CN101279242A - 用于抗体清除的血液净化吸附剂 - Google Patents
用于抗体清除的血液净化吸附剂 Download PDFInfo
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Abstract
一种用于抗体清除的血液净化吸附剂,属于生物医学技术领域。它由固相载体材料和通过化学偶联固定在载体上的配基两部分构成,配基的分子结构如上,其中A,B,C中有一个原子为N,其它为C;n为0-2。该血液净化吸附剂能够高载量地吸附血浆中的抗体组分以及类风湿因子、抗核抗体等自身抗体,对血清白蛋白等其它血浆组分非特异性吸附有限,而且制备成本低、物理化学性质稳定。此材料可作为血液净化装置的吸附填料用于血浆中自身抗体和免疫复合物的清除。
Description
技术领域
本发明涉及一种用于抗体清除的血液净化吸附剂,属于生物医学技术领域。
背景技术
自身抗体和免疫复合物已被证实与一系列疾病的产生和发展密切相关,如免疫反应(过敏,移植排斥)、自身免疫性疾病(系统性红斑狼疮,类风湿等),甚至于癌症。因此,临床上需要一种能够从人血液中选择性地清除自身抗体和循环免疫复合物的吸附剂,以缓解急性症状,遏制病情发展进而对疾病起到治疗作用。随着此类疾病尤其是自身免疫性疾病发病率的逐年提高,这种需求也越来越大。基于上述考虑,目前已有多家机构开发出不同性质的吸附剂材料,其中一些已经应用到临床。
应用于血液净化的吸附剂一般由两部分组成:作为吸附剂基质的高分子载体材料和利用化学交联固定在载体表面的配基分子,其中配基分子的结构和性质决定了吸附剂的作用效果。目前,临床中主要采用的两种用于抗体吸附的血液净化吸附剂分别以蛋白A和疏水氨基酸作为配基分子。
蛋白A是某些金黄色葡萄球菌细胞壁的一种蛋白组分,它对人类和其他哺乳动物的多种免疫球蛋白具有可逆的亲和作用,特别是对免疫球蛋白G(IgG)的Fc区具有较强的结合能力。同时,Phillips等人也发现蛋白A对循环免疫复合物(Circulating immune complexes)也具有较强的特异性相互作用(T.M.Phillips,Analytical Techniques in Immunochemistry;New York:Marcel Dekker,Inc.,1992,p.75)。目前,蛋白A作为一种典型的生物亲和配基已被用于临床中上述疾病患者体内自身抗体和免疫复合物的清除。Prosorba和Immunosorba(Fresenius,Germany)是两种目前应用最为广泛的蛋白A吸附剂,分别以硅胶和琼脂糖作为载体基质。国内也有同类产品(中国专利:99112880.X)。对于这一类采用蛋白A作为配基的吸附剂,其优点在于利用生物分子间天然的亲和作用,能够实现对目标分子的特异性识别,从而达到较高的吸附选择性。但其缺点在于蛋白A作为具有生物活性的蛋白质分子,需要从金黄色葡萄球菌或基因工程菌中获得,其生产成本很高。目前Prosorba吸附柱的市场价约为1000欧元,而一对可切换使用的Immunosorba吸附柱市场价约为10000欧元。同时,蛋白质配基在固定化和保存过程中不稳定,易失活;虽然能够再生,重复使用,但也存在难以在线清洗灭菌的问题和配基分子脱落的隐患。以上这些缺点限制了蛋白A免疫吸附剂在临床中的使用。
Noriko Hirata报道了两种分别采用苯丙氨酸和色氨酸作为吸附基团,固定在载体基质上,用作吸附血液中抗体类组分和免疫复合物的吸附剂材料(NorikoHirata,Toshiji Kuriyama,and Naokuni Yamawaki,Immusorba TR and PH;Therapeutic Apheresis and Dialysis,2003,7(1):85-90)。中国专利200410021373.3中也涉及一种利用组氨酸作为吸附基团的吸附剂材料。除此以外,亦有采用聚氨基酸作为吸附基团用在此领域的报道(中国专利03130403.6)。在吸附剂的设计合成中采用氨基酸,尤其是疏水性氨基酸作为吸附基团,以此替代蛋白A,是新一代血液净化吸附剂的特征之一。采用人工合成的小分子化合物基团的好处在于产品价格低廉,结构相对稳定。但是,采用什么样的化合物分子,以及如何提高小分子吸附基团的作用效果,是这一领域所面临的新问题。上述固定化小分子的吸附材料普遍存在的缺点在于吸附剂在实际病人血浆中对目标分子吸附容量不高。这是由所选用吸附基团的性质决定的。在Noriko Hirata的报道中(Noriko Hirata,Toshiji Kuriyama,and Naokuni Yamawaki,Immusorba TR andPH;Therapeutic Apheresis and Dialysis,2003,7(1):85-90)可以看到,吸附剂基于免疫球蛋白表面广泛分布的疏水位点和整体的正电性,在不溶性亲水载体上固定化有机小分子,利用其表面分布的负电基团和疏水基团两部分共同作用吸附抗体类分子和免疫复合物。这种吸附剂对人血清白蛋白等主要蛋白没有明显的吸附作用,但是问题在于带电基团弱化了疏水作用强度,使吸附剂与目的蛋白之间的作用力减弱,造成吸附容量不高,约7mg IgG/mL吸附剂,从而单次治疗效果不明显。
发明内容
为了克服现有技术所存在的问题:(1)蛋白A吸附剂价格昂贵,不易储存和消毒,适用范围有限;(2)以疏水氨基酸作为配基的吸附剂具有对致病因子的选择性差,治疗效果不显著等缺陷。本发明提供一种用于抗体清除的血液净化吸附剂,该血液净化吸附剂应对血浆中的致病因子具有较好的选择性和较高的吸附容量,并具有化学和物理性质稳定,成本相对低廉的优点。
本发明解决上述技术问题所采用的技术方案是:一种用于抗体清除的血液净化吸附剂,它由固相载体材料和通过化学偶联固定在载体上的配基两部分构成,配基的分子结构为:
其中A,B,C中有一个原子为N,其它为C;n为0-2。
所述的固相载体材料选自琼脂糖、纤维素、葡聚糖、壳聚糖或聚乙烯醇。所述的固相载体材料选用多孔微球的形式,其胶孔透过分子量为150,000~5,000,000。
所述的配基选自4-巯基乙基吡啶或3-巯基乙基吡啶。
吸附剂的多孔载体基质可以是任何合适的材料,包括多糖材料,例如琼脂糖、纤维素、葡聚糖、壳聚糖等;也可以是亲水性的合成高分子材料,例如经取代或未经取代的聚丙烯酰胺、聚甲基丙烯酸酯、聚乙烯醇等。本发明吸附剂的载体基质应该具有良好的亲水性,基质本身不应对蛋白质产生吸附,同时,应具有良好的血液相容性,不会造成凝血机制激活等不良反应。
吸附剂的多孔载体基质是球形颗粒,它们需要有足够的通透性和相对稳定的空间结构,其胶孔的透过分子量最好在150,000到5,000,000。因为材料要吸附的目的分子中IgG的分子量为150,000,而免疫复合物,尤其是IgM免疫复合物分子量则要大得多。
配基分子在固相载体基质上的固定化是依靠配基上的巯基基团和固相载体上的可反应基团通过化学反应共价连接。可以与上述配基上的巯基发生反应的基团包括环氧基团、卤素、烯基、甲苯磺酸、三氟乙基磺酸单甲氧基等。上面所提到的固相载体基质若不含有可与巯基反应的活性基团,则需要通过采用一些活化试剂使其产生巯基反应基团。这类活化试剂往往具有双功能团,例如环氧氯丙烷、环氧溴丙烷、二氯(溴)丙醇、二溴丁烷、二缩水甘油醚、二乙烯基砜、溴丙烯等等。
通过调节活化试剂的用量可以控制载体基质的活化程度,进而得到一系列不同配基密度的吸附剂。配基密度影响着吸附剂的吸附效果,配基偶联密度提高,单位体积吸附材料的蛋白结合容量随之提高,但密度高到一定程度之后,同时也会带来更多的非特异性吸附。
本发明的有益效果是:这种用于抗体清除的血液净化吸附剂相对于基于蛋白A、蛋白G、蛋白L、抗抗体等蛋白质类抗体亲和作用分子的吸附剂,最突出的优点在于它具有较好的稳定性,不存在被蛋白水解酶降解的隐患。同时,吸附剂所采用的配基分子都是目前商品化的化合物分子,其生产成本比蛋白质要低很多。而且吸附剂能够耐受强酸、强碱、有机溶剂、加热等苛刻的处理条件,吸附性能也不会受其影响而发生改变。相对于其他目前采用的基于小分子化合物配基的抗体吸附介质,吸附剂能表现出更高的抗体吸附选择性。该血液净化吸附剂可用作血浆灌流柱的填充材料,用于清除病人血浆中相关抗体组分,例如系统性红斑狼疮患者体内的抗核抗体、类风湿性关节炎患者体内的类风湿因子、移植排斥反应相关的抗体,或者其他类型的自身抗体和体外循环免疫复合物。
具体实施方式
下面结合实施例对本发明作进一步的说明。
实施例1:4-巯基乙基吡啶(4-Mercaptoethylpyridine,4-MEP)在带有烯基活性基团的琼脂糖凝胶(经溴丙烯活化)上的偶联
10g Sepharose CL-6B琼脂糖凝胶用200mL去离子水分多次洗涤后均匀分散在5mL 3M NaOH溶液中,取2mL溴丙烯与凝胶悬液混合,将所得混合物于30℃悬桨搅拌18小时。反应结束后,凝胶分别用100mL无水丙酮,100mL去离子水分多次洗涤。得到经溴内烯活化带有烯基活性基团的琼脂糖凝胶。
称取1g 4-MEP·HCl(盐酸盐形式),溶于1mL去离子水,用10M NaOH调pH至7,然后加入6mL磷酸盐缓冲液(0.1M,pH7)和3mL乙腈。将活化后的琼脂糖凝胶加入混合体系中,于30℃悬桨搅拌12小时。反应结束后,凝胶分别用100mL乙腈,100mL去离子水,100mL 0.1M盐酸分多次洗涤。偶联有4-MEP的琼脂糖凝胶抽干后分散在60mL 1M巯基乙醇水溶液中(pH10),于30℃悬桨搅拌3小时。反应结束后,凝胶用200mL去离子水分多次洗涤。
吸附剂的吸附性能评价实验采用生理盐水作为平衡和清洗溶液,5mL新鲜人血清以100cm/h流经装填有1mL上述吸附剂的玻璃层析柱(直径为0.66厘米),经生理盐水冲洗柱床后,用0.2M柠檬酸缓冲液(pH2.3)洗脱吸附蛋白。电泳分析显示吸附蛋白中的主要组分是免疫球蛋白,其纯度高于85%。差量法分析材料吸附免疫球蛋白的结合容量,结果显示单位体积吸附剂对免疫球蛋白G的吸附量为25.5mg。
实施例2:4-MEP在带有烯基活性基团的琼脂糖凝胶(经二乙烯基砜活化)上的偶联
取10g伯胺基取代的琼脂糖凝胶,均匀分散在60mL由0.1M碳酸缓冲液,pH9.5和乙醇(35/65,v/v)组成的混合溶液中,往反应体系中加入5mL二乙烯基砜,45℃悬桨搅拌20小时,凝胶悬液经乙醇洗涤后分散在30mL由0.05M碳酸缓冲液,pH8.6和乙醇(35/65,v/v)组成的混合溶液中。称取1g 4-MEP·HCl,溶于1mL去离子水,调pH至8.6后加入反应体系中。45℃悬桨搅拌24小时。反应结束后,凝胶用乙醇充分洗涤,然后分散在60mL 1M乙醇胺水溶液(pH10.5)中,于45℃悬桨搅拌2.5小时。反应结束后,凝胶用200mL去离子水分多次洗涤。
吸附剂的评价方式如实施例1。结果显示吸附剂对人血清中免疫球蛋白的吸附选择性与实施例1得到的结果相当,但结合容量偏低,约为18.5mg/ml。
实施例3:3-巯基乙基吡啶(3-Mercaptoethylpyridine,3-MEP)在带有烯基活性基团的琼脂糖凝胶(经溴丙烯活化)上的偶联
吸附剂合成方法和评价方式如实施例1,区别在于反应所采用的4-MEP·HCl被替换为3-MEP·HCl。评价结果显示此吸附剂从人血清中吸附免疫球蛋白的结合容量为23.2mg/ml,洗脱液中免疫球蛋白纯度大于85%。
实施例4:3-巯基甲基吡啶(3-Mercaptomethylpyridine,MMP)在带有烯基活性基团的琼脂糖凝胶上的偶联
吸附剂合成方法和评价方式如实施例1,区别在于反应所采用的4-MEP·HCl被替换为MMP·HCl。评价结果显示此吸附剂从人血清中吸附免疫球蛋白的结合容量为15.2mg/ml,洗脱液中免疫球蛋白纯度大于80%。
实施例5:2-巯基吡啶(2-Mercaptopyridine,MP)在带有烯基活性基因的琼脂糖凝胶上的偶联
吸附剂合成方法和评价方式如实施例2,区别在于反应所采用的MEP·HCl被替换为MP。评价结果显示此吸附剂从人血清中吸附免疫球蛋白的结合容量为10.6mg/ml,洗脱液中免疫球蛋白纯度大于80%。
实施例6:4-MEP在环氧活化的琼脂糖凝胶上的偶联
取10g经环氧活化的Sepharose CL-6B琼脂糖凝胶(环氧基团密度大于80μM/mL湿胶)均匀分散于50mL由0.05M碳酸缓冲液,pH8.6和乙醇(35/65,v/v)组成的混合溶液中。称取1g 4-MEP·HCl,溶于1mL去离子水,调pH至8.6后加入反应体系中。45℃悬桨搅拌16小时。反应结束后用乙醇充分洗涤,然后分散在50mL 1M乙醇胺水溶液中(pH10.5),于45℃悬桨搅拌2.5小时。反应结束后,凝胶用200mL去离子水分多次洗涤。抽干后将凝胶加入到50mL溶有2mL乙酸酐的2M乙酸钠溶液中继续反应1小时,然后用200mL去离子水分多次洗涤。
吸附剂的评价方式如实施例1。结果显示经环氧基团偶联4-MEP得到的吸附剂对免疫球蛋白的吸附容量要低于烯基加成法所得到的吸附剂,单位体积吸附量为14mg。但吸附选择性与实施例1相当。
实施例7:4-MEP在溴化琼脂糖凝胶上的偶联
称取1g 4-MEP·HCl,溶于1mL去离子水,用10M NaOH调pH至8,然后加入6mL磷酸盐缓冲液(0.1M,pH8)和3mL丙酮。取10g溴化的Sepharose CL-6B琼脂糖凝胶(烷基溴基团密度大于80μM/mL湿胶)分散其中。于30℃悬桨搅拌12小时。反应结束后,凝胶分别用100mL丙酮,100mL去离子水,100mL 0.1M盐酸分多次洗涤。偶联有4-MEP的琼脂糖凝胶抽干后分散在60mL 1M巯基乙醇水溶液中(pH10),于30℃悬桨搅拌3小时。反应结束后,凝胶分别用200mL去离子水分多次洗涤。
吸附剂的评价方式如实施例1。结果显示通过溴代烷取代反应偶联上4-MEP基团的吸附剂对血清中免疫球蛋白的吸附容量为31mg/mL湿胶;纯度大于80%。
实施例8:4-MEP在溴化纤维素微球上的偶联
操作过程如实施例7所示,区别在于用纤维素微球替代琼脂糖凝胶用作吸附剂的固相载体基质。评价结果表明纤维素基质的吸附剂对人血清中免疫球蛋白的吸附容量为26.6mg/mL湿胶;纯度大于80%。
实施例9:4-MEP在烯基活化的壳聚糖微球上的偶联
操作过程如实施例1所示,区别在于用壳聚糖微球替代琼脂糖凝胶作为吸附剂的固相载体基质。评价结果显示此吸附剂对人血清中免疫球蛋白的吸附容量为21.6mg/mL湿胶;纯度大于80%。
实施例10:MMP在环氧活化的聚乙烯醇微球上的偶联
取10g经环氧活化的聚乙烯醇微球(环氧基团密度大于80μM/mL湿胶)均匀分散于50mL由0.05M碳酸缓冲液,pH8.6和乙醇(35/65,v/v)组成的混合溶液中。称取1g MMP·HCl,溶于1mL去离子水,调pH至8.6后加入反应体系中。45℃悬桨搅拌16小时。反应结束后用乙醇充分洗涤,然后分散在50mL 1M乙醇胺水溶液中(pH10.5),于45℃悬桨搅拌2.5小时。反应结束后,凝胶用200mL去离子水分多次洗涤。抽干后将凝胶加入到50mL溶有2mL乙酸酐的2M乙酸钠溶液中继续反应1小时后用200mL去离子水分多次洗涤。
吸附评价方式如实施例1所示。结果表明此吸附剂对免疫球蛋白的吸附容量为25.5mg/mL湿胶;纯度大于75%。
实施例11:MMP在环氧活化的葡聚糖微球上的偶联
10g葡聚糖基质均匀分散于30mL去离子水中,依次向反应体系中加入5mL二缩水甘油醚,10mL 1M NaOH溶液,0.1g硼氢化钠。于30℃悬桨搅拌16小时。反应结束后,凝胶用200mL去离子水分多次洗涤。此环氧活化的葡聚糖凝胶与MMP的偶联反应和评价方法如实施例5所示。评价结果显示,此吸附剂对免疫球蛋白的吸附容量为17.2mg/mL湿胶;纯度大于80%。
实施例12:吸附剂对人血清中类风湿因子的吸附评价
取按照实施例7方法合成的吸附剂用生理盐水冲洗3遍,称取0.1g吸附剂加入到盛有0.25mL血清(材料与血清体积比例为1∶2)的样品瓶中,37℃温育2小时。检测吸附前后血清样品中RF浓度。具体结果如表1所示。评价结果表明本发明吸附剂对人血清样品中不同初始浓度的RF均有显著的祛除效果。
表1 血液净化吸附剂对类风湿因子的去除效果
“-”表示检测结果为阴性
实施例13:吸附剂对人血清中抗核抗体(ANA)的吸附评价
评价方法如实施例11所示,区别在于所采用的病人血清样品中含有高浓度的ANA,评价结果展示在表2中。结果表明本发明吸附剂对初始ANA滴度分别为1∶3200和1∶1000的血清样品均表现出明显的ANA祛除效果,对大部分样品都具有高于60%的祛除率。
表2 血液净化吸附剂对抗核抗体的去除效果
“-”表示检测结果为阴性
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