Whole-Molecule Antibody Engineering: Generation of a High-Affinity Anti-IL-6 Antibody with Extended Pharmacokinetics Academic Article uri icon

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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.

authors

  • Finch, Donna K
  • Sleeman, Matthew A
  • Moisan, Jacques
  • Ferraro, Franco
  • Botterell, Sara
  • Campbell, Jamie
  • Cochrane, Duncan
  • Cruwys, Simon
  • England, Elizabeth
  • Lane, Steven
  • Rendall, Elizabeth
  • Sinha, Monisha
  • Walker, Craig
  • Rees, Gareth
  • Bowen, Michael A
  • Schneider, Amy
  • Liang, Meina
  • Faggioni, Raffaella
  • Fung, Michael
  • Mallinder, Philip R
  • Wilkinson, Trevor
  • Kolbeck, Roland
  • Vaughan, Tristan
  • Lowe, David C

publication date

  • August 2011

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