Use of combination of Anti-her2 antibody-drug conjugate and Anti-PD-l1 antibody in preparation of drug for treating breast cancer

Abstract

A use of a combination of an anti-HER2 antibody-drug conjugate and an anti-PD-L1 antibody in the preparation of a drug for treating breast cancer. The structure of the antibody-drug conjugate is shown in formula (I).

Description

Use of anti-HER2 antibody-drug conjugates and anti-PD-L1 antibodies in the preparation of drugs for treating breast cancer.

[0001] This disclosure claims priority to CN2024115510369 and CN2025106394999, which, by reference, refer to this disclosure. Technical Field

[0002] This disclosure pertains to the pharmaceutical field and relates to the use of anti-HER2 antibody-drug conjugates (ADCs) in combination with anti-PD-L1 antibodies in the preparation of drugs for treating tumors. Background Technology

[0003] HER2 is a member of the type I transmembrane tyrosine kinase receptor family. It is essentially inactive in its monomeric state, but it can polymerize with the other three transmembrane tyrosine kinase members of the family, HER1, HER3, and HER4, leading to phosphorylation of receptor tyrosine residues and activation of multiple signaling pathways (such as MAPK, PI3K / Akt, etc.), thereby promoting cell proliferation and tumor development.

[0004] HER2-targeting antibody-drug conjugates (ADCs) exert their effects through the following mechanism: First, the antibody in the ADC specifically recognizes and binds to the HER2 receptor on the surface of target cells. Then, it enters the target cell via endocytosis, where it is broken down and released into the cell to release the cytotoxic drug. Finally, the cytotoxic drug induces apoptosis by damaging DNA or acting on microtubules, thereby exerting its anti-tumor effect. If the cytotoxic drug has high membrane permeability, it may penetrate into the extracellular space after being released from the target cell, killing surrounding HER2-negative cells; this effect is known as bypass killing. This effect may also occur if the cytotoxic drug is released before ADC endocytosis. WO2020063676A discloses a class of ADCs targeting HER2. Given the excellent efficacy of the already approved HER-2 ADC drugs Trastuzumab emtansine (T-DM1) and Trastuzumab Deruxtecan (DS-8201a) in the treatment of breast cancer and gastric cancer, it is of great significance to conduct research on the indications of the antibody-drug conjugates in WO2020063676A. Summary of the Invention

[0005] This disclosure provides the use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for treating tumors.

[0006] In some implementations, this disclosure provides the following uses or methods:

[0007] (1) Use of anti-HER2 antibody drug conjugates and immunotherapy agents in the preparation of drugs for treating tumors.

[0008] (2) Use of combinations of anti-HER2 antibody drug conjugates and immunotherapeutic agents in the preparation of drugs for treating tumors.

[0009] (3) Anti-HER2 antibody-drug conjugates for the treatment of subjects with tumors, wherein the subjects are also given immunotherapeutic agents.

[0010] (4) Use of the pharmaceutical composition in the preparation of a medicament for treating tumors; wherein the pharmaceutical composition comprises an anti-HER2 antibody-drug conjugate and an immunotherapeutic agent.

[0011] (5) Use of anti-HER2 antibody drug conjugates in the preparation of drugs for treating tumors.

[0012] (6) Methods of treating tumors, including administering anti-HER2 antibody-drug conjugates or anti-HER2 antibody-drug conjugates and immunotherapy agents to patients.

[0013] (7) The aforementioned anti-HER2 antibody-drug conjugate for the treatment of tumors, wherein the anti-HER2 antibody-drug conjugate is used in combination with an immunotherapy agent.

[0014] (8) An immunotherapy agent for treating tumors, wherein the immunotherapy agent is used in combination with the aforementioned anti-HER2 antibody drug conjugate.

[0015] (9) Pharmaceutical compositions, including anti-HER2 antibody drug conjugates and immunotherapeutic agents.

[0016] (10) A kit or article comprising an anti-HER2 antibody-drug conjugate and an immunotherapeutic agent. In some embodiments, the kit or article may further comprise one or more containers, each independently containing an anti-HER2 antibody-drug conjugate and an immunotherapeutic agent.

[0017] In some implementations, this disclosure provides the following uses or methods:

[0018] (1) Use of anti-HER2 antibody drug conjugate and anti-PD-L1 antibody in the preparation of drugs for treating tumors.

[0019] (2) Use of the combination of anti-HER2 antibody drug conjugate and anti-PD-L1 antibody in the preparation of drugs for treating tumors.

[0020] (3) Anti-HER2 antibody-drug conjugate for treating subjects with tumors, wherein the subjects are also given an anti-PD-L1 antibody.

[0021] (4) Use of the pharmaceutical composition in the preparation of a medicament for treating tumors; wherein the pharmaceutical composition comprises an anti-HER2 antibody-drug conjugate and an anti-PD-L1 antibody.

[0022] (5) Use of anti-HER2 antibody drug conjugates in the preparation of drugs for treating tumors.

[0023] (6) Methods of treating tumors, including administering anti-HER2 antibody-drug conjugates or anti-HER2 antibody-drug conjugates and anti-PD-L1 antibodies to patients.

[0024] (7) The aforementioned anti-HER2 antibody-drug conjugate for the treatment of tumors, wherein the anti-HER2 antibody-drug conjugate is used in combination with an anti-PD-L1 antibody.

[0025] (8) An anti-PD-L1 antibody for the treatment of tumors, wherein the anti-PD-L1 antibody is used in combination with the aforementioned anti-HER2 antibody drug conjugate.

[0026] (9) A pharmaceutical composition comprising an anti-HER2 antibody drug conjugate and an anti-PD-L1 antibody.

[0027] (10) A kit or article comprising an anti-HER2 antibody-drug conjugate and an anti-PD-L1 antibody. In some embodiments, the kit or article may further comprise one or more containers, each independently containing the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody.

[0028] In some embodiments, the tumor is breast cancer. In some embodiments, the breast cancer is estrogen receptor (ER) negative, progesterone receptor (PR) negative, and / or HER2 negative breast cancer.

[0029] In some embodiments, the tumor is HER2-negative breast cancer. In some embodiments, HER2-negative means that the expression level of HER2 is 0, 0-1+ or 1+ on immunohistochemistry (IHC), or 2+ and negative on unsaturated hybridization (ISH).

[0030] In some embodiments, the breast cancer is HR-negative or low-expressing, and also exhibits low HER2 expression. In some embodiments, the HR expression level is 0 ≤ HR < 10%; in other embodiments, the HR expression level is 10 ≤ HR < 50%.

[0031] In some embodiments, the breast cancer is hormone receptor negative [both estrogen receptor (ER) and progesterone receptor (PR) are negative (i.e., the proportion of positively stained tumor cells is <1% of all tumor cells)], and HER2 negative (IHC 0, 0-1+ or 1+, or IHC 2+ and ISH-).

[0032] In some implementations, the breast cancer is triple-negative breast cancer.

[0033] In some implementations, the breast cancer is unresectable or metastatic breast cancer.

[0034] In some implementations, the breast cancer referred to is triple-negative unresectable or metastatic breast cancer.

[0035] In some implementations, the PD-L1 expression level of the breast cancer patient is CPS≥1.

[0036] In some implementation schemes, subjects with breast cancer have not received systemic antitumor therapy during the recurrence and metastasis phase. In some specific implementation schemes, the breast cancer is defined as histologically or cytologically confirmed triple-negative unresectable or metastatic breast cancer, and the patient has not received systemic antitumor therapy during the recurrence and metastasis phase.

[0037] In some implementation schemes, the HER2, ER, and PR levels of breast cancer patients are determined with reference to clinical guidelines (e.g., ASCO, CSCO, ESMO clinical guidelines).

[0038] In some embodiments, the structure of the antibody-drug conjugate is shown in formula (I):

[0039] in:

[0040] n is between 3 and 8, and n is a decimal or an integer;

[0041] Pc is an anti-HER2 antibody.

[0042] In the context of this disclosure, "antibody" is used in the broadest sense and encompasses 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"), provided they exhibit the desired antigen-binding activity. In some embodiments, the antibody is a full-length antibody or an antigen-binding fragment thereof.

[0043] Anti-HER2 antibody

[0044] 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 as shown in SEQ ID NO:11-13, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:14-16.

[0045] The CDR sequences mentioned above are shown in Table 1 below:

[0046] Table 1. CDR sequences of anti-HER2 antibodies (Kabat protocol)

[0047] In some implementations, the anti-HER2 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or any combination of two, three, four, five, or six of them.

[0048] In some embodiments, the anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the VH comprises HCDR1, HCDR2, and HCDR3 of the amino acid sequence shown in SEQ ID NO: 17, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 18. The aforementioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition schemes. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.

[0049] In some implementations, the anti-HER2 antibody is a chimeric, humanized, fully human antibody or its antigen-binding fragment.

[0050] In some embodiments, the anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO: 17, and the VL comprises an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO: 18.

[0051] Heavy chain variable region:

[0052] Light chain variable region:

[0053] In some implementations, the anti-HER2 antibody comprises any one or both of the aforementioned VH and VL.

[0054] In some embodiments, the anti-HER2 antibody further comprises a heavy chain constant region and / or a light chain constant region. The heavy chain constant region of the antibody may be selected from the constant regions of human IgG1, IgG2, IgG3, IgG4, and their variants. In some embodiments, the light chain constant region may be selected from the light chain constant region of human κ, λ chains, or their variants.

[0055] In some embodiments, the anti-HER2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO:19; and / or, the light chain comprises an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO:20.

[0056] In some embodiments, the anti-HER2 antibody comprises a heavy chain with an amino acid sequence as shown in SEQ ID NO:19 and a light chain with an amino acid sequence as shown in SEQ ID NO:20.

[0057] Heavy chain sequence of anti-HER2 antibody:

[0058] Light chain sequence of anti-HER2 antibody: Note: The underlined portion is the variable region sequence of the antibody heavy or light chain, and the ununderlined portion is the constant region sequence of the antibody.

[0059] In some implementations, the anti-HER2 antibody is selected from Trastuzumab and Pertuzumab.

[0060] In some implementations, the anti-HER2 antibody is Trastuzumab.

[0061] In some embodiments, the antibody-drug conjugate has the structure shown in the following formula:

[0062] Where n is between 3 and 8, and n is a decimal or an integer.

[0063] In some implementations, n is 6 in the anti-HER2 antibody drug conjugate.

[0064] In some embodiments, n in the anti-HER2 antibody drug conjugate is 5.7 ± 0.4, for example, n is 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3 or 6.4.

[0065] In some embodiments, the anti-PD-L1 antibody is selected from any one of the following CDR region sequences or mutant sequences thereof: antibody heavy chain variable region HCDR region sequence: SEQ ID NO: 1-3; and antibody light chain variable region LCDR region sequence: SEQ ID NO: 4-6;

[0066] Specifically as follows:

[0067] HCDR1 is selected from:

[0068]

[0069] HCDR2 is selected from:

[0070]

[0071] HCDR3 is selected from:

[0072] LCDR1 is selected from:

[0073] LCDR2 is selected from:

[0074] LCDR3 is selected from:

[0075] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1-3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4-6.

[0076] In some embodiments, the anti-PD-L1 antibody comprises and amino acid sequences: SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of a light chain variable region CDR sequence, and amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of a heavy chain variable region CDR sequence.

[0077] In some implementations, the anti-PD-L1 antibody may be selected from murine antibodies, chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0078] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity for the amino acid sequence SEQ ID NO: 7, and a light chain variable region sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity for the amino acid sequence SEQ ID NO: 8.

[0079] In some embodiments, the anti-PD-L1 antibody further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or variants thereof, preferably comprising a heavy chain constant region of human IgG2 or IgG4, more preferably comprising a heavy chain constant region of IgG4 with F234A and L235A mutations introduced; the humanized antibody light chain further comprises a constant region of human κ, λ chain or variants thereof.

[0080] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity for the amino acid sequence SEQ ID NO: 9, and a light chain sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity for the amino acid sequence SEQ ID NO: 10.

[0081] In some embodiments, the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 9, and the light chain sequence is SEQ ID NO: 10. Note: Italics in the sequence indicate FR sequences; underlined sequences indicate CDR sequences.

[0082] Heavy chain sequence

[0083] Light chain sequence

[0084] In some embodiments, the anti-PD-L1 antibody is selected from Atezolizumab, Durvalumab, and Avelumab.

[0085] In the context of this disclosure, "at least 85%" encompasses 85% and above, such as 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 range between any two.

[0086] In some embodiments, the single-dose dose of the anti-HER2 antibody-drug conjugate is 1.0 mg / kg to 10.0 mg / kg, for example 1.0 mg / kg to 8.0 mg / kg, 2.0 mg / kg to 8.0 mg / kg, 3.2 mg / kg to 8.0 mg / kg, 3.2 mg / kg to 6.4 mg / kg, or 2.0 mg / kg to 6.4 mg / kg.

[0087] In some implementations, the anti-HER2 antibody-drug conjugate is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0088] In some embodiments, the single-dose dose of the anti-HER2 antibody-drug conjugate can be selected from 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 mg / kg, and 5.2 mg / kg. The dosages are 5.4 mg / kg, 5.6 mg / kg, 5.8 mg / kg, 6.0 mg / kg, 6.2 mg / kg, 6.4 mg / kg, 6.6 mg / kg, 6.8 mg / kg, 7.0 mg / kg, 7.2 mg / kg, 7.4 mg / kg, 7.6 mg / kg, 7.8 mg / kg, 8.0 mg / kg, 8.2 mg / kg, 8.4 mg / kg, 8.6 mg / kg, 8.8 mg / kg, 9.0 mg / kg, 9.2 mg / kg, 9.4 mg / kg, 9.6 mg / kg, 9.8 mg / kg, or 10.0 mg / kg, administered once every three weeks.

[0089] In some implementations, the single dose of the anti-HER2 antibody-drug conjugate is 1.0 mg / kg, and the dosing frequency is once every three weeks.

[0090] In some implementations, the single dose of the anti-HER2 antibody-drug conjugate is 2.0 mg / kg, and the dosing frequency is once every three weeks.

[0091] In some implementations, the single dose of the anti-HER2 antibody-drug conjugate is 3.2 mg / kg, and the dosing frequency is once every three weeks.

[0092] In some implementations, the single dose of the anti-HER2 antibody-drug conjugate is 4.8 mg / kg, and the dosing frequency is once every three weeks.

[0093] In some implementations, the single dose of the anti-HER2 antibody-drug conjugate is 6.4 mg / kg, and the dosing frequency is once every three weeks.

[0094] In some implementations, the single dose of the anti-HER2 antibody-drug conjugate is 8.0 mg / kg, and the dosing frequency is once every three weeks.

[0095] In some embodiments, the dosage of the anti-PD-L1 antibody can be within the following ranges: 0.1-50.0 mg / kg, 0.1-40 mg / kg, 1-40 mg / kg. For example, the dosage can be 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, etc. mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, 32mg / kg, 33mg / kg, 34mg / kg, 35mg / kg, 36mg / kg, 3 7mg / kg, 38mg / kg, 39mg / kg, 40mg / kg, 42mg / kg, 45mg / kg, 47mg / kg, 50mg / kg, more preferably 1mg / kg, 3mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 30mg / kg, 40mg / kg.

[0096] In some embodiments, the dosage of the anti-PD-L1 antibody is selected from 50-3000 mg. For example, the dosage is selected from 100mg-3000mg, 100mg-2500mg, 100mg-2000mg, 100mg-1800mg, 100mg-1500mg, 500mg-3000mg, 500mg-2500mg, 500mg-2000mg, 500mg-1800mg, 500mg-1500mg, 800mg-3000mg, 800mg-2500mg, 800mg-2000mg, 800mg-1800mg, 800mg-1500mg, 1000mg-3000mg, 1000mg-2500mg, 1000mg-2000mg, 1000mg-1800mg, 1000mg-1500mg.

[0097] In some embodiments, the dosage of the anti-PD-L1 antibody may be 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, or 1350 mg. g, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 22 00mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg.

[0098] In some implementations, the anti-PD-L1 antibody is administered once daily, once every two days, once every three days, once every five days, once a week, twice a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three to six months or longer.

[0099] In some embodiments, the dosage of the anti-PD-L1 antibody is 1 mg / kg, 3 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, or 40 mg / kg, and the dosing frequency is once every three weeks.

[0100] In some specific embodiments, the dosage of the anti-PD-L1 antibody is 20 mg / kg, and the dosing frequency is once every three weeks.

[0101] In some specific embodiments, the dosage of the anti-PD-L1 antibody is 1200 mg, and the dosing frequency is once every three weeks.

[0102] In some embodiments, the anti-HER2 antibody drug conjugate can be administered orally, parenterally, or transdermally, with parenterial administration including but not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-HER2 antibody drug conjugate is administered via intravenous injection.

[0103] In some implementations, the anti-HER2 antibody-drug conjugate is configured in an injectable form. Exemplarily, the injectable form of the antibody-drug conjugate is a solution or lyophilized powder for injection, comprising the antibody-drug conjugate and one or more pharmaceutically acceptable excipients.

[0104] In some implementations, when the anti-HER2 antibody drug conjugate is administered in combination with the anti-PD-L1 antibody or its antigen-binding fragment, the order of administration is: anti-HER2 antibody drug conjugate, anti-PD-L1 antibody or its antigen-binding fragment.

[0105] In this disclosure, "combination" refers to a route of administration that includes various situations where two drugs are administered sequentially or simultaneously. Simultaneous administration, independently prepared and co-administered drugs, or independently prepared and sequentially administered drugs all fall under the category of combined administration as described in this disclosure. "Simultaneous" here means administering at least one dose of an anti-PD-L1 antibody or its antigen-binding fragment and an anti-HER2 antibody drug conjugate within a certain time period, for example, administering two drugs within 2 days or 1 day, wherein both substances exhibit pharmacological effects. "Sequential" administration includes the situation where an anti-PD-L1 antibody or its antigen-binding fragment and an anti-HER2 antibody drug conjugate are administered separately in different dosing cycles. The time period can be within a dosing cycle, optionally within 4 weeks, 3 weeks, 2 weeks, 1 week, within 24 hours, or within 2 hours. This period includes treatments in which an anti-PD-L1 antibody or its antigen-binding fragment and an anti-HER2 antibody drug conjugate are administered via the same or different routes of administration.

[0106] In some implementations, a treatment cycle is performed every two weeks, every three weeks, or every four weeks, for example, every three weeks.

[0107] In some implementation schemes, the dosing regimen for the anti-HER2 antibody-drug conjugate combined with the immunotherapy agent is as follows:

[0108] The dosage of anti-HER2 antibody drug conjugate is 1.0 mg / kg-10.0 mg / kg, and the dosing frequency is once every 3 weeks; the dosage of anti-PD-L1 antibody is 50 mg-3000 mg, and the dosing frequency is once every 3 weeks.

[0109] The dosage of anti-HER2 antibody drug conjugates is approximately 1.0 mg / kg, approximately 2.0 mg / kg, approximately 3.2 mg / kg, approximately 4.8 mg / kg, approximately 5.6 mg / kg, approximately 6.4 mg / kg, or approximately 8.0 mg / kg, administered once every 3 weeks; the dosage of anti-PD-L1 antibody is 50 mg to 3000 mg, administered once every 3 weeks.

[0110] The dosage of anti-HER2 antibody-drug conjugates is 1.0 mg / kg-10.0 mg / kg, administered once every 3 weeks; the dosage of anti-PD-L1 antibodies is approximately 500 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, 2200 mg, 2500 mg, or 3000 mg, administered once every 3 weeks; or...

[0111] The dosage of the anti-HER2 antibody drug conjugate is approximately 4.8 mg / kg or approximately 6.4 mg / kg, administered once every 3 weeks; the dosage of the anti-PD-L1 antibody is approximately 1000 mg, approximately 1200 mg, or approximately 1500 mg, administered once every 3 weeks.

[0112] the term

[0113] To facilitate understanding of this disclosure, 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 one of ordinary skill in the art to which this disclosure pertains.

[0114] This disclosure incorporates the entire contents of application WO2020063676A.

[0115] Antibody-drug conjugates (ADCs) are drugs that link antibodies or antibody fragments to biologically active cytotoxic drugs or small molecule drugs with cytotoxic activity via stable chemical linker compounds. They fully utilize the specificity of antibodies in binding to tumor cell-specific or highly expressed antigens and the high efficiency of cytotoxic agents, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, antibody-drug conjugates can precisely bind to tumor cells and reduce the impact on normal cells.

[0116] If an antibody-drug conjugate does not exhibit significant chemical changes, then the antibody "retains its chemical stability" in the drug formulation. Chemical stability can be assessed by detecting and quantifying the chemically altered form of the protein. Degradation processes that frequently alter the chemical structure of proteins include hydrolysis or truncation (evaluated by methods such as size exclusion chromatography and CE-SDS), oxidation (evaluated by methods such as peptide mapping combined with mass spectrometry or MALDI / TOF / MS), deamidation (evaluated by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, and isofpartate measurement), and isomerization (evaluated by measuring isofpartate content, peptide mapping, etc.).

[0117] If the biological activity of an antibody-drug conjugate at a given time is within a predetermined range of the biological activity exhibited when the drug formulation is prepared, then the antibody-drug conjugate "retains its biological activity" in the drug formulation.

[0118] The term "drug loading" refers to the average number of cytotoxic drugs loaded onto each antibody or its antigen-binding fragment in a molecule of formula (I), and can also be expressed as the ratio of drug amount to antibody amount. The drug loading range can be 0-12 cytotoxic drugs (D) linked to each antibody or its antigen-binding fragment (Pc), preferably 1-10, more preferably 3-8, and most preferably 5.3-6.1. In embodiments of this disclosure, the drug loading is expressed as n, which can be an average of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, as exemplarily. The average number of drugs per ADC molecule after the coupling reaction can be identified using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA, and HPLC characterization.

[0119] In one embodiment of this disclosure, a cytotoxic drug is coupled to the N-terminal amino group, the ε-amino group of a lysine residue, and / or the thiol group of an antibody or its antigen-binding fragment via a linker unit. Generally, the number of drug molecules that can be coupled to the antibody in the coupling reaction will be less than the theoretical maximum value.

[0120] The loading of cytotoxic drugs can be controlled using the following non-limiting methods, including:

[0121] (1) Control the molar ratio of the ligation reagent and the monoclonal antibody.

[0122] (2) Control the reaction time and temperature.

[0123] (3) Choose different reaction reagents.

[0124] For the preparation of conventional pharmaceutical compositions, please refer to the Chinese Pharmacopoeia.

[0125] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, "giving" and "treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "Giving" and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and cells, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cells. "Giving" and "treatment" also mean the treatment of, for example, cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, "treatment" refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0126] "Treatment" means administering an oral or topical therapeutic agent, such as a composition comprising any of the compounds disclosed herein, to a patient who has symptoms of one or more diseases, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated patient or population in an amount that effectively relieves symptoms of one or more diseases to induce the regression of such symptoms or inhibit their progression to any clinically measurable extent. The amount of a therapeutic agent that effectively relieves any specific disease symptom (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the patient's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the patient. Whether the disease symptoms have been relieved can be evaluated using any clinical testing methods commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating symptoms of each target disease, they should reduce symptoms of the target disease in a statistically significant number of patients, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0127] An "effective amount" includes the amount sufficient to improve or prevent the symptoms or condition of a medically diagnosed disease. An effective amount also means the amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0128] In this disclosure of anti-HER2 antibody-drug conjugates, "n" refers to the average amount of cytotoxic drug loaded onto each antibody or its antigen-binding fragment in the antibody-drug conjugate molecule. It can also be expressed as the ratio of drug amount to antibody amount, and is the average amount of drug in each ADC molecule after the conjugation reaction is identified by hydrophobic chromatography (HIC) mass spectrometry. Detailed Implementation

[0129] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions, such as those described in Cold Spring Harbor Laboratory's *Antibody Technology Laboratory Manual* and *Molecular Cloning Handbook*; or under conditions recommended by the raw material or commercial manufacturer. Reagents whose specific source is not specified are commercially available, conventional reagents.

[0130] Example 1. Preparation of anti-HER2 antibody drug conjugate

[0131] According to the manufacturing method described in WO2021190581A, an anti-HER2 antibody-drug conjugate, ADC-32, with the structure shown below was prepared using Trastuzumab (anti-HER2 antibody) and an ixotecan analog. The average value calculated by the HIC method was: n = 5.7 ± 0.4.

[0132] The following is the sequence of Trastuzumab:

[0133] Light chain

[0134] Heavy chain

[0135] Example 2. Safety, tolerability, and efficacy study of anti-HER2 antibody-drug conjugate combined with anti-PD-L1 antibody in patients with triple-negative unresectable or metastatic breast cancer.

[0136] 1. Test drug

[0137] The anti-HER2 antibody-drug conjugate (ADC-32) prepared in Example 1 is a lyophilized powder for injection, with a specification of 100 mg / vial.

[0138] Anti-PD-L1 antibody, with heavy chain sequence SEQ ID NO: 9 and light chain sequence SEQ ID NO: 10. Specification: 12mL:0.6g.

[0139] 2. Enrolled subjects

[0140] 1) Women aged 18 to 75 (inclusive).

[0141] 2) Breast cancer patients must meet the following criteria:

[0142] Phase 1 (Dose Exploration):

[0143] • Cohort E: Histologically or cytologically confirmed triple-negative unresectable or metastatic breast cancer that has received at least one first-line standard therapy during the recurrence / metastasis stage. Triple-negative is defined as: hormone receptor negative [both estrogen receptor (ER) and progesterone receptor (PR) are negative (i.e., the proportion of positive tumor cells is <1% of all tumor cells)], and HER2 negative (IHC0 or 1+, or IHC2+ and ISH-).

[0144] Phase Two (Expanding Therapeutic Effects):

[0145] • Cohorts 12-14: Histologically or cytologically confirmed triple-negative unresectable or metastatic breast cancer (only patients initially diagnosed with stage IV are eligible if they have not previously received any anti-tumor therapy) and have not received systemic anti-tumor therapy during the recurrence / metastasis stage. Triple-negative is defined as: hormone receptor negative [both estrogen receptor (ER) and progesterone receptor (PR) are negative (i.e., the proportion of positively stained tumor cells is <1% of all tumor cells)], and HER2 negative (IHC0 or 1+, or IHC2+ and ISH-).

[0146] 3) ECOG score is 0 or 1.

[0147] 4) Expected survival ≥ 12 weeks.

[0148] 5) At least one measurable lesion according to RECISTv1.1 criteria.

[0149] 6) Vital organ function meets the following criteria (no corrective treatment with any blood components, cell growth factors, albumin, etc., has been used within 14 days prior to the first dose):

[0150] • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L(1,500 / mm 3 );

[0151] Platelet count ≥100×10⁹ / L (100,000 / mm³) 3 );

[0152] • Hemoglobin (Hgb) ≥ 90 g / L (9.0 g / dL);

[0153] • Albumin level ≥3.0 g / dL;

[0154] • Total bilirubin ≤ 1.5 × ULN;

[0155] • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (for patients with liver metastases, ALT and AST ≤5×ULN);

[0156] • Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL / min (calculated according to the Cockcroft-Gault formula, Appendix 2);

[0157] • Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0158] • QTcF ≤ 470 msec;

[0159] • Echocardiography (ECHO) or cardiac radionuclide scanning (MUGA) shows a left ventricular ejection fraction (LVEF) ≥50%.

[0160] 3. Administration method

[0161] Phase 1 (Dosage Exploration Phase): Anti-HER2 Antibody Drug Conjugate + Anti-PD-L1 Antibody

[0162] Anti-HER2 antibody-drug conjugate, administered intravenously at doses of 6.4 mg / kg, 4.8 mg / kg, 3.2 mg / kg, and 2.0 mg / kg, once every 3 weeks (Q3W).

[0163] Anti-PD-L1 antibody, administered intravenously at a dose of 1200 mg, once every 3 weeks, with each 3-week period constituting one treatment cycle.

[0164] Phase Two (Therapeutic Effect Expansion Phase)

[0165] Dosage group 1: After completing the dose exploration of anti-HER2 antibody drug conjugate combined with anti-PD-L1 antibody, at least one dose was selected for efficacy expansion.

[0166] 4. Results Evaluation

[0167] 1) Safety: incidence of dose-limiting toxicity (DLT), incidence and severity of adverse events (AE) and serious adverse events (SAE), and abnormal laboratory test results.

[0168] 2) Effectiveness: Objective Response Rate (ORR), Duration of Response (DoR), and Progression-Free Survival (PFS).

[0169] 5. Results

[0170] As of August 18, 2024, a total of 39 patients with triple-negative unresectable or metastatic breast cancer received treatment with anti-HER2 antibody-drug conjugate (ADC-32) in combination with an anti-PD-L1 antibody. In the dose-expansion and efficacy-enhancing phase, among the 27 patients who underwent at least one efficacy evaluation, the objective response rate (ORR) of ADC-32 combined with the anti-PD-L1 antibody was 59.3%. In the recurrent / metastatic phase (Phase II - efficacy-enhancing phase), 19 patients in the 4.8 mg / kg dose group achieved at least one efficacy evaluation, with an ORR of 57.9%. Among patients with CPS ≥ 1, the ORR was 80.0%, indicating that ADC-32 combined with the anti-PD-L1 antibody has a good therapeutic effect on PD-L1-positive tumor cells. This preliminarily demonstrates the good anti-tumor activity of ADC-32 + anti-PD-L1 antibody against triple-negative unresectable or metastatic breast cancer.

[0171] During the study, the percentage of subjects who experienced grade ≥3 TEAEs was 61.8% in the 4.8 mg / kg group and 80.0% in the 5.6 mg / kg group.

[0172] Table 2. Efficacy of ADC-32 combined with anti-PD-L1 antibody therapy in patients with triple-negative breast cancer Note: * BOR stands for Unconfirmed BOR, and ORR stands for Unconfirmed ORR.

[0173] Example 3. Safety, tolerability, and efficacy study of anti-HER2 antibody-drug conjugate combined with anti-PD-L1 antibody in patients with triple-negative unresectable or metastatic breast cancer.

[0174] 1. Method (Refer to Example 2)

[0175] 1.1 Patients with unresectable or metastatic TNBC who had previously received ≥1 line of therapy were treated in the phase 1b study with 4.8 mg / kg and 5.6 mg / kg every 3 weeks (Q3W) via intravenous injection of antiHER2 antibody-drug conjugate (ADC-32) in combination with antiPD-L1 antibody (1200 mg, Q3W) on a dose-escalation basis.

[0176] 1.2 In the phase 2 study, 33.3% of patients had ≥3 metastatic lesions, 52.4% of patients had low HER2 expression (IHC2+ / ISH- or IHC1+) / very low expression (IHC0-1), 20 patients (47.6%) were completely negative for HER2 (IHC 0), and 71.4% of patients were positive for PD-L1 (CPS≥1) (Table 3).

[0177] As of the data cutoff date (March 31, 2025), the median follow-up time in the efficacy extension cohort was 7.6 months (range 1–15 months). Patients with TNBC receiving systemic antitumor therapy received ADC-32 (4.8 mg / kg, Q3W) in combination with an anti-PD-L1 antibody.

[0178] Table 3. Patient baseline characteristics

[0179] 2. Results: A total of 50 TNBC patients were included.

[0180] Eight patients were enrolled in the phase 1b study. The ORR was 66.7% (2 / 3) in the 4.8 mg / kg dose group and 60.0% (3 / 5) in the 5.6 mg / kg dose group.

[0181] In Phase II trials, ADC-32 combined with anti-PD-L1 antibody as first-line treatment for triple-negative breast cancer achieved an objective response rate (ORR) of 69.0%. Subgroup analysis showed that this combination therapy had particularly robust antitumor activity in PD-L1-positive patients. In the CPS≥1 and CPS<1 subgroups, the ORRs were 80.0% and 41.7%, respectively, and the 6-month progression-free survival (PFS) rates were 95.8% and 80.0%, respectively (Tables 4 and 5).

[0182] The combination of ADC-32 and anti-PD-L1 antibody was well tolerated, and no new safety issues were identified. Among patients treated with 4.8 mg / kg ADC-32, 31 patients experienced grade 3 or higher treatment-related adverse events, most of which were hematologic toxicities.

[0183] Table 4. Tumor Response

[0184] BOR (Best Overall Remission); CR (Complete Response); PR (Partial Response); SD (Stable Disease); PD (Disease Progression); NE (Not Evaluable); ORR (Objective Response Rate); DCR (Disease Control Rate).

[0185] Table 5. Subgroup analysis of preliminary efficacy

[0186] 3. Conclusion: The anti-HER2 antibody-drug conjugate (ADC-32) combined with the anti-PD-L1 antibody showed good safety and tolerability, and demonstrated encouraging antitumor activity in patients with unresectable or metastatic TNBC.

[0187] Example 4. A multicenter, randomized, open-label, positive-controlled phase III clinical trial of anti-HER2 antibody-drug conjugates combined with anti-PD-L1 antibodies for the treatment of PD-L1-positive locally recurrent unresectable or metastatic triple-negative breast cancer.

[0188] 1. Test drug

[0189] Example 1 prepared an anti-HER2 antibody-drug conjugate (ADC-32), an injection (lyophilized powder), specification: 100mg / vial.

[0190] Anti-PD-L1 antibody, with heavy chain sequence SEQ ID NO: 9 and light chain sequence SEQ ID NO: 10. Injection. Specification: 12mL:0.6g.

[0191] 2. Enrolled subjects

[0192] 1) Women aged 18 to 75 (inclusive).

[0193] 2) Pathologically confirmed locally recurrent, unresectable, or metastatic triple-negative breast cancer

[0194] a. Triple-negative breast cancer is ER and PR negative (positive tumor cells account for <1% of all tumor cells) and HER2 negative as confirmed by a central laboratory (IHC test results are 0 / 0-1+ / 1+; if it is 2+, ISH confirmation is required to confirm it is negative).

[0195] b. HER2 IHC=0, approximately 10% of the population was enrolled;

[0196] c. Positive PD-L1 expression (CPS≥1) confirmed by a central laboratory.

[0197] 3) Subjects who have not received systemic antitumor therapy in the advanced / recurrent / metastatic stage; if receiving (neo)adjuvant therapy, the disease-free interval (DFI) from the end of systemic therapy (excluding endocrine therapy) to the discovery of recurrence / metastasis is 6 months. Subjects who have received immune checkpoint inhibitors (such as PD-1 / PD-L1 inhibitors) in the (neo)adjuvant stage are allowed to be enrolled and the proportion shall not exceed 10%.

[0198] 4) ECOG score is 0 or 1.

[0199] 5) Expected survival ≥ 12 weeks.

[0200] 6) At least one measurable lesion according to RECISTv1.1 criteria.

[0201] 3. Administration method

[0202] The anti-HER2 antibody-drug conjugate is administered intravenously at a dose of 4.8 mg / kg, once every 3 weeks (Q3W), with each 3-week period constituting one treatment cycle.

[0203] Anti-PD-L1 antibody, administered intravenously at a dose of 1200 mg, once every 3 weeks, with each 3-week period constituting one treatment cycle.

[0204] 4. Results Evaluation

[0205] Efficacy: Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and time to second progression (PFS2) of anti-HER2 antibody-drug conjugate combined with anti-PD-L1 antibody in the treatment of PD-L1 positive locally recurrent unresectable or metastatic triple-negative breast cancer.

[0206] Safety: adverse events (AEs), subarachnoid hemorrhages (SAEs), laboratory tests, vital signs and physical examination, 12-lead ECG, ECOG-PS score, echocardiography / cardiac radionuclide scan, blood oxygen saturation, pregnancy detection, and confirmation of concomitant treatment. Additional safety evaluations may be performed if clinically indicated or deemed necessary by the investigator.

[0207] Example 5. A multicenter, single-arm clinical study of neoadjuvant therapy with anti-HER2 antibody-drug conjugate combined with anti-PD-L1 antibody injection for newly diagnosed early or locally advanced HR-negative or low-expressing, HER2-low-expressing breast cancer.

[0208] 1. Test drug

[0209] The anti-HER2 antibody-drug conjugate prepared in Example 1 is a lyophilized powder for injection, with a specification of 100 mg / vial.

[0210] Anti-PD-L1 antibody, with heavy chain sequence SEQ ID NO: 9 and light chain sequence SEQ ID NO: 11. Specification: 12mL:0.6g.

[0211] 2. Enrolled subjects

[0212] (1) Female newly diagnosed patients aged ≥18 years and ≤75 years;

[0213] (2) Eastern Cooperative Oncology Group (ECOG) score of 0-1;

[0214] (3) Breast cancer meets the following criteria:

[0215] a) Histologically confirmed invasive breast cancer, with at least one lesion with a tumor diameter >2 cm;

[0216] b) Clinical stage of tumor: Stage II (T2N0-1M0 / T3N0M0) or Stage III (T2N2-3M0 / T3N1-3M0);

[0217] c) HER2-negative or low-expressing breast cancer with low HER2 expression, confirmed by histology or cytology: Low HER2 expression is defined as immunohistochemistry (IHC) 1+ or IHC 2+ on immune-response cells and negative in situ hybridization (ISH) results; in stage one, HR expression level is 0 ≤ HR < 10%, and in stage two, HR expression level is 10 ≤ HR < 50%.

[0218] 3. Administration method

[0219] Phase 1: Treatment-naïve early or locally advanced breast cancer patients with histologically or cytologically confirmed low HER2 expression (IHC 2+ / ISH-, IHC 1+ / ISH negative or undetected) and 0≤HR<10%.

[0220] Phase 2: Treatment-naïve early or locally advanced breast cancer patients with histologically or cytologically confirmed low HER2 expression and 10% ≤ HR < 50%.

[0221] For the administration of anti-HER2 antibody-drug conjugate plus anti-PD-L1 antibody, the anti-PD-L1 antibody injection should be administered intravenously first.

[0222] (1) Anti-HER2 antibody drug conjugate, administered by intravenous infusion, dose (4.8 mg / kg), once every 3 weeks (Q3W).

[0223] (2) Anti-PD-L1 antibody, intravenous drip, the dosage is 1200mg, once every 3 weeks, and each 3 weeks is a treatment cycle.

[0224] 4. Results Evaluation

[0225] (1) Security:

[0226] Safety evaluation includes collecting the incidence and severity of adverse events (AEs) and severe anterior exacerbations (SAEs), as well as laboratory tests (complete blood count, blood biochemistry, coagulation function, thyroid function, urinalysis, fecal occult blood test, etc.), vital signs, physical examination, weight, ECOG score, echocardiography, and 12-lead electrocardiogram.

[0227] (2) Validity:

[0228] Efficacy was evaluated based on overall pathological complete response (tpCR) (ypT0 / is, ypN0) assessed by the investigator via pathology, objective response rate (ORR) assessed during the screening period / preoperative period according to the Evaluation Criteria for Treatment of Solid Tumors (RECIST v1.1), and Ki-67 change rate assessed by pathology before and after neoadjuvant therapy. If possible, RCB grading from postoperative pathology assessments could be collected.

Claims

1. The use of an anti-HER2 antibody-drug conjugate combined with an anti-PD-L1 antibody in the preparation of a drug for treating breast cancer; the structure of the antibody-drug conjugate is shown in formula (I): in: n is selected from 3 to 8, Pc is an anti-HER2 antibody, and the breast cancer is HER2-negative breast cancer.

2. The use according to claim 1, wherein, The term HER2 negative refers to an HER2 expression level of 0, 0-1+ or 1+ on immunohistochemistry (IHC), or 2+ on IHC and negative on in situ hybridization (ISH).

3. The use according to claim 1 or 2, wherein, The breast cancer referred to is: Estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2 negative breast cancer; or, HR-negative or low-expression, and HER2-negative breast cancer; preferably, HR-negative or low-expression means that the HR expression level is 0≤HR<10%, or 10≤HR<50%.

4. The use according to any one of claims 1-3, wherein, The breast cancer mentioned is triple-negative breast cancer.

5. The use according to any one of claims 1-4, wherein the breast cancer is PD-L1 positive; preferably, the expression level of PD-L1 is CPS≥1.

6. The use according to any one of claims 1-5, wherein the anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 respectively, and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16 respectively; Preferably, the VH comprises an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO: 17, and the VL comprises an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO: 18; Preferably, the anti-HER2 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO: 19, and the light chain comprising an amino acid sequence as shown in or having at least 85% identity with SEQ ID NO: 20; Preferably, the anti-HER2 antibody is selected from Trastuzumab or Pertuzumab; Trastuzumab is preferred.

7. The use according to any one of claims 1-6, wherein the anti-HER2 antibody drug conjugate has the structure shown in the following formula: in, n is selected from 3 to 8.

8. The use according to any one of claims 1-7, wherein the anti-PD-L1 antibody comprises a heavy chain variable region and a light chain variable region, wherein, The heavy chain variable region includes HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1-3 respectively; the heavy chain variable region includes LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4-6 respectively.

9. The use according to claim 8, wherein the heavy chain variable region sequence of the anti-PD-L1 antibody comprises an amino acid sequence shown in or having at least 85% identity with SEQ ID NO: 7, and the light chain variable region sequence comprises an amino acid sequence shown in or having at least 85% identity with SEQ ID NO:

8.

10. The use according to claim 8 or 9, wherein the anti-PD-L1 antibody further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or variants thereof, preferably comprising a heavy chain constant region of human IgG2 or IgG4, more preferably comprising a heavy chain constant region of IgG4 with F234A and L235A mutations introduced; the humanized antibody light chain further comprises a constant region of human κ, λ chain or variants thereof.

11. The use according to any one of claims 1-10, wherein the heavy chain of the anti-PD-L1 antibody comprises an amino acid sequence shown in or having at least 85% identity with SEQ ID NO: 9, and the light chain comprises an amino acid sequence shown in or having at least 85% identity with SEQ ID NO:

10.

12. The use according to any one of claims 1-11, wherein 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 dosing frequency is once a week, once every two weeks, once every three weeks or once every four weeks; preferably, the single dose of the anti-HER2 antibody drug conjugate is 4.8 mg / kg, and the dosing frequency is once every three weeks.

13. The use according to any one of claims 1-12, wherein the dosage of the anti-PD-L1 antibody is 50 mg-3000 mg, and the dosing frequency is once a week, once every two weeks, once every three weeks, or once every four weeks; preferably, the dosage of the anti-PD-L1 antibody is 100 mg-2000 mg, 500 mg-2000 mg, 500 mg-1800 mg, 1000 mg-1800 mg, or 1000 mg-1500 mg, and the dosing frequency is once every two weeks or once every three weeks; most preferably, the dosage of the immunotherapy agent is 1200 mg, and the dosing frequency is once every three weeks.

14. An anti-HER2 antibody-drug conjugate for the treatment of breast cancer, said anti-HER2 antibody-drug conjugate being used in combination with an anti-PD-L1 antibody, said antibody-drug conjugate being as shown in formula (I). in: n is selected from 3 to 8, Pc is an anti-HER2 antibody, and the breast cancer is HER2-negative breast cancer; Preferably, HER2 negative means that the expression level of HER2 is 0 or 1+ on immunohistochemistry (IHC), or 2+ on IHC and negative on in situ hybridization (ISH). Preferably, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody are as described in any one of claims 6-13.

15. The anti-HER2 antibody-drug conjugate according to claim 14, wherein, Breast cancer is described as: Estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2 negative breast cancer; or, Breast cancer that is HER2-negative or has low HER2 expression; Preferably, the breast cancer is triple-negative breast cancer; Preferably, the breast cancer is PD-L1 positive; preferably, the expression level of PD-L1 is CPS≥1.

16. A method for treating a subject with breast cancer, comprising administering to the subject an anti-HER2 antibody-drug conjugate and an anti-PD-L1 antibody; wherein the anti-HER2 antibody-drug conjugate is administered at a single dose of 1.0 mg / kg to 10.0 mg / kg, and is administered once a week, once every two weeks, once every three weeks, or once every four weeks; The antibody-drug conjugate is shown in formula (I). in: n is 3 to 8, and Pc is anti-HER2 antibody; Preferably, the breast cancer is HER2-negative breast cancer; Preferably, HER2 negative means that the expression level of HER2 is 0, 0-1+ or 1+ on immunohistochemistry (IHC), or 2+ on IHC and negative on in situ hybridization (ISH). Preferably, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody are as described in any one of claims 6-13.

17. The anti-HER2 antibody drug conjugate according to claim 16, wherein, The breast cancer referred to is: Estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2 negative breast cancer; or, Breast cancer that is HER2-negative or has low HER2 expression; Preferably, the breast cancer is triple-negative breast cancer; Preferably, the breast cancer is PD-L1 positive; preferably, the expression level of PD-L1 is CPS≥1.

18. A medicine box or article comprising: Anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody; the antibody-drug conjugate is shown in formula (I). in: n is 3 to 8, and Pc is an anti-HER2 antibody; preferably, the anti-HER2 antibody drug conjugate or the anti-PD-L1 antibody is as described in any one of claims 6-13.

19. The medicament or product according to claim 18, used for treating breast cancer, wherein the breast cancer is breast cancer; preferably, the HER2 negative means that the expression level of HER2 is 0, 0-1+ or 1+ by immunohistochemistry (IHC), or 2+ and negative by in situ hybridization (ISH); Preferably, the breast cancer is: Estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2 negative breast cancer; or, Breast cancer that is HER2-negative or has low HER2 expression; Preferably, the breast cancer is triple-negative breast cancer; Preferably, the breast cancer is PD-L1 positive; preferably, the expression level of PD-L1 is CPS≥1.

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