An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy.

Background C3 glomerulopathy(C3G) is associated with dysregulation of the alternative pathwayof complement activation, and treatment options for C3G remain limited. Complement factor H(FH) is a potent regulator of the alternative pathwayand 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 cellsand 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 membraneC3 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.