Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys

MAbs. Mar-Apr 2012;4(2):267-73. doi: 10.4161/mabs.4.2.19364. Epub 2012 Mar 1.

Abstract

Engineering monoclonal antibodies (mAbs) with improved binding to the neonatal Fc receptor (FcRn) is a strategy that can extend their in vivo half-life and slow their systemic clearance. Published reports have predominantly characterized the pharmacokinetics of mAbs after intravenous administration. Recently, studies in mice suggest FcRn may also play a role in affecting the subcutaneous bioavailability of mAbs. Herein, we examined whether five mAbs engineered with the T250Q/M428L Fc mutations that improved their FcRn interactions, and subsequently their in vivo pharmacokinetics after intravenous administration, had improved subcutaneous bioavailability compared with their wild-type counterparts in cynomolgus monkeys. Similar to the intravenous administration findings, the pharmacokinetic profiles of our variant mAbs after subcutaneous injection showed improved half-life or clearance. In contrast, a clear effect was not observed on the subcutaneous bioavailability. We expect that while FcRn may play a role in determining mAb subcutaneous bioavailability, multiple biopharmaceutical and physiological factors are likely to influence the success of engineering strategies aimed at targeting this pathway for improving bioavailability.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antibodies, Monoclonal, Murine-Derived / genetics
  • Antibodies, Monoclonal, Murine-Derived / immunology
  • Antibodies, Monoclonal, Murine-Derived / pharmacokinetics*
  • Antibodies, Monoclonal, Murine-Derived / pharmacology*
  • Biological Availability
  • Cell Line
  • Half-Life
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Infusions, Subcutaneous
  • Macaca fascicularis
  • Mice
  • Mutation, Missense
  • Receptors, Fc / immunology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / pharmacology

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Histocompatibility Antigens Class I
  • Receptors, Fc
  • Recombinant Proteins
  • Fc receptor, neonatal