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Targeting Immune Complex-Mediated Hypersensitivity with Recombinant Soluble Human FcRIA (CD64A)¹

Jeff L. Ellsworth^2,*, Mark Maurer^*, Brandon Harder^*, Nels Hamacher, Megan Lantry, Kenneth B. Lewis, Shirley Rene, Kelly Byrnes-Blake, Sara Underwood, Kimberly S. Waggie, Jennifer Visich and Katherine E. Lewis^*

^* Department of Autoimmunity and Inflammation, Department of Protein Biochemistry, and Department of Pre-Clinical Development, ZymoGenetics, Seattle, WA 98102

Binding of Ag-Ab immune complexes to cellular FcR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcRIA, FcRIIA, and FcRIIIA were prepared. Binding of rh-FcRIA to IgG was of high affinity (K_D = 1.7 x 10^–10 M), whereas rh-FcRIIA and rh-FcRIIIA bound with low affinity (K_D = 0.6–1.9 x 10^–6 M). All rh-FcR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF- by cultured mast cells. Local or systemic delivery only of rh-FcRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. ¹²⁵I-labeled rh-FcRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t_1/2 of 130 h. The highest percentage of injected radioactivity accumulated in blood liver carcass > kidney. s.c. dosing of rh-FcRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcRIA is an effective inhibitor of type III hypersensitivity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in its entirety by ZymoGenetics.

² Address correspondence and reprint requests to Dr. Jeff L. Ellsworth, Department of Autoimmunity and Inflammation, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, WA 98102. E-mail address: jefe{at}zgi.com

³ Abbreviations used in this paper: rh, recombinant human; CHO, Chinese hamster ovary; i.d., intradermal; rm, recombinant murine; MPO, myeloperoxidase; TACI, transmembrane activator and CAML interactor.

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				J. L. Ellsworth, N. Hamacher, B. Harder, K. Bannink, T. R. Bukowski, K. Byrnes-Blake, S. Underwood, C. Oliver, K. S. Waggie, C. Noriega, et al. Recombinant Soluble Human Fc{gamma}R1A (CD64A) Reduces Inflammation in Murine Collagen-Induced Arthritis J. Immunol., June 1, 2009; 182(11): 7272 - 7279. [Abstract] [Full Text] [PDF]