Structure-based development and optimization of therapy antibody drugs against TNFα

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• 作者：Wenyan Fu ; Xiaoze Wang ; Weili Yang ; Hiroaki Takeda ; Shi Hu ; Zhiyong Lou…
• 关键词：TNFα ; Targeted therapy ; Adalimumab ; Epitope ; Antibody optimization
• 刊名：Amino Acids
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：47
• 期：6
• 页码：1259-1266
• 全文大小：1,231 KB
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• 作者单位：Wenyan Fu (1) (2) (3)
  Xiaoze Wang (4) (5)
  Weili Yang (5)
  Hiroaki Takeda (3) (6)
  Shi Hu (1) (2)
  Zhiyong Lou (7)
  Jian Zhao (1) (2)
  Augus N. Bethune (3) (8)
  Yajun Guo (1) (2) (5)
  
  1. Key Laboratory of Oncology, Cancer Center, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, People’s Republic of China
  2. Translational Medicine Research Institute and International Joint Cancer Institute, The Second Military Medical University, Shanghai, People’s Republic of China
  3. Tianjin Joint Academy of Biomedicine and Technology, Tianjin, 300457, People’s Republic of China
  4. Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya, Japan
  5. School of Medicine, Nankai University, Tianjin, People’s Republic of China
  6. Department of Biomedicine, Nagoya University, Showa-ku, Nagoya, Japan
  7. Laboratory of Structural Biology and MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, People’s Republic of China
  8. Molecular Drug Discovery Center, Xi’an Jinwa Pharmaceutical Co., Ltd, Xi’an, 710000, Shaanxi, People’s Republic of China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Analytical Chemistry
  Biochemical Engineering
  Life Sciences
  Proteomics
  Neurobiology
  
• 出版者：Springer Wien
• ISSN：1438-2199

文摘

Previously, we reported on the crystal structures of the Fab fragments of two food and drug administration approved therapeutic antibodies, Infliximab and Adalimumab, in complex with TNFα. The structurally identified epitopes on TNFα reveal the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the adalimumab epitope. Structural analysis, the phage display antibody isolation technology, step-by-step antibody optimization, complementarity-determining region residues random mutagenesis, phage ELISA, binding affinity characterization, and cell signaling assays were used for the development and optimization of the novel anti-TNFα antibodies. Moreover, one of the novel antibodies, hAta09, has a superior inhibitory effect on TNFα function and signaling. Taken together, our report established that the novel anti-TNFα antibody hAta09 may achieve clinical efficacy in a TNFα-associated disease.