CN105899237B - 用于治疗子宫内膜癌的倍癌霉素adc - Google Patents

用于治疗子宫内膜癌的倍癌霉素adc Download PDF

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CN105899237B
CN105899237B CN201580004140.9A CN201580004140A CN105899237B CN 105899237 B CN105899237 B CN 105899237B CN 201580004140 A CN201580004140 A CN 201580004140A CN 105899237 B CN105899237 B CN 105899237B
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her2
carcinoma
endometrium
usc
adc
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CN105899237A (zh
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亚历山德罗·达维德·桑廷
彼得·约翰内斯·戈耶丁斯
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Byodes Private Limited
Yale University
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Synthon BV
Yale University
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Abstract

本发明涉及含有倍癌霉素的抗体‑药物缀合物(ADC)，其用于治疗表达HER2的人实体瘤，其中所述表达HER2的人实体瘤是子宫内膜癌，特别是子宫浆液性癌(USC)。特别地，本发明涉及含有倍癌霉素的ADC，其用于治疗具有HER2 IHC 2+或1+和HER2 FISH阴性肿瘤组织状态的子宫内膜癌(特别是USC)。

Description

用于治疗子宫内膜癌的倍癌霉素ADC
技术领域
本发明涉及显示出改善的体内抗肿瘤活性的倍癌霉素(duocarmycin)抗体-药物缀合物(antibody-drug conjugate，ADC)，特别是用于治疗子宫内膜癌的倍癌霉素ADC。更特别地，本发明涉及用于治疗表达人表皮生长因子受体2(human epidermal growthfactor receptor 2，HER2)的人实体瘤的含有倍癌霉素的ADC，其中所述表达HER2的人实体瘤是子宫内膜癌，特别地，其中所述表达HER2的人实体瘤是子宫浆液性癌(uterine serouscarcinoma，USC)。
背景技术
子宫内膜(子宫)癌是欧洲和北美洲最常见的妇科恶性肿瘤。其为西欧妇女中癌症死亡的第七常见原因，占所有癌症死亡人数的1％至2％。根据最近的NCCN指南，病理学家综述区分了三种不同类型子宫癌：i)纯子宫内膜样癌，ii)浆液性或透明细胞腺癌，和iii)癌肉瘤，即癌和肉瘤的混合型(NCCN 第2版，2015)。子宫内膜的子宫内膜样癌和浆液性癌之间的区别对于预后和治疗目的来说很重要。子宫内膜样癌通常局限于子宫并且比子宫内膜浆液性癌具有更好的预后，所述子宫内膜浆液性癌具有频繁的腹膜播散和更差的预后(K.Garg和R.A.Soslow在Arch.Pathol.Lab.Med.，第138卷，2014年3月，335-342)。
子宫浆液性癌(USC)或子宫乳头状浆液性癌占子宫内膜癌的约10％。子宫内膜癌的这种亚型在生物学上具有高度侵略性并导致大多数子宫内膜癌死亡。分子概况分析(molecular profiling)研究已经证明HER2是USC中最多过表达的基因之一。HER2是受体酪氨酸激酶的表皮生长因子受体(epidermal growth factor receptor，EGFR)家族的成员之一。已报道在USC中HER2过表达18％至80％，这是由于多种因素，如组织样本的肿瘤类型和阶段以及所使用的免疫组织化学(IHC)技术(A.D.Santin等.在Clin.Cancer Res.，8，2002，1271-1279；B.M.Slomovitz等.在J.Clin.Onco1.22，2004，3126-3132)。通过免疫组织化学，高达35％的USC可在较高水平上过表达HER2癌基因(即，HER2 IHC 3+)，或通过荧光原位杂交可具有HER2基因扩增(即，FISH阳性)。另外45％的USC以中等水平(即，HER2 IHC 2+)或低水平(即，HER2 IHC 1+)表达HER2。
曲妥珠单抗(赫赛汀TM，Genentech/Roche)是抗HER2的胞外结构域的重组人源化IgG1单克隆抗体，并且目前已被批准用于治疗转移性乳腺癌和早期乳腺癌二者以及过表达HER2的局部晚期或转移性胃癌。案例研究报告描述了曲妥珠单抗在子宫内膜癌中的用途。在Int.J.Gynecol.Cancer 16：1370-1373，2006中，E.Jewell E等描述了向患有转移性子宫内膜癌的患者施用曲妥珠单抗的阳性结果。在Int.J.Gynecol.Obstet.102：128-131，2008中，A.D.Santin等报道了在患有过表达HER2之晚期或复发性子宫内膜癌的2名患者中用曲妥珠单抗治疗的结果。在Gyneco1.Onc01.116：15-20，2010中，Fleming等报道了患有HER2阳性子宫内膜癌并用曲妥珠单抗进行治疗的34名患者的II期试验结果。曲妥珠单抗目前尚未被批准用于治疗任何子宫内膜癌。
D.P.English等在2014年由John Wiley&Sons Ltd.出版的Cancer Medicine，pp.1-10中报道T-DM1在体外和体内对主要的HER2过表达的子宫浆液性癌(USC)高度有效。T-DM1(KadcylaTM，ado-trastuzumab emtansine，Genentech/Roche)是抗体-药物缀合物，其包含与抗微管剂DM1共价连接的曲妥珠单抗。DM1属于美登素(maytansine)类化学治疗剂。平均来说，3至4分子的DM1与每个曲妥珠单抗分子缀合。T-DM1是旨在通过受体介导的内吞作用将高度有效的DM1递送到HER2过表达细胞中的药剂。T-DM1已被批准用于治疗患有HER2阳性转移性乳腺癌且接受了用曲妥珠单抗和紫杉烷类的在先治疗的患者。作者的结论是，T-DM1在SCID小鼠的HER2阳性USC细胞系和USC(即HER2 IHC 3+)异种移植物(15mg/kg，腹膜内(i.p.)注射，每周一次)中显示有前景的抗肿瘤作用，并且当与曲妥珠单抗相比时，其活性显著更高，并且T-DM1可代表用于患有标准化疗难治性疾病的HER-2阳性USC患者的新治疗选择。目前进行的临床研究均未用T-DM1治疗子宫内膜癌。
发明简述
本发明涉及含有倍癌霉素的ADC，其用于治疗表达HER2的人实体瘤，其中所述表达HER2的人实体瘤是子宫内膜癌，特别地，其中所述表达HER2的人实体瘤是USC。
附图简述
图1.体外USC细胞系细胞毒性：SYD985相对于T-DM1。
图2.多次注射后，小鼠中体内USC细胞系异种移植物效力：SYD985相对于T-DM1。
图3.在第0天单次注射后，小鼠中体内USC细胞系异种移植物效力：SYD985相对于T-DM1。
发明详述
本发明涉及含有倍癌霉素的ADC，其用于治疗表达HER2(即HER2IHC 3+、2+或1+)的人实体瘤，其中所述表达HER2的人实体瘤是子宫内膜癌，特别地，其中所述表达HER2的人实体瘤是USC。
在一个实施方案中，本发明提供了式(I)化合物，其用于治疗表达HER2的人实体瘤，其中所述表达HER2的人实体瘤是子宫内膜癌，特别地，其中所述表达HER2的人实体瘤是USC
其中，
抗HER2 Ab是抗HER2抗体或抗体片段，
n是0至3，优选0至1，
m表示1至4的平均DAR，
R1选自：
y是1至16，并且
R2选自：
在另一个实施方案中，本发明涉及式(I)化合物，其中抗HER2 Ab是抗HER2抗体或抗体片段，n是0至1，m表示1至4、优选2至3的平均DAR，R1选自：
Y是1至16，优选1至4，并且R2选自：
在另一个实施方案中，本发明涉及式(I)化合物，其中所述抗HER2 Ab是抗HER2单克隆抗体，n是0至1，m表示2至3、优选2.5至2.9的平均DAR，R1选自：
y是1至4，并且R2选自：
在再一个实施方案中，本发明涉及式(I)化合物，其中所述抗HER2 Ab是曲妥珠单抗或其生物仿制药(biosimilar)，n是0至1，m表示2至3、优选2.5至2.9的平均DAR，R1选自：
y是1至4，并且R2选自：
在一个优选的实施方案中，本发明涉及式(II)的化合物，其包含曲妥珠单抗或其生物仿制药
在本说明书中称为SYD985的式(II)化合物具有2.6至2.9的平均DAR。
在本说明书中所示的结构式中，n表示0至3的整数，而m表示1至4的平均药物-抗体比(drug-to-antibody ratio，DAR)。如本领域中公知的，例如可通过使用疏水作用色谱(hydrophobic interaction chromatography，HIC)或反相高效液相色谱(reversed phasehigh-performance liquid chromatography，RP-HPLC)来确定DAR和药物负载分布(drugload distribution)。HIC特别适合用于确定平均DAR。
首先从链霉菌属(Streptomyces)物种的培养液中分离出来的倍癌霉素是抗肿瘤抗生素家族的成员(包括倍癌霉素A、倍癌霉素SA和CC-1065)。这些极其有效的药剂据称是从启动导致肿瘤细胞死亡的级联事件的小沟中腺嘌呤N3位顺序选择性烷基化DNA的能力中得到其生物活性。
WO2011/133039A公开了DNA-烷化剂CC-1065的一系列类似物及其HER2靶向抗体药物缀合物(ADC)。在实施例15中，在裸鼠中对许多曲妥珠单抗-倍癌霉素缀合物抗N87(即，HER2 IHC 3+胃肿瘤)异种移植物进行了测试。
可根据本发明治疗的子宫内膜(子宫)癌的典型实例包括子宫内膜样癌、浆液性或透明细胞腺癌和癌肉瘤。有利地，所述子宫内膜癌是USC。
在一个实施方案中，本发明提供了式(I)或(II)的化合物，其用于治疗显示出中等或低HER2表达(即，HER IHC 2+或1+)的子宫内膜癌(特别是USC)。
在另一个实施方案中，本发明提供了式(I)或(II)的化合物，其用于治疗无HER2基因扩增(即，HER2 FISH阴性)的子宫内膜癌(特别是USC)。
出乎意料的是，本发明人已经发现本发明的化合物特别可用于治疗具有中度或低HER2表达(即，HER2IHC 2+或1+)的和/或无HER2基因扩增(即，HER2 FISH阴性)的子宫内膜癌(尤其是USC)。曲妥珠单抗和T-DM1均未显示出抗此类肿瘤的效力。WO2011/133039A也没有教导或提示含有倍癌霉素的ADC用于治疗子宫内膜癌的用途。
在本发明的一个有利的实施方案中，子宫内膜癌是显示出中度或低HER2表达(即，HER2 IHC 2+或1+)、无HER2基因扩增(即，HER2 FISH阴性)的USC。
通常来说，在(人)肿瘤细胞系中首先在体外评估抗肿瘤活性，然后在体内评估。有利地，在动物模型(通常是荷有皮下异种移植物的裸鼠)中评价落入本发明范围之内的ADC的抗肿瘤活性。异种移植物可以是(人)肿瘤细胞系或来自于患者的(原发性)肿瘤。
根据本发明，所述抗HER2抗体或抗体片段可以是能够结合HER2的任何抗体或抗体片段，例如具有曲妥珠单抗的互补决定区(CDR)的IgG1抗体或显示出与曲妥珠单抗竞争性结合的抗体。优选的抗体是单克隆抗HER2抗体。特别优选的单克隆抗体是曲妥珠单抗或其生物仿制药。
根据本发明式(I)和(II)的抗体-药物缀合物(ADC)化合物具有通过半胱氨酸残基的S-原子与抗体缀合的接头-药物，即，它们是半胱氨酸连接的抗体-药物缀合物。半胱氨酸残基可以是存在于抗体(Ab)的重链和/或轻链中并形成链间二硫键的天然半胱氨酸残基，或者在重链和/或轻链的一个或更多个适当位置被引入到Ab中的工程化的半胱氨酸残基。本发明特别涉及ADC化合物，其中所述接头-药物通过Ab(更特别是单克隆Ab(mAb))的链间二硫键缀合。不同抗体种类的抗体包含不同数目的链间二硫键。例如，IgG1抗体通常具有四个链间二硫键，所有四个均位于铰链区，在(部分)还原二硫键后，接头-药物随机地与游离的巯基连接。
根据本发明应用的式(I)和(II)的化合物可根据本领域技术人员公知的方法和过程来获得。在完全或部分还原所述二硫键之后，可以发生通过链间二硫键的缀合。制备这样的化合物的合适的方法可以在申请人的WO2011/133039A的说明书和实施例中找到。特别地，WO2011/133039A的实施例15描述了部分还原曲妥珠单抗以使每个mAb产生2个游离巯基以及与许多接头-药物缀合产生平均DAR为约2的ADC。本领域技术人员很容易知晓如何获得平均DAR为1至4的ADC。WO 2005/084390A的实施例7和8描述了(具有接头-药物vcMMAE之)抗体的(部分)负载的部分还原、部分还原/部分再氧化和完全还原策略。
使用已知的测试、过程和设备确定了肿瘤组织的IHC和FISH状态。根据本发明，可使用荧光原位杂交(FISH)、显色原位杂交(CISH)或任何其他原位杂交测试来测量HER2基因扩增。用于测定肿瘤组织的HER2膜表达状态的合适测试(例如HercepTestTM(DakoDenmark))是商购可得的。另外的HER2 IHC测试由Ventana Medical Systems(PATHWAYanti-HER2/neu)、Biogenex Laboratories(InSiteTM HER2/neu)和Leica Biosystems(BondOracleTMHER2 IHC)市售。HER2 FISH/CISH测试可从Abbott Molecular(PathVysion HER2DNA Probe试剂盒)、Life Technologies( HER2 CISH试剂盒)、DakoDenmark(HER2 CISH PharmDxTM试剂盒)、Dako Denmark(HER2 FISH PharmDxTM试剂盒)以及Ventana Medical Systems(INFORM HER2 Dual ISH DNA Probe Cocktail)获得。
本发明还涉及式(I)或(II)的化合物用于治疗患有子宫内膜癌(特别是USC)的患者(即，妇女)(如上所述的所述子宫内膜癌为HER2 IHC 2+或1+和/或HER2 FISH阴性)的用途。
本发明还涉及式(I)或(II)的化合物与治疗性抗体和/或化学治疗剂的组合用于治疗子宫内膜癌，特别是用于治疗USC的用途。
在本发明的一个实施方案中，用于与根据本发明式(I)或(II)的化合物组合的治疗性抗体是帕妥珠单抗、贝伐珠单抗或曲妥珠单抗，并且所述化学治疗剂是i)紫杉烷类，特别是多西他赛或紫杉醇，ii)DNA损伤剂，特别是顺铂、卡铂或奥沙利铂，iii)拓扑异构酶抑制剂，特别是拓扑替康或伊立替康，iv)蒽环类，特别是多柔比星、脂质体多柔比星、表柔比星、柔红霉素或戊柔比星，更特别地是多柔比星，v)mTOR抑制剂，特别是坦罗莫司(temsirolimus)，或vi)酪氨酸激酶抑制剂，特别是拉帕替尼(lapatinib)或阿法替尼(afatinib)。
在本发明的另一个实施方案中，用于与根据本发明式(I)或(II)的化合物组合的治疗性抗体是培妥珠单抗(pertuzumab)，并且化学治疗剂是紫杉烷类，特别是多西他赛或紫杉醇；蒽环类，特别是多柔比星、表柔比星、柔红霉素或戊柔比星，更特别地是多柔比星；或者酪氨酸激酶抑制剂，特别是阿法替尼。
本发明还涉及式(I)或(II)化合物与其他ADC(例如T-DM1)的组合用于治疗表达HER2的人实体瘤和血液恶性肿瘤(特别是表达HER2的人实体瘤)的用途。
本发明还涉及药物组合物，其包含式(I)或(II)的化合物或其与上文所述的治疗性抗体和/或化学治疗剂的组合以及一种或更多种可药用赋形剂。
治疗性蛋白质(例如单克隆抗体和(单克隆)抗体-药物缀合物)的典型药物制剂采取冻干粉末或冻干饼的形式(需要在静脉输注前进行(水)溶解(即，重构))或冻结的(水)溶液(需要在使用前解冻)。特别地，以冻干饼的形式提供根据本发明的药物组合物。
用于加入到根据本发明的药物组合物中(冷冻干燥之前)的合适的可药用赋形剂包括缓冲液(例如，在水中含盐的柠檬酸、组氨酸或琥珀酸)、冻干保护剂(lyo protectant)(例如蔗糖、海藻糖)、张力调节剂(例如，氯化钠)、表面活性剂(例如，聚山梨酯)和填充剂(例如甘露醇、甘氨酸)。选择用于冷冻干燥蛋白质制剂的赋形剂，因为它们能够防止在冷冻干燥过程以及在储存期间的蛋白质变性。
赫赛汀(Herceptin)TM的无菌、冻干粉末多剂量制剂含有440mg曲妥珠单抗、400mgα，α-海藻糖二水合物、9.9mg L组氨酸、HCI、6.4mg L-组氨酸和1.8mg聚山梨酯20，USP。用20ml的抑菌或无菌注射用水(BWFI或SWFI)进行重构得到pH为约6的含有21mg/ml曲妥珠单抗的多剂量溶液。KadcylaTM的无菌、冻干粉末单次使用的制剂重构后含有20mg/ml ado-trastuzumab emtansine、0.02％w/v聚山梨酯20、10mM琥珀酸钠和6％w/v的蔗糖，pH为5.0。
根据本发明应用的式(I)或(II)的化合物的治疗有效量在约0.01mg/kg至约15mg/kg体重、特别是在约0.1mg/kg至约10mg/kg、更特别地在约0.3mg/kg至约10mg/kg体重的范围内。后一个范围大致相当于20mg至800mg的ADC化合物的平剂量(flat dose)。根据本发明应用的化合物每周、每两周、每三周或每月施用一次，例如在前12周每周施用一次，然后每三周施用一次直到疾病进展。可根据疾病的严重程度、患者的年龄、所施用的化合物以及如由治疗医生所考虑的这样的其他因素使用替代治疗方案。
实施例
体外USC细胞系细胞毒性
通过IHC和流式细胞术(FACS)评价9个原代USC细胞系的HER2表面表达以及通过FISH评价HER2基因扩增，如D.P.English等在2014年由John Wiley&Sons Ltd.出版的Cancer Medicine，pp.1-10中所描述的。
在具有HER2 IHC 1+和IHC 2+表达的原代USC细胞系中，SYD985比T-DM1更有效50至160倍。在一组三个HER2 IHC1+USC细胞系中，SYD985和T-DM1的平均IC50分别为0.07μg/ml和3.58μg/ml(p＝0.004)；在一组三个HER2 IHC 2+USC细胞系中，平均IC50分别为0.02μg/ml和1.82μg/ml(p＝0.005)；以及在一组三个HER2 IHC 3+USC细胞系中平均IC50分别为0.01μg/ml和0.04μg/ml(p＝0.06)。
图1示出了SYD985相对于T-DM1对HER2 IHC 3+、2+和1+USC细胞系的代表性体外剂量-响应曲线。
小鼠中体内USC细胞系异种移植物效力
给5至8周龄雌性SCID小鼠(Harlan，Netherlands)单次腹膜内(i.p.)注射在约400μl磷酸盐缓冲盐水溶液中的7.5×106个USC ARK-2细胞(即，HER2IHC 3+，FISH阳性)。在允许肿瘤建立7天后，用SYD985(5mg/kg/周，静脉内)或T-DM1(5mg/kg/周，静脉内)治疗两组5只小鼠。在任何治疗组中没有看到一般毒性的迹象。对所有治疗组中的小鼠进行一系列五次注射之后，对其进行追踪并观察总存活作为主要结果。
图2示出了多次注射之后SYD985相对于T-DM1的小鼠中体内USC细胞系异种移植物效力。
小鼠中体内USC细胞系异种移植物效力研究
在培养物中扩增USC ARK-2细胞(即，HER2 IHC 3+，FISH阳性)，清洗并以700万个细胞的浓度皮下注射(使用MatrigelTM)到5至8周龄SCID小鼠中。一旦肿瘤达到约200mm3的体积，将它们随机分成5组，保持各组间平均肿瘤体积相似。每组总共有8至10只动物。
用单次静脉内注射载剂、10mg/kg的T-DM1或10mg/kg的SYD985处理动物。记录动物的肿瘤大小和体重，进行21天。记录存活数据，进行30天。
图3示出了第0天单次注射后，SYD985相对于T-DM1的小鼠中体内USC细胞系异种移植物效力。

Claims (4)

1.下式化合物用于制备用于治疗表达HER2的人实体瘤的药物的用途，其中所述表达HER2的人实体瘤是子宫内膜癌，并且所述子宫内膜癌为HER2IHC 3+、2+或1+，
其中，
2.6至2.9表示所述化合物的平均DAR。
2.根据权利要求1所述的用途，其中所述子宫内膜癌为子宫浆液性癌。
3.根据权利要求1所述的用途，其中所述子宫内膜癌为HER2IHC2+或1+。
4.根据权利要求1所述的用途，其中所述子宫内膜癌为HER2FISH阴性。
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