CN113967367A - 新冠病毒治疗用细胞因子抗体组合物及治疗用吸附剂 - Google Patents
新冠病毒治疗用细胞因子抗体组合物及治疗用吸附剂 Download PDFInfo
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Abstract
本发明公开了一种新冠病毒治疗用细胞因子吸附剂，该吸附剂的核心部分是抗体组合物，由抗体组合物和载体偶联构建成治疗用吸附剂。新冠病毒治疗用细胞因子抗体组合物为抗TNF‑α、IL‑1β、IL‑6、IL‑8、IL‑12的多种细胞因子的单抗组合物。本发明通过多种细胞因子的单抗组合物与聚苯乙烯微球形成的复合抗体材料的合成，使免疫吸附疗法首创性的运用于新冠病毒引起的细胞因子风暴治疗领域；通过复合抗体材料的研发，解决单细胞因子抗体药物在特定病毒爆发环境中治疗效果不佳的问题。
Description
技术领域
本发明涉及生物技术领域，具体地指一种新冠病毒治疗用细胞因子抗体组合物及治疗用吸附剂。
背景技术
2019新型冠状病毒，2020年1月12日被世界卫生组织命名为2019-nCoV，2020年2月11日被国际病毒分类委员会命名为SARS-CoV-2。
2020年3月16日，英国伦敦大学学院的研究团队在《柳叶刀》发文称，越来越多的证据表明，患有严重COVID-19的患者可能患有细胞因子风暴综合征。
细胞因子风暴(cytokine storm)是指机体感染微生物后引起体液中多种细胞因子如TNF-α、IL-6和IL-12等迅速大量产生的现象，是引起急性呼吸窘迫综合征和多脏器衰竭的重要原因。
发明内容
本发明的目的在于提供一种新冠病毒治疗用细胞因子吸附剂。该吸附剂的核心部分是抗体组合物，由抗体组合物和载体偶联构建成治疗用吸附剂。
为实现上述目的，本发明所提供的新冠病毒治疗用细胞因子抗体组合物，所述组合物为抗TNF-α、IL-1β、IL-6、IL-8、IL-12的多种细胞因子的单抗组合物。
优选地，所述抗体组合物中各个抗体重量比为：TNF-α:IL-1β:IL-6:I L-8:IL-12＝5:5:5:3:1。
本发明还提供了一种新冠病毒治疗用细胞因子吸附材料，包括上所述抗体组合物，以及用于承载所述抗体组合物的载体微球；所述新冠病毒治疗用细胞因子吸附材料中抗体组合物和载体微球的比例为1mg:5ml。
本发明还提供了上述新冠病毒治疗用细胞因子吸附材料在制备血液净化柱中的应用。
细胞因子在炎症的中起着至关重要的作用。不同的感染和炎症创伤所分泌的细胞因子有区别，它们的作用可能是激活(促炎)或抑制(抗炎)宿主反应。新冠病毒造成肺部感染后，免疫细胞进入炎症部位后。外来入侵病原体的识别由病原体相关分子模式(PAMP)介导和白细胞产生特定促炎性细胞因子，一旦识别受体(PRR)被激活，配体结合发生，信号级联反应被触发短期会产生产生包括TNF-α、IL-6和IL-1α、β大量的细胞因子，它们都具有不同的促炎作用。TNF-α和IL-1α、β直接导致细胞损伤和组织出血，并诱导补体机制失控。爆发性病毒感染导致单核－巨噬细胞急剧分泌趋化因子IL-8，吸引和激活中性粒细胞，中性粒细胞定向游走到反应部位释放一系列大量活性产物；对自体正常细胞的杀伤远超其炎症的调节。病毒活化淋巴细胞导致IL-12可刺激活化型T细胞增殖，促进Th0细胞向Th1细胞分化，大量IL-12产生导致Th1细胞Th2细胞的比例失衡并诱导CTL和NK细胞的细胞毒活性并促进其分泌IFN-γ、TNF-α、GM-CSF等细胞因子。
通过对新冠病人血浆细胞因子的研究：TNF-α安全范围值为<13.47ng/L，IL-1β安全范围值为<9.22ng/L，IL-6安全范围值为<5.79ng/L，IL-8安全范围值为<43.10ng/L，IL-12安全范围值为<0.66μg/L；
组合物的各个抗体用量需保证1mg-5mg范围，通过试验验证IL-1β、IL-6、TNF-α为5mg，IL-12为1mg，IL-8为3mg。抗体与偶联材料比例为：1mg：5ml。所以新冠病毒治疗用细胞因子组合的偶联材料需要30ml-150ml聚苯乙烯微球。
针对配体的抗体偶联材料为：聚苯乙烯微球，且同材质产品已广泛临床应用，生产过程无有机溶剂，产物无毒。在此基础上，本项目运用高选择性吸附、低毒副作用抗体组合形成复合抗体材料，对细胞因子风暴的治疗进行了技术升级换代。
本发明的有益效果：IL-1β、IL-12、IL-6、IL-8、TNF-α的多种细胞因子的单抗组合物与聚苯乙烯微球形成的复合抗体材料的合成，使免疫吸附疗法首创性的运用于新冠病毒引起的细胞因子风暴治疗领域；通过复合抗体材料的研发，解决单细胞因子抗体药物在特定病毒爆发环境中治疗效果不佳的问题。
附图说明
图1为细胞因子抗体和载体的偶联方案原理图。
图2为采用多克隆细胞因子吸附器的血液净化系统的示意图。
图3为应用4种系统进行血液净化后TNF-α吸附率的对比图。
图4为应用4种系统进行血液净化后IL-1β吸附率的对比图。
图5为应用4种系统进行血液净化后IL-6吸附率的对比图。
图6为应用4种系统进行血液净化后IL-8吸附率的对比图。
具体实施方式
以下结合附图和具体实施例对本发明作进一步的详细描述。以下实施例中采用的试剂或产品，未标明出处的均为市售，不用于限制本发明。
实施例1：细胞因子抗体微球制备
细胞因子抗体和载体的偶联
1)细胞因子抗体来源
IL-1β：义翘神州货号：兔单抗10139-R101
IL-6：义翘神州货号：兔单抗50136-R076
IL-8：义翘神州货号：兔单抗90280-R009
IL-12：义翘神州货号：鼠单抗13190-MM03
TNF-α：同立海源生物货号：Recombinant Human TNF-α(GMP)
2)将上述抗体按IL-1β、IL-6、TNF-α为5mg，IL-12为1mg，IL-8为3mg的比例混合得到新冠病毒治疗用细胞因子抗体组合物，即抗体混合液A。
1、混匀颠倒树脂(聚苯乙烯微球)，倒出约3-4ml(树脂样品约1g)，在30ml预装填料柱中，先用ddH20，50ml冲洗一遍，之后用K2HPO4-KH2PO4缓冲液(pH＝8.0)清洗3-5遍，每遍20ml，最后滤干。
2、将清洗干净的树脂倒入50ml离心管中，加入1.5mg左右抗体混合液A，并用K2HPO4-KH2PO4缓冲液(pH＝8.0)定容至10ml，并用封口膜密闭管口，于25℃，170rpm,在摇床中振荡过夜。
3、之后重新转入预装柱中，并于1M NaCI和ddH20交替清晰5-10遍左右，每遍体积20ml，滤干后转移走偶联好的树脂，于4℃，20％乙醇溶液中保存2个小时，为下一步装柱做准备。
实施例2：单克隆抗体组合细胞因子吸附器的效果验证。
新冠病毒引起急性炎症反应导致病人细胞因子风暴，需要细胞因子指标大于正常值范围100倍以上，病人在进行内科保守治疗的同时会隔天置换出1.5-2L高细胞因子毒血浆。
隔天收集4例3.5L新冠病人高细胞因子血浆，要求细胞因子指标在正常值范围的100-115倍。
患者一：张XX,男，72岁
患者2020年3月入院，无明显诱因咳嗽，发热。CT报告：右肺门处可见不规则磨玻璃样阴影，阴影面积约：4.5×3.8cm；新型冠状病毒核酸检测：阳性；新型冠状病毒Ig抗体检测：阳性；一周后转入重症ICU治疗，血浆收集完成后，血浆细胞因子指标：IL-1β：934.2ng/L，IL-6：596.8ng/L，TNF-α：1512.4ng/L，IL-12：66.13μg/L，IL-8：4512.2ng/L。
患者二：李XX,男，66岁
患者2020年3月入院，无明显诱因发热，乏力，干咳，并伴有严重腹泻。CT报告：双侧肺斑片状阴影，阴影面积约：8.6×6.8cm；新型冠状病毒核酸检测：阳性；新型冠状病毒Ig抗体检测：阳性；5天后转入重症ICU治疗，血浆收集完成后，血浆细胞因子指标：IL-1β：940.1ng/L，IL-6：633.8ng/L，TNF-α：1508.5ng/L，IL-12：67.10μg/L，IL-8：4632.1ng/L。
患者三：闵XX,男，62岁
患者2020年3月入院，无明显诱因发热，干咳，胸闷，喘憋，呼吸困难，并伴有轻微呕吐，氧饱和度下降。CT报告：双肺渗出性病变，可见磨玻璃阴影，最大截面积约：8.8×6.1cm；新型冠状病毒核酸检测：阳性；新型冠状病毒Ig抗体检测：阳性；3天后转入重症ICU治疗，血浆收集完成后，血浆细胞因子指标：IL-1β：942.9ng/L，IL-6：615.9ng/L，TNF-α：1388.9ng/L，IL-12：66.56μg/L，IL-8：4589.3ng/L。
患者四：刘XX,女，65岁
患者2020年3月入院，无明显诱因发热，干咳，喘憋，并伴有轻微腹泻，氧饱和度下降。CT报告：双肺渗出性病变，可见磨玻璃阴影，阴影面积约：7.2×5.3cm；新型冠状病毒核酸检测：阳性；新型冠状病毒Ig抗体检测：阳性；5天后转入重症ICU治疗，血浆收集完成后，血浆细胞因子指标：IL-1β：938.1ng/L，IL-6：628.5ng/L，TNF-α：1422.3ng/L，IL-12：67.22μg/L，IL-8：4535.7ng/L。
将实施例1所偶联的抗体材料装入血浆吸附柱中，得到单克隆抗体细胞因子吸附器，并采用如图2所示的血浆净化系统模拟处理患者一置换下来的3.5L高细胞因子毒血浆；采用市售Cytosorb、Oxiris和健帆A380的血液吸附柱分别处理患者二、三、四的置换下来的3.5L高细胞因子毒血浆。
实验对象：重度感染病人血浆，血浆容量：3.5L。
治疗时间：2小时。
检测指标：TNF-α、IL-1β、IL-6、IL-8。
试验结果如图3～6(苏州仝乾为本发明方案)，通过血浆吸附实验对比我们发现：我们的单克隆抗体组合细胞因子吸附器在细胞因子清除率远超已经上市的Cytosorb、Oxiris和健帆A380产品这种非特异性材料吸附产品，在相同2h的吸附效率也远远高于非特异性材料，并且在延长时间后，单克隆抗体组合细胞因子吸附器能够让细胞因子指标恢复到正常值左右，相反无论时间如何延长，非特异性材料对细胞因子清除率不高于45％，我们都知道细胞因子风暴之所以致命，是由于细胞因子指标选超正常值百倍甚至千倍，如果吸附率只在20％到40％，病人依然处于细胞因子风暴的状态下，依旧致命。这也是目前上市产品在临床试验研究中，无法改善病人死亡率的原因。并且实施例2的单克隆抗体组合细胞因子吸附器吸附原理是特异性免疫吸附，对于血浆成分不会产生明显变化，基本没有其他副作用。
Claims (4)
1.一种新冠病毒治疗用细胞因子抗体组合物，其特征在于：所述抗体组合物为抗TNF-α、IL-1β、IL-6、IL-8、IL-12的多种细胞因子的单抗组合物。
2.根据权利要求1的新冠病毒治疗用细胞因子抗体组合物，其特征在于：所述抗体组合物中各个抗体重量比为：TNF-α:IL-1β:IL-6:IL-8:IL-12＝5:5:5:3:1。
3.一种新冠病毒治疗用细胞因子吸附材料，其特征在于：包括权利要求1或2所述抗体组合物，以及用于承载所述抗体组合物的载体微球；所述新冠病毒治疗用细胞因子吸附材料中抗体组合物和载体微球的比例为1mg:5ml。
4.权利要求3所述新冠病毒治疗用细胞因子吸附材料在制备血液净化柱中的应用。
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| CN115177803A (zh) * | 2022-06-02 | 2022-10-14 | 厦门大学附属翔安医院 | 一种新冠病毒感染患者血液中病毒的清除方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1346280A (zh) * | 1999-03-26 | 2002-04-24 | 生化研究股份公司 | 败血症治疗用免疫吸附剂 |
| CN110327894A (zh) * | 2019-06-05 | 2019-10-15 | 南京亘闪生物科技有限公司 | 一种高吸附量的血液净化高分子微球及其制备方法 |
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| CN1346280A (zh) * | 1999-03-26 | 2002-04-24 | 生化研究股份公司 | 败血症治疗用免疫吸附剂 |
| CN110327894A (zh) * | 2019-06-05 | 2019-10-15 | 南京亘闪生物科技有限公司 | 一种高吸附量的血液净化高分子微球及其制备方法 |
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| CN115177803A (zh) * | 2022-06-02 | 2022-10-14 | 厦门大学附属翔安医院 | 一种新冠病毒感染患者血液中病毒的清除方法 |
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