title: Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux.
abstract: OBJECTIVE
  The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. Our objective was to produce and characterize a human apolipoprotein AI (apoA-I) product optimized to treat clinical atherosclerotic disease.
  
  
  RESULTS
  A new formulation of full length, plasma-derived human apoA-I termed CSL112 was designed to maximize the cholesterol efflux from cells and exhibit favorable pharmacological properties. CSL112 is a disc-shaped particle that strongly elevates cholesterol esterification and shows good pharmacokinetics in rabbits. Infusion of CSL112 into rabbits caused a strong and immediate increase in the ATP binding cassette transporter A1 (ABCA1)-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent cholesterol esterification. In the presence of human plasma, CSL112 was significantly more potent than native HDL at enhancing cholesterol efflux from macrophages, and the efflux elevation was predominantly via the ABCA1 transporter. Consistent with this observation, addition of CSL112 to plasma led to generation of high levels of HDL-VS, a favorable substrate for ABCA1. The lipid profile of plasma did not affect these behaviors. In studies with whole human blood, CSL112 reduced expression of intercellular adhesion molecule 1 and cytokine secretion, and as with cholesterol efflux, these activities were substantially greater than those of native HDL assayed in parallel.
  
  
  CONCLUSIONS
  CSL112 has favorable pharmacological properties and strongly elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal and this property makes CSL112 a promising candidate therapy for acute coronary syndrome.
authors.affiliation: CSL Behring AG, Berne, Switzerland.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Diditchenko
authors.forename: Andreas
authors.initials: A
authors.lastname: Gille
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.forename: Dominik
authors.initials: D
authors.lastname: Stadler
authors.forename: Marcel
authors.initials: M
authors.lastname: Waelchli
authors.forename: Ross
authors.initials: R
authors.lastname: Hamilton
authors.forename: Andrew
authors.initials: A
authors.lastname: Leis
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000187:drug effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000097:blood*; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007262:Infusions, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010316:Particle Size; D011817:Rabbits; D015854:Up-Regulation
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; C584257:CSL112; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D016207:Cytokines; D018836:Inflammation Mediators; D008075:Lipoproteins, HDL; D002784:Cholesterol
keywords: acute coronary syndrome; apolipoproteins; cholesterol; high-density lipoproteins, pre-β; inflammation