CN113613728A - 整联蛋白αvβ3特异性的双环肽配体 - Google Patents
整联蛋白αvβ3特异性的双环肽配体 Download PDFInfo
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- CN113613728A CN113613728A CN202080020233.1A CN202080020233A CN113613728A CN 113613728 A CN113613728 A CN 113613728A CN 202080020233 A CN202080020233 A CN 202080020233A CN 113613728 A CN113613728 A CN 113613728A
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Abstract
本发明涉及与芳香族分子支架共价结合以使得两个或多个肽环在与支架的附着点之间相对的多肽。具体地,本发明描述的是整联蛋白αvβ3的高亲和力结合剂的肽。本发明还包括包含与一个或多个效应物和/或官能团缀合的所述肽的药物缀合物,包含所述肽配体和药物缀合物的药物组合物,以及所述肽配体和药物缀合物在预防、抑制或治疗整联蛋白αvβ3介导的疾病或病症中的用途。
Description
技术领域
本发明涉及与芳香族分子支架共价结合以使得两个或多个肽环在与支架的附着点之间相对的多肽。具体地,本发明描述的肽是整联蛋白αvβ3的高亲和力结合剂。本发明还包括包含与一个或多个效应物和/或官能团缀合的所述肽的药物缀合物,包含所述肽配体和药物缀合物的药物组合物,以及所述肽配体和药物缀合物在预防、抑制或治疗整联蛋白αvβ3介导的疾病或病症中的用途。
背景技术
环肽能够以高亲和力和靶向特异性结合于蛋白靶标,因此是对于治疗学的发展有吸引力的分子类型。事实上,临床上已经成功使用了几种环肽,例如抗菌肽万古霉素、免疫抑制剂药物环孢菌素或抗癌药奥曲肽(Driggers等人(2008),Nat Rev Drug Discov 7(7),608-24)。良好的结合性质源于肽和靶标之间形成的相对大的相互作用表面以及环状结构的降低的构象柔性。典型地,大环结合于数百平方埃的表面,例如环肽CXCR4拮抗剂CVX15(Wu等人(2007),Science 330,1066-71),结合整联蛋白αVb3的具有Arg-Gly-Asp基序的环肽(Xiong等人(2002),Science 296(5565),151-5),或与尿激酶型纤溶酶原激活物结合的环肽抑制剂upain-1(Zhao等人(2007),J Struct Biol 160(1),1-10)。
由于其环状结构,肽大环比线性肽的柔韧性差,导致与靶标结合后熵损失较小,并导致更高的结合亲和力。与线性肽相比,降低的柔韧性还导致锁定靶标特异性构象,增加结合特异性。这种作用已经通过一种有效的和选择性基质金属蛋白酶8(MMP-8)的抑制剂来例证,当所述抑制剂的环被打开时其失去对其它MMP的选择性(Cherney等人(1998),J MedChem 41(11),1749-51)。通过大环化实现的有利的结合性质在具有多于一个肽环的多环肽(例如在万古霉素、乳链菌肽和放线菌素中)中更为显著。
不同的研究团队以前已经将具有半胱氨酸残基的多肽连接到合成分子结构上(Kemp和McNamara(1985),J.Org.Chem;Timmerman等人(2005),ChemBioChem)。Meloen及其同事已使用三(溴甲基)苯和相关分子将多个肽环快速定量地环化到合成的支架上,以结构模拟蛋白质表面(Timmerman等人(2005),ChemBioChem)。在WO 2004/077062和WO 2006/078161中公开产生候选药物化合物的方法,其中通过将含半胱氨酸的多肽连接至分子支架(例如三(溴甲基)苯)而产生所述化合物。
已经开发了基于噬菌体展示的组合方法以产生并筛选出针对目标靶标的双环肽的大型文库(Heinis等人(2009),Nat Chem Biol 5(7),502-7和WO2009/098450)。简而言之,在噬菌体上展示包含三个半胱氨酸残基和两个区域的六个随机氨基酸的线性肽(Cys-(Xaa)6-Cys-(Xaa)6-Cys)的组合文库,并通过将半胱氨酸侧链共价连接至小分子(三(溴甲基)苯)而环化。
发明内容
根据本发明的第一方面,提供一种对整联蛋白αvβ3特异性的肽配体,其包含多肽和芳香族分子支架,所述多肽含有被至少两个环序列隔开的至少三个半胱氨酸残基,以及所述芳香族分子支架与所述多肽的半胱氨酸残基形成共价键,从而在所述分子支架上形成至少两个多肽环。
根据本发明的另一方面,提供了一种药物缀合物,其包含与一个或多个效应物和/或官能团缀合的如本文所定义的肽配体。
根据本发明的其它方面,提供一种药物组合物,其包含与一个或多个药学上可接受的赋形剂组合的如本文定义的肽配体或药物缀合物。
根据本发明的另一方面,提供如本文所定义的肽配体或药物缀合物在预防、抑制或治疗由整联蛋白αvβ3所介导的疾病或病症中的用途。
具体实施方式
在一个实施方案中,所述环序列包含2、3、4、5、6或7个氨基酸。
在又一个实施方案中,所述环序列包含5或6个氨基酸。
在另一个实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,两个环序列都由5个氨基酸组成。
在另一个实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,两个环序列都由6个氨基酸组成。
在另一个实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述环序列之一由2个氨基酸组成以及另一个由7个氨基酸组成。
在另一个实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述环序列之一由4个氨基酸组成以及另一个由3个氨基酸组成。
在一个实施方案中,所述肽配体包含选自以下的氨基酸序列:
CiLDHMECiiRGDMDCiii(SEQ ID NO:1);
CiYHAHRCiiDGGPFCiii(SEQ ID NO:2);
CiLHFSRCiiDGGMHCiii(SEQ ID NO:3);
CiILRPNCiiDLDGRCiii(SEQ ID NO:4);
CiIL(HArg)PNCiiDLDGRCiii(SEQ ID NO:5);
CiAGIVSCiiDGRPLCiii(SEQ ID NO:6);
CiKNFNPECiiLRGDSLCiii(SEQ ID NO:7);和
CiHTRAHDCiiYWESIVCiii(SEQ ID NO:8);
或其药学上可接受的盐;其中X代表任何氨基酸和X1代表任何氨基酸或不存在,以及Ci、Cii和Ciii分别代表第一、第二和第三半胱氨酸残基。
在可选择的实施方案中,所述肽配体包含选自以下的氨基酸序列:
CiNHCiiYRLDQHTCiii(SEQ ID NO:9);
CiNDLFCiiTWPCiii(SEQ ID NO:10);
CiHT(HArg)AHDCiiYWESIVCiii(SEQ ID NO:11);
CiHPGRGECiiSFSGIQCiii(SEQ ID NO:12);和
CiHTRGHDCiiDYRHSMCiii(SEQ ID NO:13);
或其药学上可接受的盐;其中Ci、Cii和Ciii分别代表第一、第二和第三半胱氨酸残基。
在另一个实施方案中,所述肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(本文称为BCY2493);
A-(SEQ ID NO:2)-A(本文称为BCY2496);
A-(SEQ ID NO:3)-A(本文称为BCY2497);
A-(SEQ ID NO:4)-A(本文称为BCY2498);
Ac-(SEQ ID NO:5)-A-Sar10-dK(本文称为BCY2615);
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558);
A-(SEQ ID NO:6)-A(本文称为BCY2499);
A-(SEQ ID NO:7)-A(本文称为BCY2502);和
A-(SEQ ID NO:8)-A(本文称为BCY2506)。
在可选择的实施方案中,所述肽配体包含选自以下的氨基酸序列:
Ac-(SEQ ID NO:4)-A-Sar6-K(本文称为BCY2553);
B-Ala-Sar5-A-(SEQ ID NO:4)(本文称为BCY2554);
Ac-(SEQ ID NO:5)-A-Sar6-K(本文称为BCY2555);
B-Ala-Sar5-(SEQ ID NO:5)(本文称为BCY2560);
A-(SEQ ID NO:9)-A(本文称为BCY2494);
A-(SEQ ID NO:10)-A(本文称为BCY2503);和
B-Ala-Sar5-A-(SEQ ID NO:11)(本文称为BCY2568)。
在一个实施方案中,所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(本文称为BCY2493);
A-(SEQ ID NO:2)-A(本文称为BCY2496);
A-(SEQ ID NO:3)-A(本文称为BCY2497);
A-(SEQ ID NO:4)-A(本文称为BCY2498);
Ac-(SEQ ID NO:5)-A-Sar10-dK(本文称为BCY2615);
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558);
A-(SEQ ID NO:6)-A(本文称为BCY2499);
A-(SEQ ID NO:7)-A(本文称为BCY2502);和
A-(SEQ ID NO:8)-A(本文称为BCY2506)。
在一个可选择的实施方案中,所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
Ac-(SEQ ID NO:4)-A-Sar6-K(本文称为BCY2553);
B-Ala-Sar5-A-(SEQ ID NO:4)(本文称为BCY2554);
Ac-(SEQ ID NO:5)-A-Sar6-K(本文称为BCY2555);
B-Ala-Sar5-(SEQ ID NO:5)(本文称为BCY2560);
A-(SEQ ID NO:9)-A(本文称为BCY2494);
A-(SEQ ID NO:10)-A(本文称为BCY2503);和
B-Ala-Sar5-A-(SEQ ID NO:11)(本文称为BCY2568)。
在另一个实施方案中,所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(本文称为BCY2493);
A-(SEQ ID NO:2)-A(本文称为BCY2496);
A-(SEQ ID NO:4)-A(本文称为BCY2498);
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558);
A-(SEQ ID NO:7)-A(本文称为BCY2502);和
A-(SEQ ID NO:8)-A(本文称为BCY2506)。
如本文中表1中所示,该实施方案的支架/肽配体显示出优异的整联蛋白αvβ3竞争性结合。
在又一个实施方案中,所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558)。
该实施方案的支架/肽配体单独(如本文表1所示)以及当与毒素DM-1缀合时(如本文表3所示)都显示出优异的整联蛋白αvβ3竞争性结合。
在一个实施方案中,肽配体另外包含荧光部分,例如荧光素(Fl)或青色素5(Cy5)。
在另一个实施方案中,肽配体另外包含荧光部分,例如荧光素(Fl)或青色素5(Cy5),并选自:
A-(SEQ ID NO:1)-A-Sar6-K-Fl(本文称为BCY2572);
Fl-G-Sar5-A-(SEQ ID NO:1)(本文称为BCY2573);
A-(SEQ ID NO:4)-A-Sar6-K-Fl(本文称为BCY2576);
Ac-(SEQ ID NO:4)-A-Sar6-K-Fl(本文称为BCY2577);
Fl-(B-Ala)-Sar5-A-(SEQ ID NO:4)(本文称为BCY2578);
Ac-(SEQ ID NO:5)-A-Sar6-K-F1(本文称为BCY2579);
Fl-(B-Ala)-Sars-A-(SEQ ID NO:5)(本文称为BCY2580);
A-(SEQ ID NO:8)-A-Sar6-K-F1(本文称为BCY2586);
A-(SEQ ID NO:10)-A-Sar6-K-F1(本文称为BCY2582);
A-(SEQ ID NO:12)-A-Sar6-K-F1(本文称为BCY2584);
A-(SEQ ID NO:13)-A-Sar6-K-F1(本文称为BCY2588);
Cy5-(B-Ala)-Sar5-A-(SEQ ID NO:1)-A(本文称为BCY8590);和
Ac-(SEQ ID NO:5)-A-Sar6-K-Cy5(本文称为BCY8591)。
除非另外定义,否则本文中使用的所有技术和科学术语具有与本领域(如肽化学、细胞培养和噬菌体展示、核酸化学和生物化学领域)普通技术人员通常理解的含义相同的含义。将标准技术用于分子生物学、遗传和生化方法(参见Sambrook等人,MolecularCloning:A Laboratory Manual,第3版,2001,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Ausubel等人,Short Protocols in Molecular Biology(1999)第4版,John Wiley&Sons,Inc.),其并入本文以作参考。
命名法
编号
当提及本发明的肽内的氨基酸残基位置时,由于半胱氨酸残基(Ci、Cii和Ciii)是不变的,因而从编号中省略半胱氨酸残基,因此,本发明的肽内的氨基酸残基的编号如下所指:
-Ci-L1-D2-H3-M4-E5-Cii-R6-G7-D8-M9-D10-Ciii-(SEQ ID NO:1)。
为了该说明书的目的,假定所有双环肽都与TBMB(1,3,5-三(溴甲基)苯)环化并生成三取代结构。与TBMB的环化反应发生在Ci、Cii和Ciii上。
分子式
双环核心序列的N-或C-末端延伸区添加到序列的左侧或右侧,并以连字符分隔。例如,N末端βAla-Sar10-Ala尾巴将表示为:
βAla-Sar10-A-(SEQ ID NO:X)。
反向肽序列
根据Nair等人(2003)J Immunol 170(3),1362-1373中的公开,设想本文公开的肽序列也将以其逆反形式使用。例如,该序列被颠倒(即,N末端变成C末端,反之亦然),它们的立体化学也被颠倒(即,D-氨基酸变成L-氨基酸,反之亦然)。
肽配体
如本文所指,肽配体是指与分子支架共价结合的肽。通常,这样的肽包含两个或更多个能够与支架形成共价键的反应性基团(即,半胱氨酸残基),以及在所述反应性基团之间相对(subtended)的序列,因为肽与支架结合时该序列形成环,因而其被称为环序列。在当前情况下,肽包含至少三个半胱氨酸残基(在本文中称为Ci、Cii和Ciii),并在支架上形成至少两个环。
肽配体的优点
本发明的某些双环肽具有许多有利的性质,使得它们能够被认为是用于注射、吸入、鼻、眼、口或局部施用的合适的药物样分子。这些有利的特性包括:
-物种交叉反应性。这是临床前药效学和药代动力学评估的典型要求;
-蛋白酶稳定性。双环肽配体理想地应展示出对血浆蛋白酶、上皮(“膜锚定”)蛋白酶、胃和肠蛋白酶、肺表面蛋白酶、细胞内蛋白酶等的稳定性。应在不同物种之间保持蛋白酶稳定性,以便可以在动物模型中开发双环先导候选物,并有信心对人施用;
-理想的溶解度曲线。这是带电荷的亲水残基与疏水残基的比例和分子内/分子间H键的函数,其对于配制和吸收目的是重要的;
-循环中的最佳血浆半衰期。根据临床适应症和治疗方案,可能需要在急性疾病管理环境中开发双环肽用于短期暴露,或开发在循环中具有增强保留的双环肽,从而对于更慢性的疾病状态的管理是最佳的。驱动想要的血浆半衰期的其它因素是为了最大治疗效率而要求持续暴露,与由于药剂持续暴露引起的伴随毒理学;以及
-选择性。本发明的某些肽配体与其它整联蛋白(例如αvβ5)相比显示良好的选择性。具体地,在本文表2所示的竞争性结合测定中,双环肽BCY2493、BCY2503和BCY2555显示出对于αvβ3的选择性超过αvβ5。此外,在本文表4所示的直接结合测定中,双环肽BCY2572、BCY2576、BCY2579、BCY2580、BCY2582、BCY2584、BCY2586和BCY2588显示出对于αvβ3的选择性超过αvβ5。
药学上可接受的盐
应当理解,盐形式属于本发明的范围内,并且提及肽配体时包括所述配体的盐形式。
可以通过常规化学方法,从包含碱性或酸性部分的母体化合物来合成本发明的盐,常规化学方法例如,在Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(编)、Camille G.Wermuth(编)ISBN:3-90639-026-8,精装388页,2002年8月描述的方法。通常,可以通过使这些化合物的游离酸或碱形式与水中、或在有机溶剂中、或在两者的混合物中适当的碱或酸进行反应,来制备这些盐。
可以用多种酸(无机和有机酸两者)形成酸加成盐(单盐或二盐)。酸加成盐的示例包括与选自以下的酸形成的单盐或二盐:乙酸、2,2-二氯乙酸、己二酸、藻酸、抗坏血酸(例如,L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸(如,D-葡萄糖醛酸)、谷氨酸(如,L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢卤酸(如氢溴酸、盐酸、氢碘酸)、羟乙基磺酸、乳酸(例如,(+)-L-乳酸、(±)-DL-乳酸)、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、丙酮酸、L-焦谷氨酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、丹宁酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一烯酸和戊酸、以及酰化氨基酸和阳离子交换树脂。
一组具体的盐由以下形成的盐组成:乙酸、盐酸、氢碘酸、磷酸、硝酸、硫酸、柠檬酸、乳酸、琥珀酸、马来酸、苹果酸、羟乙基磺酸、富马酸、苯磺酸、甲苯磺酸、硫酸、甲磺酸(甲磺酸盐)、乙磺酸、萘磺酸、戊酸、丙酸、丁酸、丙二酸、葡萄糖醛酸和乳糖酸。一种特定的盐是盐酸盐。另一种特定的盐是乙酸盐。
如果化合物是阴离子化合物,或具有可以是阴离子的官能团(例如,-COOH可以是-COO-),则可以与有机或无机碱形成盐,产生合适的阳离子。合适的无机阳离子的示例包括但不限于碱金属离子,如Li+、Na+和K+;碱土金属阳离子,如Ca2+和Mg2+;和其它阳离子,例如Al3+或Zn+。合适的有机阳离子的示例包括但不限于铵离子(即NH4+)和取代的铵离子(例如,NH3R+、NH2R2 +、NHR3 +、NR4 +)。一些合适的取代铵离子的示例是衍生自以下的那些:甲胺、乙胺、二乙胺、丙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇,以及氨基酸,如赖氨酸和精氨酸。常见的季铵离子的示例是N(CH3)4 +。
当本发明的肽含有胺官能团时,这些可以形成季铵盐,例如通过根据本领域技术人员熟知的方法与烷化剂反应。这样的季铵化合物在本发明的肽的范围内。
修饰衍生物
应当理解,本文所定义的肽配体的修饰衍生物在本发明的范围内。此类合适的修饰衍生物的示例包括选自以下的一个或多个修饰:N-末端和/或C-末端修饰;用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基(例如,用一个或多个等位或等电子氨基酸替换一个或多个极性氨基酸残基;用其它非天然等位或等电子氨基酸替换一个或多个非极性氨基酸残基);添加间隔子基团;用一个或多个氧化抗性氨基酸残基替换一个或多个氧化敏感性氨基酸残基;用丙氨酸替换一个或多个氨基酸残基,用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基;双环肽配体内一个或多个酰胺键的N-烷基化;用替代性键替换一个或多个肽键;肽主链长修饰;用另一化学基团取代一个或多个氨基酸残基的α-碳上的氢,用合适的胺、硫醇、羧酸和酚反应性试剂修饰氨基酸(例如半胱氨酸、赖氨酸、谷氨酸/天冬氨酸和酪氨酸),以官能化所述氨基酸,和引入或替换带来适于官能化的正交反应性的氨基酸,例如带有叠氮基或炔基的氨基酸,其分别允许用带有炔或叠氮的部分进行官能化。
在一个实施方案中,修饰的衍生物包括N-末端和/或C-末端修饰。在另一实施方案中,其中所述修饰的衍生物包括使用合适的氨基反应化学的N-末端修饰,和/或使用合适的羧基反应化学的C-末端修饰。在另一实施方案中,所述N-末端或C-末端修饰包括添加效应物基团,所述效应物基团包括但不限于细胞毒性剂、放射螯合剂或发色团。
在另一实施方案中,修饰的衍生物包括N-末端修饰。在另一实施方案中,N-末端修饰包括N-末端乙酰基。在该实施方案中,在肽合成过程中,N-末端半胱氨酸基团(在本文中称为Ci的基团)被乙酸酐或其它合适的试剂封端,从而产生N-末端乙酰化的分子。该实施方案提供了去除氨基肽酶的潜在识别点的优点,避免了双环肽降解的可能性。
在一个可选择的实施方案中,N-末端修饰包括添加分子间隔基团,其促进效应物基团的缀合并保留双环肽对其靶标的效力。
在另一个实施方案中,修饰的衍生物包括C-末端修饰。在另一个实施方案中,C-末端修饰包含酰胺基。在该实施方案中,C-末端半胱氨酸基团(本文中称为Ciii的基团)在肽合成过程中作为酰胺合成,从而产生C-末端被酰胺化的分子。该实施方案提供去除羧肽酶的潜在识别点的优点,降低了双环肽被蛋白水解降解的可能性。
在一个实施方案中,修饰的衍生物包括用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基。在该实施方案中,可以选择具有等位/等电子侧链的非天然氨基酸,其既不被降解蛋白酶识别,也不对靶标效力产生任何不利影响。
可选择地,可以使用具有受约束的氨基酸侧链的非天然氨基酸,使得附近肽键的蛋白水解性水解在构象和空间上受到阻碍。具体地,这涉及脯氨酸类似物、庞大的侧链、Cα-二取代的衍生物(例如,氨基异丁酸、Aib)和环氨基酸,简单的衍生物是氨基-环丙基羧酸。
在一个实施方案中,修饰的衍生物包括添加间隔子基团。在另一个实施方案中,修饰的衍生物包括向N-末端半胱氨酸(Ci)和/或C-末端半胱氨酸(Ciii)添加间隔子基团。
在一个实施方案中,修饰的衍生物包括用一个或多个氧化抗性氨基酸残基替换一个或多个氧化敏感性氨基酸残基。在另一个实施方案中,修饰的衍生物包括用萘基丙氨酸或丙氨酸残基替换色氨酸残基。该实施方案提供改善所得双环肽配体的药物稳定性谱的优点。
在一个实施方案中,修饰的衍生物包括用一个或多个疏水氨基酸残基替换一个或多个带电荷的氨基酸残基。在可选择的实施方案中,修饰的衍生物包括用一个或多个带电荷的氨基酸残基替换一个或多个疏水性氨基酸残基。带电荷的氨基酸残基与疏水性氨基酸残基的正确平衡是双环肽配体的重要特征。例如,疏水性氨基酸残基影响血浆蛋白结合的程度,从而影响血浆中可利用的游离组分的浓度,而带电荷的氨基酸残基(尤其是精氨酸)可能会影响肽与细胞表面磷脂膜的相互作用。两者的组合可能影响肽药物的半衰期、分布体积和暴露,并且可以根据临床终点进行调整。另外,带电荷的氨基酸残基与疏水性氨基酸残基的正确组合和数量可以降低注射部位的刺激性(如果肽药物已通过皮下施用)。
在一个实施方案中,修饰的衍生物包括用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基。该实施方案被认为是通过空间位阻和通过D-氨基酸来稳定β-转角构象的倾向来增加蛋白水解稳定性(Tugyi等人(2005)PNAS,102(2),413–418)。
在一个实施方案中,修饰的衍生物包括去除任何氨基酸残基并用丙氨酸取代。该实施方案提供去除潜在的蛋白水解攻击位点的优点。
应当注意的是,每个上述提到的修饰都用于有意地改善肽的效力或稳定性。通过以下机制可以实现基于修饰的进一步效能改善:
-引入疏水部分,其利用疏水效应并降低解离速率,从而获得更高的亲和力;
-引入带电荷的基团,其利用长程离子相互作用,导致更快的速率和更高的亲和力(参见例如Schreiber等人,Rapid,electrostatically assisted association ofproteins(1996),Nature Struct.Biol.3,427-31);以及
-向肽中引入额外的限制,例如,通过正确地限制氨基酸的侧链使得在靶标结合时熵的损失最小,限制骨架的扭转角使得在靶标结合时熵的损失最小,以及出于同样的原因在分子中引入额外的环化。
(综述参见Gentilucci等人,Curr.Pharmaceutical Design,(2010),16,3185-203,和Nestor等人,Curr.Medicinal Chem(2009),16,4399-418)。
同位素变异
本发明包括所有药学上可接受的(放射性)同位素标记的本发明肽配体,其中一个或多个原子被具有相同原子序数但原子质量或质量数不同于通常在自然界中发现的原子质量或质量数的原子替换;本发明的肽配体,其中附接金属螯合基团(称为“效应物”)能够保持相关的(放射性)同位素;以及本发明的肽配体,其中某些官能团被相关的(放射性)同位素或同位素标记的官能团共价替换。
适合包含在本发明的肽配体中的同位素的示例包括氢的同位素,如2H(D)和3H(T);碳,如11C、13C和14C;氯,如36Cl;氟,如18F;碘,如123I、125I和131I;氮,如13N和15N;氧,如15O、17O和18O;磷,如32P;硫,如35S;铜,如64Cu;镓,如67Ga或68Ga;钇,如90Y和镥,如177Lu;以及铋,如213Bi。
某些同位素标记的本发明的肽配体,例如引入放射性同位素的本发明的肽配体,可用于药物和/或底物组织分布研究,并用于临床评估患病组织上整联蛋白αvβ3靶标的存在和/或不存在。本发明的肽配体还可具有有价值的诊断性质,在于它们可用于检测或鉴定标记化合物与其它分子、肽、蛋白质、酶或受体之间复合物的形成。检测或鉴定方法可以使用经标记试剂标记的化合物,标记试剂如放射性同位素、酶、荧光物质、发光物质(例如,鲁米诺、鲁米诺衍生物、荧光素、水母发光蛋白和荧光素酶)等。鉴于放射性同位素氚(即3H(T))和碳-14(即14C)易于引入且有现成的检测手段,其特别适用于此目的。
用较重的同位素如氘(即2H(D))取代,可以提供某些治疗优势,这是由于更高的代谢稳定性,例如体内半衰期延长或剂量需求降低,因此在某些情况下可能是优选的。
用正电子发射同位素(如11C、18F、15O和13N)取代可用于正电子发射断层扫描(PET)研究以检查靶标占有率。
通常可以通过本领域技术人员已知的常规技术或通过与所附实施例中描述的那些类似的方法,使用适当的同位素标记的试剂代替先前使用的未标记试剂来制备本发明的肽配体的同位素标记化合物。
芳香族分子支架
本文提及的术语“芳香族分子支架”是指本文定义的任何分子支架,其包含芳香族碳环或杂环系统。
将理解,芳香族分子支架将包括芳香族部分。芳香族支架内合适的芳香族部分的示例包括亚联苯、三亚联苯、萘或蒽。
将理解芳香族分子支架将包括杂芳香族部分。芳香族支架内合适的杂芳香族部分的示例包括吡啶、嘧啶、吡咯、呋喃和噻吩。
还应理解,芳香族分子支架可包含卤代甲基芳烃部分,例如双(溴甲基)苯、三(溴甲基)苯、四(溴甲基)苯或其衍生物。
芳香族分子支架的非限制性示例包括:双-、三-、或四(卤代甲基)苯;双-、三-、或四(卤代甲基)吡啶;双-、三-、或四(卤代甲基)哒嗪;双-、三-、或四(卤代甲基)嘧啶;双-、三-、或四(卤代甲基)吡嗪;双-、三-、或四(卤代甲基)-1,2,3-三嗪;双-、三-、或四(卤代甲基)-1,2,4-三嗪;双-、三-、或四(卤代甲基)吡咯、-呋喃、-噻吩;双-、三-、或四(卤代甲基)咪唑、-恶唑、-噻唑;双-、三-、或四(卤代甲基)-3H-吡唑、-异恶唑、-异噻唑;双-、三-、或四(卤代甲基)亚联苯;双-、三-或四(卤代甲基)三亚联苯;1,8-双(卤代甲基)萘;双-、三-或四(卤代甲基)蒽;以及双-、三-或四(2-卤代甲基苯基)甲烷。
芳香族分子支架的更具体的示例包括:1,2-双(卤代甲基)苯;3,4-双(卤代甲基)吡啶;3,4-双(卤代甲基)哒嗪;4,5-双(卤代甲基)嘧啶;4,5-双(卤代甲基)吡嗪;4,5-双(卤代甲基)-1,2,3-三嗪;5,6-双(卤代甲基)-1,2,4-三嗪;3,4-双(卤代甲基)吡咯、-呋喃、-噻吩和其它区域异构体;4,5-双(卤代甲基)咪唑、-恶唑、-噻唑;4,5-双(卤代甲基)-3H-吡唑、-异恶唑、-异噻唑;2,2′-双(卤代甲基)亚联苯;2,2″-双(卤代甲基)三亚联苯;1,8-双(卤代甲基)萘;1,10-双(卤代甲基)蒽;双(2-卤代甲基苯基)甲烷;1,2,3-三(卤代甲基)苯;2,3,4-三(卤代甲基)吡啶;2,3,4-三(卤代甲基)哒嗪;3,4,5-三(卤代甲基)嘧啶;4,5,6-三(卤代甲基)-1,2,3-三嗪;2,3,4-三(卤代甲基)吡咯、-呋喃、-噻吩;2,4,5-双(卤代甲基)咪唑、-恶唑、-噻唑;3,4,5-双(卤代甲基)-1H-吡唑、-异恶唑、-异噻唑;2,4,2′-三(卤代甲基)亚联苯;2,3′,2"-三(卤代甲基)三亚联苯;1,3,8-三(卤代甲基)萘;1,3,10-三(卤代甲基)蒽;双(2-卤代甲基苯基)甲烷;1,2,4,5-四(卤代甲基)苯;1,2,4,5-四(卤代甲基)吡啶;2,4,5,6-四(卤代甲基)嘧啶;2,3,4,5-四(卤代甲基)吡咯、-呋喃、-噻吩;2,2′,6,6′-四(卤代甲基)亚联苯;2,2″,6,6″-四(卤代甲基)三亚联苯;2,3,5,6-四(卤代甲基)萘和2,3,7,8-四(卤代甲基)蒽;和双(2,4-双(卤代甲基)苯基)甲烷。
如前述文献所述,分子支架可以是小分子,例如有机小分子。
在一个实施方案中,分子支架可以是大分子。在一个实施方案中,分子支架是由氨基酸、核苷酸或碳水化合物组成的大分子。
在一个实施方案中,分子支架包含能够与多肽的官能团反应以形成共价键的反应性基团。
分子支架可以包含与肽形成连接的化学基团,例如胺、硫醇、醇、酮、醛、腈、羧酸、酯、烯烃、炔烃、叠氮化物、酸酐、琥珀酰亚胺、马来酰亚胺、烷基卤化物和酰基卤化物。
在一个实施方案中,分子支架可以包含三(溴甲基)苯,尤其是1,3,5-三(溴甲基)苯(‘TBMB’)或其衍生物,或可由其组成。
在一实施方案中,分子支架是2,4,6-三(溴甲基)均三甲苯。该分子类似于1,3,5-三(溴甲基)苯,但包含另外连接至苯环的三个甲基。这样做的优点是,另外的甲基可以与多肽形成进一步的接触,因此增加了另外的结构约束。
本发明的分子支架包含化学基团,其允许本发明的编码文库的多肽的官能团与分子支架形成共价连接。所述化学基团选自多种官能团,包括胺、硫醇、醇、酮、醛、腈、羧酸、酯、烯烃、炔烃、酸酐、琥珀酰亚胺、马来酰亚胺、叠氮化物、烷基卤化物和酰基卤化物。
可以用于在分子支架上与半胱氨酸的硫醇反应的支架反应性基团是烷基卤化物(或也称为卤代烃或卤代烷)。
示例包括溴甲基苯(以TBMB为例的支架反应性基团)或碘乙酰胺。用于选择性地将化合物与蛋白质中的半胱氨酸偶联的其它支架反应性基团是马来酰亚胺、包含αβ不饱和羰基的化合物和包含α卤代甲基羰基的化合物。可以在本发明中用作分子支架的马来酰亚胺的示例包括:三-(2-马来酰亚胺基乙基)胺、三-(2-马来酰亚胺基乙基)苯、三-(马来酰亚胺基)苯。包含α卤代甲基羰基的化合物的示例是N,N',N”-(苯-1,3,5-三基)三(2-溴乙酰胺)。硒代半胱氨酸也是一种天然氨基酸,其与半胱氨酸具有相似的反应性,可用于相同的反应。因此,无论在何处提及半胱氨酸,除非上下文另外指出,否则通常都可以用硒代半胱氨酸代替。
效应物和官能团
根据本发明的另一方面,提供了一种药物缀合物,其包含与一个或多个效应物和/或官能团缀合的如本文所定义的肽配体。
效应物和/或官能团可以连接到,例如多肽的N和/或C末端,或连接到多肽内的氨基酸、或连接到分子支架上。
适当的效应物基团包括抗体及其部分或片段。例如,效应物基团可包括抗体轻链恒定区(CL)、抗体CH1重链结构域、抗体CH2重链结构域、抗体CH3重链结构域、或其任意组合,除此之外,还有一个或多个恒定区结构域。效应物基团还可以包含抗体的铰链区(通常在IgG分子的CH1和CH2结构域之间发现这种区域)。
在本发明该方面的其它实施方案中,根据本发明的效应物基团是IgG分子的Fc区。有利地,根据本发明的肽配体-效应物基团包含肽配体Fc融合体或由其组成。所述肽配体Fc融合体具有1天或更长、2天或更长、3天或更长、4天或更长、5天或更长、6天或更长、或7天或更长的tβ半衰期。最有利地,根据本发明的肽配体包含具有1天或更长的tβ半衰期的肽配体Fc融合体或由其组成。
官能团通常包括结合基团、药物、用于连接其它实体的反应基团、有助于将大环肽摄取到细胞中的官能团等。
肽穿透到细胞中的能力将使肽有效针对细胞内的靶标。可以被具有穿透到细胞中能力的肽所接近的靶标包括转录因子、细胞内信号传导分子(如酪氨酸激酶)和参与凋亡途径的分子。能够穿透细胞的官能团包括已经添加到肽或分子支架中的肽或化学基团。如衍生自VP22、HIV-Tat、果蝇的同源盒蛋白(触角蛋白)等的肽,例如,如Chen和Harrison,Biochemical Society Transactions(2007)第35卷,第4部分,第821页;Gupta等人,Advanced Drug Discovery Reviews(2004)第57卷9637所述。已显示有效通过质膜易位的短肽的示例包括来自果蝇触角蛋白的16个氨基酸的穿透肽(Derossi等人(1994)JBiol.Chem.第269卷,第10444页)、18个氨基酸的‘模型两亲性肽’(Oehlke等人(1998)Biochim Biophys Acts第1414卷,第127页)和HIV TAT蛋白的富含精氨酸的区域。非肽方法包括使用可以容易地附着于生物分子的小分子模拟物或SMOC(Okuyama等人(2007)NatureMethods第4卷第153页)。将胍基团添加到分子中的其它化学策略也增强细胞穿透(Elson-Scwab等人(2007)J Biol Chem第282卷,第13585页)。可以将小分子量分子(如类固醇)添加到分子支架中以增强细胞的摄取。
可以与肽配体连接的一类官能团包括抗体及其结合片段,如Fab、Fv或单结构域片段。具体地,可以使用抗体,其与能够在体内增加肽配体半衰期的蛋白结合。
在一个实施方案中,根据本发明的肽配体-效应物基团具有选自以下的tβ半衰期:12小时或更长、24小时或更长、2天或更长、3天或更长、4天或更长、5天或更长、6天或更长、7天或更长、8天或更长、9天或更长、10天或更长、11天或更长、12天或更长、13天或更长、14天或更长、15天或更长或者20天或更长。有利地,根据本发明的肽配体-效应物基团或组合物将具有12至60小时的tβ半衰期。在其它实施方案中,其将具有一天或更长的tβ半衰期。在还有其它的实施方案中,其将在12至26小时范围内。
在本发明的一个具体实施方案中,官能团选自金属螯合剂,其适于络合药学相关的金属放射性同位素。
可能的效应物基团还包括酶,例如用于酶/前药疗法的羧肽酶G2,其中肽配体替换ADEPT中的抗体。
在本发明的一个具体实施方案中,官能团选自药物,如用于癌症疗法的细胞毒性剂。合适的示例包括:烷化剂,如顺铂和卡铂、以及奥沙利铂、二氯甲基二乙胺、环磷酰胺、苯丁酸氮芥、异环磷酰胺;抗代谢剂包括嘌呤类似物硫唑嘌呤和巯嘌呤或嘧啶类似物;植物生物碱和萜类化合物包括长春花生物碱,如长春新碱、长春花碱、长春瑞滨和长春地辛;鬼臼毒素及其衍生物依托泊苷和替尼泊苷;紫杉类,包括紫杉醇,最初称为Taxol;拓扑异构酶抑制剂包括喜树碱:伊立替康和拓扑替康,以及II型抑制剂,包括安吖啶、依托泊苷、磷酸依托泊苷和替尼泊苷。其它药剂可包括抗肿瘤抗生素,其包括免疫抑制剂放线菌素D(用于肾移植)、多柔比星、表柔比星、博来霉素、刺孢霉素等。
在根据本发明的另一具体实施方案中,细胞毒性剂选自美登素生物碱(例如,DM1)或单甲基澳瑞他汀(例如,MMAE)。
DM1是细胞毒性剂,其是美登素的含巯基衍生物,具有以下结构:
单甲基澳瑞他汀E(MMAE)是合成的抗肿瘤剂,具有以下结构:
在一个实施方案中,细胞毒性剂通过可切割的键(如二硫键或蛋白酶敏感的键)与双环肽连接。在其它实施方案中,修饰与二硫键相邻的基团以控制二硫键的阻碍,并由此控制细胞毒性剂的切割和伴随释放的速率。
已发表的工作建立通过在二硫键的任一侧引入空间位阻来修饰二硫键对还原的易感性的潜力(Kellogg等人(2011)Bioconjugate Chemistry,22,717)。更大程度的空间位阻降低细胞内谷胱甘肽还有细胞外(全身)还原剂的还原速率,从而降低细胞内外由此释放毒素的难易程度。因此,通过仔细选择二硫键任一侧的位阻程度,可以实现循环中二硫化物稳定性的最佳选择(使得毒素的不期望副作用最小化)与细胞内环境中的有效释放(使得治疗效果最大化)。
通过在分子构建体的靶向实体(此处,双环肽)或毒素侧引入一个或多个甲基来调节二硫键任一侧的位阻。
在一个实施方案中,细胞毒性剂和接头选自WO 2016/067035(其细胞毒性剂和接头通过引用并入本文)中描述的那些的任意组合。
在一个实施方案中,所述细胞毒性剂是DM1,双环肽是43-06-00-N018(BCY2558)以及缀合物包含式(I)的化合物:
式(I)的BDC在本文中已知为BT43BDC-1。
合成
本发明的肽可以通过标准技术合成制备,然后与分子支架在体外反应。进行此操作时,可以使用标准化学方法。这样可以快速大规模地制备可溶性材料,以用于进一步的下游实验或验证。使用诸如在Timmerman等人(同上)中公开的常规化学来完成这样的方法。
因此,本发明还涉及如本文所述选择的多肽或缀合物的制备,其中所述制备任选地包括如下所述的其它步骤。在一个实施方案中,这些步骤在通过化学合成制备的最终产物多肽/缀合物上进行。
当制备缀合物或复合物时,可任选取代目的多肽中的氨基酸残基。
肽也可以延伸,以并入例如另一个环并因此引入多种特异性。
为了延伸肽,可以使用标准固相或溶液相化学法,使用正交保护的赖氨酸(和类似物),简单地在其N-末端或C-末端或在环内化学延伸。可以使用标准(生物)缀合技术来引入活化的或可活化的N-或C-末端。可选择地,可以通过片段缩合或天然化学连接添加,例如,如(Dawson等人1994.Synthesis of Proteins by Native Chemical Ligation.Science266:776-779)所述,或者通过酶进行添加,例如,使用如(Chang等人,Proc Natl Acad SciU S A.1994,12月20;91(26):12544-8或Hikari等人,Bioorganic&Medicinal ChemistryLetters第18卷,第22期,2008年11月15日,第6000-6003页)所述的变位酶。
可选择地,可以通过二硫键的进一步缀合来延伸或修饰肽。这具有一旦处于细胞还原环境中时允许第一和第二肽彼此分离的其它优点。在这种情况下,可以在第一肽的化学合成过程中加入分子支架(例如TBMB),以便与三个半胱氨酸基团反应;然后可以将另外的半胱氨酸或硫醇附加到第一肽的N或C-末端,这样该半胱氨酸或硫醇仅与第二肽的游离半胱氨酸或硫醇反应,形成二硫键连接的双环肽-肽缀合物。
类似的技术同样适用于两个双环和双特异性大环的合成/偶联,潜在地产生四特异性分子。
此外,可以以相同的方式,使用适当的化学方法,在N-或C-末端或通过侧链的偶联来完成添加其它官能团或效应物基团。在一个实施方案中,以不阻断任一实体活性的方式进行偶联。
药物组合物
根据本发明的另一方面,提供一种药物组合物,其包含与一个或多个药学上可接受的赋形剂相组合的本文所限定的肽配体或药物缀合物。
一般地,本发明的肽配体将与药理学上适当的赋形剂或载体一起以纯化的形式使用。通常,这些赋形剂或载体包括水溶液或醇/水溶液、乳液或悬浮液,包括盐和/或缓冲的介质。肠胃外载剂(vehicle)包括氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠以及乳酸林格氏液。合适的生理学上可接受的佐剂(如果需要将多肽复合物保持在悬浮液中)可选自增稠剂,如羧甲基纤维素、聚乙烯吡咯烷酮、明胶和藻酸盐。
静脉内载剂包括液体和营养补充剂和电解质补充剂,如基于林格氏右旋糖的那些。还可以存在防腐剂和其它添加剂,例如抗微生物剂、抗氧化剂、螯合剂和惰性气体(Mack(1982)Remington's Pharmaceutical Sciences,第16版)。
本发明的肽配体可以用作单独施用的组合物,或者与其它试剂联合施用。这些可包括抗体、抗体片段和各种免疫治疗药物,如环孢菌素、甲氨蝶呤、阿霉素或顺铂以及免疫毒素。药物组合物可以包括以下的“混合物”:各种细胞毒性剂或其它药剂联合本发明的蛋白配体,或甚至具有不同特异性的根据本发明的所选多肽的组合(如使用不同的靶配体所选择的多肽),无论它们是否在施用前合并。
根据本发明的药物组合物的施用途径可以是本领域普通技术人员公知的任何一种。对于治疗,可以根据标准技术将本发明的肽配体施用至任何患者。施用可以通过任何适当的方式进行,包括肠胃外、静脉内、肌内、腹膜内、经皮、通过肺部途径、或者还可以适当地通过用导管直接输注。优选地,根据本发明的药物组合物通过吸入施用。施用的剂量和频率将取决于患者的年龄、性别和病状、其它药物的同时施用、禁忌症(counter-indication)和临床医生应考虑的其它参数。
可以冻干本发明的肽配体用于储存,并在使用前在合适的载体中重构。已经证明该技术是有效的,并且可以采用本领域已知的冻干和重构技术。本领域技术人员将理解,冻干和重构可导致不同程度的活性损失,并且可能必须向上调整水平以进行补偿。
可以施用含有本发明肽配体或其混合物的组合物用于预防性和/或治疗性处理。在某些治疗应用中,将实现所选细胞群的至少部分抑制、压制、调节、杀伤或一些其它可衡量参数的足够量定义为“治疗有效剂量”。实现该剂量所需的量将取决于疾病的严重程度和患者自身免疫系统的一般状态,但通常范围为每千克体重0.005至5.0mg所选的肽配体,更通常使用的剂量为0.05至2.0mg/kg/剂量。对于预防性应用,含有本发明肽配体或其混合物的组合物也可以以相似或稍低的剂量施用。
含有根据本发明的肽配体的组合物可用于预防和治疗环境,以帮助改变、灭活、杀伤或去除哺乳动物中选择的靶细胞群。此外,本文所述的肽配体可选择性用于在离体或体外以用于从细胞的异质集合物中杀伤、损耗或以其它方式有效除去靶细胞群。来自哺乳动物的血液可以与选择的肽配体离体组合,由此从血液中杀伤或以其它方式除去不想要的细胞,并根据标准技术将血液返回到哺乳动物中。
治疗用途
本发明的双环肽具有作为整联蛋白αvβ3结合剂的特定作用。
整联蛋白是将细胞锚定至基质并跨质膜传递外源性信号的异二聚体基质受体。整联蛋白αvβ3在体内和体外均参与破骨细胞介导的骨再吸收。这种异二聚体分子识别包含在骨基质蛋白(例如骨桥蛋白和骨涎蛋白)中的氨基酸基序Arg-Gly-Asp(RGD)。整联蛋白αvβ3在破骨细胞中表达,其表达受到再吸收的类固醇和细胞因子的调节。基于阻断实验,αvβ3整联蛋白已被鉴定为破骨细胞上的主要功能性附着受体。整联蛋白αvβ3的抑制剂降低破骨细胞结合和骨再吸收的能力。整联蛋白αvβ3在破骨细胞的功能中起着主要作用,该整联蛋白的抑制剂被考虑用于治疗或预防骨质疏松症、溶骨性转移、和恶性肿瘤诱导的高钙血症。
存在许多种与破骨细胞介导的骨质溶解有关的骨病。当骨的再吸收和形成不协调并且骨破坏超过骨构建时被诱导的最常见的一种是骨质疏松症。骨质疏松症还由其它病状引起,如激素失衡、疾病或药物(例如,皮质类固醇或抗癫痫剂)。骨是人乳腺癌、前列腺癌、肺癌和甲状腺癌以及其它癌症的最常见转移部位之一。骨质疏松症还可由绝经后雌激素缺乏引起。继发性骨质疏松症可能与类风湿性关节炎关联。骨转移显示出非常独特的在其它器官转移中未见的破骨细胞性骨再吸收步骤。广泛接受的是,与癌症相关联的骨质溶解基本上由破骨细胞介导,所述破骨细胞似乎被活化并且可以通过成骨细胞间接活化或通过肿瘤产物直接活化。另外,高钙血症(血钙浓度增加)是溶骨性骨病的重要并发症。其在骨破坏广泛的患者中相对频繁地发生,并且尤其常见于乳腺癌、肺癌、肾癌、卵巢癌和胰腺癌以及骨髓瘤中。
解联蛋白是低分子量的含RGD的肽家族,所述肽与血小板和其它细胞(包括血管内皮细胞和一些肿瘤细胞)上表达的整联蛋白αIIbβ3、α5β1和αvβ3特异性地结合。除解联蛋白有效的抗血小板活性外,对解联蛋白的研究还揭示了其在诊断心血管疾病和设计动脉血栓形成、骨质疏松症以及血管生成相关的肿瘤生长和转移的治疗剂中的新用途。马来亚蝮蛇蛇毒蛋白(Rhodostomin,Rho)是源自马来亚蝮蛇(Colloselasma rhodostoma)的毒液的解联蛋白,已发现其通过阻断血小板糖蛋白αIIbβ3在体内和体外抑制血小板聚集。
在骨疾病中αvβ3整联蛋白的作用已经有充分记载(Ross等人(2006)Journal ofClinical Investigation 116(5);Rodan等人(1997)Journal of Endocrinology 154,S47-S56;Teitelbaum(2005)Journal of Clinical Endocrinology and Metabolism 90(4),2466-2468;Teitelbaum(2000)Journal of Bone and Mineral Metabolism 18,344-349;Nakamura等人(2007)Journal of Bone and Mineral Metabolism 25,337-344;Duong等人(1999)Journal of Bone and Mineral Metabolism 17,1-6;以及Teti等人(2002)Calcified Tissue International 71,293-299)。除骨病外,αvβ3整联蛋白在与骨病无关的病状中在血管生成和肿瘤生长中发挥重要作用。
根据本发明的方法选择的多肽配体可用于体内治疗和预防应用、体外和体内诊断应用、体外测定和试剂应用等。具有选择的特异性水平的配体可应用在以下应用中,涉及在需要交叉反应的非人动物中进行测试,或者在需要小心控制与同源物或旁系同源物的交叉反应的诊断应用中。在一些应用中,如疫苗应用,可以利用对预定范围的抗原引起免疫应答的能力调整针对特定疾病和病原体的疫苗。
对于哺乳动物施用,优选具有至少90至95%同质性的基本上纯的肽配体,并且对于药物施用(尤其是当哺乳动物是人时),最优选98至99%或更高的同质性。经过纯化、部分纯化、或至所需的同质性后,所选择的多肽可以用于诊断或治疗(包括离体)、或用于开发和执行测定程序、免疫荧光染色等(Lefkovite和Pernis,(1979和1981年),ImmunologicalMethods、卷I和II,Academic Press,NY)。
根据本发明的另一方面,提供如本文所定义的肽配体或药物缀合物,其用于预防、抑制或治疗由整联蛋白αvβ3所介导的疾病或病症。
根据本发明的另一个方面,提供了一种预防、抑制或治疗由整联蛋白αvβ3介导的疾病或病症的方法,该方法包括向需要其的患者施用本文所定义的肽配体的效应物基团和药物缀合物。
在一个实施方案中,整联蛋白αvβ3是哺乳动物整联蛋白αvβ3。在另一个实施方案中,哺乳动物整联蛋白αvβ3是人整联蛋白αvβ3。
在一个实施方案中,由整联蛋白αvβ3介导的疾病或病症选自骨疾病(例如,骨质疏松症)、癌症和涉及血管生成的疾病。
在另一个实施方案中,由整联蛋白αvβ3介导的疾病或病症选自癌症。
可以治疗(或抑制)的癌症(及其良性对应物)的示例包括但不限于上皮起源的肿瘤(各种类型的腺瘤和癌,包括腺癌、鳞状癌、移行细胞癌和其它癌),例如膀胱癌和泌尿道癌、乳腺癌、胃肠道(包括食管、胃(胃部的)、小肠、结肠、直肠和肛门)癌、肝癌(肝细胞癌)、胆囊和胆道系统癌、外分泌胰腺癌、肾癌、肺癌(例如腺癌、小细胞肺癌、非小细胞肺癌、细支气管肺泡癌和间皮瘤)、头颈部癌(例如舌癌、口腔癌、喉癌、咽癌、鼻咽癌、扁桃体癌、唾液腺癌、鼻腔癌和鼻旁窦癌)、卵巢癌、输卵管癌、腹膜癌、阴道癌、外阴癌、阴茎癌、子宫颈癌、子宫肌层癌、子宫内膜癌、甲状腺癌(例如甲状腺滤泡癌)、肾上腺癌、前列腺癌、皮肤和附属物癌(例如黑素瘤、基底细胞癌、鳞状细胞癌、角化棘皮瘤、发育异常痣);血液学恶性肿瘤(即白血病、淋巴瘤)和恶变前血液病和边缘恶性肿瘤的疾病包括血液学恶性肿瘤和淋巴系统的相关病状(例如,急性淋巴细胞白血病[ALL]、慢性淋巴细胞性白血病[CLL]、B-细胞淋巴瘤如弥漫大B细胞淋巴瘤[DLBCL]、滤泡性淋巴瘤、伯基特淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤和白血病、自然杀伤[NK]细胞淋巴瘤、霍奇金氏淋巴瘤、毛细胞白血病、意义未明的单克隆丙种球蛋白血症、浆细胞瘤、多发性骨髓瘤和移植后淋巴细胞增生性疾病),以及血液学恶性肿瘤和骨髓系相关病状(例如,急性髓性白血病[AML]、慢性髓性白血病[CML]、慢性髓性单核细胞白血病[CMML]、嗜酸性粒细胞增多综合征、骨髓增生性疾病如真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化、骨髓增生综合征、骨髓增生异常综合征和早幼粒细胞性白血病);间叶细胞源的肿瘤,例如软组织、骨或软骨的肉瘤如骨肉瘤、纤维肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、脂肪肉瘤、血管肉瘤、卡波西肉瘤、尤因氏肉瘤、滑膜肉瘤、上皮样肉瘤、胃肠道间质瘤、良性和恶性组织细胞瘤、和隆突性皮肤纤维肉瘤;中枢或周围神经系统的肿瘤(例如星形细胞瘤、神经胶质瘤和成胶质细胞瘤、脑膜瘤、室管膜瘤、松果体瘤和神经鞘瘤);内分泌肿瘤(例如垂体肿瘤、肾上腺肿瘤、胰岛细胞肿瘤、甲状旁腺肿瘤、类癌瘤和甲状腺髓样癌);眼和附属器肿瘤(例如成视网膜细胞瘤);生殖细胞和滋养细胞肿瘤(例如畸胎瘤、精原细胞瘤、无性细胞瘤、葡萄胎和绒毛膜癌);以及儿科和胚胎肿瘤(例如成神经管细胞瘤、成神经细胞瘤、肾母细胞瘤和原始神经外胚层肿瘤);或先天性或其它的综合症,其使患者易患恶性肿瘤(例如,着色性干皮症)。
在其它实施方案中,癌症选自乳腺癌、肺癌、肾癌、卵巢癌和胰腺癌以及骨髓瘤。
本文对术语“预防”的提及涉及在疾病诱发之前施用保护性组合物。“抑制”是指在诱发事件之后但在临床出现疾病之前施用组合物。“治疗”涉及在疾病症状变得明显之后施用保护性组合物。
可获得可用于筛选肽配体在保护免于疾病或治疗疾病中的有效性的动物模型系统。本发明促进动物模型系统的使用,其使得可以开发可与人和动物靶标交叉反应的多肽配体,以允许使用动物模型。
参考以下实施例进一步描述本发明。
实施例
材料和方法
肽合成
使用由Peptide Instruments制造的Symphony肽合成仪和MultiSynTech制造的Syro II合成仪,基于Fmoc化学法进行肽合成。使用标准的Fmoc-氨基酸(Sigma,Merck),带有适当的侧链保护基团:在每种情况下使用适用的标准偶联条件,然后使用标准方法进行脱保护。使用HPLC纯化肽,在分离后使用1,3,5-三(溴甲基)苯(TBMB,Sigma)进行修饰。为此,将线性肽用H2O稀释至约35mL,加入约500μL的100mM TBMB的乙腈溶液,并用5mL的1MNH4HCO3的H2O溶液引发反应。使反应在RT下进行约30-60分钟,并且反应完成就立即冻干(通过MALDI判断)。冻干后,如上纯化修饰的肽,同时用Gemini C18柱(Phenomenex)替换LunaC8,并将酸更改为0.1%三氟乙酸。将含有正确的TMB修饰物质的纯级分合并,冻干并保持在-20℃下储存。
除非另有说明,所有氨基酸均以L-构型使用。
在某些情况下,在使用以下方法与毒素的游离硫醇基偶联之前,先将肽转化为活化的二硫化物;将4-甲基(琥珀酰亚胺基4-(2-吡啶硫代)戊酸酯)(100mM)在干燥DMSO(1.25mol当量)中的溶液加入到肽(20mM)在干燥DMSO(1mol当量)中的溶液中。将反应物充分混合并加入DIPEA(20mol当量)。通过LC/MS监测反应直至完成。
制备双环肽药物缀合物BT43BDC-1
以下方法描述了双环肽(称为43-06-00-N018(Ac-(SEQ ID NO:5)-A-Sar6-dK)的二硫化物活化,以生成43-06-00-N019,接着通过与细胞毒性剂(如DM-1)缀合以生成BT43BDC-1。
反应方案:
通过在合成部分描述的通用方法从43-06-00-N018制备活化的二硫化物(43-06-00-N019)。
将43-06-00-N019(55mg)溶解在DMF(0.8ml)中。加入DM1(20mg)的DMF(0.8ml)溶液,接着是二异丙基乙胺(27μL),混合物在室温搅拌2小时。加入水(17.5ml),将混合物过滤,然后上样到Luna C18(3)制备型HPLC柱(250mmX20mm)。通过用16%-55%的乙腈(含1%三氟乙酸)和水(含1%三氟乙酸)的梯度经50分钟洗脱得到产物。
LC/MS(ES+)计算为M+3124;发现为3124。
生物数据
整联蛋白αvβ3和αvβ5竞争结合测定法
使用5nM的肽作为配体,使用与Wang等人(2005)Bioconjug Chem 16(3),729-34中所描述相类似的竞争荧光偏振测定法确定本发明的肽对整联蛋白αvβ3的亲和力(Ki)(以及对αvβ5的亲和力,以检测选择性),所述作为配体的肽具有以下序列:FITC-Ahx-GRGDSP(FITC-Ahx-(SEQ ID NO:14)(在此后被称为BCY10185)。FITC是3',6'-二羟基-3-氧代螺[异苯并呋喃-1(3H)、9'-[9H]氧杂蒽,以及Ahx是氨基己酸。
在上述整联蛋白αvβ3竞争结合测定法中检测本发明的肽配体,结果如表1所示:
表1:本发明肽配体的竞争结合数据
肽 | 分子支架 | Ki(nM) | 平均值 | n |
BCY2493 | TBMB | 31.34±8.63 | 29.6 | 7 |
BCY2496 | TBMB | 59.7 | - | 1 |
BCY2497 | TBMB | 168 | - | 1 |
BCY2498 | TBMB | 45.83±45.23 | 34.1 | 4 |
BCY2615 | TBMB | 1510±235.2 | 1505.2 | 2 |
BCY2558 | TBMB | 14.8±4.34 | 14.5 | 3 |
BCY2499 | TBMB | 173 | - | 1 |
BCY2502 | TBMB | 95.6 | - | 1 |
BCY2506 | TBMB | 25.53±14.83 | 23.6 | 3 |
使用以下示踪剂作为竞争配体,在上述整联蛋白αvβ3竞争结合测定法中检验其它双环肽:
BCY3844-(半乳糖-RGD)2-AF488(根据Colombo等人(2010)Molecules 15(1),178-197的方法制备);
BCY2572-A-(SEQ ID NO:1)-A-Sar6-K-Fl;
BCY2576-A-(SEQ ID NO:4)-A-Sar6-K-Fl;以及
BCY10185-FITC-Ahx-(SEQ ID NO:14)。
在上述整联蛋白αvβ3和αvβ5竞争结合测定法中检验本发明的某些肽配体,以及结果如表2所示:
表2:本发明肽配体的竞争结合数据
在上述整联蛋白αvβ3竞争结合测定法中检验BT43BDC-1的双环药物缀合物,结果如表3所示:
表3:本发明的双环药物缀合物的生物测定数据
整联蛋白αvβ3和αvβ5直接结合测定法
使用与Schottelius等人(2009)Acc.Chem.Res.42,969–980)所述类似的人或小鼠直接结合测定法,确定本发明所选择的荧光修饰肽对整联蛋白αvβ3的亲和力(Kd)(以及对αvβ5的亲和力,以检测选择性)。在表4中显示直接结合测定法的结果:
表4:本发明的肽配体的直接结合数据
序列表
<110> 拜斯科技术开发有限公司
<120> 整联蛋白αvβ3特异性的双环肽配体
<130> BIC-C-P2514PCT
<150> GB1900528.9
<151> 2019-01-15
<160> 14
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Cys Tyr His Ala His Arg Cys Asp Gly Gly Pro Phe Cys
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<223> 合成肽
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1 5 10
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Cys Ile Leu Arg Pro Asn Cys Asp Leu Asp Gly Arg Cys
1 5 10
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<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是HArg
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Cys Ile Leu Xaa Pro Asn Cys Asp Leu Asp Gly Arg Cys
1 5 10
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<211> 13
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Cys Ala Gly Ile Val Ser Cys Asp Gly Arg Pro Leu Cys
1 5 10
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<212> PRT
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<223> 合成肽
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Cys Lys Asn Phe Asn Pro Glu Cys Leu Arg Gly Asp Ser Leu Cys
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Claims (22)
1.一种整联蛋白αvβ3特异性的肽配体,其包含多肽和芳香族分子支架,所述多肽含有被至少两个环序列隔开的至少三个半胱氨酸残基,以及所述芳香族分子支架与所述多肽的半胱氨酸残基形成共价键,从而在所述分子支架上形成至少两个多肽环。
2.根据权利要求1所限定的肽配体,其中所述环序列包含2、3、4、5、6或7个氨基酸。
3.根据权利要求1或权利要求2所限定的肽配体,其中所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列都由5个氨基酸组成。
4.根据权利要求1或权利要求2所限定的肽配体,其中所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列都由6个氨基酸组成。
5.根据权利要求1或权利要求2所限定的肽配体,其中所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述环序列之一由2个氨基酸组成以及另一个由7个氨基酸组成。
6.根据权利要求1或权利要求2所限定的肽配体,其中所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述环序列之一由4个氨基酸组成以及另一个由3个氨基酸组成。
7.根据权利要求1或权利要求2所限定的肽配体,其包含选自以下的氨基酸序列:
CiLDHMECiiRGDMDCiii(SEQ ID NO:1);
CiYHAHRCiiDGGPFCiii(SEQ ID NO:2);
CiLHFSRCiiDGGMHCiii(SEQ ID NO:3);
CiILRPNCiiDLDGRCiii(SEQ ID NO:4);
CiIL(HArg)PNCiiDLDGRCiii(SEQ ID NO:5);
CiAGIVSCiiDGRPLCiii(SEQ ID NO:6);
CiKNFNPECiiLRGDSLCiii(SEQ ID NO:7);和
CiHTRAHDCiiYWESIVCiii(SEQ ID NO:8);
或其药学上可接受的盐;其中X代表任何氨基酸和X1代表任何氨基酸或不存在,以及Ci、Cii和Ciii分别代表第一、第二和第三半胱氨酸残基。
8.根据权利要求1或权利要求2所限定的肽配体,其包含选自以下的氨基酸序列:
CiNHCiiYRLDQHTCiii(SEQ ID NO:9);
CiNDLFCiiTWPCiii(SEQ ID NO:10);
CiHT(HArg)AHDCiiYWESIVCiii(SEQ ID NO:11);
CiHPGRGECiiSFSGIQCiii(SEQ ID NO:12);和
CiHTRGHDCiiDYRHSMCiii(SEQ ID NO:13);
或其药学上可接受的盐;其中Ci、Cii和Ciii分别代表第一、第二和第三半胱氨酸残基。
9.根据权利要求1、2或7中任一项所限定的肽配体,其包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(本文称为BCY2493);
A-(SEQ ID NO:2)-A(本文称为BCY2496);
A-(SEQ ID NO:3)-A(本文称为BCY2497);
A-(SEQ ID NO:4)-A(本文称为BCY2498);
Ac-(SEQ ID NO:5)-A-Sar10-dK(本文称为BCY2615);
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558);
A-(SEQ ID NO:6)-A(本文称为BCY2499);
A-(SEQ ID NO:7)-A(本文称为BCY2502);和
A-(SEQ ID NO:8)-A(本文称为BCY2506)。
10.根据权利要求1、2或8中任一项所限定的肽配体,其包含选自以下的氨基酸序列:
Ac-(SEQ ID NO:4)-A-Sar6-K(本文称为BCY2553);
B-Ala-Sar5-A-(SEQ ID NO:4)(本文称为BCY2554);
Ac-(SEQ ID NO:5)-A-Sar6-K(本文称为BCY2555);
B-Ala-Sar5-(SEQ ID NO:5)(本文称为BCY2560);
A-(SEQ ID NO:9)-A(本文称为BCY2494);
A-(SEQ ID NO:10)-A(本文称为BCY2503);和
B-Ala-Sar5-A-(SEQ ID NO:11)(本文称为BCY2568)。
11.根据权利要求9所限定的肽配体,其中所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(本文称为BCY2493);
A-(SEQ ID NO:2)-A(本文称为BCY2496);
A-(SEQ ID NO:3)-A(本文称为BCY2497);
A-(SEQ ID NO:4)-A(本文称为BCY2498);
Ac-(SEQ ID NO:5)-A-Sar10-dK(本文称为BCY2615);
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558);
A-(SEQ ID NO:6)-A(本文称为BCY2499);
A-(SEQ ID NO:7)-A(本文称为BCY2502);和
A-(SEQ ID NO:8)-A(本文称为BCY2506)。
12.根据权利要求10所限定的肽配体,其中所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
Ac-(SEQ ID NO:4)-A-Sar6-K(本文称为BCY2553);
B-Ala-Sar5-A-(SEQ ID NO:4)(本文称为BCY2554);
Ac-(SEQ ID NO:5)-A-Sar6-K(本文称为BCY2555);
B-Ala-Sar5-(SEQ ID NO:5)(本文称为BCY2560);
A-(SEQ ID NO:9)-A(本文称为BCY2494);
A-(SEQ ID NO:10)-A(本文称为BCY2503);和
B-Ala-Sar5-A-(SEQ ID NO:11)(本文称为BCY2568)。
13.根据权利要求9或权利要求11所限定的肽配体,其中所述分子支架选自1,3,5-三(溴甲基)苯(TBMB),以及所述肽配体包含选自以下的氨基酸序列:
Ac-(SEQ ID NO:5)-A-Sar6-dK(本文称为43-06-00-N018或BCY2558)。
14.根据权利要求1或权利要求2所限定的肽配体,其还包含荧光部分,例如荧光素(Fl)或青色素5(Cy5),以及选自:
A-(SEQ ID NO:1)-A-Sar6-K-Fl(本文称为BCY2572);
Fl-G-Sar5-A-(SEQ ID NO:1)(本文称为BCY2573);
A-(SEQ ID NO:4)-A-Sar6-K-Fl(本文称为BCY2576);
Ac-(SEQ ID NO:4)-A-Sar6-K-Fl(本文称为BCY2577);
Fl-(B-Ala)-Sar5-A-(SEQ ID NO:4)(本文称为BCY2578);
Ac-(SEQ ID NO:5)-A-Sar6-K-Fl(本文称为BCY2579);
Fl-(B-Ala)-Sar5-A-(SEQ ID NO:5)(本文称为BCY2580);
A-(SEQ ID NO:8)-A-Sar6-K-Fl(本文称为BCY2586);
A-(SEQ ID NO:10)-A-Sar6-K-Fl(本文称为BCY2582);
A-(SEQ ID NO:12)-A-Sar6-K-Fl(本文称为BCY2584);
A-(SEQ ID NO:13)-A-Sar6-K-Fl(本文称为BCY2588);
Cy5-(B-Ala)-Sar5-A-(SEQ ID NO:1)-A(本文称为BCY8590);和
Ac-(SEQ ID NO:5)-A-Sar6-K-Cy5(本文称为BCY8591)。
15.根据权利要求1至14中任一项所限定的肽配体,其中所述药学上可接受的盐选自游离酸或钠、钾、钙、铵盐。
16.根据权利要求1至15中任一项所限定的肽配体,其中所述整联蛋白αvβ3是人整联蛋白αvβ3。
17.一种药物缀合物,其包含权利要求1至13和15至16中任一项所限定的肽配体,所述肽配体与一个或多个效应物和/或官能团缀合。
18.一种药物缀合物,其包含根据权利要求1至13和15至16中任一项所限定的肽配体,所述肽配体与一个或多个细胞毒性剂缀合。
19.根据权利要求18所限定的药物缀合物,其中所述细胞毒性剂选自DM-1。
21.一种药物组合物,其包含与一种或多种药学上可接受的赋形剂组合的权利要求1至13或15至16中任一项的肽配体、或权利要求17至20中任一项的药物缀合物。
22.权利要求1至13或15至16中任一项的肽配体或权利要求17至20中任一项的药物缀合物在预防、抑制或治疗整联蛋白αvβ3介导的疾病或病症中的用途。
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WO2011079015A1 (en) * | 2009-12-21 | 2011-06-30 | The Regents Of The University Of California | Rgd-containing cyclic peptides |
CN107148425A (zh) * | 2014-10-29 | 2017-09-08 | 拜斯科医疗有限公司 | 对mt1‑mmp特异性的双环肽配体 |
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CN112585157A (zh) * | 2018-06-22 | 2021-03-30 | 拜斯科技术开发有限公司 | 用于结合整联蛋白αvβ3的肽配体 |
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WO2011079015A1 (en) * | 2009-12-21 | 2011-06-30 | The Regents Of The University Of California | Rgd-containing cyclic peptides |
CN107148425A (zh) * | 2014-10-29 | 2017-09-08 | 拜斯科医疗有限公司 | 对mt1‑mmp特异性的双环肽配体 |
WO2019002842A1 (en) * | 2017-06-26 | 2019-01-03 | Bicyclerd Limited | BICYCLIC PEPTIDE LIGANDS WITH DETECTABLE FRACTIONS AND USES THEREOF |
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