CN108368511A - 单链cd137受体激动剂蛋白 - Google Patents
单链cd137受体激动剂蛋白 Download PDFInfo
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- CN108368511A CN108368511A CN201680073663.3A CN201680073663A CN108368511A CN 108368511 A CN108368511 A CN 108368511A CN 201680073663 A CN201680073663 A CN 201680073663A CN 108368511 A CN108368511 A CN 108368511A
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Abstract
本文提供特异性CD137受体激动剂蛋白,编码该蛋白的核酸,以及治疗患有CD137L相关疾病或疾患的受试者的方法。本文提供的CD137受体激动剂蛋白包括三个可溶性CD137L结构域和Fc片段。CD137受体激动剂蛋白基本上是非聚集的并且适用于治疗、诊断和/或研究应用。
Description
技术领域
本发明提供了包含三个可溶性CD137L结构域和Fc片段的特异性CD137受体激动剂蛋白,编码CD137受体激动剂蛋白的核酸分子及其用途。CD137受体激动剂蛋白基本上是非聚集的并且适用于治疗、诊断和/或研究应用。
背景技术
已知TNF超家族(TNFSF)细胞因子的三聚化对于有效的受体结合和活化是必需的。然而,TNF超家族细胞因子的三聚体复合物难以从重组单体单元制备。
WO 01/49866和WO 02/09055公开了包括TNF细胞因子和多聚化组分的重组融合蛋白,特别是来自C1q蛋白家族的蛋白质或胶原凝集素。然而,这些融合蛋白的缺点是三聚化结构域通常具有较大的分子量和/或三聚化效率相当低。
Schneider等人(J Exp Med 187(1989),1205-1213)描述了TNF细胞因子的三聚体通过N末端定位的稳定基序来稳定。在CD95L中,受体结合结构域三聚体的稳定化可能是由位于细胞质膜附近的N末端氨基酸结构域引起的。
Shiraishi等人(Biochem Biophys Res Commun 322(2004),197-202)描述了CD95L的受体结合结构域可以通过N末端定位的人工α螺旋卷曲螺旋(亮氨酸拉链)基序稳定。然而,发现多肽链彼此的取向,例如平行或反平行取向,很难预测的。此外,卷曲螺旋拉链基序中七价重复序列的最佳数目很难确定。另外,卷曲螺旋结构具有在改变pH和/或离子强度后形成大分子聚集体的倾向。
WO 01/25277涉及结合细胞受体的细胞外配体结合结构域的单链寡聚多肽,其中所述多肽包括至少三个受体结合位点,其中至少一个受体结合位点能够结合到细胞受体的配体结合结构域,并且至少一个受体结合位点不能有效结合到细胞受体的配体结合结构域,由此单链寡聚多肽能够结合到受体,但不能激活受体。例如,单体来源于TNF家族的细胞因子配体,特别是来自TNF-α。
WO 2005/103077公开了单链融合多肽,其包括TNF家族配体成员中的至少三个单体和将TNF配体家族成员的单体彼此连接的至少两个肽接头。然而,最近的实验已经表明,这些单链融合多肽表现出不想要的聚集。
WO 2010/010051公开了包括三个可溶性TNF家族细胞因子结构域和至少两个肽接头的单链融合多肽。所描述的融合多肽基本上是非聚集的。
最近的研究已经显示,抗CD137-mAb的体内抗肿瘤活性取决于Fc-γ-R驱动的机制,并且不仅仅依赖于激动性活性。
本领域需要展现出独立于基于Fc-γ-R的体内交联的高生物学活性、高稳定性和允许有效重组制造的新型的CD137受体激动剂。
发明内容
本发明提供了模拟体内CD137:CD137L相互作用的特异性CD137受体激动剂蛋白,与激动性单克隆抗体相比,其展现了低的蛋白水解降解和更短的体内半衰期。
本发明的CD137受体激动剂蛋白通常包括:(i)第一可溶性CD137L细胞因子结构域;(ii)第一肽接头;(iii)第二可溶性CD137L结构域;(iv)第二肽接头;(v)第三可溶性CD137L结构域;(vi)第三肽接头(例如,铰链接头)和(vii)抗体Fc片段。
在一种实施方式中,抗体Fc片段(vii)位于第一CD137L结构域(i)的N末端和/或第三CD137L结构域(v)的C末端。在另一种实施方式中,抗体Fc片段在C末端上位于第三CD137L结构域(v)。在一种实施方式中,该多肽基本上是非聚集的。在另一种实施方式中,第二和/或第三可溶性CD137L结构域是任选地包括氨基酸序列突变的N末端缩短结构域。在另一种实施方式中,可溶性CD137L结构域(i)、(ii)和(iii)是C末端缩短的结构域,其任选地包括氨基酸序列突变。
在一种实施方式中,该可溶性CD137L结构域中的至少一个,特别是可溶性CD137L结构域(iii)和(v)中的至少一个是具有开始于人CD137L的氨基酸D86或R88或Q89或G90的N末端序列的可溶性CD137L结构域,其中D86或R88或Q89可以被中性氨基酸,例如Ser或Gly替换。在另一种实施方式中,该可溶性CD137L结构域中的至少一个,特别是可溶性CD137L结构域(iii)和(v)中的至少一个是具有选自以下的N末端序列的可溶性CD137L结构域:(a)D86–G90和(b)(Gly/Ser)89-G90。在一种实施方式中,可溶性CD137L结构域以人CD137L的氨基酸E254结束和/或任选地包括在位置D86、L87、R88、Q89、D112、V118、A154、A174、A176、A188、T241处的一种或多种突变。在一种实施方式中,可溶性CD137L结构域(i)、(iii)和(v)包括根据SEQ ID NO:1的人CD137L的氨基酸D86–E254。
在一种实施方式中,该可溶性CD137L结构域中的至少一个,特别是至少可溶性CD137L结构域(i)是具有N末端序列的可溶性CD137L结构域,其起始于氨基酸R88并且其中R88可以被Ser或Gly替换。在一种实施方式中,该可溶性CD137L结构域中的至少一个,特别是至少可溶性CD137L结构域(iii)是以V240结束的可溶性C末端缩短的CD137L结构域。在另一种实施方式中,该可溶性CD137L结构域中的至少一个,特别是至少可溶性CD137L结构域(iii)是以T241结束的可溶性C末端缩短的CD137L结构域。在又一种实施方式中,该可溶性CD137L结构域中的至少一个,特别是至少可溶性CD137L结构域(iii)是以E243结束的可溶性C末端缩短的CD137L结构域。
在一种实施方式中,第一和第二肽接头(ii)和(iv)独立地具有3-8个氨基酸的长度,特别是3、4、5、6、7或8个氨基酸的长度,并且优选为甘氨酸/丝氨酸接头,任选地包括可被糖基化的天冬酰胺残基。在一种实施方式中,第一和第二肽接头(ii)和(iv)由根据SEQID NO:2的氨基酸序列组成。在另一种实施方式中,该多肽另外包括例如SEQ ID NO:17的N末端信号肽结构域,其可以包括蛋白酶切割位点,和/或N该端信号肽结构域包括C末端元件,该C末端元件可以包括和/或连接至识别/纯化结构域,例如连接至根据SEQ ID NO:18的丝氨酸接头的Strep标签。
在一种实施方式中,抗体Fc片段(vii)通过铰链接头,优选地通过SEQ ID NO:16的铰链接头,融合至可溶性CD137L结构域(i)和/或(v)。在另一实施方式中,抗体Fc片段(vii)由如SEQ ID NO:13或14中所示的氨基酸序列组成。
在一种实施方式中,本发明的单链融合多肽包括选自SEQ ID NO:15和25-35组成的组的氨基酸序列。
在一种实施方式中,本发明提供了包括两种单链融合多肽的二聚体的CD137受体激动剂蛋白,每种融合多肽具有SEQ ID NO:27中所示的氨基酸序列。在一种实施方式中,两种多肽通过在每种多肽的半胱氨酸残基484、490和493之间形成的三个链间二硫键来共价连接。类似的半胱氨酸残基是SEQ ID NO:28、29或32的位置484、490和493,SEQ ID NO:30的位置489、495和498,SEQ ID NO:31的位置493、499和502以及SEQ ID NO:33或34的位置487、493和496
在一种实施方式中,一种或多种成熟多肽SEQ ID NO:27、28或29的位置158和318处的天冬酰胺残基中的一个或多个是N糖基化的。在另一种实施方式中,一种或多种多肽的位置158和318处的天冬酰胺残基都是N-糖基化的。类似的天冬酰胺残基是SEQ ID NO:30或31的位置161和324以及SEQ ID NO:33或34的位置159和320
在另一种实施方式中,该一种或多种多肽进一步经翻译后修饰。在另一种实施方式中,翻译后修饰包括将第一可溶性结构域(i)的D86Q突变蛋白的N末端谷氨酰胺修饰为焦谷氨酸。在又一种实施方式中,翻译后修饰包括将起始于Q89的第一可溶性结构域(i)的N末端谷氨酰胺修饰为焦谷氨酸。
附图说明
图1包括三个CD137L结构域的单链融合多肽的结构域结构。I.、II.、III.可溶性CD137L结构域。
图2表示CD137L一般结构的示意图。
■■■细胞膜,位于细胞内的N末端,
1.受体结合结构域(RBD)的反平行β折叠,
2.RBD与细胞膜的界面,
3.蛋白酶切割位点。
图3包括另外的Fab抗体片段的单链融合多肽。
图4通过三个二硫桥将两个C末端融合的单链Fc融合多肽二聚化。
图5表示本发明的六价单链CD27受体激动剂融合蛋白的示意图。存在于内表面区域上的CH2碳水化合物(5)通常在“开放的Fc构象转变”期间通常在空间位阻上保护CH2亚结构域(2)免受蛋白酶影响,其中铰链-链间二硫键(4)被还原并且共价的链间连接被破坏。这使得CH2解离并使内表面区域和上铰链赖氨酸K223(6)暴露于蛋白酶。由于CH3结构域(3)彼此之间的高的亲和力,因此“开放阶段”中的二聚体缔合(association)仍然完整。
(1)scCD27L-RBD;(2)CH2结构域;(3)CH3结构域;(4)铰链半胱氨酸(左侧:氧化成二硫键桥;具有游离巯基的右侧还原阶段);(5)连接至位置N297(EU编号)的CH2碳水化合物;(6)上铰链赖氨酸(K223)
图6 ELISA评估CD137受体激动剂蛋白(蛋白A)与其受体的结合
图7使用Tosoh TSK凝胶G3000SWxl柱在1260无限HPLC系统上对带strep标签的蛋白A(SEQ ID NO:28)进行分析性尺寸排除层析。该柱中载有浓度为1mg/ml总体积为20μl的蛋白质。流速设定为0.5ml/min。人们在16.97min观察到蛋白A的单个主峰。样品的低分子量缓冲组分在一个柱体积后(>23.5min)洗脱。
图8蛋白A在非还原和还原条件下的SDS-PAGE结果。在含有作为还原剂的DTT的非还原(泳道1)或还原(泳道2)条件下,将360ng蛋白A加载到的SDS-PAGE 4-12%的Bis-Tris凝胶上。凝胶在130V下运行15分钟,然后在180V下运行60分钟,随后使用银染色方案染色。人们观察到A和B中主要条带之间的分子量差异约为70-80kDa。由于这是泳道1中主要条带观察到的分子量的约一半,这表明泳道2中的同二聚体通过二硫桥共价地连接。在泳道2中,该键在还原条件下丢失。
具体实施方式
本发明提供了包括由两个肽接头连接的至少三个可溶性CD137L结构域和在N末端和/或C末端上的抗体来源的二聚化结构域的单链融合多肽。本发明人已经发现通过二聚化结构域的两个单链融合多肽的二聚化产生了六价CD137受体激动剂,其提供了高生物学活性和良好的稳定性。
优选地,单链融合多肽是非聚集的。术语“非聚集的”是指制剂中单体含量≥50%,优选≥70%,更优选≥90%。单体含量与聚集体含量的比率可以通过使用尺寸排阻层析法(SEC)检查聚集体形成的量来确定。关于聚集的稳定性可以通过SEC在不同的储存条件下(例如4℃或25℃)限定的时间段(例如从数天到若干天,直至数周和数月)之后确定。对于融合蛋白,为了分类为基本上的非聚集的,优选的是,在4℃或25℃储存若干天(例如10天)的时间段之后,更优选若干周(例如2、3或4周)的时间段之后,并且最优选在若干月(例如2或3个月)的时间段之后,“单体”含量如上文所限定。关于在FC融合蛋白的情况下“单体”的限定,两条多肽链的组装由FC部分驱动,并且所得组装蛋白的功能单元由两条链组成。该单元在Fc融合蛋白的情况下被限定为“单体”,这与二聚化单链融合多肽无关。
单链融合多肽可以包括可以位于其N末端和/或C末端的另外的结构域。另外的融合结构域的实例是,例如可以包括蛋白酶切割位点的N末端信号肽结构域,或可以包含和/或连接识别/纯化结构域的C末端元件。根据优选的实施方式,融合多肽在其C末端包括经由接头融合的Strep标签。包括短的丝氨酸接头的示例性Strep标签在SEQ ID NO:18中示出。
本发明的CD137受体激动剂蛋白包含来源于CD137L的三个可溶性结构域。优选地,这些可溶性结构域来源于哺乳动物,特别是来源于包括等位基因变体的人CD137和/或其衍生物。可溶性结构域包含包括受体结合结构域而无膜定位结构域的CD137L的细胞外部分。像TNF超家族的其他蛋白质一样,CD137L经由15-30个氨基酸的N末端部分(即所谓的茎区)锚定到膜。茎区有助于三聚化,并提供了到细胞膜一定的距离。然而,茎区不是具有位于原体界面处受体结合位点的三聚体受体结合结构域(RBD)的一部分。
重要的是,肿瘤坏死因子超家族的RBD的特征在于其N末端氨基酸和C末端氨基酸的特定位置。所述氨基酸是紧邻的,并且位于三聚体的轴的附近。RBD的第一N末端氨基酸形成具有RBD的C末端区域的反平行β链。因此,RBD的上述反平行β链与细胞膜形成界面,其经由茎区的氨基酸连接并锚定在细胞膜内。
人CD137L含有茎区以及最可能的C末端延伸(V240-E254)。
特别优选的是,CD137受体激动剂蛋白的可溶性CD137L结构域包括缺少来自茎区域的任何氨基酸的CD137L的受体结合结构域。否则,需要将可溶性结构域中的一个的C末端与下一个可溶性结构域的N末端连接的长接头来补偿该下一个可溶性结构域的N末端茎区,这可能导致不稳定性和/或聚集体的形成。由于同样的原因,还特别优选的是,CD137受体激动剂蛋白的可溶性CD137L结构域包括缺少来自C末端延伸的任何氨基酸的CD137L的受体结合结构域。
这种可溶性结构域的另一个优点是RBD的N-端氨基酸不可用于任何抗药物抗体。优选地,该单链融合多肽由以下组成:(i)第一可溶性CD137L结构域;(ii)第一肽接头:(iii)第二可溶性CD137L结构域;(iv)第二肽接头;(v)第三可溶性CD137L结构域,该单链融合多肽能够形成模拟其天然配对物(counterpart)的三聚体组织的有序结构,从而包括至少一个用于相对CD137L受体的功能结合位点。因此,包括组分(i)-(v)的单链融合多肽也称为单链CD137L受体结合域(scCD137L-RBD)。重要的是,与同源三聚体野生型CD137L-RBD相比,scCD137L-RBD包括增强的稳定性,因为可溶性CD137L结构域(i)、(iii)和(v)通过接头(ii)和(iv)提供的彼此共价连接实现三聚化。
CD137受体激动剂蛋白包括三个功能性CD137受体结合位点,即能够与CD137受体形成复合物的氨基酸序列。因此,可溶性结构域能够结合到相应的CD137受体。在一种实施方式中,可溶性结构域中的至少一个能够受体激活,由此可能影响凋亡和/或增殖活性。在另一种实施方式中,可溶性结构域中的一个或多个被选作为不能受体激活。
可溶性CD137L结构域可以源自人CD137L,如SEQ ID NO:1中所示的。优选地,可溶性CD137L结构域来源于人CD137L,特别是从氨基酸86、88、89或90开始并且特别地包括SEQID NO:1的氨基酸86-254或88-254或89-254。任选地,SEQ ID NO:1的氨基酸R88可以被不带电荷的氨基酸例如Ser或Gly替换,或者被谷氨酰胺替换。
表1:野生型人CD137L蛋白的序列
如上所示,可溶性CD137L结构域可以包括如SEQ ID NO:1中所示的野生型序列。然而,应该注意的是,可能在这些可溶性结构域中的一个或多个中引入突变,例如改变(例如增加或减少)可溶性结构域的结合性质的突变。在一种实施方式中,可以选择不能与相应的细胞因子受体结合的可溶性结构域。
在本发明的另一种实施方式中,可溶性CD137L结构域(i)包括导致CD137受体亲和力降低和/或CD137受体活化降低的CD137L的突变体或其受体结合结构域。
影响受体结合和/或活性的CD137L突变蛋白
该突变体可以通过技术人员已知的任何技术生成。取代可影响CD137L的至少一个氨基酸,例如如本文所述的人CD137L(例如,SEQ ID NO:1)或其受体结合结构域。在这方面优选的取代影响SEQ ID NO:1的人CD137L的以下氨基酸中的至少一种:L115、K127、R150、R193和Q227。
在另一个优选的实施方式中,C末端区域I243-E254从可溶性结构域(i)、(Ⅲ)或(v)中的至少一个中删除。
一种或多种氨基酸取代可对于或在CD137结合或CD137诱导的信号转导方面影响CD137L(例如,人CD137L)的结合和/或活性。CD137的结合和/或活性可以被积极地影响,即更强、更具选择性或更特异性的受体结合和/或更多的受体活化。可替换地,CD137的结合和/或活性可以被消极地影响,即较弱、较少选择性或较少特异性的受体结合和/或受体较少或没有活化。
因此,一种实施方式是如本文所述的CD137受体激动剂蛋白,其中该可溶性结构域中的至少一个包括CD137L的突变体或其受体结合结构域,其与野生型CD137L相比更小程度的结合和/或激活CD137。
具有增强的稳定性/溶解度的CD137L突变蛋白
在本发明的另一种实施方式中,可溶性CD137L结构域(i)、(iii)和(v)中的一个或多个可包括CD137L突变体或其受体结合结构域,其导致自身聚集的降低和/或体内稳定性的延长。A174、A176。
在这方面优选的取代是A174[D,N]和A176[S,T]。每个CD137L结构域的一种或多种突变可以相同或不同。
本发明的单链融合分子包括三个可溶性CD137L结构域,即组分(i)、(iii)和(v)。如果第二和/或第三可溶性CD137L结构域是任选地包括氨基酸序列突变的N末端缩短的结构域,则单链CD137L融合多肽针对聚集的稳定性得到增强。因此,优选地,第二和第三可溶性CD137L结构域都是N末端缩短的结构域,其任选地包括N末端区域中优选地在可溶性CD137L结构域的N末端的前五个氨基酸内的氨基酸序列突变。这些突变可以包括用中性氨基酸,特别是丝氨酸或甘氨酸替换碱性氨基酸。
与此相反,第一可溶性CD137L结构域的选择并不重要。在此,可以使用具有全长N末端序列的可溶性结构域。然而,应该注意的是,第一可溶性CD137L结构域也可以具有N末端缩短的且任选突变的序列。
在本发明另一优选的实施方式中,可溶性CD137L结构域(i)、(iii)和(v)是可溶性人CD137L结构域。第一可溶性CD137L结构域(i)可以选自天然的、缩短的和/或突变的序列。因此,第一可溶性CD137L域(i)具有N端序列,其可起始于人CD137L的氨基酸D86或R88,并且其中R88可以由中性氨基酸替换,例如由Ser或Gly或由Gln替换,以在表达期间能够形成焦谷氨酸。第二和第三可溶性CD137L结构域(iii)和(v)具有缩短的N末端序列,其优选起始于人CD137L(SEQ ID NO:1)的氨基酸Q89或G90,并且其中Q89可以被另一个氨基酸,例如Ser或Gly替换。
优选地,可溶性CD137L结构域(iii)和(v)的N末端序列选自:
(a)D86或Q89
(b)(Gly/Ser)89
可溶性CD137L结构域优选以人CD137L的氨基酸E254结束。在某些实施方式中,CD137L结构域可以包括如上所述的内部突变。
在另一优选实施方式中,可溶性CD137L结构域优选以人CD137L的氨基酸V240结束。在某些实施方式中,CD137L结构域可以包括如上所述的内部突变。
CD137受体激动剂蛋白的组分(ii)和(iv)是分别位于组分(i)和(iii)之间或(iii)和(v)之间的肽接头元件。柔性接头元件具有3-8个氨基酸的长度,特别是3、4、5、6、7或8个氨基酸的长度。接头元件优选为甘氨酸/丝氨酸接头,即基本上由氨基酸甘氨酸和丝氨酸组成的肽接头。在其中可溶性细胞因子结构域以S或G(N-末端)开始的情况下,接头在该S或G之前结束。
应该注意的是,接头(ii)和接头(iv)不需要具有相同的长度。为了减少潜在的免疫原性,其可以优选使用较短的接头。另外,结果表明较短的接头导致单链分子具有降低形成聚集体的趋势。然而,比本文公开的接头长得多的接头可以表现出不利的聚集特性。
如果需要,接头可包括可形成糖基化位点Asn-Xaa-Ser的天冬酰胺残基。在某些实施方式中,接头之一,例如接头(ii)或接头(iv)包括糖基化位点。在其他实施方式中,两个接头(iv)二者都包含糖基化位点。为了增加CD137L激动剂蛋白的溶解度和/或为了降低潜在的免疫原性,优选接头(ii)或接头(iv)或两者都包括糖基化位点。
表2中示出了优选的接头序列。优选的接头是GSGSGNGS(SEQ ID NO:2)。
表2:接头序列实例
SEQ ID NO | 序列 |
2 | GSGSGNGS |
3 | GSGSGSGS |
4 | GGSGSGSG |
5 | GGSGSG |
6 | GGSG |
7 | GGSGNGSG |
8 | GGNGSGSG |
9 | GGNGSG |
10 | GSGSGS |
11 | GSGS |
12 | GSG |
CD137受体激动剂蛋白另外包括抗体Fc片段结构域,其可位于第一CD137L结构域(i)的N末端和/或第三CD137L结构域(v)的C末端。优选地,抗体Fc片段结构域包括降低的与Fc-γ-R受体体内相互作用的能力。优选地,抗体Fc片段结构域包括SEQ ID NO:13或14中所示的氨基酸序列或由其组成(见表3)。与野生型人IGG1-Fc相比,序列ID NO:13具有N297S突变。序列ID NO:14是具有降低的Fc-γ-R结合能力的糖基化的(N297野生型)人IGG1Fc突变蛋白。
表3:Fc片段结构域的实例
糖基化位点的数量和体内稳定性
糖基化位点的总数和三维碳水化合物的单个位置影响CD137受体激动剂蛋白质的体内稳定性。此外,碳水化合物识别取决于末端糖的局部密度,碳水化合物树(tree)的分支,以及碳水化合物与其他物质彼此的相对位置。
此外,部分降解的碳水化合物通过凝集素驱动机制降低CD137受体激动剂蛋白的体内半衰期。通过减少分子上糖基化位点的总数,所得到的化合物不易适于这些机制,从而增加半衰期。
为了避免基于Fc-γ受体的结合减少Fc结构域的CH2结构域碳水化合物是必需的。细胞上的FcR-γ受体可导致融合蛋白体内潜在的高度交联,其导致基于CD137受体超簇的毒性。另外,不需要的Fc驱动的机制如ADCC可能导致有毒事件。因此,在一种实施方式中,本发明的CD137受体激动剂蛋白上的糖基化位点的总数通过CH2糖基化位点,特别是N糖基化位点的减少而减少,导致包括产生无糖基CH2结构域的SEQ ID NO:15(蛋白A)(根据EU编号系统)的N297S等效突变的CD137受体激动剂蛋白。
CH2结构域去稳定化通过另外的铰链半胱氨酸来补偿
存在于内表面区域上的CH2糖基化通常在“开放的Fc构象转变”期间保护亚结构域免受蛋白酶影响,其中铰链-链间二硫键被还原并且共价的链间连接被破坏。这使得CH2解离并使内表面区域暴露于蛋白酶。包括具有SEQ ID NO:15(蛋白A)(根据EU编号系统)的N297S等效突变的CD137受体激动剂蛋白产生无糖基化CH2,并且因此可能经受蛋白酶消化并且与具有野生型CH2糖基化的等效结构比更不稳定。在宿主细胞蛋白酶存在并且长期作用该结构的情况下,这会影响化合物在USP/DSP/存储期间的稳定性。因此,在某些实施方式中,CD137受体激动剂缺乏CH 2糖基化位点,但在每条多肽链的接头序列(例如GSGSGNGS,SEQ ID NO:2)中包括糖基化位点。
根据本发明的优选实施方式,抗体Fc片段结构域经由铰链接头元件融合。铰链接头元件具有10-30个氨基酸的长度,特别是15-25个氨基酸的长度,例如22个氨基酸。术语“铰链接头”包括足够长以允许铰链接头元件连接的结构域获得生物学活性确认的任何接头。铰链接头元件优选包括免疫球蛋白的铰链区序列,在本文中指的是“Ig铰链区”。术语“Ig铰链区”是指包括与含有一个或多个半胱氨酸残基(例如两个半胱氨酸残基)的天然存在的Ig铰链区序列的一部分具有序列同一性或相似性氨基酸序列的任何多肽,在该Ig铰链区序列处二硫键连接免疫球蛋白的两个重链。
铰链区的衍生物和类似物可通过突变获得。本文所指的衍生物或类似物是包括与野生型(或天然存在的蛋白质)的全长序列具有序列同一性或相似性的氨基酸序列的多肽,除了其具有可归因于删除,插入和/或取代的一个或多个氨基酸序列差异。
单个CD137受体激动剂蛋白中具有开放Fc构象的分子的数目取决于存在于铰链区中的链间二硫键的数目。因此,在一种实施方式中,将第三个半胱氨酸(根据EU编号系统的C225)引入本发明的CD137受体激动剂蛋白的铰链区,以改善减少CH2糖基化位点的作用。
在铰链区中将赖氨酸交换成甘氨酸导致蛋白水解稳定性的增强
在一种实施方式中,本发明的CD137受体激动剂蛋白另外包括上铰链赖氨酸(根据EU编号系统的K223)至甘氨酸的突变,以降低在该位点的蛋白水解加工,从而增强该融合蛋白的整体稳定性。将上述第三半胱氨酸(根据EU编号系统的C225)的引入与上述在铰链区内的赖氨酸至甘氨酸突变(根据EU编号系统的K223G)组合导致本发明的整体稳定化的CD137受体激动剂蛋白质。
包括上述半胱氨酸(C225)和赖氨酸至甘氨酸突变(K223G)的特别优选的铰链接头元件包括SEQ ID NO:16中所示的氨基酸序列或由其组成(表4)。
CD137受体激动剂蛋白可另外包括N末端信号肽结构域,其允许在合适的宿主细胞中进行处理,例如细胞外分泌。优选地,N末端信号肽结构域包括蛋白酶切割位点,例如信号肽酶切割位点,因此可以在表达后或表达期间被去除以获得成熟蛋白质。特别优选的N末端信号肽结构域包括如SEQ ID NO:17中所示的氨基酸序列(表4)。
此外,CD137受体激动剂蛋白可另外包括具有例如1-50个,优选10-30个氨基酸长度的C末端元件,其可包括或连接至识别/纯化结构域,例如FLAG结构域、Strep标签或Strep标签Il结构域和/或聚His结构域。根据优选的实施方式,融合多肽包括经由如SEQ ID NO:18中所示的短的丝氨酸接头融合至C末端的Strep标签(表4)。
优选的铰链接头元件(SEQ ID NO:16、19-24)、优选的N-末端信号肽结构域(SEQID NO:17)和优选的丝氨酸接头strep标签(SEQ ID NO:18)在表4中示出。
表4:示例性结构域和接头
SEQ ID NO | 序列 |
16 | GSSSSSSSSGSCDKTHTCPPC |
17 | METDTLLVFVLLVWVPAGNG |
18 | SSSSSSAWSHPQFEK |
19 | GSSSSSSSGSCDKTHTCPPC |
20 | GSSSSSSGSCDKTHTCPPC |
21 | GSSSSSGSCDKTHTCPPC |
22 | GSSSGSCDKTHTCPPC |
23 | GSSSGSCDKTHTCPPCGS |
24 | GSSSGSCDKTHTCPPCGSGS |
在本发明的一种实施方式中,融合多肽包括由SEQ ID NO:2的肽接头元件融合的三个可溶性CD137L结构域。所有三个可溶性CD137L结构域(i)、(iii)、(v)由根据SEQ IDNO:1的人CD137L的氨基酸89-240组成。得到的scCD137L-RBD序列模块在表5b SEQ ID NO:36中示出。
在本发明进一步优选的实施方式中,融合多肽包括由SEQ ID NO:2的肽接头元件融合的三个可溶性CD137L结构域。所有三个可溶性CD137L结构域(i)、(iii)、(v)由根据SEQID NO:1的人CD137L的氨基酸86-240组成,其中在第一结构域(i)中具有D86Q突变。得到的scCD137L-RBD序列模块在表5b SEQ ID NO:39中示出。
在本发明的另一种实施方式中,融合多肽包括由SEQ ID NO:2的肽接头元件融合的三个可溶性CD137L结构域。所有三个可溶性CD137L结构域(i)、(iii)、(v)由根据SEQ IDNO:1的人CD137L的氨基酸88-240组成。得到的scCD137L-RBD序列模块在表5b SEQ ID NO:40中示出。
在本发明又一优选的实施方式中,融合多肽包括由SEQ ID NO:2的肽接头元件融合的三个可溶性CD137L结构域。所有三个可溶性CD137L结构域(i)、(iii)、(v)由根据SEQID NO:1的人CD137L的氨基酸88-240组成,其中在第一结构域(i)中具有R88Q突变并且在结构域(iii)和(v)中具有R88G突变。得到的scCD137L-RBD序列模块在表5b SEQ ID NO:41中示出。
在本发明再一优选的实施方式中,融合多肽包括由SEQ ID NO:2的肽接头元件融合的三个可溶性CD137L结构域。所有三个可溶性CD137L结构域(i)、(iii)、(v)由根据SEQID NO:1的人CD137L的氨基酸88-240组成,其中在第一结构域(i)中具有R88S突变并且在结构域(iii)和(v)中具有R88G突变。得到的scCD137L-RBD序列模块在表5b SEQ ID NO:42中示出。
在本发明再又一优选的实施方式中,融合多肽包括由SEQ ID NO:2的肽接头元件融合的三个可溶性CD137L结构域。所有三个可溶性CD137L结构域(i)、(iii)、(v)由根据SEQID NO:1的人CD137L的氨基酸89-240组成,并且包括A174N突变和A176S突变。得到的scCD137L-RBD序列模块在表5b SEQ ID NO:43中示出。
上述scCD137L-RBD模块(SEQ ID:36、39-43)非常适合于使用表2(SEQ ID NO:2-12)中所述的接头生成具有融合到N末端或C末端端部的另外结构域的融合蛋白。
优选的构象CD137L-Fc
此外,该融合多肽包括根据SEQ ID NO:13的抗体Fc片段结构域,所述抗体Fc片段结构域通过根据SEQ ID NO:16的铰链接头在C末端上融合至可溶性CD137L结构域(v)。发明人惊奇地发现,与二价激动性抗CD137-mAB相比,该特定融合多肽提供了改善的生物活性,并且与包含位置223中的赖氨酸和CH2结构域N297S突变(根据EU编号)的融合蛋白相比具有延长的稳定性。
本发明的CD137受体激动剂蛋白的示例性实施方式的氨基酸序列在SEQ ID NO:27中所示。
此外,融合多肽可包括N末端信号肽结构域,例如根据SEQ ID NO:17的N末端信号肽结构域。本发明的CD137受体激动剂蛋白的具体实例在SEQ ID NO:25中示出。
根据另一个优选实施方式,该融合多肽可另外包括C末端Strep标签,所述C末端Strep标签经由SEQ ID NO:18中所示的短的丝氨酸接头而被融合至本发明的多肽。根据本发明的这一方面,Fc片段优选由SEQ ID NO:13或14中所示的氨基酸序列组成。进一步地,Fc片段可以由较短的Fc片段组成,例如包括SEQ ID NO:13的氨基酸1-217的Fc片段。包括C末端Strep标签的融合多肽的特别优选的实例示于SEQ ID NO:15(蛋白A)。
如SEQ ID NO:15、25和26所示的示例性CD137受体激动剂蛋白,各自在每个序列的氨基酸1-20处包括N末端信号肽结构域。在每种情况下,成熟蛋白以氨基酸21开始。本发明成熟的示例性CD137受体激动剂蛋白(没有信号肽)在SEQ ID NO:27-35中所示。上文所述的示例性CD137受体激动剂蛋白示于表5中。
如在SEQ ID NO:27中所示的CD137受体激动剂的糖基化位点的总数减少(根据EU编号系统,N297S突变在CH2区中提供了无糖基化的CH2结构域)、铰链区中链间二硫键的数目增加,以及上铰链赖氨酸至甘氨酸的突变(根据EU编号系统,K223G)。这些改变提供了减少潜在的降解和CD137受体超簇(伴随有伴随的毒性)。
如在SEQ ID NO:30所示的CD137受体激动剂包括具有SEQ ID NO:36的scCD137L-RBD模块、具有SEQ ID NO:21的第三肽接头和(vii)具有SEQ ID NO:13的抗体Fc片段。
如在SEQ ID NO:31所示的CD137受体激动剂包括具有SEQ ID NO:39的scCD137L-RBD模块、具有SEQ ID NO:16的第三肽接头和(vii)具有SEQ ID NO:13的抗体Fc片段。
如在SEQ ID NO:32所示的CD137受体激动剂包括具有SEQ ID NO:40的scCD137L-RBD模块、具有SEQ ID NO:16的第三肽接头和(vii)具有SEQ ID NO:13的抗体Fc片段。
如在SEQ ID NO:33所示的CD137受体激动剂包括具有SEQ ID NO:41的scCD137L-RBD模块、具有SEQ ID NO:16的第三肽接头和(vii)具有SEQ ID NO:13的抗体Fc片段。
如在SEQ ID NO:34所示的CD137受体激动剂包括具有SEQ ID NO:42的scCD137L-RBD模块、具有SEQ ID NO:16的第三肽接头和(vii)具有SEQ ID NO:13的抗体Fc片段。
表5:示例性CD137受体激动剂蛋白
表5B:示例性scCD137L-RBD模块
本发明的另一方面涉及编码本文所述的CD137受体激动剂蛋白的核酸分子。核酸分子可以是DNA分子,例如双链或单链DNA分子,或RNA分子。核酸分子可编码CD137受体激动剂蛋白或其前体,例如CD137受体激动剂蛋白的原形式或前形式,其可包括用于分泌或纯化的信号序列或其他异源氨基酸部分,其优选位于CD137受体激动剂蛋白的N末端和/或C末端。异源氨基酸部分可以通过蛋白酶切割位点,例如因子X3、凝血酶或IgA蛋白酶切割位点连接至第一和/或第二结构域。本发明的核酸序列的具体实例示于表6中为SEQ ID NO:37。该核酸分子包括编码SEQ ID NO:25的融合多肽的开放阅读框。
表6:示例性CD137受体激动剂蛋白的核酸序列
核酸分子可操作性地连接到表达控制序列,例如允许核酸分子在所需宿主细胞中表达的表达控制序列。核酸分子可以位于载体上,例如质粒、细菌噬菌体、病毒载体、染色体整合载体等。合适的表达控制序列和载体的实例描述于例如由Sambrook等人(1989)Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Press,and Ausubel等人(1989),Current Protocols in Molecular Biology,John Wiley&Sons或其更新的版本。
各种表达载体/宿主细胞系统可用于表达编码本发明的CD137受体激动剂蛋白的核酸序列。合适的宿主细胞包括但不限于原核细胞,诸如细菌,例如大肠杆菌(E.coli),真核宿主细胞,诸如酵母细胞、昆虫细胞、植物细胞或动物细胞,优选哺乳动物细胞,更优选人细胞。此外,本发明涉及用如上所述的核酸分子转化或转染的非人生物。这种转基因生物可以通过已知的遗传转移方法产生,包括同源重组。
本发明的另一方面涉及药物或诊断组合物,其包括作为活性剂的至少一种CD137受体激动剂蛋白、编码它们的相应核酸或转化或转染的细胞,全部如本文所述的。
另一方面,本发明提供一种药物组合物,其包括本文公开的CD137受体激动剂蛋白和一种或多种药学上可接受的载体、稀释剂、赋形剂和/或佐剂。
另一方面,本发明提供编码CD137受体激动剂蛋白的核酸分子。在另一种实施方式中,本发明提供了包括核酸分子的表达载体。在另一种实施方式中,本发明提供了包括该核酸分子的细胞。在进一步的实施方式中,该细胞是真核细胞。在另一种实施方式中,该细胞是哺乳动物细胞。在另一种实施方式中,该细胞是中国仓鼠卵巢(CHO-1)细胞。在其他实施方式中,细胞选自由CHO-DBX11、CHO-DG44、CHO-S和CHO-K1细胞组成的组。在其他实施方式中,该细胞选自由Vero、BHK、HeLa、COS、MDCK、HEK-293、NIH-3T3、W138、BT483、Hs578T、HTB2、BT20、T47D、NS0、CRL7030、HsS78Bst、PER.C6、SP2/0-Agl4和杂交瘤细胞。
在另一方面,本发明提供了治疗患有CD137L相关疾病或疾患的受试者的方法,该方法包括向受试者施用有效量的CD137受体激动剂蛋白。在一种实施方式中,单独施用CD137受体激动剂蛋白。在另一种实施方式中,CD137受体激动剂蛋白在施用第二种药剂之前、同时或之后施用。在另一种实施方式中,所述疾病或疾患选自有如下组成的组:肿瘤、传染病、炎性疾病、代谢性疾病、自身免疫性疾病、退行性疾病、凋亡相关疾病和移植排斥。在一种实施方式中,肿瘤是实体肿瘤。在一种实施方式中,肿瘤来源于由肉瘤、食管癌和胃癌组成的癌症组。在另一个实施方案中,肿瘤源自尤文肉瘤(Ewing’s sarcoma)或纤维肉瘤,在另一种实施方式中,肿瘤来源于由非小细胞肺癌(NSCLC)、胰腺癌、结直肠癌、乳腺癌、卵巢癌、头颈癌和小细胞肺癌(SCLC)组成的癌症组。在一种实施方式中,肿瘤是淋巴肿瘤。在一种实施方式中,肿瘤是血液肿瘤。在另一种实施方式中,肿瘤源自非霍奇金淋巴瘤(non-Hodgkin’s lymphoma)、白血病、急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、B细胞淋巴瘤、伯基特淋巴瘤(Burkitt's lymphoma)、慢性髓细胞白血病(CML)、慢性淋巴细胞白血病(CLL)或毛细胞白血病。在另一种实施方式中,自身免疫疾病是类风湿性疾病、关节炎疾病或类风湿性和关节炎疾病。在另一种实施方式中,疾病或疾患是类风湿性关节炎。在另一种实施方式中,退行性疾病是神经退行性疾病。在另一实施方式中,神经退行性疾病是多发性硬化。
在一种实施方式中,第二剂是化疗剂、放射治疗剂或生物剂。在一种实施方式中,第二药剂选自由度维利塞(Duvelisib)、伊布替尼(Ibrutinib)、纳维妥拉(Navitoclax)和维奈妥拉(Venetoclax)组成的组,在另一种实施方式中,第二种剂是凋亡剂。在一种实施方式中,凋亡的第二剂选自由硼替佐米(Bortezomib)、氮杂胞苷(Azacitidine)、达沙替尼(Dasatinib)和吉非替尼(Gefitinib)组成的组。在一种具体实施方式中,通过静脉内或皮下施用将本文公开的药物组合物施用于患者。在其他实施方式中,通过口内、胃肠外、肌内、关节内、支气管内、腹内、囊内、软骨内、腔内、体腔内、小脑内、脑室内、结肠内、子宫颈内、胃内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜内、前列腺内、肺内、直肠内、肾内、视网膜内、椎内、滑膜内、胸腔内、子宫内、膀胱内、团注(bolus)、阴道内、直肠、口腔的、舌下的、鼻内或透皮施用将所公开的药物组合物施用于患者。
在一种实施方式中,CD137受体激动剂蛋白作为单次团注施用。在另一种实施方式中,CD137受体激动剂蛋白可以分若干次的剂量施用。CD137受体激动剂蛋白可以约0.1-100mg/kg施用。在一种实施方式中,CD137受体激动剂蛋白可以选自以下项组成的组的剂量施用:约0.1-0.5、0.1-1、0.1-10、0.1-20、0.1-50、0.1-75、1-10、1-15、1-7.5、1.25-15、1.25-7.5、2.5-7.5、2.5-15、5-15、5-7.5、1-20、1-50、7-75、1-100、5-10、5-15、5-20、5-25、5-50、5-75、10-20、10-50、10-75和10-100mg/kg。在其他实施方式中,CD137受体激动剂蛋白以约0.1-100mg/ml存在于药物组合物中。在一种实施方式中,所述CD137受体激动剂蛋白以选自以下项组成的组的量存在于药物组合物中:约0.1-0.5、0.1-1、0.1-10、0.1-20、0.1-50、0.1-75、1-10、1-20、1-50、1-75、1-100、5-10、5-15、5-20、5-25、5-50、5-75、10-20、10-50、10-75或10-100mg/ml。在其他实施方式中,将治疗有效量的CD137受体激动剂蛋白施用于受试者。在另一种实施方式中,将预防有效量的CD137受体激动剂蛋白施用于受试者。
本文所用术语“CD137L相关疾病或疾患”是可通过向需要其的受试者施用有效量的CD137受体激动剂而可以改善的任何疾病或疾患。至少一种CD137受体激动剂蛋白、相应的编码其的核酸或转化或转染的细胞,全部如本文所述的可用于治疗,例如预防和/或治疗由CD137L功能障碍引起的、与CD137L功能障碍相关的和/或伴随CD137L功能障碍的疾患,特别是增殖性疾病,诸如肿瘤,例如实体肿瘤或淋巴肿瘤;传染病;炎性疾病;代谢性疾病;自身免疫性疾病,例如类风湿性和/或关节炎疾病;退行性疾病,例如神经退行性疾病,诸如多发性硬化;凋亡相关疾病或移植排斥。
本文所用的术语“CD137L功能障碍”应理解为CD137L的任何功能或表达偏离CD137L的正常功能或表达,例如CD137L基因或蛋白的过度表达、与CD137L的正常生理表达水平相比CD137L基因或蛋白的表达减少或消除、与CD137L正常的生理活性或结合相比,CD137L活性增加、CD137L活性降低或消除、CD137L与任何结合配偶体(例如,受体,特别是CD137L受体或另一细胞因子分子)的结合增强、与任何结合配偶体(例如受体,特别是CD137L受体或另一细胞因子分子)的结合减弱或消除。
在各种实施方式中,提供了一种用于诊断和/或治疗患有可通过靶向CD137L受体诊断和/或治疗的疾患的人受试者的方法,所述方法包括向人受试者施用本文公开的CD137受体激动剂蛋白,使得对人受试者中的一种或多种靶标的活性的影响是激动性的,使得一种或多种症状减轻和/或使得治疗实现。本文提供的CD137受体激动剂蛋白可用于诊断和/或治疗患有原发性和转移性癌症的人,包括乳腺癌、结肠癌、直肠癌、肺癌(例如小细胞肺癌“SCLC”和非小细胞肺癌“NSCLC”)、口咽癌、下咽癌、食管癌、胃癌、胰腺癌、肝癌、胆囊和胆管癌、小肠癌、尿道癌(包括肾癌、膀胱癌和尿路上皮癌)、女性生殖道癌(包括宫颈癌、子宫癌和卵巢癌以及绒毛膜癌和妊娠滋养细胞疾病)、男性生殖道癌(包括前列腺癌、精囊癌、睾丸癌和生殖细胞肿瘤)、内分泌腺癌(包括甲状腺癌、肾上腺癌和垂体癌)和皮肤癌,以及血管瘤、黑色素瘤、肉瘤(包括源自骨和软组织的肉瘤以及卡波西肉瘤(Kaposi’s sarcoma))、脑肿瘤、神经肿瘤、眼睛肿瘤和脑膜肿瘤(包括星形细胞瘤、胶质瘤、胶质母细胞瘤、视网膜母细胞瘤、神经瘤、神经母细胞瘤、许旺氏细胞瘤(Schwannomas)和脑膜瘤)、源自造血系统恶性肿瘤、急性白血病、急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、B细胞淋巴瘤、伯基特淋巴瘤(Burkitt's lymphoma)、慢性粒细胞白血病(CML)、慢性淋巴细胞白血病(CLL)、毛细胞白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤(Hodgkin’s and non-Hodgkin’slymphomas)、DLBCL、滤泡性淋巴瘤、造血系统恶性肿瘤、卡波西肉瘤(Kaposi's sarcoma)、恶性淋巴瘤、恶性组织细胞增生症、恶性黑色素瘤、多发性骨髓瘤、副肿瘤综合征/恶性高钙血症或实体肿瘤。
提供了包括本文公开的CD137受体激动剂蛋白和药学上可接受的载体的药物组合物。在一些实施方式中,药物组合物包括至少一种用于治疗疾患的另外的治疗剂。例如,另外的剂可以是治疗剂、化疗剂;成像剂、细胞毒性剂、血管生成抑制剂、激酶抑制剂(包括但不限于KDR和TIE-2抑制剂)、共刺激分子调节剂或免疫检查点抑制剂(包括但不限于抗B7.1、抗B7.2、抗B7.3、抗B7.4、抗CD28、抗B7RP1、CTLA4-Ig、抗CTLA-4、抗PD-1、抗PD-L1、抗PD-L2、抗ICOS、抗LAG-3、抗Tim3、抗VISTA、抗HVEM、抗BTLA、LIGHT融合蛋白、抗CD137、抗CD137L、抗OX40、抗OX40L、抗CD70、抗CD27、抗CD27L、抗GAL9、抗A2AR、抗KIR、抗IDO-1、抗CD20)、树突状细胞/抗原呈递细胞调节剂(包括但不限于抗CD40抗体、抗CD40L、抗DC-SIGN、抗Dectin-1、抗CD301、抗CD303、抗CD123、抗CD207、抗DNGR1、抗CD205、抗DCIR、抗CD206和抗ILT7)、Toll样受体调节剂(包括但不限于抗TLR-1、抗TLR-2、抗TLR-3、抗TLR-4、抗TLR-4、抗TLR-5、抗TLR-6、抗TLR-7、抗TLR-8、抗TLR-9)、粘附分子阻滞剂(包括但不限于抗LFA-1抗体、抗E/L选择素抗体、小分子抑制剂)、抗细胞因子抗体或其功能片段(包括但不限于抗IL-18、抗TNF或抗IL-6/细胞因子受体抗体)、双特异性重定向T细胞或NK细胞细胞毒性(包括但不限于)、基于嵌合T细胞受体(CAR-T)治疗、基于T细胞受体(TCR)治疗、治疗性癌症疫苗、甲氨蝶呤(methotrexate)、环孢菌素(methotrexate)、雷帕霉素(methotrexate)、FK506、可检测标记物或报告物、TNF拮抗剂、抗风湿剂、肌肉松弛剂、麻醉剂、非甾体抗炎药(NSAID)、镇痛剂、麻醉剂、镇静剂、局部麻醉剂、神经肌肉阻滞剂、抗菌剂、抗银屑病剂、皮质类固醇、合成代谢类固醇、促红细胞生成素、免疫、免疫球蛋白、免疫抑制剂、生长激素、激素替代药物、放射性药物、抗抑郁药、抗精神病药、兴奋剂、哮喘药物、β激动剂、吸入类固醇、肾上腺素或类似物、细胞因子或细胞因子拮抗剂。
在一种实施方式中,治疗癌症或预防或抑制本文所述肿瘤转移的方法中,一种或多种CD137受体激动剂蛋白可单独使用或与一种或多种另外的剂例如化疗剂、放疗剂或生物剂组合使用。在一些实施方式中,该剂可以包括如下:13-顺式视黄酸(13-cis-Retinoic Acid);2-CdA;2-氯脱氧腺苷(2-Chlorodeoxyadenosine);5-氮杂胞苷(5-Azacitidine);5-氟尿嘧啶(5-Fluorouracil);5-FU;6-巯基嘌呤(6-Mercaptopurine);6-MP;6-TG;6-硫鸟嘌呤(6-Thioguanine);白蛋白结合型紫杉醇(Abraxane); 放线菌素-D(Actinomycin-D); 安归宁阿地白介素(Aldesleukin):阿仑单抗(Alemtuzumab);ALIMTA;阿里维A酸(Alitretinoin);奥卡班 全反式维甲酸(All-transretinoicAcid);α干扰素(Alpha Interferon);六甲蜜胺(Altretamine);氨甲蝶呤(Amethopterin);氨磷汀(Amifostine);氨鲁米特(Aminoglutethimide);阿那格雷(Anagrelide);阿那曲唑(Anastrozole);阿拉伯糖基胞嘧啶(Arabinosylcytosine);Ara-C 三氧化二砷(Arsenic Trioxide);阿泽拉TM(ArzerraTM);天冬酰胺酶(Asparaginase);ATRA; 阿扎胞苷(Azacitidine);BCG;BCNU;苯达莫司汀(Bendamustine);贝伐单抗(Bevacizumab);贝沙罗汀(Bexarotene);必卡他胺(Bicalutamide);BiCNU;博来霉素(Bleomycin);硼替佐米(Bortezomib);白消安(Busulfan); C225;甲酰四氢叶酸钙(Calcium Leucovorin); 喜树碱11(Camptothecin-11);卡培他滨(Capecitabine)喀拉克TM(CaracTM);卡铂(Carboplatin);卡莫司汀(Carmustine);卡莫司汀膜晶片(Carmustine Wafer); CC-5013;CCI-779;CCNU;CDDP;CeeNU; 西妥昔单抗(Cetuximab);苯丁酸氮芥(Chlorambucil);顺铂(Cisplatin);嗜橙菌因子(Citrovorum Factor);克拉屈滨(Cladribine);可的松(Cortisone);CPT-11;环磷酰胺(Cyclophosphamide);阿糖孢苷(Cytarabine);阿糖孢苷脂质体(Cytarabine Liposomal);赛德萨 达卡巴嗪(Dacarbazine);达克金(Dacogen);更生霉素(Dactinomycin);阿法达贝泊汀(Darbepoetin Alfa);达沙替尼(Dasatinib);道诺霉素(Daunomycin);道诺红菌素(Daunorubicin);道诺红菌素盐酸盐(Daunorubicin Hydrochloride);道诺红菌素脂质体(Daunorubicin Liposomal);地卡特隆(Decadron);地西他滨(Decitabine); 地尼白介素-毒素连接物(Denileukin Diftitox);戴破赛TM(DepoCytTM);地塞米松(Dexamethasone);地塞米松乙酸盐(Dexamethasone Acetate);地塞米松钠磷酸盐(Dexamethasone Sodium Phosphate);戴克赛松(Dexasone);右雷佐生(Dexrazoxane);DHAD;DIC;笛奥戴克(Diodex);多西他赛(Docetaxel);阿霉素(Doxorubicin);阿霉素脂质体(Doxorubicin Liposomal);得罗希亚TM(DroxiaTM);DTIC;度维里斯(Duvelisib);艾里咖TM(EligardTM);意林司TM(EllenceTM);乐沙定TM(EloxatinTM); 表柔比星(Epirubicin);阿法依泊汀(Epoetin Alfa);爱必妥(Erbitux);埃罗替尼(Erlotinib);欧文氏菌左旋天冬酰胺酶(Erwinia L-asparaginase);雌莫司汀(Estramustine);阿米福汀(Ethyol) 依托泊苷(Etoposide);磷酸依托泊苷(EtoposidePhosphate);依维莫司(Everolimus); 依西美坦(Exemestane); 非格司亭(Filgrastim);氟尿苷(Floxuridine);氟达拉滨(Fludarabine); 氟尿嘧啶(Fluorouracil);氟尿嘧啶乳(膏)(Fluorouracil(cream));氟甲睾酮(Fluoxymesterone);氟他胺(Flutamide);亚叶酸(Folinic Acid);氟维司群(Fulvestrant);吉非替尼(Gefitinib);吉西他滨(Gemcitabine);吉妥珠单抗奥唑米星(Gemtuzumab ozogamicin);健择(Gemzar);格列卫TM(GleevecTM);植入膜剂(Wafer);GM-CSF;戈舍瑞林(Goserelin);粒细胞集落刺激因子(G-CSF)(Granulocyte-Colony Stimulating Factor);粒细胞巨噬细胞集落刺激因子(G-MCSF)(Granulocyte Macrophage Colony Stimulating Factor); 海赛卓尔(Hexadrol); 六甲嘧胺(Hexamethylmelamine);HMM; (Hydrocort);氢化可的松(Hydrocortisone);氢化可的松磷酸钠(Hydrocortisone Sodium Phosphate);氢化可的松琥珀酸钠(Hydrocortisone Sodium Succinate);磷酸氢化可的松(HydrocortonePhosphate);羟基脲(Hydroxyurea);依鲁替尼(Ibrutinib);替伊莫单抗(Ibritumomab);替坦异贝莫单抗(Ibritumomab Tiuxetan);伊达比星(Idarubicin)干扰素α(Interferon-alpha);干扰素α-2b(PEG缀合物)(Interferon-alpha-2b(PEG Conjugate));异环磷酰胺(Ifosfamide);白介素11(IL-11)(Interleukin-11);白介素2(IL-2)(Interleukin-2);甲磺酸伊马替尼(Imatinibmesylate);咪唑甲酰胺(Imidazole Carboxamide);伊匹单抗(ipilimumab)、伊立替康(Irinotecan);异维甲酸(Isotretinoin);伊沙匹隆(Ixabepilone);伊赛普拉TM(IxempraTM);凯卓酶(t)(Kidrolase(t))拉帕替尼(Lapatinib);L-天冬酰胺酶(L-asparaginase);LCR;来那度胺(Lenalidomide);来曲唑(Letrozole);甲酰四氢叶酸(Leucovorin);留可然(Leukeran);瘤肯TM(LeukineTM);亮丙瑞林(Leuprolide);长春新碱(Leurocristine);禄斯得停TM(LeustatinTM);利丽单抗(Lirilumab);阿糖胞苷脂质体(Liposomal Ara-C);罗氮芥(Lomustine);L-PAM;左旋苯丙氨氮芥(L-Sarcolysin); 马希得克(Maxidex);双氯乙基甲胺(Mechlorethamine);盐酸双氯乙基甲胺(Mechlorethamine Hydrochloride); 甲地孕酮(Megestrol);醋酸甲地孕酮(Megestrol Acetate);MEK抑制剂(MEK inhibitor);美法仑(Melphalan);巯基嘌呤(Mercaptopurine);美司钠(Mesna);美司那TM(MesnexTM);甲氨蝶呤(Methotrexate);甲氨蝶呤钠(Methotrexate Sodium);甲基强的松龙(Methylprednisolone);丝裂霉素(Mitomycin);丝裂霉素C(Mitomycin-C);米托蒽醌;(Mitoxantrone);M(M-);MTC;MTX;盐酸氮芥氮芥(Mustine);麦乐赛尔TM(MylocelTM);生根粉263(Navitoclax);奈拉滨(Nelarabine);倍血添TM(NeulastaTM); 尼罗替尼(Nilotinib);尼鲁米特(Nilutamide); 氮芥(Nitrogen Mustard);纳武单抗(Nivolumab);尼普累特(Nplate);奥曲肽(Octreotide);醋酸奥曲肽(Octreotide acetate);奥法木单抗(Ofatumumab); 昂克赛尔TM(OnxalTM);奥普瑞白介素(Oprelvekin); 奥沙利铂(Oxaliplatin);紫杉醇(Paclitaxel);紫杉醇蛋白质结合物(PaclitaxelProtein-bound);帕米膦酸钠(Pamidronate);帕尼单抗(Panitumumab); 帕唑帕尼(Pazopanib);PEG干扰素(PEG Interferon);培加帕加司(Pegaspargase);培非格司亭(Pegfilgrastim);PEG-INTRONTM;PEG左旋天冬酰胺酶(PEG-L-asparaginase);PEMETREXED;派姆单抗(Pembrolizumab);喷司他丁(Pentostatin);帕妥珠单抗(Pertuzumab);苯丙氨酸氮芥(Phenylalanine Mustard);皮地利珠单抗(Pidilizumab);普拉汀诺(Platinol-);泼尼松龙(Prednisolone);泼尼松(Prednisone);甲基苄肼(Procarbazine); 聚苯丙生20载卡莫司汀植入剂(Prolifeprospan 20with Carmustine Implant);BRAF抑制剂(BRAF inhibitor);雷洛昔芬(Raloxifene); 利妥昔单抗(Rituximab);罗扰素罗米司亭(Romiplostim);盐酸红比霉素(Rubidomycin hydrochloride);善得定沙格司亭(Sargramostim); 索拉非尼(Sorafenib);SPRYCELTM;STI-571;STIVAGRATM;链脲菌素(Streptozocin);SU11248;舒尼替尼(Sunitinib);它莫西芬(Tamoxifen) 替莫唑胺(Temozolomide)替西罗莫司(Temsirolimus);替尼泊苷(Teniposide);TESPA;萨力多胺(Thalidomide);硫鸟嘌呤(Thioguanine);(Thioguanine);三胺硫磷(Thiophosphoamide);硫替哌(Thiotepa); 拓扑替康(Topotecan);托瑞米芬(Toremifene);托西莫单抗(Tositumomab);曲妥珠单抗(Trastuzumab);曲美木单抗(Tremelimumab);维甲酸(Tretinoin);曲克傲TM(TrexallTM);TSPA;乌瑞鲁单抗(Urelumab);VCR;维克替比TM(VectibixTM);万耐托克(Venetoclax); 微尔度TM(ViadurTM); 长春花碱(Vinblastine);硫酸长春花碱(Vinblastine Sulfate);万卡赛(Vincasar);长春新碱(Vincristine);长春瑞滨(Vinorelbine);酒石酸长春瑞滨(Vinorelbine tartrate);VLB;VM-26;伏立诺他(Vorinostat);福退癌(Votrient);VP-16; 泽娃灵TM(ZevalinTM); 唑来膦酸(Zoledronicacid);佐林扎(Zolinza);和/或本文未具体列出的靶向相似途径的任何其他剂。
当两种或更多种物质或原理用作组合治疗方案的一部分时,它们可以通过相同的施用途径或通过不同的施用途径、在基本上相同的时间或在不同的时间(例如基本上同时、连续或根据替换方案)施用。当物质或原理通过相同的施用途径同时施用时,它们可以作为不同的药物制剂或组合物或组合药物制剂或组合物的一部分施用,这对于本领域技术人员来说是清楚的。
此外,当两种或更多种活性物质或原理用作组合治疗方案的一部分时,每种物质或原理可以以与化合物或原理单独使用时相同的量和根据相同的方案施用,并且这种组合使用可以产生或可以不产生协同效应。然而,当两种或更多种活性物质或原理的组合使用导致协同效应时,也可以减少一种、多于一种或所有待施用的物质或原理的量,而仍然实现期望的治疗作用。当它们以通常的量使用时,这可以例如用于避免、限制或减少与一种或多种物质或原理的使用相关的任何不希望的副作用,同时仍然获得期望的药物或治疗效果。
根据本发明使用的治疗方案的有效性可以以对于所涉及的疾病或疾患本身已知的任何方式来确定和/或遵循,如对于临床医生来说将是清楚的。临床医生还能够在适当的情况下并在个案的基础上改变或修改特定的治疗方案,以便实现期望的治疗效果,避免、限制或减少不期望的副作用,和/或在一方面实现期望的治疗效果与另一方面避免、限制或减少不期望的副作用之间实现适当的平衡。
通常,将遵循治疗方案直到获得期望的治疗效果和/或只要维持期望的治疗效果。同样,这可以由临床医生确定。
在各种实施方式中,本文提供了包含一种或多种CD137受体激动剂蛋白的药物组合物,其是单独的或与预防剂、治疗剂和/或药学上可接受的载体组合的。在各种实施方式中,本文公开的药物组合物的用途的非限制性实例包括诊断、检测和/或监测疾患,预防、治疗、管理和/或改善疾患或其一种或多种症状和/或用于研究。单独的或与预防剂、治疗剂和/或药学上可接受的载体组合的药物组合物的制剂,是本领域技术人员已知的(美国专利公开No.20090311253 A1)。
如本文所用,短语“有效量”是指导致与CD137L功能障碍相关的或与CD137L相关的疾病或疾患相关的一个或多个参数的可检测的改善(例如,高于基线至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%或更多)的CD137L激动剂蛋白的量。
施用本文提供的治疗剂的方法包括但不限于口服施用、胃肠外施用(例如皮内、肌内、腹膜内、静脉内和皮下)、硬膜外施用、瘤内施用、粘膜施用(例如鼻内和口服途径)和肺部施用(例如用吸入器或喷雾器施用的雾化化合物)。用于特定施用途径的药物组合物的制剂以及各种施用方法所必需的材料和技术对于本领域技术人员是可获得的和已知的(美国专利公开No.20090311253 A1)。
在各种实施方式中,可以调节剂量方案以提供最佳所需应答(例如,治疗或预防应答)。例如,可以单次团注施用,可以随时间施用若干个分开的剂量,或者剂量可以按治疗情况的紧急指示成比例地减少或增加。在一些实施方式中,胃肠外组合物以剂量单位形式配制,以便于施用和剂量的均匀性。术语“剂量单位形式”是指适于作为待治疗的哺乳动物受试者的单一剂量的物理上离散的单位;每个单元含有预定量的活性化合物,所述预定量的活性化合物经计算以产生与所需药物载体相关的所需治疗效果。
本文提供的治疗或预防有效量的CD137受体激动剂蛋白的示例性非限制性范围为约0.1-100mg/kg(例如,约0.1-0.5、0.1-1、0.1-10、0.1-20、0.1-50、0.1-75、1-10、1-15、1-7.5、1.25-15、1.25-7.5、2.5-7.5、2.5-15、5-15、5-7.5、1-20、1-50、7-75、1-100、5-10、5-15、5-20、5-25、5-50、5-75、10-20、10-50、10-75或10-100mg/kg,或中间的任何浓度)。在一些实施方式中,所述CD137受体激动剂蛋白以治疗有效浓度存在于药物组合物中,例如约0.1-100mg/ml的浓度(例如,0.1-0.5、0.1-1、0.1-10、0.1-20、0.1-50、0.1-75、1-10、1-20、1-50、1-75、1-100、5-10、5-15、5-20、5-25、5-50、5-75、10-20、10-50、10-75或10-100mg/ml,或中间的任何浓度)。注意,剂量值可随待缓解病症的类型和/或严重程度而变化。还应当理解,对于任何特定的受试者,可以根据个体需要和/或进行组合物施用或监督组合物施用的人的专业判断随时间调节具体的剂量方案,并且本文所示的剂量范围仅是示例性的,而不旨在限制所要求保护的组合物的范围或实践。
实施例
1.1多肽结构
A)氨基酸Met1–Gly20
Ig-κ-信号肽,在氨基酸Gly20之后假定的信号肽酶切割位点。
B)氨基酸Gln21–Val172
人CD137L配体的第一可溶性细胞因子结构域(CD137L,SEQ ID NO:1的氨基酸89-240)。
C)氨基酸Gly173–Ser180
SEQ ID NO:2的第一肽接头元件。
D)氨基酸Gln181–Val332
人CD137L配体的第二可溶性细胞因子结构域(CD137L,SEQ ID NO:1的氨基酸89-240)。
E)氨基酸Gly333–Ser340。
SEQ ID NO:2的第二肽接头元件。
F)氨基酸Gln341–Val492
人CD137L配体的第三可溶性细胞因子结构域(CD137L,SEQ ID NO:1的氨基酸89-240)。
G)氨基酸Gly493–Cys513
SEQ ID NO:16的铰链接头元件。
H)氨基酸Pro514–Lys731
SEQ ID NO:13的抗体Fc片段结构域。
上述CD137受体激动剂蛋白如SEQ ID NO:25所示。
所示的接头可由其他优选的接头代替,例如如SEQ ID NO:3-12所示。
所示的铰链连接元件可由其他优选的铰链连接元件替换,例如如SEQ ID NO:19-24中所示。
应当注意,第一和第二肽接头不需要相同。
信号肽序列(A)可以被任何其他合适的例如哺乳动物信号肽序列替换。1.2编码该多肽的基因盒
合成基因可以根据用于在合适的宿主细胞例如昆虫细胞或哺乳动物细胞中表达的其密码子使用而优化。优选的核酸序列如SEQ ID NO:37所示。
实施例2.表达和纯化
2.1融合多肽的克隆、表达和纯化
上述融合蛋白使用下述方法在不同真核宿主细胞中重组表达:
小规模表达CD137受体激动剂融合蛋白的方法:
为了小规模分析前述CD137受体激动剂融合蛋白,Hek293细胞在补充有10%的FBS,100单位/ml青霉素和100[mu]g/ml链霉素的DMEM+GlutaMAX(GibCo)中生长,并且用含有融合多肽和适当选择标志物的表达盒的质粒瞬时转染,例如包含杀稻瘟菌素、嘌呤霉素或潮霉素抗性基因的功能表达盒。在需要多个多肽链以获得最终产物的那些情况下,表达盒在转染过程中结合在一种质粒上或定位在不同质粒上。转染后3天收获含有重组融合多肽的细胞培养物上清液,并通过300×g离心澄清,随后通过0.22μm无菌过滤器过滤。
大规模表达和纯化CD137受体激动剂融合蛋白的方法
为了更大规模地表达CD137受体激动剂融合蛋白,将编码上述蛋白质的合成DNA盒插入真核表达载体中,该真核表达载体包括适当的选择标志物(例如,包括杀稻瘟菌素、嘌呤霉素或潮霉素抗性基因的功能表达盒)和适于增加宿主细胞基因组内转录活性插入位点数目的遗传元件。通过电穿孔将序列验证的表达载体导入适合中国仓鼠卵巢细胞(CHO-S,Invitrogen)的悬浮液中。转染后三天将对转染细胞施加合适的选择压力。通过随后在选择压力下培养来回收携带源自于载体的抗性基因的存活细胞。当选择的细胞群在化学限定培养基(PowerCHO2-CD,Lonza)中在37℃和7%CO2气氛中在轨道震荡培养箱(100rpm,50mm震甩)中生长稳定时,通过ELISA测定法检测上述蛋白质来分析单个上清液,并且在蛋白产生之前在摇动瓶中扩增具有最高比生产率的细胞群(轨道震荡器,100rpm,震甩50mm)。
对于实验室规模的蛋白质生产,单个细胞群在化学限定的培养基(PowerCHO2-CD,Lonza)中在37℃和7%CO2气氛中在Wave生物反应器20/50EHT(GE-Healthcare)中培养7-12天。基础培养基为补充有4mM GlutaMAX的PowerCHO2-CD。Wave培养始于活细胞浓度为0.3×10e6至0.4×10e6个细胞/ml,且采用如下设定(对于五升或十升袋):震荡频率18rpm、震荡角度7°、气流0.2-0.3L/min、7%CO2、36.5℃。在Wave运行期间,向细胞培养物中补料PowerFeed A(Lonza)两次,通常在第2天(20%补料)和第5天(30%补料)。第二次补料后,震荡频率增加至22rpm,震荡角度增加到8°。
当细胞活力下降到80%以下时,生物反应器通常在第7天至第12天之间收获。首先,使用手动深度过滤系统(Millipore Millistak Pod,MC0HC 0.054m2)澄清培养物上清液。对于带Strep标签的蛋白,添加亲和素至终浓度为0.5mg/L。最后,使用瓶顶过滤器(0.22μm,PES,Corning)将含有CD137受体激动剂融合蛋白的培养物上清液无菌过滤,并储存在2-8℃直至进一步处理。
为了亲和纯化,将链霉素琼脂糖(Streptactin Sepharose)填充至柱(凝胶床2ml),用15ml缓冲液W(100mM Tris-HCl,150mM NaCl,pH 8.0)或pH 7.4的PBS平衡,并将细胞培养物上清液施于色谱柱,流速约为4ml/min。随后,用15ml缓冲液W洗柱,通过加入7×1ml缓冲液E(100mM Tris HCl,150mM NaCl,2.5mM脱硫生物素,pH8.0)逐步洗脱结合的多肽。替换地,包含2.5mM脱硫生物素的pH 7.4PBS可以用于该步骤。
可替换基于链霉素琼脂糖的方法,使用具有固定化蛋白A作为亲和配体的柱和Akta层析系统(GE-Healthcare)进行亲和纯化。选择对融合蛋白的FC结构域具有高亲和力的固相材料:MABSelect SureTM(GE Healthcare)。简而言之,将澄清的细胞培养物上清液加载到在洗涤缓冲液-1(20mM Pi,95mM NaCl,pH 7.2)中平衡的HiTrap MabSelectSure柱(CV=5ml)上,其不超过10mg融合蛋白/ml柱-床的加载。用10倍柱体积(10CV)的上述平衡缓冲液洗涤柱子,接着用四倍柱体积(4CV)的洗涤缓冲液-2(20mM Pi,95mM NaCl,pH 8.0)洗涤以去除宿主细胞蛋白和宿主-细胞DNA。然后用洗脱缓冲液(20mM Pi,95mM NaCl,pH 3.5)洗脱柱子,洗脱液以多至10个级分收集,每个级分的体积等于柱床体积(5ml)。用等体积的上述洗涤缓冲液-2中和每个级分。在上述亲和层析法过程中,线速度设定为150cm/h并保持恒定。
定量洗脱液级分的蛋白量,并通过超滤浓缩峰级分,并通过尺寸排阻层析法(SEC)进一步纯化。
使用Akta层析系统(GE-Healthcare)在葡聚糖(Superdex)200 10/300 GL或HiLoad 26/60柱上进行SEC。柱用磷酸盐缓冲盐水平衡,将浓缩的、亲和纯化的多肽加载到SEC柱上,样品体积不超过柱体积的2%(v/v)。在葡聚糖200 10/300 GL柱(GE Healthcare)中,流速为每分钟0.5ml。在HiLoad 26/60葡聚糖200柱中,流速为每分钟2.5ml。通过280nm处的吸光度监测多肽的洗脱曲线。
为了测定天然条件下纯化的融合多肽的表观分子量,向葡聚糖200柱加载有已知分子量的标准蛋白质。基于标准蛋白质的洗脱体积绘制校准曲线并确定纯化的融合多肽的分子量。包括FC结构域的CD137受体激动剂融合蛋白从葡聚糖200柱洗脱,表观分子量约为140-180kDa,这将证实Fc结构域对成熟CD137受体激动剂融合多肽的同源二聚化。
实施例3:三价对照蛋白
为了比较六价CD137受体激动剂融合蛋白和用噬菌体RB69-FOLDON稳定的同源三聚体三价CD137受体激动剂融合蛋白之间的相对结合,如前一部分所述在CHO-S细胞中表达并进行纯化。该序列在下表中示出:
实施例4:通过限制性蛋白酶消化测定CD137受体激动剂蛋白质的体外稳定性
如实施例1中所述的六价Fc融合蛋白一样,将表达并纯化待研究的所有CD137受体激动剂蛋白。该组将包括在CH2结构域中包含N297S突变[根据EU编号系统]和铰链区的CD137受体激动剂蛋白,该铰链区能够形成三个二硫桥并且另外缺少上铰链赖氨酸[K223,根据EU编号系统],其突变为甘氨酸[K223G]。在有限的蛋白酶消化测定中,将在三个二硫化物发挥铰链功能的情况下同时包括N297S突变和K223G突变的前述CD137受体激动剂蛋白与呈现在两个二硫化物或三个二硫化物实现铰链区的情况下包括N297S突变但具有K223野生型的CD137受体激动剂蛋白进行比较。
此外,具有减少至4个氨基酸的第二接头元件(iv),并且具有缩短的铰链元件(vi)的CD137受体激动剂蛋白将被研究(例如SEQ ID NO:32和34)。工程化策略(三个二硫化物实现铰链区情况下的N297S与K223G突变结合)和缩短接头元件(iv和vi)二者都对相应分子的稳定性具有潜在影响。
本发明的不同CD137激动性蛋白的稳定性可以通过体外限制的蛋白酶消化解决。对于该分析,将上述CD137受体激动剂蛋白与低浓度蛋白酶(例如胰蛋白酶、V8蛋白酶)在不同温度(例如4℃、25℃、37℃)下一起孵育不同时间。随后可以通过不同的方法,如SDS-PAGE,分析型SEC或本领域已知的分析质谱法(例如Nano-RP-HPLC-ESI-MSMS)来测量特定蛋白水解片段随时间的定量及其出现。由于被研究的蛋白质具有大部分共同的序列,随着时间的推移,来自单个蛋白质的特定蛋白水解片段的更快的出现和数量增加可用于判断它们的相对稳定性并将它们相互排序。关于所研究的上述CD137受体激动剂蛋白的基于蛋白酶的诱饵动力学,关于其蛋白水解稳定性顺序预期如下:
与在铰链区中包括N297S和野生型K223的CD137受体激动剂蛋白相比,包括N297S和K223G以及实现铰链区的三个二硫化物的CD137受体激动剂蛋白同时具有延长的稳定性。与包括SEQ ID NO:16作为铰链接头元件的CD137受体激动剂蛋白相比,包含SEQ ID NO:21作为铰链接头元件的CD137受体激动剂蛋白具有延长的稳定性。
实施例5:稳定性/聚集测试
单体和聚集体的含量通过实施例2中所述的分析性SEC测定。对于特定目的,在生理pH的含有生理盐浓缩物的缓冲液(例如,pH 7.4 0.9%NaCl;pH 7.4PBS)中进行该分析。典型的聚集分析在葡聚糖200柱(GE Healthcare)上进行。该柱分离10至800kDa范围内的蛋白。
为了测定天然条件下纯化的融合多肽的表观分子量,向葡聚糖200柱加载已知分子量的标准蛋白。基于标准蛋白的洗脱体积绘制校准曲线,并基于洗脱体积计算未知分子量的纯化融合蛋白的表观分子量。
对可溶性非聚集蛋白的SEC分析通常在限定的洗脱体积显示出明显的单个蛋白峰(在280nm或214nm处的OD处测量)。该洗脱体积对应于特定蛋白的表观天然分子量。关于在FC融合蛋白的情况下“单体”的定义,两条多肽链的组装由该蛋白质的FC部分驱动,并且功能单位是由两条链组成的蛋白质。含有两条FC连接的多肽链的该单元在Fc融合蛋白的情况下被定义为“单体”,这与二聚化单链融合多肽无关。
如果发生蛋白质聚集,SEC分析显示出具有较低保留体积的额外蛋白质峰。蛋白寡聚物可能用作聚集种子,并且高含量的寡聚物可能导致蛋白质聚集。大分子量的寡聚物和聚集体在葡聚糖200柱的空隙体积中洗脱,并且不能通过SEC对它们的天然分子量进行分析。
CD137受体激动剂融合蛋白的纯化制剂应优选仅含有限定的单体蛋白和非常少量的寡聚蛋白。特定CD137受体激动剂融合蛋白制剂的聚集/寡聚程度基于SEC分析通过分别计算所限定单体和寡聚物/聚集体级分的OD280图的峰面积来测定。基于总峰面积,限定的单体蛋白的百分比计算如下:
单体含量[%]=[单体蛋白的峰面积]/[总峰面积]×100)
实施例6:通过QCM分析测定三价和六价CD137受体配体构建体的平衡结合常数
基于用自动生物传感器系统(Attana A100)测定的动力学结合数据(k结合和k解离),计算CD137受体配体的三价和六价构建体的平衡结合常数(KD)。A100允许基于石英晶体微天平(QCM)技术来实时研究分子间的相互作用。
为此目的,将人CD137受体固定化至羧基活化的QCM芯片的表面。随后,三价或六价CD137受体配体分别以不同浓度(例如0.5、1、2、5和10μg/ml)用作分析物,用于分析配体-受体结合(k结合)和解离(k解离)的动力学结合数据。分析是实时进行的,并且可以计算相应的KD:KD=k解离/k结合。
QCM分析表明,三价CD137受体配体与相应的固定化CD137受体结合,KD在低nM范围内,预期KD为1-500nM。然而,CD137受体配体的六价构建体显示出与相应的固定化CD137受体的在pM范围内的较高的亲和力,预期KD为1pM–500nM。动力学结合数据(k结合和k解离)的共同特征是与三价构建体相比,六价构建体显示更快的k结合。此外,如果与三价配体相比,六价配体通常观察到较慢的解离(k解离)。
实施例7:T细胞增殖测定
为了评估CD137受体激动剂的T细胞活化能力,通过使用磁珠的阴性选择从人血沉棕黄层制剂中纯化T细胞。用CFSE标记细胞与或不与不同量的CD137受体激动剂一起孵育,并与抗人CD3抗体在37℃下结合2-5天。在流式细胞仪上获取CFSE稀释作为测量细胞分裂的手段的数据。通过使用细胞培养物上清液和用于捕获的抗人IFNγ抗体的ELISA测量IFNγ产生。
当CD137受体激动剂与抗人CD3抗体一起存在于T细胞培养物中时,人们期望通过CD4+和CD8+T细胞二者观察到IFNγ分泌的清楚的增加。除了更高的IFNγ产生之外,人们期望通过使用流式细胞术测量CFSE稀释来看到更多的T细胞被驱动进入细胞周期。这将证明CD137受体激动剂在T细胞活化情况中的共刺激作用。
实施例8:CD137激动剂结合测定
使用阴性选择和磁珠从新鲜血沉棕黄层制剂中分离原代人T细胞。将细胞以每孔2×10e6个细胞接种到24孔板中。将T细胞与抗人CD3抗体(克隆HIT3a,1μg/ml)、抗人CD28抗体(克隆CD28.2,5μg/ml)和不同量的蛋白A(CD137L,10-1000ng/ml)一起孵育,或简单地留在培养基中作为对照。在37℃下3天后,用抗人CD137和抗人CD4或抗人CD8抗体荧光标记细胞。在guava easyCyte流式细胞仪上在CD4+和CD8+ T细胞群内评估CD137荧光。
当将与抗CD3和抗CD28抗体一起孵育的T细胞群与单独留在培养基中的对照细胞进行比较时,人们期望观察到CD137的较低荧光信号,指示受体的活化诱导的下调。当细胞与CD137激动剂(蛋白A)共孵育时,这种作用可以更强且是剂量依赖性的,这表明由CD137激动剂(蛋白A)引起的补充作用。这些结果提示CD137激动剂(蛋白A)与其受体在体外结合。
实施例9:人体外T细胞增殖测定
通过阴性选择和磁珠(pan T细胞分离试剂盒,Miltenyi Biotec)从健康供体的外周血纯化总T细胞(人),并用CFSE(CellTraceTM CFSE细胞增殖试剂盒,用于流式细胞术,ThermoFisher)染色,并以每孔2×10e6个细胞接种到24孔板中。将细胞单独与培养基,单独与可溶性抗CD3抗体(1μg/ml的克隆OKT3),与抗CD3抗体加抗CD28抗体(1μg/ml的克隆28.2)或与抗CD3抗体加10、100或1000ng/ml的成熟蛋白A(SEQ ID NO:27)分别在37℃孵育5天。
在第5天,洗涤细胞并用DAPI(排除死细胞)和特异性抗体染色。用Guava EasyCyte12流式细胞仪(EMD Millipore)通过流式细胞术测量前向散射(FSC或大小)和增殖依赖性CFSE稀释的表达。使用FlowJo 10.1软件(FlowJo,LLC)对每个样品至少一万个记录的事件进行数据分析。响应细胞的百分比通过使用培养基对照基于前向散射和CFSE确定合适的门限位置来测定。细胞尺寸增大或CFSE水平降低的细胞被标记为响应细胞。来自一个供体的两个生物复制的个体数据示于下复制表(T细胞活化的量化)这些结果与来自其他供体的结果一致,并且清楚地表明,与单独的抗体刺激相比,用蛋白A体外处理人T细胞增强了T细胞的活化和增殖。
T细胞活化的定量。
实施例10:受体结合测定
对于评估本发明的CD137受体激动剂蛋白与其相应受体的功能性结合的ELISA测定,用1μg/ml CD137-Fc(Bio-Techne GmbH,Wiesbaden-Nordenstadt,德国)包被微量滴定板。在用StartingBlock(Life Technologies GmbH,Darmstadt,Germany)封闭后,将孔与指定浓度的带strep标签的蛋白A(SEQ ID NO:28)一起孵育。经由CD137L的Strep标签II使用抗Strep标签-过氧化物酶StrepTactin-HRP(1:5000,IBA GmbH,Goettingen,德国),以及随后在ELISA读取器中检测450nm波长处的转化的氧化物酶-底物TMB一(one)(Kem-En-TecDiagnostics,Taastrup,丹麦)检测至其相应受体的结合。图6清楚地描绘了蛋白A至其受体的浓度依赖性结合。
序列表
<110> 阿珀吉科吉尼科斯股份公司(Apogenix AG)
<120> 单链CD137受体激动剂蛋白
<130> PN18016867P
<160> 43
<170> BiSSAP 1.3.6
<210> 1
<211> 254
<212> PRT
<213> 智人(Homo sapiens)
<220>
<223> CD137配体WT
<400> 1
Met Glu Tyr Ala Ser Asp Ala Ser Leu Asp Pro Glu Ala Pro Trp Pro
1 5 10 15
Pro Ala Pro Arg Ala Arg Ala Cys Arg Val Leu Pro Trp Ala Leu Val
20 25 30
Ala Gly Leu Leu Leu Leu Leu Leu Leu Ala Ala Ala Cys Ala Val Phe
35 40 45
Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser
50 55 60
Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp
65 70 75 80
Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val
85 90 95
Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp
100 105 110
Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu
115 120 125
Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe
130 135 140
Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser
145 150 155 160
Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala
165 170 175
Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala
180 185 190
Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala
195 200 205
Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His
210 215 220
Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val
225 230 235 240
Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
245 250
<210> 2
<211> 8
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 2
Gly Ser Gly Ser Gly Asn Gly Ser
1 5
<210> 3
<211> 8
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 3
Gly Ser Gly Ser Gly Ser Gly Ser
1 5
<210> 4
<211> 8
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 4
Gly Gly Ser Gly Ser Gly Ser Gly
1 5
<210> 5
<211> 6
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 5
Gly Gly Ser Gly Ser Gly
1 5
<210> 6
<211> 4
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 6
Gly Gly Ser Gly
1
<210> 7
<211> 8
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 7
Gly Gly Ser Gly Asn Gly Ser Gly
1 5
<210> 8
<211> 8
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 8
Gly Gly Asn Gly Ser Gly Ser Gly
1 5
<210> 9
<211> 6
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 9
Gly Gly Asn Gly Ser Gly
1 5
<210> 10
<211> 6
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 10
Gly Ser Gly Ser Gly Ser
1 5
<210> 11
<211> 4
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 11
Gly Ser Gly Ser
1
<210> 12
<211> 3
<212> PRT
<213> 人造序列
<220>
<223> 接头
<400> 12
Gly Ser Gly
1
<210> 13
<211> 218
<212> PRT
<213> 人造序列
<220>
<223> IGG1-Fc N297S
<400> 13
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
1 5 10 15
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
20 25 30
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
35 40 45
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
50 55 60
Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
65 70 75 80
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
85 90 95
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
100 105 110
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
115 120 125
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
130 135 140
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
145 150 155 160
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
165 170 175
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
180 185 190
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
195 200 205
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215
<210> 14
<211> 217
<212> PRT
<213> 人造序列
<220>
<223> IGG1-Fc WT
<400> 14
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
115 120 125
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215
<210> 15
<211> 745
<212> PRT
<213> 人造序列
<220>
<223> 蛋白A (CD137L去糖基化(deglyco)Fc)
<400> 15
Met Glu Thr Asp Thr Leu Leu Val Phe Val Leu Leu Val Trp Val Pro
1 5 10 15
Ala Gly Asn Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
20 25 30
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
35 40 45
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
50 55 60
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
65 70 75 80
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
85 90 95
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
100 105 110
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
115 120 125
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
130 135 140
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
145 150 155 160
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
165 170 175
Gly Asn Gly Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
180 185 190
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
195 200 205
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
210 215 220
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
225 230 235 240
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
245 250 255
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
260 265 270
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
275 280 285
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
290 295 300
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
305 310 315 320
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
325 330 335
Gly Asn Gly Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
340 345 350
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
355 360 365
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
370 375 380
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
385 390 395 400
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
405 410 415
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
420 425 430
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
435 440 445
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
450 455 460
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
465 470 475 480
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser
485 490 495
Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro
500 505 510
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
515 520 525
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
530 535 540
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
545 550 555 560
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
565 570 575
Glu Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
580 585 590
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
595 600 605
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
610 615 620
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
625 630 635 640
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
645 650 655
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
660 665 670
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
675 680 685
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
690 695 700
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
705 710 715 720
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Ser Ser Ser Ser Ser Ser
725 730 735
Ala Trp Ser His Pro Gln Phe Glu Lys
740 745
<210> 16
<211> 21
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 16
Gly Ser Ser Ser Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His
1 5 10 15
Thr Cys Pro Pro Cys
20
<210> 17
<211> 20
<212> PRT
<213> 人造序列
<220>
<223> 通用信号肽
<400> 17
Met Glu Thr Asp Thr Leu Leu Val Phe Val Leu Leu Val Trp Val Pro
1 5 10 15
Ala Gly Asn Gly
20
<210> 18
<211> 15
<212> PRT
<213> 人造序列
<220>
<223> 带strep标签的丝氨酸接头
<400> 18
Ser Ser Ser Ser Ser Ser Ala Trp Ser His Pro Gln Phe Glu Lys
1 5 10 15
<210> 19
<211> 20
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 19
Gly Ser Ser Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr
1 5 10 15
Cys Pro Pro Cys
20
<210> 20
<211> 19
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 20
Gly Ser Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys
1 5 10 15
Pro Pro Cys
<210> 21
<211> 18
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 21
Gly Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro
1 5 10 15
Pro Cys
<210> 22
<211> 16
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 22
Gly Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10 15
<210> 23
<211> 18
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 23
Gly Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10 15
Gly Ser
<210> 24
<211> 20
<212> PRT
<213> 人造序列
<220>
<223> 铰链接头
<400> 24
Gly Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10 15
Gly Ser Gly Ser
20
<210> 25
<211> 731
<212> PRT
<213> 人造序列
<220>
<223> 蛋白A - 无strep标签
<400> 25
Met Glu Thr Asp Thr Leu Leu Val Phe Val Leu Leu Val Trp Val Pro
1 5 10 15
Ala Gly Asn Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
20 25 30
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
35 40 45
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
50 55 60
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
65 70 75 80
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
85 90 95
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
100 105 110
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
115 120 125
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
130 135 140
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
145 150 155 160
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
165 170 175
Gly Asn Gly Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
180 185 190
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
195 200 205
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
210 215 220
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
225 230 235 240
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
245 250 255
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
260 265 270
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
275 280 285
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
290 295 300
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
305 310 315 320
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
325 330 335
Gly Asn Gly Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
340 345 350
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
355 360 365
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
370 375 380
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
385 390 395 400
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
405 410 415
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
420 425 430
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
435 440 445
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
450 455 460
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
465 470 475 480
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser
485 490 495
Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro
500 505 510
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
515 520 525
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
530 535 540
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
545 550 555 560
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
565 570 575
Glu Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
580 585 590
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
595 600 605
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
610 615 620
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
625 630 635 640
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
645 650 655
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
660 665 670
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
675 680 685
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
690 695 700
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
705 710 715 720
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
725 730
<210> 26
<211> 730
<212> PRT
<213> 人造序列
<220>
<223> 融合至Seq_14的CD137L-wt
<400> 26
Met Glu Thr Asp Thr Leu Leu Val Phe Val Leu Leu Val Trp Val Pro
1 5 10 15
Ala Gly Asn Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
20 25 30
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
35 40 45
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
50 55 60
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
65 70 75 80
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
85 90 95
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
100 105 110
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
115 120 125
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
130 135 140
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
145 150 155 160
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
165 170 175
Gly Asn Gly Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
180 185 190
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
195 200 205
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
210 215 220
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
225 230 235 240
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
245 250 255
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
260 265 270
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
275 280 285
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
290 295 300
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
305 310 315 320
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
325 330 335
Gly Asn Gly Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
340 345 350
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
355 360 365
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
370 375 380
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
385 390 395 400
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
405 410 415
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
420 425 430
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
435 440 445
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
450 455 460
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
465 470 475 480
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser
485 490 495
Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro
500 505 510
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
515 520 525
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
530 535 540
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
545 550 555 560
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
565 570 575
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
580 585 590
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
595 600 605
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
610 615 620
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
625 630 635 640
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
645 650 655
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
660 665 670
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
675 680 685
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
690 695 700
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
705 710 715 720
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
725 730
<210> 27
<211> 711
<212> PRT
<213> 人造序列
<220>
<223> 融合至Seq_13的CD137L-wt (无信号(sig)、无strep标签、无糖基化(glyco))
<400> 27
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
1 5 10 15
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
20 25 30
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
35 40 45
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
50 55 60
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
65 70 75 80
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
85 90 95
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
100 105 110
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
115 120 125
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
130 135 140
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
145 150 155 160
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
165 170 175
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
180 185 190
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
195 200 205
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
210 215 220
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
225 230 235 240
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
245 250 255
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
260 265 270
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
275 280 285
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
290 295 300
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
305 310 315 320
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
325 330 335
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
340 345 350
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
355 360 365
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
370 375 380
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
385 390 395 400
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
405 410 415
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
420 425 430
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
435 440 445
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
450 455 460
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser Ser Ser Ser
465 470 475 480
Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 28
<211> 725
<212> PRT
<213> 人造序列
<220>
<223> 融合至Seq_13的CD137L-wt (无信号、 无糖基化)
<400> 28
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
1 5 10 15
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
20 25 30
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
35 40 45
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
50 55 60
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
65 70 75 80
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
85 90 95
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
100 105 110
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
115 120 125
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
130 135 140
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
145 150 155 160
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
165 170 175
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
180 185 190
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
195 200 205
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
210 215 220
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
225 230 235 240
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
245 250 255
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
260 265 270
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
275 280 285
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
290 295 300
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
305 310 315 320
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
325 330 335
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
340 345 350
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
355 360 365
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
370 375 380
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
385 390 395 400
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
405 410 415
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
420 425 430
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
435 440 445
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
450 455 460
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser Ser Ser Ser
465 470 475 480
Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Ser Ser Ser Ser Ser Ser Ala Trp Ser His
705 710 715 720
Pro Gln Phe Glu Lys
725
<210> 29
<211> 710
<212> PRT
<213> 人造序列
<220>
<223> 实例
<400> 29
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
1 5 10 15
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
20 25 30
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
35 40 45
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
50 55 60
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
65 70 75 80
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
85 90 95
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
100 105 110
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
115 120 125
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
130 135 140
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
145 150 155 160
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
165 170 175
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
180 185 190
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
195 200 205
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
210 215 220
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
225 230 235 240
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
245 250 255
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
260 265 270
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
275 280 285
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
290 295 300
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
305 310 315 320
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
325 330 335
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
340 345 350
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
355 360 365
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
370 375 380
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
385 390 395 400
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
405 410 415
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
420 425 430
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
435 440 445
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
450 455 460
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser Ser Ser Ser
465 470 475 480
Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
500 505 510
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
515 520 525
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
530 535 540
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
545 550 555 560
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
565 570 575
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
580 585 590
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
595 600 605
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
610 615 620
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
625 630 635 640
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
645 650 655
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
660 665 670
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
675 680 685
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
690 695 700
Ser Leu Ser Pro Gly Lys
705 710
<210> 30
<211> 716
<212> PRT
<213> 人造序列
<220>
<223> 实例
<400> 30
Gln Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
1 5 10 15
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
20 25 30
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
35 40 45
Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu
50 55 60
Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu
65 70 75 80
His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu
85 90 95
Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe
100 105 110
Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly
115 120 125
Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr
130 135 140
Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly
145 150 155 160
Asn Gly Ser Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln
165 170 175
Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly
180 185 190
Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr
195 200 205
Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln
210 215 220
Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser
225 230 235 240
Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala
245 250 255
Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn
260 265 270
Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln
275 280 285
Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp
290 295 300
Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser
305 310 315 320
Gly Ser Gly Asn Gly Ser Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
325 330 335
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
340 345 350
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
355 360 365
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
370 375 380
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
385 390 395 400
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
405 410 415
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
420 425 430
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
435 440 445
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
450 455 460
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
465 470 475 480
Val Gly Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro
485 490 495
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
500 505 510
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
515 520 525
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
530 535 540
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
545 550 555 560
Arg Glu Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr
565 570 575
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
580 585 590
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
595 600 605
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
610 615 620
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
625 630 635 640
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
645 650 655
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
660 665 670
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
675 680 685
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
690 695 700
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710 715
<210> 31
<211> 720
<212> PRT
<213> 人造序列
<220>
<223> 实例
<400> 31
Gln Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
1 5 10 15
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
20 25 30
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
35 40 45
Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu
50 55 60
Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu
65 70 75 80
His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu
85 90 95
Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe
100 105 110
Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly
115 120 125
Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr
130 135 140
Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly
145 150 155 160
Asn Gly Ser Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln
165 170 175
Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly
180 185 190
Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr
195 200 205
Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln
210 215 220
Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser
225 230 235 240
Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala
245 250 255
Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn
260 265 270
Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln
275 280 285
Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp
290 295 300
Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser
305 310 315 320
Gly Ser Gly Asn Gly Ser Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
325 330 335
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
340 345 350
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
355 360 365
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
370 375 380
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
385 390 395 400
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
405 410 415
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
420 425 430
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
435 440 445
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
450 455 460
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
465 470 475 480
Val Gly Ser Ser Ser Ser Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr
485 490 495
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
500 505 510
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
515 520 525
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
530 535 540
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
545 550 555 560
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val
565 570 575
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
580 585 590
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
595 600 605
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
610 615 620
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
625 630 635 640
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
645 650 655
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
660 665 670
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
675 680 685
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
690 695 700
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710 715 720
<210> 32
<211> 711
<212> PRT
<213> 人造序列
<220>
<223> 实例
<400> 32
Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile
1 5 10 15
Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser
20 25 30
Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val
35 40 45
Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg
50 55 60
Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu
65 70 75 80
Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val
85 90 95
Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe
100 105 110
Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His
115 120 125
Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly
130 135 140
Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly
145 150 155 160
Ser Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu
165 170 175
Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val
180 185 190
Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val
195 200 205
Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg
210 215 220
Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His
225 230 235 240
Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr
245 250 255
Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly
260 265 270
Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val
275 280 285
His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln
290 295 300
Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn
305 310 315 320
Gly Ser Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
325 330 335
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
340 345 350
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
355 360 365
Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu
370 375 380
Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu
385 390 395 400
His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu
405 410 415
Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe
420 425 430
Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly
435 440 445
Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr
450 455 460
Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser
465 470 475 480
Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 33
<211> 714
<212> PRT
<213> 人造序列
<220>
<223> 实例
<400> 33
Gln Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile
1 5 10 15
Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser
20 25 30
Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val
35 40 45
Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg
50 55 60
Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu
65 70 75 80
Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val
85 90 95
Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe
100 105 110
Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His
115 120 125
Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly
130 135 140
Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly
145 150 155 160
Ser Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu
165 170 175
Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val
180 185 190
Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val
195 200 205
Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg
210 215 220
Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His
225 230 235 240
Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr
245 250 255
Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly
260 265 270
Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val
275 280 285
His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln
290 295 300
Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn
305 310 315 320
Gly Ser Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
325 330 335
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
340 345 350
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
355 360 365
Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu
370 375 380
Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu
385 390 395 400
His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu
405 410 415
Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe
420 425 430
Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly
435 440 445
Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr
450 455 460
Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser
465 470 475 480
Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
485 490 495
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
500 505 510
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
515 520 525
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
530 535 540
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
545 550 555 560
Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
565 570 575
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
580 585 590
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
595 600 605
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
610 615 620
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
625 630 635 640
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
645 650 655
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
660 665 670
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
675 680 685
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
690 695 700
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 34
<211> 714
<212> PRT
<213> 人造序列
<220>
<223> 实例
<400> 34
Ser Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile
1 5 10 15
Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser
20 25 30
Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val
35 40 45
Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg
50 55 60
Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu
65 70 75 80
Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val
85 90 95
Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe
100 105 110
Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His
115 120 125
Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly
130 135 140
Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly
145 150 155 160
Ser Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu
165 170 175
Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val
180 185 190
Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val
195 200 205
Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg
210 215 220
Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His
225 230 235 240
Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr
245 250 255
Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly
260 265 270
Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val
275 280 285
His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln
290 295 300
Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn
305 310 315 320
Gly Ser Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
325 330 335
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
340 345 350
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
355 360 365
Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu
370 375 380
Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu
385 390 395 400
His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu
405 410 415
Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe
420 425 430
Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly
435 440 445
Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr
450 455 460
Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser
465 470 475 480
Ser Ser Ser Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
485 490 495
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
500 505 510
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
515 520 525
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
530 535 540
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
545 550 555 560
Glu Gln Tyr Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
565 570 575
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
580 585 590
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
595 600 605
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
610 615 620
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
625 630 635 640
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
645 650 655
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
660 665 670
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
675 680 685
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
690 695 700
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 35
<211> 711
<212> PRT
<213> 人造序列
<220>
<223> 假的序列 --> 请换成正确序列
<400> 35
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
1 5 10 15
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
20 25 30
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
35 40 45
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
50 55 60
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
65 70 75 80
Pro Leu Arg Ser Ala Asn Gly Ser Ala Ala Leu Ala Leu Thr Val Asp
85 90 95
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
100 105 110
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
115 120 125
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
130 135 140
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
145 150 155 160
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
165 170 175
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
180 185 190
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
195 200 205
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
210 215 220
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
225 230 235 240
Pro Leu Arg Ser Ala Asn Gly Ser Ala Ala Leu Ala Leu Thr Val Asp
245 250 255
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
260 265 270
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
275 280 285
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
290 295 300
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
305 310 315 320
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
325 330 335
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
340 345 350
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
355 360 365
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
370 375 380
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
385 390 395 400
Pro Leu Arg Ser Ala Asn Gly Ser Ala Ala Leu Ala Leu Thr Val Asp
405 410 415
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
420 425 430
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
435 440 445
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
450 455 460
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Ser Ser Ser Ser Ser Ser
465 470 475 480
Ser Gly Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Ser Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 36
<211> 472
<212> PRT
<213> 人造序列
<220>
<223> scCD137L-RBD模块的实例
<400> 36
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
1 5 10 15
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
20 25 30
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
35 40 45
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
50 55 60
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
65 70 75 80
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
85 90 95
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
100 105 110
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
115 120 125
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
130 135 140
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
145 150 155 160
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
165 170 175
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
180 185 190
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
195 200 205
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
210 215 220
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
225 230 235 240
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
245 250 255
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
260 265 270
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
275 280 285
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
290 295 300
Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly Ser
305 310 315 320
Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile Asp
325 330 335
Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser Leu
340 345 350
Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val Ala
355 360 365
Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg Val
370 375 380
Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu Gln
385 390 395 400
Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val Asp
405 410 415
Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe Gln
420 425 430
Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His Leu
435 440 445
His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly Ala
450 455 460
Thr Val Leu Gly Leu Phe Arg Val
465 470
<210> 37
<211> 2240
<212> DNA
<213> 人造序列
<220>
<223> 编码SEQ ID NO:25的DNA序列
<400> 37
aagctttagg gataacaggg taatagccgc caccatggag actgacaccc tgctggtgtt 60
cgtgctgctg gtctgggtgc ctgcaggaaa tggacagggc atgttcgctc aactggtcgc 120
acagaacgtg ctgctcattg acggtcccct gtcttggtac tccgatccag ggttggcagg 180
agtgtccttg acaggagggc tgtcctataa ggaggatacc aaagagctgg tggtagcaaa 240
ggctggtgtg tattacgtgt tctttcagct ggagctgcgc agagtcgtcg caggcgaagg 300
atctggtagt gtgtcactgg cactgcactt gcagcccctt cggtccgctg ccggggcagc 360
agcactggcc ctgaccgtcg atctgccacc cgcttctagc gaggcacgaa actcagcctt 420
tgggtttcag ggtcgcctgc tgcacctgag cgccggacag aggctgggcg ttcatctgca 480
caccgaggcc agagccagac acgcttggca gttgactcag ggagctacgg tcctcggtct 540
gtttcgagta ggcagcggaa gcggcaatgg ctctcagggc atgtttgctc agctggtagc 600
ccagaacgta ctcctgatcg atggccctct ttcatggtac tcagaccccg gactggccgg 660
agttagcctt acaggtgggc ttagttataa ggaggacaca aaggaattgg ttgtggccaa 720
agctggcgtg tactatgtgt tcttccagct tgagctccgc agagtcgtgg ctggggaggg 780
ctctggcagt gtgagccttg cccttcatct gcaacctttg cggagcgcag ccggcgctgc 840
tgcactggcc cttacagtgg atttgccacc cgcaagtagt gaagctcgca attccgcatt 900
cggtttccag ggccgtctgc tccatctttc tgccggtcaa cgtctgggag ttcacctcca 960
cactgaggct agggccaggc atgcttggca gctgactcaa ggagccactg tcttgggact 1020
ctttcgggta ggctccgggt ctggcaacgg ctcccagggg atgtttgccc aactggtcgc 1080
ccagaatgtc ctgctcatcg atggtcctct gagctggtat tccgaccctg gactggctgg 1140
tgtgagcctg actggcggac tctcctacaa agaggacacc aaggaactgg tggtggccaa 1200
agccggggtg tactacgtgt tcttccagtt ggaactgcgg cgggttgtgg ctggcgaggg 1260
atcaggttcc gttagtctgg ccctgcacct ccagcctctg aggtctgctg ctggtgccgc 1320
cgctctggcc ttgaccgtcg acctcccacc cgcatcttcc gaagcccgaa attcagcctt 1380
cgggttccag ggcagactgc tgcatctgag tgctggacag cgccttgggg ttcatctcca 1440
caccgaagcc agggcccgac atgcctggca gctcacacaa ggcgcaaccg ttttggggct 1500
ctttcgtgtg ggatcctcga gttcatcgtc ctcatccggc tcatgtgata agacccacac 1560
ctgccctccc tgtcctgccc ctgagctgct gggcggacct tctgtgttcc tgttcccccc 1620
caagcctaag gacaccctga tgatctccag gacccctgag gtgacctgtg tggtggtgga 1680
cgtgtctcac gaagatcccg aggtgaagtt caactggtac gtggacggcg tggaggtcca 1740
caacgccaag accaagccta gggaggagca gtacagctcc acctaccggg tggtgtctgt 1800
gctgaccgtg ctgcaccagg attggctgaa cggaaaggag tataagtgta aggtctccaa 1860
caaggccctg cctgccccca tcgagaaaac catctccaag gccaagggcc agcctcggga 1920
gcctcaggtg tacaccctgc ctcctagcag ggaggagatg accaagaacc aggtgtccct 1980
gacctgtctg gtgaagggct tctacccttc cgatatcgcc gtggagtggg agtctaatgg 2040
ccagcccgag aacaactaca agaccacccc tcctgtgctg gactctgacg gctccttctt 2100
cctgtactcc aagctgaccg tggacaagtc cagatggcag cagggcaacg tgttctcctg 2160
ctccgtgatg cacgaggccc tgcacaatca ctacacccag aagtccctgt ctctgagtcc 2220
gggcaagtaa taggcgcgcc 2240
<210> 38
<211> 229
<212> PRT
<213> 人造序列
<220>
<223> 融合至RB69 FOLDON的同源三聚体CD137L
<400> 38
Met Glu Thr Asp Thr Leu Leu Val Phe Val Leu Leu Val Trp Val Pro
1 5 10 15
Ala Gly Asn Gly Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val
20 25 30
Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala
35 40 45
Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu
50 55 60
Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu
65 70 75 80
Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala
85 90 95
Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala
100 105 110
Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala
115 120 125
Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu
130 135 140
Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu
145 150 155 160
Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser
165 170 175
Ser Gly Ser Ser Gly Ser Ser Gly Ser Gly Tyr Ile Glu Asp Ala Pro
180 185 190
Ser Asp Gly Lys Phe Tyr Val Arg Lys Asp Gly Ala Trp Val Glu Leu
195 200 205
Pro Thr Ala Ser Gly Pro Ser Ser Ser Ser Ser Ser Ala Trp Ser His
210 215 220
Pro Gln Phe Glu Lys
225
<210> 39
<211> 481
<212> PRT
<213> 人造序列
<220>
<223> 单链CD137配体RBD (实例)
<400> 39
Gln Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
1 5 10 15
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
20 25 30
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
35 40 45
Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu
50 55 60
Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu
65 70 75 80
His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu
85 90 95
Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe
100 105 110
Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly
115 120 125
Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr
130 135 140
Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly
145 150 155 160
Asn Gly Ser Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln
165 170 175
Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly
180 185 190
Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr
195 200 205
Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln
210 215 220
Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser
225 230 235 240
Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala
245 250 255
Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn
260 265 270
Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln
275 280 285
Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp
290 295 300
Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser
305 310 315 320
Gly Ser Gly Asn Gly Ser Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
325 330 335
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
340 345 350
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
355 360 365
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
370 375 380
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
385 390 395 400
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
405 410 415
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
420 425 430
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
435 440 445
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
450 455 460
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
465 470 475 480
Val
<210> 40
<211> 475
<212> PRT
<213> 人造序列
<220>
<223> 单链CD137配体RBD (实例)
<400> 40
Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu Ile
1 5 10 15
Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val Ser
20 25 30
Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val Val
35 40 45
Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg Arg
50 55 60
Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His Leu
65 70 75 80
Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr Val
85 90 95
Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly Phe
100 105 110
Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val His
115 120 125
Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln Gly
130 135 140
Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn Gly
145 150 155 160
Ser Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu Leu
165 170 175
Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly Val
180 185 190
Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu Val
195 200 205
Val Ala Lys Ala Gly Val Tyr Tyr Val Phe Phe Gln Leu Glu Leu Arg
210 215 220
Arg Val Val Ala Gly Glu Gly Ser Gly Ser Val Ser Leu Ala Leu His
225 230 235 240
Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala Ala Ala Leu Ala Leu Thr
245 250 255
Val Asp Leu Pro Pro Ala Ser Ser Glu Ala Arg Asn Ser Ala Phe Gly
260 265 270
Phe Gln Gly Arg Leu Leu His Leu Ser Ala Gly Gln Arg Leu Gly Val
275 280 285
His Leu His Thr Glu Ala Arg Ala Arg His Ala Trp Gln Leu Thr Gln
290 295 300
Gly Ala Thr Val Leu Gly Leu Phe Arg Val Gly Ser Gly Ser Gly Asn
305 310 315 320
Gly Ser Arg Gln Gly Met Phe Ala Gln Leu Val Ala Gln Asn Val Leu
325 330 335
Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp Pro Gly Leu Ala Gly
340 345 350
Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu Asp Thr Lys Glu Leu
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355 360 365
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385 390 395 400
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Claims (24)
1.一种包括单链融合多肽的CD137受体激动剂蛋白,包括:
(i)第一可溶性CD137L结构域,
(ii)第一肽接头,
(iii)第二可溶性CD137L结构域,
(iv)第二肽接头,和
(v)第三可溶性CD137L结构域,以及
(vi)铰链接头,选自包括SEQ ID NO:16和19-24的组,以及
(vii)抗体Fc片段,其中所述抗体Fc片段(vii)由SEQ ID NO:13或14中所示的氨基酸序列或SEQ ID NO:13或14的氨基酸1-217组成。
2.根据权利要求1所述的CD137受体激动剂蛋白,其中,所述抗体Fc片段(vii)通过铰链接头(vi)融合至与第三CD137L结构域(v)的C末端端部。
3.根据权利要求1-2中任一项所述的CD137受体激动剂蛋白,其基本上是非聚集的。
4.根据权利要求1-3中任一项所述的CD137受体激动剂蛋白,其中,所述第二和/或第三可溶性CD137L结构域是任选地包括氨基酸序列突变的N末端缩短的结构域。
5.根据权利要求1-4中任一项所述的CD137受体激动剂蛋白,其中,所述可溶性CD137L结构域中的至少一个,特别是所述可溶性CD137L结构域(iii)和(v)中的至少一个,是具有起始于根据SEQ ID NO:1的人CD137L的氨基酸D86或R88或Q89或G90的N末端序列的可溶性CD137L结构域,以及其中D86或R88或Q89可以被中性氨基酸例如Ser或Gly替换。
6.根据权利要求5所述的CD137受体激动剂蛋白,其中,所述可溶性CD137L结构域中的至少一个,特别是所述可溶性CD137L结构域(iii)和(v)中的至少一个,是具有N末端序列的可溶性CD137L结构域,所述N末端序列选自
(a)D86–G90,以及
(b)(Gly/Ser)89–G90。
7.根据权利要求5或6所述的CD137受体激动剂蛋白,其中,可溶性CD137L结构域以根据SEQ ID NO:1的氨基酸E254结束和/或任选地包括在位置D86、L87、R88、Q89、D112、V118、A154、A174、A176、A188、T241处或在所述位置中的两个或更多个处的突变。
8.根据权利要求5-7中任一项所述的CD137受体激动剂蛋白,其中,至少所述可溶性CD137L结构域(iii)是以V240或T241或E243结束的C末端缩短的CD137L结构域
9.根据权利要求5-8中任一项所述的CD137受体激动剂蛋白,其中,所述可溶性CD137L结构域(i)、(iii)和(v)由根据SEQ ID NO:1的人CD137L的氨基酸89-240组成。
10.根据前述权利要求中任一项所述的CD137受体激动剂蛋白,其中,所述第一和所述第二肽接头(ii)和(iv)独立地具有3-8个氨基酸的长度,特别是3、4、5、6、7或8个氨基酸的长度,并且优选地是甘氨酸/丝氨酸接头,任选地包括可以糖基化的天冬酰胺残基。
11.根据权利要求10所述的CD137受体激动剂蛋白,其中,所述第一和所述第二肽接头(ii)和(iv)由根据SEQ ID NO:2的氨基酸序列组成。
12.根据前述权利要求中任一项所述的CD137受体激动剂蛋白,其另外包含N末端信号肽结构域,例如SEQ ID NO:17的N末端信号肽结构域,其可以包括蛋白酶切割位点,和/或其另外包括C末端元件,所述C末端元件可以包含和/或连接至识别/纯化结构域,例如根据SEQID NO:18的Strep标签。
13.根据前述权利要求中任一项所述的CD137受体激动剂蛋白,包括SEQ ID No:15和2535中任一者的氨基酸序列。
14.根据前述权利要求中任一项所述的CD137受体激动剂蛋白,包括两种多肽,每种多肽具有如SEQ ID NO:27、29、30、32、33、34或35中所示的氨基酸序列
15.根据权利要求14所述的CD137受体激动剂蛋白,其中,所述两种多肽通过在以下位置处形成的三个链间二硫键而共价连接:
a)SEQ ID No:27、29、30、32、35的位置484、490和493,
或
b)SEQ ID NO:30的位置489、490和493,或
c)SEQ ID NO:31的位置493、489和502,或
d)SEQ ID NO:33或34的位置487、493和496。
16.根据权利要求14或15所述的CD137受体激动剂蛋白,包括选自SEQ ID NO:27、29的N158和NN318;SEQ ID NO:30、31的N161和N324;SEQ ID NO:33或34的N159和N320,以及SEQID NO:35的N86、N158、N246、N318和N406的列表的一种或多种N糖基化的天冬酰胺残基。
17.根据前述权利要求中任一项所述的CD137受体激动剂蛋白,其中,所述一种或多种多肽进一步翻译后修饰。
18.根据权利要求17所述的CD137受体激动剂蛋白,其中,所述翻译后修饰包括N-末端谷氨酰胺至焦谷氨酸的修饰。
19.一种核酸分子,编码权利要求1-18中任一项所述的CD137受体激动剂蛋白,优选地与表达控制序列可操作性连接。
20.一种表达载体,包括权利要求19所述的核酸分子。
21.一种细胞或非人类生物,用权利要求19所述的核酸分子或权利要求20所述的载体转化或转染,其中,所述细胞是例如原核细胞或真核细胞,优选哺乳动物细胞,或更优选人细胞或中国仓鼠卵巢(CHO)细胞。
22.一种药物或诊断组合物,包括作为活性剂的权利要求1-19中任一项所述的CD137受体激动剂蛋白、权利要求19所述的核酸分子或权利要求20所述的载体。
23.根据权利要求22所述的药物或诊断组合物,还包括一种或多种药学上可接受的载体、稀释剂、赋形剂和/或佐剂。
24.根据权利要求22或23所述的药物组合物用于治疗,更具体地用于预防和/或治疗由CD137L功能障碍引起的、与CD137L功能障碍相关的和/或伴随CD137L功能障碍的疾患,特别是增殖性疾患,诸如肿瘤,例如实体肿瘤或淋巴肿瘤;传染病;炎性疾病;代谢性疾病;自身免疫性疾病,例如类风湿性和/或关节炎疾病;退行性疾病,例如神经退行性疾病,诸如多发性硬化;凋亡相关疾病或移植排斥。
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PCT/EP2016/075543 WO2017068183A1 (en) | 2015-10-23 | 2016-10-24 | Single-chain cd137-receptor agonist proteins |
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WO2019109238A1 (en) | 2017-12-05 | 2019-06-13 | Lyvgen Biopharma Co., Ltd. | Anti-cd137 antibodies and uses thereof |
KR20220008306A (ko) | 2019-05-10 | 2022-01-20 | 리브젠 바이오파마 코., 엘티디. | 인간화 항-cd137 항체 및 이의 용도 |
WO2021229103A2 (en) | 2020-05-15 | 2021-11-18 | Apogenix Ag | Multi-specific immune modulators |
KR102251580B1 (ko) * | 2020-08-14 | 2021-05-13 | 최상호 | 이중 보온관 접속용 레듀사 및 이를 이용한 시공방법 |
WO2023088889A1 (en) | 2021-11-16 | 2023-05-25 | Apogenix Ag | CD137 ligands |
WO2023088876A1 (en) | 2021-11-16 | 2023-05-25 | Apogenix Ag | Multi-specific immune modulators |
WO2024088404A1 (en) * | 2022-10-28 | 2024-05-02 | Fbd Biologics Limited | Engineered 4-1bbl variants and methods of use thereof |
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WO2017068183A1 (en) | 2017-04-27 |
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US20210246190A1 (en) | 2021-08-12 |
JP2019500850A (ja) | 2019-01-17 |
AU2016341400A1 (en) | 2018-05-10 |
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