Background C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway of complement activation, and treatment options for C3G remain limited. Complement factor H (FH) is a potent regulator of the alternative pathway and might offer a solution, but the mass and complexity of FH makes generation of full-length FH far from trivial. We previously generated a mini-FH construct, with FH short consensus repeats 1–5 linked to repeats 18–20 (FH^{1–5^18–20}), that was effective in experimental C3G. However, the serum t_1/2 of FH^{1–5^18–20} was significantly shorter than that of serum-purified FH.

Methods We introduced the oligomerization domain of human FH-related protein 1 (denoted by R1–2) at the carboxy or amino terminus of human FH^{1–5^18–20} to generate two homodimeric mini-FH constructs (FH^{R1–2^1–5^18–20} and FH^{1–5^18–20^R1–2}, respectively) in Chinese hamster ovary cells and tested these constructs using binding, fluid-phase, and erythrocyte lysis assays, followed by experiments in FH-deficient Cfh–/– mice.

Results FH^{R1–2^1–5^18–20} and FH^{1–5^18–20^R1–2} homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FH^{R1–2^1–5^18–20}. Each construct was >10-fold more effective than FH at inhibiting cell surface complement activity in vitro and restricted glomerular basement membrane C3 deposition in vivo significantly better than FH or FH^{1–5^18–20}. FH^{1–5^18–20^R1–2} had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t_1/2 compared with that of FH^{1–5^18–20}_, and significantly better retention in the kidney than FH or FH^{1–5^18–20}.

Conclusions FH^{1–5^18–20^R1–2} may have utility as a treatment option for C3G or other complement-mediated diseases.