Anti-TNF-like ligand 1a (TL1a) antibodies

Abstract

Provided herein are novel TNF-Like Ligand 1 A (TL1A) binding domains and antibodies that include such binding domains. The TL1A binding domains and antibodies provided herein are useful, for example, in the treatment of TL1 A-associated diseases.

Description

ANTI-TNF-LIKE LIGAND 1A (TL1A) ANTIBODIESPRIORITY CLAIM

[0001] This application claims priority to U.S. Provisional Patent Application Nos. 63 / 651,887, filed May 24, 2024; 63 / 692,671, filed September 9, 2024; 63 / 705,956. filed October 10, 2024; 63 / 760.574. filed February 19, 2025; 63 / 796,265, filed April 28. 2025; 63 / 761 ,833, filed February 21, 2025; and 63 / 796,998, filed April 29, 2025, which are hereby incorporated by reference in their entirety for all intents and purposes.SEQUENCE LISTING

[0002] 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 May 23, 2025, is named 067461-5325-WO_SL.xml and is 307,303 bytes in size.BACKGROUND

[0003] Antibody-based therapeutics have been used successfully to treat a variety of diseases. There remains a need for novel therapeutics for the treatment of diseases caused by aberrant TNF-like ligand 1 A (TL1A) signaling activity, particularly those that target TNF-like ligand 1A (TL1A).SUMMARY

[0004] Provided herein are novel TNF-Like Ligand 1 A (TL1 A) binding domains and antibodies that include such binding domains. The TL1 A binding domains and antibodies provided herein are useful, for example, in the treatment of TL1 A-associated diseases.

[0005] In one aspect, provided herein is an antibody comprising a TNF-like ligand 1 A (TL1A) antigen binding domain, the TL1 A binding domain comprising a variable light domain and a variable heavy domain selected from the following sets of variable light domains and variable heavy domains: a) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3, and a vhCDR3 having an amino acid sequence of SEQ ID NO:4, and a variable lightdomain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO:7, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 8; b) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 10, a vhCDR2 having an amino acid sequence of SEQ ID NO: 11, and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO: 14, a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; c) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 18, a vhCDR2 having an amino acid sequence of SEQ ID NO: 19, and a vhCDR3 having an amino acid sequence of SEQ ID NO:20, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:22. a vlCDR2 having an amino acid sequence of SEQ ID NO:23, and a vlCDR3 having an amino acid sequence of SEQ ID NO:24; d) a variable heavy' domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:26, a vhCDR2 having an amino acid sequence of SEQ ID NO:27, and a vhCDR3 having an amino acid sequence of SEQ ID NO:28, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:30, a vlCDR2 having an amino acid sequence of SEQ ID NO:31, and a vlCDR3 having an amino acid sequence of SEQ ID NO:32; e) a variable heavy domain compnsing a vhCDRl having an amino acid sequence of SEQ ID NO:34, a vhCDR2 having an amino acid sequence of SEQ ID NO:35, and a vhCDR3 having an amino acid sequence of SEQ ID NO:36, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:38. a vlCDR2 having an amino acid sequence of SEQ ID NO:39, and a vlCDR3 having an amino acid sequence of SEQ ID NO:40;1) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:42, a vhCDR2 having an amino acid sequence of SEQ ID NO:43, and a vhCDR3 having an amino acid sequence of SEQ ID NO:44, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:46, avlCDR2 having an amino acid sequence of SEQ ID NO:47, and a vlCDR3 having an amino acid sequence of SEQ ID NO:48; g) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:50, a vhCDR2 having an amino acid sequence of SEQ ID NO:51, and a vhCDR3 having an amino acid sequence of SEQ ID NO:52, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:54, a vlCDR2 having an amino acid sequence of SEQ ID NO:55, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 56; h) a variable heavy domain compnsing a vhCDRl having an amino acid sequence of SEQ ID NO:58, a vhCDR2 having an amino acid sequence of SEQ ID NO:59, and a vhCDR3 having an amino acid sequence of SEQ ID NO:60, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:62. a vlCDR2 having an amino acid sequence of SEQ ID NO:63. and a vlCDR3 having an amino acid sequence of SEQ ID NO:64; i) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:66, a vhCDR2 having an amino acid sequence of SEQ ID NO:67, and a vhCDR3 having an amino acid sequence of SEQ ID NO:68, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:70, a vlCDR2 having an amino acid sequence of SEQ ID NO:71, and a vlCDR3 having an amino acid sequence of SEQ ID NO:72; and j) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:74, a vhCDR2 having an amino acid sequence of SEQ ID NO:75, and a vhCDR3 having an amino acid sequence of SEQ ID NO:76, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:78, a vlCDR2 having an amino acid sequence of SEQ ID NO:79, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 80.

[0006] In another aspect, provided herein is an antibody comprising a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains:a) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain compnsing a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:37;I) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NONE and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 49, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:53; h) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:57, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:6Ei) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 77.

[0007] In another aspect, provided herein is an antibody comprising a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 1, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:5; b) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:9. and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 17, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:25, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:33, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37;I) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:41, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:45;g) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:49, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:53; h) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:57 and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 61; i) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:65, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:73, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 77.

[0008] In yet another aspect, provided herein is an antibody comprising a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain having an amino acid sequence of SEQ ID NO:37; f) a variable heavy domain having an amino acid sequence of SEQ ID NO:41, and a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain having an amino acid sequence of SEQ ID NO:49, and a variable light domain having an amino acid sequence of SEQ ID NO:53;h) a variable heavy domain having an amino acid sequence of SEQ ID NO:57 and a variable light domain having an amino acid sequence of SEQ ID NO:61; i) a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain having an amino acid sequence of SEQ ID NO:77.

[0009] In some embodiments, the antibody further comprises a dimeric variant IgG Fc domain comprising a first monomeric variant IgG Fc domain and a second monomeric variant IgG Fc domain, wherein each of the first monomeric variant IgG Fc domain and the second monomeric variant IgG Fc domain each comprises amino acid substitutions E233P / L234V / L235A / G236del / S267K, and wherein numbering is according to EU numbering.

[0010] In some embodiments, the antibody further comprises a dimeric variant IgG Fc domain comprising a first monomeric variant IgG Fc domain and a second monomeric variant IgG Fc domain, wherein each of the first monomeric variant IgG Fc domain and the second monomeric variant IgG Fc domain each comprises amino acid substitutions L234A / L235A / P329A, and wherein numbering is according to EU numbering.

[0011] In some embodiments, the antibody further comprises a dimeric variant IgG Fc domain comprising a first monomeric variant IgG Fc domain and a second monomeric variant IgG Fc domain, wherein each of the first monomeric variant IgG Fc domain and the second monomeric variant IgG Fc domain each comprises amino acid substitutions M428L / N434S, and wherein numbering is according to EU numbering.

[0012] In exemplary embodiments, each of the first monomeric variant IgG Fc domain and second monomeric variant IgG Fc domain are variants of a monomeric wild-type human IgGl Fc domain.

[0013] In another aspect, provided herein is a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable light domain and a variable heavy domain selected from the following sets of variable light domains and variable heavydomains :a) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3, and a vhCDR3 having an amino acid sequence of SEQ ID NO:4, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO:7, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 8; b) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 10, a vhCDR2 having an amino acid sequence of SEQ ID NO: 11, and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO: 14, a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; c) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 18, a vhCDR2 having an amino acid sequence of SEQ ID NO: 19, and a vhCDR3 having an amino acid sequence of SEQ ID NO:20, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:22, a vlCDR2 having an amino acid sequence of SEQ ID NO:23, and a vlCDR3 having an amino acid sequence of SEQ ID NO:24; d) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:26, a vhCDR2 having an amino acid sequence of SEQ ID NO:27, and a vhCDR3 having an amino acid sequence of SEQ ID NO:28, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:30. a vlCDR2 having an amino acid sequence of SEQ ID NO:31, and a vlCDR3 having an amino acid sequence of SEQ ID NO:32; e) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:34, a vhCDR2 having an amino acid sequence of SEQ ID NO:35, and a vhCDR3 having an amino acid sequence of SEQ ID NO:36, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:38, a vlCDR2 having an amino acid sequence of SEQ ID NO:39, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 40;I) a variable heavy domain compnsing a vhCDRl having an amino acid sequence of SEQ ID NO:42, a vhCDR2 having an amino acid sequence of SEQ ID NO:43, and avhCDR3 having an amino acid sequence of SEQ ID NO:44, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:46, a vlCDR2 having an amino acid sequence of SEQ ID NO:47, and a vlCDR3 having an amino acid sequence of SEQ ID NO:48; g) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:50, a vhCDR2 having an amino acid sequence of SEQ ID NO:51, and a vhCDR3 having an amino acid sequence of SEQ ID NO:52. and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:54. a vlCDR2 having an amino acid sequence of SEQ ID NO:55, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 56; h) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:58, a vhCDR2 having an amino acid sequence of SEQ ID NO:59, and a vhCDR3 having an amino acid sequence of SEQ ID NO:60, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:62, a vlCDR2 having an amino acid sequence of SEQ ID NO:63, and a vlCDR3 having an amino acid sequence of SEQ ID NO:64; i) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:66, a vhCDR2 having an amino acid sequence of SEQ ID NO:67, and a vhCDR3 having an amino acid sequence of SEQ ID NO:68, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:70, a vlCDR2 having an amino acid sequence of SEQ ID NO:71, and a vlCDR3 having an amino acid sequence of SEQ ID NO:72; and j) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:74, a vhCDR2 having an amino acid sequence of SEQ ID NO:75, and a vhCDR3 having an amino acid sequence of SEQ ID NO:76, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:78. a vlCDR2 having an amino acid sequence of SEQ ID NO:79, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 80.

[0014] In another aspect, provided herein is a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains:a) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain compnsing a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:37;I) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NONE and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 49, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:53; h) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:57, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:6Ei) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 77.

[0015] In yet another aspect, provided herein is a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 1, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:5; b) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:9. and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 17, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:25, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:33, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37;I) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:41, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:45;g) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:49, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:53; h) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:57 and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 61; i) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:65, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:73, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 77.

[0016] In one aspect, provided herein is an TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain having an amino acid sequence of SEQ ID NO:37; f) a variable heavy domain having an amino acid sequence of SEQ ID NO:41, and a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain having an amino acid sequence of SEQ ID NO:49, and a variable light domain having an amino acid sequence of SEQ ID NO:53;h) a variable heavy domain having an amino acid sequence of SEQ ID NO:57 and a variable light domain having an amino acid sequence of SEQ ID NO:61; i) a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain having an amino acid sequence of SEQ ID NO:77.

[0017] In another aspect, provided herein is an anti-TLl A antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 123. and a light chain having an amino acid sequence of SEQ ID NO: 124.

[0018] In another aspect, provided herein is a method of inhibiting or reducing TL1 A- mediated cell apoptosis in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLl A antibody provided herein.

[0019] In yet another aspect, provided herein is a method of inhibiting or reducing TL1A- mediated NFkB signaling in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLl A antibody provided herein.

[0020] In another aspect, provided herein is a method of inhibiting or reducing TL1 A- induced cytokine secretion in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLIA antibody provided herein. In some embodiments, the cytokine is selected from the following cytokines: interferon-y (IFN-y). interleukin- 1 [3 (IL-10); tumor necrosis factor-a (TNF-a); transforming growth factor-0 (TGF-0); and granulocyte-macrophage colony stimulating factor (GM-CSF).

[0021] In some embodiments of the aforementioned methods, the subject has a TL1 A- associated disease (e g., an inflammatory’ bowel disease). In some embodiments, the TL1A- associated disease is one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary' sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

[0022] In another aspect, provided herein is a method for treating aTLIA-associated disease (e.g., an inflammatory bowel disease), wherein the method comprises administering to the subject in need thereof an anti-TLIA antibody provided herein. In some embodiments, the TL1 A-associated disease is one of the following: ulcerative colitis, Crohn’s Disease,fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

[0023] In some embodiments of the methods provided herein, the subj ect is a human.

[0024] In another aspect, provided herein an anti-TLIA antibody for use in inhibiting or reducing TLlA-mediated cell apoptosis, wherein the antibody is an anti-TLIA antibody provided herein. In some embodiments, the TLlA-mediated cell apoptosis is inhibited or reduced in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has a TL1 A-associated disease. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the TL1 A-associated disease is selected from the following: ulcerative colitis. Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary' cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

[0025] In another aspect, provided herein is a use of an anti-TLIA provided herein for the manufacture of a medicament for inhibiting or reducing TLlA-mediated cell apoptosis in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has a TL1 A-associated disease. In some embodiments, the disease is an inflammatory' bowel disease. In some embodiments, the TL1 A-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

[0026] In another aspect, provided herein an anti-TLIA antibody for use in inhibiting or reducing TLlA-mediated NFkB signaling, wherein the antibody is an anti-TLIA antibody provided herein. In some embodiments, the TLlA-mediated NFkB signaling is inhibited or reduced in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has a TL1 A-associated disease. In some embodiments, the disease is an inflammatory7bowel disease. In some embodiments, the TL1 A-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

[0027] In another aspect, provided herein is a use of an anti-TLl A provided herein for the manufacture of a medicament for inhibiting or reducing TL1 A-mediated NFkB signaling in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the TLlA-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

[0028] n another aspect, provided herein an anti-TLl A antibody for use in inhibiting or reducing TL1A- induced cytokine secretion, wherein the antibody is an anti-TLl A antibody provided herein. In some embodiments, the TL1 A- induced cytokine secretion is inhibited or reduced in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has a TL1 A-associated disease. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the TL1 A-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary7cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. In some embodiments, the cytokine is selected from one of the following: interferon-y (IFN-y); interleukin- 1(3 (IL-1(3); tumor necrosis factor-a (TNF-a); transforming growth factor-[3 (TGF-(3); granulocyte-macrophage colony stimulating factor (GM-CSF).

[0029] In another aspect, provided herein is a use of an anti-TLl A provided herein for the manufacture of a medicament for inhibiting or reducing TL1 A- induced cytokine secretion in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has a TL1 A-associated disease. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the TL1 A-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. In some embodiments, the cytokine is selected from one of the following: interferon-y (IFN-y); interleukin- 1(3 (IL-1 (3); tumor necrosis factor-a (TNF-a); transforming growth factor-(3 (TGF-J3); granulocyte-macrophage colony stimulating factor (GM-CSF).

[0030] In another aspect, provided herein is an anti-TLl A antibody for use in the treatment of a TLIA-associated disease in a subject in need thereof. In some embodiments, the subject is a human. In some embodiments, the subject has a TLIA-associated disease. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the TLlA-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary7sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. In some embodiments, the cytokine is selected from one of the following: interferon-7 / (IFN-y); interleukin- 1 [3 (IL- 1(3); tumor necrosis factor-a (TNF-a); transforming growth factor-P (TGF- (3); granulocyte-macrophage colony stimulating factor (GM-CSF).

[0031] In another aspect, provided herein is a use of an anti-TLl A antibody provided herein for the manufacture of a medicament for the treatment of a TLlA-associated disease. In some embodiments, the subject is a human. In some embodiments, the subject has a TLlA- associated disease. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the TLlA-associated disease is selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary7cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. In some embodiments, the cytokine is selected from one of the following: interferon- / (IFN-y); interleukin- 13 (IL- 1 P); tumor necrosis factor-a (TNF-a); transforming grow th factor-P (TGF-P); granulocyte-macrophage colony stimulating factor (GM-CSF).BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 depicts the sequences for human, mouse, and rat TL1A (TNF-like ligand 1 A). Such TL1 A sequences are useful for the development of TL1 A antigen binding domains. TLlA may also be referred to as tumor necrosis factor superfamily 15 (TNFS15) or vascular endothelial growth inhibitor (VEGI). Unless otherwise noted, in general references to TLla herein are directed to the human TLla protein.

[0033] Figure 2 depicts useful ablation variants that ablate FcyR binding (also referred to as “knockouts” or “KO” variants). In some embodiments, such ablation variants are included in the Fc domain of both monomers of the subject antibody described herein.

[0034] Figure 3 depicts the sequences of several useful backbones based on human IgGl, including the subject anti-TLl A antibodies and related methods disclosed herein. Fc backbone 1 is based on human IgGl (356E / 358M allotype) and includes the E233P / L234V / L235A / G236del / S267K ablation variant on both chains. Fc backbone 2 is based on human IgGl (356E / 358M allotype) and includes the E233P / L234V / L235A / G236del / S267K ablation vanant on both chains and M428L / N434S Xtend variants on both chains. Fc backbone 3 is based on human IgGl (356E / 358M allotype) and includes the L234A / L235A / P329A ablation variant on both chains and M428L / N434S Xtend variants on both chains. Included within each of these backbones are sequences that are 90, 95, 98 and 99% identical (as defined herein) to the recited sequences, and / or contain from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additional amino acid substitutions (as compared to the “parent” of the Figure, which, as will be appreciated by those in the art. already contain a number of amino acid modifications as compared to the parental human IgGl (or IgG2 or IgG4, depending on the backbone). That is, the recited backbones may contain additional amino acid modifications (generally amino acid substitutions) in addition or as an alternative to the skew, pl and ablation variants contained within the backbones of this Figure.Additionally, the backbones depicted herein may include deletion of the C-terminal glycine (K446_) and / or lysine (K447_). The C-terminal glycine and / or lysine deletion may be intentionally engineered to reduce heterogeneity. Additionally, C-terminal glycine and / or lysine deletion may occur naturally for example during production and storage.

[0035] Figure 4 depicts sequences for “CHI” that find use in embodiments of anti-TLl A antibodies.

[0036] Figure 5 depicts sequences for “hinge” that find use in embodiments of anti-TLl A antibodies.

[0037] Figure 6 depicts the constant domain of the cognate light chains that find use in embodiments of anti-TLl A antibodies.

[0038] Figure 7 depicts Fc modifications that increase serum half-life. Fc substitutions that find use in increased binding to the FcRn receptor and increased serum half-life, as specifically disclosed in USSN 12 / 341,769. hereby incorporated by reference in its entirety, including, but not limited to:

[0039] Figure 8 depicts the sequence for exemplary rat anti-TLl A antibody XENP47498, having a TL1 A binding domain designated 70416_041 [TLlA]_H0L0. CDRs are underlined and slashes indicate the borders of variable regions.

[0040] Figures 9A-9D depict the variable heavy and variable light chain sequences for TL1A binding domains which find use in the invention, including any of the subject TL1 A antibodies and related methods disclosed herein. As noted herein and is true for every sequence herein containing CDRs, the exact identification of the CDR locations may be slightly different depending on the numbering used as is shown in Table 2, and thus included herein are not only the CDRs that are underlined but also CDRs included within the VH and VL domains using other numbering systems.

[0041] Figures 10A-10C depict amino acid sequences for exemplary TL1A antibodies having the PVA_ / S267K Fc ablation variants. CDRs are underlined and slashes indicate the border(s) of variable regions.

[0042] Figures 11A-11C depict amino acid sequences for exemplary TL1 A antibodies having the M428L / N434S Xtend variants in addition to the PVA_ / S267K Fc ablation variants. CDRs are underlined and slashes indicate the border(s) of variable regions.

[0043] Figures 12A-12C depict the sequence for exemplary TL1 A mAbs having the L234A / L235A / P329AFc ablation variants and the M428L / N434S Xtend variants. CDRs are underlined and slashes indicate the borders of variable regions.

[0044] Figure 13 depicts the monovalent binding affinity data for anti-TLIAFab to scTLIA.

[0045] Figure 14 depicts TL1A induced caspase activity in TF-1 cells and resulting IC50 values.

[0046] Figure 15 depicts the pharmacokinetic profile in huFcRn mice of anti-TLIA mAbs of the invention.

[0047] Figures 16A-16D depict a summary7of the results of studies to assess the binding of exemplary subject anti-TLl A antibodies to TL1A. Figure 16A depicts binding of anti-TLl A mAbs to TL1 A transiently expressed on CHO cells. Figure 16B depicts the binding of XmAb942 to soluble recombinant human TL1 Atrimer via surface plasmon resonance. Figure 16C depicts the binding of anti-TLIAFabs (200nM) to immobilized TL1 A monomer ortrimer at 25°C via biolayer interferometry. Figure 16D summarizes the binding data of XmAb942 relative to Comparator 1 and Comparator 2.

[0048] Figure 17 depicts the results of a study showing inhibition of TLlA-induced NFKB signaling by anti-TLIA mAbs.

[0049] Figure 18 depicts the results of a study inhibition of TLlA-induced IFNy release by anti-TLIA mAbs.

[0050] Figure 19 depicts the improved half-life of XmAb942 in monkeys compared with first generation anti-TLIA mAbs Comparator 1 and Comparator 2.

[0051] Figures 20A and 20B depict the thermostability of anti-TLIA Fab domains using differential scanning calorimetry.

[0052] Figure 21 depicts Quantitative Systems Pharmacology (QSP) model simulations based on Xmab942 in vitro and NHP data (t 1 / 2 of 23 days in NHPs), and competitor human PK / PD data. These simulations predict best-in-class TL1 A suppression.

[0053] Figure 22 depicts BLI binding data from an Octet RH96 which show that XmAb942 is specific for TL1 A binding and does not bind other similar TNFa superfamily members, while Comparator 3 shows some off-target binding to LIGHT.

[0054] Figure 23 depicts binding of XmAb942 and Comparators to human FcyRs. XmAb942 was the only sample completely negative for binding to 1 pM concentrations of any of the receptors tested.

[0055] Figures 24A-24D depict the variable heavy and variable light chain sequences for TL1A binding domains of relevant comparator anti-TLIA antibodies. As noted herein and is true for even' sequence herein containing CDRs, the exact identification of the CDR locations may be different depending on the numbering used as is shown in Table 2, and thus included herein are not only the CDRs that are underlined but also CDRs included within the VH and VL domains using other numbering systems.

[0056] Figure 25 depicts the amino acid sequence for anti-TLIA antibodies having the variable heavy and variable light domains of Comparator 1 with differing Fc domains.

[0057] Figure 26 depicts the amino acid sequence for anti-TLl A antibodies having the variable heavy and variable light domains of Comparator 2 with differing Fc domains.

[0058] Figures 27A and 27B depict the amino acid sequence for anti-TLIA antibodies having the variable heavy and variable light domains of Comparator 3-1, Comparator 3-2, or Comparator 3-3 with differing Fc domains.

[0059] Figures 28A and 28B depict the amino acid sequence for anti-TLl A antibodies having the variable heavy and variable light domains of Comparator 4, or Comparator 5 with differing Fc domains.

[0060] Figure 29 depicts a summary of the results of additional studies to assess the binding of exemplary subject anti-TLIA antibodies to TL1A.

[0061] Figure 30 depicts the thermostability of anti-TLIA Fab domains.

[0062] Figures 31 depicts the PK and PD profiles obtained from Quantitative Systems Pharmacology (QSP) modelling for XmAb942 dosing regimens, wherein induction doses are administered every four weeks (qw4, iv) at weeks 0, 4, and 8 at three different doses (DI, D2, and D3), followed by maintenance doses once every eight weeks (qw8, sc) at dose Dm.

[0063] Figure 32 depicts the XmAb942 QSP modeling results as compared to the results of two comparator anti-TLIA antibodies (“Comparator 1” and “Comparator 2?’). The QSP modeling results in Figures 3 and 4 were based on human PK and PD data for the comparators and non-clinical data for XmAb942.

[0064] Figure 33 provides a clinical development plan for XmAb942.

[0065] Figure 34 provides the results of human PK data for XmAb942 administered intravenously (left) and subcutaneously (right).

[0066] Figure 35 provides the summary of a study on the pharmacodynamic effects of intravenous and subcutaneous administration of XmAb942 on human patients.

[0067] Figure 36 provides an overview of a human Phase 2b study of XmAb942 for the treatment of ulcerative colitis.

[0068] Figure 37 is a half-life study, showing that XmAb942 demonstrates increased half-life in monkeys compared with first-generation anti-TLIA antibodies.

[0069] Figure 38 provides additional results of human PK data for XmAb942 at three different doses.

[0070] Figures 39A and 39B provides the summary' of a study on the pharmacodynamic effects of intravenous and subcutaneous administration of XmAb942 on human patients at three different doses.

[0071] Figures 40 depicts the PD profiles obtained from modelling for XmAb942 dosing regimens at three different doses.DETAILED DESCRIPTIONI. Overview

[0072] Provided herein are novel TNF-Like Ligand 1 A (TL1 A) binding domains and antibodies that include such binding domains. The TL1 A binding domains and antibodies provided herein are useful, for example, in the treatment of TLlA-associated diseases. In exemplary embodiments, the novel antibodies also include Fc variants to extend serum halflife in patients.II. Definitions

[0073] In order that the application may be more completely understood, several definitions are set forth below. Such definitions are meant to encompass grammatical equivalents.

[0074] As used herein, “tumor necrosis factor-like cytokine 1 A,” “TL1 A,” “TNFSF15,” “vascular endothelial growth inhibitor,” “TNF super family member 15,” all refer to a member of the tumor necrosis family that is capable of binding to the functional receptor Death Receptor 3 (DR3) on T cells. Exemplary sequences of TL1 A are depicted in Figure 1. TL1A can activate both the NF-KB and MAPK signaling pathways, and acts as an autocrine factor to induce apoptosis in endothelial cells. TL1A is also found to inhibit endothelial cell proliferation, and thus is believed to function as an angiogenesis inhibitor. In humans, TL1 A is encoded by the TNFSF15 gene, and several TNFSF15 SNPs have been found to be associated with inflammatory bowel disease.

[0075] By "ADCC" or "antibody dependent cell-mediated cytotoxicity" as used herein is meant the cell-mediated reaction, wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC is correlated with binding to FcyRIIIa; increased binding to FcyRIIIa leads to an increase in ADCC activity.

[0076] As used herein, the term '‘antibody” refers to traditional immunoglobulin (Ig) antibodies unless stated specifically otherwise.

[0077] Traditional immunoglobulin (Ig) antibodies are “Y” shaped tetramers. Each tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one “light chain” monomer and one “heavy chain” monomer.

[0078] An antibody heavy chain typically includes a variable heavy (VH) domain (also referred to as “a heavy chain variable domain”), which includes vhCDRl-3, and an Fc domain, which includes a CH2-CH3 monomer. In some embodiments, an antibody heavy chain includes a hinge and CHI domain. Traditional antibody heavy chains are monomers that are organized, from N- to C-terminus: VH-CHl-hinge-CH2-CH3. The CHl-hinge-CH2- CH3 is collectively referred to as the heavy chain '‘constant domain” or “constant region” of the antibody, of which there are five different categories or “isotypes”: IgA, IgD, IgG, IgE and IgM.

[0079] In some embodiments, the antibodies provided herein include IgG isotype constant domains, which has several subclasses, including, but not limited to IgGl, IgG2. IgG3. and IgG4. In the IgG subclass of immunoglobulins, there are several immunoglobulin domains in the heavy chain. By “immunoglobulin (Ig) domain” herein is meant a region of an immunoglobulin having a distinct tertiary structure. Of interest in the present invention, including any of the subject TL1 A antibodies and methods disclosed herein, are the heavy chain domains, including, the constant heavy (CH) domains and the hinge domains. In the context of IgG antibodies, the IgG isotypes each have three CH regions. Accordingly, “CH” domains in the context of IgG are as follows: “CHI” refers to positions 118-215 according to the EU index as in Kabat. “Hinge” refers to positions 216-230 according to the EU index as in Kabat. “CH2” refers to positions 231-340 according to the EU index as in Kabat, and “CH3” refers to positions 341-447 according to the EU index as in Kabat. As shown in Table1 , the exact numbering and placement of the heavy chain domains can be different among different numbering systems. As shown herein and described below, the pl variants can be in one or more of the CH regions, as well as the hinge region, discussed below.

[0080] By “Fc” or “Fc region” or “Fc domain” as used herein is meant the polypeptide comprising the constant region of an antibody, in some instances, excluding all of the first constant region immunoglobulin domain (e.g., CHI) or a portion thereof, and in some cases, optionally including all or part of the hinge. For IgG, the Fc domain comprises immunoglobulin domains CH2 and CH3 (Cy2 and Cy3), and optionally all or a portion of the hinge region between CHI (Cyl) and CH2 (Cy2). In some embodiments, the Fc domain is from IgGl, IgG2, IgG3 or IgG4, with IgGl hinge-CH2-CH3 and IgG4 hinge-CH2-CH3 finding particular use in many embodiments. Although the boundaries of the Fc region may vary; the human IgG heavy chain Fc region is usually defined to include residues E216, C226, or A231 to its carboxyl-terminal, wherein the numbering is according to the EU index as in Kabat. In some embodiments, as is more fully described below, amino acid modifications are made to the Fc region, for example to alter binding to one or more FcyR or to the FcRn.

[0081] By “heavy chain constant region” or “constant heavy domain” herein is meant the CHl-hinge-CH2-CH3 portion of an antibody (or fragments thereof), excluding the variable heavy domain; in EU numbering of human IgGl this is amino acids 118-447. By “heavy chain constant region fragment” herein is meant a heavy chain constant region that contains fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another heavy chain constant region.

[0082] By “hinge” or “hinge region” or “antibody hinge region” or “hinge domain” herein is meant the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CHI domain ends at EU position 215, and the IgG CH2 domain begins at residue EU position 231. Thus, for IgG the antibody hinge is herein defined to include positions 216 (E216 in IgGl) to 230 (P230 in IgGl), wherein the numbering is according to the EU index as in Kabat.

[0083] As will be appreciated by those in the art, the exact numbering and placement of the heavy chain constant region domains (i.e., CHI, hinge, CH2 and CH3 domains) can bedifferent among different numbering systems. A useful comparison of heavy constant region numbering according to EU and Kabat is as below, see Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85 and Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, entirely incorporated by reference. Other numbering conventions are available in the art and those skilled in the art would readily be able to determine the exact numbering and placement in those other numbering convention systems based on what’ s described herein.TABLE 1

[0084] The antibody light chain generally comprises two domains: the variable light domain (VL) (also referred to as “light chain variable domain”), which includes light chain CDRs vlCDRl-3. and a constant light chain region or light chain constant region (often referred to as CL or CK). The antibody light chain is typically organized from N- to C-terminus: VL-CL.

[0085] By “antigen binding domain” or “ABD” herein is meant a set of six Complementary Determining Regions (CDRs) that, when present as part of antibody sequences, specifically binds a target antigen (e.g., human TL1 A) as discussed herein. As is known in the art, these CDRs are generally present as a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each comprising three CDRs: vhCDRl, vhCDR2, vhCDR3 variable heavy CDRs and vlCDRl, vlCDR2 and vlCDR3 variable light CDRs. The CDRs are present in the variable heavy domain (vhCDRl -3) and variable light domain (vlCDRl -3). The variable heavy’ domain and variable light domain form an Fv region.

[0086] Typically, a “full CDR set” comprises the three variable light and three variable heavy CDRs, e.g., a vlCDRl, vlCDR2, vlCDR3, vhCDRl, vhCDR2 and vhCDR3. These can be part of a larger variable light or variable heavy domain, respectfully. In addition, as more fully outlined herein, the variable heavy and variable light domains can be on separate polypeptide chains, i.e., a heavy and light chain, respectively.

[0087] As will be appreciated by those in the art, the exact numbering and placement of the CDRs can be different among different numbering systems. However, it should be understood that the disclosure of a variable heavy and / or variable light sequence includes the disclosure of the associated (inherent) CDRs. Accordingly, the disclosure of each variable heavy region is a disclosure of the vhCDRs (e.g., vhCDRl, vhCDR2 and vhCDR3) and the disclosure of each variable light region is a disclosure of the vlCDRs (e.g., vlCDRl, vlCDR2 and vlCDR3). A useful comparison of CDR numbering is as below, see Lafranc et al., Dev. Comp.Immunol. 27(l):55-77 (2003):TABLE 2

[0088] Throughout the present specification, the Kabat numbering system is generally used when referring to a residue in the variable domain (approximately, residues 1-107 of the lightchain variable region and residues 1-113 of the heavy chain variable region) and the EU numbering system for Fc regions (e.g., Kabat et al., supra (1991)). Those skilled in the art would readily be able to determine the exact numbering and placement of the CDRs in other numbering systems described herein and known in the art.

[0089] The CDRs contribute to the formation of the antigen-binding, or more specifically, epitope binding site of the antibody. “Epitope” refers to a determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. Epitopes are groupings of molecules such as amino acids or sugar side chains and usually have specific structural characteristics, as well as specific charge characteristics. A single antigen may have more than one epitope.

[0090] The epitope may comprise amino acid residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked by the specifically antigen binding peptide; in other words, the amino acid residue is within the footprint of the specifically antigen binding peptide.

[0091] Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. Conformational and nonconformational epitopes may be distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0092] An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Antibodies that recognize the same epitope can be verified in a simple immunoassay showing the ability of one antibody to block the binding of another antibody to a target antigen, for example “binning.” As outlined below, the invention, including any of the subject TL1 A antibodies and methods disclosed herein, not only includes the enumerated antigen binding domains and antibodies herein, but those that compete for binding with the epitopes bound by the enumerated antigen binding domains.

[0093] The six CDRs of the subject antibodies are contributed by a variable heavy and a variable light domain. In a “Fab” format, the set of 6 CDRs are contributed by two different polypeptide sequences, the variable heavy domain (vh or VH; containing the vhCDRl,vhCDR2 and vhCDR3) and the variable light domain (vl or VL; containing the vlCDRl, vlCDR2 and vlCDR3), with the C-terminus of the vh domain being attached to the N- terminus of the CHI domain of the heavy chain and the C-terminus of the vl domain being attached to the N-terminus of the constant light domain (and thus forming the light chain).

[0094] By "variable region" or “variable domain” as used herein is meant the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the VK. VL, and / or VH genes that make up the kappa, lambda, and heavy’ chain immunoglobulin genetic loci respectively, and contains the CDRs that confer antigen specificity. Thus, a “variable heavy domain” pairs with a “variable light domain” to form an antigen binding domain (“ABD”). In addition, each variable domain comprises three hypervariable regions (“complementary' determining regions,” “CDRs”) (vhCDRl, vhCDR2 and vhCDR3 for the variable heavy domain and vlCDRl. vlCDR2 and vlCDR3 for the variable light domain) and four framework (FR) regions, arranged from amino-terminus to carboxy -terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0095] By "Fab" or "Fab region" as used herein is meant the antibody region that comprises the VH, CHI, VL, and CL immunoglobulin domains, generally on two different polypeptide chains (e g., VH-CH1 on one chain and VL-CL on the other). Fab may refer to this region in isolation, or this region in the context of an antibody of the invention. In the context of a Fab, the Fab comprises an Fv region in addition to the CHI and CL domains.

[0096] By "Fv" or "Fv fragment" or "Fv region" as used herein is meant the antibody region that comprises the VL and VH domains.

[0097] By "modification" or “variant” herein is meant an amino acid substitution, insertion, and / or deletion in a polypeptide sequence or an alteration to a moiety chemically linked to a protein. For example, a modification may be an altered carbohydrate or PEG structure attached to a protein. By "amino acid modification" herein is meant an amino acid substitution, insertion, and / or deletion in a polypeptide sequence. For clarity, unless otherwise noted, the amino acid modification is always to an amino acid coded for by DNA, e.g., the 20 amino acids that have codons in DNA and RNA.

[0098] By "amino acid substitution" or "substitution" herein is meant the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different aminoacid. In particular, in some embodiments, the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in any organism. For example, the substitution M428L refers to a variant polypeptide, in this case an Fc variant, in which the methionine at position 272 is replaced with leucine. For clarity, a protein which has been engineered to change the nucleic acid coding sequence but not change the starting amino acid (for example exchanging CGG (encoding arginine) to CGA (still encoding arginine) to increase host organism expression levels) is not an "‘amino acid substitution / ’ that is. despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.

[0099] By "variant protein" or "protein variant", or "variant" as used herein is meant a protein that differs from that of a parent protein by virtue of at least one amino acid modification. The protein variant has at least one amino acid modification compared to the parent protein, yet not so many that the variant protein will not align with the parental protein using an alignment program such as that described below.

[0100] As described below, in some embodiments the parent polypeptide, for example an Fc parent polypeptide, is a human wild-ty pe sequence, such as the heavy' constant domain or Fc region from IgGl or IgG2. although human sequences with variants can also sen e as “parent polypeptides”, for example the IgGl / 2 hybrid of US Publication 2006 / 0134105 can be included. Accordingly, by "antibody variant" or "variant antibody" as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification, "IgG variant" or "variant IgG" as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by’ virtue of at least one amino acid modification, and "immunoglobulin variant" or "variant immunoglobulin" as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification. "Fc variant" or "variant Fc" as used herein is meant a protein comprising an amino acid modification in an Fc domain as compared to an Fc domain of human IgGl or IgG2.

[0101] "Fc variant" or "variant Fc" as used herein is meant a protein comprising an amino acid modification in an Fc domain. The modification can be an addition, deletion, or substitution. The Fc variants are defined according to the amino acid modifications thatcompose them. Thus, for example, N434S or 434S is an Fc variant with the substitution for serine at position 434 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index. Likewise, M428L / N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. The identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 428L / 434S. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L / 434S is the same Fc variant as 434S / 428L, and so on. For all positions discussed herein that relate to antibodies or derivatives and fragments thereof (e.g.. Fc domains), unless otherwise noted, amino acid position numbering is according to the EU index. The '‘EU index" or “EU index as in Kabaf ’ or “EU numbering” scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference). Those skilled in the art would readily be able to determine the corresponding positions in other numbering systems described herein and known in the art. The modification can be an addition, deletion, or substitution.

[0102] In general, variant Fc domains have at least about 80, 85, 90, 95, 97, 98 or 99 percent identity to the corresponding parental human IgG Fc domain (using the identity algorithms discussed below, with one embodiment utilizing the BLAST algorithm as is known in the art. using default parameters). Additionally, as discussed herein, the variant Fc domains described herein still retain the ability to form a dimer with another Fc domain as measured using known techniques as described herein, such as non-denaturing gel electrophoresis.

[0103] By "protein" as used herein is meant at least tw o covalently attached amino acids, which includes proteins, polypeptides, oligopeptides, and peptides. In addition, polypeptides that make up the antibodies of the invention, including any of the subject TL1 A antibodies disclosed herein, may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.

[0104] By "non-naturally occurring modification" as used herein is meant an amino acid modification that is not isotypic. For example, because none of the known human IgGs comprise a serine at position 434, the substitution 434S in IgGl or IgG2 (or hybrids thereof) is considered a non-naturally occurring modification.

[0105] By "amino acid" and "amino acid identity" as used herein is meant one of the 20 naturally occurring amino acids that are coded for by DNA and RNA.

[0106] By "effector function" as used herein is meant a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include but are not limited to ADCC, ADCP, and CDC.

[0107] By "Fc gamma receptor", "FcyR" or "FcgammaR" as used herein is meant any member of the family of proteins that bind the IgG antibody Fc region and is encoded by an FcyR gene. In humans this family includes but is not limited to FcyR! (CD64), including isoforms FcyRIa. FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIlb (including FcyRIlb-1 and FcyRIlb-2). and FcyRIIc; and FcyRIII (CD16), including isoforms FcyRIIIa (including allotypes V158 and Fl 58) and FcyRIIIb (including allotypes FcyRIIb-NAl and FcyRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, entirely incorporated by reference), as well as any undiscovered human FcyRs or FcyR isoforms or allotypes. An FcyR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcyRs include but are not limited to FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), and FcyRIII-2 (CD16-2), as well as any undiscovered mouse FcyRs or FcyR isoforms or allotypes.

[0108] By "FcRn" or "neonatal Fc Receptor" as used herein is meant a protein that binds the IgG antibody Fc region and is encoded at least in part by an FcRn gene. The FcRn may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. As is known in the art. the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain. The light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise noted herein, FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2-microglobulin. A variety of FcRn variants used to increase binding to the FcRn receptor, and in some cases, to increase serum half-life. An “FcRn variant'’ is an amino acid modification that contributes to increased binding to the FcRn receptor, and suitable FcRn variants are shown below.

[0109] By "parent polypeptide" as used herein is meant a starting polypeptide that is subsequently modified to generate a variant. The parent polypeptide may be a naturallyoccurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. Accordingly, by "parent immunoglobulin" as used herein is meant an unmodified immunoglobulin polypeptide that is modified to generate a variant, and by "parent antibody" as used herein is meant an unmodified antibody that is modified to generate a variant antibody. It should be noted that "parent antibody" includes known commercial, recombinantly produced antibodies as outlined below. In this context, a “parent Fc domain” will be relative to the recited variant; thus, a “variant human IgGl Fc domain” is compared to the parent Fc domain of human IgGl, a “variant human IgG4 Fc domain” is compared to the parent Fc domain human IgG4, etc.

[0110] By "position" as used herein is meant a location in the sequence of a protein. Positions may be numbered sequentially, or according to an established format, for example the EU index for numbering of antibody domains (e.g., a CHI, CH2, CH3 or hinge domain).

[0111] By "wild type” or “WT" or “wild-type” herein is meant an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. AWT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.

[0112] Provided herein are a number of antibody domains (e.g., Fc domains) that have sequence identity to human antibody domains. Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) "Comparison of Biosequences," Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) "A General Method Applicable To The Search For Similarities In The Amino Acid Sequence Of Two Proteins," J. Mol. Biol.48:443 [homology alignment algorithm], Pearson. WR. & Lipman, D.J. (1988) "Improved Tools For Biological Sequence Comparison." Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search for similarity method]; or Altschul, S.F. et al, (1990) "Basic Local Alignment Search Tool," J. Mol. Biol. 215:403-10 , the “BLAST” algorithm, see https: / / blast.ncbi.nlm.nih.gov / Blast.cgi. When using any of the aforementioned algorithms, the default parameters (for Window length, gap penalty, etc.) are used. In one embodiment, sequence identity is done using the BLAST algorithm, using default parameters

[0113] The antibodies of the present invention, including any of the subject TL1 A antibodies disclosed herein, are generally isolated or recombinant. “Isolated,” when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and / or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide will be prepared by at least one purification step. An “isolated antibody,” refers to an antibody that is substantially free of other antibodies having different antigenic specificities. “Recombinant” means the antibodies are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.

[0114] “Specific binding” or “specifically binds to” or is “specific for” a particular antigen or an epitope means binding that is measurably different from a non-specific interaction using an assay described herein or known in the art. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0115] Specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about IO-4M, at least about 10'5M, at least about 10’6M, at least about 10'7M, at least about 10‘8M, at least about 10’9M, alternatively at least about 10’10M, at least about 10’11M, at least about 10'12M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds an antigen will have a K that is 20-, 50-, I00-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope. A suitable control molecule is described herein including the Example sections and knowor in the art.

[0116] Also, specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-. 500-. 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody -antigen interaction. Binding affinity is generally measured using a Biacore, SPR or BLI assay.III. TL1A Binding Domains

[0117] In one aspect, provided herein are TL1 A antigen binding domains (ABDs) that bind TL1 A, and constructs (e.g., antibodies and fusion proteins) that include such TL1A antigen binding domains. The TL1A ABDs provided herein generally include a variable heavy domain (VH) and a variable light domain (VL). In exemplary embodiments, the TL1 A is capable of binding to human TL1 A (see Figure 1).

[0118] As will be appreciated by those in the art, suitable TL1 A binding domains can comprise a set of 6 CDRs as depicted in the figures, either as they are underlined or, in the case where a different numbering scheme is used as described herein and as shown in Table 2, as the CDRs that are identified using other alignments within the variable heavy (VH) domain and variable light domain (VL) sequences of those depicted in Figure 9. Suitable TL1 A ABDs can also include the entire VH and VL sequences as depicted in these sequences and figures, used as scFvs or as Fabs.

[0119] In one embodiment, the TL1 A antigen binding domain includes the 6 CDRs (i.e., vhCDRl-3 and vlCDRl-3) of any of the TL1 A binding domains described herein, including the figures. In some embodiments, the TL1A ABD is one of the following TL1A ABDs: 70416_041[TLla]_HlLl, 70417 111 [TLla]_HlLl, 70392 069 [TLla]_HlLl, 70392_189 [TLla]_HlLl, 70416_092 [TLla]_HlLl, 70392_201 [TLla]_HlLl, 70416_073 [TLla]_HlLl, 70392 074 [TLla]_HlLl, 70416 094 [TLla]_HlLl. 70392 292 [TLla]_HlLl (Figure 9).

[0120] In addition to the parental CDR sets disclosed in the figures that form the TL1A ABDs (e.g., Figure 9), provided herein are variant TL1 A ABDS having CDRs that include at least one modification of the TL1 A ABD CDRs disclosed herein (e.g., Figure 9). In one embodiment, the TL1A ABD includes a set of 6 CDRs with 1, 2, 3. 4, 5, 6, 7, 8, 9, 10 amino acid modifications as compared to the 6 CDRs of a TLIAABD as described herein, including the figures. In exemplary embodiments, the TL1 A ABD includes a set of 6 CDRs with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid modifications as compared to the 6 CDRs of one of the following TL1 A ABDs: 70416_041 [TLla]_HlLl. 70417 111 [TLla]_HlLl. 70392 069 [TLla] HILL 70392 189 [TLla] HILI. 70416 092 [TLla] HILL 70392 201[TLla]_HlLl, 70416 073 [TLla]_HlLl, 70392 074 [TLla]_HlLl, 70416 094 [TLla]_HlLl, 70392 292 [TLla]_HlLl (Figure 9). In certain embodiments, the TL1A ABD is capable of binding TL1 A antigen, as measured by at least one of a Biacore, surface plasmon resonance (SPR) and / or BLI (biolayer interferometry, e.g.. Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the TL1 A ABD is capable of binding human TL1 A antigen (see Figure 1).

[0121] In some embodiments, the TL1A ABD includes 6 CDRs that are at least 90, 95, 97, 98 or 99% identical to the 6 CDRs of a TL1A ABD as described herein, including the figures. In exemplary embodiments, the TL1 A ABD includes 6 CDRs that are at least 90, 95, 97, 98 or 99% identical to the 6 CDRs of one of the following TL1A ABDs: 70416_041[TLla]_HlLl, 70417 111 [TLla]_HlLl, 70392 069 [TLla]_HlLl, 70392 189 [TLla]_HlLl, 70416 092 [TLla]_HlLl, 70392 201 [TLla]_HlLl, 70416 073 [TLla]_HlLl, 70392 074 [TLla]_HlLl, 70416 094 [TLla]_HlLl. 70392 292 [TLlaj HILl (Figure 9). In certain embodiments, the TL1AABD is capable of binding TL1A antigen, as measured by at least one of a Biacore, surface plasmon resonance (SPR) and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the TL1A ABD is capable of binding human TL1 A antigen (see Figure 1).

[0122] In another exemplary embodiment, the TL1AABD include the variable heavy (VH) domain and variable light (VL) domain of any one of the TL1 A ABDs described herein, including the figures. In exemplary' embodiments, the TL1 A ABD is one of the following TLlAABDs: 70416_041[TLla]_HlLl, 70417 111 [TLla]_HlLl, 70392 069[TLla] HILI, 70392 189 [TLla] HILL 70416 092 [TLla] HILL 70392 201 [TLl a]_HlLl, 70416 073 [TLl a]_HlLl , 70392 074 [TLl a]_HlLl , 70416 094 [TLla]_HlLl, 70392 292 [TLla]_HlLl (Figure 9).

[0123] In addition to the parental TL1A variable heavy and variable light domains disclosed herein, provided herein are TLlAABDs that include a variable heavy domain and / or a variable light domain that are variants of a TL1 A ABD VH and VL domain disclosed herein. In one embodiment, the variant VH domain and / or VL domain has from 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes from a VH and / or VL domain of a TL1AABD described herein, including the figures. In some embodiments, the variant VH domain and / or VLdomain has includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes in a framework region (e.g., FR1, FR2, FR3, or FR4) from a VH and / or VL domain of aTLIA ABD described herein, including the figures. In exemplary embodiments, the variant VH domain and / or VL domain has from 1, 2, 3, 4. 5, 6, 7. 8, 9 or 10 amino acid changes from a VH and / or VL domain of one of the following TL 1 A ABDs : 70416_041 [TL 1 a]_H 1 L 1, 70417 111 [TLla]_HlLl, 70392 069 [TLla]_HlLl, 70392 189 [TLla]_HlLl, 70416 092 [TLla]_HlLl, 70392 201 [TLla]_HlLl, 70416 073 [TLla]_HlLl, 70392 074 [TLla]_HlLl, 70416 094 [TLla]_HlLl, 70392 292 [TLla]_HlLl (Figure 9). In exemplary embodiments, the variant VH domain and / or VL domain has from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes in a framework region (e.g., FR1, FR2, FR3, or FR4) of the VH and / or VL domain of one of the following TLlAABDs: 70416_041[TLla]_HlLl, 70417 111 [TLla]_HlLl, 70392 069 [TLla]_HlLl, 70392 189 [TLla]_HlLL 70416 092 [TLla] HILL 70392 201 [TLla] HILL 70416 073 [TLla] HILL 70392 074 [TLl a]_HlLl, 70416 094 [TLl a]_Hl Ll , 70392 292 [TLl a]_HlLl (Figure 9). In certain embodiments, the TL1 A ABD is capable of binding to TL1A , as measured at least one of a Biacore, surface plasmon resonance (SPR) and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the TL1 A ABD is capable of binding human TL1 A antigen (see Figure 1).

[0124] In one embodiment, the variant VH and / or VL domain is at least 90, 95, 97, 98 or 99% identical to the VH and / or VL of a TL1A ABD as described herein, including the figures. In exemplary embodiments, the variant VH and / or VL domain is at least 90, 95, 97, 98 or 99% identical to the VH and / or VL of one of the following TLlAABDs: 70416_041[TLla]_HlLl, 70417 111 [TLla]_HlLl, 70392_069 [TLla]_HlLl, 70392J89 [TLla]_HlLl, 70416 092 [TLla]_HlLl, 70392 201 [TLla]_HlLl, 70416 073 [TLla]_HlLl, 70392 074 [TLla]_HlLl, 70416 094 [TLla]_HlLl, 70392 292 [TLla]_HlLl (Figure 9). In certain embodiments, the TL1AABD is capable of binding to TL1 A . as measured by at least one of a Biacore, surface plasmon resonance (SPR) and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the TL1AABD is capable of binding human TL1A antigen (see Figure 1).IV. Antibodies

[0125] In one aspect provided herein are anti-TLl A antibodies that include any of the TL1A antigen binding domains described herein. In some embodiments, the anti-TLl A antibody includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of the TLlAABDs described herein. In some embodiments, the anti-TLl A antibody is a monospecific bivalent antibody.

[0126] The antibodies provided herein include different antibody domains. As described herein and known in the art, the antibodies described herein include different domains within the heavy and light chains, which can be overlapping as well. These domains include, but are not limited to, the Fc domain, the CHI domain, the CH2 domain, the CH3 domain, the hinge domain, the heavy constant domain (CHl-hinge-Fc domain or CHl-hinge- CH2-CH3), the variable heavy domain, the variable light domain, the light constant domain. Fab domains and scFv domains.

[0127] In some embodiments, the subject antibody includes one or more of the TL1 A ABDs provided herein. In some embodiments, the antibody includes one TL1 A ABD. In other embodiments, the antibody includes two TLlAABDs. In exemplary embodiments, the TL1A ABD includes the variable heavy domain and variable light domain of one of the following TLlAABDs: 70416_041[TLla]_HlLl, 70417 111 [TLla]_HlLl, 70392_069 [TLla]_HlLI, 70392 189 [TLla]_HlLl, 70416 092 [TLla]_HlLl, 70392 201 [TLla]_HlLI, 70416 073 [TLla]_HlLI, 70392 074 [TLla]_HlLl, 70416 094 [TLla] HILI, 70392 292 [TLla] HILI (Figure 9).

[0128] Exemplary sequence of domains (e.g., CHI. hinge, and CL domains) for use the subject antibodies provided herein are depicted in Figures 4-6.

[0129] In certain embodiments, the anti-TLl A antibody is a monospecific anti-TLl A antibody that includes a TL1 A antigen binding domains described herein (e.g., Figure 9 or one of the TL1 A binding domain variants described herein). In exemplary’ embodiments, the TL1A antigen binding domain includes a vhCDRl having an amino sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3, a vhCDR3 having an amino acid sequence of SEQ ID NO:4, a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO: 7 and a vlCDR3 having an amino acid sequence having an amino acid sequence of SEQ ID NO: 8. In exemplaryembodiments, the TL1 A antigen binding domain includes a variable heavy domain having an amino acid sequence of SEQ ID NO: 1 and a variable light domain having an amino acid sequence of SEQ ID NO:5. In an exemplary embodiment, the anti-TLl A antibody includes a heavy chain having an amino acid sequence of SEQ ID NO: 123, and a light chain having an amino acid sequence of SEQ ID NO: 124.

[0130] In exemplary embodiments, the anti-TLl a antibody includes a TL1A antigen binding domain that includes a variable heavy’ domain having an amino acid sequence of SEQ ID NO: 1 and a variable light domain having an amino acid sequence of SEQ ID NO:5. In exemplary embodiments, the anti-TLl A antibody further includes a variant Fc domain, wherein the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants E233P / L234V / L235A / G236del / S267K and M428L / N434S, wherein numbering is according to EU numbering.

[0131] Exemplary monospecific and bivalent subject antibodies are depicted in Figures 10-12. In some embodiments, the anti-TLl A antibody comprises a heavy chain and a light chain of an anti-TLl A antibody depicted in Figures 10-12. In exemplary' embodiments, the anti-TLl A comprises a heavy chain having the amino acid sequence of SEQ ID NO: 123, and a light chain having the amino acid sequence of SEQ ID NO: 124.A. Fc Variants for Additional Functionality

[0132] In embodiments, the antibodies described herein includes a dimeric Fc domain that includes a first and second monomeric Fc domain. In some embodiments, the dimeric Fc domain is a variant of a wild-type dimeric Fc domain. In some embodiments, the dimeric Fc domain is a variant of a wild-type human IgG (e.g., IgGl, IgG2, and IgG4) Fc domain. There are a number of useful Fc amino acid modification that can be made for a variety of reasons, including, but not limited to. altering binding to one or more FcyR receptors, altered binding to FcRn receptors, etc., as discussed below. Each set of variants can be independently and optionally included or excluded from any particular variant Fc domain described herein. In some embodiments, the variant Fc domain includes one or more FcyR variant described herein. In some embodiments, variant Fc domain includes one or more ablation variant described herein. In exemplary embodiments, the variant Fc domain includes a combinationof one or more FcyR variant (e.g., M428L / N434S) and one or more ablation variant (e.g., E233P / L234V / L235A / G236del / S267K or L234A / L235A / P329A). In some embodiments, the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants M428L / N434S, wherein numbering is according to EU numbering. In some embodiments, the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering. In some embodiments, the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants E233P / L234V / L235A / G236del / S267K and M428L / N434S. wherein numbering is according to EU numbering.1. FcyR Variants

[0133] Accordingly, there are a number of useful Fc substitutions that can be made to alter binding to one or more of the FcyR receptors. In certain embodiments, the subject antibody includes modifications that alter the binding to one or more FcyR receptors (i.e., “FcyR variants”). Substitutions that result in increased binding as well as decreased binding can be useful. For example, it is known that increased binding to FcyRIIIa generally results in increased ADCC (antibody dependent cell-mediated cytotoxicity; the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell). Similarly, decreased binding to FcyRIIb (an inhibitory receptor) can be beneficial as well in some circumstances. Amino acid substitutions that find use in the subject antibodies include those listed in US Patent Nos.8,188,321 (particularly Figure 41) and 8,084,582, and US Publ. App. Nos. 20060235208 and 20070148170, all of which are expressly incorporated herein by reference in their entirety and specifically for the variants disclosed therein that affect Fey receptor binding. Particular variants that find use include, but are not limited to, 236A, 239D, 239E, 332E, 332D, 239D / 332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V and 299T, according to EU numbering. Such modification may be included in one or both Fc domains of the subject antibody.

[0134] In some embodiments, the subject antibody includes one or more Fc modifications that increase serum half-life. Fc substitutions that find use in increased binding to the FcRn receptor and increased serum half-life, as specifically disclosed in USSN12 / 341,769, hereby incorporated by reference in its entirety, including, but not limited to, 434S, 434A, 428L, 308F, 2591, 428L / 434S, 259I / 308F, 436I / 428L, 4361 or V / 434S, 436V / 428L, 428L / 434A. M252Y / S254T / T256E, and 259I / 308F / 428L. Such modification may be included in one or both Fc domains of the subject antibody. In exemplary embodiments, the antibody includes 428L / 434S modifications (EU numbering). Additional Fc modifications that increase serum-half of the subject antibody provided herein are depicted in Figure 7.

[0135] In some embodiments, the amino acid variants 428L / 434S Fc variants are included in antibodies that include the comparator VH and VL sequences listed in Figure 24. Thus, for example, the VH and VL sequences listed in Figure 24 can be added to human IgGl, IgG2 or IgG4 backbones that include the 428L / 434S amino acid variants.

[0136] In some embodiments, the amino acid variants M252Y / S254T / T256E Fc variants are included in antibodies that include the comparator VH and VL sequences listed in Figure 24. Thus, for example, the VH and VL sequences listed in Figure 24 can be added to human IgGl, IgG2 or IgG4 backbones that include the M252Y / S254T / T256E amino acid variants.2. Ablation Variants

[0137] In some embodiments, the antibody provided herein includes one or more modifications that reduce or remove the normal binding of the Fc domain to one or more or all of the Fey receptors (e.g.. FcyRl. FcyRIIa, FcyRIIb, FcyRIIIa, etc.) to avoid additional mechanisms of action. Such modifications are referred to as "FcyR ablation variants" or "Fc knock out (FcKO or KO)” variants. In these embodiments, for some therapeutic applications, it is desirable to reduce or remove the normal binding of the Fc domain to one or more or all of the Fey receptors (e.g., FcyRl, FcyRIIa, FcyRIIb. FcyRIIIa, etc.) to avoid additional mechanisms of action. That is. for example, in many embodiments, it is generally desirable to ablate FcyRIIIa binding to eliminate or significantly reduce ADCC activity. In some embodiments, of the subject antibodies described herein, at least one of the Fc domains comprises one or more Fey receptor ablation variants. In some embodiments, of the subject antibodies described herein, both of the Fc domains comprise one or more Fey receptorablation variants. These ablation variants each can be independently and optionally included or excluded, with preferred aspects utilizing ablation variants selected from the group consisting of G236R / L328R, E233P / L234V / L235A / G236del / S239K, E233P / L234V / L235A / G236del / S267K, E233P / L234V / L235A / G236del / S239K / A327G, E233P / L234V / L235A / G236del / S267K / A327G, E233P / L234V / L235A / G236del, and L234A / L235A / P329A (EU numbering). It should be noted that the ablation variants referenced herein ablate FcyR binding but generally not FcRn binding. Additional ablation variants that can be included in the variant Fc domains provided herein are show in Figure 2.

[0138] As is known in the art, the Fc domain of human IgGl has the highest binding to the Fey receptors, and thus ablation variants can be used when the constant domain (or Fc domain) in the backbone of the subject antibody is IgGl. Alternatively, or in addition to ablation variants in an IgGl background, mutations at the glycosylation position 297 (generally to A or S) can significantly ablate binding to FcyRIIIa, for example. Human IgG2 and IgG4 have naturally reduced binding to the Fey receptors, and thus those backbones can be used with or without the ablation variants.3. Monospecific, Monoclonal Antibodies

[0139] As will be appreciated by those in the art, the novel Fv sequences outlined herein can also be used in both monospecific antibodies (e.g., “traditional monoclonal antibodies”). Accordingly, the present invention provides monospecific antibodies comprising the 6 CDRs and / or the VH and VL sequences from the figures, generally with IgGl, IgG2. IgG3 or IgG4 constant regions, with IgGl , IgG2 and IgG4 (including IgG4 constant regions comprising a S228P amino acid substitution) finding particular use in some embodiments.That is. any sequence herein with a “H L” designation can be linked to the constant region of a human IgGl antibody. In some embodiments, the monospecific antibody includes a monomer having, for N- to C-terminus, VH-CHl-hinge-CH2-CH3; and a light chain that includes a VL-CL.

[0140] In certain embodiments, the monospecific anti-TLl A antibody includes a TL1A binding domains described herein (e.g., Figure 9 or one of the TL1A binding domain variants described herein).

[0141] Exemplary monospecific and bivalent subject antibodies are depicted in Figures 10-12. In some embodiments, the antibody is a bivalent, monospecific antibody that includes a variable heavy' domain and variable light domain of any of the subject TL1 A binding domains provided herein. In some embodiments, the bivalent, monospecific antibody includes the variable heavy and variable light domain of TL1 A binding domain 70416_041 [TLla]_HlLl (see Figure 9A). . In some embodiments, the antibody includes a dimeric variant Fc domain that includes one or more FcyR variant described herein. In some embodiments, the antibody includes a dimeric variant Fc domain that includes one or more ablation vanant described herein. In exemplary embodiments, the variant Fc domain includes a combination of one or more FcyR variant (e.g., M428L / N434S) and one or more ablation variant (e.g., E233P / L234V / L235A / G236del / S267K or L234A / L235A / P329A). In some embodiments, the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants M428L / N434S, wherein numbering is according to EU numbering. In some embodiments, the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering. In some embodiments, the variant Fc domain is a variant dimeric human IgG Fc domain that includes the variants E233P / L234V / L235A / G236del / S267K and M428L / N434S, wherein numbering is according to EU numbering.V. Recombinant Methods and Compositions

[0142] In another aspect, provided herein are nucleic acid compositions encoding the TL1A antigen binding domains and anti-TLl A antibodies provided herein.

[0143] As is know n in the art, the nucleic acids encoding the components of the binding domains and antibodies disclosed herein can be incorporated into expression vectors as is known in the art and depends on the host cells used to produce the subject antibodies of the invention. Generally, the nucleic acids are operably linked to any number of regulatory elements (promoters, origin of replication, selectable markers, ribosomal binding sites, inducers, etc.). The expression vectors can be extra-chromosomal or integrating vectors.

[0144] The polynucleotides and / or expression vectors of the invention are then transformed into any number of different types of host cells as is well known in the art,including mammalian, bacterial, yeast, insect and / or fungal cells, with mammalian cells (e g., CHO cells), finding use in many embodiments.

[0145] The antibodies and ABDs provided herein are made by culturing host cells comprising the expression vector(s) as is well known in the art. Once produced, traditional antibody purification steps are done, including an ion exchange chromatography step (e.g.. techniques that utilize IEF gels, cIEF, and analytical IEX columns).VI. Biological and Biochemical Functionality of the anti-TLl A Antibodies

[0146] Generally, the anti-TLl A antibodies described herein are administered to patients with aTLIA-associated disease, disorder, or condition, and efficacy is assessed, in a number of ways as described herein. In some embodiments, the method includes administering to a subject having a TL1 A-associated disease a therapeutically effective amount of a subject TL1 A antibody as provided herein. In some embodiments, the TL1 A associated disease is selected from one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. Methods for assessing ulcerative colitis are disclosed, for example, in Schroeder et al., N Engl J Med 317: 1625-9 (1987). Methods for assessing Crohn’s Disease and fibrostenotic Crohn's Disease are disclosed for example, in Veauthier and Homecker, Am Fam Physician 98( 11):661-669 (2018) and Solitano et al.. J Clin Med. 12(9):3052 (2023). Methods for assessing systemic sclerosis are disclosed, for example, in Lafaytis and Valenzi et al.. Nature Reviews Rheumatology 18:527-541 (2022). Methods for assessing interstitial lung disease are disclosed, for example, in Gulati, Primary Care Respiratory Journal 20: 120-127 (2011). Methods of assessing primary biliary cirrhosis are disclosed, for example in Bowlus and Gershwin, Autoimmun Rev. 13(0):441-444 (2014). Methods for assessing primary sclerosing cholangitis are disclosed, for example, in Modha and Navaneethan, World J. Hepatol 7(5):799-805 (2015). Methods for assessing rheumatoid arthritis are disclosed, for example, in Wasserman, Am Fam Physician 84(11): 1245-1252 (2011). Methods for assessing atopic dermatitis are disclosed, for example, in Fishbein et al., J Allergy Clin Immunol Pract. 8(1 ):91— 101 (2019). Thus, while standard assays of efficacy can be run, such as cancer load,size of tumor, evaluation of presence or extent of metastasis, etc., immuno-oncology treatments can be assessed on the basis of immune status evaluations as well. This can be done in a number of ways, including both in vitro and in vivo assays.VII. Antibody Compositions for In Vivo Administration

[0147] Formulations of the antibodies used in accordance with the present invention are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients, or stabilizers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed.

[1980] ), 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 include buffers such as phosphate, citrate, 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 benzy l 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).

[0148] In one aspect, provided herein is a pharmaceutical composition comprising an TL1A antigen binding domain and a pharmaceutically acceptable carrier. In some embodiments, the TL1 A antigen binding domain is any one of the TL1 A antigen binding disclosed herein, including, for example those disclosed in Figure 9. In some embodiments, the TL1A antigen binding domain includes a vhCDRl having an amino sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3. a vhCDR3 having an amino acid sequence of SEQ ID NO:4, a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO:7 and a vlCDR3 having anamino acid sequence having an amino acid sequence of SEQ ID NO: 8. In exemplary embodiments, the TL1 A antigen binding domain includes a variable heavy domain having an amino acid sequence of SEQ ID NO: 1 and a variable light domain having an amino acid sequence of SEQ ID NO:5.

[0149] In another aspect, provided herein is a pharmaceutical composition comprising an anti-TLl A antibody and a pharmaceutically acceptable carrier, wherein the anti-TLl A antibody is any one of the anti-TLIA antibodies disclosed herein, including, for example those disclosed in Figures 10-12. In some embodiments, the anti-TLIA antibody comprises a TL1 A antigen binding domain of any of the TL1 A antigen binding domains disclosed in Figure 9. In exemplary embodiments, the TL1 A antigen binding domain includes a vhCDRl having an amino sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3, a vhCDR3 having an amino acid sequence of SEQ ID NO:4, a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO: 7 and a vlCDR3 having an amino acid sequence having an ammo acid sequence of SEQ ID NO: 8. In exemplary embodiments, the TL1A antigen binding domain includes a variable heavy domain having an amino acid sequence of SEQ ID NO: 1 and a variable light domain having an amino acid sequence of SEQ ID NO:5. In an exemplary embodiment, the anti-TLIA antibody includes a heavy chain having an amino acid sequence of SEQ ID NO: 123, and a light chain having an amino acid sequence of SEQ ID NO: 124.VIII. Therapeutic Uses

[0150] Provided herein are methods of reducing TL1A mediated activity and methods of treating TL1 A-associated diseases(e.g., an inflammatory bowel disease) using the subject anti-TLl A antibody disclosed herein. In some embodiments, the subject anti-TLIA antibody disclosed herein inhibits or reduces TL1 A-associated activity by inhibiting the binding of TLlAto its receptor, Death Receptor 3 (DR3). TL1 A is expressed by antigen present cells (e.g., including dendritic cells, B cells and macrophages), CD4+ and CD8+ T cells and endothelial cells and can be expressed on the cell surface or secreted as a soluble cytokine. In some embodiments, the subject anti-TLIA antibody inhibits or reduces TL1A expressed by one of the following cells: a dendritic cell, a B cell, a macrophage, a CD4+ T cells, a CD8+ T cell, or an endothelial cell. In some embodiments, the binding of TLlAto a DR3 express cell.In certain embodiments, the DR3 expressing cell is one of the following cells: a CD4+ T cell, a CD8+ T cell, an NK cell, an NKT cell or a FOXP3+ regulatory T (Treg) cell.

[0151] In one aspect, provided herein are methods of inhibiting or reducing TL1 A- mediated cell apoptosis using a subject anti-TLl A antibody as described herein. In some embodiments, the method comprises contacting a TL1 A expressing cell with a subject anti- TLl A antibody as described herein, thereby inhibiting or reducing the ability of the TL1 A expressing cell to mediate cell apoptosis. In some embodiments, the method inhibits or reduces TL1 A-mediated cell apoptosis in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLl A antibody as described herein. In some embodiments, the subject anti-TLl A antibody reduces apoptosis in a cell or a population of cells in a subject that expresses a death receptor 3 (DR3) receptor. In some embodiments, the subject anti-TLl A antibody reduces apoptosis in a cell or a population of cells in a subject that expresses DR3 by preventing the interaction of TL1 A and DR3. Without being bound by any particular theory of operation, it is believed that reduction of TL1 A-mediated apoptosis can lead to the treatment of a subject that has a TL1 A-associated disease (e.g., an inflammatory bowel disease). In some embodiments, the subject is a human subject. In embodiments, the anti-TLIA antibody includes a TLlAbinding domain of any one of the TL1 A binding domains depicted herein. In some embodiments, the anti-TLIA antibody includes a TLl A binding domain of Figure 9. In some embodiments, the anti-TLl A antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12. Any suitable technique known in the art can be used for assessing TLlA-mediated apoptosis. For example, the level of apoptosis of the cells can be assessed by detecting activation of caspases or propidium iodide uptake or other known assays. ATLla-binding protein that reduces the level of apoptosis compared to the level of apoptosis in the absence of the TL la-binding protein is considered to inhibit or reduce TL la activity or neutralize TL la activity through DR3.

[0152] In another aspect, provided herein is an anti-TLIA antibody for use in inhibiting or reducing TL1 A-mediated cell apoptosis. In one aspect, provided herein is a use of an anti-TLIA antibody for the manufacture of a medicament for inhibiting or reducing TLlA-mediated cell apoptosis. In embodiments, the anti-TLIA antibody includes a TLl A binding domain of any one of the TLlAbinding domains depicted herein. In some embodiments, the anti-TLIA antibody includes a TLlA binding domain of Figure 9. In someembodiments, the anti-TLIA antibody7is an anti-TLIA antibody disclosed in Figure 10, 11 or 12.

[0153] In one aspect, provided herein are methods of inhibiting or reducing TL1 A- mediated NFkB signaling in a cell or a population of cells in a subject using a subject anti- TL1A antibody as described herein. In some embodiments, the method comprises contacting a TL1 A expressing cell with a subject anti-TLl A antibody as described herein, thereby inhibiting or reducing the ability of the TL1 A expressing cell to mediate NFkB signaling. In some embodiments, the method inhibits or reduces TLlA-mediated NFkB signaling in a subject in need thereof, wherein the method comprises administrating to the subject an anti- TLIA antibody as described herein. In some embodiments, the subject anti-TLIA antibody reduces NFkB signaling in a cell or a population of cells in a subject that expresses DR3 receptor. In some embodiments, the subject anti-TLIA antibody reduces NFkB signaling in a cell or a population of cells in a subject that expresses DR3 by preventing the interaction of TL1 A and DR3. Without being bound by any particular theory of operation, it is believed that reduction of TL1 A-mediated NFkB signaling can lead to the treatment of a subject that has a TLlA-associated disease (e.g., an inflammatory' bowel disease). In some embodiments, the subject is a human subject. In embodiments, the anti-TLIA antibody includes a TL1 A binding domain of any one of the TL1 A binding domains depicted herein. In some embodiments, the anti-TLl A antibody includes a TL1 A binding domain of Figure 9. In some embodiments, the anti-TLIA antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12. Any suitable technique known in the art can be used for assessing TLlA-mediated NFkB signaling, for example, those disclosed in Wu and Bruggeman, Methods Mol. Biol. 1155: 1-14 (2014).

[0154] In another aspect, provided herein is an anti-TLl A antibody for use in inhibiting or reducing TLlA-mediated NFkB signaling. In one aspect, provided herein is a use of an anti-TLl A antibody for the manufacture of a medicament for inhibiting or reducing TLlA-mediated NFkB signaling. In embodiments, the anti-TLIA antibody includes a TLIA binding domain of any one of the TL1 A binding domains depicted herein. In some embodiments, the anti-TLIA antibody' includes a TLIA binding domain of Figure 9. In some embodiments, the anti-TLIA antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12.

[0155] In another aspect, provided herein are methods of inhibiting or reducing TLlA-induced cytokine secretion in a cell or a population of cells in a subject using a subject anti-TLl A antibody as described herein. In some embodiments, the method comprises contacting a TL1 A expressing cell with a subject anti-TLl A antibody as described herein, thereby inhibiting or reducing the ability’ of the TL1 A expressing cell to induce cytokine secretion. In some embodiments, the method inhibits or reduces TL1 A-induced cytokine secretion in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLIA antibody as described herein. In some embodiments, the subject anti- TL1A antibody (e.g., any of the anti-TLIA antibodies in Figures 9-11) reduces TL1A- induced cytokine secretion in a cell or a population of cells in a subject that expresses DR3 receptor. In some embodiments, the subject anti-TLIA antibody reduces cytokine secretion in a cell or a population of cells in a subject that expresses DR3 by preventing the interaction of TL1A and DR3. In some embodiments, the anti-TLIA antibody reduces the secretion of one or more of the following cytokines: interleukin- 113 (IL- 113); tumor necrosis factor-a (TNF-a): transforming growth factor-0 (TGF-0); granulocyte-macrophage colony stimulating factor (GM-CSF); and interferon-" (IFN-y). Without being bound by any particular theory' of operation, it is believed that reduction of TLlA-mediated NFkB signaling can lead to the treatment of a subject that has a TL1 A-associated disease (e.g., an inflammatory bowel disease). In some embodiments, the subject is a human subject. In embodiments, the anti- TLIA antibody includes a TL1 A binding domain of any one of the TL1 A binding domains depicted herein. In some embodiments, the anti-TLIA antibody includes a TL1A binding domain of Figure 9. In some embodiments, the anti-TLIA antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12. Any suitable technique knowm in the art can be used for assessing TLlA-cytokine secretion, for example, using ELISA.

[0156] In another aspect, provided herein is an anti-TLIA antibody for use in inhibiting or reducing TL1 A-induced cytokine secretion. In one aspect, provided herein is a use of an anti-TLl A antibody for the manufacture of a medicament for inhibiting or reducing TL1 A-induced cytokine secretion. In embodiments, the anti-TLl A antibody includes a TLIA binding domain of any one of the TL1 A binding domains depicted herein. . In some embodiments, the anti-TLIA antibody reduces the secretion of one or more of the following cytokines: interleukin- 10 (IL-10); tumor necrosis factor-a (TNF-a): transforming growth factor-0 (TGF-0): granulocyte-macrophage colony stimulating factor (GM-CSF): andinterferon-y (IFN-y). In some embodiments, the anti-TLIA antibody includes a TL1A binding domain of Figure 9. In some embodiments, the anti-TLIA antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12.

[0157] In another aspect, provided herein are methods for the treatment of a TL1 A- associated disease, disorder, or condition. In some embodiments, the method includes administering to a subject having a TL1 A-associated disease a therapeutically effective amount of a subject TL1 A antibody as provided herein. In some embodiments, the TL1 A- associated disease is an inflammatory bowel disease. In some embodiments, the TL1A associated disease is selected from one of the following: ulcerative colitis, Crohn's Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. Any suitable method known in the art may be used to assess the TL1 A-associated disease, including any of the methods disclosed herein. In certain embodiments, the subject is a human patient. In embodiments, the anti-TLIA antibody includes a TL1A binding domain of any one of the TL1 A binding domains depicted herein. In some embodiments, the anti-TLIA antibody includes a TL1 A binding domain of Figure 9. In some embodiments, the anti-TLIA antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12.

[0158] In another aspect, provided herein is an anti-TLIA antibody for use in the treatment of a TL1 A-associated disease. In one aspect, provided herein is a use of an anti- TLIA antibody for the manufacture of a medicament for i treatment of a TL1 A-associated disease. In some embodiments, the TL1 A associated disease is selected from one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. In embodiments, the anti-TLl A antibody includes a TL1 A binding domain of any one of the TL1 A binding domains depicted herein. In some embodiments, the anti-TLIA antibody includes a TL1 A binding domain of Figure 9. In some embodiments, the anti-TLIA antibody is an anti-TLIA antibody disclosed in Figure 10, 11 or 12. In some embodiments, the anti-TLIA antibody reduces the secretion of one or more of the following cytokines: interleukin- 10 (IL-10); tumor necrosis factor-a (TNF-a); transforming growth factor-0 (TGF-0); granulocyte-macrophage colony stimulating factor (GM-CSF); and interferon-y (IFN-y). In some embodiments, the anti-TLIA antibody includesa TL1 A binding domain of Figure 9. In some embodiments, the anti-TLl A antibody is an anti-TLl A antibody disclosed in Figure 10, 11 or 12.

[0159] The antibodies provided herein administered to a subject, in accord with known methods, such as intravenous administration as a bolus, intravenous push or by intravenous infusion over a period of time. In some embodiments, the anti-TLl A antibody provided herein is administered by intravenous infusion. In some embodiments, the anti- TLl A antibody provided herein is administered subcutaneously.

[0160] In the methods of the invention, therapy is used to provide a positive therapeutic response with respect to a disease, disorder or condition described herein. Positive therapeutic responses in any given disease, disorder or condition can be determined by standardized response criteria specific to that disease or condition.

[0161] In addition to these positive therapeutic responses, the subject undergoing therapy may experience the beneficial effect of an improvement in the symptoms associated with the disease.

[0162] Treatment according to the present invention includes a “therapeutically effective amount’’ of the anti-TLl A antibody used. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.

[0163] A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

[0164] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Parenteral compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compoundcalculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0165] The efficient dosages and the dosage regimens for the anti-TLl A antibodies described herein depend on the disease or condition to be treated and may be determined by the persons skilled in the art.

[0166] In one aspect provided herein is method of administering an anti-TLl A antibody or pharmaceutical composition that includes the anti-TLl A antibody to a subject (e.g., a human patient), wherein the anti-TLl A antibody is administered to the subject in a first dosing regimen and a second dosing regimen, and wherein the anti-TLl A antibody is a subject anti-TLIA antibody provided herein. In some embodiments, the first dosing regimen comprises administering the anti-TLIA antibody once every four weeks. In some embodiments, the second dosing regimen is administered once every eight weeks. In some embodiments, the first dosing regimen and second dosing regimen are administered subcutaneously or intravenously. In some embodiments, the first dosing regimen is administered intravenously. In some embodiments, the first dosing regimen is administered subcutaneously. In some embodiments, the second dosing regimen is administered intravenously. In some embodiments, the second dosing regimen is administered subcutaneously. In some embodiments, the first dosing regimen is administered intravenously, and the second dosing regimen is administered subcutaneously. In some embodiments, the anti-TLl A antibody comprises a TL1 A antigen binding domain of any of the TL1A antigen binding domains disclosed in Figure 9. In exemplary7embodiments, the TL1A antigen binding domain includes a vhCDRl having an amino sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3. a vhCDR3 having an amino acid sequence of SEQ ID NO:4, a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO:7 and a vlCDR3 having an amino acid sequence having an amino acid sequence of SEQ ID NO: 8. In exemplary embodiments, the TL1 A antigen binding domain includes a variable heavy domain having an amino acid sequence of SEQ ID NO: 1 and a variable light domain having an amino acid sequence of SEQ ID NO:5. In an exemplar}7embodiment, the anti-TLl A antibody includes a heavy chain having an amino acid sequence of SEQ ID NO: 123, and a light chain having an amino acid sequence of SEQ ID NO: 124.

[0167] All cited references are herein expressly incorporated by reference in their entirety.

[0168] Whereas particular embodiments of the invention have been described above for purposes of illustration, it will be appreciated by those skilled in the art that numerous variations of the details may be made without departing from the invention as described in the appended claims.EXAMPLES

[0169] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory' of operation. For all constant region positions discussed in the present invention, numbering is according to the EU index as in Kabat (Kabat et al.. 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, entirely incorporated by reference). Those skilled in the art of antibodies will appreciate that this convention consists of nonsequential numbering in specific regions of an immunoglobulin sequence, enabling a normalized reference to conserved positions in immunoglobulin families. Accordingly, the positions of any given immunoglobulin as defined by the EU index will not necessarily correspond to its sequential sequence.

[0170] General and specific scientific techniques are known in the art and outlined in US Publications 2015 / 0307629, 2014 / 0288275 and WO2014 / 145806, all of which are expressly incorporated by reference in their entirety and particularly for the techniques outlined therein.Example 1: Generation & engineering of TL1A antibodies

[0171] In an initial campaign, numerous novel anti-TLl A mouse and rat antibodies were generated utilizing a single plasma B-cell antibody discovery' platform from Single Cell Technologies. The sequence of an exemplary rat antibody XENP47498, having a TLIA binding domain designated 70416_041[TLlA]_H0L0, is depicted in Figure 8. Antibodies were then humanized using string content optimization (see, e.g., U.S., Patent No. 7,657,380)and exemplary humanized TL1 A binding domains along with their CDRs are depicted in Figure 9. The Fc region of the antibody was engineered to include variants to ablate effector function (FcKO variants) such as those depicted in Figure 2 Full length amino acid sequences for TL1A antibodies utilizing the PVA / S267K FcKO variant are depicted in Figure 10. The Fc region of the antibody was further engineered to include variants that extend the half-life of the antibody by increased FcRn binding, such as those depicted in Figure 7. TL1 A antibodies with the M428L / N434S variants that extend the half-life of the antibodies, in addition to the PVA_ / S267K variant, such as XENP47942 (also referred to as XmAb942), are depicted in Figure 11. Full length amino acid sequences for a TL1A antibodies alternatively utilizing the L234A / L235A / P329A FcKO variant as well as the M428L / N434S half-life extension variant is depicted in Figure 12.Example 2: Characterization of TL1A antibodies2 A: TL1 A binding affinity

[0172] Anti-TLIA mAbs were first screened for binding affinity to membrane-bound TL1A. CHO cells were transiently transfected to express TL1A, then were incubated with anti-TLIA mAbs for 1 hour at 4°C and analyzed by flow cytometry. Hundreds of anti-TLIA mAbs were screened for binding, in order to determine which were the best binders to investigate further. One exemplar}' test article, XmAb942 had an EC50 value of 1. 1 nM, while Comparator 1 had an EC50 of 12.8 nM, and Comparator 2 had an EC50 of 1.8 nM respectively. The binding data is depicted in Figure 16A.

[0173] The monovalent binding affinity of anti-TLIA mAbs were assessed with Biacore. Using a Biotin CAPture kit, human scTLIA was captured at 30nM for 40 seconds at 37°C. Serial dilutions of anti-TLIA Fab were prepared and flowed over scTLIA antigen with a 10 minute association time and 1 hour dissociation time. The results are depicted in Figure 13. Of note, test articles having TLlA binding domains such as 7O416_O41[TL1A]H1L1, 7O392_292[TL1A]H1L1 and 7O416_O94[TL1A]H1L1 all displayed significantly tighter affinities than Comparator 1 and Comparator 3. The 70416_041 [TL1 A]H1L1 binding domain is used in XmAb942. Similar studies further show that the 7O416_O41 [TL1A]H1L1 exhibited significantly tighter affinity than Comparator 4 and Comparator 5 anti-TLIA antibodies. See Figure 30.

[0174] In addition to measuring binding to scTLl A, binding to increasing concentrations of soluble recombinant human TLIAtrimer (up to lOOnM) was measured at 37C via surface plasmon resonance. Xmab942 exhibited a Krupp of 8-10pM., as depicted in Figure 16B. Comparator 1 had a Knapp of 57pM, and Comparator 2 had 14pM. This data is summarized in Figure 16D. Furthermore, the binding of anti-TLl A Fabs (at a concentration of 200nM) to immobilized active TL1 A trimer or inactive TL1 A monomer at 25°C was assessed using biolayer interferometry, and the results depicted in Figure 16C show that the binding of XmAb942 is specific to the active trimeric form of TL1A. In addition, while XmAb942 binds trimeric TL1 A with high affinity, it retains specificity and does not bind to the related TNF ligand superfamily members LIGHT, TRAIL, or FasL.2B: TL1 A antibody XmAb942 is highly thermostable

[0175] Differential scanning calorimetry' was used in order to investigate the thermostability of anti-TLIA mAbs. At a concentration of 1 mg / mL XmAb942 was evaluated from 25°C to 95°C at a ramp rate of 60°C / minute. A Tonset value of 66.0 °C and TM values of 77.2 °C and 75.9 °C w ere calculated for XmAb942 (Figure 20A). This data indicates that XmAb942 has an acceptable thermostability profile.

[0176] At a concentration of 1 mg / ml, XmAb942 and two comparator antibodies were evaluated from 25CC to 95°C at a ramp rate of l°C / minute. The results, depicted in Figure 20B, illustrate that XmAb942 has a significantly higher TMi of 81°C relative to Comparator 1, which has a TMi of 66.2°C and aTNh of 72.8°C. Comparator 2 has a very similar TMi of 81.7°C relative to XmAb942.

[0177] The results depicted in Figure 20B illustrate that XmAb942 has a significantly higher TMi of 81°C relative to Comparator 1, which has a TMi of 66.2°C and a TM2 of 72.8°C. Comparator 2 has a very similar TMi of 81.7°C relative to XmAb942.

[0178] Further studies show that an anti-TLIA antibody with the 041 [TL1 A]H1L1 binding domain of XmAb942 also exhibited a higher TMi relative to two additional anti- TLIA antibodies (Comparators 4 and 5). See Figure 30.2C: TL1A antibodies inhibit TL1A induced TF-1 apoptosis

[0179] In order to investigate the functional activity of anti-TLl A mAbs described herein, an experiment was conducted in which cycloheximide (1 ug / mL) treated 10K TF-1 cells were seeded in a 384 well plate followed by the addition of variable concentrations of anti-TLl A Ab. Subsequently, 0. 1 ug / mL recombinant TL1A was added for a 6 hour incubation. Next, Caspase-Gio 3 / 7 reagent was added for 30 min and luminescence were measured. The results, depicted in Figure 14, indicate that the TLIA mAbs disclosed herein inhibit caspase activity with competitive IC50 values relative to Comparator clones. A similar experiment was repeated using XENP47942, which is identical to XENP48083 except for that it additionally contains the Xtend variant, and showed the same results as depicted in Figure 14A.2D: TL1 A antibodies inhibit TL1 A-induced NFkB signaling

[0180] A Jurkat reporter cell line was incubated with anti-TLl A mAbs and 0.4 pg / mL of TL1 A, then luciferase activity (reflecting the induction of NFKB) was measured after 5 hours. The results are depicted in Figure 17. Data are means ± standard error of the mean (SEM).2E: TL1 A antibodies inhibit TL1 A-induced IFNy release

[0181] IL 12- and IL18-stimulated CD4+ T cells from 8 PBMC donors were treated with anti-TLl A mAbs and 0.2 pg / mL of TL1A, then IFNy release was measured after 24 hours. The results are depicted in Figure 18. Data are means ± SEM.Example 3: Anti-TLIA half-life in vivo

[0182] To investigate the pharmacokinetic profile of the anti-TLl A mAbs, a single dose study was conducted in humanized FcRn (huFcRn) mice. All mice were randomly enrolled into study groups by body weight, and each group consisted of 5 mice. After grouping, each mouse was dosed with 5 mg / kg of anti-TLIA mAb intravenously. Retro- orbital bleeds of -20-50 ul were collected at Day-1 (pre-dose, pooled from blank control group), 10 mm, 4h, Day 2 (48 h), Day 3 (72 h), Day 4 (96h), Day 7 (168 h), Day 10 (240 h), Day 12 (288 h), Day 14 (336 h), and Day 21 (504 h). Blood was collected in anti-coagulant centrifuge tube (EDTA-K2), and then centrifuged at 8000 rpm, 5 minutes, 4°C to plasma collection for PK ELISA. As depicted in Figure 15, anti-TLl A mAbs in Group A demonstrated significantly longer half -lives than those in groups B or C. XENP48083 (anXmAb942 analog) in particular was calculated to have a half-life of ~14 days. Additionally, the half-life in non-human primate studies supports Q8W- Q12W dosing in humans. . Cynomolgus monkeys received a single intravenous (IV) injection of the indicated anti-TLl A mAbs. Concentration vs time data were analyzed by noncompartmental analysis (NCA) and two-compartmental analysis (2CA). Data depicted in Figure 19 are means ± SEM; n = 3 monkey s / group. The vertical dashed line denotes the day of dosing. Allometric scaling adjusted for half-life engineered antibodies predicts that XmAb942 will have a half-life of > 70 days in humans, potentially enabling dosing intervals every 8 weeks or longer. XmAb942 was well-tolerated at all doses in a GLP study in cynomolgus monkeys.Example 4: Assessment of XmAb942 Dosing Schedule

[0183] Quantitative Systems Pharmacology (QSP) modeling was used to determine pharmacokinetics (PK) and pharmacodynamics (PD) profiles for three XmAb942 dosing schedules, wherein induction doses are administered every four weeks (qw4, iv) at weeks 0, 4, and 8 at three different dosages (DI, D2, or D3), followed by maintenance doses once every eight weeks (qw8, sc) at dose Dm (Figure 31). PK and PD profiles were also determined for two comparator anti-TLl A antibodies (“Comparator 1” and “Comparator 2”) at the dosing schedules as shown in Figure 32. The QSP modeling was based on human PK and PD data for the comparators and non-clinical data for XmAb942.

[0184] Based on these studies, it was determined that XmAb942 induction dose DI q4w dose maximizes TL1 A inhibition > -99% for the entire dosing interval, and XmAb942 induction dose D2 q4w dose achieves > 95% inhibition and meets / exceeds TL1 A inhibition with Comparator 1 and Comparator 2. Further, XmAb942 maintenance dose Dm q8w doses is expected to maintain >95% TL1 A inhibition during maintenance phase across all induction regimens.

[0185] Additional modeling predicted that sustained effective suppression of TL1A in the gut in a planned phase 2 dose regimen (see Figure 40).Example 5: Assessment of XmAb942 Pharmacokinetics and Pharmacodynamics

[0186] PK and PD properties of XmAb942 were further assessed in humans and the results are summarized in Figures 34 and 35. Preliminary PK data for XmAb942 was consistent with the QSP model predictions of Example 4 (Figure 34). In particular, XmAb942terminal half-life was observed to be greater than 2 months, consistent with model prediction of 75 days. XmAb942 also exhibited high bioavailability (-74%) and no signs of anti-drug antibodies (ADA) impacting PK were observed in the study. Longer duration data will be obtained to estimate terminal phase parameters. Additional PK studies demonstrated increased half-life in monkeys compared with first-generation anti-TLl As (Figure 37).

[0187] Additional results from a human PK study with three different doses of XmAb942 administered as a single dose IV or SC or multiple dose IV is shown in Figure 38. Based on the data of the single-dose cohorts, it was estimated that the terminal half-life for XmAb942 is 71 days. There was no apparent impact of ADA on PK profile up to 16 weeks after single dose or 10 weeks after multiple Q4W dosing. Early multiple dose PK data was consistent with single dose.

[0188] XmAb942 also exhibited significant pharmacodynamic effects in humans (Figure 35). In particular, free soluble TL1 A (sTLIA) levels fell below limit of detection at all timepoints post IV or SC administration of XmAb942. Based on the binding affinity and PK results for XmAb942, modeling predicted >95% sTLIA inhibition in blood for 12 weeks post single dose. Total sTLIA levels significantly increased post IV and SC administration, as expected from other anti-TLl A drugs. Moreover, such sTLIA levels increased up to Day 30, demonstrating the durability of TL1 A inhibition and long half-life of XmAb942.Additional results from a human pharmacodynamic study with three different doses of XmAb942 administered as a single dose IV or SC is shown in Figures 39A and B. As shown in Figure 39A, dose-dependent and durable increases in total TL1A was observed at least 16 weeks after a single dose of XmAb942, consistent with high binding potency and extended serum exposure. As shown in Figure 39B, all dose levels of VI and SC administered XmAb942 had rapid and sustained reduction of free sTLIA below LLOQ for at least 16 weeks from a single dose. All data points were below LLOQ of 20 pg / ml. Taken altogether, these results support lower dosing frequency than first-generation TLlAs.Example 6: Clinical Studies

[0189] Human clinical studies to assess XmAb942 for the treatment of ulcerative colitis, Crohn’s disease, Fibrostenotic Crohn’s disease, and other additional diseaseindications will be carried out as outlined in Figure 33. Details of a human phase 2b study in ulcerative colitis is shown in Figure 36.Embodiments:1. A means for binding an antigen comprising means for binding human TLla and means for increasing serum half-life of the means for binding the antigen.2. A means for binding an antigen comprising means for binding human TLla and means for reducing / removing binding to a cell surface receptor.3. A pharmaceutical composition comprising :(a) means for binding an antigen comprising means for binding human TLla and means for increasing serum half-life of the means for binding the antigen; and(b) a pharmaceutically acceptable carrier.4. A pharmaceutical composition comprising:(a) means for binding human TLla; and(b) a pharmaceutically acceptable carrier.5. The pharmaceutical composition of embodiment 4 further comprising means for increasing serum half-life of the means for binding human TLla.6. A pharmaceutical composition comprising:(a) means for binding an antigen comprising means for binding human TLla and means for reducing or reducing / removing binding to a cell surface receptor; and(b) a pharmaceutically acceptable carrier.7. A method of inhibiting TL1 A-mediated cell apoptosis in a subject in need thereof, wherein the method comprises administering to the subject the means for binding an antigen according to embodiments 1-2 or the pharmaceutical composition according to embodiments 3-6.8. A method of inhibiting TL1 A-mediated NFkB signaling in a subject in need thereof, wherein the method comprises administering to the subject the means for binding anantigen according to embodiments 1-2 or the pharmaceutical composition according to embodiments 3-6. A method of inhibiting TL1 A-induced cytokine secretion in a subject in need thereof, wherein the method comprises administering to the subject the means for binding an antigen according to embodiments 1-2 or the pharmaceutical composition according to embodiments 3-6. The method of embodiment 9, wherein the cytokine is selected the following interleukin-l|B (IL- ip); tumor necrosis factor-a (TNF-a); transforming growth factor- (TGF- ); granulocyte-macrophage colony stimulating factor (GM-CSF); and interferon-y (IFN-y). The method of any one of embodiments 7-10, wherein the subject has a TL 1 A- associated disease. The method of embodiment 11, wherein the TLlA-associated disease is an inflammatory bowel disease. The method of embodiment 11, wherein the TLlA-associated diseases is one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis. A method for treating a TLlA-associated disease, wherein the method comprises administering to the subject in need thereof the means for binding an antigen according to embodiments 1-2 or the pharmaceutical composition according to embodiments 3-6. The method of embodiment 13, wherein the TLlA-associated disease is an inflammatory bowel disease.16. The method of embodiment 13, wherein the TLlA-associated diseases is one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary' cholangitis, primary' sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.17. The method of any one of embodiments 7-1 , wherein the subject is a human.Table 3 below links the above listed “means” clauses to the relevant portions of the specification.

Claims

1. WHAT IS CLAIMED IS:

1. An antibody comprising a TNF-like ligand 1 A (TL1A) antigen binding domain, the TL1A binding domain comprising a variable light domain and a variable heavy domain selected from the following sets of variable light domains and variable heavy domains: a) a variable heavy domain compnsing a vhCDRl having an amino acid sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3, and a vhCDR3 having an amino acid sequence of SEQ ID NO:4, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO: 7, and a vlCDR3 having an amino acid sequence of SEQ ID NO:8; b) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 10, a vhCDR2 having an amino acid sequence of SEQ ID NO:11, and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO: 14, a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; c) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 18, a vhCDR2 having an amino acid sequence of SEQ ID NO: 19, and a vhCDR3 having an amino acid sequence of SEQ ID NO:20, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:22, a vlCDR2 having an amino acid sequence of SEQ ID NO:23, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 24; d) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:26, a vhCDR2 having an amino acid sequence of SEQ ID NO:27, and a vhCDR3 having an amino acid sequence of SEQ ID NO:28, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:

30. a vlCDR2 having an amino acid sequence of SEQ ID NO:

31. and a vlCDR3 having an amino acid sequence of SEQ ID NO:32; e) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:34, a vhCDR2 having an amino acid sequence of SEQ ID NO:35, and a vhCDR3 having an amino acid sequence of SEQ ID NO:36, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:38, avlCDR2 having an amino acid sequence of SEQ ID NO:39, and a vlCDR3 having an amino acid sequence of SEQ ID NO:40; f) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:42, a vhCDR2 having an amino acid sequence of SEQ ID NO:43, and a vhCDR3 having an amino acid sequence of SEQ ID NO:44, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:46, a vlCDR2 having an amino acid sequence of SEQ ID NO:47, and a vlCDR3 having an amino acid sequence of SEQ ID NO:48; g) a variable heavy domain compnsing a vhCDRl having an amino acid sequence of SEQ ID NO:50, a vhCDR2 having an amino acid sequence of SEQ ID NO:51, and a vhCDR3 having an amino acid sequence of SEQ ID NO:52, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:

54. a vlCDR2 having an amino acid sequence of SEQ ID NO:

55. and a vlCDR3 having an amino acid sequence of SEQ ID NO:56; h) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:58, a vhCDR2 having an amino acid sequence of SEQ ID NO:59, and a vhCDR3 having an amino acid sequence of SEQ ID NO:60 and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:62, a vlCDR2 having an amino acid sequence of SEQ ID NO:63, and a vlCDR3 having an amino acid sequence of SEQ ID NO:64; i) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:66, a vhCDR2 having an amino acid sequence of SEQ ID NO:67, and a vhCDR3 having an amino acid sequence of SEQ ID NO:68 and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:70, a vlCDR2 having an amino acid sequence of SEQ ID NO:71, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 72; and j) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:74, a vhCDR2 having an amino acid sequence of SEQ ID NO:75, and a vhCDR3 having an amino acid sequence of SEQ ID NO:

76. and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:

78. a vlCDR2 having an amino acid sequence of SEQ ID NO:79, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 80.

2. An antibody comprising a TNF-like ligand 1 A (TL1A) antigen binding domain, the TL1A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain compnsing a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain comprising a vhCDRl. vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:

33. and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:37; f) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:41, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 49, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:53;h) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:57, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:61; i) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain compnsing a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:77.

3. An antibody comprising a TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 1, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 5; b) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:

9. and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 17, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:25, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:33, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37;f) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:41, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:45; g) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:49, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:53; h) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:57 and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:61; i) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:65, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:73, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 77.

4. An antibody comprising a TNF-like ligand 1 A (TL1A) antigen binding domain, the TL1 A binding domain comprising a variable heavy domain and a variable light domain selected from the follow ing sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain having an amino acid sequence of SEQ ID NO:37;I) a variable heavy domain having an amino acid sequence of SEQ ID NO:41, and a variable light domain having an amino acid sequence of SEQ ID NO:45;g) a variable heavy domain having an amino acid sequence of SEQ ID NO:49, and a variable light domain having an amino acid sequence of SEQ ID NO:53; h) a variable heavy domain having an amino acid sequence of SEQ ID NO:57 and a variable light domain having an amino acid sequence of SEQ ID NO:61; i) a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain having an amino acid sequence of SEQ ID NO:77.

5. The antibody of any one of claims 1 to 4, wherein the antibody further comprises a dimeric variant IgG Fc domain comprising a first monomeric variant IgG Fc domain and a second monomeric variant IgG Fc domain, wherein each of the first monomeric variant IgG Fc domain and the second monomeric variant IgG Fc domain each comprises amino acid substitutions E233P / L234V / L235A / G236del / S267K, and wherein numbering is according to EU numbering.

6. The antibody of any one of claims 1 to 4, wherein the antibody further comprises a dimeric variant IgG Fc domain comprising a first monomeric variant IgG Fc domain and a second monomeric variant IgG Fc domain, wherein each of the first monomeric variant IgG Fc domain and the second monomeric variant IgG Fc domain each comprises amino acid substitutions L234A / L235A / P329A, and wherein numbering is according to EU numbering.

7. The antibody of any one of claims 1 to 4, wherein the antibody further comprises a dimeric variant IgG Fc domain comprising a first monomeric variant IgG Fc domain and a second monomeric variant IgG Fc domain, wherein each of the first monomeric variant IgG Fc domain and the second monomeric variant IgG Fc domain each comprises amino acid substitutions M428L / N434S, and wherein numbering is according to EU numbering.

8. The antibody of claim 5 or 6, wherein each of the first monomeric variant IgG Fc domain and second monomeric variant IgG Fc domain further comprising amino acid substitutions M428L / N434S, wherein numbering is according to EU numbering.

9. The antibody of any one of claims 5 to 8, wherein each of the first monomeric variant IgG Fc domain and second monomeric variant IgG Fc domain are variants of a monomeric wild-ty pe human IgGl Fc domain.

10. A nucleic acid composition encoding the antibody of any one of claims 1 to 9, wherein the composition comprises: a. a first nucleic acid encoding the variable heavy domain; and b. a second nucleic acid encoding the variable light domain.1 1. An expression vector composition comprising: a. a first expression vector comprising the first nucleic acid of claim 10; and b. a second expression vector comprising the second nucleic acid of claim 10.

12. A host cell comprising the expression vector composition of claim 11.

13. A method of making an anti-TLl A antibody comprising culturing the host cell according to claim 12 under conditions wherein anti-TLl A antibody is expressed and recovering the anti-TLl A antibody.

14. A TNF-like ligand 1 A (TL1 A) antigen binding domain, the TL1 A binding domain comprising a variable light domain and a variable heavy domain selected from the following sets of variable light domains and variable heavy domains: a) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:2, a vhCDR2 having an amino acid sequence of SEQ ID NO:3, and a vhCDR3 having an amino acid sequence of SEQ ID NO:4, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:6, a vlCDR2 having an amino acid sequence of SEQ ID NO: 7, and a vlCDR3 having an amino acid sequence of SEQ ID NO:8;b) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 10, a vhCDR2 having an amino acid sequence of SEQ ID NO:11, and a vhCDR3 having an amino acid sequence of SEQ ID NO: 12, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:

14. a vlCDR2 having an amino acid sequence of SEQ ID NO: 15, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 16; c) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO: 18, a vhCDR2 having an amino acid sequence of SEQ ID NO: 19, and a vhCDR3 having an amino acid sequence of SEQ ID NO:20, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:22, a vlCDR2 having an amino acid sequence of SEQ ID NO:23, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 24; d) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:26, a vhCDR2 having an amino acid sequence of SEQ ID NO:27, and a vhCDR3 having an amino acid sequence of SEQ ID NO:28, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:30, a vlCDR2 having an amino acid sequence of SEQ ID NO:31, and a vlCDR3 having an amino acid sequence of SEQ ID NO:32; e) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:34, a vhCDR2 having an amino acid sequence of SEQ ID NO:35, and a vhCDR3 having an amino acid sequence of SEQ ID NO:36, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:

38. a vlCDR2 having an amino acid sequence of SEQ ID NO:39, and a vlCDR3 having an amino acid sequence of SEQ ID NO:40;I) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:42, a vhCDR2 having an amino acid sequence of SEQ ID NO:43, and a vhCDR3 having an amino acid sequence of SEQ ID NO:44, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:46, a vlCDR2 having an amino acid sequence of SEQ ID NO:47, and a vlCDR3 having an amino acid sequence of SEQ ID NO:48; g) a variable heavy domain compnsing a vhCDRl having an amino acid sequence of SEQ ID NO:50, a vhCDR2 having an amino acid sequence of SEQ ID NO:51, and avhCDR3 having an amino acid sequence of SEQ ID NO:52, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:54, a vlCDR2 having an amino acid sequence of SEQ ID NO:55, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 56; h) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:58, a vhCDR2 having an amino acid sequence of SEQ ID NO:59, and a vhCDR3 having an amino acid sequence of SEQ ID NO:

60. and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:

62. a vlCDR2 having an amino acid sequence of SEQ ID NO:63, and a vlCDR3 having an amino acid sequence of SEQ ID NO: 64; i) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:66, a vhCDR2 having an amino acid sequence of SEQ ID NO:67, and a vhCDR3 having an amino acid sequence of SEQ ID NO:68, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:70, a vlCDR2 having an amino acid sequence of SEQ ID NO:71, and a vlCDR3 having an amino acid sequence of SEQ ID NO:72; and j) a variable heavy domain comprising a vhCDRl having an amino acid sequence of SEQ ID NO:74, a vhCDR2 having an amino acid sequence of SEQ ID NO:75, and a vhCDR3 having an amino acid sequence of SEQ ID NO:76, and a variable light domain comprising a vlCDRl having an amino acid sequence of SEQ ID NO:78, a vlCDR2 having an amino acid sequence of SEQ ID NO: 79, and a vlCDR3 having an amino acid sequence of SEQ ID NO:80.

15. A TNF dike ligand 1A (TL 1 A) antigen binding domain, the TL 1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain compnsing a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable lightdomain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO: 25, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain comprising a vlCDRl. vlCDR2. and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:37;I) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:41, and a variable light domain comprising a vlCDRl. vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:49, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO: 53; h) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:57, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:61; i) a variable heavy domain comprising a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain compnsing a vhCDRl, vhCDR2, and vhCDR3 of a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable lightdomain comprising a vlCDRl, vlCDR2, and vlCDR3 of a variable light domain having an amino acid sequence of SEQ ID NO:77.

16. A TNF-like ligand 1 A (TL 1 A) antigen binding domain, the TL 1 A binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable tight domains: a) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:

1. and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 5; b) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:9, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 17, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:25, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:33, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37; f) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:41, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:45; g) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:49, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:53; h) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:57 and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:61;i) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:65, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence that is at least 90% identical to SEQ ID NO:73, and a variable light domain having an amino acid sequence that is at least 90% identical to SEQ ID NO: 77.

17. ATNF-like ligand 1A (TL1A) antigen binding domain, the TLlA binding domain comprising a variable heavy domain and a variable light domain selected from the following sets of variable heavy domains and variable light domains: a) a variable heavy domain having an amino acid sequence of SEQ ID NO: 1, and a variable light domain having an amino acid sequence of SEQ ID NO:5; b) a variable heavy domain having an amino acid sequence of SEQ ID NO:9, and a variable light domain having an amino acid sequence of SEQ ID NO: 13; c) a variable heavy domain having an amino acid sequence of SEQ ID NO: 17, and a variable light domain having an amino acid sequence of SEQ ID NO:21; d) a variable heavy domain having an amino acid sequence of SEQ ID NO:25, and a variable light domain having an amino acid sequence of SEQ ID NO:29; e) a variable heavy domain having an amino acid sequence of SEQ ID NO:33, and a variable light domain having an amino acid sequence of SEQ ID NO:37;I) a variable heavy domain having an amino acid sequence of SEQ ID NO:41, and a variable light domain having an amino acid sequence of SEQ ID NO:45; g) a variable heavy domain having an amino acid sequence of SEQ ID NO:49, and a variable light domain having an amino acid sequence of SEQ ID NO:53; h) a variable heavy domain having an amino acid sequence of SEQ ID NO:57 and a variable light domain having an amino acid sequence of SEQ ID NO:61; i) a variable heavy domain having an amino acid sequence of SEQ ID NO:65, and a variable light domain having an amino acid sequence of SEQ ID NO:69; and j) a variable heavy domain having an amino acid sequence of SEQ ID NO:73, and a variable light domain having an amino acid sequence of SEQ ID NO:77.

18. A nucleic acid composition encoding the TL1 A antigen binding domain of any one of claims 14 to 17, wherein the composition comprises: a. a first nucleic acid encoding the variable heavy domain; and b. a second nucleic acid encoding the variable light domain.

19. An expression vector composition comprising: a. a first expression vector comprising the first nucleic acid of claim 18; and b. a second expression vector comprising the second nucleic acid of claim 18.

20. A host cell comprising the expression vector composition of claim 18.

21. A method of making a TL1 A binding domain comprising culturing the host cell according to claim 18 under conditions wherein the TL1 A binding domain is expressed and recovering the TL1 A binding domain.

22. An anti-TLl A antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 123, and a light chain having an amino acid sequence of SEQ ID NO: 124.

23. A nucleic acid composition encoding an anti-TLl A antibody, wherein the composition comprises: a. a first nucleic acid encoding a heavy chain having an amino acid sequence of SEQ ID NO: 123; and b. a second nucleic acid encoding a light chain having an amino acid sequence of SEQ ID NO: 124.

24. An expression vector composition comprising: a. a first expression vector comprising the first nucleic acid of claim 23; and b. a second expression vector comprising the second nucleic acid of claim 23.

25. A host cell comprising the expression vector composition of claim 24.

26. A method of making an anti-TLl A antibody comprising culturing the host cell of claim 25 under conditions wherein the anti-TLIA antibody is expressed and recovering the anti-TLIA antibody.

27. A method of inhibiting or reducing TLlA-mediated cell apoptosis in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLIA antibody of any one of claims 1 to 9 and 22.

28. A method of inhibiting or reducing TLlA-mediated NFkB signaling in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLIA antibody of any one of claims 1 to 9 and 22.

29. A method of inhibiting or reducing TL1 A-induced cytokine secretion in a subject in need thereof, wherein the method comprises administrating to the subject an anti-TLl A antibody of any one of claims 1 to 9 and 22.

30. The method of claim 29, wherein the cytokine is selected from the following cytokines: interferon-y (IFN-y), interleukin-10 (IL-1|3); tumor necrosis factor-a (TNF-a); transforming growth factor-0 (TGF-0); and granulocyte-macrophage colony stimulating factor (GM-CSF).

31. The method of any one of claims 27-30. wherein the subject has a TLIA-associated disease.

32. The method of claim 31, wherein the TLlA-associated disease is one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

33. A method for treating a TL1 A-associated disease, wherein the method comprises administering to the subject in need thereof an anti-TLIA antibody of any one of claims 1 to 9 and 22.

34. The method of claim 33, wherein the TLlA-associated disease is an inflammatory bowel disease.

35. The method of claim 33, wherein the TLlA-associated disease is one of the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

36. The method of any one of claims 27 to 35, wherein the subject is a human.

37. An anti-TLl A antibody of any one of claims 1 to 9 and 22 for use in inhibiting or reducing TLlA-mediated cell apoptosis.

38. The anti-TLl A antibody of claim 37, wherein the TL1 A-mediated cell apoptosis is inhibited or reduced in a subject in need thereof.

39. The anti-TLl A antibody of claim 38, wherein the subject is a human.

40. The anti-TLl A antibody of claim 38 or 39, wherein the subject has a TL1 A-associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis41. Use of an anti-TLIA according to any one of claims 1 to 9 and 22 for the manufacture of a medicament for inhibiting or reducing TL1 A-mediated cell apoptosis in a subject in need thereof.

42. The use according to claim 40, wherein the subject is a human.

43. The use according to claim 41 or 42. wherein the subject has a TLlA-associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’sDisease, systemic sclerosis, interstitial lung disease, primary biliary7cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis44. An anti-TLl A antibody of claims 1 to 9 and 22 for use in inhibiting or reducing TLlA-mediated NFkB signaling.

45. The anti-TLl A antibody of claim 44, wherein the TL1 A-mediated NFkB signaling is inhibited or reduced in a subject in need thereof.

46. The anti-TLl A antibody of claim 45, wherein the subject is a human.

47. The anti-TLl A antibody of claim 45 or 46, wherein the subject has a TLlA-associated disease selected from the following: ulcerative colitis. Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary7cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis48. Use of an anti-TLl A antibody according to any one of claims 1 to 9 and 22 for the manufacture of a medicament for inhibiting or reducing TL1 A-mediated NFkB signaling in a subject in need thereof.

49. The use according to claim 48. wherein the subject is a human.

50. The use of claim 48 or 49, wherein the subject has a TL1 A-associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary' cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

51. An anti-TLl A antibody according to any one of claims 1 to 9 and 22 for use in inhibiting or reducing TL1 A- induced cytokine secretion.

52. The anti-TLl A antibody of claim 51, wherein the TL1 A- induced cytokine secretion is inhibited or reduced in a subject in need thereof.

53. The anti-TLIA antibody of claim 52, wherein the subject is a human.

54. The anti-TLl A antibody of claim 52 or 53 , wherein the subject has a TL1 A- associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary7sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

55. Use of an anti-TLl A antibody according to any one of claims 1 to 9 and 22 for the manufacture of a medicament for inhibiting or reducing TL1 A- induced cytokine secretion in a subject in need thereof.

56. The use according to claim 55. wherein the subject is a human.

57. The use of claim 55 or 56, wherein the subject has a TL1 A-associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

58. The anti-TLIA antibody of any one of claims 51 to 54 or use of any one of claims 55 to 57, wherein the cytokine is selected from the following cytokines: interferon-7 / (IFN-y), interleukin- 1 [3 (IL- 1 P); tumor necrosis factor-a (TNF-a); transforming growth factor-P (TGF- P); and granulocyte-macrophage colony stimulating factor (GM-CSF).

59. An anti-TLIA antibody according to any one of claims 1 to 9 and 22 for use in the treatment of a TL1 A-associated disease in a subject in need thereof.

60. The anti-TLIA antibody of claim 59, wherein the subject is a human.

61. The anti-TLIA antibody of claim 59 or 60, wherein the TL1 A-associated disease is an inflammatory7bowel disease.

62. The anti-TLl A antibody of claim 59 or 60, wherein the subject has a TL1 A-associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary' biliary cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

63. Use of an anti-TLl A antibody according to any one of claims 1 to 9 and 22 for the manufacture of a medicament for the treatment of a TL1 A-associated disease.

64. The use according to claim 63, wherein the subject is a human.

65. The use of claim 63 or 64, wherein the TL1 A-associated disease is an inflammatory' bowel disease.

66. The use of claim 63 or 64, wherein the subject has a TL 1 A-associated disease selected from the following: ulcerative colitis, Crohn’s Disease, fibrostenotic Crohn’s Disease, systemic sclerosis, interstitial lung disease, primary biliary' cholangitis, primary sclerosing cholangitis, rheumatoid arthritis, and atopic dermatitis.

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