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Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain

文献类型：期刊论文

作者Liu, Xin-Yuan6,7; Chen, Yi-Li5,6; Liu, Guo-Jian5; Deng, Xiang-Nan4,6; Cui, Yue2,3,6; Tan, Jie6; Dong, Xing-Chen4,6; Li, Hua-Ying1,6; Chen, Gan-Jun5; Ou, Zhi-Min7
刊名FEBS OPEN BIO
出版日期2022-09-01
卷号12期号:9页码:1644-1656
ISSN号2211-5463
关键词ADCC affinity maturation antibody engineering anti-GD2 antibodies engineered Fc domain humanized
DOI10.1002/2211-5463.13464
通讯作者Chen, Yi-Li(cheny@dartsbio.com) ; Ou, Zhi-Min(oozzmm@163.com) ; Wang, Chun-He(wangc@simm.ac.cn)
英文摘要Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor-associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement-dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next-generation GD2-specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3-16 IgG1m4 antibody from ch14.18 IgG1. H3-16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2-positive cell lines as revealed by ELISA, and its cross-binding activity to other gangliosides was not altered. The CDC activity of H3-16 IgG1m4 was decreased, and the antibody-dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3-16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague-Dawley (SD) rats. In summary, H3-16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects.
WOS关键词ANTI-GD2 MONOCLONAL-ANTIBODY ; COLONY-STIMULATING FACTOR ; STAGE 4 NEUROBLASTOMA ; PHASE-I ; CELLS ; CHILDREN ; TRIAL ; 3F8 ; INTERLEUKIN-2 ; HU14.18K322A
资助项目Shanghai Mabstone Biotechonology ; Dartsbio Pharmaceuticals, Shanghai Institute of Materia Medica ; Zhejiang University of Technology of Pharmaceutical Science ; National Nature Science Foundation of China[21978267] ; National Nature Science Foundation of China[81872785] ; National Nature Science Foundation of China[81673347] ; China National Major Scientific and Technological Special for Significant New Drugs Innovation and Development[2019ZX09732002-006] ; Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)[XDA12020223] ; Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)[XDA12020330] ; Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)[XDA12020360] ; Shanghai Municipal Commission of Science and Technology of China[19431903000] ; Shanghai Municipal Commission of Science and Technology of China[17431904400] ; Shanghai Municipal Commission of Science and Technology of China[19YF1457400] ; Shanghai Municipal Commission of Science and Technology of China[21S11904500] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120202007] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120202008] ; National Key RD Program[2020YFA0509303] ; Major Scientific and Technological Special Projects of Zhongshan City[191022172638719] ; Major Scientific and Technological Special Projects of Zhongshan City[210205143867019]
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者WILEY
WOS记录号WOS:000841539300001
源URL[http://119.78.100.183/handle/2S10ELR8/302305]  
专题中国科学院上海药物研究所
通讯作者Chen, Yi-Li; Ou, Zhi-Min; Wang, Chun-He
作者单位1.Shenyang Pharmaceut Univ, Fac Life Sci & Biopharmaceut, Shenyang, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Biotherapeut Discovery Res Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
5.Dartsbio Pharmaceut Ltd, Dept Reasearch & Dev Ctr, Zhongshan, Peoples R China
6.Shanghai Mabstone Biotechonol Ltd, Dept Antibody Discovery, Shanghai 201203, Peoples R China
7.Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310014, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xin-Yuan,Chen, Yi-Li,Liu, Guo-Jian,et al. Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain[J]. FEBS OPEN BIO,2022,12(9):1644-1656.
APA Liu, Xin-Yuan.,Chen, Yi-Li.,Liu, Guo-Jian.,Deng, Xiang-Nan.,Cui, Yue.,...&Wang, Chun-He.(2022).Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain.FEBS OPEN BIO,12(9),1644-1656.
MLA Liu, Xin-Yuan,et al."Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain".FEBS OPEN BIO 12.9(2022):1644-1656.

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来源：上海药物研究所

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