Methods for treatment of metabolic dysfunction-associated steatohepatitis with an Anti-TL1a antibody

Abstract

The present disclosure provides methods and compositions for treating a disease or condition involving inflammation and / or fibrosis in the liver, e.g., metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson's disease, or alcoholic steatohepatitis, with a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody.

Description

[0001] PATENT

[0002] Attorney Docket No: 50474-372WO3

[0003] Genentech Docket No: P39784-WO-1

[0004] METHODS FOR TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS WITH AN ANTI-TL1A ANTIBODY

[0005] SEQUENCE LISTING

[0006] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 11 , 2025, is named 50474-372WO3_Sequence_Listing_9_11 > 25 and is 75,565 bytes in size.

[0007] TECHNICAL FIELD

[0008] The present invention relates to the treatment of signs and symptoms of diseases and conditions involving inflammation and / or fibrosis in the liver, e.g., metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, and alcoholic steatohepatitis, with an anti-tumor necrosis factor-like ligand 1 A (TL1 A) antibody.

[0009] BACKGROUND OF THE INVENTION

[0010] Steatotic liver disease, often referred to as fatty liver disease, is characterized by the excessive accumulation of fat in liver cells. One of its significant forms is metabolic dysfunction-associated steatohepatitis (MASH), which represents a more severe manifestation of this condition. MASH occurs when fat buildup in the liver is accompanied by inflammation and liver cell damage, leading to potential fibrosis and cirrhosis if left untreated. MASH is also known as nonalcoholic steatohepatitis (NASH). MASH is a leading cause of liver cancer and liver transplants.

[0011] The prevalence of MASH is rising globally, with estimates suggesting that around 25% of adults may be affected by some form of steatotic liver disease. Among individuals with obesity or metabolic syndrome, this prevalence can reach as high as 60% to 70%. This increasing incidence highlights the urgent need for awareness and effective management strategies.

[0012] Currently, there are no approved pharmacological treatments specifically for MASH, making its management particularly challenging. The primary approach involves lifestyle intervention. However, many patients struggle to maintain these lifestyle changes, resulting in inadequate management of the disease. The absence of specific medications for MASH underscores the need for ongoing research to develop effective therapeutic options. As the prevalence of this condition continues to rise, finding targeted treatments becomes increasingly urgent.

[0013] Binding of TL1 A to its receptor death receptor 3 (DR3) stimulates T cell-mediated signaling and cytokine production. Because increased cytokine production leads to chronic inflammation, inhibition of TL1 A is a promising therapeutic strategy for treatment of inflammatory diseases, including MASH.

[0014] Thus, there is a need in the art for methods of treating MASH with an anti-TNF-like ligand 1 A (TL1 A) antibody therapy. Further, there is a significant unmet medical need for treatments for other diseases and conditions involving inflammation and / or fibrosis in the liver, e.g., metabolic dysfunction- associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, PATENT

[0015] Attorney Docket No: 50474-372WO3

[0016] Genentech Docket No: P39784-WO-1 hemochromatosis, Wilson’s disease, and alcoholic steatohepatitis. The present disclosure addresses these needs.

[0017] SUMMARY OF THE INVENTION

[0018] In one aspect, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose, wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0019] In another aspect, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0020] In some aspects, in the first phase, the anti-TL1 A antibody is administered intravenously at a dose of about 500 mg. PATENT

[0021] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0022] In some aspects, in the first phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 500 mg.

[0023] In some aspects, the first phase has a duration of about 14 weeks. In some aspects, (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6; and (d) the fourth dose of the anti-TL1 A antibody is administered on about Day 1 of Week 10.

[0024] In some aspects, the dosing regimen further comprises a second phase.

[0025] In some aspects, in the second phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 450 mg.

[0026] In some aspects, the second phase comprises at least two doses of the anti-TL1 A antibody.

[0027] In some aspects, the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks.

[0028] In some aspects, the second phase comprises ten doses of the anti-TL1 A antibody. In some aspects, the second phase has a duration of about 36 weeks.

[0029] In some aspects, the first dose of the second phase is administered about four weeks after administration of the fourth dose of the first phase.

[0030] In some aspects, the dosing regimen has a duration of about 50 weeks. In some aspects, (a) the first dose of the first phase is administered on about Day 1 of Week 0; (b) the second dose of the first phase is administered on about Day 1 of Week 2; (c) the third dose of the first phase is administered on about Day 1 of Week 6; (d) the fourth dose of the first phase is administered on about Day 1 of Week 10; (e) the first dose of the second phase is administered on about Day 1 of Week 14; and (f) the subsequent doses of the second phase are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50.

[0031] In some aspects, the patient has advanced liver fibrosis. In some aspects, the advanced liver fibrosis is a fibrosis stage of F3 or F4. In some aspects, the patient has a FIBROSCAN® measurement of between 12.0 kPa and 30.0 kPa. In some aspects, the patient has an Enhanced Liver Fibrosis (ELF™) test score of between 9.8 and 1 1 .3. In some aspects, a biopsy from the patient has been staged as F3 or F4 according to the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System. In some aspects, the patient has a liver fibrosis stage of F3. In some aspects, the patient has a liver fibrosis stage of F4 with compensated cirrhosis.

[0032] In another aspect, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks PATENT

[0033] Attorney Docket No: 50474-372WO3

[0034] Genentech Docket No: P39784-WO-1 after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0035] In some aspects, the patient has advanced liver fibrosis.

[0036] In some aspects of any of the methods provided herein, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level.

[0037] In some aspects of any of the methods provided herein that comprise a second phase, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level at Week 52.

[0038] In some aspects, the biomarker of liver fibrosis is (a) liver stiffness; (b) serum level of N-terminal propeptide of Type III collagen (Pro-C3); (c) serum ELF™ test score; or (d) fibro-inflammation. In some aspects, (a) liver stiffness is measured using a FIBROSCAN® assay; and / or (b) fibro-inflammation is measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ).

[0039] In some aspects, the reference level is a level in a population of patients who have not been treated with an anti-TL1 A antibody. In some aspects, the reference level is a pre-treatment level in the patient.

[0040] In some aspects of any of the methods provided herein, the anti-TL1 A antibody comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1 1 ; and / or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A PATENT

[0041] Attorney Docket No: 50474-372WO3

[0042] Genentech Docket No: P39784-WO-1 antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and / or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0043] In another aspect, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising only four intravenously administered (IV) doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0044] In another aspect, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0045] In some aspects, the one or more SC doses are administered at a dose of about 450 mg of the anti-TL1 A antibody. In some aspects, the IV doses are administered at a dose of about 500 mg of the anti-TL1 A antibody.

[0046] In another aspect, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral PATENT

[0047] Attorney Docket No: 50474-372WO3

[0048] Genentech Docket No: P39784-WO-1 hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis)in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (Hi) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks at a dose of about 450 mg and the first SC dose is administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0049] In some aspects, the patient has advanced liver fibrosis.

[0050] In some aspects, the anti-TL1 A antibody is afimkibart.

[0051] In some aspects, the patient is a human.

[0052] In another aspect, the disclosure provides a kit comprising an anti-TNF-like ligand 1 A (TL1 A) antibody and a package insert comprising instructions for using the anti-TL1 A antibody for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis)in a patient in need thereof according to any one of the methods of treating such a disease or condition provided herein.

[0053] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose, and wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT

[0054] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0055] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, and wherein the anti- TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0056] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0057] In some aspects, the patient has advanced liver fibrosis.

[0058] In some aspects, the anti-TL1 A antibody is afimkibart.

[0059] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic PATENT

[0060] Attorney Docket No: 50474-372WO3

[0061] Genentech Docket No: P39784-WO-1 steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (Hi) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0062] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (Hi) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0063] In some aspects, the one or more SC doses are to be administered at a dose of about 450 mg of the anti-TL1 A antibody. In some aspects, the IV doses are to be administered at a dose of about 500 mg of the anti-TL1 A antibody.

[0064] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (Hi) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks at a dose of about 450 mg and the first SC dose is to be administered about four weeks after the fourth IV PATENT

[0065] Attorney Docket No: 50474-372WO3

[0066] Genentech Docket No: P39784-WO-1 dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0067] In some aspects, the patient has advanced liver fibrosis.

[0068] In some aspects, the anti-TL1 A antibody is afimkibart.

[0069] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose, and wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0070] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein

[0071] (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;

[0072] (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0073] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., PATENT

[0074] Attorney Docket No: 50474-372WO3

[0075] Genentech Docket No: P39784-WO-1

[0076] MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0077] In some aspects, the patient has advanced liver fibrosis.

[0078] In some aspects, the anti-TL1 A antibody is afimkibart.

[0079] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0080] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A PATENT

[0081] Attorney Docket No: 50474-372WO3

[0082] Genentech Docket No: P39784-WO-1 antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0083] In some aspects, the one or more SC doses are to be administered at a dose of about 450 mg of the anti-TL1 A antibody.

[0084] In some aspects, the IV doses are to be administered at a dose of about 500 mg of the anti-TL1 A antibody.

[0085] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti- TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks at a dose of about 450 mg and the first SC dose is to be administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0086] In some aspects, the patient has advanced liver fibrosis. In some aspects, the anti-TL1 A antibody is afimkibart.

[0087] In another aspect, the disclosure provides an article of manufacture comprising a composition comprising 150 mg / mL afimkibart contained in a drug vial, wherein the composition is formulated for intravenous administration at a dose of 500 mg or for subcutaneous administration at a dose of 450 mg.

[0088] In one aspect, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose, wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the PATENT

[0089] Attorney Docket No: 50474-372WO3

[0090] Genentech Docket No: P39784-WO-1 amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0091] In another aspect, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0092] In some aspects, in the first phase, the anti-TL1 A antibody is administered intravenously at a dose of about 500 mg.

[0093] In some aspects, in the first phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 500 mg.

[0094] In some aspects, the first phase has a duration of about 14 weeks. In some aspects, (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6; and (d) the fourth dose of the anti-TL1 A antibody is administered on about Day 1 of Week 10.

[0095] In some aspects, the dosing regimen further comprises a second phase.

[0096] In some aspects, in the second phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 450 mg.

[0097] In some aspects, the second phase comprises at least two doses of the anti-TL1 A antibody.

[0098] In some aspects, the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks.

[0099] In some aspects, the second phase comprises ten doses of the anti-TL1 A antibody. In some aspects, the second phase has a duration of about 36 weeks.

[0100] In some aspects, the first dose of the second phase is administered about four weeks after administration of the fourth dose of the first phase.

[0101] In some aspects, the dosing regimen has a duration of about 50 weeks. In some aspects, (a) the first dose of the first phase is administered on about Day 1 of Week 0; (b) the second dose of the first phase is administered on about Day 1 of Week 2; (c) the third dose of the first phase is administered on about Day 1 of Week 6; (d) the fourth dose of the first phase is administered on about Day 1 of Week 10; PATENT

[0102] Attorney Docket No: 50474-372WO3

[0103] Genentech Docket No: P39784-WO-1

[0104] (e) the first dose of the second phase is administered on about Day 1 of Week 14; and (f) the subsequent doses of the second phase are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50.

[0105] In some aspects, the MASH is advanced MASH.

[0106] In some aspects, the patient has advanced liver fibrosis. In some aspects, the advanced liver fibrosis is a fibrosis stage of F3 or F4. In some aspects, the patient has a FIBROSCAN® measurement of between 12.0 kPa and 30.0 kPa. In some aspects, the patient has an ELF™ test score of between 9.8 and 1 1 .3. In some aspects, a biopsy from the patient has been staged as F3 or F4 according to the NASH CRN System. In some aspects, the patient has a liver fibrosis stage of F3. In some aspects, the patient has a liver fibrosis stage of F4 with compensated cirrhosis.

[0107] In another aspect, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0108] In some aspects, the patient has advanced liver fibrosis.

[0109] In some aspects of any of the methods provided herein, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level.

[0110] In some aspects of any of the methods provided herein that comprise a second phase, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level at Week 52.

[0111] In some aspects, the biomarker of liver fibrosis is (a) liver stiffness; (b) serum level of N-terminal propeptide of Type III collagen (Pro-C3); (c) serum ELF™ test score; or (d) fibro-inflammation. In some aspects, (a) liver stiffness is measured using a FIBROSCAN® assay; and / or (b) fibro-inflammation is measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ). PATENT

[0112] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0113] In some aspects, the reference level is a level in a population of patients who have not been treated with an anti-TL1 A antibody. In some aspects, the reference level is a pre-treatment level in the patient.

[0114] In some aspects of any of the methods provided herein, the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 1 1 ; and / or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and / or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0115] In another aspect, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising only four intravenously administered (IV) doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0116] In another aspect, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID PATENT

[0117] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0118] NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0119] In some aspects, the one or more SC doses are administered at a dose of about 450 mg of the anti-TL1 A antibody. In some aspects, the IV doses are administered at a dose of about 500 mg of the anti-TL1 A antibody.

[0120] In another aspect, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (Hi) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks at a dose of about 450 mg and the first SC dose is administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0121] In some aspects, the patient has advanced liver fibrosis.

[0122] In some aspects, the anti-TL1 A antibody is afimkibart.

[0123] In some aspects, the patient is a human.

[0124] In another aspect, the disclosure provides a kit comprising an anti-TNF-like ligand 1 A (TL1 A) antibody and a package insert comprising instructions for using the anti-TL1 A antibody for treating MASH in a patient in need thereof according to any one of the methods of treating MASH provided herein.

[0125] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose, and wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0126] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises PATENT

[0127] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0128] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0129] In some aspects, the patient has advanced liver fibrosis.

[0130] In some aspects, the anti-TL1 A antibody is afimkibart.

[0131] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0132] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) PATENT

[0133] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0134] In some aspects, the one or more SC doses are to be administered at a dose of about 450 mg of the anti-TL1 A antibody. In some aspects, the IV doses are to be administered at a dose of about 500 mg of the anti-TL1 A antibody.

[0135] In another aspect, the disclosure provides an anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks at a dose of about 450 mg and the first SC dose is to be administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0136] In some aspects, the patient has advanced liver fibrosis.

[0137] In some aspects, the anti-TL1 A antibody is afimkibart.

[0138] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose, and wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. PATENT

[0139] Attorney Docket No: 50474-372WO3

[0140] Genentech Docket No: P39784-WO-1

[0141] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0142] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

[0143] In some aspects, the patient has advanced liver fibrosis.

[0144] In some aspects, the anti-TL1 A antibody is afimkibart.

[0145] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. PATENT

[0146] Attorney Docket No: 50474-372WO3

[0147] Genentech Docket No: P39784-WO-1

[0148] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0149] In some aspects, the one or more SC doses are to be administered at a dose of about 450 mg of the anti-TL1 A antibody.

[0150] In some aspects, the IV doses are to be administered at a dose of about 500 mg of the anti-TL1 A antibody.

[0151] In another aspect, the disclosure provides use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein (i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and (b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks at a dose of about 450 mg and the first SC dose is to be administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

[0152] In some aspects, the patient has advanced liver fibrosis. In some aspects, the anti-TL1 A antibody is afimkibart.

[0153] In another aspect, the disclosure provides an article of manufacture comprising a composition comprising 150 mg / mL afimkibart contained in a drug vial, wherein the composition is formulated for intravenous administration at a dose of 500 mg or for subcutaneous administration at a dose of 450 mg.

[0154] BRIEF DESCRIPTION OF THE DRAWINGS

[0155] FIG. 1 is a schematic diagram showing the design of the CC45687 study. IV = intravenous; SC= subcutaneous; Q4W = every 4 weeks; cT1 = iron-corrected T1 mapping; ELF = enhanced liver fibrosis; NIT= non-invasive test; Pro-C3 = propeptide of Type III collagen; SFU = safety follow-up. PATENT

[0156] Attorney Docket No: 50474-372WO3

[0157] Genentech Docket No: P39784-WO-1

[0158] DETAILED DESCRIPTION OF THE INVENTION

[0159] The present invention provides therapeutic methods and compositions for treatment of diseases or conditions involving inflammation and / or fibrosis in the liver, including liver fibrosis and / or inflammation associated with steatotic liver disease, e.g., metabolic dysfunction-associated steatohepatitis (MASH) (e.g., advanced MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, and alcoholic steatohepatitis. The invention is based, at least in part, on the discovery that anti-TL1 A antibodies, such as afimkibart, can be effective in the treatment of such diseases and conditions. Compositions, uses, and kits involving such antibodies are also provided herein.

[0160] I. Definitions

[0161] It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0162] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

[0163] As used herein, “afimkibart” (also known as RO7790121 , RVT-3101 , or PF-06480605) is an antibody that binds tumor necrosis factor (TNF) superfamily protein TNF-like 1 A (TL1 A) and comprises the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0164] The terms “antibody that binds to TL1 A” and “anti-TL1 A antibody” refer to an antibody that is capable of binding TL1 A with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting TL1 A. In one aspect, the extent of binding of an anti-TL1 A antibody to an unrelated, non-TL1 A protein is less than about 10% of the binding of the antibody to TL1 A as measured, e.g., by surface plasmon resonance (SPR). In one aspect, an antibody that binds to TL1 A has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M).The term “antibody” encompasses various antibody structures exhibiting the desired antigen-binding activity, including but not limited to: monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments.

[0165] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the antibodies forming this population are essentially identical, except for possible post-translational modifications arising e.g. during manufacturing and / or storage. These antibodies are directed against the same epitope (or the same group of epitopes in the case of multispecific monoclonal antibodies, e.g. the same pair of epitopes in the case of bispecific monoclonal antibodies). This definition expressly excludes polyclonal antibody preparations which are mixtures of antibodies directed against different epitopes. Monoclonal antibodies in accordance with the PATENT

[0166] Attorney Docket No: 50474-372WO3

[0167] Genentech Docket No: P39784-WO-1 present invention may be made by a variety of techniques, including but not limited to hybridoma methodology, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0168] The term “full-length antibody” refers to an antibody having the structure of an immunoglobulin comprising two light chains and two heavy chains, and comprising an Fc region as defined herein. In one aspect, the antibody is a full-length IgG 1 antibody.

[0169] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.

[0170] A “humanized” antibody refers to an antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In one aspect, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non- human antibody, refers to an antibody that has undergone humanization.

[0171] “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains (LC) and two identical heavy chains (HC) that are disulfide- bonded. From N- to C-terminus, each heavy chain has a heavy chain variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three heavy chain constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a light chain variable domain (VL), also called a variable light domain or a light chain variable region, followed by a light chain constant domain (CL).

[0172] An “antibody fragment” refers to a molecule other than a full-length antibody that comprises a portion of a full-length antibody that binds the antigen to which the full-length antibody binds. Examples of antibody fragments include but are not limited to Fv molecules, Fab molecules, Fab' molecules, Fab’- SH molecules, F(ab')2 molecules, diabodies, linear antibody molecules, single-chain antibody molecules (e.g., scFv and scFab molecules), and multispecific (e.g. bispecific) antibodies formed from antibody fragments.

[0173] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three complementary determining regions (CDRs). (See, e.g., Kindt et al. Kuby Immunology, 6thed., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that PATENT

[0174] Attorney Docket No: 50474-372WO3

[0175] Genentech Docket No: P39784-WO-1 binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991 ).

[0176] Glutamine or glutamate residues at the N-terminus of antibody heavy or light chains may be converted to pyro-glutamate spontaneously (see e.g. Liu et al., Journal of Pharmaceutical Sciences 97, 2426-2447 (2008), Rehder et al., Journal of Chromatography A 1 102, 164-175 (2006), Chelius et al., Anal Chem 78, 2370-2376 (2006)). Hence, variable domains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus of the antibody heavy or light chain, may comprise an N-terminal pyro-glutamate (pyroE) residue instead of the N-terminal Q or E residue. Likewise, antibody heavy chains or light chains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus, may comprise an N-terminal pyroglutamate (pyroE) residue instead of the N-terminal Q or E residue. Accordingly, for each antibody heavy chain, light chain, or variable domain sequence disclosed herein that contains an N-terminal Q or E residue, the corresponding sequence with an N-terminal pyroE residue is also encompassed.

[0177] A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991 ) NIH Publication 91 -3242 (hereinafter “Kabat 1991 ”). In one aspect, for the VL, the subgroup is subgroup kappa I as in Kabat 1991 . In one aspect, for the VH, the subgroup is subgroup III as in Kabat 1991 .

[0178] The term “complementarity determining region” or “CDR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity. Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR- H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). CDRs are defined by a variety of methods / systems by those skilled in the art. These systems and / or definitions have been developed and refined over a number of years and include Kabat, Chothia, IMGT, AbM, and Contact. The Kabat definition is based on sequence variability and generally is the most commonly used. The Chothia definition is based on the location of the structural loop regions. The IMGT system is based on sequence variability and location within the structure of the variable domain. The AbM definition is a compromise between Kabat and Chothia. The Contact definition is based on analyses of the available antibody crystal structures. Software programs (e.g., abYsis: http: / / www.abysis.org / abysis / sequence_input / key_annotation / key_annotation.cgi) are available and known to those of skill in the art for analysis of antibody sequences and determination of CDRs.

[0179] Exemplary CDRs herein include (numbering of amino acid residues according to the reference cited, i.e. Chothia numbering for the Chothia and Contact definition, Kabat numbering for the Kabat definition and IMGT numbering for the IMGT definition):

[0180] (a) hypervariable loops occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26- 32 (H1 ), 53-55 (H2), and 96-101 (H3), according to Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987) (“Chothia definition”); PATENT

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[0183] (b) CDRs occurring at amino acid residues 24-34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35B (H1 ), SO- 65 (H2), and 95-102 (H3), according to Kabat 1991 (“Kabat definition”);

[0184] (c) antigen contacts occurring at amino acid residues 30-36 (L1 ), 46-55 (L2), 89-96 (L3), 30-35 (H1 ), 47-58 (H2), and 93-101 (H3), according to MacCallum et al. J. Mol. Biol. 262: 732-745 (1996) (“Contact definition”); and

[0185] (d) CDRs occurring at amino acid residues residues 27-38 (L1 ), 56-65 (L2), 105-117 (L3), 27-38 (H1 ), 56-65 (H2), and 105-117 (H3), according to Lefranc et al. Dev. Comp. Immunol. 27: 55-77 (2003) (“IMGT definition”).

[0186] “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -CDR-H1 (CDR-L1 )-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.

[0187] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, Ig A1 , and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, s, y, and p, respectively. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.

[0188] The terms “constant region derived from human origin” or “human constant region” as used herein denotes a constant region of a human antibody, in particular a heavy chain constant region of a human antibody of the subclass IgG 1 , lgG2, lgG3, or lgG4 and / or a light chain kappa or lambda constant region. Such constant regions are well known in the state of the art and e.g. described by Kabat 1991 . Unless otherwise specified herein, numbering of amino acid residues in the constant region is according to the numbering system as described in Kabat 1991 . Specifically, the Kabat numbering system (referred to as “numbering according to Kabat” or “Kabat numbering” herein; see pages 647-660 of Kabat 1991 ) is used for the light chain constant domain of kappa and lambda isotype, and the Kabat EU index numbering system (referred to as “numbering according to Kabat EU index” or “Kabat EU index numbering” herein, see pages 661 -723 of Kabat 1991 ) is used for the heavy chain constant domains.

[0189] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C- terminus of the heavy chain. Therefore an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case in particular where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, Kabat EU numbering). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including PATENT

[0190] Attorney Docket No: 50474-372WO3

[0191] Genentech Docket No: P39784-WO-1 an Fc region are denoted herein without C-terminal lysine if not indicated otherwise. The corresponding sequence including a C-terminal lysine residue is also encompassed, however. Accordingly, in one aspect, a heavy chain including an Fc region as specified herein comprises an additional C-terminal lysine residue (K447, Kabat EU numbering). Also encompassed is the corresponding sequence without the C-terminal glycine residue. Accordingly, in one aspect, a heavy chain including an Fc region as specified herein lacks the C-terminal glycine residue (G446, Kabat EU numbering). In such a heavy chain, the C-terminal amino acid residue may be proline (P445, Kabat EU numbering) or proline amide (P445-NH2, Kabat EU numbering). Unless otherwise specified herein, numbering of amino acid residues in the Fc region or heavy chain constant region is according to the EU numbering system, also called the EU index, as described in Kabat 1991 .

[0192] “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.

[0193] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. A preferred method for measuring affinity is Surface Plasmon Resonance (SPR).

[0194] An “isolated” antibody is one which has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC, affinity chromatography, size exclusion chromatography) methods. For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. 8848:79-87 (2007).

[0195] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0196] “Isolated nucleic acid encoding an antibody” refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.

[0197] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid PATENT

[0198] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors”.

[0199] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein. Suitable host cells may include, for example, CHO cells, HEK-293 cells, Expi293F cells, PER.C6 cells, NSO cells, lymphocytic cells, prokaryotic cells such as E. coli, and other eukaryotic hosts such as plant cells and fungi. Human host cells are included with the proviso that they are not used within the human body.

[0200] A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

[0201] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity for the purposes of the alignment. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, Clustal W, MegAlign (DNASTAR) software or the FASTA program package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Alternatively, the percent identity values can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087 and is described in WO 2001 / 007611.

[0202] Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values are generated using the ggsearch program of the FASTA package version 36.3.8c or later with a BLOSUM50 comparison matrix. The FASTA program package was authored by W. R. Pearson and D. J. Lipman (1988), “Improved Tools for Biological Sequence Analysis” Proc. Nat. Acad. Sci. 85:2444-2448; W. R. Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258; and Pearson et. al. (1997) Genomics 46:24-36 and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www. ebi.ac.uk / Tools / sss / fasta. Alternatively, a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi can be used to compare the sequences, using the ggsearch (global protei protein) program and default options PATENT

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[0205] (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure a global, rather than local, alignment is performed. Percent amino acid identity is given in the output alignment header.

[0206] As used herein, the term “treatment” refers to clinical intervention in an attempt to alter the natural course of a disease or condition (e.g., a disease or condition involving inflammation and / or fibrosis in the liver, e.g., metabolic dysfunction-associated steatohepatitis (MASH) (e.g., advanced MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression of the disease or condition, ameliorating or palliating the disease state or the condition, and remission or improved prognosis. For purposes of this disclosure, beneficial or desired clinical results include reduction or improvement in signs and symptoms of the disease or condition, for example as compared to before administration of the anti-TL1 A antibody.

[0207] An “effective amount” of an agent, e.g., a pharmaceutical composition, refers to an amount of the antibody or medicament effective, at dosages and for periods of time necessary, to achieve the desired treatment as defined above. In more specific aspects, an effective amount prevents, alleviates or ameliorates signs or symptoms of a disease or condition involving inflammation and / or fibrosis in the liver, e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis, and / or prolongs the survival of the subject being treated. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease or condition, including biochemical, histological and / or behavioral symptoms of the disease or condition, its complications and intermediate pathological phenotypes presenting during development of the disease or condition. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more signs or symptoms of the disease or condition, decreasing the dose of other medications required to treat the disease or condition, enhancing the effect of another medication, and / or delaying the progression of the disease or condition in patients. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0208] Herein, an “effective amount” may refer to the amount of a therapeutic agent (e.g., an anti-TL1 A antibody (e.g., afimkibart) or a combination of therapeutic agents (e.g., an anti-TL1 A antibody and one or more additional therapeutic agents)), that achieves a therapeutic result. In some examples, the effective amount of a therapeutic agent or a combination of therapeutic agents is the amount of the agent or of the PATENT

[0209] Attorney Docket No: 50474-372WO3

[0210] Genentech Docket No: P39784-WO-1 combination of agents that achieves a clinical endpoint of decreased liver stiffness (e.g., as measured by FIBROSCAN®; decreased serum levels of N-terminal propeptide of Type III collagen (Pro-C3); decreased serum enhanced liver fibrosis (ELF) test score; decreased level of fibro-inflammation (e.g., as measured by magnetic resonance imaging (MRI) iron-corrected T1 mapping (cT1)); and / or a decrease in a soluble biomarker of hepatocyte injury (e.g., serum alanine transaminase (ALT) I aspartate transaminase (AST) ratio or serum gamma-glutamyl transferase (GGT)). Improvement may be relative to a suitable reference treatment, for example, treatment that does not include the anti-TL1 A antibody.

[0211] “Ameliorating” means a lessening or improvement of one or more signs or symptoms of a disease or condition involving inflammation and / or fibrosis in the liver, e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis, for example, as compared to not administering an anti-TL1 A antibody as described herein. “Ameliorating” also includes shortening or reduction in duration of a symptom.

[0212] The term “preventing” or “prevent” refers to (a) keeping a disorder, disease, or condition from occurring or (b) delaying the onset of a disorder, disease, or condition or onset of symptoms thereof.

[0213] Treatment “effectively improves” or “effectively reduces” when assessment of the sign or symptom of the disease or condition (e.g., disease or condition involving inflammation and / or fibrosis in the liver, e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) is quantified via a clinical measure relative to baseline and during and / or after the treatment period. The difference between the clinical measure at baseline and during / after treatment is compared and used to determine whether the sign or symptom has improved and the treatment is effective. This comparison can include comparison to placebo or to one or more of the prior therapies.

[0214] A “patient,” an “individual,” or a "subject," used interchangeably herein, is a mammal. In one aspect, the individual or subject is a human. In one aspect, the individual is in need of treatment with the medicament or antibody disclosed herein.

[0215] The term “pharmaceutical composition” or “pharmaceutical formulation” refers to a preparation of the antibody and one or more pharmaceutically acceptable carriers or excipients.

[0216] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, which is nontoxic to a subject and includes, but is not limited to, a buffer, excipient, stabilizer, surfactant, and / or preservative.

[0217] The term “subcutaneous administration” refers to the administration of a substance into the subcutaneous layer. PATENT

[0218] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0219] II. Methods of Treating a Disease Associated with Inflammation in the Liver with Anti-TL1A Antibodies

[0220] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising at least a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose.

[0221] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose.

[0222] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks.

[0223] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral PATENT

[0224] Attorney Docket No: 50474-372WO3

[0225] Genentech Docket No: P39784-WO-1 hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks.

[0226] The disclosure also provides (i) an anti-TL1 A antibody for use in treating a disease or condition involving inflammation and / or fibrosis in the liver, e.g., metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis, in a patient according to the methods provided herein and (ii) use of an anti-TL1 A antibody in the manufacture of a medicament for treating such a disease or condition according to the methods provided herein.

[0227] In some aspects of any of the methods, uses, or compositions for use provided herein, the anti- TL1 A antibody is an anti-TL1 A antibody provided in Section III herein. In some aspects, the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs): (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0228] Anti-TL1 A antibodies and methods of use thereof have been described in PCT Publication No. WO 2021 / 260577 and in U.S. Patent Application Publication No. US 2023 / 0235070 A1 , which are incorporated herein by reference for all purposes.

[0229] The methods of treatment and related uses provided herein may include one or both of a first phase and a second phase, as described below.

[0230] A. Methods of Treating Diseases and Conditions Associated With Liver Fibrosis or Inflammation I. First Phase

[0231] Any of the methods for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) provided herein may comprise administration of an anti- TL1 A antibody in at least a first phase. The first phase may comprise administration (e.g., intravenous PATENT

[0232] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 administration) of one or more doses of the anti-TL1 A antibody (e.g., may comprise administration of one, two, three, or four doses of the anti-TL1 A antibody).

[0233] In some aspects, the first phase comprises administration of four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose. In some aspects, the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0 (e.g., Day 1 ±3 days); (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 (e.g., Day 1 ±3 days); (c) the third dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6 (e.g., Day 1 ±3 days); and (d) the fourth dose of the anti-TL1 A antibody is administered on about Day 1 of Week 10 (e.g., Day 1 ±3 days). For example, in some aspects, the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and / or (d) the fourth dose of the anti-TL1 A antibody is administered on Day 1 of Week 10 (e.g., first phase doses according to one, two, three, or all four of (a), (b), (c), and (d) are administered). In some aspects, the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and (d) the fourth dose of the anti-TL1 A antibody is administered on Day 1 of Week 10.

[0234] In one aspect, the anti-TL1 A antibody is administered at a dose of about 500 mg (e.g., at a dose of 500 mg) during the first phase. Preferably, the first phase doses are administered intravenously. In some aspects, in the first phase, the anti-TL1 A antibody is administered intravenously (IV) at a dose of about 500 mg (e.g., a dose of 500 mg) (e.g., each dose in the first phase comprises IV administration of about 500 mg (e.g., 500 mg) of the anti-TL1 A antibody).

[0235] Accordingly, in some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase, wherein the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and (d) the fourth dose of the anti-TL1 A antibody is administered on Day 1 of Week 10. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID PATENT

[0236] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0237] NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0238] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising intravenous (IV) administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein the four doses of the anti-TL1 A antibody are administered over about 14 weeks, and (a) the IV first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second IV dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third IV dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and (d) the fourth IV dose of the anti-TL1 A antibody is administered on Day 1 of Week 10. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0239] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0240] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a PATENT

[0241] Attorney Docket No: 50474-372WO3

[0242] Genentech Docket No: P39784-WO-1 dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0243] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0244] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of PATENT

[0245] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0246] SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0247] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0248] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0249] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti- TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain PATENT

[0250] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0251] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0252] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0253] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the PATENT

[0254] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0255] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0256] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. PATENT

[0257] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0258] Any of the methods provided herein may comprise administration of an anti-TL1 A antibody in a second phase that follows administration of the anti-TL1 A antibody in a first phase. The second phase may comprise administration of one or more doses of the anti-TL1 A antibody.

[0259] The second phase may be initiated at any appropriate time following the first phase. In some aspects, the first dose of the second phase is administered about four weeks (e.g., four weeks) after administration of the last dose of the first phase. For example, in aspects in which the first phase comprises administration of four doses of the anti-TL1 A antibody, the first dose of the second phase may be administered about four weeks (e.g., four weeks) after administration of the fourth dose of the first phase.

[0260] In some aspects in which the second phase comprises administration of at least two doses of the anti-TL1 A antibody, the time interval between each individual dose in the second phase may be the same. In other aspects, the time interval between individual doses in the second phase is not the same.

[0261] In some aspects, the second phase comprises administration (e.g., subcutaneous administration) of the anti-TL1 A antibody every four weeks (Q4W).

[0262] In one aspect, the anti-TL1 A antibody is administered at a dose of about 450 mg (e.g., at a dose of 450 mg) during the second phase. Doses in the second phase can be administered subcutaneously In some aspects, in the second phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 450 mg (e.g., 450 mg) every four weeks.

[0263] In some aspects, the second phase comprises administration of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses of the anti-TL1 A antibody.

[0264] In some aspects, the second phase comprises ten doses of the anti-TL1 A antibody (e.g., comprises ten doses of the anti-TL1 A antibody administered in a Q4W dosing regimen). In some aspects, the second phase has a duration of about 36 weeks.

[0265] Accordingly, in some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein: (a) the first phase comprises intravenous administration of four doses of the anti- TL1 A antibody at a dose of about 500 mg, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg.

[0266] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral PATENT

[0267] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein: (a) the first phase comprises intravenous administration of four doses of the anti- TL1 A antibody at a dose of about 500 mg, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0268] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising (a) intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0269] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A PATENT

[0270] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. In some aspects, (a) the first dose of the first phase is administered on about Day 1 of Week 0; (b) the second dose of the first phase is administered on about Day 1 of Week 2; (c) the third dose of the first phase is administered on about Day 1 of Week 6; (d) the fourth dose of the first phase is administered on about Day 1 of Week 10; (e) the first dose of the second phase is administered on about Day 1 of Week 14; and (f) the subsequent doses of the second phase are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50.

[0271] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising (a) intravenous administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and (b) subcutaneous (SC) administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. In some aspects, (a) the first IV dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0; (b) the second IV dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2; (c) the third IV dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6; (d) the fourth IV dose of the anti- TL1 A antibody is administered on about Day 1 of Week 10; (e) the first SC dose of the anti-TL1 A antibody is administered on about Day 1 of Week 14; and (f) the subsequent SC doses of the anti-TL1 A antibody are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50. In some aspects, the dosing regimen comprising the first phase and second phase has a duration of about 50 weeks (e.g., has a duration of 50 weeks).

[0272] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, PATENT

[0273] Attorney Docket No: 50474-372WO3

[0274] Genentech Docket No: P39784-WO-1 the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0275] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0276] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL PATENT

[0277] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0278] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0279] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four PATENT

[0280] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 weeks; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0281] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0282] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0283] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an PATENT

[0284] Attorney Docket No: 50474-372WO3

[0285] Genentech Docket No: P39784-WO-1 anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0286] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0287] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered PATENT

[0288] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0289] (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti- TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0290] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0291] In some aspects, the disclosure provides a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. PATENT

[0292] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0293] Hi. Response to Treatment

[0294] Improvement in Biomarkers of Liver Fibrosis

[0295] Following the dosing regimen of the anti-TL1 A antibody (e.g., following the first phase and / or the second phase), the patient may experience an improvement (e.g., reduction) in liver fibrosis and / or in one or more biomarkers of liver fibrosis.

[0296] In some aspects, the biomarker of liver fibrosis is liver stiffness, e.g., as measured using a FIBROSCAN® assay; serum level of N-terminal propeptide of Type III collagen (Pro-C3); serum ELF™ test score; or fibro-inflammation, e.g., as measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ). In some aspects, the patient experiences an improvement (e.g., reduction) in one, two, three, or all four of liver stiffness, serum level of Pro-C3, serum ELF™ test score, and fibro- inflammation.

[0297] In some aspects, in a patient treated according to any one of the methods provided herein, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level. In some aspects, in a patient treated according to any one of the methods provided herein, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level.

[0298] (a) Liver Stiffness

[0299] In some aspects, the biomarker of liver fibrosis is liver stiffness, e.g., as measured using a FIBROSCAN® assay.

[0300] In some aspects, the biomarker of liver fibrosis is liver stiffness (e.g., as measured using a FIBROSCAN® assay), and the treating results in a decrease in the level of liver stiffness at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s liver stiffness is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 14 as compared to a reference level. In some aspects, liver stiffness is measured using a FIBROSCAN® assay, and the patient’s liver stiffness is decreased by at least 1 kPa, 2 kPa, 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 10 kPa, 15 kPa, 20 kPa, or more than 20 kPa (e.g., is decreased by 1 -2 kPa, 2-4 kPa, 4-6 kPa, 6-8 kPa, 8-10 kPa, 10-12 kPa, 12-14 kPa, 14-16 kPa, 16-18 kPa, or 18-20 kPa) at Week 14 as compared to a reference level.

[0301] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the level of liver stiffness at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s liver stiffness is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10- 20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 52 as compared to a reference level. In some aspects, liver stiffness is measured using a FIBROSCAN® assay, and the patient’s liver stiffness is decreased by at least 1 kPa, 2 kPa, 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, PATENT

[0302] Attorney Docket No: 50474-372WO3

[0303] Genentech Docket No: P39784-WO-1

[0304] 8 kPa, 9 kPa, 10 kPa, 15 kPa, 20 kPa, or more than 20 kPa (e.g., is decreased by 1 -2 kPa, 2-4 kPa, 4-6 kPa, 6-8 kPa, 8-10 kPa, 10-12 kPa, 12-14 kPa, 14-16 kPa, 16-18 kPa, or 18-20 kPa) at Week 52 as compared to a reference level.

[0305] (b) Serum Level of Pro-C3

[0306] In some aspects, the biomarker of liver fibrosis is serum level of Pro-C3, e.g., as measured using the NORDICPRO-C3™ assay.

[0307] In some aspects, the biomarker of liver fibrosis is serum level of Pro-C3, and the treating results in a decrease in the serum level of Pro-C3 at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s serum level of Pro- 03 is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60- 70%, 70-80%, 80-90%, or 90-100%) at Week 14 as compared to a reference level.

[0308] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the serum level of Pro-C3 at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s serum level of Pro-C3 is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 52 as compared to a reference level.

[0309] (c) Serum ELF™ Test Score

[0310] In some aspects, the biomarker of liver fibrosis is serum ELF™ test score.

[0311] In some aspects, the biomarker of liver fibrosis is serum ELF™ test score, and the treating results in a decrease in the serum ELF™ test score at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s serum ELF™ test score is decreased by at least 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or more than 6 (e.g., 1 -2, 2-4, 4-6, or 6-8) at Week 14 as compared to a reference level.

[0312] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the serum ELF™ test score at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s serum ELF™ test score is decreased by at least 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or more than 6 (e.g., 1 -2, 2-4, 4-6, or 6-8) at Week 52 as compared to a reference level.

[0313] (d) Fibro-lnflammation

[0314] In some aspects, the biomarker of liver fibrosis is fibro-inflammation, e.g., as measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ).

[0315] In some aspects, the biomarker of liver fibrosis is fibro-inflammation, and the treating results in a decrease in fibro-inflammation (e.g., as measured using MRI cT1 ) at the end of the first phase as PATENT

[0316] Attorney Docket No: 50474-372WO3

[0317] Genentech Docket No: P39784-WO-1 compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s level of fibro-inflammation is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 14 as compared to a reference level.

[0318] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the level of fibro-inflammation at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s level of fibro-inflammation is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 52 as compared to a reference level.

[0319] (e) Reference Levels

[0320] In any of the above aspects, the reference level may be any level that serves as an appropriate control. In some aspects, the reference level is a level in a population of patients having a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) who have not been treated with an anti-TL1 A antibody (e.g., have not been treated with afimkibart). In some aspects, the reference level is a pre-treatment level in the patient (e.g., a level that was measured prior to initiation of treatment with the anti-TL1 A antibody).

[0321] (f) Reduction of Liver Fibrosis in a Patient Population

[0322] In some aspects, the first phase has a duration of about 14 weeks, and the treating results in an increase in the proportion of patients who have achieved an improvement (e.g., reduction) in liver fibrosis and / or in one or more biomarkers of liver fibrosis at Week 14. For example, in some aspects, in a population of patients treated according to the methods provided herein, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 14. In some aspects, the proportion of patients in the population of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 14 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 14 in the reference population.

[0323] In some aspects, in a population of patients treated according to any one of the methods comprising a second phase provided herein, the dosing regimen has a duration of about 50 weeks, and the treating results in an increase in the proportion of patients who have achieved an improvement (e.g., PATENT

[0324] Attorney Docket No: 50474-372WO3

[0325] Genentech Docket No: P39784-WO-1 reduction) in liver fibrosis and / or in one or more biomarkers of liver fibrosis at Week 52. For example, in some aspects, in a population of patients treated according to the methods provided herein, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 52. In some aspects, the proportion of patients in the population of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 52 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 52 in the reference population.

[0326] The reference population may be any population that serves as an appropriate control. For example, in some aspects, the reference population is a population of subjects having a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) who have not been treated with an anti-TL1 A antibody.

[0327] Reduction in Soluble Biomarkers of Hepatocyte Activity

[0328] Following the dosing regimen of the anti-TL1 A antibody (e.g., following the first phase and / or the second phase), the patient may experience an improvement (e.g., reduction) one or more soluble biomarkers of hepatocyte injury. For example, the patient may experience a reduction in serum alanine transaminase (ALT) I aspartate transaminase (AST) ratio and / or a reduction in serum gamma-glutamyl transferase (GGT).

[0329] In some aspects, the treating results in a decrease in serum AST / ALT ratio and / or serum GGT at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s serum AST / ALT ratio and / or serum GGT is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80- 90%, or 90-100%) at Week 14 as compared to a reference level.

[0330] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in serum AST / ALT ratio and / or serum GGT at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s serum AST / ALT ratio and / or serum GGT is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80- 90%, or 90-100%) at Week 52 as compared to a reference level.

[0331] The reference level may be any level that serves as an appropriate control. In some aspects, the reference level is a level in a population of patients having a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, PATENT

[0332] Attorney Docket No: 50474-372WO3

[0333] Genentech Docket No: P39784-WO-1 alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) who have not been treated with an anti- TL1 A antibody (e.g., have not been treated with afimkibart). In some aspects, the reference level is a pretreatment level in the patient (e.g., a level that was measured prior to initiation of treatment with the anti- TL1 A antibody). iv. Diseases and Conditions

[0334] In some aspects, the disease or condition involves inflammation in the liver. In some aspects, the disease or condition involves fibrosis in the liver.

[0335] In some aspects, the disease or condition is metabolic dysfunction-associated steatohepatitis (MASH). In some aspects, the disease or condition is metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD). In some aspects, the disease or condition is primary biliary cholangitis. In some aspects, the disease or condition is primary sclerosing cholangitis. In some aspects, the disease or condition is alcoholic cirrhosis. In some aspects, the disease or condition is hepatitis cirrhosis. In some aspects, the disease or condition is cholestasis. In some aspects, the disease or condition is autoimmune hepatitis. In some aspects, the disease or condition is viral hepatitis B. In some aspects, the disease or condition is viral hepatitis C. In some aspects, the disease or condition is hemochromatosis. In some aspects, the disease or condition is Wilson’s disease. In some aspects, the disease or condition is alcoholic steatohepatitis. In any of the foregoing aspects, the patient may have a moderate or severe form of the disease or condition. In some aspects, the patient has a severe form of the disease or condition.

[0336] In some aspects of any of the methods, uses, or compositions for use provided herein, the patient has advanced liver fibrosis, e.g., has fibrosis stage 3 or 4 (F3 / F4) as classified using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System.

[0337] In some aspects, the patient has a FIBROSCAN® measurement of between 12.0 kPa and 30.0 kPa. FIBROSCAN® is an ultrasound technology that measures liver stiffness (hardness) in kilopascals (kPa); higher values indicate more stiffness.

[0338] In some aspects, the patient has an Enhanced Liver Fibrosis (ELF™) test score of between 9.8 and 11 .3.

[0339] In some aspects, a biopsy from the patient has been staged as F3 or F4 according to the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System. In some aspects, the patient has a liver fibrosis stage of F3. In some aspects, the patient has a liver fibrosis stage of F4 with compensated cirrhosis.

[0340] In some aspects of any of the methods, uses, or compositions for use provided herein, the patient has a fibrosis score of F3 or F4, wherein the fibrosis score is confirmed by a FIBROSCAN® measurement of > 12.0 kPa and < 30.0 kPa, and has one or both of (i) biopsy staging as F3 or F4 per nonalcoholic PATENT

[0341] Attorney Docket No: 50474-372WO3

[0342] Genentech Docket No: P39784-WO-1 steatohepatitis (NASH) Clinical Research Network (CRN) System within 12 months prior to randomization; or (ii) an ELF™ score > 9.8 and < 1 1 .3 at screening.

[0343] B. Methods of Treating MASH

[0344] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising at least a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose.

[0345] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising only four IV doses of the anti- TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose.

[0346] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks.

[0347] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks.

[0348] The disclosure also provides (i) an anti-TL1 A antibody for use in treating MASH in a patient according to the methods provided herein and (ii) use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH according to the methods provided herein. PATENT

[0349] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0350] / . First Phase

[0351] Any of the methods for treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, metabolic dysfunction-associated steatotic liver disease (MASLD), primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) provided herein may comprise administration of an anti-TL1 A antibody in at least a first phase. The first phase may comprise administration (e.g., intravenous administration) of one or more doses of the anti-TL1 A antibody (e.g., may comprise administration of one, two, three, or four doses of the anti-TL1 A antibody).

[0352] In some aspects, the first phase comprises administration of four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose. In some aspects, the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0 (e.g., Day 1 ±3 days); (b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2 (e.g., Day 1 ±3 days); (c) the third dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6 (e.g., Day 1 ±3 days); and (d) the fourth dose of the anti-TL1 A antibody is administered on about Day 1 of Week 10 (e.g., Day 1 ±3 days). For example, in some aspects, the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and / or (d) the fourth dose of the anti-TL1 A antibody is administered on Day 1 of Week 10 (e.g., first phase doses according to one, two, three, or all four of (a), (b), (c), and (d) are administered). In some aspects, the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and (d) the fourth dose of the anti-TL1 A antibody is administered on Day 1 of Week 10.

[0353] In one aspect, the anti-TL1 A antibody is administered at a dose of about 500 mg (e.g., at a dose of 500 mg) during the first phase. Preferably, the first phase doses are administered intravenously. In some aspects, in the first phase, the anti-TL1 A antibody is administered intravenously (IV) at a dose of about 500 mg (e.g., a dose of 500 mg) (e.g., each dose in the first phase comprises IV administration of about 500 mg (e.g., 500 mg) of the anti-TL1 A antibody).

[0354] Accordingly, in some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase, wherein the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein the first phase has a duration of about 14 weeks, and (a) the first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the PATENT

[0355] Attorney Docket No: 50474-372WO3

[0356] Genentech Docket No: P39784-WO-1 second dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third dose of the anti- TL1 A antibody is administered on Day 1 of Week 6; and (d) the fourth dose of the anti-TL1 A antibody is administered on Day 1 of Week 10. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0357] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising intravenous (IV) administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein the four doses of the anti-TL1 A antibody are administered over about 14 weeks, and (a) the IV first dose of the anti-TL1 A antibody is administered on Day 1 of Week 0; (b) the second IV dose of the anti-TL1 A antibody is administered on Day 1 of Week 2; (c) the third IV dose of the anti-TL1 A antibody is administered on Day 1 of Week 6; and (d) the fourth IV dose of the anti-TL1 A antibody is administered on Day 1 of Week 10. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR- H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0358] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0359] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having PATENT

[0360] Attorney Docket No: 50474-372WO3

[0361] Genentech Docket No: P39784-WO-1 at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0362] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0363] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0364] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about PATENT

[0365] Attorney Docket No: 50474-372WO3

[0366] Genentech Docket No: P39784-WO-1 four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0367] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0368] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti- TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0369] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0370] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain PATENT

[0371] Attorney Docket No: 50474-372WO3

[0372] Genentech Docket No: P39784-WO-1 comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0373] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0374] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0375] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of only four IV doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence PATENT

[0376] Attorney Docket No: 50474-372WO3

[0377] Genentech Docket No: P39784-WO-1 comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0378] Any of the methods provided herein may comprise administration of an anti-TL1 A antibody in a second phase that follows administration of the anti-TL1 A antibody in a first phase. The second phase may comprise administration of one or more doses of the anti-TL1 A antibody.

[0379] The second phase may be initiated at any appropriate time following the first phase. In some aspects, the first dose of the second phase is administered about four weeks (e.g., four weeks) after administration of the last dose of the first phase. For example, in aspects in which the first phase comprises administration of four doses of the anti-TL1 A antibody, the first dose of the second phase may be administered about four weeks (e.g., four weeks) after administration of the fourth dose of the first phase.

[0380] In some aspects in which the second phase comprises administration of at least two doses of the anti-TL1 A antibody, the time interval between each individual dose in the second phase may be the same. In other aspects, the time interval between individual doses in the second phase is not the same.

[0381] In some aspects, the second phase comprises administration (e.g., subcutaneous administration) of the anti-TL1 A antibody every four weeks (Q4W).

[0382] In one aspect, the anti-TL1 A antibody is administered at a dose of about 450 mg (e.g., at a dose of 450 mg) during the second phase. Doses in the second phase can be administered subcutaneously In some aspects, in the second phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 450 mg (e.g., 450 mg) every four weeks.

[0383] In some aspects, the second phase comprises administration of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses of the anti-TL1 A antibody.

[0384] In some aspects, the second phase comprises ten doses of the anti-TL1 A antibody (e.g., comprises ten doses of the anti-TL1 A antibody administered in a Q4W dosing regimen). In some aspects, the second phase has a duration of about 36 weeks.

[0385] Accordingly, in some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein: (a) the first phase comprises intravenous administration of four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg.

[0386] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody PATENT

[0387] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0388] (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein: (a) the first phase comprises intravenous administration of four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0389] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1 A antibody provided in Section III herein) in a dosing regimen comprising (a) intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg. In some aspects, the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0390] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. In some aspects, (a) the first dose of the first phase is administered on PATENT

[0391] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 about Day 1 of Week 0; (b) the second dose of the first phase is administered on about Day 1 of Week 2; (c) the third dose of the first phase is administered on about Day 1 of Week 6; (d) the fourth dose of the first phase is administered on about Day 1 of Week 10; (e) the first dose of the second phase is administered on about Day 1 of Week 14; and (f) the subsequent doses of the second phase are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50.

[0392] In some aspects, the disclosure provides a method of treating MASH (e.g., advanced MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising (a) intravenous administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and (b) subcutaneous (SC) administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises: (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. In some aspects, (a) the first IV dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0; (b) the second IV dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2; (c) the third IV dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6; (d) the fourth IV dose of the anti- TL1 A antibody is administered on about Day 1 of Week 10; (e) the first SC dose of the anti-TL1 A antibody is administered on about Day 1 of Week 14; and (f) the subsequent SC doses of the anti-TL1 A antibody are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50. In some aspects, the dosing regimen comprising the first phase and second phase has a duration of about 50 weeks (e.g., has a duration of 50 weeks).

[0393] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0394] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV PATENT

[0395] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

[0396] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0397] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (I) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or (II) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2, and comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID PATENT

[0398] Attorney Docket No: 50474-372WO3

[0399] Genentech Docket No: P39784-WO-1

[0400] NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0401] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0402] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks, wherein: (i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third dose; wherein the anti-TL1 A antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0403] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0404] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV PATENT

[0405] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1 doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0406] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0407] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (I) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9; and (II) a light chain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10, and wherein the anti-TL1 A antibody comprises the following CDRs: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a PATENT

[0408] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0409] CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody is afimkibart.

[0410] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising a first phase and a second phase, wherein (a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein: (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) the second phase comprises administration of the anti-TL1 A antibody every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart.

[0411] In some aspects, the disclosure provides a method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody (e.g., an anti-TL1A antibody provided in Section III herein) in a dosing regimen comprising administration of (a) only four IV doses of the anti-TL1 A antibody, wherein (i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose; (ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and (iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and (b) one or more subcutaneously administered (SC) doses of the anti- TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks; wherein the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody is afimkibart. iii. Response to Treatment

[0412] Improvement in Biomarkers of Liver Fibrosis

[0413] Following the dosing regimen of the anti-TL1 A antibody (e.g., following the first phase and / or the second phase), the patient may experience an improvement (e.g., reduction) in liver fibrosis and / or in one or more biomarkers of liver fibrosis.

[0414] In some aspects, the biomarker of liver fibrosis is liver stiffness, e.g., as measured using a FIBROSCAN® assay; serum level of N-terminal propeptide of Type III collagen (Pro-C3); serum ELF™ test score; or fibro-inflammation, e.g., as measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ). In some aspects, the patient experiences an improvement (e.g., reduction) in one, two, three, or all four of liver stiffness, serum level of Pro-C3, serum ELF™ test score, and fibro- inflammation.

[0415] In some aspects, in a patient treated according to any one of the methods provided herein, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level. In some aspects, in a patient treated according to any one of PATENT

[0416] Attorney Docket No: 50474-372WO3

[0417] Genentech Docket No: P39784-WO-1 the methods provided herein, the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level.

[0418] (a) Liver Stiffness

[0419] In some aspects, the biomarker of liver fibrosis is liver stiffness, e.g., as measured using a FIBROSCAN® assay.

[0420] In some aspects, the biomarker of liver fibrosis is liver stiffness (e.g., as measured using a FIBROSCAN® assay), and the treating results in a decrease in the level of liver stiffness at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s liver stiffness is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 14 as compared to a reference level. In some aspects, liver stiffness is measured using a FIBROSCAN® assay, and the patient’s liver stiffness is decreased by at least 1 kPa, 2 kPa, 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 10 kPa, 15 kPa, 20 kPa, or more than 20 kPa (e.g., is decreased by 1 -2 kPa, 2-4 kPa, 4-6 kPa, 6-8 kPa, 8-10 kPa, 10-12 kPa, 12-14 kPa, 14-16 kPa, 16-18 kPa, or 18-20 kPa) at Week 14 as compared to a reference level.

[0421] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the level of liver stiffness at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s liver stiffness is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10- 20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 52 as compared to a reference level. In some aspects, liver stiffness is measured using a FIBROSCAN® assay, and the patient’s liver stiffness is decreased by at least 1 kPa, 2 kPa, 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 10 kPa, 15 kPa, 20 kPa, or more than 20 kPa (e.g., is decreased by 1 -2 kPa, 2-4 kPa, 4-6 kPa, 6-8 kPa, 8-10 kPa, 10-12 kPa, 12-14 kPa, 14-16 kPa, 16-18 kPa, or 18-20 kPa) at Week 52 as compared to a reference level.

[0422] (b) Serum Level of Pro-C3

[0423] In some aspects, the biomarker of liver fibrosis is serum level of Pro-C3, e.g., as measured using the NORDICPRO-C3™ assay.

[0424] In some aspects, the biomarker of liver fibrosis is serum level of Pro-C3, and the treating results in a decrease in the serum level of Pro-C3 at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s serum level of Pro- 03 is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60- 70%, 70-80%, 80-90%, or 90-100%) at Week 14 as compared to a reference level. PATENT

[0425] Attorney Docket No: 50474-372WO3

[0426] Genentech Docket No: P39784-WO-1

[0427] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the serum level of Pro-C3 at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s serum level of Pro-C3 is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 52 as compared to a reference level.

[0428] (c) Serum ELF™ Test Score

[0429] In some aspects, the biomarker of liver fibrosis is serum ELF™ test score.

[0430] In some aspects, the biomarker of liver fibrosis is serum ELF™ test score, and the treating results in a decrease in the serum ELF™ test score at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s serum ELF™ test score is decreased by at least 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or more than 6 (e.g., 1 -2, 2-4, 4-6, or 6-8) at Week 14 as compared to a reference level.

[0431] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the serum ELF™ test score at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s serum ELF™ test score is decreased by at least 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or more than 6 (e.g., 1 -2, 2-4, 4-6, or 6-8) at Week 52 as compared to a reference level.

[0432] (d) Fibro-lnflammation

[0433] In some aspects, the biomarker of liver fibrosis is fibro-inflammation, e.g., as measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ).

[0434] In some aspects, the biomarker of liver fibrosis is fibro-inflammation, and the treating results in a decrease in fibro-inflammation (e.g., as measured using MRI cT1 ) at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s level of fibro-inflammation is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 14 as compared to a reference level.

[0435] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in the level of fibro-inflammation at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s level of fibro-inflammation is decreased by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) at Week 52 as compared to a reference level. PATENT

[0436] Attorney Docket No: 50474-372WO3

[0437] Genentech Docket No: P39784-WO-1

[0438] (e) Reference Levels

[0439] In any of the above aspects, the reference level may be any level that serves as an appropriate control. In some aspects, the reference level is a level in a population of patients having MASH (e.g., advanced MASH) who have not been treated with an anti-TL1 A antibody (e.g., have not been treated with afimkibart). In some aspects, the reference level is a pre-treatment level in the patient (e.g., a level that was measured prior to initiation of treatment with the anti-TL1 A antibody).

[0440] (f) Reduction of Liver Fibrosis in a Patient Population

[0441] In some aspects, the first phase has a duration of about 14 weeks, and the treating results in an increase in the proportion of patients who have achieved an improvement (e.g., reduction) in liver fibrosis and / or in one or more biomarkers of liver fibrosis at Week 14. For example, in some aspects, in a population of patients treated according to the methods provided herein, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 14. In some aspects, the proportion of patients in the population of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 14 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 14 in the reference population.

[0442] In some aspects, in a population of patients treated according to any one of the methods comprising a second phase provided herein, the dosing regimen has a duration of about 50 weeks, and the treating results in an increase in the proportion of patients who have achieved an improvement (e.g., reduction) in liver fibrosis and / or in one or more biomarkers of liver fibrosis at Week 52. For example, in some aspects, in a population of patients treated according to the methods provided herein, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of patients) in the population of patients have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 52. In some aspects, the proportion of patients in the population of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 52 is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients who have experienced a decrease in the level of one or more biomarkers of liver fibrosis at Week 52 in the reference population.

[0443] The reference population may be any population that serves as an appropriate control. For example, in some aspects, the reference population is a population of subjects having MASH (e.g., advanced MASH) who have not been treated with an anti-TL1 A antibody. PATENT

[0444] Attorney Docket No: 50474-372WO3

[0445] Genentech Docket No: P39784-WO-1

[0446] Reduction in Soluble Biomarkers of Hepatocyte Activity

[0447] Following the dosing regimen of the anti-TL1 A antibody (e.g., following the first phase and / or the second phase), the patient may experience an improvement (e.g., reduction) one or more soluble biomarkers of hepatocyte injury. For example, the patient may experience a reduction in serum alanine transaminase (ALT) I aspartate transaminase (AST) ratio and / or a reduction in serum gamma-glutamyl transferase (GGT).

[0448] In some aspects, the treating results in a decrease in serum AST / ALT ratio and / or serum GGT at the end of the first phase as compared to a reference level. In some aspects, the first phase has a duration of about 14 weeks, and the patient’s serum AST / ALT ratio and / or serum GGT is decreased by at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80- 90%, or 90-100%) at Week 14 as compared to a reference level.

[0449] In some aspects, in a patient treated according to any one of the methods comprising a second phase provided herein, the treating results in a decrease in serum AST / ALT ratio and / or serum GGT at the end of the second phase as compared to a reference level. In some aspects, the dosing regimen has a duration of about 50 weeks, and the patient’s serum AST / ALT ratio and / or serum GGT is decreased by at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% (e.g., 1 -10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80- 90%, or 90-100%) at Week 52 as compared to a reference level.

[0450] The reference level may be any level that serves as an appropriate control. In some aspects, the reference level is a level in a population of patients having MASH (e.g., advanced MASH) who have not been treated with an anti-TL1 A antibody (e.g., have not been treated with afimkibart). In some aspects, the reference level is a pre-treatment level in the patient (e.g., a level that was measured prior to initiation of treatment with the anti-TL1 A antibody). iv. MASH Severity and Advanced MASH

[0451] MASH is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by, e.g., excessive fat buildup in the liver, hepatocellular injury or ballooning, liver scarring, and / or collagen matrix deposition. MASH may also be referred to as nonalcoholic steatohepatitis (NASH).

[0452] In some aspects of any of the methods, uses, or compositions for use provided herein, the patient has advanced MASH (i.e. , the MASH is advanced MASH).

[0453] In some aspects of any of the methods, uses, or compositions for use provided herein, the patient has MASH with advanced liver fibrosis, e.g., has fibrosis stage 3 or 4 (F3 / F4) as classified using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System.

[0454] In some aspects, the patient has a FIBROSCAN® measurement of between 12.0 kPa and 30.0 kPa. FIBROSCAN® is an ultrasound technology that measures liver stiffness (hardness) in kilopascals (kPa); higher values indicate more stiffness. PATENT

[0455] Attorney Docket No: 50474-372WO3

[0456] Genentech Docket No: P39784-WO-1

[0457] In some aspects, the patient has an Enhanced Liver Fibrosis (ELF™) test score of between 9.8 and 1 1 .3.

[0458] In some aspects, a biopsy from the patient has been staged as F3 or F4 according to the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System. In some aspects, the patient has a liver fibrosis stage of F3. In some aspects, the patient has a liver fibrosis stage of F4 with compensated cirrhosis.

[0459] In some aspects of any of the methods, uses, or compositions for use provided herein, the patient has MASH with a fibrosis score of F3 or F4, wherein the fibrosis score is confirmed by a FIBROSCAN® measurement of > 12.0 kPa and < 30.0 kPa, and has one or both of (i) biopsy staging as F3 or F4 per nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System within 12 months prior to randomization; or (ii) an ELF™ score > 9.8 and < 1 1 .3 at screening.

[0460] C. Combination Therapies

[0461] Anti-TL1 A antibodies of the disclosure can be administered alone or used in a combination therapy (e.g., for treatment of a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis)). For instance, the combination therapy may include administering an anti-TL1 A antibody according to any of the methods provided herein and administering at least one additional therapeutic agent (e.g. one, two, three, four, five, or six additional therapeutic agents). In one aspect, the combination therapy comprises administering an antibody of the disclosure and administering at least one additional therapeutic agent.

[0462] Such combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate pharmaceutical composition(s)), and separate administration, in which case administration of the anti-TL1 A antibody can occur prior to, simultaneously with, and / or following, administration of the additional therapeutic agent or agents. In one aspect, administration of the anti-TL1 A antibody and administration of an additional therapeutic agent occur within about one, two, three, four, five, or six days, within about one, two or three weeks, or within about one month, of each other. In one aspect, the antibody and additional therapeutic agent are both administered to the patient on Day 1 of the treatment.

[0463] In some aspects, the disclosure provides a pharmaceutical composition that comprises any of the anti-TL1 A antibodies provided herein and at least one additional therapeutic agent.

[0464] Exemplary therapeutic agents that may be administered in combination with an anti-TL1 A antibody for the treatment of MASH or MASLD are provided below.

[0465] In some aspects, the anti-TL1 A antibody is administered in combination with resmetirom (REZDIFFRA™) for treatment of MASH or MASLD.

[0466] In some aspects, the anti-TL1 A antibody is administered in combination with Vitamin E, e.g., high-dose Vitamin E, for treatment of MASH or MASLD.

[0467] In some aspects, the anti-TL1 A antibody is administered in combination with pioglitazone for treatment of MASH or MASLD. PATENT

[0468] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0469] In some aspects, the anti-TL1 A antibody is administered in combination with an incretin-based therapy, e.g., a glucagon-like peptide-1 (GLP-1 ) agonist (e.g., semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide, orforglipron, or danuglipron), a dual GIP / GLP-1 agonist, e.g., tirzepatide, CT388 (RG-6640), CT-868 (RG-6641 ), VK2735, MAR701 , or HS-20094, or another incretin-based therapy, e.g., retatrutide, survodutide, mazdutide, pemvidutide, MET-097i, CagriSema, or amycretin, for treatment of MASH or MASLD.

[0470] In some aspects, the anti-TL1 A antibody is administered in combination with a fibroblast growth factor 21 (FGF21 ) analog, e.g., efruxifermin or pegozafermin, for treatment of MASH or MASLD.

[0471] In some aspects, the anti-TL1 A antibody is administered in combination with a peroxisome proliferator-activated receptor (PPAR) agonist, e.g., lanifibranor, for treatment of MASH or MASLD.

[0472] In some aspects of any of the methods, uses, or compositions for use provided herein in which the disease or condition is MASH or MASLD, the patient is also treated with a weight loss, antidiabetic, lipid-lowering, or anti-depressant medication. In some aspects, the dose of the weight loss, antidiabetic, or lipid-lowering medication is stable for at least 3 months prior to the initiation of treatment with the anti- TL1 A antibody and is not intended to be modified during treatment with the anti-TL1 A antibody. Exemplary medications that may be administered concomitantly with the anti-TL1 A antibody include, but are not limited to glucagon-like peptide-1 (GLP-1 )-based therapies (e.g., GLP-1 mono agonists, GLP-1 I gastric inhibitory peptide (GIP) dual agonists, etc.), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, statins, Vitamin E (e.g., high-dose Vitamin E), and pioglitazone. In other aspects, the patient is not treated with a weight loss, antidiabetic, or lipid-lowering medication during treatment with the anti-TL1 A antibody.

[0473] III. Anti-TL1 A Antibodies

[0474] The methods of the present disclosure include the administration of an anti-TL1 A antibody. Exemplary anti-TL1 A antibodies of the disclosure are set forth in Table 1 .

[0475] Table 1. Sequences of Exemplary Antibodies of the Disclosure PATENT

[0476] Attorney Docket No: 50474-372WO3

[0477] Genentech Docket No: P39784-WO-1 PATENT

[0478] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0479] In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody comprises one, two, three, four, five, six, seven, or all eight of the framework region sequences shown in SEQ ID NOs: 13-20.

[0480] In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the anti-TL1 A antibody comprises one, two, three, four, five, six, seven, or all eight of the framework region sequences shown in SEQ ID NOs: 14-21.

[0481] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain variable domain (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1 ) and / or comprises a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2).

[0482] In some aspects of the disclosure, the anti-TL1 A antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and / or comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

[0483] In some aspects of the disclosure, the anti-TL1 A antibody comprises a VH having the sequence shown in SEQ ID NO: 1 and a VL having the sequence shown in SEQ ID NO: 2.

[0484] In some aspects of the disclosure, the anti-TL1 A antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 11 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9 or SEQ ID NO: 11 ); and / or (b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10 (e.g., having at least 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10).

[0485] In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and / or (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-TL1 A antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0486] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 11. In some embodiments, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 11 and a light chain having the sequence shown in SEQ ID NO: 10, wherein the C-terminal lysine (K) of the heavy chain amino acid sequence of SEQ ID PATENT

[0487] Attorney Docket No: 50474-372WO3

[0488] Genentech Docket No: P39784-WO-1

[0489] NO: 1 1 is optional. In some embodiments, the heavy chain does not have the C-terminal lysine (K). In some embodiments, the heavy chain has the sequence shown in SEQ ID NO: 9. In some embodiments, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 9 and a light chain having the sequence shown in SEQ ID NO: 10. In some aspects of the disclosure, the anti-TL1 A antibody is afimkibart (also known as

[0490] RO7790121 , RVT-3101 , or PF-06480605).

[0491] Further exemplary anti-TL1 A antibodies are set forth in Table 2 and below.

[0492] Table 2. Further Sequences of Exemplary Antibodies of the Disclosure PATENT

[0493] Attorney Docket No: 50474-372WO3

[0494] Genentech Docket No: P39784-WO-1 PATENT

[0495] Attorney Docket No: 50474-372WO3

[0496] Genentech Docket No: P39784-WO-1 PATENT

[0497] Attorney Docket No: 50474-372WO3

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[0499] Attorney Docket No: 50474-372WO3

[0500] Genentech Docket No: P39784-WO-1

[0501] In some aspects of the disclosure, the anti-TL1 A antibody comprises a VH encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VH having ATCC accession number PTA-120639 and a VL encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VL having ATCC accession number PTA-120640. In some aspects of the disclosure, the anti-TL1 A antibody competes for binding with an anti-TL1 A antibody comprising a variable heavy chain region having the sequence shown in SEQ ID NO: 1 and a variable light chain region having the sequence shown in SEQ ID NO: 2.

[0502] In some aspects of the disclosure, the anti-TL1 A antibody competes for binding with an antibody comprising a VH encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VH having ATCC accession number PTA-120639 and a VL encoded by the nucleic acid sequence of the insert of the vector deposited as 1 D1 1 .31 VL having ATCC accession number PTA-120640. PATENT

[0503] Attorney Docket No: 50474-372WO3

[0504] Genentech Docket No: P39784-WO-1

[0505] In some aspects of the disclosure, the anti-TL1 A antibody comprises sequence pairs selected from the group consisting of SEQ ID NOs: 2 and 22; SEQ ID NOs: 2 and 23; SEQ ID NOs: 2 and 24; SEQ ID NOs: 2 and 25; SEQ ID NOs: 2 and 26; SEQ ID NOs: 2 and 27; SEQ ID NOs: 2 and 28; SEQ ID NOs: 2 and 29; SEQ ID NOs: 2 and 30; SEQ ID NOs: 31 and 35; SEQ ID NOs: 32 and 36; SEQ ID NOs: 33 and 37; SEQ ID NOs: 34 and 38; SEQ ID NOs: 39 and 40; SEQ ID NOs: 41 and 42; SEQ ID NOs: 43 and 44; SEQ ID NOs: 45 and 54; SEQ ID NOs: 63 and 64; SEQ ID NOs: 71 and 72; SEQ ID NOs: 73 and 74; SEQ ID NOs: 75 and 74; SEQ ID NOs: 76 and 74; and SEQ ID NOs: 77 and 74.

[0506] In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 having the sequence shown in SEQ ID NO: 47, a CDR-H2 having the sequence shown in SEQ ID NO: 49, a CDR- H3 having the sequence shown in SEQ ID NO: 51 , a CDR-L1 having the sequence shown in SEQ ID NO: 56, a CDR-L2 having the sequence shown in SEQ ID NO: 58, and a CDR-L3 having the sequence shown in SEQ ID NO: 60.

[0507] In some aspects of the disclosure, the anti-TL1 A antibody comprises heavy chain framework regions as shown in SEQ ID NOs: 46, 48, 50, and 52 and / or comprises light chain framework regions as shown in SEQ ID NOs: 55, 57, 59, and 61 .

[0508] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain variable region having the sequence shown in SEQ ID NO: 63 and a light chain variable region having the sequence shown in SEQ ID NO: 64.

[0509] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain tail sequence as provided in SEQ ID NO: 53. In some aspects of the disclosure, the anti-TL1 A antibody comprises a light chain tail sequence as provided in SEQ ID NO: 62.

[0510] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 45 and / or a light chain having the sequence shown in SEQ ID NO: 54. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 45 and a light chain having the sequence shown in SEQ ID NO: 54.

[0511] In some aspects of the disclosure, the anti-TL1 A antibody is tulisokibart.

[0512] In some aspects, the antibody used in any of the methods, compositions, uses, and compositions for use provided herein is an anti-TL1 A antibody provided in Table 2A of U.S. Patent No. 11 ,136,386, which is incorporated herein by reference in its entirety.

[0513] In some aspects of any of the methods, compositions, uses, and compositions for use provided herein, the anti-TL1 A antibody is an anti-TL1 A antibody provided in U.S. Patent No. 10,322,174, U.S. Patent No. 10,689,439, U.S. Patent No. 11 ,292,848, U.S. Patent No. 10,138,296, U.S. Patent No. 10,822,422, and U.S. Patent No. 11 ,220,549, which are incorporated herein by reference in their entirety. In some embodiments, the anti-TL1 A antibody comprises the CDR sequences of the 320-179 clone provided in U.S. Patent No. 10,689,439. In some embodiments, the anti-TL1 A antibody is the 320-179 clone provided in U.S. Patent No. 10,689,439.

[0514] In some aspects of the disclosure, the anti-TL1 A antibody comprises a CDR-H1 having the sequence shown in SEQ ID NO: 65, a CDR-H2 having the sequence shown in SEQ ID NO: 66, a CDR- H3 having the sequence shown in SEQ ID NO:67, a CDR-L1 having the sequence shown in SEQ ID NO: PATENT

[0515] Attorney Docket No: 50474-372WO3

[0516] Genentech Docket No: P39784-WO-1

[0517] 68, a CDR-L2 having the sequence shown in SEQ ID NO: 69, and a CDR-L3 having the sequence shown in SEQ ID NO: 70.

[0518] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain variable region having the sequence shown in SEQ ID NO: 71 and a light chain variable region having the sequence shown in SEQ ID NO: 72.

[0519] In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 73, 75, 76, or 77 and / or a light chain having the sequence shown in SEQ ID NO:74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 73, 75, 76, or 77 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 73 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 75 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 76 and a light chain having the sequence shown in SEQ ID NO: 74. In some aspects of the disclosure, the anti-TL1 A antibody comprises a heavy chain having the sequence shown in SEQ ID NO: 77 and a light chain having the sequence shown in SEQ ID NO: 74.

[0520] In some aspects of the disclosure, the anti-TL1 A antibody is TEV-48574.

[0521] In some aspects of the disclosure, the anti-TL1 A antibody is C03V. C03V has been described, for example, in Clarke AW, Poulton L, Shim D, Mabon D, Butt D, Pollard M, Pande V, Husten J, Lyons J, Tian C, Doyle AG. An anti-TL1 A antibody for the treatment of asthma and inflammatory bowel disease. MAbs. 2018 May / Jun;10(4) :664-677. doi: 10.1080 / 19420862.2018.1440164. Epub 2018 Mar 5. PMID: 29436901 ; PMCID: PMC5973687.

[0522] In some aspects of the disclosure, the anti-TL1 A antibody is SPY002. SPY002 has been described, for example, in Zhu, E., et al. "P91 1 Development and Characterization of SPY002, a Novel Extended Half-life Monoclonal Antibody Drug Candidate Targeting TL1 A for the Treatment of IBD." Journal of Crohn's and Colitis 18. Supplements (2024): i1666-i 1666.

[0523] In some aspects of the disclosure, the anti-TL1 A antibody is FG-M701 .

[0524] In some aspects of the disclosure, the anti-TL1 A antibody is XmAb942.

[0525] In some aspects of the disclosure, the anti-TL1 A antibody is HXN-101 1 .

[0526] In some aspects of the disclosure, the anti-TL1 A antibody is ABS-101 .

[0527] IV. Articles of Manufacture and Kits

[0528] In another aspect of the invention, an article of manufacture containing materials useful for the treatment, prevention and / or diagnosis of the disorders, diseases, and conditions described above (e.g., disease or condition involving inflammation and / or fibrosis in the liver, e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis, is provided. The article of manufacture comprises a container and a label or package PATENT

[0529] Attorney Docket No: 50474-372WO3

[0530] Genentech Docket No: P39784-WO-1 insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition (e.g., a composition comprising an anti-TL1 A antibody) which is by itself or combined with another composition effective for treating, preventing and / or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an antibody of the disclosure (e.g., an anti-TL1 A antibody, e.g., afimkibart). The label or package insert indicates that the composition is used for treating the disease or condition of choice (e.g., disease or condition involving inflammation and / or fibrosis in the liver, e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis). Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody of the disclosure; and (b) a second container with a composition contained therein, wherein the composition comprises a further therapeutic agent. The article of manufacture in this aspect of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition (e.g., disease or condition involving inflammation and / or fibrosis in the liver, e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis). Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0531] The disclosure also provides kits comprising any or all of the anti-TL1 A antibodies described herein. Kits of the disclosure include one or more containers comprising an anti-TL1 A antibody described herein and instructions for use in accordance with any of the methods of the disclosure described herein. Generally, these instructions comprise a description of administration of the anti-TL1 A antibody for the above-described therapeutic treatments. In some aspects, kits are provided for producing a single-dose administration unit. In certain aspects, the kit can contain both a first container having a dried protein and a second container having an aqueous formulation. In certain aspects, kits containing single and multichambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.

[0532] The instructions relating to the use of an anti-TL1 A antibody generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi dose packages) or sub-unit doses. Instructions supplied in the kits of the disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable. PATENT

[0533] Attorney Docket No: 50474-372WO3

[0534] Genentech Docket No: P39784-WO-1

[0535] The kits of this disclosure are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump. A kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-TL1 A antibody. The container may further comprise a second pharmaceutically active agent.

[0536] Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container.

[0537] V. Compositions and Formulations

[0538] A. Compositions

[0539] In a further aspect, provided are pharmaceutical compositions comprising an effective amount of an anti-TL1 A antibody as described herein, and such pharmaceutical compositions for use in any of the methods of treatment provided herein. In one aspect, a pharmaceutical composition comprises any of the antibodies provided herein and a pharmaceutically acceptable carrier. In another aspect, a pharmaceutical composition comprises any of the antibodies provided herein and at least one additional therapeutic agent, e.g., as described below.

[0540] Pharmaceutical compositions (formulations) of an anti-TL1 A antibody as described herein can be prepared by combining the antibody with pharmaceutically acceptable carriers or excipients known to the skilled person. See, for example Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) and Falconer R.J., Biotechnology Advances 37: 107412 (2019). Exemplary pharmaceutical compositions of an anti-TL1 A antibody as described herein may be lyophilized, aqueous, frozen, etc.

[0541] Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as histidine, phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). PATENT

[0542] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0543] The pharmaceutical composition herein may also contain more than one active ingredient as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

[0544] The pharmaceutical compositions to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0545] The anti-TL1 A antibody, and compositions thereof, can also be used in conjunction with, or administered separately, simultaneously, or sequentially with other agents that serve to enhance and / or complement the effectiveness of the agents.

[0546] B. Formulations

[0547] Therapeutic formulations of the anti-TL1 A antibody used in accordance with the present disclosure are prepared for storage by mixing the protein having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0548] Liposomes that may contain the anti-TL1 A antibody are prepared by methods known in the art, such as described in Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0549] The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatinmicrocapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and PATENT

[0550] Attorney Docket No: 50474-372WO3

[0551] Genentech Docket No: P39784-WO-1 nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000).

[0552] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained- release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L- glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0553] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Therapeutic anti-TL1 A antibody compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0554] The compositions according to the present disclosure may be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

[0555] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 to about 500 mg of the active ingredient of the present disclosure. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0556] Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary. PATENT

[0557] Attorney Docket No: 50474-372WO3

[0558] Genentech Docket No: P39784-WO-1

[0559] Suitable emulsions may be prepared using commercially available fat emulsions, such as INTRALIPID™, LIPOSYN™, INFONUTROL™, LIPOFUNDIN™ and LIPIPHYSAN™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion.

[0560] Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1 .0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0561] The emulsion compositions can be those prepared by mixing an anti-TL1A antibody with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0562] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some aspects, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0563] In aspects that refer to a method of treating a disease or condition involving inflammation and / or fibrosis in the liver (e.g., MASH, MASLD, primary biliary cholangitis, primary sclerosing cholangitis, alcoholic cirrhosis, hepatitis cirrhosis, cholestasis, autoimmune hepatitis, viral hepatitis B, viral hepatitis C, hemochromatosis, Wilson’s disease, or alcoholic steatohepatitis) as described herein, such aspects are also further aspects of an anti-TL1 A antibody for use in that treatment, or alternatively of the use of an anti-TL1 A antibody in the manufacture of a medicament for use in that treatment.

[0564] VI. Examples

[0565] Example 1. A Phase lb, Multicenter, Open-Label, Single-Arm Study to Assess the Safety, Pharmacokinetics, and Activity of Afimkibart in Patients with Advanced MASH Liver Fibrosis

[0566] The CC45687 study provided in these Examples is designed to assess the safety, pharmacokinetics, pharmacodynamics, immunogenicity and activity of afimkibart (formerly PF-06480605, RVT-3101 , or RO7790121 ) in patients having advanced metabolic dysfunction-associated steatohepatitis (MASH) fibrosis with fibrosis stage F3 and F4 compensated cirrhosis. Afimkibart is a fully human neutralizing monoclonal antibody (mAb) against the tumor necrosis factor (TNF)-like ligand 1 A (TL1 A).

[0567] The mechanism of action of afimkibart is to neutralize the binding and subsequent signaling of TL1 A to its functional receptor (death receptor 3 (DR3)) on immune cells of the innate and adaptive immune system. TL1 A is linked to both metabolic dysfunction and fibrosis as a key regulator of innate PATENT

[0568] Attorney Docket No: 50474-372WO3

[0569] Genentech Docket No: P39784-WO-1 lymphoid cell (ILC) and adaptive immune responses (Meylan et al., Mucosal Immunol, 7:958-68, 2014). TL1 A has been shown to be a modulator of metabolic dysfunction in vivo through modulation of Type 1 ILCs (ILC1 s) (Tougaard et al., Eur J Immunol, 45:865-75, 2015; Tougaard et al., Int J Obes, 44:1062-74, 2020), and a noncoding polymorphism (rs4979453) close to the TL1 A gene (Tnfsf15) locus has been linked to waist circumference in men (Tougaard et al., Int J Obes, 44:1062-74, 2020). TL1 A also serves as a key activator of profibrotic Type 2 ILCs (ILC2s), the frequency of which is correlated with severity of liver fibrosis in patients with severe fibrosis from multiple etiologies (Jeffery et al., PLoS One, 12:e0188649, 2017; Gonzalez-Polo et al., Ann Hepatol, 18:366-72, 2019). TL1 A has also been shown to exacerbate liver fibrosis in mice (Guo et al., J Immunol Res, 7657294, 2019).

[0570] MASH, formerly known as nonalcoholic steatohepatitis (NASH) (Rinella et al., Hepatology, 78:1966-86, 2023), is a liver disease with a global prevalence of 5% and is the most severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) (Younossi et al., Hepatology, 77:1335- 47, 2023). The disease is characterized by hepatocellular injury or ballooning, inflammation (Schuster et al., Nat Rev Gastroenterol Hepatol, 15:349-64, 2018), liver scarring, and collagen matrix deposition (Decaris et al., Hepatology, 65:78-88, 2017). Long-term complications of MASH include the development of progressive fibrosis and cirrhosis in 20% of patients (Khan et al., World J Hepatol, 7:2155-61 , 2015), 8% of whom will develop hepatocellular carcinoma (HCC) (White et al., Clin Gastroenterol Hepatol, 10:1342-59, 2012), making MASH an increasingly prevalent reason for liver transplantation (Younossi et al., Clin Gastroenterol Hepatol, 19:580-89, 2021 ).

[0571] Currently, the only approved treatment for metabolic dysfunction-associated steatohepatitis (MASH) is resmetirom, which is approved for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis, consistent with stages F2 to F3 fibrosis (REZDIFFRA® U.S. Package Insert). Significant unmet need remains in the most severe forms of MASH with cirrhosis, particularly in reversal of fibrosis, improvement of cirrhosis and the prevention of decompensation, hepatocellular carcinoma (HCC), and the need for liver transplantation.

[0572] Without being bound by any theory or hypotheis, by inhibiting the binding of TL1 A to DR3, afimkibart may prevent the activation of ILC1 and ILC2 cell populations underlying metabolic dysfunction and fibrogenesis and improve both metabolic dysfunction and directly inhibit the development of liver fibrosis, potentially offering benefit to patients with MASH with advanced fibrosis and compensated cirrhosis.

[0573] A. Primary objective and corresponding endpoints

[0574] The CC45687 study evaluates the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and activity of afimkibart in patients with advanced MASH liver fibrosis in F3 and F4 stages. The primary, secondary, and exploratory objectives for the study are expressed using endpoints as described below (Tables 3-6). PATENT

[0575] Attorney Docket No: 50474-372WO3

[0576] Genentech Docket No: P39784-WO-1

[0577] Table 3. Primary Objective and Endpoints

[0578] B. Secondary objectives and endpoints

[0579] Secondary objectives and corresponding endpoints are described below (Table 4).

[0580] Table 4. Secondary Objectives and Endpoints

[0581] C. Exploratory objectives and endpoints

[0582] Exploratory objectives and corresponding endpoints are described below (Tables 5 and 6).

[0583] Table 5. Key Exploratory Objective and Endpoints

[0584] Table 6. Other Exploratory Objective and Endpoints PATENT

[0585] Attorney Docket No: 50474-372WO3

[0586] Genentech Docket No: P39784-WO-1

[0587] Example 2. MASH Study Design

[0588] A. Overall design

[0589] CC45687 is a Phase lb, multicenter, open-label, single-arm study designed to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity and activity of afimkibart in participants with advanced MASH liver fibrosis (defined as a fibrosis score of F3 or F4). The study evaluates a dosing regimen of afimkibart consisting of four intravenous (IV) doses of 500 mg afimkibart each at Weeks 0, 2, 6, and 10, followed by subcutaneous (SC) injections of 450 mg afimkibart every four weeks (Q4W) starting at Week 14 until Week 50. (Fig. 1 ).

[0590] Approximately 25 sites in two countries participate to enroll approximately 50 participants.

[0591] The study consists of a screening period of up to 6 weeks, an open-label treatment period of 50 weeks, and a safety follow-up period of 12 weeks, as discussed in further detail below.

[0592] The total duration of study participation for an individual is approximately 68 weeks, which includes the screening, treatment, and follow-up periods. The total duration of study treatment for an individual is approximately 50 weeks.

[0593] B. Screening period

[0594] Participants undergo a screening period of up to 42 days, during which a FIBROSCAN® measurement is obtained, in addition to other eligibility assessments. If the participant is using weight loss, antidiabetic, or lipid-lowering medications, the doses must be stable for at least 3 months prior to baseline, including during screening. Body weight must also be stable, with no more than 5% weight loss in the previous 3 months and no more than 10% weight loss in the previous 6 months. Participants who fail to meet all of the eligibility criteria (Example 3) may be re-screened a maximum of two times.

[0595] Eligibility assessments may be repeated once during screening without the need for formal re-screening.

[0596] As soon as all the eligibility assessments are fulfilled, eligible participants may start the openlabel treatment period. PATENT

[0597] Attorney Docket No: 50474-372WO3

[0598] Genentech Docket No: P39784-WO-1

[0599] C. Open-label treatment period

[0600] The open-label treatment period extends from baseline (defined as the day of the first administration of the study drug) to Week 50. The primary endpoint of the study is assessed at Week 52. Participants receive four IV doses of the study drug afimkibart at Day 1 , Week 2, Week 6, and Week 10, followed by SC dosing Q4W from Week 14 to Week 50.

[0601] D. Follow-up period

[0602] The follow-up period starts after the last dose of afimkibart is administered (Week 50) and extends to Week 62 to evaluate the safety after treatment discontinuation.

[0603] E. Rationale for study population

[0604] Currently, the only approved treatment for MASH is resmetirom, which is approved for the treatment of adults with noncirrhotic NASH with moderate to advanced fibrosis, consistent with stages F2 to F3 fibrosis (REZDIFFRA® U.S. Package Insert). The mechanism of action of resmetirom is based on the reduction of intrahepatic triglycerides by stimulation of THR-p in the liver. Many investigational agents are currently in development for F2 and F3 stage MASH. However, despite recent advances, there is still an unmet need for safe, well-tolerated, and effective treatments for MASH F4 cirrhosis to avoid hepatocellular carcinoma (HCC) and progression to liver failure, liver transplant, and death.

[0605] Without being bound by any theory or hypothesis, inhibiting TL1 A, a key regulator of immune pathways and cell types underlying fibrosis and metabolic dysfunction, may confer benefit to patients with advanced MASH with liver fibrosis by countering fibrotic and inflammatory processes characteristic of disease.

[0606] The CC45687 study enrolls patients with advanced MASH fibrosis, including F3 fibrosis and F4 compensated cirrhosis. Patients with advanced fibrosis as evidenced by either a recent liver biopsy demonstrating F3 or F4 disease or noninvasive markers consistent with advanced fibrosis are included.

[0607] F. Start of trial and end of trial

[0608] The start of study is defined as the date the first participant is enrolled globally.

[0609] The end of this study is defined as the date of the last visit of the last participant in the study or the date at which the last data point required for statistical analysis (i.e. , efficacy, PK, or PD) or safety follow-up is received from the last participant, whichever occurs later. The end of the study occurs approximately 62 weeks after the last participant is enrolled.

[0610] Example 3. MASH Study Population

[0611] A. Description of trial population and rationale

[0612] The CC45687 study enrolls approximately 50 adult participants with advanced MASH fibrosis, including F3 or F4. Fibrosis staging as F3 or F4 is predicted based on (i) a FIBROSCAN® measurement of > 12.0 kilopascals (kPa) and < 30.0 kPa at screening and (ii) either a biopsy obtained within 12 months PATENT

[0613] Attorney Docket No: 50474-372WO3

[0614] Genentech Docket No: P39784-WO-1 prior to screening showing F3 or F4 stage fibrosis or an enhanced liver fibrosis (ELF™) score > 9.8 and < 11 .3 at screening.

[0615] B. Inclusion criteria

[0616] Potential participants are eligible to be included in the study only if all of the following criteria apply:

[0617] / '. General Inclusion Criteria

[0618] • Willingness and ability to comply with all aspects of the study protocol, in the investigator’s opinion, including safety, and other blood sample collections, MRI scan, FibroScan® and refraining from prohibited medications as specified by the protocol.

[0619] • Age > 18 and < 75 years.

[0620] • Body mass index within the range of > 25 and < 45 kg / m2.

[0621] / ' / . MASH-Specific Inclusion Criteria

[0622] • Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis score of F3 or F4 confirmed by a FIBROSCAN® measurement of > 12.0 kPa and < 30.0 kPa and either of the following:

[0623] - Biopsy staging as F3 or F4 per nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System within 12 months prior to randomization; or

[0624] - ELF™ score > 9.8 and < 11 .3 at screening.

[0625] C. Exclusion criteria

[0626] Potential participants are excluded from the study if any of the following criteria apply:

[0627] / '. General Exclusion Criteria

[0628] • Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 95 days after the final dose of study drug.

[0629] / ' / . MASH-Specific Exclusion Criteria

[0630] • Weight gain or loss > 5% in the 3 months prior to baseline or > 10% in the 6 months prior to screening.

[0631] • Bariatric surgery within 1 year prior to baseline.

[0632] • Current signs or prior history of decompensated liver disease including, but not limited to ascites, hepatic encephalopathy, or esophageal or gastric variceal bleeding.

[0633] • Complications of portal hypertension, including but not limited to any history of esophageal or gastric varices or variceal bleed or ascites.

[0634] - For participants with a platelet count < 150,000 / pL or a FibroScan® measurement > 20 kPa at screening, an upper endoscopy should be considered as clinically indicated to monitor for esophageal varices.

[0635] • Model for End-Stage Liver Disease (MELD) score > 12 at screening. PATENT

[0636] Attorney Docket No: 50474-372WO3

[0637] Genentech Docket No: P39784-WO-1

[0638] Hi. Medical History-Related Exclusion Criteria

[0639] • Lack of peripheral venous access.

[0640] • Other causes of liver disease based on medical history and / or centralized review of liver histology, including but not limited to the following: alcoholic liver disease, autoimmune liver disorders (e.g., primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1 - antitryspin deficiency requiring treatment.

[0641] • History of liver transplantation.

[0642] • Current or prior history of hepatocellular carcinoma (HCC).

[0643] • Uncontrolled hypertension (systolic blood pressure > 160 mmHg and / or diastolic blood pressure > 100 mmHg).

[0644] • Concomitant Type 1 diabetes, or Type 2 diabetes with hemoglobin A1 c or glycated hemoglobin; (HbA1 c) > 10%.

[0645] • Active autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, or autoimmune liver disease requiring systemic treatment with immunomodulators or biologic medications or corticosteroids.

[0646] • History of malignancy within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival rate > 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer, or non-metastatic basal cell or squamous cell cancer adequately treated with resection.

[0647] • Any serious, chronic, and / or unstable pre-existing medical, psychiatric, or other condition that may interfere with the potential participant's safety, provision of informed consent, or compliance with trial procedures in the investigator’s opinion.

[0648] • Evidence of any new or uncontrolled concomitant disease that, in the investigator’s judgment, precludes participation, including but not limited to nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders.

[0649] • Any major surgery within 6 weeks prior to screening or a major surgery planned during the study.

[0650] • Current, significant alcohol consumption or a history of significant alcohol consumption for a period of more than 3 consecutive months any time within 1 year prior to screening. Significant alcohol consumption is defined as equal to or greater than approximately 2 alcoholic drinks per day for males, and approximately 1 .5 alcoholic drinks per day for females. One alcoholic drink is equal to 12 ounces (355 mL) of 5% alcohol by volume (ABV) beer, 5 ounces (148 mL) of 12% ABV wine, or 1 .5 ounces (44.4 mL) of 40% ABV distilled spirits. Substance abuse within 12 months prior to screening or during screening. PATENT

[0651] Attorney Docket No: 50474-372WO3

[0652] Genentech Docket No: P39784-WO-1

[0653] • Previous severe allergic reaction or anaphylactic reaction to biologic agents, including humanized, murine, or fully human monoclonal antibodies, or known hypersensitivity to any excipients of the study drug. iv. Prohibited Medications- Related Exclusion Criteria

[0654] • Initiation of a medication of an antidiabetic, weight loss, lipid-modifying or anti-depressant drug class, including but not limited to glucagon-like peptide-1 (GLP-1 ) based therapy (i.e., GLP-1 mono agonists, GLP-1 / gastric inhibitory peptide (GIP) dual agonists, etc.), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or statins within 90 days prior to baseline. Doses of any GLP-1 -based therapy, SGLT-2 inhibitor, and / or statin must be stable for 90 days prior to baseline.

[0655] • Initiation of high-dose Vitamin E or pioglitazone within 90 days prior to baseline. Doses must be stable for 90 days prior to baseline without intent to modify.

[0656] • Treatment with oral or IV immunomodulatory or immunosuppressive medications within 90 days prior to baseline, including, but not limited to tumor necrosis factor (TNF) inhibitors, azathioprine, 6-mercaptopurine, alkylating agents (e.g., cyclophosphamide or chlorambucil), (hydroxy-)chloroquine or mycophenolate.

[0657] • Treatment with oral or IV corticosteroids during screening.

[0658] • Treatment with oral or IV corticosteroids with a dose equivalent to > 7.5 mg / day of prednisone for 7 days or equivalent to > 5 mg / day of prednisone for 14 days within 90 days prior to baseline.

[0659] • Treatment with Janus kinase (JAK) inhibitors or sphingosine 1 -phosphate receptor modulators within 2 weeks prior to baseline.

[0660] • Treatment with approved or investigational biologies within 8 weeks or 5 half-lives prior to baseline, whichever is longer.

[0661] • Treatment with oral or IV hepatotoxic medications for more than 4 weeks in the 2 months prior to baseline, including, but not limited to methotrexate, amiodarone, tamoxifen, and / or estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids or valproic acid.

[0662] • Treatment for any other fibrotic conditions, including but not limited to interstitial pulmonary fibrosis within 90 days prior to baseline.

[0663] • Use of an investigational agent within 4 weeks or within 5 half-lives of the investigational agent, whichever is longer, prior to baseline.

[0664] - Patients who are participating in a clinical trial that had not been unblinded are assumed to have received the active drug.

[0665] • Receipt of any live (attenuated) vaccine within 4 weeks (or longer if required locally) prior to baseline or expected need of live vaccination during study participation including at least 4 weeks (or longer if required locally) after the last dose of study drug PATENT

[0666] Attorney Docket No: 50474-372WO3

[0667] Genentech Docket No: P39784-WO-1 v. Infection or Infection Risk Exclusion Criteria

[0668] • Any active infection that required treatment with parenteral anti-infectives within 4 weeks or oral anti-infective treatment within 2 weeks prior to baseline.

[0669] • Acquired or congenital immunodeficiency, including HIV infection.

[0670] • Positive HIV test at screening.

[0671] • Positive test results for hepatitis B virus (HBV) infection at screening, defined as meeting either of the following criteria:

[0672] - Positive hepatitis B surface antigen (HBsAg) test at screening.

[0673] - Negative hepatitis B surface antibody (HBsAb) test and positive total hepatitis B core antibody (HBcAb) test in combination with a quantitative HBV DNA above the lower limit of quantification.

[0674] • Positive hepatitis C virus (HCV) antibody test at screening.

[0675] • Positive for tuberculosis (TB) during screening or within 3 months prior to screening, defined as a positive QUANTIFERON® TB-Gold test (QFT) or, if QFT is not available, a positive purified protein derivative (PPD) skin test according to local guidelines or regulations or other locally approved TB enzyme-linked immunosorbent assay (ELISA) tests (e.g., T-SPOT®).

[0676] - TB tests may be performed locally or at the central laboratory.

[0677] - Potential participants with a history of Bacillus Calmette-Guerin vaccination who have a positive PPD skin test are not excluded if they have a negative QFT at screening.

[0678] - Potential participants who have a positive or indeterminate QFT and those with no history of BCG vaccination who have a positive PPD skin test are not excluded if they meet all the following criteria:

[0679] - No symptoms that are consistent with TB

[0680] - Documented history of a completed course of adequate prophylaxis (completed treated for latent TB) per local standard of care prior to screening.

[0681] - No known exposure to a case of active TB after most recent prophylaxis.

[0682] - No evidence of active TB on chest X-ray performed during screening or within 3 months prior to screening.

[0683] • Active tuberculosis requiring treatment within the 12 months prior to baseline.

[0684] • History of organ transplant. vi. Laboratory Results-Related Exclusion Criteria

[0685] • Platelet count < 100, 000 / pL.

[0686] • ALT or AST > 5x upper limit of normal (ULN) or ASP > 2-fold ULN.

[0687] • Total bilirubin > 1 .5x ULN or > 1 .3 mg / dL.

[0688] - Participants with known Gilbert syndrome who have unconjugated hyperbilirubinemia are not excluded.

[0689] • ANC < 1.5x 109 / L (1500 / pL) with one exception: Participants with benign ethnic neutropenia: ANC < 1.3x 109 / L (1300 / pL). PATENT

[0690] Attorney Docket No: 50474-372WO3 Genentech Docket No: P39784-WO-1

[0691] • Hemoglobin < 11 g / dL.

[0692] • Serum albumin < 3.5 g / dL.

[0693] • International normalized ratio (INR) test >1 .3 (unless due to therapeutic anticoagulants).

[0694] • Estimated glomerular filtration rate < 60 mg / mL / 1 .73 m2as calculated by the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation.

[0695] • Clinically significant abnormality on laboratory tests during screening (hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk in administering study treatment to the potential participant.

[0696] D. Lifestyle restrictions

[0697] I. Dietary and Physical Activity Recommendations

[0698] Lifestyle modifications, such as weight loss via diet and increased exercise, can be effective in the treatment of MASH. All participants receive lifestyle counseling, including healthy nutrition and exercise recommendations, as outlined in the EASL-EASD-EASO Clinical Practice Guidelines on the management of MASLD (EASD et al., J Hepatol, 81 :492-542 2024). Participants are instructed to maintain the diet and activity level for the duration of the study. Extreme changes to either nutrition or exercise are avoided during sc...

Claims

1. PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1WHAT IS CLAIMED IS:1 . A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein:(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose, wherein the anti-TL1 A antibody comprises the following complementarity-determining regions(CDRs):(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

2. A method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising a first phase and a second phase, wherein:(a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein:(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and(b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, wherein the anti-TL1 A antibody comprises the following CDRs:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

3. The method of claim 1 or 2, wherein, in the first phase, the anti-TL1 A antibody is administered intravenously at a dose of about 500 mg.PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-14. The method of any one of claims 1 -3, wherein the first phase has a duration of about 14 weeks.

5. The method of claim 4, wherein:(a) the first dose of the anti-TL1 A antibody is administered on about Day 1 of Week 0;(b) the second dose of the anti-TL1 A antibody is administered on about Day 1 of Week 2;(c) the third dose of the anti-TL1 A antibody is administered on about Day 1 of Week 6; and(d) the fourth dose of the anti-TL1 A antibody is administered on about Day 1 of Week 10.

6. The method of any one of claims 1 and 3-5, wherein the dosing regimen further comprises a second phase.

7. The method of any one of claims 2-6, wherein, in the second phase, the anti-TL1 A antibody is administered subcutaneously at a dose of about 450 mg.

8. The method of any one of claims 2-7, wherein the second phase comprises at least two doses of the anti-TL1 A antibody.

9. The method of claim 8, wherein the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks.

10. The method of any one of claims 2-9, wherein the second phase comprises ten doses of the anti- TL1 A antibody.11 . The method of any one of claims 2-10, wherein the second phase has a duration of about 36 weeks.

12. The method of any one of claims 2-11 , wherein the first dose of the second phase is administered about four weeks after administration of the fourth dose of the first phase.

13. The method of any one of claims 2-12, wherein the dosing regimen has a duration of about 50 weeks.

14. The method of claim 13, wherein:(a) the first dose of the first phase is administered on about Day 1 of Week 0;(b) the second dose of the first phase is administered on about Day 1 of Week 2;(c) the third dose of the first phase is administered on about Day 1 of Week 6;(d) the fourth dose of the first phase is administered on about Day 1 of Week 10;(e) the first dose of the second phase is administered on about Day 1 of Week 14; andPATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(f) the subsequent doses of the second phase are administered on about Day 1 of Weeks 18, 22, 26, 30, 34, 38, 42, 46, and 50.

15. The method of any one of claims 1 -14, wherein the MASH is advanced MASH.

16. The method of any one of claims 1 -15, wherein the patient has advanced liver fibrosis.

17. The method of claim 16, wherein the advanced liver fibrosis is a fibrosis stage of F3 or F4.

18. The method of claim 16 or 17, wherein the patient has a FIBROSCAN® measurement of between12.0 kPa and 30.0 kPa.

19. The method of claim 18, wherein the patient has an Enhanced Liver Fibrosis (ELF™) test score of between 9.8 and 11 .3.

20. The method of claim 18 or 19, wherein a biopsy from the patient has been staged as F3 or F4 according to the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) System.21 . The method of any one of claims 16-20, wherein the patient has a liver fibrosis stage of F3.

22. The method of any one of claims 16-20, wherein the patient has a liver fibrosis stage of F4 with compensated cirrhosis.

23. A method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising a first phase and a second phase, wherein:(a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein:(i) the second dose of the anti-TL1 A antibody is administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is administered about four weeks after the third dose; and(b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, wherein the anti-TL1 A antibody comprises the following CDRs:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

24. The method of claim 23, wherein the patient has advanced liver fibrosis.

25. The method of any one of claims 1 -24, wherein the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level.

26. The method of claim 25, wherein the first phase has a duration of about 14 weeks, and the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the first phase as compared to a reference level.

27. The method of any one of claims 2-26, wherein the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level.

28. The method of claim 27, wherein the dosing regimen has a duration of about 50 weeks, and the treating results in a decrease in the level of one or more biomarkers of liver fibrosis at the end of the second phase as compared to a reference level at Week 52.

29. The method of any one of claims 25-28, wherein the one or more biomarkers of liver fibrosis are:(a) liver stiffness;(b) serum level of N-terminal propeptide of Type III collagen (Pro-C3);(c) serum ELF™ test score; and / or(d) fibro-inflammation.

30. The method of claim 29, wherein:(a) liver stiffness is measured using a FIBROSCAN® assay; and / or(b) fibro-inflammation is measured using magnetic resonance imaging iron-corrected T1 mapping (MRI cT1 ).31 . The method of any one of claims 25-30, wherein the reference level is a level in a population of patients who have not been treated with an anti-TL1 A antibody.

32. The method of any one of claims 25-30, wherein the reference level is a pre-treatment level in the patient.

33. The method of any one of claims 1 -32, wherein the anti-TL1 A antibody comprises:PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 ; and / or(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 2.

34. The method of claim 33, wherein the anti-TL1 A antibody comprises:(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and / or(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

35. The method of claim 34, wherein the anti-TL1 A antibody comprises:(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 1 ; and(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 2.

36. The method of any one of claims 1 -35, wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 11 ; and / or(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10.

37. The method of claim 36, wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and / or(b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.

38. The method of claim 37, wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 9; and(b) a light chain comprising the amino acid sequence of SEQ ID NO: 10.

39. The method of any one of claims 1 -38, wherein the anti-TL1 A antibody is afimkibart.

40. A method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising only four intravenously administered (IV) doses of the anti-TL1 A antibody, wherein:(i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and(Hi) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; wherein the anti-TL1 A antibody comprises:PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.41 . A method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TL1 A antibody in a dosing regimen comprising administration of:(a) only four IV doses of the anti-TL1 A antibody, wherein:(i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and(Hi) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; and(b) one or more subcutaneously administered (SC) doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

42. The method of claim 41 , wherein the one or more SC doses are administered at a dose of about 450 mg of the anti-TL1 A antibody.

43. The method of any one of claims 40-42, wherein the IV doses are administered at a dose of about 500 mg of the anti-TL1 A antibody.

44. A method of treating MASH in a patient, the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1 A (TL1 A) antibody in a dosing regimen comprising administration of:(a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein:(i) the second IV dose of the anti-TL1 A antibody is administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is administered about four weeks after the second IV dose; and(Hi) the fourth IV dose of the anti-TL1 A antibody is administered about four weeks after the third IV dose; andPATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks at a dose of about 450 mg and the first SC dose is administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

45. The method of any one of claims 40-44, wherein the patient has advanced liver fibrosis.

46. The method of any one of claims 40-45, wherein the anti-TL1 A antibody is afimkibart.

47. The method of any one of claims 1 -46, wherein the patient is a human.

48. A kit comprising an anti-TNF-like ligand 1 A (TL1 A) antibody and a package insert comprising instructions for using the anti-TL1 A antibody for treating MASH in a patient in need thereof according to the method of any one of claims 1 -47.

49. An anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein:(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose, and wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs):(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-150. An anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein:(a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein:(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and(b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, and wherein the anti-TL1 A antibody comprises the following CDRs:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.51 . An anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein:(a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein:(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and(b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, and wherein the anti-TL1 A antibody comprises the following CDRs:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-152. The anti-TL1 A antibody for use of any one of claims 49-51 , wherein the patient has advanced liver fibrosis.

53. The anti-TL1 A antibody for use of any one of claims 49-52, wherein the anti-TL1 A antibody is afimkibart.

54. An anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein:(i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and(Hi) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose, and wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

55. An anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of:(a) only four IV doses of the anti-TL1 A antibody, wherein:(i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and(Hi) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and(b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-156. The anti-TL1 A antibody for use of claim 55, wherein the one or more SC doses are to be administered at a dose of about 450 mg of the anti-TL1 A antibody.

57. The anti-TL1 A antibody for use of any one of claims 54-56, wherein the IV doses are to be administered at a dose of about 500 mg of the anti-TL1 A antibody.

58. An anti-TL1 A antibody for use in treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of:(a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein:(i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and(Hi) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and(b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks at a dose of about 450 mg and the first SC dose is to be administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

59. The anti-TL1 A antibody for use of any one of claims 54-58, wherein the patient has advanced liver fibrosis.

60. The anti-TL1 A antibody for use of any one of claims 54-59, wherein the anti-TL1 A antibody is afimkibart.61 . Use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase, wherein the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein:(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; andPATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose, and wherein the anti-TL1 A antibody comprises the following complementarity-determining regions (CDRs):(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

62. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of the anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein:(a) the first phase comprises administration of only four doses of the anti-TL1 A antibody, wherein:(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; and(iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and(b) the second phase comprises administration of the anti-TL1 A antibody every four weeks, and wherein the anti-TL1 A antibody comprises the following CDRs:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

63. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising a first phase and a second phase, wherein:(a) the first phase comprises intravenous administration of only four doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein:(i) the second dose of the anti-TL1 A antibody is to be administered about two weeks after the first dose;(ii) the third dose of the anti-TL1 A antibody is to be administered about four weeks after the second dose; andPATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(iii) the fourth dose of the anti-TL1 A antibody is to be administered about four weeks after the third dose; and(b) the second phase comprises subcutaneous administration of the anti-TL1 A antibody every four weeks at a dose of about 450 mg, and wherein the anti-TL1 A antibody comprises the following CDRs:(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3;(b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 4;(c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 5;(d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 6;(e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 7; and(f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 8.

64. The use of any one of claims 61 -63, wherein the patient has advanced liver fibrosis.

65. The use of any one of claims 61 -64, wherein the anti-TL1 A antibody is afimkibart.

66. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising only four IV doses of the anti-TL1 A antibody, wherein:(i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and(iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose, and wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

67. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of:(a) only four IV doses of the anti-TL1 A antibody, wherein:(i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; andPATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-1(iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and(b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are administered every four weeks and the first SC dose is administered about four weeks after the fourth IV dose; wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.

68. The use of claim 67, wherein the one or more SC doses are to be administered at a dose of about 450 mg of the anti-TL1 A antibody.

69. The use of any one of claims 66-68, wherein the IV doses are to be administered at a dose of about 500 mg of the anti-TL1 A antibody.

70. Use of an anti-TL1 A antibody in the manufacture of a medicament for treating MASH in a patient, wherein an effective amount of an anti-TL1 A antibody is to be administered to the patient in a dosing regimen comprising administration of:(a) only four IV doses of the anti-TL1 A antibody at a dose of about 500 mg, wherein:(i) the second IV dose of the anti-TL1 A antibody is to be administered about two weeks after the first IV dose;(ii) the third IV dose of the anti-TL1 A antibody is to be administered about four weeks after the second IV dose; and(iii) the fourth IV dose of the anti-TL1 A antibody is to be administered about four weeks after the third IV dose; and(b) one or more SC doses of the anti-TL1 A antibody, wherein the one or more SC doses are to be administered every four weeks at a dose of about 450 mg and the first SC dose is to be administered about four weeks after the fourth IV dose, and wherein the anti-TL1 A antibody comprises:(a) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 9; and(b) a light chain comprising an amino acid sequence having at least 95% sequence identity to, or having the amino acid sequence of, SEQ ID NO: 10.71 . The use of any one of claims 66-70, wherein the patient has advanced liver fibrosis.

72. The use of any one of claims 66-71 , wherein the anti-TL1 A antibody is afimkibart.PATENTAttorney Docket No: 50474-372WO3Genentech Docket No: P39784-WO-173. An article of manufacture comprising a composition comprising 150 mg / mL afimkibart contained in a drug vial, wherein the composition is formulated for intravenous administration at a dose of 500 mg or for subcutaneous administration at a dose of 450 mg.

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