CN112543661A - 治疗胶质母细胞瘤的方法 - Google Patents
治疗胶质母细胞瘤的方法 Download PDFInfo
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Abstract
本公开内容提供了一种用于治疗携带表达EGFR的肿瘤和/或肿瘤细胞(诸如胶质母细胞瘤)的患者的癌症的方法,该方法包括以下的组合:(i)向目标区域施加AC电场,其中目标区域包括表达EGFR的肿瘤或癌细胞);以及(ii)施用有效量的马德帕妥组单抗。
Description
相关申请的交叉引用
本申请要求在35 U.S.C.§119(e)下于2017年11月17日提交的美国临时申请序列第562/587,830号的权益。引用的申请的全部教导内容通过引用整体并入本文。
技术领域
本公开内容的特征在于使用马德帕妥组单抗(depatuxizumab mafodotin)和肿瘤治疗场(Tumor Treating Fields)的组合来治疗癌症,特别是胶质母细胞瘤(glioblastoma)的方法。
背景技术
抗体-药物偶联物(antibody-drug conjugate,ADC)是一类快速发展的癌症疗法,其将单克隆抗体(mAb)的靶向特异性与强效小分子的细胞毒性组合在一起。ADC的独特临床优势是其绕过与细胞内信号传导相关的下游耐药机制而将毒性有效载荷直接递送到肿瘤的能力。
肿瘤治疗场或TTFields为中频范围(100-300kHz)内的低强度(例如1-3V/cm)交变电场。这种非侵入性治疗靶向实体瘤,并且例如在美国专利第7,565,205号中有所描述,该专利通过引用整体并入本文。TTFields通过干扰有丝***所需的关键分子的组装的物理相互作用来破坏细胞***。TTFields疗法是一种经批准的针对复发性胶质母细胞瘤的单一治疗,也是一种经批准的针对新诊断患者的与化疗相组合的组合疗法。这些电场是由直接置于患者头皮上的换能器阵列(即电极阵列)非侵入性地感应的。TTFields似乎对于治疗身体其他部位中的肿瘤也是有益的。
TTFields被确立为一种抗有丝***的癌症治疗方式,因为它们在细胞周期的中期阶段期间干扰正确的微管组装,这最终导致在细胞周期的末期和胞质***阶段期间对细胞的破坏。对于癌症治疗,用电容耦合换能器开发了非侵入式设备,这些换能器直接放置在最靠近肿瘤的皮肤区上。功效随着场强的增加而增加,并且最佳频率特定于癌细胞类型,其中200kHz为已表明对胶质瘤细胞的抑制是最高的TTFields频率。对于患有多形性胶质母细胞瘤(GBM)的患者,用于递送TTFields疗法的设备称为OptuneTM。
尽管可以利用基于肿瘤治疗场的疗法,但多形性胶质母细胞瘤(GBM)仍然是成人中枢神经***的最常见和最具侵袭性的原发性恶性肿瘤。因此,在本领域中仍然需要治疗胶质母细胞瘤的有效方法。
发明内容
在实施方案中,本公开内容提供了用于治疗携带表达EGFR的肿瘤的患者的癌症的方法,该方法包括以下的组合:(i)向目标区域施加电场(其中目标区域包括表达EGFR的肿瘤或癌细胞);以及(ii)向所述患者施用有效量的马德帕妥组单抗。在实施方案中,癌症表达突变型EGFRvIII。在实施方案中,癌症为胶质母细胞瘤。
在实施方案中,本公开内容提供了用于抑制表达EGFR的肿瘤的生长的方法,该方法包括以下的组合:(i)向目标区域施加电场(其中目标区域包括表达EGFR的肿瘤或癌细胞);以及(ii)施用有效量的马德帕妥组单抗。
附图说明
图1A和图1B示出了TTFields和马德帕妥组单抗的组合治疗在U87MG胶质瘤细胞中的功效。用TTFields(200kHz,1.6V/cm RMS)治疗在各种马德帕妥组单抗浓度中生长的U87MG胶质瘤细胞72小时。在图1A中,在治疗结束时确定细胞数量,并以对照的百分比表示。通过将单独施加TTFields时存活细胞的分数乘以在每种浓度下单独施加马德帕妥组单抗时存活细胞的分数来计算预期细胞数量。如图所示,在除80nM以外的所有药物浓度下,与每种单独治疗相比,TTFields和马德帕妥组单抗(表示为“ABT-414”)的组合治疗导致U87-MG细胞数量显著减少(P<0.001),而与对照物Ab095-MMAF ADC(即靶向破伤风类毒素的基于MMAF的抗体偶联物,表示为“ADC”)的组合则没有。在图1B中,使用流式细胞术测试凋亡的诱导(7AAD-膜联蛋白V-(活细胞)、7AAD+/膜联蛋白V+(晚期凋亡)、7AAD-/膜联蛋白V+(早期凋亡)、7AAD+/膜联蛋白V-)。如图所示,在所有测试浓度下,与每种单独治疗(表示为“ABT”)相比,对于TTfields和马德帕妥组单抗的组合治疗,观察到经历凋亡(早期和晚期两者)的细胞数量快速增加,而与对照物Ab095-MMAF ADC(即靶向破伤风类毒素的基于MMAF的抗体偶联物,表示为“ADC”)的组合则没有。
图2A和图2B示出了TTFields和马德帕妥组单抗的组合治疗在U87MGde2-7细胞(一种表达突变型EGFRvIII的胶质瘤细胞系)中的功效。用TTFields(200kHz,1.6V/cm RMS)治疗在各种马德帕妥组单抗浓度中生长的U87MGde2-7胶质瘤细胞72小时。在图2A中,在治疗结束时确定细胞数量,并以对照的百分比表示。通过将单独施加TTFields时存活细胞的分数乘以在每种浓度下单独施加马德帕妥组单抗时存活细胞的分数来计算预期细胞数量。如图所示,与任一单独治疗相比,TTFields和马德帕妥组单抗(表示为“ABT-414”)的组合治疗导致U87MGde2-7细胞数量显著减少,而与对照物Ab095-MMAF ADC(即靶向破伤风类毒素的基于MMAF的抗体偶联物,表示为“ADC”)的组合则没有。在图2B中,使用流式细胞术测试凋亡的诱导(7AAD-/膜联蛋白V-(活细胞)、7AAD+/膜联蛋白V+(晚期凋亡)、8AAD-/膜联蛋白V+(早期凋亡)、8AAD+/膜联蛋白V-)。如图所示,在所有测试浓度下,对于TTFields和马德帕妥组单抗(表示为“ABT”)的组合治疗,观察到经历凋亡(早期和晚期两者)的细胞数量快速增加,而与对照物Ab095-MMAF ADC(即靶向破伤风类毒素的基于MMAF的抗体偶联物,表示为“ADC”)的组合则没有。
图3为根据一个示例性实施方案的用于施加电场以选择性破坏细胞的装置的示意框图。
图4为图3的装置的绝缘电极的等效电路的简化示意图。
图5为并入有该装置并用于放置在皮肤表面上用于***等的皮肤贴剂的截面图示。
图6为植入体内用于***等的绝缘电极的截面图示。
图7A至图7D为图3的装置的绝缘电极的各种构造的截面图示。
具体实施方式
定义
为了使本公开内容更容易理解,首先定义某些术语。另外,应该注意的是,每当引用参数的值的范围时,意图是所引用的值中间的值和范围也意图成为本公开内容的一部分。
术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”是指减轻或消除疾病和/或其伴随症状的方法。
术语“受试者”被定义成包括动物,诸如哺乳动物,包括但不限于灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔子、大鼠、小鼠等。在实施方案中,受试者为人。
术语“患者”和“受试者”在本文中可互换使用。
本文中可互换使用的术语“抗表皮生长因子抗体药物偶联物”或“抗EGFR抗体药物偶联物”和“抗EGFR ADC”是指包含特异性结合EGFR的抗体的抗体-药物偶联物,由此该抗体与药物偶联,例如细胞毒剂诸如奥利斯他汀(auristatin)(例如一甲基奥利斯他汀F(monomethyl auristatin F))。在实施方案中,抗EGFR抗体经由马来酰亚胺基己酰基(maleimidocaproyl,mc)键与MMAF偶联。在实施方案中,抗EGFR抗体为马德帕妥组单抗。
如本文所用,术语“奥利斯他汀”是指抗有丝***剂家族。奥利斯他汀衍生物也包括在“奥利斯他汀”的定义内。奥利斯他汀的示例包括,例如奥利斯他汀E(AE)、一甲基奥利斯他汀E(MMAE)、一甲基奥利斯他汀F(MMAF)和尾海兔素(dolastatin)的合成类似物。
术语“抗EGFR抗体”是指特异性结合EGFR的抗体。“结合”感兴趣的抗原(例如EGFR)的抗体是能够以足够的亲和力结合该抗原的抗体,使得该抗体可用于靶向表达该抗原的细胞。
术语“抗体”广泛地指免疫球蛋白(Ig)分子,通常由四条多肽链、两条重(H)链和两条轻(L)链构成。抗体在轻链和重链可变结构域中均包含互补决定区(CDR),也称为高变区。可变结构域中更高度保守的部分被称为框架(FR)。如本领域中已知的,划分抗体的高变区的氨基酸位置/边界可变化,这取决于上下文和本领域中已知的各种定义。可将可变结构域内的一些位置视为混合高变位置,因为在一组标准下可将这些位置视为在高变区内,而在另一组标准下可将这些位置视为在高变区外。这些位置中的一个或多个也可在扩展的高变区中找到。天然重链和轻链的可变结构域各自包含四个FR区,主要通过采用β-折叠构型,由三个CDR连接,形成环连接并且在一些情况下形成β-折叠结构的一部分。每条链中的CDR通过FR区紧密保持在一起,并且与来自另一条链的CDR一起有助于抗体的抗原结合位点的形成。参见Kabat等人,免疫学感兴趣的蛋白质序列(Sequences of Proteins ofImmunological Interest)(美国国立卫生研究所,马里兰州贝塞斯达,1987年(NationalInstitute of Health,Bethesda,Md.1987))。如本文所用,根据Kabat等人的免疫球蛋白氨基酸残基编号***对免疫球蛋白氨基酸残基进行编号,除非另有说明。
如本文所用,术语“单克隆抗体”不限于通过杂交瘤技术产生的抗体。单克隆抗体通过本领域可获得的或已知的任何方式来源于单个克隆体,包括任何真核、原核或噬菌体克隆体。可用于本公开内容的单克隆抗体可使用本领域已知的多种技术制备,包括使用杂交瘤、重组和噬菌体展示技术或其组合。在本公开内容的许多用途中,包括在人体中体内使用包括抗EGFR抗体的ADC,可适当地使用嵌合抗体、灵长类化抗体、人源化抗体或人类抗体。
非人(例如鼠科动物)抗体的“人源化”形式为含有来源于非人免疫球蛋白的最小序列的嵌合免疫球蛋白。通常,人源化抗体将包含基本上所有的至少一个(并且通常两个)可变结构域,其中所有或基本上所有的CDR区对应于非人免疫球蛋白的那些区,并且所有或基本上所有的FR区为人类免疫球蛋白序列的那些区。人源化抗体还可包含免疫球蛋白恒定区(Fc)的至少一部分,通常为人类免疫球蛋白共有序列的一部分。抗体人源化的方法是本领域已知的。参见,例如,Riechmann等人,1988,《自然(Nature)》332:323-7;美国专利第5,530,101号;第5,585,089号;第5,693,761号;第5,693,762号;以及授予Queen等人的第6,180,370号;EP239400;PCT公布WO 91/09967;美国专利第5,225,539号;EP 592106;EP519596;Padlan,1991,《分子免疫学(Mol.Immunol.)》,28:489-498;Studicka等人,1994,《蛋白质工程(Prot.Eng.)》7:805-814;Roguska等人,1994,《美国科学院院报(Proc.Natl.Acad.Sci.)》91:969-973;以及美国专利第5,565,332号,这些全部通过引用整体并入在此。
本公开内容的抗EGFR ADC可包含全长(完整)抗体分子,以及能够特异性结合EGFR的抗原结合片段。作为示例而非限制,抗体结合片段的示例包括但不限于Fab、Fab'、F(ab')2、Fv片段、单链Fv片段和单结构域片段。
如本文所用,术语“有效量”或“治疗有效量”是指足以降低或改善疾病(例如癌症)或其一种或多种症状的严重性和/或持续时间、防止疾病的进展、引起疾病的消退、防止与疾病相关联的一种或多种症状的复发、发展、发作或进展、检测疾病或者增强或改进另一种疗法(例如预防剂或治疗剂)的(一种或多种)预防或治疗效果的药物(例如,ADC诸如马德帕妥组单抗)的量。有效量的ADC可例如抑制肿瘤生长(例如,抑制肿瘤体积的增加)、降低肿瘤生长(例如,降低肿瘤体积)、减少癌细胞的数量和/或在一定程度上缓解与癌症相关联的一种或多种症状。有效量可例如提高无病存活率(DFS)、提高总体存活率(OS)或降低复发的可能性。
术语“组合”或“组合疗法”是指施用两种或更多种疗法,例如,马德帕妥组单抗和TTFields。两种疗法可同时施用,在这种情况下,两种疗法一起或基本上一起施用,或者顺序地施用,在这种情况下,一种疗法可在另一种疗法之前施用。
术语“表达EGFR的肿瘤”或“具有EGFR表达的癌症”是指表达表皮生长因子受体(EGFR)蛋白的肿瘤。在一个实施方案中,使用肿瘤细胞膜的免疫组织化学染色来确定肿瘤中的EGFR表达,其中肿瘤样品中高于背景水平的任何免疫组织化学染色都表明该肿瘤为表达EGFR的肿瘤。用于检测肿瘤中EGFR表达的方法是本领域已知的,例如EGFR pharmDxTM Kit(Dako)。相比之下,“EGFR阴性肿瘤”被定义为通过免疫组织化学技术确定的肿瘤样品中不存在高于背景的EGFR膜染色的肿瘤。
如本文所用,术语“EGFRvIII阳性肿瘤”或“具有EGFRvIII表达的癌症”是指表达含有特定突变体(称为EGFRvIII)的表皮生长因子受体(EGFR)蛋白的肿瘤。在一个实施方案中,使用肿瘤细胞膜的免疫组织化学染色确定肿瘤中的EGFRvIII表达,其中在肿瘤样品中高于背景水平的任何免疫组织化学染色都表明该肿瘤为表达EGFRvIII的肿瘤。用于检测肿瘤中EGFR表达的方法是本领域已知的,并且包括免疫组织化学测定。相比之下,“EGFRvIII阴性肿瘤”被定义为通过免疫组织化学技术确定的肿瘤样品中不存在高于背景的EGFRvIII膜染色的肿瘤。
术语“过表达(overexpress)”、“过表达(overexpression)”或“过表达(overexpressed)”可互换地指与正常细胞相比,通常在癌细胞中以可检测较高的水平转录或翻译的基因。因此,过表达是指蛋白质和RNA的过表达(由于转录增加、转录后加工、翻译、翻译后加工、稳定性改变和蛋白质降解改变),以及由于蛋白质运输模式改变(核定位增加)和功能活性增强(例如,作为在底物的酶水解增加中)而引起的局部过表达。因此,过表达是指蛋白质或RNA水平。与正常细胞或比较细胞相比,过表达也可达到50%、60%、70%、80%、90%或更高。在某些实施方案中,本文描述的方法用于治疗可能过表达EGFR的实体瘤。
如本文所用,术语“施用”意指为了实现治疗目的(例如,与EGFR相关联的疾病的治疗)的物质(例如,抗EGFR ADC,诸如马德帕妥组单抗)的递送。施用模式可为肠胃外、肠内和局部的。肠胃外施用通常通过注射进行,并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。
马德帕妥组单抗(也称为“depatux-m”或“ABT-414”,在本公开内容的附图中也缩写为“ABT”)为靶向EGFR的抗体-药物偶联物(ADC)。它由经由稳定的马来酰亚胺基己酰基键与微管蛋白抑制剂一甲基奥利斯他汀F偶联的EGFR IgG1单克隆抗体(地宁妥珠单抗(depatuxizumab))构成。马德帕妥组单抗目前正被研究用于治疗癌症,特别是1L和2L胶质母细胞瘤(GBM),并且实体瘤目前正在进行临床试验。例如,M12-356是一项具有三个升级和扩展队列的开放标示研究,其中每两周以1.25mg/kg用depatux-m治疗66例患有EGFR扩增的rGBM的患者。
如本文所用,术语“TTFields”意指肿瘤治疗场,并且通常是指使用交变电场来治疗癌症。美国专利第6,868,289号和第7,016,725号(其中的每一个均通过引用整体并入本文)公开了使用频率在50kHz和500kHz之间的在1-10V/cm范围内的AC电场来***的方法和装置,并且当使用多于一个场方向时(例如,当场在定向成彼此相距约90°的两个或三个方向之间切换时),那些场的效率增大。出于本公开内容的目的,“TTFields”的定义涵盖用于癌症治疗的设备的使用。
在实施方案中,本公开内容涉及一种用于治疗表达EGFR的癌症的方法,其中方法包括施用肿瘤治疗场(TTFields)和有效量的马德帕妥组单抗。在实施方案中,癌症表达突变型EGFRvIII。在实施方案中,癌症为胶质母细胞瘤。
在实施方案中,本公开内容涉及一种用于治疗携带表达EGFR的肿瘤的患者的癌症的方法,其中方法包括以下的组合:(i)向目标区域施加AC电场,其中目标区域包括表达EGFR的肿瘤或癌细胞,以及(ii)施用有效量的与奥利斯他汀偶联的抗EGFR抗体。在实施方案中,奥利斯他汀为MMAF。在实施方案中,MMAF通过马来酰亚胺基己酰基键与抗体偶联。在实施方案中,抗EGFR抗体包含重链可变区和轻链可变区,该重链可变区包含包含在SEQ IDNo:3、4和5中阐述的氨基酸序列的互补决定区(CDR),该轻链可变区包含包含在SEQ ID No:8、9和10中阐述的氨基酸序列的CDR。在实施方案中,抗EGFR抗体包含包含在SEQ ID NO:2中阐述的氨基酸序列的重链可变区和包含在SEQ ID NO:7中阐述的氨基酸序列轻链可变区。在实施方案中,抗EGFR抗体包含包含在SEQ ID NO:1中阐述的氨基酸序列的重链和包含在SEQ ID NO:6中阐述的氨基酸序列的轻链。在实施方案中,与奥利斯他汀偶联的抗EGFR抗体为马德帕妥组单抗。
图3为适用于用组合的TTField和药物疗法(诸如抗EGFR ADC,例如马德帕妥组单抗)治疗活体患者的装置的示例,并且它可与任何常规药物递送机制(未示出)组合使用,以实施组合的TTField和药物疗法。图3为电子装置200的简单示意图,示出了其主要部件。电子装置200产生期望的电波形。装置200包括发生器210和一对导电引线220,该对导电引线的一端附接到发生器210。引线220的相对端连接到绝缘导体230,该绝缘导体由电信号(例如,波形)激活。绝缘导体230在下文中也被称为绝缘电极230。任选地并且根据另一个实施方案,装置200包括温度传感器240和控制箱250,两者都被添加以控制所产生的电场的幅度,从而不在被治疗的区域中产生过度加热。
发生器210以在约50KHz至约500KHz(诸如约100KHz至约300KHz)范围内的频率产生交变电压波形。所需的电压使得待治疗组织中的电场强度在约0.1V/cm至约10V/cm范围内,诸如在约1V/cm和约5V/Cm之间。为了实现这样的场,由***部件的相对阻抗确定在绝缘电极230中的两个导体之间的实际电势差,如下所述。
当包括控制箱250时,其控制发生器210的输出,使得它将保持恒定在由用户预设的值,或者控制箱250将输出设定在不会引起过度加热的最大值,或者当温度(由温度传感器240感测)超过预设极限时,控制箱250发出警告等。
当包括控制箱250时,其控制发生器210的输出,使得它将保持恒定在由用户预设的值,或者控制箱250将输出设定在不会引起过度加热的最大值,或者当温度(由温度传感器240感测)超过预设极限时,控制箱250发出警告等。
装置200作为一个整体及其各个部件的规格在很大程度上受到以下事实的影响,即在TTFields的频率(50KHz-500 KHz)下,生命***根据它们的“欧姆”而不是它们的介电特性来表现。装置200中唯一表现不同的元件为绝缘电极230的绝缘体(见图5和图6)。绝缘电极200由与电介质接触的导体组成,该电介质与导电组织接触,从而形成电容器。
绝缘电极230的构造的细节是基于它们的电学行为,这可以从它们与组织接触时的简化电路中理解,如图4一般所示。在所示的布置中,不同部件之间的电势降或电场分布由它们的相对电阻抗确定,即每个部件上的场的分数由它的阻抗值除以总电路阻抗得出。例如,元件上的电势降△VA=A/(A+B+C+D+E)。因此,对于DC或低频AC,实际上所有的电势降均在电容器(充当绝缘体)上。对于相对非常高的频率,电容器实际上是短路,并且因此,实际上所有场均分布在组织中。在作为中频的TTFields的频率(例如50KHz至500KHz)下,电容器的电容阻抗占主导地位,并且决定了场分布。因此,为了增大组织两端上的有效电压降(场强度),要减小电容器的阻抗(即,增大其电容)。这可通过增加电容器的“极板”的有效面积、减小电介质的厚度或使用具有高介电常数的电介质来实现。
为了优化场分布,根据要使用绝缘电极230的应用,不同地配置绝缘电极230。施加TTFields有两种主要模式。首先,TTFields可通过外部绝缘电极施加;其次,TTFields可通过内部绝缘电极施加。
通过外部绝缘电极施加的TTFields可为局部类型或广泛分布的类型。第一类型包括例如皮肤肿瘤的治疗和皮肤表面附近的病变的治疗。图5示出了示例性实施方案,其中绝缘电极230被并入在皮肤贴剂300中。皮肤贴剂300可为具有一对或多对绝缘电极230的自粘柔性贴剂。贴剂300包括内部绝缘物310(由介电材料形成)和外部绝缘物260,并且在皮肤表面301上或略在皮肤表面301下方施加到含有肿瘤303的皮肤表面301。组织通常以305表示。为了防止内部绝缘物310两端上的电势降主导***,内部绝缘物310必须具有相对高的电容。这可通过大的表面积来实现;然而,这可能不是期望的,因为这将导致场在大面积(例如,大于***所需的面积)上的扩散。另选地,内部绝缘物310可被制成非常薄和/或内部绝缘物310可具有高介电常数。由于电极(在图4中标记为A和E)之间的皮肤电阻通常显著高于其下面的组织(在图4中标记为C)的皮肤电阻(1-10KQ对0.1-1KQ),超过绝缘电极的大部分电势降出现在那里。为了适应这些阻抗(Z),内部绝缘物310(在图4中标记为B和D)的特性应使得它们在TTFields的频率(例如,50KHz至500KHz)下具有优选低于100KQ的阻抗。例如,如果期望阻抗为约10K Ohm或更小,使得超过1%的所施加的电压落在组织上,对于表面积为10mm2的绝缘电极,在200KHz的频率下,则电容应为大约10-10F,这意味着使用介电常数为2-3的标准绝缘物,绝缘层310的厚度应为约50-100微米。使用介电常数约为20-50的绝缘体将获得10倍强的内部场。
使用具有高介电常数的绝缘材料会增大电极的电容,这导致电极对由发生器1施加的AC信号的阻抗减小(如图3所示)。因为电极A、电极E与目标组织C串联用线连接,如图4所示,所以这种阻抗的降低降低了电极中的电压降,使得施加的AC电压的较大部分出现在组织C上。由于较大部分的电压出现在组织上,因此对于组织中的给定场强,由发生器1施加的电压可有利地降低。
被治疗的组织中的期望场强可在约0.1V/cm和约10V/cm之间,诸如在约2V/cm和3V/cm之间或在约1V/cm和约5V/cm之间。如果电极中使用的介电常数足够高,则电极A、电极E的阻抗会下降到与皮肤和组织B、C、D的串联组合相同的数量级。具有极高介电常数的合适材料的一个示例为CaCu3Ti4O12,其介电常数约为11,000(在100kHz下测量)。当介电常数如此高时,可使用大约几十伏的发生器电压来获得有用的场。
由于薄的绝缘层可能非常脆弱等,因此可用介电常数非常高的绝缘材料诸如二氧化钛(例如金红石)代替绝缘物,介电常数可达到约200的值。有许多不同的适合用于预期的应用中并具有高介电常数的材料。例如,一些材料包括:铌酸锂(LiNbO3),它是一种铁电晶体,并且在光学、热电和压电器件中有许多应用;钇铁石榴石(YIG)是一种铁磁晶体和磁光器件,例如可用这种材料实现光隔离器;钛酸钡(BaTiO3)是一种具有大的电光效应的铁磁晶体;钽酸钾(KTaO3),它是一种介电晶体(在低温下为铁电的)且在低温下具有非常低的微波损耗和介电常数可调性;以及钽酸锂(LiTaO3),它是一种铁电晶体,具有与铌酸锂相似的特性,并且可用于电光、热电和压电器件。也可使用具有高介电常数的绝缘体陶瓷,诸如由铌酸铅镁和钛酸铅的组合制成的陶瓷。应当理解,在期望使用具有高介电常数的材料的情况下,上述示例性材料可与本器件组合使用。
还必须考虑影响绝缘电极230的有效电容的另一因素,即在绝缘电极230和皮肤之间存在空气。此类不易防止的存在会引入介电常数为1.0的绝缘体层,这是显著降低绝缘电极230的有效电容并中和二氧化钛(金红石)优点等的因素。为了克服这个问题,可将绝缘电极230成形为与主体结构相符和/或(2)可向该结构添加具有高电导率和高有效介电常数的中间填充物270(如图7C所示),诸如凝胶。该成形可为预结构化的(见图7A),或者该***可制造得足够柔性,使得容易实现绝缘电极230的成形。如图7C和图7C’所描绘,通过具有升高的边缘,可将凝胶容纳在适当的位置。凝胶可由水凝胶、明胶、琼脂等制成,并且其中可溶解有盐以增加其导电性。图7A至图7C示出了绝缘电极230的各种示例性构型。凝胶的确切厚度并不重要,只要它具有足够的厚度,使得凝胶层在治疗期间不会变干。在一个示例性实施方案中,凝胶的厚度为约0.5mm至约2mm。优选地,凝胶具有高导电性、是粘性的并且在长时间段内是生物相容的。一种合适的凝胶为AG603水凝胶,其可从美国加利福尼亚州福尔布鲁克传教路1667号,邮编:92028-4115的AmGel Technologies(AmGel Technologies,1667S.Mission Road,Fallbrook,Calif.92028-4115,USA)购得。
为了实现绝缘电极230的期望特征,每一个绝缘电极的电介质涂层应该非常薄,例如在1-50微米之间。由于涂层太薄,所以绝缘电极230很容易受到机械损坏或发生介电击穿。这个问题可以通过向绝缘电极的结构中添加保护性特征来克服,从而为此类损坏提供期望的保护。在公布的申请US2005/0209642中描述了一些合适的保护性特征的示例,该申请通过引用并入本文。
然而,电容并不是要考虑的唯一因素。以下两个因素也影响绝缘电极230的构造方式。内部绝缘层310的介电强度和当其经受TTFields时发生的介电损耗,即产生的热量。内部绝缘物310的介电强度决定了绝缘物将在什么场强度下“短路”并停止以充当完整的绝缘物。通常,绝缘体,诸如塑料,介电强度值为约100伏每微米或更高。当高介电常数减小内部绝缘体310内的场时,高介电常数和高介电强度的组合提供了显著的优点。这可通过使用具有期望特性的单一材料来实现,或者可通过具有正确参数和厚度的双层来实现。另外,为了进一步降低绝缘层310失效的可能性,绝缘层310的所有尖锐边缘均应该通过使用常规技术圆化拐角等来消除,如图7D所示。
图6示出了使用绝缘电极230的第二种类型的治疗,即通过内部绝缘电极230的电场产生。植入绝缘电极230的身体通常以311表示,并且包括皮肤表面313和肿瘤315。在该实施方案中,绝缘电极230可具有板、线的形状或可***皮下或身体311内较深位置以便在目标区域(肿瘤315)处产生适当场的其他形状。
为了避免治疗的组织过热,需要选择材料和场参数。绝缘电极绝缘材料应在治疗过程期间要使用的频率范围内具有最小的介电损耗。在选择治疗的特定频率时可考虑这个因素。组织的直接加热很可能是由电流引起的加热(由I*R乘积给出)主导的。此外,绝缘电极(绝缘的电极)230及其周围环境应由有利于热损失的材料制成,并且其总体结构也应有利于热损失,即,阻止热量消散到周围环境(空气)的最小结构以及高导热率。使用较大的电极也可最大程度地减少局部发热感,因为它会将传递给患者的能量散布在较大的表面积上。优选地,将加热最小化到患者皮肤温度决不超过约39℃的程度。
减少加热的另一种方式是通过施加占空比在约20%和约50%之间的场而不是使用连续场来将间歇地将场施加到被治疗的组织。例如,要实现33%的占空比,该场将重复地打开一秒,然后关闭两秒。初步实验表明,使用占空比为33%的场的治疗功效与占空比为100%的场大致相同。在替代实施方案中,可将场打开一小时,然后关闭一小时,以实现50%的占空比。当然,以每小时一次的速度进行切换并不有助于最大程度地减少短期加热。另一方面,它可为患者提供令人愉快的治疗间断。
还应当理解,本装置可进一步包括用于使TTFields相对于活体组织旋转的设备。例如并且根据一个实施方案,交变电势施加到被治疗的组织,使用常规设备(诸如机械设备)相对于组织旋转,该机械设备在激活时使本***的各个部件旋转。
可以连续的方式将TTFields施加到不同对的绝缘的电极230,以改变穿过目标区域的TTFields的方向,如公布的申请US2005/0209642中所述,该申请通过引用并入本文。场方向的改变可以逐步的方式或以连续的方式实施,也如公布的申请US2005/0209642中所述。
如公布的申请US2005/0209642中所述,将不同频率的分布施加到群体可能是有利的。例如,实验表明,使用170kHz和250kHz的两个频率破坏胶质瘤细胞群比使用200kHz的单个频率更有效。当使用多于一个频率时,可在时间上顺序地施加各种频率。例如,在胶质瘤的情况下,可在治疗的第一分钟、第二分钟、第三分钟、第四分钟、第五分钟和第六分钟期间分别施加100、150、170、200、250和300kHz的场频率。然后,将在每个连续六分钟的治疗期间重复这一频率循环。另选地,可从100kHz至300kHz以无级方式扫描场的频率。任选地,这一频率循环可与上述方向变化相组合。
在替代实施方案中,将同时含有两个或更多个频率分量(例如170kHz和250kHz)的信号施加到电极以治疗具有尺寸分布的细胞群。各种信号将通过叠加相加来创建包括所有施加的频率分量的场。
实施例
使用两种人类胶质瘤细胞系:U87-MG(ATCC)和U87MGde2-7(路德维希癌症研究所(Ludwig Institute for Cancer Research))测试TTFields和马德帕妥组单抗的组合治疗的功效。所有细胞在供应有5%CO2的加湿培养箱中生长。U-87MGde2-7和U87-MG保持在具有高葡萄糖的Dulbecco改良版Eagle培养基(Dulbecco’s Modified Eagle’s Medium,DMEM)中,补充有10%FBS(胎牛血清)和1mmol/L丙酮酸钠。用400mg/ml遗传霉素对U87MGde2-7细胞保持选择。
细胞毒性测定:使用体外***将TTFields(1.75V/cm RMS,200kHz)施加72小时(如以下中所述:Giladi M,Schneiderman RS,Voloshin T,Porat Y,Munster M,Blat R等人,交变电场引起的有丝***纺锤体破坏导致癌细胞中不适当的染色体分离和有丝***突变(Mitotic Spindle Disruption by Alternating Electric Fields Leads to ImproperChromosome Segregation and Mitotic Catastrophe in Cancer Cells.)《科学报告(SciRep.)》2015;5:18046)。体外***由TTFields发生器和底板组成,每个底板含有8个陶瓷皿。TTFields的定向每1秒切换90°,从而覆盖了细胞***的大部分定向轴线,如Kirson等人,Kirson ED,Dbaly V,Tovarys F,Vymazal J,Soustiel JF,Itzhaki A等人,交变电场阻止动物肿瘤模型和人脑肿瘤中的细胞增殖(Alternating electric fields arrest cellproliferation in animal tumor models and human brain tumors)《美国科学院院报》2007;104(24):10152-7所述。将胶质瘤细胞接种在置于体外培养皿内的22mm圆形盖玻片上。过夜孵育后,用2ml培养基填充培养皿,该培养基含有2倍稀释度的浓度为0.01-100nmol/L的马德帕妥组单抗或同种型对照物。
在治疗结束时,基于使用EC800流式细胞仪(日本索尼生物技术公司(SonyBiotechnology,Japan))进行的细胞计数,对肿瘤细胞生长的抑制进行定量分析。
流式细胞术:为了检测凋亡,按照制造商的说明书,用FITC偶联的膜联蛋白V(MEBCYTO 4700凋亡试剂盒;MBL)和7-氨基放线菌素D(7-AAD;Biolegend)对细胞进行双重染色。使用iCyt EC800(索尼生物技术)流式细胞仪获得数据采集。对于膜联蛋白V,在525/50nm的波长下收集荧光信号,对于7-AAD,在665/30nm的波长下收集荧光信号。使用Flowjo软件(TreeStar)分析数据。
统计分析:数据表示为平均值±SD,并且差异的统计显著性使用GraphPad Prism6软件(GraphPad软件,加利福尼亚州拉荷亚(La Jolla,CA))评估。将所有组之间的差异彼此进行比较,并且被认为在值0.05>*p>0.01、**p<0.01和***p<0.001时显著。所有实验重复至少三遍。
结果
TTFields和马德帕妥组单抗对U-87MG细胞的功效
滴定实验表明,抑制U87-MG细胞生长所需的马德帕妥组单抗有效剂量在nM范围内。观察到与先前报道的IC50值存在一些变化,这些变化主要归因于此研究(细胞计数)与先前研究(基于发光的测定)之间的枚举技术的差异。如图1A所示,在除80nm之外的所有药物浓度下,与每种单独治疗相比,TTFields和马德帕妥组单抗(在图1至图2中称为“ABT-414”或“ABT”)的组合治疗导致U87-MG细胞的数量显著减少(P<0.001)。相比之下,TTfields和对照物ADC,Ab095-MMAF ADC(即,Ab095,一种靶向破伤风类毒素的抗体,与MMAF偶联以形成在图1至图2中称为“ADC”的非特异性ADC,也参见Larrick等人,1992,《免疫学综述(Immunological Reviews)》,69-85)的组合,与单独TTFields治疗相比,导致细胞数量的非显著减少。在所有测试浓度下,对于TTfields和马德帕妥组单抗的组合治疗观察到经历凋亡(早期和晚期两者)的细胞的数量快速增加(与那些单独采用的治疗中的任一种相比),如图1B所示。相比之下,单独用Ab095-MMAF治疗后凋亡细胞的百分比类似于Ab095-MMAF ADC与TTFields组合的百分比。
TTFields和马德帕妥组单抗对U87MGde2-7细胞的功效
滴定实验显示,马德帕妥组单抗对U87MGde2-7细胞的有效性在pM范围内。与任一种单独治疗相比,TTFields和马德帕妥组单抗的组合治疗导致U87MGde2-7细胞的数量显著减少,如图2A所示。相比之下,与单独的TTFields治疗相比,TTFields和Ab095-MMAF的组合治疗导致细胞数量的非显著减少。如在U-87MG的情况下,在所有测试的浓度下,对于TTFields和马德帕妥组单抗的组合治疗观察到经历凋亡(早期和晚期两者)的细胞的数量快速增加,如图2B所示。相比之下,与对照培养物或单独用TTFields治疗的细胞相比,用Ab095-MMAF或TTFields+Ab095-MMAF治疗后,凋亡细胞的百分比未增加。
这些结果证明,在U87细胞中,与每种单独治疗相比,在nM范围内的TTFields和马德帕妥组单抗的组合导致细胞数量显著减少和凋亡增加。在U87EGFRvIII细胞中,与每种单独治疗相比,在pM范围内的TTFields和马德帕妥组单抗的组合治疗导致细胞数量显著减少和凋亡增加。TTfields的施加对用Ab095 MMAF非特异性ADC治疗的细胞几乎没有影响。
抗体序列表
序列表
<110> 艾伯维公司(ABBVIE INC.)
诺沃医疗有限公司(NOVOCURE LIMITED)
大卫·马格(MAAG, David)
摩西·吉拉迪(GILADI, Moshe)
罗莎·施奈德曼(SCHNAIDERMAN, Rosa)
埃纳夫·泽维(ZEEVI, Einav)
埃隆·科尔森(KIRSON, Eilon)
<120> 治疗胶质母细胞瘤的方法
<130> ABV12412WOO1
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Claims (10)
1.一种用于治疗携带表达EGFR的肿瘤的患者的癌症的方法,所述方法包括
(i)向目标区域施加AC电场,其中所述目标区域包括表达EGFR的肿瘤或癌细胞);,以及
(ii)施用有效量的马德帕妥组单抗。
2.根据权利要求1所述的方法,其中所述癌症表达突变型EGFRvIII。
3.根据权利要求1所述的方法,其中所述癌症为胶质母细胞瘤。
4.根据权利要求3所述的方法,其中所述电场的频率在50kHz和500kHz之间。
5.根据权利要求4所述的方法,其中所述电场的频率为100kHz至300kHz。
6.根据权利要求5所述的方法,其中所述电场的频率为约200kHz。
7.根据权利要求4所述的方法,其中在所述目标区域的至少一部分中的所述电场的强度在约1V/cm和约5V/cm之间。
8.根据权利要求4所述的方法,其中在所述目标区域中施加至少两个不同的频率。
9.根据权利要求5所述的方法,其中在所述目标区域中施加至少两个不同的频率。
10.一种用于抑制肿瘤生长的方法,所述方法包括:
(i)向目标区域施加AC电场,其中所述目标区域包括表达EGFR的肿瘤或癌细胞)以及
(ii)施用有效量的马德帕妥组单抗。
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US11986647B2 (en) | 2018-09-07 | 2024-05-21 | Novocure Gmbh | Treating autoinflammatory and mitochondrial diseases using an alternating electric field |
PL3984590T3 (pl) | 2018-10-15 | 2023-05-02 | Novocure Gmbh | Wytwarzanie pól leczących guzy (pól elektrycznych do leczenia nowotworów ttfields) o wysokiej równomierności w całym mózgu |
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JP7250951B2 (ja) | 2019-04-17 | 2023-04-03 | ノボキュア ゲーエムベーハー | 隔離性を損なうことなく、隔離されたシステムからデータをアップロードすること |
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CN114786764A (zh) * | 2019-12-20 | 2022-07-22 | 诺沃库勒有限责任公司 | 用于向动物试验对象提供肿瘤治疗场的治疗组件 |
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