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Vol 52(2018) N 4 p. 543-547; DOI 10.1134/S0026893318040180 Full Text

X.-J. Yu1,2, Y.-F. Shen3, J. Dong4, T. Li3 , C. Wang1 , Y.-J. Zhang1 , L.-F. Wang1, Y.-C. Meng1 , Y. Yang1,5, H.-J. Wang1,5, C.-H. Lei3, S. Hu3*, B.-H. Li5**

Development and Optimization of Therapeutic Analogues of Anti-TNFα Antibody Infliximab

1International Joint Cancer Institute, Second Military Medical University, Shanghai, 200433 People's Republic of China
2Central Laboratory, Navy General Hospital of PLA, Beijing, 100048 People's Republic of China
3Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, 200433 People's Republic of China
4Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433 People's Republic of China
5Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, 201318 People's Republic of China

*hus@smmu.edu.cn
**bohuali1020@163.com
Received - 2017-08-26; Accepted - 2017-10-28

Previously, we have reported the crystal structures of Fab fragment of Infliximab in complex with TNFα. The structurally identified epitope on TNFα revealed the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface and the possibility to optimize the binding affinity. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the infliximab epitope. To develop novel anti-TNFα antibodies, structural analysis, the phage display antibody isolation, step by step antibody optimization, CDR residues random mutagenesis, and binding affinity characterization were performed. One of the novel antibodies generated on the backbone of infliximab, Inf3D6, has the superior binding affinity to TNFα, thus, demonstrating the potential for structure guided optimization for improvement of existing antibody-based therapeutics.

TNFα, infliximab, targeted therapy



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