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Antibody-drug conjugate Pertuzumab-MCC-DM1, conjugate and Trastuzumab composition, and application of conjugate and composition

A P-DM1, drug conjugate technology, applied in the field of antibodies, can solve the problems of apoptosis, growth retardation, etc., achieve good therapeutic effect, and improve the effect of therapeutic effect

Inactive Publication Date: 2015-09-09
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of these signaling pathways leads to growth arrest and apoptosis, respectively
However, there is no relevant report on the coupling of Pertuzumab with small molecule chemotherapy drugs to treat HER2-mediated diseases

Method used

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  • Antibody-drug conjugate Pertuzumab-MCC-DM1, conjugate and Trastuzumab composition, and application of conjugate and composition
  • Antibody-drug conjugate Pertuzumab-MCC-DM1, conjugate and Trastuzumab composition, and application of conjugate and composition
  • Antibody-drug conjugate Pertuzumab-MCC-DM1, conjugate and Trastuzumab composition, and application of conjugate and composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Preparation of Pertuzumab-MCC-DM1 (P-DM1)

[0057] The preparation steps are as follows:

[0058] 1) Buffer exchange of antibodies

[0059] Use desalting chromatography (SephadexTM G25 desalting column) to replace the Pertuzumab monoantigen solution into the reaction buffer (50mM potassium phosphate / 50mM NaCl / 2mM EDTA, pH7.5), and concentrate the antibody concentration to 5mg / ml to prepare Pertuzumab antibody;

[0060] 2) Preparation of MCC-DM1 mother liquor

[0061] Weigh MCC-DM1 and fully dissolve it with dimethylacetamide (DMA) to prepare 10mg / ml MCC-DM1 mother solution;

[0062] 3) Coupling reaction

[0063] Add the MCC-DM1 master solution prepared in step (2) to the pertuzumab prepared in step (1) for conjugation reaction. Antibodies are initially titrated with several excesses of MCC-DM1 to determine the desired DM1:mAb ratio, typically in the range of 6-10 fold molar excess for human antibodies. DMA was within 5% v / v in the reaction. The reaction ...

Embodiment 2

[0075] Embodiment 2: in vitro cell proliferation assay biological activity experiment

[0076] The experimental materials used in the following experiments were obtained from: DMEM medium, F12K medium, RPMI1640 medium, 0.25% trypsin-EDTA, fetal bovine serum, 100× sodium pyruvate, and 100× penicillin streptomycin were purchased from Gibco. Sulforhodamine B (Sulforhodamine B, SRB) was purchased from Sigma. BT-474 breast cancer cells and NCI-N87 gastric cancer cells were from Kunming Cell Bank, Chinese Academy of Sciences, SK-BR-3 breast cancer cells were from Shanghai Bogu Biotechnology Co., Ltd., and Calu-3 lung cancer cells were from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences Banks, SKOV-3 ovarian cancer cells and DU-145 prostate cancer cells were from the American Type Culture Collection (ATCC). All other reagents were analytically pure. 96-well flat bottom polystyrene (Corning, catalog #3599). Synergy2 microplate reader (Bio-Tek).

[0077] I...

Embodiment 3

[0084] Embodiment 3: In vivo anti-tumor efficacy assay experiment:

[0085] The efficacy of the combinations of the invention can be measured in vivo by implanting allografts or xenografts of cancer cells in rodents and treating tumors with the combination. Test mice are treated with drug or control and monitored for several weeks or longer to measure time to tumor doubling, log cell kill, and tumor inhibition.

[0086] 1) Experimental animals

[0087] BALB / cA-nude nude mice, 6-7 weeks old, male, were purchased from Shanghai Slack Experimental Animal Co., Ltd. Certificate number: SCXK (Shanghai) 2012-0002. Breeding environment: SPF grade.

[0088] 2) Experimental steps

[0089]Nude mice were subcutaneously inoculated with human breast cancer BT-474 / T721 cells, and after the tumor grew to 100-200mm3, the animals were randomly divided into groups (D0). See Table 2 for dosage and regimen. The tumor volume was measured twice a week, the mice were weighed, and the data were r...

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Abstract

Provided are antibody-drug conjugate Pertuzumab-MCC-DM1 (that is, P-DM1) and a treating agent composition comprising the P-DM1 and an HER2 dimerisation inhibitor antibody. Also provided are uses of the P-DM1 and the treating agent composition in treating highly proliferative diseases.

Description

technical field [0001] The present invention relates to an antibody-drug conjugate and a method for treating hyperproliferative disorders, in particular to an antibody-drug conjugate Pertuzumab-MCC-DM1 (P-DM1) and its dimerization with a therapeutically effective amount of HER2 Compositions of the CL inhibitor antibody Trastuzumab, and methods of treating hyperproliferative disorders using the antibody-drug conjugates or compositions. Background technique [0002] HER2 (ErbB2) is a receptor tyrosine kinase bound to the surface of the cell membrane, encoded by the proto-oncogene HER2 / neu. Belongs to the epidermal growth factor receptor family, which includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3) and HER4 (erbB4). HER2 is involved in signaling pathways that lead to cell growth and differentiation. Overexpression of HER2 is observed in approximately 25%-30% of human breast cancers. Studies have shown that breast cancer is more invasive and more aggressive when ...

Claims

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Application Information

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IPC IPC(8): C07K16/32A61K39/395A61K31/537A61P35/00A61P35/02
CPCA61K31/5355C07K16/32A61K47/6855A61P35/00A61P35/02A61K47/68033
Inventor 沈竞康孟韬马兰萍张永良彭红丽王昕王英陈驎
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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