CN117377487A - 转铁蛋白结合抗体及其应用 - Google Patents
转铁蛋白结合抗体及其应用 Download PDFInfo
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- CN117377487A CN117377487A CN202180098396.6A CN202180098396A CN117377487A CN 117377487 A CN117377487 A CN 117377487A CN 202180098396 A CN202180098396 A CN 202180098396A CN 117377487 A CN117377487 A CN 117377487A
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- transferrin
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Abstract
本申请提供了一种通过使用转铁蛋白结合蛋白使分子转运穿过细胞膜的方法。转铁蛋白结合蛋白能够特异性结合转铁蛋白,并且不干扰转铁蛋白与转铁蛋白受体之间的相互作用。
Description
背景技术
跨膜药物递送系统可用于跨越血脑屏障(BBB)的药物递送、口服药物递送、细胞内药物递送等。目前,在诸如受体介导的跨血脑屏障药物递送等非侵入性血脑屏障药物递送技术中,转铁蛋白受体(TfR)是研究最广泛的靶蛋白。这些TfR靶向载体包括呈Fabs、scFv或双可变结构域免疫球蛋白形式的抗体克隆OX26和8D3,GYR22肽,以及具有TfR结合特性的人IgG的工程化Fc区。虽然大多数此类方法仍处于临床前阶段,但一些研究已经在临床试验中显示出有希望的结果,即使存在若干限制。
TfR抗体的亲和力和效价可以改变TfR和递送的治疗实体的细胞内运输;高亲和力的二价TfR抗体可将抗体-TfR复合物转移到溶酶体中,导致TfR降解和表达水平降低。因此,用于跨膜药物递送的TfR抗体需要在对TfR的亲和力方面是最佳的和/或单价的,以实现更高效率的胞吞转运(transcytosis)进入脑。TfR靶向递送技术的效率可因待递送实体的生物学或生物化学特性而异,抗TfR抗体也可导致急性临床症状和循环网织红细胞计数减少。TfR在全身的普遍表达表明,TfR靶向策略将可能导致TfR靶向药物进入外周区室(诸如骨髓、肝脏和脾脏)的摄取增加。
除了少数例外,口服给药目前仅是表现出可接受肠吸收的小药物分子的选择。作为一类迅速发展的药物,生物制剂目前主要通过注射给药。几十年来的重大研究努力探索了使得能够口服递送生物制剂的技术,但进展相对不太令人印象深刻。这一领域的药物递送策略主要利用吸收或渗透促进剂诸如SNAC,或专注于质量相对较小的生物制剂,诸如胰高血糖素样肽1(GLP-1)类似物。然而,安全性问题,包括用于制剂的许多表面活性剂相关的问题,阻碍了这些方法的临床转化。大分子生物制剂的口服递送领域的关键挑战涉及解决难以克服的肠上皮屏障的困难,而不是通过相对成熟的技术可以解决的额外屏障,诸如胃酸和粘膜酶。安全性是使得能够进行生物制剂的治疗相关口服递送的技术的关键要求。与其非选择性地破坏和增加肠上皮的渗透性(即,经典的渗透促进剂将展示的效果),不如设计选择性渗透肠粘膜的递送系统。
发明内容
本申请提供了一种通过使用转铁蛋白结合蛋白使分子跨细胞膜转运的方法。转铁蛋白结合蛋白能够特异性结合转铁蛋白,并且不干扰转铁蛋白与转铁蛋白受体之间的相互作用。
一方面,本申请提供了通过使用转铁蛋白结合蛋白将分子转运穿过细胞膜的方法。
在一些实施方案中,转铁蛋白结合蛋白包含转铁蛋白结合抗体或其片段。
在一些实施方案中,该方法用于将药物递送穿过极化和/或未极化细胞的细胞膜。
在一些实施方案中,极化和/或未极化细胞在其细胞膜上表达转铁蛋白受体。
在一些实施方案中,穿过极化细胞的细胞膜的药物递送包括细胞内递送药物,和/或将内吞药物再循环回到血液循环中。
在一些实施方案中,穿过未极化细胞的细胞膜的药物递送包括靶向中枢神经系统(CNS)的全身给药的药物穿过血脑屏障(BBB)、口服给药的药物穿过肠上皮、和/或药物穿透实体组织中的多层细胞。
在一些实施方案中,药物包括治疗或诊断物质。
在一些实施方案中,药物包括小分子化合物、合成肽、重组蛋白、抗体或抗体片段、酶、核苷酸序列片段、脂质体、脂质纳米颗粒、药物载体、合成核苷酸序列、经修饰的病毒和/或基因治疗载体。
在一些实施方案中,药物通过化学偶联或基因融合与转铁蛋白结合蛋白相结合。
另一方面,本申请提供了转铁蛋白结合蛋白,其能够延长其结合的实体的循环半衰期。
在一些实施方案中,转铁蛋白结合蛋白使得包含转铁蛋白结合蛋白的药物能够穿过血脑屏障(BBB)。
在一些实施方案中,转铁蛋白结合蛋白用于药物的口服递送。
在一些实施方案中,转铁蛋白结合蛋白使得其结合的实体能够通过细胞内递送至表达转铁蛋白受体的细胞。
在一些实施方案中,转铁蛋白结合蛋白能够特异性结合转铁蛋白,并且不干扰转铁蛋白与转铁蛋白受体1之间的相互作用。
在一些实施方案中,转铁蛋白是人转铁蛋白。
在一些实施方案中,转铁蛋白结合蛋白对含铁的铁饱和转铁蛋白的亲和力高于对不含铁的脱铁转铁蛋白的亲和力。
在一些实施方案中,转铁蛋白结合蛋白包括单克隆抗体、单链抗体片段、单结构域抗体片段、工程蛋白或肽。
在一些实施方案中,抗体或抗体片段包含动物来源的序列、人源化序列、全人源序列、嵌合序列或合成序列。
在一些实施方案中,抗体或抗体片段是单结构域抗体片段VHH。
在一些实施方案中,转铁蛋白结合蛋白包含CDR3,CDR3包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
在一些实施方案中,转铁蛋白结合蛋白包含CDR1、CDR2和CDR3,并且CDR3包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
在一些实施方案中,转铁蛋白结合蛋白包含重链可变区VH,重链可变区VH包含如SEQ ID NO:70-104中任一项所示的氨基酸序列。
另一方面,本申请提供了包含转铁蛋白结合蛋白和治疗实体的多肽。
在一些实施方案中,治疗实体包括工程细胞毒性假单胞菌属外毒素A(PE38)。
在一些实施方案中,治疗实体是胰高血糖素样肽-1(GLP-1)或其变体。
在一些实施方案中,将治疗实体与所述抗原结合蛋白直接或间接连接。
在一些实施方案中,治疗实体与转铁蛋白结合蛋白通过连接子连接。
在另一个方面,本申请提供了一种或多种分离的核酸分子,其编码转铁蛋白结合蛋白或SEQ ID NO:70-106中任一项所示的多肽。
在另一方面,本申请提供了载体,其包含编码如SEQ ID NO:70-106中任一项所示的多肽的核酸分子。
在另一个方面,本申请提供了细胞,其包含表达如SEQ ID NO:70-106中任一项所示的多肽的核酸分子或载体。
另一方面,本申请提供了制备转铁蛋白结合蛋白或多肽的方法,其包括在允许转铁蛋白结合蛋白或多肽表达的条件下培养细胞。
另一方面,本申请提供了药物组合物,其包含转铁蛋白结合蛋白或多肽。
另一方面,本申请提供了用于延长治疗实体的循环半衰期的方法,其中所述治疗实体与转铁蛋白结合蛋白直接或间接连接。
另一方面,本申请提供了用于将治疗药物或诊断试剂递送至表达转铁蛋白受体的细胞或器官的方法,其包括使用转铁蛋白结合实体。
另一方面,本申请提供了用于将靶向药物递送穿过血脑屏障、肠上皮和/或表达转铁蛋白受体的细胞膜的方法,其包括使用转铁蛋白结合实体。
另一方面,本申请提供了用于口服递送治疗或诊断实体的方法,所述治疗或诊断实体与所述抗原结合蛋白直接或间接连接。
另一方面,本申请提供了用于治疗实体的细胞内递送的方法,所述治疗实体与所述抗原结合蛋白直接或间接连接。
本申请提供了技术方案,其利用Tf替代TfR进行靶向,作为药物递送系统的基础。本申请获得了关于特异性、安全性、效率和循环半衰期的多个潜在有利方面。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
通过引用并入
本说明书中提及的所有公布、专利和专利申请都通过引用并入本文,其引用程度等同于每份单独的公布、专利或专利申请各自具体地且单独地通过引用并入本文一般。
附图说明
本发明的新颖特征在所附权利要求书中具体阐述。通过参考下文中阐述说明性实施例的详细说明和附图(本文中也称为“图”),可以更好地理解本发明的特征和优点,详细说明中阐述了本发明的原理,在附图中:
图1示出了在HEK293细胞中表达的代表性转铁蛋白结合蛋白-OVA-his蛋白的SDS-PAGE。
图2A-图2B示出了代表性的选定的转铁蛋白结合蛋白-OVA-His蛋白在pH7.4或pH6.0下与人转铁蛋白结合。
图3A-图3C示出了所选转铁蛋白结合蛋白-OVA-His蛋白与表达转铁蛋白受体的细胞的转铁蛋白介导的结合。
图4示出了本申请的代表性转铁蛋白结合蛋白的表位鉴定。
图5A-图5D示出了ELISA数据,其显示代表性的人源化转铁蛋白结合蛋白变体在pH7.4或pH6.0下与天然人转铁蛋白的结合。
图6A示出了与具有不同表位的本申请克隆的转铁蛋白结合蛋白融合的OVA的循环半衰期。图6B示出了GLP-1-VHH在小鼠体内的循环半衰期。图6C示出了VHH实现的循环半衰期延长是亲和力依赖性的。
图7A-图7C示出了转铁蛋白结合蛋白使得融合的OVA能够转运穿过单层Caco-2细胞或经由胞吞转运通过肠上皮。
图8A-图8B,图8Ca-图8Cf示出了转铁蛋白结合蛋白使得相关的OVA能够在小鼠中穿过血脑屏障,并且这种能力的依赖性与表位利用和亲和力相关。
图9A-图9B示出了转铁蛋白结合蛋白-PE38在不同细胞系的细胞内递送。
图10示出了系统给药后转铁蛋白结合蛋白变体的生物分布。
具体实施方式
尽管本文已示出和描述了本发明的各种实施方案,但对于本领域技术人员来说显而易见的是,这些实施方案仅以举例的方式提供。本领域技术人员可以在不脱离本发明的前提下进行多种变化、改变和替换。应理解,可以采用本文所述的本发明的实施方案的各种替代方案。
在本申请中,术语“细胞膜”通常指在细胞结构中将细胞内外的不同介质和组分分隔开的界面。质膜一般被认为表现为磷脂双分子层分子的基本单位,即磷脂双层,其上嵌合有各种类型的膜蛋白,以及与膜蛋白结合的糖和糖脂。通过跨膜蛋白的孔隙和某些性质,可以实现选择性可控的物质转运。例如,细胞膜可以属于极化的。例如,细胞膜可以属于未极化的细胞。
在本申请中,术语“极化细胞”通常指在结构和功能上具有稳定不对称性的细胞,诸如处于静息电位、准备传递神经脉冲信号的细胞。术语“未极化细胞”通常指静息电位发生变化并传递神经冲动信号的细胞。例如,极化细胞和/或未极化细胞可以属于中枢神经系统的血脑屏障。例如,极化细胞和/或未极化细胞可以属于肠上皮。例如,极化细胞和/或未极化细胞可以属于实体组织。
在本申请中,术语“转铁蛋白结合蛋白”通常指包括抗原结合部分的蛋白,并且任选地允许抗原结合部分采用促进抗原结合蛋白与抗原结合的构象中的支架或骨架部分。例如,抗原结合蛋白可包括但不限于抗体、抗原结合片段(Fab、Fab’、F(ab)2、Fv片段、F(ab’)2、scFv、di-scFv和/或dAb)、免疫缀合物、多特异性抗体(例如,双特异性抗体)、抗体片段、抗体衍生物、抗体类似物或融合蛋白,只要它们显示所需的抗原结合活性。例如,抗原结合蛋白可能能够特异性结合转铁蛋白。例如,抗原结合蛋白可能不干扰转铁蛋白与转铁蛋白受体1之间的相互作用。例如,抗原结合蛋白可能不影响Tf/TfR1结合。例如,抗原结合蛋白可以维持铁转运的正常生理功能。
在本申请中,术语“转铁蛋白”通常指能结合多价离子并转运其的糖蛋白。例如,转铁蛋白可以是单链糖蛋白。例如,转铁蛋白可具有约77,000D的分子量。例如,转铁蛋白可以具有多糖。例如,转铁蛋白可具有两个离子结合部位。例如,离子结合部位可与铁离子具有不同的亲和力。例如,多价离子可以是铁离子、铬离子、锰离子、镉离子或其镍离子。例如,每个转铁蛋白分子可结合两个三价铁原子。例如,转铁蛋白可以是含铁的铁饱和转铁蛋白,或不含铁的脱铁转铁蛋白。例如,转铁蛋白可以是小鼠转铁蛋白。例如,小鼠转铁蛋白的氨基酸序列可如GenBank:EDL21066.1、AAL34533.1或AAL34533.1中所示。例如,转铁蛋白可以是人转铁蛋白。例如,人转铁蛋白的氨基酸序列可如GenBank:AAH59367.1、AAH59367.1或AAB22049.1中所示。
在本申请中,术语“转铁蛋白受体”通常指转铁蛋白的载体蛋白。例如,转铁蛋白可以是跨膜糖蛋白。例如,转铁蛋白受体可介导与两个铁离子结合的转铁蛋白的内吞。例如,转铁蛋白受体可以维持细胞内铁的稳态。例如,转铁蛋白受体可以是转铁蛋白受体1(TfR1)或转铁蛋白受体2(TfR2)。例如,TfR1和TfR2在胞外结构域中可显示约45-66%的同源性,但在体内却呈现不同的表达模式。例如,TfR1对转铁蛋白的亲和力可高于TfR2对转铁蛋白的亲和力。例如,与TfR1对转铁蛋白的亲和力相比,TfR2对转铁蛋白的亲和力低至1/25。例如,TfR2可以主要在参与调节铁代谢的组织诸如肝脏和小肠中表达,而TfR1通常在存在于大多数体细胞的表面上。术语“转铁蛋白受体1”通常指在细胞膜中作为同二聚体表达的97-kDa2型膜蛋白。TfR1介导的转铁蛋白内化被经典地描述为规范的铁输入途径。例如,转铁蛋白受体可以是小鼠转铁蛋白受体。例如,小鼠转铁蛋白受体的氨基酸序列可如GenBank:AAH54522.1、CAA40624.1或NP_001344227.1中所示。例如,转铁蛋白受体可以是人转铁蛋白受体。例如,人转铁蛋白受体的氨基酸序列可如GenBank:AAA61153.1、AAF04564.1或AAB19499.1中所示。
在本申请中,术语“半衰期”通常指氨基酸序列、化合物或多肽的血清浓度由于所述序列或化合物被天然机制降解和/或所述序列或化合物在体内被清除或隔离而降低50%的水平所需的时间。半衰期可通过本领域技术人员已知的方法来估计。本发明的氨基酸序列、化合物或多肽的体内半衰期可以以任何已知的方式确定,诸如通过药代动力学来测定。合适的技术对于本领域技术人员来说是显而易见的,例如,如WO 08/020079第57页的段落o)中所述。同样如WO 08/020079第57页的段落o)中所述,参数如t1/2-α、t1/2-β和曲线下面积(AUC)可用于表示半衰期。在这方面,应该注意的是,本申请中的术语“半衰期”特别地指t1/2-β或终末半衰期(其中t1/2-α和/或AUC可以忽略)。例如,参考以下实验部分和标准手册,诸如Kenneth,A等人:Chemical Stability of Pharmaceuticals:A Handbook forPharmacists和Peters等人,Pharmacokinete analysis:A Practical Approach(pharmacokinetics)Analysis:Practice Method)(1996)。也参考“药代动力学”,MGibaldi&;DPerron,由Marcel Dekker出版,第二版(1982)。
在本申请中,术语“融合蛋白”通常指包含两种或更多种不同蛋白质的氨基酸序列的嵌合蛋白,尽管不同的蛋白质在其天然状态下未被组合,但它们各自的氨基和羧基末端通过肽键结合形成连续的多肽。应当理解,两种或更多种不同的蛋白质可以通过肽连接子或间隔区直接结合。例如,融合蛋白可包括与异源蛋白质、多肽或肽融合的预防性或治疗性药物。其中,异源蛋白质、多肽或肽可以是或可以不是不同类型的治疗性药物。例如,融合蛋白可包含两种不同的具有免疫调节活性的蛋白质、多肽或肽。例如,与原始多肽或蛋白质的活性相比,融合蛋白可以保留或提高活性。典型地,融合蛋白可以通过本领域公知的体外重组技术产生。例如,融合蛋白可包含抗原结合蛋白。例如,融合蛋白可包含生物分子。
在本申请中,术语“血脑屏障(BBB)”通常指外周循环与脑和脊髓之间的生理屏障。其由脑毛细血管内皮细胞的质膜中的紧密连接形成,并构成限制分子,甚至是非常小的分子诸如尿素(60道尔顿),向脑转运的紧密屏障。例如,脑毛细血管内皮细胞可具有较弱的胞饮作用。例如,血脑屏障可包括脑中的BBB、脊髓中的血脊髓屏障和视网膜中的血视网膜屏障。例如,BBB还可包括血液-CSF屏障(脉络丛),其中该屏障由室管膜细胞而不是毛细血管内皮细胞组成。
在本申请中,术语“药物的口服递送”通常是指药物口服后通过胃肠道吸收到血液中,并通过血液循环到达局部或全身组织,以达到治疗或预防疾病的目的。例如,药物可包含转铁蛋白结合蛋白。例如,药物可包括生物分子。
在本申请中,术语“相关实体”通常指与抗原结合蛋白特异性连接的任何单体或多聚体蛋白质、蛋白质片段、核苷酸序列、小分子化合物、递送媒介物或经修饰的转基因载体。相关实体包括但不限于抗体及其结合部分,诸如免疫功能性片段。例如,抗原结合蛋白可以是转铁蛋白结合蛋白。在本申请中,术语“治疗实体”通常指具有治疗或预防疾病的功能的任何单体或多聚体蛋白质或蛋白质片段。
在本申请中,术语“重链可变区(VH)”通常指免疫球蛋白重链结构的区域,其包含重链互补决定区CDR1、CDR2、CDR3和框架区FR1、FR2、FR3、FR4。重链可变区可包含与抗原相互作用的结合结构域。例如,本申请的重链可变区可包括特异性结合转铁蛋白的区域。例如,本申请的重链可变区可包括单结构域抗体的VHH。
在本申请中,术语“CDR”和“CDRs”通常指互补决定区(CDR),其中三个CDR构成轻链可变区(LCDR1、LCDR2和LCDR3)的结合特性,三个CDR构成重链可变区(HCDR1、HCDR2和HCDR3)。CDR促成抗体分子的功能活性,并被含有骨架或框架区的氨基酸序列分开。精确定义的CDR边界和长度以不同的分类和编号系统为准。
在本申请中,术语“多肽”、“肽”和“蛋白质”可互换使用,是指氨基酸残基的聚合物。该术语也适用于氨基酸聚合物,其中一个或多个氨基酸是相应的天然存在的氨基酸的化学类似物或修饰衍生物。例如,多肽可包含抗原结合蛋白和其它分子。例如,多肽可包含融合抗原。例如,抗原结合蛋白与分子可以直接或间接连接。例如,抗原结合蛋白与分子可以通过连接子连接。例如,分子可包括治疗分子。例如,分子可包含PE38。例如,分子可包含GLP-1或类似物。
在本申请中,术语“亲和力”通常指分子(例如多肽或抗体)的单个结合部位与其结合配偶体(例如靶标或抗原)之间的非共价相互作用的总和的强度。除非另有说明,否则当在本文中使用时,“结合亲和力”是指结合对的成员之间(例如,在多肽-多核苷酸-复合物中,或者在多肽和其靶标之间,或者在抗体与抗体之间)的关系。抗原之间1:1相互作用的内在结合亲和力。分子X对其配偶体Y的亲和力通常可用解离常数(Kd)来表示。亲和力可通过本领域已知的常规方法检测,诸如表面等离子体共振术,并且也包括本申请报道的那些方法。在较低的Kd和/或EC50值中可以看到分子X对结合配偶体Y的较高亲和力。
在本申请中,术语“分离的核酸分子”通常指一段编码选择性结合转铁蛋白的特定氨基酸序列诸如抗体或抗体部分(例如,VH,VL,CDR3)的核酸,并且意指编码其中具有抗体或抗体部分的融合蛋白的核酸序列。
在本申请中,术语“载体”通常指包含分离的核酸并可用于将分离的核酸递送至细胞内部的组合物。许多载体是本领域已知的,包括但不限于线性多核苷酸、与离子型化合物或两亲化合物相关的多核苷酸、质粒和病毒。因此,术语“载体”包括自主复制的质粒或病毒。该术语还应解释为包括促进核酸向细胞中转移的非质粒和非病毒化合物,例如多聚赖氨酸化合物、脂质体等。病毒载体的实例包括但不限于腺病毒载体、腺相关病毒载体、逆转录病毒载体、慢病毒载体等。
在本申请中,术语“细胞”通常指可以是或已经是受试者的质粒或载体的受者的单个细胞、细胞系或细胞培养物,其包含本申请中描述的核酸分子或本申请中描述的核酸分子。细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可能不一定与原始亲代细胞完全相同(就总DNA互补物的形态学或基因组而言)。细胞可包括用本申请中描述的载体体外转染的细胞。
在本申请中,术语“药物组合物”通常指用于预防/治疗疾病或病症的组合物。药物组合物可包含抗原结合蛋白、免疫缀合物、分离的核酸分子、载体和/或细胞,以及任选的药学上可接受的佐剂。此外,药物组合物还可包含一种或多种(药学上有效的)运载体和其它合适的制剂。组合物的可接受成分优选在所用剂量和浓度下对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干的组合物。
发明详述
转铁蛋白结合蛋白
一方面,本申请提供了转铁蛋白结合蛋白,其能够特异性结合转铁蛋白并且不干扰转铁蛋白与转铁蛋白受体1之间的相互作用。
例如,转铁蛋白结合蛋白可能能够延长其相关实体的循环半衰期。
例如,半衰期可通过本领域技术人员已知的方法来估计。例如,本发明的氨基酸序列、化合物或多肽的体内半衰期可以以任何已知的方式,诸如通过药代动力学分析来确定。合适的技术对于本领域技术人员来说是显而易见的,例如,如WO 08/020079第57页的段落o)中所述。同样如WO 08/020079第57页的段落o)中所述,参数如t1/2-α、t1/2-β和曲线下面积(AUC)可用于表示半衰期。在这方面,应该注意的是,本申请中的术语“半衰期”特别地指t1/2-β或终末半衰期(其中t1/2-α和/或AUC可以忽略)。例如,参考以下实验部分和标准手册,诸如Kenneth,A等人:Chemical Stability of Pharmaceuticals:A Handbook forPharmacists和Peters等人。
例如,相关实体可以是与抗原结合蛋白特异性连接的任何单体或多聚体蛋白质、蛋白质片段、核苷酸序列、小分子化合物、递送媒介物或经修饰的转基因载体。例如,相关实体可包括但不限于抗体及其结合部分,诸如免疫功能性片段。例如,抗原结合蛋白可以是转铁蛋白结合蛋白。
例如,转铁蛋白结合蛋白可使包含转铁蛋白结合蛋白的融合蛋白能够穿过血脑屏障(BBB)。
例如,BBB可以是外周循环与大脑和脊髓之间的生理屏障。例如,BBB可包含脑毛细血管内皮细胞的质膜中的紧密连接,并构成限制分子,甚至是非常小的分子诸如尿素(60道尔顿),向脑转运的紧密屏障。例如,脑毛细血管内皮细胞可具有较弱的胞饮作用。例如,血脑屏障可包括脑中的BBB、脊髓中的血脊髓屏障和视网膜中的血视网膜屏障。例如,BBB还可包括血液-CSF屏障(脉络丛),其中该屏障由室管膜细胞而非毛细血管内皮细胞组成。
例如,融合蛋白可通过穿越BBB进入脑组织。
例如,转铁蛋白结合蛋白可用于药物的口服递送。
例如,药物口服递送的给药形式可以是胶囊、颗粒或片剂。
例如,转铁蛋白结合蛋白可使其相关实体能够在细胞内递送至表达转铁蛋白受体的细胞。
例如,转铁蛋白结合蛋白可以能够特异性结合转铁蛋白,并且不干扰转铁蛋白与转铁蛋白受体1之间的相互作用。
例如,转铁蛋白可以是人转铁蛋白。
例如,转铁蛋白可以是含铁的铁饱和转铁蛋白。
例如,含铁的铁饱和转铁蛋白可包含转铁蛋白和Fe3+。
例如,转铁蛋白可结合Fe3+。
例如,转铁蛋白可结合两个Fe3+。
例如,含铁的铁饱和转铁蛋白可结合转铁蛋白受体。
例如,含铁的铁饱和转铁蛋白可结合转铁蛋白受体1。
例如,含铁的铁饱和转铁蛋白可以通过转铁蛋白受体转运到内体。
例如,含铁的铁饱和转铁蛋白可通过内吞作用转运。
例如,含铁的铁饱和转铁蛋白可通过胞吞转运作用运输。
例如,含铁的铁饱和转铁蛋白可与Fe3+分离。
例如,转铁蛋白可以是不含铁的脱铁转铁蛋白。
例如,不含铁的脱铁转铁蛋白可来自与Fe3+分离的含铁的铁饱和转铁蛋白。
例如,不含铁的脱铁转铁蛋白可以能够与Fe3+结合。
例如,转铁蛋白结合蛋白对含铁的铁饱和转铁蛋白的亲和力可高于对不含铁的脱铁转铁蛋白的亲和力。
例如,亲和力可通过基于表面等离子共振的测定来检测。
例如,亲和力可通过酶联免疫吸附测定(ELISA)来检测。
例如,亲和力可通过竞争测定(RIA)来检测。
例如,亲和力可通过流式细胞术(FACS)来检测。
例如,亲和力可表示为结合平衡常数(KD)。
例如,转铁蛋白结合蛋白对含铁的铁饱和转铁蛋白的亲和力可为对不含铁的脱铁转铁蛋白的亲和力的2倍、4倍、6倍、8倍、10倍、20倍、40倍、60倍、80倍、100倍。
例如,转铁蛋白结合蛋白可包括单克隆抗体。
例如,转铁蛋白结合蛋白可包括单链抗体片段。
例如,转铁蛋白结合蛋白可包括单结构域抗体片段。
例如,转铁蛋白结合蛋白可包括工程蛋白。
例如,转铁蛋白结合蛋白可包括肽。
例如,转铁蛋白结合蛋白的抗体或抗体片段可包含动物来源的序列。
例如,转铁蛋白结合蛋白的抗体或抗体片段可包含人源化序列。
例如,转铁蛋白结合蛋白的抗体或抗体片段可包含全人源序列。
例如,转铁蛋白结合蛋白的抗体或抗体片段可包含嵌合序列。
例如,转铁蛋白结合蛋白的抗体或抗体片段可包含合成序列。
例如,转铁蛋白结合蛋白的抗体或抗体片段可以是单结构域抗体片段VHH。
在本申请中,转铁蛋白结合蛋白可在重链可变区VH中包含至少一个CDR,其中VH包含如SEQ ID NO:70-104中任一项所示的氨基酸序列。
例如,VH可包含如SEQ ID NO:70-104中任一项所示的氨基酸序列。
例如,转铁蛋白结合蛋白可包含VH的HCDR3,其具有如SEQ ID NO:45-69中任一项所示的氨基酸序列。
例如,转铁蛋白结合蛋白可包含VH的HCDR2,其具有如SEQ ID NO:22-44中任一项所示的氨基酸序列。
例如,转铁蛋白结合蛋白可包含VH的HCDR1,其具有如SEQ ID NO:1-21中任一项所示的氨基酸序列。
例如,转铁蛋白结合蛋白可包含HCDR1、HCDR2和HCDR3,HCDR1可包含如SEQ ID NO:1-21中任一项所示的氨基酸序列,HCDR2可包含如SEQ ID NO:22-44中任一项所示的氨基酸序列,HCDR3可包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
例如,转铁蛋白结合蛋白可包含Fc区。
例如,Fc区可包括人Fc区。
例如,Fc区可包括人IgG Fc区。
例如,Fc区可包括人IgG1 Fc区。例如,Fc区可包括人IgG4 Fc区。
例如,转铁蛋白结合蛋白可包括抗体或其抗原结合片段。抗体可选自由以下组成的组:单克隆抗体、单链抗体、嵌合抗体、多特异性抗体、人源化抗体和全人源抗体。抗原结合片段选自由以下组成的组:Fab、Fab’、F(ab)2、F(ab’)2、sdAb、Fv、dAb和ScFv片段。
例如,转铁蛋白结合蛋白可以是VHH。
例如,VHH可包含CDR3,且CDR3可包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
例如,VHH可包含CDR2,且CDR2可包含如SEQ ID NO:22-44中任一项所示的氨基酸序列。
例如,VHH可包含CDR1,且CDR1可包含如SEQ ID NO:1-21中任一项所示的氨基酸序列。
例如,VHH可包含CDR1、CDR2和CDR3,CDR1可包含如SEQ ID NO:1-21中任一项所示的氨基酸序列,CDR2可包含如SEQ ID NO:22-44中任一项所示的氨基酸序列,CDR3可包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
例如,VHH可包含CDR1、CDR2和CDR3,CDR1、CDR2和CDR3可分别包含如SEQ ID NO:1、SEQ ID NO:22和SEQ ID NO:45中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:1、SEQ ID NO:22和SEQ ID NO:63中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:2、SEQ ID NO:23和SEQ ID NO:46中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:2、SEQ ID NO:23和SEQ ID NO:58中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:2、SEQ ID NO:40和SEQ ID NO:58中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:2、SEQ ID NO:41和SEQ ID NO:58中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:2、SEQID NO:23和SEQ ID NO:66中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQID NO:3、SEQ ID NO:24和SEQ ID NO:47中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:4、SEQ ID NO:25和SEQ ID NO:48中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:5、SEQ ID NO:26和SEQ ID NO:49中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:6、SEQ ID NO:27和SEQ ID NO:50中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:6、SEQ ID NO:27和SEQID NO:59中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:7、SEQ IDNO:28和SEQ ID NO:51中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ IDNO:8、SEQ ID NO:29和SEQ ID NO:52中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:9、SEQ ID NO:30和SEQ ID NO:53中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:10、SEQ ID NO:31和SEQ ID NO:54中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:11、SEQ ID NO:32和SEQ ID NO:55中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:12、SEQ ID NO:33和SEQ IDNO:56中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:13、SEQ IDNO:34和SEQ ID NO:57中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ IDNO:14、SEQ ID NO:35和SEQ ID NO:60中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:15、SEQ ID NO:36和SEQ ID NO:61中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:16、SEQ ID NO:37和SEQ ID NO:62中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:17、SEQ ID NO:38和SEQ ID NO:64中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:18、SEQ ID NO:39和SEQ IDNO:65中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:19、SEQ IDNO:42和SEQ ID NO:67中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ IDNO:20、SEQ ID NO:43和SEQ ID NO:68中所示的氨基酸序列;或者CDR1、CDR2和CDR3可分别包含如SEQ ID NO:21、SEQ ID NO:44和SEQ ID NO:69中所示的氨基酸序列。
例如,VHH可包含如SEQ ID NO:70-104中任一项所示的氨基酸序列。例如,SLN9056包含如SEQ ID NO:70中所示的氨基酸序列。例如,SLN9057包含如SEQ ID NO:71中所示的氨基酸序列。例如,SLN0042包含如SEQ ID NO:72中所示的氨基酸序列。例如,SLN0043包含如SEQ ID NO:73中所示的氨基酸序列。例如,SLN0044包含如SEQ ID NO:74中所示的氨基酸序列。例如,SLN0045包含如SEQ ID NO:75中所示的氨基酸序列。例如,SLN0049包含如SEQ IDNO:76中所示的氨基酸序列。例如,SLN0056包含如SEQ ID NO:77中所示的氨基酸序列。例如,SLN0057包含如SEQ ID NO:78中所示的氨基酸序列。例如,SLN0059包含如SEQ ID NO:79中所示的氨基酸序列。例如,SLN0062包含如SEQ ID NO:80中所示的氨基酸序列。例如,SLN0064包含如SEQ ID NO:81中所示的氨基酸序列。例如,SLN0065包含如SEQ ID NO:82中所示的氨基酸序列。例如,SLN0071包含如SEQ ID NO:83中所示的氨基酸序列。例如,SLN0072包含如SEQ ID NO:84中所示的氨基酸序列。例如,SLN0046包含如SEQ ID NO:85中所示的氨基酸序列。例如,SLN0058包含如SEQ ID NO:86中所示的氨基酸序列。例如,SLN9008包含如SEQ ID NO:87中所示的氨基酸序列。例如,SLN9013包含如SEQ ID NO:88中所示的氨基酸序列。例如,SLN9015包含如SEQ ID NO:89中所示的氨基酸序列。例如,SLN9025包含如SEQ ID NO:90中所示的氨基酸序列。例如,SLN9026包含如SEQ ID NO:91中所示的氨基酸序列。例如,SLN9056包含如SEQ ID NO:70中所示的氨基酸序列。
本申请的抗原结合蛋白可与参照抗体竞争结合Tf,其中参照抗体可包含重链可变区和轻链可变区,参照抗体的重链可变区可包含HCDR1、HCDR2和HCDR3,HCDR1可包含如SEQID NO:1-21中任一项所示的氨基酸序列,HCDR2可包含如SEQ ID NO:22-44中任一项所示的氨基酸序列,HCDR3可包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
多肽
另一方面,本申请提供了包含转铁蛋白结合蛋白的多肽。
例如,多肽可包含治疗实体。
例如,治疗实体可以是工程细胞毒性假单胞菌外毒素A(PE38)。例如,PE38可包含如SEQ ID NO:109中所示的氨基酸序列。
例如,治疗实体可以是胰高血糖素样肽-1(GLP-1)或其变体。例如,GLP-1可包含如SEQ ID NO:108中所示的氨基酸序列。
例如,变体可以是与亲本多肽具有显著序列同一性并保留亲本多肽的生物活性的多肽。例如,变体的氨基酸序列可与亲本多肽的氨基酸序列具有至少约50%、75%、80%、90%、95%、96%、97%、98%、98.2%、98.4%、98.6%、98.8%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99.9%或更高的同一性。例如,变体也可以是在蛋白质和/或多肽的氨基酸序列中取代、删除或添加一个或多个氨基酸的蛋白质或多肽。例如,变体可包括具有至少一个,诸如1-30个、1-20个或1-10个,以及诸如1、2、3、4或5个,氨基酸取代、缺失或插入的氨基酸改变的蛋白质或多肽。例如,取代可以是保守的。
例如,治疗实体与转铁蛋白结合蛋白可以直接连接。
例如,治疗实体与转铁蛋白结合蛋白可以通过基因融合或重组DNA技术连接。
例如,治疗实体与转铁蛋白结合蛋白可以间接连接。
例如,治疗实体与转铁蛋白结合蛋白可以通过间隔区连接。
例如,治疗实体与转铁蛋白结合蛋白可以通过连接子连接。
例如,连接子可以是具有氨基酸序列的肽。
例如,连接子可源自人工合成。
分离的核酸分子、载体、细胞
另一方面,本申请提供了一种或多种分离的核酸分子,其编码本申请的分离的转铁蛋白结合蛋白或多肽。
本申请的核酸分子可被分离。例如,其可通过以下方法产生或合成:(i)体外扩增,例如通过聚合酶链式反应(PCR)扩增产生,(ii)通过克隆和重组产生,(iii)纯化,例如通过酶消化和凝胶电泳分级分离,或(iv)合成,例如化学合成。在某些实施方案中,分离的核酸是通过重组DNA技术制备的核酸分子。
在本申请中,编码抗体或其抗原结合片段的核酸可通过本领域已知的多种方法制备,所述方法包括但不限于限制性片段操作或使用合成寡核苷酸的重叠延伸PCR。
另一方面,本申请提供了载体,其可包含本申请的核酸分子。
另一方面,本申请提供了一种或多种载体,其包含一种或多种本申请的核酸分子。每个载体可包含一个或多个核酸分子。此外,载体还可包含其它基因,例如允许在合适的宿主细胞中和在合适的条件下选择载体的标记基因。此外,载体还可包含允许编码区在合适的宿主中正确表达的表达控制元件。这种控制元件是本领域技术人员公知的,并且可包括例如启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其它控制元件。本申请的一个或多个核酸分子可以与表达控制元件可操作地连接。载体可包括,例如,质粒、粘粒、病毒、噬菌体或其它常用于例如基因工程的载体。例如,载体是表达载体。
另一方面,本申请提供了细胞,其可包含本申请的核酸分子或本申请的载体。
另一方面,本申请提供了宿主细胞,其可包含本申请的一种或多种核酸分子和/或本申请的一种或多种载体。
在某些实施方案中,每种或每个宿主细胞可包含一个或一种本申请的核酸分子或载体。在某些实施方案中,每种类型的宿主细胞或每种宿主细胞可包含多个(例如,2个或更多个)或多种的(例如,2种或更多种的)本申请的核酸分子或载体。例如,可将本申请的载体引入宿主细胞,例如真核细胞,诸如来自植物的细胞、真菌细胞或酵母细胞等。可通过本领域已知的方法(诸如电穿孔、lipofectine转染、lipofectamin转染等)将本申请的载体引入宿主细胞。
药物组合物
另一方面,本申请提供了药物组合物,其可包含本申请的转铁蛋白结合蛋白、本申请的核酸分子、本申请的载体和/或本申请的细胞,以及任选的药学上可接受的佐剂。
例如,本申请的药物组合物可直接用于治疗或诊断,因此可用于预防和治疗疾病。此外,可以同时使用其它治疗实体。
本申请的药物组合物可包含安全有效量(例如,0.001-99wt%、0.01-90wt%、或0.1-80wt%)的本申请的转铁蛋白结合蛋白和药学上可接受的佐剂(其可包含运载体或赋形剂)。这种运载体可包括但不限于盐水、缓冲液、葡萄糖、水、甘油、乙醇及其组合。药物制剂应与施用方式相匹配。可将本申请的药物组合物制成可注射形式,例如,其可通过常规方法用生理盐水或含有葡萄糖和其它佐剂的水溶液制备。应该在无菌条件下生产药物组合物,诸如注射剂或溶液。活性成分的施用量是治疗有效量。此外,本申请的转铁蛋白结合蛋白也可以与其它治疗实体一起使用。
本文所述的转铁蛋白结合蛋白或药物组合物可以以符合良好医疗实践的方式配制、施用和给药。在这种情况下,需要考虑的因素包括被治疗的特定疾病、被治疗的特定哺乳动物、个体患者的临床症状、疾患的病因、药物递送部位、施用方法和其它医生已知的因素。治疗实体不需要,但可以选择性地与一种或多种目前用于预防或治疗所关注的疾病的实体一起配制和/或同时施用。此类其它实体的有效量取决于制剂中存在的治疗剂的量、疾病或治疗的类型以及上述其它因素。通常,这些实体可以以根据经验/临床情况适当确定的任何剂量使用,以及通过任何根据经验/临床适当确定的途径使用。与单一疗法相比,在联合疗法中施用的抗体剂量可以减少。通过常规技术很容易监测这种疗法的进展。
方法
另一方面,本申请提供了一种通过使用转铁蛋白结合蛋白将分子转运穿过细胞膜的方法。
例如,所述方法可用于跨细胞膜的药物递送。
例如,细胞膜可以属于极化细胞。
例如,极化细胞可以是功能细胞。
例如,极化细胞可以是神经细胞。
例如,细胞膜可以属于未极化细胞。
例如,未极化细胞可以是神经细胞。
例如,未极化细胞可以传递神经信号。
例如,极化和/或未极化细胞可以在其细胞膜上表达转铁蛋白受体。
例如,极化和/或未极化细胞可以在其细胞膜上表达人转铁蛋白受体。
例如,极化和/或未极化细胞可以表达转铁蛋白受体1。
例如,极化和/或未极化细胞可以表达人转铁蛋白受体1。
例如,未极化细胞可以属于血脑屏障。
例如,未极化细胞可以属于肠上皮。
例如,未极化细胞可以属于实体组织中的多层细胞。
在本申请中,穿过细胞膜的药物递送方法可包括穿过血脑屏障、穿过肠上皮、穿过实体组织中的多层细胞、药物的细胞内递送和/或将被内吞的药物再循环回到血液循环中。
例如,穿过细胞膜的药物递送可以属于未极化细胞。
例如,穿过细胞膜的药物递送可包括靶向中枢神经系统的全身给药的药物穿过血脑屏障。
例如,穿过细胞膜的药物递送可包括口服施用的药物穿过肠上皮。
例如,穿过细胞膜的药物递送可包括药物穿透实体组织中的多层细胞。
例如,穿过细胞膜的药物递送可以属于极化细胞。
例如,穿过细胞膜的药物递送可包括药物的细胞内递送。
例如,穿过细胞膜的药物递送可包括将被内吞的药物再循环回到血液循环中。
例如,药物可包含小分子化合物。
例如,小分子化合物可以是化学合成的药物。
例如,小分子化合物的分子量可以小于1000道尔顿。
例如,小分子化合物可能具有治疗效果。
例如,小分子化合物可具有抗肿瘤活性。
例如,药物可包括合成肽。
例如,合成肽可包含α-氨基酸。
例如,α-氨基酸可通过肽链连接。
例如,合成肽可通过固相肽合成来合成。
例如,合成肽可通过液相肽合成来合成。
例如,药物可包含重组蛋白。
例如,重组蛋白可以是半合成或合成来源的多肽。
例如,重组蛋白可通过使用重组DNA技术连接不同来源的DNA分子来表达。
例如,重组蛋白可不再与天然状态下的蛋白完全或部分结合。
例如,可将重组蛋白连接到与其天然状态下连接的肽不同的肽上。
例如,重组蛋白可以不以天然状态存在。
例如,药物可包含抗体。例如,药物可包含抗体片段。
例如,抗原片段可以是Fab、Fab’、F(ab)2、Fv片段、F(ab’)2、scFv、di-scFv和/或dAb。
例如,药物可含酶。
例如,酶可以是具有催化活性的蛋白质。
例如,药物可包含一段核苷酸序列。
例如,核苷酸序列可以是DNA序列。
例如,核苷酸序列可以是RNA序列。
例如,核苷酸序列可以是基因组DNA、cDNA、合成DNA、前病毒DNA、病毒DNA、mRNA、合成RNA或其组合。
例如,核苷酸序列可以编码肽或蛋白质。
例如,合成RNA可以调节mRNA的稳定性或翻译。
例如,合成RNA可以是小干扰RNA(siRNA)或反义寡核苷酸(ASO)。
例如,药物可包含脂质体。
例如,脂质体可以是由一层或多层同心排列的脂双层组成的囊泡。
例如,脂质体可包含水相。
例如,水相可包含核酸。
例如,药物可包含纳米尺寸的颗粒,诸如脂质纳米颗粒。
例如,脂质纳米颗粒可包含通过分子间作用力彼此物理结合的多个脂质分子。
例如,分子间作用力可以是共价的或非共价的。
例如,脂质纳米颗粒可包含一种或多种脂质。
例如,脂质可以是阳离子脂质、非阳离子脂质和PEG-脂质。
例如,药物可包含药物载体。
例如,药物载体可以是适于人施用的标准组合物。
例如,药物载体可以是用于动物疫苗接种的典型佐剂。
例如,药物可包含经修饰的病毒。
例如,经修饰的病毒可以是基因工程病毒。
例如,经修饰的病毒可在体内或体外抑制癌细胞或过度增殖细胞的生长。
例如,经修饰的病毒可在体内或体外诱导癌细胞或过度增殖细胞死亡。
例如,经修饰的病毒可以是溶瘤病毒。
例如,药物可包含基因治疗载体。
例如,基因治疗载体能够将靶基因递送到靶细胞中。
例如,靶基因可以在靶细胞中释放。
例如,靶基因可以整合到细胞核中。
例如,基因治疗载体可以发挥靶基因的治疗功能。
例如,基因治疗载体可以是质粒载体、噬菌体载体、病毒载体或其非病毒载体。
例如,基因治疗载体可以是克隆载体或其表达载体。
例如,基因治疗载体可以是温度敏感型载体、融合表达载体或其非融合表达载体。
例如,药物可以与转铁蛋白结合蛋白结合。
例如,药物可通过基因融合与转铁蛋白结合蛋白结合。
例如,药物可通过化学偶联与转铁蛋白结合蛋白结合。
例如,该方法可用于延长治疗实体的循环半衰期。
例如,治疗实体可以直接或间接与转铁蛋白结合蛋白连接。
例如,该方法可用于将治疗药物递送至表达转铁蛋白受体的细胞或器官,包含或使用转铁蛋白结合实体。
例如,该方法可用于递送靶向药物穿过血脑屏障、肠上皮和/或表达转铁蛋白受体的细胞膜,包括使用转铁蛋白结合实体。
例如,该方法可用于治疗或诊断实体的口服递送,所述治疗或诊断实体与所述抗原结合蛋白连接。
例如,该方法可用于治疗实体的细胞内递送,所述治疗实体与所述抗原结合蛋白直接或间接连接。
实施例
阐述以下实施例是为了向本领域普通技术人员提供如何制造和使用本发明的完整公开内容和描述,并且不旨在限制本发明人认为是他们的发明的范围,也不旨在表示以下实验是所进行的全部或唯一实验。已经努力确保所用数字(例如,数量、温度等)的准确性,但是应该考虑一些实验误差和偏差。除非另有说明,否则份是重量份,分子量是重均分子量,温度是摄氏度,压力是大气压或接近大气压。可以使用标准缩写,例如bp,碱基对;kb,千碱基;pl,皮升;s或sec,秒;min,分钟;h或hr,小时;aa,氨基酸;nt,核苷酸;CPU,菌落形成单位;rpm,每分钟转数;RT,室温;i.m.,肌内注射(地);i.p.,腹膜内注射(地);s.c.,皮下注射(地);等等。
实施例1 VHH免疫文库的建立
使用人转铁蛋白(人转铁蛋白,Sigma T3309)免疫两只健康且适龄的骆驼4次。抗体滴度合格后,每只骆驼抽取200ml外周血,分离淋巴细胞,并提取总RNA。应用逆转录生成cDNA,用于构建噬菌体展示的骆驼免疫VHH抗体文库。通过对24个独立的噬菌体克隆DNA测序进行VHH抗体文库质检。数据表明,22/24个克隆的序列含有用于噬菌体展示的融合了gp3蛋白的标准VHH序列,并且22个克隆中的每一个克隆都具有独特的VHH序列,其中CDR3的长度为9个或更多个氨基酸。该文库用于之后的抗体发现。
实施例2VHH的发现
2.1-淘选
从-80℃冰箱中取出噬菌体文库,37℃孵育10min,5000rpm离心5min。将1012~1013CFU噬菌体(输入(input))转移到含有1mL PBS溶液的微量管中,PBS溶液含有1% BSA、10μg生物素化的人或小鼠转铁蛋白。将混合物在室温下孵育1h,加入100μL链霉亲和素包被的磁性Dyna珠悬浮液。于旋转转筒上室温孵育30min,将微量管放在磁性支架上30s以除去溶液混合物。用1mL PBST(含0.05%吐温20的PBS,pH7.4)洗涤磁珠10次,用PBS进行最后一次洗涤。
在PBS中加入1ml 10μg/mL胰蛋白酶,37℃孵育30min,将噬菌体从磁珠上洗脱,置于磁架上分离。将上清(输出(output))转移到含有4mL TG1(A600≈0.6)的管中以感染细菌。37℃孵育30min,4℃4,500rpm离心10min收集感染的细菌。将沉淀重悬于500μL中,并涂布于25×25cm 2×YT/Amp/Glu平板上以扩增噬菌体感染的细菌。37℃孵育过夜后,加入30mL 2×YT培养基,,4,500rpm离心10min收集。加入2mL含40%甘油的2×YT培养基重悬沉淀物,-80℃储存,或根据需要直接制备噬菌体(如下在噬菌体制备或包装中),用于下一轮淘选。
对输入和输出噬菌体进行滴定,以确定淘选过程的噬菌体富集效率。简言之,制备输入(input)/输出(output)噬菌体在PBS中的连续稀释液(10倍,通常为10-1~10-9),将10μL连续稀释的噬菌体与90μL对数生长期TG1在新管中混合,37℃孵育30min。此后,将10μL混合物点在预温热的2×YT/Amp平板上。在细菌平板37℃O/N培养前,将盖子打开以蒸发溶液。分别对输入和输出噬菌体进行菌落计数和滴度计算,每轮淘选的输出(output)/输入(input)比率用于确定淘选过程的效率。
2.2噬菌体的制备或包装
将噬菌体感染的TG1细菌接种到2×YT/Amp/Glu培养基中,37℃下振荡培养(250rpm),达到A600值为0.6(大约1-2h)。按噬菌体:细菌=1000加入辅助噬菌体M13K07。将培养物37℃下不振荡孵育30min,然后180rpm振荡培养30min。
细菌培养物在无菌离心瓶中以4,500rpm离心10min,回收细菌沉淀。将细菌沉淀重悬于100mL 2×YT/Amp/Kan(Amp:100μg/mL,Kan:50μg/mL)中,转移至250mL烧瓶中,37℃振荡(250rpm)孵育4h。
将培养物4,500rpm离心10min收集上清。加入1/4体积的PEG溶液(20%聚乙二醇6000,2.5M NaCl)从上清中沉淀出噬菌体,并在冰上孵育过夜。4℃下4,500rpm离心30min收集后,将噬菌体沉淀重悬于5mL PBS中,37℃振荡孵育30min。4,500rpm离心10min除去不溶性碎片,将上清中的可溶性噬菌体转移到新管中重复PEG沉淀一次。PBS中的终噬菌体溶液用于下一轮淘选或与甘油混合在-80℃下储存。
2.3基于噬菌体的ELISA筛选
从琼脂平板上分别挑取来自淘选输出的单个菌落,并将其接种在96孔深孔板中的2xYT/GA培养基(2%葡萄糖,100μg/mL氨苄青霉素)中,37℃下孵育过夜,振荡速度为320rpm。将10μL过夜培养物转移到新的深孔板中的400μL 2YT/GA培养基中。将培养物37℃下振荡(800rpm)培养至为0.6的A600(大约1h),按噬菌体:细菌=1000比例(100μL于100mL中)加入辅助噬菌体M13K07(4.2×1013CFU/mL)。将培养物37℃不振荡持续孵育30min,然后180rpm振荡30min。将细菌培养物4,000rpm离心30min弃上清。将细菌沉淀重悬于400μL 2×YT/AK(Amp:100μg/mL,Kan:50μg/mL)中,30℃振荡(320rpm)培养过夜。将细菌培养物4,000rpm离心30min收集上清。上清用作ELISA筛选的噬菌体溶液。
进行ELISA筛选,96孔微量滴定板用100μL/孔的浓度为1μg/mL的链霉亲和素(pH9.4的碳酸盐缓冲盐水或CBS)4℃包被过夜。用200μL/孔封闭缓冲液(PBS pH7.4/0.05%吐温20/1% BSA)室温下封闭1小时。PBST(PBS/0.05%吐温20,pH7.4)洗涤3次,加入100μL生物素化的人或小鼠转铁蛋白(1μg/mL,于封闭缓冲液中)室温孵育1h。PBST洗涤3次,加入100μL噬菌体溶液(如上)室温孵育1h。PBST洗涤3次,加入100μL/孔小鼠抗M13 IgG-HRP(封闭缓冲液中制备)室温孵育1h。PBST洗涤3次,加入100μL TMB溶液,避光室温孵育15min。100μL终止溶液终止反应后,在450nm处扫描微孔板。选择与转铁蛋白特异性结合的阳性克隆进行DNA测序,根据推导的氨基酸序列鉴定单一的VHH。
2.4重组VHH-OVA-his蛋白的生产
选择单一的VHH克隆进行亚克隆构建重组质粒,从而生产VHH-OVA-His蛋白(OVA包含如SEQ ID NO:107中所示的氨基酸序列)。通过测序验证质粒序列后,使用lipofectamine或PEI作为转染试剂,用重组质粒瞬时转染HEK293细胞进行重组蛋白的小规模生产。培养物在摇瓶培养基中以30ml至100ml的规模生长5-7天。离心去除细胞,将培养物上清用于通过Ni-NTA琼脂糖进行蛋白质纯化。在非还原或还原条件下4-12%梯度SDS-PAGE凝胶分析纯化的蛋白质(图1)。
2.5转铁蛋白结合测定
为了检测重组蛋白与转铁蛋白结合能力和特异性,链霉亲和素(1μg/ml,于CBS中,100μl/孔)包被96孔微孔板,4℃孵育过夜。PBST洗涤3次后,用含1% BSA的PBST室温封闭微孔板1hr。PBST洗涤3次,加入生物素化的人或小鼠转铁蛋白(1ug/ml,于PBS中,100ul/孔),室温孵育1h。PBST洗涤3次后,加入纯化的VHH-OVA-His蛋白室温孵育1h(在pH7.4或pH6.0的PBS中连续稀释,从10ug/ml开始,100ul/孔)。兔抗鸡卵白蛋白(OVA)和抗兔IgG-HRP二抗依次孵育,然后用PBST洗涤平板3次,并将其与底物溶液和终止液一起孵育,如上文针对噬菌体ELISA所述。代表性数据如图2A(pH7.4,铁饱和转铁蛋白)或图2B(pH6.0,脱铁转铁蛋白)所示,用以说明重组VHH-OVA-His与天然人转铁蛋白(Sigma)的结合活性。
2.6VHH的结合不干扰HEK293F-hTFR1细胞上的转铁蛋白/TfR1相互作用
通过将带有GFP标签的表达hTfR1的质粒转染到HEK293F细胞中来制备HEK293F-hTfR1细胞。稳转细胞池用于该测定。简言之,OPM-293CD05培养基在37℃,8% CO2和饱和湿度下振荡培养表达hTfR1的工程HEK293F细胞。收集HEK293F-hTfR1细胞、计数并用封闭缓冲液37℃封闭30min,每次反应使用1×106个细胞,pH7.4或pH6.0条件下,含或不含转铁蛋白(终浓度为5μg/mL),含或不含柠檬酸铁溶液(终浓度为0.2mg/mL),将其与VHH-OVA-His或对照蛋白溶液(终浓度为10μg/mL)混合。兔抗OVA抗体和抗兔IgG-AF647二抗(全部在封闭缓冲液中制备)孵育后,4℃300g离心5min洗涤细胞两次。CytoFLEX(Beckman)扫描细胞。采用CytoExpert 2.4软件分析数据,以确定1)VHH-OVA-His蛋白与细胞的差异结合(转铁蛋白结合不干扰细胞表面上的转铁蛋白/TfR1相互作用);2)对转铁蛋白的依赖性(对转铁蛋白的特异性);3)对TfR1的依赖性(对TfR1介导的细胞结合的特异性);4)对pH值和Fe3+的依赖性(对铁相关铁饱和转铁蛋白或不含铁的脱铁转铁蛋白的特异性)。数据(如下和图3)表明,所选的转铁蛋白结合VHH例如SLN0042、SLN0043、SLN0044、SLN0049、SLN0062、SLN0064、SLN0065、SLN0056、SLN0071和SLN0072不干扰转铁蛋白/TfR1相互作用,并且只能通过与转铁蛋白结合才能与细胞表面上的TfR1结合。该数据也验证了ELISA的结果,该结果显示一些选择的VHHs对铁饱和转铁蛋白和脱铁转铁蛋白具有不同的亲和力。
表1.不同PH条件下过表达hTfR1细胞表面VHH/Tf结合特征概述。
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注:+++≥15%;15%>++≥10%;10%>+≥5%;-<5%的结合
2.7表位鉴定(Epitope binning)
表位鉴定用于区分不同蛋白的不同“bin”。因为不同“bin”中的抗体结合不同的表位并显示不同的功能特征。
为进行表位鉴定,分别用每种VHH-OVA-His重组蛋白5μg/mL(在CBS缓冲液中,100μL/孔)包被96孔微孔板,4℃孵育过夜。在如上所述ELISA进行洗涤和封闭,加入生物素化的人转铁蛋白(终浓度1μg/mL)和VHH-OVA-His蛋白(终浓度5μg/mL)的混合物进行交叉检查板反应,室温孵育1h。用链霉亲和素-HRP和相应的方法检测与包被的VHH-OVA-His结合的生物素化的转铁蛋白。图4所示的数据表明所选的VHHs属于多个bin,尤其不同于参照抗体(VHH1、VHH2、VHH3)。
2.8 VHH-OVA-His蛋白穿过单层Caco-2细胞的胞吞转运
将Caco-2细胞以2×104个/孔接种于trans-well 96孔板(96-well trans-wellplate)中,培养12天,使内室中形成细胞单层(在第一周期间每隔一天更换培养基,在第二周期间每天更换培养基)。第13天,用预温热PBS洗涤单层细胞,含0.1% BSA不含FBS的MEM培养基中37℃孵育30min以去除内源性Tf。在含0.1% BSA的MEM培养基(pH 7.4)中制备含或不含天然人转铁蛋白(5μg/mL)的重组VHH-OVA-His蛋白(10μg/mL),加入内室(Caco-2细胞单层上方)中,37℃孵育2h或24h。在指定的时间点收集外室的培养基,参考相应的VHH-OVA-His蛋白作为对照而形成的标准曲线,利用ELISA方法进行定量检测。根据制造商的说明,用萤光黄(Lucifer yellow,LY)排斥测定法(rejection assay)测试Caco-2细胞单层的完整性。与内室信号相比,来自外室信号的萤光黄信号超过0.1%(被动转运的基础水平)的孔被认为是用于检测的细胞单层是有缺陷的,从而被舍弃。
通过使用特异性抗体,按照上述程序进行定量ELISA检测。简言之,用兔抗OVA多克隆抗体(5μg/mL,于CBS缓冲液中)包被微孔板,加入供标准曲线用的测试品或对照品(VHH-OVA-His蛋白),用生物素化抗OVA抗体和链霉亲和素-HRP偶联物进行检测。以稀释因子3从1000ng/mL连续稀释至0的重组VHH-OVA-His蛋白制备标准曲线。所述检测合格性为检测样品间CV小于20%且回收率大于90%。
图7中显示的数据表明,VHHs具有不同的穿越Caco-2细胞单层的能力,部分反映其对人转铁蛋白或转铁蛋白结合表位的亲和力。该结果还表明转铁蛋白在VHH使生物分子通过肠上皮细胞的跨膜吸收中的至关重要的作用(图7B)。
所选VHHs人源化
选择具有使融合的OVA蛋白能够跨膜转运的预期特性以及开发风险因素较少的VHH进行人源化。测定选择的VHH内的CDR残基,并用Kabat编号系统进行注释。N-糖基化位点,和CDR内的脱氨基位点,N-糖基化位点或CDR内或靠近CDR的半胱氨酸将被视为未来开发的危险因素。按照CDR移植和结构改良的标准程序进行VHH人源化。根据人源化设计,构建重组DNA构建载体以产生重组VHH-OVA-His,如上文基于ELISA和FACS测定的结合结果。选择具有等于或优于原始VHH对转铁蛋白的亲和力,同时具有可接受的表达和稳定性水平的人源化序列用于进一步开发。
图5表明人源化VHH变体在与转铁蛋白的结合方面具有与最初的VHH相似的特征谱。
实施例3使用Tf结合VHH延长其结合的实体的半衰期
利用重组DNA技术,通过用或不用连接子在VHH的C-末端或N-末端融合指定的蛋白质以产生融合蛋白。蛋白质纯化至同质,在适当的缓冲液中配制,并用Bradford方法定量,以用于体内测试。所有动物程序均由机构审查委员会(IRB)审查和批准。
在包括C57BL/6、Balb/c和CR6在内的不同遗传品系的小鼠根据遗传背景、性别和体重进行分组。在含或不含人转铁蛋白(5mg/kg)的共同给药的情况下,通过IV或SC注射3mg/kg测试品,例如与转铁蛋白结合蛋白融合的蛋白,以及阴性对照(以相同方式生产的,但含有不与转铁蛋白结合的VHH的重组蛋白)。对于将转铁蛋白共同给药的组,每日给药5mg/kg的人转铁蛋白,持续10天。
为了确定测试品在小鼠体内的血清半衰期,在多个时间点从外眼角的皮下静脉收集40μL全血。将收集的全血在室温放置1小时后,10000rpm离心10min回收血清,通过定量ELISA检测血清中VHH融合蛋白的浓度。对于OVA-VHH-His或GLP-1-VHH-His蛋白,将兔抗OVA多克隆抗体(Sigma C6534-2mL)或单克隆抗GLP-1抗体分别与生物素化的兔抗VHH抗体(GeneScript,A02015-200)配对,用于特异性和定量检测,参考通过使用测定间CV小于20%且回收率大于90%的合格方案,使用纯化的重组蛋白作为标准曲线。PKsovler软件计算PK参数。
如图6所示的结果表明,结合转铁蛋白的VHH能够延长其结合的OVA以及GLP-1的血清半衰期,并且这种效果依赖于VHH对转铁蛋白和其结合表位的亲和力。
实施例4结合转铁蛋白VHH实现口服递送结合实体
同半衰期研究,使用250mg/kg三溴乙醇将分组小鼠麻醉,然后将小鼠的腹部毛发剃掉并用碘酒和酒精消毒。用外科剪刀将中腹部的皮肤剪成约0.5-1cm长,以暴露十二指肠,用于注射含或不含转铁蛋白与Fe3+的混合物的测试品或对照(纯化的VHH-OVA-His蛋白)。伤口用碘酒消毒后缝合。或者,通过将管饲针插入小鼠胃中通过胃内注射来施用测试品或对照。口服给药后,如上所述在多个时间点收集血液样品以回收血清。按照实施例3中描述的方法定量VHH融合蛋白的浓度。
图7中显示的数据表明,结合转铁蛋白的VHH使得口服给药的VHH-OVA融合蛋白能够穿过肠上皮并被吸收到血流中,因此证明通过口服给药途径递送治疗性生物制剂的潜力。
实施例5结合转铁蛋白VHH实现结合实体穿过血脑屏障
同半衰期研究,通过IV注射给予小鼠10mg/kg纯化重组蛋白(例如VHH-OVA-His),通过IP注射给予或不给予10mg/kg的人转铁蛋白。在给药后的多个时间点,20mL PBS灌流后收集脑并冷冻在液氮中。按照ELISA的定量检测的标准程序提取蛋白质。一种定量ELISA形式是采用兔抗OVA多克隆抗体(Sigma C6534-2mL)包被,生物素化的兔抗VHH抗体(GeneScript,A02015-200)进行检测。图8中显示的数据表明,与阴性对照(SLN0066,一种不与转铁蛋白结合的VHH,SEQ ID NO:110)相比,测试品(证明对转铁蛋白具有结合能力的VHH)显著提高了测试品在脑组织中的水平(平均%ID或注射剂量百分比,对于选择的VHH,给药后24h为~1.03%至~3.5%)。数据还清楚地表明VHH穿越BBB与转铁蛋白相关(与VHH-OVA-His处理组相比,转铁蛋白共同给药组的%ID高约3.2倍)。
通过使用CDR相同(因此推测与转铁蛋白上的相同表位结合)但具有不同亲和力的人源化VHH变体,也确定了VHH对转铁蛋白的亲和力对介导穿越BBB的能力的影响。图8C中的数据进一步支持了VHH实现穿越BBB的能力依赖于结合转铁蛋白的结论,也清楚地表明了VHH对转铁蛋白的亲和力与其介导穿越BBB的能力之间的关系。VHH与转铁蛋白亲和力越高,穿越BBB的能力越强。
实施例6结合转铁蛋白的VHH实现细胞内递送其结合实体
多种类型的细胞(例如肿瘤细胞)膜表面转铁蛋白受体水平也升高。因此,结合转铁蛋白的VHH有利于靶向药物递送,尤其是向肿瘤细胞的胞内递送。为了验证该假设,在大肠杆菌中生产重组VHH-PE38-His蛋白并纯化至同质。在Hepa-G2细胞(持续表达TfR)和MDCK细胞(含或不含转染的重组质粒的异位TfR1表达)的单层培养物上测试细胞内递送的功效。简言之,将细胞以所需的密度接种到含100μL培养基的96孔微孔板中37℃培养过夜。新鲜的预热培养基洗涤细胞后,将在培养基中制备的含或不含人转铁蛋白连续稀释的VHH-PE38-His加入细胞培养物中。在处理后的多个时间点,按照说明书的指示,用CellTiter-试剂对活细胞进行定量。以每孔0.25-1秒的积分时间记录发光信号,采用GraphPad分析数据。
图9中显示的数据表明,结合转铁蛋白的VHH实现结合实体胞内递送到细胞表面表达转铁蛋白受体的细胞中,且此功能依赖于VHH的转铁蛋白结合活性。具有不同结合表位(属于不同的bin或具有不同的CDR序列)的VHH在胞内递送中也表现出差异效应。
实施例7结合转铁蛋白的VHH实现结合实体的器官或组织靶向递送
在具有不同遗传背景的小鼠中研究了静脉注射的重组蛋白(例如VHH-OVA-His)的生物分布。在静脉注射后的多个时间点,30mL PBS灌流血管后,采集肝脏、肺、骨髓、心脏、肌肉和血液等中样品。将样品称重并匀浆,提取可溶性蛋白质用于如上所述的定量ELISA检测。参照用纯化的重组蛋白形成的标准曲线,将数据以组织重量或体积作归一化。根据与不结合转铁蛋白的对照VHH相比的倍数变化,分析VHH-OVA-His蛋白的生物分布。图10中显示的数据表明所选结合转铁蛋白的VHH实现了向肝脏、脑、骨髓、肺、肌肉、肾、眼和表达转铁蛋白受体的其它器官或组织的靶向递送。本发明中的结合转铁蛋白的VHH具有靶向不同组织药物递送的潜在应用,尤其是脑、肝脏和骨髓。
虽然本文中已经示出和描述了本发明的优选实施方案,但是对于本领域技术人员来说,显然此类实施例仅仅是作为示例提供的。这并不意味着本发明受说明书中提供的具体实例的限制。虽然已经参考前述说明书描述了本发明,但是本文中的实施方案的描述和说明并不意味着以限制的意义来解释。在不脱离本发明的情况下,本领域技术人员将会想到许多变化、改变和替换。此外,应该理解的是,本发明的所有方面不限于本文中阐述的特定描述、配置或相对比例,其取决于各种条件和变量。应该理解,在实施本发明时,可以采用本文所述的本发明的实施方案的各种替代方案。因此,预期本发明还将涵盖任何此类替代、修改、变化或等同物。以下权利要求旨在限定本发明的范围,并且由此涵盖这些权利要求及其等同物范围内的方法和结构。
SEQUENCE LISTING
<110> 领诺(上海)医药科技有限公司
<120> 转铁蛋白结合抗体及其应用
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Ile Tyr Tyr Met Ala
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Arg Asn Cys Met Gly
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Arg Cys Cys Met Gly
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Ser Asp Cys Met Gly
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Gly His Cys Met Ala
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Arg Gly Cys Met Gly
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Gln His Cys Met Gly
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Ser Lys Cys Met Ala
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Arg Ala Cys Met Gly
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Lys Tyr Cys Met Gly
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<210> 21
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<212> PRT
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Asn Tyr Cys Met Ala
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<210> 22
<211> 17
<212> PRT
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<223> SLN9056/SLN0056/SLN9015/SLN9079/SLN0104/SLN0100/SLN0097 HCDR2
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Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
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Gly
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Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
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Gly
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Thr Ile Asn Pro Gly Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
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Gly
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<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ala Phe Val Pro Ser Ile Gly Ser Thr Phe Tyr Val Asp Ser Val Lys
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Gly
<210> 26
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
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<400> 26
Ala Ile Ala Arg Tyr Gly Asp Thr Thr Tyr Thr Asp Ser Val Lys Gly
1 5 10 15
<210> 27
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
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<400> 27
Trp Ile Ile Ala Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 28
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0049 HCDR2
<400> 28
Ala Ile Asp Ser Ile Gly Arg Thr Ser Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 29
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0057 HCDR2
<400> 29
Val Ile Tyr Arg Gly Gly Ser Thr Thr Tyr Ala Asp Ser Ala Lys Gly
1 5 10 15
<210> 30
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0059 HCDR2
<400> 30
Gly Leu Thr Arg Ala Asp Val Thr Leu Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 31
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0062 HCDR2
<400> 31
Thr Val Tyr Pro Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 32
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0064 HCDR2
<400> 32
Val Ile Asp Val Asp Ser Ile Ala Arg Tyr Gly Asp Ser Val Lys Gly
1 5 10 15
<210> 33
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0065 HCDR2
<400> 33
Val Thr Gly Arg Asp Gly Ser Thr Ile Tyr Ala Asp Ser Val Gln Gly
1 5 10 15
<210> 34
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0071 HCDR2
<400> 34
Ser Ile Asn Val Leu Gly Gly Thr Ser Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 35
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0058 HCDR2
<400> 35
Thr Ile Ala Thr Ala Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 36
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9008 HCDR2
<400> 36
Ala Ile Tyr Thr Gly Thr Gly Ser Thr Tyr Tyr Ala Asp Glu Ser Val
1 5 10 15
Lys Gly
<210> 37
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9013 HCDR2
<400> 37
Ser Phe Leu His Gly Ala Ala Ser Ala Asp Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 38
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9025 HCDR2
<400> 38
Tyr Thr Tyr Val Ser Phe Asn Val Thr His Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 39
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9026 HCDR2
<400> 39
Ala Ile Asp Thr Ser Arg Gly Arg Ala Tyr Leu Thr Asp Ser Val Lys
1 5 10 15
Gly
<210> 40
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9060 HCDR2
<400> 40
Gln Ile Gln Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 41
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9061 HCDR2
<400> 41
Gln Ile Asn Ala Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 42
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-mm-F7 HCDR2
<400> 42
Arg Val Tyr Ser Asp Gly Ser Gln Ser Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 43
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-hh-B12 HCDR2
<400> 43
Ala Ile Asp Ser Asp Gly Thr Thr Arg Tyr Ala Asp Ser Val Gln Gly
1 5 10 15
<210> 44
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-hm-D12 HCDR2
<400> 44
Asn Met Asn Ser Tyr Asp Trp Thr Asp Tyr Asp Asp Ser Val Lys Gly
1 5 10 15
<210> 45
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9056/SLN0056/SLN9079/SLN0104/SLN0100/SLN0097 HCDR3
<400> 45
Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala Arg Ala
1 5 10 15
Tyr Asn Ile
<210> 46
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9057 HCDR3
<400> 46
Arg Phe Gly Pro Thr Phe Tyr Ala Ile Asn Leu Gly Ser Asn Leu Tyr
1 5 10 15
Asn Tyr
<210> 47
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0042 HCDR3
<400> 47
Thr Gln Leu Phe Gly Cys Gly Ser Leu Ala Lys Ser Leu Phe Gly Tyr
1 5 10 15
<210> 48
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0043 HCDR3
<400> 48
Asp Pro Leu Trp Gly Arg Lys Tyr Gly Gly Ser Trp Ser Asp Pro Ser
1 5 10 15
Glu Tyr Asn Tyr
20
<210> 49
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0044 HCDR3
<400> 49
Lys Ser Pro Asn Ser Gly Cys Asp Glu Tyr Ala His Tyr Glu Thr
1 5 10 15
<210> 50
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0045 HCDR3
<400> 50
Ala Tyr Asn Gly Gly Asp Arg Cys Tyr Thr Leu Ile Gly Leu Tyr Asn
1 5 10 15
His
<210> 51
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0049 HCDR3
<400> 51
Thr Ala Trp Arg Asp Trp Ala Thr Leu Arg Glu Tyr Glu Tyr Gly Tyr
1 5 10 15
<210> 52
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0057 HCDR3
<400> 52
Ala His Val Leu His Val Ser Ser Leu Leu Pro Gly Gly Tyr Pro Tyr
1 5 10 15
<210> 53
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0059 HCDR3
<400> 53
Ala Asp Arg Phe Arg Val Gly Leu Arg Glu Ala Asp Phe Ser Ala
1 5 10 15
<210> 54
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0062 HCDR3
<400> 54
Ser Arg Arg Ile Trp Ser Cys Gly Ser Gly Ala Gly Ser Tyr Asp Tyr
1 5 10 15
<210> 55
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0064 HCDR3
<400> 55
Lys Thr Glu Arg Gln Cys Arg Trp Asn Trp Met Asp Trp Arg Thr Tyr
1 5 10 15
Asp Tyr Pro His
20
<210> 56
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0065 HCDR3
<400> 56
Asp Gln Thr Arg Tyr Ser Ser Leu Arg Leu Leu Ala Pro Asn Arg Ser
1 5 10 15
Ala Ser
<210> 57
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0071 HCDR3
<400> 57
Gly Leu Ala Ser Ala Pro Trp Arg Pro Cys Gly Thr Thr Thr Glu Glu
1 5 10 15
Tyr Lys Tyr
<210> 58
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0072/SLN9060/SLN9061/SLN9062/SLN9058/SLN0105 HCDR3
<400> 58
Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn Leu Tyr
1 5 10 15
Asn Tyr
<210> 59
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0046 HCDR3
<400> 59
Tyr Asn Gly Gly Asp Arg Cys Tyr Thr Leu Ile Gly Leu Tyr Asn His
1 5 10 15
<210> 60
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0058 HCDR3
<400> 60
Trp Gly Gly Ala Trp Trp Tyr Pro Trp Cys Glu Phe Val Phe Ser Asn
1 5 10 15
Gly Tyr
<210> 61
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9008 HCDR3
<400> 61
Thr Leu Leu Tyr Gly Cys Gly Ala Trp Ser Pro Arg Leu Phe Gly Tyr
1 5 10 15
<210> 62
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9013 HCDR3
<400> 62
Asn Pro Val Val Ala Ser Cys His Tyr Arg Leu Arg Ser Lys Tyr Ala
1 5 10 15
Tyr Asn Tyr
<210> 63
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9015 HCDR3
<400> 63
Val Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala Arg Ala
1 5 10 15
Tyr Asn Ile
<210> 64
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9025 HCDR3
<400> 64
Gly Tyr Tyr Ser Cys Gly Val Ser Thr Thr Gly Tyr Asn Tyr
1 5 10
<210> 65
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9026 HCDR3
<400> 65
Ser Asn Thr Phe Tyr Asn Cys Gly Ala Leu Asn Leu Gly Ile Gly Ala
1 5 10 15
Gly Leu Val Ala Tyr
20
<210> 66
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9077 HCDR3
<400> 66
Arg Phe Gly Pro Thr Phe Tyr Thr Gly Asn Leu Gly Ser Asn Leu Tyr
1 5 10 15
Asn Tyr
<210> 67
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-mm-F7 HCDR3
<400> 67
Leu Leu Met Ser Asp Tyr Tyr Ser Cys Arg Val Arg Phe His Gln Ser
1 5 10 15
Asp Phe Arg Asp
20
<210> 68
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-hh-B12 HCDR3
<400> 68
Asp Arg Trp Ser Met Lys Tyr Tyr Ser Asp Tyr Ala Leu Phe Pro Gly
1 5 10 15
Gly Tyr Asn Tyr
20
<210> 69
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-hm-D12 HCDR3
<400> 69
Arg Asp Cys Ala Leu Arg Tyr Cys Thr Arg Ser Tyr Cys Thr Arg Glu
1 5 10 15
Ala His Phe Phe Lys Tyr
20
<210> 70
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9056
<400> 70
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly His Ala Tyr Gly Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Glu Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 71
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9057
<400> 71
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Ala Ile Asn Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 72
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0042
<400> 72
Asp 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 Ala Ala Ser Gly Tyr Thr Arg Ser Phe Thr
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Thr Ile Asn Pro Gly Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ser Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Thr Gln Leu Phe Gly Cys Gly Ser Leu Ala Lys Ser Leu Phe
100 105 110
Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 73
<211> 129
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0043
<400> 73
Asp 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 Ala Ala Ser Gly Val Thr Trp Ser Arg Asp
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Phe Val Pro Ser Ile Gly Ser Thr Phe Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Thr Asp Pro Leu Trp Gly Arg Lys Tyr Gly Gly Ser Trp Ser Asp
100 105 110
Pro Ser Glu Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 74
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0044
<400> 74
Asp 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 Ala Ala Ser Ile Tyr Thr Tyr Ser Thr Ala
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Ala Arg Tyr Gly Asp Thr Thr Tyr Thr Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Val Ala Lys Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ser Lys Ser Pro Asn Ser Gly Cys Asp Glu Tyr Ala His Tyr Glu Thr
100 105 110
Phe Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 75
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0045
<400> 75
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 Thr Ala Ser Gly Tyr Thr Tyr Ser Arg Ala
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Ala Gly Lys Gln Arg Glu Trp Val
35 40 45
Ser Trp Ile Ile Ala Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Asp Met Thr Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Ala Tyr Asn Gly Gly Asp Arg Cys Tyr Thr Leu Ile Gly Leu Tyr
100 105 110
Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 76
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0049
<400> 76
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 Ala Ala Ser Arg Ala Thr Asn Ser Arg Tyr
20 25 30
Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Ser Ile Gly Arg Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asp Gly Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Thr Ala Trp Arg Asp Trp Ala Thr Leu Arg Glu Tyr Glu Tyr Gly
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 77
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0056
<400> 77
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 Arg Ala Ser Gly His Ala Tyr Gly Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Glu Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Lys Leu Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Leu Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 78
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0057
<400> 78
His 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 Ala Ala Ser Gly His Thr Tyr Ser Ile Tyr
20 25 30
Tyr Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Ile Tyr Arg Gly Gly Ser Thr Thr Tyr Ala Asp Ser Ala Lys
50 55 60
Gly Arg Phe Thr Val Ser Gln Asp Asn Gly Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Ala His Val Leu His Val Ser Ser Leu Leu Pro Gly Gly Tyr Pro
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 79
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0059
<400> 79
His Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Ile Ser Asn Tyr
20 25 30
Tyr Met Thr Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Gly Leu Thr Arg Ala Asp Val Thr Leu Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Ala Asp Arg Phe Arg Val Gly Leu Arg Glu Ala Asp Phe Ser Ala
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 80
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0062
<400> 80
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Arg Asn
20 25 30
Cys Met Gly Trp Phe Arg Gln Thr Pro Gly Lys Glu Arg Glu Arg Val
35 40 45
Ala Thr Val Tyr Pro Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Phe Ser Gln Asp Asn Ala Lys Asn Ala Ile Tyr
65 70 75 80
Leu Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Gly Met Tyr Tyr Cys
85 90 95
Ala Ala Ser Arg Arg Ile Trp Ser Cys Gly Ser Gly Ala Gly Ser Tyr
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 81
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0064
<400> 81
His 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 Ala Ala Ser Gly Tyr Ser Val Ser Trp Phe
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Leu Glu Arg Glu Gly Val
35 40 45
Ala Val Ile Asp Val Asp Ser Ile Ala Arg Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Gly Asn Ser Lys Asp Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Lys Thr Glu Arg Gln Cys Arg Trp Asn Trp Met Asp Trp Arg Thr
100 105 110
Tyr Asp Tyr Pro His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 82
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0065
<400> 82
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 Leu Tyr Thr Asp Ser Leu Phe Trp Met Gly
20 25 30
Trp Phe Arg Gln Thr Pro Gly Asn Glu Arg Glu Gly Val Ala Val Thr
35 40 45
Gly Arg Asp Gly Ser Thr Ile Tyr Ala Asp Ser Val Gln Gly Arg Phe
50 55 60
Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn
65 70 75 80
Ser Leu Lys Pro Asp Asp Thr Ala Met Tyr Tyr Cys Ala Ala Asp Gln
85 90 95
Thr Arg Tyr Ser Ser Leu Arg Leu Leu Ala Pro Asn Arg Ser Ala Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 83
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0071
<400> 83
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 Ala Gly Ser Glu Tyr Thr Tyr Ser Arg Cys
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Val Ser Ile Asn Val Leu Gly Gly Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Gly Leu Ala Ser Ala Pro Trp Arg Pro Cys Gly Thr Thr Thr Glu
100 105 110
Glu Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 84
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0072
<400> 84
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 Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Lys Pro Glu Asp Thr Gly Met Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 85
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0046
<400> 85
Asp 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 Thr Ala Ser Gly Tyr Thr Tyr Ser Arg Ala
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Ala Gly Lys Gln Arg Glu Trp Val
35 40 45
Ser Trp Ile Ile Ala Asp Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Asp Met Thr Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Ala Tyr Asn Gly Gly Asp Arg Cys Tyr Thr Leu Ile Gly Leu Tyr
100 105 110
Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 86
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0058
<400> 86
His 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 Thr Ala Ser Gly Tyr Met Tyr Thr Ser Asp
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Thr Ile Ala Thr Ala Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Met Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Trp Gly Gly Ala Trp Trp Tyr Pro Trp Cys Glu Phe Val Phe
100 105 110
Ser Asn Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 87
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9008
<400> 87
Asp 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 Gln Ala Ser Gly Tyr Thr Gly Gly Gly His
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Asp Arg Glu Gly Ile
35 40 45
Ala Ala Ile Tyr Thr Gly Thr Gly Ser Thr Tyr Tyr Ala Asp Glu Ser
50 55 60
Val Lys Gly Arg Phe Ile Ile Ser Gln Asp Asn Ala Arg Ser Thr Val
65 70 75 80
Tyr Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Gly Met Tyr Tyr
85 90 95
Cys Ala Ala Thr Leu Leu Tyr Gly Cys Gly Ala Trp Ser Pro Arg Leu
100 105 110
Phe Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 88
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9013
<400> 88
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 Ala Ala Ser Gly Tyr Thr Tyr Ser Arg Gly
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ser Phe Leu His Gly Ala Ala Ser Ala Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Met Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Asn Pro Val Val Ala Ser Cys His Tyr Arg Leu Arg Ser Lys
100 105 110
Tyr Ala Tyr Asn Tyr Trp Gly Glu Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 89
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9015
<400> 89
Asp 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 Arg Ala Ser Gly His Ala Tyr Ser Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Glu Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Lys Leu Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Leu Val Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 90
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9025
<400> 90
His Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Asn Val Ser Cys Ala Ala Ser Gly Tyr Thr Phe Asn Gln His
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Gly Phe
35 40 45
Leu Tyr Thr Tyr Val Ser Phe Asn Val Thr His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser His Asp Ser Ala Glu Asn Ala Met Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Gly Pro Glu Asp Ser Gly Met Tyr Tyr Cys
85 90 95
Ala Ala Gly Tyr Tyr Ser Cys Gly Val Ser Thr Thr Gly Tyr Asn Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 91
<211> 130
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9026
<400> 91
His 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 Ala Ala Ser Gly Asp Thr Tyr Ser Ser Lys
20 25 30
Cys Met Ala Trp Phe Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Thr Ser Arg Gly Arg Ala Tyr Leu Thr Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Ser Asn Thr Phe Tyr Asn Cys Gly Ala Leu Asn Leu Gly Ile
100 105 110
Gly Ala Gly Leu Val Ala Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
115 120 125
Ser Ser
130
<210> 92
<211> 129
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-mm-F7
<400> 92
His Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Ile Ser Arg Ala
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Met Val
35 40 45
Ala Arg Val Tyr Ser Asp Gly Ser Gln Ser Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asp Arg Leu Glu Pro Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ala Leu Leu Met Ser Asp Tyr Tyr Ser Cys Arg Val Arg Phe His
100 105 110
Gln Ser Asp Phe Arg Asp Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 93
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-hh-B12
<400> 93
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 Ala Ser Gly Tyr Thr Phe Gly Lys Tyr
20 25 30
Cys Met Gly Trp Ile Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Ser Asp Gly Thr Thr Arg Tyr Ala Asp Ser Val Gln
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Val Leu
65 70 75 80
Glu Met Asn Ser Leu Lys Leu Glu Asp Ser Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Asp Arg Trp Ser Met Lys Tyr Tyr Ser Asp Tyr Ala Leu Phe Pro
100 105 110
Gly Gly Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 94
<211> 130
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1902-2-1-hm-D12
<400> 94
Asp Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Tyr Thr Tyr Arg Asn Tyr
20 25 30
Cys Met Ala Trp Phe Arg Leu Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Asn Met Asn Ser Tyr Asp Trp Thr Asp Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Ala Asn Thr Trp Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Leu Arg Asp Cys Ala Leu Arg Tyr Cys Thr Arg Ser Tyr Cys Thr Arg
100 105 110
Glu Ala His Phe Phe Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
115 120 125
Ser Ser
130
<210> 95
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0097
<400> 95
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly His Ala Tyr Gly Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 96
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9079
<400> 96
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly His Ala Tyr Gly Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Glu Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 97
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9060
<400> 97
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Gln Ile Gln Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 98
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9061
<400> 98
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Gln Ile Asn Ala Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 99
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9062
<400> 99
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Cys Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Cys Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 100
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9077
<400> 100
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Thr Gly Asn Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 101
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN9058
<400> 101
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val
35 40 45
Ser Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 102
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0104
<400> 102
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly His Ala Tyr Gly Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 103
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0100
<400> 103
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly His Ala Tyr Gly Gly Asn
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Val Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala
100 105 110
Arg Ala Tyr Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 104
<211> 127
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0105
<400> 104
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ser Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 105
<211> 174
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GLP-1-9056
<400> 105
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
35 40 45
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
50 55 60
Arg Leu Ser Cys Ala Ala Ser Gly His Ala Tyr Gly Gly Asn Tyr Met
65 70 75 80
Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ala Val
85 90 95
Leu Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
100 105 110
Arg Phe Thr Ile Ser Glu Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln
115 120 125
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Leu
130 135 140
Ala Leu Gly Ser Ala Arg Trp Tyr Thr Ser Ser Leu Asp Ala Arg Ala
145 150 155 160
Tyr Asn Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
165 170
<210> 106
<211> 506
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 0072-PE38
<400> 106
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 Ala Ser Gly Tyr Thr Gly Ser Ser Ser
20 25 30
Tyr Met Gly Trp Phe Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Gln Ile Asn Ser Arg Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Thr Ser Leu Lys Pro Glu Asp Thr Gly Met Tyr Tyr Cys
85 90 95
Ala Glu Arg Phe Gly Pro Thr Phe Tyr Pro Val Pro Leu Gly Ser Asn
100 105 110
Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Glu
115 120 125
Phe Pro Lys Pro Ser Thr Pro Pro Gly Ser Ser Gly Gly Ala Pro Pro
130 135 140
Glu Gly Gly Ser Leu Ala Ala Leu Thr Ala His Gln Ala Cys His Leu
145 150 155 160
Pro Leu Glu Thr Phe Thr Arg His Arg Gln Pro Arg Gly Trp Glu Gln
165 170 175
Leu Glu Gln Cys Gly Tyr Pro Val Gln Arg Leu Val Ala Leu Tyr Leu
180 185 190
Ala Ala Arg Leu Ser Trp Asn Gln Val Asp Gln Val Ile Arg Asn Ala
195 200 205
Leu Ala Ser Pro Gly Ser Gly Gly Asp Leu Gly Glu Ala Ile Arg Glu
210 215 220
Gln Pro Glu Gln Ala Arg Leu Ala Leu Thr Leu Ala Ala Ala Glu Ser
225 230 235 240
Glu Arg Phe Val Arg Gln Gly Thr Gly Asn Asp Glu Ala Gly Ala Ala
245 250 255
Asn Ala Asp Val Val Ser Leu Thr Cys Pro Val Ala Ala Gly Glu Cys
260 265 270
Ala Gly Pro Ala Asp Ser Gly Asp Ala Leu Leu Glu Arg Asn Tyr Pro
275 280 285
Thr Gly Ala Glu Phe Leu Gly Asp Gly Gly Asp Val Ser Phe Ser Thr
290 295 300
Arg Gly Thr Gln Asn Trp Thr Val Glu Arg Leu Leu Gln Ala His Arg
305 310 315 320
Gln Leu Glu Glu Arg Gly Tyr Val Phe Val Gly Tyr His Gly Thr Phe
325 330 335
Leu Glu Ala Ala Gln Ser Ile Val Phe Gly Gly Val Arg Ala Arg Ser
340 345 350
Gln Asp Leu Asp Ala Ile Trp Arg Gly Phe Tyr Ile Ala Gly Asp Pro
355 360 365
Ala Leu Ala Tyr Gly Tyr Ala Gln Asp Gln Glu Pro Asp Ala Arg Gly
370 375 380
Arg Ile Arg Asn Gly Ala Leu Leu Arg Val Tyr Val Pro Arg Ser Ser
385 390 395 400
Leu Pro Gly Phe Tyr Arg Thr Ser Leu Thr Leu Ala Ala Pro Glu Ala
405 410 415
Ala Gly Glu Val Glu Arg Leu Ile Gly His Pro Leu Pro Leu Arg Leu
420 425 430
Asp Ala Ile Thr Gly Pro Glu Glu Glu Gly Gly Arg Leu Glu Thr Ile
435 440 445
Leu Gly Trp Pro Leu Ala Glu Arg Thr Val Val Ile Pro Ser Ala Ile
450 455 460
Pro Thr Asp Pro Arg Asn Val Gly Gly Asp Leu Asp Pro Ser Ser Ile
465 470 475 480
Pro Asp Lys Glu Gln Ala Ile Ser Ala Leu Pro Asp Tyr Ala Ser Gln
485 490 495
Pro Gly Lys Pro Pro Arg Glu Asp Leu Lys
500 505
<210> 107
<211> 385
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0041(OVA)
<400> 107
Gly Ser Ile Gly Ala Ala Ser Met Glu Phe Cys Phe Asp Val Phe Lys
1 5 10 15
Glu Leu Lys Val His His Ala Asn Glu Asn Ile Phe Tyr Cys Pro Ile
20 25 30
Ala Ile Met Ser Ala Leu Ala Met Val Tyr Leu Gly Ala Lys Asp Ser
35 40 45
Thr Arg Thr Gln Ile Asn Lys Val Val Arg Phe Asp Lys Leu Pro Gly
50 55 60
Phe Gly Asp Ser Ile Glu Ala Gln Cys Gly Thr Ser Val Asn Val His
65 70 75 80
Ser Ser Leu Arg Asp Ile Leu Asn Gln Ile Thr Lys Pro Asn Asp Val
85 90 95
Tyr Ser Phe Ser Leu Ala Ser Arg Leu Tyr Ala Glu Glu Arg Tyr Pro
100 105 110
Ile Leu Pro Glu Tyr Leu Gln Cys Val Lys Glu Leu Tyr Arg Gly Gly
115 120 125
Leu Glu Pro Ile Asn Phe Gln Thr Ala Ala Asp Gln Ala Arg Glu Leu
130 135 140
Ile Asn Ser Trp Val Glu Ser Gln Thr Asn Gly Ile Ile Arg Asn Val
145 150 155 160
Leu Gln Pro Ser Ser Val Asp Ser Gln Thr Ala Met Val Leu Val Asn
165 170 175
Ala Ile Val Phe Lys Gly Leu Trp Glu Lys Ala Phe Lys Asp Glu Asp
180 185 190
Thr Gln Ala Met Pro Phe Arg Val Thr Glu Gln Glu Ser Lys Pro Val
195 200 205
Gln Met Met Tyr Gln Ile Gly Leu Phe Arg Val Ala Ser Met Ala Ser
210 215 220
Glu Lys Met Lys Ile Leu Glu Leu Pro Phe Ala Ser Gly Thr Met Ser
225 230 235 240
Met Leu Val Leu Leu Pro Asp Glu Val Ser Gly Leu Glu Gln Leu Glu
245 250 255
Ser Ile Ile Asn Phe Glu Lys Leu Thr Glu Trp Thr Ser Ser Asn Val
260 265 270
Met Glu Glu Arg Lys Ile Lys Val Tyr Leu Pro Arg Met Lys Met Glu
275 280 285
Glu Lys Tyr Asn Leu Thr Ser Val Leu Met Ala Met Gly Ile Thr Asp
290 295 300
Val Phe Ser Ser Ser Ala Asn Leu Ser Gly Ile Ser Ser Ala Glu Ser
305 310 315 320
Leu Lys Ile Ser Gln Ala Val His Ala Ala His Ala Glu Ile Asn Glu
325 330 335
Ala Gly Arg Glu Val Val Gly Ser Ala Glu Ala Gly Val Asp Ala Ala
340 345 350
Ser Val Ser Glu Glu Phe Arg Ala Asp His Pro Phe Leu Phe Cys Ile
355 360 365
Lys His Ile Ala Thr Asn Ala Val Leu Phe Phe Gly Arg Cys Val Ser
370 375 380
Pro
385
<210> 108
<211> 28
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GLP-1
<400> 108
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys
20 25
<210> 109
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> PE-38
<400> 109
Pro Thr Gly Ala Glu Phe Leu Gly Asp Gly Gly Asp Val Ser Phe Ser
1 5 10 15
Thr Arg Gly Thr Gln Asn Trp Thr Val Glu Arg Leu Leu Gln Ala His
20 25 30
Arg Gln Leu Glu Glu Arg Gly Tyr Val Phe Val Gly Tyr His Gly Thr
35 40 45
Phe Leu Glu Ala Ala Gln Ser Ile Val Phe Gly Gly Val Arg Ala Arg
50 55 60
Ser Gln Asp Leu Asp Ala Ile Trp Arg Gly Phe Tyr Ile Ala Gly Asp
65 70 75 80
Pro Ala Leu Ala Tyr Gly Tyr Ala Gln Asp Gln Glu Pro Asp Ala Arg
85 90 95
Gly Arg Ile Arg Asn Gly Ala Leu Leu Arg Val Tyr Val Pro Arg Ser
100 105 110
Ser Leu Pro Gly Phe Tyr Arg Thr Ser Leu Thr Leu Ala Ala Pro Glu
115 120 125
Ala Ala Gly Glu Val Glu Arg Leu Ile Gly His Pro Leu Pro Leu Arg
130 135 140
Leu Asp Ala Ile Thr Gly Pro Glu Glu Glu Gly Gly Arg Leu Glu Thr
145 150 155 160
Ile Leu Gly Trp Pro Leu Ala Glu Arg Thr Val Val Ile Pro Ser Ala
165 170 175
Ile Pro Thr Asp Pro Arg Asn Val Gly Gly Asp Leu Asp Pro Ser Ser
180 185 190
Ile Pro Asp Lys Glu Gln Ala Ile Ser Ala Leu Pro Asp Tyr Ala Ser
195 200 205
Gln Pro Gly Lys Pro Pro Arg Glu Asp Leu Lys
210 215
<210> 110
<211> 129
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SLN0066
<400> 110
His 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 Ala Ser Gly Ile Gly His Gly Phe Asn
20 25 30
Asn Asn Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
35 40 45
Gly Val Ala Ala Val Tyr Thr Gly Gly Gly Thr Pro Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Leu Ser Gln Asp Asn Ala Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Gly Leu Asp Pro Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Ala Asp Ile Trp Arg Thr Tyr Arg Cys Gly Ala Gly Asp
100 105 110
Thr Thr Val Phe Asp Tyr Arg Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
Claims (38)
1.一种通过转铁蛋白结合蛋白将分子转运穿过细胞膜的方法。
2.根据权利要求1所述的方法,其中所述转铁蛋白结合蛋白包括转铁蛋白结合抗体或其片段。
3.根据权利要求1-2中任一项所述的方法,其中所述方法用于将药物递送穿过极化和/或未极化细胞的细胞膜。
4.根据权利要求3所述的方法,其中所述极化和/或未极化细胞在其细胞膜上表达转铁蛋白受体。
5.根据权利要求1-4中任一项所述的方法,其中所述穿过极化细胞的细胞膜的药物递送包括药物的细胞内递送,和/或内吞的药物再循环回到血液循环中。
6.根据权利要求1-5中任一项所述的方法,其中所述穿过未极化细胞的细胞膜的药物递送包括靶向中枢神经系统(CNS)的全身给药的药物穿过血脑屏障(BBB)、口服给药的药物穿过肠上皮、和/或药物穿透实体组织中的多层细胞。
7.根据权利要求1-6中任一项所述的方法,其中所述药物包括治疗或诊断物质。
8.根据权利要求1-7中任一项所述的方法,其中所述药物包括小分子化合物、合成肽、重组蛋白、抗体或抗体片段、酶、核苷酸序列片段、脂质体、脂质纳米颗粒、药物载体、经修饰的病毒和/或基因治疗载体。
9.根据权利要求1-8中任一项所述的方法,其中所述药物通过化学偶联或基因融合而与所述转铁蛋白结合蛋白结合。
10.一种转铁蛋白结合蛋白,能够延长其结合的实体的循环半衰期。
11.根据权利要求10所述的转铁蛋白结合蛋白,其使得包含所述转铁蛋白结合蛋白的融合蛋白能够穿过血脑屏障(BBB)。
12.根据权利要求10-11中任一项所述的转铁蛋白结合蛋白,其用于药物的口服递送。
13.根据权利要求10-12中任一项所述的转铁蛋白结合蛋白,实现其结合的实体胞内递送到表达转铁蛋白受体的细胞。
14.根据权利要求10-13中任一项所述的转铁蛋白结合蛋白,其能够特异性结合转铁蛋白并且不干扰转铁蛋白与转铁蛋白受体1之间的相互作用。
15.根据权利要求10-14中任一项所述的转铁蛋白结合蛋白,其中所述转铁蛋白是人转铁蛋白。
16.根据权利要求10-15中任一项所述的转铁蛋白结合蛋白,其对含铁的铁饱和转铁蛋白的亲和力高于对不含铁的脱铁转铁蛋白的亲和力。
17.根据权利要求10-16中任一项所述的转铁蛋白结合蛋白,其包含单克隆抗体、单链抗体片段、单结构域抗体片段、工程蛋白或肽。
18.根据权利要求10-17中任一项所述的转铁蛋白结合蛋白,其中所述抗体或抗体片段包含动物来源的序列、人源化序列、全人源序列、嵌合序列或合成序列。
19.根据权利要求10-18中任一项所述的转铁蛋白结合蛋白,其中所述抗体或抗体片段是单结构域抗体片段VHH。
20.根据权利要求10-19中任一项所述的转铁蛋白结合蛋白,其包含CDR3,其中所述CDR3包含如SEQ ID NO:45-69中任一项所示的氨基酸序列。
21.根据权利要求10-20中任一项所述的转铁蛋白结合蛋白,其包含CDR2,其中所述CDR2包含如SEQ ID NO:22-44中任一项所示的氨基酸序列。
22.根据权利要求10-21中任一项所述的转铁蛋白结合蛋白,其包含CDR1,其中所述CDR1包含如SEQ ID NO:1-21中任一项所示的氨基酸序列。
23.根据权利要求10-22中任一项所述的转铁蛋白结合蛋白,其包含重链可变区VH,且所述重链可变区VH包含如SEQ ID NO:70-104中任一项所示的氨基酸序列。
24.一种多肽,其包含权利要求10-23中任一项的转铁蛋白结合蛋白和治疗实体。
25.根据权利要求24中任一项所述的多肽,其中所述治疗实体是工程细胞毒性假单胞菌外毒素A(PE38)。
26.根据权利要求24中任一项所述的多肽,其中所述治疗实体为胰高血糖素样肽-1(GLP-1)或其变体。
27.根据权利要求24-26中任一项所述的多肽,其中所述治疗实体与所述抗原结合蛋白直接或间接连接。
28.根据权利要求24-26中任一项所述的多肽,其中所述治疗实体与所述转铁蛋白结合蛋白通过连接子连接。
29.一种或多种分离的核酸分子,其编码权利要求10-23中任一项的转铁蛋白结合蛋白或权利要求24-29中任一项的多肽。
30.一种载体,其包含权利要求29的核酸分子。
31.一种细胞,其包含权利要求32的核酸分子或权利要求30的载体。
32.一种方法,其用于制备权利要求10-23中任一项的转铁蛋白结合蛋白或权利要求24-26
中任一项的多肽,所述方法包括在允许所述转铁蛋白结合蛋白或所述多肽表达的条件下培养权利要求31的细胞。
33.一种药物组合物,其包含权利要求10-23中任一项的转铁蛋白结合蛋白、权利要求24-26中任一项的多肽。
34.一种用于延长治疗实体的循环半衰期的方法,其中所述治疗实体与权利要求10-23中任一项的转铁蛋白结合蛋白直接或间接连接。
35.一种用于将治疗药物或诊断剂递送至表达转铁蛋白受体的细胞或器官的方法,其包括使用权利要求10-23中任一项的转铁蛋白结合实体。
36.一种用于递送靶向药物穿过血脑屏障、肠上皮和/或表达转铁蛋白受体的细胞膜的方法,其包括使用权利要求10-23的转铁蛋白结合实体。
37.一种用于口服递送治疗或诊断实体的方法,其中所述治疗或诊断实体与权利要求10-23中任一项所述抗原结合蛋白直接或间接连接。
38.一种用于治疗实体的细胞内递送的方法,其中所述治疗实体与权利要求10-23中任一项所述抗原结合蛋白直接或间接连接。
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