An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy

Yi Yang, Harriet Denton, Owen R Davies, Kate Smith-Jackson, Heather Kerr, Andrew P Herbert, Paul N Barlow, Matthew C Pickering, Kevin J Marchbank

Research output: Contribution to journalArticlepeer-review

Abstract

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 (FH1-5^18-20), that was effective in experimental C3G. However, the serum t1/2 of FH1-5^18-20 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 FH1-5^18-20 to generate two homodimeric mini-FH constructs (FHR1-2^1-5^18-20 and FH1-5^18-20^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-deficientCfh-/-mice.

Results FHR1-2^1-5^18-20 and FH1-5^18-20^R1-2 homodimerized in solution and displayed avid binding profiles on clustered C3b surfaces, particularly FHR1-2^1-5^18-20 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 FH1-5^18-20 FH1-5^18-20^R1-2 had a C3 breakdown fragment binding profile similar to that of FH, a >5-fold increase in serum t1/2 compared with that of FH1-5^18-20,and significantly better retention in the kidney than FH or FH1-5^18-20 

Conclusions FH1-5^18-20^R1-2 may have utility as a treatment option for C3G or other complement-mediated diseases.

Original languageEnglish
JournalJournal of the American Society of Nephrology
Early online date27 Mar 2018
DOIs
Publication statusE-pub ahead of print - 27 Mar 2018

Keywords

  • Immunology and pathology
  • complement
  • glomerulopathy
  • membranoproliferative glomerulonephritis (MPGN)

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