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. Epub 2011 Jun 23.


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.

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / administration & dosage
  • Antibodies, Anti-Idiotypic / pharmacology*
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacokinetics*
  • Antibodies, Monoclonal / pharmacology*
  • Cells, Cultured
  • Half-Life
  • Humans
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Kidney / cytology
  • Kidney / metabolism
  • Macaca fascicularis / immunology*
  • Models, Chemical
  • Mutagenesis
  • Protein Engineering
  • Receptors, Interleukin / immunology
  • Surface Plasmon Resonance
  • T-Lymphocytes / metabolism
  • Tissue Distribution
  • Vascular Endothelial Growth Factor A / metabolism


  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal
  • Interleukin-6
  • Receptors, Interleukin
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A