CN101495144A - 含有乙酰环丙基多西他赛和曲妥单抗的抗肿瘤组合物 - Google Patents
含有乙酰环丙基多西他赛和曲妥单抗的抗肿瘤组合物 Download PDFInfo
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Abstract
描述了一种由以下组分组成的药物组合物：乙酸环丙基泰索帝或其衍生物，以及烷基化剂、抗代谢物、纺锤体抑制剂、表叶毒素、抗生素、酶、拓扑异构酶抑制剂、铂配位复合物、生物反应修饰剂、生长因子抑制剂中的至少一种。
Description
本发明涉及能有效用于治疗肿瘤性疾病的乙酰环丙基多西他赛和曲妥单抗(商品名为赫塞汀)的组合。
乙酸环丙基泰索帝的结构如下：
通常，使用剂量随待治疗患者而不同，腹膜内给药的剂量为1到100mg/kg，静脉内给药的剂量为1到100mg/kg。
抗ErbB2的单克隆抗体(也被称作曲妥单抗)在EP153114中被描述为鼠科动物抗体，该抗体结合人类乳腺癌抗原，所述抗原还结合有选自一系列杂交瘤的参比抗体。所述杂交瘤包括ATCC HB 8488(260F9)，ATCC HB 8490(113F1)，ATCC HB 8486(266B2)，ATCC HB8484C11)，ATCC HB 8697(33F8)，ATCC HB 8485(317G5)，ATCC HB8696(520C9)ATCC HB 8662(260F9-1C9)。赫塞汀通过大规模培养的基因工程中国仓鼠卵巢(Chinese Hamster Ovary(CHO))细胞系分泌抗体至培养基中生产。使用标准色谱和过滤的方法从CHO培养基中提纯该抗体。赫塞汀是在全世界注册的商品。
本发明发现，当乙酰环丙基多西他赛与至少一种在抗癌治疗中具有疗效、与所述紫杉烷衍生物具有相同或不同的作用机制且在本发明中限于曲妥单抗或赫赛汀的物质联合给药时，乙酰环丙基多西他赛的效果会有相当程度的提高。
此外，由于产品的作用依赖于使用剂量，可以通过结合使用乙酰环丙基多西他赛和造血型生长因子(例如G-CSF，GM-CSF)或者某种促白血球素或者它们与其他具有治疗作用的物质的组合来使用低剂量、提高活性并且减少毒性现象或延缓毒性发作。
本发明联合药物的改善效果可通过测定治疗的协同作用来说明。如果疗效优于各组分在以最大耐受剂量单独使用时的效果，所述联合药物显示出治疗的协同作用。
为了说明联合药物的效果，在研究过程中有必要比较联合药物的最大耐受剂量与各单独组分的最大耐受剂量。这个效果可以被量化，例如，如下方程式所确定的log10(被杀死的细胞)：
log10(被杀死的细胞)＝T-C(日)/3.32×Td
其中T-C代表的是肿瘤生长的延迟，它是肿瘤治疗组(T)和肿瘤治疗组(C)达到预定值(例如1g)的平均时间，Td代表对照动物中肿瘤体积增大到2倍所需要的时间[T.H.Corbett等，Cancer，40，2660-2680(1977)；F.M.Schabel等，Cancer Drug Development，Part B，Methods in Cancer Research，17，3-51，New York，Academic Press Inc.(1979)]。如果log10(被杀死的细胞)大于或等于0.7则认为产品有效，如果log10(被杀死的细胞)大于2.8则认为产品非常有效。
以最大耐受剂量使用的联合药物，其中各组分的剂量没有超过其最大耐受剂量，如果其log10(被杀死的细胞)的值大于最佳组分单独给药时的log10(被杀死的细胞)值，就显现出治疗协同作用。当与各组分单独使用时相比，如果log10(被杀死的细胞)的差值大于1，则甚至可以认为联合药物有更强的协同作用。
通过以下方法可以实验性地测定联合药物在固体肿瘤上的疗效：
接受实验的动物一般为小鼠。在第0天，在小鼠皮下双向接种30-60mg肿瘤片断。在接受各种治疗试验和对照试验之前，将患有肿瘤的动物混合在一起。对于晚期肿瘤的治疗，允许肿瘤生长到期望的大小，剔出肿瘤没有充分生长的动物。将选定的动物随机分组进行治疗试验和对照试验。为了从肿瘤特定的效果中分辨出毒性作用，对未患有肿瘤的动物进行同患有肿瘤的动物一样的治疗。化学疗法通常从接种后的第3到22天开始，这取决于肿瘤的类型，每天观察动物。对不同的动物组每周称重3或4次直至达到最大失重，然后对该组进行每周至少一次的称重直到试验结束。
每周测量肿瘤2或3次直到肿瘤达到大约2g；如果肿瘤达到2g前动物死亡，则每周测量肿瘤2或3次直到直到动物死亡。将死亡的动物进行尸体解剖。
根据记录的不同参数确定抗肿瘤活性。
在一项关于白血病的联合药物的研究中，给动物接种特定数量的细胞，通过与对照组对比受治疗小鼠的存活时间的增加来确定抗肿瘤活性。如果存活时间增加大于27％，则认为该产品具有活性；如果增加大于75％，则认为对P388白血病非常有效。
在如下表格中举例给出了乙酰环丙基多西他赛同赫赛汀的联合药物在以最适合剂量使用时得到的结果。
通过带有皮下移植肿瘤的小鼠来评估乙酰环丙基多西他赛同赫赛汀的联合药物。用于评估各联合药物的肿瘤模型通常基于肿瘤模型对各种药物单用治疗时的反应性来选择。使用周期性静脉注射方案，对每种药物及每种联合药物进行全剂量反应试验。在此处，选定的肿瘤是来源于恶性胸腔积液的人类乳腺癌UISO-BCA-1。原发肿瘤是分化良好的浸润性乳腺导管癌。实施了乳房切除术后(postmasectomy)的放射线疗法。在治疗左锁骨上肿块后三年进行化学疗法(10个疗程，用环磷酰胺、甲氨蝶呤、5-Fu和他莫昔芬)。治疗后一个月在疾病发展中对肿瘤细胞抽取样品(Mehta等，1992)。通过植入裸鼠2.107个细胞建立该肿瘤模型，通过连续皮下移植作为肿瘤碎片维持下来。使用液式细胞术，UISO-BCA-1肿瘤表达HER-2，而不表达PgP(mdr)。
异种移植物对多西他赛具有耐药性，对乙酰环丙基多西他赛及5-氟尿嘧啶具有敏感性，对于阿霉素、环磷酰胺及长春新碱具有较低敏感性。
研究被安排成3组剂量反应：
-单独使用乙酰环丙基多西他赛(52.1-12.4mg/kg/静脉注射，第17、21、25天)。
-单独使用赫赛汀(40-2.5mg/kg/sc注射，第17、21、25、29天)。
-联合使用，两种药物同时注射。
使用了如下的终点：
＞诱发20％体重减轻或者＞10％药物死亡时的剂量表示毒性，
由log(被杀死的细胞)＝(T-C)/[3.32×(肿瘤倍增时间(天))]确定最大无毒剂量(HNTD)。
(T代表经治疗小鼠达到1g的时间，C代表对照小鼠达到同样大小的时间(26.2天))。log(被杀死的细胞)小于0.7说明没有抗肿瘤活性，log(被杀死的细胞)大于2.8说明具有高的治疗活性。
反应速率：部分消退(PR)相当于消退大于最初肿瘤载荷的50％，完全消退(CR)相当于消退到低于触诊的极限。
治疗协同作用：如果与单独使用任意药物相比更具有活性，则联合药物具有治疗协同作用(log(被杀死的细胞)的值至少为1)。乙酸环丙泰索帝同赫赛汀组合物治疗裸鼠体中异种移植人类乳房肿瘤UISO-BCA-1
肿瘤倍增时间＝5.0天。每组肿瘤载荷中值＝125mg。
对照组达到1g的天数＝26.2天
使用的缩写：bwl＝体重减轻，T-C＝肿瘤生长延迟，CR＝完全消退
这种联合药物具有协同作用，与观察到的最好的单独药物乙酰环丙基多西他赛相比，具有高出1个log(被杀死的细胞)值的更强的活性。在本试验中，重要的是要注意到，与单独以最高无毒剂量的乙酰环丙基多西他赛的log(被杀死的细胞)值为1.3相比，以最高无毒剂量(每次注射32.3mg/kg，总剂量96.9mg/kg)给予乙酰环丙基多西他赛，同时给予最低剂量的赫赛汀(2.5mg/kg/天，总量10mg/kg)具有协同作用，其log(被杀死的细胞)值为2.6。另外，该联合药物得到了6/8完全消退及2/8长期无肿瘤存活的结果，单独使用乙酰环丙基多西他赛的没有消退。在该联合药物以7剂量水平时观察到很好的抗肿瘤活性。
特别是，所述联合药物的有益之处在于各组分可以按比各组分单独使用时的剂量低得多的剂量来使用。
上面的表格总结了研究中单独药物与各组联合药物的治疗反应及最高无毒剂量。
因此，本发明还涉及包含本发明的联合药物的药物组合物。
组成所述联合药物的各组分可以同时、半同时、单独地或者间隔一段时间给药，以达到该联合药物的最大功效；在给药过程中，给药方式可由快速给药变为连续输液。
结果，就本发明而言，所述联合药物不仅仅局限于通过各组分间物理结合得到的产物，而且还包括那些容许同时或者隔段时间单独给药的联合药物。
本发明的组合物是优选可以通过肠胃外(parentally)给药的组合物。但是就局部区域治疗的情况，所述组合物可以经口服、皮下或腹膜内给药。
用于肠胃外给药(parental administration)的组合物通常为药学上可接受的无菌溶液或者悬浮液，任选在使用的时候可以按需制备。对于非水溶液或混浮液制剂，可以使用天然植物油，如橄榄油、芝麻油或液体石油；或者可以注射的有机酯类，如油酸乙酯。无菌水溶液可以由产品的水溶液组成。只要适当的调整pH值并且使溶液等渗(例如使用足量的氯化钠或葡萄糖)，水溶液也适合静脉给药。可以采取加热或者其他不会负面影响组合物的方式灭菌。联合药物也可采用脂质体的形式或者与环糊精或聚乙二醇载体联合使用的形式。
用于口服、皮下或腹膜内给药的组合物优选为水混浮液或溶液。
在本发明的联合药物中，可以同时、单独或者间隔一段时间使用各组分，紫杉烷衍生物的量占联合药物重量的10-90％十分有利，可以依据相关物质的性质、所需达到的疗效及待治疗癌症的性质改变含量。
本发明的联合药物在治疗乳腺癌、卵巢癌、肺癌及黑色素瘤、白血病方面十分有用。它们可以主要用于对于通常使用的紫杉烷类化合物(taxoids)如泰索或泰索帝具有耐药性的癌症的治疗。它们优选用于对泰索和/或泰索帝具有耐药性的乳腺癌。
Claims (3)
1.一种联合药物，所述联合药物包含式1的化合物或者，以及至少一种抗ErbB2的单克隆抗体
2.权利要求1的联合药物，所述联合药物还包括造血类型的生长因子。
3.式1化合物在制备用于治疗对紫杉烷类化合物具有耐药性的癌症的权利要求1的联合药物中的用途。
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| EP06291264A EP1913958B1 (en) | 2006-08-03 | 2006-08-03 | Antitumor compositions containing acetylcyclopropyl docetaxel and trastuzumab |
| EP06291264.7 | 2006-08-03 |
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| US (1) | US20090196869A1 (zh) |
| EP (2) | EP1913958B1 (zh) |
| JP (1) | JP2009545580A (zh) |
| KR (1) | KR20090037444A (zh) |
| CN (1) | CN101495144A (zh) |
| AR (1) | AR062164A1 (zh) |
| AT (1) | ATE553777T1 (zh) |
| AU (1) | AU2007280099A1 (zh) |
| BR (1) | BRPI0715082A2 (zh) |
| CA (1) | CA2656887A1 (zh) |
| CL (1) | CL2007002257A1 (zh) |
| GB (1) | GB2440643B (zh) |
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| MX (1) | MX2009000856A (zh) |
| PE (1) | PE20080282A1 (zh) |
| RU (1) | RU2414930C2 (zh) |
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| US4753894A (en) | 1984-02-08 | 1988-06-28 | Cetus Corporation | Monoclonal anti-human breast cancer antibodies |
| JP3208517B2 (ja) * | 1992-07-01 | 2001-09-17 | ブリストル−マイヤーズ スクイブ カンパニー | ７，８−シクロプロパタキサン類 |
| EP0577082B1 (en) * | 1992-07-01 | 1996-04-10 | Bristol-Myers Squibb Company | Fluoro taxols with antitumor activity |
| US6441026B1 (en) * | 1993-11-08 | 2002-08-27 | Aventis Pharma S.A. | Antitumor compositions containing taxane derivatives |
| US6333348B1 (en) * | 1999-04-09 | 2001-12-25 | Aventis Pharma S.A. | Use of docetaxel for treating cancers |
| IL147017A0 (en) * | 1999-06-25 | 2002-08-14 | Genentech Inc | TREATING PROSTATE CANCER WITH ANTI-ErbB2 ANTIBODIES |
| US7041292B1 (en) * | 1999-06-25 | 2006-05-09 | Genentech, Inc. | Treating prostate cancer with anti-ErbB2 antibodies |
| KR20110008112A (ko) * | 1999-08-27 | 2011-01-25 | 제넨테크, 인크. | 항-ＥｒｂＢ2 항체 투여 치료 방법 |
| US7361343B2 (en) * | 2003-01-21 | 2008-04-22 | Arius Research Inc. | Cytotoxicity mediation of cells evidencing surface expression of CD63 |
| US7393531B2 (en) * | 2003-01-21 | 2008-07-01 | Arius Research Inc. | Cytotoxicity mediation of cells evidencing surface expression of MCSP |
| JP2006316040A (ja) * | 2005-05-13 | 2006-11-24 | Genentech Inc | Ｈｅｒｃｅｐｔｉｎ（登録商標）補助療法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| TW200820964A (en) | 2008-05-16 |
| EP2049155B1 (en) | 2012-04-18 |
| RU2009107525A (ru) | 2010-09-10 |
| GB2440643A (en) | 2008-02-06 |
| GB2440643B (en) | 2011-04-06 |
| RU2414930C2 (ru) | 2011-03-27 |
| IL195770A0 (en) | 2009-09-01 |
| CL2007002257A1 (es) | 2008-04-18 |
| EP2049155A2 (en) | 2009-04-22 |
| AR062164A1 (es) | 2008-10-22 |
| BRPI0715082A2 (pt) | 2014-11-11 |
| JP2009545580A (ja) | 2009-12-24 |
| UY30522A1 (es) | 2008-02-29 |
| AU2007280099A1 (en) | 2008-02-07 |
| MX2009000856A (es) | 2009-02-04 |
| KR20090037444A (ko) | 2009-04-15 |
| PE20080282A1 (es) | 2008-04-24 |
| ATE553777T1 (de) | 2012-05-15 |
| CA2656887A1 (en) | 2008-02-07 |
| WO2008015578A3 (en) | 2008-04-10 |
| GB0714517D0 (en) | 2007-09-05 |
| WO2008015578A2 (en) | 2008-02-07 |
| US20090196869A1 (en) | 2009-08-06 |
| EP1913958A1 (en) | 2008-04-23 |
| EP1913958B1 (en) | 2009-12-23 |
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