Targeting immune complex-mediated hypersensitivity with recombinant soluble human FcgammaRIA (CD64A).
Binding of Ag-Ab immune complexes to cellular FcgammaR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcgammaR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcgammaRIA, FcgammaRIIA, and FcgammaRIIIA were prepared. Binding of rh-FcgammaRIA to IgG was of high affinity (KD=1.7x10(-10) M), whereas rh-FcgammaRIIA and rh-FcgammaRIIIA bound with low affinity (KD=0.6-1.9x10(-6) M). All rh-FcgammaR 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-alpha by cultured mast cells. Local or systemic delivery only of rh-FcgammaRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125I-labeled rh-FcgammaRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t1/2gamma of approximately 130 h. The highest percentage of injected radioactivity accumulated in blood approximately liver approximately carcass>kidney. s.c. dosing of rh-FcgammaRIA 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-FcgammaRIA is an effective inhibitor of type III hypersensitivity.
Ellsworth
Jeff L
JL
Department of Autoimmunity and Inflammation, ZymoGenetics, Seattle, WA 98102, USA. jefe@zgi.com
Maurer
Mark
M
Harder
Brandon
B
Hamacher
Nels
N
Lantry
Megan
M
Lewis
Kenneth B
KB
Rene
Shirley
S
Byrnes-Blake
Kelly
K
Underwood
Sara
S
Waggie
Kimberly S
KS
Visich
Jennifer
J
Lewis
Katherine E
KE
D000818:Animals; D000936:Antigen-Antibody Complex / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001183:Arthus Reaction / Q000188:drug therapy / Q000473:pathology; D003165:Complement System Proteins / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007105:Immune Complex Diseases / Q000188:drug therapy* / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D017452:Receptors, IgG / Q000096:biosynthesis / Q000627:therapeutic use*
D000936:Antigen-Antibody Complex; D016207:Cytokines; C489017:FCGR1A protein, human; D007074:Immunoglobulin G; D017452:Receptors, IgG; D003165:Complement System Proteins