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

Apr 28, 2018Journal of controlled release : official journal of the Controlled Release Society

Nanodiscs activating two immune sensors as a powerful booster for vaccines and immune treatments

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Abstract

Mice immunized with the ND-MPLA/CpG adjuvant system achieved a 17-30% reduction in total plasma cholesterol levels.

Co-loading of TLR4 and TLR9 agonists into synthetic high-density lipoprotein nanodiscs created a potent adjuvant system.
ND-MPLA/CpG significantly enhanced dendritic cell activation compared to free dual adjuvants or single TLR agonist nanodiscs.
Immunization with ND-MPLA/CpG mixed with protein antigens resulted in strong humoral responses, including IgG against PCSK9.
ND-MPLA/CpG improved antigen-specific CD8+ T cell responses by 8-fold compared to free adjuvants in mice with ovalbumin.
Complete regression of established TC-1 tumors was achieved in all treated mice with E7 peptide antigen mixed with ND-MPLA/CpG.

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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 ~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.

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