CN103442715A - 包括hdac抑制剂以及类固醇的药用组合物及其用途 - Google Patents
包括hdac抑制剂以及类固醇的药用组合物及其用途 Download PDFInfo
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Abstract
本发明涉及一种药用组合物,包含一种HDAC抑制剂、它的一种药学上可接受的酸或盐或者它们的混合物以及一种类固醇或它的一种药学上可接受的盐,以及所述药用组合物在其他治疗之前作为预治疗来治疗癌症的用途。所述HDAC抑制剂或类固醇可以替代地在其他治疗之前单独给予。
Description
发明领域
本发明涉及一种药用组合物,该组合物包括一种HDAC抑制剂,它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐以及所述药用组合物在其他疗法之前作为一种预治疗用于治疗癌症的用途。所述HDAC抑制剂或者类固醇可以替代地在其他治疗之前单独使用。
发明背景
癌症可以被定义为细胞的异常生长,这些细胞显示出不受控制的增殖以及打乱的程序性细胞死亡的信号。从经典观点来看,相继的基因事件导致恶性转化,结果是不服从其他细胞和组织的完整性的细胞克隆,并且最终可能转移。癌症可以涉及身体中的任何组织并且在每个身体部位可能有很多种不同形式。
恶性淋巴瘤可以被定义为造血系统的淋巴细胞的恶性转化。淋巴瘤可以被分为进展性淋巴瘤和缓慢进展性淋巴瘤。进展性淋巴瘤的特征是快速生长型,并且可以具有显著的临床特征。但是,进展性淋巴瘤可以通过化学疗法、放射疗法和单克隆抗体等治疗得到完全治愈。相反,缓慢进展性淋巴瘤(例如滤泡性淋巴瘤)为缓慢生长型,通常是更适度的临床表现。然而,尽管缓慢进展性淋巴瘤不能通过标准淋巴瘤治疗方法得到完全治愈,但是它们有时可以通过同种异体干细胞移植得到治愈。滤泡性淋巴瘤的平均存活时间为8-10年。弥散性大B细胞淋巴瘤和何杰金氏淋巴瘤属于进展性淋巴瘤类,而滤泡性淋巴瘤和慢性淋巴细胞性白血病属于缓慢进展性淋巴瘤。骨髓瘤包括恶性转移的浆细胞。它们属于缓慢进展性淋巴瘤,但是通常被认为是它们自身的实体。预后较悲观,平均存活时间为5-7年。
弥散性大B细胞性淋巴瘤(DLBCL)是恶性淋巴瘤最常见的亚型,瑞典的发病率大约为500例/年。DLBCL占进展性淋巴瘤类的60%-70%。诊断时的平均年龄为70岁,DLBCL在男性中患病稍微多于女性。DLBCL标准的一线治疗药物是由环磷酰胺、多柔比星、长春新碱和强的松(CHOP)组合的化学疗法。近年来,添加CD20抗体利妥昔单抗成了国际临床标准用药(R-CHOP),带来改善的无进展、无不良事件、无疾病和整体存活率(Morrison(玛瑞森),Expert Rev Anticancer Ther(《抗癌疗法专家评论》),2008;8(10):pp.1651-1658)。然而,由于高达45%的患者死于所患疾病,因此有显著的临床需要来增加DLBCL患者的无进展性生存。
调节DNA转录很复杂,并且所涉及的机制仅仅部分已知。组蛋白脱乙酰基酶类(HDACs)可以调节肿瘤抑制基因的表达以及肿瘤引发和进展中都涉及的转录因子的活动。HDAC通过组蛋白脱乙酰作用改变DNA或者染色质的结构成分来起作用,因此在不改变或者不阻断其序列下影响DNA的三维构造(表观遗传修饰)。还提示它们可以通过调节染色质结构来改变DNA损失化疗的敏感性。根据这些线索,一些体外研究表明HDAC抑制剂可以与化学疗法协同增效。
最近几年开发了很多HDAC抑制剂。它们可以分为四类:异羟肟酸/氨基甲酸,环肽类,脂肪酸类和苯甲酰胺类。例如,伏林司他和罗米地新被FDA(美国食品药品监督管理局)批准用于治疗皮肤T细胞淋巴瘤,目前正在被评估用于其他恶性肿瘤的治疗。
临床上最有名的抑制剂是抗惊厥药丙戊酸,自二十世纪七十年代起就被用于治疗癫痫。丙戊酸属于脂肪族酸类抑制剂。
EP1427403披露了丙戊酸(VPA)和其药学上可接受的盐用于生产一种药剂的用途,该药剂用来与照射疗法联合治疗人类癌症,其中人类癌症选自下组,该组由以下各项组成:乳腺癌、结肠癌、头颈癌、小细胞肺癌和血细胞癌症。根据EP1602371,VPA还可以用于与一种或几种其他抗癌治疗的组合疗法中,其中这些治疗的目标机制彼此显著不同,例如化学疗法和细胞毒制剂,分化诱导制剂(例如维甲酸,维生素D,细胞因子类),激素疗法,免疫学方法,以及最近的,抗血管生成方法和基因疗法的发展。
US2008/0194690披露了一种HDAC抑制剂(即某些氨基甲酸化合物,例如贝林司他(PXD101))与环糊精、精氨酸或葡甲胺联合用于治疗许多疾病(包括癌症)的用途,其中HDAC抑制剂的溶解度通过添加一种或多种环糊精、精氨酸或葡甲胺得以提高。
发明概述
本发明涉及独特的发现,一种HDAC抑制剂与一种类固醇的组合将改善罹患癌症例如淋巴瘤的患者的存活。这些化合物是药学上可接受的化合物并且至少可以作为一种预治疗在其他治疗之前使用。这些物质可以一起使用或者单独给予并且作为药学上可接受的化合物给予。
已经发现该类固醇可被用来提高患者对使用HDAC抑制剂治疗的响应并且降低副作用,例如多寐。
在第一方面,本发明涉及一种药用组合物,包括一种HDAC抑制剂,它的一种酸或盐或者它们的混合物以及一种类固醇或它的盐。
在第二方面,本发明涉及如上定义的组合物用于治疗癌症的用途。
因此,通过提供这样一种药用组合物或这样一种组合物的用途,遭受癌症例如淋巴瘤的患者的存活率得到提高并且第一次有可能用来具有维持疗效地治疗老年人,他们需要较低的化疗剂量。
在第三方面,本发明涉及一种试剂盒,包含至少一种药用组合物,该组合物包含一种HDAC抑制剂、它的一种酸或盐或者它们的混合物以及一种类固醇或它的一种盐。
在第四方面,本发明涉及一种试剂盒,该试剂盒包括包含一种HDAC抑制剂、它的一种酸或盐或者它们的混合物的至少一个合适的容器或者合适的包装以及包含一种类固醇或它的一种盐的至少一个合适的容器或者合适的包装。
通过提供这样一种试剂盒,使得遭受癌症的患者很容易在医院其他治疗之前进行预治疗。
在第五方面本发明涉及评估一种物质对细胞系的CHOP-敏感性的影响的方法,该方法包含以下步骤
a.提供一种选自下组的细胞系,该组由以下各项组成::WSU-NHL,Karpas-422,ULA,SU-DHL-5和SU_DHL-8
b.添加环磷酰胺、多柔比星、长春新碱和强的松的一个组合
c.添加一种将有待评估的物质到每一种细胞系
d.并且评估这些细胞的存活力。
在最后的方面是一种治疗遭受癌症的患者的方法,该方法是通过给予一种药用组合物,该药用组合物包含一种HDAC抑制剂、它的一种酸或盐或者它们的混合物以及一种类固醇或它的一种盐。该药用组合物可以被用来与一种或多种其他治疗方法组合使用,包括化学疗法,免疫疗法。化学疗法可以是,例如CHOP(环磷酰胺,多柔比星,长春新碱和强的松),免疫疗法可以是DC20抗体。
发明详细说明
HDAC和类固醇
在第一方面,本发明涉及一种药用组合物,包括一种HDAC抑制剂,它的酸或盐或者它们的混合物以及一种类固醇或它的盐。该HDAC抑制剂可以是异羟肟酸/氨基甲酸,环肽,脂肪族酸或苯甲酰胺化合物,例如伏林司他,罗米地新,丙戊酸,艾斯帕比司他(aspanobinostat),贝林司他,恩替司他和瑞米司他(resminostat),其中它们中的一些使用了商标。另外该HDAC抑制剂可以是丙戊酸,例如丙戊酸钠或丙戊酸镁或它们的混合物。实例包括伏林司他(在美国上市的商标为),罗米地新(在美国上市的商标为),帕比司他。丙戊酸的一种形式是当与丙戊酸钠混合时,即酸和盐的一种混合物(丙戊酸半钠),以不同的商品名上市Depakote,Depakote ER,Depakene,Depacon,Depakine,Valparin,Stavzor和Ergenyl。丙戊酸钠在瑞典上市的商标为Absenor,Depakine,Orfiril。丙戊酸在瑞典上市的商标为Ergenyl和Depakine。
本发明中所用的类固醇可以选自糖皮质激素类并且包括强的松,泼尼松龙,地塞米松和倍他米松。在一个实例中HDAC抑制剂是丙戊酸,类固醇是强的松。
其他成分
如上所定义的药用组合物可以进一步包含一种或多种其他药学上可接受的药用成分,例如一种药学上可接受的稀释剂,载体,赋形剂和缓冲剂。“药学上可接受的”表示一种无毒的化合物,该化合物不降低这些有效成分的生物活性的效力。这些药学上可接受的添加剂,稀释剂,缓冲剂,载体或赋形剂是本领域已知的(见Remington's Pharmaceutical Sciences(《雷明顿药物科学》),第18版,A.R Gennaro(A.R格纳洛),Ed.,Mack PublishingCompany(麦克出版公司)(1990)和handbook of Pharmaceutical Excipients(药物辅料手册),第3版,A.Kibbe(A.吉布),Ed.,Pharmaceutical Press(药物出版公司)(2000))。
术语“缓冲剂”意在指一种包含酸-碱混合物的水溶液,目的是稳定pH。缓冲剂的实例是氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗的盐;林格溶液(Ringer's solution);乙醇;pH缓冲液;多酯,聚碳酸酯和/或聚酐;以及其他用于药物配制品中的无毒的相容的物质。
术语“稀释剂”意在指一种水溶液或非水溶液,目的是稀释药用制剂中的化合物。稀释剂可以是一种或多种盐,水,聚乙二醇,丙二醇或乙醇。
赋形剂可以是一种或多种碳水化合物,表面活性剂,聚合物,脂和矿物质。碳水化合物的实例包括乳糖,蔗糖,甘露醇,和环状糊精,它们被添加进该组合物中,例如用来便于冷冻干燥。聚合物的实例是淀粉,纤维素醚,纤维素羧甲基纤维素,羟丙甲基纤维素,羟乙基纤维素,乙基羟乙基纤维素,藻酸盐,鹿角菜胶,透明质酸和它们的衍生物,聚丙烯酸,聚磺酸盐,聚乙烯乙二醇/聚氧化乙烯,聚氧化乙烯/聚氧化丙烯共聚物,不同水解度的聚乙烯醇/聚乙烯乙酸酯,以及聚乙烯吡咯烷酮,所有都是不同的分子量,它们被添加至该组合物,例如为了控制粘度,为了获得生物粘附,或者为了保护脂不进行化学和蛋白质分解降解。脂的实例是脂肪酸,磷脂,单-、双-和三-甘油酯,神经酰胺,鞘脂和糖脂,所有都是不同的酰基链长和饱和度,蛋黄卵磷脂,大豆卵磷脂,氢化的蛋黄和大豆卵磷脂,它们以与聚合物相似的理由被添加进该组合物中。矿物质的实例是云母,氧化镁,氧化锌和氧化钛,它们被添加进该组合物中以便获得一些益处,例如减少液体蓄积或者有利的色素特性。
合适的含水和无水载体的实例(这些载体可以被用在本发明的药用组合物中)包括水,乙醇,多元醇(例如甘油,丙二醇,聚乙二醇,和类似物),以及它们合适的混合物,植物油,例如橄榄油,和可注射的有机酯,例如油酸乙酯。适当流动性可例如通过使用涂层材料,例如卵磷脂,在分散液的情况下通过维持所要求粒径,以及通过使用表面活性剂来维持。
这些组合物还可含有佐剂,例如防腐剂、润湿剂、乳化剂以及分散剂。预防微生物在目标化合物上的作用可以通过包含不同抗菌素和抗真菌药物来保证,例如对羟苯甲酸酯,三氯叔丁醇,苯酚山梨酸,以及类似物。还可以希望的是将等渗剂,例如糖、氯化钠、以及类似物包括于组合物中。另外,可通过包含延迟吸收的试剂(例如单硬脂酸铝以及明胶)来实现可注射药物形式的延长的吸收。
给予方式
根据本发明的药用配制品可以局部或全身使用。给予途径包含局部,眼睛,鼻子,肺,口腔,肠外(静脉,皮下,和肌肉注射),口服,阴道和直肠。最常使用的是口服给予。
该药用组合物可以药学上有效的剂量给予患者。“药学上有效的剂量”指的是足够产生与针对其所给予的状况相关的预期效果的剂量。准确剂量依赖于给予方式,疾病的性质和严重程度。取决于患者的总体健康状况,性别,年龄和体重,需要使用不同的剂量。给予剂量可以以单一剂量的形式单次给予或者给予几次较小的剂量并且还可以通过在特定间隔给予多次细分的剂量。取决于给药方式,这些活性化合物或物质还可以一起给予或者单独给予。
合适的制剂形式是,例如颗粒,粉剂,片剂,包衣片,(微型)胶囊,微型颗粒,泡腾剂粉或颗粒,栓剂,安瓿装注射液,还有活性物质的延长释放制剂形式,在这种制剂中通常如上所述使用赋形剂、稀释剂或载体。其他制剂可以是产生活性成分的不同释放特性的制剂,这些对于本领域的熟练人员是已知的。实例包括持续释放,持续作用,延长释放,延时释放或者定时释放,控制释放,修饰释放,或者连续释放。持续释放片剂或胶囊的优势是它们可以比同样药物的立即释放配制品少一些服用次数,并且它们保持药物在血流中更稳定的水平。今天,配制了最强的定时释放药物因此活性成分被植入进一种或多种不溶物质的基质中(不同物质:一些丙烯酸酯,甚至是壳多糖;这些物质通常都有专利保护),因此溶解的药物必须找到穿越基质中的孔而出来的路径。一些药物被包裹在基于聚合物的片剂中,在片剂的一侧有一个激光打孔,另一侧有一个多孔膜。胃酸通过多孔膜,因此推进药物穿过激光打孔。同时,整个药物剂量释放到全身体系,而聚合物容器保持完整,后来通过正常消化系统排出。在一些配制品中,药物溶解进基质中,该基质物理膨胀形成一个凝胶,使得药物离开凝胶的外表面。微型包囊也被认为是一种更加完整的技术来产生复杂的溶解特性。通过在一个惰性核周围包衣一种活性药用成分,并且用不溶物质层压来形成一个微球,有可能获得更加一致的和可重复的溶解速率。所有这些都是本领域的熟练人员已知的。
一种制剂形式的实例是泡腾剂产品。
泡腾是酸和碱(在水中)产生二氧化碳的反应。在这个反应中所用的酸的实例是柠檬酸,酒石酸,苹果酸,富马酸,己二酸,柠檬酸盐,琥珀酸和它们的混合物。柠檬酸最常使用,并且它给产品带来类似柑橘的口味。在这个泡腾反应中所用的碱的实例是碳酸钠,碳酸钾,碳酸氢钠,碳酸氢钾,碳酸氢钙,碳酸镁,聚乙二醇碳酸钠,羧基赖氨酸和它们的混合物。在泡腾剂配方中碳酸氢钠最常用。
这些化合物可以一起混合在泡腾产品中或者可以替代地每一种单独使用。一个实例是当两种活性物质彼此单独包裹时,得到的泡腾产品产生这两种活性物质/成分的不同释放特性。
泡腾产品可以是粉末形式或者片剂形式。
如果产品是片剂,它可以包含至少一种选自下组的添加剂,包括粘合剂,润滑剂,乳化剂,表面活性剂(例如聚山梨醇80和十二烷基硫酸钠),香料,芳香剂(产生味道的成分的实例)(例如橘子,柠檬,佛手柑,葡萄柚,香蕉,杏和草莓)以及染色剂(包括天然或合成的),维生素,甜味剂(产生味道的成分的实例)(乙酰氨基磺酸钾,糖精钠,阿斯帕坦,甜叶菊和蔗糖素),营养添加剂(例如抗氧化剂,肽),以及它们的混合物。
给泡腾剂组合物添加味道、颜色或抗氧化特性的物质可以是来自天然来源的植物多酚,例如蓝浆果,酸果蔓,葡萄和茶叶。
另外片剂可以包含适合用于该组合物中的不同润滑剂,包括水可分散的润滑剂,水溶性润滑剂,水不溶性润滑剂以及它们的组合。有用的水溶性润滑剂的实例包括苯甲酸钠,聚乙二醇,L-亮氨酸,己二酸,以及它们的组合。
片剂还可以包含水不溶性润滑剂,包括例如,硬脂酸盐(例如硬脂酸镁,硬脂酸钙和硬脂酸锌),油(例如矿物油,氢化的和部分氢化的植物油,以及棉籽油)以及它们的组合。泡腾剂还可以包含维生素和矿物质。
生产泡腾产品的生产工艺包括一些关键步骤,这些关键步骤在配制和生产过程中需要被认真对待,这些对于本领域的熟练人员都已知。泡腾产品的生产必须在非常低湿度区域进行。生产泡腾产品的最佳方式是在严格控制湿度的环境中进行。
生产片剂的工艺,被称做“压片”或“压缩”需要添加本领域的熟练人员已知的、粉剂的药用赋形剂,例如通过混合、造粒和压片。在片剂生产中造粒后添加润滑剂是非常普遍的做法;最常使用的物质是硬脂酸镁。在泡腾剂生产过程中,例如硬脂酸镁的物质可以产生问题,因为它们不溶于水,因此在片剂溶解后在水的上层会产生一层薄膜。克服这个问题的策略是使用溶于水的其他润滑剂;例如喷雾干燥的L-亮氨酸和聚乙二醇的混合物。可替代地,不使用任何润滑剂具有避免掺混步骤的优点,但是也有对生产中有特殊需要的缺点。
数量和剂量
取决于将使用的HDAC抑制剂,HDAC抑制剂可以不同的量给予。这对于本领域的熟练人员是已知的。这也适用于类固醇。活性成分可以一起给予或者单独给予。但是,以下是可以使用的量的一些实例。
给予实例包括每天给予20至200mg的强的松或泼尼松龙,例如50-200、100-150、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190或200mg。培他米松每天给予4至32mg的量,例如10-25、10-20、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31或32mg。地塞米松可以每天给予10-80mg的量,例如20-70、10、20、30、40、50、60、70或80mg。强的松可以单一剂量使用或者如果需要可以多剂量地给予。
HDAC抑制剂,例如丙戊酸,可以口服或者静脉地给予,每天从大约500mg至大约15000mg的范围,例如每天从大约4000mg至大约15000mg,例如每天从大约400mg至大约3000mg。例如口服剂量可以是每天大约800,大约1600,大约2400,大约3000,大约6000,大约9000,大约15000mg。可以理解的是每天的总量可以单一剂量给予或者以多次给药地给予,例如每天两次,三次,四次或五次。
HDAC抑制剂,例如贝林司他可以口服给予,每天从大约6mg至大约3000mg的范围,例如每天从大约40mg至大约3000mg,例如每天从大约400mg至大约3000mg。例如口服剂量可以是每天大约4,大约40,大约400,大约800,大约1600,大约2400,大约2800或大约3000mg。可以理解的是每天的总量可以单一剂量给予或者以多次给药地给予,例如每天两次,三次或四次。
对HDAC抑制剂或其药学上可接受的盐,类固醇或其药学可接受的盐的给予可以是至少每天一次(例如在早晨时间,大约早晨5至8点)将它们单独地给予或者组合地给予。但是,任何物质的给予可以每天1,2,3,4或甚至高达5次。给予的实例包括:每天给予HDAC抑制剂三次和强的松一次。通常来说,类固醇取决于配制品特性和活性物质的释放特性每天给予1-2次。对HDAC抑制剂和类固醇的给予可以在所述免疫和/或化学疗法之前至少24-72小时,例如30-60,40-50或48小时,并且类固醇和HDAC抑制剂可以同时地或者顺序地给予。但是,可以在化疗和或免疫疗法的治疗之前给予,然而也可以在治疗过程中或者之后给予,但是在之前给予是强制的。
试剂盒
在一个方面,本发明涉及一种试剂盒,包含在一个合适的容器或包装内的药用组合物,其中所述组合物如上所述。
在另一个方面本发明涉及包含一种HDAC抑制剂,或它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐或它们的混合物的一种试剂盒。
该试剂盒可以包含HDAC抑制剂和类固醇的单独容器。该试剂盒可以进一步包含一种抗体,单克隆抗体或它的功能性片段,其与CD20结合。该试剂盒还可以包含使用说明,例如如何和何时给予这些化合物或组合物的书面说明。
例如,该试剂盒可以包含一种或多种起疱剂(blister),该起疱剂包含多个片剂或颗粒。这些活性化合物可以混合在片剂中或颗粒中或分散进不同的片剂或颗粒以及通过屏障(例如被包衣)分散在片剂中或造粒。这些化合物或药用组合物还可以以相同的或单独不同的小袋保持在该试剂盒中。
该试剂盒可以包含其他部分,例如包括恰当的用于稀释的溶液(例如生理盐水溶液,葡萄糖溶液等等),试剂(例如用来调节pH),以及用于装配和使用(例如用于准备配制品以及随后给予)的装置(例如袋,管,注射器,针,转移装置)。
书面说明还可以包括配制品(例如其中的HDAC抑制剂)所合适治疗的适应症列表以及如何给予该化合物或这些化合物。
治疗方法和用途
本发明还涉及一种治疗方法,其中使用上面定义的组合物或化合物来治疗人类癌症,例如用来治疗选自下组的疾病,该组由以下各项组成:肉瘤,恶性黑色素瘤,皮肤癌,雌激素受体依赖和不依赖乳腺癌,卵巢癌,前列腺癌,肾癌,结肠和结直肠癌,胰腺癌,头颈癌,小细胞和非小细胞肺癌,以及血细胞癌。实例包括治疗选自下组的疾病,该组由以下各项组成:弥漫性大B细胞淋巴瘤(DLBCL),滤泡淋巴瘤,慢性淋巴细胞性白血病,骨髓瘤,T细胞淋巴瘤和何杰金氏淋巴瘤。
术语“治疗”在治疗一种病症的背景下一般属于在其中获得一些希望的治疗效果的对人的治疗和疗法。
术语治疗还包括其他类型的治疗和疗法,其中例如同时或顺序地组合两种或多种治疗,例如同时或顺序地给予类固醇和HDAC抑制剂。例如此处描述的化合物可以单独使用或者组合使用并且例如可以与其他试剂一起使用,例如细胞毒素剂等。实例包括化学疗法(给予活性剂,例如所披露的化合物或CHOP)。CHOP是环磷酰胺、多柔比星、长春新碱和强的松的组合,它们的给予量可以是750+/-10%mg/m2的环磷酰胺,50+/-10%mg/m2的多柔比星,1,4+/-10%mg/m2的长春新碱和50+/-10%mg/m2的强的松。免疫疗法,包括抗体,单克隆抗体或它的一种功能性片段,例如利妥昔单抗,奥法木单抗,GA101,图斯单抗(tositumumab),替伊莫单抗,ocraluzumab,维妥珠单抗,依帕珠单抗,FTBA05,AME-133V或R603。所有上面提到的抗体与B-细胞上出现的CD20结合。抗体的给予量可以为375+/-10%mg/m2。其他实例是前药;手术,放射,和基因疗法。
抗体被包括在本发明的方法中的治疗试剂中,包括它们的功能性片段。此处所用的“抗体”包括多克隆和单克隆抗体,嵌合体,单链,和人化抗体,以及Fab片段,包含Fab或其他免疫球蛋白表达库中的产物。本发明中所用的术语抗体意在包括完整的分子以及它们的片段,例如Fab和F(ab’).sub.2,Fv和SCA片段,它们能够结合感兴趣蛋白上抗原表位决定簇。一个单链抗体(“SCA”)是一种基因工程化的单链分子,其包含由合适的柔性的多肽连接子连接的一个轻链的可变区和一个重链的可变区。
本发明涉及人类。因此这些方法适用于人类疗法。
以下实例意在用来说明,但不是以任何方式,形式,或类型,明确地或暗示地限制本发明。
实例
生物学评价
基于具有对CD20抗体-CHOP诱导的细胞死亡不同敏感性的五个DLBCL细胞系,本发明的发明者已经建立了一个CD20抗体-CHOP抗性(CD20抗体是利妥昔单抗)的细胞系体外模型(Ageberg,Lindén,Linderoth,Jerkeman and Drott;Exp Cell Research(《实验细胞研究》);May1;317(8):1179-91)。在这个模型中,用丙戊酸在药理浓度的治疗显示对CHOP介导的细胞死亡的强敏感效果。这与组蛋白H3的乙酰化作用的增强有关,如通过蛋白质印迹分析测定的。还有,用丙戊酸和泼尼松龙组合对DLBCL细胞系预治疗48小时进一步提高了它们对CHOP诱导的细胞死亡的敏感性。另外,用异羟肟酸/氨基甲酸HDAC抑制剂曲古抑菌素A和贝林司他的预治疗也使得DLBCL细胞系对CHOP-诱导的细胞死亡敏感,通过添加泼尼松龙增强了效果。而且,类固醇地塞米松也增强了由单独丙戊酸诱导的对CHOP-诱导的细胞死亡的致敏效应。总而言之,结果表明HDAC抑制剂和类固醇的组合使B细胞淋巴瘤细胞系对CHOP-诱导的细胞死亡敏感。这表明用HDAC抑制剂和类固醇的组合疗法将增加淋巴瘤治疗中的化疗或免疫化疗的响应。
实例1
丙戊酸(VPA)使DLBCL细胞系对CHOP治疗敏感。
DLBCL细胞系WSU-NHL,Karpas-422,ULA,SU-DHL-5和SU-DHL-8细胞用三种不同浓度(分别是0.1mM,2mM和10mM)的丙戊酸(VPA)单独地或与CHOP组合地处理72小时。所有实例中所用的CHOP方案包括10μM环磷酰胺一水合物,20nM盐酸多柔比星,2nM硫酸长春新碱和20μg/ml泼尼松龙。(Ageberg,Lindén,Linderoth,Jerkeman以及Drott;ExpCell Research(《实验细胞研究》);May1;317(8):1179-91)。
将细胞存活力在72小时后用台盼蓝排除法进行评估并且标准化至0天(播种(seeding))的未处理对照细胞。数据以平均值±SEM表示,n=3。
如表1所示,在所有的淋巴瘤细胞系中,添加丙戊酸增加了对CHOP治疗响应的细胞死亡,表明丙戊酸与CHOP组合对于淋巴瘤患者是有益的。
表1A:ULA细胞
表1B:Karpas-422细胞
表1C:WSU-NHL细胞
表1D:SU-DHL-8细胞
表1E:SU-DHL-5细胞
实例2
生理学相关浓度的丙戊酸(VPA)使DLBCL细胞系对CHOP治疗敏感。
将DLBCL细胞系SU-DHL-8(表2A)和WSU-NHL(表2B)用0.5mM或1.5mM VPA单独地或者与CHOP联合地处理72小时。选择0.5mM VPA浓度是因为它是持续VPA治疗癫痫患者过程中的标准血清浓度。选择1.5mM VPA浓度是因为它是本发明者注意到在同情性用药时用VPA治疗5天过程中最高可耐受的血清浓度。
将细胞存活力分别在0小时(第1天),24小时(第2天),48小时(第3天)和72小时(第4天)后用台盼蓝排除法进行评估并且标准化至未处理对照细胞。数据以平均值表示,n=3。
对照单独CHOP治疗的效果来测试对存活力的治疗效果。使用Student’s不成对t-试验来评估显著差异。所有测试都是双向的。效果被认为是统计学上显著的,P<0.05(*)和P<0.01(**)。
存活力(第1天对照细胞的%)分别在表2A中(SU-DHL-8)和表2B(WSU-NHL,n=3)中显示。
如表2所示,生理学相关浓度的VPA在淋巴瘤细胞系中增强对CHOP治疗响应的细胞死亡,显示生理学相关剂量的丙戊酸和CHOP组合可以对淋巴瘤患者有益。
表2A
表2B
实例3
丙戊酸(VPA)不干扰利妥昔单抗介导的细胞的细胞毒性。
为了评估VPA对CD20抗体利妥昔单抗诱导的抗体依赖性细胞的细胞毒性(ADCC)的影响。
WSU-NHL细胞(表3A和3B)或SU-DHL-8细胞(表3C和3D)用PKH26标记,或者保持未处理或者用1.5mM VPA孵育24小时,之后添加0,0.1,或10μg/ml的利妥昔单抗。
添加NK细胞使得效应物与靶细胞的比例为10:1,之后再孵育这些细胞20小时。将死亡靶细胞鉴定为PKH26和7-AAD双阳性并且作为分析的示值读数。所显示的数据证明死亡细胞的百分比,代表两个独立的试验。数据显示VPA不影响利妥昔单抗诱导的ADCC,与在淋巴瘤患者中一起使用VPA与CD20抗体一致。
表3A:WSU-NHL细胞
表3B:WSU-NHL细胞
表3C:SU-DHL-8细胞
表3D:SU-DHL-8细胞
实例4:单独用丙戊酸(VPA)预治疗使DLBCL细胞系对CHOP治疗敏感
。与用VPA单独预治疗相比,用VPA和泼尼松龙组合的预治疗显著增加细
胞死亡。
在CHOP之前用VPA预治疗理论上可以通过诱导DNA损伤增加对CHOP疗法的响应。但是,VPA治疗可以导致患者中例如多寐的症状。这些症状可以用泼尼松龙同时治疗来缓解。为了研究在CHOP之前用VPA和泼尼松龙进行预治疗的效果,如下所示用VPA、泼尼松龙(P,20μg/ml)和CHOP的不同组合来处理WSU-NHL细胞。在标明的时间点(n=3)通过台盼蓝排除法评估存活力。使用Student’s不成对t-试验评估显著差异。所有的测试都是双向的。效果被认为统计学上显著的,*P<0.05,**P<0.01,***P<0.001。
如表4所示,用VPA单独预治疗使淋巴瘤细胞系对CHOP治疗敏感。而且,与VPA单独预治疗相比,添加泼尼松龙进一步显著增加CHOP-诱导的细胞死亡。这些数据显示在CHOP疗法之前用VPA和泼尼松龙的组合进行预治疗将对于淋巴瘤患者有益。
实例5:与单独用VPA预治疗相比,用VPA和类固醇地塞米松组合预治疗
显著提高CHOP-诱导的细胞死亡。
为了研究不同于泼尼松龙的其他类固醇是否可以致敏VPA和CHOP诱导的细胞死亡,如下所示用不同组合的VPA、类固醇地塞米松(D,1μM)和CHOP处理WSU-NHL细胞。在标明的时间点(n=3)通过台盼蓝排除法评估存活力。使用Student’s不成对t-试验评估显著差异。所有的测试都是双向的。效果被认为统计学上显著的,*P<0.05,**P<0.01,***P<0.001。
如表5所示,与VPA单独预治疗相比,用地塞米松预治疗进一步增加VPA-CHOP-诱导的细胞死亡。这些数据显示在CHOP疗法之前用VPA和其他类固醇(例如地塞米松)组合进行预治疗对于淋巴瘤患者有益。
实例6:用HDAC抑制剂制滴菌素A或贝林司他预治疗使DLBCL细胞系对
CHOP治疗敏感。与用曲古抑菌素A或贝林司他的单独预治疗相比,用曲
古抑菌素A和泼尼松龙组合预治疗显著提高CHOP-诱导的细胞死亡。
为了研究不同于其他HDAC抑制剂亚组的HDAC抑制剂进行预治疗是否也对CHOP-诱导的细胞死亡有致敏作用,如下所示将WSU-NHL细胞用不同组合的异羟肟酸/氨基甲酸HDAC抑制剂曲古抑菌素A(TSA)和贝林司他,泼尼松龙(P,20μg/ml)和CHOP进行处理。在标明的时间点(n=3)通过台盼蓝排除法评估存活力。使用Student’s不成对t-试验评估显著差异。所有的测试都是双向的。效果被认为统计学上显著的,*P<0.05,**P<0.01,***P<0.001。
如表6所示,用曲古抑菌素A单独预治疗使淋巴瘤细胞系对CHOP治疗敏感。而且,与用VPA单独预治疗相比,添加泼尼松龙显著增加CHOP-诱导的细胞死亡。这些数据显示在CHOP疗法之前用同样来自异羟肟酸/氨基甲酸组的HDAC抑制剂以及泼尼松龙的组合进行预治疗对于淋巴瘤患者有益。
贝林司他显示出相似的结果(没有展示数据)。
Claims (25)
1.一种药用组合物,包含
a.一种HDAC抑制剂,它的一种药学上可接受的酸或盐或者它们的混合物以及
b.一种类固醇或它的一种药学上可接受的盐。
2.根据权利要求1所述的药用组合物,其中该HDAC抑制剂是一种异羟肟酸/氨基甲酸,一种环肽,一种脂肪酸或者一种苯甲酰胺化合物。
3.根据权利要求2所述的组合物,其中该HDAC抑制剂选自下组,该组由以下各项组成:伏林司他,罗米地新,丙戊酸,艾斯帕比司他,帕比司他,贝林司他,恩替司他和瑞米司他。
4.根据权利要求3所述的组合物,其中该HDAC抑制剂选自下组,该组由以下各项组成:丙戊酸或丙戊酸半钠,丙戊酸钠或丙戊酸镁。
5.根据权利要求1-4中任何一项所述的组合物,其中该类固醇选自下组,该组由以下各项组成:强的松,泼尼松龙,地塞米松或培他米松。
6.根据权利要求5所述的组合物,其中该类固醇是强的松。
7.根据前述权利要求中任何一项所述的组合物,其中该HDAC抑制剂是丙戊酸,并且该类固醇是强的松。
8.根据前述权利要求中任何一项所述的组合物,进一步包含一种药学上可接受的添加剂,稀释剂,载体,赋形剂或缓冲剂。
9.根据前述权利要求中任何一项所述的组合物,该组合物选自下组,该组由以下各项组成:颗粒剂,粉剂,片剂,包衣片剂,微型胶囊,微型颗粒或泡腾剂形式。
10.根据前述权利要求中任何一项所述的组合物,其中所述泡腾剂形式选自由片剂或粉剂组成的组。
11.一种装置,选自下组,该组由以下各项组成:包含根据权利要求1-10中任何一项所述的组合物的小瓶、安瓿、小袋或输液袋,或者包含一种HDAC抑制剂、它的一种药学上可接受的酸或盐或它们的混合物的一个装置,以及包含一种类固醇或它的一种药学上可接受的盐的一个装置。
12.用于预治疗癌症的一种HDAC抑制剂,它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐。
13.一种HDAC抑制剂,它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐,用于预治疗肉瘤,恶性黑色素瘤,皮肤癌,雌激素受体依赖和不依赖乳腺癌,卵巢癌,前列腺癌,肾癌,结肠和结直肠癌,胰腺癌,头颈癌,小细胞和非小细胞肺癌,以及血细胞癌。
14.一种HDAC抑制剂,它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐,用于预治疗一种选自下组的疾病,该组由以下各项组成:弥散性大B细胞性淋巴瘤(DLBCL),滤泡性淋巴瘤,慢性淋巴细胞性白血病,T细胞淋巴瘤,骨髓瘤和何杰金氏淋巴瘤。
15.一种试剂盒,包含根据权利要求1-10中任何一项所述的药用组合物,该药用组合物提供在一个合适的容器中和/或与合适的包装以及使用说明提供。
16.一种试剂盒,包含提供在一个合适的容器中和/或与合适的包装以及使用说明提供的一种HDAC抑制剂或它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐,该使用说明是例如如何给予这些化合物。
17.根据权利要求16所述的试剂盒,其中这两种活性化合物保存在单独的容器内和/或不同包装中。
18.根据权利要求15-17所述的试剂盒,其中所述试剂盒进一步包含一种抗体、单克隆抗体或者它的功能性片段,其与CD20结合。
19.根据权利要求15-18中任何一项所述的试剂盒,其中所述容器是一个小瓶,安瓿,小袋或者输液袋。
20.通过给予根据权利要求1-10中任何一项所述的药用组合物来预治疗正在遭受癌症的人类的一种方法。
21.预治疗正在遭受癌症的人类的一种方法,该方法是通过同时或顺序地给予用来预治疗癌症的一种HDAC抑制剂、它的一种药学上可接受的酸或盐或它们的混合物以及一种类固醇或它的一种药学上可接受的盐。
22.根据权利要求20-21所述的方法,其中该预治疗之后为化学疗法和/或免疫疗法。
23.根据权利要求20-22所述的方法,用于治疗肉瘤,恶性黑色素瘤,皮肤癌,雌激素受体依赖和不依赖乳腺癌,卵巢癌,前列腺癌,肾癌,结肠和结直肠癌,胰腺癌,头颈癌,小细胞和非小细胞肺癌,以及血细胞癌。
24.根据权利要求23所述的方法,用于治疗一种选自下组的疾病,该组由以下各项组成:弥散性大B细胞性淋巴瘤(DLBCL),滤泡性淋巴瘤,慢性淋巴细胞性白血病,T-细胞淋巴瘤,骨髓瘤和何杰金氏淋巴瘤。
25.评估一种物质对细胞系的CHOP-敏感性的影响的一种方法,包含以下步骤
a.提供一种选自下组的细胞系,该组由以下各项组成::WSU-NHL,Karpas-422,ULA,SU-DHL-5和SU_DHL-8
b.添加环磷酰胺、多柔比星、长春新碱和强的松的一个组合
c.添加一种将有待评估的物质到每一种细胞系
d.并且评估这些细胞的存活力。
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PL (1) | PL2688572T3 (zh) |
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WO (1) | WO2012128709A1 (zh) |
Cited By (3)
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CN109069439A (zh) * | 2016-04-21 | 2018-12-21 | 瓦尔库里亚公司 | 用于预处理癌症的组合物和方法 |
CN109906216A (zh) * | 2016-07-20 | 2019-06-18 | 纽约哥伦比亚大学理事会 | 组蛋白乙酰基转移酶激活剂及其组合物和用途 |
CN113413389A (zh) * | 2021-07-19 | 2021-09-21 | 成都赜灵生物医药科技有限公司 | 一种组蛋白去乙酰化酶抑制剂的制剂及其制备方法和用途 |
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JO3002B1 (ar) | 2009-08-28 | 2016-09-05 | Irm Llc | مركبات و تركيبات كمثبطات كيناز بروتين |
CN108542906A (zh) | 2011-11-11 | 2018-09-18 | 诺华股份有限公司 | 治疗增生性疾病的方法 |
CN103945831A (zh) | 2011-11-23 | 2014-07-23 | 诺华股份有限公司 | 医药制剂 |
CA2890663A1 (en) * | 2012-11-08 | 2014-05-15 | Novartis Ag | Pharmaceutical combination comprising a b-raf inhibitor and a histone deacetylase inhibitor and their use in the treatment of proliferative diseases |
EP3222324B1 (en) * | 2016-03-23 | 2020-05-13 | Wayne State University | Valproate as a topical anti-fungal treatment |
KR102023845B1 (ko) | 2018-06-07 | 2019-11-04 | 계명대학교 산학협력단 | 히스톤 탈아세틸효소 억제제 및 이의 용도 |
GB202016193D0 (en) * | 2020-10-13 | 2020-11-25 | Vestlandets Innovasjonsselskap As | Synergistic combinations |
EP4282408A1 (en) | 2022-05-23 | 2023-11-29 | Valcuria AB | Method for pretreating relapsing cancer |
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- 2012-03-20 CN CN201910595467.8A patent/CN110279861A/zh active Pending
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- 2012-03-20 BR BR112013023970-0A patent/BR112013023970B1/pt active IP Right Grant
- 2012-03-20 ES ES12759898.5T patent/ES2627020T3/es active Active
- 2012-03-20 CN CN2012800127938A patent/CN103442715A/zh active Pending
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109069439A (zh) * | 2016-04-21 | 2018-12-21 | 瓦尔库里亚公司 | 用于预处理癌症的组合物和方法 |
CN109906216A (zh) * | 2016-07-20 | 2019-06-18 | 纽约哥伦比亚大学理事会 | 组蛋白乙酰基转移酶激活剂及其组合物和用途 |
CN113413389A (zh) * | 2021-07-19 | 2021-09-21 | 成都赜灵生物医药科技有限公司 | 一种组蛋白去乙酰化酶抑制剂的制剂及其制备方法和用途 |
CN113413389B (zh) * | 2021-07-19 | 2024-03-15 | 成都赜灵生物医药科技有限公司 | 一种组蛋白去乙酰化酶抑制剂的制剂及其制备方法和用途 |
Also Published As
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KR20140053871A (ko) | 2014-05-08 |
US10143697B2 (en) | 2018-12-04 |
PT2688572T (pt) | 2017-06-02 |
CA2829263C (en) | 2020-05-12 |
BR112013023970B1 (pt) | 2021-11-16 |
US20160271146A1 (en) | 2016-09-22 |
JP5999724B2 (ja) | 2016-09-28 |
BR112013023970A2 (pt) | 2016-12-13 |
CN110279861A (zh) | 2019-09-27 |
EP2688572A4 (en) | 2014-08-20 |
EP2688572A1 (en) | 2014-01-29 |
JP2014510102A (ja) | 2014-04-24 |
EP2688572B1 (en) | 2017-05-03 |
KR101909313B1 (ko) | 2018-10-17 |
PL2688572T3 (pl) | 2017-08-31 |
DK2688572T3 (en) | 2017-06-12 |
US20140093565A1 (en) | 2014-04-03 |
CA2829263A1 (en) | 2012-09-27 |
HUE032100T2 (en) | 2017-08-28 |
WO2012128709A1 (en) | 2012-09-27 |
ES2627020T3 (es) | 2017-07-26 |
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