We have previously demonstrated that active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has now been used clinically. To that end, we first charactered the responses of T cells to P210 using PBMCs from human subjects with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAM) as a vaccine formulation to reduce atherosclerosis in ApoE-/- mice and its potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE-/- background to test the efficacy of P210-PAM immunization as a bridge for future clinical testing. P210 provoked T cell activation and memory response in PBMCs of human subjects with ASCVD. Dendritic cell uptake of P210-PAM and its co-staining with MHC-I molecules supported its use as a vaccine formulation. In ApoE-/- mice, immunization with P210-PAM dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE-/- mouse model expressing chimeric HLA-A*02:01/Kb. Taken together, our data supports the experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.
Kuang-Yuh Chyu, Xiaoning Zhao, Jianchang Zhou, Paul C. Dimayuga, Nicole W.M. Lio, Bojan Cercek, Noah T. Trac, Eun Ji Chung, Prediman K. Shah