Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy
| Autor: | Lukasz J. Ochyl, Minzhi Yu, Ishina Balwani, Alireza Hassani Najafabadi, Yao Xu, Rui Kuai, Xiaoqi Sun, Lindsay Scheetz, Wenmin Yuan, Anna Schwendeman, James J. Moon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class medicine.medical_treatment T cell Pharmaceutical Science Article Mice 03 medical and health sciences Adjuvants Immunologic Antigen medicine Animals Humans Melanoma Cells Cultured Drug Carriers Vaccines biology Chemistry TLR9 Immunity Humoral Nanostructures 3. Good health Mice Inbred C57BL Toll-Like Receptor 4 Ovalbumin Lipid A 030104 developmental biology medicine.anatomical_structure Oligodeoxyribonucleotides CpG site Toll-Like Receptor 9 Cancer research biology.protein TLR4 Female Immunization Immunotherapy Adjuvant |
| Zdroj: | Journal of Controlled Release. 282:131-139 |
| ISSN: | 0168-3659 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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