CN111051350A - 包含信号调节蛋白α的免疫缀合物 - Google Patents
包含信号调节蛋白α的免疫缀合物 Download PDFInfo
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Abstract
提供了可用于抑制肿瘤生长的免疫缀合物,以及包含该免疫缀合物的组合物和/或蛋白质混合物。还提供了产生该免疫缀合物的方法,以及该免疫缀合物在抑制肿瘤生长方面的药物用途,包括但不限于癌症的治疗。
Description
背景技术
信号调节蛋白α(SIRPα),也称为SHPS-1、BIT或CD172a,是免疫球蛋白超家族蛋白,其通过其细胞质区域与蛋白酪氨酸磷酸酶SHP-1和SHP-2结合,以产生潜在的负信号。SIRPα在诸如巨噬细胞和树突状细胞等骨髓谱系造血细胞中特别丰富(Reinhold等,1997.Costimulation of T cell activation by integrin-associated protein(CD47)is an adhesion-dependent,CD28-independent signaling pathway.J Exp Med185:1-11)。CD47-SIRPα相互作用以“不要吃我”的信号发挥功能,以确保自体细胞不会被不适当地吞噬。
然而,SIRPα的全身性表达可导致不期望的副作用。另外,当SIRPα单独表达时,其体内半衰期可能相对较短,并且可能无法高效地到达作用部位。因此,需要CD47-SIRPα信号传导的新型有效的调节剂。
发明内容
本申请提供了可用于抑制肿瘤生长的免疫缀合物,以及包含该免疫缀合物的组合物和/或蛋白质混合物。本申请还提供了产生所述免疫缀合物的方法,以及所述免疫缀合物在抑制肿瘤生长中的药物用途,包括但不限于癌症的治疗。
一方面,本申请提供了免疫缀合物,其包含:a)靶向部分,其中所述靶向部分显示出对肿瘤相关抗原的结合特异性;b)由第一Fc亚基和第二Fc亚基组成的Fc结构域,其中所述第一Fc亚基与第二Fc亚基缔合以形成二聚体;以及c)单拷贝的信号调节蛋白α(SIRPα)。
在一些实施方案中,所述SIRPα不是CV1变体。
在一些实施方案中,所述SIRPα是人野生型SIRPα。
在一些实施方案中,所述SIRPα包含如SEQ ID NO:122或123中所示的氨基酸序列。
在一些实施方案中,所述靶向部分包含抗体的抗原结合结构域,并且所述抗体选自下组:抗EGFRVIII、抗HER2/neu、抗PD-L1和抗Muc1。
在一些实施方案中,所述抗体是抗PD-L1抗体。例如,抗PD-L1抗体可选自下组:阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56。
在一些实施方案中,Fc结构域是IgG Fc结构域。在一些实施方案中,所述IgG是人IgG1。
在一些实施方案中,免疫缀合物是蛋白质性质的异二聚体,其包含第一成员和不同于所述第一成员的第二成员,其中所述第一成员包含至少一个与Fc结构域的两个亚基之一融合的靶向部分,并且所述第二成员包含与Fc结构域的两个亚基中的另一个融合的所述单拷贝的SIRPα,并且所述第一Fc亚基与所述第二Fc亚基缔合,形成所述异二聚体。
在一些实施方案中,所述靶向部分与所述Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接融合,并且SIRPα的单拷贝与Fc结构域的两个亚基的另一个亚基的氨基末端氨基酸直接或间接融合。
在一些实施方案中,所述免疫缀合物包含两个靶向部分,它们是第一靶向部分和第二靶向部分。
在一些实施方案中,所述第一靶向部分与所述Fc结构域的两个亚基之一直接或间接融合,并且所述第二靶向部分与所述Fc结构域的所述两个亚基的另一个亚基直接或间接融合。
在一些实施方案中,所述免疫缀合物是蛋白质性质的异二聚体。蛋白质性质的异源二聚体可包含第一成员和不同于第一成员的第二成员,其中:所述第一成员可包含与所述Fc结构域的两个亚基之一融合的所述第一靶向部分;所述第二成员可包含单拷贝的SIRPα、第二靶向部分和Fc结构域的两个亚基中的另一个,其中单拷贝的SIRPα与所述Fc亚基的一个末端融合,并且第二靶向部分与Fc亚基的另一个末端整合;以及所述第一Fc亚基与所述第二Fc亚基缔合,形成异二聚体。例如,所述第一靶向部分可与所述Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接融合,所述第二靶向部分可与Fc结构域的两个亚基中的另一个的氨基末端氨基酸直接或间接融合,并且单拷贝的SIRPα可与第一或第二Fc亚基的羧基末端氨基酸直接或间接融合。
在一些实施方案中,所述第一Fc亚基不同于第二Fc亚基,并且所述Fc结构域包含促进所述第一Fc亚基与所述第二Fc亚基之间的异二聚体化的修饰。例如,所述第一Fc亚基可包含第一修饰,第二Fc亚基包含第二修饰,并且所述第一修饰在2-5个位置处包含氨基酸取代。例如,所述第一修饰可在选自以下任意组的位置处包含氨基酸取代:1)第一修饰:Y349和T366;和第二修饰:D356、T366、L368、Y407和F405;2)第一修饰:Y349、T366和F405;和第二修饰:D356、T366、L368和Y407;3)第一修饰:Y349、T366和K409;和第二修饰:D356、T366、L368、Y407和F405;4)第一修饰:Y349、T366、F405、K360和Q347;和第二修饰:D356、T366、L368、Y407和Q347;5)第一修饰:Y349、T366、F405和Q347;和第二修饰:D356、T366、L368、Y407、K360和Q347;6)第一修饰:Y349、T366、K409、K360和Q347;和第二修饰:D356、T366、L368、Y407、F405和Q347;7)第一修饰:Y349、T366、K409和Q347;和第二修饰:D356、T366、L368、Y407、F405、K360和Q347;8)第一修饰:T366、K409和K392;和第二修饰:T366、L368、Y407、D399和F405;9)第一修饰:T366和K409;和第二修饰:T366、L368、Y407和F405;10)第一修饰:T366、K409和Y349;和第二修饰:T366、L368、Y407、F405和E357;11)第一修饰:T366、K409、Y349和S354;和第二修饰:T366、L368、Y407、F405和E357;12)第一修饰:T366和F405;和第二修饰:T366、L368、Y407和K409;13)第一修饰:T366、F405和D399;和第二修饰:T366、L368、Y407、K409和K392;14)第一修饰:T366、F405和Y349;和第二修饰:T366、L368、Y407、K409和E357;15)第一修饰:T366、F405、Y349和S354;和第二修饰:T366、L368、Y407、K409和E357;其中氨基酸的位置根据KABAT编号的EU索引来确定。
在一些实施方案中,将单拷贝的SIRPα与包含所述第二修饰的所述第二Fc亚基直接或间接融合。
在一个方面,本申请提供了编码本申请的所述免疫缀合物的一种或多种分离的核酸。
在一个方面,本申请提供了包含本申请的一种或多种分离的核酸的一种或多种载体。
在一个方面,本申请提供了包含本申请的一种或多种分离的核酸或本申请的一种或多种载体的分离的宿主细胞。
在一个方面,本申请提供了产生本申请的免疫缀合物或蛋白质混合物的方法。该方法可包括(i)在实现本申请的免疫缀合物的表达和形成的条件下培养本申请的宿主细胞,以及(ii)收获形成的免疫缀合物或包含该免疫缀合物的蛋白质混合物。
在一个方面,本申请提供了药物组合物,其包含有效量的本申请的免疫缀合物和任选地药学上可接受的赋形剂。
在一些实施方案中,所述药物组合物还包含有效量的用于癌症治疗的另外的治疗活性组分。例如,用于癌症治疗的另外的治疗活性组分可以是化学治疗剂。在一些实施方案中,所述化学治疗剂是细胞毒性剂。例如,细胞毒性剂可包含多柔比星。
在一个方面,本申请提供了本申请的免疫缀合物、蛋白质混合物或药物组合物在制备用于治疗有此需要的受试者的疾病的药物方面的用途。
在一个方面,本申请提供了治疗有此需要的受试者的疾病的方法,该方法包括向受试者施用有效量的本申请的免疫缀合物、蛋白质混合物或药物组合物。
在一些实施方案中,所述疾病是癌症。例如,所述癌症可选自:乳腺癌、黑色素瘤和结肠癌。
通过下面的详细描述,本申请的其他方面和有利方面对于本领域技术人员将变得显而易见,其中仅显示和描述了本申请的说明性实施方案。如将会认识到的,本申请能够具有其他和不同的实施方案,并且其若干细节能够在各种显而易见的方面进行修改,所有这些都不脱离本申请。因此,附图和描述本质上应被认为是说明性的,而不是限制性的。
通过引用并入
在本说明书中提及的所有出版物,专利和专利申请都以相同的程度通过引用并入本文,就好像每个单独的出版物、专利或专利申请被明确地和单独地指出通过引用并入一样。
附图说明
在所附权利要求书中具体地阐述了本申请的新颖特征。通过参考说明性实施方案(其中采用了本申请的原理)以及附图(在本文中也称为“图(figure)”和“图(Fig)”)中阐述的下面的详细说明,可以更好地理解本申请的特征和有利方面,其中:
图1a-1b显示的是本申请的免疫缀合物的实例。
图2显示的是通过SDS-PAGE分析显示的本申请的免疫缀合物的纯化结果。
图3显示的是通过FACS分析显示的本申请的免疫缀合物的结合亲和力。
图4显示的是本申请的免疫缀合物的体外促吞噬(pro-phagocytosis)活性的结果。
图5显示的是本申请的免疫缀合物的肿瘤结合亲和力的结果。
图6a-6h显示的是通过流式细胞术结果显示的本申请的免疫缀合物的结合亲和力。
图7a-7b显示的是本申请的免疫缀合物的血小板结合结果。
图8a-8i显示的是本申请的免疫缀合物的体内抗肿瘤功效和安全性。
图9显示的是当与化学疗法联合使用时,本申请的免疫缀合物的作用。
图10显示的是本申请的免疫缀合物的体内作用。
具体实施方式
尽管本文中已显示并描述了本申请的各种实施方案,但对于本领域技术人员而言显而易见的是,此类实施方案仅以实例的方式提供。在不脱离本申请的情况下,本领域技术人员可以想到许多变化、改变和替换。应当理解,可采用本文描述的本申请的实施方案的各种替代方案。
如本文中所用,术语“免疫缀合物”通常是指通过将一种或多种抗体或其片段与一种或多种第二分子缀合而形成的蛋白质性质的分子。第二分子可以相同或不同,并且可包括例如效应蛋白。
如本文中所用,术语“靶向部分”通常是指特异性地、选择性地或优先地与靶分子、细胞、颗粒、组织或聚集体结合的分子、复合物或聚集体。例如,靶向部分可以是抗体、抗原结合抗体片段、双特异性抗体或其他基于抗体的分子或化合物。靶向部分的其他实例可包括但不限于适体、高亲合性多聚体(avimers)、受体结合配体、核酸、生物素-抗生物素结合蛋白(biotin-avidin)结合对、结合肽或蛋白质等。术语“靶向部分”和“结合部分”在本文中可互换使用。
如本文中所用,术语“结合特异性”通常是指一种物质与另一种物质特异性结合,并且不容易随机地结合任何其他物质的能力。例如,一种蛋白质可能与另一种蛋白质由于他们的特定结构而特异性结合。例如,靶向部分可表现出与相应的肿瘤相关抗原的结合特异性。
如本文中所用,术语“肿瘤相关抗原”通常是指与肿瘤细胞相关的抗原性物质,其可具有在宿主中触发免疫反应或指示宿主可能患有肿瘤的能力。例如,肿瘤相关抗原可以是蛋白质、多肽、肽或其片段,其构成肿瘤细胞的一部分并且能够诱导肿瘤特异性细胞毒性T淋巴细胞。肿瘤相关抗原肽可以是由于肿瘤相关抗原在肿瘤细胞中降解而产生的肽,并且可在表达于细胞表面时诱导或激活肿瘤特异性细胞毒性T淋巴细胞。在一些实施方案中,术语“肿瘤相关抗原”还可指在癌细胞上专门或优先或差异表达和/或被发现与癌细胞相关联,从而提供对癌症优先或特异的靶标的生物分子(例如,蛋白质、碳水化合物、糖蛋白等)。例如,优先表达可以是与生物中的任何其他细胞相比的优先表达,或在生物的特定区域内(例如在特定器官或组织内)的优先表达。
如本文中所用,术语“Fc结构域”通常是指抗体重链的Fc部分或Fc片段。例如,其可指免疫球蛋白重链恒定区的羧基末端部分,或能够结合Fc受体的类似物或其部分。众所周知,每个免疫球蛋白重链恒定区包含四个或五个结构域。结构域的命名依次如下:CH1-铰链-CH2-CH3(-CH4)。CH4存在于IgM中,所述IgM没有铰链区。可用于本申请的免疫球蛋白重链恒定区可包含免疫球蛋白铰链区,并且还可包含CH3结构域。例如,免疫球蛋白重链恒定区可包含免疫球蛋白铰链区、CH2结构域和CH3结构域。在一些实施方案中,本申请的Fc区由铰链-CH2-CH3结构域组成。
如本文中所用,术语“Fc亚基”通常是指Fc结构域的组分。例如,Fc结构域可由两个或更多个成员形成,并且每个成员可被认为是一个Fc亚基。
如本文中所用,术语“SIRPα”通常是指信号调节蛋白α或其片段。SIRPα是SIRP家族的调节性膜糖蛋白,主要由髓样细胞表达,也可由干细胞或神经元表达。SIRPα可以是人SIRPα或其功能变体。
如本文中所用,术语“CV1变体”通常是指SIRPα的共有变体1。其是由于在主要的野生型人SIRPα等位基因上进行9个移植的保守性取代而产生的,CV1变体可以以11.1pM的亲和力结合人CD 47(Kipp Weiskopf等,Science.2013年7月5日;341(6141))。因此,CV1可以与内源性SIRPα竞争结合CD47。然而,作为无Fc拮抗剂,其不能抑制体内癌症的生长。研究发现CV1与其他治疗性mAb之间的协同作用很显着,以致在ADCC存在的情况下仍有高估CD47-SIRPα相互作用的可能性(Yuting Huang等,J Thorac Dis.2017Feb;9(2):E168–E174)。
如本文中所用,术语“单拷贝”通常是指特定的蛋白质或元件或特征在分子、缀合物或复合物中仅作为一个拷贝存在的事实。
如本文中所用,术语“肽接头”通常是指连接或链接两个多肽序列,例如链接两个多肽结构域,的合成氨基酸序列。接头可通过肽键连接两个氨基酸序列。在一些实施方案中,本申请的接头以线性序列将生物活性部分与第二部分连接。术语“肽”和“蛋白质”在本文可互换使用,是指任意长度的氨基酸的聚合物。该聚合物可以是直链或支链的,其可包含经修饰的氨基酸,并且其可被非-氨基酸中断。所述肽还涵盖已修饰的氨基酸聚合物,例如通过二硫键形成、糖基化、脂化、乙酰化、磷酸化或任何其他操作(诸如与标记组分缀合)。所述肽可应用于其中一个或多个氨基酸残基是相应的天然存在的氨基酸的人工化学类似物的氨基酸聚合物,以及天然存在的氨基酸聚合物。所述肽还可包括连接构成多肽的氨基酸的常规肽键联的变体。肽也可以基本上包括任何聚氨基酸,包括但不限于肽模拟物,诸如通过醚而不是酰胺键连接的氨基酸。
如本文中所用,术语“氨基末端”通常是指肽的氨基末端处的氨基酸上的游离α-氨基或肽内任何其他位置处的氨基酸的α-氨基(参与肽键时的氨基)。
如本文中所用,术语“免疫球蛋白铰链区”通常是指免疫球蛋白的铰链区,例如,免疫球蛋白铰链区可以是IgG1铰链、IgG2铰链、IgG3铰链或IgG4铰链。术语“IgG1铰链”在本文中用于指来自天然IgG1(诸如天然人、小鼠、兔等IgG1)的铰链区、天然存在的IgG1铰链之一的衍生物,诸如与天然IgG1铰链具有至少95%、90%、85%、80%、75%、70%或65%的氨基酸同一性,并保留IgG1铰链的基本功能特征的衍生物。术语“铰链区”通常是指连接CH1结构域与CH2结构域的重链分子的部分。该铰链区可包含约25个残基并且可以是柔性的,从而允许N末端抗原结合区独立移动。铰链区域可细分为三个不同的区域:上部、中部和下部铰链结构域(Roux等J.Immunol.1998 161:4083)。
如本文中所用,术语“免疫球蛋白”通常是指由基本上由免疫球蛋白基因编码的一种或多种多肽组成的蛋白质。公认的免疫球蛋白基因包括κ、λ、α、γ(IgG1、IgG2、IgG3、IgG4)、δ、ε和μ恒定区基因,以及无数免疫球蛋白可变区基因。免疫球蛋白的一种形式构成抗体的基本结构单元。这种形式是四聚体,由两对相同的免疫球蛋白链组成,每对具有一条轻链和一条重链。在每对中,轻链和重链可变区共同负责与抗原的结合,恒定区负责抗体效应子的功能。除了抗体以外,免疫球蛋白还可以以多种其他形式存在,包括例如Fv、Fab、Fab'和(Fab')2。
如本文中所用,术语“抗体的抗原结合结构域”通常是指参与抗原结合的抗体的一部分。抗原结合结构域可由重(“H”)链和/或轻(“L”)链的N末端可变(“V”)区的氨基酸残基形成。重链和轻链的V区内的三个高度趋异的区段称为“高变区”。在抗体分子中,轻链的三个高变区和重链的三个高变区在三维空间中彼此相对布置,以形成抗原结合“表面”。该表面可介导靶抗原的识别和结合。每一个重链和轻链中的三个高变区被称为“互补决定区”或“CDR”,并且例如由Kabat等Sequences of proteins of immunological interest,第4版U.S.Dept.Health and Human Services,Public Health Services,Bethesda,Md.(1987)表征。
如本文中所用,术语“Fab”通常是指免疫球蛋白分子的一部分(诸如抗原结合片段)。Fab片段可包含一条轻链和具有单个抗原结合位点的重链的一部分。Fab片段可通过木瓜蛋白酶消化免疫球蛋白分子而获得。例如,Fab片段可以由重链和轻链各自的一个恒定结构域和一个可变结构域组成。可变结构域可在免疫球蛋白分子的氨基末端包含互补位(抗原结合位点),其包含一组互补决定区。木瓜蛋白酶可用于将免疫球蛋白分子切割成两个Fab片段和一个Fc片段。胃蛋白酶在铰链区下方切割,因此形成F(ab')2片段和Fc片段。
如本文中所用,术语“结构域抗体”通常是指单结构域抗体,也称为sdAb或纳米抗体。结构域抗体是由单个单体可变抗体结构域组成的抗体片段。像完整抗体一样,其能够选择性结合特定抗原。单结构域抗体的分子量仅为12–15kDa,远小于由两条重蛋白链和两条轻链组成的普通抗体(150–160kDa),甚至比Fab片段(~50kDa,一条轻链和半条重链)和单链可变片段(~25kDa,两个可变结构域,一个来自轻链,一个来自重链)小。
如本文中所用,术语“ScFv”通常是指单链抗体片段。ScFv可指其中抗体的轻链和重链可变区通过肽接头连接的重组单链多肽分子。尽管已知用于将此类区域添加到已知的ScFv分子(如果需要的话)的方法,单链抗体(ScFv)通常不包括参与效应子功能的抗体Fc区的一部分,因此是裸露的抗体。参见Helfrich等,Arapid and versatile method forharnessing ScFv antibody fragments with various biological functions.JImmunol Methods 237:131-145(2000)和de Haard等,Creating and engineering humanantibodies for immunotherapy.Advanced Drug Delivery Reviews 31:5-31(1998)。
如本文中所用,术语“抗EGFR抗体”通常是指特异性或优先结合EGFR的抗体。在一些情况下,抗EGFR抗体可与EGFR的突变形式(例如,EGFR变体III(也称为EGFRvIII),其为EGFR的最常见的细胞外结构域突变,这种突变导致EGFR基因的外显子2-7缺失,其特征在于具有不依赖配体的组成型活性的截短的细胞外结构域)结合。例如,抗EGFR抗体可以是西妥昔单抗(Cetuximab)、Mab806或其抗原结合片段。
如本文中所用,术语“抗HER2抗体”通常是指特异性或优先结合HER2/neu受体的抗体。例如,抗HER2/neu抗体或抗HER2抗体可以是曲妥珠单抗(Trastuzumab)、帕妥珠单抗(Pertuzumab)或其抗原结合片段。
如本文中所用,术语“抗PD-L1抗体”通常是指特异性或优先结合程序性死亡配体1(PD-L1)的抗体。例如,抗PD-L1抗体可以是阿特朱单抗(Atezolizumab)、阿维单抗(Avelumab)、度伐鲁单抗(Durvalumab)、KN035或hu56。阿特朱单抗是针对PD-L1的IgG1同种型的人源化工程单克隆抗体(来自Genentech/Roche)。KN035是PD-L1单结构域抗体Fc(IgG1同种型)融合蛋白,也称为hu56V2-Fc(如CN106397592A中所述),而hu56是针对PD-L1的人单结构域抗体(如CN106397592A中所述)。并根据抗体Kabat的定义确定抗体CDR的位置。阿维单抗是由Merck KGaA和Pfizer开发的完全人单克隆抗体,是用于免疫疗法的药物,最初用于治疗非小细胞肺癌,并靶向蛋白质PD-L1。度伐鲁单抗是可阻断PD-L1与PD1的相互作用的人免疫球蛋白G1κ(IgG1κ)单克隆抗体(来自Medimmune/AstraZeneca)。如本文中所用,术语“IgG”通常是指抗体的亚型。每个IgG具有两个抗原结合位点。作为人体中约75%的血清抗体,IgG是存在于循环中的最常见的抗体类型。一些已知的免疫球蛋白基因包括κ、λ、α和γ(IgG1、IgG2、IgG3和IgG4)。
如本文中所用,术语“框内”通常是指以维持每个原始ORF的正确阅读框的方式,连接两个或两个以上开放阅读框架(ORFs)以形成连续的更长的ORF。
如本文中所用,术语“蛋白质性质的”通常是指属于多肽或蛋白质,与多肽或蛋白质相关,类似于多肽或蛋白质或者为多肽或蛋白质的材料或分子。例如,本申请的蛋白质性质的异二聚体可以是异二聚体蛋白质,或包含两个或更多个多肽的异二聚体。
如本文中所用,术语“异二聚体”通常是指由两个不同的成员(即,两个不同的单体)组成的分子(例如,蛋白质性质的分子)。异二聚体的两个成员可以在结构、功能、活性和/或组成上不同。例如,两个不同的成员可包含多肽,这些多肽在形成这些多肽的氨基酸残基的顺序、数量或种类方面不同。异二聚体的两个不同成员中的每一个可独立地包含一个、两个或多个单元、多肽链或部分。所述两个成员可通过共价和/或非共价相互作用彼此聚集、复合或缔合。例如,所述两种不同的单体可以通过来自两种单体中的每一种的界面氨基酸残基之间的相互作用而彼此缔合。
如本文中所用,术语“促进异二聚体化的修饰”通常是指促进异二聚体化过程的修饰。并且如本文中所用的术语异二聚体化通常是指诸如通过络合、缔合或聚集在两个不同成员(例如,两个不同多肽)之间形成异二聚体(其中在两个不同成员之间形成或未形成共价键)的过程。
如本文中所用,术语“抗CD47单抗隆抗体”通常是指特异性或优先结合CD47的单克隆抗体。例如,抗CD47单克隆抗体可以是AB6.12 IgG1。在另一个实例中,抗CD47单克隆抗体可以是B6H12.2。
如本文中所用,术语“蛋白质混合物”通常是指两种或两种以上类型的蛋白质的混合物。
如本文中所用,术语“同二聚体”通常是指由两个相同的单体(例如,两个相同的成员或亚基)形成的分子。所述两个单体可通过共价和/或非共价相互作用彼此聚集、复合或缔合。例如,所述两种相同的单体可通过来自两种单体中的每一种的界面氨基酸残基之间的相互作用而彼此缔合。
如本文中所用,术语“约”通常是指对给定值的近似值,其将基于本领域普通技术人员合理地推断出,包括由于该给定值的实验和/或测量条件而引起的等效和近似值。例如,其可以指高于或低于该术语所修改的值不超过10%的值。例如,术语“约5μg/kg”是指4.5μg/kg至5.5μg/kg的范围。作为另一个实例,“约1小时”意指48分钟至72分钟的范围。
如本文中所用,术语“基本上不包含”通常是指组合物(例如,混合物)很少或几乎不包含特定物质。例如,特定物质可以以例如小于10%、小于9%、小于8%、小于7%、小于6%、小于5%、小于4%、小于3%、小于2%、小于1%、小于0.5%、小于0.1%或小于0.01%的百分比存在。
如本文中所用,术语“实现表达的条件”通常是指影响本申请的免疫缀合物的表达的条件。在一些实施方案中,实现表达的条件包括但不限于孵育时间、温度和培养基,并且可取决于细胞类型并且可由本领域普通技术人员容易地确定。在一些实施方案中,在产生本申请的免疫缀合物或蛋白质混合物的过程中,将宿主细胞在培养物中以及在可用于生长培养物的任何装置(包括发酵罐)中生长。细胞可在单层生长或附着在表面上。或者,宿主细胞可悬浮生长。细胞可在无血清的培养基中生长。培养基可以是商购可得的培养基,诸如但不限于补充有谷氨酰胺(诸如8mM L-谷氨酰胺)的Opti-CHO(Invitrogen,目录号#12681);补充有10%小牛血清、10.5ng/ml mIL-3和L-谷氨酰胺的RPMI 1640培养基;或5%FCS培养基。
如本文中所用,术语“药学上可接受的赋形剂”通常是指与药物施用相容的任何和所有溶剂、分散介质、包衣、等渗剂和吸收延迟剂等。
如本文中所用,术语“用于癌症治疗的治疗活性组分”通常是指具有用于治疗癌症的治疗活性的任何组分。例如,用于癌症治疗的治疗活性组分可以是化学治疗剂。
如本文中所用,术语“化学治疗剂”通常是指在用于癌症治疗的化学疗法中使用的试剂。例如,化学治疗剂可包括但不限于细胞毒性剂、烷化剂、抗代谢剂、抗肿瘤抗生素剂和抗肿瘤激素。
如本文中所用,术语“细胞毒性剂”通常是指具有细胞毒性的试剂。例如,细胞毒性剂可包含多柔比星。
如本文中所用,术语“有效量”通常是指足以提供足够高的浓度以对其接受者赋予有益作用的剂量。任何特定受试者的具体治疗有效剂量水平将取决于多种因素,包括所治疗的病症、病症的严重程度、特定组分的活性、施用途径、清除率、治疗持续时间、受试者的年龄、体重、性别、饮食和总体健康状况以及其他相关因素。
如本文中所用,术语“与......复合”通常是指分子(例如,抗体)的一个成员/亚基与另一成员/亚基的缔合(例如,结合)。例如,轻链可以与重链复合以形成靶向部分。在另一个实例中,第一Fc亚基可与第二Fc亚基复合以形成Fc二聚体(Fc区)。
如本文中所用,术语“结合特异性”通常是指特异性结合(例如,与......免疫反应)给定靶标(但不结合或基本上不结合非靶标)的能力。本申请的靶向部分可以是单特异性的,并且包含一个或多个特异性结合靶标的结合位点,或者可以是多特异性的(例如,双特异性或三特异性),并且包含两个或两个以上特异性结合相同或不同靶标的结合位点。
如本文中所用,术语“修饰”通常是指对多肽主链(例如氨基酸序列)的任何操作或多肽的任何翻译后修饰(例如糖基化)。例如,修饰是与相应野生型多肽的序列的比较。修饰可以是一个或多个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个或更多个)氨基酸的取代、添加和/或缺失。
如本文中所用,术语“融合蛋白”通常是指包含与异源多肽(即,与前一个多肽或其结构域无关的多肽)的氨基酸序列直接或间接(例如,通过接头)融合的多肽的氨基酸序列的多肽,或者可选地由所述融合多肽的氨基酸组成的多肽。
如本文中所用,术语“C-端”通常是指多肽的羧基端。
如本文中所用,术语“N-端”通常是指多肽的氨基端。
如本文中所用,术语“EGFR”通常是指表皮生长因子受体,例如,参见Carpenter等Ann.Rev.Biochem.56:881-914(1987),包括其天然存在的突变体形式。
如本文中所用,术语“EGFR突变体”通常是指EGFR的突变形式,例如,EGFR变体III(也称为EGFRvIII),其为EGFR的最常见的细胞外结构域突变,这种突变导致EGFR基因的外显子2-7缺失,其特征在于具有不依赖配体的组成型活性的截短的细胞外结构域。
如本文中所用,术语“HER2/neu”通常是指例如Semba等PNAS(USA)82:6497-6501(1985)和Yamamoto等Nature 319:230-234(1986)(GenBank登录号X03363)中的人HER2蛋白。
如本文中所用,术语“Muc1”通常是指由muc1基因编码的糖蛋白。Muc1主要存在于乳腺、胰腺、卵巢等的上皮组织和器官中。其在癌症上皮细胞表面高度表达,因此成为免疫反应的靶标。
如本文中所用,术语“氨基酸取代”通常是指在多肽的特定位置处的一个氨基酸被另一种氨基酸取代。
如本文中所用,术语“KABAT编号的EU索引”通常是指对应于根据Kabat等(1971)Ann.NY Acad,Sci.190:382-391和Kabat,E.A.等(1991)Insequences of Proteins ofImmunological Interest,第五版,U.S.Department of Health and Human Services,NIHPublication No.91-3242的氨基酸序列的EU编号的索引。
如本文中所用,术语“分离的多核苷酸”通常是指从其天然环境分离或人工合成的具有任意长度的核苷酸(脱氧核糖核苷酸或核糖核苷酸)的聚合形式,或其类似物。
免疫缀合物、蛋白质混合物、分离的核苷酸、载体和宿主细胞
在一个方面,本申请提供了免疫缀合物,其包含:a)靶向部分,其中所述靶向部分表现出对肿瘤相关抗原的结合特异性;b)由第一Fc亚基和第二Fc亚基组成的Fc结构域,其中第一Fc亚基与第二Fc亚基缔合以形成二聚体;以及c)单拷贝的信号调节蛋白α(SIRPα)。
可将单拷贝的SIRPα与所述Fc结构域的所述第一Fc亚基或所述第二Fc亚基的氨基末端或羧基末端氨基酸直接或间接融合。例如,单拷贝的SIRPα可通过肽接头与所述Fc结构域的第一Fc亚基或第二Fc亚基间接融合。接头可以是包含1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24、25个或更多个氨基酸的肽。例如,接头可包含1-10个氨基酸(例如,1个、2个、3个、4个、5个、6个、7个、8个、9个、10个或更多个氨基酸)、1-15个氨基酸(例如1-11个、12个、13个、14个、15个氨基酸)、1-20个氨基酸、1-30个氨基酸或更多个氨基酸。在一些实施方案中,所述接头包含如SEQ ID NO:53、58、65、68或71中所示的氨基酸序列。
例如,可将单拷贝的SIRPα与所述Fc结构域的所述第一Fc亚基或第二Fc亚基框内融合。
所述SIRPα可以是野生型信号调节蛋白α,或具有野生型信号调节蛋白α的氨基酸序列的重组或非重组多肽的氨基酸序列,或信号调节蛋白α的天然等位基因变体或天然存在的等位基因变体。在一些实施方案中,所述SIRPα是野生型哺乳动物SIRPα,例如,所述SIRPα是野生型人SIRPα。不含信号肽的主要野生型人SIRPα(SIRPαV2)的成熟形式的氨基酸序列可以如SEQ ID NO:122中所示。所述SIRPα可包括信号肽。例如,具有信号肽的人SIRPα(SIRPαV2)的氨基酸序列可以如SEQ ID NO:123中所示。
可将所述靶向部分与所述Fc结构域的第一Fc亚基和/或第二Fc亚基的氨基末端或羧基末端氨基酸直接或间接融合。例如,可将所述靶向部分通过肽接头或免疫球蛋白铰链区与Fc结构域的第一Fc亚基或第二Fc亚基间接融合。所述接头可以是包含1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个、25个或更多个氨基酸的肽。例如,接头可包含1-10个氨基酸(例如,1个、2个、3个、4个、5个、6个、7个、8个、9个、10个或更多个氨基酸)、1-15个氨基酸(例如1-11个、12个、13个、14个、15个氨基酸)、1-20个氨基酸、1-30个氨基酸或更多个氨基酸。例如,所述接头可包含如SEQ ID NO:53、58、65、68或71中所示的氨基酸序列。
所述靶向部分可包含抗体的抗原结合结构域。例如,抗体的抗原结合结构域可以是Fab部分、结构域抗体或ScFv部分。
肿瘤相关抗原可选自下组:EGFRVIII、HER2/neu、PD-L1和Muc1。例如,所述靶向部分可包含抗体的抗原结合结构域,并且所述抗体可选自:抗EGFRVIII、抗HER2/neu、抗PD-L1和抗Muc1抗体。
该抗体可以是抗EGFRVIII抗体。例如,抗EGFRVIII抗体可以是Mab 806。所述靶向部分可包括Mab 806的重链CDR1-3、Mab 806的轻链CDR1-3、Mab 806的重链可变区、Mab 806的轻链可变区和/或Mab 806的轻链。例如,所述靶向部分可以是包含Mab 806的重链可变区和轻链可变区(或轻链)两者的Fab部分。在另一个实例中,所述靶向部分可以是包含Mab806的重链可变区的结构域抗体(例如,VHH)。在另一个实例中,所述靶向部分可以是包含Mab 806的重链可变区和轻链可变区两者的ScFv部分。
例如,所述靶向部分可包含重链CDR,所述重链CDR具有与Mab 806的相应重链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。可选地或另外地,所述靶向部分可包含轻链CDR,所述轻链CDR具有与Mab 806的相应轻链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含重链可变区,所述重链可变区具有与Mab 806的相应重链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,靶向部分可包含轻链可变区,所述轻链可变区具有与Mab806的相应轻链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,靶向部分可包含轻链,所述轻链具有与Mab 806的相应轻链中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
Mab 806的重链CDR 1-3分别如SEQ ID NO:90(CDR1)、SEQ ID NO:91(CDR2)和SEQID NO:92(CDR3)中所示。Mab 806的轻链CDR 1-3分别如SEQ ID NO:86(CDR1)、SEQ ID NO:87(CDR2)和SEQ ID NO:88(CDR3)中所示。Mab 806的重链可变区如SEQ ID NO:93中所示。Mab 806的轻链可变区如SEQ ID NO:89中所示。
该抗体可以是抗HER2抗体。例如,抗HER2抗体可以是帕妥珠单抗。所述靶向部分可包括帕妥珠单抗的重链CDR1-3、帕妥珠单抗的轻链CDR1-3、帕妥珠单抗的重链可变区、帕妥珠单抗的轻链可变区和/或帕妥珠单抗的轻链。例如,靶向部分可以是包含帕妥珠单抗的重链可变区和轻链可变区(或轻链)两者的Fab部分。在另一个实例中,所述靶向部分可以是包含帕妥珠单抗的重链可变区的结构域抗体(例如,VHH)。在另一个实例中,所述靶向部分可以是包含帕妥珠单抗的重链可变区和轻链可变区两者的ScFv部分。
例如,所述靶向部分可包含重链CDR,所述重链CDR具有与帕妥珠单抗的相应重链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,可选地或另外地,所述靶向部分可包含轻链CDR,所述轻链CDR具有与帕妥珠单抗的相应轻链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含重链可变区,所述重链可变区具有与帕妥珠单抗的相应重链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链可变区,所述轻链可变区具有与帕妥珠单抗的相应轻链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链,所述轻链具有与帕妥珠单抗的相应轻链中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
所述帕妥珠单抗的重链CDR 1-3分别如SEQ ID NO:106(CDR1)、SEQ ID NO:107(CDR2)和SEQ ID NO:108(CDR3)中所示。帕妥珠单抗的轻链CDR 1-3分别如SEQ ID NO:102(CDR1)、SEQ ID NO:103(CDR2)和SEQ ID NO:104(CDR3)中所示。帕妥珠单抗的重链可变区如SEQ ID NO:109中所示。帕妥珠单抗的轻链可变区如SEQ ID NO:105中所示。
在一些实施方案中,所述抗HER2抗体是曲妥珠单抗。所述靶向部分可包括曲妥珠单抗的重链CDR1-3、曲妥珠单抗的轻链CDR1-3、曲妥珠单抗的重链可变区、曲妥珠单抗的轻链可变区和/或曲妥珠单抗的轻链。例如,所述靶向部分可以是包含曲妥珠单抗的重链可变区和轻链可变区(或轻链)两者的Fab部分。在另一个实例中,所述靶向部分可以是包含曲妥珠单抗的重链可变区的结构域抗体(例如,VHH)。在另一个实例中,所述靶向部分可以是包含曲妥珠单抗的重链可变区和轻链可变区两者的ScFv部分。
例如,所述靶向部分可包含重链CDR,所述重链CDR具有与曲妥珠单抗的相应重链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。可选地或另外地,所述靶向部分可包含轻链CDR,所述轻链CDR具有与曲妥珠单抗的相应轻链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含重链可变区,所述重链可变区具有与曲妥珠单抗的相应重链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链可变区,所述轻链可变区具有与曲妥珠单抗的相应轻链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链,所述轻链具有与曲妥珠单抗的相应轻链中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
所述曲妥珠单抗的重链CDR 1-3分别如SEQ ID NO:98(CDR1)、SEQ ID NO:99(CDR2)和SEQ ID NO:100(CDR3)中所示。曲妥珠单抗的轻链CDR 1-3分别如SEQ ID NO:94(CDR1)、SEQ ID NO:95(CDR2)和SEQ ID NO:96(CDR3)中所示。曲妥珠单抗的重链可变区如SEQ ID NO:101中所示。曲妥珠单抗的重链可变区如SEQ ID NO:97中所示。
该抗体可以是抗Muc1抗体。例如,抗Muc1抗体可以是5E5或其人源化形式。所述靶向部分可包含5E5或其人源化形式的重链CDR1-3、5E5或其人源化形式的轻链CDR1-3、5E5或其人源化形式的重链可变区、5E5或其人源化形式的轻链可变体区和/或5E5或其人源化形式的轻链。例如,所述靶向部分可以是包含5E5或其人源化形式的重链可变区和轻链可变区(或轻链)两者的Fab部分。在另一个实例中,所述靶向部分可以是包含5E5或其人源化形式的重链可变区的结构域抗体(例如,VHH)。在另一个实例中,所述靶向部分可以是包含5E5或其人源化形式的重链可变区和轻链可变区两者的ScFv部分。
例如,所述靶向部分可包含重链CDR,所述重链CDR具有与5E5或其人源化形式的相应重链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。可选地或另外地,所述靶向部分可包含轻链CDR,所述轻链CDR具有与5E5或其人源化形式的相应轻链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含重链可变区,所述重链可变区具有与5E5或其人源化形式的相应重链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链可变区,所述轻链可变区具有与5E5或其人源化形式的相应轻链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链,所述轻链具有与5E5或其人源化形式的相应轻链中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
所述5E5的重链CDR 1-3分别如SEQ ID NO:114(CDR1)、SEQ ID NO:115(CDR2)和SEQ ID NO:116(CDR3)中所示。5E5的轻链CDR 1-3分别如SEQ ID NO:110(CDR1)、SEQ IDNO:111(CDR2)和SEQ ID NO:112(CDR3)中所示。5E5的重链可变区如SEQ ID NO:117中所示。5E5的轻链可变区如SEQ ID NO:113中所示。
该抗体可以是抗PD-L1抗体。例如,所述抗PD-L1抗体可选自下组:阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56。所述靶向部分可包含阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56的重链CDR1-3,阿特朱单抗、阿维单抗、度伐鲁单抗的轻链CDR1-3,阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56的重链可变区,阿特朱单抗、阿维单抗、度伐鲁单抗的轻链可变区,和/或阿特朱单抗、阿维单抗和度伐鲁单抗的轻链。例如,所述靶向部分可以是包含阿特朱单抗、阿维单抗和度伐鲁单抗的重链可变区和轻链可变区(或轻链)两者的Fab部分。在另一个实例中,所述靶向部分可以是包含阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56的重链可变区的结构域抗体(例如,VHH)。在另一个实例中,所述靶向部分可以是包含阿特朱单抗、阿维单抗、度伐鲁单抗的重链可变区和轻链可变区两者的ScFv部分。
例如,所述抗PD-L1抗体可选自下组:阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56。例如,所述靶向部分可包含重链CDR 1-3,所述重链CDR 1-3具有与阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56的相应重链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。可选地或另外地,所述靶向部分可包含轻链CDR 1-3,所述轻链CDR 1-3具有与阿特朱单抗、阿维单抗和度伐鲁单抗的相应轻链CDR1-3中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含重链可变区,所述重链可变区具有与阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56的相应重链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链可变区,所述轻链可变区具有与阿特朱单抗、阿维单抗和度伐鲁单抗的相应轻链可变区中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。例如,所述靶向部分可包含轻链,所述轻链具有与阿特朱单抗、阿维单抗和度伐鲁单抗的相应轻链中包含的氨基酸序列具有至少60%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
所述hu56的重链CDR 1-3分别如SEQ ID NO:118(CDR1)、SEQ ID NO:119(CDR2)和SEQ ID NO:120(CDR3)中所示。hu56的重链可变区如SEQ ID NO:121中所示。
所述KN035的重链CDR 1-3分别如SEQ ID NO:118(CDR1)、SEQ ID NO:119(CDR2)和SEQ ID NO:120(CDR3)中所示。hu56的重链可变区如SEQ ID NO:121中所示。
所述阿特朱单抗的重链CDR 1-3分别如SEQ ID NO:128(CDR1)、SEQ ID NO:129(CDR2)和SEQ ID NO:130(CDR3)中所示。阿特朱单抗的轻链CDR 1-3分别如SEQ ID NO:124(CDR1)、SEQ ID NO:125(CDR2)和SEQ ID NO:126(CDR3)中所示。阿特朱单抗的重链可变区如SEQ ID NO:131中所示。阿特朱单抗的轻链可变区如SEQ ID NO:127中所示。
所述阿维单抗的重链CDR 1-3分别如SEQ ID NO:136(CDR1)、SEQ ID NO:137(CDR2)和SEQ ID NO:138(CDR3)中所示。阿维单抗的轻链CDR 1-3分别如SEQ ID NO:132(CDR1)、SEQ ID NO:133(CDR2)和SEQ ID NO:134(CDR3)中所示。阿维单抗的重链可变区如SEQ ID NO:139中所示。阿维单抗的轻链可变区如SEQ ID NO:135中所示。
所述度伐鲁单抗的重链CDR 1-3分别如SEQ ID NO:144(CDR1)、SEQ ID NO:145(CDR2)和SEQ ID NO:146(CDR3)中所示。度伐鲁单抗的轻链CDR 1-3分别如SEQ ID NO:140(CDR1)、SEQ ID NO:141(CDR2)和SEQ ID NO:142(CDR3)中所示。度伐鲁单抗的重链可变区如SEQ ID NO:147中所示。度伐鲁单抗的轻链可变区如SEQ ID NO:143中所示。
在本申请的免疫缀合物中,所述Fc结构域可以是IgG Fc结构域。例如,所述IgG可选自下组:IgG1、IgG2、IgG3和IgG4。在一些实施方案中,所述IgG是人IgG1,并且Fc结构域是人IgG1 Fc结构域(野生型或经修饰的)。
在本申请的免疫缀合物中,所述Fc结构域的第一Fc亚基不同于第二Fc亚基,并且所述Fc结构域可包含促进第一Fc亚基与第二Fc亚基之间的异二聚体化的修饰。例如,所述第一Fc亚基可包含第一修饰,并且第二Fc亚基包含第二修饰。
所述第一修饰可在位置T366处包含氨基酸取代,以及在选自以下的一个或多个位置处包含氨基酸取代:Y349、F405、K409、D399、K360、Q347、K392和S354,其中氨基酸的位置根据KABAT编号的EU索引来确定。例如,所述第一修饰所包含的氨基酸取代可选自下组:Y349C、Y349D、D399S、F405K、K360E、K409A、K409E、Q347E、Q347R、S354D、K392D和T366W。
所述第一修饰可在2-7个位置(例如,2-6、2-5、2-4、2-3或2个位置)处包含氨基酸取代。例如,所述第一修饰可在选自以下组中的任意组位置处包含氨基酸取代:1)Y349和T366;2)Y349、T366和F405;3)Y349、T366和K409;4)Y349、T366、F405、K360和Q347;5)Y349、T366、F405和Q347;6)Y349、T366、K409、K360和Q347;7)Y349、T366、K409和Q347;8)T366、K409和K392;9)T366 and K409;10)T366、K409、Y349和S354;11)T366和F405;12)T366、F405and D399;and 13)T366、F405、Y349和S354。例如,所述第一修饰可包含选自以下组中的任意组的氨基酸取代:1)Y349C和T366W;2)Y349C、T366W和F405K;3)Y349C、T366W和K409E;4)Y349C、T366W和K409A;5)Y349C、T366W、F405K、K360E和Q347E;6)Y349C、T366W、F405K和Q347R;7)Y349C、T366W、K409A、K360E和Q347E;8)Y349C、T366W、K409A和Q347R;9)T366W、K409A和K392D;10)T366W和K409A;11)T366W、K409A和Y349D;12)T366W、K409A、Y349D和S354D;13)T366W和F405K;14)T366W、F405K和D399S;15)T366W、F405K和Y349D;和16)T366W、F405K、Y349D和S354D。
所述第二修饰可在位置T366、L368和Y407处包含氨基酸取代,以及在选自下组的一个或多个位置处包含氨基酸取代:D356、D399、E357、F405、K360、K392、K409和Q347,其中氨基酸的位置根据KABAT编号的EU索引确定。例如,所述第二修饰所包含的氨基酸取代可选自下组:D356C、D399S、E357A、F405K、K360E、K392D、K409A、L368A、L368G、Q347E、Q347R、T366S、Y407A和Y407V。
所述第二修饰可在4-8个位置(例如,4-7、4-6、4-5或4个位置)处包含氨基酸取代。例如,所述第二修饰可在选自以下组中的任意组位置处包含氨基酸取代:1)D356、T366、L368、Y407和F405;2)D356、T366、L368和Y407;3)D356、T366、L368、Y407和Q347;4)D356、T366、L368、Y407、K360和Q347;5)D356、T366、L368、Y407、F405和Q347;6)D356、T366、L368、Y407、F405、K360和Q347;7)T366、L368、Y407、D399和F405;8)T366、L368、Y407和F405;9)T366、L368、Y407、F405和E357;10)T366、L368、Y407和K409;11)T366、L368、Y407、K409和K392;以及12)T366、L368、Y407、K409和E357。例如,所述第二修饰可包含选自以下组中的任意组的氨基酸取代:1)D356C、T366S、L368A、Y407V和F405K;2)D356C、T366S、L368A和Y407V;3)D356C、T366S、L368A、Y407V和Q347R;4)D356C、T366S、L368A、Y407V、K360E和Q347E;5)D356C、T366S、L368A、Y407V、F405K和Q347R;6)D356C、T366S、L368A、Y407V、F405K、K360E和Q347E;7)T366S、L368A、Y407V、D399S和F405K;8)T366S、L368G、Y407A和F405K;9)T366S、L368A、Y407V、F405K和E357A;10)T366S、L368A、Y407V和K409A;11)T366S、L368A、Y407V、K409A和K392D;12)T366S、L368G、Y407A和K409A;以及13)T366S、L368A、Y407V、K409A和E357A。
例如,所述第一Fc亚基可包含第一修饰,所述第二Fc亚基可包含第二修饰,第一修饰和第二修饰可在选自以下组中的任意组的位置处包含氨基酸取代:1)第一修饰:Y349和T366;和第二修饰:D356、T366、L368、Y407和F405;2)第一修饰:Y349、T366和F405;和第二修饰:D356、T366、L368和Y407;3)第一修饰:Y349、T366和K409;和第二修饰:D356、T366、L368、Y407和F405;4)第一修饰:Y349、T366、F405、K360和Q347;和第二修饰:D356、T366、L368、Y407和Q347;5)第一修饰:Y349、T366、F405和Q347;和第二修饰:D356、T366、L368、Y407、K360和Q347;6)第一修饰:Y349、T366、K409、K360和Q347;和第二修饰:D356、T366、L368、Y407、F405和Q347;7)第一修饰:Y349、T366、K409和Q347;和第二修饰:D356、T366、L368、Y407、F405、K360和Q347;8)第一修饰:T366、K409和K392;和第二修饰:T366、L368、Y407、D399和F405;9)第一修饰:T366和K409;和第二修饰:T366、L368、Y407和F405;10)第一修饰:T366、K409和Y349;和第二修饰:T366、L368、Y407、F405和E357;11)第一修饰:T366、K409、Y349和S354;和第二修饰:T366、L368、Y407、F405和E357;12)第一修饰:T366和F405;和第二修饰:T366、L368、Y407和K409;13)第一修饰:T366、F405和D399;和第二修饰:T366、L368、Y407、K409和K392;14)第一修饰:T366、F405和Y349;和第二修饰:T366、L368、Y407、K409和E357;15)第一修饰:T366、F405、Y349和S354;和第二修饰:T366、L368、Y407、K409和E357;其中氨基酸的位置根据KABAT编号的EU索引来确定。
例如,所述第一Fc亚基可包含第一修饰,所述第二Fc亚基可包含第二修饰,其中第一修饰和第二修饰可包含选自以下组中的任意组的氨基酸取代:Y349C和T366W;和第二修饰:D356C、T366S、L368A、Y407V和F405K;2)第一修饰:Y349C、T366W和F405K;和第二修饰:D356C,T366S,L368A和Y407V;3)第一修饰:Y349C、T366W和K409E;和第二修饰:D356C、T366S、L368A、Y407V和F405K;4)第一修饰:Y349C、T366W和K409A;和第二修饰:D356C、T366S、L368A、Y407V和F405K;5)第一修饰:Y349C、T366W、F405K、K360E和Q347E;和第二修饰:D356C、T366S、L368A、Y407V和Q347R;6)第一修饰:Y349C、T366W、F405K和Q347R;和第二修饰:D356C、T366S、L368A、Y407V、K360E和Q347E;7)第一修饰:Y349C、T366W、K409A、K360E和Q347E;和第二修饰:D356C、T366S、L368A、Y407V、F405K和Q347R;8)第一修饰:Y349C、T366W、K409A和Q347R;和第二修饰:D356C、T366S、L368A、Y407V、F405K、K360E和Q347E;9)第一修饰:T366W、K409A和K392D;和第二修饰:T366S、L368A、Y407V、D399S和F405K;10)第一修饰:T366W和K409A;和第二修饰:T366S、L368G、Y407A和F405K;11)第一修饰:T366W、K409A和Y349D;和第二修饰:T366S、L368A、Y407V、F405K和E357A;12)第一修饰:T366W、K409A、Y349D和S354D;和第二修饰:T366S、L368A、Y407V、F405K和E357A;13)第一修饰:T366W和F405K;和第二修饰:T366S、L368A、Y407A和K409A;14)第一修饰:T366W、F405K和D399S;和第二修饰:T366S、L368A、Y407V、K409A和K392D;15)第一修饰:T366W和F405K;和第二修饰:T366S、L368G、Y407A和K409A;16)第一修饰:T366W、F405K和Y349D;和第二修饰:T366S、L368A、Y407V、K409A和E357A;17)第一修饰:T366W、F405K、Y349D和S354D;和第二修饰:T366S、L368A、Y407V、K409A和E357A;其中氨基酸的位置根据KABAT编号的EU索引来确定。
在一些实施方案中,所述第一Fc亚基包含第一修饰,第二Fc亚基包含第二修饰,所述第一修饰包含氨基酸取代T366W和K409A,并且所述第二修饰包含氨基酸取代T366S、L368G、Y407A和F405K,其中氨基酸的位置根据KABAT编号的EU索引确定。
在一些实施方案中,将单拷贝的SIRPα与包含第二修饰的所述第二Fc亚基直接或间接融合。
所述第一Fc亚基的氨基酸序列可选自SEQ ID NO:39、43、47、51、54、56、59、76、80或84。
所述第二Fc亚基的氨基酸序列可选自SEQ ID NO:66或72。
所述免疫缀合物可包含一个或多个所述靶向部分。
在一些实施方案中,所述免疫缀合物仅包含一个靶向部分。在一些实施方案中,所述免疫缀合物包含两个或更多个靶向部分。
例如,所述免疫缀合物可以是包含第一成员和不同于第一成员的第二成员的蛋白质性质的异二聚体。所述第一成员可包含与所述Fc结构域的两个亚基之一融合的靶向部分,且所述第二成员可包含与所述Fc结构域的两个亚基中的另一个融合的单拷贝的SIRPα。所述第一Fc亚基可与第二Fc亚基缔合以形成异二聚体。
例如,所述靶向部分可与Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接(例如,通过所述接头)融合,并且单拷贝的SIRPα可与Fc结构域的两个亚基的另一个亚基的氨基末端氨基酸直接或间接(例如,通过所述接头)融合。
在一些实施方案中,所述免疫缀合物包含两个靶向部分,其为第一靶向部分和第二靶向部分。所述第一靶向部分和第二靶向部分可表现出对不同肿瘤相关抗原或对相同肿瘤相关抗原的结合特异性。例如,所述第一靶向部分和第二靶向部分可表现出对相同肿瘤相关抗原的结合特异性。在一些实施方案中,所述第一靶向部分和第二靶向部分是相同的。
所述第一靶向部分和第二靶向部分可以直接或间接地(例如,通过接头)彼此融合。
当所述免疫缀合物包含两个靶向部分时,所述第一靶向部分可与Fc结构域的两个亚基之一的氨基末端或羧基末端氨基酸直接或间接融合,并且所述第二靶向部分可与Fc结构域的两个亚基中的另一个亚基的氨基末端或羧基末端氨基酸直接或间接融合。
例如,所述免疫缀合物可以是蛋白质性质的异二聚体。所述蛋白质性质的异二聚体可包含第一成员和不同于第一成员的第二成员。所述第一成员可包含与所述Fc结构域的两个亚基之一融合的第一靶向部分,所述第二成员可包含单拷贝的SIRPα、第二靶向部分和所述Fc结构域的两个亚基中的另一个亚基,其中单拷贝的SIRPα与Fc亚基的一个末端融合,并且第二靶向部分与Fc亚基的另一个末端整合。第一Fc亚基可与第二Fc亚基缔合以形成异二聚体。
例如,所述第一靶向部分可与所述Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接融合,所述第二靶向部分可与Fc结构域的两个亚基中的另一个的氨基末端氨基酸直接或间接融合,并且单拷贝的SIRPα可与第一或第二Fc亚基的羧基末端氨基酸直接或间接融合。例如,所述第一靶向部分可与所述第一Fc亚基的氨基末端氨基酸融合,所述第二靶向部分可与所述第二Fc亚基的氨基末端氨基酸融合,并且所述单拷贝的SIRPα可与所述第二Fc亚基的羧基末端氨基酸融合。
在一些实施方案中,当所述免疫缀合物包含两个靶向部分时,第一靶向部分和第二靶向部分都可与Fc结构域的两个亚基中的同一个亚基直接或间接融合。
例如,所述第一靶向部分和第二靶向部分可以直接或间接地(例如,通过接头)彼此融合以形成靶向部分的二聚体。然后,可将靶向部分的二聚体与所述Fc结构域的两个亚基之一直接或间接融合。
所述免疫缀合物可以是蛋白质性质的异二聚体。所述蛋白质性质的异二聚体可包含第一成员和不同于第一成员的第二成员。所述第一成员可包含第一靶向部分和第二靶向部分两者。所述第一靶向部分和第二靶向部分可与所述Fc结构域的两个亚基的同一个亚基融合(例如,所述第一靶向部分和所述第二靶向部分可直接或间接地(例如,通过接头)彼此融合,以形成靶向部分的二聚体。然后,可将靶向部分的二聚体与Fc结构域的两个亚基之一直接或间接融合)。所述第二成员可包含单拷贝的SIRPα和Fc结构域的两个亚基中的另一个。可将单拷贝的SIRPα与Fc亚基的一个末端融合。第一Fc亚基可与第二Fc亚基缔合以形成异二聚体。
例如,所述第一靶向部分和第二靶向部分均可与所述Fc结构域的两个亚基的同一个亚基融合的氨基末端氨基酸直接或间接融合(例如,所述第一靶向部分和第二靶向部分可直接或间接地(例如,通过接头)彼此融合,以形成靶向部分的二聚体。然后,可将靶向部分的二聚体与Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接融合)。可将所述单拷贝的SIRPα与所述Fc结构域的两个亚基的另一个的氨基末端氨基酸直接或间接融合。例如,所述第一靶向部分和第二靶向部分均可与所述第一Fc亚基的氨基末端氨基酸直接或间接融合(例如,所述第一靶向部分和第二靶向部分可直接或间接地(例如,通过接头)彼此融合,以形成靶向部分的二聚体。然后,可将靶向部分的二聚体与第一Fc亚基的氨基末端氨基酸直接或间接融合),并且可将所述单拷贝的SIRPα与所述第二Fc亚基的氨基末端氨基酸融合。
所述第一Fc亚基可包含如本申请中所述的第一修饰,并且第二Fc亚基可包含如本申请中所述的第二修饰。
当将红细胞(RBC)结合平均荧光强度(MFI)%针对参考免疫缀合物标准化为100%时,本申请的免疫缀合物可具有不超过约20%,不超过约19%,不超过约18%,不超过约17%,不超过约16%,不超过约15%,不超过约14%,不超过约13%,不超过约12%,不超过约11%,不超过约10%,不超过约8%,不超过约6%,不超过约4%,不超过约2%或更少的RBC结合MFI的a%,其中所述参考免疫缀合物为由两个相同成员组成的同二聚体蛋白,所述同二聚体蛋白的每个成员由单拷贝的SIRPα组成,所述SIRPα通过肽接头与人IgG1 Fc亚基的氨基末端氨基酸融合(在本申请中也称为SIRPα-Fc)。
当将血小板结合平均荧光强度(MFI)%针对参考免疫缀合物标准化为100%时,本申请的免疫缀合物也可具有不超过约65%,不超过约60%,不超过约59%,不超过约58%,不超过约57%,不超过约56%,不超过约55%,不超过约54%,不超过约53%,不超过约52%,不超过约51%,不超过约50%,不超过约45%,不超过约40%,不超过约30%,不超过约25%或更少的血小板结合MFI的a%,其中所述参考免疫缀合物为由两个相同成员组成的同二聚体蛋白,同二聚体蛋白的每个成员由单拷贝的SIRPα组成,所述SIRPα通过肽接头与人IgG1Fc亚基的氨基末端氨基酸融合(在本申请中也称为SIRPα-Fc IgG1)。
在一些实施方案中,所述参考免疫缀合物SIRPα-Fc IgG1的每个成员具有如SEQID NO:69中所示的氨基酸序列。
当将红细胞(RBC)结合平均荧光强度(MFI)%针对参考分子标准化为100%时,所述免疫缀合物可具有不超过约10%,不超过约9%,不超过约8%,不超过约7%,不超过约6%,不超过约5%,不超过约4%,不超过约3%,不超过约2.5%,不超过约2%,不超过约1.5%,不超过约1%或更少的RBC结合MFI的a%,其中所述参考分子为抗CD47单克隆抗体AB6.12 IgG1。
当将血小板结合平均荧光强度(MFI)%针对参考分子标准化为100%时,免疫缀合物可具有不超过约50%,不超过约45%,不超过约46%,不超过约45%,不超过约44%,不超过约43%,不超过约42%,不超过约41%,不超过约40%,不超过约39%,不超过约38%,不超过约37%,不超过约36%,不超过约35%,不超过约34%,不超过约33%,不超过约32%,不超过约31%,不超过约30%,不超过约25%,不超过约20%或更少的血小板结合MFI的a%,其中所述参考分子为抗CD47单克隆抗体AB6.12 IgG1。
在另一个方面,本申请提供了编码本申请的免疫缀合物的一种或多种分离的核酸。所述分离的核酸可包含一种或多种核酸分子,其中每种核酸分子编码本申请的免疫缀合物或其片段。例如,所述分离的核酸可包含至少两种核酸分子,其中一种编码与第一Fc亚基融合的靶向部分,第二种编码与第二Fc亚基融合的单拷贝的SIRPα。在一些情况下,所述第二种核酸分子可编码包含与第二Fc亚基融合的第二靶向部分和单拷贝的SIRPα的多肽。在一些情况下,所述分离的核酸可包含至少三种核酸分子,其中一种编码靶向部分的轻链,第二种核酸编码靶向部分的重链(包含第一Fc亚基),以及第三核酸编码与第二Fc亚基融合的单拷贝的SIRPα。在一些情况下,所述分离的核酸可包含至少四种核酸分子,其中一种编码第一靶向部分的轻链,第二种核酸编码第一靶向部分的轻链(包含第一Fc亚基),第三核酸编码第二靶向部分的轻链,以及第四核酸编码与单拷贝SIRPα融合的第二靶向部分的重链(包含第二Fc亚基)。
可使用本领域公知的重组技术合成所述一种或多种分离的核酸。例如,可利用自动化DNA合成仪合成所述一种或多种分离的核酸。
标准重组DNA和分子克隆技术包括Sambrook,J.,Fritsch,E.F.和Maniatis,T.Molecular Cloning:A Laboratory Manual;Cold Spring Harbor Laboratory Press:Cold Spring Harbor,(1989)(Maniatis)以及T.J.Silhavy,M.L.Bennan和L.W.Enquist,Experiments with Gene Fusions,Cold Spring Harbor Laboratory,Cold SpringHarbor,N.Y.(1984)和Ausubel,F.M.等Current Protocols in Molecular Biology,pub.by Greene Publishing Assoc.and Wiley-Interscience(1987)描述的那些技术。简而言之,可从基因组DNA片段、cDNA和RNA制备主题核酸,所述基因组DNA片段、cDNA和RNA全部都可直接从细胞中提取或通过各种扩增方法(包括但不限于PCR和RT-PCR)重组产生。
核酸的直接化学合成通常涉及将3'-封闭和5'-封闭的核苷酸单体以此添加到生长中的核苷酸聚合物链的末端5'-羟基,其中每次添加均通过生长链的末端5’羟基对添加的单体的3’位置的亲核攻击来实现,所述添加的单体通常为磷衍生物,诸如磷酸三酯、亚磷酰胺等。参见例如,Matteuci等,Tet.Lett.521:719(1980);属于Caruthers等的美国专利第4,500,707号;和属于Southern的第5,436,327号和5,700,637号。
在另一个方面,本申请提供了包含一种或多种分离的核酸的一种或多种载体。
所述载体可以是任何线性核酸、质粒、噬菌粒、粘粒、RNA载体、病毒载体等。病毒载体的非限制性实例可包括逆转录病毒、腺病毒和腺相关病毒。在一些实施方案中,所述载体是表达载体,例如,噬菌体展示载体。
表达载体可适用于特定类型的宿主细胞而不适用于其他宿主细胞。例如,可将所述表达载体引入宿主生物中,然后监测所述载体中包含的任何基因/多核苷酸的活性和表达。
所述表达载体还可包含一种或多种选择标记基因,其在表达后赋予一种或多种表型性状,可用于选择或以其他方式鉴定携带所述表达载体的宿主细胞。真核细胞的合适选择标记的非限制性实例包括二氢叶酸还原酶和新霉素抗性。
可通过多种已建立的技术将主题载体稳定地或瞬时地引入宿主细胞。例如,一种方法涉及氯化钙处理,其中通过钙沉淀物引入表达载体。其他盐,例如磷酸钙,也可以按照类似的步骤使用。另外,可使用电穿孔(即,施加电流以增加细胞对核酸的渗透性)。转化方法的其他实例包括显微注射、DEAE葡聚糖介导的转化和在乙酸锂存在的情况下的热激。脂质复合物、脂质体和树状聚合物也可以用于转染宿主细胞。
在将异源序列引入宿主细胞后,可实践多种方法来鉴定已将主题载体引入其中的宿主细胞。一种示例性选择方法涉及将单个细胞传代培养以形成单个克隆,然后测试所需蛋白质产物的表达。另一方法需要基于通过表达载体中包含的选择标记基因的表达所赋予的表型性状,选择含有异源序列的宿主细胞。
例如,可通过诸如PCR、Southern印迹或Northern印迹杂交等方法来确认本申请的各种异源序列至宿主细胞中的引入。例如,可从所得宿主细胞制备核酸,并且可使用特异于目标序列的引物通过PCR来扩增特定目标序列。将扩增的产物进行琼脂糖凝胶电泳、聚丙烯酰胺凝胶电泳或毛细管电泳,然后用溴化乙锭、SYBR Green溶液等染色,或用UV检测法检测DNA。或者,可在杂交反应中采用特异于目标序列的核酸探针。特定基因序列的表达可通过经由PCR偶联的反转录、Northern印迹杂交检测相应的mRNA,或通过使用与编码的基因产物具有反应性的抗体进行免疫测定来确定。示例性免疫测定法包括但不限于ELISA、放射免疫测定法和夹心免疫测定法。
此外,可通过异源序列编码的酶的酶促活性(例如,酶促标记)来证实本申请的各种异源序列至宿主细胞中的引入。可通过本领域已知的多种方法来测定该酶。通常,可通过研究中的酶促反应的产物的形成或底物的转化来确定酶促活性。所述反应可在体外或体内发生。
在另一个方面,本申请提供了包含本申请的一种或多种分离的核酸或本申请的一种或多种载体的分离的宿主细胞。
细胞可表达本申请的免疫缀合物和/或蛋白质混合物、一种或多种编码本申请的免疫缀合物和/或蛋白质混合物的分离的核酸。所述细胞可以是真核细胞或原核细胞。合适的细胞可用本申请的一种或多种核酸或载体转化或转染,并用于表达和/或分泌免疫缀合物和/或蛋白质混合物。例如,细胞可以是大肠杆菌(E.coli)细胞、其他细菌宿主细胞、酵母细胞或各种高级真核细胞。
在另一方面,本申请提供了用于产生本申请的免疫缀合物的方法,该方法包括(i)在实现免疫缀合物的表达和形成的条件下培养宿主细胞,以及(ii)收获形成的免疫缀合物。
在一个方面,本申请提供了包含本申请的免疫缀合物的蛋白质混合物。免疫缀合物可以是由第一成员和第二成员形成的蛋白质性质的异二聚体。蛋白质混合物可包含由两个相同拷贝的所述第一成员形成的第一同二聚体,其中每个第一成员包含与第一Fc亚基融合的靶向部分;由两个相同拷贝的所述第二成员形成的第二同二聚体,其中每个第二成员包含与第二Fc亚基融合的单拷贝的SIRPα;其中本申请的免疫缀合物以至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%或至少约99%的百分比存在于蛋白质混合物中。
在所述蛋白质混合物中,第二同二聚体的百分比可以小于第一同二聚体的百分比。例如,第二同二聚体的百分比可以为至多约10%、至多约9%、至多约8%、至多约7%、至多约6%、至多约5%、至多约5%、至多约4%、至多约3%、至多约2%、至多约1%或至多约0.5%。例如,所述蛋白质混合物可以基本上不包含第二同二聚体。
蛋白质混合物可以直接从本社区宁的宿主细胞获得。例如,可从宿主细胞获得蛋白质混合物而无需进一步的蛋白质纯化。
在另一方面,本申请提供了用于产生蛋白质混合物的方法,其包括(i)在实现所述免疫缀合物的表达和形成的条件下培养宿主细胞,以及(ii)收获包含所述免疫缀合物的蛋白质混合物。
药物组合物
在另一个方面,本申请提供了药物组合物,其包含有效量的免疫缀合物和任选地药学上可接受的赋形剂。
药物组合物还可包含有效量的用于癌症治疗的另外的治疗活性组分。例如,用于癌症治疗的另外的治疗活性组分可以是化学治疗剂。例如,所述化学治疗剂是细胞毒性剂。例如,细胞毒性剂可以是多柔比星(doxorubicin)。每种活性成分可以以药物活性量存在于药物组合物中。
以下描述的是非限制性的示例性药物组合物及其制备方法。
药物组合物可以例如以适于口服施用(诸如片剂、胶囊剂、丸剂、粉剂、持续释放制剂、溶液、混悬剂)、肠胃外注射(诸如无菌溶液、混悬剂或乳剂)、局部施用(诸如软膏或乳膏)或适用于直肠施用(诸如栓剂)的形式存在。药物组合物可以是适合单次施用精确剂量的单位剂型。药物组合物可以是适合口服消费的液体药物组合物。
适用于口服施用的本申请的药物组合物可呈现为离散剂型,诸如胶囊剂、扁囊剂或片剂,或各自含有预定量的活性成分(作为粉剂或呈颗粒形式)的液体或气溶胶喷雾剂、溶液,或水性或非水性液体中的混悬剂、水包油型乳剂或油包水型液体乳剂。此类剂型可通过任何制药方法来制备,但所有方法通常包括使活性成分与构成一种或多种其他成分的载体结合的步骤。通常,通过将活性成分与液体载体或精细的固体载体或两者均匀且紧密地混合,然后,如果需要,将产品成型为所需的外观,来制备组合物。
根据常规药物混合技术,可将本申请的免疫缀合物或蛋白质混合物与药物载体紧密混合。载体可采取多种形式,这取决于施用所需的制剂形式。在制备用于口服剂型的组合物时,可将任何常用的药物介质用作载体,诸如在口服液体制剂(诸如混悬剂、溶液和酏剂)或气雾剂的情况下,水、二醇、油、醇、调味剂、防腐剂、着色剂等;或在一些实施方案中,在不使用乳糖的情况下,在口服固体制剂的情况下也可使用载体诸如淀粉、糖、微晶纤维素、稀释剂、制粒剂、润滑剂、粘合剂和崩解剂。例如,合适的载体包括粉剂、胶囊剂和片剂,以及固体口服制剂。如果需要,可通过标准水性或非水性技术将片剂包衣。
当需要将水性混悬剂和/或酏剂用于口服施用时,可将其中的活性成分与各种甜味剂或调味剂、着色物质或染料以及乳化剂和/或悬浮剂(如果需要)和诸如水、乙醇、丙二醇、甘油等稀释剂及其各种组合一起组合。
可通过已知技术对片剂进行未包衣或包衣,以延迟其在胃肠道中的崩解和吸收,从而在更长的时间内提供持续的作用。
可用于形成本申请的药物组合物和剂型的表面活性剂包括但不限于亲水性表面活性剂、亲脂性表面活性剂及其混合物。可使用亲水性表面活性剂的混合物,可使用亲脂性表面活性剂的混合物,或者可使用至少一种亲水性表面活性剂和至少一种亲脂性表面活性剂的混合物。
在上述组中,离子型表面活性剂包括例如:卵磷脂、溶血卵磷脂、磷脂、溶血磷脂及其衍生物;肉碱脂肪酸酯盐;烷基硫酸盐;脂肪酸盐;多库酯钠;酰基酯(acylactylates);单甘油酯和二甘油酯的单乙酰化酒石酸酯和二乙酰化酒石酸酯;琥珀酰化的单甘油酯和二甘油酯;单甘油酯和二甘油酯的柠檬酸酯;以及其混合物
组合物可包含增溶剂以确保本申请的免疫缀合物或蛋白混合物的良好增溶和/或溶解,并使本申请的免疫缀合物或蛋白混合物的沉淀减少至最少。对于非口服使用的组合物,例如注射用组合物,这可能尤其重要。还可添加增溶剂以增加亲水性药物和/或其他组分,诸如表面活性剂的溶解度,或使组合物保持为稳定或均匀的溶液或分散体。
合适的增溶剂的实例包括但不限于以下物质:醇和多元醇,诸如乙醇、异丙醇、丁醇、苄醇、乙二醇、丙二醇及其混合物。可包含的增溶剂的量没有特别限制。给定的增溶剂的量可以限于生物可接受的量,其可由本领域技术人员容易地确定。
组合物还可包含一种或多种药学上可接受的添加剂和赋形剂。此类添加剂和赋形剂包括但不限于除粘剂、消泡剂、缓冲剂、聚合物、抗氧化剂、防腐剂、螯合剂、粘度调节剂、张力调节剂(tonicifiers)、调味剂、着色剂、芳香剂、遮光剂、助悬剂、粘合剂、填充剂、增塑剂、润滑剂及其混合物。
本申请的药物组合物可包含治疗有效量的活性剂(例如,本申请的免疫缀合物或蛋白质混合物)。治疗有效量是能够预防和/或治愈(至少部分地)患有所述疾患或病症或有发展所述疾患或病症的风险的受试者的疾患或病症(例如,癌症)和/或其任何并发症的主题药物组合物的量。所包含的活性剂的具体量/浓度可根据施用方法和患者的需要而变化,并且可基于例如患者的体积、粘度和/或体重等来确定。例如,合适的剂量可为约0.1mg或1mg/kg/天至约50mg/kg/天;有时,剂量甚至可以更高。例如,所施加的剂量可为约3mg/kg/天至约3.5mg/kg/天,3.5mg/kg/天至约7.2mg/kg/天,约7.2mg/kg/天至约11.0mg/kg/天,约11.0mg/kg/天至约15.0mg/kg/天。例如,所施加的剂量可为约10mg/kg/天至约50mg/kg/天,例如每天约20mg至约50mg,每天施用2次。应当理解,本领域技术人员(例如,医生或药剂师)可基于特定患者的状况、制剂和/或疾病方便地调整这些特定剂量。
医疗用途和治疗方法
在一个方面,本申请提供了本申请的免疫缀合物、蛋白质混合物或药物组合物,用于治疗有此需要的受试者的疾病。
在另一个方面,本申请提供了本申请的免疫缀合物、蛋白质混合物或药物组合物在制备药剂方面的用途,其中所述药剂用于治疗有此需要的受试者的疾病。
在一个方面,本申请提供了所述免疫缀合物、蛋白质混合物与另外的治疗活性组分(诸如化学治疗剂,例如,细胞毒性剂,例如多柔比星)结合用于制备用于治疗有此需要的受试者的疾病的药物的用途。
在另一个方面,本申请提供了治疗有此需要的受试者的疾病的方法,该方法包括向受试者施用有效量的本申请的免疫缀合物、蛋白质混合物或药物组合物。
在另外的方面,本申请提供了用于治疗有此需要的受试者的疾病的方法,该方法包括向受试者施用有效量的本申请的免疫缀合物或蛋白质混合物,以及进一步向该受试者施用有效量的其他治疗活性成分(诸如化学治疗剂,例如细胞毒性剂,例如多柔比星)。可以同时或顺序施用本申请的免疫缀合物或蛋白质混合物和另外的治疗活性组分。
所述疾病可以是癌症。例如,癌症可包括具有升高的CD47表达的肿瘤细胞。例如,该癌症可以选自:肺癌、膀胱癌、胃癌、肾癌、肝癌、卵巢癌、胰腺癌、前列腺癌、神经胶质瘤、胶质母细胞瘤、食道癌、平滑肌肉瘤、急性髓细胞性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性粒细胞性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、边缘区淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征、乳腺癌、黑色素瘤和结肠癌。在一些实施方案中,癌症选自:乳腺癌、黑色素瘤和结肠癌。
尽管本文中已显示并描述了本申请的实施方案,但对于本领域技术人员而言显而易见的是,此类实施方案仅以实例的方式提供。在不脱离本公开的情况下,本领域技术人员可以想到许多变化、改变和替换。应当理解,可在实践本公开中采用本文描述的本公开的实施方案的各种替代方案。以下权利要求旨在限定本公开的范围,并且由此涵盖这些权利要求的范围内的方法和结构及其等同物。
实施例
提出以下实施例是为了向普通技术人员提供如何制备和使用本发明的完整公开和描述,而非意图限制本发明人视为其发明的范围,也非意图表示以下实验是进行的全部或仅有的实验。已经做出努力以确保关于数字(例如量、温度等)的正确性,但是应该占有一些错误和偏差。除非另有说明,否则温度为摄氏度,压力为大气压或接近大气压。可使用标准缩写,例如s或sec,一秒或多秒;min,分钟;h或hr,一个或多个小时;i.p.,腹膜内(地)等。
实施例1:蛋白质制备
1.1Fc修饰
对人IgG1 Fc结构域的界面残基进行氨基酸修饰(例如,氨基酸取代)以获得以下修饰的组(如下表1所示),在本申请中链A也称为Fc9或第一Fc亚基,链B也称为Fc6或第二Fc亚基:
表1.氨基酸修饰的组
随后,如下文中所详细解释的,使用ScFv-Fc/Fc系统检查包含以上表1所列的修饰的组的异二聚体蛋白的形成。
首先,从数据库Uniprot获得人免疫球蛋白γ1(IgG1)恒定区氨基酸序列(P01857),以得到野生型人IgG1-Fc区氨基酸序列(SEQ ID NO:30)。通过RT-PCR从人PBMC总RNA中获得编码野生型人IgG1-Fc的多核苷酸片段(SEQ ID NO:31,命名为Fc基因片段)。通过重叠PCR将编码小鼠KappaIII信号肽的多核苷酸片段(SEQ ID NO:32)添加到Fc基因的5'末端,然后亚克隆到载体pcDNA4(Invitrogen,Cat V86220)中,以获得用于在哺乳动物细胞中表达人IgG1-Fc的重组表达载体。
合成编码ScFv-Fc融合蛋白的核酸分子(SEQ ID NO:33),其中ScFv是指抗HER2单链抗体,ScFv-Fc融合蛋白的氨基酸序列如SEQ ID NO:34中所示。然后将ScFv-Fc基因片段亚克隆到载体pcDNA4(Invitrogen,Cat V86220)中,以获得用于在哺乳动物细胞中表达ScFv-Fc融合蛋白的重组表达载体。
在一些情况下,将骆驼单结构域抗体的可变区(VhH)的多肽与Fc基因片段的N末端融合以获得编码融合蛋白VhH-Fc(如SEQ ID NO:36)的融合基因片段(如SEQ ID NO:35)。然后将其亚克隆到载体pcDNA4(Invitrogen,Cat V86220)中,以获得用于在哺乳动物细胞中表达融合蛋白VhH-Fc的重组表达载体。
然后,通过重叠PCR将上表1中列出的氨基酸修饰分别引入ScFv-Fc(组1-17)、VhH-Fc(组2、4、9-12、14、15和17)和Fc基因片段(组1-8),其中链A指ScFv-Fc中的Fc亚基,链B是指独立的Fc亚基或VhH-Fc中的Fc亚基。将具有氨基酸修饰的基因片段分别亚克隆到载体pcDNA4(Invitrogen,Cat V86220)中,以获得用于在哺乳动物细胞中表达经修饰的ScFv-Fc融合蛋白、经修饰的Fc蛋白和经修饰的VhH-Fc融合蛋白的重组表达载体。
然后,用PEI将构建的表达载体转染至悬浮培养的HEK293细胞(ATCC CRL-1573TM)。对于每个组,以1:1的比例共转染表达A链(ScFv-Fc融合蛋白)的表达载体和表达B链(Fc蛋白或VhH-Fc融合蛋白)的表达载体。培养5-6天后,收集瞬时表达产物的上清液,并使用蛋白A亲和色谱法初步纯化包含相应蛋白质异二聚体的表达产物。每种初步纯化的表达产物均包含分别以各种百分比存在的同二聚体蛋白ScFv-Fc/ScFv-Fc、同二聚体蛋白Fc/Fc(或同二聚体蛋白VhH-Fc/VhH-Fc)和异二聚体蛋白ScFv-Fc/Fc(或异二聚体蛋白ScFv-Fc/VhH-Fc)。由于这些蛋白质(即同二聚体和异二聚体)的分子量不同,因此可根据在非还原型SDS-PAGE凝胶上反映的相应条带强度来确定它们的相应百分比。定量强度,结果概括于下表2-5中。
表2表达产物中同二聚体蛋白和异二聚体蛋白的百分比
组 | ScFv-Fc同二聚体(%) | ScFv-Fc/Fc异二聚体(%) | Fc同二聚体(%) |
2 | 17 | 60 | 23 |
5 | 14 | 72 | 14 |
6 | 14 | 62 | 24 |
4 | 21 | 69 | 10 |
7 | 24 | 64 | 12 |
8 | 21 | 71 | 8 |
表3表达产物中同二聚体蛋白和异二聚体蛋白的百分比
组 | ScFv-Fc同二聚体(%) | ScFv-Fc/VhH-Fc异二聚体(%) | VhH-Fc同二聚体(%) |
4 | 13 | 68 | 19 |
9 | 7 | 80 | 13 |
10 | 15 | 85 | 0 |
11 | 14 | 83 | 3 |
12 | 10 | 84 | 6 |
表4表达产物中同二聚体蛋白和异二聚体蛋白的百分比
组 | ScFv-Fc同二聚体(%) | ScFv-Fc/VhH-Fc异二聚体(%) | VhH-Fc同二聚体(%) |
2 | 9 | 64 | 27 |
14 | 6 | 81 | 13 |
15 | 5 | 88 | 7 |
17 | 9 | 84 | 7 |
表5表达产物中同二聚体蛋白和异二聚体蛋白的百分比
从上面的表2-5可看出,所有的组的修饰均非常有效地促进了异二聚体形成。出于说明目的,将第10组中的修饰(链A中的修饰:T366W+K409A;链B中的修饰:T366S+L368G+Y407A+F405K)在以下实施例中用于生成本申请的免疫缀合物或蛋白质混合物。
1.2T-Fc9、T-LC和T-HC的制备
根据美国专利US7879325B2(通过引用并入本文)获得曲妥珠单抗的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码曲妥珠单抗的轻链(T-LC)的核酸分子。T-LC的氨基酸序列如SEQ ID NO:37中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:38中所示。然后合成编码曲妥珠单抗的重链(T-HC)的核酸分子。T-HC的氨基酸序列如SEQ IDNO:156中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:157中所示。然后,将点突变(T366W和K409A)引入编码曲妥珠单抗重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的曲妥珠单抗重链的核酸分子(在本文称为T-Fc9),编码的相应多肽被命名为T-Fc9。T-Fc9的氨基酸序列如SEQ ID NO:39中所示的,并且编码其的相应多核苷酸序列如SEQ IDNO:40所示的。
1.3P-Fc9和P-LC的制备
根据美国专利US7879325B2(通过引用并入本文)获得帕妥珠单抗的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码帕妥珠单抗的轻链(P-LC)的核酸分子。P-LC的氨基酸序列如SEQ ID NO:41所示,编码其的相应多核苷酸序列如SEQ ID NO:42所示。然后,将点突变(T366W和K409A)引入编码帕妥珠单抗重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的帕妥珠单抗重链的核酸分子(在本文称为P-Fc9),编码的相应多肽被命名为P-Fc9。P-Fc9的氨基酸序列如SEQ ID NO:43所示,并且编码其的相应多核苷酸序列如SEQ ID NO:44所示。
1.4Mab806-Fc9和Mab806-LC的制备
根据US7589180B2(通过引用并入本文)获得Mab806的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码Mab806的轻链(Mab806-LC)的核酸分子。Mab806-LC的氨基酸序列如SEQ ID NO:45所示,编码其的相应多核苷酸序列如SEQ ID NO:46中所示。然后,将点突变(T366W和K409A)引入编码Mab806重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的Mab806重链的核酸分子(在本文称为Mab806-Fc9),编码的相应多肽被命名为Mab806-Fc9。Mab806-Fc9的氨基酸序列如SEQ ID NO:47中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:48中所示。
1.5 5E5-Fc9和5E5-LC的制备
根据US8440798B2(通过引用并入本文)获得5E5的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码5E5的轻链(5E5-LC)的核酸分子。5E5-LC的氨基酸序列如SEQID NO:49中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:50中所示。然后,将点突变(T366W和K409A)引入编码5E5重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的5E5重链的核酸分子(在本文称为5E5-Fc9),编码的相应多肽被命名为5E5-Fc9。5E5-Fc9的氨基酸序列如SEQ ID NO:51中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:52中所示。
1.6hu56-Fc9的制备
根据CN106397592A获得hu56的重链可变区的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。之后,将点突变(T366W和K409A)引入IgG1-Fc片段,由此获得的多肽被称为Fc9。然后,将接头序列“GAP”(SEQ ID NO:53)添加到Fc9的N末端,以获得接头-Fc9。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码hu56的重链可变区的多核苷酸序列添加到编码接头-Fc9的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白hu56-Fc9的多核苷酸序列。hu56-Fc9的氨基酸序列如SEQ ID NO:54中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:55中所示。
1.7hu56di-Fc9的制备
根据CN106397592A获得hu56的重链可变区的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。通过接头“GAP”(SEQ ID NO:53)连接Hu56的重链可变区的两个拷贝以获得hu56di。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。之后,将点突变(T366W和K409A)引入IgG1-Fc片段,由此获得的多肽被称为Fc9。然后,将接头序列“EPKSS”(SEQ ID NO:58)添加到Fc9的N末端,以获得接头-Fc9。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码hu56di的多核苷酸序列添加到编码接头-Fc9的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白hu56di-Fc9的多核苷酸序列。hu56di-LC的氨基酸序列如SEQ ID NO:56中所示,编码其的多核苷酸序列如SEQ ID NO:57中所示。
1.8mPD-L1-Fc9的制备
根据CN105777906A获得抗小鼠PD-L1 ScFv分子(B50-6-ScFv),并合成了编码mPD-L1-ScFv-Fc融合蛋白的核酸分子。然后合成编码mPD-L1-ScFv-Fc的重链的核酸分子。mPD-L1-ScFv-Fc的氨基酸序列如SEQ ID NO:158中所示,并且编码其的相应多核苷酸序列如SEQID NO:159中所示。然后,将点突变(T366W和K409A)引入编码mPD-L1-ScFv-Fc融合蛋白的核酸分子中以获得mPD-L1-ScFv-Fc9,编码的相应多肽被命名为mPD-L1-Fc9,氨基酸序列如SEQ ID No:59中所示,编码其的多核苷酸序列如SEQ ID NO:60中所示。
1.9CD47-muFc的制备
根据蛋白质数据库Uniprot中的人CD47(Q08722)的氨基酸序列获得人CD47细胞外结构域的氨基酸序列(即,Q08722中的第19位至第141位残基)。根据蛋白质数据库Uniprot中鼠免疫球蛋白γ1(P01868)恒定区的氨基酸序列,获得了muFc的氨基酸序列(即,P01868中的第112位残基至第213位残基)。使用DNAworks在线工具(http://helixweb.nih.gov)设计相应的编码DNA序列以获得CD47-muFc融合蛋白基因,并通过人工合成获得了DNA片段。通过Fermentas HindIII和EcoRI将合成的基因序列克隆到商业载体pcDNA4/myc-HisA(Invitrogen,V863-20)中。然后对重组质粒测序以进行确认,从而获得pcDNA4-CD47-muFc的质粒DNA。CD47-muFc的氨基酸序列如SEQ ID NO:61中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:62中所示。
1.10CD47-EGFP的制备
根据蛋白质数据库Uniprot中的人CD47(Q08722)的氨基酸序列获得人CD47的全长氨基酸序列。根据蛋白质数据库Uniprot中的增强型绿色荧光蛋白EGFP(C5MKY7)的氨基酸序列,获得了EGFP的氨基酸序列。使用DNAworks在线工具(http://helixweb.nih.gov)设计相应的编码DNA序列以获得CD47-EGFP融合蛋白基因,并通过人工合成获得了DNA片段。通过Fermentas HindIII和EcoRI将合成的基因序列克隆到商业载体pcDNA4/myc-HisA(Invitrogen,V863-20)中。然后对重组质粒测序以进行确认,从而获得pcDNA4-CD47-EGFP的质粒DNA。CD47-EGFP的氨基酸序列如SEQ ID NO:63中所示,并且编码其的多核苷酸序列如SEQ ID NO:64中所示。
1.11SIRPα-Fc6的制备
首先,从国家生物技术信息中心(NCBI)获得人SIRPα(NM_080792.2)的序列信息,并获得编码它的全长多核苷酸序列。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得了人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。之后,将点突变(T366S、L368G、Y407A和F405K)引入IgG1-Fc片段,由此获得的多肽被称为Fc6。然后,将接头序列“GGGGS”(SEQ ID NO:65)添加到Fc6的N末端,以获得接头-Fc6。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码人SIRPα的多核苷酸序列添加到编码接头-Fc6的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白人SIRPα-Fc6的多核苷酸序列。人SIRPα-Fc6(SIRPα-Fc6)的氨基酸序列如SEQ ID NO:66中所示,编码其的多核苷酸序列如SEQ ID NO:67中所示。
1.12SIRPα-Fc IgG1的制备
首先,从国家生物技术信息中心(NCBI)获得人SIRPα(NM_080792.2)的序列信息,并获得编码它的全长多核苷酸序列。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得了人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。然后,将接头序列“GAPGG”(SEQ ID NO:68)添加到IgG1-Fc的N末端,以获得接头-IgG1-Fc。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码人SIRPα的多核苷酸序列添加到编码接头-IgG1-Fc的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白人SIRPα-Fc IgG1的多核苷酸序列。人SIRPα-FcIgG1(SIRPα-Fc IgG1的简称)的氨基酸序列如SEQ ID NO:69中所示,并且编码其的多核苷酸序列如SEQ ID NO:70中所示。
1.13hu56-Fc6-SIRPα的制备
根据CN106397592A获得hu56的重链可变区的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得了人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。之后,将点突变(T366S、L368G、Y407A和F405K)引入IgG1-Fc片段,由此获得的多肽被称为Fc6。然后,将接头序列“GGGGS”(SEQ ID NO:65)添加到Fc6的N末端,以获得接头-Fc6,将接头序列“(GGGGS)3”(SEQID NO:71)添加到接头-Fc6的C末端,以获得接头-Fc6-接头。从国家生物技术信息中心(NCBI)获得人SIRPα(NM_080792.2)的序列信息,并获得编码其的全长多核苷酸序列。将编码人SIRPα的多核苷酸序列添加到编码接头-Fc6-接头的多核苷酸序列的3'末端,从而获得并合成编码融合蛋白接头-Fc6-SIRPα的多核苷酸序列。然后,将hu56的重链可变区与接头-Fc6-SIRPα的N末端融合,以获得hu56-Fc6-SIRPα。hu56-Fc6-SIRPα的氨基酸序列如SEQ IDNO:72中所示,并且编码其的多核苷酸序列如SEQ ID NO:73中所示。
1.14ate-Fc9和ate-LC的制备
从http://www.imgt.org/mAb-DB/index获得阿特朱单抗的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码阿特朱单抗的轻链(ate-LC)的核酸分子。ate-LC的氨基酸序列如SEQ ID NO:74中所示,并且编码其的相应多核苷酸序列如SEQ ID No:75中所示。然后,将点突变(T366W和K409A)引入编码阿特朱单抗重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的阿特朱单抗重链的核酸分子(在本文称为ate-Fc9),编码的相应多肽被命名为ate-Fc9。ate-Fc9的氨基酸序列如SEQ ID NO:76中所示,并且编码其的多核苷酸序列如SEQ ID NO:77中所示。
1.15ave-Fc9和ave-LC的制备
从http://www.imgt.org/mAb-DB/index获得阿维单抗的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码阿维单抗的轻链(ate-LC)的核酸分子。ave-LC的氨基酸序列如SEQ ID NO:78中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:79中所示。然后,将点突变(T366W和K409A)引入编码阿维单抗重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的阿维单抗重链的核酸分子(在本文称为ave-Fc9),编码的相应多肽被命名为ave-Fc9。ave-Fc9的氨基酸序列如SEQ ID NO:80中所示,并且编码其的多核苷酸序列如SEQ ID NO:81中所示。
1.16dur-Fc9和dur-LC的制备
从http://www.imgt.org/mAb-DB/index获得度伐鲁单抗的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码度伐鲁单抗的轻链(dur-LC)的核酸分子。dur-LC的氨基酸序列如SEQ ID NO:82中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:83中所示。然后,将点突变(T366W和K409A)引入编码度伐鲁单抗重链的Fc区基因的多核苷酸序列中,并合成编码经修饰的度伐鲁单抗重链的核酸分子(在本文称为dur-Fc9),编码的相应多肽被命名为dur-Fc9。dur-Fc9的氨基酸序列如SEQ ID NO:84中所示,并且编码其的多核苷酸序列如SEQ ID NO:85中所示。
1.17CV1-Fc6和CV1-Fc的制备
首先,在Weiskopf K.等Engineered SIRPαvariants as immunotherapeuticadjuvants to anti-cancer antibodies,Science,2013,341(6141):88-91中描述了CV1的序列信息和合成方法。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得了人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。之后,将点突变(T366S、L368G、Y407A和F405K)引入IgG1-Fc片段,由此获得的多肽被称为Fc6。然后,将接头序列“GGGGS”(SEQ ID NO:65)添加到Fc6的N末端,以获得接头-Fc6。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码CV1的多核苷酸序列添加到编码接头-Fc6的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白人CV1-Fc6的多核苷酸序列。CV1-Fc6的氨基酸序列如SEQ ID NO:148中所示,编码其的多核苷酸序列如SEQ ID NO:149中所示。
根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得了人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。然后,将接头序列“GAPGG”(SEQ ID NO:68)添加到IgG1-Fc的N末端,以获得接头-IgG1-Fc。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码人CV1的多核苷酸序列添加到编码接头-IgG1-Fc的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白人CV1-Fc的多核苷酸序列。人CV1-Fc的氨基酸序列如SEQ ID NO:154中所示,并且编码其的多核苷酸序列如SEQ ID NO:155中所示。
1.18mCD47-ScFv-Fc6的制备
合成了抗小鼠CD47 ScFv分子(miap-301-ScFv)。然后合成编码mCD47-ScFv-Fc的重链的核酸分子。mCD47-ScFv-Fc的氨基酸序列如SEQ ID NO:160中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:161中所示。然后,将点突变(T366S、L368G、Y407A和F405K)引入编码mCD47-ScFv-Fc融合蛋白的核酸分子中以获得mCD47-ScFv-Fc6,编码的相应多肽被命名为mCD47-ScFv-Fc6,其氨基酸序列如SEQ ID NO:162中所示,编码其的多核苷酸序列如SEQ ID NO:163中所示。
1.19mSIRPα-Fc6和mSIRPα-Fc的制备
首先,从国家生物技术信息中心(NCBI)获得小鼠SIRPα(NM_001177647.2)的序列信息,并获得编码它的全长多核苷酸序列。然后,根据蛋白质数据库Uniprot的人免疫球蛋白γ1(IgG1)恒定区(P01857)的氨基酸序列,获得了人IgG1-Fc的氨基酸序列(即,P01857的残基104至残基330)。然后,将接头序列“GAPGG”(SEQ ID NO:68)添加到IgG1-Fc的N末端,以获得接头-IgG1-Fc。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码mSIRPα的多核苷酸序列添加到编码接头-IgG1-Fc的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白mSIRPα-Fc的多核苷酸序列。mSIRPα-Fc的氨基酸序列如SEQ ID NO:152中所示,并且编码其的多核苷酸序列如SEQ ID NO:153中所示。之后,将点突变(T366S、L368G、Y407A和F405K)引入IgG1-Fc片段,由此获得的多肽被称为Fc6。然后,将接头序列“GGGGS”(SEQ ID NO:65)添加到Fc6的N末端,以获得接头-Fc6。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)设计编码其的相应DNA序列。将编码小鼠SIRPα的多核苷酸序列添加到编码接头-Fc6的多核苷酸序列的5'末端,从而获得并合成编码融合蛋白小鼠SIRPα-Fc6的多核苷酸序列。小鼠SIRPα-Fc6(mSIRPα-Fc6)的氨基酸序列如SEQ ID NO:150中所示,编码其的多核苷酸序列如SEQ ID NO:151中所示。
1.20AB6.12-HC和AB6.12-LC的制备
根据WO2014123580A(通过引用并入本文)获得AB6.12的重链和轻链的全长氨基酸序列。然后,使用在线工具DNAworks(helixweb.nih.gov/dnaworks/)获得编码这些氨基酸序列的相应DNA序列。然后合成编码AB6.12的轻链(AB6.12-LC)的核酸分子。AB6.12-LC的氨基酸序列如SEQ ID NO:166中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:167中所示。然后合成编码AB6.12的重链(AB6.12-HC)的核酸分子。AB6.12-HC的氨基酸序列如SEQID NO:164中所示,并且编码其的相应多核苷酸序列如SEQ ID NO:165中所示。
实施例2:重组质粒的构建
用HindIII和EcoRI(Takara)消化根据实施例1获得的核酸分子(分别编码T-Fc9,P-Fc9、Mab806-Fc9、5E5-Fc9、hu56-Fc9、hu56di-Fc9、ate-Fc9、ave-Fc9、dur-Fc9、mPD-L1-Fc9、T-LC(曲妥珠单抗轻链)、P-LC(帕妥珠单抗轻链)、Mab806-LC(Mab806轻链)、5E5-LC(5E5轻链)、AB6.12-LC(AB6.12轻链)、ate-LC、ave-LC、dur-LC、SIRPα-Fc6、SIRPα-Fc IgG1、CV1-Fc6、hu56-Fc6-SIRPα、mSIRPα-Fc6、T-HC(曲妥珠单抗重链)、AB6.12-HC(Ab6.12重链)、CV1-Fc、scFv-Fc和mCD47-scFv-Fc6),然后分别将其亚克隆到载体pcDNA4/myc-HisA(Invitrogen,V863-20)中。通过测序验证获得的质粒,正确的重组质粒被分别命名为:pcDNA4-T-Fc9、pcDNA4-P-Fc9、pcDNA4-Mab806-Fc9、pcDNA4-5E5-Fc9、pcDNA4-hu56-Fc9、pcDNA4-hu56di-Fc9、pcDNA4-ate-Fc9、pcDNA4-ave-Fc9、pcDNA4-dur-Fc9、pcDNA4-mPD-L1-Fc9、pcDNA4-T-LC、pcDNA4-P-LC、pcDNA4-Mab806-LC、pcDNA4-5E5-LC、pcDNA4-AB6.12-LC、pcDNA4-ate-LC、pcDNA4-ave-LC、pcDNA4-dur-LC、pcDNA4-SIRPα-Fc6、pcDNA4-SIRPα-FcIgG1、pcDNA4-CV1-Fc6、pcDNA4-hu56-Fc6-SIRPα、pcDNA4-mSIRPα-Fc6、pcDNA4-T-HC、pcDNA4-AB6.12-HC、pcDNA4-CV1-Fc、pcDNA4-scFv-Fc和pcDNA4-mCD47-scFv-Fc6。
实施例3:蛋白质异二聚体的表达和纯化
转染前两天,制备12X 600mL悬浮驯化的HEK293(ATCC,CRL-1573TM)细胞用于瞬时转染,并以0.8×106个细胞/ml的密度接种细胞。两天后,将三份细胞悬液等分试样离心,然后重悬于600mL Freestyle293培养基中。
将获自实施例2的重组表达载体分为以下几组:
组1:pcDNA4-T-Fc9(200μg)+pcDNA4-T-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组2:pcDNA4-P-Fc9(200μg)+pcDNA4-P-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组3:pcDNA4-Mab806-Fc9(200μg)+pcDNA4-Mab806-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组4:pcDNA4-5E5-Fc9(200μg)+pcDNA4-5E5-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组5:pcDNA4-hu56di-Fc9(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组6:pcDNA4-mPD-L1-Fc9(200μg)+pcDNA4-mSIRPα-Fc6(200μg)
组7:pcDNA4-SIRPα-Fc IgG1(200μg)Group组8:pcDNA4-CD47-muFc(200μg)
组9:pcDNA4-CD47-EGFP(200μg)
组10:pcDNA4-hu56-Fc9(200μg)+pcDNA4-hu56-Fc6-SIRPα(200μg)
组11:pcDNA4-ate-Fc9(200μg)+pcDNA4-ate-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组12:pcDNA4-ave-Fc9(200μg)+pcDNA4-ave-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组13:pcDNA4-dur-Fc9(200μg)+pcDNA4-dur-LC(200μg)+pcDNA4-SIRPα-Fc6(200μg)
组14:pcDNA4-hu56di-Fc9(200μg)+pcDNA4-CV1-Fc6(200μg)
组15:pcDNA4-mPD-L1-Fc9(200μg)+pcDNA4-CV1-Fc6(200μg)
组16:pcDNA4-T-Fc9(200μg)+pcDNA4-T-LC(200μg)+pcDNA4-mSIRPα-Fc6(200μg)
组17:pcDNA4-mPD-L1-scFv-Fc9(200μg)+pcDNA4-mCD47-scFv-Fc6(200μg)
组18:pcDNA4-mSIRPα-Fc(200μg)
组19:pcDNA4-T-HC(200μg)+pcDNA4-T-LC(200μg)
组20:pcDNA4-AB6.12-HC(200μg)+pcDNA4-AB6.12-LC(200μg)
组21:pcDNA4-mPD-L1-scFv-Fc(200μg)
组22:pcDNA4-mCD47-scFv-Fc(200μg)
组23:pcDNA4-CV1-Fc(200μg)
所有蛋白质均在瞬时转染的293F细胞中产生。简言之,将FreeStyle 293F细胞(Invitrogen)在293F培养基(Invitrogen)中生长,用非线性化质粒DNA和293Fectin试剂(Invitrogen)转染,并在37℃、5%CO2下于摇瓶批次中以80-100mL/瓶的体积生长6天。所有蛋白质均通过一步蛋白A色谱法纯化。通过SDS-PAGE确定每种蛋白质的质量。类似地,用SDS-PAGE验证并确认了本申请的其他免疫缀合物的表达和纯化结果。
将如此获得的免疫缀合物命名为(分别从组1至组23):Tmab-SIRPα、Pmab-SIRPα、Mab806-SIRPα、5E5-SIRPα、hu56di-SIRPα、mPD-L1-mSIRPα、SIRPα-Fc IgG1、CD47-muFc、CD47-EGFP、hu56-Fc6-SIRPα、ate-SIRPα、ave-SIRPα、dur-SIRPα、hu56di-CV1、mPD-L1-CV1、Tmab-mSIRPα、mPD-L1-mCD47、mSIRPα-Fc、KN034(赫赛汀Herceptin)、AB6.12 IgG1、a-mPD-L1、a-mCD47和CV1-Fc。
在图2中,泳道1上加载有SIRPα-Fc IgG1(还原性)。泳道2加载有hu56di-SIRPα(还原性);泳道3加载有AB6.12 IgG1(还原性);泳道4加载有蛋白质标记物;泳道5为空白;泳道6加载有SIRPα-Fc IgG1(非还原性);泳道7加载有hu56di-SIRPα(非还原性);泳道8加载有AB6.12 IgG1(非还原性)。图2的结果证明成功地表达和纯化了本申请的免疫缀合物。
图1a-1b举例说明本申请的免疫缀合物的实例。在以上获得的免疫缀合物(例如,蛋白质性质的异二聚体)中,ate-SIRPα可以是图1a中所示的免疫缀合物的示例性实施方案,hu56-Fc6-SIRPα可以是图1b中所示的免疫缀合物的示例性实施方案
实施例4本申请的免疫缀合物的结合动力学
hu56di-SIRPα免疫缀合物或对照抗体(SIRPα-Fc IgG1和AB6.12 IgG1)的结合动力学是使用Octet K2系统(FortéBio),通过生物层干涉测量(BLI)方法确定的。所有实验均在25℃下在含0.5%BSA和0.5%Tween 20,pH 7.2的PBS缓冲液中进行。将CD47-muFc固定在AHC Biosensors上,随后将其用于缔合(与hu56di-SIRPα、SIRPα-Fc IgG1或AB6.12 IgG1)和解离测量,每次进行分别为40秒和300秒的时间窗。完成上述步骤后,使随仪器提供的FortéBio分析软件,将减去的结合干扰数据应用于结合常数的计算。
出乎意料的是,如表6所述,hu56di-SIRPα和SIRPα-Fc IgG1对CD47具有相当的结合亲和力。
表6.
实施例5本申请的免疫缀合物的FACS结合亲和力
比较了hu56di-SIRPα、SIRPα-Fc IgG1和AB6.12 IgG1与细胞表面人CD47的结合活性。简言之,将表达CD47-EGFP的细胞与各种浓度的hu56di-SIRPα、SIRPα-Fc IgG1和AB6.12IgG1在4℃下孵育30分钟。然后洗涤细胞以除去任何未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体(eBiosciences Cat#12-4998-82)在4℃孵育20分钟。然后通过流式细胞术(Life Technology)分析细胞。
如图3所示,水平坐标是hu56di-SIRPα、SIRPα-Fc IgG1和AB6.12 IgG1的浓度,垂直坐标是MFI的值。如所期望的,由于SIRPα的单臂原因,hu56di-SIRPα的结合亲和力远低于SIRPα-Fc IgG1或AB6.12 IgG1的结合亲和力。
实施例6本申请的免疫缀合物的体外促吞噬活性
人巨噬细胞由来自Ficoll纯化的人外周血单核细胞的单核细胞产生。将单核细胞在含有50ng/ml的人单核细胞集落刺激因子1(CSF-1)和25ng/ml的人白介素10(IL-10)的培养基中培养至少1周,以促进其发展为巨噬细胞。在37℃下用5μM CFSE标记1×107个Jurket细胞,持续20分钟。标记后,将Jurket细胞与PBS、hu56di-SIRPα或同种型对照(人IgG1)在室温(RT)下孵育15分钟。然后将1×105个Jurket细胞添加到各个孔中,与1×105个巨噬细胞混合,并在37℃,5%CO2湿润的细胞培养箱中培养2小时。孵育后,将孔洗涤并通过流式细胞术(Life Technology)分析巨噬细胞。
结果示于图4中。水平坐标是PBS、同种型对照(人IgG1)和hu56di-SIRPα,垂直坐标是吞噬作用的百分比。可以看出,与PBS和同型对照组相比,hu56di-SIRPα表现出较强的促吞噬活性。
实施例7本申请的免疫缀合物的双重抗原肿瘤结合
通过FACS测定双重抗原和单抗原的肿瘤结合亲和力。将A375细胞(表达CD47)和A375-PD-L1肿瘤细胞(表达CD47和PD-L1)与各种浓度的hu56di-SIRPα在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体(eBiosciences Cat#12-4998-82)在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。
结果示于图5中。水平坐标是hu56di-SIRPα的浓度,垂直坐标是MFI的对数值。结果表明,与仅表达单抗原的细胞相比,对于表达双重抗原的细胞,hu56di-SIRPα的结合亲和力显著增加。
实施例8过量红细胞抗原库中的肿瘤结合
关于基于CD47的治疗剂的一个重要问题是靶标在红细胞表面的表达,所述靶标有可能充当较大的抗原库(antigen sink)并引起血液学毒性。实际上,已经报道了用SIRPα-Fc IgG1和CD47特异性抗体治疗的动物的贫血。因此,通过流式细胞术评估了hu56di-SIRPα与肿瘤细胞在过量人红细胞抗原库中的结合。将A375细胞(表达CD47)和A375-PD-L1肿瘤细胞(表达CD47和PD-L1)与过量15倍的RBC混合,然后与20μg/ml hu56di-SIRPα、SIRPα-FcIgG1或AB6.12 IgG1或同种型对照(人IgG1)在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。通过抗人CD235a(eBiosciences Cat#12-9987-80)评估红细胞的圈门。
结果示于图6a中。将过量15倍的RBC与各种浓度的hu56di-SIRPα混合,并显示RBC的结合。如图6a所示,hu56di-SIRPα优先与肿瘤细胞而非RBC结合。hu56di-SIRPα与RBC结合的MFI与同型对照相似。相反,SIRPα-Fc IgG1和AB6.12 IgG1同时结合肿瘤细胞和RBC。对于肿瘤结合,当肿瘤细胞表达双重抗原时,hu56di-SIRPα的结果与SIRPα-Fc IgG1和AB6.12IgG1的结果非常相似。
类似地,因此通过流式细胞术评估了hu56-SIRPα、ate-SIRPα、hu56-Fc6-SIRPα、SIRPα-Fc IgG1和AB6.12 IgG1与肿瘤细胞在过量人红细胞抗原库中的结合。
将A375-PD-L1肿瘤细胞(表达CD47和PD-L1)与过量15倍的RBC混合,然后与20μg/ml hu56di-SIRPα、ate-SIRPα、hu56-Fc6-SIRPα、SIRPα-Fc IgG1、AB6.12 IgG1或同种型对照(人IgG1)在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。通过抗人CD235a(eBiosciences Cat#12-9987-80)评估红细胞的圈门。
结果示于图6b中。在图6b中,序列号1、2、3、4、5和6分别对应于同种型对照(人IgG1)、hu56di-SIRPα、ate-SIRPα、hu56-Fc6-SIRPα、SIRPα-Fc IgG1和AB6.12 IgG1。发现与AB6.12 IgG1相比,hu56di-SIRPα、ate-SIRPα和hu56-Fc6-SIRPα表现出更强的与肿瘤细胞的结合。除此以外,hu56di-SIRPα、ate-SIRPα和hu56-Fc6-SIRPα几乎不与RBC结合。相比之下,SIRPα-Fc IgG1与RBC结合,而AB6.12 IgG1表现出与RBC的强结合。
类似地,将MCF7肿瘤细胞与过量15倍的RBC混合,然后与20μg/ml Tmab-SIRPα、SIRPα-Fc IgG1、AB6.12 IgG1或同种型对照(人IgG1)在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。通过抗人CD235a(eBiosciences Cat#12-9987-80)评估红细胞的圈门。
类似地,将T47D肿瘤细胞与过量15倍的RBC混合,然后与20μg/ml 5E5-SIRPα、SIRPα-Fc IgG1、AB6.12 IgG1或同种型对照(人IgG1)在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。通过抗人CD235a(eBiosciences Cat#12-9987-80)评估红细胞的圈门。
类似地,将U87肿瘤细胞与过量15倍的RBC混合,然后与20μg/ml mAb806-SIRPα、SIRPα-Fc IgG1、AB6.12 IgG1或同种型对照(人IgG1)在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。通过抗人CD235a(eBiosciences Cat#12-9987-80)评估红细胞的圈门。
结果示于图6c~6e中。在图6c中,序列号1、2、3和4分别对应于同种型对照(人IgG1)、SIRPα-Fc IgG1、AB6.12 IgG1和Tmab-SIRPα。图6c显示同种型对照(人IgG1)、SIRPα-Fc IgG1、AB6.12 IgG1和Tmab-SIRPα与MCF7肿瘤细胞和RBC的结合。在图6d中,序列号1、2、3和4分别对应于同种型对照(人IgG1)、SIRPα-Fc IgG1、AB6.12 IgG1和5E5-SIRPα。图6c显示同种型对照(人IgG1)、SIRPα-Fc IgG1、AB6.12 IgG1和5E5-SIRPα与T47D肿瘤细胞和RBC的结合。在图6e中,序列号1、2、3和4分别对应于同种型对照(人IgG1)、SIRPα-Fc IgG1、AB6.12IgG1和mAb806-SIRPα。图6e显示同种型对照(人IgG1)、SIRPα-Fc IgG1、AB6.12 IgG1和mAb806-SIRPα的结合。发现Tmab-SIRPα、5E5-SIRPα和mAb806-SIRPα的三种异二聚体几乎不与RBC结合,它们与相应肿瘤细胞的结合与SIRPα-FcIgG1和AB6.12 IgG1相当。
类似地,将新鲜的RBC细胞稀释2500倍,然后将其分别与20μgml-1同种型对照(人IgG1)、hu56di-SIRPα、hu56di-CV1、SIRPα-Fc IgG1和AB6.12 IgG1一起孵育。结果示于图6f中,序列号1、2、3、4和5分别对应于同种型对照、hu56di-SIRPα、hu56di-CV1、SIRPα-Fc IgG1和AB6.12 IgG1。图6f显示,hu56di-CV1表现出比hu56di-SIRPα更强的与RBC的结合,hu56di-CV1表现出与AB6.12 IgG1相当的与RBC的结合,SIRPα-Fc IgG1表现出比hu56di-CV1和AB6.12 IgG1更弱的与RBC的结合。因此,可以推断出hu56di-SIRPα表现出比hu56di-CV1、SIRPα-Fc IgG1和AB6.12 IgG1更好的安全性。
类似地,将MC38肿瘤细胞与过量15倍的小鼠RBC混合,然后与20μg/ml a-mPD-L1、mSIRPα-Fc、CV1-Fc、mPD-L1-CV1、mPD-L1-mSIRPα或同种型对照(人IgG1)在4℃下孵育30分钟。然后洗涤细胞以除去未结合的蛋白质,然后将其与抗-hIgG Fcγ特异性PE抗体在4℃孵育20分钟。通过流式细胞术(Life Technology)分析细胞。通过抗小鼠RBC抗体(abcam Cat#ab106101)评估红细胞圈门。结果示于图6g和图6h。在图6g中,序列号1、2、3和4分别对应于同种型对照(人IgG1)、mSIRPα-Fc、a-mPD-L1和mPD-L1-mSIRPα。在图6h中,序列号1、2、3和4分别对应于同种型对照(人IgG1)、CV1-Fc、a-mPD-L1和mPD-L1-CV1。图6g和图6f显示,mPD-L1-CV1表现出比mPD-L1-mSIRPα更强的与RBC的结合,mPD-L1-CV1表现出与CV1-Fc相当的与RBC的结合,mSIRPα-Fc表现出比mPD-L1-CV1更弱的与RBC的结合。因此,可以推断出mPD-L1-mSIRPα表现出比mPD-L1-CV1和mSIRPα-Fc更好的安全性。
实施例9本申请的免疫缀合物的血小板结合
血小板还表达CD47作为自身抗原,以防止巨噬细胞的吞噬。据报道,SIRPα-Fc在注射入人体后诱发血小板减少症。因此,使用流式细胞术检查了hu56di-SIRPα的血小板结合。通过离心从新鲜血液中分离出血小板。首先,将新鲜血液以200g离心10分钟,以获得富含血小板的血浆(PRP),然后将PRP以1800g离心10分钟,以获得血小板。将血小板与20μg/mlhu56di-SIRPα、SIRPα-Fc IgG1或AB6.12 IgG1或同种型对照(人IgG1)在4℃孵育30分钟。然后,洗涤血小板以除去未结合的蛋白质,然后将其与抗-hlgG Fc APC抗体在4℃孵育20分钟。然后将血小板与抗人CD42b PE抗体在4℃孵育20分钟。通过流式细胞术(LifeTechnology)分析血小板。通过抗人CD42b(Biolegend Cat#303906)评估血小板的圈门。CD42b阳性人群中APC的中值荧光强度(MFI)表明药物与血小板结合。
结果示于图7中。如图7a所示,水平坐标为hu56di-SIRPα、SIRPα-Fc IgG1、AB6.12IgG1或同种型对照的浓度,垂直坐标显示MFI值。结果示于图7b中。从图7可以看出,hu56di-SIRPα与血小板的结合远低于SIRPα-Fc IgG1和AB6.12 IgG1与血小板的结合。
实施例10体内抗肿瘤功效和安全性
SIRPα上的CD47结合位点位于IgV环结构域中。在小鼠和人SIRPα中,细胞外IgV结构域相对保守(>75%),但与CD47的结合是物种特异性的。人SIRPα与NOD小鼠的CD47牢固结合,但不与C57BL/6小鼠的CD47结合。因此,mPD-L1-mSIRPα被构建来评估MC38同基因模型的抗肿瘤功效。
结果示于图8a-8d中。水平坐标是肿瘤接种后的时间,垂直坐标是肿瘤体积的值(图8a和图8B),存活百分比(图8C)和氯化血红素的fmol数(图8d)。用MC38肿瘤细胞接种C57BL/6小鼠。当良好地建立肿瘤时,瘤内施用人IgG同种型对照、α-mPD-L1、mSIRPα-Fc或mPD-L1-mSIRPα,并监测肿瘤的生长。与同种型对照(hIgG1)、mPD-L1抗体和mSIRPα-Fc相比,mPD-L1-mSIRPα显着抑制了肿瘤生长(图8a)。
对于临床施用,为了评估利用mPD-L1-mSIRPα的全身性治疗是否可以抑制肿瘤生长,将同种型对照、mPD-L1-mSIRPα以及a-mPD-L1抗体与mSIRPα-Fc的混合物腹膜内施用到建立的荷瘤小鼠中,并监测肿瘤生长。与人IgG同种型对照以及mPD-L1抗体与mSIRPα-Fc的混合物相比,全身性mPD-L1-mSIRPα治疗始终如一且显着减缓了肿瘤生长,并延长了荷瘤小鼠的生存期(图8b和8c)。为了确定mPD-L1-mSIRPα是否可以在体内保护RBC的同时与肿瘤细胞选择性结合,测量用人IgG同种型对照、a-mCD47、mSIRPα-Fc或mPD-L1-mSIRPα处理的荷瘤小鼠血清中的氯化血红素。与a-mCD47和mSIRPα-Fc处理相比,mPD-L1-mSIRPα保护RBC免受免疫裂解作用(图8d)。
同样地,mPD-L1-mCD47、mPD-L1-mSIRPα和mPD-L1-CV1被构建来评估MC38同基因模型中的抗肿瘤功效。
在图8e中,序列号1、2、3和4对应于同种型对照(hIgG1)、mPD-L1-mCD47、mPD-L1-mSIRPα和mPD-L1-CV1。在图8f中,序列号1、2、3、4和5对应于未处理的样品、同种型对照(hIgG1)、mPD-L1-mCD47、mPD-L1-mSIRPα和mPD-L1-CV1。图8e和图8f显示mPD-L1-mSIRPα和mPD-L1-CV1在大剂量下没有治疗差异,因为少量但足够的mPD-L1-CV1可以到达肿瘤并以更高的亲和力与肿瘤细胞结合(尽管mPD-L1-CV1与RBC的结合较高)。图8G显示mPD-L1-mSIRPα在小剂量上优于mPD-L1-CV1,因为mPD-L1-CV1由于其与RBC的更高结合而不能到达肿瘤。
同样地,Tmab-mSIRPα、mSIRPα-Fc、IgG1同种型和KN034(赫赛汀)被构建来评估在C57BL/6小鼠的MC38-HER2同基因模型中的抗肿瘤功效。表7提供了上述药物的具体治疗信息。图8h显示,Tmab-mSIRPα抑制肿瘤生长明显优于mSIRPα-Fc、IgG1同种型和KN034(赫赛汀)。图8i显示了肿瘤植入后小鼠的体重。
表7
实施例11与化学疗法的组合
另外,测试了本申请的免疫缀合物与化学疗法的潜在协同作用。
然后,检查了mPD-L1-mSIRPα与多柔比星(doxorubicin)组合的作用。如图9所示,水平坐标是治疗后天数,垂直坐标是治疗后小鼠的存活百分比。用MC38肿瘤细胞接种C57BL/6小鼠,11天后,瘤内施用多柔比星,1天后施用mPD-L1-mSIRPα。与同种型对照、单独的多柔比星或单独的mPD-L1-mSIRPα相比,多柔比星与mPD-L1-mSIRPα的组合进一步显著地抑制了肿瘤生长并延长了荷瘤小鼠的生存期(图9)。
实施例12人源化小鼠模型中的体内抗肿瘤功效
还在人源化小鼠模型中测试了本申请的免疫缀合物的体内抗肿瘤功效。
人源化NSG-SGM3小鼠获自Jackson实验室,为雌性,3周龄。到12周龄时进行肿瘤植入。在第0天分别用2×106MDA-MB-231肿瘤细胞静脉内接种人源化的NSG-SGM3小鼠。然后,从第5天开始,分别向荷瘤人源化NSG-SGM3小鼠施用5剂hu56di-SIRPα或同种型对照(人IgG1)(对于每种剂,每周施用两剂)。然后,测量肿瘤体积,结果示于图10中。图10显示在施予hu56di-SIRPα或同种型对照后人源化NSG-SGM3小鼠的肿瘤体积。在图10中,水平坐标是接种后的天数,而垂直纵坐标是肿瘤体积。这些结果证明,本申请的免疫缀合物在体内有效地抑制了肿瘤生长。
还测试了本申请的其他免疫缀合物(例如,Tmab-SIRPα、Pmab-SIRPα、Mab806-SIRPα、5E5-SIRPα、hu56-Fc6-SIRPα、ate-SIRPα、ave-SIRPα和dur-SIRPα)的作用,并观察到相似的结果。
尽管本文中已显示并描述了本申请的实施方案,但对于本领域技术人员而言显而易见的是,此类实施方案仅以实例的方式提供。并非意图通过说明书中提供的特定实例来限制本申请。尽管已经参考前述说明书来描述了本申请,但本文中的实施方案的描述和说明并不意味着以限制性的意义来解释。在不脱离本申请的情况下,本领域技术人员可以想到许多变化、改变和替换。此外,应理解,本申请的所有方面不限于本文所阐述的具体描述、构型或相对比例,其取决于各种条件和变量。应当理解,可在实践本申请中采用本文描述的本申请的实施方案的各种替代方案。因此,可以预期的是,本申请还应当涵盖任何此类替代、修改、变化或等同物。以下权利要求书旨在限定本申请的范围,并且由此涵盖这些权利要求的范围内的方法和结构及其等同物。
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<110> 苏州丁孚靶点生物技术有限公司
<120> 包含信号调节蛋白α的免疫缀合物
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Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 8
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> D356C+T366S+L368A+Y407V+Q347R
<400> 8
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 9
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Y349C+T366W+F405K+Q347R
<400> 9
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 10
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> D356C+T366S+L368A+Y407V+K360E+Q347E
<400> 10
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Glu Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Glu Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 11
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Y349C+T366W+K409A+K360E+Q347E
<400> 11
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Glu Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Glu Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 12
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> D356C+T366S+L368A+Y407V+F405K+Q347R
<400> 12
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 13
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Y349C+T366W+K409A+Q347R
<400> 13
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Arg Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 14
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> D356C+T366S+L368A+Y407V+F405K+K360E+Q347E
<400> 14
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Glu Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Cys Glu Leu Thr Glu Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 15
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+K409A+K392D
<400> 15
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 16
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368A+Y407V+D399S+F405K
<400> 16
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Ser Ser Asp Gly Ser Phe Lys Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 17
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+K409A
<400> 17
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 18
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368G+Y407A+F405K
<400> 18
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Gly Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Ala Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 19
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+K409A+Y349D
<400> 19
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Asp Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 20
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368A+Y407V+F405K+E357A
<400> 20
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Ala Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 21
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+K409A+Y349D+S354D
<400> 21
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Asp Thr Leu Pro Pro Asp Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 22
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+F405K
<400> 22
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 23
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368A+Y407V+K409A
<400> 23
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 24
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+F405K+D399S
<400> 24
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Ser Ser Asp Gly Ser Phe Lys Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 25
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368A+Y407V+K409A+K392D
<400> 25
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 26
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368G+Y407A+K409A
<400> 26
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Gly Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Ala Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 27
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W +F405K +Y349D
<400> 27
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Asp Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 28
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366S+L368A+Y407V +K409A +E357A
<400> 28
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Ala Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Ala Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 29
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> T366W+F405K+Y349D+S354D
<400> 29
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Asp Thr Leu Pro Pro Asp Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 30
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> wildtype human IgG1-Fc region amino acid
<400> 30
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 31
<211> 681
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> Fc gene fragment
<400> 31
gacaagaccc acacctgccc cccctgcccc gcccccgagc tgctgggcgg ccccagcgtg 60
ttcctgttcc cccccaagcc caaggacacc ctgatgatca gccgcacccc cgaggtgacc 120
tgcgtggtgg tggacgtgag ccacgagaac cccgaggtga agttcaactg gtacgtggac 180
ggcgtggagg tgcacaacgc caagaccaag ccccgcgagg agcagtacaa cagcacctac 240
cgcgtggtga gcgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 300
tgcaaggtga gcaacaaggc cctgcccgcc cccatcgaga agaccatcag caaggccaag 360
ggccagcccc gcgagcccca ggtgtacacc ctgcccccca gccgcgacga gctgaccaag 420
aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 480
tgggagagca acggccagcc cgagaacaac tacaagacca ccccccccgt gctggacagc 540
gacggcagct tcttcctgta cagcaagctg accgtggaca agagccgctg gcagcagggc 600
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagagc 660
ctgagcctga gccccggcaa g 681
<210> 32
<211> 741
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> polynucleotide fragment encoding a mouse kappaIII signal peptide
<400> 32
atggagaccg acaccctgct gctgtgggtg ctgctgctgt gggtgcccgg cagcaccggc 60
gacaagaccc acacctgccc cccctgcccc gcccccgagc tgctgggcgg ccccagcgtg 120
ttcctgttcc cccccaagcc caaggacacc ctgatgatca gccgcacccc cgaggtgacc 180
tgcgtggtgg tggacgtgag ccacgagaac cccgaggtga agttcaactg gtacgtggac 240
ggcgtggagg tgcacaacgc caagaccaag ccccgcgagg agcagtacaa cagcacctac 300
cgcgtggtga gcgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 360
tgcaaggtga gcaacaaggc cctgcccgcc cccatcgaga agaccatcag caaggccaag 420
ggccagcccc gcgagcccca ggtgtacacc ctgcccccca gccgcgacga gctgaccaag 480
aaccaggtga gcctgacctg cctggtgaag ggcttctacc ccagcgacat cgccgtggag 540
tgggagagca acggccagcc cgagaacaac tacaagacca ccccccccgt gctggacagc 600
gacggcagct tcttcctgta cagcaagctg accgtggaca agagccgctg gcagcagggc 660
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac ccagaagagc 720
ctgagcctga gccccggcaa g 741
<210> 33
<211> 1473
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of ScFv-Fc fusion protein
<400> 33
atggagaccg acaccctgct gctgtgggtg ctgctgctgt gggtgcccgg cagcaccggc 60
gaggtgcagc tgctggagag cggcggcggc gtggtgcagc ccggccgcag cctgcgcctg 120
agctgcatcg ccagcggctt caccttcagc agctacccca tgacctgggt gcgccaggcc 180
cccggcaagg gcctggagtg ggtggccagc atcagctacg acggcagcta caagtacaag 240
gccgacagca tgaagggccg cctgaccatc agccgcgaca acagcaagaa caccctgtac 300
ctggagatga acagcctgac cgccgaggac accgccgtgt actactgcgc ccgcaccgcc 360
ttcttcaacg cctacgactt ctggggccag ggcaccctgg tgaccgtgag cagcgccagc 420
accaagggcc ccagcgtggg cggcggcggc agcggcggcg gcggcagcga gatcgtgatg 480
acccagagcc ccgccaccct gagcgtgagc cccggcgagc gcgccaccct gagctgccgc 540
gccagccaga gcgtgcgcag caacctggcc tggtaccagc agaagcccgg ccaggccccc 600
cgcctgctga tctacgccgc cagcacccgc gccaccggca tccccgcccg cttcagcggc 660
agcggcagcg gcaccgagtt caccctgacc atcagcagcc tgcagagcga ggacttcgcc 720
gtgtactact gccagcagta caacgagtgg ttccgcacca gcggccaggg caccaaggtg 780
gagatcaagc gcgacaagac ccacacctgc cccccctgcc ccgcccccga gctgctgggc 840
ggccccagcg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagccgcacc 900
cccgaggtga cctgcgtggt ggtggacgtg agccacgaga accccgaggt gaagttcaac 960
tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agccccgcga ggagcagtac 1020
aacagcacct accgcgtggt gagcgtgctg accgtgctgc accaggactg gctgaacggc 1080
aaggagtaca agtgcaaggt gagcaacaag gccctgcccg cccccatcga gaagaccatc 1140
agcaaggcca agggccagcc ccgcgagccc caggtgtaca ccctgccccc cagccgcgac 1200
gagctgacca agaaccaggt gagcctgacc tgcctggtga agggcttcta ccccagcgac 1260
atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac cacccccccc 1320
gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagagccgc 1380
tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1440
acccagaaga gcctgagcct gagccccggc aag 1473
<210> 34
<211> 471
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ScFv-Fc fusion protein
<400> 34
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ile Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Pro Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Lys Ala Asp Ser Met
50 55 60
Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Asn Ser Leu Thr Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Ala Phe Phe Asn Ala Tyr Asp Phe Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro
130 135 140
Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg
145 150 155 160
Ala Ser Gln Ser Val Arg Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Thr Arg Ala Thr
180 185 190
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr
195 200 205
Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asn Glu Trp Phe Arg Thr Ser Gly Gln Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Arg Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asn Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 35
<211> 1121
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> a fusion gene fragment encoding the fusion protein VhH-Fc
<400> 35
atggagaccg acaccctgct gctgtgggtg ctgctgctgt gggtgcccgg cagcaccggc 60
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 120
tcctgtgcag cctctgaata catctacagt agctactgca tggcctggtt ccgccaggct 180
ccagggaagg agcgcgaggg ggtcgcagtt attgggagtg atggtagcac aagctacgca 240
gactccgtga aaggccgatt caccatctcc aaagacaacg ccaagaacac tctgtatctg 300
caaatgaaca gcctgaaacc tgaggacact gccatgtact actgtgcggc catcggtggt 360
tactgctacc aaccacccta tgagtaccag tactggggcc aggggaccca ggtcaccgtc 420
tcccagaacc gaaaagcagc gacaagaccc acacctgccc cccctgcccc gcccccgagc 480
tgctgggcgg ccccagcgtg ttcctgttcc cccccaagcc caaggacacc ctgatgatca 540
gccgcacccc cgaggtgacc tgcgtggtgg tggacgtgag ccacgagaac cccgaggtga 600
agttcaactg gtacgtggac ggcgtggagg tgcacaacgc caagaccaag ccccgcgagg 660
agcagtacaa cagcacctac cgcgtggtga gcgtgctgac cgtgctgcac caggactggc 720
tgaacggcaa ggagtacaag tgcaaggtga gcaacaaggc cctgcccgcc cccatcgaga 780
agaccatcag caaggccaag ggccagcccc gcgagcccca ggtgtacacc ctgcccccca 840
gccgcgacga gctgaccaag aaccaggtga gcctgacctg cctggtgaag ggcttctacc 900
ccagcgacat cgccgtggag tgggagagca acggccagcc cgagaacaac tacaagacca 960
ccccccccgt gctggacagc gacggcagct tcttcctgta cagcaagctg accgtggaca 1020
agagccgctg gcagcagggc aacgtgttca gctgcagcgt gatgcacgag gccctgcaca 1080
accactacac ccagaagagc ctgagcctga gccccggcaa g 1121
<210> 36
<211> 354
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> fusion protein VhH-Fc
<400> 36
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Tyr Ile Tyr Ser Ser Tyr
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Val Ile Gly Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys 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 Ile Gly Gly Tyr Cys Tyr Gln Pro Pro Tyr Glu Tyr Gln Tyr Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
340 345 350
Gly Lys
<210> 37
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of T-LC
<400> 37
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 38
<211> 708
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of T-LC
<400> 38
gacatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga ccgcgtgacc 60
atcacctgcc gcgccagcca ggacgtgaac accgccgtgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180
cgcttcagcg gcagccgcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac cttcggccag 300
ggcaccaagg tggagatcaa atactactgc cagcagaaca acaactggcc caccaccttc 360
ggcgccggca ccaagctgga gctgaagcgc accgtggccg cccccagcgt gttcatcttc 420
ccccccagcg acgagcagct gaagagcggc accgccagcg tggtgtgcct gctgaacaac 480
ttctaccccc gcgaggccaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaac 540
agccaggaga gcgtgaccga gcaggacagc aaggacagca cctacagcct gagcagcacc 600
ctgaccctga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga ggtgacccac 660
cagggcctga gcagccccgt gaccaagagc ttcaaccgcg gcgagtgc 708
<210> 39
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of T-Fc9
<400> 39
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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 40
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of T-Fc9
<400> 40
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgcgcctg 60
agctgcgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggcccgc atctacccca ccaacggcta cacccgctac 180
gccgacagcg tgaagggccg cttcaccatc agcgccgaca ccagcaagaa caccgcctac 240
ctgcagatga acagcctgcg cgccgaggac accgccgtgt actactgcag ccgctggggc 300
ggcgacggct tctacgccat ggactactgg ggccagggca ccctggtgac cgtgagcagc 360
gccagcacta aggggccctc tgtgtttcca ctcgcccctt ctagcaaaag cacttccgga 420
ggaactgccg ctctgggctg tctggtgaaa gattacttcc ccgaaccagt cactgtgtca 480
tggaactctg gagcactgac atctggagtt cacacctttc ctgctgtgct gcagagttct 540
ggactgtact ccctgtcatc tgtggtcacc gtgccatctt catctctggg gacccagacc 600
tacatctgta acgtgaacca caaaccctcc aacacaaaag tggacaaacg agtcgaacca 660
aaatcttgtg acaaaaccca cacatgccca ccgtgcccag ctccggaact cctgggcgga 720
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccaag tcgggatgag 1080
ctgaccaaga accaggtcag cctgtggtgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ttggactccg acggctcctt cttcctctac agcgcgctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
cagaagagcc tctccctgtc tccgggtaaa 1350
<210> 41
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of P-LC
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 42
<211> 708
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of P-LC
<400> 42
gacatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga ccgcgtgacc 60
atcacctgca aggccagcca ggacgtgagc atcggcgtgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctacagc gccagctacc gctacaccgg cgtgcccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag tactacatct acccctacac cttcggccag 300
ggcaccaagg tggagatcaa gtactactgc cagcagaaca acaactggcc caccaccttc 360
ggcgccggca ccaagctgga gctgaagcgc accgtggccg cccccagcgt gttcatcttc 420
ccccccagcg acgagcagct gaagagcggc accgccagcg tggtgtgcct gctgaacaac 480
ttctaccccc gcgaggccaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaac 540
agccaggaga gcgtgaccga gcaggacagc aaggacagca cctacagcct gagcagcacc 600
ctgaccctga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga ggtgacccac 660
cagggcctga gcagccccgt gaccaagagc ttcaaccgcg gcgagtgc 708
<210> 43
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of P-Fc9
<400> 43
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 Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg 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 Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 44
<211> 1347
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of P-Fc9
<400> 44
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgcgcctg 60
agctgcgccg ccagcggctt caccttcacc gactacacca tggactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggccgac gtgaacccca acagcggcgg cagcatctac 180
aaccagcgct tcaagggccg cttcaccctg agcgtggacc gcagcaagaa caccctgtac 240
ctgcagatga acagcctgcg cgccgaggac accgccgtgt actactgcgc ccgcaacctg 300
ggccccagct tctacttcga ctactggggc cagggcaccc tggtgaccgt gagcagcgcc 360
agcactaagg ggccctctgt gtttccactc gccccttcta gcaaaagcac ttccggagga 420
actgccgctc tgggctgtct ggtgaaagat tacttccccg aaccagtcac tgtgtcatgg 480
aactctggag cactgacatc tggagttcac acctttcctg ctgtgctgca gagttctgga 540
ctgtactccc tgtcatctgt ggtcaccgtg ccatcttcat ctctggggac ccagacctac 600
atctgtaacg tgaaccacaa accctccaac acaaaagtgg acaaacgagt cgaaccaaaa 660
tcttgtgaca aaacccacac atgcccaccg tgcccagctc cggaactcct gggcggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccaagtcg ggatgagctg 1080
accaagaacc aggtcagcct gtggtgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgttg 1200
gactccgacg gctccttctt cctctacagc gcgctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaa 1347
<210> 45
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of Mab806-LC
<400> 45
Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly
1 5 10 15
Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn
20 25 30
Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile
35 40 45
Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 46
<211> 708
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of Mab806-LC
<400> 46
gacatcctga tgacccagag ccccagcagc atgagcgtga gcctgggcga caccgtgagc 60
atcacctgcc acagcagcca ggacatcaac agcaacatcg gctggctgca gcagcgcccc 120
ggcaagagct tcaagggcct gatctaccac ggcaccaacc tggacgacga ggtgcccagc 180
cgcttcagcg gcagcggcag cggcgccgac tacagcctga ccatcagcag cctggagagc 240
gaggacttcg ccgactacta ctgcgtgcag tacgcccagt tcccctggac cttcggcggc 300
ggcaccaagc tggagatcaa gtactactgc cagcagaaca acaactggcc caccaccttc 360
ggcgccggca ccaagctgga gctgaagcgc accgtggccg cccccagcgt gttcatcttc 420
ccccccagcg acgagcagct gaagagcggc accgccagcg tggtgtgcct gctgaacaac 480
ttctaccccc gcgaggccaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaac 540
agccaggaga gcgtgaccga gcaggacagc aaggacagca cctacagcct gagcagcacc 600
ctgaccctga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga ggtgacccac 660
cagggcctga gcagccccgt gaccaagagc ttcaaccgcg gcgagtgc 708
<210> 47
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of Mab806-Fc9
<400> 47
Asp Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Ile Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Val Thr Ala Gly Arg Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 48
<211> 1338
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of Mab806-Fc9
<400> 48
gacgtgcagc tgcaggagag cggccccagc ctggtgaagc ccagccagag cctgagcctg 60
acctgcaccg tgaccggcta cagcatcacc agcgacttcg cctggaactg gatccgccag 120
ttccccggca acaagctgga gtggatgggc tacatcagct acagcggcaa cacccgctac 180
aaccccagcc tgaagagccg catcagcatc acccgcgaca ccagcaagaa ccagttcttc 240
ctgcagctga acagcgtgac catcgaggac accgccacct actactgcgt gaccgccggc 300
cgcggcttcc cctactgggg ccagggcacc ctggtgaccg tgagcgccgc cagcactaag 360
gggccctctg tgtttccact cgccccttct agcaaaagca cttccggagg aactgccgct 420
ctgggctgtc tggtgaaaga ttacttcccc gaaccagtca ctgtgtcatg gaactctgga 480
gcactgacat ctggagttca cacctttcct gctgtgctgc agagttctgg actgtactcc 540
ctgtcatctg tggtcaccgt gccatcttca tctctgggga cccagaccta catctgtaac 600
gtgaaccaca aaccctccaa cacaaaagtg gacaaacgag tcgaaccaaa atcttgtgac 660
aaaacccaca catgcccacc gtgcccagct ccggaactcc tgggcggacc gtcagtcttc 720
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960
aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020
cagccccgag aaccacaggt gtacaccctg cccccaagtc gggatgagct gaccaagaac 1080
caggtcagcc tgtggtgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgtt ggactccgac 1200
ggctccttct tcctctacag cgcgctcacc gtggacaaga gcaggtggca gcaggggaac 1260
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320
tccctgtctc cgggtaaa 1338
<210> 49
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of 5E5-LC
<400> 49
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ile Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asp Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 50
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of 5E5-LC
<400> 50
gaactcgtga tgacccagag ccccagctct ctgacagtga cagccggcga gaaagtgacc 60
atgatctgca agtcctccca gagcctgctg aactccggcg accagaagaa ctacctgacc 120
tggtatcagc agaaacccgg ccagcccccc aagctgctga tcttttgggc cagcacccgg 180
gaaagcggcg tgcccgatag attcacaggc agcggctccg gcaccgactt taccctgacc 240
atcagctccg tgcaggccga ggacctggcc gtgtattact gccagaacga ctacagctac 300
cccctgacct tcggagccgg caccaagctg gaactgaagc gtacggtggc tgcaccatct 360
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gtaccgctag cgttgtgtgc 420
ctgctgaata acttttatcc acgggaggct aaggtgcagt ggaaagtgga caatgccctc 480
cagagcggaa atagccaaga gtccgttacc gaacaggact ctaaagactc tacatactcc 540
ctgtcctcca cactgaccct ctccaaggcc gactatgaga aacacaaggt ttacgcatgc 600
gaggtcacac accagggact ctcctctccc gtgaccaaga gcttcaaccg gggagaatgc 660
<210> 51
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of 5E5-Fc9
<400> 51
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Ala Ile His Trp Val Lys Gln Lys Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly His Phe Ser Pro Gly Asn Thr Asp Ile Lys Tyr Asn Asp Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Lys Thr Ser Thr Phe Phe Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 52
<211> 1338
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of 5E5-Fc9
<400> 52
caggtgcagc tgcagcagtc tgatgccgag ctcgtgaagc ctggcagcag cgtgaagatc 60
agctgcaagg ccagcggcta caccttcacc gaccacgcca tccactgggt caagcagaag 120
cctgagcagg gcctggaatg gatcggccac ttcagccccg gcaacaccga catcaagtac 180
aacgacaagt tcaagggcaa ggccaccctg accgtggaca gaagcagcag caccgcctac 240
atgcagctga acagcctgac cagcgaggac agcgccgtgt acttctgcaa gaccagcacc 300
ttctttttcg actactgggg ccagggcaca accctgacag tgtctagcgc cagcactaag 360
gggccctctg tgtttccact cgccccttct agcaaaagca cttccggagg aactgccgct 420
ctgggctgtc tggtgaaaga ttacttcccc gaaccagtca ctgtgtcatg gaactctgga 480
gcactgacat ctggagttca cacctttcct gctgtgctgc agagttctgg actgtactcc 540
ctgtcatctg tggtcaccgt gccatcttca tctctgggga cccagaccta catctgtaac 600
gtgaaccaca aaccctccaa cacaaaagtg gacaaacgag tcgaaccaaa atcttgtgac 660
aaaacccaca catgcccacc gtgcccagct ccggaactcc tgggcggacc gtcagtcttc 720
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900
gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960
aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020
cagccccgag aaccacaggt gtacaccctg cccccaagtc gggatgagct gaccaagaac 1080
caggtcagcc tgtggtgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgtt ggactccgac 1200
ggctccttct tcctctacag cgcgctcacc gtggacaaga gcaggtggca gcaggggaac 1260
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320
tccctgtctc cgggtaaa 1338
<210> 53
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> linker1
<400> 53
Gly Ala Pro
1
<210> 54
<211> 360
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of hu56-Fc9
<400> 54
Gln 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 Lys Met Ser Ser Arg Arg
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val
35 40 45
Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg 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 Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser
100 105 110
Gly Ala Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
130 135 140
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
145 150 155 160
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
165 170 175
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
180 185 190
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
195 200 205
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
210 215 220
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
225 230 235 240
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
245 250 255
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr
260 265 270
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
275 280 285
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
290 295 300
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
305 310 315 320
Ser Ala Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
325 330 335
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
340 345 350
Ser Leu Ser Leu Ser Pro Gly Lys
355 360
<210> 55
<211> 1473
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of hu56-Fc9
<400> 55
caggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgaggctg 60
agctgtgcag ccagcggcaa gatgagcagc aggaggtgca tggcctggtt taggcaggcc 120
cctggcaaag agcgggagag ggtggccaag ctgctgacaa ctagcggctc cacctacctg 180
gctgacagcg tgaaaggcag gttcaccatc agcagagaca acagcaaaaa caccgtgtac 240
ctgcagatga actccctgag ggccgaggac accgcagtgt actattgtgc tgcagactcc 300
ttcgaggacc ctacttgtac cctggtcact agcagcggcg catttcaata ctggggccag 360
ggaacactgg tgacagtgag ctccggcgcg ccacaggtgc agctggtgga gagcggcggc 420
ggcctggtgc agcccggcgg cagcctgagg ctgagctgtg cagccagcgg caagatgagc 480
agcaggaggt gcatggcctg gtttaggcag gcccctggca aagagcggga gagggtggcc 540
aagctgctga caactagcgg ctccacctac ctggctgaca gcgtgaaagg caggttcacc 600
atcagcagag acaacagcaa aaacaccgtg tacctgcaga tgaactccct gagggccgag 660
gacaccgcag tgtactattg tgctgcagac tccttcgagg accctacttg taccctggtc 720
actagcagcg gcgcatttca atactggggc cagggaacac tggtgacagt gagctccgag 780
cctaagagca gcgacaaaac tcacacatgc ccaccgtgcc cagctccgga actcctgggc 840
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 900
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 960
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1020
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1080
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1140
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgtcgggat 1200
gagctgacca agaaccaggt cagcctgtgg tgcctggtca aaggcttcta tcccagcgac 1260
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1320
gtgttggact ccgacggctc cttcttcctc tacagcgcgc tcaccgtgga caagagcagg 1380
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1440
acgcagaaga gcctctccct gtctccgggt aaa 1473
<210> 56
<211> 491
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of hu56di-Fc9
<400> 56
Gln 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 Lys Met Ser Ser Arg Arg
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val
35 40 45
Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg 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 Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser
100 105 110
Gly Ala Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Gly Ala Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Lys Met Ser
145 150 155 160
Ser Arg Arg Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
165 170 175
Glu Arg Val Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
195 200 205
Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Ala Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val
225 230 235 240
Thr Ser Ser Gly Ala Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr
245 250 255
Val Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro
260 265 270
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
275 280 285
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
290 295 300
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
305 310 315 320
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
325 330 335
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
340 345 350
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
355 360 365
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
370 375 380
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp
385 390 395 400
Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
405 410 415
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
420 425 430
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
435 440 445
Phe Leu Tyr Ser Ala Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
450 455 460
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
465 470 475 480
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
485 490
<210> 57
<211> 1473
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of hu56di-Fc9
<400> 57
caggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgaggctg 60
agctgtgcag ccagcggcaa gatgagcagc aggaggtgca tggcctggtt taggcaggcc 120
cctggcaaag agcgggagag ggtggccaag ctgctgacaa ctagcggctc cacctacctg 180
gctgacagcg tgaaaggcag gttcaccatc agcagagaca acagcaaaaa caccgtgtac 240
ctgcagatga actccctgag ggccgaggac accgcagtgt actattgtgc tgcagactcc 300
ttcgaggacc ctacttgtac cctggtcact agcagcggcg catttcaata ctggggccag 360
ggaacactgg tgacagtgag ctccggcgcg ccacaggtgc agctggtgga gagcggcggc 420
ggcctggtgc agcccggcgg cagcctgagg ctgagctgtg cagccagcgg caagatgagc 480
agcaggaggt gcatggcctg gtttaggcag gcccctggca aagagcggga gagggtggcc 540
aagctgctga caactagcgg ctccacctac ctggctgaca gcgtgaaagg caggttcacc 600
atcagcagag acaacagcaa aaacaccgtg tacctgcaga tgaactccct gagggccgag 660
gacaccgcag tgtactattg tgctgcagac tccttcgagg accctacttg taccctggtc 720
actagcagcg gcgcatttca atactggggc cagggaacac tggtgacagt gagctccgag 780
cctaagagca gcgacaaaac tcacacatgc ccaccgtgcc cagctccgga actcctgggc 840
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 900
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 960
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1020
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1080
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1140
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgtcgggat 1200
gagctgacca agaaccaggt cagcctgtgg tgcctggtca aaggcttcta tcccagcgac 1260
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1320
gtgttggact ccgacggctc cttcttcctc tacagcgcgc tcaccgtgga caagagcagg 1380
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1440
acgcagaaga gcctctccct gtctccgggt aaa 1473
<210> 58
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> linker 2
<400> 58
Glu Pro Lys Ser Ser
1 5
<210> 59
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of mPD-L1-scFv-Fc9
<400> 59
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Thr
20 25 30
Lys Ala Ala Trp Tyr Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Phe Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
50 55 60
Asp Ser Val Lys Ser Arg Leu Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Lys Ser Val Ser Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Arg Gly Gln Tyr Thr Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Ile Leu Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu
130 135 140
Ile Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile
145 150 155 160
Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asp Leu Val Ser
165 170 175
Trp Tyr Gln Gln Tyr Pro Gly Gln Ala Pro Arg Leu Ile Ile Tyr Glu
180 185 190
Val Ile Lys Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser Lys
195 200 205
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp
210 215 220
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Arg Arg Leu His Gly
225 230 235 240
Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu Asp Lys Thr His Thr
245 250 255
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
260 265 270
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
275 280 285
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
290 295 300
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
305 310 315 320
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
325 330 335
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
340 345 350
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
355 360 365
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
370 375 380
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
385 390 395 400
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
405 410 415
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp Lys Ser Arg Trp
435 440 445
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
450 455 460
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 60
<211> 1434
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of mPD-L1-scFv-Fc9
<400> 60
caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60
acctgtgcca tctccgggga cagtgtctct agcaccaagg ctgcttggta ctggatcagg 120
cagtcccctt cgagaggcct tgagtggctg ggaaggacat acttccggtc caagtggtat 180
aatgactatg ccgactctgt gaaaagtcga ttaaccatca acccagacac atccaagaac 240
cagttctccc tgcaacttaa gtctgtgagt cccgaggaca cggctgtgta ttactgtgca 300
agagggcaat acactgcttt tgatatctgg ggccaaggga caatggtcac cgtctcttca 360
ggaattctag gatccggtgg cggtggcagc ggcggtggtg gttccggagg cggcggttct 420
cagtctgctc tgattcagcc tgcctccgtg tctgggtccc ctggacagtc gatcactatc 480
tcctgtactg gcaccagtag tgatgttgga ggttatgacc ttgtctcctg gtaccaacag 540
tacccgggcc aagcccccag actcatcatt tatgaggtca ttaagcggcc ctcagggatt 600
tctgatcgct tctctggttc caagtctggc aacacggcct ccctgacaat ctctgggctc 660
caggctgagg acgaggctga ttattattgc tgctcatatg caggtagacg tcttcatggt 720
gtgttcggag gaggcaccca gctgaccgtc ctcgacaaaa ctcacacatg cccaccgtgc 780
ccagctccgg aactcctggg cggaccgtca gtcttcctct tccccccaaa acccaaggac 840
accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 900
gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 960
aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1020
caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa agccctccca 1080
gcccccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1140
accctgcccc caagtcggga tgagctgacc aagaaccagg tcagcctgtg gtgcctggtc 1200
aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1260
aactacaaga ccacgcctcc cgtgttggac tccgacggct ccttcttcct ctacagcgcg 1320
ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1380
gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaa 1434
<210> 61
<211> 351
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of CD47-muFc
<400> 61
Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn
1 5 10 15
Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala Gln Asn
20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp Ile Tyr
35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser
50 55 60
Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala Ser Leu
65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys
85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu Leu Lys
100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Met Asp Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Val Ser Ser Val
130 135 140
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
145 150 155 160
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
165 170 175
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
180 185 190
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
195 200 205
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
210 215 220
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
245 250 255
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
260 265 270
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
275 280 285
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asn Thr
290 295 300
Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
305 310 315 320
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
325 330 335
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
340 345 350
<210> 62
<211> 1053
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of CD47-muFc
<400> 62
cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc 60
attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120
aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180
actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240
aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300
ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360
ccaatggatc cgaaatcctc tgacaaaact cacacatgcc caccgtgccc agctccggaa 420
gtatcatctg tcttcatctt ccccccaaag cccaaggatg tgctcaccat tactctgact 480
cctaaggtca cgtgtgttgt ggtagacatc agcaaggatg atcccgaggt ccagttcagc 540
tggtttgtag atgatgtgga ggtgcacaca gctcagacgc aaccccggga ggagcagttc 600
aacagcactt tccgctcagt cagtgaactt cccatcatgc accaggactg gctcaatggc 660
aaggagttca aatgcagggt caacagtgca gctttccctg cccccatcga gaaaaccatc 720
tccaaaacca aaggcagacc gaaggctcca caggtgtaca ccattccacc tcccaaggag 780
cagatggcca aggataaagt cagtctgacc tgcatgataa cagacttctt ccctgaagac 840
attactgtgg agtggcagtg gaatgggcag ccagcggaga actacaagaa cactcagccc 900
atcatgaaca cgaatggctc ttacttcgtc tacagcaagc tcaatgtgca gaagagcaac 960
tgggaggcag gaaatacttt cacctgctct gtgttacatg agggcctgca caaccaccat 1020
actgagaaga gcctctccca ctctcctggg aaa 1053
<210> 63
<211> 550
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequences of CD47-EGFP
<400> 63
Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe Cys Asn
1 5 10 15
Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala Gln Asn
20 25 30
Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp Ile Tyr
35 40 45
Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp Phe Ser
50 55 60
Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala Ser Leu
65 70 75 80
Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr Thr Cys
85 90 95
Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu Leu Lys
100 105 110
Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ile Leu Ile Val
115 120 125
Ile Phe Pro Ile Phe Ala Ile Leu Leu Phe Trp Gly Gln Phe Gly Ile
130 135 140
Lys Thr Leu Lys Tyr Arg Ser Gly Gly Met Asp Glu Lys Thr Ile Ala
145 150 155 160
Leu Leu Val Ala Gly Leu Val Ile Thr Val Ile Val Ile Val Gly Ala
165 170 175
Ile Leu Phe Val Pro Gly Glu Tyr Ser Leu Lys Asn Ala Thr Gly Leu
180 185 190
Gly Leu Ile Val Thr Ser Thr Gly Ile Leu Ile Leu Leu His Tyr Tyr
195 200 205
Val Phe Ser Thr Ala Ile Gly Leu Thr Ser Phe Val Ile Ala Ile Leu
210 215 220
Val Ile Gln Val Ile Ala Tyr Ile Leu Ala Val Val Gly Leu Ser Leu
225 230 235 240
Cys Ile Ala Ala Cys Ile Pro Met His Gly Pro Leu Leu Ile Ser Gly
245 250 255
Leu Ser Ile Leu Ala Leu Ala Gln Leu Leu Gly Leu Val Tyr Met Lys
260 265 270
Phe Val Ala Ser Asn Gln Lys Thr Ile Gln Pro Pro Arg Lys Ala Val
275 280 285
Glu Glu Pro Leu Asn Ala Phe Lys Glu Ser Lys Gly Met Met Asn Asp
290 295 300
Glu Gly Ala Pro Gly Gly Gly Met Val Ser Lys Gly Glu Glu Leu Phe
305 310 315 320
Thr Gly Val Val Pro Ile Leu Val Glu Leu Asp Gly Asp Val Asn Gly
325 330 335
His Lys Phe Ser Val Ser Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly
340 345 350
Lys Leu Thr Leu Lys Phe Ile Cys Thr Thr Gly Lys Leu Pro Val Pro
355 360 365
Trp Pro Thr Leu Val Thr Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser
370 375 380
Arg Tyr Pro Asp His Met Lys Gln His Asp Phe Phe Lys Ser Ala Met
385 390 395 400
Pro Glu Gly Tyr Val Gln Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly
405 410 415
Asn Tyr Lys Thr Arg Ala Glu Val Lys Phe Glu Gly Asp Thr Leu Val
420 425 430
Asn Arg Ile Glu Leu Lys Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile
435 440 445
Leu Gly His Lys Leu Glu Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile
450 455 460
Met Ala Asp Lys Gln Lys Asn Gly Ile Lys Val Asn Phe Lys Ile Arg
465 470 475 480
His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln
485 490 495
Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr
500 505 510
Leu Ser Thr Gln Ser Ala Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp
515 520 525
His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr Leu Gly
530 535 540
Met Asp Glu Leu Tyr Lys
545 550
<210> 64
<211> 1650
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of CD47-EGFP
<400> 64
cagctactat ttaataaaac aaaatctgta gaattcacgt tttgtaatga cactgtcgtc 60
attccatgct ttgttactaa tatggaggca caaaacacta ctgaagtata cgtaaagtgg 120
aaatttaaag gaagagatat ttacaccttt gatggagctc taaacaagtc cactgtcccc 180
actgacttta gtagtgcaaa aattgaagtc tcacaattac taaaaggaga tgcctctttg 240
aagatggata agagtgatgc tgtctcacac acaggaaact acacttgtga agtaacagaa 300
ttaaccagag aaggtgaaac gatcatcgag ctaaaatatc gtgttgtttc atggttttct 360
ccaaatgaaa atattcttat tgttattttc ccaatttttg ctatactcct gttctgggga 420
cagtttggta ttaaaacact taaatataga tccggtggta tggatgagaa aacaattgct 480
ttacttgttg ctggactagt gatcactgtc attgtcattg ttggagccat tcttttcgtc 540
ccaggtgaat attcattaaa gaatgctact ggccttggtt taattgtgac ttctacaggg 600
atattaatat tacttcacta ctatgtgttt agtacagcga ttggattaac ctccttcgtc 660
attgccatat tggttattca ggtgatagcc tatatcctcg ctgtggttgg actgagtctc 720
tgtattgcgg cgtgtatacc aatgcatggc cctcttctga tttcaggttt gagtatctta 780
gctctagcac aattacttgg actagtttat atgaaatttg tggcttccaa tcagaagact 840
atacaacctc ctaggaaagc tgtagaggaa ccccttaatg cattcaaaga atcaaaagga 900
atgatgaatg atgaaggcgc gccaggaggt ggtatggtga gcaagggcga ggagctgttc 960
accggggtgg tgcccatcct ggtcgagctg gacggcgacg taaacggcca caagttcagc 1020
gtgtccggcg agggcgaggg cgatgccacc tacggcaagc tgaccctgaa gttcatctgc 1080
accaccggca agctgcccgt gccctggccc accctcgtga ccaccctgac ctacggcgtg 1140
cagtgcttca gccgctaccc cgaccacatg aagcagcacg acttcttcaa gtccgccatg 1200
cccgaaggct acgtccagga gcgcaccatc ttcttcaagg acgacggcaa ctacaagacc 1260
cgcgccgagg tgaagttcga gggcgacacc ctggtgaacc gcatcgagct gaagggcatc 1320
gacttcaagg aggacggcaa catcctgggg cacaagctgg agtacaacta caacagccac 1380
aacgtctata tcatggccga caagcagaag aacggcatca aggtgaactt caagatccgc 1440
cacaacatcg aggacggcag cgtgcagctc gccgaccact accagcagaa cacccccatc 1500
ggcgacggcc ccgtgctgct gcccgacaac cactacctga gcacccagtc cgccctgagc 1560
aaagacccca acgagaagcg cgatcacatg gtcctgctgg agttcgtgac cgccgccggg 1620
atcactctcg gcatggacga gctgtacaag 1650
<210> 65
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> linker3
<400> 65
Gly Gly Gly Gly Ser
1 5
<210> 66
<211> 350
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of SIRPα-Fc6
<400> 66
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
115 120 125
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
130 135 140
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
145 150 155 160
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
165 170 175
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
180 185 190
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
195 200 205
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
210 215 220
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
225 230 235 240
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
245 250 255
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Gly Val
260 265 270
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
275 280 285
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
290 295 300
Gly Ser Phe Lys Leu Ala Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
305 310 315 320
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
325 330 335
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 67
<211> 1050
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of SIRPα-Fc6
<400> 67
gaggaggagc tgcaggtgat ccagcccgac aagagcgtgt ccgtggctgc cggagagagc 60
gccatcctgc actgcaccgt gacaagcctg atccccgtgg gccccatcca gtggttcaga 120
ggagccggcc ctgccaggga gctgatctac aaccagaagg agggccactt ccccagggtg 180
accaccgtga gcgagagcac caagagggag aacatggact ttagcatcag catcagcaac 240
atcacccccg ccgacgccgg aacctactac tgcgtgaagt tcaggaaggg cagccccgac 300
accgagttca agagcggagc cggcacagag ctgagcgtga gggccaagcc cagcggaggc 360
ggtggatcag acaagaccca cacttgcccc ccttgtcccg ctccggaact cctgggcgga 420
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 480
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 540
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 600
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 660
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 720
aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 780
ctgaccaaga accaggtcag cctgagttgc ggggtcaaag gcttctatcc cagcgacatc 840
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 900
ttggactccg acggctcctt caagctcgcc agcaagctca ccgtggacaa gagcaggtgg 960
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1020
cagaagagcc tctccctgtc tccgggtaaa 1050
<210> 68
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> linker4
<400> 68
Gly Ala Pro Gly Gly
1 5
<210> 69
<211> 350
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of SIRPα-Fc IgG1
<400> 69
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Gly Ala Pro Gly Gly Asp Lys Thr His Thr
115 120 125
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
130 135 140
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
145 150 155 160
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
165 170 175
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
180 185 190
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
195 200 205
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
210 215 220
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
225 230 235 240
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
245 250 255
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
260 265 270
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
275 280 285
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
290 295 300
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
305 310 315 320
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
325 330 335
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 70
<211> 1050
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of SIRPα-Fc IgG1
<400> 70
gaggaggagc tgcaggtgat ccagcccgac aagagcgtgt ccgtggctgc cggagagagc 60
gccatcctgc actgcaccgt gacaagcctg atccccgtgg gccccatcca gtggttcaga 120
ggagccggcc ctgccaggga gctgatctac aaccagaagg agggccactt ccccagggtg 180
accaccgtga gcgagagcac caagagggag aacatggact ttagcatcag catcagcaac 240
atcacccccg ccgacgccgg aacctactac tgcgtgaagt tcaggaaggg cagccccgac 300
accgagttca agagcggagc cggcacagag ctgagcgtga gggccaagcc cagcggcgcg 360
ccaggaggtg acaaaactca cacatgccca ccgtgcccag caccggaact cctgggcgga 420
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 480
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 540
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 600
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 660
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 720
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 780
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 840
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 900
ttggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 960
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1020
cagaagagcc tctccctgtc tccgggtaaa 1050
<210> 71
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> linker5
<400> 71
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 72
<211> 493
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid sequence of hu56-Fc6-SIRPα
<400> 72
Gln 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 Lys Met Ser Ser Arg Arg
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val
35 40 45
Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg 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 Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser
100 105 110
Gly Ala Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
130 135 140
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
145 150 155 160
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
165 170 175
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
180 185 190
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
195 200 205
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
210 215 220
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
225 230 235 240
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
245 250 255
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
260 265 270
Lys Asn Gln Val Ser Leu Ser Cys Gly Val Lys Gly Phe Tyr Pro Ser
275 280 285
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
290 295 300
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Lys Leu Ala
305 310 315 320
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
325 330 335
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
340 345 350
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
355 360 365
Gly Ser Gly Gly Gly Gly Ser Glu Glu Glu Leu Gln Val Ile Gln Pro
370 375 380
Asp Lys Ser Val Ser Val Ala Ala Gly Glu Ser Ala Ile Leu His Cys
385 390 395 400
Thr Val Thr Ser Leu Ile Pro Val Gly Pro Ile Gln Trp Phe Arg Gly
405 410 415
Ala Gly Pro Ala Arg Glu Leu Ile Tyr Asn Gln Lys Glu Gly His Phe
420 425 430
Pro Arg Val Thr Thr Val Ser Glu Ser Thr Lys Arg Glu Asn Met Asp
435 440 445
Phe Ser Ile Ser Ile Ser Asn Ile Thr Pro Ala Asp Ala Gly Thr Tyr
450 455 460
Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro Asp Thr Glu Phe Lys Ser
465 470 475 480
Gly Ala Gly Thr Glu Leu Ser Val Arg Ala Lys Pro Ser
485 490
<210> 73
<211> 1479
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of hu56-Fc6-SIRPα
<400> 73
caggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgaggctg 60
agctgtgcag ccagcggcaa gatgagcagc aggaggtgca tggcctggtt taggcaggcc 120
cctggcaaag agcgggagag ggtggccaag ctgctgacaa ctagcggctc cacctacctg 180
gctgacagcg tgaaaggcag gttcaccatc agcagagaca acagcaaaaa caccgtgtac 240
ctgcagatga actccctgag ggccgaggac accgcagtgt actattgtgc tgcagactcc 300
ttcgaggacc ctacttgtac cctggtcact agcagcggcg catttcaata ctggggccag 360
ggaacactgg tgacagtgag ctccgagcct aagagcagcg acaaaactca cacatgccca 420
ccgtgcccag ctccggaact cctgggcgga ccgtcagtct tcctcttccc cccaaaaccc 480
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 540
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 600
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 660
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 720
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 780
gtgtataccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgagttgc 840
ggggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 900
gagaacaact acaagaccac gcctcccgtg ttggactccg acggctcctt caagctcgcc 960
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1020
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1080
ggcggcggcg gcagcggggg cggcggcagc ggaggaggcg gcagcgagga ggagctgcag 1140
gtgatccagc ccgacaagag cgtgtccgtg gctgccggag agagcgccat cctgcactgc 1200
accgtgacaa gcctgatccc cgtgggcccc atccagtggt tcagaggagc cggccctgcc 1260
agggagctga tctacaacca gaaggagggc cacttcccca gggtgaccac cgtgagcgag 1320
agcaccaaga gggagaacat ggactttagc atcagcatca gcaacatcac ccccgccgac 1380
gccggaacct actactgcgt gaagttcagg aagggcagcc ccgacaccga gttcaagagc 1440
ggagccggca cagagctgag cgtgagggcc aagcccagc 1479
<210> 74
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate-LC
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 75
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of ate-LC
<400> 75
gacatccaga tgacccagag ccccagcagc ctgagcgcca gcgtgggcga ccgcgtgacc 60
atcacctgcc gcgccagcca ggacgtgagc accgccgtgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag tacctgtacc accccgccac cttcggccag 300
ggcaccaagg tggagatcaa gcgcaccgtg gccgccccca gcgtgttcat cttccccccc 360
agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420
ccccgcgagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480
gagagcgtga ccgagcagga cagcaaggac agcacctaca gcctgagcag caccctgacc 540
ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600
ctgagcagcc ccgtgaccaa gagcttcaac cgcggcgagt gc 642
<210> 76
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate-Fc9
<400> 76
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 Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 77
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of ate-Fc9
<400> 77
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc gacagctgga tccactgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggcctgg atcagcccct acggcggcag cacctactac 180
gccgacagcg tgaagggccg cttcaccatc agcgccgaca ccagcaagaa caccgcctac 240
ctgcagatga acagcctgcg cgccgaggac accgccgtgt actactgcgc ccgccgccac 300
tggcccggcg gcttcgacta ctggggccag ggcaccctgg tgaccgtgag cagcgccagc 360
actaaggggc cctctgtgtt tccactcgcc ccttctagca aaagcacttc cggaggaact 420
gccgctctgg gctgtctggt gaaagattac ttccccgaac cagtcactgt gtcatggaac 480
tctggagcac tgacatctgg agttcacacc tttcctgctg tgctgcagag ttctggactg 540
tactccctgt catctgtggt caccgtgcca tcttcatctc tggggaccca gacctacatc 600
tgtaacgtga accacaaacc ctccaacaca aaagtggaca aacgagtcga accaaaatct 660
tgtgacaaaa cccacacatg cccaccgtgc ccagctccgg aactcctggg cggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc caagtcggga tgagctgacc 1080
aagaaccagg tcagcctgtg gtgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgttggac 1200
tccgacggct ccttcttcct ctacagcgcg ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaa 1344
<210> 78
<211> 216
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave-LC
<400> 78
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 79
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of ave-LC
<400> 79
cagagcgccc tgacccagcc cgccagcgtg agcggcagcc ccggccagag catcaccatc 60
agctgcaccg gcaccagcag cgacgtgggc ggctacaact acgtgagctg gtaccagcag 120
caccccggca aggcccccaa gctgatgatc tacgacgtga gcaaccgccc cagcggcgtg 180
agcaaccgct tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctg 240
caggccgagg acgaggccga ctactactgc agcagctaca ccagcagcag cacccgcgtg 300
ttcggcaccg gcaccaaggt gaccgtgctg ggccagccca aggccaaccc caccgtgacc 360
ctgttccccc ccagcagcga ggagctgcag gccaacaagg ccaccctggt gtgcctgatc 420
agcgacttct accccggcgc cgtgaccgtg gcctggaagg ccgacggcag ccccgtgaag 480
gccggcgtgg agaccaccaa gcccagcaag cagagcaaca acaagtacgc cgccagcagc 540
tacctgagcc tgacccccga gcagtggaag agccaccgca gctacagctg ccaggtgacc 600
cacgagggca gcaccgtgga gaagaccgtg gcccccaccg agtgcagc 648
<210> 80
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave-Fc9
<400> 80
Glu Val Gln Leu Leu 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 Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr 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 Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 81
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of ave-Fc9
<400> 81
gaggtgcagc tgctggagag cggcggcggc ctggtgcagc ccggcggcag cctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc agctacatca tgatgtgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtgagcagc atctacccca gcggcggcat caccttctac 180
gccgacaccg tgaagggccg cttcaccatc agccgcgaca acagcaagaa caccctgtac 240
ctgcagatga acagcctgcg cgccgaggac accgccgtgt actactgcgc ccgcatcaag 300
ctgggcaccg tgaccaccgt ggactactgg ggccagggca ccctggtgac cgtgagcagc 360
gccagcacta aggggccctc tgtgtttcca ctcgcccctt ctagcaaaag cacttccgga 420
ggaactgccg ctctgggctg tctggtgaaa gattacttcc ccgaaccagt cactgtgtca 480
tggaactctg gagcactgac atctggagtt cacacctttc ctgctgtgct gcagagttct 540
ggactgtact ccctgtcatc tgtggtcacc gtgccatctt catctctggg gacccagacc 600
tacatctgta acgtgaacca caaaccctcc aacacaaaag tggacaaacg agtcgaacca 660
aaatcttgtg acaaaaccca cacatgccca ccgtgcccag ctccggaact cctgggcgga 720
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccaag tcgggatgag 1080
ctgaccaaga accaggtcag cctgtggtgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ttggactccg acggctcctt cttcctctac agcgcgctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
cagaagagcc tctccctgtc tccgggtaaa 1350
<210> 82
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur-LC
<400> 82
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 83
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of dur-LC
<400> 83
gagatcgtgc tgacccagag ccccggcacc ctgagcctga gccccggcga gcgcgccacc 60
ctgagctgcc gcgccagcca gcgcgtgagc agcagctacc tggcctggta ccagcagaag 120
cccggccagg ccccccgcct gctgatctac gacgccagca gccgcgccac cggcatcccc 180
gaccgcttca gcggcagcgg cagcggcacc gacttcaccc tgaccatcag ccgcctggag 240
cccgaggact tcgccgtgta ctactgccag cagtacggca gcctgccctg gaccttcggc 300
cagggcacca aggtggagat caagcgcacc gtggccgccc ccagcgtgtt catcttcccc 360
cccagcgacg agcagctgaa gagcggcacc gccagcgtgg tgtgcctgct gaacaacttc 420
tacccccgcg aggccaaggt gcagtggaag gtggacaacg ccctgcagag cggcaacagc 480
caggagagcg tgaccgagca ggacagcaag gacagcacct acagcctgag cagcaccctg 540
accctgagca aggccgacta cgagaagcac aaggtgtacg cctgcgaggt gacccaccag 600
ggcctgagca gccccgtgac caagagcttc aaccgcggcg agtgc 645
<210> 84
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur-Fc9
<400> 84
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 Phe Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val 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 Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Ala Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 85
<211> 1353
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of dur-Fc9
<400> 85
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcggcag cctgcgcctg 60
agctgcgccg ccagcggctt caccttcagc cgctactgga tgagctgggt gcgccaggcc 120
cccggcaagg gcctggagtg ggtggccaac atcaagcagg acggcagcga gaagtactac 180
gtggacagcg tgaagggccg cttcaccatc agccgcgaca acgccaagaa cagcctgtac 240
ctgcagatga acagcctgcg cgccgaggac accgccgtgt actactgcgc ccgcgagggc 300
ggctggttcg gcgagctggc cttcgactac tggggccagg gcaccctggt gaccgtgagc 360
agcgccagca ctaaggggcc ctctgtgttt ccactcgccc cttctagcaa aagcacttcc 420
ggaggaactg ccgctctggg ctgtctggtg aaagattact tccccgaacc agtcactgtg 480
tcatggaact ctggagcact gacatctgga gttcacacct ttcctgctgt gctgcagagt 540
tctggactgt actccctgtc atctgtggtc accgtgccat cttcatctct ggggacccag 600
acctacatct gtaacgtgaa ccacaaaccc tccaacacaa aagtggacaa acgagtcgaa 660
ccaaaatctt gtgacaaaac ccacacatgc ccaccgtgcc cagctccgga actcctgggc 720
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc aagtcgggat 1080
gagctgacca agaaccaggt cagcctgtgg tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgttggact ccgacggctc cttcttcctc tacagcgcgc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320
acgcagaaga gcctctccct gtctccgggt aaa 1353
<210> 86
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 light chain CDR1
<400> 86
His Ser Ser Gln Asp Ile Asn Ser Asn Ile Gly
1 5 10
<210> 87
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 light chain CDR2
<400> 87
His Gly Thr Asn Leu Asp Asp
1 5
<210> 88
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 light chain CDR3
<400> 88
Val Gln Tyr Ala Gln Phe Pro Trp Thr
1 5
<210> 89
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 light chain variable region
<400> 89
Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly
1 5 10 15
Asp Thr Val Ser Ile Thr Cys His Ser Ser Gln Asp Ile Asn Ser Asn
20 25 30
Ile Gly Trp Leu Gln Gln Arg Pro Gly Lys Ser Phe Lys Gly Leu Ile
35 40 45
Tyr His Gly Thr Asn Leu Asp Asp Glu Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ala Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Val Gln Tyr Ala Gln Phe Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 90
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 heavy chain CDR1
<400> 90
Ser Asp Phe Ala Trp Asn
1 5
<210> 91
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 heavy chain CDR2
<400> 91
Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 92
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 heavy chain CDR3
<400> 92
Ala Gly Arg Gly Phe Pro Tyr
1 5
<210> 93
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Mab806 heavy chain variable region
<400> 93
Asp Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Phe Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Asn Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Ile Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Val Thr Ala Gly Arg Gly Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 94
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab light chain CDR1
<400> 94
Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala
1 5 10
<210> 95
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab light chain CDR2
<400> 95
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab light chain CDR3
<400> 96
Gln Gln His Tyr Thr Thr Pro Pro Thr
1 5
<210> 97
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab light chain variable region
<400> 97
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 98
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab heavy chain CDR1
<400> 98
Asp Thr Tyr Ile His
1 5
<210> 99
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab heavy chain CDR2
<400> 99
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 100
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab heavy chain CDR3
<400> 100
Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
1 5 10
<210> 101
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Trastuzumab heavy chain variable region
<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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 102
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab light chain CDR1
<400> 102
Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala
1 5 10
<210> 103
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab light chain CDR2
<400> 103
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 104
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab light chain CDR3
<400> 104
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr
1 5
<210> 105
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab light chain variable region
<400> 105
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 106
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab heavy chain CDR1
<400> 106
Asp Tyr Thr Met Asp
1 5
<210> 107
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab heavy chain CDR2
<400> 107
Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe Lys
1 5 10 15
Gly
<210> 108
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab heavy chain CDR3
<400> 108
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr
1 5 10
<210> 109
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Pertuzumab heavy chain variable region
<400> 109
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 Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg 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 Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 110
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 light chain CDR1
<400> 110
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asp Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 111
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 light chain CDR2
<400> 111
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 112
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 light chain CDR3
<400> 112
Gln Asn Asp Tyr Ser Tyr Pro Leu Thr
1 5
<210> 113
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 light chain variable region
<400> 113
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ile Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asp Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 114
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 heavy chain CDR1
<400> 114
Asp His Ala Ile His
1 5
<210> 115
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 heavy chain CDR2
<400> 115
His Phe Ser Pro Gly Asn Thr Asp Ile Lys Tyr Asn Asp Lys Phe Lys
1 5 10 15
Gly
<210> 116
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 heavy chain CDR3
<400> 116
Ser Thr Phe Phe Phe Asp Tyr
1 5
<210> 117
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E5 heavy chain variable region
<400> 117
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Ala Ile His Trp Val Lys Gln Lys Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly His Phe Ser Pro Gly Asn Thr Asp Ile Lys Tyr Asn Asp Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Lys Thr Ser Thr Phe Phe Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser
115
<210> 118
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hu56 heavy chain CDR1
<400> 118
Arg Arg Cys Met Ala
1 5
<210> 119
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hu56 heavy chain CDR2
<400> 119
Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 120
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hu56 heavy chain CDR3
<400> 120
Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser Gly Ala
1 5 10 15
Phe Gln Tyr
<210> 121
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> hu56 heavy variable region
<400> 121
Gln 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 Lys Met Ser Ser Arg Arg
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val
35 40 45
Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg 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 Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser
100 105 110
Gly Ala Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 122
<211> 473
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SIRPαV2 without signal peptide
<400> 122
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg
115 120 125
Ala Thr Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe
130 135 140
Ser Pro Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu
145 150 155 160
Ser Asp Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr
165 170 175
Ser Ile His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val His
180 185 190
Ser Gln Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp Pro
195 200 205
Leu Arg Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro Thr
210 215 220
Leu Glu Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn Val
225 230 235 240
Thr Cys Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr Trp
245 250 255
Leu Glu Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val Thr
260 265 270
Glu Asn Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val Asn
275 280 285
Val Ser Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu His
290 295 300
Asp Gly Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser Ala
305 310 315 320
His Pro Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly Ser
325 330 335
Asn Glu Arg Asn Ile Tyr Ile Val Val Gly Val Val Cys Thr Leu Leu
340 345 350
Val Ala Leu Leu Met Ala Ala Leu Tyr Leu Val Arg Ile Arg Gln Lys
355 360 365
Lys Ala Gln Gly Ser Thr Ser Ser Thr Arg Leu His Glu Pro Glu Lys
370 375 380
Asn Ala Arg Glu Ile Thr Gln Asp Thr Asn Asp Ile Thr Tyr Ala Asp
385 390 395 400
Leu Asn Leu Pro Lys Gly Lys Lys Pro Ala Pro Gln Ala Ala Glu Pro
405 410 415
Asn Asn His Thr Glu Tyr Ala Ser Ile Gln Thr Ser Pro Gln Pro Ala
420 425 430
Ser Glu Asp Thr Leu Thr Tyr Ala Asp Leu Asp Met Val His Leu Asn
435 440 445
Arg Thr Pro Lys Gln Pro Ala Pro Lys Pro Glu Pro Ser Phe Ser Glu
450 455 460
Tyr Ala Ser Val Gln Val Pro Arg Lys
465 470
<210> 123
<211> 503
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SIRPαV2 with signal peptide
<400> 123
Met Glu Pro Ala Gly Pro Ala Pro Gly Arg Leu Gly Pro Leu Leu Cys
1 5 10 15
Leu Leu Leu Ala Ala Ser Cys Ala Trp Ser Gly Val Ala Gly Glu Glu
20 25 30
Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala Ala Gly
35 40 45
Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro Val Gly
50 55 60
Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu Ile Tyr
65 70 75 80
Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser Glu Ser
85 90 95
Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn Ile Thr
100 105 110
Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
115 120 125
Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser Val Arg
130 135 140
Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg Ala Thr
145 150 155 160
Pro Gln His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser Pro
165 170 175
Arg Asp Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser Asp
180 185 190
Phe Gln Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr Ser Ile
195 200 205
His Ser Thr Ala Lys Val Val Leu Thr Arg Glu Asp Val His Ser Gln
210 215 220
Val Ile Cys Glu Val Ala His Val Thr Leu Gln Gly Asp Pro Leu Arg
225 230 235 240
Gly Thr Ala Asn Leu Ser Glu Thr Ile Arg Val Pro Pro Thr Leu Glu
245 250 255
Val Thr Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn Val Thr Cys
260 265 270
Gln Val Arg Lys Phe Tyr Pro Gln Arg Leu Gln Leu Thr Trp Leu Glu
275 280 285
Asn Gly Asn Val Ser Arg Thr Glu Thr Ala Ser Thr Val Thr Glu Asn
290 295 300
Lys Asp Gly Thr Tyr Asn Trp Met Ser Trp Leu Leu Val Asn Val Ser
305 310 315 320
Ala His Arg Asp Asp Val Lys Leu Thr Cys Gln Val Glu His Asp Gly
325 330 335
Gln Pro Ala Val Ser Lys Ser His Asp Leu Lys Val Ser Ala His Pro
340 345 350
Lys Glu Gln Gly Ser Asn Thr Ala Ala Glu Asn Thr Gly Ser Asn Glu
355 360 365
Arg Asn Ile Tyr Ile Val Val Gly Val Val Cys Thr Leu Leu Val Ala
370 375 380
Leu Leu Met Ala Ala Leu Tyr Leu Val Arg Ile Arg Gln Lys Lys Ala
385 390 395 400
Gln Gly Ser Thr Ser Ser Thr Arg Leu His Glu Pro Glu Lys Asn Ala
405 410 415
Arg Glu Ile Thr Gln Asp Thr Asn Asp Ile Thr Tyr Ala Asp Leu Asn
420 425 430
Leu Pro Lys Gly Lys Lys Pro Ala Pro Gln Ala Ala Glu Pro Asn Asn
435 440 445
His Thr Glu Tyr Ala Ser Ile Gln Thr Ser Pro Gln Pro Ala Ser Glu
450 455 460
Asp Thr Leu Thr Tyr Ala Asp Leu Asp Met Val His Leu Asn Arg Thr
465 470 475 480
Pro Lys Gln Pro Ala Pro Lys Pro Glu Pro Ser Phe Ser Glu Tyr Ala
485 490 495
Ser Val Gln Val Pro Arg Lys
500
<210> 124
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate light chain CDR1
<400> 124
Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 125
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate light chain CDR2
<400> 125
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 126
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate light chain CDR3
<400> 126
Gln Gln Tyr Leu Tyr His Pro Ala Thr
1 5
<210> 127
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate light chain variable region
<400> 127
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 128
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate heavy chain CDR1
<400> 128
Asp Ser Trp Ile His
1 5
<210> 129
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate heavy chain CDR2
<400> 129
Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 130
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate heavy chain CDR3
<400> 130
Arg His Trp Pro Gly Gly Phe Asp Tyr
1 5
<210> 131
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ate heavy variable region
<400> 131
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 Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala 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 Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 132
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave light chain CDR1
<400> 132
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 133
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave light chain CDR2
<400> 133
Asp Val Ser Asn Arg Pro Ser
1 5
<210> 134
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave light chain CDR3
<400> 134
Ser Ser Tyr Thr Ser Ser Ser Thr Arg Val
1 5 10
<210> 135
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave light chain variable region
<400> 135
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 136
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave heavy chain CDR1
<400> 136
Ser Tyr Ile Met Met
1 5
<210> 137
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave heavy chain CDR2
<400> 137
Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val Lys
1 5 10 15
Gly
<210> 138
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave heavy chain CDR3
<400> 138
Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr
1 5 10
<210> 139
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> ave heavy variable region
<400> 139
Glu Val Gln Leu Leu 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 Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr 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 Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 140
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur light chain CDR1
<400> 140
Arg Ala Ser Gln Arg Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 141
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur light chain CDR2
<400> 141
Asp Ala Ser Ser Arg Ala Thr
1 5
<210> 142
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur light chain CDR3
<400> 142
Gln Gln Tyr Gly Ser Leu Pro Trp Thr
1 5
<210> 143
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur light chain variable region
<400> 143
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 144
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur heavy chain CDR1
<400> 144
Arg Tyr Trp Met Ser
1 5
<210> 145
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur heavy chain CDR2
<400> 145
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 146
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur heavy chain CDR3
<400> 146
Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr
1 5 10
<210> 147
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> dur heavy variable region
<400> 147
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 Phe Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val 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 Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 148
<211> 351
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CV1-Fc6
<400> 148
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser Gly Gly Gly Gly Ser Asp Lys Thr His
115 120 125
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
130 135 140
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
145 150 155 160
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
165 170 175
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
180 185 190
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
195 200 205
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
210 215 220
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
245 250 255
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Gly
260 265 270
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
275 280 285
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
290 295 300
Asp Gly Ser Phe Lys Leu Ala Ser Lys Leu Thr Val Asp Lys Ser Arg
305 310 315 320
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
325 330 335
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 149
<211> 1053
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of CV1-Fc6
<400> 149
gaagaagaac tgcagatcat ccagccggat aaatctgttc tggttgcggc tggtgaaacc 60
gcgaccctgc gttgcaccat cacctctctg ttcccggttg gtccgatcca gtggttccgt 120
ggtgcgggtc cgggtcgtgt tctgatctac aaccagcgtc agggtccgtt cccgcgtgtt 180
accaccgttt ctgacaccac caaacgtaac aacatggact tctctatccg tatcggtaac 240
atcaccccag cggacgcggg tacctactac tgcatcaaat tccgtaaggg ttctccggac 300
gacgttgagt tcaagtctgg tgcgggtacc gaactgtctg ttcgtgcgaa accgtctgga 360
ggcggtggat cagacaaaac tcacacatgc ccaccgtgcc cagctccgga actcctgggc 420
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 480
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 540
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 600
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 660
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 720
tccaaagcca aagggcagcc ccgagaacca caggtgtgta ccctgccccc atcccgggat 780
gagctgacca agaaccaggt cagcctgagt tgcgcggtca aaggcttcta tcccagcgac 840
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 900
gtgttggact ccgacggctc cttcaagctc gtcagcaagc tcaccgtgga caagagcagg 960
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1020
acgcagaaga gcctctccct gtctccgggt aaa 1053
<210> 150
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> mSIRPα-Fc6
<400> 150
Lys Glu Leu Lys Val Thr Gln Pro Glu Lys Ser Val Ser Val Ala Ala
1 5 10 15
Gly Asp Ser Thr Val Leu Ala Cys Thr Leu Thr Ser Leu Leu Pro Val
20 25 30
Gly Pro Ile Arg Trp Tyr Arg Gly Val Gly Pro Ser Arg Leu Leu Ile
35 40 45
Tyr Ser Phe Ala Gly Glu Tyr Val Pro Arg Ile Arg Ala Val Ser Asp
50 55 60
Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ala Val
65 70 75 80
Thr Pro Ala Asp Ala Gly Ile Tyr Tyr Cys Val Lys Phe Gln Lys Gly
85 90 95
Ser Ser Glu Pro Asp Thr Glu Ile Gln Ser Gly Gly Gly Thr Glu Val
100 105 110
Tyr Val Leu Ala Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
245 250 255
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Gly Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Lys Leu Ala Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 151
<211> 1044
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of mSIRPα-Fc6
<400> 151
aaggaactga aggtgactca gcctgagaaa tcagtgtctg ttgctgctgg ggattcgacc 60
gttctggcct gcactttgac ctccttgttg ccggtgggac ccattaggtg gtacagagga 120
gtagggccaa gccggctgtt gatctacagt ttcgcaggag aatacgttcc tcgaattaga 180
gctgtttcag atactactaa gagaaacaat atggactttt ccatccgtat cagtgctgtc 240
accccagcag atgctggcat ctactactgt gtgaagttcc agaaaggatc atcagagcct 300
gacacagaaa tacaatctgg agggggaaca gaggtctatg tactcgccgg aggcggtgga 360
tcagacaaaa ctcacacatg cccaccgtgc ccagctccgg aactcctggg cggaccgtca 420
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 480
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 540
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 600
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 660
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 720
aaagggcagc cccgagaacc acaggtgtat accctgcccc catcccggga tgagctgacc 780
aagaaccagg tcagcctgag ttgcggggtc aaaggcttct atcccagcga catcgccgtg 840
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgttggac 900
tccgacggct ccttcaagct cgccagcaag ctcaccgtgg acaagagcag gtggcagcag 960
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1020
agcctctccc tgtctccggg taaa 1044
<210> 152
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> mSIRPα-Fc
<400> 152
Lys Glu Leu Lys Val Thr Gln Pro Glu Lys Ser Val Ser Val Ala Ala
1 5 10 15
Gly Asp Ser Thr Val Leu Asn Cys Thr Leu Thr Ser Leu Leu Pro Val
20 25 30
Gly Pro Ile Arg Trp Tyr Arg Gly Val Gly Pro Ser Arg Leu Leu Ile
35 40 45
Tyr Ser Phe Ala Gly Glu Tyr Val Pro Arg Ile Arg Asn Val Ser Asp
50 55 60
Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Asn Val
65 70 75 80
Thr Pro Ala Asp Ala Gly Ile Tyr Tyr Cys Val Lys Phe Gln Lys Gly
85 90 95
Ser Ser Glu Pro Asp Thr Glu Ile Gln Ser Gly Gly Gly Thr Glu Val
100 105 110
Tyr Val Leu Ala Gly Ala Pro Gly Gly Asp Lys Thr His Thr Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
245 250 255
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 153
<211> 1050
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of mSIRPα-Fc
<400> 153
aaggaactga aggtgactca gcctgagaaa tcagtgtctg ttgctgctgg ggattcgacc 60
gttctggcct gcactttgac ctccttgttg ccggtgggac ccattaggtg gtacagagga 120
gtagggccaa gccggctgtt gatctacagt ttcgcaggag aatacgttcc tcgaattaga 180
gctgtttcag atactactaa gagaaacaat atggactttt ccatccgtat cagtgctgtc 240
accccagcag atgctggcat ctactactgt gtgaagttcc agaaaggatc atcagagcct 300
gacacagaaa tacaatctgg agggggaaca gaggtctatg tactcgccgg cgcgccagga 360
ggtgacaaaa ctcacacatg cccaccgtgc ccagcaccgg aactcctggg cggaccgtca 420
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 480
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 540
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 600
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 660
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 720
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 780
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 840
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgttggac 900
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 960
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1020
agcctctccc tgtctccggg taaataatag 1050
<210> 154
<211> 351
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CV1-Fc
<400> 154
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser Gly Ala Pro Gly Gly Asp Lys Thr His
115 120 125
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
130 135 140
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
145 150 155 160
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
165 170 175
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
180 185 190
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
195 200 205
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
210 215 220
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
245 250 255
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
260 265 270
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
275 280 285
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
290 295 300
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
305 310 315 320
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
325 330 335
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 155
<211> 1053
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of CV1-Fc
<400> 155
gaagaagaac tgcagatcat ccagccggat aaatctgttc tggttgcggc tggtgaaacc 60
gcgaccctgc gttgcaccat cacctctctg ttcccggttg gtccgatcca gtggttccgt 120
ggtgcgggtc cgggtcgtgt tctgatctac aaccagcgtc agggtccgtt cccgcgtgtt 180
accaccgttt ctgacaccac caaacgtaac aacatggact tctctatccg tatcggtaac 240
atcaccccag cggacgcggg tacctactac tgcatcaaat tccgtaaggg ttctccggac 300
gacgttgagt tcaagtctgg tgcgggtacc gaactgtctg ttcgtgcgaa accgtctggc 360
gcgccaggag gtgacaaaac tcacacatgc ccaccgtgcc cagcaccgga actcctgggc 420
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 480
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 540
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 600
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 660
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 720
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 780
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 840
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 900
gtgttggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 960
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1020
acgcagaaga gcctctccct gtctccgggt aaa 1053
<210> 156
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid of T-HC
<400> 156
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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 157
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of T-HC
<400> 157
gaagtccagc tggtcgaatc cggtggcggg ctggtccagc caggaggatc tctgagactg 60
tcctgcgccg caagcggctt caacatcaag gatacataca tccactgggt gaggcaggca 120
cccggcaaag gcctggagtg ggtggcccgg atctacccaa ccaacggtta taccaggtat 180
gccgactcag tcaaaggcag gtttactatt tctgctgaca catcaaagaa tacagcctac 240
ctgcaaatga atagcctgag ggctgaagat accgctgtgt actactgctc cagatgggga 300
ggtgatggct tttatgccat ggattattgg ggacaaggca cactcgtgac cgtttcttct 360
gccagcacta aggggccctc tgtgtttcca ctcgcccctt ctagcaaaag cacttccgga 420
ggcactgcag cactcgggtg tctggtcaaa gattatttcc ctgagccagt caccgtgagc 480
tggaactctg gcgccctcac ctccggggtt cacacctttc cagccgtcct gcagtcctcc 540
ggcctgtact ccctgagcag cgtcgttacc gtgccatcct cttctctggg gacccagaca 600
tacatctgca atgtcaacca taagcctagc aacaccaagg tggacaaaaa ggtcgagcca 660
aagagctgcg ataagacaca cacctgccct ccatgccccg cacctgaact cctgggcggg 720
ccttccgttt tcctgtttcc tcccaagccc aaggatacac tgatgattag ccgcaccccc 780
gaagtcactt gcgtggtggt ggatgtgagc catgaagatc cagaagttaa gtttaactgg 840
tatgtggacg gggtcgaggt gcacaatgct aaaacaaagc ccagggagga gcaatataac 900
tccacataca gagtggtgtc cgttctgaca gtcctgcacc aggactggct gaacgggaag 960
gaatacaagt gcaaggtgtc taataaggca ctgccagccc ccatagagaa gacaatctct 1020
aaagctaaag gccaaccacg cgagcctcag gtctacacac tgccaccatc cagggacgaa 1080
ctgaccaaga atcaggtgag cctgacttgt ctcgtcaaag gattctaccc aagcgacatc 1140
gccgtggagt gggaatccaa cggccaacca gagaacaact acaagaccac cccaccagtc 1200
ctggactctg atgggagctt tttcctgtat tccaagctga cagtggacaa gtctcggtgg 1260
caacagggca acgtgttcag ctgctccgtg atgcatgaag ccctgcataa ccactatacc 1320
cagaaaagcc tcagcctgtc ccccgggaaa 1350
<210> 158
<211> 483
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid of mPD-L1-scFv-Fc
<400> 158
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Thr
20 25 30
Lys Ala Ala Trp Tyr Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Tyr Phe Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
50 55 60
Asp Ser Val Lys Ser Arg Leu Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Lys Ser Val Ser Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Arg Gly Gln Tyr Thr Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Ile Leu Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu
130 135 140
Ile Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile
145 150 155 160
Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asp Leu Val Ser
165 170 175
Trp Tyr Gln Gln Tyr Pro Gly Gln Ala Pro Arg Leu Ile Ile Tyr Glu
180 185 190
Val Ile Lys Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser Lys
195 200 205
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp
210 215 220
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Arg Arg Leu His Gly
225 230 235 240
Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu Gly Ala Pro Gly Gly
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
260 265 270
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Lys
<210> 159
<211> 1449
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of mPD-L1-scFv-Fc
<400> 159
caggtacagc tgcagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60
acctgtgcca tctccgggga cagtgtctct agcaccaagg ctgcttggta ctggatcagg 120
cagtcccctt cgagaggcct tgagtggctg ggaaggacat acttccggtc caagtggtat 180
aatgactatg ccgactctgt gaaaagtcga ttaaccatca acccagacac atccaagaac 240
cagttctccc tgcaacttaa gtctgtgagt cccgaggaca cggctgtgta ttactgtgca 300
agagggcaat acactgcttt tgatatctgg ggccaaggga caatggtcac cgtctcttca 360
ggaattctag gatccggtgg cggtggcagc ggcggtggtg gttccggagg cggcggttct 420
cagtctgctc tgattcagcc tgcctccgtg tctgggtccc ctggacagtc gatcactatc 480
tcctgtactg gcaccagtag tgatgttgga ggttatgacc ttgtctcctg gtaccaacag 540
tacccgggcc aagcccccag actcatcatt tatgaggtca ttaagcggcc ctcagggatt 600
tctgatcgct tctctggttc caagtctggc aacacggcct ccctgacaat ctctgggctc 660
caggctgagg acgaggctga ttattattgc tgctcatatg caggtagacg tcttcatggt 720
gtgttcggag gaggcaccca gctgaccgtc ctcggcgcgc caggaggtga caaaactcac 780
acatgcccac cgtgcccagc accggaactc ctgggcggac cgtcagtctt cctcttcccc 840
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 900
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 960
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1020
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1080
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1140
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc 1200
ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1260
gggcagccgg agaacaacta caagaccacg cctcccgtgt tggactccga cggctccttc 1320
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1380
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1440
ccgggtaaa 1449
<210> 160
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid of mCD47-scFv-Fc
<400> 160
Gln Val Lys Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Gln Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
Trp Val Thr Trp Val Lys Gln Ser His Gly Gln Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Ser Asn Thr Val Thr Asn Phe Asn Asp Asn Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Thr Arg Leu Gly Asn Ser Gly Tyr Arg Val Gly Trp Phe Leu Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
130 135 140
Pro Ala Leu Ala Val Ser Pro Gly Glu Arg Val Thr Ile Ser Cys Lys
145 150 155 160
Ala Ser Glu Ser Val Ser Ser His Met His Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Gln Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu Ala Ser
180 185 190
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Thr Ala Thr Tyr Phe Cys
210 215 220
Gln Gln Gly Trp Asn Gly Pro Phe Thr Phe Gly Ala Gly Thr Arg Leu
225 230 235 240
Glu Leu Lys Gly Ala Pro Gly Gly Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 161
<211> 1425
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of mCD47-scFv-Fc
<400> 161
caggtcaagc tgctgcagtc tggggctgca ctggtgaagc ctggagcctc tgtgaagatg 60
tcttgccaag cctctggtta ttcattcact gactactggg tgacctgggt gaagcagagt 120
catggacaga gccttgagtg gattggggaa atttatccta gcaatactgt tactaacttc 180
aatgataact tcaagggcaa ggccacattg actgtagaca aatccaccag cacagcctat 240
atggagctca gcagattgac atctgaggac tctgcaatct attactgtac aagattgggg 300
aattcggggt acagagttgg ttggtttctt tactggggcc aaggcactct ggtcactgtc 360
agcagcggag gaggaggaag cggaggagga ggaagcggag gaggcggcag cgacatccag 420
ctgactcagt ctcctgcttt ggctgtgtct cctggagaga gggttaccat ctcctgtaag 480
gccagtgaaa gtgtcagttc acatatgcac tggtaccaac agaaaccagg acagcaaccc 540
aaactcctca tctataaagc atcaaaccta gcatctgggg tccctgccag gttcagtggc 600
agtgggtctg ggacagactt caccctcacc attgatcctg tggaggctga tgacactgca 660
acctacttct gtcagcaggg ttggaatggt ccgttcacgt ttggagctgg gaccaggctg 720
gaactgaaag gcgcgccagg aggtgacaaa actcacacat gcccaccgtg cccagcaccg 780
gaactcctgg gcggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 900
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 960
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1020
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1080
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1140
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1200
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260
accacgcctc ccgtgttgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1320
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1425
<210> 162
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid of mCD47-scFv-Fc6
<400> 162
Gln Val Lys Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Gln Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
Trp Val Thr Trp Val Lys Gln Ser His Gly Gln Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Ser Asn Thr Val Thr Asn Phe Asn Asp Asn Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Thr Arg Leu Gly Asn Ser Gly Tyr Arg Val Gly Trp Phe Leu Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser
130 135 140
Pro Ala Leu Ala Val Ser Pro Gly Glu Arg Val Thr Ile Ser Cys Lys
145 150 155 160
Ala Ser Glu Ser Val Ser Ser His Met His Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Gln Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu Ala Ser
180 185 190
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Thr Ala Thr Tyr Phe Cys
210 215 220
Gln Gln Gly Trp Asn Gly Pro Phe Thr Phe Gly Ala Gly Thr Arg Leu
225 230 235 240
Glu Leu Lys Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Gly Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Lys Leu Ala Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 163
<211> 1425
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of mCD47-scFv-Fc6
<400> 163
caggtcaagc tgctgcagtc tggggctgca ctggtgaagc ctggagcctc tgtgaagatg 60
tcttgccaag cctctggtta ttcattcact gactactggg tgacctgggt gaagcagagt 120
catggacaga gccttgagtg gattggggaa atttatccta gcaatactgt tactaacttc 180
aatgataact tcaagggcaa ggccacattg actgtagaca aatccaccag cacagcctat 240
atggagctca gcagattgac atctgaggac tctgcaatct attactgtac aagattgggg 300
aattcggggt acagagttgg ttggtttctt tactggggcc aaggcactct ggtcactgtc 360
agcagcggag gaggaggaag cggaggagga ggaagcggag gaggcggcag cgacatccag 420
ctgactcagt ctcctgcttt ggctgtgtct cctggagaga gggttaccat ctcctgtaag 480
gccagtgaaa gtgtcagttc acatatgcac tggtaccaac agaaaccagg acagcaaccc 540
aaactcctca tctataaagc atcaaaccta gcatctgggg tccctgccag gttcagtggc 600
agtgggtctg ggacagactt caccctcacc attgatcctg tggaggctga tgacactgca 660
acctacttct gtcagcaggg ttggaatggt ccgttcacgt ttggagctgg gaccaggctg 720
gaactgaaag gaggcggtgg atcagacaaa actcacacat gcccaccgtg cccagctccg 780
gaactcctgg gcggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 840
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 900
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 960
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1020
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1080
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta taccctgccc 1140
ccatcccggg atgagctgac caagaaccag gtcagcctga gttgcggggt caaaggcttc 1200
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1260
accacgcctc ccgtgttgga ctccgacggc tccttcaagc tcgccagcaa gctcaccgtg 1320
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1380
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1425
<210> 164
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid of AB6.12-HC
<400> 164
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Thr Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Ala Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Asp Gln Gly Asp Thr Glu Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Arg Asp Arg Ser Met Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Asn Ala Ala Tyr Gly Ser Ser Ser Tyr Pro Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 165
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of AB6.12-HC
<400> 165
cagatgcagc tggtgcagag cggcgccgaa gtgaagaaga ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggctt caacatcaag gactactacc tgcactgggt gagacaggcc 120
cctggacagg ccctggagtg gatgggctgg atcgaccctg accagggcga caccgagtac 180
gcccagaagt tccaggacag ggtgaccatc accagggaca ggagcatgag caccgcctac 240
atggagctga gcagcctgag gagcgaggac accgccatgt actactgcaa cgccgcctac 300
ggcagcagca gctaccccat ggactactgg ggccagggaa ccaccgtgac cgtgagcagc 360
gccagcacta aggggccctc tgtgtttcca ctcgcccctt ctagcaaaag cacttccgga 420
ggcactgcag cactcgggtg tctggtcaaa gattatttcc ctgagccagt caccgtgagc 480
tggaactctg gcgccctcac ctccggggtt cacacctttc cagccgtcct gcagtcctcc 540
ggcctgtact ccctgagcag cgtcgttacc gtgccatcct cttctctggg gacccagaca 600
tacatctgca atgtcaacca taagcctagc aacaccaagg tggacaaaaa ggtcgagcca 660
aagagctgcg ataagacaca cacctgccct ccatgccccg cacctgaact cctgggcggg 720
ccttccgttt tcctgtttcc tcccaagccc aaggatacac tgatgattag ccgcaccccc 780
gaagtcactt gcgtggtggt ggatgtgagc catgaagatc cagaagttaa gtttaactgg 840
tatgtggacg gggtcgaggt gcacaatgct aaaacaaagc ccagggagga gcaatataac 900
tccacataca gagtggtgtc cgttctgaca gtcctgcacc aggactggct gaacgggaag 960
gaatacaagt gcaaggtgtc taataaggca ctgccagccc ccatagagaa gacaatctct 1020
aaagctaaag gccaaccacg cgagcctcag gtctacacac tgccaccatc cagggacgaa 1080
ctgaccaaga atcaggtgag cctgacttgt ctcgtcaaag gattctaccc aagcgacatc 1140
gccgtggagt gggaatccaa cggccaacca gagaacaact acaagaccac cccaccagtc 1200
ctggactctg atgggagctt tttcctgtat tccaagctga cagtggacaa gtctcggtgg 1260
caacagggca acgtgttcag ctgctccgtg atgcatgaag ccctgcataa ccactatacc 1320
cagaaaagcc tcagcctgtc ccccgggaaa 1350
<210> 166
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> amino acid of AB6.12-LC
<400> 166
Asn Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile His Arg Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys His Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 167
<211> 639
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> gene of AB6.12-LC
<400> 167
aacatccaga tgacccagag ccctagcgcc atgagcgcta gcgtgggcga cagggtgacc 60
atcacctgca aggccagcca ggacatccac cgttatttaa gctggttcca gcagaagccc 120
ggcaaggtgc ccaagcacct gatctacagg gccaacaggc tggtgagcgg cgtgcctagc 180
agatttagcg gcagcggcag cggcaccgag tttaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccacctacta ctgcctgcag tacgacgagt tcccctacac cttcggcggc 300
ggcaccaagg tggaaatcaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggtaccgct agcgttgtgt gcctgctgaa taacttttat 420
ccacgggagg ctaaggtgca gtggaaagtg gacaatgccc tccagagcgg aaatagccaa 480
gagtccgtta ccgaacagga ctctaaagac tctacatact ccctgtcctc cacactgacc 540
ctctccaagg ccgactatga gaaacacaag gtttacgcat gcgaggtcac acaccaggga 600
ctctcctctc ccgtgaccaa gagcttcaac cggggagaa 639
Claims (31)
1.一种免疫缀合物,所述免疫缀合物包含:
a)靶向部分,其中所述靶向部分表现出对肿瘤相关抗原的结合特异性;
b)由第一Fc亚基和第二Fc亚基组成的Fc结构域,其中所述第一Fc亚基与所述第二Fc亚基缔合以形成二聚体;和
c)单拷贝的信号调节蛋白α(SIRPα)。
2.根据权利要求1所述的免疫缀合物,其中所述SIRPα不是CV1变体。
3.根据权利要求1-2中任一项所述的免疫缀合物,其中所述SIRPα是人野生型SIRPα。
4.根据权利要求1-3中任一项所述的免疫缀合物,其中所述SIRPα包含如SEQ ID NO:122或123中所示的氨基酸序列。
5.根据权利要求1-4中任一项所述的免疫缀合物,其中所述靶向部分包含抗体的抗原结合结构域,并且所述抗体选自下组:抗EGFRVIII、抗HER2/neu、抗PD-L1和抗Muc1。
6.根据权利要求5所述的免疫缀合物,其中所述抗体是抗PD-L1抗体。
7.根据权利要求6所述的免疫缀合物,其中所述抗PD-L1抗体选自下组:阿特朱单抗、阿维单抗、度伐鲁单抗、KN035和hu56。
8.根据权利要求1-7中任一项所述的免疫缀合物,其中所述Fc结构域是IgG Fc结构域。
9.根据权利要求8所述的免疫缀合物,其中所述IgG是人IgG1。
10.根据权利要求1-9中任一项所述的免疫缀合物,所述免疫缀合物是蛋白质性质的异二聚体,其包含第一成员和不同于所述第一成员的第二成员,其中所述第一成员包含至少一个与所述Fc结构域的两个亚基之一融合的靶向部分,并且所述第二成员包含与所述Fc结构域的两个亚基中的另一个融合的所述单拷贝的SIRPα,并且所述第一Fc亚基与所述第二Fc亚基缔合,形成所述异二聚体。
11.根据权利要求1-10中任一项所述的免疫缀合物,其中所述靶向部分与所述Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接融合,并且所述单拷贝的SIRPα与所述Fc结构域的两个亚基中的另一个的氨基末端氨基酸直接或间接融合。
12.根据权利要求1-11中任一项所述的免疫缀合物,其中所述免疫缀合物包含两个所述靶向部分,其为第一靶向部分和第二靶向部分。
13.根据权利要求12所述的免疫缀合物,其中所述第一靶向部分与所述Fc结构域的所述两个亚基之一直接或间接融合,并且所述第二靶向部分与所述Fc结构域的所述两个亚基中的另一个直接或间接融合。
14.根据权利要求12-13中任一项所述的免疫缀合物,所述免疫缀合物为蛋白质性质的异二聚体,其包含第一成员和不同于所述第一成员的第二成员,其中:
所述第一成员包含与所述Fc结构域的两个亚基之一融合的所述第一靶向部分;
所述第二成员包含所述单拷贝的SIRPα、所述第二靶向部分和所述Fc结构域的两个亚基中的另一个,其中所述单拷贝的SIRPα与所述Fc亚基的一个末端融合,并且所述第二靶向部分与所述Fc亚基的另一个末端融合;以及
所述第一Fc亚基与所述第二Fc亚基缔合以形成所述异二聚体。
15.根据权利要求12-14中任一项所述的免疫缀合物,其中所述第一靶向部分与所述Fc结构域的两个亚基之一的氨基末端氨基酸直接或间接融合,所述第二靶向部分与所述Fc结构域的两个亚基中的另一个的氨基末端氨基酸直接或间接融合,并且所述单拷贝的SIRPα与所述第一或第二Fc亚基的羧基末端氨基酸直接或间接融合。
16.根据权利要求1-15中任一项所述的免疫缀合物,其中所述第一Fc亚基不同于所述第二Fc亚基,并且所述Fc结构域包含促进所述第一Fc亚基与所述第二Fc亚基之间的异二聚体化的修饰。
17.根据权利要求16所述的免疫缀合物,其中所述第一Fc亚基包含第一修饰,所述第二Fc亚基包含第二修饰,并且所述第一修饰和所述第二修饰包含在选自以下任意组位置处的氨基酸取代:
1)所述第一修饰:Y349和T366;和第二修饰:D356、T366、L368、Y407和F405;
2)所述第一修饰:Y349、T366和F405;和所述第二修饰:D356、T366、L368和Y407;
3)所述第一修饰:Y349、T366和K409;和所述第二修饰:D356、T366、L368、Y407和F405;
4)所述第一修饰:Y349、T366、F405、K360和Q347;和所述第二修饰:D356、T366、L368、Y407和Q347;
5)所述第一修饰:Y349、T366、F405和Q347;和所述第二修饰:D356、T366、L368、Y407、K360和Q347;
6)所述第一修饰:Y349、T366、K409、K360和Q347;和所述第二修饰:D356、T366、L368、Y407、F405和Q347;
7)所述第一修饰:Y349、T366、K409和Q347;和所述第二修饰:D356、T366、L368、Y407、F405、K360和Q347;
8)所述第一修饰:T366、K409和K392;和所述第二修饰:T366、L368、Y407、D399和F405;
9)所述第一修饰:T366和K409;和所述第二修饰:T366、L368、Y407和F405;
10)所述第一修饰:T366、K409和Y349;和所述第二修饰:T366、L368、Y407、F405和E357;
11)所述第一修饰:T366、K409、Y349和S354;和所述第二修饰:T366、L368、Y407、F405和E357;
12)所述第一修饰:T366和F405;和所述第二修饰:T366、L368、Y407和K409;
13)所述第一修饰:T366、F405和D399;和所述第二修饰:T366、L368、Y407、K409和K392;
14)所述第一修饰:T366、F405和Y349;和所述第二修饰:T366、L368、Y407、K409和E357;
15)所述第一修饰:T366、F405、Y349和S354;和所述第二修饰:T366、L368、Y407、K409和E357;
其中所述氨基酸的位置根据KABAT编号的EU索引来确定。
18.根据权利要求17所述的免疫缀合物,其中将所述单拷贝的SIRPα与包含所述第二修饰的所述第二Fc亚基直接或间接融合。
19.一种或多种分离的核酸,所述核酸编码权利要求1-18中任一项所述的免疫缀合物。
20.一种或多种载体,所述载体包含权利要求19所述的一种或多种分离的核酸。
21.一种分离的宿主细胞,所述宿主细胞包含权利要求19所述的一种或多种分离的核酸或权利要求20所述的一种或多种载体。
22.产生权利要求1-18中任一项所述的免疫缀合物的方法,所述方法包括(i)在实现所述免疫缀合物的表达和形成的条件下培养权利要求21所述的宿主细胞,以及(ii)收获所形成的免疫缀合物。
23.一种药物组合物,所述药物组合物包含有效量的权利要求1-18中任一项所述的免疫缀合物和任选地药学上可接受的赋形剂。
24.根据权利要求23所述的药物组合物,所述药物组合物还包含有效量的用于癌症治疗的另外的治疗活性组分。
25.根据权利要求24所述的药物组合物,其中所述用于癌症治疗的另外的治疗活性组分是化学治疗剂。
26.根据权利要求25所述的药物组合物,其中所述化学治疗剂是细胞毒性剂。
27.根据权利要求26所述的药物组合物,其中所述细胞毒性剂是多柔比星。
28.权利要求1-18中任一项所述的免疫缀合物在制备用于治疗有此需要的受试者的疾病的药物方面的用途。
29.权利要求1-18中任一项所述的免疫缀合物与如权利要求24-27中任一项中所述的另外的治疗活性组分的组合在制备用于治疗有此需要的受试者的疾病的药剂方面的用途。
30.根据权利要求28-29中任一项所述的用途,其中所述疾病是癌症。
31.根据权利要求30所述的用途,其中所述癌症选自:乳腺癌、黑色素瘤和结肠癌。
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CN110312736B (zh) * | 2017-01-23 | 2023-05-09 | 苏州康宁杰瑞生物科技有限公司 | Pd-l1结合多肽或化合物 |
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CN112399973B (zh) * | 2018-06-05 | 2022-12-16 | 江苏康宁杰瑞生物制药有限公司 | 二聚体及其用途 |
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