CN114867753A - 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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- CN114867753A CN114867753A CN202080069454.8A CN202080069454A CN114867753A CN 114867753 A CN114867753 A CN 114867753A CN 202080069454 A CN202080069454 A CN 202080069454A CN 114867753 A CN114867753 A CN 114867753A
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- xaa
- cys
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- acid
- bicyclic peptide
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Abstract
本发明涉及异串联双环肽复合物,其包含结合存在于癌细胞上的成分的第一肽配体,所述第一肽配体通过接头与结合存在于免疫细胞上的成分的第二肽配体偶联。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,其包含结合存在于癌细胞上的成分的第一肽配体,所述第一肽配体通过接头与结合存在于免疫细胞上的成分的第二肽配体偶联。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(tether)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 2004/077062和WO 2006/078161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)第一肽配体,其结合存在于癌细胞上的成分;所述第一肽配体通过接头与以下偶联
(b)第二肽配体,其结合存在于免疫细胞上的成分;
其中,每个所述肽配体包含多肽和分子支架,所述多肽包含被至少两个环序列隔开的至少三个反应性基团,并且所述分子支架与所述多肽的反应性基团形成共价键,使得在分子支架上形成至少两个多肽环,其特征在于所述异串联双环肽复合物包含以下第一和第二肽配体:
其中1Nal表示1-萘丙氨酸,HArg表示高精氨酸,HyP表示羟脯氨酸,B-Ala表示β-丙氨酸,PYA表示4-戊烯酸,3,3-DPA表示3,3-二苯丙氨酸,Cba表示β-环丁基丙氨酸,hGlu表示高谷氨酸,Nle表示正亮氨酸,NMeAla表示N-甲基-丙氨酸,tBuAla表示叔丁基-丙氨酸,Aad表示α-L-氨基己二酸,Ac表示乙酰基,Dap表示二氨基丙酸,或其药学上可接受的盐。
根据本发明的进一步的方面,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。
根据本发明的进一步的方面,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。
具体实施方式
第一肽配体
本文提及的术语“癌细胞”包括已知参与癌症的任何细胞。当负责调节细胞分裂的基因受损时,产生癌细胞。致癌作用(carcinogenesis)是由正常细胞遗传物质的突变和表观突变引起的,其破坏增殖和细胞死亡之间的正常平衡。这导致不受控制的细胞分裂和这些细胞在体内通过自然选择的进化。细胞增殖不受控制且通常是快速的,可以导致良性或恶性肿瘤(癌症)。良性肿瘤不会扩散到身体的其他部位或侵入其他组织。恶性肿瘤可以侵入其他器官,扩散到远处(转移)并变得危及生命。
在一个实施方案中,癌细胞选自HT1080、A549、SC-OV-3、PC3、H1376、NCI-H292、LnCap、MC38、4T1-D02和RKO肿瘤细胞。
在一个实施方案中,存在于癌细胞上的成分是粘连蛋白-4(Nectin-4)。
粘连蛋白-4是表面分子,属于蛋白质的粘连蛋白家族,该家族由4个成员组成。粘连蛋白是细胞粘附分子,在发育和成年期间在上皮细胞、内皮细胞、免疫细胞和神经元细胞的各种生物过程如极性、增殖、分化和迁移中发挥关键作用。它们在人中参与多种病理过程。它们是脊髓灰质炎病毒、单纯疱疹病毒和麻疹病毒的主要受体。编码粘连蛋白-1(PVRL1)或粘连蛋白-4(PVRL4)的基因突变导致与其他异常相关的外胚层发育不良综合征。粘连蛋白-4在胎儿发育过程中表达。在成人组织中,它的表达比其他家庭成员的表达更受限制。粘连蛋白-4是肿瘤相关抗原,分别存在于50%、49%和86%的乳腺癌、卵巢癌和肺癌中,主要在预后不良的肿瘤中。在相应的正常组织中未检测到其表达。在乳腺肿瘤中,粘连蛋白-4主要在三阴性和ERBB2+癌中表达。在患有这些癌症的患者的血清中,检测到可溶形式的粘连蛋白-4与预后不良有关。血清粘连蛋白-4水平在转移性进展期间升高,治疗后降低。这些结果表明粘连蛋白-4可能是治疗癌症的可靠靶点。因此,在现有技术中已经描述了数种抗粘连蛋白-4抗体。特别地,Enfortumab Vedotin(ASG-22ME)是靶向粘连蛋白-4的抗体药物偶联物(ADC),目前正在临床研究用于治疗实体瘤患者。
在一个实施方案中,第一肽配体包含结合粘连蛋白-4的双环肽配体。
PCT专利申请号PCT/GB2019/051740中公开了结合粘连蛋白-4的双环肽配体的合适实例,其肽通过引用并入本文。
在一个实施方案中,结合粘连蛋白-4的双环肽选自本文所述的SEQ ID NO:52至66中的任一种肽。
在可选的实施方案中,存在于癌细胞上的成分是EphA2。
Eph受体酪氨酸激酶(Eph)属于一大类受体酪氨酸激酶(RTK),即磷酸化蛋白质的酪氨酸残基的激酶。Eph及其膜结合的肝配蛋白配体(ephrin)控制细胞定位和组织结构(Poliakov等人(2004)Dev Cell 7,465-80)。功能和生化Eph反应在较高的配体寡聚状态下发生(Stein等人(1998)Genes Dev 12,667-678)。
在其他模式化功能中,已表明各种Eph和肝配蛋白在血管发育中发挥作用。敲除EphB4和肝配蛋白-B2导致缺乏将毛细血管床重建为血管的能力(Poliakov等人,同上)和胚胎致死。在新形成的成人微血管中也观察到了一些Eph受体和肝配蛋白的持续表达(Brantley-Sieders等人(2004)Curr Pharm Des 10,3431-42;Adams(2003)J Anat 202,105-12)。
还观察到一些肝配蛋白及其受体在成人中的失调的重新出现有助于肿瘤侵袭、转移和新血管生成(Nakamoto等人(2002)Microsc Res Tech 59,58-67;Brantley-Sieders等人,同上)。此外,已发现一些Eph家族成员在来自各种人肿瘤的肿瘤细胞上过度表达(Brantley-Sieders等人,同上;Marme(2002)Ann Hematol 81Suppl 2,S66;Booth等人(2002)Nat Med 8,1360-1)。
EPH受体A2(A型肝配蛋白受体2)是在人中由EPHA2基因编码的蛋白质。
EphA2在人中的多种癌症中上调,经常与疾病进展、转移和预后不良相关,例如:乳腺癌(Zelinski等人(2001)Cancer Res.61,2301-2306;Zhuang等人(2010)Cancer Res.70,299-308;Brantley-Sieders等人(2011)PLoS One 6,e24426)、肺癌(Brannan等人(2009)Cancer Prev Res(Phila)2,1039-1049;Kinch等人(2003)Clin Cancer Res.9,613-618;Guo等人(2013)J Thorac Oncol.8,301-308)、胃癌(Nakamura等人(2005)Cancer Sci.96,42-47;Yuan等人(2009)Dig Dis Sci 54,2410-2417)、胰腺癌(Mudali等人(2006)Clin ExpMetastasis 23,357-365)、前列腺癌(Walker-Daniels等人(1999)Prostate 41,275-280)、肝癌(Yang等人(2009)Hepatol Res.39,1169-1177)和胶质母细胞瘤(Wykosky等人(2005)Mol Cancer Res.3,541-551;Li等人(2010)Tumour Biol.31,477-488)。
尽管有证据表明在包括肿瘤细胞生长、存活、侵袭和血管生成在内的癌症进展的多个阶段存在相互作用,但EphA2在癌症进展中的全部作用仍未确定。下调EphA2的表达抑制肿瘤癌细胞增殖(Binda等人(2012)Cancer Cell 22,765-780),而阻断EphA2抑制VEGF诱导的细胞迁移(Hess等人(2001)Cancer Res.61,3250-3255)、出芽和血管生成(Cheng等人(2002)Mol Cancer Res.1,2-11;Lin等人(2007)Cancer 109,332-40)和转移进展(Brantley-Sieders等人(2005)FASEB J.19,1884-1886)。
已显示与EphA2偶联的抗体药物在大鼠和小鼠异种移植模型中显著减少肿瘤生长(Jackson等人(2008)Cancer Research 68,9367-9374),并且已在人中尝试了类似的方法,尽管由于治疗相关的不良事件而必须停止治疗(Annunziata等人(2013)Invest New Drugs31,77-84)。
在一个实施方案中,第一肽配体包含结合EphA2的双环肽配体。
WO 2019/122860、WO 2019/122861和WO 2019/122863中公开了结合EphA2的双环肽配体的合适实例,其肽通过引用并入本文。
在一个实施方案中,结合EphA2的双环肽选自本文所述的SEQ ID NO:10至51中的任一种肽。
在一个可选的实施方案中,存在于癌细胞上的成分是PD-L1。
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的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的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的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的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2003Immunol.170:1257-66;Dong H等人2002Nat.Med.8:793-800;Hamanishi J等人2007Proc.Natl.Acad.Sci.USA 104:3360-65;Strome SE等人2003Cancer Res.63:6501-5;Inman BA等人2007Cancer 109:1499-505;Konishi J等人2004Clin.Cancer Res.10:5094-100;Nakanishi J等人2007Cancer Immunol.Immunother.56:1173-82;Nomi T等人2007Clin.Cancer Res.13:2151-57;Thompson RH等人2004Proc.Natl.Acad.Sci.USA 101:17174-79;Wu C等人2006Acta 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2003Immunol.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2007Proc.Natl.Acad.Sci.USA 104:3360-65;Inman BA等人2007Cancer 109:1499-505;Konishi J等人2004Clin.Cancer Res.10:5094-100;Nakanishi J等人2007Cancer Immunol.Immunother.56:1173-82;Nomi T等人(2007),Clin.Cancer Res.13:2151-57;Thompson RH等人(2004),Proc.Natl.Acad.Sci.USA101:17174-79;Wu C等人(2006),Acta Histochem.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中表达,但在正常浆细胞中不表达(Liu J等人2007Blood 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,2003Immunol.170:1257-66)。PD-1在血管免疫母细胞性淋巴瘤的T细胞中高表达,而PD-L1在相关联的滤泡树突状细胞网络中表达(Dorfman DM等人2006Am.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2007Int.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细胞激活和肿瘤细胞裂解,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2007Clin.Invest.117:2570-82)。
在一个实施方案中,第一肽配体包含结合PD-L1的双环肽配体。
英国专利申请号1905631.6和1904622.6中公开了结合PD-L1的双环肽配体的合适实例,其肽通过引用并入本文。
在一个实施方案中,结合PD-L1的双环肽选自本文所述的SEQ ID NO:1至9中的任一种肽。
在可选的实施方案中,存在于癌细胞上的成分是前列腺特异性膜抗原(PSMA)。
前列腺特异性膜抗原(PSMA)(也称为谷氨酸羧肽酶II(GCPII)、N-乙酰-L-天冬氨酰-L-谷氨酸肽酶I(NAALADase I)和NAAG肽酶)是在人中由FOLH1(叶酸水解酶1)基因编码的酶。人GCPII含有750个氨基酸,重约84kDa。
人PSMA在前列腺中高度表达,大约比大多数其他组织中高一百倍。在一些前列腺癌中,PSMA是上调程度第二的基因产物,比非癌前列腺细胞中的水平增加了8至12倍。由于这种高表达,PSMA正被开发为一些癌症治疗和成像的潜在生物标志物。在人前列腺癌中,较高表达的肿瘤与较快的进展时间和较高比例的复发患者相关。
在一个实施方案中,第一肽配体包含结合PSMA的双环肽配体。
英国专利申请号1820325.7和1912723.2和PCT专利申请号PCT/EP2019/066273中公开了结合PSMA的双环肽配体的合适实例,其肽通过引用并入本文。
第二肽配体
本文提及的术语“免疫细胞”包括免疫系统内的任何细胞。合适的例子包括白细胞,如淋巴细胞(例如T淋巴细胞或T细胞、B细胞或自然杀伤细胞)。在一个实施方案中,T细胞是CD8或CD4。在进一步的实施方案中,T细胞是CD8。免疫细胞的其他例子包括树突状细胞、滤泡树突细胞和粒细胞。
在一个实施方案中,存在于免疫细胞上的成分是CD137。
CD137是肿瘤坏死因子(TNF)受体家族的成员。它的可选名称是肿瘤坏死因子受体超家族成员9(TNFRSF9)、4-IBB和由淋巴细胞激活诱导的(induced by lymphocyteactivation,ILA)。CD137可以由激活的T细胞表达,但在CD8+上的表达程度要大于在CD4+T细胞上的表达。此外,在树突状细胞、滤泡树突细胞、自然杀伤细胞、粒细胞和炎症部位的血管壁细胞上发现了CD137表达。CD137的一项特征活性是其对激活的T细胞的共刺激活性。CD137的交联增强T细胞增殖、IL-2分泌、存活和细胞溶解活性。此外,它可以增强免疫活性以在小鼠中消除肿瘤。
CD137是TCR激活诱导的T细胞共刺激受体(Nam等人,Curr.Cancer Drug Targets,5:357-363(2005);Waits等人,Annu.Rev,Immunol.,23:23-68(2005))。除了在激活的CD4+和CD8+T细胞上表达之外,CD137还在CD4+CD25+调节性T细胞、自然杀伤(NK)和NK-T细胞、单核细胞、中性粒细胞和树突状细胞上表达。已在抗原呈递细胞(包括B细胞、单核细胞/巨噬细胞和树突状细胞)上描述了其天然配体CD137L(Watts等人Annu.Rev.Immunol,23:23-68(2005))。在与其配体相互作用时,CD137导致增加TCR诱导的T细胞增殖、细胞因子产生、功能成熟和延长CD8+T细胞的存活(Nam等人,Curr.Cancer Drug Targets,5:357-363(2005),Watts等人,Annu.Rev.Immunol,23:23-68(2005))。
通过CD137L或针对CD137的激动性单克隆抗体(mAb)通过CD137的信号传导,导致增加TCR诱导的T细胞增殖、细胞因子产生、功能成熟和延长CD8+T细胞的存活。这些影响是由于:(1)激活NF-κB、c-Jun NH2-末端激酶/应激活化蛋白激酶(JNK/SAPK)和p38丝裂原活化蛋白激酶(MAPK)信号传导通路,以及(2)控制抗凋亡和细胞周期相关基因的表达。
在CD137和CD137L缺陷小鼠中进行的实验另外证明了CD137共刺激在产生完全有能力的T细胞反应中的重要性。
IL-2和IL-15激活的NK细胞表达CD137,激动性mAb与CD137的连接刺激NK细胞增殖和IFN-γ分泌,但不刺激其溶细胞活性。
此外,CD137刺激的NK细胞在体外促进激活的T细胞的扩增。
根据其共刺激功能,已表明针对CD137的激动剂mAb促进对心脏和皮肤同种异体移植物的排斥,根除已形成的肿瘤,扩大原发性抗病毒CD8+T细胞反应,并增加T细胞的溶细胞潜能。这些研究支持CD137信号传导促进T细胞功能的观点,这可能增强对肿瘤和感染的免疫力。
在一个实施方案中,第二肽配体包含结合CD137的双环肽配体。
WO 2019/025811中公开了结合CD137的双环肽配体的合适实例,其肽通过引用并入本文。
在一个实施方案中,结合CD137的双环肽选自本文所述的SEQ ID NO:67至84中的任一种肽。
接头
将理解的是,第一肽配体可以通过任何合适的接头与第二肽配体偶联。通常,所述接头的设计将使得两个双环肽以这样的方式呈现,即它们可以不受阻碍地单独地与其各自的靶标结合,或者同时与两个靶受体结合。此外,接头应当允许同时结合两个靶标,同时保持靶细胞之间的适当距离,这将导致所需的功能结果。可以调节接头的特性以增加长度、刚性或溶解度以优化所需的功能结果。接头还可以设计成允许将多于一个双环连接至同一靶标。增加任一结合肽的化合价,可以用来增加异串联物(heterotandem)对靶细胞的亲和力,或可以有助于诱导靶受体之一或两者的寡聚化。
在一个实施方案中,接头选自以下序列:-PEG5-和TCA-[PEG10]3。
这些接头的结构表示详述如下:
-PEG5-;和
异串联复合物
在一个具体的实施方案中,第一肽配体包含连接至TATA支架的结合PD-L1的双环肽配体,第二肽配体包含连接至TATA支架的结合CD137的双环肽配体,并且所述异串联复合物选自表A中列出的复合物:
表A(PD-L1:CD137;1:1)
在一个实施方案中,异串联双环肽复合物选自:BCY12375和BCY12021。
在一个具体的实施方案中,第一肽配体包含连接至TATA支架的结合EphA2的双环肽配体,第二肽配体包含连接至TATA支架的结合CD137的双环肽配体,并且所述异串联复合物选自表B中列出的复合物:
表B(EphA2:CD137;1:1)
在一个实施方案中,异串联双环肽复合物选自:BCY13035、BCY13040、BCY13253、BCY13254、BCY13340和BCY13342。
在一个具体的实施方案中,第一肽配体包含连接至TATA支架的结合粘连蛋白-4的双环肽配体,第二肽配体包含连接至TATA支架的结合CD137的双环肽配体,并且所述异串联复合物选自表C中列出的复合物:
表C(粘连蛋白-4:CD137;1:1)
在一个实施方案中,异串联双环肽复合物选自:BCY11468、BCY11618、BCY11776、BCY11860、BCY12020、BCY12661和BCY12969。
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
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
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。
反应性基团
本发明的分子支架可以通过多肽上的官能团或反应性基团与多肽结合。其通常由多肽聚合物中存在的特定氨基酸的侧链形成。这样的反应性基团可以是半胱氨酸侧链、赖氨酸侧链或N-末端胺基或任何其他合适的反应性基团,如青霉胺。合适的反应性基团的具体信息可以见于WO 2009/098450中。
天然氨基酸的反应性基团的示例是半胱氨酸的硫醇基、赖氨酸的氨基、天冬氨酸或谷氨酸的羧基、精氨酸的胍基、酪氨酸的酚基或丝氨酸的羟基。非天然氨基酸可以提供范围广泛的反应性基团,包括叠氮化物、酮羰基、炔烃、乙烯基或芳基卤基团。多肽末端的氨基和羧基也可以用作反应性基团以形成与分子支架/分子核心的共价键。
本发明的多肽包含至少三个反应性基团。所述多肽还可以包含四个或更多个反应性基团。所用的反应性基团越多,在分子支架中可以形成越多的环。
在优选的实施方案中,生成具有三个反应性基团的多肽。所述多肽与具有三重旋转对称性的分子支架/分子核心的反应生成单一产物异构体。由于多种原因,单一产物异构体的生成是有利的。化合物文库的核酸仅编码多肽的一级序列,而不编码在多肽与分子核心反应后形成的分子的异构态。如果仅可以形成一种产物异构体,则清楚地定义了产物异构体的核酸排布。如果形成多种产物异构体,则核酸不能提供关于在筛选或选择过程中分离出的产物异构体的性质的信息。如果合成的是本发明文库的特定成员,则单一产物异构体的形成也是有利的。在本案例中,多肽与分子支架的化学反应产生单一产物异构体而不是异构体的混合物。
在另一个实施方案中,生成具有四个反应性基团的多肽。所述多肽与具有四面体对称性的分子支架/分子核心的反应生成两种产物异构体。尽管所述两种不同的产物异构体由同一核酸编码,也可以通过化学合成两种异构体、分离这两种异构体并测试这两种异构体与靶配体的结合来确定分离出的异构体的异构性质。
在本发明的一个实施方案中,所述多肽的反应性基团中的至少一个与其余的反应性基团正交。正交反应性基团的使用允许将所述正交反应性基团引导至分子核心的特定位点。涉及正交反应性基团的连接策略可用于限制形成的产物异构体的数量。换言之,通过为该至少三个键中的一个或多个选择反应性基团,所述反应性基团相对于为该至少三个键的其余部分所选择的那些是独特的或不同的,可以有效地实现特定的顺序,以该特定的顺序将所述多肽的特定反应性基团键合或定向至所述分子支架上的特定位置。
在另一个实施方案中,本发明的多肽的反应性基团与分子接头反应,其中所述接头能够与分子支架反应,使得接头将以最终的键合状态插入所述分子支架和所述多肽之间。
在一些实施方案中,多肽文库或组的成员的氨基酸可以被任何天然或非天然氨基酸替换。排除在这些可交换的氨基酸之外的是具有用于使多肽交联至分子核心的官能团的那些氨基酸,使得仅环序列是可交换的。所述可交换的多肽序列具有随机序列、恒定序列或具有随机和恒定氨基酸的序列。具有反应性基团的氨基酸位于多肽内的确定位置,因为这些氨基酸的位置决定了环的大小。
在一个实施方案中,具有三个反应性基团的多肽具有序列(X)lY(X)mY(X)nY(X)o,其中Y表示具有反应性基团的氨基酸,X表示随机氨基酸,m和n是3至6之间的数字,其定义了中间的多肽片段的长度,其可以相同或不同,l和o是0至20之间的数字,其定义了侧翼的多肽片段的长度。
替代硫醇介导的偶联的方法可以用于通过共价相互作用将分子支架连接到肽上。可选地,这些技术可以用于在根据本发明选择或分离后,将进一步的部分(如不同于分子支架的感兴趣的小分子)修饰或连接到多肽上——在本实施方案中,然后显然所述连接不必是共价的并可以包含非共价的连接。这些方法可以代替硫醇介导的方法(或与其组合),通过生产展示带有具有必需化学反应性基团的非天然氨基酸的蛋白质和肽的噬菌体,与带有互补反应性基团的小分子组合使用,或在选择/分离阶段之后制备分子时,通过将所述非天然氨基酸合并至化学或重组合成的多肽使用。进一步的具体信息可见于WO 2009/098450或Heinis等人,Nat Chem Biol 2009,5(7),502-7。
在一个实施方案中,反应性基团选自半胱氨酸、3-巯基丙酸和/或半胱胺残基。
药学上可接受的盐
将理解的是,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。通常地,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这样的盐。
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
将理解的是,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含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);添加间隔基团;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,修饰衍生物包含N-末端和/或C-末端修饰。在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。在进一步的实施方案中,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。
在进一步的实施方案中,修饰衍生物包含N-末端修饰。在进一步的实施方案中,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。
在可选的实施方案中,N-末端修饰包括添加分子间隔基团,其促进效应基团的偶联和保持双环肽对其靶标的效力。
在进一步的实施方案中,修饰衍生物包含C-末端修饰。在进一步的实施方案中,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,修饰衍生物包含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,修饰衍生物包含添加间隔基团。在进一步的实施方案中,修饰衍生物包含向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,修饰衍生物包含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。在进一步的实施方案中,修饰衍生物包含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,修饰衍生物包含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。在可选的实施方案中,修饰衍生物包含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,修饰衍生物包含用一个或多个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,修饰衍生物包含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,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存在和/或不存在粘连蛋白-4靶标。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。
分子支架
分子支架描述于例如WO 2009/098450和在其中引用的参考文献中,特别是WO2004/077062和WO 2006/078161。
如上述文档中所提及,分子支架可以是小分子,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,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,分子支架可以包含六氢-1,3,5-三嗪,尤其是1,3,5-三丙烯酰六氢-1,3,5-三嗪(“TATA”)或其衍生物,或由其组成。
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、含有αβ不饱和羰基的化合物和含有α-卤代甲基羰基的化合物。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。含有αβ不饱和羰基的化合物的示例是1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA)(Angewandte Chemie,International Edition(2014),53(6),1602-1606)。含有α-卤代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。
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 Volume 18,Issue 22,15November 2008,6000-6003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子基团。在一个实施方案中,以不阻断两个实体任一个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
根据本发明的进一步的方面,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、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:
将双环1(1.0eq.)和NHS-PEG5-N3(1.6eq.)的混合物溶解在MeCN/H2O(1:1)中,通过滴加NaHCO3(0.1M)将溶液的pH值调节至8。在30℃搅拌反应混合物2小时,然后减压浓缩以除去溶剂。然后通过制备型HPLC纯化残余物,得到中间体2。
将中间体2(1.0eq)和双环2(1.0eq)的混合物溶解于t-BuOH/H2O(1:1)中,然后加入CuSO4(1.0eq)、VcNa(2.3eq)和THPTA(1.0eq)。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:BCY12375的合成
制备棕榈酸--PEG10-N3的程序
将棕榈酸(100.0mg,282.89μmol,1.0eq.)、化合物2(150.0mg,284.84μmol,1.0eq.)和DIEA(74.5mg,574.11μmol,100.0μL,2.0eq.)的混合物溶解于DMF(2mL)中。在30℃搅拌反应混合物2小时。LC-MS显示化合物1完全消耗,并检测到一个具有所需m/z(MW:765.03,观测m/z:765.22)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(中性条件)纯化残余物。获得白色固体状的棕榈酸--PEG10-N3(79.0mg,99.41μmol,35.14%产率,96.27%纯度)。
制备棕榈酸-PEG10-BCY12023的程序
将化合物3(50.0mg,22.07μmol,1.0eq.)、化合物2(17.0mg,22.22μmol,1.0eq.)和THPTA(10.0mg,23.02μmol,1.0eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,56.0μL,1.0eq.)和VcNa(10.0mg,50.48μmol,2.3eq.)。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40℃搅拌反应混合物2小时。LC-MS显示棕榈酸--PEG10-N3完全消耗,并检测到一个具有所需m/z(计算MW:3030.60,观测m/z:1010.35([M/3+H]+))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(TFA条件)纯化粗产物,获得白色固体状的棕榈酸--PEG10-BCY12023(43.0mg,13.97μmol,63.30%产率,98.46%纯度)。
制备棕榈酸--PEG10-BCY12023-PEG5-N3的程序
将化合物5(43.0mg,14.19μmol,1.0eq.)、化合物6(10.0mg,23.13μmol,1.6eq.)的混合物溶解于MeCN/H2O(1:1,1mL)中,然后通过滴加NaHCO3(0.1M)将该溶液的pH调节至8。在30℃搅拌反应混合物2小时。LC-MS显示化合物5完全消耗,并检测到一个具有所需m/z(MW:3347.94,观测m/z:1673.7([(M/2+H+]),1115.9([(M/3+H+]))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(中性条件)纯化残余物。获得白色固体状的棕榈酸--PEG10-BCY12023-PEG5-N3(16.0mg,4.43μmol,31.25%产率,92.78%纯度)。
制备BCY12375的程序
将化合物7(8.0mg,2.39μmol,1.0eq.)、化合物8(6.5mg,2.39μmol,1.0eq.)和THPTA(1.1mg,2.53μmol,1.0eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,6.0μL,1.0eq.)和VcNa(1.0mg,5.05μmol,2.1eq.)。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40℃搅拌反应混合物16小时。LC-MS显示化合物7完全消耗,并检测到一个具有所需m/z(计算MW:6064.08,观测m/z:1516.4([M/4+H]+),1212.8([M/5+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY12375(6.2mg,0.99μmol,41.62%产率,97.27%纯度)。
实施例2:BCY12021的合成
制备棕榈酸--PEG10-BCY11144的程序
将化合物3(160.0mg,69.45μmol,1.0eq.)、化合物4(56.0mg,72.20μmol,1.0eq.)和THPTA(35.0mg,80.55μmol,1.1eq.)的混合物溶解于t-BuOH/H2O(1:1,2mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,56.0μL,1.0eq.)和VcNa(30.0mg,151.43μmol,2.2eq.)。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40℃搅拌反应混合物16小时。LC-MS显示检测到一个具有所需m/z(计算MW:3068.70,观测m/z:1533.81([M/2+H]+),1023.43([M/3+H]+))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(TFA条件)纯化粗产物,获得白色固体状的棕榈酸--PEG10-BCY11144(150.0mg,46.83μmol,67.42%产率,95.80%纯度)。
制备棕榈酸--PEG10-BCY11144-PEG5-N3的程序
将化合物5(47.0mg,15.32μmol,1.0eq.)、化合物6(7.0mg,16.19μmol,1.0eq.)和DIEA(3.0mg,22.97μmol,4.0μL,1.5eq.)的混合物溶解于DMF(1mL)中。在30℃搅拌反应混合物2小时。LC-MS显示化合物5完全消耗,并检测到一个具有所需m/z(MW:3386.03,观测m/z:1693.21([M/2+H]+),1129.13([M/3+H]+))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(中性条件)纯化残余物。获得白色固体状的棕榈酸--PEG10-BCY11144-PEG5-N3(20.0mg,5.72μmol,37.33%产率,96.79%纯度)。
制备BCY12021的程序
将化合物7(10.0mg,2.95μmol,1.0eq.)、化合物8(8.2mg,3.02μmol,1.0eq.)和THPTA(1.5mg,3.45μmol,1.1eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,8.0μL,1.0eq.)和VcNa(1.5mg,7.57μmol,2.5eq.)。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40℃搅拌反应混合物16小时。LC-MS显示具有所需m/z(计算MW:6102.17,观测m/z:1525.17([M/4+H]+),1221.3([M/5+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY12021(6.6mg,1.02μmol,34.62%产率,94.54%纯度)。
实施例3:BCY11468的合成
制备COM113的程序
将化合物1(50.0mg,124.4μmol,1.0eq),EDCI(95.4mg,497.7μmol,4.0eq)、HOBt(55.5mg,410.6μmol,3.3eq)和DMAP(15.2mg,124.4μmol,1.0eq)的混合物溶解于2mL DMF中,然后加入DIEA(134.9mg,1.04mmol,181.8μL,8.4eq)以生成均匀溶液。接着向该溶液中滴加溶解于DMF(2mL)中的化合物2(200.0mg,379.8μmol,3.05eq)。在30℃搅拌反应混合物16小时。LC-MS显示化合物1完全消耗,并检测到一个具有所需m/z(MW:1891.19,观测m/z:945.8600([M/2+H+])和612.4400([(M-3H2O)/3+H+]))的主峰。直接通过制备型HPLC(TFA条件)纯化反应混合物,得到冻干后为黄色油状的COM113(161mg,85.67μmol,68%产率)。
制备COM113-BCY8928的程序
首先将COM113(50.0mg,26.44μmol,1.0eq)和BCY8928(53.0mg,23.9μmol,0.9eq)溶解于2mL t-BuOH/H2O(1:1)中,然后加入CuSO4(0.4M,66.1μL,1.0eq)、VcNa(10.5mg,53.0μmol,2.0eq)和THPTA(23.0mg,52.93μmol,2.0eq)。最后加入1M NH4HCO3以调整pH至8。所有溶剂均脱气并用N2吹扫3次。在N2气氛下、在30℃搅拌反应混合物16小时。LC-MS显示一个具有所需m/z(计算MW:4108.77观测m/z:1369.97([M/3+H]+))的主峰。通过制备型HPLC(TFA条件)纯化反应混合物,获得白色固体状的化合物2(14.0mg,3.21μmol,12.14%产率,94.16%纯度)。
制备棕榈酸NHS酯的程序
向棕榈酸(500mg,1.95mmol,586.85μL,1.0eq)、1-羟基吡咯烷-2,5-二酮(250mg,2.17mmol,1.11eq)的DCM(5mL)溶液中加入EDCI(747.60mg,3.90mmol,2.0eq)。在30℃搅拌混合物16小时。TLC表明反应物1完全消耗,形成一个新斑点。根据TLC,反应是彻底的(clean)。过滤并减压浓缩反应混合物,以得到残余物。通过柱层析纯化残余物(SiO2,DCM:MeOH=0至100:1)。将所需产物干燥以获得白色固体状的棕榈酸NHS酯(0.68g,1.92mmol,98.65%产率)。
制备棕榈酸-炔丙基丙氨酸的程序
向化合物3(120mg,339.47μmol,1.0eq)和化合物4(57.60mg,509.20μmol,1.5eq)的DMF(6mL)溶液中加入DIEA(131.62mg,1.02mmol,177.39μL,3.0eq)和DMAP(41.47mg,339.47μmol,1.0eq)。在40℃搅拌混合物16小时。LC-MS显示反应物3完全消耗并检测到一个具有所需m/z或所需质量的主峰。过滤并减压浓缩反应混合物,以得到残余物。通过制备型HPLC(TFA条件)纯化残余物。获得白色固体状的棕榈酸-炔丙基丙氨酸(90mg,256.03μmol,75.42%产率)。
制备COM113-BCY8928-棕榈酸的程序
首先将化合物2(14.0mg,3.41μmol,1.0eq)和化合物3(1.1mg,3.13μmol,0.9eq)溶解于2mL t-BuOH/H2O(1:1)中,然后加入CuSO4(0.4M,10.0μL,1.0eq)、VcNa(2.0mg,10.1μmol,2.9eq)和THPTA(2.0mg,4.6μmol,1.3eq)。最后加入0.2M NH4HCO3以调整pH至8。此处所有溶剂均脱气并用N2吹扫3次。在N2气氛下、在35℃搅拌反应混合物16小时。LC-MS显示一个具有所需m/z(计算MW:4460.29,观测m/z:1486.92([M/3+H]+),1115.58([M/4+H]+),895.83([M/5+H]+))的主峰。通过制备型HPLC(TFA条件)纯化反应混合物,获得白色固体状的化合物4(5.9mg,1.28μmol,37.66%产率,97.0%纯度)。
制备BCY11468的程序
首先将化合物4(5.9mg,1.32μmol,1.0eq)和BCY11016(3.0mg,1.29μmol,1eq)溶解于2mL t-BuOH/H2O(1:1)中,然后加入CuSO4(0.4M,8.0μL,2.4eq)、VcNa(2.0mg,7.6eq)和THPTA(2.0mg,3.5eq)。最后加入1M NH4HCO3以调整pH至8。将所有溶剂脱气并用N2吹扫3次。在N2气氛下、在30℃搅拌反应混合物16小时。LC-MS显示一个具有所需m/z(计算MW:6783.93,观测m/z:1131.7([M/6+H]+))的主峰。通过制备型HPLC(TFA条件)纯化反应混合物,获得白色固体状的BCY11468(2.2mg,0.312μmol,23.57%产率,96.16%纯度)。
制备BCY8920-PEG5-N3的程序
将BCY8920(50.0mg,23.39μmol,1.0eq.)、化合物2(10.2mg,23.51μmol,1.01eq.)和NaHCO3(2.0mg,24.8μmol,1.0eq.)的混合物溶解于MeCN/H2O(1:1,2mL)中。在40℃搅拌反应混合物2小时,直至LC-MS显示BCY8920完全消耗,并检测到一个具有所需m/z(计算MW:2454.83,观测m/z:1227.67([M/2+H]+)和818.74([M/3+H]+))的主峰。然后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(TFA条件)纯化。获得白色固体状的BCY8920-PEG5-N3(25mg,9.70μmol,41.47%产率,95.26%纯度)。
制备BCY11143-dK(棕榈酸)的程序
将BCY11143(30.0mg,12.84μmol,1.0eq.)、化合物5(5.0mg,14.12μmol,1.1eq.)、DIEA(1.7mg,12.84μmol,2.2μL,1.0eq.)和DMAP(1.6mg,12.84μmol,1.0eq.)的混合物溶解于DMF中。在N2气氛下、在40℃搅拌反应混合物2小时。LC-MS显示检测到一个具有所需m/z(计算MW:2575.14,观测m/z:1287.68([M/2+H+]))的主峰。过滤并减压浓缩反应混合物,以得到残余物,然后通过制备型HPLC(TFA条件)纯化残余物。获得白色固体状的BCY11143-dK(棕榈酸)(18.3mg,6.95μmol,54.17%产率,97.86%纯度)。
制备BCY11618的程序
将化合物3(5mg,2.04μmol,1.0eq.)、化合物6(5.8mg,2.3μmol,1.1eq.)和THPTA(0.9mg,2.07μmol,1.0eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,5.1μL,1.0eq.)和VcNa(0.4M,5.1μL,1.0eq.)。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40℃搅拌反应混合物6小时。LC-MS显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:5029.97,观测m/z:1257.8([M/4+H]+)和1006.6([M/5+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY11618(5.3mg,1.0μmol,49.15%产率,95%纯度)。
制备BCY8116-Peg5-N3的程序
将BCY8116(50.0mg,23.39μmol,1.0eq.)、化合物2(10.2mg,23.51μmol,1.01eq.)和NaHCO3(2.0mg,24.8μmol,1.0eq.)的混合物溶解于MeCN/H2O(1:1,2mL)中。在25℃搅拌反应混合物1小时,直至LC-MS显示BCY8116完全消耗,并检测到一个具有所需m/z(计算MW:2454.83,观测m/z:1227.67([M/2+H+]),818.74([M/3+H+]))的主峰。然后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(TFA条件)纯化。获得白色固体状的化合物3(25.0mg,9.70μmol,41.47%产率,95.26%纯度)。
制备化合物BCY11144-dK(棕榈酸)的程序
将BCY11144(50.0mg,21.7μmol,1.0eq.)、化合物5(8.5mg,23.87μmol,1.1eq.)、DIEA(2.81mg,21.7μmol,4.0μL,1.0eq.)和DMAP(2.7mg,21.7μmol,1.0eq.)的混合物溶解于DMF中。在N2气氛下、在25℃搅拌反应混合物2小时。LC-MS显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:2542.08,观测m/z:1271.7([M/2+H+]))的主峰。过滤并减压浓缩反应混合物,以得到残余物,然后通过制备型HPLC(TFA条件)纯化残余物。获得白色固体状的化合物6(18.3mg,6.95μmol,54.17%产率,96.68%纯度)。
制备BCY11776的程序
将化合物3(10mg,4.0μmol,1.0eq.)、化合物6(11.2mg,4.4μmol,1.1eq.)和THPTA(1.8mg,1.0eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,5.1μL,1eq.)和VcNa(0.4M,5.1μL,1eq.)。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40℃搅拌反应混合物6小时。LC-MS显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:5031.9,观测m/z:1258.52([M/4+H+]),1006.7([M/5+H+]))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(TFA条件)纯化粗产物,获得白色固体状的BCY11776(12.5mg,2.4μmol,60.11%产率,96.6%纯度)。
制备BCY8920-Peg5-BCY11143的程序
将BCY8920-PEG5-N3(20.0mg,8.15μmol,1.0eq.)、化合物2(21.0mg,8.96μmol,1.1eq.)和THPTA(0.4M,21.0μL,1.0eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,21.0μL,1.0eq.)和VcNa(0.4M,21.0μL,1.0eq.)。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40℃搅拌反应混合物4小时。LC-MS显示化合物1完全消耗,并检测到一个具有所需m/z(计算MW:4791.56,观测m/z:1597.28([M/3+H]+),1198.18([M/4+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY8920-Peg5-BCY11143(22.5mg,4.25μmol,52.13%产率,90.44%纯度)。
制备BCY11860的程序
将化合物3(5.0mg,1.04μmol,1.0eq.)、化合物4(1.08mg,1.15μmol,1.1eq.)、DIEA(0.4M,1.04μmol,3.0μL,1.0eq.)和DMAP(0.2mg,1.04μmol,1.0eq.)溶解于DMF(1.0mL)中。在30℃搅拌反应混合物2小时。LC-MS显示化合物3完全消耗,并检测到一个具有所需m/z(MW:5617.56,观测m/z:1404.56([(M/4+H+]))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(中性条件)纯化残余物。获得白色固体状的BCY11860(2.9mg,0.48μmol,45.86%产率,92.70%纯度)。
制备棕榈酸-PEG10-N3的程序
将棕榈酸-NHS(100.0mg,282.89μmol,1.0eq.)、化合物2(150.0mg,284.84μmol,1.0eq.)和DIEA(74.5mg,574.11μmol,100.0μL,2.0eq.)的混合物溶解于DMF(2mL)中。在30℃搅拌反应混合物2小时。LC-MS显示化合物1完全消耗,并检测到一个具有所需m/z(MW:765.03,观测m/z:765.22)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(中性条件)纯化残余物。获得白色固体状的棕榈酸-PEG10-N3(79.0mg,99.41μmol,35.14%产率,96.27%纯度)。
制备棕榈酸-PEG10-BCY11144的程序
将化合物3(160.0mg,69.45μmol,1.0eq.)、化合物2(56.0mg,72.20μmol,1.0eq.)和THPTA(35.0mg,80.55μmol,1.1eq.)的混合物溶解于t-BuOH/H2O(1:1,2mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,56.0μL,1.0eq.)和VcNa(30.0mg,151.43μmol,2.2eq.)。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40℃搅拌反应混合物16小时。LC-MS显示一个具有所需m/z(计算MW:3068.70,观测m/z:1533.81([M/2+H]+),1023.43([M/3+H]+))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(TFA条件)纯化粗产物,获得白色固体状的棕榈酸-PEG10-BCY11144(150.0mg,46.83μmol,67.42%产率,95.80%纯度)。
制备棕榈酸-PEG10-BCY11144-PEG5-N3的程序
将化合物5(47.0mg,15.32μmol,1.0eq.)、化合物6(7.0mg,16.19μmol,1.1eq.)和DIEA(3.0mg,22.97μmol,4.0μL,1.5eq.)的混合物溶解于DMF(1mL)中。在30℃搅拌反应混合物2小时。LC-MS显示化合物5完全消耗,并检测到一个具有所需m/z(MW:3386.03,观测m/z:1693.21([M/2+H]+),1129.13([M/3+H]+))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(中性条件)纯化残余物。获得白色固体状的棕榈酸-PEG10-BCY11144-PEG5-N3(20.0mg,5.72μmol,37.33%产率,96.79%纯度)。
制备BCY12020的程序
将化合物7(50.0mg,14.77μmol,1.0eq.)、化合物8(35.0mg,15.06μmol,1.0eq.)和THPTA(10.0mg,23.02μmol,1.5eq.)的混合物溶解于t-BuOH/H2O(1:1,2mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,38.0μL,1.0eq.)和VcNa(6.5mg,32.81μmol,2.2eq.)。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40℃搅拌反应混合物16小时。LC-MS显示一个具有所需m/z(计算MW:5709.68,观测m/z:1902.80([M/3+H]+),1427.56([M/4+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY12020(54.8mg,9.49μmol,64.24%产率,98.83%纯度)。
制备化合物2的程序
使用标准Fmoc化学合成肽。将DCM加入含有氯三苯甲基树脂(chlorotritylresin,1mmol,0.91g,1.10mmol/g)和Fmoc-Lys(N3)-OH(1eq,395.4mg,1mmol)并N2鼓泡的反应容器中。滴加DIEA(4.0eq)并混合2小时。然后加入MeOH(2mL)并混合30分钟。将树脂排干并用DMF洗涤5次。通过加入20%哌啶/DMF并混合30分钟进行Fmoc去保护。将树脂排干并用DMF洗涤5次。对于链延长,首先加入Fmoc-氨基酸溶液并混合30秒,然后加入激活缓冲液(DMF中含有HBTU和DIEA)并在连续N2鼓泡下搅拌1小时。重复去保护和偶联,直到肽完成。
# | 材料 | 偶联试剂 |
1 | Fmoc-Lys(N3)-OH(1eq) | DIEA(4.0eq) |
2 | Fmoc-γGlu(OtBu)-OH(3eq) | HBTU(2.85eq)和DIEA(6.0eq) |
3 | 棕榈酸(3eq) | HBTU(2.85eq)和DIEA(6.0eq) |
最后一次氨基酸偶联后,用MeOH洗涤树脂3次,然后真空干燥。在室温将10ml裂解混合物(95%TFA/2.5%TIS/2.5%H2O)加入含有侧链受保护的肽的烧瓶中,并搅拌1小时。过滤树脂并浓缩滤液以除去溶剂。将粗肽冻干得到最终产物化合物2(棕榈酸叠氮化物)(200mg,97.78%纯度,37.06%产率)。计算MW:539.72,观测m/z:540.4([M+H]+)。
将化合物3(35.0mg,12.48μmol,1.0eq.)、化合物4(5.4mg,12.48μmol,1.0eq.)的混合物溶解于MeCN/H2O(1:1,1mL)中,然后通过滴加NaHCO3(0.1M)将该溶液的pH值调节至8。在30℃搅拌反应混合物2小时。LC-MS显示化合物3完全消耗,并检测到一个具有所需m/z(MW:3121.63,观测m/z:1561.2([(M/2+H+]))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(中性条件)纯化残余物。获得白色固体状的BCY12023-棕榈酸-PEG5-N3(11.4mg,3.46μmol,27.71%产率,94.70%纯度)。
制备BCY12661的程序
将化合物5(11.4mg,3.65μmol,1.0eq.)、化合物6(8.3mg,3.65μmol,1.0eq.)和THPTA(1.6mg,3.65μmol,1.0eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,10.0μL,1.1eq.)和VcNa(1.5mg,7.30μmol,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40℃搅拌反应混合物4小时。LC-MS显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:5374.21,观测m/z:1344.5([M/4+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY12661(9.8mg,19.63μmol,48.73%产率,97.60%纯度)。
制备化合物1的一般程序
使用标准Fmoc化学合成肽。将DCM加入含有氯三苯甲基树脂(1mmol,0.91g,1.1mmol/g)和Fmoc-γGlu(OtBu)-OH(0.425mg,1mmol,1eq)的反应容器中,并用N2鼓泡搅拌混合物。滴加DIEA(4.0eq)并搅拌混合物2小时。然后加入MeOH(4.6mL)并混合30分钟。将树脂排干并用DMF洗涤5次。将20%哌啶/DMF加入树脂中并混合30分钟。将树脂排干并用DMF洗涤5次。将Fmoc-氨基酸溶液加入树脂中并混合30秒,然后加入激活剂和DIPEA,并在混合物中N2鼓泡1小时。用以下试剂重复脱保护和偶联步骤:
注:
# | 材料 | 偶联试剂 |
1 | Fmoc-Glu-OtBu(1eq) | DIEA(4.0eq) |
2 | Fmoc-Glu-OtBu(3eq) | HBTU(2.85eq)和DIEA(6.0eq) |
3 | 棕榈酸(3eq) | HBTU(2.85eq)和DIEA(6.0eq) |
在棕榈酸偶联后,用MeOH洗涤树脂3次,然后在真空下干燥。通过在室温加入20%HFIP/80%DCM将肽从树脂上裂解下来,并搅拌混合物1小时。将该程序再重复一次,然后过滤树脂并浓缩滤液以除去溶剂。将粗肽冻干得到最终产物(280mg,84.80%纯度,44.67%产率)。计算MW:626.8,观测m/z:627.4([M+H]+)
制备BCY12860-PEG5-N3的程序
将BCY12860(40.0mg,19.40μmol,1.0eq.)、化合物2(10.0mg,21.34μmol,1.1eq.)的混合物溶解于MeCN/H2O(1:1,1mL)中,然后通过滴加NaHCO3(0.1M)将该溶液的pH值调节至8。在25℃搅拌反应混合物1小时。LC-MS显示一个具有所需m/z的峰。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(中性条件)纯化残余物。获得白色固体状的BCY12860-PEG5-N3(39.7mg,15.02μmol,77.41%产率,90.0%纯度)。MW:2378.78,观测m/z:1190.1([(M/2+H+]),793.5([(M/3+H+])。
制备BCY13035的程序
将化合物3(39.7mg,16.69μmol,1.0eq.)、BCY8928(41.0mg,18.36μmol,1.1eq.)和THPTA(0.4M,55μL,1.3eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,55μL,1.3eq.)和VcNa(0.4M,109μL,2.6eq.)。通过滴加0.2MNH4HCO3(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40℃搅拌反应混合物2小时。LC-MS显示化合物3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(TFA条件)纯化粗产物,获得白色固体状的BCY13035(42.0mg,8.85μmol,53.04%产率,96.41%纯度)。计算MW:4596.37,观测m/z:1532.9([M/3+H]+),1149.9([M/4+H]+)。
实施例11:BCY13040的合成
制备BCY12865-PEG5-N3的程序
将BCY12865(30.0mg,13.99μmol,1.0eq)和化合物1(6.1mg,14.11μmol,1.01eq)溶解于1mL MeCN/H2O(1:1)中,然后加入1M NaHCO3以将pH调节至8。在25℃搅拌混合物2小时。LC-MS显示BCY12865完全消耗并检测到一个具有所需m/z的主峰。通过制备型HPLC(TFA条件)纯化反应混合物,获得白色固体状的化合物2(15.6mg,6.32μmol,45.19%产率,99.76%纯度)。计算MW:2461.87,观测m/z:1231.5([M/2+H]+)和821.3([M/3+H]+)。
制备BCY13040的程序
首先将化合物2(15.6mg,6.34μmol,1.0eq)和BCY8928(14.5mg,6.54μmol,1.03eq)溶解于2mL t-BuOH/H2O(1:1)中,然后加入CuSO4(0.4M,16μL,1.01eq)、VcNa(3.0mg,15.14μmol,2.39eq)和THPTA(3mg,6.90μmol,1.09eq)。最后加入1M NH4HCO3以调整pH至8。所有溶剂脱气并用N2吹扫3次。在N2气氛下、在40℃搅拌反应混合物16小时。LC-MS显示化合物2完全消耗并检测到一个具有所需m/z的主峰。通过制备型HPLC(TFA条件)纯化反应混合物,获得白色固体状的BCY13040(15.8mg,3.31μmol,52.27%产率,98.1%纯度)。计算MW:4679.45,观测m/z:1560.8([M/3+H]+),1170.9([M/4+H]+),936.6([M/5+H]+)。
制备BCY13253的程序
将化合物3(25.7mg,10.92μmol,1.0eq.)、化合物2(26.6mg,12.02μmol,1.1eq.)和THPTA(5.7mg,13.11μmol,1.2eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,33.0μL,1.2eq.)和VcNa(5.2mg,26.21μmol,2.4eq.)。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显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:4570.32,观测m/z:1143.4([M/4+H]+),914.9([M/5+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY13253(17.5mg,3.67μmol,33.58%产率,95.8%纯度)。
制备BCY13120-PEG5-N3的程序
将BCY13120(40.0mg,17.92μmol,1.0eq.)、化合物2(8.5mg,19.72μmol,1.1eq.)的混合物溶解于MeCN/H2O(1:1,1mL)中,然后通过滴加NaHCO3(0.1M)将该溶液的pH值调节至8。在25℃搅拌反应混合物1小时。LC-MS显示BCY13120完全消耗,并检测到一个具有所需m/z(计算MW:2548.99,观测m/z:1275.3([(M/2+H+]))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(中性条件)纯化残余物。获得白色固体状的BCY13120-PEG5-N3(27.3mg,10.46μmol,58.38%产率,97.7%纯度)。
制备BCY13254的程序
将化合物3(27.3mg,10.71μmol,1.0eq.)、化合物2(26.1mg,11.78μmol,1.1eq.)和THPTA(5.6mg,12.85μmol,1.2eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中。在N2下加入CuSO4(0.4M,33.0μL,1.2eq.)和VcNa(5.2mg,26.24μmol,2.4eq.)。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显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:4766.58,观测m/z:1192.5([M/4+H]+),954.1([M/5+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY13254(36.5mg,7.49μmol,69.92%产率,97.8%纯度)。
制备BCY12865-PEG5-N3的程序
将BCY12865(50mg,23.32μmol,1.0eq)和化合物1(10.5mg,24.28μmol,1.04eq)溶解于2mL MeCN/H2O(1:1)中,加入1M NaHCO3以将pH调节至8。然后在25℃搅拌混合物2小时。LC-MS显示BCY12865完全消耗,并检测到一个具有所需m/z(计算MW:2461.87,观测m/z:1231.6([M/2+H]+)和821.4([M/3+H]+))的主峰。通过制备型HPLC(TFA条件)纯化反应混合物,获得白色固体状的化合物2(31.5mg,12.62μmol,54.14%产率,98.66%纯度)。
制备BCY13340的程序
将化合物2(31.5mg,12.80μmol,1.0eq.)、BCY12353(27mg,12.92μmol,1.0eq)和THPTA(5.7mg,13.12μmol,1.0eq)的混合物溶解于t-BuOH/H2O(1:1,2mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,32μL,1.0eq)和VcNa(5.1mg,25.74μmol,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40℃搅拌反应混合物1小时。LC-MS显示化合物2完全消耗,并检测到一个具有所需m/z(计算MW:4551.32,观测m/z:1517.7([M/3+H]+)和1138.6([M/4+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY13340(34.7mg,7.62μmol,59.59%产率,89.59%纯度)。
制备BCY12860-PEG5-N3的程序
将BCY12860(28.0mg,13.58μmol,1.0eq.)和化合物2(6.5mg,14.94μmol,1.1eq.)的混合物溶解于MeCN/H2O(1:1,1mL)中,然后通过滴加NaHCO3(0.1M)将该溶液的pH值调节至8。在25℃搅拌反应混合物1小时。LC-MS显示BCY12860完全消耗,并检测到一个具有所需m/z(计算MW:2378.78,观测m/z:1190.2([(M/2+H+]))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(中性条件)纯化残余物。获得白色固体状的BCY12860-PEG5-N3(20.7mg,8.41μmol,61.95%产率,96.7%纯度)。
制备BCY13342的程序
将化合物3(20.7mg,8.70μmol,1.0eq.)、化合物4(19.0mg,9.14μmol,1.05eq.)和THPTA(5.0mg,11.31μmol,1.3eq.)的混合物溶解于t-BuOH/H2O(1:1,1mL,预脱气并用N2吹扫3次)中,然后在N2下加入CuSO4(0.4M,28.3μL,1.3eq.)和VcNa(4.5mg,22.62μmol,2.6eq.)。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显示化合物3完全消耗,并检测到一个具有所需m/z(计算MW:4468.24,观测m/z:1118.6([M/4+H]+))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(TFA条件)纯化粗产物,获得白色固体状的BCY13342(21.7mg,4.60μmol,52.85%产率,94.7%纯度)。
分析数据
使用质谱和HPLC分析了本发明的以下异串联双环肽复合物。HPLC设置如下:
流动相:A:0.1%TFA的H2O溶液B:0.1%TFA的ACN溶液
流速:1.0ml/min
柱:Gemini-NX C18 5um 110A 150*4.6mm
仪器:Agilent 1200HPLC-BE(1-614)
使用的梯度描述于下表中:
数据生成如下:
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孵育细胞和测试物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,已显示其表达粘连蛋白-4。对于EphA2,用于共培养的肿瘤细胞类型是PC-3。对于PD-L1,用于共培养的肿瘤细胞类型是RKO。
下表1显示了在与NCI-H292细胞的CD137报告基因共培养测定中,由粘连蛋白-4/CD137异串联肽诱导的诱导倍数的总结。所有化合物均与板对照BCY10000进行比较,其平均EC50为1.1±0.5nM,Emax相对于背景为28±11倍。
表1:粘连蛋白-4/CD137异串联双环肽复合物在CD137报告基因测定中诱导的诱导倍数
表2显示了在与PC3细胞的CD137报告基因共培养测定中,由EphA2/CD137异串联肽诱导的诱导倍数的总结。所有化合物均与板对照BCY9173进行比较,其平均EC50为0.54nM,Emax相对于背景为42倍。
表2:EphA2/CD137异串联双环肽复合物在CD137报告基因测定中诱导的诱导倍数
表3显示了在与RKO细胞的CD137报告基因共培养测定中,由PD-L1/CD137异串联肽诱导的诱导倍数的总结。
表3:PD-L1/CD137异串联双环肽复合物在CD137报告基因测定中诱导的诱导倍数
双环ID | EC50(nM) | 相对于背景的诱导倍数 |
BCY12229 | 18 | 8 |
BCY12230 | 46 | 10 |
BCY12242 | 20 | 13 |
BCY12375 | 22 | 3 |
2.CD137异串联双环肽复合物在SD大鼠中的药代动力学
向雄性SD大鼠给药2mg/kg的每种异串联双环肽复合物,该复合物配制于25mM组氨酸HCl、10%蔗糖pH 7中。在每个时间点,通过下颌下静脉或大隐静脉进行系列采血(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,以确定双环的浓度。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。实验的药代动力学参数如表4所示:
表4:SD大鼠中的药代动力学参数
化合物 | 给药途径 | 剂量(mg/kg) | T1/2(h) | Vdss(L/kg) | Clp(ml/min/kg) |
BCY12234 | IV输注 | 2.0 | 0.42 | 0.95 | 26 |
BCY13035 | IV输注 | 3.0 | 1.5 | 0.63 | 11 |
BCY13040 | IV输注 | 3.0 | 1.6 | 0.63 | 10 |
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-P2650PCT
<150> US 62/910,129
<151> 2019-10-03
<160> 84
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<400> 1
Asp Xaa Cys Ser Ala Gly Trp Leu Thr Met Cys Gln Lys Leu His Leu
1 5 10 15
Cys Pro Ser His
20
<210> 2
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<400> 2
Asp Xaa Cys Ser Lys Gly Trp Leu Thr Met Cys Gln Lys Leu His Leu
1 5 10 15
Cys Pro Ser His
20
<210> 3
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<400> 3
Asp Xaa Cys Ser Ala Gly Trp Leu Thr Lys Cys Gln Lys Leu His Leu
1 5 10 15
Cys Pro Ser His
20
<210> 4
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<400> 4
Asp Xaa Cys Ser Ala Gly Trp Leu Thr Met Cys Lys Lys Leu His Leu
1 5 10 15
Cys Pro Ser His
20
<210> 5
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<400> 5
Asp Xaa Cys Ser Ala Gly Trp Leu Thr Met Cys Gln Lys Leu Lys Leu
1 5 10 15
Cys Pro Ser His
20
<210> 6
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 6
Ser Asp Lys Cys Ser Ala Gly Trp Leu Thr Met Cys Gln Lys Leu His
1 5 10 15
Leu Cys Pro Ser His
20
<210> 7
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是HArg
<400> 7
Ser Asp Xaa Cys Ser Ala Gly Trp Leu Thr Met Cys Gln Xaa Leu His
1 5 10 15
Leu Cys Pro Ser His Lys
20
<210> 8
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<400> 8
Ser Asp Xaa Cys Ser Ala Gly Trp Leu Thr Met Cys Xaa Gln Leu Asn
1 5 10 15
Leu Cys Pro Ser His Lys
20
<210> 9
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 9
Ser Asp Lys Cys Ser Ala Gly Trp Leu Thr Met Cys Gln Lys Leu His
1 5 10 15
Leu Cys Pro Ser His
20
<210> 10
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 10
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 11
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 11
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys Lys
<210> 12
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 12
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Lys Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 13
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 13
Ala Xaa Asp Cys Xaa Lys Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 14
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 14
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Lys His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 15
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 15
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 16
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 16
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys Lys
<210> 17
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 17
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Lys Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 18
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 18
Ala Xaa Asp Cys Xaa Lys Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 19
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 19
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Lys His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 20
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 20
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Glu Trp
1 5 10 15
Xaa Cys
<210> 21
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 21
Ala Xaa Glu Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Glu Trp
1 5 10 15
Xaa Cys
<210> 22
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 22
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 23
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 23
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Thr Cys
<210> 24
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 24
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys
<210> 25
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 25
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys Ala
<210> 26
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 26
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Ala Trp
1 5 10 15
Thr Cys
<210> 27
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是3,3-DPA
<400> 27
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp
1 5 10 15
Thr Cys
<210> 28
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是3,3-DPA
<400> 28
Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp Thr Cys
1 5 10 15
<210> 29
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HyP
<400> 29
Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp Thr Cys Ala
1 5 10 15
<210> 30
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Cba
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 30
Ala Xaa Asp Cys Xaa Xaa Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 31
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Cba
<400> 31
Ala Xaa Asp Cys Xaa Xaa Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys
<210> 32
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Cba
<400> 32
Ala Xaa Asp Cys Xaa Xaa Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys Ala
<210> 33
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Cba
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是3,3-DPA
<400> 33
Cys Xaa Xaa Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp Thr Cys Ala
1 5 10 15
<210> 34
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是3,3-DPA
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 34
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 35
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是d1Nal
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 35
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Xaa Trp
1 5 10 15
Xaa Cys
<210> 36
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是d1Nal
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 36
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 37
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是d1Nal
<400> 37
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Xaa Trp
1 5 10 15
Thr Cys
<210> 38
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是1Nal
<400> 38
Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp Thr Cys
1 5 10 15
<210> 39
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是3,3-DPA
<400> 39
Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp Thr Cys Lys
1 5 10 15
<210> 40
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是NMeAla
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 40
Xaa Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 41
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是NMeAla
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 41
Xaa Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys
<210> 42
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Cba
<400> 42
Ala Xaa Asp Cys Xaa Xaa Val Asn Pro Leu Cys Leu Glu Pro Ala Trp
1 5 10 15
Thr Cys Ala
<210> 43
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是d1Nal
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Cba
<400> 43
Xaa Xaa Asp Cys Xaa Xaa Val Asn Pro Leu Cys Leu Glu Pro Ala Trp
1 5 10 15
Thr Cys Ala
<210> 44
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 44
Ala Glu Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys
<210> 45
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<400> 45
Ala Ala Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp
1 5 10 15
Thr Cys
<210> 46
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是HyP
<400> 46
Ala Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Glu Pro Asp Trp Thr
1 5 10 15
Cys
<210> 47
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是hGlu
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 47
Ala Xaa Asp Cys Xaa Xaa Val Asn Pro Leu Cys Leu His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 48
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是hGlu
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 48
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Xaa His Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 49
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是hGlu
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 49
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 50
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是dNle
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 50
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu His Pro Xaa Trp
1 5 10 15
Xaa Cys
<210> 51
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是HyP
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是Nle
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 51
Ala Xaa Asp Cys Xaa Leu Val Asn Pro Leu Cys Leu Xaa Pro Asp Trp
1 5 10 15
Xaa Cys
<210> 52
<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> 52
Cys Pro Xaa Asp Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 53
<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> 53
Cys Pro Xaa Lys Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 54
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是3-巯基丙酸
<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> 54
Xaa Pro Xaa Lys Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 55
<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
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是半胱胺
<400> 55
Cys Pro Xaa Lys Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Xaa
1 5 10 15
<210> 56
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是3-巯基丙酸
<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
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是半胱胺
<400> 56
Xaa Pro Xaa Lys Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Xaa
1 5 10 15
<210> 57
<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> 57
Cys Pro Xaa Lys Cys Met Xaa His Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 58
<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> 58
Cys Pro Xaa Lys Cys Met Xaa Glu Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 59
<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> 59
Cys Pro Xaa Glu Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 60
<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> 60
Cys Pro Xaa Ala Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 61
<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> 61
Cys Pro Xaa Glu Cys Leu Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 62
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是棕榈酸
<220>
<221> Xaa
<222> (2)..(3)
<223> Xaa是yGlu
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HyP
<400> 62
Xaa Xaa Xaa Cys Pro Xaa Lys Cys Met Xaa Asp Trp Ser Thr Pro Xaa
1 5 10 15
Trp Cys
<210> 63
<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> 63
Cys Pro Xaa Glu Cys Met Xaa Glu Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 64
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是PYA
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是B-Ala
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是HyP
<400> 64
Xaa Xaa Cys Pro Xaa Asp Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp
1 5 10 15
Cys
<210> 65
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是PYA
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是B-Ala
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是HyP
<400> 65
Xaa Xaa Cys Pro Xaa Lys Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp
1 5 10 15
Cys
<210> 66
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是PYA
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是HyP
<400> 66
Xaa Cys Pro Xaa Asp Cys Met Xaa Asp Trp Ser Thr Pro Xaa Trp Cys
1 5 10 15
<210> 67
<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> 67
Cys Xaa Pro Glu Xaa Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Ala
1 5 10 15
<210> 68
<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> (14)..(14)
<223> Xaa是Nle
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是Dap(PYA)
<400> 68
Cys Xaa Glu Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Xaa
1 5 10 15
<210> 69
<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> (14)..(14)
<223> Xaa是Nle
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是Dap(PYA)
<400> 69
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Xaa
1 5 10 15
<210> 70
<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> (14)..(14)
<223> Xaa是Nle
<400> 70
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Ala
1 5 10 15
<210> 71
<211> 15
<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> (14)..(14)
<223> Xaa是Nle
<400> 71
Cys Xaa Glu Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys
1 5 10 15
<210> 72
<211> 15
<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> (14)..(14)
<223> Xaa是Nle
<400> 72
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys
1 5 10 15
<210> 73
<211> 15
<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> (14)..(14)
<223> Xaa是Nle
<400> 73
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asn Pro Tyr Xaa Cys
1 5 10 15
<210> 74
<211> 15
<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> (14)..(14)
<223> Xaa是Nle
<400> 74
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Glu Pro Tyr Xaa Cys
1 5 10 15
<210> 75
<211> 15
<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> (11)..(11)
<223> Xaa是Aad
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 75
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Xaa Pro Tyr Xaa Cys
1 5 10 15
<210> 76
<211> 15
<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> (14)..(14)
<223> Xaa是Nle
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是半胱胺
<400> 76
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Xaa
1 5 10 15
<210> 77
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是3-巯基丙酸
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 77
Xaa Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys
1 5 10 15
<210> 78
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是3-巯基丙酸
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是半胱胺
<400> 78
Xaa Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Xaa
1 5 10 15
<210> 79
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是棕榈酸
<220>
<221> Xaa
<222> (2)..(3)
<223> Xaa是yGlu
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Nle
<400> 79
Xaa Xaa Xaa Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr
1 5 10 15
Xaa Cys
<210> 80
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是3-巯基丙酸
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是tBuAla
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 80
Xaa Xaa Glu Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys
1 5 10 15
<210> 81
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是Nle
<400> 81
Ala Cys Ile Glu Glu Lys Gln Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys
1 5 10 15
Ala
<210> 82
<211> 15
<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> (12)..(12)
<223> Xaa是NMeAla
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 82
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Xaa Tyr Xaa Cys
1 5 10 15
<210> 83
<211> 15
<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> (12)..(12)
<223> Xaa是NMeDAla
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Nle
<400> 83
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Xaa Tyr Xaa Cys
1 5 10 15
<210> 84
<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> (14)..(14)
<223> Xaa是Nle
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是1,2-二氨基乙烷
<400> 84
Cys Xaa Pro Glu Lys Pro Tyr Cys Phe Ala Asp Pro Tyr Xaa Cys Xaa
1 5 10 15
Claims (17)
1.一种异串联双环肽复合物,其包含:
(a)第一肽配体,其结合存在于癌细胞上的成分;所述第一肽配体通过接头与以下偶联
(b)第二肽配体,其结合存在于免疫细胞上的成分;
其中,每个所述肽配体包含多肽和分子支架,所述多肽包含被至少两个环序列隔开的至少三个反应性基团,并且所述分子支架与所述多肽的反应性基团形成共价键,使得在分子支架上形成至少两个多肽环,其特征在于所述异串联双环肽复合物包含以下第一和第二肽配体:
其中1Nal表示1-萘丙氨酸,HArg表示高精氨酸,HyP表示羟脯氨酸,B-Ala表示β-丙氨酸,PYA表示4-戊烯酸,3,3-DPA表示3,3-二苯丙氨酸,Cba表示β-环丁基丙氨酸,hGlu表示高谷氨酸,Nle表示正亮氨酸,NMeAla表示N-甲基-丙氨酸,tBuAla表示叔丁基-丙氨酸,Aad表示α-L-氨基己二酸,Ac表示乙酰基,Dap表示二氨基丙酸,或其药学上可接受的盐。
2.如权利要求1所定义的异串联双环肽复合物,其中所述免疫细胞选自:白细胞;淋巴细胞(例如T淋巴细胞或T细胞、B细胞或自然杀伤细胞);CD8或CD4;CD8;树突状细胞、滤泡树突细胞和粒细胞。
3.如权利要求1或2所定义的异串联双环肽复合物,其中所述第二肽配体包含结合CD137的双环肽配体。
4.如权利要求3所定义的异串联双环肽复合物,其中所述结合CD137的双环肽选自SEQID NO:67至84中的任一种肽。
5.如权利要求1至4中任一项所定义的异串联双环肽复合物,其中所述第一肽配体包含结合粘连蛋白-4的双环肽配体。
6.如权利要求5所定义的异串联双环肽复合物,其中所述结合粘连蛋白-4的双环肽选自SEQ ID NO:52至66中的任一种肽。
7.如权利要求5或6所定义的异串联双环肽复合物,其选自表C中列出的任一种复合物,如BCY11468、BCY11618、BCY11776、BCY11860、BCY12020、BCY12661和BCY12969。
8.如权利要求1至4中任一项所定义的异串联双环肽复合物,其中所述第一肽配体包含结合EphA2的双环肽配体。
9.如权利要求8所定义的异串联双环肽复合物,其中所述结合EphA2的双环肽选自SEQID NO:10至51中的任一种肽。
10.如权利要求8或9所定义的异串联双环肽复合物,其选自表B中列出的任一种复合物,如BCY13035、BCY13040、BCY13253、BCY13254、BCY13340和BCY13342。
11.如权利要求1至4中任一项所定义的异串联双环肽复合物,其中所述第一肽配体包含结合PD-L1的双环肽配体。
12.如权利要求11所定义的异串联双环肽复合物,其中所述结合PD-L1的双环肽选自SEQ ID NO:1至9中的任一种肽。
13.如权利要求11或12所定义的异串联双环肽复合物,其选自表A中列出的任一种复合物,如BCY12375和BCY12021。
14.如权利要求1至13中任一项所定义的异串联双环肽复合物,其中所述分子支架选自1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA)。
15.如权利要求1至14中任一项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。
16.一种药物组合物,其包含权利要求1至15中任一项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。
17.如权利要求1至15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。
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JP7551500B2 (ja) | 2018-04-04 | 2024-09-17 | バイスクルテクス・リミテッド | ヘテロタンデム二環式ペプチド複合体 |
GB201810316D0 (en) | 2018-06-22 | 2018-08-08 | Bicyclerd Ltd | Peptide ligands for binding to EphA2 |
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BR112021022315A2 (pt) | 2019-05-09 | 2021-12-28 | Bicycletx Ltd | Ligantes de peptídeo bicíclicos específicos para ox40 |
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TW202241488A (zh) * | 2021-01-11 | 2022-11-01 | 英商拜斯科技技術開發有限公司 | 治療癌症之方法 |
CN118215672A (zh) * | 2021-06-01 | 2024-06-18 | 南京明德新药研发有限公司 | 多肽偶联药物及其应用 |
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