CN114144196A - 工程痘苗病毒 - Google Patents
工程痘苗病毒 Download PDFInfo
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- CN114144196A CN114144196A CN202080050466.6A CN202080050466A CN114144196A CN 114144196 A CN114144196 A CN 114144196A CN 202080050466 A CN202080050466 A CN 202080050466A CN 114144196 A CN114144196 A CN 114144196A
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Abstract
提供了一种工程痘苗病毒、包含该病毒的药物组合物以及使用该病毒治疗有需要的受试者的方法。工程痘苗病毒包括突变的病毒序列和异源序列。突变的病毒序列用于肿瘤细胞中的选择性复制和/或免疫细胞的活化。异源序列编码免疫共刺激途径激活分子、免疫调节剂基因、截短的病毒包膜基因和/或肿瘤抑制剂。异源序列被稳定地整合到工程痘苗病毒的基因组中。该药物组合物包含有效量的工程痘苗病毒和药学上可接受的载剂。用于治疗有需要的受试者的方法包括向受试者施用工程痘苗病毒。
Description
相关应用的交叉引用
本申请要求2019年7月12日提交的美国临时专利申请第62/873,221号的优先权,所述临时专利申请的内容通过引用以其整体并入本文。
技术领域
本公开涉及用于治疗癌症的工程痘苗病毒。
技术背景
癌症是严重而危险的疾病。中国每年新增癌症病例近500万例,死于癌症的患者数量接近300万。这些数字一直在逐年增加。这表明常规的癌症治疗诸如手术、化学疗法和放射疗法对大多数癌症患者没有帮助。因此,癌症患者非常需要更有效的治疗。尽管新的癌症免疫疗法取得了一些进展,但如何更有效地治疗实体瘤患者仍然是最大的挑战之一。近年来,溶瘤病毒作为癌症免疫疗法的一种,越来越受到业界的关注。
溶瘤病毒是通过选择性感染肿瘤细胞或在肿瘤细胞中选择性复制而靶向并杀死肿瘤细胞的病毒。另外,溶瘤病毒可以有效地提供诱导和放大宿主抗肿瘤免疫反应所必需的风险信号,从而使身体的免疫系统产生强大而特异的抗肿瘤免疫反应。
痘苗病毒(VV)是双链DNA病毒,其独特的性质使其成为溶瘤病毒当中的有利选择。1)VV在作为对抗传染病的疫苗预防天花的过程中显示出良好的安全性,因此其作为溶瘤病毒的安全性可以得到保证。另外,在许多临床试验中进一步证实,使用VV作为溶瘤病毒是安全的。2)其可在细胞内快速自我复制,并且可在约6-8小时内产生新的病毒颗粒,使得感染的细胞快速裂解。3)VV的基因组约为200Kbp,这个较大的基因组携带外源基因的能力大。4)痘苗病毒不需要特定的受体来感染细胞,因此对不同类型的肿瘤具有广泛的向性。5)其可通过多种方式施用,包括瘤内局部注射、腹腔内注射、胸内注射和全身性静脉内注射。这种施用方法的多样性使得治疗身体任何部位的肿瘤成为可能。6)另外,通常在实体瘤中发现的缺氧微环境对许多类型的溶瘤病毒的复制和功效具有负作用。然而,VV可以在缺氧环境中高效复制(Hiley等人,Gene Therapy 17,281-287)(2010)。7)有多种天然和合成的启动子可以应用于VV,这使其成为携带转基因的理想选择。近年来,使用痘苗病毒的临床结果已经证明VV具有良好的抗肿瘤作用并且是安全的(Haddad等人,Annals of SurgicalOncology 19增刊3,S665-674(2012);Park等人,Lancet Oncol 9:533-542,(2008);Breitbach等人,Nature 477:99-102,(2011))。
到目前为止,已经报道了痘苗病毒的各种缺失突变体。具有胸苷激酶(TK)基因和病毒生长因子(VGF)基因缺失的Western Reserve毒株突变体能够有效地引发针对肿瘤抗原的免疫反应(McCart等人,Cancer Res 61,8751-8757(2001))。此外,插入了异源基因诸如细胞因子编码基因的病毒可以进一步激活抗肿瘤免疫反应。
VV感染肿瘤细胞后,通过裂解感染的细胞释放VV,使得病毒可以感染定位的肿瘤细胞或通过循环血液感染远离感染部位的肿瘤细胞。痘苗病毒主要有两种形式的感染性病毒颗粒,即细胞内成熟病毒(IMV)和细胞外包膜病毒(EEV)(Appleyard等人,J.Gen.Virology 13,9-17(1971))。IMV是病毒颗粒的主要感染形式。EEV被宿主细胞膜包被,因此可以拮抗宿主全身性先天(补体)和适应性(中和抗体)免疫攻击,使VV在宿主体内广泛和长距离传播(Smith,GL&Vanderplasschen,A和Law,M J.Gen.Virol.83,2915-2931(2002);Payne,LG&Kristensson,K,J.Gen.Virol.66(c),643-646(1985))。然而,大多数VV毒株仅产生少量EEV病毒(仅占不到1%的所有感染性病毒)。
VV具有6个码EEV特异性蛋白的基因编。它们分别是A33R、A34R、A36R、F13L、B5R、A56R。B5R基因编码42kDa糖蛋白,其含有四个拷贝的50-70个氨基酸的重复序列,称为“短共有重复序列”(SCR)。B5R基因的缺失导致较小的斑块和EEV形成的显著减少(≤10倍)(Blasco,R.&Moss,B.,J.Virol.65,5910-5920(1991);Engelstad,M.&Smith,GL,Virology194,627-637(1993))。B5R的跨膜和细胞质尾序列对病毒蛋白的靶向包装很重要(Katz等人,J.Virol.71,3178-3187(1997))。Vv携带缺少SCR4、SCR3、4或SCR 2、3、4的B5R基因突变体,产生较小的斑块,但产生比野生型病毒多几十倍,并形成彗星尾斑块分布的感染性EEV(Sanderson等人,J.Gen Virol.79(f),1415-1425(1998);Mathew等人,J.Virol.72,2429-2438(1998))。
在过去10年左右的时间里,尽管在溶瘤病毒研究领域取得了进展,但基于痘苗病毒的治疗性产品还没有进入临床,难点在于如何科学地对痘苗病毒进行修饰以使其具有更好的抗肿瘤作用。因此,迫切需要开发更好的溶瘤痘苗病毒产品,以满足治疗癌症的需要。
有多种痘苗病毒株对人和动物具有不同程度的毒力。作为1970年代天花根除计划的一部分,世界各地使用了许多不同的毒株。例如,纽约市卫生部(NYCBOH)毒株及其衍生物Wyeth在美国很受欢迎,而哥本哈根(Copenhagen)(CPN)和李斯特(Lister)毒株在欧洲占主导地位。以往的研究发现李斯特毒株具有很好的抗肿瘤作用。该项目选择李斯特菌株作为溶瘤病毒进行开发。
发明内容
本公开涉及溶瘤病毒,更具体地,涉及工程溶瘤痘苗病毒。本公开的工程溶瘤痘苗病毒能够选择性感染癌细胞,这可以有益地用于癌症的治疗。
本公开提供了包含突变的病毒序列和异源序列的工程痘苗病毒,其中突变的病毒序列促进肿瘤细胞中的选择性复制和/或免疫细胞的活化,异源序列编码免疫共刺激途径激活分子、免疫调节剂基因、截短的病毒包膜基因和/或肿瘤抑制剂,并且异源序列被稳定地整合到工程痘苗病毒的基因组中。
在工程痘苗病毒的实施方案中,异源序列被稳定地整合到工程痘苗病毒的突变的病毒序列中。
在工程痘苗病毒的实施方案中,突变的病毒序列包含以下的至少一种:
(a)L025、TK、A46R或其任意组合中的一个或多个突变;
(b)部分删除的L025、TK、A46R或其任意组合;
(c)删除的L025、TK、A46R或其任何组合;
(d)L025、TK或A46R的一部分或全部,其被SEQ ID NO:2、4、6、8、10、12或14中所示的序列之一替代;
(e)L025、TK或A46R的一部分或全部,其被肿瘤靶向基因替代;
(f)L025、TK或A46R的一部分或全部,其被靶向T细胞的配体或抗体替代;
(g)L025、TK或A46R的一部分或全部,其被治疗性基因或其修饰形式替代;或者
(h)L025、TK或A46R的一部分或全部被治疗性抗体替代。
在工程痘苗病毒的实施方案中,异源序列包含以下的至少一种:
(a)SEQ ID NO:2中所示的序列;
(b)SEQ ID NO:4中所示的序列;
(c)SEQ ID NO:6中所示的序列;
(d)SEQ ID NO:8中所示的序列;
(e)SEQ ID NO:10中所示的序列;
(f)SEQ ID NO:12中所示的序列;或
(g)SEQ ID NO:14中所示的序列。
在工程痘苗病毒的实施方案中,异源序列编码以下的至少一种:
(a)SEQ ID NO:1中所示的序列;
(b)SEQ ID NO:3中所示的序列;
(c)SEQ ID NO:5中所示的序列;
(d)SEQ ID NO:7中所示的序列;
(e)SEQ ID NO:9中所示的序列;
(f)SEQ ID NO:11中所示的序列;或
(g)SEQ ID NO:13中所示的序列。
在工程痘苗病毒的实施方案中,工程痘苗病毒包含下式的序列:5’-A1-X-A2-B1-Y-B2-C1-Z-C2-3’,其中A1和A2分别是第一病毒基因的左臂和右臂,B1和B2分别是第二病毒基因的左臂和右臂,C1和C2分别是第三病毒基因的左臂和右臂,其中X、Y和Z是异源基因,各自选自免疫调节基因、细胞因子、治疗性基因、截短的病毒包膜基因、肿瘤抑制基因、编码治疗性抗体的基因和编码治疗性抗体的配体的基因中的一种。
在工程痘苗病毒的实施方案中,第一病毒基因是L025,第二病毒基因是TK,第三病毒基因是A46R。
在工程痘苗病毒的实施方案中,X是IL-21与经修饰的B5R的杂交基因,Y是4-1BBL,Z是HIC1。
在工程痘苗病毒的实施方案中,突变的病毒序列包含L025、TK和A46R中的缺失突变,并且异源序列包括IL-21和4-1BBL。
在工程痘苗病毒的实施方案中,突变的病毒序列包含L025、TK和A46R中的缺失突变,并且异源序列包括IL-21与经修饰的B5R和4-1BBL的杂交基因。
在工程痘苗病毒的实施方案中,免疫调节基因是编码IL-12、IL-21、IL-2、IL-15、IL-8或其经修饰的形式的细胞因子基因。
在工程痘苗病毒的实施方案中,免疫共刺激途径激活分子包含CD40配体(CD40L)、ICOS配体、GITR配体、4-1BB配体、OX40配体、TL1A、CD30配体、CD27、Flt3配体或其经修饰的形式。
在工程痘苗病毒的实施方案中,肿瘤抑制基因是HIC1。
在工程痘苗病毒的实施方案中,工程痘苗病毒选自由以下组成的组:李斯特毒株、Western Reserve(WR)毒株、哥本哈根(Cop)毒株、Bern毒株、巴黎毒株、塔什干毒株、天坛(Tian Tan)毒株、惠氏(DRYVAX)毒株、IHD-J毒株、IHD-W毒株、布莱顿毒株、安卡拉毒株、CVA382毒株、改良安卡拉痘苗(MVA)毒株、戴仁I毒株、LC16m8毒株、LC16M0毒株、LIVP毒株、ACAM2000毒株、WR 65-16毒株、康诺特毒株、纽约市卫生局(NYCBH)毒株、EM-63毒株和NYVAC毒株。
在工程痘苗病毒的实施方案中,截短的病毒包膜基因是含有短共有重复序列(SCR)2、SCR3和SCR4结构域缺失的B5R。
在工程痘苗病毒的实施方案中,肿瘤抑制基因是HIC1。
本发明还提供了药物组合物,其包含有效量的本公开的任一实施方案的工程痘苗病毒和药学上可接受的载体。
在药物组合物的实施方案中,药物组合物被配制用于口服、局部、肠胃外递送或介入疗法。
在药物组合物的实施方案中,药物组合物被配制用于局部瘤内注射、腹膜内注射、胸内注射、全身静脉内注射、肌内注射、皮下注射、鞘内注射、直接脑室注射、心内注射、鼻内注射。
在药物组合物的实施方案中,工程痘苗病毒单独用作单一疗法;或者与一种或多种抗癌剂、免疫抑制剂和/或溶瘤病毒增强剂联合使用。
在药物组合物的实施方案中,工程痘苗病毒与5-氟尿嘧啶(FU)、亚叶酸(FA)、甲氨蝶呤、卡培他滨、奥沙利铂、贝伐单抗、西妥昔单抗、免疫检查点抑制剂(如抗PD1、抗PDL1、抗CTLA4剂)、其他类型的溶瘤病毒、帕博利珠单抗、纳武单抗、伊匹木单抗、阿替利珠单抗(atezolizumab)、阿维鲁单抗(avelumab)、腺病毒或其组合联合使用。
本公开还提供了用于治疗有需要的受试者的癌症的方法,其包括向受试者施用有效量的本公开任一实施方案的工程痘苗病毒或本公开任一实施方案的药物组合物。
在该方法的实施方案中,HIC1在癌症中失活、表达不足或丧失。
在该方法的实施方案中,癌症选自由以下组成的组:肺癌、黑色素瘤、胰腺癌、肝癌、结肠癌、乳腺癌、胶质母细胞瘤、肉瘤、胃癌、卵巢癌、间皮瘤和白血病。
一种增加痘苗病毒的肿瘤特异性感染性的方法,包括向受试者施用本公开的任一实施方案的工程痘苗病毒,其中以有效引发受试者的抗肿瘤免疫反应的量施用工程痘苗病毒。
一种在有需要的受试者中对肿瘤复发赋予持续免疫的方法,包括向受试者施用本公开的任一实施方案的工程痘苗病毒。
一种基于用本发明的任一实施方案的工程痘苗病毒感染患者癌细胞后48小时GFP阳性细胞的百分比筛选患者的方法。
一种用于诱导癌细胞死亡、调节癌细胞的生物活性、调节免疫反应、增强T细胞的增殖和/或T细胞的细胞毒性的工程痘苗病毒,其中工程溶瘤是如本公开的任一实施方案中所提供的。
一种用于诱导癌细胞死亡、调节癌细胞的生物活性、调节免疫反应、增强T细胞的增殖和/或T细胞的细胞毒性的工程痘苗病毒,其中癌细胞的生物活性包括抑制癌细胞复制、抑制癌细胞分裂、抑制癌细胞的DNA修复、抑制癌细胞迁移或促进癌症死亡,其中工程溶瘤是如本公开的任一实施方案中所提供的。
一种用于制造用于治疗肺癌、黑色素瘤、胰腺癌、肝癌、结肠癌、乳腺癌、胶质母细胞瘤、肉瘤、胃癌、卵巢癌、间皮瘤和白血病的药物的工程痘苗病毒,其中工程溶瘤是如本公开的任一实施方案中所提供的。
一种用于制备用于抑制癌细胞生长、诱导癌细胞死亡并且/或者调节癌细胞生物活性的药物的工程痘苗病毒,其中工程溶瘤是如本公开的任一实施方案中所提供的。
附图说明
为了更清楚地说明本申请的实施方案或现有技术中的技术方案,下文简要介绍实施方案中所需的附图。以下描述中的附图仅仅是本申请的实施方案的一部分。基于附图,本领域普通技术人员无需做出创造性努力就可以获得其它附图。
图1A是携带mB5R的产品的示意图。
图1B是携带sB5R的产品的示意图。
图2A是用于删除TK基因的携带小鼠4-1BBL的穿梭载体的示意图。
图2B是用于删除TK基因的携带人4-1BB的穿梭载体的示意图。
图3A显示的是用于删除L025基因的携带小鼠IL-21和修经饰的B5R(mB5R/sB5R)的穿梭载体。
图3B显示的是用于删除L025基因的携带人IL-21和经修饰的B5R(mB5R/sB5R)的穿梭载体。
图4显示的是用于删除A46R基因的携带HIC1基因的穿梭载体。
图5显示的是mB5R/sB5R基因的结构图。
图6显示的是具有L025基因缺失的重组病毒。
图7显示的是具有TK基因缺失和hSPD-41BBL基因插入的重组病毒。
图8显示的是A46R基因的重组病毒缺失和插入基因HIC1的病毒表达。
图9A至图9B.在6孔板中用剂量递增的病毒对一小组实体瘤细胞系进行2天KM1杀伤。用于感染单个孔的病毒量为0.01pfu/细胞、0.1pfu/细胞和1pfu/细胞。当实验结束时,结晶紫被用来对孔中剩余的细胞进行染色。
图10A-10C显示的是对17个细胞系进行EC50测定的实例。
图11显示的是不同细胞系的EC50值。
图12显示的是痘苗病毒对白血病细胞系的杀伤,两种细胞系上EC50测定的实例。
图13显示的是被KM1感染的白血病患者的白细胞的实例。
图14显示的是KM1感染后三天的活/死细胞。
图15显示的是KM1在叙利亚仓鼠胰腺癌HPD 1NR模型中的抗肿瘤功效。
图16显示的是使用HIC1武装的痘苗病毒及其对应物对照HY3对人乳腺癌细胞MDAMB-231进行的处理。
具体实施方式
参考附图中的绘图,相同的参考数字表示相同的组件。以下描述基于如举例说明的本公开的详细实施方案,并且不应该被解释为对本文中未详细描述的本申请的其它实施方案的限制。
请参考图1A至图1B。图1A是载有mB5R的产品的示意图,图1B是载有sB5R的产品的示意图。
本公开的痘苗病毒和病毒载体包含下式的序列:5’-A1-X-A2-B1-Y-B2-C1-Z-C2-3’,其中A1和A2分别为第一病毒基因的左臂和右臂,B1和B2分别为第二病毒基因的左臂和右臂,C1和C2分别为第三病毒基因的左臂和右臂,其中X、Y和Z各自选自免疫调节基因、细胞因子、治疗性基因和治疗性抗体、治疗性抗体的配体。获得的产品的示例性结构如图1A和图1B所示。第一病毒基因是L025,第二病毒基因是TK,第三病毒基因是A46R。X为IL-21与经修饰的B5R的杂交基因,Y为4-1BBL,Z为HIC1。
“A1-X-A2”与“B1-Y-B2”之间以及“B1-Y-B2”与“C1-Z-C2”之间的间隙可以包含痘苗病毒中已知的其它病毒基因。
产品设计和构建:
1.TK基因缺失和4-1BBL基因至TK基因位点中的整合
请参考图2A至图2B。图2A是用于删除TK基因的携带小鼠4-1BBL的穿梭载体的示意图。图2B是用于删除TK基因的携带人4-1BB的穿梭载体的示意图。
在图2A中,TK的左臂靶向TK基因的左侧(L089),并且TK的右臂靶向TK基因的右侧(L091)。Loxp位点位于H5启动子和红色荧光蛋白RFP的两侧,并位于TK左臂与小鼠4-1BBL基因的启动子H5之间。
在图2B,TK的左臂靶向TK基因的左侧(L089),TK的右臂靶向TK基因的右侧(L091)。Loxp位点位于H5启动子和红色荧光蛋白RFP的两侧,并位于TK左臂与人4-1BBL基因的启动子H5之间。
表达盒设计如下(关于示意图,参见图2A和图2B):
TK左臂-loxp-H5-RFP-loxp-H5-m/h4-1BBL-TK右臂
为了使用相同的报告蛋白(RFP)删除两个或更多个基因,重要的是使用合适的同源重组系统,诸如Cre-Lox,或Flp/FRT系统来去除报告基因。可将基因插入元件在编码一种或多种蛋白质的核酸序列周围并在驱动一种或多种蛋白质表达的启动子区上游插入表达盒中。
loxp位点分别位于H5的上游和RFP的下游,使得C5重组酶可通过作用于FRET位点来切除新重组病毒中的H5-RFP。
H5启动子驱动4-1BBL基因的表达。SPD-m4-1BBL的氨基酸序列示于SEQ ID NO:5中并且SPD-m4-1BBL的核苷酸序列示于SEQ ID NO:6中。SPD-h4-1BBL的氨基酸序列示于SEQID NO:7中并且SPD-h4-1BBL的核苷酸序列示于SEQ ID NO:8中。
为了在痘苗病毒的TK基因(L090)位点进行靶向同源重组,有必要为用于生产本公开的载体的重组区提供与TK基因和/或与TK基因相邻的基因互补的附加序列。提供TK左臂(L臂)以靶向TK基因的左侧(L089),提供TK的右臂(R臂)以靶向TK基因的右侧(L091)。然后,包含4-1BBL基因和报告基因RFP的实际表达盒可位于TK-L臂与TK-R臂之间,并且它们可以插入痘苗病毒的被靶向的TK区域。可将表达盒在痘苗病毒载体转化之前插入重组载体。
2.L025基因的缺失以及白细胞介素21(IL-21)和mB5R(或sB5R)至L025区中的整合
请参考图3A至图3B。图3A示出了用于删除L025基因的携带小鼠IL-21和修经饰的B5R(mB5R/sB5R)的穿梭载体。图3B示出了用于删除L025基因的携带人IL-21和经修饰的B5R(mB5R/sB5R)的穿梭载体。
在图3A中,L025的左臂靶向L025基因的左侧(L024),L025的右臂靶向L025基因的右侧(L026)。FRT位点位于H5启动子和红色荧光蛋白RFP的两侧,并位于L025的左臂与L025的右臂之间。
在图3B中,L025的左臂靶向L025基因的左侧(L024),L025的右臂靶向L025基因的右侧(L026)。FRT位点位于H5启动子和红色荧光蛋白RFP的两侧,并位于L025的左臂与L025的右臂之间。
表达盒设计如下(关于示意图,参见图3A和图3B):
L025左臂-FRT-H5-RFP-FRT-H5-m/sB5R-H5-m/hIL-21-L025右臂
红色荧光蛋白(RFP)被用作报告蛋白,以便于筛选新的重组病毒。在报告蛋白的上游提供启动子来驱动报告蛋白的表达,此处使用H5启动子。FRT是翻转酶(Flipase)的识别位点,使得RFP可被删除。
小鼠IL-21的氨基酸序列示于SEQ ID NO:9中,小鼠IL-21的核苷酸序列示于SEQID NO:10中。人IL-21的氨基酸序列示于SEQ ID NO:11中,人IL-21的核苷酸序列示于SEQID NO:12中。
请参考图5。图5显示了mB5R/sB5R基因的结构图。mB5R由信号肽、柄(stalk)、跨膜区(TM)和胞内尾段(CT)基因片段组成。sB5R由信号肽、短共有重复序列1(SCR1)、柄、跨膜区(TM)和胞内尾段(CT)基因片段组成。
H5启动子驱动免疫治疗性基因IL21的表达以及mB5R或sB5R的表达。关于mB5R和sB5R的结构示意图,参见图5。mB5R的氨基酸序列示于SEQ ID NO:1中,mB5R的核苷酸序列示于SEQ ID NO:2中。sB5R的氨基酸序列示于SEQ ID NO:3中,sB5R的核苷酸序列示于SEQ IDNO:4中。
需要将上述重组区插入痘苗病毒的L025基因。此处,使用同源重组的方法进行插入,并且整合位点在L025的左右臂之间。
为了在痘苗病毒的L025基因位点进行靶向同源重组,有必要为用于生产本公开的载体的重组区提供与L025基因和/或与L025基因相邻的基因互补的附加序列。L025的左臂(L臂)被提供来靶向L025基因的左侧(L024),L025的右臂(R臂)被提供来靶向L025基因的右侧(L026)。然后,将包含HIC1基因和报告基因GFP的实际表达盒置于L025-L臂与L025-R臂之间,并且它们可被插入痘苗病毒的靶向L025区域。可将表达盒在痘苗病毒载体转化之前插入重组载体。
3.将HIC1基因插入A46R区域。
请参考图4。图4显示的是用于删除A46R基因的携带HIC1基因的穿梭载体。A46R的左臂靶向A46R基因的左侧(L163),A46R的右臂靶向A46R基因的右侧(L165)。H5启动子驱动绿色荧光蛋白GFP的表达。H5启动子驱动HIC1基因的表达。
表达盒设计如下(关于示意图,参见图4):
A46R左臂-H5-GFP-H5-HIC1-A46R右臂
为了在痘苗病毒的A46R基因(L164)位点进行靶向同源重组,有必要为用于生产本公开的载体的重组区提供与A46R基因和/或与A46R基因相邻的基因互补的附加序列。A46R左臂(L臂)被提供来靶向A46R基因的左侧(L163),A46R的右臂(R臂)被提供来靶向A46R基因的右侧(L165)。然后可将包含HIC1基因和报告基因GFP的实际表达盒置于A46R-L臂与A46R-R臂之间,并且它们可被插入痘苗病毒的靶向A46R区域。可将表达盒在痘苗病毒载体转化之前插入重组载体。
材料和方法
细胞系:所使用的所有肿瘤细胞系都来自ATCC。所有人癌细胞系都通过STR测定进行了基因分型。本研究中使用的鼠肿瘤细胞系包括:结直肠癌细胞系MC38源于C57B/6小鼠。CV1是从ATCC,Virginia,USA获得的非洲绿猴“正常”肾细胞系,并被用作储备细胞系以促进病毒的大规模生产以及所有病毒滴定测定。
病毒:野生型VV李斯特病毒可从美国典型培养物保藏中心(ATCC)购得,ATCC登录号为VR-1549TM。野生型VV李斯特病毒也保藏在中国典型培养物保藏中心(CCTCC),CCTCC保藏号为:V201937。保藏日期为2019年7月4日。毒株名称为李斯特痘苗病毒01(VV01)。详细信息也可以从ATCC VR-1549TM的产品表中获得。工程VV李斯特病毒保藏在CCTCC,CCTCC保藏号为:V201938。保藏日期为2019年7月4日。毒株名称为痘苗病毒李斯特毒株KM1。野生型VV李斯特病毒和工程VV李斯特病毒都是根据布达佩斯条约保藏的。野生型VV李斯特病毒和工程VV李斯特菌保藏在College of Life Sciences,Wuhan University Wuhan 430072,China的中国典型培养物保藏中心(CCTCC)。野生型VV李斯特病毒和工程VV李斯特病毒的保藏者为Shenzhen Hua Yao Kang Ming Biopharmaceutial Co.,Ltd.,14 Jinhui road,Pingshan District,Shenzhen,China(申请人)。
TK穿梭载体的构建:
TK穿梭载体包括靶向TK基因的TK基因的左侧(L089)和靶向TK基因右侧(L091)的TK的右臂。Loxp位点位于H5启动子和红色荧光蛋白RFP的两侧,且位于TK左臂与4-1BBL基因的启动子H5之间。所有以上序列都是由我们整合在一起的,并由一家公司合成并克隆到PUC57载体中。
L025穿梭载体的构建:
L025穿梭载体的结构示意图如图3A和图3B所示。L025穿梭载体包括靶向L025基因左侧的L025左臂(L024)和靶向L025基因右侧的L025右臂(L026)。FRT位点位于H5启动子和红色荧光蛋白RFP的两侧,并位于L025的左臂与mB5R/sB5R基因的启动子H5之间。由公司将所有上述序列均拼接在一起和合成,并克隆到PUC57载体中。
A46R穿梭载体的构建:
A46R穿梭载体的结构示意图如图4所示。A46R穿梭载体包括靶向A46R基因左侧(L163)的A46R左臂和靶向A46R基因右侧(L165)的A46R右臂。H5启动子驱动绿色荧光蛋白GFP的表达。H5启动子驱动HIC1基因的表达。所有以上序列都是由我们整合在一起的,并由公司合成并克隆到PUC57载体中。
获得mB5R基因:
mB5R由信号肽、柄、跨膜(TM)和胞内尾(CT)基因区段组成。H5启动子驱动sB5R基因的表达。
获得sB5R基因:
sB5R由信号肽、SCR1、柄、跨膜(TM)和胞内尾(CT)基因区段组成。
Cas9介导的同源重组:
转染前一天,将3x 105个CV-1细胞接种到六孔板的一个孔中。将gRNA载体(靶向L025区域的L025gRNA,靶向TK区域的TKgRNA,靶向A46R区域的A46RgRNA)与Cas9在六孔板中共转染到CV-1细胞中。第二天,用0.01PFU/细胞骨架病毒感染用gRNA载体和Cas9基因转染的孔。在病毒感染后2小时,将用于同源重组的穿梭载体转染到感染的孔中。24小时后收获细胞,并将其在-80℃下冷冻以进行重组病毒纯化。
重组病毒的纯化:
将从Cas9介导的同源重组收集的细胞裂解物解冻,并用0.5μl该裂解物感染含有生长至80-90%汇合的CV1细胞的六孔板的所有6个孔。感染48小时后,在荧光显微镜下检查每个孔中的发射红色或绿色荧光的病毒。鉴定阳性感染点后,用标记物在平板下部表面上标记它们。然后在通风橱中从孔中吸取培养基用于培养细胞后,用20μl的吸头仔细选择斑块。然后将尖端浸入含有200微升细胞培养液的冷冻管中。在一次冻融循环后,将5-20μl的该病毒溶液加入到含有CV1细胞的新6孔板的每个孔中。重复该过程,直至每个斑块表达红色或绿色荧光,即所有斑块都由重组病毒形成。典型地,需要3至5轮噬斑纯化来获得纯重组病毒。在确认病毒已经纯化后,刮去感染的细胞并离心以获得细胞沉淀。然后取一些细胞提取病毒DNA。通过从提取的病毒DNA中PCR扩增靶基因来确认病毒的纯度。
病毒的扩增:
一旦重组病毒被证实是所需的重组病毒,就将50μl病毒裂解物添加到含有CV1细胞的T175烧瓶中,并在含有约30ml的细胞培养基中生长至80-90%汇合。48小时后,刮去细胞和培养基,保存“初级病毒扩增”。
验证删除了L025基因的重组病毒:
用纯化的病毒感染CV-1细胞。感染后2天收获感染的细胞,并提取VV DNA。为了验证L025基因的缺失,使用正向引物(SEQ ID NO:15:5'-TATCTAGCAATGGACCGT-3')(在L025基因内)和反向引物(SEQ ID NO:16:5'-CCGAAGGTAGTAGCATGGA-3')(在L026基因内)通过PCR扩增跨越L025基因和L026基因的DNA片段。使用正向引物(SEQ ID NO:17:5'-TTGGCTATTAAACAGTATGGA-3')和反向引物(SEQ ID NO:18:5'-GGATCCCGATAACAAATG-3')通过PCR获得跨越A46R和A47L基因的对照基因A DNA片段的扩增。用1%琼脂糖凝胶电泳分析了PCR产物。
验证表达mB5R或sB5R基因的重组病毒:
为了验证mB5R基因在重组病毒中的整合,使用正向引物(SEQ ID NO:19:5’-ATGAAAACGATTTCCGTTGTTACGT-3’)和反向引物(SEQ ID NO:20:5’-TCACGGTAGCAATTTATGGAACTT-3’)通过PCR扩增mB5R。
为了验证sB5R基因在重组病毒中的整合,使用正向引物(SEQ ID NO:21:5’-ATGAAAACGATTTCCGTTGTTACGT-3’)和反向引物(SEQ ID NO:22:5’-TCACGGTAGCAATTTATGGAACTT-3’)通过PCR扩增sB5R基因。
使用Flp重组酶切除RFP:
将pCAG-Flpe(来自Addgene)转染到CV-1细胞中的六孔板的一个孔中。在用pCAG-Flpe转染后24小时,CV-1细胞感染了100-200个重组病毒Flp-RFP VV。两天后,挑取RFP阴性斑块,并用于感染六孔板中的CV-1细胞,以纯化RFP阴性斑块。然后挑取RFP阴性斑块,并感染CV-1细胞,直至每2天在荧光显微镜下没有观察到RFP阳性斑块。
验证删除了TK基因的重组病毒:
用纯化的病毒感染CV-1细胞。感染后2天收获感染的细胞,并提取VV DNA。为了验证TK基因的缺失,使用正向引物(SEQ ID NO:23:5'-GTTATAGTAGCCGCACTCGA-3')(在TK基因内)和反向引物(SEQ ID NO:24:5'-ATTTCAGCTGAATATGAAGGA-3')(在L091基因内)进行PCR扩增。横跨TK基因和L091基因的DNA片段。使用正向引物(SEQ ID NO:17:5'-TTGGCTATTAAACAGTATGGA-3')和反向引物(SEQ ID NO:18:5'-GGATCCCGATAACAAATG-3')通过PCR扩增获得对照基因(跨越A46R和A47L基因的DNA片段)的扩增。用1%琼脂糖凝胶电泳分析了PCR产物。PD1抗体基因通过其基因片段的PCR扩增得到证实。使用的引物是:(SEQ IDNO:25:5'-TCATAAATACCCGAGCCACC-3')和(SEQ ID NO:26:5'-ACCCATTCAAGACCCTTTCC-3')。
使用Cre重组酶切除RFP:
将pCAG-Cre(来自Addgene)转染到六孔板的一个孔中的CV-1细胞中。在用pCAG-Cre转染后24小时,用100-200个Cre-RFP病毒感染CV-1细胞。两天后,选择RFP阴性斑块并用于感染六孔板中的CV-1细胞以纯化RFP阴性斑块。然后挑取RFP阴性斑块,并感染CV-1细胞,直至每2天在荧光显微镜下没有观察到RFP阳性斑块。
验证删除A46R基因的重组病毒:
用纯化的病毒感染CV-1细胞。感染后2天收获感染的细胞,并提取VV DNA。为了验证A46R基因的缺失,使用正向引物(SEQ ID NO:17:5'-TTGGCTATTAAACAGTATGGA-3')(在A46R基因内)和反向引物(SEQ ID NO:18:5'-GGATCCCGATAACAAATG-3')(在A47R基因内)进行PCR扩增。跨越A46R基因和A47R基因的DNA片段。使用正向引物(SEQ ID NO:27:5'-TGTTGTTCGCTGCTATGA-3')和反向引物(SEQ ID NO:28:5'-TGGCACAACCATATCTTGTA-3')通过PCR扩增对照基因以扩增L09基因的DNA片段。用1%琼脂糖凝胶电泳分析了PCR产物。通过获得从被重组病毒感染的细胞中提取的蛋白质,通过蛋白质印迹证实了HIC1表达的检测。
酶联免疫吸附测定:
根据试剂制造商的说明,通过酶联免疫吸附试测定ELISA检测到mIL-21和hIL-21的表达。
大规模病毒生产:
将来自上面的初级病毒扩增物快速冷冻和解冻一次,并稀释至感染36个含有CV1细胞的T175烧瓶(80-90%汇合)所需的细胞培养所需的体积。48小时后,通过刮取收集感染的CV1细胞,并通过以2000rpm(4℃)重复离心数轮来收集。将沉淀物在PBS中洗涤,重悬于12ml的10mM Tris-HCl(pH 9)缓冲液中,并在-80℃下储存以备以后纯化。
病毒纯化:
将上面浓缩的病毒裂解物悬浮液解冻一次,并涡旋数秒钟。在4℃下以2,000rpm离心5分钟后,收集上清液(包含释放的病毒体),并用10mM Tris-HCl缓冲液稀释至30ml的总体积。将平均30ml置于四个Beckman超速离心管中,然后向病毒溶液中轻轻加入17ml 36%的蔗糖溶液,并在4℃下以13,500rpm离心80分钟。将最终的沉淀物重悬于1-4ml病毒悬浮缓冲液(PBS;10%甘油;138mM NaCl;pH 7.4)。并于-80℃下保存。
病毒复制的确定:
根据生长速率,将细胞以每孔2至4x105个细胞接种在含有细胞培养基的6孔板的3个孔中,并在第二天用1PFU/细胞的痘苗病毒进行感染。分别在感染后24小时、48小时和72小时时收集感染的细胞及其培养液。然后测定病毒浓度。
体外病毒细胞毒性评价:
根据生长速度将细胞以1x103个和1x104个细胞/孔接种在96孔板中,并在16-18小时后用病毒进行感染。病毒感染后第6天的细胞活力通过MTS测定法进行测定,如前所述计算EC50值(杀死50%的肿瘤细胞的病毒剂量),所有测定至少进行三次。
体外评价实体瘤细胞对病毒感染的敏感性:
根据生长速率将细胞以3x105个细胞/孔接种在6孔板中,并在16-18小时后用病毒进行感染。通过结晶紫染色测定病毒感染后第2天的细胞活力,并如前所述扫描结果。
白血病细胞系在体外对病毒感染敏感性的评价:
根据生长速率,将细胞一式三份以3x105个细胞/孔接种在6孔板中,并在细胞接种后用病毒进行感染。病毒感染后第1天、第2天和第3天的细胞活力通过用台盼蓝染色进行细胞计数以区分活细胞和死细胞来测定。
白血病患者的样品在体外对病毒感染敏感性的评价:
征得白血病患者同意后,将五毫升血液抽入抗凝管。将血液样品以2000rpm旋转5分钟,取出血浆,向试管中加入5毫升红细胞裂解缓冲液,然后在室温下孵育10分钟。红细胞裂解后,将样品转移到含有8ml无菌PBS的15ml试管中,并以2000rpm旋转5分钟。离心后除去上清液,用5ml含10%FBS和抗生素的RPMI 1640重新悬浮细胞沉淀。将细胞以1x106个细胞/孔接种在24孔板中的两个孔中,并且在细胞接种后,一个孔用1pfu KM1病毒/细胞感染,另一个孔用作对照。病毒感染后3天,在荧光显微镜下观察并拍摄感染的细胞,然后将感染的细胞和对照细胞收集到含有10ml PBS的15ml试管中,以2000rpm旋转5分钟。将100ul在PBS中含有L/D、CD14、CD16和CD33抗体的抗体混合物加入到细胞沉淀中,并在室温下于黑暗中对细胞染色15分钟。染色后用PBS洗涤染色细胞一次,并将细胞重悬于300ul PBS中,然后在FAC上进行分析。
使用KM1治疗癌症的体内功效实验。
通过皮下注射5x106个癌细胞,在每个治疗组的10只小鼠中建立背部皮下肿瘤,并且直径为0.4-0.5cm,然后根据肿瘤尺寸将小鼠重新分组,并在第1天、第2天、第3天、第4天和第5天接受1x108PFU(具有免疫能力的小鼠)或PBS。每周测量两次肿瘤体积(体积=(长x宽2xπ)/6),直至肿瘤面积达到1.69cm2时处死小鼠。使用的动物是4-5周的雄性叙利亚仓鼠。
统计分析:
除非另有说明,否则使用Graphpad Prism 5进行比较统计分析。使用未配对t检验进行双重条件比较。对于超过一个条件的附加变量,分别进行1或2次ANOVA。生存数据表示国卡普兰-迈耶图,用对数秩分析绘制各组之间是否有统计上的显著差异。
提供了溶瘤痘苗病毒及其病毒载体,其包含以下特征中的一个或多个特征:
(a)产生病毒基因组合的缺失,并将免疫调节性基因(例如IL21和4-1BBL)、肿瘤抑制基因(例如HIC1)和新型病毒传播基因mB5R/sB5R引入感染的靶细胞。
(b)TK基因的缺失使痘苗病毒在肿瘤细胞中被靶向进行复制。痘苗病毒的胸苷激酶(TK)允许静止细胞(诸如体内绝大多数正常细胞)产生用于复制的胸苷。TK缺陷型痘苗病毒依赖于宿主细胞产生的胸苷激酶。胸苷激酶在肿瘤细胞中天然产生,但在正常细胞中不产生或少量产生。因此,TK缺陷型痘苗病毒可以在肿瘤细胞,尤其是具有激活的EGFR/Ras/ERK通路的肿瘤细胞中选择性复制。
(c)L025基因的缺失。由L025基因编码的蛋白质可以通过抑制免疫细胞中NFκB信号传导途径的激活来抑制免疫反应。L025基因的缺失可以消除免疫系统对基因产物的抑制,这可提高抗肿瘤免疫反应。
(d)A46R基因的缺失。由A46R基因编码的蛋白质通过作用于NFκB信号传导途径的上游来抑制免疫细胞的活化。该基因的缺失有助于提高抗肿瘤免疫反应。
(e)病毒携带痘苗病毒的额外B5R-部分区域缺失基因(mB5R或sB5R)。
(f)病毒携带白细胞介素21(IL-21)基因。白细胞介素21还能活化NK细胞和杀伤T细胞。携带白细胞介素21的病毒有助于增强针对肿瘤的免疫反应。治疗性基因被插入L025区域。
(g)病毒携带4-1BBL基因。4-1BB在活化的T细胞上表达,4-1BB与其配体4-1BBL的结合增强了T细胞的增殖和细胞毒性。为了使这种产品更有效,将4-1BBL基因整合到病毒中。治疗性基因被插入到TK区域。
(h)病毒携带肿瘤抑制基因HIC1基因。HIC1在许多肿瘤中失活或丢失。体内实验已表明,在失去该基因的肿瘤中表达该基因可以抑制肿瘤进展。该基因被插入A46R基因区。
(i)病毒携带白细胞介素12(IL-12)基因。已知白细胞介素12调节并激活天然杀伤细胞(NK细胞)和杀伤T细胞。该产品携带的白细胞介素12在初步功效实验中显示出活化天然杀伤细胞和T细胞。治疗性基因被插入A46R区。
(j)提供用于删除多个病毒基因的新策略。在构建病毒的过程中,本发明人率先引入CRISPR Cas9系统,以删除了用于基因筛选的荧光蛋白。为CRISPR Cas9系统设计的各种gRNA序列可用于反复删除荧光蛋白,使得可以删除具有任何基因组合的痘苗病毒。
根据本公开的特征(e),提供了包含编码结构域缺失的B5R基因的核酸序列的痘苗病毒载体。该序列被整合到痘苗病毒的L025基因中并替代了L025基因。该产品携带mB5R/sB5R,以使病毒更好地传播,从而增加其杀伤肿瘤细胞的能力。
痘苗病毒的B5R基因具有编码EEV形成所必需的膜蛋白的开放阅读框(ORF)。B5RORF的缺失导致EEV的产生显著减少,因此,病毒在体外产生小的细胞感染的斑块,并且在体内传播的能力严重下降。B5R的细胞外部分主要由四个结构域组成,所述结构域类似于补体调节蛋白中存在的短共有重复序列(SCR)。
上述部分mB5R基因或sB5R可被其上游启动子驱动表达。因此,启动子的核酸序列可以是表达盒的一部分。表达盒可以是包含启动子、开放阅读框(和3’非翻译区)的载体的一部分。启动子是具有启动其下游基因的转录的特定序列的DNA区域。用于在痘苗病毒中表达异源基因的启动子包括控制早期和晚期转录活性的启动子,诸如mH5、H5、P7.5和pE/L异源基因是通常不存在于病毒中的基因。
本公开的实施方案提供了序列,所述序列包括以下至少一个:
(a)SEQ ID NO:1中所示的序列;
(b)SEQ ID NO:3中所示的序列;
(c)SEQ ID NO:5中所示的序列;
(d)SEQ ID NO:7中所示的序列;
(e)SEQ ID NO:9中所示的序列;
(f)SEQ ID NO:11中所示的序列;
(g)SEQ ID NO:13中所示的序列;
(h)治疗性基因或其修饰形式;
(i)4-1BBL基因或其修饰形式;或
(j)靶向T细胞的配体或抗体。
本公开的实施方案提供了病毒,其包含以下至少一种:
(a)SEQ ID NO:1中所示的序列;
(b)SEQ ID NO:3中所示的序列;
(c)SEQ ID NO:5中所示的序列;
(d)SEQ ID NO:7中所示的序列;
(e)SEQ ID NO:9中所示的序列;
(f)SEQ ID NO:11中所示的序列;
(g)SEQ ID NO:13中所示的序列;
(h)治疗性基因或其修饰形式;
(i)4-1BBL基因或其修饰形式;或
(j)靶向T细胞的配体或抗体。
所述序列还可包含治疗性基因,包括免疫调节剂、免疫共刺激途径激活分子、检查点抑制剂、细胞毒性基因、肿瘤抑制基因、抗血管生成基因等。
免疫调节剂基因可以包括细胞因子基因。此类细胞因子的实例是淋巴因子、单核因子、生长因子和常规多肽激素。包括在细胞因子中的有生长激素,诸如人生长激素、N-甲硫氨酰基人生长激素和牛生长激素;甲状旁腺激素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素,诸如卵泡刺激素(FSH)、甲状腺刺激素(TSH)和促黄体激素(LH);肝生长因子;前列腺素、成纤维细胞生长因子;催乳素;胎盘催乳素,OB蛋白;肿瘤坏死因子-α和肿瘤坏死因子-β;苗勒管抑制物质;小鼠促性腺激素相关肽;抑制素;激活素;血管内皮生长因子;整联蛋白;血小板生成素(TPO);神经生长因子,诸如NGF-β;血小板生长因子;转化生长因子,诸如TGF-α和TGF-β;胰岛素样生长因子-I和胰岛素样生长因子-II;红细胞生成素(EPO);骨诱导因子;干扰素,诸如干扰素-α、干扰素-β和干扰素-γ;集落刺激因子(CSF),诸如巨噬细胞-CSF(M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);和粒细胞-CSF(G-CSF);诸如IL-1,IL-1α,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-10IL-11,IL-12;IL-13,IL-14,IL-15,IL-16,IL-17,IL-18,IL-19,IL-20,IL-24等白细胞介素(IL)、LIF、G-CSF、GM-CSF、M-CSF、EPO、kit-配体或FLT-3。最优选IL-12、IL-21、IL-2、IL-15、IL-8或这些中的任一种的修饰形式。
免疫共刺激途径激活分子可包括编码CD40配体(CD40L)、ICOS配体、GITR配体、4-1BB配体、OX40配体、TL1A、CD30配体、CD27或Flt3配体的基因或这些配体的任一种的修饰形式
检查点抑制剂可包括PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂或这些抑制剂中的任一种的修饰形式。
肿瘤抑制基因可包括HIC1等。或者这些的修饰形式。
本公开的实施方案提供了序列,其包含以下的至少一项:
(a)L025、TK、A46R或其任意组合中的一个或多个突变;
(b)部分删除的L025、TK、A46R或其任意组合;
(c)删除的L025、TK、A46R或其任何组合;
(d)L025、TK或A46R的一部分或全部被SEQ ID NO:1-2中所示的序列之一替代;
(e)L025、TK或A46R的一部分或全部被SEQ ID NO:3-4中所示的序列之一替代;
(f)L025、TK或A46R的一部分或全部被4-1BBL或其修饰形式替代;
(g)L025、TK或A46R的一部分或全部被HIC1或其修饰形式替代;
(h)L025、TK或A46R的一部分或全部被肿瘤靶向基因替代;
(i)L025、TK或A46R的一部分或全部被靶向T细胞的配体或抗体替代;
(j)L025、TK或A46R的一部分或全部被治疗性基因或其修饰形式替代;以及
(k)L025、TK或A46R的一部分或全部被治疗性抗体替代。
本公开的实施方案提供了病毒,其包含以下至少一项:
(a)L025、TK或A46R突变;
(b)部分删除L025、TK或A46R
(c)删除L025、TK或A46R
(d)L025、TK或A46R的一部分或全部被SEQ ID NO:1-2中所示的序列之一替代;
(e)L025、TK或A46R的一部分或全部被SEQ ID NO:3-4中所示的序列之一替代;
(f)L025、TK或A46R的一部分或全部被4-1BBL或其修改形式替代;
(g)L025、TK或A46R的一部分或全部被HIC1或其修饰形式替代;
(h)L025、TK或A46R的一部分或全部被肿瘤靶向基因替代;
(i)L025、TK或A46R的一部分或全部被靶向T细胞的配体或抗体替代;
(j)L025、TK或A46R的一部分或全部被治疗性基因或其修饰形式替代;以及
(k)L025、TK或A46R的一部分或全部被治疗性抗体替代。
本公开的实施方案提供了包含上述任何序列的表达载体或宿主细胞。
本公开的实施方案提供了用于治疗人体或动物体的方法的病毒,其包含以下至少一项:
(a)单独用作单一疗法;和
(b)与一种或多种抗癌剂联合使用。
本公开的实施方案提供了用于制造用于治疗人体或动物体的药物的病毒。
本公开的实施方案提供了用于诱导癌细胞死亡、调节癌细胞的生物活性、调节免疫反应、增强T细胞的增殖和/或细胞毒性的病毒。
本公开的实施方案提供了用于制造用于抑制癌细胞生长、诱导癌细胞死亡并且/或者调节癌细胞生物活性的药物的病毒。
癌细胞的生物活性包括抑制癌细胞复制、抑制癌细胞分裂、抑制癌细胞的DNA修复、抑制癌细胞迁移或促进癌症死亡。
本公开的实施方案提供了制造产品,其在无菌小瓶、安瓿或注射器中包含病毒。
本公开的实施方案提供了包含本公开的实施方案的病毒的药物组合物。
在本公开的实施方案中,所述药物组合物还包含抗癌剂和/或抗体。
在本公开的实施方案中,药物组合物还包含药学上可接受的载体、稀释剂和/或赋形剂。
本公开的实施方案提供了疾病的治疗方法,其包括施用有效量的序列、表达载体、宿主细胞、病毒、药物组合物或药剂。
如本文中所用,“药物组合物”是指本文所述的一种或多种活性成分与其它化学组分诸如生理上合适的载体和赋形剂的制剂。药物组合物的目的是促进化合物向生物体的施用。
在本文中,术语“赋形剂”是指添加到药物组合物中以进一步促进活性成分的施用的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和各种类型的淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
在下文中,可以互换使用的短语“生理上可接受的载体”和“药学上可接受的载体”是指不会对生物体造成显著刺激并且不会消除所施用的化合物的生物活性和性质的载体或稀释剂。
药物的配制和施用技术可见于最新版的“Remington’s PharmaceuticalSciences”,Mack Publishing Co.,Easton,PA,其通过引用完全并入本文(Remington:TheScience and Practice of Pharmacy,Gennaro,A.,Lippincott,Williams&Wilkins,Philadelphia,Pa.,第20版,2000)。
本发明的药物组合物可通过本领域公知的方法制备,例如通过常规的混合、溶解、制粒、制糖衣丸、研磨、乳化、胶囊化、包埋或冻干方法制备。
因此,根据本发明使用的药物组合物可使用一种或多种包含赋形剂和助剂的生理上可接受的载体以常规方式配制,这有助于将活性成分加工成可药用的制剂。正确的配方取决于所选择的施用途径。
在本公开的实施方案中,药物组合物还包含抗氧化剂,其可以保护细胞或大分子(例如,多糖)免受氧化应激(由自由基引起的氧化损伤)。因此,抗氧化剂可通过防止大分子的氧化解聚来延长其存在时间。合适的抗氧化剂的非限制性实例包括诸如谷胱甘肽、维生素C(抗坏血酸钠)、维生素E(生育酚和生育三烯酚)、N-Ac-L-半胱氨酸、氢醌、谷氨酸盐等的分子,或诸如过氧化氢酶、超氧化物歧化酶、谷胱甘肽过氧化物酶或其它过氧化物酶以及葡萄糖-6-磷酸脱氢酶(G6PD)等的酶(参见Osmen I.,Naziroglu M.,Okutan R.Comparativestudy of antioxidant enzymes in tissues surrounding implant inrabbits.Cell.Biochem.Funct.24:275-281,2006)。
潜在施用的药物组合物包括水溶性形式的活性制剂的水溶液。另外,活性成分的混悬液可以制备成合适的油性或基于水的注射混悬液。合适的亲脂性溶剂或载体包括脂肪油诸如芝麻油,或合成脂肪酸酯诸如油酸乙酯、甘油三酯或脂质体。含水注射剂混悬液可含有增加混悬液粘度的物质,诸如羧甲基纤维素钠、山梨醇或葡聚糖。任选地,混悬液还可包含合适的稳定剂或增加活性成分溶解度的剂,以允许制备高浓度溶液。
组合物通常包含一种或多种合适的稀释剂、填充剂、盐、崩解剂、粘合剂、润滑剂、助流剂、润湿剂、控释基质、着色剂、调味剂、载体、赋形剂、缓冲剂、稳定剂、增溶剂、商业助剂和/或本领域已知的其它添加剂。
或者,活性成分可呈粉末形式,以便在使用前用合适的媒个物,例如无菌、无热原的基于水的溶液来复原。
如果需要,本公开的组合物、药物组合物可以存在于包装或分配器装置,诸如FDA批准的试剂盒或制品(具有包装材料)中,所述包装或分配器装置可以包含一个或多个含有活性成分的单位剂型。所述包装可以例如包括金属或塑料箔,诸如泡罩包装。包装或分配器装置可附有施用、植入和/或治疗受试者的说明。包装或分配器还可容纳伴随容器的说明书,该说明书的形式由管理药物制造、使用或销售的政府机构规定,该说明书反映了该机构对组合物形式或者人或兽医施用的批准。例如,此类说明书可以是美国食品和药品管理局批准的处方药标签或批准的产品说明书。还可制备在相容的药物载体中配制的本发明的组合物、基质或水凝胶,将其置于合适的容器中,并标记用于治疗指定的疾患,如上面进一步详述的。
合适的施用途径可包括,例如,口服、直肠、经粘膜,特别是经鼻、肠或肠胃外递送,包括肌内、皮下和髓内注射以及鞘内、直接心室内、心内,例如,进入右心室或左心室腔、进入普通冠状动脉、静脉内、腹膜内、鼻内或眼内注射。
如本文中所用,短语“化学治疗剂”是指在癌症治疗中具有治疗用途的任何化学剂。本文所用的化学治疗剂包括化学和生物剂。这些剂的作用是抑制癌细胞赖以持续生存的细胞活性。化学治疗剂的类型包括烷化剂/生物碱剂、抗代谢物、激素或激素类似物以及各种抗肿瘤药物。这些药物如果不是全部,也是大部分对癌细胞有直接毒性,并且不需要免疫刺激。合适的化学治疗剂描述于例如Slapak和Kufe,Principles of Cancer Therapy,Harrison's Principles of Internal medicine,第14版中的第86章;Perry等人,Chemotherapeutic,Ch 17in Abeloff,Clinical Oncology第2版,2000ChrchillLivingstone,Inc.;Baltzer L.和Berkery R.(编辑):Oncology Pocket Guideto Chemotherapeutic,第2版St.Luois,mosby-Year Book,1995;Fischer D.S.,KnobfM.F.,Durivage H.J.(编辑):The Cancer Chemotherapeutic Handbook,第4版St.Luois,Mosby-Year Handbook中。
本发明的化学治疗剂可以是但不限于阿糖胞苷(胞嘧啶阿拉伯糖苷、Ara-C、Cytosar-U)、阿司匹林、舒林酸、姜黄素、烷化剂,包括:氮芥,诸如mechlor-乙胺、环磷酰胺、异环磷酰胺、美法仑和苯丁酸氮芥;亚硝基脲类,诸如卡莫司汀(BCNU)、洛莫司汀(CCNU)和司莫司汀(甲基-CCNU);乙撑亚胺/甲基密胺(methylmelamine),诸如三乙撑蜜胺(TEM)、三乙烯、硫代磷酰胺(噻替派)、六甲基蜜胺(HMM,六甲蜜胺);烷基磺酸盐,诸如白消安;三嗪类,诸如达卡巴嗪(DTIC);抗代谢物,包括叶酸类似物,诸如甲氨蝶呤和三甲曲沙、嘧啶类似物,诸如5-氟尿嘧啶、氟脱氧尿苷、吉西他滨、胞嘧啶阿拉伯糖苷(AraC,阿糖胞苷)、5-氮杂胞苷、2,2-二氟脱氧胞苷、嘌呤类似物,诸如6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、2’-脱氧科福霉素(喷司他丁)、赤羟基壬腺嘌呤(EHNA)、氟达拉滨磷酸盐和2-氯脱氧腺苷(克拉屈滨,2-CdA);天然产品,包括抗有丝分裂药物,诸如紫杉醇、长春花生物碱,包括长春碱(VLB)、长春新碱和长春瑞滨、泰索帝、雌莫司汀和雌莫司汀磷酸盐;表鬼臼毒素,诸如依托泊苷和替尼泊苷;抗生素,诸如放线菌素D、道诺霉素(柔比霉素)、多柔比星、米托蒽醌、伊达比星、博莱霉素、普卡霉素(密特拉霉素)、丝裂霉素C和放线菌素;酶,诸如L-天冬酰胺酶,细胞因子,诸如干扰素(IFN)-γ、肿瘤坏死因子(TNF)-α,TNF-β和GM-CSF、抗血管生成因子,诸如血管生长抑素和内皮抑素,FGF或VEGF的抑制剂,诸如血管生成因子受体的可溶性形式,包括可溶性VGF/VEGF受体,铂配位络合物,诸如顺铂和卡铂,蒽二酮类,诸如米托蒽醌,取代脲诸如羟基脲、甲基肼衍生物,包括N-甲基肼(MIH)和丙卡巴嗪,肾上腺皮质抑制剂,诸如米托坦(ο,ρ'-DDD)和氨鲁米特;激素和拮抗剂,包括肾上腺皮质类固醇拮抗剂,诸如泼尼松及其等效物、地塞米松和氨鲁米特;孕激素,诸如己酸羟孕酮、醋酸甲羟孕酮和醋酸甲地孕酮;雌激素,诸如己烯雌酚和乙炔雌二醇等效物;抗雌激素,诸如他莫昔芬;雄激素,包括丙酸睾丸酮和氟甲睾酮/等效物;抗雄激素,诸如氟他胺、促性腺激素释放激素类似物和亮丙瑞林;非甾体类抗雄激素,诸如氟他胺;激酶抑制剂、组蛋白去乙酰化酶抑制剂、甲基化抑制剂、蛋白酶体抑制剂、单克隆抗体、氧化剂、抗氧化剂、端粒酶抑制剂、BH3模拟物、遍在蛋白连接酶抑制剂、stat抑制剂和受体酪氨酸激酶抑制剂,诸如甲磺酸伊马替尼(作为Gleevac或Glivac市售)和埃罗替尼(一种EGF受体抑制剂),现作为Tarveca市售;以及抗病毒药,诸如磷酸奥司他韦、两性霉素B和帕利珠单抗。
在一些实施方案中,本发明的化学治疗剂(例如,阿糖胞苷)或包含其的药物组合物的日剂量在1g/平方米的身体面积至10g/平方米的身体面积、1.5g/平方米的身体面积至5g/平方米的身体面积或2g/平方米身体面积至4g/平方米的身体面积的范围内变化。
上文描述的和下文中权利要求部分要求保护的本发明的各种实施方案和方面在以下实施例中得到实验支持。
现参考以下实施例,所述实施例与上文描述一起以非限制性的方式举例说明了本发明。
实施例1:获得L025基因缺失的病毒。
请参考图6,图6显示的是具有L025基因缺失的重组病毒。M:为分子量标记,1:为对照病毒,2为具有L025基因缺失的重组病毒。A46R是扩增的对照基因片段。L025是检测到缺失的L025基因的片段。
使用VV李斯特病毒为母本,用删除了L025基因的穿梭载体进行同源重组,获得具有L025基因缺失的病毒。通过红色荧光筛选获得纯荧光感染斑后,进行小规模病毒扩增,提取病毒DNA,以通过PCR鉴定L025基因缺失。获得了具有L025基因缺失的新病毒,如图6所示。
实施例2:获得L025基因缺失和TK基因缺失的病毒。
实施例1中获得的具有L025基因缺失的新病毒在红色荧光蛋白RFP的两侧都含有FRT位点。使用翻转酶裂解FRT位点以删除RFP基因,从而获得删除了L025基因的新的RFP阴性VV。将该病毒用作骨架病毒,并将具有TK基因缺失的穿梭载体用于同源重组,以获得具有TK基因缺失并同时将PD1抗体基因插入该区域的病毒。荧光筛选后进行小规模病毒扩增,以获得纯病毒感染的斑块,提取病毒DNA,以通过PCR鉴定TK基因缺失。获得了L025基因和TK基因均缺失的新病毒,并将PD1抗体基因插入TK区(图7)。
实施例3:一种删除了L025基因、删除了TK基因以及删除了A46R基因的病毒。
实施例2中获得的L025基因和TK基因均缺失的新病毒在红色荧光蛋白RFP的两侧均含有Loxp位点。通过Cre重组酶删除Loxp位点,以删除RFP基因,从而获得缺失L025和TK基因的RFP阴性新病毒。将该病毒用作骨架病毒,对具有A46R基因缺失的穿梭载体进行同源重组,以获得具有A46R基因缺失并同时将HIC1基因插入该区域的病毒。绿色荧光筛选后进行小规模病毒扩增,以获得纯病毒感染的斑块,提取病毒DNA,以通过PCR鉴定A46R基因缺失。获得了具有L025基因缺失、TK基因缺失和A46R基因缺失的新病毒,将PD1抗体基因插入TK区,以及将HIC1基因插入A46R区域,病毒表达绿色荧光蛋白GFP。
实施例4:病毒含有L025基因缺失,该区域中插入IL21和mB5R/sB5R;TK基因缺失,该区域中插入4-1BBL基因;A46R基因缺失,该区域中插入HIC1基因。
请参考图14至图15。图7显示的是具有TK基因缺失和hSPD-41BBL基因插入的重组病毒。mV:为经修饰的病毒,V:为野生型病毒,TK:为扩增的TK基因(阴性结果表明已在被检测的重组病的毒基因组中删除了该基因),hSPD-41BBL:为扩增插入的人SPD-41BBL(阳性结果表明该基因已插入被检测的重组病毒的基因组中),L09:为扩增的对照基因片段。
图8显示的是A46R基因的重组病毒缺失和插入基因HIC1的病毒表达。A:将PCR用于鉴定A46R基因的缺失。M:为分子量标记,1:为对照病毒,2为删除A46R基因的重组病毒。L09是扩增的对照基因片段。B:将蛋白质印迹分析用于鉴定HIC1蛋白的表达。C为对照病毒,T为携带HIC1基因并删除A46R基因的新型重组病毒。HIC1是抗体检测的结果,β-肌动蛋白是蛋白质负荷对照。
将实施例3中获得的具有L025基因缺失、TK基因缺失和A46R基因缺失的新病毒用作骨架病毒,并将用于L025基因缺失的穿梭载体同源重组,以获得具有L025基因缺失并同时将IL21和mB5R/sB5R基因插入该区域的病毒。通过荧光筛选获得纯重组病毒后,对小规模病毒进行扩增,提取病毒DNA,然后通过PCR鉴定L025基因缺失。获得了删除L025基因、TK基因和A46R基因的新病毒,并将4-1BBL基因插入TK区域,将HIC1基因插入A46R区域(图8),并将IL21和mB5R/sB5R基因插入L025区域。
实施例5:一小组被KM1病毒感染的实体瘤细胞。
请参考图9A至图9B。图9A至图9B示出了在6孔板中用剂量递增的病毒剂量对一组实体瘤细胞系进行KM1杀伤,持续两天。用于感染单个孔的病毒量为0.01pfu/细胞、0.1pfu/细胞和1pfu/细胞。当实验结束时,结晶紫被用来对孔中剩余的细胞进行染色。
在以0.01pfu、0.1pfu和1fu/细胞进行病毒感染后两天,用结晶紫对细胞进行染色。染色后扫描平板,如图9A至图9B所示。
实施例6:实体瘤细胞对KM1的敏感性。EC50测定中一小组被KM1病毒感染的实体瘤细胞。
请参考图10A至图11。图10A至图10C显示的是对17种细胞系进行的EC50测定的实例,其中对单个细胞系以一式三份进行了EC50测定。图11显示的是不同细胞系的EC50值。
病毒感染后6天,用MTS测量细胞活力。在用MTS孵育后读取平板。(图10A至图10C和图11)
实施例7:白血病细胞系对KM1的敏感性。一小组白血病细胞系被KM1感染。
请参考图12。图12显示的是痘苗病毒对白血病细胞系的杀伤。对三种细胞系(K562、C8166、THP-1)进行的EC50测定被提供作为示例性实例。
子图A、B和C示出了在对照孔(无病毒感染,实线)和病毒感染孔(虚线)中在接种点、病毒感染后48小时和72小时时的细胞计数。子图D示出了感染后48小时被感染的THP1细胞的图像。发出绿色荧光的细胞代表病毒在细胞中正在复制/已复制。
本公开的痘苗病毒在72小时内感染并杀伤了大多数白血病细胞。病毒感染后24小时、48小时和73小时计数活/死细胞。显示了选择性敏感细胞的结果(图12)。
实施例8:白血病患者的细胞对KM1的敏感性。
请参考图13至图14。图13显示的是被KM1感染的白血病患者的白细胞的实例。图14示出了KM1感染后三天的活/死细胞。
在图13A中:来自CMML患者的样品;图13B:来自M5b患者的样品;以及图13C:来自M4患者的样品。
在图14A中:白血病患者0518号、6号、7号、8号和2号的对照孔(无KM1感染,上图)和KM1感染孔中活/死细胞的FAC谱。图14B:白血病患者0518号、6号、7号、8号和2号的对照孔(无KM1感染,上图)和KM1感染孔中的死细胞百分比。
白血病患者的白细胞被感染。病毒感染后72小时,用荧光显微镜和FAC检查细胞。(图13至图14)。
实施例9.叙利亚金黄仓鼠胰腺癌的KM1治疗。
请参考图15,图15示出了KM1在叙利亚仓鼠胰腺癌HPD 1NR模型中的抗肿瘤功效。左图显示用KM1治疗后和未用KM1治疗的对照组中的肿瘤体积变化。右图显示了KM1治疗组中单个动物的肿瘤体积变化。
实施例10.人乳腺癌细胞MDA MB-231的HIC1武装的痘苗病毒治疗。
请参考图16,图16示出了使用HIC1武装的痘苗病毒及其对应物对照HY3对人乳腺癌细胞MDA MB-231进行的处理。上图显示了在6孔板中使用HIC1武装的痘苗病毒(HIC1)及其对应对照HY3对人乳腺癌细胞MDA MB-231的治疗。底部图显示了根据顶部图的实验计算的EC50。
因此,本公开提供了工程痘苗病毒、包含该病毒的药物组合物以及使用该药物组合物治疗有需要的受试者的方法。工程痘苗病毒包括病毒基因的组合删除,以及免疫共刺激途径激活分子、免疫调节剂基因、截短的病毒包膜基因和/或肿瘤抑制基因至感染的靶细胞中的引入。本公开的溶瘤痘苗病毒能够选择性感染癌细胞,选择性在肿瘤细胞中复制,选择性靶向具有激活的EGFR/Ras/ERK途径的肿瘤细胞。溶瘤痘苗病毒还能够抑制肿瘤诱导的免疫抑制和激活免疫细胞中的NFκB信号传导途径。溶瘤痘苗病毒还能够激发抗肿瘤免疫反应,增强T细胞的增殖和细胞毒性。溶瘤痘苗病毒也能够抑制肿瘤进展。溶瘤痘苗病毒可以将肿瘤抑制基因整合到肿瘤抑制基因表达不足或缺失的癌细胞基因组中。
如本文中所用,术语“约”是指±10%。
如本文中所用,术语“方法”是指用于完成给定任务的方式、手段、技术和程序,包括但不限于化学、药理学、生物学、生物化学和医学领域的从业者已知的或容易从已知的方式、手段、技术和程序发展而来的那些方式、手段、技术和程序。
术语“治疗”是指阻止病状(疾病、病症或疾患)的发展和/或导致病状的减少、缓解或消退。本领域的技术人员将理解,各种方法和测定可用于评估病状的减少、缓解或消退。应当理解,治疗可以单独进行或者与其它疗法结合进行。
如本文中所用,术语“预防”是指防止疾病、病症或疾患在可能有疾病风险但尚未表现出疾病、病症或疾患的症状或尚未被诊断为患有该疾病、病症或疾患的受试者中发生。本领域的技术人员将理解,各种方法和测定可用于评估病状的发展。
如本文中所用,术语“受试者”或“有需要的受试者”包括哺乳动物,优选为任何年龄或性别的人类。受试者可能正表现出病状,例如与突变或无功能HIC1蛋白相关的疾病、病症或疾患,例如过度增生性疾病的初步体征。
通常,本文使用的术语和本发明中使用的实验室程序包括分子、生化、微生物和重组DNA技术。此类技术在文献中有详尽的解释。参见,例如,"Molecular Cloning:Alaboratory Manual"Sambrook等人,(1989);"Current Protocols in MolecularBiology”第I至III卷Ausubel,R.M.,编辑(1994);Ausubel等人,"Current Protocols inMolecular Biology",John Wiley和Sons,Baltimore,Maryland(1989);Perbal,"APractical Guide to Molecular Cloning",John Wiley&Sons,New York(1988);Watson等人,"Recombinant DNA",Scientific American Books,New York;Birren等人(编辑)"Genome Analysis:A Laboratory Manual Series",第1至4卷,Cold Spring HarborLaboratory Press,New York(1998);美国专利第4,666,828号、第4,683,202号、第4,801,531号、第5,192,659号和第5,272,057号中所示的方法学;"Cell Biology:A LaboratoryHandbook",第I-III卷Cellis,J.E.,编辑(1994);"Current Protocols in Immunology”第I-III卷Coligan J.E.,编辑(1994);Stites等人(编辑),"Basic and ClinicalImmunology"(第8版),Appleton&Lange,Norwalk,CT(1994);Mishell和Shiigi(编辑),"Selected Methods in Cellular Immunology",W.H.Freeman and Co.,New York(1980);可用的免疫测定法详尽地描述于专利和科学文献中,参见,例如,美国专利第3,791,932号、第3,839,153号、第3,850,752号、第3,850,578号、第3,853,987号、第3,867,517号、第3,879,262号、第3,901,654号、第3,935,074号、第3,984,533号、第3,996,345号、第4,034,074号、第4,098,876号、第4,879,219号、第5,011,771号和第5,281,521号;"OligonucleotideSynthesis"Gait,M.J.,等人(1984);“Nucleic Acid Hybridization"Hames,B.D.和Higgins S.J.,编辑(1985);"Transcription and Translation"Hames,B.D.和HigginsS.J.,编辑(1984);"Animal Cell Culture"Freshney,R.I.,编辑(1986);"ImmobilizedCells and Enzymes"IRL Press,(1986);"A Practical Guide to Molecular Cloning"Perbal,B.,(1984)和"Methods in Enzymology”第1-317卷,Academic Press;"PCRProtocols:A Guide To Methods And Applications",Academic Press,San Diego,CA(1990);Marshak等人,"Strategies for Protein Purification and Characterization-A Laboratory Course Manual"CSHL Press(1996);其全部通过引用并入,如同在本文中完全示出。在整个本文件中还提供了其它一般参考资料。其中的程序被认为是本领域公知的,并且是为了方便读者而提供的。其中包括的所有信息均通过引用并入本文。
应当理解,在本申请中公开的任何序列标识符(SEQ ID NO)可以指DNA序列或RNA序列,这取决于提到SEQ ID NO的上下文,即使SEQ ID NO仅以DNA序列形式或RNA形式表达。例如,SEQ ID NO:3以DNA序列形式表达(例如,胸腺嘧啶用T表示),但其可以指对应于WNT3A核酸序列的DNA序列,或者RNA分子核酸序列的RNA序列。类似地,尽管一些序列是以RNA序列的形式表达的(例如,尿嘧啶用U表示),但根据所描述的分子的实际类型,其可以指包含dsRNA的RNA分子的序列,或者对应于所示RNA序列的DNA分子的序列。在任何情况下,具有所公开的具有任何取代的序列的DNA和RNA分子都是可以预见的。
应当理解,为了清楚起见,在单独的实施方案的上下文中描述的本发明的某些特征也可以在单个实施方案中组合提供。相反,为了简洁起见,在单个实施方案的上下文中描述的本发明的各种特征也可以单独提供,或者以任何合适的子组合提供,或者适用于本发明的任何其它描述的实施方案。在各种实施方案的上下文中描述的某些特征不应被认为是那些实施方案的基本特征,除非所述实施方案在这些元件不存在的情况下是无效的。
总之,本领域普通技术人员可以根据本申请的技术方案和技术概念进行各种改变和修改,并且所有此类改变和修改都落入本申请所附权利要求的保护范围内。
序列表
<110> 深圳市华药康明生物药业有限责任公司
<120> 工程痘苗病毒
<130> 0237-PA-007CN
<150> US62/873,221
<151> 2019-07-12
<160> 28
<170> PatentIn version 3.5
<210> 1
<211> 100
<212> PRT
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(100)
<223> mB5R 氨基酸序列
<400> 1
Met Lys Thr Ile Ser Val Val Thr Leu Leu Cys Val Leu Pro Ala Val
1 5 10 15
Val Tyr Ser Cys Val Arg Thr Asn Glu Lys Phe Asp Pro Val Asp Asp
20 25 30
Gly Pro Asp Asp Glu Thr Asp Leu Ser Lys Leu Ser Lys Asp Val Val
35 40 45
Gln Tyr Glu Gln Glu Ile Glu Ser Leu Glu Ala Thr Tyr His Ile Ile
50 55 60
Ile Val Ala Leu Thr Ile Met Gly Val Ile Phe Leu Ile Ser Val Ile
65 70 75 80
Val Leu Val Cys Ser Cys Asp Lys Asn Asn Asp Gln Tyr Lys Phe His
85 90 95
Lys Leu Leu Pro
100
<210> 2
<211> 303
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(303)
<223> mB5R 核苷酸序列
<400> 2
atgaaaacga tttccgttgt tacgttgtta tgcgtactac ctgctgttgt ttattcatgt 60
gtacgaacta acgaaaaatt tgatccagtg gatgatggtc ccgacgatga gacagatttg 120
agcaaactct cgaaagacgt tgtacaatat gaacaagaaa tagaatcgtt agaagcaact 180
tatcatataa tcatagtggc gttgacaatt atgggcgtca tatttttaat ctccgttata 240
gtattagttt gttcctgtga caaaaataat gaccaatata agttccataa attgctaccg 300
tga 303
<210> 3
<211> 153
<212> PRT
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(153)
<223> sB5R 氨基酸序列
<400> 3
Met Lys Thr Ile Ser Val Val Thr Leu Leu Cys Val Leu Pro Ala Val
1 5 10 15
Val Tyr Ser Thr Cys Thr Val Pro Thr Met Asn Asn Ala Lys Leu Thr
20 25 30
Ser Thr Glu Thr Ser Phe Asn Asp Lys Gln Lys Val Thr Phe Thr Cys
35 40 45
Asp Gln Gly Tyr His Ser Ser Asp Pro Asn Ala Val Cys Glu Thr Asp
50 55 60
Lys Trp Lys Tyr Glu Asn Pro Cys Cys Val Arg Thr Asn Glu Lys Phe
65 70 75 80
Asp Pro Val Asp Asp Gly Pro Asp Asp Glu Thr Asp Leu Ser Lys Leu
85 90 95
Ser Lys Asp Val Val Gln Tyr Glu Gln Glu Ile Glu Ser Leu Glu Ala
100 105 110
Thr Tyr His Ile Ile Ile Val Ala Leu Thr Ile Met Gly Val Ile Phe
115 120 125
Leu Ile Ser Val Ile Val Leu Val Cys Ser Cys Asp Lys Asn Asn Asp
130 135 140
Gln Tyr Lys Phe His Lys Leu Leu Pro
145 150
<210> 4
<211> 462
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(462)
<223> sB5R 核苷酸序列
<400> 4
atgaaaacga tttccgttgt tacgttgtta tgcgtactac ctgctgttgt ttattcaaca 60
tgtactgtac ccactatgaa taacgctaaa ttaacgtcta ccgaaacatc gtttaatgat 120
aaacagaaag ttacatttac atgtgatcag ggatatcatt cttcggatcc aaatgctgtc 180
tgcgaaacag ataaatggaa atacgaaaat ccatgctgtg tacgaactaa cgaaaaattt 240
gatccagtgg atgatggtcc cgacgatgag acagatttga gcaaactctc gaaagacgtt 300
gtacaatatg aacaagaaat agaatcgtta gaagcaactt atcatataat catagtggcg 360
ttgacaatta tgggcgtcat atttttaatc tccgttatag tattagtttg ttcctgtgac 420
aaaaataatg accaatataa gttccataaa ttgctaccgt ga 462
<210> 5
<211> 462
<212> PRT
<213> Mus musculus
<220>
<221> 人工序列
<222> (1)..(462)
<223> SPD-m4-1BBL 氨基酸序列
<400> 5
Met Leu Pro Phe Leu Ser Met Leu Val Leu Leu Val Gln Pro Leu Gly
1 5 10 15
Asn Leu Gly Ala Glu Met Lys Ser Leu Ser Gln Arg Ser Val Pro Asn
20 25 30
Thr Cys Thr Leu Val Met Cys Ser Pro Thr Glu Asn Gly Leu Pro Gly
35 40 45
Arg Asp Gly Arg Asp Gly Arg Glu Gly Pro Arg Gly Glu Lys Gly Asp
50 55 60
Pro Gly Leu Pro Gly Pro Met Gly Leu Ser Gly Leu Gln Gly Pro Thr
65 70 75 80
Gly Pro Val Gly Pro Lys Gly Glu Asn Gly Ser Ala Gly Glu Pro Gly
85 90 95
Pro Lys Gly Glu Arg Gly Leu Ser Gly Pro Pro Gly Leu Pro Gly Ile
100 105 110
Pro Gly Pro Ala Gly Lys Glu Gly Pro Ser Gly Lys Gln Gly Asn Ile
115 120 125
Gly Pro Gln Gly Lys Pro Gly Pro Lys Gly Glu Ala Gly Pro Lys Gly
130 135 140
Glu Val Gly Ala Pro Gly Met Gln Gly Ser Thr Gly Ala Lys Gly Ser
145 150 155 160
Thr Gly Pro Lys Gly Glu Arg Gly Ala Pro Gly Val Gln Gly Ala Pro
165 170 175
Gly Asn Ala Gly Ala Ala Gly Pro Ala Gly Pro Ala Gly Pro Gln Gly
180 185 190
Ala Pro Gly Ser Arg Gly Pro Pro Gly Leu Lys Gly Asp Arg Gly Val
195 200 205
Pro Gly Asp Arg Gly Ile Lys Gly Glu Ser Gly Leu Pro Asp Ser Ala
210 215 220
Ala Leu Arg Gln Gln Met Glu Ala Leu Lys Gly Lys Leu Gln Arg Leu
225 230 235 240
Glu Val Ala Phe Ser His Tyr Gln Lys Ala Ala Leu Phe Pro Asp Gly
245 250 255
Arg Thr Glu Pro Arg Pro Ala Leu Thr Ile Thr Thr Ser Pro Asn Leu
260 265 270
Gly Thr Arg Glu Asn Asn Ala Asp Gln Val Thr Pro Val Ser His Ile
275 280 285
Gly Cys Pro Asn Thr Thr Gln Gln Gly Ser Pro Val Phe Ala Lys Leu
290 295 300
Leu Ala Lys Asn Gln Ala Ser Leu Cys Asn Thr Thr Leu Asn Trp His
305 310 315 320
Ser Gln Asp Gly Ala Gly Ser Ser Tyr Leu Ser Gln Gly Leu Arg Tyr
325 330 335
Glu Glu Asp Lys Lys Glu Leu Val Val Asp Ser Pro Gly Leu Tyr Tyr
340 345 350
Val Phe Leu Glu Leu Lys Leu Ser Pro Thr Phe Thr Asn Thr Gly His
355 360 365
Lys Val Gln Gly Trp Val Ser Leu Val Leu Gln Ala Lys Pro Gln Val
370 375 380
Asp Asp Phe Asp Asn Leu Ala Leu Thr Val Glu Leu Phe Pro Cys Ser
385 390 395 400
Met Glu Asn Lys Leu Val Asp Arg Ser Trp Ser Gln Leu Leu Leu Leu
405 410 415
Lys Ala Gly His Arg Leu Ser Val Gly Leu Arg Ala Tyr Leu His Gly
420 425 430
Ala Gln Asp Ala Tyr Arg Asp Trp Glu Leu Ser Tyr Pro Asn Thr Thr
435 440 445
Ser Phe Gly Leu Phe Leu Val Lys Pro Asp Asn Pro Trp Glu
450 455 460
<210> 6
<211> 1389
<212> DNA
<213> Mus musculus
<220>
<221> 人工序列
<222> (1)..(1389)
<223> SPD-m4-1BBL 核苷酸序列
<400> 6
atgctgccct ttctctccat gcttgtcttg cttgtacagc ccctgggaaa tctgggagca 60
gaaatgaaga gcctctcgca gagatcagta cccaacacct gcaccctagt catgtgtagc 120
ccaacagaga atggcctgcc tggtcgtgat ggacgggatg ggagagaagg tccacggggt 180
gagaagggtg atccaggttt gccaggacct atggggctct cagggttgca gggccctaca 240
ggtccagttg gacccaaagg agagaatggc tctgctggcg aacctggacc aaagggagaa 300
cgtggactaa gtggacctcc aggacttcca ggtattcctg gtccagctgg gaaagaaggt 360
ccctctggga agcaggggaa cataggacct caaggcaaac caggtcctaa aggagaggct 420
gggcccaaag gagaagtagg tgctcctggc atgcaaggat ctacaggggc aaaaggctcc 480
acaggcccca agggagaaag aggtgcccct ggtgtgcaag gagccccagg gaatgctgga 540
gcagcaggac ctgccggacc tgccggtcca cagggagctc caggttccag ggggccccca 600
ggactcaagg gggacagagg tgttcctgga gacagaggaa tcaaaggtga aagcgggctt 660
ccagacagtg ctgctctgag gcagcagatg gaggccttaa aaggaaaact acagcgtcta 720
gaggttgcct tctcccacta tcagaaagct gcattgttcc ctgatggccg caccgagcct 780
cggccagcgc tcacaatcac cacctcgccc aacctgggta cccgagagaa taatgcagac 840
caggtcaccc ctgtttccca cattggctgc cccaacacta cacaacaggg ctctcctgtg 900
ttcgccaagc tactggctaa aaaccaagca tcgttgtgca atacaactct gaactggcac 960
agccaagatg gagctgggag ctcataccta tctcaaggtc tgaggtacga agaagacaaa 1020
aaggagttgg tggtagacag tcccgggctc tactacgtat ttttggaact gaagctcagt 1080
ccaacattca caaacacagg ccacaaggtg cagggctggg tctctcttgt tttgcaagca 1140
aagcctcagg tagatgactt tgacaacttg gccctgacag tggaactgtt cccttgctcc 1200
atggagaaca agttagtgga ccgttcctgg agtcaactgt tgctcctgaa ggctggccac 1260
cgcctcagtg tgggtctgag ggcttatctg catggagccc aggatgcata cagagactgg 1320
gagctgtctt atcccaacac caccagcttt ggactctttc ttgtgaaacc cgacaaccca 1380
tgggaatga 1389
<210> 7
<211> 463
<212> PRT
<213> Homo sapiens
<220>
<221> 人工序列
<222> (1)..(463)
<223> SPD-h4-1BBL 氨基酸序列
<400> 7
Met Leu Leu Phe Leu Leu Ser Ala Leu Val Leu Leu Thr Gln Pro Leu
1 5 10 15
Gly Tyr Leu Glu Ala Glu Met Lys Thr Tyr Ser His Arg Thr Met Pro
20 25 30
Ser Ala Cys Thr Leu Val Met Cys Ser Ser Val Glu Ser Gly Leu Pro
35 40 45
Gly Arg Asp Gly Arg Asp Gly Arg Glu Gly Pro Arg Gly Glu Lys Gly
50 55 60
Asp Pro Gly Leu Pro Gly Ala Ala Gly Gln Ala Gly Met Pro Gly Gln
65 70 75 80
Ala Gly Pro Val Gly Pro Lys Gly Asp Asn Gly Ser Val Gly Glu Pro
85 90 95
Gly Pro Lys Gly Asp Thr Gly Pro Ser Gly Pro Pro Gly Pro Pro Gly
100 105 110
Val Pro Gly Pro Ala Gly Arg Glu Gly Pro Leu Gly Lys Gln Gly Asn
115 120 125
Ile Gly Pro Gln Gly Lys Pro Gly Pro Lys Gly Glu Ala Gly Pro Lys
130 135 140
Gly Glu Val Gly Ala Pro Gly Met Gln Gly Ser Ala Gly Ala Arg Gly
145 150 155 160
Leu Ala Gly Pro Lys Gly Glu Arg Gly Val Pro Gly Glu Arg Gly Val
165 170 175
Pro Gly Asn Thr Gly Ala Ala Gly Ser Ala Gly Ala Met Gly Pro Gln
180 185 190
Gly Ser Pro Gly Ala Arg Gly Pro Pro Gly Leu Lys Gly Asp Lys Gly
195 200 205
Ile Pro Gly Asp Lys Gly Ala Lys Gly Glu Ser Gly Leu Pro Asp Val
210 215 220
Ala Ser Leu Arg Gln Gln Val Glu Ala Leu Gln Gly Gln Val Gln His
225 230 235 240
Leu Gln Ala Ala Phe Ser Gln Tyr Lys Lys Val Glu Leu Phe Pro Asn
245 250 255
Gly Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly
260 265 270
Ser Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp
275 280 285
Asp Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
290 295 300
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
305 310 315 320
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
325 330 335
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
340 345 350
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
355 360 365
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
370 375 380
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
385 390 395 400
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
405 410 415
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
420 425 430
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
435 440 445
Val Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
450 455 460
<210> 8
<211> 1392
<212> DNA
<213> Homo sapiens
<220>
<221> 人工序列
<222> (1)..(1392)
<223> SPD-h4-1BBL 核苷酸序列
<400> 8
atgctgctct tcctcctctc tgcactggtc ctgctcacac agcccctggg ctacctggaa 60
gcagaaatga agacctactc ccacagaaca atgcccagtg cttgcaccct ggtcatgtgt 120
agctcagtgg agagtggcct gcctggtcgc gatggacggg atgggagaga gggccctcgg 180
ggcgagaagg gggacccagg tttgccagga gctgcagggc aagcagggat gcctggacaa 240
gctggcccag ttgggcccaa aggggacaat ggctctgttg gagaacctgg accaaaggga 300
gacactgggc caagtggacc tccaggacct cccggtgtgc ctggtccagc tggaagagaa 360
ggtcccctgg ggaagcaggg gaacatagga cctcagggca agccaggccc aaaaggagaa 420
gctgggccca aaggagaagt aggtgcccca ggcatgcagg gctcggcagg ggcaagaggc 480
ctcgcaggcc ctaagggaga gcgaggtgtc cctggtgagc gtggagtccc tggaaacaca 540
ggggcagcag ggtctgctgg agccatgggt ccccagggaa gtccaggtgc caggggaccc 600
ccgggattga agggggacaa aggcattcct ggagacaaag gagcaaaggg agaaagtggg 660
cttccagatg ttgcttctct gaggcagcag gttgaggcct tacagggaca agtacagcac 720
ctccaggctg ctttctctca gtataagaaa gttgagctct tcccaaatgg cctcgcctgc 780
ccctgggccg tgtccggggc tcgcgcctcg cccggctccg cggccagccc gagactccgc 840
gagggtcccg agctttcgcc cgacgatccc gccggcctct tggacctgcg gcagggcatg 900
tttgcgcagc tggtggccca aaatgttctg ctgatcgatg ggcccctgag ctggtacagt 960
gacccaggcc tggcaggcgt gtccctgacg gggggcctga gctacaaaga ggacacgaag 1020
gagctggtgg tggccaaggc tggagtctac tatgtcttct ttcaactaga gctgcggcgc 1080
gtggtggccg gcgagggctc aggctccgtt tcacttgcgc tgcacctgca gccactgcgc 1140
tctgctgctg gggccgccgc cctggctttg accgtggacc tgccacccgc ctcctccgag 1200
gctcggaact cggccttcgg tttccagggc cgcttgctgc acctgagtgc cggccagcgc 1260
ctgggcgtcc atcttcacac tgaggccagg gcacgccatg cctggcagct tacccagggc 1320
gccacagtct tgggactctt ccgggtgacc cccgaaatcc cagccggact cccttcaccg 1380
aggtcggaat aa 1392
<210> 9
<211> 146
<212> PRT
<213> Mus musculus
<220>
<221> 肽
<222> (1)..(146)
<223> mIL-21 氨基酸序列
<400> 9
Met Glu Arg Thr Leu Val Cys Leu Val Val Ile Phe Leu Gly Thr Val
1 5 10 15
Ala His Lys Ser Ser Pro Gln Gly Pro Asp Arg Leu Leu Ile Arg Leu
20 25 30
Arg His Leu Ile Asp Ile Val Glu Gln Leu Lys Ile Tyr Glu Asn Asp
35 40 45
Leu Asp Pro Glu Leu Leu Ser Ala Pro Gln Asp Val Lys Gly His Cys
50 55 60
Glu His Ala Ala Phe Ala Cys Phe Gln Lys Ala Lys Leu Lys Pro Ser
65 70 75 80
Asn Pro Gly Asn Asn Lys Thr Phe Ile Ile Asp Leu Val Ala Gln Leu
85 90 95
Arg Arg Arg Leu Pro Ala Arg Arg Gly Gly Lys Lys Gln Lys His Ile
100 105 110
Ala Lys Cys Pro Ser Cys Asp Ser Tyr Glu Lys Arg Thr Pro Lys Glu
115 120 125
Phe Leu Glu Arg Leu Lys Trp Leu Leu Gln Lys Met Ile His Gln His
130 135 140
Leu Ser
145
<210> 10
<211> 441
<212> DNA
<213> Mus musculus
<220>
<221> 外显子
<222> (1)..(441)
<223> mIL-21 核苷酸序列
<400> 10
atg gag agg acc ctt gtc tgt ctg gta gtc atc ttc ttg ggg aca gtg 48
Met Glu Arg Thr Leu Val Cys Leu Val Val Ile Phe Leu Gly Thr Val
1 5 10 15
gcc cat aaa tca agc ccc caa ggg cca gat cgc ctc ctg att aga ctt 96
Ala His Lys Ser Ser Pro Gln Gly Pro Asp Arg Leu Leu Ile Arg Leu
20 25 30
cgt cac ctt att gac att gtt gaa cag ctg aaa atc tat gaa aat gac 144
Arg His Leu Ile Asp Ile Val Glu Gln Leu Lys Ile Tyr Glu Asn Asp
35 40 45
ttg gat cct gaa ctt cta tca gct cca caa gat gta aag ggg cac tgt 192
Leu Asp Pro Glu Leu Leu Ser Ala Pro Gln Asp Val Lys Gly His Cys
50 55 60
gag cat gca gct ttt gcc tgt ttt cag aag gcc aaa ctc aag cca tca 240
Glu His Ala Ala Phe Ala Cys Phe Gln Lys Ala Lys Leu Lys Pro Ser
65 70 75 80
aac cct gga aac aat aag aca ttc atc att gac ctc gtg gcc cag ctc 288
Asn Pro Gly Asn Asn Lys Thr Phe Ile Ile Asp Leu Val Ala Gln Leu
85 90 95
agg agg agg ctg cct gcc agg agg gga gga aag aaa cag aag cac ata 336
Arg Arg Arg Leu Pro Ala Arg Arg Gly Gly Lys Lys Gln Lys His Ile
100 105 110
gct aaa tgc cct tcc tgt gat tcg tat gag aaa agg aca ccc aaa gaa 384
Ala Lys Cys Pro Ser Cys Asp Ser Tyr Glu Lys Arg Thr Pro Lys Glu
115 120 125
ttc cta gaa aga cta aaa tgg ctc ctt caa aag atg att cat cag cat 432
Phe Leu Glu Arg Leu Lys Trp Leu Leu Gln Lys Met Ile His Gln His
130 135 140
ctc tcc tga 441
Leu Ser
145
<210> 11
<211> 162
<212> PRT
<213> Homo sapiens
<220>
<221> 肽
<222> (1)..(162)
<223> hIL--21 氨基酸序列
<400> 11
Met Arg Ser Ser Pro Gly Asn Met Glu Arg Ile Val Ile Cys Leu Met
1 5 10 15
Val Ile Phe Leu Gly Thr Leu Val His Lys Ser Ser Ser Gln Gly Gln
20 25 30
Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln
35 40 45
Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro
50 55 60
Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln
65 70 75 80
Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile
85 90 95
Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala
100 105 110
Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr
115 120 125
Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu
130 135 140
Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu
145 150 155 160
Asp Ser
<210> 12
<211> 489
<212> DNA
<213> Homo sapiens
<220>
<221> 外显子
<222> (1)..(489)
<223> hIL-21 核苷酸序列
<400> 12
atg aga tcc agt cct ggc aac atg gag agg att gtc atc tgt ctg atg 48
Met Arg Ser Ser Pro Gly Asn Met Glu Arg Ile Val Ile Cys Leu Met
1 5 10 15
gtc atc ttc ttg ggg aca ctg gtc cac aaa tca agc tcc caa ggt caa 96
Val Ile Phe Leu Gly Thr Leu Val His Lys Ser Ser Ser Gln Gly Gln
20 25 30
gat cgc cac atg att aga atg cgt caa ctt ata gat att gtt gat cag 144
Asp Arg His Met Ile Arg Met Arg Gln Leu Ile Asp Ile Val Asp Gln
35 40 45
ctg aaa aat tat gtg aat gac ttg gtc cct gaa ttt ctg cca gct cca 192
Leu Lys Asn Tyr Val Asn Asp Leu Val Pro Glu Phe Leu Pro Ala Pro
50 55 60
gaa gat gta gag aca aac tgt gag tgg tca gct ttt tcc tgc ttt cag 240
Glu Asp Val Glu Thr Asn Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln
65 70 75 80
aag gcc caa cta aag tca gca aat aca gga aac aat gaa agg ata atc 288
Lys Ala Gln Leu Lys Ser Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile
85 90 95
aat gta tca att aaa aag ctg aag agg aaa cca cct tcc aca aat gca 336
Asn Val Ser Ile Lys Lys Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala
100 105 110
ggg aga aga cag aaa cac aga cta aca tgc cct tca tgt gat tct tat 384
Gly Arg Arg Gln Lys His Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr
115 120 125
gag aaa aaa cca ccc aaa gaa ttc cta gaa aga ttc aaa tca ctt ctc 432
Glu Lys Lys Pro Pro Lys Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu
130 135 140
caa aag atg att cat cag cat ctg tcc tct aga aca cac gga agt gaa 480
Gln Lys Met Ile His Gln His Leu Ser Ser Arg Thr His Gly Ser Glu
145 150 155 160
gat tcc tag 489
Asp Ser
<210> 13
<211> 714
<212> PRT
<213> Homo sapiens
<220>
<221> 肽
<222> (1)..(714)
<400> 13
Met Leu Asp Thr Met Glu Ala Pro Gly His Ser Arg Gln Leu Leu Leu
1 5 10 15
Gln Leu Asn Asn Gln Arg Thr Lys Gly Phe Leu Cys Asp Val Ile Ile
20 25 30
Val Val Gln Asn Ala Leu Phe Arg Ala His Lys Asn Val Leu Ala Ala
35 40 45
Ser Ser Ala Tyr Leu Lys Ser Leu Val Val His Asp Asn Leu Leu Asn
50 55 60
Leu Asp His Asp Met Val Ser Pro Ala Val Phe Arg Leu Val Leu Asp
65 70 75 80
Phe Ile Tyr Thr Gly Arg Leu Ala Asp Gly Ala Glu Ala Ala Ala Ala
85 90 95
Ala Ala Val Ala Pro Gly Ala Glu Pro Ser Leu Gly Ala Val Leu Ala
100 105 110
Ala Ala Ser Tyr Leu Gln Ile Pro Asp Leu Val Ala Leu Cys Lys Lys
115 120 125
Arg Leu Lys Arg His Gly Lys Tyr Cys His Leu Arg Gly Gly Gly Gly
130 135 140
Gly Gly Gly Gly Tyr Ala Pro Tyr Gly Arg Pro Gly Arg Gly Leu Arg
145 150 155 160
Ala Ala Thr Pro Val Ile Gln Ala Cys Tyr Pro Ser Pro Val Gly Pro
165 170 175
Pro Pro Pro Pro Ala Ala Glu Pro Pro Ser Gly Pro Glu Ala Ala Val
180 185 190
Asn Thr His Cys Ala Glu Leu Tyr Ala Ser Gly Pro Gly Pro Ala Ala
195 200 205
Ala Leu Cys Ala Ser Glu Arg Arg Cys Ser Pro Leu Cys Gly Leu Asp
210 215 220
Leu Ser Lys Lys Ser Pro Pro Gly Ser Ala Ala Pro Glu Arg Pro Leu
225 230 235 240
Ala Glu Arg Glu Leu Pro Pro Arg Pro Asp Ser Pro Pro Ser Ala Gly
245 250 255
Pro Ala Ala Tyr Lys Glu Pro Pro Leu Ala Leu Pro Ser Leu Pro Pro
260 265 270
Leu Pro Phe Gln Lys Leu Glu Glu Ala Ala Pro Pro Ser Asp Pro Phe
275 280 285
Arg Gly Gly Ser Gly Ser Pro Gly Pro Glu Pro Pro Gly Arg Pro Asp
290 295 300
Gly Pro Ser Leu Leu Tyr Arg Trp Met Lys His Glu Pro Gly Leu Gly
305 310 315 320
Ser Tyr Gly Asp Glu Leu Gly Arg Glu Arg Gly Ser Pro Ser Glu Arg
325 330 335
Cys Glu Glu Arg Gly Gly Asp Ala Ala Val Ser Pro Gly Gly Pro Pro
340 345 350
Leu Gly Leu Ala Pro Pro Pro Arg Tyr Pro Gly Ser Leu Asp Gly Pro
355 360 365
Gly Ala Gly Gly Asp Gly Asp Asp Tyr Lys Ser Ser Ser Glu Glu Thr
370 375 380
Gly Ser Ser Glu Asp Pro Ser Pro Pro Gly Gly His Leu Glu Gly Tyr
385 390 395 400
Pro Cys Pro His Leu Ala Tyr Gly Glu Pro Glu Ser Phe Gly Asp Asn
405 410 415
Leu Tyr Val Cys Ile Pro Cys Gly Lys Gly Phe Pro Ser Ser Glu Gln
420 425 430
Leu Asn Ala His Val Glu Ala His Val Glu Glu Glu Glu Ala Leu Tyr
435 440 445
Gly Arg Ala Glu Ala Ala Glu Val Ala Ala Gly Ala Ala Gly Leu Gly
450 455 460
Pro Pro Phe Gly Gly Gly Gly Asp Lys Val Ala Gly Ala Pro Gly Gly
465 470 475 480
Leu Gly Glu Leu Leu Arg Pro Tyr Arg Cys Ala Ser Cys Asp Lys Ser
485 490 495
Tyr Lys Asp Pro Ala Thr Leu Arg Gln His Glu Lys Thr His Trp Leu
500 505 510
Thr Arg Pro Tyr Pro Cys Thr Ile Cys Gly Lys Lys Phe Thr Gln Arg
515 520 525
Gly Thr Met Thr Arg His Met Arg Ser His Leu Gly Leu Lys Pro Phe
530 535 540
Ala Cys Asp Ala Cys Gly Met Arg Phe Thr Arg Gln Tyr Arg Leu Thr
545 550 555 560
Glu His Met Arg Ile His Ser Gly Glu Lys Pro Tyr Glu Cys Gln Val
565 570 575
Cys Gly Gly Lys Phe Ala Gln Gln Arg Asn Leu Ile Ser His Met Lys
580 585 590
Met His Ala Val Gly Gly Ala Ala Gly Ala Ala Gly Ala Leu Ala Gly
595 600 605
Leu Gly Gly Leu Pro Gly Val Pro Gly Pro Asp Gly Lys Gly Lys Leu
610 615 620
Asp Phe Pro Glu Gly Val Phe Ala Val Ala Arg Leu Thr Ala Glu Gln
625 630 635 640
Leu Ser Leu Lys Gln Gln Asp Lys Ala Ala Ala Ala Glu Leu Leu Ala
645 650 655
Gln Thr Thr His Phe Leu His Asp Pro Lys Val Ala Leu Glu Ser Leu
660 665 670
Tyr Pro Leu Ala Lys Phe Thr Ala Glu Leu Gly Leu Ser Pro Asp Lys
675 680 685
Ala Ala Glu Val Leu Ser Gln Gly Ala His Leu Ala Ala Gly Pro Asp
690 695 700
Gly Arg Thr Ile Asp Arg Phe Ser Pro Thr
705 710
<210> 14
<211> 2145
<212> DNA
<213> Homo sapiens
<220>
<221> 外显子
<222> (1)..(2145)
<223> HIC1 核苷酸序列
<400> 14
atg ctg gac acg atg gag gcg ccc ggc cac tcc agg cag ctg ctg ctg 48
Met Leu Asp Thr Met Glu Ala Pro Gly His Ser Arg Gln Leu Leu Leu
1 5 10 15
cag ctc aac aac cag cgc acc aag ggc ttc ttg tgc gac gtg atc atc 96
Gln Leu Asn Asn Gln Arg Thr Lys Gly Phe Leu Cys Asp Val Ile Ile
20 25 30
gtg gtg cag aac gcc ctc ttc cgc gcg cac aag aac gtg ctg gcg gcc 144
Val Val Gln Asn Ala Leu Phe Arg Ala His Lys Asn Val Leu Ala Ala
35 40 45
agc agc gcc tac ctc aag tcc ctg gtg gtg cat gac aac ctg ctc aac 192
Ser Ser Ala Tyr Leu Lys Ser Leu Val Val His Asp Asn Leu Leu Asn
50 55 60
ctg gac cat gac atg gtg agc ccg gcc gtg ttc cgc ctg gtg ctg gac 240
Leu Asp His Asp Met Val Ser Pro Ala Val Phe Arg Leu Val Leu Asp
65 70 75 80
ttc atc tac acc ggc cgc ctg gct gac ggc gca gag gcg gct gcg gcc 288
Phe Ile Tyr Thr Gly Arg Leu Ala Asp Gly Ala Glu Ala Ala Ala Ala
85 90 95
gcg gcc gtg gcc ccg ggg gct gag ccg agc ctg ggc gcc gtg ctg gcc 336
Ala Ala Val Ala Pro Gly Ala Glu Pro Ser Leu Gly Ala Val Leu Ala
100 105 110
gcc gcc agc tac ctg cag atc ccc gac ctc gtg gcg ctg tgc aag aaa 384
Ala Ala Ser Tyr Leu Gln Ile Pro Asp Leu Val Ala Leu Cys Lys Lys
115 120 125
cgc ctc aag cgc cac ggc aag tac tgc cac ctg cgg ggc ggc ggc ggc 432
Arg Leu Lys Arg His Gly Lys Tyr Cys His Leu Arg Gly Gly Gly Gly
130 135 140
ggc ggc ggc ggc tac gcg ccc tat ggt cgg ccg ggc cgg ggc ctg cgg 480
Gly Gly Gly Gly Tyr Ala Pro Tyr Gly Arg Pro Gly Arg Gly Leu Arg
145 150 155 160
gcc gcc acg ccg gtc atc cag gcc tgc tac ccg tcc cca gtc ggg cct 528
Ala Ala Thr Pro Val Ile Gln Ala Cys Tyr Pro Ser Pro Val Gly Pro
165 170 175
ccg ccg ccg cct gcc gcg gag ccg ccc tcg ggc cca gag gcc gcg gtc 576
Pro Pro Pro Pro Ala Ala Glu Pro Pro Ser Gly Pro Glu Ala Ala Val
180 185 190
aac acg cac tgc gcc gag ctg tac gcg tcg gga ccc ggc ccg gcc gcc 624
Asn Thr His Cys Ala Glu Leu Tyr Ala Ser Gly Pro Gly Pro Ala Ala
195 200 205
gca ctc tgt gcc tcg gag cgc cgc tgc tcc cct ctt tgt ggc ctg gac 672
Ala Leu Cys Ala Ser Glu Arg Arg Cys Ser Pro Leu Cys Gly Leu Asp
210 215 220
ctg tcc aag aag agc ccg ccg ggc tcc gcg gcg cca gag cgg ccg ctg 720
Leu Ser Lys Lys Ser Pro Pro Gly Ser Ala Ala Pro Glu Arg Pro Leu
225 230 235 240
gct gag cgc gag ctg ccc ccg cgc ccg gac agc cct ccc agc gcc ggc 768
Ala Glu Arg Glu Leu Pro Pro Arg Pro Asp Ser Pro Pro Ser Ala Gly
245 250 255
ccc gcc gcc tac aag gag ccg cct ctc gcc ctg ccg tcg ctg ccg ccg 816
Pro Ala Ala Tyr Lys Glu Pro Pro Leu Ala Leu Pro Ser Leu Pro Pro
260 265 270
ctg ccc ttc cag aag ctg gag gag gcc gca ccg cct tcc gac cca ttt 864
Leu Pro Phe Gln Lys Leu Glu Glu Ala Ala Pro Pro Ser Asp Pro Phe
275 280 285
cgc ggc ggc agc ggc agc ccg gga ccc gag ccc ccc ggc cgc ccc gac 912
Arg Gly Gly Ser Gly Ser Pro Gly Pro Glu Pro Pro Gly Arg Pro Asp
290 295 300
ggg cct agt ctc ctc tat cgc tgg atg aag cac gag ccg ggc ctg ggt 960
Gly Pro Ser Leu Leu Tyr Arg Trp Met Lys His Glu Pro Gly Leu Gly
305 310 315 320
agc tat ggc gac gag ctg ggc cgg gag cgc ggc tcc ccc agc gag cgc 1008
Ser Tyr Gly Asp Glu Leu Gly Arg Glu Arg Gly Ser Pro Ser Glu Arg
325 330 335
tgc gaa gag cgt ggt ggg gac gcg gcc gtc tcg ccc ggg ggg ccc ccg 1056
Cys Glu Glu Arg Gly Gly Asp Ala Ala Val Ser Pro Gly Gly Pro Pro
340 345 350
ctc ggc ctg gcg ccg ccg ccg cgc tac cct ggc agc ctg gac ggg ccc 1104
Leu Gly Leu Ala Pro Pro Pro Arg Tyr Pro Gly Ser Leu Asp Gly Pro
355 360 365
ggc gcg ggc ggc gac ggc gac gac tac aag agc agc agc gag gag acc 1152
Gly Ala Gly Gly Asp Gly Asp Asp Tyr Lys Ser Ser Ser Glu Glu Thr
370 375 380
ggt agc agc gag gac ccc agc ccg cct ggc ggc cac ctc gag ggc tac 1200
Gly Ser Ser Glu Asp Pro Ser Pro Pro Gly Gly His Leu Glu Gly Tyr
385 390 395 400
cca tgc ccg cac ctg gcc tat ggc gag ccc gag agc ttc ggt gac aac 1248
Pro Cys Pro His Leu Ala Tyr Gly Glu Pro Glu Ser Phe Gly Asp Asn
405 410 415
ctg tac gtg tgc att ccg tgc ggc aag ggc ttc ccc agc tct gag cag 1296
Leu Tyr Val Cys Ile Pro Cys Gly Lys Gly Phe Pro Ser Ser Glu Gln
420 425 430
ctg aac gcg cac gtg gag gct cac gtg gag gag gag gaa gcg ctg tac 1344
Leu Asn Ala His Val Glu Ala His Val Glu Glu Glu Glu Ala Leu Tyr
435 440 445
ggc agg gcc gag gcg gcc gaa gtg gcc gct ggg gcc gcc ggc cta ggg 1392
Gly Arg Ala Glu Ala Ala Glu Val Ala Ala Gly Ala Ala Gly Leu Gly
450 455 460
ccc cct ttt gga ggc ggc ggg gac aag gtc gcc ggg gct ccg ggt ggc 1440
Pro Pro Phe Gly Gly Gly Gly Asp Lys Val Ala Gly Ala Pro Gly Gly
465 470 475 480
ctg gga gag ctg ctg cgg ccc tac cgc tgc gcg tcg tgc gac aag agc 1488
Leu Gly Glu Leu Leu Arg Pro Tyr Arg Cys Ala Ser Cys Asp Lys Ser
485 490 495
tac aag gac ccg gcc acg ctg cgg cag cac gag aag acg cac tgg ctg 1536
Tyr Lys Asp Pro Ala Thr Leu Arg Gln His Glu Lys Thr His Trp Leu
500 505 510
acc cgg ccc tac cca tgc acc atc tgc ggg aag aag ttc acg cag cgt 1584
Thr Arg Pro Tyr Pro Cys Thr Ile Cys Gly Lys Lys Phe Thr Gln Arg
515 520 525
ggg acc atg acg cgc cac atg cgc agc cac ctg ggc ctc aag ccc ttc 1632
Gly Thr Met Thr Arg His Met Arg Ser His Leu Gly Leu Lys Pro Phe
530 535 540
gcg tgc gac gcg tgc ggc atg cgg ttc acg cgc cag tac cgc ctc acg 1680
Ala Cys Asp Ala Cys Gly Met Arg Phe Thr Arg Gln Tyr Arg Leu Thr
545 550 555 560
gag cac atg cgc atc cac tcg ggc gag aag ccc tac gag tgc cag gtg 1728
Glu His Met Arg Ile His Ser Gly Glu Lys Pro Tyr Glu Cys Gln Val
565 570 575
tgc ggc ggc aag ttc gca cag caa cgc aac ctc atc agc cac atg aag 1776
Cys Gly Gly Lys Phe Ala Gln Gln Arg Asn Leu Ile Ser His Met Lys
580 585 590
atg cac gcc gtg ggg ggc gcg gcc ggc gcg gcc ggg gcg ctg gcg ggc 1824
Met His Ala Val Gly Gly Ala Ala Gly Ala Ala Gly Ala Leu Ala Gly
595 600 605
ttg ggg ggg ctc ccc ggc gtc ccc ggc ccc gac ggc aag ggc aag ctc 1872
Leu Gly Gly Leu Pro Gly Val Pro Gly Pro Asp Gly Lys Gly Lys Leu
610 615 620
gac ttc ccc gag ggc gtc ttt gct gtg gct cgc ctc acg gcc gag cag 1920
Asp Phe Pro Glu Gly Val Phe Ala Val Ala Arg Leu Thr Ala Glu Gln
625 630 635 640
ctg agc ctg aag cag cag gac aag gcg gcc gcg gcc gag ctg ctg gcg 1968
Leu Ser Leu Lys Gln Gln Asp Lys Ala Ala Ala Ala Glu Leu Leu Ala
645 650 655
cag acc acg cac ttc ctg cac gac ccc aag gtg gcg ctg gag agc ctc 2016
Gln Thr Thr His Phe Leu His Asp Pro Lys Val Ala Leu Glu Ser Leu
660 665 670
tac ccg ctg gcc aag ttc acg gcc gag ctg ggc ctc agc ccc gac aag 2064
Tyr Pro Leu Ala Lys Phe Thr Ala Glu Leu Gly Leu Ser Pro Asp Lys
675 680 685
gcg gcc gag gtg ctg agc cag ggc gct cac ctg gcg gcc ggg ccc gac 2112
Ala Ala Glu Val Leu Ser Gln Gly Ala His Leu Ala Ala Gly Pro Asp
690 695 700
ggc cgg acc atc gac cgt ttc tct ccc acc tag 2145
Gly Arg Thr Ile Asp Arg Phe Ser Pro Thr
705 710
<210> 15
<211> 18
<212> DNA
<213> Homo sapiens
<220>
<221> 人工序列
<222> (1)..(18)
<223> L025基因的正向引物
<400> 15
tatctagcaa tggaccgt 18
<210> 16
<211> 19
<212> DNA
<213> Homo sapiens
<220>
<221> 人工序列
<222> (1)..(19)
<223> L025基因的反向引物
<400> 16
ccgaaggtag tagcatgga 19
<210> 17
<211> 21
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(21)
<223> A46R和A47L 基因的正向引物
<400> 17
ttggctatta aacagtatgg a 21
<210> 18
<211> 18
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(18)
<223> A46R和A47L 基因的反向引物
<400> 18
ggatcccgat aacaaatg 18
<210> 19
<211> 25
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(25)
<223> mB5R的正向引物
<400> 19
atgaaaacga tttccgttgt tacgt 25
<210> 20
<211> 24
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(24)
<223> mB5R的反向引物
<400> 20
tcacggtagc aatttatgga actt 24
<210> 21
<211> 25
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(25)
<223> sB5R的正向引物
<400> 21
atgaaaacga tttccgttgt tacgt 25
<210> 22
<211> 24
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(24)
<223> sB5R的反向引物
<400> 22
tcacggtagc aatttatgga actt 24
<210> 23
<211> 20
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(20)
<223> TK基因的正向引物
<400> 23
gttatagtag ccgcactcga 20
<210> 24
<211> 21
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(21)
<223> TK基因的反向引物
<400> 24
atttcagctg aatatgaagg a 21
<210> 25
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> 人工序列
<222> (1)..(20)
<223> PD1抗体基因的正向引物
<400> 25
tcataaatac ccgagccacc 20
<210> 26
<211> 20
<212> DNA
<213> Homo sapiens
<220>
<221> 人工序列
<222> (1)..(20)
<223> PD1抗体基因的反向引物
<400> 26
acccattcaa gaccctttcc 20
<210> 27
<211> 18
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(18)
<223> 对照基因的正向引物
<400> 27
tgttgttcgc tgctatga 18
<210> 28
<211> 20
<212> DNA
<213> Vaccinia virus
<220>
<221> 人工序列
<222> (1)..(20)
<223> 对照基因的反向引物
<400> 28
tggcacaacc atatcttgta 20
Claims (32)
1.一种工程溶瘤病毒,所述工程溶瘤病毒包含
突变的病毒序列,其用于在肿瘤细胞中选择性复制并且/或者活化免疫细胞;和
异源序列,其用于编码免疫共刺激途径激活分子、免疫调节剂基因、截短的病毒包膜基因和/或肿瘤抑制剂,
其中所述异源序列被稳定地整合到所述工程溶瘤病毒的基因组中。
2.根据权利要求1所述的工程痘苗病毒,其中所述异源序列被稳定地整合到所述工程痘苗病毒的所述突变的病毒序列中。
3.根据权利要求1所述的工程痘苗病毒,其中所述突变的病毒序列包含以下至少一项:
(a)L025、TK、A46R或其任意组合中的一个或多个突变;
(b)部分删除的L025、TK、A46R或其任意组合;
(c)删除的L025、TK、A46R或其任何组合;
(d)L025、TK或A46R的一部分或全部,其被SEQ ID NO:2、4、6、8、10、12或14中所示的序列之一替代;
(e)L025、TK或A46R的一部分或全部,其被肿瘤靶向基因替代;
(f)L025、TK或A46R的一部分或全部,其被靶向T细胞的配体或抗体替代;
(g)L025、TK或A46R的一部分或全部,其被治疗性基因或其修饰形式替代;或者
(h)L025、TK或A46R的一部分或全部被治疗性抗体替代。
4.根据权利要求1所述的工程痘苗病毒,其中所述异源序列包含以下至少一种:
(a)SEQ ID NO:2中所示的序列;
(b)SEQ ID NO:4中所示的序列;
(c)SEQ ID NO:6中所示的序列;
(d)SEQ ID NO:8中所示的序列;
(e)SEQ ID NO:10中所示的序列;
(f)SEQ ID NO:12中所示的序列;或
(g)SEQ ID NO:14中所示的序列。
5.根据权利要求1所述的工程痘苗病毒,其中所述异源序列编码以下至少一种:
(a)SEQ ID NO:1中所示的序列;
(b)SEQ ID NO:3中所示的序列;
(c)SEQ ID NO:5中所示的序列;
(d)SEQ ID NO:7中所示的序列;
(e)SEQ ID NO:9中所示的序列;
(f)SEQ ID NO:11中所示的序列;
(g)SEQ ID NO:13中所示的序列。
6.根据权利要求1所述的工程痘苗病毒,其中所述工程痘苗病毒包含下式的序列:5’-A1-X-A2-B1-Y-B2-C1-Z-C2-3’,其中A1和A2分别是第一病毒基因的左臂和右臂,B1和B2分别是第二病毒基因的左臂和右臂,C1和C2分别是第三病毒基因的左臂和右臂,其中X、Y和Z是异源基因,各自选自免疫调节基因、细胞因子、治疗性基因、截短的病毒包膜基因、肿瘤抑制基因、编码治疗性抗体的基因和编码所述治疗性抗体的配体的基因中的一种。
7.根据权利要求5所述的工程痘苗病毒,其中所述第一病毒基因是L025,所述第二病毒基因是TK,并且所述第三病毒基因是A46R。
8.根据权利要求5所述的工程痘苗病毒,其中X是IL-21与经修饰的B5R的杂交基因,Y是4-1BBL,并且Z是HIC1。
9.根据权利要求1所述的工程痘苗病毒,其中所述突变的病毒序列包括L025、TK和A46R中缺失的突变,并且所述异源序列包括IL-21和4-1BBL。
10.根据权利要求1所述的工程痘苗病毒,其中所述突变的病毒序列包括L025、TK和A46R中缺失的突变,并且所述异源序列包括IL-21和经修饰的B5R以及4-1BBL的杂交基因。
11.根据权利要求1所述的工程痘苗病毒,其中所述免疫调节基因是编码IL-12、IL-21、IL-2、IL-15、IL-8或其经修饰的形式的细胞因子基因。
12.根据权利要求1所述的工程痘苗病毒,其中所述免疫共刺激途径激活分子包括CD40配体(CD40L)、ICOS配体、GITR配体、4-1BB配体、OX40配体、TL1A、CD30配体、CD27、Flt3配体或其经修饰的形式。
13.根据权利要求1所述的工程痘苗病毒,其中所述肿瘤抑制基因是HIC1。
14.根据权利要求1所述的工程痘苗病毒,其中所述工程痘苗病毒选自由以下组成的组:李斯特毒株、Western Reserve(WR)毒株、哥本哈根(Cop)毒株、Bern毒株、巴黎毒株、塔什干毒株、天坛毒株、惠氏(DRYVAX)毒株、IHD-J毒株、IHD-W毒株、布莱顿毒株、安卡拉毒株、CVA382毒株、改良安卡拉痘苗(MVA)毒株、戴仁I毒株、LC16m8毒株、LC16M0毒株、LIVP毒株、ACAM2000毒株、WR 65-16毒株、康诺特毒株、纽约市卫生局(NYCBH)毒株、EM-63毒株和NYVAC毒株。
15.根据权利要求1所述的工程痘苗病毒,其中所述截短的病毒包膜基因是含有短共有重复序列(SCR)2、SCR3和SCR4结构域缺失的B5R。
16.根据权利要求1所述的工程痘苗病毒,其中所述肿瘤抑制基因是HIC1。
17.一种药物组合物,其包含有效量的权利要求1的工程痘苗病毒和药学上可接受的载体。
18.根据权利要求17所述的药物组合物,其中所述药物组合物被配制用于口服、局部、肠胃外递送或介入疗法。
19.根据权利要求17所述的药物组合物,其中所述药物组合物被配制用于局部瘤内注射、局部动脉内(供应肿瘤的血管)注射、腹膜内注射、胸内注射、全身性静脉内注射、肌内注射、皮下注射、鞘内注射、直接脑室内注射、心内注射、鼻内注射。
20.根据权利要求17所述的药物组合物,其中所述工程痘苗病毒单独用作单一疗法;或者与抗癌剂、免疫抑制剂和/或溶瘤病毒增强剂联合使用。
21.根据权利要求17所述的药物组合物,其中所述工程痘苗病毒与5-氟尿嘧啶(FU)、亚叶酸(FA)、甲氨蝶呤、卡培他滨、奥沙利铂、贝伐单抗、西妥昔单抗、免疫检查点抑制剂、其它类型的溶瘤病毒或其任意组合联合使用。
22.一种用于治疗有需要的受试者的癌症的方法,其包括向所述受试者施用有效量的权利要求1的工程痘苗病毒。
23.根据权利要求22所述的方法,其中HIC1在所述癌症中失活、表达不足或缺失。
24.根据权利要求22所述的方法,其中所述癌症选自由以下组成的组:肺癌、黑色素瘤、胰腺癌、肝癌、结肠癌、乳腺癌、胶质母细胞瘤、肉瘤、胃癌、卵巢癌、间皮瘤和白血病。
25.一种方法,其使用有效量的权利要求1的工程痘苗病毒筛选癌症组织或细胞。
26.一种增加痘苗病毒的肿瘤特异性感染性的方法,其包括向受试者施用权利要求1的工程痘苗病毒,其中以有效引起所述受试者的抗肿瘤免疫反应的量施用所述工程痘苗病毒。
27.一种赋予有需要的受试者针对肿瘤复发的持续免疫的方法,其包括向所述受试者施用权利要求1的工程痘苗病毒。
28.一种基于用权利要求1的工程痘苗病毒感染患者癌细胞后48小时GFP阳性细胞的百分比筛选患者的方法。
29.一种用于诱导癌细胞死亡、调节所述癌细胞的生物活性、调节免疫反应、增强T细胞增殖和/或T细胞的毒性的工程痘苗病毒,其中所述工程溶瘤是如权利要求1所提供的。
30.如权利要求28所述的用于诱导癌细胞死亡、调节癌细胞的生物活性、调节免疫反应、增强T细胞的增殖和/或T细胞的细胞毒性的工程痘苗病毒,其中所述癌细胞的所述生物活性包括癌细胞复制的抑制、癌细胞分裂的抑制、癌细胞的DNA修复的抑制、癌细胞迁移的抑制或促进癌症死亡,其中所述工程溶瘤是如权利要求1所提供的。
31.一种工程痘苗病毒,其用于制造用于治疗肺癌、黑色素瘤、胰腺癌、肝癌、结肠癌、乳腺癌、胶质母细胞瘤、肉瘤、胃癌、卵巢癌、间皮瘤和白血病的药剂,其中所述工程溶瘤是如权利要求1中提供的。
32.一种工程痘苗病毒,其用于制造用于抑制癌细胞生长、诱导癌细胞死亡并且/或者调节所述癌细胞的生物活性的药剂,其中所述工程溶瘤是如权利要求1中提供的。
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