Abstract 12329: Novel High-Throughput ELISAs to Measure ApoC-III on ApoB-100, ApoA-I and Lp(a): Reduction in Lipoprotein-Associated ApoC-III Levels With Volanesorsen (ISIS-APOC-IIIRx) Antisense Therapy to ApoC-III in a Phase 2 Randomized Trial
Background: Elevated apolipoprotein C-III (APOC-III) levels are associated with hypertriglyceridemia and are causally associated with cardiovascular events. ApoC-III present on LDL and HDL particles predicts increased cardiovascular risk.
Objectives: Traditional methods to detect apoC-III on LDL or HDL density fractions utilize labor-intensive immunoprecipitation of apoC-III and/or ultracentifugation methods. We developed high-throughput sandwich chemiluminescent ELISAs to detect apoC-III on individual lipoproteins in plasma.
Methods: Monoclonal antibodies MB47, LPA4 and goat anti-human apoA-I were plated to capture apoB-100, Lp(a) and apoA-I lipoproteins, respectively, and the content of apoC-III on each was detected with an anti-apoC-III monoclonal antibody. ApoC-III-apoB-100, apoCIII-Lp(a) and apoC-III-apoA-I complexes were measured at baseline and day 57, 92 and 176 in 77 patients with hypertriglyceridemia treated with 100, 200, 300mg volanesorsen (ISIS-APOC-IIIRx), a generation 2.0+ antisense drug to apoC-III or placebo, for 85 days.
Results: The ELISAs detected apoC-III-apoB, apoC-III-apoA-I and apoCIII-Lp(a) with high signal-to-noise ratios. Compared to placebo, a dose-response effect was noted with volanesorsen at day 92 with 84.2±10.1%, 80.7±16.6%, and 80.7±14.3% reductions in ApoC-III-apoB, apoCIII-Lp(a) and apoC-III-apoA-I, respectively (300 mg dose; p<0.001 for all), and return to baseline by day 176. Strong correlations in all assay measures were noted with changes in total plasma apoC-III and triglycerides.
Conclusions: Novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a) and apoA-I. Ongoing studies with cardiovascular endpoints will define whether lipoprotein-associated apoC-III biomarkers have prognostic utility and/or can be targets of apoC-III-directed therapy.
Author Disclosures: X. Yang: None. S. Lee: None. Y. Choi: None. V.J. Alexander: Employment; Significant; Isis Pharmaceuticals, Inc. Q. Yang: Employment; Significant; Isis Pharmaceuticals, Inc. J.L. Witztum: Employment; Significant; Isis Pharmaceuticals, Inc. Consultant/Advisory Board; Modest; cymabay, Intercept. Consultant/Advisory Board; Significant; Isis Pharmaceuticals, Inc. Other; Modest; Patents through UCSD. S. Tsimikas: Employment; Significant; Isis Pharmaceuticals, Inc. Other; Modest; patents through UCSD.
- © 2015 by American Heart Association, Inc.