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An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy

Lookup NU author(s): Dr Yi Yang, Harriet Denton, Dr Owen Davies, Dr Kate Smith-Jackson, Dr Kevin Marchbank

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society of Nephrology, 2018.

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Abstract

C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain limited. Factor H (FH) consists of 20 short consensus repeat (SCR) domains, is a potent regulator of the AP and might offer a solution. The mass and complexity of FH makes generation of full length FH far from trivial. We previously designed and generated a mini-FH (FH1-5^18-20) construct that was shown to be effective in experimental models of C3G. However, FH1-5^18-20 had a much reduced serum half-life compared to serum purified FH. To tackle this issue, we introduced the oligomerization domain of human FH related (FHR)-1 at either the carboxy or amino terminus of human FH1-5^18-20 to generate homodimeric mini-FH (HDM-FHor FHR1-2^1-5^18-20 and FH1-5^18-20^R1-2) constructs in Chinese hamster ovary cells. Both HDM-FH constructs homodimerize in solution and displayed avid binding profiles on clustered C3b surfaces using Biacore. HDM-FHs exhibit a 10-fold increase in surface AP inhibition compared to full length FH. Interestingly, FHR1-2^1-5^18-20 was found to be the most potent inhibitor of Es lysis. HDM-FH or controls (3 nmoles) were administered to Cfh-/- mice and plasma levels of C3 and the agents monitored for 48 hours. HDM-FH constructs demonstrate a significant and extended protection of the glomerular basement membrane from C3 deposition and have a greater than five-fold increase in serum half-life compared to mini-FH. These data suggest that HDM-FH agents may have utility as a therapeutics for treatment of C3G or other complement-mediated diseases.


Publication metadata

Author(s): Yang Y, Denton H, Davies OR, Smith-Jackson K, Kerr H, Herbert A, Barlow PN, Pickering MC, Marchbank KJ

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2018

Volume: 29

Issue: 6

Pages: 1649-1661

Print publication date: 01/06/2018

Online publication date: 31/05/2018

Acceptance date: 23/02/2018

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology

URL: https://doi.org/10.1681/ASN.2017091006

DOI: 10.1681/ASN.2017091006

Notes: JASN-2017-09-1006 - Homodimeric Mini-FH Ameliorates Experimental C3G with Excellent In vivo Pharmacodynamics - favourable reviews - accepted 23rd February 2016 An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy


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