CN110624105B - 血管性血友病因子的结构敏感多肽抗原的序列 - Google Patents

血管性血友病因子的结构敏感多肽抗原的序列 Download PDF

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CN110624105B
CN110624105B CN201910906491.9A CN201910906491A CN110624105B CN 110624105 B CN110624105 B CN 110624105B CN 201910906491 A CN201910906491 A CN 201910906491A CN 110624105 B CN110624105 B CN 110624105B
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邓巍
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Abstract

本发明涉及一段多肽抗原序列、其在人类血管性血友病因子的空间敏感位置、及其在制备诊断和/或治疗血管性血友病因子相关的血液疾病的制剂中的应用。该多肽抗原包括SEQ ID No.1所示的氨基酸序列、生物学活性片段或其变体。该多肽的空间位置在血管性血友病因子处于活性状态时由非溶剂暴露转变为溶剂暴露，从而可被抗体识别。利用上述多肽抗原备出的识别活性状态的血管性血友病因子的抗体可以对多种血管性血友病因子相关疾病进行诊断和治疗。

Description

血管性血友病因子的结构敏感多肽抗原的序列
技术领域
本发明涉及血管性血友病因子的识别制剂领域，尤其涉及一种血管性血友病因子的结构敏感多肽抗原的序列。
背景技术
血管性血友病因子是通过血管内皮细胞释放进血液循环中的一种很重要的大型多聚体蛋白质，它通过直接感受剪切应力来介导止血、血栓形成和血栓炎症。血管性血友病因子是最容易发生基因突变的分子之一。全球约600万人患有由于血管性血友病因子基因变异而导致的血液性血友病(VWD)—一种最广泛的遗传性出血性疾病。
血管性血友病因子多聚物的大小对血管性血友病因子的反应活性有直接影响，而多聚物的大小又对血液剪切应力十分敏感。血液剪切应力对血管性血友病因子的大小和反应性的精确调节对于止血至关重要。在低剪切条件下，由于血管性血友病因子单体之间的弱相互作用，血管性血友病因子多聚体采用松散卷曲的冷凝形状。在这些条件下，血管性血友病因子不结合血小板。在临界剪切速率以上，血管性血友病因子多聚体延伸并经历拉伸力。张力诱导A1周围的结构变化，使其与血小板结合导致血小板聚集和清除。血管性血友病因子构象的改变与它的活性有直接关联。对这种构象变化的调节失常会导致例如中风、心梗和肺栓塞等多种血栓类高风险疾病。
目前的血管性血友病因子活性诊断制剂的诊断原理以ristocetin瑞斯托霉素聚集方法为主，这些诊断制剂的均在非生理条件下使用，其诊断结果容易受到抗体和其他因素的干扰，可靠性差。目前治疗血管性血友病因子相关的血液疾病的制剂以激素为主，缺乏靶向性和持续性。
抗体药物具有高度靶向性，随着对导致疾病的分子靶向的识别和认知，近年来抗体药物出现井喷式发展，以抗PD-1/PD-L1的肿瘤单抗为代表的肿瘤抗体药物取得了很好的治疗效果。首个抗血管性血友病因子的抗体药物Caplacizumab(商品名：Cablivi)2019年2月通过FDA批准。该药物通过阻断血管性血友病因子与血小板的结合，减少了病人由于血栓而出现的脏器缺血症状，被用于治疗血栓性血小板减少性紫癜(TTP)
在凝血和血栓形成过程中，血管性血友病因子通过改变构象，由非活性状态转变成活性状态，才能结合血小板，发挥功能。Caplacizumab无区别地结合非活性和活性血管性血友病因子并导致其清除，因此导致血管性血友病因子整体水平下降。这种下降会导致无法预料的出血风险，并且随着血管性血友病因子的消耗，Caplacizumab的持久性差，而且用量较多，这些缺点使得该药物只能用于治疗血栓性血小板减少性紫癜(TTP)这样极端的小众病人。
因此，为了使抗血管性血友病因子的抗体能被运用于更广泛的各类血管性血友病中，寻找一种能只针对活化状态的血管性血友病因子的抗体十分必要。这种抗体将只识别活性状态的血管性血友病因子，并通过肝脏对结合抗体的血管性血友病因子进行清除，从而可以达到在减少血栓形成的风险的同时降低用药的剂量，延长其持久性。文献“Delimiting the autoinhibitory module of von WillebrandfactorW Deng,KM Voos,JK Colucci,ER Legan,EA Ortlund,P Lollar,R LiJournal of Thrombosis andHaemostasis 16(10),2097-2105”和“A discontinuous autoinhibitory module masksthe A1 domain of von WillebrandfactorW Deng,Y Wang,SA Druzak,JF Healey,AKSyed,P Lollar,R LiJournal of Thrombosis and Haemostasis 15(9),1867-1877”提出了血管性血友病因子的活化通过A1结构域两翼的短肽与A1的互动实现。但是，首先，这两篇文献仅仅是对分离出来的A1结构域进行了活性研究，与复杂的2050个氨基酸的血管性血友病因子相比，A1结构域仅含有205个氨基酸，研究A1结构域得出的结论对理解整体血管性血友病因子的结构变化仅具有有限的概念性参考价值。其次，这两篇文献的结论虽然提出了A1结构域上存在结构敏感区域这一概念，但是并没有给出具体的结构敏感的多肽位置，更没有指向利用A1结构域的结构敏感性开发抗体的思路。最后，虽然抗体的开发技术很成熟，但是对抗原的选择要求很高，即使掌握了整体结构域的结构敏感信息，也不能保证一定能获得理想的抗原信息。
发明内容
为解决上述技术问题，本发明的目的是提供一种血管性血友病因子的结构敏感多肽抗原的序列，本发明公开了血管性血友病因子活性状态敏感的多肽抗原，并以此制备出仅识别活性血管性血友病因子的抗体。
本发明的第一个目的是公开多肽抗原在制备诊断和/或治疗血管性血友病因子相关的血液疾病的制剂中的应用，所述多肽抗原包括SEQ ID No.1所示的氨基酸序列、生物学活性片段或其变体，多肽抗原来源于人类血管性血友病因子的A1结构域。
进一步地，所述多肽抗原位于人类血管性血友病因子的A1结构域中β3折叠与α2螺旋之间的loop区域。
进一步地，血管性血友病因子处于活性状态时，所述多肽抗原被其特异性抗体识别。
进一步地，多肽抗原来源于人类。
进一步地，制剂为疫苗组合物、抗体药物或诊断试剂盒。
本发明的第二个目的是提供一种抗体，所述抗体特异性识别包括SEQ ID No.1所示的氨基酸序列、生物学活性片段或其变体的多肽抗原。
进一步地，抗体识别处于活性状态的血管性血友病因子；所述多肽抗原来源于人类血管性血友病因子的A1结构域。该多肽抗原位于人类血管性血友病因子的A1结构域中β3折叠与α2螺旋之间的loop区域。
本发明的第三个目的是提供一种诊断制剂，所述诊断制剂用于确定样品中是否存在包括SEQ ID No.1所示的氨基酸序列的多肽抗原，所述诊断制剂中包括本发明的上述抗体。
本发明的第四个目的是提供一种治疗制剂，所述治疗制剂用于识别和抑制处于活性状态的血管性血友病因子；所述治疗制剂中包括本发明的上述抗体。
借由上述方案，本发明至少具有以下优点：
本发明涉及一段多肽抗原序列、其在人类血管性血友病因子的空间敏感位置、及其在制备诊断和/或治疗血管性血友病因子相关的血液疾病中的应用。该多肽抗原的空间位置在血管性血友病因子处于非活性状态下受到A1结构域两翼的短肽区域保护，抗体无法识别；当血管性血友病因子处于活性状态时由非溶剂暴露转变为溶剂暴露，从而可被抗体识别。利用上述多肽抗原备出的识别活性状态的血管性血友病因子的抗体可以对多种血管性血友病因子相关疾病进行诊断和治疗，该抗体仅仅对活性血管性血友病因子进行识别和抑制。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1是本发明所制备的单克隆抗体对活性和非活性VWF识别的测试结果图；
图2图示了多肽抗原在血管性血友病因子中的空间位置；
图3是对比例中的单克隆抗体对活性和非活性VWF识别的测试结果图。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1
血管性血友病因子有2050个氨基酸，14个结构域组成。其中的A1结构域是与之凝血功能相关的结构域，A1结构域有205个氨基酸。这些氨基酸在蛋白质的结构中的位置是已知的。从人源的血管性血友病因子A1结构域上与A1结构域两翼的短肽互动的区域选取了一段10个氨基酸长度的多肽作为抗原(GLKDRKRPSE，SEQ ID No.1)。该多肽抗原位于人类血管性血友病因子的A1结构域中β3折叠与α2螺旋之间的loop区域(图2)。利用该多肽抗原，通过标准的抗体制备方法，制备鼠源的单克隆抗体，其方法如下：
(1)免疫动物：用上述序列的多肽抗原免疫小鼠，使小鼠产生B淋巴细胞。
(2)细胞融合：将同系骨髓瘤细胞与小鼠脾细胞混合，在聚乙二醇作用下，淋巴细胞与骨髓瘤细胞发生融合，形成杂交瘤细胞。
(3)选择性培养：用HAT选择性培养基筛选融合的杂交瘤细胞。
(4)杂交瘤阳性克隆的筛选与克隆化：
采用免疫荧光的方法(ELISA)筛选出能产生所需单克隆抗体的阳性杂交瘤细胞，并进行克隆扩增。
图1是本发明所制备的不同浓度的单克隆抗体对活性和非活性血管性血友病因子识别的测试结果图，结果表明，随着抗体浓度的增大，活性血管性血友病因子在450nm波长处的紫外吸收增强，而非活性血管性血友病因子在450nm波长处的紫外吸收基本不变，表明本发明由本发明的多肽抗原所制备的单克隆抗体能够特异性识别活性血管性血友病因子。这是由于上述多肽抗原对血管性血友病因子的活性状态十分敏感，在血管性血友病因子处于非活性状态下受到A1结构域两翼的短肽区域保护，其单克隆抗体无法识别；当血管性血友病因子活化时该多肽抗原区域暴露出来，其单克隆抗体可以识别。
可利用该抗体进一步制备抗体药物，它可仅识别少数活性蛋白，所以不会导致整体蛋白水平下降，出血风险非常低；且不会引起大量蛋白的消耗，持久性强，用量少。
对比例
用多肽抗原pVWF 1346-1355:QVKYAGSQVD(SEQ ID No.2)为抗原生产的单抗检测血管性血友病因子的活性状态表明，该抗体对血管性血友病因子活性状态和非活性状态均有较高的结合(图3)，表明该抗体对血管性血友病因子活性状态不敏感。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Figure BDA0002213428580000051
序列表
<110> 苏州大学
<120> 血管性血友病因子的结构敏感多肽抗原的序列
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> pVWF1330-1339
<400> 1
Gly Leu Lys Asp Arg Lys Arg Pro Ser Glu
1 5 10
<210> 2
<211> 10
<212> PRT
<213> pVWF1346-1355
<400> 2
Gln Val Lys Tyr Ala Gly Ser Gln Val Asp
1 5 10

Claims (3)

1.一种多肽抗原，其特征在于，所述多肽抗原的氨基酸序列如SEQ ID No.1所示。
2.根据权利要求1所述的多肽抗原，其特征在于，所述多肽抗原来源于人类血管性血友病因子的A1结构域。
3.根据权利要求2所述的多肽抗原，其特征在于，所述多肽抗原位于血管性血友病因子中A1结构域的b3折叠与a2螺旋之间的loop区域。
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