Abstract 18960: Anti-PCSK9 VLP Immunization Reduces Cholesterol Levels in Mice and Non-human Primates
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protease involved in cholesterol homeostasis by enhancing endosomal and lysosomal degradation of cell surface low-density lipoprotein receptors (LDL-R). While increased activity of PCSK9 has been associated with hypercholesterolemia and atherosclerosis, several healthy patients have also been identified with loss-of-function PCSK9 mutations and exhibit a hypocholesterolemia phenotype (and an extremely low incidence of coronary artery disease - CAD). These observations indicate that PCSK9 is an attractive target for the purpose of lowering circulating LDL-cholesterol, and therefore decreasing the potential for CAD and atherosclerosis. To date, several different strategies are being attempted to target and reduce plasma levels of PCSK9 but they are based on expensive therapies that may be utilized only by a limited number of patients. Phase 2 clinical studies utilizing monoclonal antibodies targeting PCSK9 demonstrated a reduction in LDL-c up to 70%. To reach a much broader population and design a low cost, long-term treatment, we developed a Virus-like Particle (VLP) based vaccine that targets the LDLR binding domain of PCSK9.
Immunized mice (n=20) developed high-titer anti-peptide IgG responses that cross-reacted with PCSK9. Total cholesterol, free cholesterol, phospholipid and triglyceride levels were measured after the final boost. Vaccination with PCSK9-VLPs significantly reduced all four of these measures, with total cholesterol decreasing by over 30% (relative to pre-vaccination levels). We also immunized small groups (n=3) of rhesus macaques. Vaccination resulted in changes in lipoprotein profile at week 2, and decreases in TC (14.2%), ApoB (13.4%) and LDL-p (28.4%) at week 6 were observed. The PCSK9-VLP vaccine was well tolerated with no signs of overt toxicity in both species. In conclusion, these findings suggest that VLP-PCSK9 immunization may be an accessible, low cost, and effective new therapy for hypercholesterolemia and CAD.
Author Disclosures: M. Amar: None. E. Crossey: None. J.T. Schiller: None. B. Chackerian: None. A.T. Remaley: None.
- © 2014 by American Heart Association, Inc.