CN117279939A - 眼部抗体-药物偶联物 - Google Patents
眼部抗体-药物偶联物 Download PDFInfo
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- CN117279939A CN117279939A CN202180085181.0A CN202180085181A CN117279939A CN 117279939 A CN117279939 A CN 117279939A CN 202180085181 A CN202180085181 A CN 202180085181A CN 117279939 A CN117279939 A CN 117279939A
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- Prior art keywords
- compound
- antibody
- linker
- dexa
- ocular
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Abstract
本发明提供了一种眼部抗体‑药物偶联化合物。所述化合物包括:抗体,所述抗体为阻断受试者中第一靶标的经典抗体或改性生物分子;小分子药物,其包括α激动剂或选自类固醇、NSAID的抗炎小分子,且调节所述受试者中的第二或更多靶标;和接头,其连接所述抗体和所述小分子药物。本发明还提供了利用所述抗体药物偶联化合物治疗眼部疾病的方法。所述接头在一定时间内在所述受试者中水解,使得所述抗体和所述类固醇二者同时发挥它们的功能。
Description
本发明要求2020年11月3日提交的美国临时专利申请号63/108,990的优先权,其出于所有目的如同完全阐述于本文中地以引用方式并入。
技术领域
本发明涉及抗体-药物偶联化合物和使用抗体-药物偶联化合物的方法。例如,本文提供了眼部抗体-药物偶联化合物,以及可用来治疗患有眼部病症(诸如眼病)的受试者的方法。
背景技术
抗血管新生策略是针对眼部新生血管性疾病的有效治疗法,诸如渗出性AMD(也被称为湿性AMD)。几种抗VEGF抗体或工程化生物制剂在市场上用于AMD。尽管这些药物是有效的,仍需要对于这种和其他眼部疾病进行改进。例如,通过探索新作用机制来治疗抗VEGF耐受的患者;需要减少治疗注射频率或不同的方式来递送药物。本发明提供一种新颖的方式来提高针对AMD和其他眼部新生血管性疾病的有效性。
发明内容
本发明提供了在治疗受试者眼部疾病方面效力增强的化合物和方法。本文提供眼部抗体-药物偶联化合物,其包含:抗体,该抗体是经典抗体或改性生物分子,减少受试者中疾病的第一靶点-新生血管形成;小分子药物,调节受试者中疾病的第二靶点;以及抗体与药物之间的接头,以形成用于治疗眼部疾病的偶联化合物。在抗体与小分子之间共价连接的接头在一定时间段内在受试者的某些组织中水解,诸如玻璃体液,使得抗体和小分子均可被解离以在受试者中发挥它们的功能。在一些实施方案中,抗体可为抗VEGF抗体且小分子可为抗炎药。在一些实施方案中,在诸如玻璃体液的某些组织中水解并释放后,抗VEGF抗体和抗炎小分子二者可同时在受试者中发挥它们的功能。在一些实施方案中,与仅抗体或类固醇相比,偶联化合物可赋予更好的效力,或可展现两者之间的协同作用。在一些实施方案中,偶联化合物可向对抗VEGF抗体是非应答者或弱应答者的患者提供有效的治疗。在一些实施方案中,提供一种治疗受试者中的眼部疾病的方法,其包括向受试者递送化合物或偶联物,其中随着时间推移接头在受试者中水解,使得抗体和小分子类固醇均在受试者中发挥它们的功能。在一些实施方案中,偶联化合物可向患者提供长时间有效治疗,以减少因频繁的玻璃体内抗体注射所致的不利影响。
在一个实施方案中,本申请公开了一种化合物,其包括:抗体或工程化生物分子,该抗体或工程化生物分子阻断VEGF、VEGFR、PDGF、PDGFR、FGF或FGFR;小分子药物,小分子药物为肾上腺素能受体α激动剂或抗炎小分子,抗炎小分子为类固醇或非类固醇抗炎药(NSAID);以及接头,其将小分子药物连接至抗体或工程化生物分子。接头包含可在眼组织中以控释方式水解的键。
在另一个实施方案中,抗体为抗VEGF-A抗体。
在另一个实施方案中,抗体选自由贝伐单抗、雷尼珠单抗、布洛赛珠单抗、阿柏西普和康柏西普组成的组,优选地,抗体为贝伐单抗。
在另一个实施方案中,抗体被聚乙二醇化以包括线性或分支的聚乙二醇(PEG)部分。
在另一个实施方案中,PEG部分为-(CH2-CH2-O-)n-,且n为5-30,优选地,n为10-15。
在另一个实施方案中,接头经由PEG部分将小分子药物连接至抗体或工程化生物分子。
在另一个实施方案中,接头包含酯、酰胺、氨基甲酸酯、碳酸酯、亚胺、醚、磷酸酯、腙、缩醛或腙键,优选地,接头包含酯键。
在另一个实施方案中,接头为且R为H、C1-18烷基、芳基、杂芳基、C1-18烷芳基或烷基杂芳基,优选R为H、甲基、乙基、丙基、异丙基、叔丁基、苯基或苄基。
在另一个实施方案中,类固醇选自由地塞米松、倍他米松、泼尼松、泼尼松龙、去炎松、甲泼尼龙、氢化可的松、醋酸可的松、氟氢可的松和醛甾酮组成的组,优选地,类固醇为地塞米松。
在另一个实施方案中,NSAID选自由阿司匹林、塞来昔布、溴芬酸、双氯芬酸、二氟尼柳、依托度酸、布洛芬、吲哚美辛、酮洛芬、酮咯酸、萘普酮、萘普生、噁丙嗪、吡罗昔康、双水杨酯、舒林酸和托美汀组成的组,优选地,NSAID为溴芬酸。
在另一个实施方案中,肾上腺素能受体α激动剂选自由阿可乐定、米伐折醇、可乐定、溴莫尼定、α甲基多巴、胍法辛、右美托咪定、(+)-(S)-4-1-(2,3-二甲基-苯基)-乙基-1,3-二氢-咪唑-2-硫酮、1-(咪唑烷-2-基)亚氨基吲唑、甲氧胺、苯肾上腺素、替扎尼定、赛拉嗪、胍那苄和双甲脒组成的组,优选地,肾上腺素能受体α激动剂为溴莫尼定。
在另一个实施方案中,化合物包括:贝伐单抗,地塞米松,PEG部分,和接头。PEG部分为-(CH2-CH2-O-)n-,n为5-30;接头为且R为H、甲基、乙基、丙基、异丙基、叔丁基、苯基或苄基;并且接头经由PEG部分将地塞米松连接至贝伐单抗。
在另一个实施方案中,接头在眼组织中的水解是受控的,并且一半的化合物的接头水解的时间为1-60分钟、1-24小时、1-5天或1-30天,优选1-5天。
在另一个实施方案中,本申请包括一种治疗受试者中的眼部疾病的方法。方法包括将本申请的化合物递送至受试者的眼睛。
在另一个实施方案中,该方法还包括允许接头随着时间推移在受试者的眼睛的一种或多种眼组织中水解。在接头水解之后,抗体和小分子药物均在受试者中发挥它们的功能。
在另一个实施方案中,眼组织为玻璃体液、房水、Tenon囊(眼球筋膜鞘)下、角膜、结膜、视网膜、脉络膜或它们的组合,优选眼组织为玻璃体液。
在另一个实施方案中,接头在眼组织中的水解是受控的,并且一半的化合物的接头水解的时间选自1-60分钟、1-24小时或1-30天,优选1-5天。
应理解,前文的概述和下文的详述是例示和解释性的,并意图提供如所要求的对本发明另外的解释。
附图简要说明
本发明包括附图以提供对本发明的进一步理解,附图并入本说明书并构成说明书的一部分,其图示了本发明的实施方案,并且与描述一起用来解释本发明的原理。
在附图中:
图1示出例示性眼部抗体-药物偶联物技术可如何用来治疗诸如湿性AMD的眼部新生血管性疾病的图示。
具体实施方式
现将详细地提及本发明的实施方案,其实例示于附图中。
本文所公开的眼部抗体-药物偶联物利用了先前专利中未使用的三类新的小分子药物。在一些实施方案中,本文所述的化合物和方法可用来治疗眼部疾病、诸如眼部新生血管性疾病。眼部新生血管性疾病是涉及异常血管新生(血管生长)和血管渗漏的眼睛的疾病。眼部新生血管性疾病的非限制性实例包括渗出性(湿性)和非渗出性(干性)年龄相关的黄斑变性(AMD),糖尿病性黄斑水肿,视网膜静脉闭塞,糖尿病性视网膜病,角膜新生血管形成,新生血管性青光眼,青光眼手术的辅助治疗,角膜移植的辅助治疗和翼状胬肉。
抗血管新生策略是针对眼部新生血管性疾病的可用治疗法,诸如渗出性AMD(也被称为湿性AMD)。当前,有几种VEGF中和生物药上市,包括抗VEGF-A抗体,诸如贝伐单抗和雷尼珠单抗/>这两种抗体药约每月一次在玻璃体内施用。VEGFR2胞外结合域与抗体Fc区之间的融合蛋白阿柏西普/>也可被施用以治疗湿性AMD,但与雷尼比珠单抗相比可能不那么频繁地使用。最近,具有类似机制的另外的生物制剂——布洛赛珠单抗和康柏西普已上市。
尽管抗VEGF生物药取得了成功,对于治疗诸如湿性AMD的眼部新生血管性疾病仍有未满足的需要。一些患者耐受抗VEGF-A治疗。最初响应的许多患者可能随着时间推移变得耐受抗VEGF-A治疗。另一个未满足的需要是减少治疗负担和注射相关的并发症。因为AMD是具有多种致病病因学的复杂疾病,改进治疗的一种潜在方式是探索除VEGF途径以外新的疾病靶点或同时靶向多个途径。
本文所述的化合物和方法是一种新颖的方式,同时对眼部新生血管性疾病提供多种治疗。在一些情况下,本文所述的化合物和方法可提高治疗的有效性,包括在单次治疗或多次非连锁治疗内提高有效性。本文所述的化合物和方法的优点可包括:1)利用单一药物分子和单次注射抑制一个以上关键疾病机制;2)与仅单一机制可实现的相比,提高对视网膜液去除的有效性;3)降低对单一疗法发展耐性的频率;4)向玻璃体持续递送小分子药物的新颖路线;5)减少因频繁的玻璃体内注射所致的不利影响。
在一些实施方案中,本文所述的化合物和方法也可用于非眼部组织中。例如,本文所述的抗体-药物偶联物可被设计用于治疗非眼部疾病,包括自身免疫疾病、关节病、皮肤病、血液病症、骨质流失和类似物。
本文所述的化合物可包括阻断靶点(例如受试者中的靶点)的抗体或工程化生物分子。所公开的化合物和方法中的抗体可为经典抗体、抗体杂交融合体或被设计成阻断任何血管新生相关靶点的任何其他生物分子。例如,在一些实施方案中,抗体或工程化生物分子可被设计成阻断VEGF、VEGFR、PDGF、PDGFR、FGF和FGFR,但不限于上述。这类抗体或生物药的非限制性实例包括:贝伐单抗和雷尼比珠单抗,布洛赛珠单抗,阿柏西普和康柏西普。另外,也可包括任何抗血管新生蛋白药物(例如在临床测试中,但尚未被FDA批准的,或新发现的)。非限制性实例包括:抗VEGF、PDGF Darpins(Allergan),赛伐珠(Sevacizumab,抗VEGF,江苏先声药业),TK001(抗VEGF,江苏泰康生物医药),Tanibirumab(抗VEGFR2,韩国大田),LMG324(抗VEGF,爱尔康/诺华),BCD-021(贝伐单抗生物仿制药,Biocad),IMC-3G3(抗PDGFR,英克隆有限责任公司),MEDI-575(抗PDGFR,Medimmune LLC),TRC105(抗内皮糖蛋白抗体,NCI),Fovista(抗PDGF,Ophthotech),和抑制VEGF、PDGF、VEGFR或PDGFR的任何其他药物。在一些实施方案中,所公开方法中的抗体可为单靶点或双靶点或多靶点生物制剂。在一些实施方案中,本文所述的化合物可被用来治疗非眼部疾病。在一些实施方案中,抗体或工程化生物分子可为BAFF抑制剂,抗CD20抗体,RANKL抑制剂,IL-12拮抗剂,和IL-23拮抗剂,IL-1拮抗剂,IL-1β拮抗剂,TNF抑制剂,TNFα抑制剂,补体抑制剂,补体C5抑制剂,IL-6受体抑制剂,细胞粘附分子α4整联蛋白抑制剂,T细胞调节剂,CD11a结合剂或阻断剂,抗IgE抗体,IL-2竞争性拮抗剂,糖蛋白IIb/IIIa受体拮抗剂,或它们的组合。在一些实施方案中,抗体或工程化生物分子可选自:贝伐单抗,雷尼珠单抗,布洛赛珠单抗,阿柏西普,康柏西普,阿昔单抗,阿达木单抗,巴利昔单抗,贝利木单抗,卡那单抗,赛妥珠单抗或培塞利珠单抗,狄诺塞麦,依库珠单抗,依法利珠单抗,戈利木单抗,英夫利昔单抗,那他珠单抗,奥马珠单抗,托珠单抗,尤特克单抗,或它们的组合。另外,在一些实施方案中,所公开方法中的抗体可被聚乙二醇化。
本文所述的化合物包括偶联至生物大分子的药物小分子。小分子可为抗炎小分子,选自类固醇或NSAID或肾上腺素能受体α激动剂。非限制性示例类固醇包括地塞米松,倍他米松,泼尼松,泼尼松龙,去炎松,甲泼尼龙,氢化可的松,醋酸可的松,氟氢可的松,醛甾酮。非限制性示例NSAID包括溴芬酸,阿司匹林,塞来昔布,双氯芬酸,二氟尼柳,依托度酸,布洛芬,吲哚美辛,酮洛芬,酮咯酸,萘普酮,萘普生,噁丙嗪,吡罗昔康,双水杨酯,舒林酸,托美汀。非限制性示例α激动剂包括阿可乐定,米伐折醇,可乐定,溴莫尼定,α甲基多巴,胍法辛,右美托咪定,(+)-(S)-4-1-(2,3-二甲基-苯基)-乙基-1,3-二氢-咪唑-2-硫酮,1-(咪唑烷-2-基)亚氨基吲唑,甲氧胺,苯肾上腺素,替扎尼定,赛拉嗪,胍那苄,双甲脒。
本文所述的化合物包括接头。在一些实施方案中,所公开的化合物和方法中的接头可为可在诸如玻璃体液、房水、Tenon囊下(sub-tenon)、角膜、结膜、脉络膜或它们的组合的眼组织和眼部细胞中裂解的任何种类。可在眼组织或眼部细胞和其他组织中水解的非限制性示例接头包括酯,酰胺,氨基甲酸酯,碳酸酯,亚胺,醚,磷酸酯,腙,缩醛,或腙键。也可使用在传统ADC平台中使用的接头,如果它们可在眼部环境中水解。非限制性实例可包括腙,二硫,二肽,β-葡糖苷酸。在一些实施方案中,接头可被选定在诸如关节组织、肌肉组织、血液、皮肤、上皮组织、结缔组织、神经组织和类似物的其他靶组织中裂解。另外,接头可包括小分子聚合物偶联物,诸如小分子络合物中的PEG。
接头的水解速率可被设计成快速的,具有1-60分钟或1-24小时的水解半衰期。它也可被设计成缓慢的,具有1-30天的半衰期。
眼部抗体-药物偶联物可经由玻璃体内注射、结膜下注射、Tenon囊下、局部滴眼剂或其他方式递送,以递送至眼睛的后部或前部,用来治疗各种眼部新生血管性疾病。小分子剂的释放率可基于疾病进展过程决定。
本文所述的化合物和方法的一些优点可包括:1)通过使用局部递送路线,可避免全身性类固醇治疗的副作用;2)生物药不仅可具有其抗新生血管性疾病的自身效力,而且可充当类固醇的载剂以减轻炎症;3)取决于所需治疗持续时间(可由熟练医生或其他技术人员决定),可裂解接头可被设计成在几小时至几个月内,在诸如玻璃体液、房水、Tenon囊下、角膜、结膜或脉络膜中的靶组织附近水解,以延长治疗持续时间;4)在一些情况下,本文所述的化合物和方法可允许选择自身已在临床上证实效力的生物药剂和小分子剂的任何组合以实现增强的协同效应,因此增强成功的可能性。这种眼部抗体-药物偶联物将通过靶向眼部新生血管性疾病的多个致病途径来增强有效性。
本文所述的化合物和方法可用于治疗各种眼部疾病。在一些实施方案中,本文所述的化合物和方法可通过将本文所述的化合物递送至患有眼部疾病的受试者的靶组织来用于治疗各种眼部血管新生和炎性疾病。眼部血管新生和炎性疾病非限制性示例包括:年龄相关的黄斑变性(AMD),湿性AMD,脉络膜新生血管形成(CNV),脉络膜新生血管性膜(CNVM),囊样黄斑水肿(CME),视网膜外层膜(ERM)和黄斑裂洞,近视相关的脉络膜新生血管形成,血管样纹,视网膜脱离,糖尿病性视网膜病,糖尿病性黄斑水肿(DME),视网膜色素上皮(RPE)萎缩性变化,视网膜色素上皮(RPE)肥大性变化,视网膜静脉闭塞,脉络膜视网膜静脉闭塞,黄斑水肿,因视网膜静脉闭塞所致的黄斑水肿,色素性视网膜炎,斯塔加特(Stargardt)氏病,青光眼,新生血管性青光眼,青光眼手术的附加疗法,炎性病状,白内障,难治性异常,圆锥形角膜,早产儿视网膜病,视网膜下水肿和视网膜内水肿,眼睛前部中的血管新生,角膜炎之后的角膜血管新生,角膜移植或角膜成形术,因缺氧和翼状胬肉所致的角膜血管新生。在一些实施方案中,本文所述的化合物可被递送至受试者的靶标眼组织中,诸如玻璃体液、房水、Tenon囊下、角膜、结膜、脉络膜或它们的组合。在一些实施方案中,本文所述的化合物可通过局部眼部递送或注射入玻璃体内、前房内、脉络膜上、结膜下、Tenon囊下组织或它们的组合而被递送至受试者的眼睛中。
在一些实施方案中,本文所述的化合物和方法可通过将本文所述的化合物递送至患有非眼部疾病的受试者的靶组织来用于治疗各种非眼部疾病。可通过本文所述的化合物和方法的一些实施方案治疗的非眼部疾病的非限制性实例包括自身免疫疾病,关节病,皮肤病,血液病症,骨质流失和类似物。例如,在一些实施方案中,本文所述的化合物和方法可用来治疗诸如以下的病状:类风湿性关节炎,多发性硬化症,系统性红斑狼疮,骨质疏松,克隆(Crohn)氏病,溃疡性结肠炎,全身型幼年特发性关节炎,斯提耳(Still)氏病,牛皮癣性关节炎,强直性脊椎炎,阵发性夜间血红蛋白尿,非典型溶血性尿毒症综合征,视神经脊髓炎,牛皮癣,变应性哮喘,慢性自发性荨麻疹,贝切特(Behcet)氏病,扁平苔藓,移植排斥,和类似物。在一些实施方案中,本文所述的化合物可被递送至受试者的靶组织中,诸如关节组织、肌肉组织、血液、皮肤、上皮组织、结缔组织、神经组织和类似物。在一些实施方案中,本文所述的化合物可通过局部施用,诸如局部真皮施用或粘膜施用,或者通过注射,诸如关节内注射、关节周围注射、肌肉内注射、静脉内注射、真皮内注射或皮下注射递送至受试者中。
通过在玻璃体液中水解、具有2至15天的裂解半衰期的接头,贝伐单抗连接至地塞米松。在玻璃体内注射入玻璃体液后,贝伐单抗-地塞米松偶联物(BDC)将在受试者的眼内缓慢释放地塞米松,以在抗体存在的持续时间内维持有效浓度。因此,BDC化合物将同时减少血管新生和炎症以治疗眼部疾病。当用该化合物治疗湿性AMD时,患者将看到改进的效力,更不可能发展对疗法的耐性,并且将降低治疗频率。
实施例
化学品和实验室技术
化学品购自Fisher Scientific(德国施韦特)、Sigma Aldrich(德国达姆施塔特)、TCI(德国埃施伯恩)、Broadpharm(美国加州圣地亚哥)和Quanta BioDesign(美国俄亥俄州哥伦布),并且除非另外提及,未进一步纯化按原样使用。对于TLC分析,使用由SigmaAldrich(德国达姆施塔特)提供的TLC硅胶60F254板。利用Sigma Aldrich提供的碘化物对含有双键的物质进行染色,利用高锰酸钾和二硫酸铈水溶液对全部可氧化物质进行染色。利用茚三酮溶液对含胺分子进行特异性染色。紫外光(UV)的吸收借助于由Herolab GmbH(德国维斯洛赫)提供的NU-8230V 50Hz 0.18Amp UV手提灯(254nm+365nm,8瓦管)可视化。对于硅胶柱色谱,由VWR(德国德累斯顿)提供的Normasil />40-63μm硅胶和砂(硫酸洗)与由Sigma Aldrich(德国达姆施塔特)提供的/>503组合使用。
分析方法
对于高压液相色谱(HPLC),由Waters公司(美国马萨诸塞州米尔福德)提供的e2695分离模块、2998光电二极管阵列(PDA)检测器、2424蒸发光散射(ELS)检测器和肽BEH C18(/>5μm)柱与也由Waters公司提供的/>3HPLC软件组合利用。
对于1H分析,利用由Bruker(美国马萨诸塞州比尔里卡)提供的具有无屏蔽52mm孔径磁铁的600MHz Avance III系统。化学位移以百万分率(ppm)列举,并且指代作为内标的溶剂残留峰。报告的NMR数据包括:化学位移(s:单峰,d:二重峰,t:三重峰,q:四重峰,m:多重峰),积分,和偶合常数(s)、单位为赫兹(Hz)。多重峰在它们出现于谱中的范围(单位为ppm)内报告。除非另外提及,由Deutero GmbH(德国卡斯特劳恩)提供的氘化氯仿(CDCl3)被用作溶剂。
对于液相色谱-质谱(LC-MS),使用经由HESI-II离子源接合至Orbitrap Velos质谱仪的Agilent 1100微HPLC系统来分析样品。将样品(0.1μl)注入并使用20%-90%乙腈的短RP-HPLC梯度洗脱。以R=60,000的标称分辨率记录谱。
合成本申请的化合物的通用方案示于下方:
R为H、C1-18烷基、芳基、杂芳基、C1-18烷芳基或烷基杂芳基,n为5-30,优选10-15。
mPEG-RAc-Dexa经由偶联反应被偶联至抗体或工程化生物分子。例如,mPEG-RAc-Dexa可首先与马来酰亚胺偶联,并且抗体或工程化生物分子中半胱氨酸的反应性巯基可用于将含马来酰亚胺mPEG-RAc-Dexa偶联至抗体或工程化生物分子。也可使用其他偶联方法。
实施例1:合成mPEG-iVal-Dexa(化合物1)
合成mPEG-iVal-OH
将氢化钠(NaH,于油中60%)(24mg,0.60mmol,3.16当量)加入二颈烧瓶。随后,在搅拌下添加二甲基乙酰胺(DMAc)(0.5ml),从而形成悬浮液。将mPEG-OH(100mg,0.19mmol,1.0当量)加入玻璃瓶并且溶解于DMAc(0.7ml)中。接下来,在室温下借助于注射器,将mPEG-OH溶液缓慢加入NaH悬浮液。再用额外的DMAc(0.3ml)漂洗二颈烧瓶,以确保将所有反应物加入反应混合物。将2-溴异戊酸乙酯(81mg,0.39mmol,2.0当量)加入玻璃瓶,并且用0.5mlDMAc稀释。随后,借助于注射器将2-溴异戊酸乙酯溶液缓慢加入反应混合物,随着时间推移先前透明的反应混合物变成微黄。在室温下18h反应时间后,借助HPLC的分析显示出原材料未转化。因此,再将额外的2-溴异戊酸乙酯(100mg,0.48mmol,2.5当量)加入反应混合物。借助HPLC的分析显示出在另外的2h反应时间后未转化。因此,再将一些额外的NaH(刮勺)加入反应混合物。观察到形成气体H2,表明反应发生。在1h后,借助HPLC的分析未显示出任何剩余2-溴异戊酸乙酯。随后,再将额外的2-溴异戊酸乙酯(80mg,0.38mmol,2.0当量)、另一勺NaH和一些另外的DMAc(0.5ml)加入反应混合物,并且在室温下搅拌所得反应混合物19h。然后用EtOH(1ml)淬灭反应,并且用H2O(2ml)+0.2M NaOH(aq)(1.0ml)稀释反应混合物。在40℃下搅拌所得反应混合物18h(即,为了水解乙酯)。接下来,将反应混合物转移至分液漏斗,并且用甲基叔丁基醚(2×10ml)洗涤反应混合物。借助于1M HCl溶液(1.2ml)酸化水相。随后,用DCM(3×10ml)萃取水相。然后,将合并的DCM层用0.1M柠檬酸溶液洗涤(3×10ml)。此后,借助于旋转式蒸发器系统去除溶剂,并且借助质子核磁共振谱法(1H NMR)和具有ELSD监测的高压液相色谱(HPLC)表征所得产物。1H NMR[600MHz,δ(ppm),CDCl3]:4.26(d,J=7.2Hz,1H),3.61(m,2H),3.51(m,42H),3.44-3.37(m,4H),3.25(s,3H),2.11(m,1H),1.01(d,J=7.2Hz,3H),0.98(d,J=6.6Hz,3H)。
合成mPEG-iVal-Dexa
将地塞米松(21.4mg,0.0337mmol,1.0当量)、1-乙基-3-(3-二甲氨基丙基)碳二亚胺-盐酸盐(EDC.HCl)(14.0mg,0.0730mmol,1.3当量)和4-二甲氨基吡啶(DMAP)(9.5mg,0.0778mmol,1.3当量)悬浮于二氯甲烷(DCM)(1ml)中。随后,将上文制备的mPEG-iVal-OH(45mg,0.0709mmol,1.3当量)于DCM(1ml)中的溶液加入悬浮液。接下来,用另一毫升DCM漂洗烧瓶。在40℃,在排除空气(即,在氮气气氛下)回流下搅拌反应混合物。借助具有ELSD监测的HPLC进行反应过程中控制。在HPLC确认了原材料消失后,在分液漏斗中用2×3ml 0.1M柠檬酸(pH 2.0)洗涤反应混合物。随后,用2×3ml 0.15M NaHCO3(aq)(pH 8-9)洗涤有机层。最后,用1×5ml去离子水洗涤有机层,在这之后借助于无水MgSO4干燥。在减压下利用旋转式蒸发器去除溶剂,并且获得粗制物。接下来,使用于DCM中的4v%丙酮作为洗脱剂,通过柱色谱纯化粗制物。借助1H NMR、COSY NMR、LC-MS和具有ELSD监测的HPLC分析纯化产物。1HNMR[600MHz,δ(ppm),DMSO-d6]:7.29(dd,J=1.2Hz,10.2Hz,1H,Dexa),6.23(dd,1.8Hz,10.2Hz,1H,Dexa),6.01(s,1H,Dexa),5.41(ddd,J=1.2Hz,5.4Hz,16.8Hz,1H,Dexa),4.15(m,1H,Dexa),3.84(d,J=4.8Hz,0.5H,Dexa),3.80(d,J=5.4Hz,0.5H,Dexa),3.69(m,1H,mPEG-iVal),3.51(m,34H,mPEG-iVal),3.43(m,2H,mPEG-iVal),3.24(s,3H,mPEG-iVal),1.25(m,1H,Dexa),2.88(m,1H,Dexa),2.61(dt,J=5.4Hz,13.8Hz,1H,Dexa),2.42-2.28(m,2H,Dexa),1.77(m,1.19H,Dexa),1.69-1.55(m,2H,Dexa),1.49(s,3H,Dexa),1.08(m,1H,Dexa),0.79(dd,J=1.8Hz,7.8Hz,3H,Dexa)。
实施例2:合成mPEG-PrA-Dexa(化合物2)
将mPEG12-COOH(195mg,0.33mmol,1.3当量)溶解于干燥的二氯甲烷(DCM)(40ml)中。随后,将地塞米松(100mg,0.26mmol,1.0当量)、4-二甲氨基吡啶(40mg,0.33mmol,1.3当量)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺-盐酸盐(EDC.HCl)(63mg,0.33mmol,1.3当量)加入溶液。在40℃在回流下搅拌反应10小时。利用薄层色谱来确认产物的形成(流动相:于DCM中的50v%丙酮,碘化物作为着色剂)。借助柱色谱法,利用与TLC相同的流动相纯化产物。将纯化的部分合并,并且使用旋转式蒸发器在减压下去除溶剂。借助质子核磁共振谱法(1H NMR)、高压液相色谱(HPLC)和液相色谱-质谱(LC-MS)表征纯化产物。1H NMR[600MHz,δ(ppm),CDCl3]:7.21(d,J=10.2Hz,1H,Dexa),6.33(dd,J=1.8Hz,10.2Hz,1H,Dexa),6.11(s,1H,Dexa),4.90(m,2H,Dexa),4.37(d,J=9.6Hz,1H,Dexa),3.79(m,2H,mPEG-酸),3.67-3.60(m,40H,mPEG-酸),3.55(m,2H,mPEG-酸),3.38(s,3H,mPEG-酸),3.09(m,1H,Dexa),2.73(t,J=6.6Hz,2H,Dexa),2.61(dt,J=5.4Hz,12.0Hz,1H,mPEG-酸),2.45-2.33(m,3H,Dexa),2.25(s,1H,Dexa),2.18(m,2H,Dexa),1.82(m,1H,Dexa),1.76(q,J=12Hz,1H,Dexa),1.66(s,3H,Dexa),1.25(m,1H,Dexa),1.22(m,1H,Dexa),1.05(s,3H,Dexa),0.93(d,J=7.8Hz,3H,Dexa)。
实施例3:合成mPEG-tertBuG-Dexa(化合物3)
使用类似于上文方案中所示的合成化合物1的化学方式合成化合物3。1H NMR[600MHz,δ(ppm),DMSO-d6]:7.29(dd,J=1.2Hz,10.2Hz,1H,Dexa),6.23(dd,1.8Hz,10.2Hz,1H,Dexa),6.01(s,1H,Dexa),5.41(ddd,J=1.2Hz,5.4Hz,16.8Hz,1H,Dexa),4.15(m,1H,Dexa),3.84(d,J=4.8Hz,0.5H,Dexa),3.81(s,1H,mPEG-tertBuG),3.80(d,J=5.4Hz,0.5H,Dexa),3.51(m,34H,mPEG-tertBuG),3.43(m,2H,mPEG-tertBuG),3.24(s,3H,mPEG-tertBuG),1.25(m,1H,Dexa),2.88(m,1H,Dexa),2.61(dt,J=5.4Hz,13.8Hz,1H,Dexa),2.42-2.28(m,2H,Dexa),1.77(m,1.19H,Dexa),1.69-1.55(m,2H,Dexa),1.49(s,3H,Dexa),1.08(m,1H,Dexa),0.89(s,9H,tertBuG),0.79(dd,J=1.8Hz,7.8Hz,3H,Dexa)。
实施例4:合成mPEG-HCA-Dexa(化合物4)
使用类似于上文方案中所示的合成化合物1的化学方式合成化合物4。1H NMR[600MHz,δ(ppm),DMSO-d6]:7.29(dd,J=1.2Hz,10.2Hz,1H,Dexa),7.19-7.23(m,5H,mPEG-HCA),6.23(dd,1.8Hz,10.2Hz,1H,Dexa),6.01(s,1H,Dexa),4.51(d,J=7.0Hz,1H,mPEG-HCA),5.41(ddd,J=1.2Hz,5.4Hz,16.8Hz,1H,Dexa),4.15(m,1H,Dexa),3.84(d,J=4.8Hz,0.5H,Dexa),3.80(d,J=5.4Hz,0.5H,Dexa),3.51(m,34H,mPEG-HCA),3.07(dd,2H,J=1.8,7.0Hz,mPEG-HCA),1.25(m,1H,Dexa),2.88(m,1H,Dexa),2.61(dt,J=5.4Hz,13.8Hz,1H,Dexa),2.42-2.28(m,2H,Dexa),1.77(m,1.19H,Dexa),1.69-1.55(m,2H,Dexa),1.49(s,3H,Dexa),1.08(m,1H,Dexa),0.79(dd,J=1.8Hz,7.8Hz,3H,Dexa)。
实施例5:化合物1和2在玻璃体液中选择性且受控水解
玻璃体液匀浆制备:由新西兰兔制备玻璃体液匀浆。在从家兔眼睛中提取后,将玻璃体液转移至具有螺旋盖的冷的预称重离心管,并且维持在-80℃。在50mL离心管中融化玻璃体液,对于每100mL玻璃体液添加5mL 0.1%二乙基二硫代氨基甲酸钠。添加一些小豆并在0℃下搅拌成胶冻状态玻璃体液,直至粘度降至接近水。用UV吸收测定蛋白质浓度,并且稀释至10.0mg/ml的终浓度,并随后在4℃下以2500rpm离心15min。收集上清液用于测试偶联物的水解。
化合物1和2的水解评价:将198μL玻璃体液匀浆或磷酸盐缓冲液加入每个管并轻轻地混合。添加2μL试验化合物或对照化合物的工作溶液并混合。在37℃下孵化样品,并且在0、1、4、8、12、24、48和72小时添加200μL淬灭溶液并剧烈涡旋约1min来停止反应。随后在4℃下以4,000rpm离心溶液15min。移出100μL上清液,并与100μL蒸馏水混合以用于LC-MS/MS分析。将10μL标准曲线工作溶液掺入190μL磷酸盐溶液,将200μL淬灭溶液加入每个标准曲线孔。通过添加2μL MeOH/DMSO溶剂来替代工作溶液以制备空白样品。通过添加2μL MeOH/DMSO溶剂替代工作溶液并用乙腈/MeOH淬灭基质来制备双空白样品。利用LC-MS/MS分析化合物1和2(母体化合物)的浓度和地塞米松(通过水解从母体中释放)的浓度。
化合物1和2的水解速率:在体外研究中分析在玻璃体液中地塞米松从化合物1和2中的水解和释放,结果示于下表1中。在玻璃体液中观察到水解,对照水中没有。对于化合物1和2,水解和地塞米松释放的半衰期分别为约96和17小时(表1)。结果支持了本发明偶联物在玻璃体液中选择性且受控的水解以具有小分子药物和抗体药二者的持续影响。1)连接可在玻璃体液中选择性水解;2)可通过将大基团加入接头(由化合物1对比化合物2例示的)调整水解速率,以增加水解的半衰期。
表1.在玻璃体液中实施例化合物的水解和地塞米松释放的半衰期
玻璃体液中的半衰期 | 对照水中的半衰期 | |
化合物1 | 95.7小时 | 未水解 |
化合物2 | 17.2小时 | 未水解 |
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Claims (17)
1.一种化合物,包括:
抗体或工程化生物分子,其阻断VEGF、VEGFR、PDGF、PDGFR、FGF或FGFR;
小分子药物,所述小分子药物为肾上腺素能受体α激动剂或抗炎小分子,所述抗炎小分子为类固醇或非类固醇抗炎药(NSAID);和
接头,其将所述小分子药物连接至所述抗体或工程化生物分子,
其中,所述接头包含可在眼组织中以控释方式水解的键。
2.如权利要求1所述的化合物,其中所述抗体为抗VEGF-A抗体。
3.如权利要求1-2中任一项所述的化合物,其中所述抗体选自由贝伐单抗、雷尼珠单抗、布洛赛珠单抗、阿柏西普和康柏西普组成的组,优选地,所述抗体为贝伐单抗。
4.如权利要求1-3中任一项所述的化合物,其中所述抗体被聚乙二醇化以包括线性或分支的聚乙二醇(PEG)部分。
5.如权利要求4所述的化合物,其中所述PEG部分为-(CH2-CH2-O-)n-,且n为5-30,优选地,n为10-15。
6.如权利要求1-5中任一项所述的化合物,其中所述接头经由所述PEG部分将所述小分子药物连接至所述抗体或工程化生物分子。
7.如权利要求1-6中任一项所述的化合物,其中所述接头包含酯、酰胺、氨基甲酸酯、碳酸酯、亚胺、醚、磷酸酯、腙、缩醛或腙键,优选地,所述接头包含酯键。
8.如权利要求7所述的化合物,其中所述接头为其中R为H、C1-18烷基、芳基、杂芳基、C1-18烷基芳基或烷基杂芳基,优选地,R为H、甲基、乙基、丙基、异丙基、叔丁基、苯基或苄基。
9.如权利要求1-8中任一项所述的化合物,其中所述类固醇选自由地塞米松、倍他米松、泼尼松、泼尼松龙、去炎松、甲泼尼龙、氢化可的松、醋酸可的松、氟氢可的松和醛甾酮组成的组,优选地,所述类固醇为地塞米松。
10.如权利要求1-8中任一项所述的化合物,其中所述NSAID选自由阿司匹林、塞来昔布、溴芬酸、双氯芬酸、二氟尼柳、依托度酸、布洛芬、吲哚美辛、酮洛芬、酮咯酸、萘普酮、萘普生、噁丙嗪、吡罗昔康、双水杨酯、舒林酸和托美汀组成的组,优选地,所述NSAID为溴芬酸。
11.如权利要求1-8中任一项所述的化合物,其中所述肾上腺素能受体α激动剂选自由阿可乐定、米伐折醇、可乐定、溴莫尼定、α甲基多巴、胍法辛、右美托咪定、(+)-(S)-4-1-(2,3-二甲基-苯基)-乙基-1,3-二氢-咪唑-2-硫酮、1-(咪唑烷-2-基)亚氨基吲唑、甲氧胺、苯肾上腺素、替扎尼定、赛拉嗪、胍那苄和双甲脒组成的组,优选地,所述肾上腺素能受体α激动剂为溴莫尼定。
12.如权利要求1所述的化合物,其中所述化合物包含:
贝伐单抗,地塞米松,聚乙二醇(PEG)部分,和接头,
其中所述PEG部分为-(CH2-CH2-O-)n-,n为5-30;
其中所述接头为且R为H、甲基、乙基、丙基、异丙基、叔丁基、苯基或苄基;并且
其中所述接头经由所述PEG部分将地塞米松连接至贝伐单抗。
13.如权利要求1-12中任一项所述的化合物,其中所述接头在眼组织中的水解是受控的,并且一半的所述化合物的接头水解的时间为1-60分钟、1-24小时、1-5天或1-30天,优选1-5天。
14.一种治疗受试者中的眼部疾病的方法,所述方法包括:
将如权利要求1-13中任一项所述的化合物递送至所述受试者的眼睛。
15.如权利要求14所述的方法,其进一步包括:
允许所述接头随着时间推移在所述受试者的眼睛的一种或多种眼组织中水解;其中在所述接头水解之后,所述抗体和所述小分子药物均在所述受试者中发挥它们的功能。
16.如权利要求15所述的方法,其中所述眼组织为玻璃体液、房水、Tenon囊下、角膜、结膜、视网膜、脉络膜或它们的组合,优选所述眼组织为玻璃体液。
17.如权利要求14-16中任一项所述的方法,其中所述接头在眼组织中的水解是受控的,并且一半的所述化合物的接头水解的时间选自1-60分钟、1-24小时或1-30天,优选1-5天。
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