CN116056725A - 活性位点暂时灭活的功能性药物与Toll样受体7或8激动剂的缀合物及其用途 - Google Patents
活性位点暂时灭活的功能性药物与Toll样受体7或8激动剂的缀合物及其用途 Download PDFInfo
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- CN116056725A CN116056725A CN202180056797.5A CN202180056797A CN116056725A CN 116056725 A CN116056725 A CN 116056725A CN 202180056797 A CN202180056797 A CN 202180056797A CN 116056725 A CN116056725 A CN 116056725A
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Abstract
本发明涉及:一种Toll样受体7或8激动剂‑药物缀合材料,其中功能性药物和Toll样受体7或8激动剂通过含有可裂解位点的化学键键合;及其用途,其中通过利用功能性药物和Toll样受体7或8激动剂材料的协同作用,以及利用暂时灭活状态的特性,可以降低Toll样受体7或8激动剂的副作用。特别地,缀合材料被设计成使得Toll样受体7或8激动剂的免疫刺激功能由于化学键而被抑制,而免疫刺激功能在注射部位或肿瘤微环境或靶免疫细胞中恢复,因此表现出可以随时间控制免疫刺激功效的动力学特性,并最大限度地减少诱导非特异性免疫反应。此外,由于多种功能可以与药物结合,因此灭活的Toll样受体7或8激动剂‑功能药物缀合物可广泛用于药物组合物的各种应用,从而能够控制癌细胞死亡,在注射部位或肿瘤微环境中激活治疗性免疫细胞、免疫抑制细胞和环境。
Description
技术领域
本发明涉及一种功能性药物与Toll样受体7或8激动剂的活性位点结合的复合物,更具体地,涉及一种复合物,其通过将功能性药物连接到Toll样受体7或8激动剂的活性位点而暂时抑制Toll样受体7或8激动剂功能,然后在预定时间后动力学恢复,及其用途。
背景技术
体内先天性免疫反应在预防或治疗各种传染病、癌症、代谢性疾病或罕见病中起着非常重要的作用。然而,患有特定疾病的患者通常会降低正常的免疫反应功能。因此,近来,作为适用于各种疾病的预防、改善和治疗的方法,已经开发了增强体内减弱的免疫反应或重新激活被特定信号抑制或停止的免疫反应的各种功能性药物。通常,免疫反应是激活的免疫细胞针对外来和内源性物质(即抗原)引起的一系列反应,当微生物(包括细菌和病毒)或生物体中的外来物质被引入体内时,免疫细胞会识别它们以激活并分泌细胞因子等因子,从而引起炎症反应。近来,对感染初期非特异性作用的先天免疫反应阶段机制的研究正在积极进行,其中Toll样受体是一种能够在炎症早期识别病原体的受体,已知通过识别病原体的质膜成分或核酸成分来诱导免疫反应,并且利用这一点,用于激活免疫细胞的各种Toll样受体配体的研究正在积极进行中。
在各种Toll样受体配体中,基于Toll样受体7或8激动剂的材料被用作诱导细胞免疫反应的佐剂,基于咪唑并喹啉的激动剂,基于8-羟基腺嘌呤的激动剂,基于蝶酮类(pteridone)的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂(benzoazepine-based agonist)和基于7-硫杂-8-氧代鸟苷的激动剂是已知的(美国专利申请公开No.2012-0294885)。已知这样的Toll样受体7或8激动剂作为内体中的Toll样受体7或8激动剂不仅有效地诱导体液免疫而且有效地诱导细胞免疫。此外,最近又有报道称,由于Toll样受体7或8激动剂在注射部位或肿瘤微环境中发挥了佐剂功能以外的免疫抑制作用,因此免疫抑制细胞的功能有助于癌症的生长和发展。MDSCs、Tregs或M2巨噬细胞等转移受到抑制,从而提高免疫抗癌作用。然而,这种多功能的Toll样受体激动剂由于其分子结构而难以分散在水溶液中。此外,由于它们只溶于特定的有机溶剂,如DMSO和甲醇,而不溶于常用的有机溶剂,因此在制造各种剂型的免疫激活药物方面存在局限性。因此,其中混合了各种表面活性剂的乳膏型制剂(例如,Aldara乳膏)被商业化。在一些研究中,为了克服上述问题,此类激动剂被制备成盐的形式,从而可以溶解在水溶液中。然而,以盐的形式制备的Toll样受体激动剂在体内被吸收到血管中,从而在血管中诱导免疫反应(全身免疫反应),从而引起许多副作用(例如细胞因子风暴,各种非特异性超敏免疫反应等),因此不易使用。此外,由于这些副作用,实际用于治疗时,必须以比有效剂量低的浓度进行治疗,因此这也成为降低疗效的一个因素。为了克服这些问题,一些制药公司正试图通过引入亲脂性脂质或通过直接化学键合到具有大尺寸的聚合物链来防止直接吸收到血管中。但由于该方法制备的Toll样受体激动剂的活性位点仍暴露在外,在体内诱导非特异性免疫反应,仍有诱发毒性的可能。
因此,如果一类Toll样受体7或8激动剂可以通过设计使其在注射部位、肿瘤微环境或靶免疫细胞中恢复免疫激活功能的同时由于活性部位的化学键首先抑制Toll样受体7或8激动剂的免疫激活功能,从而制备表现出能够根据时间点控制免疫激活功效的动力学特征,那么Toll样受体7或8激动剂引起的非特异性毒性和免疫反应诱导可降至最低。此外,通过与各种功能性药物(抗体、小分子抗癌药、抗原、细胞因子、多肽、氨基酸、低分子化合物、脂类、寡核苷酸、靶向配体等)结合,利用功能性药物与Toll样受体7或8激动剂材料的协同作用,这种可以特异性地控制癌细胞死亡、治疗性免疫细胞、免疫抑制细胞以及注射部位或肿瘤微环境中的环境的激活的Toll样受体7或8激动剂材料有望广泛用于多种用途的药物组合物中。
发明内容
[技术问题]
为解决相关技术中存在的问题,本发明旨在提供一种功能性药物-Toll样受体7或8激动剂复合物,该复合物中Toll样受体7或8激动剂与功能性药物连接,旨在暂时抑制Toll样受体7或8激动剂免疫激活功能并且特异性恢复注射部位或肿瘤微环境或靶细胞免疫活性的化合物及其用途。
然而,本发明要解决的技术问题不限于上述问题,本领域的普通技术人员将从以下描述中充分理解本文未描述的其他问题。
[技术方案]
本发明提供了一种Toll样受体7或8激动剂-功能性药物复合物,该复合物的特征是功能性药物连接在Toll样受体7或8激动剂的活性位点上。更具体地说,该复合物是一种具有暂时无活性的Toll样受体7或8激动剂和功能性药物的复合物,暂时无活性是因为可裂解接头的一端与Toll样受体7或8激动剂的活性位点(即表现出Toll样受体7或8激动剂生物学活性的活性位点)化学键合,而该功能性药物化学键合到该接头的另一端。
在本发明的一个实施方案中,在复合物中,功能性药物起主要作用,并且在注射部位或肿瘤微环境或靶细胞中,当通过裂解接头,活性位点动力学恢复时,灭活的Toll样受体7或8激动剂起次要作用。
在本发明的另一个实施方案中,可裂解接头的化学键被选自酶、pH、氧化还原电势、温度、超声波、磁力和光源的任何一种或多种因素裂解。
在本发明的又一个实施方案中,可裂解接头优选地是选自基于苄基消除(benzylelimination-based)的接头、基于三烷基锁(trialkyl lock-based)的接头、基于N-双(羟乙基)甘氨酸(bicine-based)的接头、酸不稳定(acid labile)接头、溶酶体可裂解肽和组织蛋白酶B-可裂解肽中的任意一种或多种,更优选地,具有选自氨基甲酸酯、二硫、肼、酯、肽、叠氮化物和β-葡萄糖醛酸苷键中的任意一个或多个键的接头,以及其组合的接头。但是,可裂解接头只要能够以可裂解的形式与待连接的Toll样受体7或8激动剂和功能性药物化学结合就不受限制,并且可以具有任何能够通过以下因素裂解结合的形式:身体的内源性因素(酶、氧化还原电位、谷胱甘肽、pH值等),和/或外源性因素(氧化还原、pH值、温度、光(photo)/光(light)、磁、超声波、电响应等)。
在本发明的又一实施方案中,可裂解接头还包括在一端或两端的烷基衍生物,例如环氧乙烷或乙二醇,从而增加复合物在水溶液中的溶解度和柔性。
在本发明的又一个实施方案中,Toll样受体7或8激动剂可以是选自基于咪唑并喹啉的激动剂、基于8-羟基腺嘌呤的激动剂、基于蝶酮类的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂、基于7-硫杂-8-氧代鸟苷的激动剂中的任意一种或多种,并且只要是通过可裂解接头连接到活性位点而灭活的任何Toll样受体7或8激动剂就没有限制。
在本发明的又一个实施方案中,功能性药物可以是选自抗体、抗体片段、单链抗体、抗癌剂、抗原、细胞因子、蛋白质、肽、氨基酸、寡核苷酸、酶、脂质、低分子化合物、糖蛋白和靶向配体中的任意一种或多种,以及更优选地,选自抗体、基于蛋白质的药物、敏化剂和抗癌剂中的任何一种或多种。然而,其只要是可以使用可裂解接头与Toll样受体7或8激动剂连接的药物,就不受限制。
此外,本发明提供了一种用于控制免疫***的组合物,其包括该复合物作为活性成分。
在本发明的一个实施方案中,用于控制免疫***的组合物激活选自以下项组成的群组的任何一种或多种免疫细胞:抗原呈递细胞、B细胞、自然杀伤(NK)细胞和T细胞。
在本发明的另一个实施方案中,用于控制免疫***的组合物调节选自以下项组成的群组的任何一种或多种免疫细胞的功能:调节性T(Treg)细胞、髓源性抑制细胞(MDSC)和M2巨噬细胞。
在本发明的又一个实施方案中,用于控制免疫***的组合物可以诱导注射部位或肿瘤微环境中免疫细胞的活化或控制免疫抑制细胞的功能,并且优选地诱导抗原呈递细胞(树突细胞、巨噬细胞等)、NK细胞或T细胞的免疫激活,或通过调节具有免疫抑制作用的免疫细胞(Treg细胞、MDSC或M2巨噬细胞)的功能来调节体内的免疫***。
在本发明的又一个实施方案中,用于控制免疫***的组合物还可以包括任何一种或多种靶向免疫检查点因子的抗体,该抗体选自:抗-PD-1、抗-PD-L1、抗-CTLA-4、抗-KIR,抗LAG3,抗CD137,抗OX40,抗CD276,抗CD27,抗GITR,抗TIM3,抗41BB,抗CD226,抗CD40,抗CD70,抗ICOS,抗-CD40L、抗BTLA、抗TCR和抗TIGIT。
此外,本发明提供了一种用于预防或治疗癌症的药物组合物,其包含该复合物作为活性成分。
在本发明的一个实施方案中,药物组合物还可以包括通常用于治疗癌症的物质,例如化疗剂或免疫检查点抑制剂。该药物组合物包括本发明的复合物,并从而有效地激活体内的免疫***,从而提高常规化疗药物或免疫检查点抑制剂的疗效。
在本发明的另一个实施方案中,药物组合物抑制癌症生长、转移、复发或对化疗的抗性。
在本发明的又一个实施方案中,癌症可以是但不限于乳腺癌、结直肠癌、直肠癌、肺癌、结肠癌、甲状腺癌、口腔癌、咽癌、喉癌、***、脑癌、卵巢癌、膀胱癌、肾癌、肝癌、胰腺癌、***癌、皮肤癌、舌癌、子宫癌、胃癌、骨癌或血癌。
此外,本发明提供了一种预防或治疗癌症的方法,其包括将包含该复合物作为活性成分的组合物施用于受试者。
此外,本发明提供了包含该复合物作为活性成分的组合物用于预防或治疗癌症的用途。
此外,本发明还提供了该复合物在制备预防或治疗癌症的药物中的用途。
另外,本发明提供了一种功能性药物-Toll样受体7或8激动剂复合物的制备方法,其包括a)将可裂解接头化学结合到Toll样受体7或8激动剂的活性位点,和b)将功能性药物与接头结合。
[有益效果]
由于功能性药物起主要作用,能够与其产生协同作用的Toll样受体7或8激动剂在一定时间段内起次要作用,根据本发明功能性药物和其活性被暂时抑制的Toll样受体7或8激动剂的复合物可以最小化非特异性免疫反应和毒性并最大化协同效应。此外,在递送至注射部位、肿瘤微环境或免疫细胞后,功能性药物与Toll样受体7或8激动剂逐渐分离,Toll样受体7或8激动剂的活性位点被动力学调节,并与Toll样受体长时间持续反应,也最小化了Toll样受体7或8激动剂的毒性,所以,与单独使用Toll样受体激动剂相比治疗效果可能会显著增加,因为免疫细胞的免疫激活的持久性可能会增加。此外,在与根据本发明的功能性药物化学键合的Toll样受体7或8激动剂(功能性药物-Toll样受体7或8激动剂复合物)中,当将抗体用作功能性药物时,通过使用抗体的靶标特异性提高对特定细胞或组织的靶标效率,可以显著降低常规Toll样受体7或8激动剂的副作用和细胞毒性。此外,抗体特异性靶向的癌细胞死亡以及由此产生的癌抗原可能与Toll样受体7或8激动剂的辅助作用相结合,从而诱导所谓的原位疫苗接种效应。此外,由于功能性药物-Toll样受体7或8激动剂复合物可诱导抗原呈递细胞(树突细胞、巨噬细胞等)、NK细胞或T细胞的免疫激活,并且可以调节注射部位或肿瘤微环境中具有免疫抑制作用的免疫细胞(Treg细胞、MDSC、M2巨噬细胞等)的功能,因此复合物单独可以发挥抗癌作用,或者当使用免疫检查点抑制剂或化疗药物作为功能性药物制备复合物时,由于协同作用而可以显著提高抗癌作用。因此,由于本发明的复合物可有效地应用于所有可与Toll样受体7或8激动剂联合给药的功能性药物,可以减少副反应,以及可以增强治疗效果,因此该复合体有望能够广泛应用于各个领域。
附图说明
图1中根据本发明一个实施方案显示,用于连接Toll样受体7或8激动剂与功能性药物的代表性接头。
图2中根据本发明一个实施方案显示,具有胺基的代表性抗癌剂,含胺基的抗癌剂和Toll样受体7或8激动剂的复合物的示例,该复合物具有可被还原剂裂解的键,并且示意性地显示了被还原剂裂解的机制。
图3中根据本发明一个实施方案显示,含胺基抗癌剂与Toll样受体7或8激动剂的复合物的示例,该复合物具有在酸性条件下键断裂的键,并示意性地显示了裂解机制。
图4中根据本发明一个实施方案显示,羟基的代表性抗癌剂和抗癌剂与Toll样受体7或8激动剂的复合物的示例,该复合物具有被β-葡萄糖醛酸苷酶裂解的键,并示意性地显示了裂解机制。
图5中根据本发明一个实施方案显示,含羟基的抗癌剂和Toll样受体7或8激动剂的复合物的示例,该复合物具有被蛋白酶裂解的键,并且示意性地显示了裂解机制。
图6中根据本发明一个实施方案显示,用于合成基于蛋白质的药物和Toll样受体7或8激动剂的复合物的代表性接头和连接机制。
图7中根据本发明一个实施方案显示,基于蛋白质的药物和Toll样受体7或8激动剂的复合物的示例,该复合物具有被还原剂裂解的键,并且示意性地显示了裂解机制。
图8中根据本发明一个实施方案显示,基于蛋白质的药物和Toll样受体7或8激动剂的复合物的示例,该复合物具有被细胞中的氢离子浓度裂解的键,并且示意性地显示了裂解机制。
图9中根据本发明一个实施方案显示,基于蛋白质的药物和Toll样受体7或8激动剂的复合物的示例,该复合物具有被β-葡萄糖醛酸苷酶裂解的键,并且示意性地显示了裂解机制。
图10中根据本发明一个实施方案显示,基于蛋白质的药物和Toll样受体7或8激动剂的复合物的示例,该复合物具有被还原剂裂解的键,并且示意性地显示了裂解机制。
图11中根据本发明一个实施方案显示,基于蛋白质的药物和Toll样受体7或8激动剂的复合物的示例,该复合物具有被细胞中的氢离子浓度裂解的键,并且示意性地显示裂解机制。
图12中根据本发明一个实施方案显示,基于蛋白质的药物和Toll样受体7或8激动剂的复合物的示例,该复合物具有被β-葡萄糖醛酸苷酶裂解的键,并且示意性地显示了裂解机制。
图13中根据本发明一个实施方案显示,代表类型的敏化剂,敏化剂和Toll样受体7或8激动剂的复合物的示例,该复合物具有被还原剂裂解的键,并且示意性地裂解机制。
图14中根据本发明一个实施方案显示,含羧基敏化剂和Toll样受体7或8激动剂的复合物的示例,该复合物具有在酸性条件下裂解的键,并且示意性地显示了裂解机制。
图15中根据本发明一个实施方案显示,含羧基敏化剂与Toll样受体7或8激动剂的复合物的示例,该复合物具有被β-葡萄糖醛酸苷酶裂解的键,并且示意性地显示了裂解机制。
图16中根据本发明一个实施方案显示,通过癌症大小确认AAC-001复合物的抗癌作用的结果。
图17中根据本发明一个实施方案显示,通过存活率确认AAC-001复合物的抗癌作用的结果。
图18中根据本发明一个实施方案显示,确认AAC-001复合物对血液中炎症细胞因子分泌的影响的结果。
图19中根据本发明的一个实施方案示意性地显示,AAC-002复合物的机制。更具体地,该图是说明抗体-Toll样受体7或8激动剂复合物在细胞内的作用机制的示意图,并显示了通过细胞内环境将抗体与Toll样受体7或8激动剂分离,将灭活的Toll样受体7或8激动剂转变为激活状态的过程。
图20中根据本发明一个实施方案显示,确认AAC-002复合物对血液中炎症细胞因子分泌的影响的结果。
图21中显示了,确认具有被组织蛋白酶-B裂解的键的蛋白质抗原-雷西莫特(resiquimod)复合物在水溶液中形成尺寸为约99.7nm的纳米粒子的结果。
图22是示意图,其显示,功能性药物-Toll样受体7或8激动剂复合物的结构和功能,其中功能性药物通过可裂解接头与Toll样受体7或8激动剂的活性位点结合,从而在暂时灭活的动力学激活的复合物与传统复合物(其功能性药物结合到另一个位点,而不是活性位点)之间显示出差异。在动力学活化复合物中,功能性药物的功效在初始时有效,在可裂解接头反应后,响应于刺激,灭活的Toll样受体7或8激动剂的功效继发动力学再生,并且这种动力学作用可能无法通过初始时就保持功能性药物和Toll样受体激动剂的双重活性状态的常规复合物来实现。
具体实施方式
通过集中研究制备功能性药物和Toll样受体7或8激动剂的复合物(该复合物减少了副作用并且通过通过抑制Toll样受体7或8激动剂的非特异性早期免疫反应来连接各种功能药物,能够实现通过单次给药来共同给药),本发明人发明了一种复合物,复合物中功能性药物通过可裂解接头结合到Toll样受体7或8激动剂的活性位点,因此功能性药物主要起作用,然后免疫激活作用被暂时抑制的Toll样受体激动剂由于免疫激活功能在注射部位、或在肿瘤微环境或靶细胞中特异性地恢复而发挥次要作用(图22)。抑制可能意味着Toll样受体7或8激动剂的功能被延迟(减缓)。本发明的功能性药物-Toll样受体7或8激动剂复合物与常规复合物的不同之处在于功能性药物和Toll样受体7或8激动剂的活性可以被动力学或动态调节。
本文所称“Toll样受体激动剂”是指直接或间接作用于Toll样受体的配体,Toll样受体是一种参与先天免疫的膜蛋白,并且指能够使用信号通路通过产生内源性或外源性配体而引起信号应答的成分。本文所用的Toll样受体激动剂可以是天然的Toll样受体激动剂或合成的Toll样受体激动剂。本文中使用的Toll样受体激动剂可以是Toll样受体1激动剂、Toll样受体2激动剂、Toll样受体3激动剂、Toll样受体4激动剂、Toll样受体5激动剂、Toll样受体6激动剂、Toll样受体7或8激动剂或Toll样受体9激动剂。Toll样受体7或8激动剂是指能够通过TLR-7或8诱导信号应答的配体,并且可以是但不限于基于咪唑并喹啉的激动剂、基于8-羟基腺嘌呤的激动剂、基于蝶酮类的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂、或基于7-硫杂-8-氧代鸟苷的激动剂,并且基于咪唑并喹啉的化合物包括WO 2018 196823、WO 2011 049677、WO 2011 027022、WO 2017 102652、WO 2019 040491中公开的化合物类型或其药学上可接受的盐,但本发明不限于此。此外,基于8-羟基腺嘌呤的化合物包括以下文献中公开的化合物类型:WO 2012 080730、WO 2013 068438、WO 2019036023、WO 2019 035969、WO 2019 035970、WO 2019 035971、WO 2019 035968、CN108948016、US 2014 8846697、WO 2016 023511、WO 2017 133683、WO 2017 133686、WO2017 133684、WO 2017 133687、WO 2017 076346、WO 2018 210298、WO 2018 095426、WO2018 068593、WO 2018 068593、WO 2018 078149和WO 2018 041763,或其药学上可接受的盐,但本发明不限于此。基于蝶酮类的化合物包括以下文献中公开的化合物类型:US 20100143301、WO 2016 007765、WO 2016 044182、WO 2017 035230、WO 2017 219931、WO 2011057148和CN 1087 94486,或其药学上可接受的盐,但本发明不限于此。基于2-氨基吡啶的化合物包括以下文献中公开的化合物类型:WO 2010 133885、WO 2012066335、WO 2012066336、WO 2012 067268、WO 2013 172479、WO 2012 136834、WO 2014 053516、WO 2014053595、US 2018 0215720、WO 2012 156498、WO 2014 076221、WO 2016 141092、WO 2018045144、WO 2015 014815、WO 2018 233648、WO 2014 207082、WO 2014 056593、WO2018002319、WO 2013002319和WO 2013117615,或其药学上可接受的盐,但本发明不限于此。基于苯并氮杂卓的化合物包括以下文献中公开的化合物类型:WO 2007 024612,、WO2010 014913、WO 2010 054215、WO 2011 022508、WO 2011 022509、WO 2012 097177、WO2012 097173、WO 2016 096778、WO 2016 142250、WO 2017 202704、WO 2017 202703、WO2017 216054、WO 2017 046112和WO 2017 197624,或其药学上可接受的盐,但本发明不限于此。基于7-硫杂-8-氧代鸟苷的化合物包括以下文献中公开的化合物类型:WO 2016180691、WO 2016 055553、WO 2016 180743和WO 2016 091698,或其药学上可接受的盐,但本发明不限于此。除上述之外,Toll样受体7或8化合物还可以包括PCT/US2009/035563、PCT/US2015/028264、PCT/US2016/020499、WO 2015 023598和PCT/US 2015/039776中公开的Toll样受体7或8化合物,或其药学上的盐。替代地,Toll样受体7或8激动剂可包括但不限于咪喹莫特、雷西莫特(resiquimod)、达托利司(dactolisib)、加地喹莫德(gardiquimod)、舒马尼罗(sumanirole)、莫托莫德(motolimod)、维沙莫德(vesatolimod)、洛索立宾(10xoribine)、SM360320、CL264、3M-003、IMDQ和Compound 54,并且包括本领域普通技术人员可以容易地推测的所有Toll样受体7或8激动剂。Toll样受体7或8激动剂可以用一种或多种选自以下项的免疫激活物质代替:Toll样受体激动剂、皂苷、抗病毒肽、炎症小体诱导剂、NOD配体、细胞溶质DNA传感器(CDS)配体、干扰素基因刺激物(STING)配体、乳剂、明矾及其组合,同样的概念也可适用于递送到细胞后在内体中具有受体以与抗体合成复合物的Toll样受体3激动剂或Toll样受体9激动剂,但本发明不限于此。
本文所用的“可裂解接头”包括可裂解键,是由于体内(例如肿瘤微环境或细胞中的溶酶体和内体的生理环境内)的低pH值、酶或谷胱甘肽;或外部刺激,即温度、氧化还原电位、超声波、磁场和近红外光等特定刺激等条件可发生裂解的接头的总称。可裂解接头优选地是指包括氨基甲酸酯、二硫、肼、酯、肽、叠氮或β-葡萄糖醛酸苷键的接头,但没有限制,只要其具有可裂解形式即可。此外,在本发明的复合物中,功能性药物和Toll样受体7或8激动剂可被注射部位或肿瘤微环境或细胞中存在的各种酶分离,所述酶例如酸性磷酸酶、酸性焦磷酸酶、磷酸二酯酶、磷蛋白磷酸酶、磷脂酸磷酸酶、芳基硫酸酯酶、蛋白酶、组织蛋白酶、胶原酶、芳基酰胺酶、肽酶、酸性核糖核酸酶、酸性脱氧核糖核酸酶、脂肪酶、甘油三酯脂肪酶、磷脂酶、酯酶、羧酸酯酶、葡糖脑苷脂酶、半乳糖脑苷脂酶、鞘磷脂酶、糖苷酶、α-葡萄糖苷酶、β-葡糖苷酶、β-半乳糖苷酶、α-甘露糖苷酶、α-葡糖苷酶、β-木糖苷酶、a-N-乙酰己糖胺酶(alpha-N-acetylhexosaminidase)、β-N-乙酰己糖胺酶、唾液酸酶、溶菌酶、透明质酸酶、β-葡萄糖醛酸苷酶和γ-干扰素诱导型溶酶体硫醇还原酶。
此处所称的“功能性药物”是所有具有生物学功能并且因此可用于疾病的诊断、预防和治疗的药物的总称,优选为抗体、抗体片段、单链抗体、抗癌剂、抗原、细胞因子、蛋白质、肽、氨基酸、寡核苷酸、酶、脂质、低分子化合物、糖蛋白或靶向配体,更优选抗癌剂、抗体、基于蛋白质的药物或敏化剂,但本发明不限于此。例如,功能性药物可以是DNA拓扑异构酶抑制剂、微管抑制药物、DNA损伤剂、抗代谢物、核苷类似物、反义寡核苷酸、锁核酸(LNA)、短干扰RNA(siRNA)、microRNA(miRNA)、适体、肽核酸(PNA)、二氨基磷酸吗啉代寡核苷酸(PMO)、反义Bcl-2寡核苷酸、反义HIF-1α寡核苷酸、反义生存素(Survivin)寡核苷酸、细胞粘附肽、细胞穿透肽、受体配体、靶向碳水化合物分子、凝集素、RGD肽、选择素、TAT、渗透素、(Arg)9或叶酸。功能性药物还可以是微管蛋白结构合成抑制剂、减数***抑制剂、RNA聚合酶抑制剂、拓扑异构酶抑制剂、DNA嵌入剂、DNA烷化剂、脂质体抑制剂、蛋白毒素或用于癌症的治疗的放射性同位素。此外,功能性药物可以是美登黄素(maytansinoid)、奥利他汀(auristatin)、多司他丁(dolastatin)、微管溶素(tubulysin)、卡奇霉素(calicheamicin)、吡咯苯并二氮杂卓(pyrrolobenzodiazepine)、阿霉素(doxorubicin)、多卡霉素(duocamycin)、卡铂(铂尔定(paraplatin))、顺铂、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、尼莫司丁(nidran)、氮芥(nitrogenmustard)(盐酸氮芥,HCL)、博来霉素、丝裂霉素C、阿糖胞苷(cytarabine)、氟尿嘧啶(flurouracil)、吉西他滨(gemcitabine)、三甲蝶呤(trimetrexate)、甲氨蝶呤(methotrexate)、依托泊苷(etoposide)、长春碱(vinblastine)、长春瑞滨,(vinorelbine)、力比泰(alimta)、六甲蜜胺(altretamine)、丙卡巴肼(procarbazine)、紫杉醇(taxol)、泰索帝(taxotere)、拓扑替康(topotecan)、伊立替康(irinotecan)、单端孢霉烯(trichothecene)、CC1965、α-鹅膏蕈碱、烯二炔类抗生素或植物毒素。此外,当功能性药物为化合物时,还可以包括其立体异构体或其衍生物。另外,所述auristatin可以是单甲基auristatin E或单甲基auristatin F,只要是用于治疗癌症的材料就不受限制。另外,敏化剂可以是原卟啉、血卟啉单甲醚、脱镁叶绿酸A或光敏素,只要其是能显著促进化学反应或物理现象的化学敏化剂或光敏化剂就不受限制。
本文所称“抗体”是指作为特异性识别抗原的受体的蛋白质分子,包括免疫学上与特异性抗原具有反应性的免疫球蛋白分子,并且包括所有的多克隆抗体、单克隆抗体、全长抗体、以及包含抗原结合结构域的抗体片段。全长抗体是具有两条全长轻链和两条全长重链的结构,每条轻链通过二硫键与重链结合。全抗体包括IgA、IgD、IgE、IgM和IgG,其中IgG是亚型,包括IgG1、IgG2、IgG3和IgG4。抗体片段是指具有抗原结合功能的片段,包括Fab、Fab′、F(ab′)2、scFv和Fv。Fab是具有轻链和重链的可变结构域和重链的第一恒定结构域(CH1)的结构,并且具有抗原结合位点。Fab′与Fab的不同之处在于其重链CH1结构域的C末端具有包括一个或多个半胱氨酸残基的铰链区。F(ab′)2抗体是通过在Fab′铰链区的半胱氨酸残基之间形成二硫键而产生。可变片段(Fv)是指仅具有重链可变结构域和轻链可变结构域的最小抗体片段。在双链Fv(dsFv)中,重链可变结构域和轻链可变结构域通过二硫键连接,而在单链Fv(scFv)中,重链可变结构域和轻链可变结构域通常使用肽接头通过共价键连接。此类抗体片段可以使用蛋白酶获得(例如,Fab可以通过木瓜蛋白酶切割整个抗体获得,F(ab′)2片段可以通过胃蛋白酶切割获得),并且优选地,可以通过基因重组技术制造。此外,本发明的抗体可以是天然抗体或重组抗体。天然抗体是指未经基因操作的抗体,并且可能具有非常低的免疫原性风险(通常基因操作抗体在体内可能具有的)。重组抗体是指基因操作的抗体,并且通过基因操作可以进一步具有抗原结合力或所需的特性。抗体可以包括,例如,特异性结合DEC205、CD206、DC-SIGN、DNGR1、CD11c、FcγR、PD-L1、PD-1、CD47、SIRP-α、Ly6G、IL-6和Gr-1的抗体,以及免疫检查点抑制剂,如抗PD-1、抗PD-L1、抗CTLA-4、抗KIR、抗LAG3、抗CD137、抗OX40、抗CD276、抗CD27、抗GITR、抗TIM3、抗41BB、抗CD226、抗CD40、抗CD70、抗ICOS、抗CD40L、抗BTLA、抗TCR和抗TIGIT。
本文所称“控制免疫***的药物”是以本发明的功能性药物-Toll样受体7或8激动剂复合物为有效成分的组合物,是指激活免疫细胞、调节免疫抑制细胞的功能,从而使体内免疫***正常工作的药物。
本文所用的“预防”是指通过施用根据本发明的组合物抑制疾病例如癌症或延缓其发作的所有作用。
本文使用的“治疗”是指通过施用根据本发明的组合物参与改善或有益地改变癌症症状的所有行为。
本文所用的“个体或对象”是指施用本发明的组合物可以针对的目标,并且对该目标没有限制。
本文所称“癌症”是各种血癌、恶性实体瘤等的总称,其可以局部浸润扩散,全身转移。尽管没有特别限制,但癌症的具体示例包括结直肠癌、肾上腺癌、骨癌、脑癌、乳腺癌、支气管癌、结肠和/或直肠癌、胆囊癌、胃肠癌、头颈癌、肾癌、喉癌癌、肝癌、肺癌、神经组织癌、胰腺癌、***癌、甲状旁腺癌、皮肤癌、胃癌、以及甲状腺癌。癌症的其他实例包括腺癌、腺瘤、基底细胞癌、宫颈发育不良和原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多形性成胶质细胞瘤、毛细胞瘤、肠神经节神经瘤、增生性角膜神经瘤、胰岛细胞癌、卡波氏肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌、恶性黑色素瘤、恶性高钙血症、马方样瘤、髓样癌、转移性皮肤癌、粘膜神经瘤、骨髓增生异常综合征、骨髓瘤、蕈样肉芽肿、神经母细胞瘤、骨肉瘤、骨源性和其他肉瘤、卵巢肿瘤、嗜铬细胞瘤、真性红细胞增多症、原发性脑肿瘤、小细胞肺癌、溃疡性和***状鳞状细胞癌、***瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞瘤或肾细胞癌、网状细胞肉瘤,以及威尔姆氏瘤。此外,还包括星形细胞瘤、胃肠道间质瘤(GIST)、神经胶质瘤或胶质母细胞瘤、肝细胞癌(HCC)和胰腺神经内分泌肿瘤。
本文使用的“药物组合物”可以制备成胶囊剂、片剂、颗粒剂、注射剂、软膏剂、散剂或饮料的形式,并且该药物组合物可以预期用于人类。药物组合物可以但不限于按照常规方法配制成例如散剂、颗粒剂、胶囊剂、片剂或水混悬剂等口服剂型,外用制剂,栓剂和无菌注射液的形式。本发明的药物组合物可以包括药学上可接受的载体。药学上可接受的载体可以是粘合剂、助流剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、助悬剂、着色剂或用于口服给药的调味剂并且对于注射给药,可以使用缓冲剂、防腐剂、止痛剂、增溶剂、等渗剂和稳定剂的混合物,并且对于局部给药,可以使用基质(base)、赋形剂、润滑剂和防腐剂。本发明的药物组合物可以通过与上述药学上可接受的载体混合而制备成各种形式。例如,对于口服给药,本发明的药物组合物可以制成片剂、锭剂、胶囊剂、酏剂、混悬剂、糖浆剂和糯米纸(wafer)等多种剂型,对于注射剂,本发明的药物组合物可以制备成单位剂量安瓿或多剂量形式。此外,本发明的药物组合物可以制成溶液剂、混悬剂、片剂、胶囊剂或缓释制剂。
同时,用于制剂的载体、赋形剂和稀释剂可以包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、***胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油。此外,用于制剂的载体、赋形剂和稀释剂还可以包括填充剂、抗凝剂、润滑剂、润湿剂、调味剂、乳化剂和防腐剂。
本发明的药物组合物的给药方式不限于口服、静脉内、肌肉内、动脉内、髓内、鞘内、心内、透皮、皮下、腹膜内、鼻内、肠内、局部、舌下或直肠给药。优选口服或肠胃外给药。本文使用的术语“肠胃外”是指皮下、静脉内、肌肉内、关节内、囊内、胸骨内、鞘内、病灶内和颅内注射或输注。本发明的药物组合物可以以用于直肠给药的栓剂形式给药。
本发明的药物组合物可根据各种因素而变化,包括所用特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、***率、药物制剂和具体要预防或治疗的疾病的严重程度,以及本领域普通技术人员可以根据患者的病情和体重、疾病的严重程度、剂型、给药途径和持续时间来选择药物组合物的剂量,并且可以每天以0.0001至500mg/kg或0.001至500mg/kg的剂量给药。本申请的药物组合物可以每天给药一次或分几次给药。该剂量不以任何方式限制本申请的范围。本发明的药物组合物可以制成丸剂、糖衣片、胶囊剂、液体剂、凝胶剂、糖浆剂、浆剂或混悬剂。
在下文中,为了帮助理解本发明,将提出示例性示例。然而,以下实施方案仅为了更容易理解本发明而提供,并不用于限制本发明。
[实施方案]
实施方案1:2-甲基-1-(3-硝基喹啉-4-基氨基)丙-2-醇(2-methyl-1-(3-nitroquinolin-4-ylamino)propan-2-ol)的合成
2-甲基-1-(3-硝基喹啉-4-基氨基)丙-2-醇(化合物2)使用以下方案1的方法合成。更具体地,在10至20℃下将1-氨基-2-甲基丙-2-醇(14g)和四乙胺(9.6g)加入到化合物1(30g)-加入的二氯甲烷(450mL)中并搅拌2小时,从而制备混合物。然后,通过在真空中蒸发溶剂来浓缩混合物,然后用甲基叔丁基醚(150mL)研磨。使用过滤器分离经研磨的混合物并在低压下浓缩,从而获得化合物2(32g,85.2%,黄色固体)。所获得的化合物2的结构使用1H NMR验证。
1H NMR(400MHz,DMSO-d6):δ9.91(brs,1H),9.18(s,1H)),8.46(d,J=8.0Hz,1H),7.83-7.92(m,2H),7.56-7.60(m,1H),5.15(s,1H),3.86(d,J=4.8Hz,2H),1.15(s,6H)。
【方案1】
实施方案2:1-(3-氨基喹啉-4-基氨基)-2-甲基丙-2-醇(1-(3-aminoquinolin-4-ylamino)-2-methylpropan-2-ol)的合成
1-(3-氨基喹啉-4-基氨基)-2-甲基丙-2-醇(化合物3)使用以下方案2的方法合成。更详细地,在10至20℃的反应器中混合化合物2(32g)、甲醇(500mL)和Pd/C催化剂(3.2g)后,将混合物脱气并使用氢气冲洗三次。蒸发氢气以保持1个大气压并将混合物在室温下搅拌5小时。然后,将混合物与甲基叔丁基醚(100mL)一起研磨。使用过滤器分离经研磨的混合物并在低压下浓缩,从而获得化合物3(27g,95.4%,黄色固体)。所获得的化合物3的结构使用1H NMR验证。
1H NMR(400MHz,DMSO-d6):δ8.37(s,1H)),7.99-8.01(m,1H),7.72-7.74(m,1H),7.32-7.39(m,2H),5.04(s,2H),4.77(brs,1H),4.67-4.70(m,1H),4.12(brs,2H),1.15(s,6H)。
【方案2】
实施方案3:1-(2-乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基丙-2-醇(1-(2-ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol)的合成
1-(2-乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基丙-2-醇(化合物4)使用以下方案3的方法合成。更详细地,将化合物3(27g)和2-乙氧基乙酸(30mL)加入到10至20℃的反应器中,并在120至130℃搅拌5小时。然后,将混合物冷却至20至25℃,然后加入饱和碳酸钠(150mL)。然后,使用二氯甲烷和甲醇(10/1,v/v)的混合溶液萃取反应产物。萃取的有机溶液层用盐水洗涤,然后用硫酸钠(10g)除去水分。然后,使用过滤器过滤脱水的有机溶液层并在低压下浓缩,从而获得化合物4(30g,85.8%,黄色凝胶)。使用1H NMR验证所获得的化合物4的结构。
1HNMR(DMSO_d6400MHz):δ9.18(s,1H)),8.63(d,J=8.0Hz,1H),8.13(dd,J=1.6,8.0Hz,1H),7.63-7.71(m,2H),4.91(s,2H),4.78(brs,2H),3.54(q,J=6.8Hz,2H),1.10-1.18(m,9H)。
【方案3】
实施方案4:2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1H-咪唑并[4,5-c]喹啉5-氧化物(2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin5-oxide)的合成
2-乙氧基甲基-1-(2-羟基-2-甲基丙基)-1H-咪唑并[4,5-c]喹啉5-氧化物(化合物5)使用以下方案4的方法合成。更详细地,将化合物4(30g)、二氯甲烷(350mL)和间氯过苯甲酸(26g)加入到10至20℃的反应器中,并在室温下搅拌4小时。然后,将饱和碳酸钠溶液(150mL)和硫酸钠溶液(150mL)加入到搅拌的混合物中,然后使用二氯甲烷和甲醇的混合溶液(10/1,v/v)萃取反应产物)。将萃取的有机溶液层用硫酸钠(30g)脱水,并使用过滤器过滤,随后在低压下浓缩。然后,将浓缩的反应产物用乙酸乙酯(50mL)研磨,用过滤器分离,然后在低压下干燥,由此得到化合物5(30g,94.9%,黄色固体)。使用1H NMR验证所获得的化合物5的结构。
1HNMR(DMSO_d6400MHz):δ9.04(s,1H)),8.79(d,J=8.4Hz,1H),8.71(d,J=8.4Hz,1H),7.77-7.80(m,2H),4.93(s,2H),4.73(brs,2H),3.54(q,J=6.8Hz,2H),1.12-1.18(m,9H)。
【方案4】
实施方案5:1-(4-氨基-2-乙氧基甲基)-1H-咪唑并[4.5-c]喹啉-1-基)-2-甲基丙-2-醇(1-(4-amino-2-ethoxymethyl)-1H-imidazo[4.5-c]quinolin-1-yl)-2-methylpropan-2-ol)的合成
1-(4-氨基-2-乙氧基甲基)-1H-咪唑并[4.5-c]喹啉-1-基)-2-甲基丙-2-醇(化合物6)使用以下方案5的方法合成。更详细地,将化合物5(30g)、DCM(600mL)、4-甲基苄基-1-磺酰氯(18.2g)和氨(NH3.H2O,180mL)添加到10至20℃的反应器中,并在室温下搅拌16小时。然后,在搅拌的混合物中加入蒸馏水后,使用二氯甲烷和甲醇(10/1,v/v)的混合溶液分离混合物。分离的有机溶液层用盐水洗涤,然后用无水硫酸钠(50g)脱水。使用过滤器过滤脱水的有机溶液层,然后在低压下浓缩,然后使用甲基叔丁基醚和甲醇的混合溶液(15/1,v/v)研磨浓缩的反应产物30分钟。然后,使用过滤器分离所得产物并在低压下干燥,从而获得化合物6(18g,60%,黄色固体)。所获得的化合物6的结构使用1H NMR验证。
1H NMR(DMSO_d6400MHz):δ8.27(d,J=8.0Hz,1H),7.59(d,J=7.6Hz,1H),7.40(t,J=7.2Hz,1H),7.21(t,J=7.2Hz,1H),6.57(brs,2H),4.89(s,2H),4.68(brs,2H),3.52(q,J=6.8Hz,2H),1.11-1.17(m,9H)。
【方案5】
实施方案6:10,13-二甲基-17-(6-甲基庚烷-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环[a]菲-3-基2-(乙氧基甲基)-1-(2-羟基-2-甲基丙基)-1H-咪唑并[4,5-c]喹啉-4-基氨基甲酸酯(10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo[a]phenanthren-3-yl2-(ethoxymethy)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-ylcarbamate)的合成
10,13-二甲基-17-(6-甲基庚烷-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环[a]菲-3-基2-(乙氧基甲基)-1-(2-羟基-2-甲基丙基)-1H-咪唑并[4,5-c]喹啉-4-基氨基甲酸酯(化合物8)使用以下方案6的方法合成。首先,将化合物7(TCI,50g,氯甲酸胆固醇)进行250g硅胶填充柱层析(0%~20%乙酸乙酯正己烷溶液),得到纯化合物7(30g)。然后,将化合物6(15g)和二氯甲烷(198.9g)加入到10-20℃的反应器中,依次加入纯化合物7(30g)和四乙胺(9.6g),然后在20-25℃搅拌16小时。向搅拌的混合物中加入水后,加入二氯甲烷以萃取反应产物。将萃取的有机溶液层用盐水洗涤并用无水硫酸钠(195g)脱水。使用过滤器过滤脱水的有机溶液层,并在低压下浓缩。然后,使用甲基叔丁基醚和甲醇(10/1,v/v)的混合溶液研磨浓缩的反应产物。之后,通过使用过滤器分离和在低压下干燥得到化合物8(10.2g,55.1%,白色固体)。使用1H NMR验证获得的化合物8的结构。根据1H NMR结果,确认制备了其中雷西莫特(R848)和胆固醇通过氨基甲酸酯键连接的复合物。
1H NMR(CDCl3400MHz):δ8.13-8.19(m,2H),7.59-7.63(m,1H)),7.46-7.50(m,1H),5.42-5.43(m,1H),4.92(brs,2H),4.72-4.80(m,3H),3.68(q,J=6.8Hz,2H),3.24(s,1H),2.51-2.59(m,1H),2.36-2.47(m,1H),1.96-2.11(m,3H),1.81-1.95(m,2H),1.45-1.75(m,9H),1.02-1.35(m,27H),0.94(d,J=6.4Hz,3H),0.89(d,J=6.4Hz,6H),0.71(s,3H)。
【方案6】
实施方案7:双(2,5-二氧代吡咯烷-1-基)2,2′-二亚砜二基双(乙烷-2,1-二基)二碳酸酯(bis(2,5-dioxopyrrolidin-1-yl)2,2’-disulfanediylbis(ethane-2,1-diyl)dicarbonate)的合成
双(2,5-二氧代吡咯烷-1-基)2,2′-二亚砜二基双(乙烷-2,1-二基)二碳酸酯(化合物9)使用以下方案7的方法合成。首先,将化合物7(TCI,70g)进行350g硅胶填充柱层析(0%~20%乙酸乙酯的正己烷溶液),从而得到纯的化合物7(40g)。然后,将纯化合物7(40g)和二氯甲烷(100mL)加入到10至15℃的反应器中,并依次添加双(2-羟乙基)二硫化物-二氯甲烷(250mL)溶液和吡啶(21g)。将混合物在室温下搅拌2小时,然后加入蒸馏水(200mL)。随后,加入二氯甲烷(150mL)三次,从而萃取反应产物。将萃取的有机溶液层用盐水洗涤并用无水硫酸钠(20g)脱水。使用过滤器过滤脱水的反应产物,然后在低压下浓缩。之后,使用柱色谱法(硅胶,300g,10%~30%乙酸乙酯的正己烷溶液)得到化合物9(20g,39.6%,黄色凝胶)。所获得的化合物9的结构使用1H NMR验证。
1HNMR(CDCl3400MHz):δ5.41-5.42(m,1H),4.46-4.56(m,1H),4.41(t,J=6.8Hz,2H),3.91(t,J=6.0Hz,2H),2.98(t,J=6.8Hz,2H),2.91(t,J=6.0Hz,2H),2.35-2.47(m,2H),1.79-2.08(m,6H),1.43-1.73(m,7H),1.25-1.42(m,5H),1.06-1.22(m,7H),0.97-1.03(m,5H),0.93(d,J=6.4Hz,3H),0.88(dd,J=1.6,6.8Hz,6H),0.69(s,3H)。
【方案7】
实施方案8:化合物10的合成
使用以下方案8的方法合成化合物10。更详细地说,将化合物9(20g)和二氯甲烷(200mL)添加到10至15℃的反应器中,然后将双(2,5-二氧代吡咯烷-1-基)碳酸酯(18g)和四乙胺(10.7g)依次添加。将混合物在室温下搅拌3小时,加入蒸馏水(300mL),然后加入二氯甲烷(150mL)三次以萃取反应产物。将萃取的有机溶液层用盐水洗涤并使用无水硫酸钠(20g)脱水。使用过滤器过滤脱水的反应产物,然后将滤液减压浓缩。之后,使用柱色谱法(硅胶,200g,5%~20%乙酸乙酯的正己烷溶液)得到化合物10(18g,72%,黄色凝胶)。使用1H NMR验证所获得的化合物10的结构。
1HNMR(CDCl3400MHz):δ5.39-5.40(m,1H),4.57(t,J=6.8Hz,2H),4.43-4.52(m,1H),4.37(t,J=6.4Hz,2H),2.96-3.03(m,4H),2.84(s,4H),2.34-2.44(m,2H),1.78-2.04(m,5H),1.42-1.73(m,7H),1.22-1.40(m,5H),1.06-1.20(m,7H),0.95-1.04(m,5H),0.91(d,J=6.0Hz,3H),0.86(d,J=6.4Hz,6H),0.67(s,3H)。
【方案8】
实施方案9:2-((2-((10,13-二甲基-17-(6-甲基庚基-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环[a]菲-3-基氧基)羰氧基)乙基)二硫酰基)乙基2-(乙氧基甲基)-1-(2-羟基-2-甲基丙基)-1H-咪唑并[4,5-c]喹啉-4-基氨基甲酸酯(2-((2-((10,13-diemthyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo[a]phenanthren-3-yloxy)cabonyloxy)ethyl)disulfanyl)ethyl 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl carbamate)的合成
2-((2-((10,13-二甲基-17-(6-甲基庚基-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-十四氢-IH-环[a]菲-3-基氧基)羰氧基)乙基)二硫酰基)乙基2-(乙氧基甲基)-1-(2-羟基-2-甲基丙基)-1H-咪唑并[4,5-c]喹啉-4-基氨基甲酸酯(化合物11)使用以下方案9的方法合成。更详细地,将化合物6(15g)和二氯甲烷(198.9g)加入到10至20℃的反应器中,并依次加入化合物10(40.5g)和四乙胺(9.6g)。将混合物在20至25℃下搅拌16小时,然后加入蒸馏水(225mL)。随后,加入二氯甲烷(99.45g)五次以萃取反应产物。将萃取的有机溶液层用盐水洗涤并用无水硫酸钠(195g)脱水。然后,使用过滤器过滤脱水的反应产物,然后将滤液减压浓缩。随后,使用柱色谱法(硅胶,100g,10%~50%乙酸乙酯的正己烷溶液)得到化合物11(10.8g,37.4%,白色固体)。使用1H NMR验证所获得的化合物11的结构。由1HNMR结果证实,制备了其中R848和胆固醇通过二硫化物交联的复合物。
1H NMR(CDCl3400MHz):δ8.15-8.17(m,2H),7.60-7.64(m,1H)),7.47-7.51(m,1H),5.39-5.40(m,1H),4.93(s,2H),4.81(s,2H),4.56(t,J=6.4Hz,2H),4.45-4.54(m,1H),4.41(t,J=6.4Hz,2H),3.68(q,J=6.8Hz,2H),3.13(s,1H),3.09(t,J=6.4Hz,2H),3.01(t,J=6.4Hz,2H),2.34-2.47(m,2H),1.92-2.06(m,3H),1.79-1.90(m,2H),1.23-1.72(m,21H),1.06-1.21(m,7H),0.96-1.05(m,5H),0.93(d,J=6.4Hz,3H),0.88(dd,J=1.6,6.4Hz,6H),0.69(s,3H)。
【方案9】
实施方案10:Toll样受体7或8激动剂-抗体复合物的合成
各种抗体复合的Toll样受体7或8激动剂(基于咪唑并喹啉的激动剂、基于8-羟基腺嘌呤的激动剂,基于蝶酮类的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂和基于7-硫杂-8-氧代鸟苷的激动剂)可以通过作为Toll样受体7或8激动剂的活性位点的胺基(NH2)与抗体、抗体片段、抗体衍生物之间通过合成氨基甲酸酯、二硫、肼、酯、肽、叠氮或β-葡萄糖醛酸苷键的反应来制备。Toll样受体7或8激动剂和抗体可以通过被各种外部或内部环境刺激裂解的接头连接。代表性的接头如图1所示。下文中,为了确认其中Toll样受体7或8激动剂的功能暂时抑制并在特定条件下通过裂解激活的复合物是否基本形成作为抗体-Toll样受体7或8激动剂复合物,制备了其中作为Toll样受体7或8激动剂的雷西莫特通过各种键与抗体结合的复合物。
10.1合成Toll样受体7或8激动剂-抗体复合物,该复合物具有被蛋白酶裂解的键
为了合成其中通过将被蛋白酶裂解的肽键连接抗体和Toll样受体7或8激动剂的复合物,使用以下方案10或11的方法。作为方案10的一个具体示例,为了合成含有巯基的抗体和含有被组织蛋白酶B裂解的键的雷西莫特的复合物,合成了具有主要与其活性位点连接的接头的雷西莫特。更详细地说,将雷西莫特(10mg)和Mal-Val-Cit-PAB-PNP(47.2mg)添加到2mL N,N-二甲基甲酰胺(DMF)中,然后溶解。然后,加入N,N-二异丙基乙胺(DIPEA;6.7μL)和1-羟基苯并***水合物(1-HOBt;315μg)。然后,通过在室温下搅拌16小时来制备混合物。使用薄层色谱纯化所制备的混合物,从而获得雷西莫特(白色粉末),其中Toll样受体7或8激动剂的活性位点的功能被组织蛋白酶-B动力学恢复。
另外,为了还原抗体,将作为抗体的一种类型的抗VEGFR2抗体和三(2-羧乙基)膦(TCEP)添加到1mM EDTA溶液(pH 7.4)中,在37℃反应1小时。然后降温至22℃后,加入脱氢抗坏血酸以调节pH值至6.5,反应1小时以进行再氧化。随后,将其中被组织蛋白酶-B动力学恢复活性位点功能的Toll样受体7或8激动剂的雷西莫特复合物用1M Tris缓冲液处理以调节pH值至7.4,与抗体混合,并在22℃反应30分钟,从而制备复合物,使用PD-10柱通过凝胶电泳去除未反应物。
【方案10】
【方案11】
10.2合成Toll样受体7或8激动剂-抗体复合物,该复合物具有被β-葡萄糖醛酸苷酶裂解的键
为了合成其中通过被β-葡萄糖醛酸苷酶裂解的β-葡萄糖醛酸苷键连接抗体和Toll样受体7或8激动剂的复合物,使用以下方案12的方法。首先,为了还原抗体,将作为一种抗体的抗VEGFR2抗体和三(2-羧乙基)膦添加到1mM EDTA溶液(pH 7.4)中,并在37℃下反应1小时。然后在降温至22℃后,加入脱氢抗坏血酸调节pH值至6.5,反应1小时以进行再氧化。随后,作为一种β-葡萄糖醛酸接头连接(即灭活的)Toll样受体7或8激动剂的雷西莫特与部分还原抗体的硫氢基之间的反应被诱导。更详细地,使用1M Tris缓冲液调节pH至7.4后,将抗体与连接有β-葡萄糖醛酸接头的雷西莫特混合,并在22℃下反应30分钟,从而制备复合物,并通过使用PD-10柱进行凝胶电泳去除未反应的物质。
【方案12】
10.3合成Toll样受体7或8激动剂和抗体的复合物,该复合物具有被还原剂裂解的键
为了合成其中通过将被还原剂裂解的二硫键连接抗体和Toll样受体7或8激动剂的复合物,使用以下方案13的方法。进一步详细地,将作为一种抗体的抗SIRPα抗体(90mg)添加到通过将雷西莫特(31.4mg)(其是一种类型的Toll样受体7或8激动剂)和吡啶(100μL)添加到二氯甲烷(3mL)中而制备的溶液中并溶解,然后缓慢滴加马来酰亚胺己酰-碳酸酯-二硫化物-NHS碳酸酯(90mg)的二氯甲烷溶液(1mL)。然后,通过在4℃下搅拌16小时来制备混合物。向混合物中加入蒸馏水以分离水层和二氯甲烷层,然后向分离的二氯甲烷层中加入硫酸钠并反应16小时以除去剩余的水。然后,使用硅胶柱纯化剩余的溶液,从而获得白色粉末状的抗体连接的雷西莫特。
【方案13】
10.4合成Toll样受体7或8激动剂和抗体的复合物,该复合物具有酸性条件下裂解的键
为了合成其中通过在细胞中在酸性条件下裂解的肼键连接抗体和Toll样受体7或8激动剂的复合物,使用以下方案14的方法。更详细地,将作为一种抗体的抗SIRPα抗体(10μg)添加到通过将雷西莫特(31.4mg)(其作为一种类型的Toll样受体7或8激动剂)和吡啶(100μL)添加到二氯甲烷(3mL)中而制备的溶液中并溶解,,然后缓慢滴加马来酰亚胺己酰-碳酸酯-二硫化物-NHS碳酸酯(90mg)的二氯甲烷溶液(1mL)。然后,将混合物在4℃下制备16小时。向混合物中加入蒸馏水以分离水层和二氯甲烷层,然后向分离的二氯甲烷层中加入硫酸钠并反应16小时以除去剩余的水。然后,使用硅胶柱纯化剩余的溶液,从而获得白色粉末状的抗体连接的雷西莫特。
【方案14】
实施方案11:Toll样受体7或8激动剂-抗癌剂复合物的合成
各种抗癌剂连接的Toll样受体7或8激动剂(基于咪唑并喹啉的激动剂、8-羟基腺嘌呤的激动剂,基于蝶酮类的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂和基于7-硫杂-8-氧代鸟苷的激动剂)可以通过胺(NH2)基位点(其是Toll样受体7或8激动剂的活性位点)与各种能够合成氨基甲酸酯、二硫、肼、酯、肽、叠氮或β-葡萄糖醛酸苷键的抗癌剂之间的反应来制备。Toll样受体7或8激动剂和抗癌剂可通过能被各种外部或内部环境刺激裂解的接头连接。下文中,作为抗癌剂-Toll样受体7或8激动剂复合物,为了确认是否实质上形成其中Toll样受体7或8激动剂的功能暂时被抑制并在特定条件下通过裂解激活的复合物,制备了其中雷西莫特(其是一种Toll样受体7或8激动剂)通过各种键与抗癌剂连接的复合物。
11.1合成Toll样受体7或8激动剂和含胺基抗癌剂的复合物,该复合物具有还原剂裂解的键
为了合成其中通过将被还原剂裂解的二硫键连接含胺基抗癌剂(含胺基化学药物)和Toll样受体7或8激动剂的复合物,首先,为了还原含胺基抗癌剂,将阿霉素(一种含胺基抗癌剂)和三(2-羧乙基)膦(TCEP)加入到1mM EDTA溶液(pH 7.4)中,并在37℃反应1小时。然后降温至22℃后,加入脱氢抗坏血酸以调节pH值至6.5,反应1小时以进行再氧化。之后,诱导未被氧化的处于还原状态的二硫化物与包含雷西莫特的接头之间的反应。进一步详细地,在使用1M Tris缓冲液调节pH至7.4后,将氧化的抗癌剂和雷西莫特混合并在22℃下反应30分钟,从而制备复合物,然后使用PD-10柱通过凝胶电泳去除未反应的物质。具有胺基的抗癌剂的代表性种类、含有胺基的抗癌剂与toll样受体7或8激动剂的复合物(其具有被还原剂裂解的键)的示例、以及利用还原剂裂解的机制如图2所示。
11.2合成Toll样受体7或8激动剂和含胺基抗癌剂的复合物,该复合物具有被细胞中的氢离子浓度(pH)裂解的键
合成了一种其中通过将在细胞中的酸性条件下被裂解的肼键连接抗癌剂和Toll样受体7或8激动剂的复合物。更具体地,将添加并溶解有芳基肼(90mg)和阿霉素(31.4mg)(其是一种含胺基抗癌剂)的二氯甲烷溶液(1mL)缓慢滴加到通过在二氯甲烷(3mL)加入雷西莫特(31.4mg)(其是一种Toll样受体7或8激动剂)和吡啶(100μL)制备的溶液中。然后,通过在4℃下搅拌16小时来制备混合物。向混合物中加入蒸馏水以分离水层和二氯甲烷层,向分离的二氯甲烷层中加入硫酸钠并反应16小时,从而除去残留的水。然后,使用硅胶柱纯化剩余溶液,从而获得连接有抗癌剂的雷西莫特(白色粉末)。含胺基抗癌剂和Toll样受体7或8激动剂的复合物(复合物具有在酸性条件下裂解的键)和裂解机制的示例如图3所示。
11.3合成Toll样受体7或8激动剂和抗癌剂的复合物,该复合物具有被β-葡萄糖醛酸苷酶裂解的键
合成了一种其中通过将被β-葡萄糖醛酸苷酶裂解的β-葡萄糖醛酸苷键连接抗癌剂和Toll样受体7或8激动剂的复合物。更具体地,将添加并溶解有4-硝基苯基β-D-葡萄糖醛酸(90mg)和紫杉醇(31.4mg)(其是具有羟基的一种抗癌剂)的二氯甲烷溶液(1mL)中,缓慢滴加到通过在二氯甲烷(3mL)加入雷西莫特(31.4mg)(一种Toll样受体7或8激动剂)和吡啶(100μL)制备的溶液中。然后,通过在4℃下搅拌16小时来制备混合物。向混合物中加入蒸馏水以分离水层和二氯甲烷层,向分离的二氯甲烷层中加入硫酸钠并反应16小时,从而除去剩余的水。然后,使用硅胶柱纯化剩余溶液,从而获得连接有抗癌剂的雷西莫特(白色粉末)。具有羟基的代表性抗癌剂,和抗癌剂与Toll样受体7或8激动剂的复合物(该复合物具有被β-葡萄糖醛酸苷酶裂解的键)以及裂解机制的示例如图4所示。
11.4合成Toll样受体7或8激动剂和含羟基抗癌剂的复合物,该复合物具有被蛋白酶裂解的键
为了合成其中通过将被蛋白酶裂解的肽键连接抗癌剂和Toll样受体7或8激动剂的复合物,首先为了还原抗癌剂,将紫杉醇(其是一种含羟基抗癌剂)和三(2-羧乙基)膦(TCEP)加入到1mM EDTA溶液(pH 7.4)中,并在37℃下反应1小时。然后降温至22℃后,加入脱氢抗坏血酸调节pH值至6.5,反应1小时以进行再氧化。氧化的抗癌剂与磷酸苯酯(100mg)反应,以诱导与雷西莫特(其是一种toll样受体7或8激动剂)的反应。更详细地,在使用1MTris缓冲液调节pH至7.4后,将氧化的抗癌剂和雷西莫特混合并在22℃下反应30分钟,从而制备复合物,并使用PD-10柱通过凝胶电泳去除未反应的物质。含羟基的抗癌剂和Toll样受体7或8激动剂的复合物(该复合物具有被蛋白酶裂解的键)和裂解机制的示例如图5所示。
实施方案12:Toll样受体7或8激动剂和基于蛋白质的药物的复合物的合成
连接了基于蛋白质的药物(即由蛋白质组成的功能性药物)的各种Toll样受体7或8激动剂(基于咪唑并喹啉的激动剂、基于8-羟基腺嘌呤的激动剂,基于蝶酮类的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂和基于7-硫杂-8-氧代鸟苷的激动剂)可以通过胺基(NH2)位点(其是Toll样受体7或8激动剂的活性位点)和各种基于蛋白质的药物之间的能够合成氨基甲酸酯、二硫、肼、酯、肽、叠氮和β-葡萄糖醛酸苷键的反应制备。Toll样受体7或8激动剂和基于蛋白质的药物可以通过被各种外部或内部环境的刺激裂解的接头连接。下文中,作为基于蛋白质的药物和Toll样受体7或8激动剂的复合物,为了确认是否基本形成其中Toll样受体7或8激动剂的功能暂时被抑制并在特定条件下通过裂解激活的复合物,制备了其中作为Toll样受体7或8激动剂的雷西莫特通过各种键与基于蛋白质的药物连接的复合物。用于制备复合物的代表性接头和连接机制如图6所示。
12.1合成Toll样受体7或8激动剂和基于蛋白质的药物的复合物,该复合物通过胺基的反应具有被还原剂裂解的键
为了合成一种其中通过可被还原剂裂解的二硫键连接基于蛋白质的药物和Toll样受体7或8激动剂的复合物,使用了NHS酯反应。更具体地,在22℃下,将脱氢抗坏血酸加入到3-巯基丙基-N-羟基琥珀酰亚胺(NHS)酯中以调节pH至6.5并反应1小时,从而制备接头。之后,通过加入1M Tris缓冲液将pH值进一步升高至7.4后,将作为一种基于蛋白质的药物的蛋白质抗原卵清蛋白(OVA)与雷西莫特混合并在22℃下反应30分钟,从而制备复合物。使用PD-10柱通过凝胶电泳去除未反应的物质。基于蛋白质的药物和Toll样受体7或8激动剂的复合物(该复合物具有被还原剂裂解的键)以及裂解机制的示例如图7所示。
12.2合成Toll样受体7或8激动剂和基于蛋白质的药物的复合物,该复合物通过胺基的反应具有在细胞中的氢离子浓度(pH)裂解的键
为了合成一种基于蛋白质的药物与Toll样受体7或8激动剂通过在氢离子浓度下(即细胞中的酸性条件下)可被裂解的肼键连接的复合物,使用了NHS酯反应。更详细地说,将添加了芳基肼(90mg)的二氯甲烷(1mL)缓慢滴加到添加了3-巯基丙基-N-羟基琥珀酰亚胺(NHS)酯和吡啶(100μL)的二氯甲烷(3mL)中。然后,将作为一种基于蛋白质的药物的蛋白质抗原OVA(31.4mg)和雷西莫特(31.4mg)添加到混合物中并在4℃下搅拌16小时,从而合成复合物。然后,使用硅胶柱纯化合成的复合物,从而获得基于蛋白质的药物连接的雷西莫特(白色粉末)。基于蛋白质的药物和Toll样受体7或8激动剂的复合物(该复合物具有被细胞中的氢离子浓度裂解的键)以及裂解机制的示例如图8所示。
12.3合成Toll样受体7或8激动剂和基于蛋白质的药物的复合物,复合物通过胺基的反应具有被β-葡萄糖醛酸苷酶裂解的键
为了合成一种通过可被β-葡萄糖醛酸苷酶裂解的β-葡萄糖醛酸苷键连接基于蛋白质的药物和Toll样受体7或8激动剂的复合物,使用了NHS酯键。更详细地,将添加了4-硝基苯基β-D-葡萄糖醛酸苷(90mg)的二氯甲烷(1mL)缓慢滴加到加入了雷西莫特(31.4mg)、3-巯基丙基-N-羟基琥珀酰亚胺(NHS)酯和吡啶(100μL)的二氯甲烷(3mL)中。之后,在4℃下搅拌16小时制备混合物,加入作为基于蛋白质的药物的蛋白质抗原OVA(31.4mg),在4℃下搅拌16小时,从而合成复合物。然后,将温度调节至室温后,加入蒸馏水以分离水层和二氯甲烷层。在分离的二氯甲烷层中加入硫酸钠并且反应16小时,以除去残留的水分,将残留的溶液用硅胶柱纯化,得到基于蛋白质的药物连接的雷西莫特(白色粉末)。基于蛋白质的药物和Toll样受体7或8激动剂的复合物(该复合物具有被β-葡萄糖醛酸苷酶裂解的键)以及裂解机制的示例如图9所示。
12.4合成Toll样受体7或8激动剂和基于蛋白质的药物的复合物,该复合物通过巯基反具有被还原剂裂解的键
为了合成一种通过可被还原剂裂解的二硫键连接基于蛋白质的药物和Toll样受体7或8激动剂的复合物,使用了马来酰亚胺反应。更详细地,在22℃下将脱氢抗坏血酸添加至马来酰亚胺PEG以将pH调节至6.5并反应1小时,从而制备接头。之后,诱导含有未被氧化的处于还原状态的二硫化物的接头与属于一种基于蛋白质的药物的蛋白质抗原OVA(31.4mg)之间的反应。随后,将pH值调至9.0后,将与接头连接的基于蛋白质的药物与雷西莫特(31.4mg)混合并在22℃下反应30分钟。然后,使用PD-10柱通过凝胶电泳去除未反应的物质。基于蛋白质的药物和Toll样受体7或8激动剂的复合物(其具有通过巯基的反应被还原剂裂解的键)以及裂解机制的示例如图10所示。
12.5合成Toll样受体7或8激动剂和基于蛋白质的药物的复合物,该复合物通过巯基的反应具有在细胞中的氢离子浓度(pH)裂解的键
为了合成一种通过可在细胞中的氢离子浓度下(即酸性条件下)被裂解的二硫化物连接基于蛋白质的药物和Toll样受体7或8激动剂的复合物,使用了马来酰亚胺反应。更详细地,将添加有芳基肼(90mg)的二氯甲烷(1mL)缓慢滴加到添加有马来酰亚胺PEG和吡啶(100μL)的二氯甲烷(3mL)中。然后,将作为一种基于蛋白质的药物的蛋白质抗原OVA(31.4mg)和雷西莫特(31.4mg)添加到混合物中并在4℃下搅拌16小时,从而合成复合物。然后,使用硅胶柱纯化合成的复合物,从而获得基于蛋白质的药物连接的雷西莫特(白色粉末)。基于蛋白质的药物和Toll样受体7或8激动剂(该复合物具有被细胞中的氢离子浓度裂解的键)以及裂解机制的示例如图11所示。
12.6合成Toll样受体7或8激动剂和基于蛋白质的药物的复合物,该复合物通过巯基的反应具有被β-葡萄糖醛酸苷酶裂解的键
为了合成一种通过可被β-葡萄糖醛酸苷酶裂解的β-葡萄糖醛酸苷键连接基于蛋白质的药物和Toll样受体7或8激动剂的复合物,使用了马来酰亚胺反应。更详细地,将添加有4-硝基苯基β-D-葡萄糖醛酸苷(90mg)的二氯甲烷(1mL)缓慢滴加到添加有马来酰亚胺PEG和吡啶(100μL)的二氯甲烷(3mL)中。随后,将pH调节至9.0后,通过在4℃下搅拌16小时来制备混合物。将作为一种基于蛋白质的药物的蛋白质抗原OVA(31.4mg)和雷西莫特(31.4mg)添加到制备的混合物中,并在4℃下搅拌16小时,从而合成复合物。然后,将温度调节至室温后,加入蒸馏水以分离水层和二氯甲烷层,向分离的二氯甲烷层中加入硫酸钠并反应16小时以除去残留的水。然后,使用硅胶柱纯化剩余溶液,从而获得基于蛋白质的药物连接的雷西莫特(白色粉末)。蛋白质的药物和Toll样受体7或8激动剂的复合物(该复合物具有被β-葡萄糖醛酸糖苷酶裂解的键)以及裂解机制的示例如图12所示。
实施方案13:Toll样受体7或8激动剂和敏化剂的复合物的合成
13.1合成Toll样受体7或8激动剂和敏化剂的复合物,该复合物具有被还原剂裂解的键
为了合成一种其中通过将被还原剂裂解的二硫键连接敏化剂和Toll样受体7或8激动剂的复合物,首先,将敏化剂和三(2-羧乙基)膦添加到1mM的EDTA溶液(pH 7.4)中并且在37℃反应1小时以还原作为一种光敏剂的光敏素。降温至22℃后,接着加入脱氢抗坏血酸以调节pH值至6.5,反应1小时以进行再氧化。随后,诱导未被氧化的处于还原状态的光敏素与雷西莫特之间的反应。更具体地,在使用1M Tris缓冲液调节pH至7.4后,将氧化敏化剂和雷西莫特混合并在22℃下反应30分钟,从而制备复合物,并使用PD-10柱通过凝胶电泳去除未反应的物质。代表性类型的敏化剂、敏化剂和Toll样受体7或8激动剂的复合物(该复合物具有被还原剂裂解的键)的示例以及裂解机制如图13所示。
13.2合成Toll样受体7或8激动剂和含羧基的敏化剂的复合物,该复合物具有通过在细胞中的氢离子浓度(pH)裂解的键
合成了一种其中通过将由在细胞中的氢离子浓度(酸性条件下)裂解的肼键连接敏化剂和Toll样受体7或8激动剂的复合物。更详细地,将添加有芳基肼(90mg)的二氯甲烷(1mL)溶液缓慢滴加到通过将雷西莫特(31.4mg)(其是一种toll样受体7或8激动剂)和吡啶(100μL)添加和溶解至二氯甲烷(3mL)所制备的溶液中。随后,通过在4℃下搅拌16小时来制备混合物。向混合物中加入作为一种光敏剂的光敏素并且于22℃反应30分钟,从而制得复合物,然后加入蒸馏水以分离水层和二氯甲烷层,向分离的二氯甲烷层加入硫酸钠并反应16小时以除去剩余的水。然后,使用硅胶柱纯化剩余的溶液,从而获得连接有敏化剂的雷西莫特(白色粉末)。含羧基的敏化剂和Toll样受体7或8激动剂的复合物(该复合物在酸性条件下具有裂解的键)以及裂解机制示例如图14所示。
13.3合成Toll样受体7或8激动剂和含羧基的敏化剂的复合物,该复合物具有被β-葡萄糖醛酸苷酶裂解的键
合成了一种其中通过将被β-葡萄糖醛酸苷酶裂解的β-葡萄糖醛酸苷键连接敏化剂和Toll样受体7或8激动剂的复合物。更详细地,将添加有硝基苯基β-葡萄糖苷(90mg)的二氯甲烷(1mL)溶液缓慢滴加到通过将雷西莫特(31.4mg)(其是一种toll样受体7或8激动剂)和吡啶(100μL)添加和溶解至二氯甲烷(3mL)所制备的溶液中。随后,通过在4℃下搅拌16小时来制备混合物。向混合物中加入作为一种光敏剂的光敏素并且于22℃反应30分钟,从而制得复合物,然后加入蒸馏水以分离水层和二氯甲烷层,向分离的二氯甲烷层加入硫酸钠并反应16小时以除去剩余的水。然后,使用硅胶柱纯化剩余的溶液,从而获得连接有敏化剂的雷西莫特(白色粉末)。含有羧基的敏化剂和Toll样受体7或8激动剂的复合物(该复合物具有被β-葡萄糖醛酸苷酶裂解的键)和裂解机制的示例如图15所示。
实施方案14:含有羧基的抗体和雷西莫特的复合物的合成,该复合物具有被水解裂解的键
14.1合成含有羧基的抗体和雷西莫特的复合物,该复合物具有被水解裂解的键
为了合成具有通过水解而裂解的键的含有羧基的抗体和雷西莫特的复合物,首先,合成其中通过水解而动力学恢复活性部位的功能的toll样受体7或8激动剂。更详细地,将雷西莫特(10mg)和马来酰亚胺-dPEG4-NHS酯(19.6mg)添加到二氯甲烷(DCM;2mL),然后添加三乙胺(8.8μL)。随后,通过在室温下搅拌16小时来制备混合物,并使用薄层色谱法纯化混合物,由此获得其中通过水解而动力学恢复活性部位功能的雷西莫特(白色粉末)。之后,为了将雷西莫特与抗体结合,将抗VEGFR2抗体(4mg)分散在含有1mM二亚乙基三胺(DTPA)的1M硼酸盐缓冲液中。另外,加入120μM三(2-羧乙基)膦(TCEP)并在37℃下搅拌1小时进行还原。此外,将还原抗体和雷西莫特(210μg)混合并在4℃下搅拌1小时。然后,使用ZebaTM脱盐柱以1,000×g离心2分钟,纯化得抗体-雷西莫特复合物(AAC-001)。
14.2具有被水解裂解的键的含有羧基的抗体和雷西莫特的复合物的抗癌效果验证
为了确认以与实施方案14.1中相同的方式合成的抗体-雷西莫特复合物(AAC-001)的抗癌作用,使用B16OVA黑色素瘤评估抗癌作用。首先,将5×105个B16OVA癌细胞通过皮下注射施用到小鼠的背部,三天后,将药物直接注射到癌组织中,间隔三天,共注射4次。对于药物,使用雷西莫特、雷西莫特和抗VEGFR2的混合物、以及具有通过水解而裂解的键的抗VEGFR2抗体-雷西莫特复合物(AAC-001)。之后,通过测量癌的大小来确认癌的生长程度,以及计算存活率。之后,所有实验至少重复三次,结果表示为平均值±标准差。统计显著性由Student′st-检验证实,当P<0.05时,确定为具有统计显著性。结果如图16和17所示。
如图16和17所示,与单独施用雷西莫特(R848)以及联合施用抗VEGFR2与雷西莫特(R848+抗VEGFR2)相比,已证明复合物AAC-001不仅可以显著抑制癌症生长,还可以提高存活率。
14.3具有被水解裂解的键的含有羧基的抗体-雷西莫特的复合物的血液炎症细胞因子水平验证
为确认以与实施方案14.1相同的方式合成的抗体-雷西莫特复合物(AAC-001)对血液中炎症细胞因子分泌的影响,在将AAC-001复合物或雷西莫特静脉内注射至小鼠后,在0、1、2和4小时收集血液样品。将收集的血液样品以10,000×g离心20分钟以分离血清,并使用Invitrogen小鼠IL-6ELISA试剂盒测量血清中存在的IL-6(其是代表性的炎症细胞因子)的浓度。结果如图18所示。
如图18所示,已证明,雷西莫特一注射入体内,就促进炎症细胞因子分泌,引发细胞因子风暴,但AAC-001复合物并未表现出炎症细胞因子水平的变化。
由以上结果证明,本发明的抗体与Toll样受体7或8激动剂的复合物(即其中抗体通过可裂解接头连接至Toll样受体7或8激动剂的活性部位的复合物)与简单的联合治疗相比,表现出低副作用和显著增加的治疗效果,因为功能性药物如抗体在给药开始时起作用,而Toll样受体7或8激动剂暂时灭活,然后通过在肿瘤微环境或靶细胞中的水解酶裂解接头而被激活,从而起到继发激活免疫***的作用。
实施方案15:含有羧基的抗体和雷西莫特的复合物,该复合物具有被组织蛋白酶-B裂解的键
15.1合成含有羧基的抗体-雷西莫特的复合物,该复合物具有被组织蛋白酶-B裂解的键
为了合成具有被组织蛋白酶B裂解的键的含羧基抗体和雷西莫特的复合物,首先,合成接头连接到活性位点的雷西莫特。更详细地说,将雷西莫特(10mg)和Mal-Val-Cit-PAB-PNP(47.2mg)添加到2mL的N,N-二甲基甲酰胺(DMF)中,然后溶解。然后,加入N,N-二异丙基乙胺(DIPEA;6.7μL)和1-羟基苯并***水合物(1-HOBt;315μg)。然后,通过在室温下搅拌16小时来制备混合物。使用薄层色谱纯化制备的混合物,从而获得雷西莫特,其中Toll样受体7或8激动剂的活性部位的功能被组织蛋白酶-B(白色粉末)动力学恢复。随后,合成具有被组织蛋白酶-B裂解的键的抗体-雷西莫特复合物(AAC-002)。为此,将抗SIRPα抗体(4mg)分散在加入了1mM二亚乙基三胺(DTPA)的1M硼酸盐缓冲液中后,加入150μM三(2-羧乙基)膦(TCEP)并在37℃下搅拌1小时以还原抗体。随后,部分还原的抗体和其活性位点功能被动力学恢复的雷西莫特(480μg)混合并在4℃下搅拌1小时,从而合成复合物。然后,使用ZebaTM脱盐柱以1,000×g将所得复合物离心2分钟,从而仅分离抗体-雷西莫特复合物AAC-002。AAC-002复合物的机制如图19所示。
15.2具有被组织蛋白酶B裂解的键的含羧基抗体和雷西莫特复合物的血液炎症细胞因子水平验证
为了确认以与实施方案15.1中相同的方式合成的抗体-雷西莫特复合物(AAC-002)对血液中炎症细胞因子分泌的影响,在AAC-002复合物(缀合的TLR7/8a-被阻断活性位点)静脉注射到小鼠体内后两小时,采集血液样品。将收集的血液样品以10,000×g离心20分钟以分离血清,并使用Invitrogen小鼠IL-6ELISA试剂盒测量血清中存在的IL-6(其为代表性的炎症细胞因子)的浓度。作为对照,磷酸盐缓冲盐水注射组(空白)、仅注射雷西莫特组(裸TLR7/8a-未复合)和被注射(缀合的TLR7/8a-Live活性位点)抗体-雷西莫特复合物(其中抗体连接活性位点以外的位点)的组用于比较。结果如图20所示
如图20所示,当单独施用雷西莫特时,或者在其中抗体与活性位点以外的位点连接的抗体-雷西莫特复合物的情况下,证明由于活性位点,不必要的刺激被诱导,从而在注射初期显著增加血液中的炎症细胞因子水平。另一方面,在其中抗体连接到活性部位的复合物的情况下,证明炎症细胞因子水平没有变化。
实施方案16:具有被组织蛋白酶-B裂解的键的蛋白质抗原-雷西莫特复合物
为了合成具有被组织蛋白酶-B裂解的键的作为一种含有巯基的基于蛋白质的药物的蛋白质抗原和雷西莫特的复合物,首先,合成其活性部位连接接头的雷西莫特。更详细地说,将雷西莫特(10mg)和Mal-Val-Cit-PAB-PNP(47.2mg)添加到2mL的N,N-二甲基甲酰胺(DMF)中,然后溶解。然后,加入N,N-二异丙基乙胺(DIPEA;6.7μL)和1-羟基苯并***水合物(1-HOBt;315μg)。然后,通过在室温下搅拌16小时来制备混合物。将OVA蛋白抗原(10mg)添加到制备的混合物中并反应,从而制备复合物,然后将所得复合物通过薄层层析纯化,从而制备具有被组织蛋白酶-B裂解的键的OVA蛋白抗原-雷西莫特复合物。然后,对制备的复合物进行光谱分析以确认其大小。结果如图21所示。
如图21所示,证明OVA蛋白质抗原和雷西莫特的复合物(其具有被组织蛋白酶-B切割的键)在水溶液中形成约99.7nm的纳米颗粒。
根据上面的结果,如图22所示,本发明的复合物可能不会表现出毒性,因为它的活性通过将功能性药物连接到Toll样受体7或8激动剂而被暂时抑制,并且当将该复合物注射入体内时,抑制炎症细胞因子的分泌和非特异性免疫反应,所以会显著降低副作用,然后当复合物由于生理环境而到达所需的位置时,Toll样受体7或8激动剂与功能性药物会分离,从而增加药物递送能力。还证明,与独立地使用Toll样受体7或8激动剂和功能药物时相比,当Toll样受体7或8激动剂和功能药物共同给药时,本发明的复合物可显著提高治疗效果。因此,其中toll样受体7或8激动剂的活性部位与功能性药物通过可裂解的接头连接的本发明的复合物有望有效地用于各种疾病的治疗。
本领域的普通技术人员应当理解,本发明的上述描述是示例性的,在不脱离本发明的技术精神或本质特征的情况下,可以容易地将在此公开的示例性实施方案修改成其他具体形式。因此,上述示例性实施方案应当被解释为在任何方面是说明性的而不是进行限制。
【工业实用性】
由于本发明的复合物(其中Toll样受体7或8激动剂的活性部位和功能性药物通过可裂解的接头连接)在给药至体内时暂时无活性,但随后,通过在肿瘤微环境和/或细胞内特定条件下分离Toll样受体7或8激动剂与功能性药物而被激活,因此其能减少例如非特异性敏感免疫反应等副作用,并且由于免疫细胞受到Toll样受体7或8激动剂的有效调控,以及功能性药物同时作用,因而其也能显著提高治疗效果。因此,它可以应用于所有能够与Toll样受体7或8激动剂共同给药的功能性药物。
Claims (19)
1.一种Toll样受体7/8激动剂-功能性药物复合物,其中所述功能性药物和所述Toll样受体7或8激动剂的活性位点通过可裂解接头连接。
2.根据权利要求1所述的复合物,其中所述功能性药物先起作用,然后灭活的所述Toll样受体7或8激动剂在接头于注射部位或肿瘤微环境或靶细胞中裂解且因此动力学恢复所述活性位点时起作用。
3.根据权利要求1所述的复合物,其中所述可裂解接头由于选自酶、pH、氧化还原电势、温度、超声波、磁力、和光源中的任何一种或多种因素而在连接位点的化学键处裂解。
4.根据权利要求1所述的复合物,其中,所述可裂解接头为选自基于苄基消除的接头、基于三烷基锁的接头、基于N-双(羟乙基)甘氨酸的接头、酸不稳定接头、溶酶体可裂解肽和组织蛋白酶B-可裂解肽中的任意一种或多种。
5.根据权利要求4所述的复合物,其中所述可裂解接头包含选自氨基甲酸酯、二硫、肼、酯、肽、叠氮、β-葡萄糖醛酸苷键及其组合的任意一个或多个键。
6.根据权利要求1所述的复合物,其中所述可裂解接头在其一端或两端还包含环氧乙烷或乙二醇。
7.根据权利要求1所述的复合物,其中所述Toll样受体7或8激动剂为选自基于咪唑并喹啉的激动剂,基于8-羟基腺嘌呤的激动剂,基于蝶酮类的激动剂、基于2-氨基嘧啶的激动剂、基于苯并氮杂卓的激动剂和基于7-硫杂-8-氧代鸟苷的激动剂中的任意一种或多种。
8.根据权利要求1所述的复合物,其中所述功能性药物为选自抗体、抗体片段、单链抗体、抗癌剂、抗原、细胞因子、蛋白质、肽、氨基酸、寡核苷酸、酶、脂质、低分子化合物、糖蛋白和靶向配体中的任意一种或多种。
9.根据权利要求1所述的复合物,其中,所述功能性药物是选自抗体、基于蛋白质的药物、敏化剂和抗癌剂中的任意一种或多种。
10.一种用于控制免疫***的组合物,其包含根据权利要求1所述的复合物作为活性成分。
11.根据权利要求10所述的组合物,其中所述用于控制免疫***的组合物激活一种或多种类型的免疫细胞,所述免疫细胞选自:抗原呈递细胞、B细胞、自然杀伤(NK)细胞和T细胞。
12.根据权利要求10所述的组合物,其中所述用于控制免疫***的组合物调节一种或多种类型的免疫细胞的功能,所述免疫细胞选自调节性T(Treg)细胞、髓源性抑制细胞(MDSC)和M2巨噬细胞。
13.根据权利要求10所述的组合物,还包含一种或多种靶向免疫检查点因子的抗体,所述抗体选自:抗PD-1、抗PD-L1、抗CTLA-4、抗KIR、抗LAG3、抗CD137、抗OX40、抗CD276、抗CD27、抗GITR、抗TIM3、抗41BB、抗CD226、抗CD40、抗CD70、抗ICOS、抗CD40L、抗BTLA、抗TCR和抗TIGIT。
14.一种用于预防或治疗癌症的药物组合物,其包含根据权利要求1所述的复合物作为活性成分。
15.根据权利要求14所述的药物组合物,所述药物组合物进一步包含:化疗剂或免疫检查点抑制剂。
16.根据权利要求14所述的药物组合物,所述药物组合物抑制癌症增殖、转移、复发或对抗癌治疗的抗性。
17.一种预防或治疗癌症的方法,其包括:
将包含根据权利要求1所述的复合物作为活性成分的组合物施用于受试者。
18.一种用于预防或治疗癌症的组合物,该组合物包含根据权利要求1所述的复合物作为活性成分。
19.根据权利要求1所述的复合物在制备预防或治疗癌症的药物中的用途。
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US10487084B2 (en) | 2017-08-16 | 2019-11-26 | Bristol-Myers Squibb Company | Toll-like receptor 7 (TLR7) agonists having a heterobiaryl moiety, conjugates thereof, and methods and uses therefor |
US10494370B2 (en) | 2017-08-16 | 2019-12-03 | Bristol-Myers Squibb Company | Toll-like receptor 7 (TLR7) agonists having a pyridine or pyrazine moiety, conjugates thereof, and methods and uses therefor |
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2021
- 2021-08-04 JP JP2023507715A patent/JP2023536954A/ja active Pending
- 2021-08-04 CN CN202180056797.5A patent/CN116056725A/zh active Pending
- 2021-08-04 EP EP21852799.2A patent/EP4194010A1/en active Pending
- 2021-08-04 US US18/040,323 patent/US20230277525A1/en active Pending
- 2021-08-04 WO PCT/KR2021/010298 patent/WO2022031057A1/ko active Application Filing
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