Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy

JOURNAL OF CONTROLLED RELEASE

卷:282

Article; Proceedings Paper

Kuai, Rui^1,2  Sun, Xiaoqi^1,2  Yuan, Wenmin^1,2  Ochyl, Lukasz J.^1,2  Xu, Yao^1,2  Najafabadi, Alireza Hassani^1,2  Scheetz, Lindsay^1,2  Yu, Min-Zhi^1,2  Balwani, Ishina^1,2  Schwendeman, Anna^1,2  Moon, James J.^1,2,3 

[1] Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Biointerfaces Inst, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA

关键词: Vaccine;    Nanoparticle;    Adjuvant;    Cancer;    Immunotherapy;   

DOI  :  10.1016/j.jconrel.2018.04.041

来源: Elsevier

【 摘 要 】

Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in vivo in a manner that is effective, facile, and amenable for clinical translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with physical mixtures of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17-30% reduction of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen-specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P < 0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited similar to 20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy.

【 授权许可】

Free