title: The pharmacology study of a new recombinant TNF receptor-hyFc fusion protein.
abstract: TNF-α-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 TNF-α 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-α 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 LPS-induced 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-α blocker for the treatment of inflammatory diseases.
authors.affiliation: Biopharmaceutical Research Labs, Research Center, Dong-A Pharmaceutical Co., Ltd., Sanggal-dong, Giheung-gu, Yongin-si, Kyungki-do 446-905, Republic of Korea. jhlee@donga.co.kr
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Cho
authors.forename: Jiwoo
authors.initials: J
authors.lastname: Yeo
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Se Hwan
authors.initials: SH
authors.lastname: Yang
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Sung
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Chang-Shin
authors.initials: CS
authors.lastname: Park
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D000068800:Etanercept; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009500:Neutralization Tests; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D012772:Shock, Septic / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control; D015996:Survival Rate; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept