Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

J Immunol. 2015 Jun 1;194(11):5497-508. doi: 10.4049/jimmunol.1401218. Epub 2015 Apr 22.

Abstract

Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge-CH2 region, structurally distant from the binding site for FcRn at the CH2-CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn-IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / genetics*
  • Antibodies, Monoclonal / immunology
  • Antibody Affinity / genetics
  • Antibody Affinity / immunology
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Cell Line
  • Complement C1q / immunology*
  • HEK293 Cells
  • Hinge Exons / genetics
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immunoglobulin G / genetics*
  • Immunoglobulin G / immunology
  • Nitrohydroxyiodophenylacetate / immunology
  • Phagocytosis / immunology
  • Protein Engineering
  • Receptors, Fc / genetics
  • Receptors, Fc / immunology*
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology*
  • Surface Plasmon Resonance

Substances

  • Antibodies, Monoclonal
  • Histocompatibility Antigens Class I
  • Immunoglobulin G
  • Receptors, Fc
  • Receptors, IgG
  • Nitrohydroxyiodophenylacetate
  • Complement C1q
  • Fc receptor, neonatal