CN116077639A - 雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途 - Google Patents
雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途 Download PDFInfo
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- CN116077639A CN116077639A CN202310012605.1A CN202310012605A CN116077639A CN 116077639 A CN116077639 A CN 116077639A CN 202310012605 A CN202310012605 A CN 202310012605A CN 116077639 A CN116077639 A CN 116077639A
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Abstract
本发明公开了雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途。本发明发现使用雷公藤红素或其可药用衍生物作为疫苗佐剂能够增强机体对抗原的免疫反应。相比于在体内不易代谢且具有蓄积的风险的铝佐剂等金属盐类佐剂，本发明雷公藤红素或其可药用衍生物为小分子化合物，容易被降解排泄，安全性较高，并且其对免疫原性的增强效果优于铝佐剂。
Description
技术领域
本发明涉及生物制药领域，特别涉及雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途。
背景技术
疫苗在对抗传染性疾病方面发挥了重要作用，按不同的抗原形态，疫苗可分为减毒苗，灭活苗，重组亚单位蛋白苗以及核酸疫苗。除了抗原外，疫苗中往往需要添加佐剂，增强其免疫效果，从而诱发足够强的免疫反应。目前已批准上市的佐剂有以下几类：递送系统如水包油乳剂MF59，AS01，AS03等；铝盐以及基于铝盐的复合佐剂(如AS04，铝+CpG等)。机体对外源物质(如抗原)发生免疫反应是一个复杂的过程，但同已上市佐剂一样，现有佐剂领域的研究热点大多关注于添加物质对免疫细胞或具体免疫靶点的刺激(热门的靶点如：toll样受体，STING受体等)，一般而言，相应的刺激剂会被机体当成危险信号，营造局部的炎症环境而诱导免疫细胞的聚集，增强机体对抗原的摄取以及后续的呈递，从而增强对抗原的免疫反应。
小分子化合物单独作为疫苗佐剂目前的应用不多。小分子化合物容易被降解排泄，其安全性更高，是作为疫苗佐剂的理想目标。雷公藤红素是一种五环三萜化合物，由我国著名药学家赵承暇于上世纪30年代从雷公藤中分离得到，同青蒿素、雷公藤甲素、辣椒素和姜黄素等一起被《Cell》杂志列为最有可能开发为现代药物的五种天然化合物。现有研究已经表明，雷公藤红素在体内能发挥抗炎，降糖，减重，抗癌等作用，但是没有将其用于疫苗佐剂用途的报道。
发明内容
本发明的一个方面，是针对现有技术中缺乏小分子化合物单独作为疫苗佐剂的应用，提供了雷公藤红素或其可药用衍生物的一种新用途。
本发明提供的技术方案为：
雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途。
雷公藤红素又称南蛇藤素，是一个具有多种生物活性的天然产物，它有很强的抗氧化作用，有抗癌症新生血管生成作用，有抗类风湿作用，主要来源于卫矛科植物雷公藤的根皮，它是治疗类风湿病雷公藤片、雷公藤多甙片等制剂的有效成分之一。雷公藤红素的主要活性与药理作用：1、细胞毒活性。体外对P388和一组人癌细胞株有强的非特异性的细胞毒活性。2、免疫调节作用。明显抑制小鼠脾细胞中溶血空斑细胞的形成。明显抑制小鼠迟发超敏反应。3、抗炎作用。0.5mg/kg时，显著抑制大鼠棉球肉芽肿的形成。0.1～1.0μg/mL时抑制由酵母糖诱导的PGE2的产生；1.0μg/mL时，抑制巨噬细胞的吞噬作用。4、雷公藤红素的抗过氧化作用为生育酚的15倍，IC50为7μM。抑制线粒体膜内外的过氧化作用，直接清除自由基。5、雷公藤红素能延长戊巴比妥钠致小鼠睡眠时间。6、免疫抑制作用：抑制小鼠由PHA、ConA、LPS等诱导的脾细胞增殖，抑制淋巴细胞增殖。7、抑制豚鼠体外精子的受精能力，活性明显强于乙酸棉酚。8、抗关节炎作用。抑制小鼠腹腔巨噬细胞内外白介素-1的活性，抑制小鼠脾细胞产生白介素-2，降低兔滑膜细胞释放PGE2。
雷公藤红素的分子式为C29H38O4，分子量为450.61，结构式如下：
在本发明的某些实施方式中，上述可药用衍生物为其可药用盐的形式。例如，酸式盐、碱式盐。作为优选，在本发明的某些实施方式中，上述酸式盐包括但不限于，盐酸盐、硫酸盐、磷酸盐、枸橼酸盐、氢溴酸盐、醋酸盐、苯甲酸盐、苯磺酸盐、酒石酸盐、碳酸盐、柠檬酸盐、葡萄糖酸盐、乳酸盐、苹果酸盐、甲磺酸盐、硬脂酸盐、戊酸盐或硝酸盐；上述碱式盐包括但不限于，钠盐、钙盐、钾盐、锌盐或葡甲胺盐。
在本发明中，上述雷公藤红素或其可药用衍生物可以用作任意合适类型的疫苗佐剂。例如，包括但不限于，灭活疫苗、减毒活疫苗、蛋白疫苗、细菌多糖与多糖蛋白结合疫苗、基因工程疫苗或遗传重配疫苗。作为优选，在本发明的某些实施方式中，上述疫苗为蛋白疫苗(以蛋白质为抗原的疫苗，例如，重组亚单位疫苗)。更优选地，在本发明的一个实施方式中，上述疫苗的抗原为乙肝表面抗原。
在本发明中，上述雷公藤红素或其可药用衍生物可以包装成任意合适的形式，采用任意合适的递送系统进行给药。作为优选，在本发明的一个实施方式中，上述雷公藤红素或其可药用衍生物为纳米颗粒的形式。上述纳米药物可以利用合适的方法制备，例如，公开号为CN114886855A、CN114903872A的中国专利中记载的方法。
为了实现更好的免疫效果，在本发明的某些实施方式中，上述雷公藤红素或其可药用衍生物可以与其他佐剂形成复合佐剂。作为优选，在本发明的某些实施方式中，上述其他佐剂为选自MG-132、卡非佐米或硼替佐米中的一种或几种。
为了进一步实现更好的免疫效果，在本发明的某些实施方式中，上述复合佐剂中还包含免疫增强剂。所述免疫增强剂可以为例如，包括但不限于，细胞因子，趋化因子PAMP，TLR-配体，免疫刺激序列，包含CpG的DNA，dsRNA，胞吞模式的识别受体配体，LPS，皂树皂苷，妥卡雷琐，等。可以与所述复合佐剂包含在同一容器中，也可以分别包含在不同容器中。
本发明的另一个方面，是提供了一种疫苗佐剂，所述疫苗佐剂中包含雷公藤红素或其可药用衍生物，及其适当的载体、赋形剂、稳定剂或稀释剂。所述疫苗可以为注射剂、口服剂或鼻腔吸入剂。
本发明的有益效果为：
本发明发现了使用雷公藤红素或其可药用衍生物作为疫苗佐剂能够增强机体对抗原的免疫反应。相比于在体内不易代谢且具有蓄积的风险的铝佐剂等金属盐类佐剂，本发明雷公藤红素或其可药用衍生物为小分子化合物，容易被降解排泄，安全性较高，并且其对免疫原性的增强效果优于铝佐剂。
附图说明
图1为雷公藤红素等化合物的佐剂作用评价结果图。
具体实施方式
本发明公开了雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。需要特别指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明，并且相关人员明显能在不脱离本发明内容、精神和范围的基础上对本文所述内容进行改动或适当变更与组合，来实现和应用本发明技术。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分，而并未排除其它元件或其它组成部分。术语“如”、“例如”等旨在指示例性实施方案，而不意图限制本公开的范围。
下面就本发明中出现的部分术语作以解释。
术语“可药用衍生物”包括雷公藤红素的任意药用盐、溶剂化物、水合物或前药。
术语“佐剂”是指非特异性免疫增强剂，当与抗原一起注射或预先注入机体时，可增强机体对抗原的免疫应答或改变免疫应答类型。
为了使本领域的技术人员更好地理解本发明的技术方案，下面结合具体实施例对本发明作进一步的详细说明。
实施例1雷公藤红素作为疫苗佐剂的作用评价
本实施例中选择乙肝表面抗原(HBsAg)作为蛋白类模式抗原，以铝佐剂金标准(Alhydrogel)作为阳性对照。
除了雷公藤红素，本实施例中还选择了另外小分子化合物作为对照：硼替佐米和卡非佐米，它们在临床上用于多发性骨髓瘤的治疗，目前全球由大量同类药物被测试用于肿瘤治疗。按表1配置免疫样品进行动物免疫。
表1免疫分组与剂量
取鼠龄在6～8周的Babl/c小鼠30只，随机分成5组,分别使用上表配置的样品于0W、3W进行两次免疫，第5w采血，而后分离血清后使用酶联免疫吸附法(ELISA)测抗体滴度，结果如图1所示。
结果显示，同单独抗原组相比，铝佐剂组和雷公藤素组均能显著提高抗体滴度(p<0.05),同时出乎意料的是，5μg雷公藤的添加诱发的佐剂作用显著强于25μg铝佐剂诱发的佐剂作用(p<0.05)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.雷公藤红素或其可药用衍生物在制备疫苗佐剂中的用途。
2.根据权利要求1所述的用途，其特征在于，所述可药用衍生物为其可药用盐的形式。
3.根据权利要求2所述的用途，其特征在于，所述可药用衍生物为其可药用的酸式盐或碱式盐的形式；
优选地，所述酸式盐为盐酸盐、硫酸盐、磷酸盐、枸橼酸盐、氢溴酸盐、醋酸盐、苯甲酸盐、苯磺酸盐、酒石酸盐、碳酸盐、柠檬酸盐、葡萄糖酸盐、乳酸盐、苹果酸盐、甲磺酸盐、硬脂酸盐、戊酸盐或硝酸盐；所述碱式盐为钠盐、钙盐、钾盐、锌盐或葡甲胺盐。
4.根据权利要求1所述的用途，其特征在于，所述疫苗为灭活疫苗、减毒活疫苗、蛋白疫苗、细菌多糖与多糖蛋白结合疫苗、基因工程疫苗或遗传重配疫苗。
5.根据权利要求4所述的用途，其特征在于，所述疫苗的抗原为乙肝表面抗原。
6.根据权利要求1所述的用途，其特征在于，所述雷公藤红素或其可药用衍生物为纳米颗粒的形式。
7.根据权利要求1所述的用途，其特征在于，所述雷公藤红素或其可药用衍生物与其他佐剂形成复合佐剂。
8.根据权利要求7所述的用途，其特征在于，所述其他佐剂为选自MG-132、卡非佐米或硼替佐米中的一种或几种。
9.根据权利要求7所述的用途，其特征在于，所述复合佐剂中还包含免疫增强剂。
10.一种疫苗佐剂，其特征在于，所述疫苗佐剂中包含雷公藤红素或其可药用衍生物，及其适当的载体、赋形剂、稳定剂或稀释剂。
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| CN116617386B (zh) | 2024-01-26 |
| WO2024146068A1 (zh) | 2024-07-11 |
| CN116617386A (zh) | 2023-08-22 |
| CN118286412A (zh) | 2024-07-05 |
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