Inhibitor of complement, Compstatin, prevents polymer‐mediated Mac‐1 up‐regulation of human neutrophils independent of biomaterial type tested

Abstract

The inflammatory reaction after cell contact with polymer materials is primarily mediated by activated neutrophils and may, in some cases, lead to exhaustion of neutrophil cell function. A direct consequence of this can be impairment of local or even systemic host defense mechanisms, which in turn can result in foreign body infections. Neutrophil activation, as indicated by the up-regulation of the Mac-1 adhesion receptor, is a reliable parameter for estimating the inflammatory risk due to implanted biomaterials. Because at blood contact, biomaterials immediately acquire a material-specific layer of blood proteins on their surface, including fibrinogen, complement, and immunoglobulin G, it is generally believed that after biomaterial contact, neutrophil activation primarily occurs by interaction with this protein layer. In this study, using our recently established polymer bead in vitro assay, we investigated whether complement inhibition alone can reduce biomaterial-mediated neutrophil activation, independent of the type of polymer and, hence, also its surface chemistry. Complement inhibition was achieved by using Compstatin, a recently developed complement inhibitor that binds to the complement component C3 preventing C3 convertase formation. We revealed significantly reduced (p < or = 0.025) Mac-1 receptor expression levels after 45 min of blood contact with the following polymers (without and with Compstatin): 1. polyurethane, 98.3%, 13.6%; 2. polymethylmetacrylate, 88.5%, 11.0%; and poly-D,L-lactide, 71.8%, 8.4%. Although these three polymer types acquire material-specific protein layers because of their different surface chemistry, complement inhibition by Compstatin alone proved to be sufficient to reduce neutrophil activation after surface contact, thus reducing the risk of biomaterial-mediated inflammatory reaction.

Effect of molecular mobility of polymeric implants on soft tissue reactions: An in vivo study in rats

“…The cell binding can take place either on RGD sites on fibrinogen19 or on P1/P2 epitopes on the γ‐domain of fibrinogen20 via the Mac‐1 receptor 21. The Mac‐1 is also called complement receptor 3 (CR3) and has C3a as a ligand and along with C5a they are up‐regulating the receptor production 22…”

Structure‐kinetic relationship analysis of the therapeutic complement inhibitor compstatin

“…Even though the exact molecular mechanism of its inhibition is not yet fully understood, this cyclic tridecapeptide clearly binds to both C3 and C3b and prevents the cleavage of native C3 by the C3 convertases. Its high inhibitory efficacy was confirmed by a series of studies using in vitro and animal models that pointed to its potential as a therapeutic agent (Fiane et al , 1999a; Fiane et al , 1999b; Nilsson et al , 1998; Ricklin and Lambris, 2008; Schmidt et al , 2003; Soulika et al , 2000). Progressive optimization of compstatin has yielded analogs with dramatically improved activity (Ricklin and Lambris, 2008).…”

Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis

“…One compstatin analog (POT-4, Potentia Pharmaceuticals) was found to be safe in phase I clinical trials and is currently being evaluated in a phase II trial for the local treatment of age-related macular degeneration (AMD) by Alcon (AL-78898A; (Alcon Research 2012)). Importantly, compstatin has been shown to inhibit complement activity, leukocyte activation and binding, and cytokine induction in response to blood contact with artificial surfaces (Nilsson et al 1998; Lappegard et al 2008; Schmidt et al 2003; Kourtzelis et al 2010). The most recently disclosed compstatin analogs showed large improvements concerning target binding affinity (picomolar range), solubility and/or pharmacokinetic profiles (elimination half-life of up to 12 h), thereby rendering them much more suitable for systemic administration (Qu et al 2012).…”