2. Academic Validation
  3. Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics

Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics

  • J Mol Biol. 2011 Aug 26;411(4):791-807. doi: 10.1016/j.jmb.2011.06.031.
Donna K Finch 1,  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
Affiliations

Affiliation

  • 1 MedImmune Ltd., Milstein Building, Granta Park, Cambridge CB1 6GH, UK.
PMID: 21723291 DOI: 10.1016/j.jmb.2011.06.031
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.

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