The pharmacology study of a new recombinant TNF receptor-hyFc fusion protein

Title
The pharmacology study of a new recombinant TNF receptor-hyFc fusion protein
Authors
박창신
Keywords
TNF-a TNF blocker Fc fusion protein TNFR-hyFc Hybrid Fc
Issue Date
2013
Publisher
BIOLOGICALS
Series/Report no.
BIOLOGICALS ; Vol.41 no.2 Startpage 77 Endpage 83
Abstract
TNF-a-blocking agents such as infliximab, adalimumab and etanercept are widely used for the treatment of severe inflammatory diseases including rheumatoid arthritis and psoriasis. The currently used TNFa blockers have Fc regions of the human IgG1 subtype, which is advantageous in terms of in vivo half-life but also raise the potential for unwanted effector-mediated effects, such as antibody dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). To address this issue, we constructed a novel hybrid protein by fusing the TNF receptor (TNFR) with a hybrid Fc (hyFc) consisting of the CH2 and CH3 regions of IgG4 and the highly flexible hinge regions of IgD which would not have ADCC and CDC activity. The resulting fusion protein, TNFR-hyFc, was over-expressed in CHO and pharmacological characteristics were evaluated in comparison with the structurally similar etanercept. TNFR-hyFc effectively neutralized TNF-a in L929 bioassay and showed a 1.5-fold higher neutralizing activity compared to etanercept. In a pharmacokinetic study in cynomolgus monkeys, TNFR-hyFc showed plasma half-life and AUC comparable to etanercept. In a mouse collagen induced arthritis model, TNFR-hyFc showed significant amelioration of arthritis compared to etanercept or vehicle control. In an LPSinduced septic shock model, TNFR-hyFc showed a similar level of protection against mortality as etanercept. These results confirm the feasibility of the TNFR-hyFc as an effective TNF-a blocker for the treatment of inflammatory diseases.
URI
http://dx.doi.org/10.1016/j.biologicals.2012.09.001
http://dspace.inha.ac.kr/handle/10505/31299
ISSN
1045-1056
Appears in Collections:
Medical School/College of Medicine (의학전문대학원/의과대학) > Medical Science (의학) > Journal Papers, Reports(의학 논문, 보고서)
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