CN1867365A - 分离性输血－设备 - Google Patents
分离性输血－设备 Download PDFInfo
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- CN1867365A CN1867365A CNA2004800303263A CN200480030326A CN1867365A CN 1867365 A CN1867365 A CN 1867365A CN A2004800303263 A CNA2004800303263 A CN A2004800303263A CN 200480030326 A CN200480030326 A CN 200480030326A CN 1867365 A CN1867365 A CN 1867365A
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Abstract
本发明涉及一种分离性输血－设备，其包含可与血流或血浆流相接触的固体载体，该设备适用于治疗阿尔茨海默氏病人。
Description
本发明涉及一种分离性输血-设备，该设备包含一种可与血流或血浆流相接触的固体载体。
分离性输血意指一种治疗方法，其治疗效果是基于体外清除血液中的病原体蛋白、蛋白结合的病原体物质、游离的病原体物质或病原体细胞。如果仅从无细胞的血浆中可清除病原体蛋白，则该血浆借助于膜式血浆分离器(血浆分离器)或借助于血液离心机预先将血浆从血细胞中分离。在非选择性的血浆交换(血浆分离性输血)中，将该经交换的病人血浆进行全分离，其中除病原体外还清除所有其它的生活体的蛋白。由此需用电解质、人体清蛋白或新鲜血浆取代该取出的血浆。在选择性的血浆去除方法中，借助于吸附、沉淀或过滤可完全特定的从分离的血浆中去除病原体蛋白，其中，经分离后可将该血浆基本上无体积损失地再输入。这种选择性方法的优点是可不用置换溶液。在选择性全血分离性输血方法中，无需预先的血浆分离而特定地直接从未经处理的血液中吸附该病原体蛋白，因而与血浆分离方法相反，可不进行血浆分离也不加入置换溶液。该分离性输血的另一种方式是细胞分离性输血，其中从血液中去除细胞。由此可选择性地获得白细胞、红细肥胞、凝血细胞、粒细胞或甚至干细胞。
虽然该分离性输血(如血浆分离性输血或细胞分离性输血)目前主要用于获得供体血浆(作为血浆保存，用于分离各种血浆组分或用于获得血液产品)，分离性输血方法也在治疗领域越来越具重要性。例如下列一系列的病均可用分离性输血方法治疗：代谢病(如(家族性)高胆固醇血症、伴随隔离LP(a)-增高的进育性冠状心脏病、乳糜微粒综合症、肝衰竭、...)；肾病(古德帕斯彻优质牧草综合症、伴随肾炎的全身红斑狼疮、韦格纳肉芽肿病、溶血-尿毒综合症、自发性病灶性-硬化的肾小球性肾炎、伴随病变蛋白血的综合症、冷球蛋白血饴紫癜、肾移植时的HLA-过敏、...)；神经***病(重症肌无力、Guillain-障碍-综合症、慢性脱髓鞘多根神经炎、病变蛋白血多神经病、兰伯特-伊顿-综合症、雷弗素姆-综合症、...)；免疫***病(类风湿关节炎、免疫抑制剂血友病、天疱疮、...)；血液循环和微循环病(高血粘滞性综合症、抗磷脂抗体-综合症、骨髓移植后的血栓性微血管病、与年龄相关的斑点退化、急性听力衰退、微循环末稍障害、自发性扩张心肌炎、心脏移植后的移植血管病、纯合予性家族性高胆固醇血症、病灶性节段肾小球硬化症、溶血性-尿毒综合症、...)；中毒；急性肝机能不全；肿瘤；水分过多；甲状腺中毒等(参见Pschyrembel(257版)词目“血浆分离性输血”；www.nephrologie.de/172Apharese.htm)。
阿尔茨海默氏病(AE)是一种进行性的神经障碍，目前无有效治疗。含淀粉状蛋白-β-肽的大脑噬菌斑和由微管缔合的TAU-蛋白组成的线状神经元结构通常适于该病。虽然认为淀粉状蛋白-β和TAU在病理上是相关的，但实际的研究结果似乎表明，淀粉状蛋白-β在病理上是特别重要药剂。因此治疗剂越来越受到发展，这必须防止淀粉状蛋白-β-生产、淀粉状蛋白-β聚集或由该聚集物引发的神经毒性事件。至今对AE有效果的治疗对策的综述参见Wolfe的概述文章(Nature Review Drug Discovery 1(2002)859-866。
该淀粉状蛋白-β-噬菌斑是由所谓的淀粉状蛋白-β前体蛋白(APP)形成的，该淀粉状蛋白-β前体蛋白是一种整合跨膜蛋白(其生理作用也未清楚证明，但最新研究结果认为，APP对驱动蛋白I起所谓的膜-载荷(cargo)-受体的作用)。APP通过所谓的分泌酶经蛋白水解而***，其中，在生理上主要形成40-氨基酸长的Aβ-肽(Aβ40)。其它还有形成较短和较长的Aβ形式，特别是42-氨基酸-变体(Aβ42)，其具有高的聚集能力。因此这种Aβ42-形式也是在淀粉状蛋白噬菌斑中的主要形式。分泌酶(α-分泌酶和主要是β-分泌酶和γ-分泌酶)是导致不同***的主要原因，因而也形成可能的AE治疗对策的主要目标。由此试图在治疗AE中分别使用适于这种酶的调制剂或阻止剂(如苯并二氮杂、磺酰胺、苯并已内酰胺)。
另一种与AE有关的基因是载脂蛋白E，对此存在三种等位基因变体(APOE2、APOE3和APOE4)。已表明，具有APOE4的一种或两种拷贝的人具对AE有较高的风险。由此与全体居民相比，APOE2-携带者有较低的风险。还表明，使用抑制素(statin)即抑止胆固醇生物合成的药物的人对于AE有明显低的风险。因此治疗AE的另一对策是专注于抑止胆固醇生物合成，例如用抑制素。
用于治疗AE的另一种配方涉及抑止在大脑噬菌斑中的淀粉状蛋白-聚集，这也可通过分泌酶-抑制剂而实现。另外，还可建议降低锌含量，因为呈生理相关浓度的锌可引起Aβ的聚集作用。
最后也描述了免疫对策，例如用Aβ42的免疫法，但在临床研究范围内由于较严重的副作用而必须停止(Willke，Bild der Wissenschaft，9(2003)，24-28)。
在现有技术中所建议的另一些AE-治疗对策涉及阻止APP-表达和提高Aβ-清除率，其中为APP-表达已找到可与APP-启动子区域相互作用的物质。关于Aβ-清除率曾违议提高某些蛋白酶如胰岛素分解酶和溶肾素的活性或抗-Aβ-抗体的外周应用(De Mattos et al.，PNAS 98(15)(2001)，8850-8855)。最后还企图再溶解已存在的淀粉状蛋白-噬菌斑，例如通过降低在AE-病人血清中的淀粉状蛋白-β-量来实现。在这方面还建议通过分离性输血-方法以减少在脑中β-淀粉状蛋白-蛋白的噬菌斑-淀积(US6551266，其中建议通过分离性输血去除分子量大于500kD的大分子)，但事实上未表明这适于AE。但通过分离性输血方法不可能直接在脑细胞中进行溶解已存在的-噬菌斑(血液/脑-障碍对噬菌斑或大于500kD的分子是不可杂交的)。
因此，本发明的目的在于提供一种阿尔茨海默氏病的新治疗对策和预防对策。
因此本发明提供一种分离性输血-设备，该设备包含可与血流或血浆流相接触的固体载体，该载体是一种连接淀粉状蛋白-β-前体-蛋白(APP)的受体。在AE-病人或有AE-风险的人情况下，用现有的分离性输血-设备可通过分离性输血按需清除APP或APP-分解产物，特别是Aβ40或Aβ42。已知在中枢神经***(ZNS)和血浆之间存在Aβ42的动态平衡。鼠模型表明(DeMattos PNAS 2001，见上)，抗-Aβ-抗体的外周应用影响ZNS和血浆Aβ42清除，并减少Aβ42在脑中的负荷，没有克服血液-脑-障碍的抗-Aβ-抗体。这些结果由Matsuoka等人(Journal of Neuroscience 2003：29-33)通过另一些Aβ42连接分子(凝溶胶蛋白和GM1)的外周应用所证实。因此在脑中形成噬菌斑的过程也可通过在血液中捕获Aβ42来阻止。由此在与病人的血液或血浆接触的分离性输血-设备中受体对Aβ42或APP的其它分解形式是否是特异性并不关键，重要的通过该特异性吸附从血液中去除APP和其(蛋白水解)降解产物，特别是Aβ42，以致不会导致“错误的”蛋白降解(即降解为Aβ42)。因此本发明是基于与US 6551266完全不同的分离性输血的应用方法，即基于消除潜在的噬菌斑-结构成分，而不是噬菌斑本身。通常用分离性输血消除噬菌斑在一开始是因对AE-治疗无效而排除在外，因为血液-分离性输血甚至不能达到脑中形成噬菌斑的区域。
另一方面，与导致体内本身减少Aβ的方法(如在De Mattos et al.，PNAS 98(15)(2001)，8850-8855中采外周抗-Aβ-抗体)相比，本发明的分离性输血具有的重大优点在于，可不引发自身免疫应答。此外，本发明也不必给病人施加在体内本身可起作用的物质(将这些物质输入在某些部位后也许才起作用)，而是将病原剂有目的去除，也就是特异性地体外隔断病因，同时无需清除体内反应产物。
在所有实施形式中已有的和已知的分离性输血-设备均易于适用于本发明。特别是在选择固体载体(和分离性输血设备)时应考虑其医学技术的适用性。这类载体、方法或设备特别是描述于WO 97/48483A、US 5476715、6036614、5817528或6551266中。相应的市售分离性输血-装置也可由下列公司销售：Fresenius、Affina、Plasmaselet、ASAHI、Kaneka、Braun等，如LDL-Therasorb、Immunosorba、Prosorba、Globaffin、Ig-Therasorb、Immusorba、Liposorba、HELP、DALI、Bilirubin-Gallensaeure-Absorber BR-350、PrometheusEntgiftung、MARS、ADAsorb-System von Medicap或Plasma FLO-System。所有这些***尽管在市售形式上不总是针对各个蛋白的特定清除，但可由分离性输血专业人员将其顺利地适配于本发明，如作为免疫分离性输血和/或在分离性输血-仪器中安装本发明的固体载体(如柱)。
术语“APP-结合受体”按本发明也意指所有的对配体APP和其生物副产物特别是Aβ42具有亲合力并能从AE-病人或有AE风险的病人的血液或血浆中去除这些多肽的物质。该APP-受体或Aβ42-受体分别可优选是(多克隆或单克隆的)抗体、蛋白、肽、神经节苷脂或核酸。
特别优选是抗-APP-抗体、抗-Aβ40-抗体或抗-Aβ42-抗休、APP-结合蛋白，特别是凝溶胶蛋白、apoJ或apoE、APP-结合肽、APP-结合神经节苷脂，特别是GM1或APP结合的核酸，特别是适体(Aptamere)或这些受体的混合物。
例如这类抗体是3D6(Aβ1-5)、2H3(Aβ1-12)、2G3(Aβ33-40)、21F12(Aβ33-42)、12H7(Aβ33-42)(Johnson-Wood等人，PNAS 1997：1550-1555)、10D5、16C11(Bard等人，Nature Medicine 2000：916-919)、De Mattos等人。(2001)所描述的抗体(m266，m243)以及同样特性的抗体。例如以含APP、Aβ42或片段或其变体的疫苗配剂对哺乳动物进行免疫过程中可得到这类抗体，任选地接着进行细胞融合和克隆选择性方案(在单克隆抗体情况下实现)。
凝溶胶蛋白(Matsuoka et al 2003，见上)、apoJ或apoE(De Mattoset al 2001，见上)是APP-结合蛋白受体的另一些实例。GM1是APP-结合神经节苷脂-受体的一种实例(Matsuoka et al 2003，见上)。
APP-结合蛋白的另一些实例是CETP(胆固醇基-酯-转移蛋白)和ERAB-蛋白(261 AS gross；He等人，JBC 273(17)(1998)，10741-10746；Lustbader等人，Science 304(2004)，448-452；特别是AS 1-186或1-158)。APP-结合肽的实例是是由APP-结合肽衍生的APP-结合片段。APP-结合肽的具体实例是KTYNLKKGQT-C(“肽4077”)、GIAVASKTYNLKKGQTHTLEDFQRVLDV(ERAB 93-120)、SKTYNLKKGQTHT(ERAB98-110)、C-HQKLVFFAED(“肽1323”)、C-EVHHQKLVFFAEDVGS(“肽1324”)、C-HQKIVFFAED(“肽1325”)和FGFPEHLLVDFLQSLS-C(“肽1208”)(也可是所有其它ERAB、CETP或β-断裂子(breaker)片段，其各含有APP-结合区域)(在这类肽情况下，该终端半胱氨酸不是天然蛋白序列的一部分，而是仅仅附上偶合的肽)。
作为APP-结合受体的肽可由D-氨基酸或L-氨基酸或D-氨基酸和L-氨基酸的组合组成，并还可任选地通过其它改性、闭环或衍生而改变。适于如Aβ42的肽受体可由肽-文库查得，这些文库可从市售购到。这种肽的氨基酸长度宜至少为5，优选为6，特别是至少8个氨基酸，有利的长度可达11，优选达14或20个氨基酸。但本发明也可顺利地使用更长的肽作为APP-结合肽。此外低聚物(如聚乙烯亚胺和多赖氨酸)也可作为受体。
为制备这类APP-结合受体，当然也可例如借助于组合化学产生的噬菌体-文库、肽-文库或借助于适于大多数各种结构的高产率的筛选技术(见例如在噬菌体展示中：Carlos F.Barbas(Editor)等人的A Laboratory Manual；WillateWG，噬菌体展示：practicalities and prospects.Plant Mol Biol.2002Dec；50(6)：837-54；http：//www.microcollections.de/showpublications.php#)。除基于随机的噬菌体文库外，核蛋白体展示或细菌展示的文库也是适用的。用于其增殖的相应文库和方法是专业人员解已知的，并描述于US2004/0110281A、WO 00/72880A和WO 02/059148A中。
此外，也可应用基于核酸(“适体”；也是”Decoy”-寡脱氧核苷酸(ds寡核苷酸，其从序列显示适于转录因子的结合位点))，这些也可用大多数不同的(寡核苷酸-)文库(如用2-180核酸基)找到(如Burgstaller等人，Curr.Opin.Drug Discov.Dev.5(5)(2002)，690-700；Famulok等人，Acc.Chem.Res.33(2000)，591-599；Mayer等人，PNAS 98(2001)，4961-4965，及许多其它的)。该核酸主链例如可通过天然磷二酯-化合物也可通过硫代磷酸酯或组合或化学变异(如作为PNA)而找到，作为基质本发明首先可应用U、T、A、C、G、H和mC。本发明应用的核苷酸的2’-残基优选是H、OH、F、Cl、NH2、O-甲基、O-乙基、O-丙基或O-丁基，该核酸还可另外改性，例如为其提供如通常在寡核苷酸合成中应用的保护基。因此App-结合的适体也优选是在本发明范围中的App-结合亲合性分子。
适于APP的适体例如可用下述方法找到。使固定的APP(或上述形式的另一种)与由核酸组成的混合物接触，使高亲合结合的核酸与低亲合结合的或完全不结合的核酸分离。在与核酸混合时，通常涉及以组合化学制备的核酸文库。核酸文库包含各种各样相互不同的核酸，其中至少在部分序列范围内建立无规化(含天然的和/或-非天然的核酸)。这可能但非必须提供保持的序列范围。在n个位置中以m个不同核苷酸的无规化导致有nm个成分的文库。
APP-特异性亲合性核酸的发现由下列步骤进行。a)在柱(里面)加载APP(等)，并将APP(等)固定在柱中，b)将核酸混合物加到该柱的第一端，通过该柱，载体物质的确定体积流从柱的第一端流到柱第二端，c)该核酸随其对APP(等)的亲合力的下降以增加离柱第一端的间距进行结合和固定，d)载体物质体积的流流经柱经确定流过时间后结束，e)该柱经多次分配分成柱片段，对每一段均指定流径配位，f)由至少一片段可非特异地解吸出固定的核酸，并通过有关各段指定的流径的配位次序而得到。该柱的内侧通常意指腔的内部。该柱应可包含各类固体载体***，如也可以是不完全包封的载体***。
APP(等)固定可按通常的柱色谱法进行。作为柱可以是带有两端的腔型的各种机械结构。作为结构材料可使用所有适于柱的材料，如金属、玻璃和/或塑料。该柱可在其内侧装有与APP(等)相结合的基质和/或该结构材料可适于直接结合或可制备用于直接结合目标分子。核酸混合物是指，通常有106-1022/Mol，将别是1010-1021/Mol的相互不同的核酸种类的核酸文库。在施加到柱上的文库中，每一核酸种类从统计看代表例如存在10-1017，特别是100-1013个分子。载体物质通常是核酸在其中是溶解并稳定的液体。对此可用所有适于核酸文库的常用的缓冲剂和类似物。载体物质的体积流可在施加核酸文库前调节。然后将该核酸文库从柱的入口端加到载体物质流中。但该核酸文库也可直接加入。经由柱的结构和所调节的体积流所确定的流经时间后，在柱的出口端再次出现通过核酸文库产生的“栓塞”(通过有扩散的折合而扩展)，其中由“栓塞”分离的结合核酸并固定于柱中。宜将流过柱的体积流调节呈少扰动的或非扰动性的层流(经柱体积，特别是经柱横截面的载体物质的加速矢量的总和是最小，理想为零)。在柱中的APP-分子总数通常为在施加的核酸文库中各类核酸分子数的102-1016倍，特别是103-1015倍。核酸在APP-分子上的结合优选在分离性输血情况下在较晚使用核酸的条件下进行，例如在以温度、离子强度、pH-值和缓冲条件所相应确定的合适的缓冲剂中进行。然后依其有关成分选择载体物质和该核酸文库的溶剂。例如可通过将柱切割成段而实现将该柱分成多个柱段，该切割宜与体积流矢量成正交进行。但该柱也可预先由多个柱段组成，其中，一个柱段宜以体积流矢量方向紧密联接下一个柱段(组装横截面正交于体积流矢量)。然后通过解脱预先由柱段形成的复合体而实施分离。该非特异性的解吸可通过含足够强的配位体的淋洗以物化或热的方式对APP的排挤、络合、改性和/或破坏而实现。也可用机械法如超声法来解吸或强化解吸。也可应用上述各种解吸方法的组合、当然，该核酸不可因所用的解吸方法而分解。
上述步骤是基于发现，核酸文库类似于蛋白混合物可借助于亲合色谱法按对目的分子即这里的APP(等)的亲合力的大小在空间分离。本发明还基于发现，可通过避免因非特异性解吸产生的不同亲合力的解吸的核酸的混合，其中，在非特异性解吸之前将其中含有结合的核酸的柱按所说的分割成亲合性段，并在如此所得的亲合性段或柱段中结合的核酸可在如PCR或RT-PCR范围内容易地和没有干扰的配位-耦合非特异性地解吸和非特异性扩增。其后避免选择假象。同样，也不需要用于解吸的配位体，特别是高浓度的配位体。最后实际上使所有结合的和其后解吸的核酸分子适于扩增。这就使其可以以小的核酸浓度进行操作。这原则上是足够的，只要在核酸文库中每个类型的分子均以统计平均值存在。如果在柱段中该APP-分子的数目从统计学看是1，则甚至可按其对目标分子的亲合力分离各个核酸类型。
该方法的主要优点将在下面阐明。按亲合力分离核酸导致在柱段中的核酸有不同的特异性(不同的APP区通过APP亲合性核酸而结合或是适于APP-亲合性核酸的结合位点)情况下具有类似的亲合力。
原则上只要分配有所需亲合力的段(分离)其是经再处理而解吸。但对此有一个先决条件，在所施加的核酸文库中要有亲合力分配除了在最大亲合力的情况下其中关系到体积流矢量再进行第一柱段。因此通常优选是，由各段的固定的核酸进行分别解吸和回收，具有各段对从中回收的核酸的流径相配位的各个定位。
原则上任何的解吸均是可能的。优选是借助于通常的物化或热方法进行该非特异性解吸。热解吸是通过加热该柱段或其中所含的溶液来实现。该加热例如可通过电加热或微波辐射或IR进行。来自PCR工艺的加热技求是特别适用的、除了藉助于聚合酶的分别扩增核酸或适体外，当然也可应用其它的扩增方法如藉助于连接酶。该非特异性解吸可通过APP-的化学改性增强，如通过高碘酸钠或类似物的氧化，或通过形成非特异性络合物如藉助于硼酸盐或类似物以在烃中封端顺式-反式二醇键。
因此如果该非特异性解吸以热解吸进行则优选在延长的PCR或RT-PCR的高温期中进行是有利的。这时可达到协同效应，因为通常，特别是在用含低浓度核酸种类的核酸文库工作时扩增总是需要的。为提高产率，例如可使用5-60，优选20-60，最优选45-55个循环。在该扩增范围内，可使用至少一个标记的引物。该引可具有至少一个内切核酸酶切割位点。这种切割点例如用于排除引物序列的较大范围的放大物质。核苷酸结构组，如是在引物中或在待选择的核酸情况下例如可通过荧光颜料进行标记。作为荧光颜料例如可提及：Alexa TM氟488、氟532、氟546、氟568、氟594、俄勒岗绿488、荧光黄、若丹明6G、四甲基若丹明、若丹明B和得克萨斯红。该扩增材料也可通过在不同端部的不同化学改性来标记，只要在改性时引入的基团合适作为配位体结合在不同的亲合性基体上。
为可靠的分离非-亲合的或低亲合的核酸，建议在适用的工艺阶段之间引入洗涤工艺步骤。如果在方法步骤d)和e)之间进行至少一次洗涤工艺步骤是特别有利的。用于洗涤例如溶剂或该核酸文库的介质或该载体物质都是适用的。
优选的是，该柱子内侧用APP(等)涂层并且其固定是通过共价键，优选在用化学高反应性基(如Tresylchlorid、溴化氰和/或高碘酸盐)活化后或以化学小反应基(如氨基、羟基、酮基和/或羧基)改性后通过双官能的间隔基键进行。例如适于间隔基键的间隔主链是：取代的和未取代的C2-C10烷基、取代的和未取代的C2-C10链烯基、取代的和未取代的C2-C10炔基、取代的和未取代的C4-C7碳环烷基、取代的和未取代的C4-C7碳环链烯基、取代的和未取代的C7-C14芳烷基、含选自氮、氧、硫的杂原子的杂环分子，其中上述的取代可由下列组成：烷基、链烯基、炔基、烷氧基、硫醇基、硫烷氧基、羟基、芳基、苄基、苯基、硝基、卤素、含2-10碳原子和1-4氧原子或硫原子的醚基、聚烷基二醇、卤素、羟基、硫醇基、酮基、羧基、酰胺、醚化合物、硫醚、Arnidine衍生物、胍衍生物、谷氨酰衍生物、硝酸根(ONO2)、硝基(NO2)、腈、三氟甲基(-CF3)、三氟甲氧基(-OCF3)、O-烷基、S-烷基、NH-烷基、N-二烷基、O-芳烷基、S-芳烷基、NH-芳烷基、氨基、叠氮基(N3)、肼基(NHNH2)、羟氨基(ONH2)、亚砜(SO)、砜(SO2)、硫化物(S-)、二硫化物(S-S)、甲硅烷基。通常间隔基键是二官能的，其中官能度可相同或不同，并且例如可选自由“N-羟基琥珀酰亚胺和酰肼”构成的基。
为减少从柱段所得核酸内的可变性，优选每个柱段按统计平均值计含0.1-103，优选1-102，最优选1-10个APP(等)-分子。与此相关，如施加的核酸文库按统计平均值计可含0.1-103，优选1-102，最优选1-10个的一种种类的核酸分子。
对柱的结构材料，可使用基本上所有例如由亲合性色谱术已知的材料。其中，硅胶或聚合物制成的柱，如经化学衍生化而活化或等离子体活化后的聚乙烯。柱段的长度宜为0.1μm-1mm，优选0.1-100μm，最优选0.5-10μm。这种段片如用显微切片机(Mikrotoms)易于制备。柱内径宜为0.05-1mm，优选0.1-0.5mm，最优选0.2-0.4mm。
在核酸实际分离(结合或机械分离)前清除不希望的核酸是适宜的。不希望的核酸例如是结合在不含APP的柱内表面上的核酸。然后不含APP的柱可进行预接，并且该核酸文库预先通过该柱。
在前述的工艺方式中，可连续地即如通过连续连接的柱子运行，或间断地即如通过间歇收集来自前柱的洗脱液来运行。
为进一步改进亲合性分离，原则上可以不同的方式操作。如对从一个柱段或多个柱段解吸的核酸，需要时经扩增后重复进行本发明方法，和/或可提高在解吸时的洗脱条件(温度、离子强度、pH-值、缓冲条件)、另外可减少柱段中APP的体密度和由比该结合的核酸的体密度，即APP-分子的数目。
APP-结合的适体(按本发明上述定义的也包括Aβ42结合的适体)也是本发明中优选的APP结合受体。
因此本发明中将优选由肽、抗体或核酸组成的APP-结合受体在合适的载体材料上以用于体外清除阿尔茨海默氏-(风险)病人的APP和其蛋白水解的降解产物。
在医学例行实践中应用本发明时，必要的是该载体是无菌的和不致热的，以致满足这些必要特征的任何载体物质或任何受体-/载体-组合物按本发明都是优选的(参见如US 6030614或US 5476715)。该合适的实例有多孔均聚物、含乙烯单体的共聚物或三聚物(例如丙烯酸，如TSK Toyopearl、Fractogel TSK)、用含环氧乙烷化合物(如表氯醇)和需要时含其它与NH3、氨基或羧基反应的化合物改性的载体，或CNBr-吸附剂或CNCL-吸附剂，如在EP 110409A和DE 3617672A中所述。适用于治疗目的特别优选的吸附材料是适宜的以防止血细胞损失、不活化或仅稍微活化该辅助***和尽可能阻止体外循环中的聚集形成。此外，所用的载体材料优选是在耦合到受体时的材料对消毒措施应是足够稳定的，特别是耐环氧乙烷-饱和、耐戊二醛-饱和、耐γ-辐照、耐蒸汽处理、耐UV-处理、耐溶剂处理和/或耐洗涤剂处理等。例如也可应用基于琼脂糖凝胶、琼脂糖、丙烯酰基、乙烯基、葡聚糖等的产品，其优选具有用于结合市售可得的APP-结合受体的合适的官能基。其它合适的载体还包括整块料(基于横向交联的甲基丙烯酸缩水甘油酯-共-乙二醇二甲基丙烯酸酯-聚合物的载体)(Poschalko et al.，J AmChem Soc.2003 Nov 5；125(44)：13415-26)。
为在合适的载体上耦合受体，本专业人员可利用已知的化学资料(如Bioconjugate Techniques，Greg T Hermanson，Ed.，Academic Press，Inc，San Diege，CA，1995，758pp)。
另一方面，本发明还涉及本发明设备的应用其提供阿尔茨海默氏病的治疗或治疗设备或在用于预防这类病中，其中安排适合针对各个病人治疗的设备。在进行治疗时，使病人与分离性输血-装置相连以足够长的时间以有效清除APP-多肽，这时病人的血液流或血浆流与含APP-结合受体的固体载体相接触，APP和/或APP蛋白水解降解产物，特别是Aβ42被结合在该受体上。在分离性输血-治疗过程中当然要确保外周的或中枢静脉的静脉入口或动静脉的瘘管，如足够的抗凝作用，以及记录下所需的定量数据和测量数据。此外，在大部分分离性输血-方法中在实际血浆处理之前需要血浆和血液细胞的主-分离。需要预防措施的特殊人是有家族病史的人、老年人(＞50、＞60或＞70岁)或具有对AE有另外风险因子，特别是遗传因子的人。
依下列实施例和附图对本发明作详细阐明，当然本发明并不受限于这些实施例。
附图简介
图1表示Aβ42在肽1208上的结合(耦合在BSA上和涂于ELISA板上)；
图2表示肽1208(和1208-BSA)在Aβ42上的结合(涂在ELISA板上)；
图3表示Aβ42在肽1208-BSA上的竞争性结合。
实施例
1.载带APP-受体的载体的制备
1.1整柱
按制造商的说明，将CIMEpoxy整柱(BIA分离，ST)用pH-值为8.0的0.5M的Na-磷酸盐-缓冲液平衡，并也按按制造商的说明活化抗Aβ肽的单克隆抗体和将其耦合到CIM-柱上。用磷酸盐-缓冲液洗涤该柱多次(+1MNaCl)，并需要时中断多余的环氧-基。
通过检测洗涤流出液和平衡流出液来保证质量；只有在流出液中无活性环氧-基和无抗体-泄漏的柱子才可继续应用，并安装到分离性输血-装置中。
1.2琼脂糖凝胶-柱
将琼脂糖疏松材料(琼脂糖CL4B)以无菌方式装入无菌和无致热的容器中，并以无菌方式洗涤该材料，在每次洗涤步骤间于真空下完全干燥该凝胶材料。接着在压热釜中于115℃蒸汽消毒琼脂糖凝胶30分钟。
消毒后，将该琼脂糖凝胶放入60％丙酮/水的消毒容器中，并用CNBr和三乙胺活化(14g CNBr/96ml丙酮；30ml三乙胺于66.2ml的87％的丙酮中)。然后加入丙酮/HCl-溶液(392ml消毒的无致热的水；16.3ml的5N HCl，408ml丙酮)。洗涤经活化的琼脂糖凝胶，并在2小时内进行耦合反应，以阻止经活化基团的水解。
将经消毒过滤的抗体-溶液分别为(m226或m243)引入反应容器，并搅拌至少90分钟。最后对该反应溶液进行充分洗涤(用等渗磷酸盐-缓冲液)，直到在流出液中没有反应产物可检出，并将经抗体耦合的琼脂糖凝胶充填入消毒的和无致热的以玻璃烧结制的玻璃柱中和经受最终的质量检测(有关反应产物的洗出液、重金属等的分析；颗粒分析；致热性；无菌性)。
2.适于阿尔茨海默氏-病人的分离性输血-治疗的动物模型
“Gerhardt Katsch”糖尿病研究所研制了一种用于对小动物摸型鼠进行分离性输血-治疗的微型体外***。这种分离性输血-试验***在世界上仅在有非常有限的范围内可以得到。在相同实验动物中的重复分离性输血-治疗和接着在后续观察期中用于判断治疗结果的检查具有十分新颖性，并在国际文献上至今未描述过。
该分离性输血是一种替代治疗方法，其中，致病物质是在体外从血中去除。在人类医学中，该分离性输血至今是用于治疗多于100种的病。藉助于分离性输血，相关疾病的物质可从血液中完全或至少部分去除，特别是自身免疫病如类风湿性关节炎、重症肌无力、内分泌眼病、多发性硬化、***性红斑狼疮、僵硬-人综合症和I型糖尿病。但至今该分离性输血仅作为替代方法用于治疗一种涉及感染病人有强烈负担和明显降低生活质量的慢性的耐药性病症。其主要原因是至今对有成效的分离性输血-治疗的作用机理还缺乏详细了解。
通过应用已知的如适于1型糖尿病和类风湿性关节炎的动物模型可进一步阐明分离性输血-方法作用的机理以及以临床前检验该分离性输血-治疗的新型适应症。为实施分离性输血-治疗，首先要提供配有慢性血管导管的实验动物。接着在体外循环中，该血液的血浆和细胞成分经血浆过滤器分离。该细胞成分立即返回到动物体中，而该血浆在返回前可通过各种吸附方法(免疫吸附等)进行净化。这种重复性的分离性输血-治疗的良好耐受性在不同鼠的种系已取得证实(体重、血细胞比容、一般状态)。该分离性输血-试验***用最小重量为250g的动物体已进行试验，并在鼠-模型上用于自身免疫病(1型糖尿病、胶原蛋白II型诱发的关节炎)。
用于小型动物模型的血浆分离性输血的体外***可适用于各类吸附。这种试验***在慢性病摸型上的应用可用于(A)新型的治疗对策和预防对策的试验，(B)说明各种分离性输血-技术的作用机理和(C)确定各分离性输血-治疗方法的适应症。在新研制的分离性输血-方法的临床前试验中，该IDK是其竞争对手，其非常有利于该新型治疗方法从研发阶段经动物试验验证到病人临床应用的过渡和进入市场(http：//www.praeklinik.de/)。
在实验性分离性输血-治疗开始之前给该动物插接动脉导管和静脉导管，或使用带慢性插有导管的鼠(适用于施加试验物质和适用于取血样以及适用于在动物模型中实施分离性输血-治疗和固定检验)。在分离性输血中首先在第一步中通过血浆过滤器分离血细胞和血浆。该血细胞立即输回到动物体内(经静脉导管)，而该分离的血浆在返回动物体内之前通过实施例1中所制备的吸附装置(这时该配位体通过结合到固定的亲合性肽上而从该血浆中分离)。
3.Aβ42-适体
3.1硅胶柱经Tresylchlorid的活化
该柱经丙酮冲洗。将无水溶液(2ml丙酮、1ml Tresylchlorid、几滴吡啶)通过该柱以进行活化(10倍柱体积)，该柱在冰上培育过夜。接着用20倍柱体积的100％的丙酮(无水)淋洗该柱。该经活化的柱在1mM HCl中保存。
3.2聚乙烯柱的活化
于室温下将聚乙烯管用20倍柱体积的溶液(在浓硫酸(H2SO4)中的2％高锰酸钾(KmnO4)(w/v))淋洗，并接着用蒸馏水淋洗。为继续耦合该柱表面，应用二价分子或多价分子以交联，该分子具有至少一个反应性醛基(如1％的戊二醛)。将此在4℃下通过该柱1小时。接着通过还原性条件(如通过氰基硼氢化钠(在0.15M NaCl中的0.00025％w/v，pH3.9))稳定该反应。
3.3Aβ42在经活化的硅胶柱上的耦合
经Tresylchlorid活化的柱用0.1M Na2CO3(pH8.5)淋洗。将肽或蛋白(2mg/ml的0.1M Na2CO3，pH8,5)的溶液在37℃下多次通过该柱2小时以进行耦合，并接着在冰上放置4小时。为封端该柱的游离结合位点，接着使过量的0.2M甘氨酸(pH8)通过该柱。
3.4糖蛋白耦合到活化的聚乙烯柱上
经活化的柱用0.1m Na2CO3(pH8.5)淋洗。用于耦合，将Aβ42(2mg/ml的0.1m Na2CO3，pH8.5)在37℃下多次通过该柱2小时，并接着在冰上放置4小时。为封端该柱的游离结合位点，接着使过量的0.2M甘氨酸，pH8通过该柱。为改进反应可加入1-乙-基3-(3-二甲基氨丙基)碳化二亚胺(EDC)，5％w/v。
3.5制备用于清除不需要的分子的柱
经Tresylchlorid活化的柱用0.1M Na2CO3(pH8.5)淋洗。如果清除是针对具有一个或多个伯胺或仲胺的分子，则使该分子或混合物(2mg/ml的0.1M Na2CO3，pH8.5)在室温下多次通过该柱过夜。为封端该柱的游离的结合位点，接着使一种过量的0.2M甘氨酸(pH8)通过该柱。如果不清除一个或多个伯胺或仲胺的分子，则该柱的所有结合位点均用甘氨酸封端。
在下列文献中可以找到另外的派生方法：Patterson，W.J.，NationalAeronautics and Space Administration，Technical Memorandum，NASATMX-73311，U.S.Government Printing Office，Washington，D.C.，1976；Ma，S.M.，Gregonis，D.E.，von Wagenen，R.A.，and Andrade，J.D.，in“Hydrogels for Medical and Related Applications”(J.D.Andrade，Ed.)，Amer.Chem.Soc.Symp.Series，Vol.31，p.241，1976；Harris，J.M.，Struck，E.C.，Case，M.G.，Paley，M.S.，Van Alstine，J.M.，and Brooks，D.E.，J.Polymer Sci.，Polymer Chem.Ed.，22，341(1984)；Regnier and Noel，Regnier，F.E.，and Noel，R.J.，J.Chromatog.Sci.，14，(1976)；Yalpani，M.and Brooke，D.E.，J.Polymer Sci.，PolymerChem.Ed.，23，395(1985)。
3.6实施核酸在Aβ42上的接触和柱分离
所述涂层柱无泄漏地进行串接，首先是用于清除不需要的分子的柱，接着是Aβ42-柱。为了平衡，将合适的缓冲剂，如缓冲溶液(10mM Tris-HCl、50mM KCl、1.5mM MgCl2和明胶0.001％(w/v)，pH8.3)在冰上通过该柱1小时。该组合核酸文库的核酸放置在1ml的相同缓冲剂中并在95℃下加热10分钟以进行熔融双链，并接着以多倍(4-30倍)柱体积通过该柱。然后将该柱分离，并在冰上用所选的缓冲剂(见上)洗涤过夜。用合适的切割工具以物流方向分离。
4.Aβ42在肽1208(FGFPEHLLVDFLQSLS-C)上的结合研究
为分析淀粉状蛋白-β在肽1208上的结合，首先将肽耦合在载体蛋白(BSA)上，该肽浓度为500μMol(约1mg/ml)。将1208-BSA共轭物结合到ELISA板上，这时每孔结合100ng肽。该ELISA板用PBS，1％BSA饱和，接着在8-1000ng/孔的浓度范围内分析淀粉状蛋白-β(1-42)的结合。结合的淀粉状蛋白-β用特异性的鼠抗体检测。最后，借助于生物素化的抗-鼠抗体和链霉抗生素耦合的过氧化酶进行定量测定结合的淀粉状蛋白-β的量。使用ABTS作为基质，并在405nm波长下在ELISA-读出器上进行分析。(图1)
为分析肽1208的结合，将淀粉状蛋白-β(1-42)结合在ELISA板上(500ng/孔)。接着，该ELISA板用PBS，1％BSA饱和，然后分别加入游离肽1208或1208-BSA共轭物(1.6-50ng)。结合的肽用特异性单克隆抗体检测。使用生物素化的抗-鼠抗体和链霉抗生素耦合的过氧化酶进行最后定量测定。使用ABTS作为基质，并在405nm波长下在ELISA-读出器上进行分析。(图2)
将1208-BSA共轭物结合在ELISA板上(100mg肽/孔)，并用PBS，1％BSA饱和该板。接着在有游离肽1208或对照肽(浓度为30-2000ng/ml)存在下分析淀粉状蛋白-β(1-42)的结合。该结合的淀粉状蛋白-β的检测按所述进行。(图3)
Claims (4)
1.一种分离性输血-设备，该设备包含一种可与血流或血浆流相接触的固体载体，其特征在于，该固体载体是一种淀粉状蛋白-β-前体-蛋白(APP)-结合受体。
2.权利要求1的设备，其特征在于，该APP-结合受体选自抗-APP-抗体、抗-Aβ40-抗体、抗-Aβ42-抗体、APP结合蛋白，特别是凝胶溶蛋白、apoJ或apoE、APP结合肽、APP结合的神经节苷脂，特别是GM1或APP-结合核酸，特别是适体或这些受体的混合物。
3.权利要求1或2的设备，其特征在于，该载体是一种无菌的和无致热的柱。
4.权利要求1-3中任一设备的应用，其提供用于治疗阿尔茨海默氏病或用于预防该病。
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| US20070010435A1 (en) | 2002-12-19 | 2007-01-11 | New York University | Method for treating amyloid disease |
| AT500483B1 (de) * | 2004-07-13 | 2006-01-15 | Mattner Frank Dr | Set zur vorbeugung oder behandlung der alzheimer'schen erkrankung |
| AT501621A1 (de) * | 2005-03-15 | 2006-10-15 | Mattner Frank Dr | Zusammensetzungen zur verwendung bei der vorbeugung und behandlung der alzheimer- erkrankung |
| ES2332846B1 (es) * | 2007-10-26 | 2010-07-08 | Grifols, S.A. | Utilizacion de albumina humana terapeutica para la preparacion de un medicamento para el tratamiento de pacientes afectados por desordenes cognitivos. |
| WO2009082515A1 (en) * | 2007-12-21 | 2009-07-02 | Ge Healthcare Bio-Sciences Ab | Method for sterilization of chemically activated solid support materials |
| US20100030196A1 (en) * | 2008-07-29 | 2010-02-04 | Medtronic, Inc. | Apheresis of a target molecule from cerebrospinal fluid |
| US20100158893A1 (en) * | 2008-12-19 | 2010-06-24 | Baxter International Inc. | Systems and methods for obtaining immunoglobulin from blood |
| CN104274875A (zh) * | 2008-12-22 | 2015-01-14 | 学校法人藤田学园 | Aβ 除去材料、Aβ 除去器和Aβ 除去*** |
| US20110033463A1 (en) * | 2009-08-06 | 2011-02-10 | Medtronic, Inc. | Apheresis, administration of agent, or combination thereof |
| EP2497828A1 (en) * | 2011-03-07 | 2012-09-12 | Charité - Universitätsmedizin Berlin | Use of aptamers in therapy and/or diagnosis of autoimmune diseases |
| PL2579042T3 (pl) | 2011-10-04 | 2014-12-31 | Affiris Ag | Sposób wykrywania przeciwciał swoistych wobec Aß w próbce biologicznej |
| US9717841B2 (en) | 2012-09-11 | 2017-08-01 | Gary L. McNeil | Closed-circuit device and methods for isolation, modification, and re-administration of specific constituents from a biological fluid source |
| WO2016005545A1 (en) | 2014-07-10 | 2016-01-14 | Affiris Ag | Substances and methods for the use in prevention and/or treatment in huntington's disease |
| GB201904810D0 (en) | 2019-04-05 | 2019-05-22 | Cynapsedx Ltd | The treatment of protein aggregation diseases |
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| JPS57103649A (en) * | 1980-12-18 | 1982-06-28 | Asahi Chemical Ind | Sterilized gamma-globulin fixing column |
| WO1987001597A1 (fr) | 1985-09-19 | 1987-04-26 | Toray Industries, Inc. | COLONNE D'EXTRACTION DE beta2-MICROGLOBULINE |
| EP0476721B1 (en) * | 1987-11-20 | 1995-03-01 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | A method for removing serum amyloid protein |
| US5216127A (en) * | 1987-11-20 | 1993-06-01 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Adsorbent for serum amyloid protein |
| JPH01171638A (ja) * | 1987-12-25 | 1989-07-06 | Kanegafuchi Chem Ind Co Ltd | 血清アミロイドａ蛋白用吸着体 |
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| JPH06104122A (ja) | 1992-09-21 | 1994-04-15 | Matsushita Electric Ind Co Ltd | ロータリートランス |
| DE69534187T2 (de) | 1994-05-13 | 2005-11-17 | Miltenyi Biotec Gmbh | Sterile und pyrogenfreie säulen, gekoppelt mit einem protein, zum binden und entfernen von substanzen aus dem blut |
| DE19515554C2 (de) * | 1995-04-27 | 1999-06-17 | Braun Melsungen Ag | Verwendung eines Mittels und Vorrichtung zur simultanen extrakorporalen Elimination von Tumor-Nekrose-Faktor alpha und bakteriellen Lipopolysacchariden aus Vollblut oder/und Blutplasma |
| US5868936A (en) * | 1996-06-20 | 1999-02-09 | Baxter International Inc. | Affinity membrane system and method of using same |
| US6787523B1 (en) * | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
| DE60106394T3 (de) * | 2000-02-24 | 2013-07-25 | Washington University St. Louis | Humanisierte antikörper, die amyloid beta peptid sequestrieren |
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| US20050227941A1 (en) * | 2001-12-17 | 2005-10-13 | Karen Duff | Sequestration of ass in the periphery in the absence of immunomodulating agent as a therapeutic approach for the treatment or prevention of beta-amyloid related diseases |
| US20070010435A1 (en) * | 2002-12-19 | 2007-01-11 | New York University | Method for treating amyloid disease |
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