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

Area of Science:

• Nephrology
• Immunology
• Complement System Biology

Background:

• C3 glomerulopathy (C3G) is a severe kidney disease driven by complement alternative pathway (AP) dysregulation.
• Current treatments for C3G are limited, with off-label use of anti-C5 mAb showing inconsistent results, highlighting an unmet need for novel therapies.
• The complement system, particularly the AP, plays a critical role in C3G pathogenesis.

Purpose of the Study:

• To evaluate the therapeutic potential of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in a murine model of lethal C3G.
• To investigate the efficacy of CRIg-Fc in inhibiting AP activation and mitigating C3G progression.

Main Methods:

• A lethal C3G murine model (FH^m/mP^-/-) with AP consumption and crescentic glomerulonephritis (GN) was utilized.
• Mice were treated with CRIg-Fc, which binds C3b and inhibits AP convertases, or a control IgG.
• Key parameters assessed included AP activation markers, proteinuria, hematuria, blood urea nitrogen (BUN), glomerular deposition, and GN pathology scores.

Main Results:

• CRIg-Fc treatment significantly inhibited AP activation, evidenced by reduced consumption of plasma C3, factor B, and C5.
• FH^m/mP^-/- mice treated with CRIg-Fc demonstrated significantly improved survival rates.
• Treatment led to substantial reductions in proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores compared to controls.

Conclusions:

• Therapeutics based on soluble CRIg's mechanism of action show promise for treating C3G.
• CRIg-Fc effectively inhibited AP activation and ameliorated C3G in a preclinical model.
• Clinical exploration of CRIg-based therapies for C3G is warranted.