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

Abstract

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.

• Authors: Rui Kuai, Xiaoqi Sun, Wenmin Yuan, Lukasz J Ochyl, Yao Xu, Alireza Hassani Najafabadi, Lindsay Scheetz, Min-Zhi Yu, Ishina Balwani, Anna Schwendeman, James J Moon
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 282 Pg. 131-139 (07 28 2018) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 29702142 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Adjuvants, Immunologic
• CPG-oligonucleotide
• Drug Carriers
• Lipid A
• Oligodeoxyribonucleotides
• Toll-Like Receptor 4
• Toll-Like Receptor 9
• Vaccines
• monophosphoryl lipid A

Topics

• Adjuvants, Immunologic (administration & dosage, pharmacology, therapeutic use)
• Animals
• Cells, Cultured
• Drug Carriers (chemistry)
• Female
• Humans
• Immunity, Humoral
• Immunization
• Immunotherapy
• Lipid A (administration & dosage, analogs & derivatives, immunology, therapeutic use)
• Melanoma (immunology, therapy)
• Mice
• Mice, Inbred C57BL
• Nanostructures (chemistry)
• Oligodeoxyribonucleotides (administration & dosage, immunology, therapeutic use)
• Toll-Like Receptor 4 (agonists, immunology)
• Toll-Like Receptor 9 (agonists, immunology)
• Vaccines (administration & dosage, immunology, therapeutic use)