title: A novel C5a-neutralizing mirror-image (l-)aptamer prevents organ failure and improves survival in experimental sepsis.
abstract: Complement factor C5a is a potent proinflammatory mediator that contributes to the pathogenesis of numerous inflammatory diseases. Here, we describe the discovery of NOX-D20, a PEGylated biostable mirror-image mixed (l-)RNA/DNA aptamer (Spiegelmer) that binds to mouse and human C5a with picomolar affinity. In vitro, NOX-D20 inhibited C5a-induced chemotaxis of a CD88-expressing cell line and efficiently antagonized the activation of primary human polymorphonuclear leukocytes (PMN) by C5a. Binding of NOX-D20 to the C5a moiety of human C5 did not interfere with the formation of the terminal membrane attack complex (MAC). In sepsis, for which a specific interventional therapy is currently lacking, complement activation and elevated levels of C5a are suggested to contribute to multiorgan failure and mortality. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), NOX-D20 attenuated inflammation and organ damage, prevented the breakdown of the vascular endothelial barrier, and improved survival. Our study suggests NOX-D20 as a new therapeutic candidate for the treatment of sepsis.
authors.affiliation: NOXXON Pharma AG, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Hoehlig
authors.forename: Christian
authors.initials: C
authors.lastname: Maasch
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
authors.forename: Klaus
authors.initials: K
authors.lastname: Buchner
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.forename: Werner G
authors.initials: WG
authors.lastname: Purschke
authors.forename: Axel
authors.initials: A
authors.lastname: Vater
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000517:prevention & control*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018805:Sepsis / Q000150:complications / Q000188:drug therapy*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052157:Aptamers, Nucleotide; C000589815:NOX-D20; D015936:Complement C5a