Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor.
A recombinant soluble form of the mouse membrane complement inhibitor Crry (complement receptor-related gene y) fused to IgG1 hinge, CH2, and CH3 domains has been created and designated Crry-Ig. Crry has been used because, similar to human soluble CR1, it demonstrates decay-accelerating activity for both the classical and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. The mouse IgG1 isotype was incorporated because it is a noncomplement-activating isotype and, when fused to Crry, results in a complement inhibitor that should not be recognized as foreign when used chronically in murine models. Crry-Ig demonstrated complement-inhibitory activity in both the fluid phase and on target surfaces. Following in vivo injection, Crry-Ig manifested a two-phase serum elimination profile, a rapid initial loss most likely reflecting tissue redistribution and a second more prolonged decline with a t1/2 of 40 h. Inhibition of complement activation in mice following injection of Crry-Ig was demonstrated by a marked decrease in the ability of serum from treated mice to be activated by zymosan particles in vitro. Finally, in vivo efficacy of Crry-Ig was demonstrated by its ability to substantially diminish renal injury induced by complement-fixing nephrotoxic Ab. The use of Crry-Ig in vivo in murine models of chronic inflammatory and autoimmune disease should allow further insight into the potential therapeutic effects and possible untoward complications of continuous blockade of complement using inhibitors that act on activation products of C4 and C3.
Quigg
R J
RJ
Department of Medicine, The University of Chicago, IL 60637, USA.
Kozono
Y
Y
Berthiaume
D
D
Lim
A
A
Salant
D J
DJ
Weinfeld
A
A
Griffin
P
P
Kremmer
E
E
Holers
V M
VM
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy* / Q000276:immunology*; D000906:Antibodies; D003169:Complement Inactivator Proteins / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D017463:Receptors, Complement 3b; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D012756:Sheep
D000906:Antibodies; D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D007074:Immunoglobulin G; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011993:Recombinant Fusion Proteins