A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity
Autor: | Wan-Jian Gu, Jingyu Liu, Xiaoyu Ding, Xiaoyao Hao, Lan Luo, Yujie Zhong, Mingjiu Chen, Shukai Xia, Chunni Zhang |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Research paper Receptor ErbB-2 lcsh:Medicine Apoptosis Epitopes Mice Antineoplastic Agents Immunological 0302 clinical medicine Trastuzumab Drug Discovery Synergistic efficacy Medicine skin and connective tissue diseases lcsh:R5-920 TGI tumor growth inhibition biology Drug Synergism General Medicine Metastatic breast cancer 030220 oncology & carcinogenesis Pertuzumab Animal studies 5G9 Antibody TV tumor volume lcsh:Medicine (General) Protein Binding Signal Transduction medicine.drug TRA trastuzumab Cell Survival Endocytosis General Biochemistry Genetics and Molecular Biology 03 medical and health sciences In vivo Cell Line Tumor Animals Humans neoplasms Cell Proliferation Large-scale screening Dose-Response Relationship Drug business.industry Cell growth lcsh:R Antibody-Dependent Cell Cytotoxicity Institutional Animal Care and Use Committee medicine.disease Xenograft Model Antitumor Assays Disease Models Animal 030104 developmental biology PER pertuzumab biology.protein Cancer research Drug Screening Assays Antitumor business |
Zdroj: | EBioMedicine, Vol 60, Iss, Pp 102996-(2020) EBioMedicine |
ISSN: | 2352-3964 8147-2021 |
Popis: | Background: Pertuzumab is currently used in combination with trastuzumab as the first-line treatment for HER2-positive metastatic breast cancer. However, pertuzumab was originally developed independently from trastuzumab and was later incidentally found to have synergistic efficacy when combined with trastuzumab, it remains to be seen whether a more potent synergistic efficacy partner exists for trastuzumab. Methods: A trastuzumab-based functional assay was used to screen anti-HER2 antibodies harboring trastuzumab-synergistic antitumor activity. The lead candidate 5G9, in combination with trastuzumab, was further characterized for its bioactivities in cell proliferation, cell apoptosis, antigen-antibody endocytosis and HER2-mediated cell signaling pathway blocking. Finally, animal models were used to evaluate the in vivo synergistic antitumor efficacy of 5G9 in combination with trastuzumab. Findings: Compared to pertuzumab, 5G9 demonstrated more potent synergistic cell growth inhibitory activity when combined with trastuzumab (85% vs. 55%, P< 0.001). In addition, 5G9 exhibited a higher internalization rate than pertuzumab (20% vs. 9%, P< 0.05), and was able to further synergize with trastuzumab to promote antigen-antibody endocytosis. The internalination rate of the combination of 5G9 and trastuzumab was higher than the combination of pertuzumab and trastuzumab (35% vs. 14%, P< 0.001). In vivo animal studies demonstrated that 5G9 in combination with trastuzumab showed more potent synergistic antitumor efficacy than the combination of pertuzumab and trastuzumab. Interpretation: 5G9, together with trastuzumab, may provide a potential opportunity for more efficacious treatment of HER2-positive cancers. Funding Statement: Chunni Zhang was supported by grants from National Natural Science Foundation of China (no. 81472021 and no. 81672102) and from the State Key Laboratory of Analytical Chemistry for Life Science (no. 5431ZZXM1907). The research was funded in part by Biosion Incorporated. Declaration of Interests: Xiaoyao Hao, Shukai Xia and Jinyu Liu and Mingjiu Chen are employees of Biosion Inc.. The remaining authors declare no competing interests. Ethics Approval Statement: All animal studies were performed in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines and approved by the Animal Ethical Committee. |
Databáze: | OpenAIRE |
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