Engineered Hexavalent Fc Proteins with Enhanced Fc-gamma Receptor Avidity Provide Insights into Immune-complex Interactions

Overview

Journal Commun Biol

Specialty Biology

Date 2018 Oct 2

PMID 30272022

Citations 18

Authors

Tania F Rowley

Shirley J Peters

Mike Aylott

Robert Griffin

Nicola L Davies

Louise J Healy

Rona M Cutler

Alison Eddleston

Thomas L Pither

Joshua M Sopp

Oliver Zaccheo

Gianluca Fossati

Katharine Cain

Andrew M Ventom

Hanna Hailu

Eleanor J Ward

John Sherington

Frank R Brennan

Farnaz Fallah-Arani

David P Humphreys

Affiliations

Soon will be listed here.

Abstract

Autoantibody-mediated diseases are currently treated with intravenous immunoglobulin, which is thought to act in part via blockade of Fc gamma receptors, thereby inhibiting autoantibody effector functions and subsequent pathology. We aimed to develop recombinant molecules with enhanced Fc receptor avidity and thus increased potency over intravenous immunoglobulin. Here we describe the molecular engineering of human Fc hexamers and explore their therapeutic and safety profiles. We show Fc hexamers were more potent than IVIG in phagocytosis blockade and disease models. However, in human whole-blood safety assays incubation with IgG1 isotype Fc hexamers resulted in cytokine release, platelet and complement activation, whereas the IgG4 version did not. We used a statistically designed mutagenesis approach to identify the key Fc residues involved in these processes. Cytokine release was found to be dependent on neutrophil FcγRIIIb interactions with L234 and A327 in the Fc. Therefore, Fc hexamers provide unique insights into Fc receptor biology.

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