CN114521197A - 异串联双环肽复合物 - Google Patents
异串联双环肽复合物 Download PDFInfo
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- CN114521197A CN114521197A CN202080060998.8A CN202080060998A CN114521197A CN 114521197 A CN114521197 A CN 114521197A CN 202080060998 A CN202080060998 A CN 202080060998A CN 114521197 A CN114521197 A CN 114521197A
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Abstract
本发明涉及异串联双环肽复合物,其包含结合粘连蛋白‑4的第一肽配体,所述第一肽配体通过接头与结合CD137的两个第二肽配体偶联。本发明还涉及所述异串联双环肽复合物在预防、抑制或治疗癌症中的用途。
Description
技术领域
本发明涉及异串联(heterotandem)双环肽复合物,其包含结合粘连蛋白-4(Nectin-4)的第一肽配体,所述第一肽配体通过接头与结合CD137的两个第二肽配体偶联。本发明还涉及所述异串联双环肽复合物在预防、抑制或治疗癌症中的用途。
背景技术
环肽可以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、免疫抑制药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(tether)一个合成的分子结构上(Kemp和McNamara(1985),J.Org.Chem;Timmerman等人(2005),ChemBioChem)。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 2019/122860和WO2019/122863中公开了生成候选药物化合物的方法,其中所述化合物是通过将含有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(1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮)(TATA)。
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六随机氨基酸的区域(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)而环化。
发明内容
根据本发明的第一方面,提供了异串联双环肽复合物,其包含:
(a)结合粘连蛋白-4的第一肽配体,其具有序列CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii(SEQ ID NO:1;BCY8116);其通过N-(酸-PEG3)-N-双(PEG3-叠氮化物)接头与以下偶联
(b)结合CD137的两个第二肽配体,二者均具有序列Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A(SEQ ID NO:2;BCY8928);
其中每个所述肽配体包含多肽和分子支架,所述多肽包含被两个环序列隔开的三个反应性半胱氨酸基团(Ci、Cii和Ciii),所述分子支架是1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA),并且所述分子支架与所述多肽的反应性半胱氨酸基团形成共价键,使得在分子支架上形成两个多肽环;
其中Ac表示乙酰基,HArg表示高精氨酸,HyP表示反式-4-羟基-L-脯氨酸,1Nal表示1-萘丙氨酸,tBuAla表示叔丁基丙氨酸,PYA表示4-戊烯酸,Nle表示正亮氨酸。
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异串联双环肽复合物,与一种或多种药学上可接受的赋形剂组合。
根据本发明的另一方面,提供了用于预防、抑制或治疗癌症的如本文所定义的异串联双环肽复合物。
附图说明
图1:(A)在表达粘连蛋白-4的H292细胞存在下,在Promega CD137荧光素酶报告基因测定中,分析了粘连蛋白-4/CD137异串联双环肽复合物。BCY11617是以与BCY11863相同的亲和力与粘连蛋白-4结合、但不与CD137结合的异串联双环肽复合物。(B)在与内源性表达粘连蛋白-4或被工程化以过表达粘连蛋白-4的不同细胞系共培养的Promega CD137荧光素酶报告基因测定中,BCY11863的EC50(nM)总结。
图2:在PBMC-4T1共培养测定中,粘连蛋白-4/CD137异串联双环肽复合物诱导IFN-γ(图2A)和IL-2(图2B)细胞因子分泌。工程化4T1细胞以表达粘连蛋白-4。BCY11617是以与BCY11863相同的亲和力与粘连蛋白-4结合、但不与CD137结合的异串联双环肽复合物。图2C表示在多个人PBMC供体和肿瘤细胞系的细胞因子分泌测定中,BCY11863的EC50(nM)总结。
图3:在分别以2mg/kg(n=3)和1mg/kg(n=2)静脉给药的SD大鼠和食蟹猴(cyno)中,异串联双环肽复合物BCY11863的药代动力学。
图4:BCY11863在同基因小鼠过表达粘连蛋白-4的MC38肿瘤模型(MC38#13)中的抗肿瘤活性。BCY11863治疗期间和之后的肿瘤体积。D69时的完全应答者(CR)小鼠的数量在括号中表示。QD:每天给药;Q3D:每三天给药;ip:腹膜内施用。
图5:BCY11863治疗导致对过表达粘连蛋白-4的MC38肿瘤细胞(MC38#13)的免疫原性记忆。显示了幼稚C57BL/6J-hCD137小鼠或对BCY11863具有完全应答(CR)的小鼠接种后的肿瘤体积。注意在观察期(22天)结束时,CR小鼠均不发生肿瘤。
图6:BCY11863在小鼠同基因过表达粘连蛋白-4的CT26肿瘤模型(CT26#7)中显示出抗肿瘤活性。BCY11863治疗期间的肿瘤体积。Q3D:每三天给药;ip:腹膜内施用。
图7:在最后一次(第6次)BCY11863的Q3D给药后1h,CT26#7肿瘤组织中T细胞总数和CD8+T细胞增加。分析了最后一次BCY11863的Q3D给药后1h,CT26#7肿瘤组织中的(A)T细胞总数、CD8+T细胞、CD4+T细胞、Treg和(B)CD8+T细胞/Treg的比例。
图8:单次静脉内(iv)施用5mg/kg BCY11863后,BCY11863在CT26#7同基因荷瘤动物的血浆和肿瘤组织中的药代动力学特征。
图9:在腹膜给药15mg/kg的CD-1小鼠(n=3)中,BCY11863的血浆浓度对时间的曲线图和BCY11863的终末血浆半衰期。
图10:BCY11863与固定的(A)粘连蛋白-4和(B)CD137的表面等离子共振(SPR)结合研究。双结合SPR测定先将(C)CD137和(D)粘连蛋白-4固定在SPR芯片上,然后捕获BCY11863。通过使不同浓度的可溶性受体流过芯片,测量了结合的BCY11863对可溶性人粘连蛋白-4(C)或CD137(D)的亲和力。(E)固定在链霉亲和素SPR芯片上的BCY13582(生物素化的BCY11863)与可溶性人CD137的结合。
图11:用于探索BCY13582(生物素化的BCY11863)的非特异性脱靶相互作用的细胞微阵列技术(Retrogenix)。此处所示的筛选数据显示,将1μM BCY13582加入表达11种不同蛋白质的微阵列载玻片中,其仅与CD137和粘连蛋白-4结合(使用AlexaFluor647标记的链霉亲和素检测)。当与BCY11863孵育时,结合信号被置换。
图12:huCD137C57Bl/6小鼠中MC38#13肿瘤的肿瘤生长曲线证明了在不同剂量和给药间隔后的BCY11863的抗肿瘤活性。治疗开始后第15天时,完全应答者动物(CR;无可触及肿瘤)的数量在括号中表示。
图13:huCD137C57Bl/6小鼠中MC38#13肿瘤(n=6/队列)的肿瘤生长曲线(平均值±SEM)证明了不同剂量和给药方案的BCY11863的抗肿瘤活性。治疗开始后第52天时,完全应答者动物(CR;无可触及肿瘤)的数量在括号中表示。(A)使用载体或每周总剂量3mg/kg的BCY11863给药的队列。(B)使用载体或每周总剂量10mg/kg的BCY11863给药的队列。(C)使用载体或每周总剂量30mg/kg的BCY11863给药的队列。
图14:在以100mg/kg(n=3)静脉给药的SD大鼠中异串联双环肽复合物BCY11863的药代动力学,和血浆中BCY11863和潜在代谢物BCY15155和BCY14602的浓度测量。
具体实施方式
根据本发明的第一方面,提供了异串联双环肽复合物,其包含:
(a)结合粘连蛋白-4的第一肽配体,其具有序列CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii(SEQ ID NO:1;BCY8116);其通过N-(酸-PEG3)-N-双(PEG3-叠氮化物)接头与以下偶联
(b)结合CD137的两个第二肽配体,二者均具有序列Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A(SEQ ID NO:2;BCY8928);
其中每个所述肽配体包含多肽和分子支架,所述多肽包含被两个环序列隔开的三个反应性半胱氨酸基团(Ci、Cii和Ciii),并且所述分子支架是1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA),所述分子支架与所述多肽的反应性半胱氨酸基团形成共价键,使得在分子支架上形成两个多肽环;
其中Ac表示乙酰基,HArg表示高精氨酸,HyP表示反式-4-羟基-L-脯氨酸,1Nal表示1-萘丙氨酸,tBuAla表示叔丁基丙氨酸,PYA表示4-戊烯酸,Nle表示正亮氨酸。
本文中提及N-(酸-PEG3)-N-双(PEG3-叠氮化物)包括:
N-(酸-PEG3)-N-双(PEG3-叠氮化物)。
在一个实施方案中,所述异串联双环肽复合物是BCY11863:
BCY11863的完整细节示于下表A中:
表A:BCY11863的组成
在本文图1和表1中提供的数据显示,在CD137报告基因测定中,BCY11863显示强烈的CD137激活。此外,在本文图2和表2中提供的数据显示,BCY11863在多个肿瘤细胞系和人PBMC供体的PBMC共培养测定中诱导稳健的IL-2和IFN-γ细胞因子分泌。此外,在本文图3和表5中提供的数据显示,BCY11863表现出优异的PK特征,在SD大鼠中的终末半衰期为4.1小时,在食蟹猴中为5.3小时。图10和图11以及方法部分11和12中显示的数据证明了BCY11863对其靶标粘连蛋白-4和CD137的结合和精细的选择性。图4和图5显示了BCY11863在MC38#13同基因小鼠中显著的抗肿瘤活性,和BCY11863治疗后免疫原性记忆的形成。图6和图7显示了BCY11863在CT26#7同基因模型中的抗肿瘤活性,细胞毒性T细胞相应地浸润到肿瘤中。图12和图13清楚地显示,1.5mg/kg BIW和一周内在0、24h以5mg/kg给药产生了稳健的抗肿瘤活性,因此BCY11863不必维持可测量的血浆浓度。
本文提及了BCY11863的某些类似物(即修饰衍生物)和代谢物,其各自形成本发明的其他方面并总结于下表B中:
表B:BCY11863类似物和代谢物的组成
其中BCY14601表示具有序列Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A(SEQ ID NO:3)的双环肽配体,TATA作为分子支架;
和其中BCY13389表示具有序列[Ac]Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-K(SEQ ID NO:4)的双环肽配体,TATA作为分子支架。
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
当提及本发明的化合物内的氨基酸残基位置时,由于半胱氨酸残基(Ci、Cii和Ciii)不变而将其从编号中省略,因此,SEQ ID NO:1内氨基酸残基的编号参照如下:
Ci-P1-1Nal2-dD3-Cii-M4-HArg5-D6-W7-S8-T9-P10-HyP11-W12-Ciii(SEQ ID NO:1)。
为了该描述的目的,双环肽与1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA)环化并产生三取代的结构。与TATA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)。为避免疑义,除非另有说明,否则在本文中以其全名或以其氨基酸单字母或三字母代码提及氨基酸旨在表示L-氨基酸。如果这种氨基酸旨在表示D-氨基酸,则该氨基酸将在方括号内以小写d开头,例如[dA]、[dD]、[dE]、[dK]、[d1Nal]、[dNle]等。
肽配体的优点
本发明的某些异串联双环肽复合物具有许多有利的性质,其使它们被认为是适合注射、吸入、经鼻、经眼、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。异串联双环肽复合物应理想地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异串联双环肽先导候选物,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;
-选择性。本发明的某些异串联双环肽复合物表现出超过其他靶标的良好选择性;
-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异串联双环肽复合物;或者开发在循环中保留增强的异串联双环肽复合物,其因此对于管理更慢性的疾病状态是最佳的。驱使理想的血浆半衰期的其他因素是为了最大治疗效率而持续暴露的要求,相对于由于持续暴露于试剂而伴随的毒理。
至关重要的是,本文提供了数据,其中本发明的异串联双环肽复合物在以不维持血浆浓度高于该化合物的体外EC50的频率给药时,显示出抗肿瘤功效。这与CD137激动作用或双特异性CD137激动作用的更大的重组生物的(即基于抗体的)方法形成对比(Segal等人,Clin Cancer Res.,23(8):1929-1936(2017),Claus等人,Sci Trans Med.,11(496):eaav5989,1-12(2019),Hinner等人,Clin Cancer Res.,25(19):5878-5889(2019))。不受理论束缚,认为这种观察的原因归因于如下事实:异串联双环复合物具有相对低的分子量(通常<15kDa),它们是完全合成的,并且它们是CD137的肿瘤靶向激动剂。因此,它们具有相对短的血浆半衰期,但具有良好的肿瘤穿透率和保留。本文中提供的数据完全支持这些优势。例如,在具有人源化CD13的小鼠同基因啮齿动物模型中,每天或每3天均显示出抗肿瘤功效。此外,腹膜内药代动力学数据显示血浆半衰期<3小时,这将预示复合物的循环浓度将持续下降到在各剂量之间低于体外EC50。此外,肿瘤药代动力学数据表明,与血浆水平相比,肿瘤组织中异串联双环复合物的水平可能更高且更持久。
将理解的是,该观察形成了本发明的重要的进一步方面。因此,根据本发明的一个进一步的方面,提供了一种治疗癌症的方法,其包括施用如本文所定义的异串联双环肽复合物,其以不维持所述复合物的血浆浓度高于所述复合物的体外EC50的给药频率施用。
-免疫记忆。将结合癌细胞的双环肽配体与结合免疫细胞的双环肽配体偶联提供了免疫记忆的协同优势。本文中提供的数据表明,本发明的异串联双环肽复合物不仅根除肿瘤,而且在重新施用致瘤剂后,接种的完全应答者小鼠均不发生肿瘤(见图5)。这表明用选择的本发明的异串联双环肽复合物治疗已在完全应答者小鼠中诱导了免疫原性记忆。这具有显著的临床优势,以防止所述肿瘤在最初得到控制和根除后复发。
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反应性基团,其选自半胱氨酸、3-巯基丙酸和/或半胱胺,并且在所述支架上形成至少两个环。
药学上可接受的盐
应当理解,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,精装,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、半乳糖二酸、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。
一组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 +)。一些合适的被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 +。
当本发明的化合物含有胺官能团时,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。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,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,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,产生C-末端乙酰化的分子。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速率的疏水部分,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,Curr.Pharmaceutical Design(2010)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粘连蛋白-4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。
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.1994Dec 20;91(26):12544-8或Hikari等人,Bioorganic&Medicinal Chemistry Letters第18卷,第22期,2008年11月15日,6000-6003页)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TATA),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,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。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
根据本发明的另一方面,提供了用于预防、抑制或治疗癌症的如本文所定义的异串联双环肽复合物。
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,例如软组织肉瘤、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)和慢性骨髓性白血病(CML)。
本文提及的术语“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
通常,可以按照以下一般方法制备本发明的异串联双环肽复合物:
将所有溶剂脱气并用N2吹扫3次。将BP-23825(1.0eq)、HATU(1.2eq)和DIEA(2.0eq)的DMF溶液混合5分钟,然后加入双环1(1.2eq.)。在40℃搅拌反应混合物16小时。然后将反应混合物减压浓缩以除去溶剂,并通过制备型HPLC纯化以得到中间体2。
将中间体2(1.0eq)和双环2(2.0eq)的混合物溶解于t-BuOH/H2O(1:1)中,然后加入CuSO4(1.0eq)、VcNa(4.0eq)和THPTA(2.0eq)。最后,加入0.2M NH4HCO3以调节pH至8。在N2气氛下、在40℃搅拌反应混合物16小时。直接通过制备型HPLC纯化反应混合物。
下文提供了本发明的异串联双环肽复合物的更详细的实验:
实施例1:BCY11863的合成
制备BCY12476的程序
将N-(酸-PEG3)-N-双(PEG3-叠氮化物)(70.0mg,112.2μmol,1.0eq)、HATU(51.2mg,134.7μmol,1.2eq)和DIEA(29.0mg,224.4μmol,40μL,2.0eq)的混合物溶解于DMF(2mL)中,并混合5min。然后加入BCY8116(294.0mg,135.3μmol,1.2eq)。在40℃搅拌反应混合物16小时。LC-MS显示一个具有所需m/z的主峰。减压浓缩反应混合物以除去溶剂并产生残余物。然后通过制备型HPLC纯化残余物。获得白色固体状的BCY12476(194.5mg,66.02μmol,29%产率,94%纯度)。计算MW:2778.17,观测m/z:1389.3([M+2H]2+),926.7([M+3H]3+)。
制备BCY11863的程序
首先将BCY12476(100.0mg,36.0μmol,1.0eq)、BCY8928(160.0mg,72.0μmol,2.0eq)的混合物溶解于2mL t-BuOH/H2O(1:1)中,然后加入CuSO4(0.4M,180μL,1.0eq)和VcNa(28.5mg,143.8μmol,4.0eq)、THPTA(31.2mg,71.8μmol,2.0eq)。最后,加入0.2MNH4HCO3以调整pH至8。此处所有溶剂均脱气并用N2吹扫。在N2气氛下、在40℃搅拌反应混合物16小时。LC-MS显示保留了BCY8928,并检测到了所需m/z。直接通过制备型HPLC纯化反应混合物。第一次纯化得到BCY11863(117.7mg,15.22μmol,42.29%产率,93.29%纯度)的TFA盐,而纯度更低的部分通过制备型HPLC再次纯化,产生BCY11863(33.2mg,4.3μmol,12%产率,95%纯度)的TFA盐。计算MW:7213.32,观测m/z:1444.0([M+5H]5+)。
实施例2:BCY13390的合成
制备BCY13689的程序
将BCY12476(47.0mg,16.91μmol,1.0eq)、BCY8928(30.0mg,13.53μmol,0.8eq)和THPTA(36.7mg,84.55μmol,5.0eq)的混合物溶解于t-BuOH/H2O(1:1,8mL,预脱气并用N2吹扫)中,然后在N2下加入CuSO4(0.4M,21.0μL,0.5eq)和VcNa(67.0mg,338.21μmol,20.0eq)。通过滴加0.2M NH4HCO3(在1:1t-BuOH/H2O中)将该溶液的pH调节至8,溶液变为浅黄色。在N2气氛下、在25℃搅拌反应混合物1.5小时。LC-MS显示保留了一些BCY12476,BCY8928完全消耗,并检测到所需m/z的峰。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得白色固体状的BCY13689(25.3mg,4.56μmol,27%产率,90%纯度)。计算MW:4995.74,观测m/z:1249.4([M+4H]4+),999.9([M+5H]5+)。
制备BCY13390的程序
将BCY13689(43.6mg,8.73μmol,1.0eq)、BCY13389(20.8mg,9.16μmol,1.05eq)和THPTA(3.8mg,8.73μmol,1.0eq)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫)中,然后在N2下加入CuSO4(0.4M,22.0μL,1.0eq)和VcNa(3.5mg,17.45μmol,2.0eq)。通过滴加0.2M NH4HCO3(在1:1t-BuOH/H2O中)将该溶液的pH调节至8,溶液变为浅黄色。在N2气氛下、在25℃搅拌反应混合物2小时。LC-MS显示了对应于所需m/z的显著的峰。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得白色固体状的BCY13390(33.8mg,4.21μmol,48%产率,90%纯度)。计算MW:7270.41,观测m/z:1454.9([M+5H]5+),1213.2([M+6H]6+)。
实施例3:BCY13582的合成
制备BCY13582的程序
将BCY13390(5.0mg,0.6μmol,1.0eq)、生物素-PEG12-NHS酯(CAS 365441-71-0,0.7mg,0.72μmol,1.1eq)的混合物溶解于MeCN/H2O(1:1,2mL)中。通过滴加1.0M NaHCO3将该溶液的pH调节至8。在25℃搅拌反应混合物0.5小时。LC-MS显示BCY13390完全消耗,并检测到一个具有所需m/z的主峰。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得白色固体状的BCY13582(2.5mg,0.30μmol,43%产率,96%纯度)。计算MW:8096.43,观测m/z:1351.1([M+6H]6+),1158.5([M+7H]7+)。
实施例4:BCY13583的合成
制备BCY13583的程序
将BCY13390(15.0mg,2.06μmol,1.0eq)和Alexa488NHS酯(2.5mg,4.12μmol,2.0eq)的混合物溶解于DMF(0.5mL)中。然后滴加DIEA(2.6mg,20.63μmol,3.6μL,10eq)。在25℃搅拌反应混合物1小时。LC-MS显示保留了BCY13390,并检测到一个具有所需m/z的主峰。将另外的Alexa488NHS酯(2.0mg,3.09μmol,1.5eq)加入反应混合物中,在25℃搅拌反应混合物另外1小时。HPLC显示BCY13390完全消耗。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得红色固体状的BCY13583(5mg,0.61μmol,29%产率,95%纯度)。计算MW:7787.9,观测m/z:1948.8([M+4H+H2O]4+),1558.6([M+5H+H2O]5+),1299.1([M+7H+H2O]7+)。
实施例5:BCY13628的合成
制备BCY13628的程序
将BCY13390(5.6mg,0.77μmol,1.0eq)和青色素5NHS酯(0.5mg,0.85μmol,1.1eq)的混合物溶解于MeCN/H2O(1:1,2mL)中。通过滴加1.0M NaHCO3将该溶液的pH调节至8。在25℃搅拌反应混合物0.5小时。LC-MS显示BCY13390完全消耗并检测到一个具有所需m/z的主峰。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得蓝色固体状的BCY13628(2.9mg,0.36μmol,46%产率,95%纯度)。计算MW:7736.06,观测m/z:1289.9([M+6H]6+),1105.5([M+7H]7+)。
实施例6:BCY15155的合成
制备BCY15155的程序
将BCY13689(25.0mg,5.00μmol,1.0eq)、BCY14601(13.0mg,6.01μmol,1.2eq)和THPTA(2.0mg,5.00μmol,1.0eq)的混合物溶解于t-BuOH/0.2M NH4HCO3(1:1,0.5mL,预脱气并用N2吹扫)中,然后在N2下加入CuSO4(0.4M,12.5μL,1.0eq)和Vc(3.5mg,20.02μmol,4.0eq)。将该溶液的pH调节至8,溶液变为浅黄色。在N2气氛下、在25℃搅拌反应混合物2小时。LC-MS显示BCY13689完全消耗,保留了一些BCY14601,并检测到一个具有所需m/z的主峰。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得白色固体状的BCY15155(19.7mg,2.41μmol,36%产率,97%纯度)。计算MW:7171.3,观测m/z:1434.7([M+5H]5+),1196.2([M+6H]6+)。
实施例7:BCY14602的合成
制备BCY14602的程序
将BCY12476(100.0mg,36.00μmol,1.0eq)、BCY14601(158.0mg,72.63μmol,2.04eq)和THPTA(15.6mg,36.00μmol,1.0eq)的混合物溶解于t-BuOH/0.2M NH4HCO3(1:1,2mL,预脱气并用N2吹扫)中,然后在N2下加入CuSO4(0.4M,89.0μL,1.0eq)和VcNa(28.5mg,143.98μmol,4.0eq)。将该溶液的pH调节至8,溶液变为浅黄色。补充THPTA和VcNa两次,在N2气氛下、在25℃总共搅拌溶液48小时。LC-MS显示BCY12476完全消耗,保留了BCY14601,并检测到一个具有所需m/z的主峰。也检测到一些副产物。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC纯化粗产物,获得白色固体状的BCY14602(45.2mg,5.51μmol,15%产率,86%纯度)。计算MW:7129.2,观测m/z:1426.6([M+5H]5+),1189.1([M+6H]6+)。
分析数据
使用质谱和HPLC分析了以下的本发明的异串联双环肽复合物。HPLC设置如下:
流动相:A:H2O中的0.1%TFA B:ACN中的0.1%TFA
流速:1.0ml/min
柱:Gemini-NX C18 5um 110A 150*4.6mm
仪器:Agilent 1200HPLC-BE(1-614)
使用的梯度为20分钟内30-60%B,生成的数据如下:
复合物ID | 分析数据-质谱 | HPLC保留时间(min) |
BCY11863 | MW:7213.32,观测m/z:1444.0([M/5+H]+) | 10.649 |
生物数据
1.与肿瘤细胞共培养的CD137报告基因测定
通过将1%FBS加入RPMI-1640(Promega试剂盒CS196005的成分)中制备培养基,称为R1培养基。在无菌96孔板中制备测试物在R1中的系列稀释液。在白色细胞培养板的指定孔中加入25μL每孔的测试物或R1(作为背景对照)。收获肿瘤细胞*,并以400,000个细胞/mL的浓度重悬于R1培养基中。将25μL/孔的肿瘤细胞加入白色细胞培养板中。在水浴中解冻Jurkat细胞(Promega试剂盒CS196005,0.5mL),然后加入5ml预加温的R1培养基中。然后将25μL/孔的Jurkat细胞加入白色细胞培养板中。在37℃、5%CO2将细胞和测试物孵育6h。在6h结束时,加入75μL/孔的Bio-GloTM试剂(Promega)并孵育10min,然后在读板器(Clariostar,BMG)中读取发光值。计算相对于仅细胞(Jurkat细胞+共培养中使用的细胞系)的变化倍数,并在GraphPad Prism中绘制为log(激动剂)与响应的曲线,以确定EC50(nM)和相对于背景的诱导倍数(最大值)。
共培养中使用的肿瘤细胞类型是NCI-H292、CT26#7、MC38#13、HT1376、NCI-H322和T47D,已显示其表达粘连蛋白-4。
图1A中提供的数据显示,在CD137报告基因测定中,粘连蛋白-4/CD137异串联物(BCY11863)诱导强烈的CD137激活,并且所述激活依赖于所述异串联物与CD137的结合。BCY11617分子中CD137双环肽全部由D-氨基酸组成以消除结合,不诱导CD137激动作用。
下表1报告了在与表达粘连蛋白-4的肿瘤细胞系共培养的CD137报告基因测定中,由异串联双环肽复合物BCY11863和密切类似物诱导的EC50(nM)的总结,并在图1B中可视化。该数据证明了在与具有一系列粘连蛋白-4表达的细胞系共培养时BCY11863诱导CD137激动作用的潜力。
表1:在CD137报告基因测定中粘连蛋白-4/CD137异串联双环肽复合物诱导的相对于背景的诱导倍数的EC50(nM)
复合物ID | 肿瘤细胞系物种 | 共培养中使用的细胞系 | EC<sub>50</sub>算术平均值(nM) |
BCY11863 | 小鼠 | CT26#7 | 0.14±0.07 |
BCY11863 | 小鼠 | MC38#13 | 0.31±0.26 |
BCY11863 | 人 | NCI-H292 | 0.28±0.20 |
BCY11863 | 人 | HT1376 | 0.52±0.30 |
BCY11863 | 人 | NCI-H322 | 0.33±0.21 |
BCY11863 | 人 | T47D | 0.42±0.24 |
BCY11863 | 人 | MDA-MB-468 | 0.23±0.01 |
BCY13582 | 人 | HT1376 | 0.58±0.27 |
BCY13582 | 人 | MDA-MB-468 | 0.34±0.02 |
BCY13583 | 人 | HT1376 | 1.7±0.9 |
BCY13583 | 人 | MDA-MB-468 | 0.84±0.07 |
2.人PBMC共培养(细胞因子释放)测定
根据供应商的建议培养人和小鼠肿瘤细胞系。将来自健康人供体的冷冻PBMC解冻并在室温PBS中洗涤一次,然后重悬于R10培养基中。将100μl PBMC(1,000,000个PBMC/ml)和100μl肿瘤细胞(100,000个肿瘤细胞/ml)(效应细胞:靶细胞比例(E:T)10:1)铺于96孔平底板的每个孔中,用于共培养测定。在第0天将100ng/ml可溶性抗CD3 mAb(克隆OKT3)加入培养物中,以刺激人PBMC。在R10培养基中稀释测试、对照化合物或载体对照,并将50μL加入各个孔中,使每孔的最终体积达到250μL。用透气薄膜覆盖板并在37℃、5%CO2的加湿室中孵育三天。刺激后48小时收集上清液,用Luminex检测人IL-2和IFN-γ。简要地,将标准品和样品加入黑色96孔板中。加入微粒混合物(microparticle cocktail)(在Luminex试剂盒中提供,R&D Systems)并在室温震荡2小时。使用磁性支架,洗板3次。然后将生物素混合物加入板中并在RT震荡1小时。使用磁性支架,洗板3次。将链霉亲和素混合物加入板中并在RT震荡30分钟。使用磁性支架,洗板3次,重悬于100μL洗涤缓冲液中,在RT震荡2分钟,然后使用Luminex 2000读数。使用内置的Luminex软件分析原始数据以生成标准曲线并插入蛋白质浓度,所有其他数据分析和绘图均使用Excel和Prism软件进行。数据表示在一式三份技术重复中测试3-5个独立供体PBMC的研究。
图2A和图2B中提供的数据表明,粘连蛋白-4/CD137异串联物(BCY11863)在PBMC-4T1共培养测定中诱导稳健的IL-2和IFN-γ细胞因子分泌。BCY11617是结合粘连蛋白-4、但不结合CD137的阴性对照。
下表2报告了在人PBMC共培养(细胞因子释放)测定中,由选择的粘连蛋白-4/CD137异串联双环肽复合物诱导的EC50(nM)和最大IFN-γ细胞因子分泌(pg/ml)的总结,并在图2C中可视化。这证明了在许多表达粘连蛋白-4的不同肿瘤细胞系的存在下BCY11863诱导细胞因子分泌的潜力。
表2:人PBMC-4T1共培养(细胞因子释放)测定中选择的粘连蛋白-4/CD137异串联双环肽复合物诱导的IFN-γ细胞因子分泌的EC50
3.粘连蛋白-4/CD137异串联物BCY11863在SD大鼠中的药代动力学
通过IV推注、IV输注(15分钟)或皮下,将在25mM组氨酸HCl、10%蔗糖pH 7中配制的粘连蛋白-4/CD137异串联物BCY11863给药至雄性SD大鼠。在每个时间点通过下颌下静脉或隐静脉进行连续放血(约80μL血液/时间点)。立即将所有血样转移到预冷的含有2μL K2-EDTA(0.5M)作为抗凝剂的微量离心管中,并置于湿冰上。通过在大约4℃、3000g离心,将血样立即处理为血浆。立即将包含内标的沉淀剂加入血浆中,充分混合并在12,000rpm、4℃离心10分钟。将上清液转移到预先标记的聚丙烯微量离心管中,然后在干冰上快速冷冻。根据需要将样品储存在70℃或以下直至分析。使用Orbitrap Q Exactive在正离子模式下直接进样7.5μL上清液样品进行LC-MS/MS分析,以确定分析物的浓度。使用Phoenix WinNonlin6.3软件程序,通过非房室方法分析血浆浓度对时间的数据。报告了C0、Cl、Vdss、T1/2、AUC(0-末点)、AUC(0-无限)、MRT(0-末点)、MRT(0-无限)和血浆浓度对时间的曲线图。实验的药代动力学参数如表3所示:
表3:SD大鼠中的药代动力学参数
上表3和图5中的数据表明,BCY11863是低清除率分子,其分布体积大于血浆体积。此外,SC给药的BCY11863在大鼠中的生物利用度很高。
表4:通过IV施用100mg/kg剂量后BCY11863和潜在代谢物在SD大鼠PK研究中的药代动力学参数
表4和图14中的数据显示,在向SD大鼠IV施用BCY11863后,<1%的BCY11863被代谢为BCY15155。在研究的起初24小时内,没有注意到显著转换为BCY14602。
4.粘连蛋白-4/CD137异串联物BCY11863在食蟹猴中的药代动力学
通过静脉内输注(15或30min)到头静脉中,将在25mM组氨酸HCl、10%蔗糖pH 7中配制的1mg/kg粘连蛋白-4/CD137异串联物BCY11863给药至非幼稚食蟹猴。在每个时间点通过受约束的非镇静动物的外周血管进行连续放血(约1.2ml血液/时间点),将血液放入市售可获得的含有钾(K2)-EDTA*2H2O(0.85-1.15mg)的管中,置于湿冰上并处理以获得血浆。收集后立即将样品离心(3,000×g,在2至8℃离心10分钟)。将0.1mL血浆转移到标记的聚丙烯微量离心管中。立即将5倍的沉淀剂(包含内标100ng/mL拉贝洛尔和100ng/mL地塞米松和100ng/mL甲苯磺丁脲和100ng/mL维拉帕米和100ng/mL格列本脲和100ng/mL塞来昔布的MeOH溶液)加入血浆中,充分混合并在2至8℃、12,000rpm离心10分钟。将上清液样品转移到预先标记的聚丙烯微量离心管中,并在干冰上冷冻。样品储存在-60℃或以下直至LC-MS/MS分析。将40μL校准标准品、质量控制、单空白和双空白样品的等分试样加入1.5mL管中。分别用200μL IS1淬灭每个样品(双空白除外,双空白样品用200μL MeOH和0.5%tritonX-100淬灭),然后用涡旋器将混合物充分涡旋混合(至少15s)并在4℃、12000g离心15min。使用Orbitrap Q Exactive在正离子模式下进样10μL上清液进行LC-MS/MS分析,以确定分析物的浓度。使用Phoenix WinNonlin 6.3软件程序,通过非房室方法分析血浆浓度对时间的数据。报告了C0、Cl、Vdss、T1/2、AUC(0-末点)、AUC(0-无限)、MRT(0-末点)、MRT(0-无限)和血浆浓度对时间的曲线图。两种双特异性化合物的药代动力学参数如表5所示。
表5:食蟹猴中的药代动力学参数
图3显示了SD大鼠(n=3)中2mg/kg IV给药和食蟹猴(n=2)中1mg/kg IV输注BCY11863的血浆浓度对时间的曲线图。BCY11863在大鼠中具有的稳态分布体积(Vdss)为1.6L/kg,清除率为7.7mL/min/kg,导致终末半衰期为4.1h。BCY11863在食蟹猴中具有的稳态分布体积(Vdss)为0.62L/kg,清除率为3.3mL/min/kg,导致终末半衰期为5.3h。后续研究与这些结果一致。在食蟹猴中的IV研究的PK参数表明,它是低血浆清除率分子,其分布体积与总体水(total body water)相似。
5.粘连蛋白-4/CD137异串联物BCY11863在CD1小鼠中的药代动力学
通过腹膜内或IV施用,将在25mM组氨酸HCl、10%蔗糖pH 7中配制的15mg/kg粘连蛋白-4/CD137异串联物BCY11863给药至6只CD-1小鼠。在每个时间点通过下颌下静脉或隐静脉进行连续放血(约80μL血液/时间点)。立即将所有血样转移到预冷的含有2μL K2-EDTA(0.5M)作为抗凝剂的微量离心管中,并置于湿冰上。通过在大约4℃、3000g离心,将血样立即处理为血浆。立即将包含内标的沉淀剂加入血浆中,充分混合并在12,000rpm、4℃离心10分钟。将上清液转移到预先标记的聚丙烯微量离心管中,然后在干冰上快速冷冻。根据需要将样品储存在70℃或以下直至分析。使用Orbitrap Q Exactive在正离子模式下直接进样7.5μL上清液样品进行LC-MS/MS分析,以确定分析物的浓度。使用Phoenix WinNonlin 6.3软件程序,通过非房室方法分析血浆浓度对时间的数据。报告了C0、Cl、Vdss、T1/2、AUC(0-末点)、AUC(0-无限)、MRT(0-末点)、MRT(0-无限)和血浆浓度对时间的曲线图。
图9显示了在IP给药15mg/kg的CD1小鼠(n=3)中,BCY11863的血浆浓度对时间的曲线图和BCY11863的终末血浆半衰期。
表6:CD-1小鼠中的药代动力学参数
图9和上表6中的数据表明,BCY11863可以IV推注和IP给药至小鼠。IP给药的BCY11863在小鼠中的生物利用度很高。IV研究的PK参数表明,它是低清除率分子,其分布体积大于血浆体积。
6.BCY11863在同基因过表达粘连蛋白-4的MC38肿瘤模型(MC38#13)中的抗肿瘤活
性
在6-8周龄C57BL/6J-hCD137雌性小鼠的侧腹接种1×106个同基因过表达粘连蛋白-4的MC38细胞(MC38#13)。当肿瘤平均达到72mm3大小时,小鼠随机接受载体或BCY11863(腹膜内施用)。每天(QD)或每三天(Q3D)以1mg/kg或10mg/kg施用BCY11863(n=6只小鼠/治疗队列)。QD给药的小鼠接受了16剂BCY11863,Q3D给药的小鼠接受了10剂BCY11863。通过卡尺测量监测肿瘤生长,直至治疗开始后第69天。该实验的结果可以见图4,其中到第7天,在2个治疗队列中观察到肿瘤生长显著减少(p<0.05,双因素方差分析(2-way ANOVA),用Dunnett检验进行多重比较),到第14天所有治疗组与载体组显著不同。到第48天,24只BCY11863治疗的动物中有22只对治疗完全应答,并且没有残留可触及的肿瘤。
基于小鼠IP注射后BCY11863的循环血浆半衰期(2.5h),在BCY11863剂量(1和10mg/kg)和给药间隔(QD和Q3D)后血浆谷水平将接近于0,从而证明少于连续血浆暴露的BCY11863间歇给药足以导致显著的抗肿瘤活性,从而导致持久的完全应答。
7.BCY11863治疗在过表达粘连蛋白-4的MC38肿瘤模型中导致免疫原性记忆
在第69天,对BCY11863治疗完全应答的5只动物重新接种1×106个MC38#13细胞。一队列5只幼稚C57BL/6J-hCD137雌性小鼠接种1×106个MC38#13细胞作为对照。该实验的结果可以见图5,其中到接种后第13天,所有5只接种的幼稚C57BL/6J-hCD137雌性小鼠均长出肿瘤,而接种的完全应答小鼠均未发生肿瘤。这表明由于BCY11863治疗而获得完全抗肿瘤应答的动物已经发展出免疫原性记忆。
8.BCY11863在同基因过表达粘连蛋白-4的CT26肿瘤模型(CT26#7)中显示出抗肿
瘤活性
在6-8周龄BALB/c-hCD137雌性小鼠的侧腹接种3×105个同基因过表达粘连蛋白-4的CT26细胞(CT26#7)。当肿瘤平均达到约70mm3大小时,小鼠随机腹膜内每三天接受载体或5mg/kg BCY11863(共6剂)。通过卡尺测量监测肿瘤生长,直至治疗开始后第14天。该实验的结果可以见图6,其中自第7天起BCY11863治疗显著(p<0.0001,学生t检验)减少了肿瘤生长。
基于小鼠IP注射后BCY11863的循环血浆半衰期(2.5h),在整个给药期间血浆暴露将是非连续的,证明少于连续血浆暴露的BCY11863足以导致显著的抗肿瘤活性。
9.在最后一次(第6次)BCY11863的Q3D给药后1h,CT26#7肿瘤组织中T细胞总数和
CD8+T细胞增加
在最后一次载体或BCY11863给药后1小时,处死CD26#7荷瘤小鼠,收获并处理肿瘤以得到单细胞悬液,将其染色以进行流式细胞术分析,分析了T细胞总数(CD45+CD3+)、CD8+T细胞(CD45+CD3+CD8+)、CD4+T细胞(CD45+CD3+CD4+)和调节性T细胞(Treg;CD45+CD3+CD4+Foxp3+)。该实验的结果可以见图7,其中可以看出BCY11863治疗导致T细胞总数(p<0.0001,学生t检验)和CD8+T细胞(p<0.0001,学生t检验)显著增加,以及CD8+T细胞/Treg的比例显著增加(p<0.05,学生t检验)。
这表明在间歇给药后,BCY11863治疗可以导致T细胞在肿瘤组织中的局部水平增加。
10.单次静脉内(iv)施用5mg/kg BCY11863后,BCY11863在CT26#7同基因荷瘤动物
的血浆和肿瘤组织中的药代动力学特征
在6-8周龄BALB/c雌性小鼠的侧腹接种3×105个同基因过表达粘连蛋白-4的CT26细胞(CT26#7)。当肿瘤平均达到400mm3大小时,小鼠随机接受单次静脉给药载体或5mg/kgBCY11863。在0.25、0.5、1、2、4、8和24h时间点处死一个队列的小鼠(n=3/时间点),收获的血浆和肿瘤组织进行BCY11863分析。对于肿瘤BCY11863含量分析,通过用10体积(w:v)的匀浆溶液(MeOH/15mM PBS(1:2,v:v))匀浆肿瘤组织来制备肿瘤匀浆。用200μL IS1淬灭40μL样品,混合物在800rpm涡旋混合10min,在4℃、3220g离心15min。将上清液转移到另一个干净的96孔板中,在4℃、3220g离心5min,然后使用Orbitrap Q Exactive在正离子模式下进样10.0μL上清液进行LC-MS/MS分析,以确定分析物的浓度。对于血浆BCY11863含量分析,将血液样品收集于K2-EDTA管中,并立即通过在大约4℃、3000g离心处理为血浆。用200μL IS1淬灭40μL血浆样品,混合物在800rpm涡旋混合10min,在4℃、3220g离心15min。将上清液转移到另一个干净的96孔板中,在4℃、3220g离心5min,然后使用Orbitrap Q Exactive在正离子模式下进样10.0μL上清液进行LC-MS/MS分析,以确定分析物的浓度。
该实验的结果示于图8中,如BCY11863血浆T1/2(1.65h)和肿瘤T1/2(13.4h)的差异所表明的,可以看出在血浆BCY11863从循环中消除后,BCY11863在肿瘤组织中保留。
11.BCY11863结合四个临床前物种的粘连蛋白-4和CD137
使用表面等离子体共振(SPR)表征了BCY11863与其主要靶标粘连蛋白-4和CD137的结合。
(a)粘连蛋白-4
如通过直接结合已被生物素化并捕获到链霉亲和素传感器芯片表面上的胞外结构域所测量的,BCY11863与食蟹猴、大鼠、小鼠和人粘连蛋白-4结合,其KD在5-27nM之间。
表7:BCY11863与生物素化的粘连蛋白-4胞外结构域的结合亲和力:SPR数据
为了理解BCY11863与粘连蛋白-4的结合是否在三元复合物的情况下(即当也与CD137结合时)改变,开发了多组分SPR结合测定。首先用固定在SPR芯片表面的人CD137捕获BCY11863,然后使来自不同物种的粘连蛋白-4通过芯片,以确定它们与捕获的BCY11863的亲和力(见图10C)。与粘连蛋白-4的亲和力通常在CD137结合存在的情况下保持,如下所示:
表8:使用生物素化的人CD137作为捕获试剂时BCY11863与粘连蛋白-4胞外结构域的结合亲和力
(b)CD137
不能通过SPR准确测量BCY11863与表面结合的CD137的直接结合,因为BCY11863中的两个结合CD137的双环产生的亲合力导致极慢的koff(见图10B)。此外,食蟹猴CD137的生物素化消除了BCY11863的结合,这可能是由于修饰了食蟹猴蛋白上对于BCY11863结合很重要的赖氨酸。因此,在SPR中测试了含有C-末端生物素化赖氨酸的BCY11863类似物(BCY13582),以确定BCY11863的跨物种特异性。使用可逆的生物素捕获试剂盒将BCY13582捕获到传感器芯片上,并确定了对来自不同物种的粘连蛋白-4的亲和力。两种策略均显示这些BCY11863类似物与人和食蟹猴CD137结合,其KD<10nM,与小鼠和大鼠CD137的结合可忽略不计。
表9:生物素化BCY11863类似物与CD137胞外结构域的结合亲和力:SPR数据
为了理解BCY11863与CD137的结合是否在三元复合物的情况下(即当也与粘连蛋白-4结合时)改变,开发了双结合SPR结合测定。首先用固定在SPR芯片表面的人粘连蛋白-4捕获BCY11863,然后使来自不同物种的可溶性CD137通过芯片,以确定它们与捕获的BCY11863的亲和力(见图10D)。与CD137的亲和力通常在粘连蛋白-4结合存在的情况下保持,如下所示:
表10:使用生物素化的人粘连蛋白-4作为捕获试剂时BCY11863与CD137ECD的结合亲和力
图10A显示一个示例性传感图,表明BCY11863以4.1nM的亲和力与粘连蛋白-4(人)结合。图10B显示了BCY11863以高亲和力结合CD137(人)的传感图。由于BCY11863中存在2个CD137结合双环,从固定的CD137蛋白的解离速率非常慢,报告的KD可能被高估(图10B)。图10C显示了BCY11863与粘连蛋白-4结合,而CD137臂与固定在芯片上的CD137蛋白结合,以形成三元复合物。图10D显示了BCY11863与CD137结合,而粘连蛋白-4结合臂与固定在芯片上的粘连蛋白-4蛋白结合,以形成三元复合物。图10E表明了固定在SPR芯片上的BCY13582结合人CD137的能力。
12.BCY11863对粘连蛋白-4和CD137的选择性
粘连蛋白-4旁系同源物的筛选:使用SPR评价了BCY11863对粘连蛋白-1(2880-N1,R&D Systems)、粘连蛋白-2(2229-N2,R&D Systems)、粘连蛋白-3(3064-N3,R&D Systems)、粘连蛋白样(Nectin-like)-1(3678-S4-050,R&D Systems)、粘连蛋白样-2(3519-S4-050,R&D Systems)、粘连蛋白样-3(4290-S4-050,R&D Systems)、粘连蛋白样-4(4164-S4,R&DSystems)和粘连蛋白样-5(2530-CD-050,R&D Systems)的结合,通过用生物素标记这些蛋白和将其固定在链霉亲和素表面上进行。BCY11863在高达5000nM的浓度未表现出与这些靶标的任何结合。
CD137旁系同源物的筛选:使用SPR评价了链霉亲和素捕获的BCY13582(生物素化BCY11863)对可溶性TNF家族受体OX40和CD40的结合。BCY13582在高达100nM的浓度不与这些靶标结合。
Retrogenix微阵列筛选:细胞微阵列技术(Retrogenix)用于筛选生物素化BCY11863(称为BCY13582)的特异性脱靶结合相互作用。
研究了测试肽与固定的、未转染的HEK293细胞和过表达粘连蛋白-4和CD137(TNFRSF9)的细胞的结合水平,表明1μM测试肽是合适的筛选浓度。在这些条件下,筛选了测试肽对分别表达5484个全长人质膜蛋白和分泌蛋白的人HEK293细胞的结合。这揭示了9个主要命中(hit),包括粘连蛋白-4和CD137。
每个主要命中与两个对照受体(TGFBR2和EGFR)一起重新表达,并用以下重新测试:1μM BCY13582测试肽、在100μM BCY11863存在下的1μM BCY13582测试肽、和其他阳性和阴性对照处理(图4)。在去除非特异性的、不可重现的和非显著的命中后,测试肽仍然存在三种特异性相互作用。这些是主要靶标未栓系(untethered)和栓系(tethered)形式的粘连蛋白-4和CD137。
没有发现BCY13582的特异性脱靶相互作用,表明了对主要靶标的高度特异性。
13.在0、24h给药5mg/kg和在0h给药10mg/kg每周两次时,BCY11863在同基因过表
达粘连蛋白-4的MC38肿瘤模型(MC38#13)中的抗肿瘤活性
向6-8周龄雌性C57BL/6J-hCD137小鼠[B-hTNFRSF9(CD137)小鼠;Biocytogen]皮下移植1×106个MC38#13(工程化以过表达鼠粘连蛋白-4的MC38细胞)。当平均肿瘤体积达到约95mm3时,将小鼠随机分为治疗组(n=6/队列),并每周给药载体(25mM组氨酸,10%蔗糖,pH7)或10mg/kg BCY11863进行治疗,以两种不同的给药方案进行两个给药循环(在D0和D7的0h和24h时给药5mg/kg BCY11863,或在D0和D7的0h时给药10mg/kg BCY11863)。所有治疗均通过静脉内(IV)施用。从治疗开始到第15天监测肿瘤生长。
BCY11863在两种给药方案下均导致显著的抗肿瘤活性,但在治疗开始后第15天分析完全应答时,在0h和24h给药5mg/kg的给药方案优于在0h给药10mg/kg(图12)。在D0和D7的0h和24h时给药5mg/kg BCY11863导致6只中有4只完全肿瘤应答,而在D0和D7的0h时给药10mg/kg BCY11863导致6只中有1只完全肿瘤应答。这些数据连同BCY11863小鼠血浆PK数据表明,在MC38#13肿瘤模型中,将BCY11863血浆暴露量维持在每周循环中0h和24h给药5mg/kg所产生的水平,产生接近完全的抗肿瘤应答。
14.BCY11863在同基因过表达粘连蛋白-4的MC38肿瘤模型(MC38#13)中的抗肿瘤
活性
以3种周剂量3、10和30mg/kg剂量给药,剂量分为每周、每两周和每天给药,向6-8周龄雌性C57BL/6J-hCD137小鼠[B-hTNFRSF9(CD137)小鼠;Biocytogen]皮下移植1×106个MC38#13细胞(工程化以过表达鼠粘连蛋白-4的MC38细胞)。当平均肿瘤体积达到约107mm3时,将小鼠随机分为治疗组(n=6/队列)并用21个每日剂量的载体(25mM组氨酸,10%蔗糖,pH7)治疗。以三个不同的总剂量水平(3、10和30mg/kg总周剂量)分三个不同的方案(QD:每天;BIW:每周两次或QW:每周)进行BCY11863治疗。不同的BCY11863治疗队列接受21个每天剂量(0.43、1.4或4.3mg/kg)、6个每周两次的剂量(1.5、5或15mg/kg)或3个每周剂量(3、10或30mg/kg)。所有治疗均通过静脉内(IV)施用。监测肿瘤生长直至肿瘤达到超过2000mm3的体积,或直至治疗开始后31天。跟踪完全应答者(无可触及肿瘤的动物)直至D52。
BCY11863在许多给药方案中导致显著的抗肿瘤活性,BIW给药方案是最有效的方案,特别是5mg/kg BIW给药。通过第52天时完全应答者动物的数量证明了这一点。在治疗开始后第52天时,15/18只BCY11863 BIW治疗的小鼠是完全应答者,12/18只BCY11863 QD治疗的小鼠是完全应答者,6/18只BCY11863 QW治疗的小鼠是完全应答者。5mg/kg BIW给药导致100%的完全应答率,其中6/6只CR(图13)。这些数据连同BCY11863小鼠血浆PK数据表明,在MC38#13肿瘤模型中,对BCY11863的抗肿瘤应答不需要持续的BCY11863血浆暴露。
序列表
<110> 拜斯科技术开发有限公司
<120> 异串联双环肽复合物
<130> BIC-C-P2832PCT
<150> 62/880,191
<151> 2019-07-30
<150> 62/910,088
<151> 2019-10-03
<150> 62/931,442
<151> 2019-11-06
<150> 63/022,667
<151> 2020-05-11
<150> 63/024,715
<151> 2020-05-14
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HyP
<400> 1
Cys Pro Xaa Asp Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 2
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是D-Lys(PYA)
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 2
Cys Xaa Pro Glu Xaa Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Ala
1 5 10 15
<210> 3
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是D-Lys(PYA)
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 3
Cys Xaa Pro Glu Xaa Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Ala
1 5 10 15
<210> 4
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是D-Lys(PYA)
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 4
Cys Xaa Pro Glu Xaa Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Lys
1 5 10 15
Claims (6)
1.一种异串联双环肽复合物,其包含:
(a)结合粘连蛋白-4的第一肽配体,其具有序列CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii(SEQ ID NO:1;BCY8116);其通过N-(酸-PEG3)-N-双(PEG3-叠氮化物)接头与以下偶联
(b)结合CD137的两个第二肽配体,其均具有序列Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A(SEQ ID NO:2;BCY8928);
其中每个所述肽配体包含多肽和分子支架,所述多肽包含被两个环序列隔开的三个反应性半胱氨酸基团(Ci、Cii和Ciii),所述分子支架是1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA),并且所述分子支架与所述多肽的反应性半胱氨酸基团形成共价键,使得在分子支架上形成两个多肽环;
其中Ac表示乙酰基,HArg表示高精氨酸,HyP表示反式-4-羟基-L-脯氨酸,1Nal表示1-萘丙氨酸,tBuAla表示叔丁基丙氨酸,PYA表示4-戊烯酸,Nle表示正亮氨酸。
3.如权利要求1或2所定义的异串联双环肽复合物,其中所述药学上可接受的盐选自游离酸或钠、钾、钙、铵盐。
4.一种药物组合物,其包含权利要求1至3中任一项所述的异串联双环肽复合物,与一种或多种药学上可接受的赋形剂组合。
5.如权利要求1至3中任一项所定义的异串联双环肽复合物,其用于预防、抑制或治疗癌症。
6.一种治疗癌症的方法,其包括以不维持所述复合物的血浆浓度高于所述复合物的体外EC50的剂量频率施用如权利要求1至3中任一项所定义的异串联双环肽复合物。
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