Anti-TL1A antibodies for the treatment of ulcerative colitis and Crohn's disease

Abstract

A method for treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease using an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A) is provided. Pharmaceutical formulations containing the antibody or antigen-binding fragment thereof that specifically binds to TL1A are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 369,591, filed July 27, 2022, and U.S. Provisional Patent Application No. 63 / 387,786, filed December 16, 2022, each of which is incorporated herein by reference in its entirety.

[0002] Reference to an electronically submitted sequence listing The contents of the electronically submitted sequence listing (Name: 2873_364PC03_SequenceListing_St26.xml, Size: 67,104 bytes, Created: July 20, 2023) are hereby incorporated by reference in their entirety into this application. [Background technology]

[0003] Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract that affects 5 million people worldwide. IBD manifests as one of two major diseases: ulcerative colitis (UC) or Crohn's disease (CD). In UC, inflammation is limited to the colonic mucosa, whereas in CD, the transmural inflammatory process predominates in the terminal ileum and / or right colon (nearly 70% of disease cases) but can involve the entire gastrointestinal tract from the mouth to the anus.

[0004] The overall goal of treatment for patients with active UC is to induce and maintain remission and mucosal healing. Treatment for UC consists of anti-inflammatory and immunosuppressive therapies, selected to maximize efficacy while avoiding toxicity. While medications used to treat mild to moderate UC are generally well tolerated, as the severity of UC increases, so does the potential toxicity of the medications required to manage the disease. Pharmacotherapy for patients with CD is largely determined by the type, location, and extent of disease, the presence or absence of local and extraintestinal symptoms, and the activity of the disease.

[0005] Despite recent advances in IBD treatment, many patients experience ineffectiveness, loss of response, or intolerance to currently available therapies for UC and CD. Furthermore, some IBD treatments have significant safety issues. Therefore, there is a need to develop and commercialize highly effective drugs with favorable side effect profiles. Summary of the Invention [Means for solving the problem]

[0006] Provided herein is a method for treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A).

[0007] Also provided herein are methods of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the methods comprising: (a) determining whether the subject has previously responded inadequately, failed to respond to, or been intolerant to at least one agent selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators; and (b) if the subject has previously responded inadequately, failed to respond to, or been intolerant to the at least one agent, administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A). In some embodiments, the ulcerative colitis is moderate to severe ulcerative colitis and / or the Crohn's disease is moderate to severe Crohn's disease.

[0008] Also provided herein is a method for treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease; and (b) if the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease, administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A).

[0009] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TL1A comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0010] In some embodiments, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA). In some embodiments, the subject has had an inadequate response, failed to respond, or intolerance to one or more agents. In some embodiments, the subject has had an inadequate response, failed to respond, or intolerance to two or fewer classes of biologics. In some embodiments, the subject is treated concomitantly with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6 mercaptopurine (6-MP), and / or methotrexate.

[0011] In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 1750 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 1800 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 2000 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 2500 mg.

[0012] In some embodiments, the antibody or antigen-binding fragment thereof is administered about once every two weeks. In some embodiments, the antibody or antigen-binding fragment thereof is administered about once every four weeks. In some embodiments, the antibody or antigen-binding fragment thereof is administered about once a month.

[0013] In some embodiments, the administration comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering one or more induction doses of the antibody or antigen-binding fragment thereof, hi some embodiments, the administration comprises only administering one or more induction doses of the antibody or antigen-binding fragment thereof (i.e., the antibody or antigen-binding fragment thereof is administered without a loading dose).

[0014] In some embodiments, the loading dose comprises about 1500 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 1750 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 2000 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 2250 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 2500 mg of antibody or antigen-binding fragment thereof.

[0015] In some embodiments, one or more induction doses (which may be administered following a loading dose or without a loading dose) comprise about 300 mg of an antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 400 mg of an antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 450 mg of an antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 600 mg of an antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 750 mg of an antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 900 mg of an antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 1800 mg of an antibody or antigen-binding fragment thereof.

[0016] In some embodiments, about 6 induction doses are administered.

[0017] In some embodiments, administration occurs over a period of about 16 weeks. In some embodiments, administration of one or more induction doses occurs over a period of about 14 weeks. In some embodiments, a loading dose is administered about 2 weeks before administration of one or more induction doses.

[0018] In some embodiments, the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every two weeks.

[0019] In some embodiments, the administration further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every two weeks.

[0020] In some embodiments, the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every four weeks.

[0021] In some embodiments, the administration further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every four weeks.

[0022] In some embodiments, the one or more maintenance doses comprise about 300 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0023] In some embodiments, the one or more maintenance doses comprise about 300 mg of the antibody or antigen-binding fragment thereof.

[0024] In some embodiments, the one or more maintenance doses comprise about 400 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0025] In some embodiments, the one or more maintenance doses comprise about 400 mg of the antibody or antigen-binding fragment thereof.

[0026] In some embodiments, the one or more maintenance doses comprise about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0027] In some embodiments, the one or more maintenance doses comprise about 450 mg of the antibody or antigen-binding fragment thereof.

[0028] In some embodiments, the one or more maintenance doses comprise about 900 mg of the antibody or antigen-binding fragment thereof.

[0029] In some embodiments, about 12 maintenance doses are administered.

[0030] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0031] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0032] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof.

[0033] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof.

[0034] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof.

[0035] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 1800 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0036] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0037] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0038] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 1800 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0039] In some embodiments, the administration of one or more maintenance doses occurs over a period of about 24 weeks, hi some embodiments, the administration of one or more maintenance doses occurs over a period of about 40 weeks.

[0040] In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 200 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 225 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 250 mg / mL.

[0041] In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less. In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a volume of 2 mL or less.

[0042] In some embodiments, the antibody or antigen-binding fragment thereof is administered to the subject subcutaneously or intravenously. In some embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0043] In some embodiments, the antibody or antigen-binding fragment thereof is administered to a subject via a syringe.In some embodiments, the syringe is a pre-filled syringe.In some embodiments, the pre-filled syringe has a volume of 3 mL or less.In some embodiments, the pre-filled syringe has a volume of 2 mL or less.

[0044] In some embodiments, the subject has moderate to severe ulcerative colitis. In some embodiments, administration results in clinical remission. In some embodiments, clinical remission occurs within 14 weeks of initiating administration. In some embodiments, clinical remission occurs within 38 weeks of initiating administration.

[0045] In some embodiments, the subject has moderate to severe Crohn's disease. In some embodiments, the administration results in an endoscopic response. In some embodiments, the endoscopic response occurs within 14 weeks of initiating administration. In some embodiments, the endoscopic response occurs within 38 weeks of initiating administration.

[0046] Also provided herein are pharmaceutical formulations comprising: (a) about 100 mg / mL to about 250 mg / mL of TNF-like ligand 1A (TNF-like ligand 1B); (b) an antibody or antigen-binding fragment thereof that specifically binds to the target polypeptide (SEQ ID NO: 1A:TL1A), the antibody or antigen-binding fragment thereof comprising a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6; (b) about 5 mM to about 15 mM histidine; (c) about 50 mM to about 150 mM arginine hydrochloride (Arg-HCl); (d) about 2.5% (w / v) to about 7.5% (w / v) sucrose; and (e) about 0.01% (w / v) to about 0.03% (w / v) polysorbate-80. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an IgG1 constant region. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0047] In some embodiments, the pharmaceutical formulations disclosed herein contain about 100, about 150, about 200, about 225, or about 250 mg / mL of an antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical formulations disclosed herein contain about 5 mM, about 10 mM, or about 15 mM histidine. In some embodiments, the pharmaceutical formulations disclosed herein contain about 50 mM, about 100 mM, or about 150 mM arginine hydrochloride (Arg-HCl). In some embodiments, the pharmaceutical formulations disclosed herein contain about 2.5%, about 5%, or about 7.5% (w / v) sucrose. In some embodiments, the pharmaceutical formulations disclosed herein contain about 0.01%, about 0.02%, or about 0.03% (w / v) polysorbate-80.

[0048] In some embodiments, the pharmaceutical formulation disclosed herein comprises about 250 mg / mL of an antibody or antigen-binding fragment thereof, about 10 mM histidine, about 100 mM arginine hydrochloride (Arg-HCl), about 5% (w / v) sucrose, and about 0.02% (w / v) polysorbate-80.

[0049] In some embodiments, the pharmaceutical formulation disclosed herein comprises about 200 mg / mL of an antibody or antigen-binding fragment thereof, about 10 mM histidine, about 100 mM arginine hydrochloride (Arg-HCl), about 5% (w / v) sucrose, and about 0.02% (w / v) polysorbate-80.

[0050] In some embodiments, the pharmaceutical formulation disclosed herein comprises about 150 mg / mL of an antibody or antigen-binding fragment thereof, about 10 mM histidine, about 100 mM arginine hydrochloride (Arg-HCl), about 5% (w / v) sucrose, and about 0.02% (w / v) polysorbate-80.

[0051] In some embodiments, the pharmaceutical formulation is lyophilized. In some embodiments, the pharmaceutical formulation is liquid. In some embodiments, the pharmaceutical formulation has a pH of 6.0±0.5 after storage at room temperature for 24 hours, or at 2-8° C. for 24 hours, 72 hours, or 10 days.

[0052] In some embodiments, the pharmaceutical formulation has an osmolality of 200 mOsm / kg to 500 mOsm / kg after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has an antibody monomer content of at least 99% after storage at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has no significant change in charge heterogeneity profile after storage at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has no significant change in purity after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has a purity of at least 90% after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations have no significant change in particle concentration after storage at room temperature for 24 hours, or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations have no significant difference in visual appearance after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in protein concentration, osmolality, or viscosity after storage at 2-8°C, 25°C, or 40°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in monomer content of 95% or more, dimer content of 5.0% or less, or low molecular weight species content after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have a purity of 90% or more after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have a main species content of 50% to 90%, an acidic species content of 10% to 40%, and / or a basic species content of 0% to 20% after storage for up to 36 months at 2 to 8° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in subvisible particle content after storage for up to 36 months at 2 to 8° C., 25° C., or 40° C.In some embodiments, the pharmaceutical formulations disclosed herein show no significant difference in oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or deamidation of asparagine 317 of TEV-48574 after storage for up to 36 months at 2-8°C, 25°C, or 40°C. In some embodiments, the pharmaceutical formulations disclosed herein show a relative potency of 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage for up to 36 months at 2-8°C. In some embodiments, the pharmaceutical formulations disclosed herein show no significant difference in thermal stability after storage for up to 6 months at 2-8°C, 25°C, or 40°C. In some embodiments, the pharmaceutical formulations disclosed herein show no significant difference in thermal stability after storage for up to 36 months at 2-8°C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in secondary and / or tertiary protein structure after storage for up to 3 months at 2-8° C., 25° C., or 40° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in secondary protein structure after storage for up to 36 months at 2-8° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in polysorbate-80 concentration after storage for up to 24 months at 2-8° C.

[0053] Also provided is a container that contains the pharmaceutical preparation disclosed herein.In some embodiments, the container is a glass vial.In some embodiments, the container is a glass vial with a capacity of 3mL.In some embodiments, the container is a syringe, for example, a pre-filled syringe.In some embodiments, the pre-filled syringe has a capacity of 2mL or less.

[0054] In some embodiments, the antibody or antigen-binding fragment thereof is present in a pharmaceutical formulation or container disclosed herein.

[0055] In some embodiments, provided herein are methods of treating a disease in a subject in need thereof, the method comprising administering to the subject any of the pharmaceutical formulations provided herein, including the pharmaceutical formulations in any of the containers provided herein. In some embodiments, the disease is a gastrointestinal disease.

[0056] In some embodiments, the gastrointestinal disease is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the gastrointestinal disease is Crohn's disease or ulcerative colitis.

[0057] In some embodiments, the pharmaceutical formulation is administered intravenously. In some embodiments, the pharmaceutical formulation is administered subcutaneously.

[0058] Also provided are compositions for use in accordance with the methods disclosed herein.

[0059] Also provided herein is a pharmaceutical formulation comprising: (a) 150 mg / mL of TNF-like ligand 1A (TNF-like ligand 1B); 1A:TL1A), an antibody or antigen-binding fragment thereof that specifically binds to TL1A, comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10; (b) 10 mM histidine; (c) 100 mM arginine hydrochloride (Arg-HCl); (d) 5% (w / v) sucrose; and (e) 0.02% (w / v) polysorbate-80. In some embodiments, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0060] In some embodiments, the pharmaceutical formulation is lyophilized. In some embodiments, the pharmaceutical formulation is liquid. In some embodiments, the pharmaceutical formulation has a pH of 6.0±0.5 after storage at room temperature for 24 hours, or at 2-8° C. for 24 hours, 72 hours, or 10 days.

[0061] In some embodiments, the pharmaceutical formulation has an osmolality of 200 mOsm / kg to 500 mOsm / kg after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has an antibody monomer content of at least 99% after storage at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has no significant change in charge heterogeneity profile after storage at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has no significant change in purity after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulation has a purity of at least 90% after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations have no significant change in particle concentration after storage at room temperature for 24 hours, or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations have no significant difference in visual appearance after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in protein concentration, osmolality, or viscosity after storage at 2-8°C, 25°C, or 40°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have a monomer content of 95% or more, a dimer content of 5.0% or less, or no significant difference in low molecular weight species content after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have a purity of 90% or more after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations disclosed herein have a main species content of 50% to 90%, an acidic species content of 10% to 40%, and / or a basic species content of 0% to 20% after storage for up to 36 months at 2 to 8° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in subvisible particle content after storage for up to 36 months at 2 to 8° C., 25° C., or 40° C.In some embodiments, the pharmaceutical formulations disclosed herein show no significant difference in oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or deamidation of asparagine 317 of TEV-48574 after storage for up to 36 months at 2-8°C, 25°C, or 40°C. In some embodiments, the pharmaceutical formulations disclosed herein show a relative potency of 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage for up to 36 months at 2-8°C. In some embodiments, the pharmaceutical formulations disclosed herein show no significant difference in thermal stability after storage for up to 6 months at 2-8°C, 25°C, or 40°C. In some embodiments, the pharmaceutical formulations disclosed herein show no significant difference in thermal stability after storage for up to 36 months at 2-8°C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in secondary and / or tertiary protein structure after storage for up to 3 months at 2-8° C., 25° C., or 40° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in secondary protein structure after storage for up to 36 months at 2-8° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in polysorbate-80 concentration after storage for up to 24 months at 2-8° C.

[0062] Also provided are containers containing the pharmaceutical formulations disclosed herein. In some embodiments, the container is a glass vial. In some embodiments, the container is a 3 mL glass vial.

[0063] In some embodiments, the antibody or antigen-binding fragment thereof is present in a pharmaceutical formulation or container disclosed herein.

[0064] Also provided are compositions for use in accordance with the methods disclosed herein. [Brief explanation of the drawings]

[0065] [Figure 1]Figure 1 shows a schematic diagram of the screening, treatment and follow-up periods of the study described in Example 1. CD = Crohn's disease, FU = follow-up, I / E = inclusion / exclusion, ID = induction dose, LD = loading dose, PBO = placebo, SES-CD = Simplified Endoscopy Score for Crohn's Disease, UC = ulcerative colitis. [Figures 2A-2C] The percent (%) monomer composition of three TEV-48574 formulations (F1-F3) after storage at 2-8°C (Figure 2A), 25°C (Figure 2B), and 40°C (Figure 2C) is shown. [Figure 3A-3C] The percent (%) dimer composition of three TEV-48574 formulations (F1-F3) after storage at 2-8°C (Figure 3A), 25°C (Figure 3B), and 40°C (Figure 3C) is shown. [Figures 4A-4C] The percent (%) of low molecular weight (LWM) protein fragment composition of three TEV-48574 formulations (F1-F3) after storage at 2-8°C (Figure 4A), 25°C (Figure 4B), and 40°C (Figure 4C) is shown. [Figures 5A-5C] The purity of three TEV-48574 formulations (F1-F3) after storage at 2-8°C (Figure 5A), 25°C (Figure 5B), and 40°C (Figure 5C) was measured using CGE-non-reducing conditions (IgG+125 kDa peak (%)). [Figures 6A-6C] The purity of three TEV-48574 formulations (F1-F3) was measured using CGE-reducing conditions (heavy chain + light chain (%)) after storage at 2-8°C (Figure 6A), 25°C (Figure 6B), and 40°C (Figure 6C). [Figure 7A-7C] Charge heterogeneity profiles of formulations 1-3 (F1-F3) after storage at 2-8°C (Figure 7A), 25°C (Figure 7B), and 40°C (Figure 7C) are shown as percent (%) of the main species (main peak). [Figures 8A-8C] Charge heterogeneity profiles of Formulations 1-3 (F1-F3) after storage at 2-8°C (Figure 8A), 25°C (Figure 8B), and 40°C (Figure 8C) are shown as percent (%) of acidic species (acidic peak). [Figures 9A-9C]Charge heterogeneity profiles of Formulations 1-3 (F1-F3) after storage at 2-8°C (Figure 9A), 25°C (Figure 9B), and 40°C (Figure 9C) are shown as percent (%) of basic species (basic peak). [Figures 10A-10B] (FIG. 10A) Thermal stability of Formulations 1-3 (F1-F3) at time zero (T0) and after 3 months of storage at 2-8°C, 25°C, and 40°C. (FIG. 10B) Thermal stability of Formulations 1-3 (F1-F3) at time zero (T0) and after 6 months of storage at 2-8°C, 25°C, and 40°C. [Figure 10C] 1 shows the thermal stability of Formulations 1-3 (F1-F3) at time zero (T0) and after 36 months of storage at 2-8°C. [Figures 11A-11B] (Figure 11A) Far-ultraviolet (UV) circular dichroism analysis (CD) is used to show the secondary structure of Formulations 1-3 at time zero (T0) and after 3 months of storage at 2-8°C, 25°C, and 40°C. (Figure 11B) Far-UV CD is used to show the secondary structure of Formulations 1-3 at time zero (T0) and after 24 months of storage at 2-8°C. [Figures 11C-11D] (Figure 11C) Far-UV CD is used to show the secondary structure of Formulations 1-3 at time zero (T0) and after 36 months of storage at 2-8°C. (Figure 11D) Near-UV CD is used to show the tertiary structure of Formulations 1-3 at time zero (T0) and after 6 months of storage at 2-8°C, 25°C, and 40°C. [Figures 11E-11F] (Figure 11E) Near-UV CD is used to show the tertiary structure of Formulations 1-3 at time zero (T0) and after 24 months of storage at 2-8°C. (Figure 11F) Near-UV CD is used to show the tertiary structure of Formulations 1-3 at time zero (T0) and after 36 months of storage at 2-8°C. [Figure 12] Figure 1 shows a schematic diagram of the screening, treatment and follow-up periods of the study described in Example 4. CD = Crohn's disease, FU = follow-up investigation, I / E = inclusion / exclusion, MD = maintenance dose, SES CD = plain endoscopic score for Crohn's disease, UC = ulcerative colitis, LTE = long-term extension. [Figures 13A-13B](Figure 13A) The secondary structure of Formulation 3 stored in Nipro prefilled syringes (PFS) is shown using far-UV CD at time zero (T0) and after 3 months (3M), 6 months (6M), and 24 months (24M) of storage at 2-8°C, and after 3 months (3M) and 6 months (6M) of storage at 25°C and 40°C. (Figure 13B) The tertiary structure of Formulation 3 stored in Nipro prefilled syringes (PFS) is shown using near-UV CD at time zero (T0) and after 3 months (3M), 6 months (6M), and 24 months (24M) of storage at 2-8°C, and after 3 months (3M) and 6 months (6M) of storage at 25°C and 40°C. [Figures 14A-14C] (Figure 14A) Percent monomer composition (%) for 100 mg / mL lyophilized TEV-48574 formulations (F4) and 200 mg / mL liquid TEV-48574 formulations (F5) after storage at 2-8°C for up to 24 months. (Figure 14B) Percent dimer composition (%) for 100 mg / mL lyophilized TEV-48574 formulations (F4) and 200 mg / mL liquid TEV-48574 formulations (F5) after storage at 2-8°C for up to 24 months. (Figure 14C) Percent low molecular weight species (%) for 100 mg / mL lyophilized TEV-48574 formulations (F4) and 200 mg / mL liquid TEV-48574 formulations (F5) after storage at 2-8°C for up to 24 months. [Figures 15A-15B] (Figure 15A) Purity (%) measured using CGE-non-reducing conditions (IgG + 125 kDa peak (%)) for two TEV-48574 formulations (F4 and F5) after up to 24 months of storage at 2-8°C. (Figure 15B) Purity (%) measured using CGE-reducing conditions (heavy chain (HC) + light chain (LC) (%)) for two TEV-48574 formulations (F4 and F5) after up to 24 months of storage at 2-8°C. [Figures 16A-16C](Figure 16A) Charge heterogeneity profiles of Formulations 4 and 5 (F4 and F5) after up to 24 months of storage at 2-8°C are shown as percent (%) of the main species (main peak). (Figure 16B) Charge heterogeneity profiles of Formulations 4 and 5 (F4 and F5) after up to 24 months of storage at 2-8°C are shown as percent (%) of the acidic species (acidic peak). (Figure 16C) Charge heterogeneity profiles of Formulations 4 and 5 (F4 and F5) after up to 24 months of storage at 2-8°C are shown as percent (%) of the basic species (basic peak). [Figures 17A-17B] (FIG. 17A) The secondary structure of Formulation 4 at time zero (T0) and after 3 months (3M), 6 months (6M), and 12 months (12M) of storage at 25° C., and the secondary structure of Formulation 5 at time zero (T0) and after 3 months (3M) and 12 months (12M) of storage at 25° C. are shown using far-UV CD. (FIG. 17B) The tertiary structure of Formulation 4 at time zero (T0) and after 3 months (3M) and 12 months (12M) of storage at 25° C., and the tertiary structure of Formulation 5 at time zero (T0) and after 3 months (3M) and 12 months (12M) of storage at 25° C. are shown using near-UV CD. [Figure 18] Viscosity at 20°C of liquid formulations containing increasing concentrations of TEV-48574 (0-150 mg / mL) is shown with (1A) or without (1B) 100 mM arginine-HCl as an excipient. [Figures 19A-19C](FIG. 19A) Percent (%) monomer composition of two liquid TEV-48574 formulations, 150 mg / mL (1A) and 100 mg / mL (2A), with 100 mM arginine-HCl, and 150 mg / mL (1B) and 100 mg / mL (2B), without arginine-HCl, after storage at 40° C. for up to 8 weeks. (FIG. 19B) Percent (%) dimer composition of two liquid TEV-48574 formulations, 150 mg / mL (1A) and 100 mg / mL (2A), with 100 mM arginine-HCl, and 150 mg / mL (1B) and 100 mg / mL (2B), without arginine-HCl, after storage at 40° C. for up to 8 weeks. (FIG. 19C) Percent fragments (%) are shown for two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and two liquid TEV-48574 formulations at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after storage at 40° C. for up to 8 weeks. [Figures 20A-20B] (FIG. 20A) The percent purity (%) of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl was measured using CGE-non-reducing conditions (IgG+125 kDa peak (%)) after up to 8 weeks of storage at 40° C. (FIG. 20B) The percent purity (%) of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl was measured using CGE-reducing conditions (heavy chain (HC) + light chain (LC) (%)) after up to 8 weeks of storage at 40° C. [Figures 21A-21C](FIG. 21A) Charge heterogeneity profiles, as percent (%) of the main species (main peak), of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl, after storage at 40° C. for up to 8 weeks. (FIG. 21B) Charge heterogeneity profiles, expressed as percent (%) of acidic species (acidic peak), of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after up to 8 weeks of storage at 40° C. (FIG. 21C) Charge heterogeneity profiles, expressed as percent (%) of basic species (basic peak), of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after up to 8 weeks of storage at 40° C. [Figure 22] Figure 1 shows the thermal stability at time zero (T0) of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with 100 mM arginine-HCl and two liquid TEV-48574 formulations at 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl. [Figures 23A-23B](Figure 23A) Total TL1A measured in three cynomolgus monkeys administered a single subcutaneous dose of TEV-48574 at a dose level of 5 mg / kg. Blood samples were collected on days 0 (pre-dose), 0.25, 1, 2, 3, 4, 5, 7, 9, 11, 14, 21, 28, and 35. Bars represent the mean + / - standard error of the mean (SEM). The lower limit of quantification (BLQ) was 2.5 pg / mL (0.5 * LLOQ). (Figure 23B) Free TL1A measured in four cynomolgus monkeys administered a single subcutaneous dose of TEV-48574 at a dose level of 5 mg / kg. Blood samples were collected on days 0 (before administration), 0.25, 1, 2, 3, 4, 5, 7, 9, 11, 14, 21, 28, and 35. Bars represent the mean + / - standard error of the mean (SEM). The lower limit of quantification (BLQ) was 2.5 pg / mL (0.5 * LLOQ). [Figures 24A-24B] (Figure 24A) Simulated TEV-48574 concentrations following a 2250 mg loading dose and a 900 mg maintenance regimen administered Q2W or Q4W compared to predicted RVT-3101 exposure following a 50 mg, 150 mg, or 450 mg Q4W regimen. (Figure 24B) Simulated TEV-48574 concentrations following a 2250 mg loading dose and a 450 mg maintenance regimen administered Q2W or Q4W compared to predicted RVT-3101 exposure following a 50 mg, 150 mg, or 450 mg Q4W regimen. [Figure 25] 1 shows a schematic diagram of the screening, treatment, and follow-up periods for the dose-ranging study described in Example 9. CD = Crohn's disease, FU = follow-up, I / E = inclusion / exclusion, ID = induction dose, LD = loading dose, PBO = placebo, SES-CD = Simplified Endoscopy Score for Crohn's Disease, UC = ulcerative colitis. [Figure 26]1 shows a schematic diagram of the screening, treatment, and follow-up periods for the long-term extension study described in Example 9. CD = Crohn's disease, FU = follow-up investigation, I / E = inclusion / exclusion, MD = maintenance dose, SES CD = plain endoscopic score for Crohn's disease, UC = ulcerative colitis, LTE = long-term extension. DETAILED DESCRIPTION OF THE INVENTION

[0066] So that this disclosure may be more readily understood, certain terms are first defined. As used in this application, each of the following terms shall have the meaning set forth below, unless expressly defined otherwise herein. Additional definitions are set forth throughout this application.

[0067] definition Various terms relating to aspects of the present disclosure are used throughout the specification and claims. Such terms shall have their ordinary meaning in the art unless otherwise specified. Otherwise, specifically defined terms shall be interpreted in a manner consistent with the definitions set forth herein.

[0068] The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target (e.g., a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the above) via at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, antibody-containing fusion proteins, and any other modified immunoglobulin molecule, so long as the antibody exhibits the desired biological activity. Antibodies may belong to any of the five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) (based on the identity of the heavy chain constant domains, designated alpha, delta, epsilon, gamma, and mu, respectively). Different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. The antibody may be a naked antibody or may be conjugated to another molecule, such as a radioisotope.

[0069] Unless expressly stated otherwise or the context dictates otherwise, the term "antibody" includes monospecific antibodies, bispecific antibodies, and multispecific antibodies. In some embodiments, an antibody is a bispecific antibody. The term "bispecific antibody" refers to an antibody that binds to two different epitopes.

[0070] The term "antibody fragment" refers to a portion of an intact antibody. An "antigen-binding fragment," "antigen-binding domain," or "antigen-binding region" refers to a portion of an intact antibody that binds to an antigen. In the case of a bispecific antibody, an "antigen-binding fragment" binds to two antigens. An antigen-binding fragment may contain the antigen recognition site of the intact antibody (e.g., sufficient complementarity-determining regions (CDRs) to specifically bind to the antigen). Examples of antigen-binding fragments of antibodies include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single-chain antibodies. Antigen-binding fragments of antibodies may be derived from any animal species, including rodents (e.g., mice, rats, or hamsters) and humans, or may be artificially generated.

[0071] A "monoclonal" antibody or antigen-binding fragment thereof refers to a population of homogeneous antibodies or antigen-binding fragments responsible for highly specific binding to a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies, which typically contain different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) variants, fusion proteins containing an antibody portion, and any other modified immunoglobulin molecule containing an antigen-recognition site. Furthermore, a "monoclonal" antibody or antigen-binding fragment thereof refers to antibodies and antigen-binding fragments thereof produced by any number of methods, including, but not limited to, by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0072] As used herein, the terms "variable region" and "variable domain" are used interchangeably and are common in the art. A variable region typically refers to a portion of an antibody, generally a portion of either the light or heavy chain, typically approximately the amino-terminal 110-120 or 110-125 amino acids in a mature heavy chain and approximately 90-115 amino acids in a mature light chain, which differ in sequence among antibodies and are responsible for the binding and specificity of a particular antibody to its specific antigen. Sequence variability is concentrated in regions called complementarity-determining regions (CDRs), while the more highly conserved regions in the variable domain are called framework regions (FRs). While not wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with the antigen. In some embodiments of the present disclosure, the variable region is a human variable region. In some embodiments of the present disclosure, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In certain embodiments of the present disclosure, the variable region is a primate (e.g., non-human primate) variable region. In some embodiments of the present disclosure, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0073] The terms "VL" and "VL domain" are used interchangeably and refer to the light chain variable region of an antibody.

[0074] The terms "VH" and "VH domain" are used interchangeably and refer to the heavy chain variable region of an antibody.

[0075] The term "Kabat numbering" and similar terms are recognized in the art and refer to a system for numbering amino acid residues in the heavy and light chain variable regions of an antibody or an antigen-binding fragment thereof. In some embodiments, CDRs can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190:382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDRs in an antibody heavy chain molecule are typically located at amino acid positions 31-35, and can optionally include one or two additional amino acids following position 35 (referred to as 35A and 35B in the Kabat numbering scheme) (CDR1), amino acid positions 50-65 (CDR2), and amino acid positions 95-102 (CDR3). Using the Kabat numbering system, the CDRs in an antibody light chain molecule are typically located at amino acid positions 24-34 (CDR1), amino acid positions 50-56 (CDR2), and amino acid positions 89-97 (CDR3).

[0076] Chothia instead refers to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop, when numbered using the Kabat numbering convention, varies from H32 to H34 depending on the length of the loop (this is because the Kabat numbering scheme places insertions at H35A and H35B; if neither 35A nor 35B are present, the loop ends at 32; if only 35A is present, the loop ends at 33; and if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software.

[0077] [Table 1]

[0078] As used herein, the terms "constant region" and "constant domain" are interchangeable and have their common meaning in the art. The constant region is the portion of an antibody, e.g., the carboxyl-terminal portion of the light and / or heavy chain, that is not directly involved in binding the antibody to an antigen but may exhibit various effector functions, such as interacting with Fc receptors. The constant region of an immunoglobulin molecule generally has a conserved amino acid sequence compared to the immunoglobulin variable domain. In some embodiments, the antibody or antigen-binding fragment comprises a constant region or a portion thereof sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).

[0079] As used herein, the term "heavy chain," when used in reference to an antibody, can refer to any distinct type, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the constant domain, which give rise to the IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4. Heavy chain amino acid sequences are well known in the art. In some embodiments of the present disclosure, the heavy chain is a human heavy chain.

[0080] As used herein, the term "light chain," when used in reference to an antibody, can refer to any distinct type, e.g., κ (kappa) or λ (lambda), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. In some embodiments of the present disclosure, the light chain is a human light chain.

[0081] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof whose amino acid sequences are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody or antigen-binding fragment thereof from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capacity, while the constant regions are homologous to the sequences of an antibody or antigen-binding fragment thereof from another (usually human) species so as not to elicit an immune response in that species.

[0082] The term "humanized" antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments thereof that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequence. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues of the complementarity-determining regions (CDRs) are replaced with residues from CDRs of a non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and capacity ("CDR-grafted") (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)). In some instances, particular Fv framework region (FR) residues of a human immunoglobulin are substituted with corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and capacity. Humanized antibodies or antigen-binding fragments thereof can be further modified by substituting additional residues in the Fv framework regions and / or within non-human CDR residues to refine and optimize the specificity, affinity, and / or capacity of the antibody or antigen-binding fragment. Generally, a humanized antibody or antigen-binding fragment thereof will comprise variable domains that include all or substantially all of the CDR regions corresponding to those of a non-human immunoglobulin, while all or substantially all of the FR regions are of human immunoglobulin consensus sequences. Humanized antibodies or antigen-binding fragments thereof may also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Patent No. 5,225,539, Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-73 (1994), and Roguska et al., Protein Eng. 9(10):895-904 (1996). In some embodiments of the present disclosure, the "humanized antibody" is a resurfaced antibody.

[0083] The term "human" antibody, or antigen-binding fragment thereof, means an antibody or antigen-binding fragment thereof having an amino acid sequence derived from the human immunoglobulin locus, and such antibody or antigen-binding fragment is produced using any technique known in the art. This definition of human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0084] "Binding affinity" generally refers to the overall strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody or antigen-binding fragment thereof) and its binding partner (e.g., an antigen). Unless otherwise specified, "binding affinity" as used herein refers to the intrinsic binding affinity, which indicates a 1:1 interaction between members of a binding pair (e.g., an antibody or antigen-binding fragment thereof and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by a dissociation constant (KD). Affinity can be measured and / or expressed in several ways known in the art, including, but not limited to, the equilibrium dissociation constant (KD) and the equilibrium binding constant (KA). KD is the k off / k on KA is calculated from the quotient of k off / k on It is calculated from the quotient of K on means, for example, the association rate constant of an antibody or antigen-binding fragment thereof to an antigen, and k off k means, for example, dissociation of an antibody or antigen-binding fragment thereof from an antigen. on and k off can be determined by techniques known to those skilled in the art, such as BIAcore® or KinExA.

[0085] As used herein, "epitope" is a term of the art and refers to a localized region of an antigen to which an antibody or antigen-binding fragment thereof can specifically bind. An epitope can be, for example, consecutive amino acids of a polypeptide (a linear or continuous epitope), or can be, for example, joined together by two or more non-contiguous regions of a polypeptide (a conformational, non-linear, discontinuous, or discontinuous epitope). In some embodiments of the present disclosure, the epitope to which an antibody or antigen-binding fragment thereof specifically binds can be determined by, for example, NMR spectroscopy, X-ray diffraction crystallography studies, ELISA assays, hydrogen / deuterium exchange mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligopeptide scanning assays, and / or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray crystallography, crystallization can be achieved using any of the methods known in the art (e.g., Giege R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4):339-350; McPherson A (1990) Eur J Biochem 189:1-23; Chayen NE (1997) Structure 5:1269-1274; McPherson A (1976) J Biol Chem 251:6300-6303).Crystal structures containing complexes of antigen and antibody or antigen-binding fragments can be studied using well-known X-ray diffraction techniques and computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see, e.g., Meth Enzymol (1985) volumes 114&115, eds. Wyckoff HW et al.; see, e.g., U.S. Patent Application Publication No. 2004 / 0014194), and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1):37-60; Bricogne G (1997) Meth Enzymol 276A:361-423, ed. Carter CW; Roversi P et al., (2000) Acta Crystallogr D Biol Crystallogr 56(Pt 10):1316-1323). Mutagenesis mapping studies can be accomplished using any method known to those of skill in the art. For example, for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques, see Champe M et al., (1995) J Biol Chem 270:1388-1394 and Cunningham BC & Wells JA (1989) Science 244:1081-1085.

[0086] An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition is a polypeptide, antibody, polynucleotide, vector, cell, or composition in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in a form found in nature. In some embodiments of the present disclosure, an antibody, polynucleotide, vector, cell, or composition that is isolated is substantially pure. As used herein, "substantially pure" refers to material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0087] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The term also includes amino acid polymers that are modified, naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are polypeptides containing, for example, one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. Because the polypeptides of this disclosure are based on antibodies, it is understood that in some embodiments of this disclosure, the polypeptides can occur as single chains or associated chains.

[0088] As used herein, the term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. The formulation may be sterile. In some embodiments, the formulation is suitable for therapeutic use in human subjects.

[0089] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a drug, such as an anti-TL1A antibody or an antigen-binding fragment thereof, to a desired site of biological action (e.g., intravenous administration). Administration techniques that can be used with the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa. and Matucci, A. et al., Respiratory Research, 19(1):154 (2018).

[0090] As used herein, the term "combination" or "administered in combination" means that an antibody or antigen-binding fragment thereof described herein can be administered with one or more additional therapeutic agents. In some embodiments of the combinations provided herein, the antibody or antigen-binding fragment thereof can be administered simultaneously or sequentially with the one or more additional therapeutic agents. In some embodiments, the antibody or antigen-binding fragment thereof described herein can be administered with one or more additional therapeutic agents in the same composition or in different compositions.

[0091] The terms "subject" and "patient" are used interchangeably and include any animal. In some embodiments, the subject is a mammal, including companion animals (e.g., cats, dogs) and farm mammals (e.g., pigs, horses, cows), as well as mice, rabbits, and rats, guinea pigs, and other rodents. In some embodiments, the subject is a non-human primate, such as a cynomolgus monkey. In some embodiments, the subject is a human.

[0092] A "therapeutically effective amount" refers to an amount of an agent, e.g., an anti-TL1A antibody (e.g., TEV-48574) or an antigen-binding fragment thereof, effective to treat a disease or disorder of interest. Terms such as "treating," "treatment," "to treat," "alleviating," and "to alleviate" refer to utilizing an approach to obtain such beneficial or desired clinical results, including, but not limited to, approaches that achieve such beneficial or desired clinical results, which may include therapeutic measures that result in improvement, cure, slowing, alleviation of symptoms, and / or halting progression of a pathological condition or disorder. Accordingly, those in need of treatment include those already diagnosed with a disorder or suspected of having a disorder.

[0093] "Specificity" in the context of antibody-antigen interactions is not necessarily an absolute designation, but rather a relative term that refers to the degree of selectivity of an antibody for antigen-positive cells compared to antigen-negative cells. The specificity of an antibody for antigen-positive cells is mediated by the antibody's variable region, usually the antibody's complementarity-determining region (CDR). Constructs can have approximately 100- to 1000-fold greater specificity for antigen-positive cells compared to antigen-negative cells.

[0094] As used herein, the term "recombinant" includes expression from genes produced by genetic engineering or otherwise by laboratory manipulation.

[0095] As used herein, the term "TEV 48574" or "TEV-48574" refers to a highly potent, fully human immunoglobulin G (IgG) subclass 1 (IgG1) (lambda) monoclonal antibody (mAb) that binds with high affinity to human, cynomolgus monkey, and rat TL1A. TEV-48574 comprises a light chain of SEQ ID NO: 9 and a heavy chain of SEQ ID NO: 10. TEV-48574 is a blocking antibody that acts by competitively inhibiting the interaction of TL1A with its cognate signaling receptor, DR3. By competitively inhibiting the binding of TL1A to DR3, this antibody prevents activation of the DR3 signaling pathway. Although TEV-48574 inhibits the interaction of TL1A with DR3 more than the interaction of TL1A with DcR3, TEV-48574 also inhibits the binding of TL1A with DcR3. TEV-48574 has demonstrated anti-inflammatory and anti-fibrotic effects in animal models of colitis. TEV-48574 was safe and well tolerated in the Phase 1 study TV48574-SAD-10126. TEV-48574 is disclosed in U.S. Patent No. 10,138,296 as "320-587," the entire contents of which are incorporated herein by reference.

[0096] As used herein, the term "TL1A" refers to tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15) and vascular endothelial growth inhibitor (VEGI), a member of the TNF superfamily expressed by antigen-presenting cells (including dendritic cells, B cells, and macrophages), CD4+ and CD8+ T cells, and endothelial cells. TL1A is expressed on the cell surface or secreted as a soluble cytokine. Its cognate signaling receptor, death receptor 3 (DR3), is expressed by a variety of cells, including CD4+ and CD8+ T cells, NK cells, NKT cells, FOXP3+ regulatory T (Treg) cells, and type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). TL1A can also bind to the decoy receptor (DcR3), which competitively inhibits DR3. DcR3 also acts as a decoy receptor for Fas-ligand (Fas-L) and lymphotoxin-like-inducible protein (LTI), and competes with glycoprotein D for binding to herpesvirus entry mediator (LIGHT) on T cells. Therefore, DcR3 is a key regulator of several signaling pathways.

[0097] As used herein, "moderate to severe ulcerative colitis," "moderate to severe ulcerative colitis (UC)," or "moderate to severe UC" refers to UC with a three-component modified Mayo score of 5 to 9 (global) and an endoscopic subscore of 2 or greater (from central reading).

[0098] The three-component modified Mayo score is based on three parameters: stool frequency, rectal bleeding, and endoscopic assessment. Each parameter ranges from 0 (normal or inactive disease) to 3 (severe active disease), and the total score ranges from 0 to 9 (Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). August 2016; Naegeli et al., Am J Gastroenterol; 113:S384 (2018)). The modified Mayo score is recommended by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (Reinisch et al., Comparison of the EMA and FDA Guidelines on Ulcerative Colitis Drug Development. Clin Gastroenterol Hepatol; 17(9): 1673-1679. e1 (2019)).

[0099] As used herein, "moderate to severe Crohn's disease," "moderate to severe Crohn's disease (CD)," or "moderate to severe CD" refers to CD with a Crohn's Disease Activity Index (CDAI) score of 220 or greater and 450 or less. (Yoshida EM. Can J Gastroenterol; 13(1):65-73 (1999))

[0100] As used herein, the term "inadequate response, loss of response, or intolerance to one or more agents" refers to inadequate response, loss of response, or intolerance to conventional therapy (e.g., small molecule agents) and / or biologic agents. The following are provided as examples: Inadequate response, loss of response, or intolerance to corticosteroid treatment is defined as one or more of the following: a. Steroid-resistant: Persistent symptoms of active disease despite at least one 4-week induction therapy with ≥30 mg prednisone (oral) daily for at least 2 weeks or ≥1 week intravenous within the past 5 years. b. Steroid dependence: Within the past year, two unsuccessful attempts have been made to taper steroids to the equivalent of 10 mg of oral prednisone per day. c. Steroid intolerance: History of intolerance to corticosteroids within the past 5 years (including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia, infections). Inadequate response, loss of response, or intolerance to prior immunosuppressant therapy defined as one or more of the following: a. Signs and symptoms of active disease persist despite a history of oral AZA (≥ 2-2.5 mg / kg / day) or 6-MP (≥ 1-1.5 mg / kg / day) and / or methotrexate (≥ 25 mg / week) for ≥ 12 weeks. b. History of intolerance to AZA, 6-MP or methotrexate (including but not limited to nausea, vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, thiopurine methyltransferase gene mutation, infection). Inadequate response, loss of response, or intolerance to a previous biologic or small molecule drug was defined as one or more of the following: a. Loss of response: Persistent signs and symptoms of active disease despite at least one induction regimen and one maintenance regimen of a locally approved regimen of anti-TNF inhibitor, anti-integrin, anti-IL-12 / 23 monoclonal antibody, JAK inhibitor, or S1P receptor modulator. b. Inadequate response (primary failure): Signs and symptoms of active disease persist despite at least one induction regimen of an anti-TNF inhibitor, anti-integrin agent, anti-IL-12 / 23 monoclonal antibody, JAK inhibitor, or S1P receptor modulator at the highest locally approved dosing regimen. c. Intolerance: Discontinuation of anti-TNF inhibitors, anti-integrin agents, anti-IL-12 / 23 monoclonal antibodies, JAK inhibitors, or S1P receptor modulators due to adverse reactions at the discretion of the treating physician, including but not limited to nausea and vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, and infections.

[0101] As used herein, the term "clinical remission" of ulcerative colitis refers to clinical remission determined as follows: Clinical remission is defined as a modified Mayo score (9-point scale for rectal bleeding, bowel frequency, and endoscopy) of 2 or less, and this score is A bowel frequency subscore of 0 or 1, Rectal bleeding subscore of 0, and Endoscopic subscores are defined as 0 or 1, where a score of 1 does not include "easy bleeding."

[0102] As used herein, the term "endoscopic response" in Crohn's disease refers to an endoscopic response determined as follows: Endoscopic response, defined as a reduction of at least 50% from baseline in the Simple Endoscopic Score for Crohn's Disease (SES-CD).

[0103] As used in this disclosure and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0104] Whenever aspects of the present disclosure are described herein using the term "comprising," it is understood that other similar embodiments described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0105] Unless otherwise specified or clear from the context, as used herein, the term "or" is understood to be inclusive. When used herein in phrases such as "A and / or B," the term "and / or" is intended to include both "A and B," "A or B," "A" and "B." Similarly, when used in phrases such as "A, B and / or C," the term "and / or" is intended to include each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0106] As used herein, the terms "about" and "approximately," when used to modify a numerical value or numerical range, indicate that a deviation of ±10% of that numerical value or numerical range remains within the intended meaning of the recited value or range. As will be understood by those skilled in the art, reference herein to a value or range as "about" includes (and describes) the case itself directed to that value or range. For example, a reference to "about X" includes the description of "X."

[0107] Any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0108] Units, prefixes, and symbols are shown in their International System of Units (SI) recognized form. Numerical ranges are inclusive of the numbers defining the range. The headings provided herein are not intended to limit the various aspects of this disclosure, but may be had by reference to the specification as a whole. As such, the terms defined immediately below are more fully defined by reference to the specification as a whole.

[0109] method The present disclosure provides a method for treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A). In some aspects, the present disclosure provides a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators; and (b) if the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent described in section (a), administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds TNF-like ligand 1A (TL1A). In some embodiments, the method comprises not administering a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TL1A if the subject has not previously had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators.

[0110] In some embodiments, the present disclosure provides a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease; and (b) if the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease, administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A). In some embodiments, the method comprises not administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TL1A if the subject does not have moderate to severe ulcerative colitis or moderate to severe Crohn's disease.

[0111] In some embodiments, the antibody or antigen-binding fragment thereof inhibits the ability of TL1A to interact with DR3, and in some embodiments, also interacts with DcR3 and inhibits signaling induced by the interaction of TL1A with DR3. In some embodiments, the antibody or antigen-binding fragment thereof has enhanced potency relative to antibody 320-179. In some embodiments, the antibody or antigen-binding fragment thereof has enhanced affinity for TL1A compared to antibody 320-179.

[0112] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein comprises an antibody or antigen-binding fragment thereof comprising a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment thereof can inhibit the interaction of TL1A and DR3.

[0113] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the antibodies or antigen-binding fragments thereof comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibodies or antigen-binding fragments thereof comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0114] In some embodiments, the heavy chain variable region is attached to a heavy chain constant region. In some embodiments, the heavy chain constant region is an IgG1, IgG2, or IgG4 heavy chain constant region. In some embodiments, the heavy chain variable region of SEQ ID NO: 7 is attached to a human IgG1(ΔK) heavy chain constant region (e.g., SEQ ID NO: 14) such that the heavy chain comprises SEQ ID NO: 9. In some embodiments, the heavy chain constant regions provided herein do not comprise a C-terminal lysine. In some embodiments, the light chain variable region of SEQ ID NO: 8 is attached to a lambda human light chain constant region (e.g., SEQ ID NO: 29) such that the light chain comprises SEQ ID NO: 10.

[0115] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are monoclonal antibodies or antigen-binding fragments thereof.

[0116] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are recombinant antibodies or antigen-binding fragments thereof. In some embodiments, the recombinant antibodies are full-length antibodies. In some embodiments, the recombinant antibodies are monoclonal antibodies.

[0117] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein bind to TL1A with enhanced affinity relative to a 320-179 anti-TL1A antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein have enhanced potency relative to a 320-179 anti-TL1A antibody. The enhanced potency can be at least about 10-fold, at least about 12-fold, at least about 13-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 27-fold, at least about 40-fold, about 10-fold to about 40-fold, about 12-fold to about 40-fold, about 13-fold to about 40-fold, about 15-fold to about 40-fold, about 20-fold to about 40-fold, about 25-fold to about 40-fold, or about 27-fold to about 40-fold relative to a 320-179 anti-TL1A antibody. The fold increase in efficacy can be measured by a TL1A-induced caspase activity assay using TF-1 cells. See, for example, U.S. Patent No. 10,138,296. The 320-179 antibody has favorable biophysical properties, potently inhibits TL1A, and has a predicted low immunogenicity profile. U.S. Patent No. 10,138,296 and U.S. Patent Application Publication No. 2014 / 0255302 are incorporated herein in their entireties.

[0118] In some embodiments, the antibody disclosed herein is TEV-48574, which is also referred to as the 320-587 antibody in U.S. Pat. No. 10,138,296 (VH is SEQ ID NO: 3 and VL is SEQ ID NO: 4 in the same publication).

[0119] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8, and bind to TL1A with enhanced affinity relative to the anti-TL1A 320-179 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:12. The anti-TL1A 320-179 antibody was previously described in U.S. Patent No. 10,138,296 (VH is SEQ ID NO:1 therein, and VL is SEQ ID NO:2 therein) and U.S. Patent Application Publication No. 2014 / 0255302 (VH is SEQ ID NO:186 therein, and VL is SEQ ID NO:199 therein). The 320-179 antibody has favorable biophysical properties, potently inhibits TL1A, and has a predicted low immunogenicity profile. U.S. Patent No. 10,138,296 and U.S. Patent Application Publication No. 2014 / 0255302 are incorporated herein in their entireties.

[0120] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8, and has enhanced potency relative to the 320-179 anti-TL1A antibody. The enhanced potency can be at least about 10-fold, at least about 12-fold, at least about 13-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 27-fold, or at least about 40-fold compared to the 320-179 anti-TL1A antibody. The fold enhancement in potency can be measured according to a TL1A-induced caspase potency assay using TF-1 human erythroleukemia cells (ATCC:CRL-2003). See, e.g., U.S. Patent No. 10,138,296.

[0121] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are full-length antibodies. In some embodiments, the antibodies disclosed herein are monoclonal antibodies.

[0122] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a human IgG1 heavy chain constant region, a human IgG2 heavy chain constant region, a human IgG4 heavy chain constant region, or an allotype thereof. The human IgG1 heavy chain constant region can be selected from human IgG1 (SEQ ID NO: 13), human IgG1(ΔK) (SEQ ID NO: 14), human IgG1 252Y / 254T / 256E (SEQ ID NO: 15), human IgG1 252Y / 254T / 256E(ΔK) (SEQ ID NO: 16), human IgG1 L234A / L235A / G237A (SEQ ID NO: 17), human IgG1 L234A / L235A / G237A(ΔK) (SEQ ID NO: 18), human IgG1 L235A / G237A (SEQ ID NO: 19), and human IgG1 L235A / G237A(ΔK) (SEQ ID NO: 20). The human IgG2 heavy chain constant region can be selected from among human IgG2 with or without ΔK (SEQ ID NO: 21 and SEQ ID NO: 22) and human IgG2 A330S / P331S with or without (ΔK) (SEQ ID NO: 23 and SEQ ID NO: 24). The human IgG4 heavy chain constant region can be selected from among human IgG4 S228P (SEQ ID NO: 25), human IgG4 S228P(ΔK) (SEQ ID NO: 26), human IgG4 228P / 252Y / 254T / 256E (SEQ ID NO: 27), and human IgG4 228P / 252Y / 254T / 256E(ΔK) (SEQ ID NO: 28). It will be understood that the IgG4 heavy chain can be used without the stabilizing substitution S228P (e.g., IgG4 with YTE alone, IgG4 with YTE and ΔK, or IgG4 with ΔK alone).

[0123] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a human lambda light chain constant region or an allotype thereof. The human light chain lambda constant region can comprise SEQ ID NO:29.

[0124] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein bind to human TL1A and can bind to one or more of cynomolgus monkey TL1A, mouse TL1A, rat TL1A, guinea pig TL1A, feline TL1A, dog TL1A, pig TL1A, or rabbit TL1A. In some embodiments, the antibodies or antigen-binding fragments thereof can bind to TL1A from multiple different species, such as when an epitope is shared. In some embodiments, human TL1A comprises the amino acid sequence of SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36. In some embodiments, cynomolgus monkey TL1A comprises the amino acid sequence of SEQ ID NO: 37. In some embodiments, mouse TL1A comprises the amino acid sequence of SEQ ID NO: 38. In some embodiments, rat TL1A comprises the amino acid sequence of SEQ ID NO: 39. In some embodiments, guinea pig TL1A comprises the amino acid sequence of SEQ ID NO: 40. In some embodiments, cat TL1A comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, pig TL1A comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, rabbit TL1A comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, canine TL1A comprises the amino acid sequence of SEQ ID NO: 44.

[0125] The antibodies or antigen-binding fragments thereof disclosed herein have an equilibrium dissociation constant (K D ) which can be measured by an equilibrium exclusion method such as the KINEXA® assay (Sapidyne Instruments Inc., Boise, ID). D In some embodiments, the K of TL1A binding measured by equilibrium exclusion method is less than about 1000 pM. D In some embodiments, the K of TL1A binding measured by equilibrium exclusion method is less than about 500 pM, or less than about 400 pM, or less than about 300 pM, or less than about 200 pM. D is less than about 100 pM.

[0126] K of TL1A binding measured by equilibrium exclusion method D The K of TL1A binding measured by the equilibrium exclusion method can be from about 10 pM to about 100 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be from about 25 pM to about 75 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be from about 30 pM to about 60 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be about 30 pM to about 50 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be about 35 pM to about 50 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be from about 36 pM to about 46 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be from about 38 pM to about 44 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be from about 39 pM to about 43 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be about 40 pM to about 45 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be from about 35 pM to about 42 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be approximately 40 pM. D The K of TL1A binding measured by the equilibrium exclusion method can be approximately 41 pM. D can be about 42 pM. Equilibrium exclusion methods can use antibody molecules or TL1A molecules as constant binding partners and other molecules as titrants.

[0127] The antibodies or antigen-binding fragments thereof disclosed herein can bind to TL1A-positive cells. The antibodies or antigen-binding fragments thereof disclosed herein have an EC of less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 18 nM, less than about 15 nM, less than about 13 nM, or less than about 10 nM. 50It can bind to TL1A-positive cells at low levels.

[0128] The antibodies or antigen-binding fragments thereof disclosed herein may be monoclonal. In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are full-length antibodies comprising two heavy chains and two light chains. In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein include derivatives, fragments, or portions of antibodies that retain the antigen-binding specificity and most or all of the affinity of the full-length antibody. For example, the derivatives can comprise at least one variable region (either a heavy chain variable region or a light chain variable region). The derivatives can comprise at least two variable regions, for example, at least one heavy chain variable region and at least one light chain variable region. Other examples of suitable antibody derivatives and fragments include, but are not limited to, antibodies with multiepitopic specificity, bispecific antibodies, multispecific antibodies, diabodies, single-chain molecules, FAb, F(Ab'), Fd, Fabc, Fv molecules, single-chain (Sc) antibodies, single-chain Fv antibodies (scFv), individual antibody light chains, individual antibody heavy chains, fusions of antibody chains with other molecules, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy chain and one light chain, and other multimers. Single-chain Fv antibodies can also be multivalent. All antibody isotypes can be used to generate antibody derivatives, fragments, and portions thereof. Antibody derivatives, fragments, and / or portions thereof can be recombinantly produced and expressed by any cell type, prokaryotic or eukaryotic.

[0129] In a full-length antibody, each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains: CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is composed of one domain: CL. The VH and VL regions are further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Typically, the antigen-binding properties of an antibody are less affected by changes in FR sequences than by changes in CDR sequences. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass.

[0130] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are fully human. A fully human antibody is one in which the entire molecule is human or otherwise of human origin or contains an amino acid sequence identical to a human version of an antibody. Fully human antibodies include, for example, antibodies obtained from human V gene libraries in which human genes encoding antibody variable regions are recombinantly expressed. Fully human antibodies can be expressed in other organisms (e.g., mice and xenomouse technology) or in cells from other organisms transformed with genes encoding human antibodies. Nevertheless, fully human antibodies can contain amino acid residues not encoded by human sequences, e.g., mutations introduced by random mutation or site-directed mutagenesis.

[0131] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise a protein framework of non-immunoglobulin origin. For example, Ku & Schutz, Proc. Natl. Acad. Sci. USA, 92:6552-6 (1995), describe the four-helix bundle protein cytochrome b562, with two loops randomized to create CDRs selected for antigen binding.

[0132] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise post-translational modifications or moieties that can affect antibody activity or stability. These modifications or moieties include, but are not limited to, methylated, acetylated, glycosylated, sulfated, phosphorylated, carboxylated, amidated, and other moieties known in the art. Each moiety includes any chemical group or combination of groups typically found on immunoglobulin molecules in nature or added to antibodies by recombinant expression systems, including prokaryotic and eukaryotic expression systems.

[0133] Examples of side chain modifications contemplated by the present disclosure include modification of amino groups by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH4; amidation with methyl acetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH4, and the like.

[0134] The guanidine group of arginine residues can be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal, and glyoxal. Carboxyl groups can be modified by carbodiimide activation via O-acylisourea formation, followed by derivatization to the corresponding amides, for example. Sulfhydryl groups can be modified by carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; mixed disulfide formation with other thiol compounds; reaction with maleimide, maleic anhydride, or other substituted maleimides; formation of mercury derivatives with 4-chloromercuribenzoate, 4-chloromercuriphenylsulfonic acid, phenylmercuric chloride, 2-chloromercuri-4-nitrophenol, and other mercuric acids; and carbamoylation with cyanate at alkaline pH. Tryptophan residues can be modified by, for example, oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulfenyl halides, while tyrosine residues can be nitrated with tetranitromethane to form 3-nitrotyrosine derivatives. Modification of the imidazole ring of histidine residues can be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate.

[0135] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein comprise one or more modifications that modify serum half-life and biodistribution, including, but not limited to, modifications that modify the antibody's interaction with the neonatal Fc receptor (FcRn), a receptor that protects IgG from catabolism and plays an important role in maintaining high serum antibody concentrations. Modifications that modulate serum half-life include triple substitutions of M252Y / S254T / T256E (EU numbering system (Edelman, G. et al.), as described in U.S. Pat. No. 7,083,784). Substitutions can occur in the Fc region of IgG1, IgG2, or IgG4, including substitutions at positions 250 and 428 (see, e.g., U.S. Pat. No. 7,217,797), as well as positions 307, 380, and 434 (see, e.g., WO 00 / 042072). Substitutions affect binding to Fc receptors and subsequent activity of these receptors, including FcRn binding and serum half-life. Examples of amino acid substitutions in the constant domain that modulate functions mediated by the constant domain are described in U.S. Patent Application Publication Nos. 2009 / 0142340, 2009 / 0068175, and 2009 / 0092599. In any class of antibody, the C-terminal lysine of the heavy chain can be omitted or removed to reduce heterogeneity (ΔK). The S228P (EU numbering) substitution in human IgG4 can stabilize antibody Fab-arm exchange in vivo (Labrin et al., Nature Biotechnology 27(8):767-73 (2009)), and this substitution can occur simultaneously with YTE and / or ΔK modifications.

[0136] The antibodies or antigen-binding fragments thereof disclosed herein can be labeled, linked, or conjugated to any chemical or biomolecular moiety. Labeled antibodies can be used for therapeutic, diagnostic, and basic research applications. Such labels / conjugates can be detectable, for example, fluorescent dyes, electrochemiluminescent probes, quantum dots, radioactive labels, enzymes, fluorescent proteins, luminescent proteins, biotin, and the like.

[0137] The antibodies or antigen-binding fragments thereof disclosed herein can be derivatized with known protecting / blocking groups to prevent proteolytic cleavage or to enhance activity or stability.

[0138] Administration of the antibodies or antigen-binding fragments thereof disclosed herein can include administering the antibodies or antigen-binding fragments thereof subcutaneously. Administration can include administering the antibodies or antigen-binding fragments thereof intravenously.

[0139] In some embodiments, the subject is a human subject. In some embodiments, the subject is a non-human primate, such as a cynomolgus monkey. In some embodiments, the subject is a non-human mammal, such as a mouse, rat, guinea pig, cat, pig, rabbit, dog, etc.

[0140] In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 1750 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 1800 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 2000 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 2500 mg. In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered about once every two weeks. In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered about once every four weeks. In some embodiments, the antibody or antigen-binding fragment thereof is administered about once a month.

[0141] In some embodiments, the administration comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering one or more induction doses of the antibody or antigen-binding fragment thereof, hi some embodiments, the administration does not comprise administering a loading dose of the antibody or antigen-binding fragment thereof.

[0142] In some embodiments, the loading dose comprises about 1500 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 1750 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 2000 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 2250 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose comprises about 2500 mg of antibody or antigen-binding fragment thereof. In some embodiments, the loading dose is administered about two weeks prior to administration of the one or more induction doses.

[0143] In some embodiments, one or more induction doses comprise about 300 mg of antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 400 mg of antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 450 mg of antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 600 mg of antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 750 mg of antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 900 mg of antibody or antigen-binding fragment thereof. In some embodiments, one or more induction doses comprise about 1800 mg of antibody or antigen-binding fragment thereof.

[0144] In some embodiments, about 6 induction doses are administered.

[0145] In some embodiments, administration occurs over a period of about 16 weeks. In some embodiments, administration of one or more induction doses occurs over a period of about 14 weeks. In some embodiments, a loading dose is administered about 2 weeks before administration of one or more induction doses.

[0146] In some embodiments, the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every two weeks.

[0147] In some embodiments, the administration further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every two weeks.

[0148] In some embodiments, the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every four weeks.

[0149] In some embodiments, the administration further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every four weeks.

[0150] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered in a loading dose of about 2250 mg two weeks prior to an induction dose of about 1800 mg, which is administered every two weeks for, for example, about 14 weeks.

[0151] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered in a loading dose of about 2250 mg, two weeks prior to an induction dose of about 900 mg, which is administered every two weeks for, for example, about 14 weeks.

[0152] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered in a loading dose of about 2250 mg two weeks prior to an induction dose of about 450 mg, which is administered every two weeks for, for example, about 14 weeks.

[0153] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are administered at a dose of about 300 mg about every two weeks.

[0154] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are administered at a dose of about 400 mg about every two weeks.

[0155] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are administered at a dose of about 450 mg about every two weeks.

[0156] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are administered at a dose of about 900 mg about every two weeks.

[0157] In some embodiments, administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof. In some embodiments, administering comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering one or more induction doses of the antibody or antigen-binding fragment thereof, followed by administering one or more maintenance doses of the antibody or antigen-binding fragment thereof. In some embodiments, administering comprises administering one or more induction doses of the antibody or antigen-binding fragment thereof, followed by administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, wherein said administering does not include administering a loading dose of the antibody or antigen-binding fragment thereof. In some embodiments, administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, wherein the administering does not include administering a loading dose of the antibody or antigen-binding fragment thereof and does not include administering an induction dose of the antibody or antigen-binding fragment thereof.

[0158] In some embodiments, the one or more maintenance doses comprise about 300 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0159] In some embodiments, the one or more maintenance doses comprise about 300 mg of the antibody or antigen-binding fragment thereof.

[0160] In some embodiments, the one or more maintenance doses comprise about 900 mg of the antibody or antigen-binding fragment thereof.

[0161] In some embodiments, the one or more maintenance doses comprise about 400 mg or about 900 mg of the antibody or antigen-binding fragment thereof. In some embodiments, the one or more maintenance doses comprise about 400 mg of the antibody or antigen-binding fragment thereof.

[0162] In some embodiments, the one or more maintenance doses comprise about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof. In some embodiments, the one or more maintenance doses comprise about 450 mg of the antibody or antigen-binding fragment thereof.

[0163] In some embodiments, about 10 maintenance doses are administered.

[0164] In some embodiments, about 12 maintenance doses are administered.

[0165] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0166] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about two weeks later, one or more induction doses of about 450 mg administered about every two weeks (e.g., for about 14 weeks), and (iii) thereafter, one or more maintenance doses of about 300 mg administered every two weeks (e.g., for about 24 weeks).

[0167] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0168] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about two weeks later, one or more induction doses of about 900 mg administered about every two weeks (e.g., for about 14 weeks), and (iii) thereafter, one or more maintenance doses of about 300 mg administered every two weeks (e.g., for about 24 weeks).

[0169] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 1800 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0170] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about two weeks later, one or more induction doses of about 1800 mg administered about every two weeks (e.g., for about 14 weeks), and (iii) thereafter, one or more maintenance doses of about 300 mg administered every two weeks (e.g., for about 24 weeks).

[0171] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0172] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about two weeks later, one or more induction doses of about 450 mg administered about every two weeks (e.g., for about 14 weeks), and (iii) thereafter, one or more maintenance doses of about 900 mg administered every two weeks (e.g., for about 24 weeks).

[0173] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0174] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about two weeks later, one or more induction doses of about 900 mg administered about every two weeks (e.g., for about 14 weeks), and (iii) thereafter, one or more maintenance doses of about 900 mg administered every two weeks (e.g., for about 24 weeks).

[0175] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 1800 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0176] In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about two weeks later, one or more induction doses of about 1800 mg administered about every two weeks (e.g., for about 14 weeks), and (iii) thereafter, one or more maintenance doses of about 900 mg administered every two weeks (e.g., for about 24 weeks).

[0177] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0178] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0179] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0180] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0181] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0182] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0183] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0184] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0185] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0186] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0187] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0188] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0189] In some embodiments, the administration comprises administering (i) a loading dose, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0190] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks. In some embodiments, about 6 induction doses are administered and / or about 10 maintenance doses are administered.

[0191] In some embodiments, the administration comprises administering (i) a loading dose and (ii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof, optionally, the maintenance doses being administered about every four weeks. In some embodiments, about 10 maintenance doses are administered. In some embodiments, at least 10 (e.g., 10-50, or 10-24, or 10-20, or 10-12) maintenance doses are administered.

[0192] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, and (ii) one or more maintenance doses of about 400 mg of the antibody or antigen-binding fragment thereof, optionally, the maintenance doses being administered about every four weeks. In some embodiments, about 10 maintenance doses are administered. In some embodiments, at least 10 (e.g., 10-50, or 10-24, or 10-20, or 10-12) maintenance doses are administered.

[0193] In some embodiments, the administration comprises administering (i) a loading dose and (ii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally, the maintenance doses being administered about every four weeks. In some embodiments, about 10 maintenance doses are administered. In some embodiments, at least 10 (e.g., 10-50, or 10-24, or 10-20, or 10-12) maintenance doses are administered.

[0194] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, and (ii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally, the maintenance doses being administered about every four weeks. In some embodiments, about 10 maintenance doses are administered. In some embodiments, at least 10 (e.g., 10-50, or 10-24, or 10-20, or 10-12) maintenance doses are administered.

[0195] In some embodiments, the administration comprises administering (i) a loading dose and (ii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally, the maintenance doses are administered about every 4 weeks. In some embodiments, about 10 maintenance doses are administered. In some embodiments, about 10 maintenance doses are administered. In some embodiments, at least 10 (e.g., 10-50, or 10-24, or 10-20, or 10-12) maintenance doses are administered.

[0196] In some embodiments, the administration comprises administering (i) a loading dose of about 2250 mg, and (ii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally, the maintenance doses being administered about every 4 weeks. In some embodiments, about 10 maintenance doses are administered. In some embodiments, about 10 maintenance doses are administered. In some embodiments, at least 10 (e.g., 10-50, or 10-24, or 10-20, or 10-12) maintenance doses are administered.

[0197] In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 100 mg / ml or about 150 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 200 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 225 mg / mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 250 mg / mL.

[0198] In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL. In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less. In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a volume of 2 mL or less.

[0199] In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein are present in a pharmaceutical formulation or container disclosed herein.

[0200] In some embodiments, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA). In some embodiments, the subject has had an inadequate response, failed to respond, or intolerance to one or more agents. In some embodiments, the subject has had an inadequate response, failed to respond, or intolerance to two or fewer classes of biologics.

[0201] In some embodiments, the subject is treated concomitantly with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6 mercaptopurine (6-MP), and / or methotrexate.

[0202] In some embodiments, the methods disclosed herein further comprise administering oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

[0203] The present disclosure further provides compositions for use according to any of the methods disclosed herein.

[0204] Polynucleotides and Vectors Polynucleotide sequences encoding recombinant antibodies or antigen-binding fragments thereof, and subdomains thereof (e.g., FRs and CDRs) are disclosed herein. Polynucleotides include, but are not limited to, RNA, DNA, cDNA, hybrids of RNA and DNA, and single-, double-, or triple-stranded RNA, DNA, or hybrids thereof. Polynucleotides can include nucleic acid sequences encoding the heavy chain variable region and / or light chain variable region of an antibody described or exemplified herein. Complements of the polynucleotide sequences are also within the scope of this disclosure.

[0205] In some embodiments, the polynucleotide can comprise a nucleic acid sequence encoding an antibody heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 7. The polynucleotide encoding the amino acid sequence of SEQ ID NO: 7 can comprise the nucleic acid sequence of SEQ ID NO: 30 or SEQ ID NO: 31.

[0206] In some embodiments, the polynucleotide can comprise a nucleic acid sequence encoding an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. The polynucleotide encoding the amino acid sequence of SEQ ID NO: 8 can comprise the nucleic acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33.

[0207] In some embodiments, the polynucleotide can comprise a first nucleic acid sequence encoding an antibody heavy chain variable region and a second nucleic acid sequence encoding an antibody light chain variable region. The first nucleic acid sequence can encode an antibody heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 7, and the second nucleic acid sequence can encode an antibody light chain variable region consisting of the amino acid sequence of SEQ ID NO: 8. The first nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 7 can comprise the nucleic acid sequence of SEQ ID NO: 30 or SEQ ID NO: 31, and the second nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 8 can comprise the nucleic acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33.

[0208] In some embodiments, the polynucleotide can comprise a first nucleic acid sequence encoding an antibody heavy chain variable region and a second nucleic acid sequence encoding a heavy chain constant region. In some embodiments, the polynucleotide comprises a first nucleic acid sequence encoding an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a second nucleic acid sequence encoding an IgG1(ΔK) heavy chain constant region of SEQ ID NO: 14, e.g., a polynucleotide comprising the nucleic acid sequence of SEQ ID NO: 31.

[0209] In some embodiments, the polynucleotide can comprise a first nucleic acid sequence encoding an antibody light chain variable region and a second nucleic acid sequence encoding a light chain constant region. In some embodiments, the polynucleotide comprises a first nucleic acid sequence encoding an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO:8 and a second nucleic acid sequence encoding the lambda light chain constant region of SEQ ID NO:29, e.g., a polynucleotide comprising the nucleic acid sequence of SEQ ID NO:33.

[0210] Any of the polynucleotides described or exemplified herein can be incorporated into a vector. Thus, vectors containing polynucleotides are provided as part of the present disclosure. The vector can be an expression vector. Thus, a recombinant expression vector containing a sequence encoding a polypeptide of interest is provided. The expression vector can contain one or more additional sequences, such as, but not limited to, a regulatory sequence, a selection marker, a purification tag, or a polyadenylation signal. Such regulatory elements include a transcription promoter, an enhancer, an mRNA ribosomal binding site, or a sequence controlling the termination of transcription and translation.

[0211] Expression vectors, particularly mammalian expression vectors, can contain one or more nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, other 5' or 3' flanking nontranscribed sequences, 5' or 3' nontranslated sequences (such as necessary ribosome binding sites), a polyadenylation site, splice donor and acceptor sites, or a transcription termination sequence. An origin of replication that confers the ability to replicate in a particular host can also be incorporated.

[0212] Vectors can be used to transform any of a wide range of host cells known to those skilled in the art and capable of expressing antibodies. Vectors include, but are not limited to, plasmids, phagemids, cosmids, bacmids, bacterial artificial chromosomes (BACs), yeast artificial chromosomes (YACs), baculoviruses, and other bacterial, eukaryotic, yeast, and viral vectors. Suitable host cells include, but are not limited to, CHO cells, NS0 cells, HEK293 cells, or any known or developed eukaryotic stable cell line, including bacterial, yeast, and insect cells.

[0213] In some embodiments, the antibodies or antigen-binding fragments thereof provided herein were produced in human embryonic kidney cells. In some embodiments, the antibodies or antigen-binding fragments thereof provided herein were produced in HEK293 cells.

[0214] Antibodies or antigen-binding fragments thereof can also be produced by hybridoma cells. Methods for producing hybridomas are well known and established in the art.

[0215] Pharmaceutical Composition The present disclosure also provides pharmaceutical compositions comprising the antibodies or antigen-binding fragments thereof provided herein. The pharmaceutical compositions can include any of the antibodies or antigen-binding fragments thereof described and / or exemplified herein and an acceptable carrier, such as a pharmaceutically acceptable carrier. Suitable carriers include any medium that does not interfere with the biological activity of the antibody or antigen-binding fragment thereof and is not toxic to the host to which it is administered. The pharmaceutical compositions can be formulated for administration to a subject in any suitable dosage form.

[0216] Pharmaceutical compositions suitable for administration to human patients are typically formulated for parenteral administration, e.g., with a liquid carrier or suitable for reconstitution into a liquid solution or suspension for intravenous or subcutaneous administration.

[0217] In general, such compositions typically include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" means approved by a government regulatory agency for use in animals, particularly humans, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Such pharmaceutical carriers may be sterile liquids. Water or aqueous solutions such as saline, dextrose, and glycerol solutions may be employed as carriers, particularly for injectable solutions. Liquid compositions for parenteral administration may be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion include intravenous and subcutaneous.

[0218] In some embodiments, the pharmaceutical composition comprises: (a) about 100 mg / mL of TNF-like ligand 1A (TNF-like ligand 1B); 1A:TL1A), an antibody or antigen-binding fragment thereof that specifically binds to IL-1A (TL1A), comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and a light chain comprising the amino acid sequence of SEQ ID NO: 10; (b) about 10 mM histidine; (c) about 100 mM arginine hydrochloride (Arg-HCl); (d) about 5% (w / v) sucrose; and (e) about 0.02% (w / v) polysorbate-80. In some embodiments, the pharmaceutical formulation is lyophilized. In some embodiments, the pharmaceutical formulation is liquid.

[0219] In some embodiments, the pharmaceutical formulation comprises (a) about 150 mg / mL of TNF-like ligand 1A 1A:TL1A), an antibody or antigen-binding fragment thereof that specifically binds to TL1A, comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10; (b) about 10 mM histidine; (c) about 100 mM arginine hydrochloride (Arg-HCl); (d) about 5% (w / v) sucrose; and (e) about 0.02% (w / v) polysorbate-80. In some embodiments, the pharmaceutical formulation is lyophilized. In some embodiments, the pharmaceutical formulation is liquid.

[0220] In some embodiments, the pharmaceutical formulation comprises (a) about 100 mg / mL of TNF-like ligand 1A 1A:TL1A), an antibody or antigen-binding fragment thereof that specifically binds to TL1A, comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10; (b) about 10 mM histidine; (c) about 100 mM arginine hydrochloride (Arg-HCl); (d) about 5% (w / v) sucrose; and (e) about 0.02% (w / v) polysorbate-80.

[0221] In some embodiments, the pharmaceutical formulation comprises (a) about 150 mg / mL of TNF-like ligand 1A 1A:TL1A), an antibody or antigen-binding fragment thereof that specifically binds to TL1A, comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10; (b) about 10 mM histidine; (c) about 100 mM arginine hydrochloride (Arg-HCl); (d) about 5% (w / v) sucrose; and (e) about 0.02% (w / v) polysorbate-80.

[0222] In some embodiments, the pharmaceutical formulations provided herein have a pH of 6.0±0.5 after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have an osmolality of 200 mOsm / kg to 500 mOsm / kg after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have an antibody monomer content of at least 99% after storage at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have no significant change in charge heterogeneity profile after storage at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have no significant change in purity after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have a purity of at least 90% after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have no significant change in particle concentration after storage at room temperature for 24 hours or at 2-8°C for 24 hours, 72 hours, or 10 days. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in visual appearance after storage at 2-8°C for up to 24 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in visual appearance after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in protein concentration, osmolality, or viscosity after storage at 2-8°C, 25°C, or 40°C for up to 24 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in protein concentration, osmolality, or viscosity after storage at 2-8°C, 25°C, or 40°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have a monomer content of 95% or more, a dimer content of 5.0% or less, or no significant difference in low molecular weight species content after storage at 2-8°C for up to 24 months.In some embodiments, the pharmaceutical formulations provided herein have a monomer content of 95% or more, a dimer content of 5.0% or less, or no significant difference in low molecular weight species content after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have a purity of 90% or more after storage at 2-8°C for up to 24 months. In some embodiments, the pharmaceutical formulations provided herein have a purity of 90% or more after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have a main species content of 50%-90%, an acidic species content of 10%-40%, and / or a basic species content of 0%-20% after storage at 2-8°C for up to 24 months. In some embodiments, the pharmaceutical formulations provided herein have a main species content of 50%-90%, an acidic species content of 10%-40%, and / or a basic species content of 0%-20% after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein do not have a significant difference in subvisible particle content after storage for up to 24 months at 2-8° C., 25° C., or 40° C. In some embodiments, the pharmaceutical formulations provided herein do not have a significant difference in subvisible particle content after storage for up to 36 months at 2-8° C., 25° C., or 40° C. In some embodiments, the pharmaceutical formulations disclosed herein do not have a significant difference in oxidation of methionine 81 and / or methionine 254 of TEV-48574, and / or deamidation of asparagine 317 of TEV-48574 after storage for up to 24 months at 2-8° C., 25° C., or 40° C. In some embodiments, the pharmaceutical formulations disclosed herein have no significant difference in oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or deamidation of asparagine 317 of TEV-48574 after storage for up to 36 months at 2-8° C., 25° C., or 40° C. In some embodiments, the pharmaceutical formulations provided herein have a relative potency of 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage for up to 24 months at 2-8° C.In some embodiments, the pharmaceutical formulations provided herein have a relative potency of 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in thermal stability after storage at 2-8°C, 25°C, or 40°C for up to 6 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in thermal stability after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in secondary and / or tertiary protein structure after storage at 2-8°C, 25°C, or 40°C for up to 3 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in secondary protein structure after storage at 2-8°C for up to 36 months. In some embodiments, the pharmaceutical formulations provided herein have no significant difference in polysorbate-80 concentration after storage at 2-8°C for up to 24 months.

[0223] Kits and containers The present disclosure also features a container containing any of the pharmaceutical formulations described and exemplified herein. In some embodiments, the container is a glass vial. In some embodiments, the container is a 3 mL glass vial.

[0224] The present disclosure also features kits that include any of the pharmaceutical formulations, or antibodies or antigen-binding fragments thereof, described and exemplified herein. The kits can be used to provide, among other things, pharmaceutical formulations, antibodies, antigen-binding fragments thereof, and other agents for use in diagnostic, basic research, or therapeutic methods. In some embodiments, the kits include any one or more of the pharmaceutical formulations, antibodies, or antigen-binding fragments thereof described or exemplified herein and instructions for using the one or more pharmaceutical formulations, antibodies, or antigen-binding fragments thereof in a method for treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease. In some embodiments, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA). In some embodiments, the subject has had an inadequate response, failed to respond, or intolerance to one or more agents. In some embodiments, the subject has had an inadequate response, failed to respond, or intolerance to two or fewer classes of biologics.In some embodiments, the kit comprises any one or more of the pharmaceutical preparations, antibodies, or antigen-binding fragments thereof described or exemplified herein and instructions for using the one or more pharmaceutical preparations, antibodies, or antigen-binding fragments thereof in a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has previously received a corticosteroid, an immunosuppressant, a tumor necrosis factor-alpha (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JK) inhibitor, or a combination thereof; and (b) determining whether the subject has previously responded inadequately, failed to respond to, or been intolerant to at least one agent selected from the group consisting of: a JAK inhibitor, a sphingosine-1-phosphate (S1P) receptor modulator, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject has previously responded inadequately, failed to respond to, or been intolerant to at least one agent, administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A).

[0225] In some embodiments, the kit comprises any one or more of the pharmaceutical preparations, recombinant antibodies, or antigen-binding fragments thereof described or exemplified herein and instructions for using the one or more pharmaceutical preparations, antibodies, or antigen-binding fragments thereof in a method for treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease; and (b) if the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease, administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A).

[0226] Exemplary embodiments provided herein In one aspect (Aspect 1; A1), provided herein is a method of treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); wherein the antibody or antigen-binding fragment comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0227] In one embodiment of A1, i.e., A2, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA).

[0228] In one aspect of A2, namely A3, the subject has had an inadequate response, failed to respond to, or was intolerant to one or more medications.

[0229] In one aspect of A2 or A3, namely A4, the subject has had an inadequate response to, failed to respond to, or been intolerant to no more than two biologic agents.

[0230] In one aspect (Aspect 5; A5), provided herein is a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators; and (b) if the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent in part (a), determining whether the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent selected from the group consisting of TNF-like ligand 1A (TNF-like ligand 1B). 1A:TL1A), wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0231] In one embodiment of A5, ie, A6, the ulcerative colitis is moderate to severe ulcerative colitis, and / or wherein the Crohn's disease is moderate to severe Crohn's disease.

[0232] In one aspect (Aspect A7), provided herein is a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease; and (b) if the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease, administering TNF-like ligand 1A (TNF-like ligand 1B). and administering to a subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to a target polypeptide (e.g., a polypeptide having a polypeptide sequence of SEQ ID NO: 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1B. 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1C. 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1D. 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1E. 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1F. 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1G. 1A:TL1A) or a polypeptide having a polypeptide sequence of SEQ ID NO: 1H ...

[0233] In one embodiment of A7, i.e., A8, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA).

[0234] In one embodiment of A8, ie, A9, the subject has had an inadequate response, failed to respond to, or was intolerant to one or more medications.

[0235] In one embodiment of A8 or A9, ie, A10, the subject has had an inadequate response to, failed to respond to, or been intolerant to no more than two biologic agents.

[0236] In any one embodiment of A1 to A10, ie, A11, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0237] In any one embodiment of A1-A11, i.e., A12, the subject is concurrently treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

[0238] In any one of A1-A12, ie, A13, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

[0239] In any one of A1-A12, ie, A14, the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg.

[0240] In any one of A1-A12, ie, A15, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg.

[0241] In any one of A1-A12, ie, A16, the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg.

[0242] In any one of A1-A12, ie, A17, the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg.

[0243] In any one of A1-A12, ie, A18, the antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg.

[0244] In any one of A1-A12, ie, A19, the antibody or antigen-binding fragment thereof is administered at a dose of about 1750 mg.

[0245] In any one of A1-A12, ie, A20, the antibody or antigen-binding fragment thereof is administered at a dose of about 1800 mg.

[0246] In any one of A1-A12, ie, A21, the antibody or antigen-binding fragment thereof is administered at a dose of about 2000 mg.

[0247] In any one of A1-A12, ie, A22, the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg.

[0248] In any one of A1-A12, ie, A23, the antibody or antigen-binding fragment thereof is administered at a dose of about 2500 mg.

[0249] In any one of A1 to A23, ie, A24, the antibody or antigen-binding fragment thereof is administered approximately once every two weeks.

[0250] In any one of A1 to A23, ie, A25, the antibody or antigen-binding fragment thereof is administered approximately once a month.

[0251] In any one of A1 to A25, ie, A26, the administration consists of administering one or more induction doses of the antibody or antigen-binding fragment thereof, and no loading dose is administered.

[0252] In any one of A1 to A25, ie, A27, the administering comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering one or more induction doses of the antibody or antigen-binding fragment thereof.

[0253] In one embodiment of A27, ie, A28, the loading dose comprises about 1500 mg, about 1750 mg, about 2000 mg, about 2250 mg, or about 2500 mg of the antibody or antigen-binding fragment thereof.

[0254] In one embodiment of A28, ie, A29, the loading dose comprises about 2250 mg of the antibody or antigen-binding fragment thereof.

[0255] In any one of A26-A29, ie, A30, the one or more induction doses comprise about 450 mg of antibody or antigen-binding fragment thereof.

[0256] In any one of A26 to A29, ie, A31, the one or more induction doses comprise about 900 mg of antibody or antigen-binding fragment thereof.

[0257] In any one of A26 to A29, ie, A32, the one or more induction doses comprise about 1800 mg of antibody or antigen-binding fragment thereof.

[0258] In one embodiment of any one of A26 to A32, ie, A33, about 6 induction doses are administered.

[0259] In any one embodiment of A1-A33, ie, A34, the administration is carried out over a period of about 16 weeks.

[0260] In any one of A1-A25, i.e., A35, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every two weeks.

[0261] In any one of embodiments A1-A34, i.e., A35, the administering further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every two weeks.

[0262] In one embodiment of A35 or A36, ie, A37, the one or more maintenance doses comprise about 300 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0263] In one embodiment of A37, ie, A38, the one or more maintenance doses comprise about 300 mg of the antibody or antigen-binding fragment thereof.

[0264] In one embodiment of A37, ie, A39, the one or more maintenance doses comprise about 900 mg of the antibody or antigen-binding fragment thereof.

[0265] In one embodiment of any one of A35-A39, ie, A40, about 12 maintenance doses are administered.

[0266] In any one of embodiments A1-A12, i.e., A41, the administering comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0267] In any one of A1-A12, i.e., A42, the administering comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0268] In any one of A1-A12, i.e., A43, the administering comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 1800 mg, and (iii) one or more maintenance doses of about 300 mg of the antibody or antigen-binding fragment thereof.

[0269] In any one of A1-A12, i.e., A44, the administering comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0270] In any one of embodiments A1-A12, i.e., A45, the administering comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0271] In any one of embodiments A1-A12, i.e., A46, the administering comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 1800 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof.

[0272] In one embodiment of any one of A27 to A34 or A36 to A46, ie, A47, one or more induction doses are administered over a period of about 14 weeks.

[0273] In any one embodiment of A27-A47, ie, A48, the loading dose is administered about two weeks before the one or more induction doses are administered.

[0274] In any one embodiment of A35-A48, ie, A49, the administration of one or more maintenance doses occurs over a period of about 24 weeks.

[0275] In one embodiment of any one of A1 to A49, ie, A50, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL.

[0276] In any one embodiment of A1 to A50, ie, A51, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less.

[0277] In any one of A1 to A51, ie, A52, the antibody or antigen-binding fragment thereof is administered to the subject subcutaneously or intravenously.

[0278] In one embodiment of A52, ie, A53, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0279] In any one of A1 to A53, ie, A54, the antibody or antigen-binding fragment thereof is administered to the subject via a syringe.

[0280] In any one of A1-A54, ie, A55, the subject has moderate to severe ulcerative colitis.

[0281] In one embodiment of A55, ie, A56, the administration results in clinical remission.

[0282] In one embodiment of A56, ie, A57, clinical remission occurs within 14 weeks of initiation of administration.

[0283] In one embodiment of A56, ie, A58, clinical remission occurs within 38 weeks of initiation of administration.

[0284] In any one embodiment of A1-A54, ie, A59, the subject has moderate to severe Crohn's disease.

[0285] In one embodiment of A59, ie, A60, the administration results in an endoscopic response.

[0286] In one embodiment of A60, namely A61, the endoscopic response occurs within 14 weeks of initiating administration.

[0287] In one embodiment of A60, ie, A62, the endoscopic response occurs within 38 weeks of initiation of administration.

[0288] In one embodiment, namely A63, provided herein is a pharmaceutical formulation comprising: (a) 150 mg / mL of TNF-like ligand 1A (TNF-like ligand 1B); 1A:TL1A), an antibody or antigen-binding fragment thereof that specifically binds to TL1A, comprising: (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; (ii) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6; or (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and a light chain comprising the amino acid sequence of SEQ ID NO:10; (b) 10 mM histidine; (c) 100 mM arginine hydrochloride (Arg-HCl); (d) 5% (w / v) sucrose; and (e) 0.02% (w / v) polysorbate-80.

[0289] In one embodiment of A63, ie A64, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0290] In one embodiment of A63 or A64, ie, A65, the pharmaceutical formulation is lyophilized.

[0291] In one embodiment of A63 or A64, ie, A66, the pharmaceutical formulation is a liquid.

[0292] In any one of A63 to A66, ie, A67, the pharmaceutical composition has a pH of 6.0±0.5 after storage at room temperature for 24 hours, or at 2 to 8° C. for 24 hours, 72 hours, or 10 days.

[0293] In any one of A63 to A67, i.e., A68, the pharmaceutical composition has an osmolality of 200 mOsm / kg to 500 mOsm / kg after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0294] In any one embodiment of A63 to A68, ie, A69, the pharmaceutical composition has an antibody monomer content of at least 99% after storage at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0295] In any one embodiment of A63 to A69, ie, A70, the pharmaceutical composition shows no significant change in charge heterogeneity profile after storage at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0296] In any one embodiment of A63 to A70, i.e., A71, the pharmaceutical composition shows no significant change in purity even after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0297] In any one embodiment of A63 to A70, ie, A72, the pharmaceutical composition has a purity of at least 90% after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0298] In any one of A63 to A72, i.e., A73, the pharmaceutical composition shows no significant change in particle concentration even after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0299] In any one embodiment of A63 to A73, ie, A74, the pharmaceutical composition has no significant difference in visual appearance even after storage at 2 to 8°C for up to 36 months.

[0300] In any one of A63 to A74, i.e., A75, this pharmaceutical composition shows no significant difference in protein concentration, osmotic pressure, or viscosity after storage at 2 to 8°C, 25°C, or 40°C for up to 36 months.

[0301] In any one of A63 to A75, i.e., A76, the pharmaceutical composition has a monomer content of 95% or more, a dimer content of 5.0% or less, or no significant difference in low molecular weight species content after storage at 2 to 8°C for up to 36 months.

[0302] In any one embodiment of A63 to A76, ie, A77, the pharmaceutical composition has a purity of 90% or greater after storage at 2 to 8° C. for up to 36 months.

[0303] In any one of A63 to A77, i.e., A78, the pharmaceutical composition has a main species content of 50% to 90%, an acidic species content of 10% to 40%, and / or a basic species content of 0% to 20% after storage at 2 to 8°C for up to 36 months.

[0304] In any one embodiment of A63 to A78, ie, A79, the pharmaceutical composition has no significant difference in subvisible particle content after storage at 2 to 8°C, 25°C, or 40°C for up to 36 months.

[0305] In any one of A63 to A79, i.e., A80, the pharmaceutical composition has no significant difference in oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or deamidation of asparagine 317 of TEV-48574 after storage at 2 to 8°C, 25°C, or 40°C for up to 36 months.

[0306] In any one embodiment of A63 to A80, i.e., A81, the pharmaceutical composition has a relative potency of 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage at 2 to 8°C for up to 36 months.

[0307] In any one embodiment of A63 to A81, ie, A82, the pharmaceutical composition has no significant difference in thermal stability after storage at 2 to 8°C, 25°C, or 40°C for up to 6 months.

[0308] In any one embodiment of A63 to A82, ie, A83, the pharmaceutical composition has no significant difference in thermal stability after storage at 2 to 8°C for up to 36 months.

[0309] In any one embodiment of A63 to A83, i.e., A84, the pharmaceutical composition has no significant change in secondary and / or tertiary protein structure after storage at 2-8°C, 25°C, or 40°C for up to 3 months.

[0310] In any one embodiment of A63 to A84, ie, A85, the pharmaceutical composition has no significant change in secondary protein structure even after storage at 2 to 8° C. for up to 36 months.

[0311] In one embodiment of any one of A63 to A85, i.e., A86, the pharmaceutical composition has no significant difference in polysorbate-80 concentration after storage at 2 to 8° C. for up to 24 months. In one embodiment, i.e., A87, there is provided a container comprising the pharmaceutical formulation of any one of A63 to A86.

[0312] In one embodiment of A87, ie, A88, the container is a glass vial.

[0313] In one embodiment of A88, ie A89, the container is a glass vial of 3 mL capacity.

[0314] In any one embodiment of A1 to A62, ie, A90, the antibody or antigen-binding fragment thereof is present in a pharmaceutical formulation of any one of A63 to A86 or in a container of any one of A87 to A89.

[0315] In one aspect, namely A91, provided herein is a composition for use according to the method of any one of A1-A62 or A90.

[0316] In one embodiment of the method of any one of A1 to A62 or A90, the pharmaceutical formulation of any one of A63 to A86, or the container of any one of A87 to A89, i.e., A92, the antibody or antigen-binding fragment thereof was produced in Chinese hamster ovary cells.

[0317] In one aspect, namely B1, provided herein is a method of treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); wherein the antibody or antigen-binding fragment comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0318] In one embodiment of B1, i.e., B2, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA).

[0319] In one embodiment of B2, namely B3, the subject has had an inadequate response, failed to respond to, or was intolerant to one or more medications.

[0320] In one embodiment of B2 or B3, namely B4, the subject has had an inadequate response to, failed to respond to, or been intolerant to no more than two biologic agents.

[0321] In one aspect, namely, B5, provided herein is a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators; and (b) determining whether the subject has previously responded inadequately, failed to respond to, or intolerant to at least one agent in part (a), including TNF-like ligand 1A (TNF-like ligand 1B). 1A:TL1A), or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0322] In one embodiment of B5, ie, B6, the ulcerative colitis is moderate to severe ulcerative colitis, and / or wherein the Crohn's disease is moderate to severe Crohn's disease.

[0323] In one aspect, i.e., B7, provided herein is a method of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease; and (b) if the subject has moderate to severe ulcerative colitis or moderate to severe Crohn's disease, administering to the subject a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0324] In one embodiment of B7, i.e., B8, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA).

[0325] In one embodiment of B8, ie, B9, the subject has had an inadequate response, failed to respond to, or was intolerant to one or more medications.

[0326] In one embodiment of B8 or B9, ie, B10, the subject has had an inadequate response to, failed to respond to, or been intolerant to no more than two biologic agents.

[0327] In any one embodiment of B1 to B10, ie, B11, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0328] In any one embodiment of B1 to B10, ie, B12, the antibody or antigen-binding fragment comprises an IgG1 constant region.

[0329] In any one of embodiments B1 to B12, ie, B13, the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0330] In any one embodiment of B1-B13, i.e., B14, the subject is concomitantly treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

[0331] In any one embodiment of B1 to B14, ie, B15, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

[0332] In any one of embodiments B1 to B14, ie, B16, the antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg.

[0333] In any one embodiment of B1-B14, ie, B17, the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg.

[0334] In any one embodiment of B1-B14, ie, B18, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg.

[0335] In any one embodiment of B1 to B14, ie, B19, the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg.

[0336] In any one embodiment of B1 to B14, ie, B20, the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg.

[0337] In one embodiment of any one of B1 to B14, ie, B21, the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg.

[0338] In any one of embodiments B1 to B20, ie, B22, the antibody or antigen-binding fragment thereof is administered approximately once every two weeks.

[0339] In any one embodiment of B1 to B20, ie, B23, the antibody or antigen-binding fragment thereof is administered about once a month.

[0340] In any one embodiment of B1 to B23, ie, B24, the administration consists of administering one or more induction doses of the antibody or antigen-binding fragment thereof, and no loading dose.

[0341] In any one embodiment of B1 to B23, ie, B25, the administering comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering one or more induction doses of the antibody or antigen-binding fragment thereof.

[0342] In one embodiment of B25, ie, B26, the loading dose comprises about 2250 mg of the antibody or antigen-binding fragment thereof.

[0343] In any one of embodiments B24 to B26, ie, B27, the one or more induction doses comprise about 450 mg of the antibody or antigen-binding fragment thereof.

[0344] In any one embodiment of B24 to B26, ie, B28, the one or more induction doses comprise about 900 mg of antibody or antigen-binding fragment thereof.

[0345] In one embodiment of any one of B24-B28, ie, B29, about 6 induction doses are administered.

[0346] In one embodiment of any one of B1 to B29, ie, B30, administration occurs over a period of about 16 weeks.

[0347] In any one of embodiments B1-B23, i.e., B31, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every two weeks.

[0348] In any one embodiment of B1-B30, i.e., B32, the administering further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every two weeks.

[0349] In any one of embodiments B1-B23, i.e., B33, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, where no loading dose and / or induction dose is administered, and optionally, the maintenance doses are administered about every four weeks.

[0350] In any one of embodiments B1-B23, i.e., B34, the administering further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every four weeks.

[0351] In any one embodiment of B30 to B34, ie, B35, the one or more maintenance doses comprise about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0352] In one embodiment of B35, ie, B36, the one or more maintenance doses comprise about 450 mg of the antibody or antigen-binding fragment thereof.

[0353] In one embodiment of B35, ie, B37, the one or more maintenance doses comprise about 900 mg of the antibody or antigen-binding fragment thereof.

[0354] In any one embodiment of B30-B37, ie, B38, about 10 maintenance doses are administered.

[0355] In one embodiment of any of B1-B14, i.e., B39, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction dose is administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0356] In one embodiment of any of B1-B14, i.e., B40, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction dose is administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0357] In one embodiment of any one of B1-B14, i.e., B41, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction dose is administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0358] In one embodiment of any one of B1-B14, i.e., B42, the administration comprises administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the induction dose is administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0359] In any one embodiment of B39 to B42, ie, B43, about 6 induction doses and / or about 10 maintenance doses are administered.

[0360] In any one embodiment of B1-B14, i.e., B44, the administration comprises administering (i) a loading dose of about 2250 mg, and (ii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every four weeks.

[0361] In any one of embodiments B1-B14, i.e., B45, the administering comprises administering (i) a loading dose of about 2250 mg, and (ii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every four weeks.

[0362] In any one embodiment of B44-B45, ie, B46, at least 10 maintenance doses are administered.

[0363] In one embodiment of any one of B24-B46, ie, B47, one or more induction doses are administered over a period of about 14 weeks.

[0364] In any one embodiment of B25-B47, ie, B48, the loading dose is administered about two weeks before the one or more induction doses are administered.

[0365] In any one embodiment of B31-B48, ie, B49, the administration of the one or more maintenance doses occurs over a period of about 24 weeks.

[0366] In one embodiment of any one of B31 to B48, ie, B50, the administration of the one or more maintenance doses occurs over a period of about 40 weeks.

[0367] In one embodiment of any one of B1 to B50, ie, B51, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL.

[0368] In one embodiment of any one of B1 to B50, ie, B52, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 200 mg / mL.

[0369] In any one embodiment of B1 to B52, ie, B53, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less.

[0370] In any one of embodiments B1 to B53, ie, B54, the antibody or antigen-binding fragment thereof is administered to the subject subcutaneously or intravenously.

[0371] In one embodiment of B54, ie, B55, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0372] In any one of embodiments B1 to B55, ie, B56, the antibody or antigen-binding fragment thereof is administered to the subject via a syringe.

[0373] In an embodiment of B56, ie, B57, the syringe is a pre-filled syringe.

[0374] In any one of embodiments B1 to B57, ie, B58, the subject has moderate to severe ulcerative colitis.

[0375] In one embodiment of B58, ie, B59, the administration results in clinical remission.

[0376] In one embodiment of B59, ie, B60, clinical remission occurs within 14 weeks of initiation of treatment.

[0377] In one embodiment of B59, namely B61, clinical remission occurs within 38 weeks of initiation of treatment.

[0378] In any one embodiment of B1-B57, ie, B62, the subject has moderate to severe Crohn's disease.

[0379] In one embodiment of B62, ie, B63, the administration results in an endoscopic response.

[0380] In one embodiment of B63, namely B64, the endoscopic response occurs within 14 weeks of initiating administration.

[0381] In one embodiment of B64, namely B65, the endoscopic response occurs within 38 weeks of initiating treatment.

[0382] In one embodiment, namely B66, the antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A) is for use in the preparation of a medicament of any one of B1 to B65.

[0383] In one embodiment, namely B67, the antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A) is for use in any one of B1 to B65.

[0384] Provided herein in one aspect, namely B68, is a pharmaceutical formulation comprising: (a) about 100 mg / mL to about 250 mg / mL of TNF-like ligand 1A (TNF-like ligand 1B); (b) an antibody or antigen-binding fragment thereof that specifically binds to the target polypeptide (SEQ ID NO: 1A:TL1A), the antibody or antigen-binding fragment thereof comprising a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6; (b) about 5 mM to about 15 mM histidine; (c) about 50 mM to about 150 mM arginine hydrochloride (Arg-HCl); (d) about 2.5% (w / v) to about 7.5% (w / v) sucrose; and (e) about 0.01% (w / v) to about 0.03% (w / v) polysorbate-80.

[0385] In one embodiment of B68, ie, B69, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0386] In any one embodiment of B68 to B69, ie, B70, the antibody or antigen-binding fragment comprises an IgG1 constant region.

[0387] In any one embodiment of B68 to B70, ie, B71, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0388] In any one embodiment of B68 to B71, ie, B72, the pharmaceutical formulation contains about 100 mg / mL of the antibody or antigen-binding fragment thereof.

[0389] In any one embodiment of B68 to B71, ie, B73, the pharmaceutical formulation contains about 150 mg / mL of the antibody or antigen-binding fragment thereof.

[0390] In any one embodiment of B68 to B71, ie, B74, the pharmaceutical formulation contains about 200 mg / mL of the antibody or antigen-binding fragment thereof.

[0391] In any one embodiment of B68 to B71, ie, B75, the pharmaceutical formulation contains about 225 mg / mL of the antibody or antigen-binding fragment thereof.

[0392] In any one embodiment of B68 to B71, ie, B76, the pharmaceutical formulation contains about 250 mg / mL of the antibody or antigen-binding fragment thereof.

[0393] In any one embodiment of B68 to B76, ie, B77, the pharmaceutical preparation comprises about 5 mM histidine.

[0394] In any one embodiment of B68 to B76, ie, B78, the pharmaceutical preparation comprises about 10 mM histidine.

[0395] In any one embodiment of B68 to B76, ie, B79, the pharmaceutical preparation comprises about 15 mM histidine.

[0396] In any one embodiment of B68 to B79, ie, B80, the pharmaceutical formulation comprises about 50 mM arginine hydrochloride (Arg-HCl).

[0397] In any one embodiment of B68-B79, ie, B81, the pharmaceutical formulation comprises about 100 mM arginine hydrochloride (Arg-HCl).

[0398] In any one embodiment of B68-B79, ie, B82, the pharmaceutical formulation comprises about 150 mM arginine hydrochloride (Arg-HCl).

[0399] In any one embodiment of B68 to B82, ie, B83, the pharmaceutical formulation comprises about 2.5% (w / v) sucrose.

[0400] In any one embodiment of B68-B82, ie, B84, the pharmaceutical formulation comprises about 5% (w / v) sucrose.

[0401] In any one embodiment of B68-B82, ie, B85, the pharmaceutical formulation comprises about 7.5% (w / v) sucrose.

[0402] In any one embodiment of B68 to B85, ie, B86, the pharmaceutical formulation comprises about 0.01% (w / v) polysorbate-80.

[0403] In any one embodiment of B68 to B85, ie, B87, the pharmaceutical formulation comprises about 0.02% (w / v) polysorbate-80.

[0404] In any one embodiment of B68 to B85, ie, B88, the pharmaceutical formulation comprises about 0.03% (w / v) polysorbate-80.

[0405] In any one embodiment of B68 to B71, i.e., B89, the pharmaceutical formulation comprises about 250 mg / mL of an antibody or antigen-binding fragment thereof, about 10 mM histidine, about 100 mM arginine hydrochloride (Arg-HCl), about 5% (w / v) sucrose, and about 0.02% (w / v) polysorbate-80.

[0406] In any one of B68 to B71, i.e., B90, the pharmaceutical formulation comprises about 200 mg / mL of an antibody or antigen-binding fragment thereof, about 10 mM histidine, about 100 mM arginine hydrochloride (Arg-HCl), about 5% (w / v) sucrose, and about 0.02% (w / v) polysorbate-80.

[0407] In any one of B68 to B71, i.e., B91, the pharmaceutical formulation comprises about 150 mg / mL of an antibody or antigen-binding fragment thereof, about 10 mM histidine, about 100 mM arginine hydrochloride (Arg-HCl), about 5% (w / v) sucrose, and about 0.02% (w / v) polysorbate-80.

[0408] In any one of embodiments B68 to B91, ie, B92, the pharmaceutical formulation is lyophilized.

[0409] In any one of B68 to B91, ie, B93, the pharmaceutical formulation is a liquid.

[0410] In any one embodiment of B68 to B93, ie, B94, the pharmaceutical composition has a pH of 6.0±0.5 after storage at room temperature for 24 hours, or at 2 to 8° C. for 24 hours, 72 hours, or 10 days.

[0411] In any one of B68 to B94, i.e., B95, the pharmaceutical composition has an osmolality of 200 mOsm / kg to 500 mOsm / kg after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0412] In any one of B68 to B95, ie, B96, the pharmaceutical composition has an antibody monomer content of at least 99% after storage at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0413] In any one embodiment of B68 to B96, ie, B97, the pharmaceutical composition shows no significant change in charge heterogeneity profile after storage at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0414] In any one of B68 to B97, i.e., B98, the pharmaceutical composition has no significant change in purity even after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0415] In any one embodiment of B68 to B98, ie, B99, the pharmaceutical composition has a purity of at least 90% after storage at room temperature for 24 hours, or at 2-8°C for 24 hours, 72 hours, or 10 days.

[0416] In any one of B68 to B99, i.e., B100, the pharmaceutical composition has no significant change in particle concentration even after storage at room temperature for 24 hours, or at 2 to 8°C for 24 hours, 72 hours, or 10 days.

[0417] In any one embodiment of B68 to B100, ie, B101, the pharmaceutical composition has no significant difference in visual appearance even after storage at 2 to 8°C for up to 36 months.

[0418] In any one of B68 to B101, ie, B102, the pharmaceutical composition has no significant difference in protein concentration, osmotic pressure, or viscosity after storage at 2 to 8°C, 25°C, or 40°C for up to 36 months.

[0419] In any one of B68 to B102, i.e., B103, the pharmaceutical composition has a monomer content of 95% or more, a dimer content of 5.0% or less, or no significant difference in low molecular weight species content, after storage at 2-8°C for up to 36 months.

[0420] In any one embodiment of B68 to B103, ie, B104, the pharmaceutical composition has a purity of 90% or greater after storage at 2-8° C. for up to 36 months.

[0421] In any one of embodiments B68 to B104, i.e., B105, the pharmaceutical composition has a main species content of 50% to 90%, an acidic species content of 10% to 40%, and / or a basic species content of 0% to 20% after storage at 2 to 8°C for up to 36 months.

[0422] In any one embodiment of B68 to B105, ie, B106, the pharmaceutical composition has no significant difference in subvisible particle content after storage at 2-8°C, 25°C, or 40°C for up to 36 months.

[0423] In any one of embodiments B68 to B106, i.e., B107, the pharmaceutical composition has no significant difference in oxidation of methionine 81 and / or methionine 254 of TEV-48574, and / or deamidation of asparagine 317 of TEV-48574 after storage at 2-8°C, 25°C, or 40°C for up to 36 months.

[0424] In any one of B68 to B107, i.e., B108, the pharmaceutical composition has a relative potency of 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage at 2 to 8°C for up to 36 months.

[0425] In any one embodiment of B68 to B108, ie, B109, the pharmaceutical composition has no significant difference in thermal stability after storage at 2-8°C, 25°C, or 40°C for up to 6 months.

[0426] In any one embodiment of B68 to B109, ie, B110, the pharmaceutical composition has no significant difference in thermal stability after storage at 2-8° C. for up to 36 months.

[0427] In any one embodiment of B68 to B110, i.e., B111, the pharmaceutical composition has no significant change in secondary and / or tertiary protein structure after storage at 2-8°C, 25°C, or 40°C for up to 3 months.

[0428] In any one embodiment of B68 to B111, ie, B112, the pharmaceutical composition has no significant change in secondary protein structure after storage at 2-8° C. for up to 36 months.

[0429] In any one embodiment of B68 to B112, ie, B113, the pharmaceutical composition has no significant difference in polysorbate-80 concentration even after storage at 2 to 8° C. for up to 24 months.

[0430] In one embodiment of any one of B68 to B113, ie, B114, the antibody or antigen-binding fragment thereof was produced in Chinese hamster ovary cells.

[0431] In one embodiment, namely B115, there is provided a container comprising the pharmaceutical formulation of any one of B68-B114.

[0432] In one embodiment of B115, ie, B116, the container is a glass vial.

[0433] In one embodiment of B116, ie, B117, the container is a glass vial having a capacity of 3 mL.

[0434] In one embodiment of B115, ie, B118, the container is a syringe, and optionally, the syringe is a pre-filled syringe.

[0435] In one aspect, namely B119, provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation of any one of B68 to B114 or a container of any one of B115 to B118, optionally wherein the disease is a gastrointestinal disease.

[0436] In one embodiment of B119, ie, B120, the gastrointestinal disease is Crohn's disease or ulcerative colitis.

[0437] In one embodiment of B119 or B120, namely B121, the pharmaceutical formulation is administered intravenously.

[0438] In one embodiment of B119 or B120, ie, B122, the pharmaceutical formulation is administered subcutaneously.

[0439] In any one embodiment of B68-B114, ie, B123, the formulation is for use according to any one of the methods of B1-B65 or B115-B122.

[0440] The following examples are offered by way of illustration and not by way of limitation. [Example]

[0441] Example 1: Clinical Evaluation of TEV-48574 in Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn's Disease TEV-48574 will be evaluated in a Phase 2b, randomized, double-blind, dose-ranging study to examine the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD). This study will include adult patients (18 to 75 years of age, regardless of sex) with moderate to severe active UC or CD who have had an inadequate response, loss of response, or intolerance to at least one of the following medications, but no more than two biologic agents: corticosteroids, immunosuppressants, tumor necrosis factor-alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, or 5-aminosalicylic acid (5-ASA).

[0442] This study will evaluate the efficacy and dose-responsiveness of TEV-48574 administered subcutaneously (sc) every two weeks (Q2W) at three different dose regimens in adult patients with inflammatory bowel disease (IBD) (moderate to severe UC or CD) as assessed by induction of clinical remission (UC) and endoscopic response (CD) at 14 weeks.

[0443] The study will use a single loading dose of 2250 mg, part of an induction dosing regimen, chosen to rapidly achieve steady-state concentrations and address the significant overproduction of TL1A in the colon within the first few weeks of induction.

[0444] The dosing regimen was designed to rapidly achieve steady-state concentrations. TEV-48574 exhibited linear PK across the 200-2300 mg dose range, with an elimination half-life of 7-9 days. A 2300 mg loading dose followed by 1600 mg achieved steady-state concentrations after 2 weeks, with no observed accumulation. A population PK approach and model were used to simulate the loading and induction doses and predict resulting exposures. The three induction dose intensities in this study were selected based on a combination of safety, preclinical evidence, pharmacokinetics, immunogenicity, and clinical considerations.

[0445] Target population and eligibility criteria Approximately 570 patients will be screened, and randomization of approximately 280 will be achieved (approximately 140 UC patients and 140 CD patients).

[0446] Eligible patients must meet all of the following criteria: a. Adults of either sex (without gender restrictions) between the ages of 18 and 75 at the time of informed consent. b. More than 3 months have passed since the diagnosis of UC or CD. c.UC patients only: Patients with moderate to severe active UC, defined as a three-component modified Mayo score of 5-9, and an endoscopic subscore of 2 or more (based on central reading) d. CD patients only: Patients with moderate to severe active CD as determined by a CDAI score of 220 to 450. e. CD patients only: SES CD score ≥ 6 (≥ 4 for isolated ileal disease). f. For UC patients only: Active disease outside the rectum (active disease >15 cm on screening endoscopy [sigmoidoscopy]). g. Patients must have had an inadequate response, lost response, or intolerance to at least one of the following medications: corticosteroids, immunosuppressants, and / or TNF-α antagonist therapy, anti-integrin agents, anti-IL-12 / 23 agents, JAK inhibitors, and / or S1P receptor modulators, and no more than two biologic agents. h. If the patient is taking the following medications: oral 5-ASA or sulfasalazine at a stable dose for at least 4 weeks prior to endoscopy; oral corticosteroids at a stable dose for at least 2 weeks prior to endoscopy; 6-MP, AZA, or methotrexate at a stable dose for 4 weeks prior to endoscopy, the patient must have been taking a stable dose for the specified period as follows:

[0447] Patients who meet all inclusion criteria will be randomized to receive TEV-48574 (single loading dose / six induction doses): 2250 / 1800 mg, 2250 / 900 mg, 2250 / 450 mg, or placebo at the same dose as TEV-48574 in a 1:1:1:1 ratio, stratified by diagnosis (UC or CD) and prior treatment history, failure of biologics and small molecule therapies (including JAK inhibitors and S1P receptor modulators for UC), or biologic and small molecule treatment naive.

[0448] Drug dosage, administration method, and administration rate TEV-48574 for subcutaneous injection will be provided as a solution at a concentration of 150 mg / mL. Placebo will be provided as a solution in the same formulation as TEV-48574, but without the active protein. Specific details regarding the TEV-48574 and placebo products are provided in Table 1.

[0449] [Table 2]

[0450] Patients will receive the following regimen administered SC using a commercially available syringe-based SC infusion system: TEV-48574 2250mg (single loading dose) / 1800mg (six induction doses) TEV-48574 2250mg (single loading dose) / 900mg (six induction doses) TEV-48574 2250mg (single loading dose) / 450mg (six induction doses) TEV-48574 vs. matching placebo

[0451] Patients will receive a loading dose on the day of randomization, followed by corresponding maintenance doses every 2 weeks thereafter, for a total of seven doses (one loading dose and six induction doses) administered by subcutaneous (sc) injection.

[0452] The long-term efficacy and safety of TEV-48574 will be demonstrated in patients with moderately to severely active UC or CD at study entry who demonstrate clinical response and / or clinical remission (based on a complete Mayo score for UC subjects and CDAI for CD subjects) to initial treatment with TEV-48574. These patients will receive either 300 mg Q2W or 900 mg Q2W during the treatment period.

[0453] The commercially available syringe injection system used for administration allows for up to a 60 mL syringe of SC medication using an SC safety needle set. This system controls the rate of drug penetration into the tissue surrounding the SC injection site and the duration of the injection. The syringe injection system is a mechanical or electromechanical syringe pump that injects the medication by pushing the syringe plunger at a constant rate during the injection.

[0454] General design The study consisted of a screening period of up to 6 weeks (42 days), a treatment period of 14 weeks, and a follow-up period of 4 weeks. A schematic diagram of the study is shown in Figure 1.

[0455] Screening: Patients will be screened within 6 weeks (42 days) prior to randomization to ensure they meet all study inclusion criteria. Endoscopy will be performed within approximately 10 calendar days (Day 1) of randomization to allow for central endoscopy scoring once key eligibility criteria are met.

[0456] Randomization: Patients who meet the eligibility criteria at the end of the screening period will be randomly assigned in a 1:1:1:1 ratio (stratified by diagnosis [UC or CD] and prior exposure, failure of biologics and small molecule drugs [including JAK inhibitors and S1P receptor modulators for UC], or biologic and small molecule treatment naive) to one of four treatment arms during the double-blind treatment period (Table 2).

[0457] All treatments will be administered as a single SC intravenous infusion Q2W in a double-blind manner.

[0458] [Table 3]

[0459] During the 14-week treatment period, patients will visit the clinic for TEV-48574 / placebo administration (7 visits) Q2W on Days 1, 15, 29, 43, 57, 71, and 85 (±3 days), with an additional end-of-treatment visit scheduled for Day 99 (±3 days; Week 14). End-of-study will be defined as the last visit of the last patient. The study duration will be approximately 24 months.

[0460] The following efficacy assessments will be performed: Endoscopy and histology will be scored centrally.

[0461] Modified Mayo score (ulcerative colitis) The modified Mayo score assesses the stage of UC based on three parameters: Bowel frequency ·Rectal bleeding Endoscopic evaluation

[0462] Each parameter in the score ranges from 0 (normal or inactive disease) to 3 (severe disease activity), and the total score ranges from 0 to 9 (Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry 2016, Naegeli et al., 2018).

[0463] Endoscopy Endoscopy will be performed at screening and at the 14-week or early termination visit. Assessments and procedures performed during endoscopy, including biopsy collection, SES-CD, and modified multiplier (MM) SES-CD, are described below.

[0464] Biopsy collection Patients with CD undergo ileoscopy and colonoscopy at screening and week 14. At each endoscopy, a total of 16–18 mucosal biopsies are taken and handled as follows: Mucosal biopsies are taken from the most inflamed area of each segment. If ulcers are present, biopsies are taken from the edge of the largest ulcer. If no ulcers are present, biopsies are taken from the most affected area. If the mucosa appears normal (e.g., at follow-up), biopsies are taken randomly.

[0465] For patients with UC, flexible sigmoidoscopy is performed at screening and at week 14 (if no endoscopy has been performed in the past 12 months, colonoscopy can be performed instead of baseline endoscopy). At each endoscopy, a total of 8 to 12 biopsies are taken from the most affected area 15 to 25 cm from the anal verge. If an ulcer is present, biopsies are taken from the edge of the largest ulcer. If no ulcer is present, biopsies are taken from the most affected area. If the mucosa appears normal (e.g., at follow-up), random biopsies are taken from an area 15 to 25 cm from the anal verge.

[0466] Biopsies are used to evaluate histologic disease.

[0467] Simple endoscopic score for Crohn's disease SES-CD requires scoring in five intestinal segments (rectum, sigmoid colon and left colon, transverse colon, right colon, and ileum) taking into account four parameters: presence or absence of ulcers, percentage of ulcerated surface, affected surface, and presence or absence of stricture (Daperno et al., Gastrointest Endosc;60(4):505-12(2004)).

[0468] Modified multiplier plain endoscopic score for Crohn's disease The MM-SES-CD is an endoscopic scoring tool that considers the prognostic value of individual parameters for achieving endoscopic remission during active treatment (Narula et al., Gut;0:1-10(2021)).

[0469] Robarts histopathology index (ulcerative colitis) The final score of the Roberts Histopathology Index (RHI) is obtained by combining subscores of the following four major items: Chronic inflammatory infiltration level (level 4) Layer-specific neutrophils (4 levels) Intraepithelial neutrophils (level 4) Erosion or ulceration (level 4)

[0470] The four components are graded from 0 to 3, resulting in a final score between 0 and 33 (Mosli et al.,Gut;66(1):50-58(2017)).

[0471] Geboes score (ulcerative colitis) The Geboes score is a scoring system for microscopic disease activity that incorporates numerous histological features classified into five grades (Mosli et al., Inflamm Bowel Dis;20(3):564-75(2014)).

[0472] Comprehensive Histological Activity Score (Crohn's Disease) The Global Histological Activity Score consists of eight items that assess acute and chronic inflammatory changes, epithelial damage, and the extent of inflammation (i.e., the percentage of the biopsy specimen affected). Each item is scored and then summed (D'Haens et al., Gastroenterology; 114(2):262-7(1998)).

[0473] Crohn's Disease Activity Index The CDAI (Yoshida EM. Can J Gastroenterol; 13(1):65-73(1999)) consists of the sum of the following eight factors adjusted by weighting factors: 7 days, number of liquid or loose stools per day x 2 Daily abdominal pain for 7 days (severity rating 0-3) x 5 Seven-day, daily general well-being assessment, subjectively rated from 0 (good) to 4 (bad) Presence or absence of complications x 20 30 doses of Lomotil, Imodium, or opiates for diarrhea Presence or absence of abdominal mass (0 is absent, 2 is suspicious, 5 is certain) x 10 Hematocrit less than 0.47 for men and less than 0.42 for women x 6 Deviation rate from standard weight x 1

[0474] Two patient-reported outcomes (ulcerative colitis and Crohn's disease) UC: The two-item patient-reported outcome (PRO2) includes daily assessment of two components of the Mayo score: bowel frequency and rectal bleeding. Each parameter ranges from 0 (normal or inactive) to 3 (severely active), and the total score ranges from 0 to 6 (Dragasevic et al., Gastroenterol Res Pract;2020:2065383 (2020); Jairath et al., Aliment Pharmacol Ther;42(10):1200-10 (2015)).

[0475] CD:PRO2 is the sum of daily bowel frequency (0-3) and abdominal pain (0-3) according to the CDAI (Khanna et al., Aliment Pharmacol Ther;41(1):77-86(2015)).

[0476] Acceptable inflammatory bowel disease medications and rescue medications Concomitant UC and CD therapy must be maintained at a stable dose (except for reductions due to adverse events) during the study treatment period, and patients must be withdrawn from the study if the dose is increased. Doses of background UC and CD medications must not be changed during the screening and double-blind treatment periods.

[0477] Patients are permitted to use the medications detailed below: In combination with oral 5-ASA or sulfasalazine. The dose must be stable for at least 4 weeks prior to endoscopy and through week 14. If oral 5-ASA treatment has recently been discontinued, it must be discontinued for at least 2 weeks prior to endoscopy. A stable dose of oral corticosteroids (maximum 20 mg / day prednisone equivalent; maximum 9 mg / day budesonide equivalent) for at least 2 weeks prior to endoscopy and through week 14. If oral corticosteroids have recently been discontinued, they must be discontinued at least 2 weeks prior to endoscopy. Reductions in steroid use due to adverse events are permitted. - Stable dose of immunosuppressant (methotrexate 25 mg or less (intramuscular or subcutaneous administration once weekly) or 15 mg or less (oral administration once weekly); 6-MP 1.5 mg / kg / day or less; or AZA 2.5 mg / kg / day or less) from 4 weeks prior to endoscopy through 14 weeks. Reduction due to adverse events is permitted.

[0478] Safety and tolerability evaluation Safety will be assessed throughout the study by evaluating reported adverse events, clinical laboratory values, vital sign measurements, electrocardiogram (ECG) findings, physical examination findings, and concomitant medication use. Local tolerability assessments will be performed after each TEV-48574 / placebo dose and will include administration site findings (e.g., erythema, erythema, induration, tenderness, warmth, swelling, etc.) and pain. Blood samples for anti-drug antibody (ADA) testing will be collected throughout the study to demonstrate the lack of immunogenicity of TEV-48574. Adverse events, administration site findings, and treatment-emergent ADA responses will be recorded throughout the study to demonstrate the safety and tolerability of TEV-48574.

[0479] Efficacy and safety analysis The study will evaluate the efficacy and dose-responsiveness of TEV-48574 administered subcutaneously (sc) every two weeks (Q2W) at three different dose regimens in adult IBD patients (moderate to severe UC or CD) as assessed by induction of clinical remission (UC) and endoscopic response (CD) at Week 14. Efficacy will be demonstrated based on response (positive or negative) at Week 14, with response in UC patients defined as clinical remission and response in CD patients defined as endoscopic response.

[0480] As used herein, the term "clinical remission" of ulcerative colitis refers to clinical remission determined as follows: Clinical remission is defined as a modified Mayo score (9-point scale for rectal bleeding, bowel frequency, and endoscopy) of 2 or less, and this score is A bowel frequency subscore of 0 or 1, Rectal bleeding subscore of 0, and Endoscopic subscores are defined as 0 or 1, where a score of 1 does not include "easy bleeding."

[0481] As used herein, the term "endoscopic response" in reference to Crohn's disease refers to an endoscopic response determined as follows: Endoscopic response, defined as a reduction of at least 50% from baseline in the Simple Endoscopic Score for Crohn's Disease (SES-CD).

[0482] The following endpoints will also be measured to demonstrate efficacy in patients with moderate to severe UC: Clinical response at week 14, defined as a reduction in the rectal bleeding subscore of at least 1 or an absolute reduction from baseline of at least 30% in the rectal bleeding subscore of 1 or less, and a reduction from baseline of at least 2 points in the modified Mayo score (9-point scale for rectal bleeding, stool frequency, and endoscopy). Endoscopic improvement defined as a Mayo endoscopic subscore of 0 or 1 at week 14. Endoscopic remission defined as a Mayo endoscopic subscore of 0 at week 14. Clinical response, defined as at least a 50% reduction from baseline in two patient-reported outcomes (PRO2; rectal bleeding and stool frequency) at weeks 2, 4, 6, 8, 10, 12, and 14. Clinical remission defined as rectal bleeding = 0 and stool frequency = 0 on the PRO2 scale at weeks 2, 4, 6, 8, 10, 12, and 14. Histologic response defined as a Roberts histopathology index of 5 or less at week 14. Histologic remission defined as a Geboes index score ≤ (3.1) at 14 weeks.

[0483] The following endpoints will also be measured to demonstrate efficacy in patients with moderate to severe CD: Clinical response, defined as a reduction of ≥100 points from baseline in the Crohn's Disease Activity Index (CDAI) score at weeks 2, 4, 6, 8, 10, 12, and 14. Clinical remission, defined as a CDAI score of <150 at weeks 2, 4, 6, 8, 10, 12, and 14. Endoscopic remission defined as an SES CD score of 0-2 or an SES CD score of 0-4 with no individual subscore >1 at week 14. Clinical response, defined as a reduction of at least 50% from baseline in PRO2 (PRO2 consists of two items: abdominal pain and bowel frequency) at weeks 2, 4, 6, 8, 10, 12, and 14. Clinical remission, defined as abdominal pain ≤1 and bowel frequency ≤3 on the PRO2 scale at weeks 2, 4, 6, 8, 10, 12, and 14. Endoscopic response defined as a >50% reduction in modified multiplier (MM)-SES-CD from baseline at week 14. Histologic response, defined as a 50% or greater reduction from baseline in the Global Histologic Activity Score at week 14.

[0484] To demonstrate safety and tolerability, the following indicators / parameters will be analyzed: Adverse events Changes from baseline in clinical laboratory values (serum chemistry, hematology, urinalysis) Changes from baseline in vital sign measurements (blood pressure, pulse, temperature, respiratory rate) Changes from baseline in 12-lead electrocardiogram (ECG) findings Use of concomitant medications Patients who discontinued TEV-48574 / placebo due to adverse events Local tolerance at the injection site Device-related adverse events and malfunctions (for commercially available SC infusion systems)

[0485] To demonstrate lack of immunogenicity, the following endpoints are analyzed: Changes from baseline in treatment-induced anti-drug antibodies (ADA) at weeks 2, 4, 8, 14, and follow-up visits Presence or absence of neutralizing ADA in ADA-positive patients at weeks 2, 4, 8, 14 and follow-up visits.

[0486] Efficacy and safety outcomes will be analyzed to demonstrate the efficacy and safety of the TEV-48574 dosing regimen.

[0487] Example 2: Stability of Reconstituted TEV-48574 Drug Product Solution The in-use stability of the TEV-48574 reconstituted drug product was evaluated.

[0488] In this study, TEV-48574 was lyophilized to a protein concentration of 150 mg / mL in 10 mM histidine, 5% (w / v) sucrose, 100 mM arginine hydrochloride (Arg-HCl), 0.02% (w / v) polysorbate-80 (PS-80), pH 6.0. The lyophilized formulation was packaged in 5 cc vials with a 20 mm neck. The vials were stored at 2-8 °C and allowed to warm to room temperature before reconstitution. Approximately seven vials were reconstituted using 2.0 mL of sterile water for injection (WFI) per vial to form a stock solution. This stock solution was then diluted in different Falcon tubes to concentrations of 50, 20, and 5 mg / mL with the formulation buffer: 10 mM histidine, 5% (w / v) sucrose, 100 mM Arg-HCl, 0.02% (w / v) PS-80, pH 6.0. After dilution, 4 mL samples were incubated at 2–8°C under light protection for 24 h, 72 h, 10 days, and under normal light conditions at room temperature for 24 h. Table 3 shows the specific time points and conditions tested.

[0489] [Table 4]

[0490] At each time point and completion of each condition, samples were analyzed for visual appearance, pH, osmolality, protein concentration, and subvisible particles using size exclusion chromatography (SEC), capillary sodium dodecyl sulfate gel electrophoresis (cSDS), capillary isoelectric focusing (cIEF), and microflow imaging (MFI).

[0491] As shown in Table 4, no significant differences were observed in visual appearance, pH, osmolality, or protein concentration of the reconstituted samples after dilution. The pH and osmolality of the samples were 6.0 ± 0.5 pH, respectively, within the range of 200–500 mOsm / kg.

[0492] [Table 5]

[0493] SEC analysis showed that the antibody monomer concentration in the samples did not change significantly over the stability period (see Table 5). These results indicate that storage of the diluted reconstituted drug product at 2-8°C for up to 10 days does not affect the monomer concentration upon incubation.

[0494] [Table 6]

[0495] cIEF analysis showed that dilution of the reconstituted drug product and incubation at 2–8°C for up to 10 days did not significantly affect the charge heterogeneity profile of TEV-48574. See Table 6.

[0496] [Table 7]

[0497] As shown in Table 7, cSDS analysis revealed that the purity of the reconstituted drug product was greater than 90%, and dilution of the reconstituted drug product or incubation under various conditions did not significantly affect the purity.

[0498] [Table 8]

[0499] The 50 mg / mL sample contained slightly more subvisible particles according to the MFI analysis (see Table 8). However, no significant increase in particle concentration overall was observed in the different concentration samples when comparing the first time point sample with the later time point samples.

[0500] [Table 9]

[0501] Taken together, these results indicate that the reconstituted TEV-48574 drug product is stable for 10 days after dilution when stored protected from light at 2-8°C and under normal light conditions at room temperature for 24 hours.

[0502] Example 3: Stability of TEV-48574 Liquid Formulations at 100 mg / ml and 150 mg / ml The objective of this study was to evaluate the long-term stability of liquid and lyophilized TEV-48574 formulations. Three formulations were tested: a lyophilized drug product containing 100 mg / mL of drug product in 10 mM histidine, 5% (w / v) sucrose, 100 mM Arg-HCl, 0.02% (w / v) PS-80, pH 6.0 (Formulation 1), and two liquid formulations containing either 100 mg / mL or 150 mg / mL of drug product in 10 mM histidine, 5% (w / v) sucrose, 100 mM Arg-HCl, 0.02% (w / v) PS-80, pH 6.0 (Formulations 2 and 3, respectively). The stability of these formulations was evaluated in 5 cc vials (Type I glass) under the following conditions: "standard" conditions (2-8°C), "accelerated" conditions (25 ± 2°C / 60 ± 5% relative humidity (RH)), and "stress" conditions (40 ± 2°C / 75 ± 5% RH). Additionally, the stability of Formulation 3 was evaluated under the same conditions, except the formulation was filled into 2.25 mL Nipro prefilled syringes (Nipro PFS) fitted with waist plunger stoppers. The effect of these conditions on several product quality attributes was tested for each formulation.

[0503] Visual appearance, protein concentration, osmolality and viscosity The results of the visual appearance, protein concentration, and osmolality analyses of Formulations 1–3 are shown in Tables 9–12. No significant differences were observed between formulations at standard storage conditions of 2–8°C. Few visible particles were observed at intermittent time points. However, this may be related to the developmental testing in which the drug product was manually filled into vials. Furthermore, these particles did not increase over time and were not consistently detected in all samples at different time points, so they are not considered product-related. Regarding visual appearance under stress conditions at 40°C, the solution appeared slightly yellow at later time points. No significant differences were observed in visual appearance, protein concentration, osmolality, or viscosity of Formulation 3 filled in Nipro PFS compared with Formulation 3 stored in glass vials for up to 24 months (data not shown), indicating that these attributes of the formulations are not affected by contact with Nipro PFS.

[0504] Protein concentrations measured under standard (2-8°C), accelerated (25°C), and stressed (40°C) conditions were close to the expected nominal concentrations for all three formulations and did not change over time. Osmolality and viscosity measured under standard storage conditions at time zero (T0), 24 months (24M), and 36 months (36M) showed similar trends and no significant differences over time.

[0505] [Table 10]

[0506] [Table 11]

[0507] [Table 12]

[0508] [Table 13]

[0509] Size Exclusion Chromatography (SEC) Tables 13-15 and Figures 2A-2C, 3A-3C, and 4A-4C show the percentages (%) of monomer, dimer, and low molecular weight species measured by SEC for formulations 1, 2, and 3. All three formulations stored at standard storage conditions of 2-8°C met the acceptance criteria for monomer and dimer content up to 24 and 36 months. Compared to formulation 1, formulations 2 and 3 exhibited an increase in the percentage of low molecular weight species, while the percentage of monomer decreased slightly. However, this is an expected observation given that lyophilized formulations are typically more stable than liquid formulations. Under accelerated and stress conditions, protein fragmentation was more pronounced, indicating that the primary degradation pathway for liquid formulations is the formation of low molecular weight species. The protein degradation rates for formulations 2 and 3 were similar, indicating that protein concentration does not significantly affect degradation. No significant differences were observed in the proportions of monomers, dimers, and low molecular weight species up to 24 months for Formulation 3 filled in Nipro PFS compared with Formulation 3 stored in glass vials (data not shown), indicating that the stability profile of the formulation was not affected by contact with Nipro PFS.

[0510] [Table 14]

[0511] [Table 15]

[0512] [Table 16]

[0513] Capillary gel electrophoresis (reducing and non-reducing) For formulations 1-3, the percentage (%) of immunoglobulin G (IgG) + 125 kDa peak was measured using non-reducing capillary gel electrophoresis (CGE). Additionally, for formulations 1-3, the heavy chain + light chain ratio was measured using reducing CGE. These results are shown in Tables 16-17, Figures 5A-5C, and Figures 6A-6C, respectively. For all three formulations stored at standard storage conditions of 2-8°C, the purity percentage met the acceptance criteria up to 24 and 36 months. Under accelerated and stressed conditions, protein fragmentation was observed in formulations 2 and 3 compared to formulation 1. However, this is an expected observation given that lyophilized formulations are typically more stable than liquid formulations. Furthermore, the proteolytic degradation trends of formulations 2 and 3 were similar, indicating no significant effect of protein concentration. No significant difference was observed in the percentage of the IgG+125 kDa peak up to 24 months for Formulation 3 filled in Nipro PFS compared with Formulation 3 stored in glass vials (data not shown), indicating that the stability profile of the formulation was not affected by contact with Nipro PFS.

[0514] [Table 17]

[0515] [Table 18]

[0516] Capillary isoelectric focusing (icIEF) The percentages of main species, acidic species, and basic species for formulations 1–3 (F1–F3) were measured using capillary isoelectric focusing (icIEF). The results are shown in Tables 18–20. Figures 7A–7C, 8A–8C, and 9A–9C show the stability trends of charge heterogeneity overlaid. Under standard storage conditions at 2–8°C (Figures 7A, 8A, and 9A), all three formulations (F1–F3) met the acceptance criteria for up to 24 and 36 months. Under accelerated storage conditions (25°C; Figures 7B, 8B, and 9B) and stressed storage conditions (40°C; Figures 7C, 8C, and 9C), the percentage of the main peak decreased, while the percentage of acidic species increased, for formulations 2 and 3. No significant changes were observed for formulation 1. However, this is an expected observation, given that lyophilized formulations are typically more stable than liquid formulations. No significant differences were observed in the proportions of the main peak, acidic species, and basic species up to 24 months for Formulation 3 filled in Nipro PFS compared with Formulation 3 stored in glass vials (data not shown), indicating that the stability profile of the formulation was not affected by contact with Nipro PFS.

[0517] [Table 19]

[0518] [Table 20]

[0519] [Table 21]

[0520] Subvisible particles using Micro-flow Imaging (MFI) Subvisible particles in Formulations 1-3 were measured at different time points under standard conditions at 2-8°C, accelerated conditions at 25°C, and stress conditions at 40°C. The results are shown in Tables 21-23, respectively. No significant changes in subvisible particles were observed. More subvisible particles were observed at intermittent time points than at other time points. This may be related to the method, where greater variability and sensitivity was observed for subvisible particles measured using MFI. Overall, subvisible particles ≥10 μm (and above) were found to be less than 6,000 particles / mL. In the ≥25 μm particle size range, subvisible particles were found to be less than 600 particles / mL, which is below the USP 1000 standard, even considering the increased sensitivity of using MFI to detect subvisible particles. <788> The stability of Formulation 3 filled in Nipro PFS was within the acceptable range. No significant difference was observed in the proportion of subvisible particles up to 24 months compared with Formulation 3 stored in glass vials (data not shown), indicating that the stability profile of the formulation was not affected by contact with Nipro PFS.

[0521] [Table 22]

[0522] [Table 23]

[0523] [Table 24]

[0524] Chemical modification of primary structure by peptide mapping Formulations 1–3 were monitored for amino acids that may undergo chemical modifications over time and affect protein structure. Specifically, the amino acid residues methionine 81 and methionine 254 of TEV-48574 were monitored because they may undergo oxidation, potentially affecting the primary structure. Similarly, asparagine 317 of TEV-48574 was monitored because it may undergo deamidation to form succinimide. However, as shown in Tables 24–26, no significant changes in these modifications were observed over time. Results showed that Formulation 3 filled in Nipro PFS was comparable to Formulation 3 filled in glass vials in terms of the oxidation rate of Met81, the deamidation rate of Asn317, and the oxidation rate of Met254 under long-term storage conditions (2–8°C) for up to 24 months (data not shown), indicating that the stability profile of the formulations was not affected by contact with Nipro PFS.

[0525] [Table 25]

[0526] [Table 26]

[0527] [Table 27]

[0528] Titer evaluation by ELISA The percent potency (%) of Formulations 1-3 was measured by enzyme-linked immunosorbent assay (ELISA). The results are shown in Table 27. No significant changes were observed between the formulations under standard storage conditions (2-8°C), and the acceptance criteria of 70%-135% potency were met up to 24 and 36 months. No significant differences were observed in percent potency up to 24 months for Formulation 3 filled in Nipro PFS compared to Formulation 3 stored in glass vials (data not shown), indicating that the stability profile of the formulations is not affected by contact with Nipro PFS.

[0529] [Table 28]

[0530] Differential Scanning Calorimetry (DSC) Analysis for Thermal Stability DSC was used to evaluate the thermal stability of Formulations 1-3. DSC analysis was performed on time zero (T0) samples and 3-, 6-, and 36-month samples of Formulations 1-3 at 2-8°C, 25°C, and 40°C. Figure 10A shows the thermal stability of Formulations 1-3 at time zero (T0) and 3 months at 2-8°C, 25°C, and 40°C. Figure 10B shows the thermal stability of Formulations 1-3 at time zero (T0) and 6 months at 2-8°C, 25°C, and 40°C. Figure 10C shows the thermal stability of Formulations 1-3 at time zero (T0) and 36 months at 2-8°C. The transition temperatures (Tm) of all formulations overlapped for thermal stability at T0, 3 months, 6 months, and 36 months, and no significant differences were observed among the three formulations. A slight decrease in enthalpy was observed for formulations stored under accelerated and stressed conditions. This may be due to the enthalpy drop caused by protein fragmentation observed in the samples under these conditions.No significant differences were observed in thermal stability of Formulation 3 filled in Nipro PFS compared to Formulation 3 stored in glass vials for up to 6 months, indicating that the stability profile of the formulation is not affected by contact with Nipro PFS.

[0531] Secondary and tertiary structure analysis of proteins using circular dichroism (CD) spectroscopy The secondary protein structure of Formulations 1-3 was analyzed using far-UV circular dichroism (CD), and the tertiary protein structure of Formulations 1-3 was analyzed using near-UV CD. Secondary and tertiary structure analyses were performed on time zero (T0) samples of Formulations 1, 2, and 3, 3-month samples at 2-8°C, 25°C, and 40°C, 24-month samples at 2-8°C, and 36-month samples at 2-8°C. The results are shown in Figures 11A-11F. Specifically, Figure 11A shows the secondary structure of Formulations 1-3 at T0 and after 3 months at 2-8°C, 25°C, and 40°C using far-UV CD. Figure 11B shows the secondary structure of Formulations 1-3 at T0 and after 24 months at 2-8°C using far-UV CD. Figure 11C shows the secondary structures of Formulations 1-3 at T0 and after 36 months at 2-8°C using far-UV CD. Figure 11D shows the tertiary structures of Formulations 1-3 at T0 and after 3 months at 2-8°C, 25°C, and 40°C using near-UV CD. Figure 11E shows the tertiary structures of Formulations 1-3 at T0 and after 24 months at 2-8°C using near-UV CD. Figure 11F shows the tertiary structures of Formulations 1-3 at T0 and after 36 months at 2-8°C using near-UV CD.

[0532] The far-UV CD spectra showed a negative maximum near 217 nm, and the TO sample of all three formulations exhibited a beta-sheet structure, as expected for a monoclonal antibody. The near-UV CD spectra showed a positive maximum near 292 nm, indicating absorption due to tryptophan residues, and a negative maximum near 276 nm, indicating absorption due to tyrosine residues. No significant changes in the secondary or tertiary structure of the three formulations were observed up to 3 months. At 24 and 36 months, small changes in the CD spectra were observed near 200 nm. This is likely due to protein fragmentation, as absorption in this region is primarily due to peptide bonds. However, no significant changes in the protein's secondary structure (absorption at 217 nm) were observed.

[0533] Figure 13A shows the secondary structure of Formulation 3 stored in Nipro prefilled syringes (PFS) at time zero (T0) and after 3 months (3M), 6 months (6M), and 24 months (24M) of storage at 2-8°C, and after 3 months (3M) and 6 months (6M) of storage at 25°C and 40°C, using far-UV CD. Figure 13B shows the tertiary structure of Formulation 3 stored in Nipro prefilled syringes (PFS) at time zero (T0) and after 3 months (3M), 6 months (6M), and 24 months (24M) of storage at 2-8°C, and after 3 months (3M) and 6 months (6M) of storage at 25°C and 40°C, using near-UV CD. The spectra obtained for the Nipro PFS samples were comparable to those obtained for Formulation 3 stored in glass vials (Figures 11A-11B and 11D-11E).

[0534] Polysorbate 80 Analysis Polysorbate 80 (PS80), a surfactant / excipient contained in Formulations 1-3, can undergo degradation, resulting in reactive peroxides that may affect protein stability during product shelf life. Formulations 1-3 were analyzed for PS80 levels after 24 and 36 months of storage at 2-8°C. As shown in Table 28, the measured PS80 concentration was 0.02% (w / v) for the 24-month samples of all formulations, which correlated with the expected PS80 concentration. After 36 months, the liquid formulations, Formulations 2 and 3, showed a decrease in PS80 values. Formulation 3 filled in Nipro PFS showed no significant difference in PS80 levels after 24 months compared to Formulation 3 stored in glass vials, indicating that the stability profile of the formulations is not affected by contact with Nipro PFS.

[0535] [Table 29]

[0536] conclusion The stability of TEV-48574 in the lyophilized drug product (Formulation 1, 100 mg / mL) was comparable to that of the 100 mg / mL (Formulation 2) and 150 mg / mL (Formulation 3) liquid drug products stored at 2–8°C, the standard storage conditions for drug products. Under accelerated (25°C) and stressed (40°C) conditions, both liquid formulations exhibited protein fragmentation as the primary degradation pathway, but this was not observed in lyophilized Formulation 1. However, this is an expected observation given the greater stability of the lyophilized formulation compared to the liquid formulation.

[0537] In liquid formulations, the formation of acidic species was observed compared to lyophilized formulations, as measured by icIEF, concomitant with the protein fragmentation observed using SEC and CGE. This indicates that specific amino acid residues are deamidated, potentially leading to fragmentation. See Wang, W. et al., J. Pharm. Sci., 96:1-26 (2007).

[0538] Based on these data, lyophilized Formulation 1 can be converted to 100 mg / mL and 150 mg / mL liquid formulations with comparable stability profiles, meeting acceptance criteria of up to 24 months and up to 36 months under storage conditions at 2-8°C.

[0539] Furthermore, the stability of 150 mg / mL TEV-48574 (Formulation 3) stored in Nipro PFS was found to be comparable to that of Formulation 3 samples stored in glass vials. This data indicates that Nipro PFS is compatible with 24 months of storage at 2-8°C, the standard storage conditions for drug products.

[0540] Example 4: Further clinical evaluation of TEV-48574 in moderate to severe ulcerative colitis or moderate to severe Crohn's disease TEV-48574 will be evaluated in a 24-week Phase 2b, randomized, double-blind, long-term extension (LTE) study to evaluate the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) who have completed the treatment phase of the 14-week study described above in Example 1. A schematic diagram of the study is shown in Figure 12.

[0541] Eligible patients must meet all of the following criteria: Adults (male and female) who have achieved clinical response and / or clinical remission at the time of informed consent in the 14-week study of Example 1 (no gender restrictions). At week 14 in the Example 1 study in patients with moderate to severe UC, clinical response was assessed as a ≥2-point reduction from baseline in the modified Mayo score (9-point scale for rectal bleeding, stool frequency, and endoscopy) by at least 30%, and a ≥1-point reduction in the rectal bleeding subscore or an absolute subscore of 0 or 1. Clinical remission at week 14 of the study in patients with moderate to severe UC. Clinical remission is defined as a modified Mayo score (9-point scale for rectal bleeding, bowel frequency, and endoscopy) of 2 or less. A bowel frequency subscore of 0 or 1, Rectal bleeding subscore is 0, and Endoscopic subscore of 0 or 1, where a score of 1 is defined as not including "easy bleeding." Clinical response as assessed by a reduction of 100 points or more in the Crohn's Disease Activity Index (CDAI) score from baseline to week 14 in patients with moderate to severe CD in the study of Example 1. Clinical remission, defined as a CDAI score of less than 150 at week 14 of the study in Example 1, in patients with moderate to severe CD.

[0542] Patients who met all inclusion criteria were randomized to receive TEV-48574 (12 maintenance doses): 900 mg or 300 mg in a 1:1 ratio, stratified by diagnosis (UC or CD).

[0543] General design The study included a 24-week treatment period and a 2-week follow-up period.

[0544] Randomization: In the 14-week study described in Example 1 above, patients who meet the eligibility criteria at the end of treatment visit (EOT) will be randomly assigned 1:1 (stratified by diagnosis [UC or CD]) to one of two treatment groups for the double-blind treatment period (see Table 29 below).

[0545] All study treatments will be administered as a single SC intravenous infusion Q2W in a double-blind manner.

[0546] [Table 30]

[0547] During the 24-week treatment period, patients will visit Q2W (12 visits) on Days 1, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, and 155 (± 3 days) for TEV-48574 administration and on Day 169 (± 3 days) for endpoint assessment. After the 24-week treatment period, patients will return for follow-up (Day 183 [± 14 days]). Patients who complete the follow-up visit will be considered to have completed the study.

[0548] Patients are permitted to use the medications detailed below: In combination with oral 5-ASA or sulfasalazine. The dose must be stable throughout the transition and study period (week 24). - Stable administration of oral corticosteroids (maximum 20 mg / day prednisone equivalent, maximum 9 mg / day budesonide equivalent) throughout the transition period and the treatment period (week 24). Stable administration of immunosuppressants (methotrexate ≤25 mg intramuscularly or SC once weekly or ≤15 mg orally once weekly; 6-MP ≤1.5 mg / kg / day; or AZA ≤2.5 mg / kg / day).

[0549] To demonstrate lack of immunogenicity, the following endpoints are analyzed: Treatment-emergent anti-drug antibody (ADA) outcomes and response: change from baseline (Example 1 study) and change over the course of the study Neutralize ADA in ADA-positive patients throughout the study period. The effect of the presence of ADAs on pharmacokinetics and clinical safety will be evaluated as necessary.

[0550] To demonstrate safety and tolerability, the following indicators / parameters will be analyzed: Frequency of adverse events Changes from baseline (LTE baseline) in laboratory values (serum chemistry, hematology, urinalysis) Changes in vital sign measurements (blood pressure, pulse, temperature, respiratory rate) from baseline (LTE baseline) Changes from baseline (LTE baseline) in 12-lead electrocardiogram (ECG) findings Use of concomitant medications Number of patients who discontinued TEV-48574 due to adverse events (%) Local tolerance at the injection site · Device-related adverse events and failures (for commercially available SC infusion systems).

[0551] To demonstrate the efficacy of TEV-48574, the following efficacy endpoints will be analyzed: In patients with UC, clinical remission based on a modified Mayo score (9-point scale for rectal bleeding, stool frequency, and endoscopy) of 2 points or less, defined by a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, where a score of 1 does not include "easy bleeding" at 24 weeks. Endoscopic response, defined as at least a 50% reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 24 in patients with CD.

[0552] The following efficacy endpoints will also be analyzed to demonstrate the efficacy of TEV-48574: In patients with UC, a clinical response of at least 2 points based on the modified Mayo score (9-point scale for rectal bleeding, stool frequency, and endoscopy) and a reduction in the rectal bleeding subscore of at least 1 at week 24, or an absolute rectal bleeding subscore of 1 or less, and a reduction of at least 30% from baseline in the Example 1 study. Endoscopic improvement from baseline in Example 1 study based on Mayo endoscopic subscore of 0 or 1 at week 24 in patients with UC Endoscopic remission based on Mayo endoscopic subscore 0 at 24 weeks in patients with UC Clinical response in patients with UC, defined as a reduction of at least 50% from baseline in two patient-reported outcomes (PRO2; rectal bleeding and stool frequency) at weeks 0, 4, 8, 10, 12, 16, 20, and 24 in patients with UC. Clinical remission based on PRO2 (rectal bleeding = 0, stool frequency = 0) at weeks 0, 4, 8, 10, 12, 16, 20, and 24 in patients with UC. Histological remission based on the Roberts Histopathology Index (RHI ≤ 5) at 24 weeks in patients with UC Histological remission in UC patients based on a Geboes index score of ≤3.1 Clinical response based on the Crohn's Disease Activity Index (CDAI): A reduction of 100 points or more in the CDAI score from baseline to week 24 in patients with CD at weeks 0, 4, 8, 10, 12, 16, 20, and 24 in Example 1 study Clinical remission in patients with CD based on a CDAI score <150 at weeks 0, 4, 8, 10, 12, 16, 20, and 24. Endoscopic remission based on SES-CD: SES-CD score of 0-2 or SES-CD score of 0-4 with no subscore >1 at week 24 in patients with CD. Clinical response in CD patients, defined as a reduction in PRO2 of at least 50% from baseline in Study Example 1 at weeks 0, 4, 8, 10, 12, 16, 20, and 24. Clinical remission based on PRO2 (abdominal pain ≤1, bowel frequency ≤3) at weeks 0, 4, 8, 10, 12, 16, 20, and 24 in CD patients. In patients with CD, endoscopic response defined as a >50% reduction in modified multiplier (MM)-SES-CD from baseline at week 24 of the Example 1 study. Histologic response (≥50% reduction) in the Global Histologic Activity Score from baseline to week 24 in patients with CD in the Example 1 study.

[0553] Example 5: Stability of TEV-48574 Liquid Formulation at 200 mg / ml The objective of this study was to evaluate the long-term stability of a high-concentration liquid TEV-48574 formulation compared with a lyophilized drug product. Two formulations were tested: a lyophilized drug product (Formulation 4 or F4) containing 100 mg / mL of drug product in 10 mM histidine, 5% (w / v) sucrose, 100 mM Arg-HCl, 0.02% (w / v) PS-80, pH 6.0, and a liquid drug product (Formulation 5 or F5) containing 200 mg / mL of drug product in 10 mM histidine, 5% (w / v) sucrose, 100 mM Arg-HCl, 0.02% (w / v) PS-80, pH 6.0. The stability of these formulations was evaluated under long-term storage conditions at 2-8°C in 5 cc vials with 20 mm stoppers. The effect of these conditions on several quality attributes of the formulations was examined.

[0554] Visual appearance, protein concentration, osmolality and viscosity The results of the visual appearance, protein concentration, and osmolality analysis of Formulations 4 and 5 are shown in Tables 30-31. No significant differences were observed between the formulations under long-term storage conditions of 2-8°C.

[0555] The protein concentrations of both formulations measured under long-term storage conditions at 2-8°C were close to the expected nominal concentrations and did not vary over time. The osmolality and viscosity of the drug products were evaluated at time zero (T0). The osmolality and viscosity of the 200 mg / mL liquid formulation (F5) were observed to be higher than those observed for the 100 mg / mL lyophilized formulation (F4).

[0556] [Table 31]

[0557] [Table 32]

[0558] Size Exclusion Chromatography (SEC) Table 32 and Figures 14A-14C show the percent (%) of monomer, dimer, and low molecular weight species measured by SEC for Formulations 4 and 5. Both formulations stored under long-term storage conditions at 2-8°C met the acceptance criteria for monomer and dimer content for up to 24 months. Formulation 5 showed a slight decrease in the percentage of monomer and a concomitant increase in the percentage of low molecular weight species compared to Formulation 4.

[0559] [Table 33]

[0560] Capillary gel electrophoresis (reducing and non-reducing) For formulations 4 and 5, the percent (%) of immunoglobulin G (IgG) + 125 kDa peak was measured using non-reducing capillary gel electrophoresis (CGE). Additionally, for formulations 4 and 5, the heavy chain + light chain ratio was measured using reducing CGE. These results are shown in Tables 33-34 and Figures 15A-15B, respectively. For both formulations stored under long-term storage conditions at 2-8°C, the % purity met acceptance criteria for up to 24 months.

[0561] [Table 34]

[0562] [Table 35]

[0563] Capillary isoelectric focusing (icIEF) The percentages of main species, acidic species, and basic species for formulations 4 and 5 (F4 and F5) were measured using capillary isoelectric focusing (icIEF). The results are shown in Table 35. An overlay of the stability trends in charge heterogeneity is shown in Figures 16A-16C. Under long-term storage conditions of 2-8°C (Figures 16A, 16B, and 16C), both formulations (F4 and F5) met the acceptance criteria for 24 months.

[0564] [Table 36]

[0565] Subvisible particles using Micro-flow Imaging (MFI) Subvisible particles in Formulations 4 and 5 were measured at different time points under long-term storage conditions at 2-8°C. The results are shown in Table 36. No significant changes in subvisible particles were observed. Overall, subvisible particles ≥10 μm (or larger) were less than 6,000 particles / mL. In the ≥25 μm particle size range, subvisible particles were less than 600 particles / mL, exceeding the USP 10 ... <788> The data showed that the 200 mg / mL formulation (F5) did not significantly affect the number of subvisible particles under long-term storage conditions.

[0566] [Table 37]

[0567] Chemical modification of primary structure by peptide mapping Formulations 4 and 5 were monitored for amino acids that may undergo chemical modification over time and affect protein structure. Specifically, amino acid residues methionine 81 and methionine 254 of TEV-48574 were monitored because they may undergo oxidation, potentially affecting the primary structure. Similarly, asparagine 317 of TEV-48574 was monitored because it may undergo deamidation to succinimide. As shown in Table 37, no significant changes in the oxidation rates of Met81 and Met254 were observed over time under long-term storage conditions of 2-8°C for 24 months. At 24 months, the liquid drug product (F5) showed a higher level of Asn317 deamidation compared to the lyophilized drug product (F4). This difference in the extent of Asn deamidation is likely a result of the lower stability of the liquid drug product compared to the lyophilized drug product and is not due to the higher nominal protein concentration of F5.

[0568] [Table 38]

[0569] Titer evaluation by ELISA The percent potency (%) of formulations 4 and 5 was measured by enzyme-linked immunosorbent assay (ELISA). The results are shown in Table 38. No significant changes were observed between the formulations under long-term storage conditions (2-8°C), and the acceptance criteria of 70%-135% potency were met for 24 months.

[0570] [Table 39]

[0571] Secondary and tertiary structure analysis of proteins using circular dichroism (CD) spectroscopy The secondary protein structure of Formulations 4 and 5 was analyzed using far-UV circular dichroism (CD), and the tertiary protein structure of Formulations 4 and 5 was analyzed using near-UV CD. Secondary structure analysis was performed on the time zero (T0) sample and 3-, 6-, and 12-month samples of Formulation 4 at 25°C, and on the T0 sample and 3- and 12-month samples of Formulation 5 at 25°C. Tertiary structure analysis was performed on the time zero (T0) sample and 3- and 12-month samples of Formulation 4 at 25°C; and on the T0 sample and 3-, 6-, and 12-month samples of Formulation 5 at 25°C. The results are shown in Figures 17A-17B. Specifically, Figure 17A shows the secondary structure of Formulation 4 (F4) at time zero (T0) and after 3 months (3M), 6 months (6M), and 12 months (12M) of storage at 25° C., and the secondary structure of Formulation 5 (F5) at time T0 and after 3M and 12M storage at 25° C., using far-UV CD. Figure 17B shows the tertiary structures of F4 after 3M and 12M storage at T0 and 25° C., and F5 after 3M, 6M, and 12M storage at T0 and 25° C., using near-UV CD. No significant changes in secondary or tertiary structure were observed in either the lyophilized formulation (F4) or the concentrated liquid formulation (F5).

[0572] conclusion The stability of the lyophilized formulation (Formulation 4, 100 mg / mL) of TEV-48574 was comparable to that of the liquid formulation (Formulation 5, 200 mg / mL). Drug product stability data for both formulations were comparable under long-term storage conditions at 2-8°C.

[0573] At 24M, the liquid drug product showed a higher level of Asn317 deamidation compared to the lyophilized drug product. This difference in the extent of Asn deamidation is likely a result of the lower stability of the liquid drug product compared to the lyophilized drug product and is not due to the higher nominal protein concentration of F2. A slight decrease in the proportion of monomer, along with an increase in the proportion of low molecular weight species, was also observed in F5 compared to F4. However, lyophilized formulations are typically more stable than liquid formulations.

[0574] These data confirm that the 200 mg / mL high-concentration liquid drug product is stable at 2–8°C without significant impact on the critical quality attributes of TEV-48574.

[0575] Example 6: Evaluation of Arginine Hydrochloride as an Excipient in TEV-48574 Liquid Formulations The objective of this study was to evaluate the effectiveness of arginine hydrochloride (Arg-HCl) as an excipient and its effect on the stability of the TEV-48574 drug product. Four liquid formulations were tested. Two formulations were prepared in 10 mM histidine, 5% (w / v) sucrose, 100 mM Arg-HCl, 0.02% (w / v) PS-80, pH 6.0, with either 150 mg / mL (Formulation 1A) or 100 mg / mL (Formulation 2A) of drug product. Two formulations were prepared in 10 mM histidine, 5% (w / v) sucrose, 0.02% (w / v) PS-80, pH 6.0, with additional formulations of 150 mg / mL (Formulation 1B) and 100 mg / mL (Formulation 2B) of drug product. The stability of these formulations was evaluated under stressful storage conditions at 40°C. The effect of these conditions on product quality attributes was evaluated.

[0576] Visual appearance, protein concentration, osmolality and viscosity The results of the visual appearance, protein concentration, and osmolality analyses of Formulations 1A-2A and 1B-2B are shown in Tables 39-41. At 40°C storage conditions, a slight yellow color in the visual appearance of Formulations 1A and 1B was observed, which may be related to the deterioration of these formulations over time at elevated temperatures. Measured protein concentrations of the four formulations at 40°C were close to the expected nominal concentrations and did not change over time. Osmolality and viscosity of the drug products were evaluated and no significant differences were observed over time.

[0577] [Table 40]

[0578] [Table 41]

[0579] [Table 42]

[0580] The osmolality of Formulations 1A and 2A containing Arg-HCl was higher than that of Formulations 1B and 2B without Arg-HCl. The viscosity of Formulation 1B without Arg-HCl was observed to be higher than that of Formulation 1A with Arg-HCl at 150 mg / mL, as shown in Table 42 and Figure 18.

[0581] [Table 43]

[0582] Size Exclusion Chromatography (SEC) Tables 43-44 and Figures 19A-19C show the percent (%) of monomer, dimer, and fragment species measured by SEC for Formulations 1A-1B and 2A-2B after storage at 40°C for up to 8 weeks. No significant differences in monomer or fragment percentages were observed among the four formulations, as the reported values are within the variability of the assay. Formulations 1B and 2B without Arg-HCl showed an increased rate of dimer formation compared to Formulations 1A and 2A with Arg-HCl, indicating the stabilizing effect of Arg-HCl on the drug product.

[0583] [Table 44]

[0584] [Table 45]

[0585] Capillary gel electrophoresis (reducing and non-reducing) For Formulations 1A-1B and 2A-2B, the percent (%) of immunoglobulin G (IgG) + 125 kDa peak was measured using non-reducing capillary gel electrophoresis (CGE) under stress conditions at 40°C for up to 8 weeks. Additionally, for Formulations 1A-1B and 2A-2B, the heavy chain + light chain ratio was measured using reducing CGE under stress conditions at 40°C for up to 8 weeks. These results are shown in Tables 45-46 and Figures 20A-20B, respectively. Formulations 1B and 2B without Arg-HCl were observed to have increased rates of fragmentation compared to Formulations 1A and 2A with Arg-HCl, demonstrating the stabilizing effect of Arg-HCl on the fragmentation pattern of the drug product.

[0586] [Table 46]

[0587] [Table 47]

[0588] Capillary isoelectric focusing (icIEF) The percentages of main species (main peak), acidic species (acidic peak), and basic species (basic peak) for Formulations 1A-1B and 2A-2B were measured using capillary isoelectric focusing (icIEF) under stress conditions at 40°C for up to 8 weeks. The results are shown in Tables 47-48. An overlay of the stability trends in charge heterogeneity is shown in Figures 21A-21C. Slightly higher levels of acidic species were observed at the end of 8 weeks for Formulations 1B and 2B without Arg-HCl. This may be related to the higher fragmentation rates of these formulations compared to Formulations 1A and 2A, as reported in Table 46.

[0589] [Table 48]

[0590] [Table 49]

[0591] Chemical modification of primary structure by peptide mapping Formulations 1A-1B and 2A-2B were monitored for amino acids that may undergo chemical modification over time and affect protein structure under stress conditions at 40°C for up to 8 weeks. Specifically, the amino acid residues methionine 81 and methionine 254 of TEV-48574 were monitored because they may undergo oxidation, potentially affecting the primary structure. Similarly, asparagine 317 of TEV-48574 was monitored because it may undergo deamidation to succinimide. The oxidation rate of Met81, deamidation rate of Asn317, and oxidation rate of Met254 did not change significantly over time under storage conditions at 40°C for up to 8 weeks (data not shown), suggesting that the presence of Arg-HCl does not affect these attributes.

[0592] Titer evaluation by ELISA The percent potency of Formulations 1A-1B and 2A-2B was measured by enzyme-linked immunosorbent assay (ELISA) under stressed storage conditions at 40°C for up to 8 weeks. The results are shown in Table 49. The percent potency trends were similar across formulations, regardless of drug product concentration or Arg-HCl content.

[0593] [Table 50]

[0594] Dynamic Light Scattering (DLS) for particle size characterization DLS was employed to measure the polydispersity (%PD) and hydrodynamic radius of the potential drug product and nanoparticles contained in Formulations 1A-1B and 2A-2B. DLS analysis was performed on time zero (T0) samples of Formulations 1A-1B and 2A-2B. Table 50 shows the results of the DLS analysis. The apparent hydrodynamic radius of Formulations 1B and 2B (without Arg-HCl) was observed to be smaller compared to Formulations 1A and 2A (with Arg-HCl).

[0595] [Table 51]

[0596] Differential Scanning Calorimetry (DSC) Analysis for Thermal Stability DSC analysis was performed on time zero (T0) samples of Formulations 1A-1B and 2A-2B using DSC to assess the thermal stability of Formulations 1A-1B and 2A-2B. Figure 22 shows the thermal stability of Formulations 1A-1B and 2A-2B at time zero (T0), and Table 51 shows the DSC thermograms of all four formulations. onset The transition temperatures (Tm) were approximately 78°C for all formulations.

[0597] [Table 52]

[0598] The Tm1 of formulations 1A and 2A was slightly shifted to lower temperatures, indicating that Arg-HCl may affect the thermal stability of the molecule. This may be due to the enthalpy reduction caused by protein fragmentation observed in the samples under these conditions. However, this temperature is above the recommended storage range of 2-8°C for this drug product.

[0599] conclusion The effectiveness of arginine hydrochloride (Arg-HCl) as an excipient and its effect on the stability of TEV-48574 drug product was evaluated at two different drug product concentrations (100 mg / mL and 150 mg / mL). For all four formulations tested, the quality attributes of dimer percentage and purity, measured using reduced CGE, demonstrated a stabilizing effect of 100 mM Arg-HCl compared to formulations without Arg-HCl. The viscosity of the 150 mg / mL drug product with Arg-HCl was lower than that of the formulation without Arg-HCl. A small shift of approximately 3°C in Tm1, as analyzed by DSC, was observed for formulations containing Arg-HCl. However, because the recommended storage conditions for the drug product are 2-8°C, this Tm1 shift is not expected to significantly affect stability under typical storage and handling conditions. All other attributes showed no significant changes over 8 weeks at 40°C in any of the four formulations.

[0600] These data indicated that 100 mM Arg-HCl in the TEV-48574 formulation may stabilize the formulation and minimize viscosity even as the drug product concentration increases.

[0601] Example 7: Pharmacokinetic and Pharmacodynamic Analysis of TEV-48574 in Response to Non-Human Primates (NHPs) The purpose of this study was to evaluate the pharmacokinetic (PK) properties of TEV-48574 in cynomolgus monkeys after a single subcutaneous (sc) dose of 5 mg / kg. Pharmacodynamic (PD) analysis was also performed on free and total TL1A in serum samples. In this study, four cynomolgus monkeys received a single subcutaneous dose of TEV-48574 at 5 mg / kg. Blood samples were collected on days 0 (pre-dose) and 0.25, 1, 2, 3, 4, 5, 7, 9, 11, 14, 21, 28, and 35 for PK (TEV-48574) and PD (free and total TL1A).

[0602] For PK evaluation, serum samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) to measure TEV-48574 concentrations. PK parameters of TEV-48574 were estimated from individual serum concentration-time profiles by noncompartmental analysis (Gibaldi, M., & Perrier, D. (Eds.) (1982). Pharmacokinetics (2nd ed.) CRC Press). Serum concentrations below the limit of quantitation (i.e., <100 ng / mL) were designated "BLQ." For the purposes of calculating mean concentrations, all BLQ values were treated as zero.

[0603] Maximum serum concentration (C max ) is the maximum serum concentration observed. max is C max corresponds to the time at which the terminal rate constant of elimination from serum (λ z ) was determined by linear regression of the terminal portion of each semi-logarithmic serum concentration-time curve. The terminal phase was identified for each profile by visual inspection of the data, and each λ z A minimum of three non-BLQ concentrations were included in the determination. 1 / 2 ) is ln(2) as λ z In this case, the corrected r 2 is 0.8 or more, and λ z The time interval for which is estimated corresponds to λ z If it is approximately equal to or longer than λ zParameters related to the area under the serum concentration versus time curve (AUC) from time zero to the time of the last measurable concentration were considered reliable. 0-t The area under the serum concentration versus time curve from time zero to infinity (AUC 0-∞ ) is the AUC 0-t and the extrapolated area from the time of the last measurable serum concentration to infinity (C last / λ z ) and extrapolated AUC 0-∞ Percentage of [(AUC 0-∞ -AUC 0-t ) / (AUC 0-∞ ) × 100] was considered reliable if it was <20%. PK parameters were estimated using nominal sample collection times.

[0604] TEV-48574 concentrations were BLQ in all pre-dose samples and quantifiable in all animals at the first post-dose sampling point (i.e., 6 h). Intra-animal variability was generally small at early time points and increased from Day 11 onward. In all animals, serum concentrations remained fairly constant from Day 1 or 2 through Days 9, 11, and 21. The coefficients of variation (CV) for concentrations over these time frames were 6.1%, 8.7%, 6.4%, and 13.7% for animals SC1607075 (Days 2–11), SC1511041 (Days 1–9), SC1607037 (Days 1–9), and SC1506091 (Days 1–21), respectively, primarily reflecting absorption and distribution. Concentrations then rapidly declined and reached BLQ by Day 14 or 21, except for monkey SC1506091. Analysis of monkey anti-TEV-48574 antibodies by ELISA confirmed the presence of inducible ADA in serum samples from all animals on days 14, 21, and 35.

[0605] The serum TEV-48574 concentration-time profile of each animal was analyzed by noncompartmental analysis (NCA), and the PK parameters are shown in Table 52. Absorption after SC administration was consistent between animals. max is 3-5 days (median = 4 days), and C max The values were similar in the four monkeys (CV=18.4%). 1 / 2 The AUC and RR values varied. Target-mediated clearance of TEV-48574 was not evident in this study.

[0606] [Table 53]

[0607] NHP serum samples were tested for the presence of total TL1A (free and bound to TEV-48574) using a 96-well plate immunoassay with electrochemiluminescence (ECL) detection. Briefly, each 96-well small-spot streptavidin sector plate was blocked with diluent A (casein in phosphate-buffered saline (PBS)) (to reduce nonspecific binding). The plate was incubated for 60 minutes at 20-23°C with shaking at 500 rpm. After the blocking step, the wells were aspirated and coated with a 2 μg / mL stock of biotinylated rabbit anti-TL1A polyclonal antibody diluted in diluent A. The capture antibody coating was performed for 60 minutes at 20-23°C with shaking at 500 rpm. The wells of the 96-well plate were then washed with wash buffer (PBS containing 0.05% Tween-20). After washing, diluent A was added to each well. Assay standards were prepared using a 5000 pg / mL recombinant monkey TL1A protein stock and six subsequent 1:4 dilutions in Diluent A. Designated assay wells were loaded with either one of the recombinant monkey TL1A protein standards or a 1:4 dilution of NHP serum in Diluent A. The assay plate was then incubated for 1 hour at a temperature range of 20–23°C with shaking at 500 rpm.

[0608] After incubation with the standard and serum samples, the wells were washed with wash buffer. To saturate the free TL1A captured in the wells, 2 μg / mL of unconjugated TEV-48574 stock diluted in Diluent A was added. After 60 minutes of incubation at 20-23°C with 500 rpm shaking, the wells were washed again. For detection, 1 μg / mL of sulfo-labeled goat anti-human IgG polyclonal antibody stock diluted in Diluent A was added to the assay wells. The detection antibody was incubated for 1 hour at 20-23°C with 500 rpm shaking, protected from light. After incubation with the sulfo-labeled goat anti-human IgG polyclonal antibody, the wells were washed again with wash buffer. Read buffer was added to the assay wells, and the ECL signal was measured using a Meso Scale Discovery (MSD) Sector Imager 600. The total TL1A concentration in the NHP serum samples was then calculated. The increase in total TL1A levels in this NHP study (Figure 23A) was found to be gradual, consistent with the results obtained in the first human study.

[0609] To measure free TL1A levels (unbound TEV-48574) in NHP serum samples (i.e., the same NHP serum samples used to measure total TL1A levels), a 96-well plate immunoassay with ECL detection was performed. Briefly, each 96-well plate was blocked with Diluent A. The plate was incubated for 60 minutes at 20°C to 23°C with shaking at 500 rpm. After the blocking step, the wells were aspirated and coated with a 2 μg / mL stock of biotinylated rabbit anti-TL1A polyclonal antibody diluted in Diluent A. The capture antibody coating was performed for 60 minutes at 20°C to 23°C with shaking at 500 rpm. The wells of the 96-well plate were then washed with wash buffer. After washing, Diluent A was added to each well. A 5000 pg / mL recombinant monkey TL1A protein stock, followed by six subsequent 1:4 dilutions, was prepared in Diluent A as an assay standard. One of the recombinant monkey TL1A protein standards or a 1:4 dilution of NHP serum in Diluent A was added to designated assay wells. The assay plate was then incubated for 1 hour at 20°C–23°C with shaking at 500 rpm. After incubation with the standard and serum samples, the wells were washed with wash buffer. For detection, a 1 μg / mL stock of sulfo-labeled TEV-48574 diluted in Diluent A was added to the assay wells. The detection antibody was incubated for 1 hour at 20°C–23°C with shaking at 500 rpm (protected from light). After incubation with sulfo-labeled TEV-48574, the wells were washed with wash buffer. Read buffer was added to the assay wells. ECL signals were measured using an MSD Sector Imager 600. The free TL1A concentrations in the NHP serum samples were then calculated.

[0610] In contrast to total TL1A levels measured in NHP serum samples, free TL1A levels were found to be significantly suppressed below pre-dose baseline for at least 14 days in all animals. Pre-dose baseline TL1A values ranged from 43 to 106 pg / mL and declined to below the limit of quantitation at the earliest post-dose time point (6 hours). From days 2 to 14, low levels of only 10% to 40% of baseline persisted. Concentrations returned to baseline by day 21. Because an anti-drug antibody response was observed beginning on day 14, the observed duration of suppression may be an underestimate (Figure 23B).

[0611] The NHP data provide evidence that, unlike other monoclonal antibodies against TL1A, effective target engagement by TEV-48574, as measured by free TL1A, is not reflected as a large increase in total TL1A. Thus, TEV-48574 exhibited profound and sustained inhibition of free TL1A. The PD effect reflected by inhibition of free TL1A levels was observed over a period of time, with a half-life (T 1 / 2 This suggests that the effect was longer than predicted from the 2-week dosing interval (=3.0±1.9 days), and that a 4-week dosing interval may be feasible.

[0612] Example 8: Population Pharmacokinetic (PPK) Modeling and Simulation of TEV-48574 Dosing Regimen Comparisons of exposure between TEV-48574 and RVT-3101 (formerly known as PF-06480605 and described in PCT Publication Nos. WO 2015 / 073580A1 and WO 2021 / 260577, each incorporated herein by reference) were performed using a population pharmacokinetic (PPK) modeling and simulation approach. These calculations were intended to describe the time course of serum TEV-48574 concentrations in healthy and asthmatic participants from three clinical trials involving TEV-48574, including single ascending dose (SAD) data in healthy participants in Study TV48574-SAD-10126, multiple ascending dose (MAD) data in asthmatic patients in Study TV48574-SAD-10126, and single ascending dose data in healthy participants (Japanese and Caucasian).

[0613] Data selection and study design For each of the following studies, one or more of the following pharmacokinetic parameters were assessed: maximum observed serum drug concentration (C max ); time to maximum observed serum drug concentration (t max ); Area under the serum concentration-time curve (AUC) from time 0 to the last measurable concentration of TEV-48574 0-t ); Area under the serum concentration-time curve (AUC) extrapolated to infinity 0-∞ ); the percentage of the area extrapolated to infinity relative to the total area under the curve (AUC ext (%)), apparent serum terminal elimination rate constant (λ z ) and associated terminal (apparent elimination) half-lives (t 1 / 2 ), apparent total body clearance (CL / F), apparent volume distribution in the terminal phase (V z / F).

[0614] Single Ascending Dose (SAD) Data in Healthy Participants from the TV48574-SAD-10126 Study The SAD portion of Study TV48574-SAD-10126 was a single-center, randomized, double-blind, placebo-controlled, parallel-group Phase 1 study evaluating the safety, tolerability, PK, and immunogenicity of TEV-48574 in approximately 64 healthy adult men and women aged 18 to 60. The SAD portion consisted of a screening period, outpatient visits, ADA assessments, an end-of-treatment (EOT) visit on Day 22, and an end-of-study visit on Day 57.

[0615] On Day 1, subjects received a placebo or TEV-48574 SC injection at 1, 4, 12, 36, 90, 200, 400, or 1000 mg.

[0616] Pharmacokinetic parameters were based on the pharmacokinetic population, which consisted of subjects in the safety population who had at least one measurable concentration of TEV-48574. All 48 subjects who received TEV-48574 in the SAD study were included in the pharmacokinetic population.

[0617] After single SC administration of 1 mg and 4 mg TEV-48574, serum TEV-48574 concentrations were all below the BLQ (<200 ng / mL). Following administration of 12 mg, 36 mg, 90 mg, 200 mg, 400 mg, and 1000 mg TEV-48574, serum TEV-48574 concentrations increased with increasing dose. Serum TEV-48574 concentrations were quantifiable at 6 hours post-dose in the 12 mg, 36 mg, and 90 mg groups and at the earliest time point (1 hour post-dose) in the 200 mg, 400 mg, and 1000 mg groups. Peak serum TEV-48574 concentrations typically occurred between 72 and 96 hours post-dose. Following peak concentrations, TEV-48574 was gradually eliminated in a monophasic manner. Elimination rates were similar across dose levels.

[0618] Serum concentrations of TEV-48574 were quantifiable for up to 288 hours (12 days) in the 12 mg cohort, up to 672 hours (28 days) in the 36 mg and 90 mg cohorts, and up to 1344 hours (56 days) in the 200 mg (n=1), 400 mg (n=4), and 1000 mg (n=4) cohorts.

[0619] After a single SC administration of TEV-48574, serum TEV-48574 levels were max The median was 96 hours for the 12 mg, 36 mg, and 90 mg cohorts and 72 hours for the 200 mg, 400 mg, and 1000 mg cohorts.

[0620] Geometric mean peak serum concentration (C max ) and systemic exposure (AUC 0-t and AUC 0-∞ ) increased as dose increased from 12 mg to 1000 mg. The increases in peak and systemic exposure from 36 mg to 1000 mg appeared to be slightly more than dose-proportional. The increases in peak and systemic exposure from 200 mg to 1000 mg appeared to be dose-proportional.

[0621] average t 1 / 2 The estimated values were 155.85 to 230.88 hours (approximately 6.5 to 9.6 days). z The mean estimated values for CL / F were 0.66–1.71 L / day, V z / F ranged from 8.24 to 15.13 L / day.

[0622] The variability (CV%) of systemic exposure parameters was 0.01 across all dose levels, as shown in Table 53. max The AUC(AUC 0-t and AUC 0-∞ ) ranged from 17.03% to 61.27%.

[0623] [Table 54]

[0624] [Table 55]

[0625] Systemic absorption of SC TEV-48574 was slow in all cohorts. max The median time to death was 96 hours for the 12 mg, 36 mg, and 90 mg dose groups and 72 hours for the 200 mg, 400 mg, and 1000 mg dose groups. Due to limitations of the serum TEV-48574 bioassay, PK parameters could not be calculated after 1 mg and 4 mg administration (all concentrations were below 200 ng / mL at BLQ). Dose escalation of TEV-48574 from 12 mg to 1000 mg resulted in a peak (C max ) and systemic exposure (AUC).

[0626] Exposure parameters for TEV-48574 (C max , AUC 0-t , AUC 0-∞ Dose proportionality was assessed using the CL / F and V within a power model, which showed that the increase in exposure from 36 mg to 1000 mg was greater than dose proportional. In the dose range of 200 mg to 1000 mg, the increase in exposure was dose proportional. The half-life of TEV-48574 was generally greater than 6.5 days (range: 155.85 to 230.88 hours, or approximately 6.5 to 9.6 days), indicating no effect of dose. z The mean estimated values for CL / F were 0.66–1.71 L / day, V z / F ranged from 8.24 to 15.13 L / day.

[0627] In the SAD portion of this study, following single SC doses of 1 mg, 4 mg, 12 mg, 36 mg, 90 mg, 200 mg, 400 mg, and 1000 mg of TEV-48574 to healthy volunteers, the pharmacokinetics of TEV-48574 were characterized by slow absorption of the drug into the systemic circulation. After administration of 1 mg and 4 mg, serum concentrations of TEV-48574 were all within the BLQ. Peak serum concentrations of TEV-48574 typically occurred between 72 and 96 hours post-dose. After peak concentrations, TEV-48574 was gradually eliminated in a monophasic manner. Elimination rates were similar across dose levels.

[0628] The peak (C max ) and systemic exposure (AUC 0-t and AUC 0-∞ ) increased with increasing dose. From 36 mg to 1000 mg, the increase in TEV-48574 exposure was greater than dose-proportional, and C max The 90% CI of the estimated slope of AUC did not include 1 (1.0). Over the dose range of 200 mg to 1000 mg, the increase in exposure was dose-proportional.

[0629] TEV-48574 1 / 2 were similar across the dose ranges investigated; the half-life of TEV-48574 was generally greater than 6.5 days in all SAD cohorts (range: 155.85-230.88 hours, or approximately 6.5-9.6 days). For CL / F, mean estimates were similar across dose ranges. z / F was also similar across the dose range investigated in the SAD portion (8.24–15.13 L), indicating that TEV-48574 was mostly confined to the circulation.

[0630] Overall, statistical analysis of dose proportionality after single dose administration at the SAD (range 36-1000 mg) suggested slight superproportionality in the pharmacokinetics of TEV-48574. However, the half-life, CL / F, and V zThe / F was similar for all SAD doses, indicating linear pharmacokinetics. Dose proportionality was observed in the 200 mg to 1000 mg dose range. Therefore, the overall slightly greater than dose-proportional results may be less meaningful because only doses ≥200 mg carried over to the MAD portion.

[0631] Multiple Ascending Dose (MAD) Data for Patients with Asthma in the TV48574-SAD-10126 Study The MAD portion of Study TV48574-SAD-10126 was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety, tolerability, PK, and immunogenicity of TEV-48574 administered as three SC injections in approximately 36 male and female patients with symptomatic asthma aged 18 to 65 years. The MAD portion consisted of a prescreening (optional) and screening period, a 14- to 28-day run-in / washout period, hospitalizations, outpatient visits, ADA assessments, an EOT visit (Day 43), and an end-of-study visit (Day 92).

[0632] Patients in the MAD portion were assigned to one of three cohorts (N=12 per cohort) and received TEV-48574 or placebo Q2W SC on days 1, 15, and 29 of the study. TEV-48574 was administered at the following doses: (1) 200 mg Q2W as a single SC injection using a standardized syringe, (2) 800 mg followed by 600 mg Q2W as a SC injection using a standardized syringe, or (3) 2300 mg followed by 1600 mg as an approximately 1-hour SC infusion. Within each cohort, three participants were randomly assigned to receive TEV-48574 (N=2) or placebo (N=1) 72 hours before the other participants. If no discontinuation criteria were met and no safety concerns related to TEV-48574 were identified, the remaining patients in the cohort were randomized to TEV-48574 (n=7) or placebo (n=2) 72 hours after the first three patients received TEV-48574, at the investigator's discretion. Patients could be dosed individually or in a cohort format, at the investigator's discretion.

[0633] Geometric mean C of TEV-48574 after the first SC dose of TEV-48574 on Day 1 max , AUC 0-t , AUC τ increased by 8.10-fold, 8.26-fold, and 8.60-fold with an 11.5-fold increase in dose from 200 mg to 2300 mg. The variability in exposure was max 42.3% to 83.7%, AUC 0-t 38.0% to 77.3%, AUC τ The median serum tmax of TEV-48574 was approximately 3 days (range: 2.97-2.99 days) in the 200 mg, 800 mg, and 2300 mg dose groups.

[0634] Geometric mean C of TEV-48574 after multiple SC administrations max , AUC 0-t and AUC τ With an 8-fold increase in dose from 200 mg to 1600 mg, the C values increased to 6.85-fold, 7.93-fold, and 5.24-fold, respectively, on Day 15, and 6.38-fold, 9.26-fold, and 5.35-fold, respectively, on Day 29. The variability (geometric CV%) after multiple administration (Days 15 and 29) was 4.2% in patients without treatment-complicated ADA. max 31.1% to 78.2%, AUC 0-t 24.6% to 74.2%, AUC τ The overall exposure (C max , AUC 0-t , AUC τ ) was moderate across all cohorts and similar after each dose of TEV-48574. Furthermore, as shown in Table 54, the t max Median times were similar to those for the first dose, ranging from 2.96 to 3.00 days across the dose range studied.

[0635] [Table 56]

[0636] [Table 57]

[0637] [Table 58]

[0638] [Table 59]

[0639] The elimination phase of TEV-48574 after administration on Days 1 and 15 could not be adequately defined because the 14-day sample collection period after the first and second doses was not long enough to reliably calculate the elimination half-life. Therefore, the AUC 0-∞ , t 1 / 2 , CL / F and V z / F is only described after the final dose on Day 29. After the dose on Day 29, the mean t 1 / 2 Values ranged from 8.3 to 8.7 days across the dose range investigated. Dose did not appear to affect the elimination rate of TEV-48574. Furthermore, mean CL / F and V at 29 days z / F was similar across dose levels, ranging from 0.043 to 0.072 L / h and 11.79 to 21.06 L, respectively.

[0640] Accumulation of TEV-48574 serum exposure after multiple SC administrations was assessed by dosing interval. In Cohort 1, the mean serum exposure from the first dose to the second dose (AUC τ , 15th day / AUC τ , day 1), from the first dose to the third dose (AUC τ , Day 29 / AUC τ , day 1), from the second to the third dose (AUC τ , Day 29 / AUC τ , 15th day) obs) were 1.472, 1.64, and 1.057, respectively. Although slight accumulation was observed from the first dose to the second and third doses, no accumulation was observed from the second to third doses, suggesting that a steady state had been reached. In Cohort 2, the mean accumulation (R obs ) were 1.319, 1.374, and 1.107, respectively. Even with the loading dose, exposure in Cohort 2 appeared to accumulate slightly after this second dose. After the second dose, exposure appeared to reach a steady state. In Cohort 3, the mean cumulative doses (R ) from dose 1 to dose 2, dose 1 to dose 3, and dose 2 to dose 3 were 1.319, 1.374, and 1.107, respectively. obs ) were 1.039, 1.07, and 1.054, respectively. After the loading dose, exposure in Cohort 3 did not appear to accumulate with subsequent doses, suggesting that a steady state was reached after the loading dose.

[0641] The pharmacokinetics of TEV-48574 were characterized in patients with mild allergic asthma during the MAD portion of this study. Consistent with the results of the SAD portion in healthy volunteers, the pharmacokinetics of TEV-48574 in patients was characterized by slow absorption of TEV-48574 into the systemic circulation. 1 / 2 The mean CL / F ranged from 8.3 to 8.7 days and was not affected by dose level. Half-life estimates appear similar to those in the SAD portion of the study, where the half-life of TEV-48574 was generally greater than 6.5 days across all cohorts. For CL / F, mean estimates were similar across the dose range tested in the MAD interval and comparable to the CL / F observed in the SAD interval. z The / F was similar across the dose range in the MAD study (11.79–21.06 L), indicating that TEV-48574 was largely confined to the circulation, similar to what was observed in the SAD study.

[0642] The peak (C) of TEV-48574 was measured across the dose range tested in the single-dose and multiple-dose MAD portions.max ) and systemic exposure (AUC τ ) increased with increasing dose. From 200 mg to 2300 mg on Day 1 and from 200 mg to 1600 mg at steady state, the increase in TEV-48574 exposure was dose-proportional, with C max and AUC τ The 90% CI of the estimated slope of the MAD included 1 (1.0). The dose-proportionality results for the MAD were not consistent with those for the SAD, which suggested slight superproportionality when increasing doses from 36 mg to 1000 mg. However, in the SAD dose range of 200 mg to 1000 mg, the increase in exposure was dose-proportional.

[0643] Although factors such as physiological factors, small number of subjects per cohort, parallel design, dose, and number of injection sites may have contributed to the greater than dose-proportional increase in exposure observed when the 36 mg and 90 mg doses were included in the SAD portion, the increase in exposure was dose-proportional across the 200 mg to 1000 mg dose range in the SAD portion and the entire dose range in the MAD portion. Furthermore, the half-life, CL / F, and V of TEV-48574 were significantly higher than those observed in the 200 mg to 1000 mg dose range in the SAD portion. z The pharmacokinetics (F / F) was similar across all doses in both the SAD and MAD studies, suggesting linear pharmacokinetics. In Cohort 1, which did not receive a loading dose, accumulation after the first dose was weak (approximately 47%) during the MAD portion of the study. Weak accumulation (approximately 32%) was also observed after the loading dose in Cohort 2, suggesting that the loading dose may have been too low to achieve steady state as rapidly as intended. In contrast, the loading dose used in Cohort 3 suggests that steady state may have been achieved after the loading dose. For all dose regimens, steady state was achieved after the second dose.

[0644] Single-dose data from an additional Phase 1 study in healthy participants (Japanese and Caucasian) This was an open-label, randomized, phase 1, single-dose SC study to evaluate the PK, safety, and tolerability of TEV-48574 in healthy Japanese and Caucasian participants. On Day 1, Japanese participants received SC injections of 400 mg, 1000 mg, or 2300 mg (8 per dose level), and Caucasian participants received 2300 mg (N=8).

[0645] The first cohort included 16 Japanese subjects, randomly assigned 1:1 to receive either 400 mg or 1000 mg of TEV-48574. After a minimum 3-day and maximum 14-day observation period, if safety and tolerability were not observed, study drug administration continued in cohort 2, where eight Japanese subjects received 2300 mg of TEV-48574. Study drug administration continued through cohort 3, where eight Caucasian subjects received 2300 mg of TEV-48574. A maximum 14-day time lag between cohort 2 and cohort 3 allowed time for clinical trial sites to recruit Caucasian subjects matched to the Japanese subjects for cohort 3.

[0646] Blood samples for measuring TEV-48574 serum concentrations for pharmacokinetic evaluation were collected before TEV-48574 administration and at 1, 6, and 12 hours after administration on days 1 and 2 (24 hours), 3 (48 hours), 4 (72 hours), 5 (96 hours), 6 (120 hours), 8, 10, 15, 22, 29, 43, and 50. In addition, samples for TEV-48574 serum concentration evaluation were collected as needed in consultation with the medical monitor if a severe hypersensitivity reaction (e.g., anaphylaxis) was observed or a serious adverse event occurred.

[0647] A total of 55 healthy subjects were screened and enrolled in this study. Of the 55 screened subjects, 32 met the inclusion criteria and were randomized. 24 subjects were Japanese and 8 were Caucasian. Sixteen Japanese subjects were randomly assigned to Cohort 1 and received either 400 mg or 1000 mg of TEV-48574. Eight Japanese subjects were randomly assigned to Cohort 2 and received 2300 mg of TEV-48574. Eight Caucasian subjects were randomly assigned to Cohort 3 and received 2300 mg of TEV-48574.

[0648] All 32 randomized subjects received a single dose of TEV-48574 and were evaluated for safety in the study and included in the pharmacokinetic analysis population. All 32 subjects completed the study.

[0649] Due to the study design, the majority of subjects were Asian (24 [75%]). Japanese subjects generally weighed less than Caucasian subjects. Mean body weight was lower in the treatment group of Cohort 1 compared with Cohorts 2 and 3. Furthermore, mean weight in Cohort 2 was lower than in Cohort 3 (60.84 kg vs. 62.13 kg). Weight was a covariate for study drug exposure. Body mass index was comparable between treatment groups.

[0650] Dose selection was supported by safety, tolerability, pharmacokinetic, and immunogenicity studies of TV48574-SAD-10126, which demonstrated an acceptable safety profile for single doses of 1 mg to 1000 mg, and multiple doses of 200 mg to 2300 mg (loading dose) and 1600 mg (maintenance dose). No deaths, serious adverse events, or PDAESIs (serious hypersensitivity reactions or anaphylaxis) were reported during the single ascending dose (SAD) or multiple ascending dose (MAD) periods of the TV48574-SAD-10126 study. The pharmacokinetics of TEV-48574 in this dose range were expected to be linear, similar to that of TV48574-SAD-10126, where exposure increase was dose-proportional.

[0651] In the TV48574 SAD-10126 study, single doses of 400 mg and 1000 mg were evaluated in healthy volunteers, and it was expected that by administering similar doses as a single SC dose to healthy Japanese subjects, the pharmacokinetics, safety, tolerability, and immunogenicity of TEV-48574 in these populations could be compared in a dose-based cross-study.

[0652] In the MAD study of Study TV48574-SAD-10126, the highest dose (2300 mg) was administered to asthmatic patients, making comparison with healthy subjects impossible. Therefore, in this study, healthy Caucasian and Japanese subjects were administered 2300 mg, and the pharmacokinetics, safety, tolerability, and immunogenicity were directly compared between the two populations.

[0653] Following a single SC dose in Japanese subjects, TEV-48574 concentrations peaked 3-4 days after administration at all dose levels, and the elimination profiles were similar. The elimination half-life was 7-9 days.

[0654] Geometric mean peak serum concentration (C max ) and systemic exposure (AUC 0-t and AUC 0-∞ ) increased with increasing dose in the dose range of 400 to 2300 mg (see Table 55).

[0655] [Table 60]

[0656] [Table 61]

[0657] Dose proportionality analysis in the dose range of 400 mg to 2300 mg showed that exposure increased linearly with increasing dose in Japanese subjects.

[0658] The pharmacokinetic profile of TEV-48574 in Japanese subjects was similar to that in Caucasian subjects in terms of absorption, distribution, and elimination. The pharmacokinetic parameters in Japanese subjects were comparable to those in Caucasian subjects in the 2300 mg dose cohort and consistent with those in Caucasian subjects obtained in the previous first-in-human (FIH) study, TV48574-SAD-10126.

[0659] The pharmacokinetic parameters of the three Japanese cohorts were compared with those of the 2300 mg cohort of Caucasians. max and AUC 0-∞ was similar between comparison groups.

[0660] A Phase 1 study in healthy subjects (Japanese and Caucasian) demonstrated that the pharmacokinetic profile of TEV-48574 was similar between Japanese and Caucasian subjects, with mean serum concentrations and individual serum concentration profile plots completely overlapping between the two ethnic groups at the 2300 mg dose.

[0661] Exposure parameters of Japanese subjects (C max , AUC 0-t , AUC 0-∞ ) were comparable to Caucasians in the 2300 mg dose cohort and consistent with pharmacokinetic parameters in Caucasian subjects obtained in the previous FIH TV48574-SAD-10126 study. The mean half-life was similar between the two ethnicities and consistent with the half-life reported in TV48574-SAD-10126, ranging from 6 to 9 days across studies. CL / F and V z / F is consistent with the value reported in TV48574-SAD-10126.

[0662] An exploratory assessment of dose proportionality suggested linear exposure with increasing dose in the 400-2300 mg dose range in Japanese subjects, consistent with data reported in the TV48574-SAD-10126 study, where exposure was dose-proportional in the 200-2300 mg dose range.

[0663] These results suggest that the pharmacokinetics of TEV-48574 are not significantly affected by ethnicity.

[0664] method Data preparation was performed using SAS version 9.4. Exploratory data analysis and presentation were performed using R version 3.5.2 and various R packages. Population modeling was performed using the nonlinear mixed-effects platform NONMEM version 7.3 and Monolix version 2018R. All analyses were performed on the validated computer system Advanced Computational Environment (ACE), and all analysis files were stored in the validated storage system Bitbucket.

[0665] A previously developed population PK model consisting of a one-compartment with linear elimination, lag time, and baseline body weight as a covariate for clearance and volume of distribution was used as a starting point for the model described herein.

[0666] Population PK Modeling and Simulation of TEV-48574 and RVT-3101 During the development of the structural PK model, several variations of the 1-compartment model were evaluated. A 1-compartment model with first-order absorption, linear elimination, and baseline body weight as a covariate for clearance and volume of distribution best described the serum TEV-48574 concentration-time data (see Table 56).

[0667] [Table 62]

[0668] A population PK model for RVT-3101 was constructed based on the model described in Danese S et al. Clin. Gastroenterol. Hepatol. 2021, 19(11):2324-2332.e6, which is incorporated by reference in its entirety. RVT-3101 (also known as PF-06480605) is disclosed as antibody 1D1 1.31 and is further described in PCT Patent Publications WO 2015 / 073580 and WO 2021 / 260577). The model structure by Danese et al. included two compartments, with a clearance of 0.00575 L / h (8.26% relative standard error (RSE)), a central volume of distribution of 3.02 L (4.74% RSE), an intercompartmental clearance of 0.0141 L / h (4.53% RSE), a peripheral volume of distribution of 5.78 L (1.94% RSE), a SC bioavailability of 67.5%, and an absorption rate of 0.00671 h-1. Body weight was a significant covariate for clearance and central volume, with power-law exponents of 0.746 (49.1% RSE) and 0.578 (44.8% RSE), respectively.

[0669] Population PK models for TEV-48574 and RVT-3101 were used in simulation mode to predict various doses and administration regimens and compare the exposure of the two compounds.

[0670] As shown in Figure 24A, simulated TEV-48574 concentrations for a 2250 mg loading dose and 900 mg Q2W or Q4W maintenance regimens were compared with expected RVT-3101 exposure following administration of 50 mg, 150 mg, or 450 mg of RVT-3101 in a Q4W regimen.

[0671] As shown in Figure 24B, simulated TEV-48574 concentrations for a 2250 mg loading dose and 450 mg Q2W or Q4W maintenance regimens were compared to expected RVT-3101 exposure following administration of 50 mg, 150 mg, or 450 mg of RVT-3101 in a Q4W regimen.

[0672] The results of these two PK simulations supported the TEV-48574 regimens described in the clinical trials in Examples 1, 4, and 9. The results demonstrated that a 2250 mg loading dose of TEV-48574 followed by induction and / or maintenance doses of 450 mg and 900 mg every 4 weeks would achieve exposure levels predicted to demonstrate clinical efficacy.

[0673] Example 9: Surrogate Clinical Evaluation of TEV-48574 in Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn's Disease Initial treatment period TEV-48574 will be evaluated in a Phase 2b, randomized, double-blind, dose-ranging study to determine the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) as described in Example 1 with the following modifications.

[0674] This study will evaluate the efficacy and dose-responsiveness of TEV-48574 administered subcutaneously (sc) every two weeks (Q2W) at two different dose regimens in adult patients with inflammatory bowel disease (IBD) (moderate to severe UC or CD) as assessed by induction of clinical remission (UC) and endoscopic response (CD) at 14 weeks.

[0675] Approximately 570 patients will be screened, achieving randomization of approximately 240 (approximately 120 patients with UC and 120 patients with CD). Patients who meet all inclusion criteria will be randomized to receive TEV-48574 (single loading dose / six induction doses): 2250 / 900 mg, 2250 / 450 mg, or placebo at the same volume as TEV-48574 in a 1:1:1 ratio, stratified by diagnosis (UC or CD) and prior treatment history, biologic and small molecule failure (including JAK inhibitors and S1P receptor modulators for UC), or biologic and small molecule treatment naive. Patients will therefore receive the following regimen administered SC using a commercially available syringe-based SC infusion system: TEV-48574 2250mg (single loading dose) / 900mg (six induction doses) TEV-48574 2250mg (single loading dose) / 450mg (six induction doses) TEV-48574 vs. matching placebo

[0676] The long-term efficacy and safety of TEV-48574 will then be demonstrated in patients with moderately to severely active UC or CD at study entry who demonstrate clinical response and / or clinical remission (based on a complete Mayo score for UC subjects and CDAI for CD subjects) to initial treatment with TEV-48574 in this study. These patients will receive either 450 mg Q4W or 900 mg Q4W throughout the treatment period (see the Long-Term Extension Study section below).

[0677] A schematic diagram of the test is shown in FIG.

[0678] Randomization: Patients who meet the eligibility criteria at the end of the screening period will be randomized in a 1:1:1 ratio (stratified by diagnosis [UC or CD] and prior exposure, biologic and small molecule failure [including JAK inhibitors and S1P receptor modulators for UC], or biologic and small molecule treatment naive) to one of three treatment arms during the double-blind treatment period (Table 57).

[0679] All treatments will be administered as a single SC intravenous infusion Q2W in a double-blind manner.

[0680] [Table 63]

[0681] Results were analyzed as discussed in Example 1 and demonstrated the efficacy and dose-responsiveness of two different dosing regimens of TEV-48574 administered subcutaneously (SC) every two weeks (Q2W) in adult patients with IBD (moderate to severe UC or CD), as assessed by clinical induction of remission (UC) and endoscopic response (CD) at 14 weeks.

[0682] Long-term extension study TEV-48574 will be evaluated in a Phase 2b, randomized, double-blind, long-term extension (LTE) study to evaluate the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate to severe ulcerative colitis (UC) or Crohn's disease (CD) who achieved a clinical response and / or clinical remission during the 14-week Initial Treatment Period (ITP) described above in this Example (ITP). A schematic of the study is shown in Figure 26. The LTE study will be conducted as described in Example 4 with the following modifications: This study will be a 40-week study.

[0683] Eligible patients must meet all of the following inclusion criteria: Adults (male or female) who have achieved clinical response and / or clinical remission in 14 weeks of ITP at the time of informed consent (no gender restrictions). At week 14 of ITP in patients with moderate to severe UC, clinical response was assessed as a ≥2-point reduction from baseline in the modified Mayo score (a 9-point scale covering rectal bleeding, stool frequency, and endoscopy), a reduction of at least 30%, and a ≥1-point reduction in the rectal bleeding subscore, or an absolute subscore of 0 or 1. Clinical remission of ITP at 14 weeks in patients with moderate to severe UC. Clinical remission is defined as a modified Mayo score (9-point scale for rectal bleeding, stool frequency, and endoscopy) of 2 or less. A bowel frequency subscore of 0 or 1, Rectal bleeding subscore is 0, and Endoscopic subscore of 0 or 1, where a score of 1 is defined as not including "easy bleeding." Clinical response in patients with moderate to severe Crohn's disease as measured by a reduction of 100 or more points from baseline in the Crohn's Disease Activity Index (CDAI) score at week 14 of ITP treatment. Clinical remission, defined as a CDAI score of less than 150 at 14 weeks after the start of ITP, in patients with moderate to severe CD.

[0684] Patients who met all inclusion criteria were randomized to receive TEV-48574 (10 maintenance doses): 900 mg or 450 mg in a 1:1 ratio, stratified by diagnosis (UC or CD). Data provided herein, e.g., Examples 7 and 8, demonstrate that a 2250 mg loading dose followed by maintenance doses of 450 mg or 900 mg of TEV-48574 every 4 weeks achieves exposure levels expected to demonstrate clinical efficacy.

[0685] General design The study includes a 40-week treatment period and a 2-week follow-up period.

[0686] Randomization: In the 14-week study described above for ITP, patients who meet the eligibility criteria at the end of treatment visit (EOT) will be randomly assigned 1:1 (stratified by diagnosis [UC or CD]) to one of two treatment arms for the double-blind treatment period (see Table 58 below). Approximately 240 patients will be screened (after week 14 of ITP onset). The total number of patients in the LTE will be approximately 90 per indication (approximately 45 per treatment arm).

[0687] All study treatments will be administered as a single SC intravenous infusion Q4W in a double-blind manner.

[0688] [Table 64]

[0689] During the 40-week treatment period, patients will visit the site Q4W for 10 TEV-48574 doses on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, and 253 (± 3 days) and for endpoint assessment on Day 281 (± 3 days). After the 40-week treatment period, patients will return for follow-up (Day 309 [± 3 days]). Patients who complete the follow-up visit will be considered to have completed the study.

[0690] Patients are permitted to use the medications detailed below: In combination with oral 5-ASA or sulfasalazine. The dose must be stable throughout the transition and study periods (week 40). Stable administration of oral corticosteroids (maximum 20 mg / day prednisone equivalent, maximum 9 mg / day budesonide equivalent) throughout the transition period and treatment period (week 40). Stable administration of immunosuppressants (methotrexate ≤25 mg intramuscularly or SC once weekly or ≤15 mg orally once weekly; 6-MP ≤1.5 mg / kg / day; or AZA ≤2.5 mg / kg / day).

[0691] To demonstrate lack of immunogenicity, the following endpoints are analyzed: Treatment-emergent anti-drug antibody (ADA) outcomes and response: change from baseline (ITP) and change over the study period Neutralize ADA in ADA-positive patients throughout the study period. The effect of the presence of ADAs on pharmacokinetics and clinical safety will be evaluated as necessary.

[0692] To demonstrate the efficacy of TEV-48574, the following efficacy endpoints will be analyzed: In patients with UC, clinical remission based on a modified (9-point scale for rectal bleeding, stool frequency, and endoscopy) Mayo score of 2 points or less, as defined by a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, where a score of 1 does not include "easy bleeding" at week 40. Endoscopic response, defined as at least a 50% reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD) from baselin...

Claims

1. A composition for use in treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease in a subject in need thereof, the composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); A composition, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:

6.

2. 10. The composition of claim 1, wherein the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators, and 5-aminosalicylic acid (5-ASA).

3. 3. The composition of claim 2, wherein the subject has had an inadequate response to, failed to respond to, or was intolerant to one or more of the agents.

4. 4. The composition of claim 3, wherein the subject has had an inadequate response to, failed to respond to, or been intolerant to no more than two biological agents.

5. A composition for use in treating ulcerative colitis or Crohn's disease in a subject in need thereof, the composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6; The composition, wherein the subject has shown inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor alpha (TNF-α) antagonists, anti-integrin antibodies, anti-interleukin (IL)-12 / 23 antibodies, Janus kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators.

6. A composition for use in treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease in a subject in need thereof, the composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 6; The composition, wherein said use comprises administering said composition at a dose of about 300 mg to about 2250 mg.

7. 7. The composition of any one of claims 1 to 6, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

8. The composition of any one of claims 1 to 6, wherein the antibody or antigen-binding fragment comprises an IgG1 constant region.

9. 7. The composition of any one of claims 1 to 6, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

10. 7. The composition of any one of claims 1 to 6, wherein the subject is treated with a combination of oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

11. The composition described in any one of claims 1 to 6, wherein the use comprises administering the composition at a dose of about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 750 mg, about 900 mg, or about 2250 mg, and / or the use comprises administering the composition about once every two weeks or about once every four weeks.

12. A composition described in any one of claims 1 to 6, wherein the use comprises administering the composition at a dose of approximately 900 mg.

13. The use, (a) administering one or more induction doses of the antibody or antigen-binding fragment thereof without administering a loading dose; or (b) administering a loading dose of the antibody or antigen-binding fragment thereof, followed by one or more induction doses of the antibody or antigen-binding fragment thereof. The composition of any one of claims 1 to 6, comprising:

14. 14. The composition of claim 13, wherein the one or more induction doses comprise about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof, about 6 induction doses are administered, the one or more induction doses are administered over a period of about 14 weeks, and / or the loading dose is administered about 2 weeks before the one or more induction doses are administered.

15. The composition of any one of claims 1 to 6, wherein the use comprises administering the composition for about 16 weeks.

16. the use comprising administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, without administering a loading dose and / or induction dose, and optionally (a) the maintenance dose is administered about every two weeks or about every four weeks; (b) the one or more maintenance doses comprise about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof; (c) about 10 maintenance doses are administered; and / or (d) the one or more maintenance doses are administered for about 24 weeks or about 40 weeks; The composition according to any one of claims 1 to 6.

17. The use further comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and optionally (a) the maintenance dose is administered about every two weeks or about every four weeks; (b) the one or more maintenance doses comprise about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof; (c) about 10 maintenance doses are administered; and / or (d) the one or more maintenance doses are administered for about 24 weeks or about 40 weeks; The composition according to any one of claims 1 to 6.

18. The use, a) administering (i) a loading dose of about 1500 mg to about 2500 mg, (ii) one or more induction doses of about 300 mg to about 1800 mg, and (iii) one or more maintenance doses of about 300 mg to about 2250 mg of the antibody or antigen-binding fragment thereof, wherein optionally the induction dose is administered about every two weeks and the maintenance doses are administered about every two weeks or about every four weeks, about six induction doses are administered, and about ten maintenance doses are administered, the one or more induction doses are administered over about a 14 week period, the loading dose is administered about two weeks before the one or more induction doses, and / or the one or more maintenance doses are administered over about a 24 week period or about a 40 week period; b) administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, wherein optionally the induction dose is administered about every two weeks and the maintenance doses are administered about every four weeks, about six induction doses are administered, and about ten maintenance doses are administered, the one or more induction doses are administered over about a 14 week period, the loading dose is administered about two weeks before the one or more induction doses, and / or the one or more maintenance doses are administered over about a 24 week period or about a 40 week period; c) administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, wherein optionally the induction dose is administered about every two weeks and the maintenance doses are administered about every four weeks, about six induction doses are administered, and about ten maintenance doses are administered, the one or more induction doses are administered over about a 14 week period, the loading dose is administered about two weeks before the one or more induction doses, and / or the one or more maintenance doses are administered over about a 24 week period or about a 40 week period; d) administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, wherein optionally the induction dose is administered about every two weeks and the maintenance doses are administered about every four weeks, about six induction doses are administered, and about ten maintenance doses are administered, the one or more induction doses are administered over about a 14 week period, the loading dose is administered about two weeks before the one or more induction doses, and / or the one or more maintenance doses are administered over about a 24 week period or about a 40 week period; e) administering (i) a loading dose of about 2250 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, wherein optionally the induction dose is administered about every 2 weeks and the maintenance doses are administered about every 4 weeks, about 6 induction doses are administered, and about 10 maintenance doses are administered, the one or more induction doses are administered over about 14 weeks, the loading dose is administered about 2 weeks before the one or more induction doses, and / or the one or more maintenance doses are administered over about 24 weeks or about 40 weeks; f) administering (i) a loading dose of about 1750 mg, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, wherein optionally the induction dose is administered about every 2 weeks and the maintenance doses are administered about every 2 weeks or about every 4 weeks, about 6 induction doses are administered, and about 10 maintenance doses are administered, the one or more induction doses are administered over about 14 weeks, the loading dose is administered about 2 weeks before the one or more induction doses, and / or the one or more maintenance doses are administered over about 24 weeks or about 40 weeks; g) administering (i) a loading dose of about 1500 mg to about 2500 mg and (ii) one or more maintenance doses of about 300 mg to about 2250 mg of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every 2 weeks or about every 4 weeks, at least 10 maintenance doses are administered, and / or the one or more maintenance doses are administered over about 24 weeks or about 40 weeks; h) administering (i) a loading dose of about 2250 mg and (ii) one or more maintenance doses of about 450 mg of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every 4 weeks, at least 10 maintenance doses are administered, and / or the one or more maintenance doses are administered over about 24 weeks or about 40 weeks; i) administering (i) a loading dose of about 2250 mg and (ii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, optionally wherein the maintenance doses are administered about every 4 weeks, at least 10 maintenance doses are administered, and / or the one or more maintenance doses are administered over about 24 weeks or about 40 weeks; or j) administering (i) a loading dose of about 1750 mg and (ii) one or more maintenance doses of about 900 mg of the antibody or antigen-binding fragment thereof, wherein optionally the maintenance doses are administered about every 2 weeks or about every 4 weeks, at least 10 maintenance doses are administered, and / or the one or more maintenance doses are administered over about 24 weeks or about 40 weeks. The composition according to any one of claims 1 to 6.

19. the antibody or antigen-binding fragment thereof: (a) formulated at a concentration of about 200 mg / mL; (b) formulated in a volume of 3 mL or less; (c) administered subcutaneously or intravenously to said subject; and / or (d) administered to the subject via a syringe, optionally wherein the syringe is a pre-filled syringe, and further optionally wherein the pre-filled syringe has a volume of 2 mL or less; The composition according to any one of claims 1 to 6.

20. The subject: (a) has moderate to severe ulcerative colitis, and optionally the composition results in clinical remission, and further optionally the clinical remission occurs within 14 weeks or 38 weeks of initiating administration of the composition; and / or (b) having moderate to severe Crohn's disease, wherein optionally the composition results in an endoscopic response, and further optionally the endoscopic response occurs within 14 weeks or within 38 weeks of initiating administration of the composition.