CN1476476A - 可将抗体重新定向于病原体上的受体的配体/受体特异性交换剂 - Google Patents
可将抗体重新定向于病原体上的受体的配体/受体特异性交换剂 Download PDFInfo
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- CN1476476A CN1476476A CNA018167802A CN01816780A CN1476476A CN 1476476 A CN1476476 A CN 1476476A CN A018167802 A CNA018167802 A CN A018167802A CN 01816780 A CN01816780 A CN 01816780A CN 1476476 A CN1476476 A CN 1476476A
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Abstract
本发明一般涉及预防和治疗人类疾病(包括但不限于:病原体,如细菌、酵母、寄生虫、真菌、病毒,和癌症)的组合物和方法。更具体而言,此处所述实施方案涉及可将患者中存在的抗体重新定向于病原体上的受体的配体/受体特异性交换剂的生产和应用。
Description
发明领域
本发明普遍涉及预防和治疗人类疾病(包括但不限于:病原体,如细菌、酵母、寄生虫、真菌、病毒,和癌症)的组合物和方法。更具体而言,此处所述实施方案涉及可将患者中存在的抗体重新定向于病原体上的受体的配体/受体特异性交换剂的生产和应用。
发明背景
病原体(如细菌、酵母、寄生虫、真菌、病毒)感染和癌症的发病和扩散对于所有动物(包括人类、家畜和宠物)都是严重的健康问题。耐受接种和/或治疗的菌株增多加剧了这些健康威胁。过去,药理学工作者依靠传统的药物发现方法生产安全、有效的用于治疗这些疾病的化合物。传统的药物发现方法一般包括盲目地测试可能的药物候选分子,通常是随机选择,希望证明有一种能有效治疗某种疾病。然而,随着分子生物学的出现,药物发现的焦点已经转移到确定与病原体相关的分子靶标和设计可与这些分子靶标相互作用的化合物。
一类有前途的分子靶标是在细菌、酵母、寄生虫、真菌、病毒和癌细胞表面发现的受体,特别是可以附着于宿主细胞或宿主蛋白质(例如,胞外基质蛋白)的受体。该领域的研究主要集中于鉴定受体及其配体和发现可阻断配体与受体相互作用、从而阻断与宿主细胞或蛋白质粘附的分子。
例如,多种致病细菌(例如金黄色葡萄球菌)产生粘附受体(例如,ClfA、Efb和FnBPA),它们能结合宿主的胞外基质蛋白(例如,纤维蛋白原、纤连蛋白和层粘连蛋白)。(Flock,Mol.Med.Today 5:523-533(1999))。研究人员证实,对应于宿主胞外基质蛋白区的肽能阻断某些细菌与宿主胞外基质蛋白的粘附。(Pei等人,Infection and Immunity67(9):4525-4530(1999))。类似地,多种病毒含有能与宿主细胞表面上的蛋白质相互作用的受体。(参见,例如:美国专利号5,942,606和5,929,220)。研究人员证实,T4糖蛋白(一种宿主细胞蛋白)的一个片段能与人类免疫缺陷病毒(HIV)的gp120相互作用,T4肽能用来预防或治疗HIV感染。(参见,例如:美国专利号6,093,539)。另外,多种癌细胞表达能与宿主胞外基质蛋白相互作用的受体,研究人员证实,阻断整联蛋白受体的分子能抑制组织附着、转移、血管生成和肿瘤生长。(参见,例如:美国专利号:6,066,648;6,087,330;5,846,536;5,766,591;5,627,263)。尽管这些抑制肽具有潜在的治疗前途,但仍需要治疗和预防病原体感染和其它疾病的新组合物和方法。
发明简述
此处所述的本发明涉及能结合病原体上的受体并将患者中的抗体重新定向于病原体的新药物的制造、表征和用途。实施方案包括一种配体/受体特异性交换剂,它至少有一个包含一种受体的配体的特异性结构域,和至少一个与该特异性结构域连接的抗原结构域,其中该抗原结构域含有病原体或毒素的表位。
配体/受体特异性交换剂的一些实施方案含有一个特异性结构域,它包含一种肽的至少三个连续氨基酸,这种肽选自:胞外基质蛋白、病毒受体的配体和癌细胞受体的配体。在该实施方案的某些方面,例如,这种肽是一种胞外基质蛋白,选自纤维蛋白原、胶原蛋白、玻连蛋白、层粘连蛋白、纤溶酶原、血小板反应蛋白和纤连蛋白。优选地,这种胞外基质蛋白含有纤维蛋白原α链的至少三个氨基酸,在最优选的实施方案中,该配体含有序列精氨酸-甘氨酸-天冬氨酸(RGD)。
在其它实施方案中,上述肽是选自T4糖蛋白和乙型肝炎病毒包膜蛋白的病毒受体的配体。在该实施方案的其它方面,该肽是癌细胞上的受体的配体,选自HER-2/neu的配体和整联蛋白受体的配体。优选实施方案包含一个具有SEQ.ID.Nos.1-42之一所示序列的特异性结构域。
此处所述的配体/受体特异性交换剂与病原体上的受体相互作用。在其它实施方案中,该受体是一种细菌粘附受体,例如,选自下列的细菌粘附受体:胞外纤维蛋白原结合蛋白(Efb)、胶原蛋白结合蛋白、玻连蛋白结合蛋白、层粘连蛋白结合蛋白、纤溶酶原结合蛋白、血小板反应蛋白结合蛋白、凝集因子A(ClfA)、凝集因子B(ClfB)、纤连蛋白结合蛋白、凝固酶和胞外粘附蛋白。
此外所述的配体/受体特异性交换剂也与患者中的抗体相互作用。在某些实施方案中,例如,抗原结构域含有一种肽的至少三个氨基酸,该肽选自:单纯疱疹病毒蛋白、乙型肝炎病毒蛋白、TT病毒蛋白和脊髓灰质炎病毒蛋白。在希望的实施方案中,配体/受体特异性交换剂含有一个抗原结构域,它是一种单纯疱疹病毒蛋白,含有选自SEQ.ID.No.53和SEQ.ID.No.54的序列。在其它希望的实施方案中,抗原结构域是一种乙型肝炎病毒蛋白,含有SEQ.ID.No.49、SEQ.ID.No.50、SEQ.ID.No.52和SEQ.ID.No.59所示的序列。
一些配体/受体特异性交换剂也含有一个抗原结构域,它是一种TT病毒蛋白,含有SEQ.ID.Nos.43-47和SEQ.ID.Nos.55-58所示的序列。配体/受体特异性交换剂也可含有一个抗原结构域,它是一种脊髓灰质炎病毒蛋白,含有选自SEQ.ID.No.48和SEQ.ID.No.51的序列。优选地,该配体/受体特异性交换剂含有可与高效价抗体相互作用的抗原结构域。在某些实施方案中,例如,抗原结构域可与大约1∶100-1∶1000或更高稀释的动物血清中的抗体特异性结合。SEQ.ID.Nos.60-105的特异性交换剂是本发明的实施方案。
本发明的方面也涉及治疗或预防病原体感染或增殖的方法。例如,一种方法涉及治疗和预防细菌感染的方法。该方法如下实施:对患者施用治疗有效量的配体/受体特异性交换剂,其中该配体/受体特异性交换剂含有一个具有可与细菌上受体相互作用的配体的特异性结构域,和一个含有病原体或毒素表位的抗原结构域。治疗或预防病毒感染的方法也是一个实施方案。因此,一种治疗或预防病毒感染的方法如下实施:对患者施用治疗有效量的配体/受体特异性交换剂,其中该配体/受体特异性交换剂含有一个具有可与病毒受体相互作用的配体的特异性结构域,和一个含有病原体或毒素表位的抗原结构域。类似地,治疗或预防癌症的方法是一个实施方案,该方法能如下实施:对患者施用治疗有效量的配体/受体特异性交换剂,其中该配体/受体特异性交换剂含有一个具有可与癌细胞上受体相互作用的配体的特异性结构域,和一个含有病原体或毒素表位的抗原结构域。
发明详述
下面描述了可与病原体上的受体结合并将患者中的抗体重新定向于病原体的新药物的生产、表征和应用。术语“配体/受体特异性交换剂”在本领域中是指一种分子,其所含的氨基酸序列对应于与可结合特定抗体的氨基酸序列(例如病原体的表位)连接的抗体的氨基酸序列(例如,互补决定区)。(参见,例如:Sllberg等人,Biochemical & BiophysicalResearch Communications,205:1386-90(1994)和美国专利号5,869,232和6,040,137)。配体/受体特异性交换剂能将患者中的抗体重新定向于病原体,这些交换剂具有治疗和诊断用途。(同上)。
此处所述的实施方案涉及称为“配体/受体特异性交换剂”的第二代交换剂。与抗原/抗体特异性交换剂不同,配体/受体特异性交换剂不含在抗体中发现的序列,而是含有含受体的配体的第一结构域和含病原体或毒素表位的第二结构域。因此,对于本公开内容,术语“配体/受体特异性交换剂”是指一种含有“特异性结构域”的交换剂,该结构域至少含有一种受体的配体(“配体”不是抗体或其部分),其与至少含有病原体或毒素(例如百日咳毒素或霍乱毒素)的一个表位的“抗原结构域”连接。
配体/受体特异性交换剂可含有一个以上的特异性结构域和抗原结构域。例如,某些配体/受体特异性交换剂含有多个特异性结构域和/或抗原结构域。含有多个特异性结构域和/或抗原结构域的配体/受体特异性交换剂称为“多聚化的”,因为一个以上的特异性结构域和/或抗原结构域串联融合。其它实施方案涉及除了特异性结构域和抗原结构域以外,还含有利于纯化的序列(例如聚组氨酸尾)、接头(例如,生物素和/或亲和素或链霉亲和素或8噬菌体的柔性臂(8-接头))、提高配体/受体特异性交换剂稳定性(例如,引起蛋白酶消化抗性的修饰)或加速配体/受体特异性交换剂降解的序列或修饰(例如,蛋白酶切割位点)的配体/受体特异性交换剂。尽管特异性和抗原结构域优选地是肽,但一些配体/受体特异性交换剂含有由修饰或衍化的肽、拟肽或化学物质组成的特异性结构域和抗原结构域。
配体/受体特异性交换剂有广泛的多样性,因为此处所述的实施方案能与多种不同病原体上的多种不同受体结合。因此,术语“病原体”在此泛指动物疾病的病原体,包括但不限于细菌、寄生虫、真菌、霉菌、病毒和癌细胞。类似地,术语“受体”泛指可与配体(通常是肽,而不是抗体中发现的序列,或是碳水化合物、脂类、核酸或其组合)相互作用的分子(通常是肽,而不是抗体中发现的序列,但可以是碳水化合物、脂类或核酸)。在此使用时,“受体”不必经历信号转导,能参与大量分子相互作用,包括但不限于粘附(例如整联蛋白)和分子信号转导(例如生长因子受体)。例如,希望的特异性结构域含有一种配体,该配体具有胞外基质蛋白(例如纤维蛋白原、胶原蛋白、玻连蛋白、层粘连蛋白、纤溶酶原、血小板反应蛋白和纤连蛋白)的肽序列,某些特异性结构域含有可与细菌粘附受体(例如,胞外纤维蛋白原结合蛋白(Efb)、胶原蛋白结合蛋白、玻连蛋白结合蛋白、层粘连蛋白结合蛋白、纤溶酶原结合蛋白、血小板反应蛋白结合蛋白、凝集因子A(ClfA)、凝集因子B(ClfB)、纤连蛋白结合蛋白、凝固酶和胞外粘附蛋白)相互作用的配体。
在其它实施方案中,特异性结构域含有一种配体,该配体具有可与病毒受体(例如,可结合gp120的T4糖蛋白片段,或可结合嗜肝DNA病毒家族的gp170的preS结构域片段)相互作用的肽序列。在其它实施方案中,特异性结构域含有可与癌细胞上的受体(例如HER-2/neu(C-erbB2))或整联蛋白受体(如玻连蛋白受体、层粘连蛋白受体、纤连蛋白受体、胶原蛋白受体、纤维蛋白原受体、
受体、
受体、
受体、
受体、
受体)相互作用的配体。然而,优选实施方案含有一个特异性结构域,其含有纤维蛋白原α链的至少8个氨基酸和/或序列精氨酸-甘氨酸-天冬氨酸(RGD),最优选的实施方案含有一个特异性结构域,其含有选自SEQ.ID.Nos.60-105的序列。
希望的抗原结构域含有一种可被患者中已有的抗体识别的表位。例如,许多人针对儿科疾病进行了免疫,包括但不限于:天花、麻疹、流行性腮腺炎、风疹和脊髓灰质炎。因此,免疫者能产生针对这些病原体上表位的抗体。希望的抗原结构域含有一种在这些病原体之一上发现的表位。
某些实施方案含有可与施用给患者的抗体相互作用的抗原结构域。例如,可与配体/受体特异性交换剂的抗原结构域相互作用的抗体能与配体/受体特异性交换剂同时施用。另外,可与配体/受体特异性交换剂相互作用的抗体也许通常在患者中不存在,但是患者通过导入生物物质(例如血清、血液或组织)而获得这种抗体。例如,接受输血的患者获得多种抗体,其中一些可与配体/受体特异性交换剂的抗原结构域相互作用。
最希望的抗原结构域含有一种可被高效价抗体识别的表位。“高效价抗体”是指对抗原(例如抗原结构域上的表位)具有高亲和力的抗体。例如,在固相酶联免疫吸附测定(ELISA)中,高效价抗体对应于血清样品中存在的抗体,在用适当稀释缓冲液将血清稀释为约1∶100-1∶1000、优选地约1∶500后,在测定中仍保持阳性。然而,优选的抗原结构域含有在单纯疱疹病毒gG2蛋白、乙型肝炎病毒s抗原(HBsAg)、乙型肝炎病毒e抗原(HBeAg)、乙型肝炎病毒c抗原(HBcAg)、TT病毒、脊髓灰质炎病毒或其组合上发现的表位,或含有选自SEQ.ID.Nos.43-59的序列。
此处所述的配体/受体特异性交换剂能用常规重组工程和/或肽化学技术制备。在某些实施方案中,特异性结构域和抗原结构域分开制备,然后连接在一起(例如通过接头或与共同的载体分子结合)。在其它实施方案中,特异性结构域和抗原结构域制备为同一分子的不同部分。一种方法是,用肽合成仪制备含有与抗原结构域连接的特异性结构域的配体/受体特异性交换剂。另一种方法是,将编码与抗原结构域融合的特异性结构域的核酸克隆到一种表达构建体中,转染细胞,并从细胞或细胞上清液中纯化或分离该配体/受体特异性交换剂。
一旦制备配体/受体特异性交换剂,即可进行筛选,以确定它与病原体上的受体和/或抗原结构域特异的抗体相互作用的能力。因此,术语“表征试验”是指配体/受体特异性交换剂与病原体或癌细胞上的受体或其片段和/或抗原结构域特异的抗体相互作用的能力的实验或评价。例如,某些表征试验评价配体/受体特异性交换剂与排列有病原体受体或其片段的载体结合的能力,或者相反。其它表征试验评价配体/受体特异性交换剂与配体/受体特异性交换剂抗原结构域特异的抗体结合的能力。其它表征试验评价配体/受体特异性交换剂在培养的细胞系或患病动物中实现病原体感染或癌细胞增殖的能力。
此处所述的配体/受体特异性交换剂能作为治疗和预防动物(包括人类)中病原体感染以及癌症的药物中的活性成分。药物实施方案能以多种方法配制,除了配体/受体特异性交换剂外还可含有赋形剂、粘合剂、乳化剂、载体和其它助剂。含有配体/受体特异性交换剂的药物能通过多种途径施用,包括但不限于:局部、透皮、肠胃外、胃肠道、透过支气管和透过肺泡。配体/受体特异性交换剂也能用作预防感染或疾病扩散的医疗装置和假体(prosthetics)的包被。药物、治疗方案中所含的或用于医疗装置的配体/受体特异性交换剂的量因目的用途、患者和施用频率而不同。
公开的一些方法涉及对需要治疗和/或预防细菌感染、真菌感染、病毒感染和癌症的患者施用配体/受体特异性交换剂。一种方法是,对细菌感染患者施以含有可与细菌受体相互作用的特异性结构域的配体/受体特异性交换剂。类似地,可以对病毒感染患者施以含有可与病毒受体相互作用的特异性结构域的配体/受体特异性交换剂,对癌症患者施以含有可与癌细胞上受体相互作用的特异性结构域的配体/受体特异性交换剂。一旦形成配体/受体特异性交换剂,即可试图通过补体固定和/或巨噬细胞降解从体内清除病原体或癌细胞。
提供了疾病(例如细菌、真菌和病毒感染和癌症)的治疗和预防方法,其中确定患者或具有患病危险的对象,然后给予治疗有效量的可与病原体上的受体相互作用的配体/受体特异性交换剂。因此,通过常规临床和诊断评价确定细菌感染、真菌感染、病毒感染或癌症患者,给予治疗有效量的可与特定病原体或癌细胞相互作用的配体/受体特异性交换剂。尽管为了预防目的能对具有患病危险的所有动物施用此处所述的配体/受体特异性交换剂,但希望的是只对高危个体(例如婴儿、老人和密切接触病原体的人)施用配体/受体特异性交换剂。如上所述,通过目前可用的临床和诊断技术确定高危个体。
下一节更详细地描述了可与细菌、寄生虫、真菌、霉菌、病毒和癌细胞上的受体相互作用的不同种类配体/受体特异性交换剂。可与病原体上的受体相互作用的配体/受体特异性交换剂
可与病原体上的受体相互作用的配体/受体特异性交换剂具有多种化学结构,但是通常表征为含有至少一个受体结合区(特异性结构域)和至少一个与病原体或毒素表位特异的抗体相互作用的区域(抗原结构域)。优选的配体/受体特异性交换剂是肽,但是某些实施方案包括衍生的或修饰的肽或拟肽结构。例如,能够修饰一种基于肽的典型配体/受体特异性交换剂,使之含有在肽上通常不存在的取代基,或者含有在肽上通常不存在、但掺入异常区域的取代基。这样,基于肽的配体/受体特异性交换剂可以乙酰化、酰化或胺化,为了修饰在肽上可含有的取代基包括但不限于:H、烷基、芳基、烯烃基、炔基、芳族、醚、酯、未取代或取代的胺、酰胺、卤素,或未取代或取代的磺基,或5或6元脂肪环或芳香环。因此,术语“配体/受体特异性交换剂”广泛包括修饰或未修饰的肽结构,以及拟肽和化学结构。
有多种方法用来制备类似于基于肽的配体/受体特异性交换剂的拟肽。在肽的生物生产中使用的天然存在的氨基酸全都具有L-构型。能利用L-氨基酸、D-氨基酸或两种不同构型的氨基酸的不同组合,通过常规合成法制备合成肽。模拟一种肽的构象和希望的特征、但没有不希望的特征(例如柔性(构象破坏)和键断裂)的合成化合物称为“拟肽”。(参见,例如:Spatola,A.F.《氨基酸、肽和蛋白质的化学与生物化学》(Weistein,B编写),第7卷,267-357页,Marcel Dekker,New York(1983),其中描述了亚甲基硫生物等排体(bioisostere)[CH2S]作为脑啡肽类似物中酰胺代替物的用途;Szelke等人,“肽:结构与功能”,第八届美国肽研讨会论文集(Hruby和Rich编写);579-582页,PierceChemical Co.,Rockford,III.(1983),其中描述了在来自血管紧张肽原的6-13八肽的Leu-Val酰胺键处含有亚甲基氨基[CH2NH]和羟基乙烯基[CHOHCH2]生物等排体的肾素抑制剂)。
设计和合成类似于配体/受体特异性交换剂的拟肽通常从配体/受体特异性交换剂的序列和希望的配体/受体特异性交换剂(例如最可能模拟的肽)的构象数据(例如几何学数据,如键长和键角)开始,利用这些数据确定应当设计为拟肽的几何学。本领域周知用来进行该步骤的大量方法和技术,能采用其中任何一种。(参见,例如:Farmer,P.S.,《药物设计》(Ariens,E.J.编写),第10卷,119-143页(Academic Press,纽约,伦敦,多伦多,悉尼,旧金山)(1980);Farmer等人,TIPS,9/82,362-365页;Verber等人,TINS,9/85,392-396页;Kaltenbronn等人,J.Med.Chem.33:838-845(1990);Spatola,A.F.,《氨基酸、肽和蛋白质的化学与生物化学》(Weistein,B编写),第7卷,267-357页,第5章,“肽主链修饰:含有酰胺键替代的肽的结构-活性分析。构象约束和相关性”(B.Weisten编写;Marcel Dekker,New York pub.)(1983);Kemp,D.S.,“肽中
-折叠和-螺旋成核的拟肽和模板处理”,Tibech,第8卷,249-255(1990))。其它描述可见美国专利号5,288,707;5,552,534;5,811,515;5,817,626;5,817,879;5,821,23l;5,874,529。设计拟肽后,即可用常规肽化学和/或有机化学技术制备。
某些实施方案包含多个特异性结构域和/或多个抗原结构域。含有多个特异性结构域和/或抗原结构域的一类配体/受体特异性交换剂被称为“多聚化配体/受体特异性交换剂”,因为它含有在同一分子中串联的多个特异性结构域和/或抗原结构域。例如,多聚化特异性结构域可以含有两种或多种可与一类受体相互作用的配体,两种或多种可与病原体上不同类型的受体相互作用的配体,两种或多种可与不同病原体上不同类型的受体相互作用的配体。
类似地,能将多聚化抗原结构域构建为含有病原体相同表位或病原体不同表位的多聚体,它们也能多聚化。即,某些多聚化抗原结构域是多价的,因为同一表位重复。相反,某些多聚化抗原结构域在同一分子上含有串联的一种以上的表位,但是这些表位不同。就此而言,这些抗原结构域是多聚化的,但不是多价的。另外,也可将某些多聚化抗原结构域构建为含有不同的表位,但不同的表位本身是多价的,因为每种类型的表位重复。
某些配体/受体特异性交换剂除了特异性结构域和抗原结构域之外还含有其它元件,如便于纯化的序列,提供更高柔性且降低空间障碍的接头,和使配体/受体特异性交换剂具有更高稳定性(例如蛋白酶降解抗性)或加速降解(例如蛋白酶识别位点)的序列。例如,配体/受体特异性交换剂能含有促进肽的胞质输出的可切割信号序列,和/或便于用抗体柱、谷胱甘肽柱和金属柱纯化的序列标签。
配体/受体特异性交换剂能含有促进分子柔性、降低空间障碍或使配体/受体特异性交换剂结合于载体或其它分子上的元件。这些元件通称为“接头”。例如,能加入配体/受体特异性交换剂中的一类接头是亲和素或链霉亲和素(或其配体——生物素)。通过生物素-亲和素/链霉亲和素连接,多个配体/受体特异性交换剂能连接在一起(例如,通过载体如树脂,或直接连接),或者各个特异性结构域和抗原结构域能够连接。配体/受体特异性交换剂中可包含的接头的另一个实例称为“8接头”,因为它含有在8噬菌体上发现的序列。优选的8序列对应于噬菌体的柔性臂。配体/受体特异性交换剂中能包含(例如,在特异性结构域与抗原结构域之间或特异性结构域和/或抗原结构域多聚体之间)这些序列,以提供更高的柔性并降低空间障碍。
另外,配体/受体特异性交换剂也能包含导致蛋白酶降解抗性或促进蛋白酶降解的序列。例如,在配体/受体特异性交换剂中掺入多个半胱氨酸能获得更高的蛋白酶降解抗性。这些配体/受体特异性交换剂实施方案预计可在体内保留较长一段时间,这可能有利于某些治疗用途。相反,配体/受体特异性交换剂也能含有促进快速降解因而加速从体内快速清除的序列。作为丝氨酸、半胱氨酸和天冬氨酸蛋白酶识别位点的多种序列已知,能包含于配体/受体特异性交换剂中。
下一节更详细地描述特异性结构域。特异性结构域
配体/受体特异性交换剂能够使用的特异性结构域类型各异,因为众所周知有大量配体可与细菌、寄生虫、真菌、霉菌、病毒和癌细胞上的受体相互作用。例如,多种类型的细菌、寄生虫、真菌、霉菌、病毒和癌细胞可与胞外基质蛋白相互作用。因此,希望的特异性结构域至少含有一种配体,该配体具有胞外基质蛋白中存在的肽序列。即,特异性结构域可含有一种配体,该配体具有例如在纤维蛋白原、胶原蛋白、玻连蛋白、层粘连蛋白、纤溶酶原、血小板反应蛋白和纤连蛋白中发现的肽序列。
研究人员已经对可与几种受体相互作用的胞外基质蛋白区作图。(参见,例如:McDevvit等人,Eur.J.Biochem.,247:416-424(1997);Flock,Molecular Med.Today,5:532(1999);Pei等人,Infect.and Immun.67:4525(1999))。某些受体与胞外基质蛋白的同一区域结合,某些含有重叠的结合域,某些与不同区域结合。优选地,组成特异性结构域的配体具有确定参与粘附胞外基质蛋白的氨基酸序列。然而,应当理解,能够利用病原体上任何受体的已知配体的随机片段产生配体/受体特异性交换剂,并且能够在以下所述的表征试验中筛选这些候选配体/受体特异性交换剂,鉴定可与病原体上的受体相互作用的分子。
某些特异性结构域含有一种与细菌粘附受体相互作用的配体,这些受体包括但不限于:胞外纤维蛋白原结合蛋白(Efb)、胶原蛋白结合蛋白、玻连蛋白结合蛋白、层粘连蛋白结合蛋白、纤溶酶原结合蛋白、血小板反应蛋白结合蛋白、凝集因子A(ClfA)、凝集因子B(ClfB)、纤连蛋白结合蛋白、凝固酶和胞外粘附蛋白。含有对应于纤维蛋白原γ链C端部分的氨基酸序列的配体显示竞争性抑制纤维蛋白原与ClfA(一种金黄色葡萄球菌粘附受体)的结合。(McDevvit等人,Eur.J.Biochem.,247:416-424(1997))。此外,葡萄球菌属的生物产生多种粘附受体,如可与α链纤维蛋白原结合的Efb,可与纤维蛋白原的和
链相互作用的ClfB,可与纤维蛋白原的
链结合的Fbe。(Pei等人,Infect.and Immun.67:4525(1999))。因此,优选的特异性结构域至少含有能与细菌粘附受体结合的分子(如纤维蛋白原)中所含序列的3个氨基酸。
特异性结构域也可含有与病毒受体相互作用的配体。几种病毒受体和相应的配体众所周知,这些配体或其片段能掺入配体/受体特异性交换剂中。例如,Tong等人鉴定了一种嗜肝DNA病毒受体,它是一种可与鸭乙型肝炎病毒包膜蛋白的pre-S域相互作用的170kd细胞表面糖蛋白(美国专利号5,929,220),Maddon等人证实,T细胞表面蛋白CD4(或可溶形式,称为T4)与HIV的gp120相互作用(美国专利号6,093,539)。因此,可与病毒受体相互作用的特异性结构域能含有鸭乙型肝炎病毒包膜蛋白pre-S域的区域(例如氨基酸残基80-102或80-104)或可与HIV的gp120相互作用的T细胞表面蛋白CD4(或可溶形式,称为T4)的区域(例如,CD4/T4的胞外域或其片段)。病毒受体有多种配体,这些分子或其片段能用作特异性结构域。
特异性结构域也能含有可与癌细胞上的受体相互作用的配体。原癌基因HER-2/neu(C-erbB2)编码酪氨酸激酶家族的一种表面生长因子受体,p185HER2。20-30%的乳腺癌患者通过基因扩增过量表达编码HER-2/neu(C-erbB2)的基因。因此,含有编码HER-2/neu(C-erbB2)配体的特异性结构域的配体/受体特异性交换剂是希望的实施方案。多种类型的癌细胞也过量表达或不同程度地表达整联蛋白受体。多种优选实施方案含有可与整联蛋白受体相互作用的特异性结构域。尽管整联蛋白主要与胞外基质蛋白相互作用,但众所周知,这些受体也可与其它配体相互作用,如侵染素、含RGD的肽(即丙氨酸-甘氨酸-天冬氨酸)和化学物质。(参见,例如美国专利号6,090,944和6,090,388;Brett等人,Eur J Immunol,23:1608(1993))。整联蛋白受体的配体包括但不限于:可与玻连蛋白受体、层粘连蛋白受体、纤连蛋白受体、胶原蛋白受体、纤维蛋白原受体、
受体、
受体、
受体、
受体和
受体相互作用的分子。表1也列出了几种优选的特异性结构域。上述特异性结构域只是为了说明目的,绝不应视为限制此处所述实施方案能够采用的特异性结构域的范围。
下一节更详细地描述了抗原结构域。
表I
特异性结构域
抗原结构域
YGEGQQHHLGGAKQAGDV (SEQ.ID.No.1) |
MSWSLHPRNLILYFYALLFL (SEQ.ID.No.2) |
ILYFYALLFLSTCVAYVAT (SEQ.ID.No.3) |
SSTCVAYVATRDNCCILDER (SEQ.ID.No.4) |
RDNCCILDERFGSYCPTTCG (SEQ.ID.No.5) |
FGSYCPTTCGIADFLSTYQT (SEQ.ID.No.6) |
IADFLSTYQTKVDKDLQSLE (SEQ.ID.No.7) |
KVDKDLQSLEDILHQVENKT (SEQ.ID.No.8) |
DILHQVENKTSEVKQLIKAI (SEQ.ID.No.9) |
SEVKQLIKAIQLTYNPDESS (SEQ.ID.No.10) |
QLTYNPDESSKPNMIDAATL (SEQ.ID.No.11) |
KPNMIDAATLKSRIMLEEIM (SEQ.ID.No.12) |
KSRIMLEEIMKYEASILTHD (SEQ.ID.No.13) |
KYEASILTHDSSIRYLQEIY (SEQ.ID.No.14) |
SSIRYLQEIYNSNNQKIVNL (SEQ.ID.No.15) |
NSNNQKIVNLKEKVAQLEAQ (SEQ.ID.No.16) |
CQEPCKDTVQIHDITGKDCQ (SEQ.ID.No.17) |
IHDITGKDCQDIANKGAKQS (SEQ.ID.No.18) |
DIANKGAKQSGLYFIKPLKA (SEQ.ID.No.19) |
GLYFIKPLKANQQFLVYCEI (SEQ.ID.No.20) |
NQQFLVYCEIDGSGNGWTVF (SEQ.ID.No.21) |
DGSGNGWTVFQKRLDGSVDF (SEQ.ID.No.22) |
QKRLDGSVDFKKNWIQYKEG (SEQ.ID.No.23) |
KENWIQYKEGFGHLSPTGTT (SEQ.ID.No.24) |
FGHLSPTGTTEFWLGNEKIH (SEQ.ID.No.25) |
EFWLGNEKIHLISTQSAIPY (SEQ.ID.No.26) |
LISTQSAIPYALRVELEDWN (SEQ.ID.No.27) |
ALRVELEDWNGRTSTADYAM (SEQ.ID.No.28) |
GRTSTADYAMFKVGPEADKY (SEQ.ID.No.29) |
FKVGPEADKYRLTYAYFAGG (SEQ.ID.No.30) |
RLTYAYFAGGDAGDAGDGFD (SEQ.ID.No.31) |
DAGDAFDGFDFGDDPSDKFF (SEQ.ID.No.32) |
FGDDPSDKFFTSHNGMQFST (SEQ.ID.No.33) |
TSHNGMQFSTWDNDNDKFEG (SEQ.ID.No.34) |
WDNDNDKFEGNCAEQDGSGW (SEQ.ID.No.35) |
NCAEQDGSGWWMNKCHAGHL (SEQ.ID.No.36) |
WMNKCHAGHLNGVYYQGGTY (SEQ.ID.No.37) |
NGVYYQGGTYSKASTPNGYD (SEQ.ID.No.38) |
SKASTPNGYDNGIIWATWKT (SEQ.ID.No.39) |
NGIIWATWKTRWYSMKKTTM (SEQ.ID.No.40) |
RWYSMKKTTMKIIPFNRLTI (SEQ.ID.No.41) |
KIIPFNRLTIGEGQQHHLGGAKQAGDV (SEQ.ID.No.42) |
能在配体/受体特异性交换剂中使用的抗原结构域的多样性也极高,因为病原体或毒素能含有多种不同的表位。即,能掺入配体/受体特异性交换剂中的抗原结构域包括细菌、真菌、植物、霉菌、病毒、癌细胞和毒素所含的表位。希望的抗原结构域包含试验对象由于自然获得性免疫或接种已经含有的病原体的表位。例如,导致儿童疾病的病原体表位能用作抗原结构域。
某些实施方案含有可与已对患者施用的抗体相互作用的抗原结构域。例如,可与特异性交换剂上的抗原结构域相互作用的抗体能与特异性交换剂一起施用。此外,可与配体/受体特异性交换剂相互作用的抗体也许通常在患者中不存在,但患者通过导入生物物质(例如血清、血液或组织)获得该抗体。例如,接受输血的患者获得多种抗体,其中一些能与配体/受体特异性交换剂的抗原结构域相互作用。可用于配体/受体特异性交换剂的一些优选抗原结构域含有病毒表位,包括但限于单纯疱疹病毒、乙型肝炎病毒、TT病毒和脊髓灰质炎病毒。
在一些实施方案中,抗原结构域含有可被“高效价抗体”识别的病原体或毒素的表位也是优选的。下文列出了检测病原体或毒素的表位能否被高效价抗体识别的方法。在配体/受体特异性交换剂的抗原结构域中能够包含的病原体表位包括瑞典专利号9901601-6;美国专利号5,869,232;Mol.Immunol.28:719-726(1991);J.Med.Virol.33:248-252(1991)中公开的肽序列上的表位。表II列出了几种优选抗原结构域的氨基酸序列。
表II之后的一节更详细地描述了配体/受体特异性交换剂的制备。
表II:
抗原结构域
制备可与细菌、寄生虫、真菌、霉菌、病毒和癌细胞上的受体相互作用的配体/受体特异性交换剂的方法
GLYSSIWLSPGRSYFET (SEQ.ID.No.43) |
YTDIKYNPFTDRGEGNM (SEQ.ID.No.44) |
DQNIHMNARLLIRSPFT (SEQ.ID.No.45) |
LIRSPFTDPQLLVHTDP (SEQ.ID.No.46) |
QKESLLFPPVKLLRRVP (SEQ.ID.No.47) |
PALTAVETGAT (SEQ.ID.No.48) |
STLVPETT (SEQ.ID.No.49) |
TPPAYRPPNAPIL (SEQ.ID.No.50) |
EIPALTAVE (SEQ.ID.No.51) |
LEDPASRDLV (SEQ.ID.No.52) |
HRGGPEEF (SEQ.ID.No.53) |
HRGGPEE (SEQ.ID.No.54) |
VLICGENTVSRNYATHS (SEQ.ID.No.55) |
KINTMPPFLDTELTAPS (SEQ.ID.No.56) |
PDEKSQREILLNKIASY (SEQ.ID.No.57) |
TATTTTYAYPGTNRPPV (SEQ.ID.No.58) |
STPLPETT (SEQ.ID.No.59) |
在某些实施方案中,特异性结构域和抗原结构域分开制备,然后连接在一起(例如通过接头或与共同的载体分子结合),在其它实施方案中,特异性结构域和抗原结构域制备为同一分子的不同部分。例如,表I列出的任何特异性结构域可与表II列出的任何抗原结构域连接。尽管特异性结构域和抗原结构域能够分开制备,并通过接头或载体分子连接在一起(例如含有生物素化特异性结构域、链霉亲和素和生物素化抗原结构域的复合物),但优选的是将配体/受体特异性交换剂制备为融合蛋白。因此,优选实施方案包括含有表I列出的任何特异性结构域与表II列出的任何抗原结构域连接的融合蛋白。
配体/受体特异性交换剂能按照蛋白质工程、蛋白质化学、有机化学和分子生物学常规方法制备。另外,一些企业生产定制的肽,向这类公司提供希望的配体/受体特异性交换剂的序列,并利用它们的服务按照特定说明生产试剂,能获得配体/受体特异性交换剂(例如,Bachem AG,瑞士)。优选地,利用本领域周知的技术,通过化学合成法(如固相肽合成)制备配体/受体特异性交换剂,如下所述:Merrifield等人,J.Am.Chem.Soc.85:2149(1964),Houghten等人,Proc.Natl.Acad.Sci.USA,82:51:32(1985),Stewart和Young,《固相肽合成》,Pierce Chem Co.,Rockford,IL(1984),Creighton,1983,《蛋白质:结构与分子原理》,W.H.Freeman & Co.,N.Y.。
一种方法是,利用Applied Biosystems 430A肽合成仪(AppliedBiosystems,Foster City,CA)进行固相肽合成。每次合成使用对甲苄基羟酰胺(hydrylamine)固相支持树脂(Peptide International,Louisville,KY),当通过酸解从固体载体上切下肽时,产生羧基端酰胺。在使用前,能够切除羧基端酰胺,并可通过高效液相层析(例如,利用PepS-15 C18柱(Pharmacia,Uppsala,瑞典)的反相高效液相层析(RP-HPLC))纯化配体/受体特异性交换剂,并用Applied Biosystems 473A肽序列测定仪测序。一种备选合成法使用自动肽合成仪(Syro,Multisyntech,Tubingen,德国)和9-芴基甲氧基羰基(fmoc)保护的氨基酸(Milligen,Bedford,MA)。
虽然配体/受体特异性交换剂能够化学合成,但更有效的是利用本领域众所周知的技术通过重组DNA技术生产这些多肽。能用这些方法构建含有编码配体/受体特异性交换剂和适当转录和翻译控制信号的核苷酸序列的表达载体。这些方法包括,例如:体外重组DNA技术、合成技术和体内遗传重组。此外,编码配体/受体特异性交换剂的RNA例如也能用合成仪化学合成。参见,例如,《寡核苷酸合成》,1984,Gait,M.J.编写,IRL Press,Oxford所述的技术。
能用多种宿主表达载体系统表达配体/受体特异性交换剂。当配体/受体特异性交换剂是可溶性分子时,如果肽或多肽不是分泌的,则可从培养物中回收,即从宿主细胞中回收,如果肽或多肽由细胞分泌,则从培养基中回收。然而,表达系统也包括表达膜结合的配体/受体特异性交换剂的工程宿主细胞。从这些表达系统中纯化或富集配体/受体特异性交换剂能用本领域技术人员周知的适当的去污剂和脂微团和方法实现。
能够使用的表达系统包括但不限于:微生物,如用含有编码配体/受体特异性交换剂的核苷酸序列的重组噬菌体DNA、质粒DNA或粘粒DNA表达载体转化的细菌(如大肠杆菌或枯草杆菌);用含有编码配体/受体特异性交换剂的核苷酸序列的重组酵母表达载体转化的酵母(如酵母属、毕赤酵母属);用含有编码配体/受体特异性交换剂的核酸的重组病毒表达载体(例如杆状病毒)感染的昆虫细胞系统;或哺乳动物细胞系统(例如COS、CHO、BHK、293、3T3),其携带含有编码配体/受体特异性交换剂的核酸的重组表达构建体的。
在细菌系统中,根据配体/受体特异性交换剂的预期用途能方便地选择多种表达载体。例如,当希望大量生产时(例如,生产配体/受体特异性交换剂的药用组合物时),引导易于纯化的融合蛋白产物高水平表达的载体是希望的。这类载体包括但不限于:大肠杆菌表达载体pUR278(Ruther等人,EMBO J.,2:1791(1983),其中配体/受体特异性交换剂编码序列能连接到载体中,与lacZ编码区符合阅读框,从而产生融合蛋白;pIN载体(Inouye & Inouye,Nucleic Acids Res.,13:3101-3109(1985);VanHeeke & Schuster,J.Biol.Chem.,264:5503-5509(1989));等等。也能用pGEX载体将外源多肽表达为与谷胱甘肽S-转移酶(GST)的融合蛋白。这些融合蛋白通常是可溶的,通过吸附于谷胱甘肽-琼脂糖珠,然后在游离谷胱甘肽存在下洗脱,能够从裂解的细胞中纯化。pGEX载体设计为含有凝血酶或因子Xa蛋白酶切割位点,使得克隆的目标基因产物能从GST部分上释放。
在昆虫系统中,苜蓿银纹夜蛾(Autographa californica)核多角体病毒(AcNPV)用作表达外源基因的载体。病毒在草地夜蛾(Spodopterafrugiperda)细胞中生长。配体/受体特异性交换剂基因编码序列能克隆到病毒的非必需区(例如多角体基因)内,置于AcNPV启动子(例如多角体启动子)控制下。配体/受体特异性交换剂基因编码序列的成功插入将使多角体基因失活,产生未包封的重组病毒(即缺乏由多角体基因编码的蛋白质外壳的病毒)。然后用这些重组病毒感染草地夜蛾细胞,插入的基因在其中表达(例如,见Smith等人,J.Virol.46:584(1983);Smith,美国专利号4,215,051)。
在哺乳动物宿主细胞中,能采用多种基于病毒的表达系统。如果用腺病毒作为表达载体,编码配体/受体特异性交换剂的核苷酸序列能与腺病毒转录/翻译控制复合物(例如晚期启动子和三联前导序列)连接。这种嵌合基因能通过体外或体内重组插入腺病毒基因组中。向病毒基因组非必需区(例如E1或E3区)中插入将产生能在感染宿主中表达配体/受体特异性交换剂基因产物的活重组病毒。(参见,例如:Logan和Shenk,Proc.Natl.Acad.Sci.USA 81:3655-3659(1984))。特异起始信号也是插入的配体/受体特异性交换剂核苷酸序列有效翻译所需的(例如ATG起始密码子和相邻的序列)。在大多数情况下,应当提供外源翻译控制信号,也许包括ATG起始密码子。此外,为了确保整个插入片段的翻译,起始密码子应当与希望的编码序列的阅读框同相。这些外源翻译控制信号和起始密码子可以是多种来源的,可以是天然和合成的。含有适当转录增强元件、转录终止子等也能提高表达效率(见Bittner等人,Methods inEnzymol.,153:516-544(1987))。
另外,也能选择能调节插入序列的表达,或以希望的特定方式修饰和加工基因产物的宿主细胞株。蛋白质产物的这种修饰(例如糖基化)和加工(例如切割)对于某些实施方案十分重要。不同的宿主细胞具有特有的和特异的翻译后加工和蛋白质和基因产物修饰机制。为了确保表达的外源蛋白质正确修饰和加工,能选择适当的细胞系或宿主系统。为此可使用真核宿主细胞,它们具有适于一级转录物加工、基因产物糖基化和磷酸化的细胞机器。这类哺乳动物宿主细胞包括但不限于CHO、VERO、BHK、HeLa、COS、MDCK、293、3T3和WI38。
为了长期、高产量地生产重组蛋白,稳定的表达是优选的。例如,能构建稳定表达上述配体/受体特异性交换剂的细胞系。不用含病毒复制起点的表达载体,而用受适当表达控制元件(例如启动子、增强子序列、转录终止子、聚腺苷酸化位点等)和选择性标记控制的DNA转化宿主细胞。导入外源DNA后,工程细胞在富集培养基中培养1-2天,然后换为选择培养基。重组质粒中的选择性标记导致选择抗性,并使细胞将质粒稳定整合到染色体中,生长形成转化灶,然后克隆并增殖为细胞系。该方法可用来方便地构建表达配体/受体特异性交换剂的工程细胞系。
能使用多种选择系统,包括但不限于:单纯疱疹病毒胸苷激酶(Wigler等人,Cell 11:223(1977))、次黄嘌呤-鸟嘌呤磷酸核糖转移酶(Szybalska和Szybalski,Proc.Natl.Acad.Sci.USA 48:2026(1962))和腺嘌呤磷酸核糖转移酶(Lowy等人,Cell 22:817(1980))基因,它们能分别在tk、hgprt或aprt细胞中使用。也能用抗代谢物抗性作为筛选下列基因的基础:赋予氨甲喋呤抗性的dhfr(Wigler等人,Proc.Natl.Acad.Sci.USA 77:3567(1980);O’Hare等人,Proc.Natl.Acad.Sci.USA78:1527(1981));赋予霉酚酸抗性的gpt(Mulligan和Berg,Proc.Natl.Acad.Sci.USA 78:2072(1981));赋予氨基糖甙G418抗性的neo(Colberre-Garapin等人,J.Mol.Biol.150:1(1981));赋予潮霉素抗性的hygo(Santerre等人,Gene 30:147(1984))。
下一节更详细地描述了配体/受体特异性交换剂表征试验。配体/受体特异性交换剂表征试验
优选地,分析配体/受体特异性交换剂与一种受体相互作用的能力和/或与患者中可能存在的抗体相互作用的能力。术语“表征试验”是指对配体/受体特异性交换剂进行的测定、实验或分析,它评价配体/受体特异性交换剂与一种受体(例如细菌、病毒、霉菌或真菌的表面受体)或抗体(例如可识别病原体上的表位的抗体)相互作用的能力,或影响病原体增殖的能力。术语“表征试验”包括结合研究(例如:酶免疫测定(EIA)、酶联免疫测定(ELISA)、竞争结合测定、计算机生成的结合测定、载体结合的结合研究和一种或两种杂交系统)和传染性研究(例如,病毒传染、繁殖及与宿主细胞附着的降低)。
优选的结合测定采用多聚剂。一种多聚剂形式涉及含有排列于载体上的配体/受体特异性交换剂或其片段的组合物。另一种多聚剂形式涉及排列于载体上的受体或配体/受体特异性交换剂抗原结构域特异的抗体的组合物。“载体”可以是载体、蛋白质、树脂、细胞膜或用来连接或固定这些分子的任何大分子结构。固体载体包括但不限于:反应皿孔壁、试管、聚苯乙烯珠、磁珠、硝酸纤维素带、膜、微粒如乳胶颗粒、动物细胞、Duracyte、人工细胞等。配体/受体特异性交换剂也能与无机载体连接,如二氧化硅材料(例如硅胶、沸石、硅藻土或氨化玻璃),例如,通过载体上的羟基、羧基或氨基和活性基团以共价键连接。
在某些多聚剂中,大分子载体具有疏水表面,通过疏水非共价作用可与配体/受体特异性交换剂、受体或配体的一部分相互作用。在有些情况下,载体的疏水表面是一种聚合物,如塑料或连接疏水基团的其它任何聚合物,如聚苯乙烯、聚乙烯(polyethylene)或聚乙烯(polyvinyl)。另外,配体/受体特异性交换剂、受体或配体/受体特异性交换剂抗原结构域特异的抗体也能与包括蛋白质和寡糖/多糖(例如纤维素、淀粉、糖原、壳聚糖或胺化sepharose)在内的载体共价结合。对于后面这些多聚剂,分子上的活性基团,如羟基或氨基,用来连接载体上的活性基团,产生共价键。其它多聚剂包括这样一种载体,其含有化学激活的其它活性基团,以便结合配体/受体特异性交换剂、受体或配体/受体特异性交换剂抗原结构域特异的抗体。例如能使用溴化氰激活的基质、环氧树脂激活的基质、硫凝胶或硫丙基凝胶、氯甲酸硝基苯和N-羟基琥珀酰亚胺氯甲酸酯键,或过环氧乙烷丙烯酸载体(Sigma)。此外,在某些实施方案中,也考虑用脂质体或脂双层(天然或合成的)作为载体,配体/受体特异性交换剂、受体或配体/受体特异性交换剂抗原结构域特异的抗体通过脂质体工程技术附着于膜表面或掺入膜中。一种方法是,脂质体多聚载体含有暴露于表面的配体/受体特异性交换剂、受体或配体/受体特异性交换剂抗原结构域特异的抗体。
也涉及在配体/受体特异性交换剂、受体或配体/受体特异性交换剂抗原结构域特异的抗体与载体之间插入适当长度的接头(例如,构建的类似于λ噬菌体柔性区的“λ接头”),以得到更高的柔性,从而克服载体的任何空间障碍。在此处详述的表征试验中,通过用不同接头筛查附着的分子,能确定导致最佳结合的适当长度的接头。
几种表征配体/受体特异性交换剂的方法使用上述多聚体。例如,载体结合的配体/受体特异性交换剂能接触“游离”粘附受体,其结合可直接(例如,利用标记的粘附受体)或间接(例如,利用标记的针对粘附受体的配体)测定。因此,根据受体与载体结合的候选配体/受体特异性交换剂的结合,确定候选配体/受体特异性交换剂为真正的配体/受体特异性交换剂。此外,载体结合的粘附受体也能接触“游离”配体/受体特异性交换剂,直接(例如,使用标记的配体/受体特异性交换剂)或间接(例如,使用标记的针对配体/受体特异性交换剂抗原结构域的抗体)测定结合的配体/受体特异性交换剂的量。类似地,利用排列于载体上的配体/受体特异性交换剂抗原结构域特异的抗体和标记的配体/受体特异性交换剂(或第二种检测试剂,如标记的受体或配体/受体特异性交换剂的抗体),能测定该抗体与配体/受体特异性交换剂抗原结构域结合的能力。
某些表征试验评价配体/受体特异性交换剂与靶受体相互作用和重新定向抗体的能力,而其它表征试验用来确定配体/受体特异性交换剂能否结合靶受体并重新定向抗体。表征试验通常可分类为:(1)体外表征试验,(2)细胞表征试验,(3)体内表征试验。
下面几节描述了每种表征试验。体外表征试验
有多种体外试验能用来确定配体/受体特异性交换剂能否结合特定受体,以及患者中的抗体能否结合配体/受体特异性交换剂。最简单的是,受体与载体(例如培养皿)结合,如上所述直接或间接监测配体/受体特异性交换剂与受体的结合。类似地,针对配体/受体特异性交换剂抗原结构域的第一抗体(例如患者中发现的抗体)能与载体结合,直接(例如,使用标记的配体/受体特异性交换剂)或间接(例如,使用标记的受体或标记的第二抗体,它们可与配体/受体特异性交换剂上的一种表位相互作用,该表位不与第一抗体识别的表位竞争)测定配体/受体特异性交换剂与该第一抗体的结合。
另一种方法涉及一种夹心试验,其中受体与载体结合,配体/受体特异性交换剂与受体结合,第一抗体与配体/受体特异性交换剂结合。如果使用标记的第一抗体,能直接测定受体/特异性交换剂/第一抗体复合物的存在。也能间接测定受体/特异性交换剂/第一抗体复合物的存在,例如,使用一种标记的第二抗体,它在不干扰第一抗体与配体/受体特异性交换剂结合的表位处与第一抗体反应。有时,希望使用标记的第三抗体与未标记的第二抗体反应,从而形成受体/特异性交换剂/第一抗体/第二抗体/标记第三抗体的复合物。
下面的实施例描述了一种表征试验,其用来确定来自纤维蛋白原C端域的特异性结构域是否抑制凝集因子(Clf)与纤维蛋白原的结合。
实施例1
在该实施例中,分析了对应于纤维蛋白原(Fib)C端域的几种肽阻断凝集因子(Clf)与纤维蛋白原结合的能力。(见表III)。这些肽利用fmoc化学法(Syro,MultiSynTech,德国)通过标准肽合成技术生产。优选地通过反相HPLC纯化这些肽。然后进行竞争酶免疫测定,确定这些肽是否能阻断Clf与纤维蛋白原的相互作用。实验结果示于表III中。发现能抑制Clf与纤维蛋白原相互作用的来自纤维蛋白原的最小肽是HLGGAKQAGD(SEQ.ID.No.124)。该肽前两个氨基酸置换为丙氨酸和赖氨酸对该肽阻断Clf与纤维蛋白原相互作用的能力有显著影响(例如,肽ALGGAKQAGD(SEQ.ID.No.123)不能阻断Clf/纤维蛋白原相互作用)。
表IIISEQ.ID.No. (Fib)肽 (Fib/Clf)相互作用的抑制106 LTIGEGQQHHLGGAKQAGDV +107 GEGQQHHLGGAKQAGDV +108 QQHHLGGAKQAGDV +109 QHHLGGAKQAGDV +110 HHLGGAKQAGDV +111 HLGGAKQAGDV +112 LGGAKQAGDV -113 GGAKQAGDV -114 GAKQAGDV -115 QHHLGGAKQAGD +116 QHHLGGAKQAG +117 QHHLGGAKQA -118 QHHLGGAKQ -119 QHHLGGAK +/-120 QHHLGGA -121 HHLGGAKQAGDV +122 HHLGGAKQAGD +123 HHLGGAKQAG +124 HLGGAKQAGDV +125 HLGGAKQAGD +126 ALGGAKQAG -127 HAGGAKQAG +128 HLAGAKQAG +129 HLGAAKQAG +130 HLGGGKQAG +131 HLGGAAQAG +/-132 HLGGAKAAG +133 HLGGAKQGG +134 HLGGAKQAA +
下面的实施例描述了用来确定配体/受体特异性交换剂是否与含有ClfA受体的细菌相互作用的表征试验。
实施例2
含有对应于纤维蛋白原γ链序列不同区的特异性结构域(约20个氨基酸长)的配体/受体特异性交换剂利用fmoc化学法(Syro,MultiSynTech,德国)通过标准肽合成技术生产,并分析这些配体/受体特异性交换剂与ClfA受体和抗原结构域特异的抗体结合的能力。这些配体/受体特异性交换剂的序列在表IV中和序列表中列出(SEQ.ID.No.60-103)。该分析使用的配体/受体特异性交换剂含有一个抗原结构域,其中含有单纯疱疹病毒gG2蛋白的一种表位,该表位可被单纯疱疹病毒gG2蛋白的单克隆抗体识别。用含有2μg/ml山羊血清(Sigma Chemicals,St.Louis,MO)和0.5% Tween 20的磷酸缓冲液(PBS)(PBS-GT)系列稀释这些配体/受体特异性交换剂。受体ClfA在50mM碳酸钠缓冲液(pH9.6)中4℃过夜,以10μg/ml的浓度被动吸附于96孔微孔板上。
然后,稀释的配体/受体特异性交换剂在平板上温育60分钟。向平板中加入第一抗体并温育60分钟(1∶1000稀释的单纯疱疹病毒gG2蛋白单克隆抗体),检测配体/受体特异性交换剂与受体相互作用的能力。之后用兔抗小鼠IgG(Sigma)第二抗体和过氧化物酶标记的山羊抗-兔IgG(Sigma)第三抗体显示结合的第一单克隆抗体。平板与二硝基亚苯二胺(Sigma)温育显色,分析405nm下的吸光度。
表IV列出的每种配体/受体特异性交换剂(SEQ.ID.No.60-103)可结合固定的ClfA,也可结合HSV gG2蛋白特异的单克隆抗体。上述测定配体/受体特异性交换剂对粘附受体和第一抗体的亲和力的方法能对含有任何特异性结构域和任何抗原结构域的任何候选配体/受体特异性交换剂进行,只要使用合适的序列和粘附受体。
表IV之后的实施例描述了另一种表征试验,其用来确定配体/受体特异性交换剂是否与含有ClfA受体的细菌相互作用。
表IV
配体/受体特异性交换剂
YGEGQQHHLGGAKQAGDV HRGGPEEF (SEQ.ID.No.60) |
YGEGQQHHLGGAKQAGDVHRGGPEE (SEQ.ID.No.61) |
YGEGQQHHLGGAKQAGDVSTPLPETT (SEQ.ID.No.62) |
MSWSLHPRNLILYFYALLFLHRGGPEE (SEQ.ID.No.63) |
ILYFYALLFLSTCVAYVATHRGGPEE (SEQ.ID.No.64) |
SSTCVAYVATRDNCCILDERHRGGPEE (SEQ.ID.No.65) |
RDNCCILDERFGSYCPTTCGHRGGPEE (SEQ.ID.No.66) |
FGSYCPTTCGIADFLSTYQTHRGGPEE (SEQ.ID.No.67) |
IADFLSTYQTKVDKDLQSLEHRGGPEE (SEQ.ID.No.68) |
KVDKDLQSLEDILHQVENKTHRGGPEE (SEQ.ID.No.69) |
DILHQVENKTSEVKQLIKAIHRGGPEE (SEQ.ID.No.70) |
SEVKQLIKAIQLTYNPDESSHRGGPEE (SEQ.ID.No.71) |
QLTYNPDESSKPNMIDAATLHRGGPEE (SEQ.ID.No.72) |
KPNMIDAATLKSRIMLEEIMHRGGPEE (SEQ.ID.No.73) |
KSRIMLEEIMKYEASILTHDHRGGPEE (SEQ.ID.No.74) |
KYEASILTHDSSIRYLQEIYHRGGPEE (SEQ.ID.No.75) |
SSIRYLQEIYNSNNQKIVNLHRGGPEE (SEQ.ID.No.76) |
NSNNQKIVNLKEKVAQLEAQHRGGPEE (SEQ.ID.No.77) |
CQEPCKDTVQIHDITGKDCQHRGGPEE (SEQ.ID.No.78) |
IHDITGKDCQDIANKGAKQSHRGGPEE (SEQ.ID.No.79) |
DIANKGAKQSGLYFIKPLKAHRGGPEE (SEQ.ID.No.80) |
GLYFIKPLKANQQFLVYCEIHRGGPEE (SEQ.ID.No.81) |
NQQFLVYCEIDGSGNGWTVFHRGGPEE (SEQ.ID.No.82) |
DGSGNGWTVFQKRLDGSVDFHRGGPEE (SEQ.ID.No.83) |
QKRLDGSVDFKKNWIQYKEGHRGGPEE (SEQ.ID.No.84) |
KKNWIQYKEGFGHLSPTGTTHRGGPEE (SEQ.ID.No.85) |
FGHLSPTGTTEFWLGNEKIHHRGGPEE (SEQ.ID.No.86) |
EFWLGNEKIHLISTQSAIPYHRGGPEE (SEQ.ID.No.87) |
LISTQSAIPYALRVELEDWNHRGGPEE (SEQ.ID.No.88) |
ALRVELEDWNGRTSTADYAMHRGGPEE (SEQ.ID.No.89) |
GRTSTADYAMFKVGPEADKYHRGGPEE (SEQ.ID.No.90) |
FKVGPEADKYRLTYAYFAGGHRGGPEE (SEQ.ID.No.91) |
RLTYAYFAGGDAGDAFDGFDHRGGPEE (SEQ.ID.No.92) |
DAGDAFDGFDFGDDPSDKFFHRGGPEE (SEQ.ID.No.93) |
FGDDPSDKFFTSHNGMQFSTHRGGPEE (SEQ.ID.No.94) |
TSHNGMQFSTWDNDNDKFEGHRGGPEE (SEQ.ID.No.95) |
WDNDNDKFEGNCAEQDGSGWHRGGPEE (SEQ.ID.No.96) |
NCAEQDGSGWWMNKCHAGHLHRGGPEE (SEQ.ID.No.97) |
WMNKCHAGHLNGVYYQGGTYHRGGPEE (SEQ.ID.No.98) |
NGVYYQGGTYSKASTPNGYDHRGGPEE (SEQ.ID.No.99) |
SKASTPNGYDNGIIWATWKTHRGGPEE (SEQ.ID.No.100) |
NGIIWATWKTRWYSMKKTTMHRGGPEE (SEQ.ID.No.101) |
RWYSMKKTTMKIIPFNRLTIHRGGPEE (SEQ.ID.No.102) |
KIIPFNRLTIGEGQQHHLGGAKQAGDVHRGGPEE (SEQ.ID.No.103) |
实施例3
含有能结合凝集因子(Clf)的特异性结构域和对应于来自脊髓灰质炎病毒的表位的抗原结构域的配体/受体特异性交换剂利用fmoc化学法(Syro,MultiSynTech,德国)通过标准肽合成技术生产。见表V。分析这些配体/受体特异性交换剂抑制CLF与纤维蛋白原相互作用的能力。在这些实验中,生产表V所示的配体/受体特异性交换剂,并向含有Clf和纤维蛋白原的酶竞争免疫测定中加入不同浓度的这些分子。确定最低抑制浓度,即抑制Clf/Fib相互作用所需的最低肽浓度。因此,抑制Clf/Fib相互作用所需的浓度越低,抑制剂越有效。另外也确定最低固相结合肽浓度,即在免疫测定中可被抗脊髓灰质炎病毒抗体识别的肽的最低测试浓度。使用的某些肽(例如,CPALTAVETGCTNPLAAHHLGGAKQAG(SEQ.ID.No.135)、HHLGGAKQAG-AA-CPALTAVETGCTNPL(SEQ.ID.No.137)、CPALTAVETGC-TNPLHHLGGAKQAG(SEQ.ID.No.139)和HHLGGAKQAG-CPALTAVETGCTNPL(SEQ.ID.No.141)),在表V中以星号标出,在人工导入的两个半胱氨酸残基之间环化。实验提示,HHLGGAKQAG-AA-CPALTAVETGCTNPL(SEQ.ID.No.137)和HHLGGAKQAG-CPALTAVETGCTNPL(SEQ.ID.No.142)有效抑制Clf与纤维蛋白原的相互作用,而保留功能性脊髓灰质炎病毒表位。
表V
固相上的
最低抑
表位的
制浓度 最低浓度ID 肽序列
(μg/ml) (μg/ml)135 CPALTAVETGCTNPL-AA-HHLGGAKQAG* >625 1.6136 CPALTAVETGCTNPL-AA-HHLGGAKQAG 625 1.6137 HHLGGAKQAG-AA-CPALTAVETGCTNPL* 69 8138 HHLGGAKQAG-AA-CPALTAVETGCTNPL 625 >200139 CPALTAVETGC-TNPLHHLGGAKQAG* 625 1.6140 CPALTAVETGC-TNPLHHLGGAKQAG 208 1.6141 HHLGGAKQAG-CPALTAVETGCTNPL* 208 >200142 HHLGGAKQAG-CPALTAVETGCTNPL 23 1.6143 PALTAVETGATNPL-HHLGGAKQAG >625 1.6144 HHLGGAKQAG-PALTAVETGATNPL >625 >200
下一节描述了几种基于细胞的表征试验,它们能用来确定配体/受体特异性交换剂是否影响病原体的增殖。基于病原体的表征试验
另一类表征试验利用基于病原体的方法评价配体/受体特异性交换剂与病原体和针对配体/受体特异性交换剂抗原结构域的抗体相互作用的能力。此分析也揭示了配体/受体特异性交换剂影响病原体增殖的能力,因为在患者体内,配体/受体特异性交换剂与病原体和针对配体/受体特异性交换剂抗原结构域的抗体相互作用,之后发生从患者体内清除病原体的体液和细胞反应(例如补体固定和巨噬细胞降解)。基于病原体的表征试验通常包括向培养的病原体中添加配体/受体特异性交换剂,监测配体/受体特异性交换剂与细胞或病毒的结合。能够使用几种基于病原体的表征试验,下面的实施例更详细地描述了一些优选的表征试验。
实施例4
一种基于病原体的表征试验包括配体/受体特异性交换剂与排列于载体上的细菌结合。因此,产生Clfa的细菌(例如金黄色葡萄球菌或大肠杆菌)在培养液中或在琼脂平板上在适当生长培养基(例如LB培养液、血肉汁、LB琼脂或血琼脂)中生长。然后通过在真空下将培养物置于膜上(例如使用斑点印迹复印装置)或将膜置于菌落上保持足以实现转移的一段时间,将细胞转移到膜上(例如硝酸纤维素或尼龙膜)。然后向与膜结合的细胞添加系列稀释的配体/受体特异性交换剂(例如500ng,1μg,5μg,10μg,25μg,50μg配体/受体特异性交换剂,总体积为200μl PBS)。在一种实验中,使用表IV或表V列出的配体/受体特异性交换剂。稀释的配体/受体特异性交换剂与膜温育60分钟。随后除去未结合的配体/受体特异性交换剂,用PBS洗膜(例如每次2ml PBS,洗3次)。然后加入1∶100-1∶1000稀释的可与配体/受体特异性交换剂抗原结构域相互作用的第一抗体(例如单纯疱疹病毒gG2蛋白的单克隆抗体),结合反应进行60分钟。再次用PBS洗膜(例如每次2ml PBS,洗3次)除去未结合的第一抗体。合适的对照包括:膜本身、不含配体/受体特异性交换剂的膜上的细菌,和含有配体/受体特异性交换剂但不含第一抗体的膜上的细菌。
为了检测与膜上的细菌结合的配体/受体特异性交换剂的量,使用第二抗体(例如兔抗小鼠IgG(Sigma))和第三抗体(例如辣根过氧化物酶标记的山羊抗兔IgG(Sigma))。当然也能使用可与第一抗体相互作用的标记的第二抗体。如上所述,第二抗体与膜接触60分钟,用PBS从膜上洗去未结合的第二抗体(例如,每次2ml PBS,洗3次)。然后,第三抗体与膜接触60分钟,用PBS从膜上洗去未结合的第三抗体(例如,每次2ml PBS,洗3次)。通过膜与二硝基-亚苯基-二胺(Sigma)温育检测结合的第三抗体。
另一种方法包括使用固定的配体/受体特异性交换剂。因此,第一抗体(例如单纯疱疹病毒gG2蛋白的单克隆抗体)与培养皿结合。一旦第一抗体结合,即向包被的培养皿中加入不同稀释度的配体/受体特异性交换剂(例如表IV或表V中列出的配体/受体特异性交换剂)。这些配体/受体特异性交换剂与第一抗体结合60分钟,洗掉未结合的配体/受体特异性交换剂(例如每次2ml PBS,洗3次)。合适的对照包括不含第一抗体或配体/受体特异性交换剂的培养皿。
然后,向培养皿中加入细菌(例如大肠杆菌)混浊溶液,使细菌与固定的配体/受体特异性交换剂相互作用60分钟。用PBS洗去未结合的细菌(例如,每次2ml PBS,洗3次)。然后向培养皿中加入生长培养基(例如LB培养液),培养液温育过夜。此外,也可向培养皿中加入LB琼脂,培养物温育过夜。配体/受体特异性交换剂与细菌的相互作用可以目视观察(例如混浊的生长培养基,能利用分光光度分析或根据琼脂上菌落的出现来定量)。
本领域技术人员通过改进上述方法,能评价配体/受体特异性交换剂与一种病毒相互作用的能力。例如,T4糖蛋白的可溶性片段显示可与人类免疫缺陷病毒(HIV)包膜糖蛋白相互作用。(参见,例如美国专利号6,093,539)。含有特异性结构域(其含有可与HIV包膜糖蛋白相互作用的T4糖蛋白的片段,例如美国专利号6,093,539所述T4糖蛋白序列的氨基酸1-419或其部分)的配体/受体特异性交换剂能如下制备:合成一种融合蛋白,其含有与抗原结构域(例如表II列出的抗原结构域)连接的特异性结构域。尽管能利用肽化学法制备配体/受体特异性交换剂,但优选的是制备含有与抗原结构域连接的T4糖蛋白片段的表达构建体,并转染合适的细胞。也能采用如美国专利号6,093,539及以上所述的表达与纯化策略。
一旦构建配体/受体特异性交换剂,即进行滤纸结合试验。因此,连续10倍稀释的HIV接种物在恒定真空下加到斑点印迹装置的膜(例如硝酸纤维素或尼龙膜)上。然后将连续10倍稀释的配体/受体特异性交换剂加到结合的HIV颗粒上。配体/受体特异性交换剂与颗粒接触60分钟,之后施加真空并用PBS洗涤(例如每次2ml PBS,洗3次)。在除去未结合的配体/受体特异性交换剂后,向样品中加入连续10倍稀释的第一抗体(它们可与抗原结构域结合),结合反应进行60分钟。施加真空,用PBS洗掉未结合的第一抗体(例如,每次2ml PBS,洗3次)。结合的第一抗体的检测能如上所述进行。
配体/受体特异性交换剂与病毒相互作用的能力也能用夹心试验检测。因此,将能与配体/受体特异性交换剂的抗原结构域相互作用的第一抗体固定于微孔板孔中,向第一抗体上添加连续稀释的配体/受体特异性交换剂,形成第一抗体/特异性交换剂复合物,如上所述。然后加入10倍连续稀释的HIV接种物,结合反应进行60分钟。用PBS连续洗涤除去未结合的HIV颗粒。结合的HIV颗粒的检测能用放射标记的抗HIV抗体(例如,从HIV感染者的血清中获得的抗体)完成。
上述实施例描述了采用细菌和病毒的基于病原体的试验,但是为了研究配体/受体特异性交换剂与哺乳动物细胞的相互作用,能对这些方法进行改进。例如,配体/受体特异性交换剂与癌细胞上的整联蛋白受体相互作用的能力能如下测定。表达
受体的黑素瘤细胞(例如M21人黑素瘤细胞)结合纤维蛋白原,通过施用含RGD的肽能阻断这种相互作用(参见,例如:Katada等人,J.Biol.Chem.272:7720(1997),Felding-Habermann等人,J.Biol.Chem.271:5892-5900(1996))。其它类型的多种癌细胞也类似地表达可与RGD肽相互作用的整联蛋白。一种方法是,将表达RGD反应性整联蛋白的癌细胞(例如M21人黑素瘤细胞)培养至汇合。M21细胞能在含10%胎牛血清、20mM Hepes和1mM丙酮酸盐的DMEM培养基中生长。
优选地,细胞以20μg/ml的终浓度(2×106细胞/ml)用氢乙锭(hydroethidine)(Polysciences,Inc.,Washington,PA)在37℃下染色30分钟,然后洗涤两次除去过量的染料。氢乙锭嵌入DNA中,使细胞红色荧光标记,并且不损害细胞的粘附功能。染色是定量配体/受体特异性交换剂与细胞的结合的一种方法。即,可将氢乙锭染色细胞的总数与结合荧光标记第一抗体/特异性交换剂复合物的细胞数相比较,确定结合效率。
因此,染色的细胞与不同稀释度的含RGD序列(例如,GRGDSPHRGGPEE(SEQ.ID.No.104)或WSRGDWHRGGPEE(SEQ.ID.No.105))的配体/受体特异性交换剂温育。温育60分钟后,用含10%胎牛血清、20mM Hepes和1mM丙酮酸盐的DMEM培养基洗涤数次(例如,用5ml培养基,洗3次),除去未结合的配体/受体特异性交换剂。然后加入1∶100-1∶1000稀释的可与配体/受体特异性交换剂的抗原结构域相互作用的第一抗体(例如单纯疱疹病毒gG2蛋白的单克隆抗体),结合反应进行60分钟。随后用培养基洗涤数次,除去所有未结合的第一抗体。合适的对照包括不含配体/受体特异性交换剂的染色细胞或不含第一抗体的染色细胞。
待第一抗体结合后,加入FITC标记的山羊抗小鼠抗体(1∶100稀释)(Sigma),结合60分钟。再用培养基洗涤数次,除去所有未结合的第二抗体。对于氢乙锭用543/590nm的滤片设置,对于荧光蛋白用495/525nm的设置,通过流式细胞术进行分析。观察到第一抗体与配体/受体特异性交换剂复合物明显结合,这证明了配体/受体特异性交换剂对细胞具有影响。
下面的实施例描述了一种表征试验,它证实含RGD的配体/受体特异性交换剂可有效结合哺乳动物细胞并将抗体重新定向于这些细胞。
实施例5
肽RGDSAATPPAYR(SEQ.ID.No.145)利用fmoc化学法(Syro,MultiSynTech,德国)通过标准肽合成技术生产。该肽含有一个可结合整联蛋白受体的特异性结构域、一个间隔区(AA)和一个抗原结构域,后者含有一种可被单克隆抗体57/8识别的表位,即乙型肝炎病毒e抗原(HBeAg)上存在的表位。
用无血清培养基洗涤鼠黑素瘤细胞(SP2/0细胞),然后以50μg/ml的浓度与RGDSAATPPAYR(SEQ.ID.No.145)肽或来自丙型肝炎病毒(HCV)NS3域的对照肽一起温育。洗涤细胞,通过用57/8抗体标记细胞检测表面结合的肽的量。表面结合的抗体用1/500稀释的FITC标记的抗小鼠IgG偶联物显示,表面染色水平通过荧光显微术测定。
该实验表明,与对照肽一起温育的细胞不显染色。相反,与RGDSAATPPAYR(SEQ.ID.No.145)肽一起温育的细胞显示明显的表面染色,这与表面表达的整联蛋白的位置一致。因此,含RGD的配体/受体特异性交换剂可有效结合产整联蛋白的哺乳动物细胞,能用这些分子将靶抗体重新定向于肿瘤细胞。
下一节描述了对动物进行的表征试验。体内表征试验
表征试验也包括评价体内配体/受体特异性交换剂的实验。有多种动物模型适于评价配体/受体特异性交换剂抑制病原体感染的能力。优选小鼠,因为它们易于饲养,并且对细菌感染、病毒感染和癌症敏感。黑猩猩也是优选的,因为它们与人类紧密遗传相关。
下面的实施例描述了一种评价配体/受体特异性交换剂在小鼠中的效能的方法。
实施例6
为了检测配体/受体特异性交换剂治疗细菌感染的能力,可进行下列表征试验。对几只约8周龄、25克体重的雌性CF-1远交小鼠(CharlesRivers Laboratories)接种待测配体/受体特异性交换剂的抗原结构域。优选地,该抗原结构域与一种载体偶联,并与佐剂一起施用。例如,抗原结构域能与匙孔戚血蓝蛋白或牛血清白蛋白融合,后者作为载体和佐剂,或者能使用佐剂,如弗氏佐剂、氢氧化铝或溶血卵磷脂。例如,通过免疫扩散或EIA一旦能证实产生该抗原结构域的高效价抗体,即对免疫的小鼠腹膜内接种金黄色葡萄球菌NTCC 10649的过夜培养物。调节接种物,对于金黄色葡萄球菌达到约100×LD50或log 6.6。
配体/受体特异性交换剂(例如表IV列出的配体/受体特异性交换剂)的连续稀释液用注射用水配制,在感染1小时和5小时后经皮下(SC)或经口(PO)途径施用。在每次实验的同时,通过对未处理的小鼠接种细菌接种物的log稀释液验证攻击LD50。优选地,用5个log稀释范围的细菌攻击物接种5组各10只小鼠(每一个log稀释度10只小鼠)。在100×LD50的攻击接种物浓度下,所有未处理小鼠组都得到100%的死亡率。每日监测小鼠的死亡率,持续7天。保护50%的小鼠的平均有效剂量(ED50)能通过存活率-剂量曲线图的对数-概率分析由累积死亡率计算,如Antimicrob.Agents Chemother.31:1768-1774和Proc.Soc.Exp.Biol.Med.1994,57,261-264所述。本领域技术人员应当理解,也能利用类似的方法检测配体/受体特异性交换剂抑制病毒感染和癌症的能力。
此处所述的配体/受体特异性交换剂能配制到药物中,并对需要抑制病原体增殖的药物的患者施用。下一节描述了含有可与病原体上的受体相互作用的配体/受体特异性交换剂的几种药物。含有可与病原体上的受体相互作用的配体/受体特异性交换剂的药物
此处所述的配体/受体特异性交换剂适于掺入药物中,以对需要治疗或预防病原体感染的化合物的患者施用。这些药理活性化合物能用常规制药方法加工,以生产用于包括人类在内的哺乳动物的药物。活性成分能加以修饰或不加修饰地掺入药品中。另外,通过几种途径输送本发明的药理活性化合物的药物或治疗剂的生产也属于本发明的方面。例如,但绝非限制,本发明的实施方案可使用DNA、RNA和病毒载体,它们含有编码可与病原体上的受体相互作用的配体/受体特异性交换剂的序列。编码配体/受体特异性交换剂的核酸能单独或与其它活性成分一起施用。
这些化合物能与常规赋形剂混合使用,即,适于肠胃外、肠内(例如经口)或局部施用的药学可接受的有机或无机载体物质,它们与此处所述的药理活性成分无有害反应。合适的药学可接受的载体包括但不限于:水、盐溶液、乙醇、阿拉伯树胶、植物油、苯甲醇、聚乙二醇、明胶、糖类(如乳糖、直链淀粉或淀粉)、硬脂酸镁、滑石粉、硅酸、粘性石蜡、芳香油、脂肪酸一甘油酯和二甘油酯、五赤藓糖醇脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮等。《Remmington制药学》第15版,Easton:Mack Publishing Company,第1405-1412页和1461-1487页(1975)和《国家药典XIV》第14版,华盛顿,美国药学会(1975)中描述了能够使用的其它多种载体。药用制剂可以是灭菌的,必要时与助剂混合,如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、影响渗透压的盐、缓冲液、着色、调味和/或芳香物质等,只要助剂与配体/受体特异性交换剂无有害反应。
含有配体/受体特异性交换剂的特定药物的有效剂量和施用方法因患者的个体需要和治疗或预防措施而不同。这些化合物的治疗效果和毒性能用细胞培养物或实验动物通过标准药学程序测定,例如ED50(在50%群体中治疗有效的剂量)。例如,配体/受体特异性交换剂的有效剂量能用上述表征试验估计。然后在配制用于其它生物(包括人类)的剂量时采用由这些试验获得的数据。这些化合物的剂量优选地处于无毒、包含ED50的循环浓度范围内。根据配体/受体特异性交换剂的种类、使用的剂型、生物敏感性和施用途径,剂量在该范围内变化。
配体/受体特异性交换剂的正常剂量根据施用途径可为约1-100000微克,可达约10克的总剂量。希望的剂量包括约250μg-1mg、约50mg-200mg、约250mg-500mg。
在某些实施方案中,配体/受体特异性交换剂的剂量优选地产生约0.1μM-500mM的组织和/或血液浓度。希望的剂量产生约1-800μM的组织和/或血液浓度。优选的剂量产生超过约10μM-约500μM的组织或血液浓度。尽管产生超过800μM的组织浓度的剂量不是优选的,但仍能采用。也能持续输注配体/受体特异性交换剂,以在组织中保持稳定的浓度,这根据血液水平测定。
精确剂量由医生根据所治疗的患者选择。为了提供足够水平的活性部分或保持希望的效果,调整剂量和施用途径。考虑的其它因素包括:疾病的严重程度、所治疗生物的年龄和生物的体重或大小;饮食、施用时间和频率、药物组合、反应敏感性和对治疗的耐受/反应。短效药用组合物每日或更频繁地施用,而长效药用组合物每2天或2天以上施用一次,一周一次,或者两周一次,乃至频率更低。
药物的施用途径包括但不限于:局部、透皮、肠胃外、胃肠道、透过支气管和透过肺泡。透皮施用通过应用乳膏、漂洗剂、凝胶等实现,它们能使配体/受体特异性交换剂渗透皮肤。肠胃外施用途径包括但不限于:电或直接注射,如直接注射到中央静脉束、静脉内、肌肉内、腹膜内、皮内或皮下注射。胃肠道施用途径包括但不限于:摄食和直肠。透过支气管和透过肺泡施用途径包括但不限于经口或鼻内吸入。
适于透皮或局部施用的含有此处所述配体/受体特异性交换剂的组合物包括但不限于:直接对皮肤施用或掺入保护性载体(如透皮装置(透皮贴剂”))中的药学可接受的悬液、油、乳膏和软膏。例如,在《医生参考手册》中能见到合适的乳膏和软膏的例子。例如,在1989年4月4日授予Chinen等人的美国专利号4,818,540中描述了合适的透皮装置的例子。
适于肠胃外施用的含有药理活性化合物的组合物包括但不限于药学可接受的无菌等渗溶液。这类溶液包括但不限于用于向中央静脉束、静脉内、肌肉内、腹膜内、皮内或皮下注射的盐水和磷酸缓冲液。
适于透过支气管和透过肺泡施用的含有药理活性化合物的组合物包括但不限于多种类型的吸入型气雾剂。适于透过支气管和透过肺泡施用的装置也是实施方案。这类装置包括但不限于雾化器和汽化器。当前可以使用的多种雾化器和汽化器能用于输送含有此处所述的配体/受体特异性交换剂的组合物。
适于胃肠道施用的含有药理活性化合物的组合物包括但不限于药学可接受的粉末、供摄食的丸剂或液体和供直肠施用的栓剂。由于易于使用,胃肠道施用,特别是口服,是优选实施方案。获得含有配体/受体特异性交换剂的药物后,即能对需要治疗或预防病原体感染的生物施用。
本发明的其它方面也包括用于医疗装置(如假体、植入物和仪器)的包被。适用于医疗装置的包被可由含有配体/受体特异性交换剂的凝胶或粉末提供,或由悬浮配体/受体特异性交换剂的聚合包被提供。适用于装置包被的聚合材料是生理学可接受的材料,治疗有效量的配体/受体特异性交换剂能通过它扩散。合适的聚合物包括但不限于:聚氨酯、聚甲基丙烯酸酯、聚酰胺、聚酯、聚乙烯、聚丙烯、聚苯乙烯、聚四氟乙烯、聚氯乙烯、醋酸纤维素、弹性硅酮、胶原、丝等。例如,美国专利号4,612,337中描述了这些包被。
下一节描述了利用此处所述的配体/受体特异性交换剂治疗和预防疾病的方法。利用配体/受体特异性交换剂对疾病的治疗和预防
能对需要治疗和/或预防病原体(含有一种受体)感染的对象施用含有配体/受体特异性交换剂的药物。这些对象包括具有接触病原体危险的个体,或已感染病原体的个体。这些个体能用标准临床或诊断技术确定。
例如,一种方法是,将细菌感染患者确定为需要抑制病原体增殖的药物的患者。然后对该患者施用治疗有效量的配体/受体特异性交换剂。该方法中使用的配体/受体特异性交换剂含有可与细菌上的受体(例如:胞外纤维蛋白原结合蛋白(Efb)、胶原蛋白结合蛋白、玻连蛋白结合蛋白、层粘连蛋白结合蛋白、纤溶酶原结合蛋白、血小板反应蛋白结合蛋白、凝集因子A(ClfA)、凝集因子B(ClfB)、纤连蛋白结合蛋白、凝固酶和胞外粘附蛋白)相互作用的特异性结构域。配体/受体特异性交换剂也含有抗原结构域,该结构域含有病原体或毒素的表位,优选地含有可被患者中的高效价抗体识别的表位。在对患者施用配体/受体特异性交换剂之前,也希望根据可识别抗原结构域的高效价抗体的存在筛选需要药物的患者。如上所述,能利用固定的抗原结构域或配体/受体特异性交换剂,通过EIA或ELISA进行这种筛选。
类似地,能对需要抑制病毒感染的药物的患者施用一种可识别特定病原体上的受体的配体/受体特异性交换剂。因此,通过标准临床或诊断方法确定需要抑制病毒感染的药物的患者。然后,对需要的患者施用治疗有效量的配体/受体特异性交换剂,它可与感染个体的病毒类型上的受体相互作用。如上所述,在施用配体/受体特异性交换剂之前,希望确定患者是否含有足够效价的抗体与配体/受体特异性交换剂的抗原结构域相互作用。
同样,也能对需要抑制癌症增殖的药物的患者施用可与癌细胞上的受体相互作用的配体/受体特异性交换剂。例如,通过标准临床或诊断方法确定需要抑制癌症增殖的药物的患者;然后,对需要的患者施用治疗有效量的配体/受体特异性交换剂,它可与感染患者的癌细胞上的受体相互作用。如上所述,在施用配体/受体特异性交换剂之前,希望确定患者是否含有足够效价的抗体与配体/受体特异性交换剂的抗原结构域相互作用。
也能对研究对象施用此处所述的配体/受体特异性交换剂,作为防止疾病发作的预防药。实际上,为了预防目的(例如预防细菌感染、病毒感染或癌症)能对任何人施用此处所述的配体/受体特异性交换剂。但是,希望确定具有患特定疾病高度危险的对象,并施用配体/受体特异性交换剂。具有患病高度危险的对象包括具有疾病家族史的个体、老人或儿童或频繁接触病原体的个体(例如卫生保健人员)。因此,确定具有被含有受体的病原体感染危险的对象,并施用预防有效量的配体/受体特异性交换剂。
此处所述的配体/受体特异性交换剂的一种预防用途涉及将配体/受体特异性交换剂包被或交联医疗装置或植入物。可植入的医疗装置容易成为大量菌种的感染灶。这些生物粘附到装置表面并定居的趋势可加剧这类与装置相关的感染。因此,非常需要发展不会加剧通常伴随医疗装置植入发生的不利生物学反应的表面。
一种方法是,用含有配体/受体特异性交换剂的溶液包被医疗装置。在植入前,医疗装置(例如人工瓣膜)能贮存于例如配体/受体特异性交换剂溶液中。医疗装置也能用含有配体/受体特异性交换剂的粉末或凝胶包被。例如,手套、避孕套和子宫内装置能用含有可与细菌或病毒受体相互作用的特异性交换剂的粉末或凝胶包被。一旦植入体内,这些配体/受体特异性交换剂即成为预防病原体感染的屏障。
在某些实施方案中,配体/受体特异性交换剂固定于医疗装置上。如上所述,医疗装置是配体/受体特异性交换剂能够附着的载体。可以通过配体/受体特异性交换剂与医疗装置之间的疏水相互作用实现固定,但配体/受体特异性交换剂与医疗装置固定的一种优选方法包括共价结合。例如,能用可与特异性交换剂上的反应性基团相互作用的反应性基团生产医疗装置。
一种方法是,高碘酸盐与含有2-氨基乙醇部分的配体/受体特异性交换剂在pH约为4-9、温度约为0-50℃的水溶液中结合,形成具有醛功能的交换剂。然后,具有醛功能的交换剂与医疗装置含有伯胺部分的生物材料表面结合,配体/受体特异性交换剂通过亚胺部分固定于载体表面。然后,亚胺部分与还原剂反应,在生物材料表面通过仲胺连接形成固定的配体/受体特异性交换剂。为了固定此处所述的配体/受体特异性交换剂,能够改进分子与医疗装置的其它交联方法(如美国专利号6017741所述)。
尽管已经参照实施方案和实施例描述了本发明,但是应当理解,在不背离本发明的精神的情况下能进行多种修改。因此,本发明只受下列权利要求书的限制。
序列表<110>TRIPEP AB
SALLBERG,Matti
FLOCK,Jan-Ingmar<120>可将抗体重新定向于病原体上的受体的配体/受体特异性交换剂<130>TRIPEP.022VPC<150>US 09/664,025<151>2000-09-19<160>145<170>FastSEQ for Windows Version 4.0<210>1<211>18<212>PRT<213>人工序列<220><223>特异性结构域肽<400>1Tyr Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly1 5 10 15Asp Val<210>2<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>2Met Ser Trp Ser Leu His Pro Arg Asn Leu Ile Leu Tyr Phe Tyr Ala1 5 10 15Leu Leu Phe Leu
20<210>3<211>19<212>PRT<213>人工序列<220><223>特异性结构域肽<400>3Ile Leu Tyr Phe Tyr Ala Leu Leu Phe Leu Ser Thr Cys Val Ala Tyr1 5 10 15Val Ala Thr<210>4<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>4Ser Ser Thr Cys Val Ala Tyr Val Ala Thr Arg Asp Asn Cys Cys Ile1 5 10 15Leu Asp Glu Arg
20<210>5<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>5Arg Asp Asn Cys Cys Ile Leu Asp Glu Arg Phe Gly Ser Tyr Cys Pro1 5 10 15Thr Thr Cys Gly
20<210>6<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>6Phe Gly Ser Tyr Cys Pro Thr Thr Cys Gly Ile Ala Asp Phe Leu Ser1 5 10 15Thr Tyr Gln Thr
20<210>7<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>7Ile Ala Asp Phe Leu Ser Thr Tyr Gln Thr Lys Val Asp Lys Asp Leu1 5 10 15Gln Ser Leu Glu
20<210>8<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>8Lys Val Asp Lys Asp Leu Gln Ser Leu Glu Asp Ile Leu His Gln Val1 5 10 15Glu Asn Lys Thr
20<210>9<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>9Asp Ile Leu His Gln Val Glu Asn Lys Thr Ser Glu Val Lys Gln Leu1 5 10 15Ile Lys Ala Ile
20<210>10<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>10Ser Glu Val Lys Gln Leu Ile Lys Ala Ile Gln Leu Thr Tyr Asn Pro 1 5 10 15Asp Glu Ser Ser
20<210>11<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>11Gln Leu Thr Tyr Asn Pro Asp Glu Ser Ser Lys Pro Asn Met Ile Asp1 5 10 15Ala Ala Thr Leu
20<210>12<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>12Lys Pro Asn Met Ile Asp Ala Ala Thr Leu Lys Ser Arg Ile Met Leu1 5 10 15Glu Glu Ile Met
20<210>13<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>13Lys Ser Arg Ile Met Leu Glu Glu Ile Met Lys Tyr Glu Ala Ser Ile1 5 10 15Leu Thr His Asp
20<210>14<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>14Lys Tyr Glu Ala Ser Ile Leu Thr His Asp Ser Ser Ile Arg Tyr Leu1 5 10 15Gln Glu Ile Tyr
20<210>15<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>15Ser Ser Ile Arg Tyr Leu Gln Glu Ile Tyr Asn Ser Asn Asn Gln Lys1 5 10 15Ile Val Asn Leu
20<210>16<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>16Asn Ser Asn Asn Gln Lys Ile Val Asn Leu Lys Glu Lys Val Ala Gln1 5 10 15Leu Glu Ala Gln
20<210>17<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>17Cys Gln Glu Pro Cys Lys Asp Thr Val Gln Ile His Asp Ile Thr Gly1 5 10 15Lys Asp Cys Gln
20<210>18<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>18Ile His Asp Ile Thr Gly Lys Asp Cys Gln Asp Ile Ala Asn Lys Gly1 5 10 15Ala Lys Gln Ser
20<210>19<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>19Asp Ile Ala Asn Lys Gly Ala Lys Gln Ser Gly Leu Tyr Phe Ile Lys1 5 10 15Pro Leu Lys Ala
20<210>20<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>20Gly Leu Tyr Phe Ile Lys Pro Leu Lys Ala Asn Gln Gln Phe Leu Val1 5 10 15Tyr Cys Glu Ile
20<210>21<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>21Asn Gln Gln Phe Leu Val Tyr Cys Glu Ile Asp Gly Ser Gly Asn Gly 1 5 10 15Trp Thr Val Phe
20<210>22<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>22Asp Gly Ser Gly Asn Gly Trp Thr Val Phe Gln Lys Arg Leu Asp Gly1 5 10 15Ser Val Asp Phe
20<210>23<211>20<2l2>PRT<213>人工序列<220><223>特异性结构域肽<400>23Gln Lys Arg Leu Asp Gly Ser Val Asp Phe Lys Lys Asn Trp Ile Gln1 5 10 15Tyr Lys Glu Gly
20<210>24<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>24Lys Lys Asn Trp Ile Gln Tyr Lys Glu Gly Phe Gly His Leu Ser Pro1 5 10 15Thr Gly Thr Thr
20<210>25<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>25Phe Gly His Leu Ser Pro Thr Gly Thr Thr Glu Phe Trp Leu Gly Asn1 5 10 15Glu Lys Ile His
20<210>26<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>26Glu Phe Trp Leu Gly Asn Glu Lys Ile His Leu Ile Ser Thr Gln Ser1 5 10 15Ala Ile Pro Tyr
20<210>27<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>27Leu Ile Ser Thr Gln Ser Ala Ile Pro Tyr Ala Leu Arg Val Glu Leu1 5 10 15Glu Asp Trp Asn
20<210>28<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>28Ala Leu Arg Val Glu Leu Glu Asp Trp Asn Gly Arg Thr Ser Thr Ala1 5 10 15Asp Tyr Ala Met
20<210>29<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>29Gly Arg Thr Ser Thr Ala Asp Tyr Ala Met Phe Lys Val Gly Pro Glu1 5 10 15Ala Asp Lys Tyr
20<210>30<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>30Phe Lys Val Gly Pro Glu Ala Asp Lys Tyr Arg Leu Thr Tyr Ala Tyr1 5 10 15Phe Ala Gly Gly
20<210>31<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>31Arg Leu Thr Tyr Ala Tyr Phe Ala Gly Gly Asp Ala Gly Asp Ala Phe1 5 10 15Asp Gly Phe Asp
20<210>32<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>32Asp Ala Gly Asp Ala Phe Asp Gly Phe Asp Phe Gly Asp Asp Pro Ser 1 5 10 15Asp Lys Phe Phe
20<210>33<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>33Phe Gly Asp Asp Pro Ser Asp Lys Phe Phe Thr Ser His Asn Gly Met1 5 10 15Gln Phe Ser Thr
20<210>34<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>34Thr Ser His Asn Gly Met Gln Phe Ser Thr Trp Asp Asn Asp Asn Asp1 5 10 15Lys Phe Glu Gly
20<210>35<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>35Trp Asp Asn Asp Asn Asp Lys Phe Glu Gly Asn Cys Ala Glu Gln Asp1 5 10 15Gly Ser Gly Trp
20<210>36<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>36Asn Cys Ala Glu Gln Asp Gly Ser Gly Trp Trp Met Asn Lys Cys His1 5 10 15Ala Gly His Leu
20<210>37<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>37Trp Met Asn Lys Cys His Ala Gly His Leu Asn Gly Val Tyr Tyr Gln1 5 10 15Gly Gly Thr Tyr
20<210>38<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>38Asn Gly Val Tyr Tyr Gln Gly Gly Thr Tyr Ser Lys Ala Ser Thr Pro1 5 10 15Asn Gly Tyr Asp
20<210>39<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>39Ser Lys Ala Ser Thr Pro Asn Gly Tyr Asp Asn Gly Ile Ile Trp Ala1 5 10 15Thr Trp Lys Thr
20<210>40<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>40Asn Gly Ile Ile Trp Ala Thr Trp Lys Thr Arg Trp Tyr Ser Met Lys1 5 10 15Lys Thr Thr Met
20<210>41<211>20<212>PRT<213>人工序列<220><223>特异性结构域肽<400>41Arg Trp Tyr Ser Met Lys Lys Thr Thr Met Lys Ile Ile Pro Phe Asn1 5 10 15Arg Leu Thr Ile
20<210>42<211>27<212>PRT<213>人工序列<220><223>特异性结构域肽<400>42Lys Ile Ile Pro Phe Asn Arg Leu Thr Ile Gly Glu Gly Gln Gln His1 5 10 15His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val
20 25<210>43<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>43Gly Leu Tyr Ser Ser Ile Trp Leu Ser Pro Gly Arg Ser Tyr Phe Glu 1 5 10 15Thr<210>44<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>44Tyr Thr Asp Ile Lys Tyr Asn Pro Phe Thr Asp Arg Gly Glu Gly Asn1 5 10 15Met<210>45<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>45Asp Gln Asn Ile His Met Asn Ala Arg Leu Leu Ile Arg Ser Pro Phe1 5 10 15Thr<210>46<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>46Leu Ile Arg Ser Pro Phe Thr Asp Pro Gln Leu Leu Val His Thr Asp1 5 10 15Pro<210>47<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>47Gln Lys Glu Ser Leu Leu Phe Pro Pro Val Lys Leu Leu Arg Arg Val1 5 10 15Pro<210>48<211>11<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>48Pro Ala Leu Thr Ala Val Glu Thr Gly Ala Thr1 5 10<210>49<211>8<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>49Ser Thr Leu Val Pro Glu Thr Thr1 5<210>50<211>13<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>50Thr Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu1 5 10<210>51<211>9<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>51Glu Ile Pro Ala Leu Thr Ala Val Glu1 5<210>52<211>10<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>52Leu Glu Asp Pro Ala Ser Arg Asp Leu Val1 5 10<210>53<211>8<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>53His Arg Gly Gly Pro Glu Glu Phe1 5<210>54<211>7<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>54His Arg Gly Gly Pro Glu Glu1 5<210>55<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>55Val Leu Ile Cys Gly Glu Asn Thr Val Ser Arg Asn Tyr Ala Thr His1 5 10 15Ser<210>56<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>56Lys Ile Asn Thr Met Pro Pro Phe Leu Asp Thr Glu Leu Thr Ala Pro1 5 10 15Ser<210>57<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>57Pro Asp Glu Lys Ser Gln Arg Glu Ile Leu Leu Asn Lys Ile Ala Ser1 5 10 15Tyr<210>58<211>17<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>58Thr Ala Thr Thr Thr Thr Tyr Ala Tyr Pro Gly Thr Asn Arg Pro Pro1 5 10 15Val<210>59<211>8<212>PRT<213>人工序列<220><223>抗原性结构域肽<400>59Ser Thr Pro Leu Pro Glu Thr Thr1 5<210>60<211>26<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>60Tyr Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly1 5 10 15Asp Val His Arg Gly Gly Pro Glu Glu Phe
20 25<210>61<211>25<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>61Tyr Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly1 5 10 15Asp Val His Arg Gly Gly Pro Glu Glu
20 25<210>62<211>26<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>62Tyr Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly1 5 10 15Asp Val Ser Thr Pro Leu Pro Glu Thr Thr
20 25<210>63<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>63Met Ser Trp Ser Leu His Pro Arg Asn Leu Ile Leu Tyr Phe Tyr Ala1 5 10 15Leu Leu Phe Leu His Arg Gly Gly Pro Glu Glu
20 25<210>64<211>26<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>64Ile Leu Tyr Phe Tyr Ala Leu Leu Phe Leu ser Thr Cys Val Ala Tyr1 5 10 15Val Ala Thr His Arg Gly Gly Pro Glu Glu
20 25<210>65<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>65Ser Ser Thr Cys Val Ala Tyr Val Ala Thr Arg Asp Asn Cys Cys Ile1 5 10 15Leu Asp Glu Arg His Arg Gly Gly Pro Glu Glu
20 25<210>66<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>66Arg Asp Asn Cys Cys Ile Leu Asp Glu Arg Phe Gly Ser Tyr Cys Pro1 5 10 15Thr Thr Cys Gly His Arg Gly Gly Pro Glu Glu
20 25<210>67<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>67Phe Gly Ser Tyr Cys Pro Thr Thr Cys Gly Ile Ala Asp Phe Leu Ser1 5 10 15Thr Tyr Gln Thr His Arg Gly Gly Pro Glu Glu
20 25<210>68<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>68Ile Ala Asp Phe Leu Ser Thr Tyr Gln Thr Lys Val Asp Lys Asp Leu1 5 10 15Gln Ser Leu Glu His Arg Gly Gly Pro Glu Glu
20 25<210>69<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>69Lys Val Asp Lys Asp Leu Gln Ser Leu Glu Asp Ile Leu His Gln Val1 5 10 15Glu Asn Lys Thr His Arg Gly Gly Pro Glu Glu
20 25<210>70<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>70Asp Ile Leu His Gln Val Glu Asn Lys Thr Ser Glu Val Lys Gln Leu1 5 10 15Ile Lys Ala Ile His Arg Gly Gly Pro Glu Glu
20 25<210>71<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>71Ser Glu Val Lys Gln Leu Ile Lys Ala Ile Gin Leu Thr Tyr Asn Pro1 5 10 15Asp Glu Ser Ser His Arg Gly Gly Pro Glu Glu
20 25<210>72<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>72Gln Leu Tnr Tyr Asn Pro Asp Glu Ser Ser Lys Pro Asn Met Ile Asp1 5 10 15Ala Ala Thr Leu His Arg Gly Gly Pro Glu Glu
20 25<210>73<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>73Lys Pro Asn Met Ile Asp Ala Ala Thr Leu Lys Ser Arg Ile Met Leu1 5 10 15Glu Glu Ile Met His Arg Gly Gly Pro Glu Glu
20 25<210>74<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>74Lys Ser Arg Ile Met Leu Glu Glu Ile Met Lys Tyr Glu Ala Ser Ile1 5 10 15Leu Thr His Asp His Arg Gly Gly Pro Glu Glu
20 25<210>75<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>75Lys Tyr Glu Ala Ser Ile Leu Thr His Asp Ser Ser Ile Arg Tyr Leu1 5 10 15Gln Glu Ile Tyr His Arg Gly Gly Pro Glu Glu
20 25<210>76<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>76Ser Ser Ile Arg Tyr Leu Gln Glu Ile Tyr Asn Ser Asn Asn Gln Lys1 5 10 15Ile Val Asn Leu His Arg Gly Gly Pro Glu Glu
20 25<210>77<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>77Asn Ser Asn Asn Gln Lys Ile Val Asn Leu Lys Glu Lys Val Ala Gln1 5 10 15Leu Glu Ala Gln His Arg Gly Gly Pro Glu Glu
20 25<210>78<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>78Cys Gln Glu Pro Cys Lys Asp Thr Val Gln Ile His Asp Ile Thr Gly1 5 10 15Lys Asp Cys Gln His Arg Gly Gly Pro Glu Glu
20 25<210>79<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>79Ile His Asp Ile Thr Gly Lys Asp Cys Gln Asp Ile Ala Asn Lys Gly1 5 10 15Ala Lys Gln Ser His Arg Gly Gly Pro Glu Glu
20 25<210>80<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>80Asp Ile Ala Asn Lys Gly Ala Lys Gln Ser Gly Leu Tyr Phe Ile Lys1 5 10 15Pro Leu Lys Ala His Arg Gly Gly Pro Glu Glu
20 25<210>81<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>81Gly Leu Tyr Phe Ile Lys Pro Leu Lys Ala Asn Gln Gln Phe Leu Val1 5 10 15Tyr Cys Glu Ile His Arg Gly Gly Pro Glu Glu
20 25<210>82<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>82Asn Gln Gln Phe Leu Val Tyr Cys Glu Ile Asp Gly Ser Gly Asn Gly1 5 10 15Trp Thr Val Phe His Arg Gly Gly Pro Glu Glu
20 25<210>83<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>83Asp Gly Ser Gly Asn Gly Trp Thr Val Phe Gln Lys Arg Leu Asp Gly1 5 10 15Ser Val Asp Phe His Arg Gly Gly Pro Glu Glu
20 25<210>84<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>84Gln Lys Arg Leu Asp Gly Ser Val Asp Phe Lys Lys Asn Trp Ile Gln1 5 10 15Tyr Lys Glu Gly His Arg Gly Gly Pro Glu Glu
20 25<210>85<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>85Lys Lys Asn Trp Ile Gln Tyr Lys Glu Gly Phe Gly His Leu Ser Pro1 5 10 15Thr Gly Thr Thr His Arg Gly Gly Pro Glu Glu
20 25<210>86<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>86Phe Gly His Leu Ser Pro Thr Gly Thr Thr Glu Phe Trp Leu Gly Asn1 5 10 15Glu Lys Ile His His Arg Gly Gly Pro Glu Glu
20 25<210>87<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>87Glu Phe Trp Leu Gly Asn Glu Lys Ile His Leu Ile Ser Thr Gln Ser1 5 10 15Ala Ile Pro Tyr His Arg Gly Gly Pro Glu Glu
20 25<210>88<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>88Leu Ile Ser Thr Gln Ser Ala Ile Pro Tyr Ala Leu Arg Val Glu Leu1 5 10 15Glu Asp Trp Asn His Arg Gly Gly Pro Glu Glu
20 25<210>89<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>89Ala Leu Arg Val Glu Leu Glu Asp Trp Asn Gly Arg Thr Ser Thr Ala1 5 10 15Asp Tyr Ala Met His Arg Gly Gly Pro Glu Glu
20 25<210>90<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>90Gly Arg Thr Ser Thr Ala Asp Tyr Ala Met Phe Lys Val Gly Pro Glu1 5 10 15Ala Asp Lys Tyr His Arg Gly Gly Pro Glu Glu
20 25<210>91<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>91Phe Lys Val Gly Pro Glu Ala Asp Lys Tyr Arg Leu Thr Tyr Ala Tyr1 5 10 15Phe Ala Gly Gly His Arg Gly Gly Pro Glu Glu
20 25<210>92<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>92Arg Leu Thr Tyr Ala Tyr Phe Ala Gly Gly Asp Ala Gly Asp Ala Phe1 5 10 15Asp Gly Phe Asp His Arg Gly Gly Pro Glu Glu
20 25<210>93<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>93Asp Ala Gly Asp Ala Phe Asp Gly Phe Asp Phe Gly Asp Asp Pro Ser1 5 10 15Asp Lys Phe Phe His Arg Gly Gly Pro Glu Glu
20 25<210>94<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>94Phe Gly Asp Asp Pro Ser Asp Lys Phe Phe Thr Ser His Asn Gly Met1 5 10 15Gln Phe Ser Thr His Arg Gly Gly Pro Glu Glu
20 25<210>95<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>95Thr Ser His Asn Gly Met Gln Phe Ser Thr Trp Asp Asn Asp Asn Asp1 5 10 15Lys Phe Glu Gly His Arg Gly Gly Pro Glu Glu
20 25<210>96<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>96Trp Asp Asn Asp Asn Asp Lys Phe Glu Gly Asn Cys Ala Glu Gln Asp1 5 10 15Gly Ser Gly Trp His Arg Gly Gly Pro Glu Glu
20 25<210>97<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>97Asn Cys Ala Glu Gln Asp Gly Ser Gly Trp Trp Met Asn Lys Cys His1 5 10 15Ala Gly His Leu His Arg Gly Gly Pro Glu Glu
20 25<210>98<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>98Trp Met Asn Lys Cys His Ala Gly His Leu Asn Gly Val Tyr Tyr Gln1 5 10 15Gly Gly Thr Tyr His Arg Gly Gly Pro Glu Glu
20 25<210>99<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>99Asn Gly Val Tyr Tyr Gln Gly Gly Thr Tyr Ser Lys Ala Ser Thr Pro1 5 10 15Asn Gly Tyr Asp His Arg Gly Gly Pro Glu Glu
20 25<210>100<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>100Ser Lys Ala Ser Thr Pro Asn Gly Tyr Asp Asn Gly Ile Ile Trp Ala1 5 10 15Thr Trp Lys Thr His Arg Gly Gly Pro Glu Glu
20 25<210>101<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>101Asn Gly Ile Ile Trp Ala Thr Trp Lys Thr Arg Trp Tyr Ser Met Lys1 5 10 15Lys Thr Thr Met His Arg Gly Gly Pro Glu Glu
20 25<210>102<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>102Arg Trp Tyr Ser Met Lys Lys Thr Thr Met Lys Ile Ile Pro Phe Asn1 5 10 15Arg Leu Thr Ile His Arg Gly Gly Pro Glu Glu
20 25<210>103<211>34<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>103Lys Ile Ile Pro Phe Asn Arg Leu Thr Ile Gly Glu Gly Gln Gln His1 5 10 15His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val His Arg Gly Gly Pro
20 25 30Glu Glu<210>104<211>13<212>PRT<213>人工序列<220><223>整联蛋白特异性配体/受体特异性交换剂肽<400>104Gly Arg Gly Asp Ser Pro His Arg Gly Gly Pro Glu Glu1 5 10<210>105<211>13<212>PRT<213>人工序列<220><223>整联蛋白特异性配体/受体特异性交换剂肽<400>105Trp Ser Arg Gly Asp Trp His Arg Gly Gly Pro Glu Glu1 5 10<210>106<211>20<212>PRT<213>人工序列<220><223>血纤蛋白原<400>106Leu Thr Ile Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln1 5 10 15Ala Gly Asp Val
20<210>107<211>17<212>PRT<213>人工序列<220><223>血纤蛋白原<400>107Gly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly Asp1 5 10 15Val<210>108<211>14<212>PRT<213>人工序列<220><223>血纤蛋白原<400>108Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>109<211>13<212>PRT<213>人工序列<220><223>血纤蛋白原<400>109Gln His His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>110<211>12<212>PRT<213>人工序列<220><223>血纤蛋白原<400>110His His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>111<211>11<212>PRT<213>人工序列<220><223>血纤蛋白原<400>111His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>112<211>10<212>PRT<213>人工序列<220><223>血纤蛋白原<400>112Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>113<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>113Gly Gly Ala Lys Gln Ala Gly Asp Val1 5<210>114<211>8<212>PRT<213>人工序列<220><223>血纤蛋白原<400>114Gly Ala Lys Gln Ala Gly Asp Val1 5<210>115<211>12<212>PRT<213>人工序列<220><223>血纤蛋白原<400>115Gln His His Leu Gly Gly Ala Lys Gln Ala Gly Asp1 5 10<210>116<211>11<212>PRT<213>人工序列<220><223>血纤蛋白原<400>116Gln His His Leu Gly Gly Ala Lys Gln Ala Gly1 5 10<210>117<211>10<212>PRT<213>人工序列<220><223>血纤蛋白原<400>117Gln His His Leu Gly Gly Ala Lys Gln Ala1 5 10<210>118<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>118Gln His His Leu Gly Gly Ala Lys Gln1 5<210>119<211>8<212>PRT<213>人工序列<220><223>血纤蛋白原Gln His His Leu Gly Gly Ala Lys1 5<210>120<211>7<212>PRT<213>人工序列<220><223>血纤蛋白原<400>120Gln His His Leu Gly Gly Ala1 5<210>121<211>12<212>PRT<213>人工序列<220><223>血纤蛋白原<400>121His His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>122<211>11<212>PRT<213>人工序列<220><223>血纤蛋白原<400>122His His Leu Gly Gly Ala Lys Gln Ala Gly Asp1 5 10<210>123<211>10<212>PRT<213>人工序列<220><223>血纤蛋白原<400>123His His Leu Gly Gly Ala Lys Gln Ala Gly1 5 10<210>124<211>11<212>PRT<213>人工序列<220><223>血纤蛋白原<400>124His Leu Gly Gly Ala Lys Gln Ala Gly Asp Val1 5 10<210>125<211>10<212>PRT<213>人工序列<220><223>血纤蛋白原<400>125His Leu Gly Gly Ala Lys Gln Ala Gly Asp1 5 10<210>126<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>126Ala Leu Gly Gly Ala Lys Gln Ala Gly1 5<210>127<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>127His Ala Gly Gly Ala Lys Gln Ala Gly1 5<210>128<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>128His Leu Ala Gly Ala Lys Gln Ala Gly1 5<210>129<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>129His Leu Gly Ala Ala Lys Gln Ala Gly1 5<210>130<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>130His Leu Gly Gly Gly Lys Gln Ala Gly1 5<210>131<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>131His Leu Gly Gly Ala Ala Gln Ala Gly1 5<210>132<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>132His Leu Gly Gly Ala Lys Ala Ala Gly1 5<210>133<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>133His Leu Gly Gly Ala Lys Gln Gly Gly1 5<210>134<211>9<212>PRT<213>人工序列<220><223>血纤蛋白原<400>134His Leu Gly Gly Ala Lys Gln Ala Ala1 5<210>135<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽;在半胱氨酸间环化<400>135Cys Pro Ala Leu Thr Ala Val Glu Thr Gly Cys Thr Asn Pro Leu Ala1 5 10 15Ala His His Leu Gly Gly Ala Lys Gln Ala Gly
20 25<210>136<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>136Cys Pro Ala Leu Thr Ala Val Glu Thr Gly Cys Thr Asn Pro Leu Ala1 5 10 15Ala His His Leu Gly Gly Ala Lys Gln Ala Gly
20 25<210>137<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽;在半胱氨酸间环化<400>137His His Leu Gly Gly Ala Lys Gln Ala Gly Ala Ala Cys Pro Ala Leu1 5 10 15Thr Ala Val Glu Thr Gly Cys Thr Asn Pro Leu
20 25<210>138<211>27<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>138His His Leu Gly Gly Ala Lys Gln Ala Gly Ala Ala Cys Pro Ala Leu1 5 10 15Thr Ala Val Glu Thr Gly Cys Thr Asn Pro Leu
20 25<210>139<211>25<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽;在半胱氨酸间环化<400>139Cys Pro Ala Leu Thr Ala Val Glu Thr Gly Cys Thr Asn Pro Leu His1 5 10 15His Leu Gly Gly Ala Lys Gln Ala Gly
20 25<210>140<211>25<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>140Cys Pro Ala Leu Thr Ala Val Glu Thr Gly Cys Thr Asn Pro Leu His1 5 10 15His Leu Gly Gly Ala Lys Gln Ala Gly
20 25<210>141<211>25<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽;在半胱氨酸间环化<400>141His His Leu Gly Gly Ala Lys Gln Ala Gly Cys Pro Ala Leu Thr Ala1 5 10 15Val Glu Thr Gly Cys Thr Asn Pro Leu
20 25<210>142<211>25<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>142His His Leu Gly Gly Ala Lys Gln Ala Gly Cys Pro Ala Leu Thr Ala1 5 10 15Val Glu Thr Gly Cys Thr Asn Pro Leu
20 25<210>143<211>24<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>143Pro Ala Leu Thr Ala Val Glu Thr Gly Ala Thr Asn Pro Leu His His1 5 10 15Leu Gly Gly Ala Lys Gln Ala Gly
20<210>144<211>24<212>PRT<213>人工序列<220><223>配体/受体特异性交换剂肽<400>144His His Leu Gly Gly Ala Lys Gln Ala Gly Pro Ala Leu Thr Ala Val1 5 10 15Glu Thr Gly Ala Thr Asn Pro Leu
20<210>145<211>12<212>PRT<213>人工序列<220><223>整联蛋白特异性肽<400>145Arg Gly Asp Ser Ala Ala Thr Pro Pro Ala Tyr Arg1 5 10
Claims (22)
1.一种配体/受体特异性交换剂,其含有:
至少一个含有受体的配体的特异性结构域;和
至少一个与该特异性结构域连接的抗原结构域,其中该抗原结构域含有病原体或毒素的表位。
2.权利要求1的配体/受体特异性交换剂,其中所述特异性结构域至少含有一种肽的三个连续氨基酸,该肽选自胞外基质蛋白、病毒上受体的配体和癌细胞上受体的配体。
3.权利要求2的配体/受体特异性交换剂,其中所述肽是一种选自纤维蛋白原、胶原蛋白、玻连蛋白、层粘连蛋白、纤溶酶原、血小板反应蛋白和纤连蛋白的胞外基质蛋白。
4.权利要求2的配体/受体特异性交换剂,其中所述肽是选自T4糖蛋白和乙型肝炎病毒包膜蛋白的病毒受体的配体。
5.权利要求2的配体/受体特异性交换剂,其中所述肽是癌细胞上的受体的配体,选自HER-2/neu的配体和整联蛋白受体的配体。
6.权利要求1的配体/受体特异性交换剂,其中所述特异性结构域至少含有一种选自下列的序列: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.ID.No.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,SEQ.ID.No.15,SEQ.ID.No.16,SEQ.ID.No.17,SEQ.ID.No.18,SEQ.ID.No.19,SEQ.ID.No.20,SEQ.ID.No.21,SEQ.ID.No.22,SEQ.ID.No.23,SEQ.ID.No.24,SEQ.ID.No.25,SEQ.ID.No.26,SEQ.ID.No.27,SEQ.ID.No.28,SEQ.ID.No.29,SEQ.ID.No.30,SEQ.ID.No.31,SEQ.ID.No.32,SEQ.ID.No.33,SEQ.ID.No.34,SEQ.ID.No.35,SEQ.ID.No.36,SEQ.ID.No.37,SEQ.ID.No.38,SEQ.ID.No.39,SEQ.ID.No.40,SEQ.ID.No.41,SEQ.ID.No.42和SEQ.ID.No.124。
7.权利要求3的配体/受体特异性交换剂,其中所述胞外基质蛋白至少含有纤维蛋白原α链的三个氨基酸。
8.权利要求1的配体/受体特异性交换剂,其中所述配体含有序列精氨酸-甘氨酸-天冬氨酸(RGD)。
9.权利要求1的配体/受体特异性交换剂,其中所述受体在病原体上存在。
10.权利要求1的配体/受体特异性交换剂,其中所述受体是一种细菌粘附受体。
11.权利要求10的配体/受体特异性交换剂,其中所述细菌粘附受体选自:胞外纤维蛋白原结合蛋白(Efb)、胶原蛋白结合蛋白、玻连蛋白结合蛋白、层粘连蛋白结合蛋白、纤溶酶原结合蛋白、血小板反应蛋白结合蛋白、凝集因子A(ClfA)、凝集因子B(ClfB)、纤连蛋白结合蛋白、凝固酶和胞外粘附蛋白。
12.权利要求1的配体/受体特异性交换剂,其中所述抗原结构域含有一种肽的至少三个氨基酸,该肽选自单纯疱疹病毒蛋白、乙型肝炎病毒蛋白、TT病毒蛋白和脊髓灰质炎病毒蛋白。
13.权利要求12的配体/受体特异性交换剂,其中所述抗原结构域是一种单纯疱疹病毒蛋白,其至少含有一种选自SEQ.ID.No.53和SEQ.ID.No.54的序列。
14.权利要求12的配体/受体特异性交换剂,其中所述抗原结构域是一种乙型肝炎病毒蛋白,其至少含有一种选自SEQ.ID.No.49、SEQ.ID.No.50、SEQ.ID.No.52和SEQ.ID.No.59的序列。
15.权利要求12的配体/受体特异性交换剂,其中所述抗原结构域是一种TT病毒蛋白,其至少含有一种选自SEQ.ID.No.43、SEQ.ID.No.44、SEQ.ID.No.45、SEQ.ID.No.46、SEQ.ID.No.47、SEQ.ID.No.55、SEQ.ID.No.56、SEQ.ID.No.57和SEQ.ID.No.58的序列。
16.权利要求12的配体/受体特异性交换剂,其中所述抗原结构域是一种脊髓灰质炎病毒蛋白,其含有一种选自SEQ.ID.No.48和SEQ.ID.No.51的序列。
17.权利要求1的配体/受体特异性交换剂,其中所述抗原结构域可与高效价抗体相互作用。
18.权利要求17的配体/受体特异性交换剂,其中所述抗原结构域与约1∶100-1∶1000或更高稀释度的动物血清中存在的抗体特异结合。
19.权利要求1的配体/受体特异性交换剂,其中该配体/受体特异性交换剂的序列选自选自:SEQ.ID.No.60,SEQ.ID.No.61、SEQ.ID.No.62,SEQ.ID.No.63,SEQ.ID.No.64,SEQ.ID.No.65,SEQ.ID.No.66,SEQ.ID.No.67,SEQ.ID.No.68,SEQ.ID.No.69,SEQ.ID.No.70,SEQ.ID.No.71,SEQ.ID.No.72,SEQ.ID.No.73,SEQ.ID.No.74,SEQ.ID.No.75,SEQ.ID.No.76,SEQ.ID.No.77,SEQ.ID.No.78,SEQ.ID.No.79,SEQ.ID.No.80,SEQ.ID.No.81,SEQ.ID.No.82,SEQ.ID.No.83,SEQ.ID.No.84,SEQ.ID.No.85,SEQ.ID.No.86,SEQ.ID.No.87,SEQ.ID.No.88,SEQ.ID.No.89,SEQ.ID.No.90,SEQ.ID.No.91,SEQ.ID.No.92,SEQ.ID.No.93,SEQ.ID.No.94,SEQ.ID.No.95,SEQ.ID.No.96,SEQ.ID.No.97,SEQ.ID.No.98,SEQ.ID.No.99,SEQ.ID.No.100,SEQ.ID.No.101,SEQ.ID.No.102,SEQ.ID.No.103,SEQ.ID.No.104,SEQ.ID.No.105,SEQ.ID.No.137和SEQ.ID.No.142。
20.一种治疗或预防细菌感染的方法,包括:
对患者施用治疗有效量的配体/受体特异性交换剂,其中该配体/受体特异性交换剂包含含有可与细菌受体相互作用的配体之特异性结构域,和含有病原体或毒素的表位的抗原结构域。
21.一种治疗或预防病毒感染的方法,包括:
对患者施用治疗有效量的配体/受体特异性交换剂,其中该配体/受体特异性交换剂包含含有可与病毒受体相互作用的配体之特异性结构域,和含有病原体或毒素的表位的抗原结构域。
22.一种治疗或预防癌症的方法,包括:
对患者施用治疗有效量的配体/受体特异性交换剂,其中该配体/受体特异性交换剂包含含有可与癌细胞上的受体相互作用的配体之特异性结构,域和含有病原体或毒素的表位的抗原结构域。
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CN101987866A (zh) * | 2010-10-25 | 2011-03-23 | 中国人民解放军军事医学科学院基础医学研究所 | 金黄色葡萄球菌Efb蛋白C端抗原表位及其制备方法和用途 |
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US6660842B1 (en) | 1994-04-28 | 2003-12-09 | Tripep Ab | Ligand/receptor specificity exchangers that redirect antibodies to receptors on a pathogen |
US6933366B2 (en) | 1996-12-27 | 2005-08-23 | Tripep Ab | Specificity exchangers that redirect antibodies to bacterial adhesion receptors |
US7052849B2 (en) * | 2001-11-23 | 2006-05-30 | Syn X Pharma, Inc. | Protein biopolymer markers predictive of insulin resistance |
CN1747970A (zh) * | 2003-02-06 | 2006-03-15 | 三肽公司 | 抗原/抗体或配体/受体糖基化的特异性交换剂 |
US7335359B2 (en) | 2003-02-06 | 2008-02-26 | Tripep Ab | Glycosylated specificity exchangers |
EP2486408A4 (en) * | 2009-10-05 | 2013-04-24 | Opsonic Therapeutics Inc | HIGH-AFFINE ADAPTER MOLECULES FOR THE TRANSFER OF ANTIBODY SPECIFICATIONS |
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JPH04310861A (ja) * | 1991-04-09 | 1992-11-02 | Kazuo Yanagi | 抗ebna抗体の測定方法および抗ebna抗体測定キット |
DE69535604T2 (de) * | 1994-02-18 | 2008-05-21 | American National Red Cross | Transgenes fibrinogen |
SE9401460D0 (sv) * | 1994-04-28 | 1994-04-28 | Ferring Ab | Antigen/antibody specificity exhanger |
DE69938130T2 (de) * | 1998-05-27 | 2009-03-12 | Hadasit Medical Research Services & Development Co. Ltd. | Neue peptide |
AU775939B2 (en) * | 1998-11-05 | 2004-08-19 | Powderject Vaccines, Inc. | Nucleic acid constructs for genetic immunization |
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Cited By (2)
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CN101987866A (zh) * | 2010-10-25 | 2011-03-23 | 中国人民解放军军事医学科学院基础医学研究所 | 金黄色葡萄球菌Efb蛋白C端抗原表位及其制备方法和用途 |
CN101987866B (zh) * | 2010-10-25 | 2013-01-23 | 中国人民解放军军事医学科学院基础医学研究所 | 金黄色葡萄球菌Efb蛋白C端抗原表位及其制备方法和用途 |
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AU2002223973B2 (en) | 2007-04-05 |
RU2003106428A (ru) | 2005-01-20 |
KR20030034194A (ko) | 2003-05-01 |
WO2002024887A3 (en) | 2003-08-14 |
CN100371442C (zh) | 2008-02-27 |
PL364788A1 (en) | 2004-12-13 |
CA2421877A1 (en) | 2002-03-28 |
WO2002024887A2 (en) | 2002-03-28 |
EP1354033A2 (en) | 2003-10-22 |
AU2397302A (en) | 2002-04-02 |
JP2004509621A (ja) | 2004-04-02 |
RU2300391C2 (ru) | 2007-06-10 |
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