A Variant of TNFR2-Fc Fusion Protein Exhibits Improved Efficacy in Treating Experimental Rheumatoid Arthritis | Zendy

Tong Yang | Zendy; Zheng Wang | Zendy; Fang Wu | Zendy; Jingwei Tan | Zendy; Yijun Shen | Zendy; Erguang Li | Zendy; Dai Jing-zhi | Zendy; Ronghai Shen | Zendy; Gang Li | Zendy; Jinsong Wu | Zendy; Luochun Wang | Zendy; Haibo Wang | Zendy; Yanjun Liu | Zendy

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A Variant of TNFR2-Fc Fusion Protein Exhibits Improved Efficacy in Treating Experimental Rheumatoid Arthritis

Author(s) -

Tong Yang,

Zheng Wang,

Fang Wu,

Jingwei Tan,

Yijun Shen,

Erguang Li,

Dai Jing-zhi,

Ronghai Shen,

Gang Li,

Jinsong Wu,

Luochun Wang,

Haibo Wang,

Yanjun Liu

Publication year - 2010

Publication title -

plos computational biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.628

H-Index - 182

eISSN - 1553-7358

pISSN - 1553-734X

DOI - 10.1371/journal.pcbi.1000669

Subject(s) - etanercept , rheumatoid arthritis , fusion protein , surface plasmon resonance , tumor necrosis factor alpha , medicine , arthritis , receptor , dissociation constant , immunology , chemistry , recombinant dna , biochemistry , materials science , gene , nanotechnology , nanoparticle

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 TNFα. 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 TNFα, as compared to that of Etanercept. Surface plasmon resonance (SPR) based binding assay revealed that the equilibrium dissociation constant of W89Y/E92N to TNFα 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. These data demonstrate that W89Y/E92N is potentially a better candidate with improved efficacy in treating RA and other autoimmune diseases.

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