Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors

Sci Transl Med. 2016 Nov 16;8(365):365ra158. doi: 10.1126/scitranslmed.aaf9418.


Autoantibody immune complex (IC) activation of Fcγ receptors (FcγRs) is a common pathogenic hallmark of multiple autoimmune diseases. Given that the IC structural features that elicit FcγR activation are poorly understood and the FcγR system is highly complex, few therapeutics can directly block these processes without inadvertently activating the FcγR system. To address these issues, the structure activity relationships of an engineered panel of multivalent Fc constructs were evaluated using sensitive FcγR binding and signaling cellular assays. These studies identified an Fc valency with avid binding to FcγRs but without activation of immune cell effector functions. These observations directed the design of a potent trivalent immunoglobulin G-Fc molecule that broadly inhibited IC-driven processes in a variety of immune cells expressing FcγRs. The Fc trimer, Fc3Y, was highly efficacious in three different animal models of autoimmune diseases. This recombinant molecule may represent an effective therapeutic candidate for FcγR-mediated autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Antigen-Antibody Complex / immunology*
  • Arthritis / immunology
  • Arthritis / therapy
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / therapy
  • Autoantibodies / immunology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / therapy*
  • Cell Line
  • Epidermolysis Bullosa Acquisita / immunology
  • Epidermolysis Bullosa Acquisita / therapy
  • Humans
  • Immune Complex Diseases / immunology
  • Immune Complex Diseases / therapy*
  • Immunoglobulin Fc Fragments / immunology*
  • Immunoglobulin G / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / cytology
  • Phagocytes
  • Platelet Activation
  • Purpura, Thrombocytopenic, Idiopathic / immunology
  • Purpura, Thrombocytopenic, Idiopathic / therapy
  • Receptors, IgG / immunology*
  • Signal Transduction


  • Antibodies, Monoclonal
  • Antigen-Antibody Complex
  • Autoantibodies
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, IgG