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

Autor: Liu XY; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China., Chen YL; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China.; Department of Reasearch and Development Center, Dartsbio Pharmaceuticals Ltd., Zhongshan, China., Liu GJ; Department of Reasearch and Development Center, Dartsbio Pharmaceuticals Ltd., Zhongshan, China., Deng XN; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China.; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, China., Cui Y; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China.; Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Tan J; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China., Dong XC; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China.; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, China., Li HY; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China.; Faculty of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, China., Chen GJ; Department of Reasearch and Development Center, Dartsbio Pharmaceuticals Ltd., Zhongshan, China., Ou ZM; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China., Wang CH; Department of Antibody Discovery, Shanghai Mabstone Biotechonology, Ltd., China.; Department of Reasearch and Development Center, Dartsbio Pharmaceuticals Ltd., Zhongshan, China.; Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China.
Jazyk: angličtina
Zdroj: FEBS open bio [FEBS Open Bio] 2022 Sep; Vol. 12 (9), pp. 1644-1656. Date of Electronic Publication: 2022 Aug 18.
DOI: 10.1002/2211-5463.13464
Abstrakt: 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.
(© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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