Use of and method for using Anti-her3 antibody-drug conjugate

Abstract

The use of an anti-HER3 antibody-drug conjugate for treating cancer, in particular refractory advanced / metastatic malignant solid tumors.

Description

Use and method of use of anti-HER3 antibody drug conjugates TECHNICAL FIELD

[0001] The present application relates to the field of medicine. In particular, the present application relates to use and method of use of anti-HER3 antibody drug conjugates for the treatment of cancer. BACKGROUND

[0002] The human epidermal growth factor receptor (HER) family, also known as the human EGFR family, belongs to one of the four closely related families of type I receptor tyrosine kinases (RTKs) that are cell membrane receptors and are closely related to the occurrence and development of various tumors.

[0003] The HER family mainly has four structurally similar receptor molecules, including four members of HER1 (also known as Epidermal Growth Factor Receptor (EGFR), ErbB1), HER2 (also known as Neu, ErbB2), HER3 (also known as ErbB3) and HER4 (also known as ErbB4).

[0004] HER2 is a 185 kDa orphan receptor without an endogenous ligand binding domain, but it is recognized as the preferred and most catalytically active binding partner of other HER family members. Another feature of HER2 is that it is constitutively activated. Clinically, HER2 targeted therapy is known for its role in the treatment of breast cancer, and Trastuzumab, the first monoclonal antibody targeting HER2, was developed in 1990, which blocks HER2 signaling through several mechanisms, including promoting HER2 internalization and degradation, inhibiting dimerization, blocking downstream PI3K-AKT signaling, killing tumor cells through antibody-dependent cellular cytotoxicity (ADCC) (Klapper LN et al., Tumor-inhibitory antibodies to HER-2 / ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res, 2000. 60(13): p. 3384-3388).

[0005] HER3 lacks intrinsic tyrosine kinase activity and is often referred to as a pseudokinase. HER3 is a specific dimerizing chaperone; other HER family members, such as HER2, maximize the induction of the phosphoinositol 3-kinase (PI3K) / protein kinase B (AKT) / mTOR pathway after forming a heterodimer with HER3. Neuroregulatory proteins (NRGs) 1 and 2 are the main activating ligands of HER3, promoting heterodimerization of HER3 and HER2, leading to pathological activation of downstream signaling. Furthermore, positive HER3 expression has been reported to be associated with poor prognosis in some cancers, including breast cancer, gastric cancer, and head and neck cancer. Since HER3 directly promotes cancer signaling through PI3K / AKT / mTOR, targeting HER3 is becoming an effective strategy for treating HER3-expressing cancers; however, no specific HER3-targeting therapies have yet been approved for clinical use.

[0006] Anti-HER3 antibody-drug conjugates (anti-HER3-ADCs) are composed of a monoclonal antibody specifically targeting the HER3 antigen and a small-molecule cytotoxic drug linked by a linker. They combine the potent killing effect of traditional small-molecule chemotherapy with the tumor-targeting properties of antibody drugs. They consist of three main parts: an antibody that selectively recognizes the HER3 antigen on the surface of cancer cells, a drug payload responsible for killing cancer cells, and a linker connecting the anti-HER3 antibody and the payload. Patritumab deruxtecan (HER3-DXd; U3-1402), developed by Daiichi Sankyo, is an anti-HER3 antibody-drug conjugate covalently linked to the antibody U3-1287 (Patritumab) and a drug payload containing the topoisomerase I inhibitor exatecan (MAAA-1181a). It has shown clinical benefit in NSCLC patients with EGFR mutations; however, hematological toxicities, including thrombocytopenia and neutropenia, were the most common adverse events observed during the clinical development of Patritumab deruxtecan. PA et al., Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer, Cancer Discov. 2022; 12:74–89. Therefore, developing new uses and methods of administration for anti-HER3 antibody-drug conjugates remains an unmet need in this field. Summary of the Invention

[0007] This invention provides the use of anti-HER3 antibody drug conjugates for the treatment of cancer.

[0008] The inventors have surprisingly discovered that the anti-HER3 antibody-drug conjugates they developed can be used to treat cancer, especially advanced / metastatic malignant solid tumors.

[0009] Specifically, the present invention relates to the following aspects.

[0010] In a first aspect, the present invention provides the use of anti-HER3 antibody-drug conjugates for the treatment of cancer. In some embodiments, the cancer is selected from any of the following: lung cancer such as non-small cell lung cancer, breast cancer, esophageal squamous cell carcinoma, biliary tract cancer, prostate cancer such as castration-resistant prostate cancer, and head and neck squamous cell carcinoma.

[0011] In some embodiments, the anti-HER3 antibody drug conjugate has the structure shown in formula (I-1):

[0012] in,

[0013] Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and the Ab is not a bispecific or multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment.

[0014] For example, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; and Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment.

[0015] Preferably, the Ab is an anti-HER3 monospecific antibody, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0016] Preferably, the anti-HER3 monospecific antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8;

[0017] More preferably, the heavy chain amino acid sequence of the anti-HER3 monospecific antibody is shown in SEQ ID NO:9, and the light chain amino acid sequence is shown in SEQ ID NO:10;

[0018] L stands for connector unit;

[0019] -M- is selected from:

[0020] p represents the average number of drug linkages relative to each Ab molecule, and p is selected from an integer or decimal of 1 to 10, for example, p is an integer or decimal of 2 to 8; preferably an integer or decimal of 3 to 8.

[0021] In a second aspect, the present invention provides a method for treating cancer, particularly a method for treating advanced / metastatic malignant solid tumors, the method comprising administering a therapeutically effective amount of the anti-HER3 antibody-drug conjugate of the present invention to an individual in need.

[0022] In a third aspect, the present invention provides the use of anti-HER3 antibody drug conjugates for the preparation of drugs for treating cancer, particularly advanced / metastatic malignant solid tumors.

[0023] Other aspects and embodiments of the invention will become clear from the following detailed description. Attached Figure Description

[0024] The preferred embodiments of the invention described in the following detailed description will be better understood when read in conjunction with the accompanying drawings. The drawings show presently preferred embodiments for illustrative purposes. However, it should be understood that the invention is not limited to the precise arrangement and means of the embodiments shown in the drawings.

[0025] Figure 1 shows a waterfall plot of the best percentage change from baseline for the total tumor target lesion diameter in the Phase I clinical study, up to the data cutoff date (DCO) of October 13, 2024. The evaluable overall population (EAS) included 92 subjects, but 3 subjects withdrew early after dosing and had no post-baseline tumor assessment results. The best percentage change (%) is the lowest percentage change (best reduction percentage or smallest increase percentage) in target lesion diameter among all post-baseline measurements.

[0026] Figure 2 shows a waterfall plot of the best percentage change from baseline for the total tumor target lesion diameter in subjects up to the data cutoff date (DCO) of April 11, 2025, in the Phase I clinical study. The evaluable overall population (EAS) included 123 subjects. The best percentage change (%) is the lowest percentage change (best reduction percentage or smallest increase percentage) in target lesion diameter among all post-baseline measurements.

[0027] Figure 3 shows a waterfall plot of the best percentage change from baseline for the total diameter of tumor target lesions in subjects as of the data cutoff date (DCO) October 13, 2024, in the Phase I clinical trial. For the EGFR-mutant NSCLC population (EAS) whose efficacy is evaluable, the best percentage change (%) is the lowest percentage change (best reduction or smallest increase) in target lesion diameter among all post-baseline measurements. In the figure, "3G EGFR TKI" indicates a third-generation tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor (EGFR); "PBC" indicates platinum-based chemotherapy.

[0028] Figure 4 shows a waterfall plot of the best percentage change from baseline for the total tumor target lesion diameter in the Phase I clinical trial, up to the data cutoff date (DCO) of April 11, 2025. The evaluable EGFR-mutant non-squamous NSCLC population (EAS) included 46 subjects. The best percentage change (%) is the lowest percentage change (best reduction or smallest increase) in target lesion diameter among all post-baseline measurements.

[0029] Figure 5 shows a waterfall plot of the best percentage change from baseline for the total diameter of tumor target lesions in subjects as of the data cutoff date (DCO) October 13, 2024, in the Phase I clinical study. For the efficacy-evaluable breast cancer population (EAS), the best percentage change (%) is the lowest percentage change (best reduction percentage or minimum increase percentage) in the diameter of target lesions among all post-baseline measurements.

[0030] Figure 6 shows a waterfall plot of the best percentage change from baseline for the total tumor target lesion diameter in subjects as of the DCO date of September 19, 2025, in the Phase I clinical trial. The evaluable HR+HER2- BC population (EAS) included 18 subjects. The best percentage change (%) is the lowest percentage change (best reduction percentage or smallest increase percentage) in target lesion diameter among all post-baseline measurements.

[0031] Figure 7 shows a spider plot of the best percentage change from baseline for the total tumor target lesion diameter in subjects as of the DCO date of September 19, 2025, in the Phase I clinical trial. The evaluable HR+HER2- BC population (EAS) included 18 subjects. The best percentage change (%) is the lowest percentage change (best reduction percentage or smallest increase percentage) in target lesion diameter among all post-baseline measurements. Detailed Implementation Plan

[0032] Before describing the invention in detail, it should be understood that the invention is not limited to the specific methods and experimental conditions described herein, as these methods and conditions can be modified. Furthermore, the terminology used herein is for illustrative purposes only and is not intended to be restrictive.

[0033] I. Definition

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of this invention, the following terms are defined below.

[0035] The term “about” when used in conjunction with a numeric value means to cover a range of numeric values ​​that have a lower limit of 10% less than the specified numeric value and an upper limit of 10% greater than the specified numeric value.

[0036] When the term “and / or” is used to connect two or more options, it should be understood to mean any one of the options or any two or more of the options.

[0037] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover situations consisting of the mentioned elements, integers, or steps. For example, when referring to an antibody variable region “comprising” a specific sequence, it is also intended to cover the antibody variable region consisting of that specific sequence.

[0038] The term "antibody" is used in the broadest sense to refer to a protein containing an antigen-binding site, encompassing natural and artificial antibodies of various structures, including but not limited to complete antibodies and antigen-binding fragments of antibodies. In this invention, "anti-HER3 antibody" and "antibody that specifically binds to Her3" are used interchangeably. In this invention, anti-HER3 antibody refers to an anti-HER3 monospecific antibody unless otherwise specifically stated herein.

[0039] The terms "whole antibody," "full-length antibody," "complete antibody," and "intact antibody" are used interchangeably herein to refer to a glycoprotein comprising at least two heavy chains (H) and two light chains (L) linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated as VL) and a light chain constant region. The light chain constant region consists of one domain: CL. The VH and VL regions can be further subdivided into hypervariable regions (complementarity-determining regions (CDRs) interspersed with more conserved regions (framework regions (FRs)). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Constant regions do not directly participate in antibody-antigen binding but exhibit various effector functions. In a given VH or VL amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any of a number of well-known schemes or combinations thereof, including, for example: the Chothia numbering scheme (Chothia et al., Canonical structures for the hypervariable regions of immunoglobulins, Journal of Molecular Biology, 196, 901-917 (1987)); and the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath) and Contact (University College London); North numbering scheme (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406, 228-256 (2011)). The CDR of the anti-HER3 monospecific antibody in the anti-HER3 antibody drug conjugate of the present invention can be determined according to any scheme or combination thereof in the art and human evaluation. In one embodiment, the CDR of the antibody of the present invention is a CDR sequence defined according to the Kabat numbering scheme.

[0040] Antibodies with different specificities (i.e., different binding sites against different antigens) have different core binding receptors (CDRs). Although CDRs differ between antibodies, only a limited number of amino acid sites within a CDR are directly involved in antigen binding. Minimal overlapping regions can be determined using at least two of the Kabat, Chothia, AbM, and Contact methods, thus providing a “minimum binding unit” for antigen binding. The minimum binding unit can be a sub-part of a CDR. As will be apparent to those skilled in the art, the residues of the remaining CDR sequence can be determined by the antibody’s structure and protein folding. Therefore, the present invention also contemplates any variants of the CDRs given herein. For example, in a variant of a CDR, the amino acid residues of the minimum binding unit may remain unchanged, while the remaining CDR residues as defined by Kabat or Chothia may be substituted with conserved amino acid residues.

[0041] The term "antigen-binding fragment" refers to a portion or segment of a complete antibody with fewer amino acid residues than the complete antibody, capable of binding an antigen or competing with the complete antibody (i.e., the complete antibody from which the antigen-binding fragment originates) for antigen binding. Antigen-binding fragments can be prepared using recombinant DNA technology or by enzymatic or chemical cleavage of complete antibodies. Antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, single-chain Fv, diabody antibodies, and single-domain antibodies (sdAb). The Fab fragment is a monovalent fragment composed of VL, VH, CL, and CH1 domains; for example, a Fab fragment can be obtained by digesting a complete antibody with papain. Furthermore, digestion of a complete antibody with pepsin below the disulfide bonds in the hinge region produces F(ab')2, a dimer of Fab' and a divalent antibody fragment. F(ab')2 can be reduced under neutral conditions by breaking the disulfide bonds in the hinge region, thereby converting the F(ab')2 dimer into a Fab' monomer. Fab' monomers are essentially Fab fragments with hinge regions (for a more detailed description of other antibody fragments, see: Fundamental Immunology, edited by WE. Paul, Raven Press, NY (1993)). The Fv fragment consists of the VL and VH domains of the antibody single arm. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by independent genes, they can be linked using recombinant methods via synthetic linker peptides that enable the two domains to be produced as a single protein chain, in which the VL and VH regions pair to form a single-stranded Fv. The antibody fragment can be obtained by chemical methods, recombinant DNA methods, or protease digestion.

[0042] The term "monoclonal antibody" refers to polypeptides having substantially the same amino acid sequence or derived from the same genetic source, including antibodies and antigen-binding fragments. This term also includes formulations of antibody molecules that are single-molecule components. Monoclonal antibodies exhibit single-molecule binding specificity and affinity for a specific epitope.

[0043] The term “binding site” or “antigen binding site” refers to the region in an antibody molecule that actually binds to an antigen, including the VH / VL pair, which consists of the antibody light chain variable domain (VL) and the antibody heavy chain variable domain (VH).

[0044] The term "monospecific antibody" refers to an antibody having one or more antigen-binding sites, each of which binds to the same epitope of the same antigen. The anti-HER3 antibody in the antibody-drug conjugate described in this article is an anti-HER3 monospecific antibody.

[0045] The term "multispecific antibody" refers to an antibody having at least two antigen-binding sites, each of which binds to a different epitope of the same antigen or to a different epitope of a different antigen.

[0046] The term "humanized" antibody refers to a chimeric antibody comprising amino acid residues from a non-human CDR and amino acid residues from a human FR. In some embodiments, a humanized antibody comprises all or substantially all of its CDRs corresponding to those of the non-human antibody and all or substantially all of its FR regions corresponding to those of the human antibody. Optionally, a humanized antibody may comprise at least a portion of an antibody constant region derived from a human antibody. The "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

[0047] The term "specific binding" refers to the formation of a complex between an antibody and an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, surface plasmon resonance assays and MSD assays (Estep, P. et al., High throughput solution-based measurement of antibody-antigen affinity and epitope binning, MAbs, 2013.5(2):p.270-278).

[0048] In the context of two or more nucleic acid or polypeptide sequences, the term "% identity" refers to the percentage of identity between sequences. Two sequences are "identical" if they have the same amino acid or nucleotide sequence in the compared region. When comparing and aligning within a comparison window or specified region to seek the largest correspondence measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection, two sequences are "substantially identical" if they have a specified percentage of identity amino acid residues or nucleotides (i.e., 60% identity in the specified region or, when not specified, across the entire sequence, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identity). Sequence identity between sequences is calculated as follows.

[0049] To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., vacancies may be introduced in one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, or non-homologous sequences may be discarded for comparison purposes). In a preferred embodiment, for comparison purposes, the length of the reference sequence being aligned is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the reference sequence length. The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, the molecules are identical at that position.

[0050] Mathematical algorithms can be used to compare sequences and calculate the percentage of identity between two sequences. In a preferred embodiment, the Needlema and Wunsch ((1970) J. Mol. Biol. 48: 444-453) algorithm (available at http: / / www.gcg.com) is used in the GAP program integrated into the GCG software package, employing a Blossum 62 matrix or a PAM250 matrix and vacancy weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6, to determine the percentage of identity between two amino acid sequences. In yet another preferred embodiment, the GAP program in the GCG software package (available at http: / / www.gcg.com) is used, employing an NWSgapdna.CMP matrix and vacancy weights of 40, 50, 60, 70, or 80, and length weights of 1, 2, 3, 4, 5, or 6, to determine the percentage of identity between two nucleotide sequences. The particularly preferred set of parameters (and unless otherwise specified, a set of parameters to be used) is a Blossum 62 scoring matrix with a vacancy penalty of 12, a vacancy extension penalty of 4, and a shift vacancy penalty of 5.

[0051] Alternatively, the PAM120 weighted remainder table, a gap length penalty of 12, and a gap penalty of 4 can be used to determine the percentage of identity between two amino acid sequences or nucleotide sequences using the E. Meyers and W. Miller algorithm ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0).

[0052] Additionally or alternatively, the nucleic acid and protein sequences described herein may be further used as “query sequences” to perform searches against public databases, for example, to identify other family member sequences or related sequences.

[0053] The term "antibody-drug conjugate" generally refers to an antibody linked to a biologically active cytotoxic drug via a stable linker unit. In this invention, the terms "anti-HER3 antibody-drug conjugate," "anti-Her3 antibody-drug conjugate," or "anti-HER3 ADC" are used interchangeably to refer to an antibody-drug conjugate that couples an anti-HER3 antibody and a cytotoxic drug molecule together via a linker, including its tautomers, mesosomes, racemates, enantiomers, diastereomers, and their pharmaceutically acceptable salts or pharmaceutically acceptable salts and solvates. In this invention, the anti-HER3 antibody in the anti-HER3 antibody-drug conjugate refers to an anti-HER3 monospecific antibody.

[0054] In some embodiments of the present invention, the term "drug loading" refers to the average number of cytotoxic drugs loaded on each antibody, which may be called the average number of linkages, or expressed as the ratio of the amount of cytotoxic drug to the amount of antibody. The range of cytotoxic drug loading can be 0-12 linkages per ligand (Ab), for example, 1-10 cytotoxic drugs. The drug loading of each ADC molecule after the coupling reaction can be identified using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays, and HPLC characterization. The average number of linkages p can be an integer or decimal from 1 to 10. For example, the average number of linkages p can be an integer or decimal from 2 to 8. For example, the average number of linkages p can be an integer or decimal from 3 to 8. For example, the average number of linkages p can be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[0055] In some embodiments of the present invention, antibody-drug conjugates refer to compounds containing the same DAR distribution. The term "drug loading" refers to the number of cytotoxic drugs loaded on each ligand, which can be called the number of links or expressed as the ratio of cytotoxic drug to antibody. The range of cytotoxic drug loading can be 0-12 links per ligand (Ab), for example, 1-10 cytotoxic drugs. The number of links p can be any integer from 1 to 10. For example, the number of links p can be any integer from 3 to 9. For example, the number of links p can be any integer from 6 to 8. For example, the number of links p can be 4, 5, 6, 7, or 8.

[0056] The terms "pharmaceutically acceptable salt" and "medicinal salt" are used interchangeably and refer to salts that maintain the biological effects and properties of the anti-HER3 antibody drug conjugates of the present invention, and which are not biologically or otherwise undesirable. The anti-HER3 antibody drug conjugates of the present invention can exist in their pharmaceutically acceptable salt forms, including acid addition salts and base addition salts. In the present invention, a pharmaceutically acceptable, non-toxic acid addition salt refers to a salt formed by the anti-HER3 antibody drug conjugate of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the anti-HER3 antibody drug conjugate of the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by reacting with an organic base containing an N group.

[0057] The term "solvent" refers to an association formed by one or more solvent molecules with the anti-HER3 antibody drug conjugate of this invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0058] The terms “application” and “administration” are used interchangeably to refer to the physical introduction of the anti-HER3 antibody drug conjugate of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of the anti-HER3 antibody drug conjugate of the present invention include oral administration and parenteral administration, such as intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local, or other parenteral administration routes. The term “parenteral administration” refers to administration other than gastrointestinal administration, typically via intravenous, and non-limitingly includes intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. Accordingly, the anti-HER3 antibody drug conjugate of the present invention can be formulated as an injection (including infusion or injection solution), liposomes, etc.

[0059] The term "dosage" refers to the amount of a drug that produces a therapeutic effect. Unless otherwise stated, dosage relates to the amount of the drug in its free form. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased proportionally to the amount of the drug in its free form. For example, the dosage will be stated on the product packaging or product information sheet.

[0060] The term "effective amount" refers to the amount of medicine that provides a desired biological, therapeutic, and / or preventive outcome. This outcome can be a reduction, improvement, mitigation, alleviation, and / or delay of one or more signs or symptoms of a disease, or any other desired alteration of the organism. In the context of cancer, an effective amount includes amounts sufficient to cause tumor shrinkage and / or a decrease in the tumor growth rate (e.g., inhibition of tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay tumor development. In some embodiments, an effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount may be administered in one or more doses. An effective amount of the drug can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, delay, slow down, and possibly prevent cancer cell infiltration into surrounding organs to a certain extent; (iv) inhibit (i.e., slow down and possibly prevent) tumor metastasis to a certain extent; (v) inhibit tumor growth; (vi) prevent or delay the occurrence and / or recurrence of tumors; and / or (vii) alleviate one or more cancer-related symptoms to a certain extent. In one implementation, "effective amount" is the amount of antiHER3 antibody-drug conjugate that has been clinically proven to cause a significant reduction in tumor growth and / or slow cancer progression.

[0061] The term "pharmaceutical-grade" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0062] The term "cancer" refers to a disease characterized by the rapid and uncontrolled proliferation of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Cancer includes, but is not limited to, solid tumors and hematologic malignancies. The cancers treated by the anti-HER3 antibody drug conjugate of the present invention are preferably advanced cancers, recurrent and / or refractory cancers, or cancers resistant to chemotherapy, more preferably advanced solid tumors, such as (histologically or cytologically confirmed) unresectable or metastatic advanced solid tumors.

[0063] The term "standard of care (SOC)" in cancer refers to a widely recognized and recommended treatment regimen based on the results of a patient's examination. It typically involves a combination of surgery, chemotherapy, and radiotherapy, and may also include targeted therapy and immunotherapy. The aim is to provide patients with the most effective and universally applicable treatment methods, but the specific regimen may vary depending on the type of cancer, stage, gene mutation, and individual patient circumstances.

[0064] The term "standard systemic treatment" for cancer refers to a comprehensive approach to cancer therapy, which mainly includes four categories: chemotherapy (cytotoxic drugs that kill rapidly dividing cells), immunotherapy (activating the body's own immune system to fight cancer, such as checkpoint inhibitors), endocrine therapy (blocking hormones and affecting hormone-dependent cancers), and targeted therapy (specifically attacking molecular targets on cancer cells). These therapies are often used in combination, and optionally, they can be further combined with local therapies (e.g., surgery, radiotherapy, interventional therapy, etc.) to achieve the best therapeutic effect.

[0065] In cancer terminology, "adjuvant chemotherapy" refers to chemotherapy administered after surgical removal of a tumor. Its purpose is to kill any remaining tiny cancer cells in the body, reducing the risk of cancer recurrence and metastasis, and improving cure rates and long-term survival. Adjuvant chemotherapy typically begins after surgery and uses chemotherapeutic agents that work by interfering with the growth and division of cancer cells; it is a complementary therapy to primary treatments such as surgery.

[0066] The term "inhibition" refers to a given molecule (e.g., an anti-HER3 antibody-drug conjugate) causing a reduction in certain parameters (e.g., heterodimerization of HER2 and HER3, phosphorylation level of HER3, phosphorylation level of AKT, tumor volume). For example, the term includes inhibition of at least 5%, 10%, 20%, 30%, 40%, or more of activity. Therefore, inhibition does not have to be 100%.

[0067] The term "treatment" includes administering the anti-HER3 antibody-drug conjugate of the present invention to an individual in need of treatment with the aim of curing a disease or having an effect on disease regression or delaying disease progression. When referring to a disease, the term "treatment" means alleviating the disease (i.e., slowing or stopping or reducing the development of the disease or at least one of its clinical symptoms), preventing or delaying the onset, development, or progression of the disease.

[0068] The term "individual" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as cattle, horses, sheep, pigs, rabbits, dogs, and cats. The term "individual" is not limited to a specific age or sex. In some implementations, an individual is a human.

[0069] The term "adverse event" (AE) is any unfavorable and generally unexpected or unwanted symptom (including abnormal laboratory findings), condition, or illness associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system in response to treatment or expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatments may have one or more associated AEs, and these AEs may have the same or different levels of severity.

[0070] The term "overall survival" or "OS" refers to the time from when a patient first uses the investigated drug until they die from any cause.

[0071] The term “progression-free survival” or “PFS” refers to the time from when a patient first uses the investigational drug until disease progression or death from any cause.

[0072] All numerical ranges herein should be understood as disclosing every numerical value and subset thereof within that range, regardless of whether they are specifically disclosed otherwise. For example, reference to any numerical range should be considered as reference to every numerical value within that range, such as every integer within that range. This invention relates to all values ​​falling into these ranges, all smaller ranges, and upper or lower limits of numerical ranges.

[0073] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0074] II. Uses of the anti-HER3 antibody-drug conjugate of the present invention

[0075] -Anti-HER3 antibody drug conjugate of the present invention

[0076] Antibody-drug conjugates (ADCs) are a technology that utilizes the specific recognition ability of antibodies on the surface of tumor cells to precisely deliver anti-tumor drugs (such as cytotoxic agents, cell inhibitors, and small-molecule chemotherapeutic agents) to tumor target cells, causing intracellular accumulation and release, thereby precisely killing tumor cells. ADCs generally consist of three parts: an antibody or antibody-like ligand, a small-molecule drug, and a linker (connector) that conjugates the antibody or antibody-like ligand to the drug. Due to their suitable molecular weight, high stability, strong targeting, and low toxicity, ADCs are considered to be among the most promising anti-tumor drugs.

[0077] The anti-HER3 antibody-drug conjugate of the present invention consists of three parts: an antibody that specifically binds to Her3 or its antigen-binding fragment, a small molecule drug, and a linker (connector) that conjugates the antibody and the small molecule drug together, having the structure shown in formula (I-1):

[0078] In some embodiments, the Ab in formula (I-1) is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and the Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment.

[0079] In some embodiments, the Ab in formula (I-1) is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; and the Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment.

[0080] In some embodiments, the Ab in formula (I-1) is an anti-HER3 monospecific antibody, which includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes amino acid sequences HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively; and the light chain variable region includes amino acid sequences LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively.

[0081] In some embodiments, the Ab in formula (I-1) is an anti-HER3 monospecific antibody comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO:7 or has at least 95%, 96%, 97%, 98%, or 99% identity with it; and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:8 or has at least 95%, 96%, 97%, 98%, or 99% identity with it. For example, the Ab in formula (I-1) comprises a heavy chain variable region with the amino acid sequence shown in SEQ ID NO:7 and a light chain variable region with the amino acid sequence shown in SEQ ID NO:8.

[0082] In some embodiments, the Ab in formula (I-1) is an anti-HER3 monospecific antibody comprising a heavy chain sequence of SEQ ID NO:9 or having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with it, and a light chain sequence of SEQ ID NO:10 or having at least 90%, 95%, 96%, 97%, 98%, or 99% identity with it. For example, the Ab in formula (I-1) comprises a heavy chain with an amino acid sequence as shown in SEQ ID NO:9 and a light chain with an amino acid sequence as shown in SEQ ID NO:10.

[0083] In some embodiments, Ab in formula (I-1) is an IgG antibody; more preferably, an IgG1 antibody or an IgG4 antibody; even more preferably, an IgG1 antibody; wherein the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, single-chain Fv, or single-chain Fab.

[0084] In some embodiments, the anti-Her3 antibody or its antigen-binding fragment described in this invention is an anti-HER3 monospecific humanized antibody or its fragment.

[0085] In some embodiments, the anti-Her3 antibody described in this invention is a monoclonal antibody.

[0086] In some implementations, L in equation (I-1) is -L a -L b-L c -,

[0087] The -L a -for

[0088] Where W is -(C(R) wa (R) wb )) wn -, Y is -(OCH2CH2) yn -O yp -, Z is -(C(R) za (R) zb )) zn ;

[0089] Where wn is 1, 2, 3 or 6,

[0090] Each methylene unit of W is independently converted by -Cyr-, -N(R) wx )C(O)-、-C(O)N(R wx - or -C(O)- substitution;

[0091] Where yn is 0, 4 or 8, and yp is 0 or 1;

[0092] Where zn is 1, 2 or 3

[0093] Each of the methylene units of Z is independently converted by -Cyr-, -N(R) zx )C(O)-、-C(O)N(R zx - or -C(O)- substitution;

[0094] -Cyr- is a 3- to 10-membered saturated subcarbonyl cycloalgide, wherein -Cyr- is unsubstituted or independently substituted by 1 to 3 substituents R. cx replace;

[0095] Each R wa R wb R za R zb R wx R zx R cx Each independently represents hydrogen, halogen, -OR r Or be R r Optional substitution of C 1-6 Aliphatic groups;

[0096] Each R r Each is independently hydrogen, halogen, or C 1-6 Aliphatic groups;

[0097] The -L b -Selected from the following groups:

[0098] The -L c -for

[0099] Where R L1 R L2 Each is independently selected from the following groups: hydrogen, halogen, -OH and C. 1-6 Aliphatic groups.

[0100] In some preferred embodiments, L in equation (I-1) is -L a -L b -L c -,

[0101] Wherein, -L a -for

[0102] The -L b -for

[0103] The -L c -for

[0104] In some preferred embodiments, L in equation (I-1) is

[0105] In some implementations, -M- in formula (I-1) is selected from:

[0106] In some embodiments, p in this invention refers to the average number of connections. For example, the average number of connections p is an integer or decimal from 2 to 8. For example, the average number of connections p is an integer or decimal from 3 to 8. For example, the average number of connections p is an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10. For example, the average number of connections p is an integer or decimal from 7 to 8.

[0107] In some embodiments, p in this invention refers to the number of connections. The number of connections p in this invention is an integer from 2 to 8. For example, the number of connections p is an integer from 3 to 8. For example, the number of connections p is an integer of 2, 3, 4, 5, 6, 7, 8, 9, or 10. For example, the number of connections p is 6, 7, or 8.

[0108] In some implementations, the structure of the anti-HER3 antibody drug conjugate is shown in formula (II-1):

[0109] in,

[0110] p is as defined in any of the embodiments described herein;

[0111] Ab is an anti-HER3 antibody or its antigen-binding fragment as defined in any of the embodiments described herein;

[0112] L 2 It can be -O- or -S-;

[0113] L 3 Selected from -C(R) 1a (R) 1b - or -C(R) 1a (R) 1b )C(R 1a (R) 1b )-;

[0114] Each R 1a Or R 1b Each can be hydrogen, halogen, or C that can be optionally substituted by R. 1-6 Aliphatic groups;

[0115] Each R can be either hydrogen or halogen.

[0116] In a preferred embodiment, the anti-HER3 antibody drug conjugate has the following structural formula:

[0117] in,

[0118] p is defined as in any of the schemes described in this paper;

[0119] Ab is an anti-HER3 antibody or its antigen-binding fragment as defined in any of the embodiments described herein.

[0120] In a preferred embodiment, the anti-HER3 antibody drug conjugate has the following structural formula:

[0121] in,

[0122] p represents the average number of connections, and p is selected from an integer or decimal of 1 to 10, preferably an integer or decimal of 3 to 8, and more preferably an integer or decimal of 7 to 8;

[0123] hu3F8-2 is an anti-HER3 antibody, the heavy chain amino acid sequence of which is shown in SEQ ID NO:9 and the light chain amino acid sequence of which is shown in SEQ ID NO:10.

[0124] In a preferred embodiment, the anti-HER3 antibody drug conjugate has the following structural formula:

[0125] in,

[0126] p is the number of connections, and p is selected from an integer from 1 to 10, preferably an integer from 3 to 8, and more preferably an integer of 6, 7 and 8;

[0127] hu3F8-2 is an anti-HER3 antibody, the heavy chain amino acid sequence of which is shown in SEQ ID NO:9 and the light chain amino acid sequence of which is shown in SEQ ID NO:10.

[0128] - Drug preparation using anti-HER3 antibody drug conjugates

[0129] In some embodiments, the present invention provides a medicament prepared using the anti-HER3 antibody-drug conjugate of the present invention. In some embodiments, the medicament further comprises suitable pharmaceutical excipients, such as pharmaceutical carriers and pharmaceutical excipients known in the art, including buffers.

[0130] As used herein, "pharmaceutical carrier" includes any and all physiologically compatible solvents, dispersion media, isotonic agents, and absorption delay agents. Pharmaceutical carriers suitable for this invention can be sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is the preferred carrier when administering drugs intravenously. Saline solutions, aqueous dextran, and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. For information on the use and applications of excipients, see also "Handbook of Pharmaceutical Excipients," 5th edition, R.C. Rowe, P.J. Seskey, and S.O. Wen, Pharmaceutical Press, London, Chicago. If desired, the drug may also contain small amounts of wetting agents or emulsifiers, or pH buffers. These drugs may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may contain standard pharmaceutical carriers and / or excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, or saccharin.

[0131] Pharmaceutical formulations comprising the antiHER3 antibody drug conjugate of the present invention can be prepared by mixing the antiHER3 antibody drug conjugate of the present invention having the desired purity with one or more optional pharmaceutical excipients (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)), preferably in the form of a lyophilized formulation or an aqueous solution.

[0132] Sustained-release formulations can be prepared. Suitable examples of sustained-release formulations include a semi-permeable matrix of a solid hydrophobic polymer containing the anti-HER3 antibody drug conjugate of the present invention, said matrix being in the form of a shaped article, such as a film or microcapsule.

[0133] In some embodiments, the drug prepared using the anti-HER3 antibody drug conjugate of the present invention further includes instructions for use, wherein the instructions for use indicate the dosage, route of administration and administration regimen for administering the drug to a subject.

[0134] In some implementations, the medication is administered to the patient orally.

[0135] In some embodiments, the drug administered to the patient is in a parenteral form, such as in a liquid carrier, or suitable for reconstitution into a liquid solution or suspension. Liquid compositions for parenteral administration can be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion include intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion. In one embodiment, the anti-HER3 antibody-drug conjugate is administered intravenously.

[0136] In some implementations, the medication administered to the patient is provided as a sterile, transparent liquid solution in a disposable vial for injection, for example at a concentration of 10 mg / mL to 50 mg / mL, such as 20 mg / mL.

[0137] - Treatment of cancer with anti-HER3 antibody-drug conjugates

[0138] This invention provides the use of antiHER3 antibody-drug conjugates or pharmaceutically acceptable salts thereof as defined in any embodiment herein in the preparation of medicaments for treating cancer.

[0139] The present invention also provides anti-HER3 antibody-drug conjugates or pharmaceutically acceptable salts thereof as defined in any embodiment herein for the treatment of cancer.

[0140] The present invention also provides a method for treating cancer in a subject, comprising administering an anti-HER3 antibody-drug conjugate or a pharmaceutically acceptable salt thereof as defined in any embodiment herein to the subject.

[0141] Tumors / cancers suitable for treatment with the anti-HER3 antibody-drug conjugate of the present invention can be early, intermediate, or late-stage or metastatic cancers. Furthermore, tumors / cancers suitable for treatment with the anti-HER3 antibody-drug conjugate of the present invention can be tumors / cancers that have previously received treatment and have experienced immune escape.

[0142] According to the present invention, the term "HER3-positive cancer" refers to cancer involving cancer cells expressing HER3, preferably expressing HER3 on the surface of cancer cells.

[0143] In some embodiments, cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is characterized by an increase in HER3 expression in cancerous tissue or cancer cells compared to HER3 expression in corresponding non-cancer tissue or cells, for example, an increase of at least 10%, particularly at least 20%, at least 50%, at least 100%, at least 200%, at least 500%, at least 1000%, at least 10000%, or even more.

[0144] In some embodiments, non-limiting examples of cancers treated with the anti-HER3 antibody-drug conjugate of the present invention include: lung cancer such as non-small cell lung cancer (NSCLC), breast cancer (BC), esophageal squamous cell carcinoma (ESCC), biliary tract cancer (BTC), prostate cancer such as castration-resistant prostate cancer (CRPC), head and neck squamous cell carcinoma (HNSCC), and colorectal cancer (CRC).

[0145] In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is HER3-positive cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention includes the following HER3-positive cancers: lung cancer such as non-small cell lung cancer (NSCLC), breast cancer (BC), esophageal squamous cell carcinoma (ESCC), biliary tract cancer (BTC), prostate cancer such as castration-resistant prostate cancer (CRPC), head and neck squamous cell carcinoma (HNSCC), and colorectal cancer (CRC).

[0146] In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is refractory, advanced, unresectable, or metastatic cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is advanced and / or metastatic cancer, for example, brain metastases or liver metastases.

[0147] In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is brain metastatic lung cancer, such as brain metastatic non-small cell lung cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is liver metastatic breast cancer, such as liver metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer.

[0148] In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is unresectable cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is recurrent cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is cancer that has progressed during or after standard systemic therapy. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is refractory cancer, for example, cancer that continues to progress during or after treatment with other cancer treatment regimens. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is cancer that is intolerable to standard therapy.

[0149] The standard systemic treatment may be chemotherapy, immunotherapy, endocrine therapy combined with targeted therapy, and / or local therapy. In some embodiments, chemotherapy is platinum-based chemotherapy. In some embodiments, immunotherapy is based on immune checkpoint inhibitors, such as anti-PD-1 / PD-L1 monoclonal antibodies. In some embodiments, endocrine therapy combined with targeted therapy is endocrine therapy (ET) combined with cyclin-dependent kinase (CDK) 4 / 6 inhibitors. In some embodiments, local therapy is surgery or radiation therapy.

[0150] "Metastasis" refers to the spread of cancer cells from their original site to another part of the body. The formation of metastasis is a highly complex process, depending on the separation of malignant cells from the primary tumor, invasion of the extracellular matrix, penetration of the endothelial basement membrane into body cavities and blood vessels, and then infiltration of target organs via blood transport. Finally, the growth of new tumors at the target site depends on angiogenesis. Tumor metastasis often occurs after resection of the primary tumor because tumor cells or components may remain and develop metastatic potential. In one embodiment, the term "metastasis" according to the invention refers to "distant metastasis," which involves metastasis far from the primary tumor and the regional lymph node system. In one embodiment, the term "metastasis" according to the invention refers to lymph node metastasis.

[0151] Refractory cancer is a malignant tumor that is unresponsive to specific treatments; it is initially unresponsive to treatment or becomes unresponsive to treatment over time.

[0152] Unresectable cancer is cancer that cannot be completely removed by surgery.

[0153] Late-stage cancer is cancer that has spread (metastasized) or recurred.

[0154] In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is refractory, advanced, unresectable, or metastatic lung cancer such as non-small cell lung cancer (NSCLC), breast cancer (BC), esophageal squamous cell carcinoma (ESCC), biliary tract cancer (BTC), prostate cancer such as castration-resistant prostate cancer (CRPC), head and neck squamous cell carcinoma (HNSCC), and colorectal cancer (CRC).

[0155] In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is lung cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is refractory, advanced, unresectable, or metastatic lung cancer, such as non-small cell lung cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is HER3-positive non-small cell lung cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is squamous non-small cell lung cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is non-squamous non-small cell lung cancer. In some embodiments, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is cancer with an EGFR mutation, for example, lung cancer with an EGFR mutation, particularly non-small cell lung cancer with an EGFR mutation.

[0156] In some specific embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer. In some specific embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer with EGFR mutation. In some specific embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer with EGFR mutation.

[0157] In some specific embodiments, the EGFR-mutated non-small cell lung cancer is non-small cell lung cancer with EGFR exon 19 deletion (Ex19del). In some specific embodiments, the EGFR-mutated non-small cell lung cancer is non-small cell lung cancer with a mutation at EGFR exon 21, amino acid position 858, where leucine (L) is changed to arginine (R) (L858R).

[0158] In some specific embodiments, the non-small cell lung cancer is non-small cell lung cancer that has previously received treatment with an EGFR tyrosine kinase inhibitor (TKI). In some specific embodiments, the non-small cell lung cancer is non-small cell lung cancer that has previously received osimertinib or other third-generation TKIs.

[0159] In some specific implementations, the non-small cell lung cancer is non-small cell lung cancer that has previously received at least one platinum-based chemotherapy regimen.

[0160] In some specific implementations, the non-small cell lung cancer is non-small cell lung cancer that has previously received third-generation TKI treatment and platinum-based chemotherapy regimens.

[0161] In some specific implementations, the non-small cell lung cancer is advanced / unresectable or metastatic non-squamous NSCLC with EGFR exon 19 deletion (Ex19del) or L858R mutation, and / or non-small cell lung cancer that has progressed during or after treatment with third-generation EGFR TKIs and / or platinum-based chemotherapy.

[0162] In some specific embodiments, the non-small cell lung cancer is non-small cell lung cancer without EGFR mutation. In some specific embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer without EGFR mutation. In some specific embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer without EGFR mutation.

[0163] In some specific embodiments, the non-small cell lung cancer without EGFR mutations is non-small cell lung cancer that has previously received anti-PD-1 / PD-L1 antibody therapy. In some specific embodiments, the non-small cell lung cancer without EGFR mutations is non-small cell lung cancer that has previously received 1-2 chemotherapy regimens, with or without anti-PD-1 / anti-PD-L1 antibody-based therapy and with or without VEGF-targeting antibody-based therapy, wherein at least one platinum-based chemotherapy regimen was received.

[0164] In some implementations, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is breast cancer (BC).

[0165] In some embodiments, the breast cancer is triple-negative breast cancer (TNBC). In some embodiments, the breast cancer is HER3-positive triple-negative breast cancer (TNBC). For example, triple-negative breast cancer refers to breast cancer in which immunohistochemical examination of the cancer tissue shows negative results for estrogen receptor (ER), progesterone receptor (PR), and proto-oncogene Her-2.

[0166] In some embodiments, the breast cancer is Her2-positive breast cancer (Her2+ BC). In some embodiments, the cancer of the present invention is HER2-positive and HER3-positive breast cancer. For example, the Her2-positive breast cancer refers to breast cancer that receives a 3+ score for Her2 expression in immunohistochemistry (IHC) (IHC 3+); or breast cancer that receives a 2+ score for Her2 expression in immunohistochemistry (IHC) and is confirmed as positive for Her2 expression in in situ hybridization (ISH) (IHC 2+ and ISH+).

[0167] In some embodiments, the breast cancer is HER2-low expression breast cancer. In some embodiments, the breast cancer of the present invention is HER2-low expression and HER3-positive breast cancer. For example, the HER2-low expression breast cancer refers to breast cancer that scores 2+ for HER2 expression in immunohistochemistry and is negative for HER2 expression in in situ hybridization (IHC 2+ and ISH-); or the HER2-low expression breast cancer refers to breast cancer that scores 1+ for HER2 expression in immunohistochemistry (IHC 1+); or the HER2-low expression breast cancer is breast cancer that scores >0 and <1+ for HER2 expression in immunohistochemistry.

[0168] The in situ hybridization methods of the present invention include fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), and silver-enhanced in situ hybridization (SISH).

[0169] In some embodiments, the breast cancer is HER2-low expression breast cancer. In some embodiments, the breast cancer of the present invention is HER2-low expression and HER3-positive breast cancer. For example, the HER2-low expression breast cancer refers to breast cancer with an immunohistochemical HER2 expression score of 0 and membrane staining (IHC 0 and membrane staining).

[0170] In some embodiments, the breast cancer is hormone receptor (HR) positive breast cancer (HR+ BC). In some embodiments, the breast cancer is hormone receptor (HR) positive and HER2 negative breast cancer (HR+ and HER2- BC). In some embodiments, HER2 negative includes (1) a 0 score for Her2 expression in immunohistochemistry (IHC); or (2) a 1+ score for Her2 expression in IHC; or (3) a 2+ score for Her2 expression in IHC and negative Her2 expression in in situ hybridization (ISH).

[0171] In some implementations, the breast cancer is hormone receptor (HR) negative breast cancer.

[0172] In some specific implementations, the breast cancer is HER2-positive, HER2-low-expressing, or HER2-ultra-low-expressing breast cancer.

[0173] In some embodiments, the breast cancer is breast cancer that has previously received HER2-targeted therapy, such as a HER2-targeted antibody-drug conjugate with a topoisomerase I inhibitor. In some specific embodiments, the breast cancer is breast cancer that has previously received HER2-targeted therapy and has received no more than three lines of prior systemic therapy. In some specific embodiments, the breast cancer is breast cancer that has previously received one HER2-targeted ADC therapy with a topoisomerase I inhibitor. In some specific embodiments, the breast cancer is refractory advanced / unresectable or metastatic breast cancer, such as HR+HER2- breast cancer.

[0174] In some specific implementations, the breast cancer is advanced / unresectable or metastatic breast cancer that has progressed during or after HER2-targeted therapy and is HER2-positive (IHC3+ or IHC2+ and ISH+), HER2-low expression (IHC2+ and ISH-, IHC1+), or HER2-ultra-low expression (IHC0 with membrane staining).

[0175] In some embodiments, the breast cancer is breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy. In some embodiments, the breast cancer is hormone receptor-positive (HR+) and Her2-negative (HER2-) breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy. In some embodiments, the breast cancer is advanced / unresectable or metastatic breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy. In some embodiments, the breast cancer is adult-onset advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative (HER2-) breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy. In some specific embodiments, the breast cancer is advanced / unresectable or metastatic breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has received or not received chemotherapy at the unresectable or metastatic stage. For example, the breast cancer mentioned is an adult advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative (IHC score 0, 1+, or 2+ / in situ hybridization negative) breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has received or not received chemotherapy at the unresectable or metastatic stage.

[0176] In some specific implementations, the breast cancer is advanced / unresectable or metastatic breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has recurred within 6 months of completing adjuvant chemotherapy. For example, the breast cancer is adult-onset advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative (IHC score 0, 1+, or 2+ / in situ hybridization negative) breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has recurred within 6 months of completing adjuvant chemotherapy.

[0177] In some implementations, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is esophageal squamous cell carcinoma (ESCC).

[0178] In some implementations, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is biliary tract cancer.

[0179] In some implementations, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is castration-resistant prostate cancer (CRPC).

[0180] In some implementations, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is head and neck squamous cell carcinoma (HNSCC).

[0181] In some implementations, the cancer treated with the anti-HER3 antibody-drug conjugate of the present invention is colorectal cancer (CRC).

[0182] -Subjects

[0183] In some implementations, the subjects are those with other advanced / unresectable or metastatic solid tumors that have progressed during or after standard systemic therapy or for whom standard systemic therapy is unavailable.

[0184] In some implementations, the subjects are advanced / unresectable, metastatic non-squamous NSCLC patients who have experienced disease progression during or after receiving standard systemic therapy and have an EGFR mutation (EGFRm). For example, the EGFRm is selected from Ex19del, L858R, L718V, G719X, C797S, L792F, exon 20 insertion mutation (20Ins), L861Q, S768I, and T790M.

[0185] In some implementations, the subjects are advanced / unresectable, metastatic non-squamous NSCLC patients who have experienced disease progression during or after receiving standard systemic therapy and who do not have EGFR or KRAS mutations.

[0186] In some implementations, the subjects are other advanced / unresectable or metastatic HER2-positive, HER2-low-expressing or HER2-ultra-low-expressing breast cancer subjects whose disease has progressed during or after standard systemic therapy or who have no access to standard systemic therapy.

[0187] In some implementations, the subjects are other advanced / unresectable or metastatic HR+HER2-BC patients who have experienced disease progression during or after standard systemic therapy or who are not eligible for standard systemic therapy.

[0188] In some specific implementations, the subjects are patients with advanced / unresectable or metastatic breast cancer who have previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and have received or not received chemotherapy at the unresectable or metastatic stage. For example, the subjects are adult patients with advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative (HER2-) breast cancer (IHC score 0, 1+, or 2+ / in situ hybridization negative) who have previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and have received or not received chemotherapy at the unresectable or metastatic stage.

[0189] In some specific implementations, the subjects are patients with advanced / unresectable or metastatic breast cancer who have previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and experienced disease recurrence during or within 6 months after completing adjuvant chemotherapy. For example, the subjects are adult patients with advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative (HER2-) (IHC score 0, 1+, or 2+ / in situ hybridization negative) breast cancer who have previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and experienced disease recurrence during or within 6 months after completing adjuvant chemotherapy.

[0190] In some implementations, the subjects are those with advanced / unresectable, metastatic CRPC whose disease has progressed during or after receiving standard systemic therapy.

[0191] In some implementations, the subjects are those with advanced / unresectable, metastatic HNSCC whose disease progresses during or after receiving standard systemic therapy.

[0192] In some implementations, the subjects are advanced / unresectable or metastatic non-squamous NSCLC patients with KRAS mutations who have experienced disease progression during or after receiving standard systemic therapy.

[0193] In some implementations, the subjects are those with advanced / unresectable, metastatic ESCC whose disease progresses during or after receiving standard systemic therapy.

[0194] In some implementations, the subjects are those with advanced / unresectable, metastatic BTC whose disease has progressed during or after receiving standard systemic therapy.

[0195] In some implementation schemes, the subjects are males or females aged ≥18 years.

[0196] In some implementations, the subjects are those whose disease relapses or progresses during or after receiving standard systemic therapy, who are intolerant to standard therapy, or who have no standard therapy available.

[0197] In some implementation schemes, the subjects are those who, according to the Evaluation Criteria for Treatment of Solid Tumors (RECIST) version 1.1, are assessed by the investigator as having at least one measurable lesion.

[0198] In some implementation schemes, the subjects are those with a life expectancy of ≥3 months.

[0199] In some implementations, the subjects were those with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 1.

[0200] In some implementation schemes, the subjects had not previously received HER3-targeted therapy.

[0201] In some implementation schemes, the subjects had not previously received treatment with antibody-drug conjugates containing topoisomerase I inhibitors.

[0202] - Methods of treating cancer using anti-HER3 antibody-drug conjugates

[0203] The present invention provides a method for treating cancer in a subject using an anti-HER3 antibody-drug conjugate, the method comprising administering to the subject a therapeutically effective amount of the anti-HER3 antibody-drug conjugate of the present invention.

[0204] dose

[0205] In some implementations, the anti-HER3 antibody-drug conjugate of the present invention can be administered to the subject at any dose.

[0206] In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 0.5 mg / kg to about 10 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 1 mg / kg to about 9 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 1.5 mg / kg to about 8 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 1.5 mg / kg to about 7.5 mg / kg.

[0207] In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 1.5 mg / kg to about 6.5 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 1.5 mg / kg to about 6 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 3 mg / kg to about 6 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 4 mg / kg to about 6 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 5 mg / kg to about 6 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 5 mg / kg to about 5.5 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 3 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 4.5 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 5 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 5.5 mg / kg. In some embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 6 mg / kg. In some embodiments, the antibody-drug conjugate is administered once every three weeks.

[0208] In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 3 mg / kg to about 4.5 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 3 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 3.75 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 4.5 mg / kg. In some embodiments, the antibody-drug conjugate is administered once every two weeks.

[0209] In some embodiments, the anti-HER3 antibody-drug conjugate can be administered at a dose ranging from about 2.5 mg / kg to about 3.5 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 2.5 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 3 mg / kg. In some specific embodiments, the anti-HER3 antibody-drug conjugate is administered at a dose of about 3.5 mg / kg. In some embodiments, the antibody-drug conjugate is administered on day 1 and day 8 of every 3 weeks.

[0210] Those skilled in the art will understand that the dosage can be selected and adjusted based on the subject's age, weight, disease symptoms, disease progression and / or severity, gender, and / or any other factors that may interfere with the therapeutic effect of the anti-HER3 antibody drug conjugate described in this invention.

[0211] Application route and treatment cycle

[0212] In some embodiments, the anti-HER3 antibody drug conjugate of the present invention can be administered via, for example, oral, parenteral, intraperitoneal, systemic, intravenous (e.g., intravenous infusion or drip), intramuscular, subcutaneous, local, inhalation, rectal, sublingual, transdermal, or vaginal administration.

[0213] In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered intravenously (e.g., by injection into a subject).

[0214] In some embodiments, the anti-HER3 antibody drug conjugate of the present invention can be administered to a subject in a single dose (i.e., as a single treatment). For example, the anti-HER3 antibody drug conjugate of the present invention can be administered to a subject in a single dose over several hours or days.

[0215] In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered to a subject on multiple separate occasions (e.g., as part of an ongoing treatment). For example, the anti-HER3 antibody drug conjugate of the present invention may be administered to a subject on multiple separate occasions over a total period of hours, days, weeks, months, or years (generally described herein as a “treatment cycle” or “exposure cycle”).

[0216] In the field of oncology, the term "treatment cycle" normally refers to a period of time during which anticancer drugs are administered, followed by a rest period after the drugs are discontinued.

[0217] In some embodiments of the present invention, the anti-HER3 antibody drug conjugate of the present invention can be administered over multiple treatment cycles (as defined above). In each treatment cycle, the administration time of the anti-HER3 antibody drug conjugate of the present invention is preferably 30 minutes to 3 hours, more preferably 40 minutes to 2 hours, even more preferably 60 to 90 minutes, and the rest period is preferably 7 to 35 days, more preferably 14 to 28 days, even more preferably 18 to 23 days, and most preferably 21 days.

[0218] In some implementations, one treatment cycle is to administer the anti-HER3 antibody-drug conjugate of the present invention to the subject once every 3 weeks (Q3W).

[0219] In some implementations, one treatment cycle is to administer the anti-HER3 antibody-drug conjugate of the present invention to the subject once every two weeks (Q2W).

[0220] In some embodiments, one treatment cycle is performed by administering the anti-HER3 antibody-drug conjugate of the present invention to the subject once on day 1 and once on day 8 of every 3 weeks.

[0221] In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least one treatment cycle. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least two treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least three treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least four treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least five treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least six treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least seven treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least eight treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least nine treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least ten treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least eleven treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 12 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 13 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 14 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 15 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 16 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 17 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 18 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 19 treatment cycles. In some embodiments, the anti-HER3 antibody drug conjugate of the present invention may be administered for at least 20 treatment cycles.

[0222] Those skilled in the art will understand that there is no upper limit to the number of treatment cycles, and treatment with the anti-HER3 antibody-drug conjugate of the present invention can continue as long as clinical benefit is observed; or, treatment with the anti-HER3 antibody-drug conjugate of the present invention may continue until disease progression or unacceptable toxicity occurs, or until the subject or attending physician decides to discontinue administration of the anti-HER3 antibody-drug conjugate of the present invention.

[0223] In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 1 to 20 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 2 to 20 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 3 to 18 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 4 to 14 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 1 to 15 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 2 to 12 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 3 to 11 treatment cycles. In some embodiments, the anti-HER3 antibody-drug conjugate of the present invention can be administered over 1 to 6 treatment cycles.

[0224] In some embodiments, the dosing regimen is adjusted to provide an optimal and effective response. In some embodiments, the dosing regimen is adjusted if it is insufficient to achieve treatment (e.g., as demonstrated by clinical disease progression, symptom exacerbation, and / or lack of clinical improvement compared to baseline). Whether a particular dosing regimen is sufficient to achieve treatment can be determined by any suitable method. In some embodiments, the determination is assessed by radiographic evaluation (e.g., by computed tomography (CT), positron emission tomography (PET), and / or magnetic resonance imaging (MRI)). In other embodiments, the determination is assessed using one or more cancer markers such as carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), and / or cancer antigen 15-3 (CA 15-3).

[0225] The various embodiments / technical solutions and features described in this invention should be understood as being arbitrarily combined with each other, and all solutions obtained by such combinations are included within the scope of this invention, just as these solutions obtained by such combinations are specifically and individually listed herein, unless the context clearly indicates otherwise.

[0226] Example

[0227] The following examples provide a complete disclosure and description of how to prepare the anti-HER3 antibody-drug conjugate of the present invention and its use to those skilled in the art, and are not intended to limit the scope of the invention as understood by the inventors.

[0228] Example 1. Preparation of anti-HER3 antibody drug conjugate

[0229] According to the method described in PCT Publication No. WO 2023 / 143365, an anti-HER3 antibody-drug conjugate (also referred to as "anti-HER3 ADC") DB1001 was prepared by linking an anti-HER3 antibody hu3F8-2 (corresponding to the heavy chain amino acid sequence shown in WO 2023 / 143365 as shown in SEQ ID NO:13 and the light chain amino acid sequence shown in SEQ ID NO:12) with a linker-cytotoxic agent.

[0230] Specifically, the reducing agent and protective agent were prepared using ultrapure water as follows: 2 mg / ml TCEP (Tris-2-carboxyethyl-phosphine, manufacturer: Thermo) and 100 mmol / L sodium ethylenediaminetetraacetate (manufacturer: Sigma). 150 mg of the 7.4 mg / ml anti-HER3 antibody hu3F8-2 was placed in a 50 ml centrifuge tube, and 50 mM sodium phosphate buffer was added to dilute the antibody concentration to 5 mg / ml at pH 7.5. 100 mmol / L sodium ethylenediaminetetraacetate was added at 5% of the total reaction volume, and the mixture was shaken and mixed. Then, 2 mg / ml TCEP was added for antibody reduction. The molar ratio of TCEP to antibody was 6.0:1. After shaking and mixing, the mixture was placed in a refrigerated constant-temperature mixer at 37°C for 2 hours. A 10 mg / mL solution of linker-payload in dimethyl sulfoxide (DMSO) (manufacturer: Sinopharm Group) was prepared. The DMSO was slowly added at a drug-to-antibody molar ratio of 21:1, and the mixture was shaken and stirred. The mixture was then reacted in a refrigerated constant-temperature mixer at 4°C for 1 hour. The sample was replaced with storage buffer using an ultrafiltration tube (MWCO 30KD, manufacturer: Millipore). The sample was first ultrafiltered three times with 30 mM histidine acetate buffer containing 10% dimethyl sulfoxide at pH 5.5, followed by three more ultrafiltrations with 30 mM histidine acetate buffer without DMSO at pH 5.5. The final ultrafiltration concentration yielded the anti-HER3 antibody-drug conjugate DB1001 with a concentration of 20.56 mg / mL and a yield of 64%. Purity and DAR value were determined using size exclusion chromatography and hydrophobic chromatography. Structure of the linker-cytotoxin (linker-payload):

[0231] The structure of the anti-HER3 antibody-drug conjugate DB1001:

[0232] The purity of the anti-HER3 antibody-drug conjugate DB1001 was found to be 99.02%, and the DAR value p was 7.53.

[0233] Example 2. Phase I / IIa Clinical Study of DB1001 in Solid Tumors

[0234] The details of the First-in-human (FIH) study of DB1001 are summarized below.

[0235] 2.1 Experimental Drugs

[0236] The anti-HER3 antibody drug conjugate DB1001 described in Example 1 is a lyophilized powder for injection, specification: 50mg / vial.

[0237] 2.2 Research Design

[0238] A multicenter, open-label, multiple-dose, FIH Phase I / IIa study of DB1001 will be conducted. The study will consist of two phases: a Phase I clinical trial and a Phase IIa clinical trial.

[0239] 2.3 Research Objectives

[0240] To evaluate the safety, tolerability, pharmacokinetic (PK) characteristics, and preliminary antitumor activity of DB1001 in subjects with advanced / metastatic malignant solid tumors.

[0241] Phase I clinical trial

[0242] In the dose escalation phase of the Phase I study, a standard "3+3" design was used.

[0243] When using DB1001 monotherapy, DB1001 was administered every 3 weeks (Q3W) with 7 dose groups: 1.5 mg / kg, 3.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, and 6.5 mg / kg. DB1001 was also administered every 2 weeks (Q2W) with 3 dose groups: 3.0 mg / kg, 3.75 mg / kg, and 4.5 mg / kg. Additionally, DB1001 was administered on day 1 and day 8 of every 3 weeks with 3 dose groups: 2.5 mg / kg, 3.0 mg / kg, and 3.5 mg / kg. The aim was to investigate the safety and pharmacokinetic characteristics of DB1001 monotherapy, and to determine the maximum tolerated dose (MTD) and / or the recommended dose for Phase II studies (RP2D). In the Phase I study, the subjects included NSCLC without EGFRm or KRAS mutations, NSCLC with EGFRm, NSCLC with KRAS mutations, castration-resistant prostate cancer (CRPC), biliary tract cancer (BTC), triple-negative breast cancer (TNBC), HER2-positive breast cancer (HER2+BC), HER2-low expression breast cancer (HER2 low BC), HER2-ultralow expression breast cancer (HER2 ultralow BC), hormone receptor-positive and HER2-negative breast cancer (HR+HER2-BC), colorectal cancer (CRC), and head and neck squamous cell carcinoma (HNSCC).

[0244] Drug administration regimen

[0245] DB1001 is administered intravenously at fixed intervals (Q3W, Q2W, or day 1 and day 8 of every 3 weeks) until disease progression, loss of clinical benefit as determined by the investigator, withdrawal of study treatment or loss to follow-up, unacceptable toxicity, or other termination criteria as specified in the protocol, whichever occurs first. All treatment-related adverse events (TEAEs) are graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tumor response is assessed according to the Responsive Evaluation of Solid Tumors (RECIST) version 1.1 criteria.

[0246] 2.4 Subject Information

[0247] Deviations from the eligibility criteria may affect the scientific integrity, regulatory acceptability, and / or participant safety of the study; therefore, such deviations are not permitted. Participants must therefore meet the criteria specified in the protocol.

[0248] Inclusion criteria

[0249] 1. Male or female patients aged 18 years or older;

[0250] 2. Disease relapse or progression during or after standard systemic therapy, intolerance to standard therapy, or the absence of available standard therapy. Radiographic disease progression recorded during or after the latest treatment regimen for advanced / unresectable or metastatic disease;

[0251] 3. The investigators assessed the presence of at least one measurable lesion according to the RECIST v1.1 criteria;

[0252] 4. Life expectancy ≥ 3 months;

[0253] 5. ECOGPS score: 0-1 point;

[0254] 6. Echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days prior to enrollment showed LVEF ≥ 50%;

[0255] 7. During the first 7 days of the first cycle, the organs have adequate function;

[0256] 8. Sufficient treatment washout period before day 1 of cycle 1;

[0257] 9. Willing to provide previously removed tumor samples or undergo fresh tumor biopsy;

[0258] 10. Able to understand the research procedures and risks outlined in the informed consent form, able to provide written consent, and agree to comply with the research requirements and evaluation schedule;

[0259] 11. Male and female subjects of childbearing potential must agree to use adequate contraception during the study period and for at least 4 months (men) and 7 months (women) after the last dose of the study drug;

[0260] 12. Male subjects must not freeze or donate sperm throughout the entire study period from the start of screening and for at least 4 months after the last dose of the study drug;

[0261] 13. Female subjects may not donate eggs or retrieve eggs for their own use during the entire study period from the start of screening and for at least 7 months after the last administration of the study drug;

[0262] 14. Pathologically confirmed advanced / unresectable or metastatic solid tumors that are refractory to standard treatment, intolerant to standard treatment, or for which no standard treatment is available.

[0263] Exclusion criteria

[0264] 1. Previous HER3-targeted therapy;

[0265] 2. Previous treatment with antibody-drug conjugates containing a topoisomerase I inhibitor (except for the topoisomerase I inhibitor HER2 ADC in subjects in cohort 2e of phase IIa, which is not applicable to subjects enrolled in the phase I DLT observation period);

[0266] 3. History of symptomatic congestive heart failure (CHF) (NYHA Class II-IV) or serious arrhythmia requiring treatment;

[0267] 4. History of myocardial infarction or unstable angina within 6 months prior to enrollment;

[0268] 5. Resting electrocardiogram (ECG) shows any clinically significant rhythm, conduction, or morphological abnormalities;

[0269] 6. Based on the results of three 12-lead electrocardiogram (ECG) examinations, the average QT interval (QTcF) corrected by the Fredericia formula was prolonged to >470 milliseconds (ms) in both men and women;

[0270] 7. Unable or unwilling to discontinue concomitant medications known to prolong the QT interval;

[0271] 8. Have a history of interstitial lung disease or currently have interstitial lung disease, or have imaging results at the time of screening that suggest they may have these diseases;

[0272] 9. An uncontrolled infection requiring intravenous antibiotics, antiviral drugs, or antifungal drugs is present;

[0273] 10. Suffering from a clinically significant corneal disease;

[0274] 11. Human immunodeficiency virus (HIV) infection is known to exist;

[0275] 12. Exclude subjects with active viral hepatitis;

[0276] 13. Breastfeeding women or women who are confirmed to be pregnant by a serum pregnancy test performed within 7 days before the first day of the first cycle;

[0277] 14. Individuals with clinically active brain metastases or requiring steroid or anticonvulsant treatment to control related symptoms;

[0278] 15. The toxicity of previous anticancer treatment has not declined to ≤ grade 1 (NCI-CTCAE version 5.0) or the baseline level;

[0279] 16. Patients who have had other primary malignant tumors within the past 3 years, excluding non-melanoma skin cancer that has been fully excised, in situ diseases that have received radical treatment, other solid tumors that have received radical treatment, or contralateral breast cancer;

[0280] 17. The presence of drug abuse or any other medical condition that the investigator determines may increase the safety risk to the subject or interfere with participation in or evaluation of the clinical study;

[0281] 18. It is known that there is a hypersensitivity reaction to the investigational drug or the excipients in the drug;

[0282] 19. Other reasons why the researchers believe the patient is unsuitable to participate in this study;

[0283] 20. The presence of clinically significant pulmonary-specific complications;

[0284] 21. Patients in the Phase I / IIa cohort with 2g or 2k who have refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulation, or who have previously undergone major bowel resection that may impair adequate absorption of osimertinib are not eligible for inclusion.

[0285] 2.5 Experimental Results

[0286] 2.5.1. Overall Clinical Efficacy of Solid Tumors

[0287] As of the data cutoff date (DCO) October 13, 2024, a total of 99 subjects with advanced or metastatic solid tumors were enrolled in the Phase I clinical trial and received at least one dose of DB1001 monotherapy, including five dose levels administered at fixed-cycle Q3W: 1.5 mg / kg (3 patients), 3.0 mg / kg (10 patients), 4.5 mg / kg (25 patients), 5.0 mg / kg (52 patients), and 5.5 mg / kg (9 patients). The median age of the subjects was 61.0 years (age range: 32–81 years), and the median number of prior systemic antitumor regimens was 3.0 (range: 1–12).

[0288] As of October 13, 2024, DCO data showed a total of 92 evaluable participants (including all participants enrolled in the Phase I clinical trial, who received at least one dose of DB1001 monotherapy at a fixed Q3-week cycle, underwent baseline tumor assessment, and underwent at least one post-baseline tumor assessment or terminated the study), with a median follow-up time of 5.5 months (range: 0.5–15.2 months). The unconfirmed objective response rate (ORR) was 22.8% (21 / 92), and the unconfirmed disease control rate (DCR) was 80.4% (74 / 92), as detailed in Figure 1. A summary of the overall clinical efficacy for solid tumors is shown in Table 1.

[0289] Table 1. Overall clinical efficacy of DB1001 monotherapy in clinical trials (based on efficacy analysis set)

[0290] CR = Complete Remission, PR = Partial Remission, SD = Stable Disease, PD = Disease Progression, NE = Not Evaluable, CI = Confidence Interval, ORR = Objective Response Rate, DCR = Disease Control Rate.

[0291] [Amended 21.01.2026 according to Rule 26] As of the Data Control Date (DCO) of April 11, 2025, a total of 172 subjects with advanced or metastatic solid tumors were enrolled in the Phase I clinical trial and received at least one dose of DB1001 monotherapy, including seven dose levels administered at fixed intervals (Q3W): 1.5 mg / kg, 3.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, and 6.5 mg / kg. 82.6% of subjects had a baseline ECOGPS score of 1; 29.1% were Caucasian and 65.1% were Asian. 62.8% of subjects had NSCLC; 14.0% had brain metastases at baseline. The median number of prior systemic antitumor regimens was 3.0 (range: 1–11 prior systemic antitumor regimens). Data up to the DCO indicates that a total of 123 evaluable subjects were included (including all subjects enrolled in the Phase I clinical trial, who received at least one dose of DB1001 monotherapy at a fixed Q3W cycle, underwent baseline tumor assessment, and underwent at least one post-baseline tumor assessment) (Figure 2), with a median follow-up time of 7.52 months. The unconfirmed objective response rate (ORR) was 30.9% (38 / 123), and the disease control rate (DCR) was 83.7% (103 / 123). A summary of the overall clinical efficacy for solid tumors is provided in Table 2.

[0292] Table 2. Overall clinical efficacy of DB1001 monotherapy in Phase I clinical trials (based on efficacy analysis set)

[0293] ORR = Objective Response Rate, DoR = Duration of Response, DCR = Disease Control Rate, PFS = Progression-Free Survival, OS = Overall Survival, FU = Follow-up Duration, CI = Confidence Interval.

[0294] As of the DCO date of September 19, 2025, a total of 246 subjects with advanced or metastatic solid tumors were enrolled in the Phase I clinical trial and received at least one dose of DB1001 monotherapy, including seven dose levels administered at fixed intervals (Q3W): 1.5 mg / kg, 3.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, and 6.5 mg / kg. 83.3% of subjects had a baseline ECOGPS score of 1; 22.8% were white and 72.8% were Asian. The median follow-up time was 6.24 months (range: 0.1–22.9).

[0295] As shown in Figures 1 and 2 and Tables 1 and 2, DB1001 exhibits antitumor activity in subjects with advanced / metastatic malignant solid tumors treated with other antitumor regimens after administration of 1.5 mg / kg–6.5 mg / kg. Specifically, it demonstrates safety and tolerability, along with antitumor activity, in subjects with non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), HER2-positive breast cancer (HER2+BC), hormone receptor-positive and HER2-negative breast cancer (HR+HER2-BC), castration-resistant prostate cancer (CRPC), biliary tract cancer (BTC), colorectal cancer (CRC), and head and neck squamous cell carcinoma (HNSCC).

[0296] 2.5.2. Overall Clinical Efficacy of NSCLC with Epidermal Growth Factor Receptor (EGFR) Mutation (EGFRm)

[0297] Data from DCO as of October 13, 2024, showed that 35 patients with evaluable EGFRm NSCLC who received DB1001 monotherapy received DB1001 monotherapy at fixed-cycle Q3W doses ranging from 3.0 to 5.5 mg / kg (7 patients at 3.0 mg / kg, 9 at 4.5 mg / kg, 16 at 5.0 mg / kg, and 3 at 5.5 mg / kg). The unconfirmed ORR was 34.3% (95% CI: 19.1, 52.2), and the unconfirmed DCR was 91.4% (95% CI: 76.9, 98.2), as detailed in Figure 3. A summary of efficacy is shown in Table 3.

[0298] Table 3. Overall clinical efficacy of DB1001 monotherapy in EGFR-mutant NSCLC patients (based on efficacy analysis set)

[0299] CR = Complete Remission, PR = Partial Remission, SD = Stable Disease, PD = Disease Progression, NE = Not Evaluable, CI = Confidence Interval, ORR = Objective Response Rate, DCR = Disease Control Rate

[0300] As of the Data Control Date (DCO) of April 11, 2025, a total of 62 patients with EGFR-m NSCLC who received DB1001 Q3W monotherapy received DB1001 monotherapy at a fixed cycle of 3.0 mg / kg–6.0 mg / kg Q3W. The median age of the subjects was 56.5 years, 51.6% were male, 88.7% had a baseline ECOGPS score of 1, 16.1% were white, and 79.0% were Asian. 27.4% of the subjects had brain metastases at baseline. The median number of prior systemic antitumor regimens was 3.0 (range: 1–11). 85.5% of patients had previously received third-generation TKI therapy, and 91.9% had previously received platinum-based chemotherapy. 56.5% of the subjects had EGFR 19Del mutations, and 37.1% had EGFR L858R mutations. Of the 46 patients with EGFRm NSCLC who were evaluable for efficacy (including all enrolled in the Phase I clinical trial, those who received at least one dose of DB1001 monotherapy at a fixed Q3-week cycle, those who underwent baseline tumor assessment, and those who underwent at least one post-baseline tumor assessment) (Figure 4), the median follow-up time was 7.52 months. The unconfirmed ORR was 43.5% (20 / 46) and the DCR was 91.3% (42 / 46). In particular, at the dose levels of 5.0 mg / kg and 5.5 mg / kg, the unconfirmed ORRs were 37.5% (6 / 16) and 66.7% (8 / 12), respectively. A summary of the overall clinical efficacy in EGFRm NSCLC is shown in Table 4.

[0301] Table 4. Overall clinical efficacy of DB1001 monotherapy in EGFR-mutant NSCLC patients (based on efficacy analysis set)

[0302] Tumor remission in three subjects was confirmed after the DCO date, and was in a pending confirmation status at the DCO deadline.

[0303] ORR = Objective Response Rate, CI = Confidence Interval, DoR = Duration of Response, PFS = Progression-Free Survival, DCR = Disease Control Rate, OS = Overall Survival, FU = Follow-up Time, NR = As of the data cutoff, more than 50% of patients did not experience disease progression, therefore the specific value of median overall survival could not be calculated.

[0304] As shown in Figures 3 and 4 and Tables 3 and 4, DB1001 at doses of 3.0 mg / kg–6.0 mg / kg Q3W was safe and tolerable in NSCLC subjects with EGFR mutations (EGFRm) and exhibited antitumor activity. In particular, DB1001 demonstrated significant antitumor activity in subjects with EGFRm NSCLC who had previously received other antitumor regimens after administration of 5.0 mg / kg Q3W and 5.5 mg / kg Q3W.

[0305] 2.5.3. Overall Clinical Efficacy of Breast Cancer (BC)

[0306] Data from the DCO (Diagnosis and Treatment) panel as of October 13, 2024, showed that 13 evaluable breast cancer (BC) patients who had received DB1001 monotherapy received DB1001 monotherapy at doses ranging from 1.5 to 5.5 mg / kg on a fixed-cycle, quarter-week (Q3W) basis (2 patients received 1.5 mg / kg, 1 patient received 3 mg / kg, 5 patients received 4.5 mg / kg, 3 patients received 5 mg / kg, and 2 patients received 5.5 mg / kg). The unconfirmed objective response rate (ORR) was 30.8% (95% CI: 9.1, 61.4), and the unconfirmed disease control rate (DCR) was 76.9% (95% CI: 46.2, 95.0). See Figure 5 for details, and Table 5 for a summary of efficacy.

[0307] Table 5. Overall clinical efficacy of DB1001 monotherapy in BC subjects during clinical trials (based on efficacy analysis set)

[0308] CR = Complete Remission, PR = Partial Remission, SD = Stable Disease, PD = Disease Progression, NE = Not Evaluable, CI = Confidence Interval, ORR = Objective Response Rate, DCR = Disease Control Rate.

[0309] Population characteristics and overall clinical efficacy of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC

[0310] As of the DCO date of September 19, 2025, a total of 24 HR+HER2-BC patients who received DB1001 Q3W monotherapy received DB1001 monotherapy at a fixed cycle of 3.0 mg / kg–5.5 mg / kg Q3W. The median age of the subjects was 57 years, 95.8% were female, 83.3% had a baseline ECOGPS score of 1, 16.7% were white, and 79.2% were Chinese. 70.8% of the subjects had liver metastases at baseline. 50% of the subjects had an IHC of 0 at baseline. All subjects had previously received endocrine therapy combined with CDK 4 / 6 inhibitors, and 91.7% of the subjects had previously received chemotherapy. The baseline characteristics of the overall HR+HER2-BC population and the subjects in the 5.0–5.5 mg / kg group are shown in Table 6. Of the 20 HR+HER2-BC subjects evaluable for efficacy (including all subjects enrolled in the Phase I clinical trial, who received at least one dose of DB1001 monotherapy at a fixed Q3-week cycle, underwent baseline tumor assessment, and underwent at least one post-baseline tumor assessment), the median follow-up time was 6.32 months. The unconfirmed ORR was 50.0% (10 / 20), and the confirmed DCR was 90.0% (18 / 20). In particular, at the dose levels of 5.0–5.5 mg / kg, the confirmed ORR and confirmed DCR were 50.0% (9 / 18) and 94.4% (17 / 18), respectively. A summary of the overall clinical efficacy for HR+HER2-BC is provided in Table 7 and Figures 6 and 7.

[0311] Table 6. Baseline characteristics of subjects treated with DB1001 monotherapy in clinical trials with HR+HER2-BC

[0312] Table 7. Overall clinical efficacy of DB1001 monotherapy in HR+HER2-BC subjects in clinical trials (based on efficacy analysis set)

[0313] ORR = Objective Response Rate, CI = Confidence Interval, DoR = Duration of Response, PFS = Progression-Free Survival, DCR = Disease Control Rate, OS = Overall Survival, FU = Follow-up Time, NR = As of the data cutoff, more than 50% of patients did not experience disease progression, therefore the specific value of median overall survival could not be calculated.

[0314] As shown in Figures 5, 6, and 7 and Tables 5, 6, and 7, administration of DB1001 at doses ranging from 1.5 mg / kg to 5.5 mg / kg demonstrated safety, tolerability, and antitumor activity in subjects with triple-negative breast cancer (TNBC), HER2-positive breast cancer (HER2+BC), and hormone receptor-positive and HER2-negative breast cancer (HR+HER2-BC). Following administration of DB1001 at doses of 3.0 mg / kg–5.5 mg / kg Q3W, particularly at 5.0–5.5 mg / kg Q3W, DB1001 exhibited significant antitumor activity in subjects with HR+HER2-BC who had previously received other antitumor regimens.

[0315] 2.5.4 Overall clinical safety of solid tumors

[0316] As of the Data Control Date (DCO) of April 11, 2025, a total of 172 subjects received at least one dose of DB1001 monotherapy at a fixed cycle of 1.5 mg / kg–6.5 mg / kg Q3W. DB1001 demonstrated good tolerability and manageable safety. Among the 172 subjects, the incidence of any grade of treatment-related adverse event (TRAE) was 88.4%, and the incidence of grade 3 or higher TRAEs was 36.0%. TRAEs led to DB1001 discontinuation in 15.1% of subjects, DB1001 dose reduction in 12.2% of subjects, and discontinuation of DB1001 in 3.5% of subjects. No deaths due to TRAEs were reported. The most common TRAEs observed (>20%, any grade / ≥3) were anemia (41.9% / 4.7%), decreased neutrophil count (41.9% / 20.9%), nausea (38.4% / 0.6%), decreased platelet count (38.4% / 11.6%), decreased white blood cell count (35.5% / 8.7%), decreased appetite (26.2% / 0.6%), vomiting (22.7% / 0%), and alopecia (20.3% / 0%). Interstitial lung disease occurred in 9 patients (5.1%), of whom 8 (4.7%) were grade 1, 1 (0.6%) was grade 2, and no patients were grade ≥3.

[0317] As the dose increases, PK exposure increases, but systemic effective load exposure is low, and DB1001 does not accumulate after repeated dosing.

[0318] The above in vivo clinical trial results also indicate that DB1001 is safe and tolerable in subjects with advanced / metastatic malignant solid tumors and has anti-tumor activity.

[0319] Exemplary sequence

[0320] Although some representative embodiments and details have been shown for illustrative purposes, it will be apparent to those skilled in the art that various changes and modifications can be made to them without departing from the scope of the subject matter. In this respect, the scope of the invention is defined only by the following claims.

Claims

1. Use of an antibody-drug conjugate or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer, wherein, The antibody-drug conjugate has the structure shown in formula (I-1): in, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and the Ab is not a bispecific or multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. For example, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; and Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. Preferably, the Ab is an anti-HER3 monospecific antibody, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. Preferably, the anti-HER3 monospecific antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; More preferably, the heavy chain amino acid sequence of the anti-HER3 monospecific antibody is shown in SEQ ID NO:9, and the light chain amino acid sequence is shown in SEQ ID NO:10; L is -L a -L b -L c -, The -L a -for Where W is -(C(R) wa (R) wb )) wn -, Y is -(OCH2CH2) yn -O yp -, Z is -(C(R) za (R) zb )) zn ; Where wn is 1, 2, 3 or 6, Each methylene unit of W is independently converted by -Cyr-, -N(R) wx )C(O)-、-C(O)N(R wx - or -C(O)- substitution; Where yn is 0, 4 or 8, and yp is 0 or 1; Where zn is 1, 2 or 3 Each of the methylene units of Z is independently converted by -Cyr-, -N(R) zx )C(O)-、-C(O)N(R zx - or -C(O)- substitution; -Cyr- is a 3- to 10-membered saturated subcarbonyl cycloalgide, wherein -Cyr- is unsubstituted or independently substituted by 1 to 3 substituents R. cx replace; Each R wa R wb R za R zb R wx R zx R cx Each independently represents hydrogen, halogen, -OR r Or be R r Optional substitution of C 1-6 Aliphatic groups; Each R r Each is independently hydrogen, halogen, or C 1-6 Aliphatic groups; Preferably, the -L a -for The -L b -Selected from the following groups: Preferably, the -L b -for The -L c -for Where R L1 R L2 Each is independently selected from the following groups: hydrogen, halogen, -OH and C. 1-6 Aliphatic groups; Preferably, the -L c -for Most preferably, L is -M- is selected from: p represents the average number of drug connections relative to each Ab molecule, and p is selected from an integer or decimal from 1 to 10; for example, the average number of connections p is an integer or decimal from 2 to 8; for example, the average number of connections p is an integer or decimal from 3 to 8; for example, the average number of connections p is an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10; for example, the average number of connections p is an integer or decimal from 7 to 8. Alternatively, p represents the number of drug linkages relative to each Ab molecule, for example, the number of linkages p is an integer from 2 to 8; for example, the number of linkages p is an integer from 3 to 8; for example, the number of linkages p is an integer of 2, 3, 4, 5, 6, 7, 8, 9 or 10; for example, the number of linkages p is 6, 7 or 8; For example, the antibody-drug conjugate has the following structural formula: in, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and the Ab is not a bispecific or multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. For example, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; and Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. Preferably, the Ab is an anti-HER3 monospecific antibody, the amino acid sequence of its heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of its light chain variable region is shown in SEQ ID NO:8; preferably, the heavy chain amino acid sequence is shown in SEQ ID NO:9, and the light chain amino acid sequence is shown in SEQ ID NO:

10. p is the number of connections, and p is selected from an integer from 1 to 10, preferably an integer from 3 to 8, and more preferably an integer of 6, 7 and 8.

2. The use according to claim 1, wherein the cancer is selected from any of the following: lung cancer such as non-small cell lung cancer, breast cancer, esophageal squamous cell carcinoma, biliary tract cancer, prostate cancer such as castration-resistant prostate cancer, head and neck squamous cell carcinoma, and colorectal cancer.

3. The use according to claim 1, wherein the cancer is an early, intermediate, or late stage or metastatic cancer, preferably a late stage or metastatic solid tumor, for example, a brain metastatic solid tumor, such as brain metastatic lung cancer, such as brain metastatic non-small cell lung cancer, or, for example, a liver metastatic solid tumor, such as liver metastatic breast cancer.

4. The use according to claim 1, wherein the cancer is a refractory cancer or an unresectable solid tumor, for example, a refractory cancer is a cancer that continues to progress when or after treatment with other cancer treatment regimens.

5. The use according to claim 2, wherein the cancer is non-small cell lung cancer; For example, the non-small cell lung cancer is non-small cell lung cancer with an EGFR mutation; for example, the non-small cell lung cancer with an EGFR mutation is non-squamous non-small cell lung cancer with an EGFR mutation; or squamous non-small cell lung cancer with an EGFR mutation; For example, the non-small cell lung cancer is non-small cell lung cancer without EGFR mutation; for example, non-squamous non-small cell lung cancer without EGFR mutation, or squamous non-small cell lung cancer without EGFR mutation; For example, the non-small cell lung cancer is advanced / unresectable or metastatic non-squamous NSCLC; preferably, the non-small cell lung cancer is advanced / unresectable or metastatic non-squamous NSCLC with EGFR exon 19 deletion (Ex19del) or L858R mutation; preferably, the non-small cell lung cancer is advanced / unresectable or metastatic non-squamous NSCLC that has progressed during or after EGFR TKI (e.g., third-generation EGFR TKI) and / or platinum-based chemotherapy.

6. The use according to claim 2, wherein the cancer is breast cancer; For example, the breast cancer mentioned is triple-negative breast cancer; For example, the breast cancer is a breast cancer that is positive for human epidermal growth factor receptor 2 (Her2); for example, the breast cancer that is positive for Her2 expression refers to a breast cancer that receives a 3+ score for Her2 expression in immunohistochemistry (IHC); or a breast cancer that receives a 2+ score for Her2 expression in immunohistochemistry (IHC) and is confirmed to be positive for Her2 expression in in situ hybridization (ISH); For example, the breast cancer is HER2-low expression breast cancer; for example, HER2-low expression breast cancer refers to cancer that scores 2+ for HER2 expression in immunohistochemistry and is negative for HER2 expression in in situ hybridization; or HER2-low expression breast cancer refers to cancer that scores 1+ for HER2 expression in immunohistochemistry; or HER2-low expression breast cancer is cancer that scores >0 and <1+ for HER2 expression in immunohistochemistry. For example, the breast cancer mentioned is breast cancer with ultra-low HER2 expression; for example, the breast cancer with ultra-low HER2 expression refers to cancer with an HER2 expression score of 0 in immunohistochemistry and membrane staining. For example, the breast cancer is a hormone receptor (HR) positive breast cancer; for example, the breast cancer is a hormone receptor (HR) positive and Her2 negative breast cancer; for example, the breast cancer is a liver metastatic hormone receptor positive (HR+) and Her2 negative (HER2-) breast cancer. For example, the breast cancer is a refractory advanced / unresectable or metastatic breast cancer, such as advanced / unresectable or metastatic HR+HER2- breast cancer; For example, the breast cancer is breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy; preferably, the breast cancer is advanced / unresectable or metastatic breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy; preferably, the breast cancer is adult advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy. For example, the breast cancer is advanced / unresectable or metastatic breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has received or not received chemotherapy at the unresectable or metastatic stage; for example, the breast cancer is adult advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has received or not received chemotherapy at the unresectable or metastatic stage. For example, the breast cancer is advanced / unresectable or metastatic breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has relapsed within 6 months during or after the completion of adjuvant chemotherapy; for example, the breast cancer is adult advanced / unresectable or metastatic hormone receptor-positive (HR+) and Her2-negative breast cancer that has previously received endocrine therapy combined with CDK 4 / 6 inhibitor therapy and has relapsed within 6 months during or after the completion of adjuvant chemotherapy.

7. The use according to claim 2, wherein the cancer is esophageal squamous cell carcinoma.

8. The use according to claim 2, wherein the cancer is biliary tract cancer.

9. The use according to claim 2, wherein the cancer is colorectal cancer.

10. The use according to claim 2, wherein the cancer is castration-resistant prostate cancer.

11. The use according to claim 2, wherein the cancer is squamous cell carcinoma of the head and neck.

12. The use according to any one of claims 1-11, wherein the antibody-drug conjugate is administered to the subject at a dose of about 1.5 mg / kg to about 6.5 mg / kg; For example, administering the drug to the subject at a dose of about 3 mg / kg to about 6 mg / kg; For example, the drug was administered to the subject at a dose of about 5 mg / kg to about 6 mg / kg; For example, administering the drug to the subject at a dose of approximately 5 mg / kg; For example, administering the drug to the subject at a dose of approximately 5.5 mg / kg; For example, administering the drug to the subject at a dose of approximately 6 mg / kg; For example, the antibody-drug conjugate is administered once every three weeks.

13. The use according to any one of claims 1-11, wherein the antibody-drug conjugate is administered to the subject at a dose of about 3 mg / kg to about 4.5 mg / kg; For example, administering the drug to the subject at a dose of approximately 3 mg / kg; For example, it was administered to the subject at a dose of approximately 3.75 mg / kg; For example, administering the drug to the subject at a dose of approximately 4.5 mg / kg; For example, the antibody-drug conjugate is administered once every two weeks.

14. The use according to any one of claims 1-11, wherein the antibody-drug conjugate is administered to the subject at a dose of about 2.5 mg / kg to about 3.5 mg / kg; For example, administering the drug to the subject at a dose of approximately 2.5 mg / kg; For example, administering the drug to the subject at a dose of approximately 3 mg / kg; For example, administering the drug to the subject at a dose of approximately 3.5 mg / kg; For example, the antibody-drug conjugate is administered on day 1 and day 8 of every 3 weeks.

15. A method of treating cancer, comprising administering a therapeutically effective amount of an anti-HER3 antibody-drug conjugate to an individual in need. in, The anti-HER3 antibody-drug conjugate has the following structural formula: in, The Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region. The heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. The Ab is not a bispecific or multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. For example, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; and Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. Preferably, the Ab is an anti-HER3 monospecific antibody, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. Preferably, the anti-HER3 monospecific antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; More preferably, the heavy chain amino acid sequence of the anti-HER3 monospecific antibody is shown in SEQ ID NO:9, and the light chain amino acid sequence is shown in SEQ ID NO:10; p is an integer or decimal between 2 and 8.

16. Use of the anti-HER3 antibody drug conjugate in the preparation of a medicament for treating cancer, wherein the anti-HER3 antibody drug conjugate has the following structural formula: in, The Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region. The heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. The Ab is not a bispecific or multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. For example, Ab is an anti-HER3 antibody or its antigen-binding fragment, comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; and Ab is not a bispecific antibody or a multispecific antibody containing an anti-EGFR antibody or its antigen-binding fragment. Preferably, the Ab is an anti-HER3 monospecific antibody, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises amino acid sequences HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively; and the light chain variable region comprises amino acid sequences LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. Preferably, the anti-HER3 monospecific antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:7; and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8; More preferably, the heavy chain amino acid sequence of the anti-HER3 monospecific antibody is shown in SEQ ID NO:9, and the light chain amino acid sequence is shown in SEQ ID NO:10; p is an integer or decimal between 2 and 8.

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