CN113952469A - 一种带酸性自稳定接头的抗体-药物偶联物 - Google Patents
一种带酸性自稳定接头的抗体-药物偶联物 Download PDFInfo
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Abstract
本发明提供了一种特殊的亲水酸性稳定接头—药物偶联物,由于酸性稳定接头的引入,与较低载药量的偶联物相比,偶联物也可具有较高的载药量,即,每个靶向试剂更高数量的亲水性药物接头,同时保留希望的PK性质并且在体内具有相同或更好的活性。
Description
本申请是申请号为201810620856.7、申请日为2018年6月15日、发明名称为“一种带酸性自稳定接头的抗体-药物偶联物”的分案申请。
技术领域
本发明涉及应用抗体药物偶联物治疗肿瘤或其他疾病,尤其涉及应用一种特殊的亲水酸性稳定接头来制备抗体药物偶联物以增加药物在血浆中的稳定性,同时显著改善药物代谢动力学(PK)。
背景技术
抗体偶联药物(ADC)作为新型的靶向药物,一般由三部分组成:抗体或抗体类配体,小分子药物以及将抗体和药物偶联起来的连接子。抗体偶联药物利用抗体对抗原的特异性识别,将药物分子运输至靶细胞附近并有效释放药物分子,达到治疗目的。2011年8月,美国食品药品监督管理局(FDA)批准西雅图基因公司研制的用于治疗霍奇金淋巴瘤以及复发性变性大细胞淋巴瘤(ALCL)的ADC新药AdecteisTM上市,临床应用已经证明了此类药物的安全性和有效性。
在抗体偶联药物中,为使药物分子与抗体高效的连接,目前进入临床试验的偶联物通常通过连接子连接在配体表面的赖氨酸残基或抗体铰链区的半胱氨酸残基(由链间二硫键部分还原得到)上。然而,由于抗体表面存在大量的赖氨酸残基(超过80个)以及偶联的非选择性,导致偶联数目和位点的不确定性,进而导致抗体药物偶联物的不均一性。通过巯基偶联可有效避免产品质量均一性差的问题,其中马来酰亚胺作为连接头可与抗体巯基在温和条件下迅速,高选择性发生迈克尔加成形成硫醚产物。
然而,越来越多的研究表明,丁二酰亚胺与巯基的加成反应为可逆过程(逆迈克尔加成),当加成产物进入血浆后,由于血浆中大量含有游离巯基的蛋白的存在,可明显观察到加成产物与白蛋白巯基发生交换,导致药物分子脱落。脱落的药物分子一方面产生毒副作用,另一方面降低抗体偶联药物的药效。(见Shen,等“Conjugation site modulate thevivo stability and therapeutic activity of antibody-drug conjugates”NatureBiotech(2012)30:184-189; Baldwin&Kiick,Bioconj.Chem 2011,)22,1946-1953;Alley等Bioconjugate Chem.2008,19,759-765.
为提高抗体偶联药物在血浆中的稳定性,降低巯基逆迈克尔加成作用,许多文献进行了探索。有报道马来酰亚胺与巯基形成的环状硫醚加成产物在含水环境中可发生水解形成硫醚开环产物。与环状硫醚加成产物不同,硫醚开环产物在血浆中保持稳定,不再与其他巯基发生交换。所以,如果能在抗体偶联药物进入体内之前全部转化为开环结构,即可有效避免巯基交换的发生。
加成开环反应速度受反应条件中的PH,温度以及结构本身多种因素的影响,由于抗体对 PH及温度的敏感性,通过优化连接头结构,使其在抗体可耐受的PH、温度下快速开环成为最佳选择。专利WO2016025752公布一种在丁二酰亚胺环外引入强吸电子基团的方法,该方法利用吸电效应降低硫醚加成产物与白蛋白交换,然而也是因为吸电子基团的存在,导致整个丁二酰亚胺与药物连接物在自然条件下难以保存,带强吸电子基团的丁二酰亚胺极易水解开环而不再能与巯基进一步加成。
美国Seattle Genetics公司专利US20130309256公开一种连接头,在丁二酰亚胺旁引入碱性基团以及一个吸电子基团,在碱性基团的促进下加成产物可有效降低白蛋白交换率,在血浆中稳定性明显提高。众所周知,人体血浆PH呈弱碱性,碱性基团的引入虽可促进丁二酰亚胺的开环,但对于整个分子亲水性的改善是不利的。这一点在SeattleGenetics后来的专利WO2015057699中得到了很好的印证。该发明人在分子中引入带碱性基团的稳定接头后,发现在较高载药量的情况下,由于疏水性的原因,整个抗体偶联药物分子在小鼠体内依然被快速降解(见专利WO2015057699第225页),为改善这一情况,该发明人不得不在分子侧链中引入复杂的聚乙二醇结构以改善分子的聚集(见专利WO2015057699)。
除了降低白蛋白交换,提高血浆稳定性以外,抗体-药物偶联物设计中的另一项重要因素是:每个靶向剂能够递送的药物的量(即,连接至各靶向剂(例如,抗体)的细胞毒剂的数量,称为药物载量(drug load)。曾经有假设认为,较高的药物载量的药效将优于较低的药物载量(例如,8-单位载量对比4-单位载量应该拥有更好的体内外药效)。该理论依据是,载药量更高的偶联物将向靶细胞递送更多的药物(细胞毒剂)。体外结果也证实,具有较更高载药量的偶联物在体外对于细胞系具有更高的活性。然而,后续某些研究揭示,该假设在动物体内模型中并没有得到相应的证实。有文献观察到,具有某种奥瑞他汀药物的4单位与8 单位药物载量的偶联物在小鼠模型中出乎预料的具有相似活性,并未观察到8单位药物载量更高的药效。参见Hamblett等的报道,Clinical Cancer Res.10:7063-70(2004)。Hamblett 等揭示了上述实验现象的原因,并进一步报道了更高载体的ADC在动物模型中将被更快的清除出循环。该更快的清除表明,较高载量的偶联物相比较低载量的偶联物的PK更加不稳定的倾向。另外,较高载量的偶联物在小鼠中有较低的MTD,并且因此具有较窄的治疗指数。相反,报告单克隆抗体中工程改造的位点处载药量为2的ADC具有与某些4-单位载量ADC相比相同或更好的PK性质和治疗指数。参见Junutula等的报道,Clinical CancerRes.16:4769(2010)。
提高载药量理论上可提高单个抗体携带的进入靶向细胞药物数量,然而由于药物的疏水性,在提高药物数量的同时也提高了ADC药物的疏水性,导致ADC药物在体内聚集而降低治疗指数。克服较高载量ADC的PK降低倾向的替代方法包括向ADC结构中添加增溶基团。例如,在连接子中(例如,在药物和抗体的接合位点之间)增加包括了聚乙二醇聚合物或其它水溶性聚合物以尝试克服聚集倾向。如Seattle Genetics公司在拥有通过引入碱性基团而稳定接头的技术后,依然需要通过在接头-药物偶联物中引入侧链PEG等方法来改善高载药量下药物分子的PK。然而,添加增溶基团会增加这种偶联物的制备复杂度。
因此,在改善高载药量(DAR)带来的不利影响的新型ADC领域中亟需一种新的方法,可同时克服丁二酰亚胺巯基交换增加血浆稳定性并同时改善高DAR的抗体偶联药物的药代动力学性质。
发明内容
本发明旨在提供一种特殊的亲水酸性稳定接头—药物偶联物。发明人通过实验惊奇的发现,与US20130309256描述的引入碱性基团不同,带酸性的氨基酸或寡肽单元的引入可以降低丁二酰亚胺与抗体偶联物的巯基交换,在血浆中保持高度稳定性。同时,通过实验证明,由于氨基酸的引入,所设计的偶联物具有与未偶联的靶向试剂相似的亲水性,从而保留了与体内未偶联的靶向试剂相似的药代动力学(PK)性质。所以,酸性稳定接头的存在,通过以上两种途径共同增加药物在血浆中的稳定性,改善药物代谢动力学(PK),从而对药效带来帮助。
由于酸性稳定接头的引入,与较低载药量的偶联物相比,偶联物也可具有较高的载药量(即,每个靶向试剂更高数量的亲水性药物接头),同时保留希望的PK性质并且在体内具有相同或更好的活性。(例如,4-单位载量或8-单位载量偶联物可分别具有与其2或4单位载量对应物相比相同或更好的PK性质;这种4-单位载量或8-单位载量偶联物可分别具有与其 2或4单位载量对应物相比相同或更好的PK性质)。
具体的,本发明提供一种如式I所示的抗体药物偶联物或其药学上可接受的盐:
其中
L是抗体,抗体片段或蛋白;
M是琥珀酰亚胺或水解琥珀酰亚胺;
Ac为由氨基和酸性基团组成的片段或由多个氨基酸组成的寡肽,且以氨基部分与圆圈相连;
D是药物部分;
A是连接子部分;
圆圈表示支架,为取代或无取代C1-8亚烃基、C1-8杂亚烃基、C6-10亚芳基或C4-10杂亚芳基;
m选自1-20范围的整数,n为1或2。
优选的,所述抗体为针对细胞表面受体和肿瘤相关抗原的抗体。
优选的,Ac为整体显酸性的氨基酸单元或酸性寡肽。
更加优选的,Ac优选为等电点7.0以下的天然氨基酸或非天然氨基酸及它们组成的寡肽。
在一些优选例中,所述寡肽单元优选2-5个氨基酸组成。
在一些优选例中,所述A是可裂解连接子或不可裂解连接子。
在一些优选例中,所述药物为细胞毒性药物,治疗自身免疫疾病的药物和抗炎症的药物。
更加优选的,药物D选自美登素类药物、澳瑞他汀类药物,苯并二吡咯类药物,吡咯并苯二氮唑类药物,鹅膏毒素或其衍生物,喜树碱类化合物组成的组。
在一些优选例中,A具有下式:
其中C是末端任选的可延伸单元,E为任选的可断裂单元,F为间隔单元,下标e,f为0或 1。波浪线表示到酸性自稳定接头和药物单元的连接位点。
在一些优选例中,圆圈表示C1-8亚烃基或C1-8杂亚烃基。
更加优选的,圆圈表示C1-3亚烃基;
在一些优选例中,所述的Ac选自(D/L)甘氨酸,(D/L)丙氨酸,(D/L)亮氨酸,(D/L)异亮氨酸, (D/L)缬氨酸,(D/L)苯丙氨酸、(D/L)脯氨酸、(D/L)色氨酸、(D/L)丝氨酸、(D/L)酪氨酸、(D/L) 半胱氨酸、(D/L)蛋氨酸、(D/L)天冬酰胺、(D/L)谷氨酰胺、(D/L)苏氨酸、(D/L)天冬氨酸、(D/L) 谷氨酸或以下结构式:
本发明的另一方面,提供了一种结构如下所示的接头—药物连接物:
Ac为等电点小于7的氨基酸单元;
D是药物部分;
A是连接子部分;
q选自1-8范围的整数,n为1或2。
本发明提供了一种抗体药物偶联物或其药学上可接受的盐,以及药学上可接受的稀释剂运载体或赋形剂的药物组合物。
抗体药物偶联物或其药学上可接受的盐用于制备治疗癌症、免疫疾病、炎症药物的用途。
附图说明
图1为化合物11的MS-TOF检测结果。
图2A为H-11的SEC-HPLC检测结果。
图2B为H-20的SEC-HPLC检测结果。
图2C为H-29的SEC-HPLC检测结果。
图2D为H-39的SEC-HPLC检测结果。
图2E为H-41的SEC-HPLC检测结果。
图2F为H-43的SEC-HPLC检测结果。
图2G为MC-VC-PAB-MMAE的SEC-HPLC检测结果。
图2H为DPR-VC-PAB-MMAE的SEC-HPLC检测结果。
图3为未偶联的抗体,带酸性稳定接头的ADC和对照ADC的小鼠体内稳定性的研究结果。
图4为带酸性稳定接头的ADC和1种对照ADC的HIC色谱结果。
图5为带酸性稳定接头的ADC和1种对照ADC的体内药效结果。
图6为实施例56实验结果图。
具体实施方式
发明人经过广泛而深入的研究,惊奇的发现具有酸性稳定接头的抗体药物偶联物在血浆中具有更佳的稳定性,并且与传统的抗体药物偶联物相比,具有更好的亲水性,偶联后的结构可承受更高载药量,并且保持低载量时结构的药代动力学。更高载药量可带来更好的活性和治疗效果。
具体的,本发明提供的具有酸性稳定接头的抗体药物偶联物具有马来酰亚胺单元,在与抗体巯基偶联后,在稳定酸性基团的参与下,马来酰亚胺水解开环,所形成结构在血浆中不与其他含巯基的大分子交换,从而避免药物分子的脱落。
同时,由于亲水酸性基团的存在,所形成的开环结构抗体药物偶联物亲水性更好,可避免因提高载药量而导致的活性降低等问题。
所产生的抗体药物偶联物可用于靶向药物到达目标细胞群体,例如肿瘤细胞。抗体药物偶联物可以特异性的与细胞表面蛋白结合,所产生的结合物随机被细胞内吞。在细胞内,药物以活性药物的方式释放出来产生功效。抗体包括嵌合抗体、人源化抗体,人抗体;可与抗原结合的抗体片段;或者抗体Fc融合蛋白;或者蛋白。药物是高活性的药物,包括,但不局限于,美登素类(Maytansinoids),澳瑞他汀类药物(Auristatins),卡奇霉素类(Calicheamicins),阿霉素类(doxorubicins),苯并二吡咯类抗生素类(Duocarmycins andCC-1065),吡咯并苯二氮卓二聚体类(PBDS)类,鹅膏毒素类,喜树碱及衍生物如SN38、伊立替康、依喜替康等。
本专利的详细说明
缩写和定义
除非另有说明,否则如本文所用的以下术语和短语旨在具有以下含义。当本文中使用商标名称时,除非上下文中另有指明,否则商标名称包括所述商标名称产品的产品配方、通用药物和活性药物成分。
术语“亚烃基”是指具有1-20个碳原子的二价直链饱和烃基团,包括从1至10碳原子的基团。亚烃基基团的实施例包括但不限于亚甲基(-CH2-),亚乙基(-CH2-CH2-),亚正丙基,亚正丁基,亚正戊基和亚正己基等。除非另有说明,术语“芳基”指多不饱和、一般是芳族的羟基团,它可以是单环或者稠合或共价连接的多环(至多三个环)。术语“芳杂基”指含有1-5个选自N、O或S的杂原子的芳基(或环),其中所述氮和硫原子任选被氧化,所述氮原子任选被季铵化。杂芳基团可通过杂原子连接于分子的其余部分。芳基基团的非限制性例子包括:苯基、萘基和二苯基,而杂芳基团的非限制性例子包括:吡啶基、哒嗪基、吡嗪基、嘧啶基(pyrimindinyl)、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基 (phthalaziniyl)、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡啶并嘧啶基、咪唑并吡啶、苯并噻唑基(benzothiaxolyl)、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、以及噻吩基等。当描述为“取代的”时,上述芳环和杂芳环系统的取代基选自下述可接受的取代基。
本专利中所述亚芳基系指在上述芳基结构中存在以临位、间位或对位存在的两个共价键结构。
除非文中另有说明,烃基(包括通常为称为亚烷基、烯基、炔基和环烷基的那些)的取代基可以是选自下组的多种基团:-卤素、-OR’、-NR’R”、-SR’、-SiR’R”R”’、-OC(O)R’、-C(O)R’、 -CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O)2R’、 -NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、 -S(O)2NR’R”、-NR’S(O)2R”、-CN和-NO2,取代基数量为0至(2m’+1),其中m’为该基团中碳原子的总数。R’、R”和R”’各自独立的指代氢、未取代的C1-8烷基、未取代的芳基、由1-3个卤素取代的芳基、未取代的C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基、或未取代的芳基-C1-4烷基。R’和R”连接于同一个氮原子时,它们可与该氮原子一起形成3-,4-,5-,6- 或7-元环。例如,-NR’R”包括1-吡咯烷基和4-吗啉基。
本文中所用的化合物的“衍生物”是指具有与化合物相似的化学结构但还含有至少一个化合物中不存在的化学基团和/或缺少至少一个化合物中存在的化学基团的物质。衍生物所比较的化合物被称为“母体”化合物。通常,“衍生物”可在一个或多个化学反应步骤中由母体化合物产生。
抗体、抗体片段及蛋白
本发明实施例中抗体、抗体片段和蛋白单元是与靶标部分特异性结合的靶向剂。本发明所述抗体能够特异性结合至细胞组分或结合至其他感兴趣的靶标分子。在一些方面中,抗体单元的作用是将药物单元递送至配体单元与之相互作用的特定靶细胞群。配体包括但不限于蛋白质、多肽和肽,以及非蛋白质如糖。合适的配体单元包括,例如,抗体,例如全长(完整)抗体及其抗原结合片段。在配体单元是非抗体靶向试剂的实施方式中,其可以是肽或多肽,或非蛋白质分子。这类靶向试剂的示例包括干扰素、淋巴因子、激素、生长因子和集落刺激因子、维生素、营养转运分子、或任何其他细胞结合分子或物质。在一些实施方式中,连接子共价连接至配体的硫原子。在一些方面中,硫原子是半胱氨酸残基的硫原子,其形成抗体的链间二硫键。在另一方面中,硫原子是已经导入配体单元的半胱氨酸残基的硫原子,其形成抗体的链间二硫键。在另一方面中,硫原子是已经导入配体单元的半胱氨酸残基的硫原子(例如,通过定点诱变或化学反应)。在其他方面中,连接子结合的硫原子选自形成抗体的链间二硫键的半胱氨酸残基或已经引入配体单元的额半胱氨酸残基(例如,通过定点诱变或化学反应)。在一些实施方式中,按照Kabat(Kabat E.A等,(1991))《免疫学感兴趣的蛋白质序列》(Sequences of proteins of Immunological Interest),第五版,NIH出版物91-3242) 中的EU索引编号系统。
如本专利所用,“抗体”或“抗体单元”在其所属的范围内,包括抗体结构的任何部分。这一单元可以结合,反应性关联,或者络合一个受体,抗原,或者靶向细胞群体具有的其它受体单元。抗体可以是任何蛋白或蛋白类分子,它可以结合,络合,或者与待治疗或生物改造的细胞群体的一部分发生反应。
本专利所用抗体包括多克隆抗体和单克隆抗体其中多克隆抗体时源自免疫动物的血清的抗体分子异质群体。单克隆抗体包括但不限于鼠类、人单克隆抗体、人源化单克隆抗体或嵌合单克隆抗体和衍生自其它物种的抗体。可以通过本领域已知的任何众多技术制备人单克隆抗体(如Teng等,1983,proc.Nat1.Acad.Sci.USA.80:7308-7312.Olsson等,1982,MEthan、, Enzymol 92:3-16)
本专利中组成抗体药物偶联物的抗体最好保持其原有野生状态时的抗原结合能力。因此,本发明中的抗体能够,最好专一性的与抗原结合。涉及的抗原包括,例如,肿瘤相关抗原 (TAA),细胞表面受体蛋白和其他细胞表面分子,细胞存活调节因子,细胞增殖调节因子,与组织生长与分化相关的分子(如已知或预知的具有功能性的),淋巴因子,细胞因子,参与细胞循环调节的分子,参与血管生成的分子,以及与血管生成有关的分子(如已知或预知的具有功能性的)。肿瘤相关因子可以是簇分化因子(如CD蛋白)。
本发明中所述应用在抗体药物偶联物中的抗体包括,但不局限于,针对细胞表面受体和肿瘤相关抗原的抗体。这样的肿瘤相关抗原是业内所熟知的,可以通过业内熟知的抗体制备方法和信息来制备。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物,研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性的表达在一种或多种癌细胞表面,而在一种或多种非癌细胞表面表达很少或不表达。通常,相对于非癌细胞表面而言,这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子,可大大提高基于抗体治疗癌症的专一靶向特性。
本专利中用于制备抗体药物偶联物的蛋白质或肽可以是对表位或相应受体具有亲和力的任何随机肽或蛋白质,并且它们不一定必须属于免疫球蛋白家族。这些肽可以通过与噬菌体展示抗体相似的技术分离(Szardenings,J Recept Signal TransductRes.2003:23(4):307-49)。来自这种随机肽文库的肽的使用可以类似于抗体和抗体片段。肽或蛋白质的结合分子可以是结合或欧联在大分子或材料上,例如但不限于白蛋白、聚合物、脂质体、纳米颗粒、树状聚体,只要这种结合允许肽或蛋白质保留其抗原结合特异性。
肿瘤相关抗原包括,为业内所熟知的抗原。与肿瘤相关抗原对应的核酸和蛋白序列可参见公开数据库,例如Genbank。抗体靶向对应的肿瘤相关抗原包括所有的氨基酸序列变种和同种,与参考文献中确认的序列具有至少70%,80%,85%,90%,或者95%的同源性,或者具备与引用文献中的肿瘤相关抗原序列具有完全一致的生物性质和特征。
术语“抑制”或“的抑制”指,减少了可检测的量,或完全阻止。
术语“癌症”指的是以失调的细胞生长为特征的生理病症或疾病。“肿瘤”包括癌细胞。
术语“自身免疫疾病”是源自针对个体自身的组织或蛋白质的疾病或紊乱。
本文中所用的短语“药学上可接受的盐”指的是,化合物(例如,药物,药物-接头或配体-接头-药物偶联物)的药学上可接收到有机或无机盐。该化合物可含有至少一个氨基或羧基,并且因此可与相应的酸或碱形成加成盐。示例性的盐包括但不限于:硫酸盐、三氟乙酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、水杨酸盐、甲酸盐、本甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐,钾盐、钠盐等。另外,药学上可接受的盐在结构中具有超过一个的带点原子。其中多个带电原子是药学上可接受的盐的一部分的示例能有多个抗衡例子。例如,药学上可接受的盐具有一个或多个带电原子和/或一个或多个抗衡原子。
较佳的药物是指:一种用于癌症治疗的细胞毒性药物,包括但不局限于美登素或类美登素, 海兔毒素10(Dolastatin10)的类似物,卡奇霉素类药物阿霉素类苯并二吡咯类抗生素 (duocarmycins,CC-1065等)吡咯并苯二氮唑类(pyrrolo[2,1-c][1,4]benzodi-azepines,PBDs) 或者PBD二聚体类(PBD dimmers)以及衍生物,鹅膏毒素或者其衍生物,喜树碱类化合物包括喜树碱,羟基喜树碱,SN-38,依喜替康,伊立替康等。
另一方面,药物并不仅仅局限于上述提到的类别,还包括所有可用于抗体药物偶联物的药物。
在一些实施例中,本发明通过带酸性自稳定接头连接的药物还包括下列放射性同位素。包括但不局限于3H,11C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,125I,131I,133Xe,177Lu,211At 和213Bi。
按照在细胞内药物释放的机制,如本文所用,“连接子”或“抗体药物偶联物的连接子”可被分为两类:不可断裂连接子和可断裂连接子。
对于含有不可断裂连接子的抗体药物偶联物,其药物释放机制为:偶联物与抗原结合并被细胞内吞后,抗体在溶酶体中被酶解,释放出由小分子药物,连接子,和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性,但由于活性分子是带电荷的(氨基酸残基),从而导致其不能渗入邻近细胞。因此,此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应,bystander effect)(Ducry等, 2010,Bioconjugate Chem.21:5-13)。
可断裂连接子,顾名思义,可以在目标细胞内断裂并释放出活性药物(小分子药物本身)。可断裂连接子可分为两个主要的类别:化学不稳定连接子和酶不稳定连接子。
化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括 pH值,谷胱甘肽浓度等。
在本专利的一些实施例中,连接子为对pH值敏感的连接子,通常又称为酸断裂连接子。这样的连接子在血液的中性环境下相对稳定(pH7.3-7.5),但是在弱酸性的内涵体(pH5.0-6.5) 和溶酶体(pH4.5-5.0)内将会被水解。第一代的抗体药物偶联物大多应用这类连接子,例如腙,碳酸酯,缩醛,缩酮类。由于酸断裂连接子有限的血浆稳定性,基于此类连接子的抗体药物偶联物通常具有较短的半衰期(2-3天)。这种较短的半衰期在一定程度上限制了pH敏感连接子在新一代抗体药物偶联物中的应用。
对于谷胱甘肽敏感的连接子,又称二硫键连接子。药物释放是基于细胞内谷胱甘肽的高浓度(毫摩尔范围)与血液中相对较低的谷胱甘肽浓度(微摩尔范围)差异引起的。对于肿瘤细胞而言尤其如此,其低含氧量导致还原酶的活性增强,因而导致更高的谷胱甘肽浓度。二硫键具有热力学稳定性,因此在血浆中具有较好的稳定性。
酶不稳定连接子,如肽连接子,能够更好的控制药物释放。肽连接子能够被溶酶体内蛋白酶,如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加),有效的切断。这种肽连接被认为在血浆循环中非常稳定,这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性,酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。典型的酶不稳定性连接子包括Val-Cit(vc),Phe-Lys等。
间隔单元一般嵌合在可断裂连接子与活性药物之间,或者本身就是可断裂连接子的一部分。间隔单元的作用机制是:当可断裂连接子在合宜的条件下断裂后,间隔单元能够自发的进行结构重排,进而释放与之连接的活性药物。常见的此类间隔单元包括对氨基苄醇类(PAB) 和β-葡萄糖醛酸苷类(β-Glucuronide),取代或无取代的乙二胺等。
本专利可以使用以下缩写并具有指定的定义:Boc,叔丁氧基羰基;DCC,环二己基碳二亚胺;DCM:二氯甲烷;DIPEA:二异丙基碳二亚胺;DMF:N、N-二甲基甲酰胺;DMAP:4- (N、N-二甲基氨基)吡啶;HATU:2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;HPLC:高效液相色谱;PEG:聚乙二醇;TFA:三氟乙酸;THF:四氢呋喃;PBS:磷酸盐缓冲溶液(PH7.0-7.5)。
药学上可接受的赋形剂包括任何载体,稀释剂,佐剂或赋形剂,如防腐剂和抗氧剂,填充剂,崩解剂,湿润剂,乳化剂,悬浮剂,溶剂,分散介质,包衣剂,抗细菌剂和抗真菌剂和吸收延迟剂等。这样的介质和药剂用于药物活性物质的使用在本领域时公知的。除了任何常规的介质或试剂与活性成分不相容以外,其在治疗组合物中的用途也被考虑到。作为合适的治疗组合,还可以将补充的活性成分掺入组合物中。
本发明的主要优点在于:
1、本发明提供的具有酸性稳定接头抗体药物偶联物,可以大幅降低了偶联物在体内发生与白蛋白巯基交换,显著增加血浆稳定性。
2、本发明提供的酸性稳定接头,因为酸性基团的引入,分子具有更好的水溶性,有效的改善了抗体偶联药物的PK性质,具有更好的体内药效。
3、本发明提供的带酸性稳定接头的抗体药物偶联物在增加血浆稳定性的同时可改善最终偶联物的PK性质,以上优势可以很好的满足高载药量需求,降低高载药量下抗体药物偶联物的聚集,获得相比于低载药量更好的药效。
下面结合具体实施例,进一步阐述本发明,应理解,这些实施例只用于说明本发明,而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比例、比率、或份数按重量计。除非另行定义,文中所使用的所有专业和科学用于与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明下列实施例中采用的通用步骤是:
通用步骤A
将通过初步的纯化后单体率大于95%的抗体分子,使用超滤离心管换液至含有EDTA的磷酸盐缓冲液中,浓度10mg/ml。加入10倍于抗体摩尔分子数的TCEP,室温下反应8h。打开抗体链间二硫键,并用Ellman方法测定游离巯基数,判断二硫键是否全部打开。然后加入10 倍于抗体摩尔分子数的payload,室温下反应8h。反应结束后,使用截留分子量为30KDa的超滤离心管换液至PBS中,并去除未偶联的payload。
通用步骤B
药代动力学研究
检测血清中抗体的ELISA方法:抗抗体2ug/ml 4℃包被过夜,PBST洗板3次, 1%BSA+PBST 37℃封闭1hr;孵育血清样品,PBST洗板3次;37℃孵育检测抗体(抗Fc的单抗或多抗(HRP标记))1hr,PBST洗板3次,TMB显色,2M H2SO4终止,酶标仪读值。
通用步骤C
疏水性相互作用色谱(HIC)测定
使用疏水性相互作用色谱(HIC)来进行对ADC的分析。通过0-100%流动相B(MPB)脱,其中流动相A(MPA)由1.5M硫酸铵和.025M磷酸钠组成,并且MPB由0.025M的磷酸钠、25%异丙醇组成。样品上样量约为20μg,梯度洗脱在15分钟完成。用UV280nm进行检测,输水性越强的样品越晚出峰。
通用步骤D
血浆稳定性研究
取一定量的ADC样品,加入到已去除人IgG的人血浆中,每种ADC重复三管,放置37℃水浴中孵育,分别孵育0h、72h后,取出ADC样品,每管加入ProteinA(MabSelect SuReTMLX Lot:#10221479 GE,用取PBS洗涤过的)100ul,垂直混合仪晃动吸附2h,经过洗涤洗脱步骤, 获得孵育后的ADC.对孵育特定时间的ADC样品进行RP-HPLC检测.判定样品的血浆稳定性。
通用步骤E定点偶联制备ADC
将通过初步的纯化后单体率大于95%的抗体分子,使用超滤离心管换液至含有EDTA的磷酸盐缓冲液中,浓度10mg/ml。加入10倍于抗体摩尔分子数的TCEP,室温下反应2h,。使用超滤离心管换液至pH6.5的磷酸缓冲液中,再加入10倍于抗体摩尔分子数的DHAA,室温下反应2h。然后加入3倍于抗体摩尔分子数的payload,室温下反应4h。反应结束后,使用截留分子量为30KDa的超滤离心管换液至PBS中,并去除未偶联的payload得定点偶联ADC(DAR=2)。
实施例1
化合物1的制备
将化合物(S)-N-苄氧羰基-N’-叔丁氧羰基-2,3-二氨基丙酸50g溶于500mL二氯甲烷中,加入三氟乙酸50mL,室温搅拌反应过夜。反应完全后减压浓缩干,加入乙酸乙酯溶解,再加入正己烷搅拌析出固体,过滤,干燥得固体21g。LC-MS m/z(ES+):239.1(M+H)+。
实施例2
化合物2的制备
将200mL苯甲醇加入反应瓶中,水浴下缓慢滴入二氯亚砜(6.69mL,92.4mmol),滴完搅拌1h,分批次加入化合物1(20g,84mmol),加完室温搅拌过夜。反应结束,油泵减压蒸出苄醇,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷:甲醇=150:1)分离得到产品22g。LC-MS m/z(ES+):329.1(M+H)+。
实施例3
化合物3的制备
将化合物2(10g,30.4mmol)溶于150mL乙腈中,加入二异丙基乙基胺(DIEA,4.72mL, 36.58mmol),冰水浴下滴加溴乙酸叔丁酯(4.75g,24.4mmol),滴毕,反应30min后移至室温反应,TLC(展开剂DCM:MeOH=10:1)检测。反应完毕后,减压浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷:甲醇=100:1)分离得到产品5.9g。LC-MS m/z(ES+):443.3(M+H) +。
实施例4
化合物4的制备
将化合物3(5.9g,13.3mmol)、30mL1,4-二氧六环、30mL水加入反应瓶中,再加入DIEA (3.3mL,20mmol),室温下滴入Boc酸酐(14.5g,66.7mmol),反应液呈黄色,滴完室温反应约3-4h,TLC(展开剂DCM:MeOH=30:1)监测。反应完全后减压浓缩除去二氧六环,加入DCM萃取,减压浓缩得黄色油状物粗品,经硅胶柱层析色谱(洗脱液为二氯甲烷:甲醇=300:1)分离得产品6.6g。LC-MS m/z(ES+):443.3(M+H)+-Boc,543.2(M+H)+。
实施例5
化合物5的制备
将6.6g化合物4溶于50ml甲醇中,加入1.32g 5%Pd/C,氢气置换2-3次,室温反应,TLC (展开剂DCM:MeOH=5:1)监测。反应完全后,过滤,于40℃下减压浓缩得产品4.4g,直接用于下一步反应。
实施例6
化合物6的制备
将化合物5(4.4g,13.8mmol)溶于40mL冰乙酸中,加入马来酸酐(2.71g,27.6mmol),室温搅拌反应。TLC(DCM:MeOH=3:1)监测反应。反应完全减压浓缩,残余物用高效液相纯化。
(柱:YMC-C18,100mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=215nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 90%A,10-25min,90%A~45%A,25-55min,45%A~40%A
收集具有43min保留时间的馏分并冻干,得白色固体1.51g。LC-MS m/z(ES+):317.9(M+H) +-Boc,417.9(M+H)+。
实施例7
化合物7的制备
将化合物6(1.2g,2.88mmol)溶于25mL干燥的甲苯及2.5mLDMA溶液中,加入三乙胺(1.2mL,8.65mmol)(可加入几粒干燥的分子筛),氮气置换,升温至120℃反应,TLC(展开剂DCM:MeOH=3:1)监测反应。反应完全后,油泵减压浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇从20/1到10/1)分离得产品700mg。LC-MS m/z(ES+):299.2(M+H) +-Boc,399.3(M+H)+。
实施例8
化合物8的制备
将700mg(1.7mmol)化合物7溶于3.5mLDMF中,加入531mg(2.11mmol)EEDQ、733mg(1.93mmol)Val-Cit-PABOH,室温反应。TLC(展开剂DCM:MeOH=5:1)监测。反应完毕后于45℃下油泵浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇从50/1到20/1) 分离得520mg。LC-MS m/z(ES+):660.3(M+H)+-Boc,760.4(M+H)+。
实施例9
化合物9的制备
将520mg(0.685mmol)化合物8、1.04g(3.42mmol)NCP依次加入反应瓶中,加入10mLDMF 溶清,再加入0.33mL(2.05mmol)DIEA,室温反应。TLC(展开剂DCM:MeOH=5:1)监测。反应完毕后于45℃油泵浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇=30/1)分离得530mg。LC-MS m/z(ES+):825.3(M+H)+-Boc,925.2(M+H)+。
实施例10
化合物10的制备
将530mg(0.57mmol)化合物9、13.5mg(0.1mol)HOBT溶于5mLDMF中,加入0.17mL(1.04mmol)DIEA,室温活化1h后,加入373mg(0.52mmol)MMAE室温反应过夜。HPLC 监测,原料MMAE作用完。用高效液相纯化。
(柱:YMC-C18,50mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速50mL/min,于λ=205nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 90%A,10-25min,90%A~45%A,25-55min,45%A~40%A
收集具有34min保留时间的馏分并冻干,得产品200mg,LC-MS m/z(ES+):1503.2(M+H)+。
实施例11
化合物11的制备
将70mg化合物10溶于10mL干燥二氯甲烷,加入4mL三氟醋酸,室温反应1h,用高效液相纯化。
(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=205nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 95%A,10-30min,95%A~80%A,30-50min,80%A~50%A
收集具有33min保留时间的馏分并冻干,得产品34mg,LC-MS m/z(ES+):1347.8(M+H)+。
实施例12
化合物12的制备
将化合物L-谷氨酸二叔丁酯(8g,,30.8mmol)溶于150mL乙腈中,加入DIEA(6mL,37mmol),冰水浴下滴加2-溴代-N-苄氧羰基-L-丙氨酸苄酯(10.2g,26.1mmol),滴毕,反应40min后移至室温反应,TLC(展开剂DCM:MeOH=10:1)检测。反应完毕后,减压浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇=100/1)分离得到产品8.1g。LC-MS m/z(ES+):571.2(M+H)+。
实施例13
化合物13的制备
将8.1g(14.2mmol)化合物12、50mL1,4-二氧六环、50mL水加入反应瓶中,再加入3.5mL (21.3mmol)DIEA,室温下滴入14.5g(66.7mmol)Boc酸酐,反应液呈黄色,滴完室温反应,TLC(展开剂DCM:MeOH=30:1)监测。反应完全后减压浓缩除去二氧六环,加入DCM 萃取,减压浓缩得黄色油状物粗品,经硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇=300/1)分离得产品8.55g。LC-MS m/z(ES+):471.1(M+H)+-Boc,571.3(M+H)+。
实施例14
化合物14的制备
将8.5g化合物13溶于70ml甲醇中,加入1.7g 5%Pd/C,氢气置换2-3次,室温反应,TLC (展开剂DCM:MeOH=5:1)监测。反应完全后,过滤,于40℃下减压浓缩得产品5g,直接用于下步反应。
实施例15
化合物15的制备
将5g(11.2mmol)化合物14溶于40mL冰乙酸中,加入2.19g(22.4mmol)马来酸酐,室温搅拌反应。TLC(DCM:MeOH=3:1)监测反应。反应完全减压浓缩,残余物用高效液相纯化,
(柱:YMC-C18,100mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=215nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 90%A,10-25min,90%A~45%A,25-55min,45%A~40%A
收集具有48min保留时间的馏分并冻干,得产品2.3g。LC-MS m/z(ES+):445.2(M+H)+-Boc, 545.3(M+H)+。
实施例16
化合物16的制备
将2g(3.80mmol)化合物15溶于25mL干燥的甲苯及2.5mLDMA溶液中,加入1.58mL(11.4mmol)三乙胺,氮气置换,升温至120℃反应,TLC(展开剂DCM:MeOH=3:1)监测反应。反应完全后,油泵减压浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇从20/1 到10/1)分离得产品1.19g.LC-MS m/z(ES+):427.1(M+H)+-Boc,527.3(M+H)+。
实施例17
化合物17的制备
将1.19g(1.7mmol)化合物16溶于3.5mLDMF中,加入531mg(2.11mmol)EEDQ、733mg(1.93mmol)Val-Cit-PABOH,室温反应。TLC(展开剂DCM:MeOH=5:1)监测。反应完毕后于45℃下油泵浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇从50/1到25/1) 分离得753mg。LC-MS m/z(ES+):788.5(M+H)+-Boc,888.4(M+H)+。
实施例18
化合物18的制备
将753mg(0.849mmol)化合物17、1.28g(4.24mmol)NCP依次加入反应瓶中,加入15mLDMF 溶清,再加入0.35mL(2.55mmol)DIEA,室温反应。TLC(展开剂DCM:MeOH=5:1)监测。反应完毕后于45℃油泵浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇=25/1)分离得762mg。LC-MS m/z(ES+):1053.6(M+H)+。
实施例19
化合物19的制备
将762mg(0.71mmol)化合物18、13.5mg(0.1mol)HOBT溶于8mLDMF中,加入0.23mL(1.42mmol)DIEA,室温活化1h后,加入463mg(0.645mmol)MMAE室温反应过夜。HPLC 监测,原料MMAE反应完。用高效液相纯化。
(柱:YMC-C18,100mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=215nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 90%A,10-25min,90%A~45%A,25-55min,45%A~40%A
收集具有30min保留时间的馏分并冻干,得产品300mg。LC-MS m/z(ES+):1631.6(M+H)+。
实施例20
化合物20的制备
将100mg化合物19溶于10mL干燥二氯甲烷,加入4mL三氟醋酸,室温反应2h,用高效液相纯化。
(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=215nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 95%A,10-25min,95%A~80%A,25-55min,80%A~55%A
收集具有30min保留时间的馏分并冻干,得产品45mg。LC-MS m/z(ES+):1419.1(M+H)+。
实施例21-29
化合物21-29合成
实施例21
化合物21的制备
将化合物3-硝基-4氨基苯甲酸15g溶于100ml甲醇中,加入3g 5%Pd/C,常压氢化5h,过滤,滤饼以甲醇洗涤2次,高真空下室温浓缩至干,不经纯化直接用于下步反应。
实施例22
化合物22的制备
将化合物3,4-二氨基苯甲酸(10g,65.7mmol)溶于100mLDMF中,加入碳酸钾粉末(13.6g, 98.55mol)及碘化钾(2.2g,1.31mmol),氮气保护下滴加溴乙酸叔丁酯(12.8g,65.7mol),滴毕室温反应。TLC(展开剂DCM:MeOH=10:1)检测。反应完毕后,加入水,乙酸乙酯萃取,合并有机相,经饱和食盐水洗涤,无水硫酸钠干燥,过滤、减压浓缩,残余物用硅胶柱层析色谱纯化(洗脱液为二氯甲烷/甲醇=150/1~100/1)分离得到产品3.46g。LC-MS m/z(ES+):267.4(M+H)+;HNMR:7.51-7.53,dd,1H;7.44-7.45,d,1H;6.66-6.69,d,1H;4.69, s,2H;1.49,s,9H。
实施例23
化合物23的制备
将3g(11.2mmol)化合物22、15mL冰乙酸、顺丁烯二酸酐(0.55g,5.6mmol)水加入反应瓶中,室温反应,HPLC监测。反应完全后减压浓缩除去冰乙酸,制备纯化.(柱:YMC-C18,100mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=214nm检测) 溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-5min 80%A,5-35min,80%A~65%A,35-45min,65%A~60%A,收集具有37min-42min 保留时间的馏分并冻干,得产品2g。LC-MS m/z(ES+):365.4(M+H)+,309.3(M+H)+-tBu。 HNMR:10.48,s,1H;7.41-7.44,dd,1H;7.35-7.36,d,1H;6.92,s,2H;6.70-6.72,d,1H;4.68,s,2H; 1.42,s,9H。
实施例24
化合物24的制备
将化合物23(2g,5.49mmol)溶于30mlTHF中,加入Boc酸酐(1.44g,6.59mmol),DMAP(1.32g,10.9mmol)及DIEA(1.8mL,10.98mmol),室温反应。TLC(展开剂DCM:MeOH=10:1) 监测。反应完全后,经硅胶柱层析色谱,洗脱液为二氯甲烷/甲醇=100/1~20/1)分离得到产品2.2g.LC-MS m/z(ES+):365.4(M+H)+-Boc。HNMR:10.50,s,1H;7.46-7.48,dd,1H;7.41-7.42, d,1H;6.95,s,2H;6.73-6.75,d,1H;4.69,s,2H;1.48,s,9H;1.40,s,9H。
实施例25
化合物25的制备
将2g(4.31mmol)化合物24溶于15mL甲苯及2mLDMA中,加入(1.2mL,8.62mmol) 三乙胺,120℃反应。TLC(DCM:MeOH=10:1)监测反应。反应完全减压浓缩,残余物用硅胶柱层析色谱纯化,洗脱液为二氯甲烷/甲醇=100/1~50/1)分离得到产品1.63g.LC-MS m/z(ES+):347.4(M+H)+-Boc。HNMR:7.50-7.51,dd,1H;7.43-7.44,d,1H;6.97,s,2H;6.75-6.77 d,1H;4.67,s,2H;1.48,s,9H;1.40,s,9H。
实施例26
化合物26的制备
将1.6g(3.58mmol)化合物25溶于10mLDMF中,加入1.77g(7.17mmol)EEDQ、2.98g(7.89mmol)Val-Cit-PABOH,室温反应。TLC(展开剂DCM:MeOH=10:1)监测。反应完毕后于45℃下油泵浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇从100/1到25/1) 分离得2.1g。LC-MS m/z(ES+):709.8(M+H)+-Boc,809.7(M+H)+。
实施例27
化合物27的制备
将2g(2.47mmol)化合物26、3.71g(12.3mmol)NCP依次加入反应瓶中,加入20mLDMF溶清,再加入1.2mL(7.41mmol)DIEA,室温反应。TLC(展开剂DCM:MeOH=15:1)监测。反应完毕后于45℃油泵浓缩,残余物用硅胶柱层析色谱(洗脱液为二氯甲烷/甲醇=100/1)分离得2.1g。LC-MS m/z(ES+):973.3(M+H)+。
实施例28
化合物28的制备
将1g(1mmol)化合物27、13.5mg(0.1mol)HOBT溶于8mLDMF中,加入0.33mL(2mmol)DIEA,室温活化1h后,加入646mg(0.9mmol)MMAE室温反应过夜。HPLC监测,原料 MMAE反应完。用高效液相纯化。
(柱:YMC-C18,100mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 90%A,10-25min,90%A~45%A,25-55min,45%A~40%A
收集具有30min保留时间的馏分并冻干,得产品560mg。LC-MS m/z(ES+):1551.7(M+H)+。
实施例29
化合物29的制备
将100mg化合物28溶于10mL干燥二氯甲烷,加入4mL三氟醋酸,室温反应2h,用高效液相纯化。
(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 95%A,10-25min,95%A~80%A,25-55min,80%A~55%A
收集具有30min保留时间的馏分并冻干,得产品45mg。LC-MS m/z(ES+):1395.7(M+H)+。
实施例30-39
化合物30-39合成
实施例30
化合物30的制备
在500ml的圆底烧瓶中,将碳酸钾(24.7g,179.24mmol)溶于220ml纯水中,再加入(S) -3-氨基-2-(苄氧羰基氨基)丙酸(16g,67.16mmol),搅拌至大部分溶解,然后加入2-溴乙基磷酸二乙酯(10.98g,44.81mmol),加入完毕后置于80℃的油浴锅中搅拌反应6小时,反应完毕。反应液经高效液相制备纯化。(柱:YMC-C18,100mm*450mm,10μm,采用乙腈 /水(0.2%TFA),流速200mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min,5%B~15%B,10-15min,15%B,15-25min,15%B~20%B,25-50min,20%B~ 30%B,50-55min,30%B~50%B,55-65min,50%B~90%B。收集具有42~49min保留时间的馏分并冻干,得产品8.38g无色油状物,产率为46.5%。1H NMR data(CDCl3,400MHz):7.39-7.28 (m,5H),6.54-6.41(m,1H),5.12-5.01(m,2H),4.63-4.53(m,1H),4.16-4.03(m,4H),3.48-3.36(m, 2H),3.35-3.25(m,2H),2.35-2.23(m,2H),1.29(t,J=6.8Hz,6H);LCMS[M+H]+m/z 403.3 (calcd for C17H27N2O7P,402.16)。
实施例31
化合物31的制备
在100ml的三口瓶中,用50ml二氯甲烷溶剂将化合物30(8.3g,20.85mmol)溶解,氮气保护下置于0℃的低温反应器中,搅拌下滴入DIEA碱(6.7g,52.11mmol)的,之后再于半小时滴入Boc酸酐(5.0g,22.935mmol),滴加完毕后移至室温搅拌反应2小时,TLC检测反应完全(展开剂DCM:MeOH=4:1)。后处理:反应液中加入水洗涤三次,有机相用无水硫酸钠干燥后减压浓缩,残余物经高效液相制备纯化。(柱:YMC-C18,100mm*450mm,10 μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0min,40%B,0-10min,40%B,10-20min,40%B~45%B,20-30min,45%B,30-45min, 45%B~80%B,45-50min,80%B~95%B。收集具有26~29.5min保留时间的馏分并冻干,得4.02g 的无色油状液体,产率为38.3%。1H NMR data(CDCl3,400MHz):7.36-7.28(m,5H),5.09(s,2H), 4.63-4.43(m,1H),4..14-4.01(m,4H),3.92-3.65(m,2H),3.61-3.29(m,2H),2.34-1.95(m,2H), 1.45(s,9H),1.36-1.22(m,6H);LCMS[M+H]+m/z 503.4(calcd for C22H35N2O9P,502.21)。
实施例32
化合物32的制备
在150ml的圆底烧瓶中,用50ml甲醇将化合物31(4.0g,8.0mmol)溶解,再加入800mg 的Pd/C(含Pd量为5%),氢气置换后室温搅拌反应4小时,TLC检测(展开剂DCM:MeOH=4: 1)反应完全,停止反应。有机膜滤去钯碳,减压浓缩,残余物无需纯化,直接投入下步反应。 LCMS[M+H]+m/z 369.4(calcd for C14H29N2O7P,368.17)。
实施例33
化合物33的制备
在100ml的圆底烧瓶中加入30ml冰乙酸将未经纯化的化合物32溶解,再于搅拌下加入顺丁烯二酸酐(1.57g,16.0mmol),之后室温搅拌反应过夜。次日停止反应,45℃下用油泵减压浓缩除去冰乙酸,残余物经高效液相制备纯化。(柱:YMC-C18,100mm*450mm,10 μm,采用乙腈/水(0.2%TFA),流速200mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0min,5%B,0-10min,5%B~15%B,10-20min,15%B~30%B,20-35min,30%B~55%B, 35-45min,55%B,45-55min,55%B~80%B,55-60min,80%B~98%B。收集具有25~26.5min 保留时间的馏分并冻干,得3.35g油状物,两步产率为90%。1H NMR data(CDCl3,400MHz): 6.40(d,J=12Hz,1H),6.35(d,J=12Hz,1H),4.96-4.82(m,1H),4.19-3.99(m,4H),3.98-3.61 (m,2H),3.60-3.36(m,2H),2.22-2.00(m,2H),1.45(s,9H),1.33(t,J=7.0Hz,3H),1.32(t,J=7.0 Hz,3H);LCMS[M+H]+m/z 467.3(calcd for C18H31N2O10P,466.17)。
实施例34
化合物34的制备
在100ml的圆底烧瓶中,用40ml甲苯和4ml的DMA将化合物33(3.3g,7.07mmol)搅拌溶解,再加入三乙胺(2.1g,21.2mmol),装上分水器和回流冷凝管120℃回流搅拌反应3 小时,TLC检测反应完全(展开剂DCM:MeOH=4:1)。后处理:45℃减压浓缩除去甲苯,残余物经高效液相制备纯化。(柱:YMC-C18,100mm*450mm,10μm,采用乙腈/水 (0.2%TFA),流速200mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0min,5%B,0-10min,5%B~15%B,10-20min,15%B~30%B,20-35min,30%B~55%B, 35-45min,55%B,45-55min,55%B~80%B,55-60min,80%B~98%B。收集具有27~29min保留时间的馏分并冻干,得2.12g的白色粉末状固体(很快吸潮变为粘稠油状物),产率为67%。 LCMS[M+H]+m/z 449.3(calcd for C18H29N2O9P,448.16)。
实施例35
化合物35的制备
装有化合物34(2.1g,4.69mmol)的100ml圆底烧瓶用油泵抽干可能的残余水分,加入 20ml干燥的DMF搅拌溶解,然后加入DIEA(1.8g,14.07mmol),再顺序加入EDCI(1.81g,9.38mmol)和HoAt(1.28g,9.38mmol),之后室温搅拌活化化合物5半小时,再加入化合物 6(2.66g,7.03mmol),室温搅拌反应过夜,次日停止反应。后处理:45℃油泵减压浓缩除去DMF溶剂,残余物经柱层析纯化(洗脱剂二氯甲烷:甲醇=20:1~10:1~5:1),得1.01g白色粉末状固体,产率为26.6%。LCMS[M+H]+m/z 810.4(calcd for C36H56N7O12P,809.37)。
实施例36
化合物36的制备
在50ml的圆底烧瓶中,用15ml干燥DMF将化合物35(1.0g,1.24mmol)搅拌溶解,再加入DIEA(961mg,7.44mmol)与NPC(1.88g,6.2mmol),加入完毕室温搅拌反应过夜,次日早TLC检测反应完全(展开剂二氯甲烷:甲醇=5:1),停止反应。后处理:45℃用油泵减压浓缩,残余物制备薄层层析(展开剂二氯甲烷:甲醇=6:1)制备纯化得1.02g的白色粉末状固体,产率为84.5%。LCMS[M+H]+m/z 975.3(calcd for C43H59N8O16P,974.38)。
实施例37
化合物37的制备
在100ml的圆底烧瓶中,用10ml干燥的DMF将化合物36(1.0g,1.03mmol)溶解,再加入HoBt(28mg,0.21mmol)和DIEA(266mg,2.06mmol),搅拌反应半小时后,再加入 MMAE(740mg,1.03mmol),室温搅拌反应过夜。后处理:反应液经制备液相制备纯化。(柱: YMC-C18,50mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速50mL/min,于λ=214nm 检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0min,5%B,0-10min,5%B~15%B,10-20min,15%B~30%B,20-35min,30%B~55%B,35-45min,55%B~70%B,45-55min,70%B,55-60min,70%B~98%B。
收集具有38-40min保留时间的馏分并冻干,得320mg白色粉末状固体,产率为20%。LCMS [M+H]+m/z 1553.8(calcd for C76H121N12O20P,1552.85)。
实施例38
化合物38的制备
用5ml重蒸的二氯甲烷将化合物37(260mg,0.17mmol)溶解于25ml的圆底烧瓶中,氮气保护下于冰浴中加入三甲基溴硅烷(78mg,0.51mmol),加入完毕后移至室温搅拌反应过夜,次日早再加入1ml甲醇室温搅拌反应1小时,液相分析化合物37反应完全。后处理:减压浓缩反应液,残余物经高效液相制备纯化。(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0min,5%B,0-10min,5%B~15%B,10-20min,15%B~30%B,20-35min,30%B~55%B, 35-45min,55%B~70%B,45-55min,70%B,55-60min,70%B~98%B。
收集具有20-23min保留时间的馏分并冻干,得140mg的白色粉末状固体,产率为55%。
实施例39
化合物39的制备
在25ml的圆底烧瓶中,用2ml二氯甲烷将化合物38(120mg,0.08mmol)搅拌溶解,冰浴下滴入800微升三氟乙酸,加入完毕后,移至室温搅拌反应1小时,反应完全。后处理:减压浓缩反应液,残余物经高效液相制备纯化。(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=214nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0min,5%B,0-10min,5%B~15%B,10-20min,15%B~30%B,20-35min,30%B~55%B, 35-45min,55%B~70%B,45-55min,70%B,55-60min,70%B~98%B。
收集具有18-19.5min保留时间的馏分并冻干,得55mg白色粉末状固体,产率为49%。LC-MS m/z(ES+):1397.8(M+H)+。
实施例40
化合物40的制备
将化合物7(332mg,0.836mmol)溶于干燥二氯甲烷中,加入五氟苯酚(184mg,1mmol),二环己基碳二亚胺(2mmol),室温搅拌3h至化合物7消失。加入MMAF(460mg,0.585mmol) 及二异丙基乙胺(DIEA,0.27mL,1.67mmol)溶于15mL干燥二氯甲烷溶液,于氮气保护下室温反应4h。减压浓缩,残余物用硅胶柱层谱(洗脱液为二氯甲烷/甲醇=50/1)分离得产品 290mg。LC-MS m/z(ES+):1168.8(M+H)+。
实施例41
化合物41的制备
将100mg化合物39溶于10mL干燥二氯甲烷,加入4mL三氟醋酸,室温反应2h,用高效液相纯化。
(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=215nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 95%A,10-25min,95%A~70%A,25-55min,70%A~40%A
收集具有33min保留时间的馏分并冻干,得产品50mg。LC-MS m/z(ES+):956.6(M+H)+。
实施例42
化合物42的制备
将化合物16(400mg,0.76mmol)溶于干燥二氯甲烷中,加入五氟苯酚(184mg,1mmol),二环己基碳二亚胺(2mmol),室温搅拌4h至化合物16消失。加入MMAF(389mg,0.49mmol) 及二异丙基乙胺(DIEA,0.25mL,1.52mmol)溶于15mL干燥二氯甲烷中,氮气保护下室温反应4h。减压浓缩,残余物用硅胶柱层谱(洗脱液为二氯甲烷/甲醇=50/1)分离得产品330mg。 LC-MS m/z(ES+):1296.8(M+H)+。
实施例43
化合物43的制备
将100mg化合物41溶于10mL干燥二氯甲烷,加入4mL三氟醋酸,室温反应2h,用高效液相纯化。
(柱:YMC-C18,30mm*450mm,10μm,采用乙腈/水(0.2%TFA),流速25mL/min,于λ=215nm检测)
溶剂A:0.2%TFA水
溶剂B:乙腈
梯度:0-10min 95%A,10-25min,95%A~70%A,25-55min,70%A~40%A
收集具有30min保留时间的馏分并冻干,得产品48mg。LC-MS m/z(ES+):1028.5(M+H) +。
实施例44
抗体药物偶联物H-11的制备是按照通用方法B的方法制备得到,经反相高效液相色谱测定,其平均药物/抗体比(DAR)值为7.2。
实施例45
抗体药物偶联物H-20的制备按照通用方法B的方法制备得到,经反相高效液相色谱测定,其平均药物/抗体比(DAR)值为7.2。
实施例46
抗体药物偶联物H-29的制备按照通用方法B的方法制备得到,经反相高效液相色谱测定,其平均药物/抗体比(DAR)值为6.8。
实施例47
抗体药物偶联物H-39的制备按照通用方法B的方法制备得到,经反相高效液相色谱测定,其平均药物/抗体比(DAR)值为7.0。
实施例48
抗体药物偶联物H-41的制备按照通用方法B的方法制备得到,经反相高效液相色谱测定,其平均药物/抗体比(DAR)值为7.5。
实施例49
抗体药物偶联物H-43的制备按照通用方法B的方法制备得到,经反相高效液相色谱测定,其平均药物/抗体比(DAR)值为7.7。
实施例50
继续合成得到如下所示药物-接头连接物:
其中:Ac代表非碱性氨基酸或寡肽,且氨基酸中的氨基与烷基相连;
n=1,2,3…;
下表1总结了含不同氨基酸及寡肽的药物接头合成及特征。在该表中,左侧第一列为化合物编号,第二列为氨基酸类别,第三列为n的取值,第四列为合成的通用方法,第五、六列为药物接头的计算质量和通过质谱确定的质量。
表1
缩写:
Gly是L-甘氨酸,Ala是L-丙氨酸,Phe是L-苯丙氨酸,Trp是L-酪氨酸,Asp是L-天冬氨酸,Ser是L-丝氨酸,Val是L-缬氨酸;
实施例52-56
为了评价采用酸性自稳定接头制备的ADC的稳定性、亲水性以及药理学活性,我们依实施例制备得到带酸性稳定接头的药物-接头连接物。这类连接物均具有酸性稳定接头,通过可裂解或不可裂解的连接子连接到细胞毒性药物MMAE或MMAF。作为比较,依照文献方法合成得到经典的非自稳定药物-接头连接物(本文称为MC-VC-PAB-MMAE)以及专利描述带碱性自稳定接头的药物-接头连接物(本文称为DPR-VC-PAB-MMAE):
实施例52体外血浆稳定性
按通用步骤D血浆稳定性研究,结果如下表所示,实验结果表明,带有酸性稳定接头的 ADC在血浆孵育过程中几乎没有损失药物,而经典的MC接头ADC在孵育72h后DAR降低非常显著。实验结果证明,酸性稳定接头可显著提高ADC药物血浆稳定性。
目标偶联物 | 0h DAR | 72h DAR |
H-11 | 7.2 | 6.8 |
H-20 | 7.2 | 7.1 |
H-29 | 6.8 | 6.4 |
H-39 | 7.0 | 6.8 |
H-41 | 7.5 | 6.9 |
H-43 | 7.7 | 6.4 |
MC-VC-PAB-MMAE | 7.2 | 2.3 |
实施例53 SEC-HPLC检测
将偶联所得的ADC样品于14000rpm离心5分钟,取上清液进样分析。
仪器:Waters e2695(2489UV/Vis)
色谱柱:TSKgel G3000SWXL(7.8×300mm,5μm)
流动相:A:50mM PB,300mM NaCl,200mM Arg,5%IPA,pH6.5
流动相A等度洗脱30min,流速:0.714ml/min,柱温25℃,检测波长:280nm。
通过SEC-HPLC可得出各ADC的聚集程度SEC-HPLC峰图见图2A-2H,数据总结如下表所示,在引入酸性稳定接头的ADC中,单体率明显提高,聚集程度显著降低。
实施例54
小鼠体内PK实验
在小鼠模型中测定ADC药物(载药量8)的PK性质,小鼠尾单次静脉注射给药,给药剂量2mg/kg,按照通用步骤B检测血液中总抗体(Total Ab)浓度,结果如图3,实验结果表明,在小鼠体内,酸性稳定接头ADC表现出明显的PK改善,血液中总抗体能够更长时间维持在更高的浓度。
实施例55
疏水性相互作用色谱(HIC)测定
按照通用步骤A将抗体IgG1抗体全部还原到每抗体8硫醇后,采用非定点偶联制备相应的抗体-药物偶联物。以通过疏水作用色谱进一步分离纯化每抗体8个药物的带酸性稳定接头的ADC和传统接头ADC(即MC-VC-PAB-MMAE),并按照通用步骤C,用疏水性相互作用色谱HIC对ADC分析。具有更大疏水性,或更大数量的药物/分子的ADC在更晚的保留时间洗脱。实验结果如图4,具有酸性接头的ADC在HIC中具有相对较短的保留时间, MC-VC-PAB-MMAE的抗体偶联物具有最长的保留时间。实验结果证明,具有酸性稳定接头的ADC分子具有更好的亲水性。
实施例56
体内药效实验(Cell Proliferation Assay)
体外培养人胰腺腺癌细胞BxPc3,按细胞数量5×106接种于BALB/c裸鼠背部皮下,待肿瘤长到100~200mm3后,分组,单次给予ADC药物3mg/kg(尾静脉注射),同时设溶媒对照组,定期称体重、测量肿瘤体积,通过考察ADC药物的抑瘤疗效等指标,来评价药物对于BxPc3模型的药效。实验结果如图5、6所示。结果表明,带有酸性稳定接头的ADC药物在 DAR=2下与Dpr-MC-VC-PAB-MMAE具有相似药效,明显优于Mc-VC-PAB-MMAE。在高载药量DAR=8下,在BxPc3小鼠皮下移植瘤模型中具有很好的药效。
Claims (13)
1.一种如式I所示的抗体药物偶联物或其药学上可接受的盐:
其中:
L是抗体,抗体片段或蛋白;
M是琥珀酰亚胺或水解开环后琥珀酰亚胺;
Ac为酸性单元,为由氨基和酸性基团组成的片段或由多个氨基酸组成的寡肽,以氨基部分与圆圈相连,
Ac选自(D/L)甘氨酸,(D/L)丙氨酸,(D/L)亮氨酸,(D/L)异亮氨酸,(D/L)缬氨酸,(D/L)苯丙氨酸、(D/L)脯氨酸、(D/L)色氨酸、(D/L)丝氨酸、(D/L)酪氨酸、(D/L)半胱氨酸、(D/L)蛋氨酸、(D/L)天冬酰胺、(D/L)谷氨酰胺、(D/L)苏氨酸、(D/L)天冬氨酸、(D/L)谷氨酸或以下结构式:
其中波浪线表示到圆圈的连接位点;
D是药物部分;
A是连接子部分;
圆圈表示支架,为C1-8亚烃基、C1-8杂亚烃基、C6-10亚芳基或C4-10杂亚芳基,和任选的适合连接至Ac和D的反应位点;
m选自1-20,n为1或2。
2.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述抗体为针对细胞表面受体和肿瘤相关抗原的抗体。
3.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于:其中圆圈为C1-8亚烃基、C1-8杂亚烃基、C6-10亚芳基或C4-10杂亚芳基,所述杂亚烃基中杂原子选自O、S、N或P原子中一种或多种组成的组;亚芳基选自苯基、萘基或二苯基;杂亚芳基团选自吡啶基、哒嗪基、吡嗪基、嘧啶基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基或噻吩中一种或多种组成的组。
4.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,A是可裂解连接子或不可裂解连接子。
5.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,所述药物D为细胞毒性药物,治疗自身免疫疾病的药物和抗炎症的药物。
6.如权利要求5所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,药物D选自美登素类药物、澳瑞他汀类药物,苯并二吡咯类药物,吡咯并苯二氮唑类药物,鹅膏毒素,喜树碱类和/或任何一种上述药物的药学上可接受的盐组成的组。
8.如权利要求7所述的抗体药物偶联物或其药学上可接受的盐,可断裂单元E在e=0时不存在,在e=1时存在;当存在时,E所述的可断裂单元通过肿瘤相关蛋白酶或酸性PH实现与药物单元D或间隔单元F间的断裂。
9.如权利要求7所述的抗体药物偶联物或其药学上可接受的盐,间隔单元F在f=0时不存在,在f=1时存在;当F存在时,F选自对氨基苯甲醇或对氨基苯甲醇与乙二胺单元组成的组。
10.如权利要求1所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,圆圈为C1-8亚烃基、C1-8杂亚烃基。
11.如权利要求10所述的抗体药物偶联物或其药学上可接受的盐,其特征在于,圆圈为C1-3亚烃基。
13.一种权利要求1-12任一所述的抗体药物偶联物或其药学上可接受的盐用于制备治疗癌症、免疫疾病、炎症药物的用途。
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US20230372526A1 (en) * | 2020-09-29 | 2023-11-23 | Mabwell (shanghai) Bioscience Co., Ltd. | Preparation method for bis-substituted bridging antibody-drug conjugate |
US20230381332A1 (en) | 2020-10-12 | 2023-11-30 | Baili-Bio (Chengdu) Pharmaceutical Co., Ltd. | Deuterated Camptothecin Derivative And Antibody-drug Conjugate Thereof |
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