CN102892779B - 神经调节蛋白拮抗剂及其在治疗癌症中的用途 - Google Patents
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Abstract
本发明提供了神经调节蛋白拮抗剂和在延迟肿瘤复发前时间或预防癌细胞对用治疗剂治疗的抗性中使用神经调节蛋白拮抗剂的方法。
Description
对相关申请的交叉引用
本申请要求2010年2月18日提交的美国临时申请No.61/305878的权益,通过提及而将其公开内容完整收入本文。
发明领域
本发明涉及用神经调节蛋白拮抗剂治疗癌症。
发明背景
癌症干细胞(CSC)的身份和特性在最近数年中已经是强烈研究的一个领域。肿瘤是具有不同生物学特性的细胞的异质混合物的证据在积累。已经对许多血液学恶性肿瘤和实体瘤报告了具有启动肿瘤生长的独特能力的截然不同的细胞群体的分离。然而,已经在使用特定细胞表面标志物预期地鉴定CSC中出现不一致性。例如,已经对白血病、胰腺、结肠直肠、脑和乳腺癌报告了关于干细胞表型的根本不同的发现(综述见Brennan和Matsui2009)。此外,CSC频率的估算在肿瘤类型和患者中显著变化。CSC在维持已建立肿瘤的生长中或在化学疗法后在原发性或远距离部位再启动肿瘤中的作用仍然有待确定。
对于大多数癌症患者,化学疗法后的疾病复发是死亡的一个主要原因。因而,需要更好地了解造成复发的肿瘤再启动细胞(TRIC)以更好地治疗在最初响应化学治疗处理后经历癌症复发的患者。这对于非小细胞肺癌(NSCLC)是特别相关的,因为大于三分之二的NSCLC患者不是手术切除的候选者。大多数患者以晚期疾病呈现,并且用化学疗法、放射或两种的组合治疗(Lung Cancer Principles and Practice)。然而,尽管对治疗的初始响应良好,局部晚期疾病的5年存活率仍然为23.7%,而对于晚期疾病为3.5%(Horner等SEER)。
已经显示了经由过表达或激活突变的EGFR信号传导的脱调节(deregulation)是NSCLC中的一个频繁事件(综述见Dahabreh等,2010)。EGFR是HER酪氨酸激酶家族的原型成员,该家族包括EGFR (Her1)、Her2、Her3和Her4。Her2缺乏功能性配体结合域(Graus-Porta1997),而Her3缺乏酪氨酸激酶活性(Guy 1994),因此这些受体必须以异二聚体起作用。最近的证据显示了其它Her家族成员也可以在NSCLC中发挥作用。然而,它们对疾病的贡献是不太充分表征的,并且研究经常聚焦于其与EGFR激活的相互作用(Kuyama等2008,Hirsch2009,Zhou 2006,Johnson 2006,Ding 2008)。
神经调节蛋白是Her3和Her4受体酪氨酸激酶的一种配体。神经调节蛋白家族有4种已知的成员,即NRG1、NRG2、NRG3、和NRG4(Falls 2003)。NRG1转录物经历广泛的可变剪接,生成至少15种不同同等型。所有活性同等型共享对于活性必需且足够的EGF样域(Holmes 1992,Yarden 1991)。已经显示了NRG1自分泌信号传导调节肺上皮细胞增殖(Jinbo 2002),并且在人肺发育中发挥作用(Patel 2000),而且牵涉NSCLC对EGFR抑制剂的不敏感性(Zhou2006)。
需要提供在治疗抗性癌症和已经经历癌症复发的患者中有效的治疗剂。
发明概述
本发明的一个方面提供了一种延长癌症患者中的肿瘤复发前时间的方法,包括对所述患者施用有效量的神经调节蛋白拮抗剂。在一个实施方案中,该方法进一步包括对所述患者施用治疗剂。在一个实施方案中,治疗剂是化学治疗剂或抗体。在某些实施方案中,化学治疗剂是帕利他塞(paclitaxal)或顺铂或帕利他塞和顺铂的组合。
在某些实施方案中,抗体是EGFR、HER2、HER3、或HER4抗体。在某些实施方案中,患者患有的癌症是非小细胞肺癌、乳腺癌、卵巢癌、头和颈癌、宫颈癌、膀胱癌、食管癌、前列腺癌、或结肠直肠癌。
在一个实施方案中,肿瘤复发前时间的延长比在没有所述神经调节蛋白拮抗剂的情况中的复发前时间大至少1.25倍。在一个实施方案中,肿瘤复发前时间的延长比在没有所述神经调节蛋白拮抗剂的情况中的复发前时间大至少1.50倍。
在某些实施方案中,神经调节蛋白拮抗剂是抗体、小分子、免疫粘附素、或RNA。在一个实施方案中,神经调节蛋白拮抗剂是NRG1拮抗剂。在一个实施方案中,NRG拮抗剂是抗NRG1抗体。
附图简述
图1:用于研究肿瘤再启动细胞(TRIC)的体内模型的图示。
图2A:无胸腺裸鼠中的Calu3人NSCLC异种移植物模型,其中化学疗法由帕利他塞和顺铂组成。数据以均值肿瘤体积±SEM呈现,n=12只小鼠/组。
图2B:无胸腺裸鼠中的H441人NSCLC异种移植物模型,其中化学疗法由帕利他塞和顺铂组成。数据以均值肿瘤体积±SEM呈现,n=12只小鼠/组。
图2C:具有肿瘤细胞对SCID/beiz小鼠乳房脂肪垫的正位移植的KPL4人乳房模型,其中化学疗法由帕利他塞组成。数据以均值肿瘤体积±SEM呈现,n=12只小鼠/组。
图2D:用顺铂处理K-rasLSLG12D,CAG-LSL-GFP遗传工程小鼠NSCLC模型。数据以每个肺的GFP阳性细胞的平均数±SEM呈现,n=6只小鼠/组。
图3A:通过微阵列分析中的两种独立的探针证明NRG1mRNA在Calu3异种移植物模型的TRIC中富集。使用自独立的肿瘤样品分离的RNA通过针对NRG1a和NRG1b的定量实时PCR(qPCR)验证富集。
图3B:通过两种不同微阵列探针显示的NRG1mRNA在H441异种移植物模型的TRIC中的富集。这使用来自用于微阵列分析的相同肿瘤样品的RNA通过针对NRG1a和NRG1b的qPCR验证。
图3C:通过两种不同微阵列探针显示的NRG1mRNA在KPL4乳腺癌异种移植物模型的TRIC中的富集。
图3D:通过一种微阵列探针显示并通过qPCR验证的NRG1mRNA在K-rasLSLG12D小鼠NSCLC模型的TRIC中的富集。
图4:NRG1富集对于残留细胞是特异的,如通过对化学疗法后各个大小和时间的肿瘤中的肿瘤细胞NRG1mRNA水平的qPCR分析证明的。
图5A:图显示了在其随意的饮用水中施用媒介物(蔗糖)或dox(2gm/L)的具有已建立的Calu3-shNRG1异种移植物肿瘤的小鼠的肿瘤生长曲线。对肿瘤体积一周测量两次,持续整个研究。数据以线性混合效应(Linear Mixed Effect,LME)模型对肿瘤体积产生的拟合呈现,作为具有自动确定纽结(auto-determined knot)的三次样条(cubic splines)绘图。
图5B:图显示了用化疗+蔗糖或化疗+dox处理的具有已建立的Calu3-shNRG1异种移植物肿瘤的小鼠的肿瘤生长曲线。数据以LME模型对肿瘤体积产生的拟合呈现,作为具有自动确定纽结的三次样条绘图。
图6A:图显示了用蔗糖或dox处理的具有已建立的H441-shNRG1异种移植物肿瘤的小鼠的肿瘤生长曲线(n=12只/组)。数据以肿瘤体积的LME拟合分析呈现,作为具有自动确定纽结的三次样条绘图。
图6B:图显示了用化疗+蔗糖或化疗+dox处理的具有已建立的H441-shNRG1异种移植物肿瘤的小鼠的肿瘤生长曲线(n=12只/组)。数据以肿瘤体积的LME拟合分析呈现,作为具有自动确定纽结的三次样条绘图。
图7A:图显示了用蔗糖或dox处理的具有已建立的H1299-shNRG1异种移植物肿瘤的小鼠的肿瘤生长曲线(n=12只小鼠/组)。数据以肿瘤体积的LME拟合分析呈现,作为具有自动确定纽结的三次样条绘图。
图7B:图显示了用化疗+蔗糖或化疗+dox处理的具有已建立的H1299-shNRG1异种移植物肿瘤的小鼠的肿瘤生长曲线(n=12只/组)。数据以肿瘤体积的LME拟合分析呈现,作为具有自动确定纽结的三次样条绘图。
图8A:图显示了用媒介物+对照IgG(n=6)、顺铂+对照IgG(n=6)、或顺铂+HER4ECD-Fc(n=8)处理的LSL-K-rasG12D;p53Fl/+小鼠的平均肿瘤体积+/-SEM。豚草,对照鼠IgG2a抗体。
图8B:图显示了通过治疗方案得到的肿瘤负荷的每日倍数变化及95%置信区间。
图8C:图显示了用媒介物+对照IgG(n=10)、顺铂+对照IgG(n=11)、顺铂+HER4-ECD(n=8)或媒介物+HER4-ECD(n=7)处理的LSL-K-rasG12D;p53Fl/Fl小鼠的自基线的肿瘤负荷的平均百分比变化±SEM。
发明详述
I.定义
出于本文中的目的,“受体人框架”指包含自人免疫球蛋白框架或如下文定义的人共有框架衍生的轻链可变域(VL)框架或重链可变域(VH)框架的氨基酸序列的框架。自人免疫球蛋白框架或人共有框架“衍生”的受体人框架可以包含其相同的氨基酸序列,或者它可以含有氨基酸序列变化。在一些实施方案中,氨基酸变化的数目是10或更少、9或更少、8或更少、7或更少、6或更少、5或更少、4或更少、3或更少、或2或更少。在一些实施方案中,VL受体人框架与VL人免疫球蛋白框架序列或人共有框架序列在序列上相同。
“亲和力”指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。除非另有指示,如本文中使用的,“结合亲和力”指反映结合对的成员(例如抗体和抗原)之间1:1相互作用的内在结合亲和力。分子X对其配偶体Y的亲和力通常可以用解离常数(Kd)来表述。亲和力可以通过本领域知道的常用方法来测量,包括本文中所描述的方法。下文描述了用于测量结合亲和力的具体的说明性和例示性的实施方案。
“亲和力成熟的”抗体指在一个或多个高变区(HVR)中具有一处或多处改变的抗体,与不拥有此类改变的亲本抗体相比,此类改变导致该抗体对抗原的亲和力改善。
术语“抗NRG抗体”和“结合NRG的抗体”指能够以足够的亲和力结合NRG,使得抗体可用作靶向NRG中的诊断和/或治疗剂的抗体。在一个实施方案中,抗NRG抗体对无关的、非NRG蛋白的结合程度是抗体对NRG的结合的小于约10%,如例如通过放射性免疫测定法(RIA)测量的。在某些实施方案中,结合NRG的抗体具有≤1μM、≤100nM、≤10nM、≤1nM、≤0.1nM、≤0.01nM、或≤0.001nM(例如10-8M或更少,例如10-8M至10-13M,例如10-9M至10-13M)的解离常数(Kd)。在某些实施方案中,抗NRG抗体结合来自不同物种的NRG间保守的NRG表位。
本文中的术语“抗体”以最广义使用,并且涵盖各种抗体结构,包括但不限于单克隆抗体、多克隆抗体、多特异性抗体(例如双特异性抗体)、和抗体片段,只要它们展现出期望的抗原结合活性。
“抗体片段”指与完整抗体不同的分子,其包含完整抗体中结合完整抗体结合的抗原的部分。抗体片段的例子包括但不限于Fv、Fab、Fab’、Fab’-SH、F(ab’)2;双抗体;线性抗体;单链抗体分子(例如scFv);和由抗体片段形成的多特异性抗体。
与参照抗体“结合相同表位的抗体”指在竞争测定法中将参照抗体对其抗原的结合阻断50%或更多的抗体,且相反,参照抗体在竞争测定法中将该抗体对其抗原的结合阻断50%或更多。本文中提供了例示性的竞争测定法。
术语“嵌合”抗体指其中的重和/或轻链的一部分自特定的来源或物种衍生,而重和/或轻链的剩余部分自不同来源或物种衍生的抗体。
术语“癌症”和“癌性”指或描述哺乳动物中特征通常为细胞生长/增殖不受调节的生理状况。癌症的例子包括但不限于癌瘤、淋巴瘤(例如,何杰金(Hodgkin)氏和非何杰金氏淋巴瘤)、母细胞瘤、肉瘤、和白血病。此类癌症的更具体的例子包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺的腺癌、肺的鳞癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝瘤(hepatoma)、乳腺癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)、白血病和其它淋巴增殖性病症、和各种类型的头和颈癌。
抗体的“类”指其重链拥有的恒定域或恒定区的类型。抗体有5大类:IgA、IgD、IgE、IgG、和IgM,并且这些中的几种可以进一步分成亚类(同种型),例如,IgG1、IgG2、IgG3、IgG4、IgA1、和IgA2。与不同类免疫球蛋白对应的重链恒定域分别称作α、δ、ε、γ、和μ。
如本文中所使用的,术语“细胞毒剂”指抑制或阻止细胞功能和/或引起细胞死亡或破坏的物质。细胞毒剂包括但不限于:放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);化学治疗剂或药物(例如甲氨蝶呤(methotrexate)、阿霉素(adriamycin)、长春花生物碱类(vinca alkaloids)(长春新碱(vincristine)、长春碱(vinblastine)、依托泊苷(etoposide))、多柔比星(doxorubicin)、美法仑(melphalan)、丝裂霉素(mitomycin)C、苯丁酸氮芥(chlorambucil)、柔红霉素(daunorubicin)或其它嵌入剂);生长抑制剂;酶及其片段,诸如溶核酶;抗生素;毒素,诸如小分子毒素或者细菌、真菌、植物或动物起源的酶活性毒素,包括其片段和/或变体;及下文公开的各种抗肿瘤或抗癌剂。
“效应器功能”指那些可归于抗体Fc区且随抗体同种型而变化的生物学活性。抗体效应器功能的例子包括:C1q结合和补体依赖性细胞毒性(CDC);Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如B细胞受体)下调;和B细胞活化。
药剂(例如药物配制剂)的“有效量”指在必需的剂量和时段上有效实现期望的治疗或预防结果的量。
本文中的术语“Fc区”用于定义免疫球蛋白重链中至少含有恒定区一部分的C端区。该术语包括天然序列Fc区和变体Fc区。在一个实施方案中,人IgG重链Fc区自Cys226,或自Pro230延伸至重链的羧基端。然而,Fc区的C端赖氨酸(Lys447)可以存在或不存在。除非本文中另有规定,Fc区或恒定区中的氨基酸残基的编号方式依照EU编号系统,又称作EU索引,如记载于Kabat等,Sequences of Proteins of Immunological Interest,第5版Public Health Service,National Institutes of Health,Bethesda,MD,1991。
“框架”或“FR”指除高变区(HVR)残基外的可变域残基。一般地,可变域的FR由4个FR域组成:FR1、FR2、FR3、和FR4。因而,HVR和FR序列在VH(或VL)中一般以如下的顺序出现:FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
术语“全长抗体”、“完整抗体”、和“全抗体”在本文中可互换使用,指与天然抗体结构具有基本上类似的结构或者具有含有如本文中所限定的Fc区的重链的抗体。
术语“宿主细胞”、“宿主细胞系”、和“宿主细胞培养物”可互换使用,并且指已经导入外源核酸的细胞,包括此类细胞的后代。宿主细胞包括“转化体”和“经转化的细胞”,其包括原代的经转化的细胞及自其衍生的后代而不考虑传代的次数。后代在核酸内容物上可以与亲本细胞不完全相同,而是可以含有突变。本文中包括具有与在初始转化细胞中筛选或选择的相同功能或生物学活性的突变体后代。
“人抗体”指拥有与由人或人细胞生成的或利用人抗体全集或其它人抗体编码序列自非人来源衍生的抗体的氨基酸序列对应的氨基酸序列的抗体。人抗体的此定义明确排除包含非人抗原结合残基的人源化抗体。
“人共有框架”指代表人免疫球蛋白VL或VH框架序列选集中最常存在的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列选集来自可变域序列亚组。通常,序列亚组是如Kabat等,Sequences of Proteins of Immunological Interest,第五版,NIHPublication 91-3242,Bethesda MD(1991),第1-3卷中的亚组。在一个实施方案中,对于VL,亚组是如Kabat等,见上文中的亚组κI。在一个实施方案中,对于VH,亚组是如Kabat等,见上文中的亚组III。
“人源化”抗体指包含来自非人HVR的氨基酸残基和来自人FR的氨基酸残基的嵌合抗体。在某些实施方案中,人源化抗体会包含至少一个,通常两个基本上整个可变域,其中所有或基本上所有HVR(例如,CDR)对应于非人抗体的那些,且所有或基本上所有FR对应于人抗体的那些。任选地,人源化抗体可以至少包含自人抗体衍生的抗体恒定区的一部分。抗体,例如非人抗体的“人源化形式”指已经经历人源化的抗体。
如本文中所使用的,术语“高变区”或“HVR”指抗体可变域中在序列上高变的和/或形成结构上限定的环(“高变环”)的每个区。一般地,天然的4链抗体包含6个HVR;三个在VH中(H1、H2、H3),且三个在VL中(L1、L2、L3)。HVR一般包含来自高变环和/或来自“互补决定区”(CDR)的氨基酸残基,后一种是最高序列变异性的和/或牵涉抗原识别。例示性的高变环存在于氨基酸残基26-32(L1)、50-52(L2)、91-96(L3)、26-32(H1)、53-55(H2)、和96-101(H3)。(Chothia和Lesk,J.Mol.Biol.196:901-917(1987))。例示性的CDR (CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、和CDR-H3)存在于L1的氨基酸残基24-34、L2的50-56、L3的89-97、H1的31-35B、H2的50-65、和H3的95-102(Kabat等,Sequences of Proteins ofImmunological Interest,第5版Public Health Service,National Institutes ofHealth,Bethesda,MD(1991))。除了VH中的CDR1外,CDR一般包含形成高变环的氨基酸残基。CDR还包含“特异性决定残基”,或“SDR”,其是接触抗原的残基。SDR包含在称作缩短的-CDR,或a-CDR的CDR区内。例示性的a-CDR(a-CDR-L1、a-CDR-L2、a-CDR-L3、a-CDR-H1、a-CDR-H2、和a-CDR-H3)存在于L1的氨基酸残基31-34、L2的50-55、L3的89-96、H1的31-35B、H2的50-58、和H3的95-102(见Almagro和Fransson,Front.Biosci.13:1619-1633(2008))。除非另有指示,可变域中的HVR残基和其它残基(例如,FR残基)在本文中依照Kabat等,见上文编号。
“免疫缀合物”指与一种或多种异源分子,包括但不限于细胞毒剂缀合的抗体。
“个体”或“受试者”或“患者”是哺乳动物。哺乳动物包括但不限于驯养的动物(例如,牛、绵羊、猫、犬、和马)、灵长类(例如,人和非人灵长类诸如猴)、家兔、和啮齿类(例如,小鼠和大鼠)。在某些实施方案中,个体、受试者、或患者是人。
“分离的”抗体指已经与其天然环境的组分分开的抗体。在一些实施方案中,抗体纯化至大于95%或99%的纯度,如通过例如电泳(例如,SDS-PAGE、等电聚焦(IEF)、毛细管电泳)或层析(例如,离子交换或反相HPLC)测定的。关于用于评估抗体纯度的方法的综述,见例如Flatman等,J.Chromatogr.B 848:79-87(2007)。
“分离的”核酸指已经与其天然环境的组分分开的核酸分子。分离的核酸包括通常含有核酸分子的细胞中含有的核酸分子,但是核酸分子在染色体外或在与其天然染色体位置不同的染色体位置处存在。
“编码抗NRG抗体的分离的核酸”指编码抗体重和轻链(或其片段)的一种或多种核酸分子,包括单一载体或不同载体中的此类核酸分子,和存在于宿主细胞中的一个或多个位置的此类核酸分子。
如本文中所使用的,术语“单克隆抗体”指从一群基本上同质的抗体获得的抗体,即构成群体的各个抗体是相同的和/或结合相同表位,除了例如含有天然存在的突变或在单克隆抗体制备物的生成期间发生的可能的变体抗体外,此类变体一般以极小量存在。与通常包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物不同,单克隆抗体制备物的每种单克隆抗体针对抗原上的单一决定簇。如此,修饰语“单克隆”指示抗体自一群基本上同质的抗体获得的特性,而不应解释为要求通过任何特定方法来生成抗体。例如,可以通过多种技术来生成要依照本发明使用的单克隆抗体,包括但不限于杂交瘤方法、重组DNA方法、噬菌体展示方法、和利用含有所有或部分人免疫球蛋白基因座的转基因动物的方法,本文中描述了用于生成单克隆抗体的此类方法和其它例示性方法。
“裸抗体”指未与异源模块(例如细胞毒性模块)或放射性标记物缀合的抗体。裸抗体可以存在于药物配制剂中。
“天然抗体”指具有不同结构的天然存在的免疫球蛋白分子。例如,天然IgG抗体是约150,000道尔顿的异四聚糖蛋白,由二硫化物键合的两条相同轻链和两条相同重链构成。从N至C端,每条重链具有一个可变区(VH),又称作可变重域或重链可变域,接着是三个恒定域(CH1、CH2、和CH3)。类似地,从N至C端,每条轻链具有一个可变区(VL),又称作可变轻域或轻链可变域,接着是一个恒定轻(CL)域。根据其恒定域氨基酸序列,抗体轻链可归入两种类型中的一种,称作卡帕(κ)和拉姆达(λ)。
术语“包装插页”用于指治疗产品的商业包装中通常包含的用法说明书,其含有关于涉及此类治疗产品应用的适应症、用法、剂量、施用、联合疗法、禁忌症和/或警告的信息。
关于参照多肽序列的“百分比(%)氨基酸序列同一性”定义为比对序列并在必要时引入缺口以获取最大百分比序列同一性后,且不将任何保守替代视为序列同一性的一部分时,候选序列中与参照多肽序列中的氨基酸残基相同的氨基酸残基的百分率。为测定百分比氨基酸序列同一性目的的对比可以以本领域技术范围内的多种方式进行,例如使用公众可得到的计算机软件,诸如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以决定用于比对序列的合适参数,包括对所比较序列全长获得最大对比所需的任何算法。然而,为了本发明的目的,%氨基酸序列同一性值是使用序列比较计算机程序ALIGN-2产生的。ALIGN-2序列比较计算机程序由Genentech,Inc.编写,并且源代码已经连同用户文档一起提交给美国版权局(US Copyright Office,Washington D.C.,20559),其中其以美国版权注册号TXU510087注册。公众自Genentech,Inc.,South San Francisco,California可获得ALIGN-2程序,或者可以从源代码编译。ALIGN2程序应当编译成在UNIX操作系统,包括数码UNIX V4.0D上使用。所有序列比较参数由ALIGN-2程序设定且不变。
在采用ALIGN-2来比较氨基酸序列的情况中,给定氨基酸序列A相对于(to)、与(with)、或针对(against)给定氨基酸序列B的%氨基酸序列同一性(或者可表述为具有或包含相对于、与、或针对给定氨基酸序列B的某一%氨基酸序列同一性的给定氨基酸序列A)如下计算:
分数X/Y乘100
其中X是由序列比对程序ALIGN-2在该程序的A和B比对中评分为相同匹配的氨基酸残基数,且其中Y是B中的氨基酸残基总数。应当领会,若氨基酸序列A的长度与氨基酸序列B的长度不相等,则A相对于B的%氨基酸序列同一性将不等于B相对于A的%氨基酸序列同一性。除非另有明确说明,本文中所使用的所有%氨基酸序列同一性值都是依照上一段所述,使用ALIGN-2计算机程序获得的。
术语“药物配制剂”指处于如下的形式,使得容许其中含有的活性成分的生物学活性是有效的,且不含对会接受配制剂施用的受试者具有不可接受的毒性的别的组分的制剂。
“药学可接受载体”指药物配制剂中与活性成分不同的,且对受试者无毒的成分。药学可接受载体包括但不限于缓冲剂、赋形剂、稳定剂、或防腐剂。
如本文中所使用的,术语“NRG”指来自任何脊椎动物来源,包括哺乳动物诸如灵长类(例如人)和啮齿类(例如,小鼠和大鼠)的任何天然的神经调节蛋白(又称为调蛋白),除非另有指示。该术语涵盖“全长”、未加工的NRG及源自细胞中的加工的任何形式的NRG。该术语还涵盖NRG的天然存在的变体,例如剪接变体或等位变体。存在着4种已知形式的NRG:NRG1(Holmes,W.E.等,Science 256:1205-1210(1992));NRG2(Caraway,K.L.等,Nature387:512-516(1997));NRG3(Zhang,E.等,Proc Natl Acad Sci USA94:9562-9567));和NRG4(Harari,D.等,Oncogene 18:2681-2689))。由于可变剪接,受体结合需要的NRG1 EGF样域存在着两种活性同等型,称为NRG1阿尔法(NRG1α)和NRG1贝塔(NRGβ)。在Genbank登录号BK000383(Falls,D.L.,Ex Cell Res,284:14-30(2003)和美国专利No.5,367,060中显示了例示性的人NRG1的序列。
如本文中所使用的,“治疗/处理”(及其语法变型)指试图改变所治疗个体的天然过程的临床干预,并且可以为了预防或者在临床病理学的过程期间实施。治疗的期望效果包括但不限于预防疾病的发生或复发、减轻症状、减轻/减少疾病的任何直接或间接病理后果、预防转移、降低疾病进展速率、改善或减轻疾病状态、和消退或改善的预后。在一些实施方案中,使用本发明的NRG拮抗剂来延迟疾病的形成、减缓疾病的进展、预防复发、或延长肿瘤复发前时间。在某些实施方案中,治疗导致肿瘤再启动细胞的数目减少或完全缺乏;实体瘤中的肿瘤再启动细胞相对于肿瘤中不是肿瘤再启动细胞的细胞的数目减少;和/或抑制肿瘤再启动细胞的增殖。在某些实施方案中,用NRG拮抗剂的治疗导致比在没有用NRG拮抗剂治疗的情况中的肿瘤复发前时间大至少1.25、1.50、1.75、2.0倍的肿瘤复发前时间延长。
术语“可变区”或“可变域”指抗体重或轻链中牵涉抗体结合抗原的域。天然抗体的重链和轻链可变域(分别为VH和VL)一般具有类似的结构,其中每个域包含4个保守的框架区(FR)和3个高变区(HVR)。(见例如Kindt等Kuby Immunology,第6版,W.H.Freeman andCo.,第91页(2007))。单个VH或VL域可以足以赋予抗原结合特异性。此外,可以分别使用来自结合抗原的抗体的VH或VL域筛选互补VL或VH域的文库来分离结合特定抗原的抗体。见例如,Portolano等,J.Immunol.150:880-887(1993);Clarkson等,Nature352:624-628(1991)。
如本文中所使用的,术语“载体”指能够增殖与其连接的另一种核酸的核酸分子。该术语包括作为自身复制型核酸结构的载体及整合入接受其导入的宿主细胞的基因组中的载体。某些载体能够指导与其可操作连接的核酸的表达。此类载体在本文中称为“表达载体”。
II.组合物和方法
本发明基于如下的发现,即NRG自分泌信号传导在原本化学敏感的肿瘤中在化学疗法后在一小群肿瘤细胞的存活和增殖中发挥重要的作用。这些存活的肿瘤细胞(在本文中称为“肿瘤再启动细胞”,或“TRIC”)负责其癌症先前用治疗剂治疗的患者中的癌症的复发(relapse)和再现(recurrence)。在一个实施方案中,用于治疗患者的治疗剂是化学治疗剂。在另一个实施方案中,用于治疗患者的治疗剂是抗原结合剂,诸如抗体或其片段。
抑制NRG信号传导导致延迟或预防用治疗剂治疗后的肿瘤复发或再现。因而,本发明的一方面提供了抑制NRG诱导的信号传导的NRG拮抗剂。在一个实施方案中,NRG拮抗剂是NRG1拮抗剂。NRG拮抗剂在治疗癌症及预防抗性和/或用治疗剂治疗后的癌症再现中得到应用。本发明的另一方面提供了通过对患者施用NRG拮抗剂预防患者中对用治疗剂治疗的抗性的方法。本发明的另一方面提供了通过对患者施用NRG拮抗剂预防用治疗剂治疗后癌症再现。本发明的又一方面提供了表征TRIC的模型。如实施例和附图中描述的,此模型包含如下的细胞,其显示对处理的强力响应,导致显著的肿瘤消退,接着是在停止处理后疾病复发。该模型在筛选可以用于靶向TRIC的化合物及测定TRIC的分子基础中得到应用。
具体的方面包括预防肿瘤复发或延长肿瘤复发前时间的方法,包括对患者施用有效量的NRG拮抗剂。在一个实施方案中,已经用治疗剂,诸如化学治疗剂或抗原结合剂,诸如抗体治疗患者。在一个实施方案中,癌症包含肿瘤再启动细胞。在一个实施方案中,癌症是非小细胞肺癌。在一个实施方案中,癌症是乳腺癌。在一个实施方案中,用化学治疗剂治疗患者。在一个实施方案中,化学治疗剂是作为癌症的护理治疗标准使用的药剂。在一个实施方案中,化学治疗剂是帕利他塞(paclitaxal)或顺铂或帕利他塞和顺铂的组合。在一个实施方案中,化学治疗剂不是酪氨酸激酶抑制剂。在另一个实施方案中,化学治疗剂是酪氨酸激酶抑制剂。在一个实施方案中,化学治疗剂是EGFR、HER2、HER3和/或HER4抑制剂。另一个实施方案另外包括与NRG拮抗剂组合对患者施用化学治疗剂。
在另一个实施方案中,用抗体治疗患者。在一个实施方案中,抗体是抗酪氨酸激酶抗体。在一个实施方案中,抗体是EGFR、HER2、HER3和/或HER4抗体。另一个实施方案另外包括与NRG拮抗剂组合对患者施用抗体。
在某些实施方案中,肿瘤复发前时间比在没有神经调节蛋白拮抗剂的情况中的肿瘤复发前时间大至少1.25、1.50、1.75、2.0、2.5、5.0、10、20或50倍。
另一方面提供了治疗具有抗性癌症的患者的方法,包括对患者施用有效量的NRG拮抗剂。在一个实施方案中,癌症包含肿瘤再启动细胞。在一个实施方案中,癌症是非小细胞肺癌。在一个实施方案中,癌症是乳腺癌。在一个实施方案中,癌症对用化学治疗剂治疗有抗性。在一个实施方案中,癌症对用帕利他塞或顺铂或帕利他塞和顺铂的组合治疗有抗性。在一个实施方案中,癌症对用酪氨酸激酶抑制剂治疗有抗性。在一个实施方案中,癌症对用EGFR、HER2、HER3和/或HER4抑制剂治疗有抗性。另一个实施方案另外包括对患者施用化学治疗剂。在一个实施方案中,化学治疗剂是帕利他塞或顺铂或帕利他塞和顺铂的组合。在一个实施方案中,化学治疗剂是EGFR、HER2、HER3和/或HER4抑制剂。
在一个实施方案中,癌症对用治疗性抗体治疗有抗性。在一个实施方案中,癌症对用EGFR、HER2、HER3、或HER4抗体治疗有抗性。另一个实施方案另外包括对患者施用抗体。在一个实施方案中,抗体是曲妥单抗(trastuzumab)或帕妥珠单抗(pertuzumab)。
另一方面提供了预防癌症中的抗性的方法,包括对具有癌症的患者施用有效量的NRG拮抗剂和治疗剂。在一个实施方案中,癌症包含肿瘤再启动细胞。在一个实施方案中,癌症是非小细胞肺癌。在一个实施方案中,癌症是乳腺癌。在一个实施方案中,癌症对用化学治疗剂治疗有抗性。在一个实施方案中,癌症对用帕利他塞或顺铂或帕利他塞和顺铂的组合治疗有抗性。在一个实施方案中,化学治疗剂不是酪氨酸激酶抑制剂。在另一个实施方案中,化学治疗剂是酪氨酸激酶抑制剂。在一个实施方案中,化学治疗剂是EGFR、HER2、HER3和/或HER4抑制剂。另一个实施方案另外包括对患者施用化学治疗剂。在一个实施方案中,化学治疗剂是帕利他塞或顺铂或帕利他塞和顺铂的组合。
在一个实施方案中,癌症对用治疗性抗体治疗有抗性。在一个实施方案中,癌症对用EGFR、HER2、HER3、或HER4抗体治疗有抗性。另一个实施方案另外包括对患者施用抗体。在一个实施方案中,抗体是曲妥单抗或帕妥珠单抗。
在治疗性用途的这些方法中,NRG拮抗剂是抗体、小分子、免疫粘附素、或RNA。在一个实施方案中,NRG拮抗剂是NRG1拮抗剂。在一个实施方案中,NRG拮抗剂是抗NRG1抗体。
在又一方面,本发明提供了神经调节蛋白拮抗剂在制造或制备药物中的用途。在一个实施方案中,使用神经调节蛋白拮抗剂,或用神经调节蛋白拮抗剂制造的药物来延长患者中的肿瘤复发前时间。在另一个实施方案中,使用神经调节蛋白拮抗剂,或用神经调节蛋白拮抗剂制造的药物来治疗具有对治疗剂有抗性的癌症的患者。
A.NRG拮抗剂
可用于本发明方法的NRG拮抗剂包括特异性结合NRG的多肽,NRG抗体(抗NRG抗体),RNA,诸如RNAi、siRNA、shRNA等,小分子,受体分子和衍生物,诸如免疫粘附素(其特异性结合NRG)(见例如美国专利6,696,290和7,659,368、美国公开文本2010055093和20100278801)和融合蛋白。NRG拮抗剂还包括NRG多肽的拮抗性变体、针对NRG的RNA适体和肽体(peptibody)。下文描述了这些中每种的例子。在一个实施方案中,NRG拮抗剂是NRG1拮抗剂。在其它实施方案中,NRG拮抗剂是NRG2、NRG3、或NRG4拮抗剂。
1.抗体
可用于本发明方法的抗NRG抗体包括以足够的亲和力和特异性结合NRG,而且可以降低或抑制NRG信号传导的任何抗体。NRG抗体记载于WO1992020798、美国专利No.6,953,842、和美国专利No.6,252,051。
a)抗体亲和力
在某些实施方案中,本文中提供的抗体具有≤1μM、≤100nM、≤10nM、≤1nM、≤0.1nM、≤0.01nM、或≤0.001nM(例如10-8M或更少,例如10-8M至10-13M,例如,10-9M至10-13M)的解离常数(Kd)。
在一个实施方案中,Kd是通过如下述测定法所述用Fab型式的感兴趣抗体及其抗原实施的放射性标记抗原结合测定法(RIA)来测量的。通过在存在未标记抗原的滴定系列的情况中用最小浓度的(125I)标记抗原平衡Fab,然后用抗Fab抗体包被板捕捉结合的抗原来测量Fab对抗原的溶液结合亲和力(见例如Chen等,J.Mol.Biol.293:865-881(1999))。为了建立测定法的条件,将多孔板(Thermo Scientific)用50mM碳酸钠(pH9.6)中的5μg/ml捕捉用抗Fab抗体(Cappel Labs)包被过夜,随后用PBS中的2%(w/v)牛血清清蛋白于室温(约23°C)封闭2-5小时。在非吸附板(Nunc#269620)中,将100pM或26pM125I-抗原与连续稀释的感兴趣Fab(例如与Presta等,Cancer Res.57:4593-4599(1997)中抗VEGF抗体,Fab-12的评估一致)混合。然后将感兴趣的Fab温育过夜;然而,温育可持续更长时间(例如约65小时)以确保达到平衡。此后,将混合物转移至捕捉板,于室温温育(例如1小时)。然后除去溶液,并用PBS中的0.1%聚山梨酯20洗板8次。平板干燥后,加入150μl/孔闪烁液(MICROSCINT-20TM;Packard),然后在TOPCOUNTTM伽马计数器(Packard)上对平板计数10分钟。选择各Fab给出小于或等于最大结合之20%的浓度用于竞争性结合测定法。
依照另一个实施方案,Kd是使用表面等离振子共振测定法使用或(BIAcore,Inc.,Piscataway,NJ)于25°C使用固定化抗原CM5芯片在约10个响应单位(RU)测量的。简言之,依照供应商的用法说明书用盐酸N-乙基-N’-(3-二甲氨基丙基)-碳二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)活化羧甲基化右旋糖苷生物传感器芯片(CM5,BIACORE,Inc.)。将抗原用10mM乙酸钠pH 4.8稀释至5μg/ml(约0.2μM),然后以5μl/分钟的流速注射以获得约10个响应单位(RU)的偶联蛋白质。注入抗原后,注入1M乙醇胺以封闭未反应基团。为了进行动力学测量,于25°C以约25μl/分钟的流速注入在含0.05%聚山梨酯20(TWEEN-20TM)表面活性剂的PBS(PBST)中两倍连续稀释的Fab(0.78nM至500nM)。使用简单一对一朗格缪尔(Langmuir)结合模型Evaluation Software version3.2)通过同时拟合结合和解离传感图计算结合速率(kon)和解离速率(koff)。平衡解离常数(Kd)以比率koff/Kon计算。见例如Chen等,J.Mol.Biol.293:865-881(1999)。如果根据上文表面等离振子共振测定法,结合速率超过106M-1S-1,那么结合速率可使用荧光淬灭技术来测定,即根据分光计诸如配备了断流装置的分光光度计(Aviv Instruments)或8000系列SLM-AMINCOTM分光光度计(ThermoSpectronic)中用搅拌比色杯的测量,在存在浓度渐增的抗原的情况中,测量PBS pH 7.2中20nM抗抗原抗体(Fab形式)于25℃的荧光发射强度(激发=295nm;发射=340nm,16nm带通)的升高或降低。
b)抗体片段
在某些实施方案中,本文中提供的抗体是抗体片段。抗体片段包括但不限于Fab、Fab’、Fab’-SH、F(ab’)2、Fv、和scFv片段,及下文所描述的其它片段。关于某些抗体片段的综述,见Hudson等Nat.Med.9:129-134(2003)。关于scFv片段的综述,见例如Pluckthün,于The Pharmacology of Monoclonal Antibodies,第113卷,Rosenburg和Moore编,(Springer-Verlag,New York),第269-315页(1994);还可见WO 93/16185;及美国专利No.5,571,894和5,587,458。关于包含补救受体结合表位残基,并且具有延长的体内半衰期的Fab和F(ab’)2片段的讨论,见美国专利No.5,869,046。
双抗体是具有两个抗原结合位点的抗体片段,其可以是二价的或双特异性的。见例如EP 404,097;WO 1993/01161;Hudson等,Nat.Med.9:129-134(2003);及Hollinger等,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)。三抗体和四抗体也记载于Hudson等,Nat.Med.9:129-134(2003)。
单域抗体是包含抗体的整个或部分重链可变域或整个或部分轻链可变域的抗体片段。在某些实施方案中,单域抗体是人单域抗体(Domantis,Inc.,Waltham,MA;见例如美国专利No.6,248,516B1)。
可以通过多种技术,包括但不限于对完整抗体的蛋白水解消化及重组宿主细胞(例如大肠杆菌或噬菌体)的生成来生成抗体片段,如本文中所描述的。
c)嵌合的和人源化的抗体
在某些实施方案中,本文中提供的抗体是嵌合抗体。某些嵌合抗体记载于例如美国专利No.4,816,567;及Morrison等,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。在一个例子中,嵌合抗体包含非人可变区(例如,自小鼠、大鼠、仓鼠、家兔、或非人灵长类,诸如猴衍生的可变区)和人恒定区。在又一个例子中,嵌合抗体是“类转换的”抗体,其中类或亚类已经自亲本抗体的类或亚类改变。嵌合抗体包括其抗原结合片段。
在某些实施方案中,嵌合抗体是人源化抗体。通常,将非人抗体人源化以降低对人的免疫原性,同时保留亲本非人抗体的特异性和亲和力。一般地,人源化抗体包含一个或多个可变域,其中HVR,例如CDR(或其部分)自非人抗体衍生,而FR(或其部分)自人抗体序列衍生。任选地,人源化抗体还会至少包含人恒定区的一部分。在一些实施方案中,将人源化抗体中的一些FR残基用来自非人抗体(例如衍生HVR残基的抗体)的相应残基替代,例如以恢复或改善抗体特异性或亲和力。
人源化抗体及其生成方法综述于例如Almagro和Fransson,Front.Biosci.13:1619-1633(2008),并且进一步记载于例如Riechmann等,Nature332:323-329(1988);Queen等,Proc.Nat’l Acad.Sci.USA 86:10029-10033(1989);美国专利No.5,821,337,7,527,791,6,982,321和7,087,409;Kashmiri等,Methods 36:25-34(2005)(描述了SDR(a-CDR)嫁接);Padlan,Mol.Immunol.28:489-498(1991)(描述了“重修表面”);Dall’Acqua等,Methods 36:43-60(2005)(描述了“FR改组”);及Osbourn等,Methods 36:61-68(2005)和Klimka等,Br.J.Cancer,83:252-260(2000)(描述了FR改组的“引导选择”方法)。
可以用于人源化的人框架区包括但不限于:使用“最佳拟合(best-fit)”方法选择的框架区(见例如Sims等J.Immunol.151:2296(1993));自轻或重链可变区的特定亚组的人抗体的共有序列衍生的框架区(见例如Carter等Proc.Natl.Acad.Sci.USA,89:4285(1992);及Presta等J.Immunol.,151:2623(1993));人成熟的(体细胞突变的)框架区或人种系框架区(见例如Almagro和Fransson,Front.Biosci.13:1619-1633(2008));和通过筛选FR文库衍生的框架区(见例如Baca等,J.Biol.Chem.272:10678-10684(1997)及Rosok等,J.Biol.Chem.271:22611-22618(1996))。
d)人抗体
在某些实施方案中,本文中提供的抗体是人抗体。可以使用本领域中已知的多种技术来生成人抗体。一般地,人抗体记载于van Dijk和van de Winkel,Curr.Opin.Pharmacol.5:368-74(2001)及Lonberg,Curr.Opin.Immunol.20:450-459(2008)。
可以通过对转基因动物施用免疫原来制备人抗体,所述转基因动物已经修饰为响应抗原性攻击而生成完整人抗体或具有人可变区的完整抗体。此类动物通常含有所有或部分人免疫球蛋白基因座,其替换内源免疫球蛋白基因座,或者其在染色体外存在或随机整合入动物的染色体中。在此类转基因小鼠中,一般已经将内源免疫球蛋白基因座灭活。关于自转基因动物获得人抗体的方法的综述,见Lonberg,Nat.Biotech.23:1117-1125(2005)。还可见例如美国专利No.6,075,181和6,150,584,其描述了XENOMOUSETM技术;美国专利No.5,770,429,其描述了技术;美国专利No.7,041,870,其描述了技术,和美国专利申请公开文本No.US 2007/0061900,其描述了技术)。可以例如通过与不同人恒定区组合进一步修饰来自由此类动物生成的完整抗体的人可变区。
也可以通过基于杂交瘤的方法生成人抗体。已经描述了用于生成人单克隆抗体的人骨髓瘤和小鼠-人异骨髓瘤细胞系(见例如Kozbor J.Immunol.,133:3001(1984);Brodeur等,Monoclonal Antibody Production Techniques and Applications,第51-63页(Marcel Dekker,Inc.,New York,1987);及Boerner等,J.Immunol.,147:86(1991))。经由人B细胞杂交瘤技术生成的人抗体也记载于Li等,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)。其它方法包括那些例如记载于美国专利No.7,189,826(其描述了自杂交瘤细胞系生成单克隆人IgM抗体)和Ni,Xiandai Mianyixue,26(4):265-268(2006)(其描述了人-人杂交瘤)的。人杂交瘤技术(Trioma技术)也记载于Vollmers和Brandlein,Histologyand Histopathology,20(3):927-937(2005)及Vollmers和Brandlein,Methods andFindings in Experimental and Clinical Pharmacology,27(3):185-91(2005)。
也可以通过分离自人衍生的噬菌体展示文库选择的Fv克隆可变域序列生成人抗体。然后,可以将此类可变域序列与期望的人恒定域组合。下文描述了自抗体文库选择人抗体的技术。
e)文库衍生的抗体
可以通过对组合文库筛选具有期望的一种或多种活性的抗体来分离本发明的抗体。例如,用于生成噬菌体展示文库并对此类文库筛选拥有期望结合特征的抗体的多种方法是本领域中已知的。此类方法综述于例如Hoogenboom等于Methods in MolecularBiology 178:1-37(O’Brien等编,Human Press,Totowa,NJ,2001),并且进一步记载于例如McCafferty等,Nature348:552-554;Clackson等,Nature 352:624-628(1991);Marks等,J.Mol.Biol.222:581-597(1992);Marks和Bradbury,于Methods in Molecular Biology248:161-175(Lo编,Human Press,Totowa,NJ,2003);Sidhu等,J.Mol.Biol.338(2):299-310(2004);Lee等,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);及Lee等,J.Immunol.Methods284(1-2):119-132(2004)。
在某些噬菌体展示方法中,将VH和VL基因的全集分别通过聚合酶链式反应(PCR)克隆,并在噬菌体文库中随机重组,然后可以对所述噬菌体文库筛选抗原结合噬菌体,如记载于Winter等,Ann.Rev.Immunol.,12:433-455(1994)的。噬菌体通常以单链Fv(scFv)片段或以Fab片段展示抗体片段。来自经免疫的来源的文库提供针对免疫原的高亲和力抗体,而不需要构建杂交瘤。或者,可以(例如自人)克隆天然全集以在没有任何免疫的情况中提供针对一大批非自身和还有自身抗原的抗体的单一来源,如由Griffiths等,EMBO J,12:725-734(1993)描述的。最后,也可以通过自干细胞克隆未重排的V基因区段,并使用含有随机序列的PCR引物编码高度可变的CDR3区并在体外实现重排来合成生成未免疫文库,如由Hoogenboom和Winter,J.Mol.Biol.,227:381-388(1992)所描述的。描述人抗体噬菌体文库的专利公开文本包括例如:美国专利No.5,750,373、和美国专利公开文本No.2005/0079574,2005/0119455,2005/0266000,2007/0117126,2007/0160598,2007/0237764,2007/0292936和2009/0002360。
认为自人抗体文库分离的抗体或抗体片段是本文中的人抗体或人抗体片段。
f)多特异性抗体
在某些实施方案中,本文中提供的抗体是多特异性抗体,例如双特异性抗体。多特异性抗体是对至少两个不同位点具有结合特异性的单克隆抗体。在某些实施方案中,结合特异性之一针对NRG,而另一种针对任何其它抗原。在某些实施方案中,双特异性抗体可以结合NRG的两个不同表位。也可以使用双特异性抗体来将细胞毒剂定位于表达NRG的细胞。双特异性抗体可以以全长抗体或抗体片段制备。
用于生成多特异性抗体的技术包括但不限于具有不同特异性的两对免疫球蛋白重链-轻链对的重组共表达(见Milstein和Cuello,Nature 305:537(1983))、WO 93/08829、和Traunecker等,EMBO J.10:3655(1991))、和“突起-入-空穴”工程化(见例如美国专利No.5,731,168)。也可以通过用于生成抗体Fc-异二聚体分子的工程化静电操纵效应(WO2009/089004A1);交联两个或更多个抗体或片段(见例如美国专利No.4,676,980,及Brennan等,Science,229:81(1985));使用亮氨酸拉链来生成双特异性抗体(见例如Kostelny等,J.Immunol.,148(5):1547-1553(1992));使用用于生成双特异性抗体片段的“双抗体”技术(见例如Hollinger等,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993));及使用单链Fv(sFv)二聚体(见例如Gruber等,J.Immunol.,152:5368(1994));及如例如Tutt等J.Immunol.147:60(1991)中所描述的,制备三特异性抗体来生成多特异性抗体。
本文中还包括具有三个或更多个功能性抗原结合位点的工程化改造抗体,包括“章鱼抗体”(见例如US 2006/0025576A1)。
本文中的抗体或片段还包括包含结合NRG及另一种不同抗原的抗原结合位点的“双重作用FAb”或“DAF”(见例如US 2008/0069820)。
g)抗体变体
在某些实施方案中,涵盖本文中提供的抗体的氨基酸序列变体。例如,可以期望改善抗体的结合亲和力和/或其它生物学特性。可以通过将合适的修饰引入编码抗体的核苷酸序列中,或者通过肽合成来制备抗体的氨基酸序列变体。此类修饰包括例如对抗体的氨基酸序列内的残基的删除、和/或插入和/或替代。可以进行删除、插入、和替代的任何组合以得到最终的构建体,只要最终的构建体拥有期望的特征,例如,抗原结合。
h)替代、插入、和删除变体
在某些实施方案中,提供了具有一处或多处氨基酸替代的抗体变体。替代诱变感兴趣的位点包括HVR和FR。保守替代在表1中在“保守替代”的标题下显示。更实质的变化在表1中在“例示性替代”的标题下提供,并且如下文参照氨基酸侧链类别进一步描述的。可以将氨基酸替代引入感兴趣的抗体中,并且对产物筛选期望的活性,例如保留/改善的抗原结合、降低的免疫原性、或改善的ADCC或CDC。
表1
依照共同的侧链特性,氨基酸可以如下分组:
(1)疏水性的:正亮氨酸,Met,Ala,Val,Leu,Ile;
(2)中性、亲水性的:Cys,Ser,Thr,Asn,Gln;
(3)酸性的:Asp,Glu;
(4)碱性的:His,Lys,Arg;
(5)影响链取向的残基:Gly,Pro;
(6)芳香族的:Trp,Tyr,Phe。
非保守替代会需要用这些类别之一的成员替换另一个类别的。
一类替代变体牵涉替代亲本抗体(例如人源化或人抗体)的一个或多个高变区残基。一般地,为进一步研究选择的所得变体相对于亲本抗体会具有某些生物学特性的改变(例如改善)(例如升高的亲和力、降低的免疫原性)和/或会基本上保留亲本抗体的某些生物学特性。例示性的替代变体是亲和力成熟的抗体,其可以例如使用基于噬菌体展示的亲和力成熟技术诸如本文中所描述的那些技术来方便地生成。简言之,将一个或多个HVR残基突变,并将变体抗体在噬菌体上展示,并对其筛选特定的生物学活性(例如结合亲和力)。
可以对HVR做出变化(例如,替代),例如以改善抗体亲和力。可以对HVR“热点”,即由在体细胞成熟过程期间以高频率经历突变的密码子编码的残基(见例如Chowdhury,Methods Mol.Biol.207:179-196(2008)),和/或SDR(a-CDR)做出此类变化,其中对所得的变体VH或VL测试结合亲和力。通过次级文库的构建和再选择进行的亲和力成熟已经记载于例如Hoogenboom等于Methods in Molecular Biology 178:1-37(O’Brien等编,HumanPress,Totowa,NJ,(2001))。在亲和力成熟的一些实施方案中,通过多种方法(例如,易错PCR、链改组、或寡核苷酸指导的诱变)将多样性引入为成熟选择的可变基因。然后,创建次级文库。然后,筛选文库以鉴定具有期望的亲和力的任何抗体变体。另一种引入多样性的方法牵涉HVR指导的方法,其中将几个HVR残基(例如,一次4-6个残基)随机化。可以例如使用丙氨酸扫描诱变或建模来特异性鉴定牵涉抗原结合的HVR残基。特别地,经常靶向CDR-H3和CDR-L3。
在某些实施方案中,可以在一个或多个HVR内发生替代、插入、或删除,只要此类变化不实质性降低抗体结合抗原的能力。例如,可以对HVR做出保守变化(例如,保守替代,如本文中提供的),其不实质性降低结合亲和力。此类变化可以在HVR“热点”或SDR外部。在上文提供的变体VH和VL序列的某些实施方案中,每个HVR是未改变的,或者含有不超过1、2或3处氨基酸替代。
一种可用于鉴定抗体中可以作为诱变靶位的残基或区域的方法称作“丙氨酸扫描诱变”,如由Cunningham和Wells (1989)Science,244:1081-1085所描述的。在此方法中,将残基或靶残基的组(例如,带电荷的残基诸如arg、asp、his、lys、和glu)鉴定,并用中性或带负电荷的氨基酸(例如,丙氨酸或多丙氨酸)替换以测定抗体与抗原的相互作用是否受到影响。可以在对初始替代表明功能敏感性的氨基酸位置引入进一步的替代。或者/另外,利用抗原-抗体复合物的晶体结构来鉴定抗体与抗原间的接触点。作为替代的候选,可以靶向或消除此类接触残基和邻近残基。可以筛选变体以确定它们是否含有期望的特性。
氨基酸序列插入包括长度范围为1个残基至含有100或更多个残基的多肽的氨基和/或羧基端融合,及单个或多个氨基酸残基的序列内插入。末端插入的例子包括具有N端甲硫氨酰基残基的抗体。抗体分子的其它插入变体包括抗体的N或C端与酶(例如对于ADEPT)或延长抗体的血清半衰期的多肽的融合物。
i)糖基化变体
在某些实施方案中,改变本文中提供的抗体以提高或降低抗体糖基化的程度。可以通过改变氨基酸序列,使得创建或消除一个或多个糖基化位点来方便地实现对抗体的糖基化位点的添加或删除。
在抗体包含Fc区的情况中,可以改变其附着的碳水化合物。由哺乳动物细胞生成的天然抗体通常包含分支的、双触角寡糖,其一般通过N连接附着于Fc区的CH2域的Asn297。见例如Wright等TIBTECH 15:26-32(1997)。寡糖可以包括各种碳水化合物,例如,甘露糖、N-乙酰葡糖胺(GlcNAc)、半乳糖、和唾液酸,以及附着于双触角寡糖结构“主干”中的GlcNAc的岩藻糖。在一些实施方案中,可以对本发明抗体中的寡糖进行修饰以创建具有某些改善的特性的抗体变体。
在一个实施方案中,提供了抗体变体,其具有缺乏附着(直接或间接)于Fc区的岩藻糖的碳水化合物结构。例如,此类抗体中的岩藻糖量可以是1%至80%、1%至65%、5%至65%或20%至40%。通过相对于附着于Asn297的所有糖结构(例如,复合的、杂合的和高甘露糖的结构)的总和,计算Asn297处糖链内岩藻糖的平均量来测定岩藻糖量,如通过MALDI-TOF质谱术测量的,例如如记载于WO 2008/077546的。Asn297指位于Fc区中的约第297位(Fc区残基的Eu编号方式)的天冬酰胺残基;然而,Asn297也可以由于抗体中的微小序列变异而位于第297位上游或下游约±3个氨基酸,即在第294位和第300位之间。此类岩藻糖基化变体可以具有改善的ADCC功能。见例如美国专利公开文本No.US 2003/0157108(Presta,L.);US2004/0093621(Kyowa Hakko Kogyo Co.,Ltd)。涉及“脱岩藻糖基化的”或“岩藻糖缺乏的”抗体变体的出版物的例子包括:US 2003/0157108;WO 2000/61739;WO2001/29246;US2003/0115614;US 2002/0164328;US 2004/0093621;US2004/0132140;US 2004/0110704;US 2004/0110282;US 2004/0109865;WO2003/085119;WO 2003/084570;WO 2005/035586;WO 2005/035778;WO2005/053742;WO2002/031140;Okazaki等J.Mol.Biol.336:1239-1249(2004);Yamane-Ohnuki等Biotech.Bioeng.87:614(2004)。能够生成脱岩藻糖基化抗体的细胞系的例子包括蛋白质岩藻糖基化缺陷的Lec13 CHO细胞(Ripka等Arch.Biochem.Biophys.249:533-545(1986);美国专利申请No US2003/0157108A1,Presta,L;及WO 2004/056312A1,Adams等,尤其在实施例11),和敲除细胞系,诸如α-1,6-岩藻糖基转移酶基因FUT8敲除CHO细胞(见例如Yamane-Ohnuki等Biotech.Bioeng.87:614(2004);Kanda,Y.等,Biotechnol.Bioeng.,94(4):680-688(2006);及WO2003/085107)。
进一步提供了具有两分型寡糖的抗体变体,例如其中附着于抗体Fc区的双触角寡糖是通过GlcNAc两分的。此类抗体变体可以具有降低的岩藻糖基化和/或改善的ADCC功能。此类抗体变体的例子记载于例如WO 2003/011878(Jean-Mairet等);美国专利No.6,602,684(Umana等);及US 2005/0123546(Umana等)。还提供了在附着于Fc区的寡糖中具有至少一个半乳糖残基的抗体变体。此类抗体变体可以具有改善的CDC功能。此类抗体变体记载于例如WO 1997/30087(Patel等);WO 1998/58964(Raju,S.);及WO 1999/22764(Raju,S.)。
j)Fc区变体
在某些实施方案中,可以将一处或多处氨基酸修饰引入本文中提供的抗体的Fc区中,由此生成Fc区变体。Fc区变体可以包含在一个或多个氨基酸位置包含氨基酸修饰(例如替代)的人Fc区序列(例如,人IgG1、IgG2、IgG3或IgG4Fc区)。
在某些实施方案中,本发明涵盖拥有一些但不是所有效应器功能的抗体变体,所述效应器功能使其成为如下应用的期望候选物,其中抗体的体内半衰期是重要的,而某些效应器功能(诸如补体和ADCC)是不必要的或有害的。可以进行体外和/或体内细胞毒性测定法以确认CDC和/或ADCC活性的降低/消减。例如,可以进行Fc受体(FcR)结合测定法以确保抗体缺乏FcγR结合(因此有可能缺乏ADCC活性),但是保留FcRn结合能力。介导ADCC的主要细胞NK细胞仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。在Ravetch和Kinet,Annu.Rev.Immunol.9:457-492(1991)的第464页上的表3中汇总了造血细胞上的FcR表达。评估感兴趣分子的ADCC活性的体外测定法的非限制性例子记载于美国专利No.5,500,362(见例如Hellstrom,I.等Proc.Nat’l Acad.Sci.USA 83:7059-7063(1986))和Hellstrom,I等,Proc.Nat’l Acad.Sci.USA 82:1499-1502(1985);5,821,337(见Bruggemann,M.等,J.Exp.Med.166:1351-1361(1987))。或者,可以采用非放射性测定方法(见例如用于流式细胞术的ACTITM非放射性细胞毒性测定法(CellTechnology,Inc.Mountain View,CA;和非放射性细胞毒性测定法(Promega,Madison,WI))。对于此类测定法有用的效应细胞包括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。或者/另外,可以在体内评估感兴趣分子的ADCC活性,例如在动物模型中,诸如披露于Clynes等Proc.Nat’l Acad.Sci.USA95:652-656(1998)的。也可以实施C1q结合测定法以确认抗体不能结合C1q,并且因此缺乏CDC活性。见例如WO 2006/029879和WO 2005/100402中的C1q和C3c结合ELISA。为了评估补体激活,可以实施CDC测定法(见例如Gazzano-Santoro等,J.Immunol.Methods 202:163(1996);Cragg,M.S.等,Blood 101:1045-1052(2003);及Cragg,M.S.和M.J.Glennie,Blood103:2738-2743(2004))。也可以使用本领域中已知的方法来实施FcRn结合和体内清除/半衰期测定(见例如Petkova,S.B.等,Int’l.Immunol.18(12):1759-1769(2006))。
具有降低的效应器功能的抗体包括那些具有Fc区残基238,265,269,270,297,327和329中的一个或多个的替代的(美国专利No.6,737,056)。此类Fc突变体包括在氨基酸位置265、269、270、297和327中的两处或更多处具有替代的Fc突变体,包括残基265和297替代成丙氨酸的所谓的“DANA”Fc突变体(美国专利No.7,332,581)。
描述了具有改善的或降低的对FcR的结合的某些抗体变体(见例如美国专利No.6,737,056;WO 2004/056312,及Shields等,J.Biol.Chem.9(2):6591-6604(2001))。
在某些实施方案中,抗体变体包含具有改善ADCC的一处或多处氨基酸替代,例如Fc区的位置298、333、和/或334(残基的EU编号方式)的替代的Fc区。
在一些实施方案中,对Fc区做出改变,其导致改变的(即,改善的或降低的)C1q结合和/或补体依赖性细胞毒性(CDC),例如,如记载于美国专利No.6,194,551、WO 99/51642、及Idusogie等J.Immunol.164:4178-4184(2000)的。
具有延长的半衰期和改善的对新生儿Fc受体(FcRn)的结合的抗体记载于US2005/0014934A1(Hinton等),新生儿Fc受体(FcRn)负责将母体IgG转移至胎儿(Guyer等,J.Immunol.117:587(1976)及Kim等,J.Immunol.24:249(1994))。那些抗体包含其中具有改善Fc区对FcRn结合的一处或多处替代的Fc区。此类Fc变体包括那些在Fc区残基238,256,265,272,286,303,305,307,311,312,317,340,356,360,362,376,378,380,382,413,424或434中的一处或多处具有替代,例如,Fc区残基434的替代的(美国专利No.7,371,826)。
还可见Duncan和Winter,Nature 322:738-40(1988);美国专利No.5,648,260;美国专利No.5,624,821;及WO 94/29351,其关注Fc区变体的其它例子。
k)经半胱氨酸工程化改造的抗体变体
在某些实施方案中,可以期望创建经半胱氨酸工程化改造的抗体,例如,“thioMAb”,其中抗体的一个或多个残基用半胱氨酸残基替代。在具体的实施方案中,替代的残基存在于抗体的可接近位点。通过用半胱氨酸替代那些残基,反应性硫醇基团由此定位于抗体的可接近位点,并且可以用于将抗体与其它模块,诸如药物模块或接头-药物模块缀合,以创建免疫缀合物,如本文中进一步描述的。在某些实施方案中,可以用半胱氨酸替代下列残基之任一个或多个:轻链的V205(Kabat编号方式);重链的A118(EU编号方式);和重链Fc区的S400(EU编号方式)。可以如例如美国专利No.7,521,541所述生成经半胱氨酸工程化改造的抗体。
l)抗体衍生物
在某些实施方案中,可以进一步修饰本文中提供的抗体以含有本领域知道的且易于获得的额外非蛋白质性质模块。适合于抗体衍生化的模块包括但不限于水溶性聚合物。水溶性聚合物的非限制性例子包括但不限于聚乙二醇(PEG)、乙二醇/丙二醇共聚物、羧甲基纤维素、右旋糖苷、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二氧戊环、聚-1,3,6-三烷、乙烯/马来酸酐共聚物、聚氨基酸(均聚物或随机共聚物)、和右旋糖苷或聚(n-乙烯吡咯烷酮)聚乙二醇、丙二醇均聚物、环氧丙烷/环氧乙烷共聚物、聚氧乙烯化多元醇(例如甘油)、聚乙烯醇及其混合物。由于其在水中的稳定性,聚乙二醇丙醛在生产中可能具有优势。聚合物可以是任何分子量,而且可以是分支的或不分支的。附着到抗体上的聚合物数目可以变化,而且如果附着了超过一个聚合物,那么它们可以是相同或不同的分子。一般而言,可根据下列考虑来确定用于衍生化的聚合物的数目和/或类型,包括但不限于抗体要改进的具体特性或功能、抗体衍生物是否将用于指定条件下的治疗等。
在另一个实施方案中,提供了抗体和可以通过暴露于辐射选择性加热的非蛋白质性质模块的缀合物。在一个实施方案中,非蛋白质性质模块是碳纳米管(Kam等,Proc.Natl.Acad.Sci.USA 102:11600-11605(2005))。辐射可以是任何波长的,并且包括但不限于对普通细胞没有损害,但是将非蛋白质性质模块加热至抗体-非蛋白质性质模块附近的细胞被杀死的温度的波长。
m)重组方法和组合物
可以使用重组方法和组合物来生成抗体,例如,如记载于美国专利No.4,816,567的。在一个实施方案中,提供了编码本文中所描述的抗NRG抗体的分离的核酸。此类核酸可以编码包含抗体VL的氨基酸序列和/或包含VH的氨基酸序列(例如,抗体的轻和/或重链)。在又一个实施方案中,提供了包含此类核酸的一种或多种载体(例如,表达载体)。在又一个实施方案中,提供了包含此类核酸的宿主细胞。在一个此类实施方案中,宿主细胞包含(例如,已经用下列载体转化):(1)包含核酸的载体,所述核酸编码包含抗体的VL的氨基酸序列和包含抗体的VH的氨基酸序列,或(2)第一载体和第二载体,所述第一载体包含编码包含抗体的VL的氨基酸序列的核酸,所述第二载体包含编码包含抗体的VH的氨基酸序列的核酸。在一个实施方案中,宿主细胞是真核的,例如中国仓鼠卵巢(CHO)细胞或淋巴样细胞(例如,Y0、NS0、Sp20细胞)。在一个实施方案中,提供了生成抗NRG抗体的方法,其中该方法包括在适合于表达抗体的条件下培养包含编码抗体的核酸的宿主细胞,如上文提供的,并且任选地,自宿主细胞(或宿主细胞培养液)回收抗体。
对于抗NRG抗体的重组生成,将编码抗体的核酸(例如如上文所描述的)分离,并插入一种或多种载体中,以在宿主细胞中进一步克隆和/或表达。可以使用常规规程将此类核酸容易地分离并测序(例如,通过使用寡核苷酸探针来进行,所述寡核苷酸探针能够特异性结合编码抗体的重和轻链的基因)。
适合于克隆或表达抗体编码载体的宿主细胞包括本文中所描述的原核或真核细胞。例如,可以在细菌中生成抗体,特别是在不需要糖基化和Fc效应器功能时。对于抗体片段和多肽在细菌中的表达,见例如美国专利No.5,648,237,5,789,199和5,840,523(还可见Charlton,Methods in Molecular Biology,第248卷(B.K.C.Lo编,Humana Press,Totowa,NJ,2003),第245-254页,其描述了抗体片段在大肠杆菌(E.coli.)中的表达)。表达后,可以将抗体在可溶性级分中自细菌细胞浆分离,并可以进一步纯化。
在原核生物外,真核微生物诸如丝状真菌或酵母是适合于抗体编码载体的克隆或表达宿主,包括其糖基化途径已经“人源化”,导致生成具有部分或完全人的糖基化样式的抗体的真菌和酵母菌株。见Gerngross,Nat.Biotech.22:1409-1414(2004),及Li等,Nat.Biotech.24:210-215(2006)。
适合于表达糖基化抗体的宿主细胞也自多细胞生物体(无脊椎动物和脊椎动物)衍生。无脊椎动物细胞的例子包括植物和昆虫细胞。已经鉴定出许多杆状病毒株,其可以与昆虫细胞一起使用,特别是用于转染草地夜蛾(Spodoptera frugiperda)细胞。
也可以利用植物细胞培养物作为宿主。见例如美国专利No.5,959,177,6,040,498,6,420,548,7,125,978和6,417,429(其描述了用于在转基因植物中生成抗体的PLANTIBODIESTM技术)。
也可以使用脊椎动物细胞作为宿主。例如,适合于在悬浮液中生长的哺乳动物细胞系可以是有用的。有用的哺乳动物宿主细胞系的其它例子是经SV40转化的猴肾CV1系(COS-7);人胚肾系(293或293细胞,如记载于例如Graham等,J.Gen Virol.36:59(1977)的);幼年仓鼠肾细胞(BHK);小鼠塞托利(sertoli)细胞(TM4细胞,如记载于例如Mather,Biol.Reprod.23:243-251(1980)的);猴肾细胞(CV1);非洲绿猴肾细胞(VERO-76);人宫颈癌细胞(HELA);犬肾细胞(MDCK;牛鼠(buffalo rat)肝细胞(BRL 3A);人肺细胞(W138);人肝细胞(Hep G2);小鼠乳房肿瘤(MMT 060562);TRI细胞,如记载于例如Mather等,AnnalsN.Y.Acad.Sci.383:44-68(1982)的;MRC 5细胞;和FS4细胞。其它有用的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞,包括DHFR-CHO细胞(Urlaub等,Proc.Natl.Acad.Sci.USA77:4216(1980));和骨髓瘤细胞系诸如Y0、NS0和Sp2/0。关于适合于抗体生成的某些哺乳动物宿主细胞系的综述,见例如Yazaki和Wu,Methods in Molecular Biology,第248卷(B.K.C.Lo编,Humana Press,Totowa,NJ),第255-268页(2003)。
n)测定法
可以通过本领域中已知的多种测定法对本文中提供的NRG拮抗剂鉴定、筛选、或表征其物理/化学特性和/或生物学活性。
在一方面,对本发明的抗体测试其抗原结合活性,例如通过已知的方法诸如ELISA、Western印迹等来进行。
在另一方面,提供了用于鉴定具有生物学活性的其NRG拮抗剂的测定法。生物学活性可以包括例如,抑制NRG诱导的受体酪氨酸激酶信号传导、抑制肿瘤生长、抑制细胞增殖、等等。还提供了在体内和/或体外具有此类生物学活性的拮抗剂。
在某些实施方案中,对本发明的拮抗剂测试此类生物学活性。在一个实施方案中,可以通过在存在和没有潜在的NRG拮抗剂的情况中测定受体酪氨酸激酶的酪氨酸残基的NRG诱导的磷酸化的水平来测量拮抗剂抑制NRG诱导的受体酪氨酸激酶信号传导的能力。Holmes,等1992。以下是测定受体酪氨酸激酶的磷酸化状态的例示性测定法。在与潜在的NRG拮抗剂或缓冲液(对照)一起预温育60分钟后用10nM NRG刺激表达Her2和Her3的细胞(诸如Caov3细胞,或工程化改造为表达Her2和Her3的细胞)。在用抗磷酸酪氨酸抗体探查的Western印迹上分析全细胞裂解物以测定酪氨酸磷酸化的水平。可以扫描印迹以定量抗磷酸酪氨酸信号。与缓冲液对照相比,NRG拮抗剂会降低酪氨酸磷酸化的水平。在一个实施方案中,与未处理的对照相比,NRG拮抗剂将NRG诱导的酪氨酸激酶信号传导抑制至少30%、40%、50%、60%70%、80%、85%、90%、95%、96%、97%、98%或99%。
在某些实施方案中,对本发明的抗体测试其在体外抑制细胞生长或增殖的能力。用于抑制细胞生长或增殖的测定法是本领域中公知的。以本文中所描述的“细胞杀伤”测定法例示的用于细胞增殖的某些测定法测量细胞存活力。一种此类测定法是CellTiter-GloTM发光细胞存活力测定法,其可购自Promega(Madison,WI)。所述测定法基于指示代谢活性细胞的所存在的ATP的定量来测定培养物中的活细胞的数目。见Crouch等(1993)J.Immunol.Meth.160:81-88,美国专利No.6602677。可以以96或384孔形式进行测定法,使其适合于自动化高通量筛选(HTS)。见Cree等(1995)AntiCancer Drugs6:398-404。该测定法规程牵涉对培养的细胞直接添加单一试剂Reagent)。这导致细胞裂解,并产生由萤光素酶反应生成的发光信号。发光信号与存在的ATP量成比例,所述ATP量与存在于培养物中的活细胞数目成正比。可以通过发光计或CCD照相机成像装置记录数据。发光输出表示为相对光单位(RLU)。
用于细胞增殖的另一种测定法是“MTT”测定法,即一种比色测定法,其测量线粒体还原酶将3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物氧化成甲月替(formazan)。与CellTiter-GloTM测定法一样,此测定法指示细胞培养物中存在的代谢活性细胞的数目。见例如Mosmann(1983)J.Immunol.Meth.65:55-63及Zhang等(2005)Cancer Res.65:3877-3882。
在一方面,对NRG拮抗剂测试其在体外诱导细胞死亡的能力。用于诱导细胞死亡的测定法是本领域中公知的。在一些实施方案中,此类测定法测量例如膜完整性的丧失,如通过碘化丙啶(PI)、锥虫蓝(见Moore等(1995)Cytotechnology,17:1-11)、或7AAD的摄取指示的。在例示性的PI摄取测定法中,将细胞在补充有10%热灭活的FBS(Hyclone)和2mM L-谷氨酰胺的Dulbecco氏改良的Eagle培养基(D-MEM):Ham氏F-12(50:50)中培养。如此,在没有补体和免疫效应细胞的情况中实施测定法。将细胞在100x20mm皿中以每皿3x106的密度接种,并容许附着过夜。将培养基除去,并用单独的新鲜培养基或含有各个浓度的抗体或免疫缀合物的培养基更换。将细胞温育3天的时段。在处理后,将单层用PBS清洗,并通过胰蛋白酶处理分离。然后,将细胞以1200rpm于4°C离心5分钟,将团粒在3ml冷的Ca2+结合缓冲液(10mMHepes,pH 7.4,140mM NaCl,2.5mM CaCl2)中重悬,并等分取样入35mm滤网加帽的12x75mm管中(每管1ml,每个处理组3管)以除去细胞块。然后,管接受PI(10μg/ml)。使用FACSCANTM流式细胞仪和FACSCONVERTTMCellQuest软件(Becton Dickinson)分析样品。如此,鉴定诱导统计学显著的细胞死亡水平的抗体,如通过PI摄取测定的。
在一方面,对NRG拮抗剂测试其在体外诱导凋亡(程序性细胞死亡)的能力。一种用于诱导凋亡的抗体或免疫缀合物的例示性测定法是膜联蛋白结合测定法。在一个例示性的膜联蛋白结合测定法中,将细胞培养,并在皿中接种,如前一段中所讨论的。将培养基除去,并用单独的新鲜培养基或含有0.001至10μg/ml的抗体或免疫缀合物的培养基替换。在3天温育期后,将单层用PBS清洗,并通过胰蛋白酶处理分离。然后,将细胞离心,在Ca2+结合缓冲液中重悬,并等分取样入管中,如前一段中所讨论的。然后,管接受经标记的膜联蛋白(例如膜联蛋白V-FITC)(1μg/ml)。使用FACSCANTM流式细胞仪和FACSCONVERTTM CellQuest软件(BD Biosciences)分析样品。如此,鉴定相对于对照诱导统计学显著的膜联蛋白结合水平的抗体。用于诱导凋亡的抗体或免疫缀合物的另一种例示性测定法是用于检测基因组DNA的核小体间降解的组蛋白DNA ELISA比色测定法。可以使用例如细胞死亡检测ELISA试剂盒(Roche,Palo Alto,CA)实施此类测定法。
在任何上述体外测定法中使用的细胞包括天然表达NRG或已经工程化改造为表达NRG的细胞或细胞系。此类细胞包括相对于同一组织起源的正常细胞过表达NRG的肿瘤细胞。此类细胞还包括表达NRG的细胞系(包括肿瘤细胞系)和通常不表达NRG,但是已经用编码NRG的核酸转染的细胞系。
在一方面,对NRG拮抗剂测试其在体内抑制细胞生长或增殖的能力。在某些实施方案中,对NRG拮抗剂测试其在体内抑制肿瘤生长的能力。可以使用体内模型系统,诸如异种移植物模型来进行此类测试。在例示性的异种移植物系统中,将人肿瘤细胞导入适当地免疫受损的非人动物,例如,无胸腺“裸”鼠中。对动物施用本发明的抗体。测量抗体抑制或降低肿瘤生长的能力。在上述异种移植物系统的某些实施方案中,人肿瘤细胞是来自人患者的肿瘤细胞。此类异种移植物模型可购自Oncotest GmbH(Frieberg,Germany)。在某些实施方案中,人肿瘤细胞是来自人肿瘤细胞系的细胞。在某些实施方案中,通过皮下注射或通过移植入合适的部位,诸如乳房脂肪垫中来将人肿瘤细胞导入适当地免疫受损的非人动物中。
在某些实施方案中,与未处理的对照相比,NRG拮抗剂将细胞增殖抑制至少30%、40%、50%、60%、70%、80%、85%、90%、95%、96%、97%、98%或99%。在其它实施方案中,与未处理的对照相比,NRG拮抗剂将肿瘤生长抑制至少30%、40%、50%、60%、70%、80%、85%、90%、95%、96%、97%、98%或99%。
2.NRG结合多肽
可以在本发明的方法中使用特异性结合NGR的NRG结合多肽或其片段,例如,以结合并隔离NGR蛋白,由此阻止其信号传导。优选地,NRG多肽或其片段是可溶形式的。在一些实施方案中,多肽的可溶形式通过结合NGR,由此阻止其与其天然结合配偶体联合来对NGR的生物学活性施加抑制效果。
3.适体
适体是形成特异性结合靶分子,诸如NRG多肽的三级结构的核酸分子。适体的生成和治疗性用途是本领域中完善建立的。见例如美国专利No.5,475,096。关于适体的别的信息可见美国专利申请公开文本No.20060148748。
4.肽体
肽体是与编码免疫球蛋白分子的片段或一部分的氨基酸序列连接的肽序列。多肽可以自通过针对特异性结合的任何方法,包括但不限于噬菌体展示技术选定的随机化序列衍生。在一个优选的实施方案中,选定的多肽可以与编码免疫球蛋白的Fc部分的氨基酸序列连接。特异性结合并拮抗NRG的肽体也可用于本发明的方法。
5.拮抗性核酸
其它NRG拮抗剂是使用反义技术制备的反义RNA或DNA构建体,其中例如反义RNA或DNA分子通过与靶定的mRNA杂交,并且阻止蛋白质翻译起作用以直接阻断mRNA的翻译。可以使用反义技术经由三股螺旋形成或反义DNA或RNA来控制基因表达,这两种方法都基于多核苷酸对DNA或RNA的结合。例如,可以使用编码本文中的成熟NRG多肽的多核苷酸序列的5’编码部分来设计长度为约10至40个碱基对的反义RNA寡核苷酸。将DNA寡核苷酸设计为与牵涉转录的基因区互补(三股螺旋,见Lee等,Nucl.Acids Res.,6:3073(1979);Cooney等,Science,241:456(1988);Dervan等,Science,251:1360(1991)),由此阻止NRG多肽的转录和生成。反义RNA寡核苷酸在体内与mRNA杂交,并且阻断mRNA分子翻译成NRG多肽(反义-Okano,Neurochem.,56:560(1991);Oligodeoxynucleotides as Antisense Inhibitorsof Gene Expression(CRC Press:Boca Raton,FL,1988)。也可以将上文所描述的寡核苷酸投递至细胞,使得可以在体内表达反义RNA或DNA以抑制NRG多肽的生成。在使用反义DNA时,自翻译起始位点(,例如靶基因核苷酸序列的约-10和+10位置间)衍生的寡脱氧核糖核苷酸是优选的。
小干扰RNA(siRNA)是降低靶基因表达的长度一般小于30个核苷酸的双链RNA分子。已经证明了siRNA可用作其中传统的拮抗剂诸如小分子或抗体已经失败的调控基因表达的研究中的工具(Shi Y.,Trends in Genetics 19(1):9-12(2003))。长度是21至23个核苷酸的体外合成的、双链RNA可以充当干扰RNA(iRNA),并且能特异性抑制基因表达(FireA.,Trends in Genetics 391;806-810(1999))。这些iRNA通过介导对其靶RNA的降解来起作用。然而,因为它们的长度在30个核苷酸下,所以它们不触发细胞抗病毒防御机制。在本发明的一些实施方案中,siRNA与NRG编码多核苷酸的编码序列或其互补物的一部分具有至少约90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%核酸序列同一性。
6.寡肽
本发明的NRG结合寡肽是结合,优选特异性结合如本文中所描述的NRG的寡肽。NRG结合寡肽可以使用已知的寡肽合成方法化学合成或者可以使用重组技术来制备并纯化。NRG结合寡肽的长度通常是至少约5个氨基酸,或者长度为至少约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、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100个氨基酸或更多,其中此类寡肽能够结合,优选特异性结合如本文中所描述的NRG。可以使用公知的技术在无需过度实验的情况中鉴定NRG结合寡肽。在这点上,注意到用于对寡肽文库筛选能够特异性结合多肽靶物的寡肽的技术是本领域中公知的(见例如美国专利No.5,556,762,5,750,373,4,708,871,4,833,092,5,223,409,5,403,484,5,571,689,5,663,143;PCT公开文本No.WO 84/03506和WO84/03564;Geysen等,Proc.Natl.Acad.Sci.U.S.A.,81:3998-4002(1984);Geysen等,Proc.Natl.Acad.Sci.U.S.A.,82:178-182(1985);Geysen等,于Synthetic Peptides asAntigens,130-149(1986);Geysen等,J.Immunol.Meth.,102:259-274(1987);Schoofs等,J.Immunol.,140:611-616(1988),Cwirla,S.E.等(1990)Proc.Natl.Acad.Sci.USA,87:6378;Lowman,H.B.等(1991)Biochemistry,30:10832;Clackson,T.等(1991)Nature,352:624;Marks,J.D.等(1991),J.Mol.Biol.,222:581;Kang,A.S.等(1991)Proc.Natl.Acad.Sci.USA,88:8363,及Smith,G.P.(1991)Current Opin.Biotechnol.,2:668)。
在这点上,(细菌)噬菌体展示是一种公知的技术,其容许筛选大的寡肽文库以鉴定那些文库中能够特异性结合多肽靶物的成员。噬菌体展示是一种将变体多肽以与外壳蛋白的融合蛋白在噬菌体颗粒表面上展示的技术(Scott,J.K.和Smith,G.P.(1990)Science,249:386)。噬菌体展示的效用在于如下的实情,即可以对选择性随机化的蛋白质变体(或随机克隆的cDNA)的大文库快速且有效地分选那些以高亲和力结合靶分子的序列。已经使用噬菌体上的肽(Cwirla,S.E.等(1990)Proc.Natl.Acad.Sci.USA,87:6378)或蛋白质(Lowman,H.B.等(1991)Biochemistry,30:10832;Clackson,T.等(1991)Nature,352:624;Marks,J.D.等(1991),J.Mol.Biol.,222:581;Kang,A.S.等(1991)Proc.Natl.Acad.Sci.USA,88:8363)文库展示来对数百万种多肽或寡肽筛选具有特定结合特性的(Smith,G.P.(1991)Current Opin.Biotechnol.,2:668)。分选随机突变体的噬菌体文库需要一种用于构建并增殖大量变体的策略、一种使用靶受体进行亲和纯化的规程、和一种评估结合富集的结果的手段。美国专利No.5,223,409,5,403,484,5,571,689和5,663,143。
生成肽文库和筛选这些文库的方法也披露于美国专利No.5,723,286,5,432,018,5,580,717,5,427,908,5,498,530,5,770,434,5,734,018,5,698,426,5,763,192和5,723,323。
7.小分子
在一些实施方案中,NRG结合小分子是结合,优选特异性结合如本文中所描述的NRG的与如本文中定义的寡肽或抗体不同的有机分子。可以使用已知方法(见例如PCT公开文本No.WO00/00823和WO00/39585)鉴定并化学合成NRG结合有机小分子。NRG结合有机小分子的大小通常小于约2000道尔顿,或者大小小于约1500、750、500、250或200道尔顿,其中可以使用公知的技术在无需过度实验的情况中鉴定能够结合,优选特异性结合如本文中所描述的NRG的此类有机小分子。在这点上,注意到用于对有机小分子文库筛选能够结合多肽靶物的分子的技术是本领域中公知的(见例如PCT公开文本No.WO00/00823和WO00/39585)。NRG结合有机小分子可以是例如醛、酮、肟、腙、缩氨基脲、卡巴肼(carbazide)、伯胺、仲胺、叔胺、N-取代的肼、酰肼、醇、醚、硫醇、硫醚、二硫化物、羧酸、酯、酰胺、脲、氨基甲酸酯、碳酸酯、缩酮、酮缩硫醇(thioketal)、缩醛、硫缩醛、芳基卤、芳基磺酸酯、卤代烷、烃基磺酸酯、芳香族化合物、杂环化合物、苯胺、烯、炔、二醇、氨基醇、唑烷、唑啉、噻唑烷、噻唑啉、烯胺、磺酰胺、环氧化物、氮丙啶、异氰酸酯、磺酰氯、重氮化合物、酸性氯化物、等等。
8.免疫缀合物
本发明还提供了包含与一种或多种细胞毒剂,诸如化学治疗剂或药物、生长抑制剂、毒素(例如,蛋白质毒素、细菌、真菌、植物、或动物起源的酶活性毒素、或其片段)、或放射性同位素缀合的本文中的NRG拮抗剂的免疫缀合物。
在一个实施方案中,免疫缀合物是抗体-药物缀合物(ADC),其中抗体与一种或多种药物缀合,包括但不限于美登木素生物碱(见美国专利No.5,208,020、5,416,064和欧洲专利EP 0 425235B1);auristatin诸如单甲基auristatin药物模块DE和DF(MMAE和MMAF)(见美国专利No.5,635,483和5,780,588及7,498,298);多拉司他汀(dolastatin);加利车霉素(calicheamicin)或其衍生物(见美国专利No.5,712,374,5,714,586,5,739,116,5,767,285,5,770,701,5,770,710,5,773,001和5,877,296;Hinman等,Cancer Res.53:3336-3342(1993);及Lode等,Cancer Res.58:2925-2928(1998));蒽环类抗生素诸如道诺霉素(daunomycin)或多柔比星(doxorubicin)(见Kratz等,Current Med.Chem.13:477-523(2006);Jeffrey等,Bioorganic&Med.Chem.Letters16:358-362(2006);Torgov等,Bioconj.Chem.16:717-721(2005);Nagy等,Proc.Natl.Acad.Sci.USA 97:829-834(2000);Dubowchik等,Bioorg.&Med.Chem.Letters 12:1529-1532(2002);King等,J.Med.Chem.45:4336-4343(2002);及美国专利No.6,630,579);甲氨蝶呤;长春地辛(vindesine);紫杉烷(taxane)诸如多西他赛(docetaxel)、帕利他塞、larotaxel、tesetaxel、和ortataxel;单端孢霉素(trichothecene);和CC1065。
在另一个实施方案中,免疫缀合物包含与酶活性毒素或其片段缀合的如本文中所描述的抗体,所述酶活性毒素包括但不限于白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌(Pseudomonas aeruginosa))、蓖麻毒蛋白(ricin)A链、相思豆毒蛋白(abrin)A链、蒴莲根毒蛋白(modeccin)A链、α-帚曲霉素(sarcin)、油桐(Aleutitesfordii)毒蛋白、香石竹(dianthin)毒蛋白、美洲商陆(Phytolaca americana)蛋白(PAPI、PAPII和PAP-S)、苦瓜(Momordica charantia)抑制物、麻疯树毒蛋白(curcin)、巴豆毒蛋白(crotin)、肥皂草(sapaonaria officinalis)抑制剂、白树毒蛋白(gelonin)、丝林霉素(mitogellin)、局限曲菌素(restrictocin)、酚霉素(phenomycin)、依诺霉素(enomycin)和单端孢菌素(trichothecenes)。
在另一个实施方案中,免疫缀合物包含与放射性原子缀合以形成放射性缀合物的如本文中所描述的抗体。多种放射性同位素可用于生成放射性缀合物。例子包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素。在使用放射性缀合物进行检测时,它可以包含供闪烁法研究用的放射性原子,例如tc99m或I123,或供核磁共振(NMR)成像(又称为磁共振成像,mri)用的自旋标记物,诸如再一次的碘-123、碘-131、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。
可以使用多种双功能蛋白质偶联剂来生成抗体和细胞毒剂的缀合物,诸如N-琥珀酰亚氨基3-(2-吡啶基二硫代)丙酸酯(SPDP),琥珀酰亚氨基-4-(N-马来酰亚氨基甲基)环己烷-1-羧酸酯(SMCC),亚氨基硫烷(IT),亚氨酸酯(诸如盐酸己二酰亚氨酸二甲酯)、活性酯类(诸如辛二酸二琥珀酰亚氨基酯)、醛类(诸如戊二醛)、双叠氮化合物(诸如双(对-叠氮苯甲酰基)己二胺)、双重氮衍生物(诸如双(对-重氮苯甲酰基)-乙二胺)、二异硫氰酸酯(诸如甲苯2,6-二异氰酸酯)、和双活性氟化合物(诸如1,5-二氟-2,4-二硝基苯)的双功能衍生物。例如,可以如Vitetta等,Science 238:1098(1987)中所述制备蓖麻毒蛋白免疫毒素。碳-14标记的1-异硫氰酸苄基-3-甲基二亚乙基三胺五乙酸(MX-DTPA)是用于将放射性核苷酸与抗体偶联的例示性螯合剂。参见WO94/11026。接头可以是便于在细胞中释放细胞毒性药物的“可切割接头”。例如,可使用酸不稳定接头、肽酶敏感性接头、光不稳定接头、二甲基接头或含二硫化物接头(Chari等,Cancer Res 52:127-131(1992);美国专利No.5,208,020)。
本文中的免疫缀合物或ADC明确涵盖,但不限于用交联试剂制备的此类缀合物,所述交联试剂包括但不限于BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、SMPH、sulfo-EMCS、sulfo-GMBS、sulfo-KMUS、sulfo-MBS、sulfo-SIAB、sulfo-SMCC、和sulfo-SMPB,及SVSB(琥珀酰亚氨基-(4-乙烯基砜)苯甲酸酯),它们是商品化的(例如,来自Pierce Biotechnology,Inc.,Rockford,IL.,U.S.A)。
B.用于诊断和检测的方法和组合物
在某些实施方案中,本文中提供的NRG拮抗剂可用于检测生物学样品中NRG的存在。如本文中所使用的,术语“检测”涵盖定量或定性检测。在某些实施方案中,生物学样品包含细胞或组织,诸如肺组织或乳房组织。
在一个实施方案中,提供了在诊断或检测方法中使用的抗NRG抗体。在又一方面,提供了检测生物学样品中NRG的存在的方法。在某些实施方案中,该方法包括在容许抗NRG抗体结合NRG的条件下使生物学样品与抗NRG抗体接触,如本文中所描述的,并检测是否在抗NRG抗体与NRG间形成复合物。此类方法可以是体外或体内方法。在一个实施方案中,使用抗NRG抗体来选择适合用抗NRG抗体治疗的受试者,例如其中NRG是一种用于选择患者的生物标志。
在一个实施方案中,若患者具有要或有可能变得对疗法有抗性的癌症,则选择该患者用NRG拮抗剂治疗。本发明的一方面提供了一种测定法,其测定患者是否具有要或有可能变得对疗法有抗性的癌症。在一个实施方案中,该测定法包括对自患者采集的肿瘤细胞测定NRG表达,其中NRG的表达指示患者具有要或有可能变得对疗法有抗性的癌症。在一个实施方案中,若肿瘤中的NRG表达水平小于肿瘤TRIC中的NRG表达水平,则患者选择为具有要或有可能变得对疗法有抗性的癌症的。
在一个实施方案中,若患者具有在用治疗剂治疗后有可能复发的癌症,则选择该患者用NRG拮抗剂治疗。本发明的一方面提供了一种测定法,其测定患者是否具有在用治疗剂治疗后有可能复发的癌症。在一个实施方案中,该测定法包括对自患者采集的肿瘤细胞测定NRG表达,其中NRG的表达指示患者具有在用治疗剂治疗后有可能复发的癌症。在一个实施方案中,若肿瘤中的NRG表达水平小于肿瘤TRIC中的NRG表达水平,则患者选择为具有在用治疗剂治疗后有可能复发的癌症的。
在某些实施方案中,诊断测定法包括使用例如免疫组织化学、原位杂交、或RT-PCR测定肿瘤细胞中神经调节蛋白的表达。在其它实施方案中,诊断测定法包括使用例如定量RT-PCR测定肿瘤细胞中神经调节蛋白的表达水平。在一些实施方案中,诊断测定法进一步包括与对照组织诸如例如非癌性相邻组织相比测定神经调节蛋白的表达水平。
在某些实施方案中,提供了经标记的抗NRG抗体。标记物包括但不限于直接检测的标记物或模块(诸如荧光、发色、电子致密、化学发光、和放射性标记物)、及例如经由酶反应或分子相互作用间接检测的模块,诸如酶或配体。例示性的标记物包括但不限于放射性同位素32P、14C、125I、3H、和131I、荧光团诸如稀土螯合物或荧光素及其衍生物、罗丹明(rhodamine)及其衍生物、丹酰、伞形酮、萤光素酶,例如,萤火虫萤光素酶和细菌萤光素酶(美国专利No.4,737,456)、萤光素、2,3-二氢酞嗪二酮、辣根过氧化物酶(HRP)、碱性磷酸酶、β-半乳糖苷酶、葡糖淀粉酶、溶菌酶、糖类氧化酶,例如,葡萄糖氧化酶、半乳糖氧化酶、和葡萄糖-6-磷酸脱氢酶、杂环氧化酶诸如尿酸酶和黄嘌呤氧化酶(其与采用过氧化氢氧化染料前体的酶诸如HRP偶联)、乳过氧化物酶、或微过氧化物酶、生物素/亲合素、自旋标记物、噬菌体标记物、稳定的自由基、等等。
C.治疗性方法和组合物
可以在治疗性方法中使用本文中提供的NRG拮抗剂。
在一方面,提供了作为药物使用的NRG拮抗剂。在别的方面,提供了在治疗癌症中使用的NRG拮抗剂。在某些实施方案中,提供了在治疗方法中使用的NRG拮抗剂。在某些实施方案中,本发明提供了在治疗具有癌症的个体的方法中使用的NRG拮抗剂,所述方法包括对个体施用有效量的NRG拮抗剂。在一个此类实施方案中,所述方法进一步包括对个体施用有效量的至少一种别的治疗剂,例如,如下文所描述的。在别的实施方案中,本发明提供了在治疗已经经历癌症复发的患者中使用的NRG拮抗剂。在某些实施方案中,本发明提供了在预防个体中对用治疗剂治疗的抗性的方法中使用的NRG拮抗剂,所述方法包括对个体施用有效量的NRG拮抗剂以预防对治疗剂的抗性。
在又一方面,本发明提供了NRG拮抗剂在制造或制备药物中的用途。在一个实施方案中,药物用于治疗癌症。在又一个实施方案中,药物在治疗癌症的方法中使用,所述方法包括对具有癌症的个体施用有效量的药物。在一个此类实施方案中,所述方法进一步包括对个体施用有效量的至少一种别的治疗剂,例如如下文所描述的。在又一个实施方案中,药物用于预防患者中对用治疗剂治疗的抗性。在又一个实施方案中,药物用于预防患者中癌症的复发。
在又一方面,本发明提供了药物配制剂,其包含本文中提供的任何NRG拮抗剂,例如在任何上述治疗性方法中使用。在一个实施方案中,药物配制剂包含本文中提供的任何NRG拮抗剂和药学可接受载体。在另一个实施方案中,药物配制剂包含本文中提供的任何NRG拮抗剂和至少一种别的治疗剂,例如如下文所描述的。
一个实施方案提供了含有NRG拮抗剂和治疗惰性载体、稀释剂或赋形剂的药物组合物或药物,及使用本发明的化合物制备此类组合物和药物的方法。在一个例子中,可以通过于环境温度在合适的pH,且以期望的纯度与生理学可接受载体,即在采用的剂量和浓度对接受者无毒的载体混合成盖仑制剂施用形式来配制化合物。配制剂的pH主要取决于化合物的特定用途和浓度,但是优选地,范围为约3至约8的任何数值。在一个例子中,将化合物在乙酸盐缓冲液(为pH 5)中配制。在另一个实施方案中,化合物是无菌的。例如,可以将化合物以固体或无定形组合物,以冻干配制剂或以水性溶液贮存。
通过混合具有期望纯度的此类拮抗剂与一种或多种任选的药学可接受载体(Remington’s Pharmaceutical Sciences第16版,Osol,A.编(1980))混合以冻干配制剂或水性溶液形式制备如本文中所描述的NRG拮抗剂的药物配制剂。一般地,药学可接受载体在所采用的剂量和浓度对接受者是无毒的,而且包括但不限于缓冲剂,诸如磷酸盐、柠檬酸盐、和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如氯化十八烷基二甲基苄基铵;氯化己烷双胺;苯扎氯铵、苯索氯铵;酚、丁醇或苯甲醇;对羟基苯甲酸烃基酯,诸如对羟基苯甲酸甲酯或丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,诸如血清清蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖类,诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐相反离子,诸如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂,诸如聚乙二醇(PEG)。本文中的例示性的药学可接受载体进一步包含间质药物分散剂诸如可溶性中性活性透明质酸酶糖蛋白(sHASEGP),例如人可溶性PH-20透明质酸酶糖蛋白,诸如rHuPH20Baxter International,Inc.)。某些例示性的sHASEGP和使用方法,包括rHuPH20记载于美国专利公开文本No.2005/0260186和2006/0104968。在一方面,将sHASEGP与一种或多种别的糖胺聚糖酶诸如软骨素酶组合。
例示性的冻干抗体配制剂记载于美国专利No.6,267,958。水性抗体配制剂包括那些记载于美国专利No.6,171,586和WO2006/044908的,后一种配制剂包含组氨酸-乙酸盐缓冲液。
以与优良医学实践一致的方式配制、剂量给药和施用组合物。在此上下文中考虑的因素包括所治疗的具体病症、所治疗的具体患者、患者个体的临床状况、病症的起因、投递药剂的部位、施用的方法、施用的日程表、和医学从业人员知道的其它因素。
根据用于施用药物的方法,可以以多种方式包装应用的药物组合物(或配制剂)。一般地,销售的商品包括具有其中存放的合适形式的药物配制剂的容器。合适的容器是本领域技术人员公知的,并且包括材料诸如瓶(塑胶和玻璃)、小袋、安瓿、塑料袋、金属圆筒(cylinder)、等等。容器还可以包含防干扰组件(assemblage)以阻止不慎接近包装的内容物。另外,容器具有其上存放的标签,其描述容器的内容物。标签还可以包含合适的警告。
可以制备持续释放制剂。持续释放制剂的合适的例子包括含有化合物的固体疏水性聚合物的半透性基质,该基质为成形商品形式,例如膜,或微胶囊。持续释放基质的例子包括聚酯、水凝胶(例如聚(2-羟乙基-甲基丙烯酸酯),或聚(乙烯醇))、聚交酯、L-谷氨酸和γ-乙基-L-谷氨酸酯的共聚物、不可降解的乙烯-乙酸乙烯、可降解的乳酸-乙醇酸共聚物诸如LUPRONDEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林构成的可注射微球体)、及聚-D-(-)-3-羟基丁酸。
在一个例子中,每剂胃肠外施用的NRG拮抗剂的药学有效量会在每天约0.01-100mg/kg,或者约0.1至20mg/kg患者体重的范围中,所使用的化合物的典型的初始范围是0.3至15mg/kg/天。在另一个实施方案中,优选地,口服单位剂量形式,诸如片剂和胶囊含有约5-100mg本发明的化合物。
可以通过任何合适的手段,包括口服、表面(包括含服和舌下)、直肠、阴道、经皮、胃肠外、皮下、腹膜内、肺内、皮内、鞘内和硬膜外和鼻内,及若期望用于局部治疗的话,损伤内施用来施用NRG拮抗剂。胃肠外输注包括肌肉内、静脉内、动脉内、腹膜内、或皮下施用。
部分根据施用是短暂的还是长期的,剂量给药可以通过任何合适的路径,例如通过注射,诸如静脉内或皮下注射进行。本文中涵盖各种剂量给药日程表,包括但不限于单次施用或在多个时间点里的多次施用、推注施用、和脉冲输注。
可以以任何方便的施用形式,例如,片剂、粉末、胶囊、溶液、分散体、悬浮液、糖浆剂、喷雾、栓剂、凝胶、乳剂、贴片等施用NRG拮抗剂。此类组合物可以含有药用制剂中常规的组分,例如,稀释剂、载体、pH改性剂、增甜剂、填充剂、和别的活性剂。
通过混合本发明的化合物和载体或赋形剂制备典型的配制剂。合适的载体和赋形剂是本领域技术人员公知的,并且详细记载于例如,Ansel,Howard C.,等,Ansel’sPharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams & Wilkins,2004;Gennaro,Alfonso R.等Remington:The Scienceand Practice of Pharmacy.Philadelphia:Lippincott,Williams & Wilkins,2000;及Rowe,Raymond C.Handbook of Pharmaceutical Excipients.Chicago,PharmaceuticalPress,2005。配制剂还可以包含一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、造影剂(opaquing agent)、助流剂、加工助剂、着色剂、增甜剂、发香剂(perfuming agent)、芳香剂、稀释剂和其它已知的添加剂以提供药物(即,本发明的化合物或其药物组合物)的优雅呈现或帮助制造药物产品(即,药物)。
合适的口服剂量形式的例子是含有与约90-30mg无水乳糖、约5-40mg交联羧甲基纤维素钠、约5-30mg聚乙烯吡咯烷酮(PVP)K30、和约1-10mg硬脂酸镁混合的约25mg、50mg、100mg、250mg或500mg本发明的化合物的片剂。首先,将粉状成分混合在一起,然后与PVP的溶液混合。可以将所得的组合物干燥、粒化、与硬脂酸镁混合,并使用常规设备压缩成片剂形式。可以通过将本发明的化合物(例如5-400mg)在合适的缓冲溶液,例如磷酸盐缓冲液中溶解,若想要的话,添加张力调节剂(tonicifier),例如盐诸如氯化钠来制备气雾剂配制剂的例子。可以例如使用0.2微米滤器来过滤溶液,以除去杂质和污染物。
因此,一个实施方案包括包含化合物、或其立体异构体或药学可接受盐的药物组合物。在又一个实施方案中包括包含化合物、或其立体异构体或药学可接受盐,以及药学可接受载体或赋形剂的药物组合物。
在抗体的情况中,一次或在一系列治疗里对患者适当施用抗体。根据疾病的类型和严重性,约1μg/kg至15mg/kg(例如0.1mg/g-10mg/kg)抗体可以是对患者施用的初始候选剂量,无论例如通过一次或多次分开施用,或者通过连续输注进行。根据上文所提及的因素,一种典型的每日剂量的范围可以是约1μg/kg至100mg/kg或更多。对于几天或更长里的重复施用,根据状况,一般会持续治疗,直至发生对疾病症状的期望抑制。抗体的一种例示性剂量会在约0.05mg/kg至约10mg/kg的范围中。如此,可以对患者施用一或多剂的约0.5mg/kg、2.0mg/kg、4.0mg/kg或10mg/kg(或其任何组合)。可以例如每周或每三周间歇施用此类剂量(例如使得患者接受约2至约20,或例如约6剂抗体)。可以施用初始的较高加载剂量,接着是较低的一或多剂。然而,其它剂量方案可以是有用的。通过常规的技术和测定法容易监测此疗法的进展。
应当理解,可以替换NRG拮抗剂或在NRG拮抗剂外使用本发明的免疫缀合物实施任何上述配制剂或治疗性方法。
可以单独或与疗法中的其它药剂组合使用本发明的NRG拮抗剂。例如,可以与至少一种别的治疗剂共施用本发明的NRG拮抗剂。
在某些实施方案中,别的治疗剂是抑制酪氨酸激酶受体途径的药剂。在一个实施方案中,别的治疗剂抑制HER途径。在一个实施方案中,别的治疗剂是EGFR、HER2、HER3、和/或HER4的抑制剂。
如本文中所使用的,术语“EGFR抑制剂”指结合EGFR或以其它方式与EGFR直接相互作用,并且阻止或降低其信号传导活性的化合物,并且或者称为“EGFR拮抗剂”。此类药剂的例子包括结合EGFR的抗体和小分子。结合EGFR的抗体的例子包括单抗579(ATCC CRL HB8506)、单抗455(ATCC CRL HB8507)、单抗225(ATCC CRL 8508)、单抗528(ATCC CRL 8509)(见美国专利No.4,943,533,Mendelsohn等)及其变体,诸如嵌合化的225(C225或西妥昔单抗(Cetuximab);和重构人225(H225)(见WO96/40210,Imclone SystemsInc.);IMC-11F8,即一种完全人的、EGFR靶向性抗体(Imclone);结合II型突变体EGFR的抗体(美国专利No.5,212,290);结合EGFR的人源化的和嵌合的抗体,如记载于美国专利No.5,891,996的;和结合EGFR的人抗体,诸如ABX-EGF或帕尼单抗(Panitumumab)(见WO98/50433,Abgenix/Amgen);EMD 55900(Stragliotto等Eur.J.Cancer 32A:636-640(1996));EMD7200(马妥珠单抗(matuzumab)),即一种针对EGFR的人源化EGFR抗体,其与EGF和TGF-α两者竞争EGFR结合(EMD/Merck);人EGFR抗体HuMax-EGFR (GenMab);称为E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3并记载于US 6,235,883的完全人抗体;MDX-447(Medarex Inc);和单抗806或人源化单抗806(Johns等,J.Biol.Chem.279(29):30375-30384(2004))。可以将抗EGFR抗体与细胞毒剂缀合,如此生成免疫缀合物(见例如EP659,439A2,Merck PatentGmbH)。EGFR拮抗剂包括小分子诸如记载于美国专利No:5,616,582,5,457,105,5,475,001,5,654,307,5,679,683,6,084,095,6,265,410,6,455,534,6,521,620,6,596,726,6,713,484,5,770,599,6,140,332,5,866,572,6,399,602,6,344,459,6,602,863,6,391,874,6,344,455,5,760,041,6,002,008和5,747,498,及下列PCT公开文本:WO98/14451,WO98/50038,WO99/09016和WO99/24037的化合物。具体的小分子EGFR拮抗剂包括OSI-774(CP-358774、埃罗替尼(erlotinib),Genentech/OSI Pharmaceuticals);PD183805(CI 1033、2-丙烯酰胺、N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(4-吗啉基)丙氧基]-6-喹唑啉基]-、二氢氯化物,Pfizer Inc.);ZD1839、吉非替尼(gefitinib)(IRESSATM)4-(3’-氯-4’-氟苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉,AstraZeneca);ZM 105180((6-氨基-4-(3-甲基苯基-氨基)-喹唑啉,Zeneca);BIBX-1382(N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶并[5,4-d]嘧啶-2,8-二胺,Boehringer Ingelheim);PKI-166((R)-4-[4-[(1-苯基乙基)氨基]-1H-吡咯并[2,3-d]嘧啶-6-基]-酚);(R)-6-(4-羟基苯基)-4-[(1-苯基乙基)氨基]-7H-吡咯并[2,3-d]嘧啶);CL-387785(N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-2-丁烯酰胺(butynamide));EKB-569(N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲氨基)-2-丁烯酰胺)(Wyeth);AG1478(Pfizer);AG1571(SU 5271;Pfizer);双重EGFR/HER2酪氨酸激酶抑制剂诸如拉帕替尼(lapatinib)GSK572016或N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]6[5[[[2甲基磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺;Glaxo-SmithKline)。
如本文中所使用的,术语“HER2抑制剂”指结合HER2或以其它方式与HER2直接相互作用,并且阻止或降低其信号传导活性的化合物,并且或者称为“HER2拮抗剂”。此类药剂的例子包括结合HER2的抗体和小分子。特定的HER2抗体包括帕妥珠单抗(pertuzumab)和曲妥单抗(trastuzumab)。如本文中所使用的,术语“HER3抑制剂”指结合HER3或以其它方式与HER3直接相互作用,并且阻止或降低其信号传导活性的化合物,并且或者称为“HER3拮抗剂”。此类药剂的例子包括结合HER3的抗体和小分子。如本文中所使用的,术语“HER4抑制剂”指结合HER4或以其它方式与HER4直接相互作用,并且阻止或降低其信号传导活性的化合物,并且或者称为“HER4拮抗剂”。此类药剂的例子包括结合HER4的抗体和小分子。
涉及HER抗体的专利公开文本包括:美国专利No.5,677,171,美国专利No.5,720,937,美国专利No.5,720,954,美国专利No.5,725,856,美国专利No.5,770,195,美国专利No.5,772,997,美国专利No.6,165,464,美国专利No.6,387,371,美国专利No.6,399,063,US2002/0192211A1,美国专利No.6,015,567,美国专利No.6,333,169,美国专利No.4,968,603,美国专利No.5,821,337,美国专利No.6,054,297,美国专利No.6,407,213,美国专利No.6,719,971,美国专利No.6,800,738,US2004/0236078A1,美国专利No.5,648,237,美国专利No.6,267,958,美国专利No.6,685,940,美国专利NO.6,821,515,WO98/17797,美国专利No.6,333,398,美国专利No.6,797,814,美国专利No.6,339,142,美国专利No.6,417,335,美国专利No.6,489,447,WO99/31140,US2003/0147884A1,US2003/0170234A1,US2005/0002928A1,美国专利No.6,573,043,US2003/0152987A1,WO99/48527,US2002/0141993A1,WO01/00245,US2003/0086924,US2004/0013667A1,WO00/69460,WO01/00238,WO01/15730,美国专利No.6,627,19681,美国专利No.6,632,979B1,WO01/00244,US2002/0090662A1,WO01/89566,US2002/0064785,US2003/0134344,WO 04/24866,US2004/0082047,US2003/0175845A1,WO03/087131,US2003/0228663,WO2004/008099A2,US2004/0106161,WO2004/048525,US2004/0258685A1,美国专利No.5,985,553,美国专利No.5,747,261,美国专利No.4,935,341,美国专利No.5,401,638,美国专利No.5,604,107,WO 87/07646,WO 89/10412,WO91/05264,EP 412,116B1,EP 494,135B1,美国专利No.5,824,311,EP 444,181B1,EP 1,006,194A2,US 2002/0155527A1,WO 91/02062,美国专利No.5,571,894,美国专利No.5,939,531,EP 502,812B1,WO 93/03741,EP 554,441B1,EP 656,367A1,美国专利No.5,288,477,美国专利No.5,514,554,美国专利No.5,587,458,WO 93/12220,WO 93/16185,美国专利No.5,877,305,WO93/21319,WO 93/21232,美国专利No.5,856,089,WO 94/22478,美国专利No.5,910,486,美国专利No.6,028,059,WO 96/07321,美国专利No.5,804,396,美国专利No.5,846,749,EP 711,565,WO 96/16673,美国专利No.5,783,404,美国专利No.5,977,322,美国专利No.6,512,097,WO 97/00271,美国专利No.6,270,765,美国专利No.6,395,272,美国专利No.5,837,243,WO 96/40789,美国专利No.5,783,186,美国专利No.6,458,356,WO 97/20858,WO 97/38731,美国专利No.6,214,388,美国专利No.5,925,519,WO98/02463,美国专利No.5,922,845,WO 98/18489,WO 98/33914,美国专利No.5,994,071,WO98/45479,美国专利No.6,358,682B1,US 2003/0059790,WO 99/55367,WO01/20033,US2002/0076695A1,WO 00/78347,WO 01/09187,WO 01/21192,WO 01/32155,WO 01/53354,WO01/56604,WO 01/76630,WO02/05791,WO02/11677,美国专利No.6,582,919,US2002/0192652A1,US 2003/0211530A1,WO 02/44413,US 2002/0142328,美国专利No.6,602,670B2,WO 02/45653,WO 02/055106,US 2003/0152572,US 2003/0165840,WO 02/087619,WO03/006509,WO03/012072,WO 03/028638,US 2003/0068318,WO 03/041736,EP 1,357,132,US 2003/0202973,US 2004/0138160,美国专利No.5,705,157,美国专利No.6,123,939,EP 616,812B1,US 2003/0103973,US 2003/0108545,美国专利No.6,403,630B1,WO00/61145,WO 00/61185,美国专利No.6,333,348B1,WO 01/05425,WO 01/64246,US 2003/0022918,US2002/0051785A1,美国专利No.6,767,541,WO 01/76586,US 2003/0144252,WO01/87336,US 2002/0031515A1,WO 01/87334,WO 02/05791,WO02/09754,US 2003/0157097,US 2002/0076408,WO 02/055106,WO 02/070008,WO 02/089842,WO 03/86467和US 2010/0255010。
在某些实施方案中,别的治疗剂是化学治疗剂。“化学治疗剂”指可用于治疗癌症的化学化合物。化学治疗剂的例子包括烷化剂类(alkylating agents),诸如塞替派(thiotepa)和环磷酰胺(cyclosphosphamide)磺酸烃基酯类(alkylsulfonates),诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),诸如苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)和乌瑞替派(uredepa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢大麻酚(tetrahydrocannabinol)(屈大麻酚(dronabinol),β-拉帕醌(lapachone);拉帕醇(lapachol);秋水仙素类(colchicines);白桦脂酸(betulinicacid);喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan)CPT-11(伊立替康(irinotecan),乙酰喜树碱、东莨菪亭(scopoletin)和9-氨基喜树碱);苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐藻素类(cryptophycin)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);duocarmycin(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards),诸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(chlorophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosoureas),诸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素类,诸如烯二炔类抗生素(enediyne)(例如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(见例如Nicolaou等,Angew.Chem Intl.Ed.Engl.,33:183-186(1994));CDP323,即一种口服α-4整联蛋白抑制剂;蒽环类抗生素(dynemicin),包括蒽环类抗生素A;埃斯波霉素(esperamicin);以及新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素(aclacinomycin)、放线菌素(actinomycin)、氨茴霉素(anthramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycins)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星和盐酸多柔比星脂质体注射液脂质体多柔比星TLC D-99PEG化的脂质体多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、potfiromycin、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,诸如甲氨蝶呤、吉西他滨(gemcitabine)替加氟(tegafur)卡培他滨(capecitabine)埃博霉素(epothilone)和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨蝶呤、蝶酰三谷氨酸(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤(mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素诸如卡普睾酮(calusterone)、屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酪(testolactone);抗肾上腺类,诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(folinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate;埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼(ethylhydrazide);丙卡巴肼(procarbazine);多糖复合物(JHS NaturalProducts,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2’-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素、疣孢菌素(verrucarin)A、杆孢菌素(roridin)A和蛇行菌素(anguidin));乌拉坦(urethan);长春地辛(vindesine) 达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);塞替派(thiotepa);类紫杉醇(taxoid),例如帕利他塞(paclitaxel)清蛋白改造的纳米颗粒剂型帕利他塞(ABRAXANETM)和多西他塞(doxetaxel)苯丁酸氮芥(chloranbucil);6-硫鸟嘌呤(thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂剂,诸如顺铂(cisplatin)、奥沙利铂(oxaliplatin)(例如和卡铂(carboplatin);长春药类(vincas)(其阻止微管蛋白聚合形成微管),包括长春碱(vinblastine)长春新碱(vincristine)长春地辛(vindesine)和长春瑞滨(vinorelbine)依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);亚叶酸(leucovorin);能灭瘤(novantrone);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);伊本膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄酸(retinoids),诸如视黄酸(retinoicacid),包括贝沙罗汀(bexarotene)二膦酸盐类(bisphosphonates),诸如氯膦酸盐(clodronate)(例如或依替膦酸钠(etidronate)NE-58095、唑来膦酸/唑来膦酸盐(zoledronic acid/zoledronate)阿伦膦酸盐(alendronate)帕米膦酸盐(pamidronate)替鲁膦酸盐(tiludronate)或利塞膦酸盐(risedronate)曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,特别是抑制牵涉异常(abherant)细胞增殖的信号传导途径中的基因表达的反义寡核苷酸,诸如例如PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R);疫苗,诸如疫苗和基因疗法疫苗,例如疫苗、疫苗和疫苗;拓扑异构酶1抑制剂(例如rmRH(例如BAY439006(索拉非尼(sorafenib);Bayer);SU-11248(舒尼替尼(sunitinib),Pfizer);哌立福辛(perifosine)、COX-2抑制剂(例如塞来考昔(celecoxib)或依托昔布(etoricoxib))、蛋白体抑制剂(例如PS341);保特佐米(bortezomib)CCI-779;替吡法尼(tipifarnib)(R11577);orafenib、ABT510;Bcl-2抑制剂诸如奥利默森钠(oblimersen sodium)pixantrone;EGFR抑制剂(见下文定义);酪氨酸激酶抑制剂(见下文定义);丝氨酸-苏氨酸激酶抑制剂诸如雷帕霉素(rapamycin)(西罗莫司(sirolimus),法尼基转移酶抑制剂诸如洛那法尼(lonafarnib)(SCH 6636,SARASARTM);及任何上述物质的药学可接受盐、酸或衍生物;以及两种或更多种上述物质的组合,诸如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙联合疗法的缩写)和FOLFOX(奥沙利铂(ELOXATINTM)联合5-FU和亚叶酸的治疗方案的缩写)。
如本文中所定义的,化学治疗剂包括“抗激素剂”或“内分泌治疗剂”,其作用为调节、降低、阻断、或抑制可促进癌症生长的激素的效果。它们自身可以是激素,包括但不限于:具有混合的激动剂/拮抗剂概况的抗雌激素,包括他莫昔芬(tamoxifen)4-羟基他莫昔芬、托瑞米芬(toremifene)艾多昔芬(idoxifene)、屈洛昔芬(droloxifene)、雷洛昔芬(raloxifene)曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、和选择性雌激素受体调节剂类(SERM)诸如SERM3;没有激动剂特性的纯抗雌激素,诸如氟维司群(fulvestrant)和EM800(此类药剂可以阻断雌激素受体(ER)二聚化,抑制DNA结合,增加ER周转,和/或抑制ER水平);芳香酶抑制剂,包括类固醇芳香酶抑制剂诸如福美坦(formestane)和依西美坦(exemestane)和非类固醇芳香酶抑制剂诸如阿那曲唑(anastrazole)来曲唑(letrozole)和氨鲁米特(aminoglutethimide),而其它芳香酶抑制剂包括伏罗唑(vorozole)醋酸甲地孕酮(megestrolacetate)法倔唑(fadrozole)、和4(5)-咪唑;促黄体生成激素释放激素激动剂,包括亮丙瑞林(leuprolide)和戈舍瑞林(goserelin)、布舍瑞林(buserelin)、和曲普瑞林(tripterelin);性类固醇,包括妊娠素(progestines)诸如醋酸甲地孕酮和醋酸甲羟孕酮、雌激素诸如己烯雌酚和倍美力(premarin)、和雄激素/类视黄醇诸如氟甲睾酮(fluoxymesterone)、全反式视黄酸(transretionic acid)和芬维A胺(fenretinide);奥那司酮(onapristone);抗孕酮;雌激素受体下调剂(ERD);抗雄激素诸如氟他胺(flutamide)、尼鲁米特(nilutamide)和比卡米特(bicalutamide);及任何上述物质的药学可接受盐、酸或衍生物;以及两种或更多种上述物质的组合。
此类联合疗法还包括:(i)脂质激酶抑制剂;(ii)反义寡核苷酸,特别是那些抑制牵涉异常细胞增殖的信号传导途径中的基因表达的,诸如例如PKC-α、Ralf和H-Ras;(iii)核酶诸如VEGF表达抑制剂(例如,核酶)和HER2表达抑制剂;(iv)疫苗诸如基因疗法疫苗,例如,疫苗、疫苗、和疫苗;rIL-2;拓扑异构酶1抑制剂;rmRH;(v)抗血管生成剂诸如贝伐单抗(bevacizumab)Genentech);和任何上述物质的药学可接受盐、酸或衍生物。
上文记录的此类联合疗法涵盖联合施用(其中两种或更多种治疗剂包含在相同或不同配制剂中),和分开施用,在该情况中,可以在施用别的治疗剂和/或佐剂之前、同时、和/或之后发生本发明的NRG拮抗剂的施用。也可以与放射疗法组合使用本发明的NRG拮抗剂。
D.制品
在本发明的另一方面,提供了一种制品,其含有可用于治疗、预防和/或诊断上文所描述的病症的材料。制品包含容器和容器上或与容器联合的标签或包装插页。合适的容器包括例如瓶、管形瓶、注射器、IV溶液袋、等等。容器可以由多种材料诸如玻璃或塑料形成。容器容纳单独或与另一种组合物组合有效治疗、预防和/或诊断状况的组合物,并且可以具有无菌存取口(例如,容器可以是具有由皮下注射针可穿过的塞子的管形瓶或静脉内溶液袋)。组合物中的至少一种活性剂是本发明的抗体。标签或包装插页指示使用组合物来治疗选择的状况。此外,制品可以包含(a)具有其中含有的组合物的第一容器,其中组合物包含本发明的抗体;和(b)具有其中含有的组合物的第二容器,其中组合物包含别的细胞毒性或其它方面治疗性的药剂。在本发明的此实施方案中的制品可以进一步包含包装插页,其指示可以使用组合物来治疗特定的状况。或者/另外,制品可以进一步包含第二(或第三)容器,其包含药学可接受缓冲液,诸如抑菌性注射用水(BWFI)、磷酸盐缓冲盐水、Ringer氏溶液和右旋糖溶液。它可以进一步包含从商业和用户观点看期望的其它材料,包括其它缓冲液、稀释剂、滤器、针、和注射器。
III.实施例
以下是本发明的方法和组合物的实施例。应当理解,鉴于上文提供的一般描述,可以实施各种其它实施方案。
实施例1:方法
细胞系
NSCLC细胞系Calu3、H441、H1299、H1993、A549和H596、和KPL4乳腺癌细胞系获自美国典型培养物保藏中心(American Type Culture Collection,ATCC),Manassas,VA。将这些细胞系在含有10%FBS、Pen/Strep和L-谷氨酰胺的RPMI中维持。将Calu3在替换RPMI的ATCC培养基中培养。用TZV-b-肌动蛋白-eGFP慢病毒转导Calu3、H441和KPL4细胞系。在多次传代后,分选并扩增高GFP表达细胞以得到约95%GFP阳性细胞,并且这些亚系描述为Calu3-GFP和H441-GFP和KPL4-GFP。小鼠NSCLC细胞系LKPH1和LKPH2自来自携带KrasLSL-G12D/+;p53FL +;Z/EG肺肿瘤的小鼠的两个独立肿瘤衍生。最初,细胞系在含有5%FBS、牛垂体提取物、N2补充物、EGF、FGF、Pen/Strep和L-谷氨酰胺的DMEM/F12培养基中建立。将LKPH1和LKPH2在含有10%FBS、Pen/Strep和L-谷氨酰胺的DMEM高葡萄糖培养基中培养。诱导型shRNA慢病毒:本研究中使用的发夹寡核苷酸如下:shNRG1:5’-GATCCCCCATGGTGAACATAGCGAATTTCAAGAGAATTCGCTATGTTCACCATGTTTTTTGGAAA-3’(有义)(SEQ ID NO:1)和5’-AGCTTTTCCAAAAAACATGGTGAACATAGCGAATTCTCTTGAAATTCGCTATGTTCACCATGGGG-3’(反义)(SEQ ID NO:2)。shNRG1.2:5’GATCCCCGAGTATATGTGCAAAGTGATTCAAGAGATCACTTTGCACATATTACTCTTTTTTGGAAA-3’(有义)(SEQ ID NO:3)和5’-AGCTTTTCCAAAAAAGAGTATATGTGCAAAGTGATCTCTTGAATCACTTTGCACATATACTCGGG-3’(反义)(SEQ ID NO:4)。shErbB4:5’-GATCCCCGATCACAACTGCTGCTTAATTCAAGAGATTAAGCAGCAGTTGTGATCTTTTTTGGAAA-3”(有义)(SEQ ID NO:5)和5’AGCTTTTCCAAAAAAGATCACAACTGCTGCTTAATCTCTTGAATTAAGCAGCAGTT GTGATCGGG-3’(反义)(SEQ ID NO:6)。shErbB3:5’-GATCCCCAAGAGGATGTCAACGGTTATTCAAGAGATAACCGTTGACATCCTCTTTTTTTTGGAAA-3’(有义)(SEQ ID NO:7)和5’-AGCTTTTCCAAAAAAAAGAGGATGTCAACGGTTATCTCTTGAATAACCGTTGACATCCTCTTGGG-3’(反义)(SEQ ID NO:8)。小鼠shNRG1:5”-GATCCCCCATGGTGAACATAGCGAATTTCAAGAGAATTCGCTATGTTCACCATGTTTTTTGGAAA-3’(有义)(SEQ ID NO:9)和5’-AGCTTTTCCAAAAAACATGGTGAACATAGCGAATTCTCTTGAAATTCGCTATGTTCACCATGGGG-3”(反义)(SEQ ID NO:10)。
将互补的双链shRNA寡核苷酸插入Tet诱导型病毒基因转移载体中,如描述的(Hoeflich等Cancer Res.2006)。载体系统由穿梭载体和dsRed表达病毒载体主链组成,所述dsRed表达病毒载体主链含有经密码子优化的Tet阻抑物-内部核糖体进入位点-dsRed盒以实现Tet调节的shRNA表达。先前描述了萤光素酶shRNA构建体(Hoeflich等)。
病毒包装和细胞系生成:基于先前描述的方法使用Lipofectamine(Invitrogen,Carlsbad,CA)通过在HEK293T细胞中共转染含有期望的shRNA的pHUSH-Lenti-dsRed构建体与表达水泡性口膜炎病毒(VSV-G)包膜糖蛋白和HIV-1包装蛋白(GAG-POL)的质粒来生成携带诱导型shRNA的慢病毒构建体。用这些病毒转导靶细胞。在大于3次传代后,使用FACS分选来选择前约20%dsRed表达肿瘤细胞,将其收集、合并并扩充。
体外研究:为了诱导shRNA表达,将含有多西环素(doxycycline)诱导型shNRG1或sh萤光素酶的稳定细胞系在1ug/ml多西环素中培养总共6天。诱导第一天将细胞在10%FBS中培养,接着在4天的过程里滴定FBS。然后,在生长的最后6小时期间将细胞完全血清饥饿。然后,将细胞加工以进行RNA提取或Western印迹。对于小鼠肺肿瘤细胞系中的HER4ECD研究,将LKPH细胞在血清饥饿条件中培养24小时,之后添加2mg/ml浓度的HER4ECD。然后,将LKPH细胞再温育48小时,之后加工以进行Western印迹。如下实施在H441细胞上添加外源NRG1:将H441细胞进行血清饥饿达18小时,之后添加1uM重组人NRG1β-1胞外域(R&Dsystems)或1uM抗豚草(ragweed)IgG2A作为对照。添加NRG1或豚草后10分钟,加工细胞以进行Western印迹。
RNA分离、cDNA制备和qPCR:使用Qiagen RNeasy微试剂盒来分离RNA。使用ABI高保真度试剂盒依照制造商的用法说明书自总RNA制备互补DNA。使用ABI基因特异性引物/探针通过定量实时PCR(ABI 7500)测定NRG1α、NRG1β、HER3、HER4表达。使用GAPDH或RAB14持家基因标准化基因表达。
体内异种移植物肿瘤研究:将肿瘤细胞(1000-2000万)移植入无胸腺裸鼠的右体侧中。在肿瘤大小达到约200mm3时,将小鼠分成不同处理组。然后,对于初始研究用媒介物或化学疗法(帕利他塞,i.v.+顺铂,i.p.)处理小鼠。化学疗法剂量给药方案是每隔一天的帕利他塞20mg/kg i.v.达5剂和第1天和第7天(对于Calu3模型)及第1天和第14天(对于H441模型)的顺铂5mg/kg i.p.。在最后一剂化疗后至少1周收集消退的肿瘤和时间匹配媒介物对照。使用分散酶/胶原酶分离肿瘤,并将样品进行FACS分选以收集GFP阳性肿瘤细胞。对于NRG1敲低研究,处理组是:蔗糖、多西环素(dox)、化学疗法+蔗糖、和化学疗法+多西环素。在与第一剂化学疗法相同的时间开始用蔗糖或多西环素的处理,并且继续进行,持续整个研究。对媒介物组任意提供5%蔗糖水,并且对多西环素组提供5%蔗糖中的1mg/ml多西环素。
异种移植物肿瘤生长分析:为了适当地分析随时间来自同一动物的肿瘤体积的重复测量,使用混合建模方法(Pinheiro等2009)。此方法可以解决重复测量和由于研究结束前非处理相关动物终止所致的适度退出率(drop out rate)两者。对每个处理组使用三次回归样条来将非线性概况(profille)拟合至log2肿瘤体积的时间过程。
体内LSL-K-rasG12D;p53Fl/+和LSL-K-rasG12D;p53Fl/Fl Her4ECD研究:用Adeno-Cre病毒感染LSL-K-rasG12D;p53Fl/+,并容许肿瘤诱导后成熟16周。在肿瘤诱导后16周(研究的第0天)实施基线CT扫描,并将小鼠分组,使得每组的平均起始肿瘤体积是相等的。用顺铂(7mg/kg)或磷酸盐缓冲盐水一周一次持续三周,及用HER4ECD-Fc(25mg/kg)或抗豚草IgG2A(25mg/kg)两周一次持续整个研究对小鼠给药。在第14天、第45天和第66天实施系列CT扫描。X射线微型计算机断层摄影术(micro-CT):利用两个micro-CT系统(vivaCT40和vivaCT75,Scanco Medical,Switzerland)进行纵向肺成像。将动物在micro-CT系统间随机化,并在用于基线成像的同一系统上再扫描。以38μm(vivaCT 40)或50μm(vivaCT 75)各向同性体元大小、1000次投影(projection)、250ms(vivaCT 40)或200ms(vivaCT 75)积分时间、45keV光子能、和177mA电流获得数据。对于体内成像的持续时间,将动物用医用空气中的2%异氟烷麻醉,并通过受调节的温暖气流维持于恒定的37°C温度。每次对话的成像时间是每只动物约15分钟(vivaCT 75)或25分钟(vivaCT 40),并且估计的放射剂量是约0.2Gy(vivaCT 75)或0.1Gy(vivaCT 40)。使用图像分析软件包Analyze(AnalyzeDirect,Inc.,Lenexa,KS,USA)在冠状平面中评估成像数据。一旦鉴定出每个肿瘤的最大截面平面,测定最大肿瘤直径(d1)和最大垂直直径(d2)的估计量。总肿瘤负荷以所有肿瘤的方向估计量的向量积(d1x d2)的总和计算。先前验证了体内micro-CT肿瘤分析,并且发现与通过离体micro-CT分析(Singh等,2010)测定的总肿瘤体积良好地相关联。
微阵列分析:在两轮T7扩增方案中使用的总RNA的量范围为每份样品10ng至50ng。使用Message Amp II aRNA扩增试剂盒(Applied Biosystems,Foster City,CA)完成第一轮扩增和第二轮cDNA合成。然后,使用Agilent的快速Amp标记试剂盒(AgilentTechnologies,Palo Alto,CA)经由IVT反应掺入Cye-5染料。将每份经Cy-5标记的测试样品与经Cy-3标记的通用人参照RNA(Agilent Technologies,Palo Alto,CA)合并,并杂交至Agilent的全人基因组4x44K阵列上,如制造商的方案中所描述的。将该阵列清洗、干燥并在Agilent的DNA微阵列扫描仪上扫描。使用Agilent的特征提取软件(Feature Extractionsoftware)9.5来分析获得的阵列图像,并获得背景扣除信号强度的个别log2比率。实施改良的Cybert-T检验(Baldi和Long,2001)来比较媒介物处理和化学疗法组间的表达概况。对多重检验校正(Storey和Tibshirani,2003)应用假发现率(q值)。
siRNA:HER3(M-003127-03)、HER1(M-003114-01)、HER2、HER4和非靶向对照(D-001206-14-20)的小干扰RNA寡聚物(siRNA)集合购自Dharmacon Lafayette,CO。通过逆转染将siRNA导入H522细胞中。在96孔微量滴定板中接种细胞/孔,所述96孔微量滴定板含有50mmol/L的合并的RNAi寡聚物和按照制造商的推荐在OPTI-MEM(Invitrogen)中稀释的DharmaFECT#(T-2001-02,Dharmacon)转染试剂的预温育混合物。转染后96小时,通过AlamarBlue染色测量对细胞增殖的影响。
Western印迹:对于体外细胞培养物的Western印迹,将粘附细胞用冰冷的1x磷酸盐缓冲盐水(PBS)清洗三次,并在RIPA缓冲液(Pierce Biotechnology)、Halt蛋白酶抑制剂、和Halt磷酸酶抑制剂混合物(Thermo Scientific)中裂解。将裂解物收集,均质化,并通过离心10分钟来澄清。在不进行PBS清洗的情况中制备原发性小鼠肿瘤裂解物,如上文所述的。将上清液蛋白质在4-12%NuPAGE Novex bis-tris凝胶(Invitrogen)中分级。使用iBlot干印迹系统(Invitrogen)依照制造商的说明书实施印迹。使用Odyssey Western印迹分析和红外成像系统(Li-Cor Biosciences)依照制造商的用法说明书实施硝酸纤维素膜封闭和抗体染色。在Odyssey扫描仪(Li-Cor Biosciences)上显现印迹。抗体:在Western印迹实验中使用下列一抗:抗肌动蛋白(612656,BD Biosciences)、抗GAPDH(sc-25778,SantaCruz Biotechnology)、抗EGF受体(2232,Cell Signaling Technology)、抗Neu(sc-284,Santa Cruz Biotechnology)、抗ErbB3(sc-285,Santa Cruz Biotechnology)、抗磷酸HER3(4791,Cell Signaling Technology)、抗ErbB4(sc-283,Santa Cruz Biotechnology)、抗磷酸HER4(4757,Cell Signaling Technology)、抗Akt(4691,Cell SignalingTechnology)、抗磷酸Akt(4058,Cell Signaling Technology)、Stat/磷酸Stat抗体取样器试剂盒(9939/9914,Cell Signaling Technology)、抗MEK 1/2(9126,Cell SignalingTechnology)、抗磷酸MEK 1/2(2338,Cell Signaling Technology)。使用来自Li-CorBiosciences的下列二抗:IRDye 680缀合的山羊抗小鼠IgG、IRDye 800CW缀合的山羊抗家兔IgG。
实施例2:用于研究残留疾病和复发的体内模型的优化
产生几种癌症模型,并用于研究负责肿瘤再启动的细胞,所述癌症模型显示了响应化学疗法的显著消退,接着是停止治疗后的肿瘤复发(图1)。这些细胞是肿瘤再启动细胞(TRIC)。为了产生模型,将经GFP标记的人肿瘤细胞皮下移植,并在肿瘤大小达到约200mm3时,用媒介物或化学疗法处理小鼠,如相应的模型中显示的。在酶消化和分离后通过FACS分选将GFP+肿瘤细胞自消退的或经媒介物处理的肿瘤分离。在最后一剂化学疗法后最少一周且在肿瘤生长恢复前收集肿瘤。
将人非小细胞肺癌(NSCLC)细胞系Calu3和H441的GFP表达亚系移植入无胸腺裸鼠中以生成异种移植物模型。对于Calu3模型,化学疗法由帕利他塞(20mg/kg,i.v.每隔一天达5剂)和顺铂(5mg/kg,i.p.每7天达2剂)组成。图2A(数据以均值肿瘤体积±SEM呈现,n=15/组)。对于H441模型,化学疗法由帕利他塞(20mg/kg,i.v.每隔一天达5剂)和顺铂(5mg/kg,i.p.每14天达2剂)组成。图2B(数据以均值肿瘤体积±SEM呈现,对于经媒介物处理的,n=9/组,而对于经化学疗法处理的,n=14/组)。
将人乳腺癌细胞系KPL4的GFP表达亚系正位移植至SCID/beiz小鼠的乳房脂肪垫。对于KPL4模型,化学疗法由帕利他塞(20mg/kg,i.v每隔一天达5剂)组成。图2C(数据以均值肿瘤体积±SEM呈现,n=12只小鼠/组)。
在完成化学疗法方案后,经化疗处理的小鼠的肿瘤显著小于经媒介物处理的小鼠。消退在最后一剂化学疗法后持续几周,但是随后肿瘤复发。图2A-C。
另外,将NSCLC的LSL-K-rasG12D遗传工程小鼠模型(Jackson等,2001)与Z/EG Cre报告株(Novak等,2000)杂交,并在本研究中使用。在肺的AdenoCre感染(即,肿瘤启动)后12周开始顺铂(7mg/kg i.p.每7天达3剂)。最后一剂化学疗法后1周收集肺,并在酶消化和分离后通过FACS分离肿瘤细胞。在最后一剂顺铂后一周对肺中存在的GFP阳性肿瘤细胞的FACS分析揭示与媒介物对照相比,经顺铂处理的小鼠中的肿瘤细胞数目的显著减少。图2D(数据以每个肺的GFP阳性细胞的平均数目±SEM呈现,n=6/组)。如此,LSL-K-rasG12D小鼠的顺铂处理导致肿瘤负荷的显著降低,但是其不导致延长的存活,指示肿瘤在治疗后复发(Oliver等,2010)。
虽然上文所描述的每种模型响应化学疗法,但是肿瘤在治疗后的不同时间复发,尽管有几乎完全的细胞减少。在肿瘤再生长发生前幸免于化学疗法的经GFP标记的细胞含有TRIC,并将其分离以进行进一步研究。
实施例3:TRIC中NRG1的富集
基于每种模型的预先测定的生长曲线,在最后一次处理后1-3周,但是在经化学疗法处理的肿瘤再生长发生前收集消退的或经媒介物处理的肿瘤。将肿瘤组织用酶消化并分离,并通过荧光激活细胞分选(FACS)分离GFP阳性肿瘤细胞。
为了表征经媒介物处理的和残留的肿瘤细胞的基因表达概况的差异,自肿瘤细胞(PI–和GFP+)分离RNA,并实施表达序型分析。对Calu3和H441模型两者的微阵列分析揭示与经媒介物处理的肿瘤细胞相比,NRG1表达在残留的经化疗处理的肿瘤细胞中显著更高(图3A-B)。使用两种独立的微阵列探针测定残留的经化疗处理的细胞中的富集。对于Calu3异种移植物模型,使用第一探针测量到8.6倍富集(p=0.003,q=0.003)(图3A,左侧微阵列小图),并使用第二探针测量到5.3倍富集(p=0.001,q=0.002(n=8/组))(图3A,右侧微阵列小图)。对于H441异种移植物模型,使用第一探针测定到4.9倍富集(p<0.001,q=0.009)((图3B,左侧微阵列小图)),并使用第二探针测定到2.8倍富集(p=0.001,q=0.013(n=8/组))((图3B,右侧微阵列小图))。
由于可变剪接,受体结合需要的NRG1 EGF样域有两种活性同等性,称为NRG1阿尔法(NRG1α)和NRG1贝塔(NRG1β)。我们通过定量实时PCR(qPCR)确认NRG1α和NRG1β的富集(图3A-B)。对于Calu3异种移植物模型,使用独立的肿瘤样品,NRG1α表达富集4.7倍(p=0.02)(图3A,左侧qPCR小图),而NRG1β富集3.4倍(p=0.04)(图3A,右侧qPCR小图)(n=6/组)。对于H441异种移植物模型,使用与微阵列分析相同的肿瘤样品,NRG1α富集11.4倍(图3B,左侧qPCR小图),而NRG1β富集12.1倍(图3B,右侧qPCR小图)。
NRG1mRNA在来自KPL4乳腺癌异种移植物模型的TRIC中富集。使用两种独立的微阵列探针测定富集(图3C)。
对于LSL-K-rasG12D模型,基于微阵列,NRG1表达在残留的经化疗处理的肿瘤细胞与经散装(bulk)媒介物处理的肿瘤细胞相比显著更高。使用微阵列分析测定13.7倍富集(p<0.001,q=1)(n=6/组)(图3D,微阵列小图)。通过qPCR对独立样品确认富集,显示9倍富集(p=0.04)(图3D,qPCR小图)。
NRG1是在所有3种模型Calu3、H441和LSL-K-rasG12D中在残留的经处理的细胞中显著富集的几种基因之一。令人感兴趣地,HER3和HER4受体表达在所有模型中都没有一致地富集。
通过在磷酸HER3方面免疫染色肿瘤评估NRG1受体HER3的激活。残留肿瘤中的大多数肿瘤细胞是p-HER3阳性,而经媒介物处理的肿瘤仅显示p-HER3阳性细胞的分散簇。在残留的肿瘤细胞中没有找到另一种HER3配体NRG2的表达。如此,残留的肿瘤细胞表达NRG1,而且显示增强的受体激活,表明升高的NRG1自分泌活性。
实施例4:NRG1表达的调节
残留的肿瘤细胞中观察到的升高的NRG1表达可以源自原发性肿瘤中存在的NRG1表达细胞亚群的富集。或者,化学疗法可以诱导细胞中的NRG1表达,然后,所述细胞对其细胞毒性效应有抗性,或者表达水平可以受到肿瘤大小或生长动力学影响。为了区别这些可能性,通过qPCR在不同体积的肿瘤中并在化学疗法后的多个时间评估NRG1表达水平(图4)。NRG1 mRNA水平在单剂化学疗法(顺铂+帕利他塞)后不增加。实际上,除了残留的肿瘤外,NRG1水平在测试的所有时间和体积是等同的。这些结果表明NRG1表达不受化学疗法诱导或者不受肿瘤大小影响,并且与先前存在的NRG1表达细胞亚群的富集一致。
实施例5:NSCLC中的自分泌NRG1-HER信号传导
为了鉴定共表达配体及其受体两者的模型,检查NRG1及其受体在亲本Calu3和H441细胞及一组别的人NSCLC细胞系中的表达。虽然NRG1α和NRG1β转录物的表达水平在细胞系间是异质的,但是在与正常肺相比时,它们在大多数细胞系中高得多。令人惊讶地,在H441细胞中,NRG1转录物仅在将细胞以肿瘤在体内培养时存在。培养的H441细胞不表达可检测的NRG1α或NRG1β转录物,这突出显示了体外和体内培养的细胞的特性的差异。对4种HER受体的Western分析揭示了6种人NSCLC系间的异质表达。相对于其它细胞系,Calu3具有所有4种受体的最高的体外表达水平。
为了评估NRG1自分泌信号传导的有可能的下游介导物,生成携带针对NRG1的多西环素诱导型shRNA(Gray等,2007)(shNRG1)和组成性表达的dsRED报告基因的Calu3、H441和H1299亲本细胞系的稳定亚系。NRG-1基因含有多个启动子,并且经历广泛的可变剪接,生成至少15种不同同等型。所有活性同等型都含有RTK激活必需且足够的EGF样域(Holmes等,1992;Yarden和Peles,1991)。将shNRG1靶向至共同的EGF样域以实现对所有可能的同等型的敲低。生成具有针对萤光素酶的多西环素诱导型shRNA(shLuc)的匹配稳定细胞系作为对照。在存在多西环素(dox)的情况中培养时,仅在Calu3-shNRG1细胞中存在有NRG1α和NRG1β转录物的有效的且特异的降低(约90%)。测量到在存在dox的情况中培养的经血清饥饿的Calu3-shNRG1细胞中的p-HER3、p-AKT水平的相关降低和p-HER4的略微降低。这些裂解物中p-Stat3或p-Mek1/2水平没有可检出的变化。
因为H441细胞在体外不表达任何NRG1转录物,所以通过用外源NRG1配体刺激评估这些细胞中NRG1信号传导的介导物。在用NRG1刺激经血清饥饿的细胞后,p-HER3和p-AKT有增加。p-Stat3或p-Mek1/2的水平没有可检出的变化。
还在鼠肺癌细胞中评估NRG1效应器途径。两种独立的细胞系自LSL-K-rasG12D;p53Fl/+肺肿瘤衍生,即LKPH1和LKPH2,并且统称为LKPH系(见实施例1)。生成携带dox诱导型shNrg1或shLuc的稳定亚系。仅在存在dox的情况中在LKPH shNrg1细胞系中看到降低的Nrg1转录物。此外,在存在的dox的情况中培养的经血清饥饿的LKPH-shNRG1细胞中存在着p-HER3和p-AKT水平的降低。缺乏Nrg1 mRNA的培养物中的p-Mek1/2和p-Stat3的水平变化通过Western印迹不可检出,提示了Nrg1不参与这些效应器途径。
总之,来自H441细胞的NRG1刺激和Calu3和LKPH1/2细胞中的NRG1敲低的数据提示PI3K途径是NSCLC细胞中的NRG1信号传导的主要下游效应物。人和小鼠NSCLC模型两者中的NRG1转录物和HER受体的表达升高和培养的肿瘤细胞中的HER3信号传导的活性降低(NRG1敲低后)提示NSCLC中存在有自分泌NRG1-HER3信号传导环。另外,其在残留肿瘤细胞中的表达升高(图3)提示了NRG1自分泌信号传导可以在化学抗性和/或疾病复发中发挥作用。
实施例6:NRG1敲低延迟化学疗法后的肿瘤复发
通过评估单独的或与化学疗法组合的NRG1敲低的效果测定NRG1敲低对原发性肿瘤生长和化学疗法后的复发的影响。在本研究中使用三种人NSCLC模型,其展现出HER家族受体的不同表达样式。Calu3模型具有所有受体的高蛋白质水平,H441显示HER2和HER3的强烈表达和中等的HER1,而H1299显示中等水平HER1、2和3。
为了测定NRG1靶向在Calu3模型中的效力,将携带Calu3-shNRG1肿瘤的小鼠归入4组;1)媒介物+蔗糖,2)媒介物+dox,3)化学疗法+蔗糖,和4)化学疗法+dox。使用与上文在实施例2中所描述相同的化学治疗方案,并在任意的饮用水中口服施用5%蔗糖或dox(2g/L)。研究期间一周两次测量肿瘤体积。对研究中使用的小鼠个体(对于媒介物+蔗糖,n=12只小鼠,而对于媒介物+dox,n=13只小鼠)生成肿瘤生长曲线,并以肿瘤体积的线性混合效应(LME)模型产生的拟合呈现,在图5A和5B中作为具有自动确定纽结的三次样条绘图。媒介物+dox组(倍增前时间(TDT)=44.5天)与媒介物+蔗糖(TDT=17天)相比有肿瘤体积倍增时间的显著延迟,提示NRG1敲低部分抑制肿瘤生长(图5A)。
通过比较化学疗法+蔗糖中的肿瘤生长与那些在化学疗法+dox组中的肿瘤生长评估NRG1对肿瘤复发的影响。在化学疗法+dox组(TDT大于181天,到研究结束没有达到)中与化学疗法+蔗糖(TDT=124天)相比在肿瘤复发上有显著延迟(图5B)。此外,在有和没有化学疗法的这两种情况中来自经dox处理的小鼠的许多复发性肿瘤主要由仅具有小的可见肿瘤组织区的呈褐色/黑色粘液样液体构成。因此,dox处理组中测量的体积比实际的肿瘤体积大得相当多。在Calu3-shLuc对照研究中的任何组间没有观察到差异。另外,在最后一剂化学疗法后3天对Calu3肿瘤在增殖标志物Ki67方面实施免疫组织化学(IHC)。与化学疗法+蔗糖肿瘤相比,在经化学疗法+dox处理的肿瘤中有显著更低的Ki67阳性细胞比例,提示了NRG1信号传导在化学疗法后的残留肿瘤细胞中刺激增殖。
测定早期和晚期时间点收集的肿瘤细胞中NRG1α和NRG1β同等型的mRNA水平。NRG1转录物在晚期时间点时增加,指示敲低在体内没有得到维持。
还检查H441异种移植物模型中NRG1敲低的效果。虽然对原发性肿瘤生长有最低限度的影响(图6A(n=12/组),肿瘤生长曲线以肿瘤体积的LME拟合分析呈现,作为具有自动确定纽结的三次样条绘图,在化学疗法+dox组(TDT大于150天,到研究结束没有达到)中与化学疗法+蔗糖(TDT=94天)相比肿瘤复发有显著延迟(图6B((n=12/组))。在H441-shLuc体内研究中肿瘤体积没有此类差异。与Calu3异种移植物模型相似,H441模型在晚期时间点时也展现出升高的NRG1转录物水平。
为了调查NRG1水平恢复后面的机制,对肿瘤细胞分析经慢病毒转导的基因的表达。因为用于转导具有shRNA的细胞的慢病毒还包括dsRed标志物基因,所以通过流式细胞术比较早期和晚期时间点时的dsRED阳性肿瘤细胞的比例。通过检查表达慢病毒dsRed转基因的肿瘤细胞(人特异性ESA阳性)的比例的FACS分析在早期(5天)和晚期时间点(大于100天)对肿瘤评估慢病毒基因表达的体内损失。早期时间点的小鼠接受蔗糖或dox,而晚期时间点的小鼠接受化疗+蔗糖或化疗+dox。观察到经蔗糖和dox处理的肿瘤两者在晚期时间点的dsRed阳性细胞比例的显著降低,降低对于经dox处理的肿瘤显著更大(1.8倍对4.1倍,p=0.007)。这提示了病毒转基因表达的损失与NRG1水平的恢复相关联。
Calu3和H441细胞两者都显示升高的HER3蛋白水平,提出如下的问题,即NRG1在肿瘤复发中的作用对于具有受体过表达的肿瘤是否是特异性的。为了解决此问题,使用具有低得多的HER3水平的H1299异种移植物模型。与H441模型相似,单独的对NRG1的敲低对原发性肿瘤生长仅具有适度的影响。比较而言且尽管H1299肿瘤有非常攻击性的生长,NRG1敲低导致所得的对化学疗法的响应增强和在化学疗法+dox组(TDT=30.45天)对化学疗法+蔗糖(TDT=11.5天)中肿瘤复发的显著延迟(n=12/组)(图7A,B)。
此外,生成表达针对NRG1的不同shRNA(shNRG1.2)的H1299的稳定亚系,其导致NRG1 mRNA水平的更适度(modest)的降低。用H1299-shNRG1.2进行的体内研究还表明在NRG1敲低后对化学疗法的响应增强。然而,生长抑制的幅度在此模型中较小,这与NRG1敲低的程度较轻一致。在H1299-shLuc体内研究中在有或没有化学疗法的情况中在蔗糖和dox处理组间在肿瘤体积上没有差异。
shRNA介导的敲低对NRG1自分泌信号传导的抑制对原发性肿瘤生长仅具有适度至中等的影响,但是显著延迟化学疗法后的肿瘤复发。尽管不能在异种移植物模型中维持对NRG1的长期敲低,我们观察到NRG1敲低后肿瘤复发的显著延迟。这些发现提示了调节原发性肿瘤生长,与化学抗性和复发的关键途径上有差异。
实施例7:使用配体陷阱对NRG1信号传导的抑制延迟肿瘤复发
为了测试NRG1信号传导在LSL-K-rasG12D;p53Fl/+小鼠模型中在促进化学疗法后的复发中的作用,采用在体内隔离NRG1并阻止其结合受体的配体陷阱方法。生成与鼠IgG2AFc融合的人HER4胞外域(HER4-ECD)的融合物。HER4显示对NRG1的高亲和力结合(Tzahar等,1994)。在体外对经血清饥饿的LKPH1和LKPH2细胞添加HER4-ECD时,观察到对NRG1/HER3信号传导的抑制,如通过降低的p-HER3水平表明的。如此,分子在体外如预期的在干扰自分泌介导的NRG1信号传导中运行。
在研究开始时(第0天)通过X射线微型计算机断层摄影术(micro-CT)对携带肺肿瘤的LSL-K-rasG12D;p53Fl/+小鼠成像,将其分成相等起始肿瘤负荷的三组,并如下处理:1)PBS+对照IgG2A;2)顺铂+对照IgG2A;和3)顺铂+HER4-ECD。小鼠经历纵向micro-CT扫描以测量肿瘤负荷的变化。平均肿瘤负荷(图8A(图代表平均肿瘤体积+/-SEM,豚草,对照鼠IgG2a抗体))和肿瘤生长率((图8B(图显示了通过处理方案得到的肿瘤负荷的每日倍数变化及95%置信区间))的分析揭示了仅顺铂+HER4-ECD的组合,而不是单独的顺铂导致对肿瘤生长的显著抑制。虽然经顺铂处理的小鼠显示化学疗法后的第一次micro-CT扫描时其肿瘤生长的停滞,但是在研究结束时平均肿瘤负荷和总体肿瘤生长率在媒介物和顺铂处理组间是没有显著差异(图8A-B)。
在LSL-K-rasG12D;p53Fl/Fl小鼠中实施第二项研究,如上文所描述的。然而,在上文所描述的组外,本研究包括HER4-ECD单一药剂臂。在第28天通过micro-CT对肿瘤负荷的分析揭示了与经顺铂+媒介物处理的小鼠和所有其它组相比,经顺铂+HER4-ECD处理的小鼠中肿瘤负荷显著降低(图8C)。比较而言,单独的HER4-ECD处理对肿瘤生长没有影响,进一步支持了NRG1自分泌信号传导在化学抗性和/或肿瘤再生长中的独特作用。在此研究中,用媒介物+对照IgG(n=10)、顺铂+对照IgG(n=11)、顺铂+HER4-ECD(n=8)或媒介物+HER4-ECD(n=7)处理LSL-K-rasG12D;p53Fl/Fl小鼠。图8C中的图代表自基线的肿瘤负荷的平均百分比变化±SEM。利用Dunnett氏多重比较检验来针对媒介物对照比较所有处理组。**p=0.0016。使用未配对的t检验针对其单一疗法评估组合活性。*p<0.05,**p<0.01。
实施例8:NSCLC中的NRG1受体用法
为了了解在NSCLC中的NRG1自分泌信号传导中采用哪些HER受体,我们评估HER3和HER4敲低对肿瘤细胞增殖的影响。与其它细胞系相比,Calu3NSCLC模型表达高水平的所有HER家族受体。生成稳定的dox诱导型shHER3(Calu3-shHER3)和shHER4(Calu3-shHER4)Calu3细胞亚系,及携带针对萤光素酶的dox诱导型shRNA的对照细胞系。HER3和HER4转录物水平在存在dox(2ug/ml)的情况中在Calu3-shHER3和Calu3-shHER4中分别是降低的,如通过qPCR测量的,导致降低的蛋白质水平,如通过Western印迹测量的。令人感兴趣地,在存在dox的情况中在Calu3-shHER3中观察到的p-AKT下调程度比在Calu3-shHER4中看到的大得多,提示了HER3是介导Calu3模型中的NRG1自分泌信号传导的主要受体。
为了在体内确认此作用,使用用蔗糖或dox处理的Calu3-shHER3和Calu3-shHER4异种移植物模型实施研究。给具有建立的Calu3-shHER3或Calu3-shHer4异种移植物肿瘤的小鼠施用在其任意的饮用水中的媒介物(蔗糖)或dox(2gm/L)(n=14/组)。与接收蔗糖处理的那些小鼠(TDT=11天)相比,接收dox处理的小鼠中有对Calu3-shHER3肿瘤生长的实质性抑制(TDT=19天)。然而,在Calu3-shHER4体内研究中没有对肿瘤生长的显著抑制。
体外受体分析和体内研究指示尽管有高的HER4水平,NRG1自分泌信号传导在此模型中主要经由HER3发生。
在H522人NSCLC细胞系中评估NRG1自分泌信号传导,H522人NSCLC细胞系表达高水平的HER4,而没有可检出的HER3。生成H522-shNRG1亚系。对经血清饥饿的H522-shNRG1细胞施用dox导致降低的磷酸HER4和磷酸S6水平。在H522-shLuc对照细胞中没有观察到差异。使用siRNA介导的敲低来测试细胞增殖中对每种HER家族成员的需要。仅对HER4而非其它HER家族受体的敲低导致降低的细胞增殖。这些数据提示了NRG1自分泌信号传导在H522细胞中经由HER4发生。如此,NSCLC中的NRG1自分泌信号传导可以由HER3和HER4两者介导。
虽然出于清楚理解的目的,前述发明已经作为例示和例子相当详细地进行了描述,但是说明书和实施例不应解释为限制本发明的范围。通过提及而明确将本文中引用的所有专利和科学文献的公开内容完整收录。
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Claims (3)
1.神经调节蛋白1(NRG1)拮抗剂和化学治疗剂在制备用于延长癌症患者中的肿瘤复发前时间的药物中的用途,所述延长包括对所述患者施用有效量的神经调节蛋白1拮抗剂和化学治疗剂,其中所述化学治疗剂是帕利他塞和/或顺铂,且其中所述神经调节蛋白1拮抗剂是结合NRG1的抗NRG1抗体、RNA或NRG1受体分子,其中所述癌症选自下组:非小细胞肺癌和乳腺癌。
2.权利要求1的用途,其中所述受体分子是免疫粘附素。
3.权利要求1的用途,其中所述RNA是反义RNA、iRNA、siRNA、shRNA或RNA适体。
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WO2011103242A1 (en) | 2011-08-25 |
US20110229493A1 (en) | 2011-09-22 |
JP2013520431A (ja) | 2013-06-06 |
AU2011218125A1 (en) | 2012-07-19 |
CA2784211C (en) | 2019-12-24 |
HK1179997A1 (zh) | 2013-10-11 |
RU2587619C2 (ru) | 2016-06-20 |
SG183333A1 (en) | 2012-09-27 |
DK2536748T3 (da) | 2014-10-13 |
MY160556A (en) | 2017-03-15 |
KR20130000384A (ko) | 2013-01-02 |
PL2536748T3 (pl) | 2015-01-30 |
MX2012008958A (es) | 2012-08-23 |
SI2536748T1 (sl) | 2014-12-31 |
CN102892779A (zh) | 2013-01-23 |
AU2016201848A1 (en) | 2016-04-21 |
EP2536748A1 (en) | 2012-12-26 |
EP2536748B1 (en) | 2014-08-20 |
BR112012017405A2 (pt) | 2018-08-14 |
ZA201204423B (en) | 2015-03-25 |
CA2784211A1 (en) | 2011-08-25 |
ES2519348T3 (es) | 2014-11-06 |
US9556249B2 (en) | 2017-01-31 |
JP5981853B2 (ja) | 2016-08-31 |
RU2012139825A (ru) | 2014-03-27 |
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