Use of antibody-drug conjugates targeting HER2 in the treatment of certain breast cancers

Abstract

Provided is the use of an antibody-drug conjugate targeting Her2 in the preparation of a medicament for the treatment of breast cancer patients with liver metastasis or breast cancer patients without lung metastasis.Compared with the control drug group (lapatinib + capecitabine), the application of the provided antibody-drug conjugate in the treatment of breast cancer patients with liver metastasis and breast cancer patients without lung metastasis can significantly improve the survival time of the patients.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to Chinese Application No. CN202110189905.8, filed February 18, 2021, and Chinese Application No. CN202110506596.2, filed May 10, 2021, each of which is incorporated herein by reference in its entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Computer Readable Form (CRF) of Sequence Listing (Filename: 761682008242SEQLIST.TXT, Recorded on: February 4, 2022, Size: 9,972 bytes).

[0003] The present disclosure relates to the field of precision cancer therapy and to the use of antibody-drug conjugates targeting HER2 (human epidermal growth factor receptor 2) in the treatment of breast cancer, which has different biological behaviors, clinical indicators, and molecular types of disease. [Background technology]

[0004] As early as 1986, researchers raised the issue of dosage precision (Coops W J. Precision of dosage[J]. Tijdschr Diergeneeskd,1986,111(2):91). In 2010, the American medical community proposed the concept of "precision medicine" (Shen B, Hwang J. The clinical utility of precision medicine: properly assessing the value of emerging diagnostic tests[J]. Clinical Pharmacology and Therapeutics,2010,88(6):754-756). In 2015, then-US President Obama proposed the "Precision Medicine Initiative" in his State of the Union address, which hopes to achieve the goal of precise and personalized medicine for cancer and other diseases (Jackson D. Obama pushes'Precision Medicine Initiative'[N]. USA TODAY,2015-1-30). This is mainly because most of the current medical treatments are designed for the “average patient” and this “one-size-fits-all approach” may be highly successful in treating some patients but not others. Precision medicine is also often understood as personalized medicine, where “precision” in a broad sense refers to the optimal treatment for the right patient, i.e., it is necessary to clinically determine which therapeutic agent is most effective for a certain population, as well as which therapeutic agent may be ineffective or cause greater toxicity and side effects. Since each patient is unique, “personalized information” is needed, and clinically, it is necessary to provide more effective, safe and economical medical care for a particular patient by accurately classifying the specific disease of the particular patient and then administering the correct optimal therapeutic agent.

[0005] Breast cancer is a common malignant tumor in women. Due to the change in people's lifestyle concept and ecological environment, the incidence of breast cancer has also increased significantly. Over the past 100 years, the treatment of breast cancer has considered the proposal and promotion of breast-conserving surgery, postoperative adjuvant therapy, endocrine therapy, targeted therapy, etc. Through the results of relevant clinical practice and clinical research, a lot of experience and data on the treatment of the disease have been accumulated, and the overall level of diagnosis of the disease has been improved. However, although the clinical treatment of breast cancer is always based on histopathology, even if the same regimen is used for breast cancer patients with the same pathological type and the same clinical stage, the sensitivity of treatment and the prognosis of patients are greatly different. Obviously, traditional histopathological diagnosis and clinical staging can no longer adequately meet the development needs of tumor research. In fact, different breast cancer patients have different biological behaviors and clinical indicators, such as age, ethnicity, economic history, family history of tumors, pathological type, pathological grade, tumor location, tumor size, lymph node metastasis, clinical stage, and even disease molecular type. This is also the main reason for the obvious differences in treatment response, survival, and other aspects of breast cancer of the same histological type. Therefore, in clinical practice, to achieve the goal of precise personalized treatment (i.e., to administer optimal therapeutic drugs according to individual differences), treatment should be classified according to the different biological behaviors, clinical indicators, and disease molecular types of patients. China Patent Publication No. CN105008398A discloses an antibody-drug conjugate (i.e., Disitamab vedotin) capable of specifically binding to HER2 and having a drug moiety MMAE. Currently, the drug is being considered for the treatment of various HER2-expressing (IHC1+ or higher) cancer indications, including breast cancer, such as gastric cancer and urothelial carcinoma, as well as HER2-low expressing (IHC2+ / FISH- or IHC1+) cancer indications, such as HER2-low expressing breast cancer. In August 2020, the NMPA accepted a new drug application for Disitamab vedotin for the treatment of patients with locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma). In September of the same year, the US FDA also granted Breakthrough Therapy Designation to Disitamab vedotin as a second-line treatment for the indication of HER2-expressing (IHC2+ or IHC3+) locally advanced or metastatic urothelial carcinoma. Additionally, the new drug has also received Fast Track designation from the US FDA for the treatment of urothelial and gastric cancer. All references cited herein, including patent applications, patent publications, and UniProtKB / Swiss-Prot accession numbers, are hereby incorporated by reference in their entirety, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] China Patent Publication No. 105008398 [Non-patent literature]

[0007] [Non-Patent Document 1] Coops W J. Precision of dosage[J].Tijdschr Diergeneeskd,1986,111(2):91 [Non-Patent Document 2] Shen B, Hwang J.The clinical utility of precision medicine:properly assessing the value of emerging diagnostic tests[J].Clinical Pharmacology and Therapeutics,2010,88(6):754-756 [Non-Patent Document 3] Jackson D.Obama pushes'Precision Medicine Initiative'[N].USA TODAY,2015-1-30 Summary of the Invention [Means for solving the problem]

[0008] The present disclosure provides methods and uses for the treatment of breast cancer patients with anti-HER2 antibody drug conjugates (ADCs).These methods and uses are based at least in part on detailed analysis of clinical data presented herein that demonstrate the applicant's surprising discovery that ADCs have produced unexpected technical effects when used to treat breast cancer patients with liver metastases or without lung metastases.Compared to existing standard treatments, progression-free survival is significantly extended.

[0009] For example, in breast cancer patients with liver metastasis, the progression-free survival time of Disitamab vedotin group was 12.5 months, and the progression-free survival time of Capecitabine + Lapatinib group was 5.6 months. In breast cancer patients without lung metastasis, the progression-free survival time of Disitamab vedotin group was 10.9 months, and the progression-free survival time of Capecitabine + Lapatinib group was 5.6 months. In contrast, the efficacy of the antibody drug conjugate (ADC, especially Disitamab vedotin) provided by the present invention did not show a statistically significant advantage in the whole breast cancer patient sample and in the subgroup of breast cancer patients without bone metastasis or the subgroup of breast cancer patients without visceral metastasis, so these excellent results seen in breast cancer patients with liver metastasis or breast cancer patients without lung metastasis were surprising.

[0010] Overall, Disitamab vedotin effectively extends the disease progression-free time and survival time of breast cancer patients with liver metastasis or without lung metastasis, thereby providing patients with more precise treatment options. In other words, the antibody-drug conjugate (ADC, especially Disitamab vedotin) provided by the present invention can be applied to treat breast cancer patients with liver metastasis or without lung metastasis to achieve "precise treatment" for the corresponding patients. Compared with the control group, the clinical application of Disitamab vedotin group in breast cancer patients with liver metastasis and breast cancer patients without lung metastasis is of great significance, and significantly extends the disease progression and the survival time of the patients.

[0011] Provided herein is the use of an antibody-drug conjugate (ADC) in the preparation of a medicament for the treatment of a breast cancer patient with liver metastasis, the antibody-drug conjugate having the general formula Ab-(LU) n wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, n is an integer from 1 to 8 and represents the number of cytotoxic molecules bound to each antibody, the antibody comprises a heavy chain variable region and a light chain variable region, the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin, the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody, and the cytotoxic molecule U comprises MMAE (monomethylauristatin E). Further provided herein is the use of an antibody-drug conjugate (ADC) in the preparation of a medicament for the treatment of a breast cancer patient without lung metastasis, the antibody-drug conjugate having the general formula Ab-(LU): nwherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, n is an integer from 1 to 8 and represents the number of cytotoxic molecules bound to each antibody, the antibody comprises a heavy chain variable region and a light chain variable region, the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin, the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody, and the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

[0012] In some embodiments, the breast cancer patient is positive for HER2 expression. In some embodiments, the sample obtained from the breast cancer of the patient is HER2 positive. In some embodiments, the sample obtained from the breast cancer of the patient is HER2 positive based on fluorescent in situ hybridization (FISH) assay (FISH) and / or immunohistochemistry (IHC) assay. In some embodiments, the HER2 expression in the sample obtained from the breast cancer of the patient is IHC3+, IHC2+ or IHC3+, IHC2+ or FISH+, IHC3+ or FISH+, IHC2+ and FISH+, IHC3+ and FISH+, or IHC3+ and FISH- or not detected. In some embodiments, the sample obtained from the breast cancer of the patient is estrogen receptor (ER) positive and / or progesterone receptor (PR) positive. In some embodiments, the sample obtained from the breast cancer of the patient is estrogen receptor (ER) positive or progesterone receptor (PR) positive. In some embodiments, the sample obtained from the breast cancer of the patient is ER negative and PR negative. In some embodiments, the patient has locally advanced or metastatic breast cancer. In some embodiments, the patient has stage IV breast cancer. In some embodiments, the patient has unresectable breast cancer.

[0013] In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises an HCDR1 comprising the amino acid sequence GYTFTDYY (SEQ ID NO: 3), an HCDR2 comprising the amino acid sequence VNPDHGDS (SEQ ID NO: 4), and an HCDR3 comprising the amino acid sequence ARNYLFDH (SEQ ID NO: 5), and the VL region comprises an LCDR1 comprising the amino acid sequence QDVGTA (SEQ ID NO: 6), an LCDR2 comprising the amino acid sequence WAS (SEQ ID NO: 7), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8). In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises an HCDR1 comprising the amino acid sequence DYYIH (SEQ ID NO: 11), an HCDR2 comprising the amino acid sequence RVNPDHGDSYYNQKFKD (SEQ ID NO: 12), and an HCDR3 comprising the amino acid sequence ARNYLFDHW (SEQ ID NO: 13), and the VL region comprises an LCDR1 comprising the amino acid sequence KASQDVGTAVA (SEQ ID NO: 14), an LCDR2 comprising the amino acid sequence WASIRHT (SEQ ID NO: 15), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8). In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and / or the VL region comprises the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10).In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and the VL region comprising the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10). In some embodiments, the antibody is a murine, chimeric, or humanized antibody. In some embodiments, the antibody is a human IgG antibody. In some embodiments, the antibody is a human IgG1, IgG2, or IgG4 antibody. In some embodiments, the amino acid sequence of the antibody heavy chain is set forth in SEQ ID NO: 1 and the amino acid sequence of the antibody light chain is set forth in SEQ ID NO: 2. In some embodiments, the amino acid sequence of the antibody heavy chain is set forth in SEQ ID NO: 1 excluding the C-terminal lysine and the amino acid sequence of the antibody light chain is set forth in SEQ ID NO: 2.

[0014] In some embodiments, the antibody-drug conjugate is Disitamab vedotin or a biosimilar thereof. In some embodiments, the average DAR (i.e., drug-to-antibody ratio) value of the antibody-drug conjugate is any number between 2 and 7. In some embodiments, the average DAR value is 4±0.5.

[0015] In some embodiments, the patient has previously received one or more of the following prior therapies: chemotherapy, targeted therapy, immunotherapy, and endocrine therapy. In some embodiments, the patient has previously received taxane systemic therapy. In some embodiments, the patient has previously received at least one systemic therapy with trastuzumab or a biosimilar thereof. In some embodiments, the agent is administered intranasally, subcutaneously, intradermally, intramuscularly, or intravenously. In some embodiments, the agent is administered at a dose of 2.0 mg / kg every two weeks. In some embodiments, the agent is administered as a monotherapy. In some embodiments, administration of the antibody drug conjugate to the breast cancer patient results in an increased progression-free survival (PFS) compared to administration of capecitabine and lapatinib.

[0016] Further provided herein is a method for treating breast cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of an antibody-drug conjugate (ADC) having the general formula Ab-(LU): n wherein Ab represents an antibody that specifically binds to human epidermal growth factor receptor 2 (HER2), L represents a linker, U represents a cytotoxic molecule, and n is an integer from 1 to 8, representing the number of cytotoxic molecule(s) conjugated to each antibody, the antibody comprises a heavy chain variable region and a light chain variable region, the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin, the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody, and the cytotoxic molecule U comprises MMAE (monomethyl auristatin E). In some embodiments, the patient has liver metastasis. In some embodiments, the patient does not have lung metastasis. In some embodiments, the patient has liver metastases and no lung metastases.

[0017] In some embodiments, the sample obtained from the patient's breast cancer is HER2 positive. In some embodiments, the breast cancer expresses HER2, e.g., overexpresses HER2. In some embodiments, the sample obtained from the patient's breast cancer is HER2 positive based on fluorescent in situ hybridization (FISH) assay (FISH) and / or immunohistochemistry (IHC) assay. In some embodiments, the HER2 expression in the sample obtained from the patient's breast cancer is IHC3+, IHC2+ or IHC3+, IHC2+ or FISH+, IHC3+ or FISH+, IHC2+ and FISH+, IHC3+ and FISH+, or IHC3+ and FISH- or not detected. In some embodiments, the sample obtained from the patient's breast cancer is estrogen receptor (ER) positive and / or progesterone receptor (PR) positive. In some embodiments, the sample obtained from the patient's breast cancer is estrogen receptor (ER) positive and progesterone receptor (PR) positive. In some embodiments, the sample obtained from the patient's breast cancer is ER-negative and PR-negative.

[0018] In some embodiments, the patient has locally advanced or metastatic breast cancer. In some embodiments, the patient has stage IV breast cancer. In some embodiments, the patient has unresectable breast cancer. In some embodiments, the breast cancer is invasive locally advanced or metastatic breast cancer established by histology and / or cytology and is unresectable.

[0019] In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises an HCDR1 comprising the amino acid sequence GYTFTDYY (SEQ ID NO: 3), an HCDR2 comprising the amino acid sequence VNPDHGDS (SEQ ID NO: 4), and an HCDR3 comprising the amino acid sequence ARNYLFDH (SEQ ID NO: 5), and / or the VL region comprises an LCDR1 comprising the amino acid sequence QDVGTA (SEQ ID NO: 6), an LCDR2 comprising the amino acid sequence WAS (SEQ ID NO: 7), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8). In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises an HCDR1 comprising the amino acid sequence GYTFTDYY (SEQ ID NO: 3), an HCDR2 comprising the amino acid sequence VNPDHGDS (SEQ ID NO: 4), and an HCDR3 comprising the amino acid sequence ARNYLFDH (SEQ ID NO: 5), and the VL region comprises an LCDR1 comprising the amino acid sequence QDVGTA (SEQ ID NO: 6), an LCDR2 comprising the amino acid sequence WAS (SEQ ID NO: 7), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8). In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises an HCDR1 comprising the amino acid sequence DYYIH (SEQ ID NO: 11), an HCDR2 comprising the amino acid sequence RVNPDHGDSYYNQKFKD (SEQ ID NO: 12), and an HCDR3 comprising the amino acid sequence ARNYLFDHW (SEQ ID NO: 13), and / or the VL region comprises an LCDR1 comprising the amino acid sequence KASQDVGTAVA (SEQ ID NO: 14), an LCDR2 comprising the amino acid sequence WASIRHT (SEQ ID NO: 15), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8).In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises an HCDR1 comprising the amino acid sequence DYYIH (SEQ ID NO: 11), an HCDR2 comprising the amino acid sequence RVNPDHGDSYYNQKFKD (SEQ ID NO: 12), and an HCDR3 comprising the amino acid sequence ARNYLFDHW (SEQ ID NO: 13), and the VL region comprises an LCDR1 comprising the amino acid sequence KASQDVGTAVA (SEQ ID NO: 14), an LCDR2 comprising the amino acid sequence WASIRHT (SEQ ID NO: 15), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8). In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and / or the VL region comprises the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10). In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and the VL region comprises the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10). In some embodiments, the antibody is a human IgG antibody, e.g., a human IgG1, IgG2, or IgG4 antibody. In some embodiments, the antibody comprises a human Fc region, eg, a human IgG1, IgG2, or IgG4 Fc region.In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 excluding the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 2.

[0020] In some embodiments, the antibody-drug conjugate is disitamab vedotin or a biosimilar thereof. In some embodiments, the average drug-to-antibody ratio (DAR) of the antibody-drug conjugate is any number between 2 and 7, for example, the average DAR value is 4±0.5.

[0021] In some embodiments, prior to administration of the ADC, the patient has already undergone one or more prior therapies, including chemotherapy, targeted therapy, immunotherapy, or endocrine therapy. In some embodiments, prior to administration of the ADC, the patient has undergone taxane systemic therapy. In some embodiments, prior to administration of the ADC, the patient has undergone at least one systemic therapy with trastuzumab or a biosimilar thereof. In some embodiments, prior to administration of the ADC, the patient has undergone at least one systemic therapy with an anti-HER2 antibody. In some embodiments, the ADC is administered intranasally, subcutaneously, intradermally, intramuscularly, or intravenously. In some embodiments, the ADC is administered at a dose of 2.0 mg / kg every two weeks. In some embodiments, the ADC is administered as a monotherapy. In some embodiments, administration of the ADC extends the progression-free survival (PFS) of the patient compared to administration of capecitabine and lapatinib. In some embodiments, the ADC is administered in a pharmaceutical composition comprising the ADC and a pharma- ceutical acceptable carrier.

[0022] It should be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the present invention will become apparent to those skilled in the art. These and other embodiments of the present invention are further described in the detailed description that follows. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is a schematic diagram of the structure of monomethylauristatin E (MMAE). [Diagram 2] FIG. 1 is a schematic diagram of an exemplary structure of an antibody-drug conjugate of the present disclosure of structural general formula Ab-(LU)n under one of the possible conjugation conditions, where L is linked to one or more of the interchain disulfide bond sites of an antibody via sulfhydryl conjugation, where n is 1, 2, 3, 4, 5, 6, 7, and 8, respectively, L is maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB), U is MMAE, and the structure of "-LU" is as follows: [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art. For definitions and terms of the art, practitioners can refer to Current Protocols in Molecular Biology (Ausubel).

[0025] The three-letter and one-letter codes for amino acids used in the present invention are as described in J. Biol. Chem, 243, p. 3558 (1968).

[0026] In the present invention, methods for identifying and numbering the complementarity determining regions (CDRs) of antibody variable domains include the IMGT, Kabat, Chothia, AbM, and Contact methods, which are well known in the art.

[0027] As used herein, "antibody" encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antigen-binding fragments. As used herein, "antigen-binding fragment" refers to an antibody fragment that contains the heavy or light chain variable region of an antibody and is sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived. In particular, the antigen-binding fragment includes Fab, F(ab'), and F(ab')2, which contain at least one immunoglobulin fragment sufficient to bind a specific antigen to a polypeptide. The fragments may be prepared synthetically, enzymatically, or chemically from intact immunoglobulins, or may be genetically engineered using recombinant DNA technology. Methods for generating the fragments are well known in the art.

[0028] As used in the present invention, the term "mouse antibody" refers to a monoclonal antibody prepared according to the knowledge and skill of the art. In the course of preparation, a hybridoma expressing an antibody having a desired sequence or functional properties is isolated after injecting a test subject with the corresponding antigen. In a preferred embodiment of the present invention, the mouse antibody or antigen-binding fragment thereof may further comprise a light chain constant region of a mouse kappa or lambda chain or a variant thereof, or further comprise a heavy chain constant region of a mouse IgG1, IgG2, IgG3, or a variant thereof.

[0029] As used in the present invention, the term "chimeric antibody" refers to an antibody that is a fusion of the variable region of a mouse antibody and the constant region of a human antibody, and can reduce the immune response induced by the mouse antibody. When establishing a chimeric antibody, a hybridoma that secretes a specific mouse monoclonal antibody is first established. Then, the variable region gene is cloned from the mouse hybridoma cell, and the constant region gene is cloned from a human antibody, if necessary. The mouse variable region gene and the human constant region gene are linked to form a chimeric gene, which is then inserted into a human vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic industrial system or a prokaryotic industrial system. In a preferred embodiment of the present invention, the antibody light chain of the chimeric antibody further comprises a light chain constant region of a human kappa chain or lambda chain or a variant thereof. The antibody heavy chain of the chimeric antibody further comprises a heavy chain constant region of a human IgG1, IgG2, IgG3, IgG4, or a variant thereof. The constant region of the human antibody can be selected from the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4, or a variant thereof, and preferably includes the heavy chain constant region of human IgG2 or IgG4. Alternatively, IgG4 is used, which does not have ADCC toxicity (antibody-dependent cell-mediated cytotoxicity) after amino acid mutations are made.

[0030] As used herein, the term "humanized antibody", also known as CDR-grafted antibody, refers to an antibody generated by grafting mouse CDR sequences onto a human antibody variable region framework (i.e., a different type of human germline antibody framework sequence). It contains CDR regions derived from a non-human antibody, while the remainder of the antibody molecule is derived from a human antibody (or multiple human antibodies). Furthermore, some residues in the framework region (referred to as FR) segments can be modified to maintain binding affinity (Jones et al., Nature, 321:522-525, 1986; Verhoeyen et al., Science, 239:1534-1536, 1988; and Riechmann et al., Nature, 332:323-327, 1988). Humanized antibodies or fragments thereof according to the present invention can be prepared according to techniques known to those skilled in the art (e.g., Singer et al., J. Immun. 150:2844-2857, 1992; Mountain et al., Biotechnol. Genet. Eng. Rev., 10:1-142, 1992; or Bebbington et al., Bio / Technology, 10:169-175, 1992).

[0031] As used herein, the average "DAR" value, i.e., drug-to-antibody ratio, refers to the average number of drugs linked to the antibody contained in the antibody-drug conjugate preparation.

[0032] As used in the present invention, the term "sulfhydryl conjugation" refers to a conjugation method in which a linker is covalently linked to a free sulfhydryl group on an antibody. Cysteine ​​exists in the form of disulfide bonds in an antibody, and an IgG antibody has four pairs of interchain disulfide bonds that are susceptible to reduction. Therefore, in the process of preparing an antibody-drug conjugate, the four pairs of interchain disulfide bonds contained in an IgG antibody are often reduced, thereby generating the above-mentioned "free sulfhydryl groups on the antibody". Furthermore, an IgG antibody has four pairs of interchain disulfide bonds, which, when reduced, generate up to eight free sulfhydryl groups, so that an IgG antibody has up to eight sulfhydryl conjugation sites. Thus, the general formula Ab-(LU) n When n of the antibody drug conjugate is 1, "LU" may be covalently linked to any one of the eight sulfhydryl conjugation sites. Similarly, when n is 2, "LU" may be covalently linked to any two of the eight sulfhydryl conjugation sites. When n is 3, "LU" may be covalently linked to any three of the eight sulfhydryl conjugation sites. When n is 4, "LU" may be covalently linked to any four of the eight sulfhydryl conjugation sites. When n is 5, "LU" may be covalently linked to any five of the eight sulfhydryl conjugation sites. When n is 6, "LU" may be covalently linked to any six of the eight sulfhydryl conjugation sites. When n is 7, "LU" may be covalently linked to any seven of the eight sulfhydryl conjugation sites. When n is 8, "LU" can be covalently linked to eight sulfhydryl conjugation sites.

[0033] II. Use and Methods Certain aspects of the present disclosure relate to antibody-drug conjugates (and methods and uses thereof) that bind to HER2. In some embodiments, the antibody-drug conjugates involved have the general formula Ab-(LU): nwhere Ab represents an anti-HER2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) and represents the number of cytotoxic molecules attached to each antibody.

[0034] In some embodiments, the cytotoxic molecule is an auristatin, or an analog or derivative thereof. Auristatins are derivatives of the natural product dolastatin. Exemplary auristatins include dolostatin-10, auristatin E, auristatin T, MMAE (N-methylvaline-valine-dolaisolein-dolaproine-norephedrine or monomethylauristatin E) and MMAF (N-methylvaline-valine-dolaisolein-dolaproine-phenylalanine or dovaline-valine-dolaisolein-dolaproine-phenylalanine), AEB (ester produced by reacting auristatin E with paraacetylbenzoic acid), AEVB (ester produced by reacting auristatin E with benzoylvaleric acid), and AFP (dimethylvaline-valine-dolaisolein-dolaproine-phenylalanine-p-phenylenediamine or auristatin phenylalanine phenylenediamine). WO2015 / 057699 describes pegylated auristatins that include MMAE. Additional dolastatin derivatives contemplated for use are disclosed in US Pat. No. 9,345,785, which is incorporated herein by reference for any purpose.

[0035] In some embodiments, the cytotoxic molecule is MMAE. In other embodiments, the cytotoxic agent is MMAF.

[0036] In some embodiments, the anti-HER2 (human epidermal growth factor receptor 2) antibody or functional fragment thereof contained in the antibody-drug conjugate provided by the present invention comprises a heavy chain variable region and a light chain variable region, the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as disitamab vedotin, the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB), and the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

[0037] In some embodiments, the linker L is covalently linked to the antibody by sulfhydryl conjugation, and the linking site is the interchain disulfide bond site of the antibody.

[0038] In some embodiments, the antibody-drug conjugate of the present invention is a mixture of antibody-drug conjugates linked with 2 to 7 cytotoxic molecules, and the average DAR (i.e., drug-to-antibody ratio) value of the antibody-drug conjugates is any number between 2 and 7, and more preferably, the average DAR value of the antibody-drug conjugates of the present invention is about equal to 2, 3, 4, 5, 6, or 7. In some specific examples of the present invention, the average DAR value of the antibody-drug conjugates of the present invention is 4±0.5.

[0039] In some embodiments, the corresponding CDRs 1-3 of the heavy and light chain variable regions of the anti-HER2 antibodies involved in the invention are as follows (IMGT numbering): [Table 1]

[0040] In some embodiments, the corresponding CDRs 1-3 of the heavy and light chain variable regions of the anti-HER2 antibodies involved in the invention are as follows: [Table 2]

[0041] In some embodiments, the anti-HER2 antibody comprises corresponding CDR1-3 of the heavy chain variable region and light chain variable region represented by SEQ ID NO:3-8, but contains one, two or three substitutions (e.g., conservative substitutions), insertions or deletions relative to SEQ ID NO:3-8, and an anti-HER2 antibody comprising such sequences retains the ability to bind to HER2. In some embodiments, the anti-HER2 antibody comprises corresponding CDR1-3 of the heavy chain variable region and light chain variable region represented by SEQ ID NO:11-15, and 8, but contains one, two or three substitutions (e.g., conservative substitutions), insertions or deletions relative to SEQ ID NO:11-15, and 8, and an anti-HER2 antibody comprising such sequences retains the ability to bind to HER2.

[0042] In some embodiments, the anti-HER2 (human epidermal growth factor receptor 2) antibody contained in the antibody-drug conjugate provided by the present invention is a murine, chimeric, humanized or fully human, preferably a humanized, monoclonal antibody. In some embodiments, the antibody is a monoclonal antibody.

[0043] In some embodiments, the anti-HER2 (human epidermal growth factor receptor 2) antibody comprised in the antibody-drug conjugate provided by the present invention is an IgG, including IgG1, IgG2, IgG3, and IgG4, and more preferably IgG1, IgG2, and IgG4.

[0044] In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region has a sequence identical to at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or a sequence identical to the sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9). comprises an amino acid sequence having 100% identity, and / or the VL region comprises an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10). In certain embodiments, the VH sequence (e.g., having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:9) contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to SEQ ID NO:9, but an anti-HER2 antibody comprising the sequence retains the ability to bind to HER2. In certain embodiments, a total of 1-10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO:9. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). In certain embodiments, the VL sequence (e.g., having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10) contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to SEQ ID NO: 10, but an anti-HER2 antibody comprising that sequence retains the ability to bind to HER2.In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 10. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).

[0045] In some embodiments, the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and the VL region comprises the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10).

[0046] In some embodiments, the antibody drug conjugate of the present invention is Disitamab vedotin, which is an antibody drug conjugate targeted to the HER2 target, the linker moiety L is maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB), the cytotoxic molecule U comprises MMAE (monomethylauristatin E), the linker L is covalently linked to the antibody by sulfhydryl conjugation, and the average DAR value is 4±0.5.

[0047] In some embodiments, the amino acid sequence of the heavy chain of an antibody Ab included in an antibody-drug conjugate involved in the invention is set forth in SEQ ID NO: 1, and the amino acid sequence of its light chain is set forth in SEQ ID NO: 2. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 1 excluding the C-terminal lysine. Heavy chain amino acid sequence - SEQ ID NO:1 EVQLVQSGAE VKKPGATVKI SCKVSGYTFT DYYIHWVQQA PGKGLEWMGR 50 VNPDHGDSYY NQKFKDKATI TADKSTDTAY MELSSLRSED TAVYFCARNY 100 LFDHWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE 150 PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV 200 NHKPSNTKVD KKVEPKSCDK THTCPPCPAP ELLGGPSVFL FPPKPKDTLM 250 ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV 300 VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP 350 PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400 SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK 445 Light chain amino acid sequence - SEQ ID NO:2 DIQMTQSPSS VSASVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW 50 ASIRHTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCHQ FATYTFGGGT 100 KVEIKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN 150 ALQSGNSQES VTEQDSKDST YSLSSTLTLS KADYEKHKVY ACEVTHQGLS 200 SPVTKSFNRG EC

[0048] In some embodiments, the breast cancer involved in the present invention is a HER2-expressing positive breast cancer, preferably an invasive locally advanced or metastatic breast cancer established by histology and / or cytology, and is unresectable. In some embodiments, the patient is a stage IV breast cancer patient. In some embodiments, the patient is under 65 years old. In some embodiments, the patient is 65 years old or older.

[0049] In some embodiments, the sample from the patient's breast cancer is HER2 positive, e.g., HER2 positive based on fluorescent in situ hybridization (FISH) assay (FISH+) and / or immunohistochemistry (IHC). In some embodiments, the sample from the patient's breast cancer is IHC2+ or IHC3+. In some embodiments, the sample from the patient's breast cancer is IHC2+ or FISH+. In some embodiments, the sample from the patient's breast cancer is IHC3+ or FISH+. In some embodiments, the sample from the patient's breast cancer is IHC2+ and FISH+. In some embodiments, the sample from the patient's breast cancer is IHC3+ and FISH+. In some embodiments, the sample from the patient's breast cancer is IHC3+ and FISH- or not detected.

[0050] In some embodiments, the sample from the patient's breast cancer is estrogen receptor (ER) positive. In some embodiments, the sample from the patient's breast cancer is estrogen receptor (ER) negative. In some embodiments, the sample from the patient's breast cancer is progesterone receptor (PR) positive. In some embodiments, the sample from the patient's breast cancer is progesterone receptor (PR) negative. In some embodiments, the sample from the patient's breast cancer is ER+ and / or PR+. In some embodiments, the sample from the patient's breast cancer is ER- and PR-.

[0051] In some embodiments, patients treated according to the invention have previously been treated with one or more of the following prior chemotherapy agents, targeted therapies, immunotherapies, and endocrine therapies; preferably, the patient has previously received systemic taxane therapy, or the patient must have previously received at least one systemic therapy with trastuzumab or a biosimilar thereof.

[0052] In some embodiments, the antibody drug conjugate or agent of the present invention may be administered intranasally, subcutaneously, intradermally, intramuscularly or intravenously. It is administered at a dose of 2.0 mg / kg every two weeks. In some embodiments, the agent comprises the antibody drug conjugate and a pharma- ceutically acceptable carrier. In some embodiments, administration of the antibody drug conjugate to the breast cancer patient prolongs progression-free survival (PFS) compared to administration of capecitabine and lapatinib. In some embodiments, the antibody drug conjugate is administered as a monotherapy.

[0053] Exemplary and non-limiting embodiments of the present disclosure are provided below. Embodiment 1. Use of an antibody-drug conjugate (ADC) in the preparation of a medicament for the treatment of a breast cancer patient with liver metastasis, said antibody-drug conjugate having the general formula Ab-(LU) n wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8 and represents the number of said cytotoxic molecules bound to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The above-mentioned use, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

[0054] Embodiment 2. Use of an antibody-drug conjugate (ADC) in the preparation of a medicament for the treatment of a breast cancer patient without lung metastasis, said antibody-drug conjugate having the general formula Ab-(LU) n wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8 and represents the number of said cytotoxic molecules bound to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The above-mentioned use, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

[0055] Embodiment 3. The use of embodiment 1 or 2, wherein the breast cancer patient is positive for HER2 expression.

[0056] Embodiment 4. The use of embodiment 3, wherein the sample obtained from the patient's breast cancer is HER2 positive.

[0057] Embodiment 5. The use of embodiment 4, wherein the sample obtained from the patient's breast cancer is HER2 positive based on a fluorescent in situ hybridization (FISH) assay (FISH) and / or an immunohistochemistry (IHC) assay.

[0058] Embodiment 6. The use according to embodiment 5, wherein HER2 expression in a sample obtained from the patient's breast cancer is IHC3+, IHC2+ or IHC3+, IHC2+ or FISH+, IHC3+ or FISH+, IHC2+ and FISH+, IHC3+ and FISH+, or IHC3+ and FISH- or not detectable.

[0059] Embodiment 7. The use according to any one of embodiments 1 to 6, wherein the sample obtained from the patient's breast cancer is estrogen receptor (ER) positive and / or progesterone receptor (PR) positive, or the sample obtained from the patient's breast cancer is ER negative and PR negative.

[0060] Embodiment 8. The use of any one of embodiments 1 to 7, wherein the patient has locally advanced or metastatic breast cancer.

[0061] Embodiment 9. The use of any one of embodiments 1 to 7, wherein the patient has stage IV breast cancer.

[0062] Embodiment 10. The use of any one of embodiments 1 to 9, wherein the patient has unresectable breast cancer.

[0063] Embodiment 11. The use of embodiment 3, wherein the breast cancer is invasive locally advanced or metastatic breast cancer established by histology and / or cytology and is unresectable.

[0064] Embodiment 12. The use according to any one of embodiments 1 to 11, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising an HCDR1 comprising the amino acid sequence GYTFTDYY (sequence number 3), an HCDR2 comprising the amino acid sequence VNPDHGDS (sequence number 4), and an HCDR3 comprising the amino acid sequence ARNYLFDH (sequence number 5), and the VL region comprising an LCDR1 comprising the amino acid sequence QDVGTA (sequence number 6), an LCDR2 comprising the amino acid sequence WAS (sequence number 7), and an LCDR3 comprising the amino acid sequence HQFATYT (sequence number 8).

[0065] Embodiment 13. The use according to any one of embodiments 1 to 11, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising an HCDR1 comprising the amino acid sequence DYYIH (sequence number 11), an HCDR2 comprising the amino acid sequence RVNPDHGDSYYNQKFKD (sequence number 12), and an HCDR3 comprising the amino acid sequence ARNYLFDHW (sequence number 13), and the VL region comprising an LCDR1 comprising the amino acid sequence KASQDVGTAVA (sequence number 14), an LCDR2 comprising the amino acid sequence WASIRHT (sequence number 15), and an LCDR3 comprising the amino acid sequence HQFATYT (sequence number 8).

[0066] Embodiment 14. The use according to any one of embodiments 1 to 13, wherein the antibody is a murine, chimeric or humanized antibody.

[0067] Embodiment 15. The use according to any one of embodiments 1 to 13, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and the VL region comprising the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10).

[0068] Embodiment 16 The use according to embodiment 14 or embodiment 15, wherein the antibody is a human IgG antibody.

[0069] Embodiment 17. The use of embodiment 16, wherein the antibody is a human IgG1, IgG2, or IgG4 antibody.

[0070] Embodiment 18. The use according to any one of embodiments 1 to 11, wherein the amino acid sequence of the heavy chain of the antibody is shown in SEQ ID NO: 1 and the amino acid sequence of the light chain of the antibody is shown in SEQ ID NO: 2.

[0071] Embodiment 19. The use of any one of embodiments 1 to 11, wherein the antibody-drug conjugate is disitamab vedotin or a biosimilar thereof.

[0072] Embodiment 20. The use of any one of embodiments 1 to 19, wherein the antibody-drug conjugate has an average DAR (i.e., drug-to-antibody ratio) value of any number between 2 and 7.

[0073] Embodiment 21. The use according to embodiment 20, wherein the mean DAR value is 4±0.5.

[0074] Embodiment 22. The use of any one of embodiments 1 to 21, wherein the patient has previously been treated with one or more of the following prior therapies: chemotherapy, targeted therapy, immunotherapy, and endocrine therapy.

[0075] Embodiment 23. The use of embodiment 22, wherein the patient has previously received systemic taxane therapy.

[0076] Embodiment 24. The use of embodiment 22, wherein the patient has previously received at least one systemic therapy with trastuzumab or a biosimilar thereof.

[0077] Embodiment 25. The use of any one of embodiments 1 to 24, wherein the medicament is administered intranasally, subcutaneously, intradermally, intramuscularly, or intravenously.

[0078] Embodiment 26. The use of any one of embodiments 1 to 25, wherein the antibody-drug conjugate is administered at a dose of 2.0 mg / kg every two weeks.

[0079] Embodiment 27. The use of any one of embodiments 1 to 26, wherein the antibody-drug conjugate is administered as monotherapy.

[0080] Embodiment 28. The use of any one of embodiments 1 to 27, wherein administering the antibody-drug conjugate to the breast cancer patient extends progression-free survival (PFS) compared to administration of capecitabine and lapatinib.

[0081] Embodiment 29. A method for treating breast cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of an antibody-drug conjugate (ADC), the antibody-drug conjugate having the general formula Ab-(LU) n wherein Ab represents an antibody that specifically binds to human epidermal growth factor receptor 2 (HER2), L represents a linker, U represents a cytotoxic molecule, and n is an integer from 1 to 8 and represents the number of said cytotoxic molecule(s) conjugated to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The method, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E) and the patient has liver metastases and / or does not have lung metastases.

[0082] Embodiment 30 The method of embodiment 29, wherein the breast cancer patient is positive for HER2 expression.

[0083] Embodiment 31 The method of embodiment 30, wherein the sample obtained from the patient's breast cancer is HER2 positive.

[0084] Embodiment 32. The method of embodiment 31, wherein the sample obtained from the patient's breast cancer is HER2 positive based on a fluorescent in situ hybridization (FISH) assay (FISH) and / or an immunohistochemistry (IHC) assay.

[0085] Embodiment 33. The method of embodiment 32, wherein HER2 expression in a sample obtained from the patient's breast cancer is IHC3+, IHC2+ or IHC3+, IHC2+ or FISH+, IHC3+ or FISH+, IHC2+ and FISH+, IHC3+ and FISH+, or IHC3+ and FISH- or not detectable.

[0086] Embodiment 34. The method of any one of embodiments 29 to 33, wherein the sample obtained from the patient's breast cancer is estrogen receptor (ER) positive and / or progesterone receptor (PR) positive, or the sample obtained from the patient's breast cancer is ER negative and PR negative.

[0087] Embodiment 35. The method of any one of embodiments 29 to 34, wherein the patient has locally advanced or metastatic breast cancer.

[0088] Embodiment 36 The method of any one of embodiments 29-34, wherein the patient has stage IV breast cancer.

[0089] Embodiment 37. The method of any one of embodiments 29-36, wherein the patient has unresectable breast cancer.

[0090] Embodiment 38. The method of any one of embodiments 29 to 36, wherein the breast cancer is invasive locally advanced or metastatic breast cancer established by histology and / or cytology and is unresectable.

[0091] Embodiment 39. The method of any one of embodiments 29 to 38, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising an HCDR1 comprising the amino acid sequence GYTFTDYY (sequence number 3), an HCDR2 comprising the amino acid sequence VNPDHGDS (sequence number 4), and an HCDR3 comprising the amino acid sequence ARNYLFDH (sequence number 5), and the VL region comprising an LCDR1 comprising the amino acid sequence QDVGTA (sequence number 6), an LCDR2 comprising the amino acid sequence WAS (sequence number 7), and an LCDR3 comprising the amino acid sequence HQFATYT (sequence number 8).

[0092] Embodiment 40. The method of any one of embodiments 29 to 38, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising an HCDR1 comprising the amino acid sequence DYYIH (sequence number 11), an HCDR2 comprising the amino acid sequence RVNPDHGDSYYNQKFKD (sequence number 12), and an HCDR3 comprising the amino acid sequence ARNYLFDHW (sequence number 13), and the VL region comprising an LCDR1 comprising the amino acid sequence KASQDVGTAVA (sequence number 14), an LCDR2 comprising the amino acid sequence WASIRHT (sequence number 15), and an LCDR3 comprising the amino acid sequence HQFATYT (sequence number 8).

[0093] Embodiment 41 The method of any one of embodiments 29 to 40, wherein the antibody is a murine, chimeric, or humanized antibody.

[0094] Embodiment 42. The method of any one of embodiments 29 to 40, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), and the VL region comprising the amino acid sequence DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10).

[0095] Embodiment 43 The method of embodiment 41 or embodiment 42, wherein the antibody is a human IgG antibody.

[0096] Embodiment 44. The use of embodiment 43, wherein the antibody is a human IgG1, IgG2, or IgG4 antibody.

[0097] Embodiment 45. The method according to any one of embodiments 29 to 38, wherein the amino acid sequence of the heavy chain of the antibody is set forth in SEQ ID NO: 1, and the amino acid sequence of the light chain of the antibody is set forth in SEQ ID NO: 2.

[0098] Embodiment 46. The method of any one of embodiments 29 to 38, wherein the antibody-drug conjugate is disitamab vedotin or a biosimilar thereof.

[0099] Embodiment 47. The method of any one of embodiments 29 to 46, wherein the average DAR (i.e., drug-to-antibody ratio) value of the antibody-drug conjugate is any number from 2 to 7.

[0100] Embodiment 48. The method of embodiment 47, wherein the mean DAR value is 4±0.5.

[0101] Embodiment 49. The method of any one of embodiments 29-48, wherein prior to administration of the ADC, the patient has already undergone one or more prior therapies including a chemotherapeutic agent, a targeted therapy, an immunotherapy, or an endocrine therapy.

[0102] Embodiment 50 The method of embodiment 49, wherein prior to administration of the ADC, the patient has received systemic taxane therapy.

[0103] Embodiment 51. The method of embodiment 49, wherein prior to administration of the ADC, the patient has received at least one systemic therapy with trastuzumab or a biosimilar thereof.

[0104] Embodiment 52 The method of any one of embodiments 29-51, wherein the ADC is administered intranasally, subcutaneously, intradermally, intramuscularly, or intravenously.

[0105] Embodiment 53. The method of any one of embodiments 29-52, wherein the ADC is administered at a dose of 2.0 mg / kg every two weeks.

[0106] Embodiment 54. The method of any one of embodiments 29-53, wherein the ADC is administered as monotherapy.

[0107] Embodiment 55. The method of any one of embodiments 29-54, wherein administering the ADC extends the progression-free survival (PFS) of the patient compared to administration of capecitabine and lapatinib.

[0108] Embodiment 56 The method of any one of embodiments 29-55, wherein the ADC is administered in a pharmaceutical composition comprising the ADC and a pharma- ceutical acceptable carrier. EXAMPLES

[0109] The present invention will be further described through the following examples, but the scope of the present invention is not intended to be limited to the scope of the described examples. In the following examples, the experimental methods not specified for specific conditions are selected according to conventional methods and conditions or according to the product instructions.

[0110] Example 1: Global data analysis of the treatment of breast cancer patients This was a parallel-group, randomized, open-label clinical trial to evaluate the efficacy and safety of disitamab vedotin compared with lapatinib and capecitabine in patients with HER2-positive (positive defined as IHC3+ or FISH+) locally advanced or metastatic breast cancer. Subjects were randomized 1:1.

[0111] The primary endpoint of this study was progression-free survival (PFS), which was evaluated over 6 weeks (± 7 days).

[0112] The study has completed enrollment of 200 patients for dosing.

[0113] Investigational Drug Disitamab vedotin, i.e., RC48-ADC (mean DAR value: 4±0.5), was administered via infusion at a dose of 2.0 mg / kg once every 2 weeks for 42 days as one treatment cycle.

[0114] Control group Lapatinib was administered at 1250 mg once daily for 21 days per cycle, and capecitabine was administered at a total daily dose of 2000 mg / m2 for 21 days per cycle. 2 was administered for 14 consecutive days followed by a 7-day drug holiday.

[0115] An intention-to-treat (ITT) analysis of the 200 enrolled patients is shown in Table 1 . [Table 3-1] [Table 3-2] [Table 3-3] a Estimates of survival function and survival time were obtained using the Kaplan-Meier method, and the errors of survival function were estimated using the Greenwood formula to obtain 95% CI for different quantile times. b Consideration of actual stratification factors: number of prior chemotherapy lines received for advanced disease (≤1 vs. 2), and presence or absence of visceral metastases (yes vs. no). c Cox proportional hazards models were used to calculate hazard ratios, 95% CIs, and P values ​​for RC48-ADC versus capecitabine + lapatinib, using treatment arm and actual stratification factors (number of prior chemotherapy lines received for advanced disease (≤1 vs. 2), and presence or absence of visceral metastases (yes vs. no) as independent variables. d Cox proportional hazards models were used to calculate hazard ratios, 95% CIs, and P values ​​for RC48-ADC versus capecitabine + lapatinib, using treatment group as the independent variable. Note: The superscripts a, b, c, and d in Tables 2-6 below have the same meaning as defined above. [Table 4]

[0116] Overall data analysis showed that progression-free survival data for the experimental disitamab vedotin arm compared to the control arm (lapatinib plus capecitabine) was 9.3 months and 7.1 months, respectively. Compared to the control arm, the experimental arm did not show a statistically significant advantage in the overall sample of breast cancer patients.

[0117] Example 2: Analysis of progression-free survival (PFS) in liver metastasis subgroups This example aims to compare the effect of disitamab vedotin and control (lapatinib + capecitabine) on progression-free survival (PFS) in liver metastasis subgroups. The disitamab vedotin group included 99 subjects, including 38 cases with liver metastasis and 61 cases without liver metastasis, and the control group included 101 study subjects, including 43 cases with liver metastasis and 58 cases without liver metastasis. Data analysis of treatment outcomes (see Table 3) showed that the median progression-free survival of patients without liver metastasis in the disitamab vedotin group was 7.0 months, and the median progression-free survival of patients without liver metastasis in the control group was 9.0 months. The median progression-free survival of patients without liver metastasis in the disitamab vedotin group was 2.0 months shorter than that of the control group. However, surprisingly, the inventors found that the median progression-free survival of patients with liver metastases in the disitamab vedotin group was 12.5 months, while the median progression-free survival of patients with liver metastases in the control group was only 5.6 months. The median progression-free survival of patients with liver metastases in the disitamab vedotin group was significantly longer than that of patients with liver metastases in the control group by 6.9 months. Compared with the control group, the disitamab vedotin group can significantly prolong the disease progression-free period and survival period of patients with liver metastases, which is of great clinical value. [Table 5-1] [Table 5-2]

[0118] Example 3: Analysis of progression-free survival (PFS) in lung metastasis subgroups This example aims to compare the effect of disitamab vedotin and control (lapatinib + capecitabine) on progression-free survival (PFS) in the lung metastasis subgroup. The disitamab vedotin group included 99 study subjects, including 44 cases with lung metastasis and 55 cases without lung metastasis, and the control group included 101 study subjects, including 52 cases with lung metastasis and 49 cases without lung metastasis. Data analysis of treatment outcomes (see Table 4) showed that the median progression-free survival of patients with lung metastasis in the disitamab vedotin group was 8.2 months, and the median progression-free survival of patients with lung metastasis in the control group was 8.3 months, with no significant difference between the two. However, surprisingly, the inventors also found that the median progression-free survival of patients without lung metastases in the disitamab vedotin group was 10.9 months, while the median progression-free survival of patients without lung metastases in the control group was only 5.6 months. The median progression-free survival of patients without lung metastases in the disitamab vedotin group was significantly longer than that of patients without lung metastases in the control group by 5.3 months. Compared with the control group, the disitamab vedotin group can significantly prolong the disease progression and survival of these patients, which is of great clinical value. [Table 6-1] [Table 6-2]

[0119] Example 4: Analysis of progression-free survival (PFS) in bone metastasis subgroups This example aims to compare the effect of disitamab vedotin and control (lapatinib + capecitabine) on progression-free survival (PFS) in bone metastasis subgroups. The disitamab vedotin group included 99 study subjects, including 36 cases with bone metastasis and 63 cases without bone metastasis, and the control group included 101 study subjects, including 33 cases with bone metastasis and 68 cases without bone metastasis. Data analysis of treatment outcomes (see Table 5) showed that the median progression-free survival of patients with bone metastasis in the disitamab vedotin group was 7.8 months, and the median progression-free survival of patients with bone metastasis in the control group was 6.0 months. The median progression-free survival of patients with bone metastasis in the disitamab vedotin group was slightly longer than that of the control group, but there was no significant difference between the two. Patients without bone metastases in the disitamab vedotin group had a median progression-free survival of 9.6 months, compared with 8.0 months for patients without bone metastases in the control group. The median progression-free survival for patients without bone metastases in the disitamab vedotin group was slightly longer (1.6 months) than in the control group, but the difference between the two was not significant, limiting the benefit to patients. [Table 7-1] [Table 7-2]

[0120] Example 5: Analysis of progression-free survival (PFS) in visceral metastasis subgroups This example aims to compare the effect of disitamab vedotin and control (lapatinib + capecitabine) on progression-free survival (PFS) in the visceral metastasis subgroup. The disitamab vedotin group included 99 subjects, including 77 cases with visceral metastasis and 22 cases without visceral metastasis, and the control group included 101 study subjects, including 78 cases with visceral metastasis and 23 cases without visceral metastasis. Data analysis of treatment outcomes (see Table 6) showed that the median progression-free survival of patients with visceral metastasis in the disitamab vedotin group was 9.3 months, and the median progression-free survival of patients with visceral metastasis in the control group was 6.9 months. The median progression-free survival of patients with visceral metastases in the disitamab vedotin group was 2.4 months longer than in the control group, but the hazard ratio test showed no statistical difference between the two. The median progression-free survival of patients without visceral metastases in the disitamab vedotin group was 9.6 months, and the median progression-free survival of patients without visceral metastases in the control group was 8.1 months. The median progression-free survival of patients without visceral metastases in the disitamab vedotin group was slightly longer (1.5 months) than in the control group, but again there was no statistical difference between the two. [Table 8-1] [Table 8-2]

[0121] Table 7 shows an overview of progression-free survival in the different metastatic subgroups in the disitamab vedotin and control groups (lapatinib + capecitabine). From this table, the following was observed:

[0122] In patients with breast cancer without liver metastases, the progression-free survival was 7.0 months in the disitamab vedotin group and 9.0 months in the capecitabine plus lapatinib group. Compared with capecitabine plus lapatinib, the progression-free survival of patients with breast cancer without liver metastases in the disitamab vedotin group was 2.0 months shorter. In patients with breast cancer with liver metastases, the progression-free survival of patients with disitamab vedotin was 12.5 months and 5.6 months in the capecitabine plus lapatinib group. Compared with capecitabine + lapatinib, the disitamab vedotin group significantly extended the progression-free survival by 6.9 months, i.e., compared with capecitabine + lapatinib, the disitamab vedotin group had a 58% chance of reducing the relative risk of disease progression or death in breast cancer patients with liver metastases (hazard ratio = 0.42). This has great significance in clinical application, greatly extending the progression-free period and survival time of patients.

[0123] In breast cancer patients with lung metastases, progression-free survival was 8.2 months in the disitamab vedotin group and 8.3 months in the capecitabine plus lapatinib group. Compared with capecitabine plus lapatinib, progression-free survival was 0.1 months shorter in the disitamab vedotin group for breast cancer patients with lung metastases. In breast cancer patients without lung metastases, progression-free survival was 10.9 months in the disitamab vedotin group and 5.6 months in the capecitabine plus lapatinib group. Compared with capecitabine + lapatinib, the disitamab vedotin group significantly extended the progression-free survival time by 5.3 months, i.e., compared with capecitabine + lapatinib, the disitamab vedotin group had a 39% chance of reducing the relative risk of disease progression or death in breast cancer patients without lung metastasis (hazard ratio = 0.61). This has great significance in clinical application, greatly extending the progression-free period and survival time of patients.

[0124] In patients with breast cancer without bone metastases, the progression-free survival was 9.6 months in the disitamab vedotin group and 8.0 months in the capecitabine plus lapatinib group, and in patients with breast cancer with bone metastases, the progression-free survival was 7.8 months in the disitamab vedotin group and 6.0 months in the capecitabine plus lapatinib group. In these two groups, the progression-free survival was longer in the disitamab vedotin group than in the capecitabine plus lapatinib group, but the difference in the extended period was not statistically significant.

[0125] Similarly, in the visceral group, the progression-free survival of breast cancer patients with visceral metastases in the disitamab vedotin group was 9.3 months, and that of the capecitabine + lapatinib group was 6.9 months, while in breast cancer patients without visceral metastases, the progression-free survival of the disitamab vedotin group was 9.6 months, and that of the capecitabine + lapatinib group was 8.1 months. In these two groups, the progression-free survival of the disitamab vedotin group was longer than that of the capecitabine + lapatinib group, but the difference in the extended period was not statistically significant.

[0126] In other words, Disitamab vedotin can effectively extend the disease progression-free period and survival time of breast cancer patients with liver metastasis or breast cancer patients without lung metastasis, and its effect is not self-evident.That is, the application of Disitamab vedotin in the subgroup of breast cancer patients with liver metastasis and breast cancer patients without lung metastasis has distinctive substantial characteristics and important progress, which can bring great social benefits clinically and provide patients with more precise treatment options, effectively reducing the medical burden of the whole society. [Table 9-1] [Table 9-2]

[0127] The present invention is illustrated by specific examples. However, those skilled in the art will understand that the present invention is not limited to specific embodiments. Various modifications or changes can be made within the scope of the present invention, and various technical features mentioned throughout this specification can be combined with each other without departing from the spirit and scope of the present invention. All such modifications and changes are within the scope of the present invention.

Claims

1. 2. Use of an antibody-drug conjugate (ADC) in the preparation of a medicament for the treatment of a breast cancer patient with liver metastasis, said antibody-drug conjugate having the general formula Ab-(LU) ｎ wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8, representing the number of said cytotoxic molecules attached to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The above-mentioned use, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

2. 2. Use of an antibody-drug conjugate (ADC) in the preparation of a medicament for the treatment of a breast cancer patient without lung metastasis, said antibody-drug conjugate having the general formula Ab-(LU) ｎ wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8, representing the number of said cytotoxic molecules attached to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The above-mentioned use, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

3. A composition comprising an antibody-drug conjugate (ADC) for the treatment of breast cancer patients with liver metastases, the antibody-drug conjugate having the general formula Ab-(LU) ｎ wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8, representing the number of said cytotoxic molecules attached to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The composition, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

4. A composition comprising an antibody-drug conjugate (ADC) for the treatment of breast cancer patients without lung metastases, the antibody-drug conjugate having the general formula Ab-(LU) ｎ wherein Ab represents an anti-Her2 (human epidermal growth factor receptor 2) antibody, L represents a linker, U represents a conjugated cytotoxic molecule, and n is an integer from 1 to 8, representing the number of said cytotoxic molecules attached to each antibody; the antibody comprises a heavy chain variable region and a light chain variable region, and the CDR of the heavy chain variable region and / or the CDR of the light chain variable region have the same CDR sequence as Disitamab vedotin; the linker L comprises maleimido-caproyl-valine-citrulline-p-aminobenzyloxy (mc-vc-pAB) and is covalently linked to the antibody by sulfhydryl conjugation, the linking site being the interchain disulfide bond site of the antibody; The composition, wherein the cytotoxic molecule U comprises MMAE (monomethylauristatin E).

5. The use or composition of any one of claims 1 to 4, wherein the breast cancer patient is positive for HER2 expression.

6. 6. The use or composition of claim 5, wherein the sample obtained from the breast cancer of the patient is HER2 positive.

7. 7. The use or composition of claim 6, wherein the sample obtained from the breast cancer of the patient is HER2 positive based on a fluorescent in situ hybridization (FISH) assay (FISH) and / or an immunohistochemistry (IHC) assay.

8. 8. The use or composition of claim 7, wherein HER2 expression in the sample obtained from the breast cancer of the patient is IHC3+, IHC2+ or IHC3+, IHC2+ or FISH+, IHC3+ or FISH+, IHC2+ and FISH+, IHC3+ and FISH+, or IHC3+ and FISH- or not detectable.

9. The use or composition according to any one of claims 1 to 8, wherein the sample obtained from the breast cancer of the patient is estrogen receptor (ER) positive and / or progesterone receptor (PR) positive, or the sample obtained from the breast cancer of the patient is ER negative and PR negative.

10. The use or composition of any one of claims 1 to 9, wherein the patient has locally advanced or metastatic breast cancer.

11. The use or composition of any one of claims 1 to 10, wherein the patient has stage IV breast cancer.

12. The use or composition of any one of claims 1 to 11, wherein the patient has unresectable breast cancer.

13. The use or composition of any one of claims 1 to 12, wherein the breast cancer is invasive locally advanced or metastatic breast cancer established by histology and / or cytology and is unresectable.

14. The use or composition of any one of claims 1 to 13, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising an HCDR1 comprising the amino acid sequence GYTFTDYY (SEQ ID NO: 3), an HCDR2 comprising the amino acid sequence VNPDHGDS (SEQ ID NO: 4), and an HCDR3 comprising the amino acid sequence ARNYLFDH (SEQ ID NO: 5), and the VL region comprising an LCDR1 comprising the amino acid sequence QDVGTA (SEQ ID NO: 6), an LCDR2 comprising the amino acid sequence WAS (SEQ ID NO: 7), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO: 8).

15. The use or composition of any one of claims 1 to 13, wherein the antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising an HCDR1 comprising the amino acid sequence DYYIH (SEQ ID NO:11), an HCDR2 comprising the amino acid sequence RVNPDHGDSYYNQKFKD (SEQ ID NO:12), and an HCDR3 comprising the amino acid sequence ARNYLFDHW (SEQ ID NO:13), and the VL region comprising an LCDR1 comprising the amino acid sequence KASQDVGTAVA (SEQ ID NO:14), an LCDR2 comprising the amino acid sequence WASIRHT (SEQ ID NO:15), and an LCDR3 comprising the amino acid sequence HQFATYT (SEQ ID NO:8).

16. The use or composition according to any one of claims 1 to 15, wherein the antibody is a murine, chimeric or humanized antibody.

17. The antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, the VH region having the amino acid sequence EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (SEQ ID NO: 9), wherein the VL region comprises the amino acid sequence 17. The use or composition of any one of claims 1 to 16, comprising DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (SEQ ID NO: 10).

18. The use or composition according to any one of claims 1 to 17, wherein the antibody is a human IgG antibody.

19. 20. The use or composition of claim 18, wherein the antibody is a human IgG1, IgG2, or IgG4 antibody.

20. The use or composition according to any one of claims 1 to 19, wherein the amino acid sequence of the heavy chain of the antibody is set forth in SEQ ID NO:1 and the amino acid sequence of the light chain of the antibody is set forth in SEQ ID NO:

2.

21. The use or composition of any one of claims 1 to 20, wherein the antibody drug conjugate is Disitamab vedotin or a biosimilar thereof.

22. 22. The use or composition of any one of claims 1 to 21, wherein the antibody drug conjugate has an average DAR (i.e. drug-to-antibody ratio) value that is any number between 2 and 7.

23. 23. The use or composition of claim 22, wherein the average DAR value is 4±0.

5.

24. 24. The use or composition of any one of claims 1 to 23, wherein the patient has previously been treated with one or more of the following prior therapies: chemotherapeutic agents, targeted therapy, immunotherapy, and endocrine therapy.

25. 25. The use or composition of claim 24, wherein the patient has previously received systemic taxane therapy.

26. 25. The use or composition of claim 24, wherein the patient has previously received at least one systemic therapy with trastuzumab or a biosimilar thereof.

27. The use or composition of any one of claims 1 to 26, wherein the antibody-drug conjugate is administered intranasally, subcutaneously, intradermally, intramuscularly, or intravenously.

28. The use or composition according to any one of claims 1 to 27, characterized in that the antibody-drug conjugate is administered at a dose of 2.0 mg / kg every 2 weeks.

29. The use or composition of any one of claims 1 to 28, wherein the antibody-drug conjugate is administered as a monotherapy.

30. 30. The use or composition of any one of claims 1 to 29, wherein administration of said antibody drug conjugate to said breast cancer patient results in improved progression free survival (PFS) compared to administration of capecitabine and lapatinib.

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