CN110237250A - 抗-cd8抗体作为制备治疗心肌梗塞药物的应用 - Google Patents
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Abstract
本发明公开了抗‑CD8抗体作为制备治疗心肌梗塞药物的应用。本发明可以达到减轻心梗后心肌损伤，改善愈后心脏功能，实现心肌梗塞后损伤心肌的再生和功能恢复的目的。
Description
技术领域
本发明涉及抗-CD8抗体的应用领域，尤其涉及一种抗-CD8抗体作为制备治疗急性心肌梗塞病药物的应用。
背景技术
心肌梗塞，是一种急性发作，并且严重的心脏疾病，其主要病理机制为：部分心肌血液循环突然中断，由于缺氧而导致的心肌损伤，以及造成全身供血不足。绝大多数的心肌梗塞是由于心脏冠状动脉堵塞/血栓造成。所以，目前对于心肌梗塞的治疗，主要原则是尽早恢复血流供应缩小梗死面积、保护心脏功能、挽救濒临死亡的心肌、以及处理各种并发症。目前主流的治疗方案是经皮冠状动脉介入术溶栓，之后采取抗凝药物抑制再发血栓形成；或者严重堵塞者行冠状动脉旁路移植术(冠状动脉搭桥手术)。但无法减轻已发生的心肌炎症反应，从而无法减轻由已发生炎症导致的心肌损害。而且，心肌长时间(10-15分钟)缺血情况下造成的心肌损伤/死亡无法逆转/再生，因此该类病人在恢复血流后心脏功能将不断减弱。
更为重要的是，近几年的研究发现在心梗后自身免疫的改变对该类病人的愈后具有重要的影响，然而，目前对于急性心肌梗塞发生后对于调节自身免疫关注较少，相应的通过调节自身免疫来缓解心肌损伤，以及恢复心脏功能的制剂更为短缺。
CD8T细胞是一类具有细胞毒性的杀伤性免疫细胞，在正常人体血液中循环，一旦接触病原体就能快速激活，发挥高效的杀伤作用。然而，在正常心脏中CD8T细胞数量极少。在心梗发生后，心脏中心肌细胞因缺血而死亡，释放大量自身抗原，从而增加自身免疫反应的风险，此时CD8T细胞大量迁入心脏中，攻击受损心肌细胞，从而导致心脏功能骤减，是心脏病病程凶险、预后差的主要原因之一。
因此，本领域的技术人员致力于开发一种利用CD8蛋白抗体特异地封阻、清除CD8T细胞以达到减轻心梗后心肌损伤，改善愈后心脏功能，实现心肌梗塞后损伤心肌的恢复和功能恢复的目的。
发明内容
有鉴于现有技术的上述缺陷，本发明所要解决的技术问题是
为实现上述目的，本发明提供了抗-CD8抗体作为制备治疗心肌梗塞药物的应用。
进一步的，所述抗CD8抗体是抗CD8α抗体或抗CD8β抗体。
进一步的，所述抗体选自全抗体、抗体片段或人源化抗体。
技术效果
本发明涉及使用的抗CD8抗体通过封阻/清除CD8阳性T细胞可以减轻心梗病人已发生的心肌炎症导致的心肌损害，改善愈后心脏功能，实现心肌梗塞后损伤心肌的再生和功能恢复。
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明，以充分地了解本发明的目的、特征和效果。
附图说明
图1是本发明的一个较佳实施例的抗-CD8抗体清除小鼠血液和脾脏内的CD8T细胞的结果图；
图2是图1的直观图；
图3是本发明的一个较佳实施例的抗-CD8抗体改善愈后心脏功能(EF％)的图。
具体实施方式
以下参考说明书附图介绍本发明的多个优选实施例，使其技术内容更加清楚和便于理解。本发明可以通过许多不同形式的实施例来得以体现，本发明的保护范围并非仅限于文中提到的实施例。
本发明基于的原理是：使用抗CD8抗体特异性的封阻、清除CD8表面抗原阳性的T细胞，通过抗原-抗体之间的特异性结合，消耗/去除阳性抗原细胞。CD8抗原最主要的存在形式是由CD8α和CD8β链组成的异源二聚体，以及少量存在形式是由两个CD8α链组成的同源二聚体，所以用于封阻、清除CD8阳性细胞的抗体(主要为单克隆抗体)主要分别针对于CD8α和CD8β，研究显示抗CD8α抗体和抗CD8β抗体均能有效的封阻、清除CD8阳性细胞，但是抗-CD8α清除效果更彻底。
本文所涉及的抗-CD8α抗体，为单克隆抗体，克隆编号2.43，来源于BioCell公司(Catalog#：BP0061)。对应于同一种抗原的抗体产生，由于制作时的免疫位点的不同，可以产生不同单克隆细胞株来源的抗体蛋白。基于CD8抗原主要存在形式为一条CD8α和一条CD8β链构成的异源二聚体，以及少量由两条CD8α链构成的同源二聚体，所以对应于CD8α链产生的单克隆抗体能更为有效的封阻/清除CD8阳性T细胞，但是研究发现分别对应于CD8α和CD8β产生的单克隆抗体均能达到有效封阻/清除CD8阳性T细胞的目的。基于此，有以下几种可能的替代蛋白制剂：1、抗-CD8α抗体，克隆号：YTS 169.4，购自BioCell公司(Catalog#：BP0061)；2、抗-CD8α抗体(Lyt2)，克隆号：53-6.7，购自Biolegend公司(Catalog#：100702)，或者R&D公司(Catalog#：MAB116)，或者BioRad公司(Catalog#：MCA2694)等；3、抗CD8β抗体(Lyt3.2)克隆号：53-5.8，购自BioCell公司(Catalog#：BE0223)。
经内皮细胞特异敲除Tbx1的成年小鼠(Tbx1Cko)在急性心梗后具有严重的免疫反应缺陷。心梗模型的建立：使用体重在18-26克范围内8-12周龄的Tbx1条件性基因敲除的成年小鼠(Cko)进行左前降支截扎诱导的心梗手术(Song,K.et al.Heart repair byreprogramming non-myocytes with cardiac transcription factors.Nature 485,599–604(2012).)。通过单细胞转录测序和流式细胞筛选技术发现，在心梗7天后的Tbx1Cko小鼠心脏中具有细胞毒作用的CD8T细胞数量明显增多。过多的CD8T细胞会造成严重的自身免疫反应，在心梗后杀伤缺氧的心肌细胞，从而使心脏功能进一步恶化，也确实发现与对照组相比，Tbx1Cko小鼠心梗后的心脏功能明显恶化。
如图1-3所示,从心梗模型建立前两天起，以每天10ug/g体重的剂量对Cko小鼠腹腔注射抗-CD8抗体(Cko+Block或Block)，持续至心梗建立一周后，以相同剂量每三天注射一次直至心梗后四周；对照组则注射PBS溶液(Ctrl)。在此期间，每一周用心脏超声仪对小鼠的心脏功能进行检测。以心脏功能是否恢复和稳定为依据决定是否需要持续静脉注射抗-CD8抗体。
结果显示，三剂抗-CD8抗体即能完全清除小鼠血液和脾脏内的CD8T细胞，表明用该方法清除CD8T细胞显著有效，清楚效率超过90％，不影响CD4T细胞。连续四周心脏功能跟踪结果显示，心梗一周后，CD8T清除后的Cko小鼠心脏功能比PBS对照组Cko显著改善。EF％(射血分数)上升至与野生型小鼠水平，Cko小鼠的心脏功能明显提高，且至少能维持四周。
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。
Claims (3)
1.抗-CD8抗体作为制备治疗心肌梗塞药物的应用。
2.如权利要求1所述的应用，其中，所述抗CD8抗体是抗CD8α抗体或抗CD8β抗体。
3.如权利要求1所述的应用，其中，所述抗CD8抗体选自全抗体、抗体片段或人源化抗体。
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| WO2022017370A1 (zh) * | 2020-07-21 | 2022-01-27 | 苏州智核生物医药科技有限公司 | Cd8结合多肽及其用途 |
| WO2022183600A1 (zh) * | 2021-03-02 | 2022-09-09 | 上海交通大学医学院附属上海儿童医学中心 | 增强tbx1表达在修复心脏组织损伤中的用途 |
| WO2024105223A1 (en) * | 2022-11-17 | 2024-05-23 | Polygon Therapeutics | Anti-cd8 alpha depleting antibodies |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022017370A1 (zh) * | 2020-07-21 | 2022-01-27 | 苏州智核生物医药科技有限公司 | Cd8结合多肽及其用途 |
| WO2022183600A1 (zh) * | 2021-03-02 | 2022-09-09 | 上海交通大学医学院附属上海儿童医学中心 | 增强tbx1表达在修复心脏组织损伤中的用途 |
| WO2024105223A1 (en) * | 2022-11-17 | 2024-05-23 | Polygon Therapeutics | Anti-cd8 alpha depleting antibodies |
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