CN117500518A - Il-2突变蛋白及包含其的药物 - Google Patents
Il-2突变蛋白及包含其的药物 Download PDFInfo
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- CN117500518A CN117500518A CN202180077914.6A CN202180077914A CN117500518A CN 117500518 A CN117500518 A CN 117500518A CN 202180077914 A CN202180077914 A CN 202180077914A CN 117500518 A CN117500518 A CN 117500518A
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Abstract
提供一种IL‑2突变蛋白,其具有在SEQ ID NO:3中所示的氨基酸序列;或具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列。
Description
技术领域
[相关申请的交叉引用]
本申请要求2020年9月18日提交的日本专利申请第2020-157900号的优先权,其全部公开内容通过引用方式并入本文。本发明涉及一种IL-2突变蛋白和包含该IL-2突变蛋白的药物。
背景技术
刺激哺乳动物的免疫系统产生适应性免疫应答是有用的,其已经发展到清除进入体内的病原体。由此被激活的免疫细胞的一个重要群体是CD8+效应T细胞(细胞毒性淋巴细胞)。众所周知,IL-2刺激多种免疫细胞,其包括单核细胞、NK细胞和T细胞。IL-2在临床上用于刺激细胞介导的免疫应答,并被FDA批准用于患有转移性黑色素瘤或转移性肾癌的患者的标准治疗(例如,阿地白介素(Chiron)(也称为Proleukin(商标)))。
参与细胞介导的适应性免疫应答的T细胞库包括CD8+记忆T细胞、CD8+效应T细胞和调节性T细胞(Tregs)。通过抑制效应T细胞和记忆T细胞的活性,这些Tregs在适应性免疫程序中发挥重要作用。然而,已经观察到,IL-2也激活T细胞的Treg亚群,然后其可以起到抑制CD8+T细胞或耐受其他T细胞的作用。因此,IL-2参与了适应性免疫应答的激活及其衰减。
Treg细胞的特征在于CD4和转录因子FoxP3的表达,其又激活IL-2受体复合物(CD4+CD25+细胞)的α-亚基CD25的表达。因此,CD25在Treg细胞中是结构性表达的。CD25与IL-2受体复合物(β-亚基CD122和γ-亚基CD132)的信号传导组分的关联将中等亲和力的IL-2受体复合物转化为高亲和力的IL-2受体复合物。Treg细胞的IL-2活化是通过高亲和力IL-2受体复合物中继的信号传导通路而实施的。
高水平的CD25表达是活化T细胞的一个特征,使这些细胞通过高亲和力的IL-2受体复合物对IL-2产生应答。基于阻断CD25的疗法已经被开发出来,其基本原理是阻断CD25会抑制活化T细胞中IL-2介导的信号传导,并显示出免疫抑制作用。抗CD25抗体,如达克珠单抗(罗氏)(也称为Zenapax(商标))和巴利昔单抗(诺华)(也称为Simulect(商标)),已被FDA批准用于预防肾移植后的急性器官排斥反应。由于IL-2的双重作用,本领域仍然需要提供更有效的IL-2介导的治疗。
参与细胞介导的免疫应答的免疫细胞包括具有NK1.1+表型的NK细胞。NK细胞在适应性免疫程序中起着重要作用。然而,已经观察到,IL-2也激活T细胞的Treg亚群,然后Treg亚群可以抑制CD8+T细胞,或耐受其他T细胞。因此,IL-2参与了适应性免疫应答的激活及其衰减。
高水平的CD25表达是活化T细胞的一个特征,使这些细胞通过高亲和力的IL-2受体复合物对IL-2产生应答。基于阻断CD25的疗法已经被开发出来,其基本原理是阻断CD25会抑制活化T细胞中IL-2介导的信号传导,并显示出免疫抑制作用。抗CD25抗体,如达克珠单抗(罗氏)(也称为Zenapax(商标))和巴利昔单抗(诺华)(也称为Simulect(商标)),已被FDA批准用于预防肾移植后的急性器官排斥反应。由于IL-2的双重作用,本领域仍然需要提供更有效的IL-2介导的治疗。
引用列表
专利文献
专利文献1:WO 2020/069398 A1
专利文献2:WO 2018/215936 A1
专利文献3:WO 2018/215938 A1
专利文献4:WO 2014/028748 A1
专利文献5:JP 2015-229676 A
非专利文献
非专利文献1:Proc.Natl.Acad.Sci.U.S.A.(2006)103p.2788-93非专利文献2:Adv Drug Deliv Rev.2013Oct 15;65(10):1357-1369。
发明内容
技术问题
本发明的目的在于提供一种IL-2突变体,其对IL-2受体α的结合能力减弱,同时保持对IL-2受体β和γ的结合能力。
问题的解决方案
在这种情况下,本发明的发明人进行了广泛的研究,结果发现,当成熟的IL-2的位置35、位置38、位置42(或位置43)和位置45处的氨基酸全部被A取代时,对IL-2受体α的结合能力减弱,而对IL-2受体β和γ的结合能力保持不变。本发明即基于这样的新发现。因此,本发明提供了以下项目:
项目1、一种IL-2突变蛋白,包括:在SEQ ID NO:3中所示的氨基酸序列;或具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性,且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列。
项目2、根据项目1所述的IL-2突变蛋白,其中,所述IL-2突变蛋白是具有白蛋白和/或免疫球蛋白的融合蛋白。
项目3、根据项目2所述的IL-2突变蛋白,其中,所述融合蛋白的免疫球蛋白部分是抗体的Fc部分。
项目4、根据项目2所述的IL-2突变蛋白,其中,所述IL-2蛋白是白蛋白-IL-2、IL-2-白蛋白、白蛋白-IL-2-免疫球蛋白、免疫球蛋白-IL-2-白蛋白、白蛋白-免疫球蛋白-IL-2-白蛋白、或白蛋白-IL-2-免疫球蛋白-白蛋白。
项目5、根据项目1-4中任一项所述的IL-2突变蛋白,其中,所述IL-2突变蛋白具有激活表达IL-2受体β和γ的TPA-Mat细胞的能力,并且与SEQ ID NO:2中所示的氨基酸序列形成的IL-2突变蛋白相比,所述IL-2突变蛋白对IL-2受体α的结合能力降低。
项目6、一种药物,包括项目1-5中任一项所述的IL-2突变蛋白。
项目7、根据项目6所述的药物,其中,所述药物用于预防或治疗癌症。
项目8、一种预防或者治疗癌症的方法,包括将项目1-5中任一项所述的有效剂量的IL-2突变蛋白施用到有需要的受试者。
项目9、项目1-5中任一项所述的IL-2突变蛋白的用途,用于生产癌症用的预防药物或治疗药物。
本发明的有利效果
根据本发明,提供了对IL-2受体α具有减弱的结合能力,同时保持对IL-2受体β和γ的结合能力的IL-2突变体。因此,使用本发明的IL-2突变体可以通过抑制Tregs(CD4+CD25+)的增殖来增强IL-2疗法的功效,同时保留引起CD8+T细胞和NK1.1+细胞增殖的能力。
附图说明
图1显示了成熟的人IL-2氨基酸序列(SEQ ID NO:1)。
图2显示了成熟稳定突变的人IL-2氨基酸序列(SEQ ID NO:2)。
图3显示了成熟稳定的IL-2受体α-亚基(CD25)未结合人IL-2氨基酸序列(MK-6(SEQ ID NO:3)、MK-15(SEQ ID NO:4)和成熟稳定突变的人IL-2氨基酸序列MK-4(SEQ IDNO:5))。
图4显示了成熟的人白蛋白氨基酸序列(SEQ ID NO:6)。
图5显示了成熟的人白蛋白-MK-6-IL-2氨基酸序列(HSA-3×G4S-MK-6)(SEQ IDNo.:7),成熟的人白蛋白-MK-15-IL-2氨基酸序列(HSA-3×G4S-MK-15)(SEQ ID No.:8),成熟的人白蛋白-3×(EAAAK)-MK-6-IL-2氨基酸序列(HSA-3×(EAAAK)-MK-6)(SEQ IDNo.:9),和成熟的人白蛋白-3×(EAAAK)-MK-15-IL-2氨基酸序列(HSA-3×(EAAAK)-MK-6)(SEQID No.:10)。
图6显示了小鼠白蛋白的氨基酸序列(SEQ ID NO:11)、成熟的MK-6小鼠白蛋白融合蛋白的氨基酸序列(SEQ ID NO:12)、成熟的MK-14小鼠白蛋白融合蛋白的氨基酸序列(SEQ ID NO:13)和成熟的MK-15小鼠白蛋白融合蛋白的氨基酸序列(SEQ ID NO:14)。
图7A显示了人抗-CSPG4-scFv氨基酸序列(SEQ ID NO:15)、成熟的人白蛋白-CSPG4-scFv-MK-6-IL-2氨基酸序列(HSA-CSPG4-scFv-MK-6)(SEQ ID NO:16)和成熟的人白蛋白-CSPG4-scFv-MK-14-IL-2氨基酸序列(HSA-CSPG4-scFv-MK-14)(SEQ ID NO:17)。
图7B显示了成熟的人白蛋白-CSPG4-scFv-MK-15-IL-2氨基酸序列(HSA-CSPG4-scFv-MK-15)(SEQ ID NO:18)、成熟的小鼠白蛋白-CSPG4-scFv-MK-6-IL-2氨基酸序列(HSA-CSPG4-scFv-MK-6)(SEQ ID NO:19)和成熟的小鼠白蛋白-CSPG4-scFv-MK-14-IL-2氨基酸序列(HSA-CSPG4-scFv-MK-14)(SEQ ID NO:20)。
图8显示了将成熟的MK-6和白蛋白相互连接的接头氨基酸序列(SEQ ID No.:21和25)。
图9(上)包括IL-2与IL-2受体αβγ复合物结合的示意图。图9(下)包括IL-2与IL-2受体αβγ复合物结合以及IL-2结合的三维结构示意图。
图10显示了IL-2受体α在细胞上的结合能力(细胞上受体结合)。
图11显示了IL-2受体α在细胞上的结合能力(细胞上受体结合)。
图12显示了人CSPG4在细胞上的结合能力(细胞上受体结合)。
图13显示了IL-2、MK-14和MK-6对小鼠和人淋巴细胞IL-2依赖性细胞增殖。
图14显示了MK-4、MK-6、MK-14和MK-15对小鼠和人淋巴细胞的IL-2FP225472JP
依赖性细胞增殖。
图15显示了MK-6、HSA-3×G4S-MK-6和HSA-3x(EAAAK)-MK-6对小鼠和人淋巴细胞的IL-2依赖性细胞增殖。
图16显示了MK-6、HSA-CSPG4-scFv-3×G4S-MK-6和HSA-CSPG4-scFv-3×G4S-MK-14对小鼠和人淋巴细胞的IL-2依赖性细胞增殖。
图17显示了IL-2依赖性Treg细胞增殖。
图18显示了注射IL-2(MK-6-IL-2或MK-14-IL-2)对小鼠(BALB/c)外周免疫系统细胞计数的作用。
图19显示了连续4天且每天一次静脉注射IL-2(MK-6-IL-2或MK-14-IL-2)对小鼠(BALB/c)体重、肝脏和脾脏重量的作用。
图20显示了IL-2(MK-6-IL-2或MK-14-IL-2)对皮下植入CT26结肠癌细胞的患癌小鼠(BALB/c)的作用。
图21显示了连续5天且每天两次腹腔注射IL-2(MK-6-IL-2或MK-14-IL-2)后,CT26结肠癌细胞皮下植入小鼠(BALB/c)后切除瘤内淋巴细胞(TILs)的FACS分析。
图22显示了IL-2(MK-6-IL-2或MK-14-IL-2)对皮下植入B16F10黑色素瘤的患癌小鼠(C57BL/6)的作用。
图23显示了在患B16F10黑色素瘤小鼠模型中,通过IL-2单一治疗对瘤内淋巴细胞(TILs)的FACS分析。
图24显示了白蛋白融合IL-2(MSA-IL-2)单一治疗在CT26结肠癌小鼠模型中的抗肿瘤作用。
图25显示了腹腔注射成熟的MK-6-IL-2和成熟的MK-6-IL-2小鼠白蛋白后IL-2血药浓度的变化以及患CT26结肠癌小鼠模型瘤内IL-2的量化。
具体实施方式
在本发明中,术语“蛋白质”和“肽”各自用于包括寡肽和多肽的含义。此外,在本文中,除非另有说明,术语“蛋白质”和“肽”各自包括用聚糖或类似物修饰的蛋白质和未修饰的蛋白质。这同样适用于未被指定为蛋白质的蛋白质。
IL-2突变蛋白
本发明提供了一种IL-2突变蛋白,其具有在SEQ ID NO:3中所示的氨基酸序列;或具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列。因此,本发明提供了一种IL-2突变蛋白,其具有:在SEQ ID NO:3中所示的氨基酸序列;或具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42、和位置45处的氨基酸均为A的氨基酸序列;或具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置43、和位置45处的氨基酸均为A的氨基酸序列。与具有SEQ ID NO:3的氨基酸序列至少95%的序列一致性并且其中位置35、位置38、位置42和位置45的氨基酸均为A的氨基酸序列的一个示例是SEQ ID NO:4中所示的氨基酸序列。
在本发明中,具有SEQ ID NO:3中所示的氨基酸序列的IL-2突变蛋白不仅包括其氨基酸序列仅由SEQ ID NO:3所示的氨基酸序列构成的IL-2突变蛋白,而且还包括其氨基酸序列包含SEQ ID NO:3所示的氨基酸序列作为其一部分的IL-2突变蛋白。同样,在本发明中,具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列的IL-2突变蛋白不仅包括其氨基酸序列仅由具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列构成的IL-2突变蛋白,而且还包括其氨基酸序列包含具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列作为其一部分的IL-2突变蛋白。
SEQ ID NO:2列出了成熟稳定突变的人IL-2的氨基酸序列。SEQ ID NO:3中所示的氨基酸序列对应于将SEQ ID NO:2中位置35的K、位置38的R、位置43的K和位置45的Y全部替换为A而得到的氨基酸序列。此外,SEQ ID NO:4中所示的氨基酸序列对应于将SEQ ID NO:2中位置35的K、位置38的R、位置42的F和位置45的Y全部替换为A而得到的氨基酸序列。现在,IL-2/IL-2受体结合、以及根据本发明的一个具体实施方式的MK-6-IL-2(在稍后将描述的实施例中描述)和IL-2受体结合的概要如图9所示。具体地说,图9(上)包括IL-2与IL-2受体αβγ复合物之间结合的示意图。成熟的人IL-2(和成熟的修饰人IL-2)结合高亲和力的IL-2受体αβγ复合物。同时,成熟的MK-6-IL-2未结合到α-亚基,而与由βγ组成的中等亲和力IL-2受体结合。
图9(下)包括IL-2与IL-2受体αβγ复合物结合、以及IL-2结合的三维结构示意图。图9(下)中每个蛋白质的三维结构示意图是使用来自蛋白质数据库(PDB)的已知数据(2ERJ)创建的。
IL-2受体α广泛表达于血管内皮细胞、Treg细胞、活化T细胞等中。成熟的人IL-2(以及成熟的修饰人IL-2)与单独表达IL-2受体α的细胞结合。因此,会引起以下多种不良事件。首先,不良事件之一是血管渗漏综合征(VLS)。与单独表达IL-2受体α的血管内皮细胞结合会增加血管通透性,因此有时会引起全身性多器官水肿和多器官衰竭,这是致命的。其次,另一个不良事件是Treg的激活。Treg抑制抗肿瘤免疫,从而诱导癌症的生长和转移/侵袭。
对于IL-2受体(IL-2R),已经识别出三个亚基,即α(CD25)、β(CD122)和γc(CD132)。IL-2Rα单独作为低亲和受体,IL-2Rβ和γc的异源二聚体作为中亲和受体,αβγ作为高亲和受体。其中,只有后两者具有信号转导。酪氨酸激酶JAK1和JAK3分别与IL-2Rβ和γ-c结合,以主要激活STAT5。此外,也发生PI3K、Akt和MAPK系统的激活。IL-2作用于T细胞增殖。它的作用之一是受到抗原刺激的CD8+T细胞的增殖和激活。事实上,IL-2调节CD8+T细胞在所有分化阶段(幼稚期、效应期和记忆期)的抗原依赖性增殖。至少部分CD8+T细胞被称为细胞毒性T细胞或杀伤T细胞,且已知可杀死呈现癌症相关抗原的肿瘤细胞。此外,NK细胞表达由βγ组成的中等亲和力IL-2受体,并在IL-2刺激下增殖和激活,从而表现出包括抗肿瘤活性在内的细胞毒性活性。同时,在胸腺产生的天然Tregs(nTregs)和外周产生的诱导Tregs(iTregs)的分化都需要IL-2。Treg细胞的特点是结构性地高水平表达由IL2受体α-亚基(CD25)、IL2受体β-亚基(CD122)和IL2RG亚基(CD132)组成的高亲和力IL-2受体IL2Rαβγ,并且Treg细胞的增殖已被证明依赖于IL-2。在抗肿瘤免疫中,已知Treg细胞引起的免疫抑制阻碍了抗肿瘤免疫的有效功能和诱导抗肿瘤活性的激活,因此发生肿瘤的生长或转移/侵袭。
现在,如非专利文献1所述,在IL-2的组成氨基酸中,有10多个氨基酸存在于IL-2和IL-2受体α之间的结合部分附近。本发明的发明人设想通过大量的研究来改变这10多个氨基酸中的一些,以降低IL-2和IL-2受体α之间的结合能力,经过大量的进一步的反复试验,并将关注点放在了IL-2的位置35的K、位置38的R、位置42的F或位置43的K、和位置45的Y,获得了IL-2突变体,其显示出对IL-2受体α的结合能力减弱,同时通过用A取代这些氨基酸,保持了对IL-2受体β和γ的结合能力。因此,如本申请的实施例中所述,具有SEQ ID NO:3中所示的氨基酸序列的IL-2突变蛋白显示出在维持对IL-2受体β和γ的结合能力的同时减弱对IL-2受体α的结合能力,可以想到,这是因为与IL-2受体α结合的位置35的K、位置38的R、位置42的F或位置43的K、和位置45的Y均被A所取代。因此,本发明的IL-2突变蛋白可具有这样的氨基酸序列:其具有在SEQ ID NO:3中所示的氨基酸序列中添加、删除和/或取代的一个或多个(如1到7,1到6,1到5,1到4、1到3、1或2或1)个氨基酸以保留位置35、位置38、位置45处的所有A,以及保留位置43的A或位置42的A。在这样的实施方式中,IL-2突变蛋白优选具有SEQ ID NO:3中所示的氨基酸序列或具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性的氨基酸序列,或更优选具有与SEQ ID NO:3的氨基酸序列至少97%的序列一致性的氨基酸序列,或更优选具有与SEQ ID NO:3的氨基酸序列至少99%的序列一致性的氨基酸序列。在SEQ ID NO:3所示的氨基酸序列中添加、删除和/或取代氨基酸以保留位置35、位置38、位置45处的所有A以及保留位置43的A或位置42的A的氨基酸序列的非限制性示例是SEQ ID NO:4所示的氨基酸序列。此外,在SEQ ID NO:3所示的氨基酸序列中添加、删除和/或取代氨基酸同时在SEQ ID NO:3所示的氨基酸序列中保留位置35、位置38、位置43、位置45处的所有A的氨基酸序列的非限制性示例包括:通过删除SEQ ID NO:3中位置81和位置84之间的两个氨基酸并添加DTK而获得的氨基酸序列;通过删除SEQ ID NO:3中位置82的P而获得的氨基酸序列;用Q取代SEQ ID NO:3中位置49的K而获得的氨基酸序列;用T取代SEQ ID NO:3中位置73的A而获得的氨基酸序列;用R取代SEQ ID NO:3中位置119的N而获得的氨基酸序列;以及通过组合至少两种这些修饰而获得的氨基酸序列。
在本发明中,在获得本发明的效果的范围内,IL-2突变蛋白可以是这样的融合蛋白,其中另一种氨基酸序列融合(可选地通过接头)到SEQ ID NO:3中所示的氨基酸序列,或者到具有在SEQ ID NO:3中所示的氨基酸序列中添加、删除和/或取代一个或多个氨基酸以保留位置35、位置38和位置45上的所有A,并保留位置43上的A或具有位置42上的A的氨基酸序列。在本发明中,就融合蛋白的组分多肽而言,SEQ ID NO:3中所示的氨基酸序列所形成的部分,或者具有在SEQ ID NO:3中所示的氨基酸序列中添加、删除和/或取代一个或多个氨基酸以保留位置35、位置38和位置45上的所有A,并保留位置43上的A或具有位置42上的A的氨基酸序列所形成的部分有时简称为“IL-2突变蛋白部分”。例如,将体内具有较长半衰期的稳定蛋白与IL-2突变蛋白部分融合可以增强本发明IL-2突变蛋白的体内稳定性,因此是优选的。例如,在本发明的优选实施方式中,突变蛋白-2可以是以下的融合蛋白:SEQ IDNO:3中所示的氨基酸序列或者具有在SEQ ID NO:3中所示的氨基酸序列中添加、删除和/或取代一个或多个氨基酸以保留位置35、位置38和位置45上的所有A,并保留位置43上的A或具有位置42上的A的氨基酸序列所形成的蛋白质;以及白蛋白和/或免疫球蛋白。免疫球蛋白部分可以是(a)抗体的Fc部分和(b)包括针对抗原的可变区(Fab部分)的抗体,所述抗原针对肿瘤细胞或肿瘤细胞环境中呈递的抗原分子的。此外,在本发明中,术语“免疫球蛋白部分”不限于具有Fc部分和Fab部分的部分,并且可以指具有抗原结合能力的任何片段(例如,Fab部分片段,单链可变片段(scFv),或重链抗体的可变片段(例如,重链抗体(VHH)的重链可变结构域)。在这样的实施方式中,具有可变区域的抗体的示例包括抗EGFR抗体西妥昔单抗、抗Her2抗体曲妥珠单抗和抗CD20抗体利妥昔单抗。此外,这种融合蛋白的示例包括白蛋白-IL-2、IL-2-白蛋白、白蛋白-IL-2-免疫球蛋白、免疫球蛋白-IL-2-白蛋白、白蛋白-免疫球蛋白-IL-2-白蛋白、和白蛋白-IL-2-免疫球蛋白-白蛋白。白蛋白例如是白蛋白(HSA),或白蛋白的片段或突变体。关于这种实施方式中涉及的突变,本领域技术人员已知,可以设计具有与野生型相同的血浆半衰期延长作用的人血清白蛋白的功能突变体(截断和/或氨基酸取代的功能突变体)。例如,人血清白蛋白的结构域III已显示与FCGRT(FcRn)高度结合,并且可以制造仅包含该结构域或与其他结构域组合的突变体,具有较长的半衰期或经过修饰的半衰期(例如,Albufuse Flex Technology,Novozymes)。待与IL-2突变蛋白部分融合的蛋白质的示例包括来自哺乳动物(如人类)的蛋白质。此外,待与IL-2突变蛋白部分融合的蛋白质可以是人源化蛋白或类似物。作为本发明的一些实施方式,成熟的人白蛋白-MK-6-IL-2氨基酸序列的示例(图5,SEQ ID NO:7至10)和成熟的MK-6-IL-2-小鼠白蛋白-氨基酸序列的示例(图6,SEQ ID NO:12至14)分别示于图5和图6。此外,用于构建这些融合蛋白的成熟的小鼠白蛋白氨基酸序列(SEQ ID NO:11)如图6所示。在这些实施方式中的每一个中,IL-2突变蛋白部分和其他蛋白质可以通过接头相互结合。接头氨基酸序列可以是所谓的刚性接头和柔性接头中的任何一种。其示例包括非专利文献2中描述的,其具体示例包括下表所示的那些:
表1
更具体地,在优选实施方式中,接头氨基酸序列的示例包括:图8中SEQ ID NO:23或27中所示的氨基酸序列;以及在SEQ ID NO:23或27中所示的氨基酸序列中添加、删除和/或取代一个或多个(例如,1至7、1至6、1至5、1至4、1至3、1或2、或1)氨基酸的氨基酸序列。SEQ ID NO:23所示的氨基酸序列或其修饰序列是有用的,因为GGGGS或GGGGS的重复序列(例如GGGGS GGGGS GGGGS)具有柔性的特征,并且可以保持各个融合的蛋白质的特征。此外,SEQ ID NO:27中所示的氨基酸序列或其修饰序列是有用的,因为EAAAK或其重复序列可以可靠地保持两个蛋白质结构域之间的距离(分离结构域),从而允许融合,同时保持每个蛋白质的功能结构域固有的功能。
在本发明中,具有SEQ ID NO:3所示的氨基酸序列的IL-2突变蛋白还包括通过糖基化、乙酰化等修饰的突变蛋白。在本发明中,用糖或类似物修饰的突变蛋白是优选的。此外,用于纯化的标签(例如,多组氨酸标签或Strep标签(商标))可以通过基因工程添加到本发明突变体的N端或C端,以便于在稍后描述的纯化过程中纯化突变体。此外,本发明的突变体可具有与之结合的分泌信号序列(也称为信号肽或前序列),作为融合蛋白的N端延伸,以将融合蛋白引导到宿主细胞的分泌途径中。编码信号肽的DNA序列通常在正确的阅读框中连接到编码融合蛋白的DNA序列的5′端。信号肽可以是通常与该蛋白相关的肽,或可以来自编码另一分泌蛋白的基因或者具有人工分泌序列。
在一个典型实施方式中,本发明的IL-2突变蛋白是优选的,因为与SEQ ID NO:2中所示的氨基酸序列形成的IL-2突变蛋白相比,其具有激活表达IL-2受体β和γ的细胞的能力,并且具有降低的IL-2受体α的结合能力。
作为产生该变体的方法,可以通过适当地使用本身已知的方法(例如,JP 6640834B2中描述的方法)来产生该变体,例如,构建通过将上述突变体添加到IL-2基因中获得的基因盒,将该基因盒纳入适当的载体中,并将所得到的载体引入宿主以引起表达。在这种情况下,将表达盒连接到与正在使用的宿主兼容的适当载体上。(载体需要能够容纳编码待表达融合蛋白的DNA序列。)合适的宿主细胞包括真核细胞和原核细胞,这些细胞容易转化,在培养基中可以表现出快速增殖。具体地,优选的宿主细胞包括原核细胞,如大肠杆菌和枯草芽孢杆菌,以及真核细胞,如动物细胞和酵母菌株,如酿酒酵母。一般优选哺乳动物细胞,特别是Expi293F、ExpiCHO、HEK、ExJ558、NSO、SP2-O或CHO。其他合适的宿主包括,例如,如Sf9细胞等昆虫细胞。然后可以选择稳定转化或转染的细胞系。此外,体外转录-翻译系统也可以用作表达系统。此外,本发明的突变体可使用无细胞蛋白合成系统产生。此外,本发明的所得到的突变体可以使用本身已知的方法(例如,过滤、离心或层析)适当地纯化。
药物
在另一实施方式中,本发明提供了一种含有上述IL-2突变蛋白的药物。凭借上述IL-2突变蛋白所表现出的作用,本发明可以提供通过修饰IL-2以减弱其与IL-2受体α结合而获得的药物,以及通过修饰IL-2以增加其与由IL-2受体β和γ组成的受体结合而获得的药物。此外,例如,本发明的药物可用于预防和/或治疗癌症。
在这样的实施方式中,目标癌症的示例包括:实体癌症,例如肾癌、黑色素瘤、非小细胞肺癌、结肠癌、肝细胞癌和头颈癌;和血液学肿瘤,如非霍奇金淋巴瘤和急性髓性白血病。
在本发明中,作为本发明活性成分的IL-2突变蛋白可以单独作为药物使用,也可以作为与各种药学上可接受的载体(例如,渗透剂、螯合剂、稳定剂、pH调节剂、防腐剂、抗氧化剂、增溶剂或增稠剂)中的任何一种组合的药物组合物使用。
渗透剂的示例包括:糖,如葡萄糖、海藻糖、乳糖、果糖、甘露醇、木糖醇和山梨醇;多羟基醇,如甘油、聚乙二醇和丙二醇;以及无机盐,如氯化钠、氯化钾和氯化钙。
螯合剂的示例包括:依地酸盐,如依地酸钠、依地酸二钠钙、依地酸三钠、依地酸四钠和依地酸钙;乙二胺四乙酸盐;次氮基三乙酸或其盐;六偏磷酸钠;和柠檬酸。
稳定剂的一个示例是亚硫酸氢钠。
pH调节剂的示例包括酸,如盐酸、碳酸、醋酸和柠檬酸,还包括:碱金属氢氧化物,如氢氧化钠和氢氧化钾;碱金属碳酸盐或碳酸氢盐,如碳酸钠;碱金属醋酸盐,如醋酸钠;碱金属柠檬酸盐,如柠檬酸钠;以及碱,如氨丁三醇。
防腐剂的示例包括:山梨酸;山梨酸钾;对羟基苯甲酸酯,如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯;季铵盐,如葡萄糖酸氯己定、苯扎氯铵、苄索氯铵和西吡氯铵;烷基聚氨乙基甘氨酸;三氯叔丁醇;泊利氯铵(polyquad);聚六亚甲基双胍;和氯己定。
抗氧化剂的示例包括亚硫酸氢钠、干燥亚硫酸钠、焦亚硫酸钠和浓缩混合生育酚。
增溶剂的示例包括苯甲酸钠、甘油、D-山梨醇、葡萄糖、丙二醇、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇和D-甘露醇。
增稠剂的示例包括聚乙二醇、甲基纤维素、乙基纤维素、羧甲基纤维素钠、黄原胶、硫酸软骨素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯呲咯烷酮和聚乙烯醇。
此外,上述药物组合物除含有IL-2突变蛋白外,还可含有被认为对药物靶向的疾病具有预防或治疗作用的化合物。当所述药物用作抗肿瘤剂时,已知具有抗肿瘤作用的化合物的示例包括西妥昔单抗、曲妥珠单抗和利妥昔单抗。在本发明中,例如,优选免疫检查点抑制剂,如纳武利尤单抗(Nivolumab)、派姆单抗(Pembrolizumab)或伊匹单抗(Ipilimumab)。
在所述药物组合物的实施方式中,所述组合物中IL-2突变蛋白的含量没有特别限制,可以适当地设定在例如90质量%以上、70质量%以上、50质量%以上、30质量%以上、10质量%以上、5质量%以上和1质量%以上的条件内。
剂型没有特别的限制,其示例可包括各种剂型,包括:口服给药剂,如片剂、丸剂、胶囊、粉剂、颗粒和糖浆;以及肠外给药剂,如注射剂(例如,静脉注射、肌肉注射或局部注射)、含漱剂、滴剂、外用制剂(软膏、乳膏、贴片和吸入剂)和栓剂。在剂型中,例如,口服给药剂(例如,片剂、丸剂、胶囊、粉剂、颗粒和糖浆)和外用制剂(如吸入剂、软膏、乳膏和贴剂)是优选的。
在本发明中,IL-2突变蛋白的剂量根据,例如,施用途径、患者的年龄、体重或症状而变化,因此不能唯一地定义。然而,剂量只需要达到这样的量,即成人的日剂量通常约为5000mg以下,最好约为1000mg以下。IL-2突变蛋白的剂量下限也没有特别的限制,成人的日剂量可适当设定在通常0.1mg以上,优选0.5mg以上的范围内。当每天给药一次时,IL-2突变蛋白只需在单剂量中含有上述用量即可。当每天给药三次时,IL-2突变蛋白只需在单剂量中含有相当于上述量的三分之一的用量即可。
本发明的药物给药于诸如哺乳动物的患者。哺乳动物的示例包括人、猴子、小鼠、大鼠、兔子、猫、狗、猪、牛、马和羊。在这些动物中,人是首选。因此,在另一实施方式中,本发明提供了一种预防或治疗癌症的方法,包括将项目1至5中任何一项所述的有效剂量的IL-2突变蛋白施用于需要其的受试者。
下面通过实施例详细描述本发明的具体实施方式,但本发明不限于这些实施例。
实施例
实施例1:IL-2受体α(IL-2Rα)结合能力
质粒的构建:
根据NCBI参考序列中描述的序列信息:NM_000586.3,通过使用源自白血病细胞(#TKG 0209,购买自the Cell Resource Center for Biomedical Research,Institute ofDevelopment,Aging and Cancer,Tohoku University)和源自mRNA的cDNA(PrimeScript(商标)II 1st strand cDNA Synthesis Kit,Takara Bio Inc.,#6210A)作为模板的PCR方法,用于编码本发明的突变蛋白的编码人IL-2的质粒(pcDNA4-IL-2)被扩增,以及使用In-fusion反应(Takara Bio Inc.,In-fusion HD Cloning Kit#639648)作为产生用于编码所需融合的DNA的基本步骤,被并入用于哺乳动物细胞(pcDNA(商标)4/myc-HisA哺乳动物表达载体,Thermo Fisher Scientific K.K.)的表达载体。为了纯化,将蛋白酶可切割序列(TEV可切割氨基酸序列ENLYFQG)和Strep-tag(商标)链球菌标签和多组氨酸标签融合到IL-2基因的c端。人IL-2突变体MK-14是通过利用合成引物(PrimeSTAR(商标)Max DNAPolymerase,Takara Bio Inc.,#R045A)的PCR方法将新突变引入到并入前述质粒中的人IL-2基因中所获得的产物,以及构建了编码该结构(pcDNA4-MK-14)的质粒。分别编码本发明的突变蛋白的MK-6和MK-15均为通过以MK-14为模板的PCR方法通过引入新突变所获得的产物,并且构建了编码该结构(pcDNA4-MK-6和pcDNA4-MK-15)的质粒。此外,MK-4也是通过以MK-14为模板的PCR方法引入新突变所获得的产物,并且构建了编码该结构(pcDNA4-MK-4)的质粒。
IL-2突变蛋白的生产:
待在以下实施例中使用的IL-2突变蛋白是使用上述方法所获得的质粒按照以下描述进行生产的:
对于带有多组氨酸标签的IL-2突变蛋白,将编码该结构的质粒转化为具有NEBStable化学活性的大肠杆菌细胞(NEB(商标)#C3040H),在Amp选择琼脂板上增殖菌落,并将转化株用于在LB培养液中接种。在增殖过夜后,将成球的大肠杆菌细胞用于大规模质粒制备(NucleoBond(商标)Xtra Maxi EF(商标),MACHEREY-NAGEL GmbH&Co.KG,#740424)。
在250ml的Expi293(商标)表达培养基(Thermo Fisher Scientific K.K.,#A1435101)中增殖的悬浮培养液中,通过将质粒瞬时转染人胚胎肾(HEK)细胞(Expi293F(商标),Thermo Fisher Scientific K.K.,#A14527),测定每个IL-2突变蛋白结构的表达。Expi293细胞在37℃,8%CO2,80%湿度的条件下,在一次性无菌一次性锥形瓶(平底1000mL排气过滤器,Thermo Fisher Scientific K.K.)中进行增殖。在WakenBtech RemoteShake中,摇速为125rpm。对于每次转染,按照制造商的指令使用在11.25ml转染培养基(Opti-MEM(商标)I(1x)+GlutaMAX(商标)-I Reduced Serum medium,Thermo Fisher ScientificK.K.(商标)#51985-026)中的250μg DNA,以及在11.83ml的转染培养基中675μlExpiFectamine(商标)293Reagent(ExpiFectamine(商标)293转染试剂盒,Lifetechnologies(商标)#A14525)。转染22小时后,在培养液中加入1.25ml的增强剂1和12.5ml的增强剂2(ExpiFectamine(商标)293转染试剂盒,Thermo Fisher Scientific K.K.,#A14525)。转染约120小时后,4000g离心30分钟收获细胞培养液,澄清后的培养基在纯化前经0.22μm Rapid Filter Max Set(Bottle Top&Bottle)500ml(Techno Plastic ProductsAG,#99500,瑞士)过滤。所得液通过过滤器进行无菌过滤,用于蛋白表达的纯化。以下实施例中使用的MK-6、MK-15和MK-4的氨基酸序列分别列于SEQ ID NO:3、SEQ ID NO:4和SEQ IDNO:5中。
纯化
用AKTA go色谱系统(GE-Healthcare),经0.22μm过滤器离心过滤后的液体以低流速滴入用NPI-20缓冲液(50mM NaH2PO4,300mM NaCl,20mM咪唑,pH 8.0)平衡的5ml HisTrapHP柱(GE-Healthcare,#17524802,USA),然后用NPI-20缓冲液洗脱低亲和力结合杂质。结合融合蛋白用100%NPI-250缓冲液(50mM NaH2PO4,300mM NaCl,250mM咪唑,pH 8.0)洗脱,然后使用Unicorn(商标)软件的峰检测选项收集主峰。使用预包装的一次性PD-10色谱柱(GE-Healthcare,#17085101,USA)在1×D-PBS(-)(Gibco(商标))中进一步纯化主峰。收集1ml馏分,使用SuperSep TM Ace10至20%13孔(商标)凝胶(Fuji-Film Wako,#191-15031)还原SDS-PAGE进行分析。样品与添加10×还原剂的3×十二烷基硫酸钠(SDS)样品缓冲液混合。将混合物在95℃下加热5分钟,然后上样进行SDS-PAGE。按照制造商的说明,使用QCColloidal Coomassie染色剂(BIO-RAD,#1610803)对蛋白质进行可视化。用蛋白酶裂解蛋白质时,使用TEV蛋白酶(Applied Biological Materials Inc.,#E027)。对于蛋白质的量化,根据制造商的说明使用protein Assay BCA Kit(Nacalai Tesque,Inc.,#06385-00)进行测量。
接下来,测量IL-2受体α在细胞上的结合能力(细胞上受体结合)。具体地,从RIKEN细胞库(RCB2202)获得293T细胞。利用以人和小鼠IL-2受体α链基因(NCBI参考序列:NM_000417.2和NM_008367.3)作为卡带分别构建的慢病毒载体(pSIN-EF-RfA2-1-人IL-2Ra和pSIN-EF-RfA2-1-小鼠IL-2Ra),建立了表达293T中人和小鼠IL-2受体α(293Ta)作为稳定表达293T中的IL-2受体α的细胞。将293T和人或小鼠293Ta粘附在24孔细胞培养板(TechnoPlastic Products AG,#92424)上。之后,添加融合成熟稳定突变的人MK-4-IL-2(MK-4,pcDNA4-MK-4-NLuc,对应比较例)、成熟稳定突变的人MK-6-IL-2(MK-6,pcDNA4-MK-6-NLuc)、成熟稳定突变的人IL-2(MK-14,pcDNA4-MK-14-NLuc,IL-2阳性对照)或成熟稳定突变的人MK-15-IL-2(MK-15,pcDNA4-MK-15-NLuc)的NanoLuc(商标)荧光素酶序列(PromegaCorporation,USA)的悬浮液(10nM),将混合物置于4℃静置1小时进行反应。将细胞洗涤,然后进行量化。突变体IL-2对α-亚基的结合能力示出为与293Ta和293T结合量之(293Ta/293T)比的数值。结果如图10所示。图10示出小鼠和人IL-2受体α的结合能力。如图10a所示,MK-6和MK-15没有示出对小鼠IL-2受体α的结合能力。同时,发现MK-4具有高的小鼠IL-2受体α结合能力。此外,如图10b所示,MK-6和MK-15也没有显示出对人IL-2受体α的结合能力。
接下来,以MSA-CSPG4-scFv-MK-14或MSA-CSPG4-scFv-MK-6作为IL-2样本进行检测。MSA-CSPG4-scFv-MK-14或MSA-CSPG4-scFv-MK-6是通过与实施例1相同的方式进行质粒构建和IL-2突变蛋白生产获得的,不同的是使用编码SEQ ID NO:20或19中所示的氨基酸序列的DNA。对表达293T细胞的每个人和小鼠IL-2受体α的的结合能力进行了类似的数值检测,以确定其数量比(293Ta/293T)的数值。结果如图11所示。如图11所示,可以发现,MSA-CSPG4-scFv-MK-14与人和小鼠IL-2受体α结合,但与MK-6一样,MSA-CSPG4-scFv-MK-6不与人和小鼠IL-2受体α结合。
接下来,测量其在细胞上与人CSPG4的结合(细胞上受体结合)。具体地,CT26细胞从日本Cell Resource Center for Biomedical Research,Institute of Development,Aging and Cancer,Tohoku University(Cell Resource Center for BiomedicalResearch,Institute of Development,Aging and Cancer,Tohoku University)购买。利用以人CSPG4链基因(NCBI参考序列:NM_001897.5)作为卡带构建的慢病毒载体(LT3G-hCSPG4-myc-His,通过将人CSPG4基因cDNA插入到由Johanness Zuber博士(分子病理研究所(IMP))提供的pmiRE18_LT3GEPIR_Ren713中获得的质粒),将人CSPG4-表达CT26细胞(CT26/CSPG4)建立作为在多西环素存在下诱导表达人CSPG4的CT26细胞。将CT26和CT26/CSPG4粘附在24孔细胞培养板上(Techno Plastic Products AG,#92424),然后添加融合成熟稳定突变的人MK-6-IL-2(MK-6,pcDNA4-MK-6-NLuc),成熟稳定突变的MSA-CSPG4-scFv-MK-6(pcDNA4-MSA-CSPG4-scFv-MK-6),或成熟稳定突变的MSA-CSPG4-scFv-MK-6(pcDNA4-MSA-CSPG4-scFv-MK-6)的NanoLuc(商标)荧光素酶序列(Promega Corporation,USA)悬浮液(10nM),将混合物置于4℃下静置1小时,进行反应。将细胞洗涤,然后进行量化。每个突变体IL-2对人CSPG4的结合能力示出为NanoLuc活性的数值。结果如图12所示。如图12所示,与具有白蛋白和与之融合的CSPG-scFv的MK-14一样,具有白蛋白和与之融合的CSPG-scFv的MK-6结合到CSPG4。由结果可知,具有缀合到其的抗体样分子的MK-6结合到癌细胞上表达的靶抗原(人CSPG4)。
实施例2:IL-2依赖性细胞增殖
实施例2-1:IL-2依赖性细胞增殖
为了用IL-2使培养的细胞增殖,使用CTLL-2细胞(RIKEN Cell Bank RCB0637),其是小鼠T细胞系CTLL-2细胞。细胞以IL-2依赖性方式增殖,因此用于旨在检测IL-2的快速、灵敏的生物分析。使用1nM的人IL-2(BioLegend,#589106)、50μM的2-巯基乙醇(Gibco(商标))、补充10%胎牛血清(FBS,Hyclone)的PRMI-1640(FujiFilm-Wako,#18902025)、100单位/ml青霉素和100单位/ml链霉素,CTLL-2细胞在37℃下和5%CO2或37℃下和10% CO2下,以及97%的湿度下生长。CTLL-2是一种依赖因子的细胞系,其需要用于生长的IL-2。因此,为了进行分析,将CTLL-2细胞用补充5% FBS、5×10-5M2-巯基乙醇、50μg/ml青霉素、50μg/ml链霉素和3-4.0mM l-谷氨酰胺的高糖DMEM洗涤两次,以去除IL-2。待分析的IL-2样品用补充10%FBS的RPMI在96孔细胞培养板(Techno Plastic Products AG,#92097)中滴定。加入洗涤后的CTLL-2细胞(最终分析体积:100μl,3000个细胞/孔),该板在37℃、10%CO2条件下培养约72小时。使用TPA-Mat细胞(由信州大学Toshikazu Takeshita博士提供,J CellPhysiol.,136:319-25,1988)对培养的人T细胞用IL-2进行增殖,它们是IL-2依赖性T细胞系。细胞在37℃下和5%CO2或37℃下和10% CO2下且97%的湿度下在添加人IL-2的培养基(1nM的人IL-2(BioLegend,#589106),补充10%胎牛血清(FBS,Hyclone)的PRMI-1640(FujiFilm-Wako,#18902025),青霉素:100单位/ml,链霉素:100单位/ml)中生长。此外,对于培养的含IL-2的人T细胞的增殖试验,也使用仅表达IL-2受体βγ-链而不表达α-链的细胞。具体地,使用了KHYG-1细胞(由信州大学的Toshikazu Takeshita博士提供,只表达人IL-2受体βγ-链,不表达α-链)和TPA-MatαKO细胞(由信州大学的Toshikazu Takeshita博士提供,只表达人IL-2受体βγ-链,不表达α-链),它们是IL-2依赖性NK细胞系。将这些细胞洗涤两次,然后加入待分析的IL-2样本。MK-4-IL-2(MK-4)、MK-6-IL-2(MK-6)、MK-14-IL-2(MK-14)、MK-15-IL-2(MK-15)、HSA-CSPG4-scFv-MK-14、或HSA-CSPG4-scFv-MK-6被用作待分析的IL-2样品。HSA-CSPG4-scFv-MK-14或HSA-CSPG4-scFv-MK-6是通过与实施例1中相同的方式进行质粒构建和IL-2突变蛋白生产而获得的,不同的是使用SEQ ID NO:17或16中所示的氨基酸序列进行编码的DNA。这些IL-2样品用补充10% FBS的RPMI1640在96孔细胞培养板(Techno Plastic Products AG,#)中滴定,并制备成浓度增加的样品。加入洗涤后的TPA-Mat,或TPA-MatαKO细胞或KHYG-1细胞(最终分析体积:100μl,3000个细胞/孔),该板在37℃、10%CO2条件下孵育约72小时。使用CellTiter-Glo(商标)发光细胞活力分析试剂盒(Promega Corporation,#G7570)量化地测定每孔细胞的细胞计数,并以相对数值表示,每个IL-2(包括突变体)的Emax定义为100%。IL-2、MK-6、MK-14的检测结果如图13所示。MK-6、MK-4、MK-14和MK-15的结果如图14所示。“IL-2依赖性增殖”是一个与生物活性相关的数值,是指基于细胞的体外量化分析中生物活性的测量值。如图13所示,在使用CTLL-2的增殖试验中,与MK-14-IL-2和IL-2各50%有效浓度(EC50)相比,MK-6-IL-2的50%有效浓度(EC50)有所下降(Biolgend,#589106)。同样,在使用TPA-Mat的分析中,也获得了与CTLL-2情况中相似的结果。因此,与IL-2和MK-14-IL-2的最大增殖作用相比,MK-6对小鼠和人T细胞系呈现出相当的最大增殖作用。此外,如图14所示,MK-15对CTLL-2和TPA-Mat均表现出与MK-6相同的增殖活性。此外,MK-6和MK-15在TPA-Matα-KO细胞或KHYG-1细胞上均表现出增殖活性。由于MK-6和MK-15在仅表达IL-2受体βγ链而不表达α-链的细胞上表现出与MK-14相当的增殖活性,因此,可以发现MK-6和MK-15在表达人IL-2受体βγ链的表达细胞上均表现出与IL-2相似的增殖活性。
实施例2-2
使用CTLL-2进行增殖试验的方法与实施例2-1相同,不同的是使用MK-6-IL-2、HSA-3×G4S-MK-6或HSA-3×(EAAAK)-MK-6作为IL-2样本。HSA-3×G4S-MK-6或HSA-3×(EAAAK)-MK-6是通过将MK-6-IL-2的接头序列分别改变为3×G4S或3×(EAAAK)而获得的产物,其氨基酸序列在SEQ ID NO:7或9中所示。这些IL-2样品也通过与实施例1相同的方式进行质粒构建和IL-2突变蛋白生产而获得,不同的是使用对SEQ ID NO:7或9中所示的氨基酸序列编码的DNA。
如图15所示,在使用CTLL-2的增殖试验中,MK-6-IL-2、HSA-3×G4S-MK-6和HSA-3×(EAAAK)-MK-6都显示出彼此相当的增殖活性。同样,在使用TPA-Mat、TPA-MatαKO细胞或KHYG-1细胞的分析中,也获得了与CTLL-2情况相似的结果。因此,白蛋白融合的MK-6-IL-2在小鼠和人T细胞系上表现出与MK-6-IL-2相当的增殖作用,不论是使用柔性接头还是使用刚性接头。
实施例2-3
以与例2-1相同的方式进行IL-2依赖性增殖试验,不同的是使用MK-6-IL-2、HSA-CSPG4-scFv-MK-6和HSA-CSPG4-scFv-MK-14作为IL-2样品。实验结果如图16所示。如图16所示,HSA-CSPG4-scFv-MK-14在CTLL-2和TPA-Mat上的增殖活性均表现出高的增殖活性。同时,HSA-CSPG4-scFv-MK-6显示出与MK-6-IL-2相当的增殖活性。HSA-CSPG4-scFv-MK-6对TPA-MatαKO细胞或KHYG-1细胞的增殖活性与HSA-CSPG4-scFv-MK-14和MK-6-IL-2的增殖活性相当。这三者在仅表达IL-2受体βγ链而不表达α-链的细胞上的增殖活性相当的事实表明,即使当HSA和CSPG4通过G4S接头与MK-6连接时,所得到的结果也能在表达人IL-2受体βγ链的细胞上表现出相似的增殖活性。
实施例3:IL-2依赖性Treg细胞增殖
按照制造商的说明,通过使用CD4+CD25+调节性T细胞分离试剂盒(MiltenyiBiotec,#130-091-041),从BALB/c小鼠(8周龄,Japan SLC,Inc.)的脾脏制备Treg细胞(CD4+CD25+)。接下来,Treg细胞用1×D-PBS(-)(Gibco(商标))洗涤两次,然后重悬在1×D-PBS(-)中,然后用5,6-羧基荧光素二乙酸琥珀酰亚基酯(CFSE,BioLgend,#423801)在室温下在黑暗处染色15分钟。补充10%胎牛血清(FBS,Hyclone)的PRMI-1640(FujiFilm-Wako,#18902025)/补充50μM的2-巯基乙醇(Gibco(商标))/100单位/ml的青霉素/100单位/ml链霉素)被添加以终止反应,细胞再次悬浮在10%胎牛血清(FBS,Hyclone)-补充PRMI-1640的液体中。使用96孔细胞培养板(Techno Plastic Products AG,#92097),其预先涂有1×D-PBS(-)(Gibco(商标)),其中添加了抗CD3单克隆抗体(1μg/mL,BioLegend,纯化的抗小鼠CD3ε抗体#100301),在4℃下涂覆16小时,并用1×D-PBS(-)(Gibco(商标))洗涤3次,每孔装100000个Treg细胞,抗CD28抗体纯化的抗人CD28抗体(BioLegend,#102112),IL-2和MK-14-IL-2(其已滴定至具有增加的浓度),以及细胞在37℃、5%CO2、97%的湿度的条件下培养。72h后,回收细胞,通过流式细胞仪(FACS)量化分析CSFE染色度。结果如图17所示。细胞增殖由CSFE染色度表示,染色度随细胞分裂次数的减少而降低。如图17所示,IL-2(Biolgend,#589106)和MK-14-IL-2在浓度为1nM时诱导了超过70%的Tregs细胞分裂和增殖,但与未添加的情况(0pM)相比,MK-6对Tregs的细胞分裂增加作用没有变化,因此缺乏对Tregs的增殖活性。
实施例4:IL-2体内注射对外周免疫细胞的作用
测量了注射IL-2(MK-6-IL-2或MK-14-IL-2)对小鼠外周血免疫系统细胞计数(BALB/c)的作用。具体地,从日本SLC公司购买的BALB/c小鼠(8周龄,n=3)每天每人一次静脉注射剂量分别为2.5μg、25μg和250μg的IL-2,连续4天,并在最后一次注射后的那一天从小鼠脾脏制备外周血免疫系统细胞。分别对CD8+T细胞(CD3+CD4-CD8+:)、Treg细胞(CD3+CD4+CD25+FoxP3+)和NK细胞(CD3-CD49b+NKp46+)用抗体染色,并通过FACS分析对其细胞计数进行量化。使用的抗体如下:CD3ε:145-2C11,BioLgend,CD4:RM4-4,BioLgend,CD8a:53-6.7,BioLgend,CD25(IL-2Rα):PC61,BioLgend,NKp46:29A1.4,BioLgend,FoxP3:FJK-16s,DBBiosciences。实验结果如图18所示。如图18所示,MK-14-IL-2和MK-6均不具有增加瘤内CD8T细胞和NK细胞的能力。同时,MK-14-IL-2在注射25μg时也能增加Treg细胞,而MK-6即使注射250μg也没有增加细胞。此外,与PBS注射组相比,MK-14-IL-2没有增加CD8/Treg比值,但与MK-14-IL-2相比,注射250μg的MK-6明显增加了CD8/Treg比值。
实施例5:IL-2体内注射的副作用
将IL-2(MK-6-IL-2或MK-14-IL-2)注射到小鼠体内(BALB/c,8周龄,Japan SLC,Inc.),并研究其体内作用。具体地,每一种IL-2分别以2.5μg、25μg和250μg的剂量静脉注射,每天1次,连续4天。第5天对小鼠实施安乐死。测量体重,以及计算与注射前相比体重增加的比例。此外,切除肝脏和脾脏,测量其各自的重量。肺在切除后进行重量测量,然后用miVac(Genevac,SP Scientific)干燥并测量干重,然后用前者除以后者计算含水量。注射IL-2的副作用表现为体重和各器官重量的增加。结果如图19所示。具体地,MK-14-IL-2通过25μg注射显著增加了体重,而MK-6即使注射250μg也没有增加体重。对于脾脏和肝脏中的每一者,25μg的MK-14-IL-2均显著增加了器官的重量,但MK-6没有表现出类似的作用。肺水肿的发生以肺重除以干重(每干重的含水量值)得到的值表示。通过注射250μg的MK-14-IL-2发生肺水肿,而在注射相同体积的MK-6的情况下,没有发生肺水肿。
实施例6:IL-2单一治疗患CT26结肠癌小鼠模型的抗肿瘤作用
测量了IL-2(MK-14-IL-2或MK-6-IL-2)对CT26结肠癌细胞皮下植入的患癌小鼠(BALB/c)的作用。具体地,将5×105CT26细胞(购自Cell Resource Center forBiomedical Research,Institute of Development,Aging and Cancer,TohokuUniversity)悬浮在100μL的1×D-PBS(-)中,并将该悬浮液皮下植入与细胞(BALB/c)相同物种的小鼠背部。将1×D-PBS(-)、MK-14-IL-2(5μg)或MK-6-IL-2(100μg)每天两次腹腔注射,连续5天,并使用卡尺随时间测量肿瘤直径(最短直径“a”mm,最长直径“b”mm)。使用近似公式计算肿瘤体积(V):最长直径×最长直径×最短直径÷2(V=a×b2/2)mm3。肿瘤系统的测量结果如图20所示。如图20所示,注射1×D-PBS(-)组和MK-14-IL-2组的肿瘤生长情况相似,但与MK-14-IL-2组相比,注射MK-6-IL-2组明显抑制了肿瘤增殖。
实施例7:通过IL-2单一治疗患CT26结肠癌小鼠模型瘤内T细胞的FACS分析
通过IL-2单一治疗在患CT26结肠癌小鼠模型中制备瘤内T细胞,并进行FACS分析。具体地,将5×105CT26细胞(购自Cell Resource Center for Biomedical Research,Institute of Development,Aging and Cancer,Tohoku University)悬浮于100μL 1×D-PBS(-)中,并使用26G针头和1mL注射器将悬浮液皮下植入BALB/c小鼠(8周龄,日本SLC公司)的背部。对生长到均匀大小的肿瘤每天两次腹腔注射1×D-PBS(-)或IL-2(MK-14-IL-2或MK-6-IL-2),连续5天,然后从切除的肿瘤中制备瘤内淋巴细胞(TILs)。具体地,将切除的肿瘤用剪刀等切碎,然后浸入10mL解离缓冲液(10%胎牛血清(FBS,Hyclone)-补充PRMI-1640(FujiFilm-Wako,18902025)/青霉素:100单位/mL/链霉素:100单位/mL,DNaseI(Sigma-Aldrich#DN25-100MG,以50μg/mL加入)中,在37℃、122rpm下摇动30分钟(TaitecCorporation,BR-53FP)。将细胞悬浮液通过70μm滤网(BD Falcon)转化为单细胞,然后利用TIL(CD45)微珠、小鼠(Miltenyi Biotec,#130-110-618),用MACS Pro Separator(Miltenyi Biotec)制备造血细胞(CD45+)作为TILs。
所制备TILs的FACS分析结果如图21所示。通过FACS分析Treg细胞(CD4+CD25+FoxP3+)、CD8+T细胞、PD-1+CD8+T细胞、CD4+T细胞和NK细胞(CD3-CD49b+NKp46+),并对其各自的细胞计数进行量化。CD8/Treg比例示出为用CD8 T+细胞计数除以Treg细胞计数得到的相对值。使用的抗体如下:CD3ε:145-2C11,BioLgend,CD4:RM4-4,BioLgend,CD8a:53-6.7,BioLgend,CD25(IL-2Rα):PC61,BioLgend,NKp46:29A1.4,BioLgend,FoxP3:FJK-16s,DBBiosciences,PD-1:29F.1A12BioLegend。如图21所示,与注射MK-14-IL-2组相比,在CD4+T细胞组中,源自注射MK-6-IL-2小鼠的TILs具有显著减少的Tregs(%)(图21d)。此外,与PBS注射组相比,CD8/Treg比例显著增加。同时,在该肿瘤模型中,CD4+T细胞、CD8+T细胞、PD-1+CD8+T细胞和NK细胞均未发现差异。
实施例8:IL-2单一治疗患B16F10黑色素瘤小鼠模型的抗肿瘤作用
测量IL-2(MK-6-IL-2或MK-14-IL-2)对皮下植入B16F10黑色素瘤的患癌小鼠(C57BL/6)的作用。具体地,将5×105B16-F10细胞(购自Cell Resource Center forBiomedical Research,Institute of Development,Aging and Cancer,TohokuUniversity)悬浮于100μL 1×D-PBS(-)中,并使用26G针头和1ml注射器将该悬浮液皮下植入C57/BL6小鼠(8周龄,日本SLC公司)的背部。已生长到均匀大小的肿瘤每天两次腹腔注射1×D-PBS(-)、MK-14-IL-2(5μg)或MK-6-IL-2(100μg),连续5天,并使用卡尺随时间测量肿瘤直径(最短直径“a”mm,最长直径“b”mm)。使用近似公式计算肿瘤体积(V):最长直径×最长直径×最短直径÷2(V=a×b2/2)mm3。肿瘤系统的测量结果如图22所示。如图22所示,在IL-2注射开始后的第7天,与1×D-PBS(-)相比,MK-6显示出明显较小的肿瘤体积。
实施例9:通过IL-2单一治疗患B16F10黑色素瘤小鼠模型瘤内淋巴细胞的FACS分
析
通过IL-2单一治疗患B16F10黑色素瘤小鼠模型,对瘤内T细胞进行FACS分析。具体地,将5×105B16F10细胞(购自Cell Resource Center for Biomedical Research,Institute of Development,Aging and Cancer,Tohoku University)悬浮在100μL的1×D-PBS(-)中,并使用26G针头和1mL注射器将悬浮液皮下植入C57/BL6小鼠(8周龄,日本SLC公司)的背部。生长到均匀大小的肿瘤每天两次腹腔注射1×D-PBS(-)、MK-14-IL-2(5μg)或MK-6-IL-2(100μg),连续5天,然后从切除的肿瘤中制备瘤内淋巴细胞(TILs)。具体地,将切除的肿瘤用剪刀等切碎,然后浸入10mL解离缓冲液(10%胎牛血清(FBS,Hyclone)-补充PRMI-1640(FujiFilm-Wako,#18902025)/青霉素:100单位/mL/链霉素:100单位/mL,DNaseI(Sigma-Aldrich,#DN25-100MG,以50μg/mL加入)中,在37℃、122rpm下摇动30分钟(TaitecCorporation,BR-53FP)。将细胞悬浮液通过70μm滤网(BD Falcon)转化为单细胞,然后利用TIL(CD45)微珠、小鼠(Miltenyi Biotec,#130-110-618),用MACS Pro Separator(Miltenyi Biotec)制备造血细胞(CD45+)作为TILs。
对于所制备TILs的FACS分析结果,对切除的瘤内淋巴细胞(TILs)进行FACS分析。分别对CD8+T细胞、CD4+T细胞、Treg细胞(CD4+CD25+FoxP3+)、IFNγ+CD8+T细胞(活化的CD8+T细胞)、NK细胞(CD3-CD49b+NKp46+)、IFNγ+NK细胞(活化的NK细胞)、PD-1+CD8+T细胞和PD-1+Treg细胞+(活化的Treg细胞)各自的细胞计数进行量化。使用的抗体如下:CD3ε:145-2C11,BioLgend,CD4:RM4-4,BioLgend,CD8a:53-6.7,BioLgend,CD25(IL-2Rα):PC61,BioLgend,NKp46:29A1.4,BioLgend,FoxP3:FJK-16s,DB Biosciences,PD-1:29F.1A12,BioLgend,和IFNγ:4SB3,BioLgend。CD8/Treg比例示出为CD8+T细胞计数除以Treg细胞计数得到的相对值。结果如图23所示。如图23所示,CD8+T细胞、CD4+T细胞、Treg细胞(CD4+CD25+FoxP3+)和IFNγ+CD8+T细胞(活化+的CD8+T细胞)没有显著差异,但NK细胞(CD3-CD49b+NKp46+)和IFNγ+NK细胞在MK-6-IL-2注射组的计数均明显高于PBS注射组。
实施例10:成熟的MK-6-IL-2小鼠白蛋白(SEQ ID NO:12)单一治疗患CT26结肠癌
小鼠模型的抗肿瘤作用
测量了MSA-IL-2(MSA-MK-14-IL-2(SEQ ID NO:13)或MSA-MK-6-IL-2(SEQ ID NO:12))对皮下植入患CT26结肠癌细胞的患癌小鼠(BALB/c)的作用。具体地,将5×105CT26细胞(购自Cell Resource Center for Biomedical Research,Institute of Development,Aging and Cancer,Tohoku University)悬浮在100μL的1×D-PBS(-)中,并将该悬浮液皮下植入与细胞(BALB/c)相同物种的小鼠背部。分别在第5天和第10天分别腹腔注射1×D-PBS(-)、MSA-MK-14-IL-2(5μg)或MSA-MK-6-IL-2(100μg)共两次,并使用卡尺随时间测量肿瘤直径(最短直径“a”mm,最长直径“b”mm)。使用近似公式计算肿瘤体积(V):最长直径×最长直径×最短直径÷2(V=a×b2/2)mm3。肿瘤系统的测量结果如图24a所示。如图24a所示,注射1×D-PBS(-)的肿瘤随着时间的推移而生长,但注射MSA-MK-14-IL-2的组在肿瘤缩小效果上没有显著差异。同时,在注射MSA-MK-6-IL-2组中,与PBS组和MSA-MK-14-IL-2组中的每一个相比,肿瘤增殖明显受到抑制。
实施例11:成熟的MK-6-IL-2小鼠白蛋白(SEQ ID NO:12)单一治疗患CT26结肠癌
小鼠模型瘤内T细胞的FACS分析
制备了通过IL-2单一治疗患CT26结肠癌小鼠模型中的瘤内T细胞,并进行FACS分析。具体地,将5×105CT26细胞(购自Cell Resource Center for Biomedical Research,Institute of Development,Aging and Cancer,Tohoku University)悬浮于100μL的1×D-PBS(-)中,并使用26G针头和1mL注射器将悬浮液皮下植入BALB/c小鼠(8周龄,日本SLC公司)的背部。生长到均匀大小的肿瘤在第5天和第10天分别腹腔注射1×D-PBS(-)或白蛋白融合的IL-2(MSA-MK-14-IL-2或MSA-MK-6-IL-2)共两次,并在第12天从切除的肿瘤制备瘤内淋巴细胞(TILs)。具体地,将切除的肿瘤用剪刀等切碎,然后浸入10mL解离缓冲液(10%胎牛血清(FBS,Hyclone)-补充PRMI-1640(FujiFilm-Wako,#18902025)/青霉素:100单位/mL/链霉素:100单位/mL,DNaseI(Sigma-Aldrich,#DN25-100MG,以50μg/mL加入)中,在37℃、122rpm下摇动30分钟(Taitec Corporation,BR-53FP)。将细胞悬浮液通过70μm滤网(BDFalcon)转化为单细胞,然后利用TIL(CD45)微珠、小鼠(Miltenyi Biotec,#130-110-618),用MACS Pro Separator(Miltenyi Biotec)制备造血细胞(CD45+)作为TILs。对制备的TILs进行FACS分析的结果如图16所示。通过FACS分析Treg细胞(CD4+CD25+FoxP3+)、CD8+T细胞、PD-1+CD8+T细胞、CD4+T细胞和NK细胞(CD3-CD49b+NKp46+),并对其各自的细胞计数进行量化。CD8/Treg比例示出为用CD8+T细胞计数除以Treg细胞计数得到的相对值。使用的抗体如下:CD3ε:145-2C11,BioLgend,CD4:RM4-4,BioLgend,CD8a:53-6.7,BioLgend,CD25(IL-2Rα):PC61,BioLgend,NKp46:29A1.4,BioLgend,FoxP3:FJK-16s,DB Biosciences,PD-1:29F.1a12BioLegend。结果如图24b所示。如图24b所示,与注射成熟的MK-14-IL-2小鼠白蛋白(SEQ ID NO:13)的小鼠相比,注射成熟的MK-6-IL-2小鼠白蛋白(SEQ ID NO:13)的小鼠获得的TILs具有显著高的CD3+T细胞组比例,CD4+T细胞组中的Tregs(%)显著减少(图24b)。此外,与PBS注射组和成熟的MK-14-IL-2小鼠白蛋白注射组相比,CD8/Treg比例显著增加。
实施例12:腹腔注射成熟的MK-6-IL-2(SEQ ID NO: 3)和成熟的MK-6-IL-2小鼠白
蛋白(SEQ ID NO:12)后IL-2血药浓度的变化(a)和患CT26结肠癌小鼠模型瘤内IL-2的量化
(a)BALB/c小鼠(8周龄,Japan SLC,Inc.)被腹腔注射对应于等摩尔量的MK-6(SEQID NO:3)(25mg)和MSA-MK-6(SEQ ID NO:12)(65mg)。每个IL-2与NanoLuc(商标)荧光素酶序列融合(Promega Corporation,USA)。根据NanoLuc(商标)活性对注射后的血液IL-2进行量化。测量了注射后1小时开始β-阶段(β-phase)的半衰期(平均β半衰期(t1/2))±标准差(SD)。“%剩余”示出为注射后1小时NanoLuc活性的每个测量值除以每个时间点NanoLuc活性的测量值得到的相对值(%)。“β-阶段”是指在初始阶段(α-阶段)快速衰减后,后续血药浓度变化呈现缓慢衰减的阶段(β-阶段),在此阶段计算半衰期。结果如图24a所示。如图24a所示,药物治疗后与血液MSA融合的成熟的MK-6-IL-2小鼠白蛋白具有为5.6小时的t1/2,与具有2.9小时的t1/2的成熟的MK-6-IL-2相比,血液半衰期要长得多。(b)患CT26结肠癌小鼠模型瘤内IL-2的量化:5×105CT26细胞(购买自Cell Resource Center for BiomedicalResearch,Institute of Development,Aging and Cancer,Tohoku University)悬浮在100μL的1×D-PBS(-)中,使用26G针头和1ml注射器将该悬浮液皮下植入BALB/c小鼠(8周龄,日本SLC公司)的背部。对已生长到均匀大小的肿瘤腹腔注射成熟的MK-6-IL-2(SEQ IDNO:3)和成熟的MK-6-IL-2小鼠白蛋白(SEQ ID NO:12)仅一次。注射1小时后,切除肿瘤,加入1×D-PBS(-),随后用BioMasher(商标,Nippi,Incorporated)粉碎肿瘤。使用BertholdJapan K.K.的Lumat3 LB9508对NanoLuc活性进行量化,使用Promega K.K.公司的Nano-Glo(商标)荧光素酶分析系统制备样品,结果如图25b所示。如图25b所示,结果示出成熟的MSA-MK-6-IL-2在肿瘤中以非常高的浓度积累。
序列表
<110> 地方独立行政法人 宫城县立医院机构(MIYAGI PREFECTURAL HOSPITALORGANIZATION)
<120> IL-2突变蛋白及包含其的药物
<130> FP225472JP
<150> JP2020-157900
<151> 2020-09-18
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<170> SIPOSequenceListing 1.0
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<213> 智人(Homo sapiens)
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100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 5
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MK-4-IL-2
<400> 5
Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Ala Leu Thr Ala Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 6
<211> 585
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 7
<211> 733
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HSA-3xG4S-MK-6
<400> 7
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys
595 600 605
Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile
610 615 620
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Ala Leu Thr Ala Met Leu
625 630 635 640
Thr Phe Ala Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
645 650 655
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
660 665 670
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
675 680 685
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
690 695 700
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
705 710 715 720
Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu Thr
725 730
<210> 8
<211> 733
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys
595 600 605
Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile
610 615 620
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Ala Leu Thr Ala Met Leu
625 630 635 640
Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
645 650 655
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
660 665 670
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
675 680 685
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
690 695 700
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
705 710 715 720
Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu Thr
725 730
<210> 9
<211> 733
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HSA-3x(EAAAK)-MK-6
<400> 9
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Glu Ala Ala Ala Lys Glu Ala
580 585 590
Ala Ala Lys Glu Ala Ala Ala Lys Ala Pro Ala Ser Ser Ser Thr Lys
595 600 605
Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile
610 615 620
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Ala Leu Thr Ala Met Leu
625 630 635 640
Thr Phe Ala Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
645 650 655
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
660 665 670
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
675 680 685
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
690 695 700
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
705 710 715 720
Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu Thr
725 730
<210> 10
<211> 733
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HSA-3x(EAAAK)-MK-15
<400> 10
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Glu Ala Ala Ala Lys Glu Ala
580 585 590
Ala Ala Lys Glu Ala Ala Ala Lys Ala Pro Ala Ser Ser Ser Thr Lys
595 600 605
Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile
610 615 620
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Ala Leu Thr Ala Met Leu
625 630 635 640
Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
645 650 655
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
660 665 670
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
675 680 685
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
690 695 700
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
705 710 715 720
Trp Ile Thr Phe Ala Gln Ser Ile Ile Ser Thr Leu Thr
725 730
<210> 11
<211> 584
<212> PRT
<213> 小鼠(Mus musculus)
<400> 11
Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu
1 5 10 15
Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu
65 70 75 80
Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
100 105 110
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
115 120 125
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln
145 150 155 160
Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser
165 170 175
Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
180 185 190
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro
210 215 220
Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys
225 230 235 240
Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
260 265 270
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His
275 280 285
Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
290 295 300
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
340 345 350
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
355 360 365
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu
385 390 395 400
Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
420 425 430
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser
465 470 475 480
Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
500 505 510
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
530 535 540
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys
545 550 555 560
Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
565 570 575
Thr Arg Cys Lys Asp Ala Leu Ala
580
<210> 12
<211> 732
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MSA-MK-6
<400> 12
Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Ala Leu Thr Ala Met Leu Thr Phe Ala Phe Ala Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn
145 150 155 160
Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser
165 170 175
Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln
180 185 190
Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala
195 200 205
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala
210 215 220
Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr
225 230 235 240
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
245 250 255
Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys
260 265 270
Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His
275 280 285
Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr
290 295 300
Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala
305 310 315 320
Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys
325 330 335
Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln
340 345 350
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
355 360 365
Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr
370 375 380
Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu
385 390 395 400
Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln
405 410 415
Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu
420 425 430
Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala
435 440 445
Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys
450 455 460
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr
465 470 475 480
Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg
485 490 495
Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala
500 505 510
Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu
515 520 525
Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu
530 535 540
Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr
545 550 555 560
Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg
565 570 575
Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln
580 585 590
Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val
595 600 605
Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys
610 615 620
Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr
625 630 635 640
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr
645 650 655
Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys
660 665 670
Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr
675 680 685
Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp
690 695 700
Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly
705 710 715 720
Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala
725 730
<210> 13
<211> 732
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MSA-MK-14
<400> 13
Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn
145 150 155 160
Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser
165 170 175
Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln
180 185 190
Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala
195 200 205
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala
210 215 220
Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr
225 230 235 240
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
245 250 255
Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys
260 265 270
Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His
275 280 285
Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr
290 295 300
Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala
305 310 315 320
Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys
325 330 335
Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln
340 345 350
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
355 360 365
Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr
370 375 380
Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu
385 390 395 400
Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln
405 410 415
Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu
420 425 430
Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala
435 440 445
Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys
450 455 460
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr
465 470 475 480
Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg
485 490 495
Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala
500 505 510
Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu
515 520 525
Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu
530 535 540
Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr
545 550 555 560
Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg
565 570 575
Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln
580 585 590
Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val
595 600 605
Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys
610 615 620
Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr
625 630 635 640
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr
645 650 655
Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys
660 665 670
Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr
675 680 685
Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp
690 695 700
Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly
705 710 715 720
Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala
725 730
<210> 14
<211> 732
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MSA-MK-15
<400> 14
Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Ala Leu Thr Ala Met Leu Thr Ala Lys Phe Ala Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn
145 150 155 160
Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser
165 170 175
Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln
180 185 190
Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala
195 200 205
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala
210 215 220
Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr
225 230 235 240
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
245 250 255
Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys
260 265 270
Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His
275 280 285
Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr
290 295 300
Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala
305 310 315 320
Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys
325 330 335
Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln
340 345 350
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
355 360 365
Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr
370 375 380
Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu
385 390 395 400
Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln
405 410 415
Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu
420 425 430
Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala
435 440 445
Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys
450 455 460
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr
465 470 475 480
Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg
485 490 495
Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala
500 505 510
Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu
515 520 525
Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu
530 535 540
Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr
545 550 555 560
Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg
565 570 575
Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln
580 585 590
Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val
595 600 605
Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys
610 615 620
Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr
625 630 635 640
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr
645 650 655
Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys
660 665 670
Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr
675 680 685
Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp
690 695 700
Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly
705 710 715 720
Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala
725 730
<210> 15
<211> 251
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人抗CSPG4-scFv
<400> 15
Glu Ala Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Asp
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Thr Tyr Ser Pro Ala Phe
50 55 60
Gln Gly Asp Val Thr Ile Ser Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Gly Ile Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Gly Asn Tyr Tyr Met Asp Val Trp Gly Asn Gly Thr
100 105 110
Pro Val Thr Val Ser Ser Leu Lys Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Arg Ser Thr Gln Ser Ala Leu Thr
130 135 140
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser
145 150 155 160
Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp
165 170 175
Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val
180 185 190
Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser
195 200 205
Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu
210 215 220
Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Thr Arg His Val
225 230 235 240
Phe Gly Thr Gly Thr Gln Leu Thr Val Leu Gly
245 250
<210> 16
<211> 999
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HSA-CSPG4-scFv-MK-6
<400> 16
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Gln Leu Val Glu Ser Gly
595 600 605
Ala Glu Val Lys Lys Pro Gly Asp Ser Leu Lys Ile Ser Cys Lys Gly
610 615 620
Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met
625 630 635 640
Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser
645 650 655
Glu Thr Thr Tyr Ser Pro Ala Phe Gln Gly Asp Val Thr Ile Ser Val
660 665 670
Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala
675 680 685
Ser Asp Thr Gly Ile Tyr Tyr Cys Ala Arg Arg Arg Gly Asn Tyr Tyr
690 695 700
Met Asp Val Trp Gly Asn Gly Thr Pro Val Thr Val Ser Ser Leu Lys
705 710 715 720
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
725 730 735
Arg Ser Thr Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser
740 745 750
Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val
755 760 765
Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala
770 775 780
Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser
785 790 795 800
Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile
805 810 815
Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr
820 825 830
Thr Ser Ser Ser Thr Arg His Val Phe Gly Thr Gly Thr Gln Leu Thr
835 840 845
Val Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
850 855 860
Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
865 870 875 880
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
885 890 895
Tyr Lys Asn Pro Ala Leu Thr Ala Met Leu Thr Phe Ala Phe Ala Met
900 905 910
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
915 920 925
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
930 935 940
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
945 950 955 960
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
965 970 975
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
980 985 990
Ser Ile Ile Ser Thr Leu Thr
995
<210> 17
<211> 999
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HSA-CSPG4-scFv-MK-14
<400> 17
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Gln Leu Val Glu Ser Gly
595 600 605
Ala Glu Val Lys Lys Pro Gly Asp Ser Leu Lys Ile Ser Cys Lys Gly
610 615 620
Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met
625 630 635 640
Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser
645 650 655
Glu Thr Thr Tyr Ser Pro Ala Phe Gln Gly Asp Val Thr Ile Ser Val
660 665 670
Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala
675 680 685
Ser Asp Thr Gly Ile Tyr Tyr Cys Ala Arg Arg Arg Gly Asn Tyr Tyr
690 695 700
Met Asp Val Trp Gly Asn Gly Thr Pro Val Thr Val Ser Ser Leu Lys
705 710 715 720
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
725 730 735
Arg Ser Thr Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser
740 745 750
Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val
755 760 765
Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala
770 775 780
Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser
785 790 795 800
Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile
805 810 815
Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr
820 825 830
Thr Ser Ser Ser Thr Arg His Val Phe Gly Thr Gly Thr Gln Leu Thr
835 840 845
Val Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
850 855 860
Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
865 870 875 880
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
885 890 895
Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met
900 905 910
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
915 920 925
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
930 935 940
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
945 950 955 960
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
965 970 975
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
980 985 990
Ser Ile Ile Ser Thr Leu Thr
995
<210> 18
<211> 999
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HSA-CSPG4-scFv-MK-15
<400> 18
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Gln Leu Val Glu Ser Gly
595 600 605
Ala Glu Val Lys Lys Pro Gly Asp Ser Leu Lys Ile Ser Cys Lys Gly
610 615 620
Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met
625 630 635 640
Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser
645 650 655
Glu Thr Thr Tyr Ser Pro Ala Phe Gln Gly Asp Val Thr Ile Ser Val
660 665 670
Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala
675 680 685
Ser Asp Thr Gly Ile Tyr Tyr Cys Ala Arg Arg Arg Gly Asn Tyr Tyr
690 695 700
Met Asp Val Trp Gly Asn Gly Thr Pro Val Thr Val Ser Ser Leu Lys
705 710 715 720
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
725 730 735
Arg Ser Thr Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser
740 745 750
Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val
755 760 765
Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala
770 775 780
Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser
785 790 795 800
Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile
805 810 815
Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr
820 825 830
Thr Ser Ser Ser Thr Arg His Val Phe Gly Thr Gly Thr Gln Leu Thr
835 840 845
Val Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
850 855 860
Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
865 870 875 880
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
885 890 895
Tyr Lys Asn Pro Ala Leu Thr Ala Met Leu Thr Ala Lys Phe Ala Met
900 905 910
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
915 920 925
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
930 935 940
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
945 950 955 960
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
965 970 975
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln
980 985 990
Ser Ile Ile Ser Thr Leu Thr
995
<210> 19
<211> 998
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MSA-CSPG4-scFv-MK-6
<400> 19
Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu
1 5 10 15
Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu
65 70 75 80
Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
100 105 110
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
115 120 125
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln
145 150 155 160
Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser
165 170 175
Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
180 185 190
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro
210 215 220
Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys
225 230 235 240
Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
260 265 270
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His
275 280 285
Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
290 295 300
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
340 345 350
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
355 360 365
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu
385 390 395 400
Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
420 425 430
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser
465 470 475 480
Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
500 505 510
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
530 535 540
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys
545 550 555 560
Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
565 570 575
Thr Arg Cys Lys Asp Ala Leu Ala Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Glu Ala Gln Leu Val Glu Ser Gly Ala
595 600 605
Glu Val Lys Lys Pro Gly Asp Ser Leu Lys Ile Ser Cys Lys Gly Ser
610 615 620
Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro
625 630 635 640
Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser Glu
645 650 655
Thr Thr Tyr Ser Pro Ala Phe Gln Gly Asp Val Thr Ile Ser Val Asp
660 665 670
Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser
675 680 685
Asp Thr Gly Ile Tyr Tyr Cys Ala Arg Arg Arg Gly Asn Tyr Tyr Met
690 695 700
Asp Val Trp Gly Asn Gly Thr Pro Val Thr Val Ser Ser Leu Lys Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
725 730 735
Ser Thr Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro
740 745 750
Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
755 760 765
Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
770 775 780
Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn
785 790 795 800
Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
805 810 815
Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr
820 825 830
Ser Ser Ser Thr Arg His Val Phe Gly Thr Gly Thr Gln Leu Thr Val
835 840 845
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
850 855 860
Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
865 870 875 880
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
885 890 895
Lys Asn Pro Ala Leu Thr Ala Met Leu Thr Phe Ala Phe Ala Met Pro
900 905 910
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
915 920 925
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
930 935 940
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
945 950 955 960
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
965 970 975
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser
980 985 990
Ile Ile Ser Thr Leu Thr
995
<210> 20
<211> 998
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> MSA-CSPG4-scFv-MK-14
<400> 20
Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu
1 5 10 15
Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu
65 70 75 80
Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
100 105 110
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
115 120 125
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln
145 150 155 160
Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser
165 170 175
Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
180 185 190
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro
210 215 220
Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys
225 230 235 240
Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
260 265 270
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His
275 280 285
Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
290 295 300
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
340 345 350
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
355 360 365
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu
385 390 395 400
Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
420 425 430
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser
465 470 475 480
Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
500 505 510
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
530 535 540
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys
545 550 555 560
Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
565 570 575
Thr Arg Cys Lys Asp Ala Leu Ala Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Glu Ala Gln Leu Val Glu Ser Gly Ala
595 600 605
Glu Val Lys Lys Pro Gly Asp Ser Leu Lys Ile Ser Cys Lys Gly Ser
610 615 620
Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro
625 630 635 640
Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser Glu
645 650 655
Thr Thr Tyr Ser Pro Ala Phe Gln Gly Asp Val Thr Ile Ser Val Asp
660 665 670
Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Asn Ser Leu Lys Ala Ser
675 680 685
Asp Thr Gly Ile Tyr Tyr Cys Ala Arg Arg Arg Gly Asn Tyr Tyr Met
690 695 700
Asp Val Trp Gly Asn Gly Thr Pro Val Thr Val Ser Ser Leu Lys Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
725 730 735
Ser Thr Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro
740 745 750
Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
755 760 765
Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
770 775 780
Lys Leu Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn
785 790 795 800
Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
805 810 815
Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr
820 825 830
Ser Ser Ser Thr Arg His Val Phe Gly Thr Gly Thr Gln Leu Thr Val
835 840 845
Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
850 855 860
Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
865 870 875 880
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
885 890 895
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
900 905 910
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
915 920 925
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
930 935 940
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
945 950 955 960
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
965 970 975
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Ala Gln Ser
980 985 990
Ile Ile Ser Thr Leu Thr
995
<210> 21
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 21
Gly Gly Gly Gly Ser
1 5
<210> 22
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 22
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 23
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 23
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 24
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 24
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 25
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 25
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 26
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 26
Gly Gly Gly Gly Gly Gly
1 5
<210> 27
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 27
Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
<210> 28
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 28
Glu Ala Ala Lys
1
<210> 29
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 29
Glu Ala Ala Lys Glu Ala Ala Lys
1 5
<210> 30
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 30
Glu Ala Ala Lys Glu Ala Ala Lys Glu Ala Ala Lys
1 5 10
<210> 31
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 31
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala Leu Glu Ala Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
35 40 45
<210> 32
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 32
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
1 5 10
<210> 33
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 接头
<400> 33
Pro Ala Pro Ala Pro
1 5
Claims (7)
1.一种IL-2突变蛋白,包括:
在SEQ ID NO:3中所示的氨基酸序列;或
具有与SEQ ID NO:3的氨基酸序列至少95%的序列一致性且其中位置35、位置38、位置42或位置43、和位置45处的氨基酸均为A的氨基酸序列。
2.根据权利要求1所述的IL-2突变蛋白,其中,所述IL-2突变蛋白是具有白蛋白和/或免疫球蛋白的融合蛋白。
3.根据权利要求2所述的IL-2突变蛋白,其中,所述融合蛋白的免疫球蛋白部分是抗体的Fc部分。
4.根据权利要求2所述的IL-2蛋白,其中,所述IL-2蛋白是白蛋白-IL-2、IL-2-白蛋白、白蛋白-IL-2-免疫球蛋白、免疫球蛋白-IL-2-白蛋白、白蛋白-免疫球蛋白-IL-2-白蛋白、或白蛋白-IL-2-免疫球蛋白-白蛋白。
5.根据权利要求1所述的IL-2突变蛋白,其中,所述IL-2突变蛋白具有能够激活表达IL-2受体β和γ的细胞的能力,并且与SEQ ID NO:2中所示的氨基酸序列形成的IL-2突变蛋白相比,所述IL-2突变蛋白对IL-2受体α的结合能力降低。
6.一种药物,包括权利要求1所述的IL-2突变蛋白。
7.根据权利要求6所述的药物,其中,所述药物用于预防或治疗癌症。
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PCT/JP2021/034438 WO2022059794A1 (ja) | 2020-09-18 | 2021-09-17 | Il-2変異体タンパク質及びこれを含む医薬 |
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US (1) | US20240025956A1 (zh) |
EP (1) | EP4215542A1 (zh) |
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TW202406932A (zh) | 2020-10-22 | 2024-02-16 | 美商基利科學股份有限公司 | 介白素2-Fc融合蛋白及使用方法 |
EP4285913A1 (en) * | 2022-05-30 | 2023-12-06 | Ecole Polytechnique Fédérale de Lausanne (EPFL) | Highly effective adoptive t cell therapy |
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JPS59173773A (ja) | 1983-03-24 | 1984-10-01 | Fuji Electric Co Ltd | 電車線の漏洩電流自動測定装置 |
CU23923B1 (es) * | 2010-11-12 | 2013-07-31 | Ct De Inmunología Molecular | Polipéptidos derivados de la il-2 con actividad agonista |
CN105440123B (zh) * | 2011-02-10 | 2020-10-09 | 罗切格利卡特公司 | 突变体白介素-2多肽 |
US20210260163A1 (en) * | 2018-03-09 | 2021-08-26 | AskGene Pharma, Inc. | Novel cytokine prodrugs |
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2021
- 2021-09-17 JP JP2022550641A patent/JPWO2022059794A1/ja active Pending
- 2021-09-17 CN CN202180077914.6A patent/CN117500518A/zh active Pending
- 2021-09-17 WO PCT/JP2021/034438 patent/WO2022059794A1/ja active Application Filing
- 2021-09-17 EP EP21869476.8A patent/EP4215542A1/en active Pending
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US20240025956A1 (en) | 2024-01-25 |
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