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CN108697801A - 使用liv1-adc和化学治疗的组合疗法 - Google Patents

使用liv1-adc和化学治疗的组合疗法 Download PDF

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CN108697801A
CN108697801A CN201780013873.8A CN201780013873A CN108697801A CN 108697801 A CN108697801 A CN 108697801A CN 201780013873 A CN201780013873 A CN 201780013873A CN 108697801 A CN108697801 A CN 108697801A
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adc
cancer
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D·萨斯曼
李福�
A·科斯蒂奇
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Seagen Inc
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Seattle Genetics Inc
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Abstract

本发明提供通过施用LIV‑1抗体药物偶联物和化学治疗来医治患有或处于癌症风险的受试者的方法。

Description

使用LIV1-ADC和化学治疗的组合疗法
相关申请的交叉引用
本申请要求2016年3月15日提交的美国临时申请第62/308,639号、2016年4月4日提交的美国临时申请第62/317,792号和2016年7月27日提交的美国临时申请第62/367,510号的权益，所述申请的公开内容以全文引用的方式并入本文中用于所有目的。
参考序列表
2017年3月1日创建的16KB的命名为0710-00313PC序列表ST25.txt的序列表以引用的方式并入本文中。
技术领域
本发明涉及用于医治癌症的方法，所述方法包含施用LIV1-ADC和化学治疗。
背景技术
LIV-1为锌转运蛋白的LZT(LIV-1-ZIP锌转运体)子族的成员。Taylor等人,《生物化学与生物物理学报(Biochim.Biophys.Acta)》1611:16-30(2003)。LIV-1蛋白的计算机分析揭示潜在金属蛋白酶主结构，其拟合用于锌金属蛋白酶的催化性锌结合位点主结构的共同序列。LIV-1 mRNA主要表达在乳房、前列腺、垂体腺和脑组织中。
LIV-1蛋白还涉及某些癌条件，例如，乳癌和前列腺癌。LIV-1的检测与雌激素受体阳性乳癌(McClelland等人，《英国癌症杂志(Br.J.Cancer)》77:1653-1656(1998))和这些癌症向区域性淋巴结的转移性扩散(Manning等人,《欧洲癌症杂志(Eur.J.Cancer)》30A:675-678(1994))相关联。
SGN-LIV1A为由以下三种组分组成的LIV-1-定向抗体-药物偶联物(ADC)：1)特异于人类LIV-1的人源化抗体hLIV22，2)微管破坏剂单甲基奥瑞他汀(auristatin)E(MMAE)，和3)将MMAE与hLIV22共价附接的稳定连接基团，缬氨酸-瓜氨酸(vc)。提出的作用机理(MOA)由结合到在细胞表面上的LIV-1的SGN-LIV1A，接着内化ADC来启动。在运输到溶酶体时，递送的药物(MMAE)通过vc连接基团的蛋白水解降解而释放。将释放的药物结合到微管蛋白干扰微管网络，从而引向细胞周期停滞和凋亡。
SGN-LIV1A已经示出活体内减少肿瘤体积，并且当前在1期临床试验中针对患有LIV-1-阳性转移性乳癌的患者评估所述SGN-LIV1A。然而，在癌症治疗中需要改进。本发明解决此问题和其它问题。
发明内容
本发明提供用于医治患有或处于癌症风险的受试者的方法。方法包括向受试者施用LIV-1抗体药物偶联物(LIV-1-ADC)和化学治疗。LIV-1-ADC包括偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体，并且化学治疗为卡铂(carboplatin)、阿霉素、紫杉醇、曲妥珠单抗(trastuzumab)和mTOR抑制剂中的一种。任选地，受试者患有前列腺癌、卵巢癌、子宫内膜癌、胰腺癌、肺癌、宫颈癌、黑色素瘤、鳞状细胞癌或乳癌，如三阴性乳癌、三阳性乳癌、HER2阳性乳癌或激素受体阳性乳癌。
在一些实施例中，以在受试者的体重的1.5mg/kg和4mg/kg之间的剂量施用LIV-1-ADC。在一个实施例中，以受试者的体重的2.5mg/kg的剂量施用LIV-1-ADC。在一个实施例中，LIV-1-ADC每3周施用一次。在一个实施例中，通过静脉内注射来施用LIV-1-ADC。
在一个实施例中，化学治疗为卡铂，并且其以在200mg/m2和750mg/m2之间的剂量施用。在一个实施例中，通过静脉内注射来施用卡铂。在另一个实施例中，化学治疗为阿霉素，并且其以在40mg/m2和80mg/m2之间的剂量施用。在一个实施例中，通过静脉内注射来施用阿霉素。在另一个实施例中，化学治疗为紫杉醇，并且其以在100mg/m2到260mg/m2之间的剂量施用。在一个实施例中，通过静脉内注射来施用紫杉醇。
本发明还提供用于医治患有或处于癌症风险的受试者的方法，方法包含向受试者施用LIV-1抗体药物偶联物(LIV-1-ADC)和曲妥珠单抗恩他新(trastuzumab emtansine)或帕妥珠单抗(pertuzumab)。LIV-1-ADC包括偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体。
附图说明
图1示出根据本发明的实施例的多种制剂对MCF-7细胞的活力。
图2示出根据本发明的实施例的SGN-LIV1A和阿霉素对MCF-7细胞的影响。
图3示出根据本发明的实施例的SGN-LIV1A和紫杉醇对MCF-7细胞的影响。
图4示出根据本发明的实施例的SGN-LIV1A和吉西他滨(gemcitabine)对MCF-7细胞的影响。
图5示出根据本发明的实施例的SGN-LIV1A和依维莫司(everolimus)对MCF-7细胞的影响。
图6示出根据本发明的实施例的SGN-LIV1A和阿霉素(左侧)或阿布拉生(Abraxane)(白蛋白结合型紫杉醇)(右侧)对NOD Scidγ(NSG)小鼠体内肿瘤生长的影响。
图7示出根据本发明的实施例的SGN-LIV1A和卡铂(左侧)或环磷酰胺(右侧)对NODScidγ(NSG)小鼠体内肿瘤生长的影响。
图8示出根据本发明的实施例的SGN-LIV1A和吉西他滨(左侧)或紫杉醇(右侧)对NOD Scidγ(NSG)小鼠体内肿瘤生长的影响。
定义
术语“抗体”包括完整抗体和其结合片段。通常，抗体片段与它们从中衍生的完整抗体竞争与靶的特异性结合，包括单独重链、轻链Fab、Fab'、F(ab')2、F(ab)c、双功能抗体、Dab、纳米抗体和Fv。片段可通过重组DNA技术，或通过完整免疫球蛋白的酶促或化学分离来产生。术语“抗体”还包括双功能抗体(均二聚Fv片段)或微型抗体(VL-VH-CH3)、双特异性抗体等。双特异性或双功能抗体为具有两个不同的重/轻链对和两个不同的结合位点的人工混合型抗体(参看例如，Songsivilai和Lachmann,《临床与实验免疫学(Clin.Exp.Immunol.),79:315-321(1990)；Kostelny等人,《免疫学杂志(J.Immunol.)》,148:1547-53(1992))。术语“抗体”包括抗体自身(“裸抗体”)或偶联至细胞毒性或细胞生长抑制性药物的抗体。
“细胞毒性效应”是指耗尽、消除和/或杀死靶细胞。“细胞毒性剂”是指对细胞具有细胞毒性效应的制剂。细胞毒性剂可偶联至抗体，或与抗体组合施用。
“细胞生长抑制效应”是指抑制细胞增殖。“细胞生长抑制剂”是指对细胞具有细胞生长抑制效应的制剂，由此抑制细胞特定亚群的生长和/或扩增。细胞生长抑制剂可偶联至抗体，或与抗体组合施用。
如本文所用的术语“医药学上可接受”是指在合理医学判断的范围内，适合用于与人类和动物的组织接触，而无过度毒性、刺激性、过敏反应，或与合理的收益/风险比率相应的其它问题或并发症的那些化合物、物质、组合物和/或剂型。术语“医药学上相容性成分”是指与抗LIV-1抗体一起施用的医药学上可接受的稀释剂、助剂、赋形剂或媒剂。
短语“医药学上可接受的盐”是指抗LIV-1抗体或其偶联物，或与抗LIV-1抗体一起施用的制剂的医药学上可接受的有机或无机盐。示例性盐包括硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、丁二酸盐、顺丁烯二酸盐、龙胆酸盐、反丁烯二酸盐、葡糖酸盐、葡糖醛酸盐、葡糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1'亚甲基双-(2羟基3萘甲酸盐))。医药学上可接受的盐可涉及纳入另一种分子，如乙酸根离子、丁二酸根离子或其它抗衡离子。抗衡离子可为任何使母体化合物上的电荷稳定的有机或无机部分。此外，医药学上可接受的盐在其结构中可具有多于一个带电原子。多个反离子可出现在其中多个带电原子为医药学上可接受的盐的一部分的例子中。因此，医药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
术语“有效量”是指LIV-1-ADC例如SGN-LIV1A足以抑制受试者体内的LIV-1-相关联病症的一种或多种临床或诊断症状的发生或改善所述症状的量。根据本文所描述的方法，在“有效疗程”中施用有效量的制剂。术语“有效疗程”是指足以维持高LIV-1占用的制剂量和剂量频率的组合，其可实现LIV-1-相关联病症的医治或预防。在优选实施例中，在给药间隔期间，有效疗程维持几乎全部例如超过90％在LIV-1-表达细胞上的LIV-1占用。
如本文所用，术语“医治”和“治疗”等意指包括产生任何临床上期望或有益影响(包括(但不限于)缓解或减轻一种或多种症状，消退、减缓或停止疾病或病症的进展)的用于疾病或病症的治疗性或抑制性措施。举例来说，医治可包括通过向受试者施用抗LIV-1抗体或其它LIV-1结合剂降低或消除在开始临床或诊断症状之后的LIV-1-表达病症的临床或诊断症状。医治可由症状严重程度、症状的数量或复发的频率的降低来证明。
除在指出时之外，术语“受试者”或“患者”互换使用，并且是指哺乳动物如人类患者和非人类灵长类动物以及实验动物如兔、犬、猫、大鼠、小鼠和其它动物。因此，如本文所用的术语“受试者”或“患者”意指可向其施用本发明的LIV-1结合剂的任何哺乳动物患者或受试者。在优选实施例中，术语受试者或患者用以指人类患者。本发明的受试者包括已经诊断患有LIV-1表达癌症的那些受试者，所述癌症包括例如乳癌、前列腺癌、卵巢癌、子宫内膜癌、胰腺癌、肺癌、宫颈癌、黑色素瘤或鳞状细胞癌。在某些实施例中，受试者将患有难治性或复发的LIV-1表达癌症。
“包含”一种或多钟列举要素的组合物或方法可包括其它未特别叙述的要素。举例来说，包含抗体的组合物可仅含有抗体或与其它成分组合。
值的范围的指示包括范围内或限定范围的所有整数。
如本文所用，术语“约”表示规定值加或减10％的近似范围。举例来说，措辞“约20％”涵盖18-22％的范围。如本文所用，约还包括准确的量。因此，“约20％”意指“约20％”，同时还意指“20％”。
具体实施方式
I.概要
本发明提供用于医治癌症，具体地说乳癌的方法。本发明人已经发现具有两种不同类别的抗癌化合物：抗体-药物偶联物化合物和化疗剂的组合疗法可改进用于患有癌症的受试者的治疗益处。具体来说，本发明人已发现具有(1)偶联至奥瑞他汀化合物的抗LIV-1抗体和(2)化疗剂的组合疗法在医治癌症上提供协同治疗效应。
II.LIV-1-ADC
除非另外指明，否则LIV-1-抗体药物偶联物(LIV-1-ADC)包括特异于偶联至细胞毒性剂的人类LIV-1蛋白的抗体。示例性人类LIV-1序列分配Swiss Prot寄存编号Q13433。Q13433作为SEQ ID NO:1包括在本文中。已知三种变体同工型和一种多态性。人类LIV-1蛋白的第二版本(寄存编号AAA96258.2)作为SEQ ID NO:2包括在本文中。四个胞外结构域分别以Q13433的残基29-325、377-423、679-686和746-755为界。
SGN-LIV1A为LIV-1-定向抗体-药物偶联物(ADC)，其通过药物连接基团具有缬氨酸-瓜氨酸连接基团的单甲基奥瑞他汀E(vcMMAE)偶联至人源化抗体hLIV22来产生。hLIV22为小鼠BR2-22a抗体的人源化形式，描述于美国专利第9,228,026号中。hLIV22抗体在实验误差内大体上与BR2-22a相同并且含有七种回复突变。制得hLIV22抗体的方法还公开于美国专利第9,228,026号中。hLIV22的轻链可变区的氨基酸序列作为SEQ ID NO:3提供在本文中。hLIV22的重链可变区的氨基酸序列作为SEQ ID NO:4提供在本文中。药物连接基团vcMMAE(以下示出；也称为1006)的合成和偶联进一步描述于美国专利第9,228,026号和美国专利公开第20050238649号中。
III.化疗剂和LIV-1-ADC的组合疗法
可使用SGN-LIV1A和化疗剂的组合医治癌症。化疗剂为卡铂、阿霉素或紫杉醇、曲妥珠单抗、检查点抑制剂或mTOR抑制剂(如依维莫司)。卡铂(纽约州纽约的百时美施贵宝公司(Bristol Myers Squibb,New York,NY))为烷化剂。阿霉素为具有抗肿瘤活性的蒽环霉素(anthracycline)抗生素。紫杉醇(新泽西州萨密特的塞尔基因公司(Celgene,Summit,NJ))为抑制微管衰竭的紫杉烷。曲妥珠单抗(加利福尼亚州南旧金山的基因泰克公司(Genentech,South San Francisco,CA))为结合HER2受体的单克隆抗体。检查点抑制剂(阻断免疫检查点的抑制剂)的实例包括抗体如抗PD-1抗体(例如，MEDI0680、AMP-224、纳武单抗(nivolumab)、帕博利珠单抗(pembrolizumab)和匹立珠单抗(pidilizumab))、抗PD-L1抗体(例如，MEDI4736和MPDL3280A)和抗CTLA4抗体(例如，伊派利单抗(ipilimumab)和曲美单抗(tremelimumab))。其它检查点抑制剂/活化剂包括B7-DC-Fc、LAG3和TIM3。
可以抑制癌细胞生长同时受试者耐受的含量水平将SGN-LIV1A和化疗剂的组合给予受试者。在一个实施例中，施用组合降低由单独施用化疗剂所导致的毒性效应。在一些实施例中，SGN-LIV1A和化疗剂的组合为协同或累加的。对于一些组合，相较于在单独施用时，可以较低含量水平有效地施用在组合中的每种制剂。
如上文所论述，本发明的组合疗法可用于医治癌症。一些这类癌症示出以蛋白(例如通过使用示范性抗体中的一种的免疫检定)或mRNA含量水平测量的可检测的LIV-1含量水平。一些这类癌症示出相对于相同类型的非癌性组织(优选来自同一患者)升高的LIV-1含量水平。适用于医治的癌细胞上的示例性LIV-1含量水平为每个细胞5000到150000个LIV-1分子，但是可医治更高或更低含量水平。任选地，在进行医治之前测量癌症中的LIV-1含量水平。
与LIV-1表达相关联并且适用于用本发明的组合疗法医治的癌症的实例包括乳癌、前列腺癌、卵巢癌、子宫内膜癌、胰腺癌、宫颈癌、肝脏癌、胃癌、肾脏癌和鳞状细胞癌(例如，膀胱、头部、颈和肺)、皮肤癌例如黑色素瘤、小细胞肺癌或肺类癌。医治可施加到患有这些类别的原发性或转移性肿瘤的患者。医治还可施加到常规医治(例如，对于乳癌：激素、他莫昔芬(tamoxifen)、)难治的患者，或在对这类医治响应之后已经复发的患者。还可对三阴性乳癌使用所述方法。三阴性乳癌为用于在用这些受体(如在实例中描述的)中的任一种的抗体染色时缺乏可检测雌激素和孕酮受体并且缺乏HER2/neu的过表达的癌症的领域的术语。还可对三阳性乳癌、激素受体阳性乳癌和HER2阳性乳癌使用所述方法。可相对于不相关的对照抗体执行染色，并且表达的缺少由在实验误差内与对照相同或类似的水平的染色的背景水平示出。同样，过表达的缺少由在实验误差内非癌性乳房组织(优选地获自相同患者)的相同或类似水平下的染色示出。替代或另外地，三阴性乳癌特征为缺少对与这些受体、侵袭性行为和转移的不同模式相互作用的激素的反应性。
在一些实施例中，SGN-LIV1A和化疗剂以使得组合在医治患者体内LIV-1-相关联癌症中提供协同或累加效应的方式施用。可通过任何合适手段进行施用，条件是施用提供期望治疗效应。在优选实施例中，SGN-LIV1A和化疗剂在治疗的同一循环期间施用，例如，在治疗的一个循环期间，例如，三或四周的时间段。
在有效方案中施用SGN-LIV1A和化疗剂，意指延迟发病、减少严重程度、抑制进一步恶化和/或改善癌症的至少一种体征或症状的剂量、施用途径和施用频率。如果患者已经患有癌症，那么方案可被称作治疗上有效方案。如果患者相对于一般人群处于高癌症风险，但是尚未经历症状，那么方案可被称作防治有效方案。在一些例子中，相对于历史对照组或相同患者中的过去经验，治疗性或防治性功效可在单独患者中观察到。在其它例子中，相对于未经医治患者的对照群体，治疗性或防治性功效可在临床前或临床试验中展现在经医治患者的群体中。
用于SGN-LIV1A的示例性剂量为患者体重的0.1mg/kg到50mg/kg，更典型地1mg/kg到30mg/kg、1mg/kg到20mg/kg、1mg/kg到15mg/kg、1mg/kg到12mg/kg、1mg/kg到10mg/kg1、2mg/kg到30mg/kg、2mg/kg到20mg/kg、2mg/kg到15mg/kg、2mg/kg到12mg/kg、2mg/kg到10mg/kg、3mg/kg到30mg/kg、3mg/kg到20mg/kg、3mg/kg到15mg/kg、3mg/kg到12mg/kg或3mg/kg到10mg/kg。在一些方法中，向患者施用至少1.5mg/kg、至少2mg/kg或至少3mg/kg的剂量，每三周施用一次或更频繁。在一个实施例中，向患者施用2.5mg/kg的剂量。在另一实施例中，向患者施用2.5mg/kg的剂量，每三周施用一次。除其它因素外，剂量取决于施用频率、患者病况和对先前医治的响应(如果存在的话，不论医治为防治性或治疗性的并且不论病症为急性或慢性的)。
在与卡铂组合的情况下，SGN-LIV1A以在0.5mg/kg和6mg/kg之间的剂量施用。在组合中SGN-LIV1A的其它适当剂量范围为1mg/kg到5mg/kg和2mg/kg到3mg/kg。在一个实施例中，SGN-LIV1A以2.5mg/kg的剂量与卡铂组合施用。在与SGN-LIV1A组合的情况下，卡铂以在100mg/m2和950mg/m2之间的剂量施用。在组合中卡铂的其它适当剂量范围为200mg/m2到750mg/m2和300mg/m2到600mg/m2。在一个实施例中，卡铂以300mg/m2的剂量与SGN-LIV1A组合施用。在另一个实施例中，卡铂以AUC 6的剂量静脉内与SGN-LIV1A组合施用。
在与阿霉素组合的情况下，SGN-LIV1A以在0.5mg/kg和6mg/kg之间的剂量施用。在组合中SGN-LIV1A的其它适当剂量范围为1mg/kg到5mg/kg和2mg/kg到3mg/kg。在一个实施例中，SGN-LIV1A以2.5mg/kg的剂量与阿霉素组合施用。在与SGN-LIV1A组合的情况下，阿霉素以在30mg/m2和90mg/m2之间的剂量施用。在组合中阿霉素的其它适当剂量范围为40mg/m2到80mg/m2，和60mg/m2到75mg/m2。在一个实施例中，阿霉素以60mg/m2的剂量与SGN-LIV1A组合施用。
在与紫杉醇组合的情况下，SGN-LIV1A以在0.5mg/kg和6mg/kg之间的剂量施用。在组合中SGN-LIV1A的其它适当剂量范围为1mg/kg到5mg/kg和2mg/kg到3mg/kg。在一个实施例中，SGN-LIV1A以2.5mg/kg的剂量与紫杉醇组合施用。在与SGN-LIV1A组合的情况下，紫杉醇以在50mg/m2和300mg/m2之间的剂量施用。在组合中紫杉醇的其它适当剂量范围为100mg/m2到260mg/m2和135mg/m2到175mg/m2。在一个实施例中，紫杉醇以175mg/m2的剂量与SGN-LIV1A组合施用。在另一个实施例中，紫杉醇以80mg/m2的剂量与SGN-LIV1A组合施用。
在与曲妥珠单抗组合的情况下，SGN-LIV1A以在0.5mg/kg和2.8mg/kg之间的剂量施用。在一个实施例中，SGN-LIV1A以在1mg/kg和2.8mg/kg之间的剂量与曲妥珠单抗组合施用。在另一个实施例中，SGN-LIV1A以2.5mg/kg的剂量与曲妥珠单抗组合施用。在一个实施例中，SGN-LIV1A每周施用一次。在另一个实施例中，SGN-LIV1A为每三周施用一次。在一个实施例中，在与SGN-LIV1A组合的情况下，曲妥珠单抗以如下方式施用：在8mg/kg的初始剂量下在90分钟内静脉内输注，和然后在静脉内输注的30-90分钟内施用6mg/kg。在另一实施例中，每3周在静脉内输注的30-90分钟内施用6mg/kg。在另一实施例中，每3周，持续52周在静脉内输注的30-90分钟内施用6mg/kg。在另一个实施例中，在与SGN-LIV1A组合的情况下，曲妥珠单抗以如下方式施用：在初始剂量4mg/kg下在90分钟内静脉内输注，和然后在2mg/kg下在30分钟内静脉内输注。在另一实施例中，在30分钟内静脉内输注2mg/kg每周施用一次。在另一实施例中，在30分钟内静脉内输注2mg/kg每周施用一次，持续52周。
在与检查点抑制剂组合的情况下，SGN-LIV1A以在0.5mg/kg和2.8mg/kg之间的剂量施用。在一个实施例中，SGN-LIV1A以在1mg/kg和2.8mg/kg之间的剂量与曲妥珠单抗组合施用。在另一个实施例中，SGN-LIV1A以2.5mg/kg的剂量与曲妥珠单抗组合施用。在一个实施例中，SGN-LIV1A每周施用一次。在另一个实施例中，SGN-LIV1A为每三周施用一次。
施用SGN-LIV1A、卡铂、阿霉素、紫杉醇、曲妥珠单抗或mTOR抑制剂可为如下方式：非经肠、静脉内、口服、皮下、动脉内、颅内、鞘内、腹膜内、体表、鼻内或肌内。在一个实施例中，通过腹膜内注射来施用SGN-LIV1A。在另一个实施例中，通过静脉内注射来施用SGN-LIV1A。在另一个实施例中，通过静脉内注射来施用卡铂。在另一个实施例中，通过静脉内注射来施用紫杉醇。在另一个实施例中，通过静脉内注射来施用阿霉素。施用还可直接定位于肿瘤中。优选通过静脉内或皮下施用来施用到全身循环中。静脉内施用可例如通过在如30到90分钟的时段内输注或通过单次快速注射。
除其它因素外，组合(SGN-LIV1A、卡铂、阿霉素、紫杉醇、曲妥珠单抗或mTOR抑制剂)中的每种制剂的施用频率取决于其在循环中的半衰期，患者病况和施用途径。频率可为每天、每周、每月、每季，或响应于患者病况的改变或所医治的癌症的进展呈不规则时间间隔。静脉内施用的示例性频率为在连续医治过程内的一周两次与每季一次之间，但更频繁或更不频繁的给药也为可以的。静脉内施用的其它示例性频率为在连续医治过程内的每周一次或每四周三次之间，但更频繁或更不频繁的给药也为可以的。在一个实施例中，组合中的一种或两种制剂每三周施用一次。在另一个实施例中，组合中的一种或两种制剂每四周施用一次。对于皮下施用，示例性给药频率为每天一次到每月一次，但更频繁或更不频繁的给药也为可以的。
所施用的SGN-LIV1A的剂量的数量取决于癌症的性质(例如，是否呈递急性或慢性症状)和病症对医治的响应。对于急性病症或慢性病症的急性恶化，1与10个剂量之间通常为足够的。有时单一快速给药(任选地以分隔的形式)对于急性病症或慢性病症的急性恶化为足够的。针对急性病症或急性恶化的复发可重复医治。对于慢性病症，可以规律时间间隔施用抗体，例如每周一次、每两星期一次、每月一次、每季一次、每六个月一次，持续至少1、5或10年，或持续患者的寿命。
SGN-LIV1A的用于非经肠施用的医药组合物优选为无菌的和大体上等渗的，并且在GMP条件下制造。医药组合物可以单位剂型(即用于单次施用的剂量)提供。可使用一种或多种生理学上可接受的载剂、稀释剂、赋形剂或助剂调配医药组合物。调配物取决于所选择的施用途径。对于注射，SGN-LIV1A可调配成水溶液，优选在生理上相容的缓冲液中，如汉克氏(Hank's)溶液、林格氏(Ringer's)溶液，或生理盐水或乙酸盐缓冲液(以减少注射部位处的不适)。溶液可含有调配剂，如悬浮剂、稳定剂和/或分散剂。替代地，SGN-LIV1A可呈冻干形式，以便与合适媒剂例如无菌无热原质水一起组合，随后使用。SGN-LIV1A在液体调配物中的浓度可例如为1-100mg/ml，如10mg/ml。
借助本发明的组合疗法进行的医治可进一步与额外化疗、辐射、干细胞医治、手术、有效对抗正被医治的病症的其它医治进行组合。可与本发明的组合疗法一起施用的可用的其它制剂的类别包括例如对癌细胞表达的其它受体的抗体，包括HER2受体的其它抗体(例如，曲妥珠单抗恩他新(加利福尼亚州南旧金山的基因泰克公司)、抗微管蛋白制剂(例如，奥瑞他汀)、帕妥珠单抗(加利福尼亚州南旧金山的基因泰克公司))，或其它抗体药物偶联物如sacituzumab govitecan、检查点抑制剂(例如，抗PD-1、抗PD-L1)、DNA小沟结合剂、DNA复制抑制剂、烷化剂(例如，铂络合物如顺铂、单(铂)、双(铂)和三核铂络合物和卡铂)、蒽环霉素、抗生素、抗叶酸剂、抗代谢物、化疗敏化剂、倍癌霉素、依讬泊苷(etoposides)、氟化嘧啶、离子载体、莱克希托普森(lexitropsins)、亚硝基脲、顺氯氨铂、预形成化合物、嘌呤抗代谢物、嘌呤霉素、辐射敏化剂、类固醇、紫杉烷、拓扑异构酶抑制剂、长春花生物碱等。
相较于在没有本发明的组合疗法情况下的相同医治(例如，化疗)，借助本发明的组合疗法进行的医治可将患有肿瘤(例如，乳癌、前列腺癌、黑色素瘤)的患者的中值无进展存活期或总存活时间(尤其在复发或难治时)增加至少30％或40％，但是优选地50％、60％到70％或甚至100％或更长。另外或替代地，相较于在没有本发明的组合疗法情况下的相同医治(例如，化疗)，包括本发明的组合疗法的医治(例如，标准化疗)可将患有肿瘤的患者的完全响应速率、部分响应速率或客观响应速率(完全+部分)增加至少30％或40％，但是优选地50％、60％到70％或甚至100％。
上文或下文所引用的所有专利申请、网站、其它公开、寄存编号等出于所有目的都以全文引用的方式并入本文中，其引用程度如同每一个别的项目专门并且单独地指示为以引用的方式如此并入一样。如果序列的不同版本与不同时间的寄存编号相关，那么意指与本申请的有效申请日时的寄存编号相关联的版本。有效申请日意指实际申请日稍早或如果涉及所述寄存编号的优先申请适用，那么所述优先申请的申请日稍早。同样，除非另外指明，否则如果公开、网站等的不同版本在不同时间公布，那么意指在申请的有效申请日时最近公布的版本。除非以其它方式专门指定，否则本发明的任何特征、步骤、要素、实施例或方面可与任何其它特征、步骤、要素、实施例或方面组合使用。尽管出于清楚和理解的目的已经借助于说明和实例相当详细地描述本发明，但显而易见可在所附权利要求书的范围内实践某些变化改变和修改。
实例
提供以下实例以说明，而非限制所要求保护的发明。
I.活体外细胞毒性测试和组合测试
材料
多西他赛(Docetaxel)、紫杉醇、阿霉素、吉西他滨和NVP-BEZ235购自LC实验室(LCLaboratories)(马萨诸塞州沃本(Woburn,MA))并且在DMSO中复水以便活体外测试。环磷酰胺购自赛力克化学(Selleckchem)(德克萨斯州休斯顿(Houston,TX))。SGN-LIV1A偶联有平均4个MMAE/抗体。美国专利第9,228,026号公开用于偶联vcMMAE与hLIV22的进一步方法。
测试
MCF-7(乳癌)细胞获自ATCC。在测试之前一天，MCF-7细胞在补充有10％胎牛血清和0.01μg/mL胰岛素的Earles初代细胞培养液中以2000细胞/孔的密度涂覆在96孔平板中。
活体外细胞毒性测试用于测定每种药物对MCF-7细胞的活性。简单来说，细胞与处于浓度滴定的指示药物一起培育120小时。使用Cell-titer Glo(威斯康星的普洛麦格公司(Promega,Wisconsin))测量每种药物的活力(图1，顶部)。在另一个测试中，还使用Cell-titer Glo测量SGN-LIV1A(hLIV22-vcMMAE)的活力(图1，底部)。
SGN-LIV1A与制剂多西他赛、紫杉醇、阿霉素、吉西他滨、NVP-BEZ235、依维莫司或环磷酰胺中的一种的组合在第二天添加到细胞并且在37℃下在5％CO2孵育器中保持120小时。然后用Cell Titer Glo(华盛顿州西雅图的普洛麦格公司(Promega；Seattle,WA))裂解细胞60分钟，之后在Envison板读取器(马萨诸塞州沃尔瑟姆的珀金埃尔默(PerkinElmer；Waltham,MA))上测定活力。
为了评估组合指数(CI)，将SGN-LIV1A、阿霉素、吉西他滨和紫杉醇以其ED50浓度或者高或低2倍的浓度组合以获得10点数据集。使用CalcuSyn软件(英国剑桥的Biosoft公司(Biosoft；Cambridge,UK))测定CI值，所述软件使用由Chou和Talalay描述的中值效应方法来执行多药物剂量效应计算。参看Chou TC(2010)。使用Chou-Talalay方法.《癌症研究(Cancer Res)》70:440-446执行药物组合研究和其协同定量。表1说明如下结果：
表1：SGN-LIV1A组合
表1和图2示出SGN-LIV1A和阿霉素在其各自ED50和ED75浓度(CI<1)下具有中度协同作用，并且在其ED 90浓度下具有略微拮抗作用。表1和图3示出SGN-LIV1A和紫杉醇在ED50浓度下具有强协同作用，但是在ED75或ED90下具有拮抗作用。表1和图4示出SGN-LIV1A和吉西他滨在ED50浓度下具有协同作用，而非在ED75或ED90浓度下。表1和图5示出SGN-LIV1A和依维莫司在ED50、ED75和ED90浓度下具有协同作用。
II.活体内测试
NOD Scidγ(NSG)小鼠获自杰克逊实验室(Jackson Laboratory)并且在细胞植入之前一天植入有17-β-雌二醇团块(佛罗里达州萨拉索塔的美国创新研究公司(InnovativeResearch of America；Sarasota,FL))。借助基质胶(新泽西州富兰克林湖的碧迪生物科学公司(BD Biosciences；Franklin Lakes,NJ))将五百万MCF-7细胞皮下植入，并且使用式：体积＝1/2×长度×宽度2，通过数字测径规每周两次测定肿瘤体积。
小鼠在平均肿瘤体积达到100mm3时接收医治。用于每种制剂的医治疗程为：阿霉素，1mg/kg每4天一次共3次静脉内(IV)；SGN-LIV1，1mg/kg每4天一次共4次腹膜内(IP)；白蛋白结合型紫杉醇(纳米粒子白蛋白-结合紫杉醇)20mg/kg每4天一次共3次腹膜内；卡铂10mg/kg每7天一次共3次腹膜内；环磷酰胺，40mg/kg每7天一次共3次静脉内；吉西他滨20mg/kg每7天一次共2次腹膜内；和紫杉醇10mg/kg每3天一次共5次腹膜内。组合组在同一天接收第一剂量的SGN-LIV1A和组合药物。每组n＝6。每种药物和其组合对肿瘤生长的影响绘制在图6-8中。
为了测定活体内组合的益处，使用在未经医治动物安乐死的日期时在未经医治、单一制剂组和组合的组之间的曲线下的面积比较肿瘤生长抑制(TGI)(表2)。下式用于计算TGI：TGI＝1-AUC药物x/AUC未经医治。因此，用于组合的预期累加的TGI为(1-TGI药物x)×(1-TGI药物y)。在用于组合组的TGI比预期TGI大10％时，组合疗程被认为具有活体内协同作用。在表2中的数据示出阿霉素、10mg/kg白蛋白结合型紫杉醇和卡铂提供最高组合益处。此外，据发现，20mg/kg吉西他滨和20mg/kg白蛋白结合型紫杉醇在与SGN-LIV1A组合时几乎累加。
表2：活体内肿瘤生长抑制(TGI)的概述
序列表
<110> 西雅图遗传学公司（Seattle Genetics, Inc.）
D·萨斯曼
李福
A·科斯蒂奇
<120> 使用LIV1-ADC和化学治疗的组合疗法
<130> 0710-00313PC
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<150> US 62/317,792
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<150> US 62/367,510
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Pro Lys Asp Val Ser Ser Ser Thr Pro Pro Ser Val Thr Ser Lys Ser
210 215 220
Arg Val Ser Arg Leu Ala Gly Arg Lys Thr Asn Glu Ser Val Ser Glu
225 230 235 240
Pro Arg Lys Gly Phe Met Tyr Ser Arg Asn Thr Asn Glu Asn Pro Gln
245 250 255
Glu Cys Phe Asn Ala Ser Lys Leu Leu Thr Ser His Gly Met Gly Ile
260 265 270
Gln Val Pro Leu Asn Ala Thr Glu Phe Asn Tyr Leu Cys Pro Ala Ile
275 280 285
Ile Asn Gln Ile Asp Ala Arg Ser Cys Leu Ile His Thr Ser Glu Lys
290 295 300
Lys Ala Glu Ile Pro Pro Lys Thr Tyr Ser Leu Gln Ile Ala Trp Val
305 310 315 320
Gly Gly Phe Ile Ala Ile Ser Ile Ile Ser Phe Leu Ser Leu Leu Gly
325 330 335
Val Ile Leu Val Pro Leu Met Asn Arg Val Phe Phe Lys Phe Leu Leu
340 345 350
Ser Phe Leu Val Ala Leu Ala Val Gly Thr Leu Ser Gly Asp Ala Phe
355 360 365
Leu His Leu Leu Pro His Ser His Ala Ser His His His Ser His Ser
370 375 380
His Glu Glu Pro Ala Met Glu Met Lys Arg Gly Pro Leu Phe Ser His
385 390 395 400
Leu Ser Ser Gln Asn Ile Glu Glu Ser Ala Tyr Phe Asp Ser Thr Trp
405 410 415
Lys Gly Leu Thr Ala Leu Gly Gly Leu Tyr Phe Met Phe Leu Val Glu
420 425 430
His Val Leu Thr Leu Ile Lys Gln Phe Lys Asp Lys Lys Lys Lys Asn
435 440 445
Gln Lys Lys Pro Glu Asn Asp Asp Asp Val Glu Ile Lys Lys Gln Leu
450 455 460
Ser Lys Tyr Glu Ser Gln Leu Ser Thr Asn Glu Glu Lys Val Asp Thr
465 470 475 480
Asp Asp Arg Thr Glu Gly Tyr Leu Arg Ala Asp Ser Gln Glu Pro Ser
485 490 495
His Phe Asp Ser Gln Gln Pro Ala Val Leu Glu Glu Glu Glu Val Met
500 505 510
Ile Ala His Ala His Pro Gln Glu Val Tyr Asn Glu Tyr Val Pro Arg
515 520 525
Gly Cys Lys Asn Lys Cys His Ser His Phe His Asp Thr Leu Gly Gln
530 535 540
Ser Asp Asp Leu Ile His His His His Asp Tyr His His Ile Leu His
545 550 555 560
His His His His Gln Asn His His Pro His Ser His Ser Gln Arg Tyr
565 570 575
Ser Arg Glu Glu Leu Lys Asp Ala Gly Val Ala Thr Leu Ala Trp Met
580 585 590
Val Ile Met Gly Asp Gly Leu His Asn Phe Ser Asp Gly Leu Ala Ile
595 600 605
Gly Ala Ala Phe Thr Glu Gly Leu Ser Ser Gly Leu Ser Thr Ser Val
610 615 620
Ala Val Phe Cys His Glu Leu Pro His Glu Leu Gly Asp Phe Ala Val
625 630 635 640
Leu Leu Lys Ala Gly Met Thr Val Lys Gln Ala Val Leu Tyr Asn Ala
645 650 655
Leu Ser Ala Met Leu Ala Tyr Leu Gly Met Ala Thr Gly Ile Phe Ile
660 665 670
Gly His Tyr Ala Glu Asn Val Ser Met Trp Ile Phe Ala Leu Thr Ala
675 680 685
Gly Leu Phe Met Tyr Val Ala Leu Val Asp Met Val Pro Glu Met Leu
690 695 700
His Asn Asp Ala Ser Asp His Gly Cys Ser Arg Trp Gly Tyr Phe Phe
705 710 715 720
Leu Gln Asn Ala Gly Met Leu Leu Gly Phe Gly Ile Met Leu Leu Ile
725 730 735
Ser Ile Phe Glu His Lys Ile Val Phe Arg Ile Asn Phe
740 745
<210> 3
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> hLIV22的轻链可变区
<400> 3
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 4
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> hLIV22的重链可变区
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120

Claims (29)

1.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药LIV-1抗体药物偶联物(LIV-1-ADC)和化学治疗，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体，并且其中所述化学治疗为卡铂、阿霉素和紫杉醇中的一种。
2.根据权利要求1所述的方法，其中所述受试者患有乳腺癌。
3.根据权利要求2所述的方法，其中所述乳腺癌为三阴性乳腺癌、三阳性乳腺癌、HER2-阳性乳腺癌或激素受体阳性癌症。
4.根据权利要求3所述的方法，其中所述受试者患有三阴性乳腺癌。
5.根据权利要求1所述的方法，其中所述受试者患有前列腺癌、卵巢癌、子宫内膜癌、胰腺癌、肺癌、宫颈癌、黑色素瘤或鳞状细胞癌。
6.根据权利要求1所述的方法，其中所述LIV-1-ADC以在所述受试者的体重的1.5mg/kg和4mg/kg之间的剂量给药。
7.根据权利要求1所述的方法，其中所述LIV-1-ADC以所述受试者的体重的2.5mg/kg的剂量给药。
8.根据权利要求1所述的方法，其中所述LIV-1-ADC每3周给药一次。
9.根据权利要求1所述的方法，其中通过静脉内注射来给药所述LIV-1-ADC。
10.根据权利要求1所述的方法，其中所述化学治疗为卡铂，并且其中所述卡铂以在200mg/m2和750mg/m2之间的剂量给药。
11.根据权利要求1所述的方法，其中所述化学治疗为卡铂，并且其中通过静脉内注射来给药所述卡铂。
12.根据权利要求1所述的方法，其中所述化学治疗为阿霉素，并且其中所述阿霉素以在40mg/m2和80mg/m2之间的剂量给药。
13.根据权利要求1所述的方法，其中所述化学治疗为阿霉素，并且其中通过静脉内注射来给药所述阿霉素。
14.根据权利要求1所述的方法，其中所述化学治疗为紫杉醇，并且其中所述紫杉醇以在100mg/m2到260mg/m2之间的剂量给药。
15.根据权利要求1所述的方法，其中所述化学治疗为紫杉醇，并且其中通过静脉内注射来给药所述紫杉醇。
16.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药卡铂和LIV-1抗体药物偶联物(LIV-1-ADC)的组合，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体，其中所述LIV-1-ADC每三周一次以所述受试者的体重的2.5mg/kg的剂量经静脉内向所述受试者给药，并且其中所述卡铂以300mg/m2的剂量给药。
17.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药阿霉素和LIV-1抗体药物偶联物(LIV-1-ADC)的组合，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体，其中所述LIV-1-ADC每三周一次以所述受试者的体重的2.5mg/kg的剂量经静脉内向所述受试者给药，并且其中所述阿霉素以60mg/m2的剂量给药。
18.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药紫杉醇和LIV-1抗体药物偶联物(LIV-1-ADC)的组合，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体，其中所述LIV-1-ADC每三周一次以所述受试者的体重的2.5mg/kg的剂量经静脉内向所述受试者给药，并且其中所述紫杉醇以175mg/m2的剂量给药。
19.一种用于治疗患有或处于三阴性乳腺癌风险的受试者的方法，所述方法包含向所述受试者给药LIV-1抗体药物偶联物(LIV-1-ADC)和化学治疗，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体，并且其中所述化学治疗为卡铂、阿霉素和紫杉醇中的一种。
20.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药LIV-1抗体药物偶联物(LIV-1-ADC)和曲妥珠单抗，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体。
21.根据权利要求20所述的方法，其中所述LIV-1-ADC以在所述受试者的体重的0.5mg/kg和2.8mg/kg之间的剂量给药。
22.根据权利要求20所述的方法，其中所述LIV-1-ADC以所述受试者的体重的2.5mg/kg的剂量给药。
23.根据权利要求20所述的方法，其中所述LIV-1-ADC每3周给药一次。
24.根据权利要求20所述的方法，其中所述曲妥珠单抗以如下方式给药：在所述受试者的体重的4mg/kg的初始剂量下在90分钟内静脉内输注，然后在所述受试者的体重的2mg/kg的剂量下在30分钟内静脉内输注。
25.根据权利要求20所述的方法，其中所述曲妥珠单抗以如下方式给药：在所述受试者的体重的8mg/kg的初始剂量下在90分钟内静脉内输注，然后在所述受试者的体重的6mg/kg下在30分钟到90分钟内静脉内输注。
26.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药LIV-1抗体药物偶联物(LIV-1-ADC)和曲妥珠单抗恩他新，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体。
27.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药LIV-1抗体药物偶联物(LIV-1-ADC)和帕妥珠单抗，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体。
28.一种用于治疗患有或处于癌症风险的受试者的方法，所述方法包含向所述受试者给药LIV-1抗体药物偶联物(LIV-1-ADC)和检查点抑制剂，其中所述LIV-1-ADC包含偶联至缬氨酸-瓜氨酸-单甲基奥瑞他汀E(vcMMAE)的人源化hLIV22抗体。
29.根据权利要求29所述的方法，其中所述检查点抑制剂为抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体、B7-DC-Fc、LAG3或TIM3。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024188339A1 (zh) * 2023-03-15 2024-09-19 浙江博锐生物制药有限公司 抗liv-1抗体和抗liv-1抗体药物偶联物及其药物用途

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200145867A (ko) 2010-12-06 2020-12-30 시애틀 지네틱스, 인크. Ｌｉｖ-１에 대한 인간화 항체 및 이의 암을 치료하기 위한 용도
MA50943A (fr) * 2017-12-01 2020-10-07 Seattle Genetics Inc Anticorps anti-liv1 humanisés pour le traitement du cancer du sein
MX2021005395A (es) * 2018-11-07 2021-09-14 Crispr Therapeutics Ag Terapia del cáncer con células inmunitarias anti-liv1.
AU2020399976A1 (en) 2019-12-09 2022-06-30 Merck Sharp & Dohme B.V. Combination therapy with LIV1-ADC and PD-1 antagonist
CA3213636A1 (en) 2021-03-18 2022-09-22 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101309933A (zh) * 2005-09-07 2008-11-19 米迪缪尼有限公司 毒素偶联的Eph受体抗体
CN103533957A (zh) * 2010-12-06 2014-01-22 西雅图遗传学公司 抗liv-1的人源化抗体及其在治疗癌症中的用途
CN104334189A (zh) * 2011-10-14 2015-02-04 霍夫曼-拉罗奇有限公司 Her2二聚化抑制剂帕妥珠单抗的用途和包含her2二聚化抑制剂帕妥珠单抗的制品
CN104755497A (zh) * 2012-05-11 2015-07-01 梅里麦克制药股份有限公司 结合抗癌治疗剂的双特异性scfv轭合物的剂量和给药
CN104837502A (zh) * 2012-10-12 2015-08-12 斯皮罗根有限公司 吡咯并苯并二氮杂卓及其结合物

Family Cites Families (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4880935A (en) 1986-07-11 1989-11-14 Icrf (Patents) Limited Heterobifunctional linking agents derived from N-succinimido-dithio-alpha methyl-methylene-benzoates
FI102355B1 (fi) 1988-02-11 1998-11-30 Bristol Myers Squibb Co Menetelmä yhdistävän välikappaleen omaavien antrasykliini-immunokonjugaattien valmistamiseksi
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5514554A (en) 1991-08-22 1996-05-07 Becton Dickinson And Company Methods and compositions for cancer therapy and for prognosticating responses to cancer therapy
US5622929A (en) 1992-01-23 1997-04-22 Bristol-Myers Squibb Company Thioether conjugates
US6214345B1 (en) 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
CA2132500A1 (en) 1994-09-20 1996-03-21 David Lockwood Manning Methods for predicting the behaviour of breast tumours
ATE234635T1 (de) 1995-12-22 2003-04-15 Bristol Myers Squibb Co Verzweigte hydrazongruppen enthaltende kuppler
US6130237A (en) 1996-09-12 2000-10-10 Cancer Research Campaign Technology Limited Condensed N-aclyindoles as antitumor agents
CA2269634C (en) 1996-10-31 2010-08-17 Abbott Laboratories Reagents and methods useful for detecting diseases of the breast
US6066778A (en) 1996-11-06 2000-05-23 The Regents Of The University Of Michigan Transgenic mice expressing APC resistant factor V
WO1998034118A1 (en) 1997-01-30 1998-08-06 Yale University Diagnostic methods and compositions based on the distribution of rad51
WO1999023230A1 (en) 1997-10-31 1999-05-14 Abbott Laboratories Reagents and methods useful for detecting diseases of the breast
JP2001523472A (ja) 1997-11-18 2001-11-27 アボット・ラボラトリーズ 乳房の疾患の検出に有用な試薬および方法
JP2002507387A (ja) 1997-12-24 2002-03-12 コリクサ コーポレイション 乳癌の免疫療法および診断のための化合物ならびにそれらの使用のための方法
WO2000008210A1 (en) 1998-08-04 2000-02-17 Diadexus Llc A novel method of diagnosing, monitoring, staging, imaging and treating breast cancer
JP2002527066A (ja) 1998-10-15 2002-08-27 カイロン コーポレイション 転移性乳癌および結腸癌調節遺伝子
AU3395900A (en) 1999-03-12 2000-10-04 Human Genome Sciences, Inc. Human lung cancer associated gene sequences and polypeptides
US6762020B1 (en) 1999-03-15 2004-07-13 Protein Design Labs, Inc. Methods of diagnosing breast cancer
US20040141983A1 (en) 1999-03-15 2004-07-22 Protein Design Labs, Inc. Compositions against cancer antigen LIV-1 and uses thereof
CA2395832A1 (en) 2000-01-25 2001-08-02 Genentech, Inc. Liv-1 related protein, polynucleotides encoding the same and use thereof for treatment of cancer
AU2001264099A1 (en) 2000-06-13 2001-12-24 University College Cardiff Consultants Ltd. Zinc transporters
US6964849B2 (en) 2001-01-11 2005-11-15 Curagen Corporation Proteins and nucleic acids encoding same
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
AU2002322280A1 (en) 2001-06-21 2003-01-21 Millennium Pharmaceuticals, Inc. Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer
US20030068636A1 (en) 2001-06-21 2003-04-10 Millennium Pharmaceuticals, Inc. Compositions, kits and methods for identification, assessment, prevention, and therapy of breast and ovarian cancer
US7091186B2 (en) 2001-09-24 2006-08-15 Seattle Genetics, Inc. p-Amidobenzylethers in drug delivery agents
DK1572087T3 (da) 2002-03-08 2008-08-25 Pdl Biopharma Inc Antistoffer med cancerantigen TMEFF2 og anvendelser deraf
US7659241B2 (en) 2002-07-31 2010-02-09 Seattle Genetics, Inc. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
CN1849337A (zh) 2003-01-27 2006-10-18 比奥根艾迪克Ma公司 利用igsf9和liv－1的、用于治疗癌症的组合物及方法
WO2004067564A2 (en) 2003-01-29 2004-08-12 Protein Design Labs, Inc. Compositions against cancer antigen liv-1 and uses thereof
EP3120861B1 (en) 2003-11-06 2018-08-15 Seattle Genetics, Inc. Intermediate for conjugate preparation comprising auristatin derivatives and a linker
US7371381B2 (en) 2003-12-12 2008-05-13 Amgen Inc. Anti-galanin antibodies and uses thereof
US7501121B2 (en) 2004-06-17 2009-03-10 Wyeth IL-13 binding agents
WO2007001457A2 (en) 2004-11-12 2007-01-04 Xencor, Inc. Antibodies operably linked to selected chemoattractants
WO2006124269A2 (en) 2005-05-16 2006-11-23 Amgen Fremont Inc. Human monoclonal antibodies that bind to very late antigen-1 for the treatment of inflammation and other disorders
WO2007030642A2 (en) * 2005-09-07 2007-03-15 Medimmune, Inc. Toxin conjugated eph receptor antibodies
WO2007120787A2 (en) 2006-04-13 2007-10-25 Novartis Vaccines & Diagnostics, Inc. Methods of treating, diagnosing or detecting cancers associated with liv-1 overexpression
EP2609932B1 (en) 2006-12-01 2022-02-02 Seagen Inc. Variant target binding agents and uses thereof
MX2009011366A (es) 2007-04-23 2009-11-05 Wyeth Corp Metodos y composiciones para tratar y monitorear el tratamiento de trastornos asociados con il-13.
US20110008345A1 (en) 2007-11-30 2011-01-13 Claire Ashman Antigen-binding constructs
US20110166838A1 (en) 2008-06-16 2011-07-07 Sividon Diagnostics Algorithms for outcome prediction in patients with node-positive chemotherapy-treated breast cancer
US20110195995A1 (en) 2008-10-14 2011-08-11 Wittliff James L Methods of Optimizing Treatment of Estrogen-Receptor Positive Breast Cancers
WO2010069858A1 (en) 2008-12-19 2010-06-24 F. Hoffmann-La Roche Ag Pharmaceutical composition
US8642270B2 (en) 2009-02-09 2014-02-04 Vm Institute Of Research Prognostic biomarkers to predict overall survival and metastatic disease in patients with triple negative breast cancer
US20110165566A1 (en) 2009-07-09 2011-07-07 Wittliff James L Methods of optimizing treatment of breast cancer
EP2473637B1 (en) 2009-09-03 2017-03-29 F. Hoffmann-La Roche AG Methods for treating, diagnosing, and monitoring rheumatoid arthritis
WO2012125712A2 (en) 2011-03-14 2012-09-20 Respira Health, Llc Lung tumor classifier for current and former smokers
DE202012006349U1 (de) 2012-07-03 2013-07-05 Schuster Engineering Gmbh Schiffsladeanordnung
US10898555B2 (en) 2013-07-02 2021-01-26 Japanese Foundation For Cancer Research Cellular immunity inducing vaccine
US11185594B2 (en) 2014-04-10 2021-11-30 Daiichi Sankyo Company, Limited (Anti-HER2 antibody)-drug conjugate
MA50943A (fr) * 2017-12-01 2020-10-07 Seattle Genetics Inc Anticorps anti-liv1 humanisés pour le traitement du cancer du sein
MX2021005395A (es) 2018-11-07 2021-09-14 Crispr Therapeutics Ag Terapia del cáncer con células inmunitarias anti-liv1.
GB201908208D0 (en) 2019-06-10 2019-07-24 Univ College Cardiff Consultants Ltd An anti-mitotic agent
AU2020399976A1 (en) 2019-12-09 2022-06-30 Merck Sharp & Dohme B.V. Combination therapy with LIV1-ADC and PD-1 antagonist

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101309933A (zh) * 2005-09-07 2008-11-19 米迪缪尼有限公司 毒素偶联的Eph受体抗体
CN103533957A (zh) * 2010-12-06 2014-01-22 西雅图遗传学公司 抗liv-1的人源化抗体及其在治疗癌症中的用途
CN104334189A (zh) * 2011-10-14 2015-02-04 霍夫曼-拉罗奇有限公司 Her2二聚化抑制剂帕妥珠单抗的用途和包含her2二聚化抑制剂帕妥珠单抗的制品
CN104755497A (zh) * 2012-05-11 2015-07-01 梅里麦克制药股份有限公司 结合抗癌治疗剂的双特异性scfv轭合物的剂量和给药
CN104837502A (zh) * 2012-10-12 2015-08-12 斯皮罗根有限公司 吡咯并苯并二氮杂卓及其结合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DENNIS J. SLAMON，ET AL: ""USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY AGAINST HER2 FOR METASTATIC BREAST CANCER THAT OVEREXPRESSES HER2"", 《THE NEW ENGLAND JOURNAL OF MEDICINE》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024188339A1 (zh) * 2023-03-15 2024-09-19 浙江博锐生物制药有限公司 抗liv-1抗体和抗liv-1抗体药物偶联物及其药物用途

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