CN113226378A - 抗体-药物缀合物 - Google Patents
抗体-药物缀合物 Download PDFInfo
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- CN113226378A CN113226378A CN201980085326.XA CN201980085326A CN113226378A CN 113226378 A CN113226378 A CN 113226378A CN 201980085326 A CN201980085326 A CN 201980085326A CN 113226378 A CN113226378 A CN 113226378A
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Abstract
本发明涉及抗体‑药物缀合物,包含:(i)抗体或其抗原结合片段,(ii)包含特定重复单元的聚合物,其任选地通过接头共价结合至一个或多个生物活性部分,例如小分子药物,和(iii)聚合物‑抗体接头部分,其共价结合至聚合物和抗体或其抗原结合片段两者。此外,本发明涉及包含抗体‑药物缀合物的药物组合物以及该抗体‑药物缀合物在医学中的用途。
Description
技术领域
本发明涉及抗体-药物缀合物,包含:(i)抗体或其抗原结合片段,(ii)包含特定重复单元的聚合物,其(任选地通过接头)共价结合至一个或多个生物活性部分,例如小分子药物,和(iii)聚合物-抗体接头部分,其共价结合至聚合物和抗体或其抗原结合片段。此外,本发明涉及包括抗体-药物缀合物的药物组合物以及该抗体-药物缀合物在医学中的用途。
背景技术
抗体药物缀合物(ADC)是一类高效的生物制药药物,其具有多种治疗用途。例如,在肿瘤学领域,ADC可用于使用抗体靶向癌细胞,细胞毒性药物通过接头连接至抗体。尽管有这些好处,但由于通常可以实现的3-4的低药物对抗体比值(DAR),ADC的开发受到了限制。通常,对于传统的ADC,每个接头只能将一种药物连接至抗体。该局限限制了ADC的治疗指数和可用于ADC的药物范围,因为只有高度细胞毒性的药物能够被利用。这也增加了患者不良反应的发生率。此外,迄今为止增加DAR的尝试已导致ADC的聚集,使其无效。
因此,需要能够支持高DAR但也具有理想的物理化学性能,例如高的水溶性和稳定性的新型ADC。
发明内容
本发明提供了含有特定的聚合接头的ADC,其在水性溶液中具有良好的稳定性和高的溶解度。本发明中使用的特定的聚合接头还能够支持高的DAR,并且能够将许多不同的生物活性分子(通常,4个或更多,8个或更多,优选12个或更多,更优选16个或更多,和最优选多达20个或更多的生物活性分子)缀合至单个抗体。如此高的DAR能够提高治疗指数。
此外,本发明ADC中使用的特定的聚合物还使得生物活性分子从缀合物的释放速率得到控制。该释放速率取决于ADC内共价的聚合物-药物或接头-药物键的降解。不同类型的共价连接会在不同的(例如)pH条件下水解。
本发明的ADC中使用的特定的聚合物还使得多种不同类型的药物部分能够与聚合物缀合(conjugate)。这尤其对于使用两种或更多种活性剂实现靶向联合疗法会是有用的。联合疗法在肿瘤学和传染病的治疗中特别有用。联合疗法中使用的药物通常具有互补的作用方式和/或具有累加或协同的治疗效果。然而,使用多种药物的治疗方案总是复杂且密集。在给定的时间点频繁给药和同时施用几种不同的药物是司空见惯的。与更直接的方案相比,这种复杂的方案往往具有较低的患者依从性和耐受性。因此,将多种药物缀合至具有高DAR和有利的物理化学性能的单个抗体的能力为联合疗法提供了新的机会。
本发明因此提供了一种抗体-药物缀合物,包括:
(i)抗体或其抗原结合片段;
(ii)包含式(I’)的重复单元的聚合物:
其中:
每个n和每个p独立地为0或1和6之间的整数;
每个m独立地为0或1和4之间的整数,优选至少一个m为1;
--------是可以不存在或存在的键;
每个D1独立地为O或L1-B1;
每个D2独立地为O或L2-B2;
每个D3独立地为O或L3-B3;
L1是接头基团或键,L2是接头基团或键,L3是接头基团或键,且B1、B2和B3各自是生物活性部分;
条件是,聚合物中的至少一个D1、D2或D3基团不是O,且另一条件是当D1、D2或D3是O时,O原子和它所连接的碳原子之间有一个双键;
每个q是1和8之间的整数;
X和Y独立地选自O、NH、NR’和S;
R’是C1-20烃基;
Q选自-CH2(NMe(C=O)CH2)o-、-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-,其中T1选自二价亚甲基、亚乙基、亚丙基或亚丁基,且T2选自二价亚甲基、亚乙基、亚丙基或亚丁基;
o是0至100的整数;
s是0至150的整数;和
(iii)聚合物-抗体接头,其与抗体和聚合物两者共价结合。
优选地,聚合物包含式(I)的重复单元:
其中,变量X、Y、D1、D2、D3、n、m和p如上所述,且Q选自-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-。
替代地,聚合物包含式(I”)的重复单元:
其中,变量X、Y、Q、D1、D2、D3、n、m和p如上所述。优选地,在式(I”)的重复单元中,Q是-CH2(NMe(C=O)CH2)o-。更优选地,Q是-CH2(NMe(C=O)CH2)o-且Y是-NMe。
另一方面,本发明还提供了一种药物组合物,包括根据本发明的抗药-抗体缀合物和药学上可接受的赋形剂。
本发明进一步提供了根据任何本发明的抗体-药物缀合物用于治疗有需要的患者的疾病或病症(condition)的用途。
本发明进一步提供了一种治疗人类患者的如本文所定义的疾病或病症的方法,其中所述方法包括向有需要的患者施用至少一种根据本发明的抗体-药物缀合物。
本发明进一步提供了根据本发明的抗体-药物缀合物在制造用于治疗患者的如本文所定义的疾病或病症的药剂中的用途。
附图说明
图1:聚酰胺1合成的GPC分布图监测。示出了在第2阶段的6小时时反应混合物(线1)和第2阶段24小时后处理的聚酰胺1(线2)之间聚合物分子量的增加(GPC条件:2x(PL凝胶10μm MiniMIX-B 250x4.6mm)柱,CHCl3 0.3ml min-1,PS标准)。
图2:聚酰胺1的SEC分布图。SEC条件如下:PL-水凝胶-OH 30,8μm,300x7.5mm,H2O0.5ml min-1,PEG标准。区域1:Mn=13.9kDa;区域2:Mn=7.2kDa;区域3:Mn=3.7kDa;区域4:Mn=1.8kDa;区域5:Mn=1kDa。
图3:使用Agilent ZORBAX 300SB-C18的聚酰胺1的RP-HPLC分析色谱图;5μm,4.6x250mm柱,1.3mL min-1流速,H2O(0.1%TFA)和AcCN作为洗脱剂系统,梯度5%至90%的AcCN,15分钟,215nm进行UV-Vis检测。
图4:CDCl3中聚酰胺1的1H NMR。
图5:使用Agilent ZORBAX 300SB-C18对聚酰胺1的马来酰亚胺官能化(上图t=0时(聚酰胺1)、下图马来酰亚胺官能化后(聚酰胺2))进行RP-HPLC分析色谱图监测;5μm、4.6x250mm柱,1.3mL min-1流速,H2O(0.1%TFA)和ACN作为洗脱剂系统,梯度5%至90%的AcCN,15分钟,215nm进行UV-Vis检测。
图6:使用Agilent ZORBAX 300SB-C18进行的聚酰胺2的RP-HPLC半制备色谱图;5μm;9.4x250mm柱,4mL min-1流速,H2O(0.1%TFA)和ACN作为洗脱剂系统,梯度30%至56%的AcCN,13分钟,215nm进行UV-Vis检测。竖线显示级分收集区。
图7:通过半制备RP-HPLC纯化的聚酰胺2的RP-HPLC分析色谱图。所用柱为AgilentZORBAX 300SB-C18;5μm,4.6x250mm,1.3mL min-1流速,H2O(0.1%TFA)和ACN作为洗脱剂系统,梯度5%至90%的AcCN,15分钟,在215nm(上图)和250nm(下图)进行UV-Vis检测。
图8:在215nm观察到的与粗制聚合物(线1)相比,通过半制备RP-HPLC纯化的聚酰胺2(线2)的RP-HPLC分析色谱图。所用柱为Agilent ZORBAX 300SB-C18;5μm,4.6x250mm,1.3mL min-1流速,H2O(0.1%TFA)和ACN作为洗脱剂系统,梯度5%至90%的AcCN,15分钟。
图9:在CDCl3中通过RP-HPLC纯化后的聚酰胺2的1H NMR。
图10:在水中50mg mL-1的粗制的(左)和RP-HPLC纯化的(右)聚酰胺2。
图11:显示MMAE 5在m/z=598.95处的峰的LC-MS谱图。
图12:在CD3CN中通过RP-HPLC纯化后的聚合物-MMAE缀合物6的1H NMR。
图13:MMAE聚酰胺曲妥珠单抗ADC(赫赛汀-MMAE-聚合物缀合物)的细胞活力测定。
具体实施方式
定义
如本文所用,术语“聚合物”是指包含重复单元的化合物。聚合物通常具有大于1的多分散度。聚合物通常包含主链、侧链和末端。主链是所有侧链都悬垂在其上的线性链。侧链是悬垂在主链上或从主链上分支出来的基团。末端是主链的端部。
如本文所用,术语“生物活性部分”是指任何通过提取氢自由基而衍生自生物活性分子的部分。“生物活性分子”是任何在体内施用时能够诱导生化响应的分子。通常,生物活性分子在施用于动物(或优选人)时能够产生局部或全身生化响应;优选地,局部或全身响应是治疗活性。生物活性分子的优选例子包括药物、多肽、蛋白质、肽模拟物、抗体、抗原、DNA、RNA、mRNA、小干扰RNA、小发夹RNA、微小RNA、PNA、折叠体、碳水化合物、碳水化合物衍生物、非利平斯基分子(non-Lipinski molecule)、合成肽和合成寡核苷酸,最优选地是小分子药物。
如本文所用,术语“小分子药物”是指对动物(例如人)具有已知的生物学效应的化学化合物。通常,药物是用于治疗、预防或诊断疾病的化合物。优选的小分子药物具有生物学活性,因为它们在动物,优选哺乳动物,更优选人类中产生局部或系统作用。小分子药物可被称为“药物分子”或“药物”。通常,药物分子的MW小于或等于约5kDa。优选地,药物分子的MW小于或等于约1.5kDa。尽管不是详尽地,一个更加完整的适用于本发明的类别和特定药物列表可在Axel Kleemann和Jurgen Engel的“Pharmaceutical Substances:Syntheses,Patents,Applications”(Thieme Medical Publishing,1999)和SusanBudavari等人编辑的“Merck Index:An Encyclopedia of Chemicals,Drugs,andBiologicals”(CRC Press,1996年)中发现,两者均通过引用整体并入本文。
如本文所用,术语“肽”是指生物学存在的或合成的通过肽(酰胺)键连接的氨基酸单体的短链。当一个氨基酸的羧基与另一氨基酸的氨基反应时,形成共价化学键。最短的肽是二肽,其由两个氨基酸通过单个肽键连接而成,其次是三肽、四肽等。多肽是一条长的、连续的且无分枝的肽链。因此,肽与核酸、寡糖和多糖等一起落在生物低聚物和聚合物的广义化学类别的范围内。
如本文所用,术语“氨基酸”指任何天然的或合成的氨基酸,即,包含碳、氢、氧和氮原子且包含氨基(-NH2)和羧酸(-COOH)官能团两者的有机化合物。典型地,氨基酸是α-氨基酸、β-氨基酸、γ-氨基酸或δ-氨基酸。优选地,氨基酸是22种天然存在的蛋白原性α-氨基酸中的一种。替代地,氨基酸是合成的氨基酸,其选自α-氨基正丁酸、正缬氨酸(Norvaline)、正亮氨酸(Norleucine)、别异亮氨酸(Alloisoleucine)、t-亮氨酸、α-氨基正庚酸、哌可酸(Pipecolic acid)、α,β-二氨基丙酸、α,γ-二氨基丁酸、鸟氨酸(Ornithine)、别苏氨酸(Allothreonine)、高半胱氨酸(Homocysteine)、高丝氨酸(Homoserine)、β-丙氨酸(β-Alanine)、β-氨基正丁酸、β-氨基异丁酸、γ-氨基丁酸、α-氨基异丁酸、异缬氨酸、肌氨酸(Sarcosine)、N-乙基甘氨酸、N-丙基甘氨酸、N-异丙基甘氨酸、N-甲基丙氨酸N-乙基丙氨酸、N-甲基β-丙氨酸、N-乙基β-丙氨酸、异丝氨酸、α-羟基γ-氨基丁酸、高正亮氨酸(Homonorleucine)、O-甲基-高丝氨酸、O-乙基-高丝氨酸、硒代高半胱氨酸、硒代蛋氨酸、硒代乙硫氨酸、羧基谷氨酸(Carboxyglutamic acid)、羟脯氨酸(Hydroxyproline)、高赖氨酸(Hypusine)、焦谷氨酸(Pyroglutamic acid)、氨基异丁酸、脱氢丙氨酸、β-丙氨酸、γ-氨基丁酸、δ-氨基乙酰丙酸、4-氨基苯甲酸、瓜氨酸、2,3-二氨基丙酸和3-氨基丙酸。具备立体中心的氨基酸可以呈现为单个对映体或者呈现为对映体的混合物(例如外消旋混合物)。优选地,如果氨基酸是α-氨基酸,则氨基酸具有关于α-碳立体中心的L立体化学。
如本文所用,术语“蛋白质”是指包含氨基酸单体的聚合物的生物分子,所述聚合物基于尺寸与肽不同,并且作为任意一个基准,可以理解为包含大约50个或更多的氨基酸。蛋白质由一种或多种以生物功能方式排列的多肽组成,通常与如辅酶和辅因子等配体结合,或与另一蛋白质或其他大分子(DNA、RNA等)结合,或与复杂的大分子组装体结合。
如本文所用,术语“肽模拟物”是指设计成用于模拟肽的小蛋白样链。它们通常来自对现有肽的修饰,或通过设计模拟肽的类似系统,例如类肽和β-肽,而产生。不管采用何种方法,改变的化学结构设计成有利地调整分子特性,例如稳定性或生物活性。这可以在从现有肽开发药物类化合物中发挥作用。这些修饰涉及不会自然存在的肽的改变(例如改变的骨架和非天然氨基酸的掺入)。
如本文所用,术语“mRNA”是指信使RNA,一个将遗传信息从DNA传递到核糖体的RNA分子家族,其中它们指定基因表达的蛋白质产物的氨基酸序列。在RNA聚合酶转录初级转录本mRNA(称为前mRNA)后,经过加工的成熟mRNA被翻译成氨基酸的聚合物:蛋白质。与在DNA中一样,mRNA遗传信息位于核苷酸序列中,核苷酸序列排列成分别由三个碱基组成的密码子。除了终止蛋白质合成的终止密码子外,每个密码子都编码一个特定的氨基酸。将密码子翻译成氨基酸的这个过程需要其他两种类型的RNA:转运RNA(tRNA),其介导密码子的识别并提供相应的氨基酸;以及核糖体RNA(rRNA),其是核糖体的制造蛋白质的机器的中心组件。
如本文所用,术语“小干扰RNA”(siRNA)是指一类长度为20-25个碱基对的双链RNA分子。siRNA发挥着许多作用,但在RNA干扰(RNAi)途径中最为显著,在该途径中它干扰具有互补核苷酸序列的特定基因的表达。siRNA通过导致mRNA在转录后分解而发挥作用,从而导致不翻译。siRNA还作用于RNAi相关途径,例如作为抗病毒机制或塑造基因组的染色质结构。
如本文所用,术语“小发夹RNA”(shRNA)是指具有紧凑发夹转角(turn)的人工RNA分子,其可用于通过RNA干扰(RNAi)使靶基因表达沉默。shRNA在细胞中的表达通常是通过递送质粒或通过病毒或细菌载体来实现的。shRNA是一种有利的RNAi调节者,因为它的降解和周转率相对较低。
如本文所用,术语“微小RNA”(miRNA)是指在植物、动物和一些病毒中发现的小的非编码RNA分子(包含约22个核苷酸),其在RNA沉默和基因表达的转录后调控中起作用。
如本文所用,术语“PNA”是指肽核酸,一种类似于DNA或RNA的人工合成的聚合物,由Peter E.Nielsen(哥本哈根大学)、Michael Egholm(哥本哈根大学)、Rolf H.Berg(国家实验室)和Ole Buchardt(哥本哈根大学)于1991年发明。PNA的骨架由通过肽键连接的重复的N-(2-氨基乙基)-甘氨酸单元组成。各种嘌呤和嘧啶碱基通过亚甲基桥(-CH2-)和羰基((C=O)-)连接到骨架上。
如本文所用,术语“DNA”是指脱氧核糖核酸及其衍生物,该分子携带用于所有已知活生物体和许多病毒的发育、功能和繁殖的大部分遗传指令。大多数DNA分子由两条相互缠绕形成双螺旋的生物聚合物链组成。两条DNA链被称为多核苷酸,因为它们由更简单的被称为核苷酸的单元组成。每个核苷酸都由含氮核碱基-胞嘧啶(C)、鸟嘌呤(G)、腺嘌呤(A)或胸腺嘧啶(T)-以及被称为脱氧核糖的单糖和磷酸基团组成。核苷酸通过一个核苷酸的糖和下一个核苷酸的磷酸之间的共价键彼此连接成一条链,从而形成交替的糖-磷酸骨架。根据碱基配对规则(A与T,C与G),氢键结合两条独立多核苷酸链的含氮碱基,形成双链DNA。
如本文所用,术语“折叠体”是指在溶液中折叠成构象有序状态的离散的链分子或低聚物。它们是模拟蛋白质、核酸和多糖的能力以折叠成明确定义的构象(例如螺旋和β-折叠)的人造分子。非相邻单体之间的非共价相互作用稳定了折叠体的结构。
如本文所用,术语“碳水化合物”是指由碳(C)、氢(H)和氧(O)原子组成的生物分子,通常氢:氧原子的比例为2:1(如在水中);换句话说,具有经验公式Cm(H2O)n(其中m可能不同于n)。存在一些例外;例如,脱氧核糖,DNA的糖组分,其经验式为C5H10O4。碳水化合物在技术上是碳的水合物;在结构上,将它们视为多羟基醛和酮更为准确。该术语在生物化学中最常见,它是糖类(其为包括糖、淀粉和纤维素的组)的同义词。糖类分为四个化学组:单糖、双糖、寡糖和多糖。
如本文所用,术语“非利平斯基分子”是指不符合利平斯基五规则(Lipinski'srule of five)(也称为辉瑞五规则(Pfizer's rule of five)或简称为五规则(Rule offive,RO5))的分子,所述规则是评估药物相似性或确定具有某种药理或生物活性的化合物是否具有使其成为人类可能的口服活性药物的特性的经验法则。该规则由ChristopherA.Lipinski于1997年基于观察到大多数口服药物是相对较小且中等亲脂性的分子制定。该规则描述了对药物在人体内的药代动力学很重要的分子特性,包括它们的吸收、分布、代谢和排泄(absorption,distribution,metabolism,and excretion,“ADME”)。但是,该规则不能预测化合物是否具有药理活性。
如本文所用,术语“酸不稳定的”是指键在酸性条件下,例如pH<7时断裂。
如本文所用,术语“直接键合(direct bond)”是指没有中间原子。因此,例如,重复单元和药物之间的直接键合意味着药物的官能团连接到重复单元的原子上,即中间没有使用连接基团。
如本文所用,术语“C1-20烃基”是指包含氢和1至20个碳原子的任何一价烃基。因此,烃基由碳和氢组成。烃基的实例包括烷基、环烷基、芳基、芳烷基、烯基和炔基基团。
如本文所用,术语“烷基”是指具有前缀中所示碳原子数的直链或支链饱和一价烃基。因此,术语“C1-4烷基”是指一到四个碳原子的直链饱和一价烃基或者三或四个碳原子的支链饱和一价烃基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。优选地,烷基为C1-20烷基,更优选地为C1-12烷基,仍更优选地为C1-8烷基,最优选地为C1-4烷基。
如本文所用,术语“亚烷基”是指具有前缀中所示碳原子数的直链饱和二价烃基或支链饱和二价烃基,例如亚甲基、亚乙基、亚丙基、1-甲基亚丙基、2-甲基亚丙基、亚丁基、亚戊基等。优选地,亚烷基基团是C1-20亚烷基基团,更优选地C1-12亚烷基基团,仍更优选地C1-8亚烷基基团,最优选地C1-4亚烷基基团。
如本文所用,术语“烯基”是指具有前缀中所示的碳原子数并包含至少一个双键的直链或支链饱和一价烃基。因此,术语“C2-6烯基”是指具有至少一个双键的二至六个碳原子的直链饱和一价烃基,或具有至少一个双键的三至六个碳原子的支链饱和一价烃基,例如乙烯基、丙烯基、1,3-丁二烯基、(CH2)2CH=C(CH3)2、CH2CH=CHCH(CH3)2等。优选地,烯基基团是C2-20烯基基团,更优选地C2-12烯基基团,仍更优选地C2-8烯基基团,最优选地C2-4烯基基团。
如本文所用,术语“亚烯基”是指具有前缀中所示的碳原子数并包含至少一个双键的直链饱和二价烃基或支链饱和二价烃基,例如亚乙烯基(ethenylene)、亚丙烯基(propenylene)、1-甲基亚丙烯基(1-methylpropenylene)、2-甲基亚丙烯基(2-methylpropenylene)、亚丁烯基(butenylene)、亚戊烯基(pentenylene)等。优选地,亚烯基基团是C2-20亚烯基基团,更优选地C2-12亚烯基基团,仍更优选地C2-8亚烯基基团,最优选地C2-4亚烯基基团。
如本文所用,术语“炔基”是指具有前缀中所示碳原子数并包含至少一个三键的直链或支链饱和一价烃基。因此,术语“C2-6炔基”是指具有至少一个三键的二至六个碳原子的直链饱和一价烃基,或具有至少一个双键的四至六个碳原子的支链饱和一价烃基,例如乙炔基、丙炔基等。优选地,炔基基团是C2-20炔基基团,更优选地C2-12炔基基团,仍更优选地C2-8炔基基团,最优选地C2-4炔基基团。
如本文所用,术语“亚炔基(alkynylene)”是指具有前缀中所示碳原子数并含有至少一个三键的直链饱和二价烃基或支链饱和二价烃基,例如亚乙炔基(ethynylene)、亚丙炔基(propynylene)、1-甲基亚丙炔基(1-methylpropynylene)、2-甲基亚丙炔基(2-methylpropynylene)、亚丁炔基(butynylene)、亚戊炔基(pentynylene)等。优选地,亚炔基基团是C2-20亚炔基基团,更优选地C2-12亚炔基基团,仍更优选地C2-8亚炔基基团,最优选地C2-4亚炔基基团。
如本文所用,术语“环烷基”是指三至十个碳原子的环状饱和一价烃基,例如环丙基、环丁基、环戊基或者环己基等。
如本文所用,术语“亚环烷基(cycloalkylene)”是指三至十个碳原子的环状饱和二价烃基,例如亚环丙基(cyclopropylene)、亚环丁基(cyclobutylene)、亚环戊基(cyclopentylene)或亚环己基(cyclohexylene)等。优选地,亚环烷基基团是C3-10亚环烷基基团,更优选地C3-8亚环烷基基团,最优选地C3-6亚环烷基基团。
如本文所用,术语“杂环基(heterocycyl)”是指4至8个环原子的饱和或不饱和单价单环基团,其中一个或两个环原子是选自N、O或S(O)n的杂原子,其中n是0至2的整数,其余的环原子为C。杂环基环任选地稠合至如本文定义的(一个)芳基或杂芳基环,条件是芳基和杂芳基环是单环的。此外,杂环基环中的一个或两个环碳原子可以任选地被-CO-基团替代。更具体地,术语杂环基包括但不限于吡咯烷基(pyrrolidino)、哌啶基(piperidino)、高哌啶基(homopiperidino)、2-氧代吡咯烷基(2-oxopyrrolidinyl)、2-氧代哌啶基(2-oxopiperidinyl)、吗啉基(morpholino)、哌嗪基(piperazino)、四氢吡喃基、硫代吗啉基等。当杂环基环不饱和时,它可以包含一个或两个环双键,条件是该环不是芳香环。
如本文所用,术语“亚杂环基(heterocyclylene)”是指4至8个环原子的饱和或不饱和二价单环基团,其中一个或两个环原子是选自N、O或S(O)n的杂原子,其中n是0至2的整数,其余环原子为C。亚杂环基环任选稠合至如本文定义的(一个)芳基或杂芳基环,条件是芳基环和杂芳基环是单环的。此外,亚杂环基环中的一个或两个环碳原子可以任选地被-CO-基团替代。更具体地,术语亚杂环基包括但不限于吡咯烷基亚基(pyrrolidinylene)、哌啶基亚基(piperidinylene)、高哌啶基亚基(homopiperidinylene)、2-氧代吡咯烷基亚基(2-oxopyrrolidinylene)、2-氧代哌啶基亚基(2-oxopiperidinylene)、吗啉基亚基(morpholinylene)、哌嗪基亚基(piperazinylene)、四氢吡喃基亚基(tetrahydropyranylene)、硫代吗啉基亚基(thiomorpholinylene)等。当亚杂环基环不饱和时,它可以含有一个或两个环双键,条件是该环不是芳香环。
如本文所用,术语“芳基”指含有6到10个环原子的一价单环或双环芳族烃基,例如苯基或者萘基等。
如本文所用,术语“亚芳基(arylene)”指6到10个环原子的二价单环或双环芳族烃基,例如苯基或者萘基等。优选地,亚芳基基团是亚苯基或者亚萘基。
如本文所用,术语“芳烷基(aralkyl)”指-(亚烷基)-R基,其中R是如上定义的芳基。优选地,亚烷基基团是C1-20亚烷基基团,更优选地C1-12亚烷基基团,仍更优选地C1-8亚烷基基团,最优选地C1-4亚烷基基团。
如本文所用,术语“亚芳烷基(aralkylene)”指-(亚烷基)-R二价基,其中R是如上定义的亚芳基。优选地,亚芳烷基基团是C7-20亚芳烷基基团,更优选地C7-14亚芳烷基基团,最优选地C7-10亚芳烷基基团。
如本文所用,术语“杂芳基(heteroaryl)”指5到10个环原子的一价单环或双环芳族基,其中一个或多个,优选地一个、两个或三个环原子是选自N、O或S的杂原子,剩余的环原子是碳。代表性实例包括但不限于吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、异吲哚基、恶唑基、异恶唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、四唑基等。
如本文所用,术语“亚杂芳基(heteroarylene)”是指5到10个环原子的二价单环或双环芳族基,其中一个或多个,优选地一个、两个或三个环原子是选自N、O或S的杂原子,剩余的环原子是碳。代表性实例包括但不限于吡咯基亚基(pyrrolylene)、噻吩基亚基(thienylene)、噻唑基亚基(thiazolylene)、咪唑基亚基(imidazolylene)、呋喃基亚基(furanylene)、吲哚基亚基(indolylene)、异吲哚基亚基(isoindolylene)、恶唑基亚基(oxazolylene)、异恶唑基亚基(isoxazolylene)、苯并噻唑基亚基(benzothiazolylene)、苯并恶唑基亚基(benzoxazolylene)、喹啉基亚基(quinolinylene)、异喹啉基亚基(isoquinolinylene)、吡啶基亚基(pyridinylene)、嘧啶基亚基(pyrimidinylene)、吡嗪基亚基(pyrazinylene)、哒嗪基亚基(pyridazinylene)、三唑基亚基(triazolylene)、四唑基亚基(tetrazolylene)等。
如本文所用,术语“杂芳烷基(heteroaralkyl)”指-(亚烷基)-R基,其中R是如上定义的杂芳基。优选的亚烷基基团是如上关于芳烷基基团定义。
如本文所用,术语“亚杂芳烷基(heteroaralkylene)”指-(亚烷基)-R二价基,其中R是如上定义的亚杂芳基。优选地,亚杂芳烷基基团是C6-20亚杂芳烷基基团,更优选地C6-14亚杂芳烷基基团,最优选地C6-10亚杂芳烷基基团。
任选的可以在烷基、亚烷基、烯基、亚烯基、炔基(alkylnyl)、亚炔基、环烷基、亚环烷基、杂环基、亚杂环基、芳基、亚芳基、芳烷基、亚芳烷基、杂芳基、亚杂芳基、杂芳烷基和亚杂芳烷基基团上存在的取代基包括C1-16烷基或者C1-16环烷基(其中一个或多个不相邻的C原子可以被O、S、N、C=O和-COO-替代)、取代或未取代的C5-14芳基、取代或未取代的C5-14杂芳基、C1-16烷氧基、C1-16烷硫基、卤素、氰基和芳烷基。
如本文所用,术语“烷氧基”是指-OR基团,其中R是如上定义的烷基,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。优选地,烷氧基为C1-20烷氧基基团,更优选地为C1-12烷氧基基团,仍更优选地为C1-8烷氧基基团,最优选地为C1-4烷氧基基团。
如本文所用,术语“烷硫基”是指-SR基团,其中R是如上定义的烷基。优选地,烷硫基为C1-20烷硫基基团,更优选地为C1-12烷硫基基团,仍更优选地为C1-8烷硫基基团,最优选地为C1-4烷硫基基团。
如本文所用,术语“卤素”是指氟、氯、溴或碘,优选地氟或氯。
如本文所用,术语“酮基”是指羰基基团,其中羰基的碳原子还与两个碳原子结合。
如本文所用,术语“肼”是指式-NH-NH2的基团。
如本文所用,术语“酰肼”是指式R’(CO)-NH-NH2的基团,其中R’可以是氢或C1-20烃基。
如本文所用,术语“腙”是指式=N-NH-的基团。
如本文所用,术语“胺”是指式-NH2、NHR或NR2的基团,其中R为C1-20烃基基团。
如本文所用,术语“亚胺”是指式=N-的基团。
如本文所用,术语“羟基”是指式-OH的基团。
如本文所用,术语“缩酮”是指式-C(OR)2-的基团,其中每个R为C1-20烃基或两个R基团一起形成烃基环。
如本文所用,术语“硫醇”是指式-SH的基团。
如本文所用,术语“硫缩酮(thioketal)”是指式-C(SR)2-的基团,其中每个R为C1-20烃基或两个R基团一起形成烃基环。
如本文所用,术语“肟”是指式=N-O-的基团。
如本文所用,术语“氨氧基(aminoxy)”或“羟胺”是指式-O-NH2的基团。R-O-NH2是指烷氧基胺。
如本文所用,应用于聚合物的术语“Mn”是指聚合物的数均分子量。
如本文所用,应用于聚合物的术语“Mw”是指聚合物的重均分子量。
如本文所用,术语“多分散度”(也称为PD或)是指聚合物的重均分子量与数均分子量的比值,即它是聚合物样品均匀性的量度。低多分散度表示聚合物样品内的窄的分子质量分布,而高多分散度表示聚合物样品内的宽的分子质量分布。
抗体-药物缀合物
本发明涉及一种抗体-药物缀合物,其包含(i)抗体或其抗原结合片段,(ii)包含特定的重复单元的聚合物,其共价结合(任选地通过接头)至一个或多个生物活性部分,例如小分子药物,和(iii)聚合物-抗体接头部分,其共价结合至聚合物和抗体或其抗原结合片段。用于将生物活性部分连接到聚合物重复单元的接头基团在本领域中是众所周知的。有利地,直到聚合物与生物活性部分之间或接头基团与生物活性部分之间的共价键断裂,例如水解,生物活性部分才从聚合物中释放出来。生物活性部分的释放位置和生物活性部分的释放速率因此可以通过选择通过如下进行控制:将ADC引导至作用位点的抗体,并调整聚合物与生物活性部分之间的键或者接头基团和生物活性部分之间的键的性质。
本发明的抗体-药物缀合物包含:
(i)抗体或其抗原结合片段;
(ii)包含式(I’)的重复单元的聚合物:
其中:
每个n和每个p独立地为0或1和6之间的整数;
每个m独立地为0或1和4之间的整数,且优选地至少一个m为1;
--------是可能不存在或存在的键;
每个D1独立地是O或L1-B1;
每个D2独立地是O或L2-B2;
每个D3独立地是O或L3-B3;
其中L1是接头基团或键,L2是接头基团或键,L3是接头基团或键,且B1、B2和B3各自是生物活性部分;
条件是,聚合物中的至少一个D1、D2或D3基团不是O,且另一条件是当D1、D2或D3是O时,O原子和它所连接的碳原子之间有一个双键;
每个q是1和8之间的整数;
X和Y独立地选自O、NH、NR’和S;
R’是C1-20烃基;
Q选自-CH2(NMe(C=O)CH2)o-、-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-,其中T1选自二价亚甲基、亚乙基、亚丙基或亚丁基,且T2选自二价亚甲基、亚乙基、亚丙基或亚丁基;
o是0到100的整数;
s是0到150的整数;和
(iii)聚合物-抗体接头,其与抗体和聚合物两者共价结合。
优选地,聚合物包含式(I)的重复单元:
其中,变量X、Y、D1、D2、D3、n、m和p如上所述,且Q选自-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-。
替代地,聚合物包含式(I”)的重复单元:
其中,变量X、Y、Q、D1、D2、D3、n、m和p如上所述。优选地,在式(I”)的重复单元中,Q是CH2(NMe(C=O)CH2)o-。更优选地,Q是CH2(NMe(C=O)CH2)o-且Y是-NMe。
抗体的结构特征
该部分列举了在本发明的抗体-药物缀合物中存在的抗体的可能的结构特征。
本文所指的术语“抗体”包括完整抗体和其任何抗原结合片段(即“抗原结合部分”)或单链,以及其变体。抗体也可称为免疫球蛋白(Ig)。抗体是指包含通过二硫键相互连接的至少两条重(H)链和两条轻链(L)的糖蛋白,或其抗原结合部分。每条重链由重链可变区(本文缩写为VH)和重链恒定区组成。每条轻链由轻链可变区(本文缩写为VL)和轻链恒定区组成。重链和轻链的可变区包含与抗原相互作用的结合域。抗原是引起动物体的免疫系统产生免疫响应的任何试剂,例如化学品、细菌、病毒或花粉。VH区和VL区可以进一步细分为称为互补决定区(CDR)的高变区,其穿插有称为框架区(FR)的更保守的区域。抗体的恒定区可介导免疫球蛋白与宿主组织或因子的结合,宿主组织或因子包括免疫系统的各种细胞(例如效应细胞)和经典补体系统的第一组分(Clq)。
抗体可以是单克隆抗体或多克隆抗体。通常,抗体是单克隆抗体。替代地,抗体是多克隆抗体。多克隆抗体是源自不同B细胞系的抗体。多克隆抗体可以包含针对特定抗原的不同免疫球蛋白分子的混合物。多克隆抗体可包含结合抗原分子内的一个或多个不同表位的不同免疫球蛋白分子的混合物。多克隆抗体可以通过常规方法生产,例如用感兴趣的抗原进行免疫。例如,能够表达抗体的小鼠或绵羊可以用免疫原性缀合物进行免疫。动物可以任选地能够表达人抗体序列。随后可以移除血液并纯化Ig级分以提取多克隆抗体。
单克隆抗体(Monoclonal antibodies,mAb)是彼此相同且对特定表位具有单一结合特异性和亲和力的免疫球蛋白分子。可用于本发明的抗体-药物缀合物的mAb可以通过多种技术生产,包括常规的单克隆抗体方法,例如在“Monoclonal Antibodies;技术手册”,HZola(CRC出版社,1988年)和“Monoclonal Hybridoma Antibodies:Techniques andApplication”,SGR Hurrell(CRC出版社,1982年)中公开的那些。
术语抗体的“抗原结合部分”是指保留与抗原(例如蛋白质、多肽或肽)特异性结合的能力的抗体片段。已经表明,抗体的抗原结合功能可以通过全长抗体的片段来实现。术语抗体的“抗原结合部分”中包含的结合片段的实例包括Fab片段、F(ab')2片段、Fab'片段、Fd片段、Fv片段、dAb片段和分离的互补决定区(CDR)。单链抗体(如scFv)和重链抗体(如VHH)和骆驼抗体也旨在包含在术语抗体的“抗原结合部分”内。这些抗体片段可以使用本领域技术人员已知的常规技术获得,并且可以以与完整抗体相同的方式筛选片段的效用。
如本文所定义的抗体“片段”可以通过截短来制备,例如通过从其N末端和/或C末端去除一个或多个氨基酸。高达10个、高达20个、高达30个、高达40个或更多的氨基酸可以通过这种方式从N末端和/或C末端去除。片段也可以由一个或多个内部缺失产生。片段可包含至少10、至少15、至少20、至少25、至少30、至少35、至少40、至少45、至少55、至少60、至少65、至少70、至少75、至少80、至少85、至少90、至少95、至少100、至少105、至少120、至少150、至少200、至少250、至少300或至少400个连续的来自抗体或抗体变体序列的氨基酸。
优选地,本发明的抗体-药物缀合物中的抗体选自吉妥珠单抗(Gemtuzumab)hP67.6人源化IgG4、本妥昔单抗(Brentuximab)嵌合IgG1、曲妥珠单抗人源化IgG1、奥英妥珠单抗(Inotuzumab)G5/44人源化IgG4、格巴妥木单抗(Glembatumumab)IgG全人源IgG1、柯安妥单抗(Anetumab)抗间皮素全人源IgG1、米妥昔单抗(Mirvetuximabb)M9346A人源化IgG1、迪妥昔珠单抗(Depatuxizumabb)(ABT-806)人源化IgG1、洛伐妥珠单抗(Rovalpituzumab)(SC16)人源化IgG1和伐达妥昔单抗(Vadastuximabb)人源化IgG1。
聚合物的结构特征
本部分列出了本发明的抗体-药物缀合物中存在的聚合物的可能的结构特征。
本发明的抗体-药物缀合物的聚合物衍生自:
(i)式(IIa)的化合物:
其中R1和R2各自独立地为离去基团,并且n、m、p、q和R’如上文对于式(I’)、(I)或(I”)的重复单元所定义的;
(ii)式(IIb)的化合物:
其中X'和Y'独立地选自OH、OR'、SH、SR'、NH2、NHR'和NR'2,并且Q和R'如上文对于式(I’)、(I)或(I”)的重复单元所定义的,
(iii)一种或多种生物活性分子;和
(iv)任选地一种或多种选自HL1-LG、HL2-LG或HL3-LG的化合物,其中L1是接头基团,L2是接头基团,L3是接头基团,且LG是加成-消除反应条件下的离去基团;或
衍生自:
(i)式(IIa’)的化合物:
其中R1是离去基团,X’选自OH、OR'、SH、SR'、NH2、NHR'和NR'2,并且n、m、p、q和R'如上对于式(I')、(I)或(I”)的重复单元所定义的;
(ii)式(IIb')的化合物:
其中R2是离去基团,Y'选自OH、OR'、SH、SR'、NH2、NHR'和NR'2,Q和R'如上式(I')、(I)或(I”)的重复单元所定义的,
(iii)一种或多种生物活性分子;和
(iv)任选地一种或多种选自HL1-LG、HL2-LG或HL3-LG的化合物,其中L1是接头基团,L2是接头基团,L3是接头基团,且LG是加成-消除反应条件下的离去基团。
在本发明的抗体-药物缀合物的聚合物中,q可以是1、2、3、4、5、6、7或8。然而,优选地,q是1、2或3,仍然更优选地1或2,特别优选地1。当q是大于1的整数时,式(I')、(I)或(I”)的重复单元中存在的每个n、m和p可以是相同或不同的。
优选地,q为1。因此,优选地本发明的抗体-药物缀合物的聚合物衍生自式(IIc)或式(IIc’)的化合物:
其中R1、R2、R’、X’、n、m和p如上文关于式(IIa)和式(IIa’)所定义的。
在本发明的抗体-药物缀合物的聚合物中,每个m可以为0、1、2、3或4,条件是至少一个m为1、2、3或4。优选地至少一个m为1。这保证了至少一个酮基存在于式(I')、(I)或(I”)的重复单元中。优选地,每个m是1或2,更优选地每个m是1。当m是1并且n和p都是1或更大时,酮基被至少一个碳原子隔开,并且相信这避免了聚合物上连接的生物活性部分之间的空间冲突。
本发明的抗体-药物缀合物的聚合物中,每个n为0、1、2、3、4、5或6。优选地每个n为1、2或3,更优选地1或2。在本发明的抗体-药物组合物的聚合物中,每个p为0、1、2、3、4、5或6。优选地每个p为0、1或2,并且更优选地0或1。甚至更优选地,每个p为0。n和p基团将酮基隔开,并有利地使相对大量的生物活性分子共价结合至聚合物。
聚合物优选地衍生自式(IIa)、(IIa')、(IIc)或(IIc')的化合物,其中R1选自Cl、OH、OR'、SH、SR'、NH2、NHR'、NR'2、O-2-Cl-Trt、ODmb、O-2-PhiPr、O-EDOTn-Ph、OFm、ODmab和OCam。仍更优选地,R1选自OMe、OEt、OtBu、O-2-Cl-Trt、ODmb、O-2-PhiPr、O-EDOTn-Ph、OFm、ODmab和OCam。进一步优选的聚合物衍生自式(IIa)或(IIc)的化合物,或式(IIb')的化合物,其中R2选自Cl、OH、OR'、SH、SR'、NH2、NHR'、NR'2、O-2-Cl-Trt、ODmb、O-2-PhiPr、O-芳基-EDOTn、OFm、ODmab和OCam。仍更优选地,R2选自OMe、OEt、OtBu、O-2-Cl-Trt、ODmb、O-2-PhiPr、O-EDOTn-Ph、OFm、ODmab和OCam。R1和R2可以相同或者可以不同,但优选地是相同的。仍更优选地,R1和R2均选自OMe、OEt、OtBu、O-2-Cl-Trt、ODmb、O-2-PhiPr、O-芳基-EDOTn、OFm、ODmab和OCam。式(IIa’)化合物的一个实例是氨基-2-酮丁酸。
如本文所定义,2-Cl-Trt是指2-氯三苯甲基。如本文所定义,Dmb是指2,4-二甲氧基苄基。如本文所定义,2-PhiPr是指2-苯异丙基。如本文所定义,Fm是指9-芴基甲基。如本文所定义,Dmab是指4-(N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]-氨基)苄基。如本文所定义,Cam是指氨甲酰甲基。如本文所定义,芳基-EDOTn是指具有下式的部分:
其中R3是H或OMe,R4是H或OMe且R5是H或OMe。优选地,R3、R4和R5被选择使得(a)R3、R4和R5全部是H,(b)R3、R4和R5全部是OMe,(c)R3和R4是OMe且R5是H,或(d)R3和R4是H且R5是OMe。
当R1和/或R2包含R’基团时,R’优选地是C1-20烷基,更优选地C1-12烷基,仍更优选地C1-8烷基且尤其优选地C1-4烷基。合适的烷基基团的代表性示例包括甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。甲基、乙基和叔丁基是特别优选的烷基基团。
聚合物优选地衍生自式(IIb)或(IIb’)的化合物,其中T1为-CH2-、-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-,更优选地,其中T1为-CH2CH2-或-CH2CH2CH2-。聚合物优选地衍生自式(IIb)或(IIb’)的化合物,其中T2为-CH2-、-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-,更优选地,其中T2为-CH2CH2-或-CH2CH2CH2-。T1和T2可以相同或不同。优选地,T1和T2是相同的。通常,聚合物衍生自式(IIb)的化合物,其中T1和T2均选自-CH2-、-CH2CH2-、-CH2CH2CH2-和-CH2CH2CH2CH2-,优选地,其中T1和T2均选自-CH2CH2-和-CH2CH2CH2-,以及更优选地,其中T1和T2都是-CH2CH2CH2-。替代地,聚合物可以衍生自式(IIb)或(IIb')的化合物,其中Q是CH2(NMe(C=O)CH2)o-。
聚合物进一步优选地衍生自式(IIb)的化合物,其中X’是OH、OR’、NH2或NHR’。仍更优选地X’是OH或NH2。进一步优选的聚合物衍生自式(IIb)或(IIb’)的化合物,其中Y’是OH、OR’、NH2或NHR’。仍更优选地Y’是OH或NH2。X’和Y’可以相同或可以不同,但优选地是相同的。仍更优选地X’和Y’都是OH。因此,在一个优选的实施方式中,式(IIb)的化合物是聚乙二醇(PEG)或聚丙二醇。优选地在这种情况下,式(IIb)化合物选自PEG 400、PEG 500、PEG 600、PEG 1000、PEG 1500、PEG 2000、PEG 3000、PEG 4000和PEG 5000。仍更优选地,X'和Y'都是NH2。仍更优选地,X’和Y’都是NH2且T1和T2都是-CH2CH2CH2-。在这种情况下,式(IIb)的化合物是聚(乙二醇)双(3-氨基丙基)或聚(丙二醇)双(3-氨基丙基)。最优选地,X’和Y’都是NH2,Q是-CH2CH2CH2O(CH2CH2O)sCH2CH2CH2-。在这种情况下,式(IIb)的化合物是聚(乙二醇)双(3-氨基丙基)。优选地,聚(乙二醇)双(3-氨基丙基)的分子量为1000至2000,更优选地的分子量为1500,即,是(聚(乙二醇)双(3-氨基丙基)封端的)1500。在另一个优选的实施方式中,聚合物衍生自式(IIb')的化合物,其中Q是CH2(NMe(C=O)CH2)o-并且Y'是-NH2或-NHR',优选地-NHR',更优选地-NHMe。仍更优选地,Q为CH2(NMe(C=O)CH2)o-,Y'为-NHMe,且R2为OH或OR'。在这种情况下,式(IIb')的化合物是聚(肌氨酸)或其酯。优选地,聚(肌氨酸)的分子量为350至1800。
o优选地为0至100的整数,更优选地为1至75的整数,仍更优选地为2至50的整数,最优选地为5至25的整数。
s优选地为0至150的整数,更优选地为1至100的整数,仍更优选地为1至50的整数,仍更优选地为1至35的整数,甚至更优选地为3至30的整数,最优选地为5到21的整数。
优选地,聚合物衍生自2-氧-戊二酸二甲酯或3-氧-戊二酸二甲酯。进一步优选的聚合物衍生自聚(乙二醇)或聚(乙二醇)双(3-氨基丙基)。最优选地,聚合物衍生自2-氧-戊二酸二甲酯和聚(乙二醇)、2-氧-戊二酸二甲酯和聚(乙二醇)双(3-氨基丙基)、3-氧-戊二酸二甲酯和聚(乙二醇)或3-氧-戊二酸二甲酯和聚(乙二醇)双(3-氨基丙基)。
在式(I’)、(I)或(I”)的重复单元中,虚线键可以存在或可以不存在。当它不存在时,存在键合至D1、D2和/或D3部分的单键。当它存在时,存在键合至D1、D2和/或D3部分的双键,或键合至D1、D2和/或D3部分内不同原子的两个单键。当D1、D2或D3是氧原子时,氧原子与其连接的碳原子之间存在双键。优选地,当D1为L1-B1、D2为L2-B2或D3为L3-B3时,存在虚线键。替代地,当D1为L1-B1、D2为L2-B2或D3为L3-B3时,不存在虚线键。
优选地,式(I’)、(I)或(I”)的重复单元是式(I-i’)的重复单元,例如式(I-i)的重复单元或式(I-I”)的重复单元,其中式(I’)、(I)或(I”)中的q为1:
其中n、m、p、V、D1、D2、D3、X、Y和Q如上关于式(I’)、式(I)或式(I”)所定义的。
在式(I')、(I)、(I”)(I-i')、(I-i)或(I-i”)的聚合物重复单元中,每个D1独立地为O或L1-B1、每个D2独立地为O或L2-B2,且每个D3独立地为O或L3-B3,其中每个L1、L2和L3为接头基团或键,且每个B1、B2和B3为生物活性部分(例如药物)。一旦生物活性分子(例如药物)与聚合物重复单元的骨架或接头基团(如果存在)形成共价键,则生物活性部分是衍生自所述生物活性分子(例如药物)的部分。当聚合物重复单元或接头基团与B1、B2或B3之间的键断裂时,释放出化合物H-B1、H-B2或H-B3,其为生物活性分子。因此,如本文所用,“生物活性分子”是连接到氢原子而不是连接到聚合物重复单元或接头基团的所述生物活性部分。
通常,每个L1、L2和L3是键。因此,通常L1是键。通常L2是键。通常L3是键。如果L1、L2或L3是键,这意味着D1、D2或D3分别是B1、B2或B3,即生物活性部分。在这种情况下,所述生物活性部分通常可通过生物活性分子H-B1、H-B2或H-B3与式(IIa)、(IIa')、(IIc)或(IIc')的化合物中的羰基、优选地酮基基团反应而获得,聚合物重复单元衍生自式(IIa)、(IIa')、(IIc)或(IIc')的化合物。通常,每个B1、B2和B3是可通过药物分子内的亲核体与式(IIa)、(IIa')、(IIc)或(IIc')的化合物中的亲电羰基碳原子之间的缩合而获得的部分,聚合物重复单元衍生自式(IIa)、(IIa')、(IIc)或(IIc')的化合物。
然而,优选地,每个L1、L2和L3是接头基团。换句话说,本发明的抗体-药物缀合物通常包括聚合物主链和生物活性部分之间的接头。因此,优选地,L1是接头基团。优选地,L2是接头基团。优选地,L3是接头基团。如果L1、L2或L3是接头基团,则该接头基团可以是适合于通过共价键联接将生物活性部分连接到聚合物主链的任何接头基团。这样的接头基团是本领域公知的。优选地,L1的分子量为14Da至4000Da,更优选地为28Da至2000Da,仍更优选地为50Da至1000Da,仍更优选地为100Da至500Da。优选地,L2的分子量为14Da至4000Da,更优选地为28Da至2000Da,仍更优选地为50Da至1000Da,仍更优选地为100Da至500Da。优选地,L3的分子量为14Da至4000Da,更优选地为28Da至2000Da,仍更优选地为50Da至1000Da,仍更优选地为100Da至500Da。
优选的接头基团选自=N-NH-Z1-L’-Z2-、=N-O-Z1-L’-Z2-、=N-Z1-L’-Z2-、-NH-NH-Z1-L’-Z2-、-NH-O-Z1-L’-Z2-、-NH-Z1-L’-Z2-、-O-Z1-L’-Z2-、
L'选自键、C1-20亚烷基、C1-20亚烯基、C1-20亚炔基、C6-10亚芳基(例如亚苯基或亚萘基)、C7-20亚芳烷基、C3-10亚环烷基、C4-8亚杂环烷基、C5-10亚杂芳基、C6-20亚杂芳烷基、-(OK)i-、-(NH-K)i-、-(NR'-K)i-、分子量为116至2000Da的聚酯、分子量为114至2000Da的聚酰胺和-W-部分,其中HW-OH是氨基酸或含有2到20个天然存在或合成的氨基酸亚基的肽;
Z1选自-Z(C=O)-、-Z-O(C=O)-、-Z-NH(C=O)-、-Z-NR’(C=O)-、-ZS(C=O)-、-Z-(C=NH)-、ZO(C=NH)-、-Z-NH(C=NH)-、-Z-NR'(C=NH)-、-ZS(C=NH)-和-Z-(C=NR')-、-K-(O-K)i-、-K-(NH-K)i-、-K-(NR'-K)i-、-K(C=O)-(OK-(C=O))i-、-K(C=O)-(NH-K-(C=O))i-、-K(C=O)-(NR'-K-(C=O))i-和-P-部分,其中H2N-P-OH是氨基酸或者包含2至20个天然存在或合成的氨基酸亚基的肽;
Z2选自键、-OZ-、-NHZ-、-NR’Z-、-SZ-、-S-、-ZS-、-OZS-、-NHZS-、-NR'ZS-、-SZS-、-Z(C=O)-、-ZO(C=O)-、-Z-NH(C=O)-、-Z-NR'(C=O)-、-ZS(C=O)-、-Z-(C=NH)-、Z-O(C=NH)-、-Z-NH(C=NH)-、-Z-NR’(C=NH)-、-Z-S(C=NH)-、-Z-(C=NR')-、-ZO(C=NR')-、-Z-NH(C=NR')-、-Z-NR'(C=NR')-、-ZS(C=NR')-、-OZ(C=O)-、-OZ-O(C=O)-、-OZ-NH(C=O)-、-OZ-NR'(C=O)-、-OZ-S(C=O)-、-OZ-(C=NH)-、OZ-O(C=NH)-、-OZ-NH(C=NH)-、-OZ-NR'(C=NH)-、-OZ-S(C=NH)-、-OZ-(C=NR')-、-OZ-O(C=NR')-、-OZ-NH(C=NR')-、-OZ-NR'(C=NR')-、-OZ-S(C=NR')-、-NHZ(C=O)-、-NHZ-O(C=O)-、-NHZ-NH(C=O)-、-NHZ-NR'(C=O))-、-NHZ-S(C=O)-、-NHZ-(C=NH)-、NHZ-O(C=NH)-、-NHZ-NH(C=NH)-、-NHZ-NR’(C=NH)-、-NHZ-S(C=NH)-、-NHZ-(C=NR')-、-NHZ-O(C=NR')-、-NHZ-NH(C=NR')-、-NHZ-NR'(C=NR')-、-NHZ-S(C=NR')-、-NR'Z-(C=O)-、-NR'Z-O(C=O)-、-NR'Z-NH(C=O)-、-NR'Z-NR'(C=O)-、-NR'Z-S(C=O)-、-NR'Z-(C=NH)-、-NR'Z-O(C=NH)-、-NR'Z-NH(C=NH)-、-NR'Z-NR'(C=NH)-、-NR'Z-S(C=NH)-、-NR'Z-(C=NR')-、-NR'Z-O(C=NR')-、-NR'Z-NH(C=NR')-、-NR'Z-NR'(C=NR'))-、-NR'ZS(C=NR')-、-SZ-(C=O)-、-SZ-O(C=O)-、-SZ-NH(C=O)-、-SZ-NR'(C=O)-、-SZ-S(C=O)-、-SZ-(C=NH)-、SZ-O(C=NH)-、-SZ-NH(C=NH)-、-SZ-NR'(C=NH)-、-SZ-S(C=NH)-、-SZ-(C=NR')-、-SZ-O(C=NR')-、-SZ-NH(C=NR')-、-SZ-NR'(C=NR')-、-SZ-S(C=NR')-、-J-O(C=O)-、-O-J-O(C=O)-、-S-J-O(C=O)-、-NH-J-O(C=O)-、-NR’-J-O(C=O)-、聚醚,例如分子量为76至2000Da的聚(亚烷基二醇)、分子量为75至2000Da的聚胺、分子量为116至2000Da的聚酯、分子量为114到2000Da的聚酰胺,和-W-部分,其中H-W-OH是氨基酸或包含2到20个天然存在或合成的氨基酸亚基的肽;
Z选自C1-20亚烷基、C1-20亚烯基、C1-20亚炔基、C6-10亚芳基(例如亚苯基或亚萘基)、C7-20亚芳烷基、C3-10亚环烷基、C4-8亚杂环烷基、C5-10亚杂芳基和C6-20亚杂芳烷基;
J是苯基基团,其带有糖取代基以及相对于糖取代基为对位或邻位的亚甲基基团或-(CH=CH)k-CH2-部分,其中k是1至10的整数,进一步地,其中亚甲基基团或-(CH=CH)k-CH2-部分直接键合至接近生物活性部分B1、B2或B3的-O(C=O)-基团,以及苯基环的碳直接键合至接头基团远离生物活性部分B1、B2或B3的其余部分;
每个K相同或不同,且代表C1-10亚烷基;
i为1至100的整数,优选地1至50的整数,更优选地2至20的整数;
v为0至4的整数,优选地1或2;和
R’是C1-20烃基。
更优选地,接头基团为=NO-Z1-L'-Z2-,其中Z1和L'如上限定的,且Z2选自-Z(C=O)-、-ZO(C=O)-、-Z-NH(C=O)-、-Z-NR'(C=O)-、-ZS(C=O)-、-OZ-(C=O)-、-OZ-O(C=O)-、-OZ-NH(C=O)-、-OZ-NR'(C=O)-、-OZ-S(C=O)-、-NHZ-(C=O)-、-NHZ-O(C=O)-、-NHZ-NH(C=O)-、-NHZ-NR'(C=O)-、-NHZ-S(C=O)-、-NR'Z-(C=O)-、-NR'ZO(C=O)-、-NR'Z-NH(C=O)-、-NR'Z-NR'(C=O)-、-NR'Z-S(C=O)-、SZ-(C=O)-、-SZ-O(C=O)-、-SZ-NH(C=O)-、-SZ-NR’(C=O)-、-SZ-S(C=O)-、-J-O(C=O)-、-O-J-O(C=O)-、-S-J-O(C=O)-、-NH-JO(C=O)-、-NR'-JO(C=O)-、分子量为116Da至2000Da的聚酯、分子量为114Da至2000Da的聚酰胺,和-W-部分,或者,当L’是-W-部分时,Z2可以另外是一个键。优选地,接头基团为=N-O-Z1-L’-Z2-并且接头的远离=N-O-部分的端部以羰基终止。
特别优选的接头基团选自=N-NH-CH2-(C=O)-Val-Cit-PAB-(C=O)-、=NO-CH2-(C=O)-Val-Cit-PAB-(C=O)-、=N-CH2-(C=O)-Val-Cit-PAB-(C=O)-、-NH-NH-CH2-(C=O)-Val-Cit-PAB-(C=O)-、-NH-O-CH2-(C=O)-Val-Cit-PAB-(C=O)-和-NH-CH2-(C=O)-Val-Cit-PAB-(C=O)-,其中-Val-Cit-PAB-具有以下结构:
这是聚合物-药物缀合物领域众所周知的接头基团。
最优选地,接头基团为=N-O-CH2-(C=O)-Val-Cit-PAB-(C=O)-。
优选地,J部分是带有在糖取代基的对位或邻位的亚甲基基团的苯基基团。更优选地,亚甲基基团位于糖取代基的对位。甚至更优选地,J部分中的糖取代基通过氧原子与苯基基团键合,该氧原子也直接与糖的异头碳原子键合。仍更优选地,糖取代基是六碳糖。仍更优选地,糖取代基选自可通过酶作用转化为羟基取代基的糖取代基,例如葡萄糖醛酸(可通过β-葡萄糖醛酸酶的作用裂解)。最优选地,J部分的结构如下:
包含J部分的特别优选的接头基团选自以下结构:
其中R6选自任何氨基酸R基团或其衍生物,例如H、CH3、CH(CH3)2、CH2CH(CH3)2、CH(CH3)CH2CH3、CH2Ph、CH2NH2、CH2OH、CH2SH、CH(OH)CH3、CH2CH2SCH3、CH2CONH2、CH2CH2CONH2、CH2COOH、CH2CH2COOH、(CH2)3NH(CN)NH2、(CH2)4NH2、(CH2)3NH2、优选地,R6选自H、CH3和CH2NH2,且更优选地CH2NH2。
具有选自-NH-NH-Z1-L’-Z2-、-NH-O-Z1-L’-Z2-和-NH-Z1-L’-Z2-的接头基团的聚合物-药物缀合物可通过将分别具有式=N-NH-Z1-L’-Z2-、=N-O-Z1-L’-Z2-或=N-Z1-L’-Z2-的接头的聚合物-药物缀合物还原而得到。
为避免疑问,在接头基团的上述定义中,绘制的接头基团的左手侧(针对环状缩醛和环状硫缩醛所绘制的接头基团的顶部)连接到抗体-药物缀合物的聚合物主链上,并且所绘制的接头基团的右手侧(针对环状缩醛和环状硫缩醛所绘制的接头基团的底部)连接到生物活性部分B1、B2或B3。在对接头-Val-Cit-PAB-的上面描述中,左手侧显示到缬氨酸(Val)的外部键,顶部显示到对-氨基苯甲醇(PAB)的外部键。在上面对包含J部分的优选接头基团的描述中,左下角显示与聚合物主链的连接,右上角显示与生物活性部分B1、B2或B3的连接。
通常,L’的分子量为14Da至2000Da,优选地为28Da至1000Da,更优选地为50Da至500Da,仍更优选地为100Da至300Da。通常,Z1的分子量为14Da至2000Da,优选地为28Da至1000Da,更优选地为50Da至500Da,仍更优选地为100Da至300Da。通常,Z2的分子量为14Da至2000Da,优选地为28Da至1000Da,更优选地为50Da至500Da,仍更优选地为100Da至300Da。
当L1、L2或L3是接头基团时,L1、L2或L3通常衍生自式HL1-LG、HL2-LG或HL3-LG的化合物。LG是加成消除反应条件下的离去基团。加成-消除条件是本领域技术人员公知的。通常,加成消除条件是如下的任何反应条件:亲核(即富电子)部分可以加成到不饱和碳原子上以与该碳原子形成共价σ-键,导致与碳原子的π-键断裂,且随后重新形成所述π-键并同时使所述碳原子与它的其他取代基之一之间的σ-键断裂,以消除该取代基,所述其他取代基之一通常是净吸电子部分。优选地,LG选自卤素(优选地Cl)、OH、OR'、SH、SR'、NH2、NHR'、NR'2、O-2-Cl-Trt、ODmb、O-2-PhiPr、O-EDOTn-Ph、OFm、ODmab和OCam,其中R'、2-Cl-Trt、Dmb、EDOTn-Ph、Fm、Dmab和OCam如上所定义。
通常,聚合物重复单元或接头单元与B1、B2或B3之间的键是酸不稳定的。优选地,在这种情况下,键在各种细胞(例如巨噬细胞)中发现的例如溶酶体、内体、吞噬体、吞噬溶酶体和自噬体等细胞区室的酸性和/或水解环境中水解。优选地,在这种情况下,聚合物重复单元或接头单元与B1、B2或B3之间的键在<6的pH下水解,仍更优选地在<5的pH下水解。在酸性环境中水解的键的实例是腙键。
替代地,聚合物重复单元或接头单元与B1、B2或B3之间的键在中性条件下是不稳定的。优选地,在这种情况下,聚合物重复单元或接头单元与B1、B2或B3之间的键在中性pH下水解,优选地在6.5至7.5的pH时。
替代地,聚合物重复单元或接头单元与B1、B2或B3之间的键是碱不稳定的。优选地,聚合物重复单元或接头单元与B1、B2或B3之间的键在>8的pH下水解,更优选地在>9的pH下水解。
键水解的最佳pH将取决于相关键的精确化学性质。
替代地,聚合物重复单元或接头单元与B1、B2或B3之间的键在酶的存在下水解。优选地,在这种情况下,聚合物重复单元或接头单元与B1、B2或B3之间的键被组织蛋白酶B水解。被组织蛋白酶B酶促水解的键的实例是肽键。
替代地,聚合物重复单元或接头单元与B1、B2或B3之间的键抗水解。例如,聚合物重复单元或接头单元与B1、B2或B3之间的键可以通过与细胞内硫醇(例如谷胱甘肽)的二硫键交换而裂解。可以以这种方式裂解的键的实例是二硫键。替代地,聚合物重复单元或接头单元与B1、B2或B3之间的键可以通过细胞内蛋白水解降解而裂解。可以以这种方式裂解的键的实例是硫醚键。
聚合物重复单元或接头单元与B1、B2或B3之间的键的裂解释放所述生物活性分子(例如药物)。优选地,聚合物重复单元与B1、B2或B3部分之间存在接头基团。更优选地,重复单元与接头部分L1、L2或L3之间的键是双键。替代地,L1、L2或L3为键,即聚合物重复单元与B1、B2或B3部分之间存在直接键。在这种情况下,重复单元与B1、B2或B3部分之间的键优选地为双键。
优选地,衍生聚合物重复单元的生物活性分子包含能够与式(IIa)、(IIa')、(IIc)或(IIc')的化合物中存在的酮基基团形成共价键的官能团,或与接头L1、L2或L3中存在的羰基形成共价键的官能团。更优选地,生物活性分子(例如药物)包含至少一个肼基基团,至少一个酰肼基基团,至少一个胺基基团,至少一个氨氧基基团,至少一个、优选地两个羟基,或在至少一个、优选地两个硫醇基团。甚至更优选地,衍生聚合物重复单元的生物活性分子能够与存在于接头部分L1、L2或L3中的羰基形成酰胺键、酯键、氨基甲酸酯键或碳酸酯键,优选地形成酰胺键。替代地,衍生聚合物重复单元的生物活性分子包含能够与存在于接头L1、L2或L3中的氨基、羟基或硫醇基团形成共价键的官能团。在这种情况下,优选地,生物活性分子(例如药物)包含至少一个羧酸基团或至少一个硫醇基团。甚至更优选地,衍生聚合物重复单元的生物活性分子能够与接头部分L1、L2或L3中存在的羟基形成酯键,与接头部分L1、L2或L3中存在的氨基形成酰胺键,与接头部分L1、L2或L3中存在的硫醇基团形成硫酯键,或与接头部分L1、L2或L3中存在的硫醇基团形成二硫键。
更优选地,每个D1和D3为O。因此,优选地至少一个D2为L2-B2。一方面,每个D2是L2-B2。
一方面,每个D1和D3为O,至少一个D2为L2-B2,并且聚合物主链和D2之间的键是腙。因此优选地聚合物包含式(IA)的重复单元,例如式(Ia)的重复单元:
其中n、m、p、q、V、X、Y和Q如上文关于式(I')、(I)或(I”)所定义的,如上所定义L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B可以替代地被定义为使得B-NH-N是生物活性部分B2。n、m、p、q、X、Y和Q中每一个的优选身份(identity)如上文关于式(I')、(I)、(I”)、(IIa)、(IIa')、(IIb)、(IIb')、(IIc)和(IIc')中的每一个所阐述的。
当L”为键且生物活性部分通过C=N键在体内水解释放时,生物活性分子为B-NHNH2。有利地,腙键在<6的pH下水解。在优选的包含式(IA)或(Ia)的重复单元的聚合物中,生物活性分子是选自以下的药物:异烟肼、卡比多巴、恩曲嗪(endralazine)、双肼屈嗪、肼屈嗪、肼卡巴肼、苯异丙肼、匹尔屈嗪(pildralazine)、奥他莫辛(octamoxin)、合成肽、合成寡核苷酸、碳水化合物、肽模拟物、抗体、肼及其混合物。
另一方面,式(IA)或(Ia)中的腙键可进一步被还原。腙键的还原可通过本领域任何已知的技术实现。优选地,在这方面,聚合物包含式(IA’)的重复单元,例如式(Ia’)的重复单元:
其中所有变量如上文关于式(IA)或(Ia)所定义。
在另一方面,每个D1和D3是O,至少一个D2是L2-B2,并且聚合物主链和D2之间的键是亚胺。因此优选地,聚合物包含式(IB)的重复单元,例如式(Ib)的重复单元:
其中n、m、p、q、X、Y和Q如上文关于式(I')、(I)或(I”)所定义的,如上所定义L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B可以替代地被定义为使得B-N是生物活性部分D2。n、m、p、q、X、Y和Q中每一个的优选身份如上文关于式(I')、(I)、(I”)、(IIa)、(IIa')、(IIb)、(IIb')、(IIc)和(IIc')中的每一个所阐述的。
当L”是键并且生物活性部分通过C=N键在体内水解释放时,生物活性分子是B-NH2。在包含式(IB)或(Ib)的重复单元的优选聚合物中,生物活性分子选自阿替普酶(Alteplase)、阿达木单抗(Adalimumab)、比伐卢定(Bivalirudin)、氯普鲁卡因(Chloroprocaine)、达托霉素(Daptomycin)、多沙唑嗪(Doxazosin)、依非韦伦(Efavirenz)、氢氟噻嗪(Hydroflumethiazide)、吲达帕胺(Indapamide)、地特胰岛素(Insulin Detemir)、赖诺普利(Lisinopril)、肽模拟物、哌唑嗪(Prazosin)、沙格列汀(Saxagliptin)、小干扰RNA、磺胺甲噻唑(Sulfamethylthiazole)、磺胺美曲(Sulfametrole)、磺胺二甲异嘧啶(Sulfisomidine)、曲帕胺(Tripamide)、2-对-磺胺酰基苯胺基乙醇(2-p-Sulfanilylaninoethanol)、3-氨基-4-羟基丁酸、3-氨基吡啶-2-羧醛缩氨基硫脲(3-Aminopyridine-2-carboxaldehyde thiosemicarbazone)(3-AP)/3-氨基吡啶-4-甲基-2-羧醛缩氨基硫脲(3-AMP/Triapine/OCX-191/OCX-0191)、4,4'-亚磺酰基二苯胺、4'-(甲基氨磺酰基)磺胺(4'-(Methylsulfamoyl)sulfanilanilide)、4'-磺胺酰基磺胺(4'-Sulfanilylsulfanilamide)、4-氨基-3-羟基丁酸、4-磺胺水杨酸(4-Sulfanilamidosalicylic acid)、5-羟色氨酸、6-重氮-5-氧-L-正亮氨酸(DON)、9-氨基吖啶、9-氨基喜树碱(9-Aminocamptothecin)、阿巴卡韦(Abacavir)、阿巴西普(Abatacept)、醋地砜(Acediasulfone)、磺胺苯砜钠(Acetosulfone sodium)、阿昔洛韦(Acyclovir)、阿德福韦(Adefovir)、阿夫唑嗪(Alfuzosin)、金刚烷胺(Amantadine)、氨芬酸(Amfenac)、脒霉素(Amidinomycin),阿米卡星(Amikacin)、氨基乙酰丙酸(Aminolevulinic Acid)、氨氯地平(Amlodipine)、阿莫西林(Amoxicillin)、安非他明(Amphetamine)、双霉素(Amphomycin)、两性霉素B(Amphomycin B)、氨苄西林(Ampicillin)、安普那韦(Amprenavir)、安西他滨(Ancitabine)、抗体、抗原、阿贝卡星(Arbekacin)、阿扑西林(Aspoxicillin)、阿扎胞苷(Azacitidine)、重氮丝氨酸(Azaserine)、巴坎西林(Bacampicillin)、杆菌肽(Bacitracin)、盐酸贝奈克酯(BenexateHCl)、苄丝肼(Benserazide)、苯佐卡因(Benzocaine)、苄磺胺(Benzylsulfamide)、贝伐珠单抗(Bevacizumab)、博莱霉素(Bleomycins)、澳莫普林(Brodioprim)、溴匹立明(Bropirimine)、布那唑嗪(Bunazosin)、布替罗星(Butirosin)、卷曲霉素(Capreomycin)、碳水化合物、卡铂(Carboplatin)、卡柔比星(Carubicin)、卡芦莫南(Carumonam)、卡泊芬净(Caspofungin)、头孢克洛(Cefaclor)、头孢羟氨苄(Cefadroxil)、头孢曲嗪(Cefatrizine)、头孢卡品(Cefcapene)、头孢克定(Cefclidin)、头孢地尼(Cefdinir)、头孢托仑(Cefditoren)、头孢吡肟(Cefepime)、头孢他美(Cefetamet)、头孢甲肟(Cefinenoxime)、头孢克肟(Cefixime)、头孢米诺(Cefminox)、头孢地嗪(Cefodizime)、头孢雷特(Ceforanide)、头孢噻利(Cefoselis)、头孢噻肟(Cefotaxime)、头孢替安(Cefotiam)、头孢唑兰(Cefozopran)、头孢匹罗(Cefpirome)、头孢泊肟(Cefpodoxime)、头孢丙烯(Cefprozil)、头孢沙定(Cefroxadine)、头孢他啶(Ceftazidime)、头孢特仑(Cefteram)、头孢布丁(Ceftibuten)、头孢唑肟(Ceftizoxime)、头孢曲松(Ceftriaxone)、头孢唑南(Cefuzonam)、赛来昔布(Celecoxib)、头孢氨苄(Cephalexin)、先锋霉素(Cephaloglycin)、头孢菌素C(Cephalosporin C)、头孢拉定(Cephradine)、赛妥珠单抗(Certolizumab)、西托肟(Cetoxime)、西曲酸酯(Cetraxate)、西妥昔单抗(Cetuximab)、氯丙胍(Chlorproguanil)、西多福韦(Cidofovir)、西司他汀(Cilastatin)、克拉屈滨(Cladribine)、克林沙星(Clinafloxacin)、氯帕胺(Clopamide)、考来维纶(Colesevelam)、粘菌素(Colistin)、环己西林(Cyclacillin)、环氯胍(Cycloguanil)、环戊噻嗪(Cyclopenthiazide)、环丝氨酸(Cycloserine)、阿糖胞苷(Cytarabine)、氨苯砜(Dapsone)、阿法达贝泊汀(Darbepoetin Alfa)、地瑞那韦(Darunavir)、道诺霉素(Daunorubicin)、地西他滨(Decitabine)、地诺苏单抗(Denosumab)、右旋安非他明(Dextroamphetamine)、地佐辛(Dezocine)、地贝卡星(Dibekacin)、双脱氧腺苷(Dideoxyadenosine)、地索普西(Disoproxil)、DNA、阿法链道酶(Dornase Alfa)、多柔比星(Doxorubicin)、强力霉素(Doxycycline)、乙溴替丁(Ebrotidine)、依达曲沙(Edatrexate)、依氟鸟氨酸(Eflornithine)、恩曲他滨(Emtricitabine)、恩替卡韦(Entecavir)、恩维霉素(Enviomycin)、依西林(Epicillin)、依匹斯汀(Epinastine)、表柔比星(Epirubicin)、阿法依泊汀(Epoetin Alfa)、依那西普(Etanercept)、乙胺丁醇(Ethambutol)、艾塞那肽(Exenatide)、泛昔洛咪喹莫德韦(Famciclo Imiquimodvir)、法莫替丁(Famotidine)、非格司亭(Filgrastim)、芬戈莫德(Fingolimod)、氟胞嘧啶(Flucytosine)、氟伏沙明(Fluvoxamine)、折叠体(foldamers)、叶酸(Folic acid)、福林霉素(Forimicins)、加巴喷丁(Gabapentin)、γ-氨基丁酸、吉西他滨(Gemcitabine)、吉米沙星(Gemifloxacin)、庆大霉素(Gentamicin)、醋酸格拉替雷(Glatiramer Acetate)、戈利木单抗(Golimumab)、组胺(Histamine)、四价人乳头状瘤(Human Papilloma Quadrivalent)、氢氯噻嗪(Hydrochlorothiazide)、伊达比星(Idarubicin)、免疫球蛋白(ImmuneGlobulin)、英夫利昔单抗(Infliximab)、门冬胰岛素(Insulin Aspart)、甘精胰岛素(Insulin Glargine)、赖脯胰岛素(Insulin Lispro)、干扰素β-1a(Interferon beta-1a)、干扰素β-1b(Interferon beta-1b)、伊匹单抗(Ipilimubab)、依索拉定(Irsogladine)、异帕米星(Isepamicin)、卡那霉素(Kanamycin)、拉米夫定(Lamivudine)、拉莫三嗪(Lamotrigine)、兰瑞肽(Lanreotide)、左旋多巴(L-DOPA)、来那度胺(Lenalidomide)、来那西林(Lenampicillin)、左旋多巴(Levodopa)、左旋甲状腺素(Levothyroxine)、利拉鲁肽(Liraglutide)、利地安非他明(Lisdexamfetamine)、氯碳头孢(Loracarbef)、赖甲环素(Lymecycline)、磺胺米隆(Mafenide)、曼他定(Mantadine)、甲氯环素(Meclocycline)、美法仑(Melphalan)、美金刚胺(Memantine)、美沙拉明(Mesalamine)、美沙拉嗪(Mesalazine)、二甲双胍(Metformin)、美他环素(Methacycline)、甲氨蝶呤(Methotrexate)、氨基戊酮酸甲酯(Methyl Aminolevulinate)、甲基多巴(Methyldopa)、米铂(Miboplatin)、微诺霉素(Micronomicin)、微小RNA(microRNA)、米卡霉素(Mikamycin)、米那普仑(Milnacipran)、米诺环素(Minocycline)、米托胍腙(Mitoguazone)、吗甲吡嗪酰胺(Morphazinamide)、mRNA、N4-β-D-葡萄糖基磺胺、那他珠单抗(Natalizumab)、那他霉素(Natamycin)、尼加霉素(Negamycin)、新霉素(Neomycin)、奈替米星(Netilmicin)、尼莫司汀(Nimustine)、诺拉曲塞(Nolatrexed)、诺米芬辛(Nomifensine)、非利平斯基分子、诺普磺酰胺(Noprysulfamide)、N-磺胺酰-3,4-二甲苯甲酰胺(N-Sulfanilyl-3,4-xylamide)、制霉菌素(Nystatin)、醋酸奥克肽(Ocreotide Acetate)、奥马珠单抗(Omalizumab)、奥司他明(Oseltamivir)、奥沙利铂(Oxaliplatin)、帕利珠单抗(Palivizumab)、对氨基水杨酸、对氨基水杨酸酰肼(p-Aminosalicylic acid hydrazide)、巴龙霉素(Paromomycin)、帕沙米特(Parsalmide)、帕珠沙星(Pazufloxacin)、聚乙二醇非格司亭(Pegfilgrastim)、聚乙二醇干扰素α-2a(Peginterferon alfa-2a)、培美曲塞(Pemetrexed)、喷昔洛韦(Penciclovir)、培普霉素(Peplomycin)、肽(Peptide)、蛋白质(Protein)、培西加南(Pexiganan)、苯基氨基水杨酸酯(Phenyl aminosalicylate)、哌氯定(Picloxydine)、吡柔比星(Pirarubicin)、吡曲克辛(Piritrexim)、匹氨西林(Pivampicillin)、吡啶头孢氨苄(Pivcefalexin)、特戊酸甲酯(pivoxil)、PNA、多粘菌素(Polymyxin)、普拉曲沙(Pralatrexate)、普瑞巴林(Pregabalin)、普瑞加柏林(Pregabelin)、伯氨喹(Primaquine)、普鲁卡因(Procaine)、丙美卡因(Proparacaine)、丙氧卡因(Propoxycaine)、普罗西蒂(Proxetil)、对磺胺酰苯甲胺(p-Sulfanilylbenzylamine)、嘌呤霉素(Puromycin)、乙胺嘧啶(pyrimethamine)、喹诺酮(Quinocide)、雷莫拉宁(Ramoplanin)、兰尼单抗(Ranibizumab)、瑞加德松(Regadenoson)、瑞马西胺(Remacemide)、雷西莫特(Resiquimod)、核糖霉素(Ribostamycin)、金刚乙胺(Rimantadine)、利托菌素(Ristocetin)、利妥昔单抗(Rituximab)、罗曲酸(Rotraxate)、S-腺苷蛋氨酸、乙酰水杨酰胺(Salacetamide)、山帕曲拉(Sampatrilat)、司维拉姆(Sevelamer)、西索米星(Sisomicin)、西他沙星(Sitafloxacin)、西格列汀(Sitagliptin)、小发夹RNA、S-甲基甲硫氨酸(S-Methylmethionine)、生长激素(Somatropin)、司帕沙星(Sparfloxacin)、链霉黑素(Streptonigrin)、琥珀氨苯砜(Succisulfone)、琥氯非尼(Suclofenide)、磺胺苯酰(Sulfabenzamide)、磺胺醋酰(Sulfacetamide)、磺胺氯达嗪(Sulfachlorpyridazine)、磺胺柯定(Sulfachrysoidine)、磺胺西汀(Sulfacytine)、磺胺嘧啶(Sulfadiazine)、磺胺戊烯(Sulfadicramide)、磺胺地索辛(Sulfadimethoxine)、磺胺多辛(Sulfadoxine)、磺胺乙二唑(Sulfaethidole)、磺胺脒(Sulfaguanidine)、磺胺胍诺(Sulfaguanole)、磺胺林(Sulfalene)、磺胺甲基嘧啶(Sulfamerazine)、磺胺对甲氧嘧啶(Sulfameter)、磺胺二甲嘧啶(Sulfamethazine)、磺胺甲二唑(Sulfamethizole)、磺胺甲恶唑(Sulfamethoxazole)、磺胺甲氧嗪(ulfamethoxypyridazine)、磺胺米柯定(Sulfamidochrysoidine)、磺胺恶唑(Sulfamoxole)、磺胺(Sulfanilamide),对氨基苯磺酸(Sulfanilic acid),磺酰脲(Sulfanilylurea)、磺胺培林(Sulfaperine)、磺胺苯吡唑(Sulfaphenazole)、磺胺普罗林(Sulfaproxyline)、磺胺吡嗪(Sulfapyrazine)、磺胺异噻唑(Sulfasomizole)、磺胺均三嗪(Sulfasymazine)、磺胺噻唑(Sulfathiazole)、磺胺硫脲(Sulfathiourea)、磺胺托拉米(Sulfatolamide)、磺胺异恶唑(Sulfisoxazole)、磺酰胺(Sulfonamide)、磺胺甲基咪啶(Sulframethomidine)、舒他西林(Sultamicillin)、舒噻嗪(Sulthiame)、合成寡核苷酸、合成肽、他非诺喹(Tafenoquine)、他仑帕奈(Talampanel)、酞氨西林(Talampicillin)、替考拉宁(Teicoplanin)、替诺福韦(Tenofovir)、特拉唑嗪(Terazosin)、特里帕肽(Teriparatide)、四氧普林(Tetroxoprim)、硫咪嘌呤(Thiamiprine)、硫鸟嘌呤(Thioguanine)、替吉莫南(Tigemonam)、替诺立定(Tinoridine)、替拉扎明(Tirapazamine)、妥布霉素(Tobramycin)、托吡酯(Topiramate)、妥舒沙星(Tosufloxacin)、苯环丙胺(Tranylcypromine)、曲妥珠单抗(Trastuzumab)、曲马唑嗪(Trimazosin)、甲氧苄啶(Trimethoprim)、三甲曲沙(Trimetrexate)、曲托喹啉(Tritoqualine)、曲伐沙星(Trovafloxacin)、曲沙他滨(Troxacitabine)、结核放线菌素(Tuberactinomycin)、杀结核菌素(Tubercidin)、短杆菌酪肽(Tyrocidine)、优特克单抗(Ustekinumab)、发昔洛韦(Valacyclovir)、戊地昔布(Valdecoxib)、缬更昔洛韦(Valganciclovir)、万古霉素(Vancomycin)、阿糖腺苷(Vidarabine)、氨己烯酸(Vigabatrin)、长春地辛(Vindesine)、紫霉素(Viomycin)、扎西他滨(Zalcitabine)、唑尼沙胺(Zonisamide)及其混合物。
另一方面,式(IB)或(Ib)中的亚胺键可进一步被还原。亚胺键的还原可以通过本领域的任何已知技术实现。优选地,在这方面,聚合物包含式(IB’)的重复单元,例如式(Ib’)的重复单元:
其中所有变量如上文关于式(IB)或(Ib)所定义。
在另一方面,每个D1和D3是O,至少一个D2是L2-B2,并且聚合物主链和D2之间的键形成缩酮。其他特别优选的聚合物包含两个生物活性部分,并且聚合物主链和D2之间的键形成缩酮。因此优选地,聚合物包含式(ICi)或(ICii)的重复单元,例如式(Ici)或(Icii)的重复单元:
其中n、m、p、q、v、V、X、Y和Q如上文关于式(I')、(I)或(I”)所定义的,如上所定义L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B可以可替代地被定义为使得B-O或O-B-O是生物活性部分B2。n、m、p、q、v、V、X、Y和Q中的每一个的优选身份如上文关于式(I)、(I')、(I”)、(IIa)、(IIa')、(IIb)、(IIb')、(IIc)和(IIc')中的每一个所述。当L”是键并且生物活性部分通过C-O键体内水解而释放时,生物活性分子是B-OH或HO-B-OH。
在包含式(ICi)、(Ici)、(ICii)或(Icii)的重复单元的优选聚合物中,生物活性分子选自2,4,6-三溴-间甲酚、21-乙酰氧基孕烯醇酮、2-对-磺胺酰基苯胺基乙醇、3-氨基-4-羟基丁酸、4-氨基-3-羟基丁酸、4-己基间苯二酚、4-磺胺水杨酸、5-(甲氨基)-2-脱氧尿苷(MADU)、5-溴水杨基羟肟酸、5-羟色氨酸、9-氨基喜树碱、阿巴卡韦(Abacavir)、阿巴西普(Abatacept)、阿比特龙(Abiraterone)、醋丁洛尔(Acebutolol)、对乙酰氨基酚(Acetaminophen)、醋氨沙洛(Acetaminosalol)、阿克拉霉素类(Aclacinomycins)、阿昔洛韦(Acyclovir)、阿达木单抗(Adalimumab)、阿吗灵(Ajmaline)、阿氯米松(Alclometasone)、α-没药醇(alfa-Bisabolol)、全部红霉素酯衍生物、阿普洛尔(Alprenolol)、阿替普酶(Alteplase)、双(乙酰水杨酸)铝、阿米卡星(Amikacin)、氨氯恶嗪(Aminochlorthenoxazin)、氨丙吡酮(Aminopropylon)、阿莫待喹(amodiaquine)、氨磺洛尔(Amosulalol)、阿莫西林(Amoxicillin)、安普那韦(Amprenavir)、安西他滨(Ancitabine)、阿尼芬净(Anidulafungin)、阿尼利定(Anileridine)、氨茴霉素(Anthramycin)、抗体、抗原、阿帕西林(Apalcillin)、阿哌环素(Apicycline)、阿贝卡星(Arbekacin)、阿罗洛尔(Arotinolol)、青蒿素醇(Artemisinin alcohol)、阿佐昔芬(Arzoxifene)、阿扑西林(Aspoxicillin)、阿扎那韦(Atazanavir)、阿替洛尔(Atenolol)、苯乳胺(Atrolactamide)、阿扎胞苷(Azacitidine)、叠氮氯霉素(Azidamfenicol)、阿奇霉素(Azithromycin)、巴波霉素(Bambermycins)、巴马司他(Batimastat)、贝比碱(Bebeerines)、二丙酸倍氯米松(Beclomethasone Dipropionate)、贝氟沙通(Befloxatone)、苄丝肼(Benserazide)、苯沙酸钙(Benzoylpas)、苄吗啡(Benzylmorphine)、倍他米松(Betamethasone)、倍他洛尔(Betaxolol)、贝伐珠单抗(Bevacizumab)、比阿培南(Biapenem)、比马前列素(Bimatoprost)、比索洛尔(Bisoprolol)、博莱霉素(Bleomycins)、波生坦(Bosentan)、溴柳氯苯胺(Bromosalicylchloranilide)、溴尿苷(Broxuridine)、布西丁(Bucetin)、布新洛尔(Bucindolol)、布地奈德(Budesonide)、丁苯碘胺(Bufeniode)、丁苯羟酸(Bufexamac)、布尼洛尔(Bunitrolol)、布拉洛尔(Bupranolol)、丁丙诺啡(Buprenorphine)、安非他酮(Bupropion)、布拉氨酯(Buramate)、布舍瑞林(Buserelin)、布替罗星(Butirosin)、丁非洛尔(Butofilolol)、布托啡诺(Butorphanol)、卡屈嗪(Cadralazine)、卡普睾酮(Calusterone)、卡培他滨(Capecitabine)、卷曲霉素(Capreomycin)、辣椒素(Capsaicine)、卡拉洛尔(Carazolol)、卡比多巴(Carbidopa)、碳水化合物、卡波霉素(Carbomycin)、卡替洛尔(Carteolol)、卡柔比星(Carubicin)、卡维地洛(Carvedilol)、卡泊芬净(Caspofungin)、CC-1065、头孢羟氨苄(Cefadroxil)、头孢孟多(Cefamandole)、头孢曲嗪(Cefatrizine)、头孢拉宗(Cefbuperazone)、头孢尼西(Cefonicid)、头孢哌酮(Cefoperazone)、头孢噻利(Cefoselis)、头孢匹胺(Cefpiramide)、头孢丙烯(Cefprozil)、塞利洛尔(Celiprolol)、头孢匹林钠(Cephapirin sodium)、赛妥珠单抗(Certolizumab)、西妥昔单抗(Cetuximab)、氯霉素(Chloramphenicol)、氯丁醇(Chlorobutanol)、氯二甲苯酚(Chloroxylenol)、氯脲霉素(Chlorozotocin)、氯苯甘醚(Chlorphenesin)、氯喹多醇(Chlorquinadol)、金霉素达福普汀(Chlortetracycline Dalfopristin)、色霉素(Chromomycins)、西氯他宁(Cicletanine)、环匹罗司(Ciclopirox)、环孢霉素(Ciclosporine)、西多福韦(Cidofovir)、辛可尼定(Cinchonidine)、辛可宁(Cinchonine)、西拉马多(Ciramadol)、克拉屈滨(Cladribine)、克拉霉素(Clarithromycin)、克拉维酸(clavulanic acid)、克林霉素(Clindamycin)、氯倍他松(Clobetasone)、氯福克醇(Clofoctol)、氯莫环素(Clomocycline)、氯羟喹啉(Cloxyquin)、可待因(Codeine)、考来维纶(Colesevelam)、粘菌素(Colistin)、环孢菌素(Cyclosporin)、阿糖胞苷(Cytarabine)、阿法达贝泊汀(Darbepoetin Alfa)、地瑞那韦(Darunavir)、达沙替尼(Dasatinib)、道诺霉素(Daunorubicin)、地西他滨(Decitabine)、地夫可特(Deflazacort)、地莫司汀(Delmostatin)、地美环素(Demeclocycline)、地诺苏单抗(Denosumab)、脱氧双氢链霉素(Deoxydihydrostreptomycin)、地索吗啡(Desomorphine)、地奈德(Desonide)、地索米松(Desoximetasone)、地文拉法辛(Desvenlafaxine)、地塞米松(Dexamethasone)、地佐辛(Dezocine)、地百里砜(Diathymosulfone)、地贝卡星(Dibekacin)、地达诺新(Didanosine)、双脱氧腺苷(Dideoxyadenosine)、己烯雌酚(Diethylstilbestrol)、双氟拉松(Diflorasone)、双氟可龙(Diflucortolone)、双氟尼柳(Diflunisal)、龙胆酸(Gentisicacid)、双氟泼尼酯(Difluprednate)、双氢青蒿素(Dihydroartemisinin)、双氢可待因(Dihydrocodeine)、双氢吗啡(Dihydromorphine)、双氢链霉素(Dihydrostreptomycin)、乙酰水杨酸二羟基铝(Dihydroxyaluminum acetylsalicylate)、地来洛尔(Dilevalol)、地美庚醇(Dimepheptanol)、地红霉素(Dirithromycin)、地他唑(Ditazol)、DNA、多西紫杉醇(Docetaxel)、阿法链道酶(Dornase Alfa)、去氧氟尿苷(Doxifluridine)、多柔比星(Doxorubicin)、强力霉素(Doxycycline)、屈洛昔芬(Droloxifene)、屈莫他酮(Dromostanolone)、海鞘素(Ecteinascidins)、依度定(Edoxudine)、恩曲他滨(Emtricitabine)、依诺他滨(Enocitabine)、依诺肝素(Enoxaparin)、依诺酮(Enoxolone)、恩前列素(Enprostil)、恩他卡朋(Entacapone)、恩替卡韦(Entecavir)、恩维霉素(Enviomycin)、依帕洛尔(Epanolol)、肾上腺素(Epinephrine)、表柔比星(Epirubicin)、表甾烷醇(Epitiostanol)、阿法依泊汀(Epoetin Alfa)、依他佐辛(Eptazocine)、厄他培南(Ertapenem)、红霉素(Erythromycin)、雌莫司汀(Estramustine)、依那西普(Etanercept)、依他硝唑(Etanidazole)、乙炔雌二醇(Ethinyl Estradiol)、依托沙秦(Ethoxazene)、乙基吗啡(Ethylmorphine)、依托芬那酯(Etofenamate)、依托孕烯(Etonogestrel)、依托泊苷(Etoposide)、丁香酚(Eugenol)、依维莫司(Everolimus)、艾塞那肽(Exenatide)、依折麦布(Ezetimibe)、芬多沙(Fendosal)、非诺多泮(Fenoldopam)芬戊二醇(Fenpentadiol)、芬维A胺(Fenretinide)、非普地醇(Fepradinol)、非索非那定(Fexofenadine)、非格司亭(Filgrastim)、菲律宾菌素(Filipin)、夫拉平度(Flavopiridol)、氟比汀(Flipirtine)、夫洛非宁(Floctafenine)、氟莫昔夫(Flomoxef),氟尿定(Floxuridine),氟扎可松(Fluazacort),氟康唑(Fluconazole),氟氢可的松(Fludrocortisone)、氟米松(Flumethasone)、氟轻松(Fluocinolone)、氟轻松醋酸酯(Fluocinonide)、氟可丁(Fluocortin Butyl)、氟可龙(Fluocortolone)、醋酸氟泼尼(Fluprednidene Acetate)、丙酸氟替卡松(Fluticasone Propionate)、折叠体、福米霉素(Forimicins)、福美斯坦(Formestane)、福莫特罗(Formoterol)、膦甲酸钠(Foscarnet sodium)、磷雌酚(Fosfestrol)、福培南(Fropenem)、氟维司群(Fulvestrant)、制霉色基素(Fungichromin)、呋喃叠氮(Furonazide)、夫西地酸(Fusidic acid)、加兰他敏(Galantamine)、更昔洛韦(Ganciclovir)、吉西他滨(Gemcitabine)、庆大霉素(Gentamicin)、格拉非宁(Glafenine)、葡美辛(Glucametacin)、葡萄糖砜钠(Glucosulfone sodium)、葡烟腙(Glyconiazide)、戈利木单抗(Golimumab)、巴柳氮(Balsalazide)、戈舍瑞林(Goserelin)、短杆菌肽(Gramicidin(s))、胍甲环素(Guamecycline)、哈西奈德(Halcinonide)、丙酸卤倍他索(Halobetasol Propionate)、卤泛群(Halofantrine)、卤米松(Halometasone)、醋酸卤丙酮(Halopredone Acetate)、四价人乳头状瘤(Human Papilloma Quadrivalent)、氢化可的松(Hydrocortisone)、氢化吗啡酮(Hydromorphone)、羟基哌替啶(Hydroxypethidine)、金丝桃素(Hypericin)、布洛沙姆(Ibuproxam)、异丁普生(Idarubicin)、碘苷(Idoxuridine)、亚胺培南(Imipenem)、免疫球蛋白(Immune Globulin)、茚地洛尔(Indenolol)、茚地那韦(Indinavir)、英夫利昔单抗(Infliximab)、门冬胰岛素(Insulin Aspart)、地特胰岛素(Insulin Detemir)、甘精胰岛素(Insulin Glargine)、赖脯胰岛素(Insulin Lispro)、干扰素β-1a(Interferon beta-1a)、干扰素β-1b(Interferon beta-1b)、伊匹单抗(Ipilimubab)、异丙托溴铵(Ipratropium)、伊立替康(Irinotecan)、异帕米星(Isepamicin)、伊索昔康(Isoxicam)、卡那霉素(Kanamycin(s))、乙氧二羟丁酮(Kethoxal)、凯托米酮(Ketobemidone)、拉贝洛尔(Labetalol)、拉米夫定(Lamivudine)、拉坦前列素(Latanoprost)、L-DOPA、亮丙瑞林(Leuprolide)、左色满卡林(Levcromakalim)、左旋多巴(Levodopa)、左炔诺孕酮(Levonorgestrel)、左啡诺(Levorphanol)、左甲状腺素(Levothyroxine)、林可霉素(Lincomycin)、利拉鲁肽(Liraglutide)、洛匹那韦(Lopinavir)、氯诺昔康(Lornoxicam)、氯沙坦(Losartan)、氯替泼诺(LoteprednolEtabonate)、苯芴醇(Lumefantrine)、赖甲环素(Lymecycline)、甘露莫司汀(Mannomustine)、马立司他(Marimastat)、马泼尼酮(Mazipredone)、甲氯环素(Meclocycline)、甲氟喹(Mefloquine)、美仑孕酮(Melengestrol)、美洛昔康(Meloxicam)、美米松(Memetasone)、美诺立尔(Menogaril)、美吲哚洛尔(Mepindolol)、美普他酚(Meptazinol)、汞溴红(Merbromin)、美罗培南(Meropenem)、美沙拉明(Mesalamine)美沙拉嗪(Mesalazine)、美他佐辛(Metazocine)、美他环素(Methacycline)、甲基多巴(Methyldopa)、甲强的松龙(Methylprednisolone),美替洛尔(Metipranolol),美托酮(Metopon),美托洛尔(Metoprolol)、甲硝唑(Metronidazole)、微诺霉素(Micronomicin)、微小RNA(microRNA)、米卡霉素(Mikamycin)、米替福新(Miltefosine)、米诺环素(Minocycline)、米索前列醇(Misoprostol)、二溴甘露醇(Mitobronitol)、二溴卫矛醇(Mitolactol)、米托蒽醌(Mitoxantrone)、糠酸莫米松(Mometasone Furoate)、孟鲁司特(Montelukast)、莫哌达醇(Mopidamol)、莫普洛尔(Moprolol)、吗啡(Morphine)、拉氧头孢(Moxalactam)、mRNA、N4-β-D-葡萄糖基磺胺、那氟沙星(Nadifloxacin)、纳多洛尔(Nadolol)、萘哌地尔(Naftopidil)、纳布啡(Nalbuphine)、那他珠单抗(Natalizumab)、奈必洛尔(Nebivolol)、尼加霉素(Negamycin)、奈非那韦(Nelfinavir)、新霉素(Neomycin)、奈替米星(Netilmicin)、N-氯化羟乙异丙嗪、硝呋吡醇(Nifurpirinol)、硝呋妥因醇(Nifurtoinol)、二胺硝吖啶(Nitracrine)、硝羟喹啉(Nitroxoline)、诺加霉素(Nogalamycin)、非利平斯基分子、去甲二氢愈创木酸(Nordihydroguaiaretic Acid)、去甲左啡诺(Norlevorphanol)、去甲吗啡(Normorphine)、新生霉素(Novobiocin)、夹竹桃霉素(Oleandomycin)、橄榄霉素(Olivomycins)、奥美沙坦(Olmesartan)、奥沙拉秦(Olsalazine)、奥马珠单抗(Omalizumab)、奥匹哌醇(Opipramol)、奥诺前列素(Ornoprostil)、谷维素A(Oryzanol A).加奈索酮(Ganaxolone)、奥沙西罗(Oxaceprol)、奥沙美辛(Oxametacine)、羟考酮喷他佐辛(Oxycodone Pentazocine)、羟考酮(Oxycodone)、羟吗啡酮(Oxymorphone)、羟基保泰松(Oxyphenbutazone)、土霉素(Oxytetracycline)、紫杉醇(Paclitaxel)和其他已知的紫杉醇类似物,紫杉醇、帕利哌酮棕榈酸酯(PaliperidonePalmitate)、帕利哌酮(Paliperidone)、帕利珠单抗(Palivizumab)、对氨基水杨酸酰肼、对氨基水杨酸、帕尼培南(Panipenem)、巴龙霉素(Paromomycin)、培西洛星(Pecilocin)、聚乙二醇非格司亭(Pegfilgrastim)、聚乙二醇干扰素α-2a(Peginterferon alfa-2a)、喷布洛尔(Penbutolol)、喷昔洛韦(Penciclovir)、喷司他丁(Pentostatin)、培普霉素(Peplomycin)、肽模拟物、肽、哌立索唑(Perisoxal)、芬托氯铵(Phenactropiniumchloride),非那佐辛(Phenazocine)、非那吡啶(Phenazopyridine)、非诺可(Phenocoll)、苯哌利定(Phenoperidine)、酚妥拉明(Phentolamine)、苯基氨基水杨酸酯(Phenylaminosalicylate)、苯基雷米多(Phenylramidol)、水杨酸苯酯(Phenylsalicylate)、匹尔屈嗪(Pildralazine)、吡美莫司(Pimecrolimus)、吲哚洛尔(Pindolol)、匹哌环素(Pipacycline)、吡柔比星(Pirarubicin)、Piroxicam、对乙氧基乳酰苯胺(p-Lactophenetide)、普劳诺托(Plaunotol)、普卡霉素(Plicamycin)、PNA、足叶草毒素(Podophyllotoxin)、多粘菌素(Polymyxin)、泊沙康唑(Posaconazole)、泼尼松龙(Prednisolone)、泼尼松(Prednisone)、伯霉素(Primycin)、普那霉素(Pristinamycin)、普萘洛尔(Propranolol)、蛋白质、原藜芦碱(Protoveratrines)、嘌呤霉素(Puromycin)、吡啶琥醇(Pyrisuccideanol)、奎硫平(Quetiapine)、依折麦布(Ezetimibe)、奎宁(Quinine)、奎奴普汀(Quinupristin)、雷洛昔芬(Raloxifene)、雷替格韦(Raltegravir)、雷莫拉宁(Ramoplanin)、兰尼单抗(Ranibizumab)、雷尼莫司汀(Ranimustine)、雷诺嗪(Ranolazine)、雷夫康唑(Ravuconazole)、瑞西美托(Rescimetol)、雷西莫特(Resiquimod)、维甲酸(包括所有反式视黄酸)、病毒唑(Ribavirin)、核糖霉素(Ribostamycin)、利福布汀(Rifabutin)、利福拉齐(Rifalazil)、利福酰胺(Rifamide)、利福平(Rifampicin)、利福霉素SV(Rifamycin SV)、利福喷丁(Rifapentine)、利福昔明(Rifaximin)、利美索龙(Rimexolone)、里奥前列素(Rioprostil)、利塞膦酸(RisedronicAcid)、利托菌素(Ristocetin)、利替培南(Ritipenem)、利托那韦(Ritonavir)、利妥昔单抗(Rituximab)、罗利四环素(Rolitetracycline)、罗喹美克(Roquinimex)、罗沙前列醇(Rosaprostol)、罗沙胂(Roxarsone)、罗克吲哚(Roxindole)、罗红霉素(Roxithromycin)、红藜芦碱(Rubijervine)、鲁比替康(Rubitecan)、S-腺苷甲硫氨酸、柳氮磺嘧啶(Salazosulfadimidine)、水杨苷(Salicin)、曲马多(Tramadol)、水杨酰胺(Salicylamide)、水杨酰苯胺(Salicylanilide)、水杨烟肼(Salinazid)、沙美特罗(Salmeterol)、双水杨酯(Salsalate)、山帕曲拉(Sampatrilat)、山环素(Sancycline)、沙奎那韦(Saquinavir)、沙格列汀(Saxagliptin)、西奥骨化醇(Seocalcitol)、司维拉姆(Sevelamer)、西卡宁(Siccanin)、辛伐他汀(Simvastatin)、西罗莫司(Sirolimus)、西索米星(Sisomicin)、小发夹RNA、小干扰RNA、生长激素(Somatropin)、索立夫定(Sorivudine)、大观霉素(Spectinomycin)、司他夫定(Stavudine)、利迪链菌素(Streptolydigin)、链霉素(Streptomycin)、链霉素异烟肼(Streptonicozid)、链脲佐菌素(Streptozocin)、柳氮磺吡啶(Sulfasalazine)、硫氧洛尔(Sulfinalol)、合成寡核苷酸、合成肽、他克莫司(Tacrolimus)、他克莫司(Tacrolimus).他林洛尔(Talinolol)、替考拉宁(Teicoplanin)、泰利霉素(Telithromycin)、替莫泊芬(Temoporfin)、替尼泊苷(Teniposide)、替诺昔康(Tenoxicam)、细交链孢菌酮酸(Tenuazonic Acid)、特非那定(Terfenadine)、特里帕肽(Teriparatide)、特罗芬那酯(Terofenamate)、特他洛尔(Tertatolol)、睾酮(Testosterone)、甲砜霉素(Thiamphenicol)、硫链菌素(Thiostrepton)、噻唑羧胺核苷(Tiazofurin)、噻吗洛尔(Timolol)、噻托溴铵(Tiotropium)、替拉那韦(Tipranavir)、妥布霉素(Tobramycin)、托卡朋(Tolcapone)、托洛沙酮(Toloxatone)、托特罗定(Tolterodine)、托泊替康(Topotecan)、反式白藜芦醇[(E)-3,4′,5-三羟基二苯乙烯)、曲妥珠单抗(Trastuzumab)、曲伏前列素(Travoprost)、去炎松(Triamcinolone)、曲氟尿苷(Trifluridine)、曲马唑嗪(Trimazosin)、曲莫前列素(Trimoprostil)、丙大观霉素(Trospectomycin)、曲沙他滨(Troxacitabine)、结核放线菌素(Tuberactinomycin)、短杆菌酪肽(Tyrocidine)、优特克单抗(Ustekinumab)、戊地昔布(Valdecoxib)、缬更昔洛韦(Valganciclovir)、戊柔比星(Valrubicin)、万古霉素(Vancomycin)、文拉法辛(Venlafaxine)、阿糖腺苷(Vidarabine)、维米醇(Viminol)、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)、紫霉素(Viomycin)、维吉尼亚霉素(Virginiamycin)、伏立康唑(Voriconazole)、黄青霉素(Xanthocillin)、西博莫尔(Xibomol)、昔莫洛芬(Ximoprofen)、鹰爪甲素(Yingzhaosu A)、扎西他滨(Zalcitabine)、扎那米韦(Zanamivir)、齐多夫定(Zidovudine)、唑来膦酸(Zoledronic Acid)、唑仑膦酸(Zolendronic Acid)、佐柔比星(Zorubicin)、佐苏奎达尔(Zosuquidar)及其混合物。
在另一方面,每个D1和D3是O,至少一个D2是L2-B2,并且聚合物主链和D2之间的键形成硫缩酮。其他特别优选的聚合物包含两个生物活性部分,并且聚合物主链和D2之间的键形成硫缩酮。因此优选地,聚合物包含式(IDi)或(IDii)的重复单元,例如式(Idi)或(Idii)的重复单元:
其中n、m、p、q、v、V、X、Y和Q如上文关于式(I')、(I)或(I”)所定义的,如上所定义L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B可以替代地被定义为使得B-S或S-B-S是生物活性部分B2。n、m、p、q、v、V、X、Y和Q中的每一个的优选身份如上文关于式(I)、(I')、(I”)、(IIa)、(IIa')、(IIb)、(IIb')、(IIc)和(IIc')中的每一个所述。当L”是键并且生物活性部分通过C-O键体内水解而释放时,生物活性分子是B-SH或HS-B-SH。
在优选的包含式(IDi)或(IDii)的重复单元、例如式(Idi)或(Idii)的重复单元的聚合物中,所述生物活性分子选自肽、蛋白质、糖、肽模拟物、抗体、抗原、合成寡核苷酸、阿达木单抗(Adalimumab)、依那西普(Etanercept)、培非格司汀(Pegfilgrastim)、利妥昔单抗(Rituximab)、贝伐珠单抗(Bevacizumab)、甘精胰岛素(Insulin Glargine)、阿法依泊汀(Epoetin Alfa)、曲妥珠单抗(Trastuzumab)、干扰素β-1a(Interferon beta-1a)、雷尼珠单抗(Ranibizumab)、地特米尔胰岛素(Insulin Detemir)、门冬胰岛素(Insulin Aspart)、赖脯胰岛素(Insulin Lispro)、非格司汀(Filgrastim)、阿法达贝泊汀(DarbepoetinAlfa)、干扰素β-1b(Interferon beta-1b)、阿巴西普(Abatacept)、利拉鲁肽(Liraglutide)、帕利珠单抗(Palivizumab)、西妥昔单抗(Cetuximab)、乌司他单抗(Ustekinumab)、地诺单抗(Denosumab)、四价人乳头状瘤(Human PapillomaQuadrivalent)、聚乙二醇干扰素α-2a(Peginterferon alfa-2a)、伊匹利木巴(Ipilimubab)、免疫球蛋白(Immune Globulin)、阿法链道酶(Dornase Alfa)、赛妥珠单抗(Certolizumab)、那他珠单抗(Natalizumab)、生长激素(Somatropin)、阿替普酶(Alteplase)、戈利木单抗(Golimumab)及其混合物。
可替代地,每个D1和D3是O,至少一个D2是L2-B2,并且聚合物主链和D2之间的键是肟。因此优选地,聚合物包含式(IE)的重复单元,例如式(Ie)的重复单元:
其中n、m、p、q、v、V、X、Y和Q如上文关于式(I')、(I)或(I”)所定义的,如上所定义L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B可以替代地被定义为使得B-O-N是生物活性部分D2。n、m、p、q、V、X、Y和Q中的每一个的优选身份如上文关于式(I)、(I')、(I”)、(IIa)、(IIa')、(IIb)、(IIb')、(IIc)和(IIc')中的每一个所述。当L”是键并且生物活性部分通过C=N键体内水解而释放时,生物活性分子是B-ONH2。
另一方面,式(IE)或式(Ie)中的肟键可进一步被还原。肟键的还原可以用本领域任何已知的技术来实现。优选地,在这方面,聚合物包含式(IE’)的重复单元,例如式(Ie’)的重复单元:
其中全部的变量如上文关于式(IE)或(Ie)所定义。
尤其优选的聚合物包含式(IE)的重复单元,更优选地式(Ie)的重复单元。
聚合物-抗体接头部分的结构
本部分阐述了在本发明的抗体-药物缀合物中存在的接头部分的可能的结构特征。
本发明的抗体-药物缀合物中的接头部分可衍生自具有至少两个独立反应官能团的任何合适化合物:一个与聚合物反应以形成共价键的官能团和另一个与抗体反应以形成共价键的官能团。抗体-药物接头部分可以与用于将聚合物主链连接到生物活性部分的任何连接头基团相同或不同(当存在这样的接头基团时)。优选地,抗体-药物接头部分不同于用于将聚合物主链连接到生物活性部分的接头基团。
通常,聚合物-抗体接头通过式(I')、(I)或(I”)的重复单元中的-CD1-部分的碳原子或式(I')、(I)或(I”)的重复单元中的Y基团与聚合物共价结合。通常,聚合物-抗体接头在聚合物末端之一与聚合物共价结合。替代地,聚合物-抗体接头通过与远离聚合物末端的酮基缩合而与聚合物共价结合。然而,优选地,聚合物-抗体接头不通过与远离聚合物末端的酮基缩合而与聚合物共价结合。
通常,聚合物-抗体接头通过抗体的反应性氨基酸侧链共价结合至抗体,例如通过半胱氨酸残基的硫醇基团、赖氨酸残基的氨基基团、谷氨酸残基或天冬氨酸残基的羧酸基团、硒代半胱氨酸残基的硒醇基团、或通过抗体中多肽之一的主链的N端,或通过存在于抗体的片段可结晶(Fc)区域中的寡糖的羟基基团,或通过聚糖或非天然残基的醛或羟胺基团,或通过聚糖或非天然残基的炔基或叠氮化物基团。
聚合物与抗体可以独立地共价结合至接头部分的相同原子,或者它们可以独立地共价结合至接头部分的不同原子。优选地,聚合物和抗体独立地共价结合至接头部分的不同原子。
用于本发明的抗体-药物缀合物的合适接头部分包括但不限于衍生自以下的接头:硫醇、马来酰亚胺、单溴马来酰亚胺、马来酰亚胺类似物、乙烯基砜、双(砜)、丙二烯酰胺(allenamides)、乙烯基吡啶、脱氢丙氨酸、烯烃、全氟芳香族分子、茱莉亚子碱样(Julia-Kocienski like)的砜试剂、N-羟基琥珀酰胺-酯活化的羧酸盐种类、醛、酮、羟胺、炔烃和叠氮化物。
因此,硫醇、马来酰亚胺、单溴马来酰亚胺、马来酰亚胺类似物、乙烯基砜、双(砜)、丙二烯酰胺、乙烯基吡啶、脱氢丙氨酸、烯烃、全氟芳族种类、茱莉亚子碱样的砜试剂、N-羟基琥珀酰胺-酯活化的羧酸盐种类、醛、酮、羟胺、炔烃和叠氮化物,与(a)聚合物主链和(b)抗体两者反应导致合适的接头基团L。双(砜)在这种情况下作为(双烷基化)试剂。接头可以通过例如光引发的硫醇-烯反应从烯烃衍生。因此,抗体上的硫醇基团可以与烯烃官能团反应以生成共价连接。与脱氢丙氨酸的反应可以例如通过与抗体上的硫醇基团的迈克尔加成消除(Michael addition-elimination)而发生。N-羟基琥珀酰胺-酯活化的羧酸盐种类可与抗体中的赖氨酸基团反应。酮、醛和/或羟胺可以通过肟键形成或通过肼基-皮克特-施彭格勒(hydrazino--Pictet-Spengler)(HIPS)连接而缀合至聚糖修饰的抗体或非天然残基。炔烃和叠氮化物可以通过点击化学(叠氮化物-炔烃环加成)与聚糖修饰的抗体或非天然残基缀合。
抗体-药物缀合物的结构
最优选地,本发明的抗体-药物缀合物具有式(III)或(IV):
其中:
(I’)为如上所定义的式(I’)的重复单元,例如式(I)或式(I”)的重复单元;
Ab为如上定义的抗体或其抗原结合片段;
L为如上定义的聚合物-抗体接头;
R1选自OH、OR’、SH、SR’、NH2、NHR’和NR’2;
E选自H和R’;
R’如上定义;和
z为2至50的整数。
因此,通常本发明的抗体-药物缀合物具有式(III’)或(IV’),例如式(IIIa)、(IIIb)、(IVa)或(IVb):
其中:
Ab为如上定义的抗体或其抗原结合片段;
L为如上定义的聚合物-抗体接头;
R1选自OH、OR’、SH、SR’、NH2、NHR’和NR’2;
E为H或R’;
每个n、m、p、q、V、X、Q、Y、D1、D2、D3和R’如上定义;和
z为2至50的整数。
优选地,z是2至30的整数,更优选地为2至20的整数,更优选地为2至15的整数,最优选地为2至12的整数。
本发明的抗体-药物缀合物可进一步包含第二靶向剂。优选地,该靶向剂共价结合至聚合物。合适的靶向剂包括生物分子,如肽、蛋白质、肽模拟物、抗体、抗原、DNA、mRNA、小干扰RNA、小发夹RNA、微小RNA、PNA、折叠体、碳水化合物、碳水化合物衍生物、非利平斯基分子、合成肽和合成寡核苷酸。
本发明的抗体-药物缀合物中聚合物的重均分子量通常为500Da至500000Da,更优选地1000Da至200000Da,仍更优选地1500Da至36000Da。优选地,聚合物的数均分子量为500Da至500000Da,更优选地1000Da至200000Da,仍更优选地1500Da至25000Da,仍更优选地2000Da至20000Da。优选地,聚合物的多分散度为1至5,更优选地1.05至4.8,仍更优选地1.1至2.4,仍更优选地1.1至1.5。
本发明的抗体-药物缀合物中存在的生物活性部分优选地具有32Da至100000Da的分子量。生物活性部分可以是小分子药物,其可以是小的有机分子,即非聚合的或聚合的。优选地,基于干抗体-药物缀合物的重量,本发明的抗体-药物缀合物包含0.5wt%至90wt%、更优选地0.75wt%至70wt%、仍更优选地1wt%至60wt%、仍更优选地1.5wt%至50wt%、仍更优选地1.75wt%至25wt%且最优选地2wt%至10wt%的生物活性部分。本发明的抗体-药物缀合物的关键优点是可以将相对大量的生物活性分子并入到聚合物中。此外,多个聚合物可以结合到单个抗体上。这些因素反过来意味着可以实现高的生物活性分子负载。通常,药物抗体比值(drug-to-antibody ratio,DAR)为4:1或更高,优选地5:1或更高,更优选地8:1或更高,仍更优选地10:1或更高,仍更优选地12:1或更高,甚至更优选地15:1或更高,最优选地16:1或更高,例如20:1或更高。
本发明的抗体-药物缀合物中的每个生物活性部分B1、B2和/或B3可以是相同的。然而,优选地,本发明的抗体-药物缀合物含有至少两个不同的生物活性部分,例如2、3或4个不同的生物活性部分。
优选的本发明的抗体-药物缀合物中存在的生物活性部分是选自以下的药物:抗感染药、抗生素、抗细菌药、抗微生物剂、抗炎剂、镇痛剂、抗高血压剂、抗真菌药、抗结节药、抗病毒剂、抗癌药、抗血小板药、抗疟疾药、抗痉挛药(anticonvulsant)、保护心脏药、抗蠕虫药(antihelmintic)、抗原生动物药、抗锥虫药、抗血吸虫病药、抗肿瘤药、抗青光眼药、镇静剂、催眠药、抗惊厥药、抗帕金森病药(antiparkinson)、抗抑郁药、抗组胺药、抗糖尿病药或抗过敏药(antiallurgics)。
存在于本发明的抗体-药物缀合物中的特别优选的生物活性部分选自瑞奥西汀(auristatins)(例如单甲基瑞奥西汀E(MMAE)和MMAF)、多拉司他汀(dolastatins)、美登素类化合物(maytansinoids)(例如DM1和DM4)、微管蛋白素(tubulysins)、卡利奇霉素(calicheamicins)、倍癌霉素(duocarmycins)、苯二氮卓类、喜树碱、喜树碱类似物、蝇蕈毒素(amatoxin)、多柔比星(doxorubicin)和α-鹅膏菌素(α-amanitin)。
典型地,本发明的抗体-药物缀合物在水中的溶解度为至少10mg/mL,优选地至少30mg/mL,更优选地至少50mg/mL,仍更优选地至少75mg/mL,最优选地至少100mg/mL。
本发明还提供了如本文所述的抗体-药物缀合物,其中生物活性部分从聚合物中的释放是pH敏感的并且取决于所述生物活性部分和聚合物的重复单元之间的键的性质或它共价结合的接头基团的性质。
替代地,抗体可以被替代形式的靶向剂替代。因此,本发明还提供了靶向剂-药物缀合物,包含:
(i)靶向剂;
(ii)包含式(I’)的重复单元的聚合物:
其中:
每个n和每个p独立地为0或者为1和6之间的整数;
每个m独立地为0或者为1和4之间的整数,且优选地至少一个m为1;V为
--------为可以不存在或可以存在的键;
每个D1独立地为O或L1-B1;
每个D2独立地为O或L2-B2;
每个D3独立地为O或L3-B3;
L1为接头基团或键,L2为接头基团或键,L3为接头基团或键,且每个B1、B2和B3为生物活性部分;
条件是,聚合物中的至少一个D1、D2或D3基团不是O,且另一条件是当D1、D2或D3是O时,O原子和它所连接的碳原子之间有一个双键;
每个q为1和8之间的整数;
X和Y独立地选自O、NH、NR’和S;
R’为C1-20烃基;
Q选自-CH2(NMe(C=O)CH2)o-、-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-,其中T1选自二价亚甲基、亚乙基、亚丙基或亚丁基,且T2选自二价亚甲基、亚乙基、亚丙基或亚丁基;
O为0至100的整数;和
s为0至150的整数;和
(iii)聚合物-靶向剂接头,其与靶向剂和聚合物两者共价结合。
优选地,聚合物包含式(I)的重复单元:
其中,变量X、Y、D1、D2、D3、n、m和p如上所述,且Q选自-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-。
替代地,聚合物包含式(I”)的重复单元:
其中,变量X、Y、Q、D1、D2、D3、n、m和p如上所述。优选地,在式(I”)的重复单元中,Q是-CH2(NMe(C=O)CH2)o-。更优选地,Q是-CH2(NMe(C=O)CH2)o-且Y是-NMe。
靶向剂共价结合至聚合物。合适的靶向剂包括生物分子,诸如肽、蛋白质、肽模拟物、抗体、抗原、DNA、mRNA、小干扰RNA、小发夹RNA、微小RNA、PNA、折叠体、碳水化合物、碳水化合物衍生物、非利平斯基分子、合成肽和合成寡核苷酸。
聚合物-靶向剂接头可采用与如上定义的聚合物-抗体接头相同的任何结构。
最优选地,本发明的靶向剂-药物缀合物具有式(V)或(VI):
其中:
(I’)为如上所定义的式(I’)的重复单元,例如式(I)或式(I”)的重复单元;
Tar为如上定义的靶向剂;
L为如上定义的聚合物-靶向剂接头;
R1选自OH、OR’、SH、SR’、NH2、NHR’和NR’2;
E选自H和R’;
R’如上定义;和
z为2至50的整数。
因此,通常本发明的靶向剂-药物缀合物具有式(V’)或(VI’),例如式(Va)、(Vb)、(Via)或(VIb):
其中:
Tar为如上定义的靶向剂;
L为如上定义的聚合物-靶向剂接头;
R1选自OH、OR’、SH、SR’、NH2、NHR’和NR’2;
E选自H和R’;
每个n、m、p、q、X、Q、Y、D1、D2、D3和R’如上定义;和
z为2至50的整数。
优选地,z为2至30的整数,更优选地为2至20的整数,甚至更优选地为2至15的整数,最优选地为2至12的整数。本发明的靶向剂-药物缀合物中聚合物的重均分子量通常为500Da至500000Da,更优选地1000Da至200000Da,仍更优选地1500Da至36000Da。优选地,聚合物的数均分子量为500Da至500000Da,更优选地1000Da至200000Da,仍更优选地1500Da至25000Da,仍更优选地2000Da至20000Da。优选地,聚合物的多分散度为1至5,更优选地1.05至4.8,仍更优选地1.1至2.4,仍更优选地1.1至1.5。
本发明的靶向剂-药物缀合物中存在的生物活性部分优选地具有32Da至100000Da的分子量。生物活性部分可以是小分子药物,其可以是小的有机分子,即非聚合的或聚合的。优选地,基于干抗体-药物缀合物的重量,本发明的靶向剂-药物缀合物包含0.5wt%至90wt%、更优选地0.75wt%至70wt%、仍更优选地1wt%至60wt%、仍更优选地1.5wt%至50wt%、甚至更优选地1.75wt%至25wt%且最优选地2wt%至10wt%的生物活性部分。本发明的靶向剂-药物缀合物的关键优点是可以将相对大量的生物活性分子并入到聚合物中。此外,多个聚合物可以结合到单个靶向剂上。这些因素反过来意味着可以实现高的生物活性分子负载。通常,药物靶向剂比值(DAR)为4:1或更高,优选地5:1或更高,更优选地8:1或更高,仍更优选地10:1或更高,仍更优选地12:1或更高,甚至更优选地15:1或更高,最优选地16:1或更高,例如20:1或更高。
本发明的靶向剂-药物缀合物中的每个生物活性部分B1、B2和/或B3可以是相同的。替代地,本发明的靶向剂-药物缀合物含有至少两个不同的生物活性部分,例如2、3或4个不同的生物活性部分。在本发明的靶向剂-药物缀合物中存在的优选生物活性部分如上文关于抗体-药物缀合物所述。
通常,本发明的靶向剂-药物缀合物在水中的溶解度为至少30mg/mL,优选地至少50mg/mL,更优选地至少75mg/mL,并且最优选地至少100mg/mL。
制造抗体-药物缀合物的方法
本发明还涉及一种生产根据本发明的抗体-药物缀合物的方法。
通常,这种方法包括以下步骤:
(a)使式(IIa)的化合物与式(IIb)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(b)使步骤(a)的产物与聚合物-抗体接头反应;
(c)任选地,使步骤(b)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(d)使步骤(c)的产物与生物活性分子反应,或者如果没有执行步骤(c),则使步骤(b)的产物与生物活性分子反应;和
(e)使步骤(d)的产物与抗体或其抗原结合片段反应。
替代地,所述方法包括以下步骤:
(a)使式(IIa)的化合物与式(IIb)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(b)任选地,使步骤(b)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(c)使步骤(b)的产物与生物活性分子反应,或者如果没有执行步骤(c),则使步骤(b)的产物与生物活性分子反应;和
(d)使步骤(c)的产物与聚合物-抗体接头反应;和
(e)使步骤(d)的产物与抗体或其抗原结合片段反应。
替代地,所述方法包括以下步骤:
(a)使式(IIa)的化合物与式(IIb)的化合物和生物活性分子以及任选地式HL1-LG、HL2-LG或HL3-LG的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’、Q、L1、L2、L3和LG如上文定义;
(b)步骤(a)的产物与聚合物-抗体接头反应;和
(c)使步骤(b)的产物与抗体或其抗原结合片段反应。
替代地,所述方法包括以下步骤:
(a)使抗体或其抗原结合片段与聚合物-抗体接头反应;
(a)单独地,使式(IIa)的化合物与式(IIb)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(c)使步骤(a)的产物与步骤(b)的产物反应;
(d)任选地,使步骤(c)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(e)使步骤(d)的产物与生物活性分子反应,或者如果没有执行步骤(d),则使步骤(c)的产物与生物活性分子反应。
替代地,所述方法包括以下步骤:
(a)使抗体或其抗原结合片段与聚合物-抗体接头反应;
(b)单独地,使式(IIa)的化合物与式(IIb)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(c)任选地,使步骤(b)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(d)使步骤(c)的产物与生物活性分子反应,或者如果没有执行步骤(c),则使步骤(b)的产物与生物活性分子反应;和
(d)使步骤(a)的产物与步骤(d)的产物反应。
替代地,所述方法包括以下步骤:
(a)使式(IIa’)的化合物与式(IIb’)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(b)使步骤(a)的产物与聚合物-抗体接头反应;
(c)任选地,使步骤(b)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(d)使步骤(c)的产物与生物活性分子反应,或者如果没有执行步骤(c),则使步骤(b)的产物与生物活性分子反应;和
(e)使步骤(d)的产物与抗体或其抗原结合片段反应。
替代地,所述方法包括以下步骤:
(a)使式(IIa’)的化合物与式(IIb’)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(b)任选地,使步骤(b)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(c)使步骤(b)的产物与生物活性分子反应,或者如果没有执行步骤(c),则使步骤(b)的产物与生物活性分子反应;和
(d)使步骤(c)的产物与聚合物-抗体接头反应;和
(e)使步骤(d)的产物与抗体或其抗原结合片段反应。
替代地,所述方法包括以下步骤:
(a)使式(IIa’)的化合物与式(IIb’)的化合物和生物活性分子以及任选地式HL1-LG、HL2-LG或HL3-LG的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’、Q、L1、L2、L3和LG如上文定义;
(b)步骤(a)的产物与聚合物-抗体接头反应;和
(c)使步骤(b)的产物与抗体或其抗原结合片段反应。
替代地,所述方法包括以下步骤:
(a)使抗体或其抗原结合片段与聚合物-抗体接头反应;
(a)单独地,使式(IIa’)的化合物与式(IIb’)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(c)使步骤(a)的产物与步骤(b)的产物反应;
(d)任选地,使步骤(c)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;和
(e)使步骤(d)的产物与生物活性分子反应,或者如果没有执行步骤(d),则使步骤(c)的产物与生物活性分子反应。
替代地,所述方法包括以下步骤:
(a)使抗体或其抗原结合片段与聚合物-抗体接头反应;
(b)单独地,使式(IIa’)的化合物与式(IIb’)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(c)任选地,使步骤(b)的产物与式HL1-LG、HL2-LG或HL3-LG的化合物反应,其中L1、L2、L3和LG如上文定义;
(d)使步骤(c)的产物与生物活性分子反应,或者如果没有执行步骤(c),则使步骤(b)的产物与生物活性分子反应;和
(d)使步骤(a)的产物与步骤(d)的产物反应(d)。
在任何上述实施方案中,当所述方法包括两个连续的步骤:(i)将式HL1-LG、HL2-LG或HL3-LG的化合物加入到中间产物中,接着(ii)添加生物活性分子的步骤。所述方法的步骤(i)和(ii)也可以被修改,使得在随后的所得化合物HL1-B1、HL2-B2或HL3-B3与所述中间产物反应之前,式HL1-LG、HL2-LG或HL3-LG的化合物首先与生物活性分子反应以形成式HL1-B1、HL2-B2或HL3-B3的化合物。
特别优选的方法包括以下步骤:
(a)使式(IIa)的化合物与式(IIb)的化合物反应:
其中,R1、R2、n、m、p、q、X’、Y’和Q如上文定义;
(b)使步骤(a)的产物与聚合物-抗体接头反应;
(c)使式HL1-LG、HL2-LG或HL3-LG的化合物与生物活性分子反应,其中L1、L2、L3和LG如上文定义;
(d)使步骤(b)的产物与步骤(c)的产物反应;和
(e)使步骤(d)的产物与抗体或其抗原结合片段反应。
在本发明的优选方法中,生物活性分子如本文所定义或为如本文所定义的生物活性分子的受保护形式。在聚合、官能化和缀合反应期间可以使用本领域众所周知的常规保护基团策略。在本发明的进一步优选的方法中,抗性如本文所定义。在本发明的又一优选方法中,聚合物-抗体接头部分如本文所定义。
在本发明方法中的聚合步骤优选以酶促或通过缩聚、自由基链增长聚合或开环聚合进行,最优选以酶促进行。
药物组合物
本发明的抗体-药物缀合物可以掺入药物组合物中。因此,本发明提供了一种药物组合物,其包含如本文所定义的抗体-药物缀合物和一种或多种药学上可接受的载体、稀释剂或赋形剂。药物组合物可以任何常规方式制备。药物组合物可包含一种或多种不同的如本文所述的抗体-药物缀合物。合适的载体、稀释剂和赋形剂是本领域公知的。
本发明的药物组合物可以通过以下任何一种或多种途径施用至患者:口服、全身(例如经皮、鼻内、跨粘膜或通过栓剂)或肠胃外(例如,肌肉内、静脉内或皮下)。本发明的组合物可以采取片剂、丸剂、胶囊、半固体、粉剂、缓释制剂、溶液、悬浮液、酏剂、气雾剂、透皮贴剂、生物粘附膜或任何其他合适组合物的形式。制剂的选择取决于多种因素,例如药物施用方式(例如对于口服施用,片剂、丸剂或胶囊形式的制剂是优选的)和药物物质的生物利用度。
本发明的药物组合物还可以包括常用的药用赋形剂,如润滑剂、增稠剂、润湿剂、乳化剂、悬浮剂、防腐剂、填充剂、粘合剂、防腐剂和吸附促进剂,例如表面渗透剂。也可以使用增溶剂和/或稳定剂,例如环糊精(CD)。本领域技术人员将能够基于其目的选择合适的赋形剂。可用于本文所述的药物产品的常见赋形剂列于各种手册中(例如D.E.Bugay和W.P.Findlay(Eds)Pharmaceutical excipients(Marcel Dekker,纽约,999),E-MHoepfner,A.Reng和P.C.Schmidt(Eds)Fiedler Encyclopedia of Excipients forPharmaceuticals,Cosmetics and Related Areas(Edition Cantor,Munich,2002)和H.P.Fielder(Ed)Lexikon der Hilfsstoffe fur Pharmazie,Kosmetik und angrenzendeGebiete(Edition Cantor Aulendorf,1989))。
本发明的药物组合物可以被配制成通过采用本领域公知的程序在施用于患者后提供抗体-药物缀合物的快速、持续或延迟的释放。药物组合物中抗体-药物缀合物的浓度取决于多种因素,包括聚合物的性质、聚合物上的载药量、抗体的身份、组成、施用方式、待治疗或诊断的病症以及它所施用于的对象,并且可以通过本领域技术人员熟知的技术根据选择而改变或调整。
抗体-药物缀合物的医学用途
本文所述的抗体-药物缀合物和药物组合物可用于医学应用。因此,本发明提供如本文所述的抗体-药物缀合物用于治疗有需要的患者的疾病或病症。通常,本文所述的抗体-药物缀合物和药物组合物用于治疗选自以下的疾病:炎性疾病(例如炎性肠病、类风湿性关节炎和动脉粥样硬化)、代谢紊乱(例如糖尿病、胰岛素抵抗、肥胖症)、癌症、细菌感染(例如肺结核、肺炎、心内膜炎、败血症、沙门氏菌病、伤寒症、囊性纤维化、慢性阻塞性肺病)、病毒感染、心血管疾病、神经退行性疾病、神经障碍、行为和精神障碍、血液疾病、染色体疾病、先天与遗传疾病、结缔组织疾病、消化系统疾病、耳鼻喉疾病、内分泌疾病、环境疾病、眼部疾病、女性生殖疾病、真菌感染、心脏病、遗传性癌症综合征、免疫系统疾病、肾脏和泌尿系统疾病、肺病、男性生殖疾病、口腔疾病、肌肉骨骼疾病、骨髓增生异常综合征、神经系统疾病、新生儿筛查、营养疾病、寄生虫病、罕见癌症和皮肤病。
一般而言,将本发明的抗体-药物缀合物施用于人类患者,以便向患者递送治疗有效量的包含在其中的生物活性分子。
如本文所用,术语“治疗有效量”是指生物活性分子的下述量:足以降低或缓解正在治疗的病症的严重性、持续时间、进展或发作,防止正在治疗的病症的进展,导致与正在治疗的病症相关的症状的消退,预防与正在治疗的病症相关的症状的复发、发展、发作或进展,或增强或改善另一疗法的预防或治疗效果。施用至患者的生物活性分子的精确量将取决于疾病或病症的类型和严重性以及患者的特征,例如总体健康状况、年龄、性别、体重和对药物的耐受性。它还取决于正在治疗的病症的程度、严重性和类型。技术人员将能够根据这些和其他因素确定合适的剂量。
如本文所用,术语“治疗(treat)”、“治疗(treatment)”和“治疗(treating)”指由于施用根据本发明的薄膜给患者,而降低或缓解正在治疗的病症的进展、严重性和/或持续时间,或者缓解正在治疗的病症的一种或多种症状(优选地,一种或多种可识别的症状)。
本发明还提供了一种治疗人类患者的如本文所述的疾病或病症的方法,其中所述方法包括向有需要的患者施用至少一种如本文所述的抗体-药物缀合物。
本发明还提供了如本文所述的抗体-药物缀合物在制造用于治疗人类患者的如本文所述的疾病或病症的药剂中的用途。
本发明的任何一种抗体-药物缀合物或多种抗体-药物缀合物也可以与一种或多种其他药物或药物组合物组合,用于治疗本发明的ADC和/或其他药物或药物组合物可对其有用的疾病或病症。
所述一种或多种其他药物或药物组合物可以通过以下任何一种或多种途径施用至患者:口服、全身(例如经皮、鼻内、跨粘膜或通过栓剂)或肠胃外(例如肌肉内、静脉内或皮下)。所述一种或多种其他药物的组合物或药物组合物可以采取以下形式:片剂、丸剂、胶囊、半固体、粉剂、缓释制剂、溶液、悬浮液、酏剂、气雾剂、透皮贴剂、生物粘附膜或任何其他合适的组合物。制剂的选择取决于多种因素,例如药物施用方式(例如对于口服施用,片剂、丸剂或胶囊形式的制剂是优选的)和药物物质的生物利用度。
本文引用的出版物、专利出版物和其他专利文件通过引用方式全部并入。在文中,对单数术语的任何引用也包括其复数。在使用术语“包含(comprising)”、“包含(comprise)”或“包含(comprises)”的情况下,所述术语可以分别被“由……组成(consisting of)”、“由……组成(consist of)”或“由……组成(consists of)”代替,或分别被“基本上由……组成(consisting essentially of)”、“基本上由……组成(consistessentially of)”或“基本上由……组成(consists essentially of)”代替。对数值范围或单个数值的任何引用还包括接近该范围或单个值的值。除非另有说明,否则对具有式(I’)、(I)或(I”)的重复单元的聚合物的任何引用也包括其生理学上可接受的盐。除非另有说明,任何百分数(%)比值均基于所讨论的一种或多种组分的相对重量。
实施例
以下是阐述本发明的实施例。然而,这些实施例决不是为了限制本发明的范围。
实施例1:聚合物的制备
合成式(I’)的聚合物且将其连接至马来酰亚胺基团,用于随后通过下面的合成步骤缀合至抗体。
步骤a:聚酰胺主链的合成
通过下述两个构造块(building blocks)之间的酶促缩聚反应合成聚酰胺:二甲基-2-氧戊二酸盐,与封端的Mn~1,500的聚乙二醇双(3-氨基丙基)(PEG 1500二元胺)(方案1)。
方案1:聚酰胺1的合成
在反应前一天,将南极洲念珠菌脂肪酶B(Candida Antarctica Lipase B,CALB)作为固定化酶珠(NovozymTM 435,(N435),含有10w/w%CALB和90w/w%丙烯酸树脂)在干燥器中真空干燥2小时,并在干燥器中保持过夜。然后将其加入到含有PEG 1500二元胺的圆底烧瓶中。最后,将1.0当量的二甲基-2-氧戊二酸盐加入该圆底烧瓶中,并保持缓慢的氮气流冲洗反应混合物。总的来说,所用的酶珠相当于单体总重量的10%。在反应的第一阶段,使用油浴以200转每分钟(rpm)的磁力搅拌将该部分(bulk)在热板上加热至75℃,持续1小时。然后添加二苯基醚(300%单体重量)以降低粘度并将温度升高至105℃,同时在反应的第二阶段将搅拌提高至300rpm。耐化学隔膜真空泵连接到容器并连续运行。24小时后,停止反应并通过加入氯仿淬灭。留出时间让聚合物产物溶解后,将溶液通过棉纤维过滤以去除酶珠。最后,通过用己烷洗涤3次来纯化滤液,得到固体沉淀物。聚酰胺1在N2下且然后在真空下干燥,得到深棕色无定形固体(4批聚合物的产率=55-71%)。
凝胶渗透色谱(GPC)用于分析聚合物的分子量和多分散度。使用两根配备保护装置的分析型PLGel 10μm MiniMix-B 250x4.6mm柱进行分析。使用0.3mL min-1氯仿流量,并使用聚苯乙烯标准品对系统校准。将样品溶解在氯仿中并在进样前通过0.45μm PTFE注射器式过滤器过滤(见图1)。
尺寸排阻色谱(SEC)也用于分析聚合物的分子量和多分散度。SEC条件为:PL-水凝胶-OH 30,8μm,300x7.5mm柱,0.5ml min-1的水作为洗脱液,PEG作为标准品。将样品溶解在水中,并在进样前通过0.45μm PES注射器式过滤器过滤。聚酰胺1的SEC数据显示在具有1(Mn=1kDa和1.8kDa)和8(Mn=13.9kDa)之间的重复单元的聚合物的分布(见图2)。
通过RP-HPLC(C18柱,H2O(0.1%TFA)和ACN作为洗脱剂系统)表征聚酰胺1。聚酰胺1的RP-HPLC色谱图在图3中示出。它显示在RT(保留时间)=9.38分钟时洗脱的峰(图3)。
聚酰胺1在真空下彻底干燥并溶解在CDCl3中用于NMR分析(图4)。然而,信号并不容易解释,因为产物是不同链长的混合物。需要进一步分析以确认信号分配和临时分配如下所述:1H NMR:3.80ppm(4nH,m);3.63ppm(124nH,m);3.45(4nH,m);3.21ppm(2nH,t);2.65ppm(2nH,t);1.81ppm(2nH,m)。
步骤b:聚酰胺的马来酰亚胺官能化
在上一节中描述的步骤之后获得的聚酰胺1用马来酰亚胺基团进行官能化(参见方案2)。
方案2:聚酰胺1的马来酰亚胺官能化
聚酰胺1以60mg.ml-1的浓度溶解在二氯甲烷中。在搅拌溶液以溶解聚合物后,加入1.5当量的DIPEA使溶液的pH值高于9.0。随后,将在氮气钟(bell)下保持并称重的1.5当量的3-马来酰亚胺基丙酸N-羟基琥珀酰亚胺(NHS)酯添加到反应混合物中,在室温下搅拌3小时。此后,圆底烧瓶的内容物在至少三倍体积的己烷中沉淀。将固体沉淀溶解在二氯甲烷中并用己烷洗涤两次以上。最后,在氮气下然后在真空下干燥聚酰胺2。发现在马来酰亚胺官能化后聚酰胺合成的总产率平均约为50%。
通过RP-HPLC监测反应(见图5)。与在时间0时的保留时间9.38min相比,聚合物峰朝向更长的保留时间RT=9.5min略微移动。鉴于3-马来酰亚胺基丙酸NHS酯过量使用,在己烷洗涤后在RT=5.75min时的色谱图中可以看出这一点。
步骤c:马来酰亚胺官能化的聚酰胺的纯化
马来酰亚胺官能化的聚酰胺2通过半制备RP-HPLC纯化(见图6)。虽然这不允许按分子量分离聚合物,但该方法确实能够去除剩余的起始材料。将聚合物以50mg mL-1的浓度溶解在ACN:H2O(50:50v/v%)中,并以13000rpm离心10分钟。收集上清液,并使用4mL.min-1的流速在13分钟内以30%至56%的ACN:H2O(0.1%TFA)梯度将其注入半制备RP-HPLC系统。收集聚合物峰的基于时间的级分,然后冷冻干燥以产生RP-HPLC纯化的产物。
RP-HPLC纯化的聚合物的色谱图显示在RT=9.52分钟处有一个单峰(见图7)。聚合物峰也比纯化步骤之前更尖锐(见图8)。
图9提供了通过RP-HPLC纯化后的聚酰胺2的1H NMR谱。然而,信号并不容易解释,因为产物是不同链长的混合物。需要进一步分析以确认信号分配和临时分配描述如下:1HNMR:6.68ppm(2H,s);3.80ppm(4nH,m);3.62ppm(124nH,m);3.44(4nH,m);3.20ppm(2nH,t);2.64ppm(2nH,t);2.47ppm(2H,t);1.80-1.73ppm(2nH,m)。
1H-NMR谱证实成功形成马来酰亚胺官能化的聚酰胺2。纯化后,单个马来酰亚胺峰保留在δ=6.68ppm处,证实存在马来酰亚胺基团。
测定马来酰亚胺官能化的聚酰胺2的水溶性
测试了聚酰胺2在水性溶液中的溶解度。粗制和RP-HPLC纯化的聚酰胺2在浓度≥50mg mL-1时可溶,如图10中拍摄的样品所示。
实施例2:MMAE的制备
MMAE被选为作为用于缀合到聚酰胺2上的示例性药物。
MMAE毒素剂被用作修饰的MMAE,其中组织蛋白酶B敏感的缬氨酸-瓜氨酸(Val-Cit)二肽被自我牺牲型对-氨基苄基氧羰基(PABC)接头隔开。经由下面描述的合成步骤,在MMAE上引入接头(或交叉接头)以使MMAE能够经由肟键的形成与聚酰胺2缀合。
步骤a:从Fmoc-Val-Cit-PABC-MMAE除去Fmoc
在二乙胺存在下执行从Fmoc-Val-Cit-PABC-MMAE去除Fmoc(方案3)。
方案3:从Fmoc-Val-Cit-PABC-MMAE去除Fmoc
将135mg Fmoc-Val-Cit-PABC-MMAE(MMAE)溶解在粉末盒中的2mL无水DMF中,并转移到10mL圆底烧瓶(RBF)中。将RBF置于N2下几分钟,然后分两部分添加335μl二乙胺。将反应混合物在RT在N2下搅拌2.5小时。通过正相TLC(硅胶60F254)监测反应。反应停止后,使用合适的旋转蒸发仪系统将混合物减压浓缩。黄色残留物用二乙基醚洗涤3次。回收为黄色固体油的产物3。
步骤b:NHS-活化的氨氧基-交联接头与MMAE的偶联
(Boc-氨氧基)乙酸N-羟基琥珀酰亚胺(NHS)酯活化的(NHS-活化的氨氧基)交联接头与MMAE 3偶联(方案4)。
方案4:氨氧基交联接头与MMAE 3偶联
将MMAE 3溶解在2mL DMF中并在N2下搅拌。在玻璃小瓶中称量21mg NHS活化的氨氧基交联接头并溶解在1mL DMF中。然后将该溶液加入到反应容器中。最后,将20μL DIPEA/DMF(50:50v/v%)添加到反应混合物中。将反应在RT在N2下搅拌18小时。通过正相TLC监测反应。反应18小时后,真空蒸发反应溶剂,得到固体产物。产物MMAE 4用二乙基醚洗涤3次。
步骤c:从MMAE 4去除Boc
在TFA存在下从MMAE 4中去除Boc保护基团(方案5)。
方案5:从MMAE 4去除Boc
将45mg MMAE 4置于RBF中,然后加入3mL DCM/TFA/TIS(82.5:15:2.5v/v%)。将RBF置于冰浴中并通过TLC监测反应。2.5小时后,真空蒸发反应溶剂。MMAE 5用二乙基醚洗涤一次,然后溶解在DMA(400μL)中进行肟偶联。取样用于LC-MS和HPLC分析。因为观察到m/z=598.95的峰,故LC-MS确认获得了所需产物MMAE 5(参见图11)。
实施例3:MMAE与聚酰胺的缀合
经由肟键的形成将MMAE 5缀合至聚酰胺2(方案6)。
方案6:MMAE 5经由肟键的形成缀合至聚酰胺2
将30mg聚酰胺2在RT在1mL DMA中搅拌直至完全溶解。然后将溶液转移到反应容器中,该反应容器含有在200μL DMA中的估计20mg MMAE 5。添加额外的600μL DMA。最后,将200μL H2O添加到RBF中。将反应在RT搅拌24小时。然后添加20μL丙酮,以淬灭反应并将MMAE峰移动到更长的保留时间,以进行RP-HPLC纯化。通过半制备RP-HPLC(C18柱)纯化在2mLDMA/H2O(90:10v/v%)中的50mg MMAE聚酰胺缀合物6。
在图12中给出了通过RP-HPLC纯化后的MMAE聚酰胺缀合物6的1H NMR信号。需要进一步分析以确认信号分配和临时分配描述如下:1H NMR示出了表征在δ=3.56ppm时PEG基团的存在、在δ=6.75ppm时马来酰亚胺基团的存在和MMAE脂肪族基团(δ=0.94-0.81ppm)和芳香族基团(δ=7.59-7.32ppm)的存在的信号。
实施例4:通过将MMAE聚酰胺缀合物6缀合至曲妥珠单抗来制备ADC
MMAE聚酰胺曲妥珠单抗ADC是通过使包含马来酰亚胺基团的MMAE聚酰胺缀合物6与半胱氨酸残基的硫醇基团缀合,然后通过形成硫醚键使二硫键还原而产生的。使用部分还原的赫赛汀(Herceptin)(曲妥珠单抗)和非还原的赫赛汀建立缀合反应,如表1所述。
表1:用于将MMAE聚酰胺缀合物6缀合至曲妥珠单抗的条件(三(2-羧乙基)膦,TCEP)
利用使用了蛋白A偶联珠柱的IgG纯化试剂盒去除多余的缀合物6,仅留下MMAE聚酰胺曲妥珠单抗ADC和未偶联的曲妥珠单抗。
实施例5:针对MMAE聚酰胺曲妥珠单抗ADC的细胞活力测定
测试MMAE聚酰胺曲妥珠单抗ADC相对于SKBR3细胞(乳腺癌细胞系)的活性(参见图13)。在应用CellTitre Glo发光试剂之前,将样品加入到细胞中72h。浓度以蛋白质的pM给出。
MMAE聚酰胺曲妥珠单抗ADC对SKBR3细胞有活性,估计的蛋白质浓度IC50为158.5pM。
Claims (25)
1.一种抗体-药物缀合物,包含:
(i)抗体或其抗原结合片段;
(ii)包含式(I’)的重复单元的聚合物:
其中:
每个n和每个p独立地是0或1和6之间的整数;
每个m独立地是0或1和4之间的整数,且优选至少一个m为1;
--------是可以不存在或存在的键;
每个D1独立地是O或L1-B1;
每个D2独立地是O或L2-B2;
每个D3独立地是O或L3-B3;
其中L1是接头基团或键,L2是接头基团或键,L3是接头基团或键,且每个B1、B2和B3是生物活性部分;
条件是,所述聚合物中的至少一个D1、D2或D3基团不是O,且另一条件是当D1、D2或D3是O时,O原子和它所连接的碳原子之间有一个双键;
每个q是1和8之间的整数;
X和Y独立地选自O、NH、NR’和S;
R’是C1-20烃基;
Q选自-CH2(NMe(C=O)CH2)o-、-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-,其中T1选自二价亚甲基、亚乙基、亚丙基或亚丁基,且T2选自二价亚甲基、亚乙基、亚丙基或亚丁基;
o是0至100的整数;
s是0至150的整数;和
(iii)聚合物-抗体接头,其与所述抗体和所述聚合物两者共价结合。
3.根据权利要求1或权利要求2所述的抗体-药物缀合物,其中所述聚合物-抗体接头通过式(I’)中的-CD1-部分的碳原子或者式(I’)中的Y基团共价结合至所述聚合物。
4.根据权利要求1至3中任一项所述的抗体-药物缀合物,其中每个D1和每个D3均为O。
5.根据权利要求1至4中任一项所述的抗体-药物缀合物,其中每个q是1。
6.根据权利要求1至5中任一项所述的抗体-药物缀合物,其中每个m是1或2。
7.根据权利要求1至6中任一项所述的抗体-药物缀合物,其中每个n是1、2或3。
8.根据权利要求1至7中任一项所述的抗体-药物缀合物,其中每个p是0、1或2。
10.根据权利要求1至9中任一项所述的抗体-药物缀合物,其中所述聚合物-抗体接头衍生自马来酰亚胺、单溴马来酰亚胺、乙烯基砜、双(砜)、丙二烯酰胺、脱氢丙氨酸、烯烃、全氟芳香族种类、茱莉亚子碱样的砜试剂、N-羟基琥珀酰胺-酯活化的羧酸盐种类和酮。
12.根据权利要求1至11中任一项所述的抗体-药物缀合物,其中X是O或NH且Y是O或NH,优选地其中X和Y均是O或者其中X和Y均是NH。
13.根据权利要求1至12中任一项所述的抗体-药物缀合物,其中Q是-CH2CH2O(CH2CH2O)sCH2CH2-或-CH2CH2CH2O(CH2CH2O)sCH2CH2CH2-,优选地其中s是1至100。
14.根据权利要求1至13中任一项所述的抗体-药物缀合物,其中X-Q-Y衍生自PEG 400、PEG 500、PEG 600、PEG 1000、PEG 1500、PEG 2000或(聚(乙二醇)双(3-氨基丙基)封端的)1500。
15.根据权利要求1所述的抗体-药物缀合物,其中V是-X-(C=O)-、Q是-CH-2(NMe(C=O)CH2)o-且Y是-NMe-,其中部分Q直接结合至V部分的羰基基团,优选地其中o是5至25。
16.根据权利要求1至15中任一项所述的抗体-药物缀合物,其中每个生物活性部分是相同的或者不同的且是B1、B2和/或B3部分,其中H-B1、H-B2和/或H-B3各自独立地选自小分子药物、肽、蛋白质、肽模拟物、抗体、抗原、DNA、mRNA、小干扰RNA、小发夹RNA、微小RNA、PNA、折叠体、碳水化合物、碳水化合物衍生物、非利平斯基分子、合成肽和合成寡核苷酸,优选地小分子药物,优选地其中H-B1、H-B2和/或H-B3包含至少一个肼基团、至少一个酰肼基团、至少一个胺基团、至少一个氨氧基基团、至少一个羟基基团、至少一个硫醇基团、或者至少一个羧基基团。
17.根据权利要求1至14或16中任一项所述的抗体-药物缀合物,其中至少一个、优选全部的式(I’)的重复单元选自:
(a)式(Ia)的重复单元:
其中L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B被定义为使得B-NH-N是生物活性部分B2;
(b)式(Ib)的重复单元:
其中L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B被定义为使得B-N是生物活性部分B2;
(c)式(Ici)或(Icii)的重复单元:
其中v是0至4的整数;L”是键或-Z1-L'-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B被定义为使得B-O或O-B-O是生物活性部分B2;
(d)式(Idi)或(Idii)的重复单元:
其中v是0至4的整数;L”是键或-Z1-L’-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B被定义为使得B-S或S-B-S是生物活性部分B2;和
(e)式(Ie)的重复单元:
其中L”是键或-Z1-L’-Z2-,并且B是生物活性部分B2,或者,如果L”是键,则B被定义为使得B-O-N是生物活性部分B2;
L’选自键、C1-20亚烷基、C1-20亚烯基、C1-20亚炔基、C6-10亚芳基(例如亚苯基或亚萘基)、C7-20亚芳烷基、C3-10亚环烷基、C4-8亚杂环烷基、C5-10亚杂芳基、C6-20亚杂芳烷基、-(O-K)i-、-(NH-K)i-、-(NR’-K)i-、分子量为116Da至2000Da的聚酯、分子量为114Da至2000Da的聚酰胺,和-W-部分,其中H-W-OH是氨基酸或含有2到20个天然存在或合成的氨基酸亚基的肽;
Z1选自-Z-(C=O)-、-Z-O(C=O)-、-Z-NH(C=O)-、-Z-NR’(C=O)-、-Z-S(C=O)-、-Z-(C=NH)-、-Z-O(C=NH)-、-Z-NH(C=NH)-、-Z-NR’(C=NH)-、-Z-S(C=NH)-和-Z-(C=NR’)-、-K-(O-K)i-、-K-(NH-K)i-、-K-(NR’-K)i-、-K(C=O)-(O-K-(C=O))i-、-K(C=O)-(NH-K-(C=O))i-、-K(C=O)-(NR’-K-(C=O))i-,和-P-部分,其中H2N-P-OH是氨基酸或含有2到20个天然存在或合成的氨基酸亚基的肽;
Z2选自键、-OZ-、-NHZ-、-NR’Z-、-SZ-、-S-、-ZS-、-OZS-、-NHZS-、-NR’ZS-、-SZS-、-Z-(C=O)-、-Z-O(C=O)-、-Z-NH(C=O)-、-Z-NR’(C=O)-、-Z-S(C=O)-、-Z-(C=NH)-、-Z-O(C=NH)-、-Z-NH(C=NH)-、-Z-NR’(C=NH)-、-Z-S(C=NH)-、-Z-(C=NR’)-、-Z-O(C=NR’)-、-Z-NH(C=NR’)-、-Z-NR’(C=NR’)-、-Z-S(C=NR’)-、-OZ-(C=O)-、-OZ-O(C=O)-、-OZ-NH(C=O)-、-OZ-NR’(C=O)-、-OZ-S(C=O)-、-OZ-(C=NH)-、-OZ-O(C=NH)-、-OZ-NH(C=NH)-、-OZ-NR’(C=NH)-、-OZ-S(C=NH)-、-OZ-(C=NR’)-、-OZ-O(C=NR’)-、-OZ-NH(C=NR’)-、-OZ-NR’(C=NR’)-、-OZ-S(C=NR’)-、-NHZ-(C=O)-、-NHZ-O(C=O)-、-NHZ-NH(C=O)-、-NHZ-NR’(C=O)-、-NHZ-S(C=O)-、-NHZ-(C=NH)-、-NHZ-O(C=NH)-、-NHZ-NH(C=NH)-、-NHZ-NR’(C=NH)-、-NHZ-S(C=NH)-、-NHZ-(C=NR’)-、-NHZ-O(C=NR’)-、-NHZ-NH(C=NR’)-、-NHZ-NR’(C=NR’)-、-NHZ-S(C=NR’)-、-NR’Z-(C=O)-、-NR’Z-O(C=O)-、-NR’Z-NH(C=O)-、-NR’Z-NR’(C=O)-、-NR’Z-S(C=O)-、-NR’Z-(C=NH)-、-NR’Z-O(C=NH)-、-NR’Z-NH(C=NH)-、-NR’Z-NR’(C=NH)-、-NR’Z-S(C=NH)-、-NR’Z-(C=NR’)-、-NR’Z-O(C=NR’)-、-NR’Z-NH(C=NR’)-、-NR’Z-NR’(C=NR’)-、-NR’Z-S(C=NR’)-、-SZ-(C=O)-、-SZ-O(C=O)-、-SZ-NH(C=O)-、-SZ-NR’(C=O)-、-SZ-S(C=O)-、-SZ-(C=NH)-、-SZ-O(C=NH)-、-SZ-NH(C=NH)-、-SZ-NR’(C=NH)-、-SZ-S(C=NH)-、-SZ-(C=NR’)-、-SZ-O(C=NR’)-、-SZ-NH(C=NR’)-、-SZ-NR’(C=NR’)-、-SZ-S(C=NR’)-、-J-O(C=O)-、-O-J-O(C=O)-、-S-J-O(C=O)-、-NH-J-O(C=O)-、-NR’-J-O(C=O)-、聚醚,例如分子量为76Da至2000Da的聚(亚烷基二醇)、分子量为75Da至2000Da的聚胺、分子量为116Da至2000Da的聚酯、分子量为114Da到2000Da的聚酰胺,和-W-部分,其中H-W-OH是氨基酸或包含2到20个天然存在或合成的氨基酸亚基的肽;
Z选自C1-20亚烷基、C1-20亚烯基、C1-20亚炔基、C6-10亚芳基(例如亚苯基或亚萘基)、C7-20亚芳烷基、C3-10亚环烷基、C4-8亚杂环烷基、C5-10亚杂芳基和C6-20亚杂芳烷基;
J是苯基基团,其带有糖取代基以及相对于所述糖取代基为对位或邻位的亚甲基基团或-(CH=CH)k-CH2-部分,其中k是1至10的整数,进一步地,其中所述亚甲基基团或-(CH=CH)k-CH2部分-直接键合至位于所述生物活性部分B1、B2或B3近端的-O(C=O)-基团,以及所述苯基环的碳直接结合至所述接头基团的位于所述生物活性部分B1、B2或B3远端的其余部分;
每个K相同或不同,且代表C1-10亚烷基;
i是1至100的整数,优选地1至50的整数,更优选地2至20的整数;和
R’是C1-20烃基。
18.一种药物组合物,其包含根据权利要求1至17中任一项所述的抗体-药物缀合物和药学上可接受的赋形剂。
19.根据权利要求1至17中任一项所述的抗体-药物缀合物,用于治疗有需要的患者的疾病或病症的用途。
20.根据权利要求19所述的抗体-药物缀合物的用途,其中所述疾病选自炎性疾病(例如炎性肠病、类风湿性关节炎和动脉粥样硬化)、代谢紊乱(例如糖尿病、胰岛素抵抗、肥胖症)、癌症、细菌感染(例如肺结核、肺炎、心内膜炎、败血症、沙门氏菌病、伤寒症、囊性纤维化、慢性阻塞性肺病)、病毒感染、心血管疾病、神经退行性疾病、神经障碍、行为和精神障碍、血液疾病、染色体疾病、先天与遗传疾病、结缔组织疾病、消化系统疾病、耳鼻喉疾病、内分泌疾病、环境疾病、眼部疾病、女性生殖疾病、真菌感染、心脏病、遗传性癌症综合征、免疫系统疾病、肾脏和泌尿系统疾病、肺病、男性生殖疾病、口腔疾病、肌肉骨骼疾病、骨髓增生异常综合征、神经系统疾病、新生儿筛查、营养疾病、寄生虫病、罕见癌症和皮肤病。
21.一种治疗人类患者的如在权利要求20中定义的疾病或病症的方法,其中所述方法包含向有需要的患者施用至少一种根据权利要求1至17中任一项所述的抗体-药物缀合物。
22.根据权利要求1至17中任一项所述的抗体-药物缀合物用于制造用于治疗患者的如在权利要求20中定义的疾病或病症的药剂的用途。
23.权利要求1至17中任一项所述的抗体-药物缀合物,其中所述生物活性部分从所述聚合物的释放是pH敏感的并且取决于所述生物活性部分和所述聚合物的重复单元之间的键的性质或所述生物活性部分共价键合的接头基团的性质。
24.一种靶向剂-药物缀合物,包含:
(i)靶向剂;
(ii)包含式(I’)的重复单元的聚合物:
其中:
每个n和每个p独立地是0或者是1和6之间的整数;
每个m独立地是0或者是1和4之间的整数,且优选地至少一个m是1;
--------是可以不存在或可以存在的键;
每个D1独立地是O或L1-B1;
每个D2独立地是O或L2-B2;
每个D3独立地是O或L3-B3;
L1是接头基团或键,L2是接头基团或键,L3是接头基团或键,且每个B1、B2和B3是生物活性部分;
条件是,所述聚合物中的至少一个D1、D2或D3基团不是O,且另一条件是当D1、D2或D3是O时,O原子和它所连接的碳原子之间有一个双键;
每个q是1和8之间的整数;
X和Y独立地选自O、NH、NR’和S;
R’是C1-20烃基;
Q选自-CH2(NMe(C=O)CH2)o-、-T1O(CH2CH2O)sT2-和-T1O(CH2CH2CH2O)sT2-,其中T1选自二价亚甲基、亚乙基、亚丙基或亚丁基,且T2选自二价亚甲基、亚乙基、亚丙基或亚丁基;
o是0至100的整数;
s是0至150的整数;和
(iii)聚合物-靶向剂接头,其与所述靶向剂和所述聚合物两者共价键合。
25.根据权利要求24所述的靶向剂-药物缀合物,其中所述靶向剂选自肽、蛋白质、肽模拟物、抗体、抗原、DNA、mRNA、小干扰RNA、小发夹RNA、微小RNA、PNA、折叠体、碳水化合物、碳水化合物衍生物、非利平斯基分子、合成肽和合成寡核苷酸。
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2019
- 2019-12-19 US US17/415,624 patent/US20220054649A1/en active Pending
- 2019-12-19 CA CA3121857A patent/CA3121857A1/en active Pending
- 2019-12-19 JP JP2021536387A patent/JP2022516032A/ja active Pending
- 2019-12-19 AU AU2019411540A patent/AU2019411540A1/en active Pending
- 2019-12-19 WO PCT/GB2019/053629 patent/WO2020128488A1/en unknown
- 2019-12-19 EP EP19831828.9A patent/EP3897744A1/en active Pending
- 2019-12-19 CN CN201980085326.XA patent/CN113226378A/zh active Pending
Patent Citations (4)
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US20120321583A1 (en) * | 2011-06-10 | 2012-12-20 | Mersana Therapeutics, Inc. | Protein-Polymer-Drug Conjugates |
US20130101546A1 (en) * | 2011-06-10 | 2013-04-25 | Mersana Therapeutics, Inc. | Protein-Polymer-Drug Conjugates |
US20170224828A1 (en) * | 2014-10-13 | 2017-08-10 | Spirea Limited | Polymer composed of repeat units having a biologically active molecule attached thereto via a ph-sensitive bond |
WO2017161206A1 (en) * | 2016-03-16 | 2017-09-21 | Halozyme, Inc. | Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use |
Non-Patent Citations (1)
Title |
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DR. BO CHEN ET AL: "Design, Synthesis, and in vitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody–Drug Conjugates", 《CHEMMEDCHEM》, 8 March 2018 (2018-03-08), pages 790 - 794 * |
Also Published As
Publication number | Publication date |
---|---|
EP3897744A1 (en) | 2021-10-27 |
GB201820864D0 (en) | 2019-02-06 |
JP2022516032A (ja) | 2022-02-24 |
WO2020128488A1 (en) | 2020-06-25 |
US20220054649A1 (en) | 2022-02-24 |
AU2019411540A1 (en) | 2021-06-17 |
CA3121857A1 (en) | 2020-06-25 |
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