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

Ortiz DF, Lansing JC, Rutitzky L, Kurtagic E, Prod'Homme T, Choudhury A, Washburn N, Bhatnagar N, Beneduce C, Holte K, Prenovitz R, Child M, Killough J, Tyler S, Brown J, Nguyen S, Schwab I, Hains M, Meccariello R, Markowitz L, Wang J, Zouaoui R, Simpson A, Schultes B, Capila I, Ling L, Nimmerjahn F, Manning AM, Bosques CJ (2016)

Publication Status: Published

Publication Type: Journal article

Publication year: 2016

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 8

Pages Range: 365ra158

Journal Issue: 365

DOI: 10.1126/scitranslmed.aaf9418

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 with CRIS profile

Falk Nimmerjahn Lehrstuhl für Genetik

Involved external institutions

Momenta Pharmaceuticals US United States (USA) (US)

How to cite

APA:

Ortiz, D.F., Lansing, J.C., Rutitzky, L., Kurtagic, E., Prod'Homme, T., Choudhury, A.,... Bosques, C.J. (2016). Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors. Science Translational Medicine, 8(365), 365ra158. https://doi.org/10.1126/scitranslmed.aaf9418

MLA:

Ortiz, Daniel F., et al. "Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors." Science Translational Medicine 8.365 (2016): 365ra158.

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