Abstract
Therapeutic complement inhibition is a major focus for novel drug development. Of upstream targets, factor D (FD) is appealing because it circulates in plasma at low concentrations and has a single function: to cleave factor B to generate C3 convertase of the alternative pathway (AP). Mice with a targeted deletion of factor H (FH; Cfh-/- mice) develop C3 glomerulopathy (C3G) due to uncontrolled AP activity. To assess the impact of FD inhibition, we studied Cfh-/- Cfd-/- mice. We show that C3G in Cfh-/- mice is not rescued by removing FD. We used serum from Cfh-/- Cfd-/- mice to demonstrate that residual AP function occurs even when both FD and FH are missing and that hemolytic activity is present due to the action of C3(H2O). We propose that uncontrolled tick-over leads to slow activation of the AP in Cfh-/- Cfd-/- mice and that a minimal threshold of FH is necessary if tissue deposition of C3 is to be prevented. The FD/FH ratio dictates serum C3 level and renal C3b deposition. In C3G patients with chronic renal disease, the FD/FH ratio correlates inversely with C3 and C5 serum levels, suggesting that continuous AP control may be difficult to achieve by targeting FD.
Highlights
Therapeutic complement inhibition using eculizumab, a humanized anti-C5 mAb, was introduced for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in 2002 [1, 2]
Serum from the Cfh–/– Cfd–/– mouse mediates small amounts of C3b deposition on sepharose, as well as hemolysis of rabbit erythrocytes, thereby revealing that residual alternative pathway (AP) function is present when both factor D (FD) and factor H (FH) are missing. Consistent with this observation, we show that C3(H2O), which is produced in the tick-over reaction [12, 13], directly increases hemolytic activity in vitro and in vivo and that inactivated C3(H2O) is abundant in several tissues in the Cfh–/– Cfd–/– mouse, especially the kidney
These results indicate that both AP fluid-phase and terminal pathway activity are under control in Cfh–/– Cfd–/– mice
Summary
Therapeutic complement inhibition using eculizumab, a humanized anti-C5 mAb, was introduced for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in 2002 [1, 2]. In 2011, the FDA licensed eculizumab for the treatment of the ultra-rare disease atypical hemolytic uremic syndrome (aHUS) and assigned it orphan drug status [4] Spurred by this success and recognizing the central role of complement in both common and rare diseases, large pharmaceutical companies, small start-ups, and academic laboratories have developed programs targeting different proteins in the complement cascade. Many of these potentially new drugs are being studied in patients with C3 glomerulopathy (C3G), an ultra-rare kidney disease defined by underlying complement dysregulation and characterized by complement C3 deposition on kidney biopsy [5]. Treatment of C3G with eculizumab is unsuccessful in the majority of patients, consistent with the fact that eculizumab targets the terminal complement cascade and, primarily addresses only 1 aspect of C3G — glomerular inflammation — while leaving upstream C3 complement dysregulation untouched [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
