Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies

Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18709-14. doi: 10.1073/pnas.0606304103. Epub 2006 Nov 20.

Abstract

The MHC class I-related receptor, neonatal Fc receptor (FcRn), plays a central role in regulating the transport and in vivo persistence of immunoglobulin G (IgG). IgG-FcRn interactions can be targeted for engineering to modulate the in vivo longevity and transport of an antibody, and this has implications for the successful application of therapeutic IgGs. Although mice are widely used to preclinically test antibodies, human and mouse FcRn have significant differences in binding specificity. Here we show that an engineered human IgG1 has disparate properties in murine and human systems. The mutant shows improved transport relative to wild-type human IgG1 in assays of human FcRn function but has short in vivo persistence and competitively inhibits FcRn activity in mice. These studies indicate potential limitations of using mice as preclinical models for the analysis of engineered antibodies. Alternative assays are proposed that serve as indicators of the properties of IgGs in humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution / genetics
  • Animals
  • Binding Sites, Antibody
  • Female
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism
  • Immunoglobulin G / therapeutic use*
  • Mice
  • Mutagenesis, Site-Directed
  • Mutation
  • Protein Engineering*
  • Receptors, Fc / immunology
  • Receptors, Fc / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Immunoglobulin G
  • Receptors, Fc
  • Fc receptor, neonatal