CN108715603A - 一种治疗肿瘤的抗原肽链组及其在药物中的应用 - Google Patents
一种治疗肿瘤的抗原肽链组及其在药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种用于肿瘤个体化生物免疫治疗的抗原肽链组及其在药物中的应用，所述治疗肿瘤的抗原肽链组包括SEQ ID No：1‑101中的任意一种或至少两种氨基酸序列的组合。本发明的抗原肽链组能诱导产生肿瘤的树突状细胞，因而作为抗原呈递细胞的树突状细胞能将抗原信息呈递给T细胞，从而与T细胞相互作用，使T细胞产生特异性杀伤肿瘤细胞，起到杀伤肿瘤细胞的作用。
Description
技术领域
本发明属于恶性肿瘤生物免疫药物技术领域，特别涉及一种用于肿瘤个体化生物免疫治疗的抗原肽链组及其在药物中的应用。
背景技术
目前，全球恶性肿瘤发病率日趋上升，死亡率高，预后差。国家癌症中心全国肿瘤防治研究办公室在《国际癌症杂志》发布中国最大规模癌症生存数据汇总分析数据显示，中国癌症5年生存率为30.9％，远低于发达国家水平；同时农村患者的生存率仅为城市患者的一半。在发达国家，前列腺癌、乳腺癌占多数，在中国，肺癌、胃癌、肝癌等癌症更为常见，发病率和死亡率最高的癌症是肺癌。手术、化疗、放疗等传统治疗方法治疗效果有限，患者5年生存率仍较低；尤其是放化疗副反应大，患者生活质量差，生存率低。生物免疫治疗通过机体免疫系统性杀伤肿瘤细胞，是未来治疗肿瘤新的治疗方法，现已逐渐成为治疗肿瘤的热点。目前生物免疫治疗肿瘤的方法较多，包括普通的CIK细胞免疫治疗，DC用药治疗等，但其治疗效果并不显著，患者生存率没有得到明显提高。另有以非突变肿瘤高表达蛋白刺激的免疫细胞用药，研究有抗肿瘤免疫反应，但由于其非特异性表达，固然有副反应存在，包括视力模糊、听力下降、皮疹等。
发明内容
本发明的目的是提供一种用于肿瘤个体化生物免疫治疗的抗原肽链组及其在药物中的应用。
为此，本发明技术方案如下：
第一方面，本发明提供一种治疗肿瘤的抗原肽链组，所述治疗肿瘤的抗原肽链组包括SEQ ID No：1-101中的任意一种或至少两种氨基酸序列的组合，例如可以是SEQ IDNo：1-101中的任意一条、任意两条、任意三条、任意四条、任意五条直至任意100条或全部101条的组合，由于篇幅的限制在此不再全部列举。具体序列如表1所示：
表1 本发明的抗原肽链组
第二方面，本发明提供一种药物组合物，所述药物组合物包括如第一方面所述的SEQ ID No：1-101中的任意一种或至少两种氨基酸序列。
优选地，所述药物组合物为水性悬浮、溶液或固体状态。优选地，所述固体状态为未包衣或包衣片剂形式，例如丸剂、凝胶胶囊、胶囊或粉末等。
如果所述药物组合物处于干燥状态，则它可以与一种或多种惰性稀释剂例如淀粉、纤维素、蔗糖、乳糖或二氧化硅等混合。它在干燥状态下还可以包含其他物质，例如一种或多种润滑剂如硬脂酸镁或滑石粉、着色剂、包衣(糖包衣片剂)或清漆。如果本发明的药物组合物是液体形式，则它可以包括含有惰性稀释剂例如水、乙醇、甘油、植物油或液体石蜡的可药用的溶液、悬浮液、乳剂、糖浆剂和酏剂。所述药物组合物还可以包含除稀释剂以外的其他液体物质，例如润湿剂、甜味剂、增稠剂、调味剂或稳定剂产品。
优选地，还包括药学上接受的辅料。优选地，所述辅料为赋形剂、稀释剂、载体、调味剂、粘合剂和填充剂中的任意一种或至少两种的组合，例如可以是赋形剂，载体和稀释剂，调味剂、粘合剂和填充剂，或者稀释剂、载体、调味剂、粘合剂和填充剂的组合，由于篇幅的限制，所有组合的形式不再一一列举。
第三方面，本发明提供如第一方面所述的治疗肿瘤的抗原肽链组在制备治疗癌症的药物组合物中的应用。所述癌症为任意种类的癌症(即实体性恶性肿瘤)，因为本发明的抗原肽链组能诱导产生肿瘤特异性的树突状细胞，因而作为抗原呈递细胞的树突状细胞能将抗原信息呈递给T细胞，从而与T细胞相互作用，使T细胞产生特异性杀伤肿瘤细胞，从而起到杀伤肿瘤细胞的作用。
在本发明中，所述癌症优选为肺癌、乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤中的任意一种或至少两种的组合。另外，所述药物组合物还可与另一种或至少两种抗癌剂联合应用，例如芳香化酶抑制剂(来曲唑和/或阿那曲唑)等。
所述药物组合物可被单独使用或在给定的治疗中与其他药物联合使用，或者与放射疗法或手术联合。具体使用方法为：
(一)体内刺激法：将所述治疗肿瘤的抗原肽链组溶解于PH值为7.4PBS(Hyclone)溶液中，浓度调至2.5mg/ml，每次上臂皮下注射200ug后覆盖5％Aldara cream(iNovaPharmaceuticals Australia Pty Ltd.)，每周一次，12周为一个周期。
(二)体外刺激法：第0天：(1)使用COBE Spectra血液分析系统(Caridian BCT，Inc.美国)进行单核细胞分离采集过滤血量2500-3500ml；(2)准备1LDC-CM培养液，500mlX2份；(3)将细胞从4个离心管转移至500ml离心管内，并用10mlDC-CM冲洗原离心管，并转入500ml离心管，封盖，混匀；(4)用25ml吸管，加15mlDC-CM至每一个培养瓶；(5)加入IL-4和GM-CSF的浓度都是1000IU/ml；(6)稀释IL-4，用1％HAS在PBS里面至1000IU/ml。
第6天：加成熟混合液(7)用1％HSA-PBS稀释IL-1β、INF-α、IL-6至25ug/ml；(8)终浓度：IL-1β10ng/ml、INF-α10ng/ml、IL-6 15ng/ml；(9)稀释细胞因子于44mlDC-CM，至最后体积50ml；(10)用无菌吸管吸1ml含有细胞因子的DC-CM至每一个培养瓶；(11)把培养瓶放入培养箱(37℃，5％CO2；±10℃，±0.5％CO2)。
第7-8天：准备肽链脉冲培养液(PPM)(12)计算需要的PPM的量：培养瓶数量X30ml+300ml＝需要的PPM的量；(13)将培养瓶从培养箱取出，将瓶内细胞转移至500ml无菌离心管；(14)用30mlPPM冲洗培养瓶，并把冲洗液转入500ml离心管；(15)用2ml吸管转移所有的上清，并用25mlPPM重悬细胞，将收获的收获管DC细胞和冲洗管DC细胞合并入同一管，注明：DC细胞管；(16)取出1管冻存的一组个体化特异性突变肽链，用DC-PPM溶解肽链；(17)加肽链至DC管，浓度为5ug/ml；(18)松盖后放入培养箱(37℃,5％CO2；±10℃，±0.5％CO2)，每30min取出培养箱，混匀，总时间1.5小时；(19)取0.2ml重悬的DC细胞，转移至12X75mm管中，进行内毒素检测评估；(20)降速离心，1200rpm(309Xg)，7min，室温；(21)用2ml吸管去掉上清液；(22)收获个体化特异性DC细胞，计数并溶解于1mlPBS溶液中；(23)肿瘤引流淋巴结或其他内注射。
与现有技术相比，本发明提供的用于肿瘤个体化生物免疫治疗的抗原肽链组至少具有以下有益效果：本发明提供了一种治疗肿瘤的抗原肽链组及其在药物中的应用，所述治疗肿瘤的抗原肽链组包括SEQ ID No：1-101中的任意一种或至少两种氨基酸序列的组合。本发明的抗原肽链组能诱导产生肿瘤的树突状细胞，因而作为抗原呈递细胞的树突状细胞能将抗原信息呈递给T细胞，从而与T细胞相互作用，使T细胞产生特异性杀伤肿瘤细胞，起到杀伤肿瘤细胞的作用。用药至少6周后，通过仪器能明显观察到肿瘤大量消失，密度变淡，变化明显；副作用发生率小，对患者的伤害较少。
附图说明
图1为实施例1用药前后HLA*A3101—HVKITDFGR Tetramer染色图；
图2为实施例1用药前后的肿瘤CT扫描图；
图3为实施例2用药前后的肿瘤CT扫描图。
具体实施方式
下面结合附图及具体实施例对本发明做进一步的说明，但下述实施例绝非对本发明有任何限制。
实施例1
患者A，女，55岁。乳腺癌胸壁转移，多发肝转移，临床IV期，长春瑞滨单药化疗4次后进展，靶向药耐药，取肺部病灶组织活检，进行全外显子测序及HLA分型芯片检测后，患者携带HER2(ERBB2)20号外显子插入突变，HLA分型为HLA-A：A*3203A*3201；HLA-B:B*3012B*3101；HLA-C：C*0321C*0612；HLA-DQB1：DQB1*0202DQB1*1121；HLA-DRB1：DRB1*0201DRB1*0201。
使用本发明的特异性肿瘤抗原肽链SEQ ID No：1治疗，每周1次，共12周。检测注射抗原肽链组(以下简称“用药”)前后斑点检测特异性CD8+Tetramer+T细胞分泌情况，以及通过影像学观察用药前后12周的肿瘤大小变化，结果如图1和图2所示。
图1为HLA*A3101—HVKITDFGR Tetramer染色图，其中，图1-A为用药前染色图，CD8+Tetramer+T浓度为2.76％；图1-B为用药6周后染色图，CD8+Tetramer+T浓度为3.72％；图1-C为用药12周后染色图，CD8+Tetramer+T浓度为6.8％；从三组图中可以看出，斑点数量有明显升高的变化趋势，说明血液中肿瘤杀伤细胞CD8+Tetramer+T的比例(浓度)明显提高。
图2为用药前后右侧胸壁转移瘤CT图，其中图2-A为用药前CT图，为左肺门肿瘤，较大者2cm×5cm；图2-B为用药12周后CT图，可以看出肿瘤基本消失，仅为1×3cm，前后变化明显。
综合以上结果表明，本发明的抗原肽链组能诱导产生肿瘤的树突状细胞，作为抗原呈递细胞的树突状细胞能将抗原信息呈递给T细胞，与T细胞相互作用，使T细胞产生特异性杀伤肿瘤细胞，起到杀伤肿瘤细胞的作用，且效果明显。
实施例2
患者B，男，70岁，胃癌术后肺转移，奥沙利铂+卡培他滨方案化疗6个周，后进展。肺内转移穿刺活检进行全外显子测序及HLA分型芯片检测后，患者携带HER2(ERBB2)20号外显子插入突变，HLA分型为HLA-A：A*0302A*3501；HLA-B:B*0311B*3201；HLA-C：C*0332C*0501；HLA-DQB1：DQB1*0301DQB1*0320；HLA-DRB1：DRB1*0312DRB1*1222。
使用本发明的治疗肿瘤的抗原肽链SEQ ID No：2进行组合治疗，每周1次，共12周。
治疗前后肺部转移瘤大小变化情况如图3所示，由图3可见，用药治疗前，右肺转移瘤大小4cm×5cm(图3-A)；用药治疗后12周，右肺转移瘤基本消失(图3-B)，肿瘤较用药前明显缩小，仅为2cm×3cm，密度变淡。本实施例说明本发明的抗原肽链组能诱导产生肿瘤的树突状细胞，作为抗原呈递细胞的树突状细胞能将抗原信息呈递给T细胞，与T细胞相互作用，使T细胞产生特异性杀伤肿瘤细胞，起到杀伤肿瘤细胞的作用，且效果明显。
实施例3-101
实施例3-101取不同种类，不同程度的癌症患者，进行全外显子测序及HLA分型芯片检测后，患者均为携带HER2(ERBB2)20号外显子插入突变患者，分别使用不同的抗原肽链组的组合形式进行治疗，每周一次，共12周。实施例3-101的HLA*A3101—HVKITDFGRTetramer染色结果和治疗前后肺部肿瘤大小变化情况与实施例1-2类似，由于篇幅的限制，在此不再重复赘述。以上结果均可说明本发明的抗原肽链组能诱导产生肿瘤的树突状细胞，作为抗原呈递细胞的树突状细胞能将抗原信息呈递给T细胞，与T细胞相互作用，使T细胞产生特异性杀伤肿瘤细胞，起到杀伤肿瘤细胞的作用，且效果明显。
在对实施例1-101进行治疗期间，用ELISA检测用抗原肽链前、用药3周、7周、11周的特异性IFN-γ分泌情况，具体结果如表1所示。
对比例1-10
在对对比例1-10(进行全外显子测序及HLA分型芯片检测后，患者均为携带HER2(ERBB2)20号外显子插入突变患者)进行治疗期间，用ELISA检测用药前、用药3周、7周、11周的特异性IFN-γ分泌情况，具体结果如表2所示，用药量与实施例1-101相同；其中，对比例1-5不加入肽链。
从表2可以看出，实施例1-101在用药后11周，T细胞分泌的特异性IFN-γ水平具有明显升高的趋势，说明使用了本发明的抗原肽链组中的任意一条或其任意组合都能增加癌症患者外周血的肿瘤杀伤能力，进一步证明了本发明的效果。而对比例1-10中，IFN-γ水平在用药前后也有所增加，可能是加入的营养成分作用的结果，但总体来看浓度的增量远低于实施例1-101，说明其并未增加患者外周血的肿瘤杀伤能力或血液杀伤肿瘤的能力远低于实施例1-101，进一步证明了本发明的效果。
表2 IFN-γ分泌统计列表
随后，对实施例1-101的副反应发生率进行了统计，结果如表2所示，从表2可以看出，在使用了本发明的抗原肽链组后，副反应的发生率(即阳性比率)较低，说明其副作用较小，对患者的影响和伤害较低。
表2 副反应发生率统计结果
应该注意到并理解，在不脱离后附的权利要求所要求的本发明的精神和范围的情况下，能够对上述详细描述的本发明做出各种修改和改进。因此，要求保护的技术方案的范围不受所给出的任何特定示范教导的限制。
申请人声明，以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。
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Claims (7)
1.一种治疗肿瘤的抗原肽链组，其特征在于，所述治疗肿瘤的抗原肽链组包括SEQ IDNo：1-101中的任意一种或至少两种氨基酸序列的组合。
2.一种药物组合物，其特征在于，所述药物组合物包括权利要求1所述的SEQ ID No：1-101中的任意一种或至少两种氨基酸序列。
3.根据权利要求2所述的药物组合物，其特征在于，所述药物组合物为水性悬浮、溶液或固体状态。
4.根据权利要求3所述的药物组合物，其特征在于，所述固体状态为未包衣或包衣片剂形式。
5.根据权利要求2-4中任一项所述的药物组合物，其特征在于，还包括药学上接受的辅料。
6.根据权利要求5所述的药物组合物，其特征在于，所述辅料为赋形剂、稀释剂、载体、调味剂、粘合剂和填充剂中的任意一种或至少两种的组合。
7.根据权利要求1所述的治疗肿瘤的抗原肽链组在制备治疗癌症的药物组合物中的应用。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1597953A (zh) * | 1995-03-31 | 2005-03-23 | 华盛顿大学 | 用于预防或治疗恶性肿瘤的HER－2/neu蛋白胞内区 |
| WO2016202963A2 (en) * | 2015-06-19 | 2016-12-22 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer and other cancers |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1597953A (zh) * | 1995-03-31 | 2005-03-23 | 华盛顿大学 | 用于预防或治疗恶性肿瘤的HER－2/neu蛋白胞内区 |
| WO2016202963A2 (en) * | 2015-06-19 | 2016-12-22 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer and other cancers |
Non-Patent Citations (2)
| Title |
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| WANG 等: "Human tumor antigens for cancer vaccine development", 《IMMUNOLOGICAL REVIEWS》 * |
| 杨帆 等: "肿瘤抗原肽及CTL杀伤机理的研究进展", 《中国肿瘤》 * |
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