Background 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.

Methods 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 (FH^m/mP^−/−) develop early-onset C3G, with AP consumption, high proteinuria, and lethal crescentic GN.

Results Treatment of FH^m/mP^−/− 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 FH^m/mP^−/− mice also had significantly improved survival and reduced proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores.

Conclusions 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.

背景C3肾小球病（C3G）是一种威胁生命的肾脏疾病，由补体（AP）激活的替代途径失调引起。尽管在某些C3G患者中已在标签外使用抗C5 mAb，但尚无批准的C3G特异性疗法可用，但结果不一。因此，对于开发C3G补体的其他抑制剂的医学需求尚未得到满足。

方法我们使用了具有致死性C3G的小鼠模型来测试Ig超家族补体受体Fc融合蛋白（CRIg-Fc）在治疗C3G中的潜在功效。CRIg-Fc结合C3b并抑制AP的C3和C5转化酶。具有H因子和备解素基因（FH ^{m / m} P ^-/-）突变的小鼠会发展为早期发作的C3G，并消耗AP，高蛋白尿和致死性新月形GN。

结果用CRIg-Fc（而非对照IgG）处理FH ^{m / m} P ^-/-小鼠可抑制AP激活并减少血浆C3，B因子和C5的消耗。CRIg-Fc治疗的FH ^{m / m} P ^-/-小鼠还具有显着改善的生存率，并减少了蛋白尿，血尿，BUN，肾小球C3片段，C9和纤维蛋白沉积以及GN病理评分。

结论基于可溶性CRIg作用机理开发的治疗方法可能对C3G的治疗有效，应在临床上进行探索。