CN112094341B - 抗新型冠状病毒的IgY中和抗体及其制备方法、制剂和应用 - Google Patents
抗新型冠状病毒的IgY中和抗体及其制备方法、制剂和应用 Download PDFInfo
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Abstract
本发明提供了一种利用新型冠状病毒刺突蛋白胞外区(S‑ECD蛋白)和刺突蛋白受体结合结构域(RBD)免疫禽类(母鸡)或鸟类(母鸵鸟)制备高效的抗新型冠状病毒特异性IgY中和抗体。本发明还提供了利用该中和抗体研制的抗新型冠状病毒IgY抗体I型和II型制剂,包括I型‑吸入雾化喷雾剂和输液注射剂以及II型‑外搽剂。本发明还提供了包含上述抗体和制剂的新型冠状病毒防治药物。本发明进一步提供了上述抗体和制剂在新型冠状病毒防治药物中的应用。
Description
技术领域
本发明涉及应用IgY抗体制备抗病毒制剂,具体涉及一种抗新型冠状病毒IgY中和抗体、制备方法及新冠防御制剂,以及它们的应用。
背景技术
新型冠状病毒肺炎(简称新冠肺炎,或COVID-19)疫情是当今全球最为关注的突发急性传染病事件,已对全球公共卫生界提出了严峻挑战。新型冠状病毒(简称新冠病毒,或SARS-CoV-2)感染人数众多,传播性极强,病死率较高。截止目前为止,尽管在新冠肺炎疫苗研制和治疗手段上有了长足进展,但仍尚无特效药,尚无批准上市的主动免疫疫苗。因此,新冠肺炎疫情控制迫切需要探索防御和诊治的新方法。现今全球范围内,亟需寻求安全高效的特异制剂用于病毒感染的防治。
基于病毒感染和产生抗体的基本免疫学机制,同时借鉴既往SARS和MERS防治的经验,被动免疫防治是现阶段应对COVID-19可以采用的优选方案。新型冠状病毒特异性抗体可以中和病毒,起到阻止病毒粘附、入侵宿主细胞的作用,如何研发针对该病毒特异性的中和抗体迫在眉睫。
禽类或鸟类IgY抗体具有许多优势。IgY被动免疫治疗策略以前曾用于人类和动物的细菌和病毒感染,其优点主要包括与哺乳动物Fc受体无反应,稳定性好、安全、易于提取和生产。更为重要的是,与哺乳动物IgG相比,IgY具有更高的靶向特异性和更强的结合亲和力,在呼吸道和肺部具有显著的病原体中和活性。IgY抗体生产成本低,且易于提取,来源于鸡蛋黄的天然成分,IgY抗体系无毒安全的免疫制剂。由于IgY抗体系天然产物,不是合成药物,也避免了环境污染。
在全球范围内流感期,IgY抗体已测试用于流行性感冒的免疫治疗或预防剂,使用IgY治疗呼吸道感染,多采用鼻喷剂用作快速和安全应对大型流行性感冒的策略。IgY抗体预防性治疗的优越性可能是由于IgY抗体存在呼吸道粘膜表面,起到了吞噬作用,减少病原体增殖。鼻内喷雾制剂方便,适用于卫生保健预防和普通人群家庭预防应用。采用IgY抗体技术研制抗新型冠状病毒中和抗体并制备防护喷雾剂是可行的。
在免疫原选择方面,新型冠状病毒刺突蛋白(或S蛋白)是一种跨膜糖蛋白,也是病毒最大的结构蛋白,包含了病毒的主要抗原决定簇,能够刺激机体产生中和抗体和介导免疫反应。新型冠状病毒S蛋白由球状的受体结合亚基S1和棒状的融合亚基S2两部分组成。近N端的S1和近C端的S2是两个独特的功能结构域,决定了冠状病毒的组织嗜性(受体特异性)和膜融合特性(使病毒进入细胞)。研究发现,SARS-CoV-2的S蛋白可以单独完成包膜病毒颗粒的细胞侵入的全过程,其中包括:(1)识别并结合靶细胞受体;(2)病毒与靶细胞融合,将遗传物质释放到胞内。因为S蛋白是病毒识别宿主细胞表面受体血管紧缩素转化酶2(angiotensin-converting enzyme 2,ACE2)的关键分子,表达S蛋白的病毒颗粒可以与表达ACE2的细胞结合并诱导细胞融合。因此,S蛋白在病毒入侵机体时,这一蛋白受体结合结构域(RBD)与宿主细胞受体ACE2之间具有高亲和力,导致新型冠状病毒的跨物种传播和人与人之间的传播。由于S蛋白的胞外区(S-ECD)暴露于病毒表面,含有关键的靶蛋白-RBD,采用S-ECD蛋白将是一个比较理想和有效的免疫抗原,可有效地诱导中和抗体的产生,制备特异性的高效中和抗体,从而直接导致靶蛋白-RBD失活,不能与宿主细胞结合,破坏新型冠状病毒生命周期的每个阶段和阻断了繁殖。
发明内容
针对现阶段的迫切需求,本发明提供了一种利用新型冠状病毒刺突蛋白胞外区蛋白(S-ECD蛋白)和刺突蛋白受体结合结构域(RBD)免疫禽类(例如母鸡)或鸟类(例如母鸵鸟)制备抗新型冠状病毒特异性IgY抗体,并研制了抗新型冠状病毒IgY抗体I和II型制剂,经体外病毒中和作用检测,具有明显阻断病毒存活的效果,能够用于新型冠状病毒防治。
本发明的一个目的是提供一种抗新型冠状病毒的IgY抗体,其特征在于,是利用新型冠状病毒刺突蛋白胞外区(S-ECD蛋白)和RBD区免疫禽类或鸟类制备的,在体外对新型冠状病毒有高效中和作用。在另外的具体方案中,所述禽类是母鸡;鸟类是母鸵鸟。在另外的具体方案中,所述抗体在体外对新型冠状病毒的失活率在99%以上。在另外的具体方案中,所述抗体在37℃加速稳定性测试下放置7天或室温下放置至少180天抗体效价和蛋白含量没有明显改变。
本发明的另一个目的是提供一种抗新型冠状病毒的IgY抗体的制备方法,其特征在于使用新型冠状病毒刺突蛋白胞外区(S-ECD蛋白)做免疫抗原与弗氏佐剂按1:1比例混合,制备成乳状液后,皮下多位点注射免疫禽类或鸟类,免疫两次后,第三次及后续用KLH-RBD进行加强免疫;提取卵黄液体,采用水萃取制备抗体溶液,利用S-ECD或RBD包被的板式化学发光ELISA法筛选高特异性抗新型冠状病毒IgY抗体后,制备获得所述IgY抗体。在另外的具体方案中,所述禽类是母鸡;鸟类是母鸵鸟。在另外的具体方案中,所述抗体在体外对新型冠状病毒的失活率在99%以上。在另外的具体方案中,所述抗体在37℃加速稳定性测试下放置7天或室温下放置至少180天抗体效价和蛋白含量没有明显改变。
本发明的另一个目的是提供一种由上述制备方法制备得到的IgY抗体。
本发明的另一个目的是提供一种制剂,包含上述抗新型冠状病毒的IgY抗体。
本发明的另一个目的是提供一种抗新型冠状病毒的IgY抗体制剂,其为吸入雾化喷雾剂或输液注射剂,包含上述IgY抗体、氯化钠或甘露醇、和无菌去离子水或注射用水。在另外的具体方案中,其中IgY抗体的含量为10-500μg/mL,所述的氯化钠含量为0.9%或甘露醇含量为10-30g/L。
本发明的另一个目的是提供一种抗新型冠状病毒的IgY抗体制剂,其为外搽剂,包含上述IgY抗体、保润肤作用的两性离子表面活性剂、消毒灭菌剂和无菌去离子水。在另外的具体方案中,其中IgY抗体的含量为10-500μg/mL;保润肤作用的两性离子表面活性剂为椰油酰胺基丙基甜菜碱,其含量为1%-10%;消毒灭菌剂为双十烷基二甲基氯化铵、六甲基二硅氧烷和十二烷基二甲基苄基溴化铵,且它们的含量分别为0.05-0.3%、0.05-0.3%和0.1-10%。
本发明的另一个目的是提供本发明的上述IgY抗体或IgY抗体制剂在制备新型冠状病毒防治药物中的用途。
本发明的另一个目的是提供一种新型冠状病毒防治药物,其中含有本发明的上述IgY抗体或IgY抗体制剂。
本发明的特点在于:免疫原—新型冠状病毒刺突蛋白胞外区蛋白(S-ECD蛋白)和刺突蛋白受体结合结构域(RBD)与禽类或鸟类IgY抗体的组合。首先,选用新型冠状病毒刺突蛋白胞外区蛋白(S-ECD蛋白)作为免疫原,S蛋白的胞外区(S-ECD)暴露于病毒表面,其中包含的S1亚基中的受体结合结构域(RBD)是最关键的目标蛋白。其次,本发明以卵黄IgY抗体作为新型冠状病毒防御性中和抗体的开发思路,优点是基于禽类或鸟类的IgY抗体与哺乳动物的IgG抗体比较,有其独特的功能,包括:1)凝集:禽类或鸟类的IgY抗体对外源病原体(病毒,细菌,真菌)凝集作用,有助于持续封锁抑制粘附体外来源的病原体,导致它们的凝集化而失活。2)调理和吞噬作用:IgY抗体可以增强对入侵病原体的活性的吞噬能力。3)中和作用:特异性IgY抗体将更加有效地阻断病毒存活。4)IgY的另一个主要优点是其唾液酸含量高,与唾液酸含量较低的药物相比,IgY抗体可延长抗体的半衰期。
本发明的优异效果在于:本发明制备得到的IgY中和抗体及其I和II型制剂,在体外病毒中和作用检测中表现出优异的阻断病毒存活的效果,病毒失活率达到99%以上。
本发明以IgY为技术基础的中和抗体可以有更长的半衰期和更好的稳定性,提高防御效果。本发明提供的抗新型冠状病毒IgY中和抗体和I和II型制剂,可预防性应用于有职业暴露风险的医务人员和医疗辅助人员;可用于病毒感染确诊患者的密切接触人群、高龄易感人群、既往有基础疾病易感人群;也可用于在病毒感染高发地区,用于疫区居民的普遍性防护。IgY抗体生产成本低,易于提取,来源于鸡蛋黄的天然成分,系无毒安全的免疫制剂。由于IgY抗体系天然产物,不需要化学合成,避免了潜在的环境污染。
附图说明
图1:本发明的IgY抗体的筛选柱状图。
图2.本发明的IgY抗体的稳定性柱状图。
图3:本发明的IgY抗体的新型冠状病毒中和作用。
具体实施方式
以下结合具体实施方式详细描述本发明,不能将其解释为限制本发明的范围。
实施例1:设计和筛选抗原
本发明选用新型冠状病毒刺突蛋白胞外区蛋白(S-ECD蛋白,GenBank登录号QHD43416.1,a.a.Val16-Pro1213)和刺突蛋白受体结合结构域(RBD蛋白,GenBank登录号QHD43416.1,a.a.Arg319-Phe541)作为免疫原。S-ECD蛋白和RBD蛋白均系重组蛋白,购自南京金斯瑞生物科技有限公司。
实施例2:制备抗新型冠状病毒IgY抗体
使用新型冠状病毒刺突蛋白胞外区(S-ECD蛋白)做免疫抗原与弗氏佐剂按1:1比例混合,制备成乳状液后,皮下多位点注射免疫禽类(例如母鸡)或鸟类(例如母鸵鸟),免疫两次后,第三次及后续用KLH-RBD进行加强免疫;提取卵黄液体,采用水萃取制备抗体溶液,利用S-ECD或RBD包被的板式化学发光ELISA法筛选高特异性抗新型冠状病毒IgY抗体后,制备获得所述IgY抗体。
实施例3:板式化学发光ELISA法筛选高特异性抗新型冠状病毒IgY抗体
采用板式化学发光ELISA法(生物素-链霉亲和素-辣根过氧化物酶系统)进行测定。采用抗体浓度稀释梯度(100×,200×,400×,800×,1600×,3200×,6400×)筛选法,对每只免疫的鸵鸟或鸡,利用包被ECD或RBD的ELISA板进行免疫效果初筛鉴定。对初次筛选后获得的15个候选号(图1中,免疫号1、3、5为驼鸟号;免疫号6、7、91、93、94、95、96、97、98、99、100为母鸡号)的IgY抗体溶液,按照上述方法再进行第二次筛选。筛选的免疫反应结果如图1所示。经多次重复测定,发现鸵鸟1号和鸡7号对RBD的免疫反应特异性和灵敏度最佳,浓度稀释到6400倍时,与稀释100倍进行比较,无显著性差异(p>0.05),与空白未免疫对照组比较,有显著意义的差异(p<0.00001)。
实施例4:制备抗新型冠状病毒IgY抗体I型制剂—吸入雾化喷雾剂或注射剂
I型制剂的成分包含抗新型冠状病毒IgY抗体、氯化钠或甘露醇、无菌去离子水或注射用水。在另外的具体方案中,其中IgY抗体的含量为10-500μg/mL,所述的氯化钠含量为0.9%或甘露醇含量为10-30g/L。
I型制剂的具体制备方法如下:
第一步:将IgY抗体通过0.22μm的滤膜抽滤。
第二步:把混合抗体溶液和无菌去离子水或注射用水以1:3的比例稀释,加入氯化钠调至其终浓度为0.9%,或加入甘露醇调至其终浓度为10-30g/L,调节pH值到7.4。
第三步:用0.22μm真空抽滤瓶抽滤,分装在无菌的分装瓶中。
实施例5:制备抗新型冠状病毒IgY抗体II型制剂—外搽剂
II型制剂的成分包含抗新型冠状病毒IgY抗体、保润肤作用的两性离子表面活性剂(例如椰油酰胺基丙基甜菜碱);清洁皮肤常用消毒灭菌剂(例如阳离子表面活性剂:双十烷基二甲基氯化铵、六甲基二硅氧烷和十二烷基二甲基苄基溴化铵),无菌去离子水;所述的抗新型冠状病毒IgY中和抗体含量为10-500μg/mL,保润肤作用的两性离子表面活性剂为椰油酰胺基丙基甜菜碱,其含量为1%-10%;消毒灭菌剂(阳离子表面活性剂)为双十烷基二甲基氯化铵、六甲基二硅氧烷和十二烷基二甲基苄基溴化铵,且它们的含量分别为0.05-0.3%、0.05-0.3%和0.1-10%。
II型制剂的具体制备方法如下:
第一步:将IgY抗体通过0.22μm的滤膜抽滤。
第二步:把混合抗体溶液和无菌去离子水以1:3的比例稀释,加入椰油酰胺基丙基甜菜碱调整终浓度为1%-10%;加入双十烷基二甲基氯化铵调整终浓度为0.05-0.3%;加入六甲基二硅氧烷调整终浓度为0.05-0.3%;加入十二烷基二甲基苄基溴化铵调整终浓度为0.1-10%;,调节pH值到7.4。
第三步:用0.22μm真空抽滤瓶抽滤,分装在灭菌的分装瓶中,10-50ml/瓶。
实施例6:测定抗新型冠状病毒IgY抗体及其I和II型制剂的体外病毒中和作用
第一步:在生物安全三级(P3)实验室下,将Vero细胞铺板到96孔板中,每孔100μL,37℃细胞培养箱中培养过夜,形成细胞单层,待细胞约铺满80%-90%时,弃上清,PBS洗涤后备用。
第二步:将不同浓度的IgY抗体在37℃下与100TCID50新型冠状病毒分别混匀,37℃下孵育1小时;将上述抗体和病毒混合物接种到已备用的VERO细胞中,在培养箱37℃下吸附1h;然后,弃上清PBS洗涤后,加入细胞维持液培养。
第三步:培养3天后,利用荧光实时定量RT-PCR方法检测每孔的新型冠状病毒载量,计算出IgY抗体病毒失活率在99%以上。
实施例7:抗新型冠状病毒IgY抗体I和II型制剂的体外病毒中和作用的稳定性
利用加速试验法对制剂进行稳定性测试。将制剂置37℃恒温箱内45天,于放置前、后分别测定制剂中有效成分IgY抗体效价,结果显示有效成分下降率≤10%,II型制剂的保润肤效果在4小时以上。
实施例8:抗新型冠状病毒IgY中和抗体的加速稳定性评价
在加速条件下进行的加速稳定性试验,可以在较短的时间内,了解原料或制剂的稳定性特点,可用于预测长期稳定性。采用ELISA法测定主要有效原材料母鸵鸟IgY抗体和母鸡IgY抗体的稳定性。首先测定IgY抗体的OD值作为基值,然后分别将抗体放置37℃下,放置7天时,再次测定IgY抗体的OD值。利用t检验统计分析放置前后IgY量的变化。
稳定性结果如表1和图2所示:
表1.主要原材料IgY抗体稳定性测试结果
结果显示,抗新型冠状病毒母鸵鸟IgY抗体和母鸡IgY抗体在37℃加速稳定性实验下,放置7天时,性质均保持稳定,与放置前基值相比,37℃ 7天时的OD值均无显著性差异(P>0.05)。
实施例9:抗新型冠状病毒IgY抗体体外病毒中和作用的有效性评价
经鉴定的新型冠状病毒株由深圳市疾病预防控制中心提供。采用RT-PCR荧光实时定量方法,测定新型冠状病毒母鸵鸟IgY抗体和母鸡IgY抗体在体外对新型冠状病毒的中和作用,结果如表2和图3所示。结果显示,母鸵鸟IgY抗体和母鸡IgY抗体在体外对病毒均有高效的中和作用,平均病毒失活率均在99%以上。
表2.抗体产品对新型冠状病毒载量的影响
以上以具体实施方式描述了本发明,本领域技术人员在不背离本发明精神的情况下,可以做出等同的修改或变型,其同样在权利要求的范围之内。
Claims (12)
1.一种抗新型冠状病毒的IgY抗体,其特征在于,是利用新型冠状病毒刺突蛋白胞外区(S-ECD蛋白)和刺突蛋白受体结合结构域(RBD)免疫母鸡或母鸵鸟制备的,在体外对新型冠状病毒有高效中和作用;其中,免疫是利用S-ECD蛋白免疫,后续用RBD加强免疫;并且利用S-ECD或RBD包被的板式化学发光ELISA法筛选高特异性抗新型冠状病毒IgY抗体。
2.权利要求1所述的IgY抗体,其在体外对新型冠状病毒的失活率在99%以上。
3.权利要求1或2所述的IgY抗体,其在37℃加速稳定性测试下放置7天或室温下放置至少180天抗体效价和蛋白含量没有明显改变。
4.一种抗新型冠状病毒的IgY抗体的制备方法,其特征在于使用新型冠状病毒刺突蛋白胞外区(S-ECD蛋白)做免疫抗原与弗氏佐剂按1:1比例混合,制备成乳状液后,皮下多位点注射免疫母鸡或母鸵鸟两次后,第三次及后续用KLH-刺突蛋白受体结合结构域(RBD)进行加强免疫;提取卵黄液体,采用水萃取制备抗体溶液,利用S-ECD或RBD包被的板式化学发光ELISA法筛选高特异性抗新型冠状病毒IgY抗体后,制备获得所述IgY抗体。
5.由权利要求4所述的制备方法获得的抗新型冠状病毒的IgY抗体。
6.一种制剂,包含权利要求1-3、5任一项的抗新型冠状病毒的IgY抗体。
7.一种抗新型冠状病毒的IgY抗体制剂,其为吸入雾化喷雾剂或输液注射剂,包含权利要求1-3或5任一项的IgY抗体、氯化钠或甘露醇、无菌去离子水或注射用水。
8.权利要求7所述的IgY抗体制剂,其中IgY抗体的含量为10-500mg/mL,所述的氯化钠含量为0.9%或甘露醇含量为10-30g/L。
9.一种抗新型冠状病毒的IgY抗体制剂,其为外搽剂,包含权利要求1-3或5任一项的IgY抗体、保润肤作用的两性离子表面活性剂、消毒灭菌剂和无菌去离子水。
10.权利要求9所述的IgY抗体制剂,其中IgY抗体的含量为10-500mg/mL;保润肤作用的两性离子表面活性剂为椰油酰胺基丙基甜菜碱,其含量为1%-10%;消毒灭菌剂为双十烷基二甲基氯化铵、六甲基二硅氧烷和十二烷基二甲基苄基溴化铵,且它们的含量分别为0.05-0.3%、0.05-0.3%和0.1-10%。
11.权利要求1-3或5任一项所述的IgY抗体或者权利要求7-10任一项所述的IgY抗体制剂在制备新型冠状病毒防治药物中的用途。
12.一种新型冠状病毒防治药物,其中含有权利要求1-3或5任一项所述的IgY抗体,或者权利要求7-10任一项所述的IgY抗体制剂。
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