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Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Harder, Markus J. and Kuhn, Nadine and Schrezenmeier, Hubert and Höchsmann, Britta and von Zabern, Inge and Weinstock, Christof and Simmet, Thomas and Ricklin, Daniel and Lambris, John D. and Skerra, Arne and Anliker, Markus and Schmidt, Christoph Q.. (2017) Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood, 129 (8). pp. 970-980.

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Official URL: http://edoc.unibas.ch/55048/

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Abstract

Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Ricklin, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Hematology
ISSN:0006-4971
e-ISSN:1528-0020
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:16 Oct 2017 09:26
Deposited On:16 Oct 2017 09:26

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