Use of Anti-her2 antibody-drug conjugate in treatment of gastric cancer

Abstract

A use of an anti-HER2 antibody-drug conjugate in treatment of gastric cancer. The present disclosure also relates to a use of an anti-HER2 antibody-drug conjugate in preparation of a drug for treating gastric cancer of a subject. The present disclosure also relates to a method for treating gastric cancer of a subject, wherein the method comprises administering an anti-HER2 antibody-drug conjugate to the subject. The method provides benefits to gastric cancer subjects, and has good safety.

Description

Use of anti-HER2 antibody-drug conjugates in the treatment of gastric cancer Technical Field

[0001] The present disclosure relates to the field of biomedicine, and specifically to the use of anti-HER2 antibody-drug conjugates (ADCs) in the treatment of gastric cancer. Background Art

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

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

[0004] Treatments for stomach cancer

[0005] The present disclosure provides a method for treating gastric cancer in a subject, comprising administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject. The present disclosure provides a method for treating esophagogastric junction cancer in a subject, comprising administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject. The present disclosure also provides a method for second-line treatment or later-line treatment of gastric cancer in a subject, comprising administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject. The present disclosure also provides a method for second-line treatment or later-line treatment of esophagogastric junction cancer in a subject, comprising administering an anti-HER2 antibody drug conjugate of the present disclosure to the subject. In some embodiments, in the method, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0006] The present disclosure also provides the use of the anti-HER2 antibody-drug conjugate of the present disclosure in the preparation of a medicament for treating gastric cancer in a subject. The present disclosure also provides the use of the anti-HER2 antibody-drug conjugate of the present disclosure in the preparation of a medicament for treating esophagogastric junction cancer in a subject. The present disclosure also provides the use of the anti-HER2 antibody-drug conjugate of the present disclosure in the preparation of a medicament for second-line treatment or later-line treatment of gastric cancer in a subject. The present disclosure also provides the use of the anti-HER2 antibody-drug conjugate of the present disclosure in the preparation of a medicament for second-line treatment or later-line treatment of esophagogastric junction cancer in a subject. In some embodiments, the medicament comprises a therapeutically effective amount of the anti-HER2 antibody-drug conjugate.

[0007] The present disclosure also provides use of the anti-HER2 antibody-drug conjugate of the present disclosure for treating gastric cancer in a subject. The present disclosure also provides use of the anti-HER2 antibody-drug conjugate of the present disclosure for treating esophagogastric junction cancer in a subject.

[0008] The present disclosure also provides an anti-HER2 antibody-drug conjugate of the present disclosure for treating gastric cancer in a subject. The present disclosure also provides an anti-HER2 antibody-drug conjugate of the present disclosure for treating esophagogastric junction cancer in a subject. The present disclosure also provides an anti-HER2 antibody-drug conjugate of the present disclosure for second-line treatment or later-line treatment of gastric cancer in a subject. The present disclosure also provides an anti-HER2 antibody-drug conjugate of the present disclosure for second-line treatment or later-line treatment of esophagogastric junction cancer in a subject. In some embodiments, the anti-HER2 antibody-drug conjugate is administered to a subject in a therapeutically effective amount.

[0009] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In a specific embodiment, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or a range formed by any of the above values. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered at a dose of 7.5 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, each time at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg of the anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg of the anti-HER2 antibody drug conjugate.

[0010] In some embodiments, in the methods or uses, one treatment cycle is one week, ... In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle.

[0011] The anti-HER2 antibody drug conjugate can be formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition (or preparation). The pharmaceutical composition can be a suitable dosage form. In some embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for parenteral administration. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous or intramuscular administration. In some specific embodiments, the anti-HER2 antibody drug conjugate can be formulated as an injection. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0012] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0013] In the method or use, the dosing regimen (e.g., dosing cycle, dosing time, dosage and dosage adjustment) of the anti-HER2 antibody drug conjugate can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, the anti-HER2 antibody drug conjugate can be delayed for 1-56 days, for example, for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks. For another example, the dosage of the anti-HER2 antibody drug conjugate can be adjusted from 6 mg / kg to 4.5 mg / kg or 5 mg / kg, or from 7.5 mg / kg to 6 mg / kg.

[0014] In some embodiments, the gastric cancer is unresectable, refractory, advanced, recurrent and / or metastatic gastric cancer. In some embodiments, the gastric cancer is unresectable gastric cancer. In some embodiments, the gastric cancer is refractory gastric cancer. In some embodiments, the gastric cancer is advanced gastric cancer. In some embodiments, the gastric cancer is locally advanced gastric cancer. In some embodiments, the gastric cancer is recurrent and / or metastatic gastric cancer. In some embodiments, the gastric cancer is recurrent gastric cancer. In some embodiments, the gastric cancer is metastatic gastric cancer. In some embodiments, the gastric cancer is unresectable locally advanced or distant metastatic gastric cancer. In some embodiments, the gastric cancer is unresectable locally advanced gastric cancer. In some embodiments, the gastric cancer is distant metastatic gastric cancer.

[0015] In some embodiments, the gastric cancer is gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is unresectable, refractory, advanced, recurrent, and / or metastatic gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is unresectable gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is refractory gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is advanced gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is locally advanced gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is recurrent and / or metastatic gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is recurrent gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is metastatic gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is unresectable locally advanced or distantly metastatic gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is unresectable locally advanced gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is distantly metastatic gastric adenocarcinoma.

[0016] In some embodiments, the EGJ cancer is unresectable, refractory, advanced, recurrent, and / or metastatic EGJ cancer. In some embodiments, the EGJ cancer is unresectable EGJ cancer. In some embodiments, the EGJ cancer is refractory EGJ cancer. In some embodiments, the EGJ cancer is advanced EGJ cancer. In some embodiments, the EGJ cancer is locally advanced EGJ cancer. In some embodiments, the EGJ cancer is recurrent and / or metastatic EGJ cancer. In some embodiments, the EGJ cancer is recurrent EGJ cancer. In some embodiments, the EGJ cancer is metastatic EGJ cancer. In some embodiments, the EGJ cancer is unresectable locally advanced or distantly metastatic EGJ cancer. In some embodiments, the EGJ cancer is unresectable locally advanced EGJ cancer. In some embodiments, the EGJ cancer is distant metastatic EGJ cancer.

[0017] In some embodiments, the EGJ cancer is EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is unresectable, refractory, advanced, recurrent, and / or metastatic EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is unresectable EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is refractory EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is locally advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is recurrent and / or metastatic EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is recurrent EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is metastatic EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is unresectable locally advanced or distant metastatic EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is unresectable locally advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is distant metastatic EGJ adenocarcinoma.

[0018] In some embodiments, the gastric cancer is a HER2-expressing gastric cancer. In some embodiments, the gastric cancer is a HER2-positive gastric cancer. In some embodiments, the HER2-positive gastric cancer is a gastric cancer whose HER2 expression is 3+ (i.e., IHC 3+) as determined by immunohistochemistry (IHC). In some embodiments, the HER2-positive gastric cancer is a gastric cancer whose HER2 expression is 2+ as determined by IHC and whose HER2 expression is positive (i.e., IHC 2+ and ISH+) as determined by ISH.

[0019] In some embodiments, the gastric cancer is gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is a HER2-expressing gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is a HER2-positive gastric adenocarcinoma. In some embodiments, the HER2-positive gastric adenocarcinoma is a gastric adenocarcinoma whose HER2 expression is 3+ as determined by immunohistochemistry (IHC). In some embodiments, the HER2-positive gastric adenocarcinoma is a gastric adenocarcinoma whose HER2 expression is 2+ as determined by IHC and whose HER2 expression is positive as determined by ISH.

[0020] In some embodiments, the esophagogastric junction cancer is HER2-expressing esophagogastric junction cancer. In some embodiments, the esophagogastric junction cancer is HER2-positive esophagogastric junction cancer. In some embodiments, the HER2-positive esophagogastric junction cancer is 3+ esophagogastric junction cancer determined by immunohistochemistry (IHC). In some embodiments, the HER2-positive esophagogastric junction cancer is 2+ HER2 expression determined by IHC and positive HER2 expression determined by ISH.

[0021] In some embodiments, the esophagogastric junction cancer is esophagogastric junction adenocarcinoma. In some embodiments, the esophagogastric junction adenocarcinoma is HER2-expressing esophagogastric junction adenocarcinoma. In some embodiments, the esophagogastric junction adenocarcinoma is HER2-positive esophagogastric junction adenocarcinoma. In some embodiments, the HER2-positive esophagogastric junction adenocarcinoma is an esophagogastric junction adenocarcinoma with a HER2 expression of 3+ as determined by immunohistochemistry (IHC). In some embodiments, the HER2-positive esophagogastric junction adenocarcinoma is an esophagogastric junction adenocarcinoma with a HER2 expression of 2+ as determined by IHC and a positive HER2 expression as determined by ISH.

[0022] In some embodiments, the gastric cancer is HER2-positive, unresectable gastric cancer. In some embodiments, the gastric cancer is HER2-positive, advanced gastric cancer. In some embodiments, the gastric cancer is HER2-positive, locally advanced gastric cancer. In some embodiments, the gastric cancer is HER2-positive, metastatic gastric cancer. In some embodiments, the gastric cancer is HER2-positive, unresectable, locally advanced gastric cancer or distant metastasis gastric cancer. In some embodiments, the gastric cancer is HER2-positive, unresectable, locally advanced gastric cancer. In some embodiments, the gastric cancer is HER2-positive, distant metastasis gastric cancer.

[0023] In some embodiments, the gastric cancer is gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, unresectable gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, advanced gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, locally advanced gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, metastatic gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, unresectable, locally advanced or distantly metastatic gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, unresectable, locally advanced gastric adenocarcinoma. In some embodiments, the gastric adenocarcinoma is HER2-positive, distantly metastatic gastric adenocarcinoma.

[0024] In some embodiments, the EGJ cancer is HER2-positive, unresectable EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, advanced EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, locally advanced EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, metastatic EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, unresectable, locally advanced or distant metastatic EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, unresectable, locally advanced EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, unresectable, locally advanced EGJ cancer. In some embodiments, the EGJ cancer is HER2-positive, distant metastatic EGJ cancer.

[0025] In some embodiments, the EGJ cancer is EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, unresectable EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, locally advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, metastatic EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, unresectable, locally advanced or distantly metastatic EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, unresectable, locally advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, unresectable, locally advanced EGJ adenocarcinoma. In some embodiments, the EGJ adenocarcinoma is HER2-positive, distantly metastatic EGJ adenocarcinoma.

[0026] In some embodiments, the subject with gastric cancer has been previously treated for gastric cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric cancer has previously received at least one first-line treatment for gastric cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric cancer has previously received at least two-line treatments for gastric cancer (e.g., treatment failure or intolerance).

[0027] In some embodiments, the gastric cancer is gastric adenocarcinoma. In some embodiments, the subject with gastric adenocarcinoma has been previously treated for gastric adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric adenocarcinoma has previously received at least one first-line treatment for gastric adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric adenocarcinoma has previously received at least two lines of treatment for gastric adenocarcinoma (e.g., treatment failure or intolerance).

[0028] In some embodiments, the subject with esophagogastric junction cancer has been previously treated for esophagogastric junction cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction cancer has previously received at least one first-line treatment for esophagogastric junction cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction cancer has previously received at least two-line treatments for esophagogastric junction cancer (e.g., treatment failure or intolerance).

[0029] In some embodiments, the subject with esophagogastric junction adenocarcinoma has been previously treated for esophagogastric junction adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received at least one line of treatment for esophagogastric junction adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received at least two lines of treatment for esophagogastric junction adenocarcinoma (e.g., treatment failure or intolerance).

[0030] In some embodiments, the subject with gastric cancer has previously received trastuzumab and a platinum drug to treat gastric cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric cancer has previously received trastuzumab and a fluorouracil drug to treat gastric cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric cancer has previously received trastuzumab, a platinum drug, and a fluorouracil drug to treat gastric cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric adenocarcinoma has previously received trastuzumab and a platinum drug to treat gastric adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric adenocarcinoma has previously received trastuzumab and a platinum drug to treat gastric adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric adenocarcinoma has previously received trastuzumab and a fluorouracil drug to treat gastric adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with gastric adenocarcinoma has previously received trastuzumab, a platinum drug, and a fluorouracil drug to treat gastric adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction cancer has previously received trastuzumab and a platinum drug to treat esophagogastric junction cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction cancer has previously received trastuzumab and a fluorouracil drug to treat esophagogastric junction cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction cancer has previously received trastuzumab, a platinum drug, and a fluorouracil drug to treat esophagogastric junction cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received trastuzumab and a platinum drug to treat esophagogastric junction adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received trastuzumab and a fluorouracil drug to treat esophagogastric junction adenocarcinoma (e.g., treatment failure or intolerance). In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received trastuzumab, a platinum drug, and a fluorouracil drug to treat esophagogastric junction adenocarcinoma (e.g., treatment failure or intolerance). The platinum drug includes but is not limited to oxaliplatin and cisplatin. The fluorouracil drug includes but is not limited to 5-fluorouracil, capecitabine, and S-1.

[0031] In some embodiments, the subject with gastric cancer has previously received localized radiation therapy to treat gastric cancer. In some embodiments, the subject with gastric cancer has previously received localized radiation therapy to treat gastric cancer, and the localized radiation therapy was more than 2 weeks from the first administration of the anti-HER2 antibody drug conjugate, and the lesion targeted by the anti-HER2 antibody drug conjugate is not within the localized radiation therapy area. In some embodiments, the subject with gastric cancer has previously received localized radiation therapy to treat gastric cancer, and the localized radiation therapy was more than 2 weeks from the first administration of the anti-HER2 antibody drug conjugate, and the disease has progressed. In some embodiments, the localized radiation therapy is palliative radiation therapy or brain radiation therapy.

[0032] In some embodiments, the gastric cancer is gastric adenocarcinoma. In some embodiments, the subject with gastric adenocarcinoma has previously received localized radiation therapy to treat gastric adenocarcinoma. In some embodiments, the subject with gastric adenocarcinoma has previously received localized radiation therapy to treat gastric adenocarcinoma, and the localized radiation therapy was more than 2 weeks from the first administration of an anti-HER2 antibody drug conjugate, and the lesion targeted by the anti-HER2 antibody drug conjugate was not within the localized radiation therapy area. In some embodiments, the subject with gastric adenocarcinoma has previously received localized radiation therapy to treat gastric adenocarcinoma, and the localized radiation therapy was more than 2 weeks from the first administration of an anti-HER2 antibody drug conjugate, and the disease has progressed. In some embodiments, the localized radiation therapy is palliative radiation therapy or brain radiation therapy.

[0033] In some embodiments, the subject with esophagogastric junction cancer has previously received localized radiation therapy to treat esophagogastric junction cancer. In some embodiments, the subject with esophagogastric junction cancer has previously received localized radiation therapy to treat esophagogastric junction cancer, and the localized radiation therapy was more than 2 weeks from the first administration of an anti-HER2 antibody drug conjugate, and the lesion targeted by the anti-HER2 antibody drug conjugate was not within the localized radiation therapy area. In some embodiments, the subject with esophagogastric junction cancer has previously received localized radiation therapy to treat esophagogastric junction cancer, and the localized radiation therapy was more than 2 weeks from the first administration of an anti-HER2 antibody drug conjugate, and the disease has progressed. In some embodiments, the localized radiation therapy is palliative radiation therapy or brain radiation therapy.

[0034] In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received localized radiation therapy to treat esophagogastric junction adenocarcinoma. In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received localized radiation therapy to treat esophagogastric junction adenocarcinoma, and the localized radiation therapy was more than 2 weeks from the first administration of an anti-HER2 antibody drug conjugate, and the lesion targeted by the anti-HER2 antibody drug conjugate was not within the localized radiation therapy area. In some embodiments, the subject with esophagogastric junction adenocarcinoma has previously received localized radiation therapy to treat esophagogastric junction adenocarcinoma, and the localized radiation therapy was more than 2 weeks from the first administration of an anti-HER2 antibody drug conjugate, and the disease has progressed. In some embodiments, the localized radiation therapy is palliative radiation therapy or brain radiation therapy.

[0035] Anti-HER2 Antibody Drug Conjugates

[0036] The anti-HER2 antibody drug conjugate used in the present disclosure is formed by connecting a drug-linker having a structure shown in the following formula Ia to an antigen-binding construct targeting HER2:

[0037] in,

[0038] The 3-position of -(succinimide-3-yl-N)- in Formula Ia (i.e., The position of the connection) is connected to the antigen binding construct targeting HER2,

[0039] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a heavy chain CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0040] In some embodiments, the 3-position of the -(succinimidyl-3-yl-N)- is linked to the antigen-binding construct targeting HER2 through a thioether bond.

[0041] In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 2 to 8. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 4 to 7. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5 to 6. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5.5 to 6. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5.8 to 6.

[0042] Table 1. CDR sequences of exemplary antigen-binding constructs targeting HER2

[0043] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antigen-binding fragment or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although the CDRs claimed in the present disclosure are based on the sequences shown in Table 1 (one definition), amino acid sequences corresponding to other CDR definition rules (e.g., one or more combinations of the AbM, CCG, Kabat, Chothia, IMGT, or Contact definitions known in the art) should also fall within the scope of protection of the present disclosure.

[0044] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having the amino acid sequence of SEQ ID NO: 8. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the first antigen-binding fragment is as shown in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8.

[0045] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, and a HCDR3 having the amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence of SEQ ID NO: 5, and a LCDR3 having the amino acid sequence of SEQ ID NO: 6, and the heavy chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 8, NO:8 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0046] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:8 are located in the FR regions.

[0047] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 15, and a light chain variable region having the amino acid sequence of SEQ ID NO: 16. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the second antigen-binding fragment is as shown in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 16.

[0048] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 having the amino acid sequence of SEQ ID NO:9, a HCDR2 having the amino acid sequence of SEQ ID NO:10, and a HCDR3 having the amino acid sequence of SEQ ID NO:11, the light chain variable region comprises a LCDR1 having the amino acid sequence of SEQ ID NO:12, a LCDR2 having the amino acid sequence of SEQ ID NO:13, and a LCDR3 having the amino acid sequence of SEQ ID NO:14, and the heavy chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:15, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:15, NO:16 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0049] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16 are located in the FR regions.

[0050] In some embodiments, the HER2-targeting antigen-binding construct may further comprise an immunoglobulin constant region, or a fragment, analog, variant, or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3, and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG1 heavy chains. In some embodiments, the light chain constant region is derived from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the C-terminal lysine of the heavy chain constant region may be present or absent, and deletion of the C-terminal lysine of the heavy chain constant region typically occurs during recombinant expression. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0051] In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: NO: 19 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a third polypeptide chain. In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 19. In some specific embodiments, the antigen-binding construct targeting HER2 consists of three polypeptide chains, wherein the amino acid sequence of the first polypeptide chain is as set forth in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as set forth in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as set forth in SEQ ID NO: 19.

[0052] In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 1, a HCDR2 having an amino acid sequence as shown in SEQ ID NO: 2, a HCDR3 having an amino acid sequence as shown in SEQ ID NO: 3, a LCDR1 having an amino acid sequence as shown in SEQ ID NO: 4, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 5, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 6; the second polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 9, a HCDR2 having an amino acid sequence as shown in SEQ ID NO: 10, and a HCDR3 having an amino acid sequence as shown in SEQ ID NO: 11; the third polypeptide chain comprises a LCDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 14, and the first polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 15, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 16, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 17. NO:17, the first polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:18, the second polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:19, the third polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:20 The amino acid sequence shown in NO:19 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0053] In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 17 is deleted, as shown in SEQ ID NO: 20. In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 18 is deleted, as shown in SEQ ID NO: 21. In some embodiments, the C-terminal lysine of the first and second polypeptide chains is deleted, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 20, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 21.

[0054] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence set forth in SEQ ID NO: 17, 18 or 19 are located in the FR region or the constant region.

[0055] In other embodiments, the antigen-binding construct targeting HER2 is selected from Expi Her2-1, Expi Her2-3, Expi Her2-4, Expi Her2-5, 23C2 Her2-1, 23C2 Her2-3, 23C2 Her2-4 or 23C2 Her2-5 (see WO2021219046 or CN115279791A). In other embodiments, the antigen-binding construct targeting HER2 is selected from Zanidatamab (ZW25), KN026, MBS301, KM257 or BCD-147.

[0056] The anti-HER2 antibody drug conjugate used in the present disclosure can also be represented by the structure shown in the following formula II:

[0057] Wherein, the antigen-binding construct targeting HER2 is as described above. In some embodiments, the drug-linker is connected to the antigen-binding construct targeting HER2 via a thioether bond (position 3 of -(succinimide-3-yl-N)-). n has the same meaning as DAR and represents the average number of cytotoxic drug connections per antigen-binding construct targeting HER2. In some embodiments, n is 2 to 8. In some embodiments, n is 4 to 7. In some embodiments, n is 5 to 6. In some embodiments, n is 5.5 to 6. In some embodiments, n is 5.8 to 6.

[0058] The antibody drug conjugate preferably used in the present disclosure is formed by connecting a drug-linker having a structure shown in the following formula Ia to an antigen-binding construct targeting HER2:

[0059] in,

[0060] The 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2,

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

[0062] For one HER2-targeting antigen-binding construct, the average number of drug-linker connections was 5 to 6.

[0063] In some embodiments, the 3-position of -(succinimidyl-3-yl-N)- in Formula Ia is linked to the antigen-binding construct targeting HER2 through a thioether bond.

[0064] The antibody drug conjugates preferably used in the present disclosure can also be represented by the structure shown in the following formula II:

[0065] Where n is 5 to 6,

[0066] The HER2-targeting antigen-binding construct is composed of three polypeptide chains, the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17 or a variant thereof with a C-terminal lysine deleted, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18 or a variant thereof with a C-terminal lysine deleted, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19 (for example, the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is as shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO: 19; (See SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19.) In some embodiments, the drug-linker is linked to the HER2-targeting antigen-binding construct via a thioether bond.

[0067] In other specific embodiments, the anti-HER2 antibody drug conjugates disclosed herein are selected from MRG002, ARX788, A166, SHR-A1811, BB-1701, SYD985, FS-1502, or BAT8001.

[0068] The anti-HER2 antibody-drug conjugates disclosed herein also include isomers, pharmaceutically acceptable salts, or solvates of the anti-HER2 antibody-drug conjugates, their isomers, or their pharmaceutically acceptable salts.

[0069] Technical Effects

[0070] Administration of the anti-HER2 antibody drug conjugates disclosed herein has one or more of the following effects:

[0071] (1) Producing benefits to subjects with gastric cancer, preferably unresectable locally advanced gastric cancer or metastatic gastric cancer (e.g., distant metastatic gastric cancer);

[0072] (2) benefiting a subject with gastric adenocarcinoma, preferably an unresectable locally advanced gastric adenocarcinoma or a metastatic gastric adenocarcinoma (e.g., a distant metastatic gastric adenocarcinoma);

[0073] (3) benefiting subjects with esophagogastric junction cancer, preferably unresectable locally advanced esophagogastric junction cancer or metastatic esophagogastric junction cancer (e.g., distant metastatic esophagogastric junction cancer);

[0074] (4) Producing benefits to subjects with esophagogastric junction adenocarcinoma, preferably unresectable locally advanced esophagogastric junction adenocarcinoma or metastatic esophagogastric junction adenocarcinoma (e.g., distant metastatic esophagogastric junction adenocarcinoma);

[0075] (5) Good safety;

[0076] (6) well tolerated by subjects;

[0077] (7) It can show good clinical efficacy in subjects with HER2-positive gastric cancer and esophagogastric junction cancer.

[0078] Definition and Description

[0079] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product or its active ingredient.

[0080] As used herein, the structure of "-(succinimidyl-3-yl-N)-" is as follows:

[0081] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0082] Unless otherwise specified, when a group has a linkable site, the link between that site and other groups can be represented by a wavy line. express.

[0083] The term "antigen binding construct" refers to any agent capable of binding to an antigen, such as a polypeptide or polypeptide complex. In some aspects, an antigen binding construct is a polypeptide that specifically binds to a target antigen. An antigen binding construct can be a monomer, dimer, multimer, protein, peptide, protein or peptide complex, antibody, or antigen binding fragment thereof, etc. An antigen binding construct can be a monospecific, bispecific, or multispecific polypeptide construct. In some aspects, an antigen binding construct can include, for example, one or more antigen binding fragments (e.g., Fab or scFv) connected to one or more Fc.

[0084] The "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., HER2 protein). It has been demonstrated that the antigen-binding function of an antibody can be implemented by a fragment of a full-length antibody. Examples encompassed within the term "antigen-binding fragment" of an antibody include: (i) a Fab fragment: a monovalent fragment consisting of a VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of a VH and CH1 domain; (iv) an Fv fragment consisting of the VL and VH domains of a single-arm antibody; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341: 544-546 (1989)); and (vi) a nanobody, an antibody comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a linker, wherein VL and VH are paired to form a monovalent molecule called single-chain Fv (scFv) (see Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)), and these single-chain antibodies are also encompassed by the term antigen-binding fragment. These antibody fragments can be obtained by conventional techniques known to those skilled in the art, and the fragments can be functionally screened by the same method as full-length antibodies.

[0085] The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be aligned and, if necessary, introducing gaps to achieve maximum sequence identity, and not considering any conservative substitutions as part of sequence identity. The alignment of amino acid sequences for identity can be performed in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm needed to obtain maximum alignment over the full length of the comparison sequence.

[0086] The term "treating" means administering a compound of the present disclosure to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes but is not limited to:

[0087] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state;

[0088] (ii) inhibiting the disease or disease state, i.e., curbing its development;

[0089] (iii) alleviate the disease or condition, even if the disease or condition regresses;

[0090] (iv) reducing any direct or indirect pathological consequences of the disease or disease state.

[0091] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" may vary depending on factors such as the compound and its ability to elicit a desired response in a subject, the disease state and its severity, the route of administration, and the age, sex, and weight of the mammal to be treated.

[0092] The terms "administering" or "administering" refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0093] The route of administration of antibody drug conjugates (such as anti-HER2 antibody drug conjugates) includes intravenous, intramuscular, intraperitoneal, spinal column or other parenteral administration routes.Term used herein " parenteral administration " refers to, the mode of administration of the non-enteral administration carried out by injection usually, and includes but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, spinal column, epidural and intrasternal injection and infusion and in vivo electroporation.Administration can also be performed, for example, once, repeatedly, and / or in one or more extended time periods.

[0094] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0095] The term "pharmaceutically acceptable salt" refers to a salt of a compound (e.g., the antibody-drug conjugates of the present disclosure) that is safe and effective when used in mammals and has the desired biological activity. For example, the salt may be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, etc.

[0096] The term "excipient" refers to any ingredient other than the active ingredient (e.g., the antibody drug conjugate of the present disclosure). The choice of excipient will largely depend on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0097] The term "solvate" refers to an association of a compound with solvent molecules.

[0098] In the present disclosure, "HER2-positive" gastric cancer is not particularly limited as long as it is a gastric cancer recognized by those skilled in the art as overexpressing HER2. Preferably, it refers to a gastric cancer whose HER2 expression is 3+ as determined by immunohistochemistry (IHC) (i.e., IHC 3+), or / and a gastric cancer whose HER2 expression is 2+ as determined by IHC and whose HER2 expression is positive as determined by in situ hybridization (ISH) (i.e., IHC 2+ and ISH+). It should be noted that the in situ hybridization method disclosed herein includes, but is not limited to, fluorescence in situ hybridization (FISH) or dual-color in situ hybridization (DISH).

[0099] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "Subject," "patient," or "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject, patient, or subject is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0100] In this article, the terms "esophagogastric junction cancer," "gastroesophageal junction cancer," "esophagogastric junction cancer," and "gastroesophageal junction cancer" are used interchangeably, and the terms "esophagogastric junction adenocarcinoma," "gastroesophageal junction adenocarcinoma," "esophagogastric junction adenocarcinoma," and "gastroesophageal junction adenocarcinoma" are used interchangeably.

[0101] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients (e.g., the anti-HER2 antibody drug conjugates of the present disclosure) and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredients to a subject. As used herein, the terms "pharmaceutical composition" and "preparation" have the same meaning and are used interchangeably.

[0102] The words “comprise,” “comprise,” or “comprises,” and variations thereof such as comprises or comprising, should be construed in an open, non-exclusive sense, ie, “including but not limited to.”

[0103] Herein, singular terms encompass plural referents and vice versa unless the context clearly dictates otherwise.

[0104] As used herein, "about" means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, "about" can mean a range of up to ±5%, such as fluctuations within ±2%, within ±1%, or within ±0.5% of the specific numerical range given. When a specific value is given in the present disclosure or claims, unless otherwise indicated, the meaning of "about" should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise indicated, all values ​​for drug doses, times, step parameters, or conditions are modified by "about" by default.

[0105] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0106] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0107] Embodiment 1. A method for treating gastric cancer or esophagogastric junction cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate, wherein the anti-HER2 antibody drug conjugate is represented by the following formula Ia

[0108] The drug-linker of the structure shown is connected to the antigen-binding construct targeting HER2.

[0109] The 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2,

[0110] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0111] Embodiment 2. The method according to embodiment 1, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7.

[0112] Embodiment 3. The method according to embodiment 2, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5 to 6.

[0113] Embodiment 4. The method according to embodiment 3, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5.5 to 6.

[0114] Embodiment 5. The method according to any one of embodiments 1-4, wherein

[0115] (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:7;

[0116] (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0117] (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0118] (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 15;

[0119] (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16;

[0120] (vi) the second antigen-binding fragment comprises a heavy chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16; or

[0121] (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identical to SEQ ID NO: NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:16.

[0122] Embodiment 6. The method according to any one of embodiments 1-5, wherein

[0123] (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20;

[0124] (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21;

[0125] (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19;

[0126] (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0127] (v) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0128] (vi) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0129] (vii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of NO:19; or

[0130] (viii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: The invention also provides a method for preparing a polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in NO:19.

[0131] Embodiment 7. The method of any one of Embodiments 1-6, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0132] Embodiment 8. The method according to any one of embodiments 1-6, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg each time.

[0133] Embodiment 9. The method according to embodiment 8, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0134] Embodiment 10. The method according to any one of embodiments 1-9, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0135] Embodiment 11. The method according to any one of embodiments 1-10, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0136] Embodiment 12. The method of any one of Embodiments 1-11, wherein the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0137] Embodiment 13. The method according to any one of Embodiments 1-12, wherein the gastric cancer is locally advanced gastric cancer.

[0138] Embodiment 14. The method according to any one of Embodiments 1-12, wherein the gastric cancer is gastric cancer with distant metastasis.

[0139] Embodiment 15. The method according to any one of Embodiments 1-14, wherein the gastric cancer is unresectable gastric cancer.

[0140] Embodiment 16. The method according to any one of Embodiments 1-15, wherein the gastric cancer is HER2-expressing gastric cancer.

[0141] Embodiment 17. The method according to any one of Embodiments 1-16, wherein the gastric cancer is HER2-positive gastric cancer.

[0142] Embodiment 18. The method according to Embodiment 17, wherein the HER2-positive gastric cancer is a gastric cancer whose HER2 expression is determined to be 3+ by IHC.

[0143] Embodiment 19. The method according to Embodiment 17, wherein the HER2-positive gastric cancer is a gastric cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0144] Embodiment 20. The method of any one of Embodiments 1-19, wherein the subject with gastric cancer has previously received at least one line of treatment for gastric cancer.

[0145] Embodiment 21. The method according to any one of Embodiments 1-20, wherein the subject with gastric cancer has previously received trastuzumab and platinum drugs for treatment of gastric cancer.

[0146] Embodiment 22. The method according to any one of embodiments 1-20, wherein the subject with gastric cancer has previously received trastuzumab, platinum drugs, and fluorouracil drugs for the treatment of gastric cancer.

[0147] Embodiment 23. The method of any one of Embodiments 1-22, wherein the subject with gastric cancer has previously received localized radiation therapy to treat gastric cancer.

[0148] Embodiment 24. The method of any one of Embodiments 1-23, wherein the gastric cancer is gastric adenocarcinoma.

[0149] Embodiment 25. The method of any one of embodiments 1-12, wherein the EGJ cancer is locally advanced EGJ cancer.

[0150] Embodiment 26. The method according to any one of embodiments 1-12, wherein the EGJ cancer is EGJ cancer with distant metastasis.

[0151] Embodiment 27. The method of any one of embodiments 1-12, 25, and 26, wherein the EGJ cancer is unresectable EGJ cancer.

[0152] Embodiment 28. The method of any one of embodiments 1-12 and 25-27, wherein the EGJ cancer is HER2-expressing EGJ cancer.

[0153] Embodiment 29. The method of any one of embodiments 1-12 and 25-28, wherein the EGJ cancer is HER2-positive EGJ cancer.

[0154] Embodiment 30. The method according to embodiment 29, wherein the HER2-positive esophagogastric junction cancer is an esophagogastric junction cancer whose HER2 expression is determined to be 3+ by IHC.

[0155] Embodiment 31. The method according to embodiment 29, wherein the HER2-positive esophagogastric junction cancer is an esophagogastric junction cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is positive by ISH.

[0156] Embodiment 32. The method of any one of embodiments 1-12 and 25-31, wherein the subject with EGJ cancer has previously received at least one line of treatment for EGJ cancer.

[0157] Embodiment 33. The method of any one of embodiments 1-12 and 25-32, wherein the subject with EGJ cancer has previously received trastuzumab and a platinum drug for the treatment of EGJ cancer.

[0158] Embodiment 34. The method of any one of embodiments 1-12 and 25-32, wherein the subject with EGJ cancer has previously received trastuzumab, a platinum drug, and a fluorouracil drug for the treatment of EGJ cancer.

[0159] Embodiment 35. The method of any one of embodiments 1-12 and 25-34, wherein the subject with EGJ cancer has previously received localized radiation therapy to treat EGJ cancer.

[0160] Embodiment 36. The method of any one of embodiments 1-12 and 25-35, wherein the EGJ cancer is EGJ adenocarcinoma.

[0161] Embodiment 37. Use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for treating gastric cancer or esophagogastric junction cancer in a subject, wherein the anti-HER2 antibody drug conjugate is represented by the following formula Ia

[0162] The drug-linker of the structure shown is connected to the antigen-binding construct targeting HER2.

[0163] The 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2,

[0164] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0165] Embodiment 38. The use according to embodiment 37, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7.

[0166] Embodiment 39. The use according to embodiment 38, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5 to 6.

[0167] Embodiment 40. The use according to embodiment 39, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5.5 to 6.

[0168] Embodiment 41. The use according to any one of embodiments 37-40, wherein

[0169] (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:7;

[0170] (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0171] (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8;

[0172] (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 15;

[0173] (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 16;

[0174] (vi) the second antigen-binding fragment comprises a heavy chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:16; or

[0175] (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identical to SEQ ID NO: NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO:16.

[0176] Embodiment 42. The use according to any one of embodiments 37-41, wherein

[0177] (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20;

[0178] (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21;

[0179] (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 19;

[0180] (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17 or 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18 or 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0181] (v) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0182] (vi) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of NO:19;

[0183] (vii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 21, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: a third polypeptide chain that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of NO:19; or

[0184] (viii) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20, a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: The invention also provides a method for preparing a polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the amino acid sequence shown in NO:19.

[0185] Embodiment 43. The use according to any one of Embodiments 37-42, wherein the medicament comprises a therapeutically effective amount of the anti-HER2 antibody drug conjugate.

[0186] Embodiment 44. The use according to any one of Embodiments 37-42, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg each time.

[0187] Embodiment 45. The use according to embodiment 44, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0188] Embodiment 46. The use according to any one of Embodiments 37-45, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0189] Embodiment 47. The use according to any one of Embodiments 37-46, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0190] Embodiment 48. The use according to any one of Embodiments 37-47, wherein the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0191] Embodiment 49. The use according to any one of Embodiments 37-48, wherein the gastric cancer is locally advanced gastric cancer.

[0192] Embodiment 50. The use according to any one of Embodiments 37-48, wherein the gastric cancer is gastric cancer with distant metastasis.

[0193] Embodiment 51. The use according to any one of Embodiments 37-50, wherein the gastric cancer is unresectable gastric cancer.

[0194] Embodiment 52. The use according to any one of Embodiments 37-51, wherein the gastric cancer is HER2-expressing gastric cancer.

[0195] Embodiment 53. The use according to any one of Embodiments 37-52, wherein the gastric cancer is HER2-positive gastric cancer.

[0196] Embodiment 54. The use according to Embodiment 53, wherein the HER2-positive gastric cancer is a gastric cancer whose HER2 expression is determined to be 3+ by IHC.

[0197] Embodiment 55. The use according to Embodiment 53, wherein the HER2-positive gastric cancer is a gastric cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0198] Embodiment 56. The use according to any one of embodiments 37-55, wherein the subject with gastric cancer has previously received at least one line of treatment for gastric cancer.

[0199] Embodiment 57. The use according to any one of Embodiments 37-56, wherein the subject with gastric cancer has previously received trastuzumab and platinum drugs for the treatment of gastric cancer.

[0200] Embodiment 58. The use according to any one of Embodiments 37-56, wherein the subject with gastric cancer has previously received trastuzumab, platinum drugs and fluorouracil drugs for the treatment of gastric cancer.

[0201] Embodiment 59. The use according to any one of embodiments 37-58, wherein the subject with gastric cancer has previously received local radiation therapy to treat gastric cancer.

[0202] Embodiment 60. The use according to any one of Embodiments 37-59, wherein the gastric cancer is gastric adenocarcinoma.

[0203] Embodiment 61. The use according to any one of embodiments 37-48, wherein the EGJ cancer is locally advanced EGJ cancer.

[0204] Embodiment 62. The use according to any one of embodiments 37-48, wherein the esophagogastric junction cancer is esophagogastric junction cancer with distant metastasis.

[0205] Embodiment 63. The use according to any one of embodiments 37-48, 61 and 62, wherein the EGJ cancer is unresectable EGJ cancer.

[0206] Embodiment 64. The use according to any one of embodiments 37-48 and 61-63, wherein the EGJ cancer is HER2-expressing EGJ cancer.

[0207] Embodiment 65. The use according to any one of embodiments 37-48 and 61-64, wherein the EGJ cancer is HER2-positive EGJ cancer.

[0208] Embodiment 66. The use according to embodiment 65, wherein the HER2-positive esophagogastric junction cancer is an esophagogastric junction cancer whose HER2 expression is 3+ as determined by IHC.

[0209] Embodiment 67. The use according to embodiment 65, wherein the HER2-positive esophagogastric junction cancer is an esophagogastric junction cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is positive by ISH.

[0210] Embodiment 68. The use according to any one of embodiments 37-48 and 61-67, wherein the subject with EGJ cancer has previously received at least one line of treatment for EGJ cancer.

[0211] Embodiment 69. The use according to any one of embodiments 37-48 and 61-68, wherein the subject with EGJ cancer has previously received trastuzumab and a platinum drug for the treatment of EGJ cancer.

[0212] Embodiment 70. The use according to any one of embodiments 37-48 and 61-68, wherein the subject with EGJ cancer has previously received trastuzumab, platinum drugs, and fluorouracil drugs for the treatment of EGJ cancer.

[0213] Embodiment 71. The use according to any one of embodiments 37-48, 61-70, wherein the subject with EGJ cancer has previously received localized radiation therapy to treat EGJ cancer.

[0214] Embodiment 72. The use according to any one of embodiments 37-48 and 61-71, wherein the EGJ cancer is EGJ adenocarcinoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0215] Figure 1 shows the growth curve of tumor volume of tumor-bearing mice in the NCI-N87 / 16-8 mouse subcutaneous transplant tumor model, including the vehicle control group, ADC1 (0.5 mg / kg) administration group, ADC1 (1.5 mg / kg) administration group, ADC1 (5 mg / kg) administration group, and T-DM1 (5 mg / kg) administration group. Example

[0216] For the purpose of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure.

[0217] The entire contents of WO2022033578 or CN115702008A patent application documents are incorporated herein by reference. The anti-HER2 antibody drug conjugates in the following examples are prepared with reference to the preparation method described in WO2022033578 and are represented by the following formula (hereinafter referred to as ADC1):

[0218] The drug-linker is connected to the HER2-targeting antigen-binding construct via a thioether bond, and n is 5 to 6. In short, the nucleic acid sequences encoding the three polypeptide chains of the HER2-targeting antigen-binding construct (amino acid sequences are shown in SEQ ID NO: 17, 18, and 19, respectively) are cloned into the pcDNA3.1 expression vector, co-transfected into FUT8-knockout CHO-S cells for expression, and purified by protein A to prepare the HER2-targeting antigen-binding construct. The HER2-targeting antigen-binding construct is treated with tris(2-carboxyethyl)phosphine hydrochloride and then reacted with a linker-payload selected from the structure shown in the following formula to finally obtain ADC1:

[0219] Example 1: Anti-tumor effect of anti-HER2 antibody drug conjugate in NCI-N87 / 16-8 mouse subcutaneous transplant tumor model

[0220] BALB / c-nu nude mice (from Beijing Huafukang Biotechnology Co., Ltd.) were subcutaneously inoculated with NCI-N87 / 16-8 human gastric cancer cells (NCI-N87 cells were from ATCC and became resistant to T-DM1 after long-term treatment with T-DM1. The T-DM1-resistant NCI-N87 cells were named NCI-N87 / 16-8 cells). The cell inoculation volume was 1×10 7 When the average tumor volume in the body grows to 100-150 mm 3 Mice were randomly divided into groups at 4 hr. The day of grouping was designated Day 0 (D0). On the day of grouping, drugs were administered intravenously according to the schedule in Table 2. Roche's T-DM1 (trastuzumab emtansine) was used as a positive control, and normal saline was used as a vehicle control. After the start of dosing, mouse body weight and tumor size were measured twice weekly, and tumor growth inhibition (TGI) was calculated.

[0221] Tumor volume (mm 3 ) = 0.5 × (long diameter of tumor × short diameter of tumor 2 ); TGI(%)=(1-T / C)×100%;

[0222] T / C = (T-T0) / (C-C0) × 100%, where T and C are the tumor volumes of the treatment group and the vehicle control group at the end of the experiment, respectively; T0 and C0 are the tumor volumes of the treatment group and the vehicle control group at the beginning of the experiment, respectively.

[0223] Table 2. Dosage regimen

[0224] The results are shown in Table 3 and Figure 1 , in which ADC1 has good anti-tumor activity against T-DM1-resistant tumor cells.

[0225] Table 3. Anti-tumor effects of anti-HER2 antibody drug conjugates in the NCI-N87 / 16-8 mouse subcutaneous xenograft tumor model

[0226] Example 2: Clinical trial of HER2-expressing gastric cancer

[0227] 1. Research objectives:

[0228] 1.1 Main Purpose:

[0229] To evaluate the tolerability of ADC1 in subjects with advanced malignancies, including gastric or gastroesophageal junction cancer.

[0230] 1.2 Secondary Purpose:

[0231] To evaluate the pharmacokinetic (PK), immunogenicity, safety, and preliminary efficacy of ADC1 in subjects with advanced malignancies;

[0232] To evaluate potential biomarkers related to the mechanism of action of ADC1 in subjects with advanced malignancies.

[0233] 2. Selection Criteria

[0234] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0235] (1) The subjects voluntarily participated in this study and signed the informed consent form;

[0236] (2) Age: 18-75 years old (at the time of signing the informed consent); ECOG score: ≤1; expected survival time: more than 3 months;

[0237] (3) Dose escalation phase: Patients with advanced malignant tumors confirmed by cytology / histopathology, with priority given to subjects with HER2 expression, amplification, or mutation;

[0238] Extension study phase: Patients with unresectable locally advanced or distantly metastatic gastric cancer or gastroesophageal junction adenocarcinoma who are required to be HER2-positive by pathological examination (HER2 3+ by immunohistochemistry, or HER2 2+ and ISH-positive);

[0239] (4) Subjects with malignant tumors who have failed standard treatment or lack effective treatment; the specific requirements for the expansion cohort are as follows:

[0240] For gastric cancer, patients must have failed treatment with at least one regimen containing trastuzumab and platinum drugs and / or fluorouracil.

[0241] (5) In the dose escalation phase, at least one evaluable lesion must be confirmed according to the RECIST 1.1 standard (measurable is not required, as long as the disease status can be assessed); in the cohort expansion phase, at least one measurable lesion must be confirmed according to the RECIST 1.1 standard;

[0242] (6) The major organs function well and meet the following criteria:

[0243] 1) Routine blood test standards (no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days before the test):

[0244] i. Hemoglobin (HGB) ≥ 90 g / L;

[0245] ii. Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

[0246] iii. Platelet count (PLT) ≥ 90 × 10 9 / L;

[0247] 2) Biochemical examination must meet the following standards:

[0248] i. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

[0249] ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If accompanied by liver metastasis, ALT and AST ≤ 5 × ULN;

[0250] iii. Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 60 mL / min (using the standard Cockcroft-Gault formula);

[0251] 3) Coagulation function tests must meet the following criteria:

[0252] International normalized ratio (INR) ≤ 1.5 × ULN (no anticoagulant therapy within the past 2 weeks);

[0253] 4) Echocardiography assessment: left ventricular ejection fraction (LVEF) ≥ 50%;

[0254] (7) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before enrollment in the study, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0255] 3. Trial Drugs

[0256] ADC1 for injection (specification: 100 mg / bottle) is developed and provided by Nanjing Shunxin Pharmaceutical Co., Ltd. of Zhengda Tianqing Pharmaceutical Group.

[0257] 4. Treatment options

[0258] 4.1 Dose escalation phase:

[0259] Six dose groups were used for dose escalation, with the dose group levels being: 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg and 9 mg / kg; one treatment cycle was every 3 weeks (21 days), and ADC1 was administered once in each treatment cycle until the disease progressed or the researcher determined that it was not suitable for continued medication.

[0260] 4.2 Extended research phase:

[0261] In the dose-escalation phase, 1-2 appropriate dose groups (e.g., 6 mg / kg and 7.5 mg / kg) were selected, with one treatment cycle every 3 weeks (21 days), and ADC1 was administered once in each treatment cycle until the disease progressed or the researcher determined that it was not suitable for continued medication.

[0262] Adjustments may be made based on disease severity, disease response, any treatment-related toxicities, and the patient's age and health status.

[0263] 5. Evaluation Criteria

[0264] Effectiveness evaluation: RECIST 1.1 criteria were used to determine the disease status.

[0265] Safety evaluation: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0266] 6. Endpoint indicators

[0267] 6.1 Primary Endpoint:

[0268] Dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D);

[0269] the incidence and severity of adverse events (AEs);

[0270] 6.2 Secondary End Points:

[0271] immunogenicity (e.g., ADA incidence);

[0272] Pharmacokinetic parameters;

[0273] Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0274] 7. Results

[0275] As of the clinical data collection date, 18 patients with gastric or GEJ cancer enrolled in the 7.5 mg / kg dose group were evaluable, of whom 11 achieved a PR, with an ORR of 61.1% and a DCR of 94.4%. These results demonstrate that the anti-HER2 antibody-drug conjugates disclosed herein have a promising therapeutic effect in patients with gastric adenocarcinoma and GEJ adenocarcinoma.

[0276] What is particularly surprising is that no interstitial lung disease (ILD) was reported among the enrolled subjects, demonstrating a good safety profile.

Claims

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

14.

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

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

16.

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

19.

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

6. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 5, wherein: The anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

7. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 6, wherein: The anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion; preferably, the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

8. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 7, wherein: The gastric cancer is locally advanced gastric cancer, or the gastric cancer is distant metastatic gastric cancer; and / or The esophagogastric junction cancer is locally advanced esophagogastric junction cancer, or the esophagogastric junction cancer is distant metastatic esophagogastric junction cancer.

9. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 8, wherein: The gastric cancer is unresectable gastric cancer; The gastric cancer is HER2-expressing gastric cancer; and / or The gastric cancer is HER2-positive gastric cancer.

10. The anti-HER2 antibody-drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to claim 9, wherein The HER2-positive gastric cancer is a gastric cancer in which the HER2 expression is determined to be 3+ by IHC; or The HER2-positive gastric cancer is a gastric cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

11. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 10, wherein: The subject with gastric cancer has previously received at least one line of treatment for gastric cancer: The subject with gastric cancer has previously received trastuzumab and platinum drugs for treatment of gastric cancer; The subject with gastric cancer has previously received trastuzumab, platinum drugs and fluorouracil drugs for treatment of gastric cancer; and / or The subject with gastric cancer has previously received local radiation therapy to treat gastric cancer.

12. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 8, wherein: The esophagogastric junction cancer is unresectable esophagogastric junction cancer: The esophagogastric junction cancer is HER2-expressing esophagogastric junction cancer; and / or The esophagogastric junction cancer is HER2-positive esophagogastric junction cancer.

13. The anti-HER2 antibody-drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to claim 12, wherein: The HER2-positive esophagogastric junction cancer is an esophagogastric junction cancer whose HER2 expression is 3+ as determined by IHC and / or an esophagogastric junction cancer whose HER2 expression is positive as determined by ISH; or The HER2-positive esophagogastric junction cancer is an esophagogastric junction cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

14. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1-8 and 12-13, wherein: The subject with esophagogastric junction cancer has previously received at least one line of treatment for esophagogastric junction cancer; The subject with esophagogastric junction cancer has previously received trastuzumab and platinum drugs for the treatment of esophagogastric junction cancer; The subject with esophagogastric junction cancer has previously received trastuzumab, platinum drugs and fluorouracil drugs for the treatment of esophagogastric junction cancer; and / or The subject with esophagogastric junction cancer has previously received local radiotherapy to treat esophagogastric junction cancer.

15. The anti-HER2 antibody drug conjugate for treating gastric cancer or esophagogastric junction cancer in a subject according to any one of claims 1 to 14, wherein: The gastric cancer is gastric adenocarcinoma, and / or The esophagogastric junction cancer is esophagogastric junction adenocarcinoma.

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