An extended mini-complement factor H molecule ameliorates experimental C3 glomerulopathy

Abstract

Abnormal regulation of the complement alternative pathway is associated with C3 glomerulopathy. Complement factor H is the main plasma regulator of the alternative pathway and consists of 20 short consensus repeat (SCR) domains. Although recombinant full-length factor H represents a logical treatment for C3 glomerulopathy, its production has proved challenging. We and others have designed recombinant mini-factor H proteins in which ‘non-essential' SCR domains have been removed. Here, we report the in vitro and in vivo effects of a mini-complement factor H protein, FH1–5^18–20, using the unique factor H–deficient (Cfh−/−) mouse model of C3 glomerulopathy. FH1–5^18–20 is comprised of the key complement regulatory domains (SCRs 1–5) linked to the surface recognition domains (SCRs 18–20). Intraperitoneal injection of FH1–5^18–20 in Cfh−/− mice reduced abnormal glomerular C3 deposition, similar to full-length factor H. Systemic effects on plasma alternative pathway control were comparatively modest, in association with a short half-life. Thus, FH1–5^18–20 is a potential therapeutic agent for C3 glomerulopathy and other renal conditions with alternative pathway-mediated tissue injury.

Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H–like Protein 1 Reveal Functional Determinants of Complement Regulation

“…The crystal structure of FH1–4:C3b indicated that CCP 5 could make direct contact with C3b. This possibility is in line with a recent study (44) in which FH CCPs 1–5 were observed to have slightly higher regulatory cofactor activity than CCPs 1–4. The higher affinity for C3b of full-length FH as compared to FHL-1 can be ascribed to a contribution from the C-terminal C3b/C3d–binding site.…”

Factor H inhibits complement activation induced by liposomal and micellar drugs and the therapeutic antibody rituximab in vitro

“…FH, and showed its efficacy in reducing C3 turnover also in vivo. 31 The enhanced activity of mini-FH is likely due to the increased availability of the C-terminal glycosaminoglycan/C3d binding sites in the shorter molecules, which are probably partly hidden in the full-length FH.…”

Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury

“…Consistent with our findings, a recent study demonstrated that a recombinant form of factor H that contained the surface binding region of factor H (short consensus repeats 19 and 20) reduced the deposition of C3 fragments in the glomeruli of fH −/− mice, whereas a recombinant protein that did not contain this surface binding region and only contained the complement regulatory region (SCRs 1-5) did not reduce glomerular C3 deposition. 43 The anatomic location at which complement activation occurs may have important therapeutic implications. There are recombinant proteins that can delivers the complement regulatory region of factor H to tissue-bound C3d.…”

“…There are recombinant proteins that can delivers the complement regulatory region of factor H to tissue-bound C3d. 43, 44 On the other hand, agents that target complement proteins in solution have also been developed. 45, 46 Our results do not exclude a role for fluid phase AP activation in glomerular injury, but they suggest that therapeutic complement inhibitors that are targeted to anatomic sites of complement inhibition will be protective in C3G.…”