CN101405030B - 针对血管内皮生长因子的抗体和针对人表皮生长因子2型受体的抗体在制备治疗肿瘤的试剂盒中的应用 - Google Patents
针对血管内皮生长因子的抗体和针对人表皮生长因子2型受体的抗体在制备治疗肿瘤的试剂盒中的应用 Download PDFInfo
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Abstract
本发明提供治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病的方法，该方法包括在继续所述抗VEGF抗体治疗的同时，给所述患者施用治疗有效量的抗HER2抗体。本发明还提供相对应的产品和药物组合物的制品。
Description
发明领域
本发明涉及使用抗HER2和抗VEGF抗体的组合治疗。具体地，本发明涉及这样的抗体用来治疗在使用抗VEGF抗体的在先治疗中失败的患者的乳腺癌疾病的应用。
发明背景
血管发生参与各种病症的发病机理，其包括实体瘤、眼内新血管综合征如增殖性视网膜病或年龄相关的黄斑变性(AMD)，类风湿性关节液，和银屑病(Folkman，J.，等，J.Biol.Chem.(生物的化学杂志)267(1992)10931-10934；Klagsbrun，M.，等，Annu.Rev.Physiol.(物理学年度综述)53(1991)217-239；和Garner，A，Vascular diseases(血管疾病)，在：Pathobiology ofocular disease，A dynamic approach(眼科疾病，即动力学途径的病理学)，(eds.)Garner和A，Klintworth，G K，第二版Marcel Dekker，纽约，(1994)，第1625-1710页)。在实体瘤的情形中，与正常细胞相比较，新血管生成允许所述肿瘤细胞获得生长优势和增殖自主性。因此，在乳腺癌以及在一些其它肿瘤中，已经观察到在肿瘤切片中的微脉管密度与患者存活之间的相关性(Weidner，N.，等，N.Engl.J.Med.(新英格兰医学杂志)324(1991)1-6；Horak，E.R.，等，Lancet340(1992)1120-1124；和Macchiarini，P.，等，Lancet340(1992)145-146)。
血管内皮生长因子(VEGF)参与与肿瘤和眼内病症相关的正常和异常的血管发生与新血管生成的调控(Ferrara，N.，等，Endocr.Rev.(内分泌综述)18(1997)4-25；Berkman，R.A.，等，J.Clin.Invest.(临床研究杂志)91(1993)153-159；Brown，L.F.，等，Human Pathol.(人类病理学)26(1995)86-91；Brown，L.F.，等，Cancer Res.(癌症研究)53(1993)4727-4735； Mattern，J.，等，Brit.J.Cancer(英国癌症学杂志)73(1996)931-934；和Dvorak，H.F.，等，Am.J.Pathol.(美国病理学杂志)146(1995)1029-1039)。抗VEGF中和抗体抑制各种人肿瘤细胞系在小鼠中的生长(Kim，K.J.，等，Nature(自然)362(1993)841-844；Warren，R.S.，等，J.Clin.Invest.(临床研究杂志)95(1995)1789-1797；Borgstrom，P，等，Cancer Res.(癌症研究)56(1996)4032-4039；和Melnyk，O.，等，Cancer Res.(癌症研究)56(1996)921-924)。WO94/10202，WO98/45332，WO2005/00900和WO00/35956提及针对VEGF的抗体。人源化的单克隆抗体贝伐单抗(以商标
出售)是用于肿瘤治疗的抗VEGF抗体，并且是批准用于癌症治疗的唯一一种抗-血管发生剂(WO98/45331)。
HER2是人表皮生长因子受体家族的一员，并且在其细胞质结构域抑制蛋白激酶活性。HER2在肿瘤细胞中过量表达，并且与极低的预后和存活有关。因此，HER2是乳腺癌治疗的有价值的靶标。针对HER2的抗体从下列各项中已知：Takai，N.，等，Cancer(癌症)104(2005)2701-2708；Yeon，C.H.，等，Invest.New Drugs(新药物研究)23(2005)391-409；Wong，W.M.，等，Cancer Pract.(其中实践)7(1999)48-50；Albanell，J.，等，Drugs Today(今日药物)(Barc).35(1999)931-46。
曲妥单抗(以商标出售)是用于治疗HER2过表达的/HER2基因扩增的转移性乳腺癌的重组人源化抗HER2单克隆抗体。预临床研究表明该抗体具有体内和体外抗肿瘤活性。此外，在小鼠模型中，在各种抗肿瘤药剂的组合中观察到曲妥单抗抗肿瘤活性的附加的或协同增强。在临床研究中，在HER2过表达转移性乳腺癌患者中观察到存活的延长。
依据WO98/45331，抗VEGF抗体在预防或治疗疾病中的效用可以通过连续或与对那些目的有效的另一种药剂如能够与HER2受体结合的抗体组合施用该抗体而提高。WO2005/012531描述了在结肠直肠癌、转移性乳腺癌和肾癌的治疗中可以与抗VEGF抗体(例如，
)和/或抗ErbB抗体(例如，
组合的抗体。依据WO2005/063816，在转移性乳腺癌的治疗中，抗VEGF抗体可以与抗ErbB抗体组合。WO2005/00090和WO2003/077841还公开了抗VEGF抗体与抗ErbB2抗体的组合用于肿瘤治疗。
临床肿瘤学家一致认为癌症治疗的失败不必是由原发肿瘤的生长引起，而是由向不同器官的转移性扩散引起，所述原发肿瘤通常用手术进行处理。不同细胞毒性药物对原发肿瘤的消退本身不总是抗转移活性的指征。相反，在对一些抗癌药物的反应中，观察到增强的转移(Geldof，A.A.，等，Anticancer Res.(抗癌研究)8(1988)1335-1339；Murphy，S.B.，J.Clin.Oncol.(临床肿瘤学杂志)11(1993)199-201；和De Larco，J.E.，等，Cancer Res.(癌症研究)61(2001)2857-2861)。清楚地，存在发展不但靶向原发肿瘤而且抑制转移的疗法的需要。
发明概述
本发明包括抗HER2抗体和抗VEGF抗体用于制备用来治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病的药物中的应用，所述应用包括给所述患者施用治疗有效量的抗HER2抗体和抗VEGF抗体。
在优选的实施方案中，本发明包括曲妥单抗和贝伐单抗用于制备用来治疗在用抗VEGF抗体如贝伐单抗的在先治疗中失败的患者中的乳腺癌疾病的药物中的应用，所述乳腺癌疾病特征在于HER2受体蛋白的过量表达，该应用包括给所述患者施用治疗有效量的曲妥单抗和贝伐单抗。
本发明还包括治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病的方法，该方法包括在继续所述抗VEGF抗体治疗的同时给所述患者施用治疗有效量的抗HER2抗体。
本发明还包括治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病的方法，所述乳腺癌疾病的特征在于HER2受体蛋白的过量表达，该方法包括在继续贝伐单抗治疗的同时给所述患者施用治疗有效量的曲妥单抗。
本发明还包括用于增加在用抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者的存活持续时间的方法，该方法包括给所述患者施用有效量的抗VEGF抗体和抗HER2抗体，由此所述抗VEGF抗体和所述抗HER2抗体的共同施用有效地增加存活的持续时间。
本发明还包括用于增加在用抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者的进展性自由存活的方法，该方法包括给所述患者施用有 效量的抗VEGF抗体和抗HER2抗体，由此所述抗VEGF抗体和所述抗HER2抗体的共同施用有效地增加进展性自由存活的持续时间。
本发明还包括用于治疗一组患有乳腺癌疾病并且在用抗VEGF抗体的在先治疗中失败的患者的方法，该方法包括给所述患者施用有效量的抗VEGF抗体和抗HER2抗体，由此所述抗VEGF抗体和所述抗HER2抗体的共同施用有效地增加在该患者组中的应答率。
本发明还包括用于增加在用抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者的应答持续时间的方法，该方法包括给所述患者施用有效量的抗VEGF抗体和抗HER2抗体，由此所述抗VEGF抗体和所述抗HER2抗体的共同施用有效地增加应答的持续时间。
本发明还包括治疗在用抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者的方法，该方法包括给所述患者施用有效量的抗VEGF抗体和抗HER2抗体，由此当通过存活持续时间、进展性自由存活、应答率或应答的持续时间测量时，所述抗VEGF抗体和所述抗HER2抗体的共同施用导致被治疗的患者的统计学显著和临床有意义的改善。
本发明还包括用于减少在用抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者中的转移的方法，该方法包括给所述患者施用有效量的抗VEGF抗体和抗HER2抗体，由此所述抗VEGF抗体和所述抗HER2抗体的共同施用有效减少转移。
本发明还包括用于治疗患有乳腺癌疾病并且在用抗VEGF抗体的在先治疗中失败的一组患者的方法，该方法包括给所述患者施用有效量的抗VEGF抗体和抗HER2抗体，由此所述抗VEGF抗体和所述抗HER2抗体的共同施用有效地减少在该组患者中的转移。
本发明提供制品(an article of manufacture)，其包括容器，在所述容器内的组合物，该组合物包括抗VEGF抗体，和药品说明书，该药品说明书指导该组合物的使用者将所述抗VEGF抗体和抗HER2抗体施用给在用所述抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者。
本发明还提供制品，其包括容器，在所述容器内的组合物，该组合物包括抗HER2抗体，和药品说明书，该药品说明书指导该组合物的使用者将所述抗HER2抗体和抗VEGF抗体施用给在用所述抗VEGF抗体的在先 治疗中失败的患有乳腺癌疾病的患者。
本发明还提供一种组合物，该组合物包括抗HER2抗体和抗VEGF抗体，其有效用于治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病。优选地，所述抗HER2抗体是曲妥单抗。还优选地，所述抗VEGF抗体是贝伐单抗。
附图简述
图1在贝伐单抗治疗失败后组合曲妥单抗和贝伐单抗治疗对肿瘤生长的抗肿瘤活性。肿瘤体积(mm3)的平均值绘制在y-轴上；在肿瘤细胞注射后的天数绘制在x-轴上。赋形剂(圆圈)，以30mg/kg负荷剂量和15mg/kg维持剂量的曲妥单抗(正方形)，在治疗还包括以15mg/kg的曲妥单抗时持续到第55天的以5mg/kg的贝伐单抗(三角形)。
图2组合曲妥单抗和贝伐单抗治疗对肺转移的作用。人Alu DNA序列的平均值(ng/ml)用实时PCR从肺组织定量，并且绘制在y-轴上。
发明详述
依据本发明，术语＂VEGF＂指血管内皮细胞生长因子(瑞士-Prot号P15692)，可变剪接形式(参见，例如，Leung，D.W.，等，Science(科学)，246(1989)1306-1309；和Houck，K.A.，等，Mol.Endocrin.(分子内分泌学)5(1991)1806-1814)和活性片段，优选其N端片段。
依据本发明，术语“抗VEGF抗体”是与VEGF特异性结合的抗体。本文优选的人源化抗VEGF抗体或变体抗VEGF抗体以不大于约1×10-8M并且优选地不大于约5×10-9M的Kd值结合人VEGF。优选地所述抗VEGF抗体是单克隆抗体，其与依据Presta，L.G.，等，Cancer Res.(癌症研究)57(1997)4593-4599产生的重组人源化抗VEGF单克隆抗体结合相同的表位。优选的抗体是贝伐单抗。抗VEGF抗体及其制备方法，例如，在US6,054,297，US2003/0190317，US6,632,926，US6,884,879，和US2005/0112126中描述。
贝伐单抗包括突变的人IgG1构架区和来自鼠源抗hVEGF单克隆抗体的抗原结合互补决定区，所述抗体阻碍人VEGF与其受体的结合。贝伐单抗约93％的氨基酸序列，包括大部分构架区，是来源于人IgG1，并且约7％的序列是来自于鼠源抗体A4.6.1。贝伐单抗具有约149,000道尔顿的分子质量，并且是糖基化的。贝伐单抗及其制备方法在EP1325932中描述。
HER2是185-kDa的生长因子受体，还叫作neu和c-erbB-2(Slamon，D.J.，等，Science(科学)235(1987)177-182；瑞士-Prot P04626)，其功能与人乳腺癌细胞中的肿瘤转化相关。这种蛋白的过量表达已经在20-30％的乳腺癌患者中鉴定到，其中它与地方性晚期疾病、肿瘤复发的增加的可能性和减少的患者存活相关。多如30-40％的患有胃癌、子宫内膜癌、唾液腺癌、非小细胞肺癌、胰腺癌、卵巢癌、腹膜癌、前列腺癌或结肠直肠癌的患者也可以表现出这种蛋白的过量表达。抗HER2抗体及其制备方法，例如，在US6,054,297，WO89/06692，US6,953,842，US6,949,245，US6,399,063，US6,165,464，US6,054,297，US5,772,997，WO2003/087131，WO01/00245，WO01/00238，WO00/69460，WO00/52054，WO99/31140和WO98/17797中所述。在本发明的优选实施方案中，所述抗HER2抗体是曲妥单抗。曲妥单抗及其制备方法在EP0590058中描述。
术语HER2受体蛋白的“过量表达”意欲指，相对于在来自组织或器官的正常细胞中的表达水平，HER2受体蛋白在来自患者的特异性组织或器官内的肿瘤的细胞中的异常表达水平。患有特征在于所述HER2受体的过量表达的癌症的患者可以通过本领域已知的标准测定确定。优选地，过量表达使用免疫组织化学(IHC)检测在冷冻或石蜡-包埋的组织切片的固定的细胞中测量。当与组织学染色结合时，可以确定被靶向的蛋白的位置，并且可以定量和半定量地测量其在肿瘤内的表达程度。这样的IHC测定在本领域内是已知的，并且包括临床试验测定(CTA)、可商购的LabCorp4D5检测，和可商购的DAKO(DAKO，Carpinteria，加利福尼亚州)。后一测试使用0到3+特定范围的细胞染色(0是正常表达，3+表示最强的阳性表达)，以鉴定具有HER2蛋白过量表达的癌症(参见 
(曲妥单抗)完整处方信息，1998年9月，基因技术公司(Genentech Inc.)，旧金山，加利福尼亚州)。因此，患有特征在于在1+，2+， 或3+，优选地2+或3+，更优选3+范围内的HER2蛋白过量表达的癌症的患者将受益于本发明的治疗方法。
术语“乳腺癌疾病”指异常乳腺细胞的不受控制的生长。它包括原位导管癌、侵入性导管癌、原位小叶癌、侵入性小叶癌、髓样癌、乳头佩吉特病、和转移性乳腺癌。
当用于本文时，术语“在用抗VEFG抗体的在先治疗中失败”或“治疗失败”指不能响应用抗VEGF抗体的先前治疗的肿瘤患者(“无应答者”)或最初响应先前的治疗但是治疗反应没有保持的肿瘤患者(叫作“复发者”)。优选地，术语“在用抗VEFG抗体的在先治疗中失败”指复发者。治疗失败(分别是应答(RE)和无应答(NR))基于从业者的医学判断而确定，所述医学判断是通过来自本领域已知的通常评估患者治疗的临床和实验室数据的结果而确定。例如，这样的数据可以从临床检查、细胞学和组织学技术、内窥镜检查和腹腔镜检查、超声、CT、PET和MRI扫描，胸腔X-射线和乳房X线摄影术、并且测量肿瘤标记诸如CEA，Cyfra，CA15-3，白介素8和可溶HER2的浓度而获得。在这种情形中，“治疗失败”定义为临床改善的缺乏。备选地，RECIST标准可以用来确定肿瘤应答(Therasse，P，等，J.Nat.Cancer Institute(国家癌症研究所杂志)92(2000)205-216)。在这种情形中，“治疗失败”定义为“不完全应答/稳定的疾病”或“进展性疾病”。
依据这些RECIST标准，依赖于肿瘤体积进展或消退(例如，通过CT测量)，将实体肿瘤的肿瘤应答(Therasse，P.，等，J.Nat.Cancer Institute(国家癌症研究所杂志)92(2000)205-216)归类成4个水平：完全应答(CR)或部分应答(PR)，稳定疾病(SD)和进展性疾病(PD)(参见表1)。此外，欧洲癌症研究和治疗组织(European Organization for Research and Treatment ofCancer(EORTC))依赖于通过2-[18F]-氟-2-脱氧葡萄糖正电子发射体层摄影术(FDG-PET)测量的肿瘤的新陈代谢而提出分成4个水平的分类(Young H.，等，Eur.J.Cancer(欧洲癌症杂志)35(1999)1773-1782和Kellof，G.J.，等，Clin.Cancer Res.(临床癌症研究)11(2005)2785-2808)：完全代谢应答(CMR)或部分代谢应答(PMR)，稳定代谢疾病(SMD)和进展性代谢疾病(PMD)(参见表2)。
表1：CT-标准(依据RECIST) 表2：提议的FDG-PET标准(依据 EORTC，参见Young H.，等，Eur J Canc(欧洲癌症杂志)35(1999) 1773-1782)
因此，优选地，依据本发明，“应答(RE)”和“不应答(NR)”是使用上述RECIST和FDG-PET标准基于这样的数据而确定的，所述数据通过计算机 体层摄影术(CT)和2-[18F]-氟-2-脱氧葡萄糖正电子发射体层摄影术(FDG-PET)的结合而获得(Kellof，G.J.，等，Clin.Cancer Res.(临床癌症研究)11(2005)2785-2808，和Young H.，等，Eur.J.Canc.(欧洲癌症研究)35(1999)1773-1782)。因此，依据本发明，应答(RE)和不应答(NR)优选地如下确定：
应答(RE)：CR或PR通过CT-RECIST标准确立(表1)，并且同时CMR或PMR通过FDG-PET确立(表2)。因此，应答(RE)意指下述关于组合的CT和PET测量的4种情形中的一种：CR和CMR，PR和PMR，CR和PMR，以及PR和CMR。
不应答(NR)：SD或PD通过CT-RECIST标准确立(表1)，并且同时SMD或PMD通过FDG-PET确立(表2)。因此，下述4种关于组合的CT和PET测量的情形表示不应答(NR)：SD和SMD，SD和PMD，PD和SMD，以及PD和PMD。
通常所述应答在治疗开始后约3到8周确定，优选地在约6周确定。这种应答确定通常以4到8周，优选地6到8周的时间间隔重复。当在第一次确定鉴定了显著的应答(RE)时，那么复发(其意味着在第一次确定之后的不应答(RE))可以在第二次应答确定时最早确定。
在这种情形中，术语“在用抗VEGF抗体的在先治疗中失败的患者”指这样的患者，即，在他们中在第一次反应确定时确立为不应答(NR)(“不应答者”)或者在第一次应答确定中确立为应答(RE)，并且在第二次或随后的应答确定中确立为不应答(NR)(“复发者”)。
依据本发明，术语“转移”指癌细胞从原发性肿瘤向患者中的一个或多个其它位点转移引起继发性肿瘤。由已经扩散的细胞形成的肿瘤叫作“转移瘤”或“转移”。所述转移瘤包含与在原始(原发性)肿瘤中的细胞相似的细胞。确定癌症是否转移的方法在本领域内是已知的，并且包括肿瘤标记检测、骨扫描、胸腔X-线、计算机体层摄影术(CT)、计算机轴向体层摄影术(CAT)、分子共振成像(MRI)、正电子发射体层摄影术(PET)、单光子发射计算机体层摄影术(SPECT)、荧光成像(FI)、和生物发光成像(BLI)与肿瘤标记检测(参见，例如，Helms，M.W.，等，Contributions tomicrobiology(微生物学的贡献)13(2006)209-231，和Pantel，K.，等，J.Nat. Cancer Inst.(国家癌症研究所杂志)91(1999)1113-1124)。
当用于本文时，术语“患者”优选地指需要治疗癌症、或癌症前期病况或损害的治疗的人。然而，术语“患者”还可以指非人动物，优选地哺乳动物，其中诸如狗、猫、马、母牛、猪、绵羊和非人灵长类，其需要治疗。
术语“组”指一组患者以及亚组患者。
术语“药品说明书”指通常包含在治疗产品的商业包装中的说明，其可以包括关于适应症、使用、剂量、施用、禁忌症和/或关于所述治疗产品应用的警告的信息。
所述癌症可以是，例如，肺癌、非小细胞肺(NSCL)癌、支气管(bronchioloalviolar)细胞肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌症、胃癌(stomachcancer)、胃癌(gastric cancer)、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、膀胱癌、肾或尿道癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆囊癌、慢性或急性白血病、淋巴细胞淋巴癌、中枢神经系统(CNS)肿瘤、脊柱肿瘤、脑干神经胶质瘤、多形式成胶质细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、成神经管细胞瘤、脑膜瘤、鳞状细胞瘤、垂体腺瘤，包括上述癌症中任一种的难控制的版本，或上述癌症中一种或多种的组合。所述癌症前期病况或损害包括，例如，由下列各项组成的组：口白斑病、光化性角化病(actinic keratosis)(光化性角化病(solarkeratosis))、癌症前期的结肠或直肠息肉、胃上皮发育不良、腺瘤状发育不良、遗传性非息肉结肠癌综合征(HNPCC)、巴特雷食道病、膀胱发育不良、和癌症前期子宫颈病症。在优选实施方案中，待治疗的癌症是乳腺癌疾病。也在优选的实施方案中，所述癌症的特征在于HER2受体蛋白的过量表达。
本发明包括治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病的方法，该方法包括在继续所述抗VEGF抗体治疗的同时，给所述患者施用治疗有效量的抗HER2抗体。
当用于本文时，除非另外指明，术语“治疗”意指对患者中肿瘤生长，肿瘤转移，或其它引起癌症或瘤性细胞的部分或完全逆转、减轻、抑制发展，或者防止。当用于本文时，除非另外指明，术语“治疗”指治疗的行为。
短语“治疗方法”或其等价体，例如，当用于癌症时，指设计成减少或消除患者中的癌细胞数目或减轻癌症症状的作用方法或过程。“治疗癌症或另一种增殖性病症的方法”不必意指所述癌细胞或其它病症将实际上被消除，细胞数目或病症将实际上被减少，或者癌症或其它病症的症状将实际上被减轻。通常，治疗癌症的方法将甚至以低成功可能性而进行，但是，给出患者的医疗史和估计的存活预测，仍然认为其是一种大体上有益的作用过程。
术语“治疗有效量”或“有效量”意指将引发组织、系统、动物或人的生物或医学应答的受试化合物或组合的量，所述组织、系统、动物或人是研究者、兽医、医学医生或其他临床医师所寻找的。
本发明还包括抗HER2抗体和抗VEGF抗体用于制备用来治疗在用抗VEGF抗体的在先治疗中失败的患者中的乳腺癌疾病的药物中的应用，该应用包括在继续所述抗VEGF抗体治疗的同时，给所述患者施用治疗有效量的抗HER2抗体。所述抗体可以分开或同时施用。
术语“制备药物的方法”涉及制备用于本文所述的适应症并且特别是通常用于治疗肿瘤、肿瘤转移或癌症的药物。该术语涉及所谓的在所述适应症中的“瑞士-型”要求形式。
在本发明的上下文中，另外的其它细胞毒性的、化学治疗的或抗癌药剂、或增强所述药剂作用的化合物可以用在抗VEGF抗体加抗HER2抗体组合中。这样的药剂包括，例如：烷化剂或具有烷化作用的药剂，诸如环磷酰胺(CTX；例如，
苯丁酸氮芥(CHL；例如
顺铂(CisP；例如，川铂注射剂白消安(例如，马利兰
美法仑，卡莫司汀(BCNU)，链脲霉素，曲他胺(TEM)，丝裂霉素C等；抗代谢物，诸如甲氨蝶呤(MTX)，依托泊苷(VP16；例如，凡必士
6-巯嘌呤(6MP)，6-硫鸟嘌呤(6TG)，阿糖胞苷(Ara-C)，5-氟尿嘧啶(5-FU)，卡培他滨(例如，适罗达
)，达卡巴嗪(DTIC)，等；抗生素，诸 如放线菌素D，多柔比星(DXR；例如，阿霉素
柔红霉素(道诺霉素)，博来霉素，光辉霉等；生物碱，诸如长春生物碱如长春新碱(VCR)，长春碱等；以及其它抗肿瘤药，诸如紫杉醇(例如，
和紫杉醇衍生物，细胞生长抑制剂，糖皮质激素诸如地塞米松(DEX；例如，和皮质类固醇诸如泼尼松，核苷酶抑制剂诸如羟基脲，氨基酸耗尽酶如天冬酰胺酶，亚叶酸和其它叶酸衍生物，以及类似的、不同的抗肿瘤药。下述药剂也可以用作添加剂：amifostine(例如，
放线菌素D，氮芥(mechlorethamine)(氮芥(nitrogen mustard))，链佐星，环磷酰胺，洛莫司汀(CCNU)，多柔比星脂质体(例如，盐酸多柔比星脂质体
吉西他滨(例如，柔红霉素脂质体(例如，
丙卡巴肼，丝裂霉素，多西他赛(例如，
阿地白介素，卡铂，奥沙利铂，克拉屈滨，喜树碱，CPT11(伊立替康)，10-羟基7-乙基-喜树碱(SN38)，氟尿苷，氟达拉滨，异环磷酰胺，伊达比星，美钠，干扰素β，干扰素α，米托蒽醌，托泊替康，亮丙立德，甲地孕酮，美法仑，巯嘌呤，普卡霉素，米托坦，培门冬酶，喷司他丁，哌泊溴烷，普卡霉素，他莫昔芬，替尼泊苷，睾内酯，硫鸟嘌呤，赛替哌，乌拉莫司汀，长春瑞滨，苯丁酸氮芥。
在本发明的情形中，抗激素药可以用在抗VEGF抗体加抗HER2抗体组合中。当用于本文时，术语“抗激素药”包括天然的或合成的起作用调控或抑制激素对肿瘤的作用的有机或肽化合物。抗激素药包括，例如：类固醇受体拮抗剂，抗雌激素如他莫昔芬，雷洛昔芬，芳香酶抑制性4(5)-咪唑，其它芳香酶抑制药，42-羟基他莫昔芬，曲沃昔芬，keoxifene，LY117018，奥那司酮，和托瑞米芬(例如，
抗雄激素药如氟他胺，尼鲁米特，比卡鲁胺，亮丙立德，和戈舍瑞林；以及上述任一种的药用盐、酸或衍生物；糖蛋白激素的激动剂和/或拮抗剂，如滤泡刺激激素(FSH)，甲状腺刺激激素(TSH)，和黄体生成素(LH)与LHRH(促性腺激素释放激素)；LHRH激动剂醋酸戈舍瑞林，可以
(AstraZeneca)商购；LHRH拮抗剂D-丙氨酰胺(alaninamide)N-乙酰基-3-(2-萘基)-D-丙氨酰-4-氯-D-苯丙氨酰-3-(3-吡啶基)-D-丙氨酰-L-丝氨酰-N6-(3-吡啶基羰基)-L-赖氨酰-N6-(3-吡啶基羰基)-D-赖氨酰-L-亮氨酰-N6-(1-甲基乙基)-L-赖氨酰-L-脯氨酸(例如，
Ares-Serono)；LHRH拮抗剂醋酸加尼瑞克；类固醇抗雄 激素醋酸环丙孕酮(CPA)和醋酸甲地孕酮，可以(Bristol-MyersOncology)商购；非类固醇抗雄激素氟他胺(2-甲基-N-[4，20-硝基-3-(三氟甲基)苯基丙酰胺)，可以
(Schering公司)商购；非类固醇抗雄激素尼鲁米特，(5，5-二甲基-3-[4-硝基-3-(三氟甲基-4’-硝基苯基)-4，4-二甲基-咪唑烷二酮)；和其它非许可的受体的拮抗剂，诸如RAR(视黄酸受体)，RXR(类视黄醇X受体)，TR(甲状腺受体)，VDR(维生素-D受体)等的拮抗剂。
上述细胞毒性和其它抗癌药在化学治疗方案中的应用通常特征充分在于癌症治疗技术，并且它们的应用在这里是处于监测耐受性和功效的考虑中和控制施用途径和剂量的考虑中，具有一些调整。例如，细胞毒性剂的实际剂量可以随着通过使用组织培养方法确定的患者的培养的细胞应答而变化。通常，与不存在添加的其它药剂时所用的量相比，剂量将是减少的。
有效细胞毒性药的典型剂量可以在供应商推荐的范围内，和由体外应答或在动物模型中的应答所指示的剂量，可以减少多至约一个数量级浓度或量。因此，基于原代培养的恶性细胞或组织培养的组织样品的体外应答或在适当的动物模型中观察到的应答，实际剂量将取决于医师的判断、患者的病况、和治疗方法的功效。
在本发明的情形中，其它的抗增殖药可以用在抗VEGF抗体加抗HER2抗体组合中，其包括，例如：酶法尼基蛋白转移酶的抑制剂和受体酪氨酸激酶PDGFR的抑制剂，包括在美国专利号6,080,769；6,194,438；6,258,824；6,586,447；6,071,935；6,495,564；6,150,377；6,596,735和6,479,513，以及国际公布WO01/40217中公开和要求的化合物。
在本发明的情形中，可以实行有效量的电离辐射和/或除了抗VEGF抗体加抗HER2抗体组合之外，可以使用放射药物。放射源可以在被治疗的患者的外部或内部。当所述放射源在患者外部时，该治疗叫作外光束放射治疗(EBRT)。当放射源在患者内部时，治疗叫作近距放射治疗(BT)。用于本发明情形中的放射活性原子可以选自包括但不限于下列各项的组：镭，铯-137，铱-192，镅-241，金-198，钴-57，铜-67，锝-99，碘-123，碘-131，和铟-111。当依据本发明EGFR激酶抑制剂是抗体时，将所述抗体用这样的放射活性同位素标记也是可能的。
放射治疗是用于控制不能切除的或不宜手术的肿瘤和/或肿瘤转移的 标准治疗。当放射治疗与化学治疗组合时，已经观察到改善的结果。放射治疗是基于这样的原理，即，递送至靶点区域的高剂量的射线将导致肿瘤和正常组织中的生殖细胞的死亡。放射剂量方案通常关于吸收的射线剂量(Gy)、时间和级分而定义，并且必须由肿瘤学家认真地定义。患者接受的射线的量将取决于各种考虑，但是两种最重要的考虑是肿瘤关于机体的其它关键结构或器官的位置，以及肿瘤扩散的程度。关于进行放射治疗的患者的典型的治疗疗程应该是持续1到6周时间的治疗时间表，在10和80Gy之间的总剂量施用给患者，单次日常级分约1.8到2.0Gy，一周5天。在本发明的优选实施方案中，当人患者中的肿瘤用本发明的组合治疗和放射进行治疗时，存在增效作用。换言之，当与放射组合，任选地与其它化学治疗或抗癌药组合时，通过包括本发明的组合的药剂方式对肿瘤生长的抑制得以增强。辅佐的放射治疗的参数，例如，包含在国际公布WO99/60023中。
所述抗体按照已知的方法施用给患者，作为大丸剂(bolus)通过静脉内施用，或者通过在某一时间阶段连续输注，通过肌内，腹膜内，脑脊液内(intracerobrospinal)，皮下，关节内，滑膜内，或鞘内途径施用。优选静脉内或皮下施用抗体。
抗VEGF和抗HER2抗体施用的量和施用的时间将取决于被治疗的患者的类型(人种，性别，年龄，体重，等)和病况以及被治疗的疾病或病况的严重性。
使用本发明所述的抗体的剂量为约1μg/kg到50mg/kg(例如，0.1-20mg/kg)抗体，通过一次或多次分开的施用，或通过连续的输注。典型的日常剂量可能在约1μg/kg到约100mg/kg范围内。在优选的方面，所述抗体每两到三周施用，以在约1mg/kg到约15mg/kg范围内的剂量。贝伐单抗的优选剂量是以IV输注5mg/kg每14天一次，直到检测到疾病进展。曲妥单抗的优选剂量是在90分钟的时间周期施用的4mg/kg的负载剂量，并且随后在30分钟的时间周期施用的每周2mg/kg的输注。
本发明还提供了包括抗VEGF抗体和药品说明书的试剂盒，所述药品说明书指示该组合物的使用者将所述抗VEGF抗体和所述抗HER2抗体施用给在用抗VEGF抗体的在先治疗中失败的患有乳腺癌疾病的患者。在优 选的实施方案中，所述试剂盒容器可以进一步包括药用载体。所述试剂盒可以进一步包括无菌稀释剂，其优选地保存在独立的另外的容器中。所述试剂盒可以进一步包括药品说明书，其包括指导将所述组合治疗用作乳腺癌疾病的方法的印刷的指示。
本发明还提供药物组合物，特别用于治疗在用抗VEGF抗体的在先治疗中失败的乳腺癌疾病，所述药物组合物包括抗HER2抗体和抗VEGF抗体。这样的组合物任选地包括药用载体和/或赋形剂。在优选的实施方案中，所述抗VEGF抗体是贝伐单抗，并且所述抗HER2抗体是曲妥单抗。
提供下述实验详细资料以辅助对本发明的理解，本发明的真正的范围是在后附的权利要求中提出的。应该理解，所讨论的具体的方法和结果只是举例说明本发明，并不认为是以任何方式限制本发明。
导言
本研究在人乳腺异种移植物模型中检验了在单独的贝伐单抗治疗失败后贝伐单抗和曲妥单抗组合的抗肿瘤活性。本研究的其它目的是检验治疗对转移的作用。
检测药剂
曲妥单抗以在组氨酸-HCl，α-α海藻糖(60mM)，0.01％药用有机聚合物载体(Polysorb)，pH6.0中的25mg/ml的储液提供
贝伐单抗以在磷酸钠，α-α海藻糖(60mM)，0.01％药用有机聚合物载体(Polysorb)，pH6.0中的25mg/ml的储液提供
两种溶液都适当地稀释在PBS中用于注射。
细胞系和培养条件
人乳腺癌细胞系KPL-4建立自具有炎性皮肤转移的乳腺癌患者的恶性胸膜渗出液，并且过量表达ErbB家族受体。(Kurebayashi，J.，等，Br.J.Cancer(英国癌症杂志)79(1999)707-17)肿瘤细胞通常在补充了10％胎牛血清(PAA)和2mM L-谷氨酰胺(Gibco)中的DMEM培养基(PAA实验室，奥地利)中在37℃在水饱和的5％CO2氛围中培养。培养物的传代用胰蛋白 酶EDTA1x(PAA)进行，分裂2次/周。细胞传代P6用于体内研究。
动物
SCID beige(C.B.-17)小鼠；10-12周龄；体重18-20g(Charles River，Sulzfeld，德国)依据国际指南(GV-Solas；Felasa；TierschG)保持在无特异性病原体的条件下，每天周期12小时光照/12小时黑暗。在到达后，将动物在动物机构的检疫部门笼养1周，以适应新环境和用于观察。在常规基础上进行连续的健康监测。饮食食品(Alltromin)和水(酸化pH2.5-3)随意提供。
体内肿瘤生长抑制研究
将肿瘤细胞从培养瓶(Greiner TriFlask)收集下来(胰蛋白酶-EDTA)，并且转移到50ml培养基中，洗涤一次并重悬在PBS中。在用PBS的另一洗涤步骤和过滤(细胞过滤器；Falcon100μm)之后，将最终细胞滴度调整到0.75x108/ml。将肿瘤细胞混悬液仔细用转移移液管混合，以避免细胞聚集。使用用于小动物的Stephens吸入部件进行麻醉，其具有在封闭的循环系统中的预培育室(树脂玻璃)，个体小鼠鼻面具(硅)和Isoflurane(Pharmacia-Upjohn，德国)。在注射前两天，将动物的毛剃掉。对于乳房内脂肪垫(i.f.m.p.)注射，将细胞以20μl的体积同位(orthotopically)注射到每只麻醉小鼠的右侧倒数第二个腹股沟乳房脂肪垫中。对于同位移植，将细胞混悬液通过在乳头下的皮肤进行注射。肿瘤细胞注射对应于实验的第一天。
监测
每日控制动物，以检测不利作用的临床症状。对于在整个实验过程中的监测，动物的体重每周记录两次，并且肿瘤体积通过卡钳每周测量两次。原代肿瘤体积依据NCI方法(TW＝1/2ab2，其中a和b是肿瘤尺寸的长径和短径，单位为mm，Teicher，B.，Anticancer drug development guide(抗癌药开发指南)，Humana出版社5(1997)92)计算。计算值记录为平均值和标准偏差。
动物的治疗
当肿瘤体积约100mm3时，将带有肿瘤的小鼠随机化(每组n＝10)。在治疗之前将每组紧密地匹配，其在肿瘤细胞注射后20天开始。赋形剂组(组1)腹膜内接受10ml/kg PBS缓冲液，每周一次。曲妥单抗(组2)以30mg/kg的负荷剂量腹膜内施用，而后以15mg/kg(维持剂量)的剂量每周一次。将抗VEGF抗体贝伐单抗以5mg/kg的剂量腹膜内给与，每周两次(组3)。在第40天，将组3的治疗转换成贝伐单抗(5mg/kg，每周两次，腹膜内)和曲妥单抗(15mg/kg，每周一次，腹膜内)的组合治疗。
转移的评估
在处死的动物中确定肿瘤细胞向肺部的扩散。转移依据Schneider，T.，等，Clin.Exp.Metastasis(转移的临床实验)19(2002)571-582进行测量。概言之，收集肺组织，并且通过实时PCR定量人Alu序列。通过实时PCR定量的更高的人DNA水平对应更高的转移水平。
结果
治疗对原代肿瘤生长的效果显示在图1和表3中。在赋形剂组(组1)中的肿瘤生长迅速，并且由于肿瘤溃疡和临床症状的发展，在肿瘤细胞注射后38天将小鼠处死。使用曲妥单抗的单一治疗(组2)对肿瘤体积没有施加显著的作用，并且因此将小鼠在第44天处死。用贝伐单抗治疗显著地抑制肿瘤生长；然而，肿瘤大约在第44天开始重新生长。在第55天开始的贝伐单抗和曲妥单抗组合治疗在实验持续过程中(99天)导致对肿瘤生长的完全抑制，并且治疗是很好耐受的。
表3：在贝伐单抗治疗失败后组合的曲妥单抗和贝伐单抗治疗对肿瘤生长的抗肿瘤活性(图1的数据)。报道了以mm3为单位的平均肿瘤体积和标准偏差(SD)。
治疗对肺转移的作用显示在图2和表4中。在贝伐单抗治疗失败后曲妥单抗和贝伐单抗组合导致转移的急速降低。与在第28天处死的赋形剂治疗的动物相比，和与在第44天处死的曲妥单抗治疗的动物相比，在第99天，人Alu序列的水平(与肿瘤细胞向次级组织中的侵入相关)在用组合治疗处理的动物中显著更低。这种对转移的令人吃惊的作用与用其它细胞毒性药剂观察到的作用(Geldof，A.A.，等，Anticancer Res.(抗癌研究)8(1988)1335-1339；Murphy，J.Clin.Oncol.(临床肿瘤学杂志)11(1993)199-201，和De Larco，J.E.，等，Cancer Res.(癌症研究)61(2001)2857-2861)相反。
表4：治疗对肺转移的作用。对于每只动物通过实时PCR定量AluDNA，并且记录
组合治疗的统计学显著性
*p＝0.001 **p＝<0.001
Claims (3)
1.治疗有效量的抗HER2抗体和抗VEGF抗体用于制备治疗患者中的特征在于HER2受体蛋白过量表达的乳腺癌疾病的试剂盒中的应用，所述患者在用抗VEGF抗体的在先治疗中是失败的，其中所述抗VEGF抗体是贝伐单抗，其中所述抗HER2抗体是曲妥单抗。
2.权利要求1的应用，其中所述患者是人。
3.权利要求1到2任一项的应用，其中所述试剂盒用于减少转移。
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| PCT/EP2007/002448 WO2007107329A1 (en) | 2006-03-22 | 2007-03-20 | Tumor therapy with an antibody for vascular endothelial groeth factor and an antibody for human epithelial growth factor receptor type 2 |
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| EP1325932B1 (en) * | 1997-04-07 | 2005-04-20 | Genentech, Inc. | Anti-vegf antibodies |
| EP1579871A1 (en) * | 1998-12-22 | 2005-09-28 | Genentech, Inc. | Vascular endothelial cell growth factor antagonists and uses thereof |
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| DU MANOIR.Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast caner xenografts.《CLINICAL CANCER RESEARCH》.2006,第12卷(第3期),DISSCUSION部分. * |
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