VL framework sequence and the p40-VH framework sequence are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the human germline sequence from which they are derived.

[0178] E102. The antibody of any one of E79 to E101, comprising a p40-VL framework sequence and a p40-VH framework sequence, and wherein one or both of the p40-VL framework sequence or the p40-VH framework sequence are identical to the human germline sequence from which they are derived.

[0179] E103. An antibody as described in any one of E79 to E102, which comprises a p40-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 177, and comprises a p40-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 171.

[0180] E104. The antibody of any one of E79 to E103, wherein the p40-VL comprises the amino acid sequence according to SEQ ID NO: 177, and wherein the p40-VH comprises the amino acid sequence according to SEQ ID NO: 171.

[0181] E105. The antibody of any one of E79 to E104, comprising a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 238.

[0182] E106. The antibody of any one of E79 to E105, which comprises a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 239.

[0183] E107. The antibody of any one of E79 to E106, which comprises a p40-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127206.

[0184] E108. The antibody of any one of E79 to E107, which comprises a p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127205.

[0185] E109. An antibody comprising a p40-VH sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127206, and a p40-VL sequence encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127205.

[0186] E110. The antibody of E79 to E109, wherein the TL1A-VH is fused to the CH1 domain (TL1A-CH1), and the TL1A-VL is fused to the light chain constant domain (TL1A-CL), thereby forming a TL1A binding Fab domain (TL1A-Fab).

[0187] E111. The antibody of E110, wherein the p40-VH is fused to a CH1 domain (p40-CH1), and the p40-VL is fused to a light chain constant domain (p40-CL), thereby forming a p40 binding Fab domain (p40-Fab).

[0188] E112. The antibody of E110 to E111, wherein said TL1A-CH1 comprises a sequence according to the group consisting of: SEQ ID NO:6, and SEQ ID NO:195, and SEQ ID NO:199.

[0189] E113. The antibody of E100 to E102, wherein said TL1A-CH1 comprises the sequence according to SEQ ID NO:6.

[0190] E114. The antibody of E100 to E113, wherein the TL1A-CL comprises a sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 197 and SEQ ID NO: 201.

[0191] E115. The antibody of E100 to E114, wherein said TL1A-CL comprises the sequence according to SEQ ID NO:16.

[0192] E116. The antibody of E100 to E115, wherein said p40-CH1 comprises a sequence according to the group consisting of: SEQ ID NO:6, and SEQ ID NO:195, and SEQ ID NO:199.

[0193] E117. The antibody of E100 to E116, wherein said p40-CH1 comprises the sequence according to SEQ ID NO:6.

[0194] E118. The antibody of E100 to E117, wherein the p40-CL comprises a sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 197 and SEQ ID NO: 201.

[0195] E119. The antibody of E100 to E118, wherein said p40-CL comprises the sequence according to SEQ ID NO:16.

[0196] E120. The antibody of any one of E111 to E119, comprising an antibody Fc domain comprising a first Fc chain and a second Fc chain.

[0197] E121. The antibody of E120, wherein the Fc domain is an Fc domain of IgA (eg, IgA1 or IgA2), IgD, IgE, IgM, or IgG (eg, IgG1, IgG2, IgG3, or IgG4).

[0198] E122. The antibody of E121, wherein the Fc domain is the Fc domain of IgG1.

[0199] E123. The antibody of E120 to E122, wherein the first Fc chain comprises from N-terminus to C-terminus: a first hinge region, a first CH2 region and a first CH3 region, and the second Fc chain comprises from N-terminus to C-terminus: a second hinge region, a second CH2 region and a second CH3 region.

[0200] E124. The antibody of E123, wherein the N-terminus of said first Fc chain is connected to the C-terminus of said first TL1A-CL domain.

[0201] E125. The antibody of E123 to E124, wherein the N-terminus of the second Fc chain is connected to the C-terminus of the first p40-CH1 domain.

[0202] E126. The antibody of E123 to E125, wherein said first CH2 region and said second CH2 region each comprise a sequence according to SEQ ID NO:8.

[0203] E127. An antibody as described in E123 to E126, wherein any one or both of the first hinge regions comprise a sequence selected from the group consisting of SEQ ID NO:7, SEQ ID NO:157, SEQ ID NO:179, SEQ ID NO:182, and SEQ ID NO:189, SEQ ID NO:191, SEQ ID NO:204, and SEQ ID NO:206.

[0204] E128. The antibody of E123 to E127, wherein the first hinge region and the second hinge region each contain one or more amino acid modifications that promote binding of the first hinge region to the second hinge region.

[0205] E129. The antibody of E128, wherein the first hinge region and the second hinge region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0206] (i) SEQ ID NO:179 and SEQ ID NO:182;

[0207] (ii) SEQ ID NO:189 and SEQ ID NO:191.

[0208] E130. The antibody of E123 to E128, wherein the first hinge region comprises the sequence according to SEQ ID NO: 204.

[0209] E131. The antibody of E123 to E128, wherein the second hinge region comprises the sequence according to SEQ ID NO:7.

[0210] E132. The antibody of E123 to E131, wherein the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote binding of the first Fc chain to the second Fc chain.

[0211] E133. The antibody of E123 to E132, wherein the first Fc chain comprises a first CH3 region, and the second Fc chain comprises a second CH3 region, and the first CH3 region and the second CH3 region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0212] (i) SEQ ID NO:160 and SEQ ID NO:162;

[0213] (ii) SEQ ID NO:180 and SEQ ID NO:183;

[0214] (iii) SEQ ID NO: 155 and SEQ ID NO: 158;

[0215] (iv) SEQ ID NO:185 and SEQ ID NO:SEQ ID NO:187.

[0216] E134. The antibody of E123, wherein the first CH3 region and the second CH3 region comprise SEQ ID NO:160 and SEQ ID NO:162.

[0217] E135. The antibody of any one of E79 to E134, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain, such that the first polypeptide chain and the third polypeptide chain together form TL1A-Fab, and the second polypeptide chain and the fourth polypeptide chain together form p40-Fab.

[0218] E136. The antibody of E135, wherein the first polypeptide chain, the second polypeptide chain, the third polypeptide chain and the fourth polypeptide chain have a sequence combination according to one of the groups selected from the following list: (i) the first polypeptide sequence is according to SEQ ID NO: 205, the second polypeptide is according to SEQ ID NO: 203, the third polypeptide is according to SEQ ID NO: 207, and the fourth polypeptide is according to SEQ ID NO: 178;

[0219] (ii) the first polypeptide sequence is according to SEQ ID NO: 188, the second polypeptide is according to SEQ ID NO: 186, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178;

[0220] (iii) the first polypeptide sequence is according to SEQ ID NO: 192, the second polypeptide is according to SEQ ID NO: 190, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178;

[0221] (iv) the first polypeptide sequence is according to SEQ ID NO: 194, the second polypeptide is according to SEQ ID NO: 193, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178; and

[0222] (v) the first polypeptide sequence is according to SEQ ID NO:200, the second polypeptide is according to SEQ ID NO:196, the third polypeptide is according to SEQ ID NO:202, and the fourth polypeptide is according to SEQ ID NO:198.

[0223] E137. The antibody of E135 to E136, wherein the first polypeptide sequence is according to SEQ ID NO:205, the second polypeptide is according to SEQ ID NO:203, the third polypeptide is according to SEQ ID NO:207, and the fourth polypeptide is according to SEQ ID NO:178.

[0224] E138. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain, such that the first polypeptide chain and the third polypeptide chain together form a TL1A binding region, and the second polypeptide chain and the fourth polypeptide chain together form a p40 binding region, and wherein the first polypeptide sequence is according to SEQ ID NO:205, the second polypeptide is according to SEQ ID NO:203, the third polypeptide is according to SEQ ID NO:207, and the fourth polypeptide is according to SEQ ID NO:178.

[0225] E139. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, and a fourth polypeptide chain, such that the first polypeptide chain and the third polypeptide chain together form a TL1A binding region, and the second polypeptide chain and the fourth polypeptide chain together form a p40 binding region, and wherein the first polypeptide sequence comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127349, the second polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127346, the third polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127350, and the fourth polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127203.

[0226] E140. An isolated antibody that specifically binds to TL1A, comprising the CDRs of an antibody selected from one or more of Tables 30, 31, 32 and 33.

[0227] E141. An isolated antibody that specifically binds to TL1A, comprising the VH and VL of an antibody selected from one or more of Tables 30, 31, 32 and 33.

[0228] E142. An isolated antibody that specifically binds to TL1A selected from one or more of Tables 30, 31, 32 and 33.

[0229] E143. An isolated antibody that specifically binds TL1A and specifically binds p40, comprising the CDRs of an antibody selected from one or more of Tables 30, 31, 32 and 33.

[0230] E144. An isolated antibody that specifically binds TL1A and specifically binds p40, comprising the VH and VL of an antibody selected from one or more of Tables 30, 31, 32 and 33.

[0231] E145. An isolated antibody that specifically binds TL1A and specifically binds p40, selected from one or more of Tables 30, 31, 32 and 33.

[0232] E146. The antibody of any one of E79 to E145, characterized by having a score of less than 2 in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay.

[0233] E147. The antibody of any one of E79 to E146, wherein the charge heterogeneity of the antibody is at least 50% non-acidic and non-basic as measured in antibody-imaged capillary electrophoresis (iCE) on an unstressed sample to be evaluated (T0).

[0234] E148. The antibody of any one of E79 to E147, wherein said antibody binds to immobilized human TL1A with a binding affinity of less than 1 nM as measured by SPR.

[0235] E149. The antibody of any one of E79 to E148, wherein said antibody binds to immobilized human TL1A with a binding affinity of less than 500 pM as measured by SPR.

[0236] E150. The antibody of any one of E79 to E149, wherein said antibody binds to immobilized human TL1A with a binding affinity of less than 300 pM as measured by SPR.

[0237] E151. The antibody of any one of E79 to E150, wherein said immobilized antibody binds to human p40 with a binding affinity of less than 1 nM as measured by SPR.

[0238] E152. The antibody of any one of E79 to E151, wherein said immobilized antibody binds to human p40 with a binding affinity of less than 900 pM as measured by SPR.

[0239] E153. The antibody of any one of E79 to E152, wherein said immobilized antibody binds to human p40 with a binding affinity of less than 600 pM as measured by SPR.

[0240] E154. The antibody of any one of E79 to E153, wherein the Ab binds p40 (IL-23) and TL1A simultaneously in an SPR assay in which the antibody is injected over immobilized TL1A and the resulting complex is subsequently treated with IL-23.

[0241] E155. The antibody of E79 to E154, wherein the antibody is characterized by an IC of less than 5 nM in a human IL-12 neutralization and Kit-225 assay.50 .

[0242] E156. The antibody of E79 to E155, wherein the antibody is characterized by an IC of less than 4 nM in a human IL-12 neutralization and Kit-225 assay. 50 .

[0243] E157. The antibody of E79 to E156, wherein the antibody is characterized by an IC of less than 2 pM in a human IL-12 neutralization and Kit-225 assay. 50 .

[0244] E158. The antibody of E79 to E157, wherein the antibody is characterized by an IC of less than 5 nM in a human IL-23 neutralization and Kit-225 assay. 50 .

[0245] E159. The antibody of E79 to E158, wherein the antibody is characterized by an IC of less than 4 nM in a human IL-23 neutralization and Kit-225 assay. 50 .

[0246] E160. The antibody of E79 to E159, wherein the antibody is characterized by an IC of less than 1 nM in a human IL-23 neutralization Kit-225 assay in human whole blood. 50 .

[0247] E161. The antibody of E79 to E160, wherein the antibody is characterized by an IC of less than 0.5 nM in a Kit-225 assay for neutralization of human IL-23 in human whole blood. 50 .

[0248] E162. The antibody of E155 to E161, wherein the Kit-225 assay is in human whole blood.

[0249] E163. The antibody of E79 to E162, wherein the antibody is characterized by an IC of less than 5 nM in a cynomolgus monkey IL-23 neutralization and Kit-225 assay. 50 .

[0250] E164. The antibody of E79 to E163, wherein the antibody is characterized by an IC of less than 2 nM in a cynomolgus monkey IL-12 neutralization and Kit-225 assay. 50 .

[0251] E165. The antibody of E79 to E164, wherein the antibody is characterized by an IC of less than 1 nM in a cynomolgus monkey IL-12 neutralization and Kit-225 assay. 50 .

[0252] E166. The antibody of E79 to E165, wherein the antibody is characterized by an IC of less than 2 nM in a human whole blood assay measuring inhibition of IFNγ 50 .

[0253] E167. The antibody of E79 to E166, wherein the antibody is characterized by an IC of less than 3 nM in a human whole blood assay measuring inhibition of IFNγ 50 .

[0254] E168. The antibody of E79 to E167, wherein the antibody is characterized by an IC of less than 2 nM in a human whole blood assay measuring inhibition of IFNγ 50 .

[0255] E169. The antibody of E79 to E168, wherein the antibody is characterized by an IC of less than 500 pM in a human isolated CD4+ cell assay measuring inhibition of IFNγ 50 .

[0256] E170. The antibody of E79 to E169, wherein the antibody is characterized by an IC of less than 100 pM in a human isolated CD4+ cell assay measuring inhibition of IFNγ 50 .

[0257] E171. The antibody of E79 to E170, wherein the antibody is characterized by an IC of less than 200 nM in a human NFκB neutralization assay in TF-1 reporter cells 50 .

[0258] E172. The antibody of E79 to E171, wherein the antibody is characterized by an IC of less than 150 nM in a human NFκB neutralization assay in TF-1 reporter cells 50 .

[0259] E173. The antibody of any one of E79 to E172, wherein the terminal half-life of the antibody in TG32 mice is at least 10 days based on a two week analysis.

[0260] E174. The antibody of any one of E79 to E173, wherein the terminal half-life of the antibody in TG32 mice is at least 14 days based on a two week analysis.

[0261] E175. The antibody of any one of E79 to E174, wherein the terminal half-life of the antibody in TG32 mice is at least 16 days based on a two week analysis.

[0262] E176. The antibody of any one of E79 to E175, wherein the terminal half-life of the antibody in TG32 mice is at least 17 days based on a two week analysis.

[0263] E177. The antibody of any one of E79 to E176, wherein the terminal half-life of said antibody in cynomolgus monkeys is at least 21 days.

[0264] E178. The antibody of any one of E79 to E177, wherein the terminal half-life of said antibody in cynomolgus monkeys is at least 25 days.

[0265] E179. The antibody of any one of E79 to E178, wherein the terminal half-life of said antibody in cynomolgus monkeys is at least 28 days.

[0266] E180. The antibody of any one of E1 to E179, for use as a medicament.

[0267] E181. An antibody as E180, wherein the use is for treating one or more of the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stricturing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease. GVHD, idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary bowel disorders, uveitis and vasculitis.

[0268] E182. The antibody of any one of E180 to E181, wherein the use is for inflammatory bowel disease (IBD).

[0269] E183. The antibody of any one of E180 to E182, wherein the use is for Crohn's disease.

[0270] E184. The antibody of any one of E180 to E183, wherein the use is for ulcerative colitis.

[0271] E185. A pharmaceutical composition comprising a therapeutically effective amount of an antibody such as E1 to E184 and a pharmaceutically acceptable carrier.

[0272] E186. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody as any one of E1 to E184 or a pharmaceutical composition as E185.

[0273] E187. The method of E186, wherein the condition is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft versus host disease (GVH D), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary intestinal disorders, uveitis, and vasculitis.

[0274] E188. The method of any one of E186 to E87, comprising administering the antibody or pharmaceutical composition subcutaneously.

[0275] E189. A method as described in any one of E186 to E188, wherein the antibody or pharmaceutical composition is administered about twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, once every three months, or once every four months.

[0276] E190. An isolated polynucleotide comprising one or more nucleotide sequences encoding the antibody of any one of E1 to E184.

[0277] E191. The polynucleotide of E190, wherein said polynucleotide is RNA.

[0278] E192. The polynucleotide of E190 to E191, wherein said polynucleotide comprises at least one chemical modification.

[0279] E193. A polynucleotide as described in E192, wherein the chemical modification is selected from pseudouridine, 1-methylpseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thiol-1-methyl-pseudouridine, 2-thiol-5-aza-uridine, 2-thiol-dihydropseudouridine, 2-thiol-dihydrouridine, 2-thiol-pseudouridine, 4-methoxy-2-thiol-pseudouridine, 4-methoxy-pseudouridine, 4-thiol-1-methyl-pseudouridine, 4-thiol-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine and 2'-O-methyluridine.

[0280] E194. The polynucleotide of E190 to E191, wherein said polynucleotide does not comprise a chemical modification.

[0281] E195. An isolated polynucleotide encoding VH, VL, or both of an antibody that binds to TL1A, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 228, the nucleic acid sequence of SEQ ID NO: 229, or both.

[0282] E196. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to TL1A, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 231, the nucleic acid sequence of SEQ ID NO: 233, or both.

[0283] E197. An isolated polynucleotide encoding VH, VL or both of an antibody that binds to TL1A, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having a deposit number of PTA-127347, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having a deposit number of PTA-127348, or both.

[0284] E198. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to TL1A, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having a deposit number of PTA-127347, the nucleic acid sequence of an insert of a plasmid deposited with ATCC and having a deposit number of PTA-127348, or both.

[0285] E199. An isolated polynucleotide comprising one or more nucleic acids encoding one or more sequences of a null arm antibody that binds TL1A, wherein the null arm antibody comprises a null arm TL1A antibody comprising a first variable heavy chain and a first variable light chain and a second variable heavy chain and a second variable light chain, wherein the first variable heavy chain and the first variable light chain comprise a first Fab domain (TL1A-Fab) that binds to TL1A, and the second variable heavy chain and the second variable light chain comprise a second Fab domain (xTL1A-Fab) that comprises a non-binding TL1A binding domain that does not specifically bind to a target, and wherein the first and the second variable light chains are the same, and wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 228, the nucleic acid sequence of SEQ ID NO: 230 and / or the nucleic acid sequence of SEQ ID NO: 260.

[0286] E200. An isolated polynucleotide comprising one or more nucleic acids encoding one or more sequences of an invalid arm antibody that binds to TL1A, wherein the invalid arm antibody comprises an invalid arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (TL1A-Fab) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (xTL1A-Fab) that comprises a non-binding TL1A binding domain that does not specifically bind to a target, and wherein the first light chain and the second light chain are the same, and wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 231, the nucleic acid sequence of SEQ ID NO: 232, and / or the nucleic acid sequence of SEQ ID NO: 233.

[0287] E201. An isolated polynucleotide comprising one or more nucleic acids encoding one or more sequences of an invalid arm antibody that binds to TL1A, wherein the invalid arm antibody comprises an invalid arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain (TL1A-Fab) that binds to TL1A, and the second heavy chain and the second light chain comprise a second Fab domain (xTL1A-Fab) that comprises a non-binding TL1A binding domain that does not specifically bind to a target, and wherein the first light chain and the second light chain are the same, and wherein the polynucleotide comprises one or more of the following: a nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127347, a nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127348, and a nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127351.

[0288] E202. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising (i) a TL1A-VH sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 228; and TL1A-VL encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 229; and

[0289] (ii) a p40-VH sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 238; and a p40-VL sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 239.

[0290] E203. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising: (i) TL1A-VH carrying a polypeptide sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 234; and TL1A-VL carrying a polypeptide encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 235; and

[0291] (ii) a p40-HC sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 236; and a p40-LC sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 237.

[0292] E204. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising: (i) a TL1A-VH sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127347; and a TL1A-VL sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127348; and

[0293] (ii) a p40-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127206; and a p40-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127205.

[0294] E205. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising: (i) a TL1A-VH carrying polypeptide sequence encoded by a plasmid deposited in the ATCC and having an ATCC deposit number of PTA-127350; and a TL1A-VL carrying polypeptide sequence encoded by a plasmid deposited in the ATCC and having an ATCC deposit number of PTA-127349; and

[0295] (ii) p40-HC sequence, which is encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127346; and p40-LC sequence, which is encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127203.

[0296] E206. An isolated polynucleotide encoding a TL1A antibody VH domain, comprising the nucleic acid sequence of SEQ ID NO: 228.

[0297] E207. An isolated polynucleotide encoding a TL1A antibody VL domain, comprising the nucleic acid sequence of SEQ ID NO: 229.

[0298] E208. An isolated polynucleotide encoding a TL1A antibody VH domain engineered to eliminate TL1A binding, comprising the nucleic acid sequence of SEQ ID NO: 230.

[0299] E209. An isolated polynucleotide encoding TL1A antibody HC, comprising the nucleic acid sequence of SEQ ID NO: 231.

[0300] E210. An isolated polynucleotide encoding a TL1A antibody HC engineered to eliminate TL1A binding, comprising the nucleic acid sequence of SEQ ID NO: 232.

[0301] E211. An isolated polynucleotide encoding TL1A antibody LC, comprising the nucleic acid sequence of SEQ ID NO: 233.

[0302] E212. An isolated polynucleotide encoding the mFd chain of the TL1A antibody, comprising the nucleic acid sequence of SEQ ID NO: 234.

[0303] E213. An isolated polynucleotide encoding the TL1A antibody LC-Fc chain, comprising the nucleic acid sequence of SEQ ID NO: 235.

[0304] E214. An isolated polynucleotide encoding p40 antibody HC, comprising the nucleic acid sequence of SEQ ID NO: 236.

[0305] E215. An isolated polynucleotide encoding a p40 antibody LC, comprising the nucleic acid sequence of SEQ ID NO: 237.

[0306] E216. An isolated polynucleotide encoding a p40 antibody VH, comprising the nucleic acid sequence of SEQ ID NO: 238.

[0307] E217. An isolated polynucleotide encoding p40 antibody VL, comprising the nucleic acid sequence of SEQ ID NO: 239.

[0308] E218. A vector comprising the polynucleotides of E190 to E217.

[0309] E219. An isolated host cell comprising a polynucleotide as described in E190 to E217 or a vector as described in E218.

[0310] E220. A method of producing an isolated antibody, comprising culturing a host cell such as E219 under conditions resulting in production of the antibody and recovering the antibody.

[0311] E221. A pharmaceutical composition comprising a therapeutically effective amount of an antibody as described in any one of E1 to E189, and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0313] Figure 1 Schematic diagram of a "one-armed" antibody. The format includes an anti-TL1A binding Fab and a truncated Fc. Fc heterodimerization is driven by a KiH mutation engineered in the CH3 domain.

[0314] Figure 2 Schematic diagram of a monovalent bispecific antibody. The format includes an anti-TL1A binding Fab and a "disabled" Fab (also called null arm) with mutations that abolish TL1A binding. Fc pairing is driven via introduction of KiH mutations in both CH3 domains.

[0315] Figure 3. Most of the screened [xTL1A] bivalent antibody variants demonstrated no binding to recombinant human TL1A. All [xTL1A] bivalent antibody variants are plotted on FIG. 3A to FIG. 3C In the figure. [xTL1A] bivalent antibody variants that do not bind to recombinant human TL1A are plotted with a solid black line, and variants that show some degree of binding are plotted with a patterned line. In all three figures, binding of the positive control TL1A-0260 to TL1A is plotted with a dashed line.

[0316] Figure 4. High concentrations of [xTL1A] bivalent antibody variants do not bind to TL1A, except for [xTL1A-0322]. Sensorgrams of select [xTL1A] bivalent antibody variants binding to TL1A. Figure 4A . Binding of positive control TL1A-0260 to TL1A at 196 nM concentration. Figure 4B Binding of the [xTL1A]-0322 bivalent antibody to TL1A at 1 μM concentration; this was the only variant that showed binding to TL1A. Figure 4C Representative sensorgrams demonstrate that [xTL1A]-0349 does not bind TL1A at 1 μM concentration. The remaining [xTL1A] bivalent variants had similar sensorgrams at 1 μM concentration.

[0317] Figure 5 .High concentrations of the [xTL1A] bivalent antibody variants showed mostly no binding to human TL1A expressed on cells. Binding of the [xTL1A] bivalent antibody variants, isotype controls, and the positive control TL1A-0260 to cells overexpressing human TL1A is plotted above. The black bars show binding at a concentration of 1 μg / mL, and the gray bars show binding at a concentration of 20 μg / mL. The vertical black and gray lines are plotted at the levels of isotype control binding at concentrations of 1 μg / mL and 20 μg / mL, respectively. [xTL1A] variants that showed binding greater than the isotype control were considered to bind to cells expressing TL1A.

[0318] Figure 6. [xTL1A] bivalent antibody variants screened in competition ELISA do not compete with Bio-TL1A-0260 for binding to recombinant human TL1A protein, indicating impaired TL1A binding properties. All [xTL1A] bivalent antibody variants are plotted in panels A to D. [xTL1A] bivalent antibody variants that do not compete with bio-TL1A-0260 for recombinant human TL1A binding are plotted with solid black lines, and variants that show some degree of competition with bio-TL1A-0260 are plotted with patterned lines. In all four panels, competition of the positive control TL1A-0260 with bio-TL1A-0260 for TL1A binding is plotted with dashed lines.

[0319] Figure 7 The monovalent bispecific variants did not exhibit binding to BSA or HSA.

[0320] Figure 8. General schematic and nomenclature of bispecific molecules and Fab domains engineered with Fc heterodimerization mutations for a single cell line production approach.

[0321] Figure 9. General schematic and nomenclature of bispecific molecules engineered with knob-hole and charged Fc based heterodimerization mutations for dual cell line production approach.

[0322] Fig. 10A .P40TL1A-0033TL1A mFd sequence and numbering (SEQ ID NO:207). Fig. 10B .P40TL1A-0033TL1A LC Fc sequence and numbering (SE ID NO:205). Fig. 10C .P40TL1A-0033p40 HC sequence and numbering (SEQ ID NO: 203). Fig. 10D .P40TL1A-0033p40 LC sequence and numbering (SEQ ID NO: 178).

[0323] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0324] All references cited herein, including patent applications, patent publications, UniProtKB accession numbers, are hereby incorporated by reference as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety.

[0325] The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and are routinely employed using conventional methods, such as the widely used methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (FM Ausubel et al., eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis, 1998) Academic Press; Animal Cell Culture (RI Freshney), 1987); Introduction to Cell and Tissue Culture (JPMather and PERoberts, 1998) Plenum Press; Cell and TissueCulture Laboratory Procedures (edited by A.Doyle, JBGriffiths and DG Newell, 1993-8) J.Wiley and Sons; Handbook of Experimental Immunology (edited by DMWeir and CC Blackwell); Gene Transfer Vectors for Mammalian Cells (JMMiller and MPCalos, 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., 1994); Current Protocols in Immunology (JEColigan et al., 1991); Short Protocols in Molecular Biology (Wileyand Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (edited by D. Catty., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (edited by P. Shepherd and C. Dean, Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and updated versions thereof.

[0326] definition

[0327] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by one of ordinary skill in the art.

[0328] As used herein, the singular forms "a", "an" and "the" include plural referents unless otherwise indicated. For example, "a" antibody includes one or more antibodies.

[0329] When aspects or embodiments of the invention are described in terms of Markush groups or other alternative groups, the invention encompasses not only all groups listed as a whole, but also each member of the independent group and all possible subgroups of the main group, as well as the main group lacking one or more group members. The invention also contemplates the explicit exclusion of one or more of any group members in the claimed invention.

[0330] Any examples following the term "eg" or "for example" are not intended to be exhaustive or limiting.

[0331] As used herein, when used to modify a numerically defined parameter (e.g., a dose of ***), the term "about" means that the parameter can vary by up to 10% below or above the stated value of the parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it can vary between 4.5 mg and 5.5 mg.

[0332] Antibody

[0333] "Antibody" refers to an immunoglobulin molecule that is capable of specifically binding to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., via at least one antigen binding site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" may encompass any type of antibody (e.g., monospecific, bispecific), and includes portions of intact antibodies that retain the ability to bind to a given antigen (e.g., "antigen-binding fragments") and any other modified configurations of immunoglobulin molecules that contain an antigen binding site.

[0334] Antibodies include antibodies of any class, such as IgG, IgA or IgM (or subclasses thereof), and the antibodies need not be of any particular class. Immunoglobulins can be classified into different classes depending on the antibody amino acid sequence of the constant region of their heavy chains (HC). There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these immunoglobulins can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant regions corresponding to the different classes of immunoglobulins are referred to as α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

[0335] Examples of antibody antigen-binding fragments and modified configurations include (i) Fab fragments (monovalent fragments consisting of VL, VH, CL and CH1 domains); (ii) F(ab')2 fragments (bivalent fragments comprising two Fab fragments connected by a disulfide bridge at the hinge region); and (iii) Fv fragments consisting of the VL and VH domains of a single arm of an antibody. In addition, although the two domains of the Fv fragment, VL and VH, are encoded by independent genes, they can be joined by synthetic linkers using recombinant methods that enable them to be prepared as a single protein chain in which the VL and VH regions are paired to form monovalent molecules (called single-chain Fv (scFv)); see, for example, Bird et al., Science 1988; 242: 423-426, and Huston et al., Proc. Natl. Acad. Sci. 1988 USA 85: 5879-5883. Other forms of single-chain antibodies, such as bifunctional antibodies, are also contemplated.

[0336] In addition, antibodies lacking a C-terminal lysine (K) amino acid residue on the heavy chain polypeptide are further contemplated (e.g., human IgG1 heavy chains include a terminal lysine). As is known in the art, the C-terminal lysine is sometimes sheared off during antibody production to produce an antibody lacking a C-terminal lysine in the heavy chain. Alternatively, the antibody heavy chain can be produced using a nucleic acid that does not include a C-terminal lysine.

[0337] Variable region

[0338] The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains are each composed of four framework regions (FRs) connected by three complementary determining regions (CDRs), also known as hypervariable regions; and promote the formation of the antigen-binding site of the antibody. If a variant of an individual variable region is desired, especially in the case of amino acid residue substitutions outside the CDR region (i.e., in the framework region), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the individual variable region with the variable regions of other antibodies containing the same typical class of CDR1 and CDR2 sequences as the individual variable region (Chothia and Lesk, J. Mol. Biol. 196 (4): 901-917, 1987).

[0339] In certain embodiments, the deterministic depiction of CDR and the identification of the residues comprising the binding site of the antibody are realized by resolving the structure of the antibody or resolving the structure of the antibody-ligand complex. In certain embodiments, it can be realized by any of various techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various analytical methods can be used to identify or estimate CDR regions. In certain embodiments, various analytical methods can be used to identify or estimate CDR regions. Examples of such methods include but are not limited to Kabat definition, Chothia definition, AbM definition, contact definition, extension definition and configuration definition.

[0340] The Kabat definition is a standard for numbering residues in antibodies and is often used to identify CDR regions. See, e.g., Johnson and Wu, 2000, Nucleic Acids Res., 28:214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account the position of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83. The extended definition is a combination of the Kabat definition and the Chothia definition. The AbM definition is an integrated suite of computer programs that use model antibody structures made by the Oxford Molecular Group. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; "AbM TM, A Computer Program for Modeling Variable Regions of Antibodies", Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from the primary sequence using a combination of a knowledge database and an ab initio algorithm, such as those described by Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach", PROTEINS, Structure, Function and Genetics Suppl., 3: 194-198. The contact definition is based on analysis of available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5: 732-45. In another approach (referred to herein as "configurational definition" of CDRs), the positions of the CDRs can be identified as residues that contribute enthalpy to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283: 1156-1166. Although other CDR boundary definitions may not strictly follow one of the above methods, they will still overlap with at least a portion of the Kabat CDR, but they may be shortened or extended based on the following predictions or experimental findings: specific residues or residue groups do not significantly affect antigen binding. As used herein, CDRs may refer to CDRs defined by any method known in the art, including a combination of methods. The methods used herein can utilize CDRs defined according to any of these methods. For any given embodiment containing more than one CDR, the CDRs may be defined according to any one or more of the Kabat definition, Chothia definition, extended definition, AbM definition, contact definition, or configuration definition.

[0341] The Pfabat numbering method developed for consistent antibody numbering

[0342] The Pfabat numbering method is a definition algorithm for consistent antibody numbering based on the Kabat numbering system (Sequences of Proteins of Immunological Interest, Fifth Edition, Kabat et al., NIH Publication No.: 91-3242, 1991). Unlike many other computational implementations of Kabat numbering, Pfabat numbers the entire human IgG1 heavy and light chains, including the constant (C) region and the heavy chain hinge. Figure 10 shows example numbering, in which the complementary determining region (CDR) residues are underlined and in bold. For the light chain, CDR is defined as: CDRL1, from residues L24-L34; CDRL2, from residues L50-L56; CDRL3, from residues L89-L97; CDRH1, from residues H26-H35 (including insertion positions, such as H35B); CDRH2, from residues H50-H65; and CDRH3, from residues H95-H102. It should be noted that the definition of CDRH1 used herein includes positions H26-H29, which are not included in some other interpretations of Kabat numbering.

[0343] Constant region

[0344] The "constant region" of an antibody refers to the constant region of an antibody light chain or the constant region of an antibody heavy chain, alone or in combination. The IgG heavy chain constant region contains three sequential immunoglobulin domains (CH1, CH2, and CH3), with a hinge region located between the CH1 and CH2 domains. The IgG light chain constant region contains a single immunoglobulin domain (CL).

[0345] Fc domain and Fc chain

[0346] "Fc domain" refers to the portion of an immunoglobulin (Ig) molecule associated with a crystallizable fragment obtained by papain digestion of the Ig molecule. As used herein, the term relates to a 2-chain constant region of an antibody, each chain excluding a first constant region immunoglobulin domain. Within the Fc domain, there are two "Fc chains" (e.g., "first Fc chain" and "second Fc chain"). "Fc chain" generally refers to the C-terminal portion of an antibody heavy chain. Therefore, the Fc chain refers to the last two constant region immunoglobulin domains (CH2 and CH3) of IgA, IgD, and IgG heavy chains, and the last three constant region immunoglobulin domains of IgE and IgM heavy chains, and the optional flexible hinges at the N-termini of these domains.

[0347] Although the boundaries of the Fc chain can vary, a human IgG heavy chain Fc chain is generally defined as comprising residues C226 or P230 to its carboxyl terminus, where numbering is according to the EU index of Edelman et al., Proc. Natl. Acad. Sci. USA 1969; 63(1):78-85 and as described in Kabat et al., 1991. Typically, an Fc chain comprises about amino acid residues 236 to about 447 of the human IgG1 heavy chain constant region. "Fc chain" can refer to the polypeptide alone or in the context of a larger molecule (e.g., in an antibody heavy chain or Fc fusion protein).

[0348] A "functional" Fc domain refers to an Fc domain that has at least one effector function of a native sequence Fc domain. Exemplary "effector functions" include C1q binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation, among others. Such effector functions typically require an Fc domain in combination with a binding domain (e.g., an antibody variable region) and such antibody effector functions can be assessed using various assays known in the art.

[0349] A "native sequence" Fc chain refers to an Fc chain comprising an amino acid sequence identical to the amino acid sequence of an Fc chain found in nature. A "variant" Fc chain comprises an amino acid sequence that differs from the amino acid sequence of a native sequence Fc chain by at least one amino acid modification.

[0350] Monoclonal antibodies

[0351] "Monoclonal antibody" (mAb) refers to an antibody derived from a single copy or clone (including, for example, any eukaryotic, prokaryotic or phage clone). Monoclonal antibodies are highly specific for a single antigenic site. In addition, each monoclonal antibody is directed to a single determinant on the antigen, compared to polyclonal antibody preparations that typically include different antibodies directed to different determinants (epitopes). The modifier "monoclonal" indicates that the characteristic of the antibody is obtained from a substantially homogeneous antibody population, and should not be interpreted as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be manufactured by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or can be manufactured by a recombinant DNA method such as described in U.S. Patent No. 4,816,567. In another example, the monoclonal antibody can be isolated from a phage library, such as those produced using the techniques described in McCafferty et al., 1990, Nature 348:552-554.

[0352] Human Antibodies

[0353] "Human antibody" refers to an antibody whose amino acid sequence corresponds to the amino acid sequence of an antibody produced by a human or to the amino acid sequence of an antibody prepared using any technique for preparing a fully human antibody. For example, a fully human antibody can be obtained by using commercially available mice that have been engineered to express specific human immunoglobulins or by library (e.g., phage, yeast, or ribosome) display technology for preparing fully human antibodies. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0354] chimeric antibodies

[0355] "Chimeric antibody" refers to an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, such as an antibody in which the variable region sequence is derived from a mouse antibody and the constant region sequence is derived from a human antibody.

[0356] Humanized Antibodies

[0357] "Humanized" antibodies refer to non-human (e.g., murine) antibodies that are chimeric antibodies containing minimal sequence derived from non-human immunoglobulins. Preferably, humanized antibodies are human immunoglobulins (recipient antibodies) with the desired specificity, affinity, and capacity, in which residues from the recipient's CDRs are replaced with residues from CDRs of non-human species such as mice, rats, or rabbits (donor antibodies). Humanized antibodies may contain residues that are neither present in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance.

[0358] antigen

[0359] "Antigen" refers to a molecular entity used for immunization of immunocompetent vertebrates to produce antibodies that recognize antigens or screening expression libraries (e.g., phage, yeast or ribosome display libraries, etc.) for antibody selection. In this article, antigen is a more general term and is generally intended to include target molecules that are specifically recognized by antibodies, thus including fragments or mimetics of the molecules, which are used in immunization methods to produce antibodies or in screening libraries for selecting antibodies.

[0360] Epitope

[0361] "Epitope" refers to an area or region of an antigen to which an antibody specifically binds, such as an area or region comprising residues that interact with an antibody, determined by any method well known in the art. A variety of methods for locating and characterizing the position of an epitope on a protein are known in the art, including crystal structures, competitive analysis, gene fragment expression analysis, epitope mapping, and synthetic peptide-based analysis of the antibody-antigen complex, such as Harlow and Lane, Using Antibodies, a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, described in Chapter 11 of 1999. Additionally or alternatively, during the exploratory process, the generation and characterization of antibodies can elucidate information about desired epitopes. Based on this information, antibodies that bind to the same epitope can then be competitively screened.

[0362] Binding affinity

[0363] The term "binding affinity" refers to the sum total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (K D ) is represented by. Affinity can be measured by common methods known in the art. Low-affinity antibodies generally bind antigen slowly and tend to dissociate easily, while high-affinity antibodies generally bind antigen faster and tend to remain bound for a longer time. In particular, the term "binding affinity" is intended to refer to the dissociation rate of a specific antigen-antibody interaction. K D The rate of dissociation is also called the off-rate (k off )" or "k d ” and the association rate or “on-rate (kon )" or "k a ". Therefore, K D Equal to k off / k on (or k d / k a ) and is expressed as a molar concentration (M). Therefore, K D The smaller the K, the stronger the binding affinity. D , 1 μM K D Indicates a weaker binding affinity. The K of an antibody can be determined using methods recognized in the art. D A method for determining the K value of an antibody D An exemplary method for determining the K of an antibody is by using surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE system. BIACORE kinetic analysis involves analyzing the binding and dissociation of an antigen to a chip having immobilized molecules (e.g., molecules comprising an epitope binding domain) on the surface. Another method for determining the K of an antibody is to use surface plasmon resonance (SPR), typically using a biosensor system such as a BIACORE system. D The method is to use Bio-Layer Interferometry, usually using Technology (Octet QK e System, ForteBio). Alternatively or additionally, the KinExA (kinetic exclusion assay) assay, available from Sapidyne Instruments (Boise, ID) may also be used.

[0364] Monospecific Antibodies

[0365] "Monospecific antibody" refers to an antibody that contains one or more antigen binding sites per molecule such that any and all binding sites of the antibody specifically recognize the same epitope on the antigen. Thus, where a monospecific antibody has more than one antigen binding site, the binding sites compete with each other for binding to one antigen molecule.

[0366] Bispecific Antibodies

[0367] "Bispecific antibodies" refer to molecules that have binding specificity for at least two different epitopes. In some embodiments, bispecific antibodies can bind to two different antigens simultaneously. In other embodiments, the two different epitopes can be present on the same antigen.

[0368] One-armed antibody

[0369] A one-armed antibody is an IgG antibody comprising a complete Fc domain with two hinge domains, two CH2 domains and two CH3 domains, and only one Fab region. Since a one-armed antibody has only a single Fab domain, it is monovalent and monospecific. Figure 1 Schematic diagram depicting a one-armed antibody.

[0370] Ineffective or disabled antibodies

[0371] An antibody comprising an ineffective arm (also referred to as "disabled") is a monovalent monospecific antibody in which one of the antigen binding sites has been modified (synonymous with engineered) to eliminate binding to the target. One or more of the heavy chain CDRs may have been modified to eliminate binding to the target, and advantageously, the light chain CDRs may be unmodified to facilitate antibody production and minimize mispairing. Modification or engineering can be shown by the described methods, wherein at least one structural feature is retained in each method step. Figure 1 Schematic diagram depicting the null arm antibody.

[0372] The half maximal effective concentration (EC 50 )

[0373] The term “half maximal effective concentration (EC 50 )” refers to the concentration of therapeutic agent that elicits a response halfway between baseline and maximum after a specified exposure time. Therapeutic agents can elicit either inhibition or stimulation. EC 50 The value is commonly used and is used herein as a measure of efficacy.

[0374] Agonists

[0375] "Agonist" refers to a substance that promotes (ie, induces, causes, enhances, or increases) the biological activity or action of another molecule. The term agonist encompasses substances (such as antibodies) that bind to a molecule to promote the activity of that molecule.

[0376] Antagonists

[0377] "Antagonist" refers to a substance that prevents, blocks, inhibits, neutralizes or reduces the biological activity or action of another molecule, such as a receptor. The term antagonist encompasses substances (such as antibodies) that bind to a molecule to prevent or reduce the activity of that molecule.

[0378] compete

[0379] As used herein, the term "competition" with respect to antibodies means that the first antibody binds to the epitope in a manner sufficiently similar to the binding of the second antibody, so that the result of the binding of the second antibody to its cognate epitope in the presence of the first antibody is detectably reduced compared to the binding of the second antibody in the absence of the first antibody. An alternative is possible but not necessarily so: the binding of the first antibody to its epitope in the presence of the second antibody can also be detectably reduced. That is, the first antibody can inhibit the binding of the second antibody to its epitope, while the second antibody does not inhibit the binding of the first antibody to its corresponding epitope. However, when each antibody detectably inhibits the binding of another antibody to its cognate epitope or ligand to the same, greater or lesser extent, the antibodies are said to "cross-compete" with each other to bind to their corresponding epitopes. The present invention encompasses both competing and cross-competing antibodies. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational changes, or binding to a common epitope or a portion thereof), those skilled in the art will understand based on the teachings provided herein that such competing or cross-competing antibodies are encompassed and applicable to the methods disclosed herein.

[0380] Host cells

[0381] "Host cell" refers to an individual cell or cell culture that can be or has been a recipient of one or more vectors for incorporating a polynucleotide insert. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with one or more polynucleotides of the invention.

[0382] Carrier

[0383] "Vector" refers to a construct that is capable of delivering and preferably expressing one or more genes or sequences of interest (e.g., antibody encoding genes) in a host cell. Examples of vectors include, but are not limited to, plasmids and viral vectors, and may include naked nucleic acids, or may include nucleic acids associated with delivery auxiliary materials (e.g., cationic condensing agents, liposomes, etc.). A vector may include DNA or RNA. As used herein, "expression vector" refers to a vector that includes at least one polypeptide encoding gene and at least one regulatory element (e.g., promoter sequence, poly (A) sequence) associated with the transcription or translation of a gene. Typically, the vector used herein contains at least one antibody encoding gene, and one or more of a regulatory element or a selectable marker. Vector components may include, for example, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcription control elements (such as promoters, enhancers, and terminators). For translation, one or more translation control elements may also be included, such as a ribosome binding site, a translation initiation site, and a stop codon.

[0384] Separate

[0385] An "isolated" molecule (e.g., an antibody) is one that, by its source or derivation (1) is not associated with naturally occurring binding components that accompany it in its native state; (2) is substantially free of other molecules from the same source (e.g., species, cell expressing it, library, etc.); (3) is expressed by cells from a different species; or (4) does not occur in nature. Thus, a molecule that has been chemically synthesized or expressed in a cellular system that is different from the system of its natural source will be "isolated" from its naturally occurring binding components. A molecule can also be rendered substantially free of naturally occurring binding components by isolation, using purification techniques well known in the art.

[0386] Peptide / Protein

[0387] "Polypeptide" or "protein" (used interchangeably herein) refers to a chain of amino acids of any length. The chain may be straight or branched. The chain may contain one or more of the modified amino acids. The term also encompasses amino acid chains that have been modified naturally or by intervention; for example, formation of disulfide bonds, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more amino acid analogs (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art. It should be understood that a polypeptide may appear as a single chain or associated chains.

[0388] Polynucleotides / Nucleic Acids

[0389] "Polynucleotide" or "nucleic acid" (used interchangeably herein) refers to a chain of nucleotides of any length, and includes DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases or their analogs, or any substrate that can be incorporated into the chain by DNA or RNA polymerase. The polynucleotide may contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure may be imparted before or after chain assembly. The nucleotide sequence may be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged bonds (e.g., methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and those with charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), those containing side chain moieties such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidized metals, etc.), those containing alkylating agents, those with modified bonds (e.g., alpha mutarotomers, etc.), and unmodified forms of polynucleotides. In addition, any hydroxyl group typically present in a sugar may be replaced, for example, by a phosphonate group, a phosphate group, protected by a standard protecting group, or activated to prepare additional linkages with additional nucleotides, or may be conjugated to a solid support. The 5' and 3' terminal OH groups may be phosphorylated or substituted with amines or organic capping groups having 1 to 20 carbon atoms. Other hydroxyls may also be derivatized as standard protecting groups. Polynucleotides may also contain similar forms of ribose or deoxyribose generally known in the art, including, for example, 2'-O-methyl-ribose, 2'-O-allyl-ribose, 2'-fluoro-ribose or 2'-azido-ribose, carbocyclic sugar analogs, α- or β-mutanosaccharides, epimeric sugars (such as arabinose, xylose or lyxose); pyranose, furanose, sedoheptulose, acyclic analogs and abasic nucleoside analogs (such as methyl riboside).

[0390] Conservative substitution

[0391] "Conservative substitution" refers to replacing an amino acid by a biologically, chemically or structurally similar residue. Biologically similar means that the substituent does not destroy biological activity. Structurally similar means that the side chains of the amino acids have similar lengths (such as alanine, glycine and serine) or have similar sizes. Chemical similarity means that the residues have the same charge or are hydrophilic or hydrophobic. Specific examples include one hydrophobic residue (such as isoleucine, valine, leucine or methionine) replacing another, or one polar residue replacing another, such as arginine replacing lysine, glutamic acid replacing aspartic acid or glutamine replacing asparagine, serine replacing threonine and similar substitutions. Specific examples of conservative substitutions include one hydrophobic residue (such as isoleucine, valine, leucine or methionine) replacing another, one polar residue replacing another, such as arginine replacing lysine, glutamic acid replacing aspartic acid or glutamine replacing asparagine and similar substitutions. Conservative amino acid substitutions generally include, for example, substitutions within the following groups: glycine, alanine, valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.

[0392] Identity

[0393] The term "identity" or "identical to" refers to the overall relatedness between polymeric molecules, such as nucleic acid molecules (e.g., DNA molecules or RNA molecules) or between polypeptide molecules. "Identity" measures the percentage of identical matches between two or more sequences with gapped alignments solved by a specific mathematical model (e.g., algorithm) of computer programs well known in the art.

[0394] The terms "increase," "increase," "decrease," or "reduction" refer to values ​​relative to a baseline measurement, such as a measurement of the same individual before starting a treatment described herein, or a measurement of a control individual or subject (or multiple control individuals or subjects) in the absence of a treatment described herein. In some embodiments, a "control individual" is an individual suffering from the same form of disease or injury as the individual being treated. In some embodiments, a "control individual" is an individual who does not suffer from the same form of disease or injury as the individual being treated.

[0395] excipient

[0396] The term "excipient" refers to any material that allows the active ingredient to retain biological activity in combination with the active ingredient (e.g., antibody) of interest. The selection of excipients will depend to a large extent on factors such as mode of administration, the effect of excipients on solubility and stability, and the properties of the dosage form. As used herein, "excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, carriers, diluents, and the like that are compatible physiologically. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and isotonic agents, such as sugar, sodium chloride, or polyols (such as mannitol or sorbitol) may be included in the composition.

[0397] treat

[0398] The terms "treating", "treat" or "treatment" refer to any type of treatment, e.g., to relieve, lessen or slow the progression of a disease, disorder or condition in a patient or any tissue damage associated with the disease. In some embodiments, the disease, disorder or condition is one or more selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft versus host disease ( GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary bowel disorders, uveitis, and vasculitis.

[0399] prevention

[0400] The term "prevent" or "prevention" refers to one or more of a delay in the onset, reduction in frequency, or reduction in severity of at least one sign or symptom of a particular disease, disorder, or condition (e.g., AIDS) (e.g., AIDS specific to a particular application). In some embodiments, prevention is assessed on a population basis so that if a statistically significant reduction in the development, frequency, or intensity of one or more symptoms of a disease, disorder, or condition is observed in a population susceptible to the disease, disorder, or condition, then the agent is considered to "prevent" a particular disease, disorder, or condition. Prevention may be considered accomplished when the onset of a disease, disorder, or condition has been delayed for a predetermined period of time.

[0401] Subjects

[0402] The terms "subject", "individual" or "patient" (used interchangeably herein) refer to any animal, including mammals. Mammals according to the present invention include canines, felines, cattle, goats, horses, sheep, pigs, rodents, lagomorphs, primates, humans and the like, and encompass unborn mammals. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development. In some embodiments, the subject is a patient suffering from one or more diseases or conditions selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease GVHD, idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary bowel disorders, uveitis, and vasculitis.

[0403] Therapeutically effective amount

[0404] The term "therapeutically effective amount" refers to the amount of an active ingredient that elicits in a tissue, system, animal, individual or human the biological or medical response sought by the researcher, veterinarian, medical doctor or other clinician, which response may include one or more of the following:

[0405] (1) preventing a disease; for example, preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but who does not yet experience or display the pathology or symptomology of the disease;

[0406] (2) inhibiting a disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying pathology or symptomology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology or symptomology); and

[0407] (3) ameliorating a disease; e.g., improving a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology or symptomology).

[0408] Antibodies against TL1A

[0409] The present disclosure provides antibodies that bind to tumor necrosis factor-like ligand 1A (TL1A). TL1A is also known as vascular endothelial growth inhibitor (VEGI) and TNF superfamily member 15 (TNFSF15).

[0410] As used herein, the term "TL1A" includes variants, isoforms, homologs, orthologs, and paralogs of TL1A. In some embodiments, the antibodies disclosed herein cross-react with TL1A from species other than humans (such as TL1A from cynomolgus monkeys), as well as different forms of TL1A. In some embodiments, the antibodies may be completely specific for human TL1A and may not exhibit species cross-reactivity (e.g., not binding to mouse TL1A) or other types of cross-reactivity. As used herein, unless the context indicates otherwise, the term TL1A refers to naturally occurring human TL1A. Therefore, "TL1A antibody," "anti-TL1A antibody," or other similar designations mean any antibody that binds or reacts with TL1A, its isoforms, fragments, or derivatives (as defined herein). The full-length mature form of TL1A, as represented by UniProtKB / Swiss-Prot Accession No. AAI04463.1, is provided herein as SEQ ID NO: 208. The full length mature form of mouse TL1A, as represented by UniProtKB / Swiss-Prot Accession No. Q5UBV8, is provided herein as SEQ ID NO: 211. The full length mature form of cynomolgus monkey TL1A, as represented by UniProtKB / Swiss-Prot Accession No. XP_005581018.1, is provided herein as SEQ ID NO: 209.

[0411] TL1A, a member of the TNF superfamily, is a homotrimeric cytokine expressed by innate immune cells including monocytes, macrophages, and dendritic cells following induction or stimulation of TLRs via Fc-receptor cross-linking with ICs. Smaller subsets of activated T cells, endothelial cells, and fibroblasts also express TL1A. 20 ,twenty one ,22 . TL1A engages its receptor DR3 expressed on lymphocytes, NK cells, NKT cells, ILCs and epithelial cells in proinflammatory conditions to enhance the production of proinflammatory and profibrotic cytokines, and may also bind to the decoy receptor DcR3, which acts as a negative regulator. TL1A can act synergistically with IL-12 and IL-23 to enhance the activity of Th1 and Th17 cells by increasing cell proliferation and cytokine secretion. Importantly, TL1A can promote cytokine production in memory T cells independently of IL-12 and IL-23 in the presence of IL-15 and IL-18. In addition to direct activation of immune cells, recent studies have identified an additional role for TL1A in promoting intestinal fibrosis by exacerbating myofibroblast activity. 30 , and induces epithelial injury responses, including IL-8 secretion and decreased barrier function, via negative effects on tight junction proteins. Multiple lines of evidence suggest a significant role for TL1A in IBD, including multiple genome-wide association studies that identified several polymorphisms in the TL1A gene (TNFSF15) as an IBD susceptibility locus in European and Asian patient populations. 30,33 Additionally, increased expression of TL1A has been reported in inflamed tissues of IBD patients. 21,34

[0412] Without wishing to be bound by any particular theory, blocking TL1A cell-ligand interactions inhibits direct activation of immune cells and intestinal fibrosis.

[0413] Neutralizing or "blocking" antibodies are antibodies that bind to TL1A and do one or both of the following: (i) interfere with, limit or inhibit the interaction between TL1A and its ligand (such as the DR3 receptor); or (ii) cause inhibition of at least one biological function of ligand binding. Assays for determining neutralization by antibodies of the present disclosure are well known in the art.

[0414] The biological function or biological activity of TL1A may, but need not, be mediated by the interaction between TL1A and its ligand.

[0415] The anti-TL1A antibodies of the present disclosure may encompass monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab')2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single chains (ScFv), mutants thereof, fusion proteins comprising antibody fragments (e.g., domain antibodies), humanized antibodies, and any other modified configurations of immunoglobulin molecules comprising an antigen binding site with desired specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies may be murine, rat, human, or any other origin (including chimeric or humanized antibodies). In some embodiments, the anti-TL1A antibodies are monoclonal antibodies. In some embodiments, the anti-TL1A antibodies are human or humanized antibodies. In some embodiments, the anti-TL1A antibodies are chimeric antibodies.

[0416] In some embodiments, the invention provides a TL1A antibody having a light chain variable region (VL) sequence and a heavy chain variable region (VH) sequence as found in one or more of Tables 30, 31, 32, and 33, or a variant thereof.

[0417] The present invention also provides CDR portions of antibodies against TL1A. The determination of CDR regions is defined in Example 1. In some embodiments, the antibody comprises three CDRs of any one of the heavy chain variable regions shown in one or more of Tables 30, 31, 32, and 33. In some embodiments, the antibody comprises three CDRs of any one of the light chain variable regions shown in one or more of Tables 30, 31, 32, and 33. In some embodiments, the antibody comprises three CDRs of any one of the heavy chain variable regions shown in one or more of Tables 30, 31, 32, and 33, and three CDRs of any one of the light chain variable regions.

[0418] In some embodiments, the antibody comprises six CDRs of a TL1A antibody selected from one or more of Tables 30, 31, 32, and 33. In some embodiments, the antibody comprises a VH and a VL of a TL1A antibody each selected from one or more of Tables 83, 84, 85, 86, and 87. In some embodiments, the antibody comprises a HC and a LC of a TL1A antibody each selected from one or more of Tables 30, 31, 32, and 33.

[0419] In some embodiments, the present disclosure provides anti-TL1A antibodies containing variants of the CDR, VH, VL, HC and LC regions shown in one or more of Tables 30, 31, 32, and 33, wherein such variant polypeptides have at least 70%, at least 75%, at least 80%, at least 85%, at least 87%, at least 89%, 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% amino acid identity to any one of the amino acid sequences disclosed in one or more of Tables 30, 31, 32, and 33, these amounts are not intended to be limiting, and increments between the recited percentages are specifically contemplated as part of the present disclosure.

[0420] In some aspects, the disclosure provides an isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL) comprising a sequence selected from the group consisting of:

[0421] (i) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:42, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0422] (ii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:44, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0423] (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:47, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0424] (iv) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:49, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0425] (v) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:52, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0426] (vi) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:54, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0427] (vii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:57, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0428] (viii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:70, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0429] (ix) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:72, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0430] (x) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:78, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0431] (xi) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:80, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0432] (xii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:89, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0433] (xiii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:93, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0434] (xiv) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:95, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0435] (xv) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:97, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0436] (xvi) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:99, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:18;

[0437] (xvii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 101, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 18;

[0438] (xviii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 103, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 18;

[0439] (xix) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 105, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 18;

[0440] (xx) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 110, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 18; and

[0441] (xxi) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO: 120, and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO: 18.

[0442] In some aspects, the present disclosure provides an isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:42, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:18.

[0443] In some aspects, the present disclosure provides an isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), comprising a CDR-L1 sequence according to SEQ ID NO: 11, a CDR-L2 sequence according to SEQ ID NO: 12, and a CDR-L3 sequence according to SEQ ID NO: 13; and comprising a set of heavy chain CDRs selected from the following list:

[0444] (i) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0445] (ii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0446] (iii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:32;

[0447] (iv) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:35;

[0448] (v) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0449] (vi) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0450] (vii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0451] (viii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:35;

[0452] (ix) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0453] (x) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0454] (xi) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0455] (xii) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0456] (xiii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 31; a CDR-H3 sequence according to SEQ ID NO: 35;

[0457] (xiv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:38; a CDR-H3 sequence according to SEQ ID NO:35;

[0458] (xv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0459] (xvi) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0460] (xvii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 46; a CDR-H3 sequence according to SEQ ID NO: 35;

[0461] (xviii) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0462] (xix) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0463] (xx) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32;

[0464] (xxi) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 41; a CDR-H3 sequence according to SEQ ID NO: 35; or (xxii) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32.

[0465] In some aspects, the present disclosure provides an isolated antibody that specifically binds to TL1A, comprising a heavy chain variable region (TL1A-VH) and a light chain variable region (TL1A-VL), wherein the CDR-L1 sequence is according to SEQ ID NO: 11, the CDR-L2 sequence is according to SEQ ID NO: 12, and the CDR-L3 sequence is according to SEQ ID NO: 13; and wherein the CDR-H1 sequence is according to SEQ ID NO: 30, the CDR-H2 sequence is according to SEQ ID NO: 41, and the CDR-H3 sequence is according to SEQ ID NO: 32.

[0466] The TL1A antibody may comprise a TL1A-VH framework sequence containing a human germline VH framework sequence. The TL1A-VH framework sequence may comprise one or more amino acid substitutions, additions or deletions while still retaining functional and structural similarity to the germline from which it is derived. In some aspects, the VH framework is 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 the human germline VH framework sequence. In some aspects, the TL1A antibody comprises a TL1A-VH framework sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VH framework sequence. In some aspects, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on similarity to a VH excluding those portions defined herein as CDRs.

[0467] In some aspects, the TL1A-VH framework sequence can be derived from a human germline VH sequence selected from the group consisting of: IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, and IGHV1-2*02. The foregoing frameworks are modeled to be compatible with the TL1A-VH CDRs of the present invention. The present invention has identified that the human germline VH framework IGHV1-18*01 is highly advantageous in the context of the TL1A-VH CDRs of the present invention. In some aspects, the TL1A-VH framework sequence is derived from IGHV1-18*01.

[0468] The TL1A antibody may comprise a TL1A-VL framework sequence containing a human germline VL framework sequence. The TL1A-VL framework sequence may comprise one or more amino acid substitutions, additions or deletions while still retaining functional and structural similarity to the germline from which it is derived. In some aspects, the VL framework is 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 the human germline VL framework sequence. In some aspects, the TL1A antibody comprises a TL1A-VL framework sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VL framework sequence. In some aspects, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on similarity to a VL excluding those portions defined herein as CDRs.

[0469] The TL1A-VL framework sequence can be derived from a human germline VH sequence selected from the group consisting of: IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, and IGKV3-11*01. The aforementioned frameworks are modeled to be compatible with the TL1A-VLCDRs of the present invention. The present invention has identified that the human germline VL framework IGKV1-39*01 is highly advantageous in the context of the TL1A-VL CDRs of the present invention. In some aspects, the TL1A-VH framework sequence is derived from IGKV1-39*01.

[0470] TL1A-VL may comprise an amino acid sequence according to SEQ ID NO: 18, and TL1A-VH may comprise an amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120.

[0471] The TL1A antibody may comprise a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 42, and a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 18. The TL1A antibody may comprise a TL1A-VH sequence of SEQ ID NO: 42, and a TL1A-VL sequence of SEQ ID NO: 18.

[0472] The TL1A antibody may further comprise a heavy chain constant domain (TL1A-CH1) and a light chain constant domain (TL1A-CL). In some aspects of the disclosure, the TL1A-CH1 of the antibody comprises a sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. In some aspects of the disclosure, the TL1A-CL of the antibody comprises a sequence selected from the group consisting of: SEQ ID NO: 16 and SEQ ID NO: 201. TL1A-CH1 may comprise a sequence according to SEQ ID NO: 6. TL1A-CL may comprise a sequence according to SEQ ID NO: 16. TL1A-CH1 and TL1A-CL may each be part of a multispecific antibody.

[0473] TL1A-CH1 can be linked to TL1A-VH, and TL1A-CL can be linked to TL1A-VL, thereby forming a TL1A binding Fab domain (TL1A-Fab).

[0474] In some aspects, the antibody comprises a single TL1A-Fab domain.Examples of single TL1A-Fab domain antibodies are one-armed antibodies and bispecific antibodies.

[0475] The TL1A antibody of the present invention may comprise an antibody Fc domain comprising a first Fc chain and a second Fc chain. The Fc domain may be an Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4). The Fc domain may be an Fc domain of IgG1. The first Fc chain may comprise, from N-terminus to C-terminus: a first hinge region, a first CH2 region, and a first CH3 region, and the second Fc chain may comprise, from N-terminus to C-terminus: a second hinge region, a second CH2 region, and a second CH3 region. In some aspects, the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote binding of the first Fc chain to the second Fc chain.

[0476] The antibodies of the present invention may comprise a hinge region. The hinge region may be selected from any suitable sequence, including a sequence selected from any one of Tables 30, 31, 32 and 33. In some aspects, the hinge region is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, and SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204 and SEQ ID NO: 206.

[0477] In some aspects, the first hinge region and the second hinge region each contain one or more amino acid modifications that promote binding of the first hinge region to the second hinge region. The first hinge region and the second hinge region may each comprise different and complementary sequences, and the different and complementary sequences may be selected from one of the following different and complementary sequence pairs:

[0478] (i) SEQ ID NO: 179 and SEQ ID NO: 182; and

[0479] (ii) SEQ ID NO:189 and SEQ ID NO:191.

[0480] In some aspects particularly suitable for one-arm antibody variants, the antibody may comprise a modified full-length hinge (SEQ ID NO: 157) of a truncated Fc including a C(H230)S mutation. SEQ ID NO: 179 is a full-length hinge suitable for charge mutation variants RRR / EEE with D(H232)R and P(H241)R mutations. SEQ ID NO: 182 is a full-length hinge suitable for charge mutation variants RRR / EEE with D(H232)E and P(H241)E mutations. Thus, SEQ ID NO: 179 and SEQ ID NO: 182 are a pair of different and complementary hinge sequences. SEQ ID NO: 189 is a full-length hinge suitable for charge mutation variants RR / EE with D(H232)R mutations. SEQ ID NO: 191 is a full-length hinge suitable for charge mutation variants RR / EE with D(H232)E mutations. Thus, SEQ ID NO: 189 and SEQ ID NO: 191 are a pair of different and complementary hinge sequences. SEQ ID NO: 204 is the lower hinge region starting from D (H232) up to and including P (H243). SEQ ID NO: 206 is the upper hinge region starting from E (H226) up to and including C (H230) (it should be noted that SEQ ID NO: 204 and 206 are not the complete hinge region and are part of the mFd KiH bispecific antibody format).

[0481] The TL1A antibody of the present invention may comprise at least a first TL1A-CH1 domain, wherein the N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CH1 domain. TL1A-CL may be connected to a hinge region, which is then connected to a CH2 domain. Alternatively, TL1A-CH1 may be connected to a hinge region, which is then connected to a CH2 domain.

[0482] The CH2 region may comprise a sequence selected from any one of Tables 30, 31, 32 and 33. The CH2 domain may comprise SEQ ID NO: 8. The first CH2 region and the second CH2 region may each comprise a sequence according to SEQ ID NO: 8. The CH2 region may be connected to the CH3 region.

[0483] The CH3 region may comprise a sequence selected from any one of Tables 30, 31, 32, and 33. The CH3 region may comprise a sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 160, SEQ ID NO: 162, SEQ ID NO: 180, SEQ ID NO: 183, SEQ ID NO: 155, SEQ ID NO: 158, SEQ ID NO: 185, and SEQ ID NO: 187. In some aspects, the CH3 region on the first Fc chain and the CH3 region on the second Fc chain each comprise a sequence according to SEQ ID NO: 9. In some aspects, the first Fc chain comprises a first CH3 region, and the second Fc chain comprises a second CH3 region, and the first CH3 region and the second CH3 region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0484] (i) SEQ ID NO:160 and SEQ ID NO:162;

[0485] (ii) SEQ ID NO:180 and SEQ ID NO:183;

[0486] (iii) SEQ ID NO: 155 and SEQ ID NO: 158; and

[0487] (iv) SEQ ID NO:185 and SEQ ID NO:SEQ ID NO:187.

[0488] In some embodiments of the knob-and-hole (KiH) method of heterodimerization, the first CH3 region and the second CH3 region comprise SEQ ID NO: 160 and SEQ ID NO: 162 (including bispecific antibodies targeting TL1A and p40). In some embodiments of the knob-and-hole (KiH) method of heterodimerization, the first CH3 region and the second CH3 region comprise SEQ ID NO: 185 and SEQ ID NO: 187 (the 185 / 187 pair differs from the 160 / 162 pair in that there is no Cys residue). In some embodiments of the EEE / RRR, EE / RR or E / R method of heterodimerization, the first CH3 region and the second CH3 region comprise SEQ ID NO: 180 and SEQ ID NO: 183 (including bispecific antibodies targeting TL1A and p40).

[0489] The TL1A antibody may comprise a TL1A-VL carrying polypeptide. A TL1A-VL carrying polypeptide is a polypeptide comprising TL1A-VL, and one or more additional peptide regions, such as one or more additional antibody domains. A standard IgG light chain (LC) comprising TL1A-VL and CL is an example of a TL1A-VL carrying polypeptide. Exemplary TL1A-VL carrying polypeptides consisting essentially of TL1A-VL and CL include SEQ ID NO: 19 and SEQ ID NO: 202. The term TL1A-VL carrying polypeptide also includes polypeptides comprising TL1A-VL and other protein domains / peptides, such as hinge, CH2 and / or CH3 domains. TL1A LC-Fc (see Table 31, Fig. 8A and p40TL1A-0033) are examples of TL1A-VL carrying polypeptides comprising TL1A-VL fused to CL, which in turn is fused to a hinge domain, a CH2 domain, and a CH3 domain. Exemplary TL1A-VL carrying polypeptides comprising TL1A-VL, CL, a hinge domain, CH2, and CH3 include SEQ ID NO: 205 of p40TL1A-0033.

[0490] The TL1A antibody may comprise a TL1A-VH carrying polypeptide. A TL1A-VH carrying polypeptide is a polypeptide comprising TL1A-VH, and one or more additional peptide regions (such as one or more additional antibody domains). A standard IgG heavy chain (HC) comprising TL1A-VH, CH1, hinge domain, CH2, and CH3 is an example of a TL1A-VH carrying polypeptide. Exemplary TL1A-VH carrying polypeptides consisting essentially of TL1A-VH, CH1, hinge, CH2, and CH3 include HC sequences from Table 30, such as SEQ ID NO: 10, 23, 25, 27, 29, 34, 37, 40, 43, 45, 48, 50, 53, 55, 58, 60, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 111, 113, 115, 117, 119, 121, 123, 127, 132, 135, 138, 142, 144, 146, 150, 152, 154 and 172; TL1A HC sequence from Table 31: SEQ ID NO: 184, 188, 192, 194 and 200; TL1A HC sequence from Table 32: SEQ ID NO: 1 NO: 156, 161, 164, 165 and 166. The term TL1A-VH carrying polypeptide also includes polypeptides comprising TL1A-VH and other domains / peptides (such as only CH1 and / or short peptides). TL1A mFd (see Table 31, Fig. 8Aand p40TL1A-0033) are examples of TL1A-HL carrying polypeptides comprising TL1A-VH fused to CH1, in turn fused to a short peptide derived from IgG1 human upper hinge EPKSC and comprising Cys at position H230 (SEQ ID NO: 206). Exemplary TL1A-VH carrying polypeptides comprising TL1A-VH, CH1 and SEQ ID NO: 206 include SEQ ID NO: 207 of p40TL1A-0033.

[0491] The TL1A antibody may comprise two identical light chains (two identical TL1A-LC) and two identical heavy chains (two identical TL1A HC). The TL1A-LC may comprise a TL1A-VL fused to a CL domain. The TL1A-HC may comprise, and the TL1A-VH may comprise a sequence selected from any one of Tables 30, 31, 32, and 33. TL1A-VH may comprise a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% identical to a sequence selected from the group consisting of SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:58, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:90, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:111, and SEQ ID NO:121.

[0492] The TL1A-VL carrying polypeptide may comprise a sequence selected from any one of Tables 30, 31, 32 and 33. The TL1A-VL carrying polypeptide may comprise a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence according to SEQ ID NO: 19.

[0493] In some aspects, the TL1A antibody comprises two identical TL1A-Fab domains. In some aspects of the invention, the TL1A antibody comprises two identical light chains and two identical heavy chains. In some aspects, the TL1A antibody comprises two identical light chains comprising a sequence according to SEQ ID NO: 19. In some aspects, the TL1A antibody comprises two identical heavy chains comprising a sequence according to SEQ ID NO: 43.

[0494] In some aspects, the TL1A antibody is characterized by a TL1A IC of less than 20 nM in a competition ELISA. 50 The TL1A antibody may be characterized by a TL1A IC of less than 10 nM in a competition ELISA. 50 The TL1A antibody may be characterized by a TL1A IC of less than 50 nM in a TF-1 NFκB reporter cell bioassay 50 The TL1A antibody may be characterized by a TL1A IC of less than 30 nM in a TF-1 NFκB reporter cell bioassay 50 The TL1A antibody may be characterized by a TL1A IC of less than 1 nM in a whole blood IFNγ assay. 50 .

[0495] In some aspects, the TL1A antibody is bivalent and monospecific. Exemplary bivalent and monospecific Tl1A antibodies include a standard IgG format with two identical heavy chains and two identical light chains. Bivalent and monospecific TL1A antibodies are exemplified in Table 30. In some aspects, the antibody is characterized in that a score of less than 4 is measured in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay.

[0496] In some aspects, the TL1A antibody is a monovalent monospecific antibody. Such an antibody is monospecific because it can only bind to a single epitope or target; and is monovalent because it has only a single binding domain.

[0497] The present disclosure provides examples of two different formats of monospecific monovalent TL1A antibodies. The first format is a one-armed TL1A antibody comprising a single Fab domain fused to a functional Fc domain; and the second format is an antibody comprising a null arm, which is a TL1A antibody comprising a TL1A binding Fab domain and a second Fab domain that does not bind to TL1A or any other known target.

[0498] In some aspects, the TL1A antibody comprises a one-armed antibody. A one-armed antibody is an IgG antibody comprising a complete Fc domain with two hinge domains, two CH2 domains, and two CH3 domains, and only one Fab region. A one-armed TL1A antibody is an IgG TL1A antibody comprising a complete Fc domain with two hinge domains, two CH2 domains, and two CH3 domains, and only one TL1A-Fab region. In some aspects, the TL1A antibody comprises a monovalent monospecific antibody. A one-armed TL1A antibody is monovalent and monospecific because of its single TL1A Fab domain.

[0499] The one-armed antibody may comprise a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain is a heavy chain as described herein, and the first light chain is as described herein, and the second heavy chain does not comprise a VH domain or a CH1 domain.

[0500] The one-armed antibody may comprise a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, and wherein the first antibody heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 161, SEQ ID NO: 164, and SEQ ID NO: 165, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0501] The one-armed antibody may comprise a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0502] The one-armed antibody may comprise a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 164, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0503] The one-armed antibody may comprise a first heavy chain and a first light chain and a second heavy chain, wherein the first heavy chain and the first light chain comprise a TL1A binding site that binds to TL1A, wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 165, the first antibody light chain comprises the amino acid sequence of SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 163.

[0504] In some aspects, the antibody comprises a one-armed TL1A antibody, wherein the terminal half-life of the antibody in cynomolgus monkeys is less than 7 days. Such antibodies may be advantageous in applications where a shorter half-life is useful, such as certain oncology applications and applications in discrete organs or compartments such as the eye.

[0505] In some aspects, the TL1A antibody comprises a null arm. An antibody comprising a null arm is a monovalent monospecific antibody in which one of the antigen binding sites has been modified to eliminate binding to a target. In some aspects, the heavy chain CDRs have been modified to eliminate binding to a target. In some aspects, the light chain CDRs have not been modified. A null arm TL1A antibody is a monovalent monospecific TL1A antibody in which one of the antigen binding sites has been modified to eliminate binding to TL1A. In some aspects, one or more of the TL1AVH CDRs have been modified to eliminate binding to TL1A. A TL1A-VH comprising one or more CDRs modified to eliminate TL1A binding may be referred to as an xTL1A-VH. In some aspects, the TL1AVL CDRs have not been modified.

[0506] A null-arm TL1A antibody may comprise a single TL1A-VH and a single xTL1A-VH, and two identical TL1A-VLs.

[0507] In some aspects, CDR-H1, CDR-H2 and CDR-H3 are each derived from TL1A-VH. A CDR is derived from TL1A-binding VH if it is prepared or generated by modifying TL1A-binding VH by changing its amino acid sequence using the described methods, wherein at least one structural feature is retained at each method step.

[0508] In some aspects, the null-arm TL1A antibody comprises an xTL1A-VH comprising a sequence corresponding to a sequence selected from the group consisting of SEQ ID NO:131, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:141, SEQ ID NO:145, SEQ ID NO:149, SEQ ID NO:151, SEQ ID NO:153.

[0509] In some aspects, the antibody comprises a null-arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab) (as described herein), and the second heavy chain and the second light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to a target (xTL1A-Fab), and wherein the first and second light chains are identical.

[0510] In some aspects, the xTL1A-Fab comprises a VH comprising a sequence corresponding to a sequence selected from the group consisting of SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 149, SEQ ID NO: 151, SEQ ID NO: 153. The xTL1A-Fab can be combined with any of the TL1A-VH described herein to generate a null-arm TL1A antibody.

[0511] In some aspects, an antibody comprising TL1A-Fab and xTL1A-Fab may be referred to as a null-arm TL1A antibody.

[0512] In some aspects, the null-arm TL1A antibody comprises a sequence as set forth in Table 30. In some aspects, the null-arm TL1A antibody is selected from the group consisting of: [xTL1A]-0336; [xTL1A]-0338; [xTL1A]-0341; [xTL1A]-0347; [xTL1A]-0349; [xTL1A]-0352; [xTL1A]-0358; [xTL1A]-0360; [xTL1A]-0363, and as set forth in Table 30. Any of these antibodies can be produced using a modified Fc domain, and can, for example, incorporate LS mutations or alternative heterodimerization strategies such as KiH.

[0513] In some aspects, the antibody comprises an invalid arm TL1A antibody, wherein the second Fab domain comprises a non-binding TL1A heavy chain variable region (xTL1A-VH) and a non-binding TL1A light chain variable region (xTL1A-VL), wherein the CDR-L1 sequence is according to SEQ ID NO: 11, the CDR-L2 sequence is according to SEQ ID NO: 12, and the CDR-L3 sequence is according to SEQ ID NO: 13, and wherein (i) the CDR-H1 sequence is according to SEQ ID NO: 139; the CDR-H2 sequence is according to SEQ ID NO: 140; and the CDR-H3 sequence is according to SEQ ID NO: 133;

[0514] (ii) the CDR-H1 sequence is according to SEQ ID NO: 128; the CDR-H2 sequence is according to SEQ ID NO: 129; and the CDR-H3 sequence is according to SEQ ID NO: 130;

[0515] (iii) the CDR-H1 sequence is according to SEQ ID NO: 128; the CDR-H2 sequence is according to SEQ ID NO: 129; and the CDR-H3 sequence is according to SEQ ID NO: 133;

[0516] (iv) the CDR-H1 sequence is according to SEQ ID NO: 128; the CDR-H2 sequence is according to SEQ ID NO: 129; and the CDR-H3 sequence is according to SEQ ID NO: 136;

[0517] (v) CDR-H1 sequence is according to SEQ ID NO: 139; CDR-H2 sequence is according to SEQ ID NO: 140; CDR-H3 sequence is according to SEQ ID NO: 130;

[0518] (vi) CDR-H1 sequence is according to SEQ ID NO: 139; CDR-H2 sequence is according to SEQ ID NO: 140; CDR-H3 sequence is according to SEQ ID NO: 136;

[0519] (vii) CDR-H1 sequence is according to SEQ ID NO: 147; CDR-H2 sequence is according to SEQ ID NO: 148; CDR-H3 sequence is according to SEQ ID NO: 130;

[0520] (viii) the CDR-H1 sequence is according to SEQ ID NO:147; the CDR-H2 sequence is according to SEQ ID NO:148; and the CDR-H3 sequence is according to SEQ ID NO:133; or (ix) the CDR-H1 sequence is according to SEQ ID NO:147; the CDR-H2 sequence is according to SEQ ID NO:148; and the CDR-H3 sequence is according to SEQ ID NO:136.

[0521] In some aspects, the antibody comprises an empty arm TL1A antibody, wherein the second Fab domain comprises a heavy chain variable region (xTL1A-VH) and a light chain variable region (xTL1A-VL), wherein the CDR-L1 sequence is according to SEQ ID NO: 11, the CDR-L2 sequence is according to SEQ ID NO: 12, and the CDR-L3 sequence is according to SEQ ID NO: 13; and wherein the CDR-H1 sequence is according to SEQ ID NO: 139, the CDR-H2 sequence is according to SEQ ID NO: 140, and the CDR-H3 sequence is according to SEQ ID NO: 133.

[0522] In some aspects, the antibody comprises an invalid arm TL1A antibody, wherein the second Fab domain comprises a light chain variable region amino acid sequence according to SEQ ID NO: 18, and wherein the second Fab domain comprises a heavy chain variable region amino acid sequence according to a sequence selected from the group consisting of: SEQ ID NO: 143, SEQ ID NO: 131, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 141, SEQ ID NO: 145, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 149, SEQ ID NO: 151 and SEQ ID NO: 153.

[0523] In some aspects, the antibody comprises a null-arm TL1A antibody, wherein the second Fab domain comprises a light chain variable region amino acid sequence according to SEQ ID NO:18, and wherein the second Fab domain comprises a heavy chain variable region amino acid sequence according to SEQ ID NO:143.

[0524] In some aspects, the antibody comprises an empty arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab), and the second heavy chain and the second light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to the target (xTL1A-Fab), wherein the first antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 166.

[0525] In some aspects, the antibody comprises an empty arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab), and the second heavy chain and the second light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to the target (xTL1A-Fab), wherein the first antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 166.

[0526] In some aspects, the antibody comprises an invalid arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab), and the second heavy chain and the second light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to the target (xTL1A-Fab), wherein the first antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 161, the first antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, the second antibody light chain comprises the amino acid sequence according to SEQ ID NO: 19, and the second antibody heavy chain comprises the amino acid sequence according to SEQ ID NO: 166.

[0527] When determined by analytical size exclusion chromatography (aSEC), the null arm TL1A antibody can be characterized by a score of less than 2% high molecular mass species. aSEC analysis can be performed as described in the Examples herein.

[0528] The null-arm TL1A antibody may be characterized by a score of less than 7 in the Affinity Capture Self-Interaction Nanoparticle Spectroscopy (AC SINS) assay. The null-arm TL1A antibody may be characterized by a score of less than 6 in the Affinity Capture Self-Interaction Nanoparticle Spectroscopy (AC SINS) assay. The null-arm TL1A antibody may be characterized by a score of less than 5 in the Affinity Capture Self-Interaction Nanoparticle Spectroscopy (AC SINS) assay.

[0529] Null-arm TL1A antibodies may be characterized by a score in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay of less than 4. Null-arm TL1A antibodies may be characterized by a score in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay of less than 3. AC SINS analysis may be performed as described in the Examples herein.

[0530] Null arm TL1A antibodies may be characterized by an IC50 of less than 2 nM in a NFκB TL1A neutralization bioassay. Calculation of IC50 in a NFκB TL1A neutralization bioassay may be performed as described in the Examples herein.

[0531] In some aspects, the null-arm TL1A antibody binds to cynomolgus monkey TL1A within an order of magnitude of human TL1A as measured by SPR. In some aspects, the null-arm TL1A antibody has a binding affinity for human TL1A that is at least 500× higher than for mouse T1A as measured by SPR. In some aspects, the null-arm TL1A antibody has a binding affinity for human TL1A that is at least 2000× higher than for mouse T1A as measured by SPR. The null-arm TL1A antibody may be characterized by a KD of less than 500 pM as measured by SPR. The null-arm TL1A antibody may be characterized by a KD of less than 320 pM as measured by SPR. The null-arm TL1A antibody may be characterized by a KD of less than 300 pM as measured by SPR. Respective SPR assays may be performed as described in the Examples herein.

[0532] The null-arm TL1A antibody may be characterized by a terminal half-life in cynomolgus monkeys of at least 21 days. The null-arm TL1A antibody may be characterized by a terminal half-life in cynomolgus monkeys of at least 25 days. The null-arm TL1A antibody may be characterized by a terminal half-life in cynomolgus monkeys of at least 28 days.

[0533] The null-arm TL1A antibody may be characterized by a terminal half-life in cynomolgus monkeys between 21 days and 45 days. The null-arm TL1A antibody may be characterized by a terminal half-life in cynomolgus monkeys between 25 days and 35 days. The null-arm TL1A antibody may be characterized by a terminal half-life in cynomolgus monkeys between 28 days and 30 days.

[0534] Antibodies against p40

[0535] The present disclosure provides antibodies that bind to p40. The anti-p40 antibodies of the present invention may bind to one or more additional targets. P40 is also known as IL12B, CLMF, CLMF2, IL-12B, IMD28, NKSF, NKSF2, and IMD29. As used herein, the term "p40" includes one or more variants, isoforms, homologs, orthologs, and paralogs of p40. In some embodiments, the antibodies disclosed herein cross-react with p40 from species other than humans (such as p40 of cynomolgus monkeys) and different forms of p40. In some embodiments, the antibody may be completely specific to human p40 and may not exhibit species cross-reactivity or other types of cross-reactivity. Unless the context otherwise dictates, as used herein, the term p40 refers to naturally occurring human p40. "p40 antibody," "anti-p40 antibody," or other similar names mean any antibody (as defined herein) that binds or reacts to p40, its isoform, fragment, or derivative. The full-length mature form of p40 is represented by UniProtKB / Swiss-Prot Accession No. P29460. The full-length mature form of cynomolgus monkey p40 is represented by UniProtKB / Swiss-Prot Accession No. G7P6S2.

[0536] The p40 antibody may include a p40-VH framework sequence containing a human germline VH framework sequence. The p40-VH framework sequence may include one or more amino acid substitutions, additions or deletions while still retaining functional and structural similarities with the germline from which it is derived. In some aspects, the VH framework sequence is 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 the human germline VH framework sequence. In some aspects, the p40 antibody includes a p40-VH framework sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VH framework sequence. In some aspects, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on similarity to a VH excluding those portions defined herein as CDRs.

[0537] The present disclosure provides an isolated antibody that specifically binds to p40 via a p40 binding domain, and wherein the antibody comprises at least one additional antigen binding domain that specifically binds to TL1A, wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL) comprising the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO: 171, and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO: 177.

[0538] The present disclosure provides an isolated antibody that specifically binds to p40 via a p40 binding domain, and wherein the antibody comprises a TL1A antigen binding domain that specifically binds to aTL1A, and wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), wherein CDR-H1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 167, CDR-H2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 168, CDR-H3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 169, CDR-L1 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 173, CDR-L2 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 174, and CDR-L3 of the p40 binding domain comprises the amino acid sequence of SEQ ID NO: 175.

[0539] In some aspects, the p40-VH framework sequence can be derived from a human germline VH sequence selected from the group consisting of: DP3, DP7, DP73, DP75, and DP88. In some aspects, the p40-VH framework sequence is derived from DP73.

[0540] The p40-VH framework sequence can be derived from a human germline VH sequence selected from the group consisting of IGHV5-51*01 / 5-51*03, IGHV1-46*01 / 1-46*03, IGKV1-39*01, IGHV5-51*02, IGHV5-51*04, IGHV1-46*02, IGHV1-69-2*01, IGHV1-69*08, IGHV1-69*02, IGHV1-69*06 / 1-69*14, IGHV1-69*04 / 1-69*09, and IGHV1-2*02. In some aspects, the p40-VH framework sequence is derived from IGHV5-51*01 / 5-51*03.

[0541] The present invention has identified human germline IGHV5-51*01 / 5-51*03 (DP-73) as being highly favorable for the p40-VHCDR of the present invention. Experimental data confirm that for V L and VK1-33 (with L46S mutation), IGHV1-46*01 / 1-46*03 (DP-7) and IGKV1-39*01 or DPK9 (with L46S mutation) were advantageously able to maintain binding within a range of about 3-4 fold after transplantation. Other possible germlines suitable for use with the p40-VH CDR of the present invention include other IGHV5-51 locus germlines IGHV5-51*02 and IGHV5-51*04; other IGHV1-46 locus germlines, such as IGHV1-46*02, IGHV1-69-2*01 (DP-3); and other IGHV1-69 locus germlines IGHV1-69*08, IGHV1-69*02, IGHV1-69*06 / 1-69*14 (DP-88), IGHV1-69*04 / 1-69*09, and IGHV1-2*02 (DP-75). The aforementioned frameworks were modeled to be compatible with the p40-VH CDR of the present invention.

[0542] The p40 antibody may include a p40-VL framework sequence containing a human germline VL framework sequence. The p40-VL framework sequence may include one or more amino acid substitutions, additions or deletions while still retaining the functional and structural similarities with the germline from which it is derived. In some aspects, the VL framework is 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 the human germline VL framework sequence. In some aspects, the p40 antibody includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid substitutions, additions or deletions relative to the human germline VL framework sequence. In some aspects, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions are only in the framework region. In some aspects, the % identity is based on similarity to a VL excluding those portions defined herein as CDRs.

[0543] In some aspects, the p40-VL framework sequence can be derived from a human germline VL sequence selected from the group consisting of: DPK4, DPK5, DPK7, DPK8, and DPK9. In some aspects, the p40-VL framework sequence is derived from DPK7.

[0544] The p40-VL framework sequence can be derived from a human germline VL sequence selected from the group consisting of IGKV1D-16*01, IGKV1D-16*02, IGKV1-16*01, IGKV1-16*02, IGKV1-39*01, IGKV1-12*01 / 1-12*02 / 1D-12*01 / 1D-12*02, IGKV1-9*01, IGKV1-5*03, IGKV1-5*01, and IGKV1-27*01. In some aspects, the p40-VL framework sequence is derived from IGKV1D-16*01.

[0545] The present invention has identified that the human germline VL framework IGKV1D-16*01 (DPK7) is highly advantageous in the context of the p40-VL CDRs of the present invention. Advantageously, other VL germlines that can be used with the p40-VL region of the present invention include other IGKV1D-16 locus germlines IGKV1D-16*02, IGKV1-16*01, IGKV1-16*02, IGKV1-39*01 (DPK9), IGKV1-12*01 / 1-12*02 / 1D-12*01 / 1D-12*02 (DPK5), IGKV1-9*01 (DPK8), IGKV1-5*03, IGKV1-5*01, IGKV1-27*01 (DPK4). The aforementioned frameworks were modeled to be compatible with the p40-VL CDRs of the present invention.

[0546] In some aspects of the disclosure, the p40-CH1 of the antibody comprises a sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 195, and SEQ ID NO: 199. In some aspects of the disclosure, the p40-CL of the antibody comprises a sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201. p40-CH1 may comprise a sequence according to SEQ ID NO: 6. p40-CL may comprise a sequence according to SEQ ID NO: 16. p40-CH1 and p40-CL may each be part of a bispecific antibody.

[0547] p40-CH1 can be linked to p40-VH, and p40-CL can be linked to p40-VL, thereby forming a p40 binding Fab domain (p40-Fab).

[0548] The p40 antibody of the present invention may comprise a hinge region. The hinge region may be selected from any suitable sequence, including a sequence selected from any one of Tables 31 and 33. In some aspects, the hinge region is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, and SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204, and SEQ ID NO: 206.

[0549] p40-CL may be connected to a hinge region, which is then connected to a CH2 domain. Alternatively, p40-CH1 may be connected to a hinge region, which is then connected to a CH2 domain. The CH2 domain may comprise SEQ ID NO:8. The CH2 region may be connected to a CH3 region. The CH3 region may comprise a sequence selected from any one of Tables 31 and 33. The CH3 region may comprise a sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:160, SEQ ID NO:162, SEQ ID NO:180, SEQ ID NO:183, SEQ ID NO:155, SEQ ID NO:158, SEQ ID NO:185, and SEQ ID NO:187. In some aspects, the first Fc chain comprises a first CH3 region, and the second Fc chain comprises a second CH3 region, and the first CH3 region and the second CH3 region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0550] (i) SEQ ID NO:160 and SEQ ID NO:162;

[0551] (ii) SEQ ID NO:180 and SEQ ID NO:183;

[0552] (iii) SEQ ID NO: 155 and SEQ ID NO: 158;

[0553] (iv) SEQ ID NO:185 and SEQ ID NO:SEQ ID NO:187.

[0554] In some aspects, the first CH3 region and the second CH3 region comprise SEQ ID NO:160 and SEQ ID NO:162.

[0555] The p40-VH carrying polypeptide may comprise a sequence selected from any one of Tables 31 and 33. The p40-VH carrying polypeptide may comprise a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 181, SEQ ID NO: 186, SEQ ID NO: 190, SEQ ID NO: 193, SEQ ID NO: 196, and SEQ ID NO: 203.

[0556] The p40-VL carrying polypeptide may comprise a sequence selected from any one of Tables 31 and 33. The p40-VL carrying polypeptide may comprise a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence selected from the group consisting of SEQ ID NO: 178 and SEQ ID NO: 198.

[0557] In some aspects, the disclosure provides an isolated bispecific antibody that specifically binds p40 via a p40 binding domain and specifically binds TL1A via a TL1A binding domain, wherein the p40 binding domain comprises a heavy chain variable region (p40-VH) and a light chain variable region (p40-VL), wherein p40-VH comprises CDR-H1, CDR-H2, and CDR-H3 sequences encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127206, and p40-VL comprises CDR-L1, CDR-L2, and CDR-L3 sequences encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127205.

[0558] In some aspects, the disclosure provides a p40 antibody comprising: a p40-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127206; and a p40-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127205.

[0559] In some aspects, the disclosure provides a p40 antibody comprising a p40-VH carrying polypeptide sequence encoded by a plasmid deposited at ATCC and having ATCC deposit number PTA- 127204. In some aspects, the disclosure provides a p40 antibody comprising a p40-VL carrying polypeptide sequence encoded by a plasmid deposited at ATCC and having ATCC deposit number PTA-127203.

[0560] Antibodies against TL1A and p40

[0561] The present disclosure provides antibodies that bind to TL1A and p40. As used herein, the terms TL1A and p40 include variants, isoforms, homologs, orthologs, and paralogs of TL1A and p40, respectively. In some embodiments, the antibodies disclosed herein cross-react with one or more of TL1A and p40 from species other than humans, such as TL1A and p40 of cynomolgus monkeys. In some embodiments, the antibodies may be completely specific for TL1A and p40 and may not exhibit species cross-reactivity or other types of cross-reactivity. As used herein, unless the context dictates otherwise, the terms TL1A and p40 refer to naturally occurring human TL1A and p40. "TL1A / p40 antibody," "anti-TL1A / p40 antibody," or other similar designations mean any antibody that binds or reacts with TL1A and p40, isoforms, fragments, or derivatives thereof (as defined herein).

[0562] In some embodiments, the invention provides a TL1A / p40 antibody having a light chain variable region (VL) sequence and a heavy chain variable region (VH) sequence as found in one or more of Tables 30, 31, 32 and 33, or a variant thereof.

[0563] The present invention also provides CDR portions of TL1A / p40 antibodies. The determination of CDR regions is defined in Figure 10. In some embodiments, the TL1A / p40 antibody comprises six CDRs of a TL1A antibody selected from one of Tables 30, 31, 32, and 33. In some embodiments, the antibody comprises a VH and a VL of a TL1A antibody selected from one of Tables 30, 31, 32, and 33, and in some embodiments, the TL1A / p40 antibody comprises a sequence selected from one of Tables 30, 31, 32, and 33.

[0564] In some embodiments, the disclosure provides anti-TL1A / p40 antibodies containing variants of the CDR, VH, VL, HC, and LC regions shown in one or more of Tables 30, 31, 32, and 33, wherein such variant polypeptides have at least 70%, at least 75%, at least 80%, at least 85%, at least 87%, at least 89%, 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% amino acid identity to any one of the amino acid sequences disclosed in one or more of Tables 30, 31, 32, and 33. These amounts are not intended to be limiting, and increments between the recited percentages are specifically contemplated as being part of the disclosure.

[0565] The present disclosure provides an isolated antibody comprising a first antigen binding site that binds to TL1A and a second antigen binding site that binds to p40, wherein the first antigen binding site comprises a TL1A binding heavy chain variable region (TL1A-VH) and a TL1A binding light chain variable region (TL1A-VL), wherein the second antigen binding site comprises a p40 binding heavy chain variable region (p40-VH) and a p40 binding light chain variable region (p40-VL), and wherein the p40 binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 173, a CDR-L2 sequence according to SEQ ID NO: 174, and a CDR-L3 sequence according to SEQ ID NO: 175, a CDR-H1 sequence according to SEQ ID NO: 167, a CDR-H2 sequence according to SEQ ID NO: 168, and a CDR-H3 sequence according to SEQ ID NO: 169, and wherein the TL1A binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 11, a CDR-L2 sequence according to SEQ ID NO: 114, and a CDR-L3 sequence according to SEQ ID NO: 115. The CDR-L2 sequence according to SEQ ID NO: 12 and the CDR-L3 sequence according to SEQ ID NO: 13, and further comprising a set of heavy chain CDRs selected from the following list:

[0566] (i) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0567] (ii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0568] (iii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:32;

[0569] (iv) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:35;

[0570] (v) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0571] (vi) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0572] (vii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0573] (viii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:35;

[0574] (ix) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0575] (x) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0576] (xi) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0577] (xii) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32;

[0578] (xiii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 31; a CDR-H3 sequence according to SEQ ID NO: 35;

[0579] (xiv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:38; a CDR-H3 sequence according to SEQ ID NO:35;

[0580] (xv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32;

[0581] (xvi) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35;

[0582] (xvii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 46; a CDR-H3 sequence according to SEQ ID NO: 35;

[0583] (xviii) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32;

[0584] (xix) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35;

[0585] (xx) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32;

[0586] (xxi) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 41; a CDR-H3 sequence according to SEQ ID NO: 35; and

[0587] (xxii) CDR-H1 sequence according to SEQ ID NO: 109; CDR-H2 sequence according to SEQ ID NO: 56; CDR-H3 sequence according to SEQ ID NO: 32.

[0588] In some aspects, the disclosure provides an isolated antibody comprising a first antigen binding site that binds to TL1A and a second antigen binding site that binds to p40, wherein the first antigen binding site comprises a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), wherein the second antigen binding site comprises a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), and wherein (i) the p40 binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 173; a CDR-L2 sequence according to SEQ ID NO: 174; and a CDR-L3 sequence according to SEQ ID NO: 175; a CDR-H1 sequence according to SEQ ID NO: 167; a CDR-H2 sequence according to SEQ ID NO: 168; and a CDR-H3 sequence according to SEQ ID NO: 169, and (ii) the TL1A binding domain comprises a CDR-L2 sequence according to SEQ ID NO: 175; a CDR-L3 sequence according to SEQ ID NO: 176; a CDR-H1 sequence according to SEQ ID NO: 167; a CDR-H2 sequence according to SEQ ID NO: 168; and a CDR-H3 sequence according to SEQ ID NO: 169. according to the CDR-L1 sequence of SEQ ID NO:11; according to the CDR-L2 sequence of SEQ ID NO:12; and according to the CDR-L3 sequence of SEQ ID NO:13; according to the CDR-H1 sequence of SEQ ID NO:30; according to the CDR-H2 sequence of SEQ ID NO:41; and according to the CDR-H3 sequence of SEQ ID NO:32.

[0589] In some aspects, the TL1A / p40 antibody comprises a TL1A-VH framework sequence derived from a human germline VH sequence selected from the group consisting of IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02. In some aspects, the TL1A / p40 antibody comprises a TL1A-VH framework sequence derived from a human IGHV1-18*01 germline sequence.

[0590] In some aspects, the TL1A / p40 antibody comprises a TL1A-VL framework sequence derived from a human germline VL sequence selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV1-39*01, IGKV1-39*01, IGKV1-39*01, IGKV3D-7*01, IGKV3D-7*01, IGKV3D-7*01. In some aspects, the TL1A / p40 antibody comprises a TL1A-VL framework sequence derived from a human germline IGKV1-39*01 sequence.

[0591] In some aspects, the TL1A / p40 antibody comprises a TL1A-VL framework sequence and a TL1A-VH framework sequence, wherein one or both of the TL1A-VL framework sequence and the TL1A-VH framework sequence are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the human germline sequence from which they are derived.

[0592] In some aspects, the TL1A / p40 antibody comprises a TL1A-VL framework sequence and a TL1A-VH framework sequence, and wherein one or both of the TL1A-VL framework sequence or the TL1A-VH framework sequence are identical to the human germline sequence from which they are derived.

[0593] In some aspects, the TL1A-VL comprises an amino acid sequence according to SEQ ID NO: 18, and wherein the TL1A-VH comprises an amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO: 120.

[0594] In some aspects, the TL1A / p40 antibody comprises a TL1A-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:42 and a TL1A-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:18.

[0595] In some aspects, the TL1A / p40 antibody comprises the TL1A-VH sequence of SEQ ID NO:42, and the TL1A-VL of SEQ ID NO:18.

[0596] In some aspects, the TL1A / p40 antibody comprises a TL1A-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 228. In some aspects, the TL1A / p40 antibody comprises a TL1A-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 229.

[0597] In some aspects, the TL1A / p40 antibody comprises a TL1A-VH sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA- 127347. In some aspects, the TL1A / p40 antibody comprises a TL1A-VL sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA- 127348. In some aspects, the TL1A / p40 antibody comprises a TL1A-VH sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127347, and a TL1A-VL sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127348.

[0598] In some aspects, the TL1A / p40 antibody comprises a p40-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: DP3, DP7, DP73, DP75, and DP88. In some aspects, the TL1A / p40 antibody comprises a p40-VH framework sequence derived from a human DP73 germline sequence. In some aspects, the TL1A / p40 antibody comprises a p40-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPK4, DPK5, DPK7, DPK8, and DPK9. In some aspects, the TL1A / p40 antibody comprises a p40-VL framework sequence derived from a human germline DPK9 sequence.

[0599] In some aspects, the TL1A / p40 antibody comprises a p40-VL framework sequence and a p40-VH framework sequence, wherein one or both of the p40-VL framework sequence and the p40-VH framework sequence are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the human germline sequence from which they are derived. In some aspects, the TL1A / p40 antibody comprises a p40-VL framework sequence and a p40-VH framework sequence, and wherein one or both of the p40-VL framework sequence or the p40-VH framework sequence are identical to the human germline sequence from which they are derived.

[0600] In some aspects, the TL1A / p40 antibody comprises a p40-VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 177 and a p40-VL sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 171.

[0601] In some aspects, p40-VL comprises the amino acid sequence according to SEQ ID NO:177, and p40-VH comprises the amino acid sequence according to SEQ ID NO:171.

[0602] In some aspects, the TL1A / p40 antibody comprises a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO:238.

[0603] In some aspects, the TL1A / p40 antibody comprises a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO:239.

[0604] In some aspects, the TL1A / p40 antibody comprises a p40-VH sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127206. In some aspects, the TL1A / p40 antibody comprises a p40-VL sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127205. In some aspects, the TL1A / p40 antibody comprises a p40-VH sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127206, and a p40-VL sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127205.

[0605] In some aspects, the TL1A / p40 antibody comprises a TL1A-VH fused to a CH1 domain (TL1A-CH1) and a TL1A-VL fused to a light chain constant domain (TL1A-CL), thereby forming a TL1A binding Fab domain (TL1A-Fab). TL1A-CH1 may comprise a sequence according to a sequence selected from the group consisting of: SEQ ID NO: 6, and SEQ ID NO: 195, and SEQ ID NO: 199. TL1A-CH1 may comprise a sequence according to SEQ ID NO: 6. TL1A-CL may comprise a sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201. TL1A-CL may comprise a sequence according to SEQ ID NO: 16.

[0606] In some aspects, the TL1A / p40 antibody comprises a p40-VH fused to a CH1 domain (p40-CH1) and a p40-VL fused to a light chain constant domain (p40-CL), thereby forming a p40 binding Fab domain (p40-Fab). p40-CH1 may comprise a sequence according to a sequence selected from the group consisting of: SEQ ID NO: 6, and SEQ ID NO: 195, and SEQ ID NO: 199. p40-CH1 may comprise a sequence according to SEQ ID NO: 6. p40-CL may comprise a sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 197, and SEQ ID NO: 201. p40-CL may comprise a sequence according to SEQ ID NO: 16.

[0607] In some aspects, the TL1A / p40 antibody comprises an antibody Fc domain comprising a first Fc chain and a second Fc chain. The Fc domain may be an Fc domain of IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4). In some aspects, the Fc domain is an Fc domain of IgG1.

[0608] In some aspects, the TL1A / p40 antibody comprises: a first Fc chain, which comprises from N-terminus to C-terminus: a first hinge region, a first CH2 region, and a first CH3 region; and a second Fc chain, which comprises from N-terminus to C-terminus: a second hinge region, a second CH2 region, and a second CH3 region. In some aspects, the N-terminus of the first Fc chain is connected to the C-terminus of the first TL1A-CL domain. In some aspects, the N-terminus of the second Fc chain is connected to the C-terminus of the first p40-CH1 domain. In some aspects, the first CH2 region and the second CH2 region each comprise a sequence according to SEQ ID NO: 8.

[0609] In some aspects, either or both of the first hinge regions comprise a sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 157, SEQ ID NO: 179, SEQ ID NO: 182, and SEQ ID NO: 189, SEQ ID NO: 191, SEQ ID NO: 204, and SEQ ID NO: 206. In some aspects, the first hinge region and the second hinge region each contain one or more amino acid modifications that promote binding of the first hinge region to the second hinge region.

[0610] In some aspects, the first hinge region and the second hinge region each comprise a different and complementary sequence, and the different and complementary sequence is selected from one of the following different and complementary sequence pairs:

[0611] (i) SEQ ID NO: 179 and SEQ ID NO: 182 (EEE); and

[0612] (ii) SEQ ID NO:189 and SEQ ID NO:191 (EE).

[0613] The first hinge region may comprise a sequence according to SEQ ID NO: 204. The second hinge region may comprise a sequence according to SEQ ID NO:7.

[0614] In some aspects, the first Fc chain and the second Fc chain each contain one or more amino acid modifications that promote binding of the first Fc chain to the second Fc chain. The first Fc chain may include a first CH3 region, and the second Fc chain may include a second CH3 region, and the first CH3 region and the second CH3 region each contain different and complementary sequences, and the different and complementary sequences are selected from one of the following different and complementary sequence pairs:

[0615] (i) SEQ ID NO:160 and SEQ ID NO:162;

[0616] (ii) SEQ ID NO: 180 and SEQ ID NO: 183 (EEE, EE, E);

[0617] (iii) SEQ ID NO: 155 and SEQ ID NO: 158; and

[0618] (iv) SEQ ID NO:185 and SEQ ID NO:SEQ ID NO:187.

[0619] When the first and second CH3 domains comprise SEQ ID NO: 160 and SEQ ID NO: 162, these CH3 domains work well with complementary hinge pairs of SEQ ID NO: 179 and SEQ ID NO: 182 (EEE / RRR heterodimerization strategy), or SEQ ID NO: 189 and SEQ ID NO: 191 (EE / RR heterodimerization strategy).

[0620] In some aspects, the TL1A / p40 antibody comprises a TL1A-Fab, wherein the TL1A-CL is covalently fused to the first hinge region. In some aspects, the TL1A-CL is covalently fused to the first Fc chain. In some aspects, the TL1A-CL is covalently fused to the first Fc chain via the first hinge region.

[0621] In some aspects, the TL1A / p40 antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, and a fourth polypeptide chain, such that the first and third polypeptide chains together form a TL1A-Fab, and the second and fourth polypeptide chains together form a p40-Fab. In some aspects, the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, and the fourth polypeptide chain have a combination of sequences according to one of the groups selected from the following list: (i) the first polypeptide sequence is according to SEQ ID NO: 205, the second polypeptide is according to SEQ ID NO: 203, the third polypeptide is according to SEQ ID NO: 207, and the fourth polypeptide is according to SEQ ID NO: 178;

[0622] (ii) the first polypeptide sequence is according to SEQ ID NO: 188, the second polypeptide is according to SEQ ID NO: 186, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178;

[0623] (iii) the first polypeptide sequence is according to SEQ ID NO: 192, the second polypeptide is according to SEQ ID NO: 190, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178;

[0624] (iv) the first polypeptide sequence is according to SEQ ID NO:194, the second polypeptide is according to SEQ ID NO:193, the third polypeptide is according to SEQ ID NO:19, and the fourth polypeptide is according to SEQ ID NO:178; or (v) the first polypeptide sequence is according to SEQ ID NO:200, the second polypeptide is according to SEQ ID NO:196, the third polypeptide is according to SEQ ID NO:202, and the fourth polypeptide is according to SEQ ID NO:198.

[0625] In some aspects, the TL1A / p40 antibody comprises a first polypeptide sequence according to SEQ ID NO:205, a second polypeptide according to SEQ ID NO:203, a third polypeptide according to SEQ ID NO:207, and a fourth polypeptide according to SEQ ID NO:178.

[0626] In some aspects, the invention provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, and a fourth polypeptide chain, such that the first and third polypeptide chains together form a TL1A binding region, and the second and fourth polypeptide chains together form a p40 binding region, and wherein the first polypeptide sequence is according to SEQ ID NO: 205, the second polypeptide is according to SEQ ID NO: 203, the third polypeptide is according to SEQ ID NO: 207, and the fourth polypeptide is according to SEQ ID NO: 178.

[0627] In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, and a fourth polypeptide chain, such that the first and third polypeptide chains together form a TL1A binding region, and the second and fourth polypeptide chains together form a p40 binding region, and wherein the first polypeptide sequence comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit Number PTA-127349, the second polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit Number PTA-127346, the third polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit Number PTA-127350, and the fourth polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit Number PTA-127203.

[0628] In some aspects, the present disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, comprising CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the present disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, comprising VH and VL of an antibody that binds to TL1A selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the present disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, comprising CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the present disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, comprising CDRs of an antibody selected from one or more of Tables 30, 31, 32, and 33. In some aspects, the disclosure provides an isolated TL1A / p40 antibody that specifically binds to TL1A and p40, comprising the VH and VL of an antibody selected from one or more of Tables 30, 31, 32, and 33.

[0629] In some aspects, the TL1A / p40 antibody is characterized by a score in an affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay of less than 2. AC SINS analysis can be performed as described in the Examples herein.

[0630] In some aspects, the TL1A / p40 antibody is characterized in that the charge heterogeneity of the antibody is at least 50% non-acidic and non-basic as measured by antibody imaging capillary electrophoresis (iCE) for an unstressed sample to be evaluated (T0). The measurement of non-acidic and non-basic species by iCE can be performed as described in the Examples herein.

[0631] In some aspects, the TL1A / p40 antibody binds to immobilized human TL1A with a binding affinity of less than 1 nM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to immobilized human TL1A with a binding affinity of less than 500 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to immobilized human TL1A with a binding affinity of less than 300 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to human p40 with a binding affinity of less than 1 nM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to human p40 with a binding affinity of less than 900 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds to human p40 with a binding affinity of less than 600 pM as measured by SPR. In some aspects, the TL1A / p40 antibody binds p40 (IL-23) and TL1A simultaneously in an SPR assay in which the antibody is injected over immobilized TL1A and the resulting complex is then treated with IL-23. SPR can be performed as described in the Examples herein.

[0632] In some aspects, the TL1A / p40 antibody is characterized by an IC of less than 5 nM in a human IL-12 neutralization and Kit-225 assay. 50 The antibody may be characterized by an IC of less than 4 nM in a human IL-12 neutralization and Kit-225 assay 50 The antibody may be characterized by an IC of less than 2 pM in a human IL-12 neutralization and Kit-225 assay 50 The antibody may be characterized by an IC of less than 5 nM in a human IL-23 neutralization and Kit-225 assay 50 The antibody may be characterized by an IC of less than 4 nM in a human IL-23 neutralization and Kit-225 assay 50 The antibodies may be characterized by an IC of less than 1 nM in human IL-23 neutralization in human whole blood and in the Kit-225 assay 50 The antibodies may be characterized by an IC of less than 0.5 nM in the human IL-23 neutralization Kit-225 assay in human whole blood 50 In some aspects, the Kit-225 assay is in human whole blood. The corresponding Kit-225 assay can be performed as described herein for the examples of the corresponding assay.

[0633] In some aspects, the TL1A / p40 antibody is characterized by an IC of less than 5 nM in a cynomolgus monkey IL-23 neutralization and Kit-225 assay. 50 The antibody may be characterized by an IC of less than 2 nM in a cynomolgus monkey IL-12 neutralization and Kit-225 assay 50The antibody may be characterized by an IC50 of less than 1 nM in a cynomolgus monkey IL-12 neutralization and Kit-225 assay. The corresponding Kit-225 assay may be performed as described herein for the examples of the corresponding assay.

[0634] The antibody may be characterized by an IC of less than 2 nM in a human whole blood assay measuring inhibition of IFNγ 50 The antibody may be characterized by an IC of less than 3 nM in a human whole blood assay measuring inhibition of IFNγ 50 The antibody may be characterized by an IC of less than 2 nM in a human whole blood assay measuring inhibition of IFNγ 50 The antibody may be characterized by an IC of less than 500 pM in a human isolated CD4+ cell assay measuring inhibition of IFNγ 50 The antibody may be characterized by an IC of less than 100 pM in a human isolated CD4+ cell assay measuring inhibition of IFNγ 50 The antibodies may be characterized by an IC of less than 200 nM in a human NFκB neutralization assay in TF-1 reporter cells 50 The antibodies may be characterized by an IC of less than 150 nM in a human NFκB neutralization assay in TF-1 reporter cells 50 The respective IC-50 assays referred to in this paragraph can be performed as described in the Examples herein for the respective assays.

[0635] In some aspects, the TL1A / p40 antibody is characterized by a terminal half-life in TG32 mice of at least 10 days based on a two-week analysis. In some aspects, the terminal half-life in TG32 mice is at least 14 days based on a two-week analysis. In some aspects, the terminal half-life in TG32 mice is at least 16 days based on a two-week analysis. In some aspects, the terminal half-life in TG32 mice is at least 17 days based on a two-week analysis.

[0636] In some aspects, the TL1A / p40 antibody is characterized by a terminal half-life in cynomolgus monkeys of at least 21 days. In some aspects, the terminal half-life in cynomolgus monkeys is at least 25 days. In some aspects, the terminal half-life in cynomolgus monkeys is at least 28 days. The corresponding half-life determination assays in TG32 mice and cynomolgus monkeys can be performed as described in the examples for the corresponding assays herein.

[0637] In some aspects, the disclosure provides an isolated anti-TL1A / p40 antibody that specifically binds to TL1A via a TL1A heavy chain variable region (TL1A-VH) and a TL1A light chain variable region (TL1A-VL), and specifically binds to p40 via a p40 heavy chain variable region (p40-VH) and a p40 light chain variable region (p40-VL); wherein TL1A-VH comprises CDR-H1, CDR-H2, and CDR-H3 sequences encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127347, and TL1A-VH comprises ... L1A-VL comprises the CDR-L1, CDR-L2 and CDR-L3 sequences encoded by a plasmid deposited in the ATCC and having the ATCC deposit number PTA-127348; and p40-VH comprises the CDR-H1, CDR-H2 and CDR-H3 sequences encoded by a plasmid deposited in the ATCC and having the ATCC deposit number PTA-127206, and p40-VL comprises the CDR-L1, CDR-L2 and CDR-L3 sequences encoded by a plasmid deposited in the ATCC and having the ATCC deposit number PTA-127205.

[0638] In some aspects, the present disclosure provides an isolated anti-TL1A / p40 antibody that specifically binds to TL1A via a TL1A heavy chain variable region (TL1A-VH) and a TL1A light chain variable region (TL1A-VL), and specifically binds to p40 via a p40 heavy chain variable region (p40-VH) and a p40 light chain variable region (p40-VL); comprising a TL1A-VH sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127347, and a TL1A-VL sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127348; and comprising a p40-VH sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127206, and a p40-VL sequence encoded by a plasmid deposited at the ATCC with ATCC deposit number PTA-127205.

[0639] In some aspects, the present disclosure provides an isolated anti-TL1A / p40 antibody comprising: a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127203; a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127346; a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127349; and a sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127350.

[0640] Nucleic Acids

[0641] The disclosure also provides polynucleotides encoding any of the antibodies of the invention, including antibody portions and modified antibodies described herein. The invention also provides a method for making any of the antibodies and polynucleotides described herein. Polynucleotides and expressed proteins can be made by procedures known in the art.

[0642] If necessary, the antibody of interest (monoclonal or polyclonal) can be sequenced and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest can be maintained in a vector in a host cell, and the host cell can then be amplified and frozen for future use. The production of recombinant monoclonal antibodies in cell culture can be carried out by cloning antibody genes from B cells using means known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329, 112; U.S. Patent No. 7,314,622.

[0643] In some embodiments, a polynucleotide is provided herein, which comprises one or both sequences in the heavy chain or light chain variable region of the antibody provided herein. The sequence encoding the antibody of interest can be maintained in a vector in a host cell, and the host cell can then be amplified and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

[0644] In some embodiments, the disclosure provides polynucleotides encoding the amino acid sequence of any one of the antibodies listed in one or more of Tables 30, 31, 32, and 33. The polynucleotide may be RNA. The polynucleotide may comprise at least one chemical modification. The chemical modification can be selected from the group consisting of pseudouridine, 1-methylpseudouridine, N1-methylpseudouridine, N1-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine and 2'-O-methyluridine.

[0645] In some aspects, the polynucleotide comprises no chemical modifications.

[0646] In some aspects, an isolated polynucleotide is provided that encodes the VH, VL, or both of an antibody that binds to TL1A, wherein the nucleic acid comprises: the nucleic acid sequence of SEQ ID NO: 228, the nucleic acid sequence of SEQ ID NO: 229, or both.

[0647] E196. An isolated polynucleotide encoding a VH-carrying polypeptide and a VL-carrying polypeptide, or both, of an antibody that binds to TL1A, wherein the nucleic acid comprises the nucleic acid sequence of SEQ ID NO: 231, the nucleic acid sequence of SEQ ID NO: 233, or both.

[0648] In some aspects, an isolated polynucleotide is provided that encodes the VH, VL, or both of an antibody that binds to TL1A, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having the deposit number PTA-127347, the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having the deposit number PTA-127348, or both.

[0649] In some aspects, a VH-carrying polypeptide and a VL-carrying polypeptide or both of an antibody that binds to TL1A is provided, wherein the nucleic acid comprises the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having the deposit number PTA-127347, the nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having the deposit number PTA-127348, or both.

[0650] In some aspects, an isolated polynucleotide is provided, comprising one or more nucleic acids encoding one or more sequences of an invalid arm antibody that binds TL1A, wherein the invalid arm antibody comprises an invalid arm TL1A antibody comprising a first variable heavy chain and a first variable light chain and a second variable heavy chain and a second variable light chain, wherein the first variable heavy chain and the first variable light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab), and the second variable heavy chain and the second variable light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to a target (xTL1A-Fab), and wherein the first and second variable light chains are the same, and wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 228, the nucleic acid sequence of SEQ ID NO: 230, and / or the nucleic acid sequence of SEQ ID NO: 260.

[0651] In some aspects, an isolated polynucleotide is provided, comprising one or more nucleic acids encoding one or more sequences of an invalid arm antibody that binds TL1A, wherein the invalid arm antibody comprises an invalid arm TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab), and the second heavy chain and the second light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to a target (xTL1A-Fab), and wherein the first and second light chains are the same, and wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 231, the nucleic acid sequence of SEQ ID NO: 232, and / or the nucleic acid sequence of SEQ ID NO: 233.

[0652] In some aspects, an isolated polynucleotide is provided, comprising one or more nucleic acids encoding one or more sequences of an empty-armed antibody that binds TL1A, wherein the empty-armed antibody comprises an empty-armed TL1A antibody comprising a first heavy chain and a first light chain and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain comprise a first Fab domain that binds to TL1A (TL1A-Fab), and the second heavy chain and the second light chain comprise a second Fab domain that comprises a non-binding TL1A binding domain that does not specifically bind to a target (xTL1A-Fab), and wherein the first and second light chains are the same, and wherein the polynucleotide comprises one or more of the following: a nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127347, a nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127348, and a nucleic acid sequence of an insert of a plasmid deposited with the ATCC and having a deposit number of PTA-127351.

[0653] In some aspects, an isolated polynucleotide is provided that encodes one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising:

[0654] (iii) a TL1A-VH sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 228; and a TL1A-VL sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 229; and

[0655] (iv) a p40-VH sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 238; and a p40-VL sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 239.

[0656] In some aspects, an isolated polynucleotide is provided that encodes one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising:

[0657] (i) TL1A-VH, which carries a polypeptide sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 234; and TL1A-VL, which carries a polypeptide encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 235; and

[0658] (ii) a p40-HC sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 236; and a p40-LC sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 237.

[0659] In some aspects, an isolated polynucleotide is provided that encodes one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising:

[0660] (i) a TL1A-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127347; and a TL1A-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127348; and

[0661] (ii) a p40-VH sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127206; and a p40-VL sequence encoded by a plasmid deposited with the ATCC and having ATCC Deposit No. PTA-127205.

[0662] In some aspects, an isolated polynucleotide is provided that encodes one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising:

[0663] (i) TL1A-VH carries a polypeptide sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127350; and TL1A-VL carries a polypeptide sequence encoded by a plasmid deposited with the ATCC and having ATCC deposit number PTA-127349; and

[0664] (ii) p40-HC sequence, which is encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127346; and p40-LC sequence, which is encoded by a plasmid deposited with ATCC and having ATCC deposit number PTA-127203.

[0665] In some aspects, an isolated polynucleotide encoding a TL1A antibody VH domain is provided, comprising a nucleic acid sequence of SEQ ID NO: 228. In some aspects, an isolated polynucleotide encoding a TL1A antibody VL domain is provided, comprising a nucleic acid sequence of SEQ ID NO: 229. In some aspects, an isolated polynucleotide encoding a TL1A antibody VH domain engineered to eliminate TL1A binding is provided, comprising a nucleic acid sequence of SEQ ID NO: 230. In some aspects, an isolated polynucleotide encoding a TL1A antibody HC is provided, comprising a nucleic acid sequence of SEQ ID NO: 231. In some aspects, an isolated polynucleotide encoding a TL1A antibody HC engineered to eliminate TL1A binding is provided, comprising a nucleic acid sequence of SEQ ID NO: 232. In some aspects, an isolated polynucleotide encoding a TL1A antibody LC is provided, comprising a nucleic acid sequence of SEQ ID NO: 233. In some aspects, an isolated polynucleotide encoding a TL1A antibody mFd chain is provided, comprising a nucleic acid sequence of SEQ ID NO: 234. In some aspects, an isolated polynucleotide encoding a TL1A antibody LC-Fc chain is provided, comprising the nucleic acid sequence of SEQ ID NO: 235. In some aspects, an isolated polynucleotide encoding a p40 antibody HC is provided, comprising the nucleic acid sequence of SEQ ID NO: 236. In some aspects, an isolated polynucleotide encoding a p40 antibody LC is provided, comprising the nucleic acid sequence of SEQ ID NO: 237. In some aspects, an isolated polynucleotide encoding a p40 antibody VH is provided, comprising the nucleic acid sequence of SEQ ID NO: 238. In some aspects, an isolated polynucleotide encoding a p40 antibody VL is provided, comprising the nucleic acid sequence of SEQ ID NO: 239.

[0666] In some aspects, a vector is provided, comprising one or more of the polynucleotides provided herein.

[0667] In some aspects, an isolated host cell is provided, comprising one or more polynucleotides provided herein or vectors provided herein.

[0668] In some aspects, a method of producing an isolated antibody is provided, comprising culturing a host cell as provided herein under conditions that result in production of the antibody, and recovering the antibody.

[0669] In some aspects, a pharmaceutical composition is provided, comprising a therapeutically effective amount of an antibody as provided herein, and a pharmaceutically acceptable carrier.

[0670] Those of ordinary skill in the art will appreciate that, due to the degeneracy of the genetic code, there are many nucleotide sequences encoding polypeptides as described herein. Some of these polynucleotides have minimal homology to the nucleotide sequence of any natural gene. Nevertheless, the present invention particularly encompasses polynucleotides that change due to differences in codon usage. In addition, alleles of genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that change due to one or more mutations (such as deletions, additions or substitutions) of nucleotides. The resulting mRNA and protein may (but not necessarily) have a changed structure or function. Alleles can be identified using standard techniques (such as hybridization, amplification or database sequence comparisons).

[0671] In one embodiment, the VH and VL domains or the full-length HC or LC are encoded by separate polynucleotides. Alternatively, both VH and VL or HC and LC are encoded by a single polynucleotide.

[0672] The present disclosure also encompasses polynucleotides complementary to any such sequences. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond to DNA molecules in a one-to-one manner; and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may (but not necessarily) be present in the polynucleotides of the present disclosure, and polynucleotides may (but not necessarily) be linked to other molecules or support materials.

[0673] The polynucleotides of the present invention can be obtained using chemical synthesis, recombinant methods or PCR. Chemical polynucleotide synthesis methods are well known in the art and need not be described in detail herein. Those skilled in the art can use the sequences provided herein and commercial DNA synthesizers to produce the desired DNA sequence.

[0674] To prepare polynucleotides using recombinant methods, polynucleotides comprising the desired sequence can be inserted into a suitable vector, and the vector can then be introduced into a suitable host cell for replication and amplification, as further discussed herein. The polynucleotides can be inserted into the host cell by any means known in the art. The cells are transformed by introducing the exogenous polynucleotides using direct absorption, endocytosis, transfection, F-mating, or electroporation. Once introduced, the exogenous polynucleotides can be maintained in the cell as a non-integrating vector (such as a plasmid) or integrated into the host cell genome.

[0675] Suitable cloning vectors can be constructed according to standard techniques, or can be selected from a large number of cloning vectors available in the art. Although the selected cloning vector can vary according to the host cell intended to be used, suitable cloning vectors generally will have one or more characteristics, such as i) the ability to self-replicate, ii) a single target for a specific restriction endonuclease, or iii) a gene that can carry a marker that can be used to select clones containing the vector. Suitable examples include plasmids and bacterial viruses, such as pUC18, pUC19, Bluescript (e.g., pBS SK+) and derivatives thereof, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA, and shuttle vectors (such as pSA3 and pAT28). These and many other cloning vectors are available from commercial suppliers such as BioRad, Strategene, and Invitrogen.

[0676] An expression vector is further provided. An expression vector is generally a replicable polynucleotide construct containing a polynucleotide according to the present invention. It is implied that the expression vector must be replicable in a host cell as an episome or as an integral part of the chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, viral vectors (including adenoviruses, adeno-associated viruses, retroviruses), cosmids, and expression vectors disclosed in PCT Publication No. WO 87 / 04462. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcription control elements (such as promoters, enhancers, and terminators). For expression (i.e., translation), one or more translation control elements, such as ribosome binding sites, translation initiation sites, and stop codons, are also generally required.

[0677] The vector containing the polynucleotide of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation; transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran or other substances; microprojectile bombardment; liposome transfection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of the vector or polynucleotide to be introduced will often depend on the characteristics of the host cell.

[0678] The present invention also provides host cells comprising any of the polynucleotides described herein. Any host cell capable of overexpressing heterologous DNA can be used for the purpose of isolating the gene encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells are, but are not limited to, COS, HeLa and CHO cells. Also see PCT Publication No. WO 87 / 04462. Suitable non-mammalian host cells include prokaryotes (such as Escherichia coli (E. coli) or Bacillus subtilis (B. subtillis)) and yeast (such as Saccharomyces cerevisiae (S. cerevisae), Schizosaccharomyces pombe (S. pombe); or Kluyveromyces lactis (K. lactis)).

[0679] In addition, any number of commercially available and non-commercially available cell lines expressing polypeptides or proteins may be used in accordance with the present invention. Those skilled in the art will appreciate that different cell lines may have different nutritional requirements or may require different culture conditions to achieve optimal growth and polypeptide or protein expression, and will be able to modify the conditions as necessary.

[0680] Pharmaceutical composition

[0681] In other embodiments, the present invention comprises pharmaceutical compositions.

[0682] "Pharmaceutical composition" refers to a mixture of an antibody of the invention and one or more excipients. As used herein, a pharmaceutical composition may include one or more antibodies that bind to TL1A, and / or TL1A and p40, or one or more polynucleotides comprising sequences encoding one or more of these antibodies. These compositions may further include suitable excipients well known in the art, such as pharmaceutically acceptable excipients, including buffers.

[0683] The pharmaceutical compositions of the present invention may be in a variety of forms. These forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, and lyophilized powders. The form depends on the intended mode of administration and therapeutic application.

[0684] Other excipients and modes of administration known in pharmaceutical technology may also be used. The pharmaceutical compositions of the present invention may be prepared by any well-known pharmaceutical technology, such as effective formulation and administration procedures. The above considerations for effective formulation and administration procedures are well known in the art and described in standard textbooks. The formulation of drugs is discussed in, for example, the following: Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

[0685] Acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphates, citrates and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; alkyldimethylbenzyl ammonium chloride, anilinium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); or nonionic surfactants such as TWEEN TM 、PLURONICS TM or polyethylene glycol (PEG).

[0686] The invention provided herein further encompasses methods and compositions for treating, preventing or managing one or more disorders or diseases selected from the group consisting of: TL1A-related disorders, p40-related disorders, TL1A and p40-related disorders, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous skin inflammation, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary bowel disorders, uveitis, and vasculitis.

[0687] In one aspect, the present invention provides a method for treating a condition associated with one or more of TL1A and p40 expression in a subject. In some embodiments, the method for treating a condition associated with one or more of TL1A and p40 expression in a subject comprises administering to a subject in need thereof an effective amount of a composition (e.g., a pharmaceutical composition) comprising a corresponding anti-TL1A, anti-p40, or TL1A / p40 multispecific antibody as described herein. Conditions associated with TL1A and p40 expression include, but are not limited to, abnormal expression of one or more of TL1A and p40 expression, altered or abnormal expression of TL1A or p40.

[0688] In one aspect, the invention provides one or more of the group consisting of: anti-TL1A, anti-p40, and anti-TL1A / p40 antibodies described herein; or a pharmaceutical composition comprising such an antibody for use in therapy. In a specific embodiment, the invention also provides one or more of the anti-TL1A, anti-p40, anti-TL1A / p40 antibodies for use in treating a disorder associated with one or more TL1A and p40-related disorders.

[0689] The present invention further provides one or more selected from the group consisting of: anti-TL1A, anti-p40 and anti-TL1A / p40 antibodies as described herein; or pharmaceutical compositions comprising such antibodies for use in the manufacture of a medicament for use in therapy. In some embodiments, therapy is treatment of a condition associated with one or more of TL1A, p40 and TL1A / p40.

[0690] Treatment, diagnosis and other methods

[0691] The antibodies and antibody conjugates of the invention are useful in a variety of applications including, but not limited to, therapeutic treatment methods and diagnostic treatment methods.

[0692] The TL1A antibody of the present invention can inhibit the activity of TL1A, and can be suitable for treating, preventing, inhibiting and ameliorating TL1A-related diseases. The present invention provides a method for treating a disorder associated with TL1A expression. The present invention provides a method for treating a subject with one or more selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, Arthritis, multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary intestinal disorders, uveitis and vasculitis, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any TL1A antibody as described herein. The preceding sentence provides a list of disorders associated with TL1A expression.

[0693] In some aspects, the TL1A antibody of the present invention can inhibit the activity of TL1A and can be used to treat, prevent, inhibit and improve one or more diseases selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stricture Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic Gastroenteritis, graft-versus-host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary intestinal disorders, uveitis and vasculitis. In some aspects, the TL1A antibodies of the present invention may be suitable for treating, preventing, inhibiting and ameliorating asthma. In some aspects, the TL1A antibodies of the present invention may be suitable for treating, preventing, inhibiting and ameliorating NASH.

[0694] In another aspect, the present invention further provides an antibody or pharmaceutical composition as described herein for use in the described methods of treating one or more of the conditions associated with TL1A expression. The present invention also provides a use of an antibody as described herein for the manufacture of a medicament for treating one or more of the conditions associated with TL1A expression. In another aspect, a method of detecting, diagnosing or monitoring one or more of the conditions associated with TL1A expression is provided. For example, an anti-TL1A antibody as described herein can be labeled with a detectable moiety, such as an imaging agent and an enzyme substrate label. The antibodies as described herein can also be used in in vivo diagnostic assays, such as in vivo imaging (e.g., PET or SPECT) or staining reagents.

[0695] With respect to all methods described herein, reference to an anti-TL1A antibody also includes pharmaceutical compositions comprising an anti-TL1A antibody and one or more additional agents.

[0696] The TL1A / p40 antibody of the present invention can inhibit the activity of TL1A and / or p40, and can be used to treat, prevent, inhibit and improve TL1A and / or p40 related diseases. The present invention provides a method for treating a condition associated with TL1A expression. The present invention provides a method for treating one or more selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergy, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, graft versus host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis in a subject. , multiple sclerosis, myasthenia gravis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urinary intestinal disorders, uveitis and vasculitis, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any TL1A / p40 antibody as described herein. The preceding sentence provides a list of disorders associated with TL1A / p40 expression.

[0697] In some aspects, the TL1A / p40 antibodies of the present invention can inhibit the activity of TL1A and / or p40, and can be used to treat, prevent, inhibit and improve one or more diseases selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic edema, In some aspects, the TL1A antibody of the present invention may be used to treat, prevent, inhibit and improve asthma. In some aspects, the TL1A / p40 antibody of the present invention may be used to treat, prevent, inhibit and improve NASH.

[0698] In another aspect, the present invention further provides an antibody or pharmaceutical composition as described herein for use in the described methods of treating one or more of the conditions associated with TL1A and / or p40 expression. The present invention also provides a use of an antibody as described herein for the manufacture of a medicament for treating one or more of the conditions associated with TL1A and / or p40 expression. In another aspect, a method of detecting, diagnosing or monitoring one or more of the conditions associated with TL1A and / or p40 expression is provided. For example, an anti-TL1A / p40 antibody as described herein may be labeled with a detectable moiety, such as an imaging agent and an enzyme substrate label. The antibodies as described herein may also be used in in vivo diagnostic assays, such as in vivo imaging (e.g., PET or SPECT) or staining reagents.

[0699] With respect to all methods described herein, reference to an anti-TL1A / p40 antibody also includes pharmaceutical compositions comprising an anti-TL1A / p40 antibody and one or more additional agents.

[0700] Administration and dosing

[0701] Typically, the antibodies of the invention are administered in an amount effective to treat a condition as described herein. The antibodies of the invention can be administered as the antibodies themselves, or in the form of a pharmaceutical composition containing the antibodies.

[0702] The antibodies of the invention are administered by any appropriate route in the form of pharmaceutical compositions suitable for such route and in doses effective for the intended treatment.

[0703] In some embodiments, the antibody can be administered parenterally, for example, directly into the bloodstream, into a muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0704] In some aspects, the TL1A antibodies of the invention are administered subcutaneously. In some aspects, the TL1A / p40 antibodies of the invention are administered subcutaneously.

[0705] In another embodiment, the compounds of the present invention may also be topically applied to the skin or mucous membranes, i.e., transdermally or transdermally. In another embodiment, the compounds of the present invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may also be administered directly to the eye or ear.

[0706] The dosing regimen of the antibody of the present invention or the composition containing the antibody is based on a variety of factors, including the type, age, weight, sex and medical condition of the subject; the severity of the condition; the route of administration; and the activity of the specific antibody used. Therefore, the dosing regimen can vary widely. In one embodiment, for the treatment of the indicated condition discussed herein, the total daily dose of the antibody of the present invention is generally about 0.01 to about 100 mg / kg (i.e., mg antibody of the present invention / kg body weight). In another embodiment, the total daily dose of the antibody of the present invention is about 0.1 to about 50 mg / kg, and in another embodiment, about 0.5 to about 30 mg / kg.

[0707] Co-administration

[0708] The antibodies of the invention may be used alone or in combination with one or more other therapeutic agents.The invention provides any of the uses, methods or compositions as defined herein, wherein the antibodies of the invention are used in combination with one or more other therapeutic agents as discussed herein.

[0709] Administration of two or more agents "in combination" means that all agents are administered close enough in time to affect treatment of the subject. The two or more agents may be administered simultaneously or sequentially. Additionally, simultaneous administration may be performed by mixing the agents prior to administration or by administering the agents as separate dosage forms at the same time point but at the same or different sites of administration.

[0710] Various formulations of the antibodies of the invention (e.g., one or more of the anti-TL1A and anti-TL1A / p40 antibodies) can be used for administration. In some embodiments, the antibodies can be administered in pure form. In some embodiments, the antibodies and pharmaceutically acceptable excipients can be in various formulations. Pharmaceutically acceptable excipients are known in the art and are relatively inert substances that facilitate the administration of pharmacologically effective substances. For example, an excipient can impart form or consistency, or act as a diluent. Suitable excipients include, but are not limited to, stabilizers, wetting agents and emulsifiers, salts that change osmotic concentration, encapsulating agents, buffers, and skin penetration enhancers. Excipients and formulations for parenteral and non-parenteral drug delivery are described in Remington, The Science and Practice of Pharmacy 21st Edition Mack Publishing, 2005.

[0711] In some embodiments, these agents are formulated for administration by injection (e.g., intraperitoneal, intravenous, subcutaneous, intramuscular, etc.). Thus, these agents can be combined with a pharmaceutically acceptable vehicle, such as saline, Ringer's solution, dextrose solution, and the like. The specific dosing regimen, i.e., dosage, timing, and repetition will depend on the specific individual and the individual's medical history.

[0712] Antibodies as described herein (e.g., one or more of TL1A and TL1A / p40 antibodies) can be administered using any suitable method, including by injection (e.g., intraperitoneally, intravenously, subcutaneously, intramuscularly, etc.). Antibodies, such as monoclonal antibodies or multispecific antibodies, are also administered via inhalation as described herein. In general, for administration of the antibodies of the present invention, the dosage depends on the host being treated and the specific mode of administration. In one embodiment, the dosage range of the antibodies of the present invention will be from about 0.001 μg / kg body weight to about 20,000 μg / kg body weight. The term "body weight" is applicable when a patient is being treated. When treating isolated cells, as used herein, "body weight" refers to "total cell body weight." The term "total body weight" can be applied to both isolated cells and patient treatment. All concentrations and treatment (treatment) levels expressed as "body weight" or simply "kg" in this application are also considered to cover similar "total cell body weight" and "total body weight" concentrations. However, one of ordinary skill in the art will recognize the utility of various dosage ranges, for example, 0.01 μg / kg to 20,000 μg / kg body weight, 0.02 μg / kg to 15,000 μg / kg body weight, 0.03 μg / kg to 10,000 μg / kg body weight, 0.04 μg / kg to 5,000 μg / kg body weight, 0.05 μg / kg to 2,500 μg / kg body weight, 0.06 μg / kg to 1,000 μg / kg body weight, 0.07 μg / kg to 500 μg / kg body weight, 0.08 μg / kg to 400 μg / kg body weight, 0.09 μg / kg to 200 μg / kg body weight, or 0.1 μg / kg to 100 μg / kg body weight.In addition, those skilled in the art will recognize that a variety of different dosage levels will be used, for example, one or more selected from the group consisting of 0.0001 μg / kg, 0.0002 μg / kg, 0.0003 μg / kg, 0.0004 μg / kg, 0.005 μg / kg, 0.0007 μg / kg, 0.001 μg / kg, 0.1 μg / kg, 1.0 μg / kg, 1.5 μg / kg, 2.0 μg / kg, 5.0 μg / kg, 10.0 μg / kg, 15.0 μg / kg, 30.0 μg / kg, 50 μg / kg, 75 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg. In some embodiments, the present invention provides the present invention with the dosage of 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 12mg / kg, 15mg / kg, 20mg / kg and 30mg / kg. All these dosages are exemplary, and any dosage between these points is also expected to be used in the present invention. Any of the above dosage ranges or dosage levels can be used with the antibodies of the invention.For repeated administrations over several days or longer, depending on the condition, the treatment is continued until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved.

[0713] In general, for administration of an antibody provided herein, candidate dosages can be administered daily, weekly, every other week, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, every twelve weeks, or more than every twelve weeks.

[0714] In some embodiments, the candidate dose is administered daily in a dose range of about 1 μg / kg, to 30 μg / kg, to 300 μg / kg, to 3 mg / kg, to 30 mg / kg, to 100 mg / kg or more, depending on the factors mentioned above. For example, daily doses of about 0.01 mg / kg, about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, and about 25 mg / kg can be used.

[0715] In some embodiments, the candidate dose is administered weekly in a dose range of about 1 μg / kg, to 30 μg / kg, to 300 μg / kg, to 3 mg / kg, to 30 mg / kg, to 100 mg / kg or more, depending on the factors mentioned above. For example, weekly doses of about 0.01 mg / kg, about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, and about 30 mg / kg can be used.

[0716] In some embodiments, the candidate dose is administered every two weeks, with a dose range of about 1 μg / kg, to 30 μg / kg, to 300 μg / kg, to 3 mg / kg, to 30 mg / kg, to 100 mg / kg or more, depending on the factors mentioned above. For example, a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, and about 30 mg / kg can be used.

[0717] In some embodiments, a candidate dose is administered every three weeks in a dose range of about 1 μg / kg, to 30 μg / kg, to 300 μg / kg, to 3 mg / kg, to 30 mg / kg, to 100 mg / kg or more, depending on the factors mentioned above. For example, a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, and about 50 mg / kg every three weeks can be used.

[0718] In some embodiments, the candidate dose is administered monthly or every four weeks, depending on the factors mentioned above, with a dose range of about 1 μg / kg, to 30 μg / kg, to 300 μg / kg, to 3 mg / kg, to 30 mg / kg, to 100 mg / kg or more. For example, monthly doses of about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, and about 50 mg / kg can be used.

[0719] In other embodiments, a candidate dose is administered daily in a dosage range of about 0.01 mg to about 1200 mg or more, depending on the factors mentioned above. For example, a daily dose of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg can be used.

[0720] In other embodiments, the candidate dose is administered weekly in a dose range of about 0.01 mg to about 2000 mg or more, depending on the factors mentioned above. For example, a weekly dose of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg can be used.

[0721] In other embodiments, the candidate dose is administered every two weeks in a dosage range of about 0.01 mg to about 2000 mg or more, depending on the factors mentioned above. For example, a dose of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg every two weeks can be used.

[0722] In other embodiments, a candidate dose is administered every three weeks in a dosage range of about 0.01 mg to about 2500 mg or more, depending on the factors mentioned above. For example, a dose of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, or about 2500 mg every three weeks can be used.

[0723] In other embodiments, candidate doses are administered every four weeks or monthly, with doses ranging from about 0.01 mg to about 3000 mg or more, depending on the factors mentioned above. For example, a monthly dosage of about 0.01 mg, about 0.1 mg, about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, or about 3000 mg can be used.

[0724] Other dosing regimens may also be applicable, depending on the pharmacokinetic decay pattern that the physician wishes to achieve. In one embodiment, the antibodies of the present invention are administered with an initial priming dose, followed by a higher and / or continuous substantially constant dose. In some embodiments, administration is contemplated one to four times a week. In other embodiments, administration is contemplated once a month or every other month or every three months. The progress of this therapy is easily monitored by conventional techniques and analysis. The dosing regimen may vary over time.

[0725] For purposes of the present invention, the appropriate dosage of an antibody (e.g., one or more selected from the group consisting of TL1A and TL1A / p40 antibodies) will depend on: the antibody or composition thereof employed; the type and severity of the symptom to be treated; whether the agent is administered for therapeutic purposes; previous therapy; the patient's clinical history and response to the agent; the patient's clearance rate of the administered agent; and the judgment of the attending physician. Typically, the clinician will administer the antibody until a dose is reached that achieves the desired result. The dose and / or frequency may vary over the course of treatment. Empirical considerations, such as half-life, will generally aid in the determination of dosage. For example, antibodies that are compatible with the human immune system (such as humanized antibodies or fully human antibodies) can be used to extend the half-life of the antibody and prevent the antibody from being attacked by the host's immune system. The frequency of administration can be determined and adjusted during the course of treatment, and is generally (but not necessarily) based on the treatment and / or suppression and / or improvement and / or delay of symptoms. Alternatively, a sustained continuous release formulation of the antibody may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0726] In one embodiment, the dosage of an antibody (e.g., one or more selected from the group consisting of TL1A and TL1A / p40 antibodies) in an individual who has been given one or more administrations of the antibody can be determined empirically. Increasing doses of the antibody are given to the individual. Indicators of disease can be tracked to assess efficacy.

[0727] In some embodiments, the antibodies provided herein (e.g., one or more selected from the group consisting of TL1A and TL1A / p40 antibodies) can be administered to a subject who has previously received one or more antibodies selected from the group consisting of TL1A and TL1A / p40 antibody therapeutics to treat a disease. In some embodiments, the antibodies provided herein can be administered to a subject who has previously received an antibody selected from the group consisting of TL1A and TL1A / p40 antibody therapeutics to treat a disease, and wherein the aforementioned TL1A or TL1A / p40 antibody therapeutic had limited or no efficacy in the subject (e.g., wherein the subject's disease is resistant to treatment with the previous therapeutic).

[0728] For example, depending on the recipient's physiological condition, whether the administration is therapeutic or preventive, and other factors known to skilled physicians, administration of antibodies according to the methods of the present invention may be continuous or intermittent. Administration of antibodies may be substantially continuous over a preselected time period or may be in the form of a series of spaced dosages.

[0729] The therapeutic formulation of the antibody used according to the present invention is prepared for storage in the form of a lyophilized formulation or an aqueous solution by mixing an antibody having the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington, The Science and Practice of Pharmacy 21st edition, Mack Publishing, 2005). Acceptable carriers, excipients or stabilizers are nontoxic to the recipient at the dose and concentration employed, and may include buffers such as phosphates, citrates and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; alkyldimethylbenzyl ammonium chloride, anilinium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and metacresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0730] Reagent test kit

[0731] Another aspect of the present invention provides a kit comprising an antibody of the present invention or a pharmaceutical composition comprising the antibody. In addition to the antibody of the present invention or its pharmaceutical composition, the kit may include a diagnostic agent or a therapeutic agent. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes an antibody or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit includes an antibody or its pharmaceutical composition and one or more therapeutic agents.

[0732] A further aspect of the invention is a kit comprising one or more of the group consisting of TL1A and TL1A / p40 antibodies as disclosed herein above, and instructions for use according to any of the methods of the invention described herein. Generally, these instructions comprise a description of administering one or more of the group consisting of TL1A and TL1A / p40 antibodies for the therapeutic treatments described above.

[0733] In yet another embodiment, the invention comprises a kit suitable for performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the antibodies of the invention in an amount sufficient to perform the methods of the invention. In another embodiment, the kit comprises one or more antibodies of the invention in an amount sufficient to perform the methods of the invention, and at least a first container for the first dose and a second container for the second dose.

[0734] Several aspects of the pharmaceutical compositions, prophylactic or therapeutic agents of the invention are preferably tested in vitro, in cell culture systems, and in animal model organisms (such as rodent animal model systems) for desired therapeutic activity prior to use in humans.

[0735] Toxicity and efficacy of the prophylactic and / or therapeutic regimens of the invention can be determined by assays in cell cultures or experimental animals, such as those used to determine LD 50 (50% group lethal dose) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 / ED 50 Prophylactic and / or therapeutic agents that exhibit large therapeutic indices are preferred.

[0736] Furthermore, any assay known to those of skill in the art can be used to assess the prophylactic and / or therapeutic utility of the therapies or combination therapies disclosed herein for treating or preventing cancer.

[0737] Instructions for use of one or more of the group consisting of TL1A and TL1A / p40 antibodies as described herein generally include information on dosage, dosing schedule, and route of administration for the intended treatment. The container may be a unit dose, bulk (e.g., multi-dose packaging), or sub-unit dose. The instructions supplied in the kit of the invention are typically written instructions on a label or drug insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0738] The kit of the present invention is in a suitable packaged form. For each pharmaceutical composition and other reagents (e.g., buffer, balanced salt solution, etc.), packaging suitable for administering the pharmaceutical composition to a subject includes, but is not limited to, vials, ampoules, tubes, bottles, cans, flexible packages (e.g., sealed polyester film or plastic bags), and the like. Also contemplated are packages for combination with specific devices, such as inhalers, nasal administration devices (e.g., nebulizers), or infusion devices (such as mini-pumps). The kit may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is selected from the group consisting of TL1A and TL1A p40 antibodies. The container may further comprise a second pharmaceutically active agent.

[0739] Generally, the kit comprises a container and a label or package insert on or associated with the container.

[0740] The contents of U.S. Provisional Patent Application Nos. 62 / 949,120 (filed on December 17, 2019) and 63 / 110,693 (filed on November 6, 2020) are incorporated herein by reference for all purposes.

[0741] As used herein, "mammalian cells" include reference to cells derived from mammals, including humans, rats, mice, hamsters, guinea pigs, chimpanzees, or macaques. Cells can be cultured in vivo or in vitro.

[0742] As used herein, the term "purified product" refers to a preparation of product that has been separated from cellular components with which the product is normally associated or from other types of cells that may be present in a sample of interest.

[0743] As used herein, "substantially pure" refers to a material that is at least 50% pure (ie, free of impurities), more preferably at least 90% pure, more preferably at least 95% pure, still more preferably at least 98% pure, and optimally at least 99% pure.

[0744] Unless otherwise indicated, the term "non-human animals" of the present invention includes all non-human vertebrates, e.g., non-human mammals and non-mammals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, reptiles, mice, rats, rabbits or goats, etc.

[0745] As used herein, the term "pharmaceutically acceptable" refers to products or compounds that are approved (or approvable) by a regulatory agency of the Federal or a state government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.

[0746] As used herein, the term "pharmaceutically acceptable excipient, carrier or adjuvant" or "acceptable pharmaceutical carrier" refers to an excipient, carrier or adjuvant that can be administered to a subject with at least one antibody of the present disclosure and does not destroy the activity of the antibody. An excipient, carrier or adjuvant should be non-toxic when administered with the antibody at a dose sufficient to deliver a therapeutic effect.

[0747] As used herein, the term "improvement" means the alleviation or improvement of one or more symptoms compared to not administering the antibody molecule of the present invention."Improvement" also includes shortening or reducing the duration of symptoms.

[0748] As used herein, the terms "prevent," "preventing," and "prevention" refer to preventing the recurrence or onset of one or more symptoms of a disorder in a subject as a result of the administration of a prophylactic or therapeutic agent.

[0749] "Efficacy" is a measure of the activity of a therapeutic agent in terms of the amount required to produce an effect of a given intensity. A highly potent agent elicits a greater response at low concentrations than a less potent agent that elicits a smaller response at low concentrations. Efficacy is a function of affinity and efficacy. Efficacy refers to the ability of a therapeutic agent to produce a biological response when bound to a target ligand and the quantitative magnitude of that response.

[0750] Biological Deposit

[0751] Representative materials of the present invention were deposited on December 17, 2021 at the American Type Culture Collection, 10801 University Boulevard, Manassas, VA 20110-2209, USA.

[0752] The vector "SFab p40-LC" having ATCC deposit number PTA-127203 comprises a DNA insert encoding "SFab p40-LC" and comprises SEQ ID NO: 178. SFab p40-LC is also referred to herein as "p40-LC". The vector "p40-0003 VL" having ATCC deposit number PTA-127205 comprises a DNA insert encoding "p40-0003 VL" and comprises SEQ ID NO: 177. "p40-0003 VL" is referred to herein as "p40 VL". The vector "p40-0003VH" having ATCC deposit number PTA-127206 comprises a DNA insert encoding "p40-0003 VH" and comprises SEQ ID NO: 171. "p40-0003VH" is referred to herein as "p40 VH". The vector "p40-HC" having ATCC deposit number PTA-127346 comprises a DNA insert encoding "p40-HC" and comprises SEQ ID NO: 203. The vector "TL1A-0260-HC" having ATCC deposit number PTA-127347 comprises a DNA insert encoding "TL1A-0260-HC" and comprises SEQ ID NO: 161. "TL1A-0260-HC" is also referred to herein as TL1A HC (functional). The vector "TL1A-LC" having ATCC deposit number PTA-127348 comprises a DNA insert encoding "TL1A-LC" and comprises SEQ ID NO: 19. The vector "TL1A-LC-Fc" having ATCC deposit number PTA-127349 comprises a DNA insert encoding "TL1A-LC-Fc" and comprises SEQ ID NO: 205. The vector "TL1AmFd" having ATCC deposit number PTA-127350 comprises a DNA insert encoding "TL1AmFd" and comprises SEQ ID NO: 207. The vector "[xTL1A]-0349-HC" having ATCC deposit number PTA-127351 comprises a DNA insert encoding "[xTL1A]-0349-HC" and comprises SEQ ID NO: 166.

[0753] Antibody describe ATCC deposit number SEQ ID NO: DNA SEQ ID NO: P40TL1A-0033 SFab p40-LC PTA-127203 SEQ ID NO:178 SEQ ID NO:237 P40TL1A-0033 p40-0003VL PTA-127205 SEQ ID NO:177 SEQ ID NO:239 P40TL1A-0033 p40-0003VH PTA-127206 SEQ ID NO:171 SEQ ID NO:238 P40TL1A-0033 P40-HC PTA-127346 SEQ ID NO:203 SEQ ID NO:236 TL1A-0260 TL1A-0260-HC PTA-127347 SEQ ID NO:161 SEQ ID NO:231 TL1A-0260 TL1A-LC PTA-127348 SEQ ID NO:19 SEQ ID NO:233 P40TL1A-0033 TL1A-LC-Fc PTA-127349 SEQ ID NO:205 SEQ ID NO:235 P40TL1A-0033 TL1AmF PTA-127350 SEQ ID NO:207 SEQ ID NO:234 TL1A-0372 [xTL1A]-0349-HC PTA-127351 SEQ ID NO:166 SEQ ID NO:232

[0754] The deposit is made in accordance with the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure (Budapest Treaty) and the regulations thereunder. This ensures that active cultures of the deposit will be maintained for 30 years from the date of deposit. The deposit will be provided by ATCC under the terms of the Budapest Treaty and is subject to an agreement between Pfizer Inc. and ATCC that ensures perpetual and unrestricted public access to the progeny of the deposited cultures after the issuance of the related U.S. patent or after the publication of any U.S. or foreign patent application to the public, whichever occurs first, and to the progeny of the deposited cultures as determined by the authorized Commissioner of the United States Patent and Trademark Office pursuant to 35 U.S.C. Section 122 and the Commissioner's Rules thereunder (including 37 C.FR Section 1.14 with specific reference to 886 OG 638).

[0755] The assignee of this application has agreed that if a culture of the deposited material dies or is lost or destroyed when grown under suitable conditions, it will be replaced immediately upon notification. The availability of the deposited material should not be construed as a license to practice the invention in violation of the rights granted by any government agency under its patent laws.

[0756] Materials and methods

[0757] Various techniques have been described for producing antibodies, including the traditional hybridoma method for making monoclonal antibodies, recombinant techniques for making antibodies (including chimeric, e.g., humanized antibodies), production of antibodies in transgenic animals and the recently described phage display technology for making "fully human" antibodies.

[0758] Provided herein are methods for making any of the antibodies provided herein. The antibodies of the present invention can be made by procedures known in the art. The polypeptides can be produced by proteolysis or other degradation of the antibody, by recombinant methods as described above (i.e., single or fusion polypeptides), or by chemical synthesis. The polypeptides of the antibody (especially shorter polypeptides of up to about 50 amino acids) are preferably made by chemical synthesis. The methods of chemical synthesis are known in the art and are commercially available. For example, the antibody can be produced by an automated polypeptide synthesizer using a solid phase method. See also U.S. Patent Nos. 5,807,715; 4,816,567; and 6,331,415.

[0759] Any suitable method for making multispecific antibodies can be used to make the multispecific antibodies provided herein (eg, depending on the antibody characteristics and the choice of components).

[0760] According to a method for making a multi-specific antibody, an antibody variable domain with the desired binding specificity is fused to an immunoglobulin constant region sequence. Preferably, the immunoglobulin heavy chain constant region comprising at least part of the hinge, CH2 and CH3 regions is fused. In some embodiments, the first heavy chain constant region (CH1) containing the light chain binding site may be present in at least one of the fusions. In some embodiments, the polynucleotides encoding the immunoglobulin heavy chain fusion and (if necessary) the immunoglobulin light chain may be inserted into separate expression vectors and may be co-transfected into a suitable host organism. In other embodiments, when the expression of at least two polypeptide chains of equal ratios produces a high yield or when the ratio does not have a specific significance, the coding sequence of two or all three polypeptide chains may be inserted into an expression vector.

[0761] In one approach, a multispecific antibody is composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure (wherein an immunoglobulin light chain is in only half of the multispecific molecule) helps separate the desired multispecific compound from undesirable immunoglobulin chain combinations. This approach is described in PCT Publication No. WO 94 / 04690.

[0762] In another approach, the multispecific antibody is composed of amino acid modifications in the first hinge region in one arm, and the substituted amino acid in the first hinge region has an opposite charge to the corresponding amino acid in the second hinge region in the other arm. This approach is described in International Patent Application No. PCT / US2011 / 036419 (WO2011 / 143545).

[0763] In another approach, the formation of a desired heteromultimeric or heterodimeric protein (e.g., a bispecific antibody) is enhanced by altering or engineering the interface between the first and second Fc chains. In this approach, the multispecific antibody can be composed of a CH3 region, wherein the CH3 region comprises a first CH3 polypeptide and a second CH3 polypeptide, which interact together to form a CH3 interface, wherein one or more amino acids within the CH3 interface destabilize homodimer formation and electrostatically disfavor homodimer formation. This approach is described in International Patent Application No. PCT / US2011 / 036419 (WO2011 / 143545). In some embodiments, one Fc chain of the bispecific antibody may comprise an amino acid modification at positions 223 and 228 in the hinge region of human IgG2 (e.g., (C223E or C223R) and (P228E or P228R)) and at position 409 in the CH3 region of human IgG2 (e.g., K409R (EU numbering scheme)), and the other Fc chain of the bispecific antibody may comprise an amino acid modification at positions 223, 225, and 228 in the hinge region (e.g., (C223E or C223R), (E225R) and (P228E or P228R)) and at position 368 in the CH3 region (e.g., L368E (EU numbering scheme)). In other embodiments, one Fc chain of the bispecific antibody may comprise an amino acid modification at positions 223 and 228 in the hinge region of human IgG2 (e.g., (C223E or C223R) and (P228E or P228R)) and at position 368 in the CH3 region of human IgG2 (e.g., L368E (EU numbering scheme)), and the other Fc chain of the bispecific antibody may comprise an amino acid modification at positions 223, 225 and 228 in the hinge region (e.g., (C223E or C223R), (E225R) and (P228E or P228R)) and at position 409 in the CH3 region (e.g., K409R (EU numbering scheme)). In some embodiments, the bispecific antibody may comprise an amino acid modification at position 221 and 228 in the hinge region of human IgG1 (e.g., (D221R or D221E) and (P228R or P228E)) and at position 409 or 368 in the CH3 region (e.g., K409R or L368E (EU numbering scheme)). In some embodiments, the bispecific antibody may comprise an amino acid modification at position 228 in the hinge region of human IgG4 (e.g., (P228E or P228R)) and at position 409 or 368 in the CH3 region (e.g., R409 or L368E (EU numbering scheme)).

[0764] In some embodiments, the multispecific antibody may have a knob-in-hole mutation in the Fc chain. For example, in some embodiments, in a bispecific antibody having a knob-in-hole mutation, the first Fc chain of the antibody Fc domain has one or more mutations to form a "knob", and the second Fc chain of the antibody Fc domain has one or more mutations to form a "hole" (or vice versa). Exemplary knob-in-hole engineering of antibodies is described in U.S. Pat. No. 5,731,168, PCT Publication No. WO2009089004, U.S. Publication No. 20090182127, Marvin and Zhu, Acta Pharmacologica Sincia (2005) 26(6):649-658, and Kontermann (2005) Acta Pharacol. Sin., 26:1-9.

[0765] A "knob" refers to at least one amino acid side chain that protrudes from the interface of a first polypeptide (e.g., a first Fc chain) and can therefore be positioned in a compensatory hole in an adjacent second polypeptide (e.g., a second Fc chain) to stabilize the heterodimer and thereby promote heterodimer formation rather than homodimer formation. The knob may be present in the original interface or may be introduced synthetically (e.g., by altering the nucleic acid encoding the interface). Typically, the nucleic acid encoding the interface of the first polypeptide is altered to encode the knob. To achieve this, the nucleic acid encoding at least one original amino acid residue in the first polypeptide is replaced with a nucleic acid encoding at least one "import" amino acid residue having a larger side chain volume than the original amino acid residue. Certain import residues used to form the knob are typically naturally occurring amino acid residues and are preferably selected from arginine (R), phenylalanine (F), tyrosine (Y) and tryptophan (W).

[0766] "Hole" refers to at least one amino acid side chain that is recessed from the interface of a second polypeptide (e.g., a second Fc chain) and thus accommodates the corresponding knob in an adjacent first polypeptide (e.g., a first Fc chain). The hole may be present in the original interface or may be introduced synthetically (e.g., by altering the nucleic acid encoding the interface). Typically, the nucleic acid encoding the interface of the second polypeptide is altered to encode the hole. To achieve this, the nucleic acid encoding at least one original amino acid residue of the second polypeptide is replaced by DNA encoding at least one "import" amino acid residue having a smaller side chain volume than the original amino acid residue. Certain import residues used to form the hole are typically naturally occurring amino acid residues and are preferably selected from alanine (A), serine (S), threonine (T) and valine (V).

[0767] As used herein, the term "interface" generally refers to any amino acid residue present in a domain that may be involved in a contact point between a first polypeptide and a second polypeptide. An "original amino acid" residue is a residue that may be replaced by an "imported amino acid" residue having a side chain volume that is less than or greater than the original residue. The imported amino acid residue may be a naturally occurring or non-naturally occurring amino acid residue, but is preferably the former. "Naturally occurring" amino acid residues are those residues encoded by the genetic code. "Non-naturally occurring" amino acid residues refer to residues that are not encoded by the genetic code but are capable of covalently binding to adjacent amino acid residues in a polypeptide chain. Examples of non-naturally occurring amino acid residues are norleucine, ornithine, norvaline, homoserine, and other amino acid residue analogs, such as those described in Ellman et al., Meth. Enzym. 202: 301-336 (1991).

[0768] Once a nucleic acid sequence encoding a molecule (ie, a binding domain) of the invention has been obtained, vectors for producing the molecule can be generated by recombinant DNA technology using techniques well known in the art.

[0769] The polynucleotide encoding the antibody (binding domain) of the present invention may include an expression control polynucleotide sequence operably connected to the antibody coding sequence, including naturally associated or heterologous promoter regions known in the art. The expression control sequence may be a eukaryotic promoter system that can transform or transfect eukaryotic host cells in a vector, but the control sequence for a prokaryotic host may also be used. Once the vector has been incorporated into an appropriate host cell line, the host cell is suitable for expressing the nucleotide sequence and (optionally) collecting and purifying the antibody under the conditions of breeding. Eukaryotic cell lines include CHO cell lines, various COS cell lines, HeLa cells, myeloma cell lines, transformed B cells or human embryonic kidney cell lines.

[0770] In one embodiment, the DNA encoding the antibodies of the invention is isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to genes encoding antibody heavy and light chains). Once isolated, the DNA can be placed in an expression vector, which is then transfected into a host cell (such as a monkey COS cell, a CHO cell, or a myeloma cell) that would not otherwise produce immunoglobulin protein to achieve the synthesis of monoclonal antibodies in the recombinant host cell. The DNA may also be modified, for example, to improve one or more properties of the corresponding antibody (e.g., binding affinity, immunogenicity, etc.).

[0771] In one aspect, the invention provides a method for making any polynucleotide described herein. For example, the polynucleotide of the invention can be obtained using chemical synthesis, recombinant methods or PCR. Chemical polynucleotide synthesis methods are well known in the art and need not be described in detail herein. Those skilled in the art can use the sequences provided herein and commercial DNA synthesizers to produce the desired DNA sequence.

[0772] In order to prepare polynucleotides using recombinant methods, polynucleotides comprising the desired sequence can be inserted into a suitable vector, and then the vector can be introduced into a suitable host cell for replication and amplification, as further discussed herein. The polynucleotides can be inserted into the host cell by any means known in the art. The cells are transformed by introducing exogenous polynucleotides using direct absorption, endocytosis, transfection, F-pairing or electroporation. Once introduced, the exogenous polynucleotides can be maintained in the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The polynucleotides amplified in this way can be separated from the host cell by methods well known in the art (e.g., Sambrook et al., 1989).

[0773] Alternatively, PCR allows for replication of a DNA sequence.PCR techniques are well known in the art and are described in U.S. Pat. Nos. 4,683,195, 4,800,159, 4,754,065, and 4,683,202, and in PCR: The Polymerase Chain Reaction, Mullis et al., eds., Birkauswer Press, Boston, 1994.

[0774] RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicates and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those skilled in the art, for example, as described in Sambrook et al., 1989, supra.

[0775] Suitable cloning vectors can be constructed according to standard techniques, or can be selected from a large number of cloning vectors available in the art. Although the selected cloning vector can vary according to the host cell intended to be used, suitable cloning vectors will generally be able to replicate themselves, can have a single target for a specific restriction endonuclease, or can carry genes that can be used to select markers for clones containing the vector. Suitable examples include plasmids and bacterial viruses, such as pUC18, pUC19, Bluescript (e.g., pBS SK+) and derivatives thereof, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA, and shuttle vectors (such as pSA3 and pAT28). These and many other cloning vectors are available from commercial suppliers such as BioRad, Strategene, and Invitrogen.

[0776] An expression vector is generally a reproducible polynucleotide construct containing a polynucleotide according to the present invention. It is implied that the expression vector must be reproducible in the host cell as an episome or as an integral part of the chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, viral vectors (including adenoviruses, adeno-associated viruses, retroviruses), cosmids, and expression vectors disclosed in PCT Publication No. WO 87 / 04462. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcription control elements (such as promoters, enhancers, and terminators). For expression (i.e., translation), one or more translation control elements, such as ribosome binding sites, translation initiation sites, and stop codons, are also generally required.

[0777] The vector containing the polynucleotide of interest can be introduced into the host cell by any of a number of appropriate means, including electroporation; transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran or other substances; microprojectile bombardment; liposome transfection; and infection (e.g., where the vector is an infectious agent such as vaccinia virus). The choice of the vector or polynucleotide to be introduced will often depend on the characteristics of the host cell.

[0778] Any host cell capable of overexpressing heterologous DNA can be used for the purpose of expressing the gene encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include, but are not limited to, COS, HeLa and CHO cells. See also PCT Publication No. WO87 / 04462. Suitable non-mammalian host cells include prokaryotes (such as Escherichia coli or Bacillus subtilis) and yeast (such as Saccharomyces cerevisiae, Schizosaccharomyces pombe or Kluyveromyces lactis). Cells that overexpress the antibody or protein of interest can be identified by known screening methods.

[0779] In addition to the choice of host cells, factors that affect glycosylation during recombinant production of antibodies include growth mode, medium formulation, culture density, oxygenation, pH, purification procedures, and the like. Various methods have been proposed to alter the glycosylation pattern achieved in a particular host organism, including the introduction or overexpression of certain enzymes involved in oligosaccharide production (U.S. Pat. Nos. 5,047,335; 5,510,261 and 5,278,299). Glycosylation or certain types of glycosylation can be enzymatically removed from glycoproteins, for example using endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, endoglycosidase F3. In addition, recombinant host cells can be genetically engineered to be defective in the processing of certain types of polysaccharides. These and similar techniques are well known in the art.

[0780] Other modification methods include the use of coupling techniques known in the art, including but not limited to enzymatic means, oxidative substitution and chelation. The modification can be used, for example, to attach a label for immunoassay. The modified polypeptides can be made using procedures established in the art and can be screened using standard assays known in the art, some of which are described below and in the Examples.

[0781] In some embodiments of the invention, the antibody comprises a modified constant region, such as a constant region with increased affinity for human Fcγ receptors; it is immunologically inert or partially inert, for example, does not trigger complement-mediated lysis, does not stimulate antibody-dependent cell-mediated cytotoxicity (ADCC), or does not activate macrophages; or has reduced activity (compared to unmodified antibodies) in any one or more of the following: triggering complement-mediated lysis, stimulating antibody-dependent cell-mediated cytotoxicity (ADCC), or activating microglia. Different modifications of the constant region can be used to achieve the optimal level or combination of effector functions. See, e.g., Morgan et al., Immunology 86:319-324, 1995; Lund et al., J. Immunology 157:4963-9 157:4963-4969, 1996; Idusogie et al., J. Immunology 164:4178-4184, 2000; Tao et al., J. Immunology 143:2595-2601, 1989; and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some embodiments, the constant region is modified as described in Eur. J. Immunol., 29:2613-2624, 1999; PCT Application No. PCT / GB99 / 01441; and / or UK Application No. 9809951.8. In other embodiments, for N-linked glycosylation, the constant region is deglycosylated. In some embodiments, for N-linked glycosylation, the constant region is deglycosylated by mutating the glycosylated amino acid residues or the flanking residues as part of the N-glycosylation recognition sequence in the constant region. For example, N-glycosylation site N297 can be mutated to A, Q, K or H. See Tao et al., J.Immunology 143:2595-2601, 1989; and Jefferis et al., Immunological Reviews 163:59-76, 1998. In some embodiments, for N-linked glycosylation, the constant region is deglycosylated. For N-linked glycosylation, the constant region can be deglycosylated enzymatically (such as by removing carbohydrates by PNGase) or by expression of glycosylation-deficient host cells.

[0782] Other antibody modifications include antibodies modified as described in PCT Publication No. WO99 / 58572. In addition to the binding domain for the target molecule, these antibodies include an effector domain substantially homologous to all or part of the constant region of the human immunoglobulin heavy chain in amino acid sequence. These antibodies can bind to the target molecule without triggering significant complement dependent lysis or cell-mediated destruction of the target. In some embodiments, the effector domain can specifically bind to any one or both of FcRn or FcγRIIb. These effector domains are generally based on chimeric domains derived from two or more human immunoglobulin heavy chain CH2 domains. Antibodies modified in this way are particularly suitable for chronic antibody therapy to avoid inflammatory and other adverse reactions of conventional antibody therapy.

[0783] In some embodiments, the Fc chain of the antibodies provided herein can be modified to eliminate effector function. For example, human IgG1 Fc chain can be modified using standard primer-directed PCR mutagenesis to introduce mutations L234A, L235A and G237A to obtain effector function due to binding to FcγRIII, thereby obtaining an effector function null expression type (Canfield et al., J. Exp. Med (1991) 173: 1483-1491; Shields et al., J. Biol. Chem. (2001) 276: 6591-604).

[0784] In some embodiments, the multispecific antibodies provided herein can be engineered to include at least one cysteine ​​residue that can interact with a counterpart cysteine ​​residue on another polypeptide chain of the invention to form an interchain disulfide bond. Interchain disulfide bonds can be used to stabilize multispecific antibodies, improve expression and recovery in recombinant systems, produce stable and consistent formulations, and improve the stability of isolated and / or purified products in vivo. One or more cysteine ​​residues can be introduced as a single amino acid or as part of a larger amino acid sequence in any portion of a polypeptide chain, such as a hinge region. In a specific aspect, at least one cysteine ​​residue is engineered to be present at the C-terminus of a polypeptide chain.

[0785] The foregoing description and the following examples detail certain specific embodiments of the present disclosure, and describe the best mode contemplated by the inventors. However, it will be appreciated that no matter how the foregoing is presented in detail herein, the present disclosure can be practiced in many ways and the present disclosure should be interpreted according to the appended claims and any equivalents thereof.

[0786] Although disclosed teachings have been described with reference to different applications, methods, kits and compositions, it will be appreciated that different changes and modifications may be made without departing from the teachings herein and the disclosures claimed below. The following examples are provided to better illustrate the teachings of the present invention, and are not intended to limit the scope of the teachings presented herein. Although the present teachings have been described in terms of these exemplary embodiments, it will be readily understood by those skilled in the art that a large number of changes and modifications to these exemplary embodiments are possible without improper experimental conditions. All such changes and modifications are within the scope of this teaching. Example

[0787] The following examples for practicing specific aspects of the invention are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0788] Example 1. Generation of anti-TL1A antibody TL1A-0002.

[0789] The fully human affinity-optimized anti-TL1A heavy and light chain amino acid sequences were previously described in Arch et al., U.S. Pat. No. 9,683,998, Pfizer Inc. and Bristol-Myers Squibb Company, June 19, 2017 (SEQ ID NO: 228 and SEQ ID NO: 106) 1 . 1D1 1.31 is a human IgG1 / κ neutralizing antibody with L(247)A, L(248)A and G(250)A mutations (Pfabat numbering) within the fragment crystallizable region (Fc region) to minimize effector function, and is referred to herein as TL1A-0002. The heavy chain and light chain amino acid sequences constituting TL1A-0002 are depicted in SEQ ID NO:10 and SEQ ID NO:17, respectively. The TL1A-0002 antibody demonstrated efficacy against moderate to severe ulcerative colitis (UC) in a Phase 2a trial, but produced a high frequency of positive anti-drug antibodies (ADA) subjects, with 41 / 50 or 82% of subjects dosed having anti-drug antibodies (ADA), and 5 / 50 or 10% of subjects dosed having neutralizing antibodies (https: / / clinicaltrials.gov, identification number NCT02840721). The development and maturation of neutralizing anti-drug antibodies in patients may limit the long-term benefit of the drug.We sought to develop a biopreferred antibody that maintained the efficacy of TL1A-0002 while mitigating the risk of immunogenicity to yield a therapeutic with low ADA.

[0790] Example 2. Derivatization of an anti-TL1A binding domain engineered to reduce immunogenicity and eliminate post-translational asparagine deamidation.

[0791] The fully human anti-TL1A antibody TL1A-0002 was engineered to reduce immunogenicity and remove post-translational asparagine deamidation modifications as a subsequent biotherapeutic intended for long-term treatment of inflammatory bowel disease (IBD). The predicted immunogenicity of the amino acid sequence of TL1A-0002 was analyzed using two methods described below to identify predicted T cell epitopes in silico. For either approach, any sequence marked by the rules described herein was considered an epitope. The sequences were submitted for EpiMatrix analysis in the ISP...

Claims

1. An isolated antibody comprising a first antigen binding site that binds to TL1A and a second antigen binding site that binds to p40, wherein the first antigen binding site comprises a TL1A binding heavy chain variable region (TL1A-VH) and a TL1A binding light chain variable region (TL1A-VL), wherein the second antigen binding site comprises a p40 binding heavy chain variable region (p40-VH) and a p40 binding light chain variable region (p40-VL), and wherein the p40 binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 173, a CDR-L2 sequence according to SEQ ID NO: 174, and a CDR-L3 sequence according to SEQ ID NO: 175, a CDR-H1 sequence according to SEQ ID NO: 167, a CDR-H2 sequence according to SEQ ID NO: 168, and a CDR-H3 sequence according to SEQ ID NO: 169, and wherein the TL1A binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 11, a CDR-L2 sequence according to SEQ ID NO: 11, and a CDR-L3 sequence according to SEQ ID NO: 11 NO:12 and a CDR-L3 sequence according to SEQ ID NO:13, and further comprising a set of heavy chain CDRs selected from the following list: (i) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32; (ii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35; (iii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:32; (iv) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:46; a CDR-H3 sequence according to SEQ ID NO:35; (v) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32; (vi) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35; (vii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32; (viii) a CDR-H1 sequence according to SEQ ID NO:30; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:35; (ix) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32; (x) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35; (xi) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:32; (xii) a CDR-H1 sequence according to SEQ ID NO:61; a CDR-H2 sequence according to SEQ ID NO:56; a CDR-H3 sequence according to SEQ ID NO:32; (xiii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 31; a CDR-H3 sequence according to SEQ ID NO: 35; (xiv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:38; a CDR-H3 sequence according to SEQ ID NO:35; (xv) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:32; (xvi) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:41; a CDR-H3 sequence according to SEQ ID NO:35; (xvii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 46; a CDR-H3 sequence according to SEQ ID NO: 35; (xviii) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 51; a CDR-H3 sequence according to SEQ ID NO: 32; (xix) a CDR-H1 sequence according to SEQ ID NO:86; a CDR-H2 sequence according to SEQ ID NO:51; a CDR-H3 sequence according to SEQ ID NO:35; (xx) a CDR-H1 sequence according to SEQ ID NO: 86; a CDR-H2 sequence according to SEQ ID NO: 56; a CDR-H3 sequence according to SEQ ID NO: 32; (xxi) a CDR-H1 sequence according to SEQ ID NO: 109; a CDR-H2 sequence according to SEQ ID NO: 41; a CDR-H3 sequence according to SEQ ID NO: 35; and (xxii) CDR-H1 sequence according to SEQ ID NO: 109; CDR-H2 sequence according to SEQ ID NO: 56; CDR-H3 sequence according to SEQ ID NO:

32.

2. An isolated antibody comprising a first antigen binding site that binds to TL1A and a second antigen binding site that binds to p40, wherein the first antigen binding site comprises a TL1A-binding heavy chain variable region (TL1A-VH) and a TL1A-binding light chain variable region (TL1A-VL), wherein the second antigen binding site comprises a p40-binding heavy chain variable region (p40-VH) and a p40-binding light chain variable region (p40-VL), and wherein (i) the p40 binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 173; a CDR-L2 sequence according to SEQ ID NO: 174; and a CDR-L3 sequence according to SEQ ID NO: 175; a CDR-H1 sequence according to SEQ ID NO: 167; a CDR-H2 sequence according to SEQ ID NO: 168; and a CDR-H3 sequence according to SEQ ID NO: 169, and (ii) the TL1A binding domain comprises a CDR-L1 sequence according to SEQ ID NO: 11; a CDR-L2 sequence according to SEQ ID NO: 12; and a CDR-L3 sequence according to SEQ ID NO: 13; a CDR-H1 sequence according to SEQ ID NO: 30; a CDR-H2 sequence according to SEQ ID NO: 41; and a CDR-H3 sequence according to SEQ ID NO:

32.

3. The antibody of any one of claim 1, comprising: a TL1A-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: IGHV1-18*01, IGHV1-18*01, IGHV1-18*01, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02, IGHV1-46*01, IGHV3-7*01, IGHV1-2*02. -2*02; and a TL1A-VL framework sequence derived from a human germline VL sequence selected from the group consisting of IGKV1-39*01, IGKV3-11*01, IGKV3D-7*01, IGKV3-11*01, IGKV3-11*01, IGKV3-11*01, IGKV1-39*01, IGKV1-39*01, IGKV1-39*01, IGKV3D-7*01, IGKV3D-7*01, IGKV3D-7*01.

4. The antibody of claim 1, wherein the TL1A-VL comprises an amino acid sequence according to SEQ ID NO: 18, and wherein the TL1A-VH comprises an amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 57, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 110, and SEQ ID NO:

120.

5. The antibody of claim 1, comprising the TL1A-VH sequence of SEQ ID NO:42, and the TL1A-VL of SEQ ID NO:

18.

6. The antibody of claim 1, comprising a TL1A-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 228, and comprising a TL1A-VL sequence encoded by the nucleic acid sequence of SEQ ID NO:

229.

7. The antibody of claim 1, comprising a p40-VH framework sequence derived from a human germline VH sequence selected from the group consisting of: DP3, DP7, DP73, DP75, and DP88; and comprising a p40-VL framework sequence derived from a human germline VL sequence selected from the group consisting of: DPK4, DPK5, DPK7, DPK8, and DPK9.

8. The antibody of claim 1, wherein the p40-VL comprises the amino acid sequence according to SEQ ID NO: 177, and wherein the p40-VH comprises the amino acid sequence according to SEQ ID NO:

171.

9. The antibody of claim 1, comprising a p40-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 238, and comprising a p40-VL sequence encoded by the nucleic acid sequence of SEQ ID NO:

239.

10. The antibody of claim 1, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, and a fourth polypeptide chain, such that the first polypeptide chain and the third polypeptide chain together form TL1A-Fab, and the second polypeptide chain and the fourth polypeptide chain together form p40-Fab.

11. The antibody of claim 10, wherein the first polypeptide chain, the second polypeptide chain, the third polypeptide chain, and the fourth polypeptide chain have a sequence combination according to one of the groups selected from the following list: (i) the first polypeptide sequence is according to SEQ ID NO: 205, the second polypeptide is according to SEQ ID NO: 203, the third polypeptide is according to SEQ ID NO: 207, and the fourth polypeptide is according to SEQ ID NO: 178; (ii) the first polypeptide sequence is according to SEQ ID NO: 188, the second polypeptide is according to SEQ ID NO: 186, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178; (iii) the first polypeptide sequence is according to SEQ ID NO: 192, the second polypeptide is according to SEQ ID NO: 190, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178; (iv) the first polypeptide sequence is according to SEQ ID NO: 194, the second polypeptide is according to SEQ ID NO: 193, the third polypeptide is according to SEQ ID NO: 19, and the fourth polypeptide is according to SEQ ID NO: 178; and (v) the first polypeptide sequence is according to SEQ ID NO:200, the second polypeptide is according to SEQ ID NO:196, the third polypeptide is according to SEQ ID NO:202, and the fourth polypeptide is according to SEQ ID NO:

198.

12. The antibody of claim 11, wherein the first polypeptide sequence is according to SEQ ID NO:205, the second polypeptide is according to SEQ ID NO:203, the third polypeptide is according to SEQ ID NO:207, and the fourth polypeptide is according to SEQ ID NO:

178.

13. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain, such that the first polypeptide chain and the third polypeptide chain together form a TL1A binding region, and the second polypeptide chain and the fourth polypeptide chain together form a p40 binding region, and wherein the first polypeptide sequence is according to SEQ ID NO: 205, the second polypeptide is according to SEQ ID NO: 203, the third polypeptide is according to SEQ ID NO: 207, and the fourth polypeptide is according to SEQ ID NO:

178.

14. An isolated antibody that specifically binds to TL1A and p40, wherein the antibody comprises a first polypeptide chain, a second polypeptide chain, a third polypeptide chain, and a fourth polypeptide chain, such that the first polypeptide chain and the third polypeptide chain together form a TL1A binding region, and the second polypeptide chain and the fourth polypeptide chain together form a p40 binding region, and wherein the first polypeptide sequence comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127349, the second polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127346, the third polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127350, and the fourth polypeptide comprises a sequence encoded by a plasmid deposited with the ATCC and having an ATCC deposit number of PTA-127203.

15. The antibody of claim 1, characterized in that The score was less than 2 in the affinity capture self-interaction nanoparticle spectroscopy (AC SINS) assay.

16. The antibody of claim 1, characterized in that The charge heterogeneity of the antibody is at least 50% non-acidic and non-basic as measured in imaged capillary electrophoresis (iCE) of the antibody on an unstressed sample to be evaluated (T0).

17. The antibody of claim 1, wherein the antibody binds to immobilized human TL1A with a binding affinity of less than 1 nM as measured by SPR; and / or wherein the immobilized antibody binds to human p40 with a binding affinity of less than 1 nM as measured by SPR.

18. The antibody of claim 1, wherein the antibody is injected over immobilized TL1A and the resulting complex is subsequently treated with IL-23 in an SPR assay, wherein the Ab binds to both p40 (IL-23) and TL1A simultaneously.

19. The antibody of claim 1, wherein the antibody has a terminal half-life of at least 10 days in TG32 mice based on a two-week analysis, and / or wherein the antibody has a terminal half-life of at least 21 days in cynomolgus monkeys.

20. The antibody of claim 1 for use as a medicament, wherein the use is for the treatment of one or more selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, fibrosing stenosing Crohn's disease, irritable bowel syndrome, allergies, ankylosing spondylitis, alopecia areata, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hepatitis, autoimmune thyroiditis, Behcet's disease, bladder syndrome / interstitial cystitis, cutaneous lupus erythematosus, diabetes, eczematous dermatitis, encephalomyelitis, eosinophilic esophagitis, eosinophilic gastroenteritis, transplantation Plant versus host disease (GVHD), idiopathic pulmonary fibrosis, juvenile rheumatoid arthritis, multiple sclerosis, myasthenia gravis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-reactive celiac disease, osteoarthritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sepsis, Sjögren's syndrome, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis with interstitial lung disease (SSc-ILD), transplant rejection, ulcerative proctitis, urointestinal disorders, uveitis and vasculitis.

21. A pharmaceutical composition comprising a therapeutically effective amount of the antibody of claim 1 and a pharmaceutically acceptable carrier.

22. An isolated polynucleotide comprising one or more nucleotide sequences encoding one or more of the first polypeptide, the second polypeptide, the third polypeptide and the fourth polypeptide of the antibody of claim 1 or encoding an antibody that binds to both TL1A and p40, wherein the antibody comprises: (i) a TL1A-VH sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 228; and a TL1A-VL sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 229; and (ii) a p40-VH sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 238; and a p40-VL sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO:

239.

23. An isolated polynucleotide encoding one or more of a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide of an antibody that binds to both TL1A and p40, the antibody comprising: (i) TL1A-VH, which carries a polypeptide sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 234; and TL1A-VL, which carries a polypeptide encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 235; and (ii) a p40-HC sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 236; and a p40-LC sequence encoded by a nucleic acid comprising the nucleic acid sequence of SEQ ID NO:

237.

24. A vector comprising the polynucleotide of claim 22.

25. An isolated host cell comprising the vector of claim 24.

26. A method of producing an isolated antibody, the method comprising culturing the host cell of claim 25 under conditions resulting in production of the antibody and recovering the antibody.

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