CN1507355A - 使用抗egfr抗体和抗激素剂的联合疗法 - Google Patents
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- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
Abstract
本发明涉及用于肿瘤和肿瘤转移,优选乳腺和前列腺肿瘤治疗的联合疗法,此疗法包括施用抗EGFR(Her1)抗体和抗激素剂,以及任选地细胞毒性剂/化疗剂。本方法和含有所述药剂的药物组合物可导致各单个治疗剂对肿瘤细胞增殖的抑制效果的协同增加,得到比单组份单独使用时更有效的治疗效果。
Description
发明技术领域:
本发明涉及用于肿瘤和肿瘤转移,特别是乳腺和前列腺肿瘤治疗的联合疗法,此疗法包括施用抗EGFR(Her1)抗体和抗激素剂,以及任选地细胞毒性剂/化疗剂。本方法和含有所述药剂的药物组合物可导致各单个治疗剂对肿瘤细胞增殖的抑制效果的协同增加,得到比单组份单独使用时更有效的治疗效果。
发明背景:
酪氨酸激酶是一类酶,它催化腺苷三磷酸的末端磷酸向蛋白质底物中的酪氨酸残基转移。据信通过酪氨酸激酶的底物磷酸化,酪氨酸激酶在许多细胞功能的信号传导中起关键作用。虽然信号传导的确切机理仍不清楚,但是酪氨酸激酶在细胞增殖,癌发生和细胞分化中显示出是重要的起作用因子。
酪氨酸激酶可分为受体型和非受体型。受体型和非受体型两种酪氨酸激酶都参与细胞信号途径,这些途径可导致许多病理状况,包括癌症,牛皮癣和超免疫反应。许多酪氨酸激酶既参与细胞生长也参与血管生成。
非受体型酪氨酸激酶也由许多亚族组成,包括Src,Frk,Btk,Csk,Abl,Zap70,Fes/Fps,Fak,Jak,Ack和LIMK。这些亚族的每一个还可再分成不同的受体。利用,Src亚族是最大的亚族之一,它包括Src,Yes,Fyn,Lyn,Lck,Blk,Hck,Fgr和Yrk。Src亚族中的酶与肿瘤形成有关。对非受体型酪氨酸激酶的更详细的讨论,参见Bolen Oncogene,8:2025-2031(1993)。
受体型酪氨酸激酶包括细胞外,跨膜和细胞内部分,而非受体型酪氨酸激酶完全是细胞内的。受体连接的酪氨酸激酶是跨膜蛋白,它包含细胞外配体结合域,跨膜序列,以及胞质酪氨酸激酶功能域。受体型酪氨酸激酶由大量具有不同生物活性的跨膜受体组成。事实上,已经鉴定出了不同亚家族的受体型酪氨酸激酶。涉及的酪氨酸激酶包括成纤维细胞生长因子(FGF)受体,ErbB主要类型家族中的表皮生长因子(EGF)受体和血小板衍生生长因子(PDGF)受体。还涉及神经生长因子(NGF)受体,脑衍生的神经营养因子(BDNF)受体,以及神经营养蛋白-3(NT-3)受体和神经营养蛋白-4(NT-4)受体。
一个受体型酪氨酸激酶亚家族,被命名为HER或ErbB亚家族,由EGFR(ErbB1),HER2(ErbB2或p185neu),HER3(ErbB3)和HER4(ErbB4或tyro2)组成。此亚家族受体的配体包括表皮生长因子(EGF),TGF-a,双调蛋白(amphiregulin),HB-EGF,β-细胞调节素(betacellulin)和heregulin。PDGF亚家族包括由激酶插入域受体(KDR)组成的FLK家族。
EGFR,由erbB1基因编码,它与人类恶性肿瘤因果相关。特别是,在乳腺,膀胱,肺,头,颈和胃部癌症以及成胶质细胞瘤中已经观察到EGFR的表达增强。EGFR受体表达的增强通常伴随有同一肿瘤细胞中EGFR配体-即转化生长因子α(TGF-α)的产生增加,从而经自分泌刺激途径引起受体激活(Baselga和Mendelsohn,Pharmac.Ther.64:127-154(1994))。EGF是一种分子量为170,000的跨膜糖蛋白,并发现它存在于许多上皮细胞类型上。它可以被至少三种配体-EGF,TGF-α(转化生长因子α)和双调蛋白激活。经证明表皮生长因子(EGF)和转化生长因子α(TGF-α)都能与EGF受体结合进而引起细胞增殖和肿瘤生长。这些生长因子不能与HER2结合(Ulrich and Schlesinger,1990,Cell 61,203)。与借助自身二聚化性质诱导受体二聚化的几个生长因子家族(如PDGF)不同,单体生长因子如EGF具有2个受体结合位点,因此,它可以交联两个邻近的EGF受体(Lemmon等,1997,EMBO J.16,281)。受体二聚化对激活生长因子受体的内在催化活性以及对生长因子受体的自磷酸化是必需的。应当指出的是受体蛋白酪氨酸激酶(PTK)既能进行同二聚化,也能进行异二聚化。
已经证明抗EGF受体的抗体在阻断EGF和TGF-α与受体结合的时候,显示出对肿瘤细胞增殖的抑制。考虑到这些发现,已经研制出很多小鼠和大鼠单克隆抗EGF受体抗体,并在体内和体外检测了它们对肿瘤细胞生长进行抑制的能力(Modjtahedi和Dean,1994,J.Oncology 4,277)。人源化单克隆抗体425(hMAb 425,US 5,558,864;EP 0531 472)和嵌合型单克隆抗体225(cMAb 225,US 4,943,533和EP0359282)都是针对EGF受体的,而且在临床试验中均显示有效。已经证明C225抗体可在体外抑制由EGF介导的肿瘤细胞生长,以及在裸鼠体内抑制人肿瘤的形成。而且,最重要的是,该抗体在异种移植小鼠模型中还显示出可与某些化疗剂(即阿霉素(doxorubicin,adriamycin),紫杉醇和顺氯氨铂)协同作用根除人肿瘤。Ye等(1999,Oncogene 18,731)报道通过联合应用cMAb225和针对HER2受体的人源化MAb 4D5对人卵巢癌细胞进行了成功地治疗。
ErbB家族的第二个成员-HER2(ErbB2或p185neu),它最初被鉴定为来自经化学处理的大鼠的成神经细胞瘤的转化基因产物。neu原癌基因的激活形式是由编码蛋白的跨膜区中的点突变(缬氨酸变成谷氨酸)产生的。可在乳腺和卵巢癌症中观察到neu人同系物的扩增,其与预后不良有关(Slamon等,Science,235:177-182(1987);Slamon等,Science,244:707-712(1989);US 4,968,603)。ErbB2(HER2)的分子量为大约185,000,虽然至今对HER2的特异性配体尚未明确确定,但ErbB2(HER2)与EGF受体(HER1)有相当高的同源性。
进一步发现针对HER2受体的抗体4D5使过表达ErbB2的乳腺肿瘤细胞系对TNFα的细胞毒性效应敏感(US 5,677,171)。鼠抗-ErbB2抗体4D5的人源化重组体(huMAb4D5-8,rhuMAb HER2或HERCEPTIN;US 5,821,337)在已进行过大量抗癌前期治疗的患有ErbB2-过表达转移性乳腺癌的患者中具有临床活性(Baselga等,J.Clin.Oncol.14:737-744(1996))。HERCEPTIN在1988年被正式批准上市用于治疗患有转移性乳腺癌-即肿瘤过表达ErbB2蛋白-的患者。
前列腺和乳腺癌症是在男性/女性中诊断出的频率最高癌症,每年全球有几十万以上的人死于这两种癌症。早期的器官局制性前列腺和乳腺癌症通常实施手术或放射性疗法,直到患者死于无关原因。癌如乳腺癌,结肠癌和腺癌的特征是快速细胞分裂。因此,这类癌症适于用能抑制快速细胞分裂的化疗剂进行治疗。相反,前列腺癌不具有快速细胞分裂的特点。因此,常规化疗剂一般对前列腺癌的疗效低。前列腺癌通常对激素的处理敏感。目前批准的前列腺癌治疗方法包括外科阉割,化学阉割,或外科的和化学阉割的组合方法。
睾丸是主要产生睾酮的器官,它的切除使循环雄激素的水平减少,达到正常水平的5%以下。雄激素水平的减少可抑制前列腺肿瘤的生长。虽然外科阉割的抗肿瘤作用是直接的,但是这种抗肿瘤作用也是暂时性的。外科阉割经常会导致雄激素非依赖性的前列腺肿瘤细胞的克隆选择。这样就会导致前列腺肿瘤的重新生长,且此前列腺肿瘤可以无需睾酮或DHT的刺激进行增殖(Isaacs et al.(1981)Cancer Res.41:5070-5075;Crawfordet al.(1989)IV.Eng.J.Med.321:419-424)。作为初期治疗,化学阉割(亦称内科阉割)常替代外科阉割。
前列腺和乳腺癌共有一个独特特征,这个特征是大多数前列腺和乳腺癌受类固醇性激素的刺激而生长(雌激素和雄激素分别作用于乳腺癌和前列腺癌)。类固醇性激素通过与特异性受体结合发送其刺激信号。雌激素和雄激素受体可在大约75%的乳腺癌细胞和几乎100%的前列腺癌细胞上找到,并且这两种受体是核激素受体超家族的成员,该受体超家族包括类固醇激素、甲状腺激素、亲脂性维生素如维生素A和D的受体以及孤儿受体(即,结构与其它超家族成员的结构相符但尚未鉴定到配体的受体)(Evans(1988)Science 240:889-895)。这些受体通过与靶基因启动子中的特异性DNA序列相互作用来调节基因表达(Glass(1994)Endocr.Rev.15:391-407)。
核受体可分成两个亚族:甲状腺/视黄酸/维生素D受体(TRV)家族和类固醇受体(Rs)家族。类固醇激素受体以配体依赖性的形式与它们各自的HRE结合,而一些受体如甲状腺激素受体(T3R)和视黄酸受体(RAR/RXR)以配体非依赖性的形式与它们的效应元件结合。类固醇受体在正常健康状态和一系列疾病状态——包括癌症、炎症、内分泌失调和口服避孕中起作用。由内分泌腺体产生的天然类固醇激素与靶器官中的类固醇激素受体结合。
天然类固醇激素包括雌激素,黄体酮,雄激素,糖皮质激素和盐皮质激素。这些激素被定义为激动剂,激素-受体复合物能通过提高或降低转录速率来调节特异性基因转录。
类固醇激动剂在许多组织中具有多效生理活性。例如,雌二醇和黄体酮可在肾脏,卵巢,子宫颈,子宫,骨骼,皮肤,乳腺,心脏,垂体和脑中调节基因转录。类固醇受体亚族的激素被用于治疗许多失调病症,并且在健康人群中用于口服避孕和激素替代疗法等等。
从医学的角度常常可能期望阻断类固醇激素激动剂的活性。为此,研究人员已经合成了类固醇受体拮抗剂,它们可作为阻止癌症扩展或阻断异常生长的试剂用于乳腺、子宫内膜和前列腺癌的治疗以及用作避孕药。这些拮抗剂也是类固醇受体的配体,但是一般情况下,它们所具有的作用和激动剂产生的作用相对立。
类固醇受体拮抗剂的活性很复杂。它们通常具有激动剂/拮抗剂的双重作用。例如,一个拮抗剂可能部分地具有激动剂的生物活性;这样,该拮抗剂可以阻断激动剂的活性,结果实质上减小激动剂的活性。拮抗剂还可能在一种组织(如,乳腺)中具有所需要的拮抗剂作用,而在另一种组织(如,子宫)中具有激动剂的作用。拮抗剂的激动剂作用可能是也可能不是不期望的副作用。同样,在癌症的治疗中,拮抗剂配体最初可能具有所需要的对肿瘤的抑制作用,但是随着时间变化,配体转向类似激动剂的作用,这将使癌症重新继续生长。一个典型实例是LHRH(促黄体生成素释放激素)。给个体一次施用较高剂量的LHRH活性化合物能刺激激素的产生(激动剂作用),而连续小剂量的此化合物却充当拮抗剂抑制激素的释放作用。
血管生成也称作新血管发生,它是涉及到新生血管向组织内生长的组织血管化过程。这个过程由内皮细胞和平滑肌细胞的浸润介导。这个过程据信可以按照下面3个路径中的任何一个进行:(1)从已经存在的血管中分生出血管;(2)由前体细胞开始血管的从头发育(血管发生);或(3)已经存在的小血管扩增直径(Blood等,1990,Bioch.Biophys.Acta 1032,89)。已知血管内皮细胞至少含有5种RGD依赖性整合蛋白,其中包括玻连蛋白受体(αvβ3或αvβ5)、胶原蛋白I型和IV型受体、层粘连蛋白受体、纤连蛋白/层粘连蛋白/胶原蛋白受体和纤连蛋白受体(Davis等,1993,J.cell.Biochem.51,206)。已知平滑肌细胞含有至少6种RGD依赖性整合蛋白,其中包括有αvβ3和αvβ5。
虽然血管生成是新生期生长中的一个重要过程,但它在伤口愈合和大量临床重要疾病—包括组织炎症,关节炎,牛皮癣,癌症,糖尿病,视网膜病,黄斑变性和其它新血管眼病的病理中同样重要。这些伴有血管生成的临床病症称为生血管疾病(Folkman等,1987,Science 235,442)。
利用免疫特异性针对各种整合蛋白α或β亚基的单克隆抗体在体外抑制细胞粘连,提示玻连蛋白受体αvβ3参与了多种细胞类型(包括微血管上皮细胞)的细胞粘附(Davis等,1993,J.Cell.Biol.51,206)。
整合蛋白是一类细胞受体,已知这种细胞受体和细胞外基质蛋白结合,并介导细胞-细胞和细胞-细胞外基质间的相互作用,一般这种相互作用被称为细胞粘附事件。整合蛋白受体构成一个蛋白质家族,其共同结构特征是由α亚基和β亚基构成的非共价异二聚体糖蛋白复合物。玻连蛋白受体因其最初被发现的特征是它优先和玻连蛋白结合而得名。现已知玻连蛋白受体代表3种不同的整合蛋白,分别命名为αvβ1,αvβ3和αvβ5。αvβ1与纤连蛋白以及玻连蛋白结合。αvβ3与种类众多的配体结合,其中包括纤维蛋白,纤维蛋白原,层粘连蛋白,血小板反应蛋白,玻连蛋白和冯·维勒布兰德因子。αvβ5和玻连蛋白结合。很明显,有些不同的整合蛋白有不同的生物学功能,但是有些不同的整合蛋白和亚基却有共同的生物学特异性。对于很多整合蛋白,配体中的一个重要的识别位点是精氨酸-甘氨酸-天冬氨酸(RGD)三肽序列。RGD在上述所有鉴定到的玻连蛋白受体整合蛋白的配体中都存在。
此RGD识别位点可以用含有RGD序列的线性和环形(多)肽模拟。已知这些RGD肽分别是整合蛋白功能的抑制剂或拮抗剂。然而,很重要的是应当注意到随RGD肽的序列和结构的不同,抑制的特异性可发生改变而靶向特异的整合蛋白。已描述过许多有不同整合蛋白特异性的RGD多肽,见比如,Cheresh,等,1989,Cell 58,945,Aumailley等,1991,FEBS Letts.291,50,以及数目众多的专利申请和专利(如美国专利4,517,686、4,578,079、4,589,881、4,614,517、4,661,111、4,792,525;EP 0770 622)。
新血管发生或血管生成在恶性疾病的发展中起关键作用,并已在血管生成抑制剂研发上引起了极大的兴趣。(实例可参见Holmgren等,1995,Nature Medicine 1,149;Folkman,1995,Nature Medicine 1,27;O′Reilly等,1994,Cell 79,315)。已知用αvβ3整合蛋白拮抗剂抑制血管生成可以用于通过减少对实体肿瘤的血液供给而抑制实体肿瘤生长的方法中(实例可参见US 5,753,230以及US 5,766,591,其中描述了可与αvβ3受体结合并抑制血管生成的αvβ3拮抗剂-如αvβ3的合成多肽,单克隆抗体和模拟物-的使用)。在WO 97/45447中公开了用玻连蛋白受体αvβ5的拮抗剂抑制αvβ5介导的组织血管生成的方法和组合物。
血管生成的特征是内皮细胞的浸润、迁移和增殖,这些过程依赖于细胞与细胞外基质成分之间的相互作用。从这一点上讲,整合蛋白细胞-基质受体介导了细胞扩散和迁移。整合蛋白αvβ3的内皮粘附受体因为给抗血管生成治疗策略提供了脉管系统特异性的靶子而成为重要角色(Brooks等,1994,Science 264,569;Friedlander et.al.,1995,Science 270)。已经通过几个体内模型证明了在血管生成中需要血管整合蛋白αvβ3,所述模型中移植的人肿瘤的新血管发生完全被全身施用上面所述的整合蛋白αvβ3和αvβ5的肽拮抗剂或作为备选方案的抗αvβ3抗体LM609(Brooks等,1994,Cell79,1157;ATCC HB 9537)所抑制。此抗体可阻断αvβ3整合蛋白受体被其天然配体激活(此激活作用可以抑制增生的生血管血管细胞的细胞凋亡)并由此破坏新生成血管的成熟(这是肿瘤增殖中的必要事件)。然而,据最近的报道,黑素瘤细胞即使在没有内皮细胞的情况下也能形成网状结构的血管(Barinaga,1999,Science 285,1475),这暗示肿瘤可能能绕过一些只有在有内皮组织存在的情况下才有效的抗血管生成药物。
很多分子,包括VEGF,Ang1和bFGF,都能刺激内皮细胞的增殖、迁移和组装,它们是极其重要的存活因子。VEGF(血管内皮生长因子)经鉴定是一种选择性的生血管生长因子,它可以刺激内皮细胞的有丝分裂。特别是,VEGF被认为是原发性肿瘤和眼睛局部缺血疾病中血管生成的一个主要的介质。VEGF是同二聚体(分子量:46,000),它是一种内皮细胞特异性生血管因子(Ferrara等,1992,Endocrin.Rev.,13,18)和血管渗透因子(Senger等,1986,Cancer Res.,465629),它与有酪氨酸激酶活性的高亲和性膜结合受体结合(Jakeman等,1992,J.Clin.Invest.,89,244)。人肿瘤的活体组织检查显示,恶性细胞中的VEGF mRNA和邻近的内皮细胞中的VEGF受体mRNA表达增强。VEGF的表达似乎在邻近血管坏死区域的肿瘤部位最高。(综述参见Thomas等,1996,J.Biol.Chem271(2),603;Folkman,1995,Nature Medicine 1,27)。WO 97/45447中提示,αvβ5整合蛋参与了尤其是由VEGF、EGF和TGF-α诱导的新血管生成,并公开了αvβ5拮抗剂可抑制VEGF促进的血管生成。有效的抗肿瘤疗法也可通过单克隆抗体靶向VEGF受体来抑制血管生成(Witte等,1998,Cancer Metastasis Rev.17(2),155)。已知单抗DC-101可用于抑制肿瘤细胞的血管生成。
本发明目前描述特异性针对EGF受体(ErbB1,Her1)的抗体当与抗激素剂(尤其是核激素受体家族的抑制剂)一起施用时可以更有效地杀死或缩小尤其是前列腺和乳腺癌的肿瘤组织。此外,与抗血管生成剂和/或细胞毒性剂的共施用可提高所述联合疗法的正向协同效应。
发明概要
本发明首次描述这一肿瘤治疗新概念,即给个人施用阻断或抑制EGF受体的药剂以及抗激素剂。本发明的组合物还可任选地包含其他有治疗活性的化合物,这些化合物优选选自细胞毒性剂、化疗剂和ErbB受体酪氨酸激酶家族的抑制剂或拮抗剂或者血管生成的抑制剂或拮抗剂。
因此,本发明涉及药物组合物,其包含作为优选的抗EGFR剂的抗EGFR抗体和作为抗激素剂的核受体(优选类固醇受体)抑制剂或拮抗剂。本发明所述的治疗活性剂也可以以包含如下包装的药物试剂盒的形式提供,此包装中包含独立包装的或在单独容器内的一种或多种抗EGFR抗体、一种或多种抗激素剂及任选地一种或多种细胞毒性剂/化疗剂、抗ErbB剂、抗血管生成剂。利用本联合的治疗方法可以任选地包括放射性治疗。
然而,本发明还涉及这样的联合疗法,其包括施用仅一种既有抗EGFR活性又有抗激素活性的(融合)分子,及任选地还施用一种或多种细胞毒性剂/化疗剂。一个例子是抗EGFR抗体,如上文和下文所述的h425或c225,它利用已知的重组或化学方法通过其自身Fc部分的C末端与抗激素剂融合。再一个例子是双特异性抗体,此抗体中一个特异性针对核激素受体而另一个针对EGF受体。
大抵上,此药物施用可与放射治疗伴随进行,其中放射治疗可与药物施用基本上同时或在之前或在之后进行。本发明联合疗法中的各种药剂的施用也可以基本上同时进行或相继进行。细胞表面上有参与肿瘤血管形成的受体的肿瘤可用本发明联合疗法成功地治疗。
已知肿瘤的发育和生长有多条可替换的路线。如果一条路线被阻断,则它们常能通过表达和使用其他受体和信号途径而转换到另一条路线上。因此,由于本发明的药物联合可以阻断几种这样的可能肿瘤发育策略,因而具有多个优点。本发明的组合可用于治疗和预防那些通过激活存在于肿瘤细胞表面上的相关激素受体而发育和生长的肿瘤、肿瘤样疾病和瘤形成性疾病以及肿瘤转移。本发明的不同组合药剂优选以低剂量联合应用,即,低于常规的临床条件下使用的剂量。在给个体施用本发明的化合物、组合物、药剂和治疗的时候,降低剂量的优点包括降低了高剂量相关负反应的发生率。比如,通过降低如上文和下文所述药剂的剂量,和高剂量条件下观察到的效果相比,恶心和呕吐的频率和严重程度都得到降低。预期降低负反应发生率将能改善癌症患者的生活质量。降低负反应发生率的优点还包括改善患者的依顺性,降低因负反应产生的需要住院治疗的次数,减少在医治负反应带来的疼痛时所需止痛剂的使用。另外,本发明的方法和联合还能使高剂量时的治疗效果最大化。
本发明的联合治疗显示出令人惊异的协同效应。临床研究显示使用此药物联合可使肿瘤出现真实的萎缩和解体,同时没有可检测的明显的药物副作用。
具体的,本发明涉及:
·药物组合物,其包含治疗有效量的至少(i)一种抗EGFR抗体或此抗体的免疫治疗有效片断以及(ii)一种抗激素剂,及任选地药学上可接受的载体、赋形剂或稀释剂;
·相应的药物组合物,其中所述的抗EGFR抗体或所述的此抗体的免疫治疗有效片断是小鼠的、嵌合的或人源化的Mab425(h425)或嵌合的Mab225(c225)抑制剂/拮抗剂;
·相应的药物组合物,其中所述的抗激素剂是核激素受体家族的抑制剂;
·相应的药物组合物,其中所述的抗激素剂是类固醇受体抑制剂/拮抗剂;
·相应的药物组合物,其还包含抗血管生成剂;
·相应的药物组合物,其还包含细胞毒性剂和/或化疗剂;
·相应的药物组合物,其还包含其它的抗-HER2抗体或它的免疫治疗活性片断;
·药物组合物,其包含既具有抗EGFR活性又具有抗核激素受体活性的抗体,及任选地药学上可接受的载体、赋形剂或稀释剂;
·相应的药物组合物,其中所述抗体是双特异性抗体;
·药物试剂盒,其包含这样的包装,该包装含有至少
(i)一种抗EGFR抗体或此抗体的免疫治疗有效片断,及(ii)一种抗激素剂,及任选地(iii)细胞毒性剂和/或化疗剂;
·相应的药物试剂盒,其包含(i)单克隆抗体h425,和(ii)类固醇受体拮抗剂;
·相应的药物试剂盒,其包含(i)单克隆抗体h425,和(ii)LHRH拮抗剂;
·相应的药物试剂盒,其中所述药物活性剂在所述包装中分别于单独容器中提供;
·上文及下文中定义的药物组合物或药物试剂盒在制备用于治疗肿瘤和肿瘤转移(优选用于治疗乳腺癌和前列腺癌)的药物或药物组合物中的用途;
·相应的用途,用于治疗类固醇非依赖性乳腺癌和前列腺癌;
·治疗个体的肿瘤或肿瘤转移的方法,其包括同时或相继给所述个体施用治疗有效量的(i)抗EGFR抗体,或(ii)抗激素剂;
·相应的方法,其中所述的抗EGFR抗体是单克隆抗体h425或c225以及所述的抗激素剂是类固醇受体拮抗剂;及
·相应的方法,其包括还给所述个体施用治疗有效量的细胞毒性剂和/或化疗剂或抗血管生成剂或其它的抗ErbB受体抗体。
发明详述
本发明中使用的术语和短语,如果没有另行指明,则具有下面给定的含义和定义。而且,这些定义和含义更详细地描述了本发明,包括优选实施方案。
“生物分子”包括天然或合成分子,通常其分子量大于约300,并且优选是多聚-和寡聚糖类,寡肽和多肽,蛋白质,肽,多聚-和寡聚核苷酸以及它们的糖基化脂类衍生物。最典型地是,生物分子包括免疫治疗药剂,最重要的是抗体或抗体片断,或这些抗体或片断的功能性衍生物,包括融合蛋白。
“受体”或“受体分子”是指可溶的或膜结合/连结的蛋白或糖蛋白,其含有一个或多个可与配体结合以形成受体-配体复合物的结构域。通过与可能是激动剂或拮抗剂的配体结合,受体可以被激活或者失活,由此可以启动或阻断信号通路。
“配体”或“受体配体”是指这样的天然的或者合成的化合物,它可以和受体分子结合形成受体-配体复合物。术语配体包括激动剂、拮抗剂以及具有部分激动剂/拮抗剂活性的化合物。
“激动剂”或“受体激动剂”是指这样的天然的或者合成的化合物,它和受体结合形成受体-激动剂复合物,通过分别激活所述受体和受体-激动剂复合物而启动信号通路及进一步的生物学过程。
“拮抗剂”或“受体拮抗剂”是指和激动剂有相反的生物学效应的天然的或者合成的化合物。拮抗剂和受体结合,通过和激动剂竞争受体而阻断受体激动剂的作用。拮抗剂是根据它阻断激动剂的作用的能力来定义的。受体拮抗剂也可以是抗体或是其具有免疫治疗活性的片段。下面将举出并论述本发明优选的拮抗剂。
术语“治疗有效的”或“治疗有效量”指的是有效治疗哺乳动物的疾病或病症的药物量。对癌症而言,药物的治疗有效量可减少癌细胞的数量;降低肿瘤的大小;抑制(即,一定程度地减缓且最好终止)癌细胞浸润到周围器官中;抑制(即,一定程度地减缓且最好终止)肿瘤的转移;在一定程度上抑制肿瘤的生长;和/或将癌症相关的一种或多种症状减轻到一定程度。如果药物可以阻止已存在癌细胞的生长而且/或杀死已存在的癌细胞,则该药物可能具有细胞抑制性和/或细胞毒性。对于癌症的治疗,疗效可以比如通过估计疾病进展时间(TTP)和/或测定反应率(RR)来确定。
术语“免疫治疗活性”指的是引起哺乳动物免疫反应的生物分子。更具体地,此术语指的是可以识别和结合抗原的分子。典型地,抗体、含有其抗原结合位点(互补决定区,CDRs)的抗体片断和抗体融合蛋白具有免疫治疗活性。
“抗血管生成剂”指的是天然的或合成的化合物,它可在一定程度上阻断或干扰血管的发育。抗血管生成分子可以是,例如,和生血管生长因子或生长因子受体结合并将其阻断的生物分子。本处优选的抗血管生成分子可以与受体结合,优选与整合蛋白受体或与VEGF受体结合。本发明中此术语还包括所述抗血管生成剂的前体药物。
有很多结构和来源不同的分子都可以引起抗血管生成性质。本发明中适宜的血管生成抑制剂或阻断剂的大多数相关类型是,例如:
(i)抗有丝分裂剂,例如氟尿嘧啶,丝裂霉素C,紫杉醇;
(ii)雌激素代谢物如2-甲氧基雌二醇;
(iii)抑制锌金属蛋白酶的基质金属蛋白酶(MMP)抑制剂(例如,betimastat,BB16,TIMPs,二甲胺四环素,GM6001,或在“基质金属蛋白酶的抑制:治疗应用”中论及的那些(物质)(Golub,Annals of the New YorkAcademy of Science,Vol.878a;Greenwald,Zucker(Eds.),1999);
(iv)抗血管生成的多功能药剂和因子,如IFNα(US 4,530,901;US4,503,035;5,231,176);制管张素和纤溶酶原片段(例如kringle1-4,kringle5,kringle 1-3(O′Reilly,M.S.等,Cell(Cambridge,Mass.)79(2):315-328,1994;Cao等,J.Biol.Chem.271:29461-29467,1996;Cao等,J.BiolChem 272:22924-22928,1997);内皮生长抑素(endostatin)(O′Reilly,M.S.等,Cell 88(2),277,1997和WO 97/15666),血小板反应蛋白(TSP-1;Frazier,1991,Curr Opin Cell Biol 3(5):792);血小板因子4(PF4);
(v)纤溶酶原激活物/尿激酶抑制剂;
(vi)尿激酶受体拮抗剂;
(vii)肝素酶;
(viii)烟曲霉素类似物如TNP-470;
(ix)酪氨酸激酶抑制剂如SUI01(上面和下面提到的很多ErbB受体拮抗剂(EGFR/Her2拮抗剂)也是酪氨酸激酶抑制剂,因此它们分别可以显示出抗EGF受体阻断活性从而导致肿瘤生长受抑制,及显示出抗血管生成的活性从而导致血管发育和内皮细胞发育受抑制);
(x)苏拉明和苏拉明类似物;
(xi)制管张性(angiostatic)类固醇;
(xii)VEGF和bFGF拮抗剂;
(xiii)VEGF受体拮抗剂如抗VEGF受体抗体(DC-101);
(xiv)flk-1和flt-1拮抗剂;
(xv)环加氧酶-II抑制剂如COX-II;
(xvi)整合蛋白拮抗剂和整合蛋白受体拮抗剂如αv拮抗剂和αv受体拮抗剂,例如,抗αv受体抗体和RGD肽。本发明优选整合蛋白(受体)拮抗剂。
术语“整合蛋白拮抗剂/抑制剂”或“整合蛋白受体拮抗剂/抑制剂”指的是天然的或者合成的分子,它阻断并抑制整合蛋白受体。有时,此术语包括针对所述整合蛋白受体的配体(例如对于αvβ3:玻连蛋白,纤维蛋白,纤维蛋白原,冯·维勒布兰德因子,血小板反应蛋白,层粘连蛋白;对于αvβ5:玻连蛋白;对于αvβ1:纤连蛋白和玻连蛋白;对于αvβ6:纤连蛋白)的拮抗剂。本发明优选针对整合蛋白受体的拮抗剂。整合蛋白(受体)拮抗剂可以是天然的或合成的肽,非肽,肽模拟物(pepetidomimetica),免疫球蛋白例如抗体或抗体的功能性片段,或免疫缀合物(融合蛋白)。
本发明优选的整合蛋白抑制剂为针对αv整合蛋白受体(例如,αvβ3,αvβ5,αvβ6和亚类)的抑制剂。优选的整合蛋白抑制剂为αv拮抗剂,尤其是αvβ3拮抗剂。本发明优选的αv拮抗剂是RGD肽,肽模拟物(非肽)拮抗剂和抗整合蛋白受体抗体如阻断αv受体的抗体。
典型的非免疫学的αvβ3拮抗剂在US 5,753,230和US 5,766,591中有教导。优选的拮抗剂为含RGD的线性和环型肽。环肽通常更稳定且在血清中的半衰期更长。然而,本发明最优选的整合蛋白拮抗剂是环(Arg-Gly-Asp-DPhe-NMeVal)(EMD 121974,Cilengitide,Merck KgaA,德国;EP 0770 622),它可有效地阻断整合蛋白受体αvβ3、αvβ1、αvβ6、αvβ8、αllbβ3。
科技文献和专利文献中均描述过αvβ3/αvβ5/αvβ6整合蛋白受体的适宜肽类拮抗剂及肽模拟(非肽)拮抗剂。例如,可参见Hoekstra和Poulter,1998,Curr.Med.Chem.5,195;WO 95/32710;WO 95/37655;WO97/01540;WO 97/37655;WO 97/45137;WO 97/41844;WO 98/08840;WO98/18460;WO 98/18461;WO 98/25892;WO 98/31359;WO 98/30542;WO99/15506;WO 99/15507;WO 99/31061;WO 00/06169;EP 0853 084;EP0854 140;EP 0854 145;US 5,780,426;和US 6,048,861。公开了也适用于本发明的苯并氮杂唑及相关的苯并二氮杂唑和苯并环庚烯αvβ3整合蛋白受体拮抗剂的专利包括WO 96/00574,WO 96/00730,WO 96/06087,WO 96/26190,WO 97/24119,WO 97/24122,WO 97/24124,WO98/15278,WO 99/05107,WO 99/06049,WO 99/15170,WO 99/15178,WO 97/34865,WO 97/01540,WO 98/30542,WO 99/11626和WO99/15508。在WO 98/08840;WO 99/30709;WO 99/30713;WO 99/31099;WO 00/09503;US 5,919,792;US 5,925,655;US 5,981,546;和US 6,017,926中描述了具有主链构象环约束特征的其他整合蛋白受体拮抗剂。在US 6,048,861和WO 00/72801中公开了一系列的壬酸衍生物,它们是有效的αvβ3整合蛋白受体拮抗剂。WO 00/38665中公开了其他化学小分子整合蛋白拮抗剂(多数为玻连蛋白拮抗剂)。其它αvβ3受体拮抗剂已被证实可有效地抑制血管生成。例如,合成的受体拮抗剂如(S)-10,11-二氢-3-[3-(吡啶-2-基氨基)-1-丙氧基]-5H-二苯并[a,d]环庚烯-10-乙酸(命名为SB-265123)已经在很多哺乳动物模型系统中实验过。(Keenan等,1998,Bioorg.Med.Chem.Lett.8(22),3171;Ward等,1999,DrugMetab.Dispos.27(11),1232)。适用作拮抗剂的整合蛋白拮抗剂的甄选实验在如Smith等,1990,J.Biol.Chem.265,12267中以及参考专利文献中有描述。
抗整合蛋白受体的抗体也广为人知。可对适宜的抗整合蛋白(如αvβ3,αvβ5,αvβ6)的单克隆抗体进行修饰,使它包括自身的抗原结合片段(包括F(ab)2,Fab和工程化的Fv或单链抗体)。针对整合蛋白受体αvβ3的一个合适的且优选使用的单克隆抗体被定为LM609(Brooks等,1994,Cell 79,1157;ATCC HB 9537)。在WO 97/45447中公开了一个强特异性抗αvβ5抗体-P1 F6,它也优选用于本发明。另一合适的αvβ6选择性抗体是选择性针对整合蛋白受体的αv链的MAb 14D9.F8(WO 99/37683,DSMACC2331,Merck KGaA,德国)以及MAb 17.E6(EP 0719 859,DSMACC2160,Merck KGaA)。另一个适宜的抗整合蛋白抗体为上市的Vitraxin。
“生血管生长因子或生长因子受体”是能够通过自身的激活促进血管生长和发育的因子或受体。典型地,血管内皮生长因子(VEGF)及其受体属于此类。
此处的术语“抗体”或“免疫球蛋白”有最广义的含义,特别包括完整的单克隆抗体、多克隆抗体、由至少2个完整抗体构成的多特异性抗体(例如双特异性抗体)以及抗体片段,只要它们显示有所需的生物学活性即可。此术语一般包括由2个或多个具有不同结合特异性的抗体或抗体片段连接在一起构成的杂合抗体。
根据抗体恒定区的氨基酸序列,完整的抗体可被划分成不同的“抗体(免疫球蛋白)类型”。完整抗体有5个主要类型:IgA,IgD,IgE,IgG和IgM,其中有些可以被进一步划分成“亚类”(同种型),如IgG1,IgG2,IgG3,IgG4,IgA和IgA2。相应于不同抗体类型的重链恒定区分别称为α,δ,ε,γ和μ。本发明优选的抗体主要类型是IgG,更具体的说是IgG1和IgG2。
抗体常常是分子量约150,000的糖蛋白,由2条同样的轻(L)链和2条同样的重(H)链组成。每条轻链都通过一个共价二硫键和重链相连,而在不同免疫球蛋白同种型的重链中二硫键数目不同。每条重链和轻链还有规则间隔的链内二硫键。每条重链都在一端有一个可变区(VH)并随后有多个恒定区。每条轻链都在一个末端上有一个可变区(VL),在另一末端上有一个恒定区。轻链的恒定区和重链的第一个恒定区并列,轻链的可变区和重链的可变区并列。据信特定氨基酸残基构成轻链和重链可变区之间的介面。可将脊椎动物物种的抗体“轻链”划分成2个明确不同的类型,称为卡帕(κ)和拉姆达(λ),这取决于它们恒定区的氨基酸序列。
本处所用的术语“单克隆抗体”指从基本上均质的抗体群中获得的抗体,即,除了可能的天然发生的微量突变以外,抗体群内的每一株抗体都是相同的。单克隆抗体具有高度的特异性,它针对单一的抗原位点。而且,和多克隆抗体制品不同,多克隆抗体含有针对不同决定簇(表位)的不同抗体,而每个单克隆抗体都仅针对抗原上的一个决定簇。除了它们的特异性以外,单克隆抗体的优越之处还在于可以合成无其他抗体污染的单克隆抗体。单克隆抗体的制备方法包括Kohler和Milstein(1975,Nature 256,495)和″单克隆抗体技术,啮齿类和人类杂交瘤的制备和表征″(1985,Burdon等,Eds,Laboratory Techniques in Biochemistry and MolecularBiology,Volume 13,ElseVier Science Publishers,Amsterdam)中描述的杂交瘤法,或者可以用广为人知的重组DNA方法进行制备(实例可参见US 4,816,567)。也可用比如Clackson等,Nature,352:624-628(1991)和Marks等,J.Mol.Biol.,222:58,1-597(1991)中描述的技术从噬菌体抗体文库中分离单克隆抗体。
术语“嵌合抗体”是指这样的抗体,其重链和/或轻链的一部分和来自特定物种的抗体或属于特定抗体类型或亚类的抗体中的相应序列相同或同源,然而链的其余部分则与来自另一物种的抗体或属于另一抗体类型或亚类的抗体中的相应序列相同或同源,该术语还指此种抗体的片段,只要其具有所需的生物学活性即可(例如:US 4,816,567;Morrison等,Proc.Nat.Acad.Sci.USA,81:6851-6855(1984))。生产嵌合型和人源化抗体的方法是本领域技术人员所熟知的。例如,制备嵌合抗体的方法包括Boss(Celltech)和Cabilly(Genentech)(US 4,816,397;US 4,816,567)的专利中描述的方法。
“人源化抗体”是非人(如啮齿类)嵌合抗体形式的抗体,其含有最低量的源于非人免疫球蛋白的序列。就大部分而言,人源化抗体是人免疫球蛋白(受体抗体),其中受体的高变区(CDR)的残基被替换成非人物种(如小鼠,大鼠,兔或非人灵长类)(供体抗体)的具有所需的特异性、亲和性和作用的高变区残基。有时,人免疫球蛋白构架区(FR)残基被对应的非人残基替换。而且,人源化抗体还可以含有受体抗体和供体抗体上均没有的残基。这些修饰可以进一步限定抗体的性能。通常,人源化抗体含有至少一个,一般两个可变区的基本上全部内容,其中所有或基本上所有的高变环都对应于非人免疫球蛋白的相应部分,而所有或基本上所有的FR都是人免疫球蛋白序列中的FR。人源化抗体也可任选地含有至少一部分免疫球蛋白恒定区(Fc),特别是人免疫球蛋白的恒定区。人源化抗体的制备方法描述在例如Winter,US 5,225,539和Boss,Celltech,US 4,816,397中。
术语“可变”或“FR”指的是如下事实,即抗体与抗体之间在可变区的某些部分具有十分不同的序列,这些部分用于各特定抗体对其特定抗原的结合和特异性。然而,此可变性并不均匀分布在抗体的整个可变区。它集中在轻链和重链可变区的三个称为高变区的区段中。可变区的较高保守部分称为构架区(FR)。天然重链和轻链的可变区每一个都包含四个FR(FR1-FR4),它们主要采用β-片层构型,由三个高变区连接,而高变区形成环与β-片层连接且有时形成β-片层结构的一部分。每条链的高变区通过FR紧密邻近,并与另一条链的高度可变区一起促成抗体的抗原结合位点的形成(参见Kabat等,Sequences of Proteins of ImmunologicalInterest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。虽然恒定区没有直接参与抗体和抗原的结合,但是显示出多种效应子功能,如参与抗体的抗体依赖性细胞毒性(ADCC)。
此处所用的术语“高变区”或“CDR”指负责与抗原结合的抗体的氨基酸残基。高变区一般包含“互补决定区”或“CDR”的氨基酸残基(例如,轻链可变区的24-34位(L1),50-56位(L2)和89-97位(L3)残基,重链可变区的31-35位(H1),50-65位(H2)和95-102位(H3)残基);和/或“高变环”的氨基酸残基(例如,轻链可变区的26-32位(L1),50-52位(L2)和91-96位(L3)残基,重链可变区的26-32位(H1),53-55位(H2)和96-101位(H3)残基;Chothia和Lesk J.Mol.Biol.196:901-917(1987))。
“构架区”或“FR”残基是指除本处定义的高变区残基以外的那些可变区残基。
“抗体片段”包含完整抗体的一部分,优选包含抗体的抗原结合区或可变区。抗体片段的实例包括Fab,Fab′,F(ab′)2,Fv和Fc片段,diabodies,线性抗体,单链抗体分子;及由抗体片段构成的多特异性抗体。“完整抗体”是指包含结合抗原的可变区以及轻链恒定区(CL)和重链恒定区(CH1,CH2和CH3)的抗体。完整抗体优选具有一个或多个效应子功能。
木瓜蛋白酶消化抗体产生2个相同抗原结合片段(称之为″Fab″片段,每个片段含有一个抗原结合位点和一个CL区和一个CH1区)以及一个残余的″Fc″片段(其名称反映了其易于结晶的能力)。
抗体″Fc″区一般含有CH2,CH3和IgG1或IgG2抗体主要类型的铰链区。铰链区是具有约15个氨基酸残基的基团,它把CH1区和CH2-CH3区结合起来。
胃蛋白酶处理产生一个″F(ab′)2″片段,它有2个抗原结合位点且仍有交联抗原的能力。″Fv″是最小的抗体片段,它含有一个完整的抗原识别和抗原结合位点。此区域由一个重链可变区和一个轻链可变区通过牢固的非共价连接形成的二聚体组成。在此构型中每个可变区的3个高变区(CDR)相互作用在VH-VL二聚体表面上确定出一个抗原结合位点。总的说来,6个高变区赋予了抗体的抗原结合特异性。但是,甚至仅一个可变区(或仅含有3个抗原特异性高变区的一半Fv)也有识别并结合抗原的能力,虽然它比完整的结合位点的亲合力低。Fab片段还包括轻链的恒定区和重链的第一恒定区(CH1)。″Fab片段和Fab片段的不同之处在于在重链CH1区的羧基端多了几个残基,包括一个或多个来自抗体铰链区的半胱氨酸。F(ab′)2抗体片段最初以Fab′片段对形式产生,这两个Fab′片段之间有半胱氨酸铰链。抗体片段的其它化学偶联也是已知的(参见如Hermanson,Bioconjugate Techniques,Academic Press,1996;.US 4,342,566)。
“单链Fv″或″scFv″抗体片段包含抗体的VH和VL区,其中,这些结构域存在于一条多肽链上。Fv多肽优选在VH和VL结构域之间还含有多肽接头,它可使scFv形成抗原结合所需的结构。单链FV抗体也可从例如Plckthun(The Pharmacology of Monoclonal Antibodies,Vol.113,Rosenburg和Moore编,Springer-Verlag,New York,pp.269-315(1994)),WO93/16185;US 5,571,894;US 5,587,458;Huston等(1988,Proc.Natl.Acad.Sci.85,5879)或Skerra和Plueckthun(1988,Science 240,1038)获知。
术语“diabodies”是指有两个抗原结合位点的小抗体片断,此片断包含一个重链可变区(VH),它与轻链可变区(VL)连接在同一多肽链(VH-VL)上。通过利用不能使位于同一链上的这两个域配对的小接头,使一条链上的这些结构域被迫与另一条链的互补域配对从而产生两个抗原结合位点。例如在EP 404,097;WO 93/11161中对diabodies有更充分的描述。
“双特异性抗体”是一个双价的抗体(或其有免疫治疗活性的片段),其有2个不同特异性的抗原结合位点。例如第一个抗原结合位点可针对血管生成受体(例如整合蛋白或VEGF受体),而第二个抗原结合位点可针对ErbB受体(例如EGFR或Her 2)。双特异性抗体能用化学方法(实例参见Kranz等(1981)Proc.Natl.Acad.Sci.USA 78,5807)或″polydoma″技术(参见US 4,474,893)或重组DNA技术制备,所有这些技术均为本身已知的技术。其他方法在WO 91/00360,WO 92/05793和WO 96/04305中有描述。双特异性抗体还能用单链抗体来制备(实例参见Huston等(1988)Proc.Natl.Acad.Sci.85,5879;Skerra和Plueckthun(1988)Science 240,1038)。这些是以单条多肽链形式产生的抗体可变区类似物。为了构成双特异性结合剂,单链抗体可以通过本领域内技术人员熟知的化学方法或遗传工程方法偶联在一起。本发明的双特异性抗体也可以用亮氨酸拉链序列来制备。此序列可来自于转录因子Fos和Jun的亮氨酸拉链区(Landschulz等,1988,Science 240,1759;综述见,Maniatis和Abel,1989,Nature 341,24)。亮氨酸拉链是约20-40个残基长的特殊氨基酸序列,典型地每7个残基就有一个亮氨酸。此拉链序列形成两亲性α螺旋,亮氨酸残基在疏水侧面上排成一线以便形成二聚体。相应于Fos和Jun蛋白的亮氨酸拉链的肽优选形成异二聚体(O′Shea等,1989,Science 245,646)。含有拉链的双特异性抗体及其制备方法在WO 92/10209和WO 93/11162中有公开。本发明的双特异性抗体可以是针对VEGF受体和αvβ3受体的抗体,其中这两个受体是在上面论及单特异性抗体时讨论过的受体。
术语“免疫缀合物”指和非免疫学效应分子通过共价键融合在一起的抗体或免疫球蛋白或其有免疫学活性的片段。此融合伙伴(partner)优选为可以糖基化的肽或蛋白质。所述的非抗体分子能连接到抗体重链恒定区的C末端或连接到轻链和/或重链可变区的N末端。此融合伙伴可以通过接头分子连接,一般这种接头分子是含3-15个氨基酸残基的肽。本发明的免疫缀合物优选包含由针对血管生成受体(优选整合蛋白或VEGF受体)的免疫球蛋白或其有免疫治疗效果的片段和TNFα组成的融合蛋白或基本由TNFα和IFHγ或其他适合的细胞因子通过N末端和所述的免疫球蛋白(优选Fc部分)的C末端相连组成的融合蛋白。
术语“融合蛋白”指的是由一个或多个非免疫治疗活性(非抗体)蛋白或肽组成的天然或合成分子,其中这些蛋白或肽具有不同的特异性并任选地通过接头分子融合在一起。例如,本发明的融合蛋白可以是由环(Arg-Gly-Asp-DPhe-NMe-Val)和TNFα和/或IFNγ融合组成的分子。
“杂合抗体”是连接在一起的两个或多个抗体或抗体结合片段,它们中每个都有一个不同的结合特异性。杂合抗体可以通过两个或多个抗体或抗体片段的缀合而制备。优选的杂合抗体由交联的Fab/Fab′片段组成。很多偶联或交联试剂可用于抗体的缀合。比如蛋白A,碳二亚胺,N-琥珀酰亚胺基-S-乙酰基-硫代乙酸酯(SATA)和N-琥珀酰亚胺基-3-(2-吡啶基联硫基)丙酸酯(SPDP)(实例参见Karpovsky等(1984)J.EXP.Med.160,1686;Liu等(1985)Proc.Natl.Acad.Sci.USA 82,8648)。其他的方法还有Paulus,Behring Inst.Mitt.,No.78,118(1985);Brennan等(1985)Science30m:81或Glennie等(1987)J.Immunol.139,2367描述的方法。另一个方法使用邻苯二马来酰亚胺(oPDM)将三个Fab′片段偶联在一起(WO91/03493)。本发明中多特异性抗体也是适用的,并可按照如WO 94/13804和WO 98/50431的教导进行制备。
抗体“效应子功能”是指抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)引起的那些生物活性。抗体效应子功能的实例包括补体依赖的细胞毒性,Fc受体结合,抗体依赖性细胞介导的细胞毒性作用(ADCC),吞噬作用;细胞表面受体(如B细胞受体)的下调等。
术语“ADCC”(抗体依赖性细胞介导的细胞毒性作用)指的是这样一个细胞介导的反应,其中表达Fc受体(FcR)的非特异性细胞毒性细胞(如天然杀伤(NK)细胞,嗜中性粒细胞,和巨噬细胞)识别靶细胞上的结合抗体并随后引起靶细胞的裂解。介导ADCC的重要细胞-NK细胞只表达FcγRIII,而单核细胞可表达FcγRI,FcγRII和FcγRIII。为估计目的分子的ADCC活性,可利用例如现有技术(US 5,500,362;US 5,821,337)中描述的体外ADCC实验来进行。此实验中有用的效应细胞包括外周血单核细胞(PBMC)和天然杀伤(NK)细胞。
“人效应细胞”是能表达一个或多个FcR并执行效应子功能的白细胞。此细胞优选表达至少FcγRIII并执行ADCC效应子功能。介导ADCC的人白细胞的实例包括外周血单核细胞(PBMC),天然杀伤(NK)细胞,单核细胞,细胞毒性T细胞和嗜中性粒细胞。
术语“Fc受体”或“FcR”用于描述与抗体Fc区结合的受体。优选的FcR是天然序列的人FcR。而且,优选的FcR是结合IgG抗体的受体(γ受体)并包括FcγRI,FcγRII和FcγRIII亚类的受体-包括这些受体的等位基因变体和可变剪接形式。例如,对FcR的综述可参见Ravetch和Kinet,Annu.Rev.Immunol 9:457-92(1991)。
术语“细胞因子”是对由一个细胞群释放的作为细胞间介质作用于另一细胞的蛋白质的通称。这类细胞因子的实例有淋巴因子、单核因子以及传统的多肽激素。细胞因子包括生长激素如人生长激素,N-甲硫氨酰基人生长激素以及牛生长激素;甲状旁腺激素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素如促卵泡激素(FSH),促甲状腺激素(TSH)和黄体生成素(LH);肝生长因子;成纤维细胞生长因子;催乳素;胎盘催乳素;小鼠促性腺激素相关肽;抑制素;活化素;血管内皮生长因子(VEGF);整合蛋白;血小板生成素(TPO);神经生长因子如NGFβ;血小板生长因子;转化生长因子(TGF)如TGFα和TGFβ;红细胞生成素(EPO);干扰素如IFNα,IFNβ和IFNγ;集落刺激因子如M-CSF,GM-CSF和G-CSF;白细胞介素如IL-1,IL-1a,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-10,IL-11,IL-12;和TNFα或TNFβ。本发明优选的细胞因子为干扰素和TNFα。
本处使用的术语“细胞毒性剂”指的是可以抑制或阻止细胞功能和/或引起细胞破坏的物质。此术语旨在包括放射性同位素,化疗剂,毒素如细菌,真菌,植物或动物来源的酶活性毒素,或它们的片段。此术语还可以包括细胞因子家族的成员,优选IFNγ。
术语“化疗剂”或“抗肿瘤剂”包括具有抗肿瘤效果的化学药剂,即直接地(作用在肿瘤细胞上,比如通过抑制细胞生长或细胞毒性作用)和间接地(通过如修饰生物学反应等机制)防止肿瘤细胞的发育,成熟或扩散的化学药剂。本发明适宜的化疗剂优选为天然的或合成的化学化合物,但是生物分子如蛋白质,多肽等并不被明确地排除在外。大量的现有处于商业使用、临床评价和临床前研发阶段的抗肿瘤剂都可包括在本发明内,用于通过和TNFα及上面提到的抗血管生成剂及任选地其它药剂比如EGF受体拮抗剂相联合来治疗肿瘤/赘生物。应当指出化疗剂可以任选地与上述药剂联合一起施用。
化疗剂的实例包括烷化剂,如氮芥,吖丙啶化合物,烷基磺酸酯以及其他有烷基化作用的化合物如亚硝基脲,顺氯氨铂和达卡巴嗪;抗代谢物如叶酸、嘌呤或嘧啶拮抗剂;有丝分裂抑制剂如长春花生物碱和鬼臼毒素衍生物;细胞毒性抗生素和喜树碱衍生物。优选的化疗剂或化疗法包括氨磷汀(ethyol),顺氯氨铂,达卡巴嗪(DTIC),放线菌素D,氮芥,链脲霉素,环磷酰胺,carrnustine(BCNU),环己亚硝脲(CCNU),阿霉素(adriamycin),阿霉素微脂体(doxil),吉西他滨(gemzar),柔红霉素,柔红霉素微脂体(daunoxome),甲基苄肼,丝裂霉素,阿糖胞苷,足叶乙甙,氨甲蝶呤,5-氟尿嘧啶(5-FU),长春花碱,长春新碱,博来霉素,紫杉醇(taxol),泰索帝(多烯紫杉醇,docetaxel),阿地白介素(aldesleukin),天冬酰胺酶,白消安,卡铂,克拉立平,喜树碱,CPT-11,10-羟基-7-乙基-喜树碱(SN38),达卡巴嗪,氟尿苷,氟达拉滨,羟基脲,异环磷酰胺,伊达比星,巯乙磺酸钠,干扰素α,干扰素β,伊立替康(irinotecan),米托蒽醌,托泊替堪,亮丙瑞林,甲地孕酮,抗瘤氨酸,巯嘌呤,普卡霉素(plicamycin),氯苯二氯乙烷,天冬酰胺酶(pegaspargase),喷司他丁(pentostatin),哌酰溴烷,普卡霉素,链脲霉素,他莫西芬,替尼泊甙,睾内酯,硫鸟嘌呤,塞替派,尿嘧啶氮芥,维诺利宾,苯丁酸氮芥及其组合。本发明最优选的化疗剂是顺氯氨铂,吉西他滨,阿霉素,紫杉醇和博来霉素。
术语“癌”和“肿瘤”指的是或描述的是典型特征为无调控细胞生长的哺乳动物生理疾病。通过施用本发明的药物组合物,可对肿瘤进行治疗,如乳腺,心脏,肺,小肠,结肠,脾,肾,膀胱,头部和颈,卵巢,前列腺,脑,胰腺,皮肤,骨,骨髓,血液,胸腺,子宫,睾丸,子宫颈和肝的肿瘤。更具体地,肿瘤选自:腺瘤,血管肉瘤(angio-sarcoma),星形细胞瘤,上皮癌,生殖细胞瘤,成胶质细胞瘤,神经胶质瘤,错构瘤,血管内皮瘤,血管肉瘤(hemangio sarcoma),血肿,肝胚细胞瘤,白血病,淋巴瘤,成神经管细胞瘤,黑素瘤,成神经细胞瘤,骨肉瘤,成视网膜细胞瘤,横纹肌肉瘤,肉瘤和畸胎瘤。
详细地说,肿瘤选自:肢端色斑样黑素瘤,光化性角化病,腺癌,囊腺癌,腺瘤,腺肉瘤,腺鳞癌,星形细胞瘤,前庭大腺癌,基底细胞癌,支气管腺癌,毛细血管瘤、癌、癌肉瘤,海绵状胆管癌,软骨肉瘤,脉络丝乳头状瘤/癌,透明细胞癌,囊腺瘤,内胚窦瘤,子宫内膜增生,子宫内膜间质肉瘤,子宫内膜腺癌,室管膜肉瘤,上皮样肉瘤,尤因肉瘤,纤维板层样癌,局灶性结节性增生,胃泌素瘤,生殖细胞瘤,成神经胶质细胞瘤,胰升糖素瘤,成血管细胞瘤,血管内皮瘤,血管瘤,肝腺瘤,肝腺瘤病,肝细胞癌,胰岛素瘤,上皮内瘤形成,上皮间鳞状细胞癌,侵袭性鳞状细胞癌,大细胞癌,平滑肌肉瘤,恶性着色斑型黑素瘤,恶性黑素瘤,恶性间皮瘤,成神经管细胞瘤,髓上皮瘤,黑素瘤,脑膜肿瘤,间皮肿瘤,转移性肿瘤,粘液上皮癌,成神经细胞瘤,神经上皮腺癌,结节性黑色素瘤,燕麦细胞癌,少突神经胶质瘤,骨肉瘤,胰腺多肽,乳头状浆液性腺癌,松果体细胞瘤,垂体瘤,浆细胞瘤,假肉瘤,肺母细胞瘤,肾细胞瘤,成视网膜细胞癌,横纹肌肉瘤,肉瘤,浆液性癌,小细胞肺癌,软组织癌,抑生长素分泌细胞肿瘤,鳞癌,鳞状细胞癌,间皮下,表浅蔓延型黑素瘤,未分化的癌,眼色素层黑色素瘤,疣状癌,血管活性肠多肽瘤,完全分化的癌,和肾母细胞瘤。
“ErbB受体”是指属于ErbB受体家族的受体蛋白酪氨酸激酶,包括EGFR(ErbB1),ErbB2,ErbB3和ErbB4受体以及此家族中有待于在将来进行鉴别的其他成员。ErbB受体一般含有一个可与ErbB配体结合的细胞外结构域;一个亲脂性的跨膜结构域;一个保守的细胞内酪氨酸激酶结构域;以及一个含有若干可被磷酸化的酪氨酸残基的羧基端信号结构域。ErbB受体可以是“天然序列的”ErbB受体,或它的“氨基酸序列变异体”。优选的ErbB受体是天然序列的人ErbB受体。ErbB1指的是编码EGFR蛋白产物的基因。最优选的是EGF受体(Her1)。“ErbB1”和“HER1”在本处可互换使用且均指人HER1蛋白。“ErbB2”和“HER2”在本处可互换使用且均指人HER2蛋白。本发明优选ErbB1受体(EGFR)。
“ErbB配体”是结合并且/或者激活ErbB受体的多肽。与EGFR结合的ErbB配体包括有EGF,TGF-a,双调蛋白,β-细胞调节素(betacellulin),HB-EGF和表皮调节素(epiregulin)。
术语“ErbB受体拮抗剂/抑制剂”指的是天然或合成的能结合并阻断或抑制ErbB受体的分子。因此通过阻断受体,拮抗剂阻止了ErbB配体(激动剂)的结合以及激动剂/配体受体复合物的活化。ErbB拮抗剂可能针对HER1(EGFR)或HER2。本发明优选的拮抗剂针对EGF受体(EGFR,Her1)。ErbB受体拮抗剂可以是抗体或抗体的免疫治疗活性片段或非免疫生物学分子一如肽、多肽蛋白。化学分子也包括在内,但是本发明优选的拮抗剂为抗EGFR抗体和抗HER2抗体。
本发明优选的抗体为抗Her1和抗Her2抗体,更优选抗Her1抗体。优选的抗Her1抗体为MAb 425,优选人源化的MAb 425(hMAb 425,US5,558,864;EP 0531 472)和嵌合MAb 225(cMAb 225,US 4,943,533和EP0359 282)。最优选的是单克隆抗体h425,在单药物治疗中它已显示出高疗效和降低的负反应和副作用。最优选的抗Her2抗体是Genentech/Roche上市的HERCEPTIN。本发明的有效EGF受体拮抗剂还可以是天然的或合成的化学化合物。此类优选分子的一些实例包括有机化合物、有机金属化合物、有机化合物和有机金属化合物的盐。
HER2受体拮抗剂的实例有:苯乙烯基取代的杂芳基化合物(US5,656,655);双单环和/或双环芳基、杂芳基、碳环和杂碳环化合物(US5,646,153);三环的嘧啶化合物(US 5,679,683);有受体酪氨酸激酶抑制活性的喹唑啉衍生物(US 5,616,582);杂芳基乙烯基或杂芳基乙烯基芳基化合物(US 5,196,446);可以抑制EGFR、PDGFR和FGFR受体家族的名称为6-(2,6-二氯代苯基)-2-(4-(2-二乙基-氨基乙氧基)苯基氨基)-8-甲基-8H-吡啶并(2,3)-5-嘧啶-7-酮的化合物(Panek,等,1997,J.Pharmacol.Exp.Therap.283,1433)。
术语“酪氨酸激酶拮抗剂/抑制剂”指的是天然的或者合成的能够抑制或阻断酪氨酸激酶(包括受体酪氨酸激酶)的试剂。除了上文和下文所提及的抗ErbB受体抗体以外,更优选的酪氨酸激酶拮抗剂是在单药物治疗中表现出对乳腺癌和前列腺癌有效的化学化合物。适宜的吲哚并咔唑型酪氨酸激酶抑制剂可以利用如美国专利5,516,771;5,654,427;5,461,146;5,650,407等文献的信息获得。美国专利5,475,110;5,591,855;5,594,009和WO 96/11933公开了吡咯并咔唑型酪氨酸激酶抑制剂和前列腺癌。上面定义的化学属性酪氨酸激酶抑制剂的优选剂量为每天1pg/kg体重到1g/kg体重。更优选的酪氨酸激酶抑制剂的剂量为每天0.01mg/kg体重到100mg/kg体重。
此处所用的术语“抗激素剂”包括天然的或合成的有机或肽化合物,它们起的作用是调节或抑制激素对肿瘤的活性。更具体地来说,“抗激素剂”(1)抑制血清雄激素的产生,(2)阻断血清雄激素与雄激素受体的结合,或者(3)抑制睾酮转化为DHT或两种或多种此类化合物的组合。
本发明的抗激素剂一般包括类固醇受体拮抗剂,更具体来说抗雌激素剂,如包括他莫昔芬,raloxifene,芳香酶抑制4(5)-咪唑,4-羟基他莫昔芬,氢萘吡苯酮,keoxifene,LY117018,onapristone和托瑞米芬(toremifene)(Fareston);及抗雄激素剂,如氟他胺(flutamide),尼鲁他胺(nilutamide),bicalutamide,亮丙瑞林(1euprolide)和性瑞林(goserelin);以及上述任一种的药学可接受的盐、酸或衍生物。本术语还包括糖蛋白激素——如促卵泡成熟激素(FSH),促甲状腺素(TSH)和黄体生成素(LH)和LHRH(黄体生成激素释放激素)的激动剂和/或拮抗剂。可用于本发明的LHRH激动剂是醋酸性瑞林,其商品名称为ZOLADEX(Zeneca)。醋酸性瑞林的化学结构是pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH,醋酸。可用于本发明的LHRH拮抗剂的一个实例是ANTIDE(Ares-Serono),其化学名称是D-丙氨酰胺N-乙酰-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-NG-(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-甲乙基)-L-赖氨酰-L-脯氨酰基。另一个有用的LHRH拮抗剂实例是GANI RELIX(Roche/Akzo Nobel),其化学名称是N-Ac-D-Nal,D-pCl-Phe,D-Pal,D-hArg(Et)2,hArg(Et)2,D-Ala。类固醇抗雄激素剂的实例是醋酸环丙孕酮(CPA)和醋酸甲地孕酮,其商品为MEGACE(Bristol-Myers,Oncology)。类固醇抗雄激素剂可阻断前列腺雄激素受体。它们还可抑制LH的释放。优选给人类患者施用的CPA剂量为100mg/天到250mg/天。非类固醇抗雄激素阻断雄激素受体。它们还可引起血清LH水平和血清睾酮水平的增加。优选的非类固醇抗雄激素剂是氟他胺(2-甲基-N-[4-20硝基-3-(三氟甲基)苯基丙酰胺],其商品名为EULEXIN(Schering Corp.)。氟他胺发挥的是抗雄激素作用,其抑制雄激素摄取、抑制靶组织中雄激素的核结合或两者兼而有之。另一个非类固醇抗雄激素剂是尼鲁他胺,其化学名称为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。
在本发明的一些实施方案中,抗激素剂是LHRH激动剂如醋酸亮丙瑞林和抗雄激素剂如氟他胺或尼鲁他胺的组合。如,可通过皮下注射、肌肉注射和静脉注射施用醋酸亮丙瑞林,并同时可以口服氟他胺。
如上文指出,本发明的抗激素剂包括类固醇/甲状腺激素受体的拮抗剂,其中包括了其它非许可(non-permissive)受体——如RAR,TR,VDR等的拮抗剂。正如本领域技术人员易于明了的,多种合成的和天然的视黄酸受体(RAR)拮抗剂可应用于本发明。示例性RAR拮抗剂包括dicarba-closo-dodecaboranes(lijima等,Chem Pharm Bull(Tokyo)(1999)47(3):398-404),氢蒽基、苯并色烯基和苯并硫代色烯基类视黄醇(retinoid)(Vuligonda等,Bioorg Med Chem Lett(1999)9(5):743-8),二芳基乙炔、苯甲酸衍生物(参见如Kagechika,H.(1994)Yakugaku Zasshi114(11):847-862;Eckhardt等(1994)Toxicol Lett 70(3):299-308;Yoshimura等(1995)J Med Chem 38(16):3163-3173;30 Chen等(1995)EMBO 14(6):1187-1197;Teng等(1997)J Med Chem 40(16):2445-2451);萘基类似物(参见如Johnson等(1995)J Med Chem 38(24):4764-4767;Agarwal等J Biol Chem 271(21):12209-12212;Umemiya等(1996)Yakugaku Zasshi 116(12):928-941);芳基取代的以及芳基和(3-氧代-1-丙烯基)-取代的苯并吡喃、苯并硫代吡喃、1,2-二氢喹啉和5,6-二氢萘衍生物(Klein等U.S.Pat.Nos.5877,207和5,776,699),金刚烷基-取代的二芳族化合物(Bernardon和Charpentier,U.S.Pat.No.5,877,342),1-苯基-金刚烷衍生物(Bernardon和Bernardon EP776885),多芳族杂环化合物(Charpentier等U.S.Pat.No.5,849,798),二氢萘衍生物(Beard等,U.S.Pat.No.5,808,124和Johnson等US5,773,594),4-苯基(苯并吡喃基或萘酰基)胺基安息香酸衍生物(WO98/US/13065),二氮杂唑苯甲酸衍生物(Umemiya等,J Med Chem(1997)40(26):4222-34),四氢萘衍生物(US 5,763,635,5,741,896和5,723,666),芳基-和杂芳基环己烯基取代的烯烃(US 5,760,276),二苯并呋喃化合物——包括芳族二苯并呋喃化合物(US 5,702,710,US 5,747,530),N-芳基取代的四氢喹啉(US 5,739,338),苯并[1,2-g]-色-3-烯以及苯并[1,2g]-硫代色-3-烯衍生物(US 5,728,846),等。预期可用于本发明的具体RAR拮抗剂的实例包括LE135(Umemiya等(1996)Yakugaku Zasshi 116(12):928-941),LE511,LE540,LE550(Li等,J Biol Chem(1999)274(22):15360-6;Umemiya等(1996)Yakugaku Zasshi 116(12):928-941),Ro41-5253(Keidel等(1994)Mol Gell Biol 14(1):287-298),SR11330,SR11334,SR11335(Lee等(1996)J.Biol Chem 271(20):11897-11903),BMS453,BMS411(Chen等(1995)EMBO 14(6):1187-1197),CD2366和CD2665(Meister等,Anticancer Res.(1998)18(3A):1777-1786),ER27191(Uemo等,Leu k.Res.(1998)22(6):517-525),AGN 193 109(Johnson等,Bioorg Med Chem Lett(1999)9(4):573-6),4-[4,5,7,8,9,10-六氢-7,7,10,10-四甲基-1-(3-吡啶基甲基)蒽并[1,2-b]吡咯-3-基]安息香酸,4-[4,5,7,8,9,10-六氢-7,7,10,10-四甲基-1-(3-吡啶基甲基)-5-硫代蒽并[1,2-b]吡咯-3-基]安息香酸,4-[4,5,7,8,9,10-六氢-7,7,10,10-四甲基-1-(3-吡啶基甲基)蒽并[2,1-d]吡唑-3-基]安息香酸(Yoshimura等(1995)JMed Chem 38(16):3163-3173),AGN193109(Agarwal等J Biol Chem271(21):12209-12212),等。
“类固醇受体”或“核类固醇受体”指的是—种蛋白质,它是一种配体激活的转录因子,属于核受体的类固醇受体亚族。那些结构类似并具有类固醇激素激活的转录因子的生物活性的蛋白质都包含在类固醇受体的定义中。类固醇受体含有全部或部分的DNA结合域和激素(或配体)结合域,并且包括结构类似于类固醇受体但配体未知的孤儿受体。
“类固醇受体配体”指的是一种能够结合核类固醇受体以形成受体-配体复合物的天然或合成化合物。此术语“配体”包括激动剂、拮抗剂以及具有部分激动剂/拮抗剂活性的化合物。
“类固醇受体激动剂”指的是一种能够结合核类固醇受体以形成受体-激动剂复合物的化合物。受体-激动剂复合物能够结合被称为激素效应元件的DNA特异性区域。激动剂包括类固醇或类固醇样激素,类视黄醇,甲状腺激素,药物活性化合物,等。一种激动剂可能具有与多种受体结合的能力。天然的类固醇激素激动剂包括雌二醇,黄体酮,雄激素,糖皮质激素和盐皮质激素。如上文所指出的,一些类固醇受体激动剂随剂量的不同可显示出一些拮抗剂的功效。因此,这样的“激动剂”可能有效地作为本发明定义的抗激素剂。
“类固醇受体拮抗剂”指的是具有与激动剂相对的生物学作用的化合物。拮抗剂结合核类固醇受体并且通过与类固醇激动剂竞争受体而阻断类固醇受体激动剂的活性。拮抗剂是根据其阻断激动剂活性的能力而定义的。类固醇受体拮抗剂包括“纯”拮抗剂以及具有部分激动剂/拮抗剂活性的化合物。纯拮抗剂可有效地与激动剂竞争对受体的结合,而其本身不具有激动剂活性。部分拮抗剂可能在与激动剂竞争对受体的结合的方面效力较差,或者可能在结合受体方面效力相等但是与其所竞争的激动剂的活性相比其仅具有5-10%的激动剂活性。这样,拮抗剂可能具有比其所竞争的激动剂的激动活性效力较低的激动剂活性。
“放射性疗法”:根据本发明肿瘤还可以利用放射线或放射药物进行治疗。放射源既可以给患者外用也可以给患者内用。如果给患者外用放射源,该治疗方法称作体外照射放疗(EBRT)。如果给患者内用放射源,此治疗称为近巨放射疗法(BT)。已经使用的一些典型的放射活性原子包括镭,铯-137,和铱-192,镅-241和金-198,钴-57;铜-67;锝-99;碘-123;碘-131;以及铟-111。也可以用放射活性同位素标记本发明药剂。当前放射性疗法是控制不能切除的和不宜手术的肿瘤和/或肿瘤转移的标准治疗方法。已经看到放射性疗法和化疗组合可提高疗效。放射性疗法依据的原理是投射到靶区的高剂量辐射将导致肿瘤和正常组织中的增殖细胞的死亡。辐射剂量方案一般根据辐射吸收剂量(rad),时间和分段进行确定,并且必须由肿瘤专家进行仔细确定。患者接受的辐射量将取决于各种因素,但两个最重要的因素是肿瘤相对身体其它重要结构或器官的位置,以及肿瘤扩散的程度。对患者实施放射性疗法的一个优选治疗方案是疗程持续5-6个星期,将50-60Gy总剂量按照每星期5天每天1次1.8-2.0Gy的剂量给患者分段施用。Gy是戈瑞的缩写,指100rad剂量。在优选的实施方案中,血管生成拮抗剂和TNFα/IFNγ以及放射物对人类患者肿瘤的治疗具有协同作用。换句话说,所述化合物如果与放射物和/或化疗剂组合,则对肿瘤生长的抑制作用将增强。本发明可任选地使用放射性疗法。在不能给患者施用足量的本发明药剂的情况下建议和优选使用放射性疗法。
“药物治疗”:就步骤而言,本发明的方法包括多种实施形式。比如,本发明的药剂可以同时地,相继地或独立地使用。另外,药剂可分开施用且两次施用间隔在约3周以内,即第二种药剂在第一种活性剂施用后基本上立即开始施用到第一种药剂施用后不超过约3周的时间开始施用。本方法可在手术之后进行。或者,手术可在施用第一种活性药剂和施用第二种活性药剂之间的间隔期内进行。此方法的实例是将本发明方法和外科肿瘤摘除手术联合应用。根据本发明方法的治疗典型地包括在一个或多个施用周期内施用本治疗组合物。例如,当进行同时施用的时侯,含有2种药剂的治疗组合物在一个周期内持继施用大约2天到约3周。此后,治疗周期可根据执业医生的判断按需要进行重复。类似地,如果进行相继施用,则每种治疗剂施用的时间可调整到典型地覆盖同样的时间。两周期之间的间隔可从约0到2个月不等。
本发明的药剂可通过注射或随时间逐渐输注经肠胃外施用。体内待治疗的组织用全身给药的方法一般就可进行治疗,因此最经常使用的方法是静脉内给予治疗组合物,但是当目标组织可能含有靶分子的时候,其他组织和给药方法也是可考虑的。因此,本发明的药剂可眼内,静脉内,腹膜内,肌内,皮下,腔内,经皮,通过常位注射和输注给药,而且还可以通过蠕动方式给药。例如,包括本发明的整合蛋白拮抗剂的治疗组合物通常通过静脉方式,比如以单位剂量注射给药。本发明的治疗组合物包含生理学可耐受的载体和溶解或分散于其中作为活性成分的本处描述的相关药剂。
如在本处使用的那样,术语“药学上可接受的”指这样的组合物,载体,稀释剂和试剂,这些物质可用在哺乳动物身上而不会产生不想要的生理效应如恶心,眩晕,反胃等。其中溶解或分散有活性成分的药物组合物的制备是本领域技术人员所熟知的,不必在制剂的基础上进行限定。典型地,这种组合物可制成注射剂如液体溶液或悬液,但是,也可制成适于在使用前在液体中形成溶液或混悬液的固体形式。制剂也可进行乳化。可将活性成分和其量适于本处描述的治疗方法的药学上可接受的并与活性成分兼容的赋形剂混合。适当的赋形剂是,例如,水,盐水,葡萄糖,甘油,乙醇等以及这些的组合。另外,如果需要的话,组合物还可以包括小量可增加活性成分效用的辅助物质如润湿剂或乳化剂,pH缓冲剂等。本发明治疗组合物可在其中包括这些成分在药学上可接受的盐。药学上可接受的盐包括酸加成盐(和多肽的游离氨基基团成盐),所述酸是无机酸,例如,盐酸或磷酸,或像乙酸,酒石酸,苦杏仁酸等有机酸。也可从无机碱,例如,钠,钾,铵,钙或铁的氢氧化物,以及有机碱如异丙胺,三甲基胺,2-乙氨基乙醇,组氨酸,普鲁卡因等,得到与游离羧基基团形成的盐。在环肽αv拮抗剂制剂中特别优选使用HCl盐。生理学上可耐受的载体是本领域的技术人员所熟知的。液相载体的例子为无菌水溶液,它可以仅含有活性组分和水或可以还含有缓冲剂例如在生理pH值的磷酸钠,生理盐水或两者,如磷酸缓冲盐水。再者,含水载体可以含有一种以上的缓冲盐以及诸如氯化钠和氯化钾等盐,葡萄糖,聚乙二醇和其他溶质。液体组合物也可含有有水或无水的液相。这类其他液相的例子有甘油,植物油如棉籽油和水油乳液。
典型地,对于形式为例如,整合蛋白受体阻断抗体或抗体片段或抗体缀合物或者抗VEGF受体阻断抗体、片断或缀合物的免疫治疗剂,治疗有效量是在生理可耐受的组合物中给药时,足以使血浆浓度达到约0.01微克(μg)每毫升(ml)至约100μg/ml,优选约1μg/ml至5μg/ml,通常约5μg/ml的量。换言之,剂量可从约0.1mg/kg变化到约300mg/kg,优选约0.2mg/kg至约200mg/kg,最优选约0.5mg/kg至约20mg/kg,一日或多日持继进行一日一次或一日多次给药。当免疫治疗剂是单克隆抗体的片段或缀合物的时侯,其用量可很容易地根据片段/缀合物的质量相对于整个抗体的质量的比例进行调整。以摩尔浓度表示,优选的血浆浓度为约2微摩尔(μM)至约5毫摩尔(mM),优选约100μM到1mM抗体拮抗剂。
对于属于非免疫治疗性肽或蛋白质多肽或其他类似大小的生物分子的本发明药剂,其治疗有效的量典型地为这样的多肽量,即在生理可耐受的组合物中给药时足以使血浆浓度达到0.1微克(μg)每毫升(ml)至约200μg/ml,优选约1μg/ml至约150μg/ml的量。根据每摩尔有约500克质量的多肽来计算,优选的血浆摩尔浓度为约2微摩尔(μM)到约5毫摩尔(mM),优选约100μM至1mM多肽拮抗剂。
对于优选为本发明核激素受体拮抗剂或(化学)化疗剂(既不是免疫治疗剂,也不是非免疫治疗性肽/蛋白)的活性剂,其典型剂量为每公斤体重每天10mg至1000mg,优选约20至200mg,更优选的是50至100mg。
本发明的药物组合物优选适用于乳腺和前列腺癌的治疗。
治疗乳腺癌优选下列抗激素剂及剂量:
他莫昔芬:10.0mg-40.0mg口服给药/天
托瑞米芬:20.0mg-100.0mg/天
Anastrozole:0.5mg-5.0mg口服给药/天
Letrozole:1.0mg-10.0mg口服给药/天
福美司坦(Formestane):100.0mg-500.0mg肌内给药/2周
性瑞林:2.5mg-5.0mg皮下给药/4周
布舍瑞林(Buserelin):5.0mg-10.0mg皮下给药/8周
1.0mg-5.0mg鼻喷雾给药/天
亮丙瑞林:5.0mg-15.0mg皮下给药/3月
醋酸甲地孕醇:40.0mg-200.0mg/天
治疗乳腺癌优选下列抗激素剂及剂量:
氟他胺:250.0mg-1000.0mg/天
Bicalutamide:10.0mg-200.0mg/天
性瑞林:2.5mg-5.0mg皮下给药/4周
布舍瑞林:5.0mg-10.0mg皮下给药/8周
1.0mg-5.0mg鼻喷雾给药7天
亮丙瑞林:5.0mg-15.0mg皮下给药/3月
乙酸环丙孕酮:25.0mg-200.0mg/天口服给药
150.0mg-500.0mg肌内给药/2周
上文所述的抗激素治疗主要成分的任何类似物或其发展物可根据指示剂量使用。
本发明的“药物组合物”可以包含能降低或避免伴随本发明联合疗法出现的副作用的药剂(“辅助疗法”),这包括但不限于,如降低抗癌药物毒性作用的药剂,例如骨重吸收抑制剂,心脏保护药物。所述的辅助药剂可以防止或降低化疗,放射治疗或手术带来的恶心和呕吐的发生率,或降低施用骨髓抑制性抗癌药物带来的感染机率。辅助药剂是本领域内的技术人员所熟知的。此外,本发明的免疫治疗剂还可以和佐剂如BCG和免疫系统刺激剂一起使用。而且,组合物可包括含有具细胞毒性作用的放射性标记同位素或其他细胞毒性剂如细胞毒性肽(例如细胞因子)或细胞毒性药物等的免疫治疗剂或化疗剂。
术语用于治疗肿瘤或肿瘤转移的“药物试剂盒”指的是一种包装以及通常地药剂在肿瘤和肿瘤转移治疗方法中的使用说明书。本发明试剂盒中的药剂一般被配制成本处所描述的治疗组合物,因此可以采用任何适于试剂盒内放置的形式。这些形式可以包括液体,粉末,片剂,混悬液等以便提供本发明的拮抗剂和/或融合蛋白。这些药剂可以在适合于根据本发明方法单独给药的各单独容器中提供,或可以在此包装中的单一容器内结合在组合物中提供。包装中可含有足以按照此处描述的治疗方法施用一次或多次的药剂量。本发明试剂盒还包括包装中所含材料的“使用说明”。
Claims (20)
1.药物组合物,其包含治疗有效量的至少(i)一种抗EGFR抗体或此抗体的免疫治疗有效片断以及(ii)一种抗激素剂,及任选地药学上可接受的载体、赋形剂或稀释剂。
2.如权利要求1所述的药物组合物,其中所述的抗EGFR抗体或所述的此抗体的免疫治疗有效片断是小鼠的、嵌合的或人源化的Mab425(h425)或嵌合的Mab225(c225)抑制剂/拮抗剂。
3.如权利要求1所述的药物组合物,其中所述的抗激素剂是核激素受体家族的抑制剂。
4.如权利要求3所述的药物组合物,其中所述的抗激素剂是类固醇受体抑制剂和/或拮抗剂。
5.如权利要求1-4任一项所述的药物组合物,其还包含抗血管生成剂。
6.如权利要求1-4任一项所述的药物组合物,其还包含细胞毒性剂和/或化疗剂。
7.如权利要求1-4任一项所述的药物组合物,其还包含其它的抗-HER2抗体或它的免疫治疗活性片断。
8.药物组合物,其包含既具有抗EGFR活性又具有抗核激素受体活性的抗体,及任选地药学上可接受的载体、赋形剂或稀释剂。
9.如权利要求8所述的药物组合物,其中所述抗体是双特异性抗体。
10.药物试剂盒,其包含这样的包装,该包装含有至少
(i)一种抗EGFR抗体或此抗体的免疫治疗有效片断,及
(ii)一种抗激素剂,及任选地
(iii)细胞毒性剂和/或化疗剂。
11.如权利要求10所述的药物试剂盒,其包含
(i)单克隆抗体h425,和
(ii)类固醇受体拮抗剂。
12.如权利要求11所述的药物试剂盒,其包含
(i)单克隆抗体h425,和
(ii)LHRH拮抗剂。
13.如权利要求10-12任一项所述的药物试剂盒,其中所述药物活性剂在所述包装中分别于单独容器中提供。
14.如权利要求1-9任一项所述的药物组合物或如权利要求10-13任一项所述的药物试剂盒在制备用于治疗肿瘤和肿瘤转移的药物或药物组合物中的用途。
15.权利要求14的用途,用于治疗乳腺癌。
16.权利要求14的用途,用于治疗前列腺癌。
17.权利要求15或16的用途,用于治疗类固醇非依赖性的乳腺和前列腺癌。
18.治疗个体的肿瘤和肿瘤转移的方法,其包括同时或相继给所述个体施用治疗有效量的(i)抗EGFR抗体,和(ii)抗激素剂。
19.如权利要求18所述的方法,其中所述的抗EGFR抗体是单克隆抗体h425或c225且所述的抗激素剂是类固醇受体拮抗剂。
20.如权利要求18或19所述的方法,其包括还给所述个体施用治疗有效量的细胞毒性剂和/或化疗剂或抗血管生成剂或其它的抗ErbB受体抗体。
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EP (1) | EP1385546A1 (zh) |
JP (1) | JP2004528368A (zh) |
KR (1) | KR20040029975A (zh) |
CN (1) | CN1507355A (zh) |
AU (1) | AU2002315306B2 (zh) |
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PL (1) | PL363322A1 (zh) |
RU (1) | RU2003134180A (zh) |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN101472572A (zh) * | 2006-05-16 | 2009-07-01 | 生命医药公司 | Rar拮抗剂或反向激动剂在治疗化学疗法和/或放射疗法副作用中的用途 |
CN101472572B (zh) * | 2006-05-16 | 2012-10-10 | Io治疗有限责任公司 | Rar拮抗剂或反向激动剂在治疗化学疗法和/或放射疗法副作用中的用途 |
CN113207799A (zh) * | 2021-03-19 | 2021-08-06 | 中山大学 | 一种二型糖尿病小鼠快速心衰模型的构建方法 |
CN116333117A (zh) * | 2021-12-16 | 2023-06-27 | 徕特康(苏州)生物制药有限公司 | 抗表皮生长因子受体抗体及其制备方法和用途 |
CN116333117B (zh) * | 2021-12-16 | 2024-04-26 | 徕特康(苏州)生物制药有限公司 | 抗表皮生长因子受体抗体及其制备方法和用途 |
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BR0209147A (pt) | 2004-06-08 |
HUP0303976A2 (hu) | 2004-03-01 |
CA2449166A1 (en) | 2002-11-14 |
CZ20033226A3 (en) | 2004-07-14 |
MXPA03010121A (es) | 2004-03-10 |
RU2003134180A (ru) | 2005-02-10 |
US20070202101A1 (en) | 2007-08-30 |
WO2002089842A1 (en) | 2002-11-14 |
PL363322A1 (en) | 2004-11-15 |
JP2004528368A (ja) | 2004-09-16 |
KR20040029975A (ko) | 2004-04-08 |
AU2002315306B2 (en) | 2007-05-17 |
HUP0303976A3 (en) | 2006-11-28 |
US20040131611A1 (en) | 2004-07-08 |
EP1385546A1 (en) | 2004-02-04 |
SK14632003A3 (sk) | 2004-03-02 |
ZA200309437B (en) | 2005-03-04 |
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