title: Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management.
abstract: BACKGROUND
  Low Density Lipoprotein (LDL) hypercholesterolemia, and its associated cardiovascular diseases, are some of the leading causes of death worldwide. The ability of proprotein convertase subtilisin/kexin 9 (PCSK9) to modulate circulating LDL cholesterol (LDLc) concentrations made it a very attractive target for LDLc management. To date, the most advanced approaches for PCSK9 inhibition are monoclonal antibody (mAb) therapies. Although shown to lower LDLc significantly, mAbs face functional limitations because of their relatively short in vivo half-lives necessitating frequent administration. Here, we evaluated the long-term efficacy and safety of PCSK9-specific active vaccines in different preclinical models.
  
  
  RESULTS
  PCSK9 peptide-based vaccines were successfully selected by our proprietary technology. To test their efficacy, wild-type (wt) mice, Ldlr+/- mice, and rats were immunized with highly immunogenic vaccine candidates. Vaccines induced generation of high-affine PCSK9-specific antibodies in all species. Group mean total cholesterol (TC) concentration was reduced by up to 30%, and LDLc up to 50% in treated animals. Moreover, the PCSK9 vaccine-induced humoral immune response persisted for up to one year in mice, and reduced cholesterol levels significantly throughout the study. Finally, the vaccines were well tolerated in all species tested.
  
  
  CONCLUSIONS
  Peptide-based anti-PCSK9 vaccines induce the generation of antibodies that are persistent, high-affine, and functional for up to one year. They are powerful and safe tools for long-term LDLc management, and thus may represent a novel therapeutic approach for the prevention and/or treatment of LDL hypercholesterolemia-related cardiovascular diseases in humans.
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Gergana
authors.initials: G
authors.lastname: Galabova
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Brunner
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Winsauer
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Juno
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Wanko
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mairhofer
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Lührs
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Schneeberger
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Arne
authors.initials: A
authors.lastname: von Bonin
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Mattner
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Schmidt
authors.affiliation: AFFiRiS AG, Karl-Farkas-Gasse 22, Vienna, 1030, Austria.
authors.forename: Guenther
authors.initials: G
authors.lastname: Staffler
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000276:immunology / Q000628:therapy*; D008297:Male; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000276:immunology; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit / Q000627:therapeutic use
chemical_list: D008078:Cholesterol, LDL; D022223:Vaccines, Subunit; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases