CN103118707A - 复合药物组合物及对糖尿病和代谢紊乱进行治疗的方法 - Google Patents
复合药物组合物及对糖尿病和代谢紊乱进行治疗的方法 Download PDFInfo
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Abstract
本申请提供了用于向患有糖尿病及其它代谢紊乱的患者进行给予的药物组合物,所述组合物包含:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
Description
技术领域
本发明涉及医药领域,可用于糖尿病及其它代谢紊乱疾病的治疗和预防。
背景技术
糖尿病是一种以高血糖(血液中高的糖水平)为特征的慢性疾病。血糖水平的持续增高增大了糖尿病相关的并发症(如肾损害、视力丧失、心脏疾病和足溃疡)的风险。
糖尿病主要有两种类型:1型糖尿病和2型糖尿病。对于1型糖尿病,由于胰腺不能产生胰岛素而发展出高血糖。这一类型的糖尿病通常在儿童期或成年早期出现。在2型糖尿病中,胰腺能够生产胰岛素,但它不足以满足机体的需求。问题是机体不能恰当地对胰岛素作出应答,这反过来导致由细胞吸收的葡萄糖更少,并造成血糖水平异常升高。胰腺超负荷工作数年后,胰腺可能最终衰竭并耗尽其生产胰岛素的能力,而此时患有2型糖尿病的人可能需要胰岛素治疗。
胰岛素(由胰腺产生的天然激素)将葡萄糖从血流中转运至细胞内。因此,胰岛素的主要职责是调节葡萄糖向细胞内的转运从而降低血糖水平。
通过激活在质膜中发现的异四聚体受体来控制胰岛素的作用。胰岛素受体是一种由通过二硫键连接的两个胞外α-亚基和两个跨膜β-亚基组成的糖蛋白(Ullrich等,Nature,313:756-61,1985)。所述α-亚基含有胰岛素结合结构域,而β-亚基的胞内部分含有胰岛素调节的酪氨酸蛋白激酶(催化高能基团从供体(通常是ATP)向受体转移的酶)。
当胰岛素分子经由胰腺β细胞释放并到达细胞时,其结合至大多数细胞表面上的胰岛素受体上。一旦胰岛素结合后,胰岛素受体β-亚基固有的磷酸转移酶功能便被激活,引起大量胞内蛋白的酪氨酸磷酸化。一旦胰岛素受体激活后,所述磷酸化事件引起葡萄糖储存增多,从而使血糖水平降低。
即使在最积极的患者中用最细致的胰岛素治疗方式,也难以实现血糖水平长时间的有效控制。因此,存在着对治疗疾病及代谢紊乱具有期望疗效的新药产品的持续需要。
一氧化氮(NO)是已显示出在不同生物学过程的信号转导中发挥作用的气态分子。内皮衍生的NO是调节血管张力(vascular tone)的关键分子,其与血管病的联系早已被认视到。NO对许多已知参与动脉粥样硬化斑块(atherosclerotic plaque)形成的过程起抑制作用,所述过程包括单核细胞粘着、血小板凝聚以及血管平滑肌细胞增殖。内皮NO的另一重要作用是保护血管壁免受由其自身代谢产物及脂类和脂蛋白的氧化产物诱导的氧化应激(oxidative stress)。内皮功能障碍在动脉粥样硬化的很早阶段发生。因此,局部NO利用度不足可能是促进人类动脉粥样化形成的最终共路(final common pathway)。除了在血管内皮中的作用以外,NO利用度还显示出了对脂蛋白代谢的调节作用。NO代谢产物的血浆浓度与血浆总胆固醇水平和低密度脂蛋白(LDL)胆固醇水平的负相关性已有报道,而高密度脂蛋白(HDL)在高胆固醇血症受试者中改善血管功能。NO缺失对疾病发展具有相当重要的影响。糖尿病与主要由动脉粥样硬化疾病发展加快导致的发病率和死亡率上升有关。并且,报告显示糖尿病患者的肺功能削弱。有人提出胰岛素抵抗可导致气道炎症。Habib等,Nitric Oxide Measurement From Blood To Lungs,Is There A Link?Pak JPhysiol 2007;3(1)。
一氧化氮由内皮通过一氧化氮合酶(NO合酶)从L-精氨酸合成。NO合酶以不同亚型出现,包括组成型(cNOS)和诱导型(iNOS)。组成型NO合酶存在于正常内皮细胞、神经元和其它某些组织中。
发明内容
在一个方面,本发明提供了用于向患有糖尿病及其它代谢紊乱疾病的患者进行给予的药物组合物,所述组合物包含:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在一个方面,本发明提供了用于向患有糖尿病及其它代谢紊乱疾病的患者进行给予的药物组合物,所述组合物包含:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体(antibody to a C-terminal fragment ofthe beta subunit of human insulin receptor)、和b)活性强化形式的抗内皮NO合酶抗体。
在一个变型中,本发明这一方面的药物组合物包含:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体,其中,所述胰岛素受体分子含有至少一个α亚基和至少一个β亚基。
在一个变型中,本发明这一方面的药物组合物包含活性强化形式的抗人胰岛素受体β亚基C端片段抗体或活性强化形式的抗人胰岛素受体抗体,所述抗体处于浸渍至固态载体上的C12、C30及C200顺势疗法稀释液的混合物形式。所述活性强化形式的抗内皮NO合酶抗体处于可随后浸渍至固态载体上的C12、C30及C200顺势疗法稀释液的混合物形式。
在另一变型中,本发明这一方面的药物组合物包含活性强化形式的抗内皮NO合酶抗体,所述抗体处于浸渍至固态载体上的C12、C30及C200顺势疗法稀释液的混合物形式。所述活性强化形式的抗人胰岛素受体β亚基C端片段抗体或活性强化形式的抗人胰岛素受体抗体处于可随后浸渍至固态载体上的C12、C30及C200顺势疗法稀释液的混合物形式。
优选地,所述活性强化形式的抗人胰岛素受体β亚基C端片段抗体或活性强化形式的抗人胰岛素受体抗体为单克隆抗体、多克隆抗体或天然抗体,更优选为多克隆抗体。在本发明这一方面的一个变型中,所述活性强化形式的抗人胰岛素受体β亚基C端片段抗体或活性强化形式的抗人胰岛素受体抗体通过连续的百倍稀释、且每次稀释时均伴以振荡而制备。
优选地,所述活性强化形式的抗内皮NO合酶抗体为单克隆抗体、多克隆抗体或天然抗体,更优选为多克隆抗体。在本发明这一方面的一个变型中,所述活性强化形式的抗内皮NO合酶抗体通过连续的百倍稀释、且每次稀释时均伴以振荡而制备。
在另一方面,本发明提供了对患有I型糖尿病的患者进行治疗的方法,所述方法包括向患者给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了对患有I型糖尿病的患者进行治疗的方法,所述方法包括向患者给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了对患有II型糖尿病的患者进行治疗的方法,所述方法包括向患者给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了对患有II型糖尿病的患者进行治疗的方法,所述方法包括向患者给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了降低哺乳动物血糖水平的方法,所述方法包括向哺乳动物给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了降低哺乳动物血糖水平的方法,所述方法包括向哺乳动物给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了对哺乳动物中的胰岛素抵抗进行治疗的方法,所述方法包括向哺乳动物给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在另一方面,本发明提供了对哺乳动物中的胰岛素抵抗进行治疗的方法,所述方法包括向哺乳动物给予如下物质的复合物:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体、和b)活性强化形式的抗内皮NO合酶抗体。
在本发明这一方面的一个变型中,提供了如下技术方案:给予1-2单位剂型的活性强化形式的抗人胰岛素受体β亚基C端片段抗体或活性强化形式的抗人胰岛素受体抗体,以及1-2单位剂型的活性强化形式的抗内皮NO合酶抗体;各剂型每日给药1-4次。优选所述1-2单位剂型的各活性强化形式抗体每日给药2次。
附图说明
图1表示测试制剂对大鼠血浆葡萄糖水平的影响,所述大鼠患有链脲菌素(streptozotocin)诱导的糖尿病。
图2表示在患有链脲菌素诱导的糖尿病的大鼠的葡萄糖耐量测试中,在注射第14天时测试制剂对指标成分(indicator)的浓度-时间曲线下面积(AUC)的影响。
图3表示测试制剂对大鼠血浆葡萄糖水平的影响,所述大鼠患有自发性非胰岛素依赖性糖尿病。
图4表示在患有自发性非胰岛素依赖性糖尿病的大鼠的葡萄糖耐量测试中,在注射第28天时测试制剂对指标成分的浓度-时间曲线下面积(AUC)的影响。
图5表示在服用IR Ab+NOS Ab制剂的背景下,1型糖尿病患者中的葡萄糖和糖化血红蛋白水平的动态。
图6表示在服用IR Ab+NOS Ab制剂的背景下,2型糖尿病患者中的葡萄糖和糖化血红蛋白水平的动态。
具体实施方式
参考所附的权利要求书对本发明进行限定。考虑到权利要求书,下述术语汇编提供了有关定义。
本文所使用的术语“抗体”意味着特异性地结合至另一分子的特定空间和极性结构、并因此被定义为与另一分子的特定空间和极性结构互补的免疫球蛋白。权利要求书中所列举的抗体可包括完整的免疫球蛋白或其片段,可为天然抗体、多克隆抗体或单克隆抗体,并可包括多个类及同种型,例如IgA、IgD、IgE、IgG1、IgG2a、IgG2b和IgG3、IgM等。免疫球蛋白的片段可包括Fab、Fv和F(ab')2以及Fab'等。单数“抗体(antibody)”包括复数“抗体(antibodies)”。
相对于本文所列举的抗体,术语“活性强化形式”或“强化形式”分别用于表示任意的抗体初始溶液的顺势疗法强化产物。“顺势疗法强化”表示利用顺势疗法的方法对有关物质的初始溶液赋予顺势疗法效力(potency)。尽管不限于此,但是“顺势疗法强化”可包括例如结合外部处理、尤其是(机械)振荡的重复的连续稀释。换句话说,根据顺势疗法技术,对抗体的初始溶液进行连续的重复稀释并对每次获得的溶液进行多次竖直振荡。抗体处于溶剂(优选水或水-乙醇混合物)中的初始溶液的优选浓度范围为约0.5mg/ml至约5.0mg/ml。制备各组分(即抗体溶液)的优选过程为:使用抗体初级基质溶液(primary matrix solution)(原始酊剂,mother tincture)分别被稀释10012、10030和100200倍的3种水稀释液或水-醇稀释液的混合物,相当于百倍顺势疗法稀释液(C12、C30和C200);或者使用抗体初级基质溶液分别被稀释10012、10030和10050倍的3种水稀释液或水-醇稀释液的混合物,相当于百倍顺势疗法稀释液(C12、C30和C50)。在美国专利号7,572,441和7,582,294中描述了顺势疗法强化的实例,以引用的方式将其内容整体并入本文并用于所述目的。同时,术语“活性强化形式”用在权利要求书中,术语“极低剂量”用在实施例中。术语“极低剂量”在通过研究和使用顺势疗法稀释和强化形式的物质而产生的领域中成为行业术语。术语“极低剂量”意味着完全支持并与权利要求书中所使用的术语“活性强化”形式基本上同义。
换句话说,当存在三个因素时,抗体处于“活性强化”形式。首先,“活性强化”形式的抗体为顺势疗法领域广泛接受的制备方法的产品。其次,“活性强化”形式的抗体必须具备通过现代药物学广泛接受的方法确定的生物活性。第三,“活性强化”形式的抗体所表现出的生物活性不能由顺势疗法方法终产物中的分子形式抗体的存在加以解释。
例如,活性强化形式的抗体可通过使处于分子形式的初始独立抗体经受伴以外部作用(如机械振荡)的连续多重稀释而制备。浓度降低过程中的外部处理还可通过例如暴露至超声、电磁或其它物理因素来完成。V.Schwabe,“Homeopathic medicines”,M.,1967,美国专利号7,229,648和4,311,897(以引用的方式将其内容整体并入本文并用于所述目的)描述了顺势疗法领域中广泛接受的顺势疗法强化方法。这一过程使得初始分子形式抗体的分子浓度均匀降低。重复这一过程直至获得期望的顺势疗法效力。对于单独的抗体,可通过将中间稀释液在期望的药理学模型中进行生物测试来确定所需的顺势疗法效力。尽管不限于此,但是“顺势疗法强化”可包括例如与外部处理、尤其是竖直(机械)振荡相结合的重复的连续稀释。换句话说,根据顺势疗法技术,对抗体的初始溶液(initial solution)进行连续的重复稀释并对每次获得的溶液进行多次竖直振荡。抗体处于溶剂(优选水或水-乙醇混合物)中的初始溶液的优选浓度范围为约0.5mg/ml至约5.0mg/ml。制备各组分(即抗体溶液)的优选过程为:使用抗体初级基质溶液(原始酊剂)分别被稀释10012、10030和100200倍的3种水稀释液或水-醇稀释液的混合物,相当于百倍顺势疗法稀释液C12、C30和C200;或者使用抗体初级基质溶液(原始酊剂)分别被稀释10012、10030和10050倍的3种水稀释液或水-醇稀释液的混合物,相当于百倍顺势疗法稀释液C12、C30和C50。例如在美国专利号7,229,648和4,311,897中,也提供了如何获得期望效力的实例,以引用方式将其并入本文用于所述目的。在下文将更加详细地描述适用于本文所述的“活性强化”形式抗体的过程。
关于用顺势疗法对人类受试者进行治疗已有许多争议。虽然本发明依靠已接受的顺势疗法方法来获得“活性强化”形式的抗体,但是其并不仅仅依赖于在人类受试者中进行顺势疗法来证明其活性。本申请的发明人出乎预料地发现、并在已接受的药理学模型中充分证明,由起始分子形式的抗体进行连续多次稀释而最终得到的溶液具有明确的活性,且与痕量分子形式抗体在目标稀释液中的存在无关。将本文所提供的“活性强化”形式的抗体在广泛接受的药理学活性模型中(在适当的体外实验中或于合适的动物模型中在体内)测试其生物活性。下文进一步提供的实验提供了在此类模型中的生物活性的证据。人类临床研究(在下文中也加以提供)还特别提供了如下证据:在动物模型中观察到的活性被很好地转换至人类治疗。人类研究还提供了如下证据:本文所述的“活性强化”形式可用于对在医学科学中作为病理症状而广泛接受的具体人类疾病或紊乱进行治疗。
同样,所要求保护的“活性强化”形式的抗体仅涵盖溶液或固体制剂,所述溶液或固体制剂的生物活性不能由初始、起始溶液(startingsolution)中余留的分子形式抗体的存在进行解释。换句话说,虽然“活性强化”形式的抗体可包含痕量的初始分子形式抗体也在考虑之列,但是由于连续稀释后余留的分子形式抗体的浓度极低,因此本领域技术人员不能以任何程度的合理性将在已接受的药理学模型中观察到的生物活性归因于余留的分子形式抗体。虽然本发明并不受任何具体理论的限制,但是本发明的“活性强化”形式抗体的生物活性并不归因于初始分子形式的抗体。优选所述“活性强化”形式抗体处于液体形式或固体形式,其中,初始分子形式抗体的浓度低于所接受的分析技术(如毛细管电泳和高效液相色谱)的检测限。特别优选“活性强化”形式的抗体处于液体形式或固体形式,其中,初始分子形式抗体的浓度低于阿伏伽德罗常数。在分子形式治疗物质的药物学中,通常制作剂量-响应曲线,在该曲线中,以药理学响应水平对给予受试者或在体外进行测试的活性药物的浓度作图。产生任何可检测响应的药物最低水平被称为阈剂量(thresholddose)。特别在考虑之列并优选的是,“活性强化”形式的抗体以低于所给定生物学模型中的分子形式抗体的阈剂量的浓度包含分子抗体(如果有的话)。
本发明提供了用于向患有糖尿病及其它代谢紊乱疾病的患者进行给予的药物组合物,所述药物组合物包含:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体或活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。如上文所述,所述复合物的各单独组分由于其各自的医药用途而为大家所熟知。然而,本专利申请的发明人惊奇地发现,给予所述复合物可用来对患有糖尿病及胰岛素抵抗的患者进行治疗,并进一步降低血糖水平。虽然申请人并不受这一理论的束缚,但是“加速器(accelerator)”假说认为I型糖尿病(DM)和II型糖尿病是以胰岛素抵抗为特征的相同疾病,其发展成I型糖尿病还是II型糖尿病由患者的基因型决定。这一假说并未否认自身免疫过程的作用;但是,却使得对其起主要作用产生怀疑。所述“加速器”假说根据进展速度来区分I型糖尿病和II型糖尿病:在I型糖尿病中,病理变化的快速发展决定了疾病临床症状表现的较早发作。该假说在2001年被首次提出,目前已由6例独立的临床试验证实(参见Wilkin,T.J.,The acceleratorhypothesis:a review of the evidence for insulin resistance as the basis fortype[I]as well as type II diabetes,International Journal for Obesity,2009:Vol.33,第716-726页)。胰岛素抵抗在这两种类型的糖尿病发病机制中起关键作用,所述胰岛素抵抗的减弱使得I型糖尿病和II型糖尿病的临床过程均得以缓和(参见Cellular mechanisms of insulin resistance,WorldCongress on Insulin Resistance Syndrome,2009,Diabetes Care.2010:Vol.33,N8,第103-108页)。已知胰岛素受体β亚基在胰岛素信号通路中的作用。在胰岛素与受体结合并且β亚基激活后,所述通路可通向两个不同方向:磷脂酰肌醇3-激酶(PI3-K)或MAP激酶(MAP-K)。第一条通路对实现胰岛素的大多数代谢作用和抗凋亡作用来说似乎是必须的,而另一通路与胰岛素的非代谢作用、增殖作用和促有丝分裂作用有关。已经证明,在胰岛素抵抗中,只有与循PI3-K通路的β亚基激活有关的代谢性胰岛素抵抗才在决定糖尿病发展中起重要作用(参见Muntoni,S,Muntoni,S,Insulin Resistance:Pathophysiology and Rationale forTreatment,Ann.Nutr.Metab.,2011:Vol.58,N1,第25-36页)。所要求保护的药物组合物确保了对代谢性胰岛素抵抗的作用。
根据本发明这一方面的药物组合物可处于液态形式或固态形式。药物组合物中所含的各活性强化形式抗体由初始分子形式的抗体通过顺势疗法领域所接受的方法制备。起始抗体可为根据已知方法制备的单克隆抗体或多克隆抗体,所述已知方法例如Immunotechniques,G.Frimel,M.,“Meditsyna”,1987,第9-33页;“Hum.Antibodies.Monoclonal andrecombinant antibodies,30years after”,Laffly E.,Sodoyer R.著,2005,Vol.14.,N1-2.,第33-55页中所述,以引用的方式将其内容并入本文。
单克隆抗体可通过如杂交瘤技术获得。所述方法的初始步骤包括基于已在多克隆抗血清制备过程中开发出的原则进行免疫。工作的进一步步骤包括制备出产生具有相同特异性的抗体克隆的杂交细胞。其各自的分离使用与多克隆抗血清制备情况中相同的方法进行。
多克隆抗体可通过动物的主动免疫获得。为了这一目的,例如使合适的动物(如兔)接受适当抗原(NO合酶和人胰岛素受体β亚基C端片段、或NO合酶和人胰岛素受体)的一系列注射。动物的免疫系统产生相应的抗体,以已知方法从动物中进行收集。这一过程使得能够制备富含单特异性抗体的血清。如果需要的话,包含抗体的血清例如可通过使用亲和色谱、盐沉淀分级分离或离子交换色谱进行纯化。可将所得到的经纯化的、富含抗体的血清用作制备活性强化形式抗体的起始材料。所得到的处于溶剂(优选水或水-乙醇混合物)中的初始抗体溶液的优选浓度范围为约0.5mg/ml至约5.0mg/ml。
制备各组分的优选过程为:使用抗体初级基质溶液分别被稀释10012、10030和100200倍的3种水-醇稀释液的混合物,相当于百倍顺势疗法稀释液C12、C30和C200。为制备固体剂型,将固态载体通过顺势疗法方法所获得的期望稀释液进行处理。为获得本发明复合物的固体单位剂型,用各稀释液对载体物质进行浸渍。为制备期望的复合剂型,两种浸渍顺序都是适合的。
在优选的实施方式中,用于包含本发明所述复合物的活性强化形式制剂的起始材料是针对相应抗原(即,人胰岛素受体β亚基C端片段或人胰岛素受体和内皮NO合酶)的动物产多克隆抗体。为获得活性强化形式的抗人胰岛素受体β亚基C端片段多克隆抗体,可将期望的抗原作为免疫原注射入实验动物、优选兔中。特别感兴趣的肽可包含所述序列某一侧的至少约3个氨基酸(通常至少约10个),优选具有C端一侧的至少3个氨基酸。特别在考虑之列的是,将以下序列的人胰岛素受体作为合适的抗原:
人胰岛素受体的整个α亚基:
SEQ ID NO:1
His Leu Tyr
28 30
Pro Gly Glu Val Cys Pro Gly Met Asp Ile Arg Asn Asn Leu Thr
31 35 40 45
Arg Leu His Glu Leu Glu Asn Cys Ser Val Ile Glu Gly His Leu
46 50 55 60
Gln Ile Leu Leu Met Phe Lys Thr Arg Pro Glu Asp Phe Arg Asp
61 65 70 75
Leu Ser Phe Pro Lys Leu Ile Met Ile Thr Asp Tyr Leu Leu Leu
76 80 85 90
Phe Arg Val Tyr Gly Leu Glu Ser Leu Lys Asp Leu Phe Pro Asn
91 95 100 105
Leu Thr Val Ile Arg Gly Ser Arg Leu Phe Phe Asn Tyr Ala Leu
106 110 115 120
Val Ile Phe Glu Met Val His Leu Lys Glu Leu Gly Leu Tyr Asn
121 125 130 135
Leu Met Asn Ile Thr Arg Gly Ser Val Arg Ile Glu Lys Asn Asn
136 140 145 150
Glu Leu Cys Tyr Leu Ala Thr Ile Asp Trp Ser Arg Ile Leu Asp
151 155 160 165
Ser Val Glu Asp Asn Tyr Ile Val Leu Asn Lys Asp Asp Asn Glu
166 170 175 180
Glu Cys Gly Asp Ile Cys Pro Gly Thr Ala Lys Gly Lys Thr Asn
181 185 190 195
Cys Pro Ala Thr Val Ile Asn Gly Gln Phe Val Glu Arg Cys Trp
196 200 205 210
Thr His Ser His Cys Gln Lys Val Cys Pro Thr Ile Cys Lys Ser
211 215 220 225
His Gly Cys Thr Ala Glu Gly Leu Cys Cys His Ser Glu Cys Leu
226 230 235 240
Gly Asn Cys Ser Gln Pro Asp Asp Pro Thr Lys Cys Val Ala Cys
241 245 250 255
Arg Asn Phe Tyr Leu Asp Gly Arg Cys Val Glu Thr Cys Pro Pro
256 260 265 270
Pro Tyr Tyr His Phe Gln Asp Trp Arg Cys Val Asn Phe Ser Phe
271 275 280 285
Cys Gln Asp Leu His His Lys Cys Lys Asn Ser Arg Arg Gln Gly
286 290 295 300
Cys His Gln Tyr Val Ile His Asn Asn Lys Cys Ile Pro Glu Cys
301 305 310 315
Pro Ser Gly Tyr Thr Met Asn Ser Ser Asn Leu Leu Cys Thr Pro
316 320 325 330
Cys Leu Gly Pro Cys Pro Lys Val Cys His Leu Leu Glu Gly Glu
331 335 340 345
Lys Thr Ile Asp Ser Val Thr Ser Ala Gln Glu Leu Arg Gly Cys
346 350 355 360
Thr Val Ile Asn Gly Ser Leu Ile Ile Asn Ile Arg Gly Gly Asn
361 365 370 375
Asn Leu Ala Ala Glu Leu Glu Ala Asn Leu Gly Leu Ile Glu Glu
376 380 385 390
Ile Ser Gly Tyr Leu Lys Ile Arg Arg Ser Tyr Ala Leu Val Ser
391 395 400 405
Leu Ser Phe Phe Arg Lys Leu Arg Leu Ile Arg Gly Glu Thr Leu
406 410 415 420
Glu Ile Gly Asn Tyr Ser Phe Tyr Ala Leu Asp Asn Gln Asn Leu
421 425 430 435
Arg Gln Leu Trp Asp Trp Ser Lys His Asn Leu Thr Ile Thr Gln
436 440 445 450
Gly Lys Leu Phe Phe His Tyr Asn Pro Lys Leu Cys Leu Ser Glu
451 455 460 465
Ile His Lys Met Glu Glu Val Ser Gly Thr Lys Gly Arg Gln Glu
466 470 475 480
Arg Asn Asp Ile Ala Leu Lys Thr Asn Gly Asp Gln Ala Ser Cys
481 485 490 495
Glu Asn Glu Leu Leu Lys Phe Ser Tyr Ile Arg Thr Ser Phe Asp
496 500 505 510
Lys Ile Leu Leu Arg Trp Glu Pro Tyr Trp Pro Pro Asp Phe Arg
511 515 510 525
Asp Leu Leu Gly Phe Met Leu Phe Tyr Lys Glu Ala Pro Tyr Gln
526 530 535 540
Asn Val Thr Glu Phe Asp Gly Gln Asp Ala Cys Gly Ser Asn Ser
541 545 550 555
Trp Thr Val Val Asp Ile Asp Pro Pro Leu Arg Ser Asn Asp Pro
556 560 565 570
Lys Ser Gln Asn His Pro Gly Trp Leu Met Arg Gly Leu Lys Pro
571 575 580 585
Trp Thr Gln Tyr Ala Ile Phe Val Lys Thr Leu Val Thr Phe Ser
586 590 595 600
Asp Glu Arg Arg Thr Tyr Gly Ala Lys Ser Asp Ile Ile Tyr Val
601 605 610 615
Gln Thr Asp Ala Thr Asn pro Ser Val Pro Leu Asp Pro Ile Ser
616 620 625 630
Val Ser Asn Ser Ser Ser Gln Ile Ile Leu Lys Trp Lys Pro Pro
631 635 640 645
Ser Asp Pro Asn Gly Asn Ile Thr His Tyr Leu Val Phe Trp Glu
646 650 655 660
Arg Gln Ala Glu Asp Ser Glu Leu Phe Glu Leu Asp Tyr Cys Leu
661 665 670 675
Lys Gly Leu Lys Leu Pro Ser Arg Thr Trp Ser Pro Pro Phe Glu
676 680 685 690
Ser Glu Asp Ser Gln Lys His Asn Gln Ser Glu Tyr Glu Asp Ser
691 695 700 705
Ala Gly Glu Cys Cys Ser Cys Pro Lys Thr Asp Ser Gln Ile Leu
706 710 715 720
Lys Glu Leu Glu Glu Ser Ser Phe Arg Lys Thr Phe Glu Asp Tyr
721 725 730 735
Leu His Asn Val Val Phe Val Pro Arg Lys Thr Ser Ser Gly Thr
736 740 745 750
Gly Ala Glu Asp Pro Arg Pro Ser Arg Lys Arg Arg
751 755 760 762
人胰岛素受体α亚基的片段:
SEQ ID NO:2
Leu Gly Leu Tyr Asn
131 135
Leu Met Asn Ile Thr Arg Gly Ser Val
136 140 144
SEQ ID NO:3
Lys Gly Lys Thr Asn
191 195
Cys Pro Ala Thr Val Ile Asn Gly
196 200 203
SEQ ID NO:4
Trp Ser Lys His Asn leu Thr Ile Thr Gln
441 445 450
Gly Lys Leu
451 453
SEQ ID NO:5
Asn Val Thr Glu Phe Asp Gly Gln Asp Ala Cys Gly Ser Asn Ser
541 545 550 555
Trp Thr Val Val Asp
556 560
SEQ ID NO:6
Asp Ile Ile Tyr Val
611 615
Gln Thr Asp Ala Thr
616 620
SEQ ID NO:7
Tyr Glu Asp Ser
702 705
Ala Gly Glu Cys Cys Ser Cys Pro Lys Thr Asp Ser Gln Ile
706 710 715 719
人胰岛素受体的整个β亚基:
SEQ ID NO:8
Ser Leu Gly
763 765
Asp Val Gly Asn Val Thr Val Ala Val Pro Thr Val Ala Ala Phe
766 770 775 780
Pro Asn Thr Ser Ser Thr Ser Val Pro Thr Ser Pro Glu Glu His
781 785 790 795
Arg Pro Phe Glu Lys Val Val Asn Lys Glu Ser Leu Val Ile Ser
796 800 805 810
Gly Leu Arg His Phe Thr Gly Tyr Arg Ile Glu Leu Gln Ala Cys
811 815 820 825
Asn Gln Asp Thr Pro Glu Glu Arg Cys Ser Val Ala Ala Tyr Val
826 830 835 840
Ser Ala Arg Thr Met Pro Glu Ala Lys Ala Asp Asp Ile Val Gly
841 845 850 855
Pro Val Thr His Glu Ile Phe Glu Asn Asn Val Val His Leu Met
856 860 865 870
Trp Gln Glu Pro Lys Glu Pro Asn Gly Leu Ile Val Leu Tyr Glu
871 875 880 885
Val Ser Tyr Arg Arg Tyr Gly Asp Glu Glu Leu His Leu Cys Val
886 890 895 900
Ser Arg Lys His Phe Ala Leu Glu Arg Gly Cys Arg Leu Arg Gly
901 905 910 915
Leu Ser Pro Gly Asn Tyr Ser Val Arg Ile Arg Ala Thr Ser Leu
916 920 925 930
Ala Gly Asn Gly Ser Trp Thr Glu Pro Thr Tyr Phe Tyr Val Thr
931 935 940 945
Asp Tyr Leu Asp Val Pro Ser Asn Ile Ala Lys Ile Ile Ile Gly
946 950 955 960
Pro Leu Ile Phe Val Phe Leu Phe Ser Val Val Ile Gly Ser Ile
961 965 970 975
Tyr Leu Phe Leu Arg Lys Arg Gln Pro Asp Gly Pro Leu Gly Pro
976 980 985 990
Leu Tyr Ala Ser Ser Asn Pro Glu Tyr Leu Ser Ala Ser Asp Val
991 995 1000 1005
Phe Pro Cys Ser Val Tyr Val Pro Asp Glu Trp Glu Val Ser Arg
1006 1010 1015 1020
Glu Lys Ile Thr Leu Leu Arg Glu Leu Gly Gln Gly Ser Phe Gly
1021 1025 1030 1035
Met Val Tyr Glu Gly Asn Ala Arg Asp Ile Ile Lys Gly Glu Ala
1036 1140 1145 1050
Glu Thr Arg Val Ala Val Lys Thr Val Asn Glu Ser Ala Ser Leu
1051 1155 1160 1065
Arg Glu Arg Ile Glu Phe Leu Asn Glu Ala Ser Val Met Lys Gly
1066 1170 1175 1080
Phe Thr Cys His His Val Val Arg Leu Leu Gly Val Val Ser Lys
1081 1185 1190 1095
Gly Gln Pro Thr Leu Val Val Met Glu Leu Met Ala His Gly Asp
1096 1100 1105 1110
Leu Lys Ser Tyr Leu Arg Ser Leu Arg Pro Glu Ala Glu Asn Asn
1111 1115 1120 1125
Pro Gly Arg Pro Pro Pro Thr Leu Gln Glu Met Ile GIn Met Ala
1126 1130 1135 1140
Ala Glu Ile Ala Asp Gly Met Ala Tyr Leu Asn Ala Lys Lys Phe
1141 1145 1150 1155
Val His Arg Asp Leu Ala Ala Arg Asn Cys Met Val Ala His Asp
1156 1160 1165 1170
Phe Thr Val Lys Ile Gly Asp Phe Gly Met Thr Arg Asp Ile Tyr
1171 1175 1180 1185
Glu Thr Asp Tyr Tyr Arg Lys Gly Gly Lys Gly Leu Leu Pro Val
1186 1190 1195 1200
Arg Trp Met Ala Pro Glu Ser Leu Lys Asp Gly Val Phe Thr Thr
1201 1205 1210 1215
Ser Ser Asp Met Trp Ser Phe Gly Val Val Leu Trp Glu Ile Thr
1216 1220 1225 1230
Ser Leu Ala Glu Gln Pro Tyr Gln Gly Leu Ser Asn Glu Gln Val
1231 1235 1240 1245
Leu Lys Phe Val Met Asp Gly Gly Tyr Leu Asp Gln Pro Asp Asn
1246 1250 1255 1260
Cys Pro Glu Arg Val Thr Asp Leu Met Arg Met Cys Trp Gln Phe
1261 1265 1270 1275
Asn Pro Lys Met Arg Pro Thr Phe Leu Glu Ile Val Asn Leu Leu
1276 1280 1285 1290
Lys Asp Asp Leu His Pro Ser Phe Pro Glu Val Ser Phe Phe His
1291 1295 1300 1305
Ser Glu Glu Asn Lys Ala Pro Glu Ser Glu Glu Leu Glu Met Glu
1306 1310 1315 1320
Phe Glu Asp Met Glu Asn Val Pro Leu Asp Arg Ser Ser His Cys
1321 1325 1330 1335
Gln Arg Glu Glu Ala Gly Gly Arg Asp Gly Gly Ser Ser Leu Gly
1336 1340 1345 1350
Phe Lys Arg Ser Tyr Glu Glu His Ile Pro Tyr Thr His Met Asn
1351 1355 1360 1365
Gly Gly Lys Lys Asn Gly Arg Ile Leu Thr Leu Pro Arg Ser Asn
1366 1370 1375 1380
Pro Ser
13811382
人胰岛素受体β亚基的C端片段:
SEQ ID NO:9
Lys Lys Asn Dly Arg Ile Leu Thr Leu Pro
1368 1370 1375 1377
SEQ ID NO:10
Arg Ile leu Thr Leu Pro Arg Ser Asn
1372 1375 1380
Pro Ser
13811382
SEQ ID NO:11
Lys Asn Gly Arg Ile Leu Thr
13691370 1375
SEQ ID NO:12
Gly Gly Lys Lys Asn Gly Arg Ile Leu Thr Leu Pro Arg Ser Asn
1366 1370 1375 1380
Pro Ser
13811382
SEQ ID NO:13
Asn
1365
Gly Gly Lys Lys Asn Gly Arg Ile Leu Thr Leu Pro Arg Ser Asn
1366 1370 1375 1380
Pro Ser
13811392
将人胰岛素受体用作抗原也在考虑之列。适合此类抗原的序列如下:
SEQ ID NO:14
Met Ala Thr Gly Gly Arg Arg Gly Ala Ala Ala Ala Pro Leu Leu
1 5 10 15
Val Ala Val Ala Ala Leu Leu Leu Gly Ala Ala Gly His Leu Tyr
16 20 25 30
Pro Gly Glu Val Cys Pro Gly Met Asp Ile Arg Asn Asn Leu Thr
31 35 40 45
Arg Leu His Glu Leu Glu Asn Cys Ser Val Ile Glu Gly His Leu
46 50 55 60
Gln Ile Leu Leu Met Phe Lys Thr Arg Pro Glu Asp Phe Arg Asp
61 65 70 75
Leu Ser Phe Pro Lys Leu Ile Met Ile Thr Asp Tyr Leu Leu Leu
76 80 85 90
Phe Arg Val Tyr Gly Leu Glu Ser Leu Lys Asp Leu Phe Pro Asn
91 95 100 105
Leu Thr Val Ile Arg Gly Ser Arg Leu Phe Phe Asn Tyr Ala Leu
106 110 115 120
Val Ile Phe Glu Met Val His Leu Lys Glu Leu Gly Leu Tyr Asn
121 125 130 135
Leu Met Asn Ile Thr Arg Gly Ser Val Arg Ile Glu Lys Asn Asn
136 140 145 150
Glu Leu Cys Tyr Leu Ala Thr Ile Asp Trp Ser Arg Ile Leu Asp
151 155 160 165
Ser Val Glu Asp Asn Tyr Ile Val Leu Asn Lys Asp Asp Asn Glu
166 170 175 180
Glu Cys Gly Asp Ile Cys Pro Gly Thr Ala Lys Gly Lys Thr Asn
181 185 190 195
Cys Pro Ala Thr Val Ile Asn Gly Gln Phe Val Glu Arg Cys Trp
196 200 205 210
Thr His Ser His Cys Gln Lys Val Cys Pro Thr Ile Cys Lys Ser
211 215 220 225
His Gly Cys Thr Ala Glu Gly Leu Cys Cys His Ser Glu Cys Leu
226 230 235 240
Gly Asn Cys Ser Gln Pro Asp Asp Pro Thr lys Cys Val Ala Cys
241 245 250 255
Arg Asn Phe Tyr Leu Asp Gly Arg Cys Val Glu Thr Cys Pro Pro
256 260 265 270
Pro Tyr Tyr His Phe Gln Asp Trp Arg Cys Val Asn Phe Ser Phe
271 275 280 285
Cys Gln Asp Leu His His Lys Cys Lys Asn Ser Arg Arg Gln Gly
286 290 295 300
Cys His Gln Tyr Val Ile His Asn Asn Lys Cys Ile Pro Glu Cys
301 305 310 315
Pro Ser Gly Tyr Thr Met Asn Ser Ser Asn Leu Leu Cys Thr Pro
316 320 325 330
Cys Leu Gly Pro Cys Pro Lys Val Cys His Leu Leu Glu Gly Glu
331 335 340 345
Lys Thr Ile Asp Ser Val Thr Ser Ala Gln Glu Leu Arg Gly Cys
346 350 355 360
Thr Val Ile Asn Gly Ser Leu Ile Ile Asn Ile Arg Gly Gly Asn
361 365 370 375
Asn Leu Ala Ala Glu Leu Glu Ala Asn Leu Gly Leu Ile Glu Glu
376 380 385 390
Ile Ser Gly Tyr Leu Lys Ile Arg Arg Ser Tyr Ala Leu Val Ser
391 395 400 405
Leu Ser Phe Phe Arg Lys Leu Arg Leu Ile Arg Gly Glu Thr Leu
406 410 415 420
Glu Ile Gly Asn Tyr Ser Phe Tyr Ala Leu Asp Asn Gln Asn Leu
421 425 430 435
Arg Gln Leu Trp Asp Trp Ser Lys His Asn Leu Thr Ile Thr Gln
436 440 445 450
Gly Lys Leu Phe Phe His Tyr Asn Pro Lys Leu Cys Leu Ser Glu
451 455 460 465
Ile His Lys Met Glu Glu Val Ser Gly Thr Lys Gly Arg Gln Glu
466 470 475 480
Arg Asn Asp Ile Ala Leu Lys Thr Asn Gly Asp Gln Ala Ser Cys
481 485 490 495
Glu Asn Glu Leu Leu Lys Phe Ser Tyr Ile Arg Thr Ser Phe Asp
496 500 505 510
Lys Ile Leu Leu Arg Trp Glu Pro Tyr Trp Pro Pro Asp Phe Arg
511 515 510 525
Asp Leu Leu Gly Phe Met Leu Phe Tyr Lys Glu Ala Pro Tyr Gln
526 530 535 540
Asn Val Thr Glu Phe Asp Gly Gln Asp Ala Cys Gly Ser Asn Ser
541 545 550 555
Trp Thr Val Val Asp Ile Asp Pro Pro Leu Arg Ser Asn Asp Pro
556 560 565 570
Lys Ser Gln Asn His Pro Gly Trp Leu Met Arg Gly Leu Lys Pro
571 575 580 585
Trp Thr Gln Tyr Ala Ile Phe Val Lys Thr Leu Val Thr Phe Ser
586 590 595 600
Asp Glu Arg Arg Thr Tyr Gly Ala Lys Ser Asp Ile Ile Tyr Val
601 605 610 615
Gln Thr Asp Ala Thr Asn Pro Ser Val Pro Leu Asp Pro Ile Ser
616 620 625 630
Val Ser Asn Ser Ser Ser Gln Ile Ile Leu Lys Trp Lys Pro Pro
631 635 640 645
Ser Asp Pro Asn Gly Asn Ile Thr His Tyr Leu Val Phe Trp Glu
646 650 655 660
Arg Gln Ala Glu Asp Ser Glu Leu Phe Glu Leu Asp Tyr Cys Leu
661 665 670 675
Lys Gly Leu Lys Leu Pro Ser Arg Thr Trp Ser Pro Pro Phe Glu
676 680 685 690
Ser Glu Asp Ser Gln Lys His Asn Gln Ser Glu Tyr Glu Asp Ser
691 695 700 705
Ala Gly Glu Cys Cys Ser Cys Pro Lys Thr Asp Ser Gln Ile Leu
706 710 715 720
Lys Glu Leu Glu Glu Ser Ser Phe Arg Lys Thr Phe Glu Asp Tyr
721 725 730 735
Leu His Asn Val Val Phe Val Pro Arg Lys Thr Ser Ser Gly Thr
736 740 745 750
Gly Ala Glu Asp Pro Arg Pro Ser Arg Lys Arg Arg Ser Leu Gly
751 755 760 765
Asp Val Gly Asn Val Thr Val Ala Val Pro Thr Val Ala Ala Phe
766 770 775 780
Pro Asn Thr Ser Ser Thr Ser Val Pro Thr Ser Pro Glu Glu His
781 785 790 795
Arg Pro Phe Glu lys Val Val Asn Lys Glu Ser Leu Val Ile Ser
796 800 805 810
Gly Leu Arg His Phe Thr Gly Tyr Arg Ile Glu Leu Gln Ala Cys
811 815 820 825
Asn Gln Asp Thr Pro Glu Glu Arg Cys Ser Val Ala Ala Tyr Val
826 830 835 840
Ser Ala Arg Thr Met Pro Glu Ala Lys Ala Asp Asp Ile Val Gly
841 845 850 855
Pro Val Thr His Glu Ile Phe Glu Asn Asn Val Val His Leu Met
856 860 865 870
Trp Gln Glu Pro Lys Glu Pro Asn Gly Leu Ile Val Leu Tyr Glu
871 875 880 885
Val Ser Tyr Arg Arg Tyr Gly Asp Glu Glu Leu His Leu Cys Val
886 890 895 900
Ser Arg Lys His Phe Ala Leu Glu Arg Gly Cys Arg Leu Arg Gly
901 905 910 915
Leu Ser Pro Gly Asn Tyr Ser Val Arg Ile Arg Ala Thr Ser Leu
916 920 925 930
Ala Gly Asn Gly Ser Trp Thr Glu Pro Thr Tyr Phe Tyr Val Thr
931 935 940 945
Asp Tyr Leu Asp Val Pro Ser Asn Ile Ala Lys Ile Ile Ile Gly
946 950 955 960
Pro Leu Ile Phe Val Phe Leu Phe Ser Val Val Ile Gly Ser Ile
961 965 970 975
Tyr Leu Phe Leu Arg Lys Arg Gln Pro Asp Gly Pro Leu Gly Pro
976 980 985 990
Leu Tyr Ala Ser Ser Asn Pro Glu Tyr Leu Ser Ala Ser Asp Val
991 995 1000 1005
Phe Pro Cys Ser Val Tyr Val Pro Asp Glu Trp Glu Val Ser Arg
1006 1010 1015 1020
Glu Lys Ile Thr Leu Leu Arg Glu Leu Gly Gln Gly Ser Phe Gly
1021 1025 1030 1035
Met Val Tyr Glu Gly Asn Ala Arg Asp Ile Ile Lys Gly Glu Ala
1036 1140 1145 1050
Glu Thr Arg Val Ala Val Lys Thr Val Asn Glu Ser Ala Ser Leu
1051 1155 1160 1065
Arg Glu Arg Ile Glu Phe Leu Asn Glu Ala Ser Val Met Lys Gly
1066 1170 1175 1080
Phe Thr Cys His His Val Val Arg Leu Leu Gly Val Val Ser Lys
1081 1185 1190 1095
Gly Gln Pro Thr Leu Val Val Met Glu Leu Met Ala His Gly Asp
1096 1100 1105 1110
Leu Lys Ser Tyr Leu Arg Ser Leu Arg Pro Glu Ala Glu Asn Asn
1111 1115 1120 1125
Pro Gly Arg Pro Pro Pro Thr Leu Gln Glu Met Ile Gln Met Ala
1126 1130 1135 1140
Ala Glu Ile Ala Asp Gly Met Ala Tyr Leu Asn Ala Lys Lys Phe
1141 1145 1150 1155
Val His Arg Asp Leu Ala Ala Arg Asn Cys Met Val Ala His Asp
1156 1160 1165 1170
Phe Thr Val Lys Ile Gly Asp Phe Gly Met Thr Arg Asp Ile Tyr
1171 1175 1180 1185
Glu Thr Asp Tyr Tyr Arg Lys Gly Gly Lys Gly Leu Leu Pro Val
1186 1190 1195 1200
Arg Trp Met Ala Pro Glu Ser Leu Lys Asp Gly Val Phe Thr Thr
1201 1205 1210 1215
Ser Ser Asp Met Trp Ser Phe Gly Val Val Leu Trp Glu Ile Thr
1216 1220 1225 1230
Ser Leu Ala Glu Gln pro Tyr Gln Gly Leu Ser Asn Glu Gln Val
1231 1235 1240 1245
Leu Lys Phe Val Met Asp Gly Gly Tyr Leu Asp Gln Pro Asp Asn
1246 1250 1255 1260
Cys Pro Glu Arg Val Thr Asp Leu Met Arg Met Cys Trp Gln Phe
1261 1265 1270 1275
Asn Pro Lys Met Arg Pro Thr Phe Leu Glu Ile Val Asn Leu Leu
1276 1280 1285 1290
Lys Asp Asp Leu His Pro Ser Phe Pro Glu Val Ser Phe Phe His
1291 1295 1300 1305
Ser Glu Glu Asn Lys Ala Pro Glu Ser Glu Glu Leu Glu Met Glu
1306 1310 1315 1320
Phe Glu Asp Met Glu Asn Val Pro Leu Asp Arg Ser Ser His Cys
1321 1325 1330 1335
Gln Arg Glu Glu Ala Gly Gly Arg Asp Gly Gly Ser Ser Leu Gly
1336 1340 1345 1350
Phe Lys Arg Ser Tyr Glu Glu His Ile Pro Tyr Thr His Met Asn
1351 1355 1360 1365
Gly Gly Lys Lys Asn Gly Arg Ile Leu Thr Leu Pro Arg Ser Asn
1366 1370 1375 1380
Pro Ser
13811382
制备起始抗人胰岛素受体β亚基C端片段多克隆抗体的示例性过程可描述如下。在采血前7-9天,将期望抗原经1-3次静脉注射至兔,以增高兔血流中的多克隆抗体水平。一旦免疫后,采集血样以测试抗体水平。通常,可溶性抗原免疫反应在抗原第一次注射后40-60天内达到最高水平。第一个免疫周期结束后,兔具有30天的康复期,之后经另外的1-3次静脉注射进行再免疫。
为获得包含期望抗体的抗血清,从兔中收集免疫后的兔血液并置于50ml离心管中。用木质药匙(spatula)将管壁上所形成的产物凝块移除,将棒置于管中心的凝块中。然后将血液放置于冷却器中于约40℃的温度下过夜。第二天,将药匙上的凝块移除,将剩余液体在13000转下离心10min。上清液体为目标抗血清。所获得的抗血清通常为黄色。向抗血清中加入20wt%的NaN3至最终浓度为0.02%并在-20℃的温度下于冷冻状态贮存至使用,或者不加入NaN3而在-70℃的温度下贮存至使用。为了从抗血清中分离目标抗人胰岛素受体β亚基C端片段抗体,下述固相吸附顺序很适合:
将10ml兔抗血清用0.15M的NaCl稀释2倍,之后加入6.26g Na2SO4,混合并在4℃下孵育12-16小时。将沉淀物经离心移除,在10ml磷酸盐缓冲液中稀释并使用相同的缓冲液在环境温度下透析过夜。移除沉淀物后,将溶液加样至用磷酸盐缓冲液平衡后的DEAE-纤维素柱。通过在280nm处对洗脱液的光密度进行测量来确定抗体馏分。
使用亲和色谱法,通过将所获得的抗人胰岛素受体β亚基C端片段抗体附至色谱介质的不溶性基质上、并随后用浓的水性盐溶液洗脱,对所分离出的粗抗体进行纯化。
将所得到的缓冲溶液用作顺势疗法稀释方法的起始溶液,所述顺势疗法稀释方法用来制备活性强化形式的抗体。抗原纯化的抗人胰岛素受体β亚基C端片段多克隆兔抗体的初始基质溶液的优选浓度为0.5-5.0mg/ml,优选2.0-3.0mg/ml。
通过类似的方法学使用佐剂来获得抗内皮NO合酶多克隆抗体。为获得抗内皮NO合酶多克隆抗体,可将下述序列的牛内皮NO合酶的整个分子用作免疫原(抗原):
SEQ ID NO:15
Met Gly Asn Leu Lys Ser Val Gly Gln Glu Pro Gly Pro Pro Cys
1 5 10 15
Gly Leu Gly Leu Gly Leu Gly Leu Gly Leu Cys Gly Lys Gln Gly
16 20 25 30
Pro Ala Ser Pro Ala Pro Glu Pro Ser Arg Ala Pro Ala Pro Ala
31 35 40 45
Thr Pro His Ala Pro Asp His Ser Pro Ala Pro Asn Ser pro Thr
46 50 55 60
Leu Thr Arg Pro Pro Glu Gly Pro Lys Phe Pro Arg Val Lys Asn
61 65 70 75
Trp Glu Leu GLy ser Ile Thr Tyr Asp Thr Leu Cys Ala Gln Ser
76 80 85 90
Gln Gln Asp Gly Pro Cys Thr Pro Arg Cys Cys Leu GLy ser Leu
91 95 100 105
Val Leu Pro Arg Lys Leu Gln Thr Arg Pro Ser Pro Gly Pro Pro
106 110 115 120
Pro Ala Glu Gln Leu Leu Ser Gln Ala Arg Asp Phe Ile Asn Gln
121 125 130 135
Tyr Tyr Ser Ser Ile Lys Arg Ser GLy ser Gln Ala His Glu Glu
l36 140 145 150
Arg Leu Gln Glu Val Glu Ala Glu Val Ala Ser Thr Gly Thr Tyr
151 155 160 165
His Leu Arg Glu Ser Glu Leu Val Phe Gly Ala Lys Gln Ala Trp
166 170 175 180
Arg Asn Ala Pro Arg Cys Val Gly Arg Ile Gln Trp Gly Lys Leu
181 185 190 195
Gln Val Phe Asp Ala Arg Asp Cys Ser Ser Ala Gln Glu Met Phe
196 200 205 210
Thr Tyr Ile Cys Asn His Ile Lys Tyr Ala Thr Asn Arg Gly Asn
211 215 220 225
Leu Arg Ser Ala Ile Thr Val Phe Pro Gln Arg Ala Pro Gly Arg
226 230 235 240
Gly Asp Phe Arg Ile Trp Asn Ser Gln Leu Val Arg Tyr Ala Gly
241 245 250 255
Tyr Arg Gln Gln Asp GLy ser Val Arg Gly Asp Pro Ala Asn Val
256 260 265 270
Glu Ile Thr Glu Leu Cys Ile Gln His Gly Trp Thr Pro Gly Asn
271 275 280 285
Gly Arg Phe Asp Val Leu Pro Leu Leu Leu Gln Ala Pro Asp Glu
286 290 295 300
Ala Pro Glu Leu Phe Val Leu Pro Pro Glu Leu Val Leu Glu Val
301 305 310 315
Pro Leu Glu His Pro Thr Leu Glu Trp Phe Ala Ala Leu Gly Leu
316 320 325 330
Arg Trp Tyr Ala Leu Pro Ala Val Ser Asn Met Leu Leu Glu Ile
331 335 340 345
Gly Gly Leu Glu Phe Ser Ala Ala Pro Phe Ser Gly Trp Tyr Met
346 350 355 360
Ser Thr Glu Ile Gly Thr Arg Asn Leu Cys Asp Pro His Arg Tyr
361 365 370 375
Asn Ile Leu Glu Asp Val Ala Val Cys Met Asp Leu Asp Thr Arg
376 380 385 390
Thr Thr Ser Ser Leu Trp Lys Asp Lys Ala Ala Val Glu Ile Asn
391 395 400 405
Leu Ala Val Leu His Ser Phe Gln Leu Ala Lys Val Thr Ile Val
406 410 415 420
Asp His His Ala Ala Thr Val Ser Phe Met Lys His Leu Asp Asn
421 425 430 435
Glu Gln Lys Ala Arg Gly Gly Cys Pro Ala Asp Trp Ala Trp Ile
436 440 445 450
Val Pro Pro Ile Ser GLy ser Leu Thr Pro Val Phe His Gln Glu
451 455 460 465
Met Val Asn Tyr Ile Leu Ser Pro Ala Phe Arg Tyr Gln Pro Asp
466 470 475 480
Pro Trp Lys GLy Ser Ala Thr Lys Gly Ala Gly Ile Thr Arg Lys
481 485 490 495
Lys Thr Phe Lys Glu Val Ala Asn Ala Val Lys Ile Ser Ala Ser
496 500 505 510
Leu Met Gly Thr Leu Met Ala Lys Arg Val Lys Ala Thr Ile Leu
511 515 510 525
Tyr Ala Ser Glu Thr Gly Arg Ala Gln Ser Tyr Ala Gln Gln Leu
526 530 535 540
Gly Arg Leu Phe Arg Lys Ala Phe Asp Pro Arg Val Leu Cys Met
541 545 550 555
Asp Glu Tyr Asp Val Val Ser Leu Glu His Glu Ala Leu Val Leu
556 560 565 570
Val Val Thr Ser Thr Phe Gly Asn Gly Asp Pro Pro Glu Asn Gly
571 575 580 585
Glu Ser Phe Ala Ala Ala Leu Met Glu Met Ser Gly Pro Tyr Asn
586 590 595 600
Ser Ser Pro Arg pro Glu Gln His Lys Ser Tyr Lys Ile Arg Phe
601 605 610 615
Asn Ser Val Ser Cys Ser Asp Pro Leu Val Ser Ser Trp Arg Arg
616 620 625 630
Lys Arg Lys Glu Ser Ser Asn Thr Asp Ser Ala Gly Ala Leu Gly
631 635 640 645
Thr Leu Arg Phe Cys Val Phe Gly Leu GLy Ser Arg Ala Tyr Pro
646 650 655 660
His Phe Cys Ala Phe Ala Arg Ala Val Asp Thr Arg Leu Glu Glu
661 665 670 675
Leu Gly Gly Glu Arg Leu Leu Gln Leu Gly Gln Gly Asp Glu Leu
676 680 685 690
Cys Gly Gln Glu Glu Ala Phe Arg Gly Trp Ala Lys Ala Ala Phe
691 695 700 705
Gln Ala Ser Cys Glu Thr Phe Cys Val Gly Glu Glu Ala Lys Ala
706 710 715 720
Ala Ala Gln Asp Ile Phe Ser Pro Lys Arg Ser Trp Lys Arg Gln
721 725 730 735
Arg Tyr Arg Leu Ser Thr Gln Ala Glu Gly Leu Gln Leu Leu Pro
736 740 745 750
Gly Leu Ile His Val His Arg Arg Lys Met Phe Gln Ala Thr Val
751 755 760 765
Leu Ser Val Glu Asn Leu Gln Ser Ser Lys Ser Thr Arg Ala Thr
766 770 775 780
Ile Leu Val Arg Leu Asp Thr Ala Gly Gln Glu Gly Leu Gln Tyr
781 785 790 795
Gln Pro Gly Asp His Ile Gly Ile Cys Pro Pro Asn Arg Pro Gly
796 800 805 810
Leu Val Glu Ala Leu Leu Ser Arg Val Glu Asp Pro Pro Pro Pro
811 815 820 825
Thr Glu Ser Val Ala Val Glu Gln Leu Glu Lys Gly ser Pro Gly
826 830 835 840
Gly Pro Pro Pro Ser Trp Val Arg Asp Pro Arg Leu Pro Pro Cys
841 845 850 855
Thr Leu Arg Gln Ala Leu Thr Phe Phe Leu Asp Ile Thr Ser Pro
856 860 865 870
Pro Ser Pro Arg Leu Leu Arg Leu Leu Ser Thr Leu Ala Glu Glu
871 875 880 885
Pro Ser Glu Gln Gln Glu Leu Glu Thr Leu Ser Gln Asp Pro Arg
886 890 895 900
Arg Tyr Glu Glu Trp Lys Trp Phe Arg Cys Pro Thr Leu Leu Glu
901 905 910 915
Val Leu Glu Gln Phe Pro Ser Val Ala Leu Pro Ala Pro Leu Leu
916 920 925 930
Leu Thr Gln Leu Pro Leu Leu Gln Pro Arg Tyr Tyr Ser Val Ser
931 935 940 945
Ser Ala Pro Asn Ala His Pro Gly Glu Val His Leu Thr Val Ala
946 950 955 960
Val Leu Ala Tyr Arg Thr Gln Asp Gly Leu Gly Pro Leu His Tyr
961 965 970 975
Gly Val Cys Ser Thr Trp Leu Ser Gln Leu Lys Thr Gly Asp Pro
976 980 985 990
Val Pro Cys Phe Ile Arg Gly Ala Pro Ser Phe Arg Leu Pro Pro
991 995 1000 1005
Asp Pro Tyr Val Pro Cys Ile Leu Val Gly Pro Gly Thr Gly Ile
1006 1010 1015 1020
Ala Pro Phe Arg Gly Phe Trp Gln Glu Arg Leu His Asp Ile Glu
1021 1025 1030 1035
Ser Lys Gly Leu Gln Pro Ala Pro Met Thr Leu Val Phe Gly Cys
1036 1040 1045 1050
Arg Cys Ser Gln Leu Asp His Leu Tyr Arg Asp Glu Val Gln Asp
1051 1055 1060 1065
Ala Gln Glu Arg Gly Val Phe Gly Arg Val Leu Thr Ala Phe Ser
1066 1070 1075 1080
Arg Glu Pro Asp Ser Pro Lys Thr Tyr Val Gln Asp Ile Leu Arg
1081 1085 1090 1095
Thr Glu Leu Ala Ala Glu Val His Arg Val Leu Cys Leu Glu Arg
1096 1100 1105 1110
Gly His Met Phe Val Cys Gly Asp Val Thr Met Ala Thr Ser Val
1111 1115 1120 1125
Leu Gln Thr Val Gln Arg Ile Leu Ala Thr Glu Gly Asp Met Glu
1126 1130 1135 1140
Leu Asp Glu Ala Gly Asp Val Ile Gly Val Leu Arg Asp Gln Gln
1141 1145 1150 1155
Arg Tyr His Glu Asp Ile Phe Gly Leu Thr Leu Arg Thr Gln Glu
1156 1160 1165 1170
Val Thr Ser Arg Ile Arg Thr Gln Ser Phe Ser Leu Gln Glu Arg
1171 1175 1180 1185
His Leu Arg Gly Ala Val Pro Trp Ala Phe Asp Pro Pro Gly Pro
1186 1190 1195 1200
Asp Thr Pro Gly Pro
1201 1205
抗NO合酶多克隆抗体可使用以下序列的人NO合酶的整个分子获得:
SEQ ID NO:16
Met Gly Asn Leu Lys Ser Val Ala Gln Glu Pro Gly Pro Pro Cys
1 5 10 15
Gly Leu Gly Leu Gly Leu Gly Leu Gly Leu Cys Gly Lys Gln Gly
16 20 25 30
Pro Ala Thr Pro Ala Pro Glu Pro Ser Arg Ala Pro Ala Ser Leu
31 35 40 45
Leu Pro Pro Ala Pro Glu His Ser Pro Pro Ser Ser Pro Leu Thr
46 50 55 60
Gln Pro Pro Glu Gly Pro Lys Phe Pro Arg Val Lys Asn Trp Glu
61 65 70 75
Val GLys er Ile Thr Tyr Asp Thr Leu Ser Ala Gln Ala Gln Gln
76 80 85 90
Asp Gly Pro Cys Thr Pro Arg Arg Cys Leu GLys er Leu Val Phe
91 95 100 105
Pro Arg Lys Leu Gln Gly Arg Pro Ser Pro Gly Pro Pro Ala Pro
106 110 115 120
Glu Gln Leu Leu Ser Gln Ala Arg Asp Phe Ile Asn Gln Tyr Tyr
121 125 130 135
Ser Ser Ile Lys Arg Ser GLys er Gln Ala His Glu Gln Arg Leu
136 140 145 150
Gln Glu Val Glu Ala Glu Val Ala Ala Thr Gly Thr Tyr Gln Leu
151 155 160 165
Arg Glu Ser Glu Leu Val Phe Gly Ala Lys Gln Ala Trp Arg Asn
166 170 175 180
Ala Pro Arg Cys Val Gly Arg Ile Gln Trp Gly Lys Leu Gln Val
181 185 190 195
Phe Asp Ala Arg Asp Cys Arg Ser Ala Gln Glu Met Phe Thr Tyr
196 200 205 210
Ile Cys Asn His Ile Lys Tyr Ala Thr Asn Arg Gly Asn Leu Arg
211 215 220 225
Ser Ala Ile Thr Val Phe Pro Gln Arg Cys Pro Gly Arg Gly Asp
226 230 235 240
Phe Arg Ile Trp Asn Ser Gln Leu Val Arg Tyr Ala Gly Tyr Arg
241 245 250 255
Gln Gln Asp GLy Ser Val Arg Gly Asp Pro Ala Asn Val Glu Ile
256 260 265 270
Thr Glu Leu Cys Ile Gln His Gly Trp Thr Pro Gly Asn Gly Arg
271 275 280 285
Phe Asp Val Leu Pro Leu Leu Leu Gln Ala Pro Asp Glu Pro Pro
286 290 295 300
Glu Leu Phe Leu Leu Pro Pro Glu Leu Val Leu Glu Val Pro Leu
301 305 310 315
Glu His Pro Thr Leu Glu Trp Phe Ala Ala Leu Gly Leu Arg Trp
316 320 325 330
Tyr Ala Leu Pro Ala Val Ser Asn Met Leu Leu Glu Ile Gly Gly
331 335 340 345
Leu Glu Phe Pro Ala Ala Pro Phe Ser Gly Trp Tyr Met Ser Thr
346 350 355 360
Glu Ile Gly Thr Arg Asn Leu Cys Asp Pro His Arg Tyr Asn Ile
361 365 370 375
Leu Glu Asp Val Ala Val Cys Met Asp Leu Asp Thr Arg Thr Thr
376 380 385 390
Ser Ser Leu Trp Lys Asp Lys Ala Ala Val Glu Ile Asn Val Ala
391 395 400 405
Val Leu His Ser Tyr Gln Leu Ala Lys Val Thr Ile Val Asp His
406 410 415 420
His Ala Ala Thr Ala Ser Phe Met Lys His Leu Glu Asn Glu Gln
421 425 430 435
Lys Ala Arg Gly Gly Cys Pro Ala Asp Trp Ala Trp Ile Val Pro
436 440 445 450
Pro Ile Ser GLy ser Leu Thr Pro Val Phe His Gln Glu Met Val
451 455 460 465
Asn Tyr Phe Leu Ser Pro Ala Phe Arg Tyr Gln Pro Asp Pro Trp
466 470 475 480
Lys Gly Ser Ala Ala Lys Gly Thr Gly Ile Thr Arg Lys Lys Thr
481 485 490 495
Phe Lys Glu Val Ala Asn Ala Val Lys Ile Ser Ala Ser Leu Met
496 500 505 510
Gly Thr Val Met Ala Lys Arg Val Lys Ala Thr Ile Leu Tyr Gly
511 515 510 525
Ser Glu Thr Gly Arg Ala Gln Ser Tyr Ala Gln Gln Leu Gly Arg
526 530 535 540
Leu Phe Arg Lys Ala Phe Asp Pro Arg Val Leu Cys Met Asp Glu
541 545 550 555
Tyr Asp Val Val Ser Leu Glu His Glu Thr Leu Val Leu Val Val
556 560 565 570
Thr Ser Thr Phe Gly Asn Gly Asp Pro Pro Glu Asn Gly Glu Ser
571 575 580 585
Phe Ala Ala Ala Leu Met Glu Met Ser Gly Pro Tyr Asn Ser Ser
586 590 595 600
Pro Arg Pro Glu Gln His Lys Ser Tyr Lys Ile Arg Phe Asn Ser
601 605 610 615
Ile Ser Cys Ser Asp Pro Leu Val Ser Ser Trp Arg Arg Lys Arg
616 620 625 630
Lys Glu Ser Ser Asn Thr Asp Ser Ala Gly Ala Leu Gly Thr Leu
631 635 640 645
Arg Phe Cys Val Phe Gly Leu GLys er Arg Ala Tyr Pro His Phe
646 650 655 660
Cys Ala Phe Ala Arg Ala Val Asp Thr Arg Leu Glu Glu Leu Gly
661 665 670 675
Gly Glu Arg Leu Leu Gln Leu Gly Gln Gly Asp Glu Leu Cys Gly
676 680 685 690
Gln Glu Glu Ala Phe Arg Gly Trp Ala Gln Ala Ala Phe Gln Ala
691 695 700 705
Ala Cys Glu Thr Phe Cys Val Gly Glu Asp Ala Lys Ala Ala Ala
706 710 715 720
Arg Asp Ile Phe Ser Pro Lys Arg Ser Trp Lys Arg Gln Arg Tyr
721 725 730 735
Arg Leu Ser Ala Gln Ala Glu Gly Leu Gln Leu Leu Pro Gly Leu
736 740 745 750
Ile His Val His Arg Arg Lys Met Phe Gln Ala Thr Ile Arg Ser
751 755 760 765
Val Glu Asn Leu Gln Ser Ser Lys Ser Thr Arg Ala Thr Ile Leu
766 770 775 780
Val Arg Leu Asp Thr Gly Gly Gln Glu Gly Leu Gln Tyr Gln Pro
781 785 790 795
Gly Asp His Ile Gly Val Cys Pro Pro Asn Arg Pro Gly Leu Val
796 800 805 810
Glu Ala Leu Leu Ser Arg Val Glu Asp Pro Pro Ala Pro Thr Glu
811 815 820 825
Pro Val Ala Val Glu Gln Leu Glu Lys Gly Ser Pro Gly Gly Pro
826 830 835 840
Pro Pro Gly Trp Val Arg Asp Pro Arg Leu Pro Pro Cys Thr Leu
841 845 850 855
Arg Gln Ala Leu Thr Phe Phe Leu Asp Ile Thr Ser Pro Pro Ser
856 860 865 870
Pro Gln Leu Leu Arg Leu Leu Ser Thr Leu Ala Glu Glu Pro Arg
871 875 880 885
Glu Gln Gln Glu Leu Glu Ala Leu Ser Gln Asp Pro Arg Arg Tyr
886 890 895 900
Glu Glu Trp Lys Trp Phe Arg Cys Pro Thr Leu Leu Glu Val Leu
901 905 910 915
Glu Gln Phe Pro Ser Val Ala Leu Pro Ala Pro Leu Leu Leu Thr
916 920 925 930
Gln Leu Pro Leu Leu Gln Pro Arg Tyr Tyr Ser Val Ser Ser Ala
931 935 940 945
Pro Ser Thr His Pro Gly Glu Ile His Leu Thr Val Ala Val Leu
946 950 955 960
Ala Tyr Arg Thr Gln Asp Gly Leu Gly Pro Leu His Tyr Gly Val
961 965 970 975
Cys Ser Thr Trp Leu Ser Gln Leu Lys Pro Gly Asp Pro Val Pro
976 980 985 990
Cys Phe Ile Arg Gly Ala Pro Ser Phe Arg Leu Pro Pro Asp Pro
991 995 1000 1005
Ser Leu Pro Cys Ile Leu Val Gly Pro Gly Thr Gly Ile Ala Pro
1006 1010 1015 1020
Phe Arg Gly Phe Trp Gln Glu Arg Leu His Asp Ile Glu Ser Lys
1021 1025 1030 1035
Gly Leu Gln Pro Thr Pro Met Thr Leu Val Phe Gly Cys Arg Cys
1036 1040 1045 1050
Ser Gln Leu Asp His Leu Tyr Arg Asp Glu Val Gln Asn Ala Gln
1051 1055 1060 1065
Gln Arg Gly Val Phe Gly Arg Val Leu Thr Ala Phe Ser Arg Glu
1066 1070 1075 1080
Pro Asp Asn Pro Lys Thr Tyr Val Gln Asp Ile Leu Arg Thr Glu
1081 1085 1090 1095
Leu Ala Ala Glu Val His Arg Val Leu Cys Leu Glu Arg Gly His
1096 1100 1105 1110
Met Phe Val Cys Gly Asp Val Thr Met Ala Thr Asn Val Leu Gln
1111 1115 1120 1125
Thr Val Gln Arg Ile Leu Ala Thr Glu Gly Asp Met Glu Leu Asp
1126 1130 1135 1140
Glu Ala Gly Asp Val Ile Gly Val Leu Arg Asp Gln Gln Arg Tyr
1141 1145 1150 1155
His Glu Asp Ile Phe Gly Leu Thr Leu Arg Thr Gln Glu Val Thr
1156 1160 1165 1170
Ser Arg Ile Arg Thr Gln Ser Phe Ser Leu Gln Glu Arg Gln Leu
1171 1175 1180 1185
Arg Gly Ala Val Pro Trp Ala Phe Asp Pro Pro Gly Ser Asp Thr
1186 1190 1195 1200
Asn Ser Pro
1201 1203
特别在考虑之列的是将以下序列的内皮NO合酶片段用作合适的抗原:
SEQ ID NO:17
Pro Trp Ala Phe
1192 1195
SEQ ID NO:18
Gly Ala Val Pro
1189 1192
SEQ ID NO:19
Arg
1185
His Leu Arg Gly Ala Val Pro Trp Ala Phe Asp Pro Pro Gly Pro
1186 1190 1195 1200
Asp Thr Pro Gly Pro
1201 1205
SEQ ID NO:20
Ala Phe Asp Pro Pro Gly Pro
11941195 1200
Asp Thr Pro Gly Pro
1201 1205
SEQ ID NO:21
His Leu Arg Gly Ala Val Pro Trp Ala Phe Asp
1186 1190 11951196
SEQ ID NO:22
His Leu Arg Gly Ala Val Pro Trp Ala Phe Asp Pro Pro Gly Pro
1186 1190 1195 1200
Asp Thr Pro Gly Pro
1201 1205
活性强化形式的复合物各组分可由初始溶液经顺势疗法强化来制备,优选使用通过连续稀释来成比例降低浓度的如下方法:将1份的各在先溶液(preceding solution)(由初始溶液开始)连续稀释于9份(十倍稀释)、或连续稀释于99份(百倍稀释)、或连续稀释于999份(千倍稀释)的中性溶剂中,并伴以外部作用。所述外部作用优选包括每次稀释时的多次竖直振荡(稀释增效法,dynamization)。优选将单独容器用于后续各次稀释,直至所需效力水平或稀释系数。这一方法在顺势疗法领域中被广泛接受。参见例如V.Schwabe,“Homeopathic medicines”,M.,1967,第14-29页,以引用的方式将其并入本文用于所述目的。
例如,为了制备第12百倍稀释液(表示为C12),将1份浓度为3.0mg/ml的抗人胰岛素受体β亚基C端片段抗体的初始基质溶液稀释于99份中性水溶剂或水-醇溶剂(优选15%乙醇)中,并随后进行多次(10次以上)竖直振荡以制成第1百倍稀释液(表示为C1)。第2百倍稀释液(C2)由第1百倍稀释液C1制备。将这一过程重复11次,从而制得第12百倍稀释液C12。因此,第12百倍稀释液C12表示通过将1份浓度为3.0mg/ml的抗人胰岛素受体β亚基C端片段抗体的初始基质溶液在处于不同容器内的99份中性溶剂中连续稀释12次所获得的溶液,相当于百倍顺势疗法稀释液C12。以相应的稀释系数进行类似过程,获得C30和C200稀释液。可将中间稀释液在期望的生物模型中进行测试以检测活性。用于本发明复合物中的优选的两种活性强化形式抗体为C12、C30和C200稀释液混合物。当将活性物质的多种顺势疗法稀释液(主要为百倍稀释液)的混合物用作生物活性液体组分时,组合物的各组分(如,C12、C30、C200)分别根据上述过程制备,直至获得倒数第二份稀释液(例如,分别直至C11、C29和C199),然后根据混合物组成将1份的各组分加入一个容器中,并与所需量的溶剂(如,用97份以进行百倍稀释)进行混合。
可将活性物质作为多种顺势疗法稀释液、例如十倍和/或百倍稀释液(D20、C30、C100或C12、C30、C50等)的混合物来使用,其效力通过在合适的生物模型、例如本文实施例所述的模型中对稀释液进行测试,从而以实验的方式确定。
在强化和浓度降低的过程中,可将竖直振荡替代为外部暴露至超声、电磁场或顺势疗法领域中接受的任何类似的外部作用过程。
本发明的药物组合物优选可处于液体或固体单位剂型的形式。药物组合物优选的液体形式为混合物,优选活性强化形式的抗人胰岛素受体β亚基C端片段抗体和活性强化形式的抗内皮NO合酶抗体处于1:1比例的混合物。优选的液态载体为水或水-乙醇混合物。
可通过使用活性强化形式的活性组分水溶液或水-醇溶液的混合物对药学上可接受的固态载体进行浸渍,来制备本发明药物组合物的固体单位剂型,所述活性组分水溶液或水-醇溶液主要以1:1的比例进行混合并以液态剂型加以使用。或者,可用各所需稀释液对载体进行连续浸渍。两种浸渍顺序均可接受。
优选处于固体单位剂型的药物组合物由药学上可接受的载体的颗粒制备,所述颗粒预先用活性强化形式的抗人胰岛素受体β亚基C端片段抗体和活性强化形式的抗内皮NO合酶抗体的水稀释液或水-醇稀释液饱和。固体剂型可为药学领域中已知的任何剂型,包括片剂、胶囊、锭剂及其它。作为非活性药物成分,可使用葡萄糖、蔗糖、麦芽糖、淀粉、异麦芽糖、异麦芽酮糖醇及制药中使用的其它单糖、寡糖和多糖,还可使用上述非活性药物成分与其它药学上可接受的赋形剂的工艺混合物,所述赋形剂如异麦芽酮糖醇、交联聚维酮、甜蜜素(sodium cyclamate)、糖精钠、无水柠檬酸等,包括润滑剂、崩解剂、粘结剂和着色剂。优选的载体为乳糖和异麦芽酮糖醇。药物剂型可进一步包含标准药物赋形剂,例如微晶纤维素和硬脂酸镁。
制备固体单位剂型的实施例如下所述。为制备固体口服剂型,将乳糖的100-300μm颗粒用活性强化形式的抗人胰岛素受体β亚基C端片段抗体和活性强化形式的抗内皮NO合酶抗体的水溶液或水-醇溶液、以1kg抗体溶液对5kg或10kg乳糖(1:5至1:10)的比例进行浸渍。为有效浸渍,使乳糖颗粒在沸腾床设备(如,Hüttlin GmbH的“Hüttlin Pilotlab”)中的流化床中接受饱和灌洗(saturation irrigation),随后经由加热的空气流在低于40℃的温度下进行干燥。将用活性强化形式抗体饱和的估计量的干燥颗粒(10-34重量份)置于混合器内,并与25-45重量份的“非饱和”纯乳糖(用于在不降低治疗功效的情况下,降低成本、简化和加速工艺方法的目的)、以及0.1-1重量份的硬脂酸镁和3-10重量份的微晶纤维素一起进行混合。将所获得的片状物质进行均匀混合,并通过直接干压成型(如,在Korsch-XL400压片机中)进行压片,从而形成150-500mg、优选300mg的圆丸。压片后,获得300mg的丸剂,所述丸剂用活性强化形式的抗人胰岛素受体β亚基C端片段抗体和活性强化形式的抗内皮NO合酶抗体的复合物的水-醇溶液饱和(3.0-6.0mg/丸)。用于浸渍载体的复合物各组分均处于C12、C30和C50百倍顺势疗法稀释液的混合物的形式或C12、C30和C200百倍顺势疗法稀释液的混合物的形式。
尽管本发明并不受任何具体理论限制,但是认为,本文所述的活性强化形式抗体并不包含足够具有归因于此类分子形式的生物活性的量的分子形式抗体。本发明复合物的生物活性在所附的实施例中得以充分说明。
可将本发明的药物组合物用于向患有任何类型糖尿病的患者进行给予。
所述药物组合物可作为高血糖单药疗法(monotherapy)用于治疗糖尿病,还可作为胰岛素替代疗法的附加药(add-on)用于复方疗法;和/或与口服降血糖药剂例如双胍类药剂(二甲双胍)、磺酰脲类药剂(格列本脲、格列吡嗪、格列齐特、glicvidone、格列美脲)、噻唑烷二酮类药剂(罗格列酮)、α-葡萄糖苷酶抑制剂(拜糖平)等一起使用;以及作为糖尿病伴随疗法的附加药,用以预防糖尿病并发症。
如所附的实施例中所示,向此类患者给予本发明复合物改善了血糖水平。
实施例
实施例1
通过两个实验性研究对极低剂量的针对抗原亲和纯化的抗胰岛素受体β亚基C端片段抗体(ULD抗IR)、极低剂量的针对抗原亲和纯化的抗内皮NO合酶抗体(ULD抗eNOS)、以及极低剂量的抗胰岛素受体β亚基C端片段抗体和极低剂量的抗内皮NO合酶抗体复合物(ULD抗IR+ULD抗eNOS)的效果进行了研究,所述ULD抗IR通过将初始基质溶液高度稀释10012、10030和100200倍得到,所述ULD抗eNOS通过将初始基质溶液高度稀释10012、10030和100200倍得到。
根据世界卫生组织(WHO)的标准,糖尿病(I型和II型)的特征在于血糖水平增高(高血糖)和糖耐量扰动(glucose tolerancedisturbance)。后者可由胰岛素分泌异常和/或外周组织胰岛素敏感度降低引起。糖耐量测试(基于对机体组织利用葡萄糖的能力进行的动态评价)是对机体组织葡萄糖耐量扰动进行评价的灵敏方法。
研究1
在该研究中,使用了150只雄性Wistar大鼠(研究开始时重250-300g,3.5-4月龄)。10只大鼠原封未动。以50mg/kg的剂量向其余大鼠静脉注射链脲菌素(糖尿病实验模型)。注射链脲菌素72小时后,选择血浆葡萄糖水平不低于12mmol/l的大鼠,将其分入7个组中(每组各20只大鼠),在21天内根据如下所述的方式分别给予相应的各制剂:蒸馏水(5ml/kg/天,每天一次,经胃给予)、胰岛素(8单位/kg/天,皮下给予)、罗格列酮(8mg/kg/天,每天两次,经胃给予)、ULD抗IR(2.5ml/kg/天(以5ml/kg/天的容积),每天一次,经胃给予药)、ULD抗IR+ULD抗eNOS(5ml/kg/天,每天一次,经胃给予药)、以及罗格列酮和胰岛素或ULD抗IR+ULD抗eNOS与胰岛素原封未动大鼠接受相同体积的蒸馏水。在大鼠注射制剂第7天、第14天和第21天时,利用“葡萄糖FKD”试剂盒(俄罗斯)以酶法(葡萄糖氧化酶法)对空腹血浆葡萄糖水平进行测量。
在该研究的第14天(给予制剂的第14天),根据标准方法(DuVigneaud和Karr,1925)进行口服葡萄糖耐量测试(OGTT)。对大鼠断水18小时。在测试前60min最后一次向大鼠给予测试物质。原封未动大鼠接受同样体积的蒸馏水。通过口服50%w/w葡萄糖水溶液(1g/kg大鼠重量)来给予葡萄糖。使用“葡萄糖FKD”试剂盒(OOO“Pharamaceuticaland clinical diagnostics”,俄罗斯,www.fkd.ru)对尾静脉血样的血清葡萄糖在0min、30min、60min、90min、120min时进行测量。计算血糖浓度对时间的曲线下平均面积(AUC)。
注射链脲菌素引起大鼠的血浆葡萄糖比起原封未动动物显著增高(18mmol/l相比于3.5mmol/l,p<0.05)。在ULD抗IR组中,在注射制剂的第7天、第14天、第21天,葡萄糖水平比起对照组平均低22%-28%;然而,差异并未达到统计学上显著的水平。ULD抗IR与ULD抗eNOS的复合物更为有效:在实验的第14天和第21天,葡萄糖水平分别下降了47%和42%(与对照相比p<0.05)。到实验的第14天和第21天,参比制剂罗格列酮也降低了葡萄糖水平;然而,仅在实验第14天,所述效果达到了统计学上的显著性(36%,与对照相比p<0.05)。
在全部观察期间,以有效剂量(在初步研究中选定)的1/2注射胰岛素最有效地降低了葡萄糖水平(降至原封未动对照的水平)(图1)。应纳入考虑的是,在该研究中使用的是短效胰岛素,并且在注射该胰岛素1小时后对血浆葡萄糖进行了测量,这也影响了1/2胰岛素剂量对血糖水平的效果。鉴于这一背景,不能完全确定联合使用胰岛素和罗格列酮或胰岛素和ULD抗IR+ULD抗eNOS复方的效果如何。
葡萄糖耐量扰动(机体对葡萄糖的利用降低)是糖尿病诊断和治疗中最重要的指标之一。在原封未动动物中,在口服葡萄糖耐量测试中(注射制剂第14天),当单独给予时,复方制剂ULD抗IR+ULD抗eNOS和胰岛素最有效地增强了葡萄糖耐量。罗格列酮也减小了浓度对时间曲线下面积(增强了葡萄糖耐量);然而,其效力与对照组相比在统计学上并不显著(图2)。
研究2
在该研究中,使用了36只雄性Goto-Kakizaki大鼠(研究开始时重250-280g,10-12周龄)。这一品系大鼠的特征在于非胰岛素依赖性糖尿病的自发性发展。将动物分入3组中(各12只大鼠)并在28天内接受蒸馏水(5ml/kg,每天一次,经胃给予)、或ULD抗IR(2.5ml/kg,每天一次,经胃给予)、或ULD抗IR+ULD抗eNOS(5ml/kg,每天一次,经胃给予)。借助于葡萄糖分析仪(Beckman,Fullerton,加利福尼亚,美国),在开始注射制剂前、以及在注射制剂的第4天、第8天、第12天、第16天、第20天、第24天、第28天时对血浆葡萄糖水平进行测量。在第28天,进行葡萄糖耐量测试(葡萄糖p.o.,1g/kg)。
注射ULD抗IR使得大鼠血浆葡萄糖水平显著(p<0.05)下降;然而,使用ULD抗IR+ULD抗eNOS复方更为有效(与对照相比p<0.001)(图3)。
通过在注射制剂第28天时实现的葡萄糖耐量测试数据证实了所述结果(图4)。注射ULD抗IR引起葡萄糖耐量增强(与对照相比,AUC降低了44%,统计学上不显著)。同时,由注射ULD抗IR+ULD抗eNOS复方引起的这一参数(AUC)的降低为62%,且其与对照相比在统计学上显著(p<0.05)。
实施例2
在人类中,对极低剂量的抗胰岛素受体β亚基C端片段抗体(ULD抗IR)和极低剂量的抗内皮NO合酶抗体(ULD抗eNOS)的复合物进行了临床研究,各抗体处于浸渍至异麦芽酮糖醇上的C12、C30及C200顺势疗法稀释液的水-醇混合物形式。
在1型糖尿病(DM)患者中进行的ULD抗IR+ULD抗eNOS的效力和安全性的开放标签非比较性研究囊括了如下患者:诊断为轻度至中度的1型DM、且无严重的大血管和微血管病理征象的患者。在获得患者参与临床试验的知情同意书后,为确定患者是否符合纳入/排除标准进行了初步调查。在开始研究前,提供了2周的“洗脱期(wash-out period)”,在所述洗脱期期间,对患者进行了检查(对疾患、空腹血糖、糖化血红蛋白、日血糖谱和lipoproteinogram以及当前治疗的效力和安全性进行了评价)。在12周的研究中,在“洗脱”周、然后在治疗的第6周和第12周对关键的终点(key endpoints)进行测量。在“洗脱”期期间和该研究的末期,借助于CGMS系统,在4名患者中对血糖水平进行连续监测。所述连续血糖监测系统(CGMS)使得能够对血糖水平控制三天。测试结果显示出了在3天内葡萄糖水平根据胰岛素治疗和生活方式如何变化。这一数据有助于区分取决于饮食、药物摄入或体力负荷的高血糖水平时期或低血糖水平时期。该系统以图形方式显示出2.2mmol/L的最低血糖水平,高达22.2mmol/L的最高值,以及平均的日血糖水平。
在纳入研究前和在研究期间,处于失代偿期(decompensation stage)的、患有轻度至中度1型DM的患者接受了标准胰岛素治疗:
·早晨8-10U/天
·午餐8-12U/天
·晚餐8-13U/天。
在确认患者能参与后,将患者纳入研究,并接受ULD抗IR+ULD抗eNOS制剂作为1型DM标准治疗的附加药;给药方案取决于1型DM的严重程度和代偿程度。囊括于所述研究中的患者以不同的剂量接受ULD抗IR+ULD抗eNOS制剂的治疗:
1.4名患者:一天4次(在8:00AM、12:00PM、6:00PM、10:00PM时),每次1片。
2.2名患者:一天2次(在8:00AM、6:00PM时),每次1片。
在第3周和第8周,还对日血糖谱(daily glycemic profile)(8点测量)进行了控制,并与患者通过电话进行联系(电话“随访”)。每周进行临床检查。总计观察患者14周。
所述研究囊括了6名患者,其中5人完成了研究方案。通过在基线时和在治疗3周、6周和12周后的8点日葡萄糖谱(eight-point dailyglucose profile)对血糖进行评价。在基线时和在治疗12周后确定糖化血红蛋白的水平。
观察到,囊括于所述研究中的所有1型DM患者在用研究药物治疗6周后日血糖呈下降趋势。根据8点日葡萄糖谱,在1型DM患者中记录到血糖平均下降20%。经过12周的治疗后,相比于基线值,糖化血红蛋白平均低了10-15%。
根据用CGMS系统在所有患者中连续监测血糖的结果,通过ULD抗IR+ULD抗eNOS进行3个月治疗使得平均日血糖降低,并降低了基线15-20%的最低血糖和最高血糖振幅。
在处于失代偿期的103号1型DM患者中,出乎意料地观察到了48%的日血糖显著下降(1周——8.0mmol/L,12周——4.8mmol/L),这需要胰岛素治疗的矫正(将短效胰岛素的日剂量减至8U/d)。图5中示出了平均血糖水平和糖化血红蛋白的动态。
在该研究过程中,未记录到包括严重不良事件在内的任何不良事件,这证明了所述制剂的安全性。
实施例3
在人类中,对极低剂量的抗胰岛素受体β亚基C端片段抗体(ULD抗IR)和极低剂量的抗内皮NO合酶抗体(ULD抗eNOS)的复合物进行了临床研究,各抗体处于浸渍至异麦芽酮糖醇上的C12、C30及C200顺势疗法稀释液的水-醇混合物形式。
在2型糖尿病(DM)患者中进行的ULD抗IR+ULD抗eNOS的效力和安全性的开放标签非比较性研究囊括了如下患者:诊断为轻度至中度的2型DM、且无严重的大血管和微血管病理征象的患者,所述患者接受了平均治疗剂量的二甲双胍。在获得患者参与临床试验的知情同意书后,为确定患者是否符合纳入/排除标准进行了初步调查。在确认患者能参与研究后,除接受2型DM标准治疗外,患者以每天4次、每次1片接受Subbetta。在开始研究前,提供了2周的“洗脱期”,在所述洗脱期期间,对患者进行了检查(对疾患、空腹血糖、糖化血红蛋白、日血糖谱和lipoproteinogram、胰岛素抵抗指数指标(HOMA-IR)以及当前治疗的效力和安全性进行了评价)。在12周的研究中,在“洗脱”周、然后在治疗的第6周和第12周对关键的终点进行测量。在“洗脱”期期间和该研究的末期,借助于CGMS系统,在4名患者中对血糖水平进行连续监测。在第3周和第8周,还另外对日血糖谱(8点测量)进行了控制,并进行了电话“随访”。每周进行临床检查。总计观察患者14周。
所述研究囊括了11名处于失代偿期的2型DM患者。一名患者自愿退出研究。其余患者继续治疗。根据8点日血糖谱数据,在6周于2型DM患者中记录到了20%的血糖平均下降。在12周,观察到了基线值15-19%的糖化血红蛋白平均下降。
在12周的过程中,所有患者中的血液测试参数(红细胞、血红蛋白、白细胞、血小板、leukocyte formula、ESR)、lipoproteinogram、EKG、肝功能分析(ALT、AST、胆红素及其部分)均保持在正常界限内。由HOMA-IR测试确定的胰岛素抵抗平均降低了基线值的17-19%。
在12周的研究过程中,未记录到包括严重不良事件在内任何不良事件,这证明了所述制剂的安全性。未显示出肝功能活动异常。
图6中示出了平均血糖水平和糖化血红蛋白的动态。
实施例4
被诊断患有II型糖尿病的患者X(男性,74岁)已经以5mg剂量的每天2次接受Maninil(格列本脲,Berlin-Chemie)。尽管已经对其给予治疗,在3年前于跟骨处出现了深度坏死的足溃疡。该患者曾两次在外科病房住院;然而,治疗并未引起显著的改善。将所请求保护的药物组合物(Ab RI+Ab NOS)(250mg的片剂)附加至Maninil治疗,所述药物组合物包含作为C12、C30及C200水-乙醇顺势疗法稀释液混合物的、浸渍至异麦芽酮糖上的活性强化形式(极低剂量)的抗胰岛素受体β亚基C端片段抗体(Ab RI)和抗内皮NO合酶抗体(Ab NOS)。作为1个月治疗的结果,将的剂量减少至每日5mg(睡前1片)。血糖水平降至正常值(从8-10mmol/L至5-6mmol/L)。所给予的治疗使足溃疡得以恢复。所述溃疡处清除了坏死块并出现角质层(cuticularised)。经检查所述溃疡已不复存在,在跟骨处存在圆形白色的脱皮区域(直径3.5cm)。
Claims (39)
1.一种药物组合物,所述药物组合物包含:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体。
2.一种药物组合物,所述药物组合物包含:a)活性强化形式的抗人胰岛素受体β亚基C端片段抗体、和b)活性强化形式的抗内皮NO合酶抗体。
3.一种药物组合物,所述药物组合物包含:a)活性强化形式的抗人胰岛素受体抗体、和b)活性强化形式的抗内皮NO合酶抗体,其中,所述胰岛素受体分子由一个α亚基和一个β亚基组成。
4.一种药物组合物,所述药物组合物包含:药学上可接受的固态载体;以及a)活性强化形式抗人胰岛素受体β亚基C端片段抗体,处于浸渍至所述固态载体上的C12、C30及C200顺势疗法稀释液的混合物形式;以及b)活性强化形式的抗内皮NO合酶抗体,处于浸渍至所述固态载体上的C12、C30及C200顺势疗法稀释液的混合物形式。
5.如权利要求1、2、3或4所述的药物组合物,其中,所述抗人胰岛素受体抗体为单克隆抗体、多克隆抗体或天然抗体。
6.如权利要求5所述的药物组合物,其中,所述抗人胰岛素受体抗体为多克隆抗体。
7.如权利要求6所述的药物组合物,所述活性强化形式的抗人胰岛素受体抗体通过连续的百倍稀释、且每次稀释时均伴以振荡而制备。
8.如权利要求1、2、3或4所述的药物组合物,其中,所述抗内皮NO合酶抗体为单克隆抗体、多克隆抗体或天然抗体。
9.如权利要求8所述的药物组合物,其中,所述抗内皮NO合酶抗体为多克隆抗体。
10.如权利要求9所述的药物组合物,所述活性强化形式的抗内皮NO合酶抗体通过连续的百倍稀释、且每次稀释时均伴以振荡而制备。
11.如权利要求1所述的药物组合物,其中,所述人胰岛素受体由下述序列组成,所述序列选自于由SEQ ID No:1、SEQ ID No:2、SEQ ID No:3、SEQ ID No:4、SEQ ID No:5、SEQ ID No:6、SEQ ID No:7、SEQ IDNo:8、SEQ ID No:9、SEQ ID No:10、SEQ ID No:11、SEQ ID No:12、SEQ ID No:13、SEQ ID No:14所组成的组。
12.如权利要求1所述的药物组合物,其中,所述内皮NO合酶由SEQ.ID No.15、SEQ ID No:16、SEQ ID No:17、SEQ ID No:18、SEQ IDNo:19、SEQ ID No:20、SEQ ID No:21、SEQ ID No:22所提供的序列组成。
13.一种对人类患者中的I型糖尿病进行治疗的方法,所述方法包括向所述患者给予权利要求1、2、3或4所述的药物组合物。
14.如权利要求13所述的方法,其中,所述药物组合物每次给药时以1种固体剂型向患者进行给予。
15.如权利要求13所述的方法,其中,所述剂型为片剂。
16.如权利要求15所述的方法,其中,所述片剂通过直接压片法获得。
17.如权利要求15所述的方法,其中,所述片剂每日给药1-4次。
18.如权利要求15所述的方法,其中,所述片剂每日给药2次。
19.如权利要求15所述的方法,其中,所述片剂每日给药4次。
20.一种对人类患者中的II型糖尿病进行治疗的方法,所述方法包括向所述患者给予权利要求1、2、3或4所述的药物组合物。
21.如权利要求20所述的方法,其中,所述药物组合物每次给药时以1种固体剂型向患者进行给予。
22.如权利要求21所述的方法,其中,所述剂型为片剂。
23.如权利要求22所述的方法,其中,所述片剂通过直接压片法获得。
24.如权利要求22所述的方法,其中,所述片剂每日给药1-4次。
25.如权利要求15所述的方法,其中,所述片剂每日给药4次。
26.一种降低哺乳动物血糖水平的方法,所述方法包括向所述哺乳动物给予权利要求1、2、3或4所述的药物组合物。
27.如权利要求26所述的方法,其中,所述哺乳动物为人。
28.如权利要求27所述的方法,其中,所述药物组合物以1或2单位剂型向患者进行给予。
29.如权利要求28所述的方法,其中,所述剂型每日给药1-4次。
30.如权利要求29所述的方法,其中,所述剂型每日给药3次。
31.一种对胰岛素抵抗进行治疗的方法,所述方法包括向哺乳动物给予权利要求1、2、3或4所述的药物组合物。
32.如权利要求31所述的方法,其中,所述哺乳动物为人。
33.如权利要求32所述的方法,其中,所述药物组合物以1或2单位剂型向患者进行给予。
34.如权利要求33所述的方法,其中,所述剂型每日给药1-4次。
35.如权利要求34所述的方法,其中,所述剂型每日给药3次。
36.如权利要求13所述的方法,所述方法进一步包括给予胰岛素或其它适于治疗I型糖尿病的另外的药剂。
37.如权利要求20所述的方法,所述方法进一步包括给予适于治疗II型糖尿病的另外的药剂。
38.一种用于对患有糖尿病或其它代谢紊乱的患者进行治疗的药物组合物,所述组合物通过如下步骤获得:提供a)活性强化形式的抗人胰岛素受体抗体和b)活性强化形式的抗内皮NO合酶抗体,各抗体根据顺势疗法技术通过对每次获得的溶液进行连续重复稀释和多次振荡而制备;然后通过混合将强化后的溶液进行复合,或者用所述复合后的溶液或用各强化后的溶液单独浸渍载体物质。
39.如权利要求38所述的药物组合物,其中,所述活性强化形式的抗人胰岛素受体抗体为活性强化形式的抗人胰岛素受体C端片段抗体。
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RU2010130348/15A RU2531048C2 (ru) | 2010-07-21 | 2010-07-21 | Лекарственное средство для уменьшения резистентности к инсулину и лечения сахарного диабета и способ повышения эффективности лечения сахарного диабета инсулином и/или гипогликемическими препаратами |
RU2011127051 | 2011-07-01 | ||
RU2011127051/15A RU2509572C2 (ru) | 2011-07-01 | 2011-07-01 | Лекарственное средство для уменьшения резистентности к инсулину и для лечения сахарного диабета, способ уменьшения резистентности к инсулину, способ лечения сахарного диабета и способ лечения сахарного диабета инсулином и/или гипогликемическими препаратами |
PCT/IB2011/002177 WO2012010966A2 (en) | 2010-07-21 | 2011-07-15 | A combination pharmaceutical composition and methods of treating diabetes and metabolic disorders |
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UA76638C2 (en) | 2002-08-02 | 2006-08-15 | Oleh Illich Epshtein | Homeopathic medication based on anti-interferon antibodies and method for treating a pathological syndrome associated with interferon |
RU2309732C1 (ru) * | 2006-03-13 | 2007-11-10 | Олег Ильич Эпштейн | Спрессованная твердая оральная форма лекарственного препарата и способ получения твердой оральной формы лекарственного препарата |
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SG187038A1 (en) * | 2010-07-15 | 2013-02-28 | Oleg Iliich Epshtein | A method of increasing the effect of an activated-potentiated form of an antibody |
ITTO20110641A1 (it) | 2010-07-15 | 2012-01-16 | Oleg Iliich Epshtein | Composizioni farmaceutiche e metodi di trattamento |
CA2804967A1 (en) | 2010-07-15 | 2012-02-09 | Oleg Iliich Epshtein | Combination pharmaceutical composition and methods of treating diseases or conditions associated with neurodegenerative diseases |
MX2013000807A (es) | 2010-07-21 | 2013-10-28 | Oleg Iliich Epshtein | Un metodo para el tratamiento del trastorno de hiperactividad con deficit de atencion. |
EA029998B1 (ru) * | 2010-07-21 | 2018-06-29 | Олег Ильич ЭПШТЕЙН | Комбинированная фармацевтическая композиция и способ лечения головокружения различного генеза, кинетоза и вегетососудистой дистонии |
FR2962909A1 (fr) | 2010-07-21 | 2012-01-27 | Oleg Iliich Epshtein | Composition pharmaceutique d'association et son utilisation dans des procedes pour traiter les maladies ou affections associees avec une maladie ou affection respiratoire |
JP2013537532A (ja) * | 2010-08-06 | 2013-10-03 | イリイチ・エプシテイン オレグ | 感染性疾患を治療及び予防する組み合わせ医薬組成物及び方法 |
TWI588153B (zh) | 2012-05-18 | 2017-06-21 | 中國醫藥大學 | 多胜肽、編碼該多胜肽之核酸分子、以及該多胜肽之應用 |
RU2013111962A (ru) | 2013-03-18 | 2014-09-27 | Олег Ильич Эпштейн | Способ определения выраженности модифицирующей активности, ассоциированной с носителем |
RU2013111961A (ru) | 2013-03-18 | 2014-09-27 | Олег Ильич Эпштейн | Способ определения выраженности модифицирующей активности, ассоциированной с носителем |
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