Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy.
Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy.
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DOI：
10.1016/j.jconrel.2018.04.041
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发表时间：
2018-07-28
期刊：
影响因子：
--
通讯作者：
Moon JJ
中科院分区：
文献类型：
--
作者：
Kuai R;Sun X;Yuan W;Ochyl LJ;Xu Y;Hassani Najafabadi A;Scheetz L;Yu MZ;Balwani I;Schwendeman A;Moon JJ
最近的研究表明，Toll样受体（TLR）激动剂的某些组合可以诱导协同免疫激活。然而，以有效、简便和适合临床转化的方式在体内实现这种稳健的应答仍然具有挑战性。在这里，我们表明，MPLA，TLR 4激动剂，和CpG，TLR 9激动剂，可以有效地共同加载到合成的高密度脂蛋白纳米盘，形成一个有效的佐剂系统（ND-MPLA/CpG），可以很容易地与各种亚单位抗原，包括蛋白质和肽相结合。与递送单一TLR激动剂的游离双佐剂或纳米盘相比，ND-MPLA/CpG显著增强树突状细胞的活化。重要的是，用蛋白抗原ND-MPLA/CpG的物理混合物免疫的小鼠产生强烈的体液应答，包括诱导针对蛋白转化酶枯草杆菌蛋白酶/kexin 9（PCSK 9）的IgG应答，导致总血浆胆固醇水平降低17-30%。此外，ND-MPLA/CpG在多种小鼠肿瘤模型中表现出强的抗肿瘤功效。与游离佐剂相比，ND-MPLA/CpG与卵白蛋白混合显著提高抗原特异性CD 8 + T细胞应答8倍，并促进B16 F10-OVA黑色素瘤消退（P < 0.0001）。此外，与E7肽抗原混合的ND-MPLA/CpG引发了~20%的E7特异性CD 8 + T细胞应答，并在所有治疗动物中实现了已建立的TC-1肿瘤的完全消退。总之，我们的工作突出了双重TLR激动剂纳米盘在疫苗和癌症免疫治疗中的应用的简单性，多功能性和效力。
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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影响因子：
6.2
作者：
Bode C;Zhao G;Steinhagen F;Kinjo T;Klinman DM
通讯作者：
Klinman DM
影响因子：
11.2
作者：
Kang TH;Mao CP;Lee SY;Chen A;Lee JH;Kim TW;Alvarez RD;Roden RB;Pardoll D;Hung CF;Wu TC
通讯作者：
Wu TC
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
DOI：
10.1084/jem.192.4.595
发表时间：
2000-08-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Häcker H;Vabulas RM;Takeuchi O;Hoshino K;Akira S;Wagner H
通讯作者：
Wagner H
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G