CN115362005A - 使用波齐替尼治疗具有nrg1融合的癌症 - Google Patents
使用波齐替尼治疗具有nrg1融合的癌症 Download PDFInfo
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Abstract
本文提供了选择癌症患者以使用波齐替尼治疗的方法以及治疗如此选择的癌症患者的方法。如果癌症患者的癌症具有NRG1融合,则选择该癌症患者进行治疗。然后被选择的患者单独使用波齐替尼或与HER2/HER3靶向抗体联合治疗。
Description
相关申请的交叉参考
本申请要求2020年1月29日提交的美国临时申请号62/967,265的优先权,其全部内容通过引用并入本文。
背景技术
1.技术领域
本发明一般涉及医学和肿瘤学领域。更具体地,其涉及选择癌症患者以单独使用波齐替尼或与HER2/HER3靶向抗体联合进行治疗的方法,以及治疗如此选择的癌症患者的方法。
2.相关技术说明
NRG1融合发生在0.3%的非小细胞肺癌(NSCLC)中,并且已在包括胆囊(0.5%)、乳腺癌(0.2%)、卵巢癌(0.4%)和结肠直肠癌(0.1%)(Jonna等人,2019年)在内的其他几种癌症类型中观察到。常见的NRG1融合伙伴是CD74(29%的NRG1融合)、ATP1B1(10%的NRG1融合)和SDC4(7%的NRG1融合)(Jonna等,2019)。NRG1与HER3受体结合,导致优先与HER2异源二聚化(Shin等,2018;Jung等,2015;Fernandez-Cuesta等,2014),这是ERBB家族信号传导的最有效形式之一(Holbro等,2003)。先前的报道表明,靶向HER2/HER3信号通路可有效抑制NRG1融合驱动的ErbB信号传导(Shin等,2018;Fernandez-Cuesta等,2014;Drilon等,2018)。先前的报道还表明,波齐替尼可以抑制EGFR(Robichaux等,2018)和HER2(Robichaux等,2019)突变。然而,目前还没有针对NRG1融合患者的获批的靶向疗法。
发明内容
在一个实施方式中,本文提供了治疗患有癌症的患者的方法,该方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼治疗;(c)对选定的患者给予或已经给予治疗有效量的波齐替尼。在一些方面,步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。
在一个实施方式中,本文提供了治疗患有癌症的患者的方法,所述方法包括向所述患者给予治疗有效量的波齐替尼,其中所述癌症具有NRG1融合。在一个实施方式中,本文提供了包含治疗有效量的波齐替尼的组合物,用于治疗患者的癌症,其中患者的癌症具有NRG1融合。
在一个实施方式中,本文提供选择患有癌症的患者以使用波齐替尼治疗的方法,所述方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼治疗。在一些方面,步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。在一些方面,所述方法还包括(c)对选定的患者给予或已经给予治疗有效量的波齐替尼。
在一个实施方式中,本文提供了治疗患有癌症的患者的方法,该方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼和HER2/HER3靶向抗体治疗;(c)对选定的患者联合给予或已经联合给予治疗有效量的波齐替尼和HER2/HER3靶向抗体。在一些方面,步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。
在一个实施方式中,本文提供了治疗患有癌症的患者的方法,所述方法包括向所述患者联合给予治疗有效量的波齐替尼和HER2/HER3靶向抗体,其中所述癌症具有NRG1融合。在一个实施方式中,本文提供了包含治疗有效量的波齐替尼和HER2/HER3靶向抗体的组合物,用于治疗患者的癌症,其中患者的癌症具有NRG1融合。
在一个实施方式中,本文提供选择患有癌症的患者以使用波齐替尼和HER2/HER3靶向抗体治疗的方法,所述方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼和HER2/HER3靶向抗体治疗。在一些方面,步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。在一些方面,所述方法还包括(c)对选定的患者联合给予或已经联合给予治疗有效量的波齐替尼和HER2/HER3靶向抗体。
在任何实施方式的一些方面,所述NRG1融合是NRG1-DOC4融合、NRG1-VAMP2融合、NRG1-CLU融合、NRG1-SLC3A2融合、NRG1-CD74融合、NRG1-ATP1B1融合、或NRG1-SDC4融合。
在任何实施方式的一些方面,所述方法还包括给予患者HER2/HER3靶向抗体。在一些方面,所述HER2/HER3靶向抗体包括曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、或T-DM1。
在任何实施方式的一些方面,所述方法还包括给予患者其他抗癌疗法。在一些方面,所述其他抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。
在任何实施方式的一些方面,所述癌症是乳腺癌、肺癌、结直肠癌、神经母细胞瘤、胰腺癌、脑癌、胃癌、皮肤癌、睾丸癌、***癌、卵巢癌、肝癌、食道癌、***、头颈癌、黑色素瘤或胶质母细胞瘤。在一些方面,所述癌症是乳腺癌或肺癌。
在任何实施方式的一些方面,所述患者之前至少接受过一轮抗癌疗法。在任何实施方式的一些方面,所述方法还包括报告患者癌症中存在NRG1融合。在一些方面,报告包括准备书面或电子报告。在一些方面,所述方法还包括将报告提供给对象、医生、医院或保险公司。
如本文所用,就特定组分而言“基本上不含”在本文中用于指没有任何指定的成分被有意地配制成组合物和/或仅作为污染物或痕量存在。因此,由组合物的任何意外污染导致的特定组分的总量远低于0.05%,优选低于0.01%。最优选的是用标准分析方法不能检测到特定组分的量的组合物。
如本说明书所用,“一个”或“一种”指一个/种或多个/种。如本文在权利要求中使用的,当与词语“包括”结合使用时,词语“一”或“一个”可以表示一个或多个。
权利要求书中给予的术语“或”的使用用于表示“和/或”,除非明确指出仅指代备选方案或备选方案相互排斥,尽管本公开支持仅指代备选方案和“和/或”的定义。如本文所用,“另一个”可以表示至少第二个或更多。
在整个本申请中,术语“约”用于表示一个值包括设备的固有误差变化、用于确定该值的方法、研究对象之间存在的变化、或在规定值的10%以内的值。
本发明的其它目的、特征和优点将通过以下详细描述而变得显而易见。但是,应当理解,以下详述和具体实施例以及本发明优选实施方式仅仅是用于举例说明,本领域普通技术人员通过阅读所述详述,可以显而易见地得知本发明精神和范围之内的各种变化和改良。
附图简要说明
下列附图构成本说明书的一部分并纳入其中以进一步说明本发明的某些方面。可参照这些附图中的一幅或者多幅并结合本文提供的具体实施方式的详述来更好地理解本发明。
图1:MDA175-VII(NRG1-DOC4融合体)用波齐替尼处理72小时的IC50值条形图。
图2A:MDA175-VII(NRG1-DOC4融合)细胞系用指定的HER2/HER3抗体并且用或不用低剂量波齐替尼(0.1nM)处理72小时的剂量反应曲线。在X轴上的100ng/mL值处,线从上到下分别代表T-DM1、曲妥珠单抗、帕妥珠单抗、曲妥珠单抗+波齐替尼0.1nM、T-DM1+波齐替尼0.1nM和帕妥珠单抗+波齐替尼0.1nM。
图2B:MDA175-VII(NRG1-DOC4融合)细胞系用指定的HER2/HER3抗体并且用或不用低剂量波齐替尼(0.1nM)处理72小时的条形图。
具体实施方式
本文提供了治疗具有NRG1融合的癌症患者的方法。具体而言,本方法包括将波齐替尼(也称为HM781-36B)单独或与HER2/HER3靶向抗体组合给予鉴定为具有NRG1融合的癌症患者。此外,本方法包括通过确定患者的癌症是否具有NRG1融合来识别和选择可能受益于波齐替尼的单独给予、或波齐替尼和HER2/HER3靶向抗体的组合的给予的癌症患者。
I.NRG1融合
NRG1融合基因包含与来自不同染色***置的序列融合的至少一部分NRG1基因。“至少一部分”表示整个NRG1基因可以存在于融合物中或其一部分中。该融合物可以至少具有NRG1的外显子6、7和8的编码序列。在NRG1融合基因中定义NRG1部分的另一种方法是它包含NRG1的EGF样结构域。EGF样结构域由基因的3'端编码,是与ErbB-3结合所必需的。NRG1融合保留了EGF样结构域的框内编码区。NRG1基因部分可以融合到来自不同染色***置的序列,使得所述序列位于NRG1基因部分的5'或3'。
优选地,NRG1基因的3'末端可以融合至来自不同染色***置的序列。特别地,NRG1融合基因可以是NRG1基因的3'末端与选自下组的基因之一的5'序列的融合物:DOC4(也称为Teneurin跨膜蛋白4(TENM4);蛋白Odd Oz/Ten-M同源物4;生腱蛋白-M4;Ten-M4;Ten-4;ODZ4;TNM4;Odz,Odd Oz/Ten-M同源物4(果蝇);Odz,Odd Oz^en-M同源物4;Teneurin-4;KIAA1302;Doc4;ETM5;HGNC:29945;Entrez Gene:26011;Ensembl:ENSG00000149256;OMIM:610084;和UniProtKB:Q6N022);CD74(也称为CD74分子;CD74抗原(主要组织相容性复合物的非变异多肽,II类抗原相关);CD74分子,主要组织相容性复合物,II类非变异链;HLA-DR抗原相关的非变异链;II类抗原的γ链;1a-相关的非变异链;MHC HLA-DRγ链;HLA-DR-γ;DHLAG;P33;HLA II类组织相容性抗原γ链;1a抗原相关的非变异链;1a-γ;HLADG;HGNC:1697;Entrez Gene:972;Ensembl:ENSG00000019582;OMIM:142790,和UniProtKB:P04233);TNFRSF10B(也称为TNF受体超家族成员10b;肿瘤坏死因子受体超家族,成员10b;TNF相关的凋亡诱导配体受体2;死亡受体5;TRAIL-R2;TRAILR2;KILLER;TRICK2;ZTNFR9;DR5;P53调节的DNA损伤诱导细胞死亡受体(杀伤);肿瘤坏死因子受体超家族成员10B;肿瘤坏死因子受体样蛋白ZTNFR9;含有TRAIL/Apo-2L受体的死亡结构域;细胞凋亡诱导蛋白TRICK2A/2B;凋亡诱导受体TRAIL-R2;细胞毒性TRAIL受体2;Fas样蛋白;TRAIL受体2;CD262抗原;KILLER/DR5;TRICK2A;TRICK2B;TRICKB;CD262;HGNC:11905;Entrez Gene:8795;Ensembl:ENSG00000120889;OMIM:603612;和UniProtKB:014763);CLU(也称为凝聚素;睾酮抑制***按摩2;载脂蛋白J;补体相关的蛋白SP-40,40;补体细胞溶解抑制剂;补体溶解抑制剂;硫酸化糖蛋白2;Ku70结合蛋白1;NA1/NA2;TRPM-2;APO-J;APOJ;KUB1;CLI;聚簇蛋白(补体裂解抑制剂,SP-40,40,硫酸化糖蛋白2,睾酮-抑制***按摩2,载脂蛋白J);衰老相关基因4蛋白;衰老相关的蛋白4;SGP-2;SP-40;TRPM2;AAG4;CLU1;CLU2;SGP2;HGNC:2095;EntrezGene:1191;Ensembl:ENSG00000120885;OMIM:185430;和UniProtKB:P10909);VAMP2(也称为囊泡相关的膜蛋白2;突触素2;SYB2;囊泡相关的膜蛋白2;突触素-2;HGNC:12643;EntrezGene:6844;Ensembl:ENSG00000220205;OMIM:185881;和UniProtKB:P63027);SLC3A2(也称为溶质载体家族3成员2;淋巴细胞活化抗原4F2大亚单位;溶质载体家族3(二元和中性氨基酸转运激活剂),成员2;单克隆抗体鉴定的抗原4F2,TRA1.10,TROP4,和T43;溶质载体家族3(氨基酸转运蛋白重链),成员2;4F2细胞表面抗原重链;CD98重链;4F2HC;MDU1;单克隆抗体定义的抗原4F2,重链;单克隆抗体定义的抗原4F2;4F2重链抗原;4F2重链;CD98抗原;CD98HC;4T2HC;NACAE;CD98;4F2;HGNC:11026;Entrez Gene:6520;Ensembl:ENSG00000168003;OMIM:158070;和UniProtKB:P08195);RBPMS(也称为具有多重剪接的RNA结合蛋白;心脏和RRM表达序列;HERMES;具有多重剪接的RNA结合蛋白;RBP-MS;HGNC:19097;Entrez Gene:11030;Ensembl:ENSG00000157110;OMIM:601558;和UniProtKB:Q93062);WRN(也称为Werner综合征RecQ样解旋酶;DNA解旋酶,RecQ样类型33;RecQ蛋白样2;核酸外切酶WRN;RECQL2;RECQ3;Werner综合征ATP依赖性解旋酶;Werner综合征,RecQ解旋酶样;Werner综合征;EC 3.6.4.12;EC 3.1.-.-;EC 3.6.1;RECQL3;HGNC:12791;EntrezGene:7486;Ensembl:ENSG00000165392;OMIM:604611和UniProtKB:Q14191);SDC4(也称为多配聚糖4(双栖蛋白聚糖,抗凝蛋白聚糖);多配聚糖-蛋白聚糖4;凝蛋白聚糖核心蛋白;双栖蛋白聚糖;SYND4;凝蛋白聚糖双栖蛋白聚糖;多配聚糖--4;HGNC:10661;Entrez Gene:6385;Ensembl:ENSG00000124145;OMIM:600017;和UniProtKB:P31431);KIF13B;SLECA2;PDE7A;ATP1B1;CDK1;BMPRIB;MCPH1;和RAB2IL1。
本公开的某些实施方式涉及确定对象是否具有NRG1融合。检测方法是本领域已知的,包括PCR分析、核酸测序、荧光原位杂交(FISH)、显色原位杂交(CISH)和比较基因组杂交(CGH)。
适用于本文所述方法的样本含有遗传物质,例如基因组DNA(gDNA)。基因组DNA通常从生物样本如血液或口腔内壁的黏膜刮屑中提取,但也可以从其他生物样本中提取,包括尿液、肿瘤或祛痰剂。样本本身通常将包括从对象中(包括肿瘤组织中)取出的有核细胞(例如,血液或口腔细胞)或组织。用于获得、处理和分析样本的方法和试剂在本领域中是已知的。在一些实施方式中,样本是在医疗保健提供者的帮助下获得的,例如,用于抽血或进行肿瘤活检。在一些实施方式中,样本是在没有医疗保健提供者的帮助下获得的,例如,在样本是非侵入性获得的情况下,使用口腔拭子或刷子或漱口水样本获得的包含口腔细胞的样本。
特别地,患者样本可以是任何身体组织或流体,其包括来自对象的癌症的核酸。在某些实施方式中,样本将是包含循环肿瘤细胞或无细胞DNA的血液样本。在其他实施方式中,样本可以是组织,例如肿瘤组织。肿瘤组织可以是新鲜冷冻或***固定、石蜡包埋(FFPE)。
在某些情况下,可能会处理生物样本以进行DNA分离。例如,细胞或组织样本中的DNA可以与样本的其他成分分离。可以使用本领域已知的标准技术从生物样本中收获细胞。例如,可以通过离心细胞样本并重悬沉淀的细胞来收获细胞。可以将细胞重新悬浮在缓冲溶液中,例如磷酸盐缓冲盐水(PBS)。在将细胞悬液离心以获得细胞沉淀后,可以裂解细胞以提取DNA,例如gDNA。样本可被浓缩和/或纯化以分离DNA。从对象获得的所有样本,包括那些经过任何种类的进一步处理的样本,都被认为是从对象获得的。能使用常规方法从生物样本提取基因组DNA,包含例如苯酚提取。或者,可以使用组织试剂盒(凯捷公司(Qiagen),查茨沃斯,加州)或基因组DNA纯化试剂盒(普罗梅加公司(Promega))等试剂盒提取基因组DNA。
在需要的情况下,可以使用本领域已知的方法例如PCR来完成核酸的扩增。在一个实例中,样本(例如,包含基因组DNA的样本)从对象获得。然后检查样本中的DNA以确定如本文所述的NRG1融合的身份。NRG1融合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、RNA或cDNA中的基因与核酸探针(例如DNA探针(包括cDNA和寡核苷酸探针)或RNA探针)杂交。核酸探针可以设计为与特定的NRG1融合体特异性或优先杂交。
一组探针通常是指一组引物,通常是引物对,和/或可检测标记的探针,用于检测在本公开的可操作治疗建议中使用的目标遗传变异(例如,NRG1融合)。引物对用于扩增反应以定义对应于NRG1融合的扩增子。该组扩增子由一组匹配的探针检测。在一个示例性实施方式中,本发明的方法可以使用TaqManTM(Roche Molecular Systems,Pleasanton,CA)测定,其用于检测一组目标遗传变异,例如NRG1融合。在一个实施方式中,该组探针是一组用于产生扩增子的引物,这些扩增子通过核酸测序反应如下一代测序反应来检测。在这些实施方式中,例如,可以采用AmpliSEQTM(生命技术公司(Life Technologies)/离子激流公司(Ion torrent),卡尔斯巴德,加州)或TruSEQTM(亿明达公司(Illumina),圣迭戈,加州)技术。
可以使用本领域已知的技术(包括但不限于序列分析和电泳分析)进行核酸标志物的分析。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、固相测序、质谱测序如基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF/MS)、以及杂交测序。电泳分析的非限制性示例包括平板凝胶电泳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。此外,可以使用生命技术公司/离子激流公司的PGM或Proton、亿明达公司公司的HiSEQ或MiSEQ以及罗氏公司(Roche)/454的下一代测序***等公司的商用试剂盒和仪器执行下一代测序方法。
其他核酸分析方法可以包括直接人工测序(美国专利号5,288,644);自动荧光测序;单链构象多态性测定(SSCP);钳位变性凝胶电泳(CDGE);二维凝胶电泳(2DGE或TDGE);构象敏感凝胶电泳(CSGE);变性梯度凝胶电泳(DGGE);变性高效液相色谱(DHPLC);红外基质辅助激光解吸/电离(IR-MALDI)质谱;流动性变化分析;限制酶分析;定量实时PCR;异源双链分析;化学错配裂解(CMC);RNase保护试验;使用识别核苷酸错配的多肽,例如大肠杆菌mutS蛋白;等位基因特异性PCR,以及这些方法的组合。参见例如,美国专利公开号2004/0014095,将其全文纳入本文作参考。
在一个实例中,鉴定样本中的NRG1融合的方法包括使来自所述样本的核酸与能够与编码NRG1融合的核酸特异性杂交的核酸探针接触并检测所述杂交。在一个具体的实施方式中,所述探针被可检测地标记,如用放射性同位素(3H、32P或33P)、荧光剂(罗丹明或荧光素)或显色剂。在一个具体实施方式中,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。探针可为约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。在另一个方面,本公开的所述探针在用于鉴定样本中的NRG1融合物的试剂盒中提供,所述试剂盒包含与特定NRG1融合物特异性杂交的寡核苷酸。该试剂盒可进一步包括基于使用该试剂盒的杂交测试的结果,使用波齐替尼、或波齐替尼和HER2/HER3靶向抗体的组合治疗患有NRG1融合肿瘤的患者的说明。
II.HER2/HER3靶向抗体
如本文所用的HER2/HER3靶向抗体包括干扰HER2和/或HER3功能的任何分子。因此,HER2/HER3靶向抗体包括抗HER2抗体(例如曲妥珠单抗或帕妥珠单抗)、抗HER3抗体和抗HER2/HER3双特异性抗体(例如,WO2018/182422或MCLA-128中公开的抗体)。HER2/HER3靶向抗体可以防止HER2/HER2二聚体和/或HER2/HER3二聚体(例如曲妥珠单抗或帕妥珠单抗)的形成。在一些情况下,靶向HER2/HER3的抗体可能是抗体药物偶联物(例如,T-DM1或U3-1402)。
在某些实施方式中,HER2/HER3靶向抗体是曲妥珠单抗(基因泰克公司(Genentech)和罗氏公司),曲妥珠单抗emtansine(T-DM1;基因泰克公司和罗氏公司),帕妥珠单抗(Genentech),厄妥索单抗(ertumaxomab)(费森尤斯公司(Fresenius)),马吉妥昔单抗(margetuximab)(MacroGenics),MCLA-128(泽诺库珠单抗(zenocutuzumab);Merus公司)MM-111(Merrimack公司),MM-121(Merrimack公司),CT-P06(赛尔群公司Celltrion),GSK2849330(葛兰素史克公司(GlaxoSmithKline)),PF-05280014(辉瑞公司(Pfizer)),MM-302(Merrimack公司),SB3(Merck&Co),CMAB302(上海三生国健公司(Shanghai CPGuojian)),RG7116(雷妥珠单抗(lemretuzumab);基因泰克公司/罗氏公司),TrasGEX(Glycotope公司),ARX788(安博生物(Ambrx)和浙江医药(Zhejiang Medicine)),SYD985(Synthon),FS102(百时美施贵宝公司(Bristol-Myers Squibb)和f-star公司),BCD-022(博康公司(Biocad)),ABP 980(安进公司(Amgen)),DS-8201a(第一三共株式会社(DaiichiSankyo)),HLX02(上海复宏汉霖公司(Shanghai Henlius)),SAR256212(赛诺菲肿瘤公司(Sanofi Oncology)),RG7597(基因泰克公司),U3-1402(第一三共株式会社),或CANMAb(百康公司(Biocon)和迈兰公司(Mylan))。
曲妥珠单抗(CAS 180288-69-1,huMAb4D5-8,rhuMAb HER2,基因泰克公司)是一种人源化IgG1 kappa单克隆抗体,以高亲和力选择性结合人表皮生长因子受体2蛋白HER2(ErbB2)的细胞外结构域(美国专利号5,677,171;5,821,337;6,054,297;6,165,464;6,339,142;6,407,213;6,639,055;6,719,971;6,800,738;7,074,404)。曲妥珠单抗包含人类框架区和与HER2结合的鼠抗体(4D5)的互补决定区。曲妥珠单抗与HER2抗原结合,从而抑制癌细胞的生长。体外试验和动物试验均显示曲妥珠单抗可抑制过度表达HER2的人类肿瘤细胞的增殖。曲妥珠单抗是抗体依赖性细胞毒性ADCC的介质。
曲妥珠单抗emtansine,也称为阿杜曲妥珠单抗(ado-trastuzumab emtansine),以商品名销售,是一种抗体-药物偶联物,由与细胞毒剂emtansine(DM1)共价连接的人源化单克隆抗体曲妥珠单抗组成。曲妥珠单抗单独通过与HER2受体结合来阻止癌细胞的生长,而曲妥珠单抗emtansine经历受体介导的细胞内化,在溶酶体中分解代谢,释放含有DM1的分解代谢物,随后结合微管蛋白导致有丝***停滞和细胞死亡。曲妥珠单抗与HER2结合可防止受体的同源二聚化或异源二聚化(HER2/HER3),最终抑制MAPK和PI3K/AKT细胞信号通路的激活。因为单克隆抗体靶向HER2,而HER2仅在癌细胞中过表达,所以偶联物将细胞毒剂DM1特异性地递送至肿瘤细胞。偶联物缩写为T-DM1。T-DM1可以2-3mg/kg的剂量给予,例如3.6mg/kg。T-DM1可以通过静脉输注给予。
帕妥珠单抗(CAS Reg.No.380610-27-5,2C4,基因泰克公司)是一种重组人源化单克隆抗体,可抑制HER2二聚化(美国专利号6,054,297;6,407,213;6,800,738;6,627,196、6,949,245;7,041,292)。帕妥珠单抗包含人IgG1(x)框架序列。帕妥珠单抗和曲妥珠单抗靶向HER2酪氨酸激酶受体的不同细胞外区域。帕妥珠单抗与HER2亚结构域2内的表位结合,而曲妥珠单抗的表位定位于亚结构域4。帕妥珠单抗阻断HER2受体与其他HER受体家族成员(即HER1/EGFR、HER3和HER4)协作的能力(美国专利号6,949,245)。在癌细胞中,干扰HER2与其他HER家族受体协作的能力会阻断细胞信号传导,并可能最终导致癌细胞生长抑制和癌细胞死亡。
其他示例性HER2/HER3靶向抗体包括MM-121/SAR256212,其是一种靶向HER3受体的全人源单克隆抗体,据报道可用于治疗非小细胞肺癌(NSCLC)、乳腺癌和卵巢癌。SAR256212是一种针对HER3(ErbB3)受体的在研全人源单克隆抗体。度利戈珠单抗(Duligotuzmab)(MEHD7945A,RG7597)是一种靶向HER1和HER3的人源化IgG1单克隆抗体,已被描述为可用于治疗头颈癌。马吉妥昔单抗(margetuximab)(MGAH22)是一种针对HER2的Fc优化单克隆抗体。
根据本公开的抗体可以首先通过它们的结合特异性来定义。本领域技术人员通过使用本领域技术人员熟知的技术评估给定抗体的结合特异性/亲和力,可以确定此类抗体是否落入本权利要求的范围内。本领域普通技术人员已知的各种技术可用于确定抗体是否与多肽或蛋白质相互作用。示例性技术包括例如常规交叉阻断测定。交叉阻断可以在各种结合测定中测量,例如ELISA、生物层干涉法或表面等离子共振。其他方法包括丙氨酸扫描突变分析、肽印迹分析、肽切割分析、使用单粒子重建的高分辨率电子显微镜技术、cryoEM或断层扫描、晶体学研究和NMR分析。
本公开内容包括可以结合相同表位或表位的一部分的抗体。同样,本公开还包括与本文所述的任何特定示例性抗体竞争结合靶标或其片段的抗体。通过使用本领域已知的常规方法,可以容易地确定抗体是否与参考抗体结合相同的表位或竞争结合参考抗体。例如,为了确定测试抗体是否与参考抗体结合相同的表位,允许参考抗体在饱和条件下与靶标结合。接下来,评估测试抗体与靶分子结合的能力。如果测试抗体在与参考抗体饱和结合后能够与靶分子结合,则可以得出结论,测试抗体与参考抗体不同的表位结合。另一方面,如果测试抗体在与参考抗体饱和结合后不能与靶分子结合,则测试抗体可以结合与参考抗体结合的表位相同的表位。
如果两个抗体竞争性地抑制(阻断)另一个与抗原的结合,则两个抗体与相同或重叠的表位结合。即,如在竞争性结合测定中测量的,1、5、10、20或100倍过量的一种抗体抑制另一种抗体的结合至少50%,但优选75%、90%或甚至99%。或者,如果抗原基本导致一个抗体的结合能力减弱或消失的所有氨基酸突变导致另一个抗体的结合能力减弱或消失,则说明这两个抗体拥有相同的表位。如果抗原中一些导致一个抗体的结合能力减弱或消失的氨基酸突变导致另一个抗体的结合能力减弱或消失,则说明这两个抗体拥有重叠的表位。
然后可以进行额外的常规实验(例如,肽突变和结合分析)以确认观察到的测试抗体缺乏结合是否实际上是由于与参考抗体结合相同的表位,或者空间封闭(或其他现象)是否是缺乏观察到的结合的原因。可以使用ELISA、RIA、表面等离子共振、流式细胞术或本领域可用的任何其他定量或定性抗体结合测定来进行此类实验。使用EM或晶体学进行结构研究也可以证明两种竞争结合的抗体是否识别相同的表位。
在另一个方面,抗体可以由它们的可变序列定义,其包括额外的“框架”区域。此外,抗体序列可以与这些序列不同,任选地使用下文更详细讨论的方法。例如,核酸序列可以不同于上面列出的那些,因为(a)可变区可以与轻链和重链的恒定结构域分离,(b)核酸可与上述不同,但不影响其编码的残基,(c)核酸可以与上述那些相差给定百分比,例如,70%、75%、80%、85%、90%、91%、92%、93%、94%、95%,96%、97%、98%或99%同源性,(d)核酸可因在高严格条件下杂交的能力而不同于上述那些,例如低盐和/或高温条件,例如由约0.02M至约0.15M NaCl在约50℃至约70℃的温度,(e)氨基酸可与上述氨基酸相差给定百分比,例如80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同源性,或(f)通过允许保守替换(下文讨论),氨基酸可与上述不同。
当比较多核苷酸和多肽序列时,如果两个序列中的核苷酸或氨基酸序列在比对最大对应时相同,则称这两个序列是“相同的”,如下所述。两个序列之间的比较通常通过在比较窗口上比较序列以识别和比较序列相似性的局部区域来进行。如本文所用,“比较窗口”是指至少约20个连续位置的片段,通常为30至约75、40至约50,其中在两个序列最佳比对后,可以将序列与相同数量的连续位置的参考序列进行比较。
可使用生物信息学软件Lasergene套件(DNASTAR,Inc.,Madison,Wis.)中的Megalign程序使用默认参数进行用于比较的序列的最佳比对。该程序体现了以下参考文献中描述的几种比对方案:Dayhoff,M.O.(1978)蛋白质进化变化的模型——检测远距离关系的矩阵(A model of evolutionary change in proteins--Matrices for detectingdistant relationships)。在Dayhoff,M.O.(编辑)蛋白质序列与结构图谱,国家生物医学研究基金会,Washington D.C.卷5,增刊3,345-358页;Hein J.(1990)比对和***发育的统一方法(Unified Approach to Alignment and Phylogeny)626-645页Methods inEnzymology卷183,美国学术出版社,圣迭戈,加州;Higgins,D.G.和Sharp,P.M.(1989)CABIOS 5:151-153;Myers,E.W.和Muller W.(1988)CABIOS 4:11-17;Robinson,E.D.(1971)Comb.Theor 11:105;Santou,N.Nes,M.(1987)Mol.Biol.Evol.4:406-425;Sneath,P.H.A.和Sokal,R.R.(1973)数值分类学--数值分类学的原理与实践(NumericalTaxonomy--the Principles and Practice of Numerical Taxonomy,Freeman Press),旧金山,加州;Wilbur,W.J.和Lipman,D.J.(1983)Proc.Natl.Acad.,Sci.USA 80:726-730。
或者,可进行最优序列比对以作比较,通过Smith和Waterman的局部同源性算法,Adv.Appl.Math.2:482(1981);通过Needleman和Wunsch的同源性比对算法,J.Mol.Biol.48:443(1970);通过Pearson和Lipman的相似性搜索法,Proc.Nat’l.Acad.Sci.USA 85:2444(1988);通过计算机执行这些算法(遗传学计算组(GeneticsComputer Group)的威斯康星遗传学软件包(Wisconsin Genetics Software Package)中的GAP、BESTFIT、FASTA和TFASTA,575科学大道(Science Dr.),威斯康星州麦迪逊(Madison,WI)),或通过目测。
适用于确定百分比序列同一性和序列相似性的算法的一个特定示例是BLAST和BLAST 2.0算法,分别见Altschul等(1977)Nucleic Acids Res.25:3389-3402和Altschul等(1990)J.Mol.Biol.215:403-410所述。BLAST和BLAST 2.0可以例如与本文所述的参数一起用于确定本公开的多核苷酸和多肽的百分比序列同一性。进行BLAST分析的软件可通过国家生物技术信息中心(National Center for Biotechnology Information)从公开渠道获得。抗体序列的重排性质和每个基因的可变长度需要多轮BLAST搜索来寻找单个抗体序列。此外,不同基因的手动组装很困难且容易出错。序列分析工具IgBLAST(万维网ncbi.nlm.nih.gov/igblast/)可识别与种系V、D和J基因的匹配、重排连接处的细节、Ig V结构域框架区和互补决定区的描述。IgBLAST可以分析核苷酸或蛋白质序列,可以批量处理序列,并允许同时搜索种系基因数据库和其他序列数据库,以最大限度地减少可能丢失最佳匹配种系V基因的机会。
在一个说明性实例中,对于核苷酸序列而言,利用参数M(一对匹配残基的奖励评分;总是>0)和N(错配残基的罚分;总是<0)计算累积评分。出现以下情况时中止字命中在各个方向上的延伸:与最大获得值相比,累积比对评分减少X;由于一个或多个负评分残基比对的累积,累积评分接近零或低于零;或者到达任一序列末端。BLAST算法参数W、T和X确定对齐的灵敏度和速度。BLASTN程序(用于核苷酸序列)默认使用11的字长(W),期望值(E)10,BLOSUM62评分矩阵(参见Henikoff和Henikoff,Proc.Natl.Acad.Sci.USA 89:10915(1989))比对(B)50,期望值(E)10,M=5,N=-4,以及比较两条链。
就氨基酸序列而言,可用评分矩阵计算累积评分。出现以下情况时中止字命中在各个方向上的延伸:与最大获得值相比,累积比对评分减少X;由于一个或多个负评分残基比对的累积,累积评分接近零或低于零;或者到达任一序列末端。BLAST算法参数W、T和X确定对齐的灵敏度和速度。
在一种方法中,“序列同一性百分比”通过在至少20个位置的比较窗口上比较两个最佳比对序列来确定,其中与参考序列(其不包括添加或缺失)相比,比较窗口中的多核苷酸或多肽序列的部分可以包含20%或更少、通常是5%到15%、或10%到12%的添加或缺失(即,间隙)以实现两个序列的最佳比对。通过确定两个序列中出现相同核酸碱基或氨基酸残基的位置的数量来计算百分比,从而产生匹配位置的数量,将匹配位置的数量除以参考序列中的位置总数(即窗口大小)并将结果乘以100以产生序列同一性的百分比。
定义抗体的另一种方式是作为任何所述抗体及其抗原结合片段的“衍生物”。术语“衍生物”是指免疫特异性结合抗原但相对于“亲本”(或野生型)分子包含一、二、三、四、五个或更多个氨基酸取代、添加、缺失或修饰的抗体或其抗原结合片段。此类氨基酸取代或添加可引入天然存在的(即,DNA编码的)或非天然存在的氨基酸残基。术语“衍生物”包括例如具有改变的CH1、铰链、CH2、CH3或CH4区的变体,以形成例如抗体等,其具有表现出增强或受损的效应子或结合特性的变体Fc区。术语“衍生物”另外包括非氨基酸修饰,例如,可以糖基化(例如,改变了的甘露糖、2-N-乙酰氨基葡萄糖、半乳糖、岩藻糖、葡萄糖、唾液酸、5-N-乙酰神经氨酸、5-乙二醇神经氨酸等含量)、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知保护/封闭基团衍生、蛋白水解切割、连接到细胞配体或其他蛋白质等的氨基酸等。在一些实施方式中,改变的碳水化合物修饰调节以下一项或多项:抗体的溶解,促进抗体的亚细胞运输和分泌,促进抗体组装,构象完整性和抗体介导的效应功能。在一个具体实施方式中,相对于缺乏碳水化合物修饰的抗体,改变的碳水化合物修饰增强了抗体介导的效应器功能。导致抗体介导的效应器功能改变的碳水化合物修饰是本领域众所周知的。
衍生抗体或抗体片段可以产生具有工程化序列或糖基化状态以赋予抗体依赖性细胞毒性(ADCC)、抗体依赖性细胞吞噬作用(ADCP)、抗体依赖性中性粒细胞吞噬作用(ADNP)或抗体依赖性补体沉积(ADCD)功能的优选活性水平,如通过基于珠或基于细胞的测定法或动物模型中的体内研究测量。
可以使用本领域技术人员已知的技术通过化学修饰来修饰衍生抗体或抗体片段,包括但不限于特异性化学裂解、乙酰化、制剂、衣霉素的代谢合成等。在一个实施方式中,抗体衍生物将具有与亲本抗体相似或相同的功能。在另一个实施方式中,抗体衍生物将表现出相对于亲本抗体改变的活性。例如,衍生抗体(或其片段)可以比亲本抗体更紧密地结合其表位或对蛋白水解具有更强的抗性。
III.治疗方法
本发明提供了用波齐替尼单独或与HER2/HER3靶向抗体组合治疗癌症患者的方法。这种治疗也可以与另一种治疗方案组合,例如化学疗法或免疫疗法。本发明的某些方面可用于基于患者癌细胞中NRG1融合的存在来选择癌症患者进行治疗。在各个方面,大约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%的构成癌症的细胞可能具有NRG1融合,这表明患者是治疗的候选者。在某些方面,患者的癌细胞缺乏EGFR T790和/或EGFR C797突变。在某些方面,患者的癌细胞在HER2 T798和/或HER2 C805处缺乏突变。
在某些方面,通过分析来自对象的基因组样本确定对象具有NRG1融合。在一些方面,基因组样本从唾液、血液、尿液或肿瘤组织中分离。在特定方面,NRG1融合的存在通过核酸测序(例如,肿瘤组织的DNA测序或来自血浆的循环游离DNA)或PCR分析来确定。
某些实施方式涉及向确定具有NRG1融合的对象给予波齐替尼(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)。波齐替尼是一种基于喹唑啉的泛HER抑制剂,其不可逆地阻断通过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,美国专利第8,188,102号和美国专利公开第20130071452号;通过引用并入本文)可用于本方法。
在一些方面,波齐替尼进一步定义为波齐替尼盐酸盐。在某些方面,将波齐替尼盐酸盐配制成片剂。波齐替尼可以口服给予,例如以片剂形式给予波齐替尼可以4-25mg的剂量给予,例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25mg的剂量。在某些方面,波齐替尼以6mg、8mg、12mg或16mg的剂量给予。给药可以是每天两次、每天、每隔一天、每3天或每周一次。给药可以按连续时间表进行,例如以28天为周期。
在某些方面,波齐替尼和/或HER2/HER3靶向抗体通过静脉内、皮下、骨内、口服、经皮、缓释、控释、延迟释放、栓剂或舌下给予。在一些方面,给予波齐替尼和/或HER2/HER3靶向抗体包括局部、区域或全身给予。在特定方面,波齐替尼和/或HER2/HER3靶向抗体给予两次或更多次,例如每天、每隔一天或每周一次。
在一些方面,波齐替尼在HER2/HER3靶向抗体之前或之后给予,例如间隔1天,2天,3天,4天,5天,6天,7天,2周,3周,1个月或更长时间。在一些方面,波齐替尼与HER2/HER3靶向抗体同时给予。
如本文所用,术语“对象”或“患者”是指对其执行主题方法的任何个体。通常患者是人,尽管如本领域技术人员将理解的,患者可以是动物。因此,其他动物,包括哺乳动物,如啮齿动物(包括小鼠、大鼠、仓鼠和豚鼠)、猫、狗、兔子、农场动物,包括牛、马、山羊、绵羊、猪等,以及灵长类动物(包括猴子、黑猩猩、猩猩和大猩猩),都包括在患者的定义内。
“治疗”和“处置”是指为了获得疾病或健康相关病症的治疗益处的目的,向对象给予或应用治疗剂或对对象执行程序或方式。例如,治疗可以包括给予化学疗法、免疫疗法、放射疗法、进行手术或其任何组合。
本文所述的方法可用于抑制细胞(例如,肿瘤细胞)的存活或增殖、治疗增殖性疾病(例如,癌症、牛皮癣)和治疗致病性感染。通常,术语“癌症”和“癌”是用于描述哺乳动物的生理病症,其典型特征是细胞生长失控。更具体地,结合本文提供的方法治疗的癌症包括但不限于实体瘤、转移性癌症或非转移性癌症。在某些实施方式中,癌症可以起源于肺、肾、膀胱、血液、骨、骨髓、脑、***、结肠、食道、十二指肠、小肠、大肠、结肠、直肠、***、牙龈、头部、肝脏、鼻咽、颈部、卵巢、胰腺、***、皮肤、胃、睾丸、舌头或子宫。
癌症可能特别具有以下组织学类型,但不限于这些:肿瘤,恶性;癌;非小细胞肺癌;肾癌;肾细胞癌;透明细胞肾细胞癌;淋巴瘤;母细胞瘤;肉瘤;癌,未分化;脑膜瘤;脑癌;口咽癌;鼻咽癌;胆道癌;嗜铬细胞瘤;胰岛细胞癌;Li-Fraumeni肿瘤;甲状腺癌;甲状旁腺癌;垂体瘤;肾上腺肿瘤;成骨肉瘤;神经内分泌肿瘤;乳腺癌;肺癌;头颈癌;***癌;食道癌;气管癌;肝癌;膀胱癌;胃癌;胰腺癌;卵巢癌;子宫癌;***;睾丸癌;结肠癌;直肠癌;皮肤癌;巨细胞癌和梭形细胞癌;小细胞癌;小细胞肺癌;***状癌;口腔癌;口咽癌;鼻咽癌;呼吸道癌;泌尿生殖***癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母细胞癌;移行细胞癌;***状移行细胞癌;腺癌;胃肠癌;胃泌素瘤,恶性;胆管癌;肝细胞癌;合并肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉病;实体癌;类癌,恶性;鳃-肺泡腺癌;***状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸腺癌;嗜碱性粒细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;***状和滤泡状腺癌;非包膜硬化性癌;肾上腺皮质癌;子宫内膜癌;皮肤附件癌;大汗腺癌;皮脂腺癌;耵聍腺癌;粘液表皮样癌;囊腺癌;***状囊腺癌;***状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特病,乳腺;腺泡细胞癌;腺鳞癌;伴有鳞状化生的腺癌;胸腺瘤,恶性;卵巢间质瘤,恶性;昏迷,恶性;颗粒细胞瘤,恶性;恶性成纤维细胞瘤;支持细胞癌;***瘤,恶性;脂质细胞瘤,恶性;副神经节瘤,恶性;乳腺外副神经节瘤,恶性;嗜铬细胞瘤;血管肉瘤;恶性黑色素瘤;无色素性黑色素瘤;浅表扩散黑色素瘤;巨大色素痣中的恶性黑色素瘤;恶性雀斑样黑色素瘤;肢端黑色素瘤;结节性黑色素瘤;上皮样细胞黑色素瘤;蓝色痣,恶性;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;混合瘤,恶性;苗勒管混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间充质瘤,恶性;布伦纳肿瘤,恶性;叶状肿瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎癌;畸胎瘤,恶性;卵巢基质,恶性;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西肉瘤;恶性血管外皮细胞瘤;***肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间充质软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤;牙源性肿瘤,恶性;成釉细胞牙肉瘤;成釉细胞瘤,恶性;成釉细胞纤维肉瘤;内分泌或神经内分泌癌或造血癌;松果体瘤,恶性;脊索瘤;中枢或周围神经***组织癌;胶质瘤,恶性;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突胶质细胞瘤;原始神经外胚层;小脑肉瘤;神经节神经母细胞瘤;成神经细胞瘤;视网膜母细胞瘤;嗅觉神经源性肿瘤;脑膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞瘤,恶性;B细胞淋巴瘤;恶性淋巴瘤;霍奇金病;霍奇金的;低级别/滤泡性非霍奇金淋巴瘤;副肉芽肿;恶性淋巴瘤,小淋巴细胞;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡性;蕈样肉芽肿;套细胞淋巴瘤;华氏巨球蛋白血症;其他特定的非霍奇金淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓性白血病;嗜碱性白血病;嗜酸性粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;骨髓肉瘤;慢性淋巴细胞白血病(CLL);急性淋巴细胞白血病(ALL);毛细胞白血病;慢性粒细胞白血病;和毛细胞白血病。
本申请通篇使用的术语“治疗益处”或“治疗有效”是指任何促进或增强对象在该病症的医学治疗方面的健康的事物。这包括但不限于降低疾病体征或症状的频率或严重程度。例如,癌症的治疗可以包括例如降低肿瘤的侵袭性、降低癌症的生长速率或预防转移。癌症的治疗还可以指延长患有癌症的对象的生存期。
同样,患者的有效反应或患者对治疗的“反应性”是指赋予处于疾病或病症风险或患有疾病或病症的患者的临床或治疗益处。此类益处可包括细胞或生物反应、完全反应、部分反应、稳定的疾病(无进展或复发)或稍后复发的反应。例如,有效的反应可以是减少被诊断患有癌症的患者的肿瘤大小或无进展生存期。
关于肿瘤状态的治疗,根据肿瘤状态的阶段,肿瘤状态的治疗包括以下一种或多种疗法:手术切除肿瘤组织、放疗和化疗。其他治疗方案可以与抗癌剂的给予组合,例如治疗组合物和化疗剂。例如,用这种抗癌剂治疗的患者也可以接受放射治疗和/或可以接受手术。
对于疾病的治疗,治疗组合物的适当剂量将取决于要治疗的疾病类型,如上定义,疾病的严重程度和病程,先前的治疗,患者的临床病史和对药剂的反应,以及医生的判断。该药剂可以一次性或在一系列治疗中适当地给予于患者。
该方法和组合物,包括联合疗法,增强治疗或保护作用,和/或增加另一种抗癌或抗过度增殖疗法的治疗作用。治疗和预防方法和组合物可以以有效达到所需效果的组合量提供,例如杀死癌细胞和/或抑制细胞过度增殖。可以使组织、肿瘤或细胞与包含一种或多种药剂的一种或多种组合物或药理学制剂接触,或通过使组织、肿瘤和/或细胞与两种或更多种不同的组合物或制剂接触。此外,预期这样的联合疗法可以与放射疗法、手术疗法或免疫疗法结合使用。
联合给予可以包括在相同剂型中同时给予两种或更多种药剂、在不同剂型中同时给予和分别给予。也就是说,主题治疗组合物和另一种治疗剂可以一起配制在相同的剂型中并同时给予。或者,可以同时给予主题治疗组合物和另一种治疗剂,其中两种药剂都存在于单独的制剂中。在另一个替代方案中,治疗剂可以在其他治疗剂之后给予,反之亦然。在分开的给予方案中,主题治疗组合物和另一种治疗剂可以相隔几分钟、或相隔几个小时、或相隔几天给予。
相对于第二次抗癌治疗,可以在之前、期间、之后或以各种组合给予抗癌第一治疗。给予的时间间隔可以从同时到数分钟到数天到数周。在将第一治疗与第二治疗分开提供给患者的实施方式中,人们通常会确保在每次递送时间之间没有过期很长一段时间,这样两种化合物仍然能够对患者产生有利的联合作用。在这样的情况下,预期可以在彼此相距约12至24或72小时内,更具体地,在彼此相距约6-12小时内向患者提供第一疗法和第二疗法。但在一些情况中,可能需要显著延长治疗时间,其中各给予之间间隔数天(2、3、4、5、6或7)到数周(1、2、3、4、5、6、7或8)。
在某些实施方式中,一个疗程将持续1-90天或更长时间(该范围包括中间天数)。预期可以在第1天至第90天(这个范围包括中间天数)的任何一天或其任何组合给予一种药剂,并且在第1天至第90天(这个范围包括中间天数)的任何一天或其任何组合给予另一种药剂。在一天(24小时)内,可给予患者一次或多次给予。此外,在一个疗程之后,预期有一段时间不给予抗癌治疗。这段时间可能持续1-7天,和/或1-5周,和/或1-12个月或更长时间(这个范围包括中间天数),这取决于患者的状况,例如他们的预后、体力、健康状况等。治疗周期将根据需要重复。
可以采用各种组合。对于以下实例,(a)波齐替尼为“A”,HER2/HER3靶向抗体为“B”;或(b)波齐替尼,单独或与HER2/HER3靶向抗体联合使用为“A”,另一种抗癌疗法为“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
将本发明的任何化合物或疗法给予患者将遵循用于给予此类化合物的一般方案,考虑到药剂的毒性(如有)。因此,在一些实施方式中,有一个出于联合治疗的监测毒性的步骤。
1.化疗
根据本发明可以使用多种化疗剂。术语“化疗”是指使用药物治疗癌症。“化疗剂”用于表示在癌症治疗中给予的化合物或组合物。这些药剂或药物根据它们在细胞内的活动模式进行分类,例如,它们是否以及在什么阶段影响细胞周期。或者,可以基于其直接交联DNA、嵌入DNA或通过影响核酸合成诱导染色体和有丝***畸变的能力来表征试剂。
化疗剂的例子包括烷化剂,如噻替帕和环磷酰胺;烷基磺酸盐,如白消安、异丙硫丹和哌泊硫丹;氮丙啶类,如苯多巴、卡波醌、美多巴和乌多巴;乙烯亚胺和甲基三聚氰胺,包括三聚氰胺、三乙烯三聚氰胺、三乙烯磷酰胺、三乙烯硫代磷酰胺和三羟甲基三聚氰胺;产乙酸菌素(尤其是布拉那新和布拉他西酮);喜树碱(包括合成类似物拓扑替康);苔藓抑素;卡利他汀;CC-1065(包括其阿多唑啉、卡折来新和比折来新合成类似物);隐藻素(特别是隐藻素1和隐藻素8);多拉司他丁;多卡霉素(包括合成类似物,KW-2189和CB1-TM1);刺五加素;潘拉司他汀;一种肉毒杆菌素;海绵抑素;氮芥,如苯丁酸氮芥、氯萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、甲氯乙胺、盐酸甲氯乙胺、美法仑、诺维比辛、芬乃斯特、泼尼莫司汀、曲磷酰胺和尿嘧啶芥;亚硝基脲类,如卡莫司汀、氯脲佐菌素、氟替莫司汀、洛莫司汀、尼莫司汀和雷尼司汀;抗生素,如烯二炔抗生素(例如,加利车霉素,尤其是加利车霉素gamma1I和加利车霉素omega I1);达尼霉素,包括达尼霉素A;双膦酸盐,如氯膦酸盐;埃斯帕霉素;以及新制癌素发色团和相关的色蛋白烯二炔抗生素发色团、阿克拉霉素、放线菌素、金霉素、重氮丝氨酸、博来霉素、放线菌素、carabicin、胭脂红霉素、嗜癌菌素、色霉素、放线菌素、柔红霉素、去托比星、6-重氮-5-氧代-L-正亮氨酸、阿霉素(包括吗啉代阿霉素、氰基吗啉代阿霉素、2-吡咯啉代阿霉素和脱氧阿霉素)、表柔比星、埃柔比星、伊达比星、马赛霉素、丝裂霉素类,例如丝裂霉素C、霉酚酸、诺加拉霉素、橄榄霉素、培洛霉素、波呋莫司汀、嘌呤霉素、克拉霉素、罗多比星、链黑霉素、链脲佐菌素、结核菌素、乌笨美司、净司他丁和佐柔比星;抗代谢物,例如甲氨蝶呤和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-巯基嘌呤、硫胺嘌呤和硫鸟嘌呤;嘧啶类似物,例如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、多西氟尿苷、依西他滨和氟尿苷;雄激素,例如二***、屈他雄酮丙酸酯、环硫雄醇、美雄烷和睾内酯;抗肾上腺素,如米托坦和三氯司坦;叶酸补充剂,如叶酸;乙酰丙酮;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;吖啶;苯丁酸;比生群;依达曲沙;去氧麻黄碱;去甲高辛;二嗪酮;二甲双胍;醋酸艾立替铵;埃坡霉素;胃泌素;硝酸镓;羟基脲;香菇多糖;洛尼达宁;美登素,例如美登素和安丝霉素;米托胍;米托蒽醌;莫匹丹莫;硝基苯胺;喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;丙卡巴肼;PSK多糖复合物;雷佐生;根瘤菌素;西佐非兰;螺锗;肌松酸;三嗪酮;2,2',2"-三氯三乙胺;单端孢霉烯类(尤其是T-2毒素、维拉库林A、罗瑞丁A和蛇形菌素);聚氨酯;长春地辛;达卡巴嗪;甘露莫司汀;米托溴醇;米托内酯;哌泊溴烷;胞嘧啶;***糖苷(揂ra-C);环磷酰胺;紫杉醇,例如紫杉醇和多西他赛吉西他滨;6-硫鸟嘌呤;巯基嘌呤;铂配位络合物,例如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺万龙;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基基鸟氨酸(DFMO);类视黄醇,例如视黄酸;卡培他滨;卡铂、丙卡巴肼、普利霉素、吉西他滨、萘维滨、法尼基蛋白转移酶抑制剂、转铂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放疗的例子包括通常称为γ射线、X射线和/或将放射性同位素直接递送给肿瘤细胞的放疗方法。还考虑了其他形式的DNA损伤因子,例如微波、质子束辐照(美国专利5,760,395和4,870,287)和紫外线辐照。这些因素很有可能会对DNA、DNA前体、DNA复制和修复、染色体装配和维持造成很宽范围的损伤。X射线的剂量范围为从长时间的每日剂量50-200伦琴(3-4周)到单次剂量2000-6000伦琴。放射性同位素的剂量范围变化很大,取决于同位素的半衰期、辐射的强度和类型以及肿瘤细胞的吸收。
3.免疫治疗
本领域技术人员将理解附加的免疫疗法可以与本发明的方法组合或结合使用。在癌症治疗的背景下,免疫疗法通常依赖于使用免疫效应细胞和分子来靶向和破坏癌细胞。利妥昔单抗就是这样一个例子。免疫效应物可以是例如对肿瘤细胞表面上的某些标志物具有特异性的抗体。单独的抗体可以作为治疗的效应器,也可以招募其他细胞来实际影响细胞杀伤。所述抗体还可结合药物或毒素(化疗、放射性核素、蓖麻毒蛋白A链、霍乱毒素、百日咳毒素等)并仅作为靶向试剂。或者,效应器可以是携带表面分子的淋巴细胞,该表面分子直接或间接地与肿瘤细胞靶标相互作用。各种效应细胞包括细胞毒性T细胞和NK细胞。
在免疫疗法的一个方面,所述肿瘤细胞必须带有一些可靶向的标志物,即不在大多数其他细胞上存在。存在许多肿瘤标志物且任何这些可适于在本发明的内容中靶向。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、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,如MIP-1、MCP-1、IL-8,以及生长因子,如FLT3配体。
目前正在研究或使用的免疫疗法的例子是免疫佐剂,例如牛分枝杆菌、恶性疟原虫、二硝基氯苯和芳香族化合物(美国专利5,801,005和5,739,169;Hui和Hashimoto,Infection Immun.,66(11):5329-5336,1998;Christodolides等人,Microbiology,144(Pt11):3027-3037,1998);细胞因子治疗,例如干扰素α、β和γ、IL-1、GM-CSF和TNF(Bukowski等,Clinical Cancer Res.,4(10):2337-2347,1998;Davidson等,J.Immunother.,21(5):389-398,1998;Hellstrand等,Acta Oncologica,37(4):347-353,1998);基因治疗,例如TNF、IL-1、IL-2和p53(Qin等人,Proc.Natl.Acad.Sci.USA,95(24):14411-14416,1998;Austin-Ward和Villaseca,Revista Medica de Chile,126(7):838-845,1998;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(Hanibuchi等,Int.J.Cancer,78(4):480-485,1998;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。
在一些实施方式中,免疫疗法可以是过继性免疫疗法,其涉及离体产生的自体抗原特异性T细胞的转移。用于过继免疫治疗的T细胞可以通过抗原特异性T细胞的扩增或通过基因工程重定向T细胞来产生。肿瘤特异性T细胞的分离和转移已被证明可成功治疗黑色素瘤。通过转基因T细胞受体或嵌合抗原受体(CAR)的遗传转移,已成功产生T细胞的新特异性。CAR是合成受体,由与单个融合分子中的一个或多个信号结构域相关的靶向部分组成。通常,CAR的结合部分由单链抗体(scFv)的抗原结合结构域组成,包括通过柔性接头连接的单克隆抗体的轻片段和可变片段。基于受体或配体结构域的结合部分也已成功使用。第一代CAR的信号结构域来自CD3zeta或Fc受体γ链的细胞质区域。CAR已经成功地允许T细胞被重新定向,以对抗来自各种恶性肿瘤(包括淋巴瘤和实体瘤)的肿瘤细胞表面表达的抗原。
在一个实施方式中,本申请提供了一种用于治疗癌症的联合疗法,其中该联合疗法包括过继性T细胞疗法和检查点抑制剂。一方面,过继性T细胞疗法包括自体和/或同种异体T细胞。在另一个方面,自体和/或同种异体T细胞靶向肿瘤抗原。
免疫调节剂包括免疫检查点抑制剂、共刺激分子激动剂和免疫抑制分子拮抗剂。免疫调节剂可以是药物,例如小分子、配体或受体的重组形式,或抗体,例如人抗体(例如,国际专利公开WO2015/016718;Pardoll,Nat Rev Cancer,12(4):252-264,2012;均通过引用并入本文)。可以使用已知的免疫检查点蛋白抑制剂或其类似物,特别是可以使用嵌合、人源化或人形式的抗体。如本领域技术人员所知,替代和/或等效名称可用于本公开中提及的某些抗体。如本领域技术人员所知,替代和/或等效名称可用于本公开中提及的某些抗体。例如,众所周知,兰博利珠单抗(lambrolizumab)也以替代和等效名称MK-3475和派姆单抗(pembrolizumab)为人所知。
共刺激分子是与免疫细胞表面受体相互作用的配体,例如CD28、4-1BB、OX40(也称为CD134)、ICOS和GITR。例如,人OX40的完整蛋白质序列具有Genbank登录号NP_003318。在一些实施方式中,免疫调节剂是抗OX40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。适用于本方法的抗人OX40抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗OX40抗体。示例性抗OX40抗体是PF-04518600(参见,例如,WO2017/130076)。ATOR-1015是靶向CTLA4和OX40的双特异性抗体(参见,例如,WO 2017/182672、WO 2018/091740、WO 2018/202649、WO 2018/002339)。
可以在本文提供的方法中靶向的另一种共刺激分子是ICOS,也称为CD278。人类ICOS的完整蛋白质序列具有Genbank登录号NP_036224。在一些实施方式中,免疫检查点抑制剂是抗-ICOS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。适用于本方法的抗人ICOS抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗ICOS抗体。示例性抗ICOS抗体包括JTX-2011(参见,例如,WO 2016/154177、WO 2018/187191)和GSK3359609(参见,例如,WO 2016/059602)。
可在本文提供的方法中靶向的另一种共刺激分子是糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR),也称为TNFRSF18和AITR。人GITR的完整蛋白质序列具有Genbank登录号NP_004186。在一些实施方式中,免疫调节剂是抗GITR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。适用于本方法的抗人GITR抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗GITR抗体。示例性抗GITR抗体是TRX518(参见,例如,WO 2006/105021)。
免疫检查点阻断可能靶向的免疫检查点蛋白包括腺苷A2A受体(A2AR)、B7-H3(也称为CD276)、B和T淋巴细胞衰减剂(BTLA)、CCL5、CD27、CD38、CD8A、CMKLR1、细胞毒性T淋巴细胞相关蛋白4(CTLA-4,也称为CD152)、CXCL9、CXCR5、HLA-DRB1、HLA-DQA1、HLA-E、杀伤细胞免疫球蛋白(KIR)、淋巴细胞激活基因3(LAG-3,又称CD223)、Mer酪氨酸激酶(MerTK)、NKG7、程序性死亡1(PD-1)、程序性死亡配体1(PD-L1,又称CD274)、PDCD1LG2、PSMB10、STAT1、具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)、T细胞免疫球蛋白结构域和粘蛋白结构域3(TIM-3),以及T细胞活化的V结构域Ig抑制因子(VISTA,也称为C10orf54)。特别是,针对PD-1轴和/或CTLA-4的免疫检查点抑制剂已获得FDA对多种癌症类型的广泛批准。
在一些实施方式中,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。在一个具体方面,PD-1配体结合配偶体是PD-L1和/或PD-L2。在另一个实施方式中,PD-L1结合拮抗剂是抑制PD-L1与其结合配偶体结合的分子。在一个具体方面,PD-L1结合伴侣是PD-1和/或B7-1。在另一个实施方式中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶体结合的分子。在一个具体方面,PD-L2结合伴侣是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。示例性抗体在美国专利号8,735,553、8,354,509和8,008,449中进行了描述,所有这些都通过引用并入本文。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,例如美国专利申请公开号2014/0294898、2014/022021和2011/0008369中所述,所有这些通过引用并入本文。
在一些实施方式中,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)。在一些实施方式中,抗PD-1抗体选自由纳武单抗、派姆单抗和CT-011组成的组。在一些实施方式中,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PD-L1或PD-L2的细胞外或PD-1结合部分的免疫粘附素)。在一些实施方式中,PD-1结合拮抗剂是AMP-224。纳武利尤单抗(Nivolumab),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,是一种PD-L2-Fc融合可溶性受体,描述于WO2010/027827和WO2011/066342。
可以在本文提供的方法中靶向的另一种免疫检查点蛋白是细胞毒性T淋巴细胞相关蛋白4(CTLA-4),也称为CD152。人CTLA-4的完整cDNA序列具有Genbank登录号L15006。CTLA-4存在于T细胞表面,当与抗原呈递细胞表面的CD80或CD86结合时充当“关闭”开关。CTLA-4类似于T细胞共刺激蛋白CD28,两种分子都与抗原呈递细胞上的CD80和CD86(也分别称为B7-1和B7-2)结合。CTLA-4向T细胞传递抑制信号,而CD28传递刺激信号。细胞内CTLA-4也存在于调节性T细胞中,可能对其功能很重要。通过T细胞受体和CD28激活T细胞导致CTLA-4的表达增加,CTLA-4是B7分子的抑制性受体。
在一些实施方式中,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。适用于本方法的抗人CTLA-4抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗CTLA-4抗体。例如,公开于美国专利号8,119,129;PCT公开号WO 01/14424、WO 98/42752、WO 00/37504(CP675,206,也称为曲美木单抗(tremelimumab);以前称为替西木单抗(ticilimumab));美国专利号6,207,156;Hurwitz等人(1998)Proc NatlAcad Sci USA,95(17):10067-10071;Camacho等(2004)J Clin Oncology,22(145):Abstract No.2505(抗体CP-675206);和Mokyr等人(1998)Cancer Res,58:5301-5304的抗CTLA-4抗体可用于本文公开的方法中。上述出版物中的每一个的教导通过引用并入本文。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抗体在国际专利申请号WO2001/014424、WO2000/037504和美国专利号8,017,114中有所描述;全部通过引用并入本文。
示例性抗CTLA-4抗体是伊匹单抗(ipilimumab)(也称为10D1、MDX-010、MDX-101和)或其抗原结合片段和变体(参见,例如,WO01/14424)。在其他实施方式中,抗体包含伊匹单抗的重链和轻链CDR或VR。因此,在一个实施方式中,抗体包含伊匹单抗的VH区的CDR1、CDR2和CDR3结构域,以及伊匹单抗的VL区的CDR1、CDR2和CDR3结构域。在另一个实施方式中,抗体与上述抗体竞争结合和/或结合CTLA-4上的相同表位。在另一个实施方式中,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CTLA-4配体和受体,例如美国专利号5844905、5885796和国际专利申请号WO1995001994和WO1998042752中所述;全部以引用方式并入本文,以及免疫粘附素如美国专利No.8329867中所述,通过引用并入本文。
可以在本文提供的方法中靶向的另一种免疫检查点蛋白是淋巴细胞激活基因3(LAG-3),也称为CD223。人LAG-3的完整蛋白质序列具有Genbank登录号NP-002277。LAG-3存在于活化的T细胞、自然杀伤细胞、B细胞和浆细胞样树突状细胞的表面。LAG-3在与抗原呈递细胞表面的MHC II类结合时充当“关闭”开关。LAG-3的抑制会激活效应T细胞和抑制调节性T细胞。在一些实施方式中,免疫检查点抑制剂是抗LAG-3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。适用于本方法的抗人LAG-3抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗LAG-3抗体。示例性抗LAG-3抗体是瑞拉利单抗(relatlimab)(也称为BMS-986016)或其抗原结合片段和变体(参见,例如,WO2015/116539)。其他示例性抗LAG-3抗体包括TSR-033(参见,例如,WO 2018/201096)、MK-4280和REGN3767。MGD013是一种抗LAG-3/PD-1双特异性抗体,描述于WO 2017/019846。FS118是一种抗LAG-3/PD-L1双特异性抗体,描述于WO 2017/220569。
可以在本文提供的方法中靶向的另一种免疫检查点蛋白是T细胞活化的V域Ig抑制因子(VISTA),也称为C10或f54。人VISTA的完整蛋白质序列具有Genbank登录号NP_071436。VISTA存在于白细胞上并抑制T细胞效应功能。在一些实施方式中,免疫检查点抑制剂是抗VISTA3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。适用于本方法的抗人VISTA3抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗VISTA3抗体。示例性抗VISTA抗体是JNJ-61610588(也称为奥瓦利单抗(onvatilimab))(参见,例如,WO 2015/097536、WO2016/207717、WO2017/137830、WO 2017/175058)。VISTA也可以用小分子CA-170来抑制,CA-170选择性地靶向PD-L1和VISTA(参见,例如,WO 2015/033299、WO2015/033301)。
可以在本文提供的方法中靶向的另一种免疫检查点蛋白是CD38。人类CD38的完整蛋白质序列具有Genbank登录号NP_001766。在一些实施方式中,免疫检查点抑制剂是抗CD38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。适用于本方法的抗人CD38抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗CD38抗体。示例性抗CD38抗体是达雷木单抗(daratumumab)(参见,例如,美国专利号7,829,673)。
可以在本文提供的方法中靶向的另一种免疫检查点蛋白是具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)。人类TIGIT的完整蛋白质序列具有Genbank登录号NP_776160。在一些实施方式中,免疫检查点抑制剂是抗TIGIT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。适用于本方法的抗人TIGIT抗体(或衍生自其的VH和/或VL结构域)可以使用本领域熟知的方法产生。或者,可以使用本领域公认的抗TIGIT抗体。示例性的抗TIGIT抗体是MK-7684(参见,例如,WO 2017/030823、WO 2016/028656)。
其他可针对免疫调节的免疫抑制分子包括STAT3和吲哚胺2,3-双加氧酶(IDO)。例如,人IDO的完整蛋白质序列具有Genbank登录号NP_002155。在一些实施方式中,免疫调节剂是小分子IDO抑制剂。示例性的小分子包括BMS-986205、艾卡哚司他(epacadostat)(INCB24360)和纳沃昔莫德(navoximod)(GDC-0919)。
4.外科手术
大约60%的癌症患者将接受某种类型的手术,包括预防性、诊断性或分期、治疗性和姑息性手术。治愈性手术包括切除术,其中全部或部分癌组织被物理去除、切除和/或破坏,并可与其他疗法结合使用,例如本发明的治疗、化学疗法、放射疗法、激素疗法、基因疗法、免疫疗法和/或替代疗法。肿瘤切除术指物理移除至少部分肿瘤。除肿瘤切除外,手术治疗还包括激光手术、冷冻手术、电手术和显微镜控制手术(莫氏手术)。
在切除部分或全部癌细胞、组织或肿瘤后,体内可能会形成空腔。治疗可以通过灌注、直接注射或局部应用该区域以及额外的抗癌疗法来完成。这种治疗可以例如每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个月重复一次。这些治疗也可以有不同的剂量。
5.其他试剂
预期其他试剂可与本发明的某些方面联用以改进治疗的治疗效力。这些另外的试剂包括影响细胞表面受体和GAP连接上调的试剂、细胞生长抑制剂和分化试剂、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试剂或其他生物试剂。通过提高GAP连接的数量来增加细胞间信号传导会增加对邻近过度增殖性细胞群体的抗过度增殖效应。在其他实施方式中,细胞抑制剂或分化剂可以与本发明的某些方面组合使用以提高治疗的抗过度增殖功效。细胞粘附抑制剂预期可改善本发明的效力。细胞粘附抑制剂的例子是粘着斑激酶(FAK)抑制剂和洛伐他汀。还预期其他增加过度增殖细胞对凋亡敏感性的试剂如抗体c225可与本发明的某些方面联用以改善治疗效力。
II.试剂盒
在本发明的各个方面,设想试剂盒包含诊断剂、治疗剂和/或递送剂。在一些实施方式中,本发明考虑了一种用于检测患者肿瘤细胞中的NRG1融合的试剂盒。在一些实施方式中,本发明涉及用于制备和/或给予本发明疗法的试剂盒。该试剂盒可以包含能够用于给予本发明的活性剂或有效剂的试剂。试剂盒的试剂可以包括一种或多种联合疗法的抗癌成分,以及用于制备、配制和/或给予本发明的成分或进行本发明方法的一个或多个步骤的试剂。在一些实施方式中,试剂盒还可以包括合适的容器装置,其是不会与试剂盒的组分反应的容器,例如离心管、测定板、注射器、瓶子或试管。容器可以由可消毒的材料制成,例如塑料或玻璃。该试剂盒还可以包括概述方法的程序步骤的说明书,并且将遵循与本文所述或普通技术人员已知的基本相同的程序。
III.实施例
包括以下实施例以展示本发明的优选实施方式。本领域的普通技术人员应理解,根据本发明人揭示的技术,公开在实施例中的技术能很好地实施本发明,从而可将其视为实施本发明的优选模式。根据本发明公开的内容,本领域的普通技术人员应理解,在不偏离本发明精神和范围的前提下,可对所公开的具体实施方式进行许多变化,且仍能获得相同或类似的结果。
实施例1
NRG1-DOC4融合乳腺癌细胞系MDA175-VII的细胞活力在使用或不使用针对HER2和HER2/HER3二聚化的抗体和抗体药物偶联物(ADC)的情况下用波齐替尼治疗进行了测试。细胞活力通过细胞效价Glo Assay(Cell Titer Glo Assay)测定。波齐替尼有效抑制MDA175-VII细胞,平均IC50值为0.287nM(图1)。这些数据表明,波齐替尼在低于先前报道的TKI的浓度下有效抑制NRG1融合。
此外,用HER2靶向抗体曲妥珠单抗、T-DM1和帕妥珠单抗治疗的IC50值分别>10000ng/mL、634.5ng/mL和53.7ng/mL(图2A)。此外,HER2抗体与低剂量波齐替尼(0.1nM)的组合导致对曲妥珠单抗、帕妥珠单抗和T-DM1的敏感性增加,IC50值分别降低至1.37nM、1.23nM和1.32nM(图2B)。
实施例2
Ba/F3细胞生成。如前所述产生稳定共表达WT ErbB2和WT ErbB3或WT ErbB3和WTErbB4的Ba/F3细胞。简而言之,将逆转录病毒或慢病毒构建体转染到Phoenix 293T细胞中以产生病毒,该病毒与Ba/F3细胞系一起孵育过夜。去除病毒并将细胞在嘌呤霉素中培养10天以选择稳定表达逆转录病毒构建体的Ba/F3细胞系。选择后,使用抗HER2、抗HER3和抗HER4抗体(Biolegend)对细胞进行分类。然后用表1A中含有NRG融合质粒的慢病毒再次转导细胞系。然后通过FACS对细胞进行分类以进行NRG1表达。然后使稳定的细胞系失去IL-3。产生的稳定细胞系用于下游分析,包括药物筛选。
药物筛选和IC50测定。如前所述进行药物筛选。简而言之,将细胞以每孔2000-3000个细胞在384孔板(Greiner Bio-One)中铺板,技术一式三份。添加七种不同浓度的TKI或DMSO载体,以达到每孔40μL的最终体积。72小时后,向每个孔中加入11μL细胞效价Glo(普罗梅加公司)。将板孵育至少10分钟,并使用FLUOstar OPTIMA读板器(BMG实验室技术公司(BMG Labtech))测定生物发光。将原始生物发光值标准化为DMSO对照处理的细胞,并将值绘制在GraphPad Prism中。非线性回归用于拟合具有可变斜率的归一化数据,并且IC50值由GraphPad prism通过在50%抑制下的浓度插值确定。药物筛选在每个板上进行三次技术筛选,并进行两次或三次生物重复。
过表达模型。通过表1A中NRG1融合的慢病毒转导产生过表达模型。使用Lenti-X细胞Lenti-X单发试剂盒(single shot kit)(Takarabio)产生慢病毒。Lenti病毒是按照制造商的描述生成的。然后将慢病毒添加到表1B中的细胞系中。病毒转导24小时后,去除病毒并将细胞置于2μg/ml嘌呤霉素中进行筛选。选择10天后,从细胞系中收集蛋白质和RNA,并分别通过蛋白质印迹和RT-PCR确定NRG1融合蛋白的表达。具有NRG1融合表达的稳定细胞系用于下游分析,包括蛋白质印迹和ELISA。
通过蛋白质印迹和ELISA测定过表达细胞系中HER信号传导的抑制。将亲代和过表达(OE)细胞系置于10cm培养皿中,并用波齐替尼处理,剂量从1nm增加到100nm。细胞与抑制剂一起孵育4小时、1天和3天,并使用裂解缓冲液(Cell Signaling)收集蛋白质。NRG1-融合、磷酸化和总-EGFR、HER2、HER3和HER4的表达通过蛋白质印迹测定,并使用BioRadChemdoc成像仪曝光印迹。为了量化蛋白质表达的变化,将来自用波齐替尼处理的亲代和OE表达细胞系的蛋白质加载到ELISA(细胞信号传导)上,并按照制造商的说明完成ELISA。
表1A:NRG1融合质粒
NRG1-CD74 | NRG1-ATP1B1 | NRG1-SLC3A2 |
NRG1-SDC4 | NRG1-VAMP1 | NRG1-CLU |
NRG1-RBPMS |
表1B:人类细胞系模型
细胞系 | 原发性肿瘤 |
H324 | NSCLC |
H1819 | NSCLC |
H2170 | NSCLC |
***
根据本文公开的内容,本文描述和要求的所有方法无需过多实验即可进行和执行。虽然参考优选的实施方式描述了本发明的组合物和方法,但本领域技术人员应理解,可将各种改变给予于本文所述的方法以及本文所述方法的各个步骤或各步骤的顺序,而并不背离本发明的概念、精神和范围。更具体说,应理解,某些化学和生理相关试剂可代替本文所述的试剂,同时实现相同或类似的结果。认为本领域技术人员所明白的所有这些类似的替代品或改进都在所附权利要求所定义的本发明的精神、范围和概念内。
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Claims (54)
1.一种治疗患有癌症的患者的方法,所述方法包括向所述患者给予治疗有效量的波齐替尼,其中所述癌症具有NRG1融合。
2.一种治疗患有癌症的患者的方法,该方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼治疗;(c)对选定的患者给予或已经给予治疗有效量的波齐替尼。
3.如权利要求1或2所述的方法,所述NRG1融合是NRG1-DOC4融合、NRG1-VAMP2融合、NRG1-CLU融合、NRG1-SLC3A2融合、NRG1-CD74融合、NRG1-ATP1B1融合、或NRG1-SDC4融合。
4.如权利要求1或2所述的方法,还包括向所述患者给予HER2/HER3靶向抗体。
5.如权利要求4所述的方法,其中所述HER2/HER3靶向抗体包括曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、或T-DM1。
6.如权利要求1~5中任一项所述的方法,其中步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。
7.如权利要求1~6中任一项所述的方法,所述方法还包括给予患者其他抗癌疗法。
8.如权利要求7所述的方法,其中所述其他抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。
9.如权利要求1~8中任一项所述的方法,其中所述癌症是乳腺癌、肺癌、结直肠癌、神经母细胞瘤、胰腺癌、脑癌、胃癌、皮肤癌、睾丸癌、***癌、卵巢癌、肝癌、食道癌、***、头颈癌、黑色素瘤或胶质母细胞瘤。
10.如权利要求1~8中任一项所述的方法,其中所述癌症是乳腺癌或肺癌。
11.如权利要求1~10中任一项所述的方法,其中所述患者之前至少接受过一轮抗癌疗法。
12.如权利要求1~11中任一项所述的方法,其中所述方法还包括报告患者癌症中存在NRG1融合。
13.如权利要求12所述的方法,其中报告包括准备书面或电子报告。
14.如权利要求12或13所述的方法,所述方法还包括将报告提供给对象、医生、医院或保险公司。
15.一种选择患有癌症的患者以使用波齐替尼治疗的方法,所述方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼治疗。
16.如权利要求15所述的方法,其中步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。
17.如权利要求15或16所述的方法,所述方法还包括(c)对选定的患者给予或已经给予治疗有效量的波齐替尼。
18.如权利要求15-17中任一项所述的方法,其中所述NRG1融合是NRG1-DOC4融合、NRG1-VAMP2融合、NRG1-CLU融合、NRG1-SLC3A2融合、NRG1-CD74融合、NRG1-ATP1B1融合、或NRG1-SDC4融合。
19.如权利要求17或18所述的方法,还包括向所述患者给予HER2/HER3靶向抗体。
20.如权利要求19所述的方法,其中所述HER2/HER3靶向抗体包括曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、或T-DM1。
21.如权利要求17~20中任一项所述的方法,所述方法还包括给予患者其他抗癌疗法。
22.如权利要求21所述的方法,其中所述其他抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。
23.如权利要求15~22中任一项所述的方法,其中所述癌症是乳腺癌、肺癌、结直肠癌、神经母细胞瘤、胰腺癌、脑癌、胃癌、皮肤癌、睾丸癌、***癌、卵巢癌、肝癌、食道癌、***、头颈癌、黑色素瘤或胶质母细胞瘤。
24.如权利要求15~23中任一项所述的方法,其中所述癌症是乳腺癌或肺癌。
25.如权利要求15~24中任一项所述的方法,其中所述患者之前至少接受过一轮抗癌疗法。
26.如权利要求17~25中任一项所述的方法,其中所述方法还包括报告患者癌症中存在NRG1融合。
27.如权利要求26所述的方法,其中报告包括准备书面或电子报告。
28.如权利要求26或27所述的方法,所述方法还包括将报告提供给对象、医生、医院或保险公司。
29.一种治疗患有癌症的患者的方法,所述方法包括向所述患者联合给予治疗有效量的波齐替尼和HER2/HER3靶向抗体,其中所述癌症具有NRG1融合。
30.一种治疗患有癌症的患者的方法,该方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼和HER2/HER3靶向抗体治疗;(c)对选定的患者联合给予或已经联合给予治疗有效量的波齐替尼和HER2/HER3靶向抗体。
31.如权利要求29或30所述的方法,所述NRG1融合是NRG1-DOC4融合、NRG1-VAMP2融合、NRG1-CLU融合、NRG1-SLC3A2融合、NRG1-CD74融合、NRG1-ATP1B1融合、或NRG1-SDC4融合。
32.如权利要求29~31中任一项所述的方法,其中所述HER2/HER3靶向抗体包括曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、或T-DM1。
33.如权利要求29~32中任一项所述的方法,其中步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。
34.如权利要求29~33中任一项所述的方法,所述方法还包括给予患者其他抗癌疗法。
35.如权利要求34所述的方法,其中所述其他抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。
36.如权利要求29~35中任一项所述的方法,其中所述癌症是乳腺癌、肺癌、结直肠癌、神经母细胞瘤、胰腺癌、脑癌、胃癌、皮肤癌、睾丸癌、***癌、卵巢癌、肝癌、食道癌、***、头颈癌、黑色素瘤或胶质母细胞瘤。
37.如权利要求29~36中任一项所述的方法,其中所述癌症是乳腺癌或肺癌。
38.如权利要求29~37中任一项所述的方法,其中所述患者之前至少接受过一轮抗癌疗法。
39.如权利要求29~38中任一项所述的方法,其中所述方法还包括报告患者癌症中存在NRG1融合。
40.如权利要求39所述的方法,其中报告包括准备书面或电子报告。
41.如权利要求39或40所述的方法,所述方法还包括将报告提供给对象、医生、医院或保险公司。
42.一种选择患有癌症的患者以使用波齐替尼和HER2/HER3靶向抗体治疗的方法,所述方法包括(a)确定或已经确定患者的癌症是否具有NRG1融合;(b)当患者的癌症具有NRG1融合时,选择或已经选择患者接受波齐替尼和HER2/HER3靶向抗体治疗。
43.如权利要求42所述的方法,其中步骤(a)包括(i)从患者获得或已经获得生物样本;和(ii)对生物样本进行或已经进行了测定以确定患者的癌症具有NRG1融合。
44.如权利要求42或43所述的方法,所述方法还包括(c)对选定的患者联合给予或已经联合给予治疗有效量的波齐替尼和HER2/HER3靶向抗体。
45.如权利要求42-44中任一项所述的方法,其中所述NRG1融合是NRG1-DOC4融合、NRG1-VAMP2融合、NRG1-CLU融合、NRG1-SLC3A2融合、NRG1-CD74融合、NRG1-ATP1B1融合、或NRG1-SDC4融合。
46.如权利要求42~45中任一项所述的方法,其中所述HER2/HER3靶向抗体包括曲妥珠单抗(trastuzumab)、帕妥珠单抗(pertuzumab)、或T-DM1。
47.如权利要求44~46中任一项所述的方法,所述方法还包括给予患者其他抗癌疗法。
48.如权利要求47所述的方法,其中所述其他抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。
49.如权利要求42~48中任一项所述的方法,其中所述癌症是乳腺癌、肺癌、结直肠癌、神经母细胞瘤、胰腺癌、脑癌、胃癌、皮肤癌、睾丸癌、***癌、卵巢癌、肝癌、食道癌、***、头颈癌、黑色素瘤或胶质母细胞瘤。
50.如权利要求42~49中任一项所述的方法,其中所述癌症是乳腺癌或肺癌。
51.如权利要求42~50中任一项所述的方法,其中所述患者之前至少接受过一轮抗癌疗法。
52.如权利要求44~51中任一项所述的方法,其中所述方法还包括报告患者癌症中存在NRG1融合。
53.如权利要求52所述的方法,其中报告包括准备书面或电子报告。
54.如权利要求52或53所述的方法,所述方法还包括将报告提供给对象、医生、医院或保险公司。
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CN109476748A (zh) * | 2016-08-08 | 2019-03-15 | 豪夫迈·罗氏有限公司 | 用于癌症的治疗和诊断方法 |
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