TY - JOUR
T1 - An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy
AU - Yang, Yi
AU - Denton, Harriet
AU - Davies, Owen R
AU - Smith-Jackson, Kate
AU - Kerr, Heather
AU - Herbert, Andrew P
AU - Barlow, Paul N
AU - Pickering, Matthew C
AU - Marchbank, Kevin J
N1 - The tile of the paper has changed from: Homodimeric Minimal Factor H fusion proteins Ameliorate Experimental C3G with Improved In vivo Pharmacodynamics Compared To Mini-FH ---- To: An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy
PY - 2018/3/27
Y1 - 2018/3/27
N2 - 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.
AB - 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.
KW - Immunology and pathology
KW - complement
KW - glomerulopathy
KW - membranoproliferative glomerulonephritis (MPGN)
U2 - 10.1681/ASN.2017091006
DO - 10.1681/ASN.2017091006
M3 - Article
C2 - 29588430
SN - 1046-6673
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
ER -