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
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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