Use of an adc targeting her2 to treat breast cancer

Abstract

This disclosure pertains to the field of biomedicine and relates to the use of an anti-HER2 antibody-drug conjugate (ADC) for the treatment of breast cancer. It also relates to a method for treating a subject with breast cancer, the method comprising administering an anti-HER2 antibody-drug conjugate to the subject. Furthermore, it relates to the use of the anti-HER2 antibody-drug conjugate in the preparation of a medicament for neoadjuvant therapy of breast cancer. The method provides benefit to breast cancer subjects and has a good safety profile.

Description

Use of HER2-targeted ADCs in the treatment of breast cancer Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to the use of ADC (antibody drug conjugate) targeting HER2 to treat breast cancer. Background Art

[0002] Human epidermal growth factor receptor 2 (HER2) belongs to the human epidermal growth factor receptor family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). These receptors are located on the cell surface and share a similar structure. HER2 is a ubiquitously expressed receptor protein. Abnormal gene amplification leads to protein overexpression, which in turn causes abnormal activation of signaling pathways and is a major driver of solid tumor growth. HER2 can form homodimers and heterodimers with other HER family receptors, leading to phosphorylation of receptor tyrosine residues and activation of multiple signaling pathways, including MPK, PI3K, JAK, STAT3, and PKC, ultimately contributing to cell proliferation and tumorigenesis.

[0003] Anti-HER2 targeted therapy is an important approach to treat breast cancer. Therefore, there is an urgent need to explore drugs targeting HER2 to meet the huge clinical demand for breast cancer treatment. Summary of the Invention

[0004] Treatments for breast cancer

[0005] The present disclosure provides a method for treating breast cancer in a subject, comprising administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject. In some embodiments, the method comprises administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject prior to surgical treatment. In some embodiments, the method comprises: (1) administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject; and (2) treating the breast cancer by surgery.

[0006] The present disclosure also provides a method for neoadjuvant treatment of breast cancer in a subject, comprising administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject. In some embodiments, the method is combined with breast cancer resection for the treatment of breast cancer in the subject. In some embodiments, after implementing the method, breast cancer resection is further administered to the subject for the treatment of breast cancer.

[0007] The present disclosure also provides a method of treating early-stage or locally advanced breast cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate of the present disclosure.

[0008] In some embodiments, in the above methods, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0009] The present disclosure also provides the use of the anti-HER2 antibody drug conjugate of the present disclosure in preparing a medicament for neoadjuvant treatment of breast cancer. In some embodiments, the medicament comprises a therapeutically effective amount of the anti-HER2 antibody drug conjugate.

[0010] The present disclosure also provides anti-HER2 antibody drug conjugates for use in neoadjuvant treatment of breast cancer.

[0011] The present disclosure also provides an anti-HER2 antibody drug conjugate of the present disclosure for treating breast cancer in a subject. The present disclosure also provides an anti-HER2 antibody drug conjugate of the present disclosure for treating early or locally advanced breast cancer in a subject. In some embodiments, the anti-HER2 antibody drug conjugate is administered to a subject in a therapeutically effective amount.

[0012] The present disclosure also provides use of the anti-HER2 antibody-drug conjugate of the present disclosure for neoadjuvant treatment of breast cancer.

[0013] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In a specific embodiment, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or a range formed by any of the above values. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered at a dose of 7.5 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, each time at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg of the anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg of the anti-HER2 antibody drug conjugate.

[0014] In some embodiments, in the methods or uses, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, in the methods or uses, one treatment cycle is every 3 weeks. In some embodiments, in the methods or uses, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, and the anti-HER2 antibody drug conjugate is administered once per treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is every 3 weeks, and the anti-HER2 antibody drug conjugate is administered once per treatment cycle. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered for a total of 6-8 treatment cycles. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered for a total of 6 treatment cycles or 8 treatment cycles. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered for a total of 6 treatment cycles. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered for a total of 8 treatment cycles.

[0015] In some embodiments, every 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is continuously or intermittently administered for 6-8 treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is continuously administered for 6-8 treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is intermittently administered for 6-8 treatment cycles with a certain regularity (for example, discontinuing one treatment cycle after administering 2-3 treatment cycles). In some embodiments, every 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is irregularly and intermittently administered for 6-8 treatment cycles.

[0016] In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is administered in each treatment cycle, for a total of 6 treatment cycles or 8 treatment cycles. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 6 treatment cycles or 8 treatment cycles. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and 6 mg / kg or 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle, for a total of 6 treatment cycles or 8 treatment cycles. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and 6 mg / kg or 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 6 treatment cycles or 8 treatment cycles. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle, for a total of 6 treatment cycles or 8 treatment cycles. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 6 treatment cycles. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 8 treatment cycles. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 8 treatment cycles. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 6 treatment cycles. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, for a total of 6 treatment cycles. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle, and 8 treatment cycles are administered in total. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle, and 8 treatment cycles are administered in total.

[0017] The anti-HER2 antibody drug conjugate can be formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition (or preparation). The pharmaceutical composition can be in any suitable dosage form. In some embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for parenteral administration. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous, intramuscular or other parenteral administration. In some specific embodiments, the anti-HER2 antibody drug conjugate can be formulated into an injection. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0018] In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0019] In the method or use, the dosing regimen of the anti-HER2 antibody drug conjugate (e.g., dosing cycle, dosing time, dosage and dosage adjustment) can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, the anti-HER2 antibody drug conjugate can be delayed for 1-56 days, for example, for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks. For another example, the dosage of the anti-HER2 antibody drug conjugate can be adjusted from 6 mg / kg to 4.5 mg / kg, or from 7.5 mg / kg to 6 mg / kg.

[0020] In some embodiments, the breast cancer is early-stage breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer.

[0021] In some embodiments, the breast cancer is invasive breast cancer. In some embodiments, the invasive breast cancer does not include bilateral invasive breast cancer. In some embodiments, the breast cancer is unilateral invasive breast cancer.

[0022] In some embodiments, the breast cancer is HER2-expressing breast cancer. In some embodiments, the breast cancer is HER2-positive breast cancer. In some embodiments, the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be 3+ (i.e., IHC 3+) by immunohistochemistry (IHC). In some embodiments, the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive (i.e., IHC 2+ and ISH+) by in situ hybridization (ISH). In some embodiments, the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be positive (i.e., ISH+) by ISH (e.g., by FISH double probe detection).

[0023] In some embodiments, the breast cancer is HER2-expressing early-stage or locally advanced breast cancer. In some embodiments, the breast cancer is HER2-positive early-stage or locally advanced breast cancer. In some embodiments, the breast cancer is HER2-expressing early-stage breast cancer. In some embodiments, the breast cancer is HER2-positive early-stage breast cancer. In some embodiments, the breast cancer is HER2-expressing locally advanced breast cancer. In some embodiments, the breast cancer is HER2-positive locally advanced breast cancer.

[0024] In some embodiments, the subject's breast cancer is hormone receptor (HR) positive. In some embodiments, the subject's breast cancer is estrogen receptor (ER) positive. In some embodiments, the subject's breast cancer is progesterone receptor (PR) positive. In some embodiments, the subject's breast cancer is HR negative. In some embodiments, the breast cancer is HER2-positive, hormone receptor-positive breast cancer. In some embodiments, the breast cancer is HER2-positive, hormone receptor-positive early breast cancer. In some embodiments, the breast cancer is HER2-positive, hormone receptor-positive locally advanced breast cancer. In some embodiments, the breast cancer is HER2-positive, hormone receptor-negative breast cancer. In some embodiments, the breast cancer is HER2-positive, hormone receptor-negative early breast cancer. In some embodiments, the breast cancer is HER2-positive, hormone receptor-negative locally advanced breast cancer.

[0025] In some embodiments, the clinical stage of the breast cancer is T0 to T4 (e.g., T0, T1, T2, T3, or T4), N1 to N3 (e.g., N1, N2, or N3), and M0. In some embodiments, the clinical stage of the breast cancer is T2 to T4 (e.g., T2, T3, or T4), N0, and M0. The clinical stage is determined according to AJCC.

[0026] In some embodiments, the subject with breast cancer is suitable for surgical treatment after receiving neoadjuvant therapy. In some embodiments, the subject with HER2-positive breast cancer is suitable for surgical treatment after receiving neoadjuvant therapy. In some embodiments, the subject with HER2-positive early-stage breast cancer is suitable for surgical treatment after receiving neoadjuvant therapy. In some embodiments, the subject with HER2-positive locally advanced breast cancer is suitable for surgical treatment after receiving neoadjuvant therapy.

[0027] In some embodiments, the subject with breast cancer is a subject who is suitable for surgical treatment after receiving neoadjuvant therapy. In some embodiments, the subject with HER2-positive breast cancer is a subject who is suitable for surgical treatment after receiving neoadjuvant therapy. In some embodiments, the subject with HER2-positive early-stage breast cancer is a subject who is suitable for surgical treatment after receiving neoadjuvant therapy. In some embodiments, the subject with HER2-positive locally advanced breast cancer is a subject who is suitable for surgical treatment after receiving neoadjuvant therapy.

[0028] In some embodiments, the subject with breast cancer has not previously received treatment for breast cancer. In some embodiments, the subject with breast cancer has not previously received systemic treatment for breast cancer. In some embodiments, the subject with HER2-positive breast cancer has not previously received systemic treatment for breast cancer. In some embodiments, the subject with HER2-positive early-stage breast cancer has not previously received systemic treatment for breast cancer. In some embodiments, the subject with HER2-positive locally advanced breast cancer has not previously received systemic treatment for breast cancer. In some embodiments, the subject with breast cancer has not previously received systemic treatment for breast cancer. In some embodiments, the subject with breast cancer has not previously received systemic treatment for breast cancer. In some embodiments, the subject with HER2-positive breast cancer has not previously received systemic treatment for breast cancer.

[0029] Anti-HER2 Antibody Drug Conjugates

[0030] The anti-HER2 antibody drug conjugate used in the present disclosure is formed by connecting a drug-linker having a structure shown in the following formula Ia to an antigen-binding construct targeting HER2:

[0031] in,

[0032] R1 and R2 in Formula Ia are independently selected from hydrogen (H) or deuterium (D), and the 3-position of -(succinimide-3-yl-N)- in Formula Ia (i.e., The position of the connection) is connected to the antigen binding construct targeting HER2,

[0033] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a heavy chain CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6,

[0034] The second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0035] In some embodiments, the 3-position of the -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2 via a thioether bond. In some embodiments, R1 and R2 are hydrogen.

[0036] In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 2 to 8. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 4 to 7. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5 to 6. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5.5 to 6. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5.8 to 6.

[0037] Table 1. CDR sequences of exemplary antigen-binding constructs targeting HER2

[0038] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antigen-binding fragment or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although the CDRs claimed in the present disclosure are based on the sequences shown in Table 1 (one definition), amino acid sequences corresponding to other CDR definition rules (e.g., one or more combinations of the AbM, CCG, Kabat, Chothia, IMGT, or Contact definitions known in the art) should also fall within the scope of protection of the present disclosure.

[0039] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having the amino acid sequence of SEQ ID NO: 8. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the first antigen-binding fragment is as shown in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8.

[0040] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, and a HCDR3 having the amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence of SEQ ID NO: 5, and a LCDR3 having the amino acid sequence of SEQ ID NO: 6, and the heavy chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 8, NO:8 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0041] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:8 are located in the FR regions.

[0042] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 15, and a light chain variable region having the amino acid sequence of SEQ ID NO: 16. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the second antigen-binding fragment is as shown in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 16.

[0043] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 having the amino acid sequence of SEQ ID NO:9, a HCDR2 having the amino acid sequence of SEQ ID NO:10, and a HCDR3 having the amino acid sequence of SEQ ID NO:11, the light chain variable region comprises a LCDR1 having the amino acid sequence of SEQ ID NO:12, a LCDR2 having the amino acid sequence of SEQ ID NO:13, and a LCDR3 having the amino acid sequence of SEQ ID NO:14, and the heavy chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:15, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:15, NO:16 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0044] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16 are located in the FR regions.

[0045] In some embodiments, the antigen-binding construct targeting HER2 may further comprise an immunoglobulin constant region, or a fragment, analog, variant, or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3, and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG4 heavy chains. In some embodiments, the light chain constant region is derived from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the C-terminal lysine of the heavy chain constant region may be present or absent, and deletion of the C-terminal lysine of the heavy chain constant region typically occurs during recombinant expression. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0046] In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: NO: 19 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a third polypeptide chain. In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 19. In some specific embodiments, the antigen-binding construct targeting HER2 consists of three polypeptide chains, wherein the amino acid sequence of the first polypeptide chain is as set forth in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as set forth in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as set forth in SEQ ID NO: 19.

[0047] In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 1, a HCDR2 having an amino acid sequence as shown in SEQ ID NO: 2, a HCDR3 having an amino acid sequence as shown in SEQ ID NO: 3, a LCDR1 having an amino acid sequence as shown in SEQ ID NO: 4, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 5, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 6; the second polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 9, a HCDR2 having an amino acid sequence as shown in SEQ ID NO: 10, and a HCDR3 having an amino acid sequence as shown in SEQ ID NO: 11; the third polypeptide chain comprises a LCDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 14, and the first polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 15, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 16, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 17. NO:17, the first polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:18, the second polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:19, the third polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:20 The amino acid sequence shown in NO:19 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0048] In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 17 is deleted, as shown in SEQ ID NO: 20. In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 18 is deleted, as shown in SEQ ID NO: 21. In some embodiments, the C-terminal lysine of the first and second polypeptide chains is deleted, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 20, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 21.

[0049] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence set forth in SEQ ID NO: 17, 18, 19, 20 or 21 are located in the FR region or the constant region.

[0050] In other embodiments, the antigen-binding construct targeting HER2 is selected from Expi Her2-1, Expi Her2-3, Expi Her2-4, Expi Her2-5, 23C2 Her2-1, 23C2 Her2-3, 23C2 Her2-4 or 23C2 Her2-5 (see WO2021219046 or CN115279791A). In other embodiments, the antigen-binding construct targeting HER2 is selected from Zanidatamab (ZW25), KN026, MBS301, KM257 or BCD-147.

[0051] The anti-HER2 antibody drug conjugate used in the present disclosure can also be represented by the structure shown in the following formula II:

[0052] Wherein, R1 and R2 in Formula II are independently selected from hydrogen or deuterium, and the antigen-binding construct targeting HER2 is as described above. In some embodiments, the drug-linker is connected to the antigen-binding construct targeting HER2 via a thioether bond (position 3 of -(succinimide-3-yl-N)-). In some embodiments, R1 and R2 are hydrogen. n has the same meaning as DAR and represents the average number of cytotoxic drug connections per antigen-binding construct targeting HER2. In some embodiments, n is 2 to 8. In some embodiments, n is 4 to 7. In some embodiments, n is 5 to 6. In some embodiments, n is 5.5 to 6. In some embodiments, n is 5.8 to 6.

[0053] The antibody drug conjugate preferably used in the present disclosure is formed by connecting a drug-linker having a structure shown in the following formula Ia to an antigen-binding construct targeting HER2:

[0054] in,

[0055] The 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2,

[0056] The antigen-binding construct targeting HER2 is composed of three polypeptide chains, the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17 or a variant thereof with a C-terminal lysine deleted, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18 or a variant thereof with a C-terminal lysine deleted, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19 (for example, the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19), and

[0057] For one HER2-targeting antigen-binding construct, the average number of drug-linker connections was 5 to 6.

[0058] In some embodiments, the 3-position of -(succinimidyl-3-yl-N)- in Formula Ia is linked to the antigen-binding construct targeting HER2 through a thioether bond.

[0059] The antibody drug conjugates preferably used in the present disclosure can also be represented by the structure shown in the following formula II:

[0060] Where n is 5 to 6,

[0061] The HER2-targeting antigen-binding construct is composed of three polypeptide chains, the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17 or a variant thereof with a C-terminal lysine deleted, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18 or a variant thereof with a C-terminal lysine deleted, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19 (for example, the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; (See SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19.) In some embodiments, the drug-linker is linked to the HER2-targeting antigen-binding construct via a thioether bond.

[0062] In other specific embodiments, the anti-HER2 antibody drug conjugates disclosed herein are selected from MRG002, ARX788, A166, SHR-A1811, BB-1701, SYD985, FS-1502, or BAT8001.

[0063] The anti-HER2 antibody-drug conjugates disclosed herein also include isomers, pharmaceutically acceptable salts, or solvates of the anti-HER2 antibody-drug conjugates, their isomers, or their pharmaceutically acceptable salts.

[0064] Technical Effects

[0065] Administration of the anti-HER2 antibody drug conjugates disclosed herein has one or more of the following effects:

[0066] (1) Producing benefits to breast cancer subjects, preferably early-stage breast cancer or locally advanced breast cancer;

[0067] (2) Good safety;

[0068] (3) well tolerated by subjects;

[0069] (4) It can show good efficacy in the neoadjuvant treatment of HER2-positive breast cancer.

[0070] Definition and Description

[0071] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product or its active ingredient.

[0072] As used herein, the structure of "-(succinimidyl-3-yl-N)-" is as follows:

[0073] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0074] Unless otherwise specified, when a group has a linkable site, the link between that site and other groups can be represented by a wavy line. express.

[0075] The term "antigen binding construct" refers to any agent capable of binding to an antigen, such as a polypeptide or polypeptide complex. In some aspects, an antigen binding construct is a polypeptide that specifically binds to a target antigen. An antigen binding construct can be a monomer, dimer, multimer, protein, peptide, protein or peptide complex, antibody, or antigen binding fragment thereof, etc. An antigen binding construct can be a monospecific, bispecific, or multispecific polypeptide construct. In some aspects, an antigen binding construct can include, for example, one or more antigen binding fragments (e.g., Fab or scFv) connected to one or more Fc.

[0076] The "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., HER2 protein). It has been demonstrated that the antigen-binding function of an antibody can be implemented by a fragment of a full-length antibody. Examples encompassed within the term "antigen-binding fragment" of an antibody include: (i) a Fab fragment: a monovalent fragment consisting of a VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of a VH and CH1 domain; (iv) an Fv fragment consisting of the VL and VH domains of a single-arm antibody; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341: 544-546 (1989)); and (vi) a nanobody, an antibody comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a linker, wherein VL and VH are paired to form a monovalent molecule called single-chain Fv (scFv) (see Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)), and these single-chain antibodies are also encompassed by the term antigen-binding fragment. These antibody fragments can be obtained by conventional techniques known to those skilled in the art, and the fragments can be functionally screened by the same method as full-length antibodies.

[0077] The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be aligned and, if necessary, introducing gaps to achieve maximum sequence identity, and not considering any conservative substitutions as part of sequence identity. The alignment of amino acid sequences for identity can be performed in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm needed to obtain maximum alignment over the full length of the comparison sequence.

[0078] The term "treating" means administering a compound of the present disclosure to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes but is not limited to:

[0079] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state;

[0080] (ii) inhibiting the disease or disease state, i.e., curbing its development;

[0081] (iii) alleviate the disease or condition, even if the disease or condition regresses;

[0082] (iv) reducing any direct or indirect pathological consequences of the disease or disease state.

[0083] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" may vary depending on factors such as the compound and its ability to elicit a desired response in a subject, the disease state and its severity, the route of administration, and the age, sex, and weight of the mammal to be treated.

[0084] "Neoadjuvant treatment" or "neoadjuvant therapy" means a therapy in which a therapeutic agent is administered to a subject before surgery.

[0085] The terms "administration," "administering," or "administering" refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0086] The route of administration of antibody drug conjugates (such as anti-HER2 antibody drug conjugates) includes intravenous, intramuscular, intraperitoneal, spinal column or other parenteral administration routes.Term used herein " parenteral administration " refers to, the mode of administration of the non-enteral administration carried out by injection usually, and includes but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, spinal column, epidural and intrasternal injection and infusion and in vivo electroporation.Administration can also be performed, for example, once, repeatedly, and / or in one or more extended time periods.

[0087] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0088] The term "pharmaceutically acceptable salt" refers to a salt of a compound (e.g., the antibody-drug conjugates of the present disclosure) that is safe and effective when used in mammals and has the desired biological activity. For example, the salt may be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, etc.

[0089] The term "excipient" refers to any ingredient other than the active ingredient (e.g., the antibody drug conjugate of the present disclosure). The choice of excipient will largely depend on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0090] The term "solvate" refers to an association of a compound with solvent molecules.

[0091] In the present disclosure, "HER2-positive" breast cancer is not particularly limited as long as it is recognized by those skilled in the art as breast cancer that overexpresses HER2. Preferably, it refers to breast cancer that is determined to have HER2 expression of 3+ (i.e., IHC 3+) as determined by immunohistochemistry (IHC), or / and breast cancer that is determined to have HER2 expression positive (i.e., ISH+) as determined by ISH. It should be noted that the in situ hybridization method of the present application includes fluorescence in situ hybridization (FISH) and dual-color in situ hybridization (DISH).

[0092] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "Subject," "patient," or "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject, patient, or subject is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0093] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients (e.g., the anti-HER2 antibody drug conjugates of the present disclosure) and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredients to a subject. As used herein, the terms "pharmaceutical composition" and "preparation" have the same meaning and are used interchangeably.

[0094] The words “comprise,” “comprise,” or “comprises,” and variations thereof such as comprises or comprising, should be construed in an open, non-exclusive sense, ie, “including but not limited to.”

[0095] Herein, singular terms encompass plural referents and vice versa unless the context clearly dictates otherwise.

[0096] As used herein, "about" means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, "about" can mean a range of up to ±5%, such as fluctuations within ±2%, within ±1%, or within ±0.5% of the specific numerical range given. When a specific value is given in the present disclosure or claims, unless otherwise indicated, the meaning of "about" should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise indicated, all values ​​for drug doses, times, step parameters, or conditions are modified by "about" by default.

[0097] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0098] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0099] Embodiment 1. A method for neoadjuvant treatment of breast cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate, wherein the anti-HER2 antibody drug conjugate is represented by Formula Ia

[0100] The drug-linker of the structure shown is connected to the antigen-binding construct targeting HER2.

[0101] R1 and R2 in formula Ia are independently selected from hydrogen or deuterium, preferably, R1 and R2 are hydrogen,

[0102] The 3-position of -(succinimide-3-yl-N)- is linked to an antigen-binding construct targeting HER2,

[0103] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0104] Embodiment 2. The method according to embodiment 1, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7.

[0105] Embodiment 3. The method according to embodiment 2, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5 to 6.

[0106] Embodiment 4. The method according to embodiment 3, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5.5 to 6.

[0107] Embodiment 5. The method according to any one of embodiments 1-4, wherein

[0108] (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:7;

[0109] (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0110] (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0111] (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 15;

[0112] (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16;

[0113] (vi) the second antigen-binding fragment comprises a heavy chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16; or

[0114] (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identical to SEQ ID NO: NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:16.

[0115] Embodiment 6. The method according to any one of embodiments 1-5, wherein

[0116] (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20;

[0117] (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21;

[0118] (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19;

[0119] (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0120] (v) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0121] (vi) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0122] (vii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of NO:19; or

[0123] (viii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: The invention also provides a method for preparing a polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in NO:19.

[0124] Embodiment 7. The method of any one of Embodiments 1-6, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0125] Embodiment 8. The method according to any one of embodiments 1-7, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg each time.

[0126] Embodiment 9. The method according to embodiment 8, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0127] Embodiment 10. The method according to any one of embodiments 1-9, wherein one treatment cycle is one week, one two weeks, one three weeks, or one four weeks, and the anti-HER2 antibody-drug conjugate is administered once per treatment cycle; preferably, one treatment cycle is one three weeks, and the anti-HER2 antibody-drug conjugate is administered once per treatment cycle.

[0128] Embodiment 11. The method according to any one of embodiments 1-10, wherein the anti-HER2 antibody drug conjugate is administered for a total of 6-8 treatment cycles, preferably, the anti-HER2 antibody drug conjugate is administered continuously or intermittently for 6-8 treatment cycles, preferably, a total of 6 treatment cycles or 8 treatment cycles.

[0129] Embodiment 12. The method according to any one of embodiments 1-11, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0130] Embodiment 13. The method of any one of Embodiments 1-12, wherein the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0131] Embodiment 14. The method of any one of Embodiments 1-13, wherein the breast cancer is early-stage or locally advanced breast cancer.

[0132] Embodiment 15. The method according to any one of Embodiments 1-14, wherein the breast cancer is invasive breast cancer, preferably unilateral invasive breast cancer.

[0133] Embodiment 16. The method of any one of Embodiments 1-15, wherein the breast cancer is HER2-expressing breast cancer.

[0134] Embodiment 17. The method of any one of Embodiments 1-16, wherein the breast cancer is HER2-positive breast cancer.

[0135] Embodiment 18. The method according to embodiment 17, wherein the HER2-positive breast cancer is a breast cancer whose HER2 expression is determined to be 3+ by IHC and / or a breast cancer whose HER2 expression is determined to be positive by ISH.

[0136] Embodiment 19. The method according to embodiment 17 or 18, wherein the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0137] Embodiment 20. The method of any one of Embodiments 1-19, wherein the breast cancer is hormone receptor-positive breast cancer.

[0138] Embodiment 21. The method according to embodiment 20, wherein the breast cancer is estrogen receptor and / or progesterone receptor positive breast cancer.

[0139] Embodiment 22. The method of any one of Embodiments 1-19, wherein the breast cancer is hormone receptor-negative breast cancer.

[0140] Embodiment 23. The method according to embodiment 22, wherein the breast cancer is estrogen receptor and / or progesterone receptor negative breast cancer.

[0141] Embodiment 24. The method of any one of Embodiments 1-13, wherein the breast cancer is HER2-positive early-stage or locally advanced breast cancer.

[0142] Embodiment 25. The method of any one of Embodiments 1-13, wherein the breast cancer is HER2-positive, hormone receptor-positive, early-stage or locally advanced breast cancer.

[0143] Embodiment 26. The method of any one of Embodiments 1-13, wherein the breast cancer is HER2-positive, hormone receptor-negative early or locally advanced breast cancer.

[0144] Embodiment 27. The method of any one of Embodiments 1-26, wherein the clinical stage of the breast cancer is T0 to T4, N1 to N3, and M0.

[0145] Embodiment 28. The method of any one of Embodiments 1-26, wherein the clinical stage of the breast cancer is T2 to T4, N0, and M0.

[0146] Embodiment 29. The method of any one of Embodiments 1-28, wherein the subject with breast cancer is suitable for surgical treatment after receiving neoadjuvant therapy.

[0147] Embodiment 30. The method of any one of Embodiments 1-29, wherein the subject with breast cancer has not previously received treatment for breast cancer.

[0148] Embodiment 31. The method of embodiment 30, wherein the subject with breast cancer has not previously received systemic therapy for breast cancer.

[0149] Embodiment 32. Use of an anti-HER2 antibody drug conjugate in the preparation of a drug for neoadjuvant treatment of breast cancer, wherein the anti-HER2 antibody drug conjugate is represented by the following formula Ia

[0150] The drug-linker of the structure shown is connected to the antigen-binding construct targeting HER2.

[0151] R1 and R2 in formula Ia are independently selected from hydrogen or deuterium, preferably, R1 and R2 are hydrogen,

[0152] The 3-position of -(succinimide-3-yl-N)- is linked to an antigen-binding construct targeting HER2,

[0153] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0154] Embodiment 33. The use according to embodiment 32, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7.

[0155] Embodiment 34. The use according to embodiment 33, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5 to 6.

[0156] Embodiment 35. The use according to embodiment 34, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5.5 to 6.

[0157] Embodiment 36. The use according to any one of embodiments 32-35, wherein

[0158] (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:7;

[0159] (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0160] (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0161] (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 15;

[0162] (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16;

[0163] (vi) the second antigen-binding fragment comprises a heavy chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16; or

[0164] (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identical to SEQ ID NO: NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:16.

[0165] Embodiment 37. The use according to any one of embodiments 32-36, wherein

[0166] (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20;

[0167] (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21;

[0168] (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19;

[0169] (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: A third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence of NO:19.

[0170] (v) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0171] (vi) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0172] (vii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of NO:19; or

[0173] (viii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: The invention also provides a method for preparing a polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in NO:19.

[0174] Embodiment 38. The use according to any one of embodiments 32-37, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0175] Embodiment 39. The use according to any one of Embodiments 32-37, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg each time.

[0176] Embodiment 40. The use according to embodiment 39, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0177] Embodiment 41. The use according to any one of Embodiments 32-40, wherein one treatment cycle is one week, one two weeks, one three weeks, or one four weeks, and the anti-HER2 antibody-drug conjugate is administered once per treatment cycle; preferably, one treatment cycle is one three weeks, and the anti-HER2 antibody-drug conjugate is administered once per treatment cycle.

[0178] Embodiment 42. The use according to any one of Embodiments 32-41, wherein the anti-HER2 antibody drug conjugate is administered for a total of 6-8 treatment cycles, preferably, the anti-HER2 antibody drug conjugate is administered continuously or intermittently for 6-8 treatment cycles, preferably, a total of 6 treatment cycles or 8 treatment cycles.

[0179] Embodiment 43. The use according to any one of Embodiments 32-42, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0180] Embodiment 44. The use according to any one of Embodiments 32-43, wherein the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0181] Embodiment 45. The use according to any one of embodiments 32-44, wherein the breast cancer is early-stage or locally advanced breast cancer.

[0182] Embodiment 46. The use according to any one of Embodiments 32-45, wherein the breast cancer is invasive breast cancer, preferably unilateral invasive breast cancer.

[0183] Embodiment 47. The use according to any one of Embodiments 32-46, wherein the breast cancer is HER2-expressing breast cancer.

[0184] Embodiment 48. The use according to any one of Embodiments 32-47, wherein the breast cancer is HER2-positive breast cancer.

[0185] Embodiment 49. The use according to embodiment 48, wherein the HER2-positive breast cancer is breast cancer whose HER2 expression is 3+ as determined by IHC and / or breast cancer whose HER2 expression is positive as determined by ISH.

[0186] Embodiment 50. The use according to embodiment 48 or 49, wherein the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0187] Embodiment 51. The use according to any one of embodiments 32-50, wherein the breast cancer is hormone receptor-positive breast cancer.

[0188] Embodiment 52. The use according to embodiment 51, wherein the breast cancer is estrogen receptor and / or progesterone receptor positive breast cancer.

[0189] Embodiment 53. The use according to any one of embodiments 32-50, wherein the breast cancer is hormone receptor-negative breast cancer.

[0190] Embodiment 54. The use according to embodiment 53, wherein the breast cancer is estrogen receptor and / or progesterone receptor negative breast cancer.

[0191] Embodiment 55. The use according to any one of embodiments 32-44, wherein the breast cancer is HER2-positive early-stage or locally advanced breast cancer.

[0192] Embodiment 56. The use according to any one of embodiments 32-44, wherein the breast cancer is HER2-positive, hormone receptor-positive early or locally advanced breast cancer.

[0193] Embodiment 57. The use according to any one of Embodiments 32-44, wherein the breast cancer is HER2-positive, hormone receptor-negative early or locally advanced breast cancer.

[0194] Embodiment 58. The use according to any one of embodiments 32-57, wherein the clinical stage of the breast cancer is T0 to T4, N1 to N3 and M0.

[0195] Embodiment 59. The use according to any one of Embodiments 32-57, wherein the clinical stage of the breast cancer is T2 to T4, N0 and M0.

[0196] Embodiment 60. The use according to any one of embodiments 32-59, wherein the subject with breast cancer is a subject who is suitable for surgical treatment after receiving neoadjuvant therapy.

[0197] Embodiment 61. The use according to any one of Embodiments 32-60, wherein the subject with breast cancer has not previously received treatment for breast cancer.

[0198] Embodiment 62. The use according to embodiment 61, wherein the subject with breast cancer has not previously received systemic treatment for breast cancer. Example

[0199] For the purpose of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure.

[0200] The entire contents of the patent application documents WO2022033578 or CN115702008A are incorporated into the present disclosure. In the following examples, the anti-HER2 antibody drug conjugates were prepared by referring to the preparation method described in WO2022033578 to prepare the anti-HER2 antibody drug conjugate (hereinafter referred to as ADC1) represented by the following formula:

[0201] The drug-linker is connected to the HER2-targeting antigen-binding construct via a thioether bond, and n is 5 to 6. Briefly, the nucleic acid sequences encoding the three polypeptide chains of the HER2-targeting antigen-binding construct (amino acid sequences are shown in SEQ ID NOs: 17, 18, and 19, or SEQ ID NOs: 20, 21, and 19, respectively) are cloned into the pcDNA3.1 expression vector, co-transfected into FUT8-knockout CHO-S cells for expression, and purified by protein A to prepare the HER2-targeting antigen-binding construct. The HER2-targeting antigen-binding construct is treated with tris(2-carboxyethyl)phosphine hydrochloride and then reacted with a linker-payload selected from the structure shown in the following formula to ultimately obtain ADC1:

[0202] Example 1: Clinical trial of HER2-expressing breast cancer

[0203] 1. Research objectives:

[0204] 1.1 Main Purpose:

[0205] To evaluate the effectiveness of ADC1 in the neoadjuvant treatment of HER2-positive breast cancer.

[0206] 1.2 Secondary Purpose:

[0207] To evaluate the safety and immunogenicity of ADC1 in the neoadjuvant treatment of HER2-positive breast cancer;

[0208] 2. Trial subjects: Subjects with early or locally advanced HER2-positive breast cancer

[0209] 3. Selection criteria

[0210] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0211] (1) The subjects voluntarily participated in this study, signed the informed consent form, and had good compliance;

[0212] (2) Age: 18-75 years old (at the time of signing the informed consent); ECOG score: 0-1; expected survival time more than 3 months;

[0213] (3) Subjects with invasive breast cancer confirmed by histopathology who have not received any systemic anti-tumor treatment for breast cancer;

[0214] (4) confirmed to be HER2 positive (referring to the 2018 ASCO / CAP HER2 testing guidelines, HER2 positive is defined as: immunohistochemistry result 3+ or FISH double probe positive);

[0215] (5) HR was confirmed to be positive or negative (referring to the 2020 edition of the ASCO / CAP guidelines, HR positive includes ER positive and / or PR positive, that is, the proportion of positively stained tumor cells in all tumor cells ≥1%);

[0216] (6) clinical stage at presentation was T0-4, N1-3, M0 or T2-4, N0, M0 (determined according to the 8th edition of the AJCC breast cancer staging system);

[0217] (7) The subjects agreed to undergo breast cancer resection when they met the surgical criteria after neoadjuvant treatment;

[0218] (8) The major organs function well and meet the standards of routine blood tests, biochemical tests, coagulation function tests, and cardiac ultrasound assessment;

[0219] (9) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study enrollment, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0220] 4. Trial Drugs

[0221] ADC1 for injection (specification: 100 mg / bottle) is developed and provided by Nanjing Shunxin Pharmaceutical Co., Ltd. of Zhengda Tianqing Pharmaceutical Group.

[0222] 5. Treatment options

[0223] ADC1 was administered intravenously every 3 weeks, with each 3-week (21-day) treatment cycle consisting of one treatment cycle. Cohort 1 received 6 mg / kg for 6 cycles, cohort 2 received 6 mg / kg for 8 cycles, cohort 3 received 7.5 mg / kg for 6 cycles, and cohort 4 received 7.5 mg / kg for 8 cycles. Each cohort enrolled 26 patients.

[0224] Dosing schedules for the four cohorts can be adjusted based on disease severity, disease response, any treatment-related toxicities, and the patient's age and health status.

[0225] 6. Evaluation Criteria

[0226] Effectiveness evaluation: RECIST 1.1 criteria were used to determine the disease status.

[0227] Safety evaluation: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0228] 7. Endpoint indicators

[0229] Primary endpoint: Overall pathological complete response (tpCR) rate

[0230] Secondary endpoints: breast pathological complete response (bpCR) rate, objective response rate (ORR), event-free survival (EFS), invasive cancer-free survival (IDFS), overall survival (OS), etc.

[0231] 8. Results

[0232] 8.1 ORR (Preoperative Evaluation):

[0233] ORR was calculated for subjects in cohorts 1-4 who completed or were undergoing neoadjuvant therapy.

[0234] The 6 mg / kg group (cohort 1 + cohort 2) was 100% (52 / 52); the 7.5 mg / kg group is currently undergoing statistics and is expected to achieve an ORR result substantially equivalent to that of the 6 mg / kg group.

[0235] 8.2 tpCR (postoperative evaluation):

[0236] As of the clinical data collection date, for evaluable cases, the number of subjects who achieved tpCR and the tpCR rate were counted. (Because some patients were still in the neoadjuvant treatment stage and had not yet undergone breast cancer resection surgery, the total number of evaluable cases in each cohort was less than the number of patients enrolled in each cohort.)

[0237] As can be seen from the above table, for patients in cohort 1, a tpCR of approximately 58.3% can be achieved after 6 cycles of administration at a dose of 6 mg / kg; for patients in cohort 2, a tpCR of 80% can be achieved after 8 cycles of administration at a dose of 6 mg / kg.

[0238] The results showed that ADC1 can show good efficacy in the neoadjuvant treatment of early or locally advanced HER2-positive breast cancer; at the same time, ADC1 can show good safety in clinical practice.

Claims

1. An anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject, wherein: The anti-HER2 antibody drug conjugate is represented by the following formula Ia The drug-linker of the structure shown is connected to an antigen-binding construct targeting HER2, R1 and R2 in Formula Ia are independently selected from hydrogen or deuterium, preferably, R1 and R2 are hydrogen, The 3-position of -(succinimidyl-3-yl-N)- is linked to an antigen-binding construct targeting HER2, The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, The first antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, The second antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

14.

2. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to claim 1, wherein The average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7, 5 to 6, or 5.5 to 6.

3. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to claim 1 or 2, wherein: (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:7; (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:8; (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8; (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:15; (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:16; (vi) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16; or (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:

8. NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:

16.

4. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 3, wherein: (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 17 or 20; (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21; (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19; (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence of NO:19; (v) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:

19. a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence of NO:19; (vi) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:

22. a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence of NO:19; (vii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:

22. A third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence of NO:19; or (viii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:

19. The amino acid sequence shown in NO:19 has a third polypeptide chain that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

5. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 4, wherein: The anti-HER2 antibody drug conjugate is administered to the subject at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered to the subject at a dose of 6-7.5 mg / kg each time; or the anti-HER2 antibody drug conjugate is administered to the subject at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time.

6. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 5, wherein: One treatment cycle is one week, one two weeks, one three weeks, or one four weeks, and the anti-HER2 antibody-drug conjugate is administered once in each treatment cycle; preferably, one treatment cycle is one three weeks, and the anti-HER2 antibody-drug conjugate is administered once in each treatment cycle.

7. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 6, wherein: The anti-HER2 antibody drug conjugate is administered for a total of 6-8 treatment cycles, preferably, for a total of 6 treatment cycles or 8 treatment cycles.

8. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 7, wherein: The anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

9. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 8, wherein: The breast cancer is early-stage or locally advanced breast cancer; and / or The breast cancer is invasive breast cancer, preferably unilateral invasive breast cancer.

10. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 9, wherein: The breast cancer is HER2-expressing breast cancer; The breast cancer is HER2-positive breast cancer; and / or The breast cancer is hormone receptor positive or negative breast cancer.

11. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to claim 10, wherein: The HER2-positive breast cancer is a breast cancer in which the expression of HER2 is 3+ as determined by IHC and / or a breast cancer in which the expression of HER2 is positive as determined by ISH, or the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is 2+ as determined by IHC and the expression of HER2 is positive as determined by ISH; Preferably, the breast cancer is estrogen receptor or / and progesterone receptor positive breast cancer; or the breast cancer is estrogen receptor and progesterone receptor negative breast cancer.

12. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 11, wherein: The breast cancer is HER2-positive early or locally advanced breast cancer; The breast cancer is HER2-positive, hormone receptor-positive early-stage or locally advanced breast cancer; or The breast cancer is HER2-positive, hormone receptor-negative early or locally advanced breast cancer.

13. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 12, wherein: The clinical stage of the breast cancer is T0 to T4, N1 to N3 and M0; or The clinical stage of the breast cancer is T2 to T4, N0 and M0.

14. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 13, wherein: The breast cancer subject is suitable for surgical treatment after receiving neoadjuvant therapy; Optionally, The subject with breast cancer has not received treatment for breast cancer before; preferably, the subject with breast cancer has not received systemic treatment for breast cancer before.

15. The anti-HER2 antibody drug conjugate for neoadjuvant treatment of breast cancer in a subject according to any one of claims 1 to 14, wherein: The anti-HER2 antibody-drug conjugate is formulated into a pharmaceutical composition together with one or more pharmaceutically acceptable excipients, and the pharmaceutical composition contains a therapeutically effective amount of the anti-HER2 antibody-drug conjugate.