Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy

Abstract

C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases caused by uncontrolled activation of the alternative complement pathway. Nearly half of patients progress to end stage renal failure within 10 years. Cp40, a second-generation compstatin analog in clinical development, is a 14 amino-acid cyclic peptide that selectively inhibits complement activation in humans and non-human primates by binding to C3 and C3b. We hypothesized that by targeting C3 Cp40 would provide an effective treatment for C3G. By investigating its effects in vitro using multiple assays of complement activity, we show that Cp40 prevents complement-mediated lysis of sheep erythrocytes in sera from C3G patients, prevents complement dysregulation in the presence of patient-derived autoantibodies to the C3 and C5 convertases, and prevents complement dysregulation associated with disease-causing genetic mutations. In aggregate, these data suggest that Cp40 may offer a novel and promising therapeutic option to C3G patients as a disease-specific, targeted therapy. As such, Cp40 could represent a major advance in the treatment of this disease.

Complement in disease: a defence system turning offensive

“…By binding to C3 and C3b, compstatin analogues prevent C3 opsonization by all initiation routes, thereby impairing amplification, downstream C5 activation, and effector generation. Among other indications 155 , the lead analogue Cp40 has shown efficacy in an in vitro model of C3 glomerulopathy 160 . Although systemic inhibition of C3 had been considered restrictive because of its high plasma concentration and turnover (BOX 3), a 2014 study demonstrated that target-saturating concentrations of Cp40 can be maintained in monkeys by repetitive subcutaneous injection 161 .…”

Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40

“…The percentage of PI-positive cells (compared to total cells) was used to evaluate the degree of cell death. The inhibition percentage was calculated as described elsewhere [7,21,22], using the following equation: % inhibition = {1 – (A – C) / (B – C)} × 100%, where A, B, and C represent the percentage of cell death when incubated with 20% serum pretreated with Cp40 (A), 20% serum without any treatment (B), and 20% heat-inactivated serum (C), respectively.…”

“…In a clinically relevant study on paroxysmal nocturnal hemoglobinuria (PNH), Cp40 was found to effectively protect PNH erythrocytes from both intravascular and extravascular hemolysis in vitro , thereby showing potential therapeutic advantage over the established anti-C5 therapy [5]. In another preclinical study, Cp40 was able to inhibit complement dysregulation in vitro in C3 glomerulopathy and may therefore offer a novel therapeutic option for affected patients [7]. In addition, Cp40 has been shown to be a potent inhibitor of complement activation in several in vivo and ex vivo animal models, such as a primate model of hemodialysis-induced complement activation [8], a ligature-induced periodontitis model in nonhuman primates (NHP) [9], and a xenogeneic model of interactions between human whole blood and porcine endothelium [10].…”

Kidney Diseases Associated With Alternative Complement Pathway Dysregulation and Potential Treatment Options

“…Several clinical trials utilizing targeted complement inhibition with novel agents are ongoing and may offer hope in treating these dreadful conditions. 21 …”