Anti-human-TL1a antibody having dual-blocking activity against dcr3 and dr3

Abstract

The present invention belongs to the field of biomedicine, and relates to an anti-human-TL1A antibody having a dual-blocking activity against DcR3 and DR3, and the use thereof, which antibody is capable of blocking the binding of TL1A to DcR3 and TL1A to DR3. The present invention further relates to a nucleic acid molecule encoding the antibody, a vector, a host cell, a composition, and the use thereof for treating diseases.

Description

Anti-human TL1A antibody with dual blocking functions of DcR3 and DR3

[0001] Cross-reference to related applications

[0002] This patent application claims priority to Chinese patent application CN202510497871.7, filed on April 18, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of biomedicine and relates to anti-human TL1A antibodies with dual blocking functions of DcR3 and DR3, as well as nucleic acid molecules encoding such antibodies, vectors, host cells, compositions, multispecific molecules, conjugates, and their applications in the treatment of diseases. Background Technology

[0004] Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases affecting the digestive tract, including ulcerative colitis (UC) and Crohn's disease (CD). Treatments for IBD include aminosalicylic acid preparations, glucocorticoids, and immunosuppressants. While anti-tumor necrosis factor-alpha (TNF-α) biologics such as adalimumab have shown good efficacy, they also carry certain side effects and risks. TNF-α is a major cytokine combating intracellular infection; inhibition of its activity may lead to reactivation of intracellular infectious microorganisms, increasing the likelihood of infection and malignant tumors in patients. New inhibitors targeting different inflammatory pathways are also under extensive development, such as ustekinumab targeting IL12 and tofacitinib, a JAK inhibitor. Despite the availability of various drugs and methods for treating IBD, remission rates in induction remission clinical trials remain below 50%, indicating that current treatments cannot achieve ideal therapeutic effects. Existing therapies do not yet meet the clinical needs for IBD treatment.

[0005] TL1A, also known as TNFSF15, is a member of the tumor necrosis factor superfamily and is mainly expressed in immune cells such as monocytes, macrophages, dendritic cells, and T cells. TL1A is a 251-amino acid protein that is a single-pass transmembrane protein and forms a homotrimer under physiological conditions. Its extracellular region contains a stalk region, which can be recognized and cleaved by enzymes such as ADAMs and MMPs, and secreted in a soluble form. Both conformations of TL1A can bind to the functional receptor death receptor 3 (DR3) and decoy receptor 3 (DcR3). DR3 is mainly expressed by activated lymphocytes and innate lymphoid cells (ILCs) and possesses the TNF receptor family death domain. When TL1A binds to its receptor DR3, DR3 recruits the death structure-associated monoclonal adaptor protein TRADD-TNFRSF1A to form a signaling complex. This complex contains TNF receptor-associated factor 2 (TRAF2) and RIP, which sequentially activate the mitogen-activated protein kinase (MAPK) and nuclear factor κ-light chain enhancer (NF-κB) pathways in activated B cells, mediating co-stimulation and inflammatory spread. When the NF-κB pathway is not activated, this domain can drive apoptotic signaling, promoting caspase activation and apoptosis. DR3 and DcR3 are endogenous receptors for TL1A; DR3 binding to TL1A activates the receptor, transmitting signals downstream, while DcR3 is responsible for clearing free TL1A.

[0006] High expression of TL1A is frequently observed in patients with autoimmune inflammation, and spontaneous inflammatory bowel disease has been observed in TL1A transgenic mouse models. In ulcerative colitis and Crohn's disease models, TL1A-DR3 interaction is associated with the pathogenesis of inflammation by stimulating IL-13 production or promoting the IL-17 / IFN-γ response. Simultaneously, TL1A / DR3 signaling plays a multifaceted role in mucosal immunity. As a co-stimulatory module, the ultimate effect of TL1A / DR3 is influenced by the cytokine environment of specific tissue microenvironments, primarily Th1, Th2, Th17, and Th9, but it can also affect the regulation of lymphocyte and ILC2 / ILC3 function. Studies have shown that TL1A-DR3 signaling blockers can alleviate established chronic colitis symptoms in animal models, reduce intestinal inflammation, and decrease collagen deposition, thereby alleviating inflammatory-induced intestinal wall fibrosis. Therefore, blocking TL1A / DR3 may have significant therapeutic value for various chronic inflammatory diseases caused by different T effector cell immune phenotypes.

[0007] Overview

[0008] The inventors of this disclosure have screened for specific antibodies targeting human TL1A using various techniques. In some embodiments, the antibody is an anti-human TL1A antibody with dual blocking functions of DcR3 and DR3; in some embodiments, the antibody is capable of blocking the binding of human TL1A to DR3 and also blocking the binding of human TL1A to DcR3; in some embodiments, the antibody is capable of binding to the human TL1A antigen, thereby providing the following aspects.

[0009] In a first aspect, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein,

[0010] The heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the same amino acid sequences as HCDR1, HCDR2, and HCDR3 in VH, which have at least 80% sequence identity with any of the sequences in SEQ ID NO:48-64 and 1-5, and / or

[0011] The light chain variable regions LCDR1, LCDR2, and LCDR3 each contain the same amino acid sequences as LCDR1, LCDR2, and LCDR3 in the VL that have at least 80% sequence identity with any of the sequences in SEQ ID NO:65-78 and 6-10.

[0012] In addition, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region is as shown in any one of SEQ ID NO:48-64 and 1-5, or has at least 80% sequence identity with any one of SEQ ID NO:48-64 and 1-5, and the light chain variable region is as shown in any one of SEQ ID NO:65-78 and 6-10, or has at least 80% sequence identity with any one of SEQ ID NO:65-78 and 6-10.

[0013] In a second aspect, this disclosure provides a nucleic acid molecule encoding the anti-human TL1A antibody described in any of the preceding claims.

[0014] In a third aspect, this disclosure provides a carrier comprising the nucleic acid molecules described in any of the preceding claims.

[0015] In a fourth aspect, this disclosure provides a host cell comprising any of the nucleic acid molecules or vectors described in the preceding claims.

[0016] In a fifth aspect, this disclosure provides a method for preparing an anti-human TL1A antibody, comprising culturing the host cells described in any of the preceding claims under conditions suitable for expressing the antibody, and recovering the antibody from the cultured host cell culture.

[0017] In a sixth aspect, this disclosure provides a multispecific molecule comprising the anti-human TL1A antibody as described in any of the preceding claims.

[0018] In a seventh aspect, this disclosure provides a conjugate comprising the anti-human TL1A antibody as described in any of the preceding claims, and a conjugated portion.

[0019] In an eighth aspect, this disclosure provides a pharmaceutical composition comprising an anti-human TL1A antibody, a multispecific molecule, a conjugate, a nucleic acid molecule, a carrier or cell, and a pharmaceutically acceptable carrier as described in any of the preceding claims.

[0020] In a ninth aspect, this disclosure provides a treatment method comprising administering to a subject in need a therapeutically effective amount of any of the preceding anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, carrier, cell, or pharmaceutical composition.

[0021] In a tenth aspect, this disclosure provides the use of the anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, carrier, cell or pharmaceutical composition described in any of the preceding claims in the preparation of a medicament.

[0022] In the eleventh aspect, this disclosure provides anti-human TL1A antibodies, multispecific molecules, conjugates, nucleic acid molecules, carriers, cells, or pharmaceutical compositions as described in any of the preceding claims for use as pharmaceuticals.

[0023] In a twelfth aspect, this disclosure provides a method for detecting the presence or level of human TL1A in a sample in vitro, comprising contacting the sample with an anti-human TL1A antibody as described in any of the preceding claims, under conditions that allow the formation of a complex between the antibody and human TL1A, and detecting the formation of the complex. Attached Figure Description

[0024] The invention is further described in the following non-limiting drawings:

[0025] Figure 1: Results of FACS assay for the binding of anti-human TL1A antibody to TL1A-expressing cells;

[0026] Figure 2: Results of ELISA assay for the binding of anti-human TL1A antibody to human TL1A protein;

[0027] Figure 3: Results of ELISA assay for the binding of anti-human TL1A antibody to mouse TL1A protein;

[0028] Figure 4: Neutralization results of anti-human TL1A antibody competing with DR3 for TL1A binding;

[0029] Figure 5: Neutralization results of anti-human TL1A antibody competing with DcR3 for TL1A binding;

[0030] Figure 6: Experimental results of inhibiting apoptosis in TF1 cells with anti-human TL1A antibody.

[0031] Invention Details

[0032] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions in the embodiments of this disclosure are described clearly and completely below. However, this description should not be construed as limiting the scope of this disclosure. Where specific conditions are not specified in the embodiments, conventional conditions or conditions according to the product instructions shall apply. Where the manufacturers of reagents or instruments are not specified, they are all conventional products obtained through commercial purchase. Unless expressly defined in this disclosure, the terminology used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0033] The term "a / an" includes plural references unless the context clearly indicates otherwise. For example, "an antibody" means one or more antibodies. The terms "first" and "second" are used for descriptive purposes only and should not be construed as implying relative importance or the number of technical features indicated. The term "multiple" means at least two, such as 2, 3, etc., unless it is explicitly stated in the text that this is not the case.

[0034] The terms “include” or “have” are understood to mean “include” rather than “exclusive” or “exhaustive”; that is, “includes but is not limited to”. For example, “includes A” means that it includes A, but is not limited to A, such as including “A” or including “A and B”.

[0035] The term "and / or" has both the meanings of "and" and "or," referring to each of a specific feature or any combination thereof. For example, the phrase "A, B and / or C" is intended to cover each of the following: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0036] The term "A, B, and C are the same as a, b, and c, respectively" means that A is the same as a, B is the same as b, and C is the same as c. For example, "HCDR1, HCDR2, and HCDR3 of the heavy chain variable region are the same as HCDR1, HCDR2, and HCDR3 in VH shown in SEQ ID NO:1, respectively" means that HCDR1 of the heavy chain variable region is the same as HCDR1 in VH shown in SEQ ID NO:1, HCDR2 of the heavy chain variable region is the same as HCDR2 in VH shown in SEQ ID NO:1, and HCDR3 of the heavy chain variable region is the same as HCDR3 in VH shown in SEQ ID NO:1.

[0037] The terms “optional,” “optionally,” “optionally,” and “optionally” refer to the occurrence or non-occurrence of the event or condition described following the word, that is, including both the occurrence and non-occurrence of the event or condition. For example, “optionally, the antibody contains a constant region” means that the antibody may or may not contain a constant region.

[0038] The term "about" refers to a range of values ​​that includes a specific numerical value and that a person skilled in the art would reasonably consider similar to that specific value. In some embodiments, the term "about" refers to a range within the standard error of a measurement generally accepted in the art. For example, in some embodiments, "about" refers to a number within + / - 10% of a specific numerical value; in other embodiments, "about" refers to a number within + / - 5% of a specific numerical value.

[0039] The numerical ranges “n to m” or “nm” in this document should be considered to specifically disclose all possible subranges and the individual values ​​within those ranges. For example, the descriptions “1 to 4” or “1-4” should be considered to explicitly disclose the subranges of 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, 3 to 4, etc., and the individual numbers within those ranges: 1, 2, 3, or 4.

[0040] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem., 243, p3558 ((1968)).

[0041] The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a similar manner to naturally occurring amino acids. Naturally occurring amino acids include those encoded by the genetic code and modified amino acids, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Common naturally occurring amino acids include: alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine ​​(Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V). Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the α-carbon bound to hydrogen, carboxyl, amino, and R groups), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. Amino acid analogs typically have modified R groups (e.g., ortholeucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics are chemical compounds that have a structure different from the general chemical structure of amino acids, but function in a similar manner to naturally occurring amino acids.

[0042] The term "amino acid mutation" refers to amino acid substitution (or replacement), deletion, insertion, and modification. Those skilled in the art can substitute, delete, insert, and / or modify amino acids as needed to obtain new constructs, provided the construct has the desired function. Amino acid deletions and insertions can be performed at the amino terminus (N-terminus), middle, and / or carboxyl terminus (C-terminus) of the amino acid sequence. In some embodiments, the amino acid mutation is an amino acid substitution; in some embodiments, the amino acid mutation is a non-conservative amino acid substitution, i.e., replacing one amino acid with another amino acid having a different structure and / or chemical properties. In some embodiments, the amino acid mutation is a conserved amino acid substitution, i.e., replacing one amino acid with another amino acid having similar structure and / or chemical properties. Amino acid substitutions can be performed using non-naturally occurring amino acids or derivatives of 20 natural amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Amino acid mutations can be performed using genetic or chemical methods known in the art; for example, genetic methods include site-directed mutagenesis, PCR, gene synthesis, etc., and methods other than genetic engineering that alter the side chain groups of amino acids include, for example, chemical modification.

[0043] The term "antibody" refers to a protein molecule capable of specifically binding to an antigen. The term "antibody" is used in the broadest sense in this disclosure and encompasses a variety of antibody structures, including but not limited to: monoclonal / polyclonal antibodies, monospecific / multispecific antibodies (e.g., bispecific, trispecific, and tetraspecific antibodies), murine / chimeric / humanized / human antibodies, full-length antibodies / antigen-binding fragments (also called antigen-binding moieties), etc., provided they exhibit the desired antigen-binding activity.

[0044] "Natural antibodies" are naturally occurring immunoglobulin molecules. For example, natural IgG antibodies are heterotetraglycoproteins of approximately 150,000 Daltons, composed of two light chains and two heavy chains linked by disulfide bonds. From the N to the C-terminus, each heavy chain of a natural IgG antibody has a heavy chain variable region (VH), followed by a heavy chain constant region (CH), which includes three constant domains (CH1, CH2, and CH3); similarly, from the N to the C-terminus, each light chain has a light chain variable region (VL), followed by a light chain constant region (CL). Based on whether an antibody contains α, δ, ε, γ, and μ heavy chains, antibodies can be classified into five isotypes: IgA, IgD, IgE, IgG, and IgM. Isotype antibodies can be further divided into different subtypes. For example, the IgG isotype includes four subtypes: IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), and IgG4 (γ4 heavy chain). The IgA isotype is divided into two subtypes: IgA1 (α1 heavy chain) and IgA2 (α2 heavy chain).

[0045] The terms “full-length antibody,” “intact antibody,” and “all antibody” are used interchangeably in this disclosure to refer to antibodies that have a structure similar to that of natural antibodies or that have an Fc domain.

[0046] "Separated antibody" refers to an antibody that has been separated from its native components. In some embodiments, the antibody is purified to a purity of at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%), which can be purified and determined by methods such as electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0047] The term "variable region" or "variable domain" refers to a domain in the heavy or light chain of an antibody that is involved in antibody binding to the antigen. Natural antibodies include a heavy chain variable region (VH) and a light chain variable region (VL), each of which contains four frame regions (FR) and three hypervariable regions (also known as complementarity-determining regions, HVR, or CDR).

[0048] The terms "complementarity-determining region," "hypervariant region," or "CDR" refer to the main region within the variable region that facilitates binding to the antigen; "framework," "frame region," or "FR" refers to the structural domains within the antibody variable region other than the CDR residues. Each VH and VL typically consists of three CDRs and four FRs arranged in the following order (from the amino terminus to the carboxyl terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The variable regions of both the heavy and light chains contain three CDRs (CDR1, CDR2, and CDR3), with the three CDRs of the heavy chain labeled HCDR1, HCDR2, and HCDR3, and the three CDRs of the light chain labeled LCDR1, LCDR2, and LCDR3. The boundaries of CDRs can be defined according to known numbering systems in the field, such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196: 901-917; Chothia et al. (1989) Nature 342: 878-883), the Abm numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86: 9268–9272), and the Contact numbering system (MacCallum, RM, Martin, ACR, & Thornton, JM (1996) Antibody-antigen Interactions: Contact Analysis and Binding). Site Topography. Journal of Molecular Biology, 262(5), 732-745.) or the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003). For a given antibody variable region, those skilled in the art can readily determine the CDR according to the numbering system.Furthermore, the correspondence between different numbering systems is well known to those skilled in the art (see, for example, Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0049] The term "constant region" or "constant domain" refers to the carboxyl-terminal portion of the antibody's light and heavy chains, which does not directly participate in antibody-antigen binding. Compared to VH and VL, the constant region has a relatively conserved amino acid sequence. While the constant domain typically does not directly participate in antibody-antigen binding, it exhibits various effector functions.

[0050] The term "light chain" includes the variable region (VL) and the constant region (CL) of the light chain. The VL is located at the amino terminus of the light chain, and the CL is located at the carboxyl terminus of the light chain. The light chain can be a κ chain or a λ chain, etc.

[0051] The term "heavy chain" includes the variable region (VH) and the constant region (CH). The variable region is located at the amino terminus of the heavy chain, and the constant region is located at the carboxyl terminus. The constant region of the IgG antibody heavy chain includes three constant region domains: CH1, CH2, and CH3. The heavy chain can belong to any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgD, IgM, and IgE, etc.

[0052] The term "antigen-binding fragment" refers to a portion containing a complete antibody (which is not the complete antibody itself) that specifically binds to the antigen bound by the complete antibody. Examples of antigen-binding fragments include, but are not limited to: Fv, Fab, Fab', Fab'-SH, F(ab')2, dsFv, (dsFv)2, single-chain Fab (scFab), single-chain antibody (scFv), diabody, and multispecific antibodies formed from antigen-binding fragments.Among them, "Fab" is an antibody fragment composed of VL, VH, CL and CH1 domains; "Fv" is an antibody fragment composed of the VL and VH domains of a single arm of the antibody; "Fab'" is a Fab fragment containing part of the hinge region; it is usually obtained by reducing the disulfide bonds connecting the two heavy chain fragments in the F(ab')2 fragment, which consists of a complete light chain and a heavy chain Fd fragment (composed of VH and CH1 domains); "F(ab')2" is a bivalent fragment containing two Fab' fragments connected by disulfide bonds in the hinge region; "scFab" is a polypeptide composed of VH, CH1, VL, CL, and a linker, wherein the antibody domain and the linker have one of the following sequences in the N-terminal to C-terminal direction: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL; "scFv" is a single-chain protein containing a light chain variable region and a heavy chain variable region, wherein the light chain variable region and the heavy chain variable region are linked by a peptide linker and can be expressed as a single-chain multi-chain protein. Peptides, scFvs, typically retain the specificity of the intact antibody (parent antibody) from which they originate. The N-terminus to C-terminus of an scFv may contain: a) VL-linker-VH or b) VH-linker-VL. In some embodiments, a disulfide bond may also exist between the VH and VL of the scFv. In some implementations, scFvs can form di-scFvs (i.e., two or more individual scFvs linked together to form an antibody). In some implementations, scFvs can form (scFv)2 (i.e., two or more individual scFvs linked in parallel to form an antibody). (The antibody formed); "dsFv" is a disulfide bond-stabilized Fv fragment; (dsFv)2 is a dimerized dsFv; "Fab'-SH" is a cysteine ​​residue in the hinge region of the Fab' fragment carrying a free thiol group; "diabody" refers to the expression of VH and VL domains on a single polypeptide chain, but using a linker that is too short to allow pairing between the two domains on the same chain, thus forcing the domains to pair with the complementary domain of another chain and creating two antigen-binding sites (see, for example, Holliger P. et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993), and Poljak RJ et al., Structure 2:1121-1123 (1994)).

[0053] The term "antibody effector function" refers to those biological activities attributable to the Fc region of an antibody. Examples of antibody effector functions include, but are not limited to: C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding and antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0054] The term “antibody-dependent cell-mediated cytotoxicity” or “ADCC” is a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) on cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), enabling the cytotoxic effector cells to specifically bind to target cells carrying the antigen and kill the target cells with cytotoxins. Antibodies “arm” the cytotoxic cells, thereby exerting their cytotoxic effect. NK cells that mediate ADCC express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. Further FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet's *Annu. Rev. Immunol.* 9:457-92 (1991). To assess the ADCC activity of a target molecule (e.g., an antibody), it can be evaluated via in vitro ADCC assays (e.g., as described in U.S. Patent Nos. 5,500,362 or 5,821,337), using effector cells such as peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. The ADCC activity of a target molecule (e.g., an antibody) can also be assessed in vivo, for example, in animal models (such as those disclosed in Clynes et al., (USA) 95:652-656 (1998)).

[0055] The term “antibody-dependent phagocytosis” or (“ADCP”) refers to the mechanism by which antibody-coated target cells are eliminated through internalization by phagocytes (such as macrophages or dendritic cells).

[0056] The term "complement-dependent cytotoxicity" or "CDC" refers to a mechanism that induces cell death in which the Fc effector domain of a target-binding antibody binds to and activates the complement component C1q, which in turn activates the complement cascade, leading to target cell death. Complement activation can also result in the deposition of complement components on the surface of target cells, which promote CDC by binding to complement receptors on leukocytes (e.g., CR3).

[0057] The term "Fc," "Fc region," or "Fc domain" refers to the C-terminal region of the constant region of an antibody heavy chain; typically, the Fc includes the region comprised of the CH2 and CH3 domains of the antibody, and may also include the antibody hinge region or a portion of the hinge region. In some embodiments, the Fc region of the human IgG heavy chain extends from the amino acid residue at Cys226 to its carboxyl terminus. In some embodiments, the Fc region of the human IgG heavy chain extends from Pro230 to its carboxyl terminus. In some embodiments, the Fc may also be an antibody fragment lacking a C-terminal lysine (residue 447 according to the EU numbering system) or lacking both C-terminal glycine and lysine (residues 446 and 447 according to the EU numbering system). The Fc region of an antibody may include the Fc regions of human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4. The Fc includes both native and variant Fc regions. The natural Fc region contains an amino acid sequence identical to that of Fc regions found in nature, such as the natural human Fc regions including the natural human IgG1 Fc region, IgG2 Fc region, IgG3 Fc region, and IgG4 Fc region. The variant Fc region contains an amino acid sequence that differs from the amino acid sequence of the natural Fc region due to at least one amino acid modification. In some embodiments, the variant Fc region may possess effector functions altered compared to the natural Fc region (e.g., Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function). In some embodiments, the Fc region is a mutant Fc region with enhanced effector cell function; for example, an Fc mutant has enhanced ADCC / ADCP / CDC and / or affinity for the Fcγ receptor compared to wild-type Fc, as described in WO200042072. In other embodiments, this disclosure covers antibodies containing FC variants that possess some, but not all, effector functions, such as where the antibody's in vivo half-life is important, while certain effector functions (e.g., complement and ADCC) are unnecessary or harmful. In vitro and / or in vivo cytotoxicity assays can be performed to confirm a reduction / attenuation of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding but retains FcRn binding capacity. The primary cells mediating ADCC, NK cells, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII (Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991), p. 464, summarizes FcR expression on hematopoietic cells).Non-limiting examples of in vitro assays for assessing ADCC activity of molecules of interest are documented in numerous publications (e.g., see: Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)); Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)); non-radioactive assays can also be used (e.g., the ACTITM non-radioactive cytotoxicity assay for flow cytometry (Cell Technology, Inc. Mountain View, CA; and CytoTox). Non-radioactive cytotoxicity assays (Promega, Madison, WI) can also be used to assess ADCC activity of molecules of interest in vivo, for example, in animal models (see Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998)). C1q binding assays can also be performed to confirm whether the antibody does not bind to C1q (see, for example, C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402). To assess complement activation, CDC function assays can also be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life assays can also be performed using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006); WO 2013 / 120929 A1). Antibodies with reduced effector function include those having substitutions for one or more of Fc regions 238, 265, 269, 270, 297, 327, and 329 (see U.S. Patent No. 6,737,056). Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” Fc mutant with residues 265 and 297 substituted with alanine (U.S. Patent No. 7,332,581). In some embodiments, the antibodies of this disclosure comprise Fc mutants with amino acid substitutions that reduce FcγR binding, such as Fc mutants with amino acid substitutions at Fc positions 234 and 235 (using the EU numbering system); in one embodiment, the Fc mutant comprises L234A and L235A amino acid substitutions; in some embodiments, the Fc mutant further comprises D265A and / or P329G amino acid substitutions. In one embodiment, the antibody disclosed herein comprises an IgG1-LALAPG mutant (L234A, L235A and P329G mutations in the human IgG1 Fc region, see WO 2012 / 130831 A1).

[0058] The term "mouse antibody" refers to an antibody whose variable region and constant region are both derived from immunoglobulins of a mouse lineage (e.g., mouse or rat).

[0059] The term "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chains is derived from a specific species, while the remaining portions of the heavy and / or light chains are derived from other species. For example, a human-mouse chimeric antibody can be constructed by combining the variable region of a mouse antibody and the constant region of a human antibody.

[0060] The term "humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDR domain of a non-human antibody are replaced by corresponding amino acids derived from human immunoglobulins. For example, a humanized antibody can be constructed by retaining the CDR region of a non-human antibody and replacing the rest of the antibody with the framework and constant regions of a human antibody. In some embodiments, in a humanized antibody, some, most, or all of the amino acids outside the CDR domain have been replaced by amino acids derived from human immunoglobulins, while some, most, or all of the amino acids in one or more CDR regions remain unchanged. Generally, minor additions, deletions, insertions, substitutions, or modifications of amino acids are permitted, as long as they preserve the antibody's ability to bind to a specific antigen. ("off-rate", koff or kd) and binding ("on-rate", kon or ka) are also mentioned.

[0061] The terms “affinity” and “binding strength” refer to the overall strength of the non-covalent interaction between the antibody binding site and the antigen. Unless otherwise specified, “affinity” as used in this disclosure refers to internal binding affinity, which reflects a 1:1 interaction between the antibody and the antigen. Affinity is typically expressed as a dissociation constant (KD). Affinity can be measured using conventional methods known in the art. The terms “kassoc,” “on-rate,” kon, or “ka” refer to the association rate of the antibody-antigen interaction, and the terms “kdis,” “off-rate,” koff, or “kd” refer to the dissociation rate of the antibody-antigen interaction. The term “KD” refers to the dissociation constant, which is the ratio of kd to ka (i.e., kd / ka), and is typically expressed as a molar concentration (M). The KD value of an antibody can be determined using methods known in the art. Methods for determining antibody KD include using a biosensing system, such as a system measuring surface plasmon resonance, or by solution equilibrium titration (SET).

[0062] The term "affinity-matured antibody" refers to an antibody that has one or more amino acid residue changes in one or more CDRs, resulting in improved affinity for the antigen compared to the parent antibody. In some embodiments, affinity-matured antibodies have nanomolar or picomolar affinity for the target antigen. Affinity-matured antibodies can be generated by methods known in the art (Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation through VH and VL domain shuffling; the following literature describes random mutagenesis of CDR and / or framework residues: Barbas et al., PNAS, 91:3809-3813 (1994); Schier et al., Gene 169:147-155 (1995); Yelton et al., J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995) and Hawkins et al., J. Mol. Biol. 226:889-896 (1992)).

[0063] The term "monoclonal antibody" refers to a substantially homogeneous group of antibodies, meaning that the antibody molecules contained in this group have the same amino acid sequence (except for the possible small number of naturally occurring mutations). In contrast, polyclonal antibodies typically contain different antibodies with variable domains having different amino acid sequences, and they are usually specific to different epitopes and / or different antigens. "Monoclonal" indicates an antibody obtained from a substantially homogeneous group of antibodies. Monoclonal antibodies can be produced by methods known in the art, for example, by hybridoma methods (Kohler et al., (1975) Nature 256:495), by recombinant DNA methods (see, for example, US Patent No. 4,816,567), by isolation methods from phage antibody libraries (Clackson et al., (1991) Nature 352:624-628 and Marks et al., (1991) J. Mol. Biol. 222:581-597), and also by using transgenic animals containing all or part of the human immunoglobulin loci (see Presta (2005) J. Allergy Clin. Immunol. 116:731).

[0064] The term "antigen" refers to a protein that can selectively bind to an antibody. An antigen may have one or more epitopes that interact with different antibodies.

[0065] The term "epitope" refers to a region on an antigen that can specifically bind to an antibody. Epitopes are typically antigenic determinants consisting of specific chemical groups with a defined composition and structure. Epitopes can be formed from consecutive amino acid residues (linear epitopes) or from discontinuous amino acid residues (conformal epitopes), such as spatially close discontinuous amino acid residues formed due to antigen folding. In some embodiments, an epitope comprises at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acid residues in a unique spatial conformation. Epitopes can be determined by any method well known in the art, such as conventional immunoassays, antibody competitive binding assays, or X-ray crystallography or related structural assays (e.g., nuclear magnetic resonance spectroscopy). Antibodies that bind to specific epitopes (i.e., those that bind to the same epitope) can be obtained using methods known in the art, including but not limited to, alanine scanning, Western blotting (see Meth. Mol. Biol. 248 (2004) 443-463), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of antigens (see Prot. Sci. 9 (2000) 487-496) and cross-blocking (see “Antibodies”, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY)).

[0066] When “competition” is used to describe the competition between antigen-binding proteins (e.g., antibodies) for the same epitope, it means that antigen-binding proteins competitively bind to a common antigen, which can usually be determined by measuring that the antigen-binding protein to be detected (e.g., antibody) inhibits (e.g., reduces) the specific binding of a reference antigen-binding protein (e.g., reference antibody) to the antigen. Numerous types of competitive binding assays can be used to determine whether one antigen-binding protein competes with another, including but not limited to: solid-phase direct or indirect radioimmunoassay (RIA), solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, for example, Stahli et al., 1983, Methods in Enzymology 9: 242-253); solid-phase direct biotin-avidin EIA (see, for example, Kirkland et al., 1986, J. Immunol. 137: 3614-3619), solid-phase direct labeled sandwich assay (see, for example, Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid-phase direct labeled RIA of I-125 (see, for example, Morel et al., 1988, Molec. Immunol. 25: 7-15), etc. In some embodiments, the binding of the reference antibody to the antigen is inhibited by at least 40% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, 90%, 95%, 97%, or 98% or more) by an antibody that competitively binds to it. In some embodiments, to determine whether the test antibody binds to the same epitope as the reference antibody, the ability of the reference antibody to bind to the antigen can be detected under saturation conditions. For example, after removing excess reference antibody, the ability of the test antibody to bind to the antigen can be evaluated. If the test antibody is able to bind to the antigen after saturation binding of the reference antibody, then the test antibody binds to a different epitope than the reference antibody; however, if the test antibody is unable to bind to the antigen after saturation binding of the reference antibody, then the test antibody may bind to the same epitope as the reference antibody.

[0067] The term "specific binding" or "specifically bound" refers to a non-random binding between two molecules. For example, an antibody binds to the antigen or epitope it corresponds to with a higher affinity than it binds to other antigens or epitopes. Typically, antibodies bind with an affinity of approximately 1 × 10⁻⁶. -7 M or smaller (e.g., about 1×10⁻⁶) -8 M or smaller, approximately 1×10 -9 M or smaller, approximately 1×10 -10 M or smaller, approximately 1×10 -11 M or smaller, or about 1×10 -12The equilibrium dissociation constant (KD) of an antibody (M or less) binds to an antigen or an epitope within the antigen. In some embodiments, the KD of antibody binding to an antigen is 10%, 1%, or less of the KD of antibody binding to a nonspecific antigen (e.g., BSA, casein). The KD value can be measured using methods known in the art, such as by... Surface plasmon resonance assay is used for measurement. In some embodiments, antibodies that specifically bind to an antigen or an epitope within an antigen may be cross-reactive to other related antigens, for example, to corresponding antigens from other species (such as humans or monkeys, such as cynomolgus (Macaca fascicularis), chimpanzee (Pan troglodytes), or common marmoset (Callithrix jacchus). In some embodiments, antibodies that specifically bind to an antigen or an epitope within an antigen are not cross-reactive to other related antigens, for example, not cross-reactive to corresponding antigens from other species (e.g., mice).

[0068] The term "weak binding" refers to a weak binding activity between two protein molecules. For example, antibodies bind at a rate greater than 1 × 10⁻⁶. -7 The KD value of M binds to the antigen, and this binding can be achieved through... The surface plasmon resonance assay (SPR) is used to measure (e.g., Example 4 of this disclosure). Intermolecular binding activity can also be determined by detecting the EC50 value, which can be detected by an ELISA method (e.g., Example 3 of this disclosure). In some embodiments, the antibody binds weakly to the mouse TL1A antigen with an EC50 value greater than 100 nM (e.g., greater than 100 nM, greater than 500 nM, greater than 1000 nM, or greater); when the EC50 value between the antibody and the antigen is greater than 10000 nM, it is generally considered that the antibody and antigen do not bind.

[0069] The term "blocking the binding of A to B" refers to the ability to inhibit the binding between A and B (e.g., the binding of human TL1A to DR3, or the binding of human TL1A to DcR3). In some embodiments, the antibody blocking the binding between A and B inhibits the interaction between A and B by more than 50% (e.g., inhibition of 50%, 60%, 70%, 80%, 90%, 95%, or 100%, or any value between them). Methods for determining the ability of an antibody to block the binding of A to B are well known in the art, for example, by a biolayer interference assay. In some embodiments, the ability of an antibody to block the binding of A to B is detected by the method of Example 5 of this disclosure.

[0070] The terms "anti-human TL1A antibody" and "antibody binding to human TL1A" refer to antibodies capable of binding to human TL1A with sufficient affinity. In one embodiment, the degree of binding to an unrelated, non-human TL1A protein is less than at least 10% (e.g., 10%, at least 1%, or less) of the antibody's binding to human TL1A, said binding can be achieved through... Measured by surface plasmon resonance assay. In some embodiments, the antibody binding to human TL1A has the following dissociation constant (KD) < about 10 nM, < about 1 nM, < about 0.1 nM, < about 0.01 nM, < about 0.001 nM or less.

[0071] The terms "multispecific antibody" and "multispecific molecule" refer to antibody molecules that can bind to multiple (two or more) different antigenic epitopes of the same antigen or can bind to multiple (two or more) different antigens.

[0072] The term "conjugate" refers to an antibody chemically or biologically linked to another pharmaceutical agent (e.g., including but not limited to: protein tags, detectable markers, or therapeutic agents). Examples of conjugates include, for example, conjugates constructed by linking an anti-human TL1A antibody of this disclosure to a cytotoxic drug via a linker. The terms "nucleic acid," "polynucleotide," and "nucleic acid molecule" are used interchangeably to refer to deoxyribonucleotides or ribonucleotides in single-stranded or double-stranded form and polymers thereof. Nucleic acids include nucleic acids containing known nucleotide analogs or modified backbone residues or links. Nucleic acids can be synthetic, naturally occurring, or non-natural, such as non-natural nucleic acids having similar binding properties to a reference nucleic acid and metabolized in a manner similar to a reference nucleotide. This includes, but is not limited to, phosphate thioesters, aminophosphate esters, methylphosphonates, chiral methylphosphonates, 2-O-methylribonucleotides, and peptide-nucleic acid (PNA) modified nucleic acids.

[0073] The term "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from its components in its natural environment. Isolated nucleic acids include nucleic acid molecules contained in cells that typically contain such molecules, but which are located extrachromosomally or at a chromosomal location different from their natural chromosomal location. "Nucleic acid encoding anti-human TL1A antibody" refers to one or more nucleic acid molecules encoding the antibody heavy chain and / or light chain (or fragments thereof), including one or more nucleic acid molecules in a single or separate vector, and one or more nucleic acid molecules present at one or more locations within the host cell. In some embodiments, the nucleic acid sequence also includes conserved modified variants (e.g., degenerate codon substitutions) and complementary sequences. For example, degenerate codon substitutions can be obtained by producing sequences in which the third position of one or more codons is substituted with a mixture of bases and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081, 1991; Ohtsuka et al., J. Biol. Chem. 260:2605-2608, 1985; and Rossolini et al., Mol. Cell. Probes 8:91-98, 1994).

[0074] The term "vector" is a delivery vehicle capable of transporting a genetic element (e.g., nucleic acid) linked to it. Vectors can be used to transform, transduce, or transfect host cells, enabling the expression of the genetic element they carry within the host cells. Exemplarily, vectors include plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC), or P1-derived artificial chromosomes (PAC), bacteriophages such as λ phage or M13 phage, and animal viruses, etc. In some embodiments, the vector is a "plasmid," which is a circular double-stranded DNA loop in which additional DNA segments can be linked. In some embodiments, the vector is a viral vector, such as an adeno-associated virus vector (AAV or AAV2), in which DNA segments can be linked to a viral genome. Vectors may contain various elements controlling expression, including promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and reporter genes. Vectors may also contain replication initiation sites and may include components that facilitate their entry into cells, including, but not limited to, viral particles, liposomes, or protein coats. Vectors can be expression vectors. In some embodiments, the vector (e.g., an expression vector) contains the nucleic acid sequence of the antibody encoded by this disclosure, a promoter (e.g., SV40, CMV, EF-1α), and may also contain at least one selection marker.

[0075] The term "expression vector" or "expression construct" is a vector containing a nucleic acid sequence suitable for transformation of host cells and which directs and / or controls (together with the host cell) the expression of one or more coding regions operatively linked to it. Expression vectors may include, but are not limited to, sequences that affect or control transcription, translation, and, in the presence of introns, affect the splicing of coding regions operatively linked to them.

[0076] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably to refer to cells (including their progeny) infused with exogenous nucleic acids. Host cells include "transformers" and "transformed cells," encompassing primary transformed cells and their derived progeny cells, regardless of passage number. Progeny cells may not be identical to parental cells in their nucleic acid contents and may contain mutations. In some embodiments, host cells include mutant progeny cells that have the same function or biological activity as the initially transformed cells. Host cells include prokaryotic and eukaryotic host cells, with eukaryotic host cells including, but not limited to, mammalian cells, insect cell lines, plant cells, and fungal cells. Exemplary host cells include: Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, young hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells and HEK-293 cells, Pichia pastoris, Pichia finlandica, Candida albicans, Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei.

[0077] The terms "identity" and "sequence identity" refer to the degree (percentage) to which the amino acids (amino acid sequence identity) or nucleic acids (nucleic acid sequence identity) of two sequences are identical at equivalent positions when two sequences are optimally aligned. To achieve optimal alignment, gaps may be introduced to obtain the maximum percentage of sequence identity. For example, when two sequences are optimally aligned, if a position in the first sequence is occupied by the corresponding amino acid residue or nucleotide in the second sequence, the sequences are identical at that position. In some embodiments, the percentage identity between two sequences is determined by the number of identity positions shared by the sequences: Percentage identity = Number of identity positions / Total number of positions × 100%. The percentage of amino acid sequence identity can be determined using various methods known in the art, such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA.

[0078] A polypeptide sequence having at least 80% (e.g., 80% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%) identity with the parent sequence, including polypeptide variants with altered (through amino acid residue substitution, deletion, and / or addition) amino acid sequences (e.g., polypeptide variants obtained through conserved substitution), and also including polypeptide variants that have been modified (e.g., by covalently linking the molecule to the polypeptide) (e.g., through glycosylation, acetylation, polyethylene glycolation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linking to cellular ligands or other proteins, etc.). Polypeptide variants can be generated by chemical modification using techniques known to those skilled in the art, including but not limited to specific chemical cleavage, acetylation, formylation, and the metabolic synthesis of tunicamycin. In some implementations, the peptide variant has similar, identical, or improved functions to the peptide from which it originated (the parent peptide before mutation).

[0079] The terms "conservative substitution," "conservative replacement," or "conservative mutation" refer to amino acid substitutions that do not adversely affect or alter the intended properties of a polypeptide containing an amino acid sequence. Amino acids in a sequence can be replaced with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophilicity / hydrophobicity, skeletal structure, and rigidity) without altering the protein's biological activity. For example, conservative substitutions can be introduced using standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions involve replacing amino acid residues with amino acid residues having similar side chains, such as substitutions with residues that are physically or functionally similar to the corresponding amino acid residues (e.g., having similar size, shape, charge, chemical properties, including the ability to form covalent or hydrogen bonds). Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid and glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, and methionine), β-branched side chains (e.g., threonine, valine, and isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, and histidine). Therefore, it is preferable to replace the corresponding amino acid residue with another amino acid residue from the same side chain family. Methods for identifying conserved amino acid substitutions are well known in the art (see, for example, Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl Acad. Set USA 94:412-417 (1997), which are incorporated herein by reference).

[0080] The term "pharmaceutical composition" refers to a mixture containing one or more antibodies described in this disclosure and other components, such as physiological / pharmaceutical carriers and excipients.

[0081] The term "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical formulation that is distinct from the active ingredient and non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. Those skilled in the art will understand that other drug carriers may be used in this disclosure. If desired, the pharmaceutical composition may be contained in a kit, vial, or dispenser, for example, it may contain one or more unit doses of antibody. The kit, vial, or dispenser may be accompanied by instructions for use.

[0082] The terms “subject” or “individual” include humans and non-human animals. Non-human animals include all vertebrates (e.g., mammals and non-mammals) such as non-human primates (e.g., cynomolgus monkeys), sheep, dogs, cattle, chickens, amphibians, and reptiles. Unless specifically indicated, the terms “patient” or “subject” are used interchangeably in this disclosure, unless explicitly defined herein. In some embodiments, the subject is a human. In some embodiments, the subject has a disease associated with high TL1A expression, such as inflammatory bowel disease; in some embodiments, the subject has Crohn's disease, ulcerative colitis, fibrotic disease, and / or autoimmune disease.

[0083] "Administration" or "giving," when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refers to the contact between exogenous drugs, therapeutic agents, diagnostic agents, or compositions and animals, humans, subjects, cells, tissues, organs, or biological fluids.

[0084] The term "treatment" refers to a clinical intervention that attempts to alter the natural processes of the individual being treated, and can be implemented during prevention or in the course of clinicopathology. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing / decreasing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and remission or improved prognosis.

[0085] The term "effective dose" refers to an amount sufficient to reduce the severity or frequency of symptoms, eliminate symptoms and / or underlying causes, prevent the occurrence of symptoms and / or underlying causes, or improve damage associated with a disease state (e.g., lung disease). In some embodiments, an effective dose may be a therapeutically effective dose or a preventatively effective dose. A "therapeuticly effective dose" is an amount sufficient to treat a disease state or symptom, particularly a state or symptom associated with that disease state, or otherwise prevent, inhibit, delay, or reverse the progression of the disease state or any other undesirable symptom associated with that disease. A "preventatively effective dose" is an amount that, when administered to a subject, will have a predetermined preventative effect, such as preventing or delaying the onset (or recurrence) of the disease state, or reducing the likelihood of the onset (or recurrence) of the disease state or related symptoms. A complete therapeutic or preventative effect may not occur after a single dose is administered, but may occur after a series of doses. Thus, a therapeutically or preventatively effective dose may be administered in a single or multiple-dose manner. "Therapeutic effective dose" and "preventive effective dose" can vary depending on a number of factors, such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent to elicit the desired response in the individual.

[0086] The inventors of this disclosure have obtained a human TL1A-specific binding antibody through screening, which exhibits good binding activity in both in vivo and in vitro biological functions. In some embodiments, the anti-human TL1A antibody of this disclosure has the function of blocking the binding of human TL1A to DR3 and blocking the binding of human TL1A to DcR3. In some embodiments, in vivo and in vitro experiments have verified that the antibody of this disclosure has good antigen-binding ability and therapeutic function for diseases related to TL1A high expression (such as inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), fibrotic diseases, autoimmune diseases, etc.).

[0087] In a first aspect, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 of the heavy chain variable region each comprises an amino acid sequence identical to HCDR1, HCDR2, and HCDR3 in the VH having at least 80% (e.g., more than 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with any of the sequences in SEQ ID NO:48-64 and 1-5, and / or the LCDR1, LCDR2, and LCDR3 of the light ... 80%, 85%, 86%, 87%, 88%, 99%, or 100%) sequence identity with any of the sequences in SEQ ID NO:48-64 and 1- The LCDR1, LCDR2, and LCDR3 in VLs with at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%) sequence identity of any of the sequences NO:65-78 and 6-10 are identical amino acid sequences.

[0088] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 of the heavy chain variable region each comprise amino acid sequences identical to those shown in any of SEQ ID NO:48-64 and 1-5 or having at least 80% (e.g., more than 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) of the sequence identity in the VH, and the LCDR1, LCDR2, and LCDR3 of the light chain variable region each comprise amino acid sequences identical to those shown in SEQ ID NO:48-64 and 1-5. The amino acid sequences shown in NO:65-78 and 6-10, or those of LCDR1, LCDR2, and LCDR3 in a VL having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%) sequence identity, are identical to those of the other sequences.

[0089] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 of the heavy chain variable region each contain the same amino acid sequence as HCDR1, HCDR2, and HCDR3 in any VH of SEQ ID NO:48-64 and 1-5, and / or the LCDR1, LCDR2, and LCDR3 of the light chain variable region each contain the same amino acid sequence as LCDR1, LCDR2, and LCDR3 in any VL of SEQ ID NO:65-78 and 6-10. In some embodiments, the anti-human TL1A antibody has heavy chain variable regions HCDR1, HCDR2, and HCDR3 containing the same amino acid sequences as HCDR1, HCDR2, and HCDR3 in any VH of SEQ ID NO:48-64 and 1-5, and its light chain variable regions LCDR1, LCDR2, and LCDR3 containing the same amino acid sequences as LCDR1, LCDR2, and LCDR3 in any VL of SEQ ID NO:65-78 and 6-10.

[0090] In addition, this disclosure also provides an anti-human TL1A antibody, comprising a heavy chain variable region and a light chain variable region, wherein: the antibody heavy chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:48-64 and 1-5 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or more than 100%) sequence identity with any of SEQ ID NO:48-64 and 1-5; and / or the light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:65-78 and 6-10 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 98%, more than 99%, or more than 100%) sequence identity with any of SEQ ID NO:48-64 and 1-5; and / or the light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:65-78 and 6-10 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 97%, more than 98%, more than 99%, or more than 100%) sequence identity with any of SEQ ID NO:48-64 and 1-5. NO:65-78 and 6-10 have an amino acid sequence identity of at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%).

[0091] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0092] A) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:48-60 or 1, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:65-74 or 6, respectively;

[0093] B) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:61-64 or 2, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:75-78 or 7, respectively;

[0094] C) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:3; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:8.

[0095] D) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:4; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:9; or

[0096] E) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:5; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:10.

[0097] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0098] A) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:48-60 or 1, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:65-74 or 6, respectively;

[0099] C) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:3; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:8; or

[0100] D) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:4; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:9.

[0101] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0102] a1) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:48-60, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:65-74, respectively;

[0103] a2) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:61-64, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:75-78, respectively;

[0104] a3) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:1; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:6; or

[0105] a4) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:2; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:7.

[0106] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein,

[0107] A) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:1; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:6.

[0108] B) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:2; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:7.

[0109] C) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:3; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:8.

[0110] D) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:4; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:9.

[0111] E) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:5; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:10.

[0112] F) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:48; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:65.

[0113] G) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:49; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:65.

[0114] H) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:50; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:65.

[0115] I) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:51; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:66.

[0116] J) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:52; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:67.

[0117] K) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:51; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:68.

[0118] L) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:48; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:68.

[0119] M) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:53; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:69.

[0120] N) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:54; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:70.

[0121] O) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:55; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:71.

[0122] P) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:56; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:66.

[0123] Q) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:57; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:72.

[0124] R) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:58; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:73.

[0125] S) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:59; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:74.

[0126] T) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:60; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:66.

[0127] U) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:61; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:75.

[0128] V) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:62; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:76.

[0129] W) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:63; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:77; or

[0130] Z) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:64; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:78.

[0131] In some embodiments, the anti-human TL1A antibody described in any of the preceding claims is selected from any one or more groups of A) to Z) above (e.g., selected from any group 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 therein).

[0132] In some embodiments, the anti-human TL1A antibody is selected from antibodies of group A) and FT above, wherein,

[0133] A) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:1; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:6.

[0134] F) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:48; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:65.

[0135] G) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:49; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:65.

[0136] H) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:50; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:65.

[0137] I) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:51; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:66.

[0138] J) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:52; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:67.

[0139] K) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:51; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:68.

[0140] L) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:48; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:68.

[0141] M) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:53; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:69.

[0142] N) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:54; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:70.

[0143] O) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:55; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:71.

[0144] P) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:56; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:66.

[0145] Q) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:57; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:72.

[0146] R) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:58; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:73.

[0147] S) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:59; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:74; or

[0148] The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:60; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:66.

[0149] In some embodiments, the anti-human TL1A antibody is selected from antibodies of group B) and UZ above, wherein,

[0150] B) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:2; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:7.

[0151] U) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:61; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:75.

[0152] V) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:62; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:76.

[0153] W) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:63; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:77; or

[0154] Z) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:64; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:78.

[0155] In some embodiments, the anti-human TL1A antibody described in any of the preceding claims, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Kabat, IMGT, Abm, Contact, or Chothia numbering system.

[0156] In some implementations, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Kabat numbering system.

[0157] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Kabat numbering system.

[0158] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein...

[0159] The HCDR1-3 of the antibody heavy chain variable region is selected from any one of the following groups A1-E1:

[0160] A1) The HCDR1 of the antibody heavy chain variable region includes the amino acid sequence shown in SEQ ID NO:11, the HCDR2 includes the amino acid sequence shown in SEQ ID NO:12, and the HCDR3 includes the amino acid sequence shown in SEQ ID NO:13;

[0161] B1) The HCDR1 of the antibody heavy chain variable region includes the amino acid sequence shown in SEQ ID NO:17, the HCDR2 includes the amino acid sequence shown in SEQ ID NO:18, and the HCDR3 includes the amino acid sequence shown in SEQ ID NO:19;

[0162] C1) The HCDR1 of the antibody heavy chain variable region includes the amino acid sequence shown in SEQ ID NO:23, the HCDR2 includes the amino acid sequence shown in SEQ ID NO:24, and the HCDR3 includes the amino acid sequence shown in SEQ ID NO:25;

[0163] D1) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:29, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:30, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:31; or

[0164] E1) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:35, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:36, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:37; and / or

[0165] The LCDR1-3 of the antibody light chain variable region is selected from any one of the following groups A2-E2:

[0166] A2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:14 for LCDR1, the amino acid sequence shown in SEQ ID NO:15 for LCDR2, and the amino acid sequence shown in SEQ ID NO:16 for LCDR3.

[0167] B2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:20 for LCDR1, the amino acid sequence shown in SEQ ID NO:21 for LCDR2, and the amino acid sequence shown in SEQ ID NO:22 for LCDR3.

[0168] C2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:26 for LCDR1, the amino acid sequence shown in SEQ ID NO:27 for LCDR2, and the amino acid sequence shown in SEQ ID NO:28 for LCDR3;

[0169] D2) The variable region of the antibody light chain, LCDR1, includes the amino acid sequence shown in SEQ ID NO:32, LCDR2 includes the amino acid sequence shown in SEQ ID NO:33, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:34; or

[0170] E2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:32 for LCDR1, the amino acid sequence shown in SEQ ID NO:38 for LCDR2, and the amino acid sequence shown in SEQ ID NO:39 for LCDR3.

[0171] In some implementations, the anti-human TL1A antibody described in any of the preceding embodiments, wherein,

[0172] a) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:11, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:12, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:13; and the LCDR1 of the antibody light chain variable region comprises the amino acid sequence shown in SEQ ID NO:14, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:15, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:16;

[0173] b) The antibody heavy chain variable region HCDR1 includes the amino acid sequence shown in SEQ ID NO:17, HCDR2 includes the amino acid sequence shown in SEQ ID NO:18, and HCDR3 includes the amino acid sequence shown in SEQ ID NO:19; and the antibody light chain variable region LCDR1 includes the amino acid sequence shown in SEQ ID NO:20, LCDR2 includes the amino acid sequence shown in SEQ ID NO:21, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:22;

[0174] c) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:23, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:24, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:25; and the LCDR1 of the antibody light chain variable region comprises the amino acid sequence shown in SEQ ID NO:26, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:27, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:28;

[0175] d) The antibody heavy chain variable region HCDR1 includes the amino acid sequence shown in SEQ ID NO:29, HCDR2 includes the amino acid sequence shown in SEQ ID NO:30, and HCDR3 includes the amino acid sequence shown in SEQ ID NO:31; and the antibody light chain variable region LCDR1 includes the amino acid sequence shown in SEQ ID NO:32, LCDR2 includes the amino acid sequence shown in SEQ ID NO:33, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:34; or

[0176] e) The antibody heavy chain variable region HCDR1 includes the amino acid sequence shown in SEQ ID NO:35, HCDR2 includes the amino acid sequence shown in SEQ ID NO:36, and HCDR3 includes the amino acid sequence shown in SEQ ID NO:37; and the antibody light chain variable region LCDR1 includes the amino acid sequence shown in SEQ ID NO:32, LCDR2 includes the amino acid sequence shown in SEQ ID NO:38, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:39.

[0177] In some embodiments, the anti-human TL1A antibody is selected from any one or more of groups a) to e) above (e.g., groups 1, 2, 3, 4 or 5).

[0178] In some embodiments, the anti-human TL1A antibody is selected from the anti-human TL1A antibodies of group a) or b) above, wherein,

[0179] a) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:11, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:12, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:13; and the LCDR1 of the antibody light chain variable region comprises the amino acid sequence shown in SEQ ID NO:14, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:15, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:16;

[0180] b) The antibody heavy chain variable region HCDR1 includes the amino acid sequence shown in SEQ ID NO:17, HCDR2 includes the amino acid sequence shown in SEQ ID NO:18, and HCDR3 includes the amino acid sequence shown in SEQ ID NO:19; and the antibody light chain variable region LCDR1 includes the amino acid sequence shown in SEQ ID NO:20, LCDR2 includes the amino acid sequence shown in SEQ ID NO:21, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:22.

[0181] In some embodiments, the anti-human TL1A antibody of any of the preceding claims, wherein the antibody heavy chain variable region HCDR1 comprises the amino acid sequence shown in SEQ ID NO:11, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:12, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:13; and the antibody light chain variable region LCDR1 comprises the amino acid sequence shown in SEQ ID NO:14, LCDR2 comprises the amino acid sequence shown in SEQ ID NO:15, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:16.

[0182] In some embodiments, the anti-human TL1A antibody of any of the preceding claims, wherein the antibody heavy chain variable region HCDR1 comprises the amino acid sequence shown in SEQ ID NO:17, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:18, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:19; and the antibody light chain variable region LCDR1 comprises the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprises the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:22.

[0183] In some embodiments, the anti-human TL1A antibody of any of the preceding claims, wherein the antibody heavy chain variable region HCDR1 comprises the amino acid sequence shown in SEQ ID NO:23, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:24, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:25; and the antibody light chain variable region LCDR1 comprises the amino acid sequence shown in SEQ ID NO:26, LCDR2 comprises the amino acid sequence shown in SEQ ID NO:27, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:28.

[0184] In some embodiments, the anti-human TL1A antibody of any of the preceding claims, wherein the antibody heavy chain variable region HCDR1 comprises the amino acid sequence shown in SEQ ID NO:29, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:30, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:31; and the antibody light chain variable region LCDR1 comprises the amino acid sequence shown in SEQ ID NO:32, LCDR2 comprises the amino acid sequence shown in SEQ ID NO:33, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:34.

[0185] In some embodiments, the anti-human TL1A antibody of any of the preceding claims, wherein the antibody heavy chain variable region HCDR1 comprises the amino acid sequence shown in SEQ ID NO:35, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:36, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:37; and the antibody light chain variable region LCDR1 comprises the amino acid sequence shown in SEQ ID NO:32, LCDR2 comprises the amino acid sequence shown in SEQ ID NO:38, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO:39.

[0186] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0187] i) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11, 12 and 13 respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:14, 15 and 16 respectively.

[0188] ii) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:17, 18 and 19, respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:20, 21 and 22, respectively;

[0189] iii) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:23, 24 and 25 respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:26, 27 and 28 respectively;

[0190] iv) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:29, 30, and 31, respectively, and the light chain variable region includes LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:32, 33, and 34, respectively; or

[0191] v) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:35, 36 and 37, respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:32, 38 and 39, respectively.

[0192] In some embodiments, the anti-human TL1A antibody is selected from any one or more of groups (e.g., groups 1, 2, 3, 4 or 5) of i) to v) above.

[0193] In some embodiments, the anti-human TL1A antibody is selected from the anti-human TL1A antibodies of group i), ii), or iii) above, wherein,

[0194] i) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11, 12 and 13 respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:14, 15 and 16 respectively.

[0195] ii) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:17, 18, and 19, respectively, and the light chain variable region includes LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:20, 21, and 22, respectively; or

[0196] iii) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:23, 24 and 25, respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:26, 27 and 28, respectively.

[0197] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein: the heavy chain variable region of the anti-human TL1A antibody comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:11, 12, and 13, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:14, 15, and 16, respectively.

[0198] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein: the heavy chain variable region of the anti-human TL1A antibody comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:17, 18, and 19, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:20, 21, and 22, respectively.

[0199] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein: the heavy chain variable region of the anti-human TL1A antibody comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:23, 24, and 25, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:26, 27, and 28, respectively.

[0200] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein: the heavy chain variable region of the anti-human TL1A antibody comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:29, 30, and 31, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:32, 33, and 34, respectively.

[0201] In some embodiments, this disclosure provides an anti-human TL1A antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein: the heavy chain variable region of the anti-human TL1A antibody comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:35, 36, and 37, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:32, 38, and 39, respectively.

[0202] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments is a murine antibody, a chimeric antibody, or a humanized antibody.

[0203] In some implementations, the antibody is a murine antibody.

[0204] In some implementations, the antibody is a chimeric antibody.

[0205] In some implementations, the antibody is a humanized antibody.

[0206] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0207] The variable region of the antibody heavy chain comprises an amino acid sequence having at least 80% (e.g., more than 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity as shown in any of SEQ ID NO:48-64 and 1-5; and / or

[0208] The light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:65-78 and 6-10 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%) sequence identity with any of the sequences in SEQ ID NO:65-78 and 6-10.

[0209] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0210] A) The antibody heavy chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:48-60; and the light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:65-74;

[0211] B) The antibody heavy chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO: 61-64; and the light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO: 75-78;

[0212] C) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:1; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:6;

[0213] D) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:2; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:7;

[0214] E) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:3; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8;

[0215] F) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:4; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:9; or

[0216] G) The antibody heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:5; and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:10.

[0217] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0218] A) The antibody heavy chain variable region contains an amino acid sequence as shown in any of SEQ ID NO:48-60; and the light chain variable region contains an amino acid sequence as shown in any of SEQ ID NO:65-74.

[0219] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0220] B) The antibody heavy chain variable region contains an amino acid sequence as shown in any of SEQ ID NO:61-64; and the light chain variable region contains an amino acid sequence as shown in any of SEQ ID NO:75-78.

[0221] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0222] C) The antibody heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:1; and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:6.

[0223] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0224] D) The antibody heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:2; and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:7.

[0225] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0226] E) The antibody heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:3; and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:8.

[0227] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0228] F) The antibody heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:4; and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:9.

[0229] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0230] G) The antibody heavy chain variable region contains the amino acid sequence shown in SEQ ID NO:5; and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:10.

[0231] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments, wherein:

[0232] A) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:1; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:6;

[0233] B) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:2; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:7;

[0234] C) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:3; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8;

[0235] D) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:4; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:9;

[0236] E) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:5; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:10;

[0237] F) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:48; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:65;

[0238] G) The antibody heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:49; and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:65;

[0239] H) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:50; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:65;

[0240] I) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:51; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:66;

[0241] J) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:52; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:67;

[0242] K) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:51; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:68;

[0243] L) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:48; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:68;

[0244] M) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:53; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:69;

[0245] N) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:54; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:70;

[0246] O) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:55; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:71;

[0247] P) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:56; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:66;

[0248] Q) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:57; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:72;

[0249] R) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:58; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:73;

[0250] S) The antibody heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:59; and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:74;

[0251] T) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:60; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:66;

[0252] U) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:61; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:75;

[0253] V) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:62; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:76;

[0254] W) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:63; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:77; or

[0255] Z) The antibody heavy chain variable region contains an amino acid sequence as shown in SEQ ID NO:64; and the light chain variable region contains an amino acid sequence as shown in SEQ ID NO:78.

[0256] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments comprises:

[0257] A1) Heavy chain variable regions as shown in any of SEQ ID NO:48-60, and light chain variable regions as shown in any of SEQ ID NO:65-74;

[0258] B1) Heavy chain variable regions as shown in any of SEQ ID NO:61-64, and light chain variable regions as shown in any of SEQ ID NO:75-78;

[0259] C1) The heavy chain variable region as shown in SEQ ID NO:1, and the light chain variable region as shown in SEQ ID NO:6; or

[0260] D1) The heavy chain variable region as shown in SEQ ID NO:2, and the light chain variable region as shown in SEQ ID NO:7.

[0261] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments includes an antibody constant region.

[0262] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments has a heavy chain constant region selected from the heavy chain constant regions of human IgG1, IgG2, IgG3 and IgG4, and a light chain constant region selected from the human κ or λ chain constant region.

[0263] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments includes an Fc in the heavy chain constant region that has a reduced ADCC effector function.

[0264] In some embodiments, the heavy chain constant region includes an Fc mutant that has reduced ADCC effector function compared to wild-type Fc; for example, the ADCC induced by the antibody including the Fc mutant is 0-50% of the ADCC induced by the antibody including wild-type Fc (e.g., 50%, 30%, 20%, 10%, 1%, 0 (i.e. no ADCC effector function)).

[0265] In some implementations, the Fc region of the heavy chain constant region is a human IgG1 Fc mutant.

[0266] In some implementations, it is an IgG1Fc mutant that includes mutations in L234A, L235A, and P329G (IgG1-LALAPG mutant).

[0267] In some embodiments, the anti-human TL1A antibody described in any of the preceding claims, wherein the heavy chain constant region comprises a sequence as shown in SEQ ID NO:40 or having at least 80% (e.g., more than 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO:40, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41 ...99%, or 100%) sequence identity with SEQ ID NO:40, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41 or having at least 80% (e.g., more than 80%, 85%, 86%, 87%, 88%, 99%, or 100%) sequence identity with SEQ ID NO:40, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41, and / or the light chain constant region comprises a sequence as NO:41 is a sequence that has at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%) sequence identity.

[0268] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments comprises a heavy chain and a light chain, wherein

[0269] a1) The heavy chain comprises a sequence as shown in SEQ ID NO:79 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:79, and / or the light chain comprises a sequence as shown in SEQ ID NO:80 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:79, and / or the light chain comprises a sequence as shown in SEQ ID NO:80 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 99%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:79, and / or the light chain comprises a sequence as shown in SEQ ID NO:80 ... NO:80 is a sequence that has at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity;

[0270] b1) The heavy chain comprises a sequence as shown in SEQ ID NO:81 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:81, and / or the light chain comprises a sequence as shown in SEQ ID NO:82 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 8 ..., and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in SEQ ID NO:82, and / or the light chain comprises a sequence as shown in NO:82 is a sequence that has at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity;

[0271] c1) The heavy chain comprises a sequence as shown in SEQ ID NO:83 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:83, and / or the light chain comprises a sequence as shown in SEQ ID NO:84 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:83, and / or the light chain comprises a sequence as shown in SEQ ID NO:84 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:83, and / or the light chain comprises a sequence as shown in SEQ ID NO:84 ... NO:84 A sequence having at least 80% (e.g., 80% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%, or any value between them) sequence identity;

[0272] d1) The heavy chain comprises a sequence as shown in SEQ ID NO:42 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:42, and / or the light chain comprises a sequence as shown in SEQ ID NO:43 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 8 ..., and / or the light chain comprises a sequence as shown in SEQ ID NO:43, and / or the light chain comprises a sequence as shown in SEQ ID NO:42, and / or the light chain comprises a sequence as shown in SEQ ID NO:4 NO:43 A sequence having at least 80% (e.g., 80% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%, or any value between them) sequence identity;

[0273] e1) The heavy chain comprises a sequence as shown in SEQ ID NO:44 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity with SEQ ID NO:44, and / or the light chain comprises a sequence as shown in SEQ ID NO:45 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, or 100%, or any value between them) sequence identity with SEQ ID NO:44, and / or the light chain comprises a sequence as shown in SEQ ID NO:45 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89 ..., and / or the light chain comprises a sequence as shown in SEQ ID NO:45, and / or the light chain comprises a sequence as shown in SEQ ID NO:45, and / or the light chain comprises a sequence as shown in SEQ ID NO: NO:45 A sequence having at least 80% (e.g., 80% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%, or any value between them) sequence identity; or

[0274] f1) The heavy chain comprises a sequence as shown in SEQ ID NO:46 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:46, and / or the light chain comprises a sequence as shown in SEQ ID NO:47 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:46, and / or the light chain comprises a sequence as shown in SEQ ID NO:47 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, or 100%, or any value between therewith) sequence identity with SEQ ID NO:46, and / or the light chain comprises a sequence as shown in SEQ ID NO:47 ... NO:47 A sequence having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity.

[0275] In some embodiments, the anti-human TL1A antibody described in any of the preceding claims comprises: a heavy chain as shown in SEQ ID NO:79 and a light chain as shown in SEQ ID NO:80; a heavy chain as shown in SEQ ID NO:81 and a light chain as shown in SEQ ID NO:82; or a heavy chain as shown in SEQ ID NO:83 and a light chain as shown in SEQ ID NO:84.

[0276] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments is an scFv-Fc antibody. An scFv-Fc antibody refers to a fusion protein formed by an scFv domain and an Fc domain.

[0277] In some implementations, the Fc domain is connected to the C terminal of scFv.

[0278] In some implementations, the scFv has the structure shown in [VH]-connector-[VL].

[0279] In some embodiments, the linker is a peptide linker comprising one or more glycine (G) and / or serine (S), such as (G4S). n The flexible peptide, where n is an integer not less than 0, such as 1, 2, 3 or 4.

[0280] In some implementations, the connector is (G4S)3.

[0281] In some embodiments, the VH of the scFv-Fc antibody is as shown in any one of SEQ ID NO:61-64 and 2, and its VL is as shown in any one of SEQ ID NO:75-78 and 7.

[0282] In some embodiments, the VH of the scFv-Fc antibody is as shown in any one of SEQ ID NO:61-64, and its VL is as shown in any one of SEQ ID NO:75-78.

[0283] In some embodiments, the scFv-Fc antibody comprises:

[0284] g1) A sequence as shown in SEQ ID NO:85 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity with SEQ ID NO:85;

[0285] h1) A sequence as shown in SEQ ID NO:86 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity with SEQ ID NO:86;

[0286] i1) A sequence as shown in SEQ ID NO:87 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity with SEQ ID NO:87;

[0287] j1) A sequence as shown in SEQ ID NO:88 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity with SEQ ID NO:88;

[0288] k1) A sequence as shown in SEQ ID NO:89 or having at least 80% (e.g., more than 80%, more than 85%, more than 86%, more than 87%, more than 88%, more than 89%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100%, or any value between them) sequence identity with SEQ ID NO:89.

[0289] In some implementations, the scFv-Fc antibody can be a monomer.

[0290] In some implementations, the scFv-Fc antibody can be a dimer.

[0291] The dimer is formed by two copies of monomers via each other's Fc domains (e.g., interchain disulfide bonds and / or mutations that promote dimerization).

[0292] In some embodiments, the scFv-Fc antibody comprises: two sequences as shown in SEQ ID NO:85; two sequences as shown in SEQ ID NO:86; two sequences as shown in SEQ ID NO:87; two sequences as shown in SEQ ID NO:88; or two sequences as shown in SEQ ID NO:89.

[0293] In some embodiments, the anti-human TL1A antibody described in any of the preceding embodiments is a full-length antibody or an antigen-binding fragment selected from Fab, Fab', F(ab')2, Fd, Fv, scFv, dsFv, scFab, and (dsFv)2.

[0294] In some embodiments, an anti-human TL1A antibody that competes with the anti-human TL1A antibody described in any of the preceding claims for binding to human TL1A or that binds to the same antigenic epitope as the anti-human TL1A antibody described in any of the preceding claims is also disclosed.

[0295] In some embodiments, the anti-human TL1A antibody described in any of the preceding claims has at least one of the following functions (1) to (5):

[0296] 1) The anti-human TL1A antibody can block the binding of human TL1A to DR3 and / or block the binding of human TL1A to DcR3; in some embodiments, the anti-human TL1A antibody can block the binding of human TL1A to DR3 and TL1A to DcR3; in some embodiments, the blocking of the binding of human TL1A to DR3 and / or the blocking of the binding of human TL1A to DcR3 is detected by the method described in Example 5 of this disclosure;

[0297] (2) The anti-human TL1A antibody is capable of binding to cells expressing human TL1A; in some embodiments, the anti-human TL1A antibody can bind to cells expressing human TL1A with an EC50 value of less than 10 nM (e.g., less than 10 nM, less than 5 nM, less than 2 nM, less than 1 nM, less than 0.9 nM, less than 0.8 nM or less), the EC50 value being detected by FACS method; in some embodiments, the cells expressing human TL1A are HEK293 cells overexpressing TL1A; in some embodiments, the cells are HEK293 cells that have been stably transfected and overexpress TL1A; in some embodiments, the EC50 value is detected by the method described in Example 2 of this disclosure;

[0298] (3) The anti-human TL1A antibody can bind to the human TL1A antigen protein; optionally, the anti-human TL1A antibody can bind to the human TL1A antigen protein with an EC50 value of less than 1 nM (e.g., less than 1 nM, less than 0.9 nM, less than 0.8 nM, less than 0.5 nM, less than 0.1 nM, less than 0.05 nM, less than 0.01 nM or less), and the EC50 value is detected by an ELISA method; optionally, the antibody has lower binding activity to mouse TL1A antigen protein than to human TL1A antigen protein; in some In some embodiments, the antibody weakly binds to the mouse TL1A antigen; in some embodiments, the antibody does not bind to the mouse TL1A antigen; in some embodiments, the ratio of the EC50 value of the antibody binding to the mouse TL1A antigen to the EC50 value of the antibody binding to the human TL1A antigen is greater than 2 (e.g., greater than 2, greater than 10, greater than 50, greater than 100, greater than 200, greater than 500, greater than 1000 or greater), and the EC50 value is detected by an ELISA method, for example, the EC50 value is detected by the method described in Embodiment 3 of this disclosure;

[0299] (4) The anti-human TL1A antibody is capable of binding to human TL1A protein; in some embodiments, the anti-human TL1A antibody can bind to human TL1A protein with a KD value of less than 1.00E-9M (e.g., less than 1.00E-9M, less than 5.00E-10M, less than 1.00E-10M, less than 5.00E-11M, less than 2.00E-11M, less than 5.00E-12M, less than 4.00E-12M, less than 2.00E-12M, less than 5.00E-13M, less than 1.00E-13M, less than 1.00E-14M, less than 6.00E-15M or less), the KD value being detected by a surface plasmon resonance technique; in some embodiments, the KD value is detected by the method described in Example 4 of this disclosure;

[0300] (5) The anti-human TL1A antibody can inhibit TF1 cell apoptosis; in some embodiments, the function of inhibiting TF1 cell apoptosis is detected by the method described in Example 6 of this disclosure.

[0301] In some embodiments, any of the anti-human TL1A antibodies described above in this disclosure (e.g., Apb1 antibody) is a high-affinity humanized antibody targeting TL1A that can specifically neutralize the TL1A signaling pathway, exhibit excellent target-binding activity and blocking efficacy in in vitro functional experiments, and / or effectively inhibit T cell-mediated intestinal inflammatory responses.

[0302] In some embodiments, any of the preceding anti-human TL1A antibodies (e.g., Apb1 antibodies) of this disclosure have good drug-likeness and / or good pharmacokinetic properties, such as having an extended half-life (e.g., 10 days, 20 days, 30 days, or longer, or any value between them), good physical stability, good chemical stability, high cellular expression levels, and / or in vivo / in vitro therapeutic functions for diseases (e.g., inflammatory bowel disease, fibrotic diseases, or autoimmune diseases).

[0303] The disclosed anti-human TL1A antibody (e.g., Apb1 antibody) is expected to become a next-generation IBD treatment candidate, meeting the current urgent clinical need for long-acting and safe biologics.

[0304] Secondly, this disclosure provides a nucleic acid molecule comprising a nucleotide sequence encoding the anti-human TL1A antibody described in any of the preceding claims.

[0305] In some implementations, the nucleic acid molecule encodes the anti-human TL1A antibody described in any of the preceding embodiments.

[0306] In some embodiments, the nucleic acid molecule comprises a first nucleotide sequence encoding a heavy chain or heavy chain variable region of an anti-human TL1A antibody and a second nucleotide sequence encoding a light chain or light chain variable region of the anti-human TL1A antibody, wherein the first nucleotide sequence and the second nucleotide sequence are present on the same or different nucleic acid molecules.

[0307] Thirdly, this disclosure provides a vector comprising any of the nucleic acids described above.

[0308] In some embodiments, the vector comprises a first nucleotide sequence encoding a heavy chain or a heavy chain variable region of an anti-human TL1A antibody and a second nucleotide sequence encoding a light chain or a light chain variable region of the anti-human TL1A antibody, wherein the first nucleotide sequence and the second nucleotide sequence are present on the same or different vectors.

[0309] Fourthly, this disclosure provides a host cell comprising the nucleic acid or vector described in any of the preceding claims. Such host cells include, but are not limited to, prokaryotic cells such as bacterial cells (e.g., Escherichia coli cells), eukaryotic cells such as fungal cells (e.g., yeast cells), insect cells, plant cells, and animal cells (e.g., mammalian cells, such as mouse cells, human cells, etc.).

[0310] Fifthly, this disclosure provides a method for preparing an antibody that binds to human TL1A, comprising culturing the host cells described in any of the preceding claims under conditions suitable for expressing the antibody, and recovering the antibody from the cultured host cell culture.

[0311] In a sixth aspect, this disclosure provides a multispecific molecule comprising the anti-human TL1A antibody as described in any of the preceding embodiments. In some embodiments, the multispecific molecule specifically binds to human TL1A and specifically binds to one or more other antigens. In some embodiments, the multispecific molecule specifically binds to human TL1A and specifically binds to one other antigen.

[0312] In a seventh aspect, this disclosure provides a conjugate comprising the anti-human TL1A antibody as described in any of the preceding claims, and a conjugated portion.

[0313] In some implementations, the coupling portion is selected from protein tags, detectable markers, or therapeutic agents.

[0314] In some embodiments, the conjugation portion is a cytotoxic drug, and the conjugation portion is linked to an antibody described in any of the preceding embodiments via a linker.

[0315] Eighthly, this disclosure provides a pharmaceutical composition comprising the anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, carrier or cell, and pharmaceutically acceptable carrier as described in any of the preceding claims.

[0316] In some embodiments, the pharmaceutical composition may further comprise additional pharmaceutical agents.

[0317] In some implementations, the additional agent is selected from drugs used to treat inflammatory bowel disease, fibrotic disease, or autoimmune diseases, such as anti-inflammatory drugs.

[0318] Ninthly, this disclosure provides a method for treating a disease, the method comprising administering to a subject in need a therapeutically effective amount of any of the preceding claims an anti-human TL1A antibody, a multispecific molecule, a conjugate, a nucleic acid molecule, a carrier, a cell, or a pharmaceutical composition.

[0319] In some implementations, the disease is a disease associated with high TL1A expression. "High TL1A expression" means that the TL1A expression level of patients with the disease is increased compared to healthy individuals (e.g., increased by 1, 21, 3, 5, 10, or more times).

[0320] In some implementations, the subject is a human being.

[0321] In some embodiments, the disease is selected from inflammatory bowel disease, fibrotic diseases, and autoimmune diseases. In some embodiments, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0322] In a tenth aspect, this disclosure provides the use of the anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, carrier, cell, or pharmaceutical composition described in any of the preceding claims in the preparation of a medicament.

[0323] In some implementations, the drug is used to treat diseases associated with TL1A overexpression.

[0324] In some implementations, the anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, vector, cell, or pharmaceutical composition described in any of the preceding embodiments may be used alone or in combination with other agents.

[0325] In some implementations, the additional agent is selected from drugs used to treat inflammatory bowel disease, fibrotic disease, or autoimmune diseases, such as anti-inflammatory drugs.

[0326] In some implementations, the disease is selected from inflammatory bowel disease, fibrotic disease, and autoimmune disease.

[0327] In some implementations, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0328] In one aspect, this disclosure provides a pharmaceutical composition of any of the preceding claims, including an anti-human TL1A antibody, a multispecific molecule, a conjugate, a nucleic acid molecule, a carrier, a cell, or the like, for use as a medicament.

[0329] In some implementations, the drug is used to treat diseases associated with TL1A overexpression.

[0330] In some implementations, the anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, vector, cell, or pharmaceutical composition described in any of the preceding embodiments may be used alone or in combination with other agents.

[0331] In some implementations, the additional agent is selected from drugs used to treat inflammatory bowel disease, fibrotic disease, or autoimmune diseases, such as anti-inflammatory drugs.

[0332] In some implementations, the disease is selected from inflammatory bowel disease, fibrotic disease, and autoimmune disease.

[0333] In some implementations, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0334] In any of the foregoing aspects, the anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, carrier, cell, or pharmaceutical composition of this disclosure can be formulated into any dosage form known in the medical field. The anti-human TL1A antibody, multispecific molecule, conjugate, nucleic acid molecule, carrier, cell, or pharmaceutical composition of this disclosure can be administered by any suitable method known in the art.

[0335] In a twelfth aspect, this disclosure provides a method for detecting the presence or level of human TL1A in a sample in vitro, comprising contacting the sample with an anti-human TL1A antibody as described above, under conditions that allow the formation of a complex between the antibody and human TL1A, and detecting the formation of the complex.

[0336] In some implementations, the method is used to diagnose diseases, such as inflammatory diseases (e.g., inflammatory bowel disease), fibrotic diseases, and autoimmune diseases.

[0337] In some implementations, the method includes detecting the expression level of human TL1A in a test sample from a subject and comparing the expression level to a reference value, wherein an increase in the expression level compared to the reference value is an indication of inflammatory disease (e.g., inflammatory bowel disease), fibrotic disease, and autoimmune disease.

[0338] In some embodiments, the sample may be selected from urine, blood, serum, plasma, saliva, ascites, circulating cells, circulating tumor cells, non-tissue-associated cells (i.e., free cells), tissue (e.g., surgically removed tumor tissue, biopsy sections, or fine-needle aspiration tissue), histological preparations, etc.

[0339] In some implementations, the method may be used for diagnostic purposes or non-diagnostic purposes (e.g., the sample is a cell sample, rather than a sample from a patient).

[0340] In another aspect, the use of the antibodies disclosed herein in the preparation of kits for detecting the presence or level of human TL1A in a sample, and / or diagnosing inflammatory diseases (e.g., inflammatory bowel disease), fibrotic diseases, and autoimmune diseases is provided.

[0341] Furthermore, those skilled in the art will foresee that any of the preceding technical solutions can be freely combined with one or more other technical solutions of this disclosure to form new technical solutions (without mutual exclusion). These will not be listed one by one here, but they are all within the scope of protection claimed in this disclosure.

[0342] The present disclosure is described in the following non-limiting embodiments. Those skilled in the art will understand that the embodiments are described by way of example and are not intended to limit the scope of protection claimed by the present disclosure. Unless otherwise specified, the experimental methods in the embodiments are conventional methods. Where specific conditions are not specified in the embodiments, they are performed according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0343] Example 1: Screening and preparation of monoclonal antibodies

[0344] 1.1 Antigen preparation and animal immunization

[0345] The extracellular fraction of recombinant human TL1A protein (Uniprot ID: O95150) antigen, amino acids 72-251 (with an N-terminal His and Avi tag), was secreted and expressed by Expi293F cells (Gibco, A39241). It was affinity purified using a HisTrap Excel column (Cytiva, 29048586) and further purified using a Superdex 200 increase small-scale SEC column (Cytiva, 28990944) to obtain the homotrimeric molecule (hTL1A). The extracellular fraction of recombinant murine TL1A protein (Uniprot ID: Q5UBV8) antigen was also purified using the same method to obtain the homotrimeric molecule (mTL1A). SDS-PAGE and HPLC-SEC analysis showed a purity and homogeneity exceeding 95%. The concentrated recombinant human TL1A extracellular trimeric protein was used for subsequent animal immunization and antibody molecule screening and detection.

[0346] Mouse immunization was performed using 6-8 week old Bal b / c mice (purchased from Shanghai Silec), which were housed under SPF conditions after receipt. The primary immunization consisted of 50 μg / mouse of human TL1A extracellular trimer protein emulsified with Freund's complete adjuvant and administered intraperitoneally. A booster immunization was performed with 25 μg / mouse of human TL1A extracellular trimer protein emulsified with Freund's incomplete adjuvant and administered intraperitoneally, for a total of two booster immunizations. Two weeks were between each immunization. Blood samples were collected 7 days after each booster immunization, and the titer of specific antibodies in the serum was measured using ELISA. Mice with the highest serum titers were selected for final immunization, using the same antigen protein dose as the booster immunizations. Spleen cells and PBMCs were collected 4-5 days later for screening and identification of specific antibodies.

[0347] Healthy 6-8 week old New Zealand White rabbits (purchased from Pengli Biotechnology) were used for immunization. For the primary immunization, 400 μg / rabbit of human TL1A extracellular trimer protein was emulsified with Freund's complete adjuvant and injected intraperitoneally. For the booster immunization, 200 μg / rabbit of human TL1A extracellular trimer protein was emulsified with Freund's incomplete adjuvant and injected intraperitoneally. Two booster immunizations were administered, with a 2-week interval between each. Seven days after each booster immunization, blood samples were collected, and the titer of specific antibodies in the serum was measured using ELISA. Rabbits with the highest serum titers were selected for the final immunization, using the same antigen protein dosage as the booster immunizations. Four to five days later, spleen cells and PBMCs were collected from the rabbits for screening and identification of specific antibodies.

[0348] 1.2 Screening of anti-human TL1A antibodies

[0349] After collecting immune cells from mice or rabbits, a portion was directly lysed with Trizol lysis buffer to extract total mRNA. The corresponding nucleic acid sequences of the VH and VL fragments were amplified by PCR to construct a VH-VL V gene scFv phage display library. The phage library was enriched by two rounds of panning using biotinylated human TL1A protein antigen. Binding activity was detected by ELISA, and clones that were positive for human TL1A and negative for human TNFα were sequenced. Another portion of immune cells were isolated using single-cell B cell isolation technology. Plasma cells with IgM(-), IgD(-), and IgG(+) were isolated from the cell pool using flow cytometry. Biotinylated human TL1A protein antigen was then labeled with streptavidin conjugated with APC / PE fluorescein dye. The plasma cells were specifically stained with the fluorescently labeled antigen, and human TL1A-positive B cells were sorted. Human TL1A-positive plasma cells were selected, and single cells were isolated into 96-well plates using flow cytometry. The nucleic acid sequences corresponding to the VH and VL sequences of the antibody in the single cells were amplified by PCR. Then, the antibody expression vector (purchased from Invitrogen, catalog number V79020) was directly constructed using the VH and VL DNA sequences. The antibody expression vector molecule was sequenced, and the differential antibody sequence was selected. The antibody molecule was expressed using the method described in Example 1.3 of this embodiment, and the binding ability of the expression product was detected (the detection method is described in Example 3 of this disclosure).

[0350] 1.3 Preparation of anti-human TL1A chimeric antibody

[0351] The heavy chain and light chain variable regions of the antibodies screened in section 1.2 were extracted. DNA encoding the heavy chain variable region was directionally cloned into an expression vector (purchased from Invitrogen, catalog number V79020) containing a signal peptide and the human antibody heavy chain constant region (amino acid sequence: SEQ ID NO:40), yielding a recombinant vector. Similarly, DNA encoding the light chain variable region was directionally cloned into an expression vector (purchased from Invitrogen, catalog number V79020) containing a signal peptide and the human antibody light chain kappa constant region (amino acid sequence: SEQ ID NO:41), yielding a VL recombinant vector. The recombinant vectors were then subjected to ExpiFectamine... TM The CHO transfection kit (Invitrogen, A29130) was transiently transfected into ExpiCHO cells (Gibco, A29127) and ExpiCHO was used. TMExpression Medium (Gibco, A2910002) was cultured with shaking in a CO2 incubator at 37°C for 8–10 days. The cell culture medium was collected, centrifuged to remove cell components, and filtered through a 0.45 μm filter until the culture supernatant was clear. The supernatant was then subjected to MabSelect PrismA assay. TM Protein A affinity chromatography was performed using Cytiva (17-5498-02) resin. The Prism A column was regenerated with 0.1M NaOH, washed with pure water, and then equilibrated with PBS. The expression supernatant was bound and washed with PBS until the A280 reading returned to baseline. The target protein was eluted with 0.1M acetate buffer at pH 3.5 and neutralized with 1M Tris-HCl at pH 9.0. After appropriate concentration, the eluted sample was further purified using a PBS-equilibrated Superdex 200 gel chromatography system (Cytiva, 28-9893-35). The target protein was collected in the receiving tube and concentrated to an appropriate concentration for later use.

[0352] Five chimeric antibodies that specifically bind to human TL1A were finally obtained. The amino acid sequences of the variable region and CDR region of the chimeric antibodies are shown in Tables 1 and 2.

[0353] Table 1. Amino acid sequence of the variable region of anti-human TL1A antibody

[0354] Table 2. Amino acid sequence of anti-human TL1A antibody CDR

[0355] Note: The amino acid sequences (SEQ ID NO:40) of the constant region of human antibody heavy chain IgG1 were determined according to the Kabat numbering system for the CDRs shown in Table 2.

[0356] The amino acid sequence of the constant region of the human antibody light chain kappa (SEQ ID NO:41):

[0357] Exemplary full-length sequence of chimeric antibody:

[0358] The amino acid sequence of the Apb1 heavy chain (SEQ ID NO:42):

[0359] The amino acid sequence of the Apb1 light chain (SEQ ID NO:43):

[0360] The amino acid sequence of the Dcb2 heavy chain (SEQ ID NO:44):

[0361] The amino acid sequence of the Dcb2 light chain (SEQ ID NO:45):

[0362] The amino acid sequence of the Dpb3 heavy chain (SEQ ID NO:46):

[0363] The amino acid sequence of the Dpb3 light chain (SEQ ID NO:47):

[0364] Example 2: Detection of the binding ability of anti-human TL1A antibody to TL1A-expressing cells

[0365] The binding ability of anti-human TL1A antibody to TL1A-expressing cells was then detected using the FACS method.

[0366] Experimental Procedure: HEK293 cells overexpressing TL1A (ACRO Biosystems, CHEK-ATP142, HEK293TL1A+ cells) were cultured in T-75 cell culture flasks until 90% confluence. The culture medium was discarded, and the cells were washed twice with PBS buffer, followed by digestion with Trypsin-EDTA (Gibco, 25200-072). Cells were collected and washed twice with PBS buffer. The collected cells were resuspended in FACS buffer (PBS + 2% FBS (v / v)) to a concentration of 2 × 10⁻⁶ cells / mL. 6 Cells / mL were added at 50 μL per well to a 96-well V plate (NEST, 701201), along with an equal volume of serially diluted (200 nM, 3-fold dilution) test antibody, and incubated at 4°C for 1 hour. Cells were washed twice by centrifugation with FACS buffer. 50 μL of 1:1000 diluted goat anti-human-IgG Fc fragment-specific binding fluorescent secondary antibody (Jackson, 109-605-098) was added to each well, and the cells were incubated on ice for 1 hour. Cells were washed twice by centrifugation with FACS buffer. Cells were resuspended in 100 μL of FACS buffer, and the results were detected and analyzed using an iQue3 flow cytometer. IgG was used as a negative control in this experiment. A four-parameter logistic model was used to fit the dose-response data and fluorescence signals using GraphPad Prism.

[0367] Some experimental results are shown in Figure 1 and Table 3. The experimental results show that the anti-human TL1A antibodies disclosed in this paper can all interact with HEK293. TL1A+ Cell-specific binding.

[0368] Table 3. Detection of anti-human TL1A antibody and HEK293 by FACS method hTL1A+ Cell binding experiment results

[0369] Example 3: Detection of the binding ability of anti-human TL1A antibody to TL1A protein

[0370] The binding ability of anti-human TL1A antibody to TL1A protein was detected by ELISA.

[0371] Experimental Procedure: Add 100 μL of 1 μg / mL human TL1A protein (hTL1A, preparation as described in Example 1 of this disclosure) or mouse TL1A protein (mTL1A, preparation as described in Example 1 of this disclosure, diluted with PBS) to each well of a 96-well ELISA plate and coat overnight at 4°C. Remove the coating solution, wash the plate twice with PBST buffer, and then add 200 μL of 1% (w / v) BSA-PBST blocking buffer to each well, blocking at 37°C for 2 hours. Remove the blocking solution, wash the plate twice with PBST buffer, and add serially diluted (100 nM, 10-fold dilution) of the test antibody, 100 μL / well, binding at 37°C for 1 hour. Next, wash the plate 6 times with PBST buffer, and add 100 μL of horseradish peroxidase-labeled goat anti-human IgG diluted 1:10000 to each well. Fc antibody (Sigma, AP113P) was bound at 37℃ for 0.5 hours. The sample was washed 6 times with PBST buffer. 90 μL of TMB single-component chromogenic solution (Solepro, PR1200) was added, and the sample was incubated for 5-10 minutes. Then, 40 μL of 1M H2SO4 stop solution was added, and the signal value of each well was read at 450 nm using a microplate reader. The dose-response data and optical signals were fitted using a four-parameter logical model via GraphPad Prism. In this experiment, 1D1 1.31 was used as the control molecule (1D1 1.31 refers to the anti-TL1A antibody with the patent specification number "1D1 1.31" in WO2015073580A1, also known as PF-06480605, hereinafter the same).

[0372] Some experimental results are shown in Figures 2 and 3 and Table 4. The experimental results show that the anti-human TL1A antibodies disclosed herein can specifically bind to human TL1A protein, and Dcb2, Dpb3, Acb4, and Acb5 do not specifically bind to mouse TL1A. Apb1 binds to mouse TL1A protein, but the EC50 value of the binding is greater than that of 1D1 1.31 binding to mouse TL1A protein. This indicates that the anti-human TL1A antibodies disclosed herein have significantly better binding specificity to human TL1A protein.

[0373] Table 4. Results of ELISA assay for the binding of anti-human TL1A antibody to mouse TL1A protein.

[0374] Note: NA in the table indicates non-specific binding to mouse TL1A protein.

[0375] Example 4: Affinity Detection of Anti-human TL1A Antibody

[0376] The affinity and kinetics of the anti-human TL1A antibody for binding to the human TL1A protein were determined using a surface plasmon resonance (SPR) instrument with a Biacore 8K Plus.

[0377] The target antibody molecule was captured for 60 s at a concentration of 1 μg / mL using a protein A chip (Cytiva, 29127555). Recombinant human TL1A protein (hTL1A, preparation details are in Example 1 of this disclosure) was diluted to 10 nM and 2 nM concentrations and flowed through the sensor chip at a rate of 30 μL / min. The chip was run under PBST buffer conditions, binding for 120 s, followed by dissociation for 1800 s. Chip surface regeneration was performed using 10 mM Glycine-HCl pH 1.5 regeneration buffer at a flow rate of 10 μL / min for 30 s. Experimental data were double-subtracted (control channel and zero concentration) and fitted using a 1:1 binding model with Biacore 8K Plus insight evaluation software to obtain affinity and kinetic data. Affinity and kinetic data for the binding of anti-human TL1A antibody to cynomolgus monkey TL1A antigen protein (cynomolgus monkey TL1A, purchased from Bipsys Biotechnology) were obtained using the same detection method.

[0378] Some experimental results are shown in Table 5. The experimental results show that the anti-human TL1A antibody disclosed in this paper can bind to human TL1A protein and cynomolgus monkey TL1A protein with high affinity.

[0379] Table 5. Affinity test results of anti-human TL1A and cynomolgus monkey TL1A antibodies

[0380] Note: "LOD" refers to exceeding the maximum detection range of the instrument.

[0381] Example 5: Neutralization experiment of anti-human TL1A antibody with DR3 / DcR3 receptor

[0382] 1.1 Neutralization assay of anti-human TL1A antibody competing with DR3 for TL1A binding

[0383] Experimental Procedure: Coat a 96-well ELISA plate with 1 μg / mL DR3-Fc protein (Acro Bioscience, DR3-H5253), 100 μL / well, and incubate overnight at 4°C. Remove the coating solution, wash the plate twice with PBST buffer, and then add 200 μL of 1% (w / v) BSA-PBST blocking buffer to each well, and block at 37°C for 2 hours. Remove the blocking solution, wash the plate twice with PBST buffer, and add 100 μL / well of the test antibody (300 nM, 100 nM, 20 nM, 0 nM) pre-incubated with 1 μg / mL human TL1A protein (hTL1A, preparation see Example 1 of this disclosure) for 1 hour, and bind at 37°C for 1 hour. Next, wash the plate six times with PBST buffer. Add 100 μL of horseradish peroxidase-labeled mouse anti-His tag antibody (Genscript, A00612) diluted 1:5000 to each well and incubate at 37°C for 0.5 hours. Wash six times with PBST buffer. Add 90 μL of TMB single-component chromogenic buffer (Solepro, PR1200) and incubate for 5-10 minutes. Then add 40 μL of 1M H2SO4 stop solution and read the signal value of each well at 450 nm using a microplate reader. Process the data using GraphPad Prism.

[0384] Partial experimental results are shown in Figure 4. The results show that at an antibody concentration of 300 nM, the anti-human TL1A antibody disclosed herein can effectively block the binding of TL1A to the receptor DR3. TL1A, by binding to the receptor DR3, co-stimulates T cell activation, mediates downstream signal transduction, and promotes the production of specific cytokines. When TL1A signaling is persistent or excessive, it leads to an abnormally large production of cytokines, thereby driving chronic inflammation. Therefore, the anti-human TL1A antibody disclosed herein, by blocking the binding of TL1A to the receptor DR3 and thus inhibiting the TL1A signaling pathway, can be used to treat inflammatory diseases such as IBD.

[0385] 1.2 Neutralization assay of anti-human TL1A antibody competing with DcR3 for TL1A binding

[0386] Experimental Procedure: Coat a 96-well ELISA plate with 1 μg / mL DcR3-Fc protein (Sino Biological, 10224-H02B), 100 μL / well, and incubate overnight at 4°C. Remove the coating solution, wash the plate twice with PBST buffer, and then add 200 μL of 1% (w / v) BSA-PBST blocking buffer to each well, and block at 37°C for 2 hours. Remove the blocking solution, wash the plate twice with PBST buffer, and add 100 μL / well of the test antibody (400 nM, 2-fold dilution) that has been pre-incubated with 1 μg / mL human TL1A protein (hTL1A, preparation see Example 1 of this disclosure) for 1 hour, binding at 37°C for 1 hour. Next, wash the plate six times with PBST buffer. Add 100 μL of horseradish peroxidase-labeled mouse anti-His tag antibody (Genscript, A00612) diluted 1:5000 to each well and incubate at 37°C for 0.5 hours. Wash six times with PBST buffer. Add 90 μL of TMB single-component chromogenic solution (Solepro, PR1200) and incubate for 5-10 minutes. Then add 40 μL of 1M H2SO4 stop solution and read the signal value of each well at 450 nm using a microplate reader. Process the data using GraphPad Prism. 1D1 1.31 was used as a positive control molecule.

[0387] Some experimental results are shown in Figure 5. The results show that, compared with the control molecule 1D1 1.31, at a concentration of 400 nM, the disclosed anti-human TL1A antibodies Apb1 and Dcb2 can also completely block the binding of TL1A molecules to the DcR3 receptor, and Dpb3, Acb4, and Acb5 can block about 80% of the binding of TL1A molecules to the DcR3 receptor.

[0388] Example 6: Experiment on the inhibition of TF1 cell apoptosis by anti-human TL1A antibody

[0389] Detection of caspase activation in TF-1 cells induced by anti-TL1A antibody inhibiting soluble recombinant TL1A. This embodiment evaluates the ability of anti-TL1A antibody to block caspase activation in TF-1 cells induced by recombinant human TL1A protein (hTL1A, preparation described in Example 1 of this disclosure) by detecting caspase 3 / 7 activity using a chemiluminescent method.

[0390] The day before the experiment, TF-1 cells (from Kebai Biotechnology) were cultured at a density of 3E5 / mL in TF-1 medium containing 2 ng / mL GM-CSF (from Acro Biosystems). On the day of the experiment, 50 μL of TF-1 medium (without GM-CSF) containing double the final concentration of anti-human TL1A antibody, CHX (MCE, 20 μM), and recombinant human TL1A protein (10 nM) were prepared in 96-well plates. The final concentration of anti-human TL1A antibody was up to 100 nM, diluted 3-fold, for a total of 8 concentrations. Cells were collected, washed once with PBS, and then resuspended at a density of 7E5 / mL in GM-CSF-free TF-1 medium. 50 μL of the cell suspension was added to the antibody / TL1A / CHX solution, mixed well, and incubated at 37°C in a 5% CO2 incubator for 6 hours. For detection, 100 μL of the solution was added to each well. The reagents in the 3 / 7 assay kit (Promega, G8092) were used to read the luciferase luminescence signal after incubation in the dark for 15 minutes. An anti-GP120 antibody (an antibody that does not bind to TL1A) was obtained as a negative control according to b12 in the literature (Zwick MB, et al. J Virol. 2003).

[0391] Some experimental results are shown in Figure 6 and Table 6. The results show that the anti-human TL1A antibody disclosed in this paper can effectively inhibit TL1A-induced apoptosis, indicating that it has the activity of blocking the binding of human TL1A to the DR3 receptor on the surface of TF-1 cells, thereby inhibiting the TL1A signaling pathway for the treatment of inflammatory diseases such as IBD.

[0392] Table 6. EC50 assay results of anti-human TL1A antibody inhibiting TF1 cell apoptosis.

[0393] Example 7 Antibody Epitope Competitive Binding Assay

[0394] Biolayer interferometry (BLI) can be used to analyze antibody competitive epitopes in a group of antibodies to determine whether different antibodies recognize different epitopes of the same antigen, thereby grouping these antibodies.

[0395] This embodiment uses a SARTORIUS Octet RH16 instrument to perform epitope competition assays for the disclosed antibody. The NTA biosensor (SARTORIUS, Cat#18-5142) was used to immobilize the target hTL1A antigen protein (hTL1A, preparation as described in Example 1 of this disclosure) at a concentration of 10 μg / mL for 60 seconds. The antigen-loaded biosensor was first equilibrated in PBST solution at pH 7.4 for 30 seconds, and then immersed in 800 nM antibody molecule 1 solution diluted in PBST (pH 7.4) for a binding reaction for 600 seconds. Subsequently, the sensor was equilibrated again in PBST solution at pH 7.4 for 30 seconds, and then the biosensor saturated with antibody 1 was immersed in 800 nM antibody molecule 2 solution diluted in PBST (pH 7.4) for 240 seconds to assess whether the epitopes of antibody 1 and antibody 2 overlapped. The obtained data were analyzed using Octet Analysis Studio 12.2.2.26 software for epitope binning.

[0396] Some experimental results are shown in Table 7. The results show that the anti-human TL1A antibodies Dpb3, Apb1, and Acb4 disclosed herein can compete with each other for binding to the hTL1A antigen protein.

[0397] Table 7. Competitive binding results of anti-human TL1A antibody BLI

[0398] Example 8: Humanization of Anti-human TL1A Antibody

[0399] Antibody humanization is primarily performed using the XuperHuman platform from Shanghai Ailexi Biotechnology Co., Ltd.

[0400] The humanization method for Apb1: First, the proprietary high-throughput humanization algorithm of the XuperHuman platform was used to perform humanization sequence analysis on Apb1. This algorithm identified and selected human IGHV and IGKV genes, which are highly homologous to mouse antibodies and frequently present in human antibody libraries, as human germline gene templates. An antibody molecular model was constructed using a structure prediction model. The selected frame region templates were analyzed for sequence similarity, structural similarity, energy, and degree of humanization. The frequency of clinical frame region pairings was also comprehensively analyzed. Simultaneously, structural analysis was performed on the maternal model to identify potential key reversion mutation sites. Based on the amino acid characteristics of the reversion mutation sites, the properties of the frame regions were re-evaluated using an algorithm. Finally, sequences with low energy, high similarity, and high degree of humanization were selected for expression.

[0401] The humanization method for Dcb2: Utilizing the XuperHuman platform's rapid humanization algorithm, after selecting the human germline gene antibody backbone, homology modeling of the Fv region was performed to predict key amino acids that might determine the structure of the rabbit antibody variable region. Reverse mutations were then designed for the grafted backbone region. Based on the above algorithm principles, humanized sequences were designed for the humanization of Dcb2. The heavy chain and light chain variable regions of the humanized sequence and the maternal mouse sequence were then compared using (G4S)... n Flexible peptides are linked to form an scFv format, and an Fc tag is attached to the C-terminus for expression and purification. (For gene construction and expression purification methods, please refer to 1.3 of Example 1 of this disclosure).

[0402] The amino acid sequence of the variable region of the finally obtained humanized antibody is shown in Table 9.

[0403] Table 9. Amino acid sequence of the variable region of anti-human TL1A humanized antibody

[0404] The amino acid sequence of the heavy chain constant region of the above-mentioned humanized antibody is: SEQ ID NO:40, and the amino acid sequence of the light chain constant region is: SEQ ID NO:41;

[0405] Exemplary full-length humanized antibody sequence:

[0406] Apb1-hu1 heavy chain (SEQ ID NO:79)

[0407] Apb1-hu1 light chain (SEQ ID NO:80)

[0408] Apb1-hu5 heavy chain (SEQ ID NO:81)

[0409] Apb1-hu5 light chain: (SEQ ID NO:82)

[0410] Apb1-hu6 heavy chain (SEQ ID NO:83):

[0411] Apb1-hu6 light chain (SEQ ID NO:84):

[0412] Full-length sequence of Dcb2_scFv_hu1 (SEQ ID NO:85):

[0413] Full-length sequence of Dcb2_scFv_hu2 (SEQ ID NO:86):

[0414] Full-length sequence of Dcb2_scFv_hu3 (SEQ ID NO:87):

[0415] Full-length sequence of Dcb2_scFv_hu4 (SEQ ID NO:88):

[0416] Full-length Dcb2-scFv sequence (SEQ ID NO:89):

[0417] The affinity and kinetics of the binding between the anti-human TL1A humanized antibody and the human TL1A protein were determined using a Biacore 8K Plus instrument employing surface plasmon resonance (SPR) technology. The experiment used a protein A chip (Cytiva, 29127555) to capture the antibody molecules at a concentration of 0.5 μg / mL for 60 s. Recombinant human TL1A protein (hTL1A, preparation details are provided in Example 1 of this disclosure) was diluted to two concentrations, 50 nM and 10 nM, and flowed through the sensor chip at a rate of 30 μL / min. The chip was run under PBST buffer conditions, with binding for 120 s followed by dissociation for 1800 s. Chip surface regeneration was performed using 10 mM Glycine-HCl at pH 1.5, with the regeneration solution flowing at a rate of 10 μL / min for 30 s. After double subtraction (control channel and zero concentration), the experimental data were fitted using a 1:1 binding model with Biacore 8K Plus insight evaluation software to obtain the affinity and kinetic data.

[0418] Some experimental results are shown in Table 9. The experimental results show that the humanized anti-human TL1A antibodies disclosed in this paper can bind to human TL1A protein with high affinity.

[0419] Table 9. Affinity test results of anti-human TL1A humanized antibody and human TL1A protein

[0420] Note: "LOD" refers to exceeding the maximum detection range of the instrument.

[0421] Although specific embodiments of this disclosure have been described in detail, those skilled in the art will understand that various modifications and variations can be made to the details based on all the teachings published, and all such modifications and variations are within the scope of this disclosure. The entire scope of this disclosure is given by the appended claims and any equivalents thereof.

Claims

1. An anti-human TL1A antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein, The heavy chain variable regions HCDR1, HCDR2, and HCDR3 respectively contain the same amino acid sequences as HCDR1, HCDR2, and HCDR3 in VH, which have at least 80% sequence identity with any of the sequences in SEQ ID NO:48-64 and 1-5, and / or The LCDR1, LCDR2, and LCDR3 of the light chain variable regions respectively contain the same amino acid sequences as LCDR1, LCDR2, and LCDR3 in the VL having at least 80% sequence identity with any of the sequences in SEQ ID NO:65-78 and 6-10; Optionally, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Kabat, IMGT, Abm, Contact, or Chothia numbering system.

2. The anti-human TL1A antibody according to claim 1, wherein: A) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:48-60 or 1, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:65-74 or 6, respectively; B) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:61-64 or 2, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:75-78 or 7, respectively; C) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:3; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:

8. D) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:4; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:9; or E) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:5; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:

10. Optionally, a1) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:48-60, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:65-74, respectively; a2) The HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the antibody are identical to the HCDR1, HCDR2, and HCDR3 of any VH in SEQ ID NO:61-64, respectively; and the LCDR1, LCDR2, and LCDR3 of the light chain variable region of the antibody are identical to the LCDR1, LCDR2, and LCDR3 of any VL in SEQ ID NO:75-78, respectively; a3) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are identical to those in SEQ ID NO:1; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are identical to those in SEQ ID NO:6; or a4) The heavy chain variable regions HCDR1, HCDR2, and HCDR3 of the antibody are the same as those in SEQ ID NO:2; and the light chain variable regions LCDR1, LCDR2, and LCDR3 of the antibody are the same as those in SEQ ID NO:

7. Optionally, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Kabat numbering system.

3. The anti-human TL1A antibody according to claim 1 or 2, wherein: The HCDR1-3 of the antibody heavy chain variable region is selected from any one of the following groups A1-E1: A1) The HCDR1 of the antibody heavy chain variable region includes the amino acid sequence shown in SEQ ID NO:11, the HCDR2 includes the amino acid sequence shown in SEQ ID NO:12, and the HCDR3 includes the amino acid sequence shown in SEQ ID NO:

13. B1) The HCDR1 of the antibody heavy chain variable region includes the amino acid sequence shown in SEQ ID NO:17, the HCDR2 includes the amino acid sequence shown in SEQ ID NO:18, and the HCDR3 includes the amino acid sequence shown in SEQ ID NO:19; C1) The HCDR1 of the antibody heavy chain variable region includes the amino acid sequence shown in SEQ ID NO:23, the HCDR2 includes the amino acid sequence shown in SEQ ID NO:24, and the HCDR3 includes the amino acid sequence shown in SEQ ID NO:25; D1) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:29, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:30, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:31; or E1) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:35, HCDR2 comprises the amino acid sequence shown in SEQ ID NO:36, and HCDR3 comprises the amino acid sequence shown in SEQ ID NO:37; and / or The LCDR1-3 of the antibody light chain variable region is selected from any one of the following groups A2-E2: A2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:14 for LCDR1, the amino acid sequence shown in SEQ ID NO:15 for LCDR2, and the amino acid sequence shown in SEQ ID NO:16 for LCDR3. B2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:20 for LCDR1, the amino acid sequence shown in SEQ ID NO:21 for LCDR2, and the amino acid sequence shown in SEQ ID NO:22 for LCDR3; C2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:26 for LCDR1, the amino acid sequence shown in SEQ ID NO:27 for LCDR2, and the amino acid sequence shown in SEQ ID NO:28 for LCDR3; D2) The variable region of the antibody light chain, LCDR1, includes the amino acid sequence shown in SEQ ID NO:32, LCDR2 includes the amino acid sequence shown in SEQ ID NO:33, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:34; or E2) The variable region of the antibody light chain includes the amino acid sequence shown in SEQ ID NO:32 for LCDR1, the amino acid sequence shown in SEQ ID NO:38 for LCDR2, and the amino acid sequence shown in SEQ ID NO:39 for LCDR3.

4. The anti-human TL1A antibody according to any one of claims 1 to 3, wherein: a) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:11, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:12, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:13; and the LCDR1 of the antibody light chain variable region comprises the amino acid sequence shown in SEQ ID NO:14, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:15, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:16; b) The antibody heavy chain variable region HCDR1 includes the amino acid sequence shown in SEQ ID NO:17, HCDR2 includes the amino acid sequence shown in SEQ ID NO:18, and HCDR3 includes the amino acid sequence shown in SEQ ID NO:19; and the antibody light chain variable region LCDR1 includes the amino acid sequence shown in SEQ ID NO:20, LCDR2 includes the amino acid sequence shown in SEQ ID NO:21, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:22; c) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:23, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:24, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:25; and the LCDR1 of the antibody light chain variable region comprises the amino acid sequence shown in SEQ ID NO:26, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:27, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:28; d) The antibody heavy chain variable region HCDR1 includes the amino acid sequence shown in SEQ ID NO:29, HCDR2 includes the amino acid sequence shown in SEQ ID NO:30, and HCDR3 includes the amino acid sequence shown in SEQ ID NO:31; and the antibody light chain variable region LCDR1 includes the amino acid sequence shown in SEQ ID NO:32, LCDR2 includes the amino acid sequence shown in SEQ ID NO:33, and LCDR3 includes the amino acid sequence shown in SEQ ID NO:34; or e) The HCDR1 of the antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:35, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:36, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:37; and the LCDR1 of the antibody light chain variable region comprises the amino acid sequence shown in SEQ ID NO:32, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:38, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:39; Optionally, the anti-human TL1A antibody, wherein: i) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11, 12 and 13 respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:14, 15 and 16 respectively. ii) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:17, 18, and 19, respectively, and the light chain variable region includes LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:20, 21, and 22, respectively; or iii) The heavy chain variable region of the anti-human TL1A antibody includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:23, 24 and 25, respectively, and the light chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:26, 27 and 28, respectively.

5. The anti-human TL1A antibody according to any one of claims 1 to 4, wherein the antibody is a murine antibody, a chimeric antibody, or a humanized antibody.

6. The anti-human TL1A antibody according to any one of claims 1 to 5, wherein: The antibody heavy chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:48-64 and 1-5 or having at least 80% sequence identity with any of the sequences in SEQ ID NO:48-64 and 1-5; and / or The light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:65-78 and 6-10 or having at least 80% sequence identity with any of the sequences in SEQ ID NO:65-78 and 6-10.

7. The anti-human TL1A antibody according to any one of claims 1 to 6, wherein: A) The antibody heavy chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:48-60; and the light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO:65-74; B) The antibody heavy chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO: 61-64; and the light chain variable region comprises an amino acid sequence as shown in any of SEQ ID NO: 75-78; C) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:1; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:6; D) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:2; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:7; E) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:3; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8; F) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:4; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:9; or G) The antibody heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:5; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:10; Optionally, the anti-human TL1A antibody comprises: A1) Heavy chain variable regions as shown in any of SEQ ID NO:48-60, and light chain variable regions as shown in any of SEQ ID NO:65-74; B1) Heavy chain variable regions as shown in any of SEQ ID NO:61-64, and light chain variable regions as shown in any of SEQ ID NO:75-78; or C1) The heavy chain variable region as shown in SEQ ID NO:1 and the light chain variable region as shown in SEQ ID NO:6; D1) The heavy chain variable region as shown in SEQ ID NO:2, and the light chain variable region as shown in SEQ ID NO:

7.

8. The anti-human TL1A antibody according to any one of claims 1 to 7, comprising an antibody constant region; Optionally, the heavy chain constant region of the antibody is selected from the heavy chain constant regions of human IgG1, IgG2, IgG3 and IgG4, and the light chain constant region of the antibody is selected from the human κ or λ chain constant region. Optionally, the heavy chain constant region includes an Fc that has a reduced ADCC effect function; Optionally, the heavy chain constant region comprises a sequence as shown in SEQ ID NO:40 or having at least 80% sequence identity with SEQ ID NO:40, and / or the light chain constant region comprises a sequence as shown in SEQ ID NO:41 or having at least 80% sequence identity with SEQ ID NO:

41.

9. The anti-human TL1A antibody according to any one of claims 1 to 8, wherein, The anti-human TL1A antibody comprises a heavy chain and a light chain, wherein, a1) The heavy chain comprises a sequence as shown in SEQ ID NO:79 or having at least 80% sequence identity with SEQ ID NO:79, and / or the light chain comprises a sequence as shown in SEQ ID NO:80 or having at least 80% sequence identity with SEQ ID NO:80; b1) The heavy chain comprises a sequence as shown in SEQ ID NO:81 or having at least 80% sequence identity with SEQ ID NO:81, and / or the light chain comprises a sequence as shown in SEQ ID NO:82 or having at least 80% sequence identity with SEQ ID NO:82; c1) The heavy chain comprises a sequence as shown in SEQ ID NO:83 or having at least 80% sequence identity with SEQ ID NO:83, and / or the light chain comprises a sequence as shown in SEQ ID NO:84 or having at least 80% sequence identity with SEQ ID NO:84; d1) The heavy chain comprises a sequence as shown in SEQ ID NO:42 or having at least 80% sequence identity with SEQ ID NO:42, and / or the light chain comprises a sequence as shown in SEQ ID NO:43 or having at least 80% sequence identity with SEQ ID NO:43; e1) The heavy chain comprises a sequence as shown in SEQ ID NO:44 or having at least 80% sequence identity with SEQ ID NO:44, and / or the light chain comprises a sequence as shown in SEQ ID NO:45 or having at least 80% sequence identity with SEQ ID NO:45; or f1) The heavy chain comprises a sequence as shown in SEQ ID NO:46 or having at least 80% sequence identity with SEQ ID NO:46, and / or the light chain comprises a sequence as shown in SEQ ID NO:47 or having at least 80% sequence identity with SEQ ID NO:47; Optionally, the anti-human TL1A antibody comprises: a heavy chain as shown in SEQ ID NO:79 and a light chain as shown in SEQ ID NO:80; a heavy chain as shown in SEQ ID NO:81 and a light chain as shown in SEQ ID NO:82; or a heavy chain as shown in SEQ ID NO:83 and a light chain as shown in SEQ ID NO:

84.

10. The anti-human TL1A antibody according to any one of claims 1 to 9, wherein, The anti-human TL1A antibody is an scFv-Fc antibody; Optionally, the anti-human TL1A antibody comprises: g1) A sequence as shown in SEQ ID NO:85 or a sequence having at least 80% sequence identity with SEQ ID NO:85; h1) A sequence as shown in SEQ ID NO:86 or a sequence having at least 80% sequence identity with SEQ ID NO:86; i1) A sequence as shown in SEQ ID NO:87 or having at least 80% sequence identity with SEQ ID NO:87; j1) A sequence as shown in SEQ ID NO:88 or having at least 80% sequence identity with SEQ ID NO:88; k1) A sequence as shown in SEQ ID NO:89 or a sequence having at least 80% sequence identity with SEQ ID NO:89; Optionally, the anti-human TL1A antibody comprises: two sequences as shown in SEQ ID NO:85; two sequences as shown in SEQ ID NO:86; two sequences as shown in SEQ ID NO:87; two sequences as shown in SEQ ID NO:88; or two sequences as shown in SEQ ID NO:

89.

11. The anti-human TL1A antibody according to any one of claims 1 to 7, wherein the anti-human TL1A antibody is a full-length antibody or an antigen-binding fragment selected from Fab, Fab', F(ab')2, Fd, Fv, scFv, dsFv, scFab and (dsFv)2.

12. An antibody that competes with the anti-human TL1A antibody of any one of claims 1 to 11 for binding to human TL1A or that binds to the same antigenic epitope as the anti-human TL1A antibody of any one of claims 1 to 11.

13. The anti-human TL1A antibody according to any one of claims 1 to 12, wherein the anti-human TL1A antibody has at least one of the following functions (1) to (5): (1) The anti-human TL1A antibody can block the binding of human TL1A to DR3 and / or block the binding of human TL1A to DcR3; optionally, the anti-human TL1A antibody can block the binding of human TL1A to DR3 and TL1A to DcR3. (2) The anti-human TL1A antibody can bind to cells expressing human TL1A; optionally, the anti-human TL1A antibody can bind to cells expressing human TL1A with an EC50 value of less than 10 nM, and the EC50 value is detected by FACS method; optionally, the cells expressing human TL1A are HEK293 cells overexpressing TL1A. (3) The anti-human TL1A antibody can bind to human TL1A antigen protein; optionally, the anti-human TL1A antibody can bind to human TL1A antigen protein with an EC50 value of less than 1 nM, and the EC50 value is detected by ELISA; optionally, the antibody has a lower binding activity to mouse TL1A antigen protein than to human TL1A antigen protein. (4) The anti-human TL1A antibody can bind to human TL1A protein; in some embodiments, the anti-human TL1A antibody can bind to human TL1A protein with a KD value of less than 1.00E-9M, and the KD value is detected by surface plasmon resonance technology. (5) The anti-human TL1A antibody can inhibit TF1 cell apoptosis.

14. A nucleic acid molecule comprising a nucleotide sequence encoding the anti-human TL1A antibody according to any one of claims 1 to 13; Optionally, the nucleic acid molecule encodes the anti-human TL1A antibody according to any one of claims 1 to 13.

15. A carrier comprising the nucleic acid molecule of claim 14.

16. A host cell comprising the nucleic acid molecule of claim 14 or the vector of claim 15.

17. A method for preparing an anti-human TL1A antibody, comprising culturing the host cell of claim 16 under conditions suitable for expressing the antibody, and recovering the antibody from the cultured host cell culture.

18. A multispecific molecule comprising the anti-human TL1A antibody according to any one of claims 1 to 13; Optionally, the multispecific molecule specifically binds to human TL1A and specifically binds to one or more other antigens.

19. A conjugate comprising the anti-human TL1A antibody according to any one of claims 1 to 13, and a conjugated moiety; Optionally, the coupling portion is selected from protein tags, detectable markers, or therapeutic agents; Optionally, the coupling portion is linked to the anti-human TL1A antibody according to any one of claims 1 to 13 via a linker.

20. A pharmaceutical composition comprising the anti-human TL1A antibody of any one of claims 1 to 13, the multispecific molecule of claim 18, the conjugate of claim 19, the nucleic acid molecule of claim 14, the carrier of claim 15 or the cell of claim 16, and a pharmaceutically acceptable carrier; Optionally, the pharmaceutical composition may further comprise additional agents; optionally, the additional agents may be selected from drugs for treating inflammatory bowel disease, fibrotic disease, or autoimmune diseases, such as anti-inflammatory drugs.

21. Use of the anti-human TL1A antibody of any one of claims 1 to 13, the multispecific molecule of claim 18, the conjugate of claim 19, the nucleic acid molecule of claim 14, the carrier of claim 15, the cell of claim 16, or the pharmaceutical composition of claim 20 in the preparation of a medicament; Optionally, the drug is used to treat diseases associated with TL1A overexpression; Optionally, the diseases associated with high TL1A expression are selected from: inflammatory bowel disease, fibrotic diseases, and autoimmune diseases; optionally, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

22. A method of treating a disease, the method comprising administering to a subject in need a therapeutically effective amount of any one of claims 1 to 13, the multispecific molecule of claim 18, the conjugate of claim 19, the nucleic acid molecule of claim 14, the carrier of claim 15, the cell of claim 16, or the pharmaceutical composition of claim 20; Optionally, the disease is one associated with high TL1A expression; Optionally, the disease is selected from: inflammatory bowel disease, fibrotic disease, and autoimmune disease; Optionally, the inflammatory bowel disease is Crohn's disease or ulcerative colitis; Optionally, the anti-human TL1A antibody of any one of claims 1 to 13, the multispecific molecule of claim 18, the conjugate of claim 19, the nucleic acid molecule of claim 14, the carrier of claim 15, the cell of claim 16, or the pharmaceutical composition of claim 20 may be used alone or in combination with other agents.

23. A method for detecting the presence or level of human TL1A in a sample in vitro, comprising contacting the sample with an anti-human TL1A antibody according to any one of claims 1 to 13 under conditions that allow the formation of a complex between the antibody and human TL1A, and detecting the formation of the complex; Optionally, the method is used to diagnose diseases, such as inflammatory diseases (e.g., inflammatory bowel disease), fibrotic diseases, and autoimmune diseases; Optionally, the method includes detecting the expression level of human TL1A in a test sample from a subject, and comparing the expression level with a reference value, wherein an increase in the expression level compared with the reference value is an indicator of inflammatory diseases (e.g., inflammatory bowel disease), fibrotic diseases, and autoimmune diseases.

24. Use of the anti-human TL1A antibody according to any one of claims 1 to 13 in the preparation of a kit for detecting the presence or level of human TL1A in a sample, and / or diagnosing inflammatory diseases (e.g., inflammatory bowel disease), fibrotic diseases, and autoimmune diseases.

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