New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties

Abstract

Therapeutic modulation of the complement system has become increasingly important in line with the growing recognition of the role of complement in numerous diseases. Compstatin, a peptidic inhibitor that acts at the central level of the complement cascade, is currently in clinical evaluation but routes to improve its efficacy have not yet been fully explored. Here, we report improvements in both the inhibitory potency and pharmacokinetic parameters of compstatin that broaden its clinical applications. Selective modification of the compstatin N-terminus with non-proteinogenic amino acids resulted in the first analogue with subnanomolar binding affinity (KD = 0.5 nM) and other similarly potent derivatives with improved solubility in clinically relevant solvents. Detailed structure-activity relationship studies based on biophysical and computational methods revealed key structural determinants for the observed improvements. Importantly, pharmacokinetic evaluation in non-human primates revealed target-driven elimination kinetics with plasma half-life values exceeding expectations for peptidic drugs (close to 12 hours). This successful optimization strategy is expected to pave the way for systemic administration of compstatin in a range of clinical conditions.

Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria

“…Although Cp40 exhibits favorable pharmacokinetic properties, 18 we aimed to further increase the plasma residence of the inhibitor by adding a 40-kDa PEG moiety as a means of reducing renal filtration. The crystal structure of compstatin with a C3 fragment revealed that the terminal amino acids of this cyclic peptide are not essential for binding and may be modified.…”

“…Over the past decade, optimization studies have been conducted to develop compstatin derivatives with improved characteristics for systemic use. [17][18][19] The current lead analog Cp40 (clinically developed by Amyndas Pharmaceuticals) 13 shows strong binding affinity for C3b (K D ;0.5 nM) and a plasma half-life (t 1/2 ;12 hours) that exceeds typical peptide drugs.18 Despite these favorable properties, it is anticipated that a long-acting derivative of Cp40 based on sitespecific addition of polyethylene glycol (PEG) moieties may benefit a sustained pharmacologic complement inhibition as needed in PNH.By investigating the efficacy of Cp40 and its long-acting PEGylated derivatives regarding the protection of PNH erythrocytes in vitro and evaluating their pharmacokinetic properties in NHP, we describe a novel potential treatment option for PNH. …”

“…18 In addition, western blotting was performed to monitor C3 levels during the course of treatment. Plasma samples at various time points of each treatment were diluted 10-fold BLOOD, 27 MARCH 2014 x VOLUME 123, NUMBER 13…”

Combined Inhibition of Complement and CD14 Efficiently Attenuated the Inflammatory Response Induced byStaphylococcus aureusin a Human Whole Blood Model

“…Compstatin (CDP20), a cyclic peptide that inhibits cleavage of complement factor 3, comprised of the following sequence Ac-lle-[CysVal-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-mlle-NH2 and a corresponding control peptide were synthesized as previously described (28). The cyclic hexapeptide AcF[OPdChaWR] was used as the C5a receptor antagonist (C5aRag) (29).…”

Cholesterol crystal-induced endothelial cell activation is complement-dependent and mediated by TNF

“…Using this model we found that when CC were incubated with whole blood there was a potent, complement-dependent EC activation, which was mainly mediated by TNF. (Qu et al, 2013) were a kind gift from Professor John D. Lambris, as was the the specific C5a-receptor antagonist (AcF[OPdChaWR]), synthesized as previously described (Finch et al, 1999).…”