Antibody-drug conjugate as well as preparation method and anti-tumor application thereof

Abstract

The invention relates to an antibody-drug conjugate as well as a preparation method and an application thereof in tumor resistance, in particular to an anti-HER3 antibody or an antigen binding fragment thereof and an antibody-drug conjugate connected with the antibody. The antibody-drug conjugate has a structure as shown in Ab-(L-D) n, and is covalently linked with an effective load with cytotoxicity through a linker. The anti-HER3 antibody or the antigen binding fragment thereof and the antibody-drug conjugate can be used for preparing a therapeutic agent for diagnosing, preventing and treating tumor diseases.

Description

Antibody-drug conjugate and its preparation method and use in anti-tumor Technical Field The present disclosure relates to anti-HER3 antibodies and antibody-drug conjugates, which connect antibodies with specific targeting and anti-tumor drugs or toxins through a linker with improved hydrophobicity, and exert anti-tumor effects by targeting tumor cells expressing HER3. Background Art Antibody-drug conjugate (ADC) is a carrier-based chemotherapy that can selectively deliver effective cytotoxic drugs to tumors / cancer cells (Antibody-Drug Conjugates: The Last Decade, Nicolas Joubert et al., Pharmaceuticals (Basel). 2020 Sep 14; 13(9): 245.). The marketed ADC drugs Enhertu and Sacituzumab govitecan have excellent effects in treating tumors, especially malignant tumors. Both use DNA topoisomerase inhibitor camptothecin derivatives that are more hydrophobic than microtubule inhibitors (such as MMAE, MMAF) as cytotoxic drugs. Sacituzumab govitecan uses MCC-triazole spacer-PEG7-lysine-PABC as a linker, which is decomposed in the cell lysosome to release camptothecin SN38 (US13 / 948,732); Enhertu developed by AstraZeneca / Daiichi Sankyo uses a cathepsin B-activated GGFG (an amino acid sequence consisting of glycine-glycine-phenylalanine-glycine connected by peptide bonds) tetrapeptide as a linker, and introduces a self-cleavage structure to release the exatecan derivative Dxd (Yusuke Ogitani et al., Clin Cancer Res (2016) 22(20): 5097–5108.). However, due to the rigid structure and poor hydrophilicity of DNA topoisomerase inhibitors, the above ADC molecules produce a large number of aggregates during preparation, which directly affects the safety and efficacy of ADC treatment. HER3 (NCBI, Gene ID: 2065) is a member of the HER (EGFR / ErbB) receptor family, which consists of four closely related type 1 transmembrane receptors (EGFR, HER2, HER3 and HER4). Monoclonal antibodies and small molecule inhibitors targeting the tyrosine kinase activity of EGFR and HER2 have shown clinical benefits in the treatment of several types of cancer, but their clinical efficacy is limited by drug resistance. HER3 occupies a special position in the EGFR family. It has almost no intracellular tyrosine kinase activity and cannot form homodimers. It cannot function alone. Its kinase activity depends on forming heterodimers with other members of the EGFR family, such as EGFR or HER2. When HER3 protein and HER2 form heterodimers, its downstream pathways will be activated. Inhibiting the activation of HER3 downstream pathways can indirectly inhibit the growth, proliferation and metastasis of cancer cells. Therefore, HER3 plays an important role in the resistance to EGFR and HER2 targeted therapies (Clin Cancer Res; 20 (6) March 15, 2014). Currently, the only ADC drug targeting HER3 under development is Daiichi Sankyo's Patritumab Deruxtecan (HER3-DXd, codenamed U3-1402). The ADC structure is derived from the HER3 monoclonal antibody Patritumab and the topoisomerase 1 inhibitor exatecan. The drug (Deruxtecan) is spliced ​​with a cleavable linker GGFG, and is designed to meet the unmet clinical needs of a large group of patients with non-small lung cancer who are resistant to EGFR-TKIs and have failed chemotherapy. Therefore, there is still a need for new antibodies and antibody-drug conjugates targeting HER3. Summary of the invention The present disclosure provides an anti-HER3 antibody or an antigen-binding fragment thereof, comprising at least one VL and VH, wherein the CDR1 of the VL comprises the amino acid sequence shown in SEQ ID NO:1, the CDR2 comprises the amino acid sequence shown in SEQ ID NO:2, and the CDR3 comprises the amino acid sequence shown in SEQ ID NO:3; the CDR1 of the VH comprises the amino acid sequence shown in SEQ ID NO:4, the CDR2 comprises the amino acid sequence that differs from the amino acid sequence shown in SEQ ID NO:5 by no more than 5, 4, 3, 2, 1, 0 mutations, and the CDR3 comprises the amino acid sequence shown in SEQ ID NO:6. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, CDR2 of VH comprises one or more mutations selected from (a) or (b); (a) C52N, T62N, T66K and G67S; (b) C52Y, T62N, T66K and G67S. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, CDR2 of VH comprises a mutation of (a) or (b): (a) C52N, T62N, T66K and G67S; (b) C52Y, T62N, T66K and G67S. The present disclosure provides a nucleic acid encoding the above-mentioned anti-HER3 antibody or an antigen-binding fragment thereof. The present disclosure provides a vector comprising a nucleic acid encoding the above-mentioned anti-HER3 antibody or an antigen-binding fragment thereof. The present disclosure provides a host cell comprising the above-mentioned nucleic acid and / or vector. The present disclosure provides an antibody-drug conjugate having a structure shown in Formula I, Ab-(LD)n(I) or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, wherein Ab is the aforementioned anti-HER3 antibody or an antigen-binding fragment thereof; L is a linker covalently linked to Ab and D respectively; D is the effective load; n is a value between 1 and 10. The present disclosure provides a method for preparing an antibody-drug conjugate, comprising the following steps: the antibody or its antigen-binding fragment is subjected to reduction treatment, the interchain disulfide bonds are at least partially reduced, and the reaction is carried out with the reactive group of the linker in the linker-payload to obtain an antibody-drug conjugate having a structure shown in Formula I, Ab-(LD)n(I) or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, wherein Ab is the above-mentioned anti-HER3 antibody or an antigen-binding fragment thereof; L is a linker covalently linked to Ab and D respectively; D is the effective load; n is a value between 1 and 10. The present disclosure provides a pharmaceutical composition, which includes the above-mentioned anti-HER3 antibody or its antigen-binding fragment or antibody-drug conjugate, or its isomer, isotope variant, pharmaceutically acceptable salt, prodrug, solvate, or a combination thereof, and a pharmaceutically acceptable excipient. The present disclosure provides a kit, which includes the above-mentioned anti-HER3 antibody or its antigen-binding fragment or antibody-drug conjugate, or its isomer, isotope variant, pharmaceutically acceptable salt, prodrug, solvate, or a combination thereof. The present disclosure provides a use of the above-mentioned anti-HER3 antibody or its antigen-binding fragment, antibody-drug conjugate, antibody-drug conjugate prepared by the above-mentioned method, pharmaceutical composition or the above-mentioned kit in preparing a therapeutic agent for diagnosing, preventing and treating tumor diseases. In some embodiments, the use includes use in the preparation of a drug targeting HER3. In some embodiments, the tumor comprises a solid tumor expressing HER3. The present disclosure provides a method for diagnosing, preventing and treating tumor diseases, comprising administering a therapeutic dose of a therapeutic agent to a subject, wherein the therapeutic agent comprises the above-mentioned anti-HER3 antibody or antigen-binding fragment thereof, antibody-drug conjugate, antibody-drug conjugate prepared by the above-mentioned method, the above-mentioned pharmaceutical composition or kit. BRIEF DESCRIPTION OF THE DRAWINGS In FIG. 1 , A and B respectively show the size exclusion chromatogram and the hydrophobic chromatography chromatogram of the L1H5 antibody (naked antibody) prepared in Example 4; Figure 2 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the antibody-drug conjugate L1H5-LP3 prepared in Example 6; Figure 3 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the antibody-drug conjugate L1H5-LP1 prepared in Example 7; Figure 4 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the antibody-drug conjugate L1H5-LP2 prepared in Example 8; FIG5 shows a flow cytometry statistical diagram of the Mu4O3 antibody prepared in Example 4 and cells with different HER3 expression levels; FIG6 shows the immunofluorescence image of the Mu4O3 antibody prepared in Example 4 in HER3-GFP Tag overexpressing 293T cells; FIG7 shows the cell survival curve of the Mu4O3 antibody prepared in Example 4 in the killing SW620 cell test; FIG8 shows the affinity curves of L1H4, L1H5, L2H4, L2H5, L4H4, L4H5 and L4H7 antibodies prepared in Example 4 in the MDA-MB-453 cell line; FIG9 shows the affinity curves of L1H4, L1H5, L2H4, L2H5, L4H4, L4H5 and L4H7 antibodies prepared in Example 4 in the SW620 cell line; FIG10 shows the cell proliferation inhibition rate of the L1H5 antibody prepared in Example 4, the reference antibody and the blank control in the SK-BR-3 cell line; FIG11 shows the tumor volume-time curves of L1H5, reference antibody and blank control PBS prepared in Example 4 in BT-474 breast cancer mouse model; FIG12 shows the cell survival curves of the antibody-drug conjugates L1H4-LP1, L1H5-LP1 and L4H4-LP1 prepared in Example 7 and the reference ADC (positive control) prepared in Comparative Example 1 in the SW620 cell line; FIG13 shows the cell survival curves of the L1H5 antibody prepared in Example 4, the L1H5-LP3 prepared in Example 6, the reference antibody and the reference ADC prepared in Comparative Example 1 in the killing test on the SK-BR-3 cell line; FIG14 shows the cell survival curves of the L1H5 antibody prepared in Example 4, the L1H5-LP3 prepared in Example 6, the reference antibody and the reference ADC prepared in Comparative Example 1 in the killing test on the BXPC-3 cell line; FIG15 shows the cell survival curves of the antibody-drug conjugate L1H5-LP1 prepared in Example 7, L1H5-LP2 prepared in Example 8, and the reference ADC prepared in Comparative Example 1 in the HCT-15 cell line; Figure 16 shows the tumor volume-time change curves of the antibody-drug conjugate L1H5-LP prepared in Example 7, L1H5-LP2 prepared in Example 8, the reference ADC prepared in Comparative Example 1, and the blank control group in the HCT-15 colon cancer mouse model; Figure 17 shows the tumor volume-time change curves of the mouse colon cancer PDX model after treatment with the reference ADC prepared in Comparative Example 1, L1H5-LP3 prepared in Example 6, L1H5-LP1 prepared in Example 7, Dxd isotype control ADC prepared in Comparative Example 4, and LP3 isotype control ADC prepared in Comparative Example 5; Figure 18 shows the tumor volume-time change curve of the mouse EGFR-TKI-resistant lung adenocarcinoma PDX model after treatment with the reference ADC prepared in Comparative Example 1, L1H5-LP3 prepared in Example 6, L1H5-LP1 prepared in Example 7, Dxd isotype control ADC prepared in Comparative Example 4, and LP3 isotype control ADC prepared in Comparative Example 5; Figure 19 shows the tumor volume-time change curves of the mouse colon cancer CDX model after treatment with L1H5-DXd prepared in Comparative Example 3, the reference antibody-LP3 prepared in Comparative Example 2, L1H5-LP3 prepared in Example 6, and the reference ADC prepared in Comparative Example 1, and a negative control PBS group is set; FIG20 is a partial enlarged view of FIG19 after removing the negative control PBS group; Figure 21 shows a graph of tumor volume-time changes in the mouse pancreatic cancer CDX model after treatment with the reference ADC prepared in Comparative Example 1, L1H5-LP3 prepared in Example 6, L1H5-LP1 prepared in Example 7, Dxd isotype control ADC prepared in Comparative Example 4, and LP3 isotype control ADC prepared in Comparative Example 5; FIG22 shows a comparison of the hydrophobicity measurements of the L1H5 antibody prepared in Example 4, the antibody-drug conjugate L1H5-LP3 prepared in Example 6, the reference antibody, and the reference ADC prepared in Comparative Example 1; Figure 23 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the reference ADC prepared in Comparative Example 1; Figure 24 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the antibody-drug conjugate reference antibody-LP3 prepared in Comparative Example 2; Figure 25 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the antibody-drug conjugate L1H5-DXd prepared in Comparative Example 3; Figure 26 A and B respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the Dxd isotype control ADC prepared in Comparative Example 4; A and B in Figure 27 respectively show the size exclusion chromatogram and hydrophobic chromatography detection spectrum of the aggregates in the LP3 isotype control ADC prepared in Comparative Example 5. DETAILED DESCRIPTION Unless otherwise indicated, all numbers used in this specification and claims to indicate content, concentration, ratio, mass, volume, time, temperature, thickness, technical effect, etc. should be understood as modified by the term "about" or "approximately" in any case. Therefore, unless otherwise indicated, the numerical parameters listed in the following specification and the attached claims are approximate values. For those skilled in the art, it can vary according to the desired properties and effects sought to be obtained through the present disclosure, and each numerical parameter should be interpreted according to the number of significant digits and conventional rounding methods or in a manner understood by those skilled in the art. Although the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximate, the numerical values ​​set forth in the specific embodiments are provided as accurately as possible. However, any numerical value will inherently contain certain errors, which are necessarily caused by the standard deviation found in its corresponding test measurements. Each numerical range given in this specification will include each narrower numerical range that falls within the broader numerical range, just as if these narrower numerical ranges were all clearly written herein. [Antibody] The present disclosure provides an anti-HER3 antibody or an antigen-binding fragment thereof, comprising at least one light chain variable region (Variable Region of Light Chain, VL) and one heavy chain variable region (Variable Region of Heavy Chain, VH), wherein the VL and VH can be paired and bound. As used herein, the term "antibody" means any antigen binding molecule or molecular complex comprising at least one complementary determining region that specifically binds to or interacts with a specific antigen (e.g., HER3). The term "antibody" includes immunoglobulin molecules and polymers thereof (e.g., IgM), which include four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain includes a heavy chain variable region and a heavy chain constant region. The heavy chain constant region includes three domains, i.e., CH1, CH2, and CH3. Each light chain includes a light chain variable region and a light chain constant region. The light chain constant region includes a domain (CL1). The VH and VL regions can be further divided into hypervariable regions, called complementary determining regions (CDRs), interspersed with more conservative regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. As used herein, the term "antibody" also includes the antigen binding fragment of a complete antibody molecule. The term "antigen binding fragment" includes any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen binding fragment of an antibody can be obtained from, for example, a complete antibody molecule using any suitable standard technology. Non-limiting examples of antigen binding fragments include: Fab fragments, F(ab')2 fragments, Fd fragments, Fv fragments, single-chain Fv (scFv) molecules, dAb fragments and minimum recognition units, which consist of amino acid residues of the hypervariable region (e.g., separated complementary determining regions (CDRs), such as CDR3 peptides) or restrictive FR3-CDR3-FR4 peptides of simulated antibodies. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, mini antibodies, nano antibodies (e.g., monovalent nano antibodies, divalent nano antibodies, etc.) are also included in "antigen binding fragments" as herein. The antigen-binding fragment of an antibody will generally comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR adjacent to or in frame with one or more framework sequences. In an antigen-binding fragment having a VH domain associated with a VL domain, the VH and VL domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer and contain a VH-VH, VH-VL or VL-VL dimer. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain. In the anti-HER3 antibody or antigen-binding fragment thereof, CDR1-3 of VL comprises the amino acid sequences shown in SEQ ID NO: 1-3, respectively; CDR1 of VH comprises the amino acid sequence shown in SEQ ID NO: 4, CDR2 of VH comprises an amino acid sequence that differs from the amino acid sequence shown in SEQ ID NO: 5 by no more than 5, 4, 3, 2, 1, 0 mutations, and CDR3 of VH comprises the amino acid sequence shown in SEQ ID NO: 6. The CDRs of the anti-HER3 antibody or antigen-binding fragment thereof are defined and numbered using the Kabat system. In some embodiments, the CDR2 of VH comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 5 by no more than 4, 3, 2, 1, or 0 mutations. In some embodiments, the CDR2 of VH comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 5 by no more than 4 mutations. In some embodiments, the CDR2 of VH comprises an amino acid sequence as shown in SEQ ID NO: 5. The CDR2 of VH contains a mutation, and the mutation is selected from any one or a combination of C52N / Y, T62N, T66K and G67S. Among them, C52N / Y means that the amino acid "C" at position 52 mutates to "N" or "Y". Herein, "C", "N", "Y", "T", "K", "G", and "S" are standard amino acids represented by single letters, representing cysteine, asparagine, tyrosine, threonine, lysine, glycine, and serine, respectively. Among them, the first amino acid refers to the first amino acid from the amino terminus to the carboxyl terminus of VH, and the amino acids at other positions are deduced by analogy. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, the CDR2 of VH comprises mutations C52N, T62N, T66K and G67S. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, the CDR2 of VH comprises mutations C52Y, T62N, T66K and G67S. In the anti-HER3 antibody or antigen-binding fragment thereof, the variable region also includes a framework region (FR), which is a region with relatively small changes in amino acid composition and arrangement order except for CDR. In some embodiments, there is no mutation in the framework region or there is a mutation that does not affect the binding of the antibody variable region to the antigen, and the mutation can improve the binding affinity of the antibody to the antigen, or remain substantially unchanged. In some embodiments, the anti-HER3 antibody or its antigen-binding fragment also comprises a conservatively modified variant, which includes a single substitution, deletion or addition to the polypeptide sequence, which results in the amino acid being replaced by a chemically similar amino acid. Providing a conservative substitution table of functionally similar amino acids is well known in the art. Such conservatively modified variants are supplementary to polymorphic variants, interspecies homologs and alleles and are not excluded. The following eight groups contain amino acids that are conservatively substituted for each other: 1) alanine (A), glycine (G); 2) aspartic acid (D), glutamic acid (E); 3) asparagine (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y), tryptophan (W); 7) serine (S), threonine (T); and 8) cysteine ​​(C), methionine (M) (see, e.g., Creighton, Proteins (1984)). In some aspects, the term "conservative sequence modification" is used to refer to amino acid modifications that do not significantly affect or change the binding characteristics of the antibody comprising the amino acid sequence. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, VL comprises an amino acid sequence that is at least 70%, 75%, 77%, 78%, 80%, 82%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the framework region sequence of the amino acid sequence shown in SEQ ID NO:9, 11, 12, 13; VH comprises an amino acid sequence that is at least 70%, 75%, 77%, 78%, 80%, 82%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the framework region sequence of the amino acid sequence shown in SEQ ID NO:10, 14, 15, 16. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, VL comprises an amino acid sequence that is at least 70%, 75%, 77%, 78%, 80%, 82%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence shown in SEQ ID NO:9, 11, 12, 13; VH comprises an amino acid sequence that is at least 70%, 75%, 77%, 78%, 80%, 82%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence shown in SEQ ID NO:10, 14, 15, 16. In the present disclosure, in two or more polypeptide sequences, the term "% identity" refers to the degree to which two or more sequences or subsequences are identical. If two sequences have the same amino acid sequence in the region being compared, they are "identical". If two sequences have a specified percentage of identical amino acid residues (e.g., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% identity in a specified region, or, when not specified, over the entire sequence), when comparing and aligning to obtain maximum consistency in a comparison window or a specified region, or using a specified region measured by one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, identity is present in a region of at least about 10 amino acids in length, or more preferably in a length of 20, 50, 200 or more amino acids. Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms (Altschul et al., Nuc. Acids Res. 25:3389-3402, 1997, and Altschul et al., J. Mol. Biol. 215:403-410, 1990). In addition to the percentage of sequence identity described above, another meaning of two polypeptides being substantially identical is that the first polypeptide is immunologically cross reactive with the second polypeptide, thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only in conservative substitutions. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, VL comprises the amino acid sequence shown in SEQ ID NO:9, 11, 12 or 13, and VH comprises the amino acid sequence shown in SEQ ID NO:10, 14, 15 or 16. In some embodiments, in the anti-HER3 antibody or antigen-binding fragment thereof, VL and VH comprise an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence shown in SEQ ID NO: 9 and SEQ ID NO: 10, respectively; VL and VH comprise an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence shown in SEQ ID NO: 11 and SEQ ID NO: 14, respectively; VL and VH comprise an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence shown in SEQ ID NO: 11 and SEQ ID NO: 15, respectively; VL and VH comprise an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence shown in SEQ ID NO: 12 and SEQ ID NO: 13, respectively. NO:14 has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence shown in SEQ ID NO:14; VL and VH respectively comprise an amino acid sequence that has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence shown in SEQ ID NO:12 and SEQ ID NO:15; VL and VH respectively comprise an amino acid sequence that has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence shown in SEQ ID NO:13 and SEQ ID NO:14; VL and VH respectively comprise an amino acid sequence that has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence shown in SEQ ID NO:13 and SEQ ID NO:15; or VL and VH respectively comprise an amino acid sequence that has at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence shown in SEQ ID NO:13 and SEQ ID NO:15. The amino acid sequence shown in NO:16 has at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity. In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof comprises or has VH and VL as shown in SEQ ID NOs: 9 and 10, 11 and 14, 11 and 15, 11 and 16, 12 and 14, 12 and 15, 12 and 16, 13 and 14, 13 and 15, or 13 and 16, and conservatively substituted variants thereof, optionally with conservative substitutions in the framework regions. In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof comprises or has VH and VL as shown in SEQ ID NOs: 9 and 10, 11 and 14, 11 and 15, 12 and 14, 12 and 15, 13 and 14, 13 and 15, or 13 and 16, respectively, and conservatively substituted variants thereof, optionally with conservative substitutions in the framework regions. The HER3 antibodies or antigen binding fragments thereof provided by the present disclosure can bind to the HER3 protein of a mammal (e.g., a human or a mouse). In some embodiments, the anti-HER3 antibodies or antigen binding fragments thereof specifically bind to human HER3. In some embodiments, the anti-HER3 antibodies or antigen binding fragments thereof specifically bind to mouse HER3. The HER3 antibody or its antigen binding fragment can be of IgM, IgG, IgA, IgD or IgE category. In some embodiments, the HER3 antibody or its antigen binding fragment is an IgG molecule. In some embodiments, the HER3 antibody or its antigen binding fragment is of IgG1, IgG2, IgG3 or IgG4 subtype. In some embodiments, the HER3 antibody or its antigen binding fragment is human IgG1. The class and subclass of the antibody are confirmed according to the usual methods in the art. For example, according to the difference of heavy chain α, δ, ε, γ and μ, the composed antibodies are called IgA, IgD, IgE, IgG and IgM. Among them, human γ can be further subdivided into γ1, γ2, γ3, γ4, corresponding to the four subtypes of IgG1, IgG2, IgG3 and IgG4 respectively. The HER3 antibody or antigen-binding fragment thereof may be a human antibody, a humanized antibody or a chimeric antibody, and human antibodies, humanized antibodies or chimeric antibodies are defined in a manner generally understood in the art. For example, a human antibody refers to an antibody that is entirely encoded by human antibody genes; a humanized antibody refers to an antibody whose constant region is at least partially encoded by human genes; a chimeric antibody refers to a chimeric antibody expressed by transforming mammalian cells by inserting the light and heavy chain variable region genes of a heterologous monoclonal antibody into an expression vector containing a human antibody constant region using DNA recombination technology. The anti-HER3 antibodies or antigen-binding fragments thereof provided by the present disclosure have improved hydrophobicity, which is beneficial for improving the stability in vivo and in vitro. The anti-HER3 antibody or antigen-binding fragment thereof provided by the present disclosure has good targeting properties, can anchor tumor cells expressing HER3, and exert a tumor-killing effect. Optionally, the anti-HER3 antibody or antigen-binding fragment thereof can exert an anti-tumor effect both in vivo and in vitro. At the same time, the present disclosure provides a nucleic acid encoding the above-mentioned anti-HER3 antibody or its antigen-binding fragment, a vector comprising the nucleic acid encoding the above-mentioned anti-HER3 antibody or its antigen-binding fragment, and a host cell comprising the nucleic acid and / or the vector. Anti-HER3 antibodies or antigen-binding fragments thereof can be obtained in the following manner: by immunizing an animal with HER3 or any polypeptide selected from the amino acid sequence of HER3 according to the method commonly practiced in the art, collecting and purifying the antibodies produced in vivo. In this case, by studying the cross-reactivity of the antibodies binding to the obtained heterologous HER3 with human HER3, antibodies applicable to human diseases can be selected. In addition, antibody-producing cells producing antibodies against HER3 can be fused with myeloma cells to establish hybridomas according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, pages 495-497; Kennet, R. ed., Monoclonal Antibodies, pages 365-367, Plenum Press, NY (1980); Goding JW, Monoclonal Antibodies: Principles and Practice 3rd edition (1986) Academic Press, San Diego, CA), and monoclonal antibodies can be obtained from the hybridomas. HER3 used as an antigen can be obtained by expressing the HER3 gene in host cells using genetic engineering. Hybridomas can be engineered to obtain chimeric antibodies, for example, chimeric antibodies in which the variable regions of antibodies derived from mice or rats are linked to constant regions derived from humans (see Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)). Humanized antibodies can be generated by replacing most or all structural parts of non-human monoclonal antibodies with corresponding human antibody sequences. Examples include antibodies obtained by integrating only the complementarity determining region (CDR) into antibodies derived from humans (see Nature (1986) 321, pp. 522-525) and antibodies obtained by transplanting the amino acid residues of a part of the framework in addition to the sequence of the CDR to human antibodies by the CDR transplantation method (WO 90 / 07861). Human antibodies can be obtained by a method for producing human antibody-producing mice having human chromosome fragments containing heavy and light chain genes of human antibodies (see Tomizuka, K. et al., Nature Genetics (1997) 16, pp. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, pp. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, pp. 69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. ed., Proc. Natl. Acad. Sci. USA (2000) 97, pp. 722-727, etc.). Methods for obtaining humanized antibodies also include those described, for example, in Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. USA, 1998, 95:8910-8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natl. Acad. Sci. USA, 1989, 86:10029-10033; [Antibody-drug conjugates] The present disclosure provides an antibody-drug conjugate (ADC), which has a structure shown in Formula I. Ab-(LD)n (I) or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, wherein Ab is the above-mentioned anti-HER3 antibody or an antigen-binding fragment thereof; L is a linker covalently linked to Ab and D respectively; D is the effective load; n is a value between 1 and 10. The term "antibody-drug conjugate" or "ADC" refers to a conjugate of an anti-HER3 antibody or antigen-binding fragment thereof described herein covalently linked to a payload. Generally, the antibody-drug conjugate can include an antibody, a payload, and optionally a linker between the antibody and the payload. ADC can provide a therapeutic effect by delivering the payload to HER3 cells, particularly HER3 tumor cells, targeted by the antibody. Antibody-drug conjugates can be prepared by various methods known in the art for preparing antibody-drug conjugates. In ADC molecules, linkers, as the connecting structure between antibodies and effective loads, are key factors in the successful construction of ADC molecules. In terms of pharmacokinetics (PK) / pharmacodynamics (PD) and therapeutic window, the molecular design and properties of linkers are key determinants of the efficacy of ADCs. In order to achieve optimal efficacy, an ideal linker should have the following properties: (1) The linker is stable enough in plasma so that the ADC molecule can circulate in the bloodstream and localize to the tumor site without premature cleavage. Unstable linkers can lead to premature release of cytotoxic effective loads and damage non-target healthy cells, resulting in systemic poisoning and adverse reactions. (2) The linker needs to be able to be cleaved quickly so that once the ADC is internalized into the target tumor cells, it can quickly release the free cytotoxic effective load. (3) The design of the linker also needs to consider hydrophobicity. The combination of hydrophobic linkers and hydrophobic cytotoxic payloads usually promotes the aggregation of ADC molecules, which is not only detrimental to the efficacy of ADC, but may also cause liver toxicity or induce unwanted immune responses (Kyoji Tsuchikama et al., Antibody-drug conjugates: recent advances in conjugation and linker chemistrie, Protein Cell. 2018 Jan; 9(1): 33-46). The term "isomer" refers to compounds with the same molecular formula but different structures, also known as isomers or structural isomers, usually including structural isomers and stereoisomers. Structural isomers refer to isomers caused by different connection orders of atoms in molecules or different bonding properties, preferably including tautomers. The tautomers refer to functional group isomers produced by the rapid movement of an atom in two positions in a molecule. Stereoisomers refer to isomers caused by different spatial arrangements of atoms or atomic groups in molecules, which are the same in order of connection and bonding materials, and preferably include optical isomers. The optical isomers refer to stereoisomers with different optical properties caused by the lack of anti-axis symmetry in the molecule, such as enantiomers, diastereomers, racemates and mesosomes. The term "prodrug" refers to a compound that is inactive or less active in vitro after chemical structural modification of a drug, and releases active drugs in vivo through enzymatic or non-enzymatic conversion to exert its efficacy. In the present disclosure, the prodrug can be an ADC molecule or an effective load. In some embodiments, the linker is a cleavable linker and a non-cleavable linker. In some embodiments, the linker comprises a cleavable peptide, optionally, the cleavable peptide is cleavable by an enzyme. In some embodiments, the enzyme comprises cathepsin B. In some embodiments, the cleavable peptide or L comprises amino acid units, and the amino acid units include a dipeptide, a tripeptide, a tetrapeptide, or a pentapeptide. In some embodiments, the amino acid unit is selected from any one or a combination of Val-Cit, Val-Ala, Glu-Val-Cit, Ala-Ala-Asn, Gly-Val-Cit, Gly-Gly-Gly and Gly-Gly-Phe-Gly, wherein Val represents valine, Cit represents citrulline, Ala represents alanine, Glu represents glutamic acid, Asn represents asparagine, Gly represents glycine, and Phe represents phenylalanine. In some embodiments, the linker comprises a self-immolative unit, and optionally, the self-immolative unit comprises p-aminobenzyloxycarbonyl (PABC) or p-aminobenzyl (PAB). In some embodiments, the cleavable peptide is cleaved directly to the self-degradable unit. In some embodiments, the linker comprises a structure as shown in -L1-L2-L3-, where L1 represents -(succinimidyl-3-yl-N)-(CH2)m 1 -C(=O)-, -CH2-C(=O)-NH-(CH2)m 2 -C(=O)- or -C(=O)-(CH2)m 3 -C(=O)-, where m 1 represents an integer from 2 to 8, m 2 represents an integer from 1 to 8, m 3 represents an integer of 1 to 8; L2 represents an amino acid unit; and L3 represents a self-degradable unit. In some embodiments, m 1 represents 2, 3, 4, 5, 6, 7 or 8. In some embodiments, m 2 represents 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, m 3 Means 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the L is selected from one or more of the following groups: -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-PABC-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-PABC-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; and -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-. In some embodiments, the p-aminobenzyloxycarbonyl group (PABC) or p-aminobenzyl group (PAB) is linked to a polysarcosine (poly-N-methylglycine) residue or a methylamino group. In some embodiments, the antibody-drug conjugate comprises an antibody, a payload, and a linker as shown in Formula II, The linker shown in Formula II is covalently bonded to the reduced sulfhydryl part of the antibody interchain disulfide chain through a succinimide group through a thioether bond; The carbonyl group in the ester group of the linker represented by Formula II is connected to the amino group in the effective load; In formula II, R1 and R2 are each independently selected from hydrogen, methyl or isopropyl; R3 represents -(CR5HCONH)n 1 -(CH2CONH)n 2 - or a single bond, R5 is hydrogen or benzyl, n 1 represents an integer from 0 to 2, n 2 Represents an integer from 0 to 2; R4 represents methylamino or -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 1 to 20. The term "payload" includes compounds that are cytotoxic or capable of killing cells after release from the antibody-drug conjugate, compounds with radioactive labels, fluorophores, chromophores, imaging agents and / or metal ions as detectable markers or cell-killing effects. substances, radionuclides or polypeptides, compounds that can regulate the body's immune activity (including activation or inhibition), nucleic acids, polypeptides or proteins, enzymes, hormones or nucleic acids. In some ideal cases, the conjugated effective load in the antibody-drug conjugate has almost no cytotoxicity or the cytotoxicity is so low that the effective therapeutic dose of ADC will not cause systemic toxic reactions in the subject due to the conjugated effective load. The effective load can be a drug that has been clinically verified for the treatment of a specific disease, or a compound, radionuclide, nucleic acid, protein or polypeptide with acceptable pharmacological activity under clinical use conditions. In the present disclosure, the linker in Formula I is connected to the antibody through a thioether bond formed by the succinimide group at the end and the thiol group after the reduction of the interchain disulfide chain of the antibody. It forms a thioether bond with the reduced sulfhydryl group of the antibody interchain disulfide chain through the carbon atom at position 3. The bond represents a chemical bond to other groups. In the present disclosure, the disulfide bonds of the antibody include interchain disulfide bonds and intrachain disulfide bonds, preferably the interchain disulfide bonds are treated, for example, activated (or reduced) to become sulfhydryl groups and then bonded to the linker. The amino acid in the antibody that is chemically bonded to the succinimidyl group in the linker includes one or a combination of lysine, histidine, tyrosine and cysteine, preferably chemically bonded through cysteine. In some embodiments, the linker in Formula I can be attached to the hinge region, variable region and / or constant region of the antibody. In the present disclosure, in some embodiments, in the linker shown in Formula II, R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 represents an integer from 1 to 20. 3 Any integer among 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 may be selected. In some embodiments, in the linker of formula II, R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 represents an integer of 8 to 15. In some embodiments, in the antibody-drug conjugate, in the linker represented by Formula II, R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 10 to 12. In some embodiments, in the antibody-drug conjugate, in the linker shown in Formula II, R4 represents a methylamino group. In the linker shown in Formula II of the present disclosure, R4 contains a hydrophilic polysarcosine group or a methylamino group, which increases the hydrophilicity of the antibody-drug conjugate. In particular, when a hydrophobic effective load is conjugated to the antibody-drug conjugate, the improvement in the hydrophilicity of the ADC molecule helps to reduce the aggregation of the ADC molecules during the preparation process, thereby improving the stability, uniformity and purity of the antibody-drug conjugate. In some embodiments, in the antibody-drug conjugate, in the linker shown in Formula II, R3 represents a single bond. In some embodiments, in the antibody-drug conjugate, in the linker shown in Formula II, R3 represents -(CR5HCONH)n 1 -(CH2CONH)n 2 -, R5 is benzyl, n 1 Indicates an integer from 1 to 2, n 2 Indicates an integer from 1 to 2. In some embodiments, in the antibody-drug conjugate, in the linker shown in Formula II, R3 represents -CR5HCONH-, -CH2CONH-, -CR5HCONH-CH2CONH-; -(CR5HCONH)2-CH2CONH-; -CR5HCONH-(CH2CONH)2-; or, -(CR5HCONH)2-(CH2CONH)2-; and R5 is benzyl. In some embodiments, in the antibody-drug conjugate, in the linker of formula II, R1 is hydrogen. In some embodiments, in the linker of formula II, R1 is isopropyl. In some embodiments, in the antibody-drug conjugate, in the linker shown in Formula II, R2 is hydrogen. In some embodiments, in the linker shown in Formula II, R2 is methyl. In some embodiments, the linker in the antibody-drug conjugate is selected from one or more of the following groups: In some embodiments, the effective load in the antibody-drug conjugate is a marker containing a radioactive label, a fluorophore, a chromophore, an imaging agent and / or a metal ion as a detection marker, and the marker includes but is not limited to a chemically synthesized organic compound, a radionuclide, a metal complex or a polypeptide. Among them, a radioactive label refers to a labeled compound that replaces one or several atoms of a compound molecule with a radionuclide so that it can be identified and used as a tracer, including amino acids, polypeptides, proteins, carbohydrates, nucleotides, nucleosides, purines, pyrimidines, steroids, lipid compounds, and tumor antigens, hormones, receptors, vitamins and drugs used in medical research. Reflective nuclides are usually nuclides that can spontaneously emit radiation, including but not limited to tritium, iodine 125, iodine 131, sulfur 35, phosphorus 32 and carbon 14. Fluorophores are usually groups including conjugated double bonds, and when the molecule returns to the ground state from an excited state, the fluorophore will emit fluorescence. Chromophores refer to unsaturated groups and their related chemical bonds contained in a molecule that can absorb light radiation and have transitions. In nuclear medicine, imaging agents usually refer to radioactive drugs that can be introduced into the body to perform organ, tissue or molecular imaging. In some embodiments, the effective load in the antibody-drug conjugate is a nucleic acid, which can be ribonucleic acid and / or deoxyribonucleic acid. In some embodiments, the effective load in the antibody-drug conjugate is a hormone, a growth factor, a coagulation factor, a fibrinolytic protease (eg, a prodrug converting enzyme, a ribonuclease that can convert a prodrug into an active drug). In some embodiments, the effective load in the antibody-drug conjugate is an immunomodulator (including cytokines and chemokines that affect immune effects), an agonistic antibody or an antagonistic antibody with biological activity. In some embodiments, the effective load in the antibody-drug conjugate is a cytotoxic compound. In some embodiments, the effective load in the antibody-drug conjugate has anti-tumor activity, or is an anti-tumor drug, and the effective load is selected from a DNA topoisomerase inhibitor or a tubulin inhibitor. The DNA topoisomerase inhibitor can be a topoisomerase I inhibitor or a topoisomerase II inhibitor. In this disclosure, the term "topoisomerase inhibitor" generally refers to a compound that inhibits the activity of topoisomerase. Compounds that are topoisomerase I inhibitors are active against topoisomerase I; topoisomerase II inhibitors are active against topoisomerase II; some compounds are active against both topoisomerase I and topoisomerase II, and are referred to as topoisomerase I / II inhibitors. The term "tubulin inhibitors" generally refers to compounds that inhibit the microtubule system of eukaryotic cells, interfere with cell division and inhibit cell proliferation. In some embodiments, the effective load is camptothecin or its derivatives having topoisomerase inhibitory effect. The term "derivative" refers to a compound formed by replacing atoms or atomic groups in the molecule of the parent compound with other atoms or atomic groups, which is called a derivative of the parent compound. The term "camptothecin and its derivatives" generally includes camptothecin and camptothecin derivatives. Camptothecin exerts its pharmacological effect by irreversibly inhibiting topoisomerase I. The camptothecin derivatives include exatecan, irinotecan, topotecan, lurtotecan, silatecan, etirinotecan pegol, TAS 103. 9-aminocamptothecin, 7-ethylcamptothecin, 10-hydroxycamptothecin, 9-nitrocamptothecin, 10,11-methylenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycamptothecin, 7-(4-methylpiperazine methylene)-10,1 1-ethylenedioxy-20(S)-camptothecin (7-(4-methylpiperazinomethylene)-10,1-1-ethylenedioxy-20(S)-camptothecin), 7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-camptothecin, 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin, and the like, and stereoisomers, salts, and esters thereof. Methods for synthesizing camptothecin and camptothecin analogs or derivatives are known and are summarized and described in U.S. Pat. No. 5,244,903, which is incorporated herein by reference in its entirety. In some embodiments, the effective load is auristatin or its derivatives, maytansine or its derivatives having tubulin inhibitory effects. The term "auristatin and its derivatives" generally includes auristatin F and auristatin F derivatives, and the auristatin F derivatives include monomethyl auristatin E (monomethyl auristatin E, MMAE) and monomethyl auristatin F (monomethyl auristatin F, MMAF). The term "maytansine and its derivatives" generally includes maytansine and maytansine derivatives, and the maytansine derivatives include maytansine DM1, maytansine DM2 and maytansine DM4. In some embodiments, the effective load is the camptothecin derivative Exatecan, which can act on the entire cell cycle as a topoisomerase inhibitor, and has strong penetration and good efficacy on slow-growing solid tumors. Moreover, the number of intracellular targets is much lower than that of tubulin inhibitors, and when the ADC molecule carries the same number of effective loads into the cell, it can have a better killing effect. Exatecan molecules are not substrates of P-gp, which is conducive to reducing or alleviating the problem of drug resistance. In some embodiments, the effective load is exotecan as shown in Formula III, which is connected to the linker via the nitrogen atom of the amino group on its cyclohexane ring. The structure of the ixotecan molecule is rigid and has poor hydrophilicity. When it is connected with the GGFG tetrapeptide linker commonly used in the prior art to prepare ADC, it is easy to cause polymerization between ADC molecules, which does not meet the development requirements of ADC drugs (Bioorg. Med. Chem. Lett. 26 (2016) 1542-1545). Therefore, the selection and matching of the linker and the effective load have an impact on the safety and stability of ADC drugs. Without being bound by any theory, in the antibody-drug conjugate provided by the present disclosure, since the linker has multiple hydrophilic groups, the hydrophilicity in the linker-payload structure is improved, and the aggregation and precipitation of ADC molecules caused by the hydrophobic payload can be reduced to a certain extent. After the ADC molecule is internalized into the cell, the effective load or the compound of the linker (or part of the linker)-effective load structure is released depending on whether the linker is degraded. In some embodiments, the amino group on the cyclohexane ring of Exitecan shown in Formula III is bonded to the carbonyl group in the ester group of the linker shown in Formula II to form a linker-effective load structure including a carbamate. Without being bound by any theory, in the linker-effective load structure provided by the present disclosure, after the ADC molecule is internalized into the cell, the linker is enzymatically hydrolyzed by a tissue protease (e.g., Cathepsin B) to form an intermediate or active metabolite shown in the following formula V, R4 represents methylamino or -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 1 to 20. The PABC group in the intermediate or active metabolite shown in Formula V then undergoes 1,6-elimination to release exotecan. The mechanism of 1,6-elimination of PABC is described in detail in the document Angew.Chem.Int.Ed.2015,54,7492-7509. Therefore, the linker-payload structure in the ADC molecule provided by the present disclosure has good in vivo stability and biological activity. The cleavage site in the linker-payload structure, without being bound by any theory, can be an amide bond in the linker, for example, an amide bond between the carbon atom where the substituent represented by R2 is located and the group represented by R3, or an amide bond in the group represented by R3. In some embodiments, in the antibody-drug conjugate, n is the ratio of the number of molecules of the coupled effective load to each molecule of antibody (Drug to Antibody Ratio, DAR). In some embodiments, in the antibody-drug conjugate, n is 1-10, 1-2, 2-4, 4-6, 2-8, 4-8, 4-10, 6-10, 7-10 or 8-10, and exemplary DAR values ​​are 4, 6, 7.78, 8.038 or 9.92. DAR represents the average value of the number of coupled effective load or drug molecules per antibody molecule, i.e., the average value of the number of coupled drug molecules. In antibody-drug conjugates, the number of effective load molecules coupled to each antibody molecule is a key factor affecting its efficacy and safety. The production of antibody-drug conjugates is carried out by specifying reaction conditions such as the amount of starting materials and reagents used in the reaction to achieve a constant number of coupled effective load molecules. Usually, a mixture containing different numbers of coupled effective load molecules is obtained during the preparation of antibody-drug conjugates. Unless otherwise specified, the coupling effective load or drug molecule number per antibody molecule in the present disclosure is defined as the average value, i.e., the average number of coupling effective load or drug molecules. In some embodiments, the antibody-drug conjugate comprises any one of the following structures: Ab represents an anti-HER3 antibody or antigen-binding fragment; n is 1-10 or 4-10. The antibody in the antibody-drug conjugate is a HER3-targeting specific antibody or an antigen-binding fragment thereof, which is connected to the linker after forming an active thiol group through a disulfide bond. In some embodiments, the antibody hinge region is connected to the linker after forming an active thiol group through a disulfide bond. In some embodiments, the antibody in the antibody-drug conjugate is an anti-HER3 antibody or an antigen-binding fragment thereof provided in the above [Antibodies] section of the present disclosure. In some embodiments, the anti-HER3 antibody or an antigen-binding fragment thereof in the antibody-drug conjugate comprises a VL sequence as shown in SEQ ID NO: 11 and a VH sequence as shown in SEQ ID NO: 15. In the antibody-drug conjugates provided by the present disclosure, due to the use of anti-HER3 antibodies or antigen-binding fragments thereof with improved hydrophobicity and linkers, the hydrophilicity and uniformity of the prepared products are significantly improved, which helps to improve the killing effect of targeted cells, and improves or maintains the drug properties such as biological activity and safety, for example, the in vitro / in vivo stability is improved, and the in vivo drug metabolism properties are improved (longer half-life, lower free small molecule toxins, etc.). The antibody drug provided by the present disclosure has excellent in vivo antibody tumor effect, especially HER3-dependent cell killing or anti-tumor activity, and has different degrees of killing effect on the tumor cells according to the expression level of HER3 in the tumor cells. In some embodiments, the antibody-drug conjugate provided by the present disclosure has extremely high killing activity on tumor cells with high expression of HER3, and the level of HER3 expression can be judged according to methods known in the art, for example, H-score scoring method, low expression (H-Score = 10-99), medium expression (H-Score = 100-199), high expression (H-Score = 200-300). It should be noted that the antibody-drug conjugate of the present disclosure may absorb water, retain adsorbed water, or become hydrated due to being placed in the atmosphere or recrystallized, and such compounds and salts containing water are also included in the present disclosure. In addition, the present disclosure also includes isotope variant compounds labeled with various radioactive or non-radioactive isotopes. One or more of the atoms constituting the antibody-drug conjugate of the present disclosure may also contain atomic isotopes in non-natural proportions. As atomic isotopes, for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C) can be cited. In addition, the compounds of the present disclosure can be radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). Radiolabeled compounds are useful as therapeutic or preventive agents, research reagents such as test reagents, and diagnostic agents, such as in vivo imaging diagnostic agents. All isotopic variations of the antibody-drug conjugates of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. [Antibody-drug conjugate preparation method] The present disclosure provides a method for preparing an antibody-drug conjugate, comprising the following steps: After the reduction treatment, the interchain disulfide bonds of the antibody or antigen-binding fragment thereof are at least partially reduced, and react with the linker-payload, in particular, react with the reactive group of the linker in the linker-payload, to obtain an antibody-drug conjugate having a structure as shown in Formula I. Ab-(LD)n (I) or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, wherein Ab is the above-mentioned anti-HER3 antibody or an antigen-binding fragment thereof; L is a linker covalently linked to Ab and D respectively; D is the effective load; n is a value between 1 and 10. In some embodiments, the carbon atom at position 3 of the maleimide-N-group in LD reacts with the reduced antibody to obtain ADC after covalent bonding. In some embodiments, the preparation method comprises the following steps: after the antibody is subjected to reduction treatment, the interchain disulfide bonds are at least partially reduced, and the antibody is coupled with a linker-payload, wherein the thiol group after the disulfide bond reduction reacts with the 3-position carbon atom of the maleimide-N-group of the linker shown in Formula IV in the linker-payload, The carbonyl group in the ester group of the linker represented by Formula IV is connected to the amino group of the effective load in the antibody-drug conjugate; In formula IV, R1 and R2 are each independently selected from hydrogen, methyl or isopropyl; R3 represents -(CR5HCONH)n 1 -(CH2CONH)n 2 - or a single bond, R5 is selected from hydrogen or benzyl, n 1 represents an integer from 0 to 2, n 2 Represents an integer from 0 to 2; R4 represents methylamino or -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 1 to 20. In antibody-drug conjugates, in many practical cases, the linker of the structure shown in the above formula IV with a payload is connected to the same antibody molecule with a reactive thiol group. In some embodiments, the antibody reacts with a reducing agent such as dithiothreitol (DTT), 2-mercaptoethanol or tris(2-carboxyethyl)phosphine hydrochloride (TCEP) to form a reactive thiol group with disulfide bonds on the antibody chain. The amount of the reducing agent can be 0.3 to 10 times the molar equivalent of the antibody, for example, 1 to 10, 3 to 10, 5 to 10, 7 to 10 times the molar equivalent. In some embodiments, the method further comprises: reacting the antibody with a reducing agent in a buffer solution containing a chelating agent, and then adding a dissolving solution of the linker-payload to react. The linker-payload is specifically a compound formed by bonding the linker and the payload shown in formula IV, wherein the amino group (primary amino group) in the payload is connected to the carbonyl group in the ester group of the linker shown in IV. The payload is selected from the payloads described in [Antibody-Drug Conjugate]. In some embodiments, the payload is exotecan. The term "chelator" refers to a complex that can be combined with metal atoms or ions through coordination bonds to form a cyclic structure. In some embodiments, the reducing agent reacts with the antibody in a buffer solution containing a chelating agent to obtain an antibody in which the interchain disulfide bonds are partially or completely reduced. The chelating agent includes, but is not limited to, ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The concentration of the chelating agent is 1mM to 20mM, for example, 2mM to 20mM, 5mM to 20mM, 8mM to 20mM, 1mM to 15mM or 1mM to 10mM. The components of the buffer solution can be buffer salts commonly used in the art, such as sodium phosphate, sodium borate, sodium acetate or similar buffer salts. The reaction of the antibody with the reducing agent is carried out under the adjusted pH condition. In some embodiments, the pH of the solution when the antibody reacts with the reducing agent is 5 to 9, and can be selected as pH 6 to 8, pH 6 to 7, pH 6.5 to 7.5 or pH 7 to 8, for example, the solution is reacted at about pH 7. Acidic or alkaline chemicals can be used to adjust the pH value of the solution, and exemplary acidic or alkaline chemicals include acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide and triethylamine. The reaction of the antibody with the reducing agent is carried out under adjusted temperature conditions, exemplary reaction temperatures are -10-40°C, -5-40°C, 0-40°C, 5-40°C, 10-40°C, 15-40°C, 20-40°C, 25-40°C, 30-40°C, 35-38°C, such as about 37°C. The linker-payload may be dissolved in an organic solvent selected from any one or a combination of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA) and N-methyl-2-pyrrolidone (NMP). In some embodiments, the linker-payload solution is added to the buffer solution of the reduced or reactive thiol-containing antibody in an amount of 1-20% by volume, based on the volume of the antibody buffer. In some embodiments, the linker-payload solution is added in an amount of 1-20%, 2-20%, 5-20%, 10-20%, 15-20%, 1-18%, 1-15%, 1-13%, 1-10% or 5-15%, based on the volume of the antibody buffer. In some embodiments, the molar ratio of linker-payload to antibody is 4-20, optionally 8-20. In some embodiments, the molar ratio of linker-payload to antibody is 10-20, 14-20, 16-20 or 18-20. In some embodiments, the temperature at which the antibody and linker-payload react is 0-37° C. In some embodiments, the reaction temperature is -10-40° C., -5-40° C., 0-40° C., 5-40° C., 5-37° C., 10-37° C., 10-25° C., or 15-30° C. In some embodiments, the antibody reacts with the linker-payload for 0.5 to 2 hours. In some embodiments, the antibody reacts with the linker-payload for 0.5 to 1.75 hours, 0.5 to 1.5 hours, 0.5 to 1.25 hours, 0.75 to 2 hours, or 1 to 2 hours. The reaction can be terminated by inactivating the reactivity of the unreacted linker-payload using a thiol-containing reagent. The thiol-containing reagent includes, but is not limited to, cysteine ​​or N-acetyl-(L)-cysteine ​​(NAC). More specifically, the reaction can be terminated by adding a thiol-containing reagent in a molar equivalent of 1 to 2 times the molar equivalent of the linker-payload to the reaction solution and incubating at room temperature (10 to 25° C.) for 10 to 30 minutes. In the case where the antibody has a sulfhydryl group, the antibody-drug conjugate can also be obtained by reacting the compound using a known method (for example, it can be obtained by the method described in patent publication US2016 / 297890 (for example, it can be obtained by the method described in paragraph

[0336] Antibodies having thiol groups can be obtained by methods well known to those skilled in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). In some embodiments, the antibody in the antibody-drug conjugate is selected from the anti-HER3 antibodies or antigen-binding fragments thereof disclosed in the [Antibodies] section. In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof in the antibody-drug conjugate comprises a VL sequence as shown in SEQ ID NO: 11 and a VH sequence as shown in SEQ ID NO: 15. The antibody-drug conjugate provided by the present disclosure can be obtained by the above preparation method. In some embodiments, the prepared antibody-drug conjugate is subjected to a purification treatment, and the purification treatment includes but is not limited to gel filtration, such as purification using a gel column. In the antibody-drug conjugate prepared by the method disclosed herein, the linker and the effective load exotecan are coupled to the antibody targeting HER3 by a simple chemical method. Compared with the traditional random coupling method, the anti-HER3 antibody-drug conjugate obtained by using this linker has a higher DAR value (e.g., DAR8). [Drug composition] The present disclosure provides a pharmaceutical composition, comprising the anti-HER3 antibody or antigen-binding fragment thereof, or antibody-drug conjugate, or isomers, isotopic variants, pharmaceutically acceptable salts, prodrugs, solvates, or combinations thereof, and pharmaceutically acceptable excipients. The pharmaceutical composition disclosed herein can select a suitable administration method according to the specific applicable form, physicochemical characteristics, etc. of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition can be formed into a preparation in the form of a freeze-dried preparation or a liquid preparation, and the preparation can contain appropriate preparation additives in the art. For example, in the above-mentioned pharmaceutical composition, representatively, more than one pharmaceutical carrier is contained, such as a sterilized liquid, such as water and oil (including oils of petroleum, animal, plant, or synthetic origin (such as peanut oil, soybean oil, mineral oil, sesame oil, etc.)). In the case of intravenous administration of the above-mentioned pharmaceutical composition, water is a more representative carrier. In addition, saline solution, as well as glucose aqueous solution and glycerol aqueous solution can also be used as liquid carriers, especially for injection solutions. Suitable pharmaceutical excipients are known in the art. As needed, the above-mentioned composition can also contain a trace amount of wetting agent or emulsifier, or pH buffering agent. The administration method of the pharmaceutical composition usually selects parenteral administration, which can be intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous injection, but is not limited to these, for example, it can be administered by infusion or bolus injection. Generally, the active ingredient, e.g., an anti-HER3 antibody or antigen-binding fragment thereof, or an antibody-drug conjugate, can be prepared into a pharmaceutical composition using techniques and methods well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999). The pharmaceutical composition of the present disclosure may be a pharmaceutical composition containing only the anti-HER3 antibody or its antigen-binding fragment, or an antibody-drug conjugate of the present disclosure, or a pharmaceutical composition containing an anti-HER3 antibody or its antigen-binding fragment, or an antibody-drug conjugate, and at least one second therapeutic agent (e.g., a cancer therapeutic agent). In some embodiments, the antibody-drug conjugate of the present disclosure may also be administered together with other cancer therapeutic agents to enhance the anti-cancer effect. Other anticancer agents used for this purpose may be administered to an individual simultaneously, separately or continuously with the antibody-drug conjugate, or may be administered with a changed administration interval. Exemplary other cancer therapeutic agents such as paclitaxel, cisplatin, vinblastine, etc. are not limited as long as they are agents with anti-tumor activity. [Reagent test kit] The present disclosure also provides a kit, the kit comprising the above-mentioned anti-HER3 antibody or its antigen-binding fragment, or antibody-drug conjugate. The kit may also include a container, a buffer reagent, and a control such as a positive control and a negative control as needed. Those skilled in the art may make corresponding selections as needed. Accordingly, the kit may also include instructions for use to facilitate operation and use by those skilled in the art. [use] The present disclosure provides the use of the above-mentioned anti-HER3 antibody or its antigen-binding fragment, antibody-drug conjugate, pharmaceutical composition, and the antibody-drug conjugate and kit prepared by the above-mentioned method in preparing therapeutic agents for diagnosing, preventing and treating tumor diseases. In some embodiments, provided are uses of the HER3 antibody or its antigen-binding fragment, antibody-drug conjugate, pharmaceutical composition, and antibody-drug conjugate and kit prepared by the above method in preparing anti-tumor drugs, or in preparing drugs targeting HER3. The anti-HER3 antibody or antigen-binding fragment thereof and antibody-drug conjugate provided by the present disclosure have the function of killing cells expressing HER3 and can be used to kill cells expressing HER3 in vivo or in vitro. The tumor disease includes benign tumors and malignant tumors (e.g., cancer), and in particular, the antibody-drug conjugate is suitable for tumors or cancers in which HER3 expression is observed, and in some embodiments, the tumor or cancer is a solid tumor expressing HER3. In some embodiments, the tumor or cancer includes but is not limited to lung cancer, renal cancer, urothelial carcinoma, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, metastatic breast cancer, luminal breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumors, cervical cancer, head and neck cancer, esophageal cancer, epidermoid carcinoma, peritoneal cancer, adult glioblastoma multiforme, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, liver malignancies, anal cancer, penile cancer, and lung adenocarcinoma (including EGFR-TKI-resistant lung adenocarcinoma). In some embodiments, the cancer is of breast cancer, lung adenocarcinoma, pancreatic cancer, and colon cancer. In some embodiments, the cancer is of breast cancer, EGFR-TKI-resistant lung adenocarcinoma, pancreatic cancer, and colon cancer. When a subject suffers from or is suspected of suffering from a solid tumor expressing HER3, a therapeutic dose of a therapeutic agent is administered to the subject, wherein the therapeutic agent includes the above-mentioned anti-HER3 antibody or antigen-binding fragment thereof, antibody-drug conjugate, antibody-drug conjugate prepared by the above-mentioned method, or the above-mentioned pharmaceutical composition, which can be used for the diagnosis, prevention and treatment of tumor diseases. The present disclosure also provides a method for diagnosing, preventing and treating tumor diseases, comprising: administering a therapeutic dose of a therapeutic agent to a subject in need, wherein the therapeutic agent comprises the above-mentioned anti-HER3 antibody or its antigen-binding fragment, antibody-drug conjugate, antibody-drug conjugate prepared by the above-mentioned method, the above-mentioned pharmaceutical composition or kit. The subject is a mammal, including a human, a non-human primate, a dog, a pig, or a mouse. Preferably, the subject is a human, such as a patient with a tumor expressing HER3. The therapeutic dosage of the therapeutic agent varies depending on the specific condition being treated, the severity of the condition, individual patient parameters including age, physical condition, size, sex and weight, duration of treatment, nature of concurrent therapy (if any), the specific route of administration, and the knowledge of the health practitioner, etc. In some embodiments, the dosage of the active ingredient, such as an anti-HER3 antibody or antigen-binding fragment thereof, or antibody-drug conjugate, can be determined empirically in individuals who have been given one or more administrations of the antibody. In some embodiments, the acceptable therapeutic dose of the anti-HER3 antibody or antigen-binding fragment thereof, or antibody-drug conjugate is 0.1-30 mg / kg, 0.5-30 mg / kg, 1-30 mg / kg, 1-25 mg / kg, 0.1-25 mg / kg, 0.1-20 mg / kg, 1-20 mg / kg or 0.5-20 mg / kg. In some embodiments, the dosing frequency is once every 12 hours, daily, weekly, every 2 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks or every 10 weeks; or once every month, every 2 months or every 3 months or longer. The therapeutic dose and dosing frequency can vary with the treatment regimen. The anti-HER3 antibody or antigen-binding fragment thereof, antibody-drug conjugate or pharmaceutical composition disclosed herein may also be used in combination with one or more second therapeutic agents, which may be administered simultaneously or sequentially through the same or different administration routes. This may vary depending on the metabolic properties of the therapeutic agent itself and the disease being treated. The various embodiments and preferences of the present disclosure may be combined with each other (as long as they are not inherently contradictory to each other), and the various embodiments formed by such combination are all considered as part of the present disclosure. The technical solution of the present disclosure will be more clearly and explicitly described in the following examples in an illustrative manner. It should be understood that these examples are only for illustrative purposes and are by no means intended to limit the scope of protection of the present disclosure. The scope of protection of the present disclosure is limited only by the claims. Example The disclosure is specifically described by the following examples, but the disclosure is not limited thereto. In addition, these examples are not interpreted restrictively in any way. In addition, in this specification, reagents, solvents and starting materials not particularly described can be easily obtained from commercially available supply sources. Example 1: Preparation of Compound LP-1 Step 1: Synthesis of intermediate 11-1 Compound 11-1A (Mc-Val-Ala-OH, purchased from Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd., 2.4 g, 6.29 mmol) and 11-1B (3.18 g, 6.29 mmol) were mixed, and a mixed solution of dichloromethane (DCM) and methanol (MeOH) (v:v=2:1, 90 mL) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 1.86 g, 7.55 mmol) were added at room temperature (25°C to 30°C). The mixture was reacted at room temperature for 24 hours, the solvent was removed in vacuo, and the crude residue was purified by flash chromatography to obtain compound 11-1 (3.9 g, 71%). LC-MS (ESI, m / z): 868.49 (M+H). Step 2: Synthesis of intermediate 11-2 Compound 11-1 (2 g, 2.3 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 50 mL), and hydrogen fluoride-pyridine (4.6 g, 46 mmol) was added at 0°C under argon atmosphere. The reaction was continued for 2 hours under stirring, and water was added to quench the reaction. DCM The organic phase was extracted, dried and concentrated. The residue was purified by silica gel chromatography to obtain compound 11-2 (1.1 g, 76%). LC-MS (ESI, m / z): 630.31 (M+H). Step 3: Synthesis of intermediate 11-3 Compound 11-2 (700 mg, 1.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF, 4 mL), and N,N-diisopropylethylamine (DIPEA, 0.39 ml, 2.23 mmol) and 4,4'-dinitrodiphenyl carbonate (406 mg, 1.33 mmol) were added under argon atmosphere at room temperature, and the reaction mixture was stirred overnight at ambient temperature. The solvent was concentrated to remove the product, and methyl tert-butyl ether (MTBE) was used to precipitate the product, and the yellow solid was collected by filtration, washed with ether, and dried to obtain compound 11-3. LC-MS (ESI, m / z): 795.41 (M+H). Step 4: Synthesis of intermediate 11-4 Compound 11-3 (300 mg, 0.44 mmol) was dissolved in 4 mL of anhydrous DMF, 1 mL of dry pyridine was added, and then exatecan mesylate (purchased from Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd., 234 mg, 0.44 mmol) and 1-hydroxybenzotriazole (HOBt, 60 mg, 0.44 mmol) were added. The reaction mixture was stirred at room temperature overnight under argon. The product was purified by preparative high performance liquid chromatography (pre-HPLC) to obtain intermediate 11-4 (230 mg, 48%). LC-MS (ESI, m / z): 1091.53 (M+H). Step 5: Synthesis of intermediate 11-5 Compound 11-4 (200 mg, 0.183 mmol) was dissolved in 1 mL of anhydrous DCM, 300 μL of TFA was added at 0°C, the mixture was stirred at room temperature for 30 min, and the solvent was removed by concentration to obtain the TFA salt of intermediate 11-5. LC-MS (ESI, m / z): 991.47 (M+H). Step 6: Synthesis of Compound LP-1 Compound 11-5 (120 mg, 0.109 mmol) was dissolved in 1 mL of anhydrous DMF, N-acetyl decapolysarcosine (Ac-Sar10-COOH, 84 mg, 0.109 mmol) was added, followed by 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 50 mg, 0.130 mmol) and DIPEA (38 μL, 0.22 mmol), the reaction mixture was stirred at room temperature overnight, concentrated to remove the solvent, and the crude product was purified by pre-HPLC to obtain compound LP-1 (74 mg, 38%). LC-MS (ESI, m / z): 1743.85 (M+H). Example 2: Preparation of Compound LP-2 Synthesis of Compound LP2 According to the steps of compound LP-1, the starting material 11-1A was replaced with Mc-GGFG-OH (purchased from Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd., GGFG represents an amino acid sequence consisting of glycine-glycine-phenylalanine-glycine connected by peptide bonds) to obtain compound LP-2, which is a beige amorphous solid. LC-MS (ESI, m / z): 1891.90 (M+H). Example 3: Preparation of Compound LP-3 Compound LP-3 is an intermediate of LP-1. After removing step 6, intermediate 11-5 is LP-3. Example 4: Preparation of monoclonal antibodies Balb / c mice (8-12 weeks old) were immunized with human HER3 protein extracellular region fragment antigen (NCBI reference sequence: NM_001982.4, amino acid sequence 20-643), and their serum titer was monitored to determine the number of immunizations. After 3 to 4 booster immunizations after the initial immunization, mouse serum was taken to detect the titer according to the conventional methods in the art. After the titer detection qualified mice were impact immunized once, the whole spleen and 1 / 2 of the lymph nodes were taken and PEG fused with myeloma SP2 / 0 cell line. The fused cells were plated and cultured, the supernatants of all wells were collected, the antigens were screened using the ELISA method, and the positive wells with cells under microscopy were transferred to 96-well plates for continued cultivation. After 7 days of growth, the supernatants of all wells were collected and the reaction with the antigen was detected using the ELISA method. The positive wells further tested the antigen binding of different dilutions to perform affinity sorting. The 20 parent clones with the highest immunogenic affinity entered the subclone. Subcloning was performed by limiting dilution method and ELISA screening to obtain hybridoma cell lines. Mouse ascites was prepared from the hybridoma cell line, and the monoclonal antibody was obtained after collection and purification, named Mu4O3, and the amino acid sequences of its CDR and variable regions were determined, as shown in Table 1 below, where CDR (Kabat system definition and numbering) is underlined. Table 1 Hybridoma variable region amino acid sequences (single letter abbreviations) The hybridoma sequences were humanized to obtain humanized 4O3 antibodies (abbreviated as "Hu4O3") L1H4, L1H5, L2H4, L2H5, L4H4, L4H5 and L4H7. Among them, L1, L2, and L4 represent the numbers of the antibody light chain variable region sequences, and H4, H5, and H7 represent the numbers of the antibody heavy chain variable region sequences, that is, the L1H4 antibody includes a light chain variable region numbered L1 and a heavy chain variable region numbered H4; the L1H5 antibody includes a light chain variable region numbered L1 and a heavy chain variable region numbered H5; the L2H4 antibody includes a light chain variable region numbered L2 and a heavy chain variable region numbered H4; the L2H5 antibody includes a light chain variable region numbered L2 and a heavy chain variable region numbered H5; the L4H4 antibody includes a light chain variable region numbered L4 and a heavy chain variable region numbered H4; the L4H5 antibody includes a light chain variable region numbered L4 and a heavy chain variable region numbered H5; and the L4H7 antibody includes a light chain variable region numbered L4 and a heavy chain variable region numbered H7. The CDR sequences (underlined) and variable region sequences of Hu4O3 are shown in Table 2 below, where the mutated amino acids in CDR2 of VH are shown in bold italics. CDRs are defined and numbered using the Kabat system. Table 2 Variable region sequences of humanized 4O3 antibody (single letter abbreviations) For the purpose of example preparation and / or detection, the constant region of the above-mentioned antibody is selected from the constant region of human IgG1, wherein the heavy chain constant region sequence is selected from the amino acid sequence shown in SEQ ID NO: 17, and the light chain constant region sequence is selected from the amino acid sequence shown in SEQ ID NO: 18. Example 5: Detection method of antibody-drug conjugate The antibody-drug conjugate is concentrated, liquid is replaced, purified, and the antibody concentration is measured according to the following method, and the average number of drug molecules carried by each antibody is calculated to identify the antibody-drug conjugate. Procedure A: Concentration of Antibodies or Antibody-Drug Conjugates Take an ultrafiltration tube (Amicon Ultra, 50000 MWCO, Millipore Corporation), add the antibody or antibody-drug conjugate solution to be concentrated, centrifuge to the required volume and then take it out. Procedure B: Measurement of antibody concentration The absorbance of the antibody was measured using an ELISA reader (Multiskan GO, Thermo Fisher Scientific) according to the method defined by the manufacturer, and the ratio of the absorbance value to the absorption coefficient of the antibody at that wavelength was the concentration of the antibody. Procedure C: Antibody exchange According to the instructions provided by the manufacturer (Thermo Fisher Scientific), a zeba desalting column (5 mL, 40K MWCO) was pre-equilibrated with phosphate buffered saline (PBS7.0 / EDTA, 50 mM, pH 7.0) containing sodium chloride (50 mM) and EDTA (2 mM). 2 mL was loaded on each zeba desalting column, centrifuged (1000 g, 4 min), the flow-through fraction was collected and concentrated by operation A, the antibody concentration was determined by operation B, and the antibody concentration was adjusted with PBS7.0 / EDTA. Procedure D: Purification of Antibody-Drug Conjugates According to the instructions provided by the manufacturer (Thermo Fisher Scientific), a zeba desalting column (5 mL, 40K MWCO) was pre-equilibrated with storage buffer. The storage buffer used was histidine-acetate buffer (20 mM histidine, pH 5.5) containing 150 mM sodium chloride or phosphate buffer (50 mM, pH 7.0) containing 50 mM sodium chloride. The reaction solution (about 2 mL) containing the antibody-drug conjugate was added to the zeba desalting column, and the flow-through portion (about 2 mL) was collected after centrifugation (1000 g, 4 minutes). The elution process was repeated twice to remove unbound linker-payload and low molecular weight compounds including reducing agents. Procedure E: Measure the concentration of the antibody in the antibody-drug conjugate and the average number of drug molecules attached to each antibody (DAR value) The concentration of the drug coupled to the antibody-drug conjugate can be obtained by measuring the ultraviolet absorption value of the antibody-drug conjugate aqueous solution at 280 nm and 370 nm and calculating it using the following formula. At any given wavelength, the total absorbance of a system is equal to the sum of the absorbances of all light-absorbing chemicals present in the system (additivity of absorbance). Therefore, assuming that the molar absorption coefficients of the antibody and drug remain unchanged before and after conjugation, the antibody concentration and drug concentration in the antibody-drug conjugate can be expressed by the following formula. A 280 =A D,280 +A A,280 =ε D,280 C D +ε A,280 C A Formula (1) A 370 =A D,370 +A A,370 =ε D,370 C D +ε A,370 C A Formula (2) A 280 represents the total absorbance of the antibody-drug conjugate aqueous solution at 280 nm, A 370 A represents the total absorbance of the antibody-drug conjugate aqueous solution at 370 nm. A,280 represents the absorbance of the antibody at 280 nm, A A,370 represents the absorbance of the antibody at 370 nm, A D,280 Represents the absorbance value of drug molecules at 280nm, A D,370 represents the absorbance value of drug molecules at 370nm, ε A,280 represents the molar extinction coefficient of the antibody at 280 nm, ε A,370 represents the molar extinction coefficient of the antibody at 370 nm, ε D,280 represents the molar extinction coefficient of the drug molecule at 280nm, ε D,370 represents the molar extinction coefficient of the drug molecule at 370 nm, C A represents the concentration of antibody in the antibody-drug conjugate, C D Represents the concentration of drug molecules in the antibody-drug conjugate. ε A,280 , ε A,370 , ε D,280 and ε D,370 is a known value (calculated from the antibody sequence or measured by UV absorption of the compound). A,280It can be calculated using a known method based on the amino acid sequence of the antibody (Protein Science, 1995, Vol. 4, pp. 2411-2423). Antibodies usually have no absorption at 370 nm, so ε A,370 Usually 0. ε D,280 and ε D,370 The value of C can be calculated by measuring the change in absorbance of drug molecules at 280nm and 370nm with concentration, using the Lambert-Beer law (absorbance = molar concentration × molar extinction coefficient × optical path). A and C D The absorbance of the antibody-drug conjugate at 280 nm and 370 nm can be measured. 280 and A 370 , and then solve the two-variable linear equation system formula (1) and (2) to obtain. In addition, through C D Divide by C A , the average number of drug molecules attached to each antibody (DAR value) can be obtained. Procedure F: Measurement of Aggregates in Antibody-Drug Conjugates Aggregates in antibody-drug conjugates were detected by size exclusion chromatography in HPLC as follows: High performance liquid chromatography system: Agilent 1260 Infinity II HPLC system Detector: Ultraviolet absorption spectrometer (detection wavelength: 280nm) Chromatographic column model: TOSOH TSKgel G3000SWXL (7.8×300mm, 5μm) Mobile phase: 200mmol / L KHPO4, 150mmol / L NaCl, 15% (v / v) isopropanol, pH 7.0 Flow rate: 0.75mL / min Analysis time: 18 minutes Column temperature: room temperature Injection volume: 50 μg Data Analysis: The size exclusion chromatogram of the quality control (QC, L1H5 naked antibody, i.e., the antibody numbered L1H5 without the conjugated linker-payload) is shown in Figure 1A; the retention time of the main peak (single peak) of the 150 kDa quality control is between 9.5 and 10.5 minutes. The retention time of the aggregate should be earlier than the retention time of the above monomer. Procedure G: Hydrophobicity measurement of antibody-drug conjugates The hydrophobicity of the antibody-drug conjugate was analyzed using HPLC hydrophobicity chromatography (HIC) as follows: High performance liquid chromatography system: Agilent 1260 Infinity II HPLC system Detector: Ultraviolet absorption spectrometer (detection wavelength: 280nm) Column model: TOSOH TSKgel Butyl-NPR (4.6mm ID×3.5cm, 2.5μm) Mobile phase A: mol / L (NH4)2SO4, 50mmol / L KHPO4, pH 7.0 Mobile phase B: 50mmol / L KHPO4, 25% (v / v) isopropanol, pH 7.0 Analysis time: 25min Column temperature: room temperature Elution program (B%): 0%-25% (0-1 min), 25% (1-3 min), 25%-80% (3-13 min), 80% (13-17 min), 80%-0% (17-17.10 min), 0% (17.10-25 min) Injection volume: 10 μL Data analysis: The hydrophobic chromatography chromatograms of the quality control (QC, L1H5 naked antibody) are shown in Figure 1B and Figure 22; the hydrophobic chromatography chromatogram of the quality control reference antibody is shown in Figure 22. Generally speaking, the shorter the retention time, the weaker the hydrophobicity of the sample. Compared with the naked antibody without drug molecules, the hydrophobicity of the antibody-drug conjugate is higher, so its retention time should be longer. Example 6: Preparation of Antibody-Drug Conjugate L1H5-LP3 Antibody reduction: by operation B in Example 5 (the extinction coefficient of the antibody at 280 nm is 1.49 mL mg -1 cm -1 ) and operation C, the antibody L1H5 prepared in Example 4 was replaced with PBS7.0 / EDTA, and the antibody concentration after the replacement was 20.76 mg / mL. 93.33 μL of 5 mM TCEP solution (equivalent to 7 times the antibody content) was added to 481.70 μL of the aqueous solution of the L1H5 antibody, and 200 μL of 50 mM phosphate buffer (pH 7.0, PBS7.0) and 224.97 μL of ultrapure water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: The above mixture was incubated at 4°C for 10 minutes, and the linker-payload LP3 prepared in Example 3 was dissolved in N,N-dimethylacetamide (DMA) and added to the mixture in a volume of 93.33 μL (equivalent to 14 times the antibody content), and the mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate L1H5-LP3. Characterization of Antibody-Drug Conjugates: Using the procedure E(ε D,280 =5186 and ε D,370 =13688), and operations F and G were used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation E to be 5.73 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 7.78. FIG2A shows the detection spectrum of the aggregates, and the aggregate content of the antibody-drug conjugate L1H5-LP3 measured by operation F is 2.20%. FIG2B shows the hydrophobic chromatography detection spectrum of the antibody-drug conjugate L1H5-LP3, and the retention time of the antibody-drug conjugate measured by operation G is 6.169 min. Example 7: Preparation of Antibody-Drug Conjugate L1H5-LP1 Antibody reduction: by operation B of Example 5 (the extinction coefficient of the antibody at 280 nm is 1.49 mL mg -1 cm -1 ) and operation C to replace the antibody with PBS7.0 / EDTA, and the antibody concentration after the replacement is 11.44 mg / mL. 160 μL of 5 mM TCEP solution (equivalent to 10 times the antibody content) was added to 1048.95 μL of the aqueous solution of L1H5 antibody prepared in Example 4, and 320 μL of 50 mM PBS7.0 and 71.05 μL of ultrapure water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: The above mixture was incubated at 4°C for 10 minutes, and the linker-payload LP1 prepared in Example 1 was dissolved in DMA and added to the mixture in a volume of 120 μL (equivalent to 15 times the antibody content). The mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate L1H5-LP1. Characterization of Antibody-Drug Conjugates: Using Procedure E (εD,280 =6384 and ε D,370 =16180), and operations F and G were used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation E to be 6.12 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 8.03. FIG3A shows the detection spectrum of the aggregates, and the aggregate content of the antibody-drug conjugate L1H5-LP1 measured by operation F is 1.60%. FIG3B shows the hydrophobic chromatography detection spectrum of the antibody-drug conjugate L1H5-LP1, and the retention time of the antibody-drug conjugate L1H5-LP1 measured by operation G is 6.234 min. The preparation methods of drug conjugates of other antibodies, such as L1H4 and L4H4, and LP1 refer to the method described in Example 7. Example 8: Preparation of Antibody-Drug Conjugate L1H5-LP2 Antibody reduction: by operation B of Example 5 (the extinction coefficient of the antibody at 280 nm is 1.49 mL mg -1 cm -1 ) and operation C to replace the antibody with PBS7.0 / EDTA, and the antibody concentration after the replacement is 11.44 mg / mL. 160 μL of 5 mM TCEP solution (equivalent to the antibody content) was added to 1048.95 μL of the aqueous solution of L1H5 antibody prepared in Example 4. 10 times the equivalent of 50 μL of PBS7.0 (320 μL) and 71.05 μL of ultrapure water were added, and the mixture was placed at 37°C for 2 hours. Coupling of antibody and linker-payload: The above mixture was incubated at 4°C for 10 minutes, and the linker-payload LP2 prepared in Example 2 was dissolved in DMA and added to the mixture in a volume of 120 μL (equivalent to 15 times the antibody content). The mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate L1H5-LP2. Characterization of Antibody-Drug Conjugates: Using Procedure E (ε D,280 =5814 and ε D,370 =14742), and operations F and G were used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation E to be 6.28 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 8.89. FIG. 4A shows the detection spectrum of the aggregates, and the aggregate content of the antibody-drug conjugate L1H5-LP2 measured by operation F is 1.89%. FIG. 4B shows the hydrophobic chromatography detection spectrum of the antibody-drug conjugate L1H5-LP2, and the retention time of the antibody-drug conjugate L1H5-LP2 measured by operation G is 6.599 min. Comparative Example 1: Preparation of Antibody-Drug Conjugate Reference ADC Antibody reduction: by operation B in Example 5 (the extinction coefficient of the antibody at 280 nm was 1.77 mL mg -1 cm -1 ) and operation C to replace the antibody with PBS7.0 / EDTA, and the antibody concentration after the replacement is 9.44 mg / mL. 3.27 μL of 5 mM TCEP solution (equivalent to 7 times the antibody content) was added to 0.037 mL of the reference antibody (see SEQ ID NO: 69-72, U1-59 in patent US20190151328A1 for the antibody sequence) in aqueous solution, and 14 μL of 50 mM PBS7.0 and 15.66 μL mL of deionized water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: The mixture was incubated at 4°C for 10 minutes. The linker-payload GGFG-DXd (purchased from DC Chemicals, DC50025) was dissolved in DMA and added to the mixture at a volume of 3.27 μL (equivalent to 14 times the antibody content). The mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain an antibody-drug conjugate reference ADC. Characterization of Antibody-Drug Conjugates: Using the procedure E (ε D,280 =5178 and ε D,370 =20217), operation F and operation G are used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation B to be 3.10 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 6.63. FIG23A shows the detection spectrum of aggregates, and the aggregate content of the antibody-drug conjugate reference ADC measured by operation F was 2.04%. FIG23B shows the detection spectrum of the antibody-drug conjugate reference ADC. According to the hydrophobic chromatography detection spectrum of ADC, the retention time of the antibody-drug conjugate reference antibody-DXd measured by operation G was 8.215 min. Meanwhile, FIG. 22 shows a comparison of the hydrophobicity measurements of the L1H5 antibody prepared in Example 4, the antibody-drug conjugate L1H5-LP3 prepared in Example 6, the reference antibody, and the antibody-drug conjugate reference ADC, and Table 3 shows the retention time of each test sample. The results show that the retention time of the L1H5 antibody and L1H5-LP3 is shorter than that of the positive control reference antibody and the drug-antibody conjugate reference ADC, indicating that both the reference antibody and the drug-antibody conjugate reference ADC are more hydrophobic than the L1H5 antibody and the antibody-drug conjugate L1H5-LP3. It can be expected that due to the weak hydrophobicity of the L1H5 antibody and L1H5-LP3, they have higher stability in vivo. Table 3 Retention time of L1H5, L1H5-LP3, reference antibody and reference ADC Comparative Example 2: Preparation of Antibody-Drug Conjugate Reference Antibody-LP3 Antibody reduction: by operation B in Example 5 (the extinction coefficient of the antibody at 280 nm was 1.77 mL mg -1 cm -1 ) and operation C to replace the antibody with PBS7.0 / EDTA, and the antibody concentration after the replacement is 15.5 mg / mL. 268.80 μL of 5 mM TCEP solution (equivalent to 7 times the antibody content) was added to 1.858 mL of the reference antibody (same sequence as comparative example 1) aqueous solution, and 360 μL of 100 mM PBS7.0 and 1113.14 μL of deionized water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: The mixture was incubated at 4°C for 10 minutes. The linker-payload LP3 was dissolved in DMA and added to the mixture at a volume of 268.80 μL (equivalent to 14 times the antibody content). The mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate reference antibody-LP3. Characterization of the antibody-drug conjugate: The obtained antibody-drug conjugate was characterized using Operation E (εD,280=5186 and εD,370=13688), Operation F and Operation G in Example 5. The concentration of the antibody-drug conjugate was calculated by operation E to be 8.45 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 7.60. FIG24A shows the detection spectrum of aggregates, and the aggregate content of the antibody-drug conjugate reference antibody-LP3 measured by operation F was 1.92%. FIG24B shows the detection spectrum of the antibody-drug conjugate Referring to the hydrophobic chromatography detection spectrum of antibody-LP3, the retention time of the antibody-drug conjugate reference antibody-MCE8 measured by operation G was 6.262 min. Comparative Example 3: Preparation of Antibody-Drug Conjugate L1H5-DXd Antibody reduction: by operation B in Example 5 (the extinction coefficient of the antibody at 280 nm was 1.49 mL mg -1 cm -1 ) and operation C to replace the antibody with PBS7.0 / EDTA, and the antibody concentration after the replacement is 11.44 mg / mL. 90 μL of 5 mM TCEP solution (equivalent to 10 times the antibody content) was added to 0.59 mL of the aqueous solution of L1H5 antibody, and 180 μL of 50 mM PBS7.0 and 39.97 μL of deionized water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: The above mixture was incubated at 4°C for 10 minutes, and the linker-payload GGFG-DXd (purchased from DC Chemicals, DC50025) was dissolved in DMA and added to the mixture in a volume of 67.50 μL (equivalent to 15 times the antibody content), and the mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate L1H5-DXd. Characterization of Antibody-Drug Conjugates: Using the procedure E (ε D,280 =5178 and ε D,370 =20217), operation F and operation G are used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation E to be 5.17 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 6.54. Figure 25A shows the detection spectrum of the aggregates, and the aggregate content of the antibody-drug conjugate L1H5-DXd measured by operation F is 2.02%. Figure 25B shows the hydrophobic chromatography detection spectrum of the antibody-drug conjugate L1H5-DXd, and the retention time of the antibody-drug conjugate L1H5-DXd measured by operation G is 7.807 min. Comparative Example 4: Preparation of Antibody-Drug Conjugate Dxd Isotype Control ADC Antibody reduction: by operation B in Example 5 (the extinction coefficient of the antibody at 280 nm was 1.35 mL mg -1 cm -1 ) and operation C, the antibody was replaced with PBS7.0 / EDTA, and the antibody concentration after the replacement was 10 mg / mL. 326.67 μL of 5 mM TCEP solution (equivalent to 10 times the antibody content) was added to 2.45 mL of an aqueous solution of an isotype control antibody human IgG (purchased from Beijing Solebow Technology Co., Ltd., product model SP001), and 700 μL of 50 mM PBS7.0 and 23.33 μL of deionized water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: Incubate the above mixture at 4°C for 10 minutes, dissolve the linker-payload GGFG-DXd in DMA and add it to the mixture in a volume of 294 μL (equivalent to 18 times the antibody content), and continue to react at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate Dxd isotype control ADC. Characterization of Antibody-Drug Conjugates: Using the procedure E (ε D,280 =5178 and ε D,370 =20217), operation F and operation G are used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation E to be 8.20 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 7.08. Figure 26A shows the detection spectrum of the aggregates, and the aggregate content of the antibody-drug conjugate Dxd isotype control ADC measured by operation F is 4.25%. Figure 26B shows the hydrophobic chromatography detection spectrum of the antibody-drug conjugate Dxd isotype control ADC, and the retention time of the antibody-drug conjugate Dxd isotype control ADC measured by operation G is 8.222 min. Comparative Example 5: Preparation of Antibody-Drug Conjugate LP3 Isotype Control ADC Antibody reduction: by operation B in Example 5 (the extinction coefficient of the antibody at 280 nm was 1.35 mL mg -1 cm -1) and operation C to replace the antibody with PBS7.0 / EDTA, and the antibody concentration after replacement is 10 mg / mL. 672 μL of 5 mM TCEP solution (equivalent to 7 times the antibody content) was added to 4 mL of the aqueous solution of the isotype control antibody human IgG, and 1440 μL of 50 mM PBS7.0 and 1088 μL of deionized water were added at the same time, and the mixture was placed in a 37°C environment for reaction for 2 hours. Coupling of antibody and linker-payload: The mixture was incubated at 4°C for 10 minutes. The linker-payload LP3 was dissolved in DMA and added to the mixture at a volume of 672 μL (equivalent to 14 times the antibody content). The mixture was reacted at 22°C for 30 minutes. Purification of antibody-drug conjugate: The above reaction solution was purified by the method of operation D in Example 5 to obtain antibody-drug conjugate LP3 isotype control ADC. Characterization of Antibody-Drug Conjugates: Using the procedure E (ε D,280 =5186 and ε D,370 =13688), and operations F and G were used to characterize the obtained antibody-drug conjugate. The concentration of the antibody-drug conjugate was calculated by operation E to be 7.42 mg / mL, and the number of effective loads coupled on each antibody was calculated by operation E to be 7.28. Figure 27A shows the detection spectrum of the aggregates, and the aggregate content of the antibody-drug conjugate LP3 isotype control ADC measured by operation F is 5.37%. Figure 27B shows the hydrophobic chromatography detection spectrum of the antibody-drug conjugate LP3 isotype control ADC, and the retention time of the antibody-drug conjugate LP3 isotype control ADC measured by operation G is 6.450 min. Test example 1: Flow cytometry detection of Mu4O3 antibody and cells with different HER3 expression levels Four cell lines, MCF-7 (human breast cancer cells, purchased from the Cell Bank of the Type Culture Collection Committee of the Chinese Academy of Sciences), SW620 (human colon cancer cells, purchased from Zhejiang Meisen Cell Technology Co., Ltd.), SK-BR-3 (human breast cancer cells, purchased from Purchased from Shanghai Xunqing Biotechnology Co., Ltd.), MDA-MB-231 (human breast cancer cells, purchased from Subic (Shanghai) Biotechnology Co., Ltd.) were digested with trypsin in a culture dish, and the digested cells were centrifuged at 1000rpm for 5min and blocked with 10% goat serum (purchased from Beijing Solaibao Technology Co., Ltd., item number SL038) for 30min. After blocking, the Mu4O3 antibody prepared in Example 4 was added at a final concentration of 20μg / mL and incubated for 1h, and then washed twice with phosphate buffer (PBS, pH 7.2-7.4) and FITC-labeled goat anti-mouse secondary antibody (purchased from Jackson ImmunoResarch, item number 111-545-003) was added at 1:500 and incubated for 1h, and finally washed twice with PBS and analyzed using a flow cytometer. The results are shown in Figure 5. In the three HER3-positive cell lines (MCF-7, SW620, SK-BR-3), the detection results of the Mu4O3 antibody were all positive; in the HER3-negative cells (MDA-MB-231), the detection result was negative, and no fluorescent signal was detected. The results show that the Mu4O3 antibody is specific. Detection Example 2: Immunofluorescence detection of Mu4O3 antibody in HER3-GFP Tag overexpressing 293T cells 293T cells (purchased from the cell bank of the Chinese Academy of Sciences Typical Culture Collection Committee) were inoculated in a 24-well cell culture plate to a cell density of 70%. The human HER3 recombinant plasmid HER3-GFP Tag with a GFP tag (purchased from Hunan Keai Medical Instrument Co., Ltd., item number G109862) was transfected with a cationic polymer-polyethyleneimine (PEI) transfection method. The specific method was as follows: 0.5 μg of plasmid and 1.5 μg of PEI were mixed in 500 μL of Opti-MEM medium (purchased from Thermo Fisher Scientific (China) Co., Ltd., item number 31985070), and the mixture was slowly added to the cell culture well after stabilization at room temperature for 15 minutes, and returned to the 37°C cell culture incubator. After 24 hours, the cells were washed with PBS and fixed with 4% tissue cell fixative (PFA) for 10 minutes, and then blocked with 10% goat serum (purchased from Beijing Solebold Technology Co., Ltd., item number SL038) for 30 minutes after washing with PBS. After blocking, Mu4O3 antibody was added at a final concentration of 20 μg / mL for 1 hour, and then washed twice with PBS and then APC-labeled goat anti-mouse secondary antibody (purchased from Jackson ImmunoResarch, catalog number 111-585-003) was added at a dilution of 1:500 for 1 hour, washed twice with PBS, and then DAPI (4',6-diamidino-2-phenylindole) solution was added for 5 minutes, and then washed twice with PBS and then photographed under a fluorescence microscope. Figure 6 shows the immunofluorescence image of Mu4O3 antibody in HER3-GFP Tag overexpressing 293T cells, and the results show that HER3 protein and Mu4O3 antibody staining have obvious co-localization characteristics. In Figure 6, the picture marked with GFP only shows green fluorescence, indicating that HER3 protein was successfully transfected into 293T cells and expressed in both the cytoplasm and the cell membrane; the picture marked with Mu4O3 only shows red fluorescence, indicating that the Mu4O3 antibody successfully stained the overexpressed cells, and the staining was membrane-localized; the picture marked with DAPI only shows blue fluorescence, indicating that it was staining of the cell nucleus; the picture marked with MERGED is a merged picture after superimposing the above three separate staining pictures, in which part of the membrane-localized green light can completely overlap with the membrane-localized red light, and the fluorescence intensity is consistent, proving that the Mu4O3 antibody specifically stains the overexpressed HER3 protein, and no Mu4O3-bound red fluorescence staining was found in cells without overexpression (only the cell nucleus is stained with blue, no green light), indicating that the Mu4O3 antibody has no non-specific staining. Test Example 3: In vitro killing test of SW620 cells by Mu4O3 antibody SW620 cells (human colon cancer cells, purchased from Zhejiang Meisen Cell Technology Co., Ltd.) were cultured to a cell density of 80%. The cells were collected and plated on a 96-well plate, and the cell density was adjusted to 2-5 x 104 / ml. 100μl of Mu4O3 antibody or mouse anti-IgG (MouseIgG, purchased from Abimate Pharmaceutical Technology (Shanghai) Co., Ltd.) prepared in Example 4 was diluted 3 times from 300nM as the starting concentration. After the dilution, the cell culture medium was added, and 2μg / mL of MMAE-coupled sheep anti-mouse secondary antibody (purchased from Abimate Pharmaceutical Technology (Shanghai) Co., Ltd., item number B30008) was added at the same time, and the culture was static for 5 days. During this period, cell apoptosis was observed regularly. After 5 days, 15μl of CCK-8 stock solution was added directly to the 96-well plate, and the absorbance at 450nm was measured after reacting in a 37°C incubator for 0.5-2h. The cell survival curve was drawn according to the test results and the antibody dilution gradient. The results are shown in FIG7 , which show that the Mu4O3 antibody has an obvious specific cell killing effect. Test Example 4: Flow cytometry affinity test of Hu4O3 antibody candidate molecules in MDA-MB-453 and SW620 cell lines SW620 (human colon cancer cells) and MDA-MB-453 (human breast cancer cells, purchased from Zhejiang Meisen Cell Technology Co., Ltd.) were digested with trypsin from the culture dish, and the digested cells were centrifuged at 1000 rpm for 5 min and blocked with 10% goat serum (purchased from Beijing Solaibao Technology Co., Ltd., catalog number SL038) for 30 min. Hu4O3 antibody was diluted 3 times with a starting concentration of 500 nM. After completion, the gradient diluted Hu4O3 antibody was added to the cells and incubated for 1 hour. After washing with PBS twice, FITC-labeled goat anti-human secondary antibody (purchased from Jackson ImmunoResarch, catalog number 109-545-008) was added at 1:500 and incubated for 1 hour. Finally, after washing with PBS twice, the results were analyzed by flow cytometry. Figures 8 and 9 show the flow cytometry affinity test data of Hu4O3 antibody candidate molecules L1H4, L1H5, L2H4, L2H5, L4H4, L4H5, and L4H7 in MDA-MB-453 and SW620 cell lines. The results show that all candidate molecules have specific binding to both cell lines, and the binding affinities are different. L1H4 and L1H5 show better affinity for MDA-MB-453 cells, EC 50 L1H4, L1H5, L4H4 and L4H7 showed better affinity for SW620 cells, EC 50 They were 193.5nM, 146.7nM, 90.0nM, and 21.9nM respectively, followed by L2H4 and EC 50 It is 1203nM. Test Example 5: In vitro cell proliferation inhibition experiment of L1H5 antibody and reference antibody on SK-BR-3 cell line SK-BR-3 (human breast cancer cells) were cultured to a cell density of 80%, and the cells were collected and plated in 96-well plates. The cell density was adjusted to 2-5 x 10 4 / ml. 100μl was spread in each well, and the antibody was added to the cell culture medium at a final concentration of 100μg / ml and cultured for 5 days. During this period, cell apoptosis was observed regularly. After 5 days, 15μl of CCK-8 stock solution was added to the 96-well plate, and the absorbance at 450nm was measured after reacting in a 37℃ incubator for 0.5-2h. The cell survival ratio was calculated based on the test results compared with the blank control. Figure 10 shows the cell proliferation inhibition rates of the L1H5 antibody, the reference antibody and the blank control in the SK-BR-3 cell line prepared in Example 4. The results show that the in vitro cell proliferation inhibition effect of L1H5 on SK-BR-3 is better than that of the reference antibody. Test Example 6: In vivo tumor inhibition experiment in mouse breast cancer CDX model Six-week-old Balb / c nude mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. Five million BT-474 cells (human breast ductal carcinoma cells) were subcutaneously inoculated in each mouse. 3 The L1H5 prepared in Example 4, the reference antibody (positive control), and the blank control PBS (negative control) were subcutaneously injected at a dose of 20 mg / kg. The treatment was performed once a week for a total of two weeks. After administration, the tumor volume was measured twice a week using a vernier caliper, and the tumor volume was calculated according to the following formula: TV = (length × width) 2 / 2. FIG. 11 shows the in vivo tumor volume-time curve of the BT-474 breast cancer mouse model. The results show that L1H5 can inhibit tumor growth and is comparable to the positive reference antibody. Test Example 7: In vitro killing test of Hu4O3 antibody candidate molecule-drug conjugate on SW620 cells Culture SW620 (human colon cancer cells) to a cell density of 80%, collect the cells, spread them on a 96-well plate, and adjust the cell density to 2-5 x 10 4 / ml. 100μl was spread in each well, and the ADC molecule was diluted 3 times with a starting concentration of 300nM. After the dilution was completed, the cell culture medium was added and cultured for 5 days. During this period, cell apoptosis was observed regularly. After 5 days, 15μl of CCK-8 stock solution was added to the 96-well plate, and the absorbance at 450nm was measured after reacting in a 37℃ incubator for 0.5-2h. The cell survival curve was drawn according to the test results and the dilution gradient of ADC. Figure 12 shows the cell survival curves of the antibody-drug conjugates L1H4-LP1, L1H5-LP1, L4H4-LP1 prepared in Example 7 and the antibody-drug conjugate positive control reference ADC prepared in Comparative Example 1 in the SW620 cell line. The results show that the in vitro cell killing effects of L1H4-LP1, L1H5-LP1 and L4H4-LP1 on the SW620 cell line are better than those of the reference ADC, and L1H5-LP1 has the best cell proliferation inhibition effect on the SW620 cell line. Test Example 8: In vitro cell killing experiment of L1H5 antibody, L1H5-LP3, reference antibody, and reference ADC on SK-BR-3 and BXPC-3 cell lines SK-BR-3 (human breast cancer cells) and BXPC-3 (human pancreatic cancer cells, purchased from the Cell Bank of Typical Culture Collection Committee of the Chinese Academy of Sciences) were cultured to a cell density of 80%. The cells were collected and plated on 96-well plates. The cell density was adjusted to 2-5 x 10 4 / ml. 100μl was spread in each well, and the antibody and ADC molecules were diluted 3 times with a starting concentration of 300nM. After the dilution was completed, the cell culture medium was added and cultured for 5 days. During this period, cell apoptosis was observed regularly. After 5 days, 15μl of CCK-8 stock solution was added to the 96-well plate, and the absorbance at 450nm was measured after reacting in a 37℃ incubator for 0.5-2h. The cell survival curve was drawn according to the test results and the dilution gradient of the antibody and ADC. Figures 13 and 14 are cell survival curves of the L1H5 antibody prepared in Example 4, the antibody-drug conjugate L1H5-LP3 prepared in Example 6, the reference antibody (positive control), and the antibody-drug conjugate reference ADC (positive control) prepared in Comparative Example 1 in SK-BR-3 cell line and BXPC-3 cell line, respectively. The results show that the in vitro cell killing effect of L1H5-LP3 on the two cell lines is significantly better than that of the reference ADC, the cell proliferation inhibition effect of L1H5 antibody on the SK-BR-3 cell line is better than that of the reference antibody, and neither the L1H5 antibody nor the reference antibody exhibits in vitro killing effect on the BXPC-3 cell line. Test Example 9: In vitro killing test of L1H5-LP1 and L1H5-LP2 on HCT-15 cells HCT-15 (human colon cancer cells) were cultured to a cell density of 80%, and the cells were collected and plated in 96-well plates. The cell density was adjusted to 2-5 x 10 4 / ml. 100μl was spread in each well, and the ADC molecule was diluted 3 times with a starting concentration of 300nM. After the dilution was completed, the cell culture medium was added and cultured for 5 days. During this period, cell apoptosis was observed regularly. After 5 days, 15μl of CCK-8 stock solution was added to the 96-well plate, and the absorbance at 450nm was measured after reacting in a 37℃ incubator for 0.5-2h. The cell survival curve was drawn according to the test results and the dilution gradient of ADC. Figure 15 is a cell survival curve of the antibody-drug conjugate L1H5-LP1 prepared in Example 7, L1H5-LP2 prepared in Example 8, and the antibody-drug conjugate positive control reference ADC prepared in Comparative Example 1 in the HCT-15 cell line. The results show that the in vitro cell killing effects of L1H5-LP1 and L1H5-LP2 on the HCT-15 cell line are significantly better than those of the reference ADC. Test Example 10: In vivo tumor inhibition experiment in mouse colon cancer CDX model Six-week-old Balb / c nude mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. Five million HCT-15 cells were subcutaneously inoculated in each mouse. 3 The reference ADC prepared in comparative example 1, L1H5-LP2 prepared in example 8, and L1H5-LP1 prepared in example 7 were intravenously injected at a dose of 10 mg / kg, and a blank control (negative control) group was set up and intravenously injected with an equal dose of PBS. The administration was once a week for a total of three times. The tumor volume was measured twice a week using a vernier caliper, and the tumor volume was calculated according to the following formula: TV = (length × width) 2 Figure 16 shows the in vivo tumor volume-time curve of the HCT-15 colon cancer mouse model. The results show that both L1H5-LP1 and L1H5-LP2 can inhibit tumor growth and are slightly better than the positive reference ADC. Test Example 11: In vivo tumor inhibition experiment in mouse colon cancer PDX model NU / NU mice, 6 weeks old, female, weighing 18-21 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The mice were subcutaneously inoculated with colon cancer tumors (the specimen number of colon cancer tissue is 361795, from Xi'an Lidi Biotechnology Co., Ltd.). When the average tumor volume reached 150 mm 3The reference ADC prepared in Comparative Example 1, L1H5-LP3 prepared in Example 6, L1H5-LP1 prepared in Example 7, Dxd isotype control ADC prepared in Comparative Example 4, and LP3 isotype control ADC prepared in Comparative Example 5 were intravenously injected at a dosage of 10 mg / kg, and a blank control (negative control) group was set up and an equal dose of PBS was intravenously injected. The administration was performed once a week for a total of 3 times. After administration, the tumor volume was measured twice a week using a vernier caliper, and the tumor volume was calculated according to the following formula: TV = (length × width) 2 / 2. FIG. 17 shows a graph of the in vivo tumor volume-time changes in a colon cancer mouse model. The results show that, compared with the positive control reference ADC, L1H5-LP3 and L1H5-LP1 significantly inhibited tumor growth. Test Example 12: In vivo tumor inhibition experiment in mouse EGFR-TKI-resistant lung adenocarcinoma PDX model 6-week-old female NU / NU mice weighing 18-21 g were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Each mouse was subcutaneously inoculated with EGFR-TKI-resistant lung adenocarcinoma tumors (the specimen number of EGFR-TKI-resistant lung adenocarcinoma tissues is 0025- 200717, from Xi'an Lidi Biotechnology Co., Ltd.). When the average tumor volume reaches 150mm 3 The reference ADC prepared in Comparative Example 1, L1H5-LP3 prepared in Example 6, L1H5-LP1 prepared in Example 7, Dxd isotype control ADC prepared in Comparative Example 4, and LP3 isotype control ADC prepared in Comparative Example 5 were intravenously injected at a dose of 10 mg / kg, and a control Vehicle group was set up to intravenously inject an equal dose of PBS. The administration was performed once a week for a total of 2 times. After administration, the tumor volume was measured twice a week using a vernier caliper, and the tumor volume was calculated according to the following formula: TV = (length × width) 2 / 2. FIG. 18 shows the in vivo tumor volume-time curve of the EGFR-TKI-resistant lung adenocarcinoma mouse model. The results show that L1H5-LP3 and L1H5-LP1 significantly inhibited tumor growth compared with the positive control reference ADC. Test Example 13: In vivo tumor inhibition experiment in mouse colon cancer CDX model Six-week-old Balb / c nude mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. Five million SW620 cells were subcutaneously inoculated in each mouse, and the average tumor volume was about 150 mm 3, L1H5-DXd prepared in Comparative Example 3, reference antibody-LP3 prepared in Comparative Example 2, L1H5-LP3 prepared in Example 6, reference ADC prepared in Comparative Example 1, and negative control PBS were intravenously injected at a dose of 10 mg / kg. Once a week, for a total of three weeks. After administration, the tumor volume was measured twice a week using a vernier caliper, and the tumor volume was calculated according to the following formula: TV = (length × width) 2 / 2. FIG19 is an in vivo tumor volume-time curve of the mouse colon cancer CDX model. It can be seen that L1H5-DXd, L1H5-LP3 and reference antibody-LP3 are more advantageous than the positive control reference ADC. Figure 20 is a partial enlarged view after removing the negative control PBS group from Figure 19. It can be clearly seen from the figure that the four active molecules are arranged from high to low according to the overall in vivo tumor inhibition effect, namely L1H5-LP3>L1H5-DXd>reference antibody-LP3>reference ADC. Test Example 14: In vivo tumor inhibition experiment in mouse pancreatic cancer CDX model 6-week-old female NU / NU mice weighing 18-21 g were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Each mouse was subcutaneously inoculated with a pancreatic cancer tumor (the specimen number of pancreatic cancer tissue is: 0033-361319, from Xi'an Lidi Biotechnology Co., Ltd.). When the average tumor volume reached 150 mm 3 The reference ADC prepared in Comparative Example 1, L1H5-LP3 prepared in Example 6, and L1H5-LP1 prepared in Example 7 were intravenously injected at a dosage of 10 mg / kg; the Dxd isotype control ADC prepared in Comparative Example 4 and the LP3 isotype control ADC prepared in Comparative Example 5 were intravenously injected, and a blank control group was set up and intravenously injected with an equal dose of PBS. The administration was performed once a week for a total of three times. The tumor volume was measured twice a week using a vernier caliper, and the tumor volume was calculated according to the following formula: TV = (length × width) 2 / 2. Figure 21 is the in vivo tumor inhibition curve of the pancreatic cancer mouse model. The results show that the positive control reference ADC, L1H5-LP3 and L1H5-LP1 can significantly inhibit tumor growth in the initial stage of administration. During the administration cycle, the tumor inhibition effects of L1H5-LP3 and L1H5-LP1 are significantly better than those of the positive control reference ADC; and the duration of tumor inhibition is significantly longer than that of the reference ADC. The antibody-drug conjugate prepared in the embodiment of the present disclosure has a more excellent in vivo anti-tumor effect than the ADC coupled with GGFG-DXd. L1H5-LP3 has an in vivo efficacy superior to that of the reference ADC in multiple tumor models; and L1H5-LP3 has a more lasting tumor inhibition effect in individual models. In addition, L1H5-LP3 has a similar maximum tolerated dose (MTD) to that of GGFG-Dxd ADC. It is expected that the drug conjugate has a higher therapeutic window than the ADC coupled with GGFG-Dxd. The antibody-drug conjugate provided by the present disclosure has excellent safety.

Claims

1. An anti-HER3 antibody or an antigen-binding fragment thereof, comprising at least one light chain variable region (VL) and a heavy chain variable region (VH), wherein: CDR1 of VL comprises the amino acid sequence shown in SEQ ID NO: 1, CDR2 comprises the amino acid sequence shown in SEQ ID NO: 2, and CDR3 comprises the amino acid sequence shown in SEQ ID NO: 3; The CDR1 of VH comprises the amino acid sequence shown in SEQ ID NO:4, CDR2 comprises an amino acid sequence that differs from the amino acid sequence shown in SEQ ID NO:5 by no more than 5, 4, 3, 2, 1, or 0 mutations, and CDR3 comprises the amino acid sequence shown in SEQ ID NO:

6.

2. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 1, wherein the CDR2 of the VH comprises one or more mutations selected from (a) or (b): (a) C52N, T62N, T66K and G67S; (b) C52Y, T62N, T66K and G67S.

3. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein the CDR2 of the VH comprises the mutation of (a) or (b): (a) C52N, T62N, T66K and G67S; (b) C52Y, T62N, T66K and G67S.

4. The anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, wherein: The anti-HER3 antibody or antigen-binding fragment thereof comprises a VH and VL combination selected from one of the groups (c) to (j): (c) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO:9 and SEQ ID NO:10, respectively; (d) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO: 11 and SEQ ID NO: 14, respectively; (e) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO: 11 and SEQ ID NO: 15, respectively; (f) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 14, respectively; (g) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 15, respectively; (h) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO: 13 and SEQ ID NO: 14, respectively; (i) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequences set forth in SEQ ID NO: 13 and SEQ ID NO: 15, respectively; and (j) VL and VH comprise amino acid sequences that are at least 85%, 90%, 95%, 96%, 97%, 98%, and 99% identical to the amino acid sequences shown in SEQ ID NO: 13 and SEQ ID NO: 16, respectively.

5. The anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein: The anti-HER3 antibody or antigen-binding fragment thereof comprises a VH and VL combination selected from one of the groups (c) to (j): (c) VL comprises the amino acid sequence as shown in SEQ ID NO:9 and conservative substitution variants thereof, and VH comprises the amino acid sequence as shown in SEQ ID NO:10 and conservative substitution variants thereof; (d) VL comprises the amino acid sequence as shown in SEQ ID NO: 11 and conservative substitution variants thereof, and VH comprises the amino acid sequence as shown in SEQ ID NO: 14 and conservative substitution variants thereof; (e) VL comprises the amino acid sequence as shown in SEQ ID NO: 11 and conservative substitution variants thereof, and VH comprises the amino acid sequence as shown in SEQ ID NO: 15 and conservative substitution variants thereof; (f) VL comprises the amino acid sequence shown in SEQ ID NO: 12 and conservative substitution variants thereof, and VH comprises the amino acid sequence shown in SEQ ID NO: 14 and conservative substitution variants thereof; (g) VL comprises the amino acid sequence shown in SEQ ID NO: 12 and conservative substitution variants thereof, and VH comprises the amino acid sequence shown in SEQ ID NO: 15 and conservative substitution variants thereof; (h) VL comprises the amino acid sequence as shown in SEQ ID NO: 13 and conservative substitution variants thereof, and VH comprises the amino acid sequence as shown in SEQ ID NO: 14 and conservative substitution variants thereof; (i) VL comprises the amino acid sequence shown in SEQ ID NO: 13 and conservative substitution variants thereof, and VH comprises the amino acid sequence shown in SEQ ID NO: 15 and conservative substitution variants thereof; (j) VL comprises the amino acid sequence shown in SEQ ID NO: 13 and conservative substitution variants thereof, and VH comprises the amino acid sequence shown in SEQ ID NO: 16 and conservative substitution variants thereof.

6. The anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, wherein: The anti-HER3 antibody or antigen-binding fragment thereof specifically binds to human HER3.

7. A nucleic acid encoding the anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6. A vector comprising the nucleic acid according to claim 7.

9. A host cell comprising the nucleic acid of claim 7 and / or the vector of claim 8.

10. An antibody-drug conjugate having a structure as shown in Formula I, Ab-(LD)n (I) or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, in, Ab is the anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6; L is a linker covalently linked to Ab and D respectively; D is the effective load; n is a value between 1 and 10. The antibody-drug conjugate according to claim 10 , wherein the linker is a cleavable linker and a non-cleavable linker.

12. The antibody-drug conjugate of claim 10 or 11, wherein the linker comprises a cleavable peptide. The antibody-drug conjugate of claim 12 , wherein the cleavable peptide is cleavable by an enzyme.

14. The antibody-drug conjugate of claim 13, wherein the enzyme comprises cathepsin B.

15. The antibody-drug conjugate according to any one of claims 10 to 14, wherein the cleavable peptide or L comprises amino acid units.

16. The antibody-drug conjugate of claim 15, wherein the amino acid unit comprises a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide.

17. The antibody-drug conjugate according to claim 16, wherein the amino acid unit is selected from any one or a combination of Val-Cit, Val-Ala, Glu-Val-Cit, Ala-Ala-Asn, Gly-Val-Cit, Gly-Gly-Gly and Gly-Gly-Phe-Gly.

18. The antibody-drug conjugate according to any one of claims 10 to 17, wherein the linker comprises a self-degradable unit. The antibody-drug conjugate of claim 18 , wherein the self-degradable unit comprises p-aminobenzyloxycarbonyl (PABC) or p-aminobenzyl (PAB).

20. The antibody-drug conjugate of any one of claims 12 to 19, wherein the cleavable peptide is cleaved directly to the self-degradable unit.

21. The antibody-drug conjugate according to any one of claims 10 to 20, wherein the linker comprises a structure as shown in -L1-L2-L3-, L1 represents -(succinimidyl-3-yl-N)-(CH2)m 1 -C(=O)-, -CH2-C(=O)-NH-(CH2)m 2 -C(=O)- or -C(=O)-(CH2)m 3 -C(=O)-, where m 1 represents an integer from 2 to 8, m 2 represents an integer from 1 to 8, m 3 Represents an integer from 1 to 8; L2 represents an amino acid unit; L3 represents a self-degradable unit.

22. The antibody-drug conjugate according to any one of claims 10 to 21, wherein L is selected from: -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-PABC-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-PABC-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; and -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-.

23. The antibody-drug conjugate according to any one of claims 19 to 22, wherein the p-aminobenzyloxycarbonyl (PABC) or p-aminobenzyl (PAB) is linked to a polysarcosine (poly-N-methylglycine) residue or a methylamino group.

24. The antibody-drug conjugate according to any one of claims 10 to 23, wherein the linker is as shown in Formula II, The linker shown in formula II is bonded to the reduced sulfhydryl group of the antibody interchain disulfide chain through a succinimide group through a thioether bond; The carbonyl group in the ester group of the linker shown in Formula II is connected to the amino group in the effective load; R1, R2 are each independently selected from hydrogen, methyl or isopropyl; R3 represents -(CR5HCONH)n 1 -(CH2CONH)n 2 - or a single bond, R5 is selected from hydrogen or benzyl, n 1 represents an integer from 0 to 2, n 2 Represents an integer from 0 to 2; R4 represents methylamino or -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 1 to 20.

25. The antibody-drug conjugate according to claim 24, wherein in the linker of formula II, R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 8 to 15.

26. The antibody-drug conjugate according to claim 24 or 25, wherein in the linker shown in formula II, R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 10 to 12.

27. The antibody-drug conjugate according to any one of claims 24 to 26, wherein in the linker of formula II, R3 represents -(CR5HCONH)n 1 -(CH2CONH)n 2 - or a single bond, R5 is selected from benzyl, n 1 Indicates 1 or 2, n 2 represents 1 or 2; R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 8 to 15.

28. The antibody-drug conjugate according to any one of claims 24 to 27, wherein in the linker shown in formula II, R3 represents a single bond; R4 represents -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 8 to 15.

29. The antibody-drug conjugate according to any one of claims 24 to 28, wherein in the linker represented by formula II, R3 represents a single bond; and R4 represents a methylamino group.

30. The antibody-drug conjugate according to any one of claims 10-29, wherein the linker is selected from one or more of the following groups:

31. The antibody-drug conjugate according to any one of claims 10-30, wherein the effective load is selected from at least one of the group consisting of a cytotoxic agent, a label, a nucleic acid, a radionuclide, a hormone, an immunomodulator, a prodrug converting enzyme, a ribonuclease, an agonist antibody, an antagonist antibody, and a fragment, fusion protein or derivative thereof.

32. The antibody-drug conjugate of claim 31, wherein the cytotoxic agent comprises a tubulin inhibitor and / or a topoisomerase inhibitor; The microtubule protein inhibitors include auristatin or its derivatives, maytansine or its derivatives; The topoisomerase inhibitor includes camptothecin or its derivatives.

33. The antibody-drug conjugate according to any one of claims 10 to 32, wherein the effective load is exitecan as shown in formula III, connected to the linker via the nitrogen atom of the amino group on the cyclohexane ring, 34. The antibody-drug conjugate according to any one of claims 10 to 33, which is selected from one of the following groups n is 1-10 or 4-10.

35. A method for preparing the antibody-drug conjugate according to any one of claims 10 to 34, comprising the following steps: After the antibody or antigen-binding fragment thereof is subjected to reduction treatment, the interchain disulfide bonds are at least partially reduced and react with the reactive groups of the linker in the linker-payload to obtain an antibody-drug conjugate having a structure as shown in Formula I. Ab-(LD)n (I) or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, wherein Ab is the anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6; L is a linker covalently linked to Ab and D respectively; D is the effective load; n is a value between 1 and 10. The preparation method according to claim 35 , wherein the linker is a cleavable linker and a non-cleavable linker.

37. The preparation method according to claim 35 or 36, wherein the linker comprises a cleavable peptide.

38. The preparation method according to claim 37, wherein the cleavable peptide is cleavable by an enzyme.

39. The preparation method according to claim 38, wherein the enzyme comprises cathepsin B.

40. The preparation method according to any one of claims 35 to 39, wherein the cleavable peptide or L comprises amino acid units.

41. The preparation method according to claim 40, wherein the amino acid unit comprises a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide.

42. The preparation method according to claim 41, wherein the amino acid unit is selected from any one or a combination of Val-Cit, Val-Ala, Glu-Val-Cit, Ala-Ala-Asn, Gly-Val-Cit, Gly-Gly-Gly and Gly-Gly-Phe-Gly. The preparation method according to any one of claims 35 to 42, wherein the linker comprises a self-degradable unit. The preparation method according to claim 43, wherein the self-degradable unit comprises p-aminobenzyloxycarbonyl (PABC) or p-aminobenzyl (PAB).

45. The preparation method according to any one of claims 37 to 44, wherein the cleavable peptide is directly cleaved to the self-degradable unit.

46. ​​The preparation method according to any one of claims 35 to 45, wherein the linker comprises a structure as shown in -L1-L2-L3-, L1 represents -(succinimidyl-3-yl-N)-(CH2)m 1 -C(=O)-, -CH2-C(=O)-NH-(CH2)m 2 -C(=O)- or -C(=O)-(CH2)m 3 -C(=O)-, where m 1 represents an integer from 2 to 8, m 2 represents an integer from 1 to 8, m 3 Represents an integer from 1 to 8; L2 represents an amino acid unit; L3 represents a self-degradable unit.

47. The preparation method according to any one of claims 35 to 49, wherein L is selected from: -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-PABC-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-PABC-; -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-O-CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; and -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-.

48. The preparation method according to any one of claims 44 to 47, wherein the p-aminobenzyloxycarbonyl (PABC) or p-aminobenzyl (PAB) is linked to a polysarcosine (poly-N-methylglycine) residue or a methylamino group.

49. The preparation method according to any one of claims 35 to 48, comprising the following steps: After the anti-HER3 antibody or antigen-binding fragment thereof is subjected to reduction treatment, the interchain disulfide bond is at least partially reduced, and reacts with the 3-position carbon atom of the maleimide-N-group of the linker portion shown in Formula IV in the linker-payload. In the linker-payload, the carbonyl group in the ester group of the linker shown in Formula IV is connected to the amino group of the payload; In formula IV, R1 and R2 are each independently selected from hydrogen, methyl or isopropyl; R3 represents -(CR5HCONH)n 1 -(CH2CONH)n 2 - or a single bond, R5 is selected from hydrogen or benzyl, n 1 Integer from 0 to 2, n 2 Represents an integer from 0 to 2; R4 represents methylamino or -(NCH3COCH2)n 3 -NCH3COCH3, n 3 Indicates an integer from 1 to 20.

50. The preparation method according to claim 49, further comprising: The anti-HER3 antibody or antigen-binding fragment thereof is reacted with a reducing agent in a buffer solution containing a chelating agent, a linker-payload solution is added, and the pH is adjusted.

51. The preparation method according to claim 49 or 50, further comprising: The effective load is exitecan shown in formula III, and the nitrogen atom of the amino group on its cyclohexane ring is connected to the carbonyl group of the ester group in formula IV, 52. A pharmaceutical composition comprising the anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6 or the antibody-drug conjugate according to any one of claims 10 to 34, or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or combination thereof, and a pharmaceutically acceptable excipient.

53. A kit comprising the anti-HER3 antibody or antigen-binding fragment thereof according to any one of 1-6 or the antibody-drug conjugate according to any one of claims 10-34, or an isomer, isotopic variant, pharmaceutically acceptable salt, prodrug, solvate, or a combination thereof.

54. Use of the anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, the antibody-drug conjugate according to any one of claims 10 to 34, the antibody-drug conjugate prepared by the method according to any one of claims 35 to 51, or the pharmaceutical composition according to claim 52, or the kit according to claim 53 in the preparation of a therapeutic agent for diagnosing, preventing or treating a tumor disease.

55. The use according to claim 54, comprising use in the preparation of a medicament targeting HER3.

56. The use according to claim 54 or 55, wherein the tumor comprises a solid tumor expressing HER3.

57. The use according to any one of claims 54-56, wherein the tumor disease comprises lung cancer, renal cancer, urothelial carcinoma, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, metastatic breast cancer, luminal breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumors, cervical cancer, head and neck cancer, esophageal cancer, epidermoid carcinoma, peritoneal cancer, adult glioblastoma multiforme, liver cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, liver malignancies, anal cancer, penile cancer and lung adenocarcinoma.

58. A method for diagnosing, preventing and treating a tumor disease, comprising administering to a subject a therapeutic dose of a therapeutic agent, wherein the therapeutic agent comprises the anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, the antibody-drug conjugate according to any one of claims 10 to 34, the antibody-drug conjugate prepared by the method of any one of claims 35 to 51, the pharmaceutical composition of claim 52, or the kit of claim 53.

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