Combination therapy of anti-her2 antibody drug conjugates and her dimerization inhibitors for solid tumors

Abstract

The present invention relates to a method of treating a solid tumor comprising administering to a patient having a solid tumor an effective amount of an anti-HER2 antibody drug conjugate and another HER dimerization inhibitor.

Description

Combination therapy of anti-HER2 antibody-drug conjugates and HER dimerization inhibitors for solid tumors Technical Field

[0001] The present invention relates to the field of drug treatment methods, and in particular to the use or method of anti-HER2 antibody drug conjugates and HER dimerization inhibitors for treating patients with solid tumors. Background Art

[0002] Cancer remains a leading cause of morbidity and mortality worldwide. HER2 is associated with a variety of cancers, including breast, stomach, colon, bladder, ovarian, endometrial, and lung cancers. However, the development of drugs or treatments for cancer remains a significant challenge. There remains a need to develop clinically effective, safer drugs or treatments that can treat or prolong the lives of patients with malignant solid tumors. Summary of the Invention

[0003] The present invention provides methods or uses of anti-HER2 antibody-drug conjugates and HER dimerization inhibitors for treating solid tumors, comprising administering an effective amount of the anti-HER2 antibody-drug conjugate and HER dimerization inhibitor to a patient suffering from a solid tumor. In one aspect, the present invention provides uses of the anti-HER2 antibody-drug conjugate and HER dimerization inhibitor in preparing a pharmaceutical composition for treating solid tumors. In one aspect, the present invention provides uses of the anti-HER2 antibody-drug conjugate in preparing a pharmaceutical composition for use in combination with a HER dimerization inhibitor for treating solid tumors. In one aspect, the present invention provides uses of the HER dimerization inhibitor in preparing a pharmaceutical composition for use in combination with an anti-HER2 antibody-drug conjugate for treating solid tumors. In one aspect, the present invention provides uses of the anti-HER2 antibody-drug conjugate and HER dimerization inhibitor in treating solid tumors. In one aspect, the present invention provides uses of the anti-HER2 antibody-drug conjugate in combination with a HER dimerization inhibitor for treating solid tumors. In one aspect, the present invention provides uses of the HER dimerization inhibitor in combination with an anti-HER2 antibody-drug conjugate for treating solid tumors. In one aspect, the present invention provides a pharmaceutical composition comprising an anti-HER2 antibody drug conjugate and a HER dimerization inhibitor. In one or more embodiments, the anti-HER2 antibody drug conjugate is an antibody drug conjugate coupled to a DNA topoisomerase I inhibitor.

[0004] In one or more embodiments, the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate conjugated to a DNA topoisomerase I inhibitor, the HER dimerization inhibitor is an antibody targeting HER2, the heavy chain of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO: 9, the light chain of the antibody comprises the sequence shown in SEQ ID NO: 10, and the fucosylation level is 0%-5%.

[0005] In one or more embodiments, the anti-HER2 antibody drug conjugate has a structure or stereoisomer represented by Formula IA-1 or IA-2, or a pharmaceutically acceptable salt or solvate thereof:

[0006] wherein Abu is an antibody or an antigen-binding unit thereof that binds to HER2;

[0007] R is selected from: -(CH2) r -、-(CHR m ) r -, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclyl)-, -(C3-C8 heterocyclyl)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r-CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R m R is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0008] D is a drug, wherein D is a DNA topoisomerase I inhibitor or a salt thereof, such as exitecan or an exitecan derivative;

[0009] n is an integer from 1 to 24;

[0010] p is about 1-10.

[0011] In one or more embodiments, the anti-HER2 antibody drug conjugate has a structure or stereoisomer represented by Formula I-1 or I-2, or a pharmaceutically acceptable salt or solvate thereof:

[0012] in

[0013] Abu is an antibody or antigen-binding unit thereof that binds to HER2;

[0014] D is a DNA topoisomerase I inhibitor or a salt thereof, such as exitecan or an exitecan derivative;

[0015] n is an integer from 1 to 24; or n is an integer from 4 to 12;

[0016] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0017] In one or more embodiments, D is a DNA topoisomerase I inhibitor or a salt thereof selected from irinotecan, irinotecan hydrochloride, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivatives (such as SN-38), 22-hydroxyecliptin, topotecan, lertotecan, belotecan, exitecan, exitecan derivatives (such as Dxd), homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-xylopyranosylamino)phenyl]-4(3H)-quinazolinone, 2-cyano-3-( 3,4-dihydroxyphenyl)-N-(phenylmethyl)-(2E)-2-acrylamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-hydroxyphenylpropyl)-(E)-2-acrylamide, 12-β-D-glucopyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide dihydrochloride, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide.

[0018] In one or more embodiments, D is

[0019] where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; ** is the point of attachment.

[0020] In one or more embodiments, the C1-C6 alkyl group is -CH3.

[0021] In one or more embodiments, the halogen is F.

[0022] In one or more embodiments, X 1 and X 2 Each is independently -CH3, F or -OH.

[0023] In one or more embodiments, X 1 and X 2 Each is -CH3.

[0024] In one or more embodiments, X 1 and X 2 are each independently F, Cl, Br or I.

[0025] In one or more embodiments, X 1 and X 2 Each is F.

[0026] In one or more embodiments, X 1 and X 2 Each is independently F or -CH3.

[0027] In one or more embodiments, X 1 -CH3 and X 2 For F.

[0028] In one or more embodiments, n is an integer from 4-8.

[0029] In one or more embodiments, n is 4.

[0030] In one or more embodiments, n is 8.

[0031] In one or more embodiments, p is 2-8.

[0032] In one or more embodiments, p is 4-8.

[0033] In one or more embodiments, p is 6-8.

[0034] In one or more embodiments, p is 7-8.

[0035] In one or more embodiments, the anti-HER2 antibody drug conjugate has a structure or stereoisomer represented by Formula I-17, Formula I-18, Formula I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, or I-16, or a pharmaceutically acceptable salt or solvate thereof:

[0036] in

[0037] Abu is an antibody or antigen-binding unit thereof that binds to HER2;

[0038] n is an integer from 1 to 24; or n is an integer from 4 to 12;

[0039] p is 1-10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0040] In one or more embodiments, p is 2-8.

[0041] In one or more embodiments, p is 4-8.

[0042] In one or more embodiments, p is 6-8.

[0043] In one or more embodiments, p is 7-8.

[0044] In one or more embodiments, Abu is trastuzumab (e.g., Herceptin, Herceptin Hylecta, or a biosimilar thereof, e.g., Herzuma, Kanjinti, Hervycta, Ogivri, Ontruzant, Trazimera, HERTICAD, Vivitra, TrastuRel).

[0045] In one or more embodiments, the anti-HER2 antibody drug conjugate is an anti-HER2 antibody drug conjugate disclosed in WO2022 / 253284.

[0046] In one or more embodiments, the anti-HER2 antibody drug conjugate is ADC1 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof, and ADC1 has the structure shown in Formula II:

[0047] Where p is 7-8.

[0048] In one or more embodiments, the anti-HER2 antibody drug conjugate is ADC2 or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof, and ADC2 has the structure shown in Formula III:

[0049] Where p is 7-8.

[0050] In one or more embodiments, the HER dimerization inhibitor is an antibody targeting HER2.

[0051] In one or more embodiments, the antibody targeting HER2 is an antibody that can bind to subdomain II of the extracellular domain of the HER2 protein.

[0052] In one or more embodiments, the heavy chain variable region of the antibody targeting HER2 comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3, and the light chain variable region of the antibody targeting HER2 comprises LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.

[0053] In one or more embodiments, the heavy chain variable region of the antibody targeting HER2 comprises the sequence as shown in SEQ ID NO:7, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:7, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:7; and / or the light chain variable region of the antibody comprises the sequence shown in SEQ ID NO:8, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:8, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:8.

[0054] In one or more embodiments, the heavy chain of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO:9, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:9, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:9; and / or the light chain of the antibody comprises the sequence shown in SEQ ID NO:10, a sequence having at least 80% identity with the sequence shown in SEQ ID NO:10, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO:10.

[0055] In one or more embodiments, the heavy chain of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO:9, and the light chain of the antibody comprises the sequence shown in SEQ ID NO:10.

[0056] In one or more embodiments, the fucosylation level of the antibody targeting HER2 is 0%-5%. In one or more embodiments, the antibody targeting HER2 comprises no less than 60% GO. In one or more embodiments, the fucosylation level of the antibody targeting HER2 is 0%-1%. In one or more embodiments, the fucosylation level of the antibody targeting HER2 is 0%.

[0057] In one or more embodiments, the heavy chain of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO: 9, the light chain of the antibody comprises the sequence shown in SEQ ID NO: 10, and the fucosylation level is 0%-5%.

[0058] In one or more embodiments, the antibody targeting HER2 is an antibody with enhanced ADCC (antibody-dependent cell-mediated cytotoxicity).

[0059] In one or more embodiments, the antibody targeting HER2 is BAT0303F.

[0060] In one or more embodiments, the HER dimerization inhibitor is Pertuzumab (such as Perjeta or its biosimilar, or its corresponding ADCC-enhanced mAb, or a partially or fully defucosylated mAb).

[0061] In one or more embodiments, the effective amount refers to the amount of active compound or agent that results in the biological or medicinal response of a tissue, system, animal, individual, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, including treatment of a disease, such as a HER2-expressing solid tumor.

[0062] In one or more embodiments, the solid tumor is a HER2-expressing solid tumor.

[0063] In one or more embodiments, the solid tumor includes HER2-positive solid tumors and HER2-low expressing solid tumors.

[0064] In one or more embodiments, the solid tumor is a locally advanced or metastatic solid tumor.

[0065] In one or more embodiments, the HER2-expressing solid tumor is a HER2-expressing locally advanced or metastatic solid tumor.

[0066] In one or more embodiments, the HER2-expressing solid tumor is a solid tumor with an immunohistochemical assay of 3+ (IHC3+), an immunohistochemical assay of 2+ and a positive in situ hybridization assay (IHC2+ / ISH+), or an immunohistochemical assay of 2+ and a negative in situ hybridization assay (IHC2+ / ISH-).

[0067] In one or more embodiments, the in situ hybridization (ISH) is fluorescence in situ hybridization (FISH) or dual-color silver in situ hybridization (DISH).

[0068] In one or more embodiments, the HER2-expressing solid tumor is a solid tumor with an immunohistochemical detection of 3+ (IHC3+), an immunohistochemical detection of 2+ (IHC2+) and a positive fluorescence in situ hybridization detection (IHC2+ / FISH+), or an immunohistochemical detection of 2+ and a negative fluorescence in situ hybridization detection (IHC2+ / FISH-).

[0069] Examples of solid tumors include, but are not limited to, breast cancer, gastric cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), biliary tract cancer, colorectal cancer, ovarian cancer, uterine carcinosarcoma, endometrial cancer, fallopian tube cancer, cervical cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, hepatocellular carcinoma, liver cancer, bladder cancer, urethral cancer, urothelial carcinoma, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, and penile cancer.

[0070] In one or more embodiments, the solid tumors include breast cancer, gastric cancer, non-small cell lung cancer, biliary tract cancer, colorectal cancer, and urothelial carcinoma. In one or more embodiments, the gastric cancer includes gastric adenocarcinoma. In one or more embodiments, the gastric adenocarcinoma includes gastroesophageal junction adenocarcinoma. In one or more embodiments, the solid tumor patients include patients who have failed standard treatment or have no standard treatment options or are not suitable for standard treatment at this stage, and patients with HER2-expressing breast cancer confirmed by histopathology and cytopathology.

[0071] In one or more embodiments, the solid tumor patients include patients with histopathologically confirmed unresectable locally advanced or metastatic urothelial carcinoma, including patients with HER2-expressing urothelial carcinoma originating from the bladder, renal pelvis, ureter, or urethra.

[0072] In one or more embodiments, the solid tumor patient includes a patient with disease progression after standard treatment, or a patient with metastatic or unresectable locally advanced or metastatic HER2-expressing gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) confirmed by histology or cytology who is intolerant to standard treatment. Standard treatment generally refers to a treatment regimen that has been approved by the local drug regulatory authorities and accepted by current treatment guidelines and clinical practice. In one or more embodiments, the HER2 expression is 3+ (IHC3+) by immunohistochemistry, 2+ by immunohistochemistry and positive for fluorescence in situ hybridization (IHC2+ / FISH+), or 2+ by immunohistochemistry and negative for fluorescence in situ hybridization (IHC2+ / FISH-).

[0073] In one or more embodiments, the dose of the anti-HER2 antibody drug conjugate is about 0.5-30 mg / kg per administration. In one or more embodiments, the dose of the anti-HER2 antibody drug conjugate is about 0.5-10 mg / kg per administration. In one or more embodiments, the dose of the anti-HER2 antibody drug conjugate is about 1-5 mg / kg per administration. In one or more embodiments, the dose of the anti-HER2 antibody drug conjugate is about 2-3 mg / kg per administration. In one or more embodiments, the dosage of each administration of the anti-HER2 antibody drug conjugate is about 0.8 mg / kg, about 1 mg / kg, about 1.2 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 2.7 mg / kg, about 3 mg / kg, about 3.3 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, about 10 mg / kg, or the range (including endpoints) between any two of these numerical values ​​or any value therein. In one or more embodiments, the dosage of each administration of the anti-HER2 antibody drug conjugate is about 2.1 mg / kg, about 2.4 mg / kg or about 2.7 mg / kg, or the range (including endpoints) between any two of these numerical values ​​or any value therein.

[0074] In one or more embodiments, the dosage of each administration of the anti-HER2 antibody drug conjugate is about 50-3000 mg. In one or more embodiments, the dosage of each administration of the anti-HER2 antibody drug conjugate is about 100-2000 mg, 200-1000 mg, 300-800 mg, 400-700 mg, or 100-200 mg. In one or more embodiments, the dosage of each administration of the anti-HER2 antibody drug conjugate is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 700 mg, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein.

[0075] In one or more embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein. In one or more embodiments, the drug is administered approximately once a week, or approximately every 2 weeks, approximately every 3 weeks, approximately every 4 weeks, approximately every 5 weeks, approximately every 6 weeks, or approximately every 7 weeks. In one or more embodiments, the drug is administered approximately once every 3 weeks.

[0076] In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 0.5-30 mg / kg. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 0.5-10 mg / kg. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 1-5 mg / kg. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 2-3 mg / kg. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 0.8 mg / kg, about 1 mg / kg, about 1.2 mg / kg, about 1.5 mg / kg, about 1.8 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.4 mg / kg, about 2.7 mg / kg, about 3 mg / kg, about 3.3 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.0 mg / kg, about 7.2 mg / kg, about 8.4 mg / kg, or about 10 mg / kg, or a range (including endpoints) between any two of these values ​​or any value therein. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 2.1 mg / kg, about 2.4 mg / kg, or about 2.7 mg / kg, or a range (including endpoints) between any two of these values ​​or any value therein.

[0077] In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 50-3000 mg. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 100-2000 mg, 200-1000 mg, 300-800 mg, 400-700 mg, or 100-200 mg. In one or more embodiments, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or any two of these values ​​in a range (including endpoints) or any value therein.

[0078] In one or more embodiments, the HER dimerization inhibitor is administered at a dosage of about 1-25 mg / kg. In one or more embodiments, the HER dimerization inhibitor is administered at a dosage of about 3-20 mg / kg. In one or more embodiments, the HER dimerization inhibitor is administered at a dosage of about 1 mg / kg, about 3 mg / kg, about 6 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg, or any two of these values, or any value thereof. In one or more embodiments, the HER dimerization inhibitor is administered approximately every 3 weeks at a dosage of about 15 mg / kg.

[0079] In one or more embodiments, the HER dimerization inhibitor is administered at a dose of about 50-2000 mg. In one or more embodiments, the HER dimerization inhibitor is administered at a dose of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1050 mg, about 1500 mg, about 2000 mg, or a range (including endpoints) between any two of these values, or any value therein.

[0080] Another aspect of the present invention is a method for treating solid tumors, comprising administering an effective amount of an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor to a patient suffering from a solid tumor, wherein the anti-HER2 antibody-drug conjugate is anti-HER2-ADC-non-topo1, and the anti-HER2-ADC-non-topo1 is an anti-HER2 antibody-drug conjugate coupled to a non-DNA topoisomerase I inhibitor (such as a tubulin inhibitor or a DNA damaging agent).

[0081] In one or more embodiments, the tubulin inhibitor is selected from the group consisting of dolastatin, auristatins, maytansines, eribulin, and derivatives thereof.

[0082] In one or more embodiments, the auristatin is selected from monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and auristatin F (AF), ER300, Duo-5, DM1.

[0083] In one or more embodiments, the DNA damaging agent is selected from calicheamicins, duocarmycins, and anthramycin derivatives PBD (pyrrolobenzodiazepine).

[0084] In one or more embodiments, the anti-HER2 antibody drug conjugate is an anti-HER2 antibody drug conjugate conjugated to MMAE, MMAF, AF, ER300, Duo-5, or DM1.

[0085] In one or more embodiments, the anti-HER2 antibody drug conjugate is an anti-HER2 antibody drug conjugate of trastuzumab conjugated to MMAE, MMAF, AF, ER300, Duo-5 or DM1.

[0086] In one or more embodiments, the anti-HER2 antibody drug conjugate is trastuzumab enmetuzumab (T-DM1), vedicizumab (RC48, Disitamab-MMAE), bodu trastuzumab (A166, trastuzumab-tubulin inhibitor Duo-5), FS1502 (trastuzumab-MMAF).

[0087] In one or more embodiments, the solid tumor is a solid tumor that has been previously treated with an antibody drug conjugate conjugated to a DNA topoisomerase I inhibitor.

[0088] In one or more embodiments, the solid tumor is a solid tumor that is resistant or relapsed after previous treatment with an antibody drug conjugate conjugated to a DNA topoisomerase I inhibitor.

[0089] In one or more embodiments, the solid tumor is a solid tumor that is resistant or relapsed to an existing antibody drug conjugate conjugated to a DNA topoisomerase I inhibitor.

[0090] In one or more embodiments, the DNA topoisomerase I inhibitor is irinotecan, irinotecan hydrochloride, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivatives (such as SN-38), 22-hydroxyecliptin, topotecan, lertotecan, belotecan, exitecan, exitecan derivatives (such as Dxd), homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-xylopyranosylamino)phenyl]-4(3H)-quinazolinone, 2-cyano-3-(3, 4-dihydroxyphenyl)-N-(phenylmethyl)-(2E)-2-acrylamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-hydroxyphenylpropyl)-(E)-2-acrylamide, 12-β-D-glucopyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide dihydrochloride, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide.

[0091] In one or more embodiments, the solid tumor is a HER2-expressing solid tumor.

[0092] In one or more embodiments, the solid tumor is breast cancer, gastric cancer, esophageal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), biliary tract cancer, colorectal cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, hepatocellular carcinoma, liver cancer, bladder cancer, urethral cancer, urothelial carcinoma, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, or penile cancer.

[0093] In one or more embodiments, the HER dimerization inhibitor is an antibody targeting HER2.

[0094] In one or more embodiments, the antibody targeting HER2 is an antibody that can bind to subdomain II of the extracellular domain of the HER2 protein.

[0095] In one or more embodiments, the heavy chain of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO:9, the light chain of the antibody comprises the sequence shown in SEQ ID NO:10, the fucosylation level of the antibody targeting HER2 is 0%-5%, and the antibody comprises no less than 60% GO.

[0096] In one or more embodiments, the antibody targeting HER2 is BAT0303F.

[0097] In one or more embodiments, the antibody targeting HER2 is an antibody with enhanced ADCC (antibody-dependent cell-mediated cytotoxicity).

[0098] In one or more embodiments, the HER2-targeting antibody is administered at a dose of about 15 mg / kg per administration, the heavy chain of the HER2-targeting antibody comprises the sequence shown in SEQ ID NO: 9, the light chain comprises the sequence shown in SEQ ID NO: 10, and the HER2-targeting antibody has a fucosylation level of 0%-5%. In some embodiments, the HER2-targeting antibody comprises no less than 60% GO. In some embodiments, the antibody comprises no less than 70% GO. In some embodiments, the content of the GO glycoform is about 60%-80%. In some embodiments, the content of the GO glycoform is about 70%-80%.

[0099] In one or more embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein. In one or more embodiments, the drug is administered approximately once a week, or approximately every 2 weeks, approximately every 3 weeks, approximately every 4 weeks, approximately every 5 weeks, approximately every 6 weeks, or approximately every 7 weeks. In one or more embodiments, the drug is administered approximately once every 3 weeks.

[0100] In one or more embodiments, the HER2-targeting antibody is administered approximately every three weeks at a dose of approximately 15 mg / kg. The heavy chain of the HER2-targeting antibody comprises the sequence shown in SEQ ID NO: 9, and the light chain comprises the sequence shown in SEQ ID NO: 10. The HER2-targeting antibody has a fucosylation level of 0%-5%. In some embodiments, the HER2-targeting antibody comprises no less than 60% GO. In some embodiments, the antibody comprises no less than 70% GO. In some embodiments, the content of the GO glycoform is about 60%-80%. In some embodiments, the content of the GO glycoform is about 70%-80%.

[0101] In one or more embodiments, the patient receives one treatment cycle. In one or more embodiments, the patient receives multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 17 or more, or a range (including endpoints) between any two of these values ​​or any value therein) treatment cycles. In one or more embodiments, the patient receives treatment until the condition is alleviated and no longer requires treatment.

[0102] As described herein, "combination" is a mode of administration that includes various situations in which two or more drugs are administered sequentially or simultaneously. In one or more embodiments, the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are prepared as a single pharmaceutical composition, and the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are administered to patients in need at the same time. In one or more embodiments, the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are prepared as separate pharmaceutical compositions, and the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are administered to patients in need at the same time, or the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are administered to patients in need at different times during the treatment regimen. For example, the anti-HER2 antibody drug conjugate is administered before the HER dimerization inhibitor is administered, or the anti-HER2 antibody drug conjugate is administered after the HER dimerization inhibitor is administered, or the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are administered in an alternating regimen. Herein, the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are administered to patients in need in a single dose or multiple doses.

[0103] In one or more embodiments, the anti-HER2 antibody drug conjugate is administered after the HER dimerization inhibitor.

[0104] In one or more embodiments, the anti-HER2 antibody drug conjugate is ADC1, which is administered approximately once every 3 weeks at a dose of about 2.1 mg / kg, about 2.4 mg / kg, or about 2.7 mg / kg each time, and the HER dimerization inhibitor is BAT0303F, which is administered approximately once every 3 weeks at a dose of about 15 mg / kg each time.

[0105] In one or more embodiments, the anti-HER2 antibody drug conjugate (or preparation) and / or HER dimerization inhibitor (or preparation) is administered by injection or infusion. In one or more embodiments, the anti-HER2 antibody drug conjugate (or preparation) or HER dimerization inhibitor (or preparation) is administered by subcutaneous (sc) injection, intraperitoneal (ip) injection, parenteral injection, intra-arterial injection or intravenous (iv) infusion (i.e., intravenous infusion). The dosage of the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor will depend on the nature of the drug, the degree of internalization, transport and release of the cell surface-triggered drug, and the disease being treated and the patient's condition (such as age, sex, weight, etc.).

[0106] In one or more embodiments, the anti-HER2 antibody drug conjugate (or formulation) and / or HER dimerization inhibitor (or formulation) is administered by intravenous infusion.

[0107] In one or more embodiments, the intravenous infusion duration of the anti-HER2 antibody drug conjugate (or formulation) is about 30 to 120 minutes, for example, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 105 minutes, about 120 minutes, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein. In one or more embodiments, the first intravenous infusion time of the anti-HER2 antibody drug conjugate (or formulation) is 90 (± 10) minutes.

[0108] In one or more embodiments, the intravenous infusion duration of the HER dimerization inhibitor (or formulation) is about 30 to 120 minutes, for example, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 105 minutes, about 120 minutes, or the range (including endpoints) between any two values ​​of these numerical values ​​or any value therein. In one or more embodiments, the first intravenous infusion time of the HER dimerization inhibitor (or formulation) is 90 (± 10) minutes.

[0109] In one or more embodiments, the HER dimerization inhibitor can enhance the anti-tumor effect of the anti-HER2 antibody drug conjugate.

[0110] In one or more embodiments, the anti-HER2 antibody drug conjugate and HER dimerization inhibitor exhibit synergistic anti-tumor effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] Figure 1 shows the tumor volume growth curve of the combined administration / single administration mode of BAT0303F and ADC1 in the Calu-3 model, where the black arrows indicate the administration time points. DETAILED DESCRIPTION

[0112] "About" refers to the normal error range of the corresponding numerical value that is easily known to those skilled in the relevant art. In some embodiments, "about" mentioned herein refers to the described numerical value and its ±10%, ±5% or ±1% range.

[0113] The term "HER dimerization inhibitor" refers to a drug that binds to the HER2 protein to inhibit the formation of heterodimers between HER2 and HER1, HER3, or HER4. The HER dimerization inhibitors of the present invention are not limited, as long as they are drugs with this function. Preferably, the HER dimerization inhibitor is an antibody that can bind to subdomain II of the extracellular domain of the HER2 protein.

[0114] "Treatment" refers to therapeutic treatment and preventative or prophylactic measures, the purpose of which is to prevent, slow down, improve or stop adverse physiological changes or disorders, such as the progression of a disease, including but not limited to the following results, whether detectable or undetectable, relief of symptoms, reduction in the severity of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, alleviation, reduction or disappearance of the disease state (whether partial or complete), and prolongation of survival compared to that expected in the absence of treatment. Patients in need of treatment include patients who already have a disease or disorder, patients who are susceptible to a disease or disorder, or patients who need to prevent the disease or disorder, and patients who can or are expected to benefit from the combination therapy of the anti-HER2 antibody drug conjugate and HER2 dimerization inhibitor disclosed herein.

[0115] The pharmaceutical composition and treatment methods of the present invention can be used for solid tumors. In some embodiments, the pharmaceutical composition and treatment methods of the present invention can be used to treat HER2-expressing solid tumors. Whether HER2 expression exists can be checked by, for example, the following method: tumor tissue is collected from cancer patients, and formalin-fixed paraffin-embedded samples (FFPE) are subjected to an inspection of gene product (protein) levels, such as immunohistochemistry (IHC) methods, flow cytometry, Western blotting methods, or inspection of gene transcription levels, such as in situ hybridization methods (ISH), quantitative PCR methods (q-PCR) or microarray analysis; or, it can also be checked by the following: cell-free blood circulating tumor DNA (ctDNA) is collected from cancer patients and inspected, the inspection using methods such as next-generation sequencing (NGS).

[0116] The pharmaceutical composition and treatment method of the present invention can be used for HER2-expressing solid tumors, including HER2-positive solid tumors and HER2-low-expressing solid tumors.

[0117] The term "HER2-positive solid tumor" or "HER2-positive cancer" refers to a solid tumor or cancer that is positive for HER2 testing. Examples of HER2-positive cancers can include cancers that give a score of 3+ for the expression of HER2 in an immunohistochemistry (IHC) method, and cancers that give a score of 2+ for the expression of HER2 in an immunohistochemistry (IHC) method and are determined to be positive for the expression of HER2 in an in situ hybridization method (ISH). In some embodiments, the HER2-positive solid tumor has an immunohistochemistry (IHC) score of 2+ or 3+ and / or an in situ hybridization (ISH) amplification ratio of ≥2.0.

[0118] The term "HER2-low expressing solid tumor" is not particularly limited, as long as it is recognized as a HER2-low expressing solid tumor by a person skilled in the art. HER2-low expressing solid tumors may include solid tumors that are scored as 2+ for HER2 expression in an immunohistochemical method and are determined to be negative for HER2 expression in an in situ hybridization method, solid tumors that are scored as 1+ for HER2 expression in an immunohistochemical method, or solid tumors that are scored as 0> and <1+ for HER2 expression in an immunohistochemical method.

[0119] The method for scoring the degree of HER2 expression by immunohistochemistry or the method for determining the positive or negative expression of HER2 by in situ hybridization is not particularly limited, as long as it is recognized by those skilled in the art. Examples of the method may include the methods described in "Guidelines for Detection of HER2 in Breast Cancer (2019 Edition)" and "Guidelines for Detection of HER2 in Gastric Cancer (2016 Edition)".

[0120] The in situ hybridization methods of the present invention include fluorescence in situ hybridization (FISH) and bright-field in situ hybridization. Commonly used bright-field in situ hybridization methods include chromogenic in situ hybridization (CISH) and silver-enhanced in situ hybridization (SISH). Among SISH tests, dual-color silver in situ hybridization (DSISH) is currently the most widely used.

[0121] The HER2-expressing solid tumors described in the present invention include, but are not limited to, HER2-expressing breast cancer, gastric cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), biliary tract cancer, colorectal cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, hepatocellular carcinoma, liver cancer, bladder cancer, urethral cancer, urothelial carcinoma, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, etc.

[0122] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a drug, such as an anti-HER2 antibody drug conjugate or a HER dimerization inhibitor, that is sufficient to reduce or improve the severity and / or duration of a condition (e.g., cancer) or one or more of its symptoms; prevent the progression of the condition; cause the condition to subside; prevent the recurrence, development, onset or progression of one or more symptoms associated with the condition; detect the condition; or enhance or improve the amount of the preventive or therapeutic effect of another therapy (e.g., a preventive or therapeutic agent). For example, an effective amount of an anti-HER2 antibody drug conjugate or a HER dimerization inhibitor can inhibit tumor growth (e.g., inhibit an increase in tumor volume); reduce tumor growth (e.g., reduce tumor volume); reduce the number of cancer cells; and / or alleviate one or more symptoms associated with cancer to a certain extent. For example, an effective amount can improve progression-free survival (PFS), improve overall survival (OS), improve objective response rate (ORR), improve duration of remission (DOR), improve disease control rate (DCR), or reduce the likelihood of recurrence.

[0123] The term "patient" is used interchangeably and refers to any mammal in need of diagnosis, prognosis or treatment, including but not limited to humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, etc., particularly animals suffering from one or more conditions of HER2-expressing solid tumors. In one or more embodiments, the patient is a human.

[0124] A "patient population" refers to a group of cancer patients. Such a population can be used to demonstrate statistically significant efficacy and / or safety of a drug, such as an anti-HER2 antibody drug conjugate of the present invention and its combination with a HER dimerization inhibitor.

[0125] Anti-tumor efficacy evaluation can be performed by imaging assessment (CT / MRI), physical examination and survival assessment; anti-tumor efficacy indicators include: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) based on the RECIST 1.1 evaluation criteria (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2): 228-247) and imaging efficacy evaluation using CT / MRI as the main evaluation method.

[0126] Objective Response Rate (ORR): This refers to the proportion of patients whose tumors shrink by a certain amount and for a certain period of time, including cases of complete response (CR) and partial response (PR). In some embodiments, the objective response rate is the proportion of patients who achieve a PR or CR at the end of a certain period of treatment, such as the first 6 cycles of treatment. In some embodiments, the objective response rate is the proportion of patients who achieve a PR or CR as the best response during the entire study.

[0127] Duration of response (DoR): DoR is defined as the time from the first objective response of the tumor to the first assessment of disease progression (PD) or death from any cause before PD, reflecting the duration of ORR.

[0128] Disease control rate (DCR) refers to the proportion of patients whose tumors shrink or stabilize and remain stable for a certain period of time, including cases of CR, PR and stable disease (SD).

[0129] Progression-free survival (PFS): The time from the first dose to the occurrence of objective tumor progression or all-cause death (whichever occurs first).

[0130] Overall survival (OS) was calculated from the date of first dose until death from any cause. Patients who were still alive at the time of analysis were considered to have the last contact date as the cutoff date.

[0131] As used herein, the term "administering" refers to administering a substance to achieve a therapeutic purpose (eg, treating a tumor).

[0132] MTD definition: MTD (maximum tolerated dose) is defined as the highest dose level in a dose group at which DLT is observed in ≤1 / 6 patients during the DLT evaluation period.

[0133] The Eastern Cooperative Oncology Group (ECOG) of the United States has developed a simpler activity status scoring table, which divides the patient's activity status into 6 levels from 0 to 5. The ECOG physical condition scoring standard is scored as 0, 1, 2, 3, 4, and 5 points.

[0134] The PK (pharmacokinetic) parameters used in this article are defined as follows:

[0135] Single-dose PK parameter: C max 、T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) :

[0136] Multiple-dose PK parameters: C max,ss 、C avg,ss 、C min,ss , AUC (0-τ)ss , AUC (0-∞)ss 、T max,ss 、T 1 / 2,ss , CL, V ss , Ke, MRT, accumulation index (R ac ), Volatility Index DF:

[0137] The terms "antibody drug conjugate" or "ADC" are used interchangeably and refer to a binding protein (such as an antibody or its antigen binding unit) connected to one or more drugs, which may optionally be a therapeutic agent or a cytotoxic agent. In some embodiments, the ADC comprises an antibody, a drug (such as a cytotoxic drug), and a linker that enables the drug to be attached or coupled to the antibody. Non-limiting examples of drugs that may be included in an ADC are mitotic inhibitors, antitumor antibiotics, immunomodulators, vectors for gene therapy, alkylating agents, anti-angiogenic agents, antimetabolites, boron-containing agents, chemoprotectants, hormones, antihormonal agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclide agents, topoisomerase inhibitors, kinase inhibitors (e.g., TEC-family kinase inhibitors and serine / threonine kinase inhibitors), and radiosensitizers.

[0138] The term "drug-antibody coupling ratio" or "DAR" refers to the number of drugs (e.g., exotecan) attached to an antibody of an ADC. The DAR of an ADC can range from 1 to 10, but higher loadings (e.g., 20) are possible depending on the number of attachment sites on the antibody. The term DAR can be used when referring to the number of drugs loaded onto a single antibody, or alternatively, when referring to the average or mean DAR of a group of ADCs. In some embodiments, the value is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. When considering the average number of small molecule drugs bound, that is, the average number of drugs bound to the antibody, or the average drug-antibody coupling ratio, the value is selected from about 0 to about 10, or about 2 to about 8. In some embodiments, the drug-antibody coupling ratio is about 3 to about 6. In other embodiments, the drug-antibody coupling ratio is about 6 to about 8, or about 7 to about 8. DAR values ​​can be represented by p herein. The DAR value of an ADC can be measured using ultraviolet-visible absorption spectroscopy (UV-Vis), high-performance liquid chromatography-hydrophobic chromatography (HPLC-HIC), high-performance liquid chromatography-reverse phase chromatography (RP-HPLC), liquid chromatography-mass spectrometry (LC-MS), etc. These techniques are described in Ouyang, J. Methods Mol Biol, 2013, 1045: p. 275-83.

[0139] The various substituents are defined below.

[0140] "Alkyl" refers to a saturated aliphatic hydrocarbon group, and the term includes straight and branched hydrocarbon groups. For example, C1-C20 alkyl, such as C1-C6 alkyl. C1-C20 alkyl refers to an alkyl group with 1 to 20 carbon atoms, for example, an alkyl group with 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl etc.

[0141] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0142] "Stereoisomers" refer to isomeric compounds that have the same order of attachment of atoms but different arrangements of atoms in space. Stereoisomers can have one or more stereocenters and each center can exist as R or S. Stereoisomers can also be cis-trans isomers. Stereoisomers of the compounds provided herein include any one of all diastereomeric, enantiomeric, and cis-trans isomeric forms thereof or suitable mixtures thereof.

[0143] Pharmaceutically acceptable salts include pharmaceutically acceptable salts of the compounds with a wide variety of organic and inorganic counterions well known in the art. Exemplary salts include, when the molecule contains an acidic functional group, organic or inorganic salts such as lithium, sodium, potassium, calcium, magnesium, ammonium, isopropylamine, trimethylamine, diethylamino, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethyl, polyamine resins, and tetraalkylammonium salts; and when the molecule contains a basic functional group, organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, and oxalate. Other non-limiting examples of acids include sulfuric acid, nitric acid, phosphoric acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid salicylic acid, etc. These salts can generally be prepared by conventional methods by reacting, for example, an appropriate acid or base with the compound. Solvates include hydrates.

[0144] Other chemical terms are used herein according to conventional usage in the art, as described in The McGraw-Hill Dictionary of Chemical Terms (Parker, S., ed., McGraw-Hill, San Francisco (1985)).

[0145] All publications and patents cited herein are incorporated by reference in their entirety for all purposes.

[0146] Example

[0147] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources or known methods.

[0148] The anti-HER2 antibody drug conjugate (hereinafter referred to as ADC1) represented by formula II was prepared according to the preparation method described in patent document WO2022 / 253284.

[0149] Among them, DAR (average drug-antibody ratio), i.e., p, is 7-8.

[0150] BAT0303F is an anti-HER2 antibody with enhanced ADCC activity, a fucosylation level of 0-5%, and comprises a heavy chain as set forth in SEQ ID NO: 9 and a light chain as set forth in SEQ ID NO: 10. Its preparation and purification can be found in WO2022 / 022526. The G0 glycoform content is no less than 60%.

[0151] Example 1: Pharmacodynamic Study of ADC1 Combined with BAT0303F in Calu-3 Xenograft Tumors

[0152] This study evaluated the efficacy of BAT0303F and ADC1 in combination in a BALB / cnude mouse model with subcutaneous xenografts of human lung cancer Calu-3 cell lines (Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd.).

[0153] Calu-3 cells were cultured in MEM supplemented with 10% fetal bovine serum and 0.01 mM NEAA. Calu-3 cells were collected during the exponential growth phase and resuspended in PBS (phosphate buffered saline) to a suitable concentration for subcutaneous tumor inoculation in mice. 10 × 10 6 Calu-3 tumor cells were resuspended in PBS and Matrigel at a ratio of 1:1 (0.2 mL / cell). Tumor growth was observed regularly. 3 The day of grouping was defined as day 0.

[0154] BAT0303F and ADC1 were administered as single agents and in combination. The dosage regimen is shown in Table 1. Each group consisted of 8 mice. All mice were administered via tail vein injection (iv). After a single dose (day 0), the mice were observed until day 28. After the start of administration, the body weight and tumor size of the mice were measured twice a week. Tumor volume calculation formula: Tumor volume (mm 3 )=1 / 2×(a×b 2 )(where a represents the major diameter and b represents the minor diameter).

[0155] Under this experimental protocol, the tumor growth curve is shown in Figure 1. Table 1 provides the efficacy analysis for each group. As can be seen, a single dose of BAT0303F combined with ADC1 at 3 mg / kg + 1 mg / kg (G5) demonstrated superior tumor growth inhibition compared to BAT0303F 3 mg / kg (G2) and ADC1 1 mg / kg (G3) alone. Compared to the BAT0303F 3 mg / kg (G2) group, the combination with 1 mg / kg ADC1 demonstrated a statistically significant enhancement in tumor inhibition (p<0.001). BAT0303F can enhance the inhibitory effect of ADC1 on tumor growth, demonstrating a synergistic effect between the two.

[0156] Table 1 Analysis of drug efficacy of each group Note: *** indicates p < 0.001; ns indicates no statistical significance (p greater than 0.05).

[0157] Example 2: A multicenter, open-label, Phase Ib / IIa clinical study of the safety, tolerability, pharmacokinetic characteristics, and preliminary clinical efficacy of ADC1 combined with BAT0303F in patients with locally advanced or metastatic solid tumors

[0158] 1. Clinical study design:

[0159] This multicenter, open-label, exploratory Phase Ib / IIa clinical trial in humans primarily investigates the safety, tolerability, and PK profile of ADC1 (injectable) and BAT0303F in combination with locally advanced or metastatic solid tumors (HER-2 expression, including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-). The study aims to determine the maximum tolerated dose (MTD) and provide a recommended dose (RP2D) and appropriate dosing schedule for subsequent clinical studies, as well as to preliminarily evaluate anti-tumor efficacy. The study is broadly divided into two phases. The first phase will utilize a "3+3" dose-escalation strategy to explore the safety and tolerability of the study drug. The second phase will expand the study by selecting appropriate doses and tumor types based on the preliminary safety and efficacy results from the first phase to further explore the safety and clinical efficacy of the ADC1 and BAT0303F combination, providing a basis for subsequent clinical studies.

[0160] Phase Ib dose escalation study:

[0161] A standard "3+3" dose escalation rule was used to explore the tolerability and safety of the study drug. Three dose groups were set for injectable ADC1: A (2.1 mg / kg), B (2.4 mg / kg), and C (2.7 mg / kg). BAT0303F was administered at a fixed dose of 15 mg / kg. This is shown in the table below:

[0162] The dose escalation pattern of the "3+3" rule is as follows:

[0163] Phase IIa dose expansion cohort study: Based on the preliminary safety and efficacy results of the dose escalation study, 1 to 2 dose levels will be selected to conduct an expansion cohort study in patients with breast cancer, urothelial carcinoma, and gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) with HER-2 expression (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-).

[0164] Dosage regimen

[0165] Dosing is planned to occur every three weeks (Q3W), with BAT0303F administered first, followed by ADC1, using a mg / kg dosing schedule and administered intravenously according to the protocol's prescribed dose groups. The dose may be adjusted based on emerging safety information and / or PK data.

[0166] Administer the prepared BAT0303F intravenously. The recommended infusion time is 90 ± 10 minutes. If an infusion reaction occurs, the infusion time can be extended appropriately. If the initial infusion is well tolerated, the infusion time for subsequent treatment cycles can be shortened to 45 ± 15 minutes. Patients should be observed for 45 ± 15 minutes after the infusion. After the observation period, ADC1 administration can be resumed.

[0167] The recommended infusion duration for the first dose of ADC1 is 90 (±10) minutes. If no infusion reaction occurs after the first dose, subsequent doses are recommended to be completed within 30 to 120 minutes, depending on the actual clinical situation.

[0168] The dosage was calculated based on the patient's body weight measured on the day before each dose.

[0169] 2. Definition of Dose-Limiting Toxicity (DLT)

[0170] Adverse events (AEs) will be evaluated based on the Common Criteria for Adverse Events (CTCAE) v5.0. Dose-limiting toxicity (DLT) is defined as an AE that occurs during the DLT observation period and is considered at least possibly related to the study drug. After the first dose, if the second cycle of dosing is delayed due to an AE, the DLT observation period will be extended accordingly. The specific definitions of DLT in this study include the following:

[0171] 1) Grade 5 toxicity.

[0172] 2) Definition of hepatotoxicity (DLT): Grade 4 AST or ALT elevation; in patients with hepatocellular carcinoma or liver metastases, if the baseline AST or ALT is ≤3 times ULN, and the AST or ALT elevation is >5 times ULN and persists for >7 days during the DLT evaluation period; in patients with hepatocellular carcinoma or liver metastases, if the baseline AST or ALT is >3 times ULN, and the AST or ALT elevation is >8 times ULN and persists for >7 days during the DLT evaluation period; in patients without liver metastases, the AST or ALT elevation is >5 times ULN and persists for >7 days; AST or ALT >5 times the upper limit of normal range (ULN) with ≥Grade 2 blood bilirubin elevation.

[0173] Definition of hematological toxicity DLT: Grade 4 neutropenia lasting for >7 days; Grade 3 neutropenia with fever (single body temperature >38.3 or continuous body temperature ≥38°C for more than 1 hour); Grade 4 anemia; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia lasting for >7 days; Grade 3 thrombocytopenia with bleeding.

[0174] Definition of non-hepatotoxicity and non-hematological toxicity DLT: other ≥ grade 3 non-hepatotoxicity and non-hematological toxicity.

[0175] The following TEAEs are not considered DLTs: Grade 3 nausea, vomiting, diarrhea, anorexia, fatigue, or rash that is controlled with standard supportive care and resolves to ≤ Grade 2 within 3 days; laboratory abnormalities without clinically relevant symptoms or signs, including increased ALP, increased uric acid, increased blood amylase, increased lipase, or lymphocytopenia to Grade 3 or 4; Grade 1 hyponatremia at baseline is upgraded to Grade 3 but persists for less than 72 hours; and Grade 3 infusion reactions that resolve within 6 hours after treatment.

[0176] 3. Study Population

[0177] The target population of this study is patients who have failed standard treatment, have no standard treatment options, or are not currently suitable for standard treatment, and have locally advanced or metastatic solid tumors with HER-2 expression confirmed by histopathology or cytopathology (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH- patients). The escalation phase includes but is not limited to breast cancer, gastric cancer, non-small cell lung cancer, colorectal cancer, urothelial carcinoma, etc., and the expansion phase includes patients with breast cancer, urothelial carcinoma, and gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma).

[0178] 3.1 Inclusion criteria

[0179] 1. Age ≥ 18 years old, regardless of gender;

[0180] 2. According to the researcher's assessment, the expected survival period is ≥ 3 months;

[0181] 3. The Eastern Cooperative Oncology Group (ECOG) performance status score should be 0-1;

[0182] 4. Inclusion population:

[0183] a) Dose escalation phase: Patients who have failed standard treatment, have no standard treatment options, or are currently unsuitable for standard treatment, and whose HER-2 expression (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-) is confirmed by histopathology and cytopathology. The escalation phase includes, but is not limited to, breast cancer, gastric cancer, non-small cell lung cancer, biliary tract cancer, colorectal cancer, and urothelial carcinoma;

[0184] b) Dose expansion phase: divided into 3 cohorts

[0185] i. Cohort A: Patients with breast cancer who have failed standard treatment, have no standard treatment options, or are currently unsuitable for standard treatment, and whose breast cancer has confirmed HER2 expression (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-) as confirmed by histopathology or cytopathology;

[0186] ii. Cohort B: Patients with histologically confirmed unresectable locally advanced or metastatic urothelial carcinoma, including HER-2 expressing (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-) urothelial carcinoma originating from the bladder, renal pelvis, ureter, or urethra;

[0187] iii. Cohort C: Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced or metastatic gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) that expresses HER-2 (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-) and has disease progression after standard treatment or is intolerant to standard treatment;

[0188] 5. There must be evaluable tumor lesions in the dose escalation phase, and at least one measurable tumor lesion in the dose expansion phase (according to RECIST 1.1 criteria);

[0189] 6. Have sufficient organ and bone marrow reserve and heart function.

[0190] 3.2 Exclusion criteria

[0191] 1. Patients who have previously received HER2-targeted drugs such as trastuzumab or pertuzumab, emtansine trastuzumab (T-DM1), vedicizumab or desutuzumab (Enhertu), or topoisomerase I inhibitors (such as irinotecan), experienced AEs of grade 3 or higher that were judged to be treatment-related or of unknown drug relationship (including but not limited to infusion reactions or allergic reactions), or had a left ventricular ejection fraction (LVEF) of <50% after treatment;

[0192] 2. Previous cumulative dose of doxorubicin > 360 mg / m 2 or equivalent anthracycline patients;

[0193] 3. Patients with AEs (CTCAE 5.0) caused by previous anti-tumor treatment still have a grade of ≥1 before the first administration of the study drug, except for the following: a. alopecia; b. pigmentation; c. patients with abscotoxicity caused by chemotherapy or radiotherapy that is judged to be irreversible;

[0194] 4. Patients with primary central nervous system tumors or symptomatic central nervous system metastases, meningeal metastases, or a history of epilepsy. Patients with asymptomatic central nervous system metastases that have achieved clinical control, or those with symptoms but are judged by the investigator to be stable, may be included, but must also meet the following conditions: a. Clinical symptoms have been stable for ≥4 weeks before the first dose; b. No evidence of central nervous system disease progression was found on enhanced cranial MRI within 4 weeks before the first dose; c. Antiepileptic drugs, hormones, and other medications have been discontinued for ≥2 weeks before the first dose;

[0195] 5. Patients who have undergone major surgery within 28 days before the first use of the study drug, or if more than 21 days have passed after surgery, but postoperative complications are still ongoing;

[0196] 6. Patients who have had severe infection within 4 weeks before the first dose, or have any symptoms and signs of active infection within 2 weeks before the first dose;

[0197] 7. Patients with tuberculosis who have not been treated or are currently being treated, including but not limited to pulmonary tuberculosis (those who have received standard anti-tuberculosis treatment and have been confirmed to be cured by the researchers can be included), a history of immunodeficiency, including human immunodeficiency virus (HIV) infection, or other immunodeficiency diseases, or a history of organ transplantation;

[0198] 8. Patients with the following diseases: Active hepatitis B virus infection [Hepatitis B surface antigen (HBsAg) positive, and hepatitis B virus deoxyribonucleic acid (HBV-DNA) test > 200IU / ml or 10 3 copies / ml (or > normal high value tested by the research center)]; patients infected with hepatitis C virus [positive results of HCV antibody and viral RNA (HCV-RNA) test]; patients with positive Treponema pallidum antibody and RPR;

[0199] 9. Patients with symptomatic congestive heart failure (New York Heart Association (NYHA) class II to IV) or severe arrhythmias requiring treatment (QTc prolongation 450 milliseconds [male], 470 milliseconds [female] on 12-lead electrocardiogram), or those who have had myocardial infarction or unstable angina in the past 6 months. Atrial fibrillation or paroxysmal supraventricular tachycardia is excluded;

[0200] 10. Patients with a history of non-infectious pneumonia requiring glucocorticoid treatment or current interstitial lung disease;

[0201] 11. The presence of any other serious underlying diseases (e.g., Gilbert's syndrome, uncontrolled diabetes, uncontrolled hypertension, active gastric ulcer, uncontrolled epileptic seizures, cerebrovascular events, gastrointestinal bleeding, severe signs and symptoms of coagulation and coagulation disorders), which may affect screening, treatment, and follow-up, affect compliance, or put patients at high risk of treatment-related complications;

[0202] 12. Previous anti-tumor treatment (such as chemotherapy, endocrine therapy, targeted therapy, immunotherapy or tumor embolization, etc.) was less than 28 days from the first study drug (or if the 5-fold half-life of the drug is shorter than 28 days, the decision on inclusion should be made based on specific analysis of the specific situation). Please note that castration for prostate cancer, bisphosphonates or denosumab for osteoporosis are allowed. Previous palliative radiotherapy was less than 7 days from the first study drug, or previous wide-field radiotherapy was less than 28 days from the first study drug, or the patient has not recovered from the side effects of radiotherapy;

[0203] 13. Therapeutic radioactive drugs must be discontinued 8 weeks before the first study drug use;

[0204] 14. Patients with known allergy or intolerance to the study drug or its excipients;

[0205] 15. Pregnant or breastfeeding women.

[0206] 4. Study Endpoints

[0207] The primary objective of the dose-escalation study is to evaluate the safety and tolerability of ADC1 and BAT0303F in combination with patients with locally advanced or metastatic solid tumors, and to provide recommended doses for subsequent clinical trials. The secondary objective is to preliminarily evaluate the anti-tumor efficacy, immunogenicity, and pharmacokinetic (PK) characteristics of ADC1 and BAT0303F in combination with patients with locally advanced or metastatic solid tumors after single and multiple doses.

[0208] The primary endpoints were tolerability and safety endpoints: dose-limiting toxicity (DLT), vital signs and physical examinations, adverse events (AEs), clinical laboratory tests, and ECOG.

[0209] Secondary endpoints:

[0210] 1) Pharmacokinetic indicators: Observe the serum concentrations of BAT0303F, ADC1, total anti-HER-2 antibody, and Exatecan at the time points specified in the protocol. Pharmacokinetic evaluation parameters include single and multiple dose pharmacokinetic parameters:

[0211] Single dose: C max 、T max 、T 1 / 2 , CL, Vd, Ke, MRT, AUC (0-τ) , AUC (0-∞) ;

[0212] Multiple doses: C max,ss 、C avg,ss 、C min,ss , AUC (0-τ)ss , AUC(0-∞)ss 、T max,ss 、T 1 / 2,ss , CL, V ss , Ke, MRT, accumulation index (R ac ), volatility index DF.

[0213] 2) Immunogenicity evaluation indicators: anti-drug antibodies (ADA) / neutralizing antibodies (NAb).

[0214] 3) Preliminary efficacy evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1); key indicators include: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0215] 5. Research Results:

[0216] Table 2 Overview of tumor evaluation of ADC1 and BAT0303F combination therapy Note: BC stands for breast cancer and GC stands for gastric cancer.

[0217] To date, a total of 19 patients have undergone at least one anti-tumor efficacy evaluation. These patients include breast cancer and gastric cancer patients with HER-2 expression confirmed by histopathology and cytopathology (including IHC3+, IHC2+ / FISH+, and IHC2+ / FISH-), including patients who have previously used other ADCs (such as T-DM1, A166, RC48, FS1502, SHR-4602, BLM07D1, DS8201, or CMG901) and patients who have not been treated with ADCs. The results are shown in Table 2. In Group B (ADC1 (2.4 mg / kg) + BAT0303F (15 mg / kg)), one breast cancer patient achieved a complete remission (CR), three breast cancer patients, and one gastric cancer patient achieved a partial remission; most patients in the other dose groups achieved a partial remission (PR) or maintained stable disease (SD); the overall ORR was 42.1%, 8 / 19, and the DCR was 78.9%, 15 / 19; the ORR in the breast cancer patient group was 42.8% (6 / 14), and the ORR in the gastric cancer patient group was 40% (2 / 5), showing good therapeutic potential regardless of whether the patients had previously used ADC. This indicates that the combined administration mode of ADC1 and BAT0303F of the present invention is expected to have good safety and tolerability, or lead to at least one improvement selected from the following: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Claims

1. A method for treating solid tumors, comprising administering an effective amount of an anti-HER2 antibody drug conjugate and a HER dimerization inhibitor to a patient suffering from the solid tumor; in, The anti-HER2 antibody drug conjugate has a structure or stereoisomer as shown in Formula IA-1 or IA-2, or a pharmaceutically acceptable salt or solvate thereof: wherein Abu is an antibody or an antigen-binding unit thereof that binds to HER2; R is selected from: -(CH2) r -、-(CHR m ) r -, C3-C8 carbocyclic group, -O-(CH2) r -, arylene, -(CH2) r -Arylene-, -Arylene-(CH2) r -、-(CH2) r -(C3-C8 carbocyclyl)-, -(C3-C8 carbocyclyl)-(CH2) r -, C3-C8 heterocyclic group, -(CH2) r -(C3-C8 heterocyclyl)-, -(C3-C8 heterocyclyl)-(CH2) r -、-(CH2) r C(O)NR m (CH2) r -、-(CH2CH2O) r -、-(CH2CH2O) r -CH2-, -(CH2) r C(O)NR m (CH2CH2O) r -、-(CH2) r C(O)NR m (CH2CH2O) r -CH2-, -(CH2CH2O) r C(O)NR m (CH2CH2O) r -、-(CH2CH2O) r C(O)NR m (CH2CH2O) r -CH2- and -(CH2CH2O) r C(O)NR m (CH2) r -; each R m R is independently H, C1-C6 alkyl, C3-C8 carbocyclyl, phenyl or benzyl; and each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; D is a drug, wherein D is a DNA topoisomerase I inhibitor or a salt thereof, such as exitecan or an exitecan derivative; n is an integer from 1 to 24; p is about 1-10; Alternatively, the HER dimerization inhibitor is an antibody targeting HER2.

2. The method of claim 1, wherein the anti-HER2 antibody drug conjugate has a structure or stereoisomer as shown in Formula I-1 or I-2, or a pharmaceutically acceptable salt or solvate thereof: Formula I-1 is: The formula I-2 is: in, Abu is an antibody or antigen-binding unit thereof that binds to HER2; D is a DNA topoisomerase I inhibitor or a salt thereof, such as exitecan or an exitecan derivative; n is an integer from 1 to 24; or n is an integer from 4 to 12; or n is an integer from 4 to 8; or n is 4 or 8; p is 1-10; or p is 2-8; or p is 4-8; or p is 6-8; or p is 7-8.

3. A method for treating solid tumors, comprising administering to a patient suffering from a solid tumor an effective amount of an anti-HER2 antibody-drug conjugate and a HER dimerization inhibitor, wherein the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate conjugated to a DNA topoisomerase I inhibitor, and the HER dimerization inhibitor is an antibody targeting HER2, wherein the heavy chain of the HER2-targeting antibody comprises the sequence shown in SEQ ID NO: 9, and the light chain of the antibody comprises the sequence shown in SEQ ID NO: 10, and the fucosylation level is 0%-5%.

4. The method according to any one of claims 1 to 3, wherein D is a DNA topoisomerase I inhibitor or a salt thereof, selected from irinotecan, irinotecan hydrochloride, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 9-chloro-10-hydroxycamptothecin, camptothecin derivatives (such as SN-38), 22-hydroxyecliptin, topotecan, lertotecan, belotecan, exitecan, exitecan derivatives (such as Dxd), homosilatecan, 6,8-dibromo-2-methyl-3-[2-(D-xylopyranosylamino)phenyl]-4(3H)-quinazolinone, 2-cyano- 3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-(2E)-2-acrylamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-hydroxyphenylpropyl)-(E)-2-acrylamide, 12-β-D-glucopyranosyl-12,13-dihydro-2,10-dihydroxy-6-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide dihydrochloride, N-[2-(dimethylamino)ethyl]-4-acridinecarboxamide; or where X 1 and X 2 Each is independently C1-C6 alkyl, halogen or -OH; or the C1-C6 alkyl is -CH3; or the halogen is F; ** is the point of attachment.

5. A method for treating a solid tumor, comprising administering to a patient suffering from the solid tumor an effective amount of an anti-HER2 antibody drug conjugate and a HER dimerization inhibitor; in, The anti-HER2 antibody drug conjugate has a structure or stereoisomer as shown in Formula I-17, Formula I-18, Formula I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15 or I-16, or a pharmaceutically acceptable salt or solvate thereof, wherein Formula I-17, Formula I-18, Formula I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15 or I-16 is: in Abu is an antibody or antigen-binding unit thereof that binds to HER2; n is an integer from 1 to 24; or n is an integer from 4 to 12; p is 1-10; or p is 2-8; or p is 4-8; or p is 6-8; or p is 7-8.

6. The method according to any one of claims 1 to 5, wherein the Abu is trastuzumab.

7. The method according to any one of claims 1 to 6, wherein the anti-HER2 antibody drug conjugate has a structure or stereoisomer represented by Formula II or Formula III, or a pharmaceutically acceptable salt or solvate thereof: in, p is 7-8.

8. The method of any one of claims 1-7, wherein the HER dimerization inhibitor is an antibody targeting HER2, wherein the heavy chain variable region of the antibody targeting HER2 comprises HCDR1 set forth in SEQ ID NO: 1, HCDR2 set forth in SEQ ID NO: 2, and HCDR3 set forth in SEQ ID NO: 3, and the light chain variable region of the antibody targeting HER2 comprises LCDR1 set forth in SEQ ID NO: 4, LCDR2 set forth in SEQ ID NO: 5, and LCDR3 set forth in SEQ ID NO: 6; Alternatively, the heavy chain variable region of the antibody targeting HER2 comprises the sequence as shown in SEQ ID NO: 7, a sequence having at least 80% identity with the sequence shown in SEQ ID NO: 7, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 7; and / or the light chain variable region of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO: 8, a sequence having at least 80% identity with the sequence shown in SEQ ID NO: 8, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 8; Alternatively, the heavy chain of the HER2-targeting antibody comprises the sequence shown in SEQ ID NO: 9, a sequence having at least 80% identity with the sequence shown in SEQ ID NO: 9, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 9; and / or the light chain of the HER2-targeting antibody comprises the sequence shown in SEQ ID NO: 10, a sequence having at least 80% identity with the sequence shown in SEQ ID NO: 10, or a sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO: 10; Alternatively, the fucosylation level of the antibody targeting HER2 is 0%-5%, or the antibody comprises no less than 60% G0; Alternatively, the antibody targeting HER2 is an antibody that enhances ADCC.

9. The method according to any one of claims 1 to 8, wherein the solid tumor is a HER2-positive solid tumor or a HER2-low-expressing solid tumor; Alternatively, the solid tumor is a HER2-expressing solid tumor having an immunohistochemical detection of 3+, an immunohistochemical detection of 2+ and a positive in situ hybridization detection, or an immunohistochemical detection of 2+ and a negative in situ hybridization detection.

10. The method according to claim 9, wherein the in situ hybridization is fluorescence in situ hybridization or dual-color silver staining in situ hybridization; or, the in situ hybridization is fluorescence in situ hybridization.

11. The method according to any one of claims 1 to 10, wherein the solid tumor is a locally advanced or metastatic solid tumor expressing HER2.

12. The method according to any one of claims 1 to 11, wherein the solid tumor is breast cancer, gastric cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), biliary tract cancer, colorectal cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, hepatocellular carcinoma, liver cancer, bladder cancer, urethral cancer, urothelial carcinoma, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, or penile cancer.

13. The method according to any one of claims 1 to 12, wherein the anti-HER2 antibody drug conjugate and the HER dimerization inhibitor are administered to the patient sequentially in any order, or are administered to the patient simultaneously; Alternatively, the anti-HER2 antibody drug conjugate is administered after the HER dimerization inhibitor is administered.

14. The method according to any one of claims 1 to 13, wherein the anti-HER2 antibody drug conjugate is administered once every 1, 2, 3, 4, 5, 6 or 7 weeks, and the dose for each administration is 0.5-30 mg / kg; Alternatively, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks, with each dose being 0.5-30 mg / kg; Alternatively, the anti-HER2 antibody drug conjugate is administered approximately once every 3 weeks, with each dose being 1-5 mg / kg; Alternatively, the anti-HER2 antibody drug conjugate is administered approximately once every three weeks, with each administration dose being 2-3 mg / kg.

15. The method according to any one of claims 1 to 14, wherein the HER2 dimerization inhibitor is administered every 1, 2, 3, 4, 5, 6 or 7 weeks, with a dose of 1 to 25 mg / kg per administration; Alternatively, the HER2 dimerization inhibitor is administered approximately once every 3 weeks, with each administration dose being 3-20 mg / kg; Alternatively, the HER2 dimerization inhibitor is administered approximately once every three weeks, with each administration dose being 15 mg / kg.

16. A method for treating solid tumors, comprising administering an effective amount of an anti-HER2 antibody drug conjugate and a HER dimerization inhibitor to a patient suffering from the solid tumor; wherein, The anti-HER2 antibody drug conjugate is anti-HER2-ADC-non-topo1, which is an anti-HER2 antibody drug conjugate coupled with a non-DNA topoisomerase I inhibitor (such as a microtubule inhibitor or a DNA damaging agent). The HER dimerization inhibitor is an antibody targeting HER2, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises the sequence shown in SEQ ID NO: 8, and the fucosylation level is 0%-5%.

17. The method according to claim 16, wherein the tubulin inhibitor is dolastatin, auristatins, maytansines, eribulin and derivatives thereof, and the DNA damaging agent is calicheamicins, duocarmycins or anthramycin derivative PBD.

18. The method according to claim 16 or 17, wherein the anti-HER2 antibody drug conjugate is an antibody drug conjugate conjugated to MMAE, MMAF, AF, ER300, Duo-5 or DM1.

19. The method according to any one of claims 16 to 18, wherein the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate of trastuzumab conjugated with MMAE, MMAF, AF, ER300, Duo-5, or DM1.

20. The method according to any one of claims 16 to 19, wherein the anti-HER2 antibody drug conjugate is trastuzumab enmetuzumab (T-DM1), vedicizumab (RC48, Disitamab-MMAE), trastuzumab foeduzumab (A166, trastuzumab-tubulin inhibitor Duo-5), or FS1502 (trastuzumab-MMAF).

21. The method according to any one of claims 16 to 20, wherein the solid tumor is a solid tumor that has been previously treated with an antibody drug conjugate conjugated to a DNA topoisomerase I inhibitor.

22. The method according to any one of claims 16 to 21, wherein the solid tumor is a HER2-expressing solid tumor.

23. The method of any one of claims 16-22, wherein the solid tumor is breast cancer, gastric cancer, esophageal cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), biliary tract cancer, colorectal cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, cervical cancer, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), peritoneal cancer, pancreatic cancer, glioblastoma, hepatocellular carcinoma, liver cancer, bladder cancer, urethral cancer, urothelial carcinoma, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, or penile cancer.

24. The method of any one of claims 16-23, wherein the heavy chain of the antibody targeting HER2 comprises the sequence shown in SEQ ID NO: 9, the light chain of the antibody comprises the sequence shown in SEQ ID NO: 10, and the fucosylation level of the antibody targeting HER2 is 0%-5%.

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