title: Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors.
abstract: 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.
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortiz
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Lansing
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rutitzky
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Elma
authors.initials: E
authors.lastname: Kurtagic
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prod'homme
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Washburn
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Bhatnagar
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Beneduce
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Holte
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Prenovitz
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Child
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Killough
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Tyler
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Brown
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nguyen
authors.affiliation: Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
authors.forename: Inessa
authors.initials: I
authors.lastname: Schwab
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Maurice
authors.initials: M
authors.lastname: Hains
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Meccariello
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Markowitz
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Radouane
authors.initials: R
authors.lastname: Zouaoui
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Simpson
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schultes
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Ishan
authors.initials: I
authors.lastname: Capila
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Leona
authors.initials: L
authors.lastname: Ling
authors.affiliation: Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Manning
authors.affiliation: Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA. cbosques@momentapharma.com.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Bosques
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001168:Arthritis / Q000276:immunology / Q000628:therapy; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D016107:Epidermolysis Bullosa Acquisita / Q000276:immunology / Q000628:therapy; D006801:Humans; D007105:Immune Complex Diseases / Q000276:immunology / Q000628:therapy*; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D010586:Phagocytes; D015539:Platelet Activation; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology / Q000628:therapy; D017452:Receptors, IgG / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG