Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis

Kourtzelis, Ioannis; Markiewski, Maciej M.; Doumas, Michael; Rafail, Stavros; Kambas, Konstantinos; Mitroulis, Ioannis; Panagoutsos, Stelios; Passadakis, Ploumis; Vargemezis, Vasilios; Magotti, Paola; Qu, Hongchang; Mollnes, Tom Eirik; Ritis, Konstantinos; Lambris, John D.

doi:10.1016/j.molimm.2010.05.255

Cited by 32 publications

(47 citation statements)

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“…13 Moreover, compstatin analogs showed promising results in various disease models ranging from hemodialysis to sepsis. 12,15,16 In contrast to the local or timerestricted administration of compstatin in the above-mentioned clinical situations, therapeutic intervention in a chronic systemic disease such as PNH imposes higher demands on drug properties, particularly concerning pharmacokinetics. Over the past decade, optimization studies have been conducted to develop compstatin derivatives with improved characteristics for systemic use.…”

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confidence: 99%

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

Risitano

Ricklin

Huang

et al. 2014

Blood

166

168

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• Peptidic C3 inhibitors of the compstatin family (Cp40) efficiently prevent hemolysis and opsonization of PNH erythrocytes in vitro.• Pharmacokinetic studies show that sustained therapeutic concentrations can be achieved with both Cp40 and its PEGylated derivative, PEG-Cp40.Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the lack of CD55 and CD59 on affected erythrocytes. The anti-C5 antibody eculizumab has proven clinically effective, but uncontrolled C3 activation due to CD55 absence may result in opsonization of erythrocytes, possibly leading to clinically meaningful extravascular hemolysis. We investigated the effect of the peptidic C3 inhibitor, compstatin Cp40, and its long-acting form (polyethylene glycol [PEG]-Cp40) on hemolysis and opsonization of PNH erythrocytes in an established in vitro system. Both compounds demonstrated dose-dependent inhibition of hemolysis with IC 50 ∼4 mM and full inhibition at 6 mM. Protective levels of either Cp40 or PEG-Cp40 also efficiently prevented deposition of C3 fragments on PNH erythrocytes. We further explored the potential of both inhibitors for systemic administration and performed pharmacokinetic evaluation in nonhuman primates. A single intravenous injection of PEG-Cp40 resulted in a prolonged elimination half-life of >5 days but may potentially affect the plasma levels of C3. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration. In conclusion, peptide inhibitors of C3 activation effectively prevent hemolysis and C3 opsonization of PNH erythrocytes, and are excellent, and potentially cost-effective, candidates for further clinical investigation. (Blood. 2014;123(13):2094-2101 IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is a complex hematologic disorder characterized by the expansion of hematopoietic cells deficient in glycophosphatidylinositol-anchored surface proteins, including the complement regulators CD55 and CD59. 1 Affected erythrocytes suffer from uncontrolled complement activation on their surface, and subsequent membrane attack complex (MAC)-mediated intravascular hemolysis.2 The therapeutic anti-C5 antibody eculizumab (Soliris, Alexion) has proven effective in controlling intravascular hemolysis in vivo, leading to remarkable clinical benefit in a majority of PNH patients.3,4 Yet, persistent C3 activation occurring during eculizumab treatment may lead to progressive deposition of C3 fragments on affected erythrocytes and subsequent C3-mediated extravascular hemolysis, possibly limiting the hematologic benefit of anti-C5 treatment. 5,6 Thus, upstream inhibition of the complement cascade seems an appropriate strategy to improve the results of current complement-targeted treatment. 7,8 Indeed, it has been recently documented that protein inhibitors of the alternative pathway (AP) of complement activation, such as the CD21/factor H (FH) fusion protein TT30 (Alexion) or the engin...

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confidence: 99%

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

Risitano

Ricklin

Huang

et al. 2014

Blood

166

168

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“…The observations made here are in agreement with others who report of induction of a number of cytokines, e.g., IFN-g, IL-6, IL-8, PDGF, and eotaxin upon contact between model biomaterials and lepirudin anticoagulated whole blood. In these studies, the link to complement activation was proven either by blocking complement activation in normal blood at the levels of C3 (using compstatin) or C5 (using Eculizumab) [27,36,37] or by using blood from a C5 deficient individual [38]. In addition, it has been demonstrated that model biomaterials, e.g., PEG hydrogels, were able to selectively modulate interactions between human PMNs and monocytes resulting in expression of IL-6 and IL-8 [39], further underscoring the relevance of these cytokines as predictors of biocompatibility.…”

Section: Discussionmentioning

confidence: 99%

Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma

et al. 2015

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“…It was reported that C5a contributed to the initiation and/or amplification of various pathological conditions such as ischemia-reperfusion injury, inflammatory bowel disease, arthritis, antiglomerular basement membrane nephritis, septic shock, Alzheimer's disease, and hemodialysis in animal models and humans (1,5,7,14,16,27,40,41,44) Therefore, C5a might be a target as an anti-C therapy as a way to prevent inflammatory tissue injury. There are numerous agents for inhibition of C5a, such as C5aR antagonists (C5aRA) and monoclonal anti-C5a IgG (10,28,42).…”

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confidence: 99%

Anti-C5a complementary peptide ameliorates acute peritoneal injury induced by neutralization of Crry and CD59

Mizuno

Imai

et al. 2013

American Journal of Physiology-Renal Physiology

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Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis

Cited by 32 publications

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

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

Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma

Anti-C5a complementary peptide ameliorates acute peritoneal injury induced by neutralization of Crry and CD59

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