CN117384961A - 对病毒动力学影响最小的治疗性腺病毒中的外源基因表达 - Google Patents
对病毒动力学影响最小的治疗性腺病毒中的外源基因表达 Download PDFInfo
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Abstract
本发明描述了包括外源开放阅读框(ORF)和自切割肽编码序列的重组腺病毒基因组。进一步公开了对病毒动力学影响最小的外源基因的最佳放置。还描述了所述重组腺病毒的治疗性应用。
Description
本申请是申请号为201780013061.3,申请日为2017年02月23日,发明名称为“对病毒动力学影响最小的治疗性腺病毒中的外源基因表达”的专利申请的分案申请。
相关申请的交叉引用
本申请要求2016年2月23日提交的美国临时申请No.62/298,653的权益,通过引用将其全部并入本文
发明领域
本公开涉及在重组腺病毒构建体中外源开放阅读框的最佳放置以及该重组病毒的治疗性应用。
背景技术
腺病毒血清型5(Ad5)是在基础研究应用、鼠肺癌模型和人类基因治疗试验中选择的载体。腺病毒具有稳定的36kb双链DNA基因组,其由Ad纤维蛋白刺突(spikes)装饰的蛋白衣壳保护,所述Ad纤维蛋白刺突(spikes)靶向感染特定细胞类型上的受体。腺病毒不整合到宿主DNA中,可以使用已建立的方案将其生产至高滴度,并且在人类基因治疗和癌症应用中已经证实安全性。因此,基于Ad的载体对癌症诊断和治疗具有巨大的希望。
发明内容
本文公开包括异源开放阅读框(ORF)和自切割肽编码序列的重组腺病毒基因组。所述异源ORF可编码,例如治疗性蛋白。由所述公开的基因组产生的所述重组腺病毒基因组和重组腺病毒可用于,例如治疗性应用,诸如用于癌症的治疗。
本文提供重组腺病毒基因组,其包括异源ORF和自切割肽编码序列,两者均可操作地连接至与内源腺病毒ORF相同的阅读框中且在所述相同的阅读框中。所述自切割肽编码序列位于所述异源ORF和所述内源ORF之间。在一些实施方案中,所述内源ORF是E1B-55k且所述异源ORF在E1B-55k的3′;所述内源ORF是DNA聚合酶且所述异源ORF在DNA聚合酶的5′;所述内源ORF是DNA结合蛋白(DBP)且所述异源ORF在DBP的3′;所述内源ORF是腺病毒死亡蛋白(ADP)且所述异源ORF在ADP的5′;所述内源ORF是E3-14.7k且所述异源ORF在E3-14.7k的3′;所述内源ORF是E4-ORF2且所述异源ORF在E4-ORF2的5′;或者所述内源ORF是纤维蛋白且所述异源ORF在纤维蛋白的3′。在一些实例中,所述异源ORF编码治疗性蛋白。
本文进一步提供包括本文公开的重组腺病毒基因组的重组腺病毒。还提供包括本文公开的重组腺病毒基因组或重组腺病毒和药学上可接受的载体的组合物。
还提供通过向所述受试者施用本文公开的重组腺病毒基因组或重组腺病毒(或其组合物)将治疗性蛋白递送至受试者的方法。在这些方法中,所述重组腺病毒基因组的异源ORF或重组腺病毒的所述异源ORF编码所述治疗性蛋白。
进一步提供了通过施用本文公开的重组腺病毒基因组或重组腺病毒(或其组合物)抑制肿瘤细胞活力、抑制肿瘤细胞生长、抑制肿瘤进展、减小肿瘤体积以及治疗患有癌症的受试者的方法。在这些方法中,所述重组腺病毒基因组或重组腺病毒的所述异源ORF编码适合癌症治疗的治疗性蛋白。
根据以下参照附图进行的详细描述,本公开的前述和其他客体和特征将变得更加明显。
附图简要说明
图1是用于测试腺病毒构建体的示例性工作流程的示意图。产生全病毒基因组质粒并将其转染到多孔板中合适的细胞中,例如293-E4细胞。当转染的细胞扩增(expand),它们进行冷冻/解冻以释放病毒粒子,然后离心以沉淀细胞碎片。将上清液(含有所述病毒粒子)转移到多个、较大的培养板中。从转染的细胞中收获病毒粒子,CsCl纯化的(CsClpurified)和感染性病毒滴度通过ELISA测量。然后用纯化的病毒的已知的MOI感染感兴趣的细胞类型。在感染后48或72小时,分别通过Western印迹、q-PCR或噬斑试验来测量腺病毒晚期蛋白、腺病毒基因组或噬斑。
图2是显示指数病毒生长的示意图。溶瘤杀死肿瘤内的所有细胞需要指数病毒生长。然而,在大多数情况下,最初仅感染小百分比的肿瘤细胞。因此,每轮复制的后代数量的小差异导致仅几轮复制后粒子总数的大差异。所示为每个循环产生3个病毒粒子的病毒与每个循环产生5个病毒粒子的病毒之间的比较。如图所示,在5-6轮复制后,两种病毒的病毒滴度显著不同。
图3是显示基于荧光的病毒动力学(FBVK)测定的示例性工作流程的示意图。(例如通过Adsembly或AdSLIC)产生全病毒基因组质粒并将其用于转染多孔板中感兴趣的细胞类型。作为选择,用重组腺病毒粒子感染细胞。所述腺病毒基因组包括至少一个位于所述病毒基因组中编码荧光蛋白的开放阅读框(ORF),其基本上不改变病毒复制动力学。随时间监测荧光以计算病毒复制动力学。溶瘤病毒候选物是在肿瘤细胞和正常细胞之间表现出最大的病毒动力学差异的那些。
图4A-4B概述当用腺病毒基因组质粒开始时的动力学测定设置。该测定不需要准确知道最初的转染效率。选择转染条件以导致最初约5-10%的细胞被转染。在所示的实施例中,使用48孔板,其允许一式三份地测试14种不同的病毒构建体,连同三个模拟感染的孔和三个具有FluoresbriteTM珠子的孔以补偿工具灵敏度漂移。(图4A)所述48孔板的上半部分的孔含有用6种不同病毒的基因组质粒转染的细胞,模拟感染的细胞和空白(FluoresbriteTM珠子),每种一式三份。(图4B)所述48孔板下半部分的孔含有用8种不同病毒的基因组质粒转染的细胞,一式三份。将所述多孔板置于读板仪(诸如TECAN读板仪)上以进行连续的荧光监测。
图5概述当用重组病毒开始时的动力学测定设置。该测定不需要准确知道病毒滴度。将重组病毒连续稀释并将其用于感染铺在多孔板中的细胞。在所示的实例中,使用96孔板,每种病毒以1∶100、1∶300、1∶900、1∶2700、1∶8100、1∶24,300、1∶72,900和1∶218,700稀释,允许同时测试11种病毒。模拟感染四个孔并将FluoresbriteTM珠置于四个孔中以补偿工具灵敏度和漂移。将所述多孔板置于读板仪(例如TECAN读板仪)上以进行连续的荧光监测。
图6A-6C提供用于组合装配重组腺病毒的Adsembly和AdSLIC技术的示意概览。(图6A)将所述腺病毒基因组分成四个模块-E1、核心、E3和E4。(图6B)Adsembly涉及使用多位点通道反应的基因组重新组装。(图6C)AdSLIC利用序列和非连接依赖性克隆(SLIC)来组装腺病毒模块。
图7是显示在所述E1区中编码荧光蛋白的重组腺病毒的ln-斜率值的柱状图。显示直接融合构建体YPet-E1A,和YPet-P2A-E1A、E1A-P2A-mCherry和E1B-55k-P2A-YPet构建体的值,其各自含有P2A位点。显示所述YPet-P2A-ADP构建体用于比较。
图8是基于荧光的病毒动力测定的动力学数据分析和解释的示意图。
图9A-9C是显示来源于Ad5、Ad9或Ad34并含有在E3-14.7k ORF(或其在Ad9和Ad34中的等同物)的3′的异源ORF的重组腺病毒的ln-斜率值的柱状图。显示的是Ad5(E3-14.7k-P2A-YPet;PCMN-887)、Ad9(E3-15k-P2A-YPet;PCMN-888)和Ad34(E3-14.8k-P2A-YPet;PCMN-889)在293细胞中(图9A)、A549细胞(图9B)和U2OS细胞(图9C)中的值。每个图中还显示了包括Ad5核心(其包括E3-14.7k-P2A-YPet)和来自Ad9(Ad5/Ad9)或Ad34(Ad5/Ad34)的纤维轴/球突(fiber shaft/knob)的嵌合病毒的值。
序列表
列在所附序列表中的核酸和氨基酸序列采用针对核苷酸碱基的标准字母缩写和针对氨基酸的三字母代码显示,如37C.F.R.1.822中所定义的。仅显示了每条核酸序列的一条链,但互补链被理解为包括在对所显示链的任何引用中。该序列表作为ASCII文本文件提交,其于2017年2月21日生成的,703KB,其通过引用并入本文。在所附的序列表中:
SEQ ID NO:1是合成腺病毒基因组CMBT-379(YPet-P2A-E1A)的核苷酸序列。
SEQ ID NO:2是合成腺病毒基因组CMBT-432(E1A-P2A-YPet)的核苷酸序列。
SEQ ID NO:3是合成腺病毒基因组CMBT-456(E1B-55k-P2A-YPet)的核苷酸序列。
SEQ ID NO:4是合成腺病毒基因组CMBT-499(E1B-55k-P2A-mCherry)的核苷酸序列。
SEQ ID NO:5是合成腺病毒基因组CMBT-530(YPet-P2A-(DNA Poly))的核苷酸序列。
SEQ ID NO:6是合成腺病毒基因组CMBT-886(DBP-P2A-YPet)的核苷酸序列。
SEQ ID NO:7是合成腺病毒基因组CMBT-403(YPet-P2A-ADP)的核苷酸序列。
SEQ ID NO:8是合成腺病毒基因组CMBT-429(ADP-P2A-YPet)的核苷酸序列。
SEQ ID NO:9是合成腺病毒基因组PCMN-887(E3-14.7k-P2A-YPet)的核苷酸序列。
SEQ ID NO:10是合成腺病毒基因组CMBT-457(YPet-P2A-E4-ORF2)的核苷酸序列。
SEQ ID NO:11是合成腺病毒基因组CMBT-633(mCherry-P2A-E4-ORF2)的核苷酸序列。
SEQ ID NO:12是合成腺病毒基因组CMBT-407(YPet-P2A-纤维蛋白)的核苷酸序列。
SEQ ID NO:13是合成腺病毒基因组CMBT-445(纤维蛋白-P2A-YPet)的核苷酸序列。
SEQ ID NO:14是P2A的氨基酸序列。
SEQ ID NO:15是F2A的氨基酸序列。
SEQ ID NO:16是E2A的氨基酸序列。
SEQ ID NO:17是T2A的氨基酸序列。
SEQ ID NO:18是在N末端包括GSG的经修饰的P2A的氨基酸序列。
SEQ ID NO:19是在N末端包括GSG的经修饰的F2A的氨基酸序列。
SEQ ID NO:20是在N末端包括GSG的经修饰的E2A的氨基酸序列。
SEQ ID NO:21是在N末端包括GSG的经修饰的T2A的氨基酸序列。
SEQ ID NO:22是合成腺病毒基因组PCMN-888(Ad9 E3-15k-P2A-YPet)的核苷酸序列。
SEQ ID NO:23是合成腺病毒基因组PCMN-889(Ad34 E3-14.8k-P2A-YPet)的核苷酸序列。
发明详述
I.缩写
Ad 腺病毒
ADP 腺病毒死亡蛋白
BFP 蓝色荧光蛋白
E2A 马鼻炎A病毒2A
ELISA 酶联免疫吸附测定
ERAV 马鼻炎A病毒
F2A ***病毒2A
FACS 荧光激活细胞分选
FMDV ***病毒
GFP 绿色荧光蛋白
MOI 感染的多样性
OD 光密度
ORF 开放阅读框
P2A 猪捷申病毒-12A(porcine teschovirus-1 2A)
pIX 蛋白IX
PTV1 猪捷申病毒-1
RFP 红色荧光蛋白
SLIC 序列和连接非依赖性克隆
T2A 明脉扁刺蛾β四体病毒2A(Thosea asigna virus 2A)
TaV 明脉扁刺蛾β四体病毒(Thosea asigna virus)
YFP 黄色荧光蛋白
II.术语和方法
除非另有说明,否则技术术语按常规用法使用。对分子生物学中常见术语的定义可以在牛津大学出版社出版的Benjamin Lewin,Genes V,1994(ISBN 0-19-854287-9);Blackwell ScienceLtd.出版的Kendrew等(eds.),The Encyclopedia of MolecularBiology,1994(ISBN 0-632-02182-9);以及VCH Publishers,Inc.出版的Robert A.Meyers(ed.),Molecular Biology and Biotechnology:a Comprehensive Desk Reference,1995(ISBN 1-56081-569-8)中找到。
为了方便查看本公开的各种实施方案,提供了以下对具体术语的解释:
2A多肽:一种由一些RNA病毒编码的自切割肽的类型,例如小核糖核酸病毒。2A肽通过使核糖体跳过结合在2A元件的C末端的肽的合成而起作用,导致所述2A序列末端与下游肽之间的分离(Kim等,PLoS One 6(4):e18556,2011)。所述“切割”发生在所述2A肽的C末端上发现的甘氨酸和脯氨酸残基之间。示例性的2A肽包括但不限于,由明脉扁刺蛾β四体病毒(TaV)、马鼻炎A病毒(ERAV)、猪捷申病毒-1(PTV1)和***病毒(FMDV)编码的所述2A肽,它们在本文中如SEQ ID NO:14-17所示。在一些实施方案中,所述2A肽在N-末端包括Gly-Ser-Gly以提高切割效率(SEQ ID NO:18-21)。
腺病毒:具有线性、双链DNA基因组和二十面体衣壳的无包膜病毒。目前有68种已知的人腺病毒血清型,其分为7种(种A、B、C、D、E、F和G)。腺病毒的不同血清型与不同类型的疾病相关,一些血清型引起呼吸道疾病(主要是种B和C)、结膜炎(种B和D)和/或胃肠炎(种F和G)。
腺病毒死亡蛋白(ADP):在腺病毒感染晚期合成的蛋白,其介导细胞***并释放腺病毒以感染其他细胞。ADP是定位于核膜、内质网和高尔基体的101个氨基酸的完整膜糖蛋白。ADP以前称为E3-11.6K。
施用:将制剂(诸如治疗剂(例如重组病毒))通过任何有效的途径提供或给受试者。示例性施用途径包括,但不限于,注射(诸如皮下、肌内、皮内、腹膜内、肿瘤内和静脉内),口服、导管内、舌下、直肠、透皮、鼻内、***和吸入途径。
嵌合:由具有不同起源的至少两个部分组成。在本公开的上下文中,“嵌合腺病毒”是具有来源于至少两个不同血清型的遗传物质和/或蛋白质的腺病毒(诸如,来源于Ad5和腺病毒的第二血清型)。在这个背景下,“衣壳-交换的(capsid-swapped)”腺病毒指嵌合腺病毒,在其中所述衣壳蛋白来源于腺病毒的一种血清型,且剩下的蛋白来源于另一种腺病毒血清型。相似地,“嵌合纤维(chimeric fiber)”是具有来源于至少两种不同的腺病毒血清型的氨基酸序列的纤维蛋白。例如,嵌合纤维可由来自Ad5的纤维轴和来自腺病毒的第二血清型的纤维球突组成。在另一个实例中,嵌合纤维由Ad5尾巴和来自腺病毒的第二血清型(诸如Ad9或Ad34)的纤维轴(fiber shaft)和球突(knob)组成。
接触:置于直接的物理联系中;包括在固体和液体形式中。
简并变体:在本公开上下文中,“简并变体”指编码蛋白的多核苷酸,其包括作为遗传密码的结果而简并的(degenerate)的序列。存在20种天然氨基酸,其大多数由多于一个的密码子指定(specified)。因此,包括编码肽的所有简并核苷酸序列,只要由所述核苷酸序列编码的所述肽的氨基酸序列不变。
被删除的(deleted):编码“被删除的”蛋白质的腺病毒基因组(诸如E4orf1或E4orf6/7蛋白)指具有导致蛋白表达缺失的所述蛋白编码序列的完全删除或部分删除的腺病毒。
E2F的失调(deregulation):指所述E2F转录因子和下游靶基因的活性增加,其发生在几乎所有类型的人类癌症中。E2F途径活性和转录的失调可由所述途径的任何上游组分中的多种不同突变引起,例如Rb、p107和p130肿瘤抑制因子的功能丧失突变和缺失。Rb是第一个被鉴定的肿瘤抑制因子,并且在至少三分之一的人类肿瘤中不存在或突变。此外,p16突变和/或表观遗传沉默可激活肿瘤细胞中的E2F。细胞周期蛋白D(Cyclin D)和CDK4突变、基因扩增或过表达也可导致对人肿瘤中的E2F活性的失调。此外,E2F由生长因子受体途径突变激活,包括EGFR、RTK、RAS、RAF、PI-3K、PTEN、RAF、MYC。p16INK4a-Cyclin D:cdk4/6-RB-E2F途径中的突变通常以相互排斥的方式发生,因此一个‘命中(hit)’(例如,p16)不与其他的命中(例如,Rb突变或细胞周期蛋白D:cdk过表达)相伴随。然而,大多数目前的化学疗法是抑制E2F转录靶标的增殖性毒物,但也对正常细胞有毒并且具有经常是毁灭性的医源性并发症。如本文所公开的,一种可选择的治疗方法是使用在癌细胞损伤中经历选择性裂解性复制的病毒,所述癌细胞损伤具有失调的p16-细胞周期蛋白D:cdk4-RB-E2F途径。
DNA-结合蛋白(DBP):该腺病毒蛋白结合至单链DNA和RNA,以及双链DNA。一种72-千道尔顿蛋白DBP对腺病毒DNA的复制是必不可少的。
E1A:腺病毒早期区域1A(E1A)基因和表达自所述基因的多肽。所述E1A蛋白在病毒基因组复制中通过操纵细胞进入细胞周期而起作用。如本文中所使用的,术语“E1A蛋白”指表达自所述E1A基因的蛋白质,且所述术语包括由任何腺病毒血清型产生的E1A蛋白。
E3-RIDα/RIDβ和E3-14.7k:产自所述E3基因的早期表达蛋白。所述E3-RIDα、E3-RIDβ和E3-14.7k蛋白构成受体内化和降解复合物(RID),其定位于核膜并引起包括CD95(FasL受体)以及TNFR1和2(TNF/TRAIL受体)的多种受体的内吞作用和降解,以保护受感染的细胞免受宿主抗病毒的应答。所述E3-RIDα、E3-RIDβ和E3-14.7k编码序列按此顺序彼此相邻。
E4orf1:产自所述E4基因的腺病毒蛋白。术语“E4orf蛋白”包括由来自任何一种腺病毒血清型的所述E4基因产生的E4orf1蛋白。
E4orf6/7:由所述腺病毒E4基因编码的蛋白。术语“E4orf6/7蛋白”包括由来自任何一种腺病毒血清型的所述E4基因产生的E4orf6/7蛋白。
纤维(fiber):所述腺病毒纤维蛋白是介导结合至细胞表面受体的嵌合蛋白。所述纤维蛋白由长N末端轴和球状C末端球突组成。
荧光蛋白:当暴露于具体波长的光时,发射某种波长的光的蛋白质。荧光蛋白包括,但不限于,绿色荧光蛋白(诸如GFP、EGFP、AcGFP1、祖母绿、超折叠GFP、Azami绿(AzamiGreen)、m芥末绿(mWasabi)、标签GFP(TagGFP)、TurboGFP和Zs绿(ZsGreen)),蓝色荧光蛋白(诸如EBFP、EBFP2、天蓝色(Sapphire)、T-天蓝色(T-Sapphire)、蓝铜蓝(Azurite)和m标签BFP(mTagBFP)),蓝绿色荧光蛋白(诸如ECFP、mECFP、蔚蓝色(Cerulean)、CyPet、Am蓝绿色1(AmCyan1)、Midori-Ishi蓝绿色(Midori-Ishi Cyan)、m绿松石蓝绿色(mTurquoise)和mTFP1),黄色荧光蛋白(EYFP、黄晶黄(Topaz)、金星黄(Venus)、m黄水晶黄(mCitrine)、YPet、标签YFP(TagYFP)、PhiYFP、Zs黄1(ZsYellow1)和m香蕉黄(mBanana)),橙色荧光蛋白(Kusabira橙(Kusabira Orange)、Kusabira橙2(Kusabira Orange2)、m橙(mOrange)、m橙2(mOrange2)和m橘红(mTangerine)),红色荧光蛋白(m红宝石红(mRuby)、m苹果红(mApple)、m草莓红(mStrawberry)、As红2(AsRed2)、mRFP1、J红(JRed)、m樱桃红(mCherry)、Hc红1(HcRed1)、m覆盆子红(mRaspberry)、d桂马红-串联(dKeima-Tandem)、Hc红-串联(HcRed-Tandem)、m紫红(mPlum)、AQ143、td番茄红(tdTomato)和E2-深红(E2-Crimson)),橘色/红色荧光蛋白(d番茄红(dTomato)、d番茄红-串联(dTomato-Tandem)、标签RFP(TagRFP)、标签RFP-T(TagRFP-T)、Ds红(DsRed)、Ds红2(DsRed2)、Ds红-表达(T1)(DsRed-Express(T1))和Ds红-单体(DsRed-Monomer))及其经修饰的版本。
融合蛋白:含有来自至少两种不同(异源)蛋白或肽的氨基酸序列的蛋白。融合蛋白可例如通过核酸序列的表达生成,所述核酸序列从编码两种不同(异源)蛋白的至少一部分的核酸序列的工程化而来。为了生成融合蛋白,所述核酸序列必须在相同的阅读框中且不含有内部的终止密码子。融合蛋白,特别是短融合蛋白,也可由化学合成生成。
异源:异源蛋白或多肽指来源于不同来源或物种的蛋白质或多肽。
六邻体(Hexon):主要的腺病毒衣壳蛋白。
免疫调节剂:改变(例如,活化、提高或抑制)所述免疫***的试剂(agent)。免疫调节剂包括,但不限于,细胞因子(诸如白细胞介素2(IL-2)、IL-7、IL-12、GM-CSF、FLT3配体或干扰素)、趋化因子(诸如CCL3、CCL26、CXCL7、CXCL9和CXCL10),T细胞激活配体(诸如抗CD3Abs或同种异体抗原(alloantigen))、共刺激分子(诸如B7.1/B7.2、OX40L、4-1-BBL或CD40L)、检查点阻塞抑制剂(checkpoint blockade inhibitors)(诸如抗PD-1或抗CTLA4Abs)、和小分子免疫调节剂。
分离的(isolated):已经将”分离的”生物学组分(诸如核酸分子、蛋白、病毒或细胞)从生物体的细胞或组织中或生物体本身中的其他生物组分中基本上分开或纯化,在其中所述组分是天然发生的,诸如其他染色体的和染色体外的DNA和RNA、蛋白质和细胞。已经被“分离的”核酸分子和蛋白质包括通过标准纯化方法纯化的那些。所述术语还包括通过在宿主细胞中重组表达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。
修饰:核酸序列或蛋白质序列上的改变。例如,氨基酸序列修饰包括,例如,取代、***和缺失、或其组合。***包括氨基和/或羧基末端融合以及单个或多个氨基酸残基的序列内***。缺失的特征在于从所述蛋白质序列中除去一个或更多个氨基酸残基。在本文的一些实施方案中,所述修饰(诸如取代、***或缺失)导致功能的改变,诸如降低或加强蛋白质的具体活性。如本文所使用的,“Δ”或“delta”指缺失。取代修饰是在其中至少一个残基已被除去且将与之不同的残基***到它的位置的那些。氨基酸取代通常是单个残基,但一次可发生在许多不同的位置。因此可以组合取代、缺失、***或其任何组合以获得最终的突变序列。这些修饰可以通过修饰所述编码蛋白质的DNA中的核苷酸来制备,从而产生编码该修饰的DNA。在具有已知序列的DNA中的预定位点处进行***、缺失和取代突变的技术是本领域熟知的。“经修饰的”蛋白质、核酸或病毒是具有如上概述的一种或更多种修饰的蛋白质、核酸或病毒。
瘤形成(neoplasia)、恶性肿瘤(malignancy)、癌症(cancer)和肿瘤(tumor):瘤(neoplasm)是由于过度细胞***导致的组织或细胞的异常生长。瘤的生长可以产生肿瘤。个体中肿瘤的量是“肿瘤负荷”,其可以作为所述肿瘤的数量、体积或重量来测量。不转移的肿瘤被称为“良性的”。侵入周围组织和/或可转移的肿瘤被称为“恶性的(malignant)”。恶性的肿瘤也被称为“癌症”。
血液***癌症是血液或骨髓的癌症。血液学(或血源性)癌症的实例包括白血病,其包括急性白血病(例如急性淋巴细胞白血病、急性髓细胞白血病、急性髓性白血病以及成髓细胞的、早幼粒细胞的、髓单核细胞的、单核细胞的和红白血病)、慢性白血病(例如慢性髓细胞(粒细胞))白血病、慢性髓性白血病和慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤、霍奇金病(Hodgkin′s disease)、非霍奇金淋巴瘤(惰性和高级形式)、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症(Waldenstrom′s macroglobulinemia)、重链疾病、骨髓发育不良综合征、毛细胞白血病和骨髓发育不良。在某些情况下,淋巴瘤被认为是实体瘤。
实体瘤是通常不含有囊肿或液体区域的异常组织块。实体瘤可以是良性的或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(例如肉瘤,恶性上皮肿瘤和淋巴瘤)。实体瘤的实例,诸如肉瘤和恶性上皮肿瘤,包括纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤和其他肉瘤、滑膜瘤、间皮瘤、尤因氏瘤(Ewing′s tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、淋巴恶性肿瘤、胰腺癌、乳腺癌、肺癌、卯巢癌、***癌、肝细胞癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、甲状腺髓样癌、***状甲状腺癌、嗜铬细胞瘤皮脂腺癌(pheochromocytomas sebaceous gland carcinoma)、***状癌、人***状瘤病毒(HPV)-感染的瘤形成、***状腺癌(papillary adenocarcinomas)、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、维尔姆斯瘤(Wilms′tumor)、***、睾丸肿瘤、***瘤、膀胱癌、黑色素瘤和CNS肿瘤(如脑胶质瘤(如脑干胶质瘤和混合胶质瘤)、成胶质细胞瘤(又称多形性胶质母细胞瘤)星形细胞瘤、CNS淋巴瘤、生殖细胞瘤、成神经管细胞瘤、神经鞘瘤颅咽管瘤(Schwannoma craniopharyogioma)、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、黑色素瘤(menangioma)、成神经细胞瘤、成视网膜细胞瘤(retinoblastoma)和脑转移瘤)。
溶瘤病毒:选择性杀死增殖性疾病细胞(例如癌/肿瘤细胞)的病毒。可以通过本领域中建立的任何方法检测癌细胞的杀死,例如确定活细胞计数,或检测癌细胞中的细胞病变效应、细胞凋亡或病毒蛋白的合成(例如,通过复制所必需的病毒基因的代谢标记、免疫印迹或RT-PCR),或肿瘤大小的减小。
可操作地连接:当第一核酸序列与第二核酸序列处于功能关系时,将第一核酸序列与第二核酸序列可操作地连接。例如,如果启动子影响编码序列的转录或表达,则将所述启动子与所述编码序列可操作地连接。通常,可操作地连接的DNA序列是连续的并且,在必要时将两个蛋白质编码区连接在同一阅读框中。
药学上可接受的载体:在本公开中有用的药学上可接受的载体(媒介(vehicles))是常规的。Remington’s Pharmaceutical Sciences,by E.W.Martin,Mack PublishingCo.,Easton,PA,15th Edition(1975)描述了适用于一种或更多种治疗性化合物、分子或制剂(例如本文公开的重组病毒)的制药学递送的组合物和制剂。
通常,所述载体的性质取决于所采用的具体施用模式。例如,胃肠外制剂通常包括可注射流体,所述可注射流体包括作为媒介的药学和生理学上可接受的流体,诸如水、生理盐水、平衡盐溶液、葡萄糖水溶液、甘油等。对于固体组合物(例如,粉末、药丸、片剂或胶囊形式),常规的无毒固体载体可包括,例如药用级甘露醇、乳糖、淀粉或硬脂酸镁。除了生物学上中性载体,待施用的药物组合物还可含有小量的无毒辅助物质,例如润湿剂或乳化剂、防腐剂以及pH缓冲剂等,例如醋酸钠或脱水山梨醇单月桂酸酯。
多肽、肽或蛋白质:其中单体为氨基酸残基的多聚物,这些氨基酸残基通过酰胺键联结在一起。当所述氨基酸为α氨基酸时,L光学异构体或D光学异构体都可使用。术语“多肽”、“肽”或“蛋白质”在本文中可交换使用。这些术语应用于氨基酸聚合物,其中一种或更多种氨基酸残基是相应地天然存在的氨基酸的人工化学模拟物,以及天然发生的氨基酸聚合物和非天然发生的氨基酸聚合物。术语“残基”或“氨基酸残基”包括提及被并入到蛋白质、多肽或肽中的氨基酸。
多肽中的保守取代是将在蛋白质序列中的一个氨基酸残基取代为具有相似生物化学性质的与之不同氨基酸残基。通常,保守取代对所得多肽的活性的影响很小直至没有影响。例如,包括一个或更多个保守取代(例如不多于1、2、3、4或5个取代)的蛋白质或肽保留所述野生型蛋白质或肽的结构和功能。含有一个或更多个保守取代的多肽可以通过使用例如标准程序(如定点突变或PCR)操纵编码所述多肽的核苷酸序列而产生。在一个实例中,此类变体可以通过测试抗体交叉反应性或其诱导免疫应答的能力来容易地选择。保守取代的实例如下所示。
保守取代通常保持(a)所述取代区域中多肽骨架的结构,例如,作为片状或螺旋构象,(b)分子在靶位点的电荷或疏水性,或(c)侧链的大部分。
通常预期产生蛋白质性质的最大变化的取代将是非保守的,例如其中的变化(a)用亲水性残基(例如,丝氨酰或苏氨酰)取代(或将其取代为)疏水性残基,例如,亮氨酰、异亮氨酰、苯丙氨酰、缬氨酰或丙氨酰;(b)用半胱氨酸或脯氨酸取代(或将其取代为)任何其他残基;(c)用具有正电性侧链的残基,例如赖氨酰基,精氨酰基或组氨酰基,取代(或将其取代为)负电性残基,例如谷氨酰基或天冬氨酰基;或(d)用具有庞大侧链的残基,例如苯丙氨酸,取代(或将其取代为)不具有侧链的残基,例如甘氨酸。
预防、治疗或缓解疾病:“预防”疾病指抑制疾病的完全出现。“治疗”指在疾病或病理状况已开始出现后缓解该疾病或病理状况的体征或症状的治疗性介入。“缓解”指在疾病的体征或症状的数量或严重程度上的降低。
启动子:指导/启动核酸(例如基因)转录的DNA区。启动子包括转录起始位点附近的必需核酸序列。通常,启动子位于它们转录的基因附近。启动子还任选地包括远端增强子或阻遏物元件,其可位于距转录起始位点数千碱基对的位置。“组成型启动子”是连续有活性的且不受外部信号或分子调节的启动子。相反,“诱导型启动子”的活性受外部信号或分子(例如转录因子或四环素)的调节。
蛋白IX(Protein IX(pIX)):与所述六邻体蛋白连接的腺病毒衣壳的次要组分。
纯化的:术语“纯化的”不需要绝对纯净;相反,意欲将它作为一个相对术语。因此,例如,纯化的肽、蛋白质、病毒或其他活性化合物是从天然相关蛋白质和其他污染物中全部或部分地分离的肽、蛋白质、病毒或其他活性化合物。在某些实施方案中,术语“基本上纯化的”是指已经从细胞、细胞培养基或其他未加工的制备物中分离并经过分馏以除去初始制备物的各种组分的肽、蛋白质、病毒或其他活性化合物,如蛋白质、细胞碎片和其他组分。
重组:重组核酸分子、蛋白质或病毒是这样的核酸分子、蛋白质或病毒,其具有非天然发生的序列或具有通过人工组合两个原本分开的序列片段而形成的序列。这种人工组合可通过化学合成或者通过人工操作分离的核酸片段完成,例如通过基因工程技术来完成。术语“重组”还包括单独通过所述天然核酸分子、蛋白质或病毒的添加、取代或缺失一部分而改变的核酸、蛋白质和病毒。
复制缺陷:在非肿瘤细胞(与肿瘤细胞相比)中表现出“复制缺陷”的病毒是指与肿瘤细胞相比,在正常细胞中表现出病毒复制降低的腺病毒。复制缺陷通过以下证明,例如,与肿瘤细胞相比,在正常细胞中病毒晚期蛋白表达的缺乏、病毒DNA合成的降低、诱导E2F靶基因(例如,细胞周期蛋白A和B)的能力降低、引起S期进入的能力降低和/或诱导细胞杀死的能力降低。
复制缺陷病毒:在具有给定表型的预定细胞群中(例如,具有失调的E2F途径的肿瘤细胞),优先抑制细胞增殖、引起细胞裂解或诱导细胞凋亡(统称为杀死)的病毒。在不具有所述预定细胞表型的细胞(例如正常的,非肿瘤细胞)中,此类病毒不能减少或抑制细胞增殖、引起细胞裂解、诱导细胞凋亡或者不能复制,或在上述能力方面受限。
自切割肽:诱导核糖体跳过C末端的肽键合成的肽,导致所述肽序列和下游多肽之间的分离。病毒编码的2A肽是一种自切割肽。病毒编码的2A肽包括,例如,来自猪捷申病毒-1(PTV1)、***病毒(FMDV)、马鼻炎A病毒(ERAV)和明脉扁刺蛾β四体病毒(TaV)的2A肽。
序列一致性:两个或更多个核酸序列、或两个或更多个氨基酸序列之间的一致性或相似性,依据所述序列之间的一致性或相似性表示。序列一致性可依据百分比一致性来测量;百分比越高,序列就越一致。序列相似性可依据百分比相似性(其考虑了保守氨基酸取代)来测量;百分比越高,序列就越相似。当使用标准方法比对时,核酸或氨基酸序列的同源物或直系同源物具有相对高程度的序列同一性/相似性。与关系更远的(more distantlyrelated)物种(例如人和C.线虫(C.elegans)序列)相比,当直系同源蛋白质或cDNA来源于更密切相关的物种(例如人和小鼠序列)时,这种同源性更为显著。
用于比较的序列比对方法是本领域公知的。各种程序和比对算法描述在:Smith&Waterman,Adv.Appl.Math.2:482,1981;Needleman&Wunsch,J.Mol.Biol.48:443,1970;Pearson&Lipman,Proc.Natl.Acad.Sci.USA 85:2444,1988;Higgins&Sharp,Gene,73:237-44,1988;Higgins&Sharp,CABIOS 5:151-3,1989;Corpet等,Nuc.Acids Res.16:10881-90,1988;Huang等Computer Appls.in the Biosciences 8,155-65,1992;以及Pearson等,Meth.Mol.Bio.24:307-31,1994.Altschul等,J.Mol.Biol.215:403-10,1990中,显示了序列比对方法和同源性计算的详细考虑。
NCBI基本局部比对搜索工具(BLAST)(Altschul等,J.Mol.Biol.215:403-10,1990)可从几个来源获得,包括国家生物信息中心(National Center for BiologicalInformation (NCBI))和互联网,用于与序列分析程序blastp、blastn、blastx、tblastn和tblastx相连。额外的信息可以在NCBI网站上找到。
血清型:由一组特有的抗原相区分的一组密切相关的微生物(如病毒)。
受试者:活的多细胞脊椎动物生物体,包括人和非人哺乳动物的一个类别。
合成:在实验室中通过人工手段产生,例如合成核酸或蛋白质可在实验室中化学合成。
治疗剂:当向受试者适当地施用时能够诱导所需治疗性或预防效果的任何制剂。治疗剂包括但不限于化学化合物、小分子、重组病毒、反义化合物、抗体(或其抗原结合片段)、肽或核酸分子。例如,用于治疗癌症的治疗剂包括预防或抑制肿瘤生长、肿瘤进展或肿瘤转移的制剂。“治疗性蛋白”是治疗剂,其是蛋白质或肽,包括抗体或其抗原结合片段。在本文的一些实施方案中,所述治疗性蛋白是免疫调节剂。在其他实施方案中,所述治疗性蛋白包括毒素、Fas或FasL、可溶性死亡因子、旁立破损介导物(mediator of bystanderdestruction)、肿瘤抗原、neo抗原或同种异体抗原。
治疗有效量:特定药学试剂或治疗剂(例如重组病毒)的量,其足以在用该试剂治疗的受试者或细胞中达到所需效果。所述试剂的有效量可取决于若干因素,包括但不限于所治疗的受试者或细胞,以及治疗性组合物的施用方式。
Uexon:位于早期E3区和纤维基因之间的l链(向左转录)上的开放阅读框(Tollefson等,J Virol 81(23):12918-12926)。
除非另有说明,本文所使用的所有技术和科学术语具有与本公开所属的领域的普通技术人员所通常理解的一样的含义。单数形式的“a”、“an”和“the”包括复数指代物,除非上下文另有明确说明。“comprising A or B(包括A或B)”意指“including A,B,or A andB”(包括A、B、或A和B)。还将理解的是,针对核酸或多肽所给出的所有碱基大小或氨基酸大小,以及所有分子量或分子质量值是近似的,并且被提供用以描述。尽管与本文中所描述的那些相类似或者相等同的方法和材料可用于实施或测试本公开,但下文则描述了适合的方法和材料。通过引用将本文提及的所有出版物、专利申请、专利以及其他参考文献以其全文并入。如有矛盾,以包括术语解释的本说明书为准。此外,所述材料、方法以及实施例仅是阐释性的,而无意进行限制。
III.实施方案概述
本文公开的是包括异源开放阅读框(ORF)和自切割肽编码序列的重组腺病毒基因组。所述异源ORF可编码,例如,治疗性蛋白(诸如免疫调节剂)。由所述公开的基因组产生的所述重组腺病毒基因组和重组腺病毒可用于,例如各种不同的治疗性应用,诸如癌症的治疗。
本文提供重组腺病毒基因组,其包括异源ORF和自切割肽编码序列,两者均可操作地连接至与内源腺病毒ORF相同的阅读框中且在所述相同的阅读框中。所述自切割肽编码序列位于所述异源ORF和所述内源ORF之间。在一些实施方案中,所述内源ORF是E1B-55k,且所述异源ORF在E1B-55k的3′:所述内源ORF是DNA聚合酶,所述异源ORF在DNA聚合酶的5′;所述内源ORF是DNA结合蛋白(DBP),所述异源ORF在DBP的3′;所述内源ORF是腺病毒死亡蛋白(ADP),所述异源ORF在ADP的5′;所述内源ORF是E3-14.7k,所述异源ORF在E3-14.7k的3′;所述内源ORF是E4-ORF2,所述异源ORF在E4-ORF2的5′;或者所述内源ORF是纤维蛋白,所述异源ORF在纤维蛋白的3′。
在一些实施方案中,所述异源ORF编码治疗性蛋白。
在一些实施方案中,所述自切割肽是2A肽或其变体。在一些实例中,所述2A肽包括猪捷申病毒-1(PTV1)2A(P2A)肽、***病毒(FMDV)2A(F2A)肽、马鼻炎A病毒(ERAV)2A(E2A)肽或明脉扁刺蛾β四体病毒(TaV)2A(T2A)肽,或其变体。在一些具体的实例中,所述2A肽序列与SEQ ID NO:14或SEQ ID NO:18的氨基酸序列至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%一致。在一些实例中,所述2A肽变体包括在N末端的额外的氨基酸序列(诸如GSG)。
在具体的实例中,所述F2A肽序列与SEQ ID NO:15或SEQ ID NO:19的氨基酸序列至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%一致。在具体的实例中,所述E2A肽序列与SEQ ID NO:16或SEQ ID NO:20的氨基酸序列至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%一致。在具体的实例中,所述T2A肽序列与SEQ ID NO:17或SEQ ID NO:21的氨基酸序列至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%一致。在特定的非限制性实例中,所述自切割肽包括SEQ ID NO:14-21中的任何一个的氨基酸序列或由其组成。
在一些实施方案中,所述腺病毒是腺病毒型5(Ad5)。在其他实施方案中,所述腺病毒是Ad2、Ad3、Ad9、Ad11、Ad12或Ad34。还在其他实施方案中,所述腺病毒是嵌合腺病毒,诸如,但不限于,Ad5/Ad9或Ad5/Ad34嵌合腺病毒。
本文进一步提供重组腺病毒,其包括本文公开的重组腺病毒基因组。
本文提供的重组腺病毒(和重组腺病毒基因组)任选地包括额外的修饰,例如将病毒靶向具体细胞类型,以抑制靶向肝脏以及在肝脏中的复制,以允许在肿瘤细胞中选择性复制,和避免预先存在的针对常见腺病毒血清型的中和抗体。额外的修饰可以根据所述重组腺病毒的需要的用途而变化。腺病毒修饰描述于,例如,PCT申请号PCT/US2015/051745(2015年9月23日提交)、WO2012/024350、WO2013/138505和WO2014/153204中,通过引用将其全文并入本文。
本公开还提供包括重组腺病毒基因组或重组腺病毒,和药学上可接受的载体的组合物。
本文还提供将治疗性蛋白递送至受试者的方法。在一些实施方案中,所述方法包括向所述受试者施用本文公开的重组腺病毒基因组、重组腺病毒,或组合物。在这些方法中,所述重组腺病毒基因组或重组腺病毒的异源ORF编码所述治疗性蛋白。
进一步提供减少或抑制肿瘤细胞活力和/或肿瘤细胞生长的方法(与没有所述公开的疗法相比,例如减少至少10%、至少20%、至少30%、至少40%、至少50%、至少75%、至少90%、至少95%或至少98%)。在一些实施方案中,所述方法包括将所述肿瘤细胞与本文公开的重组腺病毒基因组、重组腺病毒或组合物接触。在这些方法中,所述异源ORF编码治疗性蛋白。在一些实例中,所述方法是体外方法。在其他实例中,所述方法是体内方法且接触所述肿瘤细胞包括向患有肿瘤的受试者施用所述重组腺病毒基因组、重组腺病毒或组合物。
本文进一步提供减少或抑制肿瘤进展的方法,诸如通过减少转移(metastasis)的数量和尺寸,或减少受试者内肿瘤的体积(例如与没有所述公开的疗法相比,减少至少10%、至少20%、至少30%、至少40%、至少50%、至少75%、至少90%、至少95%或至少98%)。在一些实施方案中,所述方法包括向所述受试者施用治疗有效量的本文公开的重组腺病毒基因组、重组腺病毒或组合物。在这些方法中,所述异源ORF编码治疗性蛋白。
进一步提供治疗受试者中癌症的方法。在一些实施方案中,所述方法包括向所述受试者施用治疗有效量的本文公开的重组腺病毒基因组、重组腺病毒或组合物。在这些方法中,所述异源ORF编码治疗性蛋白。
在本文的一些实施方案中,所述方法进一步包括向所述受试者施用额外的治疗剂。例如所述额外的治疗剂可包括抗癌剂,诸如化疗剂(a chemotherapeutic agent)、生物剂(abiologic)(诸如抗体或其片段,诸如单克隆抗体),或核酸分子,诸如抑制性核酸分子)或其他治疗性处理(therapeutic treatment),例如肿瘤的手术切除或肿瘤的照射。
本文还提供试剂盒,其包括本文公开的重组腺病毒基因组、重组腺病毒或组合物;以及一种或更多种额外的治疗剂和/或一种或更多种诊断剂。在一些实施方案中,所述一种或更多种额外的治疗剂包括化疗剂、生物剂或其组合。在一些实例中,所述一种或更多种诊断剂包括一种或更多种对肿瘤标志物特异性的抗体或核酸分子,或可用于体外或体内追踪所述病毒或肿瘤细胞的成像探针。
IV.外源ORF的最佳放置
所述36kb腺病毒基因组是紧凑的,使用顶部和底部链来编码各种基因。在所述腺病毒基因组内的许多位置,顶部和底部链都同时用于编码分开的基因。所述基因组大小已进化为对于***其衣壳是最佳的。结果,外源基因的***受到所述衣壳大小容量的限制,因为外源核酸的过量添加导致不完整的基因组加载到衣壳中并降低病毒动力学。
针对由腺病毒基因组中有限的可用空间呈现的挑战的解决方案是,将外源开放阅读框(ORF)定位在天然腺病毒ORF内作为融合产物。该策略利用已经在基因组中编码的腺病毒启动子、5′UTR和polyA尾巴。然而,天然腺病毒蛋白和外源蛋白之间融合的表达可能对一种或两种蛋白质功能有害,并导致腺病毒复制动力学的显著降低。
本公开通过使用置于所述天然(内源)ORF和所述外源(异源)ORF之间的自切割肽序列提供了对该问题的解决方案。当置于单个mRNA上的所述两个ORF之间时,自切割肽序列的存在导致核糖体跳过并释放与第二蛋白分开的第一蛋白。在本文公开的一些实施方案中,所述自切割肽是2A肽(P2A)。
本文还公开了腺病毒基因组内异源ORF的最佳放置位点的鉴定。自切割肽序列和异源ORF明智放置的组合导致高表达以及对病毒动力学的最小影响。
如下文实施例1中所述,鉴定了所述腺病毒基因组内的几个位点,在***异源ORF后,不抑制腺病毒的复制动力学。特别地,确定了可将异源ORF***到所述E1B-55kORF的C末端,所述DNA聚合酶ORF的N末端,所述DBP ORF的C末端,所述ADP ORF的N末端,所述E3-14.7kORF的C末端或所述E4-ORF2的N末端。在每种情况下,在所述腺病毒ORF和所述异源ORF之间***自切割肽序列(P2A位点)。本文进一步公开了将异源ORF***到纤维蛋白的C-末端以产生复制缺陷型腺病毒;然而,所述重组病毒能够在感染细胞中产生异常高水平的异源蛋白,其可证明在许多治疗性应用中是有用的。
因此,本公开考虑以下重组腺病毒用于治疗性应用的用途(其中“SC”是指编码自切割肽的序列,诸如P2A):
E1B-55k-SC-异源ORF
异源ORF-SC-(DNA聚合酶)
DBP-SC-异源ORF
异源ORF-SC-ADP
E3-14.7k-SC-异源ORF
异源ORF-SC-E4-ORF2
纤维蛋白-SC-异源ORF
在本文的一些实施方案中,所述自切割肽是病毒编码的2A肽,或如下文进一步描述的其经修饰的版本。
V.自切割肽序列
自切割肽序列是诱导核糖体跳过C末端肽键合成的肽,导致所述肽序列末端与下游多肽之间的分离。自切割肽的使用允许从单个ORF表达在所述自切割肽侧翼的多种蛋白。病毒编码的2A肽是一种自切割肽。
与其他自切割肽一样,2A肽通过使核糖体跳过2A元件C末端肽键合成而起作用,导致所述2A序列末端与下游肽之间的分离(Kim等,PLoS One 6(4):e18556,2011)。所述“切割”发生在所述2A肽的C末端上发现的甘氨酸和脯氨酸残基之间。示例性2A肽包括但不限于,由明脉扁刺蛾β四体病毒(TaV)、马鼻炎A病毒(ERAV)、猪捷申病毒-1(PTV1)和***病毒(FMDV)编码的2A肽或其修饰版本。
在本文具体的实例中,所述2A肽包括PTV1 2A(P2A)、FMDV 2A(F2A)、ERAV 2A(E2A)或TaV 2A(T2A),其序列如下所示,并在本文中列为SEQ ID NO:14-17。
P2A:ATNFSLLKQAGDVEENPGP(SEQ ID NO:14)
F2A:VKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:15)
E2A:QCTNYALLKLAGDVESNPGP(SEQ ID NO:16)
T2A:EGRGSLLTCGDVEENPGP(SEQ ID NO:17)
在一些实例中,所述2A肽被修饰为在N末端包括Gly-Ser-Gly以提高切割效率。经修饰的P2A、F2A、E2A和T2A的序列如下所示,并在本文中列为SEQ ID NO:18-21。
经修饰的P2A:GSGATNFSLLKQAGDVEENPGP(SEQ ID NO:18)
经修饰的F2A:GSGVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:19)
经修饰的E2A:GSGQCTNYALLKLAGDVESNPGP(SEQ ID NO:20)
经修饰的T2A:GSGEGRGSLLTCGDVEENPGP(SEQ ID NO:21)
在一些实施方案中,所述2A多肽是本文公开的2A多肽的变体。变体可包括与野生型或本文公开的经修饰的2A多肽具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%或更多序列一致性的多肽序列。变体可包括,例如,SEQ IDNO:14-21中的任何一个2A多肽的N末端至少一个氨基酸的缺失,例如1、2、3、4或5个氨基酸的缺失,包括在任何两个所列值之间的范围。变体可包括,例如,SEQ ID NO:14-21中的任何一个2A多肽的C末端至少一个氨基酸的缺失,例如1、2、3、4或5个氨基酸的缺失,包括在任何两个所列值之间的范围。变体还可包括,例如,至少1、2、3、4或5个氨基酸的取代,诸如保守氨基酸取代。
VI.药物组合物
本文提供了包括重组腺病毒或重组腺病毒基因组的组合物。所述组合物,任选地,适于体外或体内剂型(formulation)和施用。任选地,所述组合物包括所提供的制剂的一种或更多种和药学上可接受的载体。合适的载体及其剂型描述于Remington:The ScienceandPractice of Pharmacy,22nd Edition,Loyd V.Allen等编辑。药学上可接受的载体包括非生物学上或其他方面不合需要的材料,即,将所述材料施用于受试者而不会引起不需要的生物学效应或以有害的方式与包括它的药物组合物的其他组分相互作用。如果向受试者施用者,所述载体被任选地选择以使所述活性成分的降解最小化并使所述受试者中的不良副作用最小化。
将所述重组病毒(或一种或更多种编码所述重组腺病毒的核酸或载体)根据已知的方法施用,诸如静脉施用,例如,作为丸剂或通过一段时间连续灌注,通过肌肉内、腹膜内、脑脊髓内(intracerobrospinal)、皮下、关节内、滑膜内、鞘内,口服,局部、肿瘤内或吸入途径。所述施用可以是局部的或全身的。所述组合物可以通过几种施用途径中的任何一种施用,包括局部、口服、肠胃外、静脉内、关节内、腹膜内、肌肉内、皮下、腔内、透皮,肝内(intrahepatically)、颅内、雾化/吸入,或通过支气管镜安装。因此,所述组合物以多种方式施用,所述方式取决于是否需要局部或全身治疗,以及待治疗的区域。
在一些实施方案中,用于施用的所述组合物将包括溶入药学上可接受的载体(优选含水载体)的本文描述的重组腺病毒(或重组基因组)。可以使用各种含水载体,例如缓冲盐水等。这些溶液是无菌的并且通常没有不需要的物质。这些组合物可通过常规的公知的灭菌技术灭菌。所述组合物可含有接近生理条件所需的药学上可接受的辅助物质,例如pH调节剂和缓冲剂、毒性调节剂制剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。这些剂型中活性剂的浓度可以广泛变化,并且将根据所选择的具体施用模式和受试者的需要主要基于流体体积、粘度、体重等来选择。
药物剂型,特别是重组病毒的药物剂型可通过将具有所需纯度的重组腺病毒(或编码重组腺病毒的一种或更多种核酸)与任选的药学上可接受的载体、赋形剂或稳定剂混合来制备。此类制剂可以是冻干剂型或水溶液。
可接受的载体、赋形剂或稳定剂在所使用的剂量和浓度下对接受者是无毒的。可接受的载体、赋形剂或稳定剂可以是乙酸盐、磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂(如抗坏血酸)防腐剂、低分子量多肽;蛋白质如血清白蛋白或明胶,或亲水聚合物如聚乙烯吡咯烷酮(polyvinylpyllolidone);和氨基酸、单糖、二糖和包括葡萄糖、甘露糖或糊精等的其他碳水化合物;螯合剂;和离子和非离子表面活性剂(例如聚山梨醇酯);成盐抗衡离子如钠;金属络合物(例如锌-蛋白质络合物);和/或非离子表面活性剂。所述重组腺病毒(或编码重组腺病毒的一种或更多种核酸)可以以任何合适浓度的感染单位配制。
适于口服施用的制剂可以由以下组成(a)液体溶液,诸如悬浮在稀释剂,诸如水、盐水或PEG 400中的有效量的所述重组腺病毒;(b)胶囊、小袋(sachets)或片剂,每种含有预定量的活性成分,如液体、固体、颗粒或明胶;(c)适当液体中的悬浮液;以及(d)合适的乳液。片剂形式可包括乳糖、蔗糖、甘露醇、山梨糖醇、磷酸钙、玉米淀粉、马铃薯淀粉、微晶纤维素、明胶、胶体二氧化硅、滑石、硬脂酸镁、硬脂酸,和其他赋形剂、着色剂、填充剂、粘合剂、稀释剂、缓冲剂、润湿剂、防腐剂、调味剂、染料、崩解剂,和药学上相容的载体中的一种或更多种。锭剂(lozenge)形式可将活性成分包含在调味剂中,例如蔗糖,以及软锭剂(pastille)将活性成分包含在惰性基质中,例如除了活性成分之外,还包含本领域已知的载体的明胶和甘油或蔗糖和***胶乳剂、凝胶等。
所述重组腺病毒(或编码重组腺病毒的一种或更多种核酸),单独或与其他合适的组分组合,可被制成气溶胶剂型(即,它们可以被“雾化”)以通过吸入施用。可以将气溶胶剂型置于加压的可接受的推进剂中,例如二氯二氟甲烷、丙烷、氮气等。
适合于肠胃外施用的剂型,诸如,例如,通过关节内(在关节中)、静脉内、肌肉内、肿瘤内、真皮内、腹膜内和皮下途径,包括水性和非水性、等渗无菌注射溶液,其可含有使剂型与预期(intended)接受者的血液等渗的抗氧化剂、缓冲剂、抑菌剂和溶质,以及可包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的水性和非水性无菌悬浮液。在所提供的方法中,组合物可以例如通过静脉内输注、口服、局部、腹膜内、膀胱内肿瘤内或鞘内施用。肠胃外施用、肿瘤内施用和静脉内施用是优选的施用方法。化合物的所述剂型可以在单位剂量或多剂量密封容器中呈现,例如安瓿和小瓶。
注射溶液和悬浮液可由前述类型的无菌粉末、颗粒和片剂制备。用于离体治疗的由腺病毒转导或感染的细胞或用核酸转染的细胞也可以如上所述的静脉内或胃肠外施用。
在一些实例中,所述药物制剂(preparation)是单位剂型(dosage form)。在这种形式中,将所述制剂细分为含有适量所述活性成分的单位剂量(doses)。因此,根据所述施用方法,所述药物组合物可以多种单位剂量形式施用。例如,适于口服施用的单位剂型包括但不限于粉末、片剂、丸剂、胶囊和锭剂。
VII.治疗方法
可施用本文公开的重组腺病毒、重组腺病毒基因组和组合物用于治疗性或预防性治疗。特别地,提供减少或抑制受试者内肿瘤活力或生长,减少或抑制受试者内肿瘤进展,减少受试者内转移的数量,减少受试者内转移的大小和/或体积,减少受试者内肿瘤大小和/或体积和/或治疗受试者中癌症的方法。所述方法包括向所述受试者施用治疗有效量的重组腺病毒基因组或重组腺病毒(或其组合物)。如全文所描述的,所述腺病毒或药物组合物以任何数量的方式施用,所述方式包括但不限于静脉内、血管内、鞘内、肌肉内、皮下、肿瘤内、腹膜内或口服。任选地,所述方法进一步包括向所述受试者施用一种或更多种额外的治疗剂,诸如化疗剂、生物剂和/或辐射。
在一些实施方案中,所述癌症或肿瘤是肺、***、结肠直肠、乳腺、甲状腺、肾、胰腺、骨、头颈或肝的癌症或肿瘤,或者是一种类型的白血病。在一些情况下,所述癌症是转移性的。在一些实例中,所述肿瘤是乳腺、垂体、甲状腺或***的肿瘤;脑、肝、脑膜、骨、卵巢、子宫或子宫颈的肿瘤;单核细胞或髓性白血病;腺癌、腺瘤、星形细胞瘤、***、脑肿瘤、伯基特淋巴瘤(Burkitt’s lymphoma)、乳腺癌、***、结肠癌(colon carcinoma)、肾癌、肝癌、肺癌、卵巢癌、胰腺癌、***癌、直肠癌、皮肤癌、胃癌、睾丸癌、甲状腺癌、软骨肉瘤、绒毛膜癌、纤维瘤、纤维肉瘤、成胶质细胞瘤(glioblastoma)、胶质瘤、肝癌、组织细胞瘤、成平滑肌瘤(1eiomyoblastoma)、平滑肌肉瘤、淋巴瘤、脂肪肉瘤细胞、乳腺肿瘤、成神经管细胞瘤、骨髓瘤、浆细胞瘤、成神经细胞瘤、神经胶质瘤、成骨肉瘤、胰腺肿瘤、垂体肿瘤、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、睾丸肿瘤、胸腺瘤或肾母细胞瘤(Wilms tumor)。肿瘤包括原发性和转移性实体瘤,包括乳腺、结肠、直肠、肺、口咽、下咽、食道、胃、胰腺、肝、胆囊和胆管、小肠、尿路(包括肾、膀胱和尿路上皮)、女性生殖道(包括子宫颈、子宫和卵巢以及绒毛膜癌和妊娠滋养细胞疾病)、男性生殖道(包括***、精囊、睾丸和生殖细胞肿瘤)、内分泌腺(包括甲状腺、肾上腺和垂体腺),和皮肤的癌,以及血管瘤、黑色素瘤、肉瘤(包括由骨和软组织引起的肉瘤以及卡波济氏肉瘤(Kaposi′s sarcoma))和脑、神经、眼睛和脑膜的肿瘤(包括星形细胞瘤、胶质瘤、成胶质细胞瘤、成视网膜细胞瘤、神经瘤、成神经细胞瘤、神经鞘瘤(Schwannomas)和脑膜瘤)。在某些方面,可以治疗由造血***恶性肿瘤例如白血病引起的实体瘤(即绿色瘤(chloromas),浆细胞瘤和蕈样真菌病和皮肤T细胞淋巴瘤/白血病的斑块和肿瘤)以及淋巴瘤(霍奇金和非霍奇金氏淋巴瘤)的治疗中。此外,治疗可用于预防本文所描述的肿瘤的转移。
在治疗性应用中,将重组腺病毒或其组合物以治疗有效量或剂量向受试者施用。针对此用途有效的量取决于所述疾病的严重程度和患者健康的一般状态。可以根据患者所需的和耐受的剂量和频率施用组合物的单次或多次施用。“患者”或“受试者”包括人和其他动物,特别是哺乳动物。因此,所述方法适用于人类治疗和兽医应用,诸如小鼠、大鼠、兔、猫、狗、牛、马、猪、鸡等。
具有修饰序列的腺病毒的有效量是基于个体确定的,并且至少部分基于所使用的具体的重组腺病毒;个人的大小、年龄、性别;以及所述增殖细胞的大小和其他特征。例如,对于人的治疗,使用至少103个噬斑形成单位(plaque forming unit(PFU))的重组病毒,例如至少104、至少105、至少106、至少107、至少108、至少109、至少1010、至少1011或至少1012PFU,例如使用约103至1012PFU的重组病毒,取决于存在的增殖细胞或肿瘤的类型、大小和数量。所述有效量可以是从约1.0pfu/kg体重至约1015pfu/kg体重(例如,从约102pfu/kg体重至约1013pfu/kg体重)。重组腺病毒以单剂量或多剂量(例如,二、三、四、六或更多剂量)施用。多剂量可以同时或连续使用(例如,数天或数周)。
在一些实施方案中,所提供的方法包括向所述受试者施用一种或更多种额外的治疗剂,诸如抗癌剂或其他治疗性治疗(诸如所述肿瘤的手术切除)。示例性的抗癌剂包括,但不限于化疗剂,诸如,例如,有丝***抑制剂、烷化剂、抗代谢物、***抗生素(intercalating antibiotics)、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、抗生存剂、生物反应调节剂、抗激素(例如抗雄激素)、抗血管生成剂和CDK抑制剂。其他抗癌治疗包括放射治疗以及特异性靶向癌细胞的其他抗体。
烷基化剂的非限制性实例包括氮芥(例如二氯甲基二乙胺(mechlorethamine)、环磷酰胺、美法仑、尿嘧啶氮芥或苯丁酸氮芥(chlorambucil))、烷基磺酸盐(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀(lomustine)、司莫司汀(semustine)、链脲霉素或达卡巴嗪)。
抗代谢物的非限制性实例包括叶酸类似物(例如甲氨蝶呤)嘧啶类似物(例如5-FU或阿糖胞苷)和嘌呤类似物,例如巯嘌呤或硫鸟嘌呤。
天然产物的非限制性实例包括长春花生物碱(例如长春碱、长春新碱或长春地辛)、表鬼臼毒素(例如依托泊苷或替尼泊苷)、抗生素(例如放线菌素、柔红霉素、多柔比星(doxorubicin)、博来霉素、普卡霉素或丝裂霉素C)和酶(如L-天冬酰胺酶)。
混杂制剂的非限制性实例包括铂配合物(如顺-二胺-二氯铂II,也称为顺铂)、取代脲(如羟基脲)、甲基肼衍生物(如丙卡巴肼)和肾上腺抑制剂(如米托坦和氨鲁米特)。
激素和拮抗剂的非限制性实例包括肾上腺皮质激素(例如***)、孕激素(例如己酸羟孕酮、醋酸甲羟孕酮和醋酸甲地孕酮(magestrol acetate))、***(例如己烯雌酚和乙炔***)、抗***(例如三苯氧胺)和雄激素(例如丙酸***(testeroneproprionate)和氟***)。
最常用的化疗药物的实例包括阿霉素、美法仑(Alkeran)、阿糖胞苷(Ara-C)、BiCNU、白消安、CCNU,卡铂(Carboplatinum)、顺铂、环磷酰胺(Cytoxan)、道诺霉素、DTIC、5-FU、氟达拉滨、羟基脲(Hydrea)、伊达比星(Idarubicin)、异环磷酰胺、氨甲喋呤、光神霉素、丝裂霉素、米托蒽醌、氮芥、紫杉醇(或其他紫杉烷、如多西紫杉醇)、长春花碱(Velban)、长春新碱、VP-16、而一些更新的药物包括吉西他滨(健择(Gemzar))、赫赛汀、伊立替康(Irinotecan)(伊立替康(Camptosar)、CPT-11)、克拉屈滨(Leustatin)、诺维苯(Navelbine)、利妥昔单抗STI-57l、泰索帝、拓扑替康(美新(Hycamtin))、希罗达(卡培他滨)、泽文林(Zevelin)和骨化三醇。
可以使用的免疫调节剂的非限制性实例包括AS-101(Wyeth-Ayerst Labs.)、溴匹立明(bropirimine)(Upjohn)、γ干扰素(Genentech)、GM-CSF(粒细胞巨噬细胞集落刺激因子;遗传学研究所)、IL-2(Cetus或Hoffman-LaRoche)、人免疫球蛋白(CutterBiological),IMREG(来自Imreg of New Orleans,La.)、SK&F 106528和TNF(肿瘤坏死因子;Genentech)。
CDK(细胞周期蛋白依赖性激酶)抑制剂是抑制CDK功能的制剂。用于所提供的方法的CDK抑制剂的非限制性实例包括AG-024322、AT7519、AZD5438、夫拉平度(flavopiridol)、尹地苏拉姆(indisulam)、P1446A-05、PD-0332991和P276-00(参见例如Lapenna等、NatureReviews,8:547-566,2009)。其他CDK抑制剂包括LY2835219、帕布昔利布(Palbociclib)、LEE011(Novartis)、pan-CDK抑制剂AT7519、西里昔利布(seliciclib)、CYC065、丁内酯I、黑美妮奥地辛(hymenialdisine)、SU9516、CINK4、PD0183812或海洋活性生物碱(fascaplysin)。
在一些实例中,CDK抑制剂是广谱抑制剂(例如夫拉平度(flavopiridol)、奥罗莫星(olomoucine)、柔丝扣维亭(roscovitine)、肯普龙(kenpaullone)、SNS-032、AT7519、AG-024322、(S)-柔丝扣维亭或R547)。在其他实例中,CDK抑制剂是特异性抑制剂(例如、海洋活性生物碱(fascaplysin)、柔维亭(ryuvidine)、泊伐拉诺A(purvalanol A)、NU2058、BML-259、SU 9516、PD0332991或P-276-00)。
在一些实施方案中,所提供的方法进一步包括向受试者施用治疗有效量的免疫疗法。可以使用的免疫调节剂的非限制性实例包括AS-101(Wyeth-Ayerst Labs.)、溴匹立明(bropirimine)(Upjohn)、γ干扰素(Genentech)、GM-CSF(粒细胞巨噬细胞集落刺激因子;遗传学研究所)、IL-2(Cetus或Hoffman-LaRoche)、人免疫球蛋白(Cutter Biological)、IMREG(来自Imreg of New Orleans,La.)、SK&F 106528和TNF(肿瘤坏死因子;Genentech)。所述免疫治疗剂制剂可以是PD-1拮抗剂或PD-L1拮抗剂,例如特异性结合PD-1或PD-L1的抗体,例如阿特左丽珠单抗(Atezolizumab)、MPDL3280A、BNS-936558(纳武单抗(Nivolumab))、派姆单抗(Pembrolizumab)、匹地丽珠单抗(Pidilizumab)、CT011、AMP-224、AMP-514、MEDI-0680、BMS-936559、BMS935559、MEDI-4736、MPDL-3280A、MSB-0010718C。所述免疫治疗剂制剂也可以是CTLA-4、LAG-3或B7-H3拮抗剂,例如揣摩丽木单抗(Tremelimumab)、BMS-986016和MGA271。
在一些实施方案中,所提供的方法还包括向受试者施用治疗有效量的一种或更多种抗血管生成剂,例如对减少甚至抑制血管生长起作用的蛋白质、酶、多糖、寡核苷酸、DNA,RNA和重组载体以及小分子。合适的血管生成抑制剂的实例包括,但不限于血管抑制素K1-3,星形孢菌素(staurosporine)、染料木黄酮、烟曲霉素、甲羟孕酮、苏拉明、干扰素-α、金属蛋白酶抑制剂、血小板因子4、生长抑素、血小板反应蛋白(thromobospondin)、内皮抑素、沙利度胺及其衍生物和类似物。例如,在一些实施方案中,所述抗血管生成剂是特异性结合VEGF(例如,Roche)或VEGF受体(例如VEGFR2抗体)的抗体。在一个实例中,所述抗血管生成剂包括VEGFR2抗体或DMXAA(也称为伐地莫赞(Vadimezan)或ASA404;可商购,例如来自Sigma Corp.,St.Louis,MO)或两者。抗血管生成剂制剂可以是贝伐单抗、舒尼替尼、抗血管生成酪氨酸激酶抑制剂(TKI),例如舒尼替尼、西替尼(xitinib)和达沙替尼。这些可以单独使用或以任何组合使用。
在一些实施方案中,所提供的方法进一步包括向受试者施用治疗有效量的一种或更多种激酶抑制剂,例如和/>舒尼替尼,索拉非尼,阿尼替尼(anitinib)和达沙替尼,其阻止生长因子的磷酸化和激活。可以使用的抗体包括阻断生长因子和血管生成途径的/>和/>这些可以单独使用或组合使用。
在一些实施方案中,所提供的方法还包括向受试者施用治疗有效量的一种或更多种治疗性单克隆抗体,例如3F8、阿巴伏单抗(Abagovomab)、阿得妥莫单抗(Adecatumumab)、阿夫土珠(Afumzumab)、阿拉西珠(Alacizumab)、阿伦单抗(Alemtuzumab)、阿妥莫单抗三胺五乙酸(Altumomab pentetate)、阿那妥莫单抗马福纳托克斯(Anatumomab mafenatox)、阿泊朱单抗(Apolizumab)、阿西莫单抗(Arcitumomab)、巴维昔单抗(Bavituximab)、贝妥莫单抗(Bectumomab)、贝利木单抗(Belimumab)、贝索单抗(Besilesomab)、贝伐单抗(Bevacizumab)、比伐土木珠单抗莫坦辛(Bivatuzumab mertansine)、博利纳吐单抗(Blinatumomab)、伯仁土西单抗外都亭(Brentuximab vedotin)、坎土珠单抗莫坦辛(Cantuzumab mertansine)、卡罗单抗喷地肽(Capromab pendetide)、卡妥索单抗(Catumaxomab)、CC49、西妥昔单抗(Cetuximab)、西他土珠波咖托克斯(Citatuzumabbogatox)、西妥木单抗(Cixutumumab)、西利伐土珠单抗特出克斯坦(Clivatuzumabtetraxetan)、叩娜土木单抗(Conatumumab)、达西土珠单抗(Dacetuzumab)、地莫单抗(Detumomab)、艾叩莫西单抗(Ecromeximab)、依库丽单抗(Eculizumab)、依决洛单抗(Edrecolomab)、依帕珠单抗(Epratuzumab)、二土麦克斯单抗(Ertumaxomab)、伊瑞西珠(Etaracizumab)、伐勒木珠单抗(Farletuzumab)、菲吉土木珠单抗(Figitumumab)、咖利西单抗(Galiximab)、吉姆单抗奥佐米星(Gemtuzumab ozogamicin)、(Girentuximab)、吉姆单抗外都亭(Glembatumumab vedotin)、替伊莫单抗(Ibritumomab tiuxetan)、伊戈伏单抗(Igovomab)、英西单抗(Imciromab)、因特土木单抗(Intetumumab)、伊诺土珠单抗奥佐米星(Inotuzumab ozogamicin)、伊匹单抗(Ipilimumab)、伊拉土木单抗(Iratumumab)、拉博土珠单抗(Labetuzumab)、来沙木单抗(Lexatumumab)、林妥珠单抗(Lintuzumab)、罗伐土珠单抗莫坦辛(Lorvotuzumab mertansine)、鲁卡土木单抗(Lucatumumab)、昔单抗(Lumiliximab)、(Mapatumumab)、马妥珠单抗(Matuzumab)、美泊利单抗(Mepolizumab)、迈特利木单抗(Metelimumab)、利拉土珠单抗(Milatuzumab)、利土莫单抗(Mitumomab)、莫若利木单抗(Morolimumab)、那可罗单抗他发娜托克斯(Nacolomab tafenatox)、那普土莫单抗伊丝他发娜托克斯(Naptumomab estafenatox)、那西土木单抗(Necitumumab)、诺夫土莫单抗莫盆坦(Nofetumomab merpentan)、欧发土木单抗(Ofatumumab)、欧拉热土单抗(Olaratumab)、欧普热土木单抗莫娜托克斯(Oportuzumab monatox)、奥戈伏单抗(Oregovomab)、帕尼单抗(Panitumumab)、喷土莫单抗(Pemtumomab)、帕妥珠单抗(Pertuzumab)、拼土莫单抗(Pintumomab)、普托木单抗(Pritumumab)、雷莫芦单抗(Ramucirumab)、(Rilotumumab)、利妥昔单抗、罗巴土木单抗(Robatumumab)、沙妥莫单抗喷地肽(Satumomab pendetide)、西博土珠单抗(Sibrotuzumab)、索耐普西珠单抗(Sonepcizumab)、塔卡土珠单抗特出克斯坦(Tacatuzumab tetraxetan)、他普利土莫单抗帕普托克斯(Taplitumomab paptox)、泰纳土莫单抗(Tenatumomab)、TGN1412、提西丽木单抗(揣摩丽木单抗)((Ticilimumab(tremelimumab))、提噶土珠单抗(Tigatuzumab)、TNX-650、曲妥单抗(Trastuzumab)、揣摩丽木单抗(Tremelimumab)、土口土珠单抗西莫白介素(Tucotuzumab celmoleukin)、维尔土珠单抗(Veltuzumab)、维洛西单抗(Volociximab)、伏妥莫单抗(Votumumab)或扎鲁土木单抗(Zalutumumab)。在一些实例中,所述异源ORF编码这些治疗抗体中的一个。
针对一些类型的癌症的另一个常见的治疗是手术治疗,例如所述肿瘤或其部分的手术切除。治疗的另一个实例是放疗,例如向所述肿瘤部位施用放射性物质或能量(如外部束治疗)以帮助根除肿瘤或在手术切除前将其缩小。
制剂和剂量的选择可以由本领域技术人员基于所治疗的给定疾病容易地确定。药剂的组合或组合物可以附随地(concomitantly)(例如,作为混合物)、分离地但同时地(例如,通过分离的静脉内管线)或顺序地施用(例如,首先施用一种制剂,然后施用第二制剂)。因此,所述术语组合用于指两种或更多种制剂或组合物的附随、同时或顺序施用。
根据本文公开的方法,向所述受试者施用有效量的一种或更多种本文提供的制剂。将所述有效量定义为产生所需的生理学反应(例如,癌细胞杀死)所必须的任何量。治疗剂通常以每日约0.001mg/kg至约1000mg/kg的初始剂量施用。可使用约0.01mg/kg至约500mg/kg、或约0.1mg/kg至约200mg/kg、或约lmg/kg至约100mg/kg、或约10mg/kg至约50mg/kg的剂量(dose)范围。然而,所述计量,剂量可以根据所述受试者的要求、所治疗病况的严重程度和所用化合物而变化。例如,考虑在具体受试者中诊断的癌症的类型和阶段,可以凭经验确定剂量。在所提供的方法的背景下,向受试者施用的剂量应足以影响患者随时间的有益治疗反应。确定具体情况的适当剂量在从业者的技能范围内。因此,本领域技术人员可凭经验确定用于施用所述制剂的有效量和时间表。所述剂量不应大到引起实质的不良副作用,例如不需要的交叉反应、过敏反应等。如果发生任何禁忌症,个体医师可调整剂量。可以在所述文献中找到针对给定类别的药物产品的适当剂量的指导。
本文提供通过将肿瘤细胞与如本文公开的重组腺病毒、重组腺病毒基因或其组合物接触抑制所述肿瘤细胞活力或生长的方法。在一些实施方案中,所述方法是体外方法。在其他实施方案中,所述方法是体内的方法且接触所述肿瘤病毒包括向患有肿瘤的受试者施用所述重组腺病毒基因组、重组腺病毒或组合物。
进一步提供抑制肿瘤进展或减少受试者内肿瘤体积的方法,通过向所述受试者施用本文公开的治疗有效量的重组腺病毒基因组或重组腺病毒(或其组合物)。
还提供在受试者中治疗癌症的方法,通过向所述受试者施用本文公开的治疗有效量的重组腺病毒基因组或重组腺病毒(或其组合物)。
VIII.Adsembly和AdSLIC
腺病毒基因组被分成几个功能组,标记为E1、E2、E3、E4和L1-5。所述E1区编码控制所有其他病毒基因的转录并在所述宿主细胞中诱导S期的蛋白质。所述E2区编码驱动病毒DNA复制的蛋白质。所述E3区蛋白质调节宿主细胞免疫应答并且在细胞培养中是非必要的。所述E4区含有用于不同功能集的基因。以及所述L1-5区编码病毒粒子结构蛋白。
利用这种功能的自然隔离,发明人先前开发了一种重组腺病毒组装方法,其允许通过将36kb Ad基因组分成4个质粒E1、E3、E4和核心来快速且容易地操作所述36kb Ad基因组,如图6A所示(Adsembly和AdSLIC;参见WO2012/024351,其通过引用并入本文)。由于它们更合理的大小,使用标准技术操作这些较小的质粒是直截了当的。
Adsembly和AdSLIC使之能在4小时内从兼容的基因组文库部分组合性地体外组装具有新性质的腺病毒。Adsembly和AdSLIC提供了一种通用的基因组设计平台,其使之能使用四个库的功能部分组装具有新性质的合成病毒(图6A)。这些部分的库(These librariesof parts)可以使用多位点特异性重组位点(Adsembly;图6B)或非序列依赖性无缝克隆(AdSLIC;图6C)以所有可能的组合重新组装。
所述Adsembly和AdSLIC技术使分子设计和产生具有独特性能的腺病毒成为可能。开发以自动化、高通量方式设计、制造和测试病毒的性能将加速和扩展用于治疗、诊断和可研性学习的新病毒的发展。
虽然克隆步骤曾经是生产新病毒构建的瓶颈,但Adsembly和AdSLIC的出现使得构建病毒基因组的能力已经超过了测试它们的能力。同样高通量的动力学测定对于使用所述Adsembly和AdSLIC方法开发合成的和个性化病毒治疗和诊断的全部潜力和高含量组装是至关重要的。
提供以下实施例以说明某些具体特征和/或实施方案。不应将这些实施例解释为将本公开限制到所描述的具体特征或实施方案。
实施例
实施例1:外源ORF在腺病毒基因组中的最佳位置的鉴定
该实施例描述了腺病毒基因组内特定位置的鉴定,于此处可***外源ORF连同自切割肽序列,而不破坏病毒动力学动力学。
在腺病毒质粒中的外源基因的***受到衣壳大小容量的限制。外源核酸的过量添加导致不完整的基因组加载到所述衣壳中并降低病毒动力学。针对由腺病毒基因组中有限的可用空间呈现的挑战的解决方案是,将外源开放阅读框(ORF)定位在天然腺病毒ORF内作为融合产物。该策略利用已经在基因组中编码的腺病毒启动子、5′UTR和polyA尾巴。然而,天然腺病毒蛋白和外源蛋白之间融合的表达可能对一种或两种蛋白质功能都有害,并导致腺病毒复制动力学的显著降低。事实上,本文公开的研究证明了外源ORF直接融合至所述腺病毒E1A、DNA聚合酶或ADP ORE显著抑制腺病毒复制动力学。此外,发明人之前尝试使用内部核糖体进入位点(IRES)来***外源ORE,其也不能产生具有野生型动力学的重组病毒。
该实施例通过使用置于所述天然ORF和所述外源ORE之间的自切割肽序列描述了对该问题的解决方案。当置于单个mRNA上的所述两个ORE之间时,所述自切割肽序列的存在导致核糖体跳过并释放与第二蛋白分离的第一蛋白。在该实施例中生成的病毒构建体使用自切割肽P2A和荧光蛋白(例如YPet,m樱桃红(mCherry))作为异源ORE。
以下表格提供生成的构建体的列表,且表明在两种不同的细胞系(293-E4细胞和A549细胞)中,外源ORE的表达水平(低、中或高)和病毒复制动力学的水平(低、中或高)。
在两种细胞类型中都表现出“高”复制动力学(即,与野生型腺病毒相比的复制动力学)的构建体被认为是生成治疗性腺病毒构建体的候选物(粗体显示)。另外,纤维蛋白-P2A-异源ORF(fiber-P2A-异源ORF)构建体表现出了显著的病毒复制缺陷,但生成非常高的异源蛋白表达水平。因此,这些纤维蛋白构建体也用于在有复制缺陷的腺病毒的背景下产生高水平的治疗性蛋白的治疗性应用。
P2A位点的直接融合和***的比较
生成了一些构建体,其中将荧光蛋白直接融合至腺病毒ORE。具体地,生成了以下直接融合:YPet-E1A、YPet-(DNA聚合酶)和mCherry-ADP。
YPet-E1A腺病毒表现出了在病毒动力学中的显著损伤。在YPet和E1A之间的P2A位点的***(YPet-P2A-E1A)改善了病毒动力学,但没有将病毒动力学恢复至野生型水平。之后生成了另一个构建体以测试P2A和YPet与E1A的C末端的融合(E1A-P2A-YPet)。该构建体进一步改善了病毒动力学,但再一次没有将动力学恢复至野生型腺病毒的水平。
多次尝试转染所述YPet-(DNA-poly)基因组质粒都未能产生活病毒(没有斑块形成)。然而,如上表所示,YPet-P2A与DNA聚合酶N末端的融合(YPet-P2A-(DNA poly))产生了具有野生型动力学的病毒。
此外,mCherry与ADP的直接融合(mCherry-ADP)产生了具有显著受损的动力学的病毒。然而,在所述mCherryORF和所述ADP ORF之间的所述P2A位点的***导致了具有野生型动力学的病毒(mCherry-P2A-ADP)。使用不同的荧光蛋白获得了相同的结果;所述YPet-P2A-ADP构建体表现出了野生型病毒动力学。然而,将P2A和所述异源ORF放置在ADP的C末端产生了不复制的病毒。因此,对于ADP,所述异源ORF必须被放置在N末端。
与纤维蛋白(fiber)的直接融合以及在纤维蛋白和异源ORF之间的P2A位点的***都产生了具有显著受损的复制动力学的病毒。然而,所述包括纤维蛋白-P2A-异源ORF的重组腺病毒表现出所述异源蛋白的非常高的表达水平(在此实施例中YPet或绿色荧光蛋白(BFP))。
具有野生型病毒动力学的额外的构建体
图7显示六种不同构建体:YPet-E1A、YPet-P2A-ElA、E1A-P2A-mCherry、E1B-55k-P2A-YPet、YPet-P2A-ADP和Fiber-P2A-YPet的Ln-斜率的比较。如上文所讨论的,YPet与E1A的直接融合产生了具有显著受损的动力学的病毒,并且在N末端(YPet-P2A-E1A)或C末端添加P2A位点(E1A-P2A-mCherry)改善了病毒动力学但没有达到野生型水平。然而,将所述P2A位点和异源ORF***E1B-55k的C末端(E1B-55k-P2A-YPet)或ADP的N-末端(YPet-P2A-ADP)生成具有野生型病毒动力学的重组病毒。
评价在DBP的C末端或E3-14.7k的C末端具有P2A位点和异源ORF的构建体(分别为DBP-P2A-YPet或E3-14.7k-P2A-YPet),或在E4-ORF2的N-末端具有P2A位点和异源ORF的构建体(YPet-P2A-E4-ORF2和mCherry-P2A-E4-ORF2)的病毒动力学,产生具有野生型复制动力学的病毒。
这些数据的结果表明,至少以下腺病毒基因组构建体可用于开发治疗性腺病毒构建体:
E1B-55k-P2A-异源ORF
异源ORF-P2A-(DNA聚合酶)
DBP-SC-异源ORF
异源ORF-SC-ADP
E3-14.7k-SC-异源ORF
异源ORF-P2A-E4-ORF2
纤维蛋白-P2A-异源ORF
针对治疗性应用,所述异源ORF编码治疗性蛋白。
其他腺病毒血清型
先前描述的测量病毒动力学的方法都高度依赖于细胞类型特异性测定,因此由于每种腺病毒血清型的不同趋向性而具有血清型特异性。本文公开的所述腺病毒动力学测定不依赖于任何一种细胞类型,且因此可以扩展到除Ad5之外的血清型。所有腺病毒血清型都含有相当于Ad5 E3-14.7k的ORF。因此,使用Ad9(含有E3-15k)和Ad34(含有E3-14.8k)生成相当于Ad5 E3-14.7k-P2A-YPet(PCMN-887;SEQ ID NO:9)的病毒:PCMN-888(Ad9 E3-15k-P2A-YPet;SEQ ID NO:22)和PCMN-889(Ad34 E3-14.8k-P2A-YPet;SEQ ID NO:23)。还生成了含有所述Ad5核心和来自Ad9或Ad34的纤维轴和球突的嵌合病毒。然后使用293细胞(图9A)、A549细胞(图9B)和U2OS细胞(图9C)在FBVK测定中测试四种重组病毒。所有四种重组病毒都表现出高水平的YPet表达,因***外源ORF而导致的病毒动力学最小的影响。
实施例2:评价腺病毒复制动力学的方法
用于组装重组腺病毒的Adsembly和AdSLIC方法提供用于在短期内生成大量重组腺病毒基因组和病毒的方法。然而,存在用于评价为临床和治疗性用途而设计的重组腺病毒复制动力学的快速和高通量的方法的需求。该实施例描述基于荧光的病毒动力学测定,其可用于测试重组腺病毒的病毒复制动力学(图3)。所述测定可用重组腺病毒基因组质粒或重组腺病毒粒子作为起始材料进行。
当用重组腺病毒基因组起始时,所述测定包括用腺病毒基因组质粒转染细胞(诸如在实施例1中描述的那些)以及随时间监控荧光团表达(图4A-4B)。选择转染条件以致最初约5-10%的细胞被转染。最初未转染的细胞可通过初始转染产生的病毒粒子进行二次感染。对数-斜率用作基于二级、三级和四级(等)感染的动力学测量,因此不必知道最初转染的细胞的百分比。图4A和4B显示用重组腺病毒基因组质粒开始的示例性的基于病毒的动力学测定。在此实施例中,使用48孔板,其允许同时测试14种不同的病毒构建体(一式三份)。所述48孔板的上半部分(图4A)包括6种不同病毒的一式三份的孔、3个模拟-感染的孔和3个具有FLUORESBRITETM珠子的“空白”孔,其补偿工具灵敏度漂移。所述48孔板下半部分(图4B)包括用8种不同病毒构建体的一式三份的孔。一旦细胞被转染,将所述板放置在TECANTM读板仪中以进行连续的荧光监测。收集的数据用于计算每一个构建体的ln-斜率(图8)。
所述测定也可以通过用重组病毒粒子感染细胞来进行。在此测定版本中,用重组病毒粒子感染细胞,并随时间监测荧光团表达(图5)。与用所述基因组质粒测定的版本一样,不必知道起始病毒群的精确滴度。通常,稀释系列用于初始感染,诸如从1∶100至1∶218,700的范围的稀释系列,如图5所示。1∶100的稀释通常导致所有细胞的感染,而1∶218,700的稀释通常导致极少数细胞的初始感染。在此实施例中,使用96孔板,并在8种不同的稀释(1∶100、1∶300、1∶900、1∶2700、1∶8100、1∶24,300、1∶72,900和1∶218,700)下同时测试11种不同的病毒构建体。所述板还包括4个模拟感染细胞的孔和4个FLUORESBRITETM珠子的孔。一旦所述细胞被感染,将所述板置于TECANTM读板仪中以进行连续荧光监测。收集的数据用于计算每个构建体的ln-斜率(图8)。
TECANTM读板仪还提供温育功能(保持适当的温度以及CO2和O2水平)。每15分钟采集数据点以计算所述ln-斜率。使用这些方法,有可能快速有效地比较许多不同病毒之间和不同细胞类型之间的动力学。例如,为了评估具体的重组腺病毒是否可以作为溶瘤病毒在治疗上使用,此分析可用于发现在肿瘤细胞中表现出高复制动力学而在非肿瘤细胞中表现慢病毒动力学的病毒。此外,所述重组病毒的病毒动力学可通过在该测定中感染或转染感兴趣的肿瘤细胞类型来评估。
计算对数-斜率(log-slope)
为了测量对数-斜率,通过取每个时间点测量的荧光强度的自然对数,将荧光强度与时间的线性图转换为半对数图。由于所述荧光强度在病毒复制期间表现出指数增长,因此当绘制ln(荧光强度)对时间时,该转换产生直线。然后使用标准最小二乘法拟合该直线。由此拟合产生的斜率是荧光对时间的ln-斜率,且因此是病毒生长对时间的ln-斜率。方程式如下所示。
其中FI是测量的荧光强度,t是时间,F0是在时间=t0的初始荧光强度,且α是ln-斜率。
取两边的自然对数:
右手侧现在是具有ln-斜率为α的线性方程式。
鉴于可以应用所公开发明的原理的许多可能的实施方案,应该认识到,所示实施方案仅是本公开的示例,并且不应被视为限制本发明的范围。相反,本发明的范围由以下权利要求限定。因此,我们要求将这些权利要求的范围和精神内的所有内容作为我们的发明。
Claims (10)
1.重组腺病毒基因组,包括异源开放阅读框(ORF)和自切割肽编码序列,两者均可操作地连接至与内源腺病毒ORF相同的阅读框中且在所述相同的阅读框中,其中所述自切割肽编码序列位于所述异源ORF和所述内源ORF之间,且其中:
所述内源ORF是E1B-55k且所述异源ORF在E1B-55k的3';
所述内源ORF是DNA聚合酶且所述异源ORF在DNA聚合酶的5';
所述内源ORF是DNA结合蛋白(DBP)且所述异源ORF在DBP的3';
所述内源ORF是腺病毒死亡蛋白(ADP)且所述异源ORF在ADP的5';
所述内源ORF是E3-14.7k且所述异源ORF在E3-14.7k的3';
所述内源ORF是E4-ORF2且所述异源ORF在E4-ORF2的5';或者
所述内源ORF是纤维蛋白且所述异源ORF在纤维蛋白的3';
其中所述异源ORF编码治疗性蛋白。
2.如权利要求1所述的重组腺病毒基因组,其中所述治疗性蛋白包括免疫调节剂。
3.包括如权利要求1或2所述的重组腺病毒基因组和药学上可接受的载体的组合物。
4.包括如权利要求1或2所述的重组腺病毒基因组的重组腺病毒。
5.包括如权利要求4所述的重组腺病毒和药学上可接受的载体的组合物。
6.将治疗性蛋白递送至受试者的方法,包括向所述受试者施用如权利要求5所述的组合物。
7.抑制肿瘤细胞活力和/或肿瘤细胞生长的方法,包括将所述肿瘤细胞与如权利要求5所述的组合物相接触。
8.治疗受试者中癌症的方法,包括向所述受试者施用治疗有效量的如权利要求5所述的组合物,从而治疗受试者中的癌症。
9.如权利要求6-8中任一项所述的方法,进一步包括向所述受试者施用额外的治疗剂。
10.试剂盒,包括:
(i)如权利要求1或2所述的重组腺病毒基因组、如权利要求4所述的重组腺病毒、或如权利要求5所述的组合物;以及
(ii)一种或更多种额外的治疗剂和/或一种或更多种诊断剂。
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