CN113813375A - 一种新型抗新冠病毒复合物的组成及其在防治冠状病毒感染疾病药物中的应用 - Google Patents
一种新型抗新冠病毒复合物的组成及其在防治冠状病毒感染疾病药物中的应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，具体发明了一种新型抗新冠病毒双功能一体化复合物。该新型抗新冠病毒复合物由重组的抗冠状病毒的纳米抗体偶联脂质体构成，脂质体包裹免疫激动剂，并且报道了其制备工艺方法及在制备抗冠状病毒药物中的应用。该新型抗新冠病毒复合物可以有效激活诱导I型干扰素信号通路，有效中和新冠病毒、抑制冠状病毒复制及降低病毒性炎症。该新型抗新冠病毒复合物在预防和治疗光谱冠状病毒药物中有潜在应用前景。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一类新型抗新冠病毒复合物的组成、制备方法及其在防治冠状病毒疾病药物中的应用。
背景技术
目前对于新型冠状病毒所致疾病并没有特效治疗方法。新冠肺炎疫情发生以来，最受关注的焦点之一，就是可能对新冠肺炎有效的治疗方法与特效药物。但是，到目前为止，尚没有发现治疗新型冠状肺炎(COVID-19)的特效药物，也没有预防性药物和疫苗上市。人们迫切需要高效的药物来治愈COVID-19。根据目前的临床结果，可重新利用的小分子药物缺乏特异性，疗效受到影响。血浆治疗虽然表现出了一定的疗效，但恢复期血浆的供应受到限制。血浆治疗的有效成分是靶向性中和抗体。抗体药物作为一种生物制剂，已成功应用于HIV、埃博拉病毒、MERS-CoV冠状病毒等病毒的治疗。然而，要开发出适合临床使用的中和抗体，往往需要花费数月甚至数年的时间。尽管部分药物显示初步有效，但最终还有待临床结果。创新特效抗冠状病毒药物和疫苗的研发迫在眉睫！
最近的研究报道，科学家成功地从恢复期血浆中鉴定出多种针对新型冠状病毒SARS-CoV-2(导致呼吸道疾病COVID-19)的高强效中和抗体。由人体免疫系统产生的中和抗体可以有效防止病毒感染细胞。来自动物研究的新结果显示，这些中和抗体为COVID-19提供了一种潜在的治疗方法，以及短期预防手段。这标志着抵抗COVID-19疫情的一个重要里程碑。另外，从羊驼血液中也分离出多种抗冠状病毒的抗体，筛选出的纳米抗体可以交叉中和多种冠状病毒刺突蛋白，包括新冠病毒刺突蛋白。但是，这些中和抗体能否作为抗新冠病毒肺炎药物还要有待临床验证研究。
人体抵御病原体的第一道防线是先天性免疫系统，这一免疫系统由能够抵御非特异性病毒感染的细胞和其他机制组成，即以一种通用方式来对入侵的病毒做出识别和反应。人体抗病毒的第二道防线是细胞免疫，包括了称为T细胞的免疫细胞。人体中的细胞不断地将其内部蛋白质的片断展示在细胞表面(抗原呈递) 供T细胞来进行检查，一旦T细胞识别出可能的病毒片断，那么对应的细胞就会由T杀手细胞和病毒特异性T细胞扩增所消灭。诸如巨噬细胞在内的一些细胞专门负责抗原呈递。干扰素(IFN)是病毒感染之后由肌体所产生的一种激素，它能够通过杀死受感染细胞及其邻近细胞来逐步阻止病毒的复制。干扰素为细胞信号传送蛋白，是具有抗病毒功能的宿主特异性糖蛋白。细胞感染病毒后分泌的干扰素能够与周围未感染的细胞上的相关受体作用，促使这些细胞合成抗病毒蛋白防止进一步的感染，从而起到抗病毒的作用。
在感染的哺乳动物细胞中病毒DNA能通过刺激干扰素分泌诱导内源强有力的免疫应答。内质网(ER)受体蛋白(STING)对胞质DNA的免疫应答是必需的因素。研究表明，环化cGMP-AMP二核苷酸合成酶(cGAS)在结合DNA后的活化条件下，内源性地催化cGAMP的合成。cGAMP作为第二信使通过 STING刺激干扰素INF-I的感应，介导TBK1和IRF-3的活化，进而启动I型干扰素(INF-β)基因的转录。STING是内质网的跨膜蛋白，内质网上具有一种 ENPP1的水解酶。ENPP1水解酶可以降解STING的激动剂2’3’-cGAMP。因此，阻止STING激动剂cGAMP被ENPP1水解是保持免疫激动剂有效寿命和药效的必然选择。作为一种药物载体，纳米脂质体颗粒在延长药物半衰期，增强药效，靶向定点给药等方面具有广阔的应用前景。但是，如何制备稳定性好、包封率高、易于逃过细胞保护屏障的靶向纳米脂质体仍然是一个挑战。单克隆抗体等免疫靶向脂质体是一个很好的发展方向，但是，单克隆抗体有分子量大、制备成本昂贵且难于量产、免疫反应等问题，也形成了严峻挑战。如何选择分子量小，组织穿透能力好，特异性强，亲和力高，对人的免疫原性弱，避免Fc段引起的补体反应的抗体作为靶向脂质体的组成部分是科学家的理想目标。另外，容易制备，可以用原核系统发酵罐高效表达，节省制备成本，可以大规模量产，也是我们优选考虑的重要因素。
经过多个方面因素的考虑和研究筛选，我们优选制备了一种新型双功能一体化复合物，该一体化复合物包含天然免疫激活剂和能中和新冠病毒刺突蛋白的多价纳米抗体，该一体化的复合物具有双管齐下地抗新冠病毒功能。该类双功能抗新冠病毒复合物具有集多种优势的显著特征。探索研究发现该一体化复合物具有比单一免疫激活剂或新冠病毒中和纳米抗体显著提高的抗病毒活性，在制备防治新冠病毒肺炎药物方面有潜在应用价值。
发明内容
本发明提供了一种新型抗新冠病毒的双功能一体化复合物及其制备方法。该新型抗新冠病毒复合物可显著诱发抗新冠病毒的特异免疫功能，显著有效地中和新冠病毒及有效抑制冠状病毒复制和病毒性炎症。
该新型抗新冠病毒双功能一体化复合物由重组的抗新冠病毒纳米抗体偶联脂质体与免疫激动剂构成，所述免疫激动剂包封于重组纳米抗体偶联的脂质体中。
免疫激动剂为天然免疫通路(cGAS-STING-cGAMP-IRF3通路)STING 的激动剂，既环二核苷酸2’3’-cGAMP或其衍生物。
抗新冠病毒纳米抗体是指，能与新冠病毒刺突S蛋白紧密结合，且靶向中和新冠病毒的羊驼纳米抗体或抗新冠病毒的单克隆抗体的可变区结构域。
优选地，靶向新冠病毒刺突S蛋白的纳米抗体为SARS2-VHH,其氨基酸序列为：SEQID NO:1。
上述新型抗新冠病毒双功能一体化复合物的制备方法，主要包括如下步骤：
(1)运用原核表达载体，在大肠杆菌中重组表达、纯化抗新冠病毒S 蛋白的纳米抗体SARS2-VHH；
(2)对重组抗新冠病毒S蛋白的纳米抗体SARS2-VHH进行巯基化；
(3)巯基化的重组纳米抗体SARS2-VHH与脂质体化学键偶联融合，进而包封免疫激动剂。
上述新型抗新冠病毒复合物在制备预防和/或治疗冠状病毒感染疾病药物中的应用。
优选地，冠状病毒感染疾病包括但不限于人或动物感染冠状病毒引起的病毒性肺炎/呼吸道炎症、病毒性肾炎、病毒性脑炎、病毒性肠炎或病毒性肝炎。
抗新冠病毒复合物药物可单独制备成不同规格的单位制剂或通过药学上可接受的载体制备成药物制剂，包括但不限于静脉注射制剂、鼻腔滴注制剂、静脉滴注制剂、肌肉注射制剂、皮下注射制剂或口服制剂；口服制剂包括但不限于胶囊、片剂或颗粒剂。
本发明综合研究优化天然免疫激动剂、脂质体的作用和优点，亲和且能中和新冠病毒刺突蛋白的纳米抗体，优化组成一种新型抗新冠病毒的双功能一体化复合物。
本发明研究表明，新型抗新冠病毒复合物在预防和治疗冠状病毒药物中有潜在应用前景，该类新型复合物可将新型天然免疫激动剂及靶向中和新冠病毒的纳米抗体通过脂质体化学键偶联融为一体，发挥其比单一免疫激动剂/或纳米抗体显著提高的性能和药效功能。该新型抗新冠病毒复合物可以有效激活/诱导I型干扰素；能高效中和新冠病毒、有效抑制冠状病毒复制及病毒性炎症。可用于预防和治疗冠状病毒感染疾病包括新冠病毒性肺炎等病毒性炎症。
本发明提及的环二核苷酸cGAMP(即2’3’-cGAMP)，如不加特殊说明，均指C20H22N10O13P2.2NH4。
本发明提及STING，为特定蛋白质名称，如不加说明，均与多数公开文献及 NCBI数据库、欧洲基因数据库一致。其GENE名为：TMEM173；GENE ID为： 340061；STING公开的其它命名包括：Transmembrane Protein 173,ERIS,MITA, MPYS,NET23,SAVI,STING,hMITA,hSTING。
本文提及的STING激动剂，包括但不限制于cGAMP(即2’3’-cGAMP，或 c-AMP-GMP)以及其衍生物及混合物。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实施例是为了更好地阐述本发明，并不是用来限制本发明的范围。
实施例1：新型抗新冠病毒复合物的制备
(A)天然免疫激动剂的制备。环二核苷酸cGAMP按文献方法在结合DNA后的活化条件下，由环化cGMP-AMP二核苷酸合成酶(cGAS)催化合成。纯度在 98％以上(Pingwei Li，etal.,Immunity,2013,39(6),1019-1031.)。
(B)纳米抗体的制备。抗新冠病毒纳米抗体是指，能与新冠病毒刺突S 蛋白紧密结合，且靶向中和新冠病毒的纳米抗体或抗新冠病毒的单克隆抗体的可变区结构域。
优选地，靶向新冠病毒刺突S蛋白的纳米抗体为，抗新冠病毒羊驼纳米抗体基因(SARS2-VHH)由生物科技有限公司合成，质粒采用pET-22b(+)为载体，添加SMT3标签，携带Amp+抗性。SMT3-SARS2－VHH蛋白氨基酸列如下： MHHHHHHSDSEVNQEAKPEVKPEVKPETHINLKVSDGSSEIFFKIKKTTPLRR LMEAFAKRQGKEMDSLRFLYDGIRIQADQTPEDLDMEDNDIIEAHREQIGGAT YQVQLQESGGGLVQAGGSLRLSCAASGRTFSEYAMGWFRQAPGKEREFVATI SWSGGSTYYTDSVKGRFTISRDNAKNTVYLQMNSLKPDDTAVYYCAAAGLG TVVSEWDYDYYLDYWGQGTQVTVSS
抗新冠病毒纳米抗体用大肠杆菌高效表达，抗体蛋白纯化方法用NiNTA亲和柱纯化，纯度达98％。SMT3-SARS2－VHH蛋白再用SUMO蛋白酶酶切过夜后，经第二次NiNTA亲和柱去除SMT3标签蛋白，收集流穿SARS2－VHH目标蛋白，浓缩，用冷冻干燥机冻干，冻干粉蛋白(纯度达98％以上)于超低温冰箱保存备用。
(C)[纳米抗体－脂质体－免疫激动剂]复合物的制备。首先将SARS2-VHH 纳米抗体末端巯基化，在纳米抗体蛋白溶液中搅动下滴加巯基化试剂(Traut’s reagent)，水浴中搅动下避光孵育1小时。用脱盐柱除去过量巯基化试剂。用 Ellman方法测定纳米抗体蛋白上的巯基，验证纳米抗体巯基化成功。将脂质体材料(包括卵磷脂、胆固醇、1,2-二硬脂酰-SN-甘油-3-磷酰乙醇胺-N-马来酰亚胺 -聚乙二醇2000)，溶解于氯仿中，在水浴中真空旋转蒸发干成膜，然后加入(NH4)2SO4水化制成单室脂质体，向空白脂质体中加入免疫激动剂，然后加入末端巯基化的纳米抗体，室温避光孵育过夜，再用分子筛柱除去未包封的药物和未连接的纳米抗体蛋白。用TEM电镜检测所得到的复合物，双层圆形囊泡，形态良好，脂质体直径约为～195nm，Zeta电位～－25mV。免疫激动剂包封率为 78％，4度冷藏条件下稳定，3％海澡糖溶液的冻干粉冷藏保存。
实施例2：纳米抗体SARS2-VHH与新冠病毒S蛋白亲和作用研究 (1)重组新冠病毒S蛋白RBD－SD1结构域的制备重组新冠病毒S蛋白(Spike protein，刺突蛋白)RBD－SD1结构域(S蛋白第 319-591氨基酸序列如下)基因有生物技术服务公司合成。
ITNLCPFGEVFNATKFPSVYAWERKKISNCVADYSVLYNSTFFSTFKCYGVSAT KLNDLCFSNVYADSFVVKGDDVRQIAPGQTGVIADYNYKLPDDFMGCVLAW NTRNIDATSTGNYNYKYRYLRHGKLRPFERDISNVPFSPDGKPCTPPALNCYW PLNDYGFYTTTGIGYQPYRVVVLSFELLNAPATVCGPKLSTDLIKNQCVNFNF NGLTGTGVLTPSSKRFQPFQQFGRDVSDFTDSVRDPKTSEILDISPCAFGGVSVI TPGTNASGGSGGSHHHHHHHH，该RBD-SD1基因克隆到pTT5真核表达载体上，RBD－SD1结构域基因序列N端前加信号肽(MGVLLTQRTLLSLVLALLFPSMASM)，在信号肽前加入Kozak序列，末端加 8XHis组氨酸标签，基因合成由生物技术公司服务完成。表达载体用于使用聚乙烯亚胺瞬时转染FreeStyle293F细胞(Thermo Fisher)。使用NiNTA亲和柱树脂从过滤的细胞上清液中纯化蛋白质，然后使用Superdex 200通过尺寸排阻色谱进行进一步纯化(GE Healthcare)。纯化蛋白质的缓冲液使用50mM Tris pH 8.0,200mM NaCl,洗杂蛋白和洗脱目的蛋白时，分别使用含有20mM咪唑/200 mM咪唑的上述缓冲液。SDS－Page显示蛋白纯度达95％以上。
(2)纳米抗体SARS2-VHH按实施例1(B)方法制备。
(3)纳米抗体SARS2-VHH与新冠病毒S蛋白RBD-SD1的亲和作用
运用表面等离子体共振(SPR)方法，使用Biacore X100(GE Healthcare)，将带有组氨酸标签的SARS2-VHH固定在NTA传感器芯片的单个流通池中，每个循环的水平约为每个循环400个响应单位(RUs)。使用0.35M EDTA和0.1M NaOH，然后使用0.5mM NiCl2双重再生芯片。将三个仅包含运行缓冲液的样品 (分别由10mM HEPES pH 8.0、150mM NaCl和0.005％Tween 20组成)注入配体和参比流通池，然后依次从50-2nM稀释SARS-CoV-2RBD-SD1，重复浓度为3nM。使用Biacore X100评估软件，将所得数据扣除两次参考值并拟合为1：1结合模型。拟合结果显示，纳米抗体SARS2-VHH与新冠病毒S蛋白RBD-SD1 具有很好的亲和作用，亲和常数为：KD＝19nM,ka＝9.12 X 107M-1S-1,kd＝1.73 S-1。
实施例3：纳米抗体SARS2-VHH中和假型新冠病毒效价研究
(1)按照实施例1方法制备新型抗新冠病毒复合物。该复合物含有多价纳米抗体SARS2-VHH，位于纳米脂质体颗粒表面。
(2)假型新冠病毒的制备及中和活性研究
为了确定新型抗新冠病毒复合物颗粒表面纳米抗体SARS2-VHH的中和活性，进行了假型病毒中和试验。按照文献方法，(Wu et al.,Identification of Human Single-Domain Antibodies against SARS-CoV-2,Cell Host&Microbe(2020), https://doi.org/10.1016/j.chom.2020.04)，将pcDNA3.1-SARS-CoV-2-S(编码 SARS-CoV-2S蛋白)和pNL4-3.luc.RE(载有表达HIV-1骨架的荧光素酶报告基因)表达载体共转染到293T细胞。假型病毒颗粒有效地释放在细胞上清液中，收集含有SARS-CoV-2假型病毒的上清液，用含有10％胎牛血清的DMEM 系列稀释含有纳米抗体SARS2-VHH的新型抗新冠病毒复合物溶液，将其与假病毒在37℃下孵育1小时，然后将混合物添加至单层Huh-7细胞(96孔板中每孔104个)。感染12小时后，换培养基，然后再孵育48小时。然后，裂解细胞，使用Bright-Glo荧光素酶测定系统(Promega)以检测相对光单位计算荧光素酶活性。中和百分率按如下方法计算：无感染细胞中和率按100％；只有假病毒的细胞其中和率为0％；使用Prism(GraphPad)对所得曲线进行非线性回归分析，以计算半数最大抑制浓度(IC50)值。
实验结果显示该新型复合物颗粒表面多价纳米抗体中和假型SARS－2－S病毒的半数最大抑制浓度(IC50)值为15ng/ml。
实施例4：新型抗新冠病毒复合物抑制冠状病毒的复制 PBMC细胞：PBMC细胞，即人外周血单个核细胞，购买于生物科技有限公司。 PBMC细胞主要包括淋巴细胞(T cell/Bcell)，单核细胞，巨噬细胞，树突状细胞和其他少量细胞类型。其中淋巴细胞占很大一部分。PBMC属于正常原代细胞，细胞是混合体系。在37℃和5％CO2下，100U/ml青霉素(Sigma-Aldrich) 和100mg/ml链霉素(Sigma-Aldrich)。冻存条件:90％完全培养基+10％DMSO，液氮储存。销售公司QC检测:不含有HIV-1、HBV、HCV、支原体、细菌、酵母和真菌。
病毒株：适合在实验室使用的减毒病毒株购于美国ATCC公司：冠状病毒(ATCCVR－841)，该病毒为支气管肺炎冠状病毒。该研究中病毒实验操作委托美国AmericanAnimals Inc.病毒实验室完成。
PBMC细胞培养操作：
1)复苏细胞：将含1mL细胞悬液的冻存管在37℃水浴中迅速摇晃解冻，加入 4mL培养基混合均匀。在1000RPM条件下离心4分钟，弃去上清液，补加1-2mL 培养基后吹匀。然后将所有细胞悬液加入培养瓶中培养过夜。第二天换液并检查细胞密度。
2)细胞传代：细胞密度达80％-90％，进行传代培养。弃去培养上清，用不含钙、镁离子的PBS润洗细胞1-2次。加1ml消化液(0.25％Trypsin-0.53mM EDTA) 于培养瓶中，置于37℃培养箱中消化1-2分钟，然后在显微镜下观察细胞消化情况，若细胞大部分变圆并脱落，迅速拿回操作台，轻敲几下培养瓶后加少量培养基终止消化。按8ml/瓶补加培养基，轻轻打匀后吸出，在1000RPM条件下离心4分钟，弃去上清液，补加1-2mL培养液后吹匀。将细胞悬液按1：2比例分到新的含8ml培养基的新瓶中。细胞活度测定：Fixable Red Dead Cell染色试剂盒(生命技术公司)测定细胞活力，使用0.5μl染料在1ml PBS中在黑暗中将细胞染色5分钟。然后将它们用PBS洗涤两次，并在FACS Calibur上测量。作为死细胞的阳性对照，PBMC在95℃煮沸20分钟，并用相同的程序染色以确定死细胞的峰。
将培养好的PBMC细胞分成4组(每组n＝4个样)。A组，阴性对照组， PBMC；B组，PBMC+cGAMP；C组，PBMC+抗新冠病毒复合物；D组，PBMC +抗新冠病毒纳米抗体。除了A组作为对照不加药外，其它组细胞液中分别加入100微克/毫升的相应的免疫激动剂cGAMP、抗新冠病毒复合物和抗新冠病毒纳米抗体。每一个细胞样品中加入10微升的病毒液，三周后检测复合物抗病毒复制情况。选择对病毒的抑制率作为评价指标。病毒的活性滴度用荧光定量 RT－PCR检测。免疫激动剂、纳米抗体及其双功能一体化复合物对病毒的抑制效果列于表1.
表1.新型抗新冠病毒复合物对冠状病毒的抑制作用
表1结果显示，新型抗新冠病毒复合物对冠状病毒在PBMC细胞中的复制有很好的抑制作用。该新型复合物比单一的免疫激动剂cGAMP或纳米抗体 SARS2-VHH抑制病毒效果明显都好。新型抗新冠病毒复合物显示出显著提高的抑制病毒效果。
实施例5.新型抗新冠病毒复合物对小鼠肺炎的抑制作用
实验动物：C57BL/6小鼠，雄性，体重20－22g，7-8周龄，SPF级，所有小鼠均自由觅食和饮水，在室温(23±2)度下饲养。饲料及水均经高压灭菌处理，全部实验饲养过程为SPF级。
动物分组：
将30只小鼠随机分为5组(n＝6)，具体分组为：A组，正常对照组；B组，肺炎模型组，PBS；C组，给药组，新型抗新冠病毒复合物(10mg/kg)；D组，给药组，纳米抗体SARS2-VHH(10mg/kg)；E组，给药组，免疫激动剂cGAMP (10mg/kg)。
肺炎病毒模型小鼠建立：
鼻内滴注。使小鼠处于足够深的麻醉状态，将小鼠以背卧姿势固定，并慢慢地将VR－841病毒悬液通过小鼠鼻孔内壁逐滴滴入，为保证最大的肺部感染效率，滴入体积为60μL(每个鼻孔30μL)。将小鼠轻轻从工作台拿下，并将头部和胸部用折叠的纸巾小幅度垫高，以保证小鼠顺畅的呼吸。待小鼠苏醒后，放回鼠笼。肺组织病理学观察：取左肺大叶组织，切两半，用苦味酸溶液固定24小时后，脱水、透明、石蜡包埋，行5μm厚切片，然后进行苏木精－伊红(HE)染色，光镜下观察小鼠肺组织的病理形态学变化。
小鼠肺泡灌洗液获得方法：
取等体积PBS沿小鼠气管注射后吸出，反复几次，获得肺泡灌洗液。空白组和肺炎模型组腹腔注射等体积的DMEM。收集的血清，于－80度保存。采用ELISA 法，检测TNF-alpha、IL-1beta浓度。终止反应后，将酶标板放入酶标仪槽内，选择450nm波长检测，确定标准品和空白对照区域，检测相应的光密度值，然后绘制标准曲线并计算相应的浓度。在小鼠肺炎模型中，促炎性细胞因子IL-1beta 和TNF-alpha在血清和肺泡灌洗液中的含量都显著上升，三组给药后均不同程度地降低了促炎因子的含量。不同药物分别显示抑制小鼠肺炎作用的结果见表2.
实验结果表明，新型免疫激动剂－纳米抗体新型复合物抗小鼠肺炎促炎细胞因子的作用显著优于单独使用免疫激动剂或纳米抗体。该类新型免疫激动剂纳米抗体复合物药物具有抗小鼠肺炎损伤的作用。
小鼠肺组织病理学观察可见(附图1，H&E染色肺组织石蜡切片)：与正常组小鼠相比，肺炎模型组小鼠肺部炎细胞浸润增加，肺泡间隔明显增厚。免疫激动剂及其与纳米抗体新型复合物给药后小鼠肺部炎症症状明显有所缓解，新型复合物显示显著进步的药效。
表2.新型免疫激动剂纳米抗体复合物对小鼠肺炎的抑制作用
实施例6.新型抗新冠病毒复合物诱发免疫功能
小鼠免疫：C57BL/6雄性小鼠，6-8周，体重20-22克；
小鼠分组：每10只一组，共4组，分别为，
A：OVA+cGAMP；B:OVA+新型复合物；C：OVA+纳米抗体；D：OVA。
每只小鼠皮下注射10微克OVA和100微克的不同种类的cGAMP、纳米抗体或新型复合物。分别在第1，7，14天各免疫一次，在第21天获得肺灌洗液和取血样。用ELISA法测定免疫激动剂及其与纳米抗体复合物作为佐剂诱导产生抗体的效价。实验结果见表3.测定结果显示，作为免疫佐剂，新型免疫激动剂纳米抗体复合物的效果显著高于免疫激动剂cGAMP和纳米抗体。
表3.新型抗新冠病毒复合物诱发免疫效价
实施例7新型抗新冠病毒复合物诱发细胞免疫效价
小鼠饲养与病毒感染免疫、采血等见实施例5。同型对照流式抗体购自eBiosciences,抗体磁株购于Militeny Biotech,流式细胞仪购于BD公司，免疫14 天后取小鼠脾脏、肺组织，分别研磨捣碎，过40微米孔脱过滤细胞，1000rpm 离心10分钟，分离未被裂解的免疫细胞，用抗体磁株分离DC (CD40\CD80\CD86\MHCII)、T(CD8+)细胞，加入对应的FAC抗体(用FACS 缓冲液稀释)，同型对照抗体作为阴性对照，抗体加入后孵育1小时后离心，用 PBS清洗，用流式细胞仪分析样品，分选合适的细胞，测定选定细胞的荧光强度(MFI)，流式结果见表4.流式细胞测定结果显示，免疫激动剂cGAMP及其与纳米抗体靶向脂质体的免疫激动剂新型复合物均能显著活化树突状细胞DC和T 细胞，新型免疫激动剂－纳米抗体复合物的效果显著高于单独使用免疫激动剂 cGAMP。
表4.新型抗新冠病毒复合物诱发免疫细胞活化效价
实施例8新型抗新冠病毒复合物的急性毒性研究
实验材料
ICR小鼠10只(购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005])，雌雄各半，体重20～22g，动物以颗粒饲料喂养，自由摄食和饮水。
实验方法
ICR小鼠按体重分别腹腔注射1g/kg的新型免疫激动-纳米抗体剂复合物 (生理盐水液配制)，观察给药后小鼠14天内的毒性反应及死亡情况。结果发现，小鼠腹腔注射给药后，小鼠活动正常。给药后14天内，小鼠未出现死亡，第15 天，全部小鼠处死，解剖，肉眼检查各脏器，均未见明显病变。
实验结果
上述急性毒性实验结果表明，腹腔注射给药最大耐受量MTD不低于1g/Kg，说明新型免疫激动剂复合物药物的急性毒性低。
附图说明
附图1.新型免疫激动剂-纳米抗体复合物抑制小鼠肺炎效果(肺组织石蜡切片H&E染色)。
序列表
<110> 杭州星鳌生物科技有限公司
<120> 一种新型抗新冠病毒复合物的组成及其在防治冠状病毒感染疾病药物中的应用
<140> 202010564180.1
<141> 2020-06-19
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Claims (4)
1.一种新型抗新冠病毒的双功能一体化复合物，其特征在于：由重组的抗新冠病毒的羊驼纳米抗体偶联脂质体包裹的免疫激动剂构成，所述免疫激动剂包封于重组纳米抗体偶联的脂质体中。所述免疫激动剂为STING的激动剂，既环二核苷酸2’3’-cGAMP或其衍生物；抗新冠病毒的重组羊驼纳米抗体，其特征为，能与新冠病毒刺突S蛋白紧密结合，且靶向中和新冠病毒的纳米抗体或抗新冠病毒的单克隆抗体的可变区结构域。
优选地，靶向新冠病毒刺突S蛋白的纳米抗体为SARS2-VHH,其氨基酸序列为：QVQLQESGGGLVQAGGSLRLSCAASGRTFSEYAMGWFRQAPGKEREFVATISWSGGSTYYTDSVKGRFTISRDNAKNTVYLQMNSLKPDDTAVYYCAAAGLGTVVSEWDYDYYLDYWGQGTQVTVSS。
2.根据权利要求1所述的新型抗新冠病毒双功能一体化复合物的制备方法，其特征在于：
(1)运用原核表达载体，在大肠杆菌中重组表达、运用镍亲和层析柱纯化抗新冠病毒S蛋白的纳米抗体SARS2-VHH；
(2)对重组抗新冠病毒S蛋白的纳米抗体SARS2-VHH进行巯基化；
(3)巯基化的重组纳米抗体SARS2-VHH与脂质体化学键偶联融合，进而包封免疫激动剂。
3.根据权利要求1所述的新型抗新冠病毒复合物在制备预防和/或治疗冠状病毒感染疾病药物中的应用，其特征在于：
冠状病毒感染疾病包括但不限于人或动物感染冠状病毒引起的病毒性肺炎/呼吸道炎症、病毒性肾炎、病毒性脑炎、病毒性肠炎或病毒性肝炎。
4.根据权利要求1所述的新型抗新冠病毒复合物可单独制备成不同规格的单位制剂或通过药学上可接受的载体制备成药物制剂，包括但不限于静脉注射制剂、鼻腔滴注制剂、静脉滴注制剂、肌肉注射制剂、皮下注射制剂或口服制剂；口服制剂包括但不限于胶囊、片剂或颗粒剂。
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Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050002901A1 (en) * | 2003-04-01 | 2005-01-06 | Blatt Lawrence M. | Compositions and methods for treating coronavirus infection and SARS |
| US20060240551A1 (en) * | 2004-06-02 | 2006-10-26 | Shibo Jiang | Neutralizing monoclonal antibodies against severe acute respiratory syndrome-associated coronavirus |
| WO2015028888A2 (en) * | 2013-08-25 | 2015-03-05 | Sentinext Therapeutics Sdn Bhd | Pharmaceutical compositions to treat viral infection |
| CN106146662A (zh) * | 2016-07-18 | 2016-11-23 | 中山大学 | 抗cd3单域抗体 |
| CN106265715A (zh) * | 2015-05-19 | 2017-01-04 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸cGAMP在制备保健品中的应用 |
| CN106265714A (zh) * | 2015-05-19 | 2017-01-04 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸cGAMP在制备抗病毒药物中的应用 |
| CN106540256A (zh) * | 2016-03-27 | 2017-03-29 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸-脂质体偶联单克隆抗体在抗肿瘤中的应用 |
| CN106540254A (zh) * | 2015-09-22 | 2017-03-29 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸cGAMP及其衍生物是潜在免疫佐剂 |
| CN106554416A (zh) * | 2015-12-09 | 2017-04-05 | 聊城市奥润生物医药科技有限公司 | 一种抗pd-l1人源化单克隆抗体联合干扰素基因刺激蛋白（sting）激动剂在抗肿瘤中的应用 |
| CN106667914A (zh) * | 2017-03-13 | 2017-05-17 | 聊城市奥润生物医药科技有限公司 | 靶向脂质体‑环二核苷酸的组成、制备方法及其在抗肿瘤中的应用 |
| CN106727331A (zh) * | 2017-03-13 | 2017-05-31 | 聊城市奥润生物医药科技有限公司 | 免疫脂质体‑环二核苷酸的组成、制备方法及其在抗肿瘤中的应用 |
| CN108310378A (zh) * | 2018-04-28 | 2018-07-24 | 杭州星鳌生物科技有限公司 | 一类新型免疫联体抗肿瘤创新药物的制备及其应用 |
| WO2020059895A1 (ko) * | 2018-09-17 | 2020-03-26 | 주식회사 큐라티스 | 스팅 작용자를 포함하는 면역항원보강제 및 백신 조성물 |
| CN111228464A (zh) * | 2020-02-28 | 2020-06-05 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | 广谱抗冠状病毒的多肽及其用途 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1373318A2 (en) * | 2001-01-26 | 2004-01-02 | Abgenix, Inc. | Neutralizing human monoclonal antibodies against hiv-1, their production and uses |
-
2020
- 2020-06-19 CN CN202010564180.1A patent/CN113813375B/zh active Active
- 2020-12-31 WO PCT/CN2020/142599 patent/WO2021253807A1/zh active Application Filing
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050002901A1 (en) * | 2003-04-01 | 2005-01-06 | Blatt Lawrence M. | Compositions and methods for treating coronavirus infection and SARS |
| US20060240551A1 (en) * | 2004-06-02 | 2006-10-26 | Shibo Jiang | Neutralizing monoclonal antibodies against severe acute respiratory syndrome-associated coronavirus |
| WO2015028888A2 (en) * | 2013-08-25 | 2015-03-05 | Sentinext Therapeutics Sdn Bhd | Pharmaceutical compositions to treat viral infection |
| CN106265715A (zh) * | 2015-05-19 | 2017-01-04 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸cGAMP在制备保健品中的应用 |
| CN106265714A (zh) * | 2015-05-19 | 2017-01-04 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸cGAMP在制备抗病毒药物中的应用 |
| CN106540254A (zh) * | 2015-09-22 | 2017-03-29 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸cGAMP及其衍生物是潜在免疫佐剂 |
| CN106554416A (zh) * | 2015-12-09 | 2017-04-05 | 聊城市奥润生物医药科技有限公司 | 一种抗pd-l1人源化单克隆抗体联合干扰素基因刺激蛋白（sting）激动剂在抗肿瘤中的应用 |
| CN106540256A (zh) * | 2016-03-27 | 2017-03-29 | 聊城市奥润生物医药科技有限公司 | 环二核苷酸-脂质体偶联单克隆抗体在抗肿瘤中的应用 |
| CN106146662A (zh) * | 2016-07-18 | 2016-11-23 | 中山大学 | 抗cd3单域抗体 |
| CN106667914A (zh) * | 2017-03-13 | 2017-05-17 | 聊城市奥润生物医药科技有限公司 | 靶向脂质体‑环二核苷酸的组成、制备方法及其在抗肿瘤中的应用 |
| CN106727331A (zh) * | 2017-03-13 | 2017-05-31 | 聊城市奥润生物医药科技有限公司 | 免疫脂质体‑环二核苷酸的组成、制备方法及其在抗肿瘤中的应用 |
| CN108310378A (zh) * | 2018-04-28 | 2018-07-24 | 杭州星鳌生物科技有限公司 | 一类新型免疫联体抗肿瘤创新药物的制备及其应用 |
| WO2020059895A1 (ko) * | 2018-09-17 | 2020-03-26 | 주식회사 큐라티스 | 스팅 작용자를 포함하는 면역항원보강제 및 백신 조성물 |
| CN111228464A (zh) * | 2020-02-28 | 2020-06-05 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | 广谱抗冠状病毒的多肽及其用途 |
Non-Patent Citations (8)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111956797A (zh) * | 2020-07-10 | 2020-11-20 | 清华大学 | 新型疫苗佐剂及其在新冠肺炎疫苗和其他疫苗中的应用 |
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