CN113260420A - Pd-l1特异性的双环肽配体 - Google Patents
Pd-l1特异性的双环肽配体 Download PDFInfo
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- CN113260420A CN113260420A CN201980083299.2A CN201980083299A CN113260420A CN 113260420 A CN113260420 A CN 113260420A CN 201980083299 A CN201980083299 A CN 201980083299A CN 113260420 A CN113260420 A CN 113260420A
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Abstract
本发明涉及多肽,其与芳香族分子支架共价结合,使得在支架的连接点之间对向存在两个或更多个肽环。特别地,本发明描述了作为PD‑L1的高亲和力结合物的肽。本发明还包括包含与一个或多个效应子和/或官能团偶联的所述肽的药物偶联物,包含所述肽配体和药物偶联物的药物组合物,以及所述肽配体和药物偶联物在预防、抑制或治疗PD‑L1介导的疾病或疾患中的用途。
Description
技术领域
本发明涉及多肽,其与芳香族分子支架共价结合,使得在支架的连接点之间对向存在(subtended)两个或更多个肽环。特别地,本发明描述了作为PD-L1的高亲和力结合物的肽。本发明还包括包含与一个或多个效应子和/或官能团偶联的所述肽的药物偶联物,包含所述肽配体和药物偶联物的药物组合物,以及所述肽配体和药物偶联物在预防、抑制或治疗PD-L1介导的疾病或疾患中的用途。
背景技术
环肽能够以高亲和力和靶标特异性与蛋白质靶标结合,因此是对于治疗剂开发有吸引力的分子类别。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、免疫抑制剂环孢霉素或抗癌药奥曲肽(Driggers等人(2008),Nat Rev Drug Discov 7(7),608-24)。良好的结合特性是由于肽与靶标之间形成的相对较大的相互作用表面以及环状结构的构象柔韧性降低所致。通常,大环与数百平方埃的表面结合,例如环肽CXCR4拮抗剂CVX15(Wu等人(2007),Science 330,1066-71)、具有与整联蛋白αVb3结合的Arg-Gly-Asp基序的环肽(Xiong等人(2002),Science 296(5565),151-5)或结合尿激酶型纤溶酶原激活因子的环肽抑制剂upain-1(Zhao等人(2007),J Struct Biol 160(1),1-10)。
由于其环状构型,肽大环比线性肽柔韧性差,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。这种作用已通过一种基质金属蛋白酶8(MMP-8)的有效的和选择性抑制剂得到了例证,该抑制剂在开环时失去相对于其他MMP的选择性(Cherney等人(1998),J Med Chem 41(11),1749-51)。通过大环化获得的有利的结合性质在具有多于一个肽环的多环肽中更为显著,例如在万古霉素、乳酸链球菌肽和放线菌素中。
不同的研究团队先前已将具有半胱氨酸残基的多肽系于(tethered)一个合成的分子结构上(Kemp和McNamara(1985),J.Org.Chem;Timmerman等人(2005),Chem-BioChem)。Meloen和同事已使用三(溴甲基)苯和相关分子将多个肽环快速定量地环化到合成支架上,以结构模拟蛋白质表面(Timmerman等人(2005),ChemBioChem)。WO 2004/077062和WO2006/078161中公开了用于生成候选药物化合物的方法,其中所述化合物是通过将包含半胱氨酸的多肽连接到分子支架上而生成的,所述分子支架例如为三(溴甲基)苯。
已经开发了基于噬菌体展示的组合方法以生成和筛选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WO 2009/098450)。简而言之,在噬菌体上展示了包含三个半胱氨酸残基和两个有六个随机氨基酸的区域(Cys-(Xaa)6-Cys-(Xaa)6-Cys)的线性肽的组合文库,并通过将半胱氨酸侧链共价连接至小分子(三-(溴甲基)苯)进行环化。
发明内容
根据本发明的第一个方面,提供了一种PD-L1特异性的肽配体,其包含多肽和芳香族分子支架,所述多肽包含被至少两个环序列隔开的至少三个半胱氨酸残基,并且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,使得在分子支架上形成至少两个多肽环。
根据本发明的一个进一步的方面,提供了一种药物偶联物,其包含与一个或多个效应子和/或官能团偶联的如本文所定义的肽配体。
根据本发明的一个进一步的方面,提供了一种药物组合物,其包含如本文所定义的肽配体或药物偶联物,与一种或多种药学上可接受的赋形剂组合。
根据本发明的一个进一步的方面,提供了如本文所定义的肽配体或药物偶联物,其用于预防、抑制或治疗PD-L1介导的疾病或疾患。
具体实施方式
在一个实施方案中,所述环序列包含2、3或6个氨基酸。
在一个进一步的实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列的第一个由6个氨基酸组成,第二个由2个氨基酸组成。
在一个进一步的实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列的第一个由6个氨基酸组成,第二个由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:
Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQ ID NO:7);
Ci-P-D-N/P-N/H-X1-I-Cii-H-L-W-Ciii(SEQ ID NO:8);和
CiPFPPHWCiiPRQCiii(SEQ ID NO:9);
其中X1表示任何氨基酸残基,Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
在一个实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列的第一个由6个氨基酸组成,第二个由2个氨基酸组成,并且所述肽配体包含选自以下的氨基酸序列:
Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQ ID NO:7);
其中Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
在一个实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列的第一个由6个氨基酸组成,第二个由3个氨基酸组成,并且所述肽配体包含选自以下的氨基酸序列:
Ci-P-D-N/P-N/H-X1-I-Cii-H-L-W-Ciii(SEQ ID NO:8);和
CiPFPPHWCiiPRQCiii(SEQ ID NO:9);
其中X1表示任何氨基酸残基,Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
在一个实施方案中,X1选自S、G和N。
在一个进一步的实施方案中,所述Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQ ID NO:7)的肽配体包含选自SEQ ID NO:1-3中任一项的氨基酸序列:
CiPFPVEWCiiSRCiii(SEQ ID NO:1);
CiPFPEEWCiiPRCiii(SEQ ID NO:2);和
CiPFPVEWCiiPRCiii(SEQ ID NO:3);
其中Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
在一个进一步的实施方案中,所述Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQ ID NO:7)的肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(在本文中称为BCY507);
A-(SEQ ID NO:1)-A[Sar]6(其荧光素衍生物在下文中称为BCY543);
A-(SEQ ID NO:2)-A(在本文中称为BCY508);
[B-Ala][Sar]5A-(SEQ ID NO:2)-A(其荧光素衍生物在下文中称为BCY544);
A-(SEQ ID NO:3)-A(在本文中称为BCY509);
[B-Ala][Sar]5A-(SEQ ID NO:3)-A(其荧光素衍生物在下文中称为BCY545);和
A-(SEQ ID NO:3)-A[Sar]6(其荧光素衍生物在下文中称为BCY546)。
在一个进一步的实施方案中,所述Ci-P-D-N/P-N/H-X1-I-Cii-H-L-W-Ciii(SEQ IDNO:8)的肽配体包含选自SEQ ID NO:4-6中任一项的氨基酸序列:
CiPDNNSICiiHLWCiii(SEQ ID NO:4);
CiPDPHGICiiHLWCiii(SEQ ID NO:5);和
CiPDPHNICiiHLWCiii(SEQ ID NO:6);
其中Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
在一个进一步的实施方案中,所述Ci-P-D-N/P-N/H-X7-I-Cii-H-L-W-Ciii(SEQ IDNO:8)的肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:4)-A(在本文中称为BCY514);
A-(SEQ ID NO:4)-A[Sar]6(其荧光素衍生物在下文中称为BCY550);
G[Sar]5A-(SEQ ID NO:4)-A(其荧光素衍生物在下文中称为BCY583);
A-(SEQ ID NO:5)-A(在本文中称为BCY515);
G[Sar]5A-(SEQ ID NO:5)-A(其荧光素衍生物在下文中称为BCY584);
A-(SEQ ID NO:6)-A(在本文中称为BCY516);和
G[Sar]5A-(SEQ ID NO:6)-A(其荧光素衍生物在下文中称为BCY585)。
在一个进一步的实施方案中,所述CiPFPPHWCiiPRQCiii(SEQ ID NO:9)的肽配体包含选自以下的氨基酸序列:
A-(SEQ ID NO:9)-A[Sar]6(其荧光素衍生物在下文中称为BCY551)。
在一个实施方案中,所述肽配体是表1至表3中任一个所列出的肽。
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)。
除非另有定义,否则本文所用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同含义,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。分子生物学、遗传和生化方法使用了标准技术(参见Sambrook等人,Molecular Cloning:ALaboratory Manual,第3版,2001,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,NY;Ausubel等人,Short Protocols in Molecular Biology(1999),第4版,JohnWiley&Sons,Inc.),其通过引用并入本文。
术语
编号
当提及本发明的肽内的氨基酸残基位置时,由于其不变而从编号中省略了半胱氨酸残基(Ci、Cii和Ciii),因此,本发明的肽内的氨基酸残基的编号参照如下:
-Ci-P1-F2-P3-V4-E5-W6-Cii-S7-R8Ciii-(SEQ ID NO:1)。
为了本说明的目的,假设所有双环肽都被TBMB(1,3,5-三(溴甲基)苯)环化,产生三取代的结构。与TBMB的环化发生在Ci、Cii和Ciii上。
分子形式
双环核心序列的N-或C-末端延伸区添加于序列的左侧或右侧,以连字符分隔。
例如,N-末端的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,该序列逆转(即N-末端变为C-末端,反之亦然),其立体化学同样也逆转(即D-氨基酸变为L-氨基酸,反之亦然)。
肽配体
如本文所指的,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),和在所述反应性基团之间对向存在的序列,所述序列因为当所述肽与所述支架结合时形成环而被称为环序列。在本案例中,所述肽包含至少三个半胱氨酸残基(在本文中称为Ci、Cii和Ciii),并且在所述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,其使它们被认为是适合注射、吸入、鼻、眼、口服或局部施用的类药物分子。这样的有利的性质包括:
-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表现出对血浆蛋白酶、上皮(“膜锚定的”)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。蛋白酶的稳定性应当在不同物种之间保持,使得可以在动物模型中开发双环先导候选物,并可以有把握地对人施用;
-理想的溶解度曲线。其是带电荷的和亲水的残基相对于疏水的残基和分子内/分子间氢键的比例的函数,其对于制剂和吸收目的很重要;
-在循环中最佳的血浆半衰期。取决于临床适应症和治疗方案,可能需要开发在急性疾病管理环境中短时间暴露的双环肽;或者开发在循环中保留增强的双环肽,其因此对于治疗更慢性的疾病状态是最佳的。导致理想的血浆半衰期的其他因素是持续暴露以实现最大治疗效率的要求,相对于由于持续暴露于试剂而伴随的毒理;和
-选择性。本发明的某些肽配体对其他跨膜蛋白表现出良好的选择性。
药学上可接受的盐
应当领会,盐形式在本发明的范围内,并且提及肽配体包括所述配体的盐形式。
本发明的盐可以由包含碱性或酸性部分的母体化合物合成,其通过常规化学方法如Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(编辑),Camille G.Wermuth(编辑),ISBN:3-90639-026-8,Hardcover,388页,2002年8月中所述的方法。通常,这样的盐可以通过使这些化合物的游离酸或碱形式与合适的碱或酸在水中或在有机溶剂中、或在两者的混合物中反应来制备。
可以用很多种无机和有机酸形成酸加成盐(单盐或二盐)。酸加成盐的示例包括与酸形成的单盐或二盐,所述酸选自乙酸、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、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己氨磺酸、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、葡糖醛酸(例如D-葡糖醛酸)、谷氨酸(例如L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢卤酸(例如氢溴酸、盐酸、氢碘酸)、羟基乙磺酸、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-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑酸、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、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一碳烯酸和戊酸,以及酰化的氨基酸和阳离子交换树脂。
一类特别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、羟基乙磺酸、富马酸、苯磺酸、甲苯磺酸、硫酸、甲磺酸(mesylate)、乙磺酸、萘磺酸、戊酸、丙酸、丁酸、丙二酸、葡糖醛酸和乳糖酸。一种特别的盐是盐酸盐。另一种特别的盐是乙酸盐。
如果化合物是阴离子的,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,生成合适的阳离子。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+,和其他阳离子如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 +)和被取代的铵离子(例如NH3R+、NH2R2 +、NHR3 +和NR4 +)。一些合适的取代的铵离子的示例是那些衍生自以下的: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。常见的季铵离子的一个示例是N(CH3)4 +。
当本发明的肽包含胺官能团时,其可以例如根据技术人员众所周知的方法与烷基化剂反应而形成季铵盐。这样的季铵化合物在本发明的肽的范围内。
修饰衍生物
应当领会,本文所定义的肽配体的修饰衍生物在本发明的范围内。这样的合适的修饰衍生物的示例包括选自以下的一种或多种修饰: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(如用一个或多个电子等排的或等电子的氨基酸替换一个或多个极性氨基酸残基;用其它非天然电子等排的或等电子的氨基酸替换一个或多个非极性氨基酸残基);间隔基团的添加;用一个或多个抗氧化氨基酸残基替换一个或多个对氧化敏感的氨基酸残基;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;双环肽配体中一个或多个酰胺键的N-烷基化;用替代键替换一个或多个肽键;肽骨架长度的修饰;用另一个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,以及引入或替换引入适合于官能化的正交反应活性的氨基酸,例如带有叠氮基或炔基的氨基酸,其分别允许用带有炔基或叠氮基的部分进行官能化。
在一个实施方案中,所述修饰衍生物包含N-末端和/或C-末端修饰。在一个进一步的实施方案中,其中所述修饰衍生物包含使用合适的氨基反应性化学的N-末端修饰和/或使用合适的羧基反应性化学的C-末端修饰。在一个进一步的实施方案中,所述N-末端或C-末端修饰包括添加效应基团,所述效应基团包括但不限于细胞毒性剂、放射螯合剂或发色团。
在一个进一步的实施方案中,所述修饰衍生物包含N-末端修饰。在一个进一步的实施方案中,所述N-末端修饰包含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,导致分子被N-末端乙酰化。该实施方案提供了去除氨基肽酶的潜在识别点的优点,并避免了所述双环肽降解的可能性。
在一个可选的实施方案中,所述N-末端修饰包括添加分子间隔基团,其促进效应基团的偶联和保持所述双环肽对其靶标的效力。
在一个进一步的实施方案中,所述修饰衍生物包含C-末端修饰。在一个进一步的实施方案中,所述C-末端修饰包含酰胺基。在该实施方案中,在肽合成过程中,C-末端半胱氨酸基团(在本文中称为Ciii的基团)被合成为酰胺,导致分子被C-末端酰胺化。该实施方案提供了去除羧肽酶的潜在识别点的优点,并降低了所述双环肽的蛋白水解降解的可能性。
在一个实施方案中,所述修饰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,可以选择具有电子等排的/等电子的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,使得附近的肽键的蛋白水解在构象和空间上受到阻碍。特别地,其涉及脯氨酸类似物、大型侧链、Cα-二取代的衍生物(例如氨基异丁酸(Aib))和环氨基酸,一个简单的衍生物是氨基-环丙基羧酸。
在一个实施方案中,所述修饰衍生物包括添加间隔基团。在一个进一步的实施方案中,所述修饰衍生物包括在N-末端半胱氨酸(Ci)和/或C-末端半胱氨酸(Ciii)上添加间隔基团。
在一个实施方案中,所述修饰衍生物包括用一个或多个抗氧化氨基酸残基替换一个或多个对氧化敏感的氨基酸残基。在一个进一步的实施方案中,所述修饰衍生物包括用萘丙氨酸或丙氨酸残基替换色氨酸残基。该实施方案提供了改善所得双环肽配体的药物稳定性特征的优点。
在一个实施方案中,所述修饰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。在一个可选的实施方案中,所述修饰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氨基酸残基。带电荷的与疏水的氨基酸残基的正确平衡是所述双环肽配体的重要特征。例如,疏水氨基酸残基影响血浆蛋白结合的程度,从而影响血浆中游离可利用部分的浓度,而带电荷的氨基酸残基(特别是精氨酸)可以影响所述肽与细胞表面磷脂膜的相互作用。两者组合起来可以影响所述肽药物的半衰期、分布容积和暴露,并且可以根据临床终点进行调整。另外,带电荷的和疏水的氨基酸残基的正确组合和数量可以减少在注射部位的刺激(如果所述肽药物已经皮下施用)。
在一个实施方案中,所述修饰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。该实施方案被认为通过空间位阻和通过D-氨基酸稳定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,所述修饰衍生物包括去除任何氨基酸残基并用丙氨酸取代。该实施方案提供了去除潜在的蛋白水解进攻位点的优点。
应当指出的是,每个上述修饰用于有意地改善所述肽的效力或稳定性。通过修饰,可以通过以下机制进一步提高效力:
-并入利用疏水作用并导致较低的解离率的疏水部分,使得实现更高的亲和力;
-并入利用长距离离子相互作用的带电基团,导致更快的结合率和更高的亲和力(参见例如Schreiber等人,Rapid,electrostatically assisted association ofproteins(1996),Nature Struct.Biol.3,427-31);和
-将附加的约束并入肽中,例如通过正确地约束氨基酸的侧链使得在靶结合时熵的损失最小,通过限制骨架的扭转角使得在靶结合时熵的损失最小,和出于相同的原因在分子中引入另外的环化。
(综述见Gentilucci等人(2010),Curr.Pharmaceutical Design 16,3185-203和Nestor等人(2009),Curr.Medicinal Chem 16,4399-418)。
同位素变体
本发明包括本发明的所有药学上可接受的(放射性)同位素标记的肽配体,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自然界中存在的原子质量或质量数的原子替换,和本发明的肽配体,其中连接金属螯合基团(称为“效应子”),其能够持有相关的(放射性)同位素,和本发明的肽配体,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取代。
适用于包含在本发明的肽配体中的同位素的示例包括氢同位素如2H(D)和3H(T),碳同位素如11C、13C和14C,氯同位素如36Cl,氟同位素如18F,碘同位素如123I、125I和131I,氮同位素如13N和15N,氧同位素如15O、17O和18O,磷同位素如32P,硫同位素如35S,铜同位素如64Cu,镓同位素如67Ga或68Ga,钇同位素如90Y,和镥同位素如177Lu,和铋同位素如213Bi。
本发明的某些同位素标记的肽配体,例如并入放射性同位素的那些,可用于药物和/或底物的组织分布研究,和用于在临床上评估患病组织上PD-L1靶标的存在和/或不存在。本发明的肽配体进一步可以具有有价值的诊断特性,其可用于检测或鉴定标记的化合物与其它分子、肽、蛋白质、酶或受体之间的复合物的形成。检测或鉴定方法可以使用用标记剂标记的化合物,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。放射性同位素氚即3H(T)和碳-14即14C,由于其易于并入和现成的检测方法而对于这一目的特别有用。
用更重的同位素如氘即2H(D)取代,可以由于更大的代谢稳定性而提供某些治疗优势,例如增加的体内半衰期或减少的剂量要求,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,可以用于正电子发射成像(PET)研究以检查靶标占有率。
本发明的肽配体的同位素标记的化合物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方法类似的方法,使用合适的同位素标记的试剂代替之前采用的非标记的试剂来制备。
芳香族分子支架
本文提及的术语“芳香族分子支架”是指包含芳香族碳环或杂环系统的如本文所定义的任何分子支架。
应理解所述芳香族分子支架可以包含芳香族部分。所述芳香族支架内合适的芳香族部分的示例包括联苯撑、三苯撑(terphenylene)、萘或蒽。
还应理解所述芳香族分子支架可包含杂芳族部分。所述芳香族支架内合适的杂芳族部分的示例包括吡啶、嘧啶、吡咯、呋喃和噻吩。
还应理解所述芳香族分子支架可以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(卤甲基)苯;双-、三-或四(卤甲基)吡啶;双-、三-或四(卤甲基)哒嗪;双-、三-或四(卤甲基)嘧啶;双-、三-或四(卤甲基)吡嗪;双-、三-或四(卤甲基)-1,2,3-三嗪;双-、三-或四-(卤甲基)-1,2,4-三嗪;双-、三-或四(卤甲基)吡咯、-呋喃、-噻吩;双-、三-或四(卤甲基)咪唑、-恶唑、-噻唑;双-、三-或四(卤甲基)-3H-吡唑、-异恶唑、-异噻唑;双-、三-或四(卤甲基)联苯撑;双-、三-或四(卤甲基)三苯撑;1,8-双(卤甲基)萘;双-、三-或四(卤甲基)蒽;和双-、三-或四(2-卤代甲基苯基)甲烷。
芳香族分子支架的更具体例子包括:1,2-双(卤甲基)苯;3,4-双(卤甲基)吡啶;3,4-双(卤甲基)哒嗪;4,5-双(卤甲基)嘧啶;4,5-双(卤甲基)吡嗪;4,5-双(卤甲基)-1,2,3-三嗪;5,6-双(卤甲基)-1,2,4-三嗪;3,4-双(卤甲基)吡咯、-呋喃、-噻吩和其他区域异构体;4,5-双(卤甲基)咪唑、-恶唑、-噻唑;4,5-双(卤甲基)-3H-吡唑、-异恶唑、-异噻唑;2,2'-双(卤甲基)联苯撑;2,2"-双(卤甲基)三苯撑;1,8-双(卤甲基)萘;1,10-双(卤甲基)蒽;双(2-卤代甲基苯基)甲烷;1,2,3-三(卤甲基)苯;2,3,4-三(卤甲基)吡啶;2,3,4-三(卤甲基)哒嗪;3,4,5-三(卤甲基)嘧啶;4,5,6-三(卤甲基)-1,2,3-三嗪;2,3,4-三(卤甲基)吡咯、-呋喃、-噻吩;2,4,5-双(卤甲基)咪唑、-恶唑、-噻唑;3,4,5-双(卤甲基)-1H-吡唑、-异恶唑、-异噻唑;2,4,2'-三(卤甲基)联苯撑;2,3',2"-三(卤甲基)三苯撑;1,3,8-三(卤甲基)萘;1,3,10-三(卤甲基)蒽;双(2-卤代甲基苯基)甲烷;1,2,4,5-四(卤甲基)苯;1,2,4,5-四(卤甲基)吡啶;2,4,5,6-四(卤甲基)嘧啶;2,3,4,5-四(卤甲基)吡咯、-呋喃、-噻吩;2,2',6,6'-四(卤甲基)联苯撑;2,2",6,6"-四(卤甲基)三苯撑;2,3,5,6-四(卤甲基)萘和2,3,7,8-四(卤甲基)蒽;和双(2,4-双(卤甲基)苯基)甲烷。
如上述文档中所提及,所述分子支架可以是小分子,如有机小分子。
在一个实施方案中,所述分子支架可以是大分子。在一个实施方案中,所述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,所述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。
所述分子支架可以包含与肽形成连接的化学基团,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、烷基卤和酰基卤。
在一个实施方案中,所述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,或可以由其组成。
在一个实施方案中,所述分子支架是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,但包含三个附着于苯环上的额外的甲基。其具有所述额外的甲基可以与多肽形成进一步接触并因此增加额外的结构约束的优点。
本发明的分子支架包含化学基团,其允许本发明编码文库的多肽的官能团与所述分子支架形成共价连接。所述化学基团选自范围广泛的官能团,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、烷基卤和酰基卤。
可以用于分子支架上以与半胱氨酸的硫醇基团反应的支架反应性基团是烷基卤(或也称为卤代烃(halogenoalkane)或卤代烷(haloalkane))。
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他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卤甲基羰基的化合物。可以用作本发明的分子支架的马来酰亚胺的示例包括:三-(2-马来酰亚胺乙基)胺、三-(2-马来酰亚胺乙基)苯、三-(马来酰亚胺)苯。包含α卤甲基羰基化合物的示例是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并且可以用于相同的反应。因此,无论在何处提及半胱氨酸,除非上下文另有说明,否则通常可以接受取代硒代半胱氨酸。
效应子和官能团
根据本发明的一个进一步的方面,提供了一种药物偶联物,其包含与一个或多个效应子和/或官能团偶联的如本文所定义的肽配体。
效应子和/或官能团可以连接至例如多肽的N和/或C末端、多肽内的氨基酸、或分子支架。
适当的效应子基团包括抗体及其部分或片段。例如,效应子基团除了一个或多个恒定区结构域以外,可以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。效应子基团还可以包含抗体的铰链区(通常在IgG分子的CH1和CH2结构域之间存在的区)。
在本发明该方面的一个进一步的实施方案中,根据本发明的效应子基团是IgG分子的Fc区。有利地,根据本发明的肽配体-效应子基团包含肽配体Fc融合体或由其组成,所述肽配体Fc融合体的tβ半衰期为一天或更长,两天或更长,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。最有利地,根据本发明的肽配体包含tβ半衰期为一天或更长的肽配体Fc融合体或由其组成。
官能团通常包括结合基团、药物、用于连接其他实体的反应性基团、协助将大环肽摄入细胞中的官能团等。
肽穿透入细胞的能力将允许肽有效针对细胞内的靶标。具有穿透入细胞的能力的肽可以接触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通路的分子。使得能够穿透细胞的官能团包括肽或已被添加到肽或分子支架中的化学基团。肽如衍生自如VP22、HIV-Tat、果蝇的同源盒蛋白(触角足(Antennapedia))的那些,例如描述在Chen和Harrison(2007),Biochemical Society Transactions Volume 35,part 4,p821;Gupta等人(2004),Advanced Drug Discovery Reviews Volume 57,9637中。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足蛋白的16个氨基酸的穿膜肽(penetratin)(Derossi等人(1994),J Biol.Chem.Volume 269 p10444),18个氨基酸的“模型两亲性肽”(Oehlke等人(1998),Biochim Biophys Acts Volume 1414,p127)和HIV TAT蛋白的富含精氨酸的区域。非肽类方法包括使用小分子模拟物或SMOC,其可以容易地连接到生物分子上(Okuyama等人(2007),Nature Methods Volume 4,p153)。将胍基基团添加至分子的其他化学策略也增强细胞穿透(Elson-Scwab等人(2007),J Biol Chem Volume 282,p13585)。小分子量分子如类固醇可以被添加到分子支架中以增强摄入细胞。
可以连接至肽配体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。特别地,可以使用与能够增加肽配体的体内半衰期的蛋白质结合的抗体。
在一个实施方案中,根据本发明的肽配体-效应子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20天或更长。有利地,根据本发明的肽配体-效应子基团或组合物的tβ半衰期的范围将为12至60小时。在一个进一步的实施方案中,其将具有一天或更长的tβ半衰期。在另一个进一步的实施方案中,其将在12至26小时的范围内。
在本发明的一个特别的实施方案中,所述官能团选自金属螯合剂,其适合于络合药物相关的金属放射性同位素。
可能的效应子基团还包括酶,例如用于酶/前药疗法的羧肽酶G2,其中肽配体替代了ADEPT中的抗体。
在本发明的一个特别的实施方案中,所述官能团选自药物,如用于癌症治疗的细胞毒性剂。合适的示例包括:烷基化剂如顺铂和卡铂,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;抗代谢物,包括嘌呤类似物咪唑硫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;紫杉烷类,包括紫杉醇(paclitaxel),原名紫杉醇(Taxol);拓扑异构酶抑制剂,包括喜树碱:伊立替康和托泊替康,和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。进一步的试剂可包括抗肿瘤抗生素,其包括免疫抑制剂放线菌素(用于肾脏移植)、阿霉素、表柔比星、博来霉素、刺孢霉素(calicheamycins)及其它。
在本发明的一个进一步特别的实施方案中,所述细胞毒性剂选自美登木素生物碱(maytansinoids)(如DM1)或单甲基澳瑞他汀(auristatins)(如MMAE)。
DM1是一种细胞毒性剂,其为美登素的含硫醇衍生物并具有以下结构:
单甲基澳瑞他汀E(MMAE)是一种合成抗肿瘤药并具有以下结构:
在本发明的仍进一步特别的实施方案中,所述细胞毒性剂选自美登木素生物碱(如DM1)。
在一个实施方案中,所述细胞毒性剂通过可裂解键如二硫键或蛋白酶敏感键与双环肽连接。在一个进一步的实施方案中,与二硫键相邻的基团被修饰以控制二硫键的阻碍,并由此控制裂解率和伴随的细胞毒性剂的释放。
已发表的工作通过在二硫键的任一侧引入空间位阻,建立了修饰二硫键对还原的敏感性的潜力(Kellogg等人(2011),Bioconjugate Chemistry,22,717)。更大程度的空间位阻会降低通过细胞内谷胱甘肽以及细胞外(系统性)还原剂的还原率,从而降低了细胞内和细胞外毒素释放的容易程度。因此,可以通过仔细选择所述二硫键任一侧的阻碍程度,来选择循环中二硫化物稳定性(其将毒素的不期望的副作用最小化)相对于细胞内环境中的有效释放(其将治疗效果最大化)的优化。
可以通过在分子构建体的靶向实体(此处为双环肽)或毒素侧引入一个或多个甲基来调节所述二硫键任一侧的阻碍。
在一个实施方案中,所述细胞毒性剂和接头选自WO 2016/067035(其细胞毒性剂及接头通过引用并入本文)中描述的那些的任何组合。
合成
本发明的肽可以通过标准技术合成制造,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。这使得能够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。可以使用如Timmerman等人(同上)中公开的常规化学方法来完成这样的方法。
因此,本发明还涉及如本文所述选择的多肽或偶联物的制造,其中所述制造包括如下所述的任选的进一步的步骤。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/偶联物上进行。
制造偶联物或复合物时,目标多肽中的氨基酸残基可任选地被取代。
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。
为了延伸所述肽,可以使用常规固相或溶液相化学方法,使用正交保护的赖氨酸(和类似物)简单地在其N-末端或C-末端或环内进行化学延伸。可以使用标准的(生物)偶联技术来引入激活的或可激活的N-或C-末端。可选地,可以通过片段缩合或天然化学连接进行添加,例如(Dawson等人(1994),Synthesis of Proteins by Native ChemicalLigation,Science 266:776-779)中描述的,或通过酶进行添加,例如使用subtiligase,如(Chang等人,Proc Natl Acad Sci U S A.1994 Dec 20;91(26):12544-8或Hikari等人,Bioorganic&Medicinal Chemistry Letters Volume 18,Issue 22,15 November 2008,Pages 6000-6003)中描述的。
可选地,可以通过二硫键的进一步偶联来延伸或修饰所述肽。这具有额外的优点,即允许第一和第二肽一旦在细胞的还原环境中即彼此解离。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;然后可以将进一步的半胱氨酸或硫醇附加到第一肽的N-或C-末端,使得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-肽偶联物。
类似的技术同样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,可以使用适当的化学方法,以相同的方式,在N-或C-末端或经由侧链偶联来添加其他官能团或效应子基团。在一个实施方案中,以不阻断任一个实体的活性的方式进行偶联。
药物组合物
根据本发明的一个进一步的方面,提供了一种药物组合物,其包含如本文所定义的肽配体或药物偶联物,与一种或多种药学上可接受的赋形剂组合。
一般地,本发明的肽配体将以纯化形式与药理学上合适的赋形剂或载体一起使用。通常,这些赋形剂或载体包括水性或醇/水溶液,乳液或悬浮液,包括盐水和/或缓冲介质。肠胃外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠和乳酸林格氏液。如果需要使多肽复合物保持悬浮,则合适的生理学上可接受的佐剂可以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。
静脉内载体包括液体和营养补充剂和电解质补充剂,如基于林格氏葡萄糖的那些。也可以存在防腐剂和其它添加剂,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与其他试剂联用。其可以包括抗体、抗体片段和各种免疫治疗药物,如环孢霉素、甲氨蝶呤、阿霉素或顺铂和免疫毒素。药物组合物可以包括各种细胞毒性或其他试剂的“混合物(cocktails)”与本发明的蛋白质配体组合,或甚至与具有不同特异性的根据本发明选择的多肽组合,如使用不同靶标配体选择的多肽,无论其在施用前合并与否。
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通常已知的任何途径。为了治疗,可以根据标准技术将本发明的肽配体施用于任何患者。所述施用可以通过任何合适的方式进行,包括肠胃外、静脉内、肌肉内、腹膜内、经皮、经由肺途径、或者适当地通过用导管直接输注进行。优选地,根据本发明的药物组合物将通过吸入施用。施用的剂量和频率将取决于患者的年龄、性别和状况、其他药物的同时施用、禁忌症和临床医生要考虑的其他参数。
可以将本发明的肽配体冻干用于储存,并在使用前在合适的载体中重构。已经表明该技术是有效的,并且可以采用本领域已知的冻干和重构技术。本领域技术人员将认识到,冻干和重构可以导致不同程度的活性损失,并且可能必须向上调节水平以进行补偿。
可以施用包含本发明的肽配体或其混合物的组合物以进行预防性和/或治疗性治疗。在某些治疗应用中,将足以完成所选择的细胞群体的至少部分抑制(inhibition)、抑制(suppression)、调节、杀死或一些其他可测量参数的量定义为“治疗有效剂量”。达到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,但一般为每千克体重0.005至5.0mg选择的肽配体,更常用的剂量为0.05至2.0mg/kg/剂量。对于预防性应用,也可以以相似或稍低的剂量施用包含本发明的肽配体或其混合物的组合物。
包含根据本发明的肽配体的组合物可以用于预防和治疗环境,以协助哺乳动物中所选择的靶细胞群体的改变、失活、杀死或去除。另外,本文所述的肽配体可以在体外(extracorporeally)或体外(in vitro)选择性地用于从异质细胞集合中杀死、消耗或以其他方式有效地去除靶细胞群体。可以将来自哺乳动物的血液与所选择的肽配体在体外组合,从而将不期望的细胞杀死或以其他方式从血液中去除,用于根据标准技术返回至哺乳动物。
治疗用途
本发明的双环肽作为PD-L1结合剂具有特殊的用途。
程序性细胞死亡1配体1(PD-L1)是一种290个氨基酸的I型跨膜蛋白,由小鼠19号染色体和人9号染色体上的CD274基因编码。PD-L1表达参与慢性感染中涉及的免疫反应的逃逸,例如慢性病毒感染(尤其包括例如HIV、HBV、HCV和HTLV等)、慢性细菌感染(尤其包括例如幽门螺杆菌)、慢性寄生虫感染(包括例如曼氏血吸虫)。PD-L1表达已经在许多组织和细胞类型中检测到,包括T细胞、B细胞、巨噬细胞、树突状细胞和非造血细胞(包括内皮细胞、肝细胞、肌肉细胞和胎盘)。
PD-L1表达也参与抗肿瘤免疫活性的抑制。肿瘤表达可以被宿主T细胞识别的抗原,但是肿瘤的免疫清除很少。这种失败的部分原因是由于肿瘤微环境对免疫的抑制。PD-L1在许多肿瘤上的表达是这种抑制性环境的一个组成部分,并与其他免疫抑制信号协同作用。PD-L1表达已在许多种实体瘤上原位显示,包括乳腺、肺、结肠、卵巢、黑色素瘤、膀胱、肝、唾液腺、胃、神经胶质、甲状腺、胸腺上皮和头颈肿瘤(Brown JA等人(2003),Immunol.170:1257-66;Dong H等人(2002),Nat.Med.8:793-800;Hamanishi J等人(2007),Proc.Natl.Acad.Sci.USA 104:3360-65;Strome SE等人(2003),Cancer Res.63:6501-5;Inman BA等人(2007),Cancer 109:1499-505;Konishi J等人(2004),Clin.CancerRes.10:5094-100;Nakanishi J等人(2007),Cancer Immunol.Immu-nother.56:1173-82;Nomi T等人(2007),Clin.Cancer Res.13:2151-57;Thompson RH等人(2004),Proc.Natl.Acad.Sci.USA 101:17174-79;Wu C等人(2006),Acta Histochem.108:19-24)。另外,PD-L1的受体,程序性细胞死亡蛋白1(也称为PD-1和CD279)的表达在肿瘤浸润性淋巴细胞中上调,这也有助于肿瘤的免疫抑制(Blank C等人(2003),Immunol.171:4574-81)。最重要地,有关肿瘤上PD-L1表达与疾病结果的研究表明,PD-L1表达与肾癌、卵巢癌、膀胱癌、乳腺癌、胃癌和胰腺癌的不良预后密切相关(Hamanishi J等人(2007),Proc.Natl.Acad.Sci.USA 104:3360-65;Inman BA等人(2007),Cancer 109:1499-505;Konishi J等人(2004),Clin.Cancer Res.10:5094-100;Nakanishi J等人(2007),CancerImmunol.Immunother.56:1173-82;Nomi T等人(2007),Clin.Cancer Res.13:2151-57;Thompson RH等人(2004),Proc.Natl.Acad.Sci.USA 101:17174-79;Wu C等人(2006),ActaHistochem.108:19-24)。另外,这些研究显示肿瘤上较高水平的PD-L1表达可能促进肿瘤分期的进展和侵袭到更深的组织结构中。
PD-1通路也可以在血液系统恶性肿瘤中发挥作用。PD-L1在多发性骨髓瘤细胞上表达,但在正常浆细胞上不表达(Liu J等人(2007),Blood 110:296-304)。PD-L1在某些原发性T细胞淋巴瘤,特别是间变性大细胞T淋巴瘤上表达(Brown JA等人(2003),Immunol.170:1257-66)。PD-1在血管免疫母细胞性淋巴瘤的T细胞上高表达,而PD-L1在相关联的滤泡树突状细胞网络上表达(Dorfman DM等人(2006),Am.J.Surg.Pathol.30:802-10)。在结节性淋巴细胞为主的霍奇金淋巴瘤中,与淋巴细胞或组织细胞(L&H)相关联的T细胞表达PD-1。使用由PD-1连接诱导的基因的读数进行的微阵列分析表明,在霍奇金淋巴瘤中,与肿瘤相关的T细胞对PD-1信号原位响应(Chemnitz JM等人(2007),Blood 110:3226-33)。PD-1和PD-L1在HTLV-1介导的成人T细胞白血病和淋巴瘤的CD4 T细胞上表达(Shimauchi T等人(2007),Int.J.Cancer 121:2585-90)。这些肿瘤细胞对TCR信号反应低下。
动物模型研究表明,肿瘤上的PD-L1抑制T细胞活化和肿瘤细胞裂解,并在某些情况下导致肿瘤特异性T细胞死亡的增加(Dong H等人(2002),Nat.Med.8:793-800;Hirano F等人(2005),Cancer Res.65:1089-96)。肿瘤相关的APC也可以利用PD-1:PD-L1通路来控制抗肿瘤T细胞响应。肿瘤环境因素上调肿瘤相关的髓系DC群体上的PD-L1表达(Curiel TJ等人(2003),Nat.Med.9:562-67)。B16黑色素瘤的肿瘤引流淋巴结中的浆细胞样树突状细胞(DC)表达IDO,其强烈激活调节性T细胞的抑制活性。IDO处理的调节性T细胞的抑制活性需要细胞与表达IDO的DC接触(Sharma MD等人(2007),Clin.Invest.117:2570-82)。
因此,本领域中需要PD-L1相关疾病的有效疗法,所述PD-L1相关疾病如传染病,如慢性细胞内传染病,例如病毒性疾病,例如肝炎感染或细菌感染,例如结核病感染;和癌症,例如肝癌,例如肝细胞癌。
根据本发明的方法选择的多肽配体可以用于体内治疗和预防应用、体外和体内诊断应用、体外试验和试剂应用等。具有所选择的特异性水平的配体可以用于涉及在期望交叉反应性的非人动物中进行测试的应用中,或在需要小心控制与同源物或旁系同源物的交叉反应性的诊断应用中。在某些应用如疫苗应用中,可以利用对预定范围的抗原引起免疫反应的能力来调整疫苗适应特定的疾病和病原体。
对哺乳动物的施用优选具有至少90%至95%同质性的基本纯的肽配体,对于药物用途,特别是当所述哺乳动物是人时,最优选98%至99%或更高的同质性。所选择的多肽一旦部分纯化或纯化至所期望的同质性,就可以用于诊断或治疗(包括体外)或用于开发和进行试验步骤、免疫荧光染色等(Lefkovite和Pernis(1979和1981),ImmunologicalMethods,Volumes I and II,Academic Press,NY)。
根据本发明的一个进一步的方面,提供了如本文所定义的肽配体或药物偶联物,其用于预防、抑制或治疗PD-L1介导的疾病或疾患。
根据本发明的一个进一步的方面,提供了一种预防、抑制或治疗PD-L1介导的疾病或疾患的方法,其包括向需要其的患者施用效应子基团和如本文所定义的肽配体的药物偶联物。
在一个实施方案中,所述PD-L1是哺乳动物PD-L1。在一个进一步的实施方案中,所述哺乳动物PD-L1是人PD-L1(hPD-L1)。
在一个实施方案中,所述PD-L1介导的疾病或疾患选自慢性感染或疾病、实体瘤和血液系统恶性肿瘤。
在一个实施方案中,所述PD-L1介导的慢性感染或疾病选自慢性病毒感染、慢性细菌感染、慢性寄生虫感染、肝炎感染和病毒性疾病。
在一个实施方案中,所述PD-L1介导的实体瘤选自乳腺、肺、结肠、卵巢、黑色素瘤、膀胱、肝、唾液腺、胃、神经胶质瘤、甲状腺、胸腺上皮和头颈肿瘤。
在一个进一步的实施方案中,所述PD-L1介导的疾病或疾患选自癌症。
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(腺瘤和各种类型的癌,包括腺癌、鳞状癌、移行细胞癌和其他癌)如膀胱和泌尿道癌、乳腺癌、胃肠道癌(包括食道、胃(胃部)、小肠、结肠、直肠和肛门的癌症)、肝癌(肝细胞癌)、胆囊和胆道系统癌、胰腺外分泌癌、肾癌、肺癌(例如腺癌、小细胞肺癌、非小细胞肺癌、支气管肺泡癌和间皮瘤)、头颈癌(例如舌癌、颊腔癌、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、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、皮肤和附件癌(例如黑色素瘤、基底细胞癌、鳞状细胞癌、角膜棘皮瘤和增生性痣);血液系统恶性肿瘤(即白血病和淋巴瘤)和血液系统癌前疾患以及边缘恶性肿瘤,包括淋巴系的血液系统恶性肿瘤和相关状况病症(例如急性淋巴细胞性白血病[ALL]、慢性淋巴细胞性白血病[CLL]、B细胞淋巴瘤如弥漫性大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、自然杀伤性[NK]细胞淋巴瘤、霍奇金淋巴瘤、毛细胞白血病、原因不明的单克隆免疫球蛋白增多症、浆细胞瘤、多发性骨髓瘤和移植后的淋巴增生性疾病),和骨髓系的血液系统恶性肿瘤和相关病症(例如急性骨髓性白血病[AML]、慢性粒细胞性白血病[CML]、慢性骨髓单核细胞性白血病[CMML]、高嗜酸性粒细胞增多症、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、骨髓增生异常综合症和早幼粒细胞白血病);间充质起源的肿瘤,例如软组织、骨或软骨肉瘤如骨肉瘤、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(例如垂体瘤、肾上腺瘤、胰岛细胞瘤、甲状旁腺肿瘤、类癌瘤和甲状腺髓样癌);眼部和附属器肿瘤(例如视网膜母细胞瘤);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);小儿和胚胎肿瘤(例如髓母细胞瘤、神经母细胞瘤、维尔姆斯瘤和原始神经外胚层肿瘤);或先天性或其他形式的综合症,其使患者容易患恶性肿瘤(例如着色性干皮病)。
在一个进一步的实施方案中,所述癌症是肾癌、卵巢癌、膀胱癌、乳腺癌、胃癌和胰腺癌。
在一个仍进一步的实施方案中,所述癌症选自肝癌,例如肝癌和肝细胞癌。
在一个进一步的实施方案中,所述癌症选自造血系统恶性肿瘤如选自:非霍奇金淋巴瘤(NHL)、伯基特淋巴瘤(BL)、多发性骨髓瘤(MM)、慢性B淋巴细胞性白血病(B-CLL)、B和T急性淋巴细胞性白血病(ALL)、T细胞淋巴瘤(TCL)、急性骨髓性白血病(AML)、毛细胞白血病(HCL)、霍奇金淋巴瘤(HL)、慢性骨髓性白血病(CML)和结节性淋巴细胞为主的霍奇金淋巴瘤。
本文提到的术语“预防”涉及在诱导疾病之前施用保护性组合物。“抑制”是指在诱导事件之后但在疾病的临床表现之前施用组合物。“治疗”涉及在疾病症状变得明显之后施用保护性组合物。
已有可以用于筛选肽配体在预防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,其允许开发可以与人和动物靶标交叉反应的多肽配体,从而允许使用动物模型。
以下参考下列实施例进一步描述本发明。
实施例
材料与方法
肽的合成
肽的合成基于Fmoc化学,使用Peptide Instruments生产的Symphony肽合成仪和MultiSynTech生产的Syro II合成仪。使用标准的Fmoc-氨基酸(Sigma,Merck),其带有适当的侧链保护基团:在每种情况下均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,并在分离后将其用1,3,5-三(溴甲基)苯(TBMB,Sigma)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,然后用5mL的1MNH4HCO3的H2O溶液引发反应。使反应在室温进行约30至60分钟,并且一旦反应完成即冻干(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Luna C8,并将酸改为0.1%三氟乙酸。合并包含正确的TMB修饰材料的纯级分,冻干并在-20℃进行保存。
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-吡啶基硫代)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。将反应充分混合并加入DIPEA(20mol当量)。通过LC/MS监测反应直至完成。
生物数据
1.PD-L1直接结合试验
根据WO 2016/067035中公开的方法,使用荧光偏振试验确定本发明的肽对人PD-L1的亲和力(Ki)。将具有荧光标签的本发明的肽(荧光素(SIGMA)或Alexa Fluor488TM(Fisher Scientific))在含0.01%吐温20的PBS或含100mM NaCl和0.01%吐温的50mMHEPES,pH 7.4中稀释至2.5nM(二者均称为测定缓冲液)。在黑色壁和底部的低结合量低容量384孔板中,其与在与该肽相同的测定缓冲液中的蛋白质滴定液组合,得到25μL总体积中1nM肽,通常为5μL测定缓冲液、10μL蛋白质、然后是10μL荧光肽。使用1/2系列稀释得到12种不同的浓度,其最高浓度的范围从已知高亲和力结合物的500nM至低亲和力结合物和选择性试验的10μM。在配备“FP485 520 520”光学模块的BMG PHERAstar FS上进行测量,该模块在485nm激发并检测520nm的平行和垂直发射。PHERAstar FS设置为25℃,每孔闪烁200次,定位延迟为0.1秒,每孔以5至10分钟的间隔测量,持续60分钟。在所述60分钟结束时确定每个示踪剂用于分析的增益,此时孔中没有蛋白质。使用Systat Sigmaplot 12.0版分析数据。将mP值拟合到用户定义的二次方程式,以生成Kd值:f=ymin+(ymax-ymin)/Lig*((x+Lig+Kd)/2-sqrt((((x+Lig+Kd)/2)^2)-(Lig*x)))。“Lig”是所使用的示踪剂浓度的定义值。
在上述PD-L1直接结合试验中测试了以下选择的本发明的双环肽配体,其结果示于表1中:
表1:选择的本发明的双环肽配体的直接结合试验数据
**指4个实验的平均值
2.PD-L1竞争结合试验
测试了无荧光标签的肽与[Fl]-G-[Sar5]ACPDPHNICHLWCA(([Fl]G[Sar]5A-(SEQID NO:6)-A);BCY585;Kd=68.75nM–使用上述方案确定)的竞争。如直接结合试验中所描述的,将肽在测定缓冲液中稀释至适当浓度,其中最多含5%DMSO,然后以1比2的比例系列稀释。将5μL稀释的肽添加到板中,然后添加10μL人PD-L1,然后添加10μL荧光肽。按照直接结合试验进行测量,但是在第一次测量之前确定增益。数据分析使用Systat Sigmaplot 12.0版,其中将mP值拟合用户定义的三次方程式,以生成Ki值:
f=ymin+(ymax-ymin)/Lig*((Lig*((2*((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^0.5*COS(ARCCOS((-2*(Klig+Kcomp+Lig+Comp-Prot*c)^3+9*(Klig+Kcomp+Lig+Comp-Prot*c)*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp)-27*(-1*Klig*Kcomp*Prot*c))/(2*((((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^3)^0.5)))/3))-(Klig+Kcomp+Lig+Comp-Prot*c)))/((3*Klig)+((2*((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^0.5*COS(ARCCOS((-2*(Klig+Kcomp+Lig+Comp-Prot*c)^3+9*(Klig+Kcomp+Lig+Comp-Prot*c)*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp)-27*(-1*Klig*Kcomp*Prot*c))/(2*((((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^3)^0.5)))/3))-(Klig+Kcomp+Lig+Comp-Prot*c))))。
“Lig”、“KLig”和“Prot”均是分别与以下相关的定义值:荧光肽浓度、荧光肽的Kd和PD-L1浓度。
在上述PD-L1竞争结合试验中测试了以下本发明所选择的双环肽配体,其结果示于表2中:
表2:本发明所选择的双环肽配体的竞争结合试验数据
3. PD-L1 SPR结合试验
进行Biacore实验以确定单体肽与人PD-L1蛋白结合的ka(M-1s-1)、kd(s-1)和KD(nM)值。将重组人PD-L1(Sino Biologicals或R&D systems)或小鼠PD-L1(R&D systems)重悬于PBS中,并按照制造商建议的方案使用EZ-LinkTM Sulfo-NHS-LC-LC-Biotin试剂(ThermoFisher)进行生物素化。使用离心柱将蛋白质脱盐以去除未偶联的生物素,并将其移入PBS中。为了进行结合分析,使用了使用CM5传感器芯片(GE Healthcare)的Biacore 3000仪器。使用标准胺偶联化学方法,在25℃以HBS-N(10mM HEPES,0.15M NaCl,pH 7.4)作为运行缓冲液,将链霉亲和素固定在所述芯片上。以1:1比例的0.4M 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)/0.1M N-羟基琥珀酰亚胺(NHS),以10μL/min的流速注入12分钟,活化羧甲基葡聚糖表面。为了捕获链霉亲和素,将蛋白质在10mM乙酸钠(pH 4.5)中稀释至0.1mg/mL,并通过将70μL注入活化的芯片表面进行捕获。残余活化基团用1M乙醇胺(pH8.5)注射7分钟进行封闭。将生物素化的PD-L1储备液在HBS-N中1:100稀释,并以5μL/min在流动池中捕获至1000RU至1300RU的水平。将缓冲液更改为PBS/0.05%吐温20,并在该缓冲液中制备系列稀释的所述肽,其DMSO终浓度为0.5%。其最高浓度为200nM或500nM,并进行6次2倍稀释。SPR分析在25℃以50μL/min的流速进行,缔合60秒,解离400秒。数据对DMSO排除体积效应进行了校正。使用标准处理程序对所有数据针对空白注入和参照表面进行双重参照(double-referenced),并使用Scrubber软件2.0c版(Biologic Software)进行数据处理和动力学拟合。使用质量运输模型拟合数据,并在适当的情况下考虑质量运输的影响。
在上述PD-L1 SPR结合试验中测试了以下本发明所选择的双环肽配体,其结果示于表3中:
表3:本发明所选择的双环肽配体的SPR结合试验数据
序列表
<110> 拜斯科阿迪有限公司
<120> PD-L1特异性的双环肽配体
<130> BIC-C-P2498PCT
<150> GB 1820969.2
<151> 2018-12-21
<150> GB 1904622.6
<151> 2019-04-02
<160> 9
<170> PatentIn version 3.5
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<213> 人工序列
<220>
<223> 合成的
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Cys Pro Phe Pro Val Glu Trp Cys Ser Arg Cys
1 5 10
<210> 2
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Cys Pro Phe Pro Glu Glu Trp Cys Pro Arg Cys
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<212> PRT
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Cys Pro Phe Pro Val Glu Trp Cys Pro Arg Cys
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<211> 12
<212> PRT
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<223> 合成的
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Cys Pro Asp Asn Asn Ser Ile Cys His Leu Trp Cys
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<212> PRT
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<223> 合成的
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Cys Pro Asp Pro His Gly Ile Cys His Leu Trp Cys
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Cys Pro Asp Pro His Asn Ile Cys His Leu Trp Cys
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<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa表示V或E
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<221> MISC_FEATURE
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<223> Xaa表示S或P
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Cys Pro Phe Pro Xaa Glu Trp Cys Xaa Arg Cys
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Claims (16)
1.一种PD-L1特异性的肽配体,其包含多肽和芳香族分子支架,所述多肽包含被至少两个环序列隔开的至少三个半胱氨酸残基,并且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,使得在分子支架上形成至少两个多肽环。
2.如权利要求1所定义的肽配体,其中所述环序列包含2、3或6个氨基酸。
3.如权利要求1或2所定义的肽配体,其包含选自以下的氨基酸序列:
Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQ ID NO:7);
Ci-P-D-N/P-N/H-X1-I-Cii-H-L-W-Ciii(SEQ ID NO:8);和
CiPFPPHWCiiPRQCiii(SEQ ID NO:9);
其中X1表示任何氨基酸残基,Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
4.如权利要求1至3中任一项所定义的肽配体,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,所述两个环序列的第一个由6个氨基酸组成,第二个由2个氨基酸组成,并且所述肽配体包含选自以下的氨基酸序列:
Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQ ID NO:7);
其中Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
5.如权利要求1至3中任一项所定义的肽配体,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,所述两个环序列的第一个由6个氨基酸组成,第二个由3个氨基酸组成,并且所述肽配体包含选自以下的氨基酸序列:
Ci-P-D-N/P-N/H-X1-I-Cii-H-L-W-Ciii(SEQ ID NO:8);和
CiPFPPHWCiiPRQCiii(SEQ ID NO:9);
其中X1表示任何氨基酸残基,Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐。
6.如权利要求3或5所定义的肽配体,其中所述Ci-P-F-P-V/E-E-W-Cii-S/P-R-Ciii(SEQID NO:7)的肽配体包含选自SEQ ID NO:1-3中任一项的氨基酸序列:
CiPFPVEWCiiSRCiii(SEQ ID NO:1);
CiPFPEEWCiiPRCiii(SEQ ID NO:2);和
CiPFPVEWCiiPRCiii(SEQ ID NO:3);
其中Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐,
如:
选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(在本文中称为BCY507);
A-(SEQ ID NO:1)-A[Sar]6(其荧光素衍生物在下文中称为BCY543);
A-(SEQ ID NO:2)-A(在本文中称为BCY508);
[B-Ala][Sar]5A-(SEQ ID NO:2)-A(其荧光素衍生物在下文中称为BCY544);
A-(SEQ ID NO:3)-A(在本文中称为BCY509);
[B-Ala][Sar]5A-(SEQ ID NO:3)-A(其荧光素衍生物在下文中称为BCY545);和
A-(SEQ ID NO:3)-A[Sar]6(其荧光素衍生物在下文中称为BCY546)。
7.如权利要求3或5所定义的肽配体,其中所述Ci-P-D-N/P-N/H-X7-I-Cii-H-L-W-Ciii(SEQ ID NO:8)的肽配体包含选自SEQ ID NO:4-6中任一项的氨基酸序列:
CiPDNNSICiiHLWCiii(SEQ ID NO:4);
CiPDPHGICiiHLWCiii(SEQ ID NO:5);和
CiPDPHNICiiHLWCiii(SEQ ID NO:6);
其中Ci、Cii和Ciii分别表示第一、第二和第三半胱氨酸残基或其药学上可接受的盐,
如:
选自以下的氨基酸序列:
A-(SEQ ID NO:4)-A(在本文中称为BCY514);
A-(SEQ ID NO:4)-A[Sar]6(其荧光素衍生物在下文中称为BCY550);
G[Sar]5A-(SEQ ID NO:4)-A(其荧光素衍生物在下文中称为BCY583);
A-(SEQ ID NO:5)-A(在本文中称为BCY515);
G[Sar]5A-(SEQ ID NO:5)-A(其荧光素衍生物在下文中称为BCY584);
A-(SEQ ID NO:6)-A(在本文中称为BCY516);和
G[Sar]5A-(SEQ ID NO:6)-A(其荧光素衍生物在下文中称为BCY585)。
8.如权利要求3所定义的肽配体,其中所述CiPFPPHWCiiPRQCiii(SEQ ID NO:9)的肽配体包含氨基酸序列:
A-(SEQ ID NO:9)-A[Sar]6(其荧光素衍生物在下文中称为BCY551)。
9.如权利要求1或2所定义的肽配体,其为表1至表3中任一个所列出的肽。
10.如权利要求1至9中任一项所定义的肽配体,其中所述分子支架为1,3,5-三(溴甲基)苯(TBMB)。
11.如权利要求1至10中任一项所定义的肽配体,其中所述药学上可接受的盐选自游离酸或钠、钾、钙、铵盐。
12.如权利要求1至11中任一项所定义的肽配体,其中所述PD-L1为人PD-L1。
13.一种药物偶联物,其包含如权利要求1至12中任一项所定义的肽配体,所述肽配体与一个或多个效应子和/或官能团偶联。
14.药物偶联物,其包含如权利要求1至12中任一项所定义的肽配体,所述肽配体与一个或多个细胞毒性剂偶联。
15.一种药物组合物,其包含权利要求1至12中任一项的肽配体或权利要求13或14的药物偶联物,与一种或多种药学上可接受的赋形剂组合。
16.如权利要求1至12中任一项所定义的肽配体或如权利要求13或14中所定义的药物偶联物的用途,用于预防、抑制或治疗PD-L1介导的疾病或疾患。
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GBGB1820969.2A GB201820969D0 (en) | 2018-12-21 | 2018-12-21 | Bicyclic peptide ligands specific for pd-l |
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GBGB1904622.6A GB201904622D0 (en) | 2019-04-02 | 2019-04-02 | Bicyclic peptide ligands specific for pd-l1 |
GB1904622.6 | 2019-04-02 | ||
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CHRISTIAN HEINIS等: "Phage-encoded combinatorial chemical libraries based on bicyclic peptides", NATURE CHEMICAL BIOLOGY, vol. 5, no. 7, pages 503 * |
SHABNAM SHAABANI等: "A patent review on PD-1/PD-L1 antagonists: small molecules, peptides and macrocycles (2015–2018)", HHS PUBLIC ACCESS, vol. 28, no. 9, pages 6, XP055669361, DOI: 10.1080/13543776.2018.1512706 * |
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