| Literature DB >> 21723291 |
Donna K Finch1, Matthew A Sleeman, Jacques Moisan, Franco Ferraro, Sara Botterell, Jamie Campbell, Duncan Cochrane, Simon Cruwys, Elizabeth England, Steven Lane, Elizabeth Rendall, Monisha Sinha, Craig Walker, Gareth Rees, Michael A Bowen, Amy Schneider, Meina Liang, Raffaella Faggioni, Michael Fung, Philip R Mallinder, Trevor Wilkinson, Roland Kolbeck, Tristan Vaughan, David C Lowe.
Abstract
The differentiation of therapeutic monoclonal antibodies in an increasingly competitive landscape requires optimization of clinical efficacy combined with increased patient convenience. We describe here the generation of MEDI5117, a human anti-interleukin (IL)-6 antibody generated by variable domain engineering, to achieve subpicomolar affinity for IL-6, combined with Fc (fragment crystallizable) engineering to enhance pharmacokinetic half-life. MEDI5117 was shown to be highly potent in disease-relevant cellular assays. The pharmacokinetics of MEDI5117 were evaluated and compared to those of its progenitor, CAT6001, in a single-dose study in cynomolgus monkeys. The antibodies were administered, either subcutaneously or intravenously, as a single dose of 5 mg/kg. The half-life of MEDI5117 was extended by approximately 3-fold, and clearance was reduced by approximately 4-fold when compared to CAT6001. MEDI5117 therefore represents a potential 'next-generation' antibody; future studies are planned to determine the potential for affinity-driven efficacy and/or less frequent administration.Entities:
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Year: 2011 PMID： 21723291 DOI： 10.1016/j.jmb.2011.06.031
Source DB: PubMed Journal: J Mol Biol ISSN： 0022-2836 Impact factor: 5.469