CN113557246A - 靶向αvβ3整联蛋白的单域抗体 - Google Patents
靶向αvβ3整联蛋白的单域抗体 Download PDFInfo
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- CN113557246A CN113557246A CN201980093592.7A CN201980093592A CN113557246A CN 113557246 A CN113557246 A CN 113557246A CN 201980093592 A CN201980093592 A CN 201980093592A CN 113557246 A CN113557246 A CN 113557246A
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Abstract
本发明涉及靶向αvβ3整联蛋白的单域抗体及其各种应用。与现有抗体相比,本发明的靶向αvβ3整联蛋白的单域抗体对与血管生成相关的αvβ3整联蛋白表现出高结合力、优异的组织渗透性及生物稳定性。并且,本发明的单域抗体能够与荧光粒子结合来在体外、体内或离体进行简单测定,因而对血管生成的检测及与此相关的疾病的诊断有效,从而可以有效用于相关产业中。
Description
技术领域
本发明涉及靶向αvβ3整联蛋白的单域抗体及其各种应用。
背景技术
整联蛋白(Integrin)是一种细胞表面受体,其调节细胞的重要生理功能,例如细胞粘附及移动、分化、增殖等。整联蛋白充当α和β亚基由非共价键组成的异二聚体,α和β亚基配对形成22种整联蛋白家族。整联蛋白主要结合细胞外基质蛋白,如玻连蛋白、纤连蛋白、胶原蛋白、层粘连蛋白、血管性血友病因子(vWF)、纤维蛋白原等,每种整联蛋白的配体特异性都有差异,并且一种整联蛋白可以同时与多种配体结合。其中,整联蛋白αvβ3在包括皮肤癌、前列腺癌、乳腺癌、宫颈癌、结肠癌、肺癌、胆囊癌、胰腺癌和胃癌在内的各种癌症中的大多数侵袭性肿瘤细胞中表达,并且已知通过调节粘附依赖性肿瘤细胞的生长、存活和渗透来提高各种人类肿瘤的恶性。近年来,已经发现β整联蛋白通过调节细胞内信号传导而作为不依赖于粘附的介质增加肿瘤的生长及转移(David A Cheresh et al.,Naturemedicine 2009,15(10):1163)。并且,已知上述αvβ3整联蛋白在微血管生成中广泛表达。
所谓血管生成(angiogenesis),是指从现有血管生成新的毛细血管。这是一种严格调节的现象,在正常的生理条件下几乎不发生,但是在受精卵发育过程中的胚胎发育、成人的伤口愈合以及女性的生殖周期中的生殖系统变化等中发生。在成人的情况下,毛细血管内的皮细胞相对不易分裂,分裂速度通常为数月至数年。血管生成通过各种类型的细胞与水溶性因子及细胞外基质(extracellularmatrix)成分之间的相互作用引起的复杂过程而发生,其作用机理尚未查明。上述血管生成成为多种疾病的原因。
当前,虽然已报道了商业用途的抗体有300000种以上,但只能在固定化的细胞内观察到它们,由于这些原因,无法在细胞内实时观察蛋白质的接触或蛋白质之间的相互作用等。并且,由于现有抗体非常大或者化学上不稳定,无法在活细胞内有效使用。然而,在1993年Hamers-Casterman报道了单域抗体(Hamers-Casterman,C.et al.1993.Nature363:446-448),其为源自骆驼科动物的抗体,与现有抗体(两个重链(heavy chain)和两个轻链(light chain))相比,虽然只由重链组成,但功能上却起到完整的抗体的作用。现有抗体分子量为150kDa,重组抗体为25~50kDa,而源自骆驼、美洲驼、鲨鱼的单域抗体却是分子量仅为12~13kDa的非常小的抗体,因此能够轻易向细胞内移动(Cortez-Retamozo,V.etal.2004.Cancer Res.64:2853-2857),易于进行遗传操作,具有易于在细菌和酵母中表达的优点(Arbabi-Ghahroudii,M.et al.1997.FEBS Lett.414:521-526)。并且,单域抗体具有很高的水溶性,具有在极端的pH条件和高达90℃的温度条件下也很稳定的特征(Dumoulin,M.et al.2002.Protein Sciii.11:500-515,Dumoulin,m.et al.2003.Nature424:783-788)。
发明内容
技术问题
本发明的目的在于,可以提供靶向αvβ3整联蛋白(Integrin)单域抗体(Single-domain antibody)。
并且,本发明的目的在于,可以提供包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上的重组载体。
并且,本发明的目的在于,可以提供由上述重组载体转化的重组微生物。
并且,本发明的目的在于,可以提供用于检测血管生成的组合物。
并且,本发明的目的在于,可以提供用于检测血管生成的试剂盒。
并且,本发明的目的在于,可以提供包含上述单域抗体的用于诊断血管生成相关疾病的组合物。
并且,本发明的目的在于,可以提供靶向αvβ3整联蛋白的单域抗体的制备方法。
并且,本发明的目的在于,可以提供血管生成抑制剂或血管生成促进剂的筛选方法。
并且,本发明的目的在于,可以提供用于诊断血管生成相关疾病的信息的方法。
技术方案
为了实现上述目的,本发明提供一种靶向αvβ3整联蛋白(Integrin)的单域抗体(Single-domain antibody),其由选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上编码。
并且,本发明提供一种重组载体,其包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上。
并且,本发明提供一种重组微生物,其由上述重组载体转化。
并且,本发明提供一种用于检测血管生成的组合物,其包含上述单域抗体。
并且,本发明提供一种用于检测血管生成的试剂盒,其包含上述单域抗体。
并且,本发明提供一种用于诊断血管生成相关疾病的组合物,其包含上述单域抗体。
并且,本发明提供一种靶向αvβ3整联蛋白的单域抗体的制备方法,其包括:步骤(1),培养由重组载体转化的重组微生物,上述重组载体包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上;以及步骤(2),在上述微生物中表达对于αvβ3整联蛋白的单域抗体。
并且,本发明提供一种血管生成抑制剂或血管生成促进剂的筛选方法,其包括:步骤(1),在从样本分离的生物试样或动物模型中处理所要分析的候选药物;步骤(2),使上述试样与上述靶向αvβ3整联蛋白的单域抗体相结合,并测定αvβ3整联蛋白的水平;以及步骤(3),选择上述步骤(2)的αvβ3整联蛋白的水平相对于对照组被抑制或增强的候选药物。
并且,本发明提供一种提供用于诊断血管生成相关疾病的信息的方法,其包括:步骤(a),使从样本分离的生物试样与上述靶向αvβ3整联蛋白的单域抗体相结合,并测定αvβ3整联蛋白的水平;以及步骤(b),将上述αvβ3整联蛋白的水平与从对照组试样获得的基准值进行比较。
技术效果
与现有抗体相比,本发明的靶向αvβ3整联蛋白的单域抗体对与血管生成相关的αvβ3整联蛋白表现出高结合力、优异的组织渗透性及生物稳定性。并且,本发明的单域抗体通过与荧光粒子结合,来能够在体外(in vitro)、体内(in vivo)或离体(ex vivo)进行简单测定,因而对血管生成的检测及与此相关的疾病的诊断有效,从而可以有效用于相关产业中。
附图说明
图1为示出为了扩增本发明的单域抗体表达试剂盒而进行第一次聚合酶链式反应(PCR)扩增的结果的图。
图2为示出为了扩增本发明的单域抗体表达试剂盒而进行第二次PCR扩增的结果的图。
图3为确认到被切割的单域基因的片段的图。
图4为确认到被切割的噬菌粒的片段的图。
图5为示出是否插入本发明的单域抗体克隆的基因的确认结果的图。
图6a至图6i为示出20个单域抗体克隆的DNA测序的进行结果以及对此的比对结果的图。
图7为示出用于确认本发明的靶向αvβ3整联蛋的功效的αvβ3整联蛋白的十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)结果的图。
图8a至图6c为示出在进行酶联免疫吸附测定(ELISA)后表现出强阳性的克隆的氨基酸序列的图。
图9为示出单域抗体克隆中的VHH-13、VHH-22及VHH-25的表面等离子体共振(SPR,Surface Plasmon Resonance)分析结果的图。
图10a为示出包含六组氨酸标签(His6 tag)的单域抗体VHH-25的表达载体图(pALT-Avb3 VHH25)的图。
图10b为示出包含赖氨酸(Lysin)及六组氨酸标签的单域抗体VHH-25的表达载体图(pALT-Avb3 VHH25K1)的图。
图11a为示出包含六组氨酸标签的单域抗体VHH-13的十二烷基硫酸钠聚丙烯酰胺凝胶电泳减少(reduced SDS-PAGE)结果的图。
图11b为示出包含六组氨酸标签的单域抗体VHH-22的十二烷基硫酸钠聚丙烯酰胺凝胶电泳减少结果的图。
图11c为示出包含六组氨酸标签的单域抗体VHH-25的十二烷基硫酸钠聚丙烯酰胺凝胶电泳减少结果的图。
图11d为示出包含赖氨酸(Lysin)及六组氨酸标签的单域抗体VHH-25的十二烷基硫酸钠聚丙烯酰胺凝胶电泳减少结果的图。
图12为示出癌细胞中确认到本发明的单域抗体VHH-25的靶向αvβ3整联蛋的效果结果的图。
图13为示出肿瘤部位中确认到本发明的单域抗体VHH-25的靶向αvβ3整联蛋的效果结果的图。
图14为示出动脉硬化部位中确认到本发明的单域抗体VHH-25的靶向αvβ3整联蛋的效果结果的图。
优选实施方式
本发明提供一种靶向αvβ3整联蛋白(Integrin)的单域抗体(Single-domainantibody),其由选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上编码。
在本发明的术语“αvβ3整联蛋白(Integrin)”中,整联蛋白是指存在于细胞表面的受体分子,当细胞粘附于纤连蛋白、胶原蛋白等的细胞外基质时起作用。其为由α、β两个亚基的异源二聚体组成的跨膜糖蛋白,迄今已发现存在21种整联蛋白。其中,据报道,αvβ3整联蛋白在维持心血管系统或骨组织的结构中起到非常重要的作用。
本发明的术语“单域抗体(Single-domain antibody)”为其中互补决定区(CDR)为单域多肽的一部分的抗体,包括重链抗体、天然无轻链的抗体、源自现有的四链抗体的单域抗体、工程抗体以及除源自抗体之外的单域支架。为区别于四链免疫球蛋白的VH而称作重链抗体可变区(VHH,variable region of a heavy chain antibody)、纳米抗体(nanobody)或sdAb。
本发明的单域抗体为源自天然无轻链的重链的自然生成的单域抗体,作为对于αvβ3整联蛋白的特异抗体,具有约14KDa~15KDa的分子量。本发明的纳米抗体为作为源自骆驼科(Camelidae)的VHH的抗体,可以源自骆驼、独峰驼、美洲驼、羊驼及野生美洲驼,为了实现靶向与血管生成相关的αvβ3整联蛋的目的,可以由骆驼科以外的其他种类的天然无轻链的重链抗体生产,但不限于此。
本发明的单域抗体比免疫球蛋白(IgG)分子约小十倍,它们作为单域多肽非常稳定,即使在极端的pH和温度条件下也很稳定。并且,与现有抗体不同,它们对蛋白酶的作用具有抗性,在生物体外表达时,能够以高产率大量生产。
在上述单域抗体中,由上述序列编号1表示的碱基序列可以编码由序列编号11表示的氨基酸序列,由序列编号2表示的碱基序列可以编码由序列编号12表示的氨基酸序列,由序列编号3表示的碱基序列可以编码由序列编号13表示的氨基酸序列。并且,序列编号1、序列编号2或序列编号3中包含六组氨酸标签(His6 tag)的氨基酸序列可以分别由序列编号14、序列编号15及序列编号16的氨基酸表示。
在本发明的一实施例中,通过向骆驼注射靶标蛋白来免疫重组αvβ3整联蛋白,上述重组αvβ3整联蛋白在小鼠和人类中具有交叉反应性(cross reactivity)。然后,通过从骆驼血液分离的外周淋巴细胞(pheripheral lymphocyte)中分离和纯化mRNA来合成cDNA。在通过PCR扩增重链抗体(heavy chain-only)的可变域(variable domain)(VHH)之后,将其克隆到M13噬菌体基因(bacteriophage gene)中。通过进行利用固定化免疫原(immobiizedimmunogen)(磷脂酰丝氨酸(phosphatidylserine))的噬菌体展示(phage display)来选择与固定化(immobilized)抗原特异性反应的噬菌体克隆。
分析上述噬菌体克隆中的40个克隆序列的结果,确认了10个候选组的DNA序列。其中,20个DNA序列示于图6a至图6i中。其中,选择10个组中表现出高反应性的克隆14、11、29、17、15、28、12、19、13、21、27、16、18、20、30、23、24、25、22、26,其氨基酸序列示于图8a至图8c。将表现出强阳性的克隆VHH-25、VHH-13、VHH-22、VHH-11、VHH-17、VHH-15、VHH-12、VHH-16、VHH-20、VHH-23的碱基序列分别以序列编号1至序列编号10来表示。其中,将VHH-25、VHH-13、VHH-22的氨基酸序列分别以序列编号11、12或13表示。
上述碱基序列的变体包括在本发明的范围内。可以用作对组成本发明的单域抗体的蛋白质进行编码的基因的核酸分子是包括组成其的核酸分子的功能等同物,例如,虽然核酸分子的一部分碱基序列因缺失(deletion),取代(substitution)或插入(insertion)而变形,但功能上可以起到与核酸分子相同的作用的变体(variants)的概念。具体地,上述基因可以包括与本发明的碱基序列分别具有70%以上、更优选为80%以上、进一步优选为90%以上、最优选为95%以上的序列同源性的碱基序列。多核苷酸的“序列同源性百分比”是通过将两个最佳的方式比对的序列与比较区域进行比较来确定的,与两个序列的最佳比对的参考序列(不包括追加或删除),比较区域中的多核苷酸序列的一部分可包括追加或删除(即,缺口)。
本发明的单域抗体可以在可以特异性识别αvβ3整联蛋白的范围内包含所附序列表在记载的氨基酸序列的变体。例如,可以改变抗体的氨基酸序列以改善抗体的结合亲和度和/或其他生物学特性。这种变形包括例如抗体的氨基酸序列残基的缺失、插入和/或取代。
上述氨基酸变异基于氨基酸侧链取代体的相对相似性,例如疏水性、亲水性、电荷,大小等来进行。通过分析氨基酸侧链取代体的大小、形状及类型,可知精氨酸、赖氨酸及组氨酸均为带正电荷的残基;丙氨酸、甘氨酸及丝氨酸的大小相似;苯丙氨酸、色氨酸及酪氨酸具有相似的形状。因此,基于这些考虑事项,精氨酸、赖氨酸及组氨酸;丙氨酸、甘氨酸及丝氨酸;苯丙氨酸、色氨酸及酪氨酸可以视为是生物学功能等同物。
当引入变异时,可以考虑氨基酸的疏水性指数(hydropathic index)。每个氨基酸根据疏水性和电荷而被赋予如下疏水性指数:异亮氨酸(﹢4.5);缬氨酸(﹢4.2);亮氨酸(﹢3.8);苯丙氨酸(﹢2.8);半胱氨酸(﹢2.5);蛋氨酸(﹢1.9);丙氨酸(﹢1.8);甘氨酸(﹣0.4);苏氨酸(﹣0.7);丝氨酸(﹣0.8);色氨酸(﹣0.9);酪氨酸(﹣1.3);脯氨酸(﹣1.6);组氨酸(﹣3.2);谷氨酸(﹣3.5);谷氨酰胺(﹣3.5);天冬氨酸(﹣3.5);天冬酰胺(﹣3.5);赖氨酸(﹣3.9);以及精氨酸(﹣4.5)。
疏水性氨基酸指数在赋予蛋白质相互生物学功能(interactive biologicalfunction)方面非常重要。已知的事实是,只有用具有相似疏水性指数的氨基酸取代,才能够保留相似的生物学活性。当参考疏水性指数来引入变异时,在表现出疏水性指数差异的氨基酸之间进行取代,疏水性指数差异优选在±2之内,更优选在±1之内,进一步优选在±0.5之内。
另一方面,同样众所周知的是,具有相似亲水性值(hydrophilicity value)的氨基酸之间的取代导致具有等同生物学活性的蛋白质。如美国专利第4554101号所公开,每个氨基酸残基被赋予如下亲水性值:精氨酸(﹢3.0);赖氨酸(﹢3.0);沥青(﹢3.0±1);谷氨酸(﹢3.0±1);丝氨酸(﹢0.3);天冬酰胺(﹢0.2);谷氨酰胺(﹢0.2);甘氨酸(0);苏氨酸(﹣0.4);脯氨酸(﹣0.5±1);丙氨酸(﹣0.5);组氨酸(﹣0.5);半胱氨酸(﹣1.0);蛋氨酸(﹣1.3);缬氨酸(﹣1.5);亮氨酸(﹣1.8);异亮氨酸(﹣1.8);酪氨酸(﹣2.3);苯丙氨酸(﹣2.5);色氨酸(﹣3.4)。
当参照亲水性值引入变异时,在表现出亲水性值差异的氨基酸之间进行取代,亲水性值差异优选在±2之内,更优选在±1之内,进一步优选在±0.5之内。
不整体改变分子活性的蛋白质中的氨基酸交换是本领域已知的(H.Neurath,R.L.Hill,The Proteins,Academic Press,New York,1979)。最常见的交换是氨基酸残基Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Thy/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu、Asp/Gly之间的交换。
可在本发明的单域抗体进一步结合有功能分子或元素,上述功能分子可以是选自由无机粒子、化学物质、肽、多肽、核酸、碳水化合物、放射性同位素及脂质组成的组中的一种以上。
上述无机粒子为荧光标记或染色物质,可以选自由绿色荧光蛋白(GFP,GreenFluorescent Protein)、黄色荧光蛋白(YFP,Yellow Fluorescent Protein)、蓝色荧光蛋白(BFP,Blue fluorescent protein)、蓝绿色荧光蛋白(CFP,Cyan fluorescentprotein)、吖啶染料(Acridine dyes)、花青染料(Cyanine dyes)、荧光酮染料(Fluoronedyes)、恶嗪染料(Oxazine dyes)、菲啶染料(Phenanthridine dyes)及罗丹明染料(Rhodamine dyes)组成的组中,但不限于此。
上述放射性同位素的特征在于,其为选自由18F(氟)、11C(碳)、15O(氧)、13N(氮)、89Zr(锆)、C15O、13N(氨)、H2 15O及18FDG(F-脱氧葡萄糖(F-Deoxy Glucose))组成的组中的一种以上,但不限于此。
上述化学物质是抑制血管生成相关疾病的物质,抑制与此相关的疾病的化学物质可以不受限制地与本发明的单域抗体结合。例如,可以是血管生成抑制剂、抗癌剂、动脉粥样硬化抑制剂等化学物质。
作为上述血管生成抑制剂,例如是阿瓦斯汀、伊曲康唑、羧酰胺基三唑(carboxyamidotriazole)、苏拉明(suramin)、SU5416、血小板反应蛋白(thrombospondin)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、帕唑帕尼(pazopanib)、依维莫司(everolimus)及它们的混合物,但不限于此。
作为上述抗癌剂,例如是阿奇比星、阿克拉比星、阿考达唑、青霉素、阿杜唑素、丙氨酸、醛固酮、别嘌醇钠、六甲蜜胺、氨基戊二酰亚胺、阿莫那肽、安普林、阿姆沙林、雄激素、胍基、甘氨酸胆碱胆碱酯、阿萨雷、天冬酰胺酶、5-氮杂胞苷、硫唑嘌呤、镇静芽孢杆菌(BCG)、安提斯贝克(Bakers antipol)、β-2-二氧硫鸟嘌呤、盐酸双三氢萘、硫酸博来霉素、牛磺砜、丁氨酸亚磺酰亚胺、BWA 773U82、BW 502U83/HCl、BW 7U85甲磺酸盐、西拉塞米、卡贝替姆、卡铂、卡莫司汀、苯丁酸氮芥、氯喹喔啉磺酰胺、氯代人嘧啶、色霉素A3、顺铂、克拉屈滨、皮质类固醇、小棒杆菌、CPT-11、结晶糖醇、环胞苷、环磷酰胺、阿糖胞苷、色他巴、达比斯马来酸酯、去卡巴嗪、放线菌素、盐酸柔红霉素、二氮尿苷、右雷唑酸、双脱水半乳糖醇、地嗪酮、二溴调节醇、双二胺B、二乙基二硫代氨基甲酸酯、二斜醛、二氢-5-氮杂嘧啶、阿霉素、棘霉素、去氨曲酸、依德福星、依氟尼汀、Elliot's溶液、依沙芦星、表柔比星、埃索比星、磷酸雌莫司汀、雌激素、乙二胺、乙硫磷、依托泊苷、帕达唑、法扎拉滨(Fazarabine)、芬维A胺、非格司亭、非那雄胺、黄酮乙酸、福禄啶、磷酸氟达拉滨、5'-氟尿嘧啶、氟酚(Fluosol)、氟他胺、硝酸镓、吉西他滨、醋酸戈舍瑞林、乙磺胺、六亚甲基双乙酰胺、高灵敏素、硫酸肼、4-羟基雄烯二酮、氢二脲、盐酸达柔比星、异环磷酰胺、4-异丙醇、异丙醇、异维A酸、亚叶酸钙、乙酸亮丙瑞林、瑞巴米索、脂质体柔红霉素、脂质体捕获阿霉素、罗莫司汀、罗尼达明、肌氨酸、盐酸氯苯那敏、美法仑、薄荷、美宝仑、6-巯基嘌呤、梅斯纳、卡特芽孢杆菌-牛磺酸甲醇提取物、甲氨蝶呤、N-甲基甲酰胺、米非司酮、米托瓜酮、丝裂霉素C、米托坦、米托蒽醌盐酸盐、单部位/巨噬细胞集落刺激因子、纳比隆、萘普生碱、新卡他汀、醋酸奥曲肽、奥马铂、奥沙利铂、紫杉醇、帕拉、喷司他丁、哌嗪酮、皮布罗曼、吡喃比星、吡虫啉、盐酸吡咯烷酮、PIXY-321、盐酸霉素、波波钠、泼尼丁、丙卡巴嗪、孕激素、吡唑啉、丙亚胺、沙格司亭、准金属、螺旋锗、螺磷司汀、链霉菌素绿、链脲佐菌素、苏必利、苏拉明钠、他莫昔芬、紫杉醇、替加普尔、替尼泊甙、对苯二甲、特罗西酮、硫鸟嘌呤、噻替帕、胸苷注射液、噻唑嘌呤、托泊替康、托瑞芬、维甲酸、三氟哌嗪盐酸盐、三氟吡啶、曲美曲酯、肿瘤坏死因子(TNF,tumor necrosisfactor)、尿嘧啶芥末、硫酸长春碱、硫酸长春新碱、长春地辛、长春瑞滨、长春新碱、Yoshi864、佐柔比星、胞嘧啶阿拉伯糖苷、依托泊苷、美拉邦、紫杉醇及它们的混合物,但不限于此。
作为功能分子,对肽或多肽没有特别限制,包括激素、激素相似体、酶,酶抑制剂、信号传导蛋白或其一部分、抗体或其一部分、单链抗体、结合蛋白或其结合域、抗原、粘附蛋白、结构蛋白、调节蛋白、毒素蛋白、细胞因子、转录调节因子、凝血因子及疫苗等,但不限于此。更加详细地,与本发明的单域抗体进一步结合的肽或多肽可以包括胰岛素、胰岛素样生长因子1(IGF-1,insulin-like growth factor 1)、生长激素、促红细胞生成素、粒细胞集落刺激因子(G-CSFs,granulocyte-colony stimulating factors)、粒细胞/巨噬细胞集落刺激因子(GM-CSFs,granulocyte/macrophage-colony stimulating factors)、干扰素α、干扰素β、干扰素γ、白介素1α及β、白细胞介素-3,白细胞介素-4,白细胞介素-6,白细胞介素-2,表皮生长因子(EGFs,epidermal growth factors)、降钙素(calcitonin)、促肾上腺皮质激素(ACTH,adrenocorticotropic hormone)、肿瘤坏死因子(TNF,tumor necrosisfactor)、atobisban、乙基酰胺(buserelin)、西曲瑞克(cetrorelix)、德舍瑞林(deslorelin)、去氨加压素(desmopressin)、强啡肽A(dynorphin A)(1-13)、依降钙素(elcatonin)、鞘氨醇(eleidosin)、依替巴肽(eptifibatide)、生长激素释放激素-II(GHRHII,growth hormone releasing hormone-II)、促性腺激素(gonadorelin)、戈舍瑞林(goserelin)、组氨瑞林(histrelin)、亮丙瑞林(leuprorelin)、赖氨加压素(lypressin),奥曲肽(octreotide)、催产素(oxytocin)、抗利尿激素(pitressin)、促胰液素(secretin)、辛卡利特(sincalide)、特利加压素(terlipressin)、胸腺五肽(thymopentin)、胸腺素(thymosine)α1、曲普瑞林(triptorelin)、比伐卢定(bivalirudin)、卡贝托星(carbetocin)、环孢霉素、可西定(exedine)、兰瑞肽(lanreotide)、促黄体激素释放激素(LHRH,luteinizing hormone-releasing hormone)、纳法瑞林(nafarelin)、甲状旁腺激素、普兰林肽(pramlintide)、T-20(恩夫韦肽(enfuvirtide))、胸腺法新(thymalfasin)、齐考诺肽、赖氨酸、赖氨酸A链、假单胞菌外毒素、白喉毒素、商陆(pokeweed)抗病毒蛋白、红豆因(abrin)、红豆因A链、眼镜蛇毒因子、白树毒素(gelonin)、皂草素(saporin)、蒴莲根毒素(modeccin)、蒴莲根毒蛋白(volkensin)、槲寄生素(viscumin)、产气荚膜梭菌磷脂酶C及牛胰核糖核酸酶,但不限于此。
另一方面,当与单域抗体结合的功能分子为肽或多肽时,可以考虑如下因素来选择所使用的合适的肽接头的序列:(a),可以适用于柔性延伸结构的能力;(b),不生成与表位相互作用的二级结构的能力;以及(c),不存在能够与表位反应的疏水性残基或具有电荷的残基。优选的肽接头包括Gly、Asn及Ser残基。其他中性氨基酸如Thr及Ala也可以包括在接头序中。
并且,本发明提供包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上的重组载体。
在本说明书中,术语“载体”是指作为在宿主细胞中表达目的基因的手段,包括质粒载体;噬菌粒载体;粘粒载体;以及噬菌体载体、腺病毒载体、逆转录病毒载体及腺相关病毒载体等病毒载体,优选为噬菌体载体或质粒载体。
上述重组载体可以由图10a或图10b的载体图表示,具体地,图10a示出包含六组氨酸标签的单域抗体VHH-25的表达载体图(pALT-Avb3 VHH25),图10b示出包含赖氨酸(Lysin)及六组氨酸标签的单域抗体VHH-25的表达载体图(pALT-Avb3 VHH25K1),并且为了实现本发明的单域抗体表达目的,就不限于此。
根据本发明的优选实例,在本发明的载体中,编码单域抗体的核酸分子与启动子可操作地连接(operatively linked)。
在本发明中,术语“可操作地连接的”是指核酸表达调节序列(例:启动子,信号序列、或转录调节因子结合位置的阵列)与其他核酸序列之间的功能性连接,由此上述调节序列调节上述其他核酸序列的转录和/或解毒。
本发明的载体系统可通过本领域已知的各种方法来构建,其具体方法公开于Sambrook et al.(2001),Molecular Cloning,A Laboratorymanual,Cold Spring HarborLaboratory Press,该文献通过引用并入本说明书中。
典型地,本发明的载体可以被构建成用于克隆的载体或用于表达的载体。并且,本发明的载体可以使用原核细胞或真核细胞作为宿主来构建。当本发明的载体为表达载体,且使用原核细胞作为宿主时,通常包括能够进行转录的强启动子(例如,tac启动子、lac启动子、lacUV5启动子、lpp启动子、pLλ启动子、pRλ启动子、rac5启动子、amp启动子、recA启动子、SP6启动子、trp启动子及T7启动子等)、用于开始解毒的核糖体结合部位及转录/解毒终止序列。当利用大肠杆菌(E.coli)(例如,HB101、BL21、DH5α等)作为宿主细胞时,大肠杆菌色氨酸生物合成途径的启动子及操纵位点(Yanofsky,C.(1984),J.Bacteriol.,158:1018-1024)和噬菌体λ的左向启动子(pLλ启动子,Herskowitz,I.and Hagen,D.(1980),Ann.Rev.Genet.,14:399-445)可以被用作调节部位。
另一方面,可用于本发明的载体可通过操纵本领域中常用的质粒(例:pSC101、pGV1106、pACYC177、ColE1、pKT230、pME290、pBR322、pUC8/9、pUC6、pBD9、pHC79、pIJ61、pLAFR1、pHV14、pGEX系列、pET系列及pUC19等)、噬菌粒(例:pComb3X)、噬菌体(例:λgt4 B、λ-Charon及M13等)或病毒(例:SV40等)来制备。
另一方面,当本发明的载体为表达载体,且使用真核细胞作为宿主时,可以使用源自哺乳动物细胞的基因组的启动子(例:金属硫蛋白启动子)或源自哺乳动物病毒的启动子(例:腺病毒晚期启动子、牛痘病毒7.5K启动子、SV40启动子、巨细胞病毒启动子及HSV的伪启动子),并且通常具有聚腺苷酸化序列作为转录终止序列。
为了易于蛋白质的纯化,本发明的载体可以根据需要与其他序列融合,融合的序列可以使用例如谷胱甘肽S-转移酶(Pharmacia,USA)、麦芽糖结合蛋白(NEB,USA)、FLAG(IBI,USA)及六组氨酸(6x His,hexahistidine;Quiagen,USA)等,但不限于此。并且,本发明的表达载体可以包含本领域中通常用作选择标记的抗生素抗性基因,例如包括氨苄青霉素、庆大霉素、羧苄青霉素、氯霉素、链霉素、卡那霉素、遗传霉素、新霉素和四环素的抗性基因。
并且,本发明提供由上述重组载体转化的重组微生物。
能够稳定并连续克隆及表达本发明的载体的宿主细胞可以使用本领域中已知的任何宿主细胞,例如,包括:诸如大肠杆菌(Escherichia coli)、枯草芽孢杆菌及苏云金芽孢杆菌之类的芽孢杆菌属的菌株;诸如链霉菌(Streptomyces)、假单胞菌(Pseudomonas)(例如,恶臭假单胞菌(Pseudomonas putida))、奇异变形杆菌(Proteusmirabilis)或葡萄球菌(Staphylococcus)(例如,肉葡萄球菌(Staphylocus carnosus))之类的原核宿主细胞,但不限于此。上述宿主细胞优选为大肠杆菌(E.coli),更优选为大肠杆菌ER2537、大肠杆菌ER2738、大肠杆菌XL-1Blue、大肠杆菌BL21(DE3)、大肠杆菌JM109、大肠杆菌DH系列、大肠杆菌TOP10、大肠杆菌TG1及大肠杆菌HB101。本发明中通过使用大肠杆菌过量表达单域抗体,从而能够以低成本大量生产。
将本发明的载体转运到宿主细胞中的方法可通过CaCl2方法(Cohen,S.N.et al.(1973),Proc.Natl.Acac.Sci.USA,9:2110-2114)、高效的转化(Hanahan)方法(Cohen,S.N.et al.(1973),Proc.Natl.Acac.Sci.USA,9:2110-2114;及Hanahan,D.(1983),J.mol.Biol.,166:557-580)及电穿孔方法(Dower,W.J.et al.(1988),Nucleic.AcidsRes.,16:6127-6145)等来实施。
注入宿主细胞中的载体可以在宿主细胞中表达,在此情况下,可以获得大量的本发明的单域抗体。
并且,本发明提供包含上述单域抗体的用于检测血管生成的组合物。
在本发明中,术语“检测”用于检测抗原-抗体复合体,可通过使用各种标记体来实施。作为标记体的具体例,包括酶、荧光物、配体、发光物、微粒或放射性同位素。用作检测标记体的酶包括乙酰胆碱酯酶、碱性磷酸酶、β-D-半乳糖苷酶、辣根过氧化物酶、β-内酰胺酶等,荧光物包括荧光素、Eu3﹢、Eu3﹢螯合物或穴状化合物等,配体包括生物素衍生物等,发光物包括a啶酯及异鲁米诺衍生物,微粒包括胶体金和有色乳胶,放射性同位素包括57Co、3H,125I及125I-蛋白质碘化((Bonton-Hunter)试剂等。
并且,本发明提供包含上述单域抗体的用于检测血管生成的试剂盒。
本发明的试剂盒不仅可以包括本发明的单域抗体,还可以包括与标记体进行显色反应的显色底物溶液、在每个反应步骤中使用的洗涤液、酶反应终止溶液,但不限于此。
并且,本发明提供包括上述单域抗体的用于诊断血管生成相关疾病的组合物。
上述血管生成相关疾病为选自由动脉硬化症、癌症、糖尿病性视网膜症、血管生成性青光眼、晶状体后纤维增生症、增生性玻璃体视网膜病变、早产儿视网膜病变、眼科炎症、角膜溃疡、圆锥角膜、黄斑变性、斯耶格伦氏综合征、近视眼和肿瘤、角膜移植排斥反应、伤口愈合异常、沙眼(trachoma)、骨疾病、类风湿性关节炎(rheumatoid arthritis)、骨关节炎、败血症性关节炎、血管瘤(hemangiomas)、纤维性血管瘤(angiofibroma)、银屑病(psoriasis)、化脓性肉芽肿(pyogenic granuloma)、蛋白尿症、腹主动脉类疾病、外伤性关节损伤引起的退行性软骨损伤、神经系统脱髓鞘疾病、肝硬变、肾小球疾病、胚膜早破症、炎症性肠疾病、牙周膜疾病、再狭窄症、中枢神经系统的炎症疾病、阿尔茨海默病、皮肤老化、甲状腺过度增生以及格雷夫斯病(Grave's disease)组成的组中的一种以上,优选为动脉硬化症或癌症,但不限于此。
在本发明中,上述癌症为胆管癌、膀胱癌、脑肿瘤、乳腺癌、子宫颈癌、绒毛膜癌、结肠癌、子宫内膜癌、食道癌、胃癌、多发性骨髓瘤、与AIDS有关的白血病和成人T-细胞淋巴瘤/白血病、内皮细胞癌、肝癌、肺癌、淋巴瘤、神经母细胞瘤、口腔癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、肉瘤、皮肤癌、睾丸癌、甲状腺癌或肾细胞癌,并且只要是表达αvβ3整联蛋白的癌症,就不限于此。
并且,本发明提供靶向αvβ3整联蛋白的单域抗体的制备方法,其包括:步骤(1),培养由重组载体转化的重组微生物,上述重组载体包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上;以及步骤(2),在上述微生物中表达对于αvβ3整联蛋白的单域抗体。
在本发明中,术语“培养”是指在适当地人工调节的环境条件下繁育微生物。
上述微生物可以在常规培养基中繁育,培养基包含培养对象即成为培养体的微生物所需的营养物质,以培养特定微生物,并且可以是通过进一步添加用于特殊目的的物质的混合物。上述培养基也称为培养液,并且是涵盖天然培养基、合成培养基或选择性培养基的概念。
包含适当碳源、氮源、氨基酸、维生素等的用于培养的常规培养基中,在调节温度、pH等的同时需要以合适的方式满足特定菌株的条件。可将葡萄糖和木糖的混合糖用作主要碳源,此外,包括:诸如蔗糖、乳糖、果糖、麦芽糖、淀粉、纤维素之类的糖及碳水化合物;诸如豆油、葵花籽油、蓖麻油、椰子油之类的油脂;诸如棕榈酸、硬脂酸、亚油酸之类的脂肪酸;诸如甘油和乙醇之类的酒精;以及诸如乙酸之类的有机酸。这些物质可以单独使用或可以用作混合物。可以使用的氮源包括:诸如氨、硫酸铵、氯化铵、乙酸铵、磷酸铵、碳酸铵和硝酸铵之类的无机氮源;诸如谷氨酸、蛋氨酸、谷氨酰胺之类的氨基酸及蛋白胨;以及诸如NZ-胺、肉提取物、酵母提取物、麦芽提取物、玉米浆、酪蛋白水解产物、鱼类或其分解产物、脱脂大豆饼或其分解产物之类的有机氮源。这些氮源可以单独使用或组合使用。上述培养基可以包含第一磷酸钾、第二磷酸钾及对应的含钠盐作为磷源。可使用的磷源包括磷酸二氢钾或磷酸氢二钾或相应的含钠盐。并且,作为无机化合物,可以使用氯化钠、氯化钙、氯化铁、硫酸镁、硫酸铁、硫酸锰和碳酸钙。最后,除上述物质之外,还可以使用诸如氨基酸及维生素之类的必需的生长物质。
并且,可以使用适合于培养基的前体。上述原料可以在培养过程中通过适当方式以分批式、分批补料式或连续式添加到培养物中,但不特别限于此。能够以适当的方式使用诸如氢氧化钠、氢氧化钾、氨之类的基础化合物或诸如磷酸或硫酸之类的酸化合物来调节培养物的pH。
并且,本发明提供一种血管生成抑制剂或血管生成促进剂的筛选方法,其包括:步骤(1),在从样本分离的生物试样或动物模型中处理所要分析的候选药物;步骤(2),使上述试样与上述靶向αvβ3整联蛋白的单域抗体相结合,并测定αvβ3整联蛋白的水平;以及步骤(3),选择相对于对照组,诱导上述步骤(2)的αvβ3整联蛋白的水平被抑制或增强的候选药物。
并且,本发明提供一种提供用于诊断血管生成相关疾病的信息的方法,其包括:步骤(a),使从样本分离的生物试样与上述靶向αvβ3整联蛋白的单域抗体相结合,并测定αvβ3整联蛋白的水平;以及步骤(b),将上述αvβ3整联蛋白的水平与从对照组试样获得的基准值进行比较。
当与功能分子结合时,可以将本发明的单域抗体作为用于预防及治疗血管生成相关疾病的药学组合物。
除了单域抗体之外,本发明的药学组合物还可包含佐剂(adjuvant)。作为上述佐剂,可以不受限制地使用本领域已知的任何佐剂,例如,可以进一步包含弗氏(Freund)完全佐剂或不完全佐剂来增加其效果。
本发明的药学组合物能够以将有效成分掺入药学上可接受的载体中的形式制备。其中,药学上可接受的载体包括制药领域中通常使用的载体、赋形剂及稀释剂。可以用于本发明的药学组合物的药学上可接受的载体不限于此,而是可以例举乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、甲基羟基苯甲酸、丙基羟基苯甲酸酯、滑石粉、硬脂酸镁及矿物油。
本发明的药学组合物可以分别根据常规方法以散剂、颗粒剂、片剂、胶囊剂、悬浮液、乳剂、糖浆、气雾剂等口服剂型;外用剂、栓剂或无菌注射液的形式剂型化来使用。
在制剂化的情况下,可通过使用通常使用的填充剂、增量剂、粘合剂、润湿剂、崩解剂及表面活性剂等稀释剂或赋形剂来制备。用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这些固体制剂的有效成分中包含至少一种赋形剂,例如,可以通过混合淀粉、碳酸钙、蔗糖、乳糖、明胶等来制备。并且,除了简单的赋形剂之外,还可使用润滑剂,例如硬脂酸镁和滑石粉等。用于口服给药的液体制剂有混悬剂、内用液剂、乳剂、糖浆等,除了常用的稀释剂如水和液体石蜡之外,还可以包括各种赋形剂,例如润湿剂、甜味剂、芳香剂、防腐剂等。用于非口服给药的制剂包括无菌水溶液、非水溶液、悬浮液、乳剂、冻干制剂和栓剂。作为非非水溶性溶剂和悬浮剂,可以使用诸如丙二醇、聚乙二醇、橄榄油之类的植物油;诸如油酸乙酯之类的可注射酯等。作为栓剂的基质,可以使用合成脂肪酸酯(witepsol)、吐温(tween)61、可可脂、月桂精脂、甘油明胶等。
本发明的药学组合物可以通过各种途径向个体给药。可以预料所有给药方式,例如,可通过口服、静脉内、肌内、皮下、腹膜内注射来给药。
可以考虑个体的年龄、体重、性别、身体状况等来选择本发明的药学组合物的给药剂量。显而易见的是,上述药学组合物中包含的单域抗体的浓度可以根据对象以各种方式选择,优选地,其包含在药学组合物中的浓度为0.01~5000μg/ml。当其浓度小于0.01μg/ml时,可能不表现出药学活性,而当浓度大于5000μg/ml时,可能对人体表现出毒性。
具体实施方式
以下,通过下述实施例更详细地说明本发明。但下述实施例仅用于例示本发明,而本发明的内容不限于下述实施例。
<实施例1>骆驼中诱导免疫反应及血清定量
<1-1>骆驼中诱导免疫反应
为了在将在人类或小鼠中具有交叉活性的重组αvβ3整联蛋白(intergrin)接种到骆驼后诱导免疫反应,进行了如下实验。
具体地,使用2mg/ml的人类αvβ3整联蛋白ITGAVB3作为抗原,将其预先混合在1mg/ml的PBS中,并在4℃下在每个EP管分别放入800μl。首先使用了弗氏完全佐剂(CompleteFreund's Adjuvant,CFA)(Sigma)作为佐剂,然后使用了弗氏不完全佐剂(IncompleteFreund's Adjuvant,IFA)(Sigma),并将上述抗原及佐剂完全混合来制备了稳定的乳剂(emulsion)。在骆驼(骆驼属细菌(Camelus bacterianus))的背部周围皮下给药。然后,在第一次免疫的情况下,通过将采集的2ml血液(从1ml的免疫前血清中采集)、弗氏完全佐剂(CFA)和600μg的抗原混合/骆驼混合来诱导了免疫。在加强(Boost)免疫的情况下,使用弗氏不完全佐剂(IFA)诱导了600μg抗原混合/骆驼免疫,每两周间隔共进行了4次,并在进行第四次加强免疫后的第15天采集了50ml血液。
<1-2>被诱导免疫的骆驼的血清滴度(titer)
为了确认上述实施例1-1的被诱导免疫的骆驼的血清滴度,以如下方式进行了酶联免疫吸附测定(ELISA)。
在进行第四次加强免疫后的第二天,测定了血清滴度,包被100uL的靶标蛋白(包含10uL抗原的包被缓冲液)并在4度下过夜培养。使用洗涤缓冲液(PBST,包含0.05%Tween-20的PBS)洗涤两次后,使用350μL封闭缓冲液(PBSM,包含4%牛奶的PBS)封闭孔并在室温下放置2小时。然后,甩掉封闭缓冲液并使用洗涤缓冲液洗涤5次的同时,将板放在纸巾的清洁面。添加100μL稀释的血清并在室温下培养1小时后使用洗涤缓冲液洗涤5次。将兔抗-骆驼IgG pAb-HRP与PBS一同稀释,在每个孔中添加100μL稀释的抗体后,在室温下培养了1小时。以如下方式准备了辣根过氧化物酶(HRP,horseradish peroxidase)底物溶液:通过溶解22mg的OPD(Sigma),其中包含100ml的50mM柠檬酸钠,pH 4.0,来准备了邻苯二胺(OPD,o-phenylenediamine)的储备(stock)溶液。对过滤器进行消毒并在4度下保存后,在检测步骤之前,在21ml的OPD储备溶液中添加了36uL的30%H2O2。在每个孔添加100uL底物溶液并在室温下培养了30分钟。使用设置为490nm的酶标仪分析了每个板。其结果示于表1。
如表1所示,确认到上述实施例1-1的被诱导免疫的骆驼的血清表现出1/12800的滴度。因此,在测定血清滴度的第二天进行了最后加强免疫,第二天获得了外周血白细胞(PBLs,peripheral blood leukocytes),并将其用于RNA提取及cDNA分析。
[表1]
<实施例2>单域抗体的基因扩增及基因文库生成
<2-1>分离的外周血白细胞(PBLs)的RNA分离及cDNA合成
为了本发明的单域抗体的基因扩增,以如下方式进行了分离的外周血白细胞(PBLs)的RNA分离及cDNA合成。
具体地,使用Ficoll分层液(Ficoll Hypaque)法来以密度梯度离心分离的方式从被诱导上述实施例1-1的免疫的骆驼的血液中分离出外周血白细胞(PBLs)。根据制造商的方案,通过Trizol方法分离出总RNA。将分离的RNA颗粒干燥并溶解在100μl的DEPC处理过的水中,然后用于RT-PCR反应。
准备了无RNA酶(RNase-free)的0.5ml反应混合液,其包含2μl的dNTPmix(Pharmacia,每种dNTP25mM)、2ul的Oligo-dT引物(200pMol)、5μl的Super RT缓冲液及26.5μl的DEPC处理过的水。然后,在上述管中添加分离的10μl的RNA(包括1.5ug为止的mRNA)来进行混合并吸取。向上述混合液中滴入一滴矿物油(Sigma),热循环仪(thermocycler)(Biometra,Trio Thermoblock)中在67度下加热5分钟,以破坏二级结构。然后,冷却至42度后,添加2μl的RNAsin(Promega)及2.5μl的Super RT(HT Biotechnology Ltd,Cambridge,UK)来在42度下培养1小时后,在100度下加热3分钟(使用无菌针穿孔)。然后,在将包含单链cDNA的产物离心分离后,在-20度下保存。
<2-2>本发明的单域抗体表达试剂盒的扩增
通过UV光谱法定量上述2-1中合成的cDNA。为了扩增VH-CH1-FC/VHH-FC基因,使用FC下游(downstream)引物、VH/VHH-FR1上游(upstream)引物及以200倍稀释的上述2-1中合成的cDNA作为模板,来进行了VH-CH1-FC/VHH-FC基因的第一次PCR扩增。收集约600bp的上述第一次PCR扩增的DNA条带,并进行了使用凯杰试剂盒(Qiagen Kit)纯化的凝胶纯化(Gelpurification)过程。然后,为了扩增VHH基因,使用VHH-FR4下游引物、VHH-FR1上游引物及上述纯化的DNA来进行了第二次PCR扩增。其结果示于图1及图2。
如图1所示,在进行第一次PCR扩增的结果,确认到出现约600bp及900bp的条带。
并且,如图2所示,在进行第二次PCR扩增的结果,可以确认在约600bp中扩增的本发明的单域抗体的DNA条带。
<实施例3>本发明的单域抗体文库的构建
通过使用噬菌体展示法从上述实施例2中构建的单域抗体基因文库选择和搜素识别αvβ3整联蛋白的抗体,并构建了单域抗体克隆文库。
<3-1>本发明的单域抗体基因向噬菌粒(phagemid)中的插入及转化
切割本发明的单域抗体基因及噬菌粒,并将被切割的基因插入噬菌粒中之后,为了转化于E.coli TG1,进行了如下步骤。使用BssHⅡ及NheI切割上述2-2中获得的第二次PCR产物及pDisplay-3MTM,并用凯杰试剂盒同时纯化。然后,使用NEB's T4 DNA ligase连接DNA片段后,并通过电转化将上述产物转化为E.coli TG1细胞。其结果示于图3及图4。
如图3及4所示,确认为了插入噬菌粒而切割的单域基因和为了克隆单域抗体基因而切割的噬菌粒的凝胶电泳(gel-electrophoresis)的结果,确认到清楚地出现每个条带。
<3-2>噬菌体的包装及文库的准备
为了使用M13K07辅助噬菌体感染上述3-1中转化的E.coli TG1,并增加与抗原特异性结合的噬菌体,进行了如下步骤。
为了准备M13K07辅助噬菌体,将对数期(log-phase)TG1细胞和M13K07噬菌体在37度条件下用不同稀释液感染30分钟,并接种在2TY板的琼脂上。在上述3ml液体2TY培养基中接种并培养小噬菌斑(plaque)后,添加30μL过夜培养的TG1细胞,并在37度下培养了2小时。稀释1L的2TY培养基的培养液并培养1小时后,添加50μg/mL卡那霉素并在37度条件下培养了16小时。通过进行离心分离(10分钟,5000g)来除去细胞,并添加0.25体积的噬菌体沉淀物来从上清液中沉淀噬菌体。在冰上培养30分钟后,进行离心分离(10分钟,5000g)来获得了噬菌体粒子。5ml的PBS重悬颗粒后,使其经过0.22μm的过滤器。通过计数2TY板上的噬斑形成单位(plaque-forming units(pfu))的数量,在包含100μL的TG1(饱和培养物)的顶层琼脂层中确认辅助噬菌体。将噬菌体储备溶液稀释至达到1Х1013pfu/mL后,在-20度下储存。
并且,为了准备文库噬菌体,培养文库甘油储备液和500ml的2TY-G,并以250rpm摇动的同时在37度下进行培养,直到在600nm处的光学浓度达到0.8-0.9。添加M13KO7辅助噬菌体,使得最终浓度达到5×109pfu/mL,并在不摇动的情况下,在37度下培养30分钟后,通过适当摇动(200rpm)来进行了30分钟的噬菌体感染。然后,以2200g离心分离15分钟来回收细胞并在相同量的2TY-AK中重悬颗粒。进行快速摇动(300rpm)并在30度下过夜培养。在4度、15分钟、7000g的条件下通过离心分离将细胞颗粒化,并在预冷的1L瓶中获得含有噬菌体的上清液。然后,添加0.3体积的噬菌体沉淀剂并混合后,在冰上使噬菌体沉淀1小时。然后,在4度、15分钟、7000g的条件下离心分离2次来将噬菌体颗粒化。除去上清液,并用8mL的PBS重悬颗粒。然后,在10分钟、12000g的条件下将噬菌体离心分离并通过上清液回收噬菌体。最后,使用TG1细胞感染噬菌体储备稀释液并接种于2TY-AG来培养之后,确认了出现的氨苄青霉素抗性菌落的数量。通过上述过程,构建了本发明的单域文库,并测定了其滴度。其结果示于表2。
如表2所示,确认到本发明的单域抗体文库表现出5.16×1013pfu/mL的滴度。
[表2]
项目 | 多样性 | 正百分比% | 滴度(pfu/ml) |
A5b3 VHH库 | 2.33×10<sup>8</sup> | 8/10 | 5.16×10<sup>13</sup> |
<3-3>本发明的单域抗体文库中确认是否插入基因以及DNA的比对
在上述3-2中选择的本发明的单域文库选择10个代表性克隆来进行QC菌落PCR。其结果示于图5。
如图5所示,确认到10个克隆中的9个克隆约为600bp,从而确认了本发明的单域被准确插入。
通过如上所述的过程,对本发明的单域准确插入文库中的20个克隆进行了DNA测序。使用了S6下游引物,并进行了比对。其结果示于图6a及图6i。
如图6a及图6i所示,确认到20个克隆均表现出阳性。
<实施例4>通过淘选(panning)筛选特异性抗体
为了在上述实施例3中构建的本发明的单域抗体克隆文库中进行淘选,包被5-30μg/mL的靶标并在4度下培养了2小时。然后,使用洗涤缓冲液将孔洗涤3次后,填充封闭缓冲液并在4度下过夜培养后,使用洗涤缓冲液进行了一次洗涤。将PBS-M(2%牛奶)添加到预先封闭的孔(pre-blocked well)(未包被)中来混合原始文库噬菌体,并在室温下培养了30分钟。然后,将噬菌体放入预先封闭(包被的)孔中,并在室温下培养1小时。使用洗涤缓冲液洗涤10次,通过胰蛋白酶消化(digestion)洗脱结合的噬菌体。使洗脱液滴定(Titrate)并扩增。其结果示于图7及表3。
如图7所示,使用十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)验证了将用于通过淘选来筛选特异性抗体的αvβ3整联蛋白ITGAVB3抗原。
并且,如表3所示,通过三步筛选过程,筛选出与目标蛋白具有强结合力的噬菌体文库候选物。
[表3]
<实施例5>通过ELISA分析αvβ3整联蛋白特异性单域抗体
在上述实施例4的淘选过程之后,提取40个单域抗体噬菌体克隆,并使用ELISA分析了与αvβ3整联蛋白特异性单域抗体的结合力。
具体地,为了准备展示抗体噬菌体(antibody-displaying phages)的单个克隆,将单个克隆的洗脱液接种到5ml的2YT-AG培养基中,并在37度下过夜培养。准备每个克隆的甘油储备液并过夜培养,然后将100μL培养物放入20mL的2YT-AG培养基中进行了培养。在37度下培养数小时,直到OD600的光学密度达到0.4-0.5。在20个多重感染(即,噬菌体粒子/宿主细胞的数量)中添加了M13KO7辅助噬菌体。在37度下培养30分钟,并在摇动30分钟的同时感染细胞。通过离心分离(5000g下10分钟)收集感染的细胞,重悬于2YT-AK中,并在30度下培养了16小时。然后,在上清液中沉淀噬菌体粒子,并将噬菌体颗粒重悬于1mL的PBS,通过离心分离(在5000g下10分钟)除去了细胞片段。除去与噬菌体粒子无关的Ab片段,在250μL的PBS中除去噬菌体颗粒并再次进行了离心分离。
并且,为了进行噬菌体ELISA,使用包被缓冲液在4度下包被2.5-5μg/mL的靶标蛋白和对照蛋白,并用200μL的洗涤缓冲液将每个孔洗涤3次后,在室温下使用200μL的PBS-M封闭孔2小时。甩掉封闭缓冲液并使用洗涤液将板洗涤6次。然后,在每个孔中的洗涤缓冲液中添加100μL的噬菌体溶液,并在常温下培养了1~2小时。然后,使用洗涤缓冲液洗涤6次。将结合HRP的抗-M13抗体(GE healthcare)用1:5000的封闭缓冲液稀释。在每个孔添加100μL稀释的缀合体并在室温下培养了1小时后,使用洗涤缓冲液洗涤6次。以如下方式准备了HRP底物溶液:通过将22mg的OPD(Sigma)溶解于100mL的50mg柠檬酸钠(sodium citrate)(pH 4.0)来准备OPD的储备溶液,并在检测步骤之前,将36μL的30%H2O2添加到21ml的OPL储备溶液中。在每个孔中添加100μL的底物溶液并在室温下培养30分钟。使用设置为490nm的酶标仪分析了每个板。并将每个克隆的分析结果示于表4。
如表4所示,确认到40个克隆均强结合于αvβ3整联蛋白。
[表4]
<实施例6>本发明的单域抗体克隆的DNA测序及信息分析
为了对本发明的单域抗体克隆进行DNA测序,在5mL的LB-A培养基(添加100μg/mL氨苄青霉素的LB培养基)中接种具有每个阳性克隆(通过噬菌体ELISA和/或可溶性ELISA测定)质粒的2μL的甘油储备液TG1 E.coli细胞并在37度下过夜培养。使用质粒分离试剂盒(Plasmid Isolation Kit)(Qiagenminiprep kit)从上述细胞中分离出每个阳性克隆的质粒,并使用L1及S6引物进行了DNA碱基序列分析。
并且,为了分析单域抗体克隆的信息,使用Vector NTI版本(Version)10转换被返回的(returned)序列,并比对蛋白序列。然后,对编码相同蛋白序列的克隆进行了分组并分析。其结果示于表5、图8a至图8c,为了方便起见,将本发明的单域抗体克隆记载为VHH。
如表5所示,在分析40个克隆序列的结果,确认到10个候选组VHH DNA序列。
并且,如图8a至图8c所示,选择10个组中表现出高反应性的克隆14、11、29、17、15、28、12、19、13、21、27、16、18、20、30、23、24、25、22、26,并示出其氨基酸序列。
其中,将表现出强阳性的克隆VHH-25、VHH-13、VHH-22、VHH-11、VHH-17、VHH-15、VHH-12、VHH-16、VHH-20、VHH-23的碱基序列分别以序列编号1至序列编号10来表示。其中,将VHH-25、VHH-13、VHH-22的氨基酸序列分别以序列编号11、12或13表示。
[表5]
项目 | 克隆 |
VHH-1 | 11,14,1,31,9 |
VHH-2 | 17,29,5,35,6 |
VHH-3 | 15,2,3,4,39 |
VHH-4 | 12,19,28,32 |
VHH-5 | 13,21,27 |
VHH-6 | 16,187,8,34,36 |
VHH-7 | 20,30,38,40 |
VHH-8 | 23,24,37 |
VHH-9 | 25,10,33 |
VHH-10 | 22,26 |
通过进行实施例5的ELISA法来在上述表现出强阳性的克隆VHH-11、VHH-17、VHH-15、VHH-12、VHH-13、VHH-16、VHH-20、VHH-23、VHH-25、VHH-22中选择了单域抗体克隆。其结果示于表6及表7。
如表6及7所示,在10个VHH克隆候选物中,VHH-12、VHH-13、VHH-16、VHH-22、VHH-25相对表现出高结合力。
[表6]
[表7]
<实施例7>本发明的单域抗体克隆的表面等离子体共振(Surface PlasmonResonance)分析
在上述实施例6中的靶向αvβ3整联蛋白的单域抗体中,选择VHH-13、VHH-22及VHH-25,并通过与现有αvβ3整联蛋白抗体比较来进行了表面等离子体共振分析。
具体地,将涂敷有葡聚糖(Dextran)的羧甲基葡聚糖水凝胶表面传感器芯片(CMDHchip,Carboxymethyl Dextran Hydrogel Surface Sensor Chip,ReichertTechnologies)安装在表面等离子体共振设备(Reichert SR7500DC system)来进行了αvβ3整联蛋白抗原的固定化(immobilization)操作。然后,对每种浓度的所选抗体的结合力(affinity)进行了分析。其结果示于图9及表8。
如图9及表8所示,确认到VHH-13、VHH-22及VHH-25抗体的KD(平衡解离常数(Equilibrium dissociation constant))值表示8.8-15.5nm的优异的αvβ3整联蛋白结合力。
[表8]
<实施例7>本发明的单域抗体VHH-13、VHH-22及VHH-25的表达
在上述实施例6中,最终确认了本发明的单域抗体克隆中,VHH-13、VHH-22及VHH-25最优异,从而构建了生产它们的载体,并将其引入大肠杆菌来表达了单域抗体VHH-25。
具体地,为了表达本发明的所选单域抗体克隆VHH-13、VHH-22或VHH-25,将构建成包含六组氨酸标签的载体,将VHH-25的载体图(pALT-Avb3 VHH25)示于图10a。并且,为了增加与其他功能分子或元素的结合力,构建了赖氨酸(Lysin)及包含六组氨酸标签的载体,将其载体图(pALT-Avb3 VHH25K1)示于图10b。在VHH-25、VHH-13或VHH-22的每个克隆中包含六组氨酸标签的氨基酸序列显示在序列编号14、15及16中。
通过进行减少的SDS-PAGE确认了包含六组氨酸标签的VHH-13、VHH-22或VHH-25表达结果,将其示于图11a至图11c,并将包含赖氨酸(Lysin)及六组氨酸标签的VHH-25表达结果示于图11d。
结果,确认到VHH-13约为15.9kDa(图11a),VHH-22约为14.1kDa(图11b)。并且,确认到VHH-25约为14.5kDa(图11c),包含赖氨酸的VHH-25约为14.2kDa(图11d)。
<实施例8>确认本发明的单域抗体VHH-25在癌细胞中的靶向αvβ3整联蛋的效果
为了确认本发明的单域抗体VHH-25在体外(in vitro)癌细胞中的靶向αvβ3整联蛋的效果,进行了如下实验。
具体地,将0.5mg含赖氨酸的VHH-25-K1和0.25mg的Cy5.5(sulfo-Cy5.5-NHS,Lumiprobe)溶解在2ml的硼酸盐缓冲液(borate buffer)(pH 8.4)中并在常温下进行了30分钟的反应。反应结束后,使用PD-10柱(column)(GE healthcare)对引入Cy5.5的抗体VHH-25-K进行了纯化。其结果示于图12。
如图12所示,通过SDS-PAGE确认了引入Cy5.5的抗体VHH-25-K的合成及纯化,并且确认到αvβ3整联蛋白在活化的U87-MG细胞(cell)(人成胶质细胞瘤(human glioblastoma))中选择性地被细胞摄取(cellular uptake)。
<实施例9>确认本发明的单域抗体VHH-25在肿瘤部位的靶向αvβ3整联蛋的效果
为了确认本发明的单域抗体VHH-25在肿瘤小鼠模型中的靶向αvβ3整联蛋的效果,进行了如下实验。
具体地,通过将U87-MG细胞异种移植(inoculation)到无胸腺的裸鼠(Athymicnudemice)(female,6-8 weeks old)中类制备了动物模型。当肿瘤长到0.8-1cm大小时,将Cy5.5与VHH-25-K结合并注入尾静脉(1mg/kg),并使用IVIS(PerkinElmer)按时间分析了造影效果。其结果示于图13。
如图13所示,从注入后30分钟起,可以在肿瘤部位确认到造影效果,并且确认到在4小时内出现强造影信号。然后,确认到在肿瘤部位持续24小时出现连续的造影信号。
<实施例10>确认本发明的单域抗体VHH-25在动脉硬化部位中的靶向αvβ3整联蛋的效果
为了确认本发明的单域抗体VHH-25在动脉硬化小鼠模型中的靶向αvβ3整联蛋的效果,进行了如下实验。
具体地,对ApoE-/-小鼠(mice)(Female,10weeks old)进行高脂饮食36周来制备了形成血管内噬菌斑(plaque)的动物模型。然后,以与上述实施例9相同的方法将Cy5.5与准备的VHH-25-K结合并注入尾静脉(1mg/kg)后,4小时后处死小鼠并分离了主动脉。使用IVIS分析了分离的主动脉的造影效果。其结果示于图14。
如图14所示,在注入后4小时后,确认到在形成噬菌斑的部位中选择性地出现了造影效果。
<110> 天主教大学产学协力团
韩国基础科学支援研究所
<120> 靶向αvβ3整联蛋白的单域抗体
<130> PO1907-033
<160> 16
<170> KoPatentIn 3.0
<210> 1
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-25
<400> 1
gaggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgtag tctctggata cacctgtagc gtctacgaca tgatctggta ccgccagcct 120
ccagggaagg agcgcgagtt cgtctcactc attaatagta atggtagaac aacctacgca 180
gactccgtga agggccgatt caccatctcc caaaacaacg ccaagaacac ggtgtatctg 240
cagatgaaca gcctgaaacc tgaggacacg gcaatgtact actgtcatgc ggcctgctat 300
tcaccctctc ggctgaatta ttggggccag gggacccagg tcactgtctc ctca 354
<210> 2
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-13
<400> 2
catgtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagagtc tctgagactc 60
tcctgtgtag cctctggata caccgtcagt agctcctgca tggcctggtt ccgccaggct 120
ccaggaaagg agcgcgaggt ggtcgcaact attgttgtta ctagtgatac gaccagcact 180
ttctatgccg actccgtaaa gggccgattc accatctccc cagacaacgc caagaataca 240
ctaaatctgc aaatgaatag cctggaaccg tccgacactg ccatgtacta ctgtgcggca 300
gatcgcaagt ggaacgtttg tagtcgtggt tatcgctaca cccctaattg ggccaaccaa 360
tttacgttct ggggccaggg gacccaggtc accgtctcct ca 402
<210> 3
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-22
<400> 3
caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgtag tctctggata cacctgtagc gtctacgaca tgatctggta ccgccagcct 120
ccagggaagg agcgcgagtt cgtctcactc attaatagta atggtagaac aacctacgca 180
gactccgtga agggccgatt caccatctcc caaaacaacg ccaagaacac ggtgtatctg 240
cagatgaaca gcctgaaacc tgaggacacg gcaatgtact actgtcatgc ggcctgctat 300
tcaccctctc ggctgaatta ttggggccag gggaccctgg tcaccgtctc ctca 354
<210> 4
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-11
<400> 4
gatgtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagagtc tctgagactc 60
tcctgtgtag cctctggata caccgtcagt agctcctgca tggcctggtt ccgccaggct 120
ccaggaaagg agcgcgaggt ggtcgcaact attgttgtta ctagtgatac gaccagcact 180
ttctatgccg actccgtaaa gggccgattc accatctccc cagacaacgc caagaatacg 240
ctaaatctgc aaatgaatag cctggaaccg tccgacactg ccatgtacta ctgtgcggca 300
gatcgcaagt ggaacgtttg tagtcgtggt tatcgctaca cccctaattg ggccaaccaa 360
tttacgttct ggggccaggg gaccttggtc accgtctcct ca 402
<210> 5
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-17
<400> 5
gatgtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagagtc tctgagactc 60
tcctgtgtag cctctggata caccgtcagt agctcctgca tggcctggtt ccgccaggct 120
ccaggaaagg agcgcgaggt ggtcgcaact attgttgtta ctagtgatac gaccagcact 180
ttctatgccg actccgtaaa gggccgattc accatctccc cagacaacgc caagaatacg 240
ctaaatctgc aaatgaatag cctggaaccg tccgacactg ccatgtacta ctgtgcggca 300
gatcgcaagt ggaacgtttg tagtcgtggt tatcgctaca cccctaattg ggccaaccaa 360
tttacgttct ggggccaggg gaccttggtc accgtctcct ca 402
<210> 6
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-15
<400> 6
gaggtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagagtc tctgagactc 60
tcctgtgtag cctctggata caccgtcagt agctcctgca tggcctggtt ccgccaggct 120
ccaggaaagg agcgcgaggt ggtcgcaact attgttgtta ctagtgatac gaccagcact 180
ttctatgccg actccgtaaa gggccgattc accatctccc cagacaacgc caagaatacg 240
ctaaatctgc aaatgaatag cctggaaccg cccgacactg ccatgtacta ctgtgcggca 300
gatcgcaagt ggaacgtttg tagtcgtggt tatcgctaca cccctaattg ggccaaccaa 360
tttacgttct ggggccaggg gacccaggtc accgtctcct ca 402
<210> 7
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-12
<400> 7
gaggtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagagtc tctgagactc 60
tcctgtgtag cctctggata caccgtcagt agctcctgca tggcctggtt ccgccaggct 120
ccaggaaagg agcgcgaggt ggtcgcaact attgttgtta ctagtgatac gaccagcact 180
ttctatgccg actccgtaaa gggccgattc accatctccc cagacaacgc caagaatacg 240
ctaaatctgc aaatgaatag cctggaaccg tccgacactg ccatgtacta ctgtgcggca 300
gatcgcaagt ggaacgtttg tagtcgtggt tatcgctaca cccctaattg ggccaaccaa 360
tttacgttct ggggccaggg gacccaggtc accgtctcct ca 402
<210> 8
<211> 399
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-16
<400> 8
gatgtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagggtc tctgagactc 60
tcctgtgcag cctctggata caccgtcgag aactcctgca tggcctggtt ccgccaggct 120
ccagggaagg agcgcgaggt ggtcgcaact attgttacta ataatgcgac cggtactttc 180
tatgccgact ccgtgaaggg ccgattcacc gtctcccaag acaacgccaa gaatacgcta 240
aatctgcaaa tgaatagcct ggaacctgag gacacagcca tgtactactg tgcggcagat 300
accaagtgga tagtttgtag tcgtggttat cgctacaccc ctaattgggc caaccaattt 360
aagtactggg gccaggggac ccaggtcacc gtctcctca 399
<210> 9
<211> 399
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-20
<400> 9
gatgtgcagc tggtggagtc tgggggaggc tcggtgcagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggata caccgtcgat aactcctgca tggcctggtt ccgccaggct 120
ccagggaagg agcgcgaggt ggtcgcaact attgttacta ataatgcgac cagcactttc 180
tatgccgact ccgtgaaggg ccgattcacc gtctcccacg acaacgccaa gaatacgcta 240
aatctgcaaa tgaataccct ggaacctgag gacactgcca tgtactactg tgcggcagat 300
accaagtgga tagtttgtag tcgtggttat cgctacaccc ctaattgggc caaccatttt 360
aattactggg gccaggggac cctggtcacc gtctcctca 399
<210> 10
<211> 384
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-23
<400> 10
catgtgcagc tggtggagtc tgggggaggc tcggtgcaga ctggagggtc tctgagactc 60
tcctgtgcag cctctggata cacctcaagt accgtctaca tggcttggtt ccgccagact 120
ccagggaagc agcgcgaggg ggtcgcagca atttatactg gtggtggtcc tacatactat 180
gccgactccg tgaagggccg attcaccatc tcccaagaca acgccaagaa tacggtgtat 240
ctccaaatga acaccctgaa acctgaagac actgccatgt actactgtgc ggccgatcgc 300
tatgtgtacc ggttagttac taactggtac agaccgtctt tttatacata ctggggccag 360
gggacccagg tcaccgtctc ctca 384
<210> 11
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-25氨基酸
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Tyr Thr Cys Ser Val Tyr
20 25 30
Asp Met Ile Trp Tyr Arg Gln Pro Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Leu Ile Asn Ser Asn Gly Arg Thr Thr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asn Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys His
85 90 95
Ala Ala Cys Tyr Ser Pro Ser Arg Leu Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 12
<211> 134
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-13氨基酸
<400> 12
His Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Val Ser Ser Ser
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Val Val
35 40 45
Ala Thr Ile Val Val Thr Ser Asp Thr Thr Ser Thr Phe Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Pro Asp Asn Ala Lys Asn Thr
65 70 75 80
Leu Asn Leu Gln Met Asn Ser Leu Glu Pro Ser Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Ala Ala Asp Arg Lys Trp Asn Val Cys Ser Arg Gly Tyr Arg
100 105 110
Tyr Thr Pro Asn Trp Ala Asn Gln Phe Thr Phe Trp Gly Gln Gly Thr
115 120 125
Gln Val Thr Val Ser Ser
130
<210> 13
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VHH-22氨基酸
<400> 13
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Tyr Thr Cys Ser Val Tyr
20 25 30
Asp Met Ile Trp Tyr Arg Gln Pro Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Leu Ile Asn Ser Asn Gly Arg Thr Thr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asn Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys His
85 90 95
Ala Ala Cys Tyr Ser Pro Ser Arg Leu Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 14
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于纯化的带有His6标签的VHH-25
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Tyr Thr Cys Ser Val Tyr
20 25 30
Asp Met Ile Trp Tyr Arg Gln Pro Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Leu Ile Asn Ser Asn Gly Arg Thr Thr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asn Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys His
85 90 95
Ala Ala Cys Tyr Ser Pro Ser Arg Leu Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser Leu Glu His His His His His His
115 120 125
<210> 15
<211> 142
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于纯化的带有His6标签的VHH-13
<400> 15
His Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Val Ser Ser Ser
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Val Val
35 40 45
Ala Thr Ile Val Val Thr Ser Asp Thr Thr Ser Thr Phe Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Pro Asp Asn Ala Lys Asn Thr
65 70 75 80
Leu Asn Leu Gln Met Asn Ser Leu Glu Pro Ser Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Ala Ala Asp Arg Lys Trp Asn Val Cys Ser Arg Gly Tyr Arg
100 105 110
Tyr Thr Pro Asn Trp Ala Asn Gln Phe Thr Phe Trp Gly Gln Gly Thr
115 120 125
Gln Val Thr Val Ser Ser Leu Glu His His His His His His
130 135 140
<210> 16
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于纯化的带有His6标签的VHH-16
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Tyr Thr Cys Ser Val Tyr
20 25 30
Asp Met Ile Trp Tyr Arg Gln Pro Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ser Leu Ile Asn Ser Asn Gly Arg Thr Thr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asn Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys His
85 90 95
Ala Ala Cys Tyr Ser Pro Ser Arg Leu Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Leu Glu His His His His His His
115 120 125
Claims (20)
1.一种靶向αvβ3整联蛋白的单域抗体,其特征在于,由选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上编码。
2.根据权利要求1所述的靶向αvβ3整联蛋白的单域抗体,其特征在于,由上述序列编号1表示的碱基序列编码由序列编号11表示的氨基酸序列,由序列编号2表示的碱基序列编码由序列编号12表示的氨基酸序列,由序列编号3表示的碱基序列编码由序列编号13表示的氨基酸序列。
3.根据权利要求1所述的靶向αvβ3整联蛋白的单域抗体,其特征在于,上述抗体为源自骆驼科的重链抗体可变区。
4.根据权利要求1所述的靶向αvβ3整联蛋白的单域抗体,其特征在于,在上述抗体进一步结合有功能分子或元素。
5.根据权利要求4述的靶向αvβ3整联蛋白的单域抗体,其特征在于,上述功能分子或元素为选自由无机粒子、放射性同位素、化学物质、肽、多肽、核酸、碳水化合物及脂质组成的组中的一种以上。
6.根据权利要求5所述的靶向αvβ3整联蛋白的单域抗体,其特征在于,上述无机粒子为荧光标记或染色物质。
7.根据权利要求6所述的靶向αvβ3整联蛋白的单域抗体,其特征在于,上述荧光标记或染色物质为选自由绿色荧光蛋白、黄色荧光蛋白、蓝色荧光蛋白、蓝绿色荧光蛋白、吖啶染料、花青染料、荧光酮染料、恶嗪染料、菲啶染料及罗丹明染料组成的组中的一种以上。
8.根据权利要求5所述的靶向αvβ3整联蛋白的单域抗体,其特征在于,上述放射性同位素为选自由18F(氟)、11C(碳)、15O(氧)、13N(氮)、89Zr(锆)、C15O、13N(氨)、H2 15O及18FDG组成的组中的一种以上。
9.一种重组载体,其特征在于,包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上。
10.一种重组微生物,其特征在于,由权利要求9所述的重组载体转化。
11.一种用于检测血管生成的组合物,其特征在于,包含权利要求1所述的单域抗体。
12.一种用于检测血管生成的试剂盒,其特征在于,包含权利要求1所述的单域抗体。
13.一种用于诊断血管生成相关疾病的组合物,其特征在于,包含权利要求1所述的单域抗体。
14.根据权利要求13所述的用于诊断血管生成相关疾病的组合物,其特征在于,上述血管生成相关疾病为选自由动脉硬化症、癌症、糖尿病性视网膜症、血管生成性青光眼、晶状体后纤维增生症、增生性玻璃体视网膜病变、早产儿视网膜病变、眼科炎症、角膜溃疡、圆锥角膜、黄斑变性、斯耶格伦氏综合征、近视眼和肿瘤、角膜移植排斥反应、伤口愈合异常、沙眼、骨疾病、类风湿性关节炎、骨关节炎、败血症性关节炎、血管瘤、纤维性血管瘤、银屑病、化脓性肉芽肿、蛋白尿症、腹主动脉类疾病、外伤性关节损伤引起的退行性软骨损伤、神经系统脱髓鞘疾病、肝硬变、肾小球疾病、胚膜早破症、炎症性肠疾病、牙周膜疾病、再狭窄症、中枢神经系统的炎症疾病、阿尔茨海默病、皮肤老化、甲状腺过度增生以及格雷夫斯病组成的组中的一种以上。
15.一种靶向αvβ3整联蛋白的单域抗体的制备方法,其特征在于,包括:
步骤(1),培养由重组载体转化的重组微生物,上述重组载体包含选自由序列编号1、序列编号2、序列编号3、序列编号4、序列编号5、序列编号6、序列编号7、序列编号8、序列编号9及序列编号10表示的碱基序列组成的组中的一种以上;以及
步骤(2),在上述微生物中表达对于αvβ3整联蛋白的单域抗体。
16.一种血管生成抑制剂或血管生成促进剂的筛选方法,其特征在于,包括:
步骤(1),在从样本分离的生物试样或动物模型中处理所要分析的候选药物;
步骤(2),使上述试样与权利要求1所述的靶向αvβ3整联蛋白的单域抗体相结合,并测定αvβ3整联蛋白的水平;以及
步骤(3),选择上述步骤(2)的αvβ3整联蛋白的水平相对于对照组被抑制或增强的候选药物。
17.根据权利要求16所述的血管生成抑制剂或血管生成促进剂的筛选方法,其特征在于,上述步骤(1)的生物试样为血液、血浆、血清、细胞或组织试样。
18.根据权利要求16所述的血管生成抑制剂或血管生成促进剂的筛选方法,其特征在于,上述步骤(1)的动物为大鼠、小鼠、猴、狗、猫、牛、马、猪、羊或山羊。
19.根据权利要求16所述的血管生成抑制剂或血管生成促进剂的筛选方法,其特征在于,上述步骤(2)的测定使用选自由酶联免疫吸附测定、放射免疫测定、夹心测定、蛋白质印迹、免疫沉淀法、免疫组织化学染色法、流式细胞计量术、荧光激活细胞分选法、酶底物显色法及抗原-抗体凝集法组成的组中的一种以上的方法进行。
20.一种提供用于诊断血管生成相关疾病的信息的方法,其特征在于,包括:
步骤(a),使从样本分离的生物试样与权利要求1所述的靶向αvβ3整联蛋白的单域抗体相结合,并测定αvβ3整联蛋白的水平;以及
步骤(b),将上述αvβ3整联蛋白的水平与从对照组试样获得的基准值进行比较。
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