Formulated Phospholipids as Non-Canonical TLR4 Agonists.
Formulated Phospholipids as Non-Canonical TLR4 Agonists.
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DOI：
10.3390/pharmaceutics14122557
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发表时间：
2022-11-22
期刊：
影响因子：
5.4
通讯作者：
Orr MT
中科院分区：
文献类型：
--
作者：
Liang H;Lykins WR;Seydoux E;Guderian JA;Phan T;Fox CB;Orr MT
被称为佐剂的免疫原剂在许多疫苗配方中发挥着关键作用。佐剂通常通过Toll样受体(TLR)途径发出信号，包括针对TLR4的特许疫苗配方。虽然TLR4主要是对革兰氏阴性细菌膜的一种成分脂多糖(LPS)的反应，但它已被证明是包括磷脂在内的许多分子结构的受体。因此，以磷脂为基础的药物制剂可能通过TLR4信号产生偏离靶点的作用，混淆了对药物生物活性的解释。在这项研究中，我们检查了临床阶段水包油疫苗佐剂乳剂(称为稳定乳剂或SE)的单个成分及其通过小鼠和人类TLR4信号传递的能力。我们发现，磷脂1，2-二肉豆蔻-sn-甘油-3-磷胆碱(DMPC)激活TLR4，并引发许多与经典的TLR4激动剂相同的免疫表型。这一途径取决于磷脂的饱和度、大小和头基。有趣的是，DMPC对人体细胞的影响是明显的，但总体上看似乎没有乳化油成分那么有效。考虑到DMPC和其他磷脂在制药领域的普遍使用，这些发现可能与可能影响临床前和临床发展的脱靶先天免疫反应有关。
Immunogenic agents known as adjuvants play a critical role in many vaccine formulations. Adjuvants often signal through Toll-like receptor (TLR) pathways, including formulations in licensed vaccines that target TLR4. While TLR4 is predominantly known for responding to lipopolysaccharide (LPS), a component of Gram-negative bacterial membranes, it has been shown to be a receptor for a number of molecular structures, including phospholipids. Therefore, phospholipid-based pharmaceutical formulations might have off-target effects by signaling through TLR4, confounding interpretation of pharmaceutical bioactivity. In this study we examined the individual components of a clinical stage oil-in-water vaccine adjuvant emulsion (referred to as a stable emulsion or SE) and their ability to signal through murine and human TLR4s. We found that the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) activated TLR4 and elicited many of the same immune phenotypes as canonical TLR4 agonists. This pathway was dependent on the saturation, size, and headgroup of the phospholipid. Interestingly, DMPC effects on human cells were evident but overall appeared less impactful than emulsion oil composition. Considering the prevalence of DMPC and other phospholipids used across the pharmaceutical space, these findings may contextualize off-target innate immune responses that could impact preclinical and clinical development.
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DOI：
10.4049/jimmunol.1600993
发表时间：
2016-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Desbien AL;Dubois Cauwelaert N;Reed SJ;Bailor HR;Liang H;Carter D;Duthie MS;Fox CB;Reed SG;Orr MT
通讯作者：
Orr MT
影响因子：
4.4
作者：
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通讯作者：
van der Poll, Tom
影响因子：
158.5
作者：
Keech, Cheryl;Albert, Gary;Glenn, Gregory M.
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Glenn, Gregory M.
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影响因子：
4.4
作者：
Fox CB;Barnes V L;Evers T;Chesko JD;Vedvick TS;Coler RN;Reed SG;Baldwin SL
通讯作者：
Baldwin SL
影响因子：
16.6
作者：
Chu LH;Indramohan M;Ratsimandresy RA;Gangopadhyay A;Morris EP;Monack DM;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C