Anti-CDH17 antibody or antigen binding fragment thereof and application thereof

Abstract

The invention discloses an anti-CDH17 antibody or an antigen binding fragment thereof and application thereof, and relates to the technical field of biology. The antibody can specifically bind to one or more extracellular domains in CDH17 extracellular domains 1-7, has ADCC activity, can mediate endocytosis, and provides new possibility for treatment and / or prevention of cancers.

Description

[0001] Priority Statement

[0002] This application claims the priority of a Chinese patent application with the application number 202311871606.8, the filing date of November 29, 2023, and the invention title of "Anti-CDH17 Antibody or Its Antigen-Binding Fragment and Their Applications", the entire content of which is incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of biotechnology, and in particular to an anti-CDH17 antibody or its antigen-binding fragment and their applications. Background Art

[0004] The occurrence and development of tumors is a multi-factor and multi-step interaction process, in which the dysregulation of cell adhesion and motility is one of the important mechanisms for tumor occurrence and development. Cadherin-17 is a new member of the cadherin family discovered in recent years, expressed in mouse liver and small intestine, and plays an important role in cell adhesion, cell recognition, tissue and organ development, and maintenance of morphology. Studies have shown that its expression is closely related to the occurrence and development of digestive system epithelial tumors, and it is expected to become a new tumor target and biomarker.

[0005] Cadherin-17 (CDH17) is a new member of the cadherin family, first analyzed from a mouse liver cell cDNA library, and named Liver-Intestine cadherin (LI-cadherin) because it is only expressed in mouse liver and small intestine. CDH17 is often expressed in embryonic and adult intestinal epithelial cells, as well as some pancreatic duct epithelial cells, but there is almost no obvious expression in hepatocytes, esophageal epithelial cells, and gastric mucosa in healthy individuals.

[0006] Cadherin plays a biological role by mediating calcium-dependent cell-cell junctions. The ligands of classical cadherins are catenins, including α-catenin, β-catenin, γ-catenin, and P120 protein, etc. Cadherin regulates cell-cell adhesion function by interacting with the intracellular cytoskeleton through catenin. CDH17 functions as a functional Ca2+-dependent cell adhesion molecule. However, CDH17 does not interact tightly with the actin of the cytoskeleton through intracellular catenin, but directly interacts with the cytoskeleton for its cell adhesion. During tumor development, it mainly binds to integrin α2β1 on adjacent tumor cells through the extracellular domain EC6 containing the RGD domain (green), resulting in enhanced integrin activation, adhesion, proliferation, invasion, tumorigenesis, and metastasis. At the same time, studies have found that the expression of CDH17 is an independent prognostic predictor for predicting the survival of patients. The expression of CDH17 affects the prognosis of patients with lymph node-negative gastric cancer, which may reflect the role of this protein in maintaining polarity and normal cell-cell adhesion. Therefore, developing and optimizing anti-CDH17 antibodies is of great significance for preventing or treating tumor-related diseases.

[0007] In view of this, the present invention is specifically proposed. Summary of the Invention

[0008] One object of the present invention is to provide an antibody or its antigen-binding fragment that can specifically bind to CDH17 and its application.

[0009] To solve the above technical problems, the present invention specifically adopts the following technical solutions:

[0010] In the first aspect, an anti-CDH17 antibody or its antigen-binding fragment is provided. The anti-CDH17 antibody or its antigen-binding fragment specifically binds to one or more of CDH17 extracellular domain 1 (D1), CDH17 extracellular domain 2 (D2), CDH17 extracellular domain 3 (D3), CDH17 extracellular domain 4 (D4), CDH17 extracellular domain 5 (D5), CDH17 extracellular domain 6 (D6), and CDH17 extracellular domain 7 (D7).

[0011] In the second aspect, the present invention provides an anti-CDH17 antibody or its antigen-binding fragment that competitively binds to CDH17 with the anti-CDH17 antibody described in the first or second aspect, or the epitope to which it binds to the CDH17 antigen is the same as the epitope to which the anti-CDH17 antibody described in the first or second aspect binds to the CDH17 antigen.

[0012] In the third aspect, the present invention provides a biological material, and the biological material includes any one of the following (i) to (vi):

[0013] (i) A multispecific antibody, wherein the multispecific antibody comprises the anti-CDH17 antibody as shown in the first or second aspect;

[0014] (ii) A chimeric antigen receptor, wherein the chimeric antigen receptor comprises an extracellular region, and the extracellular region comprises an antigen-binding domain; and the antigen-binding domain contains the anti-CDH17 antibody or an antigen-binding fragment thereof as described in the first or second aspect;

[0015] (iii) A nucleic acid molecule encoding the anti-CDH17 antibody or an antigen-binding fragment thereof as described in the first or second aspect, or the multispecific antibody as described in (i), or the chimeric antigen receptor as described in (ii);

[0016] (iv) A vector carrying the nucleic acid molecule as described in (iii);

[0017] (v) A recombinant cell, characterized in that the recombinant cell expresses the anti-CDH17 antibody or an antigen-binding fragment thereof as described in the first or second aspect, or expresses the multispecific antibody as described in (i), or expresses the chimeric antigen receptor as described in (ii), or contains the nucleic acid molecule as described in (iii), or contains the vector as described in (iv);

[0018] (vi) An engineered immune cell, characterized in that the immune cell expresses the chimeric antigen receptor as described in (ii) or contains a nucleic acid molecule encoding the chimeric antigen receptor as described in (ii).

[0019] In the fourth aspect, the present invention provides a pharmaceutical composition containing the anti-CDH17 antibody or an antigen-binding fragment thereof as described in the first or second aspect, or the biological material as described in the third aspect.

[0020] In the fifth aspect, the present invention provides the use of the anti-CDH17 antibody or an antigen-binding fragment thereof as described in the first or second aspect, or the biological material as described in the third aspect, or the pharmaceutical composition as described in the fourth aspect in any one of the following:

[0021] (Ⅰ) Detecting CDH17 or cells expressing CDH17;

[0022] (Ⅱ) Preparing a product for detecting CDH17 or cells expressing CDH17;

[0023] (Ⅲ) For treating, preventing or alleviating diseases, disorders or conditions related to CDH17

[0024] (Ⅳ) Preparing a pharmaceutical composition for treating, preventing or alleviating diseases, disorders or conditions related to CDH17.

[0025] Sixth aspect, the present invention provides a method for generating the aforementioned anti-CDH17 antibody or its antigen-binding fragment, which comprises the following steps:

[0026] (a) Culturing the aforementioned recombinant cells under conditions for expressing an anti-CDH17 antibody or its antigen-binding fragment;

[0027] (b) Isolating and purifying the anti-CDH17 antibody or its antigen-binding fragment obtained in step (a).

[0028] Seventh aspect, the present invention provides a kit for detecting CDH17, which comprises the aforementioned anti-CDH17 antibody or its antigen-binding fragment.

[0029] Eighth aspect, the present invention provides a method for treating a disease, the method comprising administering to a subject in need a therapeutically effective amount of the anti-CDH17 antibody or its antigen-binding fragment of the first or second aspect, or the biomaterial of the third aspect, or the pharmaceutical composition of the fourth aspect; optionally, the disease is a human CDH17 overexpression-related disease;

[0030] Optionally, the disease is a tumor;

[0031] Optionally, the tumor is selected from lung cancer, prostate cancer, breast cancer, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, bladder cancer, cervical cancer, uterine cancer, ovarian cancer, liver cancer, melanoma, kidney cancer, squamous cell carcinoma, and hematological cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0033] Figure 1 It is a schematic diagram of the extracellular domain structure of human CDH17;

[0034] Figure 2 It is a schematic diagram of the structural relationship between human CDH17 and the extracellular domain fragment of human CDH17 in Example 1 of the present invention;

[0035] Figure 3 It is for detecting the binding activity of monoclonal antibodies (F1-87.15, F1-99.29, F1-76.12, F1-86.9) to CHO-hCDH17 cells by flow cytometry in Example 2;

[0036] Figure 4To detect the binding activity of monoclonal antibodies (F2-89.7, F2-155.7, F2-238.14, F2-324.7) to CHO-hCDH17 cells by flow cytometry in Example 2;

[0037] Figure 5 To detect the binding activity of monoclonal antibodies (F1-124.38, F2-55.10, F2-291.2, F3-1.5, F3-6.18) to CHO-hCDH17 cells by flow cytometry in Example 2;

[0038] Figure 6 To detect the binding activity of monoclonal antibodies (F1-87.15, F1-41.16, F2-238.14, F1-111.5, F2-55.10) to AsPC-1 cells by flow cytometry in Example 2;

[0039] Figure 7 To detect the binding activity of monoclonal antibodies (F1-86.23, F1-99.29, F1-139.6, F1-76.12, F1-124.2, F1-122.19, F1-86.9, F1-143.7, F1-124.38, F1-143.38) to AsPC-1 cells by flow cytometry in Example 2;

[0040] Figure 8 To detect the binding activity of monoclonal antibodies (F2-71.18, F2-291.2, F2-324.17, F2-89.7, F2-155.7, F2-324.7, F2-186.1, F3-1.5, F3-6.18, F3-36.14) to AsPC-1 cells by flow cytometry in Example 2;

[0041] Figure 9 To detect the binding activity of monoclonal antibodies (F1-87.15, F1-99.29, F1-127.8, F1-76.12, F1-111.5, F1-86.9, F1-143.7, F1-41.16, F1-124.38, F2-71.18) to monkey CDH17 by ELISA in Example 3;

[0042] Figure 10 To detect the binding activity of monoclonal antibodies (F2-89.7, F2-155.7, F2-186.1, F2-238.14, F2-324.7, F2-55.10, F2-291.2, F3-1.5, F3-6.18, F3-36.14) to monkey CDH17 by ELISA in Example 3;

[0043] Figure 11To determine the binding activity of the monoclonal antibodies (F1-87.15, F1-99.29, F1-127.8, F1-76.12, F1-111.5, F1-86.9, F1-143.7, F1-41.16, F1-124.38, F2-71.18) in Example 4 with murine CDH17 by ELISA;

[0044] Figure 12 To determine the binding activity of the monoclonal antibodies (F2-89.7, F2-155.7, F2-186.1, F2-238.14, F2-324.7, F2-55.10, F2-291.2, F3-1.5, F3-6.18, F3-36.14) in Example 4 with murine CDH17 by ELISA;

[0045] Figure 13 To determine the binding activity of the monoclonal antibodies (F1-87.15, F1-41.16, F2-238.14, F1-111.5, F2-55.10, F1-86.23, F1-99.29, F1-139.6, F1-76.12, F1-124.2, F1-122.19, F1-86.9) in Example 5 with human CDH17 by ELISA;

[0046] Figure 14 To determine the binding activity of the monoclonal antibodies (F1-143.7, F1-124.38, F1-143.38, F2-71.18, F2-291.2, F2-324.17, F2-89.7, F2-155.7, F2-324.7, F2-186.1, F3-1.5, F3-6.18, F3-36.14) in Example 5 with human CDH17 by ELISA;

[0047] Figure 15 To determine the binding activity of the monoclonal antibodies (F1-87.15, F1-41.16, F2-238.14, F1-111.5, F2-55.10, F1-86.23, F1-99.29, F1-139.6, F1-76.12, F1-124.2, F1-122.19, F1-86.9) in Example 6 with murine CDH17 (D1-D4) by ELISA;

[0048] Figure 16To implement the binding activity of the monoclonal antibodies (F1-143.7, F1-124.38, F1-143.38, F2-71.18, F2-291.2, F2-324.17, F2-89.7, F2-155.7, F2-324.7, F2-186.1, F3-1.5, F3-6.18, F3-36.14) detected by ELISA in Example 6 with murine CDH17 (D1-D4);

[0049] Figure 17 To implement the binding activity of the monoclonal antibodies (F1-87.15, F1-41.16, F2-238.14, F1-111.5, F2-55.10, F1-86.23, F1-99.29, F1-139.6, F1-76.12, F1-124.2, F1-122.19, F1-86.9) detected by ELISA in Example 6 with murine CDH17 (D5-D7);

[0050] Figure 18 To implement the binding activity of the monoclonal antibodies (F1-143.7, F1-124.38, F1-143.38, F2-71.18, F2-291.2, F2-324.17, F2-89.7, F2-155.7, F2-324.7, F2-186.1, F3-1.5, F3-6.18, F3-36.14) detected by ELISA in Example 6 with murine CDH17 (D5-D7);

[0051] Figure 19 To implement the killing activity mediated by the monoclonal antibodies detected by flow cytometry in Example 7 against CHO-hCDH17 overexpressing cells;

[0052] Figure 20 To implement the killing activity mediated by the monoclonal antibodies detected by the LDH method in Example 7 against AsPC-1 cells endogenously expressing human CDH17;

[0053] Figure 21 To implement the endocytosis activity of AsPC-1 cells against the monoclonal antibodies F1-87.15, F1-99.29, F1-76.12, F1-86.9, F1-143.7, F2-238.14, F2-55.10, F3-1.5, F3-6.18, F3-36.14 in Example 8;

[0054] Figure 22 To implement the binding activity of the monoclonal antibodies (R4723, R4709, R4710, R4711, R4712, R4713, R4714) detected by flow cytometry in Example 10 with CHO-CDH17 cells;

[0055] Figure 23 To detect the binding activity of monoclonal antibodies (R4723, R4715, R4716, R4717, R4718) to CHO-CDH17 cells by flow cytometry in Example 10;

[0056] Figure 24 To detect the binding activity of monoclonal antibodies (R4850, R4832, R4833, R4834, R4835, R4836, R4837) to CHO-CDH17 cells by flow cytometry in Example 10;

[0057] Figure 25 To detect the binding activity of monoclonal antibodies (R4850, R4838, R4839, R4840, R4841, R4842, R4843) to CHO-CDH17 cells by flow cytometry in Example 10;

[0058] Figure 26 To detect the binding activity of monoclonal antibodies (R4723, R4709, R4710, R4711, R4712, R4713, R4714) to AsPC-1 cells by flow cytometry in Example 10;

[0059] Figure 27 To detect the binding activity of monoclonal antibodies (R4723, R4715, R4716, R4717, R4718) to AsPC-1 cells by flow cytometry in Example 10;

[0060] Figure 28 To detect the binding activity of monoclonal antibodies (R4850, R4832, R4833, R4834, R4835, R4836, R4837) to AsPC-1 cells by flow cytometry in Example 10;

[0061] Figure 29 To detect the binding activity of monoclonal antibodies (R4850, R4838, R4839, R4840, R4841, R4842, R4843) to AsPC-1 cells by flow cytometry in Example 10;

[0062] Figure 30 To detect the binding activity of monoclonal antibodies (R4723, R4709, R4710, R4711, R4712, R4713, R4714) to OCUM-1 cells by flow cytometry in Example 10;

[0063] Figure 31 To detect the binding activity of monoclonal antibodies (R4723, R4715, R4716, R4717, R4718) to OCUM-1 cells by flow cytometry in Example 10;

[0064] Figure 32 To detect the binding activity of monoclonal antibodies (R4850, R4832, R4833, R4834, R4835, R4836, R4837) to OCUM-1 cells in Example 10 by flow cytometry;

[0065] Figure 33 To detect the binding activity of monoclonal antibodies (R4850, R4838, R4839, R4840, R4841, R4842, R4843) to OCUM-1 cells in Example 10 by flow cytometry;

[0066] Figure 34 To detect the binding activity of monoclonal antibodies (R4723, R4709, R4710, R4711, R4712, R4713, R4714) to monkey CDH17 in Example 11 by ELISA;

[0067] Figure 35 To detect the binding activity of monoclonal antibodies (R4723, R4715, R4716, R4717, R4718) to monkey CDH17 in Example 11 by ELISA;

[0068] Figure 36 To detect the binding activity of monoclonal antibodies (R4850, R4832, R4833, R4834, R4835, R4836, R4837) to monkey CDH17 in Example 11 by ELISA;

[0069] Figure 37 To detect the binding activity of monoclonal antibodies (R4850, R4838, R4839, R4840, R4841, R4842, R4843) to monkey CDH17 in Example 11 by ELISA. Detailed implementation manners

[0070] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0071] The articles "a / an" and "the" in the present invention include plural references unless the context clearly indicates otherwise. For example, "an antibody" refers to one antibody or more than one antibody.

[0072] In the present invention, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0073] In the present invention, the terms "CDH17" and "CDH-17" are used interchangeably and refer to cadherin Cadherin-17, also known as liver-intestine cadherin (LI-cadherin), which belongs to the non-classical cadherin superfamily. Its structure has a certain homology with that of classical cadherins, but CDH17 has its unique structure: 1) The extracellular region of CDH17 consists of 7 repeat sequences ( Figure 1 ), which is different from the 5 of non-classical cadherins; 2) In the extracellular D1 cell adhesion recognition region, CDH17 contains a segment of AAL sequence that replaces the corresponding HAV sequence of classical cadherins; 3) The cytoplasmic tail region of CDH17 has only 20 amino acid residues, while the cytoplasmic tail region of classical cadherins has 150-160 amino acid residues. Studies have shown that abnormal structures and dysfunction of cadherins are closely related to the invasion and metastasis of tumors. Due to the short cytoplasmic tail domain structure of CDH17, CDH17 cannot interact with the catenin network or the actin cytoskeleton. Therefore, CDH17 is classified as a variant of classical cadherin. The N-terminus of CDH17 is located extracellularly and the C-terminus is located intracellularly. CDH17 has 7 extracellular domains (i.e., the extracellular region, also known as ECD (Extra Cellular Domain), including CDH17 D1-7, or also referred to as EC1-EC7), a transmembrane region, and a cytoplasmic tail region. Its adhesion characteristics are mainly determined by the extracellular domains. The schematic diagram of the structure of human CDH17 is as Figure 2 shown. Unless otherwise stated, the term "CDH17" includes human CDH17, subtypes, and species homologs expressed by cells naturally expressing or transfected with the CDH17 gene. The term also includes artificially modified CDH17, and the artificial modification includes, but is not limited to, polypeptides or proteins after mutation, truncation, or fusion with other domains, and retains the necessary antigenic epitopes for binding to antibodies. The anti-CDH17 antibody or its antigen-binding fragment provided by the present invention can specifically bind to CDH17.

[0074] In the present invention, the term "antibody" includes any immunoglobulin that can bind to a specific antigen. The term "antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies, full-length antibodies, and antigen-binding fragments, as long as they exhibit the desired antigen-binding activity. Generally, a natural intact antibody contains two heavy (H) chains and two light (L) chains. Antibodies can be classified into five main classes or isotypes, namely IgA, IgD, IgE, IgG, and IgM, depending on whether they contain α, δ, ε, γ, and μ heavy chains, respectively. Several main antibody classes can also be further divided into subclasses, such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain), etc. Each heavy chain consists of a variable region (VH) and first, second, third, and fourth (optionally) constant regions (CH1, CH2, CH3, CH4, respectively). Mammalian light chains can be divided into λ or κ, and each light chain consists of a variable region (VL) and a constant region (CL). The variable regions of the light and heavy chains determine antigen binding. The variable region of each chain usually contains three hypervariable regions, called "complementary determining regions (CDRs)". Among them, the light chain CDRs include LCDR1, LCDR2, and LCDR3, and the heavy chain CDRs include HCDR1, HCDR2, and HCDR3. The variable regions (VH and VL) each consist of three complementary determining regions connected by four framework regions (FRs). Usually, the variable regions VL / VH of the heavy and light chains can be obtained by connecting the CDRs and FRs numbered as follows in the following combination: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0075] In the present invention, the term "antigen-binding fragment" refers to a substance that contains the CDRs of an antibody, lacks some amino acids present in the full-length chain, but is still capable of specifically binding to an antigen. Such fragments are biologically active because they bind to the target antigen and can compete with other antigen-binding molecules (including intact antibodies) for binding to a given epitope. Examples of antigen-binding fragments include but are not limited to Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized bifunctional antibodies (ds diabody), single-chain antibody molecules (scFv), scFv dimers (bivalent bifunctional antibodies), and the minimal recognition unit of an antibody. The above antigen-binding fragments are capable of binding to the same antigen as the parental antibody.

[0076] In the present invention, the term "Fab" of an antibody refers to a part of an antibody composed of a single light chain (including a variable region and a constant region) and the variable region and the first constant region of a single heavy chain bound together by a disulfide bond. The "Fab' fragment" refers to a Fab fragment containing a part of the hinge region. "F(ab')2" refers to a dimer of Fab'. The "Fv fragment" is composed of the variable region of a single light chain and / or the variable region of a single heavy chain bound together. The "single-chain Fv antibody" or "scFv" refers to an antibody fragment formed by directly connecting the variable region of the light chain and the variable region of the heavy chain or by connecting them through a peptide linker sequence. The "minimal antibody recognition unit" refers to a unit containing only a single CDR structure in the variable region. Although the minimal recognition unit has a small molecular weight and low affinity, it has the ability to bind to an antigen.

[0077] The CDR boundaries of the antibody or its antigen-binding fragment in the present invention can be defined or identified according to the IMGT, Kabat, Chothia, AbM, Contact definition methods, and the CDRs defined in other acceptable ways in the art also fall within the protection scope of the present invention (Kaas, Q et al. IMGT unique numbering for immunoglobulin and T cell receptor constant domains and Ig super family C-like domains. Dev. Comp. Immunol. 29, 185-203, (2005); R.M. MacCallum et al.. Antibody–antigen interactions: contact analysis and binding site topography J. Mol. Biol. (1996); Martin, A.C.R. Protein sequence and structure analysis of antibody variable domains (Book chapter). In Antibody engineering lab manual Eds. Duebel, S. and Kontermann, R. (2001); Marie-Paule Lefranc et al. IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains, Developmental and Comparative Immunology 27(2003)55–77).

[0078] In the present invention, the term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that act in a manner similar to naturally occurring amino acids. Naturally occurring amino acids include those encoded by the genetic code and their modified amino acids, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Common naturally occurring amino acids are, for example: 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., an α-carbon bonded to hydrogen, a carboxyl group, an amino group, and an R group), such as homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Amino acid analogs typically have a modified R group (e.g., norleucine) or a modified peptide backbone, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics are chemical compounds that have a structure different from the general chemical structure of amino acids but act in a manner similar to naturally occurring amino acids. In the present invention, the term "percent identity" refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned. Alignment for determining the percent amino acid sequence identity can be performed in a variety of ways in the art, such as using software well known in the art, such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA. Those skilled in the art can determine the appropriate parameters for aligning the sequences, including any algorithms required to achieve the maximum alignment over the full length of the comparison sequences.

[0079] In the present invention, the term "specifically binds" or "specifically binding" refers to a non-random binding reaction between two molecules, such as the reaction between an antibody and an antigen. In some specific embodiments, for example, it is determined according to fluorescence-activated cell sorting (FACS) technology.

[0080] In the present invention, the term "anti-CDH17 antibody" refers to an antibody that can specifically bind to CDH17. In some specific embodiments, the "anti-CDH17 antibody" specifically binds to human and / or monkey CDH17.

[0081] In the present invention, the term "affinity" or "avidity" refers to the strength of the non-covalent interaction between an immunoglobulin molecule (i.e., an antibody) or a fragment thereof and an antigen. The strength or affinity of an immunobinding interaction can be represented by the equilibrium dissociation constant (KD) of the interaction, where a smaller KD value indicates a higher affinity. The KD can be determined by using any conventional method known in the art, including but not limited to Biacore assays, Octet methods, microscale thermophoresis, HPLC MS methods, and fluorescence-activated cell sorting techniques.

[0082] The binding of the antibody or antigen-binding fragment thereof provided by the present invention to CDH17 can also be characterized by the "half maximal effective concentration (EC50)". The EC50 refers to the concentration of a drug or antibody that can achieve 50% of the maximum biological effect after a specific exposure time. Generally, the smaller the EC50, the better the affinity, indicating that binding to the target protein can occur at a lower concentration. The EC50 value can be determined by binding assays known in the art, such as direct or indirect binding assays (e.g., enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting techniques, and other binding assays).

[0083] In the present invention, the term "epitope" refers to any antigenic determinant on an antigen that is bound by the paratope of an antibody. An antigenic determinant is usually a special chemical group with a certain composition and structure. Epitopes can be linear (i.e., continuous) or conformational (i.e., including spaced-apart amino acid residues, non-continuous). Epitopes define the minimum binding site of an antibody and are thus specific targets for an antibody or an antigen-binding fragment thereof. 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 structure determination methods (e.g., nuclear magnetic resonance spectroscopy).

[0084] In the present invention, the term "bispecific antibody" refers to an antibody molecule that can bind to multiple (two or more) different antigenic epitopes of the same antigen or multiple (two or more) different antigens.

[0085] The "chimeric antigen receptor" in the present invention, CAR, is an artificial receptor that mimics the function of TCR and is composed of an extracellular domain, a transmembrane domain, and an intracellular signaling domain connected in sequence. When the antigen (receptor) on the surface of tumor cells binds to the antibody (ligand) of the chimeric antigen receptor, signals can be transmitted to the intracellular through the hinge region and transmembrane region. The intracellular signaling domain then converts the signals into activation signals to activate effector cells. The effector cells kill tumor cells by secreting perforin or producing cytokines. At the same time, the effector cells themselves also proliferate, further expanding the immune killing effect. The extracellular domain generally consists of a single-chain variable fragment (scFv) of a monoclonal antibody responsible for recognizing and binding antigens and a hinge region (Hinge) that plays a connecting role. The single-chain variable fragment is the antigen-binding domain of CAR, and this domain determines the specificity and function of CAR-immune cells. The hinge region is the extracellular structural region of CAR that connects the single-chain variable fragment and the transmembrane domain. It usually maintains the stability required for robust CAR expression and activity in effector cells. The hinge region of most CARs is derived from the hinge of IgG or the extracellular region of CD8α / CD28. The type and length of the hinge region have an important impact on the functional activity of CAR. The transmembrane domain connects the extracellular domain of CAR to the intracellular signal transduction domain. Commonly used transmembrane domains are derived from CD4, CD8, CD28, and CD3ζ or their derivatives. The selection of the transmembrane domain affects the activation degree of the CAR structure in cell function. The intracellular domain consists of a co-stimulatory domain and a signal transduction domain. The co-stimulatory domain usually comes from the CD28 receptor family (CD28, ICOS) or the tumor necrosis factor receptor family (4-1BB, OX40, CD27). The signal transduction domain is usually the T cell receptor TCR / CD3ζ chain or the immunoglobulin Fc receptor FcεRIγ chain.

[0086] The CAR of the present invention (including its functional parts and functional variants) can be obtained by methods known in the art, for example, it can be prepared by any suitable method for preparing polypeptides or proteins.

[0087] In the present invention, the term "engineered immune cell" refers to an immune cell expressing CAR or an immune cell modified with CAR, wherein the immune cells include but are not limited to T cells (for example, α / β T cells and γ / δ T cells), natural killer cells (NK cells), monocytes, macrophages, natural killer T cells (NKT cells), dendritic cells, granulocytes, B cells, lymphocytes, white blood cells, and / or peripheral blood mononuclear cells.

[0088] In the present invention, the term "nucleic acid molecule" refers to a polymeric form of nucleotides of any length, and nucleic acid molecules include ribonucleotides and / or deoxyribonucleotides. Examples of nucleic acid molecules include, but are not limited to, single-stranded, double-stranded or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers containing purine and pyrimidine bases or other natural, chemical or biochemical modifications, unnatural or derivatized nucleobases. When a nucleic acid molecule encodes a protein or polypeptide, the encoding optionally encodes the sense strand or the antisense strand. Nucleic acid molecules can be naturally occurring, synthetic, recombinant, or any combination thereof. The terms "nucleic acid molecule", "nucleic acid" and "polynucleotide" can be used interchangeably.

[0089] In an alternative embodiment, the nucleic acid molecule is RNA or DNA, and the nucleic acid molecule can be single-stranded or double-stranded, preferably double-stranded DNA. A nucleic acid molecule is "operably linked" when it is placed in a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence. It is preferably DNA when incorporated into a vector.

[0090] In the present invention, the term "vector" refers to a vehicle into which a genetic element (such as the aforementioned nucleic acid molecule) can be operably inserted and which enables the genetic element to be expressed, for example, to produce a protein, RNA or DNA encoded by the genetic element, or to replicate the genetic element. Vectors can be used to transform, transduce or transfect host cells so that the genetic elements they carry are expressed in the host cells. For example, vectors include: plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs) or P1-derived artificial chromosomes (PACs), bacteriophages such as lambda phage or M13 phage, and animal viruses. Vectors can contain various elements that control expression, including promoter sequences, transcription initiation sequences, enhancer sequences, selection elements and reporter genes. In addition, vectors can also contain an origin of replication. Vectors can also include components that assist their entry into cells, including but not limited to, viral particles, liposomes or protein coats. Vectors can be expression vectors or cloning vectors. In some embodiments, the vectors provided by the present invention (such as expression vectors) contain the nucleic acid sequence encoding an antibody or an antigen-binding fragment thereof according to the present invention, at least one promoter operably linked to the nucleic acid sequence (such as, SV40, CMV, EF 1α), and at least one selection marker.

[0091] In the present invention, the terms "purified" or "isolated" associated with a polypeptide or nucleic acid mean that the polypeptide or nucleic acid is not in its natural medium or natural form. Thus, the term "isolated" includes a polypeptide or nucleic acid removed from its original environment, for example, if it is naturally occurring, from its natural environment. In connection with a nucleic acid, the terms isolated or purified indicate, for example, that the nucleic acid is not in its natural genomic context (e.g., in a vector, as an expression cassette, linked to a promoter, or artificially introduced into a heterologous host cell).

[0092] In the present invention, the term "recombinant cell" refers to a cell that can or has been introduced with an exogenous polynucleotide and / or vector. The exogenous polynucleotide may or may not be integrated into the genome of the "recombinant cell". When a vector is contained in the recombinant cell, the vector can be introduced into mammalian cells to construct recombinant cells, and then these recombinant cells are used to express the antibody or antigen-binding fragment provided by the present invention. By culturing the recombinant cells, the corresponding antibody can be obtained. Available mammalian cells can be CHO cells, etc.

[0093] In the present invention, the term "pharmaceutical composition" exists in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to whom the composition will be administered. In some specific embodiments, the antibody contained in the above pharmaceutical composition or the expressed antibody can specifically target and bind to CDH17.

[0094] In the present invention, the term "binding to CDH17" includes binding to an isolated CDH17 molecule and / or a cell expressing CDH17.

[0095] In the present invention, a "pharmaceutically acceptable carrier" may include any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. that are physiologically compatible.

[0096] In the present invention, the term "subject" or "patient" refers to a mammalian subject or patient. Exemplary subjects include, but are not limited to, humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, birds, goats, and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject is a human suspected of having cancer, an autoimmune disease or condition, and / or an infection.

[0097] In the present invention, the term "diagnosis" refers to the identification of a pathological condition, disease or disorder, such as the identification of a CDH17-related disease, or refers to the identification of a subject suffering from a CDH17-related disease who may benefit from a specific treatment regimen. In some embodiments, the diagnosis includes the identification of an abnormal content or activity of CDH17. In some embodiments, the diagnosis refers to the identification of cancer or an autoimmune disease in a subject.

[0098] In the present invention, a "CDH17-related" disease, disorder or condition refers to any disease or condition caused by, exacerbated by, or associated with an increase or decrease in the expression or activity of CDH17. In some embodiments, the CDH17-related disease, disorder or condition is a disorder associated with excessive cell proliferation, such as cancer. In some embodiments, the CDH17-related disease or condition is characterized by the expression or overexpression of CDH17 and / or CDH17-related genes.

[0099] In the present invention, the term "cancer expressing CDH17" refers to a cancer that expresses CDH17 in cancer cells or tumor-infiltrating immune cells or immunosuppressive cells, and the level of CDH17 expression in cancer cells or tumor-infiltrating immune cells or immunosuppressive cells is significantly higher than that expected in normal cells.

[0100] In the present invention, the term "effective amount" refers to a therapeutic amount that is sufficient to reduce or improve the severity and / or duration of a disorder and / or one or more of its symptoms; prevent the progression of a disease; cause the regression of a disease; prevent the recurrence, development or progression of one or more symptoms associated with a disease; detect a disease; or enhance or improve the prophylactic or therapeutic effect of another therapy (such as a prophylactic agent or a therapeutic agent). The therapeutically effective dose of the antibody or its antigen-binding fragment described in the present invention depends on a variety of factors well known in the art, such as body weight, age, medical history, current treatment, the health status of the subject and the potential for cross-infection, allergies, hypersensitivity and side effects, as well as the route of administration and the degree of tumor development. Those skilled in the art (such as doctors or veterinarians) can proportionally reduce or increase the dose according to these or other conditions or requirements.

[0101] In a first aspect, there is provided an anti-CDH17 antibody or its antigen-binding fragment. The anti-CDH17 antibody or its antigen-binding fragment specifically binds to one or more of CDH17 extracellular domain 1 (D1), CDH17 extracellular domain 2 (D2), CDH17 extracellular domain 3 (D3), CDH17 extracellular domain 4 (D4), CDH17 extracellular domain 5 (D5), CDH17 extracellular domain 6 (D6) and CDH17 extracellular domain 7 (D7).

[0102] In an alternative embodiment, the amino acid sequence of the extracellular region of CDH17 is as shown in SEQ ID NO. 597;

[0103] MILQAHLHSLCLLMLYLATGYGQEGKFSGPLKPMTFSIYEGQEPSQIIFQFKANPPAVTFELTGETDNIFVIEREGLLYYNRALDRETRSTHNLQVAALDANGIIVEGPVPITIKVKDINDNRPTFLQSKYEGSVRQNSRPGKPFLYVNATDLDDPATPNGQLYYQIVIQLPMINNVMYFQINNKTGAISLTREGSQELNPAKNPSYNLVISVKDMGGQSENSFSDTTSVDIIVTENIWKAPKPVEMVENSTDPHPIKITQVRWNDPGAQYSLVDKEKLPRFPFSIDQEGDIYVTQPLDREEKDAYVFYAVAKDEYGKPLSYPLEIHVKVKDINDNPPTCPSPVTVFEVQENERLGNSIGTLTAHDRDEENTANSFLNYRIVEQTPKLPMDGLFLIQTYAGMLQLAKQSLKKQDTPQYNLTIEVSDKDFKTLCFVQINVIDINDQIPIFEKSDYGNLTLAEDTNIGSTILTIQATDADEPFTGSSKILYHIIKGDSEGRLGVDTDPHTNTGYVIIKKPLDFETAAVSNIVFKAENPEPLVFGVKYNASSFAKFTLIVTDVNEAPQFSQHVFQAKVSEDVAIGTKVGNVTAKDPEGLDISYSLRGDTRGWLKIDHVTGEIFSVAPLDREAGSPYRVQVVATEVGGSSLSSVSEFHLILMDVNDNPPRLAKDYTGLFFCHPLSAPGSLIFEATDDDQHLFRGPHFTFSLGSGSLQNDWEVSKINGTHARLSTRHTEFEEREYVVLIRINDGGRPPLEGIVSLPVTFCSCVEGSCFRPAGHQTGIPTVGM (SEQ ID NO.597).

[0104] In an alternative embodiment, the amino acid sequence of extracellular domain 1 (D1) is as shown by amino acids 30 to 128 from the N-terminus to the C-terminus of CDH17.

[0105] In an alternative embodiment, the amino acid sequence of extracellular domain 2 (D2) is as shown by amino acids 129 to 244 from the N-terminus to the C-terminus of CDH17.

[0106] In an alternative embodiment, the amino acid sequence of extracellular domain 3 (D3) is as shown by the amino acids at positions 245 to 340 of CDH17 from the N-terminus to the C-terminus.

[0107] In an alternative embodiment, the amino acid sequence of extracellular domain 4 (D4) is as shown by the amino acids at positions 341 to 449 of CDH17 from the N-terminus to the C-terminus.

[0108] In an alternative embodiment, the amino acid sequence of extracellular domain 5 (D5) is as shown by the amino acids at positions 450 to 566 of CDH17 from the N-terminus to the C-terminus.

[0109] In an alternative embodiment, the amino acid sequence of extracellular domain 6 (D6) is as shown by the amino acids at positions 567 to 667 of CDH17 from the N-terminus to the C-terminus.

[0110] In an alternative embodiment, the amino acid sequence of extracellular domain 7 (D7) is as shown by the amino acids at positions 668 to 777 of CDH17 from the N-terminus to the C-terminus.

[0111] In an alternative embodiment, the anti-CDH17 antibody or its antigen-binding fragment specifically binds to one or more of CDH17 extracellular domain 1 (D1), CDH17 extracellular domain 2 (D2), CDH17 extracellular domain 3 (D3), CDH17 extracellular domain 4 (D4), CDH17 extracellular domain 5 (D5), CDH17 extracellular domain 6 (D6), or CDH17 extracellular domain 7 (D7).

[0112] In an alternative embodiment, the anti-CDH17 antibody or its antigen-binding fragment specifically binds to one or more of CDH17 extracellular domain 1 (D1), CDH17 extracellular domain 2 (D2), CDH17 extracellular domain 3 (D3), and CDH17 extracellular domain 4 (D4).

[0113] In an alternative embodiment, the anti-CDH17 antibody or its antigen-binding fragment specifically binds to one or more of CDH17 extracellular domain 5 (D5), CDH17 extracellular domain 6 (D6), and CDH17 extracellular domain 7 (D7).

[0114] In an alternative embodiment, the antibody or its antigen-binding fragment contains complementarity-determining regions of the heavy-chain variable region, and / or complementarity-determining regions of the light-chain variable region;

[0115] The complementarity-determining regions of the heavy-chain variable region include HCDR1, HCDR2, and HCDR3, and the complementarity-determining regions of the light-chain variable region include LCDR1, LCDR2, and LCDR3;

[0116] The HCDR1 includes amino acid residues DY, EY, GY, NY, SG, SH, SY, TS or TY.

[0117] In an alternative embodiment, according to the IMGT definition, the HCDR1 includes an amino acid sequence as shown in any one of SEQ ID NOs. 45, 50, 54, 58, 63, 67, 72, 77, 81, 85, 90, 95, 100, 104, 107 and 113.

[0118] The HCDR2 includes an amino acid sequence as shown in any one of SEQ ID NOs. 184 - 186, 188, 191 - 199, 202 - 205 and 208.

[0119] In an alternative embodiment, according to the IMGT definition, the HCDR2 includes an amino acid sequence as shown in any one of SEQ ID NOs. 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 162, 167, 171, 175, 179, 183, 189 and 190.

[0120] The HCDR3 includes an amino acid sequence as shown in any one of SEQ ID NOs. 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245, 248, 251, 254, 257, 260 and 278.

[0121] In an alternative embodiment, according to the IMGT definition, the HCDR3 includes an amino acid sequence as shown in any one of SEQ ID NOs. 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262 and 266.

[0122] The LCDR1 includes amino acid residues NID, NNF, NNW, NY, SDF, SGY, SND, SSA or SY, or an amino acid sequence as shown in any one of SEQ ID NOs. 290, 294, 299, 308, 319 and 332.

[0123] In an alternative embodiment, according to the IMGT definition, the LCDR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 286, 288, 292, 293, 296, 298, 301, 303, 305, 307, 310, 312, 321, 322 and 333.

[0124] The LCDR2 comprises the amino acid residue AA, the amino acid residue DT, the amino acid residue FA, the amino acid residue GA, the amino acid residue KV, the amino acid residue RA, the amino acid residue RT, the amino acid residue SA, the amino acid residue ST, the amino acid residue WA, the amino acid residue YA or the amino acid residue YT.

[0125] In an alternative embodiment, according to the IMGT definition, the LCDR2 comprises the amino acid residue AA, the amino acid residue DT, the amino acid residue FA, the amino acid residue GA, the amino acid residue KV, the amino acid residue RA, the amino acid residue RT, the amino acid residue SA, the amino acid residue ST, the amino acid residue WA, the amino acid residue YA or the amino acid residue YT.

[0126] The LCDR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394 and 396.

[0127] In an alternative embodiment, according to the IMGT definition, the LCDR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395 and 397.

[0128] In an alternative embodiment, the complementarity determining regions of the anti-CDH17 antibody or its antigen-binding fragment comprise any one of the following (a) to (t):

[0129] (a) HCDR1 comprises the amino acid residue SY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 185, HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 209, LCDR1 comprises the amino acid residue SND, LCDR2 comprises the amino acid residue YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 386; or,

[0130] (b) The HCDR1 comprises the amino acid residues EY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 192, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 278, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 319, the LCDR2 comprises the amino acid residues WA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 376; or,

[0131] (c) The HCDR1 comprises the amino acid residues SY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 203, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 212, the LCDR1 comprises the amino acid residues NNF, the LCDR2 comprises the amino acid residues RT, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 378; or,

[0132] (d) The HCDR1 comprises the amino acid residues SY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 196, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 215, the LCDR1 comprises the amino acid residues SY, the LCDR2 comprises the amino acid residues DT, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 372; or,

[0133] (e) The HCDR1 comprises the amino acid residues GY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 197, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 218, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 332, the LCDR2 comprises the amino acid residues ST, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 374; or,

[0134] (f) The HCDR1 comprises the amino acid residues SH, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 208, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 221, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 290, the LCDR2 comprises the amino acid residues RA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 394; or,

[0135] (g) HCDR1 comprises the amino acid residue TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 191, HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 224, LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 332, LCDR2 comprises the amino acid residue ST, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 374; or,

[0136] (h) HCDR1 comprises the amino acid residue GY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 195, HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 227, LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 294, LCDR2 comprises the amino acid residue YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 382; or,

[0137] (i) HCDR1 comprises the amino acid residue SG, HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 205, HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 230, LCDR1 comprises the amino acid residue SSA, LCDR2 comprises the amino acid residue SA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 392; or,

[0138] (j) HCDR1 comprises the amino acid residue TS, HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 186, HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 233, LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 299, LCDR2 comprises the amino acid residue KV, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 370; or,

[0139] (k) HCDR1 comprises the amino acid residue EY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 194, HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 278, LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 319, LCDR2 comprises the amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 376; or,

[0140] (l) HCDR1 comprises the amino acid residues SY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.199, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.236, LCDR1 comprises the amino acid residues SY, LCDR2 comprises the amino acid residues DT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.368; or,

[0141] (m) HCDR1 comprises the amino acid residues EY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.194, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.239, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.319, LCDR2 comprises the amino acid residues WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.376; or,

[0142] (n) HCDR1 comprises the amino acid residues DY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.193, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.242, LCDR1 comprises the amino acid residues NNW, LCDR2 comprises the amino acid residues GA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.396; or,

[0143] (o) HCDR1 comprises the amino acid residues TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.202, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.245, LCDR1 comprises the amino acid residues NY, LCDR2 comprises the amino acid residues YT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.388; or,

[0144] (p) HCDR1 comprises the amino acid residues NY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.198, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.248, LCDR1 comprises the amino acid residues SDF, LCDR2 comprises the amino acid residues YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.384; or,

[0145] (q) HCDR1 comprises the amino acid residues TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.204, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.251, LCDR1 comprises the amino acid residues SGY, LCDR2 comprises the amino acid residues AA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.380; or,

[0146] (r) The HCDR1 comprises the amino acid residues TY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO.204, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO.254, the LCDR1 comprises the amino acid residues SGY, the LCDR2 comprises the amino acid residues AA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO.380; or,

[0147] (s) The HCDR1 comprises the amino acid residues NY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO.184, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO.257, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO.308, the LCDR2 comprises the amino acid residues FA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO.382; or,

[0148] (t) The HCDR1 comprises the amino acid residues DY, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO.188, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO.260, the LCDR1 comprises the amino acid residues NID, the LCDR2 comprises the amino acid residues SA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO.390.

[0149] In an alternative embodiment, according to the IMGT definition, the complementarity determining regions of the anti-CDH17 antibody or its antigen-binding fragment include any one of the following (a')-(t'):

[0150] (a') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO.45, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO.121, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO.211, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO.286, the LCDR2 comprises the amino acid residues YA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO.387; or,

[0151] (b') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO.113, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO.125, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO.266, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO.322, the LCDR2 comprises the amino acid residues WA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO.377; or,

[0152] (c') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 50, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 129, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 214, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 288, the LCDR2 comprises the amino acid residues RT, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 379; or,

[0153] (d') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 54, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 133, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 217, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 333, the LCDR2 comprises the amino acid residues DT, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 373; or,

[0154] (e') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 58, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 137, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 220, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 293, the LCDR2 comprises the amino acid residues ST, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 375; or,

[0155] (f') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 63, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 141, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 223, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 292, the LCDR2 comprises the amino acid residues RA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 395; or,

[0156] (g') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 107, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 145, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 226, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 293, the LCDR2 comprises the amino acid residues ST, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 375; or,

[0157] (h') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 67, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 149, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 229, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 296, the LCDR2 comprises the amino acid residues YA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 383; or,

[0158] (i') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 72, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 153, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 232, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 298, the LCDR2 comprises the amino acid residues SA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 393; or,

[0159] (j') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 77, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 157, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 235, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 301, the LCDR2 comprises the amino acid residues KV, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 371; or,

[0160] (k') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 113, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 189, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 266, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 322, the LCDR2 comprises the amino acid residues WA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 377; or,

[0161] (l') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 81, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 162, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 238, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 333, the LCDR2 comprises the amino acid residues DT, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 369; or,

[0162] (m') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 113, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 189, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 241, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 322, the LCDR2 comprises the amino acid residues WA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 377; or,

[0163] (n') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 85, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 167, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 244, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 303, the LCDR2 comprises the amino acid residues GA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 397; or,

[0164] (o') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 90, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 171, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 247, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 305, the LCDR2 comprises the amino acid residues YT, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 389; or,

[0165] (p') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 95, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 175, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 250, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 307, the LCDR2 comprises the amino acid residues YA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 385; or,

[0166] (q') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 107, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 190, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 253, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 321, the LCDR2 comprises the amino acid residues AA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 381; or,

[0167] (r') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 107, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 190, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 256, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 321, the LCDR2 comprises the amino acid residue AA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 381; or,

[0168] (s') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 100, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 179, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 259, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 310, the LCDR2 comprises the amino acid residue FA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 383; or,

[0169] (t') The HCDR1 comprises the amino acid sequence shown in SEQ ID NO. 104, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO. 183, the HCDR3 comprises the amino acid sequence shown in SEQ ID NO. 262, the LCDR1 comprises the amino acid sequence shown in SEQ ID NO. 312, the LCDR2 comprises the amino acid residue SA, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO. 391.

[0170] In an alternative embodiment, the anti-CDH17 antibody or its antigen-binding fragment contains the complementarity-determining regions HCDR1, HCDR2, and HCDR3 of the heavy-chain variable region, and / or the complementarity-determining regions LCDR1, LCDR2, and LCDR3 of the light-chain variable region.

[0171] The HCDR1, HCDR2, and HCDR3 comprise amino acid sequences that are identical to the HCDR1, HCDR2, and HCDR3 of the heavy-chain variable region shown in any one of SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, or 39.

[0172] The LCDR1, LCDR2, and LCDR3 comprise amino acid sequences that are identical to the LCDR1, LCDR2, and LCDR3 of the light-chain variable region shown in any one of SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40.

[0173] The above-mentioned HCDR1, HCDR2 and HCDR3, and LCDR1, LCDR2 and LCDR3 are determined according to the Kabat definition, the Chothia definition, the AbM definition, the Contact definition or the IMGT definition.

[0174] In an optional embodiment, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the anti-CDH17 antibody or antigen-binding fragment thereof can be independently selected from Tables 1 to 20.

[0175] Table 1 shows an exemplary antibody F1-41.16 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO. 1, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO. 2).

[0176] Table 1

[0177]

[0178] Table 2 shows an exemplary antibody F1-87.15 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO. 3, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO. 4).

[0179] Table 2

[0180]

[0181]

[0182] Table 3 shows an exemplary antibody F1-111.5 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO. 5, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO. 6).

[0183] Table 3

[0184]

[0185] Table 4 shows an exemplary antibody F1-143.7 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO. 7, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO. 8).

[0186] Table 4

[0187]

[0188]

[0189] Table 5 shows exemplary antibody F2-55.10 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.9, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.10).

[0190] Table 5

[0191]

[0192] Table 6 shows exemplary antibody F2-155.7 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.11, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.12).

[0193] Table 6

[0194]

[0195]

[0196] Table 7 shows exemplary antibody F2-186.1 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.13, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.14).

[0197] Table 7

[0198]

[0199] Table 8 shows exemplary antibody F2-238.14 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.15, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.16).

[0200] Table 8

[0201]

[0202]

[0203] Table 9 shows exemplary antibody F2-324.7 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.17, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.18).

[0204] Table 9

[0205]

[0206] Table 10 shows exemplary antibody F3-1.5 (the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO.19, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO.20).

[0207] Table 10

[0208]

[0209] Table 11 shows exemplary antibody F1-76.12 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.21, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.22).

[0210] Table 11

[0211]

[0212]

[0213] Table 12 shows exemplary antibody F1-86.9 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.23, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.24).

[0214] Table 12

[0215]

[0216] Table 13 shows exemplary antibody F1-99.29 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.25, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.26).

[0217] Table 13

[0218]

[0219]

[0220] Table 14 shows exemplary antibody F1-124.38 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.27, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.28).

[0221] Table 14

[0222]

[0223] Table 15 shows exemplary antibody F1-127.8 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.29, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.30).

[0224] Table 15

[0225]

[0226]

[0227] Table 16 shows the exemplary antibody F2-71.18 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.31, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.32).

[0228] Table 16

[0229]

[0230] Table 17 shows the exemplary antibody F2-89.7 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.33, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.34).

[0231] Table 17

[0232]

[0233]

[0234] Table 18 shows the exemplary antibody F2-291.2 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.35, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.36).

[0235] Table 18

[0236]

[0237] Table 19 shows the exemplary antibody F3-6.18 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.37, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.38).

[0238] Table 19

[0239]

[0240]

[0241] Table 20 shows the exemplary antibody F3-36.14 (the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.39, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO.40).

[0242] Table 20

[0243]

[0244] In an alternative embodiment, the anti-CDH17 antibody or its antigen-binding fragment comprises a heavy chain framework region and / or a light chain framework region, and the heavy chain framework region and / or the light chain framework region is derived from at least one of a murine antibody, a human antibody, a primate antibody, or a mutant thereof.

[0245] In an alternative embodiment, the three CDRs of the anti-CDH17 antibody or its antigen-binding fragment are separated by flanking portions referred to as framework regions (FRs, the light chain FRs include LFR1, LFR2, LFR3, and LFR4, and the heavy chain FRs include HFR1, HFR2, HFR3, and HFR4).

[0246] In an alternative embodiment, the HFR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 398 to 415, or comprises a sequence having at least 78% (e.g., 78%, 80%, 82%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98%, or 99%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 398 to 415.

[0247] In an alternative embodiment, the HFR2 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 416, 418, 422, 426, 428, 431, 433, 436, 439, 442, and 445 to 448, or comprises a sequence having at least 70% (e.g., 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98%, or 99%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 416, 418, 422, 426, 428, 431, 433, 436, 439, 442, and 445 to 448.

[0248] In an alternative embodiment, the HFR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 472, 474, 477, 479, 481, 483, 485, and 487, or comprises a sequence having at least 72% (e.g., 72%, 75%, 78%, 80%, 82%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98%, or 99%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 472, 474, 477, 479, 481, 483, 485, and 487.

[0249] In an alternative embodiment, the HFR4 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 488 to 493, or comprises a sequence having at least 86% (such as 86%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98% or 99%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 488 to 493.

[0250] In an alternative embodiment, the LFR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524 and 526, or comprises a sequence having at least 70% (such as 70%, 72%, 75%, 78%, 80%, 82%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98% or 99%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524 and 526.

[0251] In an alternative embodiment, the LFR2 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 528, 533, 535, 537, 539, 541, 543 and 549 to 552, or comprises a sequence having at least 80% (such as 80%, 82%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98% or 99%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 528, 533, 535, 537, 539, 541, 543 and 549 to 552.

[0252] In an alternative embodiment, the LFR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 581 and 582, or comprises a sequence having at least 79% (e.g., 79%, 80%, 82%, 85%, 87%, 89%, 90%, 91%, 92%, 93%, 95%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs. 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 581 and 582.

[0253] In an alternative embodiment, the LFR4 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 586 - 590, or comprises a sequence having at least 95% (e.g., 95%, 97%, 98% or 99%) sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs. 586 - 590.

[0254] In an alternative embodiment, the HFR1 comprises the HFR1 of the heavy chain variable region as shown in any one of SEQ ID NOs. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39.

[0255] In an alternative embodiment, the HFR2 comprises the HFR2 of the heavy chain variable region as shown in any one of SEQ ID NOs. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39.

[0256] In an alternative embodiment, the HFR3 comprises the HFR3 of the heavy chain variable region as shown in any one of SEQ ID NOs. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39.

[0257] In an alternative embodiment, the HFR4 comprises the HFR4 of the heavy chain variable region as shown in any one of SEQ ID NOs. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39.

[0258] In an alternative embodiment, the LFR1 comprises an LFR1 of a light chain variable region shown in any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40.

[0259] In an alternative embodiment, the LFR2 comprises an LFR2 of a light chain variable region shown in any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40.

[0260] In an alternative embodiment, the LFR3 comprises an LFR3 of a light chain variable region shown in any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40.

[0261] In an alternative embodiment, the LFR4 comprises an LFR4 of a light chain variable region shown in any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40.

[0262] In an alternative embodiment, the HFR1, HFR2, HFR3, and HFR4 comprise HFR1, HFR2, HFR3, and HFR4 of a heavy chain variable region shown in any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 39. The CDR regions are determined according to the Kabat definition, Chothia definition, AbM definition, Contact definition, or IMGT definition in Tables 1 to 20, and the FR regions of the corresponding definition methods are obtained according to the structure of the heavy chain variable region.

[0263] Taking the IMGT definition as an example, the heavy chain framework regions of the anti-CDH17 antibody or its antigen-binding fragment include any one of the following (A)-(T):

[0264] (A) The HFR1 comprises the amino acid sequence shown in SEQ ID NO. 414, the HFR2 comprises the amino acid sequence shown in SEQ ID NO. 417, the HFR3 comprises the amino acid sequence shown in SEQ ID NO. 450, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO. 490;

[0265] (B) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 405, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 444, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 452, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 491;

[0266] (C) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 399, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 419, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 454, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 491;

[0267] (D) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 414, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 420, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 456, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 493;

[0268] (E) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 404, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 421, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 458, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 492;

[0269] (F) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 411, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 423, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 460, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 493;

[0270] (G) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 407, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 424, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 462, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 493;

[0271] (H) The HFR1 contains the amino acid sequence shown in SEQ ID NO. 401, the HFR2 contains the amino acid sequence shown in SEQ ID NO. 425, the HFR3 contains the amino acid sequence shown in SEQ ID NO. 464, and the HFR4 contains the amino acid sequence shown in SEQ ID NO. 488;

[0272] (I) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.409, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.427, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.466, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491;

[0273] (J) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.415, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.429, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.468, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493;

[0274] (K) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.403, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.444, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.470, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491;

[0275] (L) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.410, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.430, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.471, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491;

[0276] (M) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.406, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.432, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.473, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491;

[0277] (N) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.400, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.434, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.475, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.492;

[0278] (O) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.412, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.435, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.476, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.492;

[0279] (P) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.408, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.437, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.478, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491;

[0280] (Q) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.398, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.438, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.480, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.489;

[0281] (R) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.398, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.440, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.482, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493;

[0282] (S) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.413, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.441, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.484, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.492;

[0283] (T) The HFR1 comprises the amino acid sequence shown in SEQ ID NO.402, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.443, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.486, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493.

[0284] In an alternative embodiment, the LFR1, LFR2, LFR3 and LFR4 comprise the LFR1, LFR2, LFR3 and LFR4 of the light chain variable region shown in any one of SEQ ID NOs. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 and 40. Their CDR regions are determined according to the Kabat definition, Chothia definition, AbM definition, Contact definition or IMGT definition in Tables 1 to 20, and the FR regions of the corresponding definition methods are obtained according to the structure of the light chain variable region.

[0285] Taking the IMGT definition as an example, the light chain framework regions of the anti-CDH17 antibody or its antigen-binding fragment include any one of the following (A')-(T'):

[0286] (A') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 495, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 553, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 555, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 587;

[0287] (B') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 527, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 546, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 585, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 587;

[0288] (C') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 497, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 529, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 557, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 586;

[0289] (D') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 499, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 530, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 559, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 587;

[0290] (E') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 501, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 547, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 583, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 587;

[0291] (F') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 525, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 531, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 561, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 588;

[0292] (G') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 503, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 547, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 583, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0293] (H') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 505, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 532, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 563, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0294] (I') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 507, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 534, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 565, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 589;

[0295] (J') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 509, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 536, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 567, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0296] (K') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 527, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 546, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 585, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0297] (L') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 511, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 538, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 569, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 589;

[0298] (M') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 513, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 546, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 585, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0299] (N') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 515, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 540, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 571, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 590;

[0300] (O') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 517, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 542, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 573, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 589;

[0301] (P') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 519, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 544, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 575, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587,

[0302] (Q') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 523, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 548, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 584, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0303] (R') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 523, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 548, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 584, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0304] (S') The LFR1 contains the amino acid sequence shown in SEQ ID NO. 525, the LFR2 contains the amino acid sequence shown in SEQ ID NO. 545, the LFR3 contains the amino acid sequence shown in SEQ ID NO. 577, and the LFR4 contains the amino acid sequence shown in SEQ ID NO. 587;

[0305] (T') The LFR1 comprises the amino acid sequence shown in SEQ ID NO. 521, the LFR2 comprises the amino acid sequence shown in SEQ ID NO. 553, the LFR3 comprises the amino acid sequence shown in SEQ ID NO. 579, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO. 587.

[0306] In an alternative embodiment, the anti-CDH17 antibody or antigen-binding fragment thereof has a heavy chain variable region having the amino acid sequence shown in any one of SEQ ID NOs. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39 or having at least 64% (such as 64%, 65%, 68%, 70%, 72%, 75%, 77%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 and 39.

[0307] In an alternative embodiment, the anti-CDH17 antibody or antigen-binding fragment thereof has a light chain variable region having the amino acid sequence shown in any one of SEQ ID NOs. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 and 40 or having at least 70% (such as 70%, 72%, 75%, 77%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with the amino acid sequence shown in any one of SEQ ID NOs. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 and 40.

[0308] In an alternative embodiment, the anti-CDH17 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region selected from any of the following:

[0309] (a”) a heavy chain variable region having the amino acid sequence shown in SEQ ID NO. 1; and a light chain variable region having the amino acid sequence shown in SEQ ID NO. 2;

[0310] (b”) a heavy chain variable region having the amino acid sequence shown in SEQ ID NO. 3; and a light chain variable region having the amino acid sequence shown in SEQ ID NO. 4;

[0311] (c”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.5; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.6;

[0312] (d”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.7; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.8;

[0313] (e”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.9; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.10;

[0314] (f”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.11; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.12;

[0315] (g”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.13; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.14;

[0316] (h”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.15; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.16;

[0317] (i”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.17; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.18;

[0318] (j”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.19; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.20;

[0319] (k”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.21; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.22;

[0320] (l”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.23; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.24;

[0321] (m”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.25; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.26;

[0322] (n”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.27; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.28;

[0323] (o”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.29; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.30;

[0324] (p”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.31; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.32;

[0325] (q”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.33; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.34;

[0326] (r”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.35; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.36;

[0327] (s”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.37; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.38;

[0328] (t”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.39; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.40.

[0329] In an alternative embodiment, the antigen-binding fragment comprises one or more of F(ab’)2, Fab’, Fab, Fv, scFv, dsFv, and the antibody minimal recognition unit.

[0330] In an alternative embodiment, the anti-CDH17 antibody or its antigen-binding fragment comprises a partial or full sequence of the constant region, which is derived from at least one of murine antibodies, human antibodies, primate antibodies, or their mutants;

[0331] In an alternative embodiment, the heavy chain constant region contains a partial or full sequence of any one of IgG1, IgG2a, IgG2b, IgG3, IgG4, IgA, IgM, IgE, or IgD.

[0332] In an alternative embodiment, the heavy chain constant region contains a partial or full sequence of IgG1, and the anti-CDH17 antibody or its antigen-binding fragment comprises the heavy chain variable region and the light chain variable region of any one of the following:

[0333] (a”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.1; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.2;

[0334] (c”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.5; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.6;

[0335] (t”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.39; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.40.

[0336] In an alternative embodiment, the heavy chain constant region contains the sequence of part or all of the constant region of IgG2a, and the anti-CDH17 antibody or its antigen-binding fragment comprises the heavy chain variable region and the light chain variable region of any of the following:

[0337] (d”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.7; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.8;

[0338] (f”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.11; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.12;

[0339] (g”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.13; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.14;

[0340] (i”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.17; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.18;

[0341] (j”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.19; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.20;

[0342] (n”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.27; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.28;

[0343] (o”) The heavy chain variable region of the amino acid sequence shown in SEQ ID NO.29; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.30;

[0344] (p”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.31; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.32;

[0345] (q”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.33; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.34;

[0346] (r”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.35; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.36;

[0347] (s”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.37; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.38.

[0348] In an alternative embodiment, the heavy chain constant region contains the sequence of part or all of the constant region of IgG2b, and the anti-CDH17 antibody or its antigen-binding fragment comprises the heavy chain variable region and the light chain variable region of any one of the following:

[0349] (b”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.3; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.4;

[0350] (e”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.9; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.10;

[0351] (h”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.15; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.16;

[0352] (k”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.21; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.22;

[0353] (l”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.23; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.24;

[0354] (m”) The heavy chain variable region of the amino acid sequence as shown in SEQ ID NO.25; and the light chain variable region of the amino acid sequence as shown in SEQ ID NO.26.

[0355] In an alternative embodiment, the light chain constant region is a κ or λ chain.

[0356] In alternative embodiments, the species from which the constant region is derived includes one or more combinations of mouse, rat, guinea pig, hamster, rabbit, ferret, cat, dog, goat, sheep, cow, pig, horse, monkey, and human.

[0357] In alternative embodiments, the anti-CDH17 antibody or its antigen-binding fragment has one or more of the following properties (i) to (iv):

[0358] (i) Binds to human CDH17 with an EC50 of no more than 1 μg / mL (e.g., no more than 0.01 μg / mL, 0.02 μg / mL, 0.03 μg / mL, 0.04 μg / mL, 0.05 μg / mL, 0.06 μg / mL, 0.07 μg / mL, 0.08 μg / mL, 0.09 μg / mL, 0.1 μg / mL, 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL, 0.6 μg / mL, 0.7 μg / mL, 0.8 μg / mL, 0.9 μg / mL, or 1 μg / mL), and the binding is measured by fluorescence-activated cell sorting (FACS), and the measurement method can refer to Example 2.

[0359] (ii) Binds to cynomolgus CDH17 with an EC50 of no more than 1 μg / mL (e.g., no more than 0.01 μg / mL, 0.02 μg / mL, 0.03 μg / mL, 0.04 μg / mL, 0.05 μg / mL, 0.06 μg / mL, 0.07 μg / mL, 0.08 μg / mL, 0.09 μg / mL, 0.1 μg / mL, 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL, 0.6 μg / mL, 0.7 μg / mL, 0.8 μg / mL, 0.9 μg / mL, or 1 μg / mL), and the binding is measured by enzyme-linked immunosorbent assay (ELISA), and the measurement method can refer to Example 3.

[0360] (iii) Has antibody-dependent cell-mediated cytotoxicity (ADCC) activity, and the ADCC activity is detected by fluorescence-activated cell sorting (FACS) or lactate dehydrogenase cytotoxicity assay, and the measurement method can refer to Example 5.

[0361] (iv) Has the activity of mediating endocytosis, and the activity of mediating endocytosis is detected by enzyme-linked immunosorbent assay (ELISA), and the measurement method can refer to Example 6.

[0362] In alternative embodiments, the anti-CDH17 antibody or its antigen-binding fragment binds or does not bind to murine CDH17.

[0363] In an alternative embodiment, CDH17 in the above (i)-(iii) is an isolated CDH17 molecule or a cell expressing CDH17, and the cell includes but is not limited to mammalian cells, such as tumor cells.

[0364] The anti-CDH17 antibody or its antigen-binding fragment provided in the first aspect can specifically bind to the CDH17 protein, and in some embodiments, can bind to the CDH17 protein expressed by mammalian cells (such as CHO cells), or the CDH17 endogenously expressed in tumor cells (such as AsPC-1 cells endogenously expressing CDH17). The anti-CDH17 antibody or its antigen-binding fragment provided in the first aspect has ADCC activity and can mediate endocytosis, providing new possibilities for the treatment and / or prevention of cancer.

[0365] In the second aspect, the present invention provides an anti-CDH17 antibody or its antigen-binding fragment that competitively binds to CDH17 with the anti-CDH17 antibody described in the first or second aspect, or the epitope of the CDH17 antigen it binds is the same as the epitope of the CDH17 antigen bound by the anti-CDH17 antibody described in the first or second aspect.

[0366] In the third aspect, the present invention provides a multispecific antibody that contains the anti-CDH17 antibody or its antigen-binding fragment shown in any one of the above.

[0367] In an alternative embodiment, the multispecific antibody further includes an antibody or its antigen-binding fragment that specifically binds to other target molecules. Exemplary other target molecules include but are not limited to tumor surface antigens or immune checkpoints.

[0368] Exemplary tumor surface antigens include but are not limited to MUC16, VEGFR-2 (KDR / FIK-1), K-RAS, CD2, CD3, CD19, CD19, CD20, CD21, CD22, CD30, CD32B, CD33, CD38, CD39, CD40, CD45, CD52, CD70, CD80, CD60, CD62, CD72, CD79a, CD79B, CD123, EGFR, HER2, HER3, HER4, GPC3, CLL1, TGF-β, TGF-beta RII, VEGF, GD3, CCR4, CCR5, BCMA, CTLA4, mesothelin, OX40.

[0369] Exemplary immune checkpoints include, but are not limited to, PD-1, PD-L1, PD-L2, TIGIT, CD47, CD27, CD28, CD40, CD122, CD137, CD94 / NKG2A, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, LAG3, TIM-3, VISTA, GARP, PS, CSF1R, TDO, CTLA-4, IDO, KIR, GITR, TNFR, FasR / DcR, and CEACAM1.

[0370] In a fourth aspect, the present invention provides a chimeric antigen receptor (CAR) comprising an extracellular region, the extracellular region comprising an antigen-binding domain; and the antigen-binding domain contains the anti-CDH17 antibody or an antigen-binding fragment thereof shown in any one of the foregoing.

[0371] In an optional embodiment, the anti-CDH17 antibody or an antigen-binding fragment thereof in the chimeric antigen receptor is a single-chain antibody scFv.

[0372] In a fifth aspect, there is provided a nucleic acid molecule encoding the anti-CDH17 antibody or an antigen-binding fragment thereof of the first or second aspect, or the multispecific antibody of the third aspect, or the chimeric antigen receptor of the fourth aspect.

[0373] In an optional embodiment, the nucleic acid molecule is an isolated nucleic acid molecule.

[0374] In a sixth aspect, there is provided a vector carrying the nucleic acid molecule of the fifth aspect.

[0375] In a seventh aspect, the present invention provides a recombinant cell expressing the anti-CDH17 antibody or an antigen-binding fragment thereof of the first or second aspect, or expressing the multispecific antibody of the third aspect, or expressing the chimeric antigen receptor of the fourth aspect, or containing the nucleic acid molecule of the fifth aspect, or containing the vector of the sixth aspect.

[0376] In an eighth aspect, the present invention provides an engineered immune cell expressing the chimeric antigen receptor of the fourth aspect or containing a nucleic acid molecule encoding the chimeric antigen receptor of the fourth aspect.

[0377] In a ninth aspect, the present invention provides a pharmaceutical composition containing the anti-CDH17 antibody or an antigen-binding fragment thereof of the first or second aspect, or the multispecific antibody of the third aspect, or the chimeric antigen receptor of the fourth aspect, or the nucleic acid molecule of the fifth aspect, or the vector of the sixth aspect, or the recombinant cell of the seventh aspect, or the engineered immune cell of the eighth aspect.

[0378] In an alternative embodiment, the above drug composition further comprises a pharmaceutically acceptable carrier and / or excipient. The acceptable carrier and pharmaceutically acceptable excipients can be any carrier and / or excipient known and conventional in the art. Examples of carriers include, but are not limited to, any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc.; examples of excipients include, but are not limited to, fillers, disintegrants, preservatives, solubilizers, and emulsifiers, etc.

[0379] In an alternative embodiment, the drug composition further comprises one or several drug active ingredients having other therapeutic effects, including but not limited to one or several combinations of chemotherapeutic agents, anti-cancer drugs, radiotherapy agents, immunotherapeutic agents, anti-angiogenic agents, targeted therapeutic agents, cell therapeutic agents, gene therapeutic agents, hormone therapeutic agents, antiviral agents, antibiotics, analgesics, antioxidants, metal chelators, and cytokines.

[0380] In an alternative embodiment, the drug composition is a drug for treating, preventing or alleviating a disease, disorder or condition associated with CDH17.

[0381] In a tenth aspect, the present invention provides the use of the anti-CDH17 antibody or its antigen-binding fragment of the first or second aspect, or the multispecific antibody of the third aspect, or the chimeric antigen receptor of the fourth aspect, or the nucleic acid molecule of the fifth aspect, or the vector of the sixth aspect, or the recombinant cell of the seventh aspect, or the engineered immune cell of the eighth aspect, or the drug composition of the ninth aspect in any one of the following:

[0382] (I) Detecting CDH17 or cells expressing CDH17;

[0383] (II) Preparing a product for detecting CDH17 or cells expressing CDH17;

[0384] (III) For treating, preventing or alleviating a disease, disorder or condition associated with CDH17

[0385] (IV) Preparing a drug composition for treating, preventing or alleviating a disease, disorder or condition associated with CDH17.

[0386] In an alternative embodiment, the application of the above aspect (I) can utilize the ability of an anti-CDH17 antibody or its antigen-binding fragment to specifically target and bind to CDH17, and detect CDH17 or cells expressing CDH17 based on immunoassay techniques. For example, when the antibody or its antigen-binding fragment chain is an immunoconjugate, such as conjugated with a fluorescent group, a fluorescence detection device can be used to achieve the localization or real-time detection of CDH17. For example, it can be used in immunoblotting, immunoprecipitation, flow cytometry techniques, etc., which involve using the specific binding property of the CDH17 antigen and antibody to detect CDH17 or cells expressing CDH17. Correspondingly, in the above aspect (II), those skilled in the art can select the reagent composition in the kit according to the actual detection means, including but not limited to antagonists, anti-CDH17 antibodies, or drug reference materials; protein purification columns; immunoglobulin affinity purification buffers; cell assay diluents; instructions or literature, etc. The kit can also be used to detect diseases, disorders, or conditions related to CDH17.

[0387] In an alternative embodiment, the application of the above aspect (I) is for non-diagnostic and non-therapeutic purposes.

[0388] In an alternative embodiment, a method for treating, preventing, or alleviating a disease, disorder, or condition related to CDH17 includes administering to a subject a therapeutically effective amount of the aforementioned anti-CDH17 antibody or its antigen-binding fragment and / or the aforementioned pharmaceutical composition.

[0389] In the eleventh aspect, the present invention provides a method for generating the aforementioned anti-CDH17 antibody or its antigen-binding fragment, which includes the following steps:

[0390] (a) Culturing the aforementioned recombinant cells under conditions for expressing the anti-CDH17 antibody or its antigen-binding fragment;

[0391] (b) Isolating and purifying the anti-CDH17 antibody or its antigen-binding fragment obtained in step (a).

[0392] In an alternative embodiment, the "CDH17-related" diseases, disorders, or conditions in any of the above aspects include: solid tumors or hematological tumors.

[0393] In an alternative embodiment, the "CDH17-related" diseases, disorders, or conditions are characterized by high expression of CDH17.

[0394] In an alternative embodiment, the solid tumors involved in the diseases, disorders, or conditions in any of the above aspects include one or more of the following groups: gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, breast cancer, lung cancer, colon cancer, bladder cancer, thyroid cancer, skin cancer, esophageal cancer, and cervical cancer.

[0395] In alternative embodiments, the hematologic malignancies associated with the disease, disorder or condition in any of the foregoing aspects include the following group: one or more of chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma, and T or B cell lymphoma.

[0396] In alternative embodiments, the antibody or antigen-binding fragment or pharmaceutical composition as described in the present invention can be administered at a therapeutically effective dose between about 0.001 mg / kg and about 1000 mg / kg. In some embodiments, the administered dose can vary during the course of treatment. For example, in some embodiments, the initial administered dose can be higher than the subsequent administered doses. In some embodiments, the administered dose is adjusted according to the response of the subject being treated during the course of treatment.

[0397] In alternative embodiments, the antibody or its antigen-binding fragment or pharmaceutical composition disclosed in the present invention can be administered alone or in combination with a therapeutically effective amount of a second therapeutic agent. For example, the antibody or its antigen-binding fragment or pharmaceutical composition disclosed in the present invention can be administered in combination with a second therapeutic agent (e.g., a chemotherapeutic agent, an anti-cancer drug, a radiotherapy agent, an immunotherapeutic agent, an anti-angiogenic agent, a targeted therapeutic agent, a cell therapeutic agent, a gene therapeutic agent, a hormone therapeutic agent, an antiviral agent, an antibiotic, an analgesic, an antioxidant, a metal chelator, or a cytokine).

[0398] In alternative embodiments, when the antibody or its antigen-binding fragment or pharmaceutical composition disclosed in the present invention is used in combination with one or more additional therapeutic agents, it can be administered simultaneously with the one or more additional therapeutic agents. In certain such embodiments, the antibody or its antigen-binding fragment and the additional therapeutic agent can be administered simultaneously as part of the same composition. However, the antibody or its antigen-binding fragment or pharmaceutical composition "used in combination" with other therapeutic agents does not need to be administered simultaneously or in the same composition as the therapeutic agent. The meaning of "used in combination" in the present invention also includes that the antibody or its antigen-binding fragment or pharmaceutical composition administered before or after another therapeutic agent is also considered to be "used in combination" with the therapeutic agent, that is, the antibody or its antigen-binding fragment or pharmaceutical composition and the second substance are administered by different administration methods.

[0399] In a twelfth aspect, the present invention provides a kit for detecting CDH17, which comprises the aforementioned anti-CDH17 antibody or its antigen-binding fragment.

[0400] In alternative embodiments, the product in any of the foregoing aspects, such as, but not limited to, the anti-CDH17 antibody or its antigen-binding fragment in a reagent, a kit, a blocker, and a pharmaceutical composition, is conjugated with at least one diagnostic agent and / or therapeutic agent to form an immunoconjugate.

[0401] The diagnostic agent includes one or more of a radiocontrast agent, a paramagnetic ion, a metal, a fluorescent label, a chemiluminescent label, an ultrasound contrast agent, and a photosensitizer;

[0402] The therapeutic agent includes one or more of a cytotoxin, a drug, a radionuclide, a boron atom, an immunomodulator, an anti-apoptotic agent, a photosensitive therapeutic agent, an immunoconjugate, and an oligonucleotide.

[0403] Radionuclides include, but are not limited to 110 In, 111 In, 177 Lu, 18 F, 52 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 90 Y, 89 Zr, 94 mTc, 94 Tc, 99 mTc, 120 I, 123 I, 124 I, 125 I, 131 I, 154-158 Gd, 32 P, 11 C, 13 N, 15 O, 186 Re, 188 Re, 51 Mn, 52 mMn, 55 Co, 72 As, 75 Br, 76 Br, 82 mRb and 83 one or more of Sr.

[0404] Paramagnetic ions include, but are not limited to, one or more of chromium(III), manganese(II), iron(III), iron(II), cobalt(II), nickel(II), copper(II), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), vanadium(II), terbium(III), dysprosium(III), holmium(III), and erbium(III).

[0405] Fluorescent labels include, but are not limited to, one or more of Alexa 350, Alexa 405, Alexa 430, Alexa 488, Alexa555, Alexa 647, AMCA, aminoacridine, BODIPY 630 / 650, BODIPY 650 / 665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, 5-carboxy-4′,5′-dichloro-2′,7′-dimethoxyfluorescein, 5-carboxy-2′,4′,5′,7′-tetrachlorofluorescein, 5-carboxyfluorescein, 5-carboxyrhodamine, 6-carboxyrhodamine, 6-carboxytetramethylrhodamine, Cascade Blue, Cy2, Cy3, Cy5, Cy7, 6-FAM, dansyl chloride, fluorescein, HEX, 6-JOE, NBD (7-nitrobenz-2-oxa-1,3-diazole), Oregon Green488, Oregon Green 500, Oregon Green514, PacificBlue, phthalic acid, terephthalic acid, isophthalic acid, cresol fast violet, cresol blue violet, brilliant cresyl blue, p-aminobenzoic acid, erythrosine, phthalocyanine, azomethine, cyanine, xanthine, succinylfluorescein, rare earth metal cryptates, tris-bipyridyl diamine europium, europium cryptates or chelates, diamines, dianthocyanins, La Jolla blue dye, allophycocyanin, allococyanin B, phycocyanin C, phycocyanin R, thiamine, phycoerythrocyanin, phycoerythrin R, REG, rhodamine green, rhodamine isothiocyanate, rhodamine red, ROX, TAMRA, TET, TRIT (tetramethylrhodamine isothiol), tetramethylrhodamine, and Texas red.

[0406] Oligonucleotides include, but are not limited to, one or more of shRNA, miRNA, and siRNA.

[0407] Drugs include, but are not limited to, methotrexate, fluorouracil, mercaptopurine, hydroxyurea, cytarabine, nitrogen mustard, cyclophosphamide, thiotepa, cisplatin, mitomycin, bleomycin, camptothecin, podophyllotoxin, actinomycin D, doxorubicin, daunorubicin, vinblastine, paclitaxel, cephalotaxine alkaloids, and L-asparaginase.

[0408] Immunomodulators include, but are not limited to, one or more of cytokines, chemokines, stem cell growth factors, lymphotoxins, hematopoietic factors, colony-stimulating factors (CSF), interferons, erythropoietin, thrombopoietin, tumor necrosis factor (TNF), interleukins (IL), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and stem cell growth factor.

[0409] Radionuclides include but are not limited to 111 In, 111 At, 177 Lu, 211 Bi, 212 Bi, 213 Bi, 211 At, 62 Cu, 67 Cu, 90 Y, 125 I, 131 I, 133 I, 32 P, 33 P, 47 Sc, 111 Ag, 67 Ga, 153 Sm, 161 Tb, 152 Dy, 166 Dy, 161 Ho, 166 Ho, 186 Re, 188 Re, 189 Re, 211 Pb, 212 Pb, 223 Ra, 225 Ac, 77 As, 89 Sr, 99 Mo, 105 Rh, 149 Pm, 169 Er, 194 Ir, 58 Co, 80 mBr, 99 mTc, 103 mRh, 109 Pt, 119 Sb, 189 mOs, 192 Ir, 219 Rn, 215 Po, 221 Fr, 255 Fm, 11 C, 13 N, 15 O, 75 Br, 198 Au, 199 Au, 224 Ac, 77 Br, 113 mIn, 95 Ru, 97 Ru,103 Ru, 105 Ru, 107 Hg, 203 Hg, 121 mTe, 122 mTe, 125 mTe, 165 Tm, 167 Tm, 168 Tm, 197 Pt, 109 Pd, 142 Pr, 143 Pr, 161 Tb, 57 Co, 58 Co, 51 Cr, 59 Fe, 75 Se, 201 Tl, 76 Br, and 169 one or more of Yb.

[0410] The present invention will be further described below through specific embodiments. However, it should be understood that these embodiments are only used for more detailed description and should not be construed as limiting the present invention in any form.

[0411] Example 1. Generation of mouse antibodies against CDH17

[0412] 1. Material preparation

[0413] To generate cells stably expressing human CDH17, CHO cells were transfected with a vector encoding human CDH17 (SEQ ID NO. 591). Then, the antibody (Boehringer-Ingelheim) R2800 targeting the CDH17 protein (the sequence is from Patent CN110582513A, the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO. 592, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO. 593) was used as a positive control, and CHO cells were used as a negative control by flow cytometry to screen for stable cell lines. A eukaryotic expression vector encoding the extracellular region fragment of human CDH17 (SEQ ID NO. 594, SEQ ID NO. 595, SEQ ID NO. 596) was constructed, and this vector was transiently transfected into HEK293 cells to express and purify the immunogen and the protein for screening. The schematic diagram of the structural relationship between human CDH17 and the extracellular region fragment of human CDH17 (i.e., human CDH17 ECD) is as Figure 2 shown, where human CDH17 ECD includes a total of 7 domains D1-D7 (also known as EC1-EC7), and the CDH17 ECD structure is as Figure 1 shown.

[0414] The amino acid sequence of human CDH17 is shown in SEQ ID NO.591 (only the underlined part is the AAL sequence, only the bold part is the D1-D4 domain of human CDH17, the bold and underlined part is the D5-D7 domain of human CDH17, the italic part is the transmembrane region of human CDH17, and the italic and underlined part is the intracellular region of human CDH17):

[0415]

[0416] mFc-tagged human CDH17 ECD, the amino acid sequence is shown in SEQ ID NO.594 (only the underlined part is the AAL sequence, only the bold part is human CDH17 ECD, and only the underlined part is the mFc tag):

[0417]

[0418] His-tagged human CDH17 ECD, the amino acid sequence is shown in SEQ ID NO.595 (only the underlined part is the AAL sequence, only the bold part is human CDH17 ECD, and only the underlined part is the His tag):

[0419]

[0420] His-tagged human CDH17 (D5-D7), the amino acid sequence is shown in SEQ ID NO.596 (only the bold part is the D5-D7 domain of human CDH17, and only the underlined part is the His tag):

[0421]

[0422] 2. Immunization

[0423] Mouse immunization was performed according to the following immunization protocol (Table 21).

[0424] The immunized animals were BALB / c mice, female, 5-8 weeks old. The immunization frequency was once a week. The first immunization was by subcutaneous injection in the back and abdomen, and the rest were immunized by intraperitoneal injection. The immunogen was R2426 (the amino acid sequence is shown in SEQ ID NO.594), and the immunization strategy is shown in Table 21.

[0425] Table 21: Immunization protocol for generating monoclonal antibodies

[0426]

[0427] 3. Generation of hybridomas producing anti-CDH17 mouse monoclonal antibodies

[0428] Give a boost immunization to the fusion target mice. Resuscitate and expand the culture of sufficient sp2 / mIL6 myeloma cells in advance to ensure cell quantity and viability. Sacrifice 12 feeder mice 3 days in advance, take out the peritoneal suspension and spread it evenly on the 96-well plate as the feeder fusion plate for standby, 150 μL per well. Isolate mouse splenocytes based on the standard protocol, and mix them with mouse myeloma cells at the ratios of 5×10 6 / plate, 3.1×10 6 / plate, and 4.4×10 6 / plate in a 1:1 ratio. Perform fusion under the action of an electrofusion apparatus, and add the fused cells to the feeder fusion plate in a volume of 50 μL. Place it in an incubator (Panasonic MCO-18AIC), and the culture conditions are 37 °C and 5% CO2. Six days after electrofusion, aspirate the old culture medium in the fusion plate, and supplement 200 μL of fresh culture medium to each well. On the 7th day, take the supernatant for the hCDH17-his (SEQ ID NO.595) ELISA binding experiment, and determine the positive target wells according to the experimental results, then perform aseptic medium replacement, and the volume of the supplemented medium is 200 μL. On the 8th day after electrofusion, take 100 μL of the culture supernatant for the screening of hCDH17 (D5-D7)-his (SEQ ID NO.596) ELISA binding. On the 9th day after electrofusion, take the culture supernatant for the AsPC-1 flow cytometry binding detection, and on the 12th day after electrofusion, take the culture supernatant for the flow cytometry binding screening of CHO-hCDH17. Select the positive pool according to the comprehensive screening results for subcloning. Then, select at least one clone that retains the reactivity of the parental mother cells (determined by FACS) from the in vitro cultured hybridomas, generate 9 - 20 tubes for each clone, and store them in liquid nitrogen.

[0429] 4. Select monoclonal antibodies that bind to CDH17

[0430] We performed an isotype ELISA assay to determine the isotype of the antibodies. Use a mouse monoclonal antibody Ig class / subclass identification ELISA kit (IgG1\IgG2a\IgG2b\IgG3\IgM\IgA) (Biolong, Cat#BF06001) to determine the Ig subclass of the identified CDH17-reactive monoclonal antibodies. The results of the antibody isotypes produced are shown in Table 22, the amino acid sequences of each variable region are shown in Table 23, and the CDR regions of each antibody are shown in Tables 1 - 20.

[0431] Table 22. Subtypes of mouse monoclonal antibodies

[0432]

[0433]

[0434] The amino acid sequences of the variable regions are shown in the following table:

[0435] Table 23 Amino acid sequences of variable regions

[0436]

[0437]

[0438]

[0439]

[0440] 5. Generation of monoclonal antibodies

[0441] Inoculate hybridoma cells into a dialysis-based bioreactor at 2×10 6 cells / ml, and harvest the supernatant containing antibodies once a week. Purify mouse monoclonal antibodies using Protein A (GE-MabSelect SuRe LX, Cat#17-5438-03) by FPLC. Determine the antibody concentration by BCA kit or A280 absorbance value, determine the antibody purity by SEC (size exclusion chromatography), and check the purity by SDS (sodium dodecyl sulfate) gel electrophoresis and Coomassie Brilliant Blue staining.

[0442] Example 2. Binding characteristics of monoclonal antibodies against CDH17

[0443] Use CHO-CDH17 expressing human CDH17 as the overexpression positive cell, and AsPC-1 (human metastatic pancreatic adenocarcinoma cells) as the positive cell endogenously expressing CDH17. We detected the binding activity of monoclonal antibodies to CHO-CDH17 cells and AsPC-1 cells by flow cytometry analysis.

[0444] 1. Binding to CHO-CDH17 cells

[0445] Culture sufficient CHO-CDH17 cells and collect the cells by centrifugation. At the same time, dilute the monoclonal antibody and the corresponding positive antibody with PBS + 3% FBS, starting from a concentration of 10 μg / mL, and perform 3-fold serial dilution or 4-fold serial dilution to obtain 8 concentration gradients for standby. Wash the collected cells once with PBS + 3% FBS and then resuspend the cells with PBS + 3% FBS to 2×10 6 cells / mL, plate the cells in a 96-well plate, 100 μL per well (2×10 5(Add 100 μL of the diluted antibody to the cells and incubate at 4 °C for 30 minutes; centrifuge to remove the supernatant, wash the cells twice with PBS, then resuspend the cells with the diluted PE-labeled anti-mouse IgG FC antibody (Biolegend, 405307), incubate at 4 °C in the dark for 30 minutes, wash twice with PBS, and then resuspend with 100 μL of PBS. Analyze by flow cytometry, and calculate the EC50 value of the binding affinity of the antibody to CHO-CDH17 based on the mean fluorescence intensity using the software GraphPad Prism 7.0. The results are shown as Figure 3 、 Figure 4 and Figure 5 follows. Most of the monoclonal antibodies had good binding to CHO-hCDH17. R2800 was used as a positive control antibody, with the heavy chain amino acid sequence shown in SEQ ID NO. 592 and the light chain amino acid sequence shown in SEQ ID NO. 593 (as shown in Table 23). mIgG2a was used as a negative control antibody.

[0446] 2. Binding to AsPC-1 cells

[0447] The binding activity of the monoclonal antibodies to AsPC-1 cells was detected by flow cytometry. After digesting the cells with Versene solution (Gibco, 15040066), centrifuge to collect the cells for standby. The antibody was diluted starting from 10 μg / mL or 20 μg / mL in 3-fold or 4-fold gradients, with 8 concentration gradients. After co-incubating the antibody with the cells, the subsequent experimental procedures were the same as those for the CHO-CDH17 cell binding experiment. Resuspend the cells with 100 μL of PBS, analyze by flow cytometry, and calculate the EC50 value of the binding affinity of the antibody to AsPC-1 cells based on the mean fluorescence intensity using the software GraphPad Prism 7.0.

[0448] The results are shown as Figure 6 、 Figure 7 and Figure 8 follows. Twenty mouse monoclonal antibodies had good binding to AsPC-1.

[0449] Example 3. Detection of the binding activity of monoclonal antibodies to monkey CDH17

[0450] In this example, the binding activity of the monoclonal antibody to cynomolgus CDH17 (Acrobiosystem) was detected. The cynomolgus CDH17 recombinant protein (cynomolgus CDH17) was diluted to 0.5 μg / mL with 50 mmol Coating Buffer in advance, 100 μL per well, and placed overnight at 4°C. The supernatant was discarded, and the plate was washed three times with 1×PBST buffer. Then, PBS + 1% FBS was added at 100 μL / well and incubated at 37°C for 1 hour. Meanwhile, the monoclonal antibody was diluted with PBS + 1% FBS to correspond to the positive control R2800, starting from a concentration of 10 μg / mL and serially diluted 4-fold to obtain 8 concentration gradients for standby. After the blocking was completed, the supernatant was discarded, 100 μL of the diluted antibody was added, and incubated at 37°C for 1 hour. After the incubation, the plate was washed four times with 1×PBST buffer, and then 100 μL of the diluted anti-mouse IgG c antibody conjugated with HRP (Sigma, A0168) was added and incubated at 37°C for 30 minutes. After the incubation, the plate was washed five times with 1×PBST buffer, and the color development solution was added for appropriate color development and then the color development was terminated. The value was read by an enzyme-linked immunosorbent assay reader, and then the EC50 value of the antibody binding to the cynomolgus CDH17 recombinant protein was analyzed and calculated using the software GraphPad Prism 7.0 at OD450nm.

[0451] The results are as Figure 9 and Figure 10 shown. The control antibody R2800 did not bind to cynomolgus CDH17. Among the mouse monoclonal antibodies, except for a few with slightly poor binding activity, all had good binding to cynomolgus CDH17.

[0452] Example 4. Detection of the binding activity of the monoclonal antibody to mouse CDH17

[0453] We detected the binding activity of monoclonal antibodies to murine CDH17. The recombinant murine CDH17 protein (mCDH17) was diluted to 0.5 μg / mL with 50 mmol Coating Buffer in advance, 100 μL per well, and incubated overnight at 4°C. The supernatant was discarded, and the plate was washed three times with 1×PBST buffer. Then, PBS + 1% FBS was added at 100 μL / well and incubated at 37°C for 1 hour. Meanwhile, the monoclonal antibody and the corresponding positive control R2800 were diluted with PBS + 1% FBS. Starting from a concentration of 10 μg / mL, they were serially diluted 4-fold to obtain 8 concentration gradients for standby. After the blocking was completed, the supernatant was discarded, 100 μL of the diluted antibody was added, and the mixture was incubated at 37°C for 1 hour. After incubation, the plate was washed four times with 1×PBST buffer, and then 100 μL of the diluted anti-mouse IgG c antibody conjugated with HRP (Sigma, A0168) was added per well and incubated at 37°C for 30 minutes. After incubation, the plate was washed five times with 1×PBST buffer. After adding the chromogenic solution for appropriate color development, the color development was terminated, and the values were read using an ELISA reader. Then, with OD450nm, the EC50 value of the antibody binding to the mCDH17 recombinant protein was analyzed and calculated using the software GraphPad Prism 7.0.

[0454] The results are as Figure 11 and Figure 12 shown. The positive control R2800 did not bind to mCDH17. Among the remaining monoclonal antibodies, except for F1-127.8 and F1-41.16 which had good binding to mCDH17, the other monoclonal antibodies did not bind to it.

[0455] Example 5 Detection of the Binding Activity of Monoclonal Antibodies to hCDH17

[0456] In this example, the binding activity of monoclonal antibodies to hCDH17 (ACRO, CA7-H52H3) was detected. The recombinant human CDH17 protein (hCDH17) was diluted to 0.5 μg / mL with 50 mmol Coating Buffer in advance, 100 μL per well, and incubated overnight at 4°C. The antibody was serially diluted 5-fold from a concentration of 10 μg / mL to obtain 6 concentration gradients. Other operations were the same as in Example 4. Finally, with OD450nm, the EC50 value of the antibody binding to the hCDH17 recombinant protein was analyzed and calculated using the software GraphPad Prism 7.0.

[0457] The results are shown in Figures 13 and Figure 14 as shown. Except for F2-238.14, F2-55.10, F1-139.6, F2-71.18, F2-324.17, F2-324.7, F2-186.1, F3-6.18, the binding activity of the remaining antibodies to the full-length CDH17 was better than that of the positive antibody R2800 (higher plateau or smaller EC50).

[0458] Example 6 Identification of Monoclonal Antibody Binding Epitopes

[0459] In this example, the binding epitopes of monoclonal antibodies were detected. Proteins R2795 (hCDH17 D1-D4.his) and R2796 (hCDH17 D5-D7.his) were constructed respectively. The amino acid sequence of R2795 is shown in SEQ ID NO.615, and the amino acid sequence of R2795 is shown in SEQ ID NO.616;

[0460] Amino acid sequence of R2795 huCDH17(D1-D4)-his:

[0461] PLKPMTFSIYEGQEPSQIIFQFKANPPAVTFELTGETDNIFVIEREGLLYYNRALDRETRSTHNLQVAALDANGIIVEGPVPITIKVKDINDNRPTFLQSKYEGSVRQNSRPGKPFLYVNATDLDDPATPNGQLYYQIVIQLPMINNVMYFQINNKTGAISLTREGSQELNPAKNPSYNLVISVKDMGGQSENSFSDTTSVDIIVTENIWKAPKPVEMVENSTDPHPIKITQVRWNDPGAQYSLVDKEKLPRFPFSIDQEGDIYVTQPLDREEKDAYVFYAVAKDEYGKPLSYPLEIHVKVKDINDNPPTCPSPVTVFEVQENERLGNSIGTLTAHDRDEENTANSFLNYRIVEQTPKLPMDGLFLIQTYAGMLQLAKQSLKKQDTPQYNLTIEVSDKDFKTLCFVQINVIDINDQIPIFHHHHHH(SEQ ID NO.615)

[0462] Amino acid sequence of R2796 huCDH17(D5-D7)-his:

[0463] EKSDYGNLTLAEDTNIGSTILTIQATDADEPFTGSSKILYHIIKGDSEGRLGVDTDPHTNTGYVIIKKPLDFETAAVSNIVFKAENPEPLVFGVKYNASSFAKFTLIVTDVNEAPQFSQHVFQAKVSEDVAIGTKVGNVTAKDPEGLDISYSLRGDTRGWLKIDHVTGEIFSVAPLDREAGSPYRVQVVATEVGGSSLSSVSEFHLILMDVNDNPPRLAKDYTGLFFCHPLSAPGSLIFEATDDDQHLFRGPHFTFSLGSGSLQNDWEVSKINGTHARLSTRHTEFEEREYVVLIRINDGGRPPLEGIVSLPVTFCSCVEGSCFRPAGHHHHHH(SEQ ID NO.616)

[0464] Dilute R2795 and R2796 to 0.5 μg / mL with 50 mmol Coating Buffer in advance, 100 μL per well, and place at 4 °C overnight. Discard the supernatant, wash the plate three times with 1×PBST buffer, then add PBS + 1% FBS at 100 μL / well and incubate at 37 °C for 1 hour. At the same time, dilute the monoclonal antibody and the corresponding positive control R2800 with PBS + 1% FBS, starting from a concentration of 10 μg / mL, and perform 5-fold serial dilution to obtain 6 concentration gradients for standby. After the blocking is completed, discard the supernatant, add 100 μL of the diluted antibody, incubate at 37 °C for 1 hour. After the incubation, wash the plate four times with 1×PBST buffer, then add 100 μL / well of the diluted anti-mouse IgG c antibody conjugated with HRP (Sigma, A0168), incubate at 37 °C for 30 minutes. After the incubation, wash the plate five times with 1×PBST buffer, add the chromogenic solution for appropriate color development and then terminate the color development. Read the values with an enzyme-linked immunosorbent assay reader, and then use OD450nm to analyze and calculate the antibody-binding epitope and its binding EC50 value by using the software GraphPad Prism 7.0.

[0465] The results are as Figures 15 - 18 shown. The positive control R2800 does not bind to mCDH17. Among the remaining monoclonal antibodies, except for F1-127.8 and F1-41.16 which have good binding to mCDH17, the remaining monoclonal antibodies do not bind to it.

[0466] Example 7 Detection of the cytotoxic activity mediated by monoclonal antibodies

[0467] The cytotoxic activity mediated by monoclonal antibodies against CHO-hCDH17 cells overexpressing was detected by flow cytometry.

[0468] Cultivate sufficient CHO-hCDH17 cells, collect the cells by centrifugation, resuspend the cells after labeling with the fluorescent dye CFSE (BD Bioscience, 565082), and adjust the cell density to 4×10 5 cells / mL for standby. Collect the cultured NK92 cells, resuspend them with the medium of target cells (AsPC-1 cells) after centrifugation, and adjust the cell density to 1.2×10 6 cells / mL. At the same time, dilute the monoclonal antibody and the corresponding positive control antibodies R2800 and R2803 (R2803 is a nanobody with the amino acid sequence shown in SEQ ID NO.598) with the medium of target cells. R0860 is an mIgG2a isotype control antibody (Isotype Control). Dilute from 20 μg / mL in 40-fold serial dilutions to obtain 3 concentration gradients for standby. After resuspending the collected target cells, plate them at 50 μL per well (2×10 4 cells), add 100 μL per well (1.2×10 5 cells) of the collected effector cells (NK92 cells), and then add 50 μL of the diluted antibody. Incubate at 37 °C for 6 hours; then centrifuge to remove the supernatant, resuspend the cells with the diluted Propidium Iodide Solution (Biolegend, 421301), 100 μL per well, incubate in the dark at room temperature for 20 minutes. After resuspension, perform on-machine detection, and then use FITC + PE + percentage to analyze and calculate antibody-mediated cell killing by using the software GraphPad Prism 7.0.

[0469] As Figure 19 shown, no killing activity was detected for the positive antibody. Among the monoclonal antibodies, F1-87.15, F1-127.8, F1-86.9, F1-41.16, F1-127.13, F2-71.18, F2-71.19, F2-155.7, F2-186.1, F2-324.7, F2-84.3, and F2-291.2 possess ADCC (antibody-dependent cell-mediated cytotoxicity) activity.

[0470] Meanwhile, the killing activity of the monoclonal antibody-mediated on AsPC-1 cells endogenously expressing human CDH17 was detected by using the LDH method ((lactate dehydrogenase) method for cytotoxicity detection). Cultivate sufficient AsPC-1 cells, collect the cells by centrifugation, and adjust the cell density to 4×10 5 cells / ml for standby. Collect the cultured NK92 cells, resuspend them with the medium of target cells after centrifugation, and adjust the cell density to 1.2×10 6cells / ml. At the same time, dilute the monoclonal antibody and the corresponding positive control antibodies R2800 and R2803 with the medium of the target cells (AsPC-1 cells), starting from a concentration of 20 μg / mL, and perform 40-fold serial dilutions to obtain 3 concentration gradients for standby. After resuspending the collected target cells, plate them at 50 μL per well (2×10 4 cells), add 100 μL per well (1.2×10 5 cells) of the collected effector cells (NK92 cells), then add 50 μL of the diluted antibody, and incubate at 37 °C for 6 hours; 45 minutes in advance, add 20 μL of lysis buffer to the maximum release wells of the target cells, then centrifuge and transfer 40 μL of the supernatant to a new 96-well transparent flat bottom plate, and add 40 μL of CytoTox (Promega, G1780) reagent to each well, mix well by shaking at room temperature for 30 minutes, then add 40 μL / well of the stop solution, mix well by shaking at room temperature for 5 - 10 minutes, and then read the OD490nm in the microplate reader. Analyze and calculate the antibody-mediated cell killing by using the software GraphPad Prism 7.0.

[0471] As Figure 20 shown, most antibodies in the murine monoclonal antibodies were detected to have ADCC activity, among which F1-87.15, F1-76.12, F2-155.7, F2-186.1, F2-238.14, F2-324.7, F2-55.10, F2-84.3, and F3-1.5 were better.

[0472] Example 8 Detection of Antibody-Mediated Endocytosis Activity of Monoclonal Antibodies

[0473] According to the above detection results, detect the endocytosis activities of F1-87.15, F1-99.29, F1-76.12, F1-86.9, F1-143.7, F2-238.14, F2-55.10, F3-1.5, F3-6.18, F3-36.14, and the positive antibody in AsPC-1 cells.

[0474] Culture sufficient AsPC-1 cells, digest them, centrifuge to collect the cells, adjust the cell density to 1×10 5 cells / mL, plate at 50 μL per well, and incubate overnight. Dilute the antibody starting from 10 μg / mL with the corresponding medium of AsPC-1 cells, perform 3-fold serial dilutions to obtain 8 concentration points, and at the same time dilute the secondary antibody anti-mIgG FC-MMAF (MORADEC, AM-102-AF) to 2 μg / mL. Add the antibody and the secondary antibody to each well at 25 μL per well and mix well, then place them in an incubator at 37 °C and incubate statically for 3 days. Add After mixing with the Luminescent Cell Viability Assay (Promega, G7571) in a microplate shaker, the luminescence was read in a microplate reader, and the endocytic activity of the antibody was analyzed and calculated using the software GraphPad Prism 7.0. The results are as Figure 21 shown.

[0475] Example 9 Preparation of Humanized CDH-17 Murine Conventional Antibodies

[0476] The murine antibody sequences of F2-155.7 and F2-89.7 were used to prepare the chimeric antibodies R4723 and R4850 of the hIgG1 subtype.

[0477] Humanized antibodies were prepared using the murine antibody sequences of R4723 and R4850. Three-dimensional structure homology modeling was performed on the selected sequences, and the structure was determined to be an acceptable structure by methods such as Ramachandran plot. The antibody sequences were compared with the antibody GermLine database to obtain a highly homologous human germline template. The CDRs were transplanted into the corresponding human templates. The three-dimensional structure of the transplanted antibody was simulated and analyzed again. The buried residues, residues that directly interact with the CDR region, and residues that have an important impact on the conformation of the variable region were reverted and mutated, and the chemically unstable amino acid residues in the CDR region were optimized. A series of humanized antibody molecules R4709-R4718 were generated for R4723. The amino acid sequences of the heavy chain variable region of the antibody are shown in Table 24, the amino acid sequences of the light chain variable region are shown in Table 25, and the combination modes of the heavy chain variable region and the light chain variable region are shown in Table 26; a series of humanized antibody molecules R4832-R4843 were generated for R4850. The amino acid sequences of the heavy chain variable region of the antibody are shown in Table 27, the amino acid sequences of the light chain variable region are shown in Table 28, and the combination modes of the heavy chain variable region and the light chain variable region are shown in Table 29.

[0478] Table 24 Amino Acid Sequences of the Humanized Heavy Chain Variable Region of R4723

[0479]

[0480] Table 25 Amino Acid Sequences of the Humanized Light Chain Variable Region of R4723

[0481]

[0482] Table 26 Combination Modes of the Humanized Heavy Chain Variable Region and the Light Chain Variable Region of R4723

[0483] Number Heavy chain Light chain R4709 SEQ ID NO.599 SEQ ID NO.604 R4710 SEQ ID NO.599 SEQ ID NO.605 R4711 SEQ ID NO.600 SEQ ID NO.604 R4712 SEQ ID NO.600 SEQ ID NO.605 R4713 SEQ ID NO.601 SEQ ID NO.604 R4714 SEQ ID NO.601 SEQ ID NO.605 R4715 SEQ ID NO.602 SEQ ID NO.604 R4716 SEQ ID NO.602 SEQ ID NO.605 R4717 SEQ ID NO.603 SEQ ID NO.604 R4718 SEQ ID NO.603 SEQ ID NO.605

[0484] Table 27 Amino Acid Sequences of the Humanized Heavy Chain Variable Region of R4850

[0485]

[0486]

[0487] Humanized antibody light chain variable region sequence of R4850

[0488]

[0489] Combination mode of humanized antibody heavy chain variable region and light chain variable region of R4850

[0490] Number Heavy chain Light chain R4832 SEQ ID NO.606 SEQ ID NO.613 R4833 SEQ ID NO.607 SEQ ID NO.610 R4834 SEQ ID NO.607 SEQ ID NO.611 R4835 SEQ ID NO.607 SEQ ID NO.612 R4836 SEQ ID NO.607 SEQ ID NO.613 R4837 SEQ ID NO.608 SEQ ID NO.611 R4838 SEQ ID NO.608 SEQ ID NO.612 R4839 SEQ ID NO.608 SEQ ID NO.613 R4840 SEQ ID NO.609 SEQ ID NO.611 R4841 SEQ ID NO.609 SEQ ID NO.612 R4842 SEQ ID NO.609 SEQ ID NO.613 R4843 SEQ ID NO.609 SEQ ID NO.614

[0491] Example 10 Detection of binding activity of humanized antibody

[0492] Using CHO-CDH17 expressing human CDH17 as the overexpression positive cell, and using AsPC-1 (human metastatic pancreatic adenocarcinoma cell) and OCUM-1 as the positive cells endogenously expressing CDH17. We used flow cytometry to detect the binding activities of monoclonal antibodies to CHO-CDH17 cells, AsPC-1 cells and OCUM-1 cells.

[0493] 1. Binding to CHO-CDH17 cells

[0494] Culture sufficient CHO-CDH17 cells and collect the cells by centrifugation. At the same time, dilute the monoclonal antibody and the corresponding positive antibody with PBS + 3% FBS, starting from a concentration of 10 μg / mL or 5 μg / mL, and perform 3-fold serial dilution or 4-fold serial dilution to obtain 10 or 8 concentration gradients for standby. Wash the collected cells once with PBS + 3% FBS and then resuspend the cells with PBS + 3% FBS to 2×10 6 cells / mL. Plate the cells in a 96-well plate, 100 μL per well (2×10 5 cells), add 100 μL of the diluted antibody, and incubate at 4°C for 30 minutes; centrifuge to remove the supernatant, wash the cells twice with PBS, then resuspend the cells with the diluted APC-labeled anti-human IgG FC antibody (Biolegend, 409306) or PE-labeled anti-human IgG FC antibody (Biolegend, 409304), incubate at 4°C in the dark for 30 minutes, wash twice with PBS, and then resuspend with 100 μL of PBS, and perform detection on the machine. Then, using the mean fluorescence intensity, analyze and calculate the binding affinity EC50 value of the antibody to CHO-CDH17 by using the software GraphPad Prism 7.0. The results are as follows Figures 22 - 25As shown, compared with the parental antibody R4723, the binding activity of the humanized antibody is basically the same as that of the parental antibody; compared with the parental antibody R4850, the binding activity of some of the humanized antibodies is basically the same as that of the parental antibody. R0861 is the hIgG1 negative control antibody.

[0495] 2. Binding to AsPC-1 cells

[0496] Flow cytometry was used to detect the binding activity of the monoclonal antibody to AsPC-1 cells. After digesting the cells with Versene solution, all the cells were collected by centrifugation and reserved. Starting from a concentration of 10 μg / mL or 5 μg / mL, 3-fold serial dilution or 4-fold serial dilution was performed to obtain 10 or 8 concentration gradients. After co-incubating the antibody with the cells, the subsequent experimental procedures were the same as those for the binding experiment of the antibody to CHO-CDH17 cells. The cells were resuspended with 100 μL of PBS and analyzed by flow cytometry. Then, the average fluorescence intensity was used to calculate the binding affinity EC50 value of the antibody to AsPC-1 cells by analysis with the software GraphPad Prism 7.0.

[0497] The results are as Figures 26 - 29 shown. Compared with the parental antibody R4723, the binding activity of the humanized antibody is basically the same as that of the parental antibody; compared with the parental antibody R4850, the binding activity of some of the humanized antibodies is basically the same as that of the parental antibody. R0861 is the hIgG1 negative control antibody.

[0498] 3. Binding to OCUM-1 cells

[0499] Flow cytometry was used to detect the binding activity of the monoclonal antibody to OCUM-1 cells. After collecting and centrifuging the cells, they were digested with Versene and centrifuged again for reserve. Starting from a concentration of 10 μg / mL or 5 μg / mL, 3-fold serial dilution or 4-fold serial dilution was performed to obtain 10 or 8 concentration gradients. After co-incubating the antibody with the cells, the subsequent experimental procedures were the same as those for the binding experiment of the antibody to CHO-CDH17 cells. The cells were resuspended with 100 μL of PBS and analyzed by flow cytometry. Then, the average fluorescence intensity was used to calculate the binding affinity EC50 value of the antibody to AsPC-1 cells by analysis with the software GraphPad Prism 7.0.

[0500] The results are shown in Figure 30 - Figure 33 , compared with the parental antibody R4723, the binding activity of the humanized antibody is basically the same as that of the parental antibody; compared with the parental antibody R4850, the binding activity of some of the humanized antibodies is basically the same as that of the parental antibody. R0861 is the hIgG1 negative control antibody.

[0501] Example 11. Detection of the binding activity of the humanized antibody to monkey CDH17

[0502] In this example, the binding activity of the monoclonal antibody to cynomolgus CDH17 (Acrobiosystem) was detected. The cynomolgus CDH17 recombinant protein (cynomolgus CDH17) was diluted to 0.5 μg / mL with 50 mmol Coating Buffer in advance, 100 μL per well, and placed overnight at 4°C. The supernatant was discarded, and the plate was washed three times with 1×PBST buffer. Then, PBS + 1% FBS was added at 100 μL / well and incubated at 37°C for 1 hour for blocking. Meanwhile, the antibody was diluted with PBS + 1% FBS, starting from a concentration of 10 μg / mL, and diluted in 5-fold or 3-fold gradients to obtain 8 or 10 concentration gradients for standby. After the blocking was completed, the supernatant was discarded, 100 μL of the diluted antibody was added, and incubated at 37°C for 1 hour. After the incubation, the plate was washed four times with 1×PBST buffer, and then 100 μL of the diluted anti-human IgG antibody conjugated with HRP (Sigma, A0170) was added and incubated at 37°C for 30 minutes. After the incubation, the plate was washed five times with 1×PBST buffer, and the chromogenic solution was added for appropriate chromogenic reaction and then the chromogenic reaction was terminated. The value was read by an enzyme-linked immunosorbent assay (ELISA) reader, and then the EC50 value of the antibody binding to the cynomolgus CDH17 recombinant protein was analyzed and calculated at OD450nm using the software GraphPad Prism 7.0.

[0503] The results are as Figures 34 - 37 shown. Compared with the parental antibody R4723, the binding activity of the humanized antibody is basically the same as that of the parental antibody; compared with the parental antibody R4850, the binding activity of some of the humanized antibodies is relatively close to that of the parental antibody. R0861 is the hIgG1 negative control antibody.

[0504] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An anti-CDH17 antibody or an antigen-binding fragment thereof, characterized in that: The anti-CDH17 antibody or its antigen-binding fragment specifically binds to one or more of CDH17 extracellular domain 1, CDH17 extracellular domain 2, CDH17 extracellular domain 3, CDH17 extracellular domain 4, CDH17 extracellular domain 5, CDH17 extracellular domain 6 and CDH17 extracellular domain 7.

2. The anti-CDH17 antibody or antigen-binding fragment thereof according to claim 1, characterized in that: The antibody or antigen-binding fragment thereof contains the complementarity determining regions HCDR1, HCDR2 and HCDR3 of the heavy chain variable region, and / or the complementarity determining regions LCDR1, LCDR2 and LCDR3 of the light chain variable region; the HCDR1 comprises amino acid residue DY, amino acid residue EY, amino acid residue GY, amino acid residue NY, amino acid residue SG, amino acid residue SH, amino acid residue SY, amino acid residue TS or amino acid residue TY; The HCDR2 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 184-186, 188, 191-199, 202-205 and 208; The HCDR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245, 248, 251, 254, 257, 260 and 278; The LCDR1 comprises amino acid residue NID, amino acid residue NNF, amino acid residue NNW, amino acid residue NY, amino acid residue SDF, amino acid residue SGY, amino acid residue SND, amino acid residue SSA or amino acid residue SY, or an amino acid sequence as shown in any one of SEQ ID NOs. 290, 294, 299, 308, 319 and 332; The LCDR2 comprises amino acid residue AA, amino acid residue DT, amino acid residue FA, amino acid residue GA, amino acid residue KV, amino acid residue RA, amino acid residue RT, amino acid residue SA, amino acid residue ST, amino acid residue WA, amino acid residue YA or amino acid residue YT; The LCDR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 368, 370, 372, 374, 376, 378, 380, 382, ​​384, 386, 388, 390, 392, 394 and 396; Optionally, the HCDR1, HCDR2 and HCDR3 comprise amino acid sequences consistent with HCDR1, HCDR2 and HCDR3 of the heavy chain variable region shown in any one of SEQ ID NO.1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37 or 39, and the LCDR1, LCDR2 and LCDR3 comprise amino acid sequences consistent with LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in any one of SEQ ID NO.2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 or 40; Optionally, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3 of the variable region is defined by any one system or a combination of multiple definition systems of Kabat, Chothia, IMGT, ABM or Contact; Optionally, as defined by IMGT: The HCDR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 45, 50, 54, 58, 63, 67, 72, 77, 81, 85, 90, 95, 100, 104, 107 and 113; The HCDR2 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 162, 167, 171, 175, 179, 183, 189 and 190; The HCDR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262 and 266; The LCDR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 286, 288, 292, 293, 296, 298, 301, 303, 305, 307, 310, 312, 321, 322 and 333; The LCDR2 comprises amino acid residue AA, amino acid residue DT, amino acid residue FA, amino acid residue GA, amino acid residue KV, amino acid residue RA, amino acid residue RT, amino acid residue SA, amino acid residue ST, amino acid residue WA, amino acid residue YA or amino acid residue YT; The LCDR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395 and 397.

3. The anti-CDH17 antibody or antigen-binding fragment thereof according to claim 1 or 2, characterized in that: The complementary determining region of the anti-CDH17 antibody or antigen-binding fragment thereof includes any one of the following (a) to (t): (a) HCDR1 comprises amino acid residue SY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.185, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.209, LCDR1 comprises amino acid residue SND, LCDR2 comprises amino acid residue YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.386; or, (b) HCDR1 comprises amino acid residue EY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.192, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.278, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.319, LCDR2 comprises amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.376; or, (c) HCDR1 comprises amino acid residue SY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.203, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.212, LCDR1 comprises amino acid residue NNF, LCDR2 comprises amino acid residue RT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.378; or, (d) HCDR1 comprises amino acid residue SY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.196, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.215, LCDR1 comprises amino acid residue SY, LCDR2 comprises amino acid residue DT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.372; or, (e) HCDR1 comprises amino acid residues GY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.197, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.218, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.332, LCDR2 comprises amino acid residues ST, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.374; or, (f) HCDR1 comprises the amino acid residue SH, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.208, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.221, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.290, LCDR2 comprises the amino acid residue RA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.394; or, (g) HCDR1 comprises amino acid residue TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.191, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.224, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.332, LCDR2 comprises amino acid residue ST, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.374; or, (h) HCDR1 comprises amino acid residues GY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.195, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.227, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.294, LCDR2 comprises amino acid residues YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.382; or, (i) HCDR1 comprises amino acid residues SG, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.205, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.230, LCDR1 comprises amino acid residues SSA, LCDR2 comprises amino acid residues SA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.392; or, (j) HCDR1 comprises the amino acid residue TS, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.186, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.233, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.299, LCDR2 comprises the amino acid residue KV, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.370; or, (k) HCDR1 comprises amino acid residue EY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.194, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.278, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.319, LCDR2 comprises amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.376; or, (1) HCDR1 comprises amino acid residue SY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.199, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.236, LCDR1 comprises amino acid residue SY, LCDR2 comprises amino acid residue DT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.368; or, (m) HCDR1 comprises amino acid residue EY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.194, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.239, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.319, LCDR2 comprises amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.376; or, (n) HCDR1 comprises amino acid residues DY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.193, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.242, LCDR1 comprises amino acid residues NNW, LCDR2 comprises amino acid residues GA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.396; or, (o) HCDR1 comprises amino acid residue TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.202, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.245, LCDR1 comprises amino acid residue NY, LCDR2 comprises amino acid residue YT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.388; or, (p) HCDR1 comprises amino acid residues NY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.198, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.248, LCDR1 comprises amino acid residues SDF, LCDR2 comprises amino acid residues YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.384; or, (q) HCDR1 comprises amino acid residues TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.204, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.251, LCDR1 comprises amino acid residues SGY, LCDR2 comprises amino acid residues AA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.380; or, (r) HCDR1 comprises amino acid residues TY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.204, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.254, LCDR1 comprises amino acid residues SGY, LCDR2 comprises amino acid residues AA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.380; or, (s) HCDR1 comprises the amino acid residue NY, HCDR2 comprises the amino acid sequence set forth in SEQ ID NO.184, HCDR3 comprises the amino acid sequence set forth in SEQ ID NO.257, LCDR1 comprises the amino acid sequence set forth in SEQ ID NO.308, LCDR2 comprises the amino acid residue FA, and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO.382; or, (t) HCDR1 comprises amino acid residue DY, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.188, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.260, LCDR1 comprises amino acid residue NID, LCDR2 comprises amino acid residue SA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.390; Optionally, according to the IMGT definition, the complementarity determining region of the anti-CDH17 antibody or antigen-binding fragment thereof includes any one of the following (a') to (t'): (a') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.63, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.141, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.223, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.292, LCDR2 comprises amino acid residue RA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.395; or, (b') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.113, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.125, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.266, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.322, LCDR2 comprises amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.377; or, (c') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.50, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.129, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.214, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.288, LCDR2 comprises amino acid residue RT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.379; or, (d') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.54, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.133, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.217, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.333, LCDR2 comprises amino acid residue DT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.373; or, (e') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.58, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.137, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.220, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.293, LCDR2 comprises the amino acid residue ST, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.375; or, (f') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.45, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.121, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.211, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.286, LCDR2 comprises the amino acid residue YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.387; or, (g') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.107, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.145, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.226, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.293, LCDR2 comprises the amino acid residue ST, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.375; or, (h') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.67, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.149, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.229, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.296, LCDR2 comprises the amino acid residue YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.383; or, (i') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.72, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.153, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.232, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.298, LCDR2 comprises the amino acid residue SA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.393; or, (j') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.77, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.157, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.235, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.301, LCDR2 comprises amino acid residues KV, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.371; or, (k') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.113, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.189, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.266, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.322, LCDR2 comprises amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.377; or, (1') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.81, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.162, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.238, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.333, LCDR2 comprises amino acid residue DT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.369; or, (m') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.113, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.189, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.241, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.322, LCDR2 comprises amino acid residue WA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.377; or, (n') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.85, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.167, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.244, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.303, LCDR2 comprises the amino acid residue GA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.397; or, (o') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.90, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.171, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.247, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.305, LCDR2 comprises amino acid residue YT, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.389; or, (p') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.95, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.175, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.250, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.307, LCDR2 comprises the amino acid residue YA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.385; or, (q') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.107, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.190, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.253, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.321, LCDR2 comprises amino acid residue AA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.381; or, (r') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.107, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.190, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.256, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.321, LCDR2 comprises amino acid residue AA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.381; or, (s') HCDR1 comprises the amino acid sequence shown in SEQ ID NO.100, HCDR2 comprises the amino acid sequence shown in SEQ ID NO.179, HCDR3 comprises the amino acid sequence shown in SEQ ID NO.259, LCDR1 comprises the amino acid sequence shown in SEQ ID NO.310, LCDR2 comprises the amino acid residue FA, and LCDR3 comprises the amino acid sequence shown in SEQ ID NO.383; or, (t') HCDR1 includes the amino acid sequence shown in SEQ ID NO.104, HCDR2 includes the amino acid sequence shown in SEQ ID NO.183, HCDR3 includes the amino acid sequence shown in SEQ ID NO.262, LCDR1 includes the amino acid sequence shown in SEQ ID NO.312, LCDR2 includes amino acid residue SA, and LCDR3 includes the amino acid sequence shown in SEQ ID NO.

391.

4. The anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, characterized in that: The antibody contains a heavy chain framework region and / or a light chain framework region, and the heavy chain framework region and / or the light chain framework region are derived from at least one of a murine antibody, a human antibody, a primate antibody or a mutant thereof.

5. The anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, characterized in that: The framework region of the heavy chain variable region includes HFR1, HFR2, HFR3 and HFR4, and the framework region of the light chain variable region includes LFR1, LFR2, LFR3 and LFR4, wherein, The HFR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 398 to 415, or comprises a sequence having at least 78% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs. 398 to 415; and / or, the HFR2 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 416, 418, 422, 426, 428, 431, 433, 436, 439, 442 and 445-448, or comprises a sequence having at least 70% sequence identity with an amino acid sequence as shown in any one of SEQ ID NOs. 416, 418, 422, 426, 428, 431, 433, 436, 439, 442 and 445-448; and / or, the HFR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 472, 474, 477, 479, 481, 483, 485 and 487, or comprises a sequence having at least 72% sequence identity to an amino acid sequence as shown in any one of SEQ ID NOs. 449, 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 472, 474, 477, 479, 481, 483, 485 and 487; and / or, the HFR4 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 488 to 493, or comprises a sequence having at least 86% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs. 488 to 493; and / or, the LFR1 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524 and 526, or comprises a sequence having at least 70% sequence identity to an amino acid sequence as shown in any one of SEQ ID NOs. 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524 and 526; and / or, the LFR2 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 528, 533, 535, 537, 539, 541, 543 and 549 to 552, or comprises a sequence having at least 80% sequence identity with an amino acid sequence as shown in any one of SEQ ID NOs. 528, 533, 535, 537, 539, 541, 543 and 549 to 552; and / or, the LFR3 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 581 and 582, or comprises a sequence having at least 79% sequence identity to an amino acid sequence as shown in any one of SEQ ID NOs. 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 581 and 582; and / or, the LFR4 comprises an amino acid sequence as shown in any one of SEQ ID NOs. 586 to 590, or comprises a sequence having at least 95% sequence identity with the amino acid sequence as shown in any one of SEQ ID NOs. 586 to 590; Optionally, according to the IMGT definition: the heavy chain framework region of the anti-CDH17 antibody or antigen-binding fragment thereof includes any one of the following (A) to (T): (A) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.414, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.417, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.450, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.490; (B) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.405, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.444, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.452, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (C) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.399, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.419, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.454, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (D) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.414, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.420, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.456, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493; (E) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.404, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.421, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.458, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.492; (F) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.411, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.423, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.460, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493; (G) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.407, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.424, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.462, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493; (H) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.401, HFR2 comprises the amino acid sequence shown in SEQ ID NO.425, HFR3 comprises the amino acid sequence shown in SEQ ID NO.464, and HFR4 comprises the amino acid sequence shown in SEQ ID NO.488; (I) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.409, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.427, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.466, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (J) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.415, HFR2 comprises the amino acid sequence shown in SEQ ID NO.429, HFR3 comprises the amino acid sequence shown in SEQ ID NO.468, and HFR4 comprises the amino acid sequence shown in SEQ ID NO.493; (K) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.403, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.444, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.470, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (L) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.410, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.430, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.471, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (M) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.406, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.432, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.473, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (N) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.400, HFR2 comprises the amino acid sequence shown in SEQ ID NO.434, HFR3 comprises the amino acid sequence shown in SEQ ID NO.475, and HFR4 comprises the amino acid sequence shown in SEQ ID NO.492; (O) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.412, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.435, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.476, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.492; (P) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.408, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.437, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.478, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.491; (Q) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.398, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.438, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.480, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.489; (R) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.398, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.440, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.482, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493; (S) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.413, HFR2 comprises the amino acid sequence shown in SEQ ID NO.441, HFR3 comprises the amino acid sequence shown in SEQ ID NO.484, and HFR4 comprises the amino acid sequence shown in SEQ ID NO.492; (T) the HFR1 comprises the amino acid sequence shown in SEQ ID NO.402, the HFR2 comprises the amino acid sequence shown in SEQ ID NO.443, the HFR3 comprises the amino acid sequence shown in SEQ ID NO.486, and the HFR4 comprises the amino acid sequence shown in SEQ ID NO.493; Optionally, according to the IMGT definition, the light chain framework region of the anti-CDH17 antibody or antigen-binding fragment thereof includes any one of the following (A') to (T'): (A') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.495, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.553, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.555, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (B') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.527, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.546, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.585, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (C') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.497, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.529, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.557, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.586; (D') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.499, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.530, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.559, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (E') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.501, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.547, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.583, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (F') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.525, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.531, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.561, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.588; (G') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.503, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.547, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.583, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (H') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.505, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.532, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.563, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (I') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.507, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.534, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.565, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.589; (J') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.509, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.536, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.567, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (K') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.527, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.546, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.585, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (L') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.511, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.538, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.569, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.589; (M') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.513, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.546, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.585, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (N') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.515, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.540, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.571, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.590; (O') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.517, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.542, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.573, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.589; (P') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.519, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.544, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.575, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587, (Q') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.523, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.548, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.584, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (R') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.523, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.548, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.584, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (S') the LFR1 comprises the amino acid sequence shown in SEQ ID NO.525, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.545, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.577, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.587; (T') The LFR1 comprises the amino acid sequence shown in SEQ ID NO.521, the LFR2 comprises the amino acid sequence shown in SEQ ID NO.553, the LFR3 comprises the amino acid sequence shown in SEQ ID NO.579, and the LFR4 comprises the amino acid sequence shown in SEQ ID NO.

587.

6. The anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, characterized in that: The anti-CDH17 antibody or antigen-binding fragment thereof has an amino acid sequence as shown in any one of SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 599-603, 606-609, or a heavy chain variable region having at least 64% sequence identity to an amino acid sequence as shown in any one of SEQ ID NO. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 599-603, 606-609; and / or, the anti-CDH17 antibody or antigen-binding fragment thereof has an amino acid sequence as shown in any one of SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 604, 605, 610-614, or a light chain variable region having at least 70% sequence identity to an amino acid sequence as shown in any one of SEQ ID NO. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 604, 605, 610-614; Optionally, the anti-CDH17 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of any of the following: (a") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.11; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.12; (b") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.599; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.604; (c") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.5; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.6; (d") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.7; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.8; (e") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.9; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.10; (f") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.1; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.2; (g") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.13; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.14; (h") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.15; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.16; (i") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.17; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.18; (j") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.19; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.20; (k") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.21; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.22; (l") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.23; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.24; (m") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.25; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.26; (n") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.27; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.28; (o") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.29; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.30; (p") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.31; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.32; (q") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.33; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.34; (r") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.35; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.36; (s") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.37; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.38; (t") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.39; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.40; (u") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.3; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.4; (v") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.599; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (w") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.600; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (x") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.600; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (y") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.601; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (z") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.601; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (a'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.602; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (b') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.602; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (c'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.603; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (d'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.603; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (e'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.606; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (f') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.610; (g') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.611; (h') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.612; (i'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (j') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.608; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.611; (k') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.608; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.612; (l') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.608; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (m"') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.609; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.611; (n"') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.609; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.612; (o') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.609; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (p"') the heavy chain variable region of the amino acid sequence shown in SEQ ID NO.610; and the light chain variable region of the amino acid sequence shown in SEQ ID NO.

614.

7. The anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, characterized in that: The anti-CDH17 antibody or antigen-binding fragment thereof comprises a partial or complete sequence of a constant region, wherein the constant region is derived from at least one of a murine antibody, a human antibody, a primate antibody or a mutant thereof; Optionally, the heavy chain constant region contains a sequence of a partial or complete constant region of any one of IgG1, IgG2a, IgG2b, IgG3, IgG4, IgA, IgM, IgE or IgD; the light chain constant region of the antibody is a κ or λ chain; Optionally, the heavy chain constant region contains the constant region sequence of IgG1, IgG2a or IgG2b; Optionally, the heavy chain constant region contains a sequence of part or all of the constant region of IgG1, and the anti-CDH17 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of any one of the following: (a") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.599; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.604; (c") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.5; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.6; (t") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.39; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.40; (u") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.1; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.2; (v") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.599; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (w") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.600; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (x") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.600; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (y") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.601; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (z") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.601; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (a'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.602; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (b') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.602; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (c'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.603; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.604; (d'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.603; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.605; (e'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.606; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (f') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.610; (g') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.611; (h') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.612; (i'') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.607; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (j') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.608; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.611; (k') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.608; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.612; (l') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.608; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (m"') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.609; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.611; (n"') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.609; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.612; (o') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.609; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.613; (p"') a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.610; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.614; Optionally, the heavy chain constant region contains a sequence of part or all of the constant region of IgG2a, and the anti-CDH17 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of any one of the following: (d") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.7; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.8; (f") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.11; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.12; (g") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.13; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.14; (i") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.17; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.18; (j") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.19; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.20; (n") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.27; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.28; (o") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.29; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.30; (p") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.31; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.32; (q") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.33; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.34; (r") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.35; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.36; (s") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.37; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.38; Optionally, the heavy chain constant region contains a sequence of part or all of the constant region of IgG2b, and the anti-CDH17 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region of any one of the following: (b") a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.3; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.4; (e") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.9; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.10; (h") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.15; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.16; (k") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.21; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.22; (l") a heavy chain variable region of the amino acid sequence shown in SEQ ID NO.23; and a light chain variable region of the amino acid sequence shown in SEQ ID NO.24; (m"): a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO.25; and a light chain variable region having an amino acid sequence as shown in SEQ ID NO.

26.

8. The anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, characterized in that: The antigen binding fragment includes one or more of F(ab')2, Fab', Fab, Fv, scFv, dsFv and the minimum recognition unit of an antibody.

9. The anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, characterized in that: The anti-CDH17 antibody or antigen-binding fragment thereof has one or more of the following properties (i) to (iv): (i) binds to human CDH17 with an EC50 of no more than 1 μg / mL, as determined by flow cytometric fluorescence sorting; (ii) binds to monkey CDH17 with an EC50 of no more than 1 μg / mL, as determined by ELISA technology; (iii) having ADCC activity; (iv) It has the activity of mediating cellular endocytosis.

10. An anti-CDH17 antibody or an antigen-binding fragment thereof, characterized in that: It competitively binds to CDH17 with the anti-CDH17 antibody according to any one of claims 1 to 9, or the epitope it binds to the CDH17 antigen is the same as the epitope of the anti-CDH17 antibody according to any one of claims 1 to 9 that binds to the CDH17 antigen.

11. A biomaterial, characterized in that: The biological material comprises any one of the following (i) to (vi): (i) a multispecific antibody, comprising the anti-CDH17 antibody according to any one of claims 1 to 11; (ii) a chimeric antigen receptor, comprising an extracellular region, wherein the extracellular region comprises an antigen binding domain; and the antigen binding domain comprises the anti-CDH17 antibody or antigen binding fragment thereof according to any one of claims 1 to 11; (iii) a nucleic acid molecule encoding the anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or the multispecific antibody according to (i), or the chimeric antigen receptor according to (ii); (iv) a vector carrying the nucleic acid molecule described in (iii); (v) a recombinant cell, characterized in that the recombinant cell expresses the anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, or expresses the multispecific antibody according to (i), or expresses the chimeric antigen receptor according to (ii), or contains the nucleic acid molecule according to (iii), or contains the vector according to (iv); (vi) An engineered immune cell, characterized in that the immune cell expresses the chimeric antigen receptor described in (ii) or contains a nucleic acid molecule encoding the chimeric antigen receptor described in (ii).

12. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, or the biomaterial according to claim 11; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

13. Use of the anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, or the biomaterial according to claim 11, or the pharmaceutical composition according to claim 12 in any one of the following: (Ⅰ) Detection of CDH17 or cells expressing CDH17; (II) preparing a product for detecting CDH17 or cells expressing CDH17; (III) for treating, preventing or alleviating a disease, disorder or condition associated with CDH17; (IV) Preparing a pharmaceutical composition for treating, preventing or alleviating a disease, disorder or condition associated with CDH17.

14. A method for producing the anti-CDH17 antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, characterized in that: The method comprises the following steps: (a) culturing the recombinant cell of claim 12 under conditions of expressing an anti-CDH17 antibody or an antigen-binding fragment thereof; (b) isolating and purifying the anti-CDH17 antibody or antigen-binding fragment thereof obtained in step (a).

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