CN111867598A - 肿瘤免疫赋活剂 - Google Patents
肿瘤免疫赋活剂 Download PDFInfo
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- CN111867598A CN111867598A CN201980018999.3A CN201980018999A CN111867598A CN 111867598 A CN111867598 A CN 111867598A CN 201980018999 A CN201980018999 A CN 201980018999A CN 111867598 A CN111867598 A CN 111867598A
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- tetracycline
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Abstract
本发明提供一种廉价的肿瘤免疫治疗药物。利用选自四环素系化合物及其药学上可接受的盐中的至少一种,能够激活肿瘤免疫。
Description
技术领域
本说明书中公开一种肿瘤免疫赋活剂。
背景技术
目前,作为癌症免疫疗法,在临床实践中使用以抗PD-1抗体为代表的免疫检查点抑制疗法,发挥效果,暗示其有用性。
此外,非专利文献1和2中公开了通过将化学修饰型四环素向肿瘤细胞投予而抑制肿瘤细胞的增殖,引起细胞杀伤。
现有技术文献
非专利文献
非专利文献1:Anticancer Drugs 2013Sep;24(8)799-809
非专利文献2:Curr Med Chem 2001Feb;8(3)271-279
发明内容
发明要解决的技术问题
然而,免疫检查点抑制剂仅仅对一部分的患者群有效,预测能够起效的患者的生物标志也尚处于开发途中。而且,免疫检查点抑制剂还存在药价非常昂贵的问题。作为其他癌症免疫疗法正在推进开发的嵌合抗原受体(CAR)基因改变T细胞疗法也是非常昂贵的治疗法,其价格成为实用化的障碍。从这种现状考虑,开发廉价且对更多癌症患者有效的免疫疗法是紧要的课题。
用于解决技术问题的技术方案
鉴于这种状况,本发明的发明人从专利权有效期已终止的现有药物中,发现了四环素系化合物对肿瘤免疫的赋活有效。
本说明书中所公开的发明就是基于该知识完成的,包括以下的方式。
项1.一种肿瘤免疫赋活剂,其含有选自下述通式(I)所示的四环素系化合物及其药学上可接受的盐中的至少一种:
[式中,
R1为下述通式(II)所示的基团(R8为氢原子或碳原子数1~3的低级烷基)、或碳原子数1~3的低级烷基:
R2为下述通式(III)所示的基团(R9为碳原子数1~3的低级烷基或氢原子):
R3为氢原子、羟基或碳原子数1~3的低级烷基。
R4和R5均为或者独立地为氢原子、羟基或碳原子数1~3的低级烷基,或者R4和R5一体成为亚甲基。
R6为氢原子、卤素或下述通式(IV)所示的基团(R10为氢原子、或碳原子数1~3的低级烷基):
R7为氢原子、碳原子数1~3的低级烷基、-NH-CO-CH2-NH-C(CH3)3或-CH2-NH-CH2-C(CH3)3。]。
项2.如项1所述的肿瘤免疫赋活剂,其中,上述碳原子数1~3的低级烷基为甲基。
项3.如项1所述的肿瘤免疫赋活剂,其中,上述通式(I)所示的化合物为选自去甲基金霉素、甲氯环素、四环素、金霉素、多西环素、米诺环素和土霉素中的至少一种。
项4.如项1~3中任一项所述的肿瘤免疫赋活剂,其用于与抗肿瘤药物进行联用。
项5.如项4所述的肿瘤免疫赋活剂,其中,上述抗肿瘤药物为肿瘤免疫药物。
项6.如项5所述的肿瘤免疫赋活剂,其中,上述肿瘤免疫药物为选自免疫检查点抑制剂、CAR-T细胞药物、双特异性分子药物、癌症疫苗中的至少一种。
项7.一种肿瘤治疗用组合物,其含有项1~3中任一项所述的肿瘤免疫赋活剂和肿瘤免疫药物。
项8.如项7所述的肿瘤治疗用组合物,其中,上述肿瘤免疫药物为选自免疫检查点抑制剂、CAR-T细胞药物、双特异性分子药物、癌症疫苗中的至少一种。
发明的效果
利用四环素系化合物,能够激活肿瘤免疫。
附图说明
[图1]图1表示在体外(in vitro)评价T细胞的抗肿瘤活性的系统的概要。
[图2]图2表示被检验药对体外(in vitro)的T细胞的抗肿瘤活性的效果。“BiTE”表示BiTE的单独添加;“BiTE+DMC”表示BiTE和去甲基金霉素(DMC)的联用添加。
[图3]图3表示被检验药对体外的CD8+T细胞的肿瘤细胞杀伤活性的效果。“BiTE”表示BiTE的单独添加;“BiTE+DMC”表示BiTE和DMC的联用添加。
[图4]图4表示被检验药对体外(in vitro)的颗粒酶B表达CD8+T细胞的存在比率的效果。“BiTE”表示BiTE的单独添加;“BiTE+DMC”表示BiTE和DMC的联用添加。
[图5]图5表示被检验药对体外(in vitro)的CD8+T细胞的增殖能力的效果。“BiTE”表示BiTE的单独添加;“BiTE+DMC”表示BiTE和DMC的联用添加。
[图6]图6表示被检验药对体外(in vitro)的CMV(巨细胞病毒)特异性细胞毒性T细胞的诱导的效果。A表示CMV处理后第7天和第14天的FACS解析的散点图。CMV四聚体+(CMVTetramer+)细胞分级到P7分级中。B表示CMV处理后第14天的CMV四聚体+细胞的存在比率。
[图7]图7A表示被检验药对体外(in vitro)的肺癌组织内T细胞的细胞杀伤活性的效果。图7B表示被检验药对体外(in vitro)的IFNγ产生CD8+T细胞的存在比率的效果。图7C表示FACS解析的散点图。IFNγ产生CD8+T细胞分级在P8分级中。
[图8]图8A表示被检验药的投予方案(protocol)。图8B表示肿瘤体积的变化。在图8B中,虚线表示溶剂对照(Vehicle)组,实线表示被检验药投予组。
[图9]表示去甲基金霉素和抗PD-L1抗体的联用效果。p表示显著性差异。
[图10]表示去甲基金霉素对免疫检查点抑制剂的抗肿瘤作用的增强效果依赖于CD8+T细胞的图。p表示显著性差异。
[图11]表示去甲基金霉素对小鼠外周血中的癌抗原特异性CD8阳性T细胞的存在比率的效果。p表示显著性差异。
具体实施方式
1.肿瘤免疫赋活剂
本说明书中,肿瘤免疫赋活剂含有四环素系化合物或其药学上可接受的盐作为有效成分。
肿瘤的种类没有特别限制。可以是良性肿瘤或恶性肿瘤。优选为恶性肿瘤。此外,肿瘤包括上皮性肿瘤和非上皮性肿瘤,优选为上皮性肿瘤。在本发明中,作为肿瘤最优选为上皮性恶性肿瘤。
作为恶性肿瘤,例如可以列举:从气管、支气管或肺等发生的呼吸器官系恶性肿瘤;头颈部癌;从食管、胃、十二指肠、空肠、回肠、盲肠、阑尾、升结肠、横结肠、乙状结肠、直肠或肛门部等发生的消化道系恶性肿瘤;肝癌;胰腺癌;从膀胱、输尿管或肾脏发生的泌尿器官系恶性肿瘤;从卵巣、输卵管和子宫等发生的女性生殖器官系恶性肿瘤;乳癌:前列腺癌;皮肤癌;下丘脑、垂体、甲状腺、甲状旁腺、肾上腺等的内分泌系恶性肿瘤;中枢神经系恶性肿瘤;从骨软组织发生的恶性肿瘤等的实体肿瘤、以及骨髓增生异常综合征、急性淋巴性白血病、急性骨髄性白血病、慢性淋巴性白血病、慢性骨髄性白血病、急性骨髄单核细胞性白血病、慢性骨髄单核细胞性白血病、急性单核细胞性白血病、慢性单核细胞性白血病、急性全髄性白血病、急性巨核细胞白血病、红白血病、嗜酸性粒细胞性白血病、慢性嗜酸性粒细胞性白血病、慢性中性粒细胞性白血病、成人T细胞白血病、毛细胞白血病、浆细胞性白血病、多发性骨髓瘤、恶性淋巴瘤等造血系恶性肿瘤;淋巴系恶性肿瘤等的造血器官肿瘤。更优选为肺癌(鳞状细胞癌、小细胞癌、大细胞癌、腺癌)等的呼吸器官系上皮性恶性肿瘤、恶性胸膜间皮瘤;头颈部癌;食管癌、胃癌、大肠癌(乙状结肠癌、直肠癌等)等的消化道系上皮性恶性肿瘤;肝癌;胰腺癌;肾细胞癌;膀胱癌;恶性黑色素瘤;经典型霍奇金淋巴瘤;卵巣癌;乳癌;前列腺癌。最优选为肺癌。
肿瘤免疫可以认为是基于T细胞对肿瘤细胞的杀伤活性的机体抗肿瘤反应。因此,也可以说所谓激活肿瘤免疫即为提高T细胞对肿瘤细胞的细胞杀伤活性。
本发明中使用的四环素化合物并不用于如非专利文献1和2所述那样直接对肿瘤细胞发挥增殖抑制作用或细胞杀伤作用。如后述的实施例中所示,是具有增强T细胞的肿瘤细胞杀伤活性的作用的物质。
四环素系化合物例如可以例示下述通式(I)所示的化合物。
[式中,
R1为下述通式(II)所示的基团(R8为氢原子或碳原子数1~3的低级烷基)、或碳原子数1~3的低级烷基:
R2为下述通式(III)所示的基团(R9为碳原子数1~3的低级烷基或氢原子):
R3为氢原子、羟基、或碳原子数1~3的低级烷基。
R4和R5均为或者独立地为氢原子、羟基或碳原子数1~3的低级烷基,或者R4和R5一体成为亚甲基。
R6为氢原子、卤素或下述通式(IV)所示的基团(R10为氢原子或碳原子数1~3的低级烷基):
R7为氢原子、碳原子数1~3的低级烷基、-NH-CO-CH2-NH-C(CH3)3或-CH2-NH-CH2-C(CH3)3。]。
作为碳原子数1~3的低级烷基,可以例示甲基、乙基、丙基和异丙基。优选为甲基或乙基,更优选为甲基。
卤素没有特别限制。例如可以列举氯原子、氟原子、溴原子和碘原子等。优选为氯原子。
作为四环素系化合物,优选为选自下述表1所记载的四环素化合物中的至少一种。
[表1]
作为四环素系化合物,更优选为选自去甲基金霉素、甲氯环素、四环素、金霉素、多西环素、米诺环素和土霉素中的至少一种。
本说明书中公开的四环素系化合物及其盐是公知的。因此,四环素系化合物及其盐的制造方法也是公知的。
四环素系化合物的盐只要是药学上可接受的盐就没有限制。例如,就盐而言,包含胺或其他碱性基团的四环素系化合物的酸盐能够通过使四环素系化合物与合适的有机或无机酸反应而生成阴离子盐来制造。作为阴离子盐的示例,包括:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、乙二胺四乙酸钙、樟磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、乙二胺四乙酸盐、乙二磺酸盐、依托酸盐(estolate)、乙磺酸盐(esylate)、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、乙醇酰阿散酸盐(glycollylarsanilate)、己基间苯二酚酸盐、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、硫酸二甲酯、半乳糖二酸盐(mucate)、萘磺酸盐(napsylate)、硝酸盐、扑酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱性乙酸盐、琥珀酸盐、硫酸盐、丹宁酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐和三乙基碘(triethiodide)盐等。作为盐,优选为盐酸盐或二盐酸盐。
四环素系化合物可以通过与合适的碱反应而生成阳离子盐。阳离子盐可以利用能够提供药学上可接受的阳离子的碱来制作,包括碱金属盐(特别是钠和钾)、碱土金属盐(特别是钙和镁)、铝盐和铵盐、以及三甲胺、三乙胺、吗啉、吡啶、哌啶、皮考啉、二环己基胺、N,N’-二苄基乙二胺、2-羟基乙胺、双-(2-羟基乙基)胺、三-(2-羟基乙基)胺、普鲁卡因、二苄基哌啶、脱氢、N,N’-双脱氢枞胺、葡糖胺、N-甲基葡糖胺、可力丁、奎宁、喹啉、以及赖氨酸和精氨酸等碱性氨基酸等的盐。
肿瘤免疫赋活剂含有四环素系化合物或其药学上可接受的盐。肿瘤免疫赋活剂可以将四环素系化合物或其药学上可接受的盐与适当的载体或添加剂组合来制备。作为该肿瘤免疫赋活剂的制备中使用的载体或添加剂,可以例示依据肿瘤免疫赋活剂的剂型而通常在药剂中通用的各种物质,例如赋形剂、结合剂、崩解剂、润滑剂、着色剂、矫味剂、矫臭剂、表面活性剂等。
上述肿瘤免疫赋活剂为口服投予方式时的剂型没有特别限制,可以例示片剂、散剂、颗粒剂、胶囊剂(包括硬质胶囊剂和软质胶囊剂)、液剂、丸剂、悬浮剂和乳剂等。此外,上述肿瘤免疫赋活剂为非经口投予方式时,可以例示注射剂、点滴剂、栓剂、滴鼻剂和经肺投予剂等。
在上述肿瘤免疫赋活剂为片剂、散剂、颗粒剂、丸剂、胶囊剂等口服用固态组合物的情况下,在制备时,作为载体,例如可以使用:乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素、硅酸、甲基纤维素、甘油、藻酸钠、阿拉伯胶等赋形剂;单糖浆、葡萄糖液、淀粉液、明胶溶液、聚乙烯醇、聚乙烯醚、聚乙烯吡咯烷酮、羧甲基纤维素、虫胶、甲基纤维素、乙基纤维素、水、乙醇、磷酸钾等结合剂;干燥淀粉、藻酸钠、琼脂粉、昆布多糖粉、碳酸氢钠、碳酸钙、聚氧亚乙基脱水山梨糖醇脂肪酸酯类、月桂基硫酸钠、硬脂酸单甘油酯、淀粉、乳糖等崩解剂;白糖、硬脂酸、可可脂、氢化油等崩解抑制剂;月桂基硫酸钠等吸收促进剂;甘油、淀粉等保湿剂;淀粉、乳糖、高岭土、膨润土、胶体状硅酸等吸附剂;精制滑石、硬脂酸盐、硼酸粉、聚乙二醇等润滑剂等。此外,片剂可以根据需要制成施有通常的包层的片剂,例如糖衣片、明胶包衣片、肠溶包片、薄膜包衣片、双重片、多层片等。
在上述肿瘤免疫赋活剂为丸剂的口服用固态组合物的情况下,在制备时,作为载体,例如可以使用:葡萄糖、乳糖、淀粉、可可脂、硬化植物油、高岭土、滑石等赋形剂;阿拉伯胶粉、黄芪胶粉、明胶等结合剂;昆布多糖、琼脂等崩解剂等。
在上述肿瘤免疫赋活剂为胶囊剂的口服用固态组合物的情况下,在制备时,胶囊剂通过将有效成分与上述所例示的各种载体混合并填充在硬质胶囊或软质胶囊等中来制备。
在上述制剂为液剂的情况下,可以为水性或油性的悬浮液、溶液、糖浆、酏剂,使用通常的添加剂并按照常用方法制备。
在上述肿瘤免疫赋活剂为注射剂的情况下,在制备时,作为载体,例如可以使用水、乙醇、聚乙二醇、丙二醇、乙氧基化异硬脂醇、聚氧化异硬脂醇、聚氧亚乙基脱水山梨糖醇脂肪酸酯类等稀释剂;柠檬酸钠、乙酸钠、磷酸钠等pH调整剂;磷酸二钾、磷酸三钠、磷酸氢钠、柠檬酸钠等缓冲剂;焦亚硫酸钠、EDTA、硫代甘醇酸、硫代乳酸等稳定剂;作为冻结干燥时的成形剂,例如可以使用甘露醇、肌醇、麦芽糖、蔗糖、半乳糖等糖类。另外,此时为了调整等渗性的溶液,可以使制剂中含有充分量的葡萄糖或者甘油,或者也可以添加通常的溶解辅助剂、无痛化剂、局部麻醉剂等。添加这些载体,能够利用常用方法制造皮下、肌肉内、静脉内用注射剂。
在上述制剂为点滴剂的情况下,可以将投予化合物溶解于以生理盐水、林格氏液等为基本的等渗电解质输液制剂中来制备。
本发明的肿瘤免疫赋活剂可以为口服用组合物和非口服用组合物中的任意种组合物,优选为口服用组合物。
肿瘤免疫赋活剂所含的四环素系化合物或其药学上可接受的盐既可以为一种,也可以为多种。即,肿瘤免疫赋活剂含有选自四环素系化合物及其药学上可接受的盐中的至少一种即可。
四环素系化合物或其药学上可接受的盐的投予量是公知的。因此,肿瘤免疫赋活剂的投予量也可以由公知的四环素系化合物的投予量进行换算来决定。例如,四环素系化合物或其药学上可接受的盐的投予量,在口服投予的情况下为每1天0.1mg~1,000mg/kg(成人)、或每1天0.02mg~100mg/kg(小儿)左右。在注射或静脉点滴的情况下为每1天0.1mg~500mg/kg(成人)、或每1天0.02mg~50mg/kg(小儿)左右。投予量可以依据年龄、症状、肿瘤的大小、其他药剂的投予状况等来适宜调整。在组合两种以上的四环素系化合物及其药学上可接受的盐进行投予的情况下,优选四环素系化合物或其药学上可接受的盐的总量为上述投予量。
四环素系化合物或其药学上可接受的盐可以与其他的药剂联用。可以联用的其他药剂没有特别限制,优选为抗肿瘤药物。
作为抗肿瘤药物,例如可以列举一般用作抗癌剂的药物,可以从烷基化剂、代谢拮抗剂、抗肿瘤性抗生物质、微小血管抑制剂、激素或激素类似药、铂制剂、拓扑异构酶抑制剂、细胞因子、抗体药物、肿瘤免疫药物(放射免疫疗法药物、非特异性免疫激活药物、免疫检查点抑制剂、CAR-T细胞药物、BiTE药物、癌症疫苗等)、分子靶向药物和其他抗肿瘤药物中,依据作为对象的肿瘤来适宜选择。
不限定于下述药剂,作为烷基化药,例如可以例示环磷酰胺、异环磷酰胺、白消安、美法仑、苯达莫司汀盐酸盐、尼莫司汀盐酸盐、雷莫司汀、达卡巴嗪、丙卡巴肼盐酸盐替莫唑胺等;作为代谢拮抗剂,可以例示甲氨蝶呤、培美曲塞钠、氟尿嘧啶、脱氧氟尿苷、卡培他滨、替加氟、阿糖胞苷、阿糖胞苷十八烷基磷酸盐水合物、依诺他滨、吉西他滨盐酸盐、巯基嘌呤水合物、氟达拉滨磷酸酯、奈拉滨、喷司他丁、克拉屈滨、左亚叶酸钙、亚叶酸钙、羟基脲、L-门冬酰胺酶、氮胞苷等;作为抗肿瘤性抗生物质,可以例示多柔比星盐酸盐、道诺霉素盐酸盐、吡柔比星、表柔比星盐酸盐、伊达比星盐酸盐、阿克拉霉素盐酸盐、氨柔比星盐酸盐、米托蒽醌盐酸盐、丝裂霉素C、放线菌素D、博来霉素、培洛霉素硫酸盐、净司他丁斯酯等;作为微小血管抑制剂,可以例示长春新碱硫酸盐、长春花碱硫酸盐、长春地辛硫酸盐、长春瑞滨酒石酸盐、紫杉醇、多西他赛水合物、艾日布林甲磺酸盐等;作为激素或激素类似药(激素剂),可以例示阿那曲唑、依西美坦、来曲唑、他莫昔芬柠檬酸盐、托瑞米芬柠檬酸盐、氟维司群、氟他胺、比卡鲁胺、甲羟孕酮乙酸酯、雌莫司汀磷酸酯钠水合物、戈舍瑞林乙酸盐、亮丙瑞林乙酸盐等;作为铂制剂,可以例示顺铂、米铂水合物、碳铂、奈达铂、奥沙利铂等;作为拓扑异构酶抑制剂,可以例示伊立替康盐酸盐水合物和拓扑替康盐酸盐等拓扑异构酶I抑制剂、以及依托泊苷和索布佐生等拓扑异构酶II抑制剂;作为细胞因子,可以例示干扰素γ1a、替西白介素、西莫白介素等;作为抗体药物,可以例示曲妥珠单抗、利妥昔单抗、吉妥珠单抗奥唑米星、贝伐单抗、西妥昔单抗、帕尼单抗、阿仑珠单抗等;作为放射免疫疗法药物,可以例示ibritumomab、tiuxetan配合剂(替伊莫单抗)等;作为分子靶向药物,可以例示吉非替尼、伊马替尼甲磺酸盐、硼替佐米、厄洛替尼盐酸盐、索拉非尼甲苯磺酸盐、舒尼替尼苹果酸盐、沙利度胺、尼罗替尼盐酸盐水合物、达沙替尼水合物、拉帕替尼甲苯磺酸盐水合物、依维莫司、来那度胺水合物、地塞米松、坦罗莫司、伏林司他、维甲酸和他米巴罗汀等;作为非特异性免疫激活药物,可以例示OK-432、干燥BCG、云芝多糖体制剂、香菇多糖、乌苯美司等;作为免疫检查点抑制剂,可以例示阿替利珠单抗(Atezolizumab)、纳武利尤单抗(Nivolumab)、帕博利珠单抗(Pembrolizumab)、伊只单抗(Ipilimumab)、度伐鲁单抗(Durvalumab)、阿维鲁单抗(Avelumab)、替西木单抗(Tremelimumab)等;作为CAR-T细胞药物,可以例示Tisagenlecleucel等;作为双特异性分子药物,可以例示博纳吐单抗(Blinatumomab)等的BiTE(商标)药;作为癌症疫苗,可以例示Sipuleucel-T等;其他可以例示醋葡醛内酯、卟吩姆钠、他拉泊芬钠、乙醇、三氧化砷等。其中,所谓双特异性分子,是指在一个分子内具有与肿瘤细胞中存在的至少一种表面抗原结合的抗原结合区域、以及与T细胞中存在的表面抗原的至少一种结合的抗原结合区域的分子。与表面抗原的至少一种结合的抗原结合区域,相对于1个抗原可以存在1个或2以上。例如,与表面抗原的至少一种结合的抗原结合区域,可以是同种Fab区域的组合、同种可变区域的组合、同种sc-Fv的组合、来源于1种抗体的重链Fab区域和轻链Fab区域的组合、来源于1种抗体的重链可变区域和轻链可变区域的组合、来源于1种抗体的重链sc-Fv的组合。T细胞的表面抗原只要存在于T细胞的表面、且双特异性分子或三特异性分子所含的至少一个抗原结合区域能够结合,就没有限制。作为T细胞的表面抗原,优选可以列举细胞毒性T细胞的表面抗原。例如,T细胞的表面抗原可以列举CD3、CD8、TCR、CTLA-4、PD1、Tim3、CD27、CD28、CD40、CD134(OX40)、CD137(4-1BB)、CD278(ICOS)。优选为CD3。肿瘤细胞的表面抗原只要存在于肿瘤细胞的表面、且双特异性分子所含的至少一个抗原结合区域能够结合,就没有限制。作为肿瘤细胞的表面抗原,可以列举EphA1(ephrin type-A receptor 1,肝配蛋白A型受体1)、EphA2、FolR1(folatereceptor 1,叶酸受体1)、EpCAM(Epithelial cell adhesion molecule,上皮细胞粘附分子)、CD19、Her1(v-erb-b2 erythroblastic leukemia viral oncogene homolog 1(成红细胞白血病病毒癌基因同系物1):ErbB1)、Her2、CD20、EGFR(Epidermal Growth FactorReceptor,表皮生长因子受体)、CCR4(C-C chemokine receptor type 4,C-C趋化因子受体4型)、CEA(Carcinoembryonic antigen,癌胚抗原)、GD2、GD3,CD22、CD30、CD33、CD70、CD123、EGFRvIII、MUC1(Mucin1,黏蛋白1)、PSCA(Prostate stem cell antigen,前列腺干细胞抗原)、PSMA(Prostate-specific membrane antigen,前列腺特异性膜抗原)、HLA-A1+NY-ESO1(HLA-A1限制性NY-ESO1)、HLA-A2+NY-ESO1(HLA-A2限制性NY-ESO1)、HLA-A3+NY-ESO1(HLA-A3限制性NY-ESO1)等。双特异性分子包括BiTE(商标)、双特异性抗体等。作为BiTE(商标),可以列举靶向CD19和CD3的双特异性分子、靶向EphA2和CD3的双特异性分子。另外,作为双特异性抗体,可以列举靶向EpCAM和CD3的抗体。
从四环素系化合物的作用效果的观点考虑,作为抗肿瘤药物,优选可以列举肿瘤免疫疗法药物、更优选可以列举选自免疫检查点抑制剂、CAR-T细胞药物、双特异性分子药物和癌症疫苗中的至少一种。肿瘤免疫药物中,最优选为免疫检查点抑制剂(阿替利珠单抗、纳武利尤单抗、帕博利珠单抗、伊只单抗、度伐鲁单抗、阿维鲁单抗、替西木单抗等)。
抗肿瘤药物的投予可以按照公知的方法进行。此外,在决定抗肿瘤药物的投予量时,可以按照后述的使用实施例1.外周血单核细胞的肿瘤细胞杀伤活性的测定方法,对各患者评价外周血单核细胞的T细胞的肿瘤细胞杀伤活性的强度,并根据该强度来决定投予量。
本发明的四环素系化合物或其药学上可接受的盐和抗肿瘤药物的联用(组合)方式,只要是能够发挥本发明的效果的使用方式即可,没有特别限制。例如,可以与抗肿瘤药物的投予同时并行投予四环素系化合物或其药学上可接受的盐,另外,也可以在投予抗肿瘤药物之前或投予抗肿瘤药物之后,投予四环素系化合物或其药学上可接受的盐。这种情况下,也可以交替进行四环素系化合物或其药学上可接受的盐和抗肿瘤药物的投予。此外,可以在投予抗肿瘤药物之后,配合肿瘤的组织的缩小程度等,从抗肿瘤药物投予的途中开始进行四环素系化合物或其药学上可接受的盐的联用投予;还可以相反地在投予四环素系化合物或其药学上可接受的盐之后,从途中开始进行抗肿瘤药物的联用投予。
此外,在本发明的四环素系化合物或其药学上可接受的盐为与抗肿瘤药物进行联用的方式时,可以为单次投予、连续投予或间歇式投予的任意种投予方式。例如,将在投予抗肿瘤药物之前投予本发明的四环素系化合物或其药学上可接受的盐的情况作为示例,可以例示从抗肿瘤药物的投予开始的7天前起或从3天前起,以1天1次连日投予14天至21天左右的方法。此外,也可以在抗肿瘤药物的投予疗程中连日投予四环素系化合物或药学上可接受的盐。
本发明的四环素系化合物或药学上可接受的盐根据其投予路径(投予方法)而制备成各种形态(剂型)的医药组合物,并与抗肿瘤药物组合,向对象肿瘤患者投予。
肿瘤免疫赋活剂的投予对象患者只要是可应用肿瘤免疫疗法的对象就没有限制。例如,作为患者,可以列举具有上述所记载的任一种肿瘤、并且未治疗患者或已接受某种肿瘤治疗的患者、肿瘤治疗中的患者、肿瘤再发或转移了的患者。上述肿瘤的治疗优选包括外科肿瘤切除、化学疗法、放射疗法等。
2.肿瘤治疗用组合物
肿瘤治疗用组合物含有上述1.所述的肿瘤免疫赋活剂和抗肿瘤药物。优选抗肿瘤药物为肿瘤免疫药物,更优选肿瘤免疫药物为选自免疫检查点抑制剂、CAR-T细胞药物、双特异性分子药物、癌症疫苗中的至少一种。关于投予量,在此引用上述1.所述的说明。
含有肿瘤免疫赋活剂和抗肿瘤药物的肿瘤治疗用组合物包括下述方式:
(i)处于肿瘤免疫赋活剂和抗肿瘤药物以混合在同一制剂中的方式含有的状态(配合剂)的情况;
(ii)含有肿瘤免疫赋活剂单体或肿瘤免疫赋活剂的制剂、和含有抗肿瘤药物单体或抗肿瘤药物的制剂各自作为分开的制剂包装,且两者以组合物(试剂盒)的形式售卖的情况;
(iii)含有肿瘤免疫赋活剂单体或肿瘤免疫赋活剂的制剂、和含有抗肿瘤药物单体或抗肿瘤药物的制剂各自为个别的制剂,且它们被组合而作为一个包装物进行售卖的情况;或者
(iv)含有肿瘤免疫赋活剂单体或肿瘤免疫赋活剂的制剂、和含有抗肿瘤药物单体或抗肿瘤药物的制剂各自作为分开的制剂包装,或者两者以分开的流通路径存在于市场,且在使用时组合使用的情况。
3.肿瘤的治疗方法
本发明包括使用上述肿瘤免疫赋活剂和肿瘤治疗用组合物的肿瘤的治疗方法。关于肿瘤免疫赋活剂和肿瘤治疗用组合物的投予方法和投予对象,在此引用上述1.所述的说明。
实施例
下面,示出实施例具体地说明本发明,但不应解释为本发明限定于实施例。
I.各实验方案
1.使用外周血单核细胞的肿瘤细胞杀伤活性的测定和各被检验药的评价
如图1所示,在体外使外周血单核细胞群(Peripheral Blood MononuclearCells:PBMC)和肿瘤细胞经由BiTE(注册商标)等衔接子接触并培养后,利用PBMC测定肿瘤细胞受到何种程度的伤害(肿瘤细胞杀伤活性),由此,评价PBMC中的T细胞的抗肿瘤活性。
(1)将U251细胞株在添加有10%FBS的RPMI1640培养基(添加有10%FBS的RPMI1640培养基)中培养后,用胰蛋白酶剥离,以1×105个/mL的量悬浮在添加有10%FBS的RPMI1640培养基中,制备细胞悬浮液。将上述细胞悬浮液以100μL/孔的量接种在96孔板中,在存在5%二氧化碳的湿式孵箱内以37℃孵育18小时。
(2)从健康人采集外周血(肝素采血),使用Lymphoprep TM(Alere TechnologiesAS),按照所附的方案回收PBMC。具体而言,在装入试管中的Lymphoprep TM上使采集的外周血缓慢地分层,以400g离心50分钟后,回收淋巴细胞层。向回收的溶液中加入添加有10%FBS的RPMI1640培养基进行离心后,除去上清。将细胞的细胞团沉淀利用添加有10%FBS的RPMI1640培养基悬浮,调整为1×106/mL。上述PBMC的回收在即将进行后述(3)的工序之前进行。
(3)将1个分子内具有针对EphA2的抗原结合部位和针对CD3的抗原结合部位的EphA2-CD3 BiTE(注册商标)利用添加有10%FBS的RPMI1640培养基制备成400ng/mL(称为“BiTE溶液”)。此外,各被检验药利用上述BiTE溶液调整为10μM。向(1)中孵育结束了的96孔板中每1孔添加PBMC细胞悬浮液50μL和含有各被检验药的BiTE溶液50μL。使BiTE最终浓度为100ng/mL,使各被检验药的最终浓度为2.5μM。作为对照,准备向(1)中孵育结束了的96孔板内加入PBMC细胞悬浮液50μL和不含被检验药的BiTE溶液50μL的孔、以及向(1)中孵育结束了的96孔板内加入PBMC细胞悬浮液50μL和添加有10%FBS的RPMI1640培养基50μL的孔。每1孔中添加有10%FBS的RPMI培养基的量,使最终的总量达到200μL。将添加PBMC和EphA2-CD3 BiTE(注册商标)后、或添加PBMC、EphA2-CD3 BiTE(注册商标)和被检验药后的96孔板在37℃孵育48小时。
(4)孵育结束后,将各孔的培养基与PBMC一同回收。进而,向各孔中加入添加有10%FBS的RPMI培养基200μL,将孔内清洗,回收清洗所使用的培养基。将该操作反复进行3次,将孔内清洗3次。此时,将每个孔最初回收的培养基和清洗时回收的培养基分别集中到1个试管中。向清洗后除去了培养基和PBMC的各孔中加入100μL的添加有10%FBS的RPMI培养基和20μL的CellTiter 96(注册商标)AQueous One Solution Reagent(MTS试剂:Promega)。此后,将96孔微孔板在存在5%二氧化碳的湿式孵箱内以37℃孵育30分钟~1小时左右。
(5)对于在(4)中孵育结束了的96孔微孔板,使用微孔板检测仪测定各孔的492nm时的吸光度。接着,依据下式计算肿瘤细胞杀伤活性。
仅含U251细胞株和PBMC的孔的吸光度=A
含有U251细胞株、PBMC和EphA2-CD3 BiTE(注册商标)的孔、或含有U251细胞株、PBMC、EphA2-CD3 BiTE(注册商标)和被检验药的孔的吸光度=B
肿瘤细胞杀伤活性(%)=[(A-B)/A]×100
2.颗粒酶B(Granzyme B)染色
将在上述1.(4)中回收的培养基以400g离心5分钟,除去上清,残留PBMC的细胞团沉淀。利用添加有2%FBS和10mM HEPES的HBSS培养基(以下,称作“HBSS+2%FBS+10mMHEPES”培养基)将各个抗体(CD3、CD4、CD8、CD45RA)稀释100倍,将这些抗体稀释液向除去了上清的细胞团沉淀中分别加入30μL/tube,在4℃孵育30分钟。将HBSS+2%FBS+10mM HEPES培养基分别加入200μL/tube,以400g离心5分钟后,除去上清,残留细胞团沉淀。将Fixbuffer分别加入100μL/tube,使残留的PBMC悬浮后,在4℃孵育30分钟。
将结束孵育的试管以400g离心5分钟除去上清,残留PBMC的细胞团沉淀。将洗涤缓冲液(Wash buffer)分别添加200μL/tube,使细胞团沉淀悬浮后,以400g离心5分钟除去上清,残留PBMC的细胞团沉淀。利用洗涤缓冲液将抗颗粒酶B抗体稀释100倍,利用该抗体稀释液30μL/tube使残留的PBMC悬浮,在4℃孵育30分钟。将洗涤缓冲液分别添加200μL/tube,以400g离心5分钟除去上清,残留PBMC的细胞团沉淀。利用HBSS+2%FBS+10mM HEPES培养基使残留的PBMC悬浮,将悬浮液提供FACS解析。
3.CytoTell测定
依据上述1.(1)的方法从健康人外周血回收PBMC。向回收的PBMC的细胞团沉淀中添加将CytoTell red混合在HBSS+2%FBS+10mM HEPES培养基中而得的溶液,在37℃孵育30分钟。孵育结束后,以400g离心5分钟除去上清,残留PBMC的细胞团沉淀。加入添加有10%FBS的RPMI培养基使残留的PBMC悬浮,调整为1×10 6/mL的PBMC细胞悬浮液。
与上述1.(3)同样地使U251细胞株、PBMC和BiTE、或U251细胞株、PBMC、BiTE和被检验药接触,在37℃培养96小时。
结束培养后,回收培养上清,再利用添加有10%FBS的RPMI1640培养基清洗3次,并将该培养基也进行回收。此时,每个孔最初回收的培养基和清洗时回收的培养基分别集中到1个试管中。
将回收的培养基以400g离心5分钟除去上清,残留PBMC的细胞团沉淀。利用HBSS+2%FBS+10mM HEPES培养基将各个抗体(CD3、CD4、CD8、CD45RA)稀释100倍,将这些抗体液向细胞团沉淀添加30μL/tube,使残留的PBMC悬浮,在4℃孵育30分钟。
向孵育结束的试管中,将HBSS+2%FBS+10mM HEPES培养基分别以200μL/tube添加,以400g离心5分钟后,除去上清,残留PBMC的细胞团沉淀。利用HBSS+2%FBS+10mM HEPES培养基使残留的PBMC悬浮,将悬浮液交付FACS解析。
4.CMV特异性CTL诱导(Mixed CMV peptide/Lymphocytes culture,混合CMV肽/淋巴细胞培养)
向HLA类型为24:02的健康人的PBMC加入利用添加有10%FBS的RPMI培养基调整为10μg/mL的CMV肽,在96孔板中培养3天。将培养基更换成含有10μg/mL CMV肽+20U/mL IL-2±2.5μM去甲基金霉素(DMC)的添加有10%FBS的RPMI培养基,再培养4天(培养7天)。将含有PBMC的各孔的培养基转移至24孔板,进行扩展(scale up)后,在含有10μg/mL肽+20U/mLIL-2±2.5μM DMC的添加有10%FBS的RPMI培养基中,再培养3天。将培养基更换成含有10μg/mL肽+20U/mL IL-2±2.5μM DMC的添加有10%FBS的RPMI培养基,再培养4天(培养14天)。
结束培养后,以400g离心5分钟除去上清,残留PBMC的细胞团沉淀,利用HBSS+2%FBS+10mM HEPES培养基将各个抗体稀释(将CD3、CD4、CD8)稀释100倍且将CMV Tetramer稀释10倍),向PBMC的细胞团沉淀加入30μL/tube,使PBMC悬浮,在4℃孵育30分钟。将HBSS+2%FBS+10mM HEPES培养基各添加200μL/tube,以400g离心5分钟除去上清,残留PBMC的细胞团沉淀。
利用HBSS+2%FBS+10mM HEPES培养基使残留的PBMC悬浮,将悬浮液交付FACS解析。
5.肺癌组织内T细胞的采集
关于肺癌组织内的T细胞的肿瘤细胞杀伤活性,依据以下方法从肺癌组织回收细胞。肿瘤细胞杀伤活性作为该细胞群的活性进行测定。
将癌组织转移到6cm平皿(Dish)中并切碎后,放入组织搅拌溶液(在HBSS+2%FBS+10mM HEPES中添加Tumor Dissociation Kit(Miltenyi Biotec))中并利用gentleMACS TMDissociator(Miltenyi Biotec)搅拌后,边在维持37℃的孵箱内旋转30分钟边进行孵育。此后,使含有细胞的搅拌液通过70μm筛孔,去除组织残渣,将滤液以600×g离心10分钟,回收沉淀物。向含有细胞的沉淀物添加BD Pharm lyse(BD Biosciences)并静置2分钟。向静置后的含有细胞的溶解液中加入HBSS缓冲液,以600×g离心10分钟,再次回收沉淀物。向再回收的沉淀物添加30%Percoll液,以12000xg离心30秒,再次回收沉淀物。将再回收的沉淀物利用HBSS缓冲液清洗,以12000×g离心30秒,回收组织内的细胞。回收的细胞的肿瘤细胞杀伤活性通过与上述I.1.(1)~(5)同样的方法测定。由于作为BiTE使用与CD3结合的物质,因此,可以认为从该肺癌组织内回收的细胞的肿瘤细胞杀伤活性为肺癌组织内T细胞的肿瘤细胞杀伤活性。
6.IFNγ产生测定
对上述5.中依据上述1.(4)回收的所有培养基内的细胞,利用IFN-γSecretionAssay试剂盒(Miltenyi Biotec)测定IFNγ产生能力。
将上述1.(4)中回收的培养基以400g离心5分钟,除去上清。向残留的PBMC的细胞团沉淀中,将利用添加有10%人血清的AIM培养基稀释100倍的IFNγ捕获试剂各添加100μL/tube,使PBMC悬浮后,以4℃孵育10分钟。
向孵育结束的试管中,将加热至37℃的添加有10%人血清的AIM培养基各以1mL/tube分注,边搅拌试管边在37℃下孵育45分钟。孵育结束后,再次在冰上进行冷却后,以400×g离心5分钟除去上清,残留PBMC的细胞团沉淀。
利用HBSS+2%FBS+10mM HEPES培养基使残留的PBMC悬浮,将各样品分为2个(一方用于同种型染色)后,再次以400g离心5分钟除去上清,残留细胞团沉淀。
利用HBSS+2%FBS+10mM HEPES培养基将各个抗体(CD3、CD4、CD8、CD45RA)稀释100倍并将抗i-IFNγ抗体稀释10倍,将这些抗体稀释液向残留的PBMC中各添加30μL/tube,使PBMC悬浮,在4℃孵育30分钟。
向孵育结束的试管中,将HBSS+2%FBS+10mM HEPES培养基各添加200μL/tube,以400g离心5分钟后,除去上清,再次利用HBSS+2%FBS+10mM HEPES培养基使残留的PBMC悬浮,将悬浮液交付FACS解析。
7.体内(in vivo)的肿瘤细胞增殖抑制作用的验证
接种的5天前将CT26WT细胞解冻,利用DMEM+10%FBS+1%青霉素/链霉素培养基进行培养。肿瘤细胞接种的2天前,将CT26WT细胞进行胰蛋白酶处理,进行传代。
修剪BALB/c小鼠的右背侧的毛后,将CT26WT细胞各以2×10 5cells/只进行皮内接种。在肿瘤细胞接种后的第6天测定小鼠的体重和肿瘤直径,以这些变得均匀的方式分组为被检验药投予组和溶剂对照(Vehicle)组(各n=9)。对被检验药投予组,将被检验药溶解于生理盐水调整为3.0mg/mL,各以200μL/只、30mg/kg/day的量向腹腔内投予。溶剂对照(Vehicle)组中,仅将生理盐水各以200μL/只向腹腔内投予。被检验药或生理盐水的投予连续进行10天(图8A)。肿瘤细胞投予后的10天、13天、16天测定肿瘤直径。
II.实施例1:四环素系化合物的T细胞抗肿瘤活性的赋活作用的验证依据上述I.1.所述的方法,作为被检验药,使用去甲基金霉素(DMC)、甲氯环素(MC)、四环素(TC)、金霉素(CTC)、米诺环素(MINO),验证T细胞抗肿瘤活性的赋活作用。n分别设为3(独立的健康人),将BiTE单独添加组和BiTE和被检验药联用组的差通过t检验进行计算。将其结果示于图2。
BiTE和被检验药联用组中,DMC、MC、TC、CTC和MINO全部中,与单独添加BiTE的情况相比,T细胞的抗肿瘤活性增强了(DMC、MC和CTC:p<0.01、TC和MINO:p<0.05)。由此,证实了四环素系化合物具有激活T细胞抗肿瘤活性的作用。
III.实施例2:由四环素系化合物导致的CD8+T细胞的肿瘤细胞杀伤活性的增强作用的验证
依据上述I.1.所述的方法,作为被检验药,使用去甲基金霉素(DMC:最终浓度2.5μM),验证四环素系化合物对于从3名健康人采集的各PBMC中的CD8阳性T细胞(CD8+T细胞)的肿瘤细胞杀伤活性的效果。CD8+T细胞利用CD8+T cell Isolation Kit(Miltenyi Biotec)进行负选择。如图3所示,与单独添加BiTE的CD8+T细胞相比,联用添加BiTE和被检验药的CD8+T细胞中,肿瘤细胞杀伤活性升高(p=0.05)。由此,表示四环素系化合物具有增强CD8+T细胞的肿瘤细胞杀伤活性的作用。
IV.实施例3:由四环素系化合物导致的颗粒酶B表达CD8+T细胞的存在比率的增加的验证
依据上述I.2.所述的方法,作为被检验药,使用去甲基金霉素(DMC:最终浓度2.5μM),验证四环素系化合物对于从4名健康人采集的各PBMC中的颗粒酶B表达CD8+T细胞的存在比率的效果。如图4所示,与单独添加BiTE的PBMC相比,添加BiTE和被检验药双方的PBMC中,颗粒酶B表达CD8+T细胞的存在比率升高(p=0.01)。由此,表示四环素系化合物增加颗粒酶B表达CD8+T细胞。
V.实施例4:由四环素系化合物导致的CD8+T细胞的增殖能力亢进的验证
依据上述I.3.所述的方法,作为被检验药,使用去甲基金霉素(DMC:最终浓度2.5μM),验证四环素系化合物对于从5名健康人采集的各PBMC中的CD8+T细胞的增殖能力的效果。如图5所示,与单独添加BiTE的PBMC相比,联用添加BiTE和被检验药的PBMC中,CD8+T细胞的增殖能力升高(p=0.007)。由此,表示四环素系化合物提高显示肿瘤细胞杀伤活性的CD8+T细胞的增殖能力。
VI.实施例5:由四环素系化合物导致的CMV特异性细胞毒性T细胞的诱导亢进效果的验证
依据上述I.4.所述的方法,验证四环素系化合物在将PBMC利用CMV抗原刺激从而诱导CMV特异性细胞毒性T细胞时的效果。作为被检验药,使用去甲基金霉素(DMC:最终浓度2.5μM)。PMBC从1名健康人采集。CMV特异性细胞毒性T细胞通过FACS解析来鉴定。如图6A所示,在将CMV特异性细胞毒性T细胞利用诱导抗原刺激后的第7天,未确认到CMV特异性细胞毒性T细胞(分级到图6A中的分区P7中)的诱导,但是,在第14天,确认到了CMV特异性细胞毒性T细胞的诱导。将未添加DMC的组(DMC-)和添加了DMC的组(DMC+)进行比较,DMC+中,与DMC-相比,CMV特异性细胞毒性T细胞(CMV四聚体(Tetramer)+CD8+T cells)的存在比率显著升高(图6B;p<0.05)。由此,表示四环素系化合物提高抗原特异性T细胞的增殖能力。
VII.实施例6:由四环素系化合物导致的肺癌组织内T细胞的肿瘤细胞杀伤活性的增强效果的验证
依据上述I.5.所述的方法采集肺癌患者的肿瘤组织内的T细胞,使用该细胞测定肿瘤细胞杀伤活性,验证四环素系化合物的效果。此外,依据上述I.5.所述的方法,采集肺癌患者的肿瘤组织内的T细胞,依据上述I.6.所述的方法测定IFNγ产生CD8+T细胞的存在比率,验证四环素系化合物的效果。
作为被检验药,使用去甲基金霉素(DMC),n在细胞杀伤活性测定中设为5(独立的患者),在IFNγ产生CD8+T细胞的存在比率测定中设为3(独立的患者)。
BiTE和被检验药联用组中,与单独添加BiTE的情况相比,T细胞的抗肿瘤活性增强了(图7A)。
BiTE和被检验药联用组中,与单独添加BiTEを单独的情况相比,IFNγ产生CD8+T细胞的存在比率升高了(图7B、C)。由此,提示了四环素系化合物增加IFNγ产生CD8+T细胞。
VIII.实施例7:体内(in vivo)的四环素系化合物的效果
依据上述7.中所述的方法验证四环素系化合物的体内(in vivo)的肿瘤增殖的抑制效果。与溶剂对照(Vehicle)组相比,被检验药投予组中,有肿瘤直径的增加被抑制的倾向(图8B)。
根据以上的结果,显示出四环素系化合物具有激活T细胞的抗肿瘤作用的效果。
VIII.实施例8:体内(in vivo)的四环素系化合物和抗PD-L1抗体的联用效果的验证
验证了在体内(in vivo)四环素系化合物能够增强免疫检查点抑制剂的抗肿瘤效果。
1.方法
在接种6天前解冻CT26WT细胞,利用添加有10%FBS和1%青霉素/链霉素的DMEM培养基进行培养。在肿瘤投予2天前,将CT26WT细胞进行胰蛋白酶处理,进行传代。
修剪Balb/c 6周龄的小鼠的右背侧的毛后,各以3×105cells/50μL/只,向修剪部位的皮内进行接种(Day 0)。在Day 6测定小鼠的体重和肿瘤直径,以这些变得均匀的方式各以9只分成5组。作为抗PD-L1抗体,使用BioXCell公司的InVivoMAb anti-mouse PD-L1。
各组的说明如下。
投予对照IgG和水的组(对照IgG+H2O组)
投予抗PD-L1抗体和水的组(aPD-L1+H2O组)
投予抗PD-L1抗体和DMC(300mg/kg)的组(aPD-L1+DMC(300mg/kg)组)
投予抗PD-L1抗体和DMC(100mg/kg)的组(aPD-L1+DMC(100mg/kg)组)
投予抗PD-L1抗体和DMC(30mg/kg)的组(aPD-L1+DMC(30mg/kg)组)
首先从Day 7开始DMC的投予。将DMC溶解于生理盐水后,各以200μl/只利用经口探针进行口服投予。DMC非投予组中,将蒸留水各以200μL/只进行口服投予。DMC的投予以1天1次连续进行Day 7~Day 12为止。
接下来,在Day 10将抗PD-L1抗体或对照IgG各以200μg/200μL/只向腹腔内投予。
在Day 10、Day 13测定肿瘤直径。肿瘤体积通过(短径2×长径)/2的式子进行计算。
2.结果
将测定结果示于图9。对照IgG+H2O组中,开始投予DMC时为40mm3左右的肿瘤体积增加至160mm3左右。与此相对,aPD-L1+H2O组的肿瘤体积停留在90mm3左右。此外,在预先投予DMC的组中,与aPD-L1+H2O组相比,均确认到肿瘤体积增加的抑制。特别在aPD-L1+DMC(30mg/kg)组中,确认到肿瘤体积增加的进一步的抑制效果。
由此,表示四环素系化合物的投予使免疫检查点抑制剂的抗肿瘤效果增强。
IX.实施例9:验证体内(in vivo)的由四环素系化合物导致的抗PD-L1抗体的抗肿瘤作用的增强效果依赖于CD8+T细胞
为了验证在体内四环素系化合物所表现出的免疫检查点抑制剂的抗肿瘤作用的增强效果是否依赖于CD8+T细胞的抗肿瘤作用,对于在CD8+T细胞的存在下和非存在下,四环素系化合物对免疫检查点抑制剂的抗肿瘤作用所带来的影响进行分析。
1.方法
与实施例8同样地培养CT26WT细胞,在Balb/c 6周龄的小鼠的皮下进行接种(Day0)。在Day 6测定小鼠的体重和肿瘤直径,以这些变得均匀的方式各以9只分成6组。
投予对照IgG和水的组(IgG+H2O组)
投予抗PD-L1抗体和水的组(aPD-L1+H2O组)
投予抗PD-L1抗体、水和抗CD8抗体的组(aPD-L1+H2O+CD8去除(depletion)组)
投予抗PD-L1抗体、DMC(30mg/kg)和抗CD8抗体的组(aPD-L1+DMC+CD8去除(depletion)组)
投予对照IgG和DMC(30mg/kg)的组(IgG+DMC组)
投予抗PD-L1抗体和DMC(30mg/kg)的组(aPD-L1+DMC组)
在投予DMC或水以及抗PD-L1抗体之前,在Day 6对CD8去除(depletion)组将抗CD8抗体(InVivoMAb anti-mouse CD8α,BioXCell公司)以400μg/200μL/只进行腹腔内投予。对除此以外的组投予对照IgG 400μg/200μL/只。
接着,从Day 7开始DMC的投予。将DMC溶解于生理盐水后,各以200μL/只利用经口探针进行口服投予。DMC非投予组中,将蒸留水各以200μL/只进行口服投予。DMC的投予以1天1次连续进行Day7~Day 12为止。
接着,在Day 10将抗PD-L1抗体或对照IgG以200μg/200μL/只向腹腔内投予。
在Day 10、Day 13测定肿瘤直径。肿瘤体积以与实施例8同样的方法计算。
2.结果
将结果示于图10。IgG+H2O组中,Day 13的肿瘤体积为150mm3左右。与此相对,Day13的aPD-L1+H2O组的肿瘤体积为120mm3左右。此外,IgG+DMC组中,肿瘤体积的增加相比于aPD-L1+H2O组得以抑制,Day 13的肿瘤体积为100mm3左右。此外,aPD-L1+DMC组中,Day 13的肿瘤体积为80mm3左右。与此相对,投予抗CD8抗体时,肿瘤体积的增加速度相比于IgG+H2O组加快,aPD-L1+H2O+CD8去除(depletion)组和aPD-L1+DMC+CD8去除(depletion)组中,在Day 10与IgG+H2O组相比肿瘤体积增加了。此外,肿瘤体积在Day 13,aPD-L1+H2O+CD8去除(depletion)组和aPD-L1+DMC+CD8去除(depletion)组均为300mm3左右,虽然存在抗PD-L1抗体或抗PD-L1抗体和去甲基金霉素,肿瘤体积的增加也加快了。在Day13,aPD-L1+DMC组中,与aPD-L1+H2O组相比,能够确认显著的肿瘤体积的减少,相对于此,aPD-L1+DMC+CD8去除(depletion)组和aPD-L1+H2O+CD8去除(depletion)组的肿瘤体积未确认到显著差异。
由此,表示四环素系化合物的免疫检查点抑制剂的抗肿瘤作用的增强效果依赖于CD8+T细胞。
X.实施例10:体内(in vivo)由四环素系化合物带来的对癌抗原特异性CD8+T细胞的效果的验证
验证四环素系化合物对于免疫检查点抑制剂的抗肿瘤作用增强效果是否会使体内(in vivo)癌抗原特异性CD8+T细胞增加。
1.方法
在Day 13,从实施例9的IgG+H2O组、aPD-L1+H2O组、aPD-L1+DMC组的小鼠的眼底采集血液。向装有采集的血液的试管中,加入1ml的Pharmlyse溶解红细胞,进行离心后除去上清。向含有沉淀的试管加入添加有2%FBS和10mM HEPES的HBSS培养基(以下,称作“HBSS+2%FBS+10mM HEPES”),使沉淀悬浮并且再次离心而除去上清。向含有沉淀的试管加入gp70四聚体(Tetramer)[T-Select H-2Ld MuLV gp70 Tetramer-SPSYVYHQF-PE,MBL公司],在4℃反应30分钟。作为对照,向含有沉淀的试管加入β-半乳糖苷酶四聚体[T-Select H-2Ldβ-galactosidase Tetramer-TPHPARIGL-PE,MBL公司],在4℃反应30分钟。向反应结束后的试管加入HBSS+2%FBS+10mM HEPES并混合。再次将试管进行离心,除去上清。向试管内添加抗CD8抗体,染色后,将细胞清洗,交付FACS测定,计数gp70四聚体和CD8为阳性的细胞。
2.结果
将计数结果示于图11。与IgG+H2O组相比,aPD-L1+DMC组中,癌抗原特异性CD8+细胞的存在比率增加了。由此,证明了四环素系化合物在增强免疫检查点抑制剂的抗肿瘤作用时,使癌抗原特异性CD8+T细胞增加。
Claims (7)
1.一种肿瘤免疫赋活剂,其特征在于,含有:
选自下述通式(I)所示的四环素系化合物及其药学上可接受的盐中的至少一种,
式中,
R1为下述通式(II)所示的基团或碳原子数1~3的低级烷基,其中,R8为氢原子或碳原子数1~3的低级烷基:
R2为下述通式(III)所示的基团,其中,R9为碳原子数1~3的低级烷基或氢原子:
R3为氢原子、羟基或碳原子数1~3的低级烷基;
R4和R5均为或者独立地为氢原子、羟基或碳原子数1~3的低级烷基,或者R4和R5一体成为亚甲基;
R6为氢原子、卤素或下述通式(IV)所示的基团,其中,R10为氢原子或碳原子数1~3的低级烷基:
R7为氢原子、碳原子数1~3的低级烷基、-NH-CO-CH2-NH-C(CH3)3或-CH2-NH-CH2-C(CH3)3。
2.如权利要求1所述的肿瘤免疫赋活剂,其特征在于:
所述碳原子数1~3的低级烷基为甲基。
3.如权利要求1所述的肿瘤免疫赋活剂,其特征在于:
所述通式(I)所示的化合物为选自去甲基金霉素、甲氯环素、四环素、金霉素、多西环素、米诺环素和土霉素中的至少一种。
4.如权利要求1~3中任一项所述的肿瘤免疫赋活剂,其特征在于:用于与肿瘤免疫药物进行联用。
5.如权利要求4所述的肿瘤免疫赋活剂,其特征在于:
所述肿瘤免疫药物为选自免疫检查点抑制剂、CAR-T细胞药物、双特异性分子药物和癌症疫苗中的至少一种。
6.一种肿瘤治疗用组合物,其特征在于,含有:
权利要求1~3中任一项所述的肿瘤免疫赋活剂和肿瘤免疫药物。
7.如权利要求6所述的肿瘤治疗用组合物,其特征在于:
所述肿瘤免疫药物为选自免疫检查点抑制剂、CAR-T细胞药物、双特异性分子药物和癌症疫苗中的至少一种。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020077276A1 (en) * | 1999-04-27 | 2002-06-20 | Fredeking Terry M. | Compositions and methods for treating hemorrhagic virus infections and other disorders |
WO2017133175A1 (en) * | 2016-02-04 | 2017-08-10 | Nanjing Legend Biotech Co., Ltd. | Engineered mammalian cells for cancer therapy |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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DK1071752T3 (da) * | 1998-04-21 | 2003-10-20 | Micromet Ag | CD19xCD3-specifikke polypeptider og anvendelsen deraf |
KR101339628B1 (ko) * | 2005-05-09 | 2013-12-09 | 메다렉스, 인코포레이티드 | 예정 사멸 인자 1(pd-1)에 대한 인간 모노클로날 항체, 및 항-pd-1 항체를 단독 사용하거나 기타 면역 요법제와 병용한 암 치료 방법 |
CN114835812A (zh) * | 2008-12-09 | 2022-08-02 | 霍夫曼-拉罗奇有限公司 | 抗-pd-l1抗体及它们用于增强t细胞功能的用途 |
EP3377068A4 (en) * | 2015-11-20 | 2019-06-19 | Senhwa Biosciences, Inc. | POLYTHERAPY COMPRISING TETRACYCLIC QUINOLONE ANALOGUES FOR THE TREATMENT OF CANCER |
JP2018537511A (ja) * | 2015-12-16 | 2018-12-20 | アドバクシス, インコーポレイテッド | リステリア系免疫療法およびその使用方法 |
-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020077276A1 (en) * | 1999-04-27 | 2002-06-20 | Fredeking Terry M. | Compositions and methods for treating hemorrhagic virus infections and other disorders |
WO2017133175A1 (en) * | 2016-02-04 | 2017-08-10 | Nanjing Legend Biotech Co., Ltd. | Engineered mammalian cells for cancer therapy |
Non-Patent Citations (2)
Title |
---|
H TANG等: "Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination", 《GENE THERAPY》 * |
岩崎博道等: "テトラサイクリンにより誘導されるヒト白血病細胞のアポトーシス", 《JAPANESE JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024125656A1 (zh) * | 2022-12-17 | 2024-06-20 | 中南大学湘雅二医院 | Demeclocycline及其药用盐在治疗多种肿瘤中的应用 |
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