CN113271948A - 治疗癌症的联合疗法 - Google Patents
治疗癌症的联合疗法 Download PDFInfo
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- CN113271948A CN113271948A CN201980087140.8A CN201980087140A CN113271948A CN 113271948 A CN113271948 A CN 113271948A CN 201980087140 A CN201980087140 A CN 201980087140A CN 113271948 A CN113271948 A CN 113271948A
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Abstract
本公开提供了通过施用第三代酪氨酸激酶抑制剂例如波齐替尼与HER2抗体‑药物缀合物的组合来治疗确定具有HER2突变例如插入突变的患者的癌症的方法。
Description
本申请要求于2018年12月21日提交的美国临时申请号62/784,084的权益,其全部内容通过引用并入本文。
背景
1.领域
本发明总体上涉及分子生物学和医学领域。更具体地,本发明涉及用联合疗法治疗癌症患者的方法。
2.相关技术的描述
人类表皮生长因子受体2(HER2)的扩增发生在许多癌症类型中,且已证明与单独的化疗相比,靶向药剂,如曲妥珠单抗、帕妥珠单抗、曲妥珠单抗美坦新缀合物(T-DM1)、拉帕替尼和来那替尼可以改善临床结果。迄今为止,FDA批准了几种HER2靶向剂用于治疗乳腺癌和胃癌中的HER2扩增疾病。已经在许多癌症类型中报道了HER2的激活突变;然而,目前还没有被FDA批准的用于携带HER2突变的癌症的靶向疗法。
针对HER2突变癌症的靶向药剂的最新临床研究集中在第二代共价酪氨酸激酶抑制剂(TKI),例如阿法替尼、来那替尼、达可替尼。SUMMIT泛癌(pan-cancer)研究报道了,接受来那替尼的患者对所有HER2突变的客观响应率(objective response rate,ORR)都低于15%(Hyman et al.,2018)。但是,在多项研究中,当按癌症类型对患者进行分级时,乳腺癌患者对来那替尼的ORR为12.5%-32%;而肺癌患者对作为单一药剂的来那替尼的响应率为0%-4%(Mazieres et al.,2015),这表明HER2抑制疗效的癌症特异性差异。有趣的是,在单一癌症类型中,HER2靶向药剂似乎会引起变异特异性差异。在SUMMIT试验中,具有HER2激酶结构域点突变患者的ORR为21.4%,而具有外显子20插入的患者对来那替尼的ORR为7.1%。此外,达可替尼对HER2突变性NSCLC的ORR为11.5%,但在携带HER2外显子20插入突变即Y772dupYVMA的患者中没有发生响应(Kris et al.,2015);且在阿法替尼的两项独立研究中,具有外显子20插入突变的NSCLC患者对阿法替尼的响应率为18.2%和18.8%。
对HER2单克隆抗体和药物-抗体缀合物的研究揭示了类似的结果。泛癌研究MyPathway测试了抗HER2单克隆抗体曲妥珠单抗与帕妥珠单抗的组合在35种不同肿瘤类型中的疗效,并报告了对所有HER2突变和癌症类型的ORR都为11%(Hainsworth et al.,2018)。在这项研究中,在所包括的35种肿瘤类型中,只有21%的NSCLC患者和1名胆道癌患者有响应。此外,在测试T-DM1疗效的泛HER2突变性NSCLC研究中,携带外显子20插入突变的患者的ORR为54.5%,但携带外显子19突变的患者没有部分响应(Li et al.,2018)。患者结果中这些癌症特异性和变异特异性差异表明,对不同癌症类型的HER2突变情况的详细和系统的理解以及鉴定针对已鉴别的各种HER2突变的有效疗法的需要未得到满足。
对HER2激活性突变的临床前研究也报告了对各种TKI的不同敏感性。对HER2细胞外结构域内的突变的研究表明,这些突变与对非共价抑制剂例如拉帕替尼的耐药性有关,但对包括来那替尼、阿法替尼和奥希替尼在内的共价TKI仍然具有稳健的敏感性(Greulichet al.,2012),同时外显子19内的突变对拉帕替尼和共价抑制剂表现出不同的敏感性。此外,研究表明,HER2外显子20突变对非共价和共价TKI诸如奥希替尼、纳扎替尼、诺司替尼和奥莫替尼具有广泛的耐药性(Bose et al.,2013)。
有趣的是,共价的基于氨基喹唑啉的TKI,即来那替尼、阿法替尼和达可替尼,对不同HER2外显子20突变诱导了差异化响应(Kosaka et al.,2017);然而,只有罕见的HER2突变表现出对临床相关浓度的这些TKI的敏感性。最近,据报道,波齐替尼(poziotinib)在患者可达到的浓度下有效抑制HER2外显子20插入突变;且波齐替尼治疗在一名携带HER2外显子20突变的患者中诱导了放射学响应(Robichaux et al.,2018)。然而,尚未鉴定到一种单一的HER2 TKI可靶向HER2突变性癌症的最常见变异。
发明概述
本公开的实施方案提供了用于治疗患者中的癌症的方法和组合物,该组合物包含酪氨酸激酶抑制剂(TKI)与HER2抗体的组合。在一个实施方案中,本公开提供了治疗癌症的方法,包括向受试者施用有效量的酪氨酸激酶抑制剂(TKI)和HER抗体-药物缀合物。在一些方面,癌症是肺癌。例如,肺癌是非小细胞肺癌(NSCLC)。在某些方面,受试者是人。
在一些方面,HER2抗体是曲妥珠单抗。在具体方面,HER2抗体-药物缀合物是曲妥珠单抗美坦新(T-DM1)。
在某些方面,TKI是基于氨基喹唑啉的TKI,例如波齐替尼、阿法替尼、来那替尼、达可替尼或他索替尼(tarloxotinib)。在具体方面,基于氨基喹唑啉的TKI是波齐替尼。在具体方面,以低剂量,例如1-16mg,例如小于16mg,特别是小于10mg,例如2mg、3mg、4mg、5mg、6mg、7mg、8mg或9mg施用波齐替尼。
在具体方面,向受试者施用波齐替尼和T-DM1。在具体方面,向受试者施用单剂量的T-DM1。
在一些方面,癌症是HER2突变性癌症。例如,HER2突变体在酪氨酸激酶结构域内包括跨外显子19-21的HER2激活突变。在某些方面,HER2突变性癌症包含一种或多种选自由以下组成的组的突变:L755S、L755P、D769H、D769Y、V773M、V777L、Y772dupYVMA、G776delinsVC、G776delinsVV、G776delinsLC、G778insLPS、P780insGSP、L786V、V842I和L869R。在某些方面,HER2突变性癌症具有外显子19、外显子20和/或外显子21的突变。在一些方面,HER2突变性癌症具有外显子20的突变,例如HER2的氨基酸E770-R786之间的1-18个核苷酸的一个或多个点突变、插入和/或缺失。在具体方面,外显子20突变位于残基V773、A775、G776、V777、G778、S779和/或P780处。在具体方面,外显子20突变是外显子20插入突变,例如Y772dupYVMA、G778dupGSP和/或G776delinsVC。在一些方面,外显子19突变位于残基L755或D769处,例如L755P。在具体方面,外显子20突变是点突变,例如位于残基C805处,例如C805S。在某些方面,外显子21突变是点突变。在一些方面,点突变位于残基V842或L869处,例如V842I或L869R。
在一些方面,波齐替尼被口服施用。在某些方面,波齐替尼以5-25mg的剂量,例如8mg、12mg或16mg的剂量施用。在某些方面,波齐替尼进一步限定为波齐替尼盐酸盐。可以将波齐替尼盐酸盐配制成片剂。
在一些方面,在HER2抗体-药物缀合物之前或之后,例如间隔1天、2天、3天、4天、5天、6天、7天、2周、3周、1个月或更久施用TKI。TKI与HER2抗体-药物缀合物被同时施用。
在某些方面,通过静脉内、皮下、骨内、口服、透皮、持续释放、控制释放、延迟释放、作为栓剂或舌下施用波齐替尼和/或T-DMl。
在另外的方面,该方法还包括施用其他抗癌疗法。在一些方面,其他抗癌疗法是化疗、放疗、基因疗法、手术、激素疗法、抗血管生成疗法或免疫疗法。
药物组合物包含TKI和HER抗体-药物缀合物。在具体方面,TKI是波齐替尼,而HER抗体-药物缀合物是T-DM1。
预测患有癌症的受试者对TKI与HER2抗体-药物缀合物的组合的响应的方法包括,检测从所述受试者获得的基因组样品中的HER2突变,其中如果样品对HER2的存在呈阳性,则预该测患者对波齐替尼与HER2抗体-药物缀合物的联合抗癌疗法具有有利响应。
HER2突变可包括激活酪氨酸激酶结构域内跨越外显子19-21的HER2激活突变。在某些方面,HER2突变性癌症包含一种或多种选自以下的突变:L755S、L755P、D769H、D769Y、V773M、V777L、Y772dupYVMA、G776delinsVC、G776delinsVV、G776delinsLC、G778insLPS、P780insGSP、L786V、V842I和L869R。在某些方面,HER2突变性癌症具有外显子19、外显子20和/或外显子21的突变。在一些方面,HER2突变性癌症具有外显子20突变,例如HER2的氨基酸E770-R786之间的1-18个核苷酸的一个或多个点突变、插入和/或缺失。在具体方面,外显子20突变位于残基V773、A775、G776、V777、G778、S779和/或P780处。在具体方面,外显子20突变是外显子20插入突变,例如Y772dupYVMA、G778dupGSP和/或G776delinsVC。在一些方面,外显子19突变位于残基L755或D769处,例如L755P。在具体方面,外显子20突变是点突变,例如位于残基C805处,例如C805S。在某些方面,外显子21突变是点突变。在一些方面,点突变位于残基V842或L869处,例如V842I或L869R。
在某些方面,基因组样品分离自唾液、血液、尿液、正常组织或肿瘤组织。在一些方面,通过核酸测序或PCR分析确定HER2突变的存在。在一些方面,对TKI与HER抗体-药物缀合物的组合的有利响应包括减小肿瘤尺寸或负荷、阻断肿瘤生长、减少肿瘤相关疼痛减少、减少癌症相关病理、减少癌症相关症状、癌症无进展、无病间隔期增加、进展耗时增加、诱导缓解、减少转移或增加患者生存期。
在一些方面,TKI是波齐替尼,并且HER抗体-药物缀合物是T-DM1。在一些方面,该方法还包括将波齐替尼与T-DM1的组合施用于被预测具有有利响应的所述受试者。
根据以下详细描述,本发明的其他目的、特征和优点会变得明显。然而,应当理解,详细说明和具体实施例虽然指出了本发明的优选实施方案,但仅以示例的方式给出,因为根据该详细描述,本发明精神和范围内的各种变化和修改对于本领域技术人员而言会变得明显。
附图简述
下列附图构成本说明书的一部分,并被包括以进一步阐述本发明的某些方面。通过参考这些附图中的一幅或多幅并结合本文呈现的具体实施方案的详细描述,可以更好地理解本发明。
图1:HER2突变发生在多种癌症类型中,其中突变热点遍布该受体发生。cBioportal和MD Anderson数据库中报告的HER2突变位置频率饼图(N=2338)。
图2A-2D:HER2突变热点因癌症类型而异。(A)cBioPortal和MD Anderson报告的所有癌症中11种最常见HER2突变的棒棒糖图(N=2338个HER2突变)。柱的长度与突变频率有关。(B-D)在cBioPortal和MD Anderson数据库中,NSCLC(B,N=177)、乳腺癌(C,N=143)和结直肠癌(D,N=219)中最常见的(>3%)HER2突变的棒棒糖图;柱的长度与报告的突变频率有关。
图3A-3C:酪氨酸激酶结构域中最常见的HER2变异是激活突变。表达HER2外显子19突变(A)、HER2外显子20突变(B)和HER2外显子21突变(C)的稳定Ba/F3细胞系在无IL-3条件下生长14天的细胞活力。通过Cell Titer Glo测定每三天测定细胞活力。绘制每个细胞系的平均值±SEM(n=3个生物学独立实验)。
图4A-4F:波齐替尼是对在Ba/F3细胞中测试的HER2突变的最有效抑制剂。(A)针对稳定表达所示突变的Ba/F3细胞在药物处理72小时后,在GraphPad中计算的药物log IC50值的热图。通过Cell Titer Glo测定(N≥3)测定细胞活力。表达HER2突变的所有Ba/F3细胞系(B)、表达HER2外显子19突变的细胞系(C)、表达HER2外显子20突变的细胞系(D)或表达HER2外显子21突变的细胞系(E)用药物来那替尼、他索替尼-TKI和波齐替尼处理72小时后的平均IC50值。柱表示平均值±SEM(N≥3)。(C-E)使用单因素ANOVA与Dunn多重比较检验来确定组间的统计学显著性。(F)表达L755S或L755P的Ba/F3细胞用所示抑制剂的平均IC50值。点表示平均值±SEM(N≥3)。通过配对t检验确定统计学显著性。
图5A-5D:HER2突变体的分子动力学模拟揭示了Y772dupYVMA和L755P突变的药物敏感性降低的可能机制。(A)在150ns加速分子动力学模拟过程中,HER2 V777L和Y772dupYVMA外显子20突变体的α-C-螺旋位置。(B)所述HER2外显子20突变体呈α-C-螺旋“内(in)”与“外(out)”构象的分子动力学快照的群体百分比。(C)V777L突变体(白色主链,浅绿色P-环)和Y772dupYVMA突变体(灰色主链,深绿色P-环)的分子动力学快照。P-环和激酶铰链构象存在细微差异,但α-C-螺旋位置有显著改变(蓝色V777L为“外”位置,紫色Y772dupYVMA为“内”位置)。(D)L755P HER2突变体(白色主链、浅绿色P-环、黄色铰链、蓝色α-C-螺旋)和L755S HER2突变体(灰色主链、深绿色P-环、橙色铰链、紫色α-C-螺旋)的分子动力学快照。L755P突变体缺乏与V790的主链氢键,导致激酶铰链不稳定和P-环向结合位点收缩。
图6A-6F:表达HER2突变的人类细胞系也对波齐替尼最敏感。表达外显子20插入突变,HER2 G776delinsVC(A)、HER2 Y772dupYVMA(B)、HER2 G778dupGSP(C)的MCF10A细胞被所示抑制剂处理72小时的剂量响应曲线。(D)MCF10A HER2选择性指数的柱状图。对于每种所示药物,对突变细胞系的IC50值除以表达HER2 WT的细胞系的平均IC50值。点表示每个细胞系的平均值±SEM,柱表示所有三个细胞系的平均值±最小值/最大值(对于每个细胞系,N≥3)。(E)携带HER2外显子19突变L755S的CW-2大肠细胞被所示抑制剂处理72小时的剂量响应曲线。(A-C,E)曲线表示平均值±SEM,N=3。(F)第21天CW-2肿瘤体积的柱状图。用媒介物对照(N=5)、30mg/kg来那替尼(N=5)、20mg/kg阿法替尼(N=5)或5mg/kg波齐替尼(N=5)治疗小鼠(5天/周),随机选择350mm3的肿瘤,如虚线表示。这些点表示单个肿瘤,柱表示平均值±SEM。通过单因素ANOVA确定统计学显著性。
图7A-7D:具有HER2突变的NSCLC患者对波齐替尼具有已证实的42%响应率。(A)临床试验NCT03066206中前12名HER2外显子20患者的响应的瀑布图。显示了患者7、8、10、11和12(5)的客观部分响应,并显示了患者9(1)的未经证实的响应,显示了患者3-6(5)的稳态病情,以及患者1(1)的疾病进展。(B)前12名HER2外显子20患者的无进展生存期的Kaplan-meier图表明,截至到2018年11月,mPFS为5.6个月。(C)具有HER2 Y772dupYVMA突变的患者在波齐替尼治疗前1天和治疗后8周的CT扫描图。(D)具有HER2 L755P突变性NSCLC的患者在波齐替尼治疗前1天和治疗4周后的PET扫描图。患者之前曾接受过铂基化疗与曲妥珠单抗、纳武单抗和抗TDM1的组合的治疗并历经这些组合治疗而发生进展,但使用波齐替尼治疗后目标病灶减少了-12%。患者保持病情稳定>7个月。
图8A-8G:波齐替尼治疗诱导HER2在细胞表面积累,波齐替尼与T-DM1治疗的组合增强了抗肿瘤活性。(A)10nM波齐替尼治疗24小时后,表达HER2 Y772dupYVMA、HER2G778dupGSP和HER2 G776delinsVC的MC10A细胞系上的HER2受体表达的FACS分析。柱表示平均值±SEM,通过学生t检验确定DMSO和波齐替尼治疗组之间的显著性差异。(B)用波齐替尼、T-DM1或波齐替尼和所示剂量的T-DM1处理表达HER2Y772dupYVMA、HER2 G778dupGSP和HER2 G776delinsVC的MCF10A细胞系的IC50值条形图。柱表示平均值±SEM(n=3个独立实验),显著性差异通过单因素ANOVA和Dunn事后多重比较确定。(C)用所示抑制剂处理的HER2Y772dupYVMA NSCLC PDX的肿瘤生长曲线。每周5天施用波齐替尼治疗,而T-DM1在治疗开始时施用一次。(D)无进展生存期(PFS)的Kaplan-Meier曲线,其中PFS定义为从最佳响应开始肿瘤倍增的时间。使用Mantel-Cox对数秩检验确定组间的显著性差异。在安乐死时对小鼠进行检查。(E)用所示抑制剂治疗的小鼠在第14天的肿瘤体积百分比变化的点图。(F)第14天和第30天每组中荷瘤小鼠数量的图表。(G)用所示抑制剂治疗的HER2 Y772dupYVMA小鼠肿瘤体积的蜘蛛图。
图9:外显子20插入突变多样性因癌症类型而异。所有癌症(A)、肺癌(B)、乳腺癌(C)和其他癌症(D)中HER2外显子20插入突变频率的饼图。
图10A-10B:常见的HER2突变是组成性磷酸化的,而p-HER2表达与药物敏感性无关。(A)采用ELISA确定的p-HER2与总HER2的比率来确定相对p-HER2表达。柱表示平均值±SEM,并且n=3。ND=低于检测限。(B)绘制Ba/F3 HER2突变细胞系的波齐替尼IC50值与相对HER2表达的相关性。皮尔逊相关性和p值通过GraphPad Prism确定(n=3)。
图11A-11B:分子建模揭示,HER2突变体的结合口袋尺寸不同。(A)HER2激酶结构域的外显子19、20和21蛋白主链分别为蓝色、粉红色和橙色。来自模板X射线结构(PDB 3PP0)的配体以绿色棒(stick)呈现,并为突变的残基/插入位置提供了标记。(B)取自加速分子动力学模拟的HER2突变体结合口袋体积特征。结合最高的是HER2 V777L和HER2L869RFIGS。
图12:波齐替尼抑制HER2突变细胞系中的p-HER2。在所示药物和剂量处理2小时后表达G776delinsVC的MCF10A细胞的蛋白质印迹。
图13:波齐替尼抑制外显子19突变性结直肠癌的异种移植物的肿瘤生长。将携带HER2 L755S突变的CW-2细胞注射到6周龄雌性nu/nu裸鼠的侧腹。当肿瘤达到350mm3时,将小鼠随机分为4组:20mg/kg阿法替尼、5mg/kg波齐替尼、30mg/kg来那替尼或媒介物对照。每周测量肿瘤体积3次,且小鼠周一至周五(每周5天)接受药物。符号表示每个时间点的平均值±SEM。使用双因素ANOVA和Tukey多重比较检验来确定统计学显著性。星号表示媒介物和波齐替尼(红色)或来那替尼(灰色)之间的显著性。下方列出了第一次检测到显著性差异的第10天开始,每次比较的P值。
例证性实施方案的描述
在本研究中,确定了各种恶性肿瘤中HER2突变的最常见基因组变异的频率。系统地证明了16种最常见的HER2突变的激活潜力,并遍及11种常用的EGFR和HER2 TKI中评估了它们的药物敏感性。发现外显子20插入突变和外显子19中的L755P(但不是L755S)突变是许多测试的TKI难治的。耐药性HER2变异,L755P和外显子20插入的分子动力学建模表明,这些突变影响受体的构象状态,减小药物结合口袋的整体尺寸。此外,波齐替尼被确定为所评估的所有HER2突变的有效抑制剂;并且,波齐替尼在携带最具抗性的HER2变异,外显子20插入和L755P的NSCLC患者中具有临床活性。最后,已经表明,波齐替尼介导的细胞表面受体积累增强了T-DM1活性,T-DM1活性可用以增加体内抗肿瘤活性,从而在HER2突变性NSCLC的PDX模型中导致肿瘤完全消退。
因此,在某些实施方案中,本公开提供了包含TKI和HER2抗体缀合物(例如波齐替尼和T-DM1)的联合疗法用于治疗癌症,例如HER2突变性癌症,包括NSCLC。
I.定义
如本文在说明书中所用,“一个/种(a)”或“一个/种(an)”可表示一个/种或多个/种。如本文在权利要求中所用,词语“一/种(a)”或“一个/种(an)”当与词语“包含/括(comprising)”结合使用时,可意指一个/种或多个/种。
权利要求书中使用术语“或”用来指“和/或”,除非明确指明其仅指替代方案或替代方案是相互排斥的,但是本说明书支持仅指替代方案和“和/或”的定义。本文所用“另一个/种(another)”可意指至少第二个/种或更多个/种。
术语“约”通常是指所述值±5%。
“治疗(treatment)”或“治疗(treating)”包括(1)抑制正在经历或表现出一种疾病的病理或症状的受试者或患者中的该疾病(例如,阻止病理和/或症状的进一步发展),(2)改善在正在经历或表现出一种疾病病理或症状的受试者或患者中的该疾病(例如,逆转病理和/或症状),和/或(3)在正在经历或表现出一种的疾病病理或症状的受试者或患者中实现该疾病的任何可测量的减轻。例如,治疗可包括施用有效量的波齐替尼。
“预防性治疗”包括:(1)降低或减小可能处于患一种疾病的风险和/或易患该疾病但尚未经历或表现出该疾病的任一种或所有病理或症状的受试者或患者发生该疾病的风险,(2)减慢可能处于患一种疾病的风险和/或易患该疾病但尚未经历或表现出该疾病的任一种或所有病理或症状的受试者或患者中该疾病病理或症状的发作。
如本文所用,术语“患者”或“受试者”是指活的哺乳动物生物体,例如人、猴、牛、绵羊、山羊、狗、猫、小鼠、大鼠、豚鼠或其转基因物种。在某些实施方案中,患者或受试者是灵长类动物。人类患者的非限制性实例是成人、青少年、婴儿和胎儿。
在说明书和/或权利要求中使用的术语“有效”意指足以实现期望的、预期的或想要的结果。“有效量”、“治疗有效量”或“药学有效量”,当在用化合物治疗患者或受试者的上下文中使用时是指,当向受试者或患者施用以治疗或预防疾病时该化合物的足以实现该疾病的这种治疗或预防的量。
本文所用术语“IC50”是指获得最大响应的50%的抑制性剂量。这种定量测量指示需要多少特定药物或其他物质(抑制剂)才能抑制给定的生物、生化或化学过程(或过程的组分,即酶、细胞、细胞受体或微生物)的一半。
“抗癌”剂能够对受试者的癌细胞/肿瘤产生负面影响,例如,通过促进癌细胞杀伤,诱导癌细胞凋亡,降低癌细胞的生长速率,降低发病率或转移灶的数量,减小肿瘤尺寸,抑制肿瘤生长,减少对肿瘤或癌细胞的血液供应,促进针对癌细胞或肿瘤的免疫应答,预防或抑制癌症的进展,或增加患有癌症的受试者的寿命。
术语“插入”或“插入突变”是指将一个或多个核苷酸碱基对添加到DNA序列中。在一个实例中,HER2外显子20插入突变包括氨基酸770-785之间的3-18个核苷酸的一个或多个插入。
本文通常使用的“药学上可接受的”是指,在合理医学判断范围内适合用于与人类和动物的组织、器官和/或体液接触,而没有过多毒性、刺激、过敏反应或与合理的收益/风险比相称的其他问题或并发症的化合物、材料、组合物和/或剂型。
“药学上可接受的盐”是指本发明化合物的盐,如上所定义的,其为药学上可接受的,并且具有所需的药理学活性。此类盐的非限制性实例包括与无机酸或与有机酸形成的酸加成盐,无机酸例如盐酸、氢溴酸、硫酸、硝酸和磷酸,有机酸例如1,2-乙二磺酸、2-羟基乙磺酸、2-萘磺酸、3-苯基丙酸、4,4'-亚甲基双(3-羟基-2-烯-1-羧酸)、4甲基双环[2.2.2]辛-2-烯-1-羧酸、乙酸、脂肪族一元和二元羧酸、脂肪族硫酸、芳族硫酸、苯磺酸、苯甲酸、樟脑磺酸、碳酸、肉桂酸、柠檬酸、环戊烷丙酸、乙磺酸、富马酸、葡糖庚酸、葡糖酸、谷氨酸、乙醇酸、庚酸、己酸、羟基萘甲酸、乳酸、月桂基硫酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘康酸、邻(4-羟基苯甲酰基)苯甲酸、草酸、对氯苯磺酸、苯基取代的链烷酸、丙酸、对甲苯磺酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、酒石酸、叔丁基乙酸和三甲基乙酸。药学上可接受的盐还包括,当存在的酸性质子能够与无机碱或有机碱反应时可以形成的碱加成盐。可接受的无机碱包括氢氧化钠、碳酸钠、氢氧化钾、氢氧化铝和氢氧化钙。可接受的有机碱的非限制性实例包括乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇和N-甲基葡糖胺。应当认识到,构成本发明任何盐的一部分的具体阴离子或阳离子并不是关键的,只要该盐作为一个整体是药理学上可接受的即可。药学上可接受的盐的其他实例及其制备和使用方法在Handbook ofPharmaceutical Salts:Properties,and Use(P.H.Stahl&C.G.Wermuth编辑,VerlagHelvetica Chimica Acta,2002)中给出。
II.HER2突变
本公开的某些实施方案涉及确定受试者是否具有一种或多种HER2突变,例如HER2外显子19突变、外显子20突变或外显子21突变,例如插入、缺失或点突变。受试者可以具有2、3、4或更多种HER2突变。突变检测方法是本领域已知的,包括PCR分析和核酸测序,以及FISH和CGH。在具体的方面,通过DNA测序,例如从来自肿瘤的DNA或来自血浆的循环游离DNA检测HER2突变。
示例性的HER2外显子19突变包括位于L755或D769处的突变,例如L755P。示例性的HER2外显子21突变包括位于V842或L869处的突变,例如V842I或L869R。
HER2外显子20突变可包含氨基酸770-786之间的1-18个例如3-18个核苷酸的一个或多个点突变、插入和/或缺失。一种或多种HER2外显子20突变可以位于残基Y772、V773、A775、G776、V777、G778、S779和/或P780处。一种或多种HER2外显子20突变可以是A775insVG776C、A775insYVMA、G776V、G776C V777insV、G776C V777insC、G776del insVV、G776delinsVC、P780insGSP、V777L、G778insLPS和/或V773M。特别地,HER外显子20插入突变可以是Y772dupYVMA、G778dupGSP和/或G776delinsVC。
患者样品可以是包括来自受试者的肺癌的核酸的任何身体组织或体液。在某些实施方案中,样品是包含循环肿瘤细胞或无细胞DNA的血液样品。在其他实施方案中,样品可以是组织,例如肺组织。肺组织可以来自肿瘤组织,并且可以是新鲜冷冻的或福尔马林固定石蜡包埋的(FFPE)。在某些实施方案中,获得了肺肿瘤FFPE样品。
适合用于本文所述方法的样品含有遗传材料,例如基因组DNA(gDNA)。基因组DNA通常从生物样品中提取,例如血液或口腔内壁的粘膜刮屑,但也可以从其他生物样品中提取,包括尿液、肿瘤或吐出物。样品本身通常包括从受试者取出的有核细胞例如血细胞或口腔细胞或组织,包括正常组织或肿瘤组织。用于获得、处理和分析样品的方法和试剂是本领域已知的。在一些实施方案中,在医疗保健提供者的帮助下获得样品,例如抽血。在一些实施方案中,在没有医疗保健提供者的帮助下获得样品,例如,以无创方式获得样品的情况,例如使用口腔拭子或刷子获得的包含口腔细胞的样品,或漱口水样品。
在某些情况下,可以处理生物样品以进行DNA分离。例如,可以将细胞或组织样品中的DNA与样品的其他成分分离。可以使用本领域已知的标准技术从生物样品中收获细胞。例如,可以通过离心细胞样品并重悬沉淀的细胞来收获细胞。可以将细胞重悬浮在缓冲溶液例如磷酸盐缓冲盐水(PBS)中。在离心细胞悬浮液以获得细胞沉淀物后,可以裂解细胞以提取DNA,例如gDNA。参见,例如Ausubel et al.(2003)。可以浓缩和/或纯化样品以分离DNA。从受试者获得的所有样品,包括经过任何种类的进一步处理的样品,都视为是从受试者获得的。可使用常规方法从生物样品中提取基因组DNA,包括例如苯酚提取。或者,可以使用试剂盒例如组织试剂盒(Qiagen,Chatsworth,Calif.)和基因组DNA纯化试剂盒(Promega)提取基因组DNA。样品来源的非限制性实例包括尿液、血液和组织。
可以使用本领域已知的方法来确定本文所述HER2突变的存在或不存在。例如,凝胶电泳、毛细管电泳、尺寸排阻色谱、测序和/或阵列可用于检测插入突变的存在或不存在。在需要核酸扩增时,可以使用本领域已知的方法例如PCR来完成。在一个实例中,从受试者获得样品(例如,包含基因组DNA的样品)。然后检查样品中的DNA,以确定如本文所述的插入突变的身份。插入突变可通过本文所述的任何方法检测,例如通过测序,或通过将基因组DNA中的基因、RNA或cDNA与核酸探针,例如DNA探针(其包括cDNA探针和寡核苷酸探针)或RNA探针杂交。可以将核酸探针设计成与特定变异特异性杂交或优先杂交。
探针集通常是指用于检测本公开的可执行治疗建议中所用的靶遗传变异(例如,HER2突变)的引物集,通常是引物对集,和/或可检测地标记的探针集。引物对用于扩增反应以界定跨越上述每个基因的靶遗传变异区的扩增子。通过匹配的探针集检测扩增子集。在示例性实施方案中,本发明的方法可以使用用以检测靶遗传变异集例如HER2突变集的TaqManTM(Roche Molecular Systems,Pleasanton,Calif.)测定。在一个实施方案中,探针集是用于生成扩增子的引物集,该扩增子通过核酸测序反应,例如下一代测序反应来检测。在这些实施方案中,例如,可以采用AmpliSEQTM(Life Technologies/Ion Torrent,Carlsbad,Calif.)或TruSEQTM(Illumina,San Diego,Calif.)技术。
核酸标志物的分析可以使用本领域已知的技术进行,包括但不限于序列分析和电泳分析。序列分析的非限制性实例包括Maxam-Gilbert测序、Sanger测序、毛细管阵列DNA测序、热循环测序(Sears et al.,1992)、固相测序(Zimmerman et al.,1992)、质谱测序例如基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF/MS;Fu et al.,1998)测序和杂交测序(Chee et al.,1996;Drmanac et al.,1993;Drmanac et al.,1998)。电泳分析的非限制性实例包括平板凝胶电泳,例如琼脂糖或聚丙烯酰胺凝胶电泳、毛细管电泳和变性梯度凝胶电泳。另外,下一代测序方法可以使用来自公司的市场上可获得的试剂盒和仪器(例如来自Life Technologies/Ion Torrent PGM或Proton、Illumina HiSEQ或MiSEQ等公司的试剂盒和仪器)以及Roche/454下一代测序系统来进行。
其他核酸分析方法可以包括直接人工测序(Church and Gilbert,1988;Sangeret al.,1977;美国专利号5,288,644);自动荧光测序;单链构象多态性分析(single-stranded conformation polymorphism assay,SSCP)(Schafer et al.,1995);夹持型变性梯度凝胶电泳(clamped denaturing gradient gel electrophoresis,CDGE);二维凝胶电泳(two-dimensional gel electrophoresis,2DGE或TDGE);构象敏感凝胶电泳(conformational sensitive gel electrophoresis,CSGE);变性梯度凝胶电泳(Sheffield et al.,1989);变性高效液相色谱(DHPLC,Underhill et al.,1997);红外基质辅助激光解吸/电离(IR-MALDI)质谱(WO 99/57318);迁移率变动分析(mobility shiftanalysis,Orita et al.,1989);限制酶分析(Flavell et al.,1978;Geever et al.,1981);定量实时PCR(Raca et al.,2004);异源双链分析;化学错配切割(CMC)(Cotton etal.,1985);RNA酶保护测定(Myers et al.,1985);使用识别核苷酸错配的多肽,例如大肠杆菌(E.coli)mutS蛋白;等位基因特异性PCR,以及这类方法的组合。参见,例如,美国专利公开号2004/0014095,其全部内容通过引用并入本文。
在一个实例中,鉴定样品中HER2突变的方法包括,使来自所述样品的核酸与能够与编码突变HER2蛋白或其掺入突变的片段的核酸特异性杂交的核酸探针接触,和检测所述杂交。在具体实施方案中,例如用放射性同位素(3H、32P或33P)、荧光剂(罗丹明或荧光素)或生色剂可检测地标记所述探针。在具体实施方案中,探针是反义寡聚体,例如PNA、吗啉代-氨基磷酸酯、LNA或2'-烷氧基烷氧基。探针可以是约8个核苷酸至约100个核苷酸,或约10至约75,或约15至约50,或约20至约30个核苷酸。在另一方面,本公开的所述探针被提供在用于鉴定样品中的HER2突变的试剂盒中,所述试剂盒包含与HER2基因中的突变位点特异性杂交或在该突变位点附近特异性杂交的寡核苷酸。基于使用试剂盒进行杂交测试的结果,该试剂盒还可以包括用波齐替尼治疗患有含HER2插入突变的肿瘤的患者的说明书。
另一方面,用于检测样品中外显子20突变的方法包括,从所述样品扩增对应于所述HER基因的外显子20的核酸或其疑似含有突变的片段,并比较扩增的核酸的电泳迁移率与相应野生型HER2基因或其片段的电泳迁移率。迁移率的差异指示扩增的核酸序列中存在突变。电泳迁移率可以在聚丙烯酰胺凝胶上测定。
或者,可以使用酶促突变检测(Enzymatic Mutation Detection,EMD)(Del Titoet al.,1998)分析核酸以检测突变。EMD使用噬菌体解离酶T4内切核酸酶VII,它沿着双链DNA进行扫描,直到它检测到由点突变、插入和缺失导致的碱基对错配引起的结构扭曲并切割该结构扭曲。通过例如凝胶电泳检测到解离酶切割形成的两个短片段指示存在突变。EMD方法的优点是,单一方案鉴定从PCR反应直接检测的点突变、缺失和插入,无需进行样品纯化,从而缩短了杂交时间并提高了信噪比。可以分析含有量超过正常DNA高达20倍且尺寸高达4kb的片段的混合样品。然而,EMD扫描不能鉴定突变阳性样品中发生的具体碱基变化,从而当鉴定该突变的身份是必要的时,需要额外的测序程序来鉴定。如美国专利号5,869,245中所证明的,可类似于解离酶T4内切核酸酶VII,可以使用CEL I酶。
III.治疗方法
本文还提供了治疗个体的癌症或延缓其进展的方法,包括向向该个体,即患有癌症例如HER2突变癌症的受试者施用有效量的波齐替尼或结构相似的抑制剂和T-DM1。可以确定受试者具有HER2突变,例如外显子19、20或21突变,例如外显子20插入或L755P突变。该受试者可能具有不止一种HER突变。
被考虑治疗的癌症的实例包括肺癌、头颈癌、乳腺癌、胰腺癌、前列腺癌、肾癌、骨癌、睾丸癌、宫颈癌、胃肠癌、淋巴瘤、肺癌前病变、结肠癌、黑素瘤和膀胱癌。在具体方面,癌症是非小细胞肺癌。
在一些实施方案中,受试者是哺乳动物,例如灵长类动物,优选高等灵长类动物,例如人(例如,患有本文所述病症或处于患本文所述病症的风险的患者)。在一个实施方案中,受试者需要增强免疫应答。在某些实施方案中,受试者是免疫功能受损的,或处于免疫功能受损的风险中。例如,受试者正在接受或已经接受化疗和/或放疗。或者,或联合地,受试者由于感染而免疫功能受损或处于免疫功能受损的风险中。
某些实施方案涉及施用波齐替尼(也称为HM781-36B、HM781-36和1-[4-[4-(3,4-二氯-2-氟苯胺)-7-甲氧基喹唑啉-6-基]氧哌啶-1-基]丙-2-烯-1-酮)。波齐替尼是基于喹唑啉的泛HER抑制剂,不可逆地阻断通过HER酪氨酸激酶受体家族包括HER1、HER2和HER4的信号传导。波齐替尼或结构相似的化合物(例如,美国专利号8,188,102和美国专利公开号20130071452;通过引用并入本文)可用于本发明的方法中。
可以口服,例如以片剂形式施用波齐替尼,例如波齐替尼盐酸盐。可以以4-25mg的剂量,例如以5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg或24mg的剂量施用波齐替尼。给药可以是每天、每隔一天、每3天或每周一次。给药可以连续式进行,例如以28天为周期。
曲妥珠单抗美坦新也称为ado-曲妥珠单抗美坦新,并以商品名Kadcyla出售,它是由人源化单克隆抗体曲妥珠单抗(赫赛汀(Herceptin))与细胞毒剂美坦新(emtansine)(DM1)共价连接组成的抗体-药物缀合物。单独的曲妥珠单抗通过与HER2受体结合来阻止癌细胞的生长,而曲妥珠单抗美坦新经历受体介导的内化而进入细胞,在溶酶体中分解代谢,在溶酶体中释放含有DM1的分解代谢物,并随后与微管蛋白结合导致有丝分裂阻滞和细胞死亡。曲妥珠单抗与HER2结合阻止受体的同二聚化或异二聚化(HER2/HER3),最终抑制MAPK和PI3K/AKT细胞信号传导途径的激活。由于单克隆抗体靶向HER2,而仅癌细胞过度表达HER2,因此该缀合物可将细胞毒剂DM1特异性递送至肿瘤细胞。缀合物缩写为T-DM1。可以以2-3mg/kg的剂量,例如3.6mg/kg施用T-DM1。可以通过静脉输注施用T-DM1。
A.药物组合物
本文还提供了包含波齐替尼和T-DM1以及药学上可接受的载体的药物组合物和制剂,例如用于被确定具有HER2外显子20突变,例如外显子20插入的受试者。
本文所述的药物组合物和制剂可以通过将具有所需纯度的活性成分(例如抗体或多肽)与一种或多种任选的药学上可接受的载体混合制备成冻干制剂或水溶液的形式(Remington's Pharmaceutical Sciences第22版,2012)。药学上可接受的载体在所采用的剂量和浓度通常对接受者无毒,并且包括但不限于:缓冲剂例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵;苄索氯铵;酚醇、丁醇或苯甲醇;对羟基苯甲酸烷基酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;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,例如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,例如EDTA;糖,例如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐反离子,如钠;金属配合物(例如锌-蛋白质配合物);和/或非离子表面活性剂,例如聚乙二醇(PEG)。在本文中,示例性药学上可接受的载体还包括间质药物分散剂,例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rHuPH20(Baxter International,Inc.)。美国专利公开号2005/0260186和2006/0104968描述了某些示例性的sHASEGP和使用方法,包括rHuPH20。在一个方面,将sHASEGP与一种或多种其他糖胺聚糖酶如软骨素酶组合。
B.联合疗法
在某些实施方案中,本发明实施方案的组合物和方法涉及波齐替尼和T-DM1与至少一种其他疗法的组合。其他疗法可以是放疗、手术(例如乳房肿瘤切除术和乳房切除术)、化疗、基因疗法、DNA疗法、病毒疗法、RNA疗法、免疫疗法、骨髓移植、纳米疗法、单克隆抗体疗法或前述的组合。其他疗法可呈辅助疗法或新辅助疗法的形式。
在一些实施方案中,其他疗法是施用小分子酶抑制剂或抗转移剂。在一些实施方案中,其他疗法是施用副作用限制剂(例如,旨在减少治疗副作用的发生和/或严重程度的剂,例如抗恶心剂等)。在一些实施例中,其他疗法是放疗。在一些实施方案中,其他疗法是手术。在一些实施方案中,其他疗法是放疗和手术的组合。在一些实施方案中,其他疗法是伽马辐射。在一些实施方案中,其他疗法是靶向PBK/AKT/mTOR途径的疗法、HSP90抑制剂、微管蛋白抑制剂、细胞凋亡抑制剂和/或化学预防剂(chemopreventative agent)。其他疗法可以是本领域已知的一种或多种化学治疗剂。
相对于其他癌症疗法例如免疫检查点疗法,可以在其之前、过程中、之后或以各种组合施用波齐替尼和T-DM1。施用间隔可以从同时到几分钟到几天到几周。在将波齐替尼和T-DM1与其他治疗剂分开提供给患者的实施方案中,通常会确保在每次递送时间之间没有历时很长时间,使得这两种化合物仍然能够对患者产生有利的组合效果。在这种情况下,考虑了可以在抗体疗法和抗癌疗法彼此相隔约12至24或72小时内,更特别地,在彼此的约6-12小时内,向患者提供抗体疗法和抗癌疗法。在某些情况下,可能需要极大地延长治疗时间,其中在各自施用之间间隔几天(2、3、4、5、6或7天)到几周(1、2、3、4、5、6、7、或8周)。
可以采用各种组合。对于下面的实例,波齐替尼和T-DM1是“A”,抗癌疗法是“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B B/B/B/A B/B/A/BA/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
考虑到药剂的毒性(如果有的话),本发明实施方案的任何化合物或疗法对患者的施用应当遵循施用此类化合物的一般方案。因此,在一些实施方案中,存在监测归因于联合疗法的毒性的步骤。
1.化疗
根据本发明的实施方案,可以使用多种化疗剂。术语“化学疗法”是指使用药物治疗癌症。“化学治疗剂”用于表示在癌症治疗时施用的化合物或组合物。这些药剂或药物根据它们在细胞内的活性模式进行分类,例如,它们是否影响细胞周期以及在哪个阶段影响细胞周期。或者,药剂可基于其直接交联DNA、嵌入DNA或通过影响核酸合成诱导染色体和有丝分裂畸变的能力来表征。
化疗剂的实例包括烷化剂,例如噻替哌和环磷酰胺;烷基磺酸盐,如白消安、英丙舒凡(improsulfan)和哌泊舒凡;氮丙啶类,如苯并多巴(benzodopa)、卡巴醌、美托多巴(meturedopa)和乌多巴(uredopa);乙烯亚胺类和甲基戊胺类,包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺(trimethylolomelamine);乙酸衍生物(acetogenin)(尤其是布拉它辛和布拉它辛酮);喜树碱(包括合成类似物拓扑替康);苔藓抑素;callystatin;CC-1065(包括其合成类似物,阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin));念珠藻素(cryptophycin)(特别是念珠藻素1和念珠藻素8);尾海兔素(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);五加素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素(spongistatin);氮芥类,例如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、二氯甲基二乙胺、二氯甲基二乙胺氧化物盐酸盐(mechlorethamineoxide hydrochloride)、美法仑、新恩比兴、苯芥胆甾醇、泼尼莫司汀、曲磷胺和乌拉莫司汀;硝基脲类,例如卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀和雷尼司汀(ranimnustine);抗生素,例如烯二炔抗生素(例如,卡奇霉素(calicheamicin),尤其是卡奇霉素γlI和卡奇霉素ωI1);达内霉素(dynemicin),包括达内霉素A;双膦酸盐,例如氯膦酸盐;埃斯培拉霉素(esperamicin);以及及新制癌菌素(neocarzinostatin)发色团和相关色素蛋白烯二炔类抗生素发色团、阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、蒽霉素、重氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、卡柔比星(carabicin)、洋红霉素、嗜癌菌素(carzinophilin)、色霉素、放线菌素D(dactinomycin)、柔红霉素、地托比星、6-重氮-5-氧代-L正亮氨酸(6-diazo-5-oxo-L-norleucine)、多柔比星(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉-多柔比星(2-pyrrolino-doxorubicin)和脱氧多柔比星(deoxydoxorubicin))、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺加霉素、橄榄霉素、培洛霉素、甲基丝裂霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星、链黑霉素、链脲霉素、杀结核菌素、乌苯美司、净司他丁和佐柔比星;抗代谢物,例如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸、蝶罗呤和三甲曲沙;嘌呤类似物,例如氟达拉滨、6-巯嘌呤、硫咪嘌呤(thiamiprine)和硫鸟嘌呤(thioguanine);嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷(6-azauridine)、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)和氟尿苷;雄性激素,例如卡普睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷和睾内酯;抗肾上腺素药类(anti-adrenals),例如米托坦(mitotane)和曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸;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);阿莫司汀(bestrabucil);比生群(bisantrene);依达曲沙;defofamine;秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfornithine);依利醋铵(elliptinium acetate);埃博霉素;依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),例如美登素(maytansine)和安丝菌素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);尼曲吖啶;喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinicacid);2-乙基酰胼(2-ethylhydrazide);丙卡巴胼(procarbazine);PSK多糖复合物(PSKpolysaccharide complex);雷佐生(razoxane);利索新(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺(2,2’,2”-trichlorotriethylamine);单端孢霉烯族毒素类(trichothecenes)(特别是T-2毒素、疣孢菌素(verracurin)A、漆斑菌素A(roridinA)和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);噶萨托辛(gacytosine);阿糖胞昔(arabinoside)("Ara-C");环磷酰胺(cyclophosphamide);紫杉烷类(taxoids),例如紫杉醇(paclitaxel)和多西他赛、吉西他滨;6-硫鸟嘌呤(6-thioguanine);巯嘌呤(mercaptopurine);铂配合物(platinum coordination complex),例如顺铂(cisplatin)、奥沙利铂(oxaliplatin)和卡铂(carboplatin);长春碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);诺安托(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基喋呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);伊立替康(irinotecan)(例如CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(difluorometlhylornithine)(DMFO);类维生素A(retinoids),例如视黄酸(retinoic acid);卡培他滨(capecitabine);卡铂、甲基苄肼(procarbazine)、普卡霉素(plicomycin)、吉西他滨、诺维本(navelbine)、法呢基-蛋白转移酶抑制剂、反铂(transplatinum)和上述任何物质的药学上可接受的盐、酸或衍生物。
2.放疗
导致DNA损伤并已被广泛使用的其他因素包括通常已知的对肿瘤细胞定向递送γ射线、X射线和/或放射性同位素的那些因素。还考虑了其他形式的DNA损伤因素,例如微波、质子束照射(美国专利5,760,395和4,870,287)和UV照射。很可能所有这些因素都会对DNA、DNA前体、DNA的复制和修复以及染色体的组装和维持产生广泛的损伤。X射线的剂量范围在从每天50-200伦琴的长时间(3-4周)剂量到2000-6000伦琴单次剂量。放射性同位素的剂量范围变化很大,并且取决于同位素的半衰期、发出的辐射的强度和类型以及肿瘤细胞的吸收。
3.免疫疗法
本领域技术人员应当理解,其他免疫疗法可以与所述实施方案的方法联合或结合使用。在治疗癌症的背景下,免疫疗法通常依赖于免疫效应细胞和靶向并破坏癌细胞的分子的使用。利妥昔单抗就是这样一个实例。免疫效应物可以是,例如,对肿瘤细胞表面上的某些标志物特异的抗体。单独的抗体可以用作治疗的效应物,或者它可以招募其他细胞来实际地影响细胞杀伤。抗体还可以与药物或毒素(化疗剂、放射性核素、蓖麻毒素A链、霍乱毒素、百日咳毒素等)偶联并用作靶向剂。或者,效应物可以是携带直接或间接与肿瘤细胞的靶相互作用的表面分子的淋巴细胞。各种效应细胞包括细胞毒性T细胞和NK细胞。
抗体-药物缀合物已作为开发癌症疗法的突破性方法应运而生。癌症是世界上导致死亡的主要原因之一。抗体-药物缀合物(ADC)包含与细胞杀伤药物共价连接的单克隆抗体(MAb)。这种方法将MAb对其抗原靶的高特异性与高效细胞毒性药物相结合,从而产生将有效载荷(药物)递送至具有富集的抗原水平的肿瘤细胞的“武装”MAb。药物的靶向递送也最大限度地减少了其在正常组织中的暴露,从而降低了毒性并提高了治疗指数。FDA批准的两种ADC药物,即2011年批准的(本妥昔单抗维多丁(brentuximabvedotin))和2013年批准的(曲妥珠单抗美坦新或T-DM1)验证了该方法。目前有30多种ADC候选药物处于癌症治疗临床试验的各个阶段(Leal et al.,2014)。随着抗体工程化和接头-有效荷载(linker-payload)优化越来越成熟,新ADC的发现和开发越来越依赖于对适合这种方法的新靶标的鉴定和验证以及靶向MAb的生成。ADC靶标的两个标准是在肿瘤细胞中表达上调/高水平表达以及稳健内化。
在免疫疗法的一个方面,肿瘤细胞必须带有适合被靶向的某个标志物,即在大多数其他细胞上不存在的标志物。存在许多肿瘤标志物并且在本实施方案的上下文中这些标志物中的任何一个都可能适合靶向。常见的肿瘤标志物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸路易斯抗原(Sialyl Lewis Antigen)、MucA、MucB、PLAP、层粘连蛋白受体、erb B和p155。免疫疗法的另一个方面是将抗癌作用与免疫刺激作用相结合。还存在免疫刺激分子,包括:细胞因子,例如IL-2、IL-4、IL-12、GM-CSF、γ-IFN,趋化因子,例如MIP-1、MCP-1、IL-8,和生长因子,例如FLT3配体。
免疫疗法的实例包括免疫佐剂,例如牛分枝杆菌(Mycobacterium bovis)、镰状疟原虫(Plasmodium falciparum)、二硝基氯苯和芳族化合物(美国专利5,801,005和5,739,169;Hui and Hashimoto,1998;Christodoulides et al.,1998);细胞因子疗法,例如干扰素α、β和γ,IL-1、GM-CSF和TNF(Bukowski et al.,1998;Davidson et al.,1998;Hellstrand et al.,1998);基因疗法,例如TNF、IL-1、IL-2和p53(Qin et al.,1998;Austin-Ward and Villaseca,1998;美国专利5,830,880和5,846,945);和单克隆抗体,例如抗CD20、抗神经节苷脂GM2和抗p185(Hollander,2012;Hanibuchi et al.,1998;美国专利5,824,311)。预期一种或多种抗癌疗法可与本文所述的抗体疗法一起使用。
在一些实施方案中,免疫疗法可以是免疫检查点抑制剂。免疫检查点调高信号(例如,共刺激分子)或者调低信号。可以被免疫检查点阻断剂靶向的抑制性免疫检查点包括腺苷A2A受体(A2AR)、B7-H3(也称为CD276)、B和T淋巴细胞衰减子(BTLA)、细胞毒性T淋巴细胞相关蛋白4(CTLA-4,也称为CD152)、吲哚胺2,3-双加氧酶(IDO)、杀伤细胞免疫球蛋白(KIR)、淋巴细胞激活基因3(LAG3)、程序性死亡因子1(PD-1)、T细胞免疫球蛋白结构域和粘蛋白结构域3(TIM-3)和T细胞活化V结构域Ig抑制剂(VISTA)。特别是,免疫检查点抑制剂靶向PD-1轴和/或CTLA-4。
免疫检查点抑制剂可以是诸如小分子、重组形式的配体或受体等药物,或者特别地是抗体,例如人抗体(例如,国际专利公开WO2015016718;Pardoll,Nat Rev Cancer,12(4):252-64,2012;两者均通过引用并入本文)。可以使用免疫检查点蛋白的已知抑制剂或其类似物,特别是可以使用嵌合、人源化或人源形式的抗体。如技术人员应当知晓的,对于本公开提及的某些抗体,可能正在使用的是别名和/或等效名称。在本发明的上下文中,这样的别名和/或等效名称是可互换的。例如,已知兰博利珠单抗(lambrolizumab)也以别名和等效名称MK-3475和派姆单抗(pembrolizumab)为人所知。
在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其配体结合配偶体结合的分子。在具体方面,PD-1配体结合配偶体是PDL1和/或PDL2。在另一个实施方案中,PDL1结合拮抗剂是抑制PDL1与其结合配偶体结合的分子。在具体方面,PDL1结合配偶体是PD-1和/或B7-1。在另一个实施方案中,PDL2结合拮抗剂是抑制PDL2与其结合配偶体结合的分子。在具体方面,PDL2结合配偶体是PD-1。拮抗剂可以是抗体、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。示例性抗体描述于美国专利号8,735,553、8,354,509和8,008,449中,上述专利均通过引用并入本文。用于本文提供的方法中的其他PD-1轴拮抗剂是本领域已知的,例如描述在美国专利公开号US20140294898、US2014022021和US20110008369中,上其均通过引用并入本文。
在一些实施方案中,PD-1结合拮抗剂是抗PD-1抗体(例如,人抗体、人源化抗体或嵌合抗体)。在一些实施方案中,抗PD-1抗体选自由纳武单抗、派姆单抗和CT-011组成的组。在一些实施方案中,PD-1结合拮抗剂是免疫粘附素(例如,包含融合到恒定区(例如,免疫球蛋白序列的Fc区)的PDL1或PDL2的细胞外部分或PD-1结合部分的免疫粘附素)。在一些实施方案中,PD-1结合拮抗剂是AMP-224。纳武单抗,也称为MDX-1106-04、MDX-1106、ONO-4538、BMS-936558和是WO2006/121168中描述的抗PD-1抗体。派姆单抗,也称为MK-3475、Merck 3475、兰博利珠单抗、和SCH-900475,是WO2009/114335中描述的抗PD-1抗体。CT-011,也称为hBAT或hBAT-1,是WO2009/101611中描述的抗PD-1抗体。AMP-224,也称为B7-DCIg,是WO2010/027827和WO2011/066342中描述的PDL2-Fc融合可溶性受体。
在本文提供的方法可靶向的另一个免疫检查点是细胞毒性T淋巴细胞相关蛋白4(CTLA-4),也称为CD152。人CTLA-4的完整cDNA序列的Genbank登录号为L15006。CTLA-4存在于T细胞表面,并且当与抗原呈递细胞表面的CD80或CD86结合时充当“关闭”开关。CTLA4是免疫球蛋白超家族的成员,在辅助T细胞表面表达并向T细胞传递抑制信号。CTLA4与T细胞共刺激蛋白CD28相似,并且两个分子均与抗原呈递细胞上的CD80和CD86(分别也称为B7-1和B7-2)结合。CTLA4向T细胞传递抑制信号,而CD28则传递刺激信号。细胞内CTLA4也存在于调节性T细胞中,并且对其功能可能是重要的。通过T细胞受体和CD28激活T细胞会导致B7分子的抑制性受体,CTLA-4表达增加。
在一些实施方案中,免疫检查点抑制剂是抗CTLA-4抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。
适合用于本发明方法的抗人CTLA-4抗体(或由其衍生的VH和/或VL结构域)可以使用本领域公知的方法生成。或者,可以使用本领域公认的抗CTLA-4抗体。例如,抗CTLA-4抗体,其公开于:美国专利号8,119,129;国际专利公开号WO 01/14424、WO 98/42752和WO 00/37504(CP675,206,也称为替西木单抗(tremelimumab);以前称为托珠单抗(Tocilizumab));美国专利号6,207,156;Hurwitz et al.,1998;Camacho et al.,2004和Mokyr et al.,1998,可用于本文公开的方法中。前述出版物中每一个的教导在此通过引用并入。也可以使用与任何这些本领域公认的抗体竞争结合CTLA-4的抗体。例如,人源化CTLA-4抗体被描述于国际专利申请号WO2001014424和WO2000037504,以及美国专利号8,017,114;三者全部通过引用方式并入本文。
示例性抗CTLA-4抗体是伊匹单抗(也称为10D1、MDX-010、MDX-101和)或其抗原结合片段和变体(参见,例如,WO 01/14424)。在其他实施方案中,抗体包含伊匹单抗的重链和轻链CDR或VR。因此,在一个实施方案中,抗体包含伊匹单抗VH区的CDR1、CDR2和CDR3结构域,以及伊匹单抗VL区的CDR1、CDR2和CDR3结构域。在另一个实施方案中,该抗体与上述抗体竞争结合(binding with and/or binding to)CTLA-4上的同一表位。在另一个实施方案中,该抗体与上述抗体具有至少约90%的可变区氨基酸序列同一性(例如,与伊匹单抗具有至少约90%、95%或99%的可变区同一性)。
用于调节CTLA-4的其他分子包括描述于例如美国专利号5,844,905、5,885,796以及国际专利申请号WO1995001994和WO1998042752中的CTLA-4配体和受体(上述文献均通过引用并入本文);以及描述于例如美国专利号8,329,867中的免疫粘附素(该专利通过引用并入本文)。
4.手术
大约60%的患癌症的人会经历某种类型的手术,包括预防、诊断或分级、治愈和姑息手术。治愈手术包括切除术,其中物理去除、切除和/或破坏全部或部分癌组织,并且可以与其他疗法结合使用,例如本发明实施方案的疗法、化疗、放疗、激素疗法、基因疗法,免疫疗法和/或替代疗法。肿瘤切除是指物理切除肿瘤的至少一部分。除肿瘤切除外,手术治疗还包括激光手术、冷冻手术、电外科学和显微镜控制的手术(莫氏手术(Mohs’surgery))。
在切除部分或全部癌细胞、癌组织或肿瘤后,可在体内形成空腔。治疗可以通过用其他抗癌疗法对该区域进行灌注、直接注射或局部应用来完成。此类治疗可例如每1、2、3、4、5、6或7天或每1、2、3、4和5周或每1、2、3、4、5、6、7、8、9、10、11或12个月进行重复。这些治疗也可能有不同的剂量。
5.其他药剂
考虑了其他药剂可与本发明实施方案的某些方面联合使用,以提高治疗的疗效。这些其他药剂包括影响细胞表面受体上调和GAP连接的药剂、细胞生长抑制剂和分化剂、细胞粘附抑制剂、增加过度增殖细胞对凋亡诱导剂的敏感性的药剂或其他生物药剂。通过提高GAP连接数量来增加细胞间信号传导,会增加对邻近的过度增殖细胞群的抗过度增殖作用。在其他实施方案中,细胞生长抑制剂或分化剂可与本发明实施方案的某些方面联合使用,以提高治疗的抗过度增殖功效。考虑了细胞粘附抑制剂以提高本发明实施方案的疗效。细胞粘附抑制剂的实例是黏着斑激酶(FAK)抑制剂和洛伐他汀。还考虑了,增加过度增殖细胞对细胞凋亡的敏感性的其他药剂,例如抗体c225可与本发明实施方案的某些方面联合使用,以提高疗效。
IV.试剂盒
用于检测EGFR和/或HER2外显子20突变,例如本文公开的那些突变的试剂盒也在本公开内容的范围内。这种试剂盒的实例可以包括外显子20突变特异性引物集。该试剂盒还可包括使用引物检测本文所述具体EFGR和/或HER2外显子20突变的存在或不存在的说明书。该试剂盒还可包含用于诊断目的的说明书,其指出在来自癌症患者的样品中阳性鉴定到本文所述EGFR和/或HER2外显子20突变指示对酪氨酸激酶抑制剂波齐替尼或结构相似的抑制剂和T-DM1敏感。该试剂盒还可以包括说明,其指出在来自癌症患者的样品中阳性鉴定到本文所述EGFR和/或外显子20突变指示该患者应当用波齐替尼或结构相似的抑制剂和T-DM1治疗。
V.实施例
包括以下实施例以例证本发明的优选实施方案。本领域技术人员应当认识到,以下实施例中公开的技术代表了发明人发现在本发明的实践中充分发挥作用的技术,且因此可以视为构成实施本发明的优选方式。然而,本领域技术人员根据本公开应当理解,在不脱离本发明的精神和范围的情况下,可以对所公开的具体实施方案进行许多改变并且仍然获得类似或相似的结果。
实施例1–治疗HER2癌症
HER2突变最常发生在膀胱癌、胃癌和胆管癌中:为了了解癌症类型中HER2突变的多样性,在cBioPortal(N=44,037)和MD Anderson癌症中心(N=19,926)中查询了几个数据库。
HER2突变最常发生在HER2的酪氨酸激酶结构域:接下来,分析了cBioPortal和MDAnderson报道的HER2受体的各个区域内的突变的频率。在所有癌症类型中,HER2突变最常发生在酪氨酸激酶结构域(46%),该结构域包括外显子20(20%)、外显子19(11%)和外显子21(9%)中的突变(图1);此外,细胞外结构域突变占HER2突变的37%。
HER2突变热点因恶性肿瘤类型而异:在所有查询的癌症中,最常见的HER2突变是:310F/Y(11.0%)、Y772_A775dupYVMA(5.7%)、L755P/S(4.6%)、V842I(4.4%)和V777L/M(4.0%)(图2A)。在肺癌中,大多数HER2突变发生在外显子20内(47%),其中Y772_A775dupYVMA占所有HER2突变的34%(图2B)。在乳腺癌中,大多数HER2突变发生在外显子19内(37%),其中L755突变最普遍,占HER2突变的22%。然而,与一种变异占优势的肺癌不同,在乳腺癌中,外显子19突变之间存在更多的突变多样性(图2C)。在结直肠癌中,HER2突变最常发生在外显子21(22%)中,其中V842I变体最为普遍(19%)(图2D)。
经常检测到的HER2改变是激活突变:为了评估常见HER2突变的功能影响,使Ba/F3细胞稳定表达遍及外显子19、20和21的16种最常检测到的HER2突变。发现测试的所有16种HER2突变都诱导Ba/F3细胞的IL-3非依赖性存活(图3A-C),并表达磷酸化的HER2,表明这些突变导致受体激活。
波齐替尼是测试最多的TKI,并在体外抑制最常见的HER2突变:虽然最近的报告强调了共价基于氨基喹唑啉的TKI(即阿法替尼、达可替尼、波齐替尼、来那替尼)在HER2突变体疾病的临床前模型中的有效性(Nagano et al.,2018),但对阿法替尼、达可替尼和来那替尼的临床研究在患者的结果中具有低ORR、癌症特异性差异和变体特异性差异。为了系统地评估最常检测到的HER2变异的药物敏感性,针对11种共价和非共价EGFR和HER2 TKI筛选了一组HER2突变的Ba/F3细胞。HER2突变体显示出对非共价抑制剂,拉帕替尼和沙巴替尼(sapatinib)的稳健耐药性(图4A)。共价的基于喹啉胺的TKI,奥希替尼、依鲁替尼(ibrutinib)和纳扎替尼(nazartinib)在表达外显子20突变的细胞中不能有效抑制细胞活力;然而,这些TKI确实表现出针对表达D769外显子19变异和外显子21变异的细胞的活性(图4A)。通过比较,共价的基于氨基喹唑啉的TKI,阿法替尼、来那替尼、达可替尼、他索替尼-TKI和波齐替尼,对所有三个外显子的HER2突变体都具有抑制活性(图4A)。在测试的所有HER2突变变异和TKI中,波齐替尼的平均IC50最低,并且在降低细胞活力方面远比来那替尼和他索替尼-TKI更有效(分别为p<0.001和p=0.018,图4B)。此外,虽然波齐替尼比来那替尼或他索替尼-TKI对HER2外显子19和20突变更有效,但在对于外显子21突变体的平均IC50方面没有显著差异(图4C-4E),表明突变位置影响药物结合。此外,在外显子19内,L755S和L755P变异在所有测试的TKI中在药物敏感性上具有显著差异(图4F),表明该位点的特定氨基酸变化影响药物结合亲和力。
HER2突变位置和氨基酸变化影响药物结合亲和力:为了进一步了解突变位置和氨基酸变化如何能够影响药物结合亲和力和抑制功效,使用分子动力学模拟来研究这些突变如何影响HER2激酶结构域的结构和动力学。使用公众可获得的X射线结构(PDB 3PP0)作为模板构建L755S、L755P、Y772dupYVMA、V777L和L869R HER2突变体的分子模型,并对其进行加速分子动力学以增加蛋白质构象采样。所采样的蛋白质构象范围,特别是关于P-环和α-C-螺旋位置,在这些HER2突变体中有所不同。甚至在外显子20突变之间,尤其是在α-C-螺旋区中差异是很明显的,其中α-C-螺旋构象的持续时间在“内”构象(具有较小结合口袋的活性构象)与“外”构象(具有更大结合口袋的非活性构象)之间有所不同。V777L突变体大量采样到“外”构象,而Y772dupYVMA突变体采样到“内”和“外”构象二者(图5A)。总体而言,构象状态的这些差异导致Y772dupYVMA突变体驻留于“内”构象的频率是V777L突变体的10倍(图5B),并且平均而言,与V777L相比,Y772dupYVMA的结合口袋尺寸更小(图5C)。此外,与V777L相比,Y772dupYVMA的较小结合口袋可能是来那替尼对Y772dupYVMA效力较弱的原因,因为来那替尼含有朝着α-C螺旋定向的吡啶环。
对HER2突变体结合袋体积的进一步分析(图10B)表明,相同残基处的突变对蛋白质构象具有截然不同的影响。特别地,L755P突变的脯氨酸残基缺乏氢键供体,这破坏了分别在β3和β5链之间、在L755和V790之间的主链氢键。这两条β-链之间缺乏稳定性导致β-折叠不稳定和激酶铰链区的结构重排(图5D)。特别地,L755P突变体的L800残基突出进入活性位点,并大大减小了口袋的尺寸。β3链构象的变化还导致P环向内塌陷,从而进一步减少口袋体积并使该突变体对大多数TKI不太敏感。此外,铰链可移动性的变化也可能在激酶激活中起作用。L755P突变体确认的这些独特变化与L755S突变体的表现形成对比,L755S突变体具有更类似于野生型HER2的构象和口袋体积特征。
HER2突变的人类癌细胞系对波齐替尼表现出增强的敏感性:测试HER2抑制剂的临床研究揭示了药物敏感性的癌症类型特异性差异(Hyman et al.,2018)。为了确定共价的基于氨基喹唑啉的TKI在HER2突变疾病模型中是否具有显著活性,在人类癌细胞系中测试了一组EGFR/HER2 TKI。用HER2外显子20突变转染肿瘤前MCF10A乳腺上皮细胞,并体外评估对12种EGFR/HER2 TKI的敏感性。表达G776del insVC、Y772dupYVMA或G778dupGSP HER2突变的MCF10A细胞对波齐替尼最敏感,IC50值分别为12nM、8.3nM、4.5nM(图6A-6C)。相比之下,他索替尼-TKI和来那替尼产生的平均IC50值分别为21nM和150nM(图6A-6C),表明波齐替尼的效力分别是他索替尼-TKI和来那替尼的2.6倍和19倍(p<0.001)。此外,MCF10A HER2G776delinsVC细胞与波齐替尼和来那替尼的蛋白质印迹表明,波齐替尼,而不是来那替尼,在10nM时完全抑制p-HER2(图12A)。由于野生型(WT)HER2不会将Ba/F3细胞转化为独立于IL-3生长,因此,用MCF10A细胞来测定与WT HER2相比TKI对突变HER2的选择性。为此,计算了每种抑制剂的选择性指数(SI,突变体的IC50值/WT的IC50值),并发现波齐替尼是在MCF10A细胞系(SI=0.028)中测试的对突变体最具选择性的TKI,其次是吡咯替尼(pyrotinib)(SI=0.063)和他索替尼-TKI(SI=0.111)(图6D)。与使用Ba/F3细胞获得的数据(图3C)一致,在HER2外显子19突变结直肠癌(CW-2)模型中,波齐替尼、他索替尼-TKI和来那替尼之间的敏感性差异不太大,但仍然显著(p=0.02和p=0.0004),平均IC50值分别为3.19nM、4.24nM和68.8nM(图6E)。此外,在CW-2结肠直肠细胞的异种移植物小鼠模型中,在第21天,与媒介物治疗组相比,波齐替尼(5mg/kg)治疗的动物的肿瘤体积减少58%(p=0.011)。相比之下,与媒介物对照相比,来那替尼(30mg/kg)治疗的动物表现出肿瘤体积增加(28%)(p=0.023),并且与媒介物对照相比,阿法替尼(20mg/kg)治疗没有显著影响肿瘤生长(图6F、图13)。
波齐替尼在具有HER2突变的NSCLC患者中具有抗肿瘤活性:基于这些临床前数据和先前发表的关于外显子20突变的工作(Robichaux et al.,2018),研究人员发起的波齐替尼对EGFR和HER2外显子20突变性NSCLC(NCT03066206)的II期临床试验已开始。患者每天口服波齐替尼16mg来治疗,直至进展、死亡或停药。根据RECIST v1.1,每八周评估一次客观响应。在前12名可评估的携带HER2外显子20插入突变的患者中,6/12(50%)患者具有部分响应(PR)的最佳响应;2个月后的重复扫描以5/12证实了这种响应(证实的客观响应率,42%)(图7A)。在这些患者中,两名患者在首次响应评估时出现疾病进展(PD),导致疾病控制率(DCR)为83%。截至2018年11月,12名患者中的7名出现进展,且前12名患者的中位PFS为5.7个月(图7B)。该研究中包括的所有患者迄今都携带两种最常见的外显子20插入即Y772dupYVMA和G778dupGSP之一(图7A)。一名具有Y772dupYVMA突变的NSCLC患者在治疗前和治疗后(8周)的代表性图像显示右肺肿瘤明显收缩(图7C)。患者特征,包括既往治疗线数,可见于表3。此外,根据同情护理使用协议(C-IND18-0014)治疗了一名携带HER2外显子19点突变即L755P的重度预治疗NSCLC患者。每天用16mg波齐替尼治疗患者,并且该患者的肿瘤在4周时收缩(图7D,白框)。根据RECIST v1.1,患者病情稳定(SD)(-12%靶标区减小)。该患者继续服用波齐替尼,疾病被控制超过7个月,直到成像显示疾病进展并停用波齐替尼。患者在波齐替尼治疗结束时临床状况良好,并继续接受进一步的系统治疗。
波齐替尼与T-DM1治疗的组合增强了抗肿瘤活性:先前在HER阳性乳腺癌模型中对HER2 TKI拉帕替尼及在EGFR突变性NSCLC模型中对EGFR抑制剂进行的研究表明,TKI治疗导致细胞表面上受体积累增加,并且增加的细胞表面HER2/EGFR提高了对抗体依赖性细胞毒性(ADCC)的敏感性。为了确定波齐替尼治疗是否增加细胞表面上的总HER2受体表达,在波齐替尼治疗24小时后通过FACS分析了细胞表面HER2表达。发现平均而言,波齐替尼治疗使细胞表面HER2表达增加2倍(图8A,p<0.0001)。接下来,测试了波齐替尼与T-DM1的组合是否会体外降低细胞活力,且发现尽管单独的T-DM1不抑制MCF10A HER2突变细胞系的细胞活力,但T-DM1与波齐替尼组合产生的IC50值比单独的任一种药剂都低(图8B)。为了在体内验证这些发现,在HER2突变性NSCLC PDX模型(HER2 Y772dupYVMA)中测试了低剂量波齐替尼与单剂量T-DM1的组合。发现在第14天,与仅接受T-DM1的2/9小鼠或接受低剂量波齐替尼的0/9小鼠相比,低剂量波齐替尼(2.5mg/kg)与单剂量T-DM1(10mg/kg)的组合导致8/8小鼠的肿瘤完全消退(图8C-D,p<0.0001)。到四周时,仅接受T-DM1的小鼠的肿瘤生长重新开始;然而,在接受联合治疗的所有小鼠中,没有肿瘤复发的迹象(图8E)。
本研究表明,HER2突变仍发生在多种肿瘤类型中,但是特定突变热点因恶性肿瘤而异。此外,对HER2 TKI的敏感性是跨突变位置异质性的,HER2外显子20插入和L755P突变对大多数HER2 TKI具有耐药性,可能是由于药物结合袋的体积减小所致。此外,波齐替尼被确定为有效的泛HER2突变选择性抑制剂,对携带HER2外显子20插入和L755P突变的NSCLC患者具有临床疗效。最后,确立了波齐替尼治疗诱导HER2在细胞表面的积累,并且波齐替尼与T-DM1治疗的组合在体外和体内都增强了抗肿瘤活性。
表1:用以生成稳定细胞系的载体。
表2:患者特征和既往治疗线数。
实施例2–材料和方法
HER2突变普遍率和变异频率分析:为了确定来自MD Anderson癌症中心和cBioPortal的数据库中报告的每个HER2突变的频率,逐个查询每个数据库,然后根据每个数据库中的患者总数对频率进行加权,并报告为加权平均值。为了确定cBioPortal中跨癌症类型的HER2突变频率,选择并导出所有非重叠研究。对于重叠研究,仅使用最大的数据集。为了确定MD Anderson癌症中的HER2突变频率,查询了个性化癌症治疗(PersonalizedCancer Therapy)研究所的数据库中所有独立于癌症类型的HER2突变。
Ba/F3细胞系生成和IL-3剥夺:Ba/F3细胞系的建立如前所述(Robichaux et al.,2018)。简而言之,通过对Ba/F3细胞系进行12小时的逆转录病毒转导来生成稳定的Ba/F3细胞系。通过使用Lipofectamine 2000(Invitrogen)将表1(Addgene和Bioinnovatise)中总结的基于pBabe-Puro的载体转染到Phoenix 293T-ampho细胞(Orbigen)中生成逆转录病毒。转导三天后,将2μg/ml嘌呤霉素(Invitrogen)添加到RPMI培养基中。在5天的选择后,对细胞用FITC-HER2(Biolegend)染色、FACS分选。然后使细胞系在不存在IL-3的情况下生长两周,并每三天使用Cell Titer Glo测定(Progema)评估细胞活力。将所得稳定细胞系维持在含有10%FBS而无IL-3的RPMI-1640培养基中。
细胞活力测定和IC50估计:如前所述(Robichaux et al.,2018),使用Cell TiterGlo测定(Promega)测定细胞活力。简而言之,将每孔2000-3000个细胞以三次技术重复平铺在384孔板(Greiner Bio-One)中。用七种不同浓度的酪氨酸激酶抑制剂或单独的媒介物处理细胞,最终体积为每孔40μL。3天后,将11μL Cell Titer Glo添加到每个孔中。将板摇动15分钟,并使用FLUOstar OPTIMA多模式酶标仪(BMG LABTECH)测定生物发光。将生物发光值针对DMSO处理的细胞归一化,并在GraphPad Prism中对归一化值作图,使用非线性回归拟合成具有可变斜率的归一化数据。通过GraphPad Prism计算50%抑制时的IC50值。
对于磷酸化HER2和总HER2的ELISA以及与IC50值的相关性:如上所述,从亲本Ba/F3细胞系和表达HER2突变的每个Ba/F3细胞系收获蛋白质。向每个ELISA板中添加5μg/ml的蛋白质,并按照制造商说明书所描述的对磷酸化HER2(Cell signaling,#7968)和总HER2(Cell signaling,#7310)进行ELISA。通过采用ELISA测定的p-HER2与总HER2的比值来确定相对p-HER2表达。针对如上所述计算的相对p-HER2比值与波齐替尼IC50值作图。皮尔逊相关性(Pearson correlation)和p值通过GraphPad Prism确定。
酪氨酸激酶抑制剂和T-DM1:除了EGF816和吡咯替尼购自MedChem Express以外,所有抑制剂均购自Selleck Chemical。所有抑制剂均以10mM的浓度溶解在DMSO中,并储存在-80℃下。在丢弃之前,抑制剂限于两次冻融/循环。T-DM1从M.D.Anderson癌症中心机构药房以重构形式购得。
分子动力学模拟:使用MOE计算机程序(Chemical Computing Group),通过向PDB3PP0 X射线结构计算机模拟地引入突变来构建HER2突变体的蛋白质结构模型(Aertgeertset al.,2011)。使用NAMD模拟包进行经典和加速分子动力学模拟(Phillips et al.,2005)。
人细胞系:MCF10A细胞购自ATCC,并在补充有1%青霉素/链霉素、5%马血清(sigma)、20ng/ml EGF、0.5mg/ml氢化可的松和10μg/ml胰岛素的DMEM/F12培养基中培养。通过逆转录病毒转导产生稳定的细胞系,并通过使用Lipofectamine 2000(Invitrogen)将表1总结的基于pBabe-Puro的载体(Addgene和Bioinnovatise)转染到Phoenix 293T-ampho细胞(Orbigen)中生成逆转录病毒。转导两天后,将0.5μg/ml嘌呤霉素(Invitrogen)添加到RPMI培养基中。选择14天后,如上所述地在细胞活力测定中测试细胞。根据MTA,CW-2细胞由Riken细胞系数据库提供,并维持在含有10%FBS和1%青霉素/链霉素的RPMI中。
体内异种移植物研究:通过将50%基质胶中的1x106个细胞注射到6周龄雌性nu/nu裸鼠中产生CW-2细胞系异种移植物。当肿瘤达到350mm3时,将小鼠随机分为4组:20mg/kg阿法替尼、5mg/kg波齐替尼、30mg/kg来那替尼或媒介物对照(含0.5%甲基纤维素、2%Tween-80的dH2O)。测量肿瘤体积,每周三次。小鼠周一至周五(每周5天)接受药物,但从周三开始给药,允许前3天给药后有2天的假期。
Y772dupYVMA PDX小鼠购自Jax Labs(Model#TM01446)。将来自肿瘤的表达HER2Y772dupYVMA的片段接种到5-6周龄雌性NSG小鼠(Jax Labs#005557)中。测量小鼠,每周3次,并当肿瘤体积达到200-300mm3时,将小鼠随机分为四个治疗组:媒介物对照(含0.5%甲基纤维素、0.05%Tween-80的dH2O)、2.5mg/kg波齐替尼、10mg/kg T-DM1或2.5mg/kg波齐替尼与10mg/kg T-DM1的组合。测量肿瘤体积和体重,每周3次。用2.5mg/kg波齐替尼治疗的小鼠周一至周五(每周5天)口服接受药物。用10mg/kg T-DM1治疗的小鼠在随机化当天接受了一个静脉内(IV)剂量的T-DM1。用波齐替尼与T-DM1组合治疗的小鼠接受了一个IV剂量的T-DM1,并在该T-DM1剂量后3天,开始2.5mg/kg的波齐替尼,每周5天。如果小鼠的体重下降超过10%或如果体重下降到20克以下,则小鼠接受一个免于给药的假期。实验的完成符合良好动物实践(Good Animal Practices),并得到了MD Anderson癌症中心机构动物护理和使用委员会(Houston,TX))的批准。
FACS:将过度表达HER2突变的MCF10A细胞过夜平铺在6孔板中,然后用10nM波齐替尼处理。24小时后,用PBS将细胞洗涤两次,并用胰蛋白酶消化。然后将细胞重悬于含0.5%FBS的PBS中,并用来自Biolegend的抗HER2-FITC抗体(#324404)在冰上染色45分钟。用含0.5%FBS的PBS将细胞洗涤两次,并通过流式细胞术分析。IgG和未染色的对照用于门控。
蛋白质印迹:对于蛋白质印迹,在PBS中洗涤细胞,并在具有蛋白酶抑制剂混合片(Protease inhibitor cocktail tablet,Roche)的RIPPA裂解缓冲液(ThermoFisher)中裂解。将蛋白质(30-40μg)加载到从BioRad购买的凝胶中。使用BioRad半干转印(BioRadsemi-dry transfer),然后用针对pHER2、HER2、pPI3K、PI3K、p-AKT、AKT、p-ERK1/2和ERK1/2的抗体(1:1000;Cell Signaling)进行探测。探测印迹,用针对黏着斑蛋白或β-肌动蛋白的抗体(Sigma-Aldrich)作为上样对照,并使用ECL蛋白质印迹底物(Promega)使印迹曝光。
HER2表达水平以及与Ba/F3突变体IC50的相关性:从Ba/F细胞系收获蛋白质,并按照制造商说明书(Cell Signaling,#7310)所述的对总HER2进行ELISA。针对通过ELISA测定的相对表达与如上所述计算的IC50值作图。皮尔逊相关性和p值通过GraphPad Prism确定。
临床试验和CIND标识:关于同情使用协议(MD Anderson Cancer Center CIND-18-0014)或临床试验NCT03066206,患者提供了对于使用波齐替尼治疗的书面知情同意书。该方案已获MD Anderson癌症中心机构审查委员会和食品药品监督管理局批准。
本文公开和要求保护的所有方法可根据本公开在没有过度实验的情况下进行和执行。尽管已经按照优选的实施方案描述了本发明的组合物和方法,但是对于本领域技术人员而言明显的是,在不脱离本发明的概念、精神和范围的情况下,可以对本文所述方法以及所描述方法的步骤或步骤顺序进行改变。更具体而言,明显的是,化学和生理学上均相关的某些试剂可以代替本文所述的试剂,同时会获得相同或相似的结果。所有这些对本领域技术人员明显的类似替代和修改都视为在所附权利要求书限定的本发明的精神、范围和概念之内。
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序列表
<110> 得克萨斯大学体系董事会
<120> 治疗癌症的联合疗法
<130> UTFC.P1432WO
<140> PCT/US2019/068153
<141> 2019-12-20
<150> US 62/784,084
<151> 2018-12-21
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 12
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 合成的寡核苷酸
<400> 1
tatgtcatgg ct 12
Claims (55)
1.一种治疗受试者中的癌症的方法,包括向所述受试者施用有效量的酪氨酸激酶抑制剂(TKI)和HER抗体-药物缀合物。
2.根据权利要求1所述的方法,其中所述HER2抗体是曲妥珠单抗。
3.根据权利要求1所述的方法,其中所述HER2抗体-药物缀合物是曲妥珠单抗美坦新(T-DM1)。
4.根据权利要求1-3中任一项所述的方法,其中所述TKI是基于氨基喹唑啉的TKI。
5.根据权利要求4所述的方法,其中所述基于氨基喹唑啉的TKI是波齐替尼、阿法替尼、来那替尼、达可替尼或他索替尼。
6.根据权利要求4所述的方法,其中所述基于氨基喹唑啉的TKI是波齐替尼。
7.根据权利要求6所述的方法,其中以小于16mg的剂量施用所述波齐替尼。
8.根据权利要求1-7中任一项所述的方法,其中向所述受试者施用波齐替尼和T-DM1。
9.根据权利要求8所述的方法,其中向所述受试者施用单剂量的T-DM1。
10.根据权利要求1-9中任一项所述的方法,其中在所述HER2抗体-药物缀合物之前施用所述TKI。
11.根据权利要求1-9中任一项所述的方法,其中在所述HER2抗体-药物缀合物之后施用所述TKI。
12.根据权利要求1-9中任一项所述的方法,其中同时施用所述TKI与所述HER2抗体-药物缀合物。
13.根据权利要求1-12中任一项所述的方法,其中所述癌症是HER2突变性癌症。
14.根据权利要求13所述的方法,其中所述HER2突变性癌症包含所述激活酪氨酸激酶结构域内跨外显子19-21的HER2激活突变。
15.根据权利要求13所述的方法,其中所述HER2突变性癌症包含一种或多种选自由以下组成的组的突变:V754M、L755S、L755P、D769H、D769N、D769Y、V773M、V777L、Y772dupYVMA、G776delinsVC、G776delinsVV、G776delinsLC、V777insCG、G778insLPS、P780insGSP、L786V、V842I和L869R。
16.根据权利要求13所述的方法,其中所述HER2突变性癌症具有外显子19突变、外显子20突变和/或外显子21突变。
17.根据权利要求16所述的方法,其中所述HER2突变性癌症具有外显子20突变。
18.根据权利要求17所述的方法,其中所述外显子20突变包括HER2的氨基酸E770-R786之间的1-18个核苷酸的一个或多个点突变、插入和/或缺失。
19.根据权利要求18所述的方法,其中所述外显子20突变位于残基Y772、V773、A775、G776、V777、G778、S779和/或P780处。
20.根据权利要求17所述的方法,其中所述外显子20突变是外显子20插入突变。
21.根据权利要求20所述的方法,其中所述外显子20插入突变是Y772dupYVMA、G778dupGSP和/或G776delinsVC。
22.根据权利要求16所述的方法,其中所述外显子19突变位于残基L755或D769处。
23.根据权利要求16所述的方法,其中所述外显子19突变是L755P。
24.根据权利要求16的方法,其中所述外显子20突变是点突变。
25.根据权利要求24所述的方法,其中所述外显子20点突变位于残基C805处。
26.根据权利要求25所述的方法,其中所述外显子20点突变是C805S。
27.根据权利要求16所述的方法,其中所述外显子21突变是点突变。
28.根据权利要求27所述的方法,其中所述点突变位于残基V842或L869处。
29.根据权利要求28所述的方法,其中所述点突变是V842I或L869R。
30.根据权利要求1-29中任一项所述的方法,其中所述癌症是肺癌。
31.根据权利要求30所述的方法,其中所述肺癌是非小细胞肺癌(NSCLC)。
32.根据权利要求6所述的方法,其中口服施用所述波齐替尼。
33.根据权利要求32所述的方法,其中以5-25mg的剂量施用所述波齐替尼。
34.根据权利要求32所述的方法,其中以8mg、12mg或16mg的剂量施用所述波齐替尼。
35.根据权利要求34所述的方法,其中所述波齐替尼被进一步限定为波齐替尼盐酸盐。
36.根据权利要求35所述的方法,其中将所述波齐替尼盐酸盐配制成片剂。
37.根据权利要求6-36中任一项所述的方法,其中通过静脉内、皮下、骨内、口服、透皮、持续释放、控制释放、延迟释放、作为栓剂或舌下施用所述波齐替尼和/或T-DMl。
38.根据权利要求1-37中任一项所述的方法,还包括施用其他抗癌疗法。
39.根据权利要求38所述的方法,其中所述其他抗癌疗法是化疗、放疗、基因疗法、手术、激素疗法、抗血管生成疗法或免疫疗法。
40.根据权利要求1-39中任一项所述的方法,其中所述受试者是人。
41.一种药物组合物,包含TKI和HER抗体-药物缀合物。
42.根据权利要求41所述的组合物,其中所述TKI是波齐替尼,且所述HER抗体-药物缀合物是T-DM1。
43.一种预测患有癌症的受试者对TKI与HER2抗体-药物缀合物的组合的响应的方法,包括检测从所述受试者获得的基因组样品中的HER2突变,其中如果所述样品对所述HER2突变的存在呈阳性,则预测所述患者对所述波齐替尼与所述HER2抗体-药物缀合物的联合抗癌疗法具有有利响应。
44.根据权利要求43所述的方法,其中所述HER2突变是外显子19突变、外显子20突变和/或外显子21突变。
45.根据权利要求44所述的方法,其中所述外显子20突变包括HER2的氨基酸E770-R786之间的1-18个核苷酸的一个或多个点突变、插入和/或缺失。
46.根据权利要求44所述的方法,其中所述外显子20突变位于残基Y772、V773、A775、G776、V777、G778、S779和/或P780处。
47.根据权利要求45所述的方法,其中所述外显子20插入突变是Y772dupYVMA、G778dupGSP和/或G776delinsVC。
48.根据权利要求44所述的方法,其中所述外显子19突变位于残基L755或D769处。
49.根据权利要求44所述的方法,其中所述外显子20突变位于残基C805处。
50.根据权利要求43-49中任一项所述的方法,其中所述基因组样品分离自唾液、血液、尿液、正常组织或肿瘤组织。
51.根据权利要求43-50中任一项所述的方法,其中通过核酸测序或PCR分析确定HER2突变的存在。
52.根据权利要求43-51中任一项的方法,其中对所述TKI与所述HER抗体-药物缀合物的组合的有利响应包括减小肿瘤尺寸或负荷、阻断肿瘤生长、减少肿瘤相关疼痛、减少癌症相关病理、减少癌症相关症状、癌症无进展、无病间隔期增加、进展耗时增加、诱导缓解、减少转移或增加患者生存期。
53.根据权利要求43-53中任一项所述的方法,其中所述TKI是波齐替尼,并且所述HER抗体-药物缀合物是T-DM1。
54.根据权利要求43-53中任一项所述的方法,还包括向被预测具有有利响应的受试者施用所述TKI与所述HER2抗体-药物缀合物的组合。
55.根据权利要求43-54中任一项所述的方法,还包括向被预测具有有利响应的受试者施用波齐替尼与T-DM1的组合。
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