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

🥉 Top 5% JournalApr 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

AI simplified

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.

AI simplified

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.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

Abstract

Full Text

Related papers