Yu X-J, Shen Y-F, Dong J, Li T, Wang C, Zhang Y-J, Wang L-F, Meng Y-C, Yang Y, Wang H-J, Lei C-H, Hu S, Li B-H
International Joint Cancer Institute, Second Military Medical University, Shanghai, 200433 People's Republic of China.
Central Laboratory, Navy General Hospital of PLA, Beijing, 100048 People's Republic of China.
Mol Biol (Mosk). 2018 Jul-Aug;52(4):628-633. doi: 10.1134/S0026898418040183.
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.
此前，我们报道了英夫利昔单抗Fab片段与TNFα复合物的晶体结构。在TNFα上通过结构鉴定的表位揭示了通过与TNFα-受体界面部分重叠来抑制TNFα的机制以及优化结合亲和力的可能性。在本研究中，我们基于英夫利昔单抗表位开展了噬菌体展示文库筛选，以分离新型抗TNFα抗体。为开发新型抗TNFα抗体，进行了结构分析、噬菌体展示抗体分离、逐步抗体优化、互补决定区（CDR）残基随机诱变以及结合亲和力表征。在英夫利昔单抗骨架上产生的一种新型抗体Inf3D6对TNFα具有优异的结合亲和力，因此证明了基于结构指导优化以改进现有抗体类疗法的潜力。
