CN114173825A - 抗体-药物偶联物及其在治疗中的应用 - Google Patents
抗体-药物偶联物及其在治疗中的应用 Download PDFInfo
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- CN114173825A CN114173825A CN202080050751.8A CN202080050751A CN114173825A CN 114173825 A CN114173825 A CN 114173825A CN 202080050751 A CN202080050751 A CN 202080050751A CN 114173825 A CN114173825 A CN 114173825A
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Abstract
本发明涉及细胞毒性偶联物和抗体‑药物偶联物,并涉及它们在治疗中的用途、特别是它们在治疗HER2+癌症中的用途。
Description
技术领域
本发明涉及有用的细胞毒性偶联物,所述细胞毒性偶联物包含附着头、连接臂、间隔区和细胞毒性剂。
本发明还涉及新型抗体-药物偶联物,所述抗体-药物偶联物包含与细胞毒性药物联结的针对HER2(人表皮生长因子受体2)抗原的抗体;并涉及其作为药物的用途、特别是在抗癌治疗中的用途。
背景技术
抗体-药物偶联物(ADC)构成了用于选择性递送细胞毒性药物的手段。因此,抗体-药物偶联物使得能够通过偶联的试剂将抗体靶向的特异性与新型的强大效应功能相结合。
抗体-药物偶联物的一般结构为式(II)的结构。连接抗体和药物的部分称为连接臂或接头。其可以通过形成四个链间二硫键的八个半胱氨酸中的至少一个来接枝到抗体上。接枝到抗体上的细胞毒性药物分子的数量决定了所谓的药物抗体比(Drug-to-Antibody Ratio,DAR)。
抗体在与其靶抗原结合后通过受体介导的内吞在细胞中被内化。囊泡与溶酶体融合,在其中,细胞毒性药物通过各种机制从抗体释放。然后,活性细胞毒性药物通过诱导细胞死亡而直接作用于细胞,有时经由转运或扩散到环境中而作用于邻近的癌细胞。因此,抗体主要用作载体并将细胞毒性药物递送到细胞中。
已将抗HER2抗体与细胞毒性药物(包括单甲基奥瑞他汀E,MMAE)偶联。已开发出一种名为“vedotin”的携带MMAE的细胞毒性偶联物。这种细胞毒性药物已与各种单克隆抗体一起用于制备抗体-药物偶联物。例如可以提及本妥昔单抗-vedotin或格巴妥木单抗(glembatumumab)-vedotin。
如文献Bryant等,Mol.Pharmaceutics,2015,12(6),第1872-1879页中所述,将MMAE与曲妥珠单抗(trastuzumab)偶联。不过,该文献中描述的曲妥珠单抗-MMAE的疗效并不令人满意,特别是对于希望有效治疗HER2+癌症而言。这可能是由于低DAR。
因此,需要开发更有效且更稳定的抗HER2-细胞毒性药物偶联物。
发明内容
本发明的第一主题涉及下式(I)的细胞毒性偶联物:
其中:
所述附着头由下列两个分子式中的任一个表示:
所述连接臂为选自以下分子式的可裂解的连接臂:
所述间隔区由以下分子式表示:
X为Br、Cl、I或F;
m为1-10的整数,优选等于4或5。
本发明的第二主题涉及下式(II)的抗体-药物偶联物:
其中:
A为抗HER2抗体或抗体片段;
所述附着头由以下的两个分子式中的任一个表示:
所述连接臂为选自以下分子式的可裂解的连接臂:
所述间隔区由以下分子式表示:
m为1-10的整数,优选等于4或5;
n为1-4的整数。
本发明的第三主题涉及包含一种或多种根据本发明的抗体-药物偶联物的组合物。
本发明的第四主题涉及根据本发明的抗体-药物偶联物或根据本发明的组合物用作药剂的用途。
本发明的第五主题涉及根据本发明的抗体-药物偶联物或根据本发明的组合物在治疗HER2+癌症中的用途。
本发明的第六主题涉及用于制备根据本发明的细胞毒性偶联物的方法,所述方法包括包含使附着头与化合物联结的步骤,其中,
所述附着头的分子式为:
所述化合物具有下式:
其中:
所述连接臂为选自以下分子式的可裂解的连接臂:
所述间隔区由以下分子式表示:
X为Br、Cl、I或F;
m为1-10的整数,优选等于4或5。
优选地,用于制备根据本发明的细胞毒性偶联物的方法包括包含如下的步骤:使6-(2,6-双(溴甲基)吡啶-4-基)氨基己酸或6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酸与缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE或所述化合物的盐进行联结。
本发明的第七主题涉及用于制备根据本发明的抗体-药物偶联物的方法,所述方法包括以下步骤:
(i)根据本发明的方法来制备细胞毒性偶联物;以及
(ii)使步骤(i)中获得的细胞毒性偶联物与抗HER2抗体或抗HER2抗体片段反应。
优选地,用于制备根据本发明的抗体-药物偶联物的方法包括包含以下的步骤:使6-(2,6-双(溴甲基)吡啶-4-基)酰胺基-N-己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE或6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE与抗HER2抗体或抗HER2抗体片段进行反应。
具体实施方式
定义
术语“细胞毒性偶联物”表示包含细胞毒性药物的偶联物。
术语“细胞毒性药物”表示能够抑制或阻止细胞功能的任何天然或合成分子。术语“细胞毒性”应理解为是指化学或生物试剂改变细胞的特性,可能达到破坏细胞的程度。
在本发明的具体实施方式中,细胞毒性药物选自于已获得上市许可并用于抗癌或抗炎治疗的任何化合物,或正在经历抗癌或抗炎治疗方面的临床评价的任何分子。例如,细胞毒性药物将选自于紫杉醇或多西他赛或其衍生物之一、拓扑替康、硼替佐米、柔红霉素、柔红霉素类似物、长春新碱、丝裂霉素C、视黄酸、甲氨蝶呤、伊洛前列素(Ilomedin)、阿司匹林、IMiD、来那度胺、泊马度胺(pomalidomide)。
在本发明的另一具体实施方式中,细胞毒性药物选自于由如下药物所组成的组:倍癌霉素(duocarmycin)及其类似物、dolastatins、康普瑞丁(combretastatin)及其类似物、卡奇霉素(calicheamicin)、N-乙酰基-γ-卡奇霉素(CMC)、卡奇霉素的衍生物、美登素(maytansine)及其类似物(例如美登素类化合物(maytansinoid type)的衍生物,例如DM1和DM4)、奥瑞他汀(auristatins)及其衍生物(例如奥瑞他汀E、奥瑞他汀EB(AEB)、奥瑞他汀EFP(AEFP)、单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF))、tubulysin、disorazole、埃博霉素(epothilones)、棘霉素(echinomycin)、雌莫司汀(estramustine)、西马多丁(cemadotin)、eleutherobin、甲喋呤(methopterin)、放线菌素、丝裂霉素A、喜树碱、喜树碱的衍生物、SN38、TK1、鹅膏蕈碱、吡咯并苯并二氮杂(pyrrolobenzodiazepine)、吡咯并苯并二氮杂二聚体(pyrrolobenzodiazepine dimer)、吡咯并吡啶并二氮杂(pyrrolopyridodiazepine)、吡咯并吡啶并二氮杂二聚体(pyrrolopyridodiazepinedimer)、DNA嵌入剂、组蛋白去乙酰化酶抑制剂或酪氨酸激酶抑制剂。在本发明的另一具体实施方式中,药物M选自于假单胞菌外毒素(Pseudomonas exotoxin,PE)、deBouganin、Bouganin、白喉毒素(diphtheria toxin,DT)和蓖麻毒蛋白(ricin)。
在具体的实施方式中,细胞毒性药物选自于甲氨蝶呤、IMiD、倍癌霉素、康普瑞丁、卡奇霉素、单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)、美登素、DM1、DM4、SN38、鹅膏蕈碱、吡咯并苯并二氮杂、吡咯并苯并二氮杂二聚体、吡咯并吡啶并二氮杂、吡咯并吡啶并二氮杂二聚体、组蛋白去乙酰化酶抑制剂、酪氨酸激酶抑制剂和蓖麻毒蛋白;优选MMAE,由以下的分子式表示:
术语“抗体”,也称为“免疫球蛋白”表示由两条各约50-70kDa的重链(重链称为H链)和两条各约25kDa的轻链(轻链称为L链)通过链内和链间二硫键连接在一起所组成的异四聚体。每条链在N末端位置由可变区或可变结构域组成,对于轻链称为VL,对于重链称为VH,并在每条链的C末端位置由恒定区组成,所述恒定区在轻链中由称为CL的单个结构域构成,在重链中由称为CH1、CH2、CH3、CH4的三个或四个结构域组成。
术语“嵌合抗体”被理解为指轻链可变区和重链可变区的序列与轻链恒定区和重链恒定区的序列属于不同物种的抗体。为了本发明的目的,重链可变区和轻链可变区的序列优先来自鼠类来源,而重链恒定区和轻链恒定区的序列属于非鼠类物种。在这点上,对于恒定区,可以使用所有种类的非鼠类哺乳动物,特别是人、猴、猪科、牛科、马科、猫科、犬科甚至鸟类,该列表并非穷举。优选地,根据本发明的嵌合抗体包含人源的重链和轻链恒定区序列和鼠源的重链和轻链可变区序列。
术语“人源化抗体”被理解为是指如下抗体:其所有或一些参与抗原识别的区域的序列(高变区或CDR:互补决定区)和(有时)FR区(框架区)的某些氨基酸为非人源的,而不参与抗原识别的恒定区和可变区的序列为人源的。
术语“人抗体”被理解为是指对于轻链的可变区和恒定区以及重链的可变区和恒定区均仅包含人序列的抗体。
术语“抗体片段”被理解为是指通过酶促消化获得或通过生物生产获得并包含至少一个二硫键的免疫球蛋白的任何部分,例如Fab、Fab'、F(ab')2、Fab'-SH、scFv-Fc或Fc。
木瓜蛋白酶对免疫球蛋白的酶促消化产生两个相同的片段,它们被称为Fab(抗原结合片段)片段和Fc片段(可结晶片段)。胃蛋白酶对免疫球蛋白的酶促消化产生分裂成多个肽的Fc片段和F(ab')2片段。F(ab')2由通过链间二硫键连接的两个Fab'片段组成。Fab部分由可变区和CH1和CL结构域组成。Fab'片段由Fab区和铰链区组成。Fab'-SH指其中铰链区的半胱氨酸残基带有游离硫醇基团的Fab'片段。scFv(单链可变片段)是从蛋白质工程获得的片段,其仅由VH和VL可变结构域组成。该结构由位于两个结构域之间的称为接头的短的柔性肽臂稳定。scFv片段可以连接到Fc片段以形成scFv-Fc。
术语“HER2”表示“人表皮生长因子受体2”,其为人表皮生长因子受体家族的膜蛋白。“HER2”也经常被称为“ErbB2”。
术语“HER2+癌症”或“HER2阳性癌症”是指涉及HER2的扩增激活的癌症。特别是,术语“HER2+癌症”表示其中癌细胞表现出解除调控(deregulation)HER2基因的任何癌症病例。优选地,在本发明的上下文中,HER2+癌症选自于乳腺癌、雌性生殖道的癌症(例如子宫内膜癌、子宫癌或卵巢癌)、膀胱癌、肛门癌、结肠直肠癌、特别是子宫乳头状浆液性癌、肺癌(特别是非小细胞肺癌)、肝癌、肾癌、胃食管癌、胃癌、胰腺癌和胃部癌。在优选的实施方式中,HER2+癌症选自HER2+乳腺癌、HER2+卵巢癌、HER2+膀胱癌、HER2+结肠直肠癌、HER2+子宫乳头状浆液性癌和HER2+胃部癌,优选HER2+乳腺癌。
就根据本发明的抗体而言,术语“纯化的”和“分离的”被理解为是指该抗体以基本上不存在其它相同类型的生物大分子的情况存在。如本文所用的术语“纯化的”意指相对于存在的所有大分子,抗体优选为至少75wt%,更优选为至少85wt%,甚至更优选为至少95wt%,最优选为至少98wt%。
术语“药学上可接受的”是指经联邦或州管理机构批准或者列入美国药典或欧洲药典或其它公认的药典,旨在用于动物和人。“药物组合物”表示包含药学上可接受的载体的组合物。例如,药学上可接受的载体可为与治疗剂一起给予的稀释剂、佐剂、赋形剂或载体。这些载体可为无菌液体,例如水和油(包括石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等)。当药物组合物静脉内给予时,水是优选的载体。右旋糖和甘油的盐水溶液和水溶液也可用作液体载体,特别是用于可注射溶液。药学上可接受的赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。当药物组合物适合于口服给予时,片剂或胶囊剂可通过常规手段使用药学上可接受的赋形剂制备,所述药学上可接受的赋形剂例如粘合剂(例如预糊化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂(例如乳糖、微晶纤维素或磷酸氢钙);润滑剂(例如硬脂酸镁、滑石或二氧化硅);崩解剂(例如马铃薯淀粉或羟基乙酸淀粉钠);或润湿剂(例如十二烷基硫酸钠)。片剂可以通过现有技术中众所周知的方法进行包衣。用于口服给予的液体制剂可以采用例如溶液剂、糖浆剂或悬浮剂的形式,或者可以以在使用前用水或另一合适的载体重构的干燥产品的形式提供。此类液体制剂可以通过常规手段使用药学上可接受的载体制备,所述药学上可接受的载体例如助悬剂(例如山梨糖醇糖浆、纤维素衍生物或氢化的食用脂肪);乳化剂(例如卵磷脂或阿拉伯胶(acacia));非水性载体(例如杏仁油、油性酯、乙醇或分馏的植物油);和防腐剂(例如对羟基苯甲酸甲酯或丙酯或者山梨酸)。药物组合物还可包含缓冲盐、调味剂、着色剂和甜味剂(视情况而定)。根据本发明的组合物优选为药物组合物。
术语“治疗”涵盖对病状或病理状态的症状的任何有益或期望的效果,并且甚至可以包括病状或病理状态的一种或多种可测量标志物的最小减少。例如,治疗可以包括减轻或改善病状或病理状态的症状,或延迟疾病或病理状态的进展。术语“治疗”并不一定意味着完全根除或治愈病状或相关症状。
细胞毒性偶联物
本发明涉及下式(I)的细胞毒性偶联物:
其中:
所述附着头由以下两个分子式中的任一个表示:
所述连接臂为选自以下分子式的可裂解的连接臂:
所述间隔区由以下分子式表示:
X为Br、Cl、I或F,有利地为Br;
m为1-10的整数,有利地为2-7、3-6的整数,有利地等于4或5。
在特别优选的实施方式中,所述细胞毒性偶联物对应于下列两个分子式(Ia)之一:
抗体-药物偶联物
本发明还涉及下式(II)的抗体-药物偶联物:
其中:
A为抗HER2抗体或抗体片段;
所述附着头由以下两个分子式中的任一个表示:
所述连接臂为选自以下分子式的可裂解的连接臂:
所述间隔区由以下分子式表示:
m为1-10的整数,有利地为2-7、3-6的整数,有利地等于4或5;
n为1-4的整数。
根据本发明的抗HER2抗体或抗体片段可为哺乳动物来源的(例如人或小鼠)、人源化的或嵌合的抗HER2抗体或抗体片段。优选地,所述抗HER2抗体或抗体片段为由根据现有技术中广泛描述的技术遗传修饰的细胞重组产生的单克隆抗体。
当A为抗HER2抗体时,其优选为人IgG,例如IgG1、IgG2、IgG3或IgG4。在特定的实施方式中,A为曲妥珠单抗。
在具体的实施方式中,本发明的抗体-药物偶联物具有下列两个分子式之一:
在具体实施方式中,本发明的抗体-药物偶联物具有下列两个分子式(IIa)之一:
分子式(IIa)的抗体-药物偶联物在实施例中分别以术语“McSAF-吡啶(McSAF-pyridine)”或“McSAF-吡啶逆酰胺(McSAF-pyridine retroamide)”标识。
有利地,根据本发明的抗体-药物偶联物使用已知的纯化技术进行纯化(或分离),例如在色谱和/或亲和柱上纯化。
当n等于1时,所述抗体-药物偶联物通常被称为“DAR1”。当n等于2时,所述抗体-药物偶联物通常称为“DAR2”。当n等于3时,所述抗体-药物偶联物通常称为“DAR3”。当n等于4时,所述抗体-药物偶联物通常称为“DAR4”。
在具体的实施方式中,所述抗体-药物偶联物具有由减弱的Fc部分介导的一种或多种效应功能。优选地,由Fc部分介导的一种或多种效应功能选自ADCC(抗体依赖性细胞介导的细胞毒性)和CDC(补体依赖性细胞毒性)。就现有技术的教导而言,本领域技术人员在减弱由Fc部分介导的一种或多种效应功能方面将没有困难,例如通过对Fc部分进行突变。已知许多用于降低由Fc部分介导的效应功能的突变。例如,其可以是旨在使Fc部分去糖基化的突变,特别是删除第297位天冬酰胺的糖基化的突变。
在具体的实施方式中,所述抗体-药物偶联物在Fc部分被去糖基化,例如所述抗体-药物偶联物在第297位天冬酰胺处不再具有糖基化。
组合物
本发明还涉及组合物,所述组合物包含一种或多种如上定义的式(II)的抗体-药物偶联物。所述组合物可为包含一种或多种如上定义的式(II)的抗体-药物偶联物和药学上可接受的载体的药物组合物。
根据本发明的组合物具有特别同质的特征,与非同质的组合物相比,这可导致组合物更好的稳定性、更好的功效和/或副作用减少。
有利地,当A为抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征在于以下特征:
a)所述组合物的抗体-药物偶联物的至少50%、优选至少55%、至少60%、至少65%(例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%)为n等于4;
b)平均药物抗体比(平均DAR)在3.5到4.5之间;优选在3.8到4.2之间,在3.9到4.1之间,在3.9到4.0之间;例如等于4.0±0.2、4.0±0.1,例如等于3.93±0.01。平均DAR通常由HIC(疏水相互作用色谱)方法或由天然质谱(native mass spectrometry)确定。文献中广泛描述了HIC方法和天然质谱法。例如,可以提及关于HIC方法的参考文献[1]和关于天然质谱法的参考文献[2];
c)至少95%(例如至少96%、至少97%、至少98%或至少99%)的抗体-药物偶联物以单体形式存在。单体百分比通常通过SEC(尺寸排阻色谱)方法确定。SEC方法在文献中有广泛描述,例如在参考文献[3]中;
d)一个或多个下面定义的n的比率;或者
e)选自a)、b)、c)和d)中的两个、三个或四个特性的组合。
当A为抗体时,根据本发明的组合物可包含DAR0,即不具有细胞毒性偶联物的抗体。优选小于5%、小于4%、小于3%、小于2%、小于1%、小于0.5%、小于0.4%、小于0.2%或小于0.1%DAR0,例如约0%DAR0。DAR0百分比可以通过HIC(疏水相互作用色谱)方法或通过天然质谱来确定。
根据本发明的组合物还可包含DAR5,即具有5个细胞毒性偶联物的抗体-药物偶联物。优选小于25%、小于20%、小于15%、小于10%、小于9%、小于8%、小于7%、小于6%或小于5%DAR5。文献中广泛描述了抗体-药物偶联物组合物中DAR5的存在,但对DAR5的确切结构研究甚少。因此,考虑了组合物中存在的所有DAR,即DAR0、DAR1(即n=1)、DAR2(即n=2)、DAR3(即n=3)、DAR4(即n=4)、DAR5等,来计算平均DAR。优选地,当A为抗体时,根据本发明的组合物包含少于1%的比DAR5大的DAR,例如DAR6、DAR7等。优选地,根据本发明的组合物不包含任何比DAR5大的DAR,例如DAR6、DAR7等。DAR5和更高的的百分比可通过HIC(疏水相互作用色谱)方法或通过天然质谱来确定。
当A为抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征可在于以下n比率:
-组合物的小于5%、小于4%、小于3%、小于2%、小于1%、小于0.75%、小于0.5%、小于0.25%、小于0.1%(例如约0.1%或约0%)的抗体-药物偶联物的n等于1;
-组合物的小于5%、小于4%、小于3%、小于2%、小于1%、小于0.75%、小于0.5%、小于0.25%、小于0.1%(例如约0.5%或约0%)的抗体-药物偶联物的n等于2;
-组合物的小于20%、小于15%、小于10%、小于5%、小于4%、小于3%、小于2%、小于1%(例如约8%或约10%)的抗体-药物偶联物的n等于3;和
-组合物的至少50%、至少55%、至少60%、至少65%、例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%(例如约80%或约70%±5%)的抗体-药物偶联物的n等于4。
当A为抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征还可在于以下n比率:
-组合物的0%-5%之间、0%-2%之间、0%-1%之间、0%-0.75%之间、0%-0.5%之间、0%-0.25%之间、0%-0.1%之间的抗体-药物偶联物的n等于1;
-组合物的0%-5%之间、0%-2%之间、0%-1%之间、0%-0.75%之间、0%-0.5%之间、0%-0.25%之间、0%-0.1%之间的抗体-药物偶联物的n等于2;
-组合物的0%-5%之间、5%-15%之间、8%-12%之间、8%-9%之间、9%-11%之间的抗体-药物偶联物的n等于3;和
-组合物的50%-75%之间、65%-70%之间、70%-85%之间、75%-80%之间、例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的抗体-药物偶联物的n等于4。
n的比率可以通过HIC(疏水相互作用色谱)方法或通过天然质谱来确定。
在第一具体实施方式中,当A为抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征可在于以下n比率,其通过HIC(疏水相互作用色谱)方法确定:
-组合物的小于5%、小于4%、小于3%、小于2%、小于1%、小于0.75%、小于0.5%、小于0.25%(例如约0.1%)的抗体-药物偶联物的n等于1;
-组合物的小于5%、小于4%、小于3%、小于2%、小于1%、小于0.75%(例如约0.5%)的抗体-药物偶联物的n等于2,
-组合物的小于20%、小于15%、小于10%、小于5%、小于4%、小于3%、小于2%、小于1%(例如约10%)的抗体-药物偶联物的n等于3;和/或
-组合物的至少50%、至少55%、至少60%、至少65%、例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%(例如约70%±5%)的抗体-药物偶联物的n等于4。
因此,当A为抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征还可在于以下n比率,其通过HIC(疏水相互作用色谱)方法确定:
-组合物的0%-5%之间、0%-2%之间、0%-1%之间、0%-0.75%之间、0%-0.5%之间、0%-0.25%之间的抗体-药物偶联物的n等于1;
-组合物的0%-5%之间、0%-2%之间、0%-1%之间、0%-0.75%之间的抗体-药物偶联物的n等于2;
-组合物的0%-5%之间、5%-15%之间、8%-12%之间、9%-11%之间的抗体-药物偶联物的n等3;和
-组合物的50%-75%之间、65%-70%之间、70%-85%之间、75%-80%之间、例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的抗体-药物偶联物的n等于4。
在第二具体实施方式中,当A为抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征可在于以下n比率,其通过天然质谱确定:
-组合物的小于5%、小于4%、小于3%、小于2%、小于1%、小于0.75%、小于0.5%、小于0.25%、小于0.1%(例如约0.1%或约0%)的抗体-药物偶联物的n等于1;
-组合物的小于5%、小于4%、小于3%、小于2%、小于1%、小于0.75%、小于0.5%、小于0.25%、小于0.1%(例如约0.5%或约0%)的抗体-药物偶联物的n等于2;
-组合物的小于20%、小于15%、小于10%、小于5%、小于4%、小于3%、小于2%、小于1%(例如约8%)的抗体-药物偶联物的n等于3;和/或
-组合物的至少50%、至少55%、至少60%、至少65%、例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%(例如约80%)的抗体-药物偶联物的n等于4。
因此,当A是抗体(例如曲妥珠单抗)时,根据本发明的组合物的特征还可在于以下n比率,其通过天然质谱确定:
-组合物的0%-5%之间、0%-2%之间、0%-1%之间、0%-0.75%之间、0%-0.5%之间、0%-0.25%之间、0%-0.1%之间的抗体-药物偶联物的n等于1;
-组合物的0%-5%之间、0%-2%之间、0%-1%之间、0%-0.75%之间、0%-0.5%之间、0%-0.25%之间、0%-0.1%之间的抗体-药物偶联物的n等于2;
-组合物的0%-5%之间、5%-15%之间、8%-12%之间、8%-9%之间的抗体-药物偶联物的n等于3;和
-组合物的50%-75%之间、65%-70%之间、70%-85%之间、75%-80%之间、例如至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的抗体-药物偶联物的n等于4。
在非常具体的实施方式中,根据本发明的组合物具有图1的HIC谱图或图19的HIC谱图,或者图5的天然质谱谱图或图21的天然质谱谱图。
治疗用途
本发明还涉及根据本发明的式(II)的抗体-药物偶联物或包含根据本发明的式(II)的抗体-药物偶联物的组合物作为药剂,例如用于治疗HER2+癌症(例如HER2+乳腺癌)的药剂的用途。
根据本发明的抗体-药物偶联物或组合物优选被配制用于肠胃外给予,例如血管内(静脉内或动脉内)、腹膜内或肌内给予。如本文所用,术语“肠胃外给予”表示除肠和局部给予之外的给予方式(通常通过注射),并且包括但不限于血管内给予、静脉内给予、肌内给予、动脉内给予、鞘内(intrathapsale)给予、囊内给予、眶内给予、瘤内给予、心内给予、皮内给予和腹膜内给予、通过注射给予、通过经气管灌注给予、以及皮下给予、关节内给予、囊下给予、蛛网膜下给予、脊柱内给予和胸骨内给予。在本发明的上下文中优先考虑静脉内给予,例如通过静脉内灌注。
给予有需要的受试者的抗体-药物偶联物的剂量将根据许多因素而变化,包括但不限于给药途径、所治疗病状的类型和严重程度、患者的状况、患者的体型、患者的年龄等。本领域技术人员基于他们在该领域的知识可以容易地根据这些和其它因素确定所需的剂量范围。也可以使用动物模型或临床试验来确定适当的剂量。例如,抗体-药物偶联物的典型剂量可为1mg/kg、2mg/kg、3mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg或更多。给药可以以单剂量进行,或更普遍地,可以以多剂量进行。给予方案可包括初始负荷剂量,随后是维持剂量(例如每周、每两周、每三周、每月或更长)。治疗的持续时间可以根据所治疗的病状和受试者而变化。
根据本发明的抗体-药物偶联物或组合物可用于单一疗法或者与在所考虑的病状中具有公认治疗益处的药物联用。例如这些药物可包括紫杉醇、多西他赛、多柔比星、环磷酰胺、芳香酶抑制剂(如阿那曲唑)、或用于抗癌免疫疗法的抗体(如抗PD1抗体)。
本说明书还涉及用于治疗受试者中的HER2+癌症的方法,所述方法包括给予所述受试者治疗有效量的根据本发明的式(II)的抗体-药物偶联物或包含根据本发明的式(II)的抗体-药物偶联物的组合物。
制备方法
本说明书还涉及用于制备根据本发明的细胞毒性偶联物的方法。
本说明书还涉及用于制备如上定义的式(II)的抗体-药物的方法,其中,如上定义的式(I)的细胞毒性偶联物与抗HER2抗体或抗体片段反应。
本发明的另一主题涉及用于制备根据本发明的细胞毒性偶联物的方法,所述方法包括包含使附着头与化合物联结的步骤,其中,
所述附着头的分子式为:
所述化合物具有下式:
其中:
所述连接臂为选自以下分子式的可裂解的连接臂:
所述间隔区由以下分子式表示:
X为Br、Cl、I或F;
m为1-10的整数,并且优选等于4或5。
在上文的“细胞毒性偶联物”和“抗体-药物偶联物”部分更详细地描述了附着头,不同之处在于该方法中使用的附着头包含末端羧酸官能团。
在上文的“细胞毒性偶联物”和“抗体-药物偶联物”部分更详细地描述了连接臂,不同之处在于该方法中使用的连接臂包含末端胺官能团。
在上文的“细胞毒性偶联物”和“抗体-药物偶联物”部分更详细的描述了间隔区。
在上文的“细胞毒性偶联物”和“抗体-药物偶联物”部分中更详细地描述了细胞毒性药物。
在具体的实施方式中,用于制备根据本发明的细胞毒性偶联物的方法包括包含如下的步骤:使6-(2,6-双(溴甲基)吡啶-4-基)氨基己酸(实施例1A中的参考号(7))或6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酸(实施例1B中的参考号(16))与缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE或所述化合物的盐进行联结。在该特定实施方式中,根据本发明的用于制备细胞毒性偶联物的方法分别能够获得6-(2,6-双(溴甲基)吡啶-4-基)酰胺基-N-己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE(实施例1A中的参考号(8))或6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE(实施例1B中的参考号(17))。
本发明的另一主题涉及用于制备根据本发明的抗体-药物偶联物的方法,所述方法包括以下步骤:
(i)根据本发明的方法制备细胞毒性偶联物,以及
(ii)使步骤(i)中获得的细胞毒性偶联物与抗HER2抗体或抗HER2抗体片段反应。
抗HER2抗体更详细地描述于上文的“细胞毒性偶联物”和“抗体-药物偶联物”部分。
在具体的实施方式中,制备根据本发明的抗体-药物偶联物的方法包括包含如下的步骤:使6-(2,6-双(溴甲基)吡啶-4-基)酰胺基-N-己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE(实施例1A中的参考号(8))或6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE(实施例1B中的参考号(17))与抗HER2抗体或抗HER2抗体片段进行反应。
附图说明
图1表示根据本发明的McSAF-吡啶抗体-药物偶联物组合物的HIC(疏水相互作用色谱)谱图。该图显示所述组合物富含DAR4,具有约69%的DAR4。
图2表示根据本发明的McSAF-吡啶抗体-药物偶联物组合物的SEC(尺寸排阻色谱)分析。该图显示出所述组合物非常同质,具有超过99%的单体。
图3表示在1mg规模上14个独立生物偶联的DAR的分布。这证明了用于获得McSAF-吡啶抗体-药物偶联物的生物偶联的高可重复性。
图4表示在各种规模(1mg、2.5mg和5mg规模)上各种生物偶联的DAR分布。这证明了无论规模如何,用于获得McSAF-吡啶抗体-药物偶联物的生物偶联的高可重复性。
图5表示用于获得McSAF-吡啶抗体-药物偶联物的代表性生物偶联的DAR分布(通过天然质谱分析)。该图展示了偶联物的化学性质,并显示出所述组合物富含DAR4,具有约80%的DAR4。
图6表示McSAF-吡啶、T-DM1和曲妥珠单抗对HER2抗原的识别。
图7表示与单独的T-DM1和MMAE相比,McSAF-吡啶对表达HER2的细胞或不表达HER2的细胞的体外细胞毒性。
图8表示McSAF-吡啶与使用马来酰亚胺偶联化学制备的ADC(McSAF-马来酰亚胺1)相比,在人血浆中释放的MMAE的量(通过LC-MS/MS)。该图反映了McSAF-吡啶抗体-药物偶联物的稳定性。
图9表示与使用马来酰亚胺偶联化学制备的ADC(McSAF-马来酰亚胺1)相比,McSAF-吡啶在37℃的溶液中平均DAR的变化。该图反映了McSAF-吡啶抗体-药物偶联物的稳定性。
图10表示与使用马来酰亚胺偶联化学制备的ADC(McSAF-马来酰亚胺1)相比,在37℃下,在HSA(人血清白蛋白)存在时,McSAF-吡啶在溶液中平均DAR的变化。该图反映了McSAF-吡啶抗体-药物偶联物的稳定性。
图11表示与使用马来酰亚胺偶联化学制备的ADC(McSAF-马来酰亚胺1)相比,在40℃下McSAF-吡啶在溶液中28天的平均DAR的变化(通过HIC方法测量)。该图反映了McSAF-吡啶抗体-药物偶联物的稳定性。
图12表示与使用马来酰亚胺偶联化学制备的ADC(McSAF-马来酰亚胺1)相比,在40℃下McSAF-吡啶在溶液中28天的DAR4百分比变化(通过HIC方法测量)。该图反映了McSAF-吡啶抗体-药物偶联物的稳定性。
图13表示与使用马来酰亚胺偶联化学制备的ADC(McSAF-马来酰亚胺1)相比,40℃下McSAF-吡啶在溶液中28天的单体百分比变化(通过SEC方法测量)。
图14表示用5mg/kg McSAF-吡啶、5mg/kg T-DM1或不具有ADC的媒介处理的小鼠的肿瘤体积变化。
图15表示用5mg/kg McSAF-吡啶、5mg/kg T-DM1或不具有ADC的媒介处理的所有小鼠在第70天时的肿瘤体积分布。该图反映了对5mg/kg抗体-药物偶联物的抗肿瘤反应的均匀性。
图16表示用1mg/kg McSAF-吡啶、1mg/kg T-DM1或不具有ADC的媒介处理的小鼠的肿瘤体积变化。
图17表示用1mg/kg McSAF-吡啶、1mg/kg T-DM1或不具有ADC的媒介处理的所有小鼠在第70天时的肿瘤体积分布。该图反映了关于1mg/kg的抗体-药物偶联物和T-MD1的不同的抗肿瘤反应。
图18表示McSAF-吡啶偶联物的变性质谱谱图。该图显示了完全重建并偶联的种类(LHHL DAR4)的存在。
图19表示根据本发明的McSAF-吡啶逆酰胺抗体-药物偶联物组合物的HIC(疏水相互作用色谱)谱图。该图显示所述组合物富含DAR4,具有约68%的DAR4。
图20表示McSAF-吡啶逆酰胺偶联物的变性质谱谱图。该图显示了完全重建并偶联的种类(LHHL DAR4)的存在。
图21表示用于获得McSAF-吡啶逆酰胺抗体-药物偶联物的代表性生物偶联的DAR分布(通过天然质谱分析)。该图展示了偶联物的化学性质,并显示所述组合物富含DAR4,具有约75%的DAR4。
图22表示在250μg规模上5个独立生物偶联的DAR的分布。这证明了用于获得McSAF-吡啶逆酰胺抗体-药物偶联物的生物偶联的高可重复性。
实施例
实施例1A:根据本发明的细胞毒性偶联物(吡啶)的合成
一般反应方案
(a)BnOH、SOCl2、DCM,18h,75℃;(b)APS、MeOH、H2O、H2SO4,1h,50℃;(c)H2、Pd/C、MeOH,2h,RT;(d)HATU、2,6-二甲基吡啶、DMF、H2N-(CH2)5-COOMe,15h,0℃,然后RT;(e)PBr3、MeCN,2h,45℃;(f)LiOH、THF、H2O,8.5h,RT;(g)EEDQ、DIPEA、DMF、MeCN、H2N-VCPABC-MMAE,2h20,25℃。
详细反应方案
苄基异烟酸酯的制备(2)
将异烟酸(1)(5.00g;40.614mmol;1.0eq)溶解在亚硫酰氯(15mL;206.77mmol;5.1eq)中并回流过夜。回到室温后,减压下通过蒸发除去过量的亚硫酰氯,然后将所得残留物溶解在无水二氯甲烷(55mL)中。加入苯甲醇(4.2mL;40.614mmol;1.0eq)并将混合物回流搅拌10h。回到室温后,将反应介质用饱和碳酸氢钠溶液中和并用二氯甲烷(3×100mL)萃取。将有机相合并,用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩。将获得的产物通过快速色谱(SiO2,环己烷/乙酸乙酯50:50)进行纯化,得到无色油状的(2)(6.97g;80%)。
1H NMR(300MHz,DMSO)δ8.80(dd;J=6.1;1.6Hz;2H1,5),7.86(dd;J=6.1;1.6Hz,2H2,4),7.56-7.29(m;5H9-13),5.39(s;2H7)。
13C NMR(75MHz,DMSO)δ165.0(1C6);151.3(2C1,5);137.2(1C3);136.1(1C8);129.0(2C10,12);128.8(1C11);128.6(2C9,13);123.0(2C2,4);67.4(1C7)。
HRMS(ESI):C13H11NO2计算的中性质量[M]:213.0790;观测为213.0796。
苄基2,6-双(羟甲基)异烟酸酯(3)的制备
将苄基异烟酸酯(2)(2.48g;11.630mmol;1.0eq)溶于甲醇(43mL)中,在50℃下搅拌并加入浓硫酸(320μL;6.016mmol;0.52eq)。分两步添加处于水中的过硫酸铵(26.500g;116.000mmol;10.0eq)溶液(43mL):首先快速添加30滴,形成白色悬浮液,然后快速滴加5min。反应上升至75℃,然后将获得的黄色溶液在50℃下再搅拌1h。回到室温后,减压下蒸发甲醇。添加50mL乙酸乙酯并通过添加饱和碳酸氢钠溶液来中和介质。用乙酸乙酯(3×100mL)萃取水相,将合并的有机相用饱和氯化钠溶液洗涤,硫酸镁干燥,然后减压浓缩。通过快速色谱(SiO2,二氯甲烷/甲醇,95:5)纯化粗产物,得到米色固体状的(3)(1.56g;49%)。
1H NMR(300MHz,DMSO)δ7.81(s;2H2,4);7.55-7.32(m;5H9-13);5.60(t;J=5.9Hz;2H15,17);5.40(s;2H7);4.59(d;J=5.9Hz;4H14,16)。
13C NMR(75MHz,DMSO)δ165.0(1C6);162.8(2C1,5);138.0(1C3);135.7(1C8);128.6(2C10,12);128.4(1C11);128.3(2C9,13);117.0(2C2,4);66.9(1C7);63.9(2C14,16)。
HRMS(ESI):C15H15NO4计算的中性质量[M]:273.1001;观测为273.1001。
2,6-双(羟甲基)异烟酸(4)的制备
将苄基2,6-双(羟甲基)异烟酸酯(3)(1.33g;4.867mmol;1.0eq)溶于甲醇(50mL)中,并将溶液用氩脱气15min。添加10wt%的钯/炭(palladium-on-charcoal,133mg)并将反应介质在氢气氛下于室温搅拌2h。在dicalite上过滤(甲醇冲洗)反应介质。在减压下浓缩滤液,得到米色固体状的(4)(849mg;95%)。
1H NMR(300MHz,DMSO)δ7.78(s;2H2,4);5.54(s broad;2H9,11);4.59(s;4H8,10)。
13C NMR(75MHz,DMSO)δ166.7(1C6);162.5(2C1,5);139.4(1C3);117.3(2C2,4);64.0(2C8,10)。
HRMS(ESI):C8H9NO4计算的中性质量[M]:183.0532;观测为183.0526。
6-((2,6-双(羟甲基)吡啶-4-基)氨基己酸甲酯(5)的制备
将2,6-双(羟甲基)异烟酸(4)(50mg;0.273mmol;1eq)溶于无水N,N-二甲基甲酰胺(3.0mL)中,将溶液冷却至0℃,然后添加HATU(156mg;0.410mmol;1.5eq)和2,6-二甲基吡啶(147.0μL;1.260mmol;4.7eq)。将活化溶液在0℃搅拌15min,然后添加6-氨基己酸甲酯(59mg;0.322mmol;1.2eq)。用2mL无水N,N-二甲基甲酰胺冲洗烧瓶壁,将反应介质在室温下搅拌15h。将反应混合物稀释于乙酸乙酯中,用饱和氯化钠溶液洗涤3次,用硫酸镁干燥,过滤并减压浓缩。通过快速色谱(二氯甲烷/甲醇,90:10)纯化产物,得到灰白色固体状的(5)(76mg;91%)。
1H NMR(300MHz,DMSO)δ8.79(t;J=5.6Hz;1H7);7.71(s;2H2,4);5.50(t;J=5.8Hz;2H16,18);4.57(d;J=5.8Hz;4H15,17);3.57(s;3H14);3.25(m;2H8);2.30(t;J=7.4Hz;2H12);1.62-1.45(m;4H9,11);1.37-1.21(m;2H10)。
13C NMR(75MHz,DMSO)δ173.3(1C13);165.1(1C6);161.8(21,5);142.9(1C3);115.8(2C2,4);64.1(2C15,17);51.2(1C14);38.5在DMSO下(1C8);33.2(1C12);28.6(1C9);25.9(1C11);24.2(1C10)。
HRMS(ESI):C15H22N2O5计算的中性质量[M]:310.1529;观测为310.1526。
6-(2,6-双(溴甲基)吡啶-4-基)氨基己酸甲酯(6)的制备
使6-((2,6-双(羟甲基)吡啶-4-基)氨基己酸甲酯(5)(55mg;0.177mmol;1eq)悬浮在无水乙腈(10.5mL)中,然后滴加三溴化磷(50μL;0.532mmol;3.0eq)。将反应介质在45℃下搅拌2h。将溶液冷却至0℃,用水(10mL)中和并用乙酸乙酯(3×15mL)萃取。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩。通过快速色谱(SiO2,环己烷/乙酸乙酯60:40)纯化产物,得到白色固体状的(6)(57mg;74%)。
1H NMR(300MHz;DMSO)δ8.83(t,J=5.6Hz;1H7);7.84(s;2H2,4);4.74(s;4H15,16);3.57(s,3H14);3.31-3.20(m;2H8);2.31(t;J=7.4Hz;2H12);1.64-1.45(m;4H9,11);1.39-1.22(m,2H10)。
13C NMR(75MHz,DMSO)δ173.3(1C13);163.8(1C6);157.5(2C1,5);144.2(1C3);120.8(2C2,4);51.2(1C14);38.9under DMSO(1C8);34.1(2C15,16);33.2(1C12);28.5(1C9);25.9(1C11);24.2(1C10)。
HRMS(ESI):C15H20Br2N2O3计算的中性质量[M]:433.9841;观测为433.9832。
6-(2,6-双(溴甲基)吡啶-4-基)氨基己酸(7)的制备
将6-(2,6-双(溴甲基)吡啶-4-基)氨基己酸甲酯(6)(57mg;0.131mmol;1.0eq)溶于四氢呋喃(4mL),缓慢添加处于水中的水合氢氧化锂(8mg;0.327mmol;2.5eq)溶液(4mL)。将反应介质在室温下搅拌8.5h。将四氢呋喃减压蒸发,将水性残留物用1N盐酸水溶液处理并用乙酸乙酯(3×10mL)萃取。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩。产物通过快速色谱(二氯甲烷/甲醇,90:10)进行纯化,得到灰白色固体状的(7)(44mg;80%)。
1H NMR(300MHz;DMSO)δ12.00(s;1H14);8.83(t;J=5.5Hz;1H7);7.84(s;2H2,4);4.74(s;4H15,17);3.31-3.21(m;2H8);2.21(t;J=7.3Hz;2H12);1.60-1.46(m;4H9,11);1.39-1.25(m;2H10)。
13C NMR(75MHz;DMSO)δ174.4(1C13);163.8(1C6);157.5(2C1,5);144.1(1C3);120.8(2C2,4);39.0under DMSO(1C8);34.1(2C15,16);33.6(1C12);28.6(1C9);26.0(1C11);24.2(1C10).
HRMS(ESI):C14H19Br2N2O3计算的m/z[M+H]+:420.9757;观测为420.9752。
[6-(2,6-双(溴甲基)吡啶-4-基)酰胺基-N-己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE(8)的制备
在非活性气氛、黑暗和无水条件下,将6-(2,6-双(溴甲基)吡啶-4-基)氨基己酸(7)(13.2mg;0.0313mmol;2.28eq)溶于无水乙腈(1.2mL)中,然后添加N-乙氧羰基-2-乙氧基-1,2-二氢喹啉(EEDQ)(21.2mg;0.0857mmol;6.25eq)。将活化介质在25℃搅拌1h20。将在N,N-二异丙基乙胺(9.4μL;0.0537mmol;3.92eq)的存在下,溶解在无水N,N-二甲基甲酰胺(300μL)中的缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMEA三氟乙酸盐(17.0mg;0.0137mmol;1.0eq)溶液加入到活化介质中。将所获得的反应介质在25℃下搅拌1h。将混合物用N,N-二甲基甲酰胺稀释两倍,并通过半制备型高压液相色谱纯化(tR=22.1min;在Gilson PLC 2050系统[ARMEN V2(泵)和ECOM TOYDAD600(UV检测器)]上,在254nm、25℃下UV检测;Waters XBridgeTMC-18柱;5μm(250mm×19.00mm);用处于水中的0.1%三氟乙酸(体积比)(溶剂A)和乙腈(溶剂B)洗脱;梯度32min内20%至100%B,然后100%B 6min,以17.1mL/min),得到白色固体状的(8)(18.2mg;87%)。
1H NMR(300MHz,DMSO)δ(ppm)10.04-9.95(m;1H);8.94-8.79(m;1H);8.20-8.06(m;2H);7.98-7.87(m;1H);7.84(s;2H);7.81(s;1H);7.70-7.61(m;1H);7.58(d;J=8.2Hz;2H);7.38-7.11(m;6H);6.07-5.92(m;1H);5.47-5.37(m;1H);5.15-4.96(m;1H);4.73(s;4H);4.54-4.29(m;2H);4.32-4.12(m;1H);4.05-3.92(m;1H);3.30-3.08(m;9H);3.06-2.93(m;2H);2.91-2.77(m;2H);2.24-2.05(m;2H);2.21-2.11(m;3H);2.02-1.88(m;1H);1.60-1.44(m;5H);1.36-1.13(m;4H);1.08-0.93(m;6H);0.93-0.67(m;28H)。
HRMS(ESI):C72H111Br2N12O14计算的m/z[M+H]+:1525.6704;观测为1525.6700。
实施例1B:根据本发明的细胞毒性偶联物(吡啶逆酰胺)的合成
一般反应方案
(a)TBDMSOTf,2,6-二甲基吡啶,DCM,19h,0℃,然后RT;(b)H2、Pd/C、MeOH、AcOEt,5h,RT;(c)氯甲酸乙酯,三乙胺,THF,1h15,-10℃,NaN3,H2O,1h45,0℃,BnOH,甲苯,18h,90℃;(d)H2、Pd/C、MeOH,16h,RT;(e)ClCO-(CH2)4-COOMe,三乙胺,21h,0℃,然后RT;(f)TFA,17h,30℃;(g)PBr3,MeCN,2h,45℃;(h)LiOH、H2O、THF,3h,RT;(i)TFA.H2N-VCPABC-MMAE、IIDQ、DIPEA、DMF、MeCN,1h20,25℃。
详细反应方案
苄基2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)异烟酸酯(9)的制备
将苄基2,6-双(羟甲基)异烟酸酯(3)(1.56g;5.708mmol;1.0eq)溶于无水二氯甲烷(12mL)中,添加2,6-二甲基吡啶(3.6mL;28.542mmol;5.0eq)并将溶液冷却至0℃。在10min内滴加叔丁基二甲基硅烷基三氟甲磺酸酯(5.5mL;23.974mmol;4.2eq),然后将反应介质在氩下于室温(20℃)下搅拌19h。将介质冷却至0℃,然后通过添加饱和碳酸氢钠溶液进行中和。用二氯甲烷(3×100mL)萃取水相,并将合并的有机相用饱和氯化钠溶液洗涤,硫酸镁干燥,过滤,然后减压浓缩。将粗产物通过快速色谱(SiO2,环己烷/乙酸乙酯90:10)进行纯化,得到米色固体状的(9)(2.50g;87%)。
1H NMR(300MHz,DMSO)δ7.83(s;2H2,4);7.50-7.36(m,5H9-13);5.38(s;2H7);4.79(s;4H14,21);0.90(s;18H18-20,25-27);0.09(s;12H16,15,22,23)。
2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)异烟酸(10)的制备
将苄基2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)异烟酸酯(9)(2.50g;4.982mmol;1.0eq)溶于60mL的甲醇/乙酸乙酯混合物(5:1)中,然后将溶液用氩脱气15min。添加10wt%的钯/炭(250mg,10%m/m)并将反应介质在氢气氛下于室温(20℃)下搅拌5h。将反应介质在dicalite上过滤(甲醇冲洗)。将滤液在减压下浓缩,得到白色固体状的(10)(1.93g;94%)。
1H NMR(300MHz,DMSO)δ7.78(s;2H2,4);4.78(s;4H8,15),0.92(s;18H12-14,19-21);0.10(s;12H9,10,16,17)。
苄基(2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)吡啶-4-基)氨基甲酸酯(11)的制备
将2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)异烟酸(10)(519.4mg;1.262mmol;1.0eq)溶于无水四氢呋喃(4mL)中。将溶液冷却至-10℃。在搅拌下添加三乙胺(227.0μL;1.637mmol;1.3eq),然后滴加氯甲酸乙酯(180.7μL;1.890mmol;1.5eq)。将反应介质在氩下于-10℃下搅拌1h15。然后,添加处于水中的叠氮化钠(139.8mg;2.142mmol;1.7eq)溶液(300μL)。将反应介质在0℃下搅拌1h45。滤出三乙胺盐,然后将滤液减压浓缩(最高浴温度40℃,最高真空100mbar)。然后将残留物带到10mL水中并且将产物用乙酸乙酯(3×10mL)进行萃取。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩。得到黄色油状的酰基叠氮化物。将其溶解在甲苯(14mL)中,然后添加苯甲醇(522μL;5.044mmol;4.0eq)。将反应介质在90℃搅拌18h。减压蒸发甲苯。将产物通过快速色谱(SiO2,环己烷/乙酸乙酯90:10)进行纯化,得到黄色油状的(11)(535.6mg;82%)。
1H NMR(300MHz,CDCl3)δ7.50-7.32(m;7H2,4,10-14);6.85(s;1H6);5.23(s;2H8);4.75(s;4H15,22);0.96(s;18H19-21,26-28);0.12(s;12H16,17,23,24)。
2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)吡啶-4-胺(12)的制备
将苄基(2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)吡啶-4-基)氨基甲酸酯(11)(528.6mg;1.020mmol;1.0eq)溶于甲醇(30mL)中。将溶液用氩脱气15min。然后,添加10wt%的钯/炭(57.4mg,10%m/m)。将反应介质在氢气氛下室温(20℃)搅拌16h。将钯/炭在dicalite上过滤(甲醇漂洗),然后将滤液减压浓缩。以盐化形式(吡啶的氮)获得产物。将其放入水(160mL)中,然后在0℃下添加处于水中的10%氢氧化钠溶液直至获得pH为9。然后用二氯甲烷(5×50mL)萃取产物。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩,得到黄色油状的(12)(312.2mg;80%)。
1H NMR(300MHz;DMSO)δ6.44(s;2H2,4);6.04(s;2H6);4.47(s;4H7,14);0.91(s;18H11-13,18-20);0.07(s;12H8,9,15;16)。
甲基6-((2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)吡啶-4-基)氨基)-6-氧代己酸酯(13)的制备
将2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)吡啶-4-胺(12)(146.7mg;0.383mmol;1.0eq)溶于无水二氯甲烷(2.8mL)中。将溶液冷却至0℃,并逐滴添加三乙胺(106.7μL;0.765mmol;2.0eq),然后滴加甲基己二酰氯(59.7μL;0.383mmol;1.0eq)。将反应介质在室温(20℃)下搅拌15h30。然后将无水二氯甲烷(1mL)以及甲基己二酰氯(26.8μL;0.172mmol;0.5eq)加入到反应介质中。将反应介质在室温(20℃)下搅拌1h30。然后,将无水二氯甲烷(1mL)加入到反应介质中,然后是甲基己二酰氯(59.7μL;0.383mmol;1.0eq)和三乙胺(26.7μL;0.191mmol;0.5eq)。将反应介质在室温(20℃)下搅拌4h。通过在0℃加入饱和碳酸氢钠溶液(3mL)使反应停止并用二氯甲烷(3×10mL)萃取。将合并的有机相用硫酸镁干燥并减压浓缩。将产物通过快速色谱(SiO2,环己烷/乙酸乙酯50:50)进行纯化,得到无色油状的(13)(144.0mg;72%)。
1H NMR(300MHz,DMSO)δ10.25(s;1H6);7.58(s;2H2,4);4.63(s;4H14,21);3.58(s;3H13);2.41–2.28(m;4H8,11);1.62–1.51(m;4H9,10);0.92(s,18H18-20,25-27);0.09(s;12H15,16,22,23)。
甲基6-((2,6-双(羟甲基)吡啶-4-基)氨基)-6-氧代己酸酯(14)的制备
将甲基6-((2,6-双(((叔丁基二甲基硅烷基)氧基)甲基)吡啶-4-基)氨基)-6-氧代己酸酯(13)(136.9mg;0.261mmol;1.0eq)溶于三氟乙酸(3mL)中。将反应介质在30℃下搅拌17h。减压蒸发三氟乙酸。将残留物放入乙酸乙酯(10mL)中并添加饱和碳酸氢钠溶液(10mL)。将乳液剧烈搅拌。用乙酸乙酯(5×10mL)萃取产物。将合并的有机相用硫酸镁干燥并减压浓缩。将产物通过快速色谱(SiO2,二氯甲烷/甲醇80:20)进行纯化,得到无色油状的(14)(72.2mg;93%)。
1H NMR(300MHz,DMSO)δ10.24(s;1H6);7.57(s;2H2,4);5.37(t;J=5.8Hz;2H15,17);4.45(d;J=5.8Hz;4H14,16);3.58(s;3H13);2.40-2.29(m;4H8,11);1.72-1.45(m;4H9,10)。
甲基6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酸酯(15)的制备
将甲基6-((2,6-双(羟甲基)吡啶-4-基)氨基)-6-氧代己酸酯(14)(93.5mg;0.316mmol;1.0eq)溶于无水乙腈(6mL),然后缓慢添加三溴化磷(90μL;0.958mmol;3.0eq)。将反应介质在45℃下搅拌2h。将溶液冷却至0℃,用水(5mL)中和并用乙酸乙酯(3×10mL)萃取。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩。获得盐化形式(吡啶的氮)的产物。将其放入水中,然后在0℃下添加处于水中的10%氢氧化钠溶液直至获得pH为9。然后用二氯甲烷(3×20mL)萃取产物。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩。将产物通过快速色谱(SiO2,二氯甲烷/甲醇90:10)进行纯化,得到淡粉色固体状的(15)(80.8mg;62%)。
1H NMR(300MHz,CDCl3)δ7.87(s;1H6);7.64(s;2H2,4);4.49(s;4H14,15);3.71(s;3H13);2.53-2.32(m;4H8,11);1.84-1.66(m;4H9,10)。
6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酸(16)的制备
将甲基6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酸酯(15)(35.2mg;0.083mmol;1.0eq)溶于四氢呋喃(2.2mL)并且添加处于水中的水合氢氧化锂(8.7mg;0.208mmol;2.5eq)溶液(2.1mL)。将反应介质在室温(20℃)下搅拌3h。将反应介质在0℃下用0.1N盐酸水溶液酸化,然后用乙酸乙酯(3×20mL)萃取。将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并减压浓缩,得到白色结晶固体状的(16)(33.4mg;99%)。
1H NMR(300MHz,DMSO)δ12.06(s;1H13);10.46(s;1H6);7.66(s;2H2,4);4.63(s;4H14,15);2.39-2.33(m;2H8);2.26-2.20(m;2H11);1.67-1.45(m;4H9,10)。
6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酰胺-缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE(17)的制备
在非活性气氛、黑暗和无水条件下,将6-((2,6-双(溴甲基)吡啶-4-基)氨基)-6-氧代己酸(16)(3.1mg;7.60μmol;1.8eq)溶于无水乙腈(110μL)中,然后添加异丁基1,2-二氢-2-异丁氧基-1-喹啉羧酸酯(IIDQ)(2.28μL;7.68μmol;1.8eq)。将活化介质在25℃下搅拌30min。将在N,N-二异丙基乙胺(2.98μL;17.11μmol;4.0eq)存在下溶于无水N,N-二甲基甲酰胺(200μL)中并预先在室温(20℃)下搅拌30min的缬氨酸-瓜氨酸-对氨基苄基氨基甲酸酯-MMAE三氟乙酸盐(5.3mg;4.28μmol;1.0eq)加入到活化介质中。将获得的反应介质在25℃下搅拌1h20。用乙腈将混合物稀释两倍,用半制备高压液相色谱进行纯化(tR=23.5min;在Gilson PLC2050系统上[ARMEN V2(泵)和ECOM TOYDAD600(UV检测器)],在254nm、25℃下UV检测;Waters XBridgeTMC-18柱;5μm(250mm×19.00mm);用处于水中的0.1%三氟乙酸(按体积计)(溶剂A)和乙腈(溶剂B)洗脱;梯度:30%至60%B,26min;然后60%至100%B,2min;以及,100%B,3min,以17.1mL/min),得到白色冻干物形式的(17)(2.7mg;42%)。
1H NMR(300MHz,CDCl3):δ7.97(s;1H);7.58-7.41(m;1H);7.40-7.29(m;5H);5.42-5.14(m;1H);5.00-4.85(m;2H);4.76-4.64(m;1H);4.63-4.45(m;5H);4.23-4.01(m;1H);4.02-3.72(m;2H);3.60-3.43(m;3H);3.43-3.35(m;3H);3.34-3.25(m;4H);3.23-3.08(m;4H);3.07-2.97(m;3H);2.95-2.81(m;3H);2.62-2.29(m;6H);1.84-1.40(m;21H);1.35-1.11(m;6H);1.10-0.92(m;17H);0.93-0.69(m;16H);0.71-0.53(m;3H)。
HRMS(ESI):C71H109Br2N12O14计算的m/z[M+H]+:1511.6547;观测为1511.6557。
实施例2A:根据本发明的抗体-药物偶联物(吡啶)的合成
合成的产物的代码:McSAF-吡啶(对应于式(IIa),在下文中也称为“根据本发明的抗体-药物偶联物”或通常称为“ADC”)。
使用的抗体:曲妥珠单抗。
溶液的制备
生物偶联缓冲液:1×盐水缓冲液,例如磷酸盐、硼酸盐、乙酸盐、甘氨酸、三(羟甲基)氨基甲烷、4-(2-羟乙基)-1-哌嗪乙磺酸,pH范围在6-9之间,NaCl终浓度在50-300mM之间,EDTA终浓度在0.1-10mM之间。例如,pH为8.3的1×磷酸盐缓冲液,其中,NaCl终浓度为180mM,EDTA终浓度为1mM。
生物偶联缓冲液中曲妥珠单抗的浓度为1-10mg/mL之间(例如5mg/mL)。
还原剂:还原剂溶液选自在生物偶联缓冲液中的浓度为0.1-10mM之间的二硫苏糖醇、β-巯基乙醇、三(2-羧乙基)膦盐酸盐、三(羟丙基)膦。例如,处于生物偶联缓冲液中的1mM的三(2-羧乙基)膦盐酸盐溶液。
连接溶液:在有机溶剂混合物中浓度为0.1-10mM之间的细胞毒性偶联物(8),所述有机溶剂选自二甲亚砜、N,N-二甲基甲酰胺、甲醇、四氢呋喃、乙腈、N,N-二甲基乙酰胺、二噁烷。例如,处于由20%N,N-二甲基甲酰胺和80%甲醇组成的有机溶剂混合物中的1mM溶液。
生物偶联反应
在非活性气氛下,将还原剂(4-100eq,例如8eq)加入处于生物偶联缓冲液中的曲妥珠单抗(2.5mg;1eq),并将反应介质在15-40℃之间(例如37℃)孵育,0.25h-3h(例如2h),然后在非活性气氛下添加连接溶液(4-100eq,例如12eq),并将反应介质在15-40℃之间(例如37℃)搅动0.5-15h(例如2.5h)。将该反应以平行的方式重复进行(必要时重复多次),以获得所需的最终量的ADC,即五次。
ADC的纯化
使用Gibco PBS pH 7.4缓冲液在PD-10(GE Healthcare)上对反应混合物进行纯化(必要时纯化多次),以去除残留的化学试剂,即纯化两次。
结果
上述步骤能够获得7.43mg McSAF-吡啶(57%)。
实施例2B:根据本发明的抗体-药物偶联物(吡啶逆酰胺)的合成
合成的产物的代码:McSAF-吡啶逆酰胺(对应于式(IIa),在下文中也称为“根据本发明的抗体-药物偶联物”或通常称为“ADC”)。
使用的抗体:曲妥珠单抗。
溶液的制备
生物偶联缓冲液:1×硼酸盐缓冲液,pH为8.3,其中,NaCl终浓度为25mM,EDTA终浓度为1mM。
生物偶联缓冲液中曲妥珠单抗的浓度为5mg/mL。
还原剂:处于生物偶联缓冲液中浓度为1mM的三(2-羧乙基)膦盐酸盐溶液。
连接溶液:在由70%N,N-二甲基甲酰胺和30%甲醇组成的有机溶剂混合物中浓度为2mM的细胞毒性偶联物(17)。
生物偶联反应
将处于生物偶联缓冲液中的曲妥珠单抗(0.25mg;1eq)溶液置于氩下。然后添加还原剂(8eq)并将反应介质在37℃下孵育2h。然后,在氩下添加连接溶液(17eq),并将反应介质在37℃下搅拌2h30。
实施例3A:抗体-药物偶联物(McSAF-吡啶)的分析
HIC(疏水相互作用色谱)分析
材料与方法
在通过0.22μm过滤之前,用PBS(pH 7.4)将McSAF-吡啶ADC稀释至1mg/mL。将50μg产物注射到MAbPac HIC-Butyl,5μm,4.6×100mm,柱(ThermoScientific)上,该柱与配备有PDA(e2998)的Waters Alliance HPLC系统(e2695)相连,设置用于在280nm处检测。以1mL/min的流速洗脱McSAF-吡啶ADC,梯度为:在2分钟内从100%缓冲液A(1.5M硫酸铵、50mM磷酸二氢钠、5%异丙醇(v/v),pH 7.0)至20%缓冲液B(50mM磷酸二氢钠、20%异丙醇(v/v),pH7.0),然后在30分钟内至85%缓冲液B,然后将该梯度保持1min。在整个分离过程中温度保持在25℃。
结果示于图1和下表1中。
表1
SEC(尺寸排阻色谱)分析
材料与方法
在通过0.22μm过滤之前,用PBS(pH 7.4)将McSAF-吡啶ADC稀释至1mg/mL。将50μg产品注射到AdvanceBio SEC 2.7μm,7.8×300mm柱(Agilent Technologies)上,该柱与配备有PDA(2998)并具有MALLS Wyatt(miniDawnTM)检测器和Wyatt(T-rEX)折光率检测器的Waters Alliance HPLC系统(e2695)相连,设置用于在280nm处检测。用等度缓冲液C(1mM磷酸二氢钠、155mM氯化钠、3mM磷酸氢二钠、3mM叠氮化钠,pH 7.0)在24分钟内以1mL/min的流速洗脱McSAF-吡啶ADC。在整个分离过程中温度保持在25℃。
结果示于图2和下表2中。
表2
McSAF-吡啶 | 可溶性聚集体 | 寡聚体 | 单体 |
保留时间(min) | 3,73 | 6,45 | 7,27 |
面积(%) | 0,03 | 0,38 | 99,14 |
可重复性
可重复性结果示于图3(14个独立生物偶联的可重复性(采用1mg曲妥珠单抗的规模),通过HIC分析)和图4(不同规模上的可重复性,通过HIC分析)。
结论:生物偶联在相同规模和不同规模上都是完全可重复的。
天然MA(天然质谱)分析
材料和方法
在与来自Waters(Wilmslow,UK)的Acquity UPLC H-Class系统相连的Vion IMSQtof质谱仪上进行质谱分析。在MS分析之前,将样品(20μg)在BEH SEC 2.1×150mm脱盐柱上用等度梯度(50mM醋酸铵,pH 6.5)以40μL/min进行脱盐。旁通阀被编程为仅在6.5-9.5min之间允许溶剂进入光谱仪。在正模式下用ESI源在500-8000的m/z范围内以1Hz获取MS数据,并关于解卷积使用UNIFI 1.9软件和MaxEnt算法进行分析。
结果示于图5和下表3中。
表3
1:G0F/G0F糖型的分子量
2:未观测到
变性HRMS(变性高分辨率质谱)分析
在与Dionex Ultimate 3000 RSLC系统相连的Bruker maXis质谱仪上进行McSAF-吡啶ADC的质谱分析。在MS分析之前,在加热至80℃的MassPREP脱盐柱(2.1×10mm,Waters)上对样品(5μg)进行脱盐,以500μL/min使用0.1%甲酸水溶液作为溶剂A,处于乙腈中的0.1%甲酸溶液作为溶剂B。1min后,应用在1.5min内5%至90%B的线性梯度。在正模式下用ESI源在900-5000的m/z范围内以1Hz获取MS数据,并且对于解卷积使用DataAnalysis 4.4软件(Bruker)和MaxEnt算法进行分析。使用观测的峰的强度来确定DAR的种类。
结果示于图18和下表4中。
表4
未观测到种类H。
1:G0F/G0F糖型的分子量
2:未观测到
实施例3B:抗体-药物偶联物(McSAF-吡啶逆酰胺)的分析
HIC(疏水相互作用色谱)分析
材料和方法
通过执行实施例3A中描述的方案来分析McSAF-吡啶逆酰胺ADC。
结果示于图19和下表5中。
表5
1:未观测到
变性HRMS(变性高分辨率质谱)分析
通过执行实施例3A中描述的方案来分析McSAF-吡啶逆酰胺ADC。
结果示于图20和下表6中。
表6
未观测到种类LHH、HH和H。
1:G0F/G0F糖型的分子量
2:未观测到
天然MS(天然质谱)分析
材料和方法
如实施例3A中所述进行质谱分析。
结果示于图21和下表7中。
表7
1:G0F/G1F糖型的分子量
2:G0F/G0F糖型的分子量
3:未观测到
可重复性
可重复性结果示于图22(5个独立生物偶联的可重复性(采用250μg曲妥珠单抗规模),通过HIC分析)。
实施例4:抗体-药物偶联物(McSAF-吡啶)的体外评价
与HER-2抗原的结合:在阳性系(BT-474)和阴性系(MCF-7)上识别HER2抗原,与现有技术中描述的参比曲妥珠单抗-细胞毒性药物偶联物(称为曲妥珠单抗emtansine,以下称为“T-DM1”)进行比较。
材料和方法
细胞获得自ATCC(BT-474和MCF-7)。取一份冷冻细胞在37℃下在水浴中快速解冻,并用培养基(补充有8%FCS、100μg/mL青霉素G钠、100μg/mL硫酸链霉素的F12/DMEM)洗涤两次,然后以至少10000个细胞/cm2的密度置于150cm2细胞培养瓶中。将细胞在37℃下以具有5%CO2的潮湿气氛中保持至少一周。
然后收集细胞,并在4℃下,将80μL中的100000-500000个细胞与20μL ADC(McSAF-吡啶或T-DM1)(ADC浓度范围0.1-20μg/mL,8个浓度-0.1;0.5;1;2.5;5;10;15;20μg/mL))或与相同浓度的靶向HER2的抗体(曲妥珠单抗,阳性对照)孵育0.5-1h。在0℃下用标记缓冲液(1×PBS-2mM EDTA-0.5%BSA)将细胞洗涤3次,并在4℃下与二抗(100μL至1/100,F(ab')2-山羊抗人IgG Fc-PE,Life Technologies,#H10104)孵育0.5-1h。与二抗孵育后,在0℃下用标记缓冲液洗涤细胞两次。
洗涤后,在通过流式细胞术分析之前,将细胞离心并在0℃下重悬于100-500μL染色缓冲液中。在流式细胞仪上测定每个样品所用探针的相对平均荧光发射(MFI),并通过诸如FCS Express 5Flow Cytometry(De Novo Software)的软件进行分析。
结果
图6中呈现的结果表明,McSAF-吡啶对HER2的识别类似于天然抗体(曲妥珠单抗)和T-DM1对HER2的识别,并且取决于HER2的存在。
细胞毒性(MTS测定):与T-DM1相比,McSAF-吡啶对阳性系和阴性系的细胞毒性作用。
材料和方法
细胞获得自ATCC(BT-474和MCF-7)。取一份冷冻细胞在37℃下在水浴中快速解冻,并用培养基(补充有8%FCS、100μg/mL青霉素G钠、100μg/mL硫酸链霉素的F12/DMEM)洗涤两次,并以至少10000个细胞/cm2的密度置于150cm2细胞培养瓶中。将细胞在37℃下在具有5%CO2的潮湿气氛中保持至少一周。
然后收集细胞并以每孔1.25-2.5×103个细胞之间的密度置于96孔板中,用于细胞毒性测定。在添加测试的ADC和添加媒介(PBS)之前,将细胞在37℃下孵育48h。DMSO百分比不超过0.5%。所测试的ADC以下列终浓度添加:225;75;25;8.33;2.78;0.926;0.309;0.103;0.034;0.011nM;并孵育72h(+/-2h)。
在添加测试的ADC之前(D0)以及添加测试的化合物后72h(D3),在细胞的沉积物(D-2)上,通过以下方式来确定细胞活力:根据供应商的使用建议,使用Luminescent细胞活力测定试剂盒(Promega)测量细胞ATP的量。在光度计(EnVisionTM)上测量荧光素酶活性。
每个浓度的化合物以三重复进行,并进行两个独立的实验。
结果
图7中呈现的结果显示了McSAF-吡啶的细胞毒作用,其与T-DM1相比更高,并且取决于HER2的存在。
实施例5:生物偶联的稳定性
血浆稳定性:通过LC-MS/MS量化在37℃下在人血浆中孵育后释放的MMAE的量。McSAF-吡啶和用马来酰亚胺附着头(单键)生产的ADC(=以下分子式的McSAF-马来酰亚胺1)之间的比较:
材料与方法
MMAE校准曲线
将25μL RP424(H2O+0.1%FA)添加到25μL样品(MMAE-d8标准品或MMAE浓度范围),然后搅动混合物。添加75μL的0.04μg/mL标准溶液“MMAE-d8”,然后搅动30秒。将混合物在4℃下以20000g离心10分钟。去除上清液并转移到聚丙烯烧瓶中。在注射进LC-MS/MS前,在4℃下以2500g进行新的离心5min。将样品注射到Acquity BEH UPLC C18、50×2.1mm、1.7μm柱上,该柱与LC-20AD和LC-20ADXR系统(Shimadzu)相连,该系统与带有ESI+源的Shimadzu质量检测器(8060)偶联。通过以下梯度进行洗脱:在5分钟中,从处于25%缓冲液E(乙腈)中的75%缓冲液D(10mM醋酸铵)到处于95%缓冲液E中的5%缓冲液D,然后在5.1分钟中,增加至处于25%缓冲液E中的75%缓冲液D。结果用Labsolution 6.60软件进行处理。
人血浆孵育
将样品以初始浓度为100μg/mL在无菌人EDTA-2K血浆(BioIVT)中孵育。在以下时间收集3个样品:搅动混合物(T0)后立即,然后在37℃孵育6h、12h、24h、48h和96h后。在如上所述对其进行LC-MS/MS分析之前,将样品储存在-80℃。
结果
图8中呈现的结果表明,与McSAF-马来酰亚胺1相比,McSAF-吡啶向血浆中释放更少的MMAE。因此,在生理条件下,McSAF-吡啶比McSAF-马来酰亚胺1更稳定。
存在或不存在HSA(人血清白蛋白)的情况下在37℃的稳定性
材料和方法
将PBS缓冲液(1mM磷酸二氢钠、3mM磷酸氢二钠、155mM氯化钠、1mM叠氮化钠,pH7.4)中的McSAF-吡啶和McSAF-马来酰亚胺1的浓度调节至2mg/mL。将十二(12)个20μLMcSAF-吡啶和McSAF-马来酰亚胺1样品置于十二个聚丙烯烧瓶(Fisher Scientific,0.6mL)中,然后将20μL PBS缓冲液(1mM磷酸二氢钠、3mM磷酸氢二钠、155mM氯化钠、1mM叠氮化钠、pH 7.4)或20μL处于PBS缓冲液(1mM磷酸二氢钠、3mM磷酸氢二钠、155mM氯化钠、1mM叠氮化钠,pH 7.4)中的20mg/mL HSA溶液加入到每个烧瓶中。搅动后,将12个烧瓶中的每一个以5000g离心30秒,然后在培养箱(VWR INCU-line IL23)中以37℃孵育。将烧瓶三个三个地从培养箱中取出并在1分钟(T0)、24h、48h和120h后储存在-80℃。
在用PBS缓冲液(1mM磷酸二氢钠、3mM磷酸氢二钠、155mM氯化钠、1mM叠氮化钠,pH7.4)以2倍进行稀释后,使12个烧瓶中每一个的内容物通过0.22μm进行过滤并由HIC进行分析。对于McSAF-吡啶,将50μg产品注射到MAbPac HIC-Butyl,5μm,4.6×100mm柱(ThermoScientific)上,该柱与配备有PDA(e2998)的Waters Alliance HPLC系统(e2695)相连,设置用于在280nm处检测。将样品以1mL/min的流速用如下梯度进行洗脱:在50分钟内,从100%缓冲液A(1.5M硫酸铵、50mM磷酸二氢钠、5%异丙醇(v/v),pH7.0)到100%缓冲液B(50mM磷酸二氢钠、20%异丙醇(v/v),pH7.0)。在整个分离中温度保持在25℃。
对于McSAF-马来酰亚胺1,将50μg产物注射到TSKgel Butyl NPR,2.5μm,4.6×100mm柱(Tosoh),所述柱与配备有PDA(e2998)的Waters Alliance HPLC系统(e2695)相连,设置为在280nm处检测。将样品以0.6mL/min的流速用如下梯度进行洗脱:在60分钟内,从100%缓冲液A(1.5M硫酸铵、50mM磷酸二氢钠,pH 7.0)至20%缓冲液B(50mM磷酸二氢钠、20%异丙醇(v/v),pH 7.0),然后保持该梯度6min。在整个分离中温度保持在30℃。
结果
在37℃孵育后通过HIC方法监测平均DAR的变化示于图9。结果显示McSAF-吡啶在37℃下具有完美的稳定性,而McSAF-马来酰亚胺1的情况并非如此。这通过根据本发明的抗体-药物偶联物的稳定性增加得到解释。
在与过量HSA在37℃孵育后通过HIC方法监测平均DAR的变化示于图10。结果显示McSAF-吡啶在HAS存在下具有完美的稳定性,McSAF-马来酰亚胺1的情况并非如此。这通过根据本发明的抗体-药物偶联物的稳定性增加得到解释。
在40℃下的稳定性
材料和方法
将PBS缓冲液(1mM磷酸二氢钠、3mM磷酸氢二钠、155mM氯化钠,pH 7.4)中的McSAF-吡啶和McSAF-马来酰亚胺1的浓度调节至1mg/mL。将六(6)个150μL McSAF-吡啶和McSAF-马来酰亚胺1样品置于六个聚丙烯烧瓶(Eppendorf Protein LoBind,0.5mL)中。搅动后,将样品在培养箱(VWR INCU-line IL23)中以40℃培养。将烧瓶三个三个地从培养箱中取出,以5000g离心2分钟,并在1分钟和4周后储存在-80℃。
6个烧瓶中的每一个的内容物通过0.22μm进行过滤并由HIC和SEC进行分析。
HIC
通过执行实施例3A中描述的方案来分析McSAF-吡啶ADC。
对于McSAF-马来酰亚胺1,将50μg产物注射到TSKgel Butyl NPR,2.5μm,4.6×100mm柱(Tosoh),所述柱与配备有PDA(e2998)的Waters Alliance HPLC系统(e2695)相连,设置为在280nm处检测。将样品以0.6mL/min的流速以如下梯度进行洗脱:在45分钟内,从100%缓冲液A(1.5M硫酸铵、50mM磷酸二氢钠,pH 7.0)至处于缓冲液A中的80%缓冲液B(50mM磷酸二氢钠、20%异丙醇(v/v),pH 7.0),然后将该梯度保持6min。在整个分离中温度保持在30℃。
SEC
将50μg产物注射到AdvanceBio SEC,2.7μm,7.8×300mm柱(AgilentTechnologies)上,所述柱与配备有PDA(2998)的Waters Alliance HPLC系统(e2695)相连,设置为在280nm处检测。将ADC用等度缓冲液C(1mM磷酸二氢钠、155mM氯化钠、3mM磷酸氢二钠、3mM叠氮化钠,pH 7.4)在24分钟内以1mL/min的流速洗脱。在整个分离中温度保持在25℃。
结果
在40℃孵育28天后通过HIC方法监测平均DAR的变化示于图11(N=3)。结果表明McSAF-马来酰亚胺1的平均DAR从4.00(t0)变化到2.61(t28),证明在模拟的压力条件下缺乏稳定性,而McSAF-吡啶的平均DAR变化很小(3.93(t0)到3.98(t28)),证明与使用马来酰亚胺技术的McSAF-马来酰亚胺1相比其稳定性提高。
在40℃孵育28天后通过HIC方法监测DAR4百分比的变化示于图12(N=3)。结果表明,McSAF-马来酰亚胺1的DAR4百分比随着时间降低(t0时为30%,t28时为20%),而McSAF-吡啶的DAR4百分比变化很小(t0时为67%,t28时为63%)。这表明与使用马来酰亚胺技术的McSAF-马来酰亚胺1相比,McSAF-吡啶的DAR4百分比的更好保存以及稳定性增加。
在40℃孵育28天后通过SEC方法监测单体百分比的变化示于图13(N=3)。结果表明,McSAF-马来酰亚胺1(t28时为77%)和McSAF-吡啶(t28时为80%)的单体百分比以相同的方式降低。
实施例6:抗体-药物偶联物(McSAF-吡啶)的体内评价
材料和方法
所有实验均在符合法国当局(授权号B 21 231 011 EA)和FELASA的建议的环境中进行。存活研究在BT-474异种移植模型上进行。在用γ源(2Gy,60Co,BioMep,Bretenières,法国)完全照射后24-72h,将肿瘤细胞悬浮液皮下植入免疫抑制的BALB/c裸鼠(CharlesRiver)。进行移植肿瘤后,一旦平均体积达到150-200mm3,将小鼠随机分组(N=8)。在第1天和第26天通过静脉内途径(IV,推注)将ADC(McSAF-吡啶或T-DM1参比)以1mg/kg或5mg/kg的量给予至小鼠的尾静脉。使用以下公式每周两次计算作为时间函数的肿瘤体积:(长度×厚度2)/2。当肿瘤体积达到动物体重的10%或大约2000mm3时,将动物安乐死。
结果
给予5mg/kg剂量的结果示于图14和图15中。给予1mg/kg剂量的结果示于图16和图17中。结果表明,在两种剂量(1mg/kg和5mg/kg)下,McSAF-吡啶均比T-DM1更有效。在5mg/kg的McSAF-吡啶下,观察到完全和持久的肿瘤消退,处理的8只小鼠中有8只治愈。
在研究结束时对小鼠进行补充免疫组织化学(complementaryimmunohistochemistry,IHC)分析。对于用5mg/kg处理的所有小鼠,可以确认对于McSAF-吡啶ADC的情况对应于异种移植物的区域中的HER2+细胞完全根除,从而确认肿瘤完全消退。
序列表
以“[参考编号]”格式引用的参考文献:
1.Fekete,S.et al.,J.Pharm.Biomed.Anal.,130,3-18,2016
2.Barran,P.et al.,EuPA Open Proteomics,11,23-27,2016
3.Goyon,A et al.,J.Chromatogr.B,1065-1066,35-43,2017
序列表
<110> Mc SAF
<120> 抗体-药物偶联物及其在治疗中的应用
<130> 1H317490 - 0001
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Claims (17)
2.如权利要求1所述的细胞毒性偶联物,其中,X为Br且m等于4或5。
6.如权利要求5所述的抗体-药物偶联物,其中,X为Br且m等于4或5。
8.如权利要求5-7中任一项所述的抗体-药物偶联物,其中,A为曲妥珠单抗。
10.一种组合物,所述组合物包含一种或多种如权利要求5-9中任一项所述的抗体-药物偶联物。
11.如权利要求10所述的组合物,其中,所述抗体-药物偶联物的至少50%、优选至少65%的n等于4。
12.如权利要求10或11所述的组合物,其中,A为抗体,并且平均药物抗体比(平均DAR)在3.5到4.5之间、优选在3.8到4.2之间,例如等于4.0±0.2。
13.如权利要求10-12中任一项所述的组合物,所述组合物进一步包含:紫杉醇;多西他赛;多柔比星;环磷酰胺;芳香酶抑制剂,如阿那曲唑;和/或用于抗癌免疫疗法的抗体,如抗PD1抗体。
14.如权利要求4-9中任一项所述的抗体-药物偶联物或如权利要求10-13中任一项所述的组合物用作药剂的用途。
15.如权利要求4-9中任一项所述的抗体-药物偶联物或如权利要求10-13中任一项所述的组合物用于治疗HER2+癌症、优选HER2+乳腺癌的用途。
17.一种用于制备如权利要求5-9中任一项所述的抗体-药物偶联物的方法,所述方法包括以下步骤:
(i)根据权利要求16的方法制备细胞毒性偶联物;以及
(ii)使步骤(i)中获得的细胞毒性偶联物与抗HER2抗体或抗HER2抗体片段进行反应。
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FR3125965B1 (fr) * | 2021-08-05 | 2024-06-21 | Mc Saf | Conjugués anticorps-médicament |
FR3131836A1 (fr) * | 2022-01-17 | 2023-07-21 | Mc Saf | Conjugués anticorps-médicament pour utilisation thérapeutique |
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CN105592859A (zh) * | 2013-07-11 | 2016-05-18 | 图尔大学 | 新型抗体-药物缀合物以及其在疗法中的用途 |
CN107921030A (zh) * | 2015-08-14 | 2018-04-17 | Rc生物技术公司 | 抗体‑药物偶联物的共价连接子及其制备方法与应用 |
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CN105592859A (zh) * | 2013-07-11 | 2016-05-18 | 图尔大学 | 新型抗体-药物缀合物以及其在疗法中的用途 |
CN107921030A (zh) * | 2015-08-14 | 2018-04-17 | Rc生物技术公司 | 抗体‑药物偶联物的共价连接子及其制备方法与应用 |
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BRYANT等: "In Vitro and In Vivo Evaluation of Cysteine Rebridged Trastuzumab–MMAE Antibody Drug Conjugates with Defined Drug-to-Antibody Ratios", MOLECULAR PHARMACEUTICS, vol. 12, no. 6, pages 1872 - 1879, XP055668586, DOI: 10.1021/acs.molpharmaceut.5b00116 * |
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US20230102207A1 (en) | 2023-03-30 |
JP2022533854A (ja) | 2022-07-26 |
WO2020234541A1 (fr) | 2020-11-26 |
CA3138498A1 (fr) | 2020-11-26 |
FR3096259A1 (fr) | 2020-11-27 |
EP3972652A1 (fr) | 2022-03-30 |
FR3096259B1 (fr) | 2023-12-15 |
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