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

Abstract

Provided are an anti-TL1A antibody or an antigen-binding fragment thereof and use thereof. The anti-TL1A antibody or the antigen-binding fragment thereof comprises: HCDR1: X1YX2MH; HCDR2: X3X4NPYX5X6X7TX8YX9X10KFKG; HCDR3: XI1X12X13X14X15X16X17X18X19Y; LCDR1: X20ASX21X22VX23X24X25X26X27; LCDR2: X28X29X30X31X32X33X34; and LCDR3: QQX35SSX36PX37T.

Description

Anti-tl1a antibodies or antigen-binding fragments thereof and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of biopharmaceuticals, and specifically relates to anti-TL1A antibodies or antigen-binding fragments thereof and uses thereof, more particularly to anti-TL1A antibodies or antigen-binding fragments thereof, nucleic acid molecules, expression vectors, recombinant cells, conjugates, reagents or kits, pharmaceutical compositions and their uses, methods for detecting TL1A. BACKGROUND

[0002] The tumor necrosis factor (TNF) and TNF-receptor (TNFR) superfamily, i.e. TNFSF and TNFRSF, plays a key role in the establishment and function of the immune system. TL1A is a TNF-like cytokine, which is a type II membrane protein encoded by the TNFSF15 gene. TL1A can exist in a membrane-bound form and a soluble form, both of which have biological activity and play an immune regulatory function. TL1A and its functional receptor death receptor 3 (DR3, also known as TNFRSF25) are the most homologous molecules to TNFR1 among the TNFRSF members. The TL1A / DR3 cytokine system is a key factor in mucosal immunity and intestinal homeostasis. Preclinical studies have found that TL1A plays a key and multi-faceted role in the immune response during inflammation, which reveals the potential of targeting TL1A to treat inflammatory bowel disease (IBD).

[0003] In a steady-state environment or various inflammatory environments, the interaction of TL1A with its functional receptor DR3 deeply affects the intestinal mucosal immunity; many genetic studies have shown that there are genetic polymorphisms of TL1A and DcR3 (TNFRSF6B, decoy receptor 3), which can be either protective factors or risk factors; after TL1A binds to DR3, TRADD signal is activated, which activates NFκB signaling pathway through TRAF2, causing a series of pro-inflammatory factor expression; on the other hand, intracellular FADD activates Caspase-3 / 7 apoptosis signaling pathway, and initiates apoptosis. As can be seen, by blocking the TL1A signaling pathway, the inflammatory response can be reduced to achieve a therapeutic effect.

[0004] The most advanced antibody currently under development, PF-06480605, is an anti-TL1A monoclonal antibody that blocks the TL1A signaling pathway and has demonstrated good safety and tolerability in clinical trials. It showed significant efficacy in a 12-week treatment of ulcerative colitis (UC). Another blocking anti-TL1A monoclonal antibody, PRA023, successfully achieved the primary endpoint of clinical remission at week 12 in a clinical trial for moderate to severe ulcerative colitis. These studies support the view that TL1A is a potential target for the treatment of IBD. Therefore, developing a novel anti-TL1A antibody or its antigen-binding fragment is crucial. Summary of the Invention

[0005] This application aims to at least partially address one of the technical problems existing in the prior art. To this end, this application provides an anti-TL1A antibody or an antigen-binding fragment thereof.

[0006] In a first aspect of this application, an anti-TL1A antibody or an antigen-binding fragment thereof is proposed. According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3; wherein HCDR1, HCDR2, HCDR3 are amino acid sequences identical to HCDR1, HCDR2, HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41; wherein LCDR1, LCDR2, LCDR3 are amino acid sequences identical to HCDR1, HCDR2, HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:2, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:41; and LCDR1, LCDR2, LCDR3 are amino acid sequences identical to HCDR1, HCDR2, HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:2, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:41. The light chain variable region defined by any one of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, and SEQ ID NO:42 contains an amino acid sequence identical to LCDR1, LCDR2, and LCDR3 of the variable region. The anti-TL1A antibody or its antigen-binding fragment of this application has TL1A binding affinity, particularly specific binding to TL1A, and can be used for the detection of TL1A; it can also block the activity of TL1A-activated transcription factor NFκB, and has an inhibitory effect on IFN-γ, and can be used for the prevention and / or treatment of TL1A-mediated diseases.

[0007] In a second aspect, this application provides an anti-TL1A antibody or its antigen-binding fragment. According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment includes HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3; HCDR1: X1YX2MH or X1YX2MN, wherein X1 is S, G, R, or V, and X2 is I or T; HCDR2: X3X4NPYX5X6X7TX8YX9X 10 KFKG, where X3 is Y or L, X4 is V or I, X5 is N or S, X6 is D or G, X7 is V or G, X8 is N, T or K, X9 is I or N, X 10 For E or Q; HCDR3:X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 Y, where X 11 For Y, V, or H, X 12 For Y, Q, or R, X 13 For Y or L, X 14 For G or R, X 15 For N, Y, H, A, R, E, M or P, X 16 For P, D, V, L or S, X 17 For G or W, X 18 For F, L, M or Y, X 19 For A or D; LCDR1: X 20 ASX 21 X 22 VX 23 X 24 X 25 X 26 X 27 , where X 20 For K or S, X 21 For Q or S, X 22 For D or S, X 23 For G, T, or S, X 24 For T, Y, or A, X 25 For M or A, X 26 For V or H, X 27 For A or empty; LCDR2: X 28 X 29 X 30 X 31 X 32 X 33 X 34 , where X 28For W or D, X 29 For T or A, X 30 For S or A, X 31 For T or K, X 32 For R or L, X 33 For H or A, X 34 For T or S; LCDR3: QQX 35 SSX 36 PX 37 T, where X 35 For Y, W, or H, X 36 For Y, D, or S, X 37 The value is Y or W. The anti-TL1A antibody or its antigen-binding fragment of this application has TL1A binding affinity, especially specific binding to TL1A, and can be used to detect TL1A; it can also block the activity of TL1A-activated transcription factor NFκB, and has an inhibitory effect on IFN-γ, and can be used to prevent and / or treat TL1A-mediated diseases.

[0008] In a third aspect of this application, a nucleic acid molecule is provided. According to embodiments of this application, the nucleic acid molecule encodes the anti-TL1A antibody or its antigen-binding fragment described in the first or second aspect.

[0009] In a fourth aspect, this application provides an expression vector. According to an embodiment of this application, the expression vector carries the nucleic acid molecule described in the third aspect.

[0010] In a fifth aspect of this application, a recombinant cell is provided. According to embodiments of this application, the recombinant cell comprises carrying the nucleic acid molecule described in the third aspect or the expression vector described in the fourth aspect; or expressing the anti-TL1A antibody or its antigen-binding fragment described in the first or second aspect.

[0011] In a sixth aspect, this application provides a conjugate. According to embodiments of this application, the conjugate comprises the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect; and a conjugation portion linked to the anti-TL1A antibody or its antigen-binding fragment. The conjugate of this application has TL1A binding affinity and can be used for the detection of TL1A, or for the prevention and / or treatment of TL1A-mediated diseases.

[0012] In a seventh aspect of this application, a reagent or kit is provided. According to embodiments of this application, the reagent or kit comprises the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect, the nucleic acid molecule as described in the third aspect, the expression vector as described in the fourth aspect, the recombinant cells as described in the fifth aspect, or the conjugate as described in the sixth aspect. The kit of this application has TL1A binding affinity and can effectively detect TL1A.

[0013] In an eighth aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect, the nucleic acid molecule as described in the third aspect, the expression vector as described in the fourth aspect, the recombinant cell as described in the fifth aspect, or the conjugate as described in the sixth aspect. The pharmaceutical composition of this application has TL1A binding affinity and can effectively prevent and / or treat TL1A-mediated diseases.

[0014] In a ninth aspect of this application, this application provides an anti-TL1A antibody or antigen-binding fragment thereof as described in the first or second aspect, a nucleic acid molecule as described in the third aspect, an expression vector as described in the fourth aspect, a recombinant cell as described in the fifth aspect, a conjugate as described in the sixth aspect, or a pharmaceutical composition as described in the seventh aspect, for the prevention and / or treatment of TL1A-mediated diseases or for the detection of TL1A, or for the following uses:

[0015] Use in the preparation of multispecific antibodies, fusion proteins, pharmaceuticals or kits, or in the use of pharmaceuticals for the prevention and / or treatment of TL1A-mediated diseases, or in the use of kits for the detection of TL1A;

[0016] Prevention and / or treatment of TL1A-mediated diseases;

[0017] Detect TL1A.

[0018] In a tenth aspect of this application, a method for detecting TL1A is proposed. According to an embodiment of this application, the method includes: contacting a sample to be tested with an anti-TL1A antibody or its antigen-binding fragment described in the first or second aspect, a conjugate described in the sixth aspect, or a reagent or kit described in the seventh aspect to form an immune complex. As is known from the foregoing, the aforementioned anti-TL1A antibody or its antigen-binding fragment, conjugate, reagent, or kit all possess TL1A binding affinity. Therefore, using the aforementioned anti-TL1A antibody or its antigen-binding fragment, conjugate, reagent, or kit can effectively detect TL1A, especially for in vitro detection (e.g., detection for non-disease diagnosis and treatment purposes), offering advantages such as high detection accuracy.

[0019] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0020] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0021] Figure 1 shows the ability of different anti-TL1A antibodies in Example 4 of this application to block the human TL1A-activated NFκB signaling pathway.

[0022] Figure 2 shows the ability of antibody HC503H6M in Example 10 of this application to block the human TL1A-activated NFκB signaling pathway.

[0023] Figure 3 shows the solubility results of antibody HC503H6M in Example 12 of this application;

[0024] Figure 4 shows the ability of each antibody in Example 13 of this application to block the coordinated stimulation of human PBMCs by TL1A and IL12 / 18 to produce IFN-γ. Detailed Implementation

[0025] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0026] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0027] This application details

[0028] Definitions and General Terms

[0029] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0030] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0031] In this paper, the term "fragment" refers to a target protein or polypeptide, and a target protein or polypeptide that has been truncated at an N-terminus (N-terminus) or C-terminus (C-terminus) and / or internally deleted.

[0032] To facilitate understanding of this application, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this application pertains. Abbreviations for amino acid residues are the standard 3-letter and / or 1-letter codes used in the art to refer to one of the 20 commonly used L-amino acids.

[0033] The antibody or antigen-binding fragments described in this application are typically prepared using biosynthetic methods. Based on the nucleotide sequence described in this application, those skilled in the art can readily prepare the encoded nucleic acid using various known methods. These methods include, but are not limited to, PCR, artificial DNA synthesis, etc., and specific methods can be found in J. Sambrook, *Molecular Cloning: A Laboratory Manual*. As one embodiment of this application, the encoded nucleic acid sequence can be constructed by segmenting and synthesizing the nucleotide sequence followed by overlap extension PCR. The antibody or antigen fragments are numbered and defined using the Kabat numbering system.

[0034] In this document, the term "conservatively modified amino acid sequence" refers to an amino acid modification that does not significantly affect or alter the binding properties of an antibody containing that amino acid sequence. Such modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies of this application using standard techniques such as site-directed mutagenesis and PCR-mediated mutagenesis. A conserved amino acid substitution is the replacement of an amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been identified in the art. These families include amino acids with basic side chains (such as lysine, arginine, and histidine), amino acids with acidic side chains (such as aspartic acid and glutamic acid), amino acids with uncharged polar side chains (such as glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan), amino acids with nonpolar side chains (such as alanine, valine, leucine, isoleucine, proline, phenylalanine, and methionine), amino acids with β-branched side chains (such as threonine, valine, and isoleucine), and amino acids with aromatic side chains (such as tyrosine, phenylalanine, tryptophan, and histidine).

[0035] In this paper, the terms “identity,” “homology,” or “similarity” are used to describe the percentage of identical amino acids or nucleotides between two amino acid sequences or nucleic acid sequences relative to a reference sequence, determined by conventional methods, for example, see Ausubel et al., eds. (1995), Current Protocols in Molecular Biology, Chapter 19 (Greene Publishing and Wiley-Interscience, New York); and the ALIGN procedure (Dayhoff (1978), Atlas of Protein Sequence and Structure 5: Suppl. 3 (National Biomedical Research Institute)). Foundation, Washington, DC). There are many algorithms for aligning sequences and determining sequence identity, including: Needleman et al. (1970) J. Mol. Biol. 48: 443, a homology alignment algorithm; Smith et al. (1981) Adv. Appl. Math. 2: 482, a local homology algorithm; Pearson et al. (1988) Proc. Natl. Acad. Sci. 85: 2444, a similarity search method; and the Smith-Waterman algorithm (Meth. Mol. Biol). .70:173-187 (1997); and the BLASTP, BLASTN, and BLASTX algorithms (see Altschul et al. (1990) J.Mol.Biol. 215:403-410). Computer programs utilizing these algorithms are also available, including but not limited to: ALIGN or Megalign (DNASTAR) software, or WU-BLAST-2 (Altschul et al., Meth.Enzym., 266:460-480 (1996)); or GAP, BESTFIT, BLAST Altschul et al., above, FASTA, and TFASTA, available in Genetics Computing Group (GCG) package, version 8, Madison, Wisconsin, USA; and CLUSTAL in the PC / Gene program provided by Intelligenetics, Mountain View, California.

[0036] In this document, the term "at least 80% identity" refers to an identity of at least 80% with each reference sequence, which may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

[0037] In this paper, the term "at least 90% identity" means at least 90% identity with each reference sequence, which may be 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

[0038] In this paper, the term "fusion protein" refers to a novel protein formed by the fusion of at least two proteins or peptides. This fusion is typically achieved through techniques such as genetic engineering, for example, the expression product of two recombinant genes obtained through DNA recombination technology. In this paper, it refers to the fusion of an anti-TL1A antibody or its antigen-binding fragment with a bioactive protein or its fragment.

[0039] In this document, the term "expression vector" generally refers to a nucleic acid molecule capable of self-replication within a suitable host, containing a nucleotide sequence that expresses a target protein, and capable of being transferred to host cells and / or between host cells. The expression vector may include vectors primarily for inserting DNA or RNA into cells, vectors primarily for replicating DNA or RNA, and expression vectors primarily for transcription and / or translation of DNA or RNA. The expression vector also includes vectors having multiple of the aforementioned functions. The expression vector may be a polynucleotide capable of being transcribed and translated into a polypeptide when introduced into a suitable host cell. Typically, by culturing suitable host cells containing the expression vector, the expression vector can produce the desired expression product.

[0040] In this document, the term "recombinant cell" generally refers to a cell in which the genetic material of a recipient cell (or host cell) is modified or recombined using genetic engineering or cell fusion techniques to obtain a unique trait with stable inheritance. The term "host cell" refers to a prokaryotic or eukaryotic cell into which a recombinant expression vector can be introduced. The terms "transformed" or "transfected" as used herein refer to the introduction of nucleic acids (e.g., expression vectors) into cells using various techniques known in the art. Suitable host cells can be transformed or transfected with the DNA sequence of this application and can be used for the expression and / or secretion of target proteins. Examples of suitable host cells that can be used in this application include immortalized hybridoma cells, NS / 0 myeloma cells, 293 cells, Chinese hamster ovary (CHO) cells, HeLa cells, Cap cells (cells derived from human amniotic fluid), and CoS cells.

[0041] In this document, the term "pharmaceutical composition" generally refers to a unit dose form and can be prepared by any method well known in the pharmaceutical industry. All methods involve the step of combining the active ingredient with a carrier constituting one or more adjunct components. Typically, compositions are prepared by uniformly and adequately combining an active antibody or antigen-binding fragment with a liquid carrier, a finely fragmented solid carrier, or both.

[0042] In this document, the term "pharmaceuticalally acceptable excipient" may include any solvent, solid excipient, diluent, or other liquid excipient, etc., suitable for a specific target dosage form. The use of any conventional excipients is also within the scope of consideration for this application, except for any range of incompatibility between the excipient and the antibody or antigen-binding fragment of this application, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition.

[0043] In this document, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner. The antibodies or antigen-binding fragments, multispecific antibodies, or pharmaceutical compositions of this application may be administered via any common route, as long as it can reach the intended tissue. Various routes of administration are foreseeable, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but this application is not limited to these exemplified routes of administration. Preferably, the compositions of this application are administered via intravenous or subcutaneous injection.

[0044] In this document, the term "treatment" refers to the use of a drug or antibody or antigen-binding fragment to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of disease or its symptoms, and / or therapeutic in terms of partial or complete cure of disease and / or adverse effects caused by disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of disease in individuals susceptible to disease but not yet diagnosed with the disease; (b) suppression of disease, such as inhibiting disease progression; or (c) alleviating disease, such as reducing disease-related symptoms. As used herein, "treatment" encompasses any medication that administers a drug or antibody or antigen-binding fragment to an individual to treat, cure, alleviate, improve, reduce, or suppress the individual's disease, including but not limited to administering a drug containing the antibody or antigen-binding fragment described herein to an individual in need.

[0045] This application provides a detailed description of the anti-TL1A antibody or its antigen-binding fragment and its uses.

[0046] This application discloses an anti-TL1A antibody or its antigen-binding fragment, nucleic acid molecule, expression vector, recombinant cell, conjugate, reagent or kit, pharmaceutical composition, and their uses, as well as methods for detecting TL1A, which will be described in detail below.

[0047] Anti-TL1A antibody or its antigen-binding fragment

[0048] In a first aspect of this application, an anti-TL1A antibody or an antigen-binding fragment thereof is proposed. According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3; wherein HCDR1, HCDR2, HCDR3 are amino acid sequences identical to HCDR1, HCDR2, HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41; wherein LCDR1, LCDR2, LCDR3 are amino acid sequences identical to HCDR1, HCDR2, HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:2, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:41; and LCDR1, LCDR2, LCDR3 are amino acid sequences identical to HCDR1, HCDR2, HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:2, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:41. The amino acid sequence of the light chain variable region defined by any one of SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42 is consistent with the amino acid sequence of the LCDR1, LCDR2, LCDR3 of the light chain variable region defined by any one of SEQ ID NO:4.

[0049] The anti-TL1A antibody or its antigen-binding fragment of this application has TL1A binding affinity, especially the ability to specifically bind to TL1A, and can be used to detect TL1A; it can also block the activity of TL1A-activated transcription factor NFκB, and has the effect of inhibiting IFN-γ, and can be used to prevent and / or treat TL1A-mediated related diseases.

[0050] According to embodiments of this application, HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to HCDR1, HCDR2, and HCDR3 of the heavy chain variable region defined in SEQ ID NO:1; and LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to LCDR1, LCDR2, and LCDR3 of the light chain variable region defined in SEQ ID NO:2; or

[0051] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of HCDR1, HCDR2, and HCDR3 in the heavy chain variable region defined in SEQ ID NO:3; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of LCDR1, LCDR2, and LCDR3 in the light chain variable region defined in SEQ ID NO:4; or

[0052] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:5; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:6; or

[0053] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:7; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:8; or

[0054] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:9; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:10; or

[0055] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:10; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:12; or

[0056] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:13; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:14; or

[0057] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:15; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:16; or

[0058] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:17; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:18; or

[0059] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:19; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:20; or

[0060] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:21; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:22; or

[0061] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:23; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:24; or

[0062] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:25; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:26; or

[0063] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:27; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:28; or

[0064] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:29; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:30; or

[0065] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:31; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:32; or

[0066] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the HCDR1, HCDR2, and HCDR3 in the heavy chain variable region defined in SEQ ID NO:33; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the LCDR1, LCDR2, and LCDR3 in the light chain variable region defined in SEQ ID NO:34; or

[0067] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:35; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:36; or

[0068] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:37; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:38; or

[0069] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:39; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:40; or

[0070] The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:41; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:42.

[0071] According to embodiments of this application, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined by a Kabat, Chothia, AbM, Contact, or IMGT system.

[0072] According to the embodiments of this application, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 adopt the same system definition.

[0073] In a second aspect, this application provides an anti-TL1A antibody or an antigen-binding fragment thereof. According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment includes HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3;

[0074] HCDR1: X1YX2MH or X1YX2MN, where X1 is S, G, R or V, and X2 is I or T;

[0075] HCDR2: X3X4NPYX5X6X7TX8YX9X 10 KFKG, where X3 is Y or L, X4 is V or I, X5 is N or S, X6 is D or G, X7 is V or G, X8 is N, T or K, X9 is I or N, X 10 For E or Q;

[0076] HCDR3:X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 Y, where X 11 For Y, V, or H, X 12 For Y, Q, or R, X 13 For Y or L, X 14 For G or R, X 15 For N, Y, H, A, R, E, M or P, X 16 For P, D, V, L or S, X 17 For G or W, X 18 For F, L, M or Y, X 19 The answer is either A or D;

[0077] LCDR1:X 20 ASX 21 X 22 VX 23 X 24 X 25 X 26 X 27 , where X 20 For K or S, X 21 For Q or S, X 22 For D or S, X 23 For G, T, or S, X 24 For T, Y, or A, X 25 For M or A, X 26 For V or H, X 27 It can be A or empty;

[0078] LCDR2:X 28 X 29 X 30 X 31 X 32 X 33 X 34 , where X 28For W or D, X 29 For T or A, X 30 For S or A, X 31 For T or K, X 32 For R or L, X 33 For H or A, X 34 For T or S;

[0079] LCDR3: QQX 35 SSX 36 PX 37 T, where X 35 For Y, W, or H, X 36 For Y, D, or S, X 37 It can be Y or W.

[0080] The anti-TL1A antibody or its antigen-binding fragment of this application has TL1A binding affinity, especially the ability to specifically bind to TL1A, and can be used to detect TL1A; it can also block the activity of TL1A-activated transcription factor NFκB, and has the effect of inhibiting IFN-γ, and can be used to prevent and / or treat TL1A-mediated related diseases.

[0081] In this document, the term "antigen-binding fragment" refers to a fragment containing part or all of an antibody that lacks at least some of the amino acids present in the full-length chain but still possesses the performance activity of specifically binding to an antigen. For example, the fragment may contain part or all of the antibody's CDR. Such fragments are biologically active because they bind to the antigen and can compete with other antigen-binding molecules (including intact antibodies) for binding to a given epitope. Such fragments are selected from Fab, Fv, or scFv. Such fragments can be generated using recombinant nucleic acid technology or through enzymatic or chemical cleavage of antigen-binding molecules (including intact antibodies).

[0082] In this article, the term "antibody" is used in the broadest sense, encompassing full-length monoclonal antibodies, multispecific antibodies (polyclonal antibodies), and chimeric antibodies, with no specific structural restrictions as long as they exhibit the desired biological activity. Antibody molecules typically consist of a lighter light chain and a heavier heavy chain linked by disulfide bonds. The amino-terminal (N-terminus) amino acid sequence of the peptide chain varies considerably and is called the variable region (V-terminus); the carboxyl-terminus (C-terminus) is relatively stable and changes very little, and is called the constant region (C-terminus). The V-termini of the L-chain and H-chain are referred to as VL and VH, respectively.

[0083] In this paper, heavy chain complementarity-determining regions (heavy chain variable regions CDRs) are denoted by "HCDRs" or "HCDR", which include HCDR1 (also known as CDR-H1), HCDR2 (also known as CDR-H2), and HCDR3 (also known as CDR-H3); light chain complementarity-determining regions (light chain variable regions CDRs) are denoted by "LCDRs" or "LCDR", which include LCDR1 (also known as CDR-L1), LCDR2 (also known as CDR-L2), and LCDR3 (also known as CDR-L3). Commonly used CDR definition schemes in this field include: Kabat definition, Chothia definition, IMGT definition, Contact definition, and AbM definition.

[0084] However, the heavy chain variable region CDRs (amino acid sequences shown in SEQ ID NO: 1-3 or SEQ ID NO: 7-9) and light chain variable region CDRs (amino acid sequences shown in SEQ ID NO: 4-6 or SEQ ID NO: 10-12) mentioned above in this application are numbered and defined using the Kabat numbering system. Those skilled in the art can readily convert the heavy chain variable region CDR sequences and light chain variable region CDR sequences obtained from this application according to the Kabat numbering into "HCDRs" and / or "LCDRs" under other numbering systems (including but not limited to IMGT, Kabat, Chothia, Contact). CDRs determined based on the heavy chain and light chain variable regions disclosed in this application using other rules disclosed in the art also fall within the scope of protection of this application.

[0085] As described in this article, the “Kabat definition” refers to the definition system described by Kabat et al., USDept. of Health and Human Services, “Sequence of Proteins of Immunological Interest” (1983). The “IMGT” definition refers to the definition system described by Lefranc et al., *Dev. Comp. Immunol.*, 2003, 27:55-77. The “Chothia definition” is found in Chothia et al., J Mol Biol 196:901-917 (1987). The “Contact definition” is found in MacCallum et al., 1996, *Molecular Biology* 262:732-745. The “AbM definition” refers to the CDR defined using the “AbM” antibody modeling software from Oxford Molecular.

[0086] According to embodiments of this application, in HCDR1, X1 is G, R, or V, and X2 is T; or

[0087] X1 is S, and X2 is I.

[0088] According to an embodiment of this application, in HCDR2, X3 is L, X4 is I, X5 is S, X6 is G, X7 is V, X8 is T, X9 is N, and X... 10 For Q; or

[0089] X3 is Y, X4 is V or I, X5 is N, X6 is D, X7 is G, X8 is N or K, X9 is I, X 10 The value is E.

[0090] According to an embodiment of this application, in the HCDR3, X 11 Let V, X 12 For Q or R, X 13 For Y or L, X 14 Let R, X 15 For Y, A, R, E, M or P, X 16 For D, V, L, or S, X 17 For G, X 18 For L, M, or Y, X 19 It is either A or D; or

[0091] X 11 For Y or H, X 12 Let Y and X be the numbers. 13 For Y or L, X 14 For G, X 15 For N or H, X 16 Let P, X 17 For W, X 18 Let F, X 19 The answer is A.

[0092] According to an embodiment of this application, in the LCDR1, X 20 Let S and X be the values ​​of S and X. 21 Let S and X be the values ​​of S and X. 22 Let S and X be the values ​​of S and X. 23 Let T, X 24 Let Y and X be the numbers. 25 Let M and X be the numbers. 26 For H, X 27 Empty; or

[0093] X 20 Let K, X 21 For Q, X 22 For D, X 23 For G or S, X 24 For T or A, X 25 Let A and X be the two numbers. 26 Let V, X 27 The answer is A.

[0094] According to an embodiment of this application, in the LCDR2, X 28 For D, X 29 Let T, X 30 Let S and X be the values ​​of S and X. 31 Let K, X 32 Let L and X be the numbers. 33 Let A and X be the two numbers. 34 For S; or

[0095] X 28 For W, X 29 For T or A, X 30 For S or A, X 31 Let T, X 32 Let R, X 33 For H, X 34 Let T be the value.

[0096] According to an embodiment of this application, in the LCDR3, X 35 For W, X 36 For D, X 37 For Y; or

[0097] X 35 For Y or H, X 36 For Y or S, X 37 It can be Y or W.

[0098] According to an embodiment of this application, HCDR1: X1YTMH, where X1 is G, R, or V;

[0099] HCDR2: LINPYSGVTTYNQKFKG;

[0100] HCDR3: VX 12 X 13 RX 15 X 16 GX 18 X 19 Y, where X 12 For Q or R, X 13 For Y or L, X 15 For Y, A, R, E, M or P, X 16 For D, V, L, or S, X 18 For L, M, or Y, X 19 The answer is either A or D;

[0101] LCDR1: SASSSVTYMH;

[0102] LCDR2: DTSKLAS;

[0103] LCDR3:QQWSSDPYT.

[0104] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment described in the first and second aspects above may further include at least one of the following technical features:

[0105] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises:

[0106] Having the amino acid sequence shown in SEQ ID NO:43 for HCDR1, the amino acid sequence shown in SEQ ID NO:44 for HCDR2, the amino acid sequence shown in SEQ ID NO:45 for HCDR3, and the amino acid sequence shown in SEQ ID NO:46 for LCDR1, the amino acid sequence shown in SEQ ID NO:47 for LCDR2, and the amino acid sequence shown in SEQ ID NO:48 for LCDR3; or

[0107] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:51 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0108] Having the amino acid sequence shown in SEQ ID NO:43 for HCDR1, the amino acid sequence shown in SEQ ID NO:55 for HCDR2, the amino acid sequence shown in SEQ ID NO:56 for HCDR3, and the amino acid sequence shown in SEQ ID NO:57 for LCDR1, the amino acid sequence shown in SEQ ID NO:58 for LCDR2, and the amino acid sequence shown in SEQ ID NO:59 for LCDR3; or

[0109] Having the amino acid sequence shown in SEQ ID NO:60 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:51 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0110] Having the amino acid sequence shown in SEQ ID NO:61 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:51 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0111] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, having the amino acid sequence shown in SEQ ID NO:50 for HCDR2, having the amino acid sequence shown in SEQ ID NO:62 for HCDR3, and having the amino acid sequence shown in SEQ ID NO:52 for LCDR1, having the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and having the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0112] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:63 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0113] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:64 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0114] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, having the amino acid sequence shown in SEQ ID NO:50 for HCDR2, having the amino acid sequence shown in SEQ ID NO:65 for HCDR3, and having the amino acid sequence shown in SEQ ID NO:52 for LCDR1, having the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and having the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0115] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:66 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0116] Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:67 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0117] Having the amino acid sequence shown in SEQ ID NO:60 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:68 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0118] Having the amino acid sequence shown in SEQ ID NO:60 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:69 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or

[0119] The amino acid sequences shown are as follows: HCDR1 (as shown in SEQ ID NO:60), HCDR2 (as shown in SEQ ID NO:50), HCDR3 (as shown in SEQ ID NO:65), LCDR1 (as shown in SEQ ID NO:52), LCDR2 (as shown in SEQ ID NO:53), and LCDR3 (as shown in SEQ ID NO:54).

[0120] In this application, the phrase "as shown by the amino acid sequence of SEQ ID NO:A" or "amino acid sequence as shown by SEQ ID NO:A" includes the amino acid sequence of SEQ ID NO:A or a conservatively modified amino acid sequence of SEQ ID NO:A, all of which are within the scope of protection of this application. For example, "HCDR1 as shown by the amino acid sequence of SEQ ID NO:43" refers to HCDR1 being the amino acid sequence of SEQ ID NO:43 or a conservatively modified amino acid sequence of SEQ ID NO:43 (e.g., an amino acid sequence differing from SEQ ID NO:43 by 1-2 amino acids), all of which are within the scope of protection of this application; the same applies to "amino acid sequences as shown by SEQ ID NO:44-69".

[0121] In this paper, the term "or an amino acid sequence that differs from the aforementioned amino acid sequence by 1 to 2 amino acids" means that there is a difference of 1 or 2 amino acids compared to the aforementioned amino acid sequence, and that the difference does not significantly affect or change the binding properties of the antibody containing the amino acid sequence. This modification includes amino acid substitution, addition, and deletion.

[0122] The amino acid sequences shown in SEQ ID NO:43~69 are shown in the table below:

[0123] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment includes a heavy chain framework region and / or a light chain framework region.

[0124] According to embodiments of this application, at least a portion of the heavy chain framework region and / or light chain framework region is derived from at least one of mouse antibodies, primate antibodies, bovine antibodies, equine antibodies, dairy bovine antibodies, porcine antibodies, sheep antibodies, goat antibodies, canine antibodies, feline antibodies, rabbit antibodies, camel antibodies, donkey antibodies, deer antibodies, mink antibodies, chicken antibodies, duck antibodies, goose antibodies, turkey antibodies, fighting rooster antibodies, or mutants thereof.

[0125] According to embodiments of this application, at least a portion of the heavy chain framework region and / or light chain framework region is derived from at least one of rabbit-derived antibodies or mutants thereof, mouse-derived antibodies or mutants thereof, and human-derived antibodies or mutants thereof.

[0126] According to embodiments of this application, the heavy chain framework region and / or light chain framework region are derived from human antibodies.

[0127] For example, as shown in the HC503H6M antibody, the frame region is selected from HFR1 as represented by the amino acid of SEQ ID NO:72, HFR2 as represented by the amino acid of SEQ ID NO:73, HFR3 as represented by the amino acid of SEQ ID NO:74, HFR4 as represented by the amino acid of SEQ ID NO:75, and LFR1 as represented by the amino acid of SEQ ID NO:76, LFR2 as represented by the amino acid of SEQ ID NO:77, LFR3 as represented by the amino acid of SEQ ID NO:78, and LFR4 as represented by the amino acid of SEQ ID NO:79.

[0128] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises:

[0129] The heavy chain variable region shown in any of the amino acid sequences of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41; and

[0130] The light chain variable region is shown in any of the amino acid sequences of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, and SEQ ID NO:42.

[0131] In this document, "the heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:1" refers to the heavy chain variable region being the amino acid sequence of SEQ ID NO:1 or an amino acid sequence of a conservatively modified form of SEQ ID NO:1 (e.g., an amino acid sequence that differs from SEQ ID NO:1 by 1 to 20 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)). All of these are within the scope of protection of this application; the same applies to "the amino acid sequence of any one of SEQ ID NO:2 to 42".

[0132] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises:

[0133] The heavy chain variable region is represented by any one of the amino acid sequences of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, or an amino acid sequence having at least 80% identity with it; and

[0134] The light chain variable region is represented by any of the amino acid sequences SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, and SEQ ID NO:42, or an amino acid sequence having at least 80% identity with them.

[0135] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises:

[0136] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:1 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:2 or an amino acid sequence having at least 80% identity with it; or

[0137] The heavy chain variable region, as shown in the amino acid sequence of SEQ ID NO:3 or an amino acid sequence having at least 80% identity with it, and the light chain variable region, as shown in the amino acid sequence of SEQ ID NO:4 or an amino acid sequence having at least 80% identity with it; or

[0138] The heavy chain variable region, as shown by the amino acid sequence of SEQ ID NO:5 or an amino acid sequence having at least 80% identity with it, and the light chain variable region, as shown by the amino acid sequence of SEQ ID NO:6 or an amino acid sequence having at least 80% identity with it; or

[0139] The heavy chain variable region, as shown in the amino acid sequence of SEQ ID NO:7 or an amino acid sequence having at least 80% identity with it, and the light chain variable region, as shown in the amino acid sequence of SEQ ID NO:8 or an amino acid sequence having at least 80% identity with it; or

[0140] The heavy chain variable region, as shown by the amino acid sequence of SEQ ID NO:9 or an amino acid sequence having at least 80% identity with it, and the light chain variable region, as shown by the amino acid sequence of SEQ ID NO:10 or an amino acid sequence having at least 80% identity with it; or

[0141] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:11 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:12 or an amino acid sequence having at least 80% identity with it; or

[0142] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:13 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:14 or an amino acid sequence having at least 80% identity with it; or

[0143] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:15 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:16 or an amino acid sequence having at least 80% identity with it; or

[0144] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:17 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:18 or an amino acid sequence having at least 80% identity with it; or

[0145] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:19 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:20 or an amino acid sequence having at least 80% identity with it; or

[0146] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:21 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:22 or an amino acid sequence having at least 80% identity with it; or

[0147] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:23 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:24 or an amino acid sequence having at least 80% identity with it; or

[0148] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:25 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:26 or an amino acid sequence having at least 80% identity with it; or

[0149] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:27 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:28 or an amino acid sequence having at least 80% identity with it; or

[0150] The heavy chain variable region, as shown by the amino acid sequence of SEQ ID NO:29 or an amino acid sequence having at least 80% identity with it, and the light chain variable region, as shown by the amino acid sequence of SEQ ID NO:30 or an amino acid sequence having at least 80% identity with it; or

[0151] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:31 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:32 or an amino acid sequence having at least 80% identity with it; or

[0152] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:33 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:34 or an amino acid sequence having at least 80% identity with it; or

[0153] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:35 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:36 or an amino acid sequence having at least 80% identity with it; or

[0154] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:37 or an amino acid sequence having at least 80% identity with it, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:38 or an amino acid sequence having at least 80% identity with it; or

[0155] Heavy chain variable regions as shown by the amino acid sequence of SEQ ID NO:39 or an amino acid sequence having at least 80% identity with it, and light chain variable regions as shown by the amino acid sequence of SEQ ID NO:40 or an amino acid sequence having at least 80% identity with it; or

[0156] The heavy chain variable region, as shown by the amino acid sequence of SEQ ID NO:41 or an amino acid sequence having at least 80% identity with it, and the light chain variable region, as shown by the amino acid sequence of SEQ ID NO:42 or an amino acid sequence having at least 80% identity with it.

[0157] According to embodiments of this application, the anti-TL1A antibody or its antigen-binding fragment comprises:

[0158] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:1, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:2; or

[0159] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:3, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:4; or

[0160] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:5, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:6; or

[0161] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:7, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:8; or

[0162] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:9, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:10; or

[0163] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:11, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:12; or

[0164] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:13, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:14; or

[0165] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:15, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:16; or

[0166] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:17, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:18; or

[0167] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:19, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:20; or

[0168] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:21, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:22; or

[0169] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:23, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:24; or

[0170] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:25, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:26; or

[0171] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:27, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:28; or

[0172] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:29, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:30; or

[0173] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:31, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:32; or

[0174] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:33, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:34; or

[0175] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:35, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:36; or

[0176] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:37, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:38; or

[0177] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:39, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:40; or

[0178] The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:41, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:42.

[0179] The amino acid sequences shown in SEQ ID NO:1-2 (see antibody C2C1L in the examples) are as follows:

[0180] The amino acid sequences shown in SEQ ID NO:3-4 (see antibody C5A8A in the examples) are as follows:

[0181] The amino acid sequences represented by SEQ ID NO:5-6 (see antibody C19E58 in the examples) are shown below:

[0182] The amino acid sequences shown in SEQ ID NO:7-8 (see antibody PO16-C5AA in the examples) are as follows:

[0183] The amino acid sequences shown in SEQ ID NO:9-10 (see antibody PO16-C5AB in the examples) are as follows:

[0184] The amino acid sequences shown in SEQ ID NO:11-12 (see antibody PO16-C5AC in the examples) are as follows:

[0185] The amino acid sequences shown in SEQ ID NO:13-14 (see antibody PO16-C5AD in the examples) are as follows:

[0186] The amino acid sequences shown in SEQ ID NO:15-16 (see antibody PO16-C5AE in the examples) are as follows:

[0187] The amino acid sequences shown in SEQ ID NO:17-18 (see antibody C5T5 in the examples) are as follows:

[0188] The amino acid sequences shown in SEQ ID NO:19-20 (see antibody C5T15 in the examples) are as follows:

[0189] The amino acid sequences shown in SEQ ID NO:21-22 (see antibody C5T18 in the examples) are as follows:

[0190] The amino acid sequences shown in SEQ ID NO:23-24 (see antibody C5T20 in the examples) are as follows:

[0191] The amino acid sequences shown in SEQ ID NO:25-26 (see antibody C5T28 in the examples) are as follows:

[0192] The amino acid sequences shown in SEQ ID NO:27-28 (see antibody C5T35 in the examples) are as follows:

[0193] The amino acid sequences represented by SEQ ID NO:29-30 (see antibody C50301 in the examples) are shown below:

[0194] The amino acid sequences shown in SEQ ID NO:31-32 (see antibody C5033307 in the examples) are as follows:

[0195] The amino acid sequences shown in SEQ ID NO:33-34 (see antibody C503H6M in the examples) are as follows:

[0196] The amino acid sequences shown in SEQ ID NO:35-36 (see antibody C503H4 in the examples) are as follows:

[0197] The amino acid sequences shown in SEQ ID NO:37-38 (see antibody C50301H6M in the examples) are as follows:

[0198] The amino acid sequences shown in SEQ ID NO:39-40 (see antibody C503013307 in the examples) are as follows:

[0199] The amino acid sequences shown in SEQ ID NO:41-42 (see antibody HC503H6M in the examples) are as follows:

[0200] According to embodiments of this application, it further includes a heavy chain constant region and / or a light chain constant region.

[0201] According to embodiments of this application, at least a portion of at least one of the heavy chain constant region and the light chain constant region is derived from at least one of mouse antibodies, primate antibodies, bovine antibodies, equine antibodies, dairy bovine antibodies, porcine antibodies, sheep antibodies, goat antibodies, canine antibodies, feline antibodies, rabbit antibodies, camel antibodies, donkey antibodies, deer antibodies, mink antibodies, chicken antibodies, duck antibodies, goose antibodies, turkey antibodies, fighting rooster antibodies, or mutants thereof.

[0202] According to embodiments of this application, the heavy chain constant region includes a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD.

[0203] According to embodiments of this application, the light chain constant region includes light chain constant regions selected from κ-type or λ-type.

[0204] According to embodiments of this application, the light chain constant region and the heavy chain constant region are both derived from at least one of rabbit-derived antibodies or mutants thereof, mouse-derived antibodies or mutants thereof, and human-derived antibodies or mutants thereof.

[0205] According to embodiments of this application, the heavy chain constant regions are all derived from human wild-type IgK antibodies or their mutants.

[0206] According to embodiments of this application, the heavy chain constant regions are all derived from human wild-type IgK antibodies.

[0207] According to an embodiment of this application, the heavy chain constant region is a human IgK mutant.

[0208] According to embodiments of this application, the heavy chain constant region has an amino acid sequence as shown in SEQ ID NO:70:

[0209] According to an embodiment of this application, the light chain constant region has the amino acid sequence shown in SEQ ID NO:71.

[0210] According to embodiments of this application, the N-end of the heavy chain constant region is connected to the C-end of the heavy chain variable region; and / or

[0211] The N-terminus of the constant region of the light chain is connected to the C-terminus of the variable region of the light chain.

[0212] According to embodiments of this application, the antibody comprises at least one selected from polyclonal antibodies, full-length monoclonal antibodies, Fab antibodies, Fab' antibodies, F(ab')2 antibodies, Fv antibodies, single-chain antibodies, and the smallest recognition unit; or

[0213] The antigen-binding fragment includes at least one selected from the following: F(ab')2 fragment, Fab' fragment, Fab fragment, F(ab)2 fragment, Fv fragment, scFv fragment, scFv-Fc fusion protein, scFv-Fv fusion protein, and minimum recognition unit.

[0214] In this article, the terms “full-length antibody”, “full-length monoclonal antibody” or “full-length monoclonal antibody” refer to antibodies composed of at least two identical light chains and at least two identical heavy chains linked by interchain disulfide bonds, such as immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin D (IgD), or immunoglobulin E (IgE).

[0215] In this document, the terms "polyclonal antibody" and "multispecific antibody" are synonymous, both referring to antibodies that can recognize multiple antigenic epitopes. For example, antibodies that recognize two antigenic epitopes (bispecific antibodies, abbreviated as biantibodies), three antigenic epitopes, or four antigenic epitopes are used in a broad sense, and their specific structures are not limited, as long as they can recognize multiple antigenic epitopes. In this application, at least one of the multiple antigenic epitopes is derived from TL1A.

[0216] In this article, the term "Fab antibody" or "Fab fragment" generally refers to an antibody or fragment containing only Fab molecules, which consists of the VH and CH1 of the heavy chain and the complete light chain, linked by a disulfide bond.

[0217] In this paper, the term “F(ab')2 antibody” or “F(ab')2 fragment” has two antigen-binding F(ab') parts linked together by disulfide bonds.

[0218] In this article, the term "Fv antibody" or "Fv fragment" generally refers to an antibody or fragment consisting only of a light chain variable region (VL) and a heavy chain variable region (VH) linked by non-covalent bonds. It is the smallest functional fragment of an antibody that retains the complete antigen-binding site.

[0219] In this paper, the terms "single-chain antibody" and "scFv fragment" refer to antibodies or fragments formed by linking the variable regions of the antibody heavy chain and light chain through short peptides.

[0220] In this article, the terms "minimum recognition unit" and "MRU" both refer to antibodies or fragments consisting of only one CDR, with a very small molecular weight, accounting for only about 1% of a complete antibody.

[0221] Nucleic acid molecules, expression vectors and recombinant cells

[0222] In a third aspect of this application, a nucleic acid molecule is provided. According to embodiments of this application, the nucleic acid molecule encodes the anti-TL1A antibody or its antigen-binding fragment described in the first or second aspect. The nucleic acid molecule of this application may encode the anti-TL1A antibody or its antigen-binding fragment described in the first or second aspect.

[0223] According to embodiments of this application, the nucleic acid molecule is DNA.

[0224] It should be noted that those skilled in the art will understand that the nucleic acid molecules mentioned herein actually include any one or both of the complementary double strands. For convenience, although only one strand is given in most cases in this specification and claims, the other complementary strand is also disclosed. Furthermore, the nucleic acid sequences in this application include DNA or RNA forms; disclosure of one implies that the other is also disclosed.

[0225] In a fourth aspect, this application provides an expression vector. According to an embodiment of this application, the expression vector carries the nucleic acid molecule described in the third aspect. When the nucleic acid molecule is linked to the expression vector, the nucleic acid molecule can be directly or indirectly connected to control elements on the expression vector, as long as these control elements can control the translation and expression of the nucleic acid molecule. Of course, these control elements can be directly derived from the expression vector itself, or they can be exogenous, i.e., not derived from the expression vector itself. Naturally, the nucleic acid molecule and the control elements only need to be operably linked.

[0226] In this article, "operable ligation" refers to ligating a foreign gene into an expression vector so that the control elements within the expression vector, such as transcriptional and translational control sequences, can perform their intended functions of regulating the transcription and translation of the foreign gene. Commonly used expression vectors include plasmids and bacteriophages.

[0227] According to some specific embodiments of this application, after the expression vector is introduced into suitable recipient cells, it can effectively realize the expression of the aforementioned anti-TL1A antibody or its antigen-binding fragment under the mediation of the regulatory system, thereby realizing the large-scale in vitro acquisition of anti-TL1A antibody or its antigen-binding fragment.

[0228] According to embodiments of this application, the expression vector includes those selected from eukaryotic expression vectors or prokaryotic expression vectors.

[0229] In one optional embodiment of this application, the expression vector is a plasmid expression vector or a viral expression vector, such as a lentiviral expression vector.

[0230] In a fifth aspect of this application, a recombinant cell is provided. According to embodiments of this application, the recombinant cell includes a nucleic acid molecule carried by the third aspect or an expression vector carried by the fourth aspect; or expresses an anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect. Using this recombinant cell, under suitable conditions, the aforementioned anti-TL1A antibody or its antigen-binding fragment can be effectively expressed intracellularly.

[0231] According to some specific embodiments of this application, the recombinant cells can efficiently and extensively express antibodies or their antigen-binding fragments under suitable conditions. The antibodies or their antigen-binding fragments have stronger specificity and higher efficacy, enabling effective treatment or prevention of TL1A-mediated diseases with a smaller drug dosage.

[0232] It should be noted that "suitable conditions" refers to conditions suitable for the expression of the anti-TL1A antibody or its antigen-binding fragment described in this application. Those skilled in the art will readily understand that suitable conditions for the expression of the anti-TL1A antibody or its antigen-binding fragment include, but are not limited to, suitable transformation or transfection methods, suitable transformation or transfection conditions, healthy host cell state, suitable host cell density, suitable cell culture environment, and suitable cell culture time. "Suitable conditions" are not particularly limited, and those skilled in the art can optimize the optimal conditions for the expression of the anti-TL1A antibody or its antigen-binding fragment according to the specific environment of their laboratory.

[0233] According to embodiments of this application, the recombinant cells are obtained by introducing the expression vector described in the fifth aspect into host cells.

[0234] It should be noted that the recombinant cells described in this application are not particularly limited and can be prokaryotic cells, eukaryotic cells, or bacteriophages. The prokaryotic cells can be Escherichia coli, Bacillus subtilis, Streptomyces, or Proteus mirabilis, etc. The eukaryotic cells include fungi such as Pichia pastoris, Saccharomyces cerevisiae, Schizosoma, and Trichoderma; insect cells such as armyworms; plant cells such as tobacco; and mammalian cells such as BHK cells, CHO cells, COS cells, and myeloma cells. In some embodiments, the recombinant cells described in this application are preferably mammalian cells, including BHK cells, CHO cells, NSO cells, or COS cells, and do not include animal germ cells, fertilized eggs, or embryonic stem cells.

[0235] According to embodiments of this application, the recombinant cells are eukaryotic cells, preferably mammalian cells.

[0236] Conjugates, pharmaceutical compositions, and reagents or kits

[0237] In a sixth aspect, this application provides a conjugate. According to embodiments of this application, the conjugate comprises the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect; and a conjugation portion linked to the anti-TL1A antibody or its antigen-binding fragment. The conjugate of this application has TL1A binding affinity and can be used for the detection of TL1A, or for the prevention and / or treatment of TL1A-mediated diseases.

[0238] According to embodiments of this application, the coupling portion is selected from at least one of purification tags or labels, carriers, drugs, toxins, cytokines, and modifiers.

[0239] In this document, the carrier can be a substance capable of suspension or dispersion in a liquid phase (e.g., solid-phase carriers such as particles and magnetic beads), or a solid phase capable of containing or carrying a liquid phase (e.g., supports such as plates, membranes, and test tubes, as well as containers such as well plates, microfluidic pathways, glass capillaries, nanopillars, and monolithic columns); it can also be a labeling carrier for labeling anti-TL1A antibodies or their antigen-binding fragments, fusion proteins, or multispecific antibodies, such as enzymes (e.g., peroxidase, alkaline phosphatase, luciferin, β-phosphatase). β-galactosidase), affinity substances (e.g., one of streptavidin and biotin, one of complementary sense and antisense nucleic acids), fluorescent dyes (e.g., fluorescein, fluorescein isothiocyanate, rhodamine, green fluorescent protein, red fluorescent protein), luminescent substances (e.g., insect luciferin, jellyfish luminescent protein (Aequorin), acridinium ester, tris(2,2'-bipyridine)ruthenium, luminol), radioactive isotopes (e.g., 3H, 14C, 32P, 35S, 125I), and gold colloids, etc.

[0240] According to embodiments of this application, the carrier comprises a fluorescent dye.

[0241] According to embodiments of this application, the carrier is selected from at least one of magnetic microspheres, plastic microspheres, plastic microparticles, microporous plates, glass, capillaries, nylon, and nitrocellulose membranes.

[0242] According to embodiments of this application, the drug is a small molecule drug that can bind to an anti-TL1A antibody or its antigen-binding fragment.

[0243] According to embodiments of this application, the purification tag or label is selected from at least one of protein tags, colloidal gold, radioactive labels, luminescent substances, colored substances, enzymes, biotin / antibiotin proteins, and spin labels.

[0244] According to embodiments of this application, the purification tag or label is selected from at least one of fluorescent tags, chromophore tags, and electron-dense tags.

[0245] According to embodiments of this application, the protein tag includes, but is not limited to, His tag, Flag tag, GST tag, MBP tag, SUMO tag, and C-Myc tag.

[0246] According to embodiments of this application, the term "modifier" should be interpreted broadly and may refer to substances used to modify proteins. Exemplarily, it may be polyethylene glycol or a derivative thereof.

[0247] It should be noted that the binding method between the conjugated portion and the anti-TL1A antibody or its antigen-binding fragment, fusion protein, or multispecific antibody can use methods known in the art. For example, methods such as physical adsorption, covalent binding, methods using affinity substances (e.g., biotin, streptavidin), and ion binding can be used.

[0248] According to an embodiment of this application, the conjugate is a staining reagent, and the conjugate portion is a fluorescent dye.

[0249] According to embodiments of this application, the fluorescent dye includes any one or more of the following: FITC, PE, Cy5, PI, 7-AAD, APC, AlexaFluor, eFluor, PE-Cy7, APC-Cy7, PerCP, PerCPcy5.5, PB, BV series, QDot series, and BUV series dyes.

[0250] In a seventh aspect of this application, a reagent or kit is provided. According to embodiments of this application, the reagent or kit comprises the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect, the nucleic acid molecule as described in the third aspect, the expression vector as described in the fourth aspect, the recombinant cells as described in the fifth aspect, or the conjugate as described in the sixth aspect. The kit of this application has TL1A binding affinity and can effectively detect TL1A.

[0251] As previously mentioned, the anti-TL1A antibodies or their antigen-binding fragments according to certain embodiments of this application can effectively bind to human TL1A protein. Therefore, reagents or kits containing the anti-TL1A antibodies or their antigen-binding fragments can effectively perform qualitative or quantitative detection of human TL1A protein. The reagents or kits provided in this application can be used, for example, in immunoblotting, immunoprecipitation, and other reagents or kits involving the detection of human TL1A using the specific binding of antibodies. These kits may contain any one or more of the following: antagonists, anti-TL1A antibodies, or drug reference materials; protein purification columns; immunoglobulin affinity purification buffers; cell assay diluents; instructions or literature, etc. Anti-TL1A antibodies can be used for different types of diagnostic tests, such as detecting the presence of drugs, toxins, or other proteins in vitro, or for scientific research, using the kits to detect human TL1A protein in test samples. The binding molecules are also applicable to the above applications and will not be elaborated further here.

[0252] According to some specific embodiments of this application, the kit may also include commonly used components for detecting TL1A, such as coating solutions.

[0253] In an eighth aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect, the nucleic acid molecule as described in the third aspect, the expression vector as described in the fourth aspect, the recombinant cell as described in the fifth aspect, or the conjugate as described in the sixth aspect. The pharmaceutical composition of this application has TL1A binding affinity and can effectively prevent and / or treat TL1A-mediated diseases.

[0254] According to embodiments of this application, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0255] The pharmaceutical compositions of this application can be administered via any acceptable method of administration. The pharmaceutical compositions of this application can be formulated into solid, semi-solid, liquid, or gaseous forms, such as injections or lyophilized powders, as currently known or readily apparent to those skilled in the art. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, subcutaneous injection, intravenous, intramuscular, intradermal, intrasternal injection, or infusion techniques. The pharmaceutical compositions of this application are formulated to ensure that the bioactive components contained therein are bioavailable after administration to a patient.

[0256] use

[0257] In a ninth aspect of this application, the use of an anti-TL1A antibody or antigen-binding fragment thereof as described in the first or second aspect, a nucleic acid molecule as described in the third aspect, an expression vector as described in the fourth aspect, a recombinant cell as described in the fifth aspect, a conjugate as described in the sixth aspect, or a pharmaceutical composition as described in the seventh aspect in the preparation of a multispecific antibody, a fusion protein, a drug or kit, or a drug.

[0258] According to an embodiment of this application, the kit is used to detect TL1A.

[0259] According to embodiments of this application, the drug is used to prevent and / or treat TL1A-mediated diseases.

[0260] According to embodiments of this application, the TL1A-mediated related diseases include inflammatory or immune diseases.

[0261] According to embodiments of this application, the TL1A-mediated related diseases include allergies, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, fibrosis-related diseases, systemic lupus erythematosus, psoriasis, type 1 diabetes, and transplant rejection.

[0262] According to embodiments of this application, the inflammatory or immune diseases include Crohn's disease, ulcerative colitis, medically refractory ulcerative colitis (MR-UC), intestinal fibrosis, pulmonary fibrosis, and liver fibrosis.

[0263] This application proposes an anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect, a nucleic acid molecule as described in the third aspect, an expression vector as described in the fourth aspect, a recombinant cell as described in the fifth aspect, or a conjugate as described in the sixth aspect, for detecting TL1A or preventing and / or treating TL1A-mediated diseases.

[0264] According to embodiments of this application, the TL1A-mediated related diseases include inflammatory or immune diseases.

[0265] According to embodiments of this application, the TL1A-mediated related diseases include allergies, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, fibrosis-related diseases, systemic lupus erythematosus (SLE), psoriasis, type 1 diabetes, and transplant rejection.

[0266] According to embodiments of this application, the inflammatory or immune diseases include Crohn's disease, ulcerative colitis, medically refractory ulcerative colitis (MR-UC), intestinal fibrosis, pulmonary fibrosis, and liver fibrosis.

[0267] This application proposes the use of an anti-TL1A antibody or antigen-binding fragment thereof as described in the first or second aspect, a nucleic acid molecule as described in the third aspect, an expression vector as described in the fourth aspect, a recombinant cell as described in the fifth aspect, or a conjugate as described in the sixth aspect in detecting TL1A or preventing and / or treating TL1A-mediated related diseases or in detecting TL1A.

[0268] According to embodiments of this application, the TL1A-mediated related diseases include inflammatory or immune diseases.

[0269] According to embodiments of this application, the TL1A-mediated related diseases include allergies, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, fibrosis-related diseases, systemic lupus erythematosus (SLE), psoriasis, type 1 diabetes, and transplant rejection.

[0270] According to embodiments of this application, the inflammatory or immune diseases include Crohn's disease, ulcerative colitis, medically refractory ulcerative colitis (MR-UC), intestinal fibrosis, pulmonary fibrosis, and liver fibrosis.

[0271] method

[0272] In a tenth aspect of this application, a method for detecting TL1A is proposed. According to an embodiment of this application, the method includes: contacting a sample to be tested with an anti-TL1A antibody or its antigen-binding fragment described in the first or second aspect, a conjugate described in the sixth aspect, or a reagent or kit described in the seventh aspect to form an immune complex. As is known from the foregoing, the aforementioned anti-TL1A antibody or its antigen-binding fragment, conjugate, reagent, or kit all possess TL1A binding affinity. Therefore, using the aforementioned anti-TL1A antibody or its antigen-binding fragment, conjugate, reagent, or kit can effectively detect TL1A, especially for in vitro detection (e.g., detection for non-disease diagnosis and treatment purposes), offering advantages such as high detection accuracy.

[0273] According to embodiments of this application, based on the signal of the immune complex, it is determined whether the sample to be tested contains TL1A or whether it contains TL1A-expressing cells, or the content of TL1A or TL1A-expressing cells in the sample to be tested is determined.

[0274] According to embodiments of this application, the signal of the immune complex is detected by at least one of ELISA, WB, and IHC.

[0275] According to embodiments of this application, the immune complex further includes a second antibody, which binds to the anti-TL1A antibody or its antigen-binding fragment.

[0276] According to embodiments of this application, the signal includes a fluorescence signal.

[0277] In its eleventh aspect, this application provides a method for preventing and / or treating TL1A-mediated diseases. According to embodiments of this application, the method includes administering to a subject a pharmaceutically acceptable amount of the anti-TL1A antibody or its antigen-binding fragment as described in the first or second aspect, or the pharmaceutical composition as described in the eighth aspect. The method of this application can effectively prevent and / or treat TL1A-mediated diseases.

[0278] The effective amount of the anti-TL1A antibody or its antigen-binding fragment described in this application, or the pharmaceutical composition, can vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0279] The anti-TL1A antibody or its antigen-binding fragment, and pharmaceutical composition of this application, can be incorporated into drugs suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms, such as liquid, semi-solid, and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. Typical drugs are in the form of injection solutions or infusion solutions. The aforementioned anti-TL1A antibody or its antigen-binding fragment, and pharmaceutical composition can be administered by intravenous infusion or injection, or by intramuscular or subcutaneous injection.

[0280] In this document, the term "subject" refers to a vertebrate, preferably a mammal, and most preferably a human. Mammals include, but are not limited to, rodents, apes, humans, livestock, racing animals, and pets. Tissues, cells, and their progeny from biological entities obtained in vivo or cultured in vitro are also included.

[0281] According to embodiments of this application, the administration route of the method is subcutaneous injection or intravenous injection.

[0282] According to embodiments of this application, the TL1A-mediated related diseases include inflammatory or immune diseases.

[0283] According to embodiments of this application, the TL1A-mediated related diseases include allergies, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, fibrosis-related diseases, systemic lupus erythematosus (SLE), psoriasis, type 1 diabetes, and transplant rejection.

[0284] According to embodiments of this application, the inflammatory or immune diseases include Crohn's disease, ulcerative colitis, medically refractory ulcerative colitis (MR-UC), intestinal fibrosis, pulmonary fibrosis, and liver fibrosis.

[0285] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0286] Example 1: Screening of monoclonal antibodies against TL1A

[0287] Balb / c mice were immunized multiple times with soluble recombinant human TL1A protein (KaiKa, FSF-HM415). The antigen protein was mixed with an adjuvant to form an immunogen reagent, which was then injected subcutaneously through the mouse's back. In the first round of immunization, each mouse was immunized with a solution of 50 μg human TL1A protein emulsified with complete Freund's adjuvant (Sigma, F5881) at a 1:1 volume ratio. In each subsequent round of booster immunization, each mouse was immunized with a solution of 50 μg human TL1A protein emulsified with incomplete Freund's adjuvant (Sigma, F5506) at a 1:1 volume ratio. The interval between each round of booster immunizations was at least 2–3 weeks. A final booster immunization was administered 3 days before cell fusion, with each mouse receiving 50 μg of human TL1A protein.

[0288] Once the titer of TL1A-specific antibodies in mouse serum reached a certain level, mouse spleen cells were extracted and fused with myeloma cell lines to obtain hybridoma cells. After multiple rounds of screening and subcloning, several hybridoma cells expressing monoclonal antibody molecules against TL1A protein were isolated. The amino acid sequences encoding the variable domains of the antibody molecules were obtained using conventional hybridoma sequencing techniques. The variable region sequences and CDR sequences of each monoclonal antibody are shown in Table 1.

[0289] Table 1: Serial numbers of amino acids in the variable region of anti-TL1A monoclonal antibodies

[0290] Example 2: Recombinant Expression of TL1A Monoclonal Antibody

[0291] 1. The light chain variable region sequence and heavy chain variable region sequence (see Table 1) of each hybridoma clone were ligated to the light chain constant region of human IgK (amino acid sequence as shown in SEQ ID NO:71) or the heavy chain constant region sequence of human IgG1 (amino acid sequence as shown in SEQ ID NO:70), respectively. The spliced ​​amino acid sequences were codon optimized to obtain the corresponding nucleotide sequences. Then, the heavy and light chain nucleotide sequences of each clone were synthesized into the expression plasmid pcDNA3.4 and amplified and the plasmid was extracted. The expression plasmid was filtered through a 0.22 μm filter membrane, mixed with CHO cells and electroporation buffer, and added to a 1 ml electroporation tube. After electroporation, the cells in the electroporation tube were aliquoted into shake flasks containing 20 ml of culture medium and incubated statically for 40 min. After incubation, the shake flasks were placed in a 37°C, 270 rpm, 8% CO2 environment for 24 hours. After 24 hours, feed / sodium butyrate / double antibody were added, and the cells were cultured for another 3-6 days. The cell supernatant was then collected. The cell supernatant was added to a Protein A affinity chromatography column, and the column was washed with 20 mL of PBS buffer. Then, 5 mL of sodium acetate buffer (pH 3.4) was added to elute the column. The eluent was collected into a dialysis bag and dialyzed into PBS buffer to obtain the recombinant monoclonal antibody against human TL1A, namely antibodies C2C1L, C5A8A, and C19E5B.

[0292] 2. The preparation methods of the control antibodies RVT-3101 (amino acid sequence of the heavy chain variable region as shown in SEQ ID NO:80, amino acid sequence of the light chain variable region as shown in SEQ ID NO:81), PRA023 (amino acid sequence of the heavy chain variable region as shown in SEQ ID NO:82, amino acid sequence of the light chain variable region as shown in SEQ ID NO:83), and TEV-48574 (amino acid sequence of the heavy chain variable region as shown in SEQ ID NO:84, amino acid sequence of the light chain variable region as shown in SEQ ID NO:85) in subsequent embodiments are the same as those in step 1 of this embodiment.

[0293] Example 3: Detection of TL1A monoclonal antibody affinity using BLI

[0294] Using Sartorius R8 was used to detect the affinity of different anti-human TL1A recombinant monoclonal antibodies:

[0295] First, the AHC2 sensor was pre-wetted in 1x Kinetic buffer (1x KB) for at least 10 minutes. Then, different anti-human TL1A monoclonal antibody samples (antibodies C2C1L, C5A8A, and C19E5B) were diluted to 10 μg / mL using 1x KB. KB diluted human TL1A protein (KaiKa, catalog number FSF-HM415) to corresponding molar concentrations (100 nmol / L, 50 nmol / L, 25 nmol / L, 12.5 nmol / L, 6.25 nmol / L, 3.125 nmol / L, 1.5625 nmol / L, 0 nmol / L), and prepared 10 mM glycine for sensor regeneration. The prepared solutions were transferred to 96-well plates, and the detection program was set up according to the cyclic sequence of baseline 1 (equilibration), Loading (antibody binding), baseline 2 (equilibration), Association (antigen binding), Dissociation (antigen dissociation), Regeneration, and Neutralization, so that each antibody could bind to different concentrations of human TL1A antigen. Finally, the results were analyzed using Octet Analysis Studio. The software 12.2 was used to analyze the data, and the specific affinity data of each antibody to human TL1A protein was obtained by fitting the binding and dissociation curves; the smaller the KD value, the stronger the binding activity. The specific data are shown in Table 2.

[0296] Table 2: Affinity (BLI) of different anti-human TL1A monoclonal antibodies to human TL1A protein.

[0297] Example 4: Study on the activity of anti-TL1A monoclonal antibody in blocking TL1A-activated transcription factor NFκB

[0298] The NFκB-Luc-TF-1 cell line was stimulated with human TL1A, and anti-TL1A antibody was added to block the TL1A-activated transcription factor NFκB. The expression of luciferase was detected to determine the activity of anti-TL1A antibody in blocking the TL1A-activated transcription factor NFκB.

[0299] First, NFκB-Luc-TF-1 cells were plated at a density of 8*102. 5Cells / ml were inoculated with 50 μl per well; then, antibodies (antibodies C2C1L, C5A8A, C19E5B, control antibody RVT-3101 (amino acid sequence of heavy chain variable region as shown in SEQ ID NO:80, amino acid sequence of light chain variable region as shown in SEQ ID NO:81) or PRA023 (amino acid sequence of heavy chain variable region as shown in SEQ ID NO:82, amino acid sequence of light chain variable region as shown in SEQ ID NO:83)) were prepared and serially diluted 3-fold in each well. Cells were incubated at 37°C for 4 hours. Luciferase in the supernatant was detected using a one-lite luciferase detection kit (Vazyme, DD1203-01). Data processing and plotting were performed using GraphPad Prism 8.0 software. Binding curves and IC50 were obtained through four-parameter nonlinear fitting. 50 Values ​​and other parameters; IC 50 The smaller the value, the stronger the blocking activity. The results are shown in Table 3 and Figure 1.

[0300] The RVT-3101 heavy chain variable region sequence is:

[0301] The RVT-3101 light chain variable region sequence is:

[0302] The PRA023 heavy chain variable region sequence is:

[0303] The variable region sequence of the PRA023 light chain is:

[0304] Table 3: Ability of different anti-TL1A monoclonal antibodies to block the TL1A-activated NFκB signaling pathway

[0305] Example 5: Virtual affinity maturation of anti-TL1A monoclonal antibody

[0306] 1. Based on antibody C5A8A, the amino acid sequence of the variable region of the anti-TL1A monoclonal antibody was modeled using Discovery Studio software. The antibody model and the crystal structure of human TL1A protein numbered 2RE9 in PDB were used as ligand and receptor, respectively, for molecular docking simulation to obtain a series of docking conformations. The rationality of different docking conformations was judged and screened, and the conformations that were consistent with the experimental results were selected. The specific sites on the antibody that interact with the antigen were analyzed and amino acid scanning mutations were performed. The mutation with the largest binding free energy was selected for recombinant expression to obtain the mutated antibody variants (i.e., antibodies PO16-C5AA and PO16-C5AE). The variable region sequence and CDR sequence of each antibody are shown in Table 4-1.

[0307] Table 4-1: Serial numbers of amino acids in the variable region of anti-TL1A humanized antibodies

[0308] 2. Based on antibodies C5A8A and PO16-C5AA, the amino acid sequence of the framework region of the anti-TL1A monoclonal antibody was mutated using Discovery Studio software to obtain mutated antibody variants (i.e., antibodies PO16-C5AB, PO16-C5AC, and PO16-C5AD). The variable region sequence and CDR sequence of each antibody are shown in Table 4-2.

[0309] Table 4-2: Serial numbers of amino acids in the variable region of anti-TL1A humanized antibodies

[0310] Example 6: Phage affinity maturation of anti-TL1A monoclonal antibody

[0311] Based on antibody C5A8A, the heavy chain variable region of the anti-TL1A monoclonal antibody was annotated using Kabat. Saturation mutations were performed on heavy chains CDRH1, CDRH2, and CDRH3 to construct libraries. The mutant libraries were then packaged and expressed using M13K07 helper phage (NEB, N0315S). After blocking both libraries, four rounds of screening were performed using biotinylated TL1A antigen: 200 ng for the first round, 20 ng for the second, 1 ng for the third, and 0.1 ng for the fourth. The phages were incubated overnight at room temperature or 4°C. After each phage-antigen binding, the phages were washed 15 times with PBST*NaCl, followed by two washes with PBS to remove non-specifically bound phages. Then, 500 μL of 100 mM Glycine-HCl (pH 2.2) was added to each library, and the mixture was eluted by rotation at room temperature for 10 minutes. Immediately afterwards, 22 μL of 2M Glycine-HCl was added. TRIS-HCl (pH 9.1) was used to elute and neutralize phages that specifically bind to the TL1A protein; finally, the aggregated clones were sequenced to express recombinant eukaryotic antibodies; Table 5 lists the variable region sequences and CDR sequences of the enriched single-clonal mutant clones obtained by screening.

[0312] Table 5: Serial numbers of amino acids in the variable region of anti-TL1A humanized antibodies

[0313] Example 7: Detection of the affinity of anti-human TL1A humanized antibody for human TL1A protein using SPR

[0314] Affinity assays were performed on different anti-human TL1A humanized antibodies using the Biacore T200:

[0315] First, anti-human Fc antibodies were immobilized onto a CM5 chip (Cytiva, BR100530). Then, different anti-human TL1A humanized antibody samples (i.e., antibodies C5A8A, PO16-C5AA, PO16-C5AB, PO16-C5AC, PO16-C5AD, PO16-C5AE, C5T5, C5T15, C5T18, C5T20, C5T28, and C5T35) were diluted to 2 μg / mL using 1X HBS-EP buffer, and 10 mM glycine (pH 1.5) was prepared to regenerate the chip. The contact time between the different antibodies and the chip immobilized with anti-human Fc antibodies was adjusted so that the antibody binding response value on the chip reached 100 RU. Then, 1X HBS-EP buffer was used to further refine the chip. The HBS-EP+buffer was used to dilute human TL1A protein (KaiKa, catalog number FSF-HM415) at an initial concentration of 100 nM, and then serially diluted in three-fold increments to a total of eight concentrations. The assays were performed in a cyclical sequence: Capture (binding to different anti-TL1A monoclonal antibodies), Contact (binding to different concentrations of human TL1A protein), Dissociation (dissociating the protein), and Regeneration. After the program completed, the data were analyzed using Biacore T200 Evaluation Software. Binding and dissociation curves were used to fit the specific affinity data of each antibody for human TL1A protein. A smaller KD value indicates stronger binding activity. The results are shown in Table 6.

[0316] Table 6: Affinity (SPR) of different anti-human TL1A humanized antibodies to human TL1A protein.

[0317] Example 8: Recombinant expression of variant antibodies with mutation sites from maturation sources of different affinities and their SPR detection

[0318] 1. The molecules with enhanced affinity verified in Example 7 were analyzed for origin and sequence. Clones with better mutation sites that do not overlap with the parent antibody CDR were selected for recombination expression. The variable region sequence and CDR sequence of the recombinant variant are shown in Table 7-1.

[0319] Table 7-1: Serial numbers of amino acids in the variable region of anti-TL1A humanized antibodies

[0320] 2. Based on antibodies PO16-C5AA, C5033307, and C503H6M, the amino acid sequence of the framework region of the anti-TL1A monoclonal antibody was mutated using Discovery Studio software to obtain mutated antibody variants (i.e., antibodies C50301, C503013307, and C50301H6M). The variable region sequence and CDR sequence of each antibody are shown in Table 7-2.

[0321] Table 7-2: Serial numbers of amino acids in the variable region of anti-TL1A humanized antibodies

[0322] 3. The anti-TL1A antibodies obtained in steps 1 and 2 of this embodiment, which combine mutation sites with different maturation sources with different affinities, were tested for their affinity for human TL1A protein by SPR. The results are shown in Table 8.

[0323] Table 8: Affinity (SPR) of different anti-human TL1A monoclonal antibodies combined with mutant variants to human TL1A protein.

[0324] Example 9: Humanization of Combined Affinity Maturation Antibodies and its SPR Detection

[0325] Humanization of the mature variant with merging affinity:

[0326] First, Discovery Studio was used to model the antibody. A human antibody with a sequence close to that of the mouse antibody was selected for CDR transplantation. Key amino acids responsible for structural stability in the mouse antibody model were reverse-mutated. This application exemplarily demonstrates the humanized antibody HC503H6M based on antibody C503H6M. The variable region sequence and CDR sequence of antibody HC503H6M are shown in Table 9. The affinity results of antibody HC503H6M, control antibody TEV-48574 (amino acid sequence of heavy chain variable region as shown in SEQ ID NO:84, amino acid sequence of light chain variable region as shown in SEQ ID NO:85), and PRA023, as shown in Table 10, were obtained by SPR detection.

[0327] The heavy chain variable region sequence of TEV-48574 is:

[0328] The variable region sequence of the TEV-48574 light chain is:

[0329] Table 9: Serial numbers of amino acids in the variable region of antibody HC503H6M

[0330] Table 10: Affinity test results (SPR) of antibody HC503H6M to human TL1A protein

[0331] Example 10: Detection of the activity of anti-TL1A humanized antibody in blocking TL1A-activated transcription factor NFκB

[0332] The DR3-NFKB-Luc-Jurkat cell line was stimulated with human TL1A, and different anti-TL1A humanized antibodies were added to block the TL1A-activated transcription factor NFκB. The expression of luciferase was detected to determine the activity of the anti-TL1A humanized antibody in blocking the TL1A-activated transcription factor NFκB.

[0333] First, DR3-NFKB-Luc-Jurkat cells were plated at a density of 4*102. 5 Cells / ml were seeded at a concentration of 50 μl per well. Antibodies (the antibodies obtained in Examples 5, 6, and 9, and the control antibody RVT-3101) were then prepared and serially diluted with 200 ng / ml human TL1A protein solution. The initial antibody concentration in each well was 10 nM, with 5-fold serial dilutions to obtain a total of 9 concentrations. Cells were incubated at 37°C for 3 hours. Luciferase in the supernatant was detected using a one-lite luciferase detection kit (Vazyme, DD1203-01). Data processing and plotting were performed using GraphPad Prism 8.0 software. Binding curves and IC50 values ​​were obtained through four-parameter nonlinear fitting. 50 Values ​​and other parameters; IC 50 The smaller the value, the stronger the blocking activity. The results showed that all antibodies possessed the ability to block the human TL1A protein-activated NFκB signaling pathway. The results for antibody HC503H6M, which is exemplarily shown in this application, are detailed in Table 6 and Figure 2.

[0334] Table 6: Ability of different anti-TL1A humanized antibodies to block the human TL1A protein-activated NFκB signaling pathway

[0335] Example 11: Hydrophilicity / Hydrophobicity Study of Anti-TL1A Monoclonal Antibody

[0336] The anti-TL1A monoclonal antibodies (the antibodies obtained in Examples 5, 6, and 9) were diluted with mobile phase A (1.8M ammonium sulfate + 0.1M sodium dihydrogen phosphate solution, pH 6.5) to prepare a final test solution containing 1.0M ammonium sulfate. Mobile phases A (1.8M ammonium sulfate + 0.1M sodium dihydrogen phosphate solution, pH 6.5) and B (0.1M sodium dihydrogen phosphate solution, pH 6.5) were used. The chromatographic column (manufacturer: Saifen Technology, model: Protemix HIC Butyl-NP5 4.6*10mm, 5μm), wavelength 214nm, flow rate 1.0mL / min, injection volume 5μg, column temperature 25℃, and sample chamber temperature 8℃ were used. The gradient elution method was as follows: 0–5 min, 44% B; 5–15 min, 44% B → 100% B; 15–20 min, 100% B; 20.1–25 min, 44% B. Elution was performed, and the hydrophilicity of the target protein was determined by comparing the retention times of the elution peaks. Shorter elution times indicated stronger hydrophilicity, and stronger hydrophilic proteins had better solubility. The results for antibody HC503H6M are exemplarily shown in Table 12.

[0337] Table 12: Hydrophilicity and hydrophobicity of anti-TL1A monoclonal antibodies

[0338] Example 12: Solubility Study of Anti-TL1A Monoclonal Antibody

[0339] Rapid concentration and solubility assay of anti-TL1A monoclonal antibody:

[0340] First, 50 mg of the test sample (the antibodies obtained in Examples 5, 6, and 9, and the control antibody RVT-3101) was changed to 20 mM His-HCl solvent, and then transferred to an ultrafiltration concentration tube for multiple centrifugations. Each time, samples were taken for dilution and concentration testing. All antibodies showed good solubility. This example exemplifies the solubility of some samples, as shown in Figure 3. After three concentrations of the test sample, the concentration of antibody HC503H6M reached 149.0 mg / ml.

[0341] Example 13: Detection of the ability of anti-TL1A monoclonal antibody to block the coordinated stimulation of human PBMCs by human TL1A and IL12 / 18 to produce IFN-γ.

[0342] Human PBMCs (PB050C) were stimulated in a coordinated manner with human TL1A (Kaika, FSF-HM415) and IL12 / 18 (Acro, IL2-H4210 / IL8-H5113), while different anti-TL1A antibodies or their variants (antibodies obtained in Examples 5, 6, and 9, as well as control antibodies TEV-48574, RVT-3101, and PRA023) were added to block the production of IFN-γ. The ability of different antibodies to block the production of IFN-γ was detected by the Human IFN-γ ELISA Kit (Elabscience, E-EL-H0108).

[0343] First, the frozen PMBCs were thawed at a cell density of 1.05*10⁻⁶. 6 Cells / ml: Human IL-12 (final concentration 2 ng / ml), human IL-18 (final concentration 100 μg / ml), and human TL1A protein (final concentration 100 ng / ml) were added to cells. 190 μl of the above suspension was added to each well, followed by 10 μl of different concentrations of anti-TL1A antibody (antibodies obtained in Examples 5, 6, and 9, and control antibodies TEV-48574, RVT-3101, and PRA023). The antibody concentration in each well was decreased three-fold from an initial concentration of 200 nM to 0.09 nM, resulting in eight inhibitory concentrations for each antibody. The IFN-γ concentration in each well was calculated based on the kit's standard curve. Data processing and plotting were performed using GraphPad Prism 8.0 software. Binding curves and IC50 values ​​were obtained through four-parameter nonlinear fitting. 50 Values ​​and other parameters; IC 50 The smaller the value, the stronger the blocking activity. The results showed that the antibodies in this application could block the coordinated stimulation of human TL1A and IL12 / 18 by human PBMCs to produce IFN-γ. This application provides illustrative results for some antibodies, see Table 13 and Figure 4.

[0344] Table 13: Ability of each antibody to block the coordinated stimulation of human PBMCs by TL1A and IL12 / 18 to produce IFN-γ

[0345] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0346] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. An anti-TL1A antibody or its antigen-binding fragment, characterized in that, Including HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3; The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the HCDR1, HCDR2, and HCDR3 of the heavy chain variable region defined by any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, and SEQ ID NO:

41. The LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the LCDR1, LCDR2, and LCDR3 of the light chain variable region defined by any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, and SEQ ID NO:

42.

2. The anti-TL1A antibody or its antigen-binding fragment according to claim 1, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of HCDR1, HCDR2, and HCDR3 in the heavy chain variable region defined by SEQ ID NO:1; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of LCDR1, LCDR2, and LCDR3 in the light chain variable region defined by SEQ ID NO:2; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of HCDR1, HCDR2, and HCDR3 in the heavy chain variable region defined in SEQ ID NO:3; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of LCDR1, LCDR2, and LCDR3 in the light chain variable region defined in SEQ ID NO:4; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:5; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:6; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:7; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:8; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:9; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:10; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:10; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:12; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:13; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:14; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:15; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:16; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:17; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:18; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:19; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:20; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:21; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:22; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:23; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:24; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:25; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:26; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:27; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:28; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:29; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:30; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:31; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:32; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the HCDR1, HCDR2, and HCDR3 in the heavy chain variable region defined in SEQ ID NO:33; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the LCDR1, LCDR2, and LCDR3 in the light chain variable region defined in SEQ ID NO:34; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:35; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:36; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:37; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:38; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:39; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:40; or The HCDR1, HCDR2, and HCDR3 are amino acid sequences identical to those of the heavy chain variable region defined in SEQ ID NO:41; the LCDR1, LCDR2, and LCDR3 are amino acid sequences identical to those of the light chain variable region defined in SEQ ID NO:

42. 2) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined by the Kabat, Chothia, AbM, Contact, or IMGT system.

3. An anti-TL1A antibody or its antigen-binding fragment, characterized in that, Including HCDR1, HCDR2, HCDR3 and LCDR1, LCDR2, LCDR3; HCDR1: X1YX2MH or X1YX2MN, where X1 is S, G, R or V, and X2 is I or T; HCDR2: X3X4NPYX5X6X7TX8YX9X 10 KFKG, where X3 is Y or L, X4 is V or I, X5 is N or S, X6 is D or G, X7 is V or G, X8 is N, T or K, X9 is I or N, X 10 For E or Q; HCDR3:X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 Y, where X 11 For Y, V, or H, X 12 For Y, Q, or R, X 13 For Y or L, X 14 For G or R, X 15 For N, Y, H, A, R, E, M or P, X 16 For P, D, V, L or S, X 17 For G or W, X 18 For F, L, M or Y, X 19 The answer is either A or D; LCDR1:X 20 ASX 21 X 22 VX 23 X 24 X 25 X 26 X 27 , where X 20 For K or S, X 21 For Q or S, X 22 For D or S, X 23 For G, T, or S, X 24 For T, Y, or A, X 25 For M or A, X 26 For V or H, X 27 It can be A or empty; LCDR2:X 28 X 29 X 30 X 31 X 32 X 33 X 34 , where X 28 For W or D, X 29 For T or A, X 30 For S or A, X 31 For T or K, X 32 For R or L, X 33 For H or A, X 34 For T or S; LCDR3: QQX 35 SSX 36 PX 37 T, where X 35 For Y, W, or H, X 36 For Y, D, or S, X 37 It can be Y or W.

4. The anti-TL1A antibody or its antigen-binding fragment according to claim 3, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) In HCDR1, X1 is G, R, or V, and X2 is T; or X1 is S, X2 is I; 2) In HCDR2, X3 is L, X4 is I, X5 is S, X6 is G, X7 is V, X8 is T, X9 is N, and X... 10 For Q; or X3 is Y, X4 is V or I, X5 is N, X6 is D, X7 is G, X8 is N or K, X9 is I, X 10 E; 3) In the HCDR3, X 11 Let V, X 12 For Q or R, X 13 For Y or L, X 14 Let R, X 15 For Y, A, R, E, M or P, X 16 For D, V, L or S, X 17 For G, X 18 For L, M, or Y, X 19 It is either A or D; or X 11 For Y or H, X 12 Let Y and X be the numbers. 13 For Y or L, X 14 For G, X 15 For N or H, X 16 Let P, X 17 For W, X 18 Let F, X 19 A; 4) In the LCDR1, X 20 Let S and X be the values ​​of S and X. 21 Let S and X be the values ​​of S and X. 22 Let S and X be the values ​​of S and X. 23 Let T, X 24 Let Y and X be the numbers. 25 Let M and X be the numbers. 26 For H, X 27 Empty; or X 20 Let K, X 21 For Q, X 22 For D, X 23 For G or S, X 24 For T or A, X 25 Let A and X be the two numbers. 26 Let V, X 27 A; 5) In the LCDR2, X 28 For D, X 29 Let T, X 30 Let S and X be the values ​​of S and X. 31 Let K, X 32 Let L and X be the numbers. 33 Let A and X be the two numbers. 34 For S; or X 28 For W, X 29 For T or A, X 30 For S or A, X 31 Let T, X 32 Let R, X 33 For H, X 34 Let T be the value of T. 6) In the LCDR3, X 35 For W, X 36 For D, X 37 For Y; or X 35 For Y or H, X 36 For Y or S, X 37 It can be Y or W.

5. The anti-TL1A antibody or its antigen-binding fragment according to claim 3, characterized in that, HCDR1: X1YTMH, where X1 is G, R, or V; HCDR2: LINPYSGVTTYNQKFKG; HCDR3: VX 12 X 13 RX 15 X 16 GX 18 X 19 Y, where X 12 For Q or R, X 13 For Y or L, X 15 For Y, A, R, E, M or P, X 16 For D, V, L or S, X 18 For L, M, or Y, X 19 The answer is either A or D; LCDR1: SASSVTYMH; LCDR2: DTSKLAS; LCDR3:QQWSSDPYT.

6. The anti-TL1A antibody or its antigen-binding fragment according to any one of claims 1 to 5, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) The anti-TL1A antibody or its antigen-binding fragment comprises: Having the amino acid sequence shown in SEQ ID NO:43 for HCDR1, the amino acid sequence shown in SEQ ID NO:44 for HCDR2, the amino acid sequence shown in SEQ ID NO:45 for HCDR3, and the amino acid sequence shown in SEQ ID NO:46 for LCDR1, the amino acid sequence shown in SEQ ID NO:47 for LCDR2, and the amino acid sequence shown in SEQ ID NO:48 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:51 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:43 for HCDR1, the amino acid sequence shown in SEQ ID NO:55 for HCDR2, the amino acid sequence shown in SEQ ID NO:56 for HCDR3, and the amino acid sequence shown in SEQ ID NO:57 for LCDR1, the amino acid sequence shown in SEQ ID NO:58 for LCDR2, and the amino acid sequence shown in SEQ ID NO:59 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:60 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:51 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:61 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:51 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, having the amino acid sequence shown in SEQ ID NO:50 for HCDR2, having the amino acid sequence shown in SEQ ID NO:62 for HCDR3, and having the amino acid sequence shown in SEQ ID NO:52 for LCDR1, having the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and having the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:63 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:64 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, having the amino acid sequence shown in SEQ ID NO:50 for HCDR2, having the amino acid sequence shown in SEQ ID NO:65 for HCDR3, and having the amino acid sequence shown in SEQ ID NO:52 for LCDR1, having the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and having the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:66 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:49 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:67 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:60 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:68 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or Having the amino acid sequence shown in SEQ ID NO:60 for HCDR1, the amino acid sequence shown in SEQ ID NO:50 for HCDR2, the amino acid sequence shown in SEQ ID NO:69 for HCDR3, and the amino acid sequence shown in SEQ ID NO:52 for LCDR1, the amino acid sequence shown in SEQ ID NO:53 for LCDR2, and the amino acid sequence shown in SEQ ID NO:54 for LCDR3; or The amino acid sequences shown in SEQ ID NO:60 are HCDR1, SEQ ID NO:50 are HCDR2, SEQ ID NO:65 are HCDR3, and SEQ ID NO:52 are LCDR1, SEQ ID NO:53 are LCDR2, and SEQ ID NO:54 are LCDR3. 2) The anti-TL1A antibody or its antigen-binding fragment includes a heavy chain framework region and / or a light chain framework region.

7. The anti-TL1A antibody or its antigen-binding fragment according to claim 6, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) At least a portion of the heavy chain framework region and / or light chain framework region is derived from at least one of the following: mouse antibody, primate antibody, bovine antibody, equine antibody, dairy bovine antibody, porcine antibody, sheep antibody, goat antibody, canine antibody, feline antibody, rabbit antibody, camel antibody, donkey antibody, deer antibody, mink antibody, chicken antibody, duck antibody, goose antibody, turkey antibody, fighting rooster antibody, or mutants thereof; 2) The anti-TL1A antibody or its antigen-binding fragment comprises: The heavy chain variable region shown in any of the amino acid sequences of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41; and The light chain variable region is shown in any of the amino acid sequences of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, and SEQ ID NO:

42.

8. The anti-TL1A antibody or its antigen-binding fragment according to claim 6, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) At least a portion of the heavy chain framework region and / or light chain framework region is derived from at least one of rabbit antibody or its mutant, mouse antibody or its mutant, and human antibody or its mutant; 2) The anti-TL1A antibody or its antigen-binding fragment comprises: The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:1, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:2; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:3, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:4; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:5, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:6; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:7, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:8; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:9, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:10; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:11, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:12; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:13, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:14; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:15, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:16; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:17, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:18; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:19, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:20; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:21, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:22; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:23, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:24; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:25, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:26; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:27, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:28; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:29, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:30; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:31, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:32; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:33, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:34; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:35, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:36; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:37, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:38; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:39, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:40; or The heavy chain variable region as shown in the amino acid sequence of SEQ ID NO:41, and the light chain variable region as shown in the amino acid sequence of SEQ ID NO:

42.

9. The anti-TL1A antibody or its antigen-binding fragment according to any one of claims 1 to 5, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) Further includes a heavy chain constant region and / or a light chain constant region; 2) The antibody comprises at least one selected from polyclonal antibodies, full-length monoclonal antibodies, Fab antibodies, Fab' antibodies, F(ab')2 antibodies, Fv antibodies, single-chain antibodies, and the smallest recognition unit; or The antigen-binding fragment includes at least one selected from the following: F(ab')2 fragment, Fab' fragment, Fab fragment, F(ab)2 fragment, Fv fragment, scFv fragment, scFv-Fc fusion protein, scFv-Fv fusion protein, and minimum recognition unit.

10. The anti-TL1A antibody or its antigen-binding fragment according to claim 9, characterized in that, The anti-TL1A antibody or its antigen-binding fragment meets one or more of the following conditions: 1) At least a portion of at least one of the heavy chain constant region and the light chain constant region is derived from at least one of mouse antibodies, primate antibodies, bovine antibodies, equine antibodies, dairy bovine antibodies, porcine antibodies, sheep antibodies, goat antibodies, canine antibodies, feline antibodies, rabbit antibodies, camel antibodies, donkey antibodies, deer antibodies, mink antibodies, chicken antibodies, duck antibodies, goose antibodies, turkey antibodies, fighting rooster antibodies, or mutants thereof; 2) The heavy chain constant region includes a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD; or The light chain constant region includes a light chain constant region selected from κ-type or λ-type; 3) The light chain constant region and the heavy chain constant region are both derived from at least one of rabbit-derived antibodies or their mutants, mouse-derived antibodies or their mutants, and human-derived antibodies or their mutants; 4) The N-end of the heavy chain constant region is connected to the C-end of the heavy chain variable region; and / or The N-end of the constant region of the light chain is connected to the C-end of the variable region of the light chain; 5) The heavy chain constant region has an amino acid sequence as shown in SEQ ID NO:70; 6) The light chain constant region has an amino acid sequence as shown in SEQ ID NO:

71.

11. A nucleic acid molecule, expression vector, or recombinant cell, characterized in that, The nucleic acid molecule encodes the anti-TL1A antibody or its antigen-binding fragment as described in any one of claims 1 to 4; The expression vector carries the aforementioned nucleic acid molecules; The recombinant cells include: Carrying the aforementioned nucleic acid molecules or the aforementioned expression vectors; or, Express the anti-TL1A antibody or antigen-binding fragment thereof as described in any one of claims 1 to 10.

12. The nucleic acid molecule, expression vector, or recombinant cell according to claim 11, characterized in that, One or more of the following conditions must be met: 1) The nucleic acid molecule is DNA; 2) The expression vector includes those selected from eukaryotic expression vectors or prokaryotic expression vectors; 3) The recombinant cells are obtained by introducing the above-mentioned expression vector into the host cells.

13. A coupling, characterized in that, Include: The anti-TL1A antibody or its antigen-binding fragment according to any one of claims 1 to 10; and The coupling portion is linked to the anti-TL1A antibody or its antigen-binding fragment.

14. The coupling according to claim 13, characterized in that, The coupling portion is selected from at least one of purification tags or labels, carriers, drugs, toxins, cytokines, and modifiers.

15. The coupling according to claim 14, characterized in that, The coupling satisfies one or more of the following conditions: 1) The carrier is selected from at least one of magnetic microspheres, plastic microspheres, plastic microparticles, microporous plates, glass, capillaries, nylon and nitrocellulose membranes; 2) The purification tag or label is selected from at least one of protein tags, colloidal gold, radioactive labels, luminescent substances, colored substances, enzymes, biotin / antibiotin protein, and spin labels; 3) The purification tag or label is selected from at least one of fluorescent labels, chromophore labels, and electron-dense labels; 4) The protein tag includes at least one of the following: His tag, Flag tag, GST tag, MBP tag, SUMO tag and C-Myc tag.

16. A reagent or kit, characterized in that, include: The anti-TL1A antibody or its antigen-binding fragment as described in any one of claims 1 to 10, or the conjugate as described in any one of claims 13 to 15.

17. A pharmaceutical composition, characterized in that, include: The anti-TL1A antibody or its antigen-binding fragment according to any one of claims 1 to 10; the nucleic acid molecule, expression vector, recombinant cell according to any one of claims 11 to 12; or the conjugate according to any one of claims 13 to 15; and Optional pharmaceutically acceptable excipients.

18. The anti-TL1A antibody or antigen-binding fragment according to any one of claims 1 to 10, the nucleic acid molecule, expression vector, or recombinant cell according to any one of claims 11 to 12, the conjugate according to any one of claims 13 to 15, or the pharmaceutical composition according to claim 17, for the prevention and / or treatment of TL1A-mediated diseases or for the detection of TL1A, or having the following uses: Use in the preparation of multispecific antibodies, fusion proteins, pharmaceuticals, or kits, wherein the pharmaceuticals are used to prevent and / or treat TL1A-mediated diseases, and the kits are used to detect TL1A; Prevention and / or treatment of TL1A-mediated diseases; Detect TL1A.

19. A method for treating TL1A-mediated related diseases, characterized in that, include: Administer to a subject a pharmaceutically acceptable dose of the anti-TL1A antibody or antigen-binding fragment of any one of claims 1 to 10, the nucleic acid molecule, expression vector, or recombinant cell of any one of claims 11 to 12, the conjugate of any one of claims 13 to 15, or the pharmaceutical composition of claim 17.

20. The use according to claim 18 or the method according to claim 19, characterized in that, The TL1A-mediated diseases include inflammatory or immune diseases.

21. The use or method according to claim 20, characterized in that, The inflammatory or immune diseases mentioned include allergies, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, fibrosis-related diseases, medically refractory ulcerative colitis, systemic lupus erythematosus, psoriasis, type 1 diabetes, and transplant rejection; or The inflammatory or immune diseases mentioned include Crohn's disease, ulcerative colitis, intestinal fibrosis, pulmonary fibrosis, and liver fibrosis.

22. A method for detecting TL1A, characterized in that, include: An immune complex is formed by contacting the anti-TL1A antibody or its antigen-binding fragment as described in any one of claims 1 to 10, the conjugate as described in any one of claims 13 to 15, or the reagent or kit as described in claim 16 with the sample to be tested. Based on the signal from the immune complex, determine whether the sample to be tested contains TL1A or whether it contains TL1A-expressing cells, or determine the content of TL1A or TL1A-expressing cells in the sample to be tested.

23. The method according to claim 22, characterized in that, The signal of the immune complex is detected by at least one of ELISA, WB, and IHC; or The signal includes a fluorescence signal.

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