Anti-HER2 antibody drug conjugate combined with anti-HER2 antibody for treating tumors

Abstract

The present disclosure relates to treatment of tumors with an anti-HER2 antibody drug conjugate in combination with an anti-HER2 antibody. Specifically, the invention relates to an application of an antibody drug conjugate combined with an antigen binding protein combined with HER2 in preparation of drugs for treating tumors, and the structure of the antibody drug conjugate is as shown in formula (I). # imgabs0 #

Description

[0001] This disclosure claims the Chinese patent application filed on September 11, 2023, with application number CN202311164553.6, which is incorporated into this disclosure by reference. Technical Field

[0002] The present invention belongs to the field of medicine and relates to the use of an anti-HER2 antibody-drug conjugate (ADC) in combination with an antigen binding protein that binds to HER2 in the preparation of a drug for treating tumors. Background Art

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

[0004] ADCs targeting HER2 work in the following ways: first, the antibody in the ADC specifically recognizes and binds to the HER2 receptor on the surface of the target cell, then enters the target cell through endocytosis, and releases the cytotoxic drug after decomposition inside the cell. Finally, the cytotoxic drug induces cell apoptosis by damaging DNA or acting on tubulin, thereby exerting an anti-tumor effect. If the cytotoxic drug has high membrane permeability, it may penetrate into the extracellular space after being released in the target cell, killing the surrounding HER2-negative cells. This effect is called the bypass killing effect. If the cytotoxic drug is released before the ADC endocytosis occurs, this effect may also occur. WO2020063676A discloses a class of ADCs targeting HER2. In view of the excellent effects of the approved HER-2 ADC drugs Trastuzumab emtansine (TDM-1) and Trastuzumab Deruxtecan (DS-8201) in the treatment of breast cancer and gastric cancer, it is of great significance to study the indications of the antibody-drug conjugates in WO2020063676A. Summary of the invention

[0005] The present disclosure provides uses and methods of treating tumors by combining an antibody drug conjugate with an antigen binding protein that binds to HER2.

[0006] In one aspect, the present disclosure provides use of an antibody drug conjugate in combination with an antigen binding protein that binds to HER2 in the preparation of a drug for treating tumors.

[0007] In another aspect, the present disclosure provides use of a combination of an antibody drug conjugate and an antigen binding protein that binds to HER2 in the preparation of a medicament for treating tumors.

[0008] In yet another aspect, the present disclosure provides a pharmaceutical composition or combination comprising an antibody drug conjugate, and an antigen binding protein that binds to HER2.

[0009] In yet another aspect, the present disclosure provides use of a pharmaceutical composition or combination in preparing a medicament for treating a tumor.

[0010] In yet another aspect, the present disclosure provides an antibody drug conjugate for use in treating a subject having a tumor; wherein the subject is also treated with an antigen binding protein that binds to HER2.

[0011] In yet another aspect, the present disclosure provides a combination of an antibody drug conjugate and an antigen binding protein that binds to HER2 for use in treating a subject having a tumor.

[0012] In yet another aspect, the present disclosure provides a method of treating a subject having a tumor, comprising administering to the subject an antibody drug conjugate and an antigen binding protein that binds to HER2.

[0013] In some embodiments, the tumor is selected from breast cancer, gastric cancer, esophageal gastric junction cancer, colorectal cancer, or non-small cell lung cancer.

[0014] In some embodiments, the tumor is breast cancer.

[0015] In some embodiments, the tumor is HER2-positive breast cancer.

[0016] In some embodiments, the tumor is HER2-positive recurrent, unresectable and / or metastatic breast cancer. For example, HER2-positive recurrent or metastatic breast cancer, HER2-positive unresectable or metastatic breast cancer.

[0017] In some embodiments, the "HER2 positive" refers to immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive, that is, IHC3+ or ISH+.

[0018] In some embodiments, the tumor is HER2-positive recurrent or metastatic breast cancer, HER2-positive unresectable or metastatic breast cancer; and the subject with the tumor has not received systemic anti-tumor treatment at the recurrent or metastatic stage.

[0019] In some embodiments, the tumor is HER2-positive recurrent or metastatic breast cancer, HER2-positive unresectable or metastatic breast cancer; and the subject with the tumor has received trastuzumab and at least one line of chemotherapy at the recurrent or metastatic stage.

[0020] The method of determining the positivity or negativity of HER2 expression by histology or cytology, or the method of scoring the degree of HER2 expression is not particularly limited as long as it is recognized by those skilled in the art.

[0021] Antibody Drug Conjugates

[0022] In some embodiments, the structure of the antibody drug conjugate is as shown in formula (I):

[0023]

[0024] in:

[0025] n is 3 to 8, and n is a decimal or an integer;

[0026] Pc is a first anti-HER2 antibody or an antigen-binding fragment thereof. In some embodiments, n is an integer or decimal of 5.3-6.4.

[0027] In some embodiments, the first HER2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 1-3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NOs: 4-6.

[0028] Among them, the CDR sequences mentioned above are shown in Table 1 below:

[0029] Table 1. CDR sequences of the first anti-HER2 antibody (Kabat scheme)

[0030] Antibody sequence HCDR1 DTYIH (SEQ ID NO: 1) HCDR2 RIYPTNGYTRYADSVKG (SEQ ID NO: 2) HCDR3 WGGDGFYAMDY (SEQ ID NO: 3) LCDR1 RASQDVNTAVA (SEQ ID NO: 4) LCDR2 SASFLYS (SEQ ID NO: 5) LCDR3 QQHYTTPPT (SEQ ID NO: 6)

[0031] In some embodiments, the first anti-HER2 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, or a combination of any 2, 3, 4, 5 or 6 thereof.

[0032] In some embodiments, the first anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the VH comprises HCDR1, HCDR2 and HCDR3 in the amino acid sequence shown in SEQ ID NO: 7, and the VL comprises LCDR1, LCDR2 and LCDR3 in the amino acid sequence shown in SEQ ID NO: 8. The above CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact definition schemes. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.

[0033] In some embodiments, the first anti-HER2 antibody is a chimeric, humanized, fully human antibody or an antigen-binding fragment thereof.

[0034] In some embodiments, the first anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in SEQ ID NO: 7, or at least 80%, 90% identical thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8, or at least 80%, 90% identical thereto.

[0035] Heavy chain variable region:

[0036] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0037] SEQ ID NO: 7;

[0038] Light chain variable region:

[0039] DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYS GVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

[0040] SEQ ID NO: 8;

[0041] In some embodiments, the first anti-HER2 antibody comprises any one or both of the aforementioned VH and VL.

[0042] In some embodiments, the first anti-HER2 antibody further comprises a heavy chain constant region and / or a light chain constant region. Wherein, the heavy chain constant region of the antibody can be selected from the constant region of human IgG1, IgG2, IgG3, IgG4 and variants thereof. In some embodiments, the light chain constant region can be selected from the light chain constant region of human κ, λ chain or variants thereof.

[0043] In some embodiments, the first anti-HER2 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO:9, or having at least 80%, at least 90% sequence identity thereto; and / or the light chain comprises an amino acid sequence as shown in SEQ ID NO:10, or having at least 80%, at least 90% identity thereto.

[0044] In some embodiments, the first anti-HER2 antibody comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO:9, and a light chain having an amino acid sequence as shown in SEQ ID NO:10.

[0045] Heavy chain sequence of the first anti-HER2 antibody:

[0046] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFT ISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0047] SEQ ID NO: 9;

[0048] Light chain sequence of the first anti-HER2 antibody:

[0049] DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGT DFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0050] SEQ ID NO: 10;

[0051] Note: The underlined part is the variable region sequence of the antibody heavy chain or light chain, and the ununderlined part is the antibody constant region sequence.

[0052] In some embodiments, the first anti-HER2 antibody is selected from Trastuzumab or an antigen-binding fragment thereof, Pertuzumab or an antigen-binding fragment thereof.

[0053] In some embodiments, the first anti-HER2 antibody is Trastuzumab.

[0054] In some embodiments, the antibody drug conjugates described in the present disclosure have a structure as shown in the following formula:

[0055]

[0056] Wherein, n is 3 to 8, and n is a decimal or an integer. In some embodiments, n is an integer or a decimal of 5.3-6.4. In an optional embodiment, n is 6 in the antibody drug conjugate described in the present disclosure.

[0057] In some embodiments, the dosage of the antibody drug conjugates described in the present disclosure is about 1.0 mg / kg to about 10.0 mg / kg. In optional embodiments, the dosage of the antibody drug conjugates described in the present disclosure is about 1.0 mg / kg, about 1.2 mg / kg, about 1.4 mg / kg, about 1.6 mg / kg, about 1.8 mg / kg, about 2.0 mg / kg, about 2.2 mg / kg, about 2.4 mg / kg, about 2.6 mg / kg, about 2.8 mg / kg, about 3.0 mg / kg, about 3.2 mg / kg, about 3.4 mg / kg, about 3.6 mg / kg, about 3.8 mg / kg, about 4.0 mg / kg, about 4.2 mg / kg, about 4.4 mg / kg, about 4.6 mg / kg, about 4.8 mg / kg, about 5.0 mg / kg, about 5.2 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 5.8 mg / kg, about 6.0 mg / kg, about 6.2 mg / kg, about 6.4 mg / kg, about 6.6 mg / kg, about 6.8 mg / kg, about 7.0 mg / kg, about 7.2 mg / kg, about 7.4 mg / kg, about 7.6 mg / kg, about 7.8 mg / kg, about 8.0 mg / kg, about 8.2 mg / kg, about 8.4 mg / kg, about 8.6 mg / kg, about 8.8 mg / kg, about 9.0 mg / kg, about 9.2 mg / kg, about 9.4 mg / kg, about 9.6 mg / kg, about 9.8 mg / kg or about 10.0 mg / kg. In alternative embodiments, the dosage of the antibody drug conjugates disclosed herein is about 1.0 mg / kg, about 2.0 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg.

[0058] In some embodiments, the antibody drug conjugates described in the present disclosure are administered at least once a week, at least once every two weeks, at least once every three weeks, at least once every four weeks, or at least once every six weeks. In an optional embodiment, the administration frequency is once a week, once every two weeks, once every three weeks, or once every four weeks. In an optional embodiment, the administration frequency is once every two weeks or once every three weeks.

[0059] In optional embodiments, the dosage of the anti-HER2 antibody drug conjugate described in the present disclosure is about 1.0 mg / kg, 2.0 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or 8.0 mg / kg, and the administration frequency is once every two weeks or once every three weeks.

[0060] In an optional embodiment, the single dosage of the antibody drug conjugate is about 1.0 mg / kg, and the administration frequency is once every three weeks.

[0061] In an optional embodiment, the single dosage of the antibody drug conjugate is about 2.0 mg / kg, and the administration frequency is once every three weeks.

[0062] In an optional embodiment, the single dosage of the antibody drug conjugate is about 3.2 mg / kg, and the administration frequency is once every three weeks.

[0063] In an optional embodiment, the single dosage of the antibody drug conjugate is about 4.8 mg / kg, and the administration frequency is once every three weeks.

[0064] In an optional embodiment, the single dosage of the antibody drug conjugate is about 6.4 mg / kg, and the administration frequency is once every three weeks.

[0065] In an optional embodiment, the single dosage of the antibody drug conjugate is about 8.0 mg / kg, and the administration frequency is once every three weeks.

[0066] Antigen binding protein that binds to HER2

[0067] In some embodiments, the antigen binding protein combined with HER2 is selected from the second anti-HER2 antibody or its antigen binding fragment. In some embodiments, the second HER2 antibody or its antigen binding fragment is selected from Trastuzumab or its antigen binding fragment, Pertuzumab or its antigen binding fragment.

[0068] In some embodiments, the first anti-HER2 antibody and the second anti-HER2 antibody are the same antibody; in some embodiments, the HER2 antibody and the second anti-HER2 antibody are different antibodies, for example, the CDR sequences, VH or VL sequences, heavy chain or light chain sequences of the two are different.

[0069] In some embodiments, the antigen binding protein that binds to HER2 is selected from Pertuzumab or an antigen binding fragment thereof.

[0070] In some embodiments, the antigen binding protein that binds to HER2 is administered at a dose of about 100 mg to about 1000 mg; for example, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 840 mg, about 100 mg to about 700 mg, about 100 mg to about 750 mg, about 100 mg to about 650 mg, about 100 mg to about 600 mg, about 100 mg to about 550 mg, about 100 mg to about 500 mg, about 100 mg to about 420 mg. 0 mg, about 100 mg to about 350 mg, about 200 mg to about 840 mg, about 200 mg to about 900 mg, about 200 mg to about 750 mg, about 200 mg to about 700 mg, 200 mg to about 650 mg, 200 mg to about 600 mg, 200 mg to about 550 mg, 200 mg to about 500 mg, about 400 mg to about 900 mg, about 400 mg to about 850 mg, about 420 mg to about 840 mg, or any range therebetween, or any range therebetween.

[0071] In some embodiments, the dosage of the antigen binding protein bound to HER2 includes an initial dose and a maintenance dose. The initial dose is selected from about 600 mg to about 1000 mg, and the maintenance dose is selected from about 200 mg to about 600 mg. In some embodiments, the initial dose is selected from about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 950 mg, about 1000 mg. In some embodiments, the maintenance dose is selected from about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 550 mg, and about 600 mg.

[0072] In some specific embodiments, the initial dose of the antigen binding protein that binds to HER2 is about 840 mg, and the maintenance dose is about 420 mg.

[0073] In some embodiments, the frequency of administration of the antigen binding protein that binds to HER2 is at least once a week, at least once every two weeks, at least once every three weeks, at least once every four weeks, or at least once every six weeks. In an optional embodiment, the frequency of administration is once a week, once every two weeks, once every three weeks, or once every four weeks. In an optional embodiment, the frequency of administration is once every two weeks or once every three weeks.

[0074] In some embodiments, the antigen binding protein that binds to HER2 is administered in the following dosage regimen: an initial dose of the antigen binding protein that binds to HER2 is administered on the first day of the treatment cycle, and then the antigen binding protein that binds to HER2 is administered once every three weeks at a maintenance dose. In some specific embodiments, the initial dose is preferably about 840 mg, and the maintenance dose is preferably about 420 mg.

[0075] In some embodiments, the administration regimen of the antibody drug conjugate combined with the antigen binding protein that binds to HER2 is selected from:

[0076] (a1) the dosage of the antibody drug conjugate is about 1.0 mg / kg to about 10.0 mg / kg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks;

[0077] The dosage of the antigen binding protein that binds to HER2 is about 100 mg to about 1000 mg, and the frequency of administration is once a week, once every two weeks, once every three weeks, or once every four weeks;

[0078] (a2) the dosage of the antibody drug conjugate is about 1.0 mg / kg to about 10.0 mg / kg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks;

[0079] The dosage of the antigen-binding protein that binds to HER2 includes an initial dose and a maintenance dose, wherein the initial dose is selected from about 600 mg to about 1000 mg, and the maintenance dose is selected from about 200 mg to about 600 mg; the frequency of administration of the antigen-binding protein that binds to HER2 is once a week, once every two weeks, once every three weeks, or once every four weeks;

[0080] (a3) the dosage of the antibody drug conjugate is about 1.0 mg / kg, about 2.0 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg; the frequency of administration is once a week, once every two weeks, once every three weeks or once every four weeks;

[0081] The dosage of the antigen-binding protein that binds to HER2 includes an initial dose and a maintenance dose, the initial dose is about 840 mg, and the maintenance dose is about 420 mg; the frequency of administration of the antigen-binding protein that binds to HER2 is once a week, once every two weeks, once every three weeks, or once every four weeks;

[0082] (a4) the dosage of the antibody drug conjugate is about 1.0 mg / kg, about 2.0 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg; the administration frequency is once every two weeks, or once every three weeks;

[0083] The dosage of the antigen-binding protein that binds to HER2 includes an initial dose and a maintenance dose, the initial dose is about 840 mg, and the maintenance dose is about 420 mg; the frequency of administration of the antigen-binding protein that binds to HER2 is once every two weeks, or once every three weeks;

[0084] (a5) the dosage of the antibody drug conjugate is about 1.0 mg / kg, about 2.0 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg; the administration frequency is once every three weeks;

[0085] An initial dose of the antigen-binding protein that binds to HER2 is administered on the first day of the treatment cycle, and then the antigen-binding protein that binds to HER2 is administered once every three weeks at a maintenance dose, wherein the initial dose is about 840 mg and the maintenance dose is about 420 mg.

[0086] In some embodiments, the administration route of the antibody drug conjugate can be oral administration, parenteral administration, or transdermal administration, wherein the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the administration route of the antibody drug conjugate is intravenous injection.

[0087] In some embodiments, the antibody drug conjugate is configured in an injectable form. Exemplarily, the injectable form of the antibody drug conjugate is an injection solution or a lyophilized powder injection, which comprises the antibody drug conjugate and one or more pharmaceutically acceptable excipients.

[0088] In some embodiments, the order of administration of the antibody drug conjugate and the antigen binding protein that binds to HER2 is: antibody drug conjugate, antigen binding protein that binds to HER2.

[0089] In the present disclosure, the so-called "combination" is a mode of administration, which includes various situations in which two drugs are administered successively or simultaneously. The modes of administration of simultaneous administration, independent preparation and co-administration, or independent preparation and sequential administration all belong to the combined administration described in the present disclosure. The so-called "simultaneous" here refers to the administration of at least one dose of antigen-binding protein and antibody-drug conjugate bound to HER2 within a certain time limit, for example, within 2 days, or within 1 day, where both drugs show pharmacological effects. The so-called "sequential" administration includes the situation in which the antigen-binding protein and antibody-drug conjugate bound to HER2 are respectively administered in different administration cycles. The time limit can be within a dosing cycle, and can be selected within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 24 hours, and within 2 hours. This time limit includes such treatment, in which the antigen-binding protein and antibody-drug conjugate bound to HER2 are administered by the same administration route or different administration routes.

[0090] In some embodiments, the treatment cycle is every two weeks, every three weeks, or every four weeks, for example, every three weeks.

[0091] the term

[0092] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure belongs.

[0093] The present disclosure introduces all the contents of applications WO2020063676A and WO2021190581A into the present application.

[0094] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including, but not limited to,".

[0095] "About" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by a person of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" may mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially including" may mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each case in which a number or numerical range is preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially including" should be assumed to be within an acceptable error range for that specific value.

[0096] "Antibody drug conjugate (ADC)" is to connect antibodies or antibody fragments with biologically active cytotoxins or small molecule drugs with cell-killing activity through stable chemical linker compounds, making full use of the antibody's specificity for tumor cell-specific or highly expressed antigens and the high efficiency of cytotoxins to avoid toxic side effects on normal cells. Compared with traditional chemotherapy drugs, antibody drug conjugates can accurately bind to tumor cells and reduce the impact on normal cells.

[0097] As used herein, the term "antibody" is used in the broadest sense, covering various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. Antibodies may refer to immunoglobulins, which are tetrapeptide chain structures formed by two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of the heavy chain of immunoglobulins are different, so their antigenicity is also different. Based on this, immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain, respectively. The same class of Ig can be divided into different subclasses according to the difference in the amino acid composition of its hinge region and the number and position of the heavy chain disulfide bonds, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4. Light chains are divided into κ chains or λ chains by different constant regions. Each of the five types of Ig can have a kappa chain or a lambda chain. The sequences of about 110 amino acids near the N-terminus of the antibody heavy chain and light chain vary greatly, which is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable, which is the constant region (C region). The variable region includes three hypervariable regions (CDRs) and four relatively conservative framework regions (FRs). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDR regions and four FR regions, arranged in the order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0098] The "antibody or its antigen binding" or "functional fragment" described in the present disclosure refers to the Fab fragment, Fab' fragment, F(ab')2 fragment, and the Fv fragment scFv fragment that binds to the antibody, which has antigen binding activity. The Fv fragment contains the antibody heavy chain variable region and light chain variable region, but has no constant region, and is the smallest antibody fragment with all antigen binding sites. Generally, the Fv antibody also contains a polypeptide linker between the VH and VL domains, and is capable of forming the structure required for antigen binding. Two antibody variable regions can also be connected into a polypeptide chain using different connectors, which is called a single chain antibody or single chain Fv (sFv).

[0099] The term "drug loading" refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the molecule of formula (I), and can also be expressed as the ratio of the amount of drug to the amount of antibody. The range of drug loading can be 0-12, for example, selected from 1-10, selected from 3-8, selected from 5.3-6.4 cytotoxic drugs (D) connected to each antibody or antigen-binding fragment thereof (Pc). In the embodiments of the present disclosure, the drug loading is expressed as n, which can be exemplified as the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. The average number of drugs per ADC molecule after the coupling reaction can be identified by conventional methods such as UV / visible light spectroscopy, mass spectrometry, ELISA experiments and HPLC characteristics.

[0100] In one embodiment of the present disclosure, the cytotoxic drug is coupled to the N-terminal amino group, the ε-amino group of the lysine residue and / or the thiol group of the antibody or its antigen-binding fragment through a linker. Generally, the number of drug molecules that can be coupled to the antibody in the coupling reaction will be less than the theoretical maximum value.

[0101] The loading of cytotoxic drugs can be controlled by the following non-limiting methods, including:

[0102] (1) Control the molar ratio of the linking reagent and the monoclonal antibody,

[0103] (2) Control the reaction time and temperature,

[0104] (3) Select different reaction reagents.

[0105] The preparation of conventional pharmaceutical compositions is described in the Chinese Pharmacopoeia.

[0106] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. "Administering" and "treating" can refer to, for example, treatment, pharmacokinetics, diagnosis, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic, a combination composition, or by another cell. "Treatment" as applied to humans, veterinary medicine, or research subjects refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0107] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or inhibit the development of such symptoms to any clinically measurable degree. The amount of therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") may vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the disease symptom has been alleviated can be evaluated by any clinical test method commonly used by physicians or other professional health care personnel to evaluate the severity or progression of the symptom. Although embodiments of the present disclosure (e.g., treatment methods or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0108] An "effective amount" includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical disease. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's general health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0109] In the anti-HER2 antibody drug conjugate of the present disclosure, "n" refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the antibody drug conjugate molecule, and can also be expressed as the ratio of the amount of drug to the amount of antibody, which is the average number of drugs per ADC molecule after the coupling reaction is identified by hydrophobic chromatography (HIC) mass spectrometry. DETAILED DESCRIPTION

[0110] The present disclosure is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples of the present disclosure that do not specify specific conditions are usually carried out under conventional conditions, such as the Antibody Technology Laboratory Manual and the Molecular Cloning Manual published by the Cold Spring Harbor Laboratory; or under the conditions recommended by the raw material or product manufacturer. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0111] Example 1. Preparation of anti-HER2 antibody drug conjugates

[0112] According to the production method described in WO2021190581A, Trastuzumab (anti-HER2 antibody) and exotecan analogs were used to prepare an anti-HER2 antibody drug conjugate shown in the following structure, where n is 5.3-6.4.

[0113]

[0114] The following is the sequence of Trastuzumab:

[0115] Light chain

[0116] DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0117] SEQ ID NO: 10

[0118] Heavy chain

[0119] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0120] SEQ ID NO: 9

[0121] Example 2. Safety, tolerability and efficacy study of anti-HER2 antibody drug conjugate combined with pertuzumab in the treatment of HER2-positive unresectable or metastatic breast cancer

[0122] 1. Experimental drugs

[0123] 1) Anti-HER2 antibody drug conjugate prepared in Example 1; dosage form: injection (lyophilized powder); specification: 100 mg / bottle.

[0124] 2) Pertuzumab; Dosage form: injection; Specification: 420 mg (14 mL) / bottle.

[0125] 2. Enrolled subjects

[0126] 1) Females aged 18 to 75 years (inclusive).

[0127] 2) HER2-positive (IHC3+ or ISH+) unresectable or metastatic breast cancer confirmed by histology or cytology.

[0128] 3) Previous treatments in the recurrence and metastasis stage are as follows:

[0129] Phase I (dose finding): Recurrent / metastatic stage, patients who have received trastuzumab and at least 1 line of chemotherapy.

[0130] Phase II (expansion of efficacy): Patients who have not received systemic anti-tumor treatment (except endocrine therapy) during the recurrence / metastasis stage.

[0131] 4) ECOG performance status (Appendix 1) is 0 or 1.

[0132] 5) Expected survival period ≥ 12 weeks.

[0133] 6) At least one measurable lesion according to RECIST v1.1 criteria.

[0134] 7) The function of important organs meets the following criteria (no blood components or cell growth factors were used for corrective treatment within 14 days before the first medication):

[0135] Absolute neutrophil count (ANC) ≥1.5×109 / L (1,500 / mm3);

[0136] Platelet count ≥100 × 109 / L (100,000 / mm3);

[0137] Hemoglobin (Hgb) ≥ 90 g / L (9.0 g / dL);

[0138] Albumin level ≥ 3.0 g / dL;

[0139] Total bilirubin ≤1.5×ULN;

[0140] Alanine aminotransferase (ALT) and glutamate aminotransferase (AST) ≤ 2.5 × ULN (for patients with liver metastasis, ALT and AST ≤ 5 × ULN);

[0141] Serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL / min;

[0142] Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0143] QTcF ≤ 470 msec;

[0144] Echocardiography (ECHO) or cardiac radionuclide scanning (MUGA) shows left ventricular ejection fraction (LVEF) ≥ 50%.

[0145] 3. Method of administration

[0146] Anti-HER2 antibody-drug conjugate: Administered by intravenous drip, the dosage is 3.2mg / kg, 4.8mg / kg or 6.4mg / kg, once every 3 weeks, and each 3 weeks is a treatment cycle.

[0147] Pertuzumab: The initial dose is 840 mg, administered by intravenous drip, followed by 420 mg once every 3 weeks. Every 3 weeks is a treatment cycle.

[0148] When pertuzumab and anti-HER2 antibody-drug conjugates are used in combination, they must be administered sequentially, with intravenous infusion of the anti-HER2 antibody-drug conjugate being preferred.

[0149] 4. Results

[0150] A total of 74 patients received anti-HER2 antibody drug conjugate combined with pertuzumab (15 patients in the anti-HER2 antibody drug conjugate 3.2 mg / kg dose group, 25 patients in the 4.8 mg / kg group, and 34 patients in the 6.4 mg / kg group). During the dose escalation phase, no DLT occurred in 10 patients in the three dose groups. All 74 patients experienced adverse events (TEAEs) during treatment, 35 (47.3%) patients experienced grade 3 or 4 TEAEs, and no TEAEs leading to death occurred. The most common grade 3 or 4 TEAEs were decreased neutrophil count (36.5%), decreased white blood cell count (17.6%), and decreased lymphocyte count (5.4%). Among the 55 patients who had at least one post-baseline tumor efficacy assessment, 47 patients responded, with an ORR of 85.5% (95% CI, 73.3-93.5). The safety and efficacy of each dose group are summarized in Table 2. Compared with the 6.4 mg / kg dose group, the ORR in the 4.8 mg / kg group was numerically slightly higher (92.0% versus 87.5%) and had better safety (Grade 4 TEAEs, 12.0% versus 29.4%; TESAEs, 4.0% versus 11.8%; TEAEs leading to dose reduction of anti-HER2 antibody drug conjugates, 8.0% versus 11.8%).

[0151] Table 2: Summary of safety and efficacy of anti-HER2 antibody drug conjugates combined with pertuzumab

[0152]

[0153]

[0154] TEAE: treatment-emergent adverse event; SAE: serious adverse event; EES: efficacy evaluable analysis set; ORR: objective response rate; DCR: disease control rate.

[0155] 5. Conclusion

[0156] Anti-HER2 antibody-drug conjugate combined with pertuzumab showed good tolerability and safety as well as strong anti-tumor activity in the treatment of HER2-positive unresectable or metastatic breast cancer.

[0157] Example 3. Clinical study of anti-HER2 antibody drug conjugates with or without pertuzumab versus trastuzumab, pertuzumab, and docetaxel in the treatment of HER2-positive recurrent or metastatic breast cancer

[0158] 1. Experimental drugs

[0159] 1) Anti-HER2 antibody drug conjugate prepared in Example 1; dosage form: injection (lyophilized powder); specification: 100 mg / bottle.

[0160] 2) Pertuzumab; Dosage form: injection; Specification: 420 mg (14 mL) / bottle.

[0161] 3) Trastuzumab; Dosage form: injection (lyophilized powder); Specification: 150 mg.

[0162] 4) Docetaxel; Dosage form: injection; Specifications: 0.5mL: 20mg; 1.5mL: 60mg.

[0163] 2. Enrolled subjects

[0164] 1) Females aged 18 to 75 years (inclusive).

[0165] 2) Breast cancer must meet the following criteria:

[0166] HER2-positive (IHC3+ or ISH+) recurrent or metastatic breast cancer confirmed by histology or cytology (if no anti-tumor treatment has been received before, only patients with first-diagnosed stage IV disease are allowed to be included);

[0167] Patients who have not received systemic anti-tumor treatment during the recurrence / metastasis stage (can receive ≤1 line of endocrine therapy).

[0168] 3) ECOG performance score of 0 or 1.

[0169] 4) Expected survival period ≥ 12 weeks.

[0170] 5) At least one measurable lesion according to RECISTv1.1.

[0171] 6) The function of important organs meets the following criteria (no blood components, cell growth factors, albumin, etc. were used for corrective treatment within 14 days before the first medication):

[0172] Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L (1,500 / mm 3 );

[0173] Platelets ≥100×109 / L (100,000 / mm 3 );

[0174] Hemoglobin (Hgb) ≥ 90 g / L (9.0 g / dL);

[0175] Albumin level ≥ 3.0 g / dL;

[0176] Total bilirubin (TBIL) ≤ upper limit of normal (ULN); for patients with known Gilbert syndrome, TBIL ≤ 2 × ULN;

[0177] Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN (for patients with liver metastasis, ALT and AST ≤ 5 × ULN);

[0178] Urea / urea nitrogen (BUN) and creatinine (Cr) ≤ 1.5 × ULN;

[0179] Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0180] QTcF ≤ 470 msec;

[0181] Left ventricular ejection fraction (LVEF) ≥ 50% as shown by echocardiography (ECHO) or cardiac radionuclide scanning (MUGA)

[0182] 3. Dosage regimen

[0183] Experimental Group A: Anti-HER2 Antibody Drug Conjugate

[0184] Anti-HER2 antibody drug conjugate: intravenous drip, the initial dose is 4.8 mg / kg, the total amount of the first dose of anti-HER2 antibody drug conjugate is calculated based on the weight of the subject before the first dose. The drug is administered once every 3 weeks (Q3W), and every 3 weeks (21 days) is a treatment cycle.

[0185] Trial Group B: Anti-HER2 Antibody Drug Conjugate + Pertuzumab

[0186] Anti-HER2 antibody drug conjugate: intravenous drip, the initial dose is 4.8 mg / kg, the total amount of the first dose of anti-HER2 antibody drug conjugate is calculated based on the weight of the subject before the first dose. The drug is administered once every 3 weeks (Q3W), and every 3 weeks (21 days) is a treatment cycle.

[0187] Pertuzumab: Intravenous drip, starting dose is 840 mg, followed by 420 mg Q3W. 3 weeks

[0188] (21 days) is one cycle.

[0189] Control group: trastuzumab + pertuzumab + docetaxel

[0190] Trastuzumab: intravenous drip, the initial dose is 8 mg / kg, the total amount of trastuzumab for the first time is calculated based on the weight of the subject before the first dose. Thereafter, Q3W, the dose is 6 mg / kg. Every 3 weeks (21 days) is a treatment cycle.

[0191] Pertuzumab: Intravenous drip, starting dose is 840 mg, followed by 420 mg Q3W. 3 weeks

[0192] (21 days) is one cycle. When co-administered with anti-HER2 antibody-drug conjugate, the anti-HER2 antibody-drug conjugate is first intravenously administered.

[0193] Docetaxel: intravenous infusion, starting dose 75 mg / m 2 The total amount of docetaxel for the first time was calculated based on the subject's body surface area before the first dose. The drug was administered once every 3 weeks (Q3W).

[0194] 4. Result evaluation

[0195] 1) To evaluate the effectiveness of anti-HER2 antibody-drug conjugates alone or in combination with pertuzumab as first-line treatment for patients with HER2-positive recurrent or metastatic breast cancer in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and duration of objective response (DoR).

[0196] 2) To evaluate the safety and tolerability of anti-HER2 antibody-drug conjugates alone or in combination with pertuzumab as first-line treatment for patients with HER2-positive recurrent or metastatic breast cancer.

Claims

1. Use of an antibody-drug conjugate in combination with an antigen-binding protein that binds to HER2 in the preparation of a drug for treating tumors, wherein: The structure of the antibody-drug conjugate is shown in formula (I): in: n is 3 to 8, and n is a decimal or an integer; Pc is selected from a first anti-HER2 antibody or an antigen-binding fragment thereof, and the antigen-binding protein that binds to HER2 is selected from a second anti-HER2 antibody or an antigen-binding fragment thereof.

2. The use according to claim 1, wherein The first anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; Preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7, or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8, or having at least 80%, 90% identity thereto; Preferably, the first anti-HER2 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, 90% identity thereto, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, 90% identity thereto; Preferably, the first anti-HER2 antibody is trastuzumab, and the antibody-drug conjugate has a structure as shown in the following formula: wherein n is selected from 3 to 8, and n is a decimal or an integer.

3. The use according to claim 1 or 2, wherein: The second anti-HER2 antibody is independently selected from Trastuzumab or Pertuzumab; preferably Pertuzumab.

4. The use according to any one of claims 1 to 3, wherein: (a) the single dosage of the antibody drug conjugate is about 1.0 mg / kg to about 10.0 mg / kg, preferably about 1.0 mg / kg, about 2.0 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg, more preferably about 4.8 mg / kg; the frequency of administration of the antibody drug conjugate is once a week, once every two weeks, once every three weeks or once every four weeks; (b) the antigen binding protein that binds to HER2 is administered at a dosage of about 100 mg to about 1000 mg; Preferably, the dosage of the antigen protein binding to HER2 includes a starting dose and a maintenance dose, the starting dose is about 840 mg, and the maintenance dose is about 420 mg; the frequency of administration of the antigen binding protein binding to HER2 is once a week, once every two weeks, once every three weeks, or once every four weeks; Preferably, the administration regimen of the antigen binding protein that binds to HER2 comprises: An initial dose of the antigen-binding protein that binds to HER2 is administered on the first day of the treatment cycle, and then the antigen-binding protein that binds to HER2 is administered once every three weeks at a maintenance dose; the initial dose is preferably about 840 mg, and the maintenance dose is preferably about 420 mg.

5. The use according to any one of claims 1 to 4, wherein The tumor is selected from breast cancer, gastric cancer, esophagogastric junction adenocarcinoma, colorectal cancer or non-small cell lung cancer, preferably breast cancer; preferably, the breast cancer patient has been introduced to trastuzumab and at least one line of chemotherapy at the recurrence and metastasis stage; or, the breast cancer patient has not received systemic anti-tumor treatment at the recurrence and metastasis stage.

6. The use according to any one of claims 1 to 5, wherein The tumor is HER2-positive breast cancer; preferably, the HER2-positive breast cancer is selected from breast cancers expressing HER2 as IHC3+ or ISH+; Preferably, the HER2-positive breast cancer is HER2-positive recurrent, unresectable and / or metastatic breast cancer.

7. A pharmaceutical composition comprising an antibody drug conjugate and an antigen binding protein that binds to HER2, wherein: The structure of the antibody-drug conjugate is shown in formula (I): in: n is 3 to 8, and n is a decimal or an integer; Pc is selected from a first anti-HER2 antibody or an antigen-binding fragment thereof, and the antigen-binding protein that binds to HER2 is selected from a second anti-HER2 antibody or an antigen-binding fragment thereof; Preferably, the first anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the VL comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; Preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7, or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8, or having at least 80%, 90% identity thereto; Preferably, the first anti-HER2 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, 90% identity thereto, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, 90% identity thereto; Preferably, the first anti-HER2 antibody is trastuzumab, and the antibody-drug conjugate has a structure as shown in the following formula: wherein n is selected from 3 to 8, and n is a decimal or an integer.

8. The pharmaceutical composition according to claim 7, wherein The second anti-HER2 antibody is independently selected from Trastuzumab or Pertuzumab; preferably Pertuzumab.

9. Use of the pharmaceutical composition according to any one of claims 7 to 8 in preparing a drug for treating tumors; Preferably, the tumor is selected from breast cancer, gastric cancer, esophagogastric junction adenocarcinoma, colorectal cancer or non-small cell lung cancer, preferably breast cancer; preferably, the breast cancer patient has been introduced to trastuzumab and at least one line of chemotherapy at the recurrence and metastasis stage; or, the breast cancer patient has not received systemic anti-tumor treatment at the recurrence and metastasis stage.

10. The use according to claim 9, wherein the tumor is HER2-positive breast cancer; Preferably, the HER2-positive breast cancer is selected from breast cancers expressing HER2 as IHC3+ or ISH+; Preferably, the HER2-positive breast cancer is HER2-positive recurrent, unresectable and / or metastatic breast cancer.

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