Abstract 15205: Atheroprotective Effect of the AFFITOPE®-based Anti-PCSK9 Vaccine (AT04A) in APOE*3Leiden.CETP Mice
Background: Elevated low density lipoprotein cholesterol (LDLc) is one of the major risk factors for premature cardiovascular diseases (CVD). Thus, therapeutic approaches aim at reducing LDLc. PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) has been shown to be a key regulator of the LDLR-mediated cholesterol clearance pathway. Many preclinical and clinical studies confirm the LDLc-lowering effect of PCSK9 inhibition, and emphasize PCSK9 as a potential novel target for the treatment of CVD.
Aim: Proof of concept study for AFFITOPE®-based (AT04A) anti-PCSK9 immunization in the APOE*3Leiden.CETP mouse model and its safety aspects.
Methods: AT04A vaccine was administered subcutaneously in APOE*3Leiden.CETP mice. Control and vaccine treated mice were fed Western-type diet for 18 weeks. Antibody titers and concentration, and their affinity towards PCSK9, as well as plasma lipids were monitored throughout the whole study by ELISA, Biacore® and FPLC, respectively. Moreover, body weight (BW), food intake (FI) and liver enzymes (ALT and AST) were measured. The progression of atherosclerotic lesion development was evaluated by histological analysis of serial cross-sections from the aortic sinus.
Results: AT04A vaccine induced antibodies (mean titers up to ODmax/2=12,000 and mean concentration up to 250 μg/mL), which significantly reduced the plasma total cholesterol (TC) (-53%, P<0.001) and triglycerides (TG) (-46%, P<0.001), contained in the apoB-containing lipoproteins, in comparison to the control. Moreover, immunization neither altered FI or BW, nor plasma liver enzymes concentration. Furthermore, anti-PCSK9 immunization resulted in a higher percentage of undiseased aortic segments (+119%, p=0.026), decreased segments with severe lesions (-64%, p=0.051) and a decrease in atherosclerotic lesion area (-64%, P=0.004) as compared to the control.
Conclusions and Outcome: AT04A vaccine is highly immunogenic and atheroprotective in APOE*3Leiden.CETP mice. The induced antibodies are able to decrease significantly plasma lipids and atherosclerotic lesions progression in the aorta. A phase I clinical study with AT04A and with a second vaccine candidate AT06A is scheduled for Q3/2015.
Author Disclosures: G. Galabova: Employment; Significant; employee of AFFiRiS AG. C. Juno: Employment; Significant; AFFiRiS AG. A. Mairhofer: Employment; Significant; AFFiRiS AG. J.W. van der Hoorn: Research Grant; Significant; The Study was sponsored by AFFiRiS AG. E.J. Pieterman: Research Grant; Significant; The Study was sponsored by AFFiRiS AG. M. Pouwer: Research Grant; Significant; The Study was sponsored by AFFiRiS AG. J.W. Jukema: None. H.M. Princen: Research Grant; Significant; The Study was sponsored by AFFiRiS AG. A. Schneeberger: Employment; Significant; AFFiRiS AG. G. Staffler: Employment; Significant; AFFiRiS AG.
- © 2015 by American Heart Association, Inc.