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

Abstract

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

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This international application claims the benefit of priority to U.S. Provisional Application No. 63 / 369,591, filed on July 27, 2022, and U.S. Provisional Application No. 63 / 387,786, filed on December 16, 2022, each of which is incorporated herein by reference in its entirety. References to electronically submitted sequence listings

[0002] The contents of the electronically submitted Sequence Listing (name 2873_364PC03_SequenceListing_St26.xml; size: 67,104 bytes; and creation date: July 20, 2023) submitted with this application are incorporated herein by reference in its entirety. Background Art

[0003] Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract that affects 5 million people worldwide. IBD presents in one of two major forms, ulcerative colitis (UC) or Crohn's disease (CD). In UC, inflammation is confined to the colonic mucosa, while in CD, a transmural inflammatory process can affect the entire GI tract from mouth to anus, although it is preferentially localized to the terminal ileum and / or right colon (in nearly 70% of forms).

[0004] The overall goal of treatment for patients with active UC is to induce and maintain remission and mucosal healing. Treatment of UC consists of anti-inflammatory and immunosuppressive therapies selected to maximize efficacy while avoiding toxicity. Although agents used to treat mild to moderate UC are generally well tolerated, as UC disease severity increases, so does the potential toxicity of the drug therapies required to manage the disease. Medical therapy for patients with CD is primarily influenced by the type, site, and extent of lesions and the presence of local and extraintestinal manifestations and activity of the disease.

[0005] Despite recent advances in IBD therapeutics, many patients still do not respond, lose response, or are intolerant to currently available UC and CD treatments. In addition, some available IBD therapeutics are associated with significant safety issues. Therefore, there remains a need to develop and implement highly effective drugs with favorable side effect profiles for patients. Summary of the invention

[0006] 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).

[0007] Also 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 previously had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject previously had an inadequate response, loss of response, or intolerance 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 aspects, 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 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).

[0009] In some aspects, 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 aspects, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0010] In some aspects, the subject was previously treated with one or more agents selected from the group consisting of: corticosteroids, immunosuppressants, tumor necrosis factor-α (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 aspects, the subject has an insufficient response, loss of response, or intolerance to one or more of these agents. In some aspects, the subject has an insufficient response, loss of response, or intolerance to no more than two classes of biological agents. In some aspects, the subject is treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate simultaneously.

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

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

[0013] In some aspects, the administration includes administering a loading dose of an antibody or its Fab, followed by one or more induction doses of the antibody or its Fab. In some aspects, the administration includes only administering one or more induction doses of an antibody or its Fab (i.e., administering an antibody or its Fab without a loading dose).

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

[0015] In some aspects, the one or more induction doses (which can be administered after a loading dose or without a loading dose) include about 300 mg of an antibody or its antigen binding fragment. In some aspects, the one or more induction doses include about 400 mg of an antibody or its antigen binding fragment. In some aspects, the one or more induction doses include about 450 mg of an antibody or its antigen binding fragment. In some aspects, the one or more induction doses include about 600 mg of an antibody or its antigen binding fragment. In some aspects, the one or more induction doses include about 750 mg of an antibody or its antigen binding fragment. In some aspects, the one or more induction doses include about 900 mg of an antibody or its antigen binding fragment. In some aspects, the one or more induction doses include about 1800 mg of an antibody or its antigen binding fragment.

[0016] In some aspects, about six induction doses are administered.

[0017] In some aspects, the administration is performed within about 16 weeks. In some aspects, the administration of the one or more induction doses is performed within about 14 weeks. In some aspects, the loading dose is administered about 2 weeks prior to the administration of the one or more induction doses.

[0018] In some aspects, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered about every 2 weeks.

[0019] In some aspects, 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 2 weeks.

[0020] In some aspects, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered about every 4 weeks.

[0021] In some aspects, 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 4 weeks.

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

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

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

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

[0029] In some aspects, about twelve maintenance doses are administered.

[0030] In some aspects, 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.

[0031] In some aspects, 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.

[0032] In some aspects, the administering 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 aspects, 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 450 mg of the antibody or antigen-binding fragment thereof.

[0034] In some aspects, 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 450 mg of the antibody or antigen-binding fragment thereof.

[0035] In some aspects, 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.

[0036] In some aspects, 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.

[0037] In some aspects, 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.

[0038] In some aspects, 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.

[0039] In some aspects, the administration of the one or more maintenance doses is performed within about 24 weeks. In some aspects, the administration of the one or more maintenance doses is performed within about 40 weeks.

[0040] In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 150 mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 200 mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 225 mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 250 mg / mL.

[0041] In some aspects, the antibody or its Fab is prepared in a volume of about 3 mL. In some aspects, the antibody or its Fab is prepared in a volume of 3 mL or less. In some aspects, the antibody or its Fab is prepared in a volume of 2 mL or less.

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

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

[0044] In some aspects, the subject suffers from moderate to severe ulcerative colitis. In some aspects, the administration results in clinical remission. In some aspects, the clinical remission occurs within 14 weeks after administration begins. In some aspects, the clinical remission occurs within 38 weeks after administration begins.

[0045] In some aspects, the subject suffers from moderate to severe Crohn's disease. In some aspects, the administration results in an endoscopic response. In some aspects, the endoscopic response occurs within 14 weeks after administration begins. In some aspects, the endoscopic response occurs within 38 weeks after administration begins.

[0046] Also provided herein is a pharmaceutical formulation comprising: (a) about 100 mg / mL to about 250 mg / mL of an antibody or an antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A); wherein the antibody or the 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. NO:6; (b) about 5mM to about 15mM histidine; (c) about 50mM to about 150mM 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 aspects, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO:8. In some aspects, the antibody or antigen-binding fragment thereof comprises an IgG1 constant region. In some aspects, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:9 and a light chain comprising an amino acid sequence of SEQ ID NO:10.

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

[0048] In some aspects, 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 aspects, 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 aspects, 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 aspects, the pharmaceutical formulation is lyophilized. In some aspects, the pharmaceutical formulation is liquid. In some aspects, the pharmaceutical formulation has a pH of 6.0 ± 0.5 after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0052] In some aspects, the drug formulation is stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having an osmotic pressure of from 200mOsm / kg to 500mOsm / kg. In some aspects, the drug formulation has at least 99% antibody monomer content after being stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the drug formulation has no significant change in charge heterogeneity characteristics after being stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the drug formulation has no significant change in purity after being stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the drug formulation has at least 90% purity after being stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the pharmaceutical formulation is stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after there is no significant change in particle concentration. In some aspects, the pharmaceutical formulation is stored at 2 ° C-8 ° C for up to 36 months and there is no significant difference in visual appearance. In some aspects, the pharmaceutical formulation disclosed herein is stored at 2 ° C-8 ° C, 25 ° C or 40 ° C for up to 36 months and there is no significant difference in protein concentration, osmotic pressure or viscosity. In some aspects, the pharmaceutical formulation disclosed herein has ≥ (greater than or equal to) 95% monomer content, ≤ (less than or equal to) 5.0% dimer content or low molecular weight material content after being stored at 2 ° C-8 ° C for up to 36 months. There is no significant difference. In some aspects, the pharmaceutical formulation disclosed herein has ≥ (greater than or equal to) 90% purity after being stored at 2 ° C-8 ° C for up to 36 months. In some aspects, the pharmaceutical formulation disclosed herein has a main substance content of 50% to 90%, an acidic substance content of 10% to 40%, and / or a basic substance content of 0% to 20% after storage for up to 36 months at 2°C-8°C. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in sub-visible particle content after storage for up to 36 months at 2°C-8°C, 25°C or 40°C. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in the oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or the deamidation of asparagine 317 of TEV-48574 after storage for up to 36 months at 2°C-8°C, 25°C or 40°C. In some aspects, the pharmaceutical formulation disclosed herein has a relative potency of 70% to 135% measured by enzyme-linked immunosorbent assay (ELISA) after storage for up to 36 months at 2°C-8°C. In some aspects, the pharmaceutical formulations disclosed herein have no significant differences in thermal stability after storage at 2°C-8°C, 25°C, or 40°C for up to 6 months.In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in thermal stability after being stored at 2°C-8°C for up to 36 months. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in secondary and / or tertiary protein structure after being stored at 2°C-8°C, 25°C or 40°C for up to 3 months. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in secondary protein structure after being stored at 2°C-8°C for up to 36 months. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in the concentration of polysorbate-80 after being stored at 2°C-8°C for up to 24 months.

[0053] Also provided herein is a container comprising a pharmaceutical formulation disclosed herein. In some aspects, the container is a glass vial. In some aspects, the container is a glass vial with a 3 mL fill volume. In some aspects, the container is a syringe, such as a pre-filled syringe. In some aspects, the pre-filled syringe has a volume of 2 mL or less.

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

[0055] In some aspects, provided herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject any pharmaceutical formulation provided herein, including a pharmaceutical formulation in any container provided herein. In some aspects, the disease is a gastrointestinal disease.

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

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

[0058] Also provided herein is a composition for use according to the methods disclosed herein.

[0059] Also provided herein is a pharmaceutical formulation comprising: (a) 150 mg / mL of 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: (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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. NO: light chain of the amino acid sequence of 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 aspects, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

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

[0061] In some aspects, the drug formulation is stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having an osmotic pressure of from 200mOsm / kg to 500mOsm / kg. In some aspects, the drug formulation has at least 99% antibody monomer content after being stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the drug formulation has no significant change in charge heterogeneity characteristics after being stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the drug formulation has no significant change in purity after being stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the drug formulation has at least 90% purity after being stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days. In some aspects, the pharmaceutical formulation is stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after there is no significant change in particle concentration. In some aspects, the pharmaceutical formulation is stored at 2 ° C-8 ° C for up to 36 months and there is no significant difference in visual appearance. In some aspects, the pharmaceutical formulation disclosed herein is stored at 2 ° C-8 ° C, 25 ° C or 40 ° C for up to 36 months and there is no significant difference in protein concentration, osmotic pressure or viscosity. In some aspects, the pharmaceutical formulation disclosed herein has ≥ (greater than or equal to) 95% monomer content, ≤ (less than or equal to) 5.0% dimer content or low molecular weight material content after being stored at 2 ° C-8 ° C for up to 36 months. There is no significant difference. In some aspects, the pharmaceutical formulation disclosed herein has ≥ (greater than or equal to) 90% purity after being stored at 2 ° C-8 ° C for up to 36 months. In some aspects, the pharmaceutical formulation disclosed herein has a main substance content of 50% to 90%, an acidic substance content of 10% to 40%, and / or a basic substance content of 0% to 20% after storage for up to 36 months at 2°C-8°C. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in sub-visible particle content after storage for up to 36 months at 2°C-8°C, 25°C or 40°C. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in the oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or the deamidation of asparagine 317 of TEV-48574 after storage for up to 36 months at 2°C-8°C, 25°C or 40°C. In some aspects, the pharmaceutical formulation disclosed herein has a relative potency of 70% to 135% measured by enzyme-linked immunosorbent assay (ELISA) after storage for up to 36 months at 2°C-8°C. In some aspects, the pharmaceutical formulations disclosed herein have no significant differences in thermal stability after storage at 2°C-8°C, 25°C, or 40°C for up to 6 months.In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in thermal stability after being stored at 2°C-8°C for up to 36 months. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in secondary and / or tertiary protein structure after being stored at 2°C-8°C, 25°C or 40°C for up to 3 months. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in secondary protein structure after being stored at 2°C-8°C for up to 36 months. In some aspects, the pharmaceutical formulation disclosed herein has no significant difference in the concentration of polysorbate-80 after being stored at 2°C-8°C for up to 24 months.

[0062] Also provided herein is a container comprising a pharmaceutical formulation disclosed herein. In some aspects, the container is a glass vial. In some aspects, the container is a glass vial with a 3 mL fill volume.

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

[0064] Also provided herein is a composition for use according to the methods disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 A schematic diagram of the screening, treatment, and follow-up periods of the study described in Example 1 is shown. CD = Crohn's disease; FU = follow-up; I / E = inclusion / exclusion; ID = induction dose; LD = loading dose; PBO = placebo; SES-CD = simplified endoscopic score for Crohn's disease; UC = ulcerative colitis.

[0066] Figures 2A-2C Three TEV-48574 formulations (F1-F3) are shown at 2°C-8°C ( Figure 2A )、25℃( Figure 2B ) and 40℃( Figure 2C ) after storage under .

[0067] Figures 3A-3C Three TEV-48574 formulations (F1-F3) are shown at 2°C-8°C ( Figure 3A )、25℃( Figure 3B ) and 40℃( Figure 3C ) after storage at 4 °C.

[0068] Figures 4A-4C Three TEV-48574 formulations (F1-F3) are shown at 2°C-8°C ( Figure 4A )、25℃( Figure 4B ) and 40℃( Figure 4C) after storage under low molecular weight (LWM) protein fragment composition percentage (%).

[0069] Figures 5A-5C Three TEV-48574 formulations (F1-F3) are shown at 2°C-8°C ( Figure 5A )、25℃( Figure 5B ) and 40℃( Figure 5C ) after storage under 4% purity, determined using CGE non-reducing conditions (IgG+125 kDa peak %).

[0070] Figures 6A-6C Three TEV-48574 formulations (F1-F3) are shown at 2°C-8°C ( Fig. 6A )、25℃( Figure 6B ) and 40℃( Figure 6C ) after storage under reduced pressure, determined using CGE reducing conditions (heavy chain + light chain %).

[0071] Figures 7A-7C It is shown that the formulations 1-3 (F1-F3) at 2°C-8°C ( Fig. 7A )、25℃( Figure 7B ) and 40℃( Figure 7C ) after storage under , as the percentage (%) of the main species (main peak).

[0072] Figures 8A-8C It is shown that the formulations 1-3 (F1-F3) at 2°C-8°C ( Fig. 8A )、25℃( Figure 8B ) and 40℃( Figure 8C ) after storage under , expressed as the percentage (%) of acidic substances (acidic peak).

[0073] Figures 9A-9C It is shown that the formulations 1-3 (F1-F3) at 2°C-8°C ( Fig.9A )、25℃( Fig. 9B ) and 40℃( Fig. 9C ) after storage under , expressed as the percentage (%) of basic substances (basic peak).

[0074] Fig. 10A The thermal stability of Formulations 1-3 (F1-F3) at time zero (T0) and after 3 months storage at 2-8°C, 25°C and 40°C is shown.

[0075] Fig. 10B The thermal stability of Formulations 1-3 (F1-F3) at time zero (TO) and after 6 months storage at 2-8°C, 25°C and 40°C is shown.

[0076] Fig. 10C Shown are the thermal stabilities of Formulations 1-3 (F1-F3) at time zero (TO) and after storage for 36 months at 2-8°C.

[0077] Fig.11A Shown are the secondary structures of Formulations 1-3 at time zero (T0) and after 3 months storage at 2-8°C, 25°C, and 40°C, as determined using far ultraviolet (UV) circular dichroism (CD).

[0078] Fig. 11B Shown are the secondary structures of Formulations 1-3 at time zero (TO) and after storage for 24 months at 2-8°C, as determined using far UV CD.

[0079] Fig. 11C Shown are the secondary structures of Formulations 1-3 at time zero (T0) and after storage for 36 months at 2°C-8°C, as determined using far UV CD.

[0080] Fig.11D Shown are the tertiary structures of Formulations 1-3 at time zero (TO) and after storage for 6 months at 2-8°C, 25°C and 40°C, as determined using near UV CD.

[0081] Fig.11E Shown are the tertiary structures of Formulations 1-3 at time zero (TO) and after storage for 24 months at 2-8°C, as determined using near UV CD.

[0082] Fig.11F Shown are the tertiary structures of Formulations 1-3 at time zero (TO) and after storage for 36 months at 2-8°C, as determined using near UV CD.

[0083] Fig.12 Schematic diagram showing the screening, treatment and follow-up periods of the study described in Example 4. CD = Crohn's disease; FU = follow-up; I / E = inclusion / exclusion criteria; MD = maintenance dose; SES CD = simplified endoscopic Crohn's score; UC = ulcerative colitis; LTE = long-term extension.

[0084] Fig.13A Shown are the secondary structures 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) at 2°C-8°C, and after 3 months (3M) and 6 months (6M) at 25°C and 40°C, as determined using far UV CD.

[0085] Fig. 13BShown is the tertiary structure of Formulation 3 stored in a Nipro prefilled syringe (PFS) at time zero (T0) and after 3 months (3M), 6 months (6M) and 24 months (24M) storage at 2°C-8°C, and after 3 months (3M) and 6 months (6M) storage at 25°C and 40°C, as determined using near UV CD.

[0086] Fig.14A Shown are the monomer composition percentages (%) of a 100 mg / mL lyophilized TEV-48574 formulation (F4) and a 200 mg / mL liquid TEV-48574 formulation (F5) after storage at 2°C-8°C for up to 24 months.

[0087] Fig. 14B Shown are the dimer composition percentage (%) of a 100 mg / mL lyophilized TEV-48574 formulation (F4) and a 200 mg / mL liquid TEV-48574 formulation (F5) after storage at 2°C-8°C for up to 24 months.

[0088] Fig. 14C Shown are the percentage (%) of low molecular weight species for a 100 mg / mL lyophilized TEV-48574 formulation (F4) and a 200 mg / mL liquid TEV-48574 formulation (F5) after storage at 2°C-8°C for up to 24 months.

[0089] Fig.15A Shown are the percent (%) purity of two TEV-48574 formulations (F4 and F5) after storage at 2°C-8°C for up to 24 months, as determined using CGE non-reducing conditions (IgG+125 kDa peak %).

[0090] Fig. 15B Shown are the percent (%) purity of two TEV-48574 formulations (F4 and F5) after storage at 2°C-8°C for up to 24 months, as determined using CGE reducing conditions (heavy chain (HC) + light chain (LC) %).

[0091] Fig.16A The charge heterogeneity characteristics of Formulations 4 and 5 (F4 and F5) after storage at 2°C-8°C for up to 24 months are shown as the percentage (%) of the major species (main peak).

[0092] Fig. 16B Shown are the charge heterogeneity characteristics of Formulations 4 and 5 (F4 and F5) after storage at 2°C-8°C for up to 24 months, expressed as the percentage (%) of acidic species (acidic peak).

[0093] Fig. 16CShown are the charge heterogeneity characteristics of Formulations 4 and 5 (F4 and F5) after storage at 2°C-8°C for up to 24 months, expressed as the percentage (%) of basic material (basic peak).

[0094] Fig.17A Shown are the secondary structures of Formulation 4 at time zero (T0) and after 3 months (3M), 6 months (6M) and 12 months (12M) storage at 25°C, and Formulation 5 at T0 and after 3M and 12M storage at 25°C, as determined using far UV CD.

[0095] Fig. 17B Shown are the tertiary structures of Formulation 4 at time zero (T0) and after 3 months (3M) and 12 months (12M) storage at 25°C, and Formulation 5 at T0 and after 3M, 6 months (6M) and 12M storage at 25°C, as determined using near UV CD.

[0096] Fig.18 Shown are the viscosities of liquid formulations at 20°C with increasing concentrations of TEV-48574 (0 to 150 mg / mL), with the addition of 100 mM arginine-HCl as an excipient (1A) or without the addition of arginine-HCl (1B).

[0097] Fig.19A Shown are the monomer composition percentages (%) of two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after storage at 40°C for up to 8 weeks.

[0098] Fig.19B Shown are the dimer composition percentage (%) of two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after storage at 40°C for up to 8 weeks.

[0099] Fig.19C Shown are the percentage (%) of fragments after storage at 40°C for up to 8 weeks for two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl.

[0100] Fig. 20A Shown are the percent (%) purity of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 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, as determined using CGE non-reducing conditions (IgG+125 kDa peak %).

[0101] Fig. 20B Shown are the percent purity (%) of two liquid TEV-48574 formulations at 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 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, as determined using CGE reducing conditions (heavy chain (HC) + light chain (LC) %).

[0102] Fig.21A Shown are the charge heterogeneity characteristics of two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after storage at 40°C for up to 8 weeks as the percentage (%) of the main species (main peak).

[0103] Fig. 21B Shown are the charge heterogeneity characteristics of two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after storage at 40°C for up to 8 weeks, expressed as the percentage (%) of acidic species (acidic peak).

[0104] Fig. 21C Shown are the charge heterogeneity characteristics of two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl after storage at 40°C for up to 8 weeks, expressed as the percentage (%) of basic species (basic peak).

[0105] Fig. 22 Shown are the thermal stabilities at time zero (T0) of two liquid TEV-48574 formulations of 150 mg / mL (1A) and 100 mg / mL (2A) with the addition of 100 mM arginine-HCl and two liquid TEV-48574 formulations of 150 mg / mL (1B) and 100 mg / mL (2B) without arginine-HCl.

[0106] Fig.23A Total TL1A measured in 3 cynomolgus monkeys treated with a single subcutaneous dose of TEV-48574 at a dose level of 5 mg / kg is shown. Blood sampling was performed on Day 0 (pre-dose), Day 0.25, 1, 2, 3, 4, 5, 7, 9, 11, 14, 21, 28, and 35. Bars represent mean + / - standard error of the mean (SEM). BLQ (below limit of quantitation) was set at 2.5 pg / mL (0.5*LLOQ (lower limit of quantitation)).

[0107] Fig. 23B Shown are free TL1A measured in 4 cynomolgus monkeys treated with a single subcutaneous dose of TEV-48574 at a dose level of 5 mg / kg. Blood sampling was performed on Day 0 (pre-dose), Day 0.25, 1, 2, 3, 4, 5, 7, 9, 11, 14, 21, 28, and 35. Bars represent mean + / - standard error of the mean (SEM). BLQ (below limit of quantitation) was set at 2.5 pg / mL (0.5*LLOQ (lower limit of quantitation)).

[0108] Fig.24A Shown are simulated TEV-48574 concentrations for a 2250 mg loading dose and a 900 mg Q2W or Q4W maintenance regimen compared to expected exposure to RVT-3101 following administration of 50 mg, 150 mg, or 450 mg according to a Q4W regimen.

[0109] Fig. 24B Shown are simulated TEV-48574 concentrations for a 2250 mg loading dose and a 450 mg Q2W or Q4W maintenance regimen compared to expected exposure to RVT-3101 following administration of 50 mg, 150 mg, or 450 mg according to a Q4W regimen.

[0110] Fig.25 A schematic diagram showing the screening, treatment, and follow-up periods of 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 endoscopic score for Crohn's disease; UC = ulcerative colitis.

[0111] Fig.26Schematic diagram showing the screening, treatment and follow-up periods of the long-term extension study described in Example 9. CD = Crohn's disease; FU = follow-up; I / E = inclusion / exclusion criteria; MD = maintenance dose; SES CD = simplified endoscopic Crohn's score; UC = ulcerative colitis; LTE = long-term extension. DETAILED DESCRIPTION

[0112] In order to more easily understand the present disclosure, some terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms should have the meaning described below. Additional definitions are set forth throughout the application. definition

[0113] Various terms related to various aspects of the present disclosure are used throughout this specification and claims. Unless otherwise specified, such terms will be given their ordinary meanings in the art. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0114] The term "antibody" means an immunoglobulin molecule that is recognized by at least one antigen recognition site in the variable region of an immunoglobulin molecule and specifically binds to a target (such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination thereof). As used herein, the term "antibody" encompasses complete polyclonal antibodies, complete monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising antibodies, and any other modified immunoglobulin molecules, as long as these antibodies exhibit the desired biological activity. The antibody can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM (referred to as α, δ, ε, γ, and μ, respectively, based on the identity of their heavy chain constant domains), or its subclass (isotype) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. The antibody can be a naked antibody or conjugated with other molecules (such as radioisotopes).

[0115] In the absence of explicit indication, and unless the context indicates otherwise, the term "antibody" includes monospecific antibodies, bispecific antibodies, or multispecific antibodies. In some aspects, the antibody is a bispecific antibody. The term "bispecific antibody" refers to an antibody that binds to two different epitopes.

[0116] The term "antibody fragment" refers to a part of a complete antibody. "Antigen binding fragment", "antigen binding domain" or "antigen binding region" refers to a part of a complete antibody that binds to an antigen. In the context of bispecific antibodies, an "antigen binding fragment" binds two antigens. An antigen binding fragment may contain the antigen recognition site of a complete antibody (e.g., a complementary determining region (CDR) sufficient to specifically bind to an 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, such as rodents (e.g., mice, rats or hamsters) and humans, or may be artificially produced.

[0117] "Monoclonal" antibody or its antigen binding fragment refers to a homogeneous antibody or antigen binding fragment population that participates in a single antigenic determinant or epitope with high specificity. This is in contrast to polyclonal antibodies that typically include different antibodies for different antigenic determinants. The term "monoclonal" antibody or its antigen binding fragment encompasses complete and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single-chain (scFv) mutants, fusion proteins comprising antibody portions, and any other modified immunoglobulin molecules comprising antigen recognition sites. In addition, "monoclonal" antibody or its antigen binding fragment refers to such antibodies and their antigen binding fragments prepared in any number of ways, including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0118] As used herein, the terms "variable region" or "variable region domain" are used interchangeably and are common in the art. A variable region typically refers to a part of an antibody, usually a part of a light chain or a heavy chain, typically around the amino terminal 110 to 120 amino acids or 110 to 125 amino acids in a mature heavy chain and about 90 to 115 amino acids in a mature light chain, whose sequence is different between antibodies and is used for the binding and specificity of a specific antibody to its specific antigen. The variability of the sequence is concentrated in those regions called complementary determining regions (CDRs), while the more highly conserved regions in the variable domains are referred to as framework regions (FRs). Without wishing to be constrained by any particular mechanism or theory, it is believed that the CDRs of light and heavy chains are primarily responsible for the interaction and specificity of antibodies to antigens. In some aspects of the present disclosure, the variable region is a human variable region. In some aspects of the present disclosure, the variable region comprises rodent or mouse CDRs and human framework regions (FRs). In a particular aspect of the present disclosure, the variable region is a primate (e.g., non-human primate) variable region. In some aspects of the disclosure, the variable regions comprise rodent or murine CDRs and primate (eg, non-human primate) framework regions (FRs).

[0119] The terms "VL" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody.

[0120] The terms "VH" and "VH domain" are used interchangeably to refer to the heavy chain variable region of an antibody.

[0121] The term "Kabat numbering" and similar terms are well-known in the art, and refer to a system in which the amino acid residues in the heavy chain and light chain variable region of an antibody or its antigen-binding fragment are numbered. In some aspects, CDR can be determined according to the Kabat numbering system (see, for example, Kabat EA and Wu TT (1971) Ann NY Acad Sci [Annuals of the New York Academy of Sciences] 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest [sequences of immunology-related proteins], the 5th edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDR in the antibody heavy chain molecule is typically present in amino acid positions 31 to 35 (which optionally can include one or two additional amino acids (referred to as 35A and 35B in the Kabat numbering scheme) after 35) (CDR1), amino acid positions 50 to 65 (CDR2) and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molecule typically occur at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).

[0122] Chothia refers to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). When numbered using the Kabat numbering convention, the ends of the Chothia CDR-H1 loop vary between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion 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; 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.

[0123] As used herein, the terms "constant region" or "constant domain" are interchangeable and have common meanings in the art. The constant region is an antibody portion, such as the carboxyl terminal portion of a light chain and / or a heavy chain, which is not directly involved in the binding of the antibody to an antigen, but can exhibit various effector functions, such as interactions with Fc receptors. The constant region of an immunoglobulin molecule typically has an amino acid sequence that is more conservative relative to an immunoglobulin variable domain. In some aspects, an antibody or antigen-binding fragment comprises a constant region or portion thereof sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC).

[0124] As used herein, the term "heavy chain" when used with respect to an antibody can refer to any of the different types, such as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the constant domain, which respectively produce the IgA, IgD, IgE, IgG, and IgM classes of antibodies, including subclasses of IgG, such as IgG1, IgG2, IgG3, and IgG4. Heavy chain amino acid sequences are well known in the art. In some aspects of the present disclosure, the heavy chain is a human heavy chain.

[0125] As used herein, the term "light chain" when used with respect to an antibody can refer to any of the different types, such as kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. In some aspects of the present disclosure, the light chain is a human light chain.

[0126] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof in which the amino acid sequence is 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 derived from one mammalian species (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capacity, while the constant regions are homologous to sequences in an antibody or antigen-binding fragment thereof derived from another species (usually human) to avoid eliciting an immune response in this species.

[0127] The term "humanized" antibody or antigen-binding fragment thereof refers to a form of a non-human (e.g., murine) antibody or antigen-binding fragment that is a specific immunoglobulin chain, chimeric immunoglobulin, or fragment thereof containing minimal non-human (e.g., murine) sequence. Typically, a humanized antibody or antigen-binding fragment thereof is a human immunoglobulin in which residues from a complementary determining region (CDR) are replaced with residues from a CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) with the desired specificity, affinity, and capacity ("CDR-grafted") (Jones et al., Nature [Nature] 321: 522-525 (1986); Riechmann et al., Nature [Nature] 332: 323-327 (1988); Verhoeyen et al., Science [Nature] 239: 1534-1536 (1988)). In some cases, some Fv framework region (FR) residues of human immunoglobulin are replaced by corresponding residues with desired specificity, affinity and ability in antibodies or fragments from non-human species. Humanized antibody or its Fab can be further modified by replacing other residues in Fv framework region and / or in non-human CDR residues, to improve and optimize the specificity, affinity and / or ability of antibody or its Fab. Usually, humanized antibody or its Fab will comprise variable domains, and these variable domains contain all or substantially all CDR regions corresponding to non-human immunoglobulin, and all or substantially all FR regions are those FR regions of human immunoglobulin consensus sequence. Humanized antibody or its Fab can also comprise at least a portion of immunoglobulin constant region or domain (Fc), typically at least a portion of constant region or domain of human immunoglobulin. Examples of methods for generating humanized antibodies are described in: U.S. Pat. No. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA [Proceedings of the National Academy of Sciences of the United States of America], 91(3):969-73 (1994), and Roguska et al., Protein Eng. [Protein Engineering] 9(10):895-904 (1996). In some aspects of the present disclosure, a "humanized antibody" is a resurfaced antibody.

[0128] The term "human" antibody or antigen-binding fragment thereof refers to an antibody or antibody-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin locus, wherein such antibody or antigen-binding fragment is prepared using any technique known in the art. This definition of human antibodies or antigen-binding fragments thereof includes complete or full-length antibodies and fragments thereof.

[0129] "Binding affinity" generally refers to the strength of the sum 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 indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody or antigen-binding fragment thereof and an antigen). The affinity of a molecule X for its partner Y can generally be expressed as a dissociation constant (KD). Affinity can be measured and / or expressed in a variety of ways known in the art, including, but not limited to, the equilibrium dissociation constant (KD) and the equilibrium association constant (KA). KD is given by k off / k on , and KA is calculated by k off / k on The quotient of K is calculated. on refers to, for example, the association rate constant of an antibody or antigen-binding fragment thereof with an antigen, and k off Refers to, for example, the dissociation of an antibody or its antigen-binding fragment from an antigen. on and k off This can be done by techniques known to those of ordinary skill in the art (such as or KinExA) to determine.

[0130] As used herein, "epitope" is a term in the art, and refers to a local region of an antigen to which an antibody or its Fab can specifically bind. An epitope can be, for example, a continuous amino acid (linear or continuous epitope) of a polypeptide, or an epitope can be, for example, from two or more non-continuous regions (conformational, non-linear, discontinuous or non-continuous epitopes) of one or more polypeptides. In some aspects of the present disclosure, the epitope to which an antibody or its Fab specifically binds can be determined by, for example, NMR spectroscopy, X-ray diffraction crystallography, ELISA assay, hydrogen / deuterium exchange coupled to 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 method known in the art (e.g., Giege R et al., (1994) Acta Crystallogr DBiol 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 comprising an antigen in complex with an antibody or antigen-binding fragment can be studied using well-known X-ray diffraction techniques and can be improved using computer software such as X-PLOR (Yale University, 1992, published by Molecular Simulations, Inc.; see, e.g., Meth Enzymol (1985) Vols. 114 and 115, Wyckoff HW et al., eds.; US2004 / 0014194) and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1):37-60; Bricogne G (1997) Meth Enzymol 276A:361-423, Carter CW ed.; Roversi P et al., (2000) Acta Crystallogr D Biol Crystallogr 50(Pt 2):54-57. Crystallogr [Acta Crystallogrica Sinica D - Structural Biology] 56 (Pt 10): 1316-1323). Mutagenesis mapping studies can be performed using any method known to those skilled in the art.For a description of mutagenesis techniques, including alanine scanning mutagenesis, see, for example, Champe M et al., (1995) J Biol Chem 270: 1388-1394 and Cunningham BC & Wells JA (1989) Science 244: 1081-1085.

[0131] "Separated" polypeptides, antibodies, polynucleotides, vectors, cells or compositions are polypeptides, antibodies, polynucleotides, vectors, cells or compositions that are in a form that does not exist in nature. Separated polypeptides, antibodies, polynucleotides, vectors, cells or compositions include those that have been purified to the extent that they are no longer in the form in which they are found in nature. In some aspects of the present disclosure, separated antibodies, polynucleotides, vectors, cells or compositions are substantially pure. As used herein, "substantially pure" refers to at least 50% pure (i.e., free of contaminants), at least 90% pure, at least 95% pure, at least 98% pure or at least 99% pure material.

[0132] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. A polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included in the definition are, for example, polypeptides containing one or more analogs of amino acids (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art. It should be understood that because the polypeptides of the present disclosure are antibody-based, in some aspects of the present disclosure, the polypeptides may exist as single chains or associated chains.

[0133] As used herein, the term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient to be effective and does not contain additional components that are unacceptably toxic to the subject to which the formulation is to be administered. The formulation can be sterile. In some aspects, the formulation is suitable for therapeutic use in human subjects.

[0134] As used herein, the terms "administer / administering / administration" and the like refer to methods that can be used to enable delivery of a drug (e.g., an anti-TL1A antibody or 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 found, 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).

[0135] As used herein, the term "combination" or "administered in combination" means that the antibodies or antigen-binding fragments thereof described herein can be administered together with one or more additional therapeutic agents. In some aspects of the combinations provided herein, the antibodies or antigen-binding fragments thereof can be administered simultaneously or sequentially with one or more additional therapeutic agents. In some aspects, the antibodies or antigen-binding fragments thereof described herein can be administered together with one or more additional therapeutic agents in the same composition or in different compositions.

[0136] The terms "subject" and "patient" are used interchangeably and include any animal. In some aspects, the subject is a mammal, including companions (e.g., cats, dogs) and farm mammals (e.g., pigs, horses, cattle) and rodents, including mice, rabbits and rats, guinea pigs and other rodents. In some aspects, the subject is a non-human primate, such as a cynomolgus monkey. In some aspects, the subject is a human.

[0137] The term "therapeutically effective amount" refers to an amount of a drug (e.g., an anti-TL1A antibody (e.g., TEV-48574) or an antigen-binding fragment thereof) that is effective to treat a disease or disorder in a subject. Terms such as "treating / treatment / to treat" and "alleviating / to alleviate" refer to utilizing a method to obtain a beneficial or desired clinical result, including but not limited to methods for achieving such a beneficial or desired clinical result, wherein the clinical result may include a therapeutic measure that improves, cures, alleviates, attenuates the symptoms of a pathological condition or disorder, and / or stops the progression of a pathological condition or disorder. Those in need of treatment may include those who have been diagnosed with a disorder or are suspected of having a disorder.

[0138] In the context of antibody-antigen interactions, "specificity" is not necessarily an absolute term, but can constitute a relative term, indicating the degree of selectivity of the antibody for antigen-positive cells compared to antigen-negative cells. The specificity of the antibody for antigen-positive cells is mediated by the variable region of the antibody, and usually by the complementarity determining region (CDR) of the antibody. The construct can have from about 100-fold to about 1000-fold specificity for antigen-positive cells compared to antigen-negative cells.

[0139] As used herein, the term "recombinant" includes the expression of genes produced by genetic engineering or otherwise by laboratory manipulation.

[0140] As used herein, the term "TEV 48574" or "TEV-48574" refers to a highly potent, fully human immunoglobulin G (IgG) subclass 1 (IgG1) (λ) monoclonal antibody (mAb) that binds to human, cynomolgus monkey, and rat TL1A with high affinity. 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, the antibody prevents activation of the DR3 signaling pathway. TEV-48574 also inhibits the binding of TL1A to DcR3, although TEV-48574 inhibits the TL1A-DR3 interaction more than the TL1A-DcR3 interaction. TEV-48574 exhibits 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 as "320-587" in US Patent No. 10,138,296, which is incorporated herein by reference in its entirety.

[0141] 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, which is expressed by antigen presenting cells (including dendritic cells, B cells and macrophages), CD4+ and CD8+ T cells and endothelial cells. TL1A can be expressed on the cell surface or secreted as a soluble cytokine. TL1A's cognate signaling receptor death receptor 3 (DR3) is expressed by a variety of cells, including CD4+ and CD8+ T cells, NK cells, NKT cells and FOXP3+ regulatory T (Treg) cells and type 2 and type 3 innate lymphoid cells (ILC2 and ILC3). TL1A can also bind to a decoy receptor (DcR3), which is a competitive inhibitor of DR3. DcR3 also acts as a decoy receptor for Fas-ligand (Fas-L) and lymphotoxin-like inducible protein, which competes with glycoprotein D for binding to herpes virus entry mediator (LIGHT) on T cells. Thus, DcR3 is an important regulator of several signal transduction pathways.

[0142] As used herein, "moderate to severe ulcerative colitis," "moderate to severe ulcerative colitis (UC)," or "moderate to severe UC" refers to UC with a 3-component modified Mayo score of 5 to 9 (inclusive), with an endoscopic score ≥ (greater than or equal to) 2 (from a central read).

[0143] The 3-component modified Mayo score is based on the following 3 parameters: bowel movement frequency, rectal bleeding, and endoscopic evaluation. Each parameter of the score ranges from 0 (normal or inactive disease) to 3 (severe activity), and the total score ranges from 0 to 9. (Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry. US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). August 2016; Naegeli et al., Am J Gastroenterol [American Journal of Gastroenterology]; 113: S384 (2018)). Determination of disease severity by 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 EMAand FDA Guidelines on Ulcerative Colitis Drug Development. Clin Gastroenterol Hepatol; 17(9): 1673-1679.e1 (2019)).

[0144] 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 ≥ (greater than or equal to) 220 and ≤ (less than or equal to) 450. (Yoshida EM. Can J Gastroenterol [Canadian Journal of Gastroenterology and Hepatology]; 13(1): 65-73 (1999))

[0145] As used herein, the term "has an inadequate response, loss of response, or intolerance to one or more agents" refers to having an inadequate response, loss of response, or intolerance to conventional therapies (e.g., small molecules) and / or biological agents. The following is provided by way of example. Inadequate response, loss of response, or intolerance to corticosteroid therapy is defined as 1 or more of the following: a. Steroid-refractory: persistent symptoms of active disease despite treatment with at least a 4-week induction regimen that included daily doses of ≥ (greater than or equal to) 30 mg of prednisone (orally) for at least 2 weeks or intravenously (iv) for at least 1 week within the previous 5 years; b. Steroid dependence: 2 failed attempts to reduce steroids to a dose below the equivalent of 10 mg prednisone (oral) per day within the previous year; and c. Steroid Intolerance: History of intolerance to corticosteroids within the previous 5 years (including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia, and infection). Inadequate response, loss of response, or intolerance to previous immunosuppressive therapy defined by 1 or more of the following: a. Persistent signs and symptoms of active disease despite a history of at least a 12-week regimen of oral AZA (≥(greater than or equal to) 2 to 2.5 mg / kg / day) or 6-MP (≥(greater than or equal to) 1 to 1.5 mg / kg / day) and / or methotrexate (≥(greater than or equal to) 25 mg / week); and 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, genetic mutations in thiopurine methyltransferase, and infection). Inadequate response, loss of response, or intolerance to prior biologics or small molecules defined as 1 or more of the following: a. Loss of response: persistent signs and symptoms of active disease despite at least one induction and one maintenance regimen of a locally approved anti-TNF inhibitor, anti-integrin, anti-IL-12 / 23 monoclonal antibody, JAK inhibitor, or S1P receptor modulator. b. Inadequate response (primarily non-response): persistent signs and symptoms of active disease despite at least one induction regimen at the highest dose of a locally approved anti-TNF inhibitor, anti-integrin, anti-IL-12 / 23 mAb, JAK inhibitor, or S1P receptor modulator. c. Intolerance: Discontinuation of anti-TNF inhibitors, anti-integrins, anti-IL-12 / 23 monoclonal antibodies, JAK inhibitors, or S1P receptor modulators due to adverse drug reactions, as determined by the attending physician. Such adverse drug reactions include, but are not limited to, nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphocytopenia, and infection.

[0146] As used herein, the term "clinical remission" of ulcerative colitis refers to clinical remission as determined by: Clinical remission is a modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score ≤ (less than or equal to) 2 points, which is defined by: The stool frequency subscore is 0 or 1, Rectal bleeding subscore of 0, and Endoscopic score is 0 or 1, where score 1 does not include "friability"

[0147] As used herein, the term "endoscopic response" in Crohn's disease refers to endoscopic response as determined by: Endoscopic response was defined as a reduction of at least 50% from baseline in the simplified endoscopic score for Crohn's disease (SES-CD).

[0148] As used in the disclosure and claims, the singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise.

[0149] It should be understood that wherever aspects of the present disclosure are described herein with the language "comprising," otherwise similar aspects described with the phrases "consisting of" and / or "consisting essentially of" are also provided.

[0150] Unless expressly stated or obvious from the context, as used herein, the term "or" is to be understood to be inclusive. The term "and / or" as used in phrases such as "A and / or B" herein is intended to include both "A and B", "A or B", "A" and "B". Similarly, the term "and / or" as used in phrases such as "A, B and / or C" is intended to cover each of the following: 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).

[0151] 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 the value or range remains within the intended meaning of the listed value or range. As will be appreciated by those skilled in the art, references herein to "about" values ​​or ranges include (and describe) references to the value or range itself. For example, a description referring to "about X" includes a description of "X".

[0152] Any composition or method provided herein can be combined with one or more of any other compositions and methods provided herein.

[0153] Units, prefixes and symbols are all expressed in the form accepted by the International System of Units (SI). Numerical ranges include numbers that limit the range. The titles provided herein are not limitations on the various aspects of the present disclosure, which can be obtained by reference to the entire specification. Therefore, the terms of the definitions immediately below are more fully defined by reference to the specification (in its entirety). method

[0154] 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 for treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject previously had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject previously had an inadequate response, loss of response, or intolerance to at least one agent described in part (a), 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 aspects, 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 a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator.

[0155] 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 suffers from moderate to severe ulcerative colitis or moderate to severe Crohn's disease; and (b) if the subject suffers from 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 aspects, the method comprises not administering a composition comprising an antibody or antigen-binding fragment thereof that specifically binds to TL1A if the subject does not suffer from moderate to severe ulcerative colitis or moderate to severe Crohn's disease.

[0156] In some aspects, the antibody or antigen-binding fragment thereof inhibits the ability of TL1A to interact with DR3, and in some aspects, also inhibits the ability of TL1A to interact with DcR3 and further inhibits signal transduction induced by the interaction of TL1A with DR3. In some aspects, the antibody or antigen-binding fragment thereof has enhanced potency relative to antibody 320-179. In some aspects, the antibody or antigen-binding fragment thereof has enhanced affinity for TL1A relative to antibody 320-179.

[0157] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein 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. In some aspects, the antibody or antigen-binding fragment thereof is capable of inhibiting the interaction between TL1A and DR3.

[0158] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7. In some aspects, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, 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.

[0159] In some aspects, the heavy chain variable region is connected to a heavy chain constant region. In some aspects, the heavy chain constant region is an IgG1, IgG2 or IgG4 heavy chain constant region. In some aspects, the heavy chain variable region of SEQ ID NO:7 is connected 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 aspects, the heavy chain constant region provided herein does not comprise a C-terminal lysine. In some aspects, the light chain variable region of SEQ ID NO:8 is connected to a lambda human light chain constant region (e.g., SEQ ID NO:29) such that the light chain comprises SEQ ID NO:10.

[0160] In some aspects, the antibodies or antigen-binding fragments thereof as disclosed herein are monoclonal antibodies or antigen-binding fragments thereof.

[0161] In some aspects, the antibody or antigen-binding fragment thereof disclosed herein is a recombinant antibody or antigen-binding fragment thereof. In some aspects, the recombinant antibody is a full-length antibody. In some aspects, the recombinant antibody is a monoclonal antibody.

[0162] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein binds to TL1A with enhanced affinity relative to the 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 aspects, an antibody or antigen-binding fragment thereof as disclosed herein has enhanced potency relative to the 320-179 anti-TL1A antibody. The enhanced potency can be at least about 10 times, at least about 12 times, at least about 13 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 27 times, at least about 40 times, about 10 times to about 40 times, about 12 times to about 40 times, about 13 times to about 40 times, about 15 times to about 40 times, about 20 times to about 40 times, about 25 times to about 40 times, or about 27 times to about 40 times greater potency relative to the 320-179 anti-TL1A antibody. The potency enhancement factor can be determined in TF-1 cells according to a TL1A-induced caspase potency assay. See, e.g., U.S. Patent No. 10,138,296. The 320-179 antibody has favorable biophysical properties, is an effective inhibitor of TL1A, and has a low predicted immunogenicity profile. U.S. Patent No. 10,138,296 and U.S. Publication No. 2014 / 0255302 are incorporated herein by reference in their entirety.

[0163] In some aspects, an antibody as disclosed herein is TEV-48574, also referred to as the 320-587 antibody in US Pat. No. 10,138,296 (in this disclosure, VH is SEQ ID NO: 3 and VL is SEQ ID NO: 4).

[0164] In some aspects, an antibody or antigen-binding fragment thereof as 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 binds to TL1A with enhanced affinity relative to an 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. Anti-TL1A 320-179 antibodies have been previously described in U.S. Pat. No. 10,138,296 (in this publication, VH is SEQ ID NO: 1 and VL is SEQ ID NO: 2) and U.S. Publication No. 2014 / 0255302 (in this publication, VH is SEQ ID NO: 186 and VL is SEQ ID NO: 199). The 320-179 antibody has favorable biophysical properties, is a potent inhibitor of TL1A, and has a low predicted immunogenicity profile. US Patent No. 10,138,296 and US Publication No. 2014 / 0255302 are incorporated herein by reference in their entirety.

[0165] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region anti-TL1A antibody 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 times, at least about 12 times, at least about 13 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 27 times, or at least about 40 times greater potency relative to the 320-179 anti-TL1A antibody. The potency enhancement factor can be determined in TF-1 human erythroleukemia antibody cells (ATCC: CRL-2003) according to the TL1A-induced caspase potency assay. See, e.g., U.S. Pat. No. 10,138,296.

[0166] In some aspects, the antibodies or antigen-binding fragments thereof as disclosed herein are full-length antibodies. In some aspects, the antibodies as disclosed herein are monoclonal antibodies.

[0167] In some aspects, the antibodies or antigen-binding fragments thereof disclosed herein comprise a human IgG1 heavy chain constant region, a human IgG2 heavy chain constant region, or a human IgG4 heavy chain constant region, or any allotype thereof. The human IgG1 heavy chain constant region may 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 may be selected from 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 may be selected from 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 should be understood that the IgG4 heavy chain can be used without the stabilizing substitution S228P (e.g., IgG4 and YTE alone, IgG4 and YTE and ΔK, or IgG4 and ΔK alone).

[0168] In some aspects, the antibodies or antigen-binding fragments thereof as disclosed herein comprise a human lambda light chain constant region or an allotype thereof. The human light chain lambda constant region may comprise SEQ ID NO:29.

[0169] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein binds to human TL1A, and may bind to one or more of cynomolgus monkey TL1A, mouse TL1A, rat TL1A, guinea pig TL1A, cat TL1A, dog TL1A, pig TL1A, or rabbit TL1A. In some aspects, for example, if the epitope is shared, the antibody or antigen-binding fragment thereof may bind to TL1A of multiple different species. In some aspects, human TL1A comprises the amino acid sequence of SEQ ID NO:34, SEQ ID NO:35, or SEQ ID NO:36. In some aspects, cynomolgus monkey TL1A comprises the amino acid sequence of SEQ ID NO:37. In some aspects, mouse TL1A comprises the amino acid sequence of SEQ ID NO:38. In some aspects, rat TL1A comprises the amino acid sequence of SEQ ID NO:39. In some aspects, guinea pig TL1A comprises the amino acid sequence of SEQ ID NO:40. In some aspects, cat TL1A comprises the amino acid sequence of SEQ ID NO:41. In some aspects, the pig TL1A comprises the amino acid sequence of SEQ ID NO: 42. In some aspects, the rabbit TL1A comprises the amino acid sequence of SEQ ID NO: 43. In some aspects, the dog TL1A comprises the amino acid sequence of SEQ ID NO: 44.

[0170] The antibodies or antigen-binding fragments thereof disclosed herein have a binding affinity for an epitope on TL1A, the binding affinity comprising an equilibrium dissociation constant (K D ), the equilibrium dissociation constant can be determined by kinetic exclusion (such as The K of TL1A binding determined by kinetic exclusion assay was measured using the kinetic exclusion assay (Sapidyne Instruments, Boise, ID). D Less than about 1000 pM. In some aspects, the K of TL1A binding determined by kinetic exclusion assay is D In some aspects, the K of TL1A binding determined by kinetic exclusion assay 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 Less than about 100 pM.

[0171] K of TL1A binding determined by kinetic exclusion assay D The K of TL1A binding determined by kinetic exclusion assay is from about 10 pM to about 100 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 25 pM to about 75 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 30 pM to about 60 pM.D The K of TL1A binding determined by kinetic exclusion assay is from about 30 pM to about 50 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 35 pM to about 50 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 36 pM to about 46 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 38 pM to about 44 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 39 pM to about 43 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 40 pM to about 45 pM. D The K of TL1A binding determined by kinetic exclusion assay is from about 35 pM to about 42 pM. D The K of TL1A binding determined by kinetic exclusion assay is about 40 pM. D The K of TL1A binding determined by kinetic exclusion assay is about 41 pM. D It may be about 42 pM. Kinetic exclusion assays may use either an antibody molecule or a TL1A molecule as a constant binding partner and another molecule as a titrant.

[0172] The antibodies or antigen-binding fragments thereof disclosed herein can bind to TL1A positive cells. The antibodies or antigen-binding fragments thereof disclosed herein can bind to TL1A positive cells with an EC 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. 50 Values ​​were combined with TL1A-positive cells.

[0173] As disclosed herein, the antibody or its antigen-binding fragment can be monoclonal. In some aspects, as disclosed herein, the antibody or its antigen-binding fragment is a full-length antibody comprising two heavy chains and two light chains. In some aspects, as disclosed herein, the antibody or its antigen-binding fragment comprises a derivative or fragment or part of the antibody that retains the antigen-binding specificity of the full-length antibody and also retains most or all of the affinity. For example, the derivative can include at least one variable region (heavy chain or light chain variable region). The derivative can include at least two variable regions, such as 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 multi-epitope specificity, bispecific antibodies, multispecific antibodies, double antibodies, single-chain molecules, and FAb, F(Ab')2, Fd, Fabc and Fv molecules, single-chain (Sc) antibodies, single-chain Fv antibodies (scFv), single antibody light chains, single antibody heavy chains, fusions between antibody chains and other molecules, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy chain and one light chain, and other polymers. Single-chain Fv antibodies can be multivalent. All antibody isotypes can be used to produce antibody derivatives, fragments and parts. Antibody derivatives, fragments and / or parts can be recombinantly produced and expressed by any cell type of prokaryotic or eukaryotic.

[0174] In a full-length antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions can be further subdivided into regions of high variability, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Typically, the antigen binding properties of an antibody are less likely to be disturbed by changes in the FR sequences than by changes in the CDR sequences. The immunoglobulin molecule 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 of immunoglobulin molecule.

[0175] In some aspects, antibodies or their antigen-binding fragments as disclosed herein are fully human. Fully human antibodies are those antibodies wherein the entire molecule is human or otherwise human-derived, or comprising the same amino acid sequence as the human form of the antibody. Fully human antibodies include those obtained from human V gene libraries, for example, wherein the human genes encoding the variable regions of antibodies are recombinantly expressed. Fully human antibodies can be expressed in cells of other organisms (e.g., mice and xenomouse technology) or from other organisms transformed with genes encoding human antibodies. However, fully human antibodies may include amino acid residues not encoded by human sequences, such as mutations introduced by random or site-directed mutagenesis.

[0176] In some aspects, antibodies or antigen-binding fragments thereof as disclosed herein comprise a non-immunoglobulin derived protein framework. For example, reference can be made to Ku and Schutz, Proc. Natl. Acad. Sci. USA, 92:6552-6 (1995), which describes a four-helix bundle protein cytochrome b562 having two randomized loops to generate CDRs that have been selected for antigen binding.

[0177] In some aspects, antibodies or antigen-binding fragments thereof as disclosed herein comprise post-translational modifications or moieties that may affect antibody activity or stability. These modifications or moieties include, but are not limited to, methylated, acetylated, glycosylated, sulfated, phosphorylated, carboxylated and amidated moieties and other moieties well known in the art. Moieties include any chemical group or combination of groups that are often found on immunoglobulin molecules in nature or added to antibodies by recombinant expression systems (including prokaryotic and eukaryotic expression systems).

[0178] Examples of side chain modifications contemplated by the present disclosure include modifications of amino groups, such as reductive alkylation by reaction with an aldehyde followed by reduction with NaBH4; amidination with methyl acetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2,4,6-trinitrobenzenesulfonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH4.

[0179] The guanidinium group of arginine residues can be modified by forming heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal. Carboxyl groups can be formed via O-acylisourea followed by derivatization to, for example, the corresponding amide for modification by carbodiimide activation. Sulfonyl groups can be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; oxidation with performic acid to cysteine; formation of mixed disulfides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimides; formation of mercury derivatives using 4-chloromercurybenzoate, 4-chloromercurybenzenesulfonic acid, phenylmercuric chloride, 2-chloromercury-4-nitrophenol and other mercury compounds; 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 sulfinyl halides. On the other hand, tyrosine residues can be modified by nitration with tetranitromethane to form 3-nitrotyrosine derivatives. Modification of the imidazole ring of histidine residues can be achieved by alkylation with iodoacetic acid derivatives or N-carboethoxylation with diethylpyrocarbonate.

[0180] In some aspects, antibodies or their antigen-binding fragments as disclosed herein comprise one or more modifications that regulate serum half-life and biodistribution, including but not limited to modifications that regulate the interaction of antibodies with neonatal Fc receptors (FcRn), which are receptors that play a key role in protecting IgG from catabolism and maintaining high serum antibody concentrations. Serum half-life regulation modifications can occur in the Fc region of IgG1, IgG2, or IgG4, including triple substitutions of M252Y / S254T / T256E ("YTE" substitutions, numbered according to the EU numbering system (Edelman, GM et al., Proc. Natl. Acad. USA [Proceedings of the National Academy of Sciences of the United States], 63: 78-85 (1969)), as described in U.S. Patent No. 7,083,784. Other substitutions can occur at positions 250 and 428 (see, e.g., U.S. Patent No. 7,217,797) and positions 307, 380, and 434 (see, e.g., PCT Publication No. WO 00 / 042072). Examples of constant domain amino acid substitutions that modulate binding to Fc receptors and subsequent functions mediated by these receptors (including FcRn binding and serum half-life) are described in U.S. Publication Nos. 2009 / 0142340, 2009 / 0068175, and 2009 / 0092599. Antibodies of any class may omit or remove the heavy chain C-terminal lysine to reduce heterogeneity (ΔK). Substitution of S228P (EU numbering) 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 be present simultaneously with YTE and / or ΔK modifications.

[0181] Antibodies or their antigen-binding fragments as disclosed herein can be labeled, bound or conjugated to any chemical or biomolecular moiety. Labeled antibodies can be used for treatment, diagnosis or basic research applications. Such labels / conjugates can be detectable, such as fluorescent dyes, electrochemiluminescent probes, quantum dots, radioactive labels, enzymes, fluorescent proteins, luminescent proteins and biotin.

[0182] The antibodies or antigen-binding fragments thereof as disclosed herein can be derivatized with known protecting / blocking groups to prevent proteolytic cleavage or to enhance activity or stability.

[0183] Administering an antibody or antigen-binding fragment thereof as disclosed herein may include administering the antibody or antigen-binding fragment thereof subcutaneously. Administering may include administering the antibody or antigen-binding fragment thereof intravenously.

[0184] In some aspects, the subject is a human subject. In some aspects, the subject is a non-human primate, such as a cynomolgus monkey. In some aspects, the subject is a non-human mammal, such as a mouse, rat, guinea pig, cat, pig, rabbit or dog.

[0185] In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 300 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 400 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 450 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 600 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 750 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 900 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 1500 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 1750 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 1800 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 2000 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 2250 mg. In some aspects, the antibody or its antigen binding fragment is administered at a dose of about 2500 mg. In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered about once every two weeks. In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered about once every four weeks. In some aspects, the antibody or antigen-binding fragment thereof is administered about once a month.

[0186] In some aspects, the administration comprises administering a loading dose of the antibody or its antigen-binding fragment, followed by administering one or more induction doses of the antibody or its antigen-binding fragment. In some aspects, the administration does not comprise administering a loading dose of the antibody or its antigen-binding fragment.

[0187] In some aspects, the loading dose comprises about 1500 mg of an antibody or an antigen-binding fragment thereof. In some aspects, the loading dose comprises about 1750 mg of an antibody or an antigen-binding fragment thereof. In some aspects, the loading dose comprises about 2000 mg of an antibody or an antigen-binding fragment thereof. In some aspects, the loading dose comprises about 2250 mg of an antibody or an antigen-binding fragment thereof. In some aspects, the loading dose comprises about 2500 mg of an antibody or an antigen-binding fragment thereof. In some aspects, the loading dose is administered about two weeks prior to administering one or more induction doses.

[0188] In some aspects, the one or more induction doses include about 300 mg of an antibody or its antigen-binding fragment. In some aspects, the one or more induction doses include about 400 mg of an antibody or its antigen-binding fragment. In some aspects, the one or more induction doses include about 450 mg of an antibody or its antigen-binding fragment. In some aspects, the one or more induction doses include about 600 mg of an antibody or its antigen-binding fragment. In some aspects, the one or more induction doses include about 750 mg of an antibody or its antigen-binding fragment. In some aspects, the one or more induction doses include about 900 mg of an antibody or its antigen-binding fragment. In some aspects, the one or more induction doses include about 1800 mg of an antibody or its antigen-binding fragment.

[0189] In some aspects, about six induction doses are administered.

[0190] In some aspects, the administration is performed within about 16 weeks. In some aspects, the administration of the one or more induction doses is performed within about 14 weeks. In some aspects, the loading dose is administered about 2 weeks prior to the administration of the one or more induction doses.

[0191] In some aspects, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered about every 2 weeks.

[0192] In some aspects, 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 2 weeks.

[0193] In some aspects, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered about every 4 weeks.

[0194] In some aspects, 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 4 weeks.

[0195] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a loading dose of about 2250 mg 2 weeks prior to an induction dose of about 1800 mg, which is administered every 2 weeks, for example, for about 14 weeks.

[0196] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a loading dose of about 2250 mg 2 weeks prior to administration of an induction dose of about 900 mg, which is administered every 2 weeks, for example, for about 14 weeks.

[0197] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a loading dose of about 2250 mg 2 weeks prior to administration of an induction dose of about 450 mg, which is administered every 2 weeks, for example, for about 14 weeks.

[0198] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a dose of about 300 mg for about 2 weeks.

[0199] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a dose of about 400 mg for about 2 weeks.

[0200] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a dose of about 450 mg for about 2 weeks.

[0201] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered at a dose of about 900 mg for about 2 weeks.

[0202] In some aspects, the administration includes administering one or more maintenance doses of an antibody or its antigen binding fragment. In some aspects, the administration includes administering a loading dose of an antibody or its antigen binding fragment, followed by administering one or more induction doses of an antibody or its antigen binding fragment, followed by administering one or more maintenance doses of an antibody or its antigen binding fragment. In some aspects, the administration includes administering one or more induction doses of an antibody or its antigen binding fragment, followed by administering one or more maintenance doses of an antibody or its antigen binding fragment, wherein the administration does not include administering a loading dose of an antibody or its antigen binding fragment. In some aspects, the administration includes administering one or more maintenance doses of an antibody or its antigen binding fragment, wherein the administration does not include administering a loading dose of an antibody or its antigen binding fragment, and does not include administering an induction dose of an antibody or its antigen binding fragment.

[0203] In some aspects, the one or more maintenance doses comprise about 300 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

[0204] In some aspects, the one or more maintenance doses comprise about 300 mg of the antibody or antigen-binding fragment thereof.

[0205] In some aspects, the one or more maintenance doses comprise about 900 mg of the antibody or antigen-binding fragment thereof.

[0206] In some aspects, the one or more maintenance doses include about 400 mg or about 900 mg of the antibody or its antigen-binding fragment. In some aspects, the one or more maintenance doses include about 400 mg of the antibody or its antigen-binding fragment.

[0207] In some aspects, the one or more maintenance doses include about 450 mg or about 900 mg of the antibody or its antigen-binding fragment. In some aspects, the one or more maintenance doses include about 450 mg of the antibody or its antigen-binding fragment.

[0208] In some aspects, about ten maintenance doses are administered.

[0209] In some aspects, about twelve maintenance doses are administered.

[0210] In some aspects, 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.

[0211] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about 2 weeks later at one or more induction doses of about 450 mg about every 2 weeks (e.g., within about 14 weeks), and (iii) then at one or more maintenance doses of about 300 mg every 2 weeks (e.g., within about 24 weeks).

[0212] In some aspects, 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.

[0213] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about 2 weeks later at one or more induction doses of about 900 mg about every 2 weeks (e.g., within about 14 weeks), and (iii) then at one or more maintenance doses of about 300 mg every 2 weeks (e.g., within about 24 weeks).

[0214] In some aspects, 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.

[0215] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about 2 weeks later at one or more induction doses of about 1800 mg about every 2 weeks (e.g., within about 14 weeks), and (iii) then at one or more maintenance doses of about 300 mg every 2 weeks (e.g., within about 24 weeks).

[0216] In some aspects, 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.

[0217] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about 2 weeks later at one or more induction doses of about 450 mg about every 2 weeks (e.g., within about 14 weeks), and (iii) then at one or more maintenance doses of about 900 mg every 2 weeks (e.g., within about 24 weeks).

[0218] In some aspects, 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.

[0219] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about 2 weeks later at one or more induction doses of about 900 mg about every 2 weeks (e.g., within about 14 weeks), and (iii) then at one or more maintenance doses of about 900 mg every 2 weeks (e.g., within about 24 weeks).

[0220] In some aspects, 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.

[0221] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is administered (i) at a loading dose of about 2250 mg, (ii) about 2 weeks later at one or more induction doses of about 1800 mg approximately every 2 weeks (e.g., within about 14 weeks), and (iii) then at one or more maintenance doses of about 900 mg every 2 weeks (e.g., within about 24 weeks).

[0222] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 400 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0223] In some aspects, 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 dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0224] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 400 mg, and (iii) one or more maintenance doses of about 900 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0225] In some aspects, 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 dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0226] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 400 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0227] In some aspects, 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 dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0228] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 450 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0229] In some aspects, 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 dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0230] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 450 mg, and (iii) one or more maintenance doses of about 900 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0231] In some aspects, 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 dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0232] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 450 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0233] In some aspects, 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 dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0234] In some aspects, the administration comprises administering (i) a loading dose of the antibody or antigen-binding fragment thereof, (ii) one or more induction doses of about 900 mg, and (iii) one or more maintenance doses of about 900 mg, optionally wherein the induction dose is administered about every two weeks and / or the maintenance dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0235] In some aspects, 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 dose is administered about every four weeks. In some aspects, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0236] In some aspects, the administration comprises administering (i) a loading dose of the antibody or its antigen-binding fragment and (ii) one or more maintenance doses of about 400 mg, optionally wherein these maintenance doses are administered about every four weeks. In some aspects, about ten maintenance doses are administered. In some aspects, at least ten (e.g., ten to fifty or ten to twenty-four or ten to twenty or ten to twelve) maintenance doses are administered.

[0237] In some aspects, 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 its antigen-binding fragment, optionally wherein these maintenance doses are administered about every four weeks. In some aspects, about ten maintenance doses are administered. In some aspects, at least ten (e.g., ten to fifty or ten to twenty-four or ten to twenty or ten to twelve) maintenance doses are administered.

[0238] In some aspects, the administration comprises administering (i) a loading dose of the antibody or its antigen-binding fragment and (ii) one or more maintenance doses of about 450 mg, optionally wherein these maintenance doses are administered about every four weeks. In some aspects, about ten maintenance doses are administered. In some aspects, at least ten (e.g., ten to fifty or ten to twenty-four or ten to twenty or ten to twelve) maintenance doses are administered.

[0239] In some aspects, 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 its antigen-binding fragment, optionally wherein these maintenance doses are administered about every four weeks. In some aspects, about ten maintenance doses are administered. In some aspects, at least ten (e.g., ten to fifty or ten to twenty-four or ten to twenty or ten to twelve) maintenance doses are administered.

[0240] In some aspects, the administration comprises administering (i) a loading dose of the antibody or its antigen-binding fragment and (ii) one or more maintenance doses of about 900 mg, optionally wherein these maintenance doses are administered approximately every four weeks. In some aspects, about ten maintenance doses are administered. In some aspects, about ten maintenance doses are administered. In some aspects, at least ten (e.g., ten to fifty or ten to twenty-four or ten to twenty or ten to twelve) maintenance doses are administered.

[0241] In some aspects, 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 its antigen-binding fragment, optionally wherein these maintenance doses are administered approximately every four weeks. In some aspects, about ten maintenance doses are administered. In some aspects, about ten maintenance doses are administered. In some aspects, at least ten (e.g., ten to fifty or ten to twenty-four or ten to twenty or ten to twelve) maintenance doses are administered.

[0242] In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 100mg / ml or about 150mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 150mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 200mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 225mg / mL. In some aspects, the antibody or its antigen binding fragment is prepared at a concentration of about 250mg / mL.

[0243] In some aspects, the antibody or its Fab is prepared in a volume of about 3 mL. In some aspects, the antibody or its Fab is prepared in a volume of 3 mL or less. In some aspects, the antibody or its Fab is prepared in a volume of 2 mL or less.

[0244] In some aspects, an antibody or antigen-binding fragment thereof as disclosed herein is present in a pharmaceutical formulation or container disclosed herein.

[0245] In some aspects, the subject has previously been treated with one or more agents selected from the group consisting of corticosteroids, immunosuppressants, tumor necrosis factor-α (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 aspects, the subject has an insufficient response, loss of response, or intolerance to one or more of these agents. In some aspects, the subject has an insufficient response, loss of response, or intolerance to no more than two classes of biologics.

[0246] In some aspects, the subject is concurrently treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

[0247] In some aspects, the methods as disclosed herein further comprise administering oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

[0248] The disclosure further provides compositions for use according to any of the methods disclosed herein. Polynucleotides and vectors

[0249] Disclosed herein are polynucleotide sequences encoding recombinant antibodies or their antigen-binding fragments and their subdomains (e.g., FR and CDR). Polynucleotides include, but are not limited to, RNA, DNA, cDNA, hybrids of RNA and DNA, and single-stranded, double-stranded or triple-stranded chains of RNA, DNA or their hybrids. Polynucleotides may include nucleic acid sequences encoding the heavy chain variable region and / or light chain variable region of an antibody as described or exemplified herein. The complement sequence of a polynucleotide sequence is also within the scope of this disclosure.

[0250] In some aspects, the polynucleotide may comprise a nucleic acid sequence encoding an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7. The polynucleotide encoding the amino acid sequence of SEQ ID NO: 7 may comprise a nucleic acid sequence of SEQ ID NO: 30 or SEQ ID NO: 31.

[0251] In some aspects, the polynucleotide may 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 may comprise a nucleic acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33.

[0252] In some aspects, the polynucleotide may include 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 may encode an antibody heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7, and the second nucleic acid sequence may encode an antibody light chain variable region comprising an amino acid sequence of SEQ ID NO: 8. The first nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 7 may include a 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 may include a nucleic acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33.

[0253] In some aspects, the polynucleotide may include 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 aspects, the polynucleotide includes a first nucleic acid sequence encoding an antibody heavy chain variable region comprising an 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, for example, a polynucleotide comprising a nucleic acid sequence of SEQ ID NO: 31.

[0254] In some aspects, the polynucleotide may include 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 aspects, the polynucleotide includes a first nucleic acid sequence encoding an antibody light chain variable region comprising an amino acid sequence of SEQ ID NO: 8 and a second nucleic acid sequence encoding a lambda light chain constant region of SEQ ID NO: 29, for example, a polynucleotide comprising a nucleic acid sequence of SEQ ID NO: 33.

[0255] Any polynucleotide described or exemplified herein may be contained in a vector. Therefore, vectors containing polynucleotides are provided as part of the present disclosure. These vectors may be expression vectors. Therefore, a recombinant expression vector containing a sequence encoding a polypeptide of interest is provided. The expression vector may contain one or more additional sequences, such as but not limited to regulatory sequences, selection markers, purification tags, or polyadenylation signals. Such regulatory elements may include transcriptional promoters, enhancers, mRNA ribosome binding sites, or sequences that control transcription and translation termination.

[0256] Expression vectors, especially mammalian expression vectors, can include one or more non-transcribed elements, such as a replication origin, a suitable promoter and enhancer linked to the gene to be expressed, other 5' or 3' flanking non-transcribed sequences, 5' or 3' non-translated sequences (such as essential ribosome binding sites), polyadenylation sites, splice donor and acceptor sites, or transcription termination sequences. A replication origin that confers replication ability in a specific host can also be incorporated.

[0257] These vectors can be used to transform any of a variety of host cells well known to those skilled in the art and host cells capable of expressing antibodies. Vectors include, but are not limited to, plasmids, phagemids, cosmids, baculovirus shuttle vectors, bacterial artificial chromosomes (BAC), yeast artificial chromosomes (YAC) and baculovirus, as well as other bacteria, eukaryotic, yeast and viral vectors. Suitable host cells include, but are not limited to, CHO cells, NSO cells, HEK293 cells, or any eukaryotic stable cell lines known or produced, and also include bacteria, yeast and insect cells.

[0258] In some aspects, the antibodies or antigen-binding fragments thereof provided herein are produced in human embryonic kidney cells. In some aspects, the antibodies or antigen-binding fragments thereof provided herein are produced in HEK293 cells.

[0259] The antibodies or antigen-binding fragments thereof may also be produced by hybridoma cells; methods for producing hybridomas are well known and established in the art. Pharmaceutical composition

[0260] The present disclosure also provides pharmaceutical compositions comprising antibodies or antigen-binding fragments thereof provided herein. The pharmaceutical compositions may comprise any antibody or antigen-binding fragment thereof described and / or exemplified herein and an acceptable carrier, such as a pharmaceutically acceptable carrier. Suitable carriers include any culture medium that does not interfere with the biological activity of the antibody or antigen-binding fragment thereof and is nontoxic to the host to which it is applied. The pharmaceutical composition may be formulated for administration to a subject in any suitable dosage form.

[0261] Pharmaceutical compositions suitable for administration to human patients are typically formulated for parenteral administration, for example in a liquid vehicle, or suitable for reconstitution into a liquid solution or suspension for intravenous or subcutaneous administration.

[0262] Generally, such compositions typically include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" means approved by a government regulatory agency or listed in the U.S. Pharmacopeia or another generally recognized pharmacopoeia for use in animals, particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle used together with the compound. Such pharmaceutical carriers can be sterile liquids. Water or saline solutions and aqueous glucose and glycerol solutions can also be used as carriers, particularly for injection solutions. Liquid compositions for parenteral administration can be formulated for administration by injection or continuous infusion. The route of administration by injection or infusion includes intravenous and subcutaneous.

[0263] In some aspects, the pharmaceutical composition comprises: (a) about 100 mg / mL of 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: (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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. NO:10 light chain of the amino acid sequence; (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 aspects, the pharmaceutical formulation is lyophilized. In some aspects, the pharmaceutical formulation is liquid.

[0264] In some aspects, the pharmaceutical formulation comprises: (a) about 150 mg / mL of 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: (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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. NO:10 light chain of the amino acid sequence; (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 aspects, the pharmaceutical formulation is lyophilized. In some aspects, the pharmaceutical formulation is liquid.

[0265] In some aspects, the pharmaceutical formulation comprises: (a) about 100 mg / mL of 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: (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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. NO: light chain of the amino acid sequence of 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.

[0266] In some aspects, the pharmaceutical formulation comprises: (a) about 150 mg / mL of 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: (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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. NO: light chain of the amino acid sequence of 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.

[0267] In some aspects, the pharmaceutical formulations provided herein are stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having a pH of 6.0 ± 0.5. In some aspects, the pharmaceutical formulations provided herein are stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having an osmotic pressure from 200mOsm / kg to 500mOsm / kg. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having at least 99% antibody monomer content. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having no significant changes in charge heterogeneity characteristics. In some aspects, the pharmaceutical formulations provided herein are stored at room temperature for 24 hours or at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after having no significant changes in purity. In some aspects, the pharmaceutical formulations provided herein are stored at room temperature for 24 hours or stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days with at least 90% purity. In some aspects, the pharmaceutical formulations provided herein are stored at room temperature for 24 hours or stored at 2 ° C-8 ° C for 24 hours, 72 hours or 10 days after there is no significant change in particle concentration. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ° C-8 ° C for up to 24 months and there is no significant difference in visual appearance. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ° C-8 ° C for up to 36 months and there is no significant difference in visual appearance. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ° C-8 ° C, 25 ° C or 40 ° C for up to 24 months and there is no significant difference in protein concentration, osmotic pressure or viscosity. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ° C-8 ° C, 25 ° C or 40 ° C for up to 36 months and there is no significant difference in protein concentration, osmotic pressure or viscosity. In some respects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 24 months and have ≥ (greater than or equal to) 95% monomer content, ≤ (less than or equal to) 5.0% dimer content or no significant difference in low molecular weight content. In some respects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 36 months and have ≥ (greater than or equal to) 95% monomer content, ≤ (less than or equal to) 5.0% dimer content or no significant difference in low molecular weight content. In some respects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 24 months and have ≥ (greater than or equal to) 90% purity. In some respects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 36 months and have ≥ (greater than or equal to) 90% purity.In some aspects, the pharmaceutical formulations provided herein have a main substance content of from 50% to 90%, an acidic substance content of from 10% to 40%, and / or a basic substance content of from 0% to 20% after being stored at 2°C-8°C for up to 24 months. In some aspects, the pharmaceutical formulations provided herein have a main substance content of from 50% to 90%, an acidic substance content of from 10% to 40%, and / or a basic substance content of from 0% to 20% after being stored at 2°C-8°C for up to 36 months. In some aspects, the pharmaceutical formulations provided herein have no significant differences in sub-visible particle content after being stored at 2°C-8°C, 25°C or 40°C for up to 24 months. In some aspects, the pharmaceutical formulations provided herein have no significant differences in sub-visible particle content after being stored at 2°C-8°C, 25°C or 40°C for up to 36 months. In some aspects, the pharmaceutical formulations provided herein are stored at 2°C-8°C, 25°C or 40°C for up to 24 months after the oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or the deamidation of asparagine 317 of TEV-48574. In some aspects, the pharmaceutical formulations provided herein are stored at 2°C-8°C, 25°C or 40°C for up to 36 months after the oxidation of methionine 81 and / or methionine 254 of TEV-48574 and / or the deamidation of asparagine 317 of TEV-48574. In some aspects, the pharmaceutical formulations provided herein have a relative potency of from 70% to 135% measured by enzyme-linked immunosorbent assay (ELISA) after storage at 2°C-8°C for up to 24 months. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 36 months and have a relative efficacy of 70% to 135% measured by enzyme-linked immunosorbent assay (ELISA). In some aspects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃, 25 ℃ or 40 ℃ for up to 6 months and have no significant difference in thermal stability. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 36 months and have no significant difference in thermal stability. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃, 25 ℃ or 40 ℃ for up to 3 months and have no significant difference in secondary and / or tertiary protein structure. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 36 months and have no significant difference in secondary protein structure. In some aspects, the pharmaceutical formulations provided herein are stored at 2 ℃-8 ℃ for up to 24 months and have no significant difference in the concentration of polysorbate-80. Kits and Containers

[0268] The present disclosure is also characterized by a container comprising any pharmaceutical formulation described and exemplified herein. In some aspects, the container is a glass vial. In some aspects, the container is a glass vial with a 3 mL fill volume.

[0269] The present disclosure is also characterized by comprising a kit of any pharmaceutical preparation described and exemplified herein, or an antibody or its antigen-binding fragment. These kits can be used to provide pharmaceutical preparations, antibodies, their antigen-binding fragments, and other agents for diagnosis, basic research or methods of treatment, etc. In some aspects, these kits include any one or more of the pharmaceutical preparations, antibodies or their antigen-binding fragments described or exemplified herein, and instructions for using the one or more pharmaceutical preparations, antibodies or their antigen-binding fragments in the method for treating moderate to severe ulcerative colitis or moderate to severe Crohn's disease. In some aspects, the subject was previously treated with one or more agents selected from the group consisting of the following: corticosteroids, immunosuppressants, tumor necrosis factor-α (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 aspects, the subject has an inadequate response, loss of response, or intolerance to one or more of these agents. In some aspects, the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics. In some aspects, the kits comprise 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 of treating ulcerative colitis or Crohn's disease in a subject in need thereof, the method comprising: (a) determining whether the subject previously had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject had an inadequate response, loss of response, or intolerance to at least one of these agents, administering to the subject a composition comprising an antibody, or antigen-binding fragment thereof, that specifically binds to TNF-like ligand 1A (TL1A).

[0270] In some aspects, the kits comprise any one or more of the pharmaceutical formulations, recombinant 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 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). Exemplary aspects provided herein

[0271] In one aspect (Aspect 1; A1), 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); 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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. Light chain of the amino acid sequence of NO:10.

[0272] In one aspect 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-α (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).

[0273] In one aspect of A2, A3, the subject has an inadequate response, loss of response, or intolerance to one or more of the agents.

[0274] In one aspect of A2 or A3, ie, A4, the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics.

[0275] In one aspect (Aspect 5; A5), 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 previously had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject had an inadequate response, loss of response, or intolerance to at least one of the agents in part (a), administering to the subject a composition comprising an antibody or an antigen-binding fragment thereof that specifically binds to TNF-like ligand 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 light chain variable region comprising the amino acid sequence of SEQ ID NO: 9; NO:1, a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR2 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.

[0276] In one aspect of A5, i.e. A6, the ulcerative colitis is moderate to severe ulcerative colitis, and / or wherein the Crohn's disease is moderate to severe Crohn's disease.

[0277] In one aspect (Aspect; A7), 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 an antigen-binding fragment thereof that specifically binds to TNF-like ligand 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, and a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5. NO:5, and a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:6, 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.

[0278] In one aspect 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-α (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).

[0279] In one aspect of A8, A9, the subject has an inadequate response, loss of response, or intolerance to one or more of the agents.

[0280] In one aspect of A8 or A9, i.e. A10, the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics.

[0281] In one aspect of any one of A1-A10, ie A11, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0282] In one aspect of any one of A1-A11, ie A12, the subject is concurrently treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP) and / or methotrexate.

[0283] In one aspect of any one of A1-A12, ie A13, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

[0284] In one aspect of any one of A1-A12, ie A14, the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg.

[0285] In one aspect of any one of A1-A12, ie A15, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg.

[0286] In one aspect of any one of A1-A12, ie A16, the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg.

[0287] In one aspect of any one of A1-A12, ie A17, the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg.

[0288] In one aspect of any one of A1-A12, ie A18, the antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg.

[0289] In one aspect of any one of A1-A12, ie A19, the antibody or antigen-binding fragment thereof is administered at a dose of about 1750 mg.

[0290] In one aspect of any one of A1-A12, ie A20, the antibody or antigen-binding fragment thereof is administered at a dose of about 1800 mg.

[0291] In one aspect of any one of A1-A12, ie A21, the antibody or antigen-binding fragment thereof is administered at a dose of about 2000 mg.

[0292] In one aspect of any one of A1-A12, ie A22, the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg.

[0293] In one aspect of any one of A1-A12, ie A23, the antibody or antigen-binding fragment thereof is administered at a dose of about 2500 mg.

[0294] In one aspect of any one of A1-A23, ie A24, the antibody or antigen-binding fragment thereof is administered about once every two weeks.

[0295] In one aspect of any one of A1-A23, ie, A25, the antibody or antigen-binding fragment thereof is administered about once a month.

[0296] In one aspect of any one of A1-A25, ie A26, the administering comprises administering one or more induction doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose is administered.

[0297] In one aspect of any one of A1-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.

[0298] In one aspect 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.

[0299] In one aspect of A28, i.e., A29, the loading dose comprises about 2250 mg of the antibody or antigen-binding fragment thereof.

[0300] In one aspect of any one of A26-A29, ie A30, the one or more induction doses comprises about 450 mg of the antibody or antigen-binding fragment thereof.

[0301] In one aspect of any one of A26-A29, ie A31, the one or more induction doses comprises about 900 mg of the antibody or antigen-binding fragment thereof.

[0302] In one aspect of any one of A26-A29, ie A32, the one or more induction doses comprises about 1800 mg of the antibody or antigen-binding fragment thereof.

[0303] In one aspect of any one of A26-A32, i.e. A33, about six induction doses are administered.

[0304] In one aspect of any one of A1-A33, i.e. A34, the administering is performed within about 16 weeks.

[0305] In one aspect of 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, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered about every 2 weeks.

[0306] In one aspect of any one of A1-A34, ie 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 2 weeks.

[0307] In one aspect 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.

[0308] In one aspect of A37, ie, A38, the one or more maintenance doses comprise about 300 mg of the antibody or antigen-binding fragment thereof.

[0309] In one aspect of A37, ie, A39, the one or more maintenance doses comprise about 900 mg of the antibody or antigen-binding fragment thereof.

[0310] In one aspect of any one of A35-A39, ie A40, about twelve maintenance doses are administered.

[0311] In one aspect of any one of A1-A12, i.e. A41, 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.

[0312] In one aspect of any one of A1-A12, i.e. A42, 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.

[0313] In one aspect of any one of A1-A12, i.e. A43, 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.

[0314] In one aspect of any one of A1-A12, i.e. A44, 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.

[0315] In one aspect of any one of A1-A12, i.e. A45, 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.

[0316] In one aspect of any one of A1-A12, i.e. A46, 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.

[0317] In one aspect of any one of A27-A34 or A36-A46, ie A47, administering the one or more induction doses is performed over about 14 weeks.

[0318] In one aspect of any one of A27-A47, ie A48, the loading dose is administered about 2 weeks prior to administration of the one or more induction doses.

[0319] In one aspect of any one of A35-A48, ie A49, administering the one or more maintenance doses is performed over about 24 weeks.

[0320] In one aspect of any one of A1-A49, ie, A50, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL.

[0321] In one aspect of any one of A1-A50, ie A51, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less.

[0322] In one aspect of any one of A1-A51, ie, A52, the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously to the subject.

[0323] In one aspect of A52, i.e., A53, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0324] In one aspect of any one of A1-A53, ie A54, the antibody or antigen-binding fragment thereof is administered to the subject via a syringe.

[0325] In one aspect of any one of A1-A54, ie A55, the subject has moderate to severe ulcerative colitis.

[0326] In one aspect of A55, namely A56, the administration results in clinical remission.

[0327] In one aspect of A56, i.e. A57, the clinical remission occurs within 14 weeks after initiation of the administering.

[0328] In one aspect of A56, i.e., A58, the clinical remission occurs within 38 weeks after initiation of the administering.

[0329] In one aspect of any one of A1-A54, ie A59, the subject has moderate to severe Crohn's disease.

[0330] In one aspect of A59, namely A60, the administration results in an endoscopic response.

[0331] In one aspect of A60, namely A61, the endoscopic response occurs within 14 weeks after initiation of the administration.

[0332] In one aspect of A60, namely A62, the endoscopic response occurs within 38 weeks after initiation of the administration.

[0333] In one aspect, i.e., A63, provided herein is a pharmaceutical formulation comprising: (a) 150 mg / mL of 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: (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 variable region CDR1 comprising the amino acid sequence of SEQ ID NO:10. Light chain of the amino acid sequence of 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.

[0334] In one aspect of A63, ie A64, the antibody or antigen-binding fragment of (i) or (ii) comprises an IgG1 constant region.

[0335] In one aspect of A63 or A64, ie A65, the pharmaceutical formulation is lyophilized.

[0336] In one aspect of A63 or A64, ie A66, the pharmaceutical formulation is liquid.

[0337] In one aspect of any one of A63-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°C-8°C for 24 hours, 72 hours or 10 days.

[0338] In one aspect of any one of A63-A67, ie A68, the pharmaceutical composition has an osmotic pressure of from 200 to 500 mOsm / kg after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0339] In one aspect of any one of A63-A68, ie A69, the pharmaceutical composition has an antibody monomer content of at least 99% after storage at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0340] In an aspect of any one of A63-A69, ie A70, the pharmaceutical composition has no significant change in charge heterogeneity characteristics after storage at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0341] In one aspect of any one of A63-A70, ie A71, the pharmaceutical composition has no significant change in purity after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0342] In one aspect of any one of A63-A70, ie A72, the pharmaceutical composition has at least 90% purity after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0343] In one aspect of any one of A63-A72, ie A73, the pharmaceutical composition has no significant change in particle concentration after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0344] In an aspect of any one of A63-A73, ie A74, the pharmaceutical composition has no significant difference in visual appearance after storage at 2°C-8°C for up to 36 months.

[0345] In an aspect of any one of A63-A74, ie A75, the pharmaceutical composition has no significant difference in protein concentration, osmotic pressure or viscosity after storage at 2°C-8°C, 25°C or 40°C for up to 36 months.

[0346] In one aspect of any one of A63-A75, ie A76, the pharmaceutical composition has ≥95% monomer content, ≤5.0% dimer content, or no significant difference in low molecular weight material content after storage at 2°C-8°C for up to 36 months.

[0347] In an aspect of any one of A63-A76, ie A77, the pharmaceutical composition has ≥90% purity after storage at 2°C-8°C for up to 36 months.

[0348] In one aspect of any one of A63-A77, i.e. A78, the pharmaceutical composition has a main substance content from 50% to 90%, an acidic substance content from 10% to 40%, and / or a basic substance content from 0% to 20% after storage at 2°C-8°C for up to 36 months.

[0349] In an aspect of any one of A63-A78, ie A79, the pharmaceutical composition has no significant difference in subvisible particulate content after storage at 2°C-8°C, 25°C or 40°C for up to 36 months.

[0350] In one aspect of any one of A63-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°C-8°C, 25°C or 40°C for up to 36 months.

[0351] In one aspect of any one of A63-A80, ie A81, the pharmaceutical composition has a relative potency of from 70% to 135% after storage at 2°C-8°C for up to 36 months as measured by enzyme-linked immunosorbent assay (ELISA).

[0352] In an aspect of any one of A63-A81, ie A82, the pharmaceutical composition has no significant difference in thermal stability after storage at 2°C-8°C, 25°C or 40°C for up to 6 months.

[0353] In an aspect of any one of A63-A82, ie A83, the pharmaceutical composition has no significant difference in thermal stability after storage at 2°C-8°C for up to 36 months.

[0354] In an aspect of any one of A63-A83, ie A84, the pharmaceutical composition has no significant differences in secondary and / or tertiary protein structure after storage at 2°C-8°C, 25°C or 40°C for up to 3 months.

[0355] In an aspect of any one of A63-A84, ie A85, the pharmaceutical composition has no significant difference in secondary protein structure after storage at 2°C-8°C for up to 36 months.

[0356] In one aspect of any one of A63-A85, i.e. A86, the pharmaceutical composition has no significant difference in the concentration of polysorbate-80 after storage at 2°C-8°C for up to 24 months. In one aspect, i.e. A87, a container is provided, comprising a pharmaceutical formulation as described in any one of A63-A86.

[0357] In one aspect of A87, namely A88, the container is a glass vial.

[0358] In one aspect of A88, namely A89, the container is a glass vial having a 3 mL fill volume.

[0359] In one aspect of any one of A1-A62, ie A90, the antibody or antigen-binding fragment thereof is present in a pharmaceutical formulation as described in any one of A63-A86 or in a container as described in any one of A87-A89.

[0360] In one aspect, A91, provided herein is a composition for use according to the method of any one of A1-A62 or A90.

[0361] In one aspect of the method of any one of A1-A62 or A90, the pharmaceutical formulation of any one of A63-A86 or the container of any one of A87-A89, i.e., A92, the antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells.

[0362] In one aspect, i.e., B1, 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 an 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.

[0363] In one aspect 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-α (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).

[0364] In one aspect of B2, B3, the subject has an inadequate response, loss of response, or intolerance to one or more of the agents.

[0365] In one aspect of B2 or B3, ie, B4, the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics.

[0366] In one aspect, i.e., B5, 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 previously had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject has an inadequate response, loss of response, or intolerance to at least one of these agents in part (a), administering to the subject a composition comprising an antibody or an 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, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 3. The heavy chain variable region CDR3 comprises the amino acid sequence of SEQ ID NO:3, the light chain variable region CDR1 comprises the amino acid sequence of SEQ ID NO:4, the light chain variable region CDR2 comprises the amino acid sequence of SEQ ID NO:5, and the light chain variable region CDR3 comprises the amino acid sequence of SEQ ID NO:6.

[0367] In one aspect 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.

[0368] In one aspect, i.e., B7, 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 an 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.

[0369] In one aspect 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-α (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).

[0370] In one aspect of B8, B9, the subject has an inadequate response, loss of response, or intolerance to one or more of the agents.

[0371] In one aspect of B8 or B9, i.e., B10, the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics.

[0372] In one aspect of any one of B1-B10, i.e. B11, 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.

[0373] In one aspect of any one of B1-B10, ie B12, the antibody or antigen-binding fragment comprises an IgG1 constant region.

[0374] In one aspect of any one of B1-B12, i.e. 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.

[0375] In one aspect of any one of B1-B13, ie B14, the subject is concurrently treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP) and / or methotrexate.

[0376] In one aspect of any one of B1-B14, ie, B15, the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

[0377] In one aspect of any one of B1-B14, ie, B16, the antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg.

[0378] In one aspect of any one of B1-B14, ie, B17, the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg.

[0379] In one aspect of any one of B1-B14, ie, B18, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg.

[0380] In one aspect of any one of B1-B14, ie, B19, the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg.

[0381] In one aspect of any one of B1-B14, ie, B20, the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg.

[0382] In one aspect of any one of B1-B14, ie, B21, the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg.

[0383] In one aspect of any one of B1-B20, ie, B22, the antibody or antigen-binding fragment thereof is administered about once every two weeks.

[0384] In one aspect of any one of B1-B20, ie, B23, the antibody or antigen-binding fragment thereof is administered about once a month.

[0385] In one aspect of any one of B1-B23, ie, B24, the administering comprises administering one or more induction doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose is administered.

[0386] In one aspect of any one of B1-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.

[0387] In one aspect of B25, namely B26, the loading dose comprises about 2250 mg of the antibody or antigen-binding fragment thereof.

[0388] In one aspect of any one of B24-B26, ie, B27, the one or more induction doses comprises about 450 mg of the antibody or antigen-binding fragment thereof.

[0389] In one aspect of any one of B24-B26, ie, B28, the one or more induction doses comprises about 900 mg of the antibody or antigen-binding fragment thereof.

[0390] In one aspect of any one of B24-B28, i.e. B29, about six induction doses are administered.

[0391] In one aspect of any one of B1-B29, ie B30, the administering is performed within about 16 weeks.

[0392] In one aspect of any one of B1-B23, i.e. B31, the administering comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered about every 2 weeks.

[0393] In one aspect of any one of B1-B30, ie, 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 2 weeks.

[0394] In one aspect of any one of B1-B23, i.e. B33, the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered approximately every 4 weeks.

[0395] In one aspect of any one of B1-B23, ie, 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 4 weeks.

[0396] In one aspect of B30-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.

[0397] In one aspect of B35, i.e., B36, the one or more maintenance doses comprise about 450 mg of the antibody or antigen-binding fragment thereof.

[0398] In one aspect of B35, ie, B37, the one or more maintenance doses comprises about 900 mg of the antibody or antigen-binding fragment thereof.

[0399] In one aspect of any one of B30-B37, i.e. B38, about ten maintenance doses are administered.

[0400] In one aspect of any one 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 doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0401] In one aspect of any one 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 doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0402] In one aspect 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 doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0403] In one aspect 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 doses are administered about every two weeks and / or the maintenance doses are administered about every four weeks.

[0404] In one aspect of any one of B39-B42, ie B43, about 6 induction doses are administered and / or about ten maintenance doses are administered.

[0405] In one aspect of any one 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.

[0406] In one aspect of any one of B1-B14, i.e. B45, 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 wherein the maintenance doses are administered about every four weeks.

[0407] In one aspect of B44 or B45, ie, B46, at least ten maintenance doses are administered.

[0408] In one aspect of any one of B24-B46, ie B47, administering the one or more induction doses is performed within about 14 weeks.

[0409] In one aspect of any one of B25-B47, i.e. B48, the loading dose is administered about 2 weeks prior to administration of the one or more induction doses.

[0410] In one aspect of any one of B31-B48, ie B49, administering the one or more maintenance doses is performed over about 24 weeks.

[0411] In one aspect of any one of B31-B48, ie B50, administering the one or more maintenance doses is performed over about 40 weeks.

[0412] In one aspect of any one of B1-B50, ie, B51, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL.

[0413] In one aspect of any one of B1-B50, ie, B52, the antibody or antigen-binding fragment thereof is formulated at a concentration of about 200 mg / mL.

[0414] In one aspect of any one of B1-B52, ie, B53, the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less.

[0415] In one aspect of any one of B1-B53, ie, B54, the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously to the subject.

[0416] In one aspect of B54, i.e., B55, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0417] In one aspect of any one of B1-B55, ie, B56, the antibody or antigen-binding fragment thereof is administered to the subject via a syringe.

[0418] In one aspect of B56, namely B57, the syringe is a pre-filled syringe.

[0419] In one aspect of any one of B1-B57, i.e. B58, the subject suffers from moderate to severe ulcerative colitis.

[0420] In one aspect of B58, namely B59, the administration results in clinical remission.

[0421] In one aspect of B59, i.e. B60, the clinical remission occurs within 14 weeks after initiation of the administration.

[0422] In one aspect of B59, namely B61, the clinical remission occurs within 38 weeks after initiation of the administration.

[0423] In one aspect of any one of B1-B57, i.e. B62, the subject has moderate to severe Crohn's disease.

[0424] In one aspect of B62, namely B63, the administration results in an endoscopic response.

[0425] In one aspect of B63, namely B64, the endoscopic response occurs within 14 weeks after initiation of the administration.

[0426] In one aspect of B64, namely B65, the endoscopic response occurs within 38 weeks after the start of the administration.

[0427] In one aspect, B66, an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A), is used in the preparation of a medicament of any one of B1-B65.

[0428] In one aspect, B67, an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A), is used in any one of B1-B65.

[0429] In one aspect, i.e., B68, provided herein is a pharmaceutical formulation comprising: (a) about 100 mg / mL to about 250 mg / mL of 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. NO:6 amino acid sequence of light chain variable region CDR3; (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.

[0430] In one aspect of B68, namely 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.

[0431] In one aspect of B68 or B69, ie, B70, the antibody or antigen-binding fragment comprises an IgG1 constant region.

[0432] In one aspect of any one of B68-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.

[0433] In one aspect of any one of B68-B71, ie, B72, the pharmaceutical formulation comprises about 100 mg / mL of the antibody or antigen-binding fragment thereof.

[0434] In one aspect of any one of B68-B71, ie, B73, the pharmaceutical formulation comprises about 150 mg / mL of the antibody or antigen-binding fragment thereof.

[0435] In one aspect of any one of B68-B71, ie, B74, the pharmaceutical formulation comprises about 200 mg / mL of the antibody or antigen-binding fragment thereof.

[0436] In one aspect of any one of B68-B71, ie, B75, the pharmaceutical formulation comprises about 225 mg / mL of the antibody or antigen-binding fragment thereof.

[0437] In one aspect of any one of B68-B71, ie, B76, the pharmaceutical formulation comprises about 250 mg / mL of the antibody or antigen-binding fragment thereof.

[0438] In one aspect of any one of B68-B76, ie B77, the pharmaceutical formulation comprises about 5 mM histidine.

[0439] In one aspect of any one of B68-B76, ie, B78, the pharmaceutical formulation comprises about 10 mM histidine.

[0440] In one aspect of any one of B68-B76, ie, B79, the pharmaceutical formulation comprises about 15 mM histidine.

[0441] In one aspect of any one of B68-B79, ie B80, the pharmaceutical formulation comprises about 50 mM arginine-hydrochloride (Arg-HCl).

[0442] In one aspect of any one of B68-B79, ie, B81, the pharmaceutical formulation comprises about 100 mM arginine-hydrochloride (Arg-HCl).

[0443] In one aspect of any one of B68-B79, ie, B82, the pharmaceutical formulation comprises about 150 mM arginine-hydrochloride (Arg-HCl).

[0444] In one aspect of any one of B68-B82, ie, B83, the pharmaceutical formulation comprises about 2.5% (w / v) sucrose.

[0445] In one aspect of any one of B68-B82, ie, B84, the pharmaceutical formulation comprises about 5% (w / v) sucrose.

[0446] In one aspect of any one of B68-B82, ie, B85, the pharmaceutical formulation comprises about 7.5% (w / v) sucrose.

[0447] In one aspect of any one of B68-B85, ie, B86, the pharmaceutical formulation comprises about 0.01% (w / v) polysorbate-80.

[0448] In one aspect of any one of B68-B85, ie, B87, the pharmaceutical formulation comprises about 0.02% (w / v) polysorbate-80.

[0449] In one aspect of any one of B68-B85, ie, B88, the pharmaceutical formulation comprises about 0.03% (w / v) polysorbate-80.

[0450] In one aspect of any one of B68-B71, i.e. B89, the pharmaceutical formulation comprises about 250 mg / mL of the 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.

[0451] In one aspect of any one of B68-B71, i.e. B90, the pharmaceutical formulation comprises about 200 mg / mL of the 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.

[0452] In one aspect of any one of B68-B71, i.e. B91, the pharmaceutical formulation comprises about 150 mg / mL of the 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.

[0453] In one aspect of any one of B68-B91, ie B92, the pharmaceutical formulation is lyophilized.

[0454] In one aspect of any one of B68-B91, ie B93, the pharmaceutical formulation is liquid.

[0455] In one aspect of any one of B68-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°C-8°C for 24 hours, 72 hours, or 10 days.

[0456] In one aspect of any one of B68-B94, ie B95, the pharmaceutical composition has an osmotic pressure from 200 to 500 mOsm / kg after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0457] In one aspect of any one of B68-B95, ie B96, the pharmaceutical composition has an antibody monomer content of at least 99% after storage at 2°C-8°C for 24 hours, 72 hours or 10 days.

[0458] In one aspect of any one of B68-B96, ie, B97, the pharmaceutical composition has no significant change in charge heterogeneity characteristics after storage at 2°C-8°C for 24 hours, 72 hours, or 10 days.

[0459] In one aspect of any one of B68-B97, ie, B98, the pharmaceutical composition has no significant change in purity after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

[0460] In one aspect of any one of B68-B98, ie, B99, the pharmaceutical composition has at least 90% purity after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

[0461] In one aspect of any one of B68-B99, ie, B100, the pharmaceutical composition has no significant change in particle concentration after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

[0462] In an aspect of any one of B68-B100, ie, B101, the pharmaceutical composition has no significant difference in visual appearance after storage at 2°C-8°C for up to 36 months.

[0463] In one aspect of any one of B68-B101, ie, B102, the pharmaceutical composition has no significant difference in protein concentration, osmotic pressure, or viscosity after storage at 2°C-8°C, 25°C, or 40°C for up to 36 months.

[0464] In one aspect of any one of B68-B102, ie, B103, the pharmaceutical composition has ≥95% monomer content, ≤5.0% dimer content, or no significant difference in low molecular weight material content after storage at 2°C-8°C for up to 36 months.

[0465] In one aspect of any one of B68-B103, ie, B104, the pharmaceutical composition has a purity of ≥ 90% after storage at 2°C-8°C for up to 36 months.

[0466] In one aspect of any one of B68-B104, i.e. B105, the pharmaceutical composition has a main substance content from 50% to 90%, an acidic substance content from 10% to 40%, and / or a basic substance content from 0% to 20% after storage at 2°C-8°C for up to 36 months.

[0467] In an aspect of any one of B68-B105, ie, B106, the pharmaceutical composition has no significant difference in subvisible particulate content after storage at 2°C-8°C, 25°C or 40°C for up to 36 months.

[0468] In one aspect of any one of B68-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°C-8°C, 25°C or 40°C for up to 36 months.

[0469] In one aspect of any one of B68-B107, ie, B108, the pharmaceutical composition has a relative potency of from 70% to 135% after storage at 2°C-8°C for up to 36 months as measured by enzyme-linked immunosorbent assay (ELISA).

[0470] In one aspect of any one of B68-B108, ie, B109, the pharmaceutical composition has no significant difference in thermal stability after storage at 2°C-8°C, 25°C, or 40°C for up to 6 months.

[0471] In an aspect of any one of B68-B109, ie, B110, the pharmaceutical composition has no significant difference in thermal stability after storage at 2°C-8°C for up to 36 months.

[0472] In one aspect of any one of B68-B110, ie, B111, the pharmaceutical composition has no significant differences in secondary and / or tertiary protein structure after storage at 2°C-8°C, 25°C or 40°C for up to 3 months.

[0473] In one aspect of any one of B68-B111, ie, B112, the pharmaceutical composition has no significant difference in secondary protein structure after storage at 2°C-8°C for up to 36 months.

[0474] In an aspect of any one of B68-B112, ie, B113, the pharmaceutical composition has no significant difference in the concentration of polysorbate-80 after storage at 2°C-8°C for up to 24 months.

[0475] In one aspect of any one of B68-B113, ie, B114, the antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells.

[0476] In one aspect, B115, a container is provided, comprising a pharmaceutical formulation as described in any one of B68-B114.

[0477] In one aspect of B115, namely B116, the container is a glass vial.

[0478] In one aspect of B116, namely B117, the container is a glass vial having a fill volume of 3 mL.

[0479] In one aspect of B115, i.e., B118, the container is a syringe, optionally wherein the syringe is a pre-filled syringe.

[0480] 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 as described in any one of B68-B114 or a container as described in any one of B115-B118, optionally wherein the disease is a gastrointestinal disease.

[0481] In one aspect of B119, namely B120, the gastrointestinal disease is Crohn's disease or ulcerative colitis.

[0482] In one aspect of B119 or B120, ie, B121, the pharmaceutical formulation is administered intravenously.

[0483] In one aspect of B119 or B120, ie, B122, the pharmaceutical formulation is administered subcutaneously.

[0484] In an aspect of any one of B68-B114, ie B123, the formulation is for use according to the method of any one of B1-B65 or B115-B122.

[0485] The following examples are offered by way of illustration and not by way of limitation. Examples Example 1: Clinical Evaluation of TEV-48574 in Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn's Disease

[0486] TEV-48574 was 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). The study enrolled adult patients (18 to 75 years, inclusive) of both sexes with moderate to severe active UC or CD who had demonstrated an inadequate response, loss of response, or intolerance to at least 1 and no more than 2 biologics from the following classes: corticosteroids, immunosuppressants, tumor necrosis factor-α (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).

[0487] This study demonstrated the efficacy and dose response of 3 different dosing regimens of TEV-48574 administered subcutaneously (sc) every 2 weeks (Q2W) 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 week 14.

[0488] A single loading dose of 2250 mg was used in this study. The loading dose as part of the induction dosing regimen has been chosen to rapidly achieve steady-state concentrations and to account for the significant overproduction of TL1A in the colon during the first few weeks of induction.

[0489] The dosing regimen is designed to achieve steady-state concentrations quickly. TEV-48574 has linear PK for a dose range of 200 mg to 2300 mg, with an elimination half-life of 7-9 days. A 2300 mg loading dose followed by a 1600 mg dose reached steady state after 2 weeks, and no accumulation was observed. Population PK methods and models are used to simulate loading and induction doses, and thus predict the resulting exposure. Based on a combination of safety, preclinical evidence, pharmacokinetics, immunogenicity, and clinical considerations, 3 induction dose strengths in this study were selected. Subject population and eligibility criteria

[0490] Approximately 570 patients were screened to obtain approximately 280 randomized patients (approximately 140 UC patients and 140 CD patients).

[0491] Eligible patients met all of the following criteria: a. Male and female adults (regardless of sex) aged between 18 and 75 years (inclusive) at the time of informed consent. b. Diagnosis of UC or CD ≥ (greater than or equal to) 3 months. c. UC patients only: patients with moderately to severely active UC as defined by a 3-component modified Mayo score of 5 to 9 (inclusive) with an endoscopic score ≥ (greater than or equal to) 2 (from central reading) d. CD patients only: patients with moderately to severely active CD, as determined by a CDAI score of ≥ (greater than or equal to) 220 and ≤ (less than or equal to) 450. e. CD patients only: SES CD score ≥ (greater than or equal to) 6 (for isolated ileal disease, ≥ (greater than or equal to) 4). f. Patients with UC only: Active disease outside the rectum (>15 cm of active disease at screening endoscopy [sigmoidoscopy]). g. Patients must have had an inadequate response, loss of response, or intolerance to at least 1 and no more than 2 of the following classes of biologics: corticosteroids, immunosuppressant drugs and / or TNF-α antagonist therapy, anti-integrin, anti-IL-12 / 23, JAK inhibitors, and / or S1P receptor modulators. h. If the patient was taking the following medications, the patient must have been taking stable doses for the specified time periods: oral 5-ASA or sulfasalazine stable dose for at least 4 weeks before endoscopy, oral corticosteroids stable dose for at least 2 weeks before endoscopy, and 6-MP, AZA, or methotrexate stable dose for 4 weeks before endoscopy.

[0492] Patients meeting all inclusion criteria were randomized to receive TEV-48574 (single loading dose / 6 induction doses): 2250 / 1800 mg, 2250 / 900 mg, 2250 / 450 mg, or matching TEV-48574 placebo in a 1:1:1:1 ratio, stratified by diagnosis (UC or CD) and prior exposure, failure of biologics and small molecules (including JAK inhibitors and S1P receptor modulators for UC) or first-time biologics and small molecule therapy. Drug dosage, mode of administration, and rate of administration

[0493] TEV-48574 for subcutaneous (sc) injection is provided as a liquid solution at a concentration of 150 mg / mL. Placebo is provided as a liquid solution in the same formulation as TEV-48574, except that no active protein is present. Specific details about the TEV-48574 and placebo products are provided in Table 1. Table 1: TEV-48574 and Placebo Products

[0494] Patients received the following regimen as SC administration using a commercial syringe-based SC infusion system: TEV-48574 2250 mg (single loading dose) / 1800 mg (6 induction doses) TEV-48574 2250 mg (single loading dose) / 900 mg (6 induction doses) TEV-48574 2250 mg (single loading dose) / 450 mg (6 induction doses) Placebo matched to TEV-48574

[0495] Patients received a loading dose on the day of randomization and subsequent corresponding maintenance doses every 2 weeks for a total of 7 doses (1 loading dose and 6 induction doses). Administration was by subcutaneous (sc) infusion.

[0496] The long-term efficacy and safety of TEV-48574 will be demonstrated in patients who have moderate to severe active UC or CD at the start of the study and who also show clinical response and / or clinical remission (based on the complete Mayo score for UC and CDAI in CD subjects) to initial treatment with TEV-48574 in the study. These patients will receive 300 mg Q2W or 900 mg Q2W during the administration period.

[0497] Commercial syringe infusion systems for administration are capable of SC drug administration of up to 60 mL syringes using a SC safety needle device. The system controls the rate at which the drug enters the tissue surrounding the SC infusion site as well as the duration of the infusion. A syringe infusion system is a mechanical or electromechanical syringe pump that pushes the syringe plunger at a constant rate throughout the infusion to infuse the drug. Universal Design

[0498] The study consisted of a 6-week (42-day) screening period, a 14-week treatment period, and a 4-week follow-up period. Figure 1 Presented in.

[0499] Screening Patients were screened within 6 weeks (42 days) prior to randomization to confirm that they had met all selection criteria for the study. Endoscopy was performed after key eligibility criteria were met and within approximately 10 calendar days of randomization (Day 1) to allow for central endoscopic scoring.

[0500] Randomization Patients who met eligibility criteria at the end of the screening period were randomized in a 1:1:1:1 ratio (stratified by diagnosis [UC or CD] and prior exposure, failure of biologics and small molecules [including JAK inhibitors and S1P receptor modulators for UC] or first-time biologics and small molecule therapy) to 1 of 4 treatment groups for a double-blind treatment period (Table 2).

[0501] All treatments were administered in a double-blind fashion as 1 SC infusion Q2W. Table 2: Randomization Scheme CD = Crohn's disease; Q2W = every 2 weeks; UC = ulcerative colitis.

[0502] During the 14-week treatment period, patients will visit sites Q2W on Days 1, 15, 29, 43, 57, 71, and 85 (±3 days) for TEV-48574 / placebo administration (7 visits), and an end-of-treatment visit on Day 99 (±3 days; Week 14). The end of the study is defined as the last visit of the last patient. The study duration is approximately 24 months.

[0503] The following efficacy assessments will be performed. Endoscopic and histological evaluations will be scored centrally. Modified Mayo Score (Ulcerative Colitis)

[0504] The modified Mayo score evaluates the UC stage based on the following three parameters: Frequency of bowel movements Rectal bleeding Endoscopic evaluation

[0505] Each parameter of the score ranges from 0 (normal or inactive disease) to 3 (severe activity) and the total score ranges from 0 to 9, respectively (Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry 2016, Naegeli et al., 2018). Endoscopy

[0506] Endoscopy was performed at Screening and Week 14 or Early Termination Visit. Assessments and procedures performed during endoscopy, including biopsy collection, SES-CD, and modified multiplier (MM)-SES-CD are described below. Biopsy collection

[0507] For patients with CD, ileocolonoscopy was performed at screening and at week 14. During each endoscopy, a total of 16 to 18 mucosal biopsies were collected and processed as outlined below. Mucosal biopsies were obtained from the area with the greatest inflammation in each segment. If an ulcer was present, a biopsy was taken from the edge of the largest ulcer. If no ulcer was present, a biopsy was taken from the most affected area of ​​the segment. If the mucosa appeared normal (e.g., at follow-up), a random biopsy of the segment was obtained.

[0508] For patients with UC, flexible sigmoidoscopy is performed at screening and at week 14 (if not performed in the previous 12 months, a colonoscopy can be performed instead for baseline endoscopy). During each endoscopy, a total of 8 to 12 biopsies are obtained from the area with the most severe disease 15 to 25 cm from the anal verge. 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), random biopsies are taken from the area 15 to 25 cm from the anal verge.

[0509] Biopsies are used to measure histological disease. Simplified Endoscopic Score for Crohn's Disease

[0510] The SES-CD takes into account 4 parameters (presence of ulcers, percentage of ulcerated surface, affected surface and presence of strictures) that need to be scored in 5 intestinal segments (rectum, sigmoid colon and left colon, transverse colon, right colon and ileum) (Daperno et al., Gastrointest Endosc; 60(4):505-12 (2004)). Modified Multiplier-Simplified Endoscopic Score for Crohn's Disease

[0511] MM-SES-CD is an endoscopic scoring tool that takes into account the prognostic value of each single parameter to achieve endoscopic remission during active treatment (Narula et al., Gut; 0: 1-10 (2021)). Robarts Histopathology Index (Ulcerative Colitis)

[0512] The Robarts Histopathology Index (RHI) final score is obtained by combining the sub-scores of 4 major items: Chronic inflammatory infiltration level (4 levels) Lamina propria neutrophils (4 levels) Neutrophils in the epithelium (4 levels) Erosion or ulcer (4 levels)

[0513] The 4 components were classified from 0 to 3, resulting in a final score ranging between 0 and 33 (Mosli et al., Gut; 66(1):50-58 (2017)). Geboes score (ulcerative colitis)

[0514] The Geboes score is a scoring system for microscopic disease activity that combines a number of histological items classified into 5 grades (Mosli et al., Inflamm Bowel Dis; 20(3):564-75 (2014)). Global Histologic Activity Score (Crohn's disease)

[0515] The overall histologic activity score consists of 8 items that assess acute and chronic inflammatory changes, epithelial damage, and the extent of inflammation (i.e., the proportion of biopsy specimens affected). Each of the 8 items is scored and the sums are then added together (D'Haens et al., Gastroenterology; 114(2):262-7 (1998)). Crohn's disease activity index

[0516] The CDAI (Yoshida EM. Can J Gastroenterol; 13(1):65-73 (1999)) consists of 8 factors that are summed after adjustment with a weighting factor: Number of liquid or soft stools per day for 7 days x 2 Abdominal pain (severity from 0 to 3) every day for 7 days x 5 Daily subjective assessment of general health, from 0 (good) to 4 (poor), for 7 days x 7 Presence of complications × 20 · Atropine (Lomotil), Imodium, or opiates for diarrhea x 30 Presence of abdominal mass (0: no, 2: doubtful, 5: definite) × 10 Hematocrit < 0.47 for men and < 0.42 x 6 for women ·Percentage of deviation from standard weight × 1 Two patient-reported outcomes (ulcerative colitis and Crohn's disease)

[0517] UC: 2 patient-reported outcomes (PRO2) included daily assessment of 2 items with Mayo scores: bowel movement frequency and rectal bleeding. Each parameter of the score ranges from 0 (normal or inactive disease) to 3 (severe activity) and the total score ranges from 0 to 6, respectively (Dragasevic et al., Gastroenterol Res Pract; 2020: 2065383 (2020); Jairath et al., Aliment Pharmacol Ther; 42(10): 1200-10 (2015)).

[0518] CD: PRO2 is the sum of daily bowel movement frequency (0 to 3) and abdominal pain (0 to 3) from the CDAI (Khanna et al., Aliment Pharmacol Ther; 41(1):77-86 (2015)). Permitted inflammatory bowel disease medications and rescue medications

[0519] Concomitant treatments allowed for UC and CD must be maintained at a stable dose (no increases or decreases) during the study treatment period (except for reductions due to adverse events); if the dose is increased, the patient must be withdrawn from the study. The dose of any background medication for UC and CD should not be changed during the screening and double-blind treatment periods.

[0520] Patients will be allowed to take the following medications as detailed below: Concomitant use of oral 5-ASA or sulfasalazine. The dose must be stable for at least 4 weeks before endoscopy, up to week 14. If oral 5-ASA therapy has been recently discontinued, it must be stopped for at least 2 weeks before endoscopy. Stable dose of oral corticosteroids (prednisone equivalents up to 20 mg / day; budesonide up to 9 mg / day) for at least 2 weeks prior to endoscopy, through week 14. If oral corticosteroids were recently discontinued, they must be stopped for at least 2 weeks prior to endoscopy. Reductions in steroid use due to adverse events were allowed. Stable dose of immunosuppressant medication (methotrexate ≤ (less than or equal to) 25 mg once weekly intramuscularly or SC, or ≤ (less than or equal to) 15 mg once weekly orally; 6-MP ≤ (less than or equal to) 1.5 mg / kg / day; or AZA ≤ (less than or equal to) 2.5 mg / kg / day) for 4 weeks prior to endoscopy, through week 14. Reductions due to adverse events were allowed. Safety and Tolerability Assessment

[0521] Safety was assessed throughout the study by evaluating reported adverse events, clinical laboratory test results, vital sign measurements, electrocardiogram (ECG) findings, physical examination findings, and the use of concomitant medications. Local tolerance assessments were performed after each administration of TEV-48574 / placebo, and included application site findings (e.g., erythema, ecchymosis, induration, tenderness, fever, and swelling) and pain. Blood samples for anti-drug antibody (ADA) testing were collected throughout the study to show that TEV-48574 was not immunogenic. Adverse events, application site findings, and ADA reactions that occurred during treatment were recorded throughout the study to show that TEV-48574 was safe and tolerable. Efficacy and Safety Analysis

[0522] Results were analyzed to demonstrate the efficacy and dose response of 3 different dosing regimens of TEV-48574 administered subcutaneously (sc) every 2 weeks (Q2W) in adult patients with IBD (moderate to severe UC or CD) as assessed by induction of clinical remission (UC) and endoscopic response (CD) at Week 14. Efficacy was demonstrated based on response (yes or no) at Week 14, with response for UC patients defined as clinical remission and response for CD patients defined as endoscopic response.

[0523] As used herein, the term "clinical remission" of ulcerative colitis refers to clinical remission as determined by: Clinical remission is a modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score ≤ (less than or equal to) 2 points, which is defined by: The stool frequency subscore is 0 or 1, Rectal bleeding subscore of 0, and Endoscopic score is 0 or 1, where score 1 does not include "friability"

[0524] As used herein, the term "endoscopic response" in Crohn's disease refers to endoscopic response determined as follows: Endoscopic response was defined as a reduction of at least 50% from baseline in the simplified endoscopic score for Crohn's disease (SES-CD).

[0525] The following endpoints were also measured to demonstrate efficacy in patients with moderate to severe UC: Clinical response at Week 14, defined as a decrease of at least 2 points from baseline and at least 30% in the Modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score, with a decrease of at least 1 in the rectal bleeding subscore or an absolute rectal bleeding subscore of less than or equal to 1 Endoscopic improvement, defined as a Mayo endoscopic score of 0 or 1 at week 14 Endoscopic remission, defined as a Mayo endoscopic score of 0 at week 14 Clinical response, defined as at least a 50% reduction from baseline in 2 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 score = 0 and bowel movement frequency score = 0 on the PRO2 scale at weeks 2, 4, 6, 8, 10, 12, and 14 Histologic remission, defined as Robarts histopathology index ≤ (less than or equal to) 5 at week 14 Histologic response, defined as a Geboes Index score ≤ (less than or equal to) 3.1 at week 14

[0526] The following endpoints were also measured to demonstrate efficacy in patients with moderate to severe CD: Clinical response, defined as a decrease in Crohn's Disease Activity Index (CDAI) score of ≥ (greater than or equal to) 100 points from baseline at Weeks 2, 4, 6, 8, 10, 12, and 14 Clinical remission, defined as CDAI scores <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 at least a 50% reduction from baseline in PRO2 (PRO2 defined as having 2 components, abdominal pain and stool frequency) at Weeks 2, 4, 6, 8, 10, 12, and 14 Clinical remission, defined as upper abdominal pain ≤ (less than or equal to) 1 and bowel movement frequency ≤ (less than or equal to) 3 on the PRO2 scale at weeks 2, 4, 6, 8, 10, 12, and 14 Endoscopic response, defined as a >50% decrease from baseline in the modified multiplier (MM)-SES-CD at week 14 Histologic response, defined as a ≥50% reduction in the overall histologic activity score from baseline at Week 14

[0527] The following measures / parameters were analyzed to demonstrate safety and tolerability: Adverse events Changes from baseline in clinical laboratory test results (serum chemistry, hematology, and urinalysis) Changes from baseline in vital sign measurements (blood pressure, pulse rate, temperature, and 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 commercial SC infusion systems)

[0528] The following endpoints were analyzed to demonstrate lack of immunogenicity: Change from baseline in treatment-emergent anti-drug antibodies (ADA) at Weeks 2, 4, 8, 14 and follow-up Neutralizing ADA was present in ADA-positive patients at weeks 2, 4, 8, 14 and follow-up.

[0529] Efficacy and safety results were analyzed to demonstrate the efficacy and safety of the TEV-48574 dosing regimen. Example 2: Stability of Reconstituted TEV-48574 Drug Product Solution

[0530] To evaluate the in-use stability of the TEV-48574 reconstituted drug product.

[0531] For this study, TEV-48574 is presented in lyophilized form, at pH 6.0, in 10mM histidine, 5% (w / v) sucrose, 100mM arginine-hydrochloride (Arg-HCl), 0.02% (w / v) polysorbate-80 (PS-80), the protein concentration is 150mg / mL. The lyophilized formulation is contained in a 5cc vial with a bottleneck size of 20mm. The vial is stored at 2°C-8°C and allowed to reach room temperature before reconstitution. About 7 vials are reconstituted in each vial using 2.0mL sterile water for injection (WFI) to prepare a stock solution. The stock solution is then diluted into different falcon tubes using a formulation buffer (pH 6.0) of 10mM histidine, 5% (w / v) sucrose, 100mM Arg-HCl and 0.02% (w / v) PS80 to a concentration of 50, 20 and 5mg / mL. After dilution, 4 mL samples were incubated at 2°C-8°C in the dark for 24 hours, 72 hours and 10 days, and at room temperature under normal light conditions for 24 hours. Table 3 shows the specific time points and conditions tested. Table 3: Conditions and time points tested for stability study of reconstituted TEV-48574 Note: T0 = time zero

[0532] At each time point and at the end of the condition, samples were analyzed by visual appearance, pH, osmolarity, protein concentration, size exclusion chromatography (SEC), sodium dodecyl sulfate capillary gel electrophoresis (cSDS), capillary isoelectric focusing (cIEF), and subvisible particle analysis using microfluidics imaging (MFI).

[0533] No significant differences were observed in visual appearance, pH, osmolarity, and protein concentration among the reconstituted samples after dilution as shown in Table 4. In addition, the pH and osmolarity values ​​of the samples were within the limits of 6.0 ± 0.5 pH and 200-500 mOsm / kg, respectively. Table 4: Visual appearance, pH, osmolarity and protein concentration of the reconstituted product Note: T0 = time zero; RT = room temperature; C = clear solution, L = colorless, F = no visible particles

[0534] SEC analysis showed that the % monomer level of the antibody in the samples did not change significantly over the duration of the stability evaluation. See Table 5. These results indicate that storage of the diluted reconstituted drug product at 2°C-8°C for up to 10 days did not have any effect on the % monomer level after incubation. Table 5: Percentage levels of monomers in reconstituted products Note: T0 = time zero; RT = room temperature; HMW = high molecular weight species

[0535] cIEF analysis showed that dilution of the reconstituted drug product and its incubation at 2°C-8°C for up to 10 days did not have any significant effect on the charge heterogeneity profile of TEV-48574. See Table 6. Table 6: cIEF analysis of reconstituted products Conditions and timing Acidic substances% Main peak% Alkaline substances% 5mg / mL, T0 22.8 72.3 4.9 5 mg / mL, RT, 24 hours 23.1 71.8 5.1 5 mg / mL, 2°C-8°C, 24 hours 23.1 71.9 4.9 5 mg / mL, 2°C-8°C, 72 hours 24.2 70.1 4.7 5 mg / mL, 2°C-8°C, 10 days 23.0 72.6 4.4 20mg / mL, T0 20.2 75.3 4.5 20 mg / mL, RT, 24 hours 19.7 76.0 4.3 20 mg / mL, 2°C-8°C, 24 hours 19.9 75.1 5.1 20 mg / mL, 2°C-8°C, 72 hours 20.2 75.3 4.4 20 mg / mL, 2°C-8°C, 10 days 19.6 75.8 4.5 50mg / mL, T0 20.l 75.0 4.9 50 mg / mL, RT, 24 hours 19.5 76.2 4.2 50 mg / mL, 2°C-8°C, 24 hours 19.8 75.7 4.5 50 mg / mL, 2°C-8°C, 72 hours 19.7 76.1 4.3 50 mg / mL, 2°C-8°C, 10 days 19.0 76.8 4.2 Note: T0 = time zero

[0536] As shown in Table 7, cSDS analysis revealed that the reconstituted drug product had a purity of >90%, and dilution and incubation of the reconstituted drug product at different conditions and time points had no significant effect on the purity. Table 7: cSDS analysis of reconstituted products Note: NR = non-reducing; R = reducing; HC = heavy chain; LC = light chain; HMW = high molecular weight species; T0 = time zero; RT = room temperature

[0537] MFI analysis showed that the 50 mg / mL sample contained a slightly higher number of subvisible particles. See Table 8. However, when comparing the initial time point samples to the later time point samples, no significant increase in particle concentration was observed overall for the different concentration samples. Table 8: Particle size concentration of reconstituted products Note: T0 = time zero; RT = room temperature

[0538] In summary, these results show that the reconstituted TEV-48574 drug product is stable upon dilution after storage at 2°C-8°C protected from light for 10 days and at room temperature under normal light conditions for 24 hours. Example 3: Stability of TEV-48574 liquid formulations at 100 mg / ml and 150 mg / ml

[0539] The purpose of this study was to evaluate the long-term stability of liquid and lyophilized TEV-48574 formulations. Three formulations were tested: a lyophilized form 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 at pH 6.0 (Formulation 1); and two liquid forms 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 at pH 6.0 (Formulations 2 and 3, respectively). The stability of these formulations was evaluated in 5cc vials (Type I glass) under the following conditions: "standard" conditions (2°C-8°C), "accelerated" conditions (25°C±2°C / 60%±5% relative humidity (RH)), and "stressed" conditions (40°C±2°C / 75%±5% RH). In addition, the stability of Formulation 3 was evaluated under the same conditions, but the formulation was filled into a 2.25mL Nipro prefilled syringe (Nipro PFS) equipped with a West plunger stopper. The effects of these conditions on several product quality attributes were tested for the formulations. Visual appearance, protein concentration, osmolarity, and viscosity

[0540] The results of the visual appearance, protein concentration and osmotic pressure analysis of formulations 1-3 are shown in Tables 9-12. No significant differences were observed across formulations under standard storage conditions of 2°C-8°C. At intermittent time points, very few visible particles were observed. However, this may be related to the development nature of the study, in which the drug product was manually filled into vials. In addition, these particles are unlikely to be product-related because they do not increase over time and are not consistently detected at different time points in all samples. For the visual appearance under stress conditions of 40°C, the solution looks slightly yellow at a later time point. Compared to formulation 3 stored in glass vials for up to 24 months, no significant differences were observed between formulation 3 filled into Nipro PFS in terms of visual appearance, protein concentration, osmotic pressure and viscosity (data not shown), indicating that these attributes of the formulation are not affected by contact with Nipro PFS.

[0541] Under standard (2°C-8°C), accelerated (25°C) and stressed (40°C) conditions, the measured protein concentrations of all three formulations were close to the expected nominal concentrations and did not change over time. Similar trends were observed for osmotic pressure and viscosity measured under standard storage conditions at time zero (T0), 24 months (24M) and 36 months (36M), with no significant differences observed over time. Table 9: Visual appearance and protein concentration results at 2°C-8°C T0: time zero; M: month; F1: formulation 1; F2: formulation 2; F3: formulation 3; S: slightly milky; L: colorless; FFVP: contains no visible particles; SY: slightly yellow; NT: not tested Table 10: Osmotic pressure and viscosity results at 2°C-8°C T0: time zero; M: month; F1: formulation 1; F2: formulation 2; F3: formulation 3; NT: not tested Table 11: Visual appearance and protein concentration results at 25°C T0: time zero; WK: week; M: month; F1: formulation 1; F2: formulation 2; F3: formulation 3; S: slightly milky; L: colorless; FFVP: no visible particles; SY: slightly yellow; NT: not tested Table 12: Visual appearance and protein concentration results at 40°C T0: time zero; WK: week; M: month; F1: formulation 1; F2: formulation 2; F3: formulation 3; S: slightly milky; L: colorless; FFVP: no visible particles; SY: slightly yellow; NT: not tested Size Exclusion Chromatography (SEC)

[0542] Table 13-15 and Figures 2A-2C , 3A-3C and 4A-4C show the monomer percentage (%), dimer % and low molecular weight substances % of formulations 1, 2 and 3 measured by SEC. All three formulations stored under standard storage conditions of 2°C-8°C meet the acceptance criteria for monomer % and dimer % levels for up to 24 months and up to 36 months. Compared with formulation 1, a slight decrease in monomer % and a simultaneous increase in low molecular weight substances % were observed for formulations 2 and 3. However, considering that lyophilized formulations are typically more stable than liquid formulations, this is an expected observation. Under accelerated and stressed conditions, protein fragmentation is more common, indicating the formation of low molecular weight substances as the main degradation pathway for liquid formulations. The protein degradation rates of formulations 2 and 3 are similar, indicating that protein concentration has no significant effect on degradation. No significant differences were observed in the % monomer, % dimer, and % low molecular weight species up to 24 months between Formulation 3 filled into Nipro PFS compared to Formulation 3 stored in glass vials (data not shown), indicating that the stability characteristics of the formulations were not affected by contact with Nipro PFS. Table 13: Monomer %, dimer % and low molecular weight species % at 2°C-8°C LMW: low molecular weight substances Table 14: Monomer %, dimer % and low molecular weight species % at 25°C LMW: low molecular weight substances Table 15: Monomer %, dimer % and low molecular weight % at 40°C LMW: low molecular weight substances Capillary gel electrophoresis (reducing and non-reducing)

[0543] The percentage (%) of immunoglobulin G (IgG) + 125 kDa peak of formulations 1-3 was determined using non-reducing capillary gel electrophoresis (CGE). In addition, the heavy chain + light chain % of formulations 1-3 was determined using reducing CGE. These results are shown in Tables 16-17 and Figures 5A-5Cand 6A-6C. In all three formulations stored under standard storage conditions of 2°C-8°C, the purity % met the acceptance criteria for up to 24 months and up to 36 months. Under accelerated and stressed conditions, protein fragmentation was observed for Formulations 2 and 3 compared to Formulation 1. However, this was an expected observation, considering that lyophilized formulations are typically more stable than liquid formulations. In addition, the protein degradation trends for Formulations 2 and 3 were similar, indicating that protein concentration had no significant effect. No significant differences were observed between Formulation 3 filled into Nipro PFS in terms of IgG+125kDa peak % for up to 24 months compared to Formulation 3 stored in glass vials (data not shown), indicating that the stability characteristics of the formulations were not affected by contact with Nipro PFS. Table 16: % IgG + 125 kDa peak measured using non-reducing CGE at 2°C-8°C, 25°C and 40°C for Formulations 1, 2 and 3 NT: Not tested Table 17: Heavy and light chain % measured using reduced CGE at 2°C-8°C, 25°C and 40°C for Formulations 1, 2 and 3 NT: Not tested Capillary isoelectric focusing (icIEF)

[0544] Capillary isoelectric focusing (icIEF) was used to measure the content percentage (%) of the main substance (main peak), acidic substance (acidic peak) % and basic substance (basic peak) % of Formulations 1-3 (F1-F3). The results are shown in Tables 18-20. Figures 7A-7C , 8A-8C and 9A-9C. Under standard storage conditions of 2°C-8°C ( Fig. 7A , 8A and 9A), all three formulations (F1-F3) met the acceptance criteria for up to 24 months and up to 36 months. At accelerated (25°C; Figure 7B , 8B and 9B) and stress (40°C; Figure 7C , 8CUnder the storage conditions of 9C and 9C), a decrease in the main peak % and a simultaneous increase in the acidic substance % were observed for formulations 2 and 3. No significant changes were observed for formulation 1. However, considering that lyophilized formulations are typically more stable than liquid formulations, this is an expected observation. Compared to formulation 3 stored in glass vials, no significant differences were observed between formulation 3 filled into Nipro PFS in terms of the main peak %, acidic substance % and basic substance % for up to 24 months (data not shown), indicating that the stability characteristics of the formulations were not affected by contact with Nipro PFS. Table 18: Main peak %, acidic % and basic % determined using icIEF at 2°C-8°C for Formulations 1, 2 and 3 Table 19: Main peak %, acidic species % and basic species % determined using icIEF at 25°C for Formulations 1, 2 and 3 Table 20: Main peak %, acidic species % and basic species % determined using icIEF at 40°C for Formulations 1, 2 and 3 Subvisible particles using microfluidics imaging (MFI)

[0545] The subvisible particles in Formulations 1-3 were measured at different time points under standard conditions of 2°C-8°C, accelerated conditions of 25°C, and stressed conditions of 40°C. The results are shown in Tables 21-23, respectively. No significant changes in subvisible particles were observed. At intermittent time points, higher subvisible particles were observed compared to other time points. This may be related to the method in which greater variability and sensitivity of subvisible particles measured using MFI have been observed. Overall, the subvisible particles in the size range of ≥ (greater than or equal to) 10 μm were less than 6,000 particles / mL. In the size range of ≥ (greater than or equal to) 25 μm, even considering the increased sensitivity of using MFI for subvisible particle detection, the subvisible particles were less than 600 particles / mL and were well within the USP <788> No significant differences were observed in subvisible particles up to 24 months between Formulation 3 filled into Nipro PFS compared to Formulation 3 stored in glass vials (data not shown), indicating that the stability profile of the formulations was not affected by contact with Nipro PFS. Table 21: Subvisible particles of Formulations 1-3 at 2°C-8°C SbVP: Subvisible particles Table 22: Subvisible particles of Formulations 1-3 at 25°C SbVP: Subvisible particles Table 23: Subvisible particles of Formulations 1-3 at 40°C Chemical modification of primary structure using peptide mapping

[0546] The amino acids that may potentially undergo chemical modification and affect protein structure over time in formulations 1-3 were monitored. In particular, the amino acid residues methionine 81 and methionine 254 of TEV-48574 may potentially undergo oxidation, thereby affecting the primary structure, and were monitored. Similarly, asparagine 317 of TEV-48574 may potentially undergo deamidation, thereby producing succinimide, and were monitored. However, as shown in Tables 24-26, no significant changes in these modifications over time were observed. Under long-term storage conditions (2°C-8°C) for up to 24 months, compared to formulation 3 stored in glass vials, the results in terms of Met81 oxidation %, Asn317 deamidation % and Met254 oxidation % between formulation 3 filled into Nipro PFS were comparable (data not shown), indicating that the stability characteristics of the formulations were not affected by contact with Nipro PFS. Table 24: % Oxidation of Met81 in Formulations 1-3 NT: not tested; F1: Formulation 1; F2: Formulation 2; F3: Formulation 3; Met81: Methionine residue 81 of TEV-48574 Table 25: % Deamidation of Asn317 in Formulations 1-3 NT: not tested; F1: Formulation 1; F2: Formulation 2; F3: Formulation 3; Asn317: Asparagine residue 317 of TEV-48574 Table 26: % Oxidation of Met254 in Formulations 1-3 NT: not tested; F1: Formulation 1; F2: Formulation 2; F3: Formulation 3; Met254: methionine residue 254 of TEV-48574 Potency determined by ELISA

[0547] The percent potency (%) of Formulations 1-3 was determined by enzyme-linked immunosorbent assay (ELISA). The results are shown in Table 27. Under standard storage conditions (2°C-8°C), no significant changes were observed between the formulations, and the acceptance criteria of 70%-135% potency were met for up to 24 months and up to 36 months. No significant differences were observed between Formulation 3 filled into Nipro PFS in terms of potency % for up to 24 months compared to Formulation 3 stored in glass vials (data not shown), indicating that the stability characteristics of the formulations were not affected by contact with Nipro PFS. Table 27: Relative % potency of Formulations 1-3 as determined by ELISA NT: Not tested Differential Scanning Calorimetry (DSC) Analysis of Thermal Stability

[0548] DSC was used to evaluate the thermal stability of Formulations 1 to 3. DSC analysis was performed on time zero (T0) samples and 3-month, 6-month, and 36-month samples of Formulations 1 to 3 at 2°C-8°C, 25°C, and 40°C. Fig. 10A ( Fig. 10A ) shows the thermal stability of Formulations 1-3 at time zero (T0) and after 3 months at 2°C-8°C, 25°C and 40°C. Fig. 10B ( Fig. 10B ) shows the thermal stability of Formulations 1-3 at time zero (T0) and after 6 months at 2°C-8°C, 25°C and 40°C. Fig. 10C ( Fig. 10C ) shows the thermal stability of formulations 1-3 at time zero (T0) and after 36 months at 2°C-8°C. For the three formulations, no significant differences in thermal stability were observed at T0, 3 months, 6 months and 36 months because the transition temperatures (Tm) of all formulations overlap. A slight decrease in enthalpy was observed for formulations stored under accelerated and stressed conditions. This may be due to protein fragmentation observed in the samples under these conditions, resulting in a decrease in enthalpy. Compared to formulation 3 stored in glass vials, no significant differences were observed between formulation 3 filled into Nipro PFS in terms of thermal stability for up to 6 months, indicating that the stability characteristics of the formulations were not affected by contact with Nipro PFS. Secondary and tertiary protein structure analysis using circular dichroism (CD) spectroscopy

[0549] The secondary protein structure of Formulations 1-3 was analyzed using far ultraviolet (far UV) circular dichroism (CD), and the tertiary protein structure of Formulations 1-3 was analyzed using near UV CD. Secondary and tertiary structure analysis was performed on: time zero (T0) samples of Formulations 1, 2, and 3; 3 month samples at 2°C-8°C, 25°C, and 40°C; 24 month samples at 2°C-8°C; and 36 month samples at 2°C-8°C. The results are in Figures 11A-11F ( Figures 11A-11F ). In particular, Fig.11A Shown are the secondary structures of Formulations 1-3 at T0 and after 3 months at 2-8°C, 25°C and 40°C, determined using far UV CD. Fig. 11B Shown are the secondary structures of Formulations 1-3 at T0 and after 24 months at 2°C-8°C, determined using far UV CD. Fig. 11C Shown are the secondary structures of Formulations 1-3 at T0 and after 36 months at 2°C-8°C, determined using far UV CD. Fig.11D Shown are the tertiary structures of Formulations 1-3 at T0 and after 3 months at 2-8°C, 25°C and 40°C, determined using near UV CD. Fig.11E The tertiary structures of Formulations 1-3 at T0 and after 24 months at 2°C-8°C, determined using near UVCD, are shown. Fig.11F Shown are the tertiary structures of Formulations 1-3 at T0 and after 36 months at 2°C-8°C, determined using near UVCD.

[0550] The far UV CD spectra show a negative maximum at about 217 nm, indicating a beta-folded structure of the T0 sample in all three formulations, which is expected for a monoclonal antibody. The near UV CD spectra show a positive maximum at about 292 nm, indicating the absorption of tryptophan residues, and a negative maximum at 276 nm, indicating the absorption of tyrosine residues. For the three formulations, no significant changes in secondary or tertiary structure were observed for up to 3 months. At 24 and 36 months, slight changes in the CD spectra were observed at about 200 nm. This may be due to protein fragmentation, because the absorption in this region is mainly due to peptide bond absorption. However, no significant changes in the secondary structure of the protein (absorption at 217 nm) were observed.

[0551] Fig.13A Shown are the secondary structures 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) at 2°C-8°C, and after 3 months (3M) and 6 months (6M) at 25°C and 40°C, as determined using far UV CD. Fig. 13BThe tertiary structure of Formulation 3 stored in a Nipro prefilled syringe (PFS) at time zero (T0) and after 3 months (3M), 6 months (6M), and 24 months (24M) storage at 2°C-8°C and after 3 months (3M) and 6 months (6M) storage at 25°C and 40°C, as determined using near-UV CD, is shown. The spectra obtained for the Nipro PFS sample are comparable to those obtained for Formulation 3 stored in glass vials ( Figures 11A-11B and Figures 11D-11E ). Polysorbate 80 Analysis

[0552] The polysorbate 80 (PS80) present as surfactant / excipient in formulations 1-3 may potentially undergo degradation, which produces reactive peroxides that may affect protein stability during the shelf life of the product. After storage at 2°C-8°C for 24 months and 36 months, formulations 1-3 were subjected to PS80 analysis by testing PS80 levels. As shown in Table 28, in the 24-month samples in all formulations, the PS80 level measured was 0.02% (w / v), which was related to the expected PS80 concentration. At 36 months, the PS80 level in formulations 2 and 3 as liquid formulations showed a reduction. Compared with formulation 3 stored in a glass vial, no significant differences were observed in the PS80 level at 24 months between formulation 3 filled in Nipro PFS, indicating that the stability characteristics of the formulation were not affected by contact with Nipro PFS. Table 28: Polysorbate 80 (PS80) levels detected in Formulations 1-3 after 24 and 36 months storage at 2°C-8°C Preparations at 2°C-8°C PS80 level at 24M (w / v) PS80 level at 36M (w / v) Preparation 1 0.02％ 0.02％ Preparation 2 0.02％ 0.01％ Preparation 3 0.02％ 0.01％ in conclusion

[0553] The stability of TEV-48574 in lyophilized form (Formulation 1 at 100 mg / mL) was comparable to that of the liquid formulations at 100 mg / mL (Formulation 2) and 150 mg / mL (Formulation 3) stored at 2°C-8°C (standard storage conditions for drug products). Under accelerated (25°C) and stressed (40°C) conditions, both liquid formulations showed protein fragmentation as the major degradation pathway, which was not observed for lyophilized Formulation 1. However, this was an expected observation given that the lyophilized formulations were more stable compared to the liquid formulations.

[0554] Compared to the lyophilized formulation, the formation of acidic species was observed in the liquid formulation (measured using icIEF), and concomitant protein fragmentation was observed using SEC and CGE. This indicates deamidation of certain amino acid residues, potentially leading to fragmentation. See Wang, W. et al., J. Pharm. Sci., 96: 1-26 (2007).

[0555] Based on these data, lyophilized Formulation 1 can be bridged to 100 mg / mL and 150 mg / mL liquid formulations that have comparable stability characteristics and meet acceptance criteria for up to 24 months and up to 36 months at 2°C-8°C storage conditions.

[0556] Furthermore, the stability of 150 mg / mL TEV-48574 (Formulation 3) stored in Nipro PFS was found to be comparable to Formulation 3 samples stored in glass vials. Based on this data, storage for 24 months at 2°C-8°C (standard storage conditions for drug products) is compatible with Nipro PFS. Example 4: Further Clinical Evaluation of TEV-48574 in Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn's Disease

[0557] TEV-48574 was evaluated in a 24-week Phase 2b, randomized, double-blind long-term extension (LTE) study to assess 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 had completed the 14-week treatment period of the study described in Example 1 above. Fig.12 Presented in.

[0558] Eligible patients met all of the following criteria: Male and female adults (regardless of sex) who achieved clinical response and / or clinical remission at the time of informed consent in the 14-week study of Example 1. In patients with moderate to severe UC, clinical response at Week 14 in the Example 1 study was assessed by a decrease of ≥2 points from baseline and at least 30% in the modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score, with a decrease of ≥1 point in the rectal bleeding subscore or an absolute subscore of 0 or 1. Clinical remission in patients with moderate to severe UC at week 14 of the Example 1 study. Clinical remission is a modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score ≤ 2 points, which is defined by: ○ The bowel movement frequency subscore is 0 or 1, ○ Rectal bleeding subscore of 0, and o Endoscopic score was 0 or 1, where a score of 1 did not include "friability". - In patients with moderate to severe CD, clinical response assessed by a decrease in the Crohn's Disease Activity Index (CDAI) score of ≥ 100 points from baseline at Week 14 of the study in Example 1. - Clinical remission, defined as a CDAI score < 150 at Week 14 of the study in Example 1 for patients with moderate to severe CD.

[0559] Patients meeting 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). Universal Design

[0560] The study consisted of a 24-week treatment period and a 2-week follow-up period.

[0561] Randomization : In the 14-week study described in Example 1 above, patients who met the eligibility criteria at the end-of-treatment visit (EOT) were randomized in a 1:1 ratio (stratified by diagnosis [UC or CD]) to 1 of 2 treatment groups for a double-blind treatment period (see Table 29 below).

[0562] All study treatments were administered in a double-blind fashion as 1 SC infusion Q2W. Table 29: Randomization Scheme Randomization ratio Approximate number of planned randomizations Treatment (Q2W) 1 32UC+32CD TEV-48574 300 mg (12 maintenance doses) 1 32UC+32CD TEV-48574 900 mg (12 maintenance doses) CD = Crohn's disease; Q2W = every 2 weeks; UC = ulcerative colitis.

[0563] During the 24-week treatment period, patients visited the site Q2W for TEV-48574 administration (12 visits) on days 1, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, and 155 (±3 days), and visited the site on day 169 (±3 days) for endpoint assessment. After the 24-week treatment period, patients returned to the site for follow-up (Day 183 [±14 days]). Patients who completed follow-up were considered to have completed the study.

[0564] Patients were allowed to take the following medications as detailed below: Concomitant use of oral 5-ASA or sulfasalazine. Dosage must be stable during the transition period and throughout the study (Week 24). - Stable doses of oral corticosteroids (prednisone equivalents up to 20 mg / day; budesonide up to 9 mg / day) during the transition period and throughout the study (Week 24). Stable dose of immunosuppressant medication (methotrexate ≤ 25 mg intramuscularly or subcutaneously once a week, or ≤ 15 mg orally once a week; 6-MP ≤ 1.5 mg / kg / day; or AZA ≤ 2.5 mg / kg / day).

[0565] The following endpoints were analyzed to demonstrate lack of immunogenicity: Treatment-emergent anti-drug antibody (ADA) outcomes and responses: changes from baseline (Example 1 study) and across the study Neutralizing ADA in ADA-positive patients throughout the study If applicable, the impact of the presence of ADA on pharmacokinetics and clinical safety will be evaluated.

[0566] The following measures / parameters were analyzed to demonstrate safety and tolerability: Frequency of adverse events Changes from baseline (LTE baseline) in clinical laboratory test results (serum chemistry, hematology, and urinalysis) Changes in vital sign measurements (blood pressure, pulse rate, temperature, and 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 malfunctions (for commercial SC infusion systems).

[0567] The following efficacy endpoints were analyzed to demonstrate the efficacy of TEV-48574: Patients with UC who were in clinical remission at week 24 based on a modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo score ≤ 2, 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 "friability" • Endoscopic response, defined as at least a 50% reduction in the Simplified Endoscopic Score for Crohn's Disease (SES-CD) from Example 1 study baseline at Week 24 in patients with CD.

[0568] The following endpoints were also analyzed to demonstrate the efficacy of TEV-48574: Clinical response, based on a decrease of at least 2 points and at least 30% from baseline in the Example 1 study Modified (9-point rectal bleeding, stool frequency, and endoscopy) Mayo Score at Week 24 in patients with UC, with a decrease in the rectal bleeding subscore of at least 1 or an absolute rectal bleeding subscore of less than or equal to 1 Endoscopic improvement relative to baseline in the Example 1 study, based on a Mayo Endoscopic Score of 0 or 1 at Week 24 in patients with UC Endoscopic remission, based on a Mayo endoscopic score of 0 at week 24 in patients with UC Clinical response, defined as at least a 50% reduction from baseline in the Example 1 study in 2 patient-reported outcomes (PRO2; rectal bleeding and stool frequency) at Weeks 0, 4, 8, 10, 12, 16, 20, and 24 in patients with UC Based on clinical remission of PRO2 (rectal bleeding = 0 and stool frequency = 0) at weeks 0, 4, 8, 10, 12, 16, 20 and 24 in patients with UC Based on histologic remission of the Robarts Histopathology Index (RHI ≤ 5) at week 24 in patients with UC Histologic remission based on a Geboes index score ≤ 3.1 in patients with UC Clinical response based on the Crohn's Disease Activity Index (CDAI): A decrease of ≥ 100 points from baseline in the Example 1 study at Week 24 in patients with CD at Weeks 0, 4, 8, 10, 12, 16, 20, and 24 Based on clinical remission of patients with CD with a CDAI score <150 at weeks 0, 4, 8, 10, 12, 16, 20, and 24 Endoscopic remission based on SES-CD: Patients with CD who had an SES-CD score of 0-2 or an SES-CD score of 0-4 with no individual subscore >1 at week 24 Clinical response, defined as at least a 50% reduction in PRO2 from baseline in the Example 1 study at Weeks 0, 4, 8, 10, 12, 16, 20, and 24 in patients with CD Based on clinical remission of PRO2 (abdominal pain ≤ 1 and stool frequency ≤ 3) at weeks 0, 4, 8, 10, 12, 16, 20, and 24 in patients with CD Endoscopic response, defined as a >50% reduction in the modified multiplier (MM)-SES-CD from baseline in the Example 1 study at Week 24 in patients with CD - Histologic response of the global histologic activity score at Week 24 from Example 1 study baseline (≥50% reduction) in patients with CD. Example 5: Stability of 200 mg / ml TEV-48574 liquid formulation

[0569] The purpose of this study was to evaluate the long-term stability of a high concentration liquid TEV-48574 formulation compared to a lyophilized drug product. Two formulations were tested: a lyophilized form 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 at pH 6.0 (Formulation 4 or F4); and a liquid form 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 at pH 6.0 (Formulation 5 or F5). The stability of these formulations was evaluated in 5 cc vials with 20 mm sized stops under long-term storage conditions of 2°C-8°C. The effects of these conditions on several product quality attributes were tested for the formulations. Visual appearance, protein concentration, osmolarity, and viscosity

[0570] The results of the visual appearance, protein concentration and osmotic pressure analysis of Formulations 4 and 5 are shown in Tables 30 - 31. Under long-term storage conditions of 2°C - 8°C, no significant differences across formulations were observed.

[0571] Under long-term storage conditions of 2°C-8°C, the measured protein concentrations of both formulations were close to the expected nominal concentrations and did not change over time. The osmotic pressure and viscosity of the drug product were evaluated at time zero (T0). The osmotic pressure 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). Table 30: Visual appearance and protein concentration results at 2°C-8°C T0: time zero; M: month; F4: formulation 4; F5: formulation 5; S: slightly milky; O: milky; V: distinctly milky; L: colorless; FFVP: contains no visible particles; C: clear; VSY: distinctly slightly yellow; SP: slightly pink; NT: not tested Table 31: Osmotic pressure and viscosity results at 2°C-8°C T0: time zero; F4: preparation 4; F5: preparation 5 Size Exclusion Chromatography (SEC)

[0572] Table 32 and Figures 14A-14CThe monomer percentage (%), dimer % and low molecular weight species % of Formulations 4 and 5 measured by SEC are shown. Both formulations stored under long-term storage conditions of 2°C-8°C met the acceptance criteria for monomer % and dimer % levels for up to 24 months. A slight decrease in monomer % and a concurrent increase in low molecular weight species % were observed for Formulation 5 compared to Formulation 4. Table 32: Monomer %, dimer % and low molecular weight species % at 2°C-8°C LMW: low molecular weight substances; NT: not tested Capillary gel electrophoresis (reducing and non-reducing)

[0573] Non-reducing capillary gel electrophoresis (CGE) was used to determine the percentage (%) of the immunoglobulin G (IgG) + 125 kDa peak for Formulations 4 and 5. Additionally, reducing CGE was used to determine the heavy chain + light chain % for Formulations 4 and 5. These results are shown in Tables 33-34 and Figures 15A-15B In both formulations stored at long term storage conditions of 2°C-8°C, the % purity met the acceptance criteria for up to 24 months. Table 33: % IgG + 125 kDa peak measured using non-reducing CGE at 2°C-8°C for Formulations 4 and 5 Table 34: Heavy and light chain % measured using reduced CGE at 2°C-8°C for Formulations 4 and 5 Capillary isoelectric focusing (icIEF)

[0574] Capillary isoelectric focusing (icIEF) was used to measure the content percentage (%) of the main substance (main peak), acidic substance (acidic peak) % and basic substance (basic peak) % of Formulations 4 and 5 (F4 and F5). The results are shown in Table 35. The stability trend of charge heterogeneity is superimposed on Figures 16A-16C Under long-term storage conditions of 2°C-8°C ( Fig.16A , 16B and 16C), both formulations (F4 and F5) met the acceptance criteria for 24 months. Table 35: Main peak %, acidic % and basic % determined using icIEF at 2°C-8°C for Formulations 1 and 2 Subvisible particles using microfluidics imaging (MFI)

[0575] Subvisible particles were measured in Formulations 4 and 5 at different time points under long-term storage conditions at 2°C-8°C. The results are shown in Table 36. No significant changes in subvisible particles were observed. Overall, subvisible particles in the size range of ≥ (greater than or equal to) 10 μm were less than 6,000 particles / mL. In the size range of ≥ (greater than or equal to) 25 μm, even considering the increased sensitivity of using MFI for subvisible particle detection, subvisible particles were less than 600 particles / mL and well within the USP <788> This data indicates that the 200 mg / mL formulation (F5) has no significant effect on subvisible particle counts under long-term storage conditions. Table 36: Subvisible particles of Formulations 4 and 5 at 2°C-8°C SbVP: subvisible particles; NT: not tested Chemical modification of primary structure using peptide mapping

[0576] The amino acids that may potentially undergo chemical modification and affect the protein structure over time in formulations 4 and 5 were monitored. In particular, the amino acid residues methionine 81 and methionine 254 of TEV-48574 may potentially undergo oxidation, thereby affecting the primary structure, and are monitored. Similarly, asparagine 317 of TEV-48574 may potentially undergo deamidation, thereby producing succinimide, and is monitored. As shown in Table 37, under long-term storage conditions of 2°C-8°C, no significant changes in Met81 oxidation % and Met254 oxidation % over time were observed within 24 months. At the 24M time point, the liquid drug product (F5) showed a higher level of Asn317 deamidation compared to the lyophilized drug product (F4). This difference in the degree of Asn deamidation may be a result of the lower stability of the liquid drug product compared to the lyophilized drug product, and may not be attributed to the high nominal protein concentration in F5. Table 37: % oxidation of Met81, % deamidation of Asn317, and % oxidation of Met254 in Formulations 4 and 5 F4: Formulation 4; F5: Formulation 5; Met81: methionine residue 81 of TEV-48574; Asn317: asparagine residue 317 of TEV-48574; Met254: methionine residue 254 of TEV-48574 Potency determined by ELISA

[0577] The percent (%) potency of Formulations 4 and 5 was determined by enzyme-linked immunosorbent assay (ELISA). The results are shown in Table 38. Under long-term storage conditions (2°C-8°C), no significant changes were observed between the formulations, and the acceptance criteria of 70%-135% potency were met within 24 months. Table 38: Relative % potency of Formulations 4 and 5 as determined by ELISA Secondary and tertiary protein structure analysis using circular dichroism (CD) spectroscopy

[0578] The secondary protein structure of Formulations 4 and 5 was analyzed using far ultraviolet (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-month, 6-month, and 12-month samples of Formulation 4 at 25°C; and secondary structure analysis was performed on the T0 sample and 3-month and 12-month samples of Formulation 5 at 25°C. Tertiary structure analysis was performed on the time zero (T0) sample and 3-month and 12-month samples of Formulation 4 at 25°C; and tertiary structure analysis was performed on the T0 sample and 3-month, 6-month, and 12-month samples of Formulation 5 at 25°C. The results were Figures 17A-17B ( Figures 17A-17B ). In particular, Fig.17A Shown are the secondary structures of Formulation 4 (F4) at time zero (T0) and after 3 months (3M), 6 months (6M) and 12 months (12M) storage at 25°C, and Formulation 5 (F5) at T0 and after 3M and 12M storage at 25°C, as determined using far UV CD. Fig. 17B The tertiary structure of F4 at T0 and after storage at 25°C for 3M and 12M and F5 at T0 and after storage at 25°C for 3M, 6M and 12M, determined using near UV CD, is shown. No significant changes in secondary or tertiary structure were observed for the lyophilized formulation (F4) or the high concentration liquid formulation (F5). in conclusion

[0579] The stability of TEV-48574 in lyophilized form (100 mg / mL Formulation 4) was comparable to the 200 mg / mL liquid formulation (Formulation 5). Under long-term storage conditions of 2°C-8°C, drug product stability data was observed to be comparable for both formulations.

[0580] At the 24M time point, 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 may be a result of the lower stability of the liquid drug product compared to the lyophilized drug product and may not be due to the high nominal protein concentration in F2. A slight decrease in the % monomer and a concurrent increase in the % low molecular weight species were also observed for F5 compared to F4. However, lyophilized formulations are typically more stable than liquid formulations.

[0581] Based on these data, it was observed that the 200 mg / mL high concentration liquid drug product was stable at 2°C-8°C with no significant impact on the critical quality attributes of TEV-48574. Example 6: Evaluation of Arginine-HCl as an Excipient in TEV-48574 Liquid Formulations

[0582] The objective of this study was to evaluate the effectiveness of arginine-HCl (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 at pH 6.0 with either 150 mg / mL (Formulation 1A) or 100 mg / mL (Formulation 2A) of the drug product. Two additional formulations were prepared in 10 mM histidine, 5% (w / v) sucrose, 0.02% (w / v) PS-80 at pH 6.0 with either 150 mg / mL (Formulation 1B) or 100 mg / mL (Formulation 2B) of the drug product. The stability of these formulations was evaluated under stress storage conditions at 40°C. The effect of these conditions on product quality attributes was evaluated. Visual appearance, protein concentration, osmolarity, and viscosity

[0583] The results of the visual appearance, protein concentration and osmotic pressure analysis of formulations 1A-2A and 1B-2B are shown in Tables 39-41. Under stress storage conditions at 40°C, the visual appearance of formulations 1A and 1B was observed to be slightly yellow, potentially related to the degradation of these formulations over time at elevated temperatures. At 40°C, the measured protein concentrations of the four formulations were close to the expected nominal concentrations and did not change over time. The osmotic pressure and viscosity of the drug product were evaluated, and no significant differences were observed over time. Table 39: Visual appearance results at 40°C T0: time zero; WK: week; 1A: formulation 1A; 1B: formulation 1B; 2A: formulation 2A; 2B: formulation 2B; L: colorless; FFVP: contains no visible particles; O: milky white; SY: slightly yellow; VSY: clearly slightly yellow; S: slightly milky white Table 40: Protein concentration results at 40°C T0: time zero; WK: week; 1A: preparation 1A; 1B: preparation 1B; 2A: preparation 2A; 2B: preparation 2B Table 41: Osmotic pressure results at 40°C T0: time zero; WK: week; 1A: preparation 1A; 1B: preparation 1B; 2A: preparation 2A; 2B: preparation 2B

[0584] The osmotic pressure of Formulations 1A and 2A containing Arg-HCl was higher than that of Formulations 1B and 2B without Arg-HCl. It was observed that at 150 mg / mL, the viscosity of the Formulation without Arg-HCl (1B) was higher than that of the Formulation with Arg-HCl (1A), as shown in Tables 42 and Fig.18 as shown in . Table 42: Viscosity of Formulations 1A and 1B at 20°C T0: time zero; 1A: preparation 1A; 1B: preparation 1B Size Exclusion Chromatography (SEC)

[0585] Table 43-44 and Figures 19A-19C The monomer percentage (%), dimer % and fragment species % of formulations 1A-1B and 2A-2B measured by SEC after storage at 40°C for up to 8 weeks are shown. No significant differences in monomer % or fragment % were observed among the 4 formulations, as the reported values ​​were within the method variability. Formulations 1B and 2B without Arg-HCl showed an increased rate of dimer formation compared to formulations 1A and 2A containing Arg-HCl, indicating the stabilizing effect of Arg-HCl on the drug product. Table 43: % Monomer, % Dimer and % Fragment Species of Formulations 1A-1B at 40°C T0: time zero; WK: week Table 44: % Monomer, % Dimer and % Fragment Species of Formulations 2A-2B at 40°C T0: time zero; WK: week Capillary gel electrophoresis (reducing and non-reducing)

[0586] The percentage (%) of immunoglobulin G (IgG) +125 kDa peak of formulations 1A-1B and 2A-2B was determined using non-reducing capillary gel electrophoresis (CGE) under stress conditions at 40°C for up to 8 weeks. In addition, the heavy chain + light chain % of formulations 1A-1B and 2A-2B was determined 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 An increased fragmentation rate was observed for Formulations 1B and 2B lacking Arg-HCl compared to Formulations 1A and 2A containing Arg-HCl, demonstrating the stabilizing effect of Arg-HCl on the fragmentation pattern of the drug product. Table 45: % IgG + 125 kDa peak measured using non-reducing CGE at 40°C for Formulations 1A-1B and 2A-2B Time Preparation 1A Preparation 1B Preparation 2A Preparation 2B T0 98.5 98.4 98.4 98.4 1WK 98.0 98.1 98.1 98.2 2WK 97.7 97.8 97.8 97.9 3WK 97.5 97.5 97.3 97.4 4WK 96.9 97.0 96.9 97.1 6WK 96.2 96.1 96.2 96.5 8WK 95.5 95.3 95.4 95.6 T0: time zero; WK: week Table 46: % Heavy and Light Chains Measured Using Reduced CGE at 40°C for Formulations 1A-1B and 2A-2B Time Preparation 1A Preparation 1B Preparation 2A Preparation 2B T0 97.9 98.0 98.0 98.0 1WK 97.8 97.4 97.7 97.6 2WK 97.6 97.3 97.4 97.3 3WK 97.1 96.7 97.0 96.7 4WK 96.8 96.3 96.8 96.4 6WK 96.1 95.3 95.9 95.4 8WK 95.3 94.4 95.1 94.6 T0: time zero; WK: week Capillary isoelectric focusing (icIEF)

[0587] The content percentage (%) of the main species (main peak), acidic species (acidic peak) % and basic species (basic peak) % of 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. Figures 21A-21C For Formulations 1B and 2B lacking Arg-HCl, slightly higher levels of acidic species were observed at the end of 8 weeks. This may be related to the significantly higher fragmentation rates of these formulations compared to Formulations 1A and 2A, as reported in Table 46. Table 47: Main peak %, acidic % and basic % determined using icIEF at 40°C for Formulations 1A and 1B T0: time zero; WK: week Table 48: Main Peak %, Acidic %, and Basic % determined using icIEF at 40°C for Formulations 2A and 2B T0: time zero; WK: week Chemical modification of primary structure using peptide mapping

[0588] Formulations 1A-1B and 2A-2B were monitored for amino acids that could potentially undergo chemical modification over time and affect protein structure under stress conditions at 40°C for up to 8 weeks. In particular, amino acid residues methionine 81 and methionine 254 of TEV-48574 could potentially undergo oxidation, thereby affecting primary structure, and were monitored. Similarly, asparagine 317 of TEV-48574 could potentially undergo deamidation, thereby producing succinimide, and were monitored. No significant changes were observed over time in Met81 oxidation %, Asn317 deamidation %, or Met254 oxidation % under stress storage conditions at 40°C for up to 8 weeks (data not shown), indicating that the presence of Arg-HCl did not appear to have an effect on this property. Potency determined by ELISA

[0589] The percent potency (%) of Formulations 1A-1B and 2A-2B was determined by enzyme-linked immunosorbent assay (ELISA) under stress storage conditions at 40° C. for up to 8 weeks. The results are shown in Table 49. The trend of the potency % was comparable among the formulations regardless of drug product concentration or the inclusion of Arg-HCl. Table 49: Relative % potency of Formulations 1A-1B and 2A-2B as determined by ELISA T0: time zero; WK: week; 1A: preparation 1A; 1B: preparation 1B; 2A: preparation 2A; 2B: preparation 2B Dynamic Light Scattering (DLS) for Particle Size Characterization

[0590] DLS was used to measure the polydispersity % (PD%) and hydrodynamic radius of the drug product and nanoparticles that may be present 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. It was observed that the apparent hydrodynamic radius of formulations 1B and 2B (without Arg-HCl) was smaller than that of formulations 1A and 2A (with Arg-HCl). Table 50: Polydispersity % (PD%) and Radius of Particles of Formulations 1A-1B and 2A-2B T0: Time Zero Differential Scanning Calorimetry (DSC) Analysis of Thermal Stability

[0591] DSC was used to evaluate the thermal stability of Formulations 1A-1B and 2A-2B.DSC analysis was performed on time zero (T0) samples of Formulations 1A-1B and 2A-2B. Fig. 22 The thermal stability of Formulations 1A-1B and 2A-2B at time zero (T0) is shown, and Table 51 shows the DSC thermograms for all four formulations. onset is about 60°C, and the T of Formulations 1B and 2B onset was about 63° C. For all formulations, the transition temperature (Tm) was about 78° C. Table 51: DSC Thermograms of Formulations 1A-1B and 2A-2B Preparations Tm1(℃) Tm2(℃) 1A 67.9 78.8 1B 71.2 79.8 2A 67.5 78.6 2B 70.7 79.5

[0592] The Tm1 of Formulations 1A and 2A was found to be slightly shifted to lower temperatures, demonstrating that Arg-HCl may affect the thermal stability of the molecule. This may be due to protein fragmentation observed in the samples under these conditions, resulting in a decrease in enthalpy. However, this temperature is higher than the recommended storage condition of 2°C-8°C for this drug product. in conclusion

[0593] The effectiveness of arginine-HCl (Arg-HCl) as an excipient and its effect on the stability of the TEV-48574 drug product were evaluated in two different drug product concentrations (100 mg / mL and 150 mg / mL). For all 4 formulations tested, the quality attributes of dimer% and purity% measured using reduced CGE indicated the stabilizing effect of 100 mM Arg-HCl compared to formulations without Arg-HCl. The viscosity of the drug product with Arg-HCl at 150 mg / mL was lower than that of the formulation without Arg-HCl. A slight shift of about 3 ° C of Tm1 analyzed by DSC was observed for the formulation containing Arg-HCl. However, the recommended storage conditions for drug products are 2 ° C-8 ° C, so it is expected that this observed shift of Tm1 will not significantly affect the stability during typical storage and handling conditions. At 40 ° C, all other attributes did not show significant changes in 8 weeks in all 4 formulations.

[0594] Based on these data, 100 mM Arg-HCl in the TEV-48574 formulation has shown the potential to stabilize the formulation and minimize viscosity as the concentration of drug product increases. Example 7: Pharmacokinetic and Pharmacodynamic Analysis of Non-Human Primate (NHP) Response to TEV-48574

[0595] The purpose of this study is to evaluate the pharmacokinetic (PK) properties of TEV-48574 in cynomolgus monkeys after a single subcutaneous (sc) administration of TEV-48574 at a dose of 5 mg / kg. Pharmacodynamic (PD) analysis was also performed on free and total TL1A in serum samples. In this study, 4 cynomolgus monkeys were treated with a single subcutaneous dose of TEV-48574 at a dose level of 5 mg / kg. Blood sampling was performed on day 0 (pre-dose) and days 0.25, 1, 2, 3, 4, 5, 7, 9, 11, 14, 21, 28 and 35 and analyzed for PK (TEV-48574) and PD (free and total TL1A).

[0596] For PK assessment, serum samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) method to determine TEV-48574 concentrations. PK parameters for TEV-48574 were estimated by non-compartmental analysis from individual serum concentrations versus time curves (Gibaldi, M. and Perrier, D. (eds.) (1982). Pharmacokinetics [pharmacokinetics] (2nd edition) CRC Press). Serum concentrations below the limit of quantitation (i.e., <100 ng / mL) were designated as "BLQ". For the purpose of calculating the mean concentration, all BLQ values ​​were considered zero.

[0597] Maximum serum concentration (C max ) is the highest serum concentration observed. max It is observed that C max The terminal rate constant (λ) for elimination from serum was determined by linear regression of the terminal portion of the semi-logarithmic serum concentration versus time curve. z The terminal phase of each curve was identified by visual inspection of the data. z Determine, including at least 3 non-BLQ concentrations. Terminal half-life (t 1 / 2 ) is calculated as ln(2) divided by λ z If the adjusted r 2 ≥0.8 and estimate λ z The time interval is approximately the same as the corresponding λ z is the same length or longer, then λ z The area under the serum concentration versus time curve (AUC) from time zero to the time of the last measurable concentration was determined by linear trapezoidal summation. 0-t The area under the serum concentration versus time curve from time zero to infinity (AUC 0-∞ ) is calculated as AUC 0-t and the area extrapolated to infinity from the time of the last measurable serum concentration (C last / λ z ), and if the extrapolated AUC0-∞ The percentage of [(AUC 0-∞ -AUC 0-t ) / (AUC 0-∞ )×100] < 20%, it was considered reliable. PK parameters were estimated using nominal sample collection times.

[0598] The concentration of TEV-48574 was BLQ in all pre-dose samples and was quantifiable in all animals at the first post-dose sampling point (i.e., at 6 hours). Intra-animal variability was generally low at early time points and then increased from day 11. In all animals, serum concentrations were fairly constant from day 1 or 2 to day 9, 11, or 21; for animals SC1607075 (days 2-11), SC1511041 (days 1-9), SC1607037 (days 1-9), and SC1506091 (days 1-21), the coefficients of variation (CV) of concentrations within these timetables were 6.1%, 8.7%, 6.4%, and 13.7%, respectively, and mainly reflected absorption and distribution. Thereafter, concentrations dropped sharply and were BLQ from day 14 or day 21, except for monkey SC1506091. Analysis of monkey anti-TEV-48574 antibodies by ELISA confirmed the presence of inducible ADA in day 14, day 21, and day 35 serum samples from all animals.

[0599] The serum TEV-48574 concentration-time profile of each animal was analyzed by non-compartmental analysis (NCA), and the PK parameters are presented in Table 52. Absorption after SC administration was consistent among animals. max The range was 3 to 5 days (median = 4 days), and in 4 monkeys C max are similar (CV = 18.4%). However, t 1 / 2 The AUC values ​​were variable. Target-mediated clearance of TEV-48574 was not evident in this study. Table 52: Pharmacokinetic parameters of TEV-48574 in cynomolgus monkeys administered a single 5-mg / kg SC dose of TEV-48574 a: Adjusted R 2 <0.8; b: median; c: extrapolated %>20%

[0600] The presence of total TL1A (free and bound to TEV-48574) in NHP serum samples was tested 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 plates were incubated for 60 minutes at 500 rpm shaking at a temperature range of 20°C-23°C. After the blocking step, the wells were aspirated and then coated with a 2 μg / mL stock solution of biotinylated rabbit anti-TL1A polyclonal antibody diluted into diluent A. Capture antibody coating was performed for 60 minutes, shaking at 500 rpm at a temperature range of 20°C-23°C. The wells in 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. For use as an assay standard, a 5000 pg / mL recombinant cynomolgus monkey TL1A protein stock solution and six subsequent 1:4 dilutions were prepared in Diluent A. To designated assay wells, either the recombinant monkey TL1A protein standard or one of the 1:4 dilutions of NHP serum in Diluent A was added. The assay plate was then incubated at 20°C-23°C with shaking at 500 rpm for 1 hour.

[0601] After incubation with standards and serum samples, the wells were washed with wash buffer. To saturate any free TL1A captured in the wells, a 2 μg / mL stock solution of unconjugated TEV-48574 diluted in diluent A was added. After incubation for 60 minutes at 500 rpm with shaking at a temperature range of 20°C-23°C, the wells were washed again. For detection, a 1 μg / mL stock solution of sulfonyl-labeled goat anti-human IgG polyclonal antibody diluted in diluent A was added to the assay wells. The detection antibody was incubated at 500 rpm with shaking in the dark at a temperature range of 20°C-23°C for 1 hour. After incubation with sulfonyl-labeled goat anti-human IgG polyclonal antibody, the wells were washed again with wash buffer. Reading buffer was added to the assay wells and the ECL signal was measured using a MesoScale Discovery (MSD) Sector Imager 600. The calculated total TL1A concentration in the NHP serum samples was then determined. An increase in total TL1A ( Fig.23A ) were modest and consistent with results obtained in first-in-human studies.

[0602] To determine the levels of free TL1A (not bound to TEV-48574) in NHP serum samples (i.e., the same NHP serum samples used to determine total TL1A levels), a 96-well plate immunoassay and ECL detection were performed. Briefly, each 96-well plate was blocked with diluent A. The plate was incubated for 60 minutes at 500 rpm with shaking at a temperature range of 20°C-23°C. After the blocking step, the wells were aspirated and then coated with a 2 μg / mL stock solution of a biotinylated rabbit anti-TL1A polyclonal antibody diluted into diluent A. Capture antibody coating was performed for 60 minutes with shaking at 500 rpm at a temperature range of 20°C-23°C. The wells in the 96-well plate were then washed with wash buffer. After washing, diluent A was added to each well. For use as an assay standard, a 5000 pg / mL recombinant cynomolgus monkey TL1A protein stock solution and six subsequent 1:4 dilutions were prepared in diluent A. Add one of the 1:4 dilutions of recombinant monkey TL1A protein standards or NHP serum in diluent A to the designated assay wells. The assay plate is then incubated at 500 rpm for 1 hour at a temperature range of 20°C-23°C with shaking. After incubation with the standards and serum samples, the wells are washed with wash buffer. For detection, a 1 μg / mL stock solution of sulfo-labeled TEV-48574 diluted in diluent A is added to the assay wells. The detection antibody is incubated at 500 rpm for 1 hour at a temperature range of 20°C-23°C with shaking (protected from light). After incubation with sulfo-labeled TEV-48574, the wells are washed with wash buffer. Read buffer is added to the assay wells. The ECL signal is measured using an MSD Sector Imager 600. The calculated free TL1A concentration in the NHP serum sample is then determined.

[0603] Compared to total TL1A levels measured in NHP serum samples, free TL1A levels were found to be suppressed in all animals, well below pre-dose baseline, for at least 14 days. Pre-dose baseline TL1A levels ranged from 43 to 106 pg / mL and fell below the limit of quantification at the earliest time point after dosing (6 hours). From days 2 to 14, levels remained low, only 10% to 40% of baseline. By day 21, levels returned to baseline. The observed duration of suppression may be an underestimate due to anti-drug antibody responses observed from day 14 ( Fig. 23B ).

[0604] This NHP data provides evidence that, unlike other mAbs against TL1A, effective target engagement of TEV-48574 as measured by free TL1A is not reflected as a large increase in total TL1A. Thus, TEV-48574 results in deep and sustained inhibition of free TL1A. The PD effect reflected in the inhibition of free TL1A levels is more pronounced than that reflected by the half-life (T 1 / 2=3.0+ / -1.9 days) predicted a longer effect, suggesting that a dosing interval of every 4 weeks could also be used. Example 8: Population Pharmacokinetic (PPK) Modeling and Simulation of TEV-48574 Dosing Regimens

[0605] A comparison of exposure between TEV-48574 and RVT-3101 (formerly known as PF-06480605 and described in PCT Publication Nos. WO 2015 / 073580 A1 and WO 2021 / 260577, each of which is incorporated herein by reference) was performed using population pharmacokinetic (PPK) modeling and simulation methods. These calculations were intended to describe the time course of serum TEV-48574 concentrations in healthy and asthmatic participants obtained from three clinical studies involving TEV-48574, including single ascending dose (SAD) data from healthy participants in the TV48574-SAD-10126 study, multiple ascending dose (MAD) data from asthmatic patients in the TV48574-SAD-10126 study, and single dose data from healthy participants (Japanese and Caucasians). Data selection and one or more study designs

[0606] 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 reach maximum observed serum drug concentration (t max ); the area under the serum concentration-time curve (AUC 0-t ); the area under the serum concentration-time curve extrapolated to infinity (AUC 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 the associated terminal (apparent elimination) half-life (t 1 / 2 ); apparent total body clearance (CL / F); and apparent volume of distribution during the terminal phase (V z / F). Single Ascending Dose (SAD) Data from the TV48574-SAD-10126 Study in Healthy Participants

[0607] The SAD portion of the TV48574-SAD-10126 study is a single-center, randomized, double-blind, placebo-controlled, parallel-group Phase 1 study to evaluate the safety, tolerability, PK, and immunogenicity of TEV-48574 in approximately 64 healthy adult men and women aged 18 to 60 years. The SAD portion consists of a screening period, an ambulatory visit, an ADA assessment, an end-of-treatment (EOT) visit on Day 22, and an end-of-study visit on Day 57.

[0608] On Day 1, subjects were administered placebo or a SC injection of 1, 4, 12, 36, 90, 200, 400, or 1000 mg TEV-48574.

[0609] Pharmacokinetic parameters were based on the pharmacokinetic analysis set, which consisted of those subjects in the safety analysis set who had at least 1 measurable concentration of TEV-48574. All 48 subjects who received TEV-48574 in the SAD portion of the study were eligible for the pharmacokinetic analysis set.

[0610] After the single dose SC administration of 1mg and 4mg TEV-48574, all serum TEV-48574 concentrations were BLQ (<200ng / mL). After the administration of 12mg, 36mg, 90mg, 200mg, 400mg and 1000mg TEV-48574, serum TEV-48574 concentration increased with increasing dose. For 12mg, 36mg and 90mg doses, 6 hours after administration, and for 200mg, 400mg and 1000mg dose levels, at the first time point (1 hour after administration), TEV-48574 serum concentration is quantifiable. Typically, TEV-48574 peak serum concentration is reached between 72 and 96 hours after administration. After reaching peak concentration, TEV-48574 is gradually eliminated in a monophasic manner. The elimination rate across dose levels seems similar.

[0611] TEV-48574 serum concentrations were quantifiable 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.

[0612] Following a single SC dose of TEV-48574, the median t values ​​of TEV-48574 in serum were 1.3 % for the 12 mg, 36 mg, and 90 mg dose cohorts. max occurred at 96 hours and at 72 hours for the 200 mg, 400 mg, and 1000 mg dose cohorts.

[0613] Geometric mean peak serum concentration (C max ) and total systemic exposure (AUC 0-t and AUC 0-∞ ) increased with increasing dose from 12 mg to 1000 mg. Peak and total systemic exposure increased from 36 mg to 1000 mg and appeared to be slightly greater than dose proportional. Peak and total systemic exposure increased from 200 mg to 1000 mg and appeared to be dose proportional.

[0614] Average t 1 / 2 The estimated values ​​range from 155.85 to 230.88 hours (i.e., approximately 6.5 to 9.6 days). Average CL / F and V z The estimated values ​​for V / F ranged from 0.66 to 1.71 L / day for CL / F and from 8.24 to 15.13 L / day for V z / F).

[0615] The variability (CV%) of systemic exposure parameters ranged from 23.57% to 53.43% at all dose levels (for C max ) and 17.03% to 61.27% (AUC 0-t and AUC 0-∞ ), as shown in Table 53. Table 53: Summary of TEV-48574 Serum Pharmacokinetic Parameters by SAD Cohort According to SAP, if the extrapolation percentage is > 20% and / or the estimated λ z The interval is shorter than the corresponding t 1 / 2 , then λ is not reported z parameter. BLQ = below limit of quantitation; max = maximum; Min = minimum; N = total number of subjects; n = number of subjects with evaluable data; SAD = single ascending dose; SAP = statistical analysis plan; SD = standard deviation. Note: Serum pharmacokinetic parameters could not be calculated for Cohort 1 (1 mg) and Cohort 2 (4 mg) because all serum TEV-48574 concentrations were BLQ (<200 ng / mL).

[0616] Systemic absorption of SC TEV-48574 was slow in all cohorts. Median t max96 hours in the 12 mg, 36 mg, and 90 mg dose cohorts and 72 hours in the 200 mg, 400 mg, and 1000 mg dose cohorts. PK parameters could not be calculated after the 1 mg and 4 mg doses due to serum TEV-48574 bioassay limitations (BLQ < 200 ng / mL for all concentrations). The dose increase of TEV-48574 from 12 mg to 1000 mg resulted in a peak TEV-48574 (C max ) and total (AUC) systemic exposure were increased.

[0617] Use TEV-48574 exposure parameters (C max , AUC 0-t and AUC 0-∞ ) Evaluation of dose proportionality indicated that the increase in exposure from 36 mg to 1000 mg was greater than dose proportional. Within the 200 mg to 1000 mg dose range, the increase in exposure was proportional to the dose. TEV-48574 was shown to have a half-life of generally more than 6.5 days (range: 155.85 to 230.88 hours, i.e., approximately 6.5 to 9.6 days) and was not affected by dose level. Mean CL / F and V z The estimated values ​​for V / F ranged from 0.66 to 1.71 L / day for CL / F and from 8.24 to 15.13 L / day for V z / F).

[0618] In the SAD part of this study, after a single SC dose of 1mg, 4mg, 12mg, 36mg, 90mg, 200mg, 400mg and 1000mg TEV-48574 in healthy volunteers, the pharmacokinetics of TEV-48574 are characterized by the slow absorption of the drug into the systemic circulation. After 1mg and 4mg doses, all TEV-48574 serum concentrations are BLQ. Typically, TEV-48574 peak serum concentrations are reached between 72 and 96 hours after administration. After reaching peak concentrations, TEV-48574 is gradually eliminated in a monophasic manner. The elimination rate across dose levels seems similar.

[0619] In the SAD part, TEV-48574 peak (C max ) and total (AUC 0-t and AUC 0-∞ ) Systemic exposure increased with increasing dose. From 36 mg to 1000 mg, the increase in TEV-48574 exposure was greater than dose proportional, which was reflected by C max The 90% CIs for the estimated slopes and AUC do not include a unity (1.0) indication. Over the 200 mg to 1000 mg dose range, increases in exposure were dose proportional.

[0620] TEV-48574 in the SAD section 1 / 2 was similar across the dose range studied; TEV-48574 had a half-life generally exceeding 6.5 days in all SAD cohorts (range: 155.85 to 230.88 hours, i.e., approximately 6.5 to 9.6 days). For CL / F, mean estimates were similar across the dose range. z / F was also similar over the dose range studied in the SAD portion (8.24 to 15.13 L), indicating that TEV-48574 was primarily confined to the circulatory system.

[0621] Overall, statistical analysis of dose proportionality following single doses (ranging from 36 to 1000 mg) in the SAD indicated slight supraproportionality in TEV-48574 pharmacokinetics. However, TEV-48574 half-life, CL / F, and V z / F appears to be similar, 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 not be very relevant because only doses of 200 mg or greater were introduced in the MAD part. Multiple Ascending Dose (MAD) Data from the TV48574-SAD-10126 Study in Asthma Patients

[0622] The MAD portion of the TV48574-SAD-10126 study is a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety, tolerability, PK, and immunogenicity of TEV-48574 in approximately 36 male and female symptomatic asthma patients aged 18 to 65 years after three doses administered as SC injections. The MAD portion consists of a prescreening period (optional) and screening period, a 14- to 28-day run-in / washout period, an internal period, an ambulatory visit, an ADA assessment, an EOT visit (Day 43), and an end-of-study visit (Day 92).

[0623] Patients in the MAD portion of the study were assigned to 1 of 3 cohorts (N=12 per cohort) to receive SC doses of TEV-48574 or placebo Q2W 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 as a SC injection using a standardized syringe, followed by 600 mg Q2W; or (3) 2300 mg as an approximately 1-hour SC infusion, followed by 1600 mg. In each cohort, 3 participants were randomized to TEV-48574 (N=2) or placebo (N=1) 72 hours prior to the other participants. If stopping criteria are not met and no safety issues related to TEV-48574 have been identified 72 hours after administration of TEV-48574 to the first 3 patients, as determined by the principal investigator, the remaining patients in the cohort will be randomized to receive TEV-48574 (7 patients) or placebo (2 patients). Patients may be dosed individually or in cohorts at the discretion of the principal investigator.

[0624] After the first SC dose of TEV-48574 on day 1, the geometric mean C max , AUC 0-t and AUC τ The variability in exposure ranged from 42.3% to 83.7% (for C max ), 38.0% to 77.3% (for AUC 0-t ) and 40.8% to 92.6% (for AUC τ )(Geometric CV%). For the 200 mg, 800 mg, and 2300 mg dose cohorts, the median tmax of TEV-48574 in serum occurred at approximately 3 days (range: 2.97 to 2.99 days).

[0625] After multiple SC doses, TEV-48574 geometric mean C max , AUC 0-t and AUC τ The increases were 6.85-fold, 7.93-fold, and 5.24-fold on Day 15, and 6.38-fold, 9.26-fold, and 5.35-fold on Day 29, respectively, with an 8-fold increase from 200 mg to 1600 mg. For patients without treatment-emergent ADA, the variability (geometric CV%) after multiple dose exposure (Days 15 and 29) ranged from 31.1% to 78.2% (for C max ), 24.6% to 74.2% (for AUC0-t ) and 23.0% to 74.1% (for AUC τ Overall, the variability of exposure (C max , AUC 0-t and AUC τ ) were moderate and were similar after each administration of TEV-48574. In addition, the median t max Similar to the first dose, and ranged from 2.96 to 3.00 days over the dose range studied, as shown in Table 54. Table 54: Summary of TEV-48574 Serum Pharmacokinetic Parameters by MAD Cohort CV = coefficient of variation; ld = loading dose; MAD = multiple ascending dose; max = maximum value; md = maintenance dose; min = minimum value; N = total number of patients; n = number of patients with evaluable data; PK = pharmacokinetics; SD = standard deviation. Note: AUC τ Represents the AUC over the 14-day dosing interval. Concentration values ​​at three PK sample time points were considered physiologically implausible and removed from the non-compartmental analysis; Patient 14072011 (Cohort 2, Day 29, 120 hours), Patient 14071008 (Cohort 2, Day 29, 24 hours), and Patient 14074014 (Cohort 3, Day 29, 120 hours).

[0626] The elimination period of TEV-48574 was not well defined after administration of TEV-48574 on days 1 and 15, as the 14-day sample collection period after the first and second doses was insufficient to reliably calculate the elimination half-life. 0-∞ ,t 1 / 2 , CL / F and V z / F is discussed only after the last dose was administered on Day 29. After Day 29, the mean t 1 / 2 The values ​​ranged from 8.3 to 8.7 days within the dose range studied. Dose level did not appear to affect TEV-48574 elimination rate. In addition, at day 29, mean CL / F and V z / F was similar between dose levels, ranging from 0.043 to 0.072 L / h and 11.79 to 21.06 L, respectively.

[0627] For each dosing interval, the accumulation of TEV-48574 serum exposure after multiple SC dosing was evaluated. For Cohort 1, the serum exposure from the first dose to the second dose (AUC τ , Day 15 / AUC τ , day 1), from the first dose to the third dose (AUC τ , Day 29 / AUC τ , day 1) and from the second to the third dose (AUC τ , Day 29 / AUC τ , day 15) observed average accumulation ratio (R obs ) were 1.472, 1.64, and 1.057, respectively. There was some accumulation from the first dose to the second dose and the third dose, but since there was no accumulation from the second dose to the third dose, steady state appeared to be reached. For cohort 2, the observed mean accumulation (R obs ) were 1.319, 1.374, and 1.107, respectively. Even at 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. For cohort 3, the observed mean accumulation (R) from the first dose to the second dose, from the first dose to the third dose, and from the second dose to the third dose was obs ) were 1.039, 1.07, and 1.054, respectively. After the loading dose, cohort 3 exposure did not appear to accumulate with subsequent dosing, suggesting that steady state was reached after the loading dose was administered.

[0628] The pharmacokinetics of TEV-48574 were characterized in patients with mild allergic asthma in the MAD portion of this study. Consistent with the results of the SAD portion of healthy volunteers, the pharmacokinetics of TEV-48574 in patients were characterized by slow absorption of TEV-48574 into the systemic circulation. The t of TEV-48574 at steady state was 1 / 2 (MAD portion) ranged from 8.3 to 8.7 days and was not affected by dose level. The half-life estimates appeared similar to those in the SAD portion of the study, where TEV-48574 half-life was generally greater than 6.5 days in all cohorts. For CL / F, the mean estimates were similar across the dose range tested in the MAD portion and were similar to the CL / F observed in the SAD portion. z / F was similar across the dose range studied in the MAD portion (11.79 to 21.06 L), indicating that TEV-48574 was primarily restricted to the circulatory system, consistent with results observed in the SAD portion of the study.

[0629] TEV-48574 peak (C max ) and total (AUC τ ) Systemic exposure increased with increasing dose. TEV-48574 exposure increased in a dose-proportional manner from 200 mg to 2300 mg on day 1 and from 200 mg to 1600 mg at steady state, as measured by C max The 90% CI and AUC of the estimated slope τ The MAD dose proportionality results did not match those of the SAD portion of the study, indicating slight supraproportionality when increasing the dose from 36 mg to 1000 mg; however, the increase in exposure was dose proportional over the 200 mg to 1000 mg dose range in the SAD portion.

[0630] Factors such as physiological factors, low subject numbers per cohort, parallel design, dose volume, 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 for the SAD portion of the study, but the increase in exposure was dose-proportional over the 200 mg to 1000 mg dose range in the SAD portion and across the dose range in the MAD portion. In addition, TEV-48574 half-life, CL / F, and V z / F appears to be similar in all doses, indicating linear pharmacokinetics. In the absence of a loading dose, there was a weak accumulation (approximately 47%) after the first dose in cohort 1 in the MAD portion of the study. After the loading dose was administered to cohort 2, there was also a weak accumulation (approximately 32%), indicating that the loading dose may be too low to achieve steady state as quickly as expected, while the loading dose for cohort 3 achieved steady state conditions after the loading dose was administered. For all dose regimens, steady state was achieved after the second dose. Single-dose data from an additional Phase 1 study in healthy participants (Japanese and Caucasians)

[0631] This study is an open-label, randomized, Phase 1 SC single-dose study to evaluate the PK, safety, and tolerability of TEV-48574 in healthy Japanese and Caucasian participants. On Day 1, Japanese participants received 400 mg, 1000 mg, or 2300 mg SC injections (8 participants per dose level), and Caucasian participants received 2300 mg (N=8).

[0632] The first cohort included 16 Japanese subjects, randomized 1:1 to receive 400 or 1000 mg of TEV-48574. After an observation period of at least 3 days and up to 14 days, and if there were no safety and tolerability issues, study drug administration continued for cohort 2, and 8 Japanese subjects received 2300 mg of TEV-48574. Study drug administration continued for cohort 3, and 8 Caucasian subjects received 2300 mg of TEV-48574. A lag time of up to 14 days was allowed from dosing cohort 2 to dosing cohort 3 to achieve the time for recruiting Japanese-matched Caucasian subjects to the study center of cohort 3.

[0633] Blood samples for TEV-48574 serum concentration measurements for pharmacokinetic assessments were collected prior to TEV-48574 administration and 1, 6, and 12 hours after TEV-48574 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, attempts were made to obtain samples for TEV-48574 serum concentration assessments, as appropriate, in consultation with the Medical Monitor, at the time point when any severe hypersensitivity reactions (e.g., anaphylaxis) were observed or in the event of a serious adverse event.

[0634] A total of 55 healthy subjects were screened for participation in this study. Of the 55 subjects screened, 32 subjects met the entry criteria and were randomized to the study: 24 Japanese and 8 Caucasian subjects. Sixteen Japanese subjects were randomly assigned to cohort 1 and received 400 or 1000 mg of TEV-48574, 8 Japanese subjects were assigned to cohort 2 and received 2300 mg TEV-48574, and 8 Caucasian subjects were assigned to cohort 3 and received 2300 mg TEV-48574.

[0635] All 32 subjects were randomized to receive 1 dose of TEV-48574; were evaluated for safety in the study; and were eligible for the pharmacokinetic analysis group. All 32 subjects completed the study.

[0636] Due to the design of the study, the majority of subjects were Asian (24 subjects [75%]). In general, Japanese subjects weigh less than Caucasian subjects. The mean body weight was lower in the treatment group in cohort 1 compared with cohorts 2 and 3. In addition, the mean body weight was less in cohort 2 than in cohort 3 (60.84 kg vs. 62.13 kg). Body weight was a covariate for study drug exposure. Body mass index was comparable among the treatment groups.

[0637] The selection of dosage is supported by TV48574-SAD-10126 safety, tolerability, pharmacokinetics and immunogenicity studies, wherein a single dose of 1mg to 1000mg and multiple doses of 200mg to 2300mg (loading dose) and 1600mg (maintenance dose) show acceptable safety characteristics. During the single ascending dose (SAD) or multiple ascending dose (MAD) part of the TV48574-SAD-10126 study, no death, serious adverse events or PDAESI (serious hypersensitivity or anaphylaxis) were reported. It is expected that the pharmacokinetics of TEV-48574 in this dosage range is linear, as in TV48574-SAD-10126, wherein the increase in exposure is proportional to the dose.

[0638] Since single doses of 400 mg and 1000 mg were evaluated in healthy volunteers in Study TV48574 SAD-10126, it is contemplated that similar doses administered as single SC doses to healthy Japanese subjects will be used to allow for a dose-based crossover study comparison of the pharmacokinetics, safety, tolerability, and immunogenicity of TEV-48574 in these populations.

[0639] Since the highest dose (2300 mg) was administered to asthma patients in the MAD portion of the TV48574-SAD-10126 study, such a crossover study comparison with healthy subjects was not feasible. Therefore, in this study, 2300 mg was administered to healthy Caucasian and Japanese subjects for direct comparison of pharmacokinetics, safety, tolerability, and immunogenicity between the two populations.

[0640] After a single dose SC administration in Japanese subjects, TEV-48574 concentrations peaked between days 3 and 4 after administration at all dose levels and showed similarity in the elimination curves. The elimination half-life ranged between 7 and 9 days.

[0641] Geometric mean peak serum concentration (C max ) and total systemic exposure (AUC 0-t and AUC 0-∞ ) increased with increasing dose within the dose range of 400 to 2300 mg (see Table 55). Table 55: Summary of Pharmacokinetic Parameters by Cohort, Ethnic Group and Dose Level AUC ext % = Area extrapolated to infinity relative to the total area under the curve; AUC0-t = Area under the serum concentration-time curve from time 0 to the time of the last measurable TEV-48574 concentration; AUC 0-∞ = area under the serum concentration-time curve extrapolated to infinity; CL / F = apparent total body clearance; C max = maximum observed serum drug concentration; CV = coefficient of variation; Max = maximum value; Min = minimum value; N = total number of subjects; n = number of subjects with evaluable data; SD = standard deviation; SE = standard error; t 1 / 2 = terminal phase (apparent elimination) half-life; T max = time to reach maximum observed serum drug concentration; V z / F = apparent volume of distribution during the terminal phase.

[0642] Dose proportionality analysis over the dose range of 400 to 2300 mg indicated linear exposure with increasing dose in Japanese subjects.

[0643] The pharmacokinetic profile of TEV-48574 in Japanese subjects was similar to that in Caucasian subjects in terms of absorption, distribution, and elimination period; the pharmacokinetic parameters in Japanese subjects were comparable to those in Caucasian subjects in the 2300 mg dose cohort and were consistent with the pharmacokinetic parameters in Caucasian subjects obtained from the previous first-in-human (FIH) TV48574-SAD-10126 study.

[0644] Pooled dose-normalized pharmacokinetic parameters in Japanese subjects from all 3 cohorts were compared with those from the 2300 mg dose cohort in Caucasian subjects. max and AUC 0-∞ It's similar.

[0645] Phase 1 study in healthy subjects (Japanese and Caucasian) demonstrated comparability of the pharmacokinetic profile of TEV-48574 between Japanese and Caucasian subjects. The plots of mean serum concentrations and individual subject serum concentration profiles were completely overlapping between the 2 ethnic groups at the 2300 mg dose.

[0646] Exposure parameters in Japanese subjects (C max , AUC 0-t and AUC 0-∞) were comparable to Caucasian subjects in the 2300 mg dose cohort and...

Claims

1. 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); 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. The method of claim 1, wherein the subject was previously treated with one or more agents selected from the group consisting of: Corticosteroids, immunosuppressants, tumor necrosis factor-α (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. The method of claim 2, wherein the subject has an inadequate response, loss of response, or intolerance to one or more of the agents.

4. The method of claim 3, wherein the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics.

5. 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 had an inadequate response, loss of response, or intolerance to at least one agent selected from the group consisting of a corticosteroid, an immunosuppressant, a tumor necrosis factor-α (TNF-α) antagonist, an anti-integrin antibody, an anti-interleukin (IL)-12 / 23 antibody, a Janus kinase (JAK) inhibitor, and a sphingosine-1-phosphate (S1P) receptor modulator; and (b) if the subject has an inadequate response, loss of response, or intolerance to at least one of the agents in part (a), administering to the subject a 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.

6. The method of claim 5, wherein the ulcerative colitis is moderate to severe ulcerative colitis, and / or wherein the Crohn's disease is moderate to severe Crohn's disease.

7. 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); 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.

8. The method of claim 7, wherein the subject was previously treated with one or more agents selected from the group consisting of: Corticosteroids, immunosuppressants, tumor necrosis factor-α (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).

9. The method of claim 8, wherein the subject has an inadequate response, loss of response, or intolerance to one or more of the agents.

10. The method of claim 8 or 9, wherein the subject has an inadequate response, loss of response, or intolerance to no more than two classes of biologics.

11. The method of any one of claims 1-10, 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.

12. The method of any one of claims 1-10, wherein the antibody or antigen-binding fragment comprises an IgG1 constant region.

13. The method of any one of claims 1-12, 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.

14. The method of any one of claims 1-13, wherein the subject is concurrently treated with oral corticosteroids, oral 5-ASA, sulfasalazine, azathioprine (AZA), 6-mercaptopurine (6-MP), and / or methotrexate.

15. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 300 mg.

16. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 400 mg.

17. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 450 mg.

18. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg.

19. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 750 mg.

20. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 900 mg.

21. The method of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 2250 mg.

22. The method of any one of claims 1-20, wherein the antibody or antigen-binding fragment thereof is administered about once every two weeks.

23. The method of any one of claims 1-20, wherein the antibody or antigen-binding fragment thereof is administered about once every four weeks.

24. The method of any one of claims 1-23, wherein the administering comprises administering one or more induction doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose is administered.

25. The method of any one of claims 1-23, wherein the administering comprises 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.

26. The method of claim 25, wherein the loading dose comprises about 2250 mg of the antibody or antigen-binding fragment thereof.

27. The method of any one of claims 24-26, wherein the one or more induction doses comprises about 450 mg of the antibody or antigen-binding fragment thereof.

28. The method of any one of claims 24-26, wherein the one or more induction doses comprises about 900 mg of the antibody or antigen-binding fragment thereof.

29. The method of any one of claims 24-28, wherein about six induction doses are administered.

30. The method of any one of claims 1-29, wherein the administering is performed within about 16 weeks.

31. The method of any one of claims 1-23, wherein the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered approximately every 2 weeks.

32. The method of any one of claims 1-30, wherein 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 2 weeks.

33. The method of any one of claims 1-23, wherein the administration comprises administering one or more maintenance doses of the antibody or antigen-binding fragment thereof, and wherein no loading dose and / or induction dose is administered, optionally wherein the maintenance doses are administered approximately every 4 weeks.

34. The method of any one of claims 1-30, wherein 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 4 weeks.

35. The method of any one of claims 30-34, wherein the one or more maintenance doses comprises about 450 mg or about 900 mg of the antibody or antigen-binding fragment thereof.

36. The method of claim 35, wherein the one or more maintenance doses comprises about 450 mg of the antibody or antigen-binding fragment thereof.

37. The method of claim 35, wherein the one or more maintenance doses comprises about 900 mg of the antibody or antigen-binding fragment thereof.

38. The method of any one of claims 30-37, wherein about ten maintenance doses are administered.

39. The method of any one of claims 1-14, wherein 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.

40. The method of any one of claims 1-14, wherein 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.

41. The method of any one of claims 1-14, wherein 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.

42. The method of any one of claims 1-14, wherein 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.

43. The method of any one of claims 39-42, wherein about 6 induction doses are administered and / or about ten maintenance doses are administered.

44. The method of any one of claims 1-14, wherein 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.

45. The method of any one of claims 1-14, wherein 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 wherein the maintenance doses are administered about every four weeks.

46. ​​The method of claim 44 or 45, wherein at least ten maintenance doses are administered.

47. The method of any one of claims 24-46, wherein administration of the one or more induction doses is performed within about 14 weeks.

48. The method of any one of claims 25-47, wherein the loading dose is administered about 2 weeks prior to administration of the one or more induction doses.

49. The method of any one of claims 31-48, wherein administration of the one or more maintenance doses is performed over about 24 weeks.

50. The method of any one of claims 31-48, wherein administration of the one or more maintenance doses is performed over about 40 weeks.

51. The method of any one of claims 1-50, wherein the antibody or antigen-binding fragment thereof is formulated at a concentration of about 150 mg / mL.

52. The method of any one of claims 1-50, wherein the antibody or antigen-binding fragment thereof is formulated at a concentration of about 200 mg / mL.

53. The method of any one of claims 1-52, wherein the antibody or antigen-binding fragment thereof is formulated in a volume of 3 mL or less.

54. The method of any one of claims 1-53, wherein the antibody or antigen-binding fragment thereof is administered to the subject subcutaneously or intravenously.

55. The method of claim 54, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

56. The method of any one of claims 1-55, wherein the antibody or antigen-binding fragment thereof is administered to the subject via a syringe.

57. The method of claim 56, wherein the syringe is a pre-filled syringe, optionally wherein the pre-filled syringe has a volume of 2 mL or less.

58. The method of any one of claims 1-57, wherein the subject has moderate to severe ulcerative colitis.

59. The method of claim 58, wherein the administration results in clinical remission.

60. The method of claim 59, wherein the clinical remission occurs within 14 weeks after initiation of the administering.

61. The method of claim 59, wherein the clinical remission occurs within 38 weeks after initiation of the administering.

62. The method of any one of claims 1-57, wherein the subject has moderate to severe Crohn's disease.

63. The method of claim 62, wherein the administration results in an endoscopic reaction.

64. The method of claim 63, wherein the endoscopic reaction occurs within 14 weeks after the start of the administration.

65. The method of claim 64, wherein the endoscopic reaction occurs within 38 weeks after the start of the administration.

66. Use of an antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A) in the preparation of a medicament for use in the method of any one of claims 1 to 65.

67. An antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A), for use in the method of any one of claims 1-65.

68. A pharmaceutical formulation comprising: (a) about 100 mg / mL to about 250 mg / mL of 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; (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.

69. The pharmaceutical formulation of claim 68, wherein 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.

70. The pharmaceutical formulation of claim 68 or 69, wherein the antibody or antigen-binding fragment comprises an IgG1 constant region.

71. The pharmaceutical formulation of any one of claims 68-70, wherein 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.

72. The pharmaceutical formulation of any one of claims 68-71, comprising about 100 mg / mL of the antibody or antigen-binding fragment thereof.

73. The pharmaceutical formulation of any one of claims 68-71, comprising about 150 mg / mL of the antibody or antigen-binding fragment thereof.

74. The pharmaceutical formulation of any one of claims 68-71, comprising about 200 mg / mL of the antibody or antigen-binding fragment thereof.

75. The pharmaceutical formulation of any one of claims 68-71, comprising about 225 mg / mL of the antibody or antigen-binding fragment thereof.

76. The pharmaceutical formulation of any one of claims 68-71, comprising about 250 mg / mL of the antibody or antigen-binding fragment thereof.

77. The pharmaceutical formulation of any one of claims 68-76, comprising about 5 mM histidine.

78. The pharmaceutical formulation of any one of claims 68-76, comprising about 10 mM histidine.

79. The pharmaceutical formulation of any one of claims 68-76, comprising about 15 mM histidine.

80. The pharmaceutical formulation of any one of claims 68-79, comprising about 50 mM arginine-hydrochloride (Arg-HCl).

81. The pharmaceutical formulation of any one of claims 68-79, comprising about 100 mM arginine-hydrochloride (Arg-HCl).

82. The pharmaceutical formulation of any one of claims 68-79, comprising about 150 mM arginine-hydrochloride (Arg-HCl).

83. The pharmaceutical formulation of any one of claims 68-82, comprising about 2.5% (w / v) sucrose.

84. The pharmaceutical formulation of any one of claims 68-82, comprising about 5% (w / v) sucrose.

85. The pharmaceutical formulation of any one of claims 68-82, comprising about 7.5% (w / v) sucrose.

86. The pharmaceutical formulation of any one of claims 68-85, comprising about 0.01% (w / v) polysorbate-80.

87. The pharmaceutical formulation of any one of claims 68-85, comprising about 0.02% (w / v) polysorbate-80.

88. The pharmaceutical formulation of any one of claims 68-85, comprising about 0.03% (w / v) polysorbate-80.

89. The pharmaceutical formulation of any one of claims 68-71, comprising about 250 mg / mL of the 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.

90. The pharmaceutical formulation of any one of claims 68-71, comprising about 200 mg / mL of the 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.

91. The pharmaceutical formulation of any one of claims 68-71, comprising about 150 mg / mL of the 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.

92. The pharmaceutical formulation of any one of claims 68-91, wherein the pharmaceutical formulation is lyophilized.

93. The pharmaceutical formulation of any one of claims 68-91, wherein the pharmaceutical formulation is liquid.

94. The pharmaceutical formulation of any one of claims 68-93, having a pH of 6.0±0.5 after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

95. The pharmaceutical formulation of any one of claims 68-94, having an osmotic pressure of from 200 to 500 mOsm / kg after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

96. The pharmaceutical formulation of any one of claims 68-95, having an antibody monomer content of at least 99% after storage at 2°C-8°C for 24 hours, 72 hours or 10 days.

97. The pharmaceutical formulation of any one of claims 68-96, which has no significant change in charge heterogeneity characteristics after storage at 2°C-8°C for 24 hours, 72 hours or 10 days.

98. The pharmaceutical formulation of any one of claims 68-97, which has no significant change in purity after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

99. The pharmaceutical formulation of any one of claims 68-98, having a purity of at least 90% after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

100. The pharmaceutical formulation of any one of claims 68-99, which has no significant change in particle concentration after storage at room temperature for 24 hours or at 2°C-8°C for 24 hours, 72 hours, or 10 days.

101. The pharmaceutical formulation of any one of claims 68-100, which has no significant difference in visual appearance after storage at 2°C-8°C for up to 36 months.

102. The pharmaceutical formulation of any one of claims 68-101, which has no significant difference in protein concentration, osmotic pressure, or viscosity after storage at 2°C-8°C, 25°C, or 40°C for up to 36 months.

103. The pharmaceutical formulation of any one of claims 68-102, having ≥95% monomer content, ≤5.0% dimer content, or no significant difference in the content of low molecular weight species after storage at 2°C-8°C for up to 36 months.

104. The pharmaceutical formulation of any one of claims 68-103, having a purity of ≥ 90% after storage at 2°C-8°C for up to 36 months.

105. The pharmaceutical formulation of any one of claims 68-104, having a main substance content of from 50% to 90%, an acidic substance content of from 10% to 40%, and / or a basic substance content of from 0% to 20% after storage at 2°C-8°C for up to 36 months.

106. The pharmaceutical formulation of any one of claims 68-105, which has no significant difference in subvisible particle content after storage at 2°C-8°C, 25°C or 40°C for up to 36 months.

107. The pharmaceutical formulation of any one of claims 68-106, which 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°C-8°C, 25°C or 40°C for up to 36 months.

108. The pharmaceutical formulation of any one of claims 68-107, having a relative potency of from 70% to 135% as measured by enzyme-linked immunosorbent assay (ELISA) after storage at 2°C-8°C for up to 36 months.

109. The pharmaceutical formulation of any one of claims 68-108, which has no significant difference in thermal stability after storage at 2°C-8°C, 25°C or 40°C for up to 6 months.

110. The pharmaceutical formulation of any one of claims 68-109, which has no significant difference in thermal stability after storage at 2°C-8°C for up to 36 months.

111. The pharmaceutical formulation of any one of claims 68-110, which has no significant difference in secondary and / or tertiary protein structure after storage at 2°C-8°C, 25°C or 40°C for up to 3 months.

112. The pharmaceutical formulation of any one of claims 68-111, which has no significant difference in secondary protein structure after storage at 2°C-8°C for up to 36 months.

113. The pharmaceutical formulation of any one of claims 68-112, which has no significant difference in the concentration of polysorbate-80 after storage at 2°C-8°C for up to 24 months.

114. The pharmaceutical formulation of any one of claims 68-113, wherein the antibody or antigen-binding fragment thereof is produced in Chinese hamster ovary cells.

115. A container comprising the pharmaceutical formulation of any one of claims 68-114.

116. The container of claim 115, wherein the container is a glass vial.

117. The container of claim 116, wherein the container is a glass vial with a fill volume of 3 mL.

118. The container of claim 115, wherein the container is a syringe, optionally wherein the syringe is a pre-filled syringe.

119. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 68-114 or the container of any one of claims 115-118, optionally wherein the disease is a gastrointestinal disease.

120. The method of claim 119, wherein the gastrointestinal disease is Crohn's disease or ulcerative colitis.

121. The method of claim 119 or 120, wherein the pharmaceutical formulation is administered intravenously.

122. The method of claim 119 or 120, wherein the pharmaceutical formulation is administered subcutaneously.

123. The formulation of any one of claims 68-114, for use according to the method of any one of claims 1-65 or 115-122.

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