CN101489593A - 通过脂质体酶的治疗剂肿瘤特异性递送 - Google Patents
通过脂质体酶的治疗剂肿瘤特异性递送 Download PDFInfo
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- CN101489593A CN101489593A CNA2007800270013A CN200780027001A CN101489593A CN 101489593 A CN101489593 A CN 101489593A CN A2007800270013 A CNA2007800270013 A CN A2007800270013A CN 200780027001 A CN200780027001 A CN 200780027001A CN 101489593 A CN101489593 A CN 101489593A
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Abstract
诺维梭状芽孢杆菌(Clostridium novyi)是一种专性厌氧菌,其可以感染实验肿瘤内的低氧区域。我们发现用诺维梭状芽孢杆菌(C.novyi)加单剂量脂质体阿霉素治疗时,具有大的已建立肿瘤的小鼠通常被治愈。负责这种现象的分泌因子已被鉴定,并且意料不到的是,证实其是脂肪酶家族的成员。编码被称为脂质体酶(liposomase)的蛋白质的基因具有被引入不同的治疗方法用以向肿瘤特异性地提供各种化学治疗剂的潜力。
Description
【01】本申请要求2007年6月19日提交的美国临时申请序列号60/814,546的权益,其公开内容明确引入于此。
【02】根据NIH,CA62924的基金规定,美国政府保留本发明中的某些权利。
发明技术领域
【03】本发明涉及肿瘤学领域。具体而言,其涉及增强抗癌剂选择性毒性的肿瘤治疗。
发明背景
【04】能够杀死癌细胞的药物并不缺乏;挑战是实现特异性,即杀死癌细胞而同时保留正常细胞。目前存在三种基本策略正被用于实现这种特异性。一种(选择性毒性)是使用药物,其对肿瘤细胞比对正常细胞具有更有效的生长抑制效果(1,2)。该策略强调常规化学治疗剂的成效,也强调更新的靶向治疗如伊马替尼(imatinib)的成效。第二种策略(递送)使用药剂,如抗体或基因,其分别与肿瘤细胞特异性反应或在肿瘤细胞内突出表达(3,4)。第三种策略(血管生成)通过药剂如阿瓦斯丁(Avastin)(5,6)或药物被引入脂质体(7)中而利用肿瘤血管的异常方面。脂质体是相对大的颗粒,其能够穿透存在于肿瘤和几个其它器官的有孔内皮(fenestrated endothelium)(8,9)。一旦它们进入肿瘤,它们持续并最终释放其内含物,并通过增强的通透性和保持性(enhanced permeabilization and retention,EPR)效应来提高局部药物浓度(10)。虽然已经证明这些策略中每个策略的优点,但是获得的治疗结果通常不理想。出现问题的部分原因是其中任何一个所达到的特异性不完善,限制了可安全施用而不会引起全身毒性的药物用量。
【05】在本领域中对开发更高效和更低毒的癌症治疗存在持续的需要。
发明概述
【06】根据本发明的一种实施方式,提供用于递送治疗剂的组合物。所述组合物包括毒素缺陷型诺维梭状芽孢杆菌(Clostridium novyi)芽孢和包含抗肿瘤药物或生物制剂的脂质体。
【07】根据本发明的另一种实施方式,提供另一种组合物。所述组合物包括依照SEQ ID NO:1或依照在GXSXG脂肪酶基序(SEQ ID NO:1的残基160-164)中具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶;和包含抗肿瘤药物或生物制剂的脂质体。
【08】本发明的另一方面是试剂盒。所述试剂盒包括依照SEQ ID NO:1或依照在GXSXG脂肪酶基序中具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶;和包含抗肿瘤药物或生物制剂的脂质体。
【09】本发明仍另一方面是试剂盒。所述试剂盒包括毒素缺陷型诺维梭状芽孢杆菌芽孢;和包含抗肿瘤药物或生物制剂的脂质体。
【10】本发明的又一种实施方式是治疗癌症患者的方法。第一种药剂——其是毒素缺陷型诺维梭状芽孢杆菌芽孢——和第二种药剂——其是包含抗肿瘤药物或生物制剂的脂质体,被施用给癌症患者。由此肿瘤退化或它的生长被减慢或被抑制。
【11】本发明另外的方面是治疗癌症患者的方法,其中将第一种药剂和第二种药剂施用给癌症患者。第一种药剂是依照SEQ ID NO:1或依照在GXSXG脂肪酶基序中具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶,而第二种药剂是包含抗肿瘤药物或生物制剂的脂质体。由此肿瘤退化或它的生长被减慢或被抑制。
【12】本发明还提供治疗癌症患者的方法,其中第一种和第二种药剂被施用给癌症患者。第一种药剂是载体,其编码依照SEQ ID NO:1或依照在GXSXG脂肪酶基序中具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶;以及第二种药剂是包含抗肿瘤药物或生物制剂脂质体。由此肿瘤退化或它的生长被减慢或被抑制。
【13】本发明还提供组合物,其包括依照SEQ ID NO:1或依照在GXSXG脂肪酶基序中具有置换突变的SEQ ID NO:1的分离和纯化的毒素缺陷型诺维梭状芽孢杆菌脂质体酶蛋白质。
【14】本发明进一步提供结合蛋白质,其包括依照SEQ ID NO:1或依照在GXSXG脂肪酶基序中具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶蛋白质;和多肽配体,其与肿瘤细胞上的受体结合。还提供编码该结合蛋白质的多核苷酸。
【15】本发明还进一步提供组合物,该组合物包括分离并纯化的多核苷酸,该多核苷酸编码依照SEQ ID NO:1或依照在GXSXG脂肪酶基序中具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶蛋白质。
【16】这些和其它实施方式——对本领域普通技术人员而言,在阅读说明书后其将变得显而易见,为本领域提供一套用于治疗癌症的工具,其对一系列肿瘤和一系列治疗剂可具有广泛的适用性。
附图简述
【17】图1A-1D。使用诺维梭状芽孢杆菌-NT加盐酸多柔比星(Doxil)的治疗效果。在第0天使用所示药剂的各种组合处理具有所示肿瘤的小鼠。游离阿霉素加诺维梭状芽孢杆菌-NT芽孢导致所有动物在两周内死亡,这未示出。图示了从每组至少五只小鼠收集到的数据的平均值和标准误差。诺维梭状芽孢杆菌-NT加盐酸多柔比星与其它组之间的差异显著(p<0.0006,对数秩检验(log-rank test))。图1A和1B显示对CT26肿瘤的效果。图1C和1D显示对HT116肿瘤的效果。图1A和1C显示肿瘤体积,并且图1B和1D显示存活百分比。
【18】图2A-2B。使用诺维梭状芽孢杆菌-NT治疗后,盐酸多柔比星的药物动力学分布。(图2A)在0小时,将盐酸多柔比星施用给具有~300mm3大小肿瘤的无胸腺裸鼠。另一组小鼠在施用盐酸多柔比星之前16小时被静脉注射诺维梭状芽孢杆菌-NT芽孢。在所示时间点处死小鼠,并且从组织中提取阿霉素并通过荧光测定法测量。显示了每时间点三只小鼠的平均值和标准偏差。(图2B)在注射盐酸多柔比星后16hr突然冰冻肿瘤,并且使用荧光显微镜检测中央区域的恒冷箱切片。来自脂质体内阿霉素的荧光信号被猝灭(见补充材料和方法),而释放的阿霉素在590nm处发射荧光。在用诺维梭状芽孢杆菌-NT芽孢处理的肿瘤内,观察到阿霉素荧光与用DAPI染色的核DNA的共定位。
【19】图3A-3C。脂质体-破裂活性(Liposome-Disrupting activity)的生化纯化和鉴定。(图3A)诺维梭状芽孢杆菌-NT在培养基内生长直至对数晚期,并通过离心将培养基从细胞中清除。用40%饱和硫酸铵沉淀后,进行离子交换层析,对组分进行脂质体-破裂活性评估。(图3B)来自(图3A)的峰组分(30-31)被合并,并且用凝胶过滤层析法分离。(图3C)来自(图3B)的峰组分(29-30)用SDS-聚丙烯酰胺凝胶电泳分馏。
【20】图4A-4D。脂质体酶的功能分析。携带野生型或突变型形式的NT01CX2047基因的质粒被引入大肠杆菌(E.coli)中。“消除的”(“cured”)细菌代表那些最初含有野生型基因并在缺乏选择性抗生素时生长直到质粒丢失的细菌。每株细菌菌株三个独立克隆的细胞裂解液在通过IPTG诱导表达后产生并被用于下述:(图4A)用寡组氨酸的抗体进行蛋白质印迹法,确证细菌中存在相似数量的野生型和突变型蛋白质。(图4B)使用荧光脂肪酶底物1,2-二油酰-3-芘癸酰-外消旋-甘油(1,2-dioleoyl-3-pyrenedecanoyl-rac-glycerol)分析脂肪酶活性。(图4C)脂质体-破裂活性使用盐酸多柔比星评估。(图4D)从十种不同生物体纯化的脂肪酶的脂质体-破裂活性使用盐酸多柔比星评估。来自至少两次独立实验的数据的平均值和标准偏差显示于(图4B)至(图4D)。
【21】图5。使用诺维梭状芽孢杆菌-NT加脂质体CPT-11的治疗效果。在第0天使用所示药剂的不同组合处理具有所示肿瘤的小鼠。显示从每组至少五只小鼠计算的数据平均值和标准误差。诺维梭状芽孢杆菌-NT加盐酸多柔比星与其它组之间的差异显著(p<0.0003,对数秩检验)。
【22】图6A-6B。脂质体-破裂活性。(图6A)在存在来自诺维梭状芽孢杆菌-NT培养物的生长培养基的情况下(“条件培养基”),从盐酸多柔比星释放阿霉素的时程。诺维梭状芽孢杆菌-NT生长至对数晚期,并通过离心将培养基从细胞中清除。显著的脂质体-破裂活性被标注(红色标记),而在所示对照中没有观察到荧光的增加。(图6B)作为培养物中生长时间函数的脂质体-破裂活性。诺维梭状芽孢杆菌-NT芽孢在生长培养基中接种并在其后的不同时间收获。清除细菌细胞后,测量上清液中的脂质体-破裂活性并与600nm处的吸光率关联。显示了来自至少两次脂质体-破裂活性独立试验的数据的平均值和标准偏差。当代表标准偏差的线条小于相关数据点的符号时,标准偏差不可见。
发明详述
【23】本发明人已经开发出治疗肿瘤的方法。所述方法提高肿瘤治疗的特异性,从而减少全身毒性。使用由诺维梭状芽孢杆菌-NT制备的蛋白质和脂质体包囊的药物或生物制剂的组合,大大增加消除肿瘤的功效。所述蛋白质,尽管具有脂肪酶的酶活性,却显示出作为脂质体破裂剂(disruptor)发挥非酶促功能。脂肪酶的酶活性对于脂质体破裂活性不是必要的。因此,野生型和脂肪酶阴性突变体均可用于这一功能。此外,脂质体破裂功能可以通过蛋白质来递送,如同由活性诺维梭状芽孢杆菌-NT或由蛋白质本身的无细胞制备物原位精确实施。此外,所述蛋白质可作为结合或融合蛋白的一部分递送,其提供给脂质体酶蛋白质额外的期望功能。
【24】于此所述方法的潜在优势之一在于,其普遍适用于任何可被包封在脂质体内的化学治疗药物或生物制剂。作为实例,这些包括以下种类的药物:拓扑异构酶抑制剂、DNA合成抑制剂、细胞分裂抑制剂、血管生成抑制剂和微管抑制剂。抗体和抗体偶联物,如美罗华(rituxan)、赫赛汀(herceptin)和爱必妥(erbitux),也可包封在脂质体内。此外,可以使用可提高患者内源性肿瘤对抗系统的细胞因子和其它生物活性蛋白质。这类细胞因子包括但不限于:IL-2和干扰素-α2b和GM-CSF。可使用的具体药物、细胞因子和抗体包括但不限于:阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿伦单抗(Alemtuzumab)、阿利维A酸(alitretinoin)、别嘌呤醇(allopurinαl)、六甲蜜胺(altretamine)、氨磷汀(amifostine)、阿那白滞素(anakinra)、阿那曲唑(anastrozole)、三氧化二砷(arsenic trioxide)、天冬酰胺酶(asparaginase)、阿扎胞苷(azacitidine)、BCG Live、贝伐单抗(bevacizumab)、蓓萨罗丁胶囊(bexarotene capsules)、蓓萨罗丁凝胶(bexarotene gel)、博莱霉素(bleomycin)、硼替佐米(bortezombi)、bortezomib、白消安(busulfan)、卡普睾酮(calusterone)、卡培他滨(capecitabine)、卡铂(carboplatin)、卡氮芥(carmustine)、塞来昔布(celecoxib)、西妥昔单抗(cetuximab)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯伐拉滨(clofarabine)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、更生霉素(dactinomycin,放线菌素D(actinomycin D))、达肝素钠(dalteparin sodium)、darbepoetinalfa、达沙替尼(dasatinib)、道诺红菌素(daunorubicin)、道诺霉素(daunomycin)、地西他滨(decitabine)、地尼白介素(denileukin)、地尼白介素2(Denileukin diftitox)、右雷佐生(dexrazoxane)、右雷佐生(dexrazoxane)、紫杉萜(docetaxel)、阿霉素(doxorubicin)、丙酸屈他雄酮(dromostanolone propionate)、eculizumab、Elliott′s B溶液、表阿霉素(epirubicin)、表阿霉素盐酸(epirubicin hcl)、重组人红细胞生成素(epoetin alfa)、埃罗替尼(erlotinib)、埃罗替尼(erlotinib)、雌莫司汀(estramustine)、依托泊甙磷酸盐(etoposide phosphate)、依托泊甙(etoposide,VP-16)、依西美坦(exemestane)、芬太尼柠檬酸盐(fentanylcitrate)、非格司亭(Filgrastim)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟脲嘧啶(fluorouracil,5-FU)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、吉西他滨(gemcitabine)、吉西他滨盐酸(gemcitabinehcl)、gemicitabine、吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)、乙酸戈舍瑞林(goserelin acetate)、乙酸组氨瑞林(histrelin acetate)、羟基脲(hydroxyurea)、替伊莫单抗(Ibritumomab Tiuxetan)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、甲磺酸伊马替尼(imatinibmesylate)、干扰素α-2a(Interferon alfa-2a)、干扰素α-2b(Interferonalfa-2b)、伊立替康(irinotecan)、二甲苯磺酸拉帕替尼(lapatinibditosylate)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、亚叶酸(leucovorin)、亚叶酸(leucovorin)、亚叶酸(leucovorin)、乙酸亮丙瑞林(Leuprolide Acetate)、左旋咪唑(levamisole)、洛莫司汀(lomustine,CCNU)、氮芥(meclorethamine,nitrogen mustard)、乙酸甲地孕酮(megestrol acetate)、美法兰(melphalan,L-PAM)、巯基嘌呤(mercaptopurine,6-MP)、美司钠(mesna)、甲氨蝶呤(methotrexate)、甲氧沙林(methoxsalen)、丝裂霉素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、苯丙酸诺龙(nandrolone phenpropionate)、奈拉滨(nelarabine)、诺非单抗(Nofetumomab)、奥普瑞白介素(Oprelvekin)、奥普瑞白介素(oprelvekin)、奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、紫杉醇蛋白质-结合颗粒(paclitaxel-bound particles)、palifermin、帕米膦酸(pamidronate)、帕尼单抗(panitumumab)、培加酶(pegademase)、培门冬酶(pegaspargase)、Pegfilgrastim、Peginterferon α-2b、培美曲塞二钠(pemetrexed disodium)、喷司他丁(pentostatin)、哌泊溴烷(pipobroman)、光辉霉素(plicamycin,mithramycin)、卟吩姆钠(porfimersodium)、甲苄肼(procarbazine)、喹纳克林(quinacrine)、拉布立酶(Rasburicase)、利妥昔单抗(Rituximab)、沙格司亭(sargramostim)、索拉非尼(sorafenib)、链脲佐菌素(streptozocin)、舒尼替尼(sunitinib)、舒尼替尼马来酸盐(sunitinib maleate)、滑石(talc)、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷(teniposide,VM-26)、睾内酯(testolactone)、沙利度胺(thalidomide)、6-硫代鸟嘌呤(thioguanine,6-TG)、塞替派(thiotepa)、拓扑替康(topotecan)、拓扑替康盐酸盐(topotecan hcl)、托瑞米芬(toremifene)、托西莫单抗(Tositumomab)、托西莫单抗/I-131托西莫单抗(Tositumomab/I-131 tositumomab)、曲妥珠单抗(trastuzumab)、维甲酸(tretinoin,ATRA)、尿嘧啶氮芥(Uracil Mustard)、戊柔比星(valrubicin)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、vorinostat、唑来膦酸盐(zoledronate)和唑来膦酸(zoledronic acid)。
【25】编码所述脂质体酶的基因具有如GenBank的登记号CP000382所示的序列(SEQ ID NO:2)。所述蛋白质具有登记号ABK60711所示的序列(SEQ ID NO:1)。前35个氨基酸被预测作为信号序列而被切割。在高度保守的GXSXG脂肪酶基序(SEQ ID NO:1的残基160-164)中具有氨基酸置换的突变体,还保留脂质体酶活性并且可以使用。例如,S127G突变体(在SEQ ID NO:1的丝氨酸162上的突变)可以用来提供脂质体酶活性。其它脂肪酶缺陷型突变体也可使用。丝氨酸-127的其它置换(在SEQ ID NO:1中的残基162)可以是与氨基酸A、C、D、E、F、G、H、I、K、L、M、N、P、Q、R、T、V、W或Y的置换。
【26】根据本发明的组合物可在施用于人或其它哺乳动物之前或之后制造。因此,所述组合物的成分可被单独或混合施用。如果单独施用,所述成分可以任何顺序施用。当它们在患者或其它哺乳动物体内时,所述成分可形成所述组合物。所述组合物的成分可以在试剂盒内一起或单独包装。因此,可向最终使用者提供在单一包装中的多个器皿或容器。最终使用者可一次或一次以上单独或混合施用所述成分。
【27】包括用于实践本发明抗肿瘤方法的有用成分的试剂盒,可被包装在分开或未分开的容器内,所述容器如纸盒、瓶、安瓿、管等。所述芽孢、脂质体酶和抗肿瘤剂可以以例如干燥、冻干或液体形式进行包装。提供的附加成分可包括用于干燥成分重构的赋形剂。优选地,所有这类赋形剂是无菌且不致热的,以便于它们适于注射至哺乳动物中而不产生副作用。除芽孢之外的抗肿瘤剂也优选是无菌的。所述芽孢优选地是微生物学纯的,即除了期望的形成芽孢的厌氧菌之外,不含有其它细菌。
【28】用于制造脂质体的方法是本领域熟知的。参见例如:Mozafari,Cell Mol Biol Lett.2005;10(4):711-9;Andresen等,Prog Lipid Res.2005 Jan;44(1):68-97;Jensen等,Mol Cancer Ther.2004 Nov;3(11):1451-8;Pupo等,J Control Release.2005 May 18;104(2):379-96p;Brandl,Biotechnol AnnuRev.2001;7:59-85。本领域已知用于制造脂质体的任何技术均可使用。
【29】诺维梭状芽孢杆菌芽孢可如本领域已知进行制备。优选地,所述芽孢将来自毒素缺陷型菌株。参见例如:美国专利申请20050079157,其内容明确引用于此。通过细菌噬菌体或质粒自愈的方法可以消除毒素。作为原材料使用的诺维梭状芽孢杆菌(ATCC19402)可从美国典型培养物保藏中心(the American Type Culture Collection,10801 UniversityBoulevard,Manassas,VA,20110-2209)获得。
【30】虽然菌株没有必要是完全无毒素的,但是期望的是,至少一种毒素基因被突变、缺失或被另外灭活以使细菌对宿主的有害性更小。如果毒素基因是游离的或在噬菌体上,则游离基因或噬菌体的消除可被用于去除毒素基因。技术是本领域中用于突变体诱变和筛选以及用于消除游离基因领域所熟知的。
【31】根据本发明的分离的且细菌学纯的无性繁殖的细菌或芽孢,是没有受到其它细菌或芽孢污染的那些。用于获得这类纯培养物的微生物学技术是本领域熟知的。典型地,挑取单个菌落并涂布于琼脂营养培养基上,分离菌落以产生为单细胞后代的新菌落。该过程通常被重复以确保纯培养物。可选地,液体培养物可连续稀释并涂板以形成单菌落。为确保来自单细胞的菌落形成,连续重复是期望的。参见例如:J.H.Miller,Experimentals in Molecular Genetics(分子遗传学实验),Cold Spring HarborLaboratory(冷泉港实验室),NY,1972。
【32】芽孢、脂质体酶、脂质体酶偶联物和编码脂质体酶或其融合蛋白的核酸,可通过任何能提供接近肿瘤的方法施用给具有肿瘤的哺乳动物。芽孢可静脉注射、皮内注射、皮下注射、肌肉内注射、腹膜内注射、肿瘤内注射、鞘内注射、外科手术注射等。优选的技术是静脉内和肿瘤内注射。具有肿瘤的哺乳动物可以是例如:人类;宠物,如狗和猫;农业动物,如奶牛、绵羊、山羊和猪;以及实验动物,如大鼠、仓鼠、猴子、小鼠和兔子。
【33】本递送系统用于蛋白质治疗或基因治疗或它们的组合。因此,脂质体酶可作为蛋白质或作为编码脂质体酶的多核苷酸来提供。类似地,所述抗肿瘤药物或生物制剂可以是蛋白质或多核苷酸,以及小化学实体,例如不是生物聚合物。多核苷酸可以提供在病毒或非病毒载体中。任何本领域已知的载体可使用而不受限制。载体构建物可含有肿瘤特异性启动子以增强治疗的特异性。这些启动子的实例是本领域已知的。CXCR4启动子在黑素瘤中是肿瘤特异性的;己糖激酶II型启动子在肺癌中是肿瘤特异性的;TRPM4(瞬时受体电位-Melastatin 4,Transient ReceptorPotential-Melastatin 4)启动子优先在前列腺癌具有活性。所述抗肿瘤药物可以是直接或间接对肿瘤起作用的药物。因此,例如它可以是刺激对肿瘤的天然免疫反应的蛋白质。可选地,它可以是调动免疫系统其它成分来破坏肿瘤细胞的抗体。还有其它物质可对肿瘤细胞具有毒性。对试剂的选择正好在本领域普通技术人员技能内。
【34】结合蛋白质是翻译后被连接的蛋白质;它们可通过两个多肽的化学连接——直接或通过中间体——而连接。可选地,所述蛋白质可通过单一开放读码框内的两个编码区的共翻译来连接。任何用于连接两个未被天然连接的多肽的方法均可使用。可使用的一种偶联物类型采用抗体分子或其部分作为第二种蛋白质。因此,作为实例,脂质体酶可以被连接到抗体的可变区,从而提供给所述脂质体酶靶向表达与抗体结合的抗原的机体内特定位点的途径。连接物可根据期望在结合蛋白质的部分之间使用。
【35】根据本发明的分离并纯化的脂质体酶蛋白质是这样的制备物,其中所述脂质体酶活性占组合物中的蛋白质的至少10%、25%、40%、55%、70%、85%或95%。编码分离并纯化的脂质体酶的多核苷酸是从诺维梭状芽孢杆菌基因组的其它基因中分离出的多核苷酸。因此,它与编码假设蛋白质NT01CX_2046和NT01CX_2048的基因组邻近序列是分开的。诺维梭状芽孢杆菌-NT的完整基因组已被测定并在NCBI中以NC_008593可用。它是2,5478,720nt的环状DNA。
【36】本发明的方法和组合物可用于任何肿瘤类型。本发明依赖的原理(如脂质体穿透存在于肿瘤和几个其它器官的有孔内皮的选择性能力(8,9),和在脂质体酶存在情况下来自脂质体的内含物的释放增强)适用于任何肿瘤。因此,本发明可用于治疗胃肠道如胃、小肠、结肠、直肠、食道的肿瘤,肾、乳房、肺、肝、头颈和脑的肿瘤。
【37】上述公开内容概括描述本发明。所有于此公开的参考通过引用明确引入。更完整的理解可通过参考以下具体实施例获得,所述实施例提供于此的目的仅用于说明,并不企图限制本发明的范围。
实施例1
材料与方法
【38】细胞系。HCT116(CCL-247,人结直肠癌)和CT26(CRL-2638,小鼠结直肠腺癌)购自美国典型培养物保藏中心。两种细胞系在37℃ 5%CO2中生长于补充5%FBS(Hyclone)的McCoy′s 5A培养基(Invitrogen)中。
【39】试剂。阿霉素购自Bedford Laboratories,Bedford,OH。PEG化的脂质体阿霉素购自Tibotec Therapeutics,Raritan,NJ。鸡蛋L-α-磷酸卵磷脂(Egg L-α-Phosphatidylcholine,EPC),氢化鸡蛋L-α-磷酸卵磷脂(Hydrogenated Chicken Egg L-α-Phosphatidylcholine,HEPC)、1,2-双十八烷酰-sn-甘油-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)-2000](1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine-N-[MethoxyPolyethylene glycol)-2000],DSPE-PEG2000)和胆固醇(Chol)均购自Avanti Polar Lipids,Alabaster,AL。盐酸伊立替康(Camptosar)购自Pharmacia & Upjohn Co.,Kalamazoo,MI。卡西霉素(Calcimycin)A23187和甘油三油酸酯(Triolein)从Sigma(St.Louis,MO)获得。1,2-二油酰-3-芘癸酰-外消旋-甘油(DPG)从MarkerGene Technologies(Eugene,OR)获得。一组九种纯化脂肪酶购自瑞士Fluka。诺维梭状芽孢杆菌-NT芽孢如前所述制备(1)。
【40】脂质体制备。HEPC:Chol:DSPE-PEG2000摩尔比为50:45:5的混合物溶解于氯仿,并在旋转蒸发下干燥成薄膜,然后在真空下进一步干燥2小时。该膜用300mM MnSO4水合,并浸没在65℃超声处理浴中(Bransonic,Danbury,CT),以形成大的多层脂质体(Large MultilamellarVesicles,MLVs)。这种脂类悬浮物使用Lipex Thermobarrel挤压机(Northern Lipids,Vancouver,BC,加拿大)通过双层0.1um Nuclepore滤器(Whatman,Florham Park,NJ)挤压10次。所产生的单一单层脂质体(Single Unilamellar Vesicles,SUV)的胶态悬浮体被无菌过滤,然后在4℃使用300mM蔗糖透析,以交换脂质体外部环境。SUV的平均大小为100.2nm(多分散指数=0.129),如使用Malvern Zetasizer 3000(Malvern,Worcestershire,UK)通过准弹性光散射测定。
【41】脂质体CPT-11。使用硫酸锰pH梯度装载法将CPT-11主动填充到脂质体中(2-4)。伊立替康与脂质体以1:3的药物:脂质摩尔比混合,并在65℃温育10min。然后以1μg卡西霉素:10μmol脂质比率添加卡西霉素,并在65℃温育悬浮液45min。然后,将所述填充药物的脂质体无菌过滤并用300mM蔗糖在4℃透析,以去除未包囊的CPT-11。透析在黑暗中进行以最小化药物的光降解。包囊效率通常>99%,如使用1-丁醇对脂质体破裂以及利用荧光板阅读器(Fluostar Galaxy,BMG LabTech,GmbH)进行荧光测量(在390nm激发,在460nm发射)测定。通过参考CPT-11标准曲线得出浓度。
【42】动物模型。所有动物实验由约翰霍普金斯大学动物福利委员会(the Animal Welfare Committee of Johns Hopkins University)监督和批准并遵守大学标准。购自Harlan Breeders,IN的6到8周龄的小鼠用于肿瘤移植研究。Balb/c小鼠用于建立CT26肿瘤,无胸腺裸鼠(athymic nu/numice)用于建立HCT116异种移植。每实验组使用最少五只动物。将500万个肿瘤细胞皮下注射至每只小鼠的右肋腹并在随机选择和处理前使其生长~10天。诺维梭状芽孢杆菌-NT芽孢以丸尾静脉注射悬浮在0.2ml磷酸盐缓冲液中的3亿芽孢来施用。在相关组中游离的和含脂质体的药物在16小时后通过同样的途径施用。盐酸多柔比星、阿霉素、脂质体伊立替康和伊立替康的剂量分别为10mg/kg和25mg/kg。肿瘤体积被计算为长度×宽度2×0.5。
【43】药物动力学研究。在无胸腺裸鼠中建立HCT116异种移植物并如上所述处理。在处理后不同时间收获组织样品,悬浮于70%乙醇、0.3N HCl中并匀浆( T25Basic,IKA,NC)以提取阿霉素。离心后,用荧光板阅读器(FluoStar Galaxy,BMG LabTech,GmbH)测定上清液中的阿霉素荧光(在470nm激发,在590nm发射)。通过参考阿霉素标准曲线得出浓度。
【44】脂质体破裂测定。样品与盐酸多柔比星混合(在96孔板中100μl样品+5μl盐酸多柔比星或在384孔板中50μl样品+2μl盐酸多柔比星)。使用470nm处的激发和590nm处的发射,在30-60分钟内,动力学测量由释放阿霉素的去猝灭(dequench)引起的荧光增加(5)。所有测量在37℃在荧光板阅读器中进行。典型的读数示于图S1中。脂质体破裂活性被定义为释放曲线的最大斜率。
【45】生化纯化。诺维梭状芽孢杆菌-NT芽孢接种于20ml Bagadi培养基(6)中并在厌氧室(A型,Coy Labs,Grass Lake,MI)中于37℃温育~16小时。1ml这种发酵剂培养物(starter culture)用于接种100ml已在厌氧室中预平衡的Bagadi培养基。这种培养物生长至对数后期,随后5,000g离心去除细菌。上清液用50%饱和硫酸铵在4℃沉淀1小时,然后5,000g离心。弃上清液后,沉淀溶解于TN缓冲液(100mM Tris-HCl,pH7.5,0.1M NaCl)并无菌过滤。所有随后的层析都在 PurifierFPLC系统(Amersham Biosciences,Piscataway,NJ)上进行。所过滤的样品装填至在TN缓冲液中平衡的单Q5/50GL(Amersham)柱。蛋白质用由TN缓冲液和100mM Tris-HCl7.5,1M NaCl形成的10倍柱体积线性梯度洗脱。如上所述测定收集组分的阿霉素释放活性。收集来自单Q柱的两种最具活性的组分并装填至在100mM Tris-HCl pH7.5、0.5M NaCl中平衡的HiLoad 16/60Superdex 200(Amersham)柱上。用超过1.5柱体积的相同缓冲液无梯度洗脱柱。如上所述测定组分的阿霉素破裂活性。两种最具活性组分中的蛋白质通过经过SDS-聚丙烯酰胺凝胶的电泳进行分离,并使用SilverSNAP染色试剂盒II(Pierce,Rockford,IL)进行银染色。切取单一显著条带(≈45kD)用于LC/MS/MS分析。
【46】LC/MS/MS肽分析。使用胰蛋白酶在凝胶中消化切取的蛋白条带并对其进行如前所述的分析(7)。简言之,使用Agilent 1100 SeriesCapillary-LC系统,在5%缓冲液B中将纯化的胰蛋白酶片段注入到150×0.3mmVydac反相柱上,以10μL/min进行5分钟。缓冲液A(0.1%乙酸)和B(99.9%乙腈和0.1%乙酸)用于LC/MS/MS分析的液相层析(LC)步骤。使用10-65%的缓冲液B梯度,以2μL/min的速度,在90分钟内,将肽从柱上洗脱。使用LCQ DECA XP质谱仪(Thermo,MA)检测洗脱的肽,该质谱仪配有电喷雾电离源、以数据依赖型模式操作的低流量金属针装配。该方法由两种扫描事件组成,即全面扫描和二级数据依赖型MS/MS扫描。全面扫描的动态质量范围设定在300至3000m/z。所产生的MS/MS数据依赖型扫描拒绝下述的已知“污染”值:371.0、391.0、445.0、462.0、1221.89、1321.9、1421.9、1521.8、1521.9、1621.9、1721.9和1821.9m/z。其它方法设置包括设定为4的默认充电状态,带有重复计数设定为2的动态排除,重复期间1min,排除列表大小25和排除期间3分钟。所有其它方法参数都是由Xcaliber软件v.1.2(Thermo,MA)设定的默认值。
【47】寡组氨酸-融合蛋白的克隆。缺乏N-端分泌信号(如SignalP 3.0预测)的NT01CX2047编码序列用Phusion Taq聚合酶(Finnzymes,Espoo,Finland)进行PCR扩增,利用正向引物5′-TGCACCACCACCACCACCACAAAGAAAATCAAAAAGTATCACAAAATAATTATCCTATAATACTTTGTCATGG(SEQ ID NO:3)和反向引物5′-CTGACCGGTTTATTATTCAGTTACAGGAAGATTTCTAAGCATTTGAGCC(SEQ ID NO:4)。正向引物中的(CAC)6序列在编码蛋白质的N-端增加6个组氨酸残基。用Age I消化这种PCR产物以产生具有一个粘性末端的插入。用Nde I消化克隆载体pCR2.1/T7-GFP(Invitrogen,Carlsbad,CA),使用T4 DNA聚合酶平端化,然后使用Age I消化以产生单个粘性末端。连接载体和插入以产生pLip。通过DNA测序验证预期的插入序列。
【48】S127G和S127X变体的克隆。用SnaB I消化pLip质粒以切出含有要被突变的丝氨酸残基的45bp片段。pLip(S127G)质粒是通过平端连接所消化的质粒与45bp置换双链寡核苷酸产生的,所述双链寡核苷酸具有序列5′-GTAAAGTTCATTTAATAGGACACGGTCAAGGTGGACAAACTATAC(SEQ ID NO:5)。质粒pLip(S127X)质粒是利用双链寡核苷酸5′-GTAAAGTTCATTTAATAGGACACTAATAAGGTGGACAAACTATAC(SEQ ID NO:6)以同样的方式产生。靶向更替(上面下划线处)和插入方向用DNA测序验证。
【49】蛋白质表达。通过热休克将如上所述的表达载体转化至大肠杆菌Rosetta-gami(DE3)pLysS菌株(Novagen,Madison,WI)。每个表达构建物挑选三个克隆,每个克隆在室温下在20ml具有抗生素选择(100μg/ml氨苄青霉素+34μg/ml氯霉素)的HyperBroth(AthenaES,Baltimore,MD)培养。作为阴性对照,携带pLip质粒的细菌通过在选择性抗生素不存在时生长,它们的质粒被“消除(cured)”。质粒的丢失通过PCR验证。使用IPTG诱导表达1小时,达到OD600~0.2时,之后,通过离心来沉淀细菌并将其悬浮于100mM Tris-HCl,pH7.5。裂解液通过在Bioruptor超声浴(Diagenode,Belgium)中超声处理来制备,并进行~14,000g离心以去除不溶物。使用α-多组氨酸小鼠mAb(R&D Systems,MN)进行的蛋白质印迹用于确定期望蛋白质的存在。
【50】脂肪酶分析。EPC:三油酸甘油酯:DPG以摩尔比2:5:1在氯仿中混合并在旋转蒸发下干燥成薄脂质膜,然后在高真空下进一步干燥2小时。该膜用100mM甘氨酸缓冲液pH9.5、19mM脱氧胆酸钠水合以产生1mM的DPG终浓度。剧烈涡旋这种悬浮物以形成用做底物的乳状液。在384-孔板中将样品与该底物混合(30μl样品+5μl样品)。动力学测量由芘癸酸催化释放引起的荧光增加2小时,使用320nm下的激发和405nm下的发射。所有测量在37℃在FluoStar Galaxy荧光板阅读器中进行。脂肪酶活性单位通过参考洋葱假单胞菌(Pseudomonas cepacia)脂肪酶标准曲线得出。1个单位(unit,U)对应相同数量的洋葱假单胞菌脂肪酶活性,其每分钟从甘油三油酸酯释放1μmol油酸。
【51】脂肪酶平板实验。将纯化的NT01CX2047酶和九种其它纯化的脂肪酶溶解于100mM Tris-HCl,pH7.5至浓度为1mg/ml。用移液管将50μl的检测缓冲液(100mM Tris-HCl pH7.5+0.125M NaCl))加至384-孔板,随后加入2μl相关的脂肪酶和1μl盐酸多柔比星。如上所述重复测定样品的脂质体破裂活性。
实施例2——在第一个模型中体内芽孢加脂质体
【52】我们在BALB/c小鼠中使用同系CT26结直肠肿瘤。静脉注射诺维梭状芽孢杆菌-NT芽孢,并且一旦在肿瘤中开始萌发(注射后~16小时),通过尾静脉施用10mg/kg单剂量盐酸多柔比星。盐酸多柔比星是包封阿霉素的脂质体配制物,阿霉素是一种DNA损伤剂和广泛使用的化学治疗药物。在多种实验和临床研究中,脂质体包封的阿霉素与未包封的阿霉素相比已经显示出产生改进的结果(18-21)。在盐酸多柔比星中的脂质体通过PEG化进行表面修饰以提高其循环时间(18)。如前所记录(11,12),用诺维梭状芽孢杆菌-NT芽孢单独治疗在肿瘤中央低氧区域内产生萌发和坏死,但留下最终再生的充分氧化的可生存边缘(图1A)。单独使用阿霉素和盐酸多柔比星在这些小鼠中都不能产生长期治疗效果。但是,当盐酸多柔比星与诺维梭状芽孢杆菌-NT芽孢组合时,效果显著,在所有小鼠中产生完全的肿瘤退化(图1A)并且其一半以上治愈(图1B)。值得注意的是,用相同剂量的诺维梭状芽孢杆菌-NT和游离阿霉素处理的小鼠表现出显著的发病率,100%小鼠在2周内死亡,这强调了脂质体包囊在减少全身毒性上的关键作用(18)。
实施例3——在第二种模型中体内芽孢加脂质体
【53】为测定在其它肿瘤模型系统中是否可以观察到这些明显的抗肿瘤效果,我们用相同方法处理在裸鼠中生长的人结直肠癌异种移植物[HCT116]。如图1C和1D所示,诺维梭状芽孢杆菌-NT芽孢与盐酸多柔比星组合使用时,导致肿瘤HCT116肿瘤退化,类似于在CT26肿瘤中观察到的结果。在这些肿瘤模型中使用的脂质体阿霉素剂量与目前用于临床治疗癌症患者的那些剂量相匹配(19-21)。
实施例4——体内盐酸多柔比星分布
【54】在上所述实验中观察到的协同效应推测是由于诺维梭状芽孢杆菌-NT感染导致阿霉素在肿瘤内的浓度增加。为证实这一推测,比较仅接受盐酸多柔比星的小鼠和用盐酸多柔比星加诺维梭状芽孢杆菌-NT芽孢处理的小鼠体内的阿霉素的分布。如图2A所示,在诺维梭状芽孢杆菌-NT存在下施用盐酸多柔比星时,阿霉素的肿瘤内浓度有显著增加。相反,在存在或缺乏芽孢的情况下,在心脏、肝、脾、肾和肌肉中的阿霉素水平相似(图2A)。在感染肿瘤内发现的阿霉素已从脂质体释放并结合到肿瘤细胞核,如免疫荧光显示(图2B)。注意,以前显示常规治疗肿瘤内阿霉素浓度,在施用盐酸多柔比星后比施用阿霉素后更高且更稳定(22)。实际上,在不增加正常组织中药物浓度的情况下,施用诺维梭状芽孢杆菌-NT芽孢加盐酸多柔比星引起的肿瘤药物暴露与同等剂量的游离阿霉素所实现的肿瘤药物暴露相比,具有大于100倍的增加。
实施例5——可能的脂质体破裂因子的尝试性鉴定
【55】我们下一步试图鉴定解释在注射盐酸多柔比星后诺维梭状芽孢杆菌-NT在肿瘤中释放阿霉素能力的机制。我们发现通过诺维梭状芽孢杆菌-NT生长而调节的培养基含有强大的脂质体破裂因子,并且这种因子的浓度在对数后期为最大值(图6)。我们预测该因子是磷脂酶,因为已知这些酶破坏脂质体的脂质双层以及红细胞的脂质双层(17)。两种磷脂酶C酶已从诺维梭状芽孢杆菌纯化,并且其中一种具有溶血活性(23-25)。所述诺维梭状芽孢杆菌-NT基因组包含四个预测编码磷脂酶的基因(26)。这四个基因(NT0lCX0979)中的一个编码在生长细菌中高水平表达的(26)细胞外磷脂酶C蛋白(23,25)。
【56】迄今为止因为已经证实诺维梭状芽孢杆菌-NT排斥通过外源DNA的转化,我们采取不同的策略来测试脂质体破裂因子是磷脂酶CNT01CX0979的假设。在MNNG-介导的诱变后,我们在血琼脂平板上平板接种~10,000个细菌,并鉴定一个可繁殖地缺乏溶血活性的菌落。通过DNA测序证明该克隆在NT01CX0979磷脂酶C基因内具有971G>A的转换,导致相当保守的甘氨酸向谷氨酰胺的突变(25)。意料不到的是,这种溶血阴性克隆的生长培养基保持其脂质体破裂活性,这说明这种活性不是NT01CX0979的结果,或者实际上是足以溶血的任何其它酶的结果。
实施例6——脂质体破裂因子及其编码序列的鉴定
【57】为了鉴定脂质体破裂因子,我们通过硫酸铵沉淀、离子交换层析和凝胶过滤的组合分离来自对数晚期诺维梭状芽孢杆菌-NT的培养基。观察到脂质体破裂活性的单一主峰(图3A、B)。SDS-聚丙烯酰胺凝胶电泳显示在活性成分中的主要银染色条带(图3C)。纯化该条带,用胰蛋白酶消化并用液相色谱串联质谱分析。利用诺维梭状芽孢杆菌-NT基因组作为参考,发现该多肽由NT01CX2047编码,NT01CX2047是一种假定的脂肪酶。这两种在诺维梭状芽孢杆菌-NT基因组中鉴定的细胞外脂肪酶(NT01CX0630和NT01CX2047)互相之间(47%的氨基酸同一性)或与其它细菌中最接近的相似物(与破伤风梭菌脂肪酶具有50~55%的氨基酸同一性)不具有高度同源性。对作为NT01CX2047产物的脂质体破裂因子的鉴定与来自诺维梭状芽孢杆菌-NT基因组分析的信息一致,这显示出NT01CX2047优先在对数晚期表达,预测其将在细胞外,并且用诺维梭状芽孢杆菌-NT感染后在肿瘤中高度表达(26)。
实施例7——脂质体破裂因子的ORF的克隆
【58】为了检测通过NT01CX2047编码的蛋白质的性质,我们克隆其ORF至诱导表达载体中,然后将该表达载体引入遗传修饰的大肠杆菌菌株以允许诺维梭状芽孢杆菌-NT基因的表达(其具有与大肠杆菌差别很大的密码子使用)。通过IPTG诱导蛋白表达后,转化的大肠杆菌生长不佳,推测是因为基因产物有毒。通过1,2-二油酰-3-芘癸酰-外消旋-甘油的水解进行测量来测试来自这些细胞的裂解液的脂肪酶活性。表达NT01CX2047的克隆显示出脂肪酶活性,而消除载体的克隆(见下文)没有显示(图4B)。作为进一步的对照,产生127位氨基酸处的丝氨酸残基用终止密码子置换的衍生物(S127X)。我们还产生了其中在127位残基处的丝氨酸被甘氨酸置换的突变体(S127G)。发现S127位于高度保守的GXSXG脂肪酶基序内,并预测其是负责脂酶活性的主要催化丝氨酸(27)。因此,S127G错义突变体和S127X截断突变体都缺乏脂酶活性,虽然每种突变型均产生相似数量的NT01CX2047多肽(图4A、B)。有趣的是,非催化S127G突变体表现出与野生型NT01CX2047一样差的生长,而S127X突变体的生长要有力得多。不具备脂酶活性的S127G突变体的明显毒性令人费解,但其通过下述实验进行说明。
实施例8——脂肪酶活性和脂质体破裂活性的基因分离
【59】为了测试如上所述裂解液的脂质体破裂活性,我们将它们与脂质体阿霉素共温育。在该试验中,含有NT01CX2047野生型形式的菌株具有有效活性(图4C)。当在无选择性抗生素的情况下培养该菌株直至细菌通过随机分离丢失表达载体时,脂质体破裂活性消失(图4C)。此外,已丢失质粒的细胞能够如同其亲本大肠杆菌和S127X突变体一样有力生长。如所预期的,S127X截断突变体没有可检测的脂质体破裂活性(图4C)。然而,意料不到的是,缺乏脂肪酶活性的S127G突变体保留了基本的脂质体破裂活性(图4C)。为了测定破坏脂质体的能力是否是诺维梭状芽孢杆菌-NT的NT01CX2047脂肪酶特定的,我们测试了9种具有明确脂肪酶活性的商用酶的脂质体破裂活性,它们都不具有显著的脂质体破裂活性(图4D)。
实施例9——带有其他药剂的脂质体也有效
【60】因此,我们测试含有CPT-11(伊立替康)的脂质体,CPT-11是一种异构酶抑制剂,类似阿霉素,其被广泛用于癌症治疗。单剂量的脂质体CPT-11单独或在施用诺维梭状芽孢杆菌-NT后16小时注射,正如在所述盐酸多柔比星实验中。当单独注射时,两种肿瘤类型(同系小鼠中的CT26和裸鼠中的人结直肠癌细胞异种移植物)对脂质体CPT-11具有相对抗性。但是,在芽孢存在情况下,所有肿瘤退化并在>60%的小鼠中实现长期治愈(图5)。
【61】同样值得注意的是在这些和所述脂质体阿霉素实验中,脂质体酶策略在小肿瘤以及大肿瘤中是有效的,在体积小至136mm3的肿瘤中观察到治愈。在以前的研究中,证明小肿瘤对溶菌治疗具有抗性,因为在小肿瘤内具有相对小的坏死区域(11)。我们猜想脂质体药物和诺维梭状芽孢杆菌-NT芽孢组合的有效性是因为它们彼此相互增强:通过EPR效应在肿瘤中积累的细胞毒性药物导致坏死和缺氧,这导致诺维梭状芽孢杆菌-NT的萌发,这进而导致通过脂质体酶的更多药物释放。
【62】在肿瘤内阿霉素从盐酸多柔比星的部分释放(图2)理论上可能是由于从诺维梭状芽孢杆菌-NT或感染的肿瘤细胞释放的其它酶。但是,分泌自诺维梭状芽孢杆菌-NT的主要盐酸多柔比星破裂因子是脂质体酶(图3),并且其基因在感染肿瘤中高水平表达(26),这表明脂质体酶明显有助于体内作用。此外,现在已鉴定并克隆脂质体酶,它可以被纳入其它抗癌药物策略中。这些策略包括癌症基因治疗,其使用病毒或非病毒递送系统和抗体介导的酶前体药物治疗(3,4,31,32)。在过去,这类方法受限于可用前体药物的量小和获得在细胞中代谢的药物以对其它肿瘤细胞发挥旁观者效应的必要性(31,32)。利用脂质体酶,种类繁多的“前体药物”已经商业可得,因为可被包封在脂质体内的任何化学治疗药物在理论上均可使用。也可以设想多药物治疗——其中每种药物在单独的脂质体中结合。最后,因为脂质体酶被分泌并且脂质体在肿瘤细胞外部,所以基本的旁观者效应是可以预期的。
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Claims (47)
1.组合物,其包括:
毒素缺陷型诺维梭状芽孢杆菌芽孢;和
脂质体,其包含抗肿瘤药物或生物制剂。
2.组合物,其包括:
依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶;和
脂质体,其包含抗肿瘤药物或生物制剂。
3.根据权利要求1或2所述的组合物,其中所述组合物在体内形成。
4.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是阿霉素。
5.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是伊立替康。
6.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是抗体。
7.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是多核苷酸。
8.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是在病毒载体中的多核苷酸。
9.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是在非病毒载体中的多核苷酸。
10.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是蛋白质。
11.根据权利要求1或2所述的组合物,其中所述抗肿瘤药物或生物制剂是细胞因子。
12.试剂盒,其包括:
依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶;和
脂质体,其包含抗肿瘤药物或生物制剂。
13.试剂盒,其包括:
毒素缺陷型诺维梭状芽孢杆菌芽孢;和
包括抗肿瘤药物或生物制剂的脂质体。
14.根据权利要求12或13所述的试剂盒,其中所述抗肿瘤药物或生物制剂是阿霉素。
15.根据权利要求12或13所述的试剂盒,其中所述抗肿瘤药物或生物制剂是伊立替康。
16.根据权利要求12或13所述的试剂盒,其中所述抗肿瘤药物或生物制剂是抗体。
17.根据权利要求12或13所述的试剂盒,其中所述抗肿瘤药物或生物制剂是多核苷酸。
18.根据权利要求12或13所述的试剂盒,其中所述抗肿瘤药物或生物制剂是在病毒载体中的多核苷酸。
19.根据权利要求12或13所述的试剂盒,其中所述抗肿瘤药物或生物制剂是在非病毒载体中的多核苷酸。
20.治疗癌症患者的方法,其包括:
向癌症患者施用第一种药剂和第二种药剂,所述第一种药剂是毒素缺陷型诺维梭状芽孢杆菌芽孢,所述第二种药剂是包含抗肿瘤药物或生物制剂的脂质体,藉此所述肿瘤退化或其生长被减慢或被抑制。
21.治疗癌症患者的方法,其包括:
向癌症患者施用第一种药剂和第二种药剂,所述第一种药剂是依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶,所述第二种药剂是包含抗肿瘤药物或生物制剂的脂质体,藉此所述肿瘤退化或其生长被减慢或被抑制。
22.治疗癌症患者的方法,其包括:
向癌症患者施用第一种药剂和第二种药剂,所述第一种药剂是载体,该载体编码依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶,所述第二种药剂是包括抗肿瘤药物或生物制剂的脂质体,藉此所述肿瘤退化或其生长被减慢或被抑制。
23.根据权利要求20、21或22所述的方法,其中所述第一种药剂和所述第二种药剂被顺序施用。
24.根据权利要求20、21或22所述的方法,其中所述第一种药剂和所述第二种药剂被同时施用。
25.根据权利要求20、21或22所述的方法,其中所述抗肿瘤药物或生物制剂是阿霉素。
26.根据权利要求20、21或22所述的方法,其中所述抗肿瘤药物或生物制剂是伊立替康。
27.根据权利要求20、21或22所述的方法,其中所述抗肿瘤药物或生物制剂是抗体。
28.根据权利要求20、21或22所述的方法,其中所述抗肿瘤药物或生物制剂是多核苷酸。
29.根据权利要求20、21或22所述的方法,其中所述抗肿瘤药物或生物制剂是在病毒载体中的多核苷酸。
30.根据权利要求20、21或22所述的方法,其中所述抗肿瘤药物或生物制剂是在非病毒载体中的多核苷酸。
31.根据权利要求22所述的方法,其中所述载体是病毒载体。
32.根据权利要求22所述的方法,其中所述载体是非病毒载体。
33.组合物,其包括依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的分离的和纯化的毒素缺陷型诺维梭状芽孢杆菌脂质体酶蛋白质。
34.结合蛋白质,其包括:
依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶蛋白质;和
多肽配体,其在肿瘤细胞上与受体结合。
35.根据权利要求34所述的结合蛋白质,其中所述多肽配体是抗体的重链或轻链可变区。
36.根据权利要求34所述的结合蛋白质,其进一步包括在所述脂质体酶蛋白质与所述多肽配体之间的连接肽。
37.根据权利要求34所述的结合蛋白质,其中所述多肽配体包括抗体的重链可变区和轻链可变区。
38.根据权利要求37所述的结合蛋白质,其包括在所述重链可变区与所述轻链可变区之间的连接肽。
39.根据权利要求34所述的结合蛋白质,其是翻译后结合的。
40.根据权利要求34所述的结合蛋白质,其作为单一多肽链被翻译。
41.多核苷酸,其编码根据权利要求40所述的结合蛋白质。
42.组合物,其包括分离的和纯化的多核苷酸,所述多核苷酸编码依照SEQ ID NO:1或依照在GXSXG脂肪酶基序的残基160-164处具有置换突变的SEQ ID NO:1的毒素缺陷型诺维梭状芽孢杆菌脂质体酶蛋白质。
43.根据权利要求42所述的组合物,其中所述多核苷酸包括依照SEQID NO:2的核苷酸序列。
44.根据权利要求42所述的组合物,其中所述多核苷酸包括载体。
45.根据权利要求42所述的组合物,其中所述多核苷酸包括病毒载体。
46.根据权利要求42所述的组合物,其中所述多核苷酸包括非病毒载体。
47.根据权利要求42所述的组合物,其中所述多核苷酸包括启动子,其在肿瘤中的转录活性比在正常组织中高出至少两倍。
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CN108136031A (zh) * | 2015-10-07 | 2018-06-08 | 盐水港精糖株式会社 | 包含紫杉烷化合物的脂质体 |
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EP2601934A1 (en) * | 2009-01-22 | 2013-06-12 | Ludwig-Maximilians-Universität München | Vesicular phospholipid gels comprising proteinaceous substances |
WO2012054717A2 (en) * | 2010-10-21 | 2012-04-26 | The Johns Hopkins University | Detecting and treating solid tumors through selective disruption of tumor vasculature |
WO2014010758A1 (ja) | 2012-07-13 | 2014-01-16 | 学校法人帝京平成大学 | 抗腫瘍剤、腫瘍検出用マーカー及び経口ワクチン剤 |
CA2977397A1 (en) | 2015-03-03 | 2016-09-09 | Cureport, Inc. | Dual loaded liposomal pharmaceutical formulations |
CN107530283A (zh) | 2015-03-03 | 2018-01-02 | 奎尔波特股份有限公司 | 组合脂质体药物制剂 |
WO2021123391A1 (en) | 2019-12-18 | 2021-06-24 | Exomnis Biotech B.V. | Genetically modified clostridium strains and uses thereof |
TW202345881A (zh) * | 2022-03-23 | 2023-12-01 | 國立研究開發法人理化學研究所 | 用以治療惡性腫瘤的組合醫藥 |
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US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
FI20031528A0 (fi) * | 2003-10-17 | 2003-10-17 | Ctt Cancer Targeting Tech Oy | Terapeuttinen liposomikoostumus ja menetelmä sen valmistamiseksi |
JP2005298486A (ja) * | 2004-03-15 | 2005-10-27 | Nipro Corp | リポソームを含む癌治療用医薬組成物 |
US7740861B2 (en) * | 2004-06-16 | 2010-06-22 | University Of Massachusetts | Drug delivery product and methods |
US20090117176A1 (en) * | 2004-10-26 | 2009-05-07 | Pharma Mar, S.A. Sociedad Unipersonal | Anticancer Treatments |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108136031A (zh) * | 2015-10-07 | 2018-06-08 | 盐水港精糖株式会社 | 包含紫杉烷化合物的脂质体 |
CN108136031B (zh) * | 2015-10-07 | 2022-02-18 | 盐水港精糖株式会社 | 包含紫杉烷化合物的脂质体 |
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CN101489593B (zh) | 2015-11-25 |
WO2007149433A2 (en) | 2007-12-27 |
US20130315986A1 (en) | 2013-11-28 |
US20110250258A1 (en) | 2011-10-13 |
JP5319523B2 (ja) | 2013-10-16 |
US20130142862A1 (en) | 2013-06-06 |
KR20090027674A (ko) | 2009-03-17 |
US20150306184A1 (en) | 2015-10-29 |
US8444963B2 (en) | 2013-05-21 |
WO2007149433A3 (en) | 2008-11-06 |
KR101376634B1 (ko) | 2014-03-27 |
US8901100B2 (en) | 2014-12-02 |
US8568708B2 (en) | 2013-10-29 |
JP2009541319A (ja) | 2009-11-26 |
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