CN110859968A - 激活对肿瘤的系统免疫反应的基因生物药物 - Google Patents

激活对肿瘤的系统免疫反应的基因生物药物 Download PDF

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CN110859968A
CN110859968A CN201911149314.7A CN201911149314A CN110859968A CN 110859968 A CN110859968 A CN 110859968A CN 201911149314 A CN201911149314 A CN 201911149314A CN 110859968 A CN110859968 A CN 110859968A
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余力
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Abstract

本发明公开了一种激活对肿瘤的系统免疫反应的基因生物药物，涉及生物医药领域。其有效成分包括至少一种表达载体和搭载在表达载体上且表达为人源T细胞共激活因子的外源基因片段；所述表达载体为复制型基因载体；所述人源T细胞共激活因子异位表达于肿瘤细胞表面，靶向系统免疫反应。本发明公开的一种激活对肿瘤的系统免疫反应的基因生物药物，含有表达人源T细胞共激活因子外源基因片段的溶瘤病毒载体。该药物实现T细胞共激活因子异位表达在肿瘤细胞膜上，并与T细胞表面的配体/受体相互作用，来活化肿瘤微环境中的无能T细胞，进而激活T细胞对肿瘤的系统免疫反应，用于癌症治疗。

Description

激活对肿瘤的系统免疫反应的基因生物药物
技术领域
本发明为生物医药领域，涉及一种激活对肿瘤的系统免疫反应的基因生物药物。
背景技术
癌症严重威胁人类健康。最新全球癌症统计，预计全球新增1810万例癌症病例，死亡人数达960万。中国是癌症发病和死亡大国。平均每天超过1万人被确诊为癌症。癌症负担呈持续上升态势，寻找更有效的治疗肿瘤方法面临着巨大挑战。
近几年，免疫疗法应运而生，成为抗癌斗争的强心剂。免疫系统对癌症的发生和发展至关重要。免疫系统中的B细胞和T细胞及其亚群是识别和清除癌细胞的主要力量。B细胞释放抗体以抵御有害的细胞。肿瘤反应性抗体可以与癌细胞结合，破坏它们的活性以及刺激针对它们的免疫应答。B细胞中的抗原呈递细胞(APC)在免疫反应的启动中发挥关键作用.APC消化外来或癌细胞并在其表面呈递其蛋白质(抗原)，帮助其他免疫细胞更好地识别并破坏有害细胞。此外，APC表达T细胞共激活因子，联同MHC抗原复合物，激活T细胞免疫应答。CD4+辅助T细胞释放一类淋巴因子，向其他免疫细胞(例如CD8+杀伤T细胞)发送“帮助”信号，以更好地指导其反应并确保它们尽可能快速有效地破坏有害细胞。一些CD4+T细胞还与产生抗体的B细胞交流，并保存对癌抗原的记忆。CD8+杀伤T细胞，摧毁感染的细胞和直接靶向破坏癌细胞。
T细胞完全激活需要两个信号。所有的T细胞反应都具有同源T细胞受体(TCR)的幼稚T细胞表达特异性表位。其与APC膜上的肽-MHC分子相互作用。通过TCR提供抗原特异性的第一信号不足以完全激活细胞，并且还会导致T细胞无能(T细胞无反应性或对同源抗原的低反应性)，T细胞缺失或产生免疫耐受。第二信号即共刺激信号是抗原非特异性的，是由APC膜上表达的共激活因子与T细胞之间的相互作用提供。双信号共刺激，对于T细胞增殖，分化和存活是必需的。已有大量研究表明，有效共刺激的存在对于免疫系统清除肿瘤至关重要。将T细胞共激活因子用于肿瘤治疗的临床实验也证实，T细胞共激活因子疫苗或这些因子的激动剂(抗体)能够有效的抑制肿瘤生长。
肿瘤微环境内通常存在无能(anergy)T细胞。这是因为肿瘤抗原变异或隐藏逃避了免疫监视；而一些癌细胞可以产生共抑制性分子来阻断APC与T细胞的相互作用或抑制T细胞对癌细胞的攻击，从而阻碍免疫反应。例如，研究已经证明几乎80％的肿瘤细胞组成性地产生了抑制性检查点CTLA-4(细胞毒性T淋巴细胞相关蛋白)。与调节淋巴器官中的T细胞活化相反，CTLA-4通过结合APC细胞上的刺激检查点CD80和CD86并通过中和T细胞上CD28受体的功能，抑制T细胞功能，且主要影响幼稚T细胞。另一类抑制性检查点PD-1/程序性死亡配体1或2(PD-L1或PD-L2)主要下调组织和肿瘤内的效应T细胞活性。此外，肿瘤微环境中缺乏由B细胞产生的共刺激信号，也导致无反应性T细胞的产生，并因此缺乏适当的抗肿瘤免疫应答。
发明内容
本发明公开了一种激活对肿瘤的系统免疫反应的基因生物药物，该药物通过携带有表达人源T细胞共激活因子的外源基因片段的RNA病毒载体在肿瘤微环境中表达T细胞共激活因子，实现T细胞共激活因子异位表达在肿瘤细胞膜上，并与T细胞表面的配体/受体相互作用，来活化肿瘤微环境中的无能T细胞，进而激活T细胞对肿瘤的系统免疫反应。
为实现以上发明目的，本发明提供以下技术方案：
一种激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：有效成分包括至少一种表达载体和搭载在表达载体上且表达为人源T细胞共激活因子的外源基因片段；所述表达载体为复制型基因载体；所述人源T细胞共激活因子异位表达于肿瘤细胞表面，激活肿瘤细胞微环境内无免疫应答的T细胞。
表达载体能感染肿瘤细胞，并在肿瘤细胞中自我复制，裂解肿瘤细胞；人源T细胞共激活因子，随着表达载体进入肿瘤细胞，表达载体在自我复制的同时，表达其携带的人源T细胞共激活因子，激活肿瘤微环境内无应答的T细胞。
进一步地，所述表达载体为溶瘤病毒或DNA质粒。
进一步地，所述溶瘤病毒为减毒或未减毒的病毒株、疫苗或非疫苗株、氨基酸突变或者非编码区核苷酸序列突变株、不同溶瘤病毒的组间膜蛋白杂交株中的任一种或者多种。专利201910705823.7中详述了所述不同溶瘤病毒的组间膜蛋白杂交株的得到过程，在此不一一详述。
所述溶瘤病毒通过基因工程减毒；所述人源T细胞共激活因子的基因片段通过基因工程插入溶瘤病毒的核苷酸序列中，且不影响溶瘤病毒的感染性，也不影响溶瘤病毒在感染肿瘤细胞中转录表达人源T细胞共激活因子。
进一步地，所述外源基因片段表达的人源T细胞共激活因子为原本在抗原呈递细胞表达的共激活T细胞因子。
进一步地，所述共激活T细胞因子为可特异激活不同类型的T细胞亚群的活化因子，包括CD80/86、ICOSL、OX40L、CD40、4-1BBL、CD70、CD30L、CD48中的任一种。
进一步地，所述T细胞亚群包括CD4细胞、CD8细胞、NK细胞、细胞毒性T细胞、淋巴因子T细胞、诱导性T细胞、辅助性T细胞中的任一种。
进一步地，所述人源T细胞共激活因子表达为多个活化T细胞因子同源或异源融合分子。
进一步地，所述外源基因片段表达的人源T细胞共激活因子为有功能活性的蛋白质或经过剪接修饰或突变的蛋白多肽。
所述人源T细胞共激活因子的功能活性对于激活T细胞有着必须的第二信号活性和对肿瘤的特异免疫反应。
进一步地，所述药物包括不同的表达载体和携带的表达为不同人源T细胞共激活因子的外源基因片段。
进一步地，治疗肿瘤适应症为黑色素瘤、肺癌、子宫颈癌、肺上皮细胞癌、前列腺癌、乳腺癌、肾癌、结肠癌或上皮癌。
进一步地，本发明公开的药物其化学结构性质为DNA/RNA或者感染性病毒颗粒的生物大分子；可以以DNA质粒或病毒两种制剂形式在肿瘤内给药，用于肿瘤的免疫治疗。
优选地，将几种包括不同表达载体和不同外源基因片段的药物制定在一个治疗疗程组里，最大化的激活对肿瘤的系统免疫。
本发明通过表达载体将T细胞共激活因子从APC移植到肿瘤细胞表面进行异位表达，激活T细胞；同时表达载体在肿瘤细胞内自我复制，反复感染裂解肿瘤细胞，暴露肿瘤抗原，提供了T细胞免疫应答的双信号，有效活化T细胞对肿瘤的免疫应答，进而治疗肿瘤。
图1本发明中溶瘤病毒在细胞中的复制和所搭载的人源T细胞共激活因子的表达；
图2本发明中小鼠药效实验免疫抑制结果；
图3本发明中小鼠药效实验肿瘤病理切片；
图4本发明中小鼠动物药效实验的抑制肿瘤率比较。
具体实施方式
下面结合附图，对本发明作详细的说明。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明中，人源T细胞共激活因子的表达部位和功能如下表所示。
Figure BDA0002283095100000041
表1人源T细胞共激活因子表达部位和功能
下述实施例中，采用的表达载体为黄热病毒，表达人源T细胞共激活因子的外源基因片段通过常规的基因工程方法插入不同类型的黄热病毒基因组里，且不影响黄热病毒的自我复制。
本发明用减毒的黄热病毒中的West Nile virus(WNV)作为载体，将外源基因片段按常规基因工程方法插入进了WNV基因组里。
其插入方法是：PCR合成各人或鼠源T细胞共激活因子的基因片段或者GFP基因片段,将这些基因片段分别连接于相同酶切割的减毒WNV cDNA中，插入的部位与Myrna CBonaldo，et al.2007.Virology Journal,4:115中黄热病毒(YF)17D/GFP的构建基本相同，插入后用免疫荧光法也检测到插入的外源基因在病毒感染细胞中的表达，如图1所示。
携带外源基因片段的溶瘤病毒治疗肿瘤药效的动物药效实验：
将表达人源T细胞共激活因子的不同外源基因片段基因：鼠源B7基因片段a、鼠源B7基因片段b、鼠源Icos-L基因片段c、鼠源CD48基因片段d分别插入WNV基因组中，并分别制备成：WN/Mc86-1溶液、WN/Mc86-2溶液、WN/MIcos-L溶液、WN/Mc48溶液。
于4-6周龄雌性小鼠(C57)的双侧背侧皮下接种肺癌LL2细胞，而建立了小鼠肺癌双侧背同源肿瘤模型.接种细胞约7天后，观察小鼠肿瘤生长约80mm3时(约7-9天)，进行动物药效实验：
将接种肺癌LL2细胞的小鼠随机分为3组，分别于右侧肿瘤瘤内注射给药。
对照组:注射100μl PBS。
实验组A:注射100ul载体DNA溶液，含WN/Mc86-1(WNV病毒携带有鼠源B7基因片段a).
实验组B:注射100ul载体DNA溶液，含200ug的WN/Mc86-2(WNV病毒携带鼠源B7基因片段b)
实验组C：注射100ul载体DNA溶液，含200ug的WN/MIcos-L(WNV病毒携带鼠源Icos-L基因片段c)
实验组D：注射100ul载体DNA溶液，含200ug的WN/Mc48(WNV病毒携带鼠源CD48基因片段d)
给药10天后观察小鼠，得到以下实验结果：
(1)所有9只成瘤小鼠,在给药后10天内均未观察到发病症状，30天内也没有死亡。
(2)给药结束后，对照组小鼠右侧肿瘤肿瘤平均体积：1309.85mm3，左侧肿瘤平均体积：1260.67mm3；实验组A小鼠在给药后第7天，右侧肿瘤消失，直至实验结束，肿瘤未复发，左侧肿瘤与对照组小鼠左侧肿瘤体积大小相比，无明显差异；实验组B小鼠左侧肿瘤几乎消失，右侧肿瘤与对照组小鼠右侧肿瘤体积大小相比，明显小于对照组。
给药结束后，剥离肿瘤组织进行HE染色。病理切片观察到：
对照组：左右两侧肿瘤细胞均分布致密，且细胞形态及大小不一致。核的大小形状和染色不均一，核染色质深，病理性核分裂象多见(病理性核分裂象：不对称性、多极性核分裂象)，细胞质嗜碱性蓝染。
实验组A：左侧肿瘤细胞与对照组肿瘤细胞病理表现基本一致，而右侧肿瘤细胞则出现较大面积肿瘤细胞坏死浅染区。光镜可见坏死区域细胞核固缩、核碎裂、核溶解及胞质呈嗜酸性红染，但组织结构的轮廓依然存在。
实验组B：右侧肿瘤细胞同样出现部分面积肿瘤细胞坏死浅染区，而左侧肿瘤组织病理切片结果显示，肿瘤细胞全部消失，光镜下只可见大量正常肌肉细胞。
给药结束时，测量小鼠肿瘤终体积。与对照组相对，携带了外源基因片段B7(CD86)、Icos-L、CD48的几组实验组，其左右侧肿瘤体积均明显小于对照组。
小鼠肺癌(LL2)的免疫治疗结论：
携带有外源基因片段(B7基因片段a)的WNV溶瘤病毒抑制了肺癌肿瘤生长(实验组A)。
携带有外源基因片段(B7基因片段b)的WNV溶瘤病毒清除了肺癌肿瘤(实验组B)。
携带有外源基因片段(Icos-L基因片段c和CD48基因片段d)的WNV溶瘤病毒具有抑制肿瘤生长的作用(实验组C和D)。
敏感小鼠实验证实，WNV溶瘤病毒药物的安全性。没有显示神经侵袭性疾病的证据，也没有出现发病死亡。
本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的组合。
序列表
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Claims (10)

1.一种激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：有效成分包括至少一种表达载体和搭载在表达载体上且表达为人源T细胞共激活因子的外源基因片段；所述表达载体为复制型基因载体；所述人源T细胞共激活因子异位表达于肿瘤细胞内，激活或增强对肿瘤的系统免疫反应。
2.根据权利要求1所述的激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：所述外源基因片段表达的人源T细胞共激活因子为天然在B细胞或抗原呈递细胞表达的T细胞共激活因子。
3.根据权利要求2所述的激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：所述外源基因片段表达的人源T细胞共激活因子有其相对应的T细胞受体/配体；所述活化T细胞因子为特异激活不同类型的T细胞亚群的活化因子，包括CD80/86、ICOSL、OX40L、CD40、4-1BBL、CD70、CD30L，CD48中的任一种。
4.根据权利要求3所述的激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：所述T细胞亚群包括CD4细胞、CD8细胞、NK细胞、细胞毒性T细胞、淋巴因子T细胞、诱导性T细胞、辅助性T细胞中的任一种。
5.根据权利要求1-4任一种所述的激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：所述人源T细胞共激活因子在肿瘤细胞内表达为各个活化T细胞因子的同源或异源融合分子。
6.根据权利要求5所述的对肿瘤的系统免疫反应的基因生物药物，其特征在于：所述外源基因片段表达的人源T细胞共激活因子在肿瘤细胞内表达为有功能活性的蛋白质或经过剪接修饰或突变的蛋白多肽。
7.根据权利要求1-4、6任一项所述的激活对肿瘤系统免疫反应的基因生物药物，其特征在于：所述表达载体为溶瘤病毒和/或质粒DNA载体；溶瘤病毒和/或质粒DNA载体以供价体分子携带并能够表达不同人源T细胞共激活因子外源基因片段。
8.根据权利要求7所述的激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：所述溶瘤病毒为减毒或未减毒的病毒株、疫苗或非疫苗株、氨基酸突变或者非编码区核苷酸序列突变株、不同溶瘤病毒的组间膜蛋白杂交株中的任一种或者多种。
9.根据权利要求1-4、7任一项所述的激活对肿瘤的系统免疫反应的基因生物药物，其特征在于：化学结构性质为DNA/RNA或者感染性病毒颗粒的生物大分子；可以以DNA质粒或病毒两种制剂形式在肿瘤内给药，用于肿瘤的免疫治疗。
10.根据权利要求1-4、6、8任一项所述的激活肿瘤微环境中T细胞免疫应答的基因生物药物，其特征在于：肿瘤为黑色素瘤、肺癌、子宫颈癌、肺上皮细胞癌、前列腺癌、乳腺癌、肾癌、结肠癌或上皮癌。
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CN111574611A (zh) * 2020-05-25 2020-08-25 南通大学 一种促进stat3活化的人源蛋白及其药物应用
CN111588843A (zh) * 2020-04-30 2020-08-28 四川骋誉生物制品有限公司 一种病毒抗原-免疫共激活因子的双分子dna疫苗
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