Enhanced antibody-mediated cellular cytotoxicity of germline-like anti-HER2 antibodies through a point mutation in complementarity-determining regions
文献类型：期刊论文
| 作者 | Zhou, Guangyu2; Zhang, Yunsen3; Gu, Yuheng2; Cao, Bihui4; Fan, Xin2; Yu, Di2; Fu, Shengyu2; Liu, Manting5; Assaraf, Yehuda G.6; Li, Yaping1,7
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| 刊名 | JOURNAL OF IMMUNOLOGY
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| 出版日期 | 2025-04-23 |
| 页码 | 11 |
| 关键词 | affinity maturation antibody-mediated cellular cytotoxicity gremlin-like antibody HER2 in silicon |
| ISSN号 | 0022-1767 |
| DOI | 10.1093/jimmun/vkaf063 |
| 英文摘要 | Human epidermal growth factor receptor 2 (HER2) is highly overexpressed on the surface of breast cancer cells, presenting an attractive target for therapeutic antibodies. Antibody-dependent cellular cytotoxicity (ADCC) is a central mechanism underlying the antitumor activities of anti-HER2 monoclonal antibodies. Here, we engineered Ab5, a germline-like anti-HER2 monoclonal antibody derived from a na & iuml;ve human antibody library. Our aim was to enhance the ADCC properties of Ab5 by affinity maturation. Through an in silico aided mutagenesis analysis, we identified an Ab5 mutant termed Ab5m, exhibiting enhanced affinity compared with the parental Ab5. Computational modeling predicted that a crucial interacting residue, aspartic acid 31 on the complementarity-determining region 1 of the heavy chain involved in the important charged interactions with HER2 domain II. Substitution of aspartic acid with glutamic acid decreased the interaction energies, resulting in a remarkable affinity enhancement of Ab5m-scFv (KD = 0.2 nM) compared with parental Ab5-scFv (KD = 1.5 nM). This affinity maturation translated into the obvious improvement in ADCC and notable enhancement of tumor ablation in vivo, either alone or in combination with anti-B7-H3 antibodies. These findings suggest that the potential of affinity optimization as a strategy to enhance the ADCC properties of human germline antibodies. |
| WOS关键词 | AFFINITY MATURATION ; CANCER ; BINDING |
| 资助项目 | Natural Science Foundation of Guangdong Province ; MoE Frontiers Science Center for Precision Oncology, Animal Research Core and Biological Imaging and Stem Cell Core, University of Macau ; Macau Blood Donation Center |
| WOS研究方向 | Immunology |
| 语种 | 英语 |
| WOS记录号 | WOS:001472684600001 |
| 出版者 | OXFORD UNIV PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317470]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Yaping; Ouyang, Defang; Zhao, Qi |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Macau, Fac Hlth Sci, MOE Frontiers Sci Ctr Precis Oncol, Taipa, Macau, Peoples R China 3.Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Peoples R China 4.Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Guangdong Acad Med Sci, Guangzhou, Peoples R China 5.Guangzhou Med Univ, Affiliated Hosp 2, Dept Radiol, Guangzhou, Guangdong, Peoples R China 6.Technion Israel Inst Technol, Fac Biol, Fred Wyszkowski Canc Res Lab, Haifa, Israel 7.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Guangyu,Zhang, Yunsen,Gu, Yuheng,et al. Enhanced antibody-mediated cellular cytotoxicity of germline-like anti-HER2 antibodies through a point mutation in complementarity-determining regions[J]. JOURNAL OF IMMUNOLOGY,2025:11. |
| APA | Zhou, Guangyu.,Zhang, Yunsen.,Gu, Yuheng.,Cao, Bihui.,Fan, Xin.,...&Zhao, Qi.(2025).Enhanced antibody-mediated cellular cytotoxicity of germline-like anti-HER2 antibodies through a point mutation in complementarity-determining regions.JOURNAL OF IMMUNOLOGY,11. |
| MLA | Zhou, Guangyu,et al."Enhanced antibody-mediated cellular cytotoxicity of germline-like anti-HER2 antibodies through a point mutation in complementarity-determining regions".JOURNAL OF IMMUNOLOGY (2025):11. |
入库方式： OAI收割
来源：上海药物研究所
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