Anti-TL1a antibody or antigen-binding fragment thereof and use

Abstract

The present invention relates to an anti-TL1A antibody or an antigen-binding fragment thereof, and further provides a polynucleotide encoding the antibody, a vector and host cell for expressing the antibody, a pharmaceutical composition comprising the antibody, a method for treating a TL1A-related disease using the antibody, and pharmaceutical use of the antibody.

Description

An anti-TL1A antibody or its antigen-binding fragment and its uses Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to anti-TL1A antibodies or their antigen-binding fragments, pharmaceutical compositions, and uses. Background Technology

[0002] Tumor necrosis factor-like cytokine 1A (TL1A, also known as TNFSF15) belongs to the TNF superfamily and is expressed in various immune cells such as monocytes, macrophages, dendritic cells, and T cells, as well as non-immune cells such as synovial fibroblasts and endothelial cells. TL1A is a type II transmembrane protein that exists in membrane-bound or soluble forms and plays different immune roles. The membrane-bound form of TL1A self-assembles into a stable trimer through interactions with TNF homologous domains. The soluble form of TL1A is produced through selective splicing or cleavage by TNF-α convertase (TACE).

[0003] TL1A binds to death receptor 3 (DR3) and activates multiple downstream pathways, exerting pro-inflammatory effects, regulating cytokine and chemokine secretion, promoting apoptosis, and participating in innate immunity, adaptive immunity, and fibrosis. For example, in innate immunity, mouse models have demonstrated that high expression of TL1A can disrupt the tightness of connective proteins in the intestinal physical barrier, enhancing its permeability and making it more susceptible to inflammation caused by pathogens or other external stimuli. In adaptive immunity, TL1A promotes Th1 cell proliferation and the expression of related cytokines IFN-γ, TNFα, and IL-2. In fibrosis, TL1A antibodies or knockout of TL1A / DR3 can prevent or partially alleviate the fibrotic process.

[0004] TL1A plays a crucial mediating role in inflammation and fibrosis, and is associated with the occurrence and development of diseases such as rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, asthma, and psoriasis. TL1A / DR3 cytokines have become key components of mucosal immunity and intestinal homeostasis. Clinical trials of antibody drugs targeting TL1A, such as PRA023 and PF-06480605, have demonstrated their feasibility for the treatment of inflammatory bowel disease (IBD).

[0005] There remains an unmet clinical need for novel antibodies to treat or improve IBD, as well as other TL1A-mediated diseases and symptoms. This invention provides a more desirable therapeutic agent. Summary of the Invention

[0006] On the one hand, the present invention provides an anti-TL1A antibody or its antigen-binding fragment thereof, wherein the antibody or its antigen-binding fragment can specifically bind to TL1A monomers or trimers with high affinity, effectively inhibiting or blocking the binding of TL1A to receptor DR3 and reducing inflammation levels.

[0007] On one hand, the present invention provides an anti-TL1A antibody or its antigen-binding fragment thereof, the anti-TL1A antibody or its antigen-binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 regions, and the VL comprises LCDR1, LCDR2, and LCDR3 regions, wherein the HCDR1-3 regions sequentially have sequences identical to the HCDR1-3 of any VH shown in SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, or sequences having at most 5, 4, 3, 2, or 1 mutations compared to each CDR in the HCDR1-3 of any VH shown in SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and the LCDR1-3 regions sequentially have sequences identical to ... The LCDR1-3 sequence of any VL shown in SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 is identical to or has at most 5, 4, 3, 2 or 1 mutations compared to each CDR in LCDR1-3 of any VL shown in SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20.

[0008] In some embodiments, the HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.1, or sequences that have undergone at most 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.1, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.2, or sequences that have undergone at most 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.2;

[0009] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.3, or sequences that have undergone at most 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.3, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.4, or sequences that have undergone at most 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.4;

[0010] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 5, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 5, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 6, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 6;

[0011] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.7, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.7, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.8, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.8;

[0012] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 9, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 9, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 10, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 10;

[0013] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 11, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 11, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 12, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 12;

[0014] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 13, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 13, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 14, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 14;

[0015] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 15, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 15, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 16, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 16;

[0016] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 17, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 17, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 18, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 18; or

[0017] The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 19, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 19, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 20, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 20.

[0018] The HCDR1 has the same sequence as HCDR1 of any VH shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24), or the HCDR1 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to HCDR1 of any VH shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24); the HCDR2 has the same sequence as HCDR2 of any VH shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24), or the HCDR2 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to HCDR2 of any VH shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24); and the HCDR3 has the same sequence as HCDR3 of any VH shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24), or the HCDR3 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to HCDR2 of any VH shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24). The sequence having undergone at most 5, 4, 3, 2, or 1 mutations compared to HCDR3 of any of the VH sequences shown in NO.1, 23-25 ​​(preferably SEQ ID NO.24); and,

[0019] The LCDR1 has the same sequence as the LCDR1 of any VL shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27), or the LCDR1 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the LCDR1 of any VL shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27); the LCDR2 has the same sequence as the LCDR2 of any VL shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27), or the LCDR2 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the LCDR2 of any VL shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27); and the LCDR3 has the same sequence as the LCDR3 of any VL shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27), or the LCDR3 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the LCDR1 of any VL shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27). The sequence having undergone at most 5, 4, 3, 2 or 1 mutations compared to the LCDR3 of any of the VLs shown in NO.2, 26-28 (preferably SEQ ID NO.27).

[0020] The HCDR1 has the same sequence as HCDR1 of any VH shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31), or the HCDR1 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to HCDR1 of any VH shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31); the HCDR2 has the same sequence as HCDR2 of any VH shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31), or the HCDR2 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to HCDR2 of any VH shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31); and the HCDR3 has the same sequence as HCDR3 of any VH shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31), or the HCDR3 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to HCDR2 of any VH shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31). The sequence having undergone at most 5, 4, 3, 2, or 1 mutations compared to HCDR3 of any of the VH sequences shown in NO.7, 29-31 (preferably SEQ ID NO.31); and,

[0021] The LCDR1 has the same sequence as the LCDR1 of any VL shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33), or the LCDR1 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the LCDR1 of any VL shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33); the LCDR2 has the same sequence as the LCDR2 of any VL shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33), or the LCDR2 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the LCDR2 of any VL shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33); and the LCDR3 has the same sequence as the LCDR3 of any VL shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33), or the LCDR3 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the LCDR2 of any VL shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33). The sequence having at most 5, 4, 3, 2 or 1 mutations compared to the LCDR3 of any of the VLs shown in NO.8, 32-34 (preferably SEQ ID NO.33).

[0022] The HCDR1 has the same sequence as the HCDR1 of any of the VHs shown in SEQ ID NO. 19, 35-38, or the HCDR1 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the HCDR1 of any of the VHs shown in SEQ ID NO. 19, 35-38; the HCDR2 has the same sequence as the HCDR2 of any of the VHs shown in SEQ ID NO. 19, 35-38, or the HCDR2 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the HCDR2 of any of the VHs shown in SEQ ID NO. 19, 35-38; and the HCDR3 has the same sequence as the HCDR3 of any of the VHs shown in SEQ ID NO. 19, 35-38, or the HCDR3 has a sequence with at most 5, 4, 3, 2, or 1 mutations compared to the HCDR2 of any of the VHs shown in SEQ ID NO. 19, 35-38. The sequences in NO.19, 35-38 that show at most 5, 4, 3, 2, or 1 mutations compared to the HCDR3 of any VH; and,

[0023] The LCDR1 has the same sequence as the LCDR1 of any VL shown in SEQ ID NO. 20, 39-40, or the LCDR1 has a sequence with up to 5, 4, 3, 2, or 1 mutations compared to the LCDR1 of any VL shown in SEQ ID NO. 20, 39-40; the LCDR2 has the same sequence as the LCDR2 of any VL shown in SEQ ID NO. 20, 39-40, or the LCDR2 has a sequence with up to 5, 4, 3, 2, or 1 mutations compared to the LCDR2 of any VL shown in SEQ ID NO. 20, 39-40; and the LCDR3 has the same sequence as the LCDR3 of any VL shown in SEQ ID NO. 20, 39-40, or the LCDR3 has a sequence with up to 5, 4, 3, 2, or 1 mutations compared to the LCDR3 of any VL shown in SEQ ID NO. 20, 39-40.

[0024] In some preferred embodiments, the HCDR1, HCDR2, and HCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.1, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as LCDR1, LCDR2, and LCDR3 of VL as shown in SEQ ID NO.2; the HCDR1, HCDR2, and HCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.7, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as LCDR1, LCDR2, and LCDR3 of VL as shown in SEQ ID NO.8; or the HCDR1, HCDR2, and HCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.19, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.1, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.1, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VL as shown in SEQ ID NO.1, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH ... The VL shown in NO.20 has the same sequence for LCDR1, LCDR2 and LCDR3.

[0025] In some specific embodiments, the HCDR1, HCDR2, and HCDR3 regions sequentially have the same sequences as HCDR1, HCDR2, and HCDR3 of VH as shown in any of SEQ ID NO. 23-25, and the LCDR1, LCDR2, and LCDR3 regions sequentially have the same sequences as LCDR1, LCDR2, and LCDR3 of VL as shown in any of SEQ ID NO. 26-28; the HCDR1, HCDR2, and HCDR3 regions sequentially have the same sequences as HCDR1, HCDR2, and HCDR3 of VH as shown in any of SEQ ID NO. 29-31, and the LCDR1, LCDR2, and LCDR3 regions sequentially have the same sequences as LCDR1, LCDR2, and LCDR3 of VL as shown in any of SEQ ID NO. 32-34; or, the HCDR1, HCDR2, and HCDR3 regions sequentially have the same sequences as shown in SEQ ID NO. 23-25. The VH shown in any of NO.35-38 has the same HCDR1, HCDR2 and HCDR3 sequences as the LCDR1, LCDR2 and LCDR3 regions, which in turn have the same sequences as the VL shown in any of SEQ ID NO.39-40.

[0026] The mutation is selected from insertions, deletions and / or substitutions that do not affect function, and the substitution is preferably a substitution of a conserved amino acid.

[0027] In some implementations, the HCDR1, HCDR2, and HCDR3 of the VH, and the LCDR1, LCDR2, and LCDR3 of the VL are defined according to IMGT, Kabat, Chothia, AbM, Contact, or any combination thereof.

[0028] In some preferred embodiments, the HCDR1-3 of VH and the HCDR1-3 of VL are selected from the HCDR1-3 and LCDR1-3 of any of the antibodies shown in Table A.

[0029] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20.

[0030] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 23-25, 29-31, 35-38, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 26-28, 32-34, 39-40.

[0031] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 23-25, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 26-28.

[0032] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 29-31, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 32-34.

[0033] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 35-38, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 39-40.

[0034] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 1, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 2; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 3, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 1 ... NO.4 has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.5; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.6, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.5; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.5. NO.7 has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.8; VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.9; and VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO.8. NO. 10 has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 11; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 11; and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 12; the VH has an amino acid sequence that is identical to SEQ ID NO. 11.13. An amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO. 14, and the VL having an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO. 14; the VH having an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO. 15, and the VL having an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO. 15, and the VL having an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO. 14. NO. 16 has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 17; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 17, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 18; or the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 18; NO. 19 has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 20, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 20.

[0035] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 23, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 26-28; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 24, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 23, and the VL ... The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 25; and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 26-28.

[0036] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 29, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 32-34; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 30, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 29 ... The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 31; and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 32-34.

[0037] In some embodiments, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 35, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 39 or 40; the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 36, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 35 ... The amino acid sequence of SEQ ID NO. 39 or 40 is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 37; the VH has an amino acid sequence at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 37, and the VL has an amino acid sequence at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 39 or 40; the VH has an amino acid sequence at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 39 or 40; the VH has an amino acid sequence at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 40. NO. 38 has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 39 or 40, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 39 or 40.

[0038] In some embodiments, the VH has a sequence with up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mutation compared to any of the sequences shown in SEQ ID NO. 1, 23-25 ​​(preferably SEQ ID NO. 24), and / or the VL has a sequence with up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mutation compared to any of the sequences shown in SEQ ID NO. 2, 26-28 (preferably SEQ ID NO. 27); the mutations are preferably substitutions of conserved amino acids. In some embodiments, the VH has a sequence with up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mutation compared to any of the sequences shown in SEQ ID NO. 7, 29-31 (preferably SEQ ID NO. 31), and / or the VL has a sequence with up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mutation compared to any of the sequences shown in SEQ ID NO. 8, 32-34 (preferably SEQ ID NO. 33); the mutations are preferably substitutions of conserved amino acids.

[0039] In some preferred embodiments, the VH and VL are selected from the group consisting of:

[0040] (1) The VH contains or is the sequence shown in SEQ ID NO.1 and the VL contains or is the sequence shown in SEQ ID NO.2;

[0041] (2) The VH contains or is the sequence shown in SEQ ID NO.3 and the VL contains or is the sequence shown in SEQ ID NO.4;

[0042] (3) The VH contains or is the sequence shown in SEQ ID NO.5 and the VL contains or is the sequence shown in SEQ ID NO.6;

[0043] (4) The VH contains or is the sequence shown in SEQ ID NO.7 and the VL contains or is the sequence shown in SEQ ID NO.8;

[0044] (5) The VH contains or is the sequence shown in SEQ ID NO. 9 and the VL contains or is the sequence shown in SEQ ID NO. 10;

[0045] (6) The VH contains or is the sequence shown in SEQ ID NO.11 and the VL contains or is the sequence shown in SEQ ID NO.12;

[0046] (7) The VH contains or is the sequence shown in SEQ ID NO.13 and the VL contains or is the sequence shown in SEQ ID NO.14;

[0047] (8) The VH contains or is the sequence shown in SEQ ID NO.15 and the VL contains or is the sequence shown in SEQ ID NO.16;

[0048] (9) The VH comprises or is the sequence shown in SEQ ID NO. 17 and the VL comprises or is the sequence shown in SEQ ID NO. 18; or

[0049] (10) The VH contains or is the sequence shown in SEQ ID NO.19 and the VL contains or is the sequence shown in SEQ ID NO.20.

[0050] In some embodiments, the VH comprises any amino acid sequence selected from SEQ ID NO.23-25, 29-31, 35-38, and / or the VL comprises any amino acid sequence selected from SEQ ID NO.26-28, 32-34, 39-40.

[0051] In some embodiments, the VH comprises any amino acid sequence selected from SEQ ID NO. 23-25, and / or the VL comprises any amino acid sequence selected from SEQ ID NO. 26-28; the VH comprises any amino acid sequence selected from SEQ ID NO. 29-31, and / or the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34; or, the VH comprises any amino acid sequence selected from SEQ ID NO. 35-38, and / or the VL comprises any amino acid sequence selected from SEQ ID NO. 39-40.

[0052] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO.23, and the VL comprises any amino acid sequence selected from SEQ ID NO.26-28; the VH comprises the amino acid sequence of SEQ ID NO.24, and the VL comprises any amino acid sequence selected from SEQ ID NO.26-28; the VH comprises the amino acid sequence of SEQ ID NO.25, and the VL comprises any amino acid sequence selected from SEQ ID NO.26-28.

[0053] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO. 29, and the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34; the VH comprises the amino acid sequence of SEQ ID NO. 30, and the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34; the VH comprises the amino acid sequence of SEQ ID NO. 31, and the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34.

[0054] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO. 35, and the VL comprises the amino acid sequence of SEQ ID NO. 39 or 40; the VH comprises the amino acid sequence of SEQ ID NO. 36, and the VL comprises the amino acid sequence of SEQ ID NO. 39 or 40; the VH comprises the amino acid sequence of SEQ ID NO. 37, and the VL comprises the amino acid sequence of SEQ ID NO. 39 or 40; the VH comprises the amino acid sequence of SEQ ID NO. 38, and the VL comprises the amino acid sequence of SEQ ID NO. 39 or 40.

[0055] In some preferred embodiments, VH and VL are selected from any one of the following groups:

[0056] (1) The VH may contain or be the sequence shown in SEQ ID NO.31 and the VL may contain or be the sequence shown in SEQ ID NO.33;

[0057] (2) The VH contains or is the sequence shown in SEQ ID NO.24 and the VL contains or is the sequence shown in SEQ ID NO.27;

[0058] (3) The VH contains or is the sequence shown in SEQ ID NO.25 and the VL contains or is the sequence shown in SEQ ID NO.27.

[0059] In some embodiments, the anti-TL1A antibody provided by the present invention further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region is selected from the constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE or variants thereof, preferably from, for example, the constant regions of human IgG1, IgG2, IgG3, and IgG4 or variants thereof; the light chain constant region is selected from the κ and λ chain constant regions or variants thereof, preferably from the human κ and λ chain constant regions or variants thereof. The variant has altered effector functions mediated by the Fc region (e.g., ADCC and / or CDC activity and / or ADCP, affinity for FcγRIIIa and / or C1q), but does not alter the function of the antibody variable region. In some embodiments, the variant Fc region has at least one amino acid substitution compared to its derived wild-type Fc region, for example, about 1-10 amino acid substitutions, or about 1-5 amino acid substitutions, or about 1-3 amino acid substitutions in the wild-type Fc region. The variant Fc region may have at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homology with its derived wild-type Fc region. In some embodiments, the antibody or its antigen-binding fragment comprises a constant region variant of human IgG (e.g., human IgG1) that has reduced CDC and / or ADCC activity compared to its derived wild-type sequence. In some embodiments, the antibody or its antigen-binding fragment comprises a constant region variant of human IgG1, the variant having one or more of the following amino acid substitutions compared to its derived wild-type sequence: L234A, L235A, P329A, P329G, D265S, N297A, M252Y, S254T, T256E, M428L, N434S (according to the position in the EU numbering system); preferably one or any combination of the following amino acid substitutions: (1) L234A / L235A (LAL) (A) ;(2) L234A / L235A / P329A (LALAPA) ;(3) L234A / L235A / D265S (LALADS) ;(4) L234A / L235A / P329G (LALAPG) ;(5) M252Y / S254T / T256E (YTE) ;(6) M428L / N434S (LS) ;More preferably, the amino acid substitutions include any one of LALA, LALAPA, LALADS and / or any one of YTE, LS.

[0060] In some preferred embodiments, the heavy chain constant region and the light chain constant region comprise sequences as shown in Table 2, or amino acid sequences that are at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to them.

[0061] In some preferred embodiments, the heavy chain constant region comprises any of the sequences shown in SEQ ID NO. 21, 48-50, 52-55, or an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to it.

[0062] In some preferred embodiments, the light chain constant region comprises the sequence shown in either SEQ ID NO. 22 or 51, or an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to it.

[0063] In some embodiments, the anti-TL1A antibody or its antigen-binding fragment provided by the present invention is selected from any one of the antibodies shown in Tables 1, 4, and 7.

[0064] In some embodiments, the anti-TL1A antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to the heavy chain of hTL01-05 of the present invention, or comprising an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with the heavy chain of hTL01-05 of the present invention. Optionally, the mutation comprises any one of LALA, LALAPA, LALADS and / or any one of YTE, LS; and,

[0065] The light chain comprises an amino acid sequence that has undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to the light chain of hTL01-05 of the present invention, or comprises an amino acid sequence that has at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with the light chain of hTL01-05 of the present invention.

[0066] In some embodiments, the anti-TL1A antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to the heavy chain of hTL01-08 of the present invention, or comprising an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with the heavy chain of hTL01-08 of the present invention. Optionally, the mutation comprises any one of LALA, LALAPA, LALADS and / or any one of YTE, LS; and,

[0067] The light chain comprises an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to the light chain of hTL01-08 of the present invention, or comprises an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with the light chain of hTL01-08 of the present invention.

[0068] In some embodiments, the anti-TL1A antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to the heavy chain of hTL04-08 of the present invention, or comprising an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with the heavy chain of hTL04-08 of the present invention; optionally, the mutation comprises any one of LALA, LALAPA, LALADS and / or any one of YTE, LS; and,

[0069] The light chain comprises an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to the light chain of hTL04-08 of the present invention, or comprises an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with the light chain of hTL04-08 of the present invention.

[0070] In some embodiments, the anti-TL1A antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to SEQ ID NO. 46, or comprising an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with SEQ ID NO. 46, and the heavy chain comprises LALAPA and YTE mutations; and,

[0071] The light chain comprises an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to SEQ ID NO. 45, or comprises an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with SEQ ID NO. 45.

[0072] In some embodiments, the anti-TL1A antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to SEQ ID NO. 47, or comprising an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with SEQ ID NO. 47, and the heavy chain comprising LALAPA and YTE mutations; and,

[0073] The light chain comprises an amino acid sequence having undergone at most 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 mutations compared to SEQ ID NO. 42, or comprises an amino acid sequence having at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identity with SEQ ID NO. 42.

[0074] In some embodiments, the mutation occurs at the N-terminus or C-terminus of the heavy chain and / or light chain, for example, the heavy chain and / or light chain of hTL01-05, or the C-terminus of SEQ ID NO.47 or 42, is missing up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residues; the heavy chain and / or light chain of hTL01-08 is missing up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residues; or the heavy chain and / or light chain of hTL04-08, or the C-terminus of SEQ ID NO.46 or 45, is missing up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residues.

[0075] In some embodiments, the heavy chain constant region lacks a C-terminal lysine. In some embodiments, the N-terminal amino acid (e.g., glutamine or glutamate) of the antibody or its antigen-binding fragment may be cyclized to pyroglutamic acid or a pyroglutamate salt.

[0076] In some embodiments, the anti-TL1A antibody or its antigen-binding fragment is selected from any one of hTL01-05, hTL01-08, hTL04-08, hTL01-05F, or hTL04-08F of the present invention. In some preferred embodiments, the anti-TL1A antibody provided by the present invention is of type IgG1.

[0077] On the one hand, the present invention provides an anti-TL1A antibody or its antigen-binding fragment thereof, which binds to the same TL1A epitope or competitively binds to TL1A with the aforementioned anti-TL1A antibody or its antigen-binding fragment.

[0078] In some embodiments, the anti-TL1A antibody or its antigen-binding fragment provided by the present invention has at least one of the following functions:

[0079] (1) When binding to TL1A (e.g., human TL1A), the antibody or its antigen-binding fragment has a KD of not more than 10 nM, not more than 5 nM, not more than 1 nM, not more than 0.5 nM, not more than 0.4 nM, not more than 0.3 nM, not more than 0.2 nM, not more than 0.1 nM, not more than 0.09 nM, not more than 0.08 nM, not more than 0.07 nM, not more than 0.06 nM, not more than 0.05 nM, not more than 0.04 nM, not more than 0.03 nM, not more than 0.02 nM, or not more than 0.01 nM;

[0080] (2) When bound to TL1A (e.g., human TL1A), the KD of the antibody or its antigen-binding fragment is substantially the same as or better than that of the reference TL1A antibody;

[0081] (3) The antibody or its antigen-binding fragment binds to a homopolymer of TL1A (e.g., human TL1A), such as a homodimer or homotrimer;

[0082] (4) The antibody or its antigen-binding fragment inhibits or blocks the binding of TL1A to receptor DR3, for example, to an extent that at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% inhibit or block the binding of TL1A to receptor DR3.

[0083] (5) When the binding of TL1A (e.g., human TL1A) to receptor DR3 is inhibited or blocked, the inhibitory or blocking effect of the antibody or its antigen-binding fragment is substantially the same as or better than that of the reference TL1A antibody.

[0084] (6) The antibody or its antigen-binding fragment binds to TL1A from different species, for example, binding to human TL1A and TL1A from at least one other mammal selected from mice, rats and monkeys (e.g., cynomolgus monkeys); preferably binding to human, cynomolgus monkey and mouse TL1A, or binding to human and cynomolgus monkey TL1A.

[0085] (7) The antibody or its antigen-binding fragment is used as an antagonistic antibody against TL1A;

[0086] (8) The antibody or its antigen-binding fragment attenuates TL1A activity or attenuates TL1A-mediated signal transduction, for example at least by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%.

[0087] (9) The antibody or its antigen-binding fragment reduces the level of inflammation, for example, by reducing the secretion of IFN-γ; preferably, the antibody or its antigen-binding fragment reduces inflammation at a level substantially the same as or lower than that of the reference TL1A antibody.

[0088] In some embodiments, the ability to antagonize, inhibit, block, attenuate, or reduce TL1A activity is described by IC50 or EC50 values. In some embodiments, if the antibody of the present invention or its antigen-binding fragment reduces TL1A activity by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more relative to TL1A activity in the absence of antibody, it is considered to block, antagonize, inhibit, or reduce TL1A activity.

[0089] KD can be determined using methods known to those skilled in the art, such as biolayer interferometry (BLI) and surface plasmon resonance (SPR).

[0090] The reference TL1A antibody can be prepared with reference to patents CN105814081B and CN114901311A, for example, antibody 1D1 1.31 (also known as PF-06480605, see WO2021260577A2) described in CN105814081B. In some specific embodiments, the reference TL1A antibody may be PRA023.

[0091] PRA023 (also known as Tulisokibart) is an anti-TL1A antibody drug from Prometheus Biosciences. This antibody can bind to both membrane-bound and soluble forms of TL1A and is currently in Phase III clinical trials. PRA023 can be prepared by autonomously cloning the sequence disclosed in WHO Drug Information, Volume 36, Number 2, 2022, Proposed INN: List 127.

[0092] In some embodiments, the anti-TL1A antibody provided by the present invention is a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody. In one specific embodiment, the anti-TL1A antibody provided by the present invention is a humanized antibody. In some embodiments, the anti-TL1A antibody is a monoclonal antibody.

[0093] In some embodiments, the antigen-binding fragment of the present invention is selected from: Fab, F(ab')2, Fab', Fd, Fv, dsFv, scFv and biantibodies.

[0094] On one hand, the present invention provides a conjugate comprising the anti-TL1A antibody of the present invention or its antigen-binding fragment.

[0095] In one embodiment, the conjugate further comprises an effector molecule. In some embodiments, the effector molecule is selected from antitumor agents, drugs, toxins, bioactive proteins (e.g., enzymes), other antibodies or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof such as DNA, RNA and fragments thereof, radionuclides (e.g., radioiodides), radioisotopes, chelated metals, nanoparticles and reporter groups (e.g., fluorescent compounds), or compounds detectable by NMR or ESR spectroscopy.

[0096] On the one hand, the present invention provides a bispecific antibody comprising the anti-TL1A antibody of the present invention or its antigen-binding fragment.

[0097] In some embodiments, the bispecific antibody comprises a first antigen-binding domain targeting TL1A and at least one second antigen-binding domain targeting other targets, wherein the first antigen-binding domain comprises the aforementioned anti-TL1A antibody or its antigen-binding fragment. In some embodiments, each antigen-binding domain of the bispecific antibody retains its original binding specificity.

[0098] On one hand, the present invention provides a polynucleotide encoding the anti-TL1A antibody of the present invention or its antigen-binding fragment, conjugate, or bispecific antibody. The polynucleotide of the present invention may be, for example, DNA or RNA, and may or may not contain intron sequences. In a preferred embodiment, the polynucleotide is a cDNA molecule. The polynucleotide of the present invention can be prepared or obtained by known methods based on information of the amino acid sequence of the present invention, for example by automated DNA synthesis and / or recombinant DNA technology.

[0099] As is well known in the art, multiple codons can encode the same amino acid. Therefore, nucleic acids encoding protein sequences include those with codon degeneracy. The amino acid sequences described in this invention can be encoded by a variety of nucleic acids. The genetic code is universal and well-known. Nucleic acids encoding any of the amino acid sequences described in this invention can be readily conceived based on common knowledge in the art and can be optimized for production. Although the number of possible nucleic acid sequences encoding a given amino acid is large, given a standard table of the genetic code and with the aid of a calculator, those skilled in the art can readily generate every possible combination of nucleic acid sequences encoding a given amino acid.

[0100] On one hand, the present invention provides a vector comprising the polynucleotides of the present invention. The vector is capable of delivering and preferably expressing constructs of one or more target genes or sequences in host cells. The vector includes eukaryotic expression vectors, prokaryotic expression vectors, viral vectors such as bacterial plasmids, bacteriophages, yeast plasmids, plant cell viruses, mammalian cell viruses such as adenoviruses, retroviruses, or other vectors.

[0101] On one hand, the present invention provides a host cell comprising the polynucleotide or vector of the present invention. The host cell is capable of producing or secreting the complete antibody of the present invention or its antigen-binding fragment, conjugate, or bispecific antibody. The host cell comprises prokaryotic cells, fungal cells, or mammalian cells, such as CHO cells, NSO cells, or other mammalian cells, *Escherichia coli* or other prokaryotic cells, yeast cells, or other fungal cells. In some embodiments, a particular eukaryotic host cell is selected based on its ability to perform desired post-translational modifications to the heavy chain and / or light chain.

[0102] On one hand, the present invention provides a pharmaceutical composition comprising the anti-TL1A antibody of the present invention or its antigen-binding fragment, conjugate, bispecific antibody, polynucleotide, expression vector or host cell, and at least one pharmaceutically acceptable vector.

[0103] In some preferred embodiments, the pharmaceutical composition contains a therapeutically effective amount of the anti-TL1A antibody of the present invention or its antigen-binding fragment, conjugate, bispecific antibody or nucleic acid molecule, and one or more pharmaceutically acceptable carriers, diluents, buffers or excipients.

[0104] In some embodiments, the pharmaceutical composition may contain any number of excipients. Excipients that may be used include carriers, surfactants, thickeners or emulsifiers, solid binders, dispersants or suspending agents, solubilizers, colorants, flavoring agents, coating agents, disintegrants, lubricants, sweeteners, preservatives, isotonic agents, or combinations thereof. The selection and use of appropriate excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th edition (Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference.

[0105] In some embodiments, the pharmaceutical composition further comprises one or more other therapeutic agents.

[0106] On one hand, the present invention provides a kit comprising the anti-TL1A antibody of the present invention or its antigen-binding fragment, conjugate, bispecific antibody or pharmaceutical composition.

[0107] On one hand, the present invention provides a method for preventing and / or treating TL1A-mediated diseases or conditions in subjects, comprising administering to subjects in need a therapeutically or preventively effective amount of the anti-TL1A antibody of the present invention or its antigen-binding fragment, conjugate, bispecific antibody, polynucleotide, expression vector, host cell, or pharmaceutical composition.

[0108] On the one hand, the present invention provides the use of the aforementioned anti-TL1A antibody or its antigen-binding fragment, conjugate, bispecific antibody, polynucleotide, expression vector, host cell or pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of TL1A-mediated diseases or conditions in subjects.

[0109] In some embodiments, the TL1A-mediated disease or condition is a disease or condition caused by TL1A overexpression. In some embodiments, the TL1A-mediated disease or condition is a disease or condition mediated by TL1A binding to DR3. In some preferred embodiments, the TL1A-mediated disease or condition is selected from TL1A-induced autoimmune diseases or conditions, inflammatory diseases or conditions, fibrosis, and gastrointestinal abnormalities.

[0110] In some specific implementations, the TL1A-mediated diseases or conditions are selected from inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, asthma, allergies, diabetes, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, transplant rejection, graft-versus-host disease (GVHD), spondyloarthritis, primary sclerosing cholangitis, primary biliary cirrhosis, atherosclerosis, bladder syndrome / interstitial cystitis, urinary and bowel dysfunction, sepsis, uveitis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus, cutaneous lupus erythematosus, autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's syndrome, scleroderma, and vasculitis.

[0111] On one hand, the present invention provides the use of the aforementioned anti-TL1A antibody or its antigen-binding fragment, or conjugate, in the detection of TL1A or the preparation of reagents for detecting TL1A. The detection of TL1A can be performed in vivo or in vitro and can be for non-disease diagnostic purposes. The TL1A is preferably human TL1A or its homomer, such as homotrimer.

[0112] On the one hand, the present invention provides the use of the aforementioned anti-TL1A antibody or its antigen-binding fragment, or conjugate, in the preparation of reagents for monitoring treatment response.

[0113] The present invention also provides a method for preparing the anti-TL1A antibody or its antigen-binding fragment of the present invention.

[0114] The anti-TL1A antibody or its antigen-binding fragment described in this invention can be obtained using conventional techniques, such as the Cold Spring Harbor Laboratory Antibody Techniques Guide, Chapters 5-8 and 15. For example, mice can be immunized with human TL1A or its fragments, and the resulting antibody can be renatured, purified, and sequenced using conventional methods. The antigen-binding fragment can also be prepared using conventional methods. The antibody or antigen-binding fragment described in this invention uses genetic engineering methods to add one or more human FR regions to a non-human CDR region. Human FR germline sequences can be obtained from the ImMunoGeneTics (IMGT) website by comparing with the IMGT Human Antibody Variable Region Germplasm Database and MOE software, or from the Journal of Immunoglobulins, 2001 ISBN012441351. Alternatively, for example, cDNA sequences encoding the heavy and light chains can be cloned into an expression vector. The recombinant immunoglobulin expression vector can be stably transfected into CHO cells. Stable clones are obtained by expressing antibodies that specifically bind to human TL1A. Positive clones are scaled up in serum-free medium in a bioreactor to produce antibodies.

[0115] The anti-TL1A antibody or its antigen-binding fragment of the present invention can be expressed intracellularly, on the cell membrane, or secreted extracellularly. If desired, the recombinant protein can be isolated and purified using various separation methods based on its physical, chemical, and other properties. These methods are well known to those skilled in the art. Typically, host cells transformed with the present invention are cultured under conditions suitable for antibody expression, and then purified using conventional immunoglobulin purification steps, such as protein A-Sepharose affinity chromatography, ion exchange chromatography, hydrophobic chromatography, molecular sieve chromatography, hydroxyapatite chromatography, gel electrophoresis, dialysis, and other conventional separation and purification methods, or combinations thereof, to obtain the anti-TL1A antibody or its antigen-binding fragment of the present invention. The antibody can be concentrated by filtration using conventional methods.

[0116] As a preferred embodiment of the preparation method of the anti-TL1A antibody or its antigen-binding fragment according to the present invention, the method for separating and purifying the anti-TL1A antibody or its antigen-binding fragment is protein A affinity chromatography, cation exchange, or anion exchange.

[0117] The resulting monoclonal or bispecific antibodies can be identified using conventional methods. For example, the binding specificity of an antibody can be determined by immunoprecipitation or in vitro binding assays, such as enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA). The binding affinity of an antibody can be determined, for example, by Scatchard analysis as described by Munson et al., Anal. Biochem., 107:220 (1980), or by surface plasmon resonance (SPR).

[0118] For clarity, this article defines the general terminology used in the description of compounds.

[0119] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0120] The terms “tumor necrosis factor-like cytokine 1A,” “TL1A,” and “TNFSF15” are used interchangeably to refer to any TL1A molecule and its functional homologs (whether monomeric or polymeric), including dimers, trimers, etc., known to those skilled in the art. Unless otherwise stated, TL1A includes, but is not limited to, those derived from humans, rodents, mice, rats, primates, monkeys, and guinea pigs. The term also refers to fragments or variants of native TL1A that retain at least one in vivo or in vitro activity of native TL1A, such as DR3 binding activity and receptor-inducing regulatory activity. The term includes both the full-length, unprocessed precursor form of TL1A and the mature form resulting from post-translational cleavage of the signal peptide. As used herein, TL1A also refers to a specific polypeptide expressed in cells via naturally occurring DNA sequence variations in the TL1A gene, such as single nucleotide polymorphisms of the TL1A gene. Examples include the amino acid sequence corresponding to human TL1A registered with GenBank accession number NP_005109. Other examples of TL1A amino acid sequences are available from, for example, GenBank, UniProt, and OMIM.

[0121] TL1A can be in isomeric form. A isomeric polymer may contain two, three, four, five, six, or more TL1A monomer units. In some aspects, the isomeric polymer may be a isodimer or an isotrimer. In some aspects, three TL1A monomers are present in the isomeric polymer, and the TL1A isomeric polymer is an isotrimer. In some aspects, two TL1A monomers are present in the TL1A isomeric polymer, and the isomeric polymer is an isodimer.

[0122] The term "antibody" refers to an immunoglobulin molecule that has the ability to specifically bind to a particular antigen. As used herein, the term "antibody" includes complete antibodies and any antigen-binding fragment (i.e., the "antigen-binding part") or its single chain. A complete antibody is a glycoprotein consisting of two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated as VH) and a heavy chain constant region (abbreviated as CH). The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated as VL) and a light chain constant region (abbreviated as CL). The light chain constant region consists of one domain: CL. The VH and VL regions can be further subdivided into hypervariable regions (called complementarity-determining regions (CDRs)) separated by more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations at glycosylation sites. Antibodies also include post-translational modified antibodies, fusion proteins containing antigenic determinants of the antibody, and immunoglobulin molecules containing any other modifications to antigen recognition sites, provided that these antibodies exhibit the desired biological activity.

[0123] The heavy chain of an immunoglobulin molecule can be divided into three functional regions: the Fd region, the hinge region, and the Fc region (crystallizable fragment). The Fd region contains the VH and CH1 domains and binds to the light chain to form the Fab (antigen-binding fragment). The Fc region contains the CH2 and CH3 domains, which are responsible for immunoglobulin effector functions, including, for example, complement binding and binding to homologous Fc receptors on effector cells. The hinge region, found in the IgG, IgA, and IgD immunoglobulin classes, acts as a flexible spacer, allowing the Fab portion to move freely in space relative to the Fc region. The hinge domain is structurally diverse, differing in sequence and length between immunoglobulin classes and subclasses.

[0124] The determination or definition of a CDR can be accomplished by resolving the structure of the antibody and / or the structure of the antibody-ligand complex, thereby enabling the definitive depiction of the CDR and the identification of residues containing the antibody binding site. This can be achieved using any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. Various analytical methods (including combinations of methods) can be used to identify CDRs, including but not limited to Kabat definition, Chothia definition, AbM definition, IMGT definition, Contact definition, and conformational definition. All of these techniques are well-known in the art; see, for example, Kabat, E.A. et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, et al. (1989), Nature 342:877; Chothia, C. et al. (1987), J. Mol. Biol. 196:901-917; Allazikani et al. (1997), J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). The boundaries of a given CDR can vary depending on the method used for identification. Therefore, unless otherwise stated, the term "CDR" for a given antibody or its regions (such as variable regions), and individual CDRs (e.g., HCDR1, HCDR2) for an antibody or its regions, should be understood to encompass complementarity-determining regions as defined above by any known method described herein. In some cases, schemes for identifying a particular CDR or multiple CDRs (such as CDRs defined by the IMGT, Kabat, Chothia, or Contact methods) are described. CDRs can also be identified using software programs, including but not limited to AbRSA (http: / / cao.labshare.cn / AbRSA / cdrs.php), abYsis (www.abysis.org / abysis / sequence_input / key_annotation / key_annotation.cgi), and IMGT (http: / / www.imgt.org / 3Dstructure-DB / cgi / DomainGapAlign.cgi#results). In other cases, the specific amino acid sequence of the CDR is given. It should be noted that CDR areas can also be defined by combinations of various numbering systems (e.g., combinations of Kabat and Chothia or Kabat and IMGT).Therefore, once a variable region (e.g., VH or VL) is given, those skilled in the art will understand that the CDRs within that region can be defined by different numbering systems or combinations thereof.

[0125] The positions of amino acid residues included in an exemplary defined CDR are listed in the table below: Note 1: Definitions vary slightly across different literature, especially the Chothia definition scheme; Note 2: Except for the Contact definition which uses the Chothia or Martin numbering scheme, other definition schemes are compatible with various numbering schemes; Note 3: When using Kabat numbering, the end of Chothia HCDR1 varies between H32 and H34 depending on the loop length (this is because the Kabat numbering scheme places the insertion at H35A and H35B). Note: Amino acid numbers on the heavy chain are represented by "H + number", and amino acid numbers on the light chain are represented by "L + number"; for example, L24-L34 in the second row and second column of the table refers to the amino acid sequence determined from residue 24 to 34 according to the Kabat coding scheme, starting from the N-terminus of the variable region of the antibody light chain; the rest follow the same pattern.

[0126] The term “antigen-binding fragment” (or simply “antibody fraction”) refers to one or more fragments of an antibody that specifically bind to an antigen (e.g., TL1A). Antigen-binding functionality of antibodies has been demonstrated to be achieved through fragments of full-length antibodies. Examples of binding fragments covered by the term “antigen-binding fragment” of an antibody include: (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments containing two Fab fragments linked by disulfide bonds in a hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains in a single arm of an antibody; (v) dAb fragments consisting of a VH domain (Ward et al., (1989) Nature 341: 544-546); (vi) separated complementarity-determining regions (CDRs); and (vii) nanobodies, heavy-chain variable regions containing a single variable domain and two constant domains. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked together via adapters using recombination methods, thus forming a single protein chain in which the VL and VH regions pair to form a monovalent molecule (called a single-chain Fv (scFv); see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also included within the scope of the term "antigen-binding fragment" in the term antibody. These antibody fragments can be obtained using conventional techniques known to those skilled in the art, and the fragment screening for use is performed in the same manner as for intact antibodies.

[0127] As used herein, the term "monoclonal antibody" refers to a formulation of an antibody molecule having a single molecular composition. Monoclonal antibody compositions exhibit single binding specificity and affinity for a specific epitope.

[0128] The term "mouse antibody" refers to a monoclonal antibody against human TL1A prepared in accordance with the knowledge and skills of the art. Preparation involves injecting a test subject (rat or mouse) with the TL1A antigen, followed by isolating a hybridoma expressing an antibody with the desired sequence or functional characteristics. The aforementioned mouse anti-TL1A antibody or its antigen-binding fragment may further include a light chain constant region of a mouse κ, λ chain, or a variant thereof, or further include a heavy chain constant region of mouse IgG1, IgG2, IgG3, or a variant thereof.

[0129] The term "chimeric antibody" refers to an antibody formed by fusing the variable region of a heterologous (e.g., murine) antibody with the constant region of a parental antibody (e.g., human antibody). Chimeric antibodies can mitigate the immune response induced by heterologous antibodies. For example, to create a human-mouse chimeric antibody, a hybridoma that secretes murine-specific monoclonal antibodies must first be established. Then, the variable region gene is cloned from the murine hybridoma cells. Next, the constant region gene of the human antibody is cloned as needed. The murine variable region gene and the human constant region gene are then linked to form a chimeric gene, which is inserted into an expression vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic system.

[0130] The term "humanized antibody," also known as a CDR-grafted antibody, refers to an antibody generated by grafting a mouse CDR sequence into a human antibody variable region framework, i.e., a human germline antibody framework sequence of different types. This can overcome the heterologous response induced by chimeric antibodies carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases that include germline antibody gene sequences or from publicly available references. For example, germline DNA sequences of human heavy chain and light chain variable region genes can be obtained from the VBase human germline sequence database and from Kabat, E.A. et al., 1991, Sequences of Proteins of Immunological Interest, 5th edition. To avoid a decrease in activity along with a decrease in immunogenicity, minimal reverse or reversion mutations can be performed on the aforementioned human antibody variable region framework sequences to maintain activity.

[0131] The terms "fully human antibody" and "fully human antibody" are used interchangeably, generally referring to antibodies whose entire composition (including the variable and constant regions) is encoded by genes of human origin. Fully human antibodies can significantly reduce the immune side effects caused by heterologous antibody components. Methods for obtaining fully human antibodies in this field include phage display technology, transgenic mouse technology, and ribosome display technology.

[0132] The term "bispecific" refers to the ability of an antibody and / or antigen-binding molecule to specifically bind to two different antigenic determinants. Typically, a bispecific antibody or antigen-binding molecule contains two antigen-binding sites, each specific to a different antigenic determinant.

[0133] The term "variants" of the heavy chain constant region and light chain constant region refers to human-derived heavy chain constant regions or light chain constant regions that do not alter the structure and function of the antibody variable region, as disclosed in the prior art. Exemplary variants include IgG1, IgG2, IgG3, or IgG4 heavy chain constant region variants that involve site-specific modifications and amino acid substitutions in the heavy chain constant region. Specific substitutions include known prior art mutations such as YTE mutation, L234A and / or L235A mutation, S228P mutation, mutations that yield a knock-in-hole structure (resulting in a knock-Fc and hole-Fc combination in the antibody heavy chain), and L234A / L235A / P329G (LALA-PG) mutation. These mutations have been shown to impart novel properties to the antibody without altering the function of the antibody variable region.

[0134] The amino acid sequences of the constant region, κ chain, and λ chain of wild-type human IgG are summarized in the table below:

[0135] The term "mutation" in amino acid terminology encompasses the substitution (replacement, substitution), deletion, insertion, and modification of amino acids. Any combination of substitution, deletion, insertion, and modification can be performed to obtain the final construct, provided that the final construct possesses the desired characteristics. Amino acid mutations can be generated using any genetic engineering or chemical method well known in the art, such as site-directed mutagenesis, PCR, gene synthesis, chemical modification altering amino acid side chain groups, etc.

[0136] As used herein, the terms “substitution,” “replacement,” or “alternation” for amino acids are used interchangeably and refer to the substitution of an amino acid residue by another amino acid residue. Preferably, the term “substitution” refers to the substitution of an amino acid residue by another amino acid residue selected from the standard 20 naturally occurring amino acid residues, rare naturally occurring amino acid residues (e.g., hydroxyproline, hydroxylysine, allohydroxylysine, 6-N-methyllysine, N-ethylglycine, N-methylglycine, N-ethylasparagine, alloleucine, N-methylisoleucine, N-methylvaline, pyroglutamine, GABA, ornithine, ortholeucine, orthovaline), and non-naturally occurring amino acid residues that are typically synthesized (e.g., cyclohexylalanine). Preferably, the term “alternation” refers to the substitution of an amino acid residue by another amino acid residue selected from the standard 20 naturally occurring amino acid residues (G, P, A, V, L, I, M, C, F, Y, W, H, K, R, Q, N, E, D, S, and T). In this document, amino acid substitutions are referred to as follows: for example, replacing proline at position 329 of the Fc region with glycine is represented as P329G. Substitutions can be conservative or non-conservative. Conservative substitutions refer to the mutual substitution of amino acids belonging to the same class or having similar characteristics (e.g., charge, side chain size, hydrophobicity, hydrophilicity, main chain conformation, and rigidity). Examples of conservative substitutions include basic amino acids (arginine, lysine, and histidine), acidic amino acids (glutamic acid and aspartic acid), polar amino acids (glutamine, asparagine, and threonine), hydrophobic amino acids (methionine, leucine, isoleucine, cysteine, and valine), aromatic amino acids (phenylalanine, tryptophan, and tyrosine), and small amino acids (glycine, alanine, and serine).

[0137] The term "conjugate" refers to the linkage between an antibody or its antigen-binding fragment and an effector molecule such as a chemotherapeutic agent, toxin, immunotherapeutic agent, bioactive protein, or imaging probe. The linkage can be covalent or non-covalent, such as through electrostatic forces. Linkage can be achieved chemically or through recombination. Various linkers known in the art can be used to form conjugates.

[0138] In one embodiment, the linker is chemical, wherein a reaction between the antibody or its antigen-binding fragment and the effector molecule produces a covalent bond formed between the two molecules to form a single molecule. Peptides typically contain multiple functional groups; such as carboxylic acid (COOH), free amine (-NH2), or thiol (-SH) groups, which can be used to react with suitable functional groups on the antibody to result in the binding of the chemical moiety. In the case where both the antibody and the effector molecule are peptides, the linker can be attached via their side groups to the constituent amino acids (e.g., via disulfide bonds to cysteine) or to the α-carbon amino and carboxyl groups of the terminal amino acid.

[0139] In one implementation, the linking is recombinant, and the conjugate can be provided as a fusion protein, possibly from the expression of a polynucleotide encoding the conjugate. As used herein, a "fusion protein" refers to a protein produced by linking two or more genes or gene segments that originally encode separate proteins (including peptides and polypeptides). Translation of the fusion gene produces a single protein having functional properties derived from each of the original proteins.

[0140] The term "affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise stated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y is typically expressed by the dissociation constant (KD). Affinity can be measured using conventional methods known in the art, including those described herein.

[0141] The term "isotype" refers to an antibody class (e.g., IgM or IgG1) encoded by a gene in the heavy chain constant region.

[0142] As used herein, the terms “comprising,” “including,” and “having” are used interchangeably to indicate the inclusiveness of a scheme, meaning that the scheme may contain elements other than those listed. It should also be understood that the use of “comprising,” “including,” and “having” in this document also provides for schemes “consisting of…”.

[0143] The terms “about” and “approximately” mean within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of a given value or range.

[0144] As used herein, the terms “substantially non-binding” or “non-binding” mean that the antibody or binder of this disclosure does not exhibit detectable binding to a given target, for example, reactivity with the given target not exceeding 30%, not exceeding 20%, not exceeding 10%, or not exceeding 9%, 8%, 7%, 6%, 5%, or 3%.

[0145] The term "antibody" in this article includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), monovalent antibodies, multivalent antibodies, intact antibodies, antigen-binding fragments, naked antibodies, conjugated antibodies, humanized antibodies, or fully human antibodies.

[0146] The term "conservative amino acid" in this document generally refers to amino acids that belong to the same class or have similar characteristics (e.g., charge, side chain size, hydrophobicity, hydrophilicity, main chain conformation, and rigidity). For example, the amino acids in each of the following groups belong to each other's conserved amino acid residues, and substitutions of amino acid residues within a group constitute substitutions of conserved amino acids:

[0147] 1) Alanine (A), Serine (S), Threonine (T);

[0148] 2) Aspartic acid (D), glutamic acid (E);

[0149] 3) Asparagine (N), glutamine (Q);

[0150] 4) Arginine (R), Lysine (K), Histidine (H);

[0151] 5) Isoleucine (I), leucine (L), methionine (M), valine (V); and

[0152] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

[0153] The terms "identity," "sequence consistency," and "homology" used herein are interchangeable and are calculated as follows: To determine the percentage of "identity" between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., vacancies may be introduced in one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, or non-homologous sequences may be discarded for comparison purposes). The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. The molecules are identical at that position when a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence.

[0154] The term "epitope" refers to a region or site of an antigen that specifically binds to an antibody, such as a region or site containing contact residues that interact with the antibody. Therefore, the term "epitope" refers to a portion of a molecule that can be recognized and bound by an antibody at one or more antibody-antigen binding regions. Typically, an epitope is defined in the context of molecular interactions between an antibody or its antigen-binding fragment and its corresponding antigen. Epitopes are typically composed of surface groups of molecules such as amino acids or sugar side chains and have specific three-dimensional structural features and specific charge features. In some embodiments, an epitope may be a protein epitope. Protein epitopes can be linear or conformational. In a linear epitope, all interaction sites between the protein and the interacting molecule (such as an antibody) are linear along the primary amino acid sequence of the protein. A "non-linear epitope" or "conformational epitope" is a non-neighboring polypeptide (or amino acid) contained within an antigen protein to which an antibody specific to that epitope binds. As used herein, the term "antigen epitope" is defined as a portion of an antigen that can specifically bind to an antibody, as determined by any method known in the art (e.g., by conventional immunoassay). Alternatively, antibody generation and characterization during the discovery process may reveal information about the desired epitope. Based on this information, antibodies that bind to the same epitope can then be competitively screened. This can be achieved by conducting competitive and cross-competitive studies to find antibodies that compete or cross-competitively bind to TL1A, such as antibodies that compete to bind to the antigen.

[0155] When the term "competition" is used in cases where antigen-binding proteins (e.g., neutralizing antigen-binding proteins or neutralizing antibodies) compete for the same epitope, it refers to competition between antigen-binding proteins, which is determined by an assay in which the antigen-binding protein to be detected (e.g., an antibody or an immunologically functional fragment thereof) prevents or inhibits (e.g., reduces) the specific binding of a reference antigen-binding protein (e.g., a ligand or a reference antibody) to a common antigen (e.g., a TL1A antigen or a fragment thereof). Numerous types of competitive binding assays can be used to determine whether one antigen-binding protein competes with another. These assays include: solid-phase direct or indirect radioimmunoassay (RIA), solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, for example, Stahli et al., 1983, Methods in Enzymology 9: 242-253); solid-phase direct biotin-avidin EIA (see, for example, Kirkland et al., 1986, J. Immunol. 137: 3614-3619), solid-phase direct labeling assay, and solid-phase direct labeling sandwich assay (see, for example, Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor). Press); solid-phase direct labeling of RIA with I-125 label (see, for example, Morel et al., 1988, Molec. Immunol. 25: 7-15); solid-phase direct biotin-avidin EIA (see, for example, Cheung et al., 1990, Virology 176: 546-552); and directly labeled RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32: 77-82). The assay typically involves using a solid surface or cell to bind purified antigen loaded with either an unlabeled detection antigen-binding protein or a labeled reference antigen-binding protein. Competitive inhibition is measured by measuring the amount of label bound to the solid surface or cell in the presence of the detection antigen-binding protein. Typically, the detection antigen-binding protein is present in excess. Antigen-binding proteins identified by competitive assays (competitive antigen-binding proteins) include: antigen-binding proteins that bind to the same epitope as a reference antigen-binding protein; and antigen-binding proteins that bind to a neighboring epitope sufficiently close to the binding epitope of the reference antigen-binding protein, wherein the two epitopes spatially prevent each other from binding. Typically, when a competing antigen-binding protein is present in excess, it will inhibit (e.g., reduce) at least 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, or 75% or more of the specific binding of the reference antigen-binding protein to the common antigen. In some cases, binding is inhibited by at least 80-85%, 85-90%, 90-95%, 95-97%, or 97% or more.

[0156] The term "antagonist" refers to the inhibition of receptor signaling to suppress a biological response associated with receptor activation. Antagonistic antibodies are used in the broadest sense to include antibodies that partially or completely block, inhibit, or neutralize the biological activity of an epitope, peptide, or cell to which they specifically bind. Methods for identifying antagonistic antibodies may include contacting a peptide or cell to which a candidate antagonistic antibody specifically binds with the candidate antagonistic antibody and measuring detectable changes in one or more biological activities typically associated with the peptide or cell.

[0157] The term "IC" 50 "IC" refers to the half-maximal inhibitory concentration, which measures the efficacy of a substance (e.g., an antibody) in inhibiting a specific biological or biochemical reaction. 50 The smaller the value, the stronger the indicator effect.

[0158] The term "EC" 50 "EC" refers to the half-maximal effective concentration, which measures the efficacy of a substance (e.g., an antibody) in inducing a specific biological or biochemical reaction. 50 The smaller the value, the stronger the indicator effect.

[0159] The terms “ka” and “kon” are used interchangeably in this document and refer to the binding rate constant of a specific antibody-antigen interaction. The terms “kd” and “koff” are used interchangeably in this document and refer to the dissociation rate constant of a specific antibody-antigen interaction. As used herein, the term “KD” refers to the equilibrium dissociation constant, which is calculated from the ratio of kd to ka (i.e., kd / ka) and expressed as a molar concentration (M).

[0160] The term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, for example, non-human primates, rodents, rabbits, pigs, dogs, cats, chickens, amphibians, and reptiles, although mammals such as non-human primates and rodents are preferred.

[0161] The term "therapeutic effective amount" refers to the amount of the anti-TL1A antibody or its antigen-binding fragment of the present invention sufficient to prevent or improve symptoms associated with a disease or condition (e.g., IBD) and / or reduce the severity of the disease or condition. Therapeutic effective amount should be understood in the context of the condition being treated, where the actual effective amount can be readily identified by those skilled in the art.

[0162] The heavy chain variable region and light chain variable region (CDR) of the antibodies of the present invention can be determined according to the definitions of Kabat, Chothia, IMGT, AbM, Contact, or combinations thereof. Table A below provides the amino acid sequences of the heavy chain / light chain CDRs of exemplary anti-TL1A antibodies of the present invention identified using abYsis. Antibodies having the same heavy chain and light chain CDR1, CDR2, and CDR3 regions as the anti-TL1A antibodies of the present invention are also within the scope of the present invention.

[0163] Table A

[0164] The table below provides the full-length amino acid sequences of the heavy / light chains of an exemplary anti-TL1A antibody of the present invention.

[0165] Other features and advantages of the present invention will become apparent from the following detailed description and examples, and should not be construed as limiting. All references, Genbank entries, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. Attached Figure Description

[0166] Figure 1 shows the purity identification results of SDS-PAGE electrophoresis. In Figures 1A to 1C, lane M represents the marker; in Figure 1A, lane 4 corresponds to TL01, lane 6 corresponds to TL02, lane 9 corresponds to TL03, lane 10 corresponds to TL04, and lane 11 corresponds to TL05; in Figure 1B, lane 2 corresponds to TL06; in Figure 1C, lane 1 corresponds to TL07, lane 3 corresponds to TL08, lane 8 corresponds to TL09, and lane 11 corresponds to TL10.

[0167] Figure 2 shows the ELSIA binding curve of the recombinant antibody to human TL1A trimer.

[0168] Figure 3 shows the ELISA binding curves of the recombinant antibody and the human TL1A monomer.

[0169] Figures 4A and 4B show the blocking effect of the recombinant antibody on the TL1A-induced TF-1 / NF-κB reporter gene pathway.

[0170] Figure 5 shows the inhibitory effect of recombinant antibody on TL1A-induced release of PBMC cytokines.

[0171] Figure 6 shows the ELISA curves of humanized antibodies binding to human TL1A monomers. The x-axis represents the logarithm (log10) of the humanized antibody concentration. The figure also includes the EC50 values ​​of each humanized antibody binding to human TL1A monomers from Table 4. 50 <0.1nM.

[0172] Figure 7 shows the binding of the humanized antibody to membrane-expressed human TL1A.

[0173] Figure 8 shows the weight changes in Example 8.

[0174] Figure 9 shows the changes in DAI scores in Example 8.

[0175] Figures 10-12 show the changes in colon weight, colon length, and density in Example 8.

[0176] Figures 13-14 show the histopathological scores and H&E staining results of colon tissue in Example 8.

[0177] The positive control antibody 1D1 1.31 in the examples was independently cloned and prepared according to the antibody 1D1 1.31 described in patent CN105814081B; PRA023 was independently cloned and prepared according to the Tulisokibart sequence disclosed in WHO Drug Information, Volume 36, Number 2, 2022, Proposed INN: List 127. Specific Implementation

[0178] Example 1: Preparation of mouse anti-human TL1A monoclonal antibody

[0179] 1.1 Animal immunization and positive clone screening

[0180] Several Balb / c and SJL mice were selected for animal immunization. Human TL1A monomer or trimer protein (purchased from Acrobiosystems) was injected subcutaneously or intraperitoneally into mice for multiple immunizations. Serum was collected from mice several days before and after the third immunization to determine serum titers. Mice with high serum titers responsive to TL1A were selected. Spleen and bone marrow were removed to prepare cell suspensions. SP2 / 0 myeloma cells and plasma cells from immunized mice were electrofused to prepare hybridomas, or plasma cells from immunized mice were selected using Beacon screening.

[0181] Hybridoma screening for positive clones: ELISA was used to screen for positive clones that bind to human, cynomolgus monkey, and / or mouse TL1A but not TNFα. These positive clones were then subcloned using limiting dilution to obtain stable, single-cell hybridoma cells. Further validation of the subclones was achieved through ELISA and binding inhibition assays. Selected positive subclones were subjected to Sanger sequencing to obtain variable region sequences.

[0182] Beacon screening for positive clones: Spleen and bone marrow from mice with high antibody titers after immunization were ground, filtered, and used to prepare cell suspensions. EasySep was then used for this purpose. TM The Mouse CD138 Positive Selection Kit was used to separate CD138 from cell suspension according to the instructions. + B cells; then, plasma B cells capable of secreting antigen-specific antibodies were screened using a Beacon instrument and exported to PCR plates for storage and gene sequencing.

[0183] 1.2 Recombinant antibody expression and purification

[0184] The cloned sequences obtained from sequencing were used to construct plasmids for recombinant antibody expression. Following the sequence combinations shown in Table 1, the antibody VH region coding gene fragment was inserted into a heavy chain plasmid carrying an hIgG1 constant region coding gene fragment (hIgG1 constant region as shown in SEQ ID NO. 21), and the antibody VL region coding gene fragment was inserted into a light chain plasmid carrying a human Kappa chain coding gene fragment (human Kappa chain as shown in SEQ ID NO. 22). ExpiCHO-S cells were cultured, and the constructed heavy and light chain plasmids, along with transfection reagents, were added and thoroughly mixed. Transfection and culture were then performed. After 6-7 days, the cell supernatant was collected, and the antibody was purified using protein A technology. Purity was identified by SDS-PAGE, and ELISA, FACS, and SPR assays were performed.

[0185] Table 1 Note: The underlined amino acid residues represent the CDR region defined by Kabat as identified by abYsis.

[0186] Table 2

[0187] Figure 1 shows the SDS-PAGE results identifying the purity of the recombinant antibody. The binding of the purified antibody to TL1A was detected by ELISA, specifically as follows: The following human, cynomolgus monkey, and mouse TL1A antigens were diluted to 0.5 μg / mL with coating buffer: hTL1A trimer (Acrobiosystems, TLA-H5243), CynoTL1A (Acrobiosystems, TLA-C5241), mTL1A (Acrobiosystems, TLA-M5243), and the antigen hTL1A monomer (Acrobio... The recombinant antibody (TLA-H5246) was diluted to 0.05 μg / mL, and 100 μL / well was added to the designed strips. The strips were incubated overnight at 4°C. The coating solution was discarded, the plate was washed and dried, and 150 μL of blocking buffer was added to each well. The plate was incubated at 37°C for 1 hour. The blocking buffer was discarded, and the recombinant antibody was serially diluted, with 100 μL / well added to each well (initial concentration 10 nM). The plate was incubated at 37°C for 1 hour. The plate was removed, the internal solution was discarded, the plate was washed, and 100 μL of diluted enzyme-labeled secondary antibody (anti-Goat) was added to each well. Anti-Human IgG (H+L) (min X Bov, Hrs, Ms Sr Prot) Jackson ImmunoResearch, 109-035-088) was incubated at 37℃. The plate was removed, the inner liquid discarded, the plate washed and dried, and 100 μL of chromogenic solution was added. The reaction was carried out at 25℃ for 15 min. 50 μL of 1M HCl was added to terminate the reaction. The OD450nm reading was taken using a microplate reader, and the data were analyzed using GraphPad Prism 6 software. The binding of the recombinant antibody to human TL1A monomers or trimers is shown in Figures 2-3. It can be seen that the antibody of this invention can effectively bind to both the active trimer and inactive monomeric forms of TL1A, that is, it specifically binds to both soluble and membrane-bound TL1A, thereby achieving more stable target binding. In addition, ELISA experiments with CynoTL1A showed that TL01, TL04, TL10, and their humanized antibodies can all react with monkey TL1A.

[0188] Example 2: Cell-level activity verification

[0189] 2.1 TL1A-induced TF-1 / NF-κB reporter pathway

[0190] The inhibitory effect of recombinant antibody on the TL1A-induced TF-1-NF-κB reporter gene pathway was evaluated by co-incubating TF-1-NF-κB target cells with a certain concentration of TL1A and serially diluted antibody for 6 hours, followed by detection using a firefly luciferase system. TF-1-NF-κB cells are a luciferase reporter gene cell line. When TL1A binds to its receptor, it activates downstream signaling pathways, thereby activating luciferase expression. The luciferase reading represents the activation effect of the signaling pathway and can therefore be used to evaluate the activation effect of TL1A.

[0191] TF-1 / NF-κB cells (GenescriptProbio, SC1993) were collected by centrifugation, resuspended in buffer (RPMI 1640 + 10% FBS), and plated to a cell density of 2 × 10⁶ cells per well. 4 Cells were used to prepare TL1A trimer (Acrobiosystems, TLA-H5243) working solution and serially diluted antibody working solution. The final concentration of TL1A working solution was 80 ng / mL, and the initial concentration of antibody working solution was 100 nM, serially diluted 5-fold. 50 μL of TL1A working solution and 50 μL of serially diluted antibody working solution were added to the wells of the experimental plate and pre-incubated at room temperature for 30 minutes. The incubated mixture was then transferred to the wells of the experimental plate containing cells and incubated at 37°C and 5% CO2 for 6 hours. After incubation, the 96-well experimental plate was removed, and Bio-Lite luciferase detection system working solution was added to the wells. The chemiluminescence values ​​were read using a microplate reader, and the data were analyzed using GraphPad Prism 6 software. The results are shown in Figures 4A and 4B. The recombinant antibody of this invention can block the TL1A-induced TF-1 / NF-κB reporter gene pathway.

[0192] 2.2 TL1A-induced release of PBMC cytokines

[0193] Peripheral blood mononuclear cells (PBMCs) were co-incubated for 3 days with specific concentrations of IL-12, IL-18, TL1A, and serially diluted antibodies. The IFN-γ release level in the supernatant of the co-culture system was then measured to assess the inhibitory effect of recombinant antibody on TL1A-induced PBMC cytokine release. PBMCs were resuscitated in complete medium (RPMI 1640 + 10% FBS) and cultured overnight. The next day, working solutions of IL-18, IL-12, TL1A (Acrobiosystems, TLA-H5243), and serially diluted antibody were prepared using buffer (RPMI 1640 + 10% FBS). PBMCs were collected by centrifugation, resuspended in buffer, and plated to a cell density of 2 × 10⁶ cells per well. 5Cells were collected, and then 0.5 ng / mL IL-18, 0.5 ng / mL IL-12, 40 ng / mL TL1A working solution, and serially diluted antibody (50 μL each) were added to the corresponding wells of the experimental plate. The plate was incubated at 37°C and 5% CO2 for 72 h. After incubation, the 96-well plate was removed, the supernatant was collected by centrifugation, and IFN-γ in the supernatant was detected using an HTRF assay kit. The data were analyzed using GraphPad Prism 6 software. The results are shown in Figure 5. The recombinant antibody of this invention can reduce the level of IFN-γ and has a certain inhibitory effect on inflammation.

[0194] Example 3: In vitro blocking assessment of receptor DcR3

[0195] The effect of purified antibody on blocking the binding of TL1A to decoy receptor 3 (DcR3) was detected by ELISA. Human DcR3 protein was diluted to 0.5 μg / mL using coating buffer, and 100 μL / well was added to a pre-designed 96-well plate. The plate was sealed and incubated. The coating buffer was discarded, the plate was washed and dried, and 150 μL of blocking buffer was added to each well. The plate was sealed and incubated, and then the blocking buffer was discarded. Antibody was serially diluted 3-fold and added to each 96-well plate (200 nM for the first well), along with 50 μL of TL1A (4 ng / mL) and 50 μL of sample dilution buffer. The enzyme-labeled secondary antibody was diluted to 50.0 ng / mL using blocking buffer, and 100 μL / well was added to a 96-well plate. The plate was sealed and incubated. The solution was discarded, the plate was washed and dried, and 100 μL of TMB substrate was added to each well. The plate was incubated at 25 °C. Finally, 50 μL of stop solution was added to each well to terminate the reaction. The OD450 nm reading was taken using a microplate reader, and the data were analyzed using GraphPad Prism 6 software.

[0196] Example 4: Preparation of humanized antibodies

[0197] The following humanized sequences of mouse antibodies were designed and prepared: (1) The amino acid sequences of various heavy chain variable regions (VH) and light chain variable regions (VL) obtained after humanization of TL01 are shown in Table 3.1; (2) The amino acid sequences of various heavy chain variable regions (VH) and light chain variable regions (VL) obtained after humanization of TL04 are shown in Table 3.2; (3) The amino acid sequences of various heavy chain variable regions (VH) and light chain variable regions (VL) obtained after humanization of TL10 are shown in Table 3.3.

[0198] Table 3.1 VH and VL sequences after humanization of TL01 Note: The underlined amino acid residues represent the CDR region defined by Kabat as identified by abYsis.

[0199] Table 3.2 VH and VL sequences after humanization of TL04 Note: The underlined amino acid residues represent the CDR region defined by Kabat as identified by abYsis.

[0200] Table 3.3 VH and VL sequences after humanization of TL10 Note: The underlined amino acid residues represent the CDR region defined by Kabat as identified by abYsis.

[0201] IgG1 antibodies were prepared according to the VH and VL combinations of each humanized antibody in Table 4. The constant regions required for each humanized antibody were derived from human IgG1 and Kappa chains. The complete sequences of each antibody were obtained by directly splicing the constant region sequences with the VH and VL sequences shown in Table 4. The DNA coding sequences of the variable regions in Table 4 were synthesized. The VH DNA was inserted into a mammalian cell expression vector containing the heavy chain constant region coding gene shown in SEQ ID NO. 21, and the VL DNA was inserted into a mammalian cell expression vector containing the light chain constant region coding gene shown in SEQ ID NO. 22, respectively, to construct heavy chain expression plasmids and light chain expression plasmids for the antibodies. The heavy chain expression plasmids and light chain expression plasmids of each antibody were co-transfected into mammalian cells capable of expressing the aforementioned vectors. After culturing for several days, the cell supernatant was collected for purification and antibody harvesting.

[0202] Table 4. Humanized Antibody Sequence Information

[0203] Example 5: In vitro evaluation of humanized antibodies

[0204] 5.1 Assessment of protein and cellular binding capacity

[0205] The reactivity between each humanized antibody in Table 4 and the hTL1A monomer (Acrobiosystems, TLA-H5246) was evaluated according to the ELISA method described in Example 1.2. The results showed that each humanized antibody was also able to bind to the inactive monomeric form of TL1A with high affinity (Figure 6).

[0206] The binding of some of the humanized antibodies listed in Table 4 to human TL1A expressed on the cell membrane was tested using FACS experiments. The specific procedures were as follows: The humanized antibodies were serially diluted and added to HEK293 cells (HEK293-hTL1A) overexpressing human TL1A protein, and incubated at 4°C for 1 h. After centrifugation and discarding the intracellular fluid, 100 μL of diluted fluorescently labeled secondary antibody (FITC anti-human IgG Fc Antibody, Biolegend) was added to each cell culture well and incubated at 4°C for 1 h. After centrifugation and discarding the intracellular fluid, the FITC signal intensity was detected by flow cytometry, and the data were analyzed using GraphPad Prism 6 software. The results are shown in Figure 7, demonstrating that the antibodies of this invention can bind to membrane-expressed human TL1A with a superior affinity to PRA023.

[0207] 5.2 In vitro assessment of inflammation suppression

[0208] The effects of the partially humanized antibodies in Table 4 on TL1A-induced PBMC cytokine release were evaluated according to the method described in Example 2.2. The results are shown in Table 5. The antibodies of the present invention have better anti-inflammatory effects than PRA023.

[0209] Table 5 IFN-γ inhibition

[0210] Example 6 Antibody Modification

[0211] Further modifications to the Fc region of the antibody are made to remove antibody effector functions and / or prolong the antibody half-life. Specifically, the heavy chain constant region of the aforementioned antibodies of this invention is replaced with any of the heavy chain constant region sequences listed in Table 6 to obtain a series of modified antibodies. Antibodies obtained by mutating the Fc region of humanized antibodies with LALAPA and YTE are named with the suffix "F". For example, antibodies obtained by mutating hTL04-01, hTL04-05, hTL04-06, hTL04-07, and hTL04-08 with LALAPA and YTE are named hTL04-01F, hTL04-05F, hTL04-06F, hTL04-07F, and hTL04-08F, respectively. Table 7 lists, for example, the full-length heavy and light chain sequences of some Fc mutant antibodies of hTL04-08 and hTL01-05.

[0212] Table 6. Amino acid sequence of the heavy chain constant region of the antibody.

[0213] Table 7. Full-length heavy and light chain sequences of the antibody.

[0214] The inflammatory suppression activities of PRA023, 1D1 1.31 and some of the antibodies of the present invention were further compared according to the method described in Example 2.2. The results are shown in Table B. It can be seen that the antibody of the present invention has a better inflammatory suppression effect.

[0215] Table B IFN-γ inhibition

[0216] Example 7: SPR Affinity Determination

[0217] 7.1 Determination of SPR affinity of antibody for human TL1A

[0218] The binding affinity of some antibodies to TL1A was detected using a Biacore 1K (Cytiva) instrument. A Protein A sensor chip was used, with PBST (pH=6.0) buffer as the mobile phase. The buffer composition was as follows: 2 mM KH₂PO₄, 10 mM Na₂HPO₄, 137 mM NaCl, 2.7 mM KCl, and 0.05% Tween-20. Each antibody was prepared as a ligand using HBS-EP+ buffer, and captured by the Protein A protein on the chip channel. Human TL-1A antigen protein (ACRO, TLA-H5243) was used as the analyte. The antibody was serially diluted 2-fold with PBST (pH=6.0) buffer to eight concentration points. The analyte at each concentration was flowed through the experimental and reference channels at a flow rate of 30 μL / min, with a binding time of 120 s and a dissociation time of 1500 s. The regeneration buffer PBS (pH = 7.4) was run at a flow rate of 30 μl / min for 30 s. Data processing was performed using Biacore 1K Evaluation software. The signal value of the detection channel (Fc 2) was subtracted from the corresponding reference channel (Fc 1) signal value to obtain the corrected signal curve. The affinity kinetics curve was fitted according to a 1:1 binding model, and the binding rate Ka, dissociation rate Kd, and dissociation constant (i.e., affinity KD value) were calculated. The results are shown in Tables 8.1-8.4 below.

[0219] Table 8.1

[0220] Table 8.2

[0221] Table 8.3

[0222] Table 8.4

[0223] 7.2 Determination of SPR affinity of modified antibody for FcRn

[0224] The binding affinity of the modified antibody to human FcRn was detected using a Biacore 1K (Cytiva) instrument. The CM5 sensor chip was used, and the mobile phase consisted of PBST (pH 6.0) buffer with the following composition: 2 mM KH₂PO₄, 10 mM Na₂HPO₄, 137 mM NaCl, 2.7 mM KCl, and 0.05% Tween-20. The CM5 chip was conjugated with recombinant human FcRn protein (ACRO, FCM-H5286). The antibody was serially diluted 2-fold from 500 nM to 6 concentrations using PBST (pH 6.0). The antibody at each concentration was flowed through the experimental and reference channels at a flow rate of 30 μL / min, with a binding time of 60 s and a dissociation time of 60 s. The regeneration buffer PBS (pH 7.4) was run at a flow rate of 30 μL / min for 30 s. Data were processed using Biacore 1K Evaluation software. The signal value of the detection channel (Fc2) was subtracted from the corresponding reference channel (Fc1) signal value to obtain the corrected signal curve. The affinity kinetics curve was fitted using a 1:1 binding model, and the binding rate Ka, dissociation rate Kd, and dissociation constant (i.e., affinity KD value) were calculated. The results showed that the antibody with the YTE mutation had a stronger affinity for human FcRn protein than wild-type hIgG1 (Table 8.5).

[0225] Table 8.5

[0226] Example 8: In vivo efficacy experiment

[0227] The efficacy of the antibody in a trinitrobenzenesulfonic acid (TNBS)-induced mouse enteritis model was evaluated. Several TL1A humanized mice (B-hTL1A mice, purchased from Biocytogen) were prepared and randomly divided into groups. All mice underwent modeling after fasting on Day 0: the Sham group (n=5) received 100 μL of 50% ethanol rectally, while the other model groups (n=10) received 100 μL of 1.5% TNBS solution rectally (1.5% TNBS: 50% ethanol: 48.5% ddH2O). On Day-1 and Day 2, the antibody was administered intravenously according to the grouping information in Table 9. On Day 5, the mice were euthanized, and serum and colon samples were collected.

[0228] Table 9 Animal grouping and administration regimen Note: Sham mice and model control mice were intravenously injected with equal volumes of the solvent Duchenne phosphate-buffered saline (DPBS) to intervene.

[0229] Animal weight was recorded daily and DAI scores were calculated. The DAI scoring criteria are shown in Table 10. The pathological scoring criteria for H&E staining of mouse colon tissue are shown in Table 11. All experimental data were plotted using GraphPad Prism 10.1.2 and expressed as mean ± standard error (Mean ± SEM). Mouse weight and disease activity index scores were analyzed using two-way ANOVA, while data on colon length, weight, density, and other parameters were analyzed using one-way ANOVA. Dunnett's test was used for intergroup comparisons. Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0230] Table 10

[0231] Table 11

[0232] As shown in Figures 8 and 9, compared with the Sham group, the model control group showed a significant decrease in body weight and a significant increase in DAI score after modeling. Compared with the model control group, mice treated with hTL04-08F or PRA023 showed effective relief of body weight loss from Day 3 to the experimental endpoint, and the differences were statistically significant.

[0233] In a TNBS-induced acute colitis model in mice, inflammation leads to shortening of the colon and an increase in colon weight and density (weight-to-length ratio). As shown in Figures 10-12, compared to the model control group, mice treated with hTL04-08F or PRA023 showed significantly reduced colon density, significantly increased colon length, and significantly reduced colon weight.

[0234] Colon tissues from each group of animals were used for H&E staining and analysis. After modeling, the colon tissues of the control group mice showed pathological features such as crypt distortion, inflammatory cell infiltration, mild fibrosis of the muscle layer, and crypt abscesses, with significantly higher histopathological scores than those of the Sham group mice. As shown in Figures 13-14, compared with the control group, mice treated with hTL04-08F or PRA023 showed significant improvement in colonic crypt damage, inflammatory cell infiltration, muscle layer sclerosis, and crypt abscesses, with statistically significant differences.

[0235] Overall, hTL04-08F was more effective than PAR023 in alleviating weight loss and DAI score, reducing colonic shortening and weight gain, and improving colonic pathology in a mouse enteritis model.

[0236] Although the invention has been described through one or more embodiments, it should be understood that the invention is not limited to these embodiments, and the specification is intended to cover all alternatives, modifications, and variations falling within the spirit and broad scope of the appended claims. All references cited in this invention are incorporated herein by reference in their entirety.

Claims

1. An anti-TL1A antibody or its antigen-binding fragment, characterized in that, The anti-TL1A antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 regions, and the VL comprises LCDR1, LCDR2, and LCDR3 regions, wherein... The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.1, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.1, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.2, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.2; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.3, or sequences that have undergone at most 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.3, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.4, or sequences that have undergone at most 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.4; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 5, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 5, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 6, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 6; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.7, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.7, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.8, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.8; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 9, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 9, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 10, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 10; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 11, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 11, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 12, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 12; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 13, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 13, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 14, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 14; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 15, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 15, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 16, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 16; The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO. 17, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO. 17, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO. 18, or sequences with up to 5, 4, 3, 2, or 1 mutation compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO. 18; or The HCDR1-3 regions sequentially have sequences identical to those of HCDR1-3 in VH as shown in SEQ ID NO.19, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in HCDR1-3 in VH as shown in SEQ ID NO.19, and the LCDR1-3 regions sequentially have sequences identical to those of LCDR1-3 in VL as shown in SEQ ID NO.20, or sequences with up to 5, 4, 3, 2, or 1 mutations compared to each CDR in LCDR1-3 in VL as shown in SEQ ID NO.20; The mutation is selected from insertions, deletions and / or substitutions that do not affect function, and the substitution is preferably a substitution of a conserved amino acid.

2. The antibody or its antigen-binding fragment according to claim 1, characterized in that, The HCDR1, HCDR2, and HCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.1, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as LCDR1, LCDR2, and LCDR3 of VL as shown in SEQ ID NO.2; the HCDR1, HCDR2, and HCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.7, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as LCDR1, LCDR2, and LCDR3 of VL as shown in SEQ ID NO.8; the HCDR1, HCDR2, and HCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.19, and the LCDR1, LCDR2, and LCDR3 regions have the same sequence as HCDR1, HCDR2, and HCDR3 of VH as shown in SEQ ID NO.1 ... The VL shown in NO. 20 has LCDR1, LCDR2, and LCDR3 having the same sequences as those of the VH shown in any of SEQ ID NO. 23-25, and the LCDR1, LCDR2, and LCDR3 having the same sequences as those of the VL shown in any of SEQ ID NO. 26-28; the HCDR1, HCDR2, and HCDR3 having the same sequences as those of the VH shown in any of SEQ ID NO. 29-31, and the LCDR1, LCDR2, and LCDR3 having the same sequences as those of the VL shown in any of SEQ ID NO. 32-34; or, the HCDR1, HCDR2, and HCDR3 having the same sequences as those of the VH shown in any of SEQ ID NO.

20. The VH shown in any of NO.35-38 has the same HCDR1, HCDR2 and HCDR3 sequences as the LCDR1, LCDR2 and LCDR3 regions, which in turn have the same sequences as the VL shown in any of SEQ ID NO.39-40.

3. The antibody or antigen-binding fragment thereof according to any one of claims 1-2, characterized in that, The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 23-25, 29-31, 35-38, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 26-28, 32-34, 39-40, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of the sequences shown in SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 26-28, 32-34, 39-40. Preferably, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 23-25, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 26-28; Preferably, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 29-31, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 32-34; Preferably, the VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 35-38, and / or the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence shown in any of SEQ ID NO. 39-40.

4. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, characterized in that, The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 1, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 2; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 3, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 4; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 5, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 6; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 7, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 8; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 9, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 10; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 11, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 12; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 13, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 14; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 15, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 16; The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 17, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO. 18; or, The VH has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 19, and the VL has an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to that of SEQ ID NO. 20; Preferably, VH and VL are selected from the group consisting of: (1) The VH contains or is the sequence shown in SEQ ID NO.1 and the VL contains or is the sequence shown in SEQ ID NO.2; (2) The VH contains or is the sequence shown in SEQ ID NO.3 and the VL contains or is the sequence shown in SEQ ID NO.4; (3) The VH contains or is the sequence shown in SEQ ID NO.5 and the VL contains or is the sequence shown in SEQ ID NO.6; (4) The VH contains or is the sequence shown in SEQ ID NO.7 and the VL contains or is the sequence shown in SEQ ID NO.8; (5) The VH contains or is the sequence shown in SEQ ID NO. 9 and the VL contains or is the sequence shown in SEQ ID NO. 10; (6) The VH contains or is the sequence shown in SEQ ID NO.11 and the VL contains or is the sequence shown in SEQ ID NO.12; (7) The VH contains or is the sequence shown in SEQ ID NO.13 and the VL contains or is the sequence shown in SEQ ID NO.14; (8) The VH contains or is the sequence shown in SEQ ID NO.15 and the VL contains or is the sequence shown in SEQ ID NO.16; (9) The VH comprises or is the sequence shown in SEQ ID NO. 17 and the VL comprises or is the sequence shown in SEQ ID NO. 18; or (10) The VH may contain or be the sequence shown in SEQ ID NO.19 and the VL may contain or be the sequence shown in SEQ ID NO.20; Preferably, the VH comprises the amino acid sequence of SEQ ID NO. 23, and the VL comprises any amino acid sequence selected from SEQ ID NO. 26-28; the VH comprises the amino acid sequence of SEQ ID NO. 24, and the VL comprises any amino acid sequence selected from SEQ ID NO. 26-28; the VH comprises the amino acid sequence of SEQ ID NO. 25, and the VL comprises any amino acid sequence selected from SEQ ID NO. 26-28; the VH comprises the amino acid sequence of SEQ ID NO. 29, and the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34; the VH comprises the amino acid sequence of SEQ ID NO. 30, and the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34; the VH comprises the amino acid sequence of SEQ ID NO. 31, and the VL comprises any amino acid sequence selected from SEQ ID NO. 32-34; the VH comprises the amino acid sequence of SEQ ID NO. 3 ...4, and the VL comprises any amino acid sequence selected from SEQ ID NO. 26-28; the VH comprises the amino acid sequence of SEQ ID NO. 29 The amino acid sequence of SEQ ID NO. 39 or 40; the VH contains the amino acid sequence of SEQ ID NO. 36, and the VL contains the amino acid sequence of SEQ ID NO. 39 or 40; the VH contains the amino acid sequence of SEQ ID NO. 37, and the VL contains the amino acid sequence of SEQ ID NO. 39 or 40; the VH contains the amino acid sequence of SEQ ID NO. 38, and the VL contains the amino acid sequence of SEQ ID NO. 39 or 40.

5. The antibody or antigen-binding fragment thereof according to any one of claims 1-4, further comprising a heavy chain constant region and a light chain constant region; Preferably, the antibody or its antigen-binding fragment comprises a constant region variant of human IgG1, which has reduced CDC and / or ADCC and / or ADCP activity compared to the wild-type sequence from which it is derived; More preferably, the antibody or its antigen-binding fragment comprises a constant region variant of human IgG1, which has one or more of the following amino acid substitutions compared to the wild-type sequence from which it is derived: L234A, L235A, P329A (according to the position in the EU numbering system); Most preferably, the heavy chain constant region and the light chain constant region contain sequences as shown in Table 2, or amino acid sequences that are at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequences shown in Table 2.

6. An anti-TLl A antibody or antigen-binding fragment thereof, characterized in that, The antibody or its antigen-binding fragment binds to the same TL1A epitope or competitively binds to TL1A with the anti-TL1A antibody or its antigen-binding fragment as described in any one of claims 1-5.

7. The antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein, The antibody or its antigen-binding fragment has at least one of the following functions: (1) When binding to TL1A, the antibody or its antigen-binding fragment has a KD of not more than 10 nM, not more than 5 nM, not more than 1 nM, not more than 0.5 nM, not more than 0.4 nM, not more than 0.3 nM, not more than 0.2 nM, not more than 0.1 nM, not more than 0.09 nM, not more than 0.08 nM, not more than 0.07 nM, not more than 0.06 nM, not more than 0.05 nM, not more than 0.04 nM, not more than 0.03 nM, not more than 0.02 nM, or not more than 0.01 nM; (2) When bound to TL1A, the KD of the antibody or its antigen-binding fragment is substantially the same as or better than that of the reference TL1A antibody; (3) The antibody or its antigen-binding fragment bound to a homopolymer of TL1A; (4) The antibody or its antigen-binding fragment inhibits or blocks the binding of TL1A to receptor DR3; (5) When the binding of TL1A to receptor DR3 is inhibited or blocked, the inhibitory or blocking effect of the antibody or its antigen-binding fragment is basically the same as or better than that of the reference TL1A antibody. (6) The antibody or its antigen-binding fragment binds to TL1A from different species; (7) The antibody or its antigen-binding fragment is used as an antagonistic antibody against TL1A; (8) The antibody or its antigen-binding fragment weakens TL1A activity or weakens TL1A-mediated signal transduction; (9) The antibody or its antigen-binding fragment reduces the level of inflammation.

8. A conjugate or bispecific antibody, characterized in that, It comprises the anti-TL1A antibody or its antigen-binding fragment as described in any one of claims 1-7.

9. A polynucleotide encoding an anti-TL1A antibody or antigen-binding fragment thereof as described in any one of claims 1-7, or a conjugate or bispecific antibody as described in claim 8.

10. A vector comprising the polynucleotide of claim 9.

11. A host cell comprising the polynucleotide of claim 9 or the vector of claim 10.

12. A pharmaceutical composition comprising an anti-TL1A antibody or an antigen-binding fragment thereof as described in any one of claims 1-7, a conjugate or bispecific antibody as described in claim 8, a polynucleotide as described in claim 9, a vector as described in claim 10 or a host cell as described in claim 11, and at least one pharmaceutically acceptable vector.

13. A kit comprising the anti-TL1A antibody or antigen-binding fragment thereof as described in any one of claims 1-7, the conjugate or bispecific antibody as described in claim 8, the polynucleotide as described in claim 9, the vector as described in claim 10, the host cell as described in claim 11, or the pharmaceutical composition as described in claim 12.

14. Use of the anti-TLl A antibody or antigen binding fragment thereof of any one of claims 1-7, the conjugate or bispecific antibody of claim 8, the polynucleotide of claim 9, the vector of claim 10, the host cell of claim 11, the pharmaceutical composition of claim 12, or the kit of claim 13 in the manufacture of a medicament for preventing and / or treating a disease or disorder mediated by TLl A in a subject.

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