Toggle Main Menu Toggle Search

Open Access padlockePrints

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, Professor Kevin MarchbankORCiD

Downloads


Licence

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

For re-use rights please refer to the publisher's terms and conditions.


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

Date deposited: 21/09/2017

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


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
MRC
Royal Society
Wellcome Trust
WT082291MA

Share