CN116710554A - 基因工程改造获得的分泌能力和凝血活性增强的人类八因子 - Google Patents
基因工程改造获得的分泌能力和凝血活性增强的人类八因子 Download PDFInfo
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Abstract
本发明提供了一种经过改造的人源凝血因子VIII(hFVIII)多肽,其中在hFVIII的A1结构域中包含至少两个被替代的氨基酸。该发明还提供了编码此hFVIII多肽的核酸片段,以及含有该核酸片段的表达载体或rAAV载体,以及使用改造的hFVIII多肽治疗血友病A患者的方法。
Description
申请相关的交叉引用
本申请是2022年2月11日提交的PCT申请号PCT/CN2022/075976的国家阶段申请,该申请要求取得对2021年11月25日提交的PCT申请号为PCT/CN2021/133004的专利申请的优先权,其各自的内容通过引用全部纳入本文。
背景技术
人类FⅧ因子是一种由位于X染色体上的F8基因编码的蛋白质,由2351个氨基酸组成。F8基因的缺陷导致它所编码的FⅧ蛋白的缺失或不足。A型血友病(Hemophilia A,HA)是一种由FⅧ蛋白缺乏引起的遗传性出血性疾病,包括因产生有缺陷的FⅧ、FⅧ分泌不足或缺失而导致凝血活性缺失、或因抑制剂对FⅧ的部分或全部抑制而引起的凝血活性不足。由于FⅧ的缺乏,A型血友病人的血液不能正常凝结而控制出血。
治疗HA的常见方法是替代疗法。浓缩的FⅧ因子被缓慢地滴入或注射到HA患者的静脉中。这些输液有助于替代患者体内缺失或低下的FⅧ。然而,这种替代疗法可能产生因注射或获得的FⅧ的抑制剂,导致这种替代疗法的失败。
发明摘要
本发明提供了工程化的人FVIII多肽、编码FVIII蛋白的核酸和表达FVIII蛋白的载体、含有FVIII的药物组合物,以及该药物的使用方法,以解决本领域的需求,例如A型血友病的治疗。
第一,本发明提供了一种工程化的人FVIII(hFVIII)多肽,其在hFVIII的A1结构域中包括至少两个替代的氨基酸。
在一些实施方案中,所述替代的氨基酸包括A1结构域中的L50和L152位点。
在一些实施方案中,所述替代的氨基酸包括A1结构域中的L50V和L152P。
在一些实施方案中,替代的氨基酸进一步包括A1结构域D20、G22、I61、D115、F129、G132、Q139和L159中的一个或多个。
在一些实施方案中,替代的氨基酸进一步包括A1结构域D20S、G22L、I61T、A115E、F129I、G132D、Q139E和L159F中的一个或多个。
在一些实施方案中,替代的氨基酸包括A1结构域中的D20S、L50V和L152P。
在一些实施方案中,替代的氨基酸包括A1结构域中D20S、G22L、L50V和L152P。
在一些实施方案中,工程化的hFVIII多肽包括SEQ ID NO:3、SEQ ID NO:4、SEQ IDNO:5或SEQ ID NO:6的氨基酸序列。
第二,本发明提供了一个游离的核酸片段,其编码本文公开的工程化hFVIII多肽。
第三,本发明提供了一种表达载体,其中包括了与启动子可操作地连接的本文公开的核酸片段。
第四,本发明提供了一种重组AAV(rAAV)载体,其中包括了与启动子可操作地连接的本文公开的核酸片段。
第五,本发明提供了一种药物组合物,其包括了本文公开的表达载体或本文公开的rAAV载体。
第六,本发明提供了一种治疗A型血友病的方法。该方法包括了给患者注射有效量的、本文公开的药物组合物。
本发明的以上信息、特征和优点将在以下描述和所附权利要求中得到更好的解释。
附图说明
本发明的创新点在所附的权利要求中作了详细阐述。通过参考以下详细描述以及附图中的内容,可以更好地理解本发明的特点和优点,该详细描述给出了说明性的实施方案,其中利用了本发明的原理。
图1是人类野生型FVIII和FVIII-SQ的示意图。
图2A-2C显示的是杂合FVIII的凝固时间结果。图2A是hHC与mHC的活性比较;图2B是hHC与dHC的活性比较;图2C是hHC与maHC的活性比较。
图3A显示,对人(human)和巨型蝙蝠(megabat)FVIII的A1和A2结构域进行组合和配对以构建杂交的FVIII,M1H2和H1M2。图3B显示了各种FVIII蛋白的凝血时间。
图4显示,重链中的A1结构域可以细分为D1和D2区域,A2结构域可以细分为D3和D4区域。
图5A显示的是巨型蝙蝠(megabat)FVIII的D1或D4结构域被人(human)相对应的结构取代以构建杂交的巨型蝙蝠FVIIIs:hD1和hD4。图5B显示了各种FVIII蛋白的凝血时间。
图6A是显示人(huamn)FVIII的D1-D4区域被巨型蝙蝠(megabat)FVIII中相对应的区域取代以构建杂交的人FVIIIs:mD1mD3、mD2、mD3和mD4的图。图6B显示了各种FVIII蛋白的凝血时间。
图7显示了人(human)和巨型蝙蝠(megabat)FVIII的D1区域的序列比对。
图8A是ELISA结果,显示V51L、T62I、E116D、I130F、D133G、E140Q、P153L和F160L 8个氨基酸的突变会导致FVIII蛋白表达水平降低。图8B是aPTT结果,显示V51L、T62I、E116D、I130F、D133G、E140Q、P153L和F160L这8个氨基酸的突变会导致凝血活性的降低。
图9显示了各种突变体FVIII的凝血活性。
具体实施方式
在上面的摘要部分和详细描述部分以及下面的权利要求中,提到了本发明的特定特征。应该注意的是,本说明书中对本发明的披露包括此类特定特征的所有可能的组合。例如,在本发明的特定方面或实施方案或特定权利要求的背景下公开了特定特征,该特征也可以在可能的范围内与本发明的其他方面和实施方案以及在本发明的一般情况下结合和/或使用。
治疗A型血友病的替代疗法可能产生注射或获得性的FVIII抑制剂,而导致替代疗法的失败。
治疗A型血友病的另一种方法是基于rAAV载体的基因疗法。rAAV载体可以在体内长期、稳定地表达目的基因以达到治疗的目的。F8的编码区长为7035bp,分为A1、A2、B、A3、C1、C2六个结构域(图1,下层图)。为了使rAAV载体能有效地包装到腺相关病毒(AAV)的外壳中,rAAV载体包括一个治疗基因的表达盒和两个ITR的,其大小约为5kb。
由于AAV包装能力的限制,全长F8编码区不能被完整的包装成AAV。为了解决这个问题,需要缩短F8基因的编码区。以前的研究表明,FVIII的B domain结构域(908aa)可以被SQ结构域(14aa)取代,同时保留FVIII的凝血活性。这种工程化的FVIII被称为FVIII-SQ,分为A1、A2、SQ、A3、C1和C2六个结构域。A1、A2和SQ结构域构成FVIII-SQ的重链,A3、C1、C2构成FVIII-SQ的轻链。编码FVIII-SQ的核苷酸为4371bp(图1,上图),因此它可以被完整的包装到AAV中。
然而,即使缩短后FVIII的表达元件约为5kb,A型血友病rAAV基因治疗的一个关键限制因素是FVIII的低效分泌,这可能是由于FVIII在内质网中的缓慢折叠过程造成的。为了弥补这一点,需要向A型血友病患者体内注射大量的rAAV载体以产生足够的、有活性的FVIII。而大量注射的rAAV载体可能会导致患者出现免疫反应等副作用。
由于FVIII是一种分泌蛋白,为了将所需的病毒载体剂量降低到可容忍的水平,一种策略是通过修改FVIII的氨基酸来增加rAAV载体产生的FVIII的分泌活性。分泌的FVIII越多,FVIII的凝血活性越高。研究发现,猪FVIII的分泌能力比人FVIII高10-100倍,猪FVIII的重链有利于提高FVIII的分泌能力(Identification of Porcine CoagulationFactor VIII Domains Responsible for High Level Expression via EnhancedSecretion.JBC,279,6546-6552)。因此,本申请的发明人提出了一种理论,但不受这种理论的约束,即人FVIII的重链可以被改造以增强其分泌能力,用于rAAV基因治疗。
第一,本发明提供了一种工程化的人FVIII(hFVIII)多肽,其在hFVIII的A1结构域中包括至少两个替代的氨基酸。
如本文所使用的,"工程化"是指通过操纵遗传物质、化学合成或使用其他方式将蛋白质从其野生型状态改变为另一种状态的修改。根据上下文,工程化的FVIII可被称为突变体FVIII、杂合FVIII或FVIII突变体。
如本文所用,“替代”或“替换”是指氨基酸的替换,即因DNA序列中的点突变而使蛋白质中的一个氨基酸变为另一个氨基酸。“替代的氨基酸”指的是新的氨基酸,它已经取代了现有的氨基酸。
如本文所使用的,“结构域”是指连续的氨基酸序列,其特点是与结构相关的结构域的内部氨基酸序列相同,并由凝血酶的蛋白裂解位点来定义。图1(下层图)显示了一个含有A1、A2、B、A3、C1和C2结构域的人类野生型FVIII。
为了确定A1结构域中负责增强分泌能力的较小区域的氨基酸序列,人FVIII的A1结构域被细分为D1和D2区域。
人D1区的氨基酸序列在SEQ ID NO:1中规定如下:
ATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFNTSVVYKKTLFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKE
在一些实施方案中,替代的氨基酸位点包括A1结构域中的L50和L152。这里,L50指的是在SEQ ID NO:1的第50位的亮氨酸(L)被其他未指定的氨基酸取代,而L152指的是在SEQ ID NO:1的第152位的亮氨酸(L)被其他未指定的氨基酸取代。
在一些实施方案中,替代的氨基酸包括A1结构域中的L50V和L152P。这里,L50V指的是在SEQ ID NO:1的第50位的亮氨酸(L)被缬氨酸(V)取代,而L152P指的是在SEQ ID NO:1的第152位的亮氨酸(L)被脯氨酸(P)取代。
在一些实施方案中,A1结构域中D20、G22、I61、A115、F129、G132、Q139和L159的一个或多个氨基酸被取代。
在一些实施方案中,D20、G22、I61、D115、F129、G132、Q139和L159的氨基酸分别替换为D20S、G22L、I61T、D115E、F129I、G132D、Q139E和L159F。
在一些实施方案中,替代的氨基酸包括D20S、L50V和L152P。
在一些实施方案中,所述替代的氨基酸包括D20S、G22L、L50V和L152P。
在一些实施方案中,工程化的hFVIII多肽包括SEQ ID NO:3、SEQ ID NO:4、SEQ IDNO:5或SEQ ID NO:6的氨基酸序列。
SEQ ID NO:3:
ATRRYYLGAVELSWDYMQSSLLELPVDARFPPRVPKSFPFNTSVVYKKTVFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPPCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLR
SEQ ID NO:4:
ATRRYYLGAVELSWDYMQSSLGELPVDARFPPRVPKSFPFNTSVVYKKTVFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPPCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLR
SEQ ID NO:5:
MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSSLLELPVDARFPPRVPKSFPFNTSVVYKKTVFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPPCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNPPVLKRHQREITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLY
SEQ ID NO:6:
MQIELSTCFFLCLLRFCFSATRRYYLGAVELSWDYMQSSLGELPVDARFPPRVPKSFPFNTSVVYKKTVFVEFTDHLFNIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYDDQTSQREKEDDKVFPGGSHTYVWQVLKENGPMASDPPCLTYSYLSHVDLVKDLNSGLIGALLVCREGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVNGYVNRSLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQTLLMDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSEMDVVRFDDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNGPQRIGRKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYPHGITDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSFVNMERDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPNPAGVQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGYTFKHKMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKNTGDYYEDSYEDISAYLLSKNNAIEPRSFSQNPPVLKRHQREITRTTLQSDQEEIDYDDTISVEMKKEDFDIYDEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNRAQSGSVPQFKKVVFQEFTDGSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASRPYSFYSSLISYEEDQRQGAEPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDVDLEKDVHSGLIGPLLVCHTNTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRAPCNIQMEDPTFKENYRFHAINGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMALYNLYPGVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDFQITASGQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSSLYISQFIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSIRSTLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGRSNAWRPQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLFFQNGKVKVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLY
第二,本发明提供了编码本文公开的工程化hFVIII多肽的游离的核酸片段。游离的核酸片段包括所有可能的核酸序列,它们编码本文所述的FVIII突变体。所有可能的核酸序列都考虑但不限于密码子的退化原则。
第三,本发明提供了一种表达载体,其中包括了与启动子可操作地连接的本文公开的核酸片段。
术语“可操作地连接”意思是表达编码序列所需的调控序列被置于DNA分子中适当的位置,以实现编码序列的表达。
第四,本发明提供了一种重组AAV(rAAV)载体,其中包括了与启动子可操作地连接的本文公开的核酸片段。
人类腺相关病毒(AAV)是一种非致病性的病毒,只有在与辅助病毒(通常是腺病毒或疱疹病毒)共感染的细胞中才能有效复制。该病毒的宿主范围很广,可以有效地感染各种物种的诸多细胞类型。然而,尚未有研究表明,AAV与人类或动物疾病有关联。
AAV通过一个硫酸肝素蛋白多糖受体与细胞结合。一旦附着,AAV进入细胞的过程取决于受体,即成纤维细胞生长因子受体或αvβ5整合素分子。在被感染的细胞中,AAV以单链DNA(ssDNA)的形式进入,进而被转化为双链转录模板。感染了AAV和辅助病毒的细胞在细胞裂解前会进行AAV的复制,这是由辅助病毒而不是AAV本身诱导的。辅助病毒编码的蛋白质或RNA转录物是转录调节器,参与DNA复制或改变细胞环境,以保证病毒高效的生产。
重组AAV(rAAV)载体通常是将病毒的编码序列替换成目的基因。这些载体已被证明在体外和体内的一些不同部位具有高效的表达和基因靶向性。研究表明,AAV在呼吸道、中枢神经***、骨骼肌、肝脏和眼睛的研究中是安全的,且可以稳定持续地表达。随着rAAV制剂滴度和纯度的提高,rAAV介导的转导的效率也在提高。
AAV基因组的反向末端重复序列(ITR),是合成rAAV载体所需的唯一顺式元件。两个ITRs序列加上目的基因以及表达元件组建成大小约为5kb的ssDNA载体基因组,并在AAVrep和cap基因和辅助病毒的存在下包装成AAV颗粒,并具有成熟的生产和纯化rAAV的方法和技术。
在rAAV载体中,编码本文所述的工程化FVIII的核酸片段小于5kb,该片段被***到含有两个ITRs的表达框中,以实现高效地包装AAV载体。
在表达载体或rAAV载体中,编码本文公开的工程因子FVIII的核酸序列与启动子可操作地连接。该启动子可以是但不限于组成型启动子、诱导型启动子、肝脏特异性启动子、肝细胞特异性启动子或合成启动子。
组成型启动子可以是但不限于单纯疱疹病毒(HSV)启动子、胸苷激酶(TK)启动子、劳斯肉瘤病毒(RSV)启动子、猿猴病毒40(SV40)启动子。小鼠乳腺肿瘤病毒(MMTV)启动子、腺病毒E1A启动子、巨细胞病毒(CMV)启动子、哺乳动物管家基因启动子、或β-肌动蛋白启动子。
诱导性启动子可以是但不限于细胞色素P450基因启动子、热休克蛋白基因启动子、金属硫蛋白基因启动子、激素诱导性基因启动子、***基因启动子或对四环素有反应的tetVP16启动子。
肝脏特异性启动子可以是但不限于白蛋白启动子、α-1-抗胰蛋白酶启动子,或乙肝病毒核心蛋白启动子。
合成启动子可以包括已知启动子的区域、调节元件、转录因子结合点、增强元件、抑制元件等。例如,一个合成启动子可以由天然启动子和来自转录因子的增强子的组合。为了达到目的核酸、蛋白质或多肽表达水平提高的目的,可以采用适合在目的宿主细胞中表达的任何一种启动子。
第五,本发明提供一种药物组合物,其包括本文公开的表达载体或本文公开的rAAV载体。
术语“药物组合物”是指本文公开的表达载体或本文公开的rAAV载体与其他化学成分,例如稀释剂或载体的混合物。药物组合物有利于靶向生物体组织。药物组合物一般会根据特定的预期给药途径进行调整。药物组合物适用于人类和/或兽医的应用。
本文所述的药物组合物可以给人类患者本身服用,或在药物组合物中与其他活性成分混合,如联合治疗,或载体、稀释剂、赋形剂或其组合。正确的配方取决于所选择的给药途径。
第六,本发明提供一种治疗A型血友病患者的方法。该方法包括向患者注射有效量的本发明公开的药物组合物。
术语“有效量”或“治疗有效量”是指组合物的数量,例如包括rAAV载体的组合物,该组合物在给需要的受试者注射时应保证能获得预期的活性。术语“治疗有效”指足以缓解本公开的方法所治疗疾病的表现、阻止其发展、缓解或减轻其至少一种症状。
本领域的技术人员认识到,即使病情没有完全根除或预防,但它或其症状和/或影响在受试者中得到部分改善或缓解,也可以认为是治疗性的“有效”。具备判断治疗A型血友病患者是否有效的方法和指标。
如本文所述,术语“treating”、“treatment”、“therapeutic”或“therapy”并不一定意味着完全治愈或消除疾病或病症。任何程度上疾病或病症得到了缓解,都可以被认为是治疗和/或疗法。此外,治疗可包括可能使病人的整体幸福感提升或恶化的行为。
其他成分可包括在所要求的组合物中,例如其他活性剂、防腐剂、缓冲剂、盐、药学上可接受的载体或其他药学上可接受的成分。
如本文所使用的,“溶剂”是指有利于将化合物导入细胞或组织的化合物。例如,在没有限制的情况下,二甲亚砜(DMSO)、乙醇(EtOH)或PEG400是常用的溶剂,有利于有机化合物被吸收到受试者的细胞或组织中。
定义
除非另有定义,本文使用的所有技术和科学术语与本领域普通技术人员通常理解的含义相同。如果这里的某个术语有多个定义,除非另有说明,否则以本节中的定义为准。
本文使用的术语仅用于描述特定情况,并不意味着是限制性的。如本文所使用的,单数形式“一”、“一个”和“一种”也包括复数形式,除非上下文明确指出。此外,在详细描述和/或权利要求中使用“包含”、“具有”、“含有”等术语的情况下,这些术语旨在说明类似于“包括”的术语具有包容性。
如本文所用,术语“个体”、“患者”或“受试者”可互换使用。这些术语都不要求或限于因医护人员(例如医生、注册护士、执业护士、医生助理、护理员或临终关怀人员)的身份(例如持续或间歇)为转移。
游离的:一个“游离的”生物成分(如核酸分子、蛋白质、病毒或细胞)从生物体细胞或组织中的其他生物成分中分离或者纯化出来,或生物体本身在自然中存在,如其他染色体和染色体外的DNA、RNA、蛋白质和细胞。“游离”的核酸分子和蛋白质包括那些通过标准纯化方法纯化的核酸分子和蛋白质。该术语还包括通过在宿主细胞中重组表达而制备的核酸分子和蛋白质,以及化学合成的核酸分子和蛋白质。
重组的:重组核酸分子是一种具有非自然存在序列的核酸分子。包括一个或多个碱基的替换、缺失或***,和/或具有由两个原本游离序列的片段经过人工重组而成的序列。这种人工重组可以通过化学合成来完成,或者更常见的是通过对游离的核酸片段进行人工编辑,例如通过基因工程技术。
术语“启动子区域”或“启动子”是指诱导/启动核酸(如基因)转录的DNA区域。启动子包括转录起始部位附近的必要核酸序列。通常情况下,启动子位于它们转录的基因附近。启动子还可选择包括远端增强子或抑制子元件,这些元件可位于离转录起始点多达几千个碱基对的地方。组织特异性启动子是指主要在单一类型的组织或细胞中诱导/启动转录的启动子。例如,肝脏特异性启动子是指在肝脏组织中指导/启动转录的效果远远高于其他组织类型的启动子。
增强子:通过增加启动子的活性而增加转录效率的核酸序列。
术语“载体”是指一个小的载体DNA分子,其中的DNA序列可以被***到宿主细胞中,在那里它将被复制。“表达载体”是一种专门的载体,它含有目的基因或核酸序列,并带有在宿主细胞中表达所需的必要调控元件。
术语“可操作连接”是指编码序列表达所需的调控序列被放置在DNA分子中的适当位置,以实现编码序列的表达。这个定义有时也适用于表达载体中编码序列和转录控制元件(如启动子、增强子和终止元件)的排列。这个定义有时也适用于第一和第二核酸分子产生的混合核酸分子序列的排列。
本文所用的术语“核苷酸”一般是指由碱基-糖-磷酸盐组合而成的分子。一个核苷酸可以包括合成核苷酸。一个核苷酸可以包括一个合成的核苷酸类似物。核苷酸可以是核酸序列(如脱氧核糖核酸(DNA)和核糖核酸(RNA))的单体单位。术语核苷酸可以包括三磷酸腺苷(ATP)、三磷酸尿苷(UTP)、三磷酸胞苷(CTP)、三磷酸鸟苷(GTP)和脱氧核苷三磷酸,如dATP、dCTP、dITP、dUTP、dGTP、dTTP或其衍生物。这样的衍生物可以包括,[αS]dATP、7-deaza-dGTP和7-deaza-dATP,以及具有核酸酶抗性的核苷酸衍生物。这里所用的术语核苷酸可以指二脱氧核苷三磷酸酯(ddNTPs)及其衍生物。二脱氧核苷三磷酸盐可以包括但不限于:ddATP、ddCTP、ddGTP、ddITP和ddTTP。一个核苷酸可以是未标记的,也可以通过相关技术对核苷酸加入可检测的标签,也可以用量子点进行标记。可检测的标签包括:放射性同位素、荧光标签、化学发光标签、生物发光标签和酶标签。核苷酸的荧光标签可以包括但不限于荧光素、5-羧基荧光素(FAM)、2,7-二甲氧基-4,5-二氯-6-羧基荧光素(JOE)、罗丹明、6-羧基罗丹明(R6G)、N,N,N',N'-四甲基-6-羧基罗丹明(TAMRA),6-羧基-X-罗丹明(ROX),4-(4'二甲基氨基苯基偶氮)苯甲酸(DABCYL),卡斯特蓝,俄勒冈绿,德州红,氰化物和5-(2'-氨基乙基)氨基萘-1-磺酸(EDANS)。荧光标记的核苷酸的具体例子可以包括[R6G]dUTP,[TAMRA]dUTP,[R110]dCTP,[R6G]dCTP,[TAMRA]dCTP,[JOE]ddATP,[R6G]ddATP,[FAM]ddCTP,[R110]ddCTP,[TAMRA]ddGTP,[ROX]ddTTP,[dR6G]ddATP,[dR110]ddCTP,[dTAMRA]ddGTP和[dROX]ddTTP(Perkin Elmer,Foster City,Calif);FluoroLinkDeoxyNucleotides,FluoroLink Cy3-dCTP,FluoroLink Cy5-dCTP,FluoroLink Fluor X-dCTP,FluoroLink Cy3-dUTP和FluoroLink Cy5-dUTP(Amersham,Arlington Heights,Ill);荧光素-15-dATP,荧光素-12-dUTP,四甲基罗丹明-6-dUTP,IR770-9-dATP,荧光素-12-ddUTP,荧光素-12-UTP和荧光素-15-2′-dATP(Boehringer Mannheim,Indianapolis,Ind.)。染色体标记的核苷酸有BODIPY-FL-14-UTP,BODIPY-FL-4-UTP,BODIPY-TMR-14-UTP,BODIPY-TMR-14-dUTP,BODIPY-TR-14-UTP,BODIPY-TR-14-dUTP,Cascade Blue-7-UTP,Cascade Blue-7-dUTP,荧光素-12-UTP,荧光素-12-dUTP,Oregon Green 488-5-dUTP,Rhodamine Green-5-UTP,Rhodamine Green-5-dUTP,tetramethylrhodamine-6-UTP,tetramethylrhodamine-6-dUTP,Texas Red-5-UTP,Texas Red-5-dUTP和Texas Red-12-dUTP(Molecular Probes,Eugene,Oreg)。核苷酸也可以通过化学修饰进行标记或标注。化学修饰的单一核苷酸可以是生物素-dNTP。一些非限制性的生物素化dNTPs的例子可以包括,生物素-dATP(例如生物-N6-ddATP和生物素-14-dATP),生物素-dCTP(例如生物素-11-dCTP和生物素-14-dCTP)和生物素-dUTP(例如生物素-11-dUTP,生物素-16-dUTP和生物素-20-dUTP)。
术语“多核苷酸”、“寡核苷酸”和“核酸”可互换使用,指核苷酸不同的聚合形式,包括脱氧核苷酸、核糖核苷酸、核苷酸类似物,形式上包括单链、双链或者多链形式。多核苷酸可以是外源性或内源性的。一个多核苷酸可以存在于细胞外,可以是一个基因或其片段,可以是DNA或者RNA,可以有任何三维结构,并具有已知或未知的功能。一个多核苷酸可以包括一个或多个类似物(例如,改变了骨架、糖或核碱基),对核苷酸结构的修饰可以在聚合物组装之前或之后。一些非限制性的类似物的例子包括5-溴尿嘧啶、肽核酸、异种核酸、吗啉、锁定核酸、乙二醇核酸、苏糖核酸、双脱氧核苷酸、虫草素、7-脱氮GTP、荧光剂(如罗丹明或荧光素与糖连接),含硫醇的核苷酸,生物素连接的核苷酸,荧光碱基类似物,CpG岛,甲基-7-鸟苷,甲基化的核苷酸,肌苷,硫尿苷,假尿苷,二氢尿苷,奎宁和维奥辛。多核苷酸的非限制性例子包括基因或基因片段的编码或非编码区域、由连锁分析定义的位点(locus)、外显子、内含子、信使RNA(mRNA)、转移RNA(tRNA)、核糖体RNA(rRNA)、短干扰RNA(siRNA)、短发夹RNA(shRNA)。小分子RNA(microRNAs)、核酶、cDNA、重组多核苷酸、支链多核苷酸、质粒、载体、任何序列的分离DNA、任何序列的分离RNA、无细胞多核苷酸(无细胞DNA(cfDNA)和无细胞RNA(cfRNA))、核酸探针和引物。非核苷酸成分嵌入在核苷酸序列中。
本文所用的术语“基因”是指参与编码RNA转录的核酸(如基因组DNA和cDNA)及其相应的核苷酸序列。本文中提到的基因组DNA的术语包括编码区、非编码区以及调控元件,以及5'和3'端。在一些使用中,该术语包括转录序列、5'和3'非翻译区(5'-UTR和3'-UTR)、外显子和内含子。在一些基因中,转录区包含编码多肽的“开放阅读框”。在该术语的某些用法中,“基因”仅包括编码多肽所需的编码序列(如“开放阅读框”或“编码区”)。在某些情况下,基因并不编码多肽,例如核糖体RNA基因(rRNA)和转移RNA(tRNA)基因。在某些情况下,术语“基因”不仅包括转录序列,而且还包括非转录区域,包括上游和下游调控区、增强子和启动子。基因可以指“内源性基因”或在生物体本身基因组中存在的基因,也可以指“外源性基因”或非机体本身存在的基因。外源性基因通常指不存在于宿主生物体中的基因,但它可以通过基因转导被引入宿主生物体内。外源性基因也可以指不在生物体基因组中存在的基因或者机体发生的核酸或多肽序列的改变,它包括突变、***和/或缺失(如非野生序列)。
cDNA(互补DNA)。cDNA是指从实验室细胞中提取的信使RNA通过反转录实验而获得的DNA。cDNA也可以包含非翻译区(UTRs),负责相应RNA分子中的翻译调控。
5'和/或3':核酸分子(如DNA和RNA)的方向分为“5'端”和“3'端”。单核苷酸通过3'端羟基与相邻戊糖环5'端磷酸残基发生酯化反应形成磷酸二酯键,从而形成多核苷酸。因此,当线性多核苷酸的5'端磷酸基团没有与单核苷酸戊糖环的3'端氧连接时,被称为5'端。当多核苷酸的3'端氧没有与另一个单核苷酸戊糖环的5'磷酸基团连接时,被称为3'端。尽管多核苷酸中戊糖环的5'磷酸基团与相邻的3'氧相连,内部的单个核酸也分为5'端和3'端。
在线性或环形核酸分子中,游离的内部基团被称为“上游”(5'端)或者“下游”(3'端)。就DNA而言,这一术语反映了转录是沿着DNA链的5'端到3'端方向进行的。指导相关基因转录的启动子和增强子元件通常位于编码区的5'端或上游。然而,即使增强子元件位于启动子元件和编码区的3'端,该元件也能发挥其作用。转录终止子和聚腺苷酸化(PolyA)信号位于编码区的3'端或下游。
转录因子(Transcription Factor,TF)。一种与特定DNA序列结合的蛋白质,调控遗传信息从DNA到RNA的转变(或转录)。TFs通过增强(作为激活剂)或抑制(作为抑制剂)RNA聚合酶(执行遗传信息从DNA到RNA转录的酶)对特定基因的招募,单独或与其他蛋白组合成复合物执行这一功能。TF与之结合的特定DNA序列被称为反应元件(Response Element,RE)或调控元件。其他术语包括顺式元件和顺式作用的转录调控元件。
本文所用的“相应的”核酸或氨基酸或二者之一的序列,是指存在于FVIII或其片段中的一个位点,其结构和/或功能与另一物种的FVIII分子中的一个位点相同,尽管二者核苷酸或氨基酸数量可能不完全相同。
对照:对照是指用作反应调查或实验结果的比较标准的个体或一组样品。在某些情况下,对照组被作为参考对象。
本文所使用的人类或动物FVIII的“亚基”是指FVIII蛋白的重链和轻链。FVIII的重链包含三个结构域,即A1、A2和B;FVIII的轻链也包含三个结构域,即A3、C1和C2。
本文所用的“FVIII缺乏症”包括因产生有缺陷的FVIII、FVIII缺乏或不产生、或因抑制剂对FVIII的部分或全部抑制而导致的凝血活性缺失。A型血友病是一种因X染色体上连锁基因的缺陷和它所编码的FVIII蛋白的缺失或不足而导致凝血功能障碍的疾病。
如本文所用,“稀释剂”是指药物组合物中缺乏药效但可能是药学上必要或理想的组成成分。例如,当药物因质量太小或者无法生产和/或施用时,稀释剂可用于增加有效药物的体积。稀释剂也可以是一种液体,用于溶解将通过注射、摄取或吸入给药的药物。本领域中常见的稀释剂形式是缓冲水溶液,包括但不限于模拟人类血液成分的磷酸盐缓冲液。
如本文所用,“赋形剂”是指添加到药物组合物中的惰性物质,以保证(但不限于)组合物的体积、一致性、稳定性、结合能力、润滑性、崩解能力等。“稀释剂”是赋形剂的一种。
本文使用的术语“treatment”和“treating”是指获得有效或预期结果的方法,包括但不限于有效性治疗和/或有效性预防。例如,治疗可以包括针对本文公开的***或细胞群。治疗性有效可指对一种或多种疾病、状况或症状的治疗性改善或影响。对于有效性预防,可将药物组合物用于有可能罹患特定疾病、状况或症状的受试者,或用于患有一种或多种疾病生理症状的受试者,即使该疾病、状况件或症状可能尚未表现出来。
如果被治疗的症状发生改变,就会出现“治疗效果”,改变可能是积极的或消极的。例如,“阳性效应”可使受试者中激活的T细胞数量增加;在另一个例子中,“阴性效应”可能对应于受试者体内肿瘤的数量或大小的减少。治疗中的“变化”,可以指病情至少有1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、25%、50%、75%或100%的变化。该变化可以基于个体治疗过程中病情严重程度改善的情况,或基于有和没有治疗的个体群体中病情改善程度的差异。同样的,本公开的方法可以衡量使受试者达到“治疗有效”效果的的细胞量。术语“治疗有效”的定义为“具有治疗效果”。
以下的举例说明是为了向本领域普通技术人员提供关于如何制造和使用本发明的完整展示和描述,而不是为了限制本发明人发明的范围,也不是为了表示以下实验是所有或唯一进行的实验。本文已努力确保所用数字的准确性(如数量、温度等),但应考虑到一些实验误差和偏差。除非另有说明,重量是指物体的重量,分子量是指重量平均分子量,温度是指摄氏度,压力是指大气压或接近大气压。
实例
方法和材料
质粒的构建
为了生产含有FVIII重链突变体的质粒,使用质粒pAAV-CB-FVIII-SQ作为载体。该质粒含有CB启动子和编码人类FVIII-SQ的FVIII基因,CB启动子是由巨细胞病毒增强子和人β肌动蛋白启动子组成,通过PCR扩增***重链突变位点,人和巨型蝙蝠的FVIII基因作为模板,由擎科生物技术公司合成引物。载体和目的基因片段用Not I-HF和Kpn I-HF(NEB)限制性内切酶进行酶切,然后用E.Z.N.A.凝胶提取试剂盒(Omega Bio-Tech)进行纯化,利用酶切出来的粘性末端将载体和目的基因连接产生具有各种重链突变体的质粒。
组织培养和转染
HEK293细胞在含有10%胎牛血清(Gibco)、100μg青霉素/mL和100U链霉素/mL的Dulbecco’s改良的Eagle’s培养基(Invitrogen)中培养。为了进行转染,将0.75ug的FVIII质粒与2.25μL的PolyJet(SignaGen实验室)进行混合,并根据制造商说明书的操作添加到12孔板的每个孔中。转染后6小时,将培养基换成含2%热灭活胎牛血清的Ham's F12培养基(Corning)。在更换培养基24小时后,收集上清培养基进行aPTT(Activated PartialThromboplastin Time,活化部分凝血活酶时间)和ELISA(Enzyme Linked ImmunosorbentAssay,酶联免疫吸附测定)检测。
aPTT
在体外检测中,标准品为Refacto(Genetics Institute,Cambridge,MA)用培养基从1U/mL(200ng/mL)按1/2对半稀释至1/512;检测样品为从转染的哺乳动物细胞中收集的上清培养基在13,000rpm下离心1分钟中所得。将STA-PTT试剂、FVIII缺陷血浆和样品(或稀释后的标准品)各50μL在STAGO血凝杯中混合,37℃下孵育170秒,然后启动记录凝固时间,同时加入50μL 25mM的CaCl2来测量,根据标准曲线求得FVIII的活性。
ELISA
Refacto作为标准品,用培养基从1U/mL(200ng/mL)按1/2对半稀释至1/512。如上所述,转染质粒后的上清培养基作为样品。小鼠血浆样品在HEPES缓冲液中以1:10的稀释比例进行稀释。捕获抗体(PAH-FVIII-S,7.1mg/mL,1:2000)用包被液(0.1M碳酸氢钠和碳酸盐,pH9.6)稀释,然后包被在96孔板中,4℃过夜孵育;3%的BSA封闭液进行封闭,封闭液用PBST缓冲液(140mM NaCl,2.5mM KCl,8mM Na2HPO4,2mM KH2PO4和0.05%Tween 20,pH 8.4)稀释,在室温下孵育1小时;用PBST缓冲液洗三次后,加入100μL的标准品和样品,在室温下孵育1小时;PBST缓冲液洗板三次,加入检测抗体(GMA-8021-HRP,1:200),室温下孵育1小时,用PBST缓冲液洗三次;使用1x SureBlue TMB单组分微孔过氧化物酶底物进行显色,显色在室温下进行1-10分钟,加入0.5M H2SO4终止。用分光光度计在450nm和630nm处分别测定OD值,根据标准曲线计算FVIII的蛋白含量。
实例1,巨型蝙蝠FVIII重链A1结构域中具有增强分泌能力的结构的确定
有研究表明,猪FVIII的分泌能力比人FVIII高10-100倍,猪FVIII的重链有利于分泌能力的提高(Identification of Porcine Coagulation Factor VIII DomainsResponsible for High Level Expression via Enhanced Secretion.JBC,279,6546-6552)。本发明人假设其他动物的FVIII也有可能具有增强分泌的能力,并设计了实验来确定增强分泌能力的重链区域。
为此,对各种动物的F8基因核苷酸序列进行了排列。选择猴子、巨型蝙蝠和海豚的FVIIIs是因为猴子是在陆地上跳跃的,巨型蝙蝠是在天上飞的,海豚是在水中游动的动物。将这些动物的FVIII重链序列与人的FVIII轻链序列进行杂合,形成杂交的FVIII分子,然后将含有这些杂交FVIII分子的质粒分别转染到细胞中。转染后24小时,收集上清培养基进行aPTT检测,以测量FVIII分子的凝血活性。
图2A-2C显示了aPPT的结果。mHC是由巨型蝙蝠FVIII的重链和人FVIII的轻链组成的杂合FVIII,dHC是由海豚FVIII的重链和人FVIII的轻链组成的杂合FVIII。在图2A-2C中,人FVIII(hHC,指FVIII-SQ)作为对照;图2A是hHC和mHC的活性比较;图2B是hHC和dHC的活性比较;图2C是hHC和maHC的活性比较。
如图2A-2C所示,含有巨型蝙蝠FVIII重链和人FVIII轻链的杂合FVIII(mHC)的凝血时间最短,说明其分泌水平最高,从而导致凝血活性最高。mHC与人FVIII的不同之处在于mHC含有巨型蝙蝠FVIII的重链。该结果表明,巨型蝙蝠FVIII的重链有利于提高杂合mHCFVIII的分泌能力。
接下来,对人和巨型蝙蝠FVIII的A1和A2结构域分别进行替换,以构建更多的杂合FVIII分子-M1H2和H1M2。M1H2包括巨型蝙蝠重链(mHC)的A1结构域和人重链(hHC)的A2结构域,H1M2包括hHC的A1结构域和mHC的A2结构域(图3A)。
如图3B所示,与人FVIII(hHC)相比,M1H2的凝固时间更短,说明其分泌水平更高,从而导致更高的凝固活性。该数据表明,用mHC的A1结构域替换成hHC的A1结构域可以提高凝血活性。
实例2,A1结构域中增强分泌能力较小区域的确定
为了进一步细分A1结构域,使用Phymol软件来预测FVIII的重链结构。根据这种预测,重链的A1结构域被细分为D1和D2,A2结构域被细分为D3和D4,以便于进一步确定重链中有利于增强分泌的区域(图4)。
负向选择和正向选择策略都被采用。在负向选择策略中,巨型蝙蝠FVIII D1或者D4结构域替换成了人FVIII的D1或D4结构域,构建杂合的巨型蝙蝠FVIII:hD1和hD4(图5A)。如图5A所示,hD1包含人FVIII重链(hHC)的D1区域和巨型蝙蝠FVIII重链的D2-D4区域;hD4包含人FVIII重链(hHC)的D4区域和巨型蝙蝠FVIII重链的D1-D3区域。所有的FVIII突变体含有相同的轻链和其他必要的调控元件,相同的结构域或者表达元件没有在图中显示。因为人的FVIII具有较低的分泌活性,会降低杂合巨型蝙蝠FVIII突变体的分泌效率。事实上,如图5B所示,与人FVIII(hHC)相比,hD1的凝固时间更长。这一结果表明,人FVIII D1结构域可能会降低巨型蝙蝠FVIII的分泌活性,这反过来又导致其凝血活性降低。因此,D1结构域可能对FVIII的分泌很重要。
在正向选择策略中,人FVIII的D1-D4区域替换成巨型蝙蝠FVIII中的对应的区域,以构建杂合的人FVIII突变体:mD1mD3、mD2、mD3和mD4(图6A)。因为巨型蝙蝠FVIII具有更高的分泌活性,这种突变将提高杂合人FVIIIs的分泌效率。如图6B所示,所有杂交人FVIII突变体的凝固时间都比人FVIII hHC)短,其中mD1mD3的凝固时间最短。该结果表明,D1结构域可能是FVIII分泌的关键区域。
负向选择和正向选择实验的结果表明:巨型蝙蝠D1区可能是提高巨型蝙蝠FVIIII分泌能力的关键结构域。
实例3,D1结构域中负责增强分泌氨基酸的确定
将人类D1(SEQ ID NO:1)和巨型蝙蝠D1(SEQ ID NO:2,其序列见下文)区域进行比对,发现二者有23个氨基酸的差异(图7,用星号标记)。值得注意的是,巨型蝙蝠D1区域比人类D1区域多了一个氨基酸(图7,人类序列中的"-"代表一个氨基酸的缺失)。在下文中,将构建具有多种突变位点的巨型蝙蝠FVIII和人FVIII突变体。人FVIII突变体中氨基酸的位置参照SEQ ID NO:1,巨型蝙蝠FVIII突变体中氨基酸的位置参照SEQ ID NO:2。
SEQ ID NO:2的氨基酸序列如下:
ATRRYYLGAVELSWDYMQSELLSELHMDTRFPPEVPRSFPFNTSVIYKKTVFVEFTDHLFNTAKPRPPWMGLLGPTIRAEVSDTVVITLKNMASHAVSLHAVGVSYWKASEGAQYEDQTSQREKEDDKVIPGDSHTYVWEVLKENGPMASDPPCLTYSYFSHVDLVKDLNAGLIGTLLVCREGSLAKE
为了确定影响FVIII蛋白分泌的氨基酸,将巨型蝙蝠D1中23个不同的氨基酸中的8个分别用人类D1中的相对应的氨基酸进行替换,得到相对应的FVIII突变体:V51L、T62I、E116D、I130F、D133G、E140Q、P153L和F160L。V51L指的是巨型蝙蝠FVIII突变体中SEQ IDNO:2的第51位的氨基酸V突变为L(见图7),其他突变体的定义依次类推。图8A是ELISA结果,该结果表明分别含有8个氨基酸的突变体,即V51L、T62I、E116D、I130F、D133G、E140Q、P153L和F160L,会导致FVIII蛋白表达水平的降低(图8A)。图8B是aPTT结果,该结果表明分别含有8个氨基酸的突变体,即V51L、T62I、E116D、I130F、D133G、E140Q、P153L和F160L突变体的凝血活性降低(图8B)。这些数据表明,这8个氨基酸对增强巨型蝙蝠FVIII的分泌能力起着重要作用,人FVIII中相应的8个氨基酸的突变可能提高人FVIII的分泌能力。由于巨型蝙蝠FVIII的D1区域比人FVIII多一个氨基酸(见图7),人FVIII突变体L50V、I61T、D115E、F129I、G132D、Q139E、L152P和L159F可能增加人FVIII的分泌。
值得注意的是,含有两个氨基酸突变的突变体:V51L和P153L,可以最大幅度地降低巨型蝙蝠FVIII的分泌(图8A-8B)。在人FVIII中,L50V和L152P的突变可能是增加人类FVIII的分泌和凝血活性的两个关键氨基酸的突变。
实例4,有助于增强分泌活性的其他氨基酸的确定
在巨型蝙蝠D1区第20个氨基酸到第23个氨基酸的位置,巨型蝙蝠FVIII的氨基酸序列是ELLS(图7),人类FVIII序列中相对应的氨基酸序列是DLG(图7)。由于FVIII是一种分泌性蛋白,它从细胞的合成部位释放出来后必须经过内质网。据推测,D1可能与内质网的Bip区相互作用。研究表明,FVIII从细胞中转运出来会消耗ATP。由于细胞内ATP的储存量有限,消耗ATP少的蛋白质可以更多的被运出细胞,产生更多的分泌蛋白。对蛋白质的亲和力和疏水性进行分析,人类FVIII中DLG序列被突变为SLG(D20S)或SLL(D20S,G22L)。由于这些是人的FVIII突变体,氨基酸的位置是基于SEQ ID NO:1中的序列。例如,这里的G22L指的是突变体FVIII的第22位的氨基酸G被突变为L(参考SEQ ID NO:1)。
人类FVIII D1区突变体包括SLL(D20S,G22L)、SLG(D20S)或两者分别与其他氨基酸突变相结合,各种FVIII突变体如表1。
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表1各种含有DLG序列突变的FVIII突变体。人类D1区域的DLG序列被突变为SLL(D20S,G22L)或SLG(D20S),或者分别与其他氨基酸突变相结合,形成各种具有3-5个突变氨基酸的FVIII突变体。
为了比较FVIII突变体与人FVIII(hFVIII-SQ)的凝血活性,进行了aPTT实验。如图9所示,所有人FVIII突变体的凝血活性都高于hFVIII-SQ。这些结果表明,这些突变的氨基酸可以提高人FVIII的分泌。
综上所述,人FVIII中共有10个突变:D20S、G22L、L50V、I61T、D115E、F129I、G132D、Q139E、L152P和L159F,这些位点被确定为增强人FVIII分泌能力和活性的关键突变位点。
实例5,生产包括本文公开的工程化hFVIII多肽的重组AAV(rAAV)载体
在3L生物反应器中接种密度为0.8×106个细胞/mL的293悬浮细胞。三个质粒(pAAV-hFVIII、pAd-helper、pRep/Cap)按1:1:1的比例混合,然后与PEI按1:2的比例混合(1ug质粒:2uL PEI)。混合物在室温下孵育15分钟,然后加入到生物反应器中。在转染后72小时,用含有1%Tween-20的裂解缓冲液裂解细胞。然后,在生物反应器中加入50U/mLBenzonase核酸酶和1mM MgCl2,在37℃下孵育3小时,消化未进行包装的细胞、病毒和质粒的DNA和RNA。消化后的细胞裂解液进行离心和过滤浓缩后,用AAVX亲和柱纯化rAAV载体,再用阴离子柱纯化。更换缓冲液后,rAAV经过无菌过滤后于-80℃中保存。
实例6,制作包括本文公开的工程hFVIII多肽的药物组合物
将例证5中纯化的rAAV载体与其他活性剂、防腐剂、缓冲剂、盐、药学上可接受的载体或其他药学上可接受的成分进行混合,制成用于治疗A型血友病患者的药物组合物。
实例7,用包括本文公开的工程hFVIII多肽的药物组合物治疗A型血友病患者
招募A型血友病患者进行1期临床试验。待进行试验的工程化hFVIII多肽的剂量为0.5x1012Vg/Kg到6x1013Vg/Kg。
A型血友病患者通过静脉注射药物组合物,药物组合物中包括表达本文公开的工程化hFVIII多肽的rAAV载体。患者注射药物后,将对患者进行为期4年的随访,以跟踪检测FVIII的表达水平。第一个检查点是初次注射后的第7天,随后注射6个月内,每间隔1-2周即进行检测,此后间隔周期为1-3个月。初次注射一年后,患者的FVIII表达量高于正常水平的2%。
SEQUENCE LISTING
<110> 四川至善唯新生物科技有限公司
<120> 基因工程改造获得的分泌能力和凝血活性增强的人类八因子
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Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn
1310 1315 1320
Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln
1325 1330 1335
Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu
1340 1345 1350
Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val
1355 1360 1365
Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys
1370 1375 1380
Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu
1385 1390 1395
Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp
1400 1405 1410
Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr
1415 1420 1425
Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala
1430 1435 1440
Leu Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1445 1450 1455
<210> 6
<211> 1457
<212> PRT
<213> Homo sapiens
<400> 6
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Cys Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Ser Leu Gly Glu Leu Pro Val Asp Ala Arg
35 40 45
Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val
50 55 60
Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile
65 70 75 80
Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln
85 90 95
Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser
100 105 110
His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser
115 120 125
Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp
130 135 140
Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu
145 150 155 160
Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr Ser
165 170 175
Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile
180 185 190
Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys Thr
195 200 205
Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly
210 215 220
Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp
225 230 235 240
Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr
245 250 255
Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val
260 265 270
Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile
275 280 285
Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser
290 295 300
Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met
305 310 315 320
Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His
325 330 335
Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro
340 345 350
Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp
355 360 365
Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser
370 375 380
Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys Thr
385 390 395 400
Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro
405 410 415
Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn
420 425 430
Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met
435 440 445
Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu
450 455 460
Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr Leu
465 470 475 480
Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro
485 490 495
His Gly Ile Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro Lys
500 505 510
Gly Val Lys His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile Phe
515 520 525
Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp
530 535 540
Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg
545 550 555 560
Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu
565 570 575
Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val
580 585 590
Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu
595 600 605
Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp
610 615 620
Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr Val
625 630 635 640
Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp
645 650 655
Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe
660 665 670
Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr
675 680 685
Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro
690 695 700
Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly
705 710 715 720
Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp
725 730 735
Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys
740 745 750
Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn Pro Pro Val Leu
755 760 765
Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp Gln
770 775 780
Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu
785 790 795 800
Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe
805 810 815
Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp
820 825 830
Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln
835 840 845
Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr
850 855 860
Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu His
865 870 875 880
Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile
885 890 895
Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser
900 905 910
Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg
915 920 925
Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val
930 935 940
Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp
945 950 955 960
Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu
965 970 975
Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His
980 985 990
Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe
995 1000 1005
Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn
1010 1015 1020
Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys
1025 1030 1035
Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr
1040 1045 1050
Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr
1055 1060 1065
Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe
1070 1075 1080
Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met
1085 1090 1095
Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met
1100 1105 1110
Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly
1115 1120 1125
Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser
1130 1135 1140
Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg
1145 1150 1155
Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro
1160 1165 1170
Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser
1175 1180 1185
Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro
1190 1195 1200
Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe
1205 1210 1215
Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp
1220 1225 1230
Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu
1235 1240 1245
Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn
1250 1255 1260
Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro
1265 1270 1275
Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly
1280 1285 1290
Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys
1295 1300 1305
Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn
1310 1315 1320
Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln
1325 1330 1335
Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu
1340 1345 1350
Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Val
1355 1360 1365
Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys
1370 1375 1380
Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp Thr Leu
1385 1390 1395
Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp
1400 1405 1410
Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr
1415 1420 1425
Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala
1430 1435 1440
Leu Arg Met Glu Val Leu Gly Cys Glu Ala Gln Asp Leu Tyr
1445 1450 1455
Claims (13)
1.一种工程化的人FVIII(hFVIII)多肽,其在hFVIII的A1结构域中包括至少两个替代的氨基酸。
2.根据权利要求1中所述的工程化hFVIII多肽,其中替代的氨基酸位点包括A1结构域中的L50和L152。
3.根据权利要求1或2中所述的工程化hFVIII多肽,其中替代的氨基酸包括A1结构域中的L50V和L152P。
4.根据权利要求2或3中所述的工程化hFVIII多肽,其中替代的氨基酸位点进一步包括A1结构域中的D20、G22、I61、D115、F129、G132、Q139和L159的一个或多个氨基酸突变位点。
5.根据权利要求4中的工程化hFVIII多肽,其中D20、G22、I61、D115、F129、G132、Q139和L159的氨基酸分别替代为D20S、G22L、I61T、D115E、F129I、G132D、Q139E和L159F。
6.根据权利要求1-5中任一工程化hFVIII多肽,其中替代的氨基酸包括D20S、L50V和L152P。
7.根据权利要求1-6中任一工程化hFVIII多肽,其中所述替代的氨基酸包括D20S、G22L、L50V和L152P。
8.根据权利要求1-5中任一工程化hFVIII多肽,含有SEQ ID NO:3、SEQ ID NO:4、SEQID NO:5、或SEQ ID NO:6中的氨基酸序列。
9.一个游离的核酸片段,其编码权利要求1-8中任一工程化hFVIII多肽。
10.一种表达载体,包括权利要求9中的核酸片段,该核酸片段与启动子是可操作地连接在一起的。
11.一种重组AAV(rAAV)载体,包括权利要求9中的核酸片段,其中该核酸片段是和启动子可操作地连接在一起的。
12.一种药物组合物,包括权利要求10中的表达载体或权利要求11中的rAAV载体。
13.一种治疗A型血友病患者的方法,包括向该患者注射有效量的权利要求12中的药物组合物。
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PCT/CN2022/075976 WO2023092864A1 (en) | 2021-11-25 | 2022-02-11 | Engineered human fviii with enhanced secretion ability and clotting activity |
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WO2013123457A1 (en) * | 2012-02-15 | 2013-08-22 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
WO2015023894A1 (en) * | 2013-08-14 | 2015-02-19 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
CN105431451A (zh) * | 2013-06-24 | 2016-03-23 | 肖卫东 | 突变型因子viii组合物和方法 |
WO2017222330A1 (ko) * | 2016-06-24 | 2017-12-28 | 재단법인 목암생명과학연구소 | 재조합 단쇄 fviii 및 그 화학 접합물 |
CN113614104A (zh) * | 2019-01-16 | 2021-11-05 | 百深公司 | 用于a型血友病的基因疗法的编码表达增加的重组fviii变体的病毒载体 |
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EP1502921A1 (en) * | 2003-07-29 | 2005-02-02 | ZLB Behring GmbH | Recombinant mutated human factor VIII (FVIII) with improved stability |
EP1985631A1 (en) * | 2007-04-20 | 2008-10-29 | LFB Biotechnologies | Demannosylated recombinant factor VIII for the treatment of patients with hemophiila A |
EP3250226B1 (en) * | 2015-01-30 | 2020-07-15 | Emory University | Factor viii proteins having ancestral sequences, expression vectors, and uses related thereto |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013123457A1 (en) * | 2012-02-15 | 2013-08-22 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
CN105431451A (zh) * | 2013-06-24 | 2016-03-23 | 肖卫东 | 突变型因子viii组合物和方法 |
WO2015023894A1 (en) * | 2013-08-14 | 2015-02-19 | Biogen Idec Ma Inc. | Recombinant factor viii proteins |
WO2017222330A1 (ko) * | 2016-06-24 | 2017-12-28 | 재단법인 목암생명과학연구소 | 재조합 단쇄 fviii 및 그 화학 접합물 |
CN113614104A (zh) * | 2019-01-16 | 2021-11-05 | 百深公司 | 用于a型血友病的基因疗法的编码表达增加的重组fviii变体的病毒载体 |
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CN116710554B (zh) | 2024-06-07 |
EP4211153A1 (en) | 2023-07-19 |
US20240254197A1 (en) | 2024-08-01 |
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