CN111743884A - 苄丝肼或其衍生物的用途 - Google Patents
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Abstract
本发明涉及医药技术领域，尤其涉及苄丝肼或其衍生物的用途。本发明研究表明苄丝肼或其衍生物能够抑制CRS引起的细胞因子水平的升高，抑制因CRS引起的体温升高，维持接受过继性免疫治疗动物的体重，缓解和/或治疗CRS。与现有技术中以抗体药物只能抑制一种细胞因子的活性的方案相比，本发明的技术方案的成本更低，能够同时抑制多种细胞因子的活性，且效果显著。
Description
技术领域
本发明涉及医药技术领域，尤其涉及苄丝肼或其衍生物的用途。
背景技术
近年来发展的利用基因改造技术表达肿瘤特异性嵌合抗原受体(Car)的T细胞治疗技术进展迅猛。Car T在临床上和临床试验中显示出良好的杀伤活性、靶向性和持久性，为肿瘤的治疗提供了新的有效解决方案，展示了巨大的应用潜力和发展前景，美国临床肿瘤学会将其评为2017年最大的研究突破。2017年8月31日FDA批准诺华制药Kymriah用于治疗复发或难治性儿童和年轻成人B细胞急性淋巴细胞白血病，2017年10月18日又批准了全球第二个CAR T疗法Yescarta上市。这些产品的上市使得Car T细胞疗法受到世人的瞩目。
CAR-T细胞技术的设计原理是使T细胞不需要依赖MHC分子和抗原呈递细胞(APC)，将识别肿瘤相关抗原(TAA)的单链抗体(scFv)、跨膜的共刺激结构域(如CD28和CD4-1BB)和T细胞的活化基序结合为一体，通过基因转导的方法转染T淋巴细胞，经基因修饰的T细胞通过表达单链抗体增强结合肿瘤细胞的能力，同时激活T细胞，使其增殖并激活其细胞毒活性，从而使其能特异性地识别和杀伤肿瘤细胞。
虽然Car T细胞疗法在肿瘤治疗领域取得了较大的进展，但是它在治疗过程中会产生较大的副作用：如细胞因子释放综合征(CRS)、神经毒性和脱靶效应等。其中，CRS是目前最常见、最严重的CAR-T细胞注射后免疫反应副作用，会导致患者血液细胞因子水平显著上升，出现发烧、头痛、腹泻、恶心、心动过速、低血压、缺氧、癫痫发作、精神混乱等症状，严重时可导致患者多器官衰竭和死亡。Car T导致细胞因子大量释放的机制尚不明确，可能包括过度活化的CAR-T细胞、死亡的肿瘤细胞、活化的巨噬细胞(以及其他先天免疫细胞)和血管内皮细胞等。目前在临床上用于防治细胞因子释放综合征的药物主要是抗白介素6(IL-6)的抗体托珠单抗(tocilizumab)、抗肿瘤坏死因子α(TNF-α)的抗体依那西普(etanercept)等。但这些抗体不仅价格昂贵，效果也非常有限。
苄丝肼是一种化学合成的酪氨酸羟化酶小分子抑制剂，其结构如式I。
它可以通过抑制酪氨酸羟化酶的活性而限制儿茶酚胺类物质的合成，但尚未见关于苄丝肼对CRS影响的报道。
发明内容
有鉴于此，本发明要解决的技术问题在于提供苄丝肼或其衍生物的用途，研究表明，苄丝肼或其衍生物能够缓解CRS。
本发明提供了苄丝肼或其衍生物在制备抑制细胞因子活性的制剂中的应用。
本发明中，所述细胞因子为血清淀粉样蛋白A、IL-6、IL-10和/或TNF-α。
具体的，本发明所述苄丝肼抑制的细胞因子活性为CRS中过度活化的细胞因子。
本发明还提供了苄丝肼或其衍生物在制备缓解和/或治疗CRS的药物中的应用。
本发明中，所述CRS为过继性免疫治疗引起的CRS。
本发明中，所述缓解和/或治疗CRS包括维持动物体重，抑制体温的升高，抑制血清中IL-6、IL-10、TNF-α水平，抑制血清淀粉样蛋白A水平。
一些实施例中，所述过继性免疫治疗的细胞为嵌合抗原受体的T细胞、嵌合抗原受体的NK细胞、肿瘤抗原特异性TCR转基因T细胞、肿瘤浸润性淋巴细胞、细胞因子诱导的杀伤性细胞或自然杀伤细胞。
具体实施例中，所述过继性免疫治疗为嵌合抗原受体的T细胞治疗技术。
一些实施例中，所述嵌合抗原受体的T细胞中：
T细胞来自自体T细胞、异体T细胞或iPSC诱导的T细胞；
其靶向CD19、BCMA、CD20、CD33、EGFR或Mesothelin。
本发明实施例中，所述Car T细胞为靶向CD19的Car T细胞。
本发明还提供了一种药物组合，其包括过继性免疫治疗的细胞和苄丝肼或其衍生物。
本发明中，所述过继性免疫治疗的细胞为嵌合抗原受体的T细胞、嵌合抗原受体的NK细胞、肿瘤抗原特异性TCR转基因T细胞、肿瘤浸润性淋巴细胞、细胞因子诱导的杀伤性细胞或自然杀伤细胞。
一些实施例中，所述嵌合抗原受体的T细胞中：
T细胞来自自体T细胞、异体T细胞或iPSC诱导的T细胞；
其靶向CD19、BCMA、CD20、CD33、EGFR或Mesothelin。
本发明所述药物组合物中，细胞、苄丝肼或其衍生物和混合存在也可相互独立存在。作为药物使用，二者可以同时给予，也可先后给予或以不同的给药方式给予。例如，细胞的给予方式为注射，而苄丝肼或其衍生物的给予方式为口服、静脉注射、皮下注射、肌肉注射、舌下给药、喷雾鼻腔给药等。
本发明所述的药物组合在制备治疗肿瘤的制剂中的应用。
本发明中，所述肿瘤包括：白血病、多发性骨髓瘤、恶性淋巴瘤、脑胶质瘤、肝癌、肺癌、胃癌、结肠癌、胰腺癌或乳腺癌。
本发明还提供了一种治疗肿瘤的方法，其为给予本发明所述的药物组合物。
本发明研究表明苄丝肼或其衍生物能够抑制CRS引起的细胞因子水平的升高，抑制因CRS引起的体温升高，维持接受过继性免疫治疗动物的体重，缓解和/或治疗CRS。与现有技术中以抗体药物只能抑制一种细胞因子的活性的方案相比，本发明的技术方案的成本更低，能够同时抑制多种细胞因子的活性，且效果显著。
具体实施方式
本发明提供了苄丝肼或其衍生物的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明采用的试材皆为普通市售品，皆可于市场购得。
本发明所述“苄丝肼的衍生物”还包括本领域技术人员能够通过简单的化学方法，如还原、取代等方法对于骨架上的侧链基团进行修饰，而仍然保留治疗Car T导致的CRS的各种衍生物。这些衍生物的合成方法可以参考现有技术中的教科书。同吋，苄丝肼的衍生物还包括其各种酸碱形式的盐、水合物、光学异构体等。
下面结合实施例，进一步阐述本发明：
实施例1
1.新生(0-2天)SGM3(NSG TgCMV-IL3,CSF2,KITLG1Eav/MloySzJ)小鼠亚致死剂量(150cGy)辐照，立即肝内注射1×105人脐带血CD34+细胞，制备nHuSGM3人源化小鼠。使用nHuSGM3人源化小鼠T细胞制备CD19 Car T细胞。
2.成年(6-8周)SGM3(NSG TgCMV-IL3,CSF2,KITLG1Eav/MloySzJ)小鼠亚致死剂量(200cGy)辐照，立即尾静脉注射1×105人脐带血CD34+细胞，制备HuSGM3人源化小鼠。
3.4周后，尾静脉注射2×106个由nHuSGM3人源化小鼠制备的CD19 Car T细胞。
4.注射Car T细胞后，立即每天腹腔注射苄丝肼10mg/kg或等体积的PBS，连续给药5天。
5.注射Car T细胞后，每天称量小鼠体重，测量小鼠的体温；每两天取血一次，测量血清中人IL-6、IL-10、TNF-α的含量和小鼠血清淀粉样蛋白A的含量。连续检测以上CRS相关指标21天。
结果表明：苄丝肼可以抑制多种细胞因子的活性，抑制血清淀粉样蛋白A的水平。抑制因CRS引起的体温升高，维持接受过继性免疫治疗动物的体重。
以上仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.苄丝肼或其衍生物在制备抑制细胞因子活性的制剂中的应用。
2.根据权利要求1所述的应用，其特征在于，所述细胞因子为血清淀粉样蛋白A、IL-6、IL-10和/或TNF-α。
3.苄丝肼或其衍生物在制备缓解和/或治疗CRS的药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述CRS为过继性免疫治疗引起的CRS。
5.根据权利要求4所述的应用，其特征在于，所述过继性免疫治疗的细胞为嵌合抗原受体的T细胞、嵌合抗原受体的NK细胞、肿瘤抗原特异性TCR转基因T细胞、肿瘤浸润性淋巴细胞、细胞因子诱导的杀伤性细胞或自然杀伤细胞。
6.根据权利要求5所述的应用，其特征在于，所述嵌合抗原受体的T细胞中：
T细胞来自自体T细胞、异体T细胞或iPSC诱导的T细胞；
其靶向CD19、BCMA、CD20、CD33、EGFR或Mesothelin。
7.一种药物组合，其包括过继性免疫治疗的细胞和苄丝肼或其衍生物。
8.根据权利要求7所述的药物组合，其特征在于，所述过继性免疫治疗的细胞为嵌合抗原受体的T细胞、嵌合抗原受体的NK细胞、肿瘤抗原特异性TCR转基因T细胞、肿瘤浸润性淋巴细胞、细胞因子诱导的杀伤性细胞或自然杀伤细胞。
9.根据权利要求8所述的药物组合，其特征在于，所述嵌合抗原受体的T细胞中：
T细胞来自自体T细胞、异体T细胞或iPSC诱导的T细胞；
其靶向CD19、BCMA、CD20、CD33、EGFR或Mesothelin。
10.权利要求7～9任一项所述的药物组合在制备治疗肿瘤的制剂中的应用。
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