Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily

Abstract

C3 glomerulopathy (C3G) is a life-threatening kidney disease caused by dysregulation of the alternative pathway of complement (AP) activation. No approved specific therapy is available for C3G, although an anti-C5 mAb has been used off-label in some patients with C3G, with mixed results. Thus, there is an unmet medical need to develop other inhibitors of complement for C3G. We used a murine model of lethal C3G to test the potential efficacy of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in the treatment of C3G. CRIg-Fc binds C3b and inhibits C3 and C5 convertases of the AP. Mice with mutations in the factor H and properdin genes (FHP) develop early-onset C3G, with AP consumption, high proteinuria, and lethal crescentic GN. Treatment of FHP mice with CRIg-Fc, but not a control IgG, inhibited AP activation and diminished the consumption of plasma C3, factor B, and C5. CRIg-Fc-treated FHP mice also had significantly improved survival and reduced proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores. Therapeutics developed on the basis of the mechanism of action of soluble CRIg may be effective for the treatment of C3G and should be explored clinically.

Nanobodies Provide Insight into the Molecular Mechanisms of the Complement Cascade and Offer New Therapeutic Strategies

“…Besides being involved in regulation of T cell immunity, Vsig4 is also a complement receptor expressed exclusively on tissue resident macrophages, where it mediates the clearance of circulating complement-opsonized cells, through recognition of the MG4 and MG5 domains of C3b and iC3b [ 47 , 115 ]. The ectodomain of Vsig4 is a possible therapeutic molecule that through binding to C3b and iC3b may control diseases associated to excessive CP and AP activation [ 116 ]. Vsig4 specific nanobodies were selected from a library obtained after immunization of an alpaca with the extracellular domain of murine Vsig4.…”

“…An additional example is offered by the Vsig4 specific nanobody Nb119 labeled with 99m Tc [102]. This allows imaging of inflamed joints in collagen induced arthritis (CIA) mice, a model that mimics the human rheumatoid arthritis immunologic state [117]. The accumulation of 99m Tc-Nb119 in CIA mice joints correlated well with disease severity assigned by the macroscopic arthritis scoring system, but the nanobody also allowed detection of knee inflammation prior to onset of macroscopic symptoms [102].…”

Nanobodies Provide Insight Into the Molecular Mechanisms of the Complement Cascade and Offer New Therapeutic Strategies

“…domains of C3b and iC3b [48,114]. The ectodomain of Vsig4 is a possible therapeutic molecule that through binding to C3b and iC3b may control diseases associated to excessive CP and AP activation [115]. Vsig4 specific nanobodies were selected from a library obtained after immunization of an alpaca with the extracellular domain of murine Vsig4.…”

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

“…Secondly, a fusion protein of CRIg and Fc of a murine IgG1 (CRIg-Fc) is a soluble version of CRIg and was designed to inhibit the AP selectively by binding to cells opsonized with antibodies and inhibiting C3 convertase ( 210 , 211 ). Successful reduction of inflammation was shown in vivo in mouse models of experimental arthritis, ischemia/reperfusion injury and FH-deficient mice that mimick C3 glomerulopathy ( 210 , 212 , 213 ).…”