Compstatin Cp40 blocks hematin-mediated deposition of C3b fragments on erythrocytes: Implications for treatment of malarial anemia

Abstract

During malarial anemia, 20 uninfected red blood cells (RBCs) are destroyed for every RBC infected by Plasmodium falciparum (Pf). Increasing evidence indicates an important role for complement in destruction of uninfected RBCs. Products of RBC lysis induced by Pf, including the digestive vacuole and hematin, activate complement and promote C3 fragment deposition on uninfected RBCs. C3-opsonized cells are then subject to extravascular destruction mediated by fixed tissue macrophages which express receptors for C3 fragments. The Compstatin family of cyclic peptides blocks complement activation at the C3 cleavage step, and is under investigation for treatment of complement-mediated diseases. We demonstrate, that under a variety of stringent conditions, second-generation Compstatin analogue Cp40 completely blocks hematin-mediated deposition of C3 fragments on naïve RBCs. Our findings indicate that prophylactic provision of Compstatin for malaria-infected individuals at increased risk for anemia may provide a safe and inexpensive treatment to prevent or substantially reduce malarial anemia.

Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment

“…C3 plays a central role in the activation of the 3 complement pathways: classical, alternative, and lectin. Compstatins are a family of peptides that inhibit complement activation by binding to native C3 and interfering with convertase formation and C3 cleavage, and they are being developed as therapeutics for complement-driven disorders (32,33). To test the role of C3 activation in the PMN suppressor phenotype, we treated ascites with compstatin (CS-ASC; 250 μM; n = 27) ( Figure 3, E-G) and Cp40 (Cp40-ASC; 20 μM; n = 10) ( Figure 3H) prior to coculture with PMN and T cells.…”

Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles

“…Evidence for a pathogenic role of complement activation in hemolysis-induced renal manifestations comes from the observed attenuation of the expression of NGAL and Kim-1 in complement C3-deficient mice. Moreover, targeting C5 with a blocking antibody was shown to inhibit VOCs in transgenic mice with SCD (49), while inhibiting C3 with compstatin CP40 has been investigated in vitro in a model of malaria (50,51). However, CP40 is still unavailable for clinical use.…”

Complement activation during intravascular hemolysis: Implication for sickle cell disease and hemolytic transfusion reactions

“…The opsonization of the RBC with C3d could promote the clearance of these erythrocytes by CR2 expressing B cells in the spleen. These C3b/C3d deposits and RBC lysis were efficiently inhibited by the C3b-binding peptide Cp40, derived from compstatin (102). More recently, we showed that heme induces alternative complement pathway activation directly in serum and on endothelial cells (56,58), by promoting hydrolysis of C3 and formation of a fluid phase C3 convertase.…”