CN115028710A - 放射性核素标记的靶向新冠病毒的中和抗体及其制备方法与应用 - Google Patents
放射性核素标记的靶向新冠病毒的中和抗体及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了放射性核素标记的靶向新冠病毒的中和抗体及其制备方法与应用。所述放射性核素标记的中和抗体是将纳米抗体Nb11‑59进行NBS修饰后,或者纳米抗体Nb11‑59与双功能螯合剂偶联后,经放射性核素标记得到的。其可作为靶向SARS‑CoV‑2‑RBD的显像剂,性质稳定,制作简易,对RBD有良好的亲和活力。体内显像表明,该显像剂可以有效监测到RBD在体内的分布,且探针的摄取量与RBD剂量成正相关,有望被开发成检测新冠病毒体内分布和代谢的有效工具,在分析新冠病毒感染机制,观测病毒体内变化方面提供助力。
Description
技术领域
本发明涉及放射性化学、核医学及生物制药领域,具体地说,涉及放射性核素标记的靶向新冠病毒的中和抗体及其制备方法与应用。
背景技术
新冠病毒(COVID-19)给全球人类的健康和经济造成了巨大的威胁。病毒变异使得开发新的SARS-CoV-2治疗方法成为研究热点。
在病毒感染过程中,病毒入侵是病毒生命周期的第一步,通过阻断共受体相互作用或病毒-细胞膜融合是一个很好的干预点。SARS-CoV-2和其他冠状病毒具有相似的感染机制,SARS-CoV-2表面的受体结合域(RBD)通过人类的血管紧张素转换酶2(ACE2)受体完成对人体细胞入侵和感染。
骆驼体内可以分泌重链抗体,这些抗体的重链可变区(VHH)可以表达出特异性结合抗原、体积小的功能性片段,这些片段被称为纳米抗体。纳米抗体具有较高的目标结合力和抗原结合力,对人体免疫原型弱,生物相容性好,可以有效避免补体反应。另外,纳米抗体的体积小,稳定性高,穿透能力强,且生产成本低廉。研究表明,多种纳米抗体可以阻断SARS-CoV-2-RBD与ACE2的结合,可以对病毒起到中和作用,这些抗体也被称为中和抗体。其中中和抗体Nb11-59表现出对SARS-CoV-2-RBD优良的靶向性和特异性,有望被开发成为新冠病毒诊断试剂或治疗药物。
发明内容
本发明的目的是提供一种新型的放射性核素标记的靶向新冠病毒的中和抗体及其制备方法与应用。
为了实现本发明目的,第一方面,本发明提供一种放射性核素标记的靶向新冠病毒的中和抗体,所述放射性核素标记的中和抗体是将纳米抗体Nb11-59进行NBS(N-溴代琥珀酰亚胺)修饰后,或者纳米抗体Nb11-59与双功能螯合剂偶联后,经放射性核素标记得到的。
本发明中,所述双功能螯合剂偶联可选自NOTA、DFO等。
所述放射性核素可选自碘的放射性同位素、68Ga、64Cu或89Zr等。
优选地,所述碘的放射性同位素可选自124I、123I、125I或131I。
第二方面,本发明提供碘的放射性同位素标记的靶向新冠病毒的中和抗体的制备方法,所述制备方法包括:将纳米抗体Nb11-59与碘的放射性同位素的盐和NBS在反应缓冲液中进行标记反应,然后向反应体系中加入人血清白蛋白终止反应;所得反应产物经PD-10柱纯化即得。
其中,纳米抗体Nb11-59、碘的放射性同位素的盐和NBS的用量比为(0.1-0.5mg):(3×107-1.5×108Bq):(20-100μg)。
进一步地,所述反应缓冲液为0.05-0.2M、pH7-7.5的PB缓冲液;所述反应缓冲液占反应体系总体积的30%-75%。
进一步地,所述标记反应在常温反应0.8-1.2min,以8-12%的人血清白蛋白终止反应。
第三方面,本发明提供64Cu或89Zr标记的靶向新冠病毒的中和抗体的制备方法,所述制备方法包括以下步骤:
(1)将纳米抗体Nb11-59与双功能螯合剂(如NOTA、DFO)混合反应得到标记前体,所述纳米抗体Nb11-59与双功能螯合剂的用量摩尔比为1:(5-10);
(2)采用64Cu或89Zr对所述标记前体进行标记反应,反应产物经PD-10柱纯化即得;所述标记前体与64Cu或89Zr的用量比为(0.1-0.5mg):(6×107-3×108Bq)。
进一步地,步骤(1)中,以去离子化处理的0.05-0.1M碳酸氢钠溶液调节反应体系的pH值至8.0-8.5,于37℃反应0.5-2h。
进一步地,步骤(2)中,将所述标记前体加入至0.05-0.15M、pH5.0-5.5的醋酸钠溶液中,再加入64Cu或89Zr溶液,调整pH值至7.0-7.2,于37℃孵育30-60min。
第四方面,本发明提供68Ga标记的靶向新冠病毒的中和抗体的制备方法,所述制备方法包括以下步骤:
(1)将纳米抗体Nb11-59与双功能螯合剂NOTA混合反应得到标记前体NOTA-Nb1159,所述纳米抗体Nb11-59与NOTA的用量摩尔比为1:(5-10);
(2)采用68Ga对所述标记前体NOTA-Nb1159进行标记反应,取1-2mL(优选1.5mL)0.05M HCl溶液淋洗68Ga至65-130μL(优选97μL)1M NaAc中;将200μg的标记前体NOTA-Nb1159加入上述体系,混匀,于35-37℃反应10-20min(优选37℃反应15min),反应产物经PD-10柱纯化即得;
进一步地,步骤(1)中,用DIEA调节反应体系的pH值为8-9(优选pH8.5);于37℃反应0.5-2h,得到标记前体NOTA-Nb1159。
第五方面,本发明提供按照所述方法制备的标记抗体。
第六方面,本发明提供所述放射性核素标记的靶向新冠病毒的中和抗体或所述标记抗体的以下任一应用:
1)用于制备靶向新冠病毒的(PET/CT)分子诊断显像剂或分子探针;
2)用于制备治疗新冠病毒感染以及由其感染所致疾病的放射性药物;
3)用于新冠病毒感染的诊断和治疗。
借由上述技术方案,本发明至少具有下列优点及有益效果:
(一)本发明通过对中和抗体Nb11-59进行放射性标记,可以得到靶向新冠病毒的新型核素探针。该探针性质稳定,制作简易,对RBD有良好的亲和活力。体内显像表明,可以有效监测到RBD在体内的分布,且探针的摄取量与RBD剂量成正相关,有望被开发成检测新冠病毒体内分布和代谢的有效工具,在分析新冠病毒感染机制,观测病毒体内变化方面提供助力。
(二)68Ga-NOTA-Nb1159的体外稳定性分析结果显示,其在0.01M PBS溶液中4小时内保持良好的稳定性,Radio-TLC检测其放射性化学纯度在95%以上。在5%人血清白蛋白溶液中孵育4小时内也能保持良好的稳定性,Radio-TLC检测其放射性化学纯度在95%以上。体内稳定性分析结果显示,在小鼠尿液中0.5小时内能保持良好的稳定性,Radio-TLC检测其放化纯保持在95%以上,在小鼠血液中0.5小时内有较好的稳定性,Radio-TLC检测其放化纯保持70%以上,
68Ga-NOTA-Nb1159在正常Kunming雌性小鼠体内的生物分布实验结果表明,其在小鼠体内清除迅速并主要通过肾脏代谢,在肾脏中摄取较高。小动物PET/CT显像实验结果表明,在构建的RBD小鼠模型(皮下、肺部)中,68Ga-NOTA-Nb1159能明显观测到RBD的病变区,并且摄取值同RBD的剂量成正相关。而常规显像剂18F-FDG在模型小鼠的RBD病变区无明显摄取。
本发明提供的64Cu或89Zr、碘的放射性同位素标记的靶向SARS-CoV-2-RBD的显像剂,标记方法简单,显像剂性质稳定。
本发明提供的68Ga标记的靶向SARS-CoV-2-RBD的显像剂,性质稳定,显像效果好,对RBD有高的亲和力和特异性,经进一步临床前动物实验研究证实,其有望被开发成为观测病毒分布及代谢的临床显像剂。
附图说明
图1为本发明较佳实施例中经PD-10柱纯化后68Ga-NOTA-Nb1159的放射化学纯度分析结果。
图2为本发明较佳实施例中68Ga-NOTA-Nb1159在生理盐水及5%的HSA溶液中的体外稳定性分析结果。
图3为本发明较佳实施例中68Ga-NOTA-Nb1159在正常Kunming小鼠体内稳定性分析结果。
图4为本发明较佳实施例中68Ga-NOTA-Nb1159在正常Kunming小鼠体内生物分布结果。
图5为本发明较佳实施例中68Ga-NOTA-Nb1159在RBD模型小鼠体内Micro-PET/CT显像结果。
具体实施方式
本发明提供放射性核素标记的靶向新冠病毒(SARS-CoV-2)表面受体结合域(RBD)的中和抗体Nb11-59及其制备方法与应用。
SARS-CoV-2与其他冠状病毒具有相似的感染机制,SARS-CoV-2表面的受体结合域(RBD)通过人类的血管紧张素转换酶2(ACE2)受体完成对人体细胞入侵和感染。中和抗体可以与SARS-CoV-2-RBD结合,从而阻断RBD与ACE2的结合,有效中止病毒的感染。其中中和抗体Nb11-59表现出对SARS-CoV-2-RBD优良的靶向性和特异性。本发明提供的放射核素标记的靶向SARS-CoV-2-RBD的显像剂,其性质稳定,制作简易,对RBD有良好的亲和活力。体内显像表明,该显像剂可以有效监测到RBD在体内的分布,且探针的摄取量与RBD剂量成正相关。
本发明采用如下技术方案:
第一方面,本发明提供放射性核素标记的中和抗体Nb11-59,所述放射性核素标记的中和抗体Nb11-59由中和抗体Nb11-59以N-溴代琥珀酰亚胺介导,或者与双功能螯合剂偶联后,进行放射性核素标记得到。本发明中,所述放射性核素优选为碘的放射性同位素、68Ga、64Cu或89Zr,所述碘的放射性同位素优选为124I、123I、125I或131I。
第二方面,本发明提供所述放射性核素标记的中和抗体Nb11-59在制备靶向新冠病毒受体结合域的PET/CT分子诊断显像剂中的应用。
第三方面,本发明提供所述放射性核素标记的中和抗体Nb11-59的制备方法,所述制备方法可根据核素种类不同分为两个并列技术方案。
本发明提供的68Ga标记的靶向SARS-CoV-2-RBD的中和抗体可以按照如下步骤制备得到:
(1)向浓度为2-5mg/ml的中和抗体Nb11-59溶液中加入相当于中和抗体Nb11-59约5-10倍摩尔当量的NOTA,以N,N-二异丙基乙胺(DIEA)调节反应体系的pH值为8.5;37℃条件下反应0.5-2h,得到标记前体NOTA-Nb1159;
取1-2mL(优选1.5mL)0.05M HCl溶液淋洗68Ga至65-130μL(优选97μL)1M NaAc中;将0.2mL(200μg)的NOTA-Nb1159前体加入上述体系,混匀,35-37℃反应10-20min(优选37℃反应15min),标记率小于90%时,用PD-10柱分离纯化,其中PD-10柱需用25mL 0.01M PBS活化以备用。样品溶液上柱后,使用0.01M PBS洗脱目标化合物68Ga-NOTA-Nb1159。使用Radio-TLC测定标记率及放射化学纯度。
作为并列技术方案,当采用碘的放射性同位素(如124I)或64Cu、89Zr标记中和抗体Nb11-59时,以N-溴代琥珀酰亚胺介导、或者与双功能螯合剂(如NOTA或DFO)偶联后分别实现124I或64Cu、89Zr标记中和抗体Nb11-59。
当采用碘的放射性同位素(如124I)标记时,所述制备方法包括:
每0.5-1.0mL的60-90KBq/μL的Na124I溶液中加入0.5-1.0mL、0.1M pH 7.2的PB缓冲液、0.1-0.5mg中和抗体Nb11-59和20-100μg N-溴代琥珀酰亚胺,于常温反应1min,向反应体系中加入0.05-0.2mL、10%人血清白蛋白终止反应;所得反应液用PD-10柱纯化后,得到124I标记的中和抗体Nb11-59。
对于其他碘的放射性同位素,如123I、125I、或131I,所用的盐相应为123I盐、125I盐、或131I盐。
当以64Cu或89Zr标记中和抗体Nb11-59时,通过双功能螯合剂(如NOTA或DFO)分别实现64Cu或89Zr标记中和抗体Nb11-59。所述制备方法包括:
(1)向浓度为2-5mg/ml的中和抗体Nb11-59溶液中加入相当于中和抗体Nb11-59约6倍摩尔当量的DFO,以去离子化处理的0.1M碳酸氢钠溶液调节反应体系的pH值为8.5;37℃条件下反应0.5-2h,得到标记前体DFO-Nb11-59;
(2)取0.1-0.5mg标记前体,加入0.1-1.0ml、0.1M pH 5.5的醋酸钠溶液中,然后加入60-300MBq新鲜配制的64Cu或89Zr溶液,调整pH值到7.0,然后控制温度为37℃,孵育1h;所得反应液经PD-10柱分离纯化,得到64Cu或89Zr标记的中和抗体Nb11-59。
本发明所述的制备方法中,当标记率大于90%,使用PD-10柱纯化后,目标产物的放射性化学纯度大于99%。
在进行PD-10柱分离纯化时,PD-10柱先用0.01M pH 7.4的PBS缓冲液平衡柱体,每次加5mL,重力流速流干,重复5次;然后再用0.01M pH7.4的PBS缓冲液纯化获得核素标记的中和抗体Nb11-59。
以下实施例用于说明本发明,但不用来限制本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段,所用原料均为市售商品。
以下实施例中使用的PD-10柱购自思拓凡公司(型号:#17371260)。
实施例1放射性核素标记的靶向新冠病毒的中和抗体68Ga-NOTA-Nb1159的制备
向浓度为2mg/ml的中和抗体Nb11-59溶液中加入相当于中和抗体Nb11-59约10倍摩尔当量的NOTA,以N,N-二异丙基乙胺(DIEA)调节反应体系的pH值为8.5;37℃条件下反应2h,得到标记前体NOTA-Nb1159。
取1.5mL 0.05M HCl溶液淋洗68Ga至97μL 1M NaAc中;将0.2mL(200μg)的NOTA-Nb1159前体加入上述体系,混匀,37℃反应15min,标记率小于90%时,用PD-10柱分离纯化,其中PD-10柱需用25mL 0.01M PBS活化以备用。样品溶液上柱后,使用0.01M PBS洗脱目标化合物68Ga-NOTA-Nb1159。使用Radio-TLC测定标记率及放射化学纯度。
标记率的测定采用放射性薄层色谱扫描仪(Radio-TLC)分析,分析方法:分别取2μL含74kBq(2μCi)放射性活度的游离68Ga和纯化后的68Ga-NOTA-Nb1159加至20ul饱和EDTA中混匀,进行Radio-TLC分析。取2μL样品滴在距新华一号滤纸底端1cm处,置于生理盐水展开体系中,待完全展开后,取出滤纸并晾干,进行Radio-TLC检测。结果显示:68Ga-NOTA-Nb1159的标记率大于50%;68Ga和68Ga-NOTA-Nb1159的Rf值分别为0.9-1和0-0.1;放射化学纯度大于95%(n>5);具体分析结果见图1。
实施例2 68Ga-NOTA-Nb1159的体内外稳定性分析
体外稳定性分析:取50μL纯化后的68Ga-NOTA-Nb1159与1mL 0.01M PBS混合,分别在0.5小时、1小时、2小时、4小时、6小时和8小时后取适量溶液用Radio-TLC测定其放射性化学纯度,结果表明68Ga-NOTA-Nb1159在0.01M PBS中具有较高的稳定性。取500μL纯化后的68Ga-NOTA-Nb1159与等体积10%的HSA溶液混合,分别在0.5小时、1小时、2小时、4小时、6小时和8小时后取适量溶液用Radio-TLC测定其放射性化学纯度,结果表明68Ga-NOTA-Nb1159在5%的HSA溶液中具有较高的稳定性,结果如图2所示。
体内稳定性分析:取1mCi纯化后的68Ga-NOTA-Nb1159经尾静脉注入Kunming小鼠体内,每组3只,分别在注射后5分钟、30分钟处死小鼠,分别取其血液和尿液。血液离心后取血浆,用Radio-TLC分析其放射性化学纯度。尿液离心后,取上清液,Radio-TLC分析其放射性化学纯度,结果表明68Ga-NOTA-Nb1159在小鼠尿液中稳定性高,血液中有较好的稳定性,结果如图3所示。
实施例3 68Ga-NOTA-Nb1159在正常Kunming小鼠体内的生物分布
取15只正常的Kunming雌性小鼠(18-20g),分别通过尾静脉注射0.2mL68Ga-NOTA-Nb1159(1.11MBq),分别于注射后5分钟、30分钟、60分钟、120分钟和240分钟后断颈处死,取其血液、心脏、肝脏、脾脏、肺脏、肾脏、胃、小肠、大肠、肌肉、骨、脑等有关组织和器官,擦净后称重,并用γ-Counter测其放射性计数,每个时相3只小鼠,计算每克组织百分注射剂量率,记为%ID/g,结果如图4所示,68Ga-NOTA-Nb1159在血液中快速清除,迅速经肾脏通过尿路代谢出体内,在其他主要器官如心脏、肝脏、脾脏、肺脏、脑等脏器中的摄取较低且代谢快,具有良好的代谢性质。
实施例4 68Ga-NOTA-Nb1159和18F-FDG在RBD模型小鼠的Micro-PET/CT显像
通过向Kunming小鼠皮下注射RBD以及气道给药RBD的方式,构建RBD模型小鼠。经尾静脉分别注射0.2mL 68Ga-NOTA-Nb1159显像剂和18F-FDG显像剂(约7.4MBq/只),分别于注射后60分钟进行Micro-PET/CT显像。显像前将小鼠在用混有3%(体积分数)异氟烷的氧气麻醉,显像过程中维持含1%(体积分数)异氟烷的氧气麻醉,PET采集时间为10分钟。显像结果见图5。结果显示,在构建的RBD小鼠模型(皮下、肺部)中,68Ga-NOTA-Nb1159能明显观测到RBD的病变区,并且摄取值同RBD的剂量成正相关。而常规显像剂18F-FDG在模型小鼠的RBD病变区无明显摄取。
本发明提供的68Ga标记的靶向SARS-CoV-2-RBD的显像剂,是正电子核素68Ga标记的放射性示踪剂68Ga-NOTA-Nb1159。该显像剂体内外稳定性好,显像效果明显,对RBD有高的亲和力和特异性,经进一步临床前动物实验研究证实,可用于观测体内病毒分布及代谢的PET/CT临床显像剂。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之做一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
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Claims (10)
1.放射性核素标记的靶向新冠病毒的中和抗体,其特征在于,所述放射性核素标记的中和抗体是将纳米抗体Nb11-59进行NBS修饰后,或者纳米抗体Nb11-59与双功能螯合剂偶联后,经放射性核素标记得到的。
2.根据权利要求1所述放射性核素标记的靶向新冠病毒的中和抗体,其特征在于,所述双功能螯合剂偶联选自NOTA、DFO;
所述放射性核素选自碘的放射性同位素、68Ga、64Cu或89Zr;
优选地,所述碘的放射性同位素选自124I、123I、125I或131I。
3.碘的放射性同位素标记的靶向新冠病毒的中和抗体的制备方法,其特征在于,所述制备方法包括:将纳米抗体Nb11-59与碘的放射性同位素的盐和NBS在反应缓冲液中进行标记反应,然后向反应体系中加入人血清白蛋白终止反应;所得反应产物经PD-10柱纯化即得;
其中,纳米抗体Nb11-59、碘的放射性同位素的盐和NBS的用量比为(0.1-0.5mg):(3×107-1.5×108Bq):(20-100μg);
优选地,所述碘的放射性同位素选自124I、123I、125I或131I。
4.根据权利要求3所述的方法,其特征在于,所述反应缓冲液为0.05-0.2M、pH7-7.5的PB缓冲液;所述反应缓冲液占反应体系总体积的30%-75%;
所述标记反应在常温反应0.8-1.2min,以8-12%的人血清白蛋白终止反应。
5.64Cu或89Zr标记的靶向新冠病毒的中和抗体的制备方法,其特征在于,所述制备方法包括以下步骤:
(1)将纳米抗体Nb11-59与双功能螯合剂混合反应得到标记前体,所述纳米抗体Nb11-59与双功能螯合剂的用量摩尔比为1:(5-10);
(2)采用64Cu或89Zr对所述标记前体进行标记反应,反应产物经PD-10柱纯化即得;所述标记前体与64Cu或89Zr的用量比为(0.1-0.5mg):(6×107-3×108Bq);
优选地,所述双功能螯合剂偶联选自NOTA、DFO。
6.根据权利要求5所述的方法,其特征在于,步骤(1)中,以去离子化处理的0.05-0.1M碳酸氢钠溶液调节反应体系的pH值至8.0-8.5,于37℃反应0.5-2h;
步骤(2)中,将所述标记前体加入至0.05-0.15M、pH5.0-5.5的醋酸钠溶液中,再加入64Cu或89Zr溶液,调整pH值至7.0-7.2,于37℃孵育30-60min。
7.68Ga标记的靶向新冠病毒的中和抗体的制备方法,其特征在于,所述制备方法包括以下步骤:
(1)将纳米抗体Nb11-59与双功能螯合剂NOTA混合反应得到标记前体NOTA-Nb1159,所述纳米抗体Nb11-59与NOTA的用量摩尔比为1:(5-10);
(2)采用68Ga对所述标记前体NOTA-Nb1159进行标记反应,取1-2mL 0.05M HCl溶液淋洗68Ga至65-130μL 1M NaAc中;将200μg的标记前体NOTA-Nb1159加入上述体系,混匀,于35-37℃反应10-20min,反应产物经PD-10柱纯化即得。
8.根据权利要求7所述的方法,其特征在于,步骤(1)中,用DIEA调节反应体系的pH值为8-9;于37℃反应0.5-2h,得到标记前体NOTA-Nb1159。
9.按照权利要求3-8任一项所述方法制备的标记抗体。
10.权利要求1或2所述放射性核素标记的靶向新冠病毒的中和抗体、或权利要求9所述标记抗体的以下任一应用:
1)用于制备靶向新冠病毒的分子诊断显像剂;
2)用于制备治疗新冠病毒感染以及由其感染所致疾病的放射性药物。
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