Anti-HER3 antibody-drug conjugate, composition thereof and use thereof

Abstract

The present invention provides an anti-HER3 antibody-drug conjugate comprising a linked antibody moiety, an intermediate linker moiety and a cytotoxic drug moiety. The provided antibody-drug conjugate has excellent antitumor activity and / or good safety. The provided antibody-drug conjugate can be used for the treatment of cancer.

Description

[Technical field]

[0001] The present invention relates to an antibody-drug conjugate comprising a linked antibody moiety, an intermediate linker moiety and a cytotoxic drug moiety. The present invention also relates to the use of said antibody-drug conjugate in the manufacture of a medicament for treating cancer. [Background technology]

[0002] HER3 (human epidermal growth factor receptor 3), also known as ErbB-3 (receptor tyrosine-protein kinase erbB-3), is a member of the human epidermal growth factor receptor (HER / EGFR / ERBB) family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). HER3 has an extracellular ligand-binding domain (ECD), a dimerization domain within the ECD, a transmembrane domain, a protein tyrosine kinase domain (TKD) and a C-terminal phosphorylation domain, but lacks intracellular tyrosine kinase activity.

[0003] Neuregulin (NRG, also known as heregulin, HRG), a ligand of HER3, activates receptor-mediated signaling pathways by binding to the extracellular domain of HER3 and promoting dimerization with other HER family members and transphosphorylation of its intracellular domain. Dimerization of HER3 with other HER family members extends the signaling capacity of HER3 and is used as a means of signal diversification as well as signal amplification. For example, HER2 / HER3 heterodimer induces one of the most important mitogenic signals among HER family members. HER3 is commonly expressed in a variety of cancers, including breast, ovarian, colon, gastric, lung, skin, and pancreatic cancers.

[0004] Antibody-drug conjugates (ADCs) are drugs that combine the high specificity of a therapeutic antibody with the high killing activity of a cytotoxic drug, in which the therapeutic antibody moiety and the cytotoxic drug moiety are linked by an intermediate linker moiety. At present, there are at least 10 ADC drugs on the market worldwide. Among them, the antibody moieties of brentuximab vedotin, polatuzumab vedotin and enfortumab vedotin target CD30, CD79b and Nectin-4, respectively; the antibody moieties of trastuzumab emtansine and trastuzumab deruxtecan target HER2; the antibody moieties of gemtuzumab ozogamicin and inotuzumab ozogamicin target CD33 and CD22, respectively; and sacituzumab govitecan target HER2. The antibody portion of govitecan targets TROP2, and the newly approved belantamab mafodotin and loncastuximab tesirine target BCMA and CD19, respectively.The cytotoxic drug moieties brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, and belantamab mafodotin all use auristatins that act on microtubules; trastuzumab emtansine uses maytansinoid toxin molecules that act on microtubules; gemtuzumab ozogamicin and inotuzumab ozogamicin use calicheamicins toxin molecules that act on DNA; and trastuzumab deruxtecan. Both of the molecules (deruxtecan and sacituzumab govitecan) use camptothecin-like toxin molecules, while (loncastuximab tesirine) uses a PBD dimer that acts on DNA. The middle linker moieties (trastuzumab emtansine and belantamab mafodotin) use non-cleavable linkers, while the other eight molecules all use cleavable linkers.

[0005] Eribulin (formula I) is a synthetic analogue of the marine natural product halichondrin B, which can inhibit the growth phase of microtubules and acts through a tubulin-based antimitotic mechanism, causing G2 / M cell cycle arrest, spindle disruption in mitosis, and finally apoptosis after prolonged mitotic arrest. Currently, eribulin is approved for the treatment of metastatic breast cancer and soft tissue sarcoma. [ka]

[0006] ADC drugs combine the two advantages of the high efficacy of cytotoxic small molecules and the high selectivity of antibodies to specific tumor cells. Currently, there is still a need to develop effective and low-toxicity ADC drugs for more indications. Summary of the Invention

[0007] Antibody-drug conjugates (ADCs): The present invention provides an antibody-drug conjugate, wherein an antibody or antigen-binding fragment thereof is conjugated to the cytotoxic drug eribulin or a derivative thereof, preferably, said antibody or antigen-binding fragment thereof specifically binds to HER3.

[0008] In one aspect of the invention, the general formula Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, comprising the formula: where Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and n is an integer or decimal selected from 1 to 10. In some embodiments, the antibody moiety Ab and the linker moiety are linked by a specific functional group, and the antibody moiety can specifically bind to an antigen.

[0009] In one aspect of the invention, the general formula is Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, wherein the cytotoxic drug moiety U and the antibody moiety Ab are conjugated by a linker moiety L. In some specific embodiments, in the antibody drug conjugates or pharma- ceutically acceptable salts or solvates thereof provided by the invention, each cytotoxic drug moiety U and antibody moiety Ab is conjugated by one linker moiety L. The linker moiety L of the invention may be linked to the antibody moiety by any method known in the art, preferably, the linker moiety and the antibody moiety are linked by a mercapto group and / or an amino group. In some more preferred embodiments, the linker moiety of the invention is linked to the antibody moiety by a mercapto group.

[0010] In one aspect of the invention, the general formula is Ab-(LU)n or a pharma- ceutically acceptable salt or solvate thereof, wherein the cytotoxic drug moiety U and the antibody moiety Ab are conjugated by a linker moiety L, which may be a cleavable linker or a non-cleavable linker. In some embodiments, the linker moiety of the present invention is a cleavable linker, such as a low pH degradable type (including hydrazone bond, carbonate bond, etc.), a protease degradable type (including peptide bond), or a high glutathione concentration degradable type (including disulfide bond). The cleavable linker can be cleaved in the target cell, thereby releasing the cytotoxic drug. In some embodiments, the linker moiety of the present invention is a non-cleavable linker, such as a maleimidocaproyl group.

[0011] In one aspect of the invention, the general formula is Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, wherein the antibody moiety Ab is conjugated to one or more cytotoxic drug moieties U; and the cytotoxic drug may be selected from, for example, alkaloids, antimetabolites, antitumor antibiotics, alkylating agents, platinums, etc., with preferred cytotoxic drugs being microtubule inhibitors (including maytansinoids, auristatins, eribulins, etc.) or DNA acting cytotoxic drugs (including calicheamicins, duocarmycins, PBDs (pyrrolobenzodiazepines), topoisomerase I inhibitors, etc.).

[0012] In some specific embodiments, the general formula provided by the present invention is Ab-(LU) n The cytotoxic drug moiety U of the antibody drug conjugate, which is:

[0013] In some specific embodiments, the general formula provided by the present invention is Ab-(LU) nor a pharma- ceutically acceptable salt or solvate thereof is eribulin or a derivative thereof.

[0014] In some embodiments, the cytotoxic drug moiety and the linker moiety are linked by a functional group, and within tumor cells, the cytotoxic drug molecule is liberated to exert an anti-tumor effect.

[0015] In one aspect of the invention, the general formula Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and n is selected from an integer or decimal point of 1 to 10, with the proviso that said antibody drug conjugate comprises a structure represented by the following formula IIa: [ka] During the ceremony, R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, Or, R a and R b and the atoms connected thereto form an optionally substituted 5-8 membered heterocyclyl group. a and R bare each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group. a and R b is a hydrogen atom.

[0016] In some embodiments, the antibody-drug conjugate comprises the structure set forth in formula IIa-1: [ka]

[0017] In some embodiments of the invention, the general formula Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, comprising the formula: wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and n is selected from an integer or decimal number of 1 to 10, with the proviso that -U is a structure represented by formula IIa: During the ceremony, R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 Heteroaryl groups are selected from Or, R a and R b and the atoms connected thereto form an optionally substituted 5-8 membered heterocyclyl group. a and R bare each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group. a and R b is a hydrogen atom. In some embodiments, -U is a structure represented by formula IIa-1:

[0018] In some embodiments, the general formula provided by the present invention is Ab-(LU) n The antibody-drug conjugate, or a pharma- ceutically acceptable salt or solvate thereof, comprises the structure shown in Formula IIIa: [ka] During the ceremony, R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, Or, R a and R b and the atoms connected thereto form an optionally substituted 5-8 membered heterocyclyl group. a and R b are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group. a and R b is a hydrogen atom.

[0019] In some embodiments, the antibody-drug conjugate comprises the structure set forth in formula IIIa-1: [ka]

[0020] In some embodiments, the general formula provided by the present invention is Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof has the structure represented by formula IV: [ka] During the ceremony, Ab represents the antibody moiety; n is an integer or decimal number selected from 1 to 10; R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, Or, R a and R b and the atoms connected thereto form an optionally substituted 5-8 membered heterocyclyl group. a and R b are each a hydrogen atom or C 1~5 independently selected from alkyl groups (preferably C 1~4 is an alkyl group, e.g., C1~3 In some embodiments, R a and R b are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group. a and R b is a hydrogen atom.

[0021] In a specific embodiment of the present invention, there is provided an antibody-drug conjugate having the following formula IV-1, or a pharma- ceutically acceptable salt or solvate thereof: [ka] During the ceremony, Ab is the antibody moiety, n is selected from integers or decimals of 1 to 10.

[0022] In some embodiments, in the antibody-drug conjugate or pharma- ceutically acceptable salt or solvate thereof, n is 2 to 4.8, 2.6 to 4.8, 3.5 to 4.8, 4 to 4.8, 2 to 4.5, 2.6 to 4.5, 3.5 to 4.5, 4 to 4.5, 3.5 to 4.2, 3.5 to 4, 4 to 4.2, 7 to 8, 7 to 7.9, 7 to 7.6, 7 to 7.5, 7.1 to 8, 7.1 to 7.9, 7.1 to 7.6, 7.5 to 8, 7.6 to 8, or 7.6 to 7.9. In some embodiments, n is about 2.6, about 4, about 4.2, about 4.8, about 7, about 7.1, about 7.5, about 7.6, about 7.9, or about 8.

[0023] The number of cytotoxic agents conjugated to the antibody moiety in an antibody-drug conjugate (ADC) of the invention may vary, such that the antibody-drug conjugates, or pharma- ceutically acceptable salts or solvates thereof, provided by the invention may be heterogeneous, i.e., the antibody-drug conjugates, or pharma- ceutically acceptable salts or solvates thereof, of the invention comprise antibodies or antigen-binding fragments thereof having differing numbers of cytotoxic agents conjugated thereto, e.g., 0 (i.e., no cytotoxic agent), 1, 2, 3, 4, 5, 6, 7, 8 or more molecules of cytotoxic agent conjugated to one antibody or antigen-binding fragment thereof.

[0024] By controlling the ratio of the antibodies or antigen-binding fragments thereof conjugated with different numbers of cytotoxic drugs, antibody-drug conjugates or pharma- ceutically acceptable salts or solvates thereof with different drug-antibody ratios (DARs) can be obtained. In the present specification, "DAR" and "n" may be used interchangeably. The DAR or n is the average molar ratio of the cytotoxic drug to the antibody or antigen-binding fragment thereof in the ADC, i.e., the number of cytotoxic drugs conjugated per molecule of the antibody or antigen-binding fragment thereof. For example, "DAR is about 4" or "n is about 4" refers to an antibody-drug conjugate or pharma-ceutically acceptable salts or solvates thereof that is a heterogeneous mixture containing antibodies or antigen-binding fragments thereof conjugated with different numbers of cytotoxic drugs per molecule (e.g., 0, 1, 2, 3, 4, 5, 6, 7, or 8 cytotoxic drugs conjugated to each antibody or antigen-binding fragment thereof), where the average molar ratio of the cytotoxic drug to the antibody or antigen-binding fragment thereof is about 4. Similarly, "the DAR is about 8" or "n is about 8" refers to an average molar ratio of cytotoxic drug to antibody or antigen-binding fragment thereof in the ADC that is about 8.

[0025] In one embodiment, the present invention provides a compound of the general formula Ab-(LU) nor a pharma- ceutically acceptable salt or solvate thereof, wherein Ab (antibody moiety) is capable of specific binding to a tumor antigen, said tumor antigen may be selected from any tumor therapeutic target known in the art, non-limiting examples of which include HER2, HER3, EGFR, CD20, CD30, CD33, CD47, CD79b, VEGF, VEGFR, MET, RET, PD-1, or PD-L1. In some embodiments of the invention, there is provided an antibody-drug conjugate of formula IV-1, or a pharma-ceutically acceptable salt or solvate thereof, wherein Ab (antibody moiety) is capable of specific binding to a tumor antigen, said tumor antigen may be selected from any tumor therapeutic target known in the art, non-limiting examples of which include HER2, HER3, EGFR, CD20, CD30, CD33, CD47, CD79b, VEGF, VEGFR, MET, RET, PD-1, or PD-L1.

[0026] In some embodiments, in the antibody-drug conjugate, or a pharma- ceutically acceptable salt, or solvate thereof, Ab is an anti-HER3 antibody, or an antigen-binding fragment thereof.

[0027] In some embodiments, the Ab is an anti-HER3 antibody or an antigen-binding fragment thereof, and the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain CDR (HCDR) 1 of the amino acid sequence set forth in SEQ ID NO: 1, an HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, an HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3, a light chain CDR (LCDR) 1 of the amino acid sequence set forth in SEQ ID NO: 4, an LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and an LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6.

[0028] The amino acid sequences of the CDRs of the anti-HER3 antibodies or antigen-binding fragments thereof are provided in Table S1 below.

[0029] In some embodiments, the general formula provided by the present invention is Ab-(LU) nThe antibody portion of the antibody-drug conjugate, or a pharma- ceutically acceptable salt or solvate thereof, is Patritumab, having the sequence shown in Table S1 below. [Table 1]

[0030] In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region has an amino acid sequence that matches at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%. 8, wherein the light chain variable region comprises an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the amino acid sequence of the heavy chain variable region of the anti-HER3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 7 and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 8.

[0031] In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof may further comprise an immunoglobulin constant region, or a fragment, analog, variant, or derivative of the constant region. In some embodiments, the constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3, and IgG4, or other classes of immunoglobulin heavy chains, preferably an IgG1 heavy chain. In some embodiments, the constant region may comprise any of the modifications described herein, such as amino acid insertions, deletions, substitutions, or chemical modifications. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be replaced by an amino acid residue of any allotype.

[0032] In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, and the heavy chain has an amino acid sequence that matches at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequence set forth in SEQ ID NO:9. 100%, and the light chain comprises an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 9 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the amino acid sequence of the heavy chain of the anti-HER3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 9 and the amino acid sequence of the light chain is set forth in SEQ ID NO: 10. QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 9) DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10)

[0033] In some embodiments, the anti-HER3 antibody is selected from the group consisting of the following antibodies: Patritumab, Seribantumab, Elgemtumab, Durigotuzumab, CDX-3379, Lumretuzumab, or GSK2849330. In some specific embodiments, the anti-HER3 antibody is Patritumab.

[0034] In some embodiments, the anti-HER3 antibody, or antigen-binding fragment thereof, is selected from a monoclonal antibody, a multispecific antibody, a Fab fragment, a Fab' fragment, a F(ab)'2 fragment, an Fd fragment, an Fv fragment, a dAb fragment, an isolated CDR region, an scFv, a nanobody, or a fusion protein.

[0035] In some embodiments, the antibody-drug conjugate of the invention, or a pharma- ceutically acceptable salt or solvate thereof, has the general formula Ab-(LU): n where the Ab may be modified, e.g., by one or more amino acid sequence changes, additions, or deletions, provided that the modified Ab retains the activity of specifically binding to its corresponding antigen.

[0036] In some embodiments, the antibody drug conjugate provided by the present invention, or a pharma- ceutically acceptable salt or solvate thereof, has the structure shown below: [ka] In some such embodiments, n is 2 to 4.8, 2.6 to 4.8, 3.5 to 4.8, 4 to 4.8, 2 to 4.5, 2.6 to 4.5, 3.5 to 4.5, 4 to 4.5, 3.5 to 4.2, 3.5 to 4, 4 to 4.2, 7 to 8, 7 to 7.9, 7 to 7.6, 7 to 7.5, 7.1 to 8, 7.1 to 7.9, 7.1 to 7.6, 7.5 to 8, 7.6 to 8, or 7.6 to 7.9. In some specific embodiments, n is about 2.6, about 4, about 4.2, about 4.8, about 7, about 7.1, about 7.5, about 7.6, about 7.9, or about 8.

[0037] In one embodiment, the present invention provides a compound of the general formula Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, having the following properties: (a) Binding to HER3 (b) blocking the binding of HER3 to a ligand; (c) Demonstrate endocytosis in cells expressing HER3 (d) It has killing activity against tumor cells expressing HER3. (e) There is a bystander effect. One or more combinations of the above are shown.

[0038] In some embodiments, the antibody drug conjugate, or a pharma- ceutically acceptable salt or solvate thereof, binds to human HER3.

[0039] In some embodiments, the antibody-drug conjugates or pharma- ceutically acceptable salts or solvates thereof provided by the present invention exhibit strong endocytosis in cells with different HER3 expression levels, and can continuously accumulate the amount of endocytosed ADC with increasing endocytosis time.

[0040] Pharmaceutical Compositions: In one aspect of the invention, a pharmaceutical composition is provided comprising an antibody-drug conjugate of the invention or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments of the invention, a pharmaceutical composition is provided comprising an antibody-drug conjugate according to the invention or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier. Pharmaceutically acceptable carriers include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other agents.

[0041] Usage: In one aspect of the present invention, there is provided a use of the antibody-drug conjugate of the present invention or a pharma- ceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating cancer. In one aspect of the present invention, there is provided a use of a pharmaceutical composition comprising the antibody-drug conjugate of the present invention or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier in the manufacture of a medicament for treating cancer. In one aspect of the present invention, there is provided a use of the pharmaceutical composition of the present invention in the manufacture of a medicament for treating cancer.

[0042] In one aspect of the present invention, there is provided an antibody-drug conjugate, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described above, for treating cancer.

[0043] In one aspect of the invention, there is provided a method for treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody-drug conjugate of the invention, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising an antibody-drug conjugate of the invention, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier. In one aspect of the invention, there is provided a method for treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention. In some embodiments, the method comprises contacting tumor cells with the antibody-drug conjugate, or a pharma- ceutically acceptable salt or solvate thereof, or the pharmaceutical composition, thereby killing or inhibiting the growth of tumor cells.

[0044] In some embodiments, administering to a patient a therapeutically effective amount of an antibody-drug conjugate of the present invention, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention can kill tumor cells or inhibit the growth of tumor cells.

[0045] In one aspect of the present invention, there is provided a use of the antibody-drug conjugate of the present application or a pharma- ceutically acceptable salt or solvate thereof for treating cancer. In one aspect of the present invention, there is provided a use of the pharmaceutical composition of the present application, comprising the antibody-drug conjugate of the present application or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier, for treating cancer. In another aspect of the present invention, there is provided a use of the pharmaceutical composition of the present invention for treating cancer.

[0046] In some embodiments, in the above methods or uses, the patient is unsuitable for treatment with a drug that targets HER2. In some embodiments, in the above methods or uses, the patient is resistant to a drug that targets HER2.

[0047] In some embodiments, in the above method or use, the cancer is a HER3 positive cancer. In some embodiments, the antibody-drug conjugate of the present invention or a pharma- ceutically acceptable salt or solvate thereof can be used to treat a cancer that expresses HER3 protein. In some embodiments, administering to a patient a therapeutically effective amount of the antibody-drug conjugate of the present invention or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present invention, can kill tumor cells that express HER3 or inhibit the growth of tumor cells that express HER3. Examples of cancer include, but are not limited to, biliary tract cancer, carcinosarcoma, esophageal cancer, esophagogastric junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer, renal cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, melanoma, pharyngeal cancer, oral cancer, skin cancer, lung cancer, glioblastoma multiforme, glioblastoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, liver cancer, salivary gland cancer, vulvar cancer, thyroid cancer, testicular cancer, anal cancer, or penile cancer.

[0048] Linker-drug intermediate compounds: In some embodiments of the present invention, there are provided linker-drug intermediate compounds having the structure shown in Formula III: [ka] During the ceremony, R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C5~12 heteroaryl groups, Or R a and R b and the atoms connected thereto form an optionally substituted 5- to 8-membered heterocyclyl group.

[0049] In some embodiments, the linker-drug intermediate compound has the structure of formula III, wherein R a and R b are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group.

[0050] In one specific embodiment of the present invention, there is provided a linker-drug intermediate compound having the structure shown in formula III-1: [ka] Effect of the Invention

[0051] The linker structure used in the present invention links the antitumor compound eribulin or a derivative thereof with an antibody or an antigen-binding fragment thereof, and the provided antibody-drug conjugate has excellent antitumor effect and / or safety. In some embodiments, the antitumor effect and / or safety of the antibody-drug conjugate is superior to that of eribulin. In some embodiments, the antitumor effect and / or safety of the antibody-drug conjugate is superior to that of anti-HER3 antibody-drug conjugate U3-1402 (Patritumab deruxtecan) of Daiichi Sankyo Co., Ltd. In some embodiments, the provided anti-HER3 antibody-drug conjugate shows good killing activity against tumor cells, and shows good killing activity against various tumor cells and / or cells with different HER3 expression levels (high and / or moderate and / or low). In some embodiments, the provided anti-HER3 antibody-drug conjugate shows good killing activity against trastuzumab-resistant tumor cells. In some embodiments, the provided anti-HER3 antibody-drug conjugate has excellent safety. In some embodiments, the provided antibody-drug conjugate, for example, the anti-HER3 antibody-drug conjugate, is less prone to aggregation. Some studies have shown that using the linker structure of the present invention to link the anti-tumor compound eribulin or a derivative thereof to an antibody or an antigen-binding fragment thereof can improve the anti-aggregation properties of the antibody-drug conjugate. [Brief description of the drawings]

[0052] [Figure 1A] FIG. 1A shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab at different DAR values ​​against cells with different HER3 expression levels. [Figure 1B] FIG. 1B shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab with different DAR values ​​against cells with different HER3 expression levels. [Figure 1C] FIG. 1C shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab with different DAR values ​​to cells with different HER3 expression levels. [Figure 1D] FIG. 1D shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab with different DAR values ​​against cells with different HER3 expression levels. [Figure 1E] FIG. 1E shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab with different DAR values ​​to cells with different HER3 expression levels. [Figure 1F] FIG. 1F shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab with different DAR values ​​against cells with different HER3 expression levels. [Figure 1G] FIG. 1G shows the binding activity of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab with different DAR values ​​against cells with different HER3 expression levels. [Figure 2A] FIG. 2A shows endocytosis of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab at different DAR values ​​in cells with different HER3 expression levels. [Figure 2B] Figure 2B shows the endocytosis of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab at different DAR values ​​in cells with different HER3 expression levels. [Figure 2C] FIG. 2C shows endocytosis of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab at different DAR values ​​in cells with different HER3 expression levels. [Figure 2D] Figure 2D shows the endocytosis of patritumab-eribulin conjugate, patritumab-DDDXd-D8, and patritumab at different DAR values ​​in cells with different HER3 expression levels. [Figure 3A] FIG. 3A shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3B]FIG. 3B shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3C] FIG. 3C shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3D] FIG. 3D shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3E] FIG. 3E shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3F] FIG. 3F shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3G] FIG. 3G shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3H] FIG. 3H shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 3I] FIG. 3I shows the cell killing rates of patritumab-eribulin conjugate and patritumab-DDDXd-D8 with different DAR values ​​against cells with different HER3 expression levels. [Figure 4] FIG. 4 shows the effects of patritumab-eribulin conjugate, patritumab-DDDXd-D8 and solvent control with different DAR values ​​on the change in tumor volume in mice subcutaneously implanted in nude mice with JIMT-1 human breast cancer cells. [Diagram 5]FIG. 5 shows the effects of patritumab-eribulin conjugate, patritumab-DDDXd-D8 and solvent control with different DAR values ​​on tumor weight in mice subcutaneously implanted in nude mice with JIMT-1 human breast cancer cells. [Figure 6] FIG. 6 shows the effects of patritumab-eribulin conjugate, patritumab-DDDXd-D8 and solvent control with different DAR values ​​on mouse body weight change in a nude mouse subcutaneous tumor model of JIMT-1 human breast cancer cells.

[0053] Description and definition: Unless otherwise specified, the following terms used in this application have the following meanings: Certain terms, unless otherwise defined, are to be understood in their ordinary sense in the art and not as open ended or unclear. When trade names are mentioned in this specification, they refer to the corresponding products or their active ingredients.

[0054] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the compound after substitution is stable. When the substituent is an oxygen substituent (=O), two hydrogen atoms are replaced. Oxygen substitution does not occur in aryl groups.

[0055] The term "optional" or "optionally" refers to the fact that the subsequently described item or circumstance may or may not occur, including the occurrence of the item or circumstance and the absence of the item or circumstance. The term "optionally substituted" refers to substituted or unsubstituted, for example, an ethyl group is "optionally" substituted with a halogen, and the ethyl group may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (e.g., CF2CF3). As will be understood by those skilled in the art, a group containing one or more substituents does not allow for substitution or substitution forms that are not spatially possible and / or cannot be synthesized.

[0056] In this specification, C m~n means that the moiety has an integer or fractional number of carbon atoms within a given range. For example, "C 1~6 " means that the subject group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0057] When a particular variable (e.g., R) occurs more than one time in a compound composition or structure, each occurrence is independently defined. Thus, for example, if a subject group is substituted with two R, each R is independently selected.

[0058] When the number of a particular connecting group is 0, for example, -(CH2)0-, this indicates that the connecting group is a covalent bond.

[0059] When a variable is selected from a covalent bond, it represents a direct connection between the two groups that are connected by it, for example, when L represents a covalent bond in ALZ, it represents that the structure is actually AZ.

[0060] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0061] The term "hydroxy" refers to an -OH group.

[0062] The term "cyano" refers to the radical -CN.

[0063] The term "mercapto" refers to -SH.

[0064] The term "amino group" refers to the -NH2 group.

[0065] The term "nitro" refers to the -NO2 group.

[0066] The term "alkyl group" refers to a group having the general formula C n H 2n+1The alkyl group may be linear or branched. For example, the term "C 1~6 The term "alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the above definition applies to the alkyl group portion (i.e., alkyl group) of an alkoxy group, an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group.

[0067] The term "alkoxy" refers to an -O-alkyl group.

[0068] The term "alkylamino" refers to the group -NH-alkyl.

[0069] The term "dialkylamino" refers to an -N(alkyl)2 group.

[0070] The term "alkylsulfonyl" refers to the group -SO2-alkyl.

[0071] The term "alkylthio" refers to an -S-alkyl group.

[0072] The term "alkenyl group" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms in a straight or branched chain and having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl groups.

[0073] The term "alkynyl group" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms in a straight or branched chain and having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl groups (-C≡CH), 1-propynyl groups (-C≡C-CH), 2-propynyl groups (-CH2-C≡CH), 1,3-diacetylenyl groups (-C≡CC≡CH), and the like.

[0074] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring generally has 3 to 10 members. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, and the like.

[0075] The term "cycloalkenyl group" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring is generally 5-8 membered. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0076] The term "heterocyclyl group" refers to a non-aromatic ring that may be fully saturated or partially unsaturated (but not fully unsaturated heteroaryl groups) and may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycle is generally a 3-7 membered ring containing 1-3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

[0077] The term "heterocycloalkyl group" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycloalkyl group is generally a 3- to 7-membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl ... thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl, thia Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

[0078] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic aromatic cyclic group having a conjugated pi-electron system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene, and the like.

[0079] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O or S, the remaining ring atoms being C, and at least one aromatic ring. Preferably, the heteroaryl group has one 4-8 membered ring, especially a 5-8 membered ring, or multiple fused rings containing 6-14, especially 6-10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, and the like.

[0080] A "derivative" is a compound formed by replacing an atom or an atomic group of a parent compound molecule with another atom or an atomic group, and is called a derivative of the parent compound.

[0081] The compounds and intermediates of the present application may exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted by a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions by proton transfer, such as ketone-enol isomerization, imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can be transferred between two ring nitrogen atoms. Valence tautomers include interconversions by rearrangement of some bond electrons.

[0082] The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included. Compounds of the present application that contain asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized using asymmetric starting materials or reagents.

[0083] Any atom of the compound synthesized by labeling according to the present invention may represent any stable isotope of that atom unless otherwise specified. Unless otherwise specified, when a position of a structure is defined as H, i.e., hydrogen (H-1), that position contains only naturally occurring isotopes. Similarly, unless otherwise specified, when a position of a structure is defined as D, i.e., deuterium (H-2), the amount of isotope at that position is at least 3340 times more than the amount of naturally occurring isotope (0.015%) (i.e., contains at least 50.1% deuterium isotope), and when one or more positions in the structure of a compound synthesized by labeling are defined as D, i.e., deuterium (H-2), the content of the compound represented by the structure may be at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98.5%, at least 99%, or at least 99.5%. The deuteration ratio of the compound synthesized by labeling according to the present invention refers to the ratio of the isotope content of the compound synthesized by labeling to the amount of naturally occurring isotopes. The deuteration ratio of each target deuterium atom of the compound synthesized by labeling according to the present invention may be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times (99%), or at least 6633.3 times (99.5%). In the present invention, isotopologues refer to compounds that differ only in their isotopic composition in terms of their chemical structure. Compounds synthesized by labeling according to the present invention have the same chemical structure, and differ only in the isotopic composition of the atoms of the molecules. Therefore, a compound containing deuterium at a specific position that is labeled and synthesized according to the present invention also contains a small amount of a hydrogen isotope species at that position, and the amount of a hydrogen isotope species at a certain position in a compound labeled and synthesized according to the present invention is determined by many factors, such as the purity of the deuterium isotope in the deuteration reagent (D2O, D2, NaBD4, LiAlD4, etc.) and the effectiveness of the synthesis method for introducing the deuterium isotope.However, the total amount of hydrogen isotope species at such a position is less than 49.9%. The total amount of hydrogen isotope species at a position of a compound synthesized by labeling according to the present invention is less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5%.

[0084] In this invention, each atom not designated as deuterium is present in its natural isotopic abundance.

[0085] The term "bystander effect" as used herein refers to the effect that a cytotoxic drug conjugated to an antibody or antigen-binding fragment thereof by a cleavable or non-cleavable linker has the ability to diffuse across the cell membrane upon release from the antibody or antigen-binding fragment thereof, resulting in killing of adjacent cells. The ability to diffuse across the cell membrane is related to the hydrophobicity of the cytotoxic drug or the combination of the cytotoxic drug and the linker. Such cytotoxic drugs are, for example, eribulin or MMAE. The bystander effect is particularly desirable for tumors with heterogeneous target expression and solid tumors with limited antibody penetration.

[0086] The term "treatment" means administering a compound or pharmaceutical composition described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with said disease, and includes, but is not limited to, the following: (i) Preventing the appearance of a disease or disease state in a mammal, particularly when a mammal susceptible to the disease state has not been diagnosed with the disease state. (ii) inhibiting the disease or disease state, i.e. inhibiting its progression; (iii) alleviating a disease or disease state, i.e., eliminating the disease or disease state; (iv) reducing either the direct or indirect pathological effects of the disease or disease state.

[0087] The term "therapeutically effective amount" refers to a dose of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The "therapeutically effective amount" of a compound or pharmaceutical composition of the present application depends on several factors, for example, the compound or pharmaceutical composition and its ability to elicit a desired response in an individual, the state of the disease and its severity, the mode of administration, and the age, sex, and weight of the mammal to be treated. The effective amount may generally be determined by one of skill in the art based on his or her knowledge or the contents of this disclosure.

[0088] The term "pharmacologically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are medically determined to be suitable for use in contact with the tissues of humans and animals, not toxic or irritating, and not likely to cause an allergic reaction or other problem or complication, and for which the benefit-to-risk ratio is reasonable.

[0089] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0090] The term "solvate" refers to a substance formed when a compound is associated with solvent molecules.

[0091] The term "antibody" is used in the broadest sense to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, multifunctional antibodies, and antibody fragments, so long as they possess the desired biological activity.

[0092] The term "humanized antibody" refers to an antibody that contains CDR regions derived from a non-human antibody, while the remaining portions of the antibody molecule are derived from one or more human antibodies.

[0093] The term "mutant" refers to a peptide that contains an amino acid sequence that is derived from the amino acid sequence of the peptide by replacing one or more amino acids with amino acids different from the original peptide, deleting one or more wild-type amino acids, inserting one or more amino acids not present in the wild-type, and / or adding amino acids not present in the wild-type to the amino-terminus (N-terminus) and / or carboxy-terminus (C-terminus) of the wild-type (collectively referred to as "mutations"). In the present invention, "insertion" is also included in "addition".

[0094] The term "CDR (complementarity determining region)", also called "hypervariable region", refers to each region of an antibody variable domain that forms loops that are highly variable in sequence and / or have a defined structure. Natural tetrabodies generally contain six CDRs, three in the heavy chain variable region and three in the light chain variable region.

[0095] The term "variable region" refers to a domain of about 100 to 110 or more amino acids that is defined by the N-terminal domain of the light chain or heavy chain of an antibody and is mainly responsible for antigen recognition. The terms "light chain variable region (VL)" and "heavy chain variable region (VH)" refer to these light chain and heavy chain domains, respectively.

[0096] The term "Fab" refers to a molecule that contains a light chain constant domain (CL) and a heavy chain first constant domain (CH1), as well as variable domains VL (light chain variable region) and VH (heavy chain variable region) in the light and heavy chains, respectively. The variable domains contain the complementarity determining regions (CDRs) involved in antigen binding.

[0097] The term "scFv" comprises the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In some embodiments, the scFv further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the required structure for antigen binding.

[0098] The term "antibody moiety" refers to the portion of the antibody of an antibody-drug conjugate that, in certain embodiments, is linked to an intermediate linker moiety by a specific functional group and that is capable of specifically binding to an antigen.

[0099] The term "linker moiety" refers to the moiety that links the antibody moiety and the cytotoxic drug moiety in an antibody-drug conjugate and may be cleavable or non-cleavable; a cleavable linker can be cleaved within the target cell, thereby releasing the cytotoxic drug.

[0100] The term "cytotoxic drug moiety" refers to the portion of the cytotoxic drug in the antibody-drug conjugate, which in some particular embodiments is linked to an intermediate linker moiety by a functional group, and in tumor cells, the cytotoxic drug molecule is liberated to exert an antitumor effect.

[0101] The term "trastuzumab" (generic name Trastuzumab) is a recombinant humanized monoclonal antibody that selectively acts on the ECD4 of human epidermal growth factor receptor-2 (HER2) and can be used to treat HER2-positive cancers. One example is the therapeutic monoclonal antibody product sold under the trade name HERCEPTIN®.

[0102] The term "Patritumab" or "Patritumab" is a fully human anti-HER3 monoclonal antibody that can be used to treat cancers that express the HER3 protein.

[0103] The term "HER2" refers to the second member of the EGFR family and has tyrosine kinase activity, but the expression level of HER2 can be detected by immunohistochemistry, and HER2 positive refers to IHC3+, HER2 negative refers to IHC1+ / 0, and IHC2+ needs to be further confirmed by ISH detection.

[0104] The term "HER3" (human epidermal growth factor receptor 3, also known as ErbB3) is a receptor protein tyrosine kinase that belongs to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases, which also includes HER1 (also called EGFR), HER2, and HER4. HER3 is a transmembrane receptor composed of an extracellular ligand-binding domain (ECD), a dimerization domain within the ECD, a transmembrane domain, an intracellular protein tyrosine kinase domain (TKD), and a C-terminal phosphorylation domain. HER3 has been found to be overexpressed in several types of cancer (e.g., breast, gastrointestinal, and pancreatic cancers). A correlation has been shown between HER2 / HER3 expression and progression from non-invasive to invasive stages.

[0105] The term "triple-negative breast cancer" refers to breast cancer that is negative for the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2.

[0106] The term “EC 50 " refers to the effective concentration that elicits 50% of the maximal response of an antigen-binding construct. EC 50 can be measured by ELISA or FACS analysis or any other method known in the art.

[0107] The term "identity" is also referred to as match. The "percent identity" of an amino acid sequence refers to the percentage of amino acid residues in the compared sequence that are the same as those in the specific amino acid sequence shown herein, after comparing the compared sequence with the specific amino acid sequence shown herein and introducing gaps, if necessary, to reach the maximum sequence identity percentage, and not considering any conservative substitutions as part of the sequence identity. Comparison of amino acid sequences for identity may be performed using various methods within the skill of the art, for example, using the software BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR). Those skilled in the art can determine appropriate parameters for sequence comparison, including any algorithm that will give the maximum comparison coverage over the entire length of the compared sequences.

[0108] As used herein, the terms "subject," "patient," or "subject" may be used interchangeably. In some embodiments, the term "subject," "patient," or "subject" is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0109] As used herein, "about" refers to an acceptable range of error for a particular value as determined by a person skilled in the art, which is determined in part by the limits of the measurement method, i.e., the measurement system, of the value. For example, according to common knowledge in the art, "about" refers to within 1 or more than 1 standard deviation. Or, "about" refers to a range of up to ±5%, for example, within a range of ±2%, within a range of ±1%, or within a range of ±0.5% of the indicated numerical range. When a particular value is indicated in the present specification or claims, unless otherwise specified, the meaning of "about" is understood to be within an acceptable error range for the particular value. In the present specification, unless otherwise specified, the value indicated for a parameter or condition of a step is considered to be modified by "about". DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0110] The present invention also provides the following several specific embodiments, but the protection scope of the present invention is not limited thereto. (Embodiment 1) General formula Ab-(LU) n or a pharma- ceutically acceptable salt or solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and n is selected from an integer or decimal number of 1 to 10, with the proviso that said antibody drug conjugate comprises a structure represented by the following formula IIa: [ka] During the ceremony, R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, Or, R a and R b and the atoms linked thereto form an optionally substituted 5-8 membered heterocyclyl group, or a pharma- ceutically acceptable salt or solvate thereof.

[0111] (Embodiment 2) The antibody-drug conjugate of embodiment 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate comprises the structure shown in formula IIIa: [ka]

[0112] (Embodiment 3) The antibody-drug conjugate has a structure represented by formula IV: [ka] During the ceremony, Ab represents the antibody moiety; The antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof according to embodiment 1 or 2, wherein n is an integer or decimal selected from 1 to 10.

[0113] (Embodiment 4) R a and R b are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group, or the antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 3.

[0114] (Embodiment 5) The antibody-drug conjugate of embodiment 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate comprises a structure shown in the following formula IIIa-1: [ka]

[0115] (Embodiment 6) The antibody-drug conjugate of embodiment 3, or a pharma- ceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate has a structure represented by the following formula IV-1: [ka]

[0116] (Embodiment 7) The antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 6, wherein n is 2 to 4.8, 2.6 to 4.8, 3.5 to 4.8, 4 to 4.8, 2 to 4.5, 2.6 to 4.5, 3.5 to 4.5, 4 to 4.5, 3.5 to 4.2, 3.5 to 4, 4 to 4.2, 7 to 8, 7 to 7.9, 7 to 7.6, 7 to 7.5, 7.1 to 8, 7.1 to 7.9, 7.1 to 7.6, 7.5 to 8, 7.6 to 8, or 7.6 to 7.9.

[0117] (Embodiment 8) The antibody-drug conjugate or pharma- ceutically acceptable salt or solvate thereof described in embodiment 7, wherein n is about 2.6, about 4, about 4.2, about 4.8, about 7, about 7.1, about 7.5, about 7.6, about 7.9, or about 8.

[0118] (Embodiment 9) The antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 8, wherein the Ab is an anti-HER3 antibody or an antigen-binding fragment thereof.

[0119] (Embodiment 10) The antibody-drug conjugate or pharma- ceutically acceptable salt or solvate thereof described in embodiment 9, wherein the anti-HER3 antibody or antigen-binding fragment thereof comprises an HCDR1 having an amino acid sequence shown in SEQ ID NO: 1, an HCDR2 having an amino acid sequence shown in SEQ ID NO: 2, an HCDR3 having an amino acid sequence shown in SEQ ID NO: 3, an LCDR1 having an amino acid sequence shown in SEQ ID NO: 4, an LCDR2 having an amino acid sequence shown in SEQ ID NO: 5, and an LCDR3 having an amino acid sequence shown in SEQ ID NO: 6.

[0120] (Embodiment 11) The antibody-drug conjugate or pharma- ceutically acceptable salt or solvate thereof described in embodiment 10, wherein the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region comprises an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO: 7 and the light chain variable region comprises an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO: 8, or the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 8.

[0121] (Embodiment 12) The antibody-drug conjugate or pharma- ceutically acceptable salt or solvate thereof described in embodiment 10 or 11, wherein the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 9, and the light chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0122] (Embodiment 13) The antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof described in embodiment 9, wherein the anti-HER3 antibody is patritumab.

[0123] (Embodiment 14) The antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof has the following characteristics: (a) Binding to HER3 (b) blocking the binding of HER3 to a ligand; (c) Demonstrate endocytosis in cells expressing HER3 (d) It has killing activity against tumor cells expressing HER3. (e) There is a bystander effect. The antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof according to any one of embodiments 9 to 13, wherein the antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof is a pharma-ceutically acceptable salt or solvate thereof,

[0124] (Embodiment 15) A pharmaceutical composition comprising the antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 14, and optionally further comprising a pharma- ceutically acceptable carrier.

[0125] (Embodiment 16) Use of the antibody-drug conjugate or a pharma- ceutical acceptable salt or solvate thereof according to any one of Embodiments 1 to 14, or the pharmaceutical composition according to Embodiment 15, in the manufacture of a medicament for treating cancer, wherein preferably the cancer is a HER3-positive cancer, and preferably the cancer is biliary tract cancer, carcinosarcoma, esophageal cancer, esophago-gastric junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer, renal cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, melanoma, pharyngeal cancer, oral cancer, skin cancer, lung cancer, glioblastoma multiforme, glioblastoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, liver cancer, salivary gland cancer, vulvar cancer, thyroid cancer, testicular cancer, anal cancer, or penile cancer.

[0126] (Embodiment 17) A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof described in any one of Embodiments 1 to 14, or the pharmaceutical composition described in Embodiment 15, preferably wherein the cancer is a HER3-positive cancer.

[0127] (Embodiment 18) The method of embodiment 17, comprising contacting tumor cells with the antibody-drug conjugate or a pharma- ceutically acceptable salt or solvate thereof, or the pharmaceutical composition, thereby killing or inhibiting the growth of tumor cells.

[0128] (Embodiment 19) The method according to embodiment 17 or 18, wherein the cancer is biliary tract cancer, carcinosarcoma, esophageal cancer, esophagogastric junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer, renal cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, melanoma, pharyngeal cancer, oral cancer, skin cancer, lung cancer, glioblastoma multiforme, glioblastoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, liver cancer, salivary gland cancer, vulvar cancer, thyroid cancer, testicular cancer, anal cancer or penile cancer.

[0129] (Embodiment 20) A linker-drug intermediate compound having the structure shown in Formula III, [ka] During the ceremony, R a is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, R b is a hydrogen atom, a deuterium atom, or an optionally substituted C 1~6 Alkyl groups, optionally substituted C 3~7 Cycloalkyl groups, optionally substituted C 3~7 Heterocyclyl Groups, Optionally Substituted C 6~10 Aryl groups, optionally substituted C 5~12 heteroaryl groups, Or R a and R b and the atoms connected thereto form an optionally substituted 5- to 8-membered heterocyclyl group.

[0130] (Embodiment 21) R a and R band R are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group.

[0131] In the following, the present invention will be further described with reference to examples in order to make the present invention clearer, but the scope of the present application is not limited to the examples. The reagents used in the present application are generally commercially available products and can be used without purification.

[0132] Patritumab used in the examples of this application is an antibody produced by a conventional method, which first constructs an expression vector (including, for example, pcDNA3.1 vector disclosed in CN107001463A, pCHO1.0 vector disclosed in CN109422811A, etc.), transfects Expi-CHO host cells, and then expresses and purifies using protein A affinity chromatography. The amino acid sequences of the heavy and light chains of Patritumab are as shown in SEQ ID NOs: 9 and 10, respectively. The synthesis of deuterated MC-GGFG-DXd (MC-GGFG-DDDXd) refers to the method of Example 14 of patent disclosure WO2022033578A1.

[0133] The cells and their sources used in the examples of this application are as shown in the following table. [Table 2]

[0134] Example 1: Preparation of Compound III-1 [ka] 100 mg of compound A (0.12 mmol) and 75 mg of compound B (0.145 mmol) were weighed and added to a 20 mL reaction tube (CAS number of compound A is 2413428-36-9, CAS number of compound B is 441045-17-6), 2 mL of N,N-dimethylformamide was added, the temperature was lowered to 0 ° C, 70 mg of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.18 mmol) and 49 mg of N,N-diisopropylethylamine (0.36 mmol) were added, and the mixture was reacted at 0 ° C for 1 hour, and purified by preparative liquid chromatography to obtain about 70 mg of compound III-1 (MC-GGFG-Eribulin, MC-GGFG-Eribulin). When analyzed by ESI-MS, compound III-1 had m / z=1241.72 [M+H] + Compound III-1 1 The 1 H NMR spectrum was as follows: 1H NMR(500MHz,DMSO)δ 8.22(t,J=5.3Hz,1H),8.12(d,J=8.0Hz,1H),8.06(t,J=5.4Hz,1H),7.99(t,J=5.3Hz,1H) ,7.65(d,J=5.2Hz,1H),7.30-7.21(m,4H),7.18(d,J=6.4Hz,1H),6.99(s,2H),5.02(d,J= 26.0Hz,2H),4.79(d,J=38.9Hz,2H),4.65-4.60(m,2H),4.56(d,J=3.7Hz,1H),4.50-4.42 (m,1H),4.26(d,J=10.1Hz,1H),4.21-4.14(m,1H),4.10(s,3H),4.05-3.98(m,1H),3.86- 3.64(m,8H),3.60-3.45(m,4H),3.37-3.30(m,2H),3.26(s,4H),3.17-3.09(m,1H),3.08- 2.99(m,2H),2.84(d,J=10.4Hz,1H),2.86-2.66(m,3H),2.56-2.50m,1H),2.37-2.18(m,5 H),2.15-2.05(m,3H),2.05-1.96(m,2H),1.95-1.84(m,4H),1.75-1.57(m,6H),1.55-1.3 8(m,6H),1.35-1.25(m,3H),1.23-1.12(m,3H),1.03(d,J=6.0Hz,3H),1.00-0.92(m,1H).

[0135] Example 2: Preparation of antibody-drug conjugates reagent: Solution A: PBS buffer with a pH of 7.4 Solution B: 10 mM TCEP (tris(2-carboxyethyl)phosphine hydrochloride) aqueous solution Solution C: DMSO Solution D: Histidine buffer (containing 0.89 mg / mL L-histidine and 4.04 mg / mL L-histidine hydrochloride monohydrate) Solution E: 700 mg / mL sucrose solution (prepared in solution D) Solution F: 20 mg / mL polysorbate 80 (prepared in solution D) Test procedure: 1. Antibody Replacement a. A 30 kD ultrafiltration centrifuge tube was thoroughly wetted with Solution A. b. The antibody was replaced with solution A. c. An appropriate amount of solution A was added to adjust the antibody concentration. 2. Antibody Reduction The molar amount of antibody was calculated and designated as N1. b. An appropriate amount of solution B was added to the antibody solution to make the molar amount of TCEP in the reaction system N2. c. Wrap the mixture in aluminum foil, place it in a rotary incubator, shake it at low speed (20 rpm), and react it at 37°C in the dark for 1 hour. 3.Composite a. An appropriate amount of linker-payload was dissolved in DMSO to a final concentration of 10 mg / mL. b. DMSO was added to the antibody solution to make the concentration 5%, and an appropriate amount of linker-payload solution was further added to make the molar amount N3. c. Wrap the mixture in aluminum foil, place it in a rotary incubator, shake it at low speed (20 rpm), and react it in the dark at 22°C for 1.5 hours. 4. Compound Stop a. Wet the ultrafiltration centrifuge tube with Solution D. b. The antibody was replaced with solution D, and appropriate amounts of solutions E and F were added, followed by freezing and storing at -80°C. Determination of DAR (average number of drugs per antibody molecule) of antibody-drug conjugates: The DAR value was measured using an LC-MS method. 1 μL of glycosidase PNGase F (Rui'an Bio, China) was added to 50 μg of ADC sample and incubated at 37 °C for 20 h. The mass spectrometer used in the study was a high-resolution Xevo G2-XS (Waters, USA). The concentration of the sample was adjusted to 5 μM, and mass spectrometry data was collected in positive ion mode using the direct injection method. The collected non-denatured mass spectrometry data was analyzed and processed using the software UNIFI 1.8.2.169 (Waters, USA).

[0136] Measurement of antibody drug conjugate protein concentration: Protein concentration was detected using the Lowry method. The absorbance value OD of the sample at wavelength 650 was measured using a microplate reader, and a standard curve was fitted. The absorbance value of the sample was substituted into the standard curve to calculate the protein concentration.

[0137] The antibody-drug conjugates of formula IV-1 (including IV-1 (Patritumab)) and other antibody-drug conjugates of formula IV series were prepared by the above method. [ka] [ka]

[0138] Sample 1 and Sample 2 were prepared, respectively. Sample 1: DAR=4.8, protein concentration=1.71 mg / mL, Sample 2: DAR=7.1, protein concentration=1.65 mg / mL.

[0139] Example 3: Cellular activity of small molecule cytotoxic compounds and antibody drug conjugates For small molecule cytotoxic compounds, medium was used to dilute the compounds from 35,000 ng / mL to 0.0896 ng / mL, for a total of nine concentrations. Tumor cells in logarithmic growth phase were used at a density of 1 × 10 5 The plated wells were adjusted to cells / mL and 100 μL was added to each well, and a blank well without cells was placed as a control. The above gradient diluted samples were added, and each well was 50 μL. The plates were cultured for 5 days in a 5% CO2 incubator at 37°C. The culture medium was discarded, and CCK-8 (Dojindo Chemical, product number CK04) working solution was added, and each well was 100 μL. The plates were incubated for 4 to 5 hours to develop color, and then placed on a microplate reader (manufacturer Thermo, model number VarioskanFlash) to read and record the absorbance values ​​of the well plate at a wavelength of 450 nm with a reference wavelength of 630 nm. The tumor cell proliferation inhibition rate was calculated.

[0140] Antibody-drug conjugates were diluted using culture medium from 5000 ng / mL to 0.0128 ng / mL for a total of nine concentrations. Tumor cells in logarithmic growth phase were used at a density of 2 × 10 4 The plated cells were adjusted to cells / mL, 100 μL was added to each well, and a blank well without cells was set up as a control. The above-mentioned gradient diluted samples were added, and each well was 50 μL. The plates were cultured at 37°C in a 5% CO2 incubator. The culture medium was discarded, and CTG detection solution (Promega, product number G7572) was added, and each well was 100 μL. After incubation for 10 minutes to develop the color, the plates were placed in a multi-function plate reader (manufacturer Thermo, model number VarioskanFlash) to read the chemiluminescence value. The tumor cell proliferation inhibition rate was calculated. [Table 3]

[0141] Example 4: Preparation of antibody-drug conjugates reagent: Solution G: Histidine / histidine hydrochloride buffer (1.43 mg / mL L-histidine, 2.27 mg / mL L-histidine hydrochloride monohydrate) Solution H: 10 mM TCEP (tris(2-carboxyethyl)phosphine hydrochloride) aqueous solution Solution I: DMSO (dimethyl sulfoxide) Solution J: 500 mg / mL sucrose solution (prepared in solution G) Solution K: 30 mg / mL polysorbate 80 (prepared in solution G) Solution L: Solution G of 10% DMSO Solution M: 0.3M Na2HPO4 Antibody: Patritumab Linker-payload (linker-drug intermediate compound): Compounds having the structure shown in formula III-1 in Example 1, MC-GGFG-eribulin (used for preparing patritumab-eribulin conjugate), MC-GGFG-DDDXd (used for preparing patritumab-DDDXd conjugate).

[0142] (1) According to the following test procedure, patritumab-eribulin conjugates with DAR of 2.6 or 7.6 were prepared and named patritumab-eribulin-D2 and patritumab-eribulin-D8, respectively. According to the following test procedure, patritumab-DDDXd conjugates with DAR of 7.9 were prepared and named patritumab-DDDXd-D8. Test procedure: 1. Antibody replacement: A 30 kD ultrafiltration centrifuge tube was thoroughly wetted with solution G, the antibody was replaced with solution G, and an appropriate amount of solution G was added to adjust the antibody concentration to 10 mg / mL. Next, an appropriate amount of solution M was added to adjust the pH of the antibody solution to about 7.0.

[0143] 2. Reduction of the antibody: The molar amount of the antibody was calculated and recorded as N1. An appropriate amount of solution H was added to the antibody solution to make the molar amount of TCEP in the reaction system N2. The resulting mixture was shaken at 37°C in the dark for 1 hour, which reduced the disulfide bond of the antibody to obtain reaction solution 1.

[0144] 3. Conjugation of antibody and linker-drug intermediate compound: An appropriate amount of linker-payload was dissolved in 50% aqueous acetone solution, and the final concentration was 10 mg / mL. Solution I (solution I: reaction solution 1 (v / v) = 1:10) was added to reaction solution 1, mixed uniformly, and an appropriate amount of the linker-payload solution dissolved using the above-mentioned aqueous acetone solution was added to give a molar amount of linker-payload of N3. The reaction mixture was shaken in the dark at 22°C for 1 hour to obtain reaction solution 2.

[0145] 4. Stopping the complex reaction: An ultrafiltration centrifuge tube was wetted with solution L. Reaction solution 2 was ultrafiltered with 20 volumes of solution L and then with 20 volumes of solution G, and appropriate amounts of solutions J and K were added, followed by freezing and storing at -80°C.

[0146] The test conditions and group settings were as shown in Table 1-1 below. [Table 4]

[0147] (2) According to the following test procedure, a patritumab-eribulin conjugate with a DAR of 4.0-4.2 was prepared and named patritumab-eribulin-D4. Test procedure: 1. Antibody replacement: A 30 kD ultrafiltration centrifuge tube was thoroughly wetted with solution G, the antibody was replaced with solution G, and an appropriate amount of solution G was added to adjust the antibody concentration to 10 mg / mL. Next, an appropriate amount of solution M was added to adjust the pH of the antibody solution to about 7.0.

[0148] 2. Reduction of the antibody: The molar amount of the antibody was calculated and recorded as N1. An appropriate amount of solution H was added to the antibody solution to make the molar amount of TCEP in the reaction system N2. The resulting mixture was reacted at 5-10°C in the dark for 6 hours, whereby the disulfide bond of the antibody was reduced, and reaction solution 3 was obtained.

[0149] 3. Conjugation of antibody and linker-drug intermediate compound: An appropriate amount of linker-payload was dissolved in 50% acetone aqueous solution, and the final concentration was 10 mg / mL. An appropriate amount of the linker-payload solution dissolved using the above acetone aqueous solution was added to reaction solution 3, and the molar amount of linker-payload was set to N3. The reaction mixture was reacted at 5 to 10 °C in the dark for 40 minutes to obtain reaction solution 4.

[0150] 4. Stopping the complex reaction: An ultrafiltration centrifuge tube was wetted with solution L. Next, reaction solution 4 was ultrafiltered with 20 times the amount of solution L, and then with 20 times the amount of solution G. Appropriate amounts of solutions J and K were added, and the mixture was frozen and stored at -80°C.

[0151] The test conditions and group settings were as shown in Table 1-2 below. [Table 5]

[0152] Example 5: Determination of DAR value of antibody drug conjugate A non-porous polystyrene / divinylbenzene (PS / DVB) filler with butyl groups is used to isolate each component of the patritumab-eribulin conjugate prepared in Example 4 above, and a neutral high-salt mobile phase is used to improve the hydrophobic properties of the protein molecules, thereby binding them to the hydrophobic bonds of the column. The salt concentration is then gradually decreased while the proportion of isopropyl alcohol is gradually increased to elute the substances, so that the less hydrophobic components are eluted first and the more hydrophobic components are eluted later.

[0153] The column specifications were Sepax HIC-Butyl, 4.6×100 mm, 5 μm, and the column temperature was 25° C. Mobile phase A was 10 mM phosphate buffer-1.5 M ammonium sulfate, pH 7.0 (1.42 g of anhydrous disodium hydrogen phosphate and 198.21 g of ammonium sulfate were weighed, about 800 mL of ultrapure water was added, and the mixture was stirred until fully dissolved, and then the pH was adjusted to 7.0±0.1 with phosphoric acid, and the mixture was made up to 1 L, mixed uniformly, and filtered through a 0.22 μm filter membrane). Mobile phase B was 10 mM phosphate buffer, pH 7.0 (1.42 g of anhydrous disodium hydrogen phosphate was weighed, about 800 mL of ultrapure water was added, and the mixture was stirred until fully dissolved, and then the pH was adjusted to 7.0 ± 0.1 with phosphoric acid, and the solution was made up to 1 L, mixed uniformly, and filtered through a 0.22 μm filter membrane). Mobile phase C was 100% isopropyl alcohol. The flow rate was 0.5 mL / min, and gradient elution was performed for 30 min, with the mobile phase parameters increasing from 75% mobile phase A and 25% mobile phase B to 75% mobile phase B and 25% mobile phase C from 0 to 15 min, 75% mobile phase B and 25% mobile phase C from 15 to 20 min, and 75% mobile phase A and 25% mobile phase B from 20 to 30 min). In the initial mobile phase at 0 min, the patritumab-eribulin conjugate was diluted 1-fold to prepare the test solution, and 50 μg of protein was injected by adjusting the injection volume based on the concentration of the patritumab-eribulin conjugate, and the absorbance value was detected at a wavelength of 280 nm.

[0154] In data processing, the area percentage method was used to quantitatively analyze the results. The peak area percentages of ADCs containing 0, 1, 2, 3, 4, 5, 6, 7 and 8 cytotoxic drugs were calculated, respectively, and the DAR values ​​were calculated to obtain the results. The calculation formula was: DAR value=(percentage of peak area of ​​ADC without cytotoxic drug×0+percentage of peak area of ​​ADC containing 1 cytotoxic drug×1+percentage of peak area of ​​ADC containing 2 cytotoxic drugs×2+percentage of peak area of ​​ADC containing 3 cytotoxic drugs×3+percentage of peak area of ​​ADC containing 4 cytotoxic drugs×4+percentage of peak area of ​​ADC containing 5 cytotoxic drugs×5+percentage of peak area of ​​ADC containing 6 cytotoxic drugs×6+percentage of peak area of ​​ADC containing 7 cytotoxic drugs×7+percentage of peak area of ​​ADC containing 8 cytotoxic drugs×8) / 100%.

[0155] Using the methods of Examples 4 and 5, a patritumab-eribulin conjugate having the following structure was produced and measured. [ka] However, the DAR value measured for patritumab-eribulin-D2 was 2.6, the DAR value measured for patritumab-eribulin-D4 was 4 to 4.2, and the DAR value measured for patritumab-eribulin-D8 was 7.6.

[0156] Patritumab-DDDXd-D8 having the following structure was produced and measured by the methods of Examples 4 and 5. [ka] The measured DAR value was 7.9.

[0157] Example 6: Verification of Aggregation of Antibody-Drug Conjugates Each component of the patritumab-drug conjugate prepared in Example 4 above was isolated using gel filtration chromatography. The components were eluted in order of decreasing molecular weight using a neutral pH buffer solution containing 10% isopropyl alcohol as the mobile phase. The column was a gel filtration column with the specifications ACQUITY UPLC Protein BEH SEC Column 200 Å, 1.7 μm, 4.6×300 mm, and the column temperature was 25° C. The mobile phase was 50 mM phosphate buffer-200 mM sodium chloride-10% isopropyl alcohol, pH 7.0 (12.53 g of disodium hydrogen phosphate dodecahydrate, 2.33 g of sodium dihydrogen phosphate dihydrate, 11.69 g of sodium chloride were weighed, added with about 800 mL of ultrapure water, stirred until fully dissolved, added with ultrapure water to make 1000 mL for use, added 100 mL of isopropyl alcohol to the above solution to make 1000 mL, mixed uniformly, and then filtered through a 0.22 μm filter membrane). 20 μg of Patritumab-drug conjugate was accurately weighed and injected into the liquid chromatograph and detected at a wavelength of 280 nm. The flow rate was 0.3 mL / min, and eluted isocratically for 15 min.

[0158] In data processing, the area percentage method was used to quantitatively analyze the results. The peak area percentages of aggregates, immunoglobulin monomers and low molecular weight impurities were calculated respectively, among which the area before the main peak was aggregates, the main peak was immunoglobulin monomers, and the area after the main peak was low molecular weight impurities. The content ratios of monomers, aggregates and low molecular weight impurities in Patritumab-drug conjugates are shown in Table 2. [Table 6]

[0159] Example 7: Cell-binding activity of antibody-drug conjugates Using FACS method, the binding activity of the patritumab-eribulin conjugate prepared in the above Example 4 against cells with different HER3 expression levels, including MCF-7, HCC1569, BT474 cells with high HER3 expression levels, MDA-MB-468, JIMT-1 cells with moderate HER3 expression levels, SW620 cells with low HER3 expression levels, and HER3 negative A549 cells, was analyzed using patritumab-DDDXd-D8 and patritumab as controls.

[0160] 1×10 5 The cells were added to each well of a 96-well cell culture plate, and the patritumab-eribulin conjugate was diluted in FACS buffer (Miltenyi Biotec, product number 130-091-221) from a starting concentration of 135.14 nM to nine concentration gradients in 4-fold dilutions, incubated at 4° C. for 60 min, then centrifuged at 1000 rpm for 5 min, the supernatant was discarded, washed three times with pre-chilled PBS (pH 7.4), and a goat anti-human IgG Fcγ-PE secondary antibody (Jackson immunoresearch, product number 109-116-170) diluted 1:200 (v / v) was added, 100 μL / well, and incubated for 30 min at 4° C. Washed three times with pre-chilled PBS (pH 7.4), resuspended in 100 μL PBS (pH 7.4), and then the detected fluorescent signal was analyzed using a flow cytometer (Sartorius, iQUE). The binding activity of the patritumab-eribulin conjugate and the control to each of the above cells was measured by the mean fluorescence intensity (MFI) of staining. The data was analyzed using GraphPad Prism5, and the results are shown in Figure 1A to Figure 1G, and the calculated EC 50 The results are shown in Table 3 below. The results revealed that the binding activity of the patritumab-eribulin conjugate with each DAR value to cells with high, medium, and low HER3 expression levels was equivalent to that of patritumab, and it did not bind to HER3-negative A549 cells. [Table 7]

[0161] Example 8: Endocytosis test of antibody-drug conjugates Using FACS, the endocytosis status of the patritumab-eribulin conjugate prepared in Example 4 above was analyzed in cells with different HER3 expression levels, including MCF-7 cells with high HER3 expression levels, BT474 cells with HER3 high expression levels, NCI-N87 cells with moderate HER3 expression levels, and SW620 cells with low HER3 expression levels, with patritumab-DDDXd-D8 and patritumab as controls.

[0162] Cell density was 1 x 10 6 The concentration of each sample was adjusted to 100 μg / mL and added to a 96-well cell culture plate at 50 μL / well. For sample preparation, the patritumab-eribulin conjugate was pre-diluted to a concentration of 20 μg / mL and marked as S1, and then diluted in a 3-fold concentration gradient to obtain nine samples S1-S9. The gradient-diluted sample solution was added to the cell culture plate, 50 μL was added to each well, and incubated at 4°C for 30 minutes. After the end of incubation, the 96-well cell culture plate was removed and centrifuged at 400 g for 4 minutes at 4°C, and the supernatant was discarded. AffiniPure Goat Anti-Human IgG, Fcγ fragment specific (Jackson Immuno, product number 109-005-190) labeled with pHrodo™ Green Maleimide (Invitrogen, product number P35370) was diluted at 1:200 (v / v) and 50 μL was added to each well and incubated at 4°C. After 30 minutes, the wells were washed and 50 μL of cell culture medium was added to each well. After uniform mixing, the wells were internalized at 37°C for 2 hours and placed in a flow cytometer (Sartorius, iQUE) to measure the fluorescence value of the BL1 channel. The data was analyzed using GraphPad Prism5, and the results are shown in Figure 2A-D. The calculated EC 50 The results are shown in Table 4 below. The results revealed that the patritumab-eribulin conjugates with each DAR value showed obvious endocytosis in cells with high and moderate HER3 expression levels, and weak endocytosis in SW620 cells with low HER3 expression levels. [Table 8]

[0163] Example 9: Cell killing activity of antibody drug conjugates To detect the growth-inhibitory effect of the patritumab-eribulin conjugate prepared in Example 4 above on tumor cells, patritumab-DDDXd-D8 was used as a control to detect the killing activity in cells with different HER3 expression levels, including BT474, MCF-7, and HCC1569 cells with high HER3 expression levels, SKBR3, NCI-N87, JIMT-1, and MDA-MB-468 cells with moderate HER3 expression levels, and SW620 and WiDr cells with low HER3 expression levels.

[0164] Add cells in logarithmic growth phase to a 96-well plate at 100 μL / well and a cell density of 1 x 10 4 / mL or 2 x 10 4 The cell density was 1 / mL. The cells were attached to the wall and cultured overnight at 37°C and 5% CO2. To prepare the samples, patritumab-eribulin complex was prepared as the test sample (9 gradients, 5-fold dilution from 5 μg / mL) using basal medium containing 10% FBS. The cells that had been attached to the wall and cultured overnight were removed, and the test group was added with 50 μL / well of the diluted test sample, and the control group was added with 50 μL / well of basal medium containing 10% FBS. After further culture for 96, 120 or 144 hours, detection was performed using a CellTiter-Glo Luminescent Cell Kit (Promega, product number G7572). The 96-well plate was removed, and 75 μL of CTG detection solution (Promega, product number G7572) was added to each well, shaken to mix evenly, and incubated at room temperature in the dark for 10 minutes. After that, 180 μL was drawn out from each well and transferred to a white opaque plate, and air bubbles were removed. The chemiluminescence value was read and the killing rate was calculated. Kill rate (%) = (1-luminescence value of test group / luminescence value of control group) x 100%

[0165] Data were analyzed and processed using Graphpad Prism5, and the results are shown in Figures 3A-I. EC 50 The results are shown in Tables 5-1 and 5-2 below. The results show that the larger the DAR value, the stronger the killing activity of the patritumab-eribulin conjugate against cells with high, medium, and low HER3 expression levels, and the killing activity of the patritumab-eribulin conjugate at each DAR value is superior to that of patritumab-DDDXd-D8. [Table 9] [Table 10]

[0166] Example 10: Pharmacodynamic evaluation of antibody-drug conjugates in a nude mouse subcutaneous tumor model of JIMT-1 human breast cancer cells The in vivo pharmacodynamics of the patritumab-eribulin conjugate prepared in Example 4 above was evaluated in a nude mouse subcutaneous tumor model of trastuzumab-resistant cell line JIMT-1 human breast cancer cells.

[0167] JIMT-1 cells were subcutaneously inoculated into the right axilla of SPF female nude mice (provided by Changzhou Kawenis Experimental Animal Co., Ltd.) at a dose of 2 × 10 6 The mean tumor volume was 100-300 mm 3 When the animals reached the target dose, they were divided into 5 groups, each with 6 animals. The specific grouping and dosing schedule are shown in Table 6. [Table 11]

[0168] The day of grouping was day 0, and the mice were administered the drug via the tail vein on the first day after grouping. The tumor volume was measured two to three times a week, and the mice were weighed and the data was recorded. The mice's daily behavior was observed and recorded every day. After the test was completed, the tumors were excised, weighed, and photographed.

[0169] Detection indicators include the following: Tumor volume (mm 3 )=1 / 2×(a×b 2 ) where a is the major axis and b is the minor axis.

[0170] Relative tumor volume RTV=TV t / TV0, where TV0 is the tumor volume on day 0 and TV t is the tumor volume at each measurement.

[0171] Relative tumor growth rate T / C(%)=T RTV / C RTV × 100%, where T RTV is the RTV of the treatment group, and C RTV is the RTV of the control group.

[0172] The tumor growth inhibition rate was 1-T / C.

[0173] Tumor inhibition rate TGI(%)=(1-TW / TW0)×100%, where TW is the tumor weight of the treatment group and TW0 is the tumor weight of the control group.

[0174] Weight change rate WCR(%)=(Wt t -Wt0) / Wt0 × 100%, where Wt0 is the body weight of the animal on day 0 and Wt t is the body weight of the animal at each measurement.

[0175] The effects of each drug on tumor volume, tumor weight, and mouse body weight are shown in Figures 4 to 6, and the results of the detection indexes are shown in Table 7 below. At the end of the test on the 21st day, no animals died, the weight gain of the mice in each treatment group was similar to that of the model group, and the drugs had no obvious toxic effects and were safe. All of the patritumab-eribulin conjugates with each DAR value showed good in vivo tumor growth inhibitory activity, which was superior to patritumab-DDDXd-D8, and the larger the DAR value of the patritumab-eribulin conjugate, the stronger the in vivo tumor growth inhibitory activity. [Table 12]

[0176] In accordance with the disclosure herein, the method of the present application is described based on a preferred embodiment, but those skilled in the art may modify the method described herein and the steps or the order of steps of the method without departing from the concept, spirit and scope of the present application.

[0177] The disclosures of all references mentioned herein are incorporated by reference and are hereby incorporated by reference to provide exemplary, procedural and other details supplementary to the disclosures herein.

Claims

1. General formula Ab-(LU) ｎ wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, and n is an integer or decimal number selected from 1 to 10, or a pharmaceutically acceptable salt or solvate thereof; The antibody-drug conjugate comprises a structure represented by the following formula IIa, or a pharmaceutically acceptable salt or solvate thereof: 【Chemical 1】 (In the formula, R ａ represents a hydrogen atom, a deuterium atom, an optionally substituted C １～６ alkyl groups, optionally substituted C ３～７ Cycloalkyl groups, optionally substituted C ３～７ Heterocyclyl group, optionally substituted C ６～１０ aryl group, optionally substituted C ５～１２ heteroaryl groups, R ｂ represents a hydrogen atom, a deuterium atom, an optionally substituted C １～６ alkyl groups, optionally substituted C ３～７ Cycloalkyl groups, optionally substituted C ３～７ Heterocyclyl group, optionally substituted C ６～１０ aryl group, optionally substituted C ５～１２ heteroaryl groups, Or, R ａ and R ｂ and the atoms connected thereto form an optionally substituted 5- to 8-membered heterocyclyl group.

2. 2. The antibody-drug conjugate of claim 1, wherein the antibody-drug conjugate comprises the structure shown in Formula IIIa: 【Chemistry 2】

3. 3. The antibody-drug conjugate of claim 2, wherein the antibody-drug conjugate has the structure shown in Formula IV: 【Chemistry 3】 (In the formula, Ab represents the antibody moiety; n is an integer or decimal number selected from 1 to 10.

4. R ａ and R ｂ are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group, or the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3.

5. 3. The antibody-drug conjugate of claim 2, wherein the antibody-drug conjugate comprises the structure shown in Formula IIIa-1: 【Chemistry 4】

6. The antibody-drug conjugate of claim 3, wherein the antibody-drug conjugate has a structure represented by the following formula IV-1: 【Chemistry 5】

7. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein n is 2 to 4.8, 2.6 to 4.8, 3.5 to 4.8, 4 to 4.8, 2 to 4.5, 2.6 to 4.5, 3.5 to 4.5, 4 to 4.5, 3.5 to 4.2, 3.5 to 4, 4 to 4.2, 7 to 8, 7 to 7.9, 7 to 7.6, 7 to 7.5, 7.1 to 8, 7.1 to 7.9, 7.1 to 7.6, 7.5 to 8, 7.6 to 8, or 7.6 to 7.

9.

8. 8. The antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof of claim 7, wherein n is about 2.6, about 4, about 4.2, about 4.8, about 7, about 7.1, about 7.5, about 7.6, about 7.9, or about 8.

9. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein the Ab is an anti-HER3 antibody or an antigen-binding fragment thereof.

10. The antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof of claim 9, wherein the anti-HER3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the amino acid sequence shown in SEQ ID NO: 1, an HCDR2 having the amino acid sequence shown in SEQ ID NO: 2, an HCDR3 having the amino acid sequence shown in SEQ ID NO: 3, an LCDR1 having the amino acid sequence shown in SEQ ID NO: 4, an LCDR2 having the amino acid sequence shown in SEQ ID NO: 5, and an LCDR3 having the amino acid sequence shown in SEQ ID NO:

6.

11. The antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof of claim 10, wherein the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 7 and the light chain variable region comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 8, or the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:

8.

12. The antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof of claim 10, wherein the anti-HER3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 9, and the light chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO:

10.

13. 10. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof of claim 9, wherein the anti-HER3 antibody is patritumab.

14. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof has the following characteristics: (a) HER3-binding property (b) the property of blocking the binding of HER3 to a ligand (c) The property of exhibiting endocytosis in cells expressing HER3. (d) the property of having killing activity against HER3-expressing tumor cells; (e) Characteristics that have a bystander effect 10. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof of claim 9, wherein the antibody-drug conjugate exhibits one or more combinations of:

15. A pharmaceutical composition comprising the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof described in any one of claims 1 to 3, and optionally further comprising a pharmaceutically acceptable carrier.

16. 10. Use of the antibody-drug conjugate according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, in the manufacture of a drug for treating cancer.

17. The use described in claim 16, wherein the cancer is a HER3-positive cancer.

18. The use according to claim 17, wherein the cancer is biliary tract cancer, carcinosarcoma, esophageal cancer, gastroesophageal junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer, renal cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, melanoma, pharyngeal cancer, oral cancer, skin cancer, lung cancer, glioblastoma multiforme, glioblastoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, liver cancer, salivary gland cancer, vulvar cancer, thyroid cancer, testicular cancer, anal cancer, or penile cancer.

19. A linker-drug intermediate compound having the structure shown in Formula III: 【Chemistry 6】 (In the formula, R ａ represents a hydrogen atom, a deuterium atom, an optionally substituted C １～６ alkyl groups, optionally substituted C ３～７ Cycloalkyl groups, optionally substituted C ３～７ Heterocyclyl group, optionally substituted C ６～１０ aryl group, optionally substituted C ５～１２ heteroaryl groups, R ｂ represents a hydrogen atom, a deuterium atom, an optionally substituted C １～６ alkyl groups, optionally substituted C ３～７ Cycloalkyl groups, optionally substituted C ３～７ Heterocyclyl group, optionally substituted C ６～１０ aryl group, optionally substituted C ５～１２ heteroaryl groups, Or, R ａ and R ｂ and the atoms connected thereto form an optionally substituted 5- to 8-membered heterocyclyl group.

20. R ａ and R ｂ The linker-drug intermediate compound according to claim 19, characterized in that each of is independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group.

21. A linker-drug intermediate compound having a structure shown in formula III-1. 【Chemistry 7】

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