CN118201954A - 精氨酸酶-胰岛素融合蛋白 - Google Patents
精氨酸酶-胰岛素融合蛋白 Download PDFInfo
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- CN118201954A CN118201954A CN202280071720.XA CN202280071720A CN118201954A CN 118201954 A CN118201954 A CN 118201954A CN 202280071720 A CN202280071720 A CN 202280071720A CN 118201954 A CN118201954 A CN 118201954A
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- fusion protein
- insulin
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- arginase
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Abstract
本发明公开了胰岛素和精氨酸酶的融合蛋白,其作为抗肿瘤药物、抗肥胖症药物或2‑型糖尿病药物是有用的。
Description
本发明涉及精氨酸酶和胰岛素的融合蛋白,以及其在医学中的用途,特别是用于治疗癌症和代谢病症,例如肥胖病或糖尿病,例如2型糖尿病。
发明背景
精氨酸耗竭已显示出在治疗一些癌症(例如,肝细胞癌和黑素瘤,和基于体外工作,可能许多其他癌症)中具有效用。精氨酸耗竭酶例如精氨酸酶在癌症疗法中的使用已经例如由Shen等人(Cell Death&Disease 8(2017),e2720)、Zou等人(Biomedicine&Pharmacotherapy118(2019),109210)、Al-Koussa等人(Cancer Cell International 20(2020)Article number 150)和Zhang等人(Cancer Letters 502(2012),58-70)作了描述,这些文献的内容通过提及而合并入本文。
精氨酸转化酶的使用是必需的,但是我们自己的研究已显示它不足以引起和维持对于引起癌细胞的快速且选择性的杀伤来说需要的精氨酸的全身性深度耗竭。
与精氨酸的酶促降解相平行地胰岛素/葡萄糖钳夹(insulin/glucose clamp)的使用使得深度精氨酸耗竭的任务易管理得多。胰岛素是生长因子,并且因此促进蛋白质合成和抑制蛋白质分解。当任务是从循环中去除任何氨基酸特别是精氨酸(其在严格内环境稳定控制下是半必需氨基酸)时,这具有至关紧要的重要性。
通过胰岛素的血管渗透性的增加也有助于使治疗性酶进入间质液空间,其更接近于大多数癌细胞所居留的地方。
最后,胰岛素也可以通过刺激性胞吞作用而在将精氨酸降解酶运输入癌细胞中发挥作用。为了让这工作,在胰岛素分子附着至胰岛素受体的之,酶分子需要非常接近,这取决于酶的机会和浓度。
本发明的目标是克服与以前的牵涉氨基酸耗竭(例如,精氨酸耗竭)的治疗规划相关的缺点。
发明描述
本发明的第一个方面涉及融合蛋白,其包含第一结构域和第二结构域,其中所述第一结构域包含氨基酸降解酶并且所述第二结构域包含胰岛素。
本发明的一个进一步的方面涉及编码所述融合蛋白的核酸分子。
本发明的一个进一步的方面涉及用所述核酸分子转染的宿主细胞。
本发明的一个进一步的方面涉及通过下述方式来产生所述融合蛋白的方法:培养所述宿主细胞,并且从所述宿主细胞中或从培养基中获得所述融合蛋白。
本发明的一个进一步的方面涉及用于在医学中使用的所述融合蛋白。
在某些实施方案中,所述第一结构域(酶)位于所述第二结构域(胰岛素)的N-末端处。在进一步的实施方案中,所述第二结构(胰岛素)位于所述第一结构域(酶)的N-末端处。
在某些实施方案中,所述融合蛋白为基因融合物,其可以通过下述方式在重组宿主细胞中产生:表达核酸分子,特别是编码所述融合蛋白或其前体的DNA分子,和任选地随后进行加工。
在某些实施方案中,所述融合蛋白为非基因融合物,其中所述第一结构域和所述第二结构域分开地产生,例如在重组宿主细胞中,随后相互连接,例如通过共价键。
所述融合蛋白的第一结构域包含氨基酸降解酶。在某些实施方案中,所述氨基酸降解酶为精氨酸降解酶,例如精氨酸脱亚胺酶(ADI;EC 3.5.3.6;UniProt-P23793)或精氨酸酶。在特别的实施方案中,所述氨基酸降解酶为人肝脏精氨酸酶(人精氨酸酶-1;ARG1;EC3.5.3.1;Uni-Prot-P05089)或人肾脏精氨酸酶(人精氨酸酶-2;ARG2;EC 3.5.3.1;Uni-Prot-P78540)。
用钴代替锰并且将最佳pH移动至血浆pH的对于人肝脏精氨酸酶(ARG1)或人肾脏精氨酸酶(ARG2)的修饰也特别适合于根据本发明的与胰岛素的融合物。经Co2+修饰的重组人精氨酸酶I由Stone EM,Glazer ES,Chantranupong L等人(Replacing Mn(2+)with Co(2+)in human arginase enhances cytotoxicity toward L-arginine auxotrophiccancer cell lines,ACS Chem Biol.2010,5(3):333-342,doi:10.1021/cb900267j)和在US20121/0189371A1中作了描述,这些文献的内容通过提及而合并入本文。
几种其他氨基酸已作为靶标以用于癌症治疗,例如,通过色氨酸双加氧酶(TDO2;EC 1.13.11.11,UniProt-P48775)的色氨酸,或者通过S-腺苷甲硫氨酸合酶(MAT1A;EC2.5.1.6;UniProt-Q00266)的甲硫氨酸。然而,精氨酸耗竭被认为是对于癌症治疗的最有效方法。
自七十年代早期以来,天冬酰胺酶已是最成功使用的用于癌症,特别是用于儿童急性淋巴细胞白血病(ALL)的酶治疗。天冬酰胺酶仅以其四聚体形式才是有活性的,处于大约130kDa的四聚体形式太大而无法如此进行使用。根据本发明,它以经解离的形式进行递送,例如以其单体形式溶解在尿素中,如在WO 2020/245041(其内容通过提及而合并入本文)中所描述的,其中所述单体中的每一个与胰岛素相融合。在这样的情况下,外渗是可能的,并且随后为在间质液中重构为四聚体,它可以产生该酶的活性形式。因此,天冬酰胺酶也是用于在本发明中使用的优选的酶。
在某些实施方案中,所述氨基酸降解酶为单体蛋白质,例如单体精氨酸酶。
所述融合蛋白的第二结构域包含胰岛素,包括其前体,例如胰岛素原,从其中可以通过酶促切割(包括自切割)来获得胰岛素。
在某些实施方案中,所述胰岛素为人胰岛素或胰岛素类似物,例如,速效胰岛素,例如格鲁辛胰岛素、门冬胰岛素、赖脯胰岛素,或者长效胰岛素,例如NPH胰岛素、甘精胰岛素、地特胰岛素或德谷胰岛素(insulin degludec)。这些胰岛素典型地包含通过S-S桥相连接的A-链和B-链,并且可以通过切割从相应的胰岛素原获得。
在某些实施方案中,本发明的融合蛋白作为前体来产生,其中所述第一结构域包含胰岛素原,其随后被切割为相应的胰岛素,例如通过自催化。
备选地,所述胰岛素可以为单链胰岛素,例如胰岛素或胰岛素类似物,其中胰岛素B-链和胰岛素A-链(其任选地包含至少一个氨基酸修饰)通过永久的连接体相连结。单链胰岛素例如由Glidden等人(J.Biol.Chem.293(2018),47-68)或Mao等人(Appl.Microbiol.Biotechnol.103(2019),8737-8751)作了描述,这些文献的内容通过提及而合并入本文。单链胰岛素也描述在专利US 8,192,957;8,501,440;8,921,313;8,993,516;9,079,975;9,200,053;9,388,228;9,499,600;9,624,287;9,758,563;9,975,940;10,392,429;10,472,406;和10,822,386中,这些文献的内容通过提及而合并入本文。在一个特别的实施方案中,所述单链胰岛素为SCI-57,其在B-链和A-链之间包含永久的六肽连接体GGGPRR(SEQ ID NO.12),如在Hua QX,Nakagawa SH,Jia W等人,Design of an activeultrastable single-chain insulin analog:synthesis,structure,and therapeuticimplications.J Biol Chem.2008,283(21):14703-14716.doi:10.1074/jbc.M800313200(其内容通过提及而合并入本文)中所描述的。
在某些实施方案中,所述第一结构域和所述第二结构域直接相互连结。在进一步的实施方案中,所述第一结构域和所述第二结构域通过连接体(例如,包含1-100个,特别是10-60个氨基酸的连接体)相互连结。
所述连接体可以为柔性连接体,例如由氨基酸G和S组成的连接体,例如(GmS)n连接体,其中m为1-5并且n为1-10。备选地,所述连接体可以为刚性连接体,例如包含至少一个P残基。在某些实施方案中,所述连接体可以为可切割连接体,例如包含蛋白水解切割位点。
在某些实施方案中,所述融合蛋白可以包含另外的结构域,包括纯化结构域例如His-标签、FLAG结构域等,分泌结构域,或另一个功能结构域。
在某些实施方案中,可以将所述融合蛋白缀合至异源的,例如非蛋白质性质的部分,例如聚乙二醇(PEG),或者缀合至异源蛋白质,以延长其血浆半寿期。在这样的情况下,有利的将会是选择小的缀合伙伴,由此仍然允许外渗。在优选的实施方案中,所述融合蛋白具有低于大约70kDa的分子量,例如60kDa或更低。在进一步优选的实施方案中,所述融合蛋白是未PEG化的。
本发明的融合蛋白在医学(包括兽医学和人类医学)中是有用的,例如在治疗癌症(例如,白血病、淋巴瘤、肝细胞癌、黑素瘤、结肠癌、骨肉瘤、软组织肉瘤、肥大细胞肿瘤)中,或者在预防或治疗代谢病症(例如,肥胖症或糖尿病,特别是2型糖尿病)中作为药物。
本发明的融合蛋白典型地通过注射或输注来进行施用。在特别的实施方案中,施用伴随有葡萄糖的共施用,包括提供葡萄糖的寡糖或多糖(例如麦芽糖、糊精、淀粉等)的施用,以便维持足够的葡萄糖水平,例如大约4.0至大约10mM。进一步地,所述融合蛋白的施用可以伴随有某些用于补偿精氨酸耗竭的副作用的措施,例如输注氧化氮(NO)供体,例如硝普钠(SNP),和/或升压肽,例如血管升压素,以平衡NO-诱导的血管舒张。精氨酸是用于合成短寿命NO的唯一前体。所有升压肽都包含精氨酸并且是短寿命的。已发现伊洛前列素(一种前列环素类似物)的共输注在维持血小板中是有用的。
所述融合蛋白可以作为单一疗法或者与进一步的活性试剂(例如,抗癌试剂、抗肥胖症试剂或抗糖尿病试剂)相组合地进行施用。在某些实施方案中,所述融合蛋白可以与胰岛素一起,优选地与胰岛素/葡萄糖钳夹一起共施用。在某些实施方案中,所述融合蛋白可以与靶向与所述融合蛋白相同或另一个的氨基酸的未融合的氨基酸酶一起共施用。在某些实施方案中,精氨酸酶融合蛋白可以与天冬酰胺酶一起进行施用,例如在上面所描述的以其单体形式的天冬酰胺酶,其是未融合的或者也处于胰岛素融合物的形式。
本发明允许氨基酸降解酶的经改善的由胰岛素介导的胞吞转运作用和胞吞作用,这通过提供在所述胰岛素和所述酶之间的融合蛋白来实现,而不要求诱捕附近的酶分子的机会。最令人感兴趣的是在精氨酸酶和胰岛素之间的融合蛋白,但是其他精氨酸降解酶以及一些其他降解其他氨基酸的酶可以与胰岛素相融合以增加其抗肿瘤效力。
除了使用胰岛素和精氨酸酶的融合蛋白作为抗肿瘤药物外,相同的融合蛋白还可以用于治疗肥胖症,特别是如果肥胖症与已经在用胰岛素进行治疗的糖尿病同时发生。将精氨酸酶带入作为胰岛素的首要靶标的脂肪细胞中将会抑制脂肪细胞生长和增殖,并且可能甚至引起它们中的一些死亡,取决于细胞内精氨酸耗竭的水平。
实验观察和从其得出的结论
在健康的实验狗和几只具有在1995年开始并且仍然在进展中的癌症的狗上进行的发明人的对于精氨酸和天冬酰胺的全身耗竭(作为抗癌治疗)的研究已提供了关于胰岛素在增加这些依赖于所靶向的氨基酸的酶促降解的治疗的效用中的作用的强大证据。
在该计划的第一阶段,通过选择性透析来进行所靶向的氨基酸的体外去除。使用经改动的透析设备,将血液逆包含血浆的大多数已知的低分子量水溶性组分(总共52+种电解质)(除了所靶向的氨基酸外)的透析液进行透析。通过在透析过滤器的入口和出口处测量所有氨基酸来验证该过程的功效。在这些实验中靶向必需氨基酸中的大多数,一次一种,其中精氨酸是主要感兴趣的,因为其耗竭功效在体外针对不同的所测试的肿瘤系得到了建立。然而,持续数天的连续透析未能显著地降低必需氨基酸中的任一种的血浆浓度,尽管通过过滤器几乎完全洗去了所靶向的氨基酸。在过滤器的出口处的所靶向的氨基酸浓度低于检测极限,但是在入口处浓度保持接近正常。对于大约30kg体重的狗,血流量是非常高的,直至300ml/分钟。该方法的失败被正确地归因于必需氨基酸的内环境稳定控制,据估计其导致多达10%的总身体蛋白质损失/天。
在后续的实验研究中,发明人转向使用胰岛素/葡萄糖钳夹来抑制蛋白质分解和刺激蛋白质合成。虽然仍然使用具有相同参数的选择性透析,但是血浆精氨酸的浓度现在可以被降低大约十倍,从大约100μM至大约10μM,如在图1中所显示的。虚线显示了在2只没有胰岛素/葡萄糖钳夹的狗中的血浆精氨酸浓度。实线显示了在6只具有胰岛素/葡萄糖钳夹的狗中的血浆精氨酸。
然而,对淋巴***进行取样显示出精氨酸浓度没有降低,其处于大约200μM,甚至高于正常血浆浓度。结论是清楚的:虽然透析可以降低血浆中的精氨酸浓度,但是在血液和间质液之间通过扩散和对流转运的分子交换无法补偿来自身体中的蛋白质转换(大部分来自肌肉蛋白质)的氨基酸的流入。
其后,发明人转向使用所靶向的氨基酸的酶促降解。在第一种方法中,靶向精氨酸以进行去除,发明人使用经部分纯化的富含精氨酸酶的肝脏提取物。在健康狗中的终末前实验中,在总共18小时期间每3个小时通过推注式输注来递送自体肝脏提取物。在没有胰岛素/葡萄糖钳夹的情况下,血浆精氨酸水平跌落至接近零并且在3小时后的下一次推注式输注前返回至正常水平,图2,曲线A。在具有胰岛素/葡萄糖钳夹的情况下,血浆精氨酸降低至低于检测极限并且在实验的18小时持续时间中保持在那里,图2,曲线B,尽管仍然通过推注式输注来递送提取物。
在这些试验性实验后,发明人转向连续输注来自不同来源的酶促活性物质,包括重组酶。
直至数年后才忘记了在没有胰岛素/葡萄糖钳夹的情况下用推注式注射的血浆精氨酸的快速跌落和增加,以及在该抗癌治疗样式中胰岛素效应的进一步的证据。
在所有的在健康的实验狗和那些少数具有癌症的狗上的超过一百期研究中,发明人注意到在采用胰岛素/葡萄糖钳夹的情况下的白蛋白损失和中度水肿。血浆白蛋白的损失归因于蛋白质转换,并且水肿归因于不想要的但是非限制性的副作用。
然而,对于先前观察到的在推注式输注肝脏提取物的情况下的精氨酸的振荡进行的更靠近的检查为除了其蛋白质转换调节效应外的胰岛素的新的出人意料的作用提供了线索。
肝脏精氨酸酶是分子量为大约35kDa的单体,正好在肾小球过滤可以将其从血浆中去除的分子量范围(直至大约70kDa)的中间。白蛋白分子量为72kDa,并且通过扩散到血管外液中或通过肾小球过滤,它的损失非常小。然而,已知胰岛素增加毛细血管的渗透性,并且因此长时间将胰岛素浓度维持在超生理学浓度将会允许白蛋白的一些外渗,其引起水肿。如所叙述的,这对于所述实验方案不是限制性的并且可以通过使用标准利尿药物来进行补偿。
然而,在使得通过精氨酸酶的精氨酸耗竭成为血管***以外的有效机制中胰岛素的作用是至关紧要的。在35kDa下,精氨酸酶通过肾小球过滤被迅速消除。胰岛素/葡萄糖钳夹的使用引起毛细血管渗透性的增加,其足以引起精氨酸酶的外渗,因此保护它免于被肾脏消除。它还将所述酶递送至间质液,在那里精氨酸耗竭对于癌症的真正效应必须存在。清除血浆中的精氨酸是酶促抗癌效用的差的替代者。在作为抗癌治疗的所有目前的临床试验中,精氨酸酶和精氨酸脱亚胺酶是经PEG化的。PEG化这些酶防止了其外渗,这解释了尽管从血浆消除了精氨酸,但是仍然缺乏临床成功。
上面的观察结果提供了在精氨酸酶的外渗中胰岛素/葡萄糖作用的貌似合理的解释。
我们的用犬癌细胞系进行的体外工作(Wells JW,Evans CH,Scott MC,RütgenBC,O'Brien TD,Modiano JF,Cvetkovic G,Tepic S.Arginase treatment prevents therecovery of canine lymphoma and osteosarcoma cells resistant to the toxiceffects of prolonged arginine deprivation.PLoS One.2013,8(1):e54464.doi:10.1371/journal.pone.0054464.Epub 2013Jan 24.PMID:23365669;PMCID:PMC3554772)已暗示,在快速杀伤癌细胞中精氨酸酶的不寻常的效用部分地归因于精氨酸酶附着至癌细胞或进入癌细胞中。耗竭在细胞外环境中的精氨酸是需要的,但不是充分的。相对于健康细胞的对于癌细胞的选择性可以部分地归因于由癌细胞所展示出的增加的胞吞作用速率。
已知癌细胞和快速增殖的健康细胞具有更高的胰岛素受体表达。然而,与癌细胞相反,健康细胞通过退出细胞周期来对于精氨酸的耗竭做出应答,其中在静止期中它们可以存活直至3周。相反,缺乏周期控制(所有癌症的特点)在大多数情况下导致它们进入代谢死亡。
本发明旨在通过提供胰岛素和精氨酸酶(特别是人胰岛素和人肝脏精氨酸酶(精氨酸酶-1))的融合蛋白来利用以前的发现。对于所述融合物使用合适的连接体保持了胰岛素和精氨酸酶两者的活性。
在我们迄今为止已进行的体内工作中,胰岛素和精氨酸酶的平均有效剂量接近化学计量。然而,如果用融合蛋白质的进一步体内工作证明了融合蛋白质与单个蛋白质相比的有差别的效力,那么可以使用所述融合分子和常规胰岛素和/或常规精氨酸酶的组合。
附图图例
图1:在狗中精氨酸酶施用对于血浆精氨酸浓度的影响。虚线显示了在2只没有胰岛素/葡萄糖钳夹的狗中的血浆精氨酸浓度。实线显示了在6只具有胰岛素/葡萄糖钳夹的狗中的血浆精氨酸浓度。组合的精氨酸酶和胰岛素/葡萄糖钳夹显示出从大约100μM至大约10μM的大约十倍降低。
图2:在没有胰岛素/葡萄糖钳夹(曲线A)和具有胰岛素/葡萄糖钳夹(曲线B)的情况下,在总共18小时期间每3个小时通过推注式输注来施用富含精氨酸酶的自体的经部分纯化的肝脏提取物。在没有胰岛素/葡萄糖钳夹的情况下,血浆精氨酸水平跌落至接近零并且在3小时后的下一次推注式输注前返回至正常水平。在具有胰岛素/葡萄糖钳夹的情况下,血浆精氨酸降低至低于检测极限并且保持在那里18小时。
图3:融合蛋白,其具有人肝脏精氨酸酶(ARG-1)作为第一结构域(包括组氨酸标签),和通过柔性连接体相连结的人胰岛素原作为第二结构域。
图4:融合蛋白,其具有人肝脏精氨酸酶(ARG-1)作为第一结构域(包括组氨酸标签),和在二硫化物交联和胰岛素原C-肽切割后通过柔性连接体相连结的人胰岛素作为第二结构域。
图5:融合蛋白,其具有人肝脏精氨酸酶(ARG-1)作为第一结构域(包括组氨酸标签),和通过柔性连接体相连结的人胰岛素原作为第二结构域,显示了通过PC 1/3和cpE酶的C-肽切割位点。
图6:融合蛋白,其具有人肝脏精氨酸酶(ARG-1)作为第一结构域(包括组氨酸标签),和在B和A链之间具有永久的六肽连接体(C-连接体)的单链胰岛素类似物(SCI-57),包括4个有利的氨基酸置换(在B10、B28、B29和A8处)。
实施例1
提供了融合蛋白,其包含的人肝脏精氨酸酶(UniProtKB,精氨酸酶-1,P05089)作为N-末端结构域,和人胰岛素原作为C-末端结构域。将人胰岛素原用其N-末端(其是B-链的起点)(UniProtKB,人胰岛素,P01308)与精氨酸酶相融合。
为此目的,将合适的宿主细胞,例如,原核细胞例如大肠杆菌(E.coli),或者真核细胞例如酵母、昆虫或哺乳动物细胞,用编码所述融合蛋白的核酸分子进行转染,所述核酸分子与适应于各自宿主细胞的表达控制序列可操作地连接。在适合于表达所述融合蛋白的条件下培养所述宿主细胞。按照已知技术从细胞中或从培养基中纯化所述融合蛋白。
在重组产生后,通过二硫键来进行B和A链的交联并且酶促去除C-肽。
发明人已使用下面的总长度为331个氨基酸的具有为了亲和纯化而添加的组氨酸标签的ARG-1的序列来在大肠杆菌中产生高度有活性的人肝脏精氨酸酶:
MGHHHHHHGSSAKSRTIGIIGAPFSKGQPRGGVEEGPTVLRKA
GLLEKLKEQECDVKDYGDLPFADIPNDSPFQIVKNPRSVGKASE
QLAGKVAEVKKNGRISLVLGGDHSLAIGSISGHARVHPDLGVIW
VDAHTDINTPLTTTSGNLHGQPVSFLLKELKGKIPDVPGFSWVT
PCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGKV
MEETLSYLLGRKKRPIHLSFDVDGLDPSFTPATGTPVVGGLTYR
EGLYITEEIYKTGLLSGLDIMEVNPSLGKTPEEVTRTVNTAVAITLACFGLAREGNHKPIDYLNPPK(SEQ ID NO.1)。
人胰岛素的胰岛素原序列的长度为86个氨基酸:FVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVE LGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN(SEQ ID NO.2)。
在胰岛素原的起点处的B-链序列的长度为30个氨基酸:FVNQHLCGSHLVEALYLVCGERGFFYTPKT(SEQ ID NO.3)。
C-肽(在上面的胰岛素原序列中加有下划线的)的长度为35个氨基酸并且在B和A链的交联后被酶促去除:
RREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKR(SEQ ID NO.4)。
A-链序列的长度为21氨基酸:
GIVEQCCTSICSLYQLENYCN(SEQ ID NO.5)。
二硫键连接在B和A链两者中在第7个位置处的半胱氨酸残基,以及在B-链中在第19个位置处和在A-链中在第20个位置处的半胱氨酸。在A-链内在位置6和11处的半胱氨酸残基之间还存在额外的二硫键。
知晓B-链的前3个(FVN)和最后4个(TPKT)氨基酸不与A-链或胰岛素受体相互作用。相反,知晓A-链中的仅最后一个氨基酸(N)不参与任何相互作用。
可以在精氨酸酶的C-末端(K)和胰岛素原的B-链的N-末端(F)之间***连接体X。由于知晓在N-末端处B-链的仅3个氨基酸不参与任何相互作用,因而GS-类型的柔性连接体是第一选择。可以在精氨酸酶的N-末端处(S)掺入连接体Y,例如短的GS连接体,以将纯化标签(例如His-标签)连接至精氨酸酶。
最常使用的GS-类型连接体之一为(G4S)n。连接体的长度决定于其预期的功能——在本情况下,为了增加精氨酸酶和胰岛素的空间分隔并且因此保存其独立的活性。在某些实施方案中,使用(G4S)10(SEQ ID NO.6)。
在一个特别的实施方案中,包含His纯化标签、人精氨酸酶I和胰岛素原的融合蛋白的氨基酸序列如下(图3):MGHHHHHH*Y*SAKSRTIGIIGAPFSKGQPRGGVEEGPTVLRKA GLLEKLKEQECDVKDYGDLPFADIPNDSPFQIVKNPRSVGKASEQLAGKVAEVKKNGRISLVLGGDHSLAIGSISGHARVHPDLGVIWVDAHTDINTPLTTTSGNLHGQPVSFLLKELKGKIPDVPGFSWVTPCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGKVMEETLSYLLGRKKRPIHLSFDVDGLDPSFTPATGTPVVGGLTYREGLYITEEIYKTGLLSGLDIMEVNPSLGKTPEEVTRTVNTAVAITLACFGLAREGNHKPIDYLNPPK*X*FVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPGAGSLQPLALEGSL QKRGIVEQCCTSICSLYQLENYCN(SEQ IDNO.7),
其中Y为连接体,特别是GS连接体,并且X为连接体,特别是(GGGGS)n连接体,其中n为1至10。
在去除C-肽后,所述融合蛋白由两个多肽组成,其中多肽(i)由His-标签、精氨酸酶结构域、连接体和胰岛素B肽组成,并且多肽(ii)由胰岛素A-链组成,并且其中多肽(i)和(ii)通过二硫键进行交联,如下所示(图4):
多肽(i):
MGHHHHHH*Y*SAKSRTIGIIGAPFSKGQPRGGVEEGPTVLRKA GLLEKLKEQECDVKDYGDLPFADIPNDSPFQIVKNPRSVGKASEQLAGKVAEVKKNGRISLVLGGDHSLAIGSISGHARVHPDLGVIWVDAHTDINTPLTTTSGNLHGQPVSFLLKELKGKIPDVPGFSWVTPCISAKDIVYIGLRDVDPGEHYILKTLGIKYFSMTEVDRLGIGKVMEETLSYLLGRKKRPIHLSFDVDGLDPSFTPATGTPVVGGLTYREGLYITEEIYKTGLLSGLDIMEVNPSLGKTPEEVTRTVNTAVAITLACFGLAREGNHKPIDYLNPPK*X*FVNQHLCGSHLVEALYLVC GERGFFYTPKT(SEQID NO.8),
其中Y为连接体,特别是GS连接体,并且X为连接体,特别是(GGGGS)n连接体,其中n为1至10。
多肽(ii):
GIVEQCCTSICSLYQLENYCN(SEQ ID NO.5)。
胰岛素链的二硫化物交联和C-肽的酶促去除优选地用通过其亲和标签与纯化材料(例如纯化柱或过滤器)相结合的融合蛋白来进行。在某些实施方案中,所述纯化材料为亲和过滤器或柱,例如融合蛋白通过其His-标签与之相结合的Ni过滤器或柱(图5)。
具有G4S连接体(SEQ ID NO.9)的融合蛋白的长度为331+5+30+21=387个残基,并且分子量为大约42.0kDa。
在用(G4S)10(SEQ ID NO.6)连接体的情况下,长度为432个残基,并且分子量为大约45.6kDa。
假定归因于胰岛素的血管***的渗透性增加是其通过胞吞转运作用而大量转运通过内皮细胞(这也可能引起35.8kDa的精氨酸酶(具有His-标签)的外渗)的结果,那么合理的是预期到大约42至46kDa的融合蛋白的相似的,但是由于胰岛素对于精氨酸酶的“紧随(tag-along)”效应而潜在地更加高的胞吞转运作用速率。
对于通过胞吞作用进入靶细胞也是如此,特别是已知过表达胰岛素受体的癌细胞。在许多我们已通过使用精氨酸酶和胰岛素来进行的体内实验中,不存在有对于健康细胞的重大不良作用——仅有瞬时降低的增殖速率。
实施例2
本发明的一个进一步的实施方案为胰岛素与人精氨酸酶-2的融合蛋白,所述精氨酸酶-2主要在肾脏和几种其他组织中发现但未在肝脏中发现(备选的名称:精氨酸酶II、肾型精氨酸酶、非肝精氨酸酶)。精氨酸酶-2(UniProt P78540)的长度为354个残基并且具有38,578Da的分子量。如果在N-末端处使用与关于精氨酸酶-1相同的His-标签(GHHHHHHGS)(SEQ ID NO.10),该蛋白质将会具有363个氨基酸和大约39.7kDa的分子量。用在上面所描述的(G4S)n连接体,人精氨酸酶-2和胰岛素的融合蛋白将会具有46至50kDa的分子量。
实施例3
本发明的一个进一步的实施方案为胰岛素与人的钴替换的精氨酸酶I或精氨酸酶II的融合蛋白。该融合蛋白可以如在US 20121/0189371(见上)中所描述的那样来产生,包括使表达所述融合蛋白的大肠杆菌细胞进行发酵以产生融合蛋白,并且在重组蛋白质中用钴替换锰以提供Co-替换的融合蛋白,其可以被进一步纯化。
实施例4
本发明的一个进一步的实施方案为人精氨酸酶-1和SCI-57的融合蛋白(图6)。除了替代天然胰岛素原的C-肽的永久的六肽C-连接体GGGPRR(SEQ ID NO.12)外,SCI-57的B-链(SEQ ID NO.11)和A-链(SEQ ID NO.13)还包含进一步的对于人胰岛素的修饰,即4个置换:ThrA8至His,HisB10至Asp,ProB28至Asp,和LysB29至Pro,在图6上以灰色显示。SCI-57(SEQID NO.14)为具有高的与胰岛素受体的结合能力的超稳定单链胰岛素。对于本发明来说特别感兴趣的是在SCI-57中使用永久的肽连接体,从而允许具有单体精氨酸酶的融合蛋白的单步骤产生。
实施例5
通过输注向患者施用本发明的融合蛋白。对于在抗肿瘤疗法中所要求的全身的深度耗竭,所述融合蛋白的递送优选地用葡萄糖和任选地另外的措施的共输注,例如氧化氮供体(例如,SNP)和/或血管升压素的共输注(例如,精氨酸-血管升压素)来进行,以补偿低精氨酸的副作用。
对于治疗肥胖症和/或2-型糖尿病将会需要较低的剂量,具有接近于单独胰岛素的标准使用的用量。
根据本发明的以SEQ ID NO.1至SEQ ID NO.14列出的序列如下进行定义:
SEQIDNO.1(ARG-1,具有组氨酸标签)
Met Gly His His His His His His Gly Ser Ser Ala Lys Ser Arg Thr
Ile Gly Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly
Val Glu Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys
Leu Lys Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe
Ala Asp Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg
Ser Val Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val
Lys Lys Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu
Ala Ile Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly
Val Ile Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr
Thr Ser Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu
Leu Lys Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro
Cys Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp
Pro Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser
Met Thr Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr
Leu Ser Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe
Asp Val Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro
Val Val Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu
Ile Tyr Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn
Pro Ser Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr
Ala Val Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn
His Lys Pro Ile Asp Tyr Leu Asn Pro Pro Lys
SEQIDNO.2(人蛋白质)
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg
Glu Ala Glu Asp Leu Gln Val Gly Gln Val Glu Leu Gly Gly Gly Pro
Gly Ala Gly Ser Leu Gln Pro Leu Ala Leu Glu Gly Ser Leu Gln Lys
Arg Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln
Leu Glu Asn Tyr Cys Asn
SEQIDNO.3(B-链)
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr
SEQIDNO.4(C-肽)
Arg Arg Glu Ala Glu Asp Leu Gln Val Gly Gln Val Glu Leu Gly Gly
Gly Pro Gly Ala Gly Ser Leu Gln Pro Leu Ala Leu Glu Gly Ser Leu
Gln Lys Arg
SEQIDNO.5(A-链/多肽(ii))
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu
Glu Asn Tyr Cys Asn
SEQIDNO.6((G4S)10连接体)
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
Gly Ser
SEQIDNO.7(人工序列)
在位置9处的Xaa=连接体,特别是GS连接体。
在位置331处的Xaa=连接体,特别是(GGGGS)n连接体,其中n为1至10。
Met Gly His His His His His His Xaa Ser Ala Lys Ser Arg Thr Ile
Gly Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val
Glu Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu
Lys Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala
Asp Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser
Val Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys
Lys Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala
Ile Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val
Ile Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr
Ser Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu
Lys Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Cys
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
Thr Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu
Ser Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp
Val Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val
Val Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile
Tyr Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro
Ser Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala
Val Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn His
Lys Pro Ile Asp Tyr Leu Asn Pro Pro Lys Xaa Phe Val Asn Gln His
Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu
Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg Glu Ala Glu Asp Leu
Gln Val Gly Gln Val Glu Leu Gly Gly Gly Pro Gly Ala Gly Ser Leu
Gln Pro Leu Ala Leu Glu Gly Ser Leu Gln Lys Arg Gly Ile Val Glu
Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys
Asn
SEQIDNO.8(多肽(i))
在位置9处的Xaa=连接体,特别是GS连接体。
在位置331处的Xaa=连接体,特别是(GGGGS)n连接体,其中n为1至10。
Met Gly His His His His His His Xaa Ser Ala Lys Ser Arg Thr Ile
Gly Ile Ile Gly Ala Pro Phe Ser Lys Gly Gln Pro Arg Gly Gly Val
Glu Glu Gly Pro Thr Val Leu Arg Lys Ala Gly Leu Leu Glu Lys Leu
Lys Glu Gln Glu Cys Asp Val Lys Asp Tyr Gly Asp Leu Pro Phe Ala
Asp Ile Pro Asn Asp Ser Pro Phe Gln Ile Val Lys Asn Pro Arg Ser
Val Gly Lys Ala Ser Glu Gln Leu Ala Gly Lys Val Ala Glu Val Lys
Lys Asn Gly Arg Ile Ser Leu Val Leu Gly Gly Asp His Ser Leu Ala
Ile Gly Ser Ile Ser Gly His Ala Arg Val His Pro Asp Leu Gly Val
Ile Trp Val Asp Ala His Thr Asp Ile Asn Thr Pro Leu Thr Thr Thr
Ser Gly Asn Leu His Gly Gln Pro Val Ser Phe Leu Leu Lys Glu Leu
Lys Gly Lys Ile Pro Asp Val Pro Gly Phe Ser Trp Val Thr Pro Cys
Ile Ser Ala Lys Asp Ile Val Tyr Ile Gly Leu Arg Asp Val Asp Pro
Gly Glu His Tyr Ile Leu Lys Thr Leu Gly Ile Lys Tyr Phe Ser Met
Thr Glu Val Asp Arg Leu Gly Ile Gly Lys Val Met Glu Glu Thr Leu
Ser Tyr Leu Leu Gly Arg Lys Lys Arg Pro Ile His Leu Ser Phe Asp
Val Asp Gly Leu Asp Pro Ser Phe Thr Pro Ala Thr Gly Thr Pro Val
Val Gly Gly Leu Thr Tyr Arg Glu Gly Leu Tyr Ile Thr Glu Glu Ile
Tyr Lys Thr Gly Leu Leu Ser Gly Leu Asp Ile Met Glu Val Asn Pro
Ser Leu Gly Lys Thr Pro Glu Glu Val Thr Arg Thr Val Asn Thr Ala
Val Ala Ile Thr Leu Ala Cys Phe Gly Leu Ala Arg Glu Gly Asn His
Lys Pro Ile Asp Tyr Leu Asn Pro Pro Lys Xaa Phe Val Asn Gln His
Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu
Arg Gly Phe Phe Tyr Thr Pro Lys Thr
SEQIDNO.9(G4S连接体)
Gly Gly Gly Gly Ser
SEQIDNO.10(His-标签)
Gly His His His His His His Gly Ser
SEQIDNO.11(B-链)
Phe Val Asn Gln His Leu Cys Gly Ser Asp Leu Val Glu Ala Leu Tyr
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Asp Pro Thr
SEQIDNO.12(C-连接体)
Gly Gly Gly Pro Arg Arg
SEQIDNO.13(A-链)
Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser Leu Tyr Gln Leu
Glu Asn Tyr Cys Asn
SEQIDNO.14(SCI-57)
Phe Val Asn Gln His Leu Cys Gly Ser Asp Leu Val Glu Ala Leu Tyr
Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Asp Pro Thr Gly Gly
Gly Pro Arg Arg Gly Ile Val Glu Gln Cys Cys His Ser Ile Cys Ser
Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
Claims (15)
1.融合蛋白,其包含第一结构域和第二结构域,其中所述第一结构域包含氨基酸降解酶并且所述第二结构域包含胰岛素。
2.根据权利要求1所述的融合蛋白,其中所述第一结构域(酶)位于所述第二结构域(胰岛素)的N-末端处。
3.根据权利要求1或2所述的融合蛋白,其为基因融合物。
4.根据前述权利要求中任一项所述的融合蛋白,其中所述氨基酸降解酶为精氨酸降解酶,例如精氨酸脱亚胺酶(ADI)或精氨酸酶。
5.根据前述权利要求中任一项所述的融合蛋白,其中所述氨基酸降解酶为人精氨酸酶,例如人肝脏精氨酸酶(人精氨酸酶-1)或人肾脏精氨酸酶(人精氨酸酶-2)。
6.根据前述权利要求中任一项所述的融合蛋白,其中所述氨基酸降解酶为单体蛋白质,例如单体精氨酸酶。
7.根据前述权利要求中任一项所述的融合蛋白,其中所述胰岛素为人胰岛素或胰岛素类似物,包括单链胰岛素。
8.根据前述权利要求中任一项所述的融合蛋白,其中所述第一结构域和所述第二结构域通过连接体相互连结。
9.根据权利要求8所述的融合蛋白,其中所述连接体为柔性连接体,例如由氨基酸G和S组成的连接体,例如(GmS)n连接体,其中m为1-5并且n为1-10;刚性连接体;或可切割连接体。
10.核酸分子,其编码根据前述权利要求中任一项所述的融合蛋白。
11.用根据权利要求10所述的核酸分子转染的宿主细胞。
12.通过下述方式来产生根据权利要求1-9中任一项所述的融合蛋白的方法:培养根据权利要求11所述的宿主细胞,并且从所述宿主细胞中或从培养基中获得所述融合蛋白。
13.根据权利要求1-9中任一项所述的融合蛋白,其用于在医学中使用。
14.根据权利要求1-9中任一项所述的融合蛋白,其用于在治疗癌症中,或者在预防或治疗代谢病症,例如肥胖症或糖尿病,特别是2型糖尿病中用作药物。
15.根据权利要求1-9中任一项所述的融合蛋白,其用于根据权利要求13或14所述的用途,其中所述融合蛋白的施用伴随有葡萄糖的共施用,和任选地伴随有用于补偿精氨酸耗竭的副作用的措施。
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