Anti-HER2 antibody-drug conjugates for treating breast cancer

Abstract

The present disclosure relates to an anti-HER2 antibody-drug conjugate for treating breast cancer. Specifically, the present disclosure relates to the use of the anti-HER2 antibody-drug conjugate in the preparation of a medicament for treating HER2-low-expressing breast cancer, the structure of which is shown in formula (I). [Formula 1] JPEG2026503435000023.jpg80166

Description

Priority of Chinese patent applications

[0001] This disclosure claims priority to Chinese patent application Ser. No. 202310066299X, filed on January 19, 2023, and Chinese patent application Ser. No. 2023101211954, filed on February 15, 2023, the contents of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] The present disclosure is in the field of medicine and relates to the use of anti-HER2 antibody-drug conjugates (ADCs) in the preparation of medicaments for treating breast cancer. [Background technology]

[0003] Breast cancer is the most common malignant tumor worldwide. According to GLOBOCAN 2020 statistics, breast cancer ranks first in both incidence and mortality rates among all malignant tumors in women. There are approximately 2.26 million new cases of breast cancer and 685,000 deaths worldwide each year, making it the leading cause of incidence and mortality among all malignant tumors in women.

[0004] In clinical practice, approximately 55% of breast cancer patients have HER2 low expression, which refers to an immunohistochemistry (IHC) score of 1+ or an IHC score of 2+ and in situ hybridization (ISH) score of -. Existing HER2-targeted drugs have not shown significant benefit. HER2 low-expressing metastatic breast cancer has significant unmet clinical needs. First, for HER2 low-expressing patients, past treatments have been comparable to those for HER2-negative patients, and late-stage treatment options are limited. Second, for HR+ / HER2- patients, disease progression occurs after resistance to CDK4 / 6 inhibitors or endocrine therapy, and subsequent treatment options are limited.

[0005] HER2 is a member of the type I transmembrane tyrosine kinase receptor family, which is essentially inactive in its monomeric state but can undergo polymerization with the other three transmembrane tyrosine kinase members of the family, HER1, HER3, and HER4, resulting in phosphorylation of receptor tyrosine residues and initiation of various signaling pathways (e.g., MAPK, PI3K / Akt, etc.), thereby promoting cell proliferation and tumor initiation and development.

[0006] HER2-targeting ADCs first specifically recognize and bind to the HER2 receptor on the surface of target cells via the antibody in the ADC, then are endocytosed and degraded within the cell, releasing the cytotoxic drug. Finally, the cytotoxic drug induces apoptosis of the cell by disrupting DNA or acting on tubulin, thereby exerting its antitumor effect. If the cytotoxic drug has high membrane permeability, it may penetrate into the extracellular space after release into the target cell and kill surrounding HER2-negative cells, a process known as the bypass killing effect. This effect can also occur if the cytotoxic drug is released before ADC endocytosis occurs. WO2020063676A discloses ADCs targeting HER2. In view of the excellent efficacy of the already commercially available HER-2 ADC drugs Trastuzumab emtansine (TDM-1) and Trastuzumab Deruxtecan (DS-8201) in the treatment of breast cancer and gastric cancer, the research into the indications for antibody-drug conjugates in WO2020063676A is of great significance.

[0007] Taken together, there is a need to provide safer and more effective clinical treatment regimens for patients with HER2-low expressing breast cancer. Summary of the Invention

[0008] The present disclosure provides pharmaceutical uses and methods of anti-HER2 antibody drug conjugates for treating tumors.

[0009] In some embodiments, the disclosure provides any one of the following uses or methods of an anti-HER2 antibody-drug conjugate:

[0010] (1) Use of an anti-HER2 antibody-drug conjugate in the preparation of a medicament for treating HER2-low-expressing breast cancer; (2) Anti-HER2 antibody-drug conjugates for treating HER2-low-expressing breast cancer; (3) A method for treating HER2-low-expressing breast cancer, comprising administering an anti-HER2 antibody-drug conjugate to a subject in need thereof.

[0011] In some embodiments, the structure of the antibody-drug conjugate is shown in formula (I): [ka] Among them, n is 3 to 8, and n is a decimal number or an integer, for example, n is 3, 4, 5, 6, 7, 8, or any integer or decimal number between any two of the above numbers.

[0012] Pc is an anti-HER2 antibody.

[0013] In this disclosure, "antibody" is used in the broadest sense, provided that the desired antigen-binding activity is exhibited, and covers a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, or antigen-binding fragments thereof (also referred to as "antigen-binding portions").

[0014] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof described herein is selected from trastuzumab or an antigen-binding fragment thereof, or pertuzumab or an antigen-binding fragment thereof.

[0015] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof described herein is trastuzumab or an antigen-binding fragment thereof.

[0016] In some embodiments, the anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

[0017] Among them, the CDR sequences are as shown in Table 1 below. [Table 1]

[0018] In some specific embodiments, the CDRs are defined by the Kabat numbering system.

[0019] In some embodiments, the anti-HER2 antibody comprises any one, two, three, four, five, or six of the above HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0020] In some embodiments, the anti-HER2 antibody is a humanized antibody. In some specific embodiments, the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:9, or an amino acid sequence having at least 80% sequence identity thereto, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10, or an amino acid sequence having at least 80% sequence identity thereto.

[0021] Heavy chain variable region: [ka] Light chain variable region: [ka] In some embodiments, an anti-HER2 antibody comprising any one or any two combinations of the above VH and VL.

[0022] In some embodiments, the anti-HER2 antibody further comprises a heavy chain constant region and / or a light chain constant region. Illustratively, the light chain / heavy chain constant regions are combined with the variable regions of the antibody to form a complete antibody, whose light chain / heavy chain sequences are as follows:

[0023] Heavy chain: [ka] Light chain: [ka] In some embodiments, the heavy chain of the anti-HER2 antibody comprises the amino acid sequence set forth in SEQ ID NO:2, or an amino acid sequence having at least 80% sequence identity thereto, and the light chain comprises the amino acid sequence set forth in SEQ ID NO:1, or an amino acid sequence having at least 80% sequence identity thereto.

[0024] In some embodiments, the present disclosure provides anti-HER2 antibodies comprising any one or a combination of any two of the above heavy chains, light chains.

[0025] In the context of the present disclosure, "at least 80%" includes 80% or more, e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical ranges between two thereof.

[0026] In some embodiments, the above-mentioned anti-HER2 antibody-drug conjugates can be prepared by referring to the methods of WO2021190581A. The present disclosure incorporates by reference the contents of WO2021190581A relating to the ADC structure, antibody sequence, and preparation method.

[0027] In some embodiments, the anti-HER2 antibody-drug conjugate described in the present disclosure has a structure represented by the following formula.

[0028] [Chemical formula] Among them, n is from 3 to 8, and n is a decimal or an integer.

[0029] In some embodiments, n is 6 ± 0.8. For example, n is 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.

[0030] In a selective embodiment, in the anti-HER2 antibody-drug conjugate described in the present disclosure, n is 6.

[0031] In the present disclosure, the above-mentioned "HER2-low-expressing breast cancer" is not particularly limited as long as those skilled in the art recognize it as HER2-low-expressing breast cancer. Preferred examples of HER2-low-expressing breast cancer may include IHC2+ and ISH negative, IHC1+ and ISH negative, IHC1+ and ISH unmeasured, and 0 < IHC < 1+.

[0032] In some embodiments, the above-mentioned HER2-low-expressing breast cancer is a breast cancer determined by immunohistochemistry to have a HER2 expression level of 1+. That is, IHC1+, for example, IHC1+ / ISH- or IHC1+ / ISH unmeasured.

[0033] In some embodiments, the above-mentioned HER2-low-expressing breast cancer is a breast cancer determined by immunohistochemistry to have a HER2 expression level of 2+ and determined by in situ hybridization to have a negative HER2 expression. That is, IHC2+ / ISH-.

[0034] In some embodiments, the above-mentioned HER2-low-expressing breast cancer is an inoperable, recurrent, and / or metastatic breast cancer with low HER2 expression.

[0035] In some embodiments, the HER2-low-expressing breast cancer is HER2-low-expressing unresectable or metastatic breast cancer.

[0036] In some embodiments, the HER2-low-expressing breast cancer is a patient with HER2-low-expressing recurrent or metastatic breast cancer.

[0037] In some embodiments, the breast cancer patient is an HR positive patient or an HR negative patient.

[0038] In some embodiments, the breast cancer patient has received at least one line of endocrine therapy.

[0039] In some embodiments, the breast cancer patient has not received or has received previous chemotherapy.

[0040] In some embodiments, the HER2-low expressing breast cancer patient has previously been treated with an anti-HER2 agent. In some embodiments, the HER2-low expressing breast cancer patient has previously been treated with an anti-HER2 agent and subsequently developed resistance or refractory disease.

[0041] In the present disclosure, "resistance" or "refractory" refers to the property of not responding to treatment with an anticancer drug, and can also be expressed as "unresponsiveness" or "non-responsiveness."

[0042] In some embodiments, the anti-HER2 antibody-drug conjugates provided by the present disclosure are used to treat patients with HER2-low-expressing breast cancer and can significantly improve the patient's tumor objective remission rate and progression-free survival, particularly at a dose of 6.4 mg / kg, which can reach a cORR of 64.9% and an mPFS of 13.8 months, demonstrating significant therapeutic advantages over other ADC drugs targeting the same target and providing a positively effective clinical treatment regimen for patients with HER2-low-expressing breast cancer.

[0043] In some embodiments, the anti-HER2 antibody-drug conjugates provided by the present disclosure can be administered to a subject to significantly reduce the incidence of interstitial pneumonia, improving clinical safety and favoring a wider clinical administration window.

[0044] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a second therapeutic agent.

[0045] In some embodiments, the second therapeutic agent is selected from one or a combination of two or more of a CDK4 / 6 inhibitor, a SERD, a VEGF ligand inhibitor, an aromatase inhibitor, and a CDK4 / 6 inhibitor.

[0046] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a CDK4 / 6 inhibitor.

[0047] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a SERD (selective estrogen receptor degrader).

[0048] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a VEGF ligand inhibitor.

[0049] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with an aromatase inhibitor.

[0050] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a CDK4 / 6 inhibitor and an aromatase inhibitor.

[0051] In some embodiments, the CDK4 / 6 inhibitor described herein is selected from abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925, INOC-005, G1T28-1, BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, staurosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC-625987, CGP-82996, PD-171851, and a compound represented by formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof: [ka]

[0052] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula II above is an isethionate salt.

[0053] In some embodiments, the SERD described herein is selected from fulvestrant, AZD-9496, RAD1901, and ZB-716. In some embodiments, the SERD is fulvestrant.

[0054] In some embodiments, the VEGF ligand inhibitor described herein is selected from the group consisting of bevacizumab, ramucirumab, ranibizumab, aflibercept, conbercept, abicipar pegol, brolucizumab, LMG-324, nesvacumab, sevacizumab, tanibirumab, navicixizumab, RG-7716, LHA-510, OPT-302, TK-001, GZ-402663, VGX-100, PG-545, BI-836880, GNR-011, BR-55, OT In some embodiments, the VEGF ligand inhibitor is selected from SGC-A24, PAN-90806, AVA-101, ODM-203, TAS-115, X-82, MP-0250, sitravatinib, 4SC-203, AL-2846, ABT-165, SIM-010603, BI-836880, HL-217, CS-2164, RGX-314, AMC-303, and VXM-01. In some embodiments, the VEGF ligand inhibitor is bevacizumab.

[0055] In some embodiments, the aromatase inhibitor described herein is selected from formestane, exemestane, fadrozole, letrozole, vorozole, and anastrozole, hi some embodiments, the aromatase inhibitor is letrozole or anastrozole.

[0056] In some embodiments, the dose of an anti-HER2 antibody-drug conjugate described herein is 1.0 mg / kg to 10.0 mg / kg. In alternative embodiments, the dose of an anti-HER2 antibody-drug conjugate described herein is 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4.0 mg / kg, 4.2 mg / kg, 4.4 mg / kg, 4.6 mg / kg, 4.8 mg / kg, 5.0 ... In alternative embodiments, the dose of an anti-HER2 antibody drug conjugate described herein is 1.0 mg / kg, 2.0 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg, or 8.0 mg / kg.

[0057] In some embodiments, the administration frequency of an anti-HER2 antibody-drug conjugate described herein is at least once per week, at least once per two weeks, at least once per three weeks, at least once per four weeks, or at least once per six weeks. In alternative embodiments, the administration frequency is once per week, once per two weeks, once per three weeks, or once per four weeks. In alternative embodiments, the administration frequency is once per two weeks or once per three weeks.

[0058] In alternative embodiments, the dosage of the anti-HER2 antibody-drug conjugate described herein is 1.0 mg / kg, 2.0 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg, or 8.0 mg / kg, and the dosing frequency is once every two weeks or once every three weeks.

[0059] In some embodiments, the dose of a CDK4 / 6 inhibitor described herein is 1-1000 mg. In alternative embodiments, the dose of a CDK4 / 6 inhibitor described herein may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, or 1000 mg. In alternative embodiments, the dose is 100 mg, 125 mg, or 150 mg.

[0060] The dosing frequency may be once daily, twice daily, three times daily, once weekly, once every two weeks, once every three weeks, or once monthly. In alternative embodiments, the dosing frequency is once daily.

[0061] In alternative embodiments, the dosage of the CDK4 / 6 inhibitors described herein is 75 mg, 100 mg, 125 mg, 150 mg, and the dosing frequency is once daily.

[0062] In some embodiments, the dosage of a SERD described herein is 1-1000 mg. In alternative embodiments, the dosage of a SERD described herein may be 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, or 1000 mg. In alternative embodiments, the dosage of a SERD described herein is 500 mg.

[0063] In some embodiments, the administration frequency of a SERD described herein can be once daily, twice daily, three times daily, weekly, biweekly, triweekly, or monthly. In some embodiments, the administration frequency can be once daily, weekly, biweekly, triweekly, or monthly, for example, once every two weeks or once a month.

[0064] In alternative embodiments, the dosage of a SERD described herein is 500 mg and the dosing frequency is once every two weeks or once a month.

[0065] In some embodiments, the dose of a VEGF ligand inhibitor described herein is 0.1-100 mg / kg. In alternative embodiments, the dose of a VEGF ligand inhibitor described herein may be 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12.5 mg / kg, 12 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg. In alternative embodiments, the dose of a VEGF ligand inhibitor described herein is 15 mg / kg.

[0066] In some embodiments, the administration frequency of a VEGF ligand inhibitor described herein may be once daily, once weekly, once every two weeks, once every three weeks, or once monthly. In alternative embodiments, the administration frequency may be once weekly, once every two weeks, once every three weeks, or once monthly. In alternative embodiments, the administration frequency is once every three weeks.

[0067] In an alternative embodiment, the dosage of the VEGF ligand inhibitor described in the present disclosure is 15 mg / kg and the dosing frequency is once every three weeks.

[0068] In some embodiments, the dosage of an aromatase inhibitor described herein is 0.1 to 50 mg. In alternative embodiments, the dosage of an aromatase inhibitor described herein may be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In alternative embodiments, the dosage of the aromatase inhibitors described herein may be 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, or 5.0 mg.

[0069] In alternative embodiments, the administration frequency of the aromatase inhibitors described herein is once daily or twice daily. In alternative embodiments, the administration frequency is once daily or twice daily.

[0070] In alternative embodiments, the dosage of the aromatase inhibitors described herein is 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, or 5.0 mg, and the dosing frequency is once daily or twice daily.

[0071] In an alternative embodiment, the aromatase inhibitor described in the present disclosure is letrozole, the dosage is 2.5 mg, and the dosing frequency is once daily.

[0072] In an alternative embodiment, the aromatase inhibitor described in the present disclosure is anastrozole, the dosage is 1 mg, and the dosing frequency is once daily.

[0073] In some embodiments, the anti-HER2 antibody-drug conjugate described herein is administered once every two weeks or once every three weeks, and the CDK4 / 6 inhibitor described herein is administered once daily, with either continuous administration for the first two weeks (days 1-14) followed by a one-week rest (non-administration) period thereafter (days 15-21), or continuous administration for the first three weeks followed by a one-week rest period.

[0074] In an alternative embodiment, the anti-HER2 antibody-drug conjugate described herein is administered once every two weeks or once every three weeks, and the treatment cycle for the SERD described herein is four weeks, with the conjugate administered on days 1 and 15 of the first cycle and on day 1 of each cycle thereafter.

[0075] In alternative embodiments, the anti-HER2 antibody drug conjugate described herein is administered every two weeks or every three weeks, and the VEGF ligand inhibitor described herein is administered every three weeks.

[0076] In alternative embodiments, the anti-HER2 antibody drug conjugate described herein is administered once every two weeks or once every three weeks, and the aromatase inhibitor described herein is administered once daily and is administered continuously.

[0077] In alternative embodiments, the anti-HER2 antibody-drug conjugate described herein is administered once every two weeks or once every three weeks, and the CDK4 / 6 inhibitor described herein is administered once daily, with either continuous administration for the first two weeks (days 1-14) followed by a one-week rest (non-administration) period thereafter (days 15-21), or continuous administration for the first three weeks followed by a one-week rest period, and the aromatase inhibitor described herein is administered once daily and continuously.

[0078] In some embodiments, the treatment cycle is a 2-week cycle, a 3-week cycle, or a 4-week cycle.

[0079] The present disclosure further provides a use of an anti-HER2 antibody-drug conjugate in combination with a second therapeutic agent in the preparation of a medicament for treating breast cancer, wherein the structure of the antibody-drug conjugate is shown in formula (I): [ka] Among them, n is 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody or an antigen-binding fragment thereof; The second therapeutic agent is selected from one or more of a CDK4 / 6 inhibitor, a SERD, a VEGF ligand inhibitor, and an aromatase inhibitor.

[0080] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a CDK4 / 6 inhibitor.

[0081] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a SERD.

[0082] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a VEGF ligand inhibitor.

[0083] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with an aromatase inhibitor.

[0084] In some embodiments, the anti-HER2 antibody-drug conjugate is used in combination with a CDK4 / 6 inhibitor and an aromatase inhibitor.

[0085] In some embodiments, the breast cancer is a HER2-low expressing breast cancer.

[0086] In some embodiments, the HER2-low-expressing breast cancer is a breast cancer in which HER2 expression has been determined to be 1+ by immunohistochemistry, i.e., IHC1+, for example, IHC1+ / ISH- or IHC1+ / ISH-unmeasured.

[0087] In some embodiments, the HER2-low-expressing breast cancer is a breast cancer whose HER2 expression is determined to be 2+ by immunohistochemistry and whose HER2 expression is determined to be negative by in situ hybridization, i.e., IHC2+ / ISH-.

[0088] In some embodiments, the HER2-low-expressing breast cancer is HER2-low-expressing unresectable, recurrent and / or metastatic breast cancer.

[0089] In alternative embodiments, the breast cancer is unresectable or metastatic breast cancer.

[0090] In alternative embodiments, the breast cancer patient is an HR positive patient or an HR negative patient.

[0091] In an alternative embodiment, the breast cancer patient has received at least one line of endocrine therapy.

[0092] In alternative embodiments, the breast cancer patient has not received or has received prior chemotherapy.

[0093] In some embodiments, the treatment cycle of the present disclosure is a 2-week cycle, a 3-week cycle, or a 4-week cycle, for example, a 3-week cycle.

[0094] In another aspect, the present disclosure provides a pharmaceutical composition comprising the anti-HER2 antibody-drug conjugate and a second therapeutic agent, and one or more pharmaceutically acceptable carriers, wherein the second therapeutic agent is selected from one or more of a CDK4 / 6 inhibitor, a SERD, a VEGF ligand inhibitor, and an aromatase inhibitor.

[0095] In another aspect, the present disclosure provides the above-described anti-HER2 antibody-drug conjugate for treating HER2-low-expressing breast cancer.

[0096] In another aspect, the present disclosure provides the above-described anti-HER2 antibody-drug conjugate for treating breast cancer, in combination with the above-described therapeutic agent.

[0097] The pharmaceutical compositions, uses, and treatment methods of the present disclosure can also be used in combination with surgical procedures as adjuvant chemotherapy. The treatment methods of the present disclosure can be administered before surgical procedures to reduce tumor size (called neoadjuvant chemotherapy or neoadjuvant therapy), or after surgical procedures to prevent tumor recurrence (called postoperative adjuvant chemotherapy or adjuvant therapy).

[0098] The method for scoring the degree of HER2 expression by immunohistochemistry or the method for determining whether HER2 expression is positive or negative by in situ hybridization is not particularly limited, as long as it is recognized by a person skilled in the art. term

[0099] In order that the present disclosure may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art.

[0100] The present disclosure incorporates the entire contents of application WO2020063676A into this application.

[0101] Antibody drug conjugates (ADCs) are compounds that link antibodies or antibody fragments to biologically active cytotoxins or small molecule drugs with cytotoxic activity via stable chemical linker compounds, taking advantage of the specificity of antibodies for tumor cells or highly expressed antigens and the high efficacy of cytotoxins, while avoiding toxicity and side effects on normal cells. Compared with conventional chemotherapy drugs, antibody drug conjugates can bind precisely to tumor cells and reduce the impact on normal cells.

[0102] An antibody "retains its chemical stability" in a drug formulation if the antibody-drug conjugate does not undergo significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that frequently alter the chemical structure of proteins include hydrolysis or cleavage (e.g., assessed by methods such as size exclusion chromatography and CE-SDS), oxidation (e.g., assessed by methods such as mass spectrometry or peptide mapping coupled with MALDI / TOF / MS), deamidation (e.g., assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, or isoaspartic acid content measurement), and isomerization (e.g., assessed by isoaspartic acid content measurement, peptide mapping, etc.).

[0103] An antibody-drug conjugate "retains its biological activity" in a drug formulation if the biological activity at a given time is within a predetermined range of the biological activity exhibited when the drug formulation is prepared.

[0104] The term "antibody" as used herein is used in the broadest sense, provided that it exhibits the desired antigen-binding activity, and covers a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments or antigen-binding portions). For example, an antibody may refer to an immunoglobulin, and a complete antibody has a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and sequence order of the immunoglobulin heavy chain constant regions vary, resulting in different antigenicities. Therefore, immunoglobulins can be divided into five types, or immunoglobulin isotypes: IgM, IgD, IgG, IgA, and IgE, and the corresponding heavy chains are μ, δ, γ, α, and ε, respectively. Ig of the same type can be further divided into different subclasses depending on the amino acid composition of the hinge region and the number and position of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are divided into κ chains and λ chains depending on the constant region. Each of the five types of Ig may have either κ chains or λ chains.

[0105] In the present disclosure, "antibody or antigen-binding fragment thereof" or "functional fragment" refers to Fab fragments, Fab' fragments, F(ab')2 fragments that have antigen-binding activity, as well as Fv fragments and scFv fragments that bind to the antibody. Fv fragments contain the antibody heavy chain variable region and light chain variable region but lack the constant region and contain the minimum antibody fragment containing all of the antigen-binding site. Generally, Fv antibodies further contain a polypeptide linker between the VH and VL domains and are capable of forming the structure necessary for antigen binding. Two antibody variable regions may be linked by different linkers to form a single polypeptide chain called a single-chain antibody or single-chain Fv (sFv).

[0106] The term "linker unit" or "linking fragment" or "linking unit" refers to a chemical structural fragment or bond that is linked at one end to an antibody or antigen-binding fragment thereof and at the other end to a drug, and may be linked to another linker before being linked to a drug. A preferred form of the present disclosure is a linker unit comprising L and L 1 ~L 4 Among them, L 1 The end is linked to an antibody, and the L 4 The terminus is linked to a structural unit Y which is then linked to a compound or toxin.

[0107] The linker may comprise an extender, a spacer, and an amino acid unit and may be synthesized by methods known in the art, such as those described in US2005-0238649A1. The linker may be a "cleavable linker" that facilitates drug release in cells. For example, an acid-labile linker (e.g., hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker (Chari et al., Cancer Research 52:127-131 (1992), U.S. Patent No. 5,208,020) may be used.

[0108] The term "drug loading" refers to the average amount of cytotoxic drugs loaded onto each antibody or antigen-binding fragment thereof in a molecule of Formula (I), and may be expressed as the ratio of the drug amount to the antibody amount. The drug loading ranges from 0 to 12, preferably 1 to 10, more preferably 3 to 8, and most preferably 5.3 to 6.1 cytotoxic drugs (D) per antibody or antigen-binding fragment thereof (Pc). In embodiments of the present disclosure, the drug loading is represented by n, which may illustratively be an average value of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The average drug amount per ADC molecule after the coupling reaction can be characterized by conventional methods, such as UV / visible spectroscopy, mass spectrometry, ELISA experiments, and HPLC.

[0109] In one embodiment of the present disclosure, a cytotoxic drug is coupled to the N-terminal amino group, the ε-amino group of a lysine residue, and / or a mercapto group of an antibody or antigen-binding fragment thereof via a linking unit, and generally, the number of drug molecules that can be coupled to an antibody in a coupling reaction is less than the theoretical maximum.

[0110] The loading of the cytotoxic drug is (1) controlling the molar ratio of the linking reagent to the monoclonal antibody; (2) controlling the reaction time and temperature; (3) selecting different reaction reagents; The amount of oxygen can be controlled by a number of methods, including but not limited to:

[0111] For the preparation of conventional pharmaceutical compositions, reference is made to the Chinese Pharmacopoeia.

[0112] "Administration" and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. "Administration" and "treatment" can refer, for example, to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of cells includes contact of a reagent with a cell and contact of a reagent with a fluid, where the fluid contacts the cell. "Administration" and "treatment" also refer to treating, for example, cells, in vitro and ex vivo, with a reagent, diagnostic, binding composition, or via another cell. "Treatment," when applied to a human, veterinary, or research subject, refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic uses.

[0113] "Treatment" refers to administering to a patient, for example, an oral or topical therapeutic agent comprising a composition of any one of the binding compounds disclosed herein, wherein the patient has one or more disease symptoms, and the therapeutic agent is known to have a therapeutic effect on those symptoms. Typically, the patient or population being treated is administered an amount of therapeutic agent that effectively alleviates one or more disease symptoms, thereby inducing regression of such symptoms or inhibiting the progression of such symptoms to any clinically measurable extent. The amount of therapeutic agent that effectively alleviates any particular disease symptom (also referred to as a "therapeutically effective amount") can vary depending on various factors, including the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Reduction of disease symptoms can be assessed by any clinical detection method commonly used by physicians or other professional health care providers to assess the severity or progression of the condition. Although an embodiment of the present disclosure (e.g., a method of treatment or product) may be ineffective in alleviating each target disease symptom, any statistical testing method known in the art, such as a Student t-test, a chi-squared test, a Mann and Whitney U test, a Kruskal-Wallis test (H test), a Jonckheere-Terpstra test, and a Wilcoxon test, will confirm that the embodiment should reduce the target disease symptom in a statistically significant number of patients.

[0114] An "effective amount" includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disease. An effective amount also refers to an amount sufficient to allow or facilitate diagnosis. The effective amount used in a particular patient or veterinary subject can vary depending on factors such as the condition being treated, the patient's overall health, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0115] In the anti-HER2 antibody-drug conjugates of the present disclosure, "n" refers to the average number of cytotoxic drugs loaded onto each antibody or antigen-binding fragment thereof in an antibody-drug conjugate molecule, which can also be expressed as the ratio of drug amount to antibody amount, and is the average number of drugs per ADC molecule after the coupling reaction by hydrophobic chromatography (HIC) or mass spectrometry.

[0116] In the present disclosure, "combination" refers to various administration methods, including administration of two or more drugs before, after, or simultaneously. Simultaneous administration, coadministration of independently formulated drugs, or sequential administration of independently formulated drugs are all included in the combined administration described in the present disclosure. "Simultaneous" refers to administration of at least one dose of an anti-HER2 antibody-drug conjugate and another therapeutic agent within a certain period of time, for example, within two days or within one day of administration of two drugs, both of which exhibit pharmacological effects. "Before and after" administration includes administration of an anti-HER2 antibody-drug conjugate and another therapeutic agent in different administration cycles. The above-mentioned period may be within one administration cycle, or alternatively, within four weeks, three weeks, two weeks, one week, 24 hours, or two hours. Such a period includes treatments in which the anti-HER2 antibody-drug conjugate and another therapeutic agent are administered via the same or different administration routes. DETAILED DESCRIPTION OF THE INVENTION

[0117] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. In the examples of the present disclosure, experimental methods for which specific conditions are not specified generally follow standard conditions, such as those in the "Antibody Technology Laboratory Manual" and "Molecular Cloning Manual" published by Cold Spring Harbor Laboratory, or the conditions recommended by raw material or product manufacturers. Reagents for which specific sources are not specified are standard commercially available reagents.

[0118] Example 1. Preparation of anti-HER2 antibody-drug conjugate Based on the production method described in WO2021190581A, an anti-HER2 antibody-drug conjugate shown in the following structure was prepared using trastuzumab (anti-HER2 antibody) and an exatecan analog, and the average value was calculated by the HIC method: n = 6.0, i.e., ADC-32.

[0119] JPEG2026503435000011.jpg61166 Below is the sequence of Trastuzumab.

[0120] Light chain: [ka] Heavy chain: [ka] Note: Underlined are CDR sequences as defined by the Kabat numbering system, italics are constant region sequences.

[0121] Example 2. Clinical study of anti-HER2 antibody-drug conjugates in HER2-low-expressing breast cancer (BC) patients 1. Test drug The anti-HER2 antibody-drug conjugate described in Example 1, freeze-dried powder for injection, specification: 100 mg / bottle.

[0122] II. Subjects of registration 1. Age ≥ 18 years. 2. Patients with pathologically or cytologically diagnosed recurrent or metastatic breast cancer with low HER2 expression (IHC2+ and ISH negative, IHC1+ and ISH negative, or IHC1+ and ISH not measured).

[0123] 3. Administration Method Subjects who qualify for screening will be administered the corresponding anti-HER2 antibody-drug conjugate at a dose of 1.0 mg / kg, 2.0 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 6.4 mg / kg, or 8.0 mg / kg by intravenous infusion once every three weeks, with one cycle consisting of three weeks (21 days).

[0124] 4. Test results Part of the treatment efficacy data is shown in Table 2. A total of 77 patients were enrolled, among which the ORR for patients with HER2-low expressing BC was 55.8% (43 / 77, 95% CI 44.1-67.2).

[0125] [Table 2-1] [Table 2-2]

[0126] ORR is presented as %(n / N, 95% CI) or %(n / N). *ORR was calculated using the number of subjects who received prior anti-HER2 cancer therapy in the advanced / metastatic setting as the denominator, and two-sided 95% CIs were estimated using the Clopper-Pearson method.

[0127] **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103 and BAT8001.

[0128] After the clinical trial, 110 evaluable patients with HER2-low expressing breast cancer were subsequently enrolled, and the evaluation results of their therapeutic effects are shown in Tables 3 and 4.

[0129] [Table 3]

[0130] Note: Subjects are required to undergo treatment response assessments every 6 weeks (± 7 days) within the first 48 weeks after the first dose, and then every 12 weeks (± 7 days) thereafter. Imaging assessments are not affected by interruptions or delays in treatment. Subjects initially assessed as having a CR or PR should be confirmed after 4 weeks (the next planned time point).

[0131] cBOR is the confirmed tumor best overall treatment response, cORR is the confirmed objective response rate, and uORR is the awaiting confirmation objective response rate.

[0132] As can be seen from the results in Table 3, in each dosage group, the tumor objective response rate (cORR) of confirmed HER2-low expressing breast cancer patients was 64.9% (6.4 mg / kg administration) and 60.6% (5.6 mg / kg administration). In addition, in all HER2-low expressing breast cancer patients receiving different doses, the cORR reached 59.1% and the uORR reached 67.3%. This demonstrates that the anti-HER2 antibody-drug conjugates provided by the present disclosure can be used to treat HER2-low expressing breast cancer patients and exert significant tumor-inhibiting effects.

[0133] [Table 4]

[0134] Note: PFS is progression-free survival, mPFS is median progression-free survival, 06-mo PFS rate is 6-month progression-free survival rate, 12-mo PFS rate is 12-month progression-free survival rate, and 18-mo PFS rate is 18-month progression-free survival rate. mDoR is median duration of remission.

[0135] As can be seen from the results in Table 4, in patients with HER2-low-expressing breast cancer treated with the anti-HER2 antibody-drug conjugate, the median progression-free survival (mPFS) could reach 13.8 months (6.4 mg / kg dose), and the median duration of remission (mDoR) could reach 16.7 months (6.4 mg / kg dose). Furthermore, in 110 patients with HER2-low-expressing breast cancer treated with the anti-HER2 antibody-drug conjugate, the median progression-free survival (mPFS) could reach 10.9 months, and the median duration of remission (mDoR) could reach 12.2 months. The anti-HER2 antibody-drug conjugates provided by the present disclosure can be used to treat patients with HER2-low-expressing breast cancer, significantly extending their progression-free survival and tumor duration, demonstrating that they can effectively treat patients with HER2-low-expressing breast cancer.

[0136] Example 3. Phase I clinical study of anti-HER2 antibody-drug conjugate In a phase I clinical study of an anti-HER2 antibody-drug conjugate, 243 patients (97.2%) with advanced solid tumors reported treatment-related adverse events (TRAEs). 131 (52.4%), 31 (12.4%), and 3 (1.2%) patients reported grade ≥ 3 TRAEs, severe TRAEs, and treatment-related death, respectively. Eight (3.2%) subjects were reported to have developed interstitial lung disease (AESI). Exposure to the anti-HER2 antibody-drug conjugate, total antibody, and payload was generally directly proportional to the dose, ranging from 3.2 to 8.0 mg / kg. The ORR for all patients was 61.6% (154 / 250, 95% CI 55.3-67.7).

[0137] Example 4. Open, multicenter phase Ib / II clinical study of anti-HER2 antibody drug conjugate in combination with compound of formula (II) isethionate, fulvestrant, bevacizumab, letrozole / anastrozole to treat HER2-low-expressing unresectable or metastatic breast cancer 1. Test drug The anti-HER2 antibody-drug conjugate described in Example 1, freeze-dried powder for injection, specification: 100 mg / bottle. Isethionate salt of the compound represented by formula (II), tablets, specifications: 25 mg / tablet, 50 mg / tablet, 125 mg / tablet, 150 mg / tablet.

[0138] Fulvestrant injection (Furaiwa), injection, specifications: 5mL: 0.25g.

[0139] Letrozole tablets (Fuzui), tablets, specifications: 2.5 mg.

[0140] Anastrozole tablets (Ishu Chi), tablets, specifications: 1 mg.

[0141] Bevacizumab injection (Ai Rui Te), injection, specification: 100 mg (4 mL) per bottle.

[0142] II. Subjects of registration 1. Women aged 18 to 75 years (inclusive).

[0143] 2. Histologically or cytologically confirmed unresectable or metastatic breast cancer with low HER2 expression (IHC2+ / ISH-, IHC1+ / ISH-, or unmeasured). Recurrent / metastatic stage requires clarification of estrogen receptor / progestin receptor (ER / PR) status (ER-positive and / or PR-positive should be defined according to the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines). Low HER2 expression must be confirmed by pathology verification at the participating institutions.

[0144] 3. For HR-positive subjects, one of the following must be met: a) Previous bilateral oophorectomy or age ≥ 60 years, or b) Age <60, natural postmenopausal state (defined as the spontaneous cessation of regular menstruation for at least 12 consecutive months and in the absence of other pathological or physiological causes), with postmenopausal levels of estradiol (E2) and follicle-stimulating hormone (FSH), or c) Pre- or peri-menopausal female patients may also be enrolled, but must be willing to undergo luteinizing hormone-releasing hormone (LHRH) agonist treatment during the study.

[0145] 4. Radiographic or objective evidence of disease progression during or after the last systemic treatment prior to initiation of study treatment.

[0146] 5. Previous treatments included: HR positive subjects: a) Stage 1 (dose-finding): At least one line of endocrine therapy was received, and ≤2 lines of chemotherapy were permitted.

[0147] b) Second stage (expanded therapeutic response): ≤1 line of endocrine therapy is allowed, and recurrent / metastatic stage has never received chemotherapy.

[0148] HR negative subjects: c) Stage 1 (dose-finding): received at least one line of chemotherapy.

[0149] d) Stage 2 (expansion of therapeutic effect): Recurrent / metastatic stage has not received systemic anti-tumor treatment.

[0150] e) Disease recurrence within the first 24 months after adjuvant endocrine therapy is considered as one line of treatment, and the occurrence of recurrence within 6 months after (neo)adjuvant chemotherapy is considered as one line of chemotherapy regimen.

[0151] 3. Administration Method Subjects who qualify for screening are administered the corresponding drug.

[0152] Phase 1 (dose-finding phase): The dose-finding phase aims to evaluate the safety, tolerability, pharmacokinetic properties, and immunogenicity of the combination of the anti-HER2 antibody-drug conjugate with the compound represented by formula (II) isethionate, fulvestrant, and bevacizumab, as well as to preliminarily observe their antitumor therapeutic effects.

[0153] Combination of anti-HER2 antibody drug conjugate with compound isethionate of formula (II): The dose of the anti-HER2 antibody-drug conjugate is 2.0 mg / kg, 3.2 mg / kg, or 4.8 mg / kg, and is administered by intravenous infusion once every three weeks, with one cycle being three weeks (21 days). The doses of compound isethionate of formula (II) are 100 mg, 125 mg, and 150 mg, orally administered once daily, with a treatment course consisting of 2 weeks on and 1 week off.

[0154] If the relevant dose group is poorly tolerated, the administration cycle, timing, and method / dosage of the study drug may be adjusted, including, but not limited to, a. adjusting the administration cycle of the anti-HER2 antibody-drug conjugate to once every two weeks and adjusting the corresponding dosage; b. adjusting the treatment course of the isethionate salt of compound of Formula (II) to 3 weeks on / 1 week off; or c. adjusting the administration timing of the anti-HER2 antibody-drug conjugate and the isethionate salt of compound of Formula (II), for example, to administer them every few days.

[0155] Anti-HER2 antibody-drug conjugate in combination with fulvestrant: The dose of the anti-HER2 antibody-drug conjugate is 2.0 mg / kg, 3.2 mg / kg, or 4.8 mg / kg, administered once every three weeks.

[0156] The dose of fulvestrant is 500 mg, with one treatment course every 4 weeks, administered on days 1 and 15 of the first course and on day 1 of each subsequent course.

[0157] If the relevant dose group is poorly tolerated, the administration cycle, timing, method, and dosage of the investigational agent may be adjusted, including, but not limited to, adjusting the administration cycle of the anti-HER2 antibody-drug conjugate to once every two weeks and making a corresponding dosage adjustment.

[0158] Anti-HER2 antibody-drug conjugate in combination with bevacizumab: The dose of the anti-HER2 antibody-drug conjugate is 2.0 mg / kg, 3.2 mg / kg, or 4.8 mg / kg, administered once every three weeks.

[0159] The bevacizumab dose is fixed at 15 mg / kg and is administered once every 3 weeks.

[0160] If the relevant dose group is poorly tolerated, the administration cycle, timing, method, and dosage of the investigational agent may be adjusted, including, but not limited to, adjusting the administration cycle of the anti-HER2 antibody-drug conjugate to once every two weeks and making a corresponding dosage adjustment.

[0161] Phase 2 (expansion of treatment effect): The therapeutic expansion phase aims to observe and evaluate the preliminary efficacy, safety, pharmacokinetic properties, and immunogenicity of the anti-HER2 antibody-drug conjugate and compound isethionate of formula (II) in combination with letrozole / anastrozole, fulvestrant, letrozole / anastrozole, and bevacizumab.

[0162] Anti-HER2 antibody drug conjugate and compound isethionate of formula (II) in combination with letrozole / anastrozole: After the first stage of dose exploration is completed by combining the anti-HER2 antibody-drug conjugate and the compound isethionate of formula (II), at least one dose group of the anti-HER2 antibody-drug conjugate and the compound isethionate of formula (II) is selected and combined with letrozole or anastrozole to expand the therapeutic effect.

[0163] Letrozole is administered orally, 2.5 mg once daily, in continuous doses.

[0164] Anastrozole is administered orally, 1 mg once daily, in continuous doses.

[0165] Anti-HER2 antibody-drug conjugate in combination with fulvestrant: After completing the first dose exploration with the combination of anti-HER2 antibody-drug conjugate and fulvestrant, one to two doses will be selected for therapeutic expansion. Subjects who qualify for screening will be placed in the anti-HER2 antibody-drug conjugate and fulvestrant combination group for therapeutic expansion.

[0166] Anti-HER2 antibody-drug conjugate in combination with letrozole / anastrozole: After the first stage of dose exploration is completed using the combination of anti-HER2 antibody-drug conjugate and fulvestrant, one to two doses will be selected and used in combination with the anti-HER2 antibody-drug conjugate and letrozole / anastrozole, based on the safety of the dose group, to expand the therapeutic effect.

[0167] Letrozole is administered orally, 2.5 mg once daily, in continuous doses.

[0168] Anastrozole is administered orally, 1 mg once daily, in continuous doses.

[0169] Anti-HER2 antibody-drug conjugate in combination with bevacizumab: After the first phase of dose-finding is completed with the combination of anti-HER2 antibody-drug conjugate and bevacizumab, at least one dose group will be selected for therapeutic expansion.

Claims

1. 1. Use of an anti-HER2 antibody-drug conjugate in the preparation of a medicament for treating HER2-low-expressing breast cancer, wherein the structure of the antibody-drug conjugate is shown in formula (I): 【Chemistry 1】 Among them, n is 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody; use.

2. The anti-HER2 antibody is selected from trastuzumab, pertuzumab, or an antigen-binding fragment thereof, and is preferably trastuzumab or an antigen-binding fragment thereof.

2. The use according to claim 1.

3. the anti-HER2 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NOs: 3, 4, and 5, respectively, and LCDR1, LCDR2, and LCDR3 shown in SEQ ID NOs: 6, 7, and 8, respectively; Preferably, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 9 or having at least 90% identity thereto, and the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 10 or having at least 90% identity thereto; Preferably, the anti-HER2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:2 or having at least 90% identity thereto, and the light chain comprises the amino acid sequence set forth in SEQ ID NO:1 or having at least 90% identity thereto.

3. Use according to claim 1 or 2.

4. The anti-HER2 antibody-drug conjugate has the structure shown in the following formula: 【Chemistry 2】 wherein n is 3 to 8, n is a decimal or integer, preferably 6±0.8; Use according to any one of claims 1 to 3.

5. The HER2 low-expressing breast cancer is a breast cancer in which HER2 expression is determined to be 1+ by immunohistochemistry, or Breast cancer in which HER2 expression is determined to be 2+ by immunohistochemistry and HER2 expression is determined to be negative by in situ hybridization. Use according to any one of claims 1 to 4.

6. The HER2 low-expressing breast cancer is unresectable, recurrent and / or metastatic breast cancer with low HER2 expression. Use according to any one of claims 1 to 5.

7. The HER2 low-expressing breast cancer has previously been treated with an anti-HER2 drug, preferably a HER2 low-expressing breast cancer that has become resistant or refractory to previous treatment with an anti-HER2 drug. Use according to any one of claims 1 to 6.

8. The anti-HER2 drug is at least one selected from the group consisting of trastuzumab, pertuzumab, pyrotinib, lapatinib, and T-DM1.

8. The use according to claim 7.

9. The use is in the preparation of a medicament for treating HER2-low-expressing breast cancer by combining the anti-HER2 antibody-drug conjugate with a second therapeutic agent. Use according to any one of claims 1 to 8.

10. the second therapeutic agent is a CDK4 / 6 inhibitor; Preferably, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925, INOC-005, G1T28-1, BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, stau rosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC-625987, CGP-82996, PD-171851, and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, more preferably the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and most preferably the isethionate salt of the compound represented by formula (II); 【Transformation 3】 Preferably, the dosage of the CDK4 / 6 inhibitor is 1-1000 mg, preferably 100 mg, 125 mg, 150 mg, and preferably the administration frequency may be once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, or once a month; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks, and the CDK4 / 6 inhibitor is administered once daily, with continuous administration for the first two weeks followed by a one-week rest period, or continuous administration for the first three weeks followed by a one-week rest period.

10. The use according to claim 9.

11. the second therapeutic agent is an aromatase inhibitor, preferably the aromatase inhibitor is selected from formestane, exemestane, fadrozole, letrozole, vorozole and anastrozole, more preferably letrozole or anastrozole; Preferably, the dosage of the aromatase inhibitor is 0.1 to 50 mg, preferably 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg or 5.0 mg, and preferably the administration frequency is once a day or twice a day; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks, and the aromatase inhibitor is administered once daily, and the administration is continuous.

10. The use according to claim 9.

12. the second therapeutic agent is a CDK4 / 6 inhibitor and an aromatase inhibitor; Use according to any one of claims 9 to 11.

13. the second therapeutic agent is a SERD, and the SERD is preferably fulvestrant, AZD-9496, RAD1901 or ZB-716, more preferably fulvestrant; Preferably, the dose of the SERD is 1-1000 mg, preferably 500 mg, and preferably the administration frequency is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, or once a month; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks, and the treatment cycle for SERD is four weeks, with the anti-HER2 antibody-drug conjugate being administered on days 1 and 15 of the first cycle and on day 1 of each subsequent cycle.

10. The use according to claim 9.

14. The second therapeutic agent is a VEGF ligand inhibitor, and the VEGF ligand inhibitor is preferably selected from the group consisting of bevacizumab, ramucirumab, ranibizumab, aflibercept, conbercept, abicipag, brolucizumab, LMG-324, nesvacumab, sevacizumab, tanibirumab, navicixizumab, RG-7716, LHA-510, OPT-302, TK-001, GZ-402663, VGX-100, PG-545, BI-836880, GNR-011, BR-55, and OTSGC-A24. selected from PAN-90806, AVA-101, ODM-203, TAS-115, X-82, MP-0250, sitravatinib, 4SC-203, AL-2846, ABT-165, SIM-010603, BI-836880, HL-217, CS-2164, RGX-314, AMC-303 or VXM-01, more preferably bevacizumab; Preferably, the dosage of the VEGF ligand inhibitor is 0.1 to 100 mg / kg, preferably 15 mg / kg, and the administration frequency is preferably once a day, once a week, once every two weeks, once every three weeks, or once a month; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks, and the VEGF ligand inhibitor is administered once every three weeks.

10. The use according to claim 9.

15. The single dose of the anti-HER2 antibody-drug conjugate is 1.0 mg / kg to 10.0 mg / kg, preferably 1.0 mg / kg, 2.0 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg, or 8.0 mg / kg, and the administration frequency is preferably once a week, once every two weeks, once every three weeks, or once every four weeks. Use according to any one of claims 1 to 14.

16. A method for treating HER2-low-expressing breast cancer, comprising administering to a subject in need thereof an anti-HER2 antibody-drug conjugate, wherein the structure of the anti-HER2 antibody-drug conjugate is shown in formula (I): 【Chemistry 4】 Among them, n is 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody, the anti-HER2 antibody-drug conjugate is as defined in any one of claims 1 to 4 and 15, and the HER2 low-expressing breast cancer is as defined in any one of claims 5 to 8; Preferably, the method comprises administering to a subject in need thereof an anti-HER2 antibody-drug conjugate and a second therapeutic agent, wherein the second therapeutic agent is selected from one or more of a CDK4 / 6 inhibitor, a SERD, a VEGF ligand inhibitor, and an aromatase inhibitor. method.

17. A pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate and a second therapeutic agent, and one or more pharmaceutically acceptable carriers, wherein the structure of the anti-HER2 antibody-drug conjugate is shown in formula (I): 【Transformation 5】 Among them, n is 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody, the anti-HER2 antibody-drug conjugate is preferably as defined in any one of claims 1 to 4 and 15, and the second therapeutic agent is preferably as defined in any one of claims 9 to 14. Pharmaceutical compositions.

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