a variant of tnfr2-fc fusion protein exhibits improved efficacy in treating experimental rheumatoid arthritis的变种tnfr2-fc融合蛋白展品疗效在治疗实验性类风湿关节炎.pdfVIP

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a variant of tnfr2-fc fusion protein exhibits improved efficacy in treating experimental rheumatoid arthritis的变种tnfr2-fc融合蛋白展品疗效在治疗实验性类风湿关节炎.pdf

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a variant of tnfr2-fc fusion protein exhibits improved efficacy in treating experimental rheumatoid arthritis的变种tnfr2-fc融合蛋白展品疗效在治疗实验性类风湿关节炎

A Variant of TNFR2-Fc Fusion Protein Exhibits Improved Efficacy in Treating Experimental Rheumatoid Arthritis 1. 1. 1 1 1 2 3 Tong Yang , Zheng Wang , Fang Wu , Jingwei Tan , Yijun Shen , Erguang Li , Jingzhi Dai , Ronghai 3 1 1 1 1 1,4 Shen , Gang Li , Jinsong Wu , Luochun Wang , Haibo Wang , Yanjun Liu * 1 Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China, 2 School of Medicine, Nanjing University, Nanjing, China, 3 Shanghai Institute of Pharmaceutical Industry, Shanghai, China, 4 Taizhou Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Taizhou City, Jiangsu Province, China Abstract Etanercept, a TNF receptor 2-Fc fusion protein, is currently being used for the treatment of rheumatoid arthritis (RA). However, 25% to 38% of patients show no response which is suspected to be partially due to insufficient affinity of this protein to TNFa. By using computational protein design, we found that residue W89 and E92 of TNFR2 were critical for ligand binding. Among several mutants tested, W89Y/E92N displayed 1.49-fold higher neutralizing activity to TNFa, as compared to that of Etanercept. Surface plasmon resonance (SPR) based binding assay revealed that the equilibrium dissociation constant of W89Y/E92N to TNFa was 3.65-fold higher than that of Etanercept. In a rat model of collagen- induced arthritis (CIA), W89Y/E92N showed a significantly better ability than Etanercept in reducing paw swelling and improvement of arthritic joint histopathologically. T