CN115103681B - 一种重组病毒载体、包含其的免疫组合物以及用途 - Google Patents
一种重组病毒载体、包含其的免疫组合物以及用途 Download PDFInfo
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Abstract
一种重组病毒载体、包含其的免疫组合物以及用途。所述重组病毒载体包含编码细胞因子的多核苷酸,所述细胞因子选自IL‑7、IL‑15、IL‑21或GM‑CSF中的一种或多种,该重组病毒载体可用于制备抗肿瘤疫苗。
Description
技术领域
本发明属于分子生物学和免疫学领域。具体地,本发明涉及一种重组病毒载体、包含其的免疫组合物以及用途,特别地,本发明涉及一种可以用于制备肿瘤疫苗,从而用于预防和/或治疗多种肿瘤的重组病毒载体。
背景技术
随着肿瘤生物学和免疫学的发展,肿瘤免疫治疗取得了长足的进步,逐步成为当前肿瘤治疗的重要发展方向。特别是伴随PD-1/PD-L1免疫疗法的巨大成功,开发肿瘤免疫疗法成为当前肿瘤治疗新兴的热点。
肿瘤疫苗通过激发体内的针对肿瘤的特异性免疫应答,活化产生庞大的免疫细胞,来杀伤肿瘤细胞和控制肿瘤细胞的生长,从而达到减小或控制肿瘤生长的效果。肿瘤疫苗的开发也是当前肿瘤免疫治疗的重点研究方向。
研究表明细胞毒(CD8+)和辅助(CD4+)T细胞在肿瘤排斥反应中起了关键的作用。因此,大多数肿瘤疫苗的目标都致力于诱导细胞的特异性的T细胞反应。肿瘤细胞在合成肿瘤抗原的过程中,分解的多肽通过MHC I类分子被提呈致肿瘤细胞表面激活CD8+T细胞。MHCII类分子为CD4+T细胞所识别,主要位于特殊的抗原提呈细胞(APC)表面,包括树突状细胞、B细胞和巨噬细胞。肿瘤细胞分泌或肿瘤溶解释放外源性蛋白被APC俘获。在APC内,抗原被加工成多肽片断并由II类MHC提呈给CD4+细胞。激活的抗原特异性CD8+细胞最终成为细胞毒性T细胞并溶解肿瘤细胞。
理想的肿瘤特异性抗原应具有较强的免疫原性,为肿瘤细胞所表达,但不表达于正常的细胞。不幸的是,大多数肿瘤抗原都没有足够的免疫原性以诱导有效的免疫反应,而且,许多肿瘤抗原在某种程度上表达于正常的组织,从而导致体内存在免疫耐受。因此,这些肿瘤抗原天然存在免疫原性弱的特点,设计的肿瘤疫苗必须要克服机体的免疫耐受障碍,激活针对肿瘤抗原的免疫应答产生。
肿瘤疫苗主要分为全细胞疫苗、蛋白疫苗、多肽疫苗、病毒疫苗和树突状细胞疫苗。而DNA疫苗和RNA疫苗实际上仍属于分子疫苗,只是采用了不同的表达系统。
细胞疫苗:过去,对肿瘤抗原与其临床的相关性方面并不十分清楚,因此采用全细胞作为肿瘤疫苗,以便可以提供那些未知的肿瘤抗原来激活免疫系统。在小鼠肿瘤模型中,通常使用辐射灭活的肿瘤细胞免疫小鼠,以保护小鼠免受接种的肿瘤的侵袭。但当肿瘤细胞疫苗使用的时间推迟到接种肿瘤细胞后一周时,疫苗就失去了保护小鼠的能力。肿瘤细胞疫苗的临床治疗反应比较差,仅仅适用于无特殊肿瘤抗原的肿瘤病人的预防复发。对于进展期病人在临床研究方面很少获得良好效果。近年来,由于在识别分析肿瘤抗原方面的进展,特别是T细胞识别抗原的机制的深入了解,肿瘤抗原疫苗已基本取代细胞疫苗被用于肿瘤的免疫治疗。
多肽和蛋白疫苗:T细胞识别MHC分子表面的抗原多肽表位一般为7-12个氨基酸,因此,抗原多肽可以与免疫佐剂混合应用以达到在体内装载于空虚的MHC分子的目的。到目前为止,几乎所有的以多肽为基础的疫苗都是MHC I类抗原限制性多肽。多肽疫苗应用有一些限制。所应用的多肽疫苗必需与病人的MHC I类抗原分子相匹配,即所谓的个体化,但由于不同的病人MHC I类分子的亚型不同,所使用的肿瘤抗原多肽的序列也不同,因而这给肿瘤抗原多肽的临床应用带来很大的困难。
重组分子疫苗:肿瘤抗原蛋白疫苗的应用可以克服这种困难,但是单纯使用蛋白并不能激活机体的免疫反应。灵长类动物试验研究证实最佳的免疫效果需要将肿瘤蛋白与强免疫原性蛋白相交联。弱抗原要诱导出有效的免疫反应,就必须联合使用免疫佐剂,提供一个非特异性的信号以激活免疫系统,许多免疫佐剂都有一定的毒性而不能应用于临床,所以抗原蛋白疫苗大都是以重组形式出现的。
用重组形式增强肿瘤蛋白的免疫原性的方法就是将肿瘤抗原与细胞因子,如GM-CSF、白细胞介素等重组形成融合蛋白。肿瘤弱抗原与细菌或病毒抗原、毒素如白喉毒素、假单胞菌毒素等的重组可以明显提高肿瘤抗原的抗原性,促进DC对肿瘤抗原的吞噬提呈,取得了一定的效果。但肿瘤抗原与毒素的单独重组的方法到目前为止仍然还没有达到理想的效果。
树突状细胞疫苗:对于有效的T细胞介导的免疫反应,T细胞需要抗原被提呈并致敏初始T细胞,致敏的T淋巴细胞获得再刺激。要启动有效的T细胞介导的肿瘤免疫,来源于体内任何部位的肿瘤抗原多肽必须被T细胞所识别。因此,抗原的提呈是获得有效免疫反应的关键性步骤。疫苗刺激的免疫反应主要依赖于有效的APC对抗原的初加工和进一步的提呈。
白介素7(Interleukin 7,IL-7)是骨髓和胸腺基质细胞分泌的造血生长因子。它也可由角质细胞、树突细胞、肝细胞、神经元细胞和上皮细胞产生,但正常的淋巴细胞不会分泌产生IL-7。IL-7促进造血干细胞分化成淋巴样前体细胞。它也能刺激淋巴系所有细胞的增殖,例如B细胞、T细胞和NK细胞。它对于特定阶段的B细胞成熟,T细胞和天然杀伤细胞(Natural Killer Cells,NK细胞)的存活、发育和平衡至关重要。
白介素15(Interleukin 15,IL-15)是在病毒感染后由单核吞噬细胞分泌产生。其结构类似白介素2(Interleukin 2,IL-2),IL-15通过结合IL-2/IL-15受体β链(CD122)和共有受体γ链(CD132)复合体来传递信号。该细胞因子调节T细胞和NK细胞的活化与增值。但抗原不存在时,IL-15可提供维持记忆T细胞的存活信号。IL-15在临床前研究中显示出可以增强CD8+T细胞的抗肿瘤作用。IL-15也可作疫苗佐剂,增加疫苗免疫原性。
白介素21(Interleukin 21,IL-21)由活化的CD4+T细胞分泌产生,可对免疫系统多种细胞起调节作用。IL-21可以通过持续增加CD8+T细胞应答实现抗肿瘤效果(Journalof Immunology.173(2):900–9)。IL-21在控制慢性病毒感染中也发挥重要作用。在HIV感染者中,IL-21可增强HIV特异性细胞毒性T细胞应答(Blood.109(9):3873–80.)和NK细胞功能(Journal of Leukocyte Biology.87(5):857–67.)
粒细胞-巨噬细胞集落刺激因子(Granulocyte-macrophage colony-stimulatingfactor,GM-CSF),又被称为集落刺激因子2(colony-stimulating factor 2,CSF2)是由巨噬细胞、T细胞、肥大细胞、NK细胞,内皮细胞和成纤维细胞分泌产生的一种单体糖蛋白。GM-CSF具有多种功能,可刺激干细胞产生多种粒细胞和单核细胞,快速活化增殖大量巨噬细胞,从而实现抗感染的效果。安进(Amgen)公司开发的带有GM-CSF的溶瘤病毒疗法已经被FDA批准用于黑色素瘤治疗。
发明内容
因此,为了提高肿瘤抗原的免疫原性,激发肿瘤特异性免疫应答,从根本上治愈肿瘤,本发明将多个与免疫相关的细胞因子联合表达在一种重组病毒载体上,以期提高疫苗的免疫效果和发挥细胞因子的抗肿瘤作用。
本发明的目的是提供一种重组病毒载体,该重组病毒载体可以用于制备肿瘤疫苗,从而用于预防和/或治疗多种肿瘤。
在本发明的一个实施方案中,所述重组病毒载体包含编码细胞因子的多核苷酸。
为了本发明的目的,以下定义下列术语。
“细胞因子(cytokine,CK)”是指由免疫细胞(如单核细胞、巨噬细胞、T细胞、B细胞、NK细胞等)和某些非免疫细胞(内皮细胞、表皮细胞、纤维母细胞等)经刺激而合成、分泌的一类具有广泛生物学活性的小分子蛋白质。细胞因子一般通过结合相应受体调节细胞生长、分化和效应,调控免疫应答。细胞因子是免疫原、丝裂原或其他刺激剂诱导多种细胞产生的低分子量可溶性蛋白质,具有调节固有免疫和适应性免疫、血细胞生成、细胞生长、APSC多能细胞以及损伤组织修复等多种功能。细胞因子可被分为白细胞介素、干扰素、肿瘤坏死因子超家族、集落刺激因子、趋化因子、生长因子等。在本发明的实施方案中,所述细胞因子选自IL-7、IL-15,IL-21和GM-CSF中的一种或多种。在本发明的一个实施方案中,所述IL-15为人IL-15;优选地,所述人IL-15的氨基酸序列如SEQ ID NO:2所示;优选地,其编码核酸序列如SEQ ID NO:1所示。在本发明的一个实施方案中,所述GM-CSF为人GM-CSF;优选地,所述人GM-CSF的氨基酸序列如SEQ ID NO:4所示;优选地,其编码核酸序列如SEQ IDNO:3所示。在本发明的一个实施方案中,所述IL-7为人IL-7;优选地,所述人IL-7的氨基酸序列如SEQ ID NO:6所示;优选地,其编码核酸序列如SEQ ID NO:5所示。在本发明的一个实施方案中,所述IL-21为人IL-21;优选地,所述人IL-21的氨基酸序列如SEQ ID NO:8所示;优选地,其编码核酸序列如SEQ ID NO:7所示。在本发明的一个优选实施方案中,所述细胞因子包括人IL-15、人GM-CSF、人IL-7和人IL-21;优选地,所述编码细胞因子的多核苷酸的核酸序列如SEQ ID NO:15所示;优选地,其编码的氨基酸序列如SEQ ID NO:16所示。
“肿瘤抗原”是指在肿瘤发生、发展过程中新出现或过度表达的抗原物质。肿瘤抗原包括但不限于肿瘤特异性抗原、肿瘤相关抗原、组织分化抗原、原癌病毒抗原和肿瘤-睾丸抗原(cancer-testis antigens,CT抗原)等。
“肿瘤特异性抗原”(Tumor-Specific Antigens,TSA)是指仅在肿瘤细胞中表达,不在正常细胞中表达的抗原物质。例如突变的抗原,特别是原癌基因和肿瘤抑制基因的突变产物,包括ras和p53等。
“肿瘤相关抗原”(Tumor-Associated Antigens,TAA)是指在肿瘤细胞中和一些正常细胞中表达的抗原物质。
优选地,所述病毒载体是痘苗病毒载体,优选为复制型痘苗病毒载体,例如痘苗病毒天坛株,例如752-1株,或者为非复制型痘苗病毒载体,例如痘苗病毒减毒疫苗安卡拉株(Modified Vaccinia Ankara,MVA)。
本发明的另一目的是提供一种免疫组合物,所述免疫组合物包含预防和/或治疗有效量的根据本发明的重组病毒载体,以及药学上可接受的载体。
本发明的另一目的是提供一种肿瘤疫苗,所述肿瘤疫苗包含预防和/或治疗有效量的根据本发明的重组病毒载体,以及药学上可接受的载体。
本发明的另一目的是提供一种药盒,所述药盒包含根据本发明的重组病毒载体、免疫组合物或肿瘤疫苗,以及其使用说明。
本发明还提供了根据本发明的重组病毒载体、免疫组合物或肿瘤疫苗在制备治疗和/或预防肿瘤的药物或疫苗中用途。优选地,所述肿瘤为恶性肿瘤。更优选地,所述恶性肿瘤为乳腺癌或结肠癌。
本发明还提供了一种用于治疗和/或预防肿瘤的方法,所述方法包括给予有需要的受试者预防和/或治疗有效量的根据本发明的重组病毒载体、免疫组合物或肿瘤疫苗;优选地,所述肿瘤为恶性肿瘤;更优选地,所述恶性肿瘤为乳腺癌或结肠癌。
本发明提供的重组病毒载体能够激发肿瘤特异性免疫应答,有效抑制肿瘤细胞生长,延长肿瘤患者的生存时间。
附图的简要说明
以下,结合附图来详细说明本发明的实施方案,其中:
图1和图2分别是带有细胞因子编码序列的穿梭载体载体pSC65CY的质粒图谱和双酶切鉴定图。
图3为实施例5中的人GM-CSF活性检测结果。
图4为实施例6中的人IL-21活性检测结果。
实施发明的最佳方式
下面结合实施例进一步说明本发明,应当理解,实施例仅用于进一步说明和阐释本发明,并非用于限制本发明。
除非另外定义,本说明书中有关技术的和科学的术语与本领域内的技术人员所通常理解的意思相同。虽然在实验或实际应用中可以应用与此间所述相似或相同的方法和材料,本文还是在下文中对材料和方法做了描述。在相冲突的情况下,以本说明书包括其中定义为准,另外,材料、方法和例子仅供说明,而不具限制性。
实施例1穿梭载体pSC65CY构建
所有人细胞因子氨基酸及其核酸序列均来自NCBI数据库。将人细胞因子IL-15(NM_000585.4,核酸序列如SEQ ID NO:1所示,氨基酸序列如SEQ ID NO:2所示),GM-CSF(NM_000758.3,核酸序列如SEQ ID NO:3所示,氨基酸序列如SEQ ID NO:4所示),IL-7(NM_000880.3,核酸序列如SEQ ID NO:5所示,氨基酸序列如SEQ ID NO:6所示),IL-21(NM_001207006.2,核酸序列如SEQ ID NO:7所示,氨基酸序列如SEQ ID NO:8所示)序列去掉终止密码子后串联在一起,各个细胞因子核酸序列之间间隔有普通技术人员熟知的P2A核酸序列(核酸序列如SEQ ID NO:9所示,氨基酸序列如SEQ ID NO:10所示,内源性蛋白酶切位点,可以有效切割融合蛋白,形成有活性的细胞因子单体,见参考文献Kim JH,Lee S-R,LiL-H,Park H-J,Park J-H,et al.(2011)High Cleavage Efficiency of a 2A PeptideDerived from Porcine Teschovirus-1in Human Cell Lines,Zebrafish and Mice.PLoSONE 6(4):e18556.),最后串联一段普通技术人员熟知的绿色荧光蛋白核酸表达序列EGFP(核酸序列如SEQ ID NO:11所示,氨基酸序列如SEQ ID NO:12所示)用于标记筛查,最终形成四联细胞因子核酸表达序列CY(核酸序列如SEQ ID NO:13所示,氨基酸序列如SEQ IDNO:14所示)。将序列经苏州金唯智公司合成后,通过分子克隆技术插入穿梭载体pSC65(addgene,货号:30327)上的Xho I和Bam HI酶切位点之间,构建成可表达4个细胞因子的穿梭载体pSC65CY(质粒图谱如图1),经测序鉴定正确后入库。用限制内切酶EcoR V鉴定载体pSC65CY(酶切体系如表1),其酶切验证图谱如图2所示。
表1质粒pSC65CY的酶切鉴定体系(37℃酶切2小时)
酶切体系 | 体积 |
质粒pSC65CY | 3μL,约1μg |
EcoRV(宝生物,货号1068A) | 1μL |
酶切缓冲液 | 1μL |
ddH2O | 补至10μL |
实施例2重组痘苗病毒载体rvv-CY构建
在143B细胞中获得重组痘苗病毒载体,具体方法如下。第1天,在6孔细胞培养板(JET,TCP-010-006)铺143B细胞(CRL-8303),1×106/孔,于37℃在二氧化碳细胞培养箱中过夜孵育。第二天,以0.05MOI(即5×104PFU(空斑形成单位)/孔)加入痘苗病毒野生株752-1(由北京生物制品所提供),然后置于37℃二氧化碳细胞培养箱中孵育两个小时,期间准备穿梭载体/转染试剂复合物。其中穿梭载体为实施例1中获得的pSC65CY,转染试剂为Turbofect(Thermo Fisher Scientific,R0531),转染剂量与复合方法可参见转染试剂说明书。复合体系完成后,将143B细胞上清换为2mL/孔的含2%胎牛血清(FBS)的DMEM维持培养基,然后加入穿梭载体/转染试剂复合物。转染48小时后,去上清,收集细胞,并在0.5mL维持培养基中重悬,反复冻融三次,然后将重组细胞裂解物接入新的143B细胞上(含50μg/mL BrdU),37℃孵育1到2天。期间观察细胞病变,待病毒噬斑出现合适数量时(低于20空斑/孔),进行单斑纯化。
单斑纯化:
在荧光显微镜下观察表达绿色荧光的病毒噬斑,做好标记。
去上清,每孔挑取若干个分散较好的绿色荧光噬斑,分别转移至含0.5mL维持培养液的Ep管中。
振荡混匀含病毒的Ep管,反复冻融三次(-80℃冰箱约5分钟,室温约2分钟),最后振荡混匀,-80℃冻存。
重复至少六轮单斑纯化,直至纯度至100%。
实施例3重组痘苗病毒载体rvv-CY扩增制备与滴定
将实施例2中构建的重组痘苗病毒载体rvv-CY以及痘苗病毒野生株(rvv-WT)分别在Vero细胞(CCL-81)上扩增,扩增方法如下:
前一天,准备汇集度100%的Vero单层细胞(1×107细胞/皿),共10皿。
去上清,换为维持培养基,将待扩增的痘病毒接种到细胞上(0.01PFU/细胞),37℃培养箱中孵育2-3天,观察可见明显的细胞病变。
将细胞刮下并收集,1800g离心5分钟,去上清。
用5mL维持培养基进行重悬,在冰上用超声波细胞粉粹机超声,超声条件为:50瓦,5秒超声/5秒间隔,共15分钟。
反复冻融两次(-80℃冰箱约5分钟,室温约2分钟),最后振荡混匀;
在二级生物安全柜中进行分装至1.5mL离心管中,1mL/支,-80℃冻存。
扩增制备好的痘苗病毒在Vero细胞上进行感染效价滴定,具体方法如下:
前一天,在24孔板中,准备汇集度100%的Vero细胞,3×105/孔。
去上清,每孔添加200μL维持培养液,以防止细胞干涸。
取100μL待测痘病毒加入900μL维持培养基,十倍稀释,连续稀释101,102,103,……,直到109倍。注意:进行稀释时,因为由高浓度向低浓度稀释,每次向低浓度稀释应更换枪头。
从病毒浓度由小到大(109,108,……104)添加到24孔板中,每孔400μL稀释液,两个重复,连续测定6个稀释倍数。将添加完的24孔板放入37℃细胞培养箱中孵育2天。
显微镜下数出病毒蚀斑的数目,多于20的,记为20+。将可以数出的20以内(含20)蚀斑数目的两复孔求平均×2.5(1000μL/400μL)×相应孔的稀释倍数,即为重组病毒滴度(PFU/mL)。
痘苗病毒载体效价滴定结果如表2所示。
表2痘苗病毒载体效价滴定
痘苗病毒 | 效价(PFU/mL) |
痘苗病毒野生型rvv-wt | 1.5×108 |
重组痘苗病毒rvv-CY | 1.0×108 |
实施例4细胞因子表达检测
从实施例3中分别获取痘苗病毒野生型rvv-wt和重组痘苗病毒rvv-CY感染vero细胞的上清液,并用ELISA法检测感染上清中细胞因子的含量。其中用于检测人IL-7(货号:SEK11821)、人IL-15(货号:SEK10360)、人GM-CSF(货号:SEK10015)的ELISA试剂盒购自北京义翘神州。用于检测人IL-21(货号:88-8218)的ELISA试剂盒在赛默飞世尔科技公司购买。检测方法参考试剂盒说明书。病毒感染上清中所测的各个细胞因子含量如表3所示,结果表明痘苗病毒野生型rvv-wt感染上清中无细胞因子表达,检测均小于检测限(<0.01ng/mL)。而制备的带有细胞因子核酸序列的重组痘苗病毒rvv-CY均能检测到各个细胞因子的表达,其中人GM-CSF分泌最强,达到144.6ng/mL水平,其余细胞因子分泌相当,在1-6ng/mL的水平之间。
表3细胞因子含量检测(ng/mL)
样本 | 人IL-7 | 人IL-15 | 人GM-CSF | 人IL-21 |
rvv-WT感染上清 | <0.01 | <0.01 | <0.01 | <0.01 |
rvv-CY感染上清 | 3.7 | 1.9 | 144.6 | 5.7 |
实施例5细胞因子人GM-CSF活性检测
TF-1细胞(CRL-2003)在完全RPMI-1640培养基(10%胎牛血清(FBS)、1%青链霉素(PS)、2ng/mL人IL-3)中培养至对数期,125g离心10分钟收集细胞,用无血清RPMI-1640培养基重悬,再次离心收集细胞,用完全RPMI-1640培养基稀释细胞至1×105个/mL,充分混匀,加入96孔板,每孔100微升(1×104个细胞)。
人GM-CSF标准品(近岸蛋白,货号:CC79)按两倍梯度逐级稀释,从低浓度到高浓度分别加入96孔板,并做空白对照,每个浓度做两复孔,共12个梯度。放置在37℃、5%CO2培养箱中培养96小时。
然后在96孔板中,每孔加入10微升CCK-8(MCE,货号:HY-K0301)试剂,放回培养箱继续培养2-4小时,用酶标仪测定OD450。
检测结果如图3所示,实施例3中制备的带有细胞因子核酸序列的重组痘苗病毒rvv-CY感染上清中分泌的人GM-CSF具有活性(半数有效浓度(EC50)为4.2ng/mL),且与人GM-CSF标准品(EC50为2.8ng/mL)相当。
实施例6细胞因子人IL-21活性检测
Mino细胞(CRL-3000)在完全RPMI-1640培养基(10%胎牛血清(FBS)、1%青链霉素(PS))培养至对数期,125g离心收集细胞,完全培养基稀释至2×105个/mL。
人IL-21标准品(北京义翘神州,货号:10584-HNAE)在96孔板中按两倍梯度逐渐稀释,并作空白对照,共12个梯度,每孔100微升,稀释完成后加入50微升混匀的细胞(1×104个细胞),每孔共150微升液体;96孔板放置于37℃、5%CO2培养箱中培养6-7天。
培养好的96孔板每孔加入10微升CCK-8试剂(MCE,货号:HY-K0301),放回培养箱继续培养4-8h(随颜色变化确定时间),用酶标仪测定OD450。
检测结果如图4所示,实施例3中制备的带有细胞因子核酸序列的重组痘苗病毒rvv-CY感染上清中分泌的人IL-21具有活性(EC50为1.1ng/mL),且与人IL-21标准品(EC50为7ng/mL)相当。
实施例5和实施例6的结果表明制备的带有细胞因子核酸序列的重组痘苗病毒rvv-CY能正确表达具有生物学活性的细胞因子。
实施例7肿瘤治疗实验
从苏州大学动物实验中心购买20只6-8周龄的雌性BAL B/c小鼠,并饲养于苏州大学动物实验中心SPF级动物房中。在第0天,所有小鼠皮下接种肿瘤细胞CT26(CRL-2638),接种剂量为1×105细胞/只,然后随机分成两组。在肿瘤细胞接种后第1天、第14天和第28天,给小鼠分别接种实施例3制备的重组病毒载体rvv-CY或对照痘苗病毒载体野生株rvv-WT。相应地,在肿瘤细胞接种后第1天、第14天和第28天,痘苗组小鼠小腿胫骨前肌接种实施例3中制备的痘苗病毒载体(具体疫苗接种规划见表4)。接种后连续观察并测量肿瘤生长情况。按照以下公式计算肿瘤体积:
肿瘤体积(mm3)=长×宽2/2。
当小鼠肿瘤体积超过2000mm3时,对小鼠处死。
表4实验动物分组与疫苗接种规划
痘苗病毒载体疫苗rvv-CY治疗组小鼠总体生存期显著优于对照组小鼠。结果表明痘苗病毒载体疫苗rvv-CY能提高患有表达肿瘤的小鼠的生存。
尽管本发明已进行了一定程度的描述,明显地,在不脱离本发明的精神和范围的条件下,可进行各个条件的适当变化。可以理解,本发明不限于所述实施方案,而归于权利要求的范围,其包括所述每个因素的等同替换。
序列表
<110> 苏州工业园区唯可达生物科技有限公司
<120> 一种重组病毒载体、包含其的免疫组合物以及用途
<130> EIC20310007P
<160> 16
<170> SIPOSequenceListing 1.0
<210> 1
<211> 489
<212> DNA
<213> Artificial Sequence
<400> 1
atgagaattt cgaaaccaca tttgagaagt atttccatcc agtgctactt gtgtttactt 60
ctaaacagtc attttctaac tgaagctggc attcatgtct tcattttggg ctgtttcagt 120
gcagggcttc ctaaaacaga agccaactgg gtgaatgtaa taagtgattt gaaaaaaatt 180
gaagatctta ttcaatctat gcatattgat gctactttat atacggaaag tgatgttcac 240
cccagttgca aagtaacagc aatgaagtgc tttctcttgg agttacaagt tatttcactt 300
gagtccggag atgcaagtat tcatgataca gtagaaaatc tgatcatcct agcaaacaac 360
agtttgtctt ctaatgggaa tgtaacagaa tctggatgca aagaatgtga ggaactggag 420
gaaaaaaata ttaaagaatt tttgcagagt tttgtacata ttgtccaaat gttcatcaac 480
acttcttga 489
<210> 2
<211> 162
<212> PRT
<213> Artificial Sequence
<400> 2
Met Arg Ile Ser Lys Pro His Leu Arg Ser Ile Ser Ile Gln Cys Tyr
1 5 10 15
Leu Cys Leu Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His
20 25 30
Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys Thr Glu Ala
35 40 45
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
50 55 60
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
65 70 75 80
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
85 90 95
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
100 105 110
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
115 120 125
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
130 135 140
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
145 150 155 160
Thr Ser
<210> 3
<211> 435
<212> DNA
<213> Artificial Sequence
<400> 3
atgtggctgc agagcctgct gctcttgggc actgtggcct gcagcatctc tgcacccgcc 60
cgctcgccca gccccagcac gcagccctgg gagcatgtga atgccatcca ggaggcccgg 120
cgtctcctga acctgagtag agacactgct gctgagatga atgaaacagt agaagtcatc 180
tcagaaatgt ttgacctcca ggagccgacc tgcctacaga cccgcctgga gctgtacaag 240
cagggcctgc ggggcagcct caccaagctc aagggcccct tgaccatgat ggccagccac 300
tacaagcagc actgccctcc aaccccggaa acttcctgtg caacccagat tatcaccttt 360
gaaagtttca aagagaacct gaaggacttt ctgcttgtca tcccctttga ctgctgggag 420
ccagtccagg agtga 435
<210> 4
<211> 144
<212> PRT
<213> Artificial Sequence
<400> 4
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His
20 25 30
Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp
35 40 45
Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe
50 55 60
Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys
65 70 75 80
Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met
85 90 95
Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser
100 105 110
Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys
115 120 125
Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu
130 135 140
<210> 5
<211> 534
<212> DNA
<213> Artificial Sequence
<400> 5
atgttccatg tttcttttag gtatatcttt ggacttcctc ccctgatcct tgttctgttg 60
ccagtagcat catctgattg tgatattgaa ggtaaagatg gcaaacaata tgagagtgtt 120
ctaatggtca gcatcgatca attattggac agcatgaaag aaattggtag caattgcctg 180
aataatgaat ttaacttttt taaaagacat atctgtgatg ctaataagga aggtatgttt 240
ttattccgtg ctgctcgcaa gttgaggcaa tttcttaaaa tgaatagcac tggtgatttt 300
gatctccact tattaaaagt ttcagaaggc acaacaatac tgttgaactg cactggccag 360
gttaaaggaa gaaaaccagc tgccctgggt gaagcccaac caacaaagag tttggaagaa 420
aataaatctt taaaggaaca gaaaaaactg aatgacttgt gtttcctaaa gagactatta 480
caagagataa aaacttgttg gaataaaatt ttgatgggca ctaaagaaca ctga 534
<210> 6
<211> 177
<212> PRT
<213> Artificial Sequence
<400> 6
Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile
1 5 10 15
Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys
20 25 30
Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu
35 40 45
Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe
50 55 60
Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe
65 70 75 80
Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser
85 90 95
Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr
100 105 110
Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala
115 120 125
Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu
130 135 140
Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu
145 150 155 160
Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu
165 170 175
His
<210> 7
<211> 462
<212> DNA
<213> Artificial Sequence
<400> 7
atgagatcca gtcctggcaa catggagagg attgtcatct gtctgatggt catcttcttg 60
gggacactgg tccacaaatc aagctcccaa ggtcaagatc gccacatgat tagaatgcgt 120
caacttatag atattgttga tcagctgaaa aattatgtga atgacttggt ccctgaattt 180
ctgccagctc cagaagatgt agagacaaac tgtgagtggt cagctttttc ctgctttcag 240
aaggcccaac taaagtcagc aaatacagga aacaatgaaa ggataatcaa tgtatcaatt 300
aaaaagctga agaggaaacc accttccaca aatgcaggga gaagacagaa acacagacta 360
acatgccctt catgtgattc ttatgagaaa aaaccaccca aagaattcct agaaagattc 420
aaatcacttc tccaaaaggt atctacctta agtttcattt ga 462
<210> 8
<211> 153
<212> PRT
<213> Artificial Sequence
<400> 8
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 Val Ser Thr Leu Ser Phe Ile
145 150
<210> 9
<211> 66
<212> DNA
<213> Artificial Sequence
<400> 9
ggaagcggag ctactaactt cagcctgctg aagcaggctg gagacgtgga ggagaaccct 60
ggacct 66
<210> 10
<211> 22
<212> PRT
<213> Artificial Sequence
<400> 10
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
1 5 10 15
Glu Glu Asn Pro Gly Pro
20
<210> 11
<211> 720
<212> DNA
<213> Artificial Sequence
<400> 11
atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 60
ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 120
ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 180
ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 240
cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 300
ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 360
gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 420
aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 480
ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 540
gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 600
tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 660
ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 720
<210> 12
<211> 239
<212> PRT
<213> Artificial Sequence
<400> 12
Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu
1 5 10 15
Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly
20 25 30
Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile
35 40 45
Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr
50 55 60
Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys
65 70 75 80
Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu
85 90 95
Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu
100 105 110
Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly
115 120 125
Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr
130 135 140
Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys Asn
145 150 155 160
Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser
165 170 175
Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly
180 185 190
Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu
195 200 205
Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe
210 215 220
Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
225 230 235
<210> 13
<211> 2931
<212> DNA
<213> Artificial Sequence
<400> 13
atgagaattt cgaaaccaca tttgagaagt atttccatcc agtgctactt gtgtttactt 60
ctaaacagtc attttctaac tgaagctggc attcatgtct tcattttggg ctgtttcagt 120
gcagggcttc ctaaaacaga agccaactgg gtgaatgtaa taagtgattt gaaaaaaatt 180
gaagatctta ttcaatctat gcatattgat gctactttat atacggaaag tgatgttcac 240
cccagttgca aagtaacagc aatgaagtgc tttctcttgg agttacaagt tatttcactt 300
gagtccggag atgcaagtat tcatgataca gtagaaaatc tgatcatcct agcaaacaac 360
agtttgtctt ctaatgggaa tgtaacagaa tctggatgca aagaatgtga ggaactggag 420
gaaaaaaata ttaaagaatt tttgcagagt tttgtacata ttgtccaaat gttcatcaac 480
acttctggaa gcggagctac taacttcagc ctgctgaagc aggctggaga cgtggaggag 540
aaccctggac ctatgtggct gcagagcctg ctgctcttgg gcactgtggc ctgcagcatc 600
tctgcacccg cccgctcgcc cagccccagc acgcagccct gggagcatgt gaatgccatc 660
caggaggccc ggcgtctcct gaacctgagt agagacactg ctgctgagat gaatgaaaca 720
gtagaagtca tctcagaaat gtttgacctc caggagccga cctgcctaca gacccgcctg 780
gagctgtaca agcagggcct gcggggcagc ctcaccaagc tcaagggccc cttgaccatg 840
atggccagcc actacaagca gcactgccct ccaaccccgg aaacttcctg tgcaacccag 900
attatcacct ttgaaagttt caaagagaac ctgaaggact ttctgcttgt catccccttt 960
gactgctggg agccagtcca ggagggaagc ggagctacta acttcagcct gctgaagcag 1020
gctggagacg tggaggagaa ccctggacct gatatcgcgg ccgcgatgtt ccatgtttct 1080
tttaggtata tctttggact tcctcccctg atccttgttc tgttgccagt agcatcatct 1140
gattgtgata ttgaaggtaa agatggcaaa caatatgaga gtgttctaat ggtcagcatc 1200
gatcaattat tggacagcat gaaagaaatt ggtagcaatt gcctgaataa tgaatttaac 1260
ttttttaaaa gacatatctg tgatgctaat aaggaaggta tgtttttatt ccgtgctgct 1320
cgcaagttga ggcaatttct taaaatgaat agcactggtg attttgatct ccacttatta 1380
aaagtttcag aaggcacaac aatactgttg aactgcactg gccaggttaa aggaagaaaa 1440
ccagctgccc tgggtgaagc ccaaccaaca aagagtttgg aagaaaataa atctttaaag 1500
gaacagaaaa aactgaatga cttgtgtttc ctaaagagac tattacaaga gataaaaact 1560
tgttggaata aaattttgat gggcactaaa gaacacggaa gcggagctac taacttcagc 1620
ctgctgaagc aggctggaga cgtggaggag aaccctggac ctatgagatc cagtcctggc 1680
aacatggaga ggattgtcat ctgtctgatg gtcatcttct tggggacact ggtccacaaa 1740
tcaagctccc aaggtcaaga tcgccacatg attagaatgc gtcaacttat agatattgtt 1800
gatcagctga aaaattatgt gaatgacttg gtccctgaat ttctgccagc tccagaagat 1860
gtagagacaa actgtgagtg gtcagctttt tcctgctttc agaaggccca actaaagtca 1920
gcaaatacag gaaacaatga aaggataatc aatgtatcaa ttaaaaagct gaagaggaaa 1980
ccaccttcca caaatgcagg gagaagacag aaacacagac taacatgccc ttcatgtgat 2040
tcttatgaga aaaaaccacc caaagaattc ctagaaagat tcaaatcact tctccaaaag 2100
gtatctacct taagtttcat tccatgggat atcggaagcg gagctactaa cttcagcctg 2160
ctgaagcagg ctggagacgt ggaggagaac cctggacctg aattcgagct catggtgagc 2220
aagggcgagg agctgttcac cggggtggtg cccatcctgg tcgagctgga cggcgacgta 2280
aacggccaca agttcagcgt gtccggcgag ggcgagggcg atgccaccta cggcaagctg 2340
accctgaagt tcatctgcac caccggcaag ctgcccgtgc cctggcccac cctcgtgacc 2400
accctgacct acggcgtgca gtgcttcagc cgctaccccg accacatgaa gcagcacgac 2460
ttcttcaagt ccgccatgcc cgaaggctac gtccaggagc gcaccatctt cttcaaggac 2520
gacggcaact acaagacccg cgccgaggtg aagttcgagg gcgacaccct ggtgaaccgc 2580
atcgagctga agggcatcga cttcaaggag gacggcaaca tcctggggca caagctggag 2640
tacaactaca acagccacaa cgtctatatc atggccgaca agcagaagaa cggcatcaag 2700
gtgaacttca agatccgcca caacatcgag gacggcagcg tgcagctcgc cgaccactac 2760
cagcagaaca cccccatcgg cgacggcccc gtgctgctgc ccgacaacca ctacctgagc 2820
acccagtccg ccctgagcaa agaccccaac gagaagcgcg atcacatggt cctgctggag 2880
ttcgtgaccg ccgccgggat cactctcggc atggacgagc tgtacaagta a 2931
<210> 14
<211> 976
<212> PRT
<213> Artificial Sequence
<400> 14
Met Arg Ile Ser Lys Pro His Leu Arg Ser Ile Ser Ile Gln Cys Tyr
1 5 10 15
Leu Cys Leu Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His
20 25 30
Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys Thr Glu Ala
35 40 45
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
50 55 60
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
65 70 75 80
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
85 90 95
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
100 105 110
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
115 120 125
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
130 135 140
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
145 150 155 160
Thr Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly
165 170 175
Asp Val Glu Glu Asn Pro Gly Pro Met Trp Leu Gln Ser Leu Leu Leu
180 185 190
Leu Gly Thr Val Ala Cys Ser Ile Ser Ala Pro Ala Arg Ser Pro Ser
195 200 205
Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg
210 215 220
Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu Met Asn Glu Thr
225 230 235 240
Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu
245 250 255
Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr
260 265 270
Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His
275 280 285
Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe
290 295 300
Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe
305 310 315 320
Asp Cys Trp Glu Pro Val Gln Glu Gly Ser Gly Ala Thr Asn Phe Ser
325 330 335
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Asp Ile
340 345 350
Ala Ala Ala Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro
355 360 365
Pro Leu Ile Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile
370 375 380
Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile
385 390 395 400
Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn
405 410 415
Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu
420 425 430
Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys
435 440 445
Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu
450 455 460
Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys
465 470 475 480
Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn
485 490 495
Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys
500 505 510
Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly
515 520 525
Thr Lys Glu His Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
530 535 540
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Arg Ser Ser Pro Gly
545 550 555 560
Asn Met Glu Arg Ile Val Ile Cys Leu Met Val Ile Phe Leu Gly Thr
565 570 575
Leu Val His Lys Ser Ser Ser Gln Gly Gln Asp Arg His Met Ile Arg
580 585 590
Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn
595 600 605
Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn
610 615 620
Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser
625 630 635 640
Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys
645 650 655
Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His
660 665 670
Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys
675 680 685
Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Val Ser Thr Leu
690 695 700
Ser Phe Ile Pro Trp Asp Ile Gly Ser Gly Ala Thr Asn Phe Ser Leu
705 710 715 720
Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Glu Phe Glu
725 730 735
Leu Met Val Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile
740 745 750
Leu Val Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser
755 760 765
Gly Glu Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe
770 775 780
Ile Cys Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr
785 790 795 800
Thr Leu Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met
805 810 815
Lys Gln His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln
820 825 830
Glu Arg Thr Ile Phe Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala
835 840 845
Glu Val Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys
850 855 860
Gly Ile Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu
865 870 875 880
Tyr Asn Tyr Asn Ser His Asn Val Tyr Ile Met Ala Asp Lys Gln Lys
885 890 895
Asn Gly Ile Lys Val Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly
900 905 910
Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp
915 920 925
Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala
930 935 940
Leu Ser Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu
945 950 955 960
Phe Val Thr Ala Ala Gly Ile Thr Leu Gly Met Asp Glu Leu Tyr Lys
965 970 975
<210> 15
<211> 2121
<212> DNA
<213> Artificial Sequence
<400> 15
atgagaattt cgaaaccaca tttgagaagt atttccatcc agtgctactt gtgtttactt 60
ctaaacagtc attttctaac tgaagctggc attcatgtct tcattttggg ctgtttcagt 120
gcagggcttc ctaaaacaga agccaactgg gtgaatgtaa taagtgattt gaaaaaaatt 180
gaagatctta ttcaatctat gcatattgat gctactttat atacggaaag tgatgttcac 240
cccagttgca aagtaacagc aatgaagtgc tttctcttgg agttacaagt tatttcactt 300
gagtccggag atgcaagtat tcatgataca gtagaaaatc tgatcatcct agcaaacaac 360
agtttgtctt ctaatgggaa tgtaacagaa tctggatgca aagaatgtga ggaactggag 420
gaaaaaaata ttaaagaatt tttgcagagt tttgtacata ttgtccaaat gttcatcaac 480
acttctggaa gcggagctac taacttcagc ctgctgaagc aggctggaga cgtggaggag 540
aaccctggac ctatgtggct gcagagcctg ctgctcttgg gcactgtggc ctgcagcatc 600
tctgcacccg cccgctcgcc cagccccagc acgcagccct gggagcatgt gaatgccatc 660
caggaggccc ggcgtctcct gaacctgagt agagacactg ctgctgagat gaatgaaaca 720
gtagaagtca tctcagaaat gtttgacctc caggagccga cctgcctaca gacccgcctg 780
gagctgtaca agcagggcct gcggggcagc ctcaccaagc tcaagggccc cttgaccatg 840
atggccagcc actacaagca gcactgccct ccaaccccgg aaacttcctg tgcaacccag 900
attatcacct ttgaaagttt caaagagaac ctgaaggact ttctgcttgt catccccttt 960
gactgctggg agccagtcca ggagggaagc ggagctacta acttcagcct gctgaagcag 1020
gctggagacg tggaggagaa ccctggacct gatatcgcgg ccgcgatgtt ccatgtttct 1080
tttaggtata tctttggact tcctcccctg atccttgttc tgttgccagt agcatcatct 1140
gattgtgata ttgaaggtaa agatggcaaa caatatgaga gtgttctaat ggtcagcatc 1200
gatcaattat tggacagcat gaaagaaatt ggtagcaatt gcctgaataa tgaatttaac 1260
ttttttaaaa gacatatctg tgatgctaat aaggaaggta tgtttttatt ccgtgctgct 1320
cgcaagttga ggcaatttct taaaatgaat agcactggtg attttgatct ccacttatta 1380
aaagtttcag aaggcacaac aatactgttg aactgcactg gccaggttaa aggaagaaaa 1440
ccagctgccc tgggtgaagc ccaaccaaca aagagtttgg aagaaaataa atctttaaag 1500
gaacagaaaa aactgaatga cttgtgtttc ctaaagagac tattacaaga gataaaaact 1560
tgttggaata aaattttgat gggcactaaa gaacacggaa gcggagctac taacttcagc 1620
ctgctgaagc aggctggaga cgtggaggag aaccctggac ctatgagatc cagtcctggc 1680
aacatggaga ggattgtcat ctgtctgatg gtcatcttct tggggacact ggtccacaaa 1740
tcaagctccc aaggtcaaga tcgccacatg attagaatgc gtcaacttat agatattgtt 1800
gatcagctga aaaattatgt gaatgacttg gtccctgaat ttctgccagc tccagaagat 1860
gtagagacaa actgtgagtg gtcagctttt tcctgctttc agaaggccca actaaagtca 1920
gcaaatacag gaaacaatga aaggataatc aatgtatcaa ttaaaaagct gaagaggaaa 1980
ccaccttcca caaatgcagg gagaagacag aaacacagac taacatgccc ttcatgtgat 2040
tcttatgaga aaaaaccacc caaagaattc ctagaaagat tcaaatcact tctccaaaag 2100
gtatctacct taagtttcat t 2121
<210> 16
<211> 707
<212> PRT
<213> Artificial Sequence
<400> 16
Met Arg Ile Ser Lys Pro His Leu Arg Ser Ile Ser Ile Gln Cys Tyr
1 5 10 15
Leu Cys Leu Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His
20 25 30
Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys Thr Glu Ala
35 40 45
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
50 55 60
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
65 70 75 80
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
85 90 95
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
100 105 110
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
115 120 125
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
130 135 140
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
145 150 155 160
Thr Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly
165 170 175
Asp Val Glu Glu Asn Pro Gly Pro Met Trp Leu Gln Ser Leu Leu Leu
180 185 190
Leu Gly Thr Val Ala Cys Ser Ile Ser Ala Pro Ala Arg Ser Pro Ser
195 200 205
Pro Ser Thr Gln Pro Trp Glu His Val Asn Ala Ile Gln Glu Ala Arg
210 215 220
Arg Leu Leu Asn Leu Ser Arg Asp Thr Ala Ala Glu Met Asn Glu Thr
225 230 235 240
Val Glu Val Ile Ser Glu Met Phe Asp Leu Gln Glu Pro Thr Cys Leu
245 250 255
Gln Thr Arg Leu Glu Leu Tyr Lys Gln Gly Leu Arg Gly Ser Leu Thr
260 265 270
Lys Leu Lys Gly Pro Leu Thr Met Met Ala Ser His Tyr Lys Gln His
275 280 285
Cys Pro Pro Thr Pro Glu Thr Ser Cys Ala Thr Gln Ile Ile Thr Phe
290 295 300
Glu Ser Phe Lys Glu Asn Leu Lys Asp Phe Leu Leu Val Ile Pro Phe
305 310 315 320
Asp Cys Trp Glu Pro Val Gln Glu Gly Ser Gly Ala Thr Asn Phe Ser
325 330 335
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Asp Ile
340 345 350
Ala Ala Ala Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro
355 360 365
Pro Leu Ile Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile
370 375 380
Glu Gly Lys Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile
385 390 395 400
Asp Gln Leu Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn
405 410 415
Asn Glu Phe Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu
420 425 430
Gly Met Phe Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys
435 440 445
Met Asn Ser Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu
450 455 460
Gly Thr Thr Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys
465 470 475 480
Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn
485 490 495
Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys
500 505 510
Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly
515 520 525
Thr Lys Glu His Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
530 535 540
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Arg Ser Ser Pro Gly
545 550 555 560
Asn Met Glu Arg Ile Val Ile Cys Leu Met Val Ile Phe Leu Gly Thr
565 570 575
Leu Val His Lys Ser Ser Ser Gln Gly Gln Asp Arg His Met Ile Arg
580 585 590
Met Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn
595 600 605
Asp Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn
610 615 620
Cys Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser
625 630 635 640
Ala Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys
645 650 655
Leu Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His
660 665 670
Arg Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys
675 680 685
Glu Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Val Ser Thr Leu
690 695 700
Ser Phe Ile
705
Claims (12)
1.一种重组病毒载体,所述重组病毒载体包含编码细胞因子的多核苷酸,所述细胞因子为人IL-15、人GM-CSF、人IL-7和人IL-21;所述编码细胞因子的多核苷酸的核酸序列如SEQ ID NO:15所示;所述病毒载体是痘苗病毒载体。
2.根据权利要求1所述的重组病毒载体,所述编码细胞因子的多核苷酸的核酸序列编码的氨基酸序列如SEQ ID NO:16所示。
3.根据权利要求1所述的重组病毒载体,其中,所述病毒载体为复制型痘苗病毒载体或者为非复制型痘苗病毒载体。
4.根据权利要求3所述的重组病毒载体,其中,所述复制型痘苗病毒载体为痘苗病毒天坛株。
5.根据权利要求4所述的重组病毒载体,其中,所述复制型痘苗病毒载体为752-1株。
6.根据权利要求3所述的重组病毒载体,其中,所述非复制型痘苗病毒载体为痘苗病毒减毒疫苗安卡拉株(Modified Vaccinia Ankara,MVA)。
7.一种免疫组合物,其包含预防和/或治疗有效量的根据权利要求1-6中任一项所述的重组病毒载体,以及药学上可接受的载体。
8.一种肿瘤疫苗,其包含预防和/或治疗有效量的根据权利要求1-6中任一项所述的重组病毒载体,以及药学上可接受的载体。
9.一种药盒,其包含根据权利要求1-6中任一项所述的重组病毒载体、根据权利要求7所述的免疫组合物或根据权利要求8所述的肿瘤疫苗,以及其使用说明。
10.根据权利要求1-6中任一项所述的重组病毒载体、根据权利要求7所述的免疫组合物或根据权利要求8所述的肿瘤疫苗在制备治疗和/或预防肿瘤的药物中的用途。
11.根据权利要求10所述的用途,其中,所述肿瘤为恶性肿瘤。
12.根据权利要求11所述的用途,其中,所述恶性肿瘤为乳腺癌或结肠癌。
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CN103038343A (zh) * | 2010-03-23 | 2013-04-10 | 英特瑞克斯顿股份有限公司 | 条件表达治疗蛋白的载体,包含所述载体的宿主细胞,及其应用 |
CN103110939A (zh) * | 2012-10-23 | 2013-05-22 | 郑州大学 | 诱导肿瘤特异性免疫的疫苗及其应用 |
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AU2003297155B2 (en) * | 2002-12-16 | 2010-03-18 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Recombinant vaccine viruses expressing IL-15 and methods of using the same |
EP1765988B1 (en) * | 2004-05-27 | 2017-09-20 | The Trustees of The University of Pennsylvania | Novel artificial antigen presenting cells and uses therefor |
JP2015523412A (ja) * | 2012-07-30 | 2015-08-13 | ワウ ヒン イェウング,アレックス | 腫瘍細胞、GM‐CSFのトランスジェニック発現を伴う腫瘍溶解性ウイルスベクター、および免疫チェックポイントモジュレーターなどの成分の少なくとも2種または全3種の同時投与により作られる生のinvivo腫瘍特異的がんワクチンシステム |
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JP2023514337A (ja) | 2023-04-05 |
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