CN109790210A - 包含重组人类cd38细胞外结构域的组合物、方法和/或试剂盒 - Google Patents
包含重组人类cd38细胞外结构域的组合物、方法和/或试剂盒 Download PDFInfo
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Abstract
结合抗CD38抗体的组合物,所述组合物包括干扰抗CD38抗体的结合活性的重组的可溶性形式的CD38的细胞外结构域和/或其片段的的特定序列。该组合物可被包括在用于生物监测研究和诊断测定的试剂盒中。该组合物可用于中和样品中的抗CD38抗体和/或用于为用抗CD38抗体治疗的患者选择合适的红细胞单元。
Description
描述
电子格式的序列表
本申请与经由EFS-Web作为ASCII文本文件的电子序列表一起提交。电子序列表以标题为SEQLISTCD38PCT.txt的文件提供,所述文件被创建并最后保存于2018年5月31日,大小为73,000个字节。电子序列表的信息通过引用以其整体被并入本文。
背景
领域
本公开内容涉及药物产品的领域。本公开内容的一些实施方案涉及包含在哺乳动物细胞和/或在细菌中表达的可溶性重组形式的CD38-细胞外结构域和/或其片段的组合物、方法和/或试剂盒。本公开内容还涉及包含寡聚化标签的融合蛋白和用于使用所述标签将重组融合蛋白寡聚化的方法。
相关技术描述
人类CD38跨膜蛋白在某些恶性骨髓瘤上高表达。抗CD38单克隆抗体用作治疗剂以杀伤多发性骨髓瘤和其他血液肿瘤。
概述
在一些实施方案中,提供了用于结合抗CD38抗体的组合物。在一些实施方案中,该组合物包含干扰抗CD38抗体的结合活性的重组的可溶性形式的CD38的细胞外结构域和/或其片段,其中重组的可溶性形式的CD38的细胞外结构域和/或其片段的序列选自由以下组成的组:SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、和SEQ ID NO:11、SEQ IDNO:12、SEQ ID NO:13、和SEQ ID NO:14。
在组合物的一些实施方案中,重组的可溶性形式的CD38的细胞外结构域和/或其片段的大小范围从约5个氨基酸至约300个氨基酸。
在组合物的一些实施方案中,该抗CD38抗体是针对人类CD38、非人类CD38、或其组合。
在组合物的一些实施方案中,该抗CD38抗体是单克隆的、多克隆的、或其组合。
在组合物的一些实施方案中,抗CD38抗体选自由Darzalex、isatuximab和MOR202组成的组。
在组合物的一些实施方案中,重组的可溶性形式的CD38的细胞外结构域和/或其片段在真核表达系统或原核表达系统中表达。
在组合物的一些实施方案中,重组的可溶性形式的CD38的细胞外结构域和/或其片段的浓度范围从约1mg/ml至约400mg/ml。
在一些实施方案中,提供了用于生物监测研究和诊断测定的试剂盒。在一些实施方案中,该试剂盒包含组合物、平板、和用于鉴定抗体存在的试剂,所述组合物包含干扰抗CD38抗体的结合活性的重组的可溶性形式的CD38的细胞外结构域和/或其片段,其中重组的可溶性形式的CD38的细胞外结构域和/或其片段的序列选自由以下组成的组:SEQ IDNO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ IDNO:13、和SEQ ID NO:14。
在试剂盒的一些实施方案中,试剂盒的平板和试剂被构造用于ELISA测定。
在试剂盒的一些实施方案中,试剂盒的平板和试剂是来自在本申请的申请日之前以商标销售的测定试剂盒的那些平板和试剂。
在一些实施方案中,提供了中和样品中的抗CD38抗体或阻断样品中的抗CD38抗体结合的方法。在一些实施方案中,中和抗CD38抗体或阻断抗CD38抗体结合的方法包括提供一定体积的包含抗CD38抗体的样品,和与足以中和样品中的抗CD38抗体的一定量的根据权利要求1所述的组合物一起孵育。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,样品选自由以下组成的组:血液、血浆和血清。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,抗CD38抗体选自由Darzalex、isatuximab和MOR202组成的组。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,样品的体积范围从约25μl至约250μl。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,组合物的体积范围从约0.5μl至约50μl。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,样品中抗CD38抗体的浓度范围从约0.005μg/ml至约2000μg/ml。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,组合物中所述重组的可溶性形式的CD38的细胞外结构域和/或其片段的浓度范围从约1mg/ml至约400mg/ml。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,重组的可溶性形式的CD38的细胞外结构域和/或其片段的中和效应范围从约70%至约100%。
在中和抗CD38抗体或阻断抗CD38抗体结合的方法的一些实施方案中,抗CD38抗体的结合活性选自由以下组成的组:干扰血液输注前测试、干扰血液相容性测试、和干扰抗体疗法。
在一些实施方案中,提供了用于为用抗CD38抗体治疗的患者选择合适的红细胞单元的方法。在一些实施方案中,选择合适的红细胞单元的方法包括从患者获得样品,所述样品为患者的血液或源自患者血液的样品,根据本文提供的中和样品中的抗CD38抗体或阻断抗CD38抗体结合的方法中和样品中的抗CD38抗体,测试样品与特定红细胞单元的相容性,并基于该测试选择与样品相容的红细胞单元。
在一些实施方案中,提供了用于在人类血浆、血清、和/或血液处理期间去除血浆、血清和/或血液中的抗CD38的方法。在一些实施方案中,用于去除抗CD38的方法包括将血浆、血清和/或血液暴露于包含干扰抗CD38抗体的结合活性的重组的可溶性形式的CD38的细胞外结构域和/或其片段的组合物,其中重组的可溶性形式的CD38的细胞外结构域和/或其片段的序列选自由以下组成的组:SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、和SEQ ID NO:14,其中重组的可溶性形式的CD38的细胞外结构域和/或其片段亲和力标签加标签。
在去除抗CD38的方法的一些实施方案中,处理包括选自以下组成的组的处理:血液透析、腹腔透析、血液过滤、血液透析过滤、血浆置换疗法和血浆取出法。
在去除抗CD38的方法的一些实施方案中,亲和力标签选自由以下组成的组:谷胱甘肽S-转移酶(GST)、小泛素样修饰物(SUMO)、AviTag、钙调蛋白-标签、聚谷氨酸标签、E-标签、FLAG-标签、HA-标签、His-标签、Myc-标签、NE-标签、S-标签、SBP-标签、Softag 1、Softag 3、Strep-标签、TC标签、V5标签、VSV-标签、Xpress标签、Isopeptag、SpyTag、SnoopTag、生物素羧基载体蛋白(BCCP)、谷胱甘肽-S-转移酶-标签、绿色荧光蛋白-标签、其他荧光蛋白标签、HaloTag、麦芽糖结合蛋白-标签、Nus-标签、硫氧还蛋白-标签、Fc-标签、设计的包含紊乱促进性氨基酸的固有地紊乱标签(Designed Intrinsically Disorderedtags containing disorder promoting amino acids)、Ty标签。
在一些实施方案中,提供了融合蛋白。在一些实施方案中,融合蛋白包含与寡聚化标签融合的重组多肽。在一些实施方案中,寡聚化标签包括免疫球蛋白Fc区域或其片段和polyHis结构域。
在融合蛋白的一些实施方案中,寡聚化标签能够形成更高阶的二聚体,高达2聚体的12聚体或6聚体,和可能更高程度的寡聚体。
在融合蛋白的一些实施方案中,polyHis结构域具有4至24个之间的组氨酸残基。
在融合蛋白的一些实施方案中,polyHis结构域具有6至10个之间的组氨酸残基。
在融合蛋白的一些实施方案中,polyHis结构域具有6、8或10个组氨酸残基。
在融合蛋白的一些实施方案中,免疫球蛋白Fc区域的序列是SEQ ID NO 15。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%同一性。
在融合蛋白的一些实施方案中,重组多肽和/或其片段的序列选自由SEQ ID NO1、SEQ ID NO 25、SEQ ID NO 26和SEQ ID NO 27组成的组。
在融合蛋白的一些实施方案中,融合蛋白和/或其片段的序列选自由SEQ ID NO:7、SEQ ID NO:12、SEQ ID NO 20或SEQ ID NO 21组成的组。
在一些实施方案中,提供了用于重组蛋白的寡聚化标签。在一些实施方案中,寡聚化标签包括免疫球蛋白Fc区域或其片段和polyHis结构域。
在用于重组蛋白的寡聚化标签的一些实施方案中,polyHis结构域具有4至24个之间的组氨酸残基。
在用于重组蛋白的寡聚化标签的一些实施方案中,polyHis结构域具有6至10个之间的组氨酸残基。
在用于重组蛋白的寡聚化标签的一些实施方案中,polyHis结构域具有6、8或10个组氨酸残基。
在用于重组蛋白的寡聚化标签的一些实施方案中,免疫球蛋白Fc区域的序列是SEQ ID NO 15。
在用于重组蛋白的寡聚化标签的一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%同一性。
在用于重组蛋白的寡聚化标签的一些实施方案中,寡聚化标签的序列选自由SEQID NO 5、SEQ ID NO 16、SEQ ID NO 17和SEQ ID NO 18组成的组。
在一些实施方案中,提供了用于将重组融合蛋白寡聚化的方法。在一些实施方案中,用于将重组融合蛋白寡聚化的方法包括以下步骤:
a)遗传融合编码根据本发明的寡聚化标签的核苷酸序列与编码多肽的核苷酸序列;
b)在宿主细胞中表达步骤a)所得的核苷酸序列;
c)纯化步骤b)获得的重组融合蛋白。
附图简述
图1显示编码重组CD38ecd-Fc-10H(SEQ ID NO:7)的合成设计的氨基酸的实施方案。
图2显示编码重组CD38ecd-10H(SEQ ID NO:8)的合成设计的氨基酸的实施方案。
图3显示编码重组10H-MBPt-CD38ecd(SEQ ID NO:9)的合成设计的氨基酸的实施方案。
图4显示编码重组10Ht-CD38ecd(SEQ ID NO:10)的合成设计的氨基酸的实施方案。
图5显示编码重组10H-MBPt-DARA表位(SEQ ID NO:11)的合成设计的氨基酸的实施方案。
图6显示CD38细胞外结构域(CD38ecd)(SEQ ID NO:1)的氨基酸序列的实施方案。
图7显示DARA表位(SEQ ID NO:2)的氨基酸序列的实施方案。
图8显示DARA表位(表位#1)(SEQ ID NO:3)的氨基酸序列的实施方案。
图9显示DARA表位(表位#2)(SEQ ID NO:4)的氨基酸序列的实施方案。
图10显示小鼠Fc-10H(SEQ ID NO:5)的氨基酸序列的实施方案。
图11显示10H-MBPt(SEQ ID NO:6)的氨基酸序列的实施方案。
图12描绘使用可选的支架的各种重组CD38蛋白的示意图。
图13显示在通过CD38ecd-Fc-10H抑制抗CD38后,低滴度抗D抗体的鉴定相关的数据。
图14显示在通过CD38ecd-Fc-10H抑制抗CD38后,几乎不可检测的意外抗体的鉴定相关的数据。
图15显示通过CD38ecd-Fc-10H或rhCD38抑制抗CD38相关的数据。
图16显示用CD38ecd-Fc-10H在不同温度和孵育时间预处理的等价功能性。
图17显示CD38ecd-Fc-10H和CD38ecd-flex-Fc-10H相比于CD38ecd-10H的更好功能性。
详细描述
重组人类CD38ecd
Daratumumab(DARA)是一种免疫球蛋白(Ig)G1k人类单克隆抗体(mAb),靶向在恶性骨髓瘤细胞上高表达的CD38跨膜蛋白(de Weers M,等Daratumumab,a noveltherapeutic human CD38monoclonal antibody,induces killing of multiple myelomaand other hematological tumors.J Immunol.2011Feb 1;186(3):1840-8;Lokhorst HM,等Targeting CD38with Daratumumab monotherapy in multiple myeloma.N Engl JMed.2015Sep24;373(13):1207-19),并用于人类疗法。在2016年,美国食品和药物管理局(FDA)批准DARA单一疗法用于治疗患有多发性骨髓瘤的先前接受过至少三种疗法方案的患者。
DARA已被报告干扰常规血液相容性测试(Chapuy CI等Resolving the DARAinterference with blood compatibility testing.Transfusion.2015Jun;55(6Pt 2):1545-54;Oostendorp M等When blood transfusion medicine becomes complicated dueto interference by monoclonal antibody therapy.Transfusion.2015Jun;55(6Pt 2):1555-62)。DARA特异性识别红细胞(RBC)细胞表面的内源CD38细胞外结构域,在某些体外诊断测试中引起假阳性反应。
来自DARA治疗的患者的血浆样品在间接抗球蛋白测试(IAT)如抗体检测(筛选)测试、抗体鉴定组和抗人球蛋白(AHG)交叉配型中始终引起阳性反应。在最后一次DARA输注后,患者血浆中的不规则抗体的检测被掩盖多达6个月。意外抗体/不规则抗体,如同种抗体和自身抗体,都是可能导致血液输注不相容的抗体。不规则的抗体最常见的是IgG型。这种干扰阻止了常规的输血前测试,并且使为DARA治疗的患者选择合适的RBC单元复杂化。除DARA外,其他两种CD38特异性抗体(isatuximab和MOR202)处于临床开发中,其他几种处于临床前开发中(van de Donk NW,等Monoclonal antibodies targeting CD38inhematological malignancies and beyond.Immunol Rev.2016Mar;270(1):95-112)。
为了克服这个问题,已经开发和报告了不同的解决方案。每个解决方案有其自身的优点和缺点,如表1所示(Chapuy C.I.等DARA-DTT Study Group*for the BESTCollaborative.International validation of a dithiothreitol(DTT)-based methodto resolve the daratumumab interference with blood compatibilitytesting.Transfusion.2016Dec;56(12):2964-2972)。
表1-目前的抗CD38干扰缓和方法的优点和缺点。
通过可溶性形式的CD38细胞外结构域和/或其片段(sCD38ecd,在本文也称为sCD38)的中和抗CD38是一种有吸引力的方法,因为它不损伤RBC表面上的任何表位,它可以中和任何抗CD38抗体,且其在常规实验室测试中的实施仅要求将患者的血液、血浆和/或血清样品与sCD38一起孵育。主要缺点是重组sCD38ecd的可能高成本。这个缺点是主观的,因为重组蛋白被广泛用于各种体外诊断(IVD),允许对于常规使用成本保持可承受。使用sCD38的另一个可能的缺点是使用sCD38溶液中和抗CD38时发生患者血液和/或血浆的稀释,这可能导致在随后的抗体筛选中和/或鉴定错过临床相关的不规则血型抗体。因此,希望有高度浓缩的sCD38可得,从而当在患者血液和/或血浆样品中中和抗CD38抗体时仅需要小体积的sCD38。
替代解决方案包括使用具有非常广泛和非特异性作用的化学变性剂来处理RBC。目前,用于消除DARA干扰的选择方法是DTT处理RBC引起CD38降低,使其不被DARA抗体识别。然而,这种处理也破坏了一些其他血型抗原,针对该其他血型抗原的抗体不再能够在相应细胞上检测和鉴定。例如,用还原剂二硫苏糖醇(DTT)处理试剂红细胞(Reagent Red BloodCells)试剂盒中的RBC并重做测试将有效地消除DARA与红细胞表面上CD38的结合。然而,DTT通过非特异性破坏二硫键灭活和破坏红细胞表面上的几种抗原,例如在血液分型和输血反应中重要的抗原的Kell系统。
与之相比,只要sCD38包含一个或更多个可以被抗CD38抗体结合的表位,sCD38就不会损伤RBC表面上的任何表位,并且可以中和任何抗CD38抗体。
本公开内容涉及包含重组人sCD38及其片段的组合物、方法和/或试剂盒。本公开内容还涉及包含在真核和/或原核表达系统中表达的重组人sCD38和其片段的组合物、方法和/或试剂盒。
在一些实施方案中,重组sCD38和/或其片段使用本领域已知的方法溶解。在一些实施方案中,本发明人开发了重组sCD38作为干扰DARA和/或正在开发的其他抗CD38治疗性抗体的阻断剂。因此,在一些实施方案中,本公开内容涉及干扰结合CD38的一种或更多种抗体的重组sCD38和/或其片段。在一些实施方案中,重组sCD38和/或其片段干扰结合CD38的一种或更多种多克隆抗体。在一些实施方案中,重组sCD38和/或其片段干扰结合CD38的一种或更多种单克隆抗体。在一些实施方案中,重组sCD38和/或其片段干扰结合CD38的一种或更多种多克隆和单克隆抗体。在一些实施方案中,重组sCD38和/或其片段干扰结合CD38的一种或更多种蛋白。
在一些实施方案中,本公开内容涉及干扰DARA结合的重组sCD38蛋白和/或其片段。在一些实施方案中,重组sCD38和/或其片段干扰isatuximab结合。在一些实施方案中,重组sCD38和/或其片段干扰MOR202结合。在一些实施方案中,重组sCD38和/或其片段干扰DARA、isatuximab或MOR202结合的一种或更多种。在一些实施方案中,sCD38和/或其片段是指人类CD38蛋白和/或其片段。在一些实施方案中,sCD38和/或其片段是指非人类CD38蛋白。CD38的非人类来源的非限制性实例包括犬、猫、兔、小鼠、豚鼠、猴、牛、绵羊、山羊、斑马等。
在一些实施方案中,CD38ecd(作为sCD38表达)如图6中公开的。在一些实施方案中,CD38ecd(作为sCD38表达)如SEQ ID NO:1中公开的。在一些实施方案中,CD38ecd是包含根据UniProt#P28907的氨基酸序列人类CD38的残基45至300(SEQ ID NO:1)的CD38蛋白的片段。在一些实施方案中,CD38ecd是当在细胞表面上自然表达时预测暴露于细胞表面的CD38蛋白质部分的片段。在一些实施方案中,CD38ecd是当在细胞表面上自然表达时CD38蛋白的推定的细胞外结构域。
在一些实施方案中,本公开内容涉及作为sCD38的CD38ecd(SEQ ID NO:1)的表达,其中CD38ecd(SEQ ID NO:1)是预测暴露于细胞表面的人CD38蛋白的部分。在一些实施方案中,本公开内容涉及作为sCD38的CD38ecd(SEQ ID NO:1)的片段的表达,其中CD38ecd(SEQID NO:1)是预测暴露于细胞表面的人CD38蛋白的部分。
本领域普通技术人员可以想到,重组CD38ecd或其片段可以使用本领域已知的一种或更多种表达系统来表达。非限制性实例包括细菌表达系统、和/或真核表达系统,包括但不限于昆虫细胞、酵母和哺乳动物细胞类型。
在一些实施方案中,表达系统是包含哺乳动物细胞、酵母细胞、昆虫细胞等的真核表达系统。在一些实施方案中,真核表达系统选自由CHO、HEK、BHK、NSO、Sp2/0、COS、C127、HT-10780、PER.C6、HeLa和/或Jurkat细胞组成的组。在一些实施方案中,与sCD38或其片段的表达有关的真核表达系统(例如,包含哺乳动物细胞)的非限制性优点包括用于被抗CD38抗体结合的sCD38或其片段的正确折叠、正确的翻译后修饰、适当的分选进入分泌通路隔室、适当的功能等。
在一些实施方案中,sCD38表达为如图1所示的包含免疫球蛋白IgG1Fc区域的融合蛋白(在本文称为CD38ecd-Fc-10H;SEQ ID NO:7)。在一些实施方案中,CD38ecd-Fc-10H是由合成设计的编码免疫球蛋白IgG1恒定区片段的核酸编码的重组蛋白。在一些实施方案中,CD38ecd-Fc-10H是由合成设计的编码免疫球蛋白IgG2恒定区片段的核酸编码的重组蛋白。在一些实施方案中,CD38ecd-Fc-10H是由合成设计的编码免疫球蛋白IgG3恒定区片段的核酸编码的重组蛋白。在一些实施方案中,CD38ecd-Fc-10H是由合成设计的编码免疫球蛋白IgG4恒定区片段的核酸编码的重组蛋白。在一些实施方案中,CD38ecd-Fc-10H是由合成设计的编码任何上述IgG同种型的恒定区和改变的铰链区的免疫球蛋白的片段的核酸编码的重组蛋白,从而表达单体Fc-融合蛋白。在一些实施方案中,CD38ecd-Fc-10H包含融合到SEQ ID NO:5(图10)的N-末端的CD38ecd,SEQ ID NO:5(图10)包含免疫球蛋白IgG恒定区的片段,该片段包含铰链区、CH2结构域和CH3结构域,CH3结构域在C-末端融合至10个组氨酸标签和终止密码子。在一些实施方案中,CD38ecd-Fc-10H在细胞表面上表达。在一些实施方案中,鼠IgG1恒定区改善表达的蛋白的表达、溶解度和稳定性的一个或更多个。在一些实施方案中,鼠IgG1恒定区改善细胞表面表达的蛋白的表达、溶解度和稳定性的一个或更多个。在一些实施方案中,His标签允许通过固定金属亲和层析(IMAC)纯化来纯化CD38ecd-Fc-10H。
如本文所用的,“核酸”可以是基于DNA的、基于RNA的或其组合。非限制性实例包括本领域公知的质粒、粘粒、相、病毒载体、腺病毒载体、微环、修饰的核酸、核酸类似物等。在一些实施方案中,核酸被设计用于在真核表达系统、原核表达系统或两者中有效表达蛋白质、肽或两者。还包括基于核酸的疫苗载体。非限制性实例包括DNA疫苗载体、RNA疫苗载体、基于病毒的疫苗载体(例如基于腺伴随病毒的疫苗载体)等。
不受任何理论的束缚,本领域认为,膜中CD38的天然状态是二聚体和/或四聚体(Bruzzone S等Dimeric and tetrameric forms of catalytically activetransmembrane CD38in transfected HeLa cells.FEBS Lett.1998Aug21;433(3):275-8)。在一些实施方案中,CD38ecd-Fc-10H表达为二聚蛋白。在一些实施方案中,二聚蛋白是CD38ecd-Fc-10H的同二聚体。在一些实施方案中,CD38ecd-Fc-10H可表达为包含多于两个拷贝的CD38ecd-Fc-10H的寡聚蛋白。在一些实施方案中,CD38ecd-Fc-10H表达为寡聚蛋白。在一些实施方案中,CD38ecd-Fc-10H表达为包含从两个拷贝的CD38ecd-Fc-10H至12个拷贝的CD38ecd-Fc-10H的寡聚蛋白。在一些实施方案中,His标签允许通过IMAC纯化来纯化CD38ecd-Fc-10H。
在一些实施方案中,sCD38表达为如图2所示的融合蛋白(在本文称为CD38ecd-10H;SEQ ID NO:8)。在一些实施方案中,CD38ecd-10H是由合成设计的编码带有His标签(即,包含10个组氨酸残基的标签)的CD38ecd的核酸编码的重组蛋白。在一些实施方案中,His标签允许通过IMAC纯化来纯化CD38ecd-10H。
在一些实施方案中,在溶液中、固体表面上或两者,寡聚CD38ecd-Fc-10H的活性优于单体CD38ecd-10H的活性。在一些实施方案中,“活性”是指sCD38中和抗CD38抗体的能力。在一些实施方案中,“活性”是指sCD38在固体表面上或溶液中或两者中和与抗CD38抗体相关的一种或更多种效应的能力。在一些实施方案中,“活性”的效力/效率范围为从约>70%至约100%。在一些实施方案中,“活性”的效力/效率为约70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%、或者由上述任何两个值所限定的范围内的值。在一些实施方案中,“活性”的效力/效率范围为从约>90%至100%。在一些实施方案中,“活性”的效力/效率为约>90%、91%、92%、93%、94%、95%、96%、97%、98%、98.5%、99%、99.5%或100%、或者由上述任何两个值所限定的范围内的值。
在一些实施方案中,sCD38在细菌表达系统中表达。在一些实施方案中,细菌表达系统的非限制性优点包括低成本但维持真核蛋白的功能性。在一些实施方案中,表达系统是细菌表达系统。在一些实施方案中,sCD38表达为如图3所示的融合蛋白(在本文称为10H-MBPt-CD38ecd;SEQ ID NO:9)。在一些实施方案中,10H-MBPt-CD38ecd是由合成设计的核酸编码的重组蛋白,该核酸编码的重组蛋白编码在其N-末端融合于10H-MBPt标签(SEQ IDNO:6;图11,或SEQ ID NO:19)的CD38ecd,该10H-MBPt标签包含10个组氨酸残基和完整的细菌麦芽糖结合蛋白(MBP)(Uniprot#P0AEX9;氨基酸残基29至393)。在一些实施方案中,10个组氨酸标签用于IMAC纯化。在一些实施方案中,MBP改善表达、溶解度或折叠的一个或更多个。
在一些实施方案中,10H-MBPt-CD38ecd包含烟草花叶病毒(TEV)蛋白酶裂解序列。在一些实施方案中,10H-MBPt-CD38ecd在MBP与CD38ecd之间包含TEV蛋白酶裂解序列(图3)。在一些实施方案中,MBP与CD38ecd之间的TEV蛋白酶裂解序列允许从CD38ecd裂解掉10H-MBP,产生无任何另外的序列的纯化的CD38ecd。
也设想了一个或更多个其他蛋白酶和非蛋白酶裂解位点。非限制性实例包括口蹄疫病毒(FMDV)蛋白酶、Arg-C蛋白酶、Asp-N内肽酶、BNPS-粪臭素、半胱天冬酶、胰凝乳蛋白酶-高特异性、胰凝乳蛋白酶-低特异性、梭菌蛋白酶(梭菌肽酶B)、CNBr、肠激酶、因子Xa、甲酸、谷氨酰内肽酶、粒酶B、羟胺、碘代苯甲酸、LysC、LysN、NTCB(2-硝基-5-硫氰基苯甲酸)、嗜中性粒细胞弹性蛋白酶、胃蛋白酶、脯氨酸内肽酶、蛋白酶K、葡萄球菌肽酶I、嗜热菌蛋白酶、凝血酶、胰蛋白酶和本领域普通技术人员已知的其他位点特异性酶。
在一些实施方案中,sCD38表达为如图4所示的融合蛋白(在本文称为10Ht-CD38ecd;SEQ ID NO:10)。在一些实施方案中,10Ht-CD38ecd是由合成设计的核酸编码的重组蛋白,该核酸编码的重组蛋白编码在其N-末端与包含10个组氨酸残基的标签融合的CD38ecd。在一些实施方案中,10个组氨酸标签用于IMAC纯化。在一些实施方案中,10H-CD38ecd包含烟草花叶病毒(TEV)蛋白酶裂解序列。在一些实施方案中,10H-CD38ecd在10H与CD38ecd之间包含TEV蛋白酶裂解序列(图4)。在一些实施方案中,10H与CD38ecd之间的TEV蛋白酶裂解序列允许从CD38ecd裂解掉10H,产生无任何另外的序列的纯化的CD38ecd。
在一些实施方案中,sCD38表达为如图5所示的融合蛋白(在本文称为10H-MBPt-DARA表位;SEQ ID NO:11)。在一些实施方案中,如图5所示的,10H-MBPt-DARA表位是由合成设计的核酸编码的重组蛋白,该合成设计的核酸编码包含在其N-末端融合于10个组氨酸标签和麦芽糖结合蛋白的人类CD38的氨基酸残基(Uniprot#P28907的残基230至280;如SEQID NO:2所示)。在一些实施方案中,两个DARA表位是DARA表位#1(Uniprot#P28907残基235至246;如SEQ ID NO:3所示的)和DARA表位#2(Uniprot#P28907残基267至280;如SEQ IDNO:4所示的)。
在一些实施方案中,sCD38的一个或更多个表位可以以为约10e-6(肽亲和力)至10e-10(非常强的抗体亲和力)的可测量的亲和力结合抗CD38抗体。
在一些实施方案中,10个组氨酸标签用于IMAC纯化。在一些实施方案中,10H-MBPt-DARA表位包含烟草花叶病毒(TEV)蛋白酶裂解序列。在一些实施方案中,10H-MBPt-DARA表位在MBP与DARA表位之间包含TEV蛋白酶裂解序列(图5)。在一些实施方案中,MBP与DARA表位之间的TEV蛋白酶裂解序列允许从DARA表位裂解掉10H-MBP,产生无任何另外的序列的纯化的DARA表位。在一些实施方案中,MBP改善表达、溶解度或折叠的一种或更多种。
在一些实施方案中,sCD38的片段是CD38ecd中的一个或更多个表位,它们被一个或更多个抗CD38多克隆和/或单克隆抗体结合。在一些实施方案中,sCD38和/或其片段的大小范围从约5个氨基酸至约300个氨基酸。在一些实施方案中,大小范围为从约10个至约150个氨基酸。在一些实施方案中,大小为约5、10、25、50、100、150、200、250、300或350个氨基酸、或者由上述任何两个值所限定的范围内的值。
也可以设想用于纯化、溶解、检测等的一个或更多个其他标签。非限制性实例包括GST、SUMO、AviTag、钙调蛋白-标签、聚谷氨酸标签、E-标签、FLAG-标签、HA-标签、His-标签、Myc-标签、NE-标签、S-标签、SBP-标签、Softag 1、Softag 3、Strep-标签、TC标签、V5标签、VSV-标签、Xpress标签、Isopeptag、SpyTag、SnoopTag、BCCP(生物素羧基载体蛋白)、谷胱甘肽-S-转移酶-标签、绿色荧光蛋白-标签、其他荧光蛋白标签、HaloTag、麦芽糖结合蛋白-标签、Nus-标签、硫氧还蛋白-标签、Fc-标签、设计的包含紊乱促进性氨基酸(例如P、E、S、T、A、Q、G)的固有地紊乱标签、Ty标签等。
本公开内容涉及包含本文所述的sCD38和/或其片段的任何一个或更多个实施方案及其变体的一种或更多种组合物、方法和/或试剂盒。
在一些实施方案中,包含sCD38和/或其片段的一种或更多种组合物、方法和/或试剂盒涉及通用的血液、血清和/或血浆预处理。在一些实施方案中,预处理缓和了通过本领域普通技术人员已知的一种或更多种技术检测和/或鉴定不规则抗体以及其他抗体的样品中抗CD38抗体的任何干扰。
在一些实施方案中,抗CD38抗体的干扰包括干扰血液相容性测试、干扰抗体疗法、红细胞的凝集、干扰血液输注前测试等的一种或更多种。
在一些实施方案中,预处理中和了任何抗CD38抗体以允许通过本领域普通技术人员已知的一种或更多种技术检测和/或鉴定样品中的不规则抗体以及其他抗体。本领域普通技术人员已知的一种或更多种技术的非限制性实例包括常规管测试、多卡、固相红细胞粘附测试、凝胶技术、用于检测/鉴定不规则抗体的任何其他当前或未来技术。
通过预处理缓和被抗CD38抗体干扰和/或中和抗CD38抗体允许检测和/或鉴定不规则抗体以及与相容性测试相关且重要的其他抗体。因此,在一些实施方案中,通过sCD38和/或其片段中和血浆、血液和/或血清样品中的抗CD38可以与诊断用途例如抗体筛选、不规则血型抗体的鉴定等组合。
在一些实施方案中,sCD38和/或其片段可用作不规则抗体以及其他抗体的血液筛选、血浆筛选、血清筛选或其组合的预处理试剂。在一些实施方案中,sCD38和/或其片段可用作生物监测研究和诊断测定中的抗原。例如,在一些实施方案中,sCD38和/或其片段可用在ELISA中以测试用生物疗法开处方以治疗慢性炎症疾病和其他适应症(例如多发性骨髓瘤)的患者中抗CD38抗体如DARA、isatuximab或MOR202的药物生物利用度和免疫原性。在一些实施方案中,sCD38可以用于家族的测试,以通过验证的ELISA测量药物水平和抗药物抗体水平二者。家族的测试小册子作为附录A附在此处。
在一些实施方案中,可以使用本领域普通技术人员已知的一种或更多种技术测试通过预处理缓和被抗CD38抗体干扰和/或中和抗CD38抗体的效力。例如,在一些实施方案中,本文提供的一种或更多种组合物可用于DG一种基于柱凝集技术的用于血型分型和意外抗体研究的独特8柱凝胶卡。因此,在一些实施方案中,本文提供的组合物可以用作DG卡中的试剂以测定抗CD38中和的效率。在一些实施方案中,效力范围为从约>70%至约100%。在一些实施方案中,效力为约70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%、或者由上述任何两个值所限定的范围内的值。在一些实施方案中,效力范围为从约>90%至100%。在一些实施方案中,效力为约>90%、91%、92%、93%、94%、95%、96%、97%、98%、98.5%、99%、99.5%或100%、或者由上述任何两个值所限定的范围内的值。在一些实施方案中,在DG卡中使用的包含sCD38的一种或更多种组合物的体积范围可以从约0.1μl至约40μl。在一些实施方案中,在DG卡中使用的包含sCD38的组合物的体积范围可以从约0.4μl至约10μl。在一些实施方案中,在DG卡中使用的包含sCD38的组合物的体积为约2μl。
在一些实施方案中,本文提供的组合物可用在阻断和/或中和患者血液、血清和/或血浆样品中的DARA、isatuximab或MOR202的一种或更多种的测定中。
在一些实施方案中,本文提供的组合物、方法和/或试剂盒可用在从患者血液、血清、和/或血浆样品去除一种或更多种抗CD38抗体的测定中。例如,可以将包含抗CD38抗体的患者样品与包含sCD38和/或其片段的组合物一起孵育,所述sCD38和/或其片段包含本文公开的一个或更多个标签,以允许加标签的sCD38和/或其片段结合抗CD38抗体。然后可以通过本领域普通技术人员已知的一种或更多种亲和层析技术去除sCD38-抗CD38复合物。
在一些实施方案中,加标签的sCD38和/或其片段可用于在血液透析、腹腔透析、血液过滤、血液透析过滤、血浆置换疗法、血浆取出法、血浆分离置换法和白细胞减少术期间去除人血浆、血清和/或血液中的抗CD38。例如,加标签的sCD38和/或其片段可用于去除患者血液、血清和/或血浆样品中的DARA、isatuximab或MOR202的一种或更多种。
在一些实施方案中,样品中抗CD38抗体的浓度范围从约0.005μg/ml至约2000μg/ml。在一些实施方案中,样品中抗CD38抗体的浓度范围从约0.05μg/ml至约1000μg/ml。在一些实施方案中,样品中抗CD38抗体的浓度范围从约0.05μg/ml至约500μg/ml。在一些实施方案中,样品中抗CD38抗体的浓度范围从约0.05μg/ml至约20μg/ml。在一些实施方案中,样品中抗CD38抗体的浓度范围从约0.05μg/ml至约100μg/ml。在一些实施方案中,样品范围中抗CD38抗体的浓度范围为约0.005、0.05、0.1、0.25、0.5、1、5、25、50、75、100、150、250、300、400、500、750、1000、1500或2000μg/ml、或者由上述任何两个值所限定的范围内的值。在其他实施方案中,样品中抗CD38抗体的浓度范围的范围从约0.05μg/ml至约2000μg/ml。
在一些实施方案中,在本文公开的方法和/或试剂盒中使用的包含sCD38和/或其片段的一种或更多种组合物的体积范围可以从约0.05μl至约50μl。在一些实施方案中,在本文公开的方法和/或试剂盒中使用的包含sCD38和/或其片段的一种或更多种组合物的体积范围可以从约0.25μl至约10μl。在一些实施方案中,在本文公开的方法和/或试剂盒中使用的包含sCD38的一种或更多种组合物的体积为约2μl。
在一些实施方案中,样品(例如血液、血浆、血清等)的体积范围可以从约1μl至约100μl。在一些实施方案中,样品(例如血液、血浆、血清等)的体积范围可以从约100μl至约5ml。在一些实施方案中,样品(例如血液、血浆、血清等)的体积范围可以从约5ml至约500ml。在一些实施方案中,样品(例如血液、血浆、血清等)的体积范围可以从约250ml至约10,000ml。在一些实施方案中,样品(例如血液、血浆、血清等)的体积范围可以从约25μl至约250μl。
在一些实施方案中,本文提供的组合物中sCD38和/或其片段的浓度范围从约0.25mg/ml至约400mg/ml。在一些实施方案中,本文提供的组合物和其试剂盒中的组合物中sCD38和/或其片段的浓度范围从约4mg/ml至约100mg/ml。在一些实施方案中,本文提供的组合物中sCD38和/或其片段的浓度是约0.25、0.5、1、2.5、5、7.5、10、15、20、25、30、50、75、100、125、150、175、200、225、250、275、300、325、350、375或400mg/ml、或者由上述任何两个值所限定的范围内的值。在一些实施方案中,本文提供的组合物中sCD38和/或其片段的浓度为约20mg/ml。
在一些实施方案中,用于最佳抑制抗CD38的sCD38和/或其片段的浓度范围从约1mg/ml至约500mg/ml。在一些实施方案中,用于最佳抑制抗CD38的sCD38和/或其片段的浓度范围从约5mg/ml至约100mg/ml。
在一些实施方案中,根据本公开内容的sCD38和/或其片段的实施方案的稳定性范围为在37℃从约30天至约300天。在一些实施方案中,sCD38和/或其片段的稳定性范围为在2至8℃约6个月至约48个月。
在一些实施方案中,本文公开的组合物可以以一个或更多个试剂盒的形式提供。
在一些实施方案中,组合物和其试剂盒中的组合物以液体、固体或半固体形式提供。非限制性实例包括胶囊、片剂、卵形物、插入物、薄片、颗粒剂、小药丸、珠剂、丸剂、小药囊、喷洒剂、薄膜剂、霜剂、凝胶、糖浆、可重构固体、悬浮剂、乳剂、锭剂、粉末剂、研磨剂、小片(platelet)等等。
在一些实施方案中,组合物和其试剂盒中的组合物包含活性成分、非活性成分、赋形剂、添加剂和/或药学上可接受的载体。非限制性实例包括聚合物化合物、无机盐、氨基酸(非限制性实例包括精氨酸、组氨酸、脯氨酸等)、粘合剂、润滑剂、崩解剂、表面活性剂、增稠剂、包衣剂、pH调节剂、抗氧化剂、调味剂、防腐剂、着色剂等。其他药学上可接受的载体的非限制性实例包括液体载体,例如水、醇、乳液,和固体载体,例如凝胶、粉末等。在一些实施方案中,组合物和其试剂盒中的组合物可以包含合适的盐和缓冲剂以使递送赋形剂稳定并允许被靶细胞吸收。
在一些实施方案中,药学上可接受的载体可包括一种或更多种溶剂、缓冲剂、溶液、分散介质、涂层、抗菌剂和抗真菌剂、金属螯合剂(例如EDTA)、等渗剂和吸收延迟剂等。
水性组合物和其试剂盒中的组合物包含溶解或分散在药学上可接受的载体或水性介质中的在递送媒介物(例如脂质体、纳米颗粒或其他复合物)中的有效量的sCD38和/或其片段(例如作为蛋白质、核酸或两者)。其他赋形剂包括水溶性聚合物、水不溶性聚合物、疏水性物质、亲水性物质、蜡、崩解剂、超级崩解剂、稀释剂、粘合剂等。
如本文所用,术语“受试者”或“患者”是指任何脊椎动物,包括但不限于人、非人灵长类、牛、绵羊、猪、山羊、马、犬、猫、小鼠、大鼠、豚鼠、鸡、火鸡、鸭、鹅。在一些实施方案中,受试者是哺乳动物。在一些实施方案中,受试者是人。在一些实施方案中,受试者是雄性或雌性。
用于融合蛋白的寡聚化标签
本公开内容还涉及包含寡聚化标签的融合蛋白和用于将重组融合蛋白寡聚化的方法。本公开内容还涉及用于重组融合蛋白的寡聚化标签,包括免疫球蛋白Fc区域或其片段和polyHis结构域。
融合蛋白可以任选地与寡聚化标签融合以形成寡聚体例如二聚体、三聚体、四聚体、五聚体和/或更高级寡聚体。寡聚化标签可以有利于特定的化学计量,例如二聚体、三聚体、四聚体或五聚体,或寡聚化标签可允许具有不同化学计量的寡聚物的分布。可以设计寡聚化标签以形成同型寡聚物,尽管同型寡聚物和异型寡聚物之间的区别并不特别限制。在一些实施方案中,寡聚化标签能够形成同型二聚体、同型三聚体、同型四聚体或同型五聚体,例如,其中重组多肽的寡聚化产生主要单分散寡聚物。寡聚化标签为测定中使用的融合蛋白提供了几个优点。寡聚化标签可以使重组多肽彼此相对定位。寡聚化标签也可增加重组多肽对靶的亲和力。寡聚化标签也可以增加重组多肽的亲合力,这是指以多个结合基团的亲和力的功能积累。
在一些实施方案中,融合蛋白包含与寡聚化标签融合的重组多肽。在一些实施方案中,重组多肽和/或其片段的序列选自由SEQ ID NO 1、SEQ ID NO 25、SEQ ID NO 26和SEQ ID NO 27组成的组。在一些实施方案中,寡聚化标签包括免疫球蛋白Fc区域或其片段和polyHis结构域。在一些实施方案中,融合蛋白和/或其片段的序列选自由SEQ ID NO:7、SEQ ID NO:12、SEQ ID NO 20和SEQ ID NO 21组成的组。
在一些实施方案中,polyHis结构域是与重组蛋白融合的纯化结构域。在一些实施方案中,polyHis结构域是与重组蛋白融合的亲和力标签。在一些实施方案中,polyHis结构域是与重组蛋白融合的寡聚化标签。在一些实施方案中,polyHis结构域与其他结构域一起被包含在寡聚化标签内。在一些实施方案中,polyHis结构域与免疫球蛋白Fc区域或其片段一起被包含在寡聚化标签内。根据本文的实施方案的polyHis结构域通常包含2至24个组氨酸残基。在一些实施方案中,polyHis结构域包含6个至12个组氨酸残基。根据本文的实施方案的polyHis结构域通常包含6、7、8、9、10、11或12个组氨酸残基。
在一些实施方案中,本文的融合蛋白与包含免疫球蛋白Fc区或其片段的寡聚化标签融合表达。在一些实施方案中,寡聚化标签包括免疫球蛋白Fc结构域铰链区的氨基酸序列。在一些实施方案中,本文的融合蛋白与包含免疫球蛋白Fc区或其片段的寡聚化标签融合表达。在一些实施方案中,寡聚化标签包括免疫球蛋白IgG1恒定区。在一些实施方案中,寡聚化标签包括免疫球蛋白IgG2恒定区。在一些实施方案中,寡聚化标签包括免疫球蛋白IgG3恒定区。在一些实施方案中,寡聚化标签包括免疫球蛋白IgG4恒定区。在一些实施方案中,寡聚化标签包含任何上述IgG同种型的恒定区和改变的铰链区的免疫球蛋白的片段,从而表达单体Fc-融合蛋白。在一些实施方案中,寡聚化标签包含免疫球蛋白IgG恒定区的片段,该片段包含铰链区、CH2结构域和CH3结构域,CH3结构域在C-末端融合至polyHis标签和终止密码子。
免疫球蛋白Fc结构域的种类可基于融合蛋白的期望用途来选择。例如,免疫球蛋白Fc结构域的种类可以选择为使得特定试剂在测定中靶向或忽略免疫球蛋白Fc结构域。例如,如果在测定中不使用抗小鼠二抗来检测其他小鼠抗体,则小鼠Fc结构域可以是有用的。类似地,使用抗小鼠抗体,小鼠Fc结构域可用于将融合蛋白交联至固体支持物或测定的其他组分。Fc结构域的种类可以是人、小鼠、兔、大鼠、仓鼠、豚鼠、山羊、绵羊、马、鸡或任何上述种类的嵌合体,尽管Fc结构域的种类没有特别限制。
示例性的寡聚化标签是包含铰链区的小鼠IgG Fc结构域,其允许包含寡聚化标签的重组多肽形成共价同二聚体。
在一些实施方案中,寡聚化标签的Fc区域的氨基酸序列是SEQ ID NO15。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%同一性。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有在90%和100%之间的同一性。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%、至少95%或至少98%同一性。
除了上述的寡聚化标签的益处之外,Fc结构域通常增加表达细胞中重组多肽的表达和/或分泌。
由于纯化包含Fc结构域的多肽的方法是公知的,Fc结构域也可以帮助重组多肽的纯化。
其他寡聚化标签在本领域中是已知的,并且寡聚化标签的具体选择没有特别限制。在一些实施方案中,本文的融合蛋白包含重组多肽和/或其片段。在一些实施方案中,重组多肽和/或其片段是可以与根据本发明的寡聚化标签融合的任何感兴趣的蛋白质。在一些实施方案中,重组多肽是重组的可溶性形式的CD38或其片段的细胞外结构域。在一些实施方案中,重组多肽是CD47或其片段的修饰的细胞外结构域。在一些实施方案中,重组多肽是血小板糖蛋白Ibα(GpIbα)或其片段的修饰的细胞外结构域。在一些实施方案中,重组多肽和/或其片段的序列选自由SEQ ID NO 1、SEQ ID NO 25、SEQ ID NO 26和SEQ ID NO 27组成的组。
在一些实施方案中,寡聚化标签的序列选自由SEQ ID NO 5、SEQ ID NO 16、SEQID NO 17和SEQ ID NO 18组成的组。
在一些实施方案中,寡聚化标签还包含具有选自由SEQ ID NO 28、SEQ ID NO 29和SEQ ID NO 30组成的组的序列的区域或结构域。
本公开内容还涉及用于将重组融合蛋白寡聚化的方法。在一些实施方案中,用于将重组融合蛋白寡聚化的方法包括以下步骤:a)遗传融合编码根据本公开内容的实施方案的寡聚化标签的核苷酸序列与编码多肽的核苷酸序列;b)在宿主细胞中表达步骤a)所得的核苷酸序列;c)纯化步骤b)获得的重组融合蛋白。
在一些实施方案中,在重组融合蛋白的寡聚化方法中使用的寡聚化标签包括免疫球蛋白Fc区域或其片段和polyHis结构域。在一些实施方案中,polyHis结构域包含2个至24个组氨酸残基。在一些实施方案中,polyHis结构域包含6个至12个组氨酸残基。根据本文的实施方案的polyHis结构域通常包含6、7、8、9、10、11或12个组氨酸残基。在一些实施方案中,用于将重组融合蛋白寡聚化的方法的寡聚化标签的Fc区域的氨基酸序列为SEQ ID NO15。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%同一性。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有在90%和100%之间的同一性。在一些实施方案中,免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%、至少95%或至少98%同一性。
在一些实施方案中,在重组融合蛋白的寡聚化方法中使用的寡聚化标签的序列选自由SEQ ID NO 5、SEQ ID NO 16、SEQ ID NO 17和SEQ ID NO 18组成的组。
在一些实施方案中,在重组融合蛋白的寡聚化方法中使用的寡聚化标签还包含具有选自由SEQ ID NO 28、SEQ ID NO 29和SEQ ID NO 30组成的组的序列的区域或结构域。
在一些实施方案中,本文公开的用于将重组融合蛋白寡聚化的方法的步骤c)中获得的重组融合蛋白的序列选自由SEQ ID NO:7、SEQ ID NO:12、SEQ ID NO 20和SEQ ID NO21组成的组。
实施例
以下实施例是非限制性的,并且本领域普通技术人员设想的其他变体被包括在本公开内容的范围内。
实施例1
构建了多种版本的CD38蛋白质,以试图再创建正确折叠的CD38ecd并阻止治疗性mAb引起不规则抗体测定的检测中的问题。一个版本是与亲和力标签(CD38ecd-10His)融合的单体细胞外结构域。第二种版本CD38ecd-Fc融合物,CD38ecd融合至鼠Fc区域(铰链-CH2-CH3),由此产生通过Fc区域保持在一起的二聚体版本(双联体)。在另一版本,CD38ecd-Fc-10H融合物中,CD38ecd融合至寡聚体标签,由此产生多聚体版本。在另一版本CD38ecd-Clath中,CD38ecd融合至网格蛋白结构域。网格蛋白结构域允许三聚化。另一个版本CD38ecd-p53涉及融合至p53结构域。已知p53结构域导致四聚化。在所有情况下,这些是新的自然界中不存在的组合物。将这些版本在哺乳动物细胞中表达以保留任何对维持CD38功能至关重要的翻译后修饰。
实施例2
重组CD38蛋白由几家公司出售用于研究用途。然而,商业上可得的CD38价格的数量和成本对于许多目的是令人望而生畏的。其他公司生产重组CD38的试图伴随着问题,包括溶解度问题,达到高浓度和通过支架的表位亲合力,并且这些商业上可得的CD38蛋白都没有如本文所提供的CD38蛋白和/或其片段的组成。
用本文描述的表达系统的初始测试显示,CD38ecd-Fc-10H是可溶的和功能性的。重要的是,重组CD38ecd-Fc-10H在高浓度(高达35mg/ml)是可溶的,允许在DG卡中使用少至2μl CD38ecd Fc的浓溶液。
实施例3-患者样品中的抗CD38滴度
本实验的目标是建立广泛地抑制和完全中和患者血浆样品中发现的未知浓度和滴度的抗CD38抗体所需的最低量的CD38ecd-Fc-10H蛋白,以便完全消除抗CD38抗体的效应。用抗CD38处理的三名患者的血浆在间接抗球蛋白试验(IAT)中用商业的用于抗体筛选的试剂红细胞(Reagent Red Blood Cell for Antibody Screening)进行滴定。实验如下进行:
血浆滴定:将每名患者的75μl含有抗CD38的血浆在PBS,pH 7.4中算术滴定至1:8192。
抗体筛选:将50μl的一种细胞(one cell)的Screen-Cyte 0.8%(Medion GrifolsDiagnostics,Duedingen,Switzerland)和25μl各自的血浆滴度移液进在DG Gel Coombs卡(Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。
建立的滴度范围在1:1和1:4096之间。结论是,为了用sCD38有效预处理患者血浆,必须中和至少1:2048,更好的是1:8192的抗CD38的滴度。
实施例4-sCD38抑制抗CD38抗体
实施例4a:使用包含2.2mg/ml CD38ecd-Fc-10H的制品抑制
样品制备(抑制测试):将25μl来自患者1的含有抗CD38的血浆,未稀释或在PBS,pH7.4中算术滴定,与2μl至32μl含有2.2mg/ml CD38ecd-Fc-10H的制品一起孵育并在37℃孵育15分钟。作为对照实验,将2μl至32μl PBS,pH 7.4代替CD38ecd-Fc-10H被移液至血浆。
抗体筛选:将50μl的Screen-Cyte 0.8%细胞#3,批次17005(Medion GrifolsDiagnostics,Duedingen,Switzerland)和25μl如以上预处理的血浆移液进DG Gel Coombs卡(批次17612.01exp 2018-02;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
用2μl的CD38ecd-Fc10H-20170313-NTAEPCPBS,可以完全抑制血浆的1:16稀释物。用32μl的2.2mg/ml CD38ecd-Fc10H-20170313-NTAEPCPBS,可以完全抑制稀释的血浆中的抗CD38。
实施例4b:使用包含35mg/ml CD38ecd-Fc-10H的制品抑制
样品制备(抑制测试):将25μl来自患者2的含有抗CD38的血浆(展示1:4096的抗CD38滴度)与2μl的35mg/ml CD38ecd-Fc-10H一起孵育并在37℃孵育15分钟。作为对照实验,将2μl PBS,pH 7.4代替CD38ecd-Fc-10H移液至血浆。
抗体筛选:将50μl的一种细胞的Screen-Cyte 0.8%,批次17017(Medion GrifolsDiagnostics,Duedingen,Switzerland)和25μl如以上预处理的血浆移液进DG Gel Coombs卡(批次16681.01exp 2017-11;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(细胞在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
用2μl的CD38ecd-Fc10H-20170915-PROTA,可以完全抑制来自患者2的血浆。
实施例4c:使用包含33mg/ml CD38ecd-Fc-10H的制品抑制模拟的DARA患者血浆(0.5mg/ml)
带有掺入的DARA的模拟患者血浆的产生:将抗CD38治疗药物(Darzalex)以0.5mg/ml的终浓度掺入人AB血浆中。
样品制备(抑制测试):将25μl模拟的DARA患者血浆与2μl的33mg/ml CD38ecd-Fc-10H一起孵育并在37℃孵育15分钟。作为对照实验,将2μl PBS,pH 7.4代替CD38ecd-Fc-10H移液至血浆。
抗体筛选:将50μl的每种细胞的Screen-Cyte 0.8%,批次180005(MedionGrifols Diagnostics,Duedingen,Switzerland)和25μl如以上预处理的模拟血浆移液进DG Gel Coombs卡(批次17133.01exp 2018-10;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(细胞在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
用2μl的CD38ecd-FC10H-GDS20171106,可以完全抑制掺入供体血浆的0.5mg/ml浓度。
实施例5-抗CD38被CD38ecd-Fc-10H的抑制是特异性的且不干扰根本的血型相关
的同种抗体
实施例5a:用2.2mg/ml CD38ecd-Fc-10H预处理后模拟DARA血浆中低滴度抗D的检测
将在Darzalex治疗下的患者的模拟血浆被掺入人多克隆抗D,其仅在用sCD38预处理后才变得能被商业筛选组检测到。在用PBS预处理的模拟掺入的血浆中,由于Darzalex干扰了抗体筛选程序,因此不可能正确地检测到抗D,因此导致来自筛选细胞与Darzalex的反应的抗体筛选测定的所有细胞中的阳性反应。
(1)药物滴定实验:使用抗CD38治疗药物(Darzalex;批次GHS0901,Janssen,USA)在人AB血浆中稀释后制备模拟患者血浆,其中人AB血浆掺有人抗D多克隆抗体。在人AB血浆中算术地滴定75μl抗CD38治疗药物(Darzalex)以产生模拟患者血浆。将50μl的Screen-Cyte 0.8%细胞#3,批次17005(Medion Grifols Diagnostics,Duedingen,Switzerland)和25μl的每种滴定度的Darzalex移液进DG Gel Coombs卡(批次17612.01exp 2018-02;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。该实验确定Darzalex中所含的抗CD38的滴度为1:64,000。
(2)抗D滴定:将高滴度抗D的供体血清在人AB血浆中算术滴定。将50μl的Screen-Cyte 0.8%细胞#1,批次17005(Medion Grifols Diagnostics,Duedingen,Switzerland)和25μl的每种滴定度的Darzalex移液进DG Gel Coombs卡(批次17612.01exp 2018-02;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。该实验确定供体血清中抗D的滴度对于细胞1为1:16,000。
(3)模拟的患者血浆:为了获得具有可被2μl的2.2mg/ml CD38ecd-Fc-10H抑制的抗CD38浓度和具有接近检测限值的抗D的模拟血浆,将抗D在人类AB血浆中的1:512的稀释物掺入Darzalex的1:16,000和1:8,000的稀释物中。在如以下(5)中提供的进行的抗体筛选中,模拟掺入的血浆与所有3种细胞阳性反应。另外,将100μl患者2的含抗CD38的血浆(TF1707/527)掺入抗D的1:4000稀释物。
(4)样品制备(抑制测试):将25μl如以上(1)至(3)所述制备的模拟掺入血浆分别与2μl或32μl的2.2mg/ml CD38ecd-Fc-10H(CD38ecd-Fc10H-20170313-NTAEPCPBS)一起孵育并在37℃孵育15分钟。作为对照实验,将2μl或32μl PBS,pH 7.4代替CD38ecd-Fc-10H移液至血浆。
(5)抗体筛选:将50μl的Screen-Cyte 0.8%细胞#1-3,批次17005(MedionGrifols Diagnostics,Duedingen,Switzerland)和25μl如以上预处理的血浆移液进DGGel Coombs卡(批次17612.01exp 2018-02;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(细胞在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
以2μl 2.2mg/ml CD38ecd-Fc10H-20170313-NTAEPCPBS,可以在抗体筛选组的D阴性细胞#3中完全抑制模拟的掺入血浆。以32μl CD38ecd-Fc10H-20170313-NTAEPCPBS,可以在抗体筛选组的Darzalex阴性细胞#3中完全抑制患者2的掺入血浆。抑制后细胞1和2保持阳性,表明,如(4)中进行的抑制测试对掺入的抗D抗体的反应性没有影响。用未掺入的模拟血浆(细胞#1-3的完全抑制)和使用PBS代替CD38ecd-Fc-10H的模拟血浆(完全无抑制)的对照实验显示了预期结果(图13)。
实施例5b:抗CD38被CD38ecd-Fc-10H的抑制允许抗CD38掺入的供体血浆中相关的意外抗体的检测
使用含有意外抗体的抗CD38掺入的供体血浆来评价CD38ecd-Fc-10H完全抑制抗CD38后对意外抗体的检测。只有在用CD38ecd-Fc-10H预处理后才能通过商业筛选板检测到抗-D、-E、-c、-Cw、-K、-Fya、-Jka、-S、-s、-M、-Lua、-Cob。
(1)生成模拟患者血浆:掺有抗CD38并掺有同种抗体的供体AB血浆:将抗CD38治疗药物(Darzalex)以0.5mg/ml的终浓度掺入人AB血浆中。将上面列出的每种同种抗体在人AB血浆中进行算术滴定:将50μl的Screen-Cyte 0.8%(对于每种抗体,基于产物抗原基质(matrix)选择对对应抗原阳性的组的细胞)和25μl测试的同种抗体的每种稀释物移液进DGGel Coombs卡(批次17133.01exp 2018-10;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。使用几乎检测不到阳性反应的最后一次稀释物作为稀释物,用于在抗CD38掺入的供体血浆中掺入意外抗体。
(2)样品制备(抑制测试):将25μl含有意外抗体的抗CD38掺入供体血浆与2μl33.4mg/mL CD38ecd-Fc-10H混合,并在37℃孵育15分钟。
(3)抗体筛选:将50μl的Screen-Cyte 0.8%细胞#1-3,批次17026或18003(MedionGrifols Diagnostics,Duedingen,Switzerland)和25μl预处理的模拟血浆移液进DG GelCoombs卡(批次17133.01exp 2018-10;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。
每25μl血浆2μl CD38ecd-Fc-10H(33.4mg/ml)的比率,允许检测以几乎不可检测的量掺入DARA掺入的供体血浆中的16/16潜在抗体(图14、表2)。抗体特异性包括抗-D、-E、-c、-Cw、-K、-Fya、-Jka、-S、-s、-M、-Lua、-Cob。
表2.DARA掺入的供体血浆中潜在抗体的检测
实施例6-CD38ecd-Fc-10H的稳定性投射(加速稳定性)
实施例6a:未稀释的抗CD38血浆的完全抑制
将五个等份的100μl CD38ecd-Fc-10H制剂CD38ecd-Fc10H-20170313-NTAEPCPBS等分在用螺帽封闭的单独的管中,并置于在恒温37℃的培养箱中。在开始孵育之前(即第0天)和第7、14、21和31天,将一个试管转移在2-8℃,直至第31天。在第31天,根据以下程序测试所有等份:
样品制备(抑制测试):将25μl患者1的未稀释的含有抗CD38的血浆(TF1715-197)与32μl的CD38ecd-Fc-10H一起孵育并在37℃孵育15分钟。作为对照实验,将32μl PBS,pH7.4代替CD38ecd-Fc-10H移液至血浆。可选地,仅将血浆在37℃孵育15分钟。
抗体筛选:将50μl的O型红细胞在DG Gel Sol(批次16015exp2018-04;DiagnosticGrifols,Barcelona,Spain)中的1%稀释物和25μl如以上预处理的血浆移液进DG GelCoombs卡(批次17612.01exp 2018-02;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。第0、7、14、21和31天的结果同样显示完全抑制,而对照实验显示反应评分为2,即无抑制。基于阿累尼乌斯曲线图,在37℃时CD38ecd-Fc-10H 31天的证明稳定性可以转化为在2至8℃储存时至少24个月的稳定性。
实施例6b:滴定的抗CD38血浆被2μl 2.2mg/ml CD38ecd-Fc-10H抑制
将五个等份的100μl CD38ecd-Fc-10H制剂CD38ecd-Fc10H-20170313-NTAEPCPBS等分在用螺帽封闭的单独的管中,并置于在恒温37℃的培养箱中。在开始孵育之前和第7、14、21和31天,将一个试管转移在2-8℃,直至第31天。在第31天,根据以下程序测试所有等份:在初步实验中确立25μl 1:8稀释的血浆可以用被2μl体积的CD38ecd-Fc-10H完全抑制后,将200μl患者1的含有抗CD38的血浆(TF1715-197)在PBS,pH 7.4(1:2、1:4、1:8、1:16)中进行算术滴定。
样品制备(抑制测试):将25μl患者1的含有抗CD38的血浆的各自滴定液TF1715-197)与2μl的2.2mg/ml CD38ecd-Fc-10H一起孵育并在37℃孵育15分钟。作为对照实验,将2μl PBS,pH 7.4代替CD38ecd-Fc-10H移液至血浆。
抗体筛选:将50μl的O型红细胞在DG Gel Sol(批次16015exp2018-04;DiagnosticGrifols,Barcelona,Spain)中的1%稀释物和25μl如以上预处理的血浆移液进DG GelCoombs卡(批次17612.01exp 2018-02;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。第0、7、14、21和31天的结果在滴度1:8同样显示完全抑制,而对照实验在整个滴度显示反应评分为2,即无抑制。基于阿累尼乌斯曲线图,在37℃时CD38ecd-Fc-10H 31天的证明稳定性可以转化为在2至8℃储存时至少24个月的稳定性。
实施例7–CD38ecd-Fc-10H vs重组人CD38(rhCD38)的功能性比较
带有掺入的DARA的模拟患者血浆的产生:将抗CD38治疗药物(Darzalex)以0.5mg/ml的终浓度掺入人AB血浆中。
样品制备(抑制测试):将25μl抗CD38掺入的供体血浆与2μl 33.4mg/mL CD38ecd-Fc10H或0.447mg/ml rhCD38(CD38-6H,R&D Systems,目录#2404-AC-010,批次PEH0417081,Minneapolis,USA)或与PBS,pH 7.4混合并在37℃孵育15分钟。
抗体筛选:将50μl的Screen-Cyte 0.8%细胞#1-3,批次18001(Medion GrifolsDiagnostics,Duedingen,Switzerland)和25μl预处理的模拟血浆移液进DG Gel Coombs卡(批次17108.01exp 2018-09;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
2μl的重组CD38ecd-Fc10H允许完全抑制0.5mg/ml抗CD38。与之相比,在相同的实验设置中使用的商业rhCD38不能抑制相同的抗CD38负荷(图15)。
实施例8–抗CD38被CD38ecd-Fc10H抑制的孵育时间和孵育温度的比较
样品制备(抑制测试):将抗CD38治疗药物(Darzalex;批次GHS0901,Janssen,USA)以2mg/ml的终浓度在BPS ph 7.4中稀释。将150μl这一溶液在PBS,pH 7.4中算术滴定至1:8。将25μl的每种抗CD38稀释液与2μl33.4mg/mL CD38ecd-Fc10H混合,并在37℃孵育15分钟、在室温孵育15分钟或在室温孵育30分钟。
抗体筛选:将50μl的Screen-Cyte 0.8%细胞#3,批次17025(Medion GrifolsDiagnostics,Duedingen,Switzerland)和25μl以上预处理的样品移液进DG Gel Coombs卡(批次17108.01exp 2018-09;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
用2μl CD38ecd-Fc10H,在所有三种预处理中可完全抑制样品的1:4稀释物(对应于0.5mg/ml抗CD38)(图16)。
实施例9–CD38ecd-Fc-10H对CD38ecd-flex-Fc-10H对CD38ecd-10H的活性比较
样品制备(抑制测试):将抗CD38治疗药物(Darzalex;批次GHS0901,Janssen,USA)以1mg/ml的终浓度在BPS ph 7.4中稀释。将150μl这一溶液在PBS,pH 7.4中算术滴定至1:8。将25μl的各抗CD38稀释液与2μl的~8.5mg/ml CD38ecd-Fc-10H或~8.5mg/ml CD38ecd-flex-Fc-10H或~5mg/ml CD38ecd-10H混合并在37℃孵育15分钟。
抗体筛选:将50μl的Screen-Cyte 0.8%细胞#3,批次18009(Medion GrifolsDiagnostics,Duedingen,Switzerland)和25μl以上预处理的样品移液进DG Gel Coombs卡(批次17133.01exp 2018-10;Diagnostic Grifols,Barcelona,Spain)中的微柱的孵育室中并在37℃孵育15分钟。然后将该卡在用于DG凝胶卡的离心机中离心并读取结果。完全阴性的结果(在微柱底部的扁平扣状细胞团)指示患者样品中存在的抗CD38的完全抑制。
用2μl的CD38ecd-Fc-10H和用2μl的CD38ecd-flex-Fc-10H,可以完全抑制样品的1:8稀释物(对应于0.125mg/ml抗CD38)。用2μl的CD38ecd-10H,不能完全抑制样品的1:8稀释物。仅样品的1:128稀释物(对应于0.008mg/ml抗CD38)(图17)可用2μl的CD38ecd-10H完全抑制。
实施例10–Fc-PolyHis融合蛋白的寡聚化
为了研究形成所得重组融合蛋白形成寡聚体的能力,将三种感兴趣的蛋白质CD38ecd、CD47ecd1和Gp1bα重组融合到不同版本的Fc-polyHis寡聚化标签上。
一个版本是融合到Fc-10His标签的重组sCD38蛋白。该蛋白被表达和纯化至50mg/ml,未检测到可见的聚集。在第二版本中,重组sCD38蛋白融合到flex-Fc-10His标签。在此融合蛋白版本中,Fc的铰链区被无半胱氨酸的柔性接头取代。在第三版本中,重组sCD38蛋白融合到Fc区域。在第四版本中,重组sCD38蛋白融合到10His标签。
为了将融合蛋白寡聚化的方法应用于其他感兴趣的蛋白,在一个版本的此类蛋白中,将寡聚化标签Fc-10His融合到CD47ecd1蛋白。不同版本的寡聚化标签也与Gp1bα蛋白融合。在第一版本中,重组Gp1bα蛋白融合到Fc-8His标签。在第二版本中,重组Gp1bα蛋白融合到6His标签。在第三版本中,重组Gp1bα蛋白融合到SBP-6H标签。在第四版本中,重组Gp1bα蛋白融合到p53-6His标签。标签Fc-10His和Flex-Fc-10His本身也用作对照。
将多个版本的融合蛋白在真核表达系统中表达和纯化。通过尺寸排阻层析动态光散射(SEC-MALS/DLS)测量溶液中蛋白质的质量(Mw)、流体动力学半径(Rh(w))和多分散性(Mw/Mn)(表3)。从测量质量(Mw)与理论质量(Th.Mw)之间的比率来计算寡聚化的程度。
对于sCD38融合蛋白,还使用CD38ecd-Fc-10H作为参考测试了如在(DARATUMUMAB)抑制IAT中的蛋白质滴定抗体的能力。
表3.重组融合蛋白的寡聚化程度
*小于9nm的分子的Rh(w)是不可靠的。
包含Fc区域和多聚-His结构域的特定组合(Fc-polyHis)的寡聚化标签触发在N-末端与其融合的至少3种感兴趣的蛋白质(sCD38、CD47ecd1和Gp1bα)的寡聚化(二聚体的至少12聚体或6聚体)。没有融合感兴趣的蛋白的Fc-10His标签本身也形成寡聚体。表3中显示的数据强烈表明,寡聚化是Fc-polyHis标签的固有性质,其与所使用的感兴趣的蛋白不相关。感兴趣的蛋白质的寡聚化不依赖于Fc的铰链区,因为与Flex-Fc-10His融合的蛋白质也显示寡聚化。仅包含polyHis标签、无Fc区域的蛋白质融合物不触发任何寡聚化,并且所获得的蛋白质如预期的是单体。包含寡聚化标签Fc-polyHis的所有蛋白融合物是高度单分散的,表明它们不是未折叠分子的聚集体。
最后,Fc-polyHis寡聚化标签向sCD38蛋白的融合增加了CD38ecd在滴定抗CD38中的亲合力。
虽然本公开内容在某些实施方案和实例的上下文中,但是本领域技术人员将理解,本公开内容超出具体公开的实施方案而延伸到其他替代实施方案和/或实施方案及其明显修改和等同物的使用。此外,尽管已经详细示出和描述了实施方案的几个变型,但是基于本公开内容,在本公开内容的范围内的其他修改对于本领域技术人员而言将是容易明显的。还设想的是,可以做出实施方案的具体特征和方面的各种组合或子组合,并且仍然落入本公开内容的范围内。应该理解的是,所公开的实施方案的各种特征和方面可以彼此组合或替代以形成本公开内容的不同模式或实施方案。因此,意图是本文公开的本公开内容的范围不应受上述具体公开的实施方案限制。
如本文使用的,章节标题仅用于组织目的,并且不被解释为以任何方式限制所描述的主题。出于任何目的,本申请中引用的所有文献和类似材料,包括但不限于专利、专利申请、文章、书籍、论文和互联网网页,均明确地通过引用以其整体并入。当并入的参考文献中的术语的定义表现为不同于本教导中提供的定义时,以本教导中提供的定义为准。应该理解的是,在本教导中讨论的温度、浓度、时间等之前存在暗示的“约”,使得轻微的和非实质性的偏差在本文的教导的范围内。
在本申请中,除非另有特别说明,单数的使用包括复数。此外,使用“包含(comprise)”、“包含(comprises)”、“包含(comprising)”、“含有(contain)”、“含有(contains)”、“含(containing)”、“包括(include)”、“包括(includes)”、“包括(including)”并非旨在限制。
除非内容另外清楚地规定,否则如本说明书和权利要求中使用的单数形式“一(a)”、“一(an)”和“所述(the)”包含复数指示物。
本公开内容中引用的所有参考文献通过引用以其整体并入本文。
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<110> 盖立复诊断解决方案公司
<120> 包含重组人类CD38细胞外结构域的组合物、方法和/或试剂盒
<130> 62543788
<150> 62/543788
<151> 2017-08-10
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Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys Gly Glu Phe Asn
500 505 510
Thr Ser Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp Arg Lys Asp Cys
515 520 525
Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr Val Ser Arg Arg Phe
530 535 540
Ala Glu Ala Ala Cys Asp Val Val His Val Met Leu Asn Gly Ser Arg
545 550 555 560
Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser Val Glu Val His
565 570 575
Asn Leu Gln Pro Glu Lys Val Gln Thr Leu Glu Ala Trp Val Ile His
580 585 590
Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp Pro Thr Ile Lys
595 600 605
Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln Phe Ser Cys Lys
610 615 620
Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val Lys Asn Pro Glu
625 630 635 640
Asp Ser Ser Cys Thr Ser Glu Ile
645
<210> 10
<211> 278
<212> PRT
<213> 合成的
<400> 10
Met His His His His His His His His His His Gly Ser Gly Glu Asn
1 5 10 15
Leu Tyr Phe Gln Gly Thr Arg Trp Arg Gln Gln Trp Ser Gly Pro Gly
20 25 30
Thr Thr Lys Arg Phe Pro Glu Thr Val Leu Ala Arg Cys Val Lys Tyr
35 40 45
Thr Glu Ile His Pro Glu Met Arg His Val Asp Cys Gln Ser Val Trp
50 55 60
Asp Ala Phe Lys Gly Ala Phe Ile Ser Lys His Pro Cys Asn Ile Thr
65 70 75 80
Glu Glu Asp Tyr Gln Pro Leu Met Lys Leu Gly Thr Gln Thr Val Pro
85 90 95
Cys Asn Lys Ile Leu Leu Trp Ser Arg Ile Lys Asp Leu Ala His Gln
100 105 110
Phe Thr Gln Val Gln Arg Asp Met Phe Thr Leu Glu Asp Thr Leu Leu
115 120 125
Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys Gly Glu Phe Asn Thr Ser
130 135 140
Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp Arg Lys Asp Cys Ser Asn
145 150 155 160
Asn Pro Val Ser Val Phe Trp Lys Thr Val Ser Arg Arg Phe Ala Glu
165 170 175
Ala Ala Cys Asp Val Val His Val Met Leu Asn Gly Ser Arg Ser Lys
180 185 190
Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser Val Glu Val His Asn Leu
195 200 205
Gln Pro Glu Lys Val Gln Thr Leu Glu Ala Trp Val Ile His Gly Gly
210 215 220
Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp Pro Thr Ile Lys Glu Leu
225 230 235 240
Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln Phe Ser Cys Lys Asn Ile
245 250 255
Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val Lys Asn Pro Glu Asp Ser
260 265 270
Ser Cys Thr Ser Glu Ile
275
<210> 11
<211> 443
<212> PRT
<213> 合成的
<400> 11
Met His His His His His His His His His His Gly Ser Lys Thr Glu
1 5 10 15
Glu Gly Lys Leu Val Ile Trp Ile Asn Gly Asp Lys Gly Tyr Asn Gly
20 25 30
Leu Ala Glu Val Gly Lys Lys Phe Glu Lys Asp Thr Gly Ile Lys Val
35 40 45
Thr Val Glu His Pro Asp Lys Leu Glu Glu Lys Phe Pro Gln Val Ala
50 55 60
Ala Thr Gly Asp Gly Pro Asp Ile Ile Phe Trp Ala His Asp Arg Phe
65 70 75 80
Gly Gly Tyr Ala Gln Ser Gly Leu Leu Ala Glu Ile Thr Pro Asp Lys
85 90 95
Ala Phe Gln Asp Lys Leu Tyr Pro Phe Thr Trp Asp Ala Val Arg Tyr
100 105 110
Asn Gly Lys Leu Ile Ala Tyr Pro Ile Ala Val Glu Ala Leu Ser Leu
115 120 125
Ile Tyr Asn Lys Asp Leu Leu Pro Asn Pro Pro Lys Thr Trp Glu Glu
130 135 140
Ile Pro Ala Leu Asp Lys Glu Leu Lys Ala Lys Gly Lys Ser Ala Leu
145 150 155 160
Met Phe Asn Leu Gln Glu Pro Tyr Phe Thr Trp Pro Leu Ile Ala Ala
165 170 175
Asp Gly Gly Tyr Ala Phe Lys Tyr Glu Asn Gly Lys Tyr Asp Ile Lys
180 185 190
Asp Val Gly Val Asp Asn Ala Gly Ala Lys Ala Gly Leu Thr Phe Leu
195 200 205
Val Asp Leu Ile Lys Asn Lys His Met Asn Ala Asp Thr Asp Tyr Ser
210 215 220
Ile Ala Glu Ala Ala Phe Asn Lys Gly Glu Thr Ala Met Thr Ile Asn
225 230 235 240
Gly Pro Trp Ala Trp Ser Asn Ile Asp Thr Ser Lys Val Asn Tyr Gly
245 250 255
Val Thr Val Leu Pro Thr Phe Lys Gly Gln Pro Ser Lys Pro Phe Val
260 265 270
Gly Val Leu Ser Ala Gly Ile Asn Ala Ala Ser Pro Asn Lys Glu Leu
275 280 285
Ala Lys Glu Phe Leu Glu Asn Tyr Leu Leu Thr Asp Glu Gly Leu Glu
290 295 300
Ala Val Asn Lys Asp Lys Pro Leu Gly Ala Val Ala Leu Lys Ser Tyr
305 310 315 320
Glu Glu Glu Leu Ala Lys Asp Pro Arg Ile Ala Ala Thr Met Glu Asn
325 330 335
Ala Gln Lys Gly Glu Ile Met Pro Asn Ile Pro Gln Met Ser Ala Phe
340 345 350
Trp Tyr Ala Val Arg Thr Ala Val Ile Asn Ala Ala Ser Gly Arg Gln
355 360 365
Thr Val Asp Glu Ala Leu Lys Asp Ala Gln Thr Asn Ser Ser Ser Gly
370 375 380
Glu Asn Leu Tyr Phe Gln Gly Thr Leu Gln Pro Glu Lys Val Gln Thr
385 390 395 400
Leu Glu Ala Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu
405 410 415
Cys Gln Asp Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg
420 425 430
Asn Ile Gln Phe Ser Cys Lys Asn Ile Tyr Arg
435 440
<210> 12
<211> 497
<212> PRT
<213> 合成的
<400> 12
Val Asp Arg Trp Arg Gln Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg
1 5 10 15
Phe Pro Glu Thr Val Leu Ala Arg Cys Val Lys Tyr Thr Glu Ile His
20 25 30
Pro Glu Met Arg His Val Asp Cys Gln Ser Val Trp Asp Ala Phe Lys
35 40 45
Gly Ala Phe Ile Ser Lys His Pro Cys Asn Ile Thr Glu Glu Asp Tyr
50 55 60
Gln Pro Leu Met Lys Leu Gly Thr Gln Thr Val Pro Cys Asn Lys Ile
65 70 75 80
Leu Leu Trp Ser Arg Ile Lys Asp Leu Ala His Gln Phe Thr Gln Val
85 90 95
Gln Arg Asp Met Phe Thr Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala
100 105 110
Asp Asp Leu Thr Trp Cys Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr
115 120 125
Gln Ser Cys Pro Asp Trp Arg Lys Asp Cys Ser Asn Asn Pro Val Ser
130 135 140
Val Phe Trp Lys Thr Val Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp
145 150 155 160
Val Val His Val Met Leu Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys
165 170 175
Asn Ser Thr Phe Gly Ser Val Glu Val His Asn Leu Gln Pro Glu Lys
180 185 190
Val Gln Thr Leu Glu Ala Trp Val Ile His Gly Gly Arg Glu Asp Ser
195 200 205
Arg Asp Leu Cys Gln Asp Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile
210 215 220
Ser Lys Arg Asn Ile Gln Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp
225 230 235 240
Lys Phe Leu Gln Cys Val Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser
245 250 255
Glu Ile Pro Pro Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
260 265 270
Ser Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys
275 280 285
Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val
290 295 300
Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp
305 310 315 320
Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe
325 330 335
Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp
340 345 350
Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe
355 360 365
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys
370 375 380
Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys
385 390 395 400
Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp
405 410 415
Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys
420 425 430
Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser
435 440 445
Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr
450 455 460
Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser
465 470 475 480
Leu Ser His Ser Pro Gly Ile His His His His His His His His His
485 490 495
His
<210> 13
<211> 488
<212> PRT
<213> 合成的
<400> 13
Val Asp Arg Trp Arg Gln Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg
1 5 10 15
Phe Pro Glu Thr Val Leu Ala Arg Cys Val Lys Tyr Thr Glu Ile His
20 25 30
Pro Glu Met Arg His Val Asp Cys Gln Ser Val Trp Asp Ala Phe Lys
35 40 45
Gly Ala Phe Ile Ser Lys His Pro Cys Asn Ile Thr Glu Glu Asp Tyr
50 55 60
Gln Pro Leu Met Lys Leu Gly Thr Gln Thr Val Pro Cys Asn Lys Ile
65 70 75 80
Leu Leu Trp Ser Arg Ile Lys Asp Leu Ala His Gln Phe Thr Gln Val
85 90 95
Gln Arg Asp Met Phe Thr Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala
100 105 110
Asp Asp Leu Thr Trp Cys Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr
115 120 125
Gln Ser Cys Pro Asp Trp Arg Lys Asp Cys Ser Asn Asn Pro Val Ser
130 135 140
Val Phe Trp Lys Thr Val Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp
145 150 155 160
Val Val His Val Met Leu Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys
165 170 175
Asn Ser Thr Phe Gly Ser Val Glu Val His Asn Leu Gln Pro Glu Lys
180 185 190
Val Gln Thr Leu Glu Ala Trp Val Ile His Gly Gly Arg Glu Asp Ser
195 200 205
Arg Asp Leu Cys Gln Asp Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile
210 215 220
Ser Lys Arg Asn Ile Gln Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp
225 230 235 240
Lys Phe Leu Gln Cys Val Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser
245 250 255
Glu Ile Pro Pro Gly Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile
260 265 270
Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro
275 280 285
Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val
290 295 300
Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val
305 310 315 320
Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln
325 330 335
Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln
340 345 350
Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala
355 360 365
Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro
370 375 380
Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala
385 390 395 400
Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu
405 410 415
Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr
420 425 430
Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr
435 440 445
Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe
450 455 460
Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys
465 470 475 480
Ser Leu Ser His Ser Pro Gly Ile
485
<210> 14
<211> 281
<212> PRT
<213> 合成的
<400> 14
Val Asp Arg Trp Arg Gln Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg
1 5 10 15
Phe Pro Glu Thr Val Leu Ala Arg Cys Val Lys Tyr Thr Glu Ile His
20 25 30
Pro Glu Met Arg His Val Asp Cys Gln Ser Val Trp Asp Ala Phe Lys
35 40 45
Gly Ala Phe Ile Ser Lys His Pro Cys Asn Ile Thr Glu Glu Asp Tyr
50 55 60
Gln Pro Leu Met Lys Leu Gly Thr Gln Thr Val Pro Cys Asn Lys Ile
65 70 75 80
Leu Leu Trp Ser Arg Ile Lys Asp Leu Ala His Gln Phe Thr Gln Val
85 90 95
Gln Arg Asp Met Phe Thr Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala
100 105 110
Asp Asp Leu Thr Trp Cys Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr
115 120 125
Gln Ser Cys Pro Asp Trp Arg Lys Asp Cys Ser Asn Asn Pro Val Ser
130 135 140
Val Phe Trp Lys Thr Val Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp
145 150 155 160
Val Val His Val Met Leu Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys
165 170 175
Asn Ser Thr Phe Gly Ser Val Glu Val His Asn Leu Gln Pro Glu Lys
180 185 190
Val Gln Thr Leu Glu Ala Trp Val Ile His Gly Gly Arg Glu Asp Ser
195 200 205
Arg Asp Leu Cys Gln Asp Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile
210 215 220
Ser Lys Arg Asn Ile Gln Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp
225 230 235 240
Lys Phe Leu Gln Cys Val Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser
245 250 255
Glu Ile Pro Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His
260 265 270
His His His His His His His His His
275 280
<210> 15
<211> 252
<212> PRT
<213> 合成的
<400> 15
Val Asp Arg Ser Arg Ile Arg Thr Ile Ser Ala Arg Leu Glu Tyr Thr
1 5 10 15
Arg Pro His Arg Ser Asp Leu Pro Gly Val Pro Arg Asp Cys Gly Cys
20 25 30
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
35 40 45
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
50 55 60
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
65 70 75 80
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
85 90 95
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
100 105 110
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
115 120 125
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
130 135 140
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
145 150 155 160
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
165 170 175
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
180 185 190
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
195 200 205
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
210 215 220
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
225 230 235 240
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Ile
245 250
<210> 16
<211> 262
<212> PRT
<213> 合成的
<400> 16
Val Asp Arg Ser Arg Ile Arg Thr Ile Ser Ala Arg Leu Glu Tyr Thr
1 5 10 15
Arg Pro His Arg Ser Asp Leu Pro Gly Val Pro Arg Asp Cys Gly Cys
20 25 30
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
35 40 45
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
50 55 60
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
65 70 75 80
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
85 90 95
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
100 105 110
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
115 120 125
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
130 135 140
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
145 150 155 160
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
165 170 175
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
180 185 190
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
195 200 205
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
210 215 220
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
225 230 235 240
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Ile His His His His
245 250 255
His His His His His His
260
<210> 17
<211> 261
<212> PRT
<213> 合成的
<400> 17
Val Asp Arg Ser Arg Ile Arg Thr Ile Ser Ala Arg Leu Glu Tyr Thr
1 5 10 15
Arg Pro His Arg Ser Asp Leu Pro Gly Gly Gly Gly Ser Gly Gly Gly
20 25 30
Ser Gly Gly Gly Ser Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro
35 40 45
Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr
50 55 60
Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser
65 70 75 80
Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg
85 90 95
Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile
100 105 110
Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn
115 120 125
Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
130 135 140
Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu
145 150 155 160
Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe
165 170 175
Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala
180 185 190
Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr
195 200 205
Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly
210 215 220
Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His
225 230 235 240
Thr Glu Lys Ser Leu Ser His Ser Pro Gly Ile His His His His His
245 250 255
His His His His His
260
<210> 18
<211> 236
<212> PRT
<213> 合成的
<400> 18
Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu
1 5 10 15
Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr
20 25 30
Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys
35 40 45
Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val
50 55 60
His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
65 70 75 80
Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val
115 120 125
Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser
130 135 140
Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu
145 150 155 160
Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro
165 170 175
Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val
180 185 190
Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu
195 200 205
His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser
210 215 220
Pro Gly Ile Gly His His His His His His His His
225 230 235
<210> 19
<211> 421
<212> PRT
<213> 合成的
<400> 19
Met His His His His His His His His His His Gly Ser Lys Thr Glu
1 5 10 15
Glu Gly Lys Leu Val Ile Trp Ile Asn Gly Asp Lys Gly Tyr Asn Gly
20 25 30
Leu Ala Glu Val Gly Lys Lys Phe Glu Lys Asp Thr Gly Ile Lys Val
35 40 45
Thr Val Glu His Pro Asp Lys Leu Glu Glu Lys Phe Pro Gln Val Ala
50 55 60
Ala Thr Gly Asp Gly Pro Asp Ile Ile Phe Trp Ala His Asp Arg Phe
65 70 75 80
Gly Gly Tyr Ala Gln Ser Gly Leu Leu Ala Glu Ile Thr Pro Asp Lys
85 90 95
Ala Phe Gln Asp Lys Leu Tyr Pro Phe Thr Trp Asp Ala Val Arg Tyr
100 105 110
Asn Gly Lys Leu Ile Ala Tyr Pro Ile Ala Val Glu Ala Leu Ser Leu
115 120 125
Ile Tyr Asn Lys Asp Leu Leu Pro Asn Pro Pro Lys Thr Trp Glu Glu
130 135 140
Ile Pro Ala Leu Asp Lys Glu Leu Lys Ala Lys Gly Lys Ser Ala Leu
145 150 155 160
Met Phe Asn Leu Gln Glu Pro Tyr Phe Thr Trp Pro Leu Ile Ala Ala
165 170 175
Asp Gly Gly Tyr Ala Phe Lys Tyr Glu Asn Gly Lys Tyr Asp Ile Lys
180 185 190
Asp Val Gly Val Asp Asn Ala Gly Ala Lys Ala Gly Leu Thr Phe Leu
195 200 205
Val Asp Leu Ile Lys Asn Lys His Met Asn Ala Asp Thr Asp Tyr Ser
210 215 220
Ile Ala Glu Ala Ala Phe Asn Lys Gly Glu Thr Ala Met Thr Ile Asn
225 230 235 240
Gly Pro Trp Ala Trp Ser Asn Ile Asp Thr Ser Lys Val Asn Tyr Gly
245 250 255
Val Thr Val Leu Pro Thr Phe Lys Gly Gln Pro Ser Lys Pro Phe Val
260 265 270
Gly Val Leu Ser Ala Gly Ile Asn Ala Ala Ser Pro Asn Lys Glu Leu
275 280 285
Ala Lys Glu Phe Leu Glu Asn Tyr Leu Leu Thr Asp Glu Gly Leu Glu
290 295 300
Ala Val Asn Lys Asp Lys Pro Leu Gly Ala Val Ala Leu Lys Ser Tyr
305 310 315 320
Glu Glu Glu Leu Ala Lys Asp Pro Arg Ile Ala Ala Thr Met Glu Asn
325 330 335
Ala Gln Lys Gly Glu Ile Met Pro Asn Ile Pro Gln Met Ser Ala Phe
340 345 350
Trp Tyr Ala Val Arg Thr Ala Val Ile Asn Ala Ala Ser Gly Arg Gln
355 360 365
Thr Val Asp Glu Ala Leu Lys Asp Ala Gln Thr Asn Ser Ser Ser Gly
370 375 380
Glu Asn Leu Tyr Phe Gln Gly Thr Gly Thr Ser Asn Ala Ser Arg Ser
385 390 395 400
Ala Gly Ser Thr Pro Gly Ser Ser Gly Arg Thr Ser Pro Ser Pro Ser
405 410 415
Leu Ser Leu Ile Ser
420
<210> 20
<211> 365
<212> PRT
<213> 合成的
<400> 20
Val Asp Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe
1 5 10 15
Cys Asn Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala
20 25 30
Gln Asn Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp
35 40 45
Ile Tyr Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp
50 55 60
Phe Ser Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala
65 70 75 80
Ser Leu Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr
85 90 95
Thr Cys Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu
100 105 110
Leu Lys Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Gly Pro Gly
115 120 125
Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu
130 135 140
Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr
145 150 155 160
Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys
165 170 175
Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val
180 185 190
His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
195 200 205
Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly
210 215 220
Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile
225 230 235 240
Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val
245 250 255
Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser
260 265 270
Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu
275 280 285
Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro
290 295 300
Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val
305 310 315 320
Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu
325 330 335
His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser
340 345 350
Pro Gly Ile His His His His His His His His His His
355 360 365
<210> 21
<211> 526
<212> PRT
<213> 合成的
<400> 21
His Pro Ile Cys Glu Val Ser Lys Val Ala Ser His Leu Glu Val Asn
1 5 10 15
Cys Asp Lys Arg Asn Leu Thr Ala Leu Pro Pro Asp Leu Pro Lys Asp
20 25 30
Thr Thr Ile Leu His Leu Ser Glu Asn Leu Leu Tyr Thr Phe Ser Leu
35 40 45
Ala Thr Leu Met Pro Tyr Thr Arg Leu Thr Gln Leu Asn Leu Asp Arg
50 55 60
Ser Glu Leu Thr Lys Leu Gln Val Asp Gly Thr Leu Pro Val Leu Gly
65 70 75 80
Thr Leu Asp Leu Ser His Asn Gln Leu Gln Ser Leu Pro Leu Leu Gly
85 90 95
Gln Thr Leu Pro Ala Leu Thr Val Leu Asp Val Ser Phe Asn Arg Leu
100 105 110
Thr Ser Leu Pro Leu Gly Ala Leu Arg Gly Leu Gly Glu Leu Gln Glu
115 120 125
Leu Tyr Leu Lys Gly Asn Glu Leu Lys Thr Leu Pro Pro Gly Leu Leu
130 135 140
Thr Pro Thr Pro Lys Leu Glu Lys Leu Ser Leu Ala Asn Asn Asn Leu
145 150 155 160
Thr Glu Leu Pro Ala Gly Leu Leu Asn Gly Leu Glu Asn Leu Asp Thr
165 170 175
Leu Leu Leu Gln Glu Asn Ser Leu Tyr Thr Ile Pro Lys Gly Phe Phe
180 185 190
Gly Ser His Leu Leu Pro Phe Ala Phe Leu His Gly Asn Pro Trp Leu
195 200 205
Cys Asn Cys Glu Ile Leu Tyr Phe Arg Arg Trp Leu Gln Asp Asn Ala
210 215 220
Glu Asn Val Tyr Val Trp Lys Gln Thr Val Asp Val Lys Ala Met Thr
225 230 235 240
Ser Asn Val Ala Ser Val Gln Cys Asp Asn Ser Asp Lys Phe Pro Val
245 250 255
Tyr Lys Tyr Pro Gly Lys Gly Cys Pro Thr Leu Gly Asp Glu Gly Asp
260 265 270
Thr Asp Leu Tyr Asp Tyr Tyr Pro Glu Glu Asp Thr Glu Gly Asp Lys
275 280 285
Val Arg Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val
290 295 300
Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val
305 310 315 320
Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile
325 330 335
Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val
340 345 350
Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser
355 360 365
Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu
370 375 380
Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala
385 390 395 400
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro
405 410 415
Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys
420 425 430
Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr
435 440 445
Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr
450 455 460
Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu
465 470 475 480
Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser
485 490 495
Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser
500 505 510
His Ser Pro Gly Ile Gly His His His His His His His His
515 520 525
<210> 22
<211> 334
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Claims (40)
1.一种用于结合抗CD38抗体的组合物,所述组合物包含干扰抗CD38抗体的结合活性的重组的可溶性形式的CD38的细胞外结构域和/或其片段,其中重组的可溶性形式的CD38的细胞外结构域和/或其片段的序列选自由以下组成的组:SEQ ID NO:7、SEQ ID NO:8、SEQID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、和SEQ ID NO:14。
2.根据权利要求1所述的组合物,所述重组的可溶性形式的CD38的细胞外结构域和/或其片段的大小范围从约5个氨基酸至约300个氨基酸。
3.根据权利要求1所述的组合物,其中所述抗CD38抗体是针对人类CD38、非人类CD38、或其组合。
4.根据权利要求1所述的组合物,其中所述抗CD38抗体是单克隆的、多克隆的、或其组合。
5.根据权利要求1所述的组合物,其中所述抗CD38抗体选自由Darzalex、isatuximab和MOR202组成的组。
6.根据权利要求1所述的组合物,其中所述重组的可溶性形式的CD38的细胞外结构域和/或其片段在真核表达系统或原核表达系统中表达。
7.根据权利要求1所述的组合物,其中所述重组的可溶性形式的CD38的细胞外结构域和/或其片段的浓度范围从约1mg/ml至约400mg/ml。
8.一种用于生物监测研究和诊断测定的试剂盒,包含根据权利要求1所述的组合物、平板、和用于鉴定抗体存在的试剂。
9.根据权利要求8所述的试剂盒,其中所述试剂盒的所述平板和所述试剂被构造用于ELISA测定。
10.根据权利要求9所述的试剂盒,其中所述试剂盒的所述平板和所述试剂是来自在本申请的申请日之前以商标销售的测定试剂盒的那些平板和试剂。
11.中和样品中的抗CD38抗体或阻断样品中的抗CD38抗体结合的方法,所述方法包括:
提供一定体积的包含所述抗CD38抗体的样品;和
与足以中和所述样品中的所述抗CD38抗体的一定体积的根据权利要求1所述的组合物一起孵育。
12.根据权利要求11所述的方法,其中所述样品选自由以下组成的组:血液、血浆和血清。
13.根据权利要求11所述的方法,其中所述抗CD38抗体选自由Darzalex、isatuximab和MOR202组成的组。
14.根据权利要求11所述的方法,其中所述样品的体积范围从约25μl至约250μl。
15.根据权利要求11所述的方法,其中所述组合物的体积范围从约0.5μl至约50μl。
16.根据权利要求11所述的方法,其中所述样品中所述抗CD38抗体的浓度范围从约0.005μg/ml至约2000μg/ml。
17.根据权利要求11所述的方法,其中所述组合物中所述重组的可溶性形式的CD38的细胞外结构域和/或其片段的浓度范围从约1mg/ml至约400mg/ml。
18.根据权利要求11所述的方法,其中所述重组的可溶性形式的CD38的细胞外结构域和/或其片段的中和效应范围从约70%至约100%。
19.根据权利要求11所述的方法,其中抗CD38抗体的结合活性选自由以下组成的组:干扰血液输注前测试、干扰血液相容性测试、和干扰抗体疗法。
20.用于为用抗CD38抗体治疗的患者选择合适的红细胞单元的方法,包括:
从所述患者获得样品,所述样品为所述患者的血液或源自所述患者血液的样品;
根据权利要求11所述的方法中和所述样品中的抗CD38抗体;
测试所述样品与特定红细胞单元的相容性;并
基于所述测试选择与所述样品相容的红细胞单元。
21.用于在人类血浆、血清、和/或血液处理期间去除所述血浆、血清和/或血液中的抗CD38的方法,包括将所述血浆、血清和/或血液暴露于权利要求1所述的组合物,其中所述重组的可溶性形式的CD38的细胞外结构域和/或其片段用亲和力标签加标签。
22.根据权利要求21所述的方法,其中所述处理包括选自以下组成的组的处理:血液透析、腹腔透析、血液过滤、血液透析过滤、血浆置换疗法和血浆取出法。
23.根据权利要求21所述的方法,其中所述亲和力标签选自由以下组成的组:谷胱甘肽S-转移酶(GST)、小泛素样修饰物(SUMO)、AviTag、钙调蛋白-标签、聚谷氨酸标签、E-标签、FLAG-标签、HA-标签、His-标签、Myc-标签、NE-标签、S-标签、SBP-标签、Softag 1、Softag3、Strep-标签、TC标签、V5标签、VSV-标签、Xpress标签、Isopeptag、SpyTag、SnoopTag、生物素羧基载体蛋白(BCCP)、谷胱甘肽-S-转移酶-标签、绿色荧光蛋白-标签、其他荧光蛋白标签、HaloTag、麦芽糖结合蛋白-标签、Nus-标签、硫氧还蛋白-标签、Fc-标签、设计的包含紊乱促进性氨基酸的固有地紊乱标签、Ty标签。
24.一种融合蛋白,包含与寡聚化标签融合的重组多肽,其中所述寡聚化标签包括免疫球蛋白Fc区域或其片段和polyHis结构域。
25.根据权利要求24所述的融合蛋白,其中所述寡聚化标签能够形成更高阶的二聚体,高达2聚体的12聚体或6聚体。
26.根据权利要求24所述的融合蛋白,其中所述polyHis结构域具有4至24个之间的组氨酸残基。
27.根据权利要求24所述的融合蛋白,其中所述polyHis结构域具有6至10个之间的组氨酸残基。
28.根据权利要求24所述的融合蛋白,其中所述polyHis结构域具有6、8或10个组氨酸残基。
29.根据权利要求24至28的任一项所述的融合蛋白,其中所述免疫球蛋白Fc区域的序列是SEQ ID NO 15。
30.根据权利要求24至28的任一项所述的融合蛋白,其中所述免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%同一性。
31.根据权利要求24至30的任一项所述的融合蛋白,其中所述重组多肽和/或其片段的序列选自由SEQ ID NO 1、SEQ ID NO 25、SEQ ID NO26和SEQ ID NO 27组成的组。
32.根据权利要求24至30的任一项所述的融合蛋白,其中所述融合蛋白和/或其片段的序列选自由SEQ ID NO:7、SEQ ID NO:12、SEQ ID NO20和SEQ ID NO 21组成的组。
33.一种用于重组融合蛋白的寡聚化标签,包括免疫球蛋白Fc区域或其片段和polyHis结构域。
34.根据权利要求33所述的寡聚化标签,其中所述polyHis结构域具有4至24个之间的组氨酸残基。
35.根据权利要求33所述的寡聚化标签,其中所述polyHis结构域具有6至10个之间的组氨酸残基。
36.根据权利要求33所述的寡聚化标签,其中所述polyHis结构域具有6、8或10个组氨酸残基。
37.根据权利要求33至36的任一项所述的寡聚化标签,其中所述免疫球蛋白Fc区域的序列是SEQ ID NO 15。
38.根据权利要求33至36的任一项所述的寡聚化标签,其中所述免疫球蛋白Fc区域的序列与SEQ ID NO 15具有至少90%同一性。
39.根据权利要求33所述的寡聚化标签,所述寡聚化标签的序列选自由SEQ ID NO 5、SEQ ID NO 16、SEQ ID NO 17和SEQ ID NO 18组成的组。
40.一种用于将重组融合蛋白寡聚化的方法,包括以下步骤:
a)遗传融合编码根据权利要求33至39的任一项的寡聚化标签的核苷酸序列与编码多肽的核苷酸序列;
b)在宿主细胞中表达步骤a)所得的核苷酸序列;
c)纯化步骤b)获得的重组融合蛋白。
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Cited By (5)
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CN112048019A (zh) * | 2019-06-06 | 2020-12-08 | 鲁南制药集团股份有限公司 | 抗人cd47单克隆抗体 |
CN112285361A (zh) * | 2020-09-27 | 2021-01-29 | 中国人民解放军空军军医大学 | 排除抗-cd38单克隆抗体药物对抗人球蛋白检测干扰的试剂 |
CN114917413A (zh) * | 2022-06-14 | 2022-08-19 | 健诺维(成都)生物科技有限公司 | 一种负载重组多肽的羊膜及其制备方法 |
CN117723749A (zh) * | 2024-02-07 | 2024-03-19 | 南昌大学 | 基于分子粘合剂的动态光散射免疫传感检测方法 |
CN117723749B (zh) * | 2024-02-07 | 2024-06-04 | 南昌大学 | 基于分子粘合剂的动态光散射免疫传感检测方法 |
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BR112020013419A8 (pt) * | 2018-02-20 | 2022-07-05 | Grifols Diagnostic Solutions Inc | Composição compreendendo proteína receptora de gplb¿lfa recombinante |
KR20230066404A (ko) * | 2020-09-10 | 2023-05-15 | 카시 파마슈티컬스, 인코포레이티드 | 혈액 스크리닝 방법 |
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CN112048019A (zh) * | 2019-06-06 | 2020-12-08 | 鲁南制药集团股份有限公司 | 抗人cd47单克隆抗体 |
CN112048019B (zh) * | 2019-06-06 | 2023-05-09 | 鲁南制药集团股份有限公司 | 抗人cd47单克隆抗体 |
CN112285361A (zh) * | 2020-09-27 | 2021-01-29 | 中国人民解放军空军军医大学 | 排除抗-cd38单克隆抗体药物对抗人球蛋白检测干扰的试剂 |
CN112285361B (zh) * | 2020-09-27 | 2023-12-05 | 中国人民解放军空军军医大学 | 排除抗-cd38单克隆抗体药物对抗人球蛋白检测干扰的试剂 |
CN114917413A (zh) * | 2022-06-14 | 2022-08-19 | 健诺维(成都)生物科技有限公司 | 一种负载重组多肽的羊膜及其制备方法 |
CN117723749A (zh) * | 2024-02-07 | 2024-03-19 | 南昌大学 | 基于分子粘合剂的动态光散射免疫传感检测方法 |
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