CN115551529A - 增强房水流出并降低眼内压的方法 - Google Patents
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Abstract
本公开涉及在有此需要的受试者中促进经由眼中常规流出道的房水流出的方法,或在有此需要的受试者中降低眼内压的方法。
Description
技术领域
本公开特别涉及用于通过Tie2/TEK受体的激动性活化治疗血管疾病的血管生成素-1模拟物。
背景技术
血管生成素-Tie2信号传导通路是血管发育、血管重塑、产后血管发生和血管通透性的主要调节剂(Saharinen P,Eklund L,Alitalo K.Therapeutic targeting of theangiopoietin-TIE pathway.Nat Rev Drug Discov.2017;16(9):635–661)。该通路主要通过内皮酪氨酸激酶受体Tie2(TEK)与其细胞外配体血管生成素-1(Ang1)和2(Ang)的直接结合起作用(Saharinen P,Eklund L,Alitalo K.Therapeutic targeting of theangiopoietin-TIE pathway.Nat Rev Drug Discov.2017;16(9):635–661)。尽管Ang1的强的规范激动剂功能有明确的定义,但Ang2通常被认为是Tie2的背景依赖性拮抗剂(SoumaT,et al.Context-dependent functions of angiopoietin 2are determined by theendothelial phosphatase VEPTP.Proc Natl Acad Sci U S A.2018;115(6):1298–1303)。此外,Ang-Tie2信号传导通路的强度由负调节剂(例如,血管内皮蛋白酪氨酸磷酸酶(VEPTP/PTPRB))调节,并且该通路还与整联蛋白信号传导具有串扰(Saharinen P,EklundL,Alitalo K.Therapeutic targeting of the angiopoietin-TIE pathway.Nat RevDrug Discov.2017;16(9):635–661)。在Tie2下游的许多细胞内信号转导通路可被激活,导致ERK1/2、AKT和eNOS磷酸化(Saharinen P,Eklund L,Alitalo K.Therapeutic targetingof the angiopoietin-TIE pathway.Nat Rev Drug Discov.2017;16(9):635–661)。
血管生成素-Tie2信号转导系统已被研究作为治疗极其多种疾病的潜在治疗靶点。大量文献描述了如何激活该通路对防止血管渗漏和炎症具有有效作用(ParikhSM.Angiopoietins and Tie2 in vascular inflammation.Curr Opin Hematol.2017;24(5):432–438;Saharinen P,Eklund L,Alitalo K.Therapeutic targeting of theangiopoietin-TIE pathway.Nat Rev Drug Discov.2017;16(9):635–661)。适应症包括但不限于癌症、败血症、缺血性中风、急性肾损伤、慢性肾病、糖尿病性肾病和视网膜病变、创伤愈合、急性肺损伤、同种异体移植物排斥等疾病和病况(Saharinen P,Eklund L,AlitaloK.Therapeutic targeting of the angiopoietin-TIE pathway.Nat Rev DrugDiscov.2017;16(9):635–661)。通过外源性干预调节该通路提供了通过防止炎症和血管渗漏的有害作用,从而保持内皮屏障完整性,来稳定血管内皮的治疗机会(ParikhSM.Angiopoietins and Tie2 in vascular inflammation.Curr Opin Hematol.2017;24(5):432–438)。
学术实验室和生物技术公司已经付出了相当大的努力来生产用于治疗用途的生物等效或生物更好(biobetter)的Ang类似物或模拟物。已经尝试了几种Ang1模拟物设计,但没有一种达到了临床测定阶段,主要是因为在实现期望药效方面遇到了障碍(KohGY.Orchestral actions of angiopoietin-1in vascular regeneration.Trends MolMed.2013;19(1):31–39)。
血管生成素共享相似的分子域结构,其具有C端纤维蛋白原样域(FLD)(其赋予与细胞表面受体Tie2的结合)、中间卷曲螺旋域(CCOD)(介导单体的同多聚化)以及较短的N端超簇集域(SCD)区段(其使得血管生成素二聚体能够通过分子内二硫键簇集成多聚体结构)(图1A)(Koh GY.Orchestral actions of angiopoietin-1in vascularregeneration.Trends Mol Med.2013;19(1):31–39)。较高的寡聚化是效力的主要决定因素,并且虽然单体血管生成素配体可以结合Tie2,但它们不诱导Tie2受体酪氨酸磷酸化以及调节微血管系统且对血管和淋巴管发育、维持和功能至关重要的下游细胞内信号传导的激活(Saharinen P,Eklund L,Alitalo K.Therapeutic targeting of theangiopoietin-TIE pathway.Nat Rev Drug Discov.2017;16(9):635–661))。Ang1是主要以更高级的多聚体形式存在的Tie2的有效激动剂,其促进Tie2受体簇集并引发下游信号传导级联(Koh GY.Orchestral actions of angiopoietin-1in vascularregeneration.Trends Mol Med.2013;19(1):31–39)。更高级的多聚体配体是Tie2的最佳结合剂,并且由于亲和力而强烈诱导配体复合的Tie2受体的酪氨酸磷酸化(Kim KT,etal.Oligomerization and multimerization are critical for angiopoietin-1to bindand phosphorylate Tie2.J Biol Chem.2005;280(20):20126–20131)。相反,Ang2最常作为二聚体存在,因此在存在Ang1时使其成为Tie2的竞争性拮抗剂,但是在Ang1和VE-PTP相对不存在的情况下,使其成为Tie2的部分激动剂,这似乎建立了Tie2对每种配体的反应性的阈值(Souma T,et al.Context-dependent functions of angiopoietin 2aredetermined by the endothelial phosphatase VEPTP.Proc Natl Acad Sci U SA.2018;115(6):1298–1303)。除多聚化和Tie2接合的差异之外,Ang1还与细胞外基质和透明质酸(内皮糖萼的主要结构成分)结合(van den Berg BM,et al.Glomerular Functionand Structural Integrity Depend on Hyaluronan Synthesis by GlomerularEndothelium.J Am Soc Nephrol.2019;30(10):1886–1897)。天然Ang1主要由血管周细胞产生。它通过其N端域和接头与细胞外基质(ECM)结合,并通过C端Tie2结合纤维蛋白原样域(FLD)激活邻近内皮上的Tie2受体(Koh GY.Orchestral actions of angiopoietin-1invascular regeneration.Trends Mol Med.2013;19(1):31–39)。这种作用模式使得使用天然形式的Ang1达到全身性药物疗效具有挑战性。可从生物技术供应商获得的作为实验试剂的重组Ang1以三聚体、四聚体和五聚体寡聚物的异质多聚体形式生产(Koh GY.Orchestralactions of angiopoietin-1in vascular regeneration.Trends Mol Med.2013;19(1):31–39)。由于其独特的分子结构,SCD-CCOD具有呈粘性的固有趋势,与ECM非特异性结合,并形成不溶性聚集体,导致沉淀和活性损失(Koh GY.Orchestral actions ofangiopoietin-1in vascular regeneration.Trends Mol Med.2013;19(1):31–39)。因此,认为天然Ang1形式不是良好的候选药物。为了克服这些问题,已经使用不同的设计,生物工程化改造几种Ang1模拟物,以期改善溶解度、稳定性和多聚性。一种方法使用如下的设计:其使用来自IgG1中的二聚化可结晶片段(Fc)取代SCD-CCOD,创建具有2的低多聚性的Bow-ANG1(Davis S,et al.Angiopoietins have distinct modular domains essential forreceptor binding,dimerization and superclustering.Nat Struct Biol.2003;10(1):38–44)。为了提高多聚性,构建了另一种形式的BOW-ANG1,其在每条链中在串联排列中放置有两个FLD,以将多聚性提高至4,这显示出增强的与Tie2受体的结合亲和力(Davis S,etal.Angiopoietins have distinct modular domains essential for receptorbinding,dimerization and superclustering.Nat Struct Biol.2003;10(1):38–44)。另一种方法使用与FLD融合的来自软骨寡聚基质蛋白的更短且更稳定的CCOD,生成称为COMP:Ang1的五聚体,其能够强烈激活Tie2(Cho CH,et al.Designed angiopoietin-1variant,COMP-Ang1,protects against radiation-induced endothelial cell apoptosis.ProcNatl Acad Sci U S A.2004;101(15):5553–5558.)。即使Bow-Ang1和COMP:Ang1在体内激活Tie2中确实显示出一些功效,但它们的缺点,如与细胞外基质的非特异性结合、在COMP-Ang1的情况下血液半衰期短,以及BOW-Ang1的多聚体性低和效力弱,使得它们不适合临床测定(Koh GY.Orchestral actions of angiopoietin-1in vascularregeneration.Trends Mol Med.2013;19(1):31–39)。因此,仍然需要创建具有改进溶解度、稳定性和多聚性的Ang1模拟物。
补体结合蛋白(C4BP)是一种丰富的人血浆糖蛋白,其天然功能是抑制补体激活的经典途径和凝集素途径(Ermert D,Blom AM.C4b-binding protein:The good,the badand the deadly.Novel functions of an old friend.Immunol Lett.2016;169:82–92)。由于在人类血液中的主要形式由七条相同的α链和单一β链组成,因此C4BP呈现在C端末端保持在一起的七臂蜘蛛或章鱼状结构(Hofmeyer T,et al.Arranged sevenfold:structural insights into the C-terminal oligomerization domain of human C4b-binding protein.J Mol Biol.2013;425(8):1302–1317)。该C端核心区域负责在蛋白质合成期间组装成多聚体,其中来自一个单体的半胱氨酸与另一个单体的胱氨酸形成分子间二硫键(Hofmeyer T,et al.Arranged sevenfold:structural insights into the C-terminal oligomerization domain of human C4b-binding protein.J Mol Biol.2013;425(8):1302–1317)。C4BP支架足以使全长C4BP寡聚化,具有显著的稳定性,并且对苛刻条件(如暴露于极端的pH和温度)耐受良好(Hofmeyer T,et al.Arranged sevenfold:structural insights into the C-terminal oligomerization domain of human C4b-binding protein.J Mol Biol.2013;425(8):1302–1317)。在嵌合融合体中,预测C4BP也能够使其他连接的域寡聚化,并且这里我们描述了C4BP与Ang1的融合体(图1B)。
发明内容
通过合理的设计,本文描述了一种血管生成素-1(ANG1)的新的“生物更好”模拟物,其可以用作可注射治疗剂以通过Tie2激活治疗血管病况。本公开涉及ANG1的C端Tie2结合纤维蛋白原样域(FLD)和补体C4结合蛋白(C4BP)的C端支架区段之间的嵌合融合体的设计、构建、生产和治疗用途。重组融合体,根据域排列的其N至C端顺序,称为ANG1-C4BP或C4BP-ANG1,通过C4BP区段天然折叠成七聚体结构,并以“郁金香花束”样的构型(图1B)展示了ANG1的7个FLD,类似于天然ANG1的(图1A)。重组产生的ANG1-C4BP和C4BP-ANG1在人细胞和小鼠模型中有效激活Tie2。本公开的各方面还涉及表达此类重组融合蛋白的细胞系,以及降低或抑制血管渗漏或血浆通透性以及促进血管系统的生长、维持血管结构完整性的方法。ANG1-C4BP系列生物制剂治疗用途的示例性预期适应症包括血管性眼病,例如角膜缘毛细血管丛(limbus capillary plexus)或Schlemm管排流系统(Schlemm’s canal drainagesystem)缺陷引起的原发性开角型青光眼(primary open angle glaucoma)和各种类型的原发性或继发性视网膜病变,以及癌症新生血管形成、炎症病况等中血管渗漏的系统性治疗。
本文所提及的专利和科学文献确立了本领域技术人员可获得的知识。本文所引用的所有美国专利和公开或未公开的美国专利申请均通过引用并入本文。本文所引用的所有公开的外国专利和专利申请均通过引用并入本文。本文所引用的所有其它公开的参考文献、词典、文献、手稿、基因组数据库序列和科学文献均通过引用并入本文。
根据附图和下文的具体实施方式,包括实施方案和权利要求书,本公开的其它特征和优点是显而易见的。
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图1示出了七聚体C4BP-ANG1的示意图和实际形成。A)天然ANG1按N至C端的顺序由超簇集域(supercluster domain,SCD)、卷曲螺旋域(CCOD)和与Tie2结合的纤维蛋白原样域(上图)组成。CCOD介导ANG1分子之间的CCOD-CCOD相互作用(中图),并且通过其与FLD的接头片段也与ECM结合。SCD还将ANG1簇集成较高程度的复合体(下图)。B)C4BP的C端通过相邻亚单位之间相互连接的二硫键(红色)自然折叠成“桶状”结构。这些亚单位的总共7个(或8个)完成桶状结构(上图),其在C4BP-ANG1或ANG1-C4BP中展示与天然ANG1的排列类似的排列中的七个FLD(下图,与图A相比)。C)C4BP-ANG1通过将编码质粒转染到HEK-293细胞中来表达,并从培养基中收集。如所预期的,C4BP-ANG1在非还原(NR)条件下在SDS PAGE上形成七聚体。D.电子显微照片(EM)图像显示出簇集的C4BP-ANG1。
图2是在HEK293和CHO细胞中产生和表达的不同形式血管生成素和C4BP嵌合融合构建体的概述。
图3示出了培养基中CHO和HEK293对ANG1-C4BP七聚体的表达。各种血管生成素-C4bp融合构建体在CHO和HEK293(测试的三种转染条件1-3)细胞两者中的瞬时表达。构建体H6EKC4BPAng1和H6EKAng1C4BP以最高水平表达,在还原条件下正确形成约280kDa七聚体(上图)和约35kDa单体(下图),如A)非还原和还原条件下的丽春红S(Ponceau S)溶液染色,以及B)使用抗His标签抗体进行的非还原和还原性SDS PAGEwestern印迹所示。
图4示出了C4BP和ANG1融合变体都在近同质性中形成七聚体(第1部分)。按照N端至C端的顺序,构建了4个用于哺乳动物细胞表达的质粒:1.具有C端6xHis标签的C4BP-ANG1(1),2.具有N端6xHis标签的C4BP-ANG(2),3.具有C端6xHis标签的ANG1-C4BP(1),以及4.具有N端6xHis标签的ANG1-C4BP(2)。蛋白质在无血清培养基中培养的CHO细胞中表达,随后从培养基中采集。通过在非还原条件(N.R.:左图)或还原条件(右图)下进行SDS PAGE分析,确定了C4BP-ANG1蛋白(以红色框突出显示),无论其N至C顺序如何,都通过二硫键自然形成约280kDa的七聚体(多聚度为7)。所有的融合蛋白都可以在还原条件下还原为它们的约35kDa单体形式。
图5示出了形成七聚体的纯化ANG1-C4BP变体(第2部分)。在非还原性SDS PAGE分离和使用抗His标签抗体的western印迹分析之后,在所有构建体中均发现了预期分子量的嵌合融合蛋白产物。#2表示使用C4BPAng1H6的备选表达载体进行比较。CHO-BRI稳定池(pool)表达平台技术用于产生这些ANG-C4BP变体。
图6示出了形成七聚体的纯化ANG1-C4BP变体(第3部分)。在非还原性SDS-PAGE分离和使用抗His标签抗体的western印迹分析之后,在所有构建体中均发现了预期分子量的嵌合融合蛋白产物。#2表示使用C4BPANG1H6的备选表达载体进行比较。CHO-BRI稳定池表达平台技术用于产生这些ANG-C4BP变体。
图7示出了含有ANG1-C4BP变体七聚体的峰#2的IMAC纯化。A)IMAC纯化级分的非还原性和还原性SDS PAGE考马斯蓝染色。峰#2具有重组融合蛋白产物的正确分子量——在非还原条件下形成七聚体,在还原条件下形成单体。B)IMAC纯化级分的概述,突出显示了峰#2。
图8示出了ANG1-C4BP嵌合融合蛋白在冻融循环后的稳定性。纯化的ANG1-C4BP在UPLC-SEC分析七聚体质量(在峰值2.610处)之前进行一次或两次冻融循环(F/T)。七聚体级分的无损失是明显的(将1F/T和2F/T与4℃下储存的对照组进行比较)。
图9示出了ANG1-C4BP和C4BP-ANG1与Tie2的结合。使用Fc融合体形式的Tie2的胞外域(Tie2-Fc),在免疫共沉淀测定中测试了Tie2和天然ANG1序列的重组ANG1(rANG1)、ANG1-C4BP或C4BP-ANG1之间的直接相互作用。抗Fc免疫沉淀后,通过抗His标签印迹法检测ANG1变体的存在。免疫印迹法图像来自用抗His抗体和抗Fc抗体的复合双重染色。
图10显示了在培养的HUVEC中,ANG1-C4BP以剂量依赖性方式激活Tie2。用ANG1-C4BP的预制备SEC峰#2处理20分钟后,在HUVEC中观察到AKT的磷酸化水平(pAKT)提高。Ang1-C4bp在经20分钟处理的HUVEC中激活pAKT的半数最大响应(EC50)为87ng/mL。
图11示出了ANG1-C4BP变体以剂量依赖性方式激活Tie2。ANG1和C4BP之间的嵌合融合体是Tie2受体的体外有效激动剂,如A)Tie2的磷酸化提高以及B)其下游靶AKT证明的。实验在HUVEC中进行,用指定浓度或500ng/mL每种重组嵌合融合蛋白作为处理20分钟。rhAngpt1是来自R&DSystems的重组血管生成素-1。
图12示出了C4BP-ANG1诱导Tie2重定位至细胞外周中的基因座。将HUVEC细胞用FLAG-Tie2(全长)转基因转染,并进行媒介物对照或C4BP-ANG1处理。绿色的Tie2图像从抗FLAG免疫荧光染色显现(示出了每组的代表性单细胞图像)。
图13示出了静脉内和腹腔内注射C4BP-ANG1激活小鼠体内的内源性Tie2。给小鼠注射C4BP-ANG1,并通过肺中内源性Tie2的磷酸化(pTyr-Tie2)来测量体内活性。A)根据体重(BW)给小鼠静脉内注射不同剂量的媒介物或C4BP-ANG1,并在30分钟后采集肺组织。抗Tie2免疫沉淀后,通过用抗pTyr抗体的免疫印迹法测量磷酸-Tie2水平。B)和C)示出了在0.5μg/g体重下磷酸-Tie2对C4BP-ANG1响应的时程研究。
图14示出了玻璃体内注射的C4BP-ANG1在兔眼中的药代动力学。使3只兔子各自进行单剂的C4BP-ANG1玻璃体内注射,每天收集房水(注射前样品:第0天),持续7天。通过使用抗His捕获抗体和抗ANG1检测抗体的ELISA测量C4BP-ANG1水平(OD450值)(左)。在第7天,将动物处死,并收集玻璃体液样品用于检测C4BP-ANG1水平(右图,星号:p<0.01)。
图15示出了在小鼠Miles测定中,C4BP-ANG1减少VEGF诱导的血管渗漏。血管渗漏研究是利用Miles测定进行的,该测定量化伊文斯蓝染料(Evans Blue dye)的组织水平。如所示(上图),对小鼠进行30分钟注射日程表。进行VEGF和C4BP-ANG1的组合的皮下(SQ)注射,并且显现伊文斯蓝的泄露(下图)并将其量化为按组织重量标准化的OD360值(图像和量化,右星号:p<0.001)。
图16示出了静脉内注射C4BP-ANG1减少VEGF诱导的血管渗漏。血管渗漏研究是利用Miles测定进行的,该测定量化伊文斯蓝染料的组织水平。如所示(上图),对小鼠进行30分钟注射日程表。代替局部注射C4BP-ANG1,在皮下(SQ)注射VEGF诱导渗漏前60分钟经由静脉内预防性注射生物制剂。观察到伊文斯蓝泄漏(下图)。
图17示出了静脉内注射C4BP-ANG1减少化学诱导的血管渗漏。血管渗漏研究是利用Miles测定进行的,该测定量化伊文斯蓝染料的组织水平。在通过向耳局部施用芥子油诱导渗漏之前60分钟经由静脉内预防性注射C4BP-ANG1(图像和量化,星号:p<0.01)。
图18示出了C4BP-ANG1保护小鼠免受脂多糖诱导的肺损伤。在脂多糖(LPS)诱导的肺损伤的小鼠模型中,遵循LPS吸入(INH)、C4BP-ANG1注射和伊文斯蓝注射的时间过程,如在上图中所示。伊文斯蓝注射后1小时,采集肺以测量血管渗漏(图像和量化,星号:p<0.05)。
图19野生型和神经嵴特异性血管生成素-1敲除(Angpt1 dNC)小鼠在出生后第0-14天通过每日IP注射用Angpt1-C4PB处理。在P14,收集眼并量化Schlemm管面积。在野生型和Angpt1 dNC眼两者中,Angpt1-C4BP处理导致Schlemm管大小的明显增加。在WT动物中,分化的Schlemm管标志物PROX1的表达在治疗后得到维持,而在Angpt1 dNC眼中,仅在Angpt1-C4BP处理后观察到PROX1表达。
图20示出了无标签Ang1C4bp构建体的表达、纯化以及体外和体内Tie2激活。以N端至C端顺序,表达构建体含有信号肽,随后是Ang1 FLD、“GGGS”接头和C4bp序列。利用CHO细胞系统,表达无标签的Ang1-接头-C4bp融合体,并将其分泌到培养基中。A)离子交换层析后,从柱上洗脱蛋白质峰(左图)。收集物的非还原性SDS PAGE分析显示,无标签的靶蛋白Ang1C4bp在级分F4和F5中浓缩(右图:用红色框突出显示,大小由红色箭头指示)。B)将级分F4和F5合并,并加载到尺寸排阻层析柱上以“精炼”靶蛋白,从而进一步富集(左图:层析图追踪示出了靶蛋白,由红色箭头所示;右图:SDS PAGE证实,级分F2中靶蛋白成功富集,红色箭头所示)。C)分别在激活的细胞内Akt磷酸化(pAkt)和Tie2磷酸化(pTie2)中用无标签Ang1C4bp对HUVEC和HEK293细胞进行处理(稳定表达Tie2-FLAG转基因)。媒介物对照(Ctr)和天然Ang1分别用作阴性对照和阳性对照。D)用无标签Ang1C4bp重组蛋白静脉内注射小鼠,以诱导肺中的Tie2磷酸化。在注射后1小时采集来自媒介物注射的肺组织(Ctr:n=3)和来自无标签Ang1C4bp注射(n=3)的肺组织。从肺组织匀浆免疫沉淀(IP)总Tie2(抗Tie2IP),并通过用抗磷酸酪氨酸抗体(pTie2)的IP样品的免疫印迹法来测定Tie2磷酸化水平。
具体实施方式
为了更容易地理解本公开,下文中对某些术语进行了定义。以下术语和其它术语的其它定义在整个说明书中进行了阐述。
除非上下文另有明确说明,否则如在本说明书和所附权利要求书中所使用的,单数形式“一个”、“一种”和“所述/该”包括复数指示物。
除非上下文中明确说明或显而易见,否则如本文所使用的,术语“或”应理解为包含性的,且涵盖“或”和“和”两者。
本文使用时的术语“和/或”应视为对两个指定特征或部件中的每一个的具体公开,包括或不包括另一个。因此,如本文中在诸如“A和/或B”的短语中使用的术语“和/或”旨在包括A和B、A或B、A(单独)以及B(单独)。同样地,如在诸如“A、B和/或C”的短语中使用的术语“和/或”旨在涵盖以下方面中的每一个:A、B和C;A、B或C;A或C;A或B;B或C;A和C;A和B;B和C;A(单独);B(单独);和C(单独)。
如本文所使用的,术语“例如”和“即”仅作为示例使用,而不旨在进行限制,并且不应解释为仅指代在说明书中明确列举的那些项目。
术语“或更多”、“至少”、“多于”等,例如“至少一个”,应理解为包括但不限于至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或大于所述值。还包括其间的任何更大的数值或分数。
相反,术语“不超过”包括小于所述值的每个值。例如,“不超过100个核苷酸”包括100、99、98、97、96、95、94、93、92、91、90、89、88、87、86、85、84、83、82、81、80、79、78、77、76、75、74、73、72、71、70、69、68、67、66、65、64、63、62、61、60、59、58、57、56、55、54、53、52、51、50、49、48、47、46、45、44、43、42、41、40、39、38、37、36、35、34、33、32、31、30、29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1和0个核苷酸。还包括其间的任何更小的数值或分数。
术语“多个”、“至少两个”、“两个或更多个”、“至少第二”等应理解为包括但不限于至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或更多。还包括其间的任何更大的数值或分数。
在整个说明书中,词语“包括”或诸如“含有”或“包含”的变体应理解为暗示包括所述要素、整数或步骤,或要素、整数或步骤的组,但不排除任何其它要素、整数或步骤,或要素、整数或步骤的组。应当理解,在本文中用语言“包含”描述的任何方面,也提供以“由…组成”和/或“基本上由…组成”描述的其他方面类似的方面。
除非上下文明确说明或显而易见,如本文所使用的,术语“约”是指在本领域普通技术人员确定的特定值或组成的可接受误差范围内的值或组成,其将部分取决于如何测量或确定该值或组成,即测量系统的限制。例如,根据本领域的实践,“约”或“基本上由...组成”可意指在一个或超过一个标准偏差内。“约”或“基本上由...组成”可意指至多10%(即±10%)的范围。因此,“约”可理解为比所述值大或小10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%、0.01%或0.001%内。例如,约5mg可包括4.5mg至5.5mg之间的任何量。此外,特别是对于生物系统或方法,术语可以指数值的高达一个数量级或高达5倍。当在本公开中提供特定值或组成时,除非另有说明,否则“约”或“基本上由...组成”的含义应视为在该特定值或组成的可接受误差范围内。
“结合亲和力”通常是指分子(例如,抗体)的单个结合位点与其结合配偶体(例如,抗原)之间的非共价相互作用的总和的强度。除非另有说明,如本文所使用的,“结合亲和力”、“结合”、或“与...结合”是指反映结合对成员(例如,抗体Fab片段和抗原)之间1:1相互作用的固有结合亲和力。分子X对其配偶体Y的亲和力通常可以用解离常数(KD)表示。亲和力可通过本领域已知的常规方法测量,包括本文所述的那些。低亲和力抗体通常缓慢地与抗原结合并且容易解离,而高亲和力抗体通常更快地与抗原结合并且趋于较长保持结合。测量结合亲和力的各种方法是本领域已知的,其中任何一种都可用于本发明的目的。基于表面等离子体共振(SPR)的无标记物生物传感器,例如BIACORE方法、MM/PBSA方法和KinExA,是通常优选的标准方法。已知结合亲和力可以根据测定方法而变化。因此,出于本公开的目的,当通过本领域标准的至少一种方法进行测量时,结合亲和力落入所述范围内就足够了。
如本文所述,除非另外说明,任何浓度范围、百分比范围、比率范围或整数范围均应理解为包括所述范围内的任何整数的值,并且在适当情况下包括其分数(例如,整数的十分之一和百分之一)。
本文所使用的单位、前缀和符号均采用国际单位制(SI)认可的形式提供。数值范围包括限定该范围的数值。
除非另有说明,否则本文所使用的所有技术和科学术语均具有与本公开相关领域普通技术人员通常理解的相同含义。例如,以下文献为本领域技术人员提供了本公开中使用的许多术语的通用词典:Juo,“The Concise Dictionary of Biomedicine andMolecular Biology”,第2版,(2001),CRC Press;“The Dictionary of Cell&;amp;Molecular Biology”,第5版,(2013),Academic Press;和“The Oxford Dictionary OfBiochemistry And Molecular Biology”,Cammack et al.编,第2版,(2006),OxfordUniversity Press。
“施用”是指使用本领域技术人员已知的各种方法和递送系统中的任一种将药剂物理引入受试者体内。本说明书的嵌合多肽、核酸和宿主细胞及其(药物)组合物可以通过本领域已知的途径施用于有此需要的受试者,并且可以根据用途(例如,待治疗的眼部疾病的类型)而有所变化。在一个实施方案中,所述施用是静脉内注射、腹腔内注射、皮下注射、玻璃体内注射。在一个实施方案中,施用途径包括例如局部施用(例如眼内)和肠胃外施用(例如皮下、腹腔内、肌内、静脉内、门静脉内和肝内)。在优选实施方案中,本公开的嵌合多肽、核酸或宿主细胞,或其药物组合物通过局部输注(例如使用输注泵和/或导管系统)至待治疗部位(例如实体瘤)而施用至受试者。在一个实施方案中,将本说明书的组合物输注至实体瘤、供给实体瘤的血管和/或实体瘤周围的区域中。本文所公开的制剂的其它示例性施用途径包括静脉内、肌内、皮下、腹腔内、脊柱或其它肠胃外施用途径,例如通过注射或输注。如本文所使用的短语“肠胃外施用”是指除肠和局部施用之外的施用方式,通常通过注射施用,并且包括但不限于静脉内、肌内、动脉内、鞘内、淋巴内、病灶内、囊内、眶内、心内、皮内、腹腔内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注,以及体内电穿孔。在一些实施方案中,该制剂通过非肠胃外途径施用,例如口服。其它非肠胃外途径包括局部、表皮或粘膜施用途径,例如鼻内、阴道、直肠、舌下或局部施用。施用也可以例如进行一次、多次和/或在一个或多个延长时期内进行。
如本文所使用的,术语“测定”、“评估”、“确定”、“测量”和“检测”是指定量和定性测定两者,并且因此,术语“测定”在本文中可与“确定”、“测量”等可互换使用。当想要进行定量测定时,可以使用短语“测定分析物的量”等。当想要进行定性和/或定量测定时,使用短语“测定分析物的水平”或“检测”分析物。
术语“重组宿主细胞”或“宿主细胞”是指已向其中引入外源(例如重组)DNA的细胞。这些术语不仅指特定的受试细胞,还指此类细胞的后代。因为由于突变或环境影响可能会在后代中发生某些修饰,所以这些后代实际上可能与亲代细胞不同,但仍包括在本文所用的术语“宿主细胞”的范围内。在一个实施方案中,宿主细胞包括原核细胞和真核细胞。在一个实施方案中,真核细胞包括原生生物细胞、真菌细胞、植物细胞和动物细胞。在另一个实施方案中,宿主细胞包括但不限于原核细胞系大肠杆菌;哺乳动物细胞系CHO、HEK 293、COS、NS0、SP2和PER.C6;昆虫细胞系Sf9;以及真菌细胞酿酒酵母。
“载体”是指能够在生物系统内复制或可以在这些系统之间移动的多核苷酸。载体多核苷酸通常含有诸如复制起点、多腺苷酸化信号或选择标记的元件,其功能是促进这些多核苷酸在生物系统(例如细胞、病毒、动物、植物和重建生物系统)中的复制或保持。“表达载体”是指可用于在生物系统或重建生物系统中指导由存在于表达载体中的多核苷酸序列所编码的多肽的翻译的载体。“表达载体”是指可用于在生物系统或重建生物系统中指导由存在于表达载体中的多核苷酸序列所编码的多肽的翻译的载体。
除非另有说明,否则本文所公开的任何范围均旨在包括该范围的端点。本文所提供的范围应理解为该范围内所有值的简写。例如,1至50的范围应理解为包括选自由1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50所构成的组的任何数字、数字组合或子范围。
通过对“对照”的“参考”是指一种比较标准。该标准可以是本领域的既有方法。对照参考方法是一种参考方法,其中除了被测试的变量外,所有的参数均与被比较的方法的参数相同。其也可以是本领域通常使用或已知的测量参数的平均值。
多种类型的竞争性结合测定可用于确定一种抗原结合分子是否与另一种竞争,例如:固相直接或间接放射免疫测定(RIA)、固相直接或间接酶免疫测定(EIA)、夹心式竞争性测定(Stahli et al.,1983,Methods in Enzymology9:242-253)、固相直接生物素-抗生物素蛋白EIA(Kirkland et al.,1986,J.Immunol.137:3614-3619)、固相直接标记测定、固相直接标记夹心式测定(Harlow and Lane,1988,Antibodies,A Laboratory Manual,ColdSpring Harbor Press)、使用1-125标记物的固相直接标记RIA(Morel et al.,1988,Molec.Immunol.25:7-15)、固相直接生物素-抗生物素蛋白EIA(Cheung,et al.,1990,Virology 176:546-552)以及直接标记RIA(Moldenhauer et al.,1990,Scand.J.Immunol.32:77-82)。
治疗剂(例如工程化嵌合多肽)的“治疗有效量”、“有效剂量”、“有效量”或“治疗有效剂量”是当单独使用或与另一种治疗剂组合使用时保护受试者免于疾病发作或促进疾病消退的任何量,所述疾病消退由疾病症状严重性的降低、无疾病症状期的频率及持续时间的增加,或由疾病痛苦引起的损害或残疾的预防来证明。治疗剂促进疾病消退的能力可以利用熟练技术人员已知的各种方法进行评估,例如临床试验期间在人类受试者中、在预测人类中疗效的动物模型系统中,或通过在体外测定中测定药剂的活性。本公开的分子的剂量可以在较宽的限度内变化,这取决于待治疗的疾病或病症、待治疗个体的年龄和状况。
本公开的药物组合物中活性成分的实际剂量水平可以变化,以便获得针对特定患者、施用模式和组合物有效实现所需治疗反应而对患者无毒的活性成分的量。所选择的剂量水平取决于多种药代动力学因素,包括所采用的本公开所述特定组合物的活性、施用途径、施用时间、所采用的特定化合物的排泄速率、治疗的持续时间、与所采用的特定组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、状况、总体健康状况和既往病史,以及医学领域中熟知的类似因素。拥有本领域普通技术的医师或兽医可容易地确定和开出所需药物组合物的有效量。例如,医师或兽医开始可以以低于实现期望治疗效果所需的水平开始药物组合物中的本公开所述化合物的剂量,并逐渐增加剂量,直至实现期望效果。通常,本公开所述组合物的合适日剂量为有效产生治疗效果的最低剂量的化合物量。此类有效剂量通常取决于上述因素。该组合物可以用本领域已知的医疗装置进行施用。非限制性实施方案包括针、无针型皮下注射装置、用于连续药物递送的可变速植入式输注装置、具有多室区室的渗透型药物递送系统。
如果需要,则药物组合物的有效日剂量可以以两个、三个、四个、五个、六个或更多个亚剂量施用,所述亚剂量在全天以适当的间隔分开施用,可选地以单位剂型施用。虽然本公开的化合物可以单独施用,但优选将该化合物作为药物制剂(组合物)施用。
术语“核酸”、“核酸序列”、“核苷酸序列”或“多核苷酸序列”和“多核苷酸”可互换使用。它们是指任何长度的核苷酸(如脱氧核糖核苷酸或核糖核苷酸或其类似物)的聚合形式。多核苷酸可以是单链或双链的,如果是单链的,可以是编码链或非编码(反义)链。多核苷酸可包含修饰核苷酸,例如甲基化核苷酸和核苷酸类似物。核苷酸的序列可以被非核苷酸组分中断。聚合后可进一步修饰多核苷酸,例如通过与标记组分缀合。该核酸可以是重组多核苷酸,或基因组、cDNA、半合成或合成来源的多核苷酸,其非天然存在或以非自然排列的形式与另一个多核苷酸连接。cDNA是合成多核苷酸的典型示例。
术语“肽”、“多肽”和“蛋白”可互换使用,并且是指由通过肽键共价连接的氨基酸残基组成的化合物。蛋白或肽含有至少两个氨基酸,并且不限制可构成蛋白或肽序列的氨基酸的最大数目。多肽包括含有通过肽键彼此连接的两个或更多个氨基酸的任何肽或蛋白。如本文所使用的,该术语既指本领域中通常也称为例如肽、寡肽和寡聚体的短链,也指本领域中通常称为蛋白(其中有许多类型)的较长链。“多肽”包括例如生物活性片段、基本上同源的多肽、寡肽、同二聚体、异二聚体、多肽的变体、修饰多肽、衍生物、类似物、融合蛋白等。该多肽包括天然肽、重组肽、合成肽或其组合。
术语“减少”和“降低”在本文中可互换使用,并且表示小于原始情况的任何变化。“减少”和“降低”是相对性术语,需要在测量前和后之间进行比较。“减少”和“降低”包括完全耗尽。
受试者的“治疗”是指对受试者进行的任何类型的干预或过程,或向受试者施用活性剂,目的是逆转、减轻、改善、抑制、减缓或预防症状、并发症或病症的发作、进展、发展、严重性或复发,或与疾病相关的生物化学指标。在一个实施方案中,术语“治疗”是指降低或改善病症(例如增殖性病症)的进展、严重性和/或持续时间,或改善由施用一种或多种疗法引起的病症的一种或多种症状(优选一种或多种可辨别症状)。在一些实施方案中,其中所述一种或多种改善的症状选自由以下各项所构成的组:虚弱、疲劳、呼吸短促、容易瘀伤和出血、频繁感染、淋巴结增大、腹部膨胀或疼痛、骨或关节疼痛、骨折、非计划体重减轻、食欲不振、盗汗、持续轻度发热和排尿减少。在具体实施方案中,术语“治疗”是指改善增殖性病症的至少一种可测量物理参数,例如患者不一定能够识别的肿瘤生长。在其它实施方案中,术语“治疗”是指在物理上通过例如稳定可辨别症状、在生理上通过例如稳定身体参数或二者来抑制增殖性病症的进展。
本文所使用的术语“受试者”包括人和非人动物。非人动物包括所有脊椎动物,例如哺乳动物和非哺乳动物,如非人灵长类动物、绵羊、狗、猫、牛、马、鸡、两栖动物和爬行动物。
为了计算同一性百分比,所比较的序列通常以使序列之间的匹配最大的方式进行比对。可用于测定同一性百分比的计算机程序的一个示例是GCG程序包,其包括GAP(Devereux et al.,1984,Nucl.Acid Res.12:387;Genetics Computer Group,Universityof Wisconsin,Madison,Wis.)。计算机算法GAP用于比对待测定序列同一性百分比的两种多肽或多核苷酸。对序列进行比对是为了实现它们各自氨基酸或核苷酸的最佳匹配(该算法所测定的“匹配跨度”)。在某些实施方案中,该算法还使用标准比较矩阵(参见Dayhoffet al.,1978,Atlas of Protein Sequence and Structure 5:345-352for the PAM250comparison matrix;Henikoff et al.,1992,Proc.Natl.Acad.Sci.U.S.A.89:10915-10919for the BLOSUM 62comparison matrix)。
嵌合多肽/融合蛋白
ANG1-C4BP和C4BP-ANG1分别是指在任意方向上以N至C端次序的ANG1 C端FLD和C4BP C端区段之间的嵌合融合体。通常,ANG1-C4BP变体是指ANG1-C4BP和C4BP-ANG1的域排列类型,并且还包括具有不同接头排列和标签位置的融合体的所有形式。
在一个实施方案中,本公开涉及血管生成素-1的C端Tie2结合纤维蛋白原样域(FLD)和C4BP的C端支架区段之间的嵌合融合体的设计、构建、产生和治疗用途。本公开提供了一种可用于通过Tie2激活而治疗血管病症的新的血管生成素-1(ANG1)模拟物。在一个实施方案中,本公开提供了一种迄今尚未探索的策略,通过用C4BP血浆蛋白区段替代ANG1的SCD-CCOD以获得循环系统中自由循环的能力进行。在一些实施方案中,该嵌合融合蛋白是“生物更好”ANG1。
在一个实施方案中,本公开提供了重组融合体(根据域排列的N至C端次序的称为ANG1-C4BP或C4BP-ANG1的)通过C4BP区段天然折叠成七聚体结构,并以“郁金香花束”样的构型(图1B)展示了ANG1的7个FLD,类似于天然ANG1的构型(图1A)。
在一个实施方案中,人血清C4BPα链的C端支架区段通过接头与人ANG1 FLD融合为C4BP-ANG1或ANG1-C4BP。在一个实施方案中,在具有ANG1的嵌合融合蛋白中,C4BP区段形成闭合的环结构,其锚定多聚体C4BP组装体并折叠成显示七个ANG1头部基(七价)的稳定七聚体中心柄结构(图1)。由于七聚体多聚化通过链间二硫键键合的设计特征,嵌合融合蛋白中的七个ANG1 FLD形成关联Tie2受体的高亲和力配体,导致Tie2的有效结合和激动性激活。
在一个实施方案中,ANG1和C4BP之间的重组融合体可包括额外的纯化标签序列,例如6xHis标签,并且有或没有用于标签去除的内肽酶切割序列。
在一些实施方案中,重组ANG1-C4BP融合体包括变体,其具有ANG1和C4BP区段之间的替代域排列(和这些区间之间的排列)以及其他纯化标签和内肽酶切割序列。
在一个实施方案中,C4BP蛋白包含NCBI登录号NP_000706.1提供的序列。在一个实施方案中,血管生成素1蛋白包含NCBI登录号NP_001137.2提供的序列。
在一个实施方案中,本公开提供了一种选自以下多肽及其功能片段或衍生物中的任一种的多肽。
SEQ ID NO:0001:c4bp组分
ETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKEL
SEQ ID NO:0002:Ang1组分
KPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDF
SEQ ID NO:0003:Ang2组分
ISFRDCAEVFKSGHTTNGIYTLTFPNSTEEIKAYCDMEAGGGGWTIIQRREDGSVDFQRTWKEYKVGFGNPSGEYWLGNEFVSQLTNQQRYVLKIHLKDWEGNEAYSLYEHFYLSSEELNYRIHLKGLTGTAGKISSISQPGNDFSTKDGDNDKCICKCSQMLTGGWWFDACGPSNLNGMYYPQRQNTNKFNGIKWYYWKGSGYSLKATTMMIRPADF
SEQ ID NO:0004:GGGGS接头
GGGGS
SEQ ID NO:0005:IL2信号肽
MYRMQLLSCIALSLALVTNS
SEQ ID NO:0006:CD33信号肽
MPLLLLLPLLWAGALA
SEQ ID NO:0007:肠激酶切割位点
DDDDK
SEQ ID NO:0008:Ang1-c4bp-H6(聚His标签)
KPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFGGGGSETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKELHHHHHH
SEQ ID NO:0009:L2SP-Ang1-c4bp-H6
MYRMQLLSCIALSLALVTNSKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFGGGGSETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKELHHHHHH
SEQ ID NO:0010:c4bp-Ang1-H6
ETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKELGGGGSKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFHHHHHH
SEQ ID NO:0011:IL2SP-c4bp-Ang1-H6
MYRMQLLSCIALSLALVTNSETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSAR QSTLDKELGGGGSKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFHHHHHH
SEQ ID NO:0012:c4bp-Ang2-H6
ETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKELGGGGSISFRDCAEVFKSGHTTNGIYTLTFPNSTEEIKAYCDMEAGGGGWTIIQRREDGSVDFQRTWKEYKVGFGNPSGEYWLGNEFVSQLTNQQRYVLKIHLKDWEGNEAYSLYEHFYLSSEELNYRIHLKGLTGTAGKISSISQPGNDFSTKDGDNDKCICKCSQMLTGGWWFDACGPSNLNGMYYPQRQNTNKFNGIKWYYWKGSGYSLKATTMMIRPADFHHHHHH
SEQ ID NO:0013:IL2SP-c4bp-Ang2-H6
MYRMQLLSCIALSLALVTNSETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSAR QSTLDKELGGGGSISFRDCAEVFKSGHTTNGIYTLTFPNSTEEIKAYCDMEAGGGGWTIIQRREDGSVDFQRTWKEYKVGFGNPSGEYWLGNEFVSQLTNQQRYVLKIHLKDWEGNEAYSLYEHFYLSSEELNYRIHLKGLTGTAGKISSISQPGNDFSTKDGDNDKCICKCSQMLTGGWWFDACGPSNLNGMYYPQRQNTNKFNGIKWYYWKGSGYSLKATTMMIRPADFHHHHHH
SEQ ID NO:0014:H6-EK-Ang1-c4bp
HHHHHHGDDDDKKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFGGGGSETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKEL
SEQ ID NO:0015:IL2SP-H6-EK-Ang1-c4bp
MYRMQLLSCIALSLALVTNSEHHHHHHGDDDDKKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFGGGGSETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQ RDSARQSTLDKEL
SEQ ID NO:0016:H6-EK-c4bp-Ang1
HHHHHHGGDDDDKETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTLDKE LGGGGSKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDF
SEQ ID NO:0017:IL2SP-H6-EK-c4bp-Ang1
MYRMQLLSCIALSLALVTNSEHHHHHHGGDDDDKETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLS LEIEQLELQRDSARQSTLDKELGGGGSKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDF
SEQ ID NO:0018:IL2SP-Ang1-c4bp
MYRMQLLSCIALSLALVTNSEKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFGGGGSETPEGCEQVLTGKRLMQCLPNPEDVKMALE
SEQ ID NO:0019:CD33SP-c4bp-Ang1-H6
MPLLLLLPLLWAGALAETPEGCEQVLTGKRLMQCLPNPEDVKMALEVYKLSLEIEQLELQRDSARQSTL DKELGGGGSKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDFHHHHHH
在一个实施方案中,本公开提供了一种多肽,其包含与上述序列中的任一个具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在一个实施方案中,该多肽与本文所述的ANG1-C4BP或C4BP-ANG1中的至少一个在体外和/或体内竞争与Tie-2结合。在一个实施方案中,该多肽以约100μM或更小、约50μM或更小、约25μM或更小、或约10μM或更小的亲和力与Tie-2结合;更优选地具有约1μM或更小、约100nM或更小、约50nM或更小、约25nM或更小的高亲和力;优选地,结合亲和力在约1nM至约10nM、约10nM至约20nM、约20nM至约30nM、约30nM至约40nM、约40nM至约50nM、约50nM至约60nM、约60nM至约70nM、约70nM至约80nM、约80nM至约90nM、或约90nM至约100nM的范围内。
在一个实施方案中,该多肽用于检测。在一个实施方案中,该多肽与标记缀合。在一个实施方案中,该标记是放射性标记或荧光标记。
核酸、载体和细胞
在一个实施方案中,本公开提供了编码本公开所述多肽的核酸。在一个实施方案中,该核酸包含以下序列中的一个或多个:
SEQ ID NO:0019:IL2SP-Ang1-c4bp-H6的DNA[匹配0008(无SP)和0009(IL2SP)]
ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCACGAATTCGAAACCATTTAGAGACTGTGCAGATGTATATCAAGCTGGTTTTAATAAAAGTGGAATCTACACTATTTATATTAATAATATGCCAGAACCCAAAAAGGTGTTTTGCAATATGGATGTCAATGGGGGAGGTTGGACTGTAATACAACATCGTGAAGATGGAAGTCTAGATTTCCAAAGAGGCTGGAAGGAATATAAAATGGGTTTTGGAAATCCCTCCGGTGAATATTGGCTGGGGAATGAGTTTATTTTTGCCATTACCAGTCAGAGGCAGTACATGCTAAGAATTGAGTTAATGGACTGGGAAGGGAACCGAGCCTATTCACAGTATGACAGATTCCACATAGGAAATGAAAAGCAAAACTATAGGTTGTATTTAAAAGGTCACACTGGGACAGCAGGAAAACAGAGCAGCCTGATCTTACACGGTGCTGATTTCAGCACTAAAGATGCTGATAATGACAACTGTATGTGCAAATGTGCCCTCATGTTAACAGGAGGATGGTGGTTTGATGCTTGTGGCCCCTCCAATCTAAATGGAATGTTCTATACTGCGGGACAAAACCATGGAAAACTGAATGGGATAAAGTGGCACTACTTCAAAGGGCCCAGTTACTCCTTACGTTCCACAACTATGATGATTCGACCTTTAGATTTTGGTGGCGGTGGCTCAGAGACCCCCGAAGGCTGTGAACAAGTGCTCACAGGCAAAAGACTCATGCAGTGTCTCCCAAACCCAGAGGATGTGAAAATGGCCCTGGAGGTATATAAGCTGTCTCTGGAAATTGAACAACTGGAACTACAAAGGGACAGCGCAAGACAATCCACTTTGGATAAAGAACTACATCACCATCACCATCACTAA
SEQ ID NO:0020:IL2SP-c4bp-Ang1-H6的DNA[匹配0010(无SP)和0011(IL2SP)]
ATGTACAGAATGCAGCTGCTGTCCTGTATCGCCCTGAGCCTGGCTCTGGTGACCAACTCTGAGACACCAGAGGGATGTGAGCAGGTGCTGACCGGCAAGCGCCTGATGCAGTGCCTGCCCAATCCTGAGGATGTGAAGATGGCCCTGGAGGTGTACAAGCTGTCCCTGGAGATCGAGCAGCTGGAGCTGCAGAGGGATTCCGCCCGGCAGTCTACACTGGACAAGGAGCTGGGAGGAGGAGGCAGCAAGCCTTTCAGGGATTGTGCCGACGTGTATCAGGCTGGCTTTAACAAGTCTGGCATCTACACCATCTATATCAACAATATGCCAGAGCCCAAGAAGGTGTTCTGCAACATGGACGTGAATGGCGGCGGCTGGACAGTGATCCAGCACAGGGAGGATGGCAGCCTGGACTTCCAGCGGGGCTGGAAGGAGTACAAGATGGGCTTTGGCAACCCATCTGGCGAGTATTGGCTGGGCAATGAGTTCATCTTTGCCATCACCTCCCAGAGACAGTACATGCTGCGCATCGAGCTGATGGATTGGGAGGGCAATAGGGCTTACTCTCAGTATGACCGGTTCCATATCGGCAACGAGAAGCAGAATTACCGGCTGTATCTGAAGGGACACACCGGAACAGCTGGCAAGCAGTCCAGCCTGATCCTGCATGGCGCCGATTTTTCCACCAAGGACGCTGATAACGACAATTGCATGTGCAAGTGCGCCCTGATGCTGACAGGAGGATGGTGGTTCGACGCTTGCGGACCAAGCAACCTGAATGGCATGTTTTATACAGCTGGCCAGAACCACGGCAAGCTGAATGGCATCAAGTGGCATTACTTCAAGGGCCCTTCTTATTCCCTGAGATCCACCACAATGATGATCCGCCCACTGGATTTTCACCATCACCATCACCATTAA
SEQ ID NO:0021:CD33SP-c4bp-Ang1-H6的DNA[匹配0010(无SP)和0020(CD33SP)]
ATGCCTCTGCTGCTGCTGCTGCCACTGCTGTGGGCTGGCGCTCTGGCCGAGACACCAGAGGGCTGTGAGCAGGTGCTGACAGGCAAGAGACTGATGCAGTGCCTGCCCAACCCTGAGGATGTGAAGATGGCTCTGGAGGTGTACAAGCTGTCTCTGGAGATCGAGCAGCTGGAGCTGCAGAGGGATAGCGCCCGGCAGTCTACCCTGGACAAGGAGCTGGGAGGAGGAGGCTCTAAGCCCTTCCGCGATTGTGCTGACGTGTATCAGGCCGGCTTTAATAAGTCCGGCATCTACACCATCTATATCAACAATATGCCAGAGCCCAAGAAGGTGTTCTGCAACATGGACGTGAATGGCGGCGGCTGGACAGTGATCCAGCACAGGGAGGATGGCTCCCTGGACTTCCAGCGGGGCTGGAAGGAGTACAAGATGGGCTTTGGCAACCCTTCCGGCGAGTATTGGCTGGGCAATGAGTTCATCTTTGCTATCACAAGCCAGAGACAGTACATGCTGCGCATCGAGCTGATGGATTGGGAGGGCAACAGGGCCTACAGCCAGTATGACCGGTTCCATATCGGCAACGAGAAGCAGAATTACAGGCTGTATCTGAAGGGCCACACCGGCACAGCTGGCAAGCAGTCCAGCCTGATCCTGCATGGCGCTGACTTCTCCACCAAGGACGCCGATAACGACAATTGCATGTGCAAGTGCGCTCTGATGCTGACAGGAGGATGGTGGTTCGACGCTTGTGGACCATCTAACCTGAATGGCATGTTTTATACCGCCGGCCAGAACCACGGCAAGCTGAATGGCATCAAGTGGCATTACTTCAAGGGCCCCTCTTATTCCCTGAGATCCACCACAATGATGATCCGCCCTCTGGATTTTCACCATCACCATCACCATTAA
SEQ ID NO:0022:IL2SP-c4bp-Ang2-H6的DNA[匹配0012(无SP)和0013(IL2SP)]
ATGTACAGAATGCAGCTGCTGAGCTGTATCGCCCTGTCTCTGGCTCTGGTGACCAACTCTGAGACACCAGAGGGCTGTGAGCAGGTGCTGACCGGCAAGCGCCTGATGCAGTGCCTGCCCAATCCTGAGGATGTGAAGATGGCCCTGGAGGTGTATAAGCTGTCCCTGGAGATCGAGCAGCTGGAGCTGCAGAGAGATTCTGCTCGCCAGTCCACCCTGGACAAGGAGCTGGGAGGAGGAGGCAGCATCTCTTTCAGAGATTGTGCCGAGGTGTTTAAGAGCGGCCACACCACAAACGGCATCTACACCCTGACATTCCCTAATTCTACAGAGGAGATCAAGGCCTATTGCGACATGGAGGCTGGAGGAGGAGGATGGACCATCATCCAGAGGCGGGAGGATGGCAGCGTGGACTTCCAGAGGACATGGAAGGAGTACAAAGTGGGCTTTGGCAACCCATCTGGCGAGTATTGGCTGGGCAACGAGTTCGTGTCCCAGCTGACCAATCAGCAGCGGTACGTGCTGAAGATCCATCTGAAGGATTGGGAGGGCAACGAGGCCTACTCTCTGTATGAGCACTTTTACCTGTCCAGCGAGGAGCTGAATTATCGCATCCATCTGAAGGGCCTGACCGGCACAGCTGGCAAGATCTCTTCCATCTCCCAGCCCGGCAACGATTTCAGCACCAAGGACGGCGATAATGACAAGTGCATCTGTAAGTGCTCCCAGATGCTGACAGGAGGATGGTGGTTCGACGCTTGCGGACCAAGCAACCTGAATGGCATGTACTATCCCCAGAGGCAGAACACAAATAAGTTTAATGGCATCAAGTGGTACTATTGGAAGGGCTCCGGCTATAGCCTGAAGGCCACCACAATGATGATCCGGCCTGCTGACTTTCACCATCACCATCACCATTAA
SEQ ID NO:0023:IL2SP-H6-EK-Ang1-c4bp[匹配0014(无SP)和0015(IL2SP)两者]
ATGTACAGAATGCAGCTGCTGTCCTGTATCGCCCTGAGCCTGGCTCTGGTGACCAACTCTGAGCACCATCACCATCACCATGGCGACGATGACGATAAGAAGCCATTCCGCGATTGTGCCGACGTGTATCAGGCTGGCTTTAATAAGTCCGGCATCTACACCATCTATATCAACAATATGCCCGAGCCTAAGAAGGTGTTCTGCAACATGGATGTGAATGGCGGCGGCTGGACAGTGATCCAGCACAGGGAGGATGGCAGCCTGGACTTCCAGCGGGGCTGGAAGGAGTACAAGATGGGCTTTGGCAACCCCTCTGGCGAGTATTGGCTGGGCAATGAGTTCATCTTTGCCATCACATCCCAGAGACAGTACATGCTGCGCATCGAGCTGATGGATTGGGAGGGCAACAGGGCTTACTCTCAGTATGACCGGTTCCATATCGGCAACGAGAAGCAGAATTACAGGCTGTATCTGAAGGGACACACCGGAACAGCTGGCAAGCAGTCCAGCCTGATCCTGCATGGCGCCGATTTTTCCACCAAGGACGCTGATAACGACAATTGCATGTGCAAGTGCGCCCTGATGCTGACAGGAGGATGGTGGTTCGACGCTTGCGGACCAAGCAACCTGAATGGCATGTTTTACACCGCTGGCCAGAACCACGGCAAGCTGAATGGCATCAAGTGGCATTACTTCAAGGGCCCTTCTTATTCCCTGAGAAGCACCACAATGATGATCAGGCCTCTGGATTTTGGAGGAGGAGGCTCTGAGACACCAGAGGGATGTGAGCAGGTGCTGACAGGCAAGCGGCTGATGCAGTGCCTGCCAAATCCCGAGGACGTGAAGATGGCCCTGGAGGTGTATAAGCTGTCCCTGGAGATCGAGCAGCTGGAGCTGCAGAGGGATTCCGCCCGGCAGTCTACACTGGACAAGGAGCTGTAA
SEQ ID NO:0024:IL2SP-H6-EK-c4bp-Ang1的DNA[匹配0016(无SP)和0017(IL2SP)两者]
ATGTACAGAATGCAGCTGCTGTCCTGTATCGCCCTGAGCCTGGCTCTGGTGACCAACTCTGAGCACCATCACCATCACCATGGCGGCGACGATGACGATAAGGAGACACCCGAGGGCTGTGAGCAGGTGCTGACAGGCAAGCGCCTGATGCAGTGCCTGCCCAATCCTGAGGATGTGAAGATGGCCCTGGAGGTGTACAAGCTGTCCCTGGAGATCGAGCAGCTGGAGCTGCAGAGGGATTCCGCCCGGCAGTCTACACTGGACAAGGAGCTGGGAGGAGGAGGCAGCAAGCCTTTCAGGGATTGTGCCGACGTGTATCAGGCTGGCTTTAACAAGTCTGGCATCTACACCATCTATATCAACAATATGCCAGAGCCCAAGAAGGTGTTCTGCAACATGGACGTGAATGGCGGCGGCTGGACAGTGATCCAGCACAGGGAGGATGGCAGCCTGGACTTCCAGCGGGGCTGGAAGGAGTACAAGATGGGCTTTGGCAACCCATCTGGCGAGTATTGGCTGGGCAATGAGTTCATCTTTGCCATCACCTCCCAGAGACAGTACATGCTGCGCATCGAGCTGATGGATTGGGAGGGCAATAGGGCTTACTCTCAGTATGACCGGTTCCATATCGGCAACGAGAAGCAGAATTACCGGCTGTATCTGAAGGGACACACCGGAACAGCTGGCAAGCAGTCCAGCCTGATCCTGCATGGCGCCGATTTTTCCACCAAGGACGCTGATAACGACAATTGCATGTGCAAGTGCGCCCTGATGCTGACAGGAGGATGGTGGTTCGACGCTTGCGGACCAAGCAACCTGAATGGCATGTTTTATACAGCTGGCCAGAACCACGGCAAGCTGAATGGCATCAAGTGGCATTACTTCAAGGGCCCTTCTTATTCCCTGAGATCCACCACAATGATGATCCGCCCACTGGATTTTTAA
SEQ ID NO:0025:IL2SP-Ang1-c4bp的DNA(无标签)[匹配0018]
ATGTACAGAATGCAGCTGCTGTCCTGTATCGCCCTGAGCCTGGCTCTGGTGACCAACTCTGAGAAGCCATTCCGCGATTGTGCCGACGTGTATCAGGCTGGCTTTAATAAGTCCGGCATCTACACCATCTATATCAACAATATGCCCGAGCCTAAGAAGGTGTTCTGCAACATGGATGTGAATGGCGGCGGCTGGACAGTGATCCAGCACAGGGAGGATGGCAGCCTGGACTTCCAGCGGGGCTGGAAGGAGTACAAGATGGGCTTTGGCAACCCCTCTGGCGAGTATTGGCTGGGCAATGAGTTCATCTTTGCCATCACATCCCAGAGACAGTACATGCTGCGCATCGAGCTGATGGATTGGGAGGGCAACAGGGCTTACTCTCAGTATGACCGGTTCCATATCGGCAACGAGAAGCAGAATTACAGGCTGTATCTGAAGGGACACACCGGAACAGCTGGCAAGCAGTCCAGCCTGATCCTGCATGGCGCCGATTTTTCCACCAAGGACGCTGATAACGACAATTGCATGTGCAAGTGCGCCCTGATGCTGACAGGAGGATGGTGGTTCGACGCTTGCGGACCAAGCAACCTGAATGGCATGTTTTACACCGCTGGCCAGAACCACGGCAAGCTGAATGGCATCAAGTGGCATTACTTCAAGGGCCCTTCTTATTCCCTGAGAAGCACCACAATGATGATCAGGCCTCTGGATTTTGGAGGAGGAGGCTCTGAGACACCAGAGGGATGTGAGCAGGTGCTGACAGGCAAGCGGCTGATGCAGTGCCTGCCAAATCCCGAGGACGTGAAGATGGCCCTGGAGGTGTATAAGCTGTCCCTGGAGATCGAGCAGCTGGAGCTGCAGAGGGATTCCGCCCGGCAGTCTACACTGGACAAGGAGCTGTAA
在一个实施方案中,本公开提供了一种核酸,该核酸包含与上述序列中的任一个具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在一个实施方案中,该核酸序列是密码子优化的。
在一个实施方案中,本公开提供了一种载体,该载体包含本公开所述核酸序列的一种或多种。某些载体能够在它们引入的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其它载体(例如,非附加型哺乳动物载体)可以在引入宿主细胞后整合到宿主细胞的基因组中,从而与宿主基因组一起复制。某些载体能够指导与其可操作连接的基因的表达。这种载体在本文中称为“重组表达载体”(或简称为“表达载体”)。一般情况下,用于重组DNA技术的表达载体通常是质粒的形式。在本说明书中,“质粒”和“载体”可以互换使用,因为质粒是最常见的载体形式。但也包括具有同等功能的其它形式的表达载体,例如病毒载体(如慢病毒、逆转录病毒、复制缺陷型逆转录病毒、腺病毒和腺相关病毒、疱疹病毒)。术语“慢病毒”是指逆转录病毒科的属。慢病毒在能够感染非分裂细胞的逆转录病毒中是独特的;它们可以将大量遗传信息传递到宿主细胞的DNA中,因此它们是最有效的基因递送载体方法之一。在一些实施方案中,该慢病毒载体是人类免疫缺陷病毒1(HIV-1)、人类免疫缺陷病毒2(HIV-2)、梅迪-维斯纳病病毒(visna-maedi virus,VMV)、山羊关节炎-脑炎病毒(CAEV)、马传染性贫血病毒(EIAV)、猫免疫缺陷病毒(FIV)、牛免疫缺陷病毒(BIV)或猴免疫缺陷病毒(SIV)载体。遗传修饰细胞以表达本公开的spFv分子的其它方法包括转座酶、mRNA转染、非整合性慢病毒、“Sleeping Beauty(SB)”转座子、核酸内切酶、用DNA纳米载体进行原位转染。
在一些实施方案中,该载体是腺病毒载体、腺病毒相关载体、DNA载体、慢病毒载体、质粒、逆转录病毒载体或RNA载体。在一些实施方案中,该载体是病毒载体。在一些实施方案中,该载体是逆转录病毒载体。在一些实施方案中,该载体是慢病毒载体。
在一个实施方案中,本公开提供了包含本公开所述多肽的宿主细胞。在一个实施方案中,本公开提供了包含本公开所述核酸的宿主细胞。
在一个实施方案中,本公开提供了包含本公开所述载体的宿主细胞。本说明书的其他部分提供了宿主细胞的示例。
组合物
在一个方面中,本公开提供了包含本文所公开的多肽的组合物。在一个方面中,本公开提供了本文所述的核酸。在一个方面中,本公开提供了包含所述载体的组合物。在一个方面中,本公开提供了包含本文所述宿主细胞的组合物。
在一个实施方案中,该组合物是药物组合物,其包含本文所述的多核苷酸、本文所述的载体、本文所述的多肽或本文所述的宿主细胞。在一些实施方案中,该组合物包含药学上可接受的载体、稀释剂、增溶剂、乳化剂、防腐剂和/或佐剂。
在具体实施方案中,术语“药学上可接受的”是指由联邦或州政府的管理机构批准或在美国药典或其他公认的药典中列出用于动物,更具体地用于人。术语“载体”是指与治疗剂一起施用的稀释剂、佐剂赋形剂或媒介物。此类药物载体可以是无菌液体,例如水和油,包括石油、动物、植物或合成来源的油,如花生油、大豆油、矿物油,芝麻油等。当静脉内施用该药物组合物时,水是优选的载体。盐水溶液和右旋糖水溶液和甘油溶液也可用作液体载体,特别是用于可注射溶液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、磷酸钠、乙酸钠、L-组氨酸、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如果需要,该组合物还可含有少量的润湿剂或乳化剂,或pH缓冲剂。这些组合物可以采取溶液、悬浮剂、乳剂、片剂、丸剂、胶囊剂、粉末、缓释制剂等形式。通常,本公开的组合物的成分以单位剂型单独或混合在一起提供,例如,对于基于载体和多肽的组合物,在指示活性剂的量的密封容器(例如安瓿或小袋)中作为干燥冻干粉末或无水浓缩物。当该组合物通过输注施用时(例如宿主细胞组合物),其可以用含有无菌药物级水或盐水的输注瓶分配。当该组合物通过注射施用时,可提供无菌注射用水或盐水的安瓿,以便在施用前可以混合各成分。
本公开所述的组合物包括可用于制备药物组合物(例如,非纯或非无菌组合物)的散装药物组合物和可用于制备单位剂型的药物组合物(即,适于向受试者或患者施用的组合物)。此类组合物包含预防或治疗有效量的本文所公开的预防和/或治疗性双特异性多肽分子(药剂)或该药剂与药学上可接受的载体的组合。优选地,本公开的组合物包含预防或治疗有效量的一种或多种本公开的分子和药学上可接受的载体。该药物组合物优选包含游离形式或盐形式的分子。优选地,该盐是分子的药学上可接受的盐,诸如例如氯化物或乙酸盐(三氟乙酸盐)。必须注意的是,根据本公开的分子的盐与其体内状态的分子显著不同,因为所述分子在体内不是盐。在一个方面中,水性载体含有多种组分,例如水以及非水载体组分(如本文所述的那些组分)。在另一个方面中,当与本文所述的肽或其它分子组合时,水性载体能够赋予改进的性质,例如改进的溶解度、功效和/或改进的免疫疗法。此外,该组合物可含有赋形剂,例如缓冲剂、粘合剂、爆破剂(blasting agent)、稀释剂、调味剂、润滑剂等。例如,“药学上可接受的稀释剂”可包括生理上相容的溶剂、填充剂、稳定剂、分散介质、包衣材料、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。药学上可接受的稀释剂的示例包括盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等及其组合中的一种或多种。在许多情况下,优选该组合物中包括一种或多种等渗剂,例如诸如海藻糖和蔗糖的糖、诸如甘露糖醇、山梨糖醇的多元醇,或氯化钠。药学上可接受的物质,例如润湿剂或少量的辅助物质(例如润湿或乳化剂、防腐剂或缓冲剂)也在本公开的范围内。此外,该组合物可含有赋形剂,例如缓冲剂、粘合剂、爆破剂、稀释剂、调味剂和润滑剂。
在一个方面中,本文所述的肽或其它分子可与水性载体组合。在一个方面中,该水性载体选自以下各项:离子交换剂、氧化铝、硬脂酸铝、硬脂酸镁、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸二钙、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-乙酸乙烯酯、纤维素基物质(例如微晶纤维素、羟丙基甲基纤维素、醋酸羟丙基甲基纤维素琥珀酸酯、羟丙基甲基纤维素酞酸酯)、淀粉、单水乳糖、甘露糖醇、海藻糖十二烷基硫酸钠和交联羧甲基纤维素钠、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、聚甲基丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
在其它实施方案中,该组合物选择为肠胃外递送、吸入或通过消化道递送,如口服。此类药学上可接受的组合物的制备在本领域技术人员的能力范围内。在某些实施方案中,使用缓冲剂将该组合物维持在生理pH或稍低的pH,通常在约5至约8的pH范围内。在某些实施方案中,当考虑肠胃外施用时,该组合物为无热原的肠胃外可接受的水溶液的形式,其包含在药学上可接受的媒介物中的本文所述的组合物,含有或不含其他治疗剂。在某些实施方案中,该用于肠胃外注射的媒介物是无菌蒸馏水,其中本文所述的组合物(具有或不具有至少一种其他治疗剂)配制为适当保存的无菌等渗溶液。在某些实施方案中,制备涉及用聚合化合物(例如聚乳酸或聚乙醇酸)、微球或脂质体配制所需分子(其提供产品的受控或持续释放),然后通过积存注射法递送。在某些实施方案中,可植入药物递送装置用于引入所需分子。
该组合物的pH通常不应等于本公开所述的特定嵌合多肽的等电点,并且可以在约4.0至约7.0、约5.0至约6.0,或约5.5至约6.0的范围内。在某些实施方案中,本公开的组合物或制剂的pH为约5.5、5.6、5.7、5.8、5.9或6.0。缓冲剂可有助于将本公开所述组合物的pH维持在接近生理条件的范围内。它们可以以约2mM至约50mM的浓度存在。用于本公开的合适的缓冲剂包括有机酸和无机酸及其盐,例如柠檬酸盐缓冲剂(例如,柠檬酸单钠-柠檬酸二钠混合物、柠檬酸-柠檬酸三钠混合物、柠檬酸-柠檬酸单钠混合物等)、琥珀酸盐缓冲剂(例如,琥珀酸-琥珀酸单钠混合物、琥珀酸-氢氧化钠混合物、琥珀酸-琥珀酸二钠混合物等)、酒石酸盐缓冲剂(例如酒石酸-酒石酸钠混合物、酒石酸-酒石酸钾混合物、酒石酸-氢氧化钠混合物等)、富马酸盐缓冲剂(例如富马酸-富马酸单钠混合物、富马酸-富马酸二钠混合物、富马酸单钠-富马酸二钠混合物等)、葡萄糖酸盐缓冲剂(例如葡萄糖酸-葡萄糖酸钠混合物、葡萄糖酸-氢氧化钠混合物、葡萄糖酸-葡萄糖酸钾混合物等)、草酸盐缓冲剂(例如草酸-草酸钠混合物、草酸-氢氧化钠混合物、草酸-草酸钾混合物等)、乳酸盐缓冲剂(例如乳酸-乳酸钠混合物、乳酸-氢氧化钠混合物、乳酸-乳酸钾混合物等),以及醋酸盐缓冲剂(例如醋酸-醋酸钠混合物、醋酸-氢氧化钠混合物等)。此外,可以使用磷酸盐缓冲剂、组氨酸缓冲剂和三甲胺盐(如Tris)。
可以加入防腐剂以延缓微生物生长,并且可以以0.2%-1%(w/v)的量加入。用于本公开的合适的防腐剂包括酚、苯甲醇、间甲酚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、十八烷基二甲基苄基氯化铵、苯扎卤铵(benzalconium halides)(例如苯扎氯铵、苯扎溴铵和苯扎碘铵)、氯化六甲双铵,以及对羟基苯甲酸烷基酯(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯)、儿茶酚、间苯二酚、环己醇和3-戊醇。可添加有时称为“稳定剂”的等渗剂,以确保本公开的液体组合物的等渗性,并且等渗剂包括多元糖醇,例如三元或更高元糖醇,如甘油、赤藓糖醇、阿拉伯糖醇、木糖醇、山梨糖醇和甘露糖醇。稳定剂是指广泛种类的赋形剂,其功能范围可从填充剂到使治疗剂溶解或有助于防止变性或粘附于容器壁的添加剂。典型的稳定剂可以是多元糖醇(以上列举的);氨基酸,例如精氨酸、赖氨酸、甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、丙氨酸、鸟氨酸、L-亮氨酸、2-苯丙氨酸、谷氨酸、苏氨酸等;有机糖或糖醇,例如乳糖、海藻糖、水苏糖、甘露糖醇、山梨糖醇、木糖醇、核糖醇、肌肉肌醇、半乳糖醇、甘油等,包括环多醇(如肌醇);聚乙二醇;氨基酸聚合物;含硫还原剂,例如尿素、谷胱甘肽、硫辛酸、硫代乙醇酸钠、硫代甘油、α-硫代甘油和硫代硫酸钠;低分子量多肽(例如10个残基或更少的肽);蛋白,例如人血清白蛋白、牛血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮单糖(如木糖、甘露糖、果糖、葡萄糖)、双糖(例如乳糖、麦芽糖、蔗糖)和三糖(例如棉子糖),以及多糖(例如葡聚糖)。稳定剂可以以基于活性蛋白的重量而言,0.1-10,000重量份的范围存在。
可以加入非离子表面活性剂或去污剂(也称为“润湿剂”),帮助治疗剂溶解,以及保护含Ang1的分子免于因搅动而诱导的聚集,这也使制剂暴露于剪切表面应力,而不引起蛋白变性。合适的非离子表面活性剂包括聚山梨醇酯(20、80等)、泊洛沙姆(184、188等)、普卢兰尼克(Pluronic)多元醇、聚氧乙烯脱水山梨醇单醚(TWEEN-20、TWEEN-80等)。非离子表面活性剂可以以约0.05mg/mL至约1.0mg/mL,例如约0.07mg/mL至约0.2mg/mL的范围存在。
还提供了用于工程化、制备和产生细胞的方法、含有该细胞的组合物,以及含有和用于使用、产生和施用该细胞的试剂盒和装置。本文所述的任何组合物均可包含在试剂盒中。试剂盒组分以合适的容器提供。
使用方法
在一个实施方案中,本公开提供了重组产生的ANG1-C4BP和C4BP-ANG1在体外、体内,在人细胞和/或小鼠模型中强效激活Tie2。
在一个实施方案中,本公开提供了降低或抑制血管渗漏或血浆通透性的方法。在一个实施方案中,本公开提供了促进血管系统的生长和维持血管系统的内皮结构完整性的方法。
在一个实施方案中,ANG1-C4BP系列生物制剂的治疗用途的预期适应症包括血管性眼病,例如角膜缘毛细血管丛或Schlemm管排流系统缺陷引起的原发性开角型青光眼和各种类型的原发性或继发性视网膜病变,以及如癌症新生血管形成、炎症病症等中血管渗漏的系统性治疗。在一些实施方案中,本公开的嵌合多肽比迄今为止描述的任何其他血管生成素相关生物制剂(包括Bow-Ang1和COMP:Ang1)都更具生物活性,因为其具有意想不到的有利特性。
在一个实施方案中,本公开提供了一种降低有此需要的受试者中血管通透性或渗漏的方法,该方法包括向受试者施用有效量的本公开的多肽、本公开的细胞、本公开的核酸、本公开的载体、本公开的蛋白复合物和/或本公开的药物组合物。在一个实施方案中,皮肤、眼、肺、肾、脑、肝、心脏和/和肠中的血管通透性或渗漏增加。在一个实施方案中,血管通透性或渗漏已经响应于选自VEGF、包括毒性气体的化学剂、感染性细菌和病毒、自身免疫性抗体以及引起内皮功能障碍和血管损伤的抗体药物的试剂的水平的增加而增加。
在一个实施方案中,本公开提供了一种治疗有此需要的受试者中的伴有血管通透性或渗漏异常的疾病或病症的方法,该方法包括向受试者施用有效量的本公开的多肽、本公开的细胞、本公开的核酸、本公开的载体、本公开的蛋白复合物和/或本公开的药物组合物。
在一个实施方案中,本公开提供了一种治疗有此需要的受试者中对Tie2激活响应的疾病或病症的方法,该方法包括向受试者施用有效量的本公开的多肽、本公开的细胞、本公开的核酸、本公开的载体、本公开的蛋白复合物和/或本公开的药物组合物。在一个实施方案中,对Tie2激活响应的疾病或病症是其中至少一种体征或症状的严重性、患者经历此类症状的频率或两者通过Tie2激活而减少或消除的任何疾病或病症。
在一个实施方案中,该病症选自肿瘤血管生成和转移中的癌症、眼部疾病或病症(例如青光眼)、细菌性败血症、严重病毒感染、原生动物感染(例如恶性疟疾)、炎症、致死性炭疽、慢性肾病、急性肾损伤和肾功能障碍、急性肺损伤和支气管功能障碍、急性呼吸窘迫综合征、阻塞性肺病、急性肝衰竭、急性胰腺炎、中风、心肌梗死、充血性心力衰竭、肌萎缩性侧索硬化、阿尔茨海默氏病、亨丁顿氏症、帕金森氏症、外周神经病、糖尿病肾病和视网膜病变、创伤愈合、关节炎、纤维化病症、缺血-再灌注损伤、创伤性脑损伤、癫痫、多发性硬化、器官移植和同种异体移植物排斥。
在一个实施方案中,该癌症选自以下中的任何一种:急性淋巴细胞性癌、急性髓样白血病、小泡型横纹肌肉瘤(alveolar rhabdomyosarcoma)、骨癌、脑癌、乳腺癌、肛门癌、肛管癌或肛门直肠癌、眼癌、肝内胆管癌、关节癌、颈癌、胆囊癌或胸膜癌、鼻癌、鼻腔癌或中耳癌、口腔癌、阴道癌、外阴癌、慢性淋巴细胞白血病、慢性髓样癌、结肠癌、食道癌、宫颈癌、胃肠道类癌肿瘤、神经胶质瘤、霍奇金淋巴瘤、下咽癌、肾癌、喉癌、肝癌、肺癌、恶性间皮瘤、黑色素瘤、多发性骨髓瘤、鼻咽癌、非霍奇金淋巴瘤、口咽癌、卵巢癌、阴茎癌、胰腺癌、腹膜癌、网膜癌和肠系膜癌、咽癌、前列腺癌、直肠癌、肾癌、皮肤癌、小肠癌、软组织癌、胃癌、睾丸癌、甲状腺癌、子宫癌、输尿管癌和膀胱癌。在一个实施方案中,使用本公开的化合物的治疗与其它癌症疗法(包括但不限于化疗和照射)组合进行。
在一个实施方案中,本公开涉及一种治疗有此需要的受试者的血管生成介导疾病的方法。该方法包括施用有效量的包含上述任何其它药剂的组合物。能够治疗的示例性血管生成介导疾病包括非眼出血、心肌梗死、中风、癌症、动脉粥样硬化、缺血性心脏病、冠心病、外周动脉疾病、创伤愈合病症等。
在一个实施方案中,该眼部疾病或病症选自由以下各项所构成的组:年龄相关的黄斑变性(AMD)、黄斑变性、黄斑水肿、糖尿病性黄斑水肿(DME)(包括局灶性、非中心型DME,和弥漫性、中心型DME)、视网膜病变、糖尿病性视网膜病变(DR)(包括增殖性DR(PDR)、非增殖性DR(NPDR)和高海拔DR)、其它缺血相关性视网膜病变、早产儿视网膜病(ROP)、视网膜静脉阻塞(RVO)(包括中央(CRVO)和分支(BRVO)形式)、CNV(包括近视性CNV)、角膜新生血管形成、与角膜新生血管形成相关的疾病、视网膜新生血管形成、与视网膜/脉络膜新生血管形成相关的疾病、病理性近视、von Hippel-Lindau病、眼组织胞浆菌病、家族性渗出性玻璃体视网膜病变(familial exudative vitreoretinopathy,FEVR)、寇茨氏病(Coats'disease)、诺里病(Norrie Disease)、骨质疏松-假性神经胶质瘤综合征(OPPG)、结膜下出血、发红、新生血管性眼病、新生血管性青光眼、视网膜色素变性(RP)、高血压性视网膜病变、视网膜血管瘤性增生、黄斑毛细管扩张、虹膜新生血管形成、眼内新生血管形成、视网膜变性、囊样黄斑水肿(CME)、血管炎、视盘水肿、视网膜炎、结膜炎(包括感染性结膜炎和非感染性(例如变应性)结膜炎)、利伯先天性黑矇(Leber congenital amaurosis)、葡萄膜炎(包括感染性和非感染性葡萄膜炎)、脉络膜炎、眼组织胞浆菌病、睑缘炎、干眼、外伤性眼损伤和斯耶格伦病(disease)。在一个实施方案中,该眼部疾病或病症是青光眼、AMD或DME。
在一个实施方案中,本公开提供了在有此需要的受试者中增强通过眼中的常规流出道的房水流出的方法,其包括向受试者施用有效量的本公开的多肽、本公开的细胞、本公开的核酸、本公开的载体、本公开的蛋白质复合物和/或本公开的药物组合物,从而增强通过受试者中的眼中的常规流出道的房水流出。
在有此需要的受试者中降低眼内压的方法,其包括向受试者施用有效量的本公开的多肽、本公开的细胞、本公开的核酸、本公开的载体、本公开的蛋白质复合物和/或本公开的药物组合物,从而降低受试者中的眼内压。
在一个实施方案中,该方法还包括施用第二药剂。在一个实施方案中,该第二药剂选自抗体、抗炎剂、抗血管生成剂、细胞因子、细胞因子拮抗剂、皮质类固醇和止痛剂。
在一个实施方案中,该抗血管生成剂包括选自以下各项的化合物:VE-PTP抑制剂、贝伐珠单抗(bevacizumab)、伊曲康唑(itraconazole)、羧基氨基三唑(carboxyamidotriazole)、TNP-470、CM101、IFN-α、IL-12、血小板因子-4、苏拉明(suramin)、SU5416、凝血酶敏感蛋白(thrombospondin)、VEGFR拮抗剂、血管抑制类固醇加肝素、软骨源性血管生成抑制因子、基质金属蛋白酶抑制剂、血管抑素、内皮抑素、2-甲氧基雌二醇、替可加兰(tecogalan)、四硫代钼酸盐、沙利度胺(thalidomide)、凝血酶敏感蛋白、催乳素、利诺胺(linomide)、ανβ3抑制剂、雷莫芦单抗(ramucirumab)、他喹莫德(tasquinimod)、雷珠单抗(ranibizumab)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、帕唑帕尼(pazopanib)和依维莫司(everolimus)。
在一个实施方案中,该抗血管生成剂是VEGF拮抗剂。在一个实施方案中,该VEGF拮抗剂是抗VEGF抗体、抗VEGF受体抗体、可溶性VEGF受体融合蛋白、适体(例如培加他尼(pegaptanib)(MACUGEN))、抗-VEGFDARPin(例如abicipar pegol)或VEGFR酪氨酸激酶抑制剂(例如4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(ZD6474)、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171)、瓦他拉尼(vatalanib)(PTK787)、semaxaminib(SU5416)和SUTENT(舒尼替尼))。在一个实施方案中,该抗VEGF抗体是雷珠单抗(ranibizumab)(LUCENTIS)、RTH-258或双特异性抗VEGF抗体。在一个实施方案中,该双特异性抗VEGF抗体是抗VEGF/抗Ang2抗体。在一个实施方案中,该抗VEGF/抗Ang2抗体是RG-7716。在一个实施方案中,可溶性VEGF受体融合蛋白是阿柏西普(aflibercept)(EYLEA)。
适合与本文所公开的组合物和方法组合使用的其它治疗剂包括但不限于依鲁替尼(ibrutinib)(IMBRUVICA)、奥法木单抗(ofatumumab)(ARZERRA)、利妥昔单抗(RITUXAN)、贝伐珠单抗(AVASTIN)、曲妥珠单抗(HERCEPTIN)、恩美曲妥珠单抗(trastuzumab emtansine)(KADCYLA)、伊马替尼(imatinib)(GLEEVEC)、西妥昔单抗(cetuximab)(ERBITUX)、帕尼单抗(panitumumab)(VECTIBIX)、卡妥索单抗(catumaxomab)、替伊莫单抗(ibritumomab)、奥法木单抗(ofatumumab)、托西莫单抗(tositumomab)、布伦妥昔单抗(brentuximab)、阿仑单抗(alemtuzumab)、吉妥珠单抗(gemtuzumab)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、来那替尼(neratinib)、阿西替尼(axitinib)、马赛替尼(masitinib)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、托西尼布(toceranib)、来他替尼(lestaurtinib)、阿西替尼(axitinib)、西地尼布(cediranib)、仑伐替尼(lenvatinib)、尼达尼布(nintedanib)、帕唑帕尼(pazopanib)、瑞戈非尼(regorafenib)、司马沙尼(semaxanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替沃扎尼(tivozanib)、托西尼布(toceranib)、凡德他尼(vandetanib)、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊马替尼(imatinib)、达沙替尼(dasatinib)、尼洛替尼(nilotinib)、普纳替尼(ponatinib)、拉多替尼(radotinib)、博舒替尼(bosutinib)、来他替尼(lestaurtinib)、鲁索替尼(ruxolitinib)、帕瑞替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、比美替尼(binimetinib)、阿来替尼(alectinib)、塞瑞替尼(ceritinib)、克唑替尼(crizotinib)、阿柏西普(aflibercept)、adipotide、地尼白介素(denileukindiftitox)、mTOR抑制剂(例如依维莫司(Everolimus)和替西罗莫司(Temsirolimus))、hedgehog抑制剂(例如索尼德吉(sonidegib)和维莫德吉(vismodegib)),以及CDK抑制剂(例如CDK抑制剂(帕布昔利布(palbociclib)))。
抗炎剂或抗炎药包括但不限于类固醇和糖皮质激素(包括倍他米松(betamethasone)、布地奈德(budesonide)、地塞米松、醋酸氢化可的松(hydrocortisoneacetate)、氢化可的松、甲泼尼龙、泼尼松龙、泼尼松、曲安奈德)、非类固醇类抗炎药(NSAIDS)(包括阿司匹林、布洛芬、萘普生、甲氨蝶呤、柳氮磺胺吡啶、来氟米特、抗TNF药物、环磷酰胺和霉酚酸酯)。示例性NSAID包括布洛芬、萘普生、萘普生钠、Cox-2抑制剂和唾液酸化物(sialylates)。示例性止痛剂包括对乙酰氨基酚、羟考酮、盐酸丙氧芬曲马多。示例性糖皮质激素包括可的松、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙或泼尼松。示例性生物反应调节剂包括针对细胞表面标记物(例如,CD4、CD5等)的分子、细胞因子抑制剂,例如TNF拮抗剂(例如依那西普(ENBREL)、阿达木单抗(HUMIRA)和英夫利昔单抗(REMICADE)、趋化因子抑制剂和粘附分子抑制剂。生物反应调节剂包括单克隆抗体以及重组形式的分子。示例性DMARD包括硫唑嘌呤、环磷酰胺、环孢菌素、甲氨蝶呤、青霉胺、来氟米特、柳氮磺胺吡啶、羟氯喹、金(口服(金诺芬(auranofin))和肌内)和米诺环素。
该方法还可包括在动物模型中测定ANG1-C4BP及其变体的功效的步骤,以及评价Tie2的全身激活(例如肺中)从而确定生物制品的功效的步骤。在该方法中使用的动物可以是啮齿动物,或较大的动物,如兔。但任何合适的动物均可用作体内动物模型。Tie2相关疾病或病症的体内动物模型是本领域熟知的。
实施例
实施例1:
构建体设计和小规模表达
在GenScript公司进行编码ANG1-C4BP嵌合融合构建体(图2)的cDNA的基因合成。将构建体的密码子优化的(CHO密码子偏好)cDNA亚克隆到pTT81表达载体或类似物中,并瞬时转染CHO和HEK293细胞用于小规模生产分析(图3)。利用瞬时表达来测试融合至C4BP的ANG1和ANG2的不同嵌合构建体。所有重组融合蛋白均以约280kDa的七聚体形式分泌,构建体H6EKC4BPAng1和H6EKAng1C4BP以最高水平表达,如非还原和还原条件下的丽春红S溶液染色所示(图3A),以及使用抗His标签抗体的非还原性和还原性SDS-PAGE western印迹所示(图3B)。通过比较在存在和不存在还原剂β-巯基乙醇的情况下蛋白在SDS-PAGE凝胶上的行为,来证实重组融合蛋白的多聚体状态。
实施例2:
血管生成素-C4BP和C4BP-血管生成素的大规模表达
为了稳定表达不同的ANG1-C4BP构建体,对加拿大国家研究委员会(NRC)的CHO-BRI(克隆55E1)细胞进行转染并且通过添加甲硫氨酸硫酰亚胺(MSX)达约两周选择。随后在摇瓶中进行稳定CHO-BRI的池表达和补料分批生产。将培养物在于期望温度且覆盖5%的CO2保持的加湿培养箱中的定轨摇床上搅动。将细胞维持在化学限定的PowerCHO2培养基中,使用BalanCD生长A作为基础培养基(补充有MSX和0.3%pluronic F68)进行补料-分批培养。对于补料-分批培养,每天调节补料速率以维持培养物中规定的恒定葡萄糖水平。CHO-BRI是一种用于重组蛋白生产的稳定表达系统,其使用cumate诱导型表达平台生成CHO池,其在转染后4周内稳定表达200至1000mg/L-2周用于池选择和扩增,2周用于生产(Poulain A,et al.Rapid protein production from stable CHO cell pools usingplasmid vector and the cumate gene-switch.J Biotechnol.2017;255:16–27)。
通过SDS-PAGE考马斯蓝染色(图4),以及非还原性(图5)和还原性(图6)SDS-PAGE分离和用抗His标签抗体进行免疫印迹法后,以预期分子量发现嵌合融合血管生成素-C4BP构建体的重组蛋白产物。因此,ANG1-C4BP和C4BP-ANG1嵌合融合蛋白的稳定CHO表达显示自组装体为细胞培养基中的预测七聚体。
在摇瓶中进行补料-分批生产来获得重组蛋白,采集所述重组蛋白并通过离心和过滤进行纯化,然后通过利用洗脱梯度进行固定化金属亲和层析(IMAC)纯化,脱盐并将缓冲剂交换到DPBS中,浓缩,无菌过滤,并通过280nm处的吸光度定量。通过UPLC-SEC(超高效液相层析法-尺寸排阻层析法)对纯化的材料进行进一步分析,以测定聚集水平,并通过SDS-PAGE(还原和非还原)进行纯度测定。在峰#2级分中以正确分子量发现重组融合蛋白产物(图7A)。根据所产生的每种重组融合蛋白的体积和总量,峰1和峰2的IMAC纯化级分的概述(图7B)。
将纯化的ANG1-C4BP在-80℃下冷冻储存,并进行至多两轮的冻融(F/T)循环,以测定蛋白稳定性(图8)。在这些条件下没有观察到明显的UPLC-SEC分析曲线变化,证明具有稳定性。
实施例3:
ANG1-C4BP和C4BP-ANG1的体外生物学活性
测试纯化的ANG1-C4BP和C4BP-ANG1在与Fc的重组融合体(称为Tie2-Fc)中与Tie2的胞外域的功能性结合。ANG1-C4BP和C4BP-ANG1均可与Tie2-Fc结合(图9)。
为了测定ANG1-C4BP的效力,在处理20分钟的HUVEC中测量半数最大有效浓度(EC50)。ANG1-C4BP的磷酸-AKT(pAKT)EC50为87ng/mL(图10)。
为了评估生物活性和效力,使用从嵌合融合构建体获得的不同重组蛋白产物在不同浓度下对HUVEC处理20分钟。ANG1和C4BP之间的嵌合融合构建体的重组蛋白产物可以有效激活(磷酸化)Tie2受体酪氨酸激酶(图11A)和诱导其下游靶AKT的磷酸化(图11B)。唯一的例外是由与血管生成素-2FLD融合的C4BP制备的嵌合构建体产物(C4bpAng2H6)。在细胞水平上,C4BP-ANG1刺激Tie2,并重新组织其在培养的HUVEC中的亚细胞分布。在C4BP-ANG1处理后,细胞表面Tie2簇集,并汇集到连接处(图12)。总之,两种构型的ANG1-C4BP和C4BP-ANG1重组融合蛋白形成稳定的七聚体,其与关联的Tie2受体结合,导致其激活,这与预期的ANG1-C4BP变体的七价簇集效果一致。
实施例4:
C4BP-ANG1的体内生物学活性
为了测定C4BP-ANG1的体内生物学活性,以范围为0.2至1ug/g体重的不同浓度静脉内注射BALB/c小鼠(图13A)。所使用的三种浓度以剂量依赖的方式导致肺中Tie2激活。C4BP-ANG1在治疗后一到15分钟就激活Tie2(图13B)并持续至少6小时,在治疗后16小时,较低的激活水平明显(图13C)。
用三只白色新西兰兔进行了眼药代动力学实验,来测定单次玻璃体内注射重组融合蛋白后房水中的C4BP-ANG1水平。在向每只兔的右眼中玻璃体内注射100μg的C4BP-ANG1之前,以及注射后第1天至第7天,通过每天进行房水抽取收集来收集房水。第7天对兔执行安乐死后收集玻璃体液。如通过ELISA测量的,兔的玻璃体内注射显示,在房水(AH)中持续的C4BP-ANG1达少数天,在前2或3天出现峰值,然后逐渐整平至基线(图14)。需要灵敏度更高的方法来检测在玻璃体内注射后三天C4BP-ANG1的AH水平。甚至在治疗之后7天后,右眼的玻璃体液(VH)中也检测到C4BP-ANG1,而左VH用作媒介物阴性对照(图14)。
为了测定C4BP-ANG1在体内的效力,在BALB/c小鼠中使用伊文斯蓝染料进行四种不同的血管通透性研究(Miles测定)。伊文斯蓝染料对血清白蛋白具有非常高的亲和力,并且其在间质间隙中的存在可以指示蛋白的血管渗漏。在VEGF诱导的皮下通透性Miles测定中,C4BP-ANG1显著减少血管渗漏(图15)。将VEGF和C4BP-ANG1单独或一起皮下注射到小鼠体内,并通过测量630nm处的光密度对伊文斯蓝染料进行定量(图15)。与局部皮下注射C4BP-ANG1不同,在皮下VEGF前30分钟静脉内注射生物制剂也显示用C4BP-ANG1治疗减少血管渗漏(图16)。类似地,全身静脉内注射C4BP-ANG1也降低化学诱导的血管渗漏的严重性(图17)。在肺血管通透性测定中,静脉内注射C4BP-ANG1改善吸入细菌脂多糖(LPS)以诱导肺中血管渗漏的小鼠中的血管渗漏(图18)。总的伊文斯蓝染料提取和测量显示,用C4BP-ANG1治疗的小鼠中渗漏减少(图18)。总的来说,这些体内测定结果都表明C4BP-ANG1的稳健生物学活性及其血管保护作用。
实施例5
C4BP-ANG1的体内生物学活性的青光眼模型血管生成素模拟物的递送激活SC中内源性TEK信号传导并通过增强流出设施(facility)降低IOP以及在啮齿类青光眼模型中改善TM-SC结构和功能并且保护RGC
升高的眼内压(IOP)是青光眼发展和进展的主要风险因素,并且源自对房水流出的阻力增加。已显示了IOP的降低降低了患有眼高血压的眼中转化为青光眼的风险,并降低患有存在的青光眼损伤的眼中疾病恶化的风险。先前已经示出,受损的血管生成素/Tie2信号传导会损害Schlemm管的完整性并诱发青光眼。
虽然旨在恢复增加流出阻力的患病组织功能的疗法是特别需要的,但目前很少有此类疗法存在。这些患病组织位于由近管组织、小梁网(TM)和Schlemm管(SC)组成的常规流出道中(Stamer,W.D.,et al.,Biomechanics of Schlemm's canal endothelium andintraocular pressure reduction.Progress in Retinal&Eye Research,2015.44:p.86-98.)。血管生成素(Angpt)-TEK血管信号传导通路的活性降低在小鼠中导致严重形式的原发性先天性青光眼(PCG),并且在患有PCG的儿童中存在已知的TEK基因突变。SC的发育需要血管酪氨酸激酶受体TEK(在SC内皮中表达)被其配体血管生成素(由TM表达)激活,所述SC是眼边缘区域的特化圆形血管,对房水流出和维持IOP至关重要。小鼠中SC缺陷的严重程度,眼高血压和视网膜神经节细胞(RGC)损失与Angpt/TEK信号传导的活性成反比,并且增强TEK活性可以降低IOP并防止RGC死亡。TEK基因或编码其配体ANGPT1的基因的功能丧失突变导致PCG(在20名患者中鉴定出20种独特的突变)。ANGPT1基因组区域的变体与成人原发性开角型青光眼(POAG)相关,并且据报道,减少的Angpt/TEK信号传导导致成年猴的青光眼。
C4BP-ANG1蛋白使用CellFactoryTM系统生产,并通过FPLC纯化。通过ELISA测量,玻璃体内注射显示AH中持续的Angpt1长达6小时。基于注射到玻璃体中的其他蛋白质的药代动力学,预测在眼和前房中的持久表达。
在眼病症的三种小鼠模型中显示C4BP-ANG1的体内活性:
a.Prox1+-GFP血压正常小鼠[Truong,T.N.,et al.,Novel characterizationand live imaging of Schlemm's canal expressing Prox-1.2014.9(5):p.e98245](Prox1-GFP与C57Bl6背景上的荧光SC)
b.TEK+/-小鼠(有缓慢RGC细胞损失的轻度下效(hypomorphic)的SC管);对照是经过媒介物治疗的眼
c.NC-Angpt1 KO(严重下效SC,PCG模型);对照是经过媒介物治疗的眼
由于C4-ANPGT1蛋白的大小,它不穿透成熟的血液-视网膜屏障,因此通过玻璃体内注射递送它。
流出设施,来自具有荧光SC的对照小鼠的正常血压眼的IOP
使用正常血压眼的小鼠模型来测定C4BP-ANG1是否可以降低IOP并增强正常血压眼中的流出设施以及TEK在SC中多么长地保持激活。在Prox1启动子下表达增强的绿色荧光蛋白(GFP)的3个月龄B57Bl6小鼠[Truong,T.N.,et al.,Novel characterization andlive imaging of Schlemm's canal expressing Prox-1.2014.9(5):p.e98245]允许容易鉴定SC;IOP是使用回弹式眼压测量法(rebound tonometry)测量的;测量对流出设施的影响[Sherwood,J.M.,et al.,Measurement of Outflow Facility UsingiPerfusion.2016.11(3):p.e0150694];TEK激活是通过使用磷酸特异性TEK抗体对SC进行免疫组织化学测定的[Kim,J.,et al.,Impaired angiopoietin/Tie2 signalingcompromises Schlemm's canal integrity and induces glaucoma.Journal ofClinical Investigation,2017.127(10):p.3877-3896];为了测定药物是否发生全身吸收,收获肺和对侧对照眼,并通过Western印迹和免疫染色测定这些组织中的TEK活化。
时间点:将3个月龄WT小鼠组玻璃体内注射1ul的1ug/ul纯化的C4BP-ANG1蛋白、媒介物(1ug/ul白蛋白),或用0.01%的拉坦前列素(latanoprost)进行局部治疗作为阳性对照。在注射后2小时、6小时、24小时和1周测定Tie2/TEK的定位和磷酸染色。在解剖前立即测量流出设施。在第二组动物中,在基线、治疗后1小时、2小时、4小时、8小时和24小时测量IOP。测量一式三份进行。在1周组中,收获SC和TM并分析组织学,如先前所述[Thomson,B.R.,et al.,Angiopoietin-1is required for Schlemm'scanal development in miceand humans.Journal of Clinical Investigation,2017.127(12):p.4421-4436]。
青光眼模型(TEK+/1,NC-Angpt1)的ANGPT1-模拟物治疗:
小鼠模型用于确定SC和流出道是否有任何结构或功能挽救,以及在上面列出的2种青光眼模型中的任一种(一种轻度和一种重度)中是否可以预防进行性RGC损失。测试了两个时间点:1)正常发生活跃SC生长的产后早期阶段和2)已经有升高的IOP和RGC损失但尚未达到终末期的6周龄小鼠。
早期:在出生后第3天(P3)和P5进行两次注射,并在P7收获眼。读数与上述类似。量化SC形态、免疫染色、大小和卷积,并且分析TM组织学,如先前所述[Thomson,B.R.,et al.,Angiopoietin-1is required for Schlemm'scanal development in mice andhumans.Journal of Clinical Investigation,2017.127(12):p.4421-4436;Thomson,B.R.,Carota,I.A.,Souma,T.,Soman,S.,Vestweber,D.,Quaggin,S.E.,Targeting thevascularspecific phosphatase PTPRB protects against retinal ganglion cellloss in a pre-clinical model of glaucoma.eLife,2019]。主要读数是在此早期时间点的结构挽救,考虑到在此类幼小鼠中难以测量流出或测量IOP。时间点的选择基于在小鼠中关闭SC生长的Angpt-VEGF pepti-body注射的相似的给药日程表[Thackaberry,E.A.,etal.,Rapid Development of Glaucoma Via ITV Nonselective ANGPT 1/2Antibody:APotential Role for ANGPT/TIE2 Signaling in Primate Aqueous HumorOutflow.2019.60(13):p.4097-4108]。
患有青光眼的幼成年小鼠,6周:首先寻找对照小鼠的详细药代动力学数据的结果,以测定最佳注射间隔和给药。选择的间隔给药允许在如下的浓度时注射剂量的约50%的Angpt1水平最低点,所述浓度经证实增强Western印迹上定量的TEK磷酸化。读数包括收获时(12周龄)的SC免疫染色、大小、卷积、形态和TM组织学。IOP在基线时和每周通过回弹式眼压测量法测量。
实施例6
C4BP-ANG1的体内生物活性
挽救Schlemm管的大小
野生型和神经嵴特异性血管生成素-1敲除(Angpt1 dNC)小鼠从出生后第0-4天开始通过每日IP注射用C4BP-ANG1治疗。在P14,收集眼并量化Schlemm管面积。在野生型和Angpt1 dNC眼两者中,C4BP-Ang1治疗导致Schlemm管大小的明显增加。在WT动物中,分化的Schlemm管标志物PROX1的表达在治疗后维持,而在Angpt1 dNC眼中,仅在C4BP-Ang1治疗后观察到PROX1表达。图19。
序列表
<110> 西北大学
曼宁研究公司
<120> 作为血管生成素模拟物和Tie2激动剂治疗血管疾病的C4结合蛋白C端区段和血管生成素-1纤维蛋白原样域之间的嵌合融合体
<130> 14002.6006-00134
<140>
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<151> 2020-02-28
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Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg
225 230 235 240
Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe Gly Gly Gly Gly Ser
245 250 255
Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg Leu Met
260 265 270
Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu Val Tyr
275 280 285
Lys Leu Ser Leu Glu Ile Glu Gln Leu Glu Leu Gln Arg Asp Ser Ala
290 295 300
Arg Gln Ser Thr Leu Asp Lys Glu Leu
305 310
<210> 16
<211> 293
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 16
His His His His His His Gly Gly Asp Asp Asp Asp Lys Glu Thr Pro
1 5 10 15
Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg Leu Met Gln Cys Leu
20 25 30
Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu Val Tyr Lys Leu Ser
35 40 45
Leu Glu Ile Glu Gln Leu Glu Leu Gln Arg Asp Ser Ala Arg Gln Ser
50 55 60
Thr Leu Asp Lys Glu Leu Gly Gly Gly Gly Ser Lys Pro Phe Arg Asp
65 70 75 80
Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr
85 90 95
Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe Cys Asn Met
100 105 110
Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg Glu Asp Gly
115 120 125
Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly
130 135 140
Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile
145 150 155 160
Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met Asp Trp Glu
165 170 175
Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile Gly Asn Glu
180 185 190
Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly Thr Ala Gly
195 200 205
Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser Thr Lys Asp
210 215 220
Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met Leu Thr Gly
225 230 235 240
Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn Gly Met Phe
245 250 255
Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile Lys Trp His
260 265 270
Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr Met Met Ile
275 280 285
Arg Pro Leu Asp Phe
290
<210> 17
<211> 314
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 17
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Glu His His His His His His Gly Gly Asp Asp Asp
20 25 30
Asp Lys Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg
35 40 45
Leu Met Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu
50 55 60
Val Tyr Lys Leu Ser Leu Glu Ile Glu Gln Leu Glu Leu Gln Arg Asp
65 70 75 80
Ser Ala Arg Gln Ser Thr Leu Asp Lys Glu Leu Gly Gly Gly Gly Ser
85 90 95
Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys
100 105 110
Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys
115 120 125
Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln
130 135 140
His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr
145 150 155 160
Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu
165 170 175
Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu
180 185 190
Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe
195 200 205
His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His
210 215 220
Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp
225 230 235 240
Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala
245 250 255
Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn
260 265 270
Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn
275 280 285
Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser
290 295 300
Thr Thr Met Met Ile Arg Pro Leu Asp Phe
305 310
<210> 18
<211> 274
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 18
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln
20 25 30
Ala Gly Phe Asn Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met
35 40 45
Pro Glu Pro Lys Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly
50 55 60
Trp Thr Val Ile Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg
65 70 75 80
Gly Trp Lys Glu Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr
85 90 95
Trp Leu Gly Asn Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr
100 105 110
Met Leu Arg Ile Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser
115 120 125
Gln Tyr Asp Arg Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu
130 135 140
Tyr Leu Lys Gly His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile
145 150 155 160
Leu His Gly Ala Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys
165 170 175
Met Cys Lys Cys Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala
180 185 190
Cys Gly Pro Ser Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn
195 200 205
His Gly Lys Leu Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser
210 215 220
Tyr Ser Leu Arg Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe Gly
225 230 235 240
Gly Gly Gly Ser Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly
245 250 255
Lys Arg Leu Met Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala
260 265 270
Leu Glu
<210> 19
<211> 302
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 19
Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala
1 5 10 15
Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg Leu Met
20 25 30
Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu Val Tyr
35 40 45
Lys Leu Ser Leu Glu Ile Glu Gln Leu Glu Leu Gln Arg Asp Ser Ala
50 55 60
Arg Gln Ser Thr Leu Asp Lys Glu Leu Gly Gly Gly Gly Ser Lys Pro
65 70 75 80
Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly
85 90 95
Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe
100 105 110
Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg
115 120 125
Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met
130 135 140
Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile
145 150 155 160
Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met
165 170 175
Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile
180 185 190
Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly
195 200 205
Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser
210 215 220
Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met
225 230 235 240
Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn
245 250 255
Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile
260 265 270
Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr
275 280 285
Met Met Ile Arg Pro Leu Asp Phe His His His His His His
290 295 300
<210> 20
<211> 254
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 20
Glu Lys Pro Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn
1 5 10 15
Lys Ser Gly Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys
20 25 30
Lys Val Phe Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile
35 40 45
Gln His Arg Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu
50 55 60
Tyr Lys Met Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn
65 70 75 80
Glu Phe Ile Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile
85 90 95
Glu Leu Met Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg
100 105 110
Phe His Ile Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly
115 120 125
His Thr Gly Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala
130 135 140
Asp Phe Ser Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys
145 150 155 160
Ala Leu Met Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser
165 170 175
Asn Leu Asn Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu
180 185 190
Asn Gly Ile Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg
195 200 205
Ser Thr Thr Met Met Ile Arg Pro Leu Asp Phe Gly Gly Gly Gly Ser
210 215 220
Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg Leu Met
225 230 235 240
Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu
245 250
<210> 21
<211> 921
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 21
atgtacagga tgcaactcct gtcttgcatt gcactaagtc ttgcacttgt cacgaattcg 60
aaaccattta gagactgtgc agatgtatat caagctggtt ttaataaaag tggaatctac 120
actatttata ttaataatat gccagaaccc aaaaaggtgt tttgcaatat ggatgtcaat 180
gggggaggtt ggactgtaat acaacatcgt gaagatggaa gtctagattt ccaaagaggc 240
tggaaggaat ataaaatggg ttttggaaat ccctccggtg aatattggct ggggaatgag 300
tttatttttg ccattaccag tcagaggcag tacatgctaa gaattgagtt aatggactgg 360
gaagggaacc gagcctattc acagtatgac agattccaca taggaaatga aaagcaaaac 420
tataggttgt atttaaaagg tcacactggg acagcaggaa aacagagcag cctgatctta 480
cacggtgctg atttcagcac taaagatgct gataatgaca actgtatgtg caaatgtgcc 540
ctcatgttaa caggaggatg gtggtttgat gcttgtggcc cctccaatct aaatggaatg 600
ttctatactg cgggacaaaa ccatggaaaa ctgaatggga taaagtggca ctacttcaaa 660
gggcccagtt actccttacg ttccacaact atgatgattc gacctttaga ttttggtggc 720
ggtggctcag agacccccga aggctgtgaa caagtgctca caggcaaaag actcatgcag 780
tgtctcccaa acccagagga tgtgaaaatg gccctggagg tatataagct gtctctggaa 840
attgaacaac tggaactaca aagggacagc gcaagacaat ccactttgga taaagaacta 900
catcaccatc accatcacta a 921
<210> 22
<211> 921
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 22
atgtacagaa tgcagctgct gtcctgtatc gccctgagcc tggctctggt gaccaactct 60
gagacaccag agggatgtga gcaggtgctg accggcaagc gcctgatgca gtgcctgccc 120
aatcctgagg atgtgaagat ggccctggag gtgtacaagc tgtccctgga gatcgagcag 180
ctggagctgc agagggattc cgcccggcag tctacactgg acaaggagct gggaggagga 240
ggcagcaagc ctttcaggga ttgtgccgac gtgtatcagg ctggctttaa caagtctggc 300
atctacacca tctatatcaa caatatgcca gagcccaaga aggtgttctg caacatggac 360
gtgaatggcg gcggctggac agtgatccag cacagggagg atggcagcct ggacttccag 420
cggggctgga aggagtacaa gatgggcttt ggcaacccat ctggcgagta ttggctgggc 480
aatgagttca tctttgccat cacctcccag agacagtaca tgctgcgcat cgagctgatg 540
gattgggagg gcaatagggc ttactctcag tatgaccggt tccatatcgg caacgagaag 600
cagaattacc ggctgtatct gaagggacac accggaacag ctggcaagca gtccagcctg 660
atcctgcatg gcgccgattt ttccaccaag gacgctgata acgacaattg catgtgcaag 720
tgcgccctga tgctgacagg aggatggtgg ttcgacgctt gcggaccaag caacctgaat 780
ggcatgtttt atacagctgg ccagaaccac ggcaagctga atggcatcaa gtggcattac 840
ttcaagggcc cttcttattc cctgagatcc accacaatga tgatccgccc actggatttt 900
caccatcacc atcaccatta a 921
<210> 23
<211> 909
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 23
atgcctctgc tgctgctgct gccactgctg tgggctggcg ctctggccga gacaccagag 60
ggctgtgagc aggtgctgac aggcaagaga ctgatgcagt gcctgcccaa ccctgaggat 120
gtgaagatgg ctctggaggt gtacaagctg tctctggaga tcgagcagct ggagctgcag 180
agggatagcg cccggcagtc taccctggac aaggagctgg gaggaggagg ctctaagccc 240
ttccgcgatt gtgctgacgt gtatcaggcc ggctttaata agtccggcat ctacaccatc 300
tatatcaaca atatgccaga gcccaagaag gtgttctgca acatggacgt gaatggcggc 360
ggctggacag tgatccagca cagggaggat ggctccctgg acttccagcg gggctggaag 420
gagtacaaga tgggctttgg caacccttcc ggcgagtatt ggctgggcaa tgagttcatc 480
tttgctatca caagccagag acagtacatg ctgcgcatcg agctgatgga ttgggagggc 540
aacagggcct acagccagta tgaccggttc catatcggca acgagaagca gaattacagg 600
ctgtatctga agggccacac cggcacagct ggcaagcagt ccagcctgat cctgcatggc 660
gctgacttct ccaccaagga cgccgataac gacaattgca tgtgcaagtg cgctctgatg 720
ctgacaggag gatggtggtt cgacgcttgt ggaccatcta acctgaatgg catgttttat 780
accgccggcc agaaccacgg caagctgaat ggcatcaagt ggcattactt caagggcccc 840
tcttattccc tgagatccac cacaatgatg atccgccctc tggattttca ccatcaccat 900
caccattaa 909
<210> 24
<211> 921
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 24
atgtacagaa tgcagctgct gagctgtatc gccctgtctc tggctctggt gaccaactct 60
gagacaccag agggctgtga gcaggtgctg accggcaagc gcctgatgca gtgcctgccc 120
aatcctgagg atgtgaagat ggccctggag gtgtataagc tgtccctgga gatcgagcag 180
ctggagctgc agagagattc tgctcgccag tccaccctgg acaaggagct gggaggagga 240
ggcagcatct ctttcagaga ttgtgccgag gtgtttaaga gcggccacac cacaaacggc 300
atctacaccc tgacattccc taattctaca gaggagatca aggcctattg cgacatggag 360
gctggaggag gaggatggac catcatccag aggcgggagg atggcagcgt ggacttccag 420
aggacatgga aggagtacaa agtgggcttt ggcaacccat ctggcgagta ttggctgggc 480
aacgagttcg tgtcccagct gaccaatcag cagcggtacg tgctgaagat ccatctgaag 540
gattgggagg gcaacgaggc ctactctctg tatgagcact tttacctgtc cagcgaggag 600
ctgaattatc gcatccatct gaagggcctg accggcacag ctggcaagat ctcttccatc 660
tcccagcccg gcaacgattt cagcaccaag gacggcgata atgacaagtg catctgtaag 720
tgctcccaga tgctgacagg aggatggtgg ttcgacgctt gcggaccaag caacctgaat 780
ggcatgtact atccccagag gcagaacaca aataagttta atggcatcaa gtggtactat 840
tggaagggct ccggctatag cctgaaggcc accacaatga tgatccggcc tgctgacttt 900
caccatcacc atcaccatta a 921
<210> 25
<211> 942
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 25
atgtacagaa tgcagctgct gtcctgtatc gccctgagcc tggctctggt gaccaactct 60
gagcaccatc accatcacca tggcgacgat gacgataaga agccattccg cgattgtgcc 120
gacgtgtatc aggctggctt taataagtcc ggcatctaca ccatctatat caacaatatg 180
cccgagccta agaaggtgtt ctgcaacatg gatgtgaatg gcggcggctg gacagtgatc 240
cagcacaggg aggatggcag cctggacttc cagcggggct ggaaggagta caagatgggc 300
tttggcaacc cctctggcga gtattggctg ggcaatgagt tcatctttgc catcacatcc 360
cagagacagt acatgctgcg catcgagctg atggattggg agggcaacag ggcttactct 420
cagtatgacc ggttccatat cggcaacgag aagcagaatt acaggctgta tctgaaggga 480
cacaccggaa cagctggcaa gcagtccagc ctgatcctgc atggcgccga tttttccacc 540
aaggacgctg ataacgacaa ttgcatgtgc aagtgcgccc tgatgctgac aggaggatgg 600
tggttcgacg cttgcggacc aagcaacctg aatggcatgt tttacaccgc tggccagaac 660
cacggcaagc tgaatggcat caagtggcat tacttcaagg gcccttctta ttccctgaga 720
agcaccacaa tgatgatcag gcctctggat tttggaggag gaggctctga gacaccagag 780
ggatgtgagc aggtgctgac aggcaagcgg ctgatgcagt gcctgccaaa tcccgaggac 840
gtgaagatgg ccctggaggt gtataagctg tccctggaga tcgagcagct ggagctgcag 900
agggattccg cccggcagtc tacactggac aaggagctgt aa 942
<210> 26
<211> 945
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 26
atgtacagaa tgcagctgct gtcctgtatc gccctgagcc tggctctggt gaccaactct 60
gagcaccatc accatcacca tggcggcgac gatgacgata aggagacacc cgagggctgt 120
gagcaggtgc tgacaggcaa gcgcctgatg cagtgcctgc ccaatcctga ggatgtgaag 180
atggccctgg aggtgtacaa gctgtccctg gagatcgagc agctggagct gcagagggat 240
tccgcccggc agtctacact ggacaaggag ctgggaggag gaggcagcaa gcctttcagg 300
gattgtgccg acgtgtatca ggctggcttt aacaagtctg gcatctacac catctatatc 360
aacaatatgc cagagcccaa gaaggtgttc tgcaacatgg acgtgaatgg cggcggctgg 420
acagtgatcc agcacaggga ggatggcagc ctggacttcc agcggggctg gaaggagtac 480
aagatgggct ttggcaaccc atctggcgag tattggctgg gcaatgagtt catctttgcc 540
atcacctccc agagacagta catgctgcgc atcgagctga tggattggga gggcaatagg 600
gcttactctc agtatgaccg gttccatatc ggcaacgaga agcagaatta ccggctgtat 660
ctgaagggac acaccggaac agctggcaag cagtccagcc tgatcctgca tggcgccgat 720
ttttccacca aggacgctga taacgacaat tgcatgtgca agtgcgccct gatgctgaca 780
ggaggatggt ggttcgacgc ttgcggacca agcaacctga atggcatgtt ttatacagct 840
ggccagaacc acggcaagct gaatggcatc aagtggcatt acttcaaggg cccttcttat 900
tccctgagat ccaccacaat gatgatccgc ccactggatt tttaa 945
<210> 27
<211> 906
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多核苷酸"
<400> 27
atgtacagaa tgcagctgct gtcctgtatc gccctgagcc tggctctggt gaccaactct 60
gagaagccat tccgcgattg tgccgacgtg tatcaggctg gctttaataa gtccggcatc 120
tacaccatct atatcaacaa tatgcccgag cctaagaagg tgttctgcaa catggatgtg 180
aatggcggcg gctggacagt gatccagcac agggaggatg gcagcctgga cttccagcgg 240
ggctggaagg agtacaagat gggctttggc aacccctctg gcgagtattg gctgggcaat 300
gagttcatct ttgccatcac atcccagaga cagtacatgc tgcgcatcga gctgatggat 360
tgggagggca acagggctta ctctcagtat gaccggttcc atatcggcaa cgagaagcag 420
aattacaggc tgtatctgaa gggacacacc ggaacagctg gcaagcagtc cagcctgatc 480
ctgcatggcg ccgatttttc caccaaggac gctgataacg acaattgcat gtgcaagtgc 540
gccctgatgc tgacaggagg atggtggttc gacgcttgcg gaccaagcaa cctgaatggc 600
atgttttaca ccgctggcca gaaccacggc aagctgaatg gcatcaagtg gcattacttc 660
aagggccctt cttattccct gagaagcacc acaatgatga tcaggcctct ggattttgga 720
ggaggaggct ctgagacacc agagggatgt gagcaggtgc tgacaggcaa gcggctgatg 780
cagtgcctgc caaatcccga ggacgtgaag atggccctgg aggtgtataa gctgtccctg 840
gagatcgagc agctggagct gcagagggat tccgcccggc agtctacact ggacaaggag 900
ctgtaa 906
<210> 28
<211> 280
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 28
Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg Leu Met
1 5 10 15
Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu Val Tyr
20 25 30
Lys Leu Ser Leu Glu Ile Glu Gln Leu Glu Leu Gln Arg Asp Ser Ala
35 40 45
Arg Gln Ser Thr Leu Asp Lys Glu Leu Gly Gly Gly Gly Ser Lys Pro
50 55 60
Phe Arg Asp Cys Ala Asp Val Tyr Gln Ala Gly Phe Asn Lys Ser Gly
65 70 75 80
Ile Tyr Thr Ile Tyr Ile Asn Asn Met Pro Glu Pro Lys Lys Val Phe
85 90 95
Cys Asn Met Asp Val Asn Gly Gly Gly Trp Thr Val Ile Gln His Arg
100 105 110
Glu Asp Gly Ser Leu Asp Phe Gln Arg Gly Trp Lys Glu Tyr Lys Met
115 120 125
Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Ile
130 135 140
Phe Ala Ile Thr Ser Gln Arg Gln Tyr Met Leu Arg Ile Glu Leu Met
145 150 155 160
Asp Trp Glu Gly Asn Arg Ala Tyr Ser Gln Tyr Asp Arg Phe His Ile
165 170 175
Gly Asn Glu Lys Gln Asn Tyr Arg Leu Tyr Leu Lys Gly His Thr Gly
180 185 190
Thr Ala Gly Lys Gln Ser Ser Leu Ile Leu His Gly Ala Asp Phe Ser
195 200 205
Thr Lys Asp Ala Asp Asn Asp Asn Cys Met Cys Lys Cys Ala Leu Met
210 215 220
Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn
225 230 235 240
Gly Met Phe Tyr Thr Ala Gly Gln Asn His Gly Lys Leu Asn Gly Ile
245 250 255
Lys Trp His Tyr Phe Lys Gly Pro Ser Tyr Ser Leu Arg Ser Thr Thr
260 265 270
Met Met Ile Arg Pro Leu Asp Phe
275 280
<210> 29
<211> 280
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
多肽"
<400> 29
Glu Thr Pro Glu Gly Cys Glu Gln Val Leu Thr Gly Lys Arg Leu Met
1 5 10 15
Gln Cys Leu Pro Asn Pro Glu Asp Val Lys Met Ala Leu Glu Val Tyr
20 25 30
Lys Leu Ser Leu Glu Ile Glu Gln Leu Glu Leu Gln Arg Asp Ser Ala
35 40 45
Arg Gln Ser Thr Leu Asp Lys Glu Leu Gly Gly Gly Gly Ser Ile Ser
50 55 60
Phe Arg Asp Cys Ala Glu Val Phe Lys Ser Gly His Thr Thr Asn Gly
65 70 75 80
Ile Tyr Thr Leu Thr Phe Pro Asn Ser Thr Glu Glu Ile Lys Ala Tyr
85 90 95
Cys Asp Met Glu Ala Gly Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg
100 105 110
Glu Asp Gly Ser Val Asp Phe Gln Arg Thr Trp Lys Glu Tyr Lys Val
115 120 125
Gly Phe Gly Asn Pro Ser Gly Glu Tyr Trp Leu Gly Asn Glu Phe Val
130 135 140
Ser Gln Leu Thr Asn Gln Gln Arg Tyr Val Leu Lys Ile His Leu Lys
145 150 155 160
Asp Trp Glu Gly Asn Glu Ala Tyr Ser Leu Tyr Glu His Phe Tyr Leu
165 170 175
Ser Ser Glu Glu Leu Asn Tyr Arg Ile His Leu Lys Gly Leu Thr Gly
180 185 190
Thr Ala Gly Lys Ile Ser Ser Ile Ser Gln Pro Gly Asn Asp Phe Ser
195 200 205
Thr Lys Asp Gly Asp Asn Asp Lys Cys Ile Cys Lys Cys Ser Gln Met
210 215 220
Leu Thr Gly Gly Trp Trp Phe Asp Ala Cys Gly Pro Ser Asn Leu Asn
225 230 235 240
Gly Met Tyr Tyr Pro Gln Arg Gln Asn Thr Asn Lys Phe Asn Gly Ile
245 250 255
Lys Trp Tyr Tyr Trp Lys Gly Ser Gly Tyr Ser Leu Lys Ala Thr Thr
260 265 270
Met Met Ile Arg Pro Ala Asp Phe
275 280
<210> 30
<211> 6
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223>/注释="人工序列的描述:合成
6xHis标签"
<400> 30
His His His His His His
1 5
<210> 31
<211> 4
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽
<400> 31
Gly Gly Gly Ser
1
<210> 32
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽
<400> 32
Glu Ala Ala Ala Lys
1 5
<210> 33
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽
<400> 33
Pro Ala Pro Ala Pro
1 5
<210> 34
<211> 12
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽
<400> 34
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala
1 5 10
<210> 35
<211> 18
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽
<400> 35
Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser
1 5 10 15
Leu Asp
<210> 36
<211> 14
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽
<400> 36
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr
1 5 10
Claims (20)
1.在有此需要的受试者中增强经由眼中的常规流出道的房水流出,或在有此需要的受试者中降低眼内压的方法,其包括向所述受试者施用治疗有效量的:
(i)嵌合多肽,所述嵌合多肽包含补体蛋白C4结合蛋白(C4bp)的C端域与血管生成素(Ang)的纤维蛋白原样域(FLD);
(ii)编码所述多肽的核酸;
(iii)包含所述核酸的重组载体;
(iv)包含所述多肽、核酸和/或重组载体的细胞;和/或
(v)包含所述多肽、核酸、重组载体或细胞和药学上可接受的赋形剂的药物组合物;
从而在所述有此需要的受试者中增强经由所述眼中的所述常规流出道的房水流出,或在所述有此需要的受试者中降低眼内压。
2.根据权利要求1所述的方法,其中所述C4bp域位于所述多肽的N端,并且所述Ang域位于所述多肽的C端,从而形成C4bp-Ang多肽。
3.根据权利要求1所述的方法,其中所述Ang域位于所述多肽的N端,并且所述C4bp域位于所述多肽的C端,从而形成Ang-C4bp多肽。
4.根据权利要求1至3中任一项所述的方法,其中所述Ang是Ang1或Ang2。
5.根据权利要求1至4中任一项所述的方法,其中所述C4bp的C端域包含SEQ ID NO.:1。
6.根据权利要求1至5中任一项所述的方法,其中所述Ang1的纤维蛋白原样域包含SEQID NO.:2,并且所述Ang2的纤维蛋白原样域包含SEQ ID NO.:3。
7.根据权利要求1至6中任一项所述的方法,其中所述Ang1-C4bp包含SEQ ID NO.:8,所述C4bp-Ang1多肽包含SEQ ID NO.:10;并且所述C4bp-Ang2包含SEQ ID NO.:12、其无HIS标签形式和其含有信号肽的形式。
8.根据权利要求1至7中任一项所述的方法,其中所述多肽进一步包含信号肽。
9.根据权利要求8所述的方法,其中所述信号肽选自IL2的信号肽和人CD33的信号肽。
10.根据权利要求1至9中任一项所述的方法,其中所述多肽包含具有和不具有C端标记物/标签的信号肽。
11.根据权利要求1至9中任一项所述的方法,其中所述多肽进一步包含位于所述C4bp域和所述Ang域之间的接头肽。
12.根据权利要求1至11中任一项所述的方法,其中所述接头肽选自包含氨基酸序列GGGGS、EAAAK、PAPAP、AEAAAKEAAAKA、KESGSVSSEQLAQFRSLD和EGKSSGSGSESKST的接头。
13.根据权利要求1至12中任一项所述的方法,其中所述多肽包含接头,其不具有所述C端标记物。
14.根据权利要求1至13中任一项所述的方法,其中所述多肽进一步包含N端和/或C端标记物。
15.根据权利要求1至14中任一项所述的方法,其中所述标记物选自聚His、GST、MBP、Flag、CBP和蛋白A标记物/标签。
16.根据权利要求1至15中任一项所述的方法,其中所述多肽包含SEQ ID NO.:9、10、11、12、13或18。
17.根据权利要求1至16中任一项所述的方法,其进一步包含肠激酶切割位点。
18.根据权利要求1至15中任一项所述的方法,其中所述多肽包含SEQ ID NO.:15、16或17。
19.根据权利要求1所述的方法,其中所述嵌合多肽在7个自根据权利要求1至22所述的嵌合多肽选择的嵌合多肽的复合物中。
20.根据权利要求1至19中任一项所述的方法,其中在玻璃体内、眼部、眼内、近巩膜、眼球筋膜囊下(subtenonly)、脉络膜上、局部、静脉内、肌内、皮内、经皮、动脉内、腹腔内、病灶内、颅内、关节内、前列腺内、胸膜内、气管内、鞘内、鼻内、阴道内、直肠内、局部、瘤内、腹腔内、腹膜、心室内、皮下、结膜下、囊泡内(intravesicularly)、粘膜、心包内、脐带内、眶内、口服、透皮、通过吸入、通过注射、通过滴眼剂、通过植入、通过输注、通过连续输注、通过直接浸洗靶细胞的局部灌注、通过导管、通过灌洗、在霜剂中或在脂质组合物中施用所述多肽、核酸、载体、细胞或药物组合物。
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US202063029369P | 2020-05-22 | 2020-05-22 | |
US63/029,369 | 2020-05-22 | ||
PCT/US2021/019910 WO2021173999A1 (en) | 2020-02-28 | 2021-02-26 | Method of enhancing aqueous humor outflow and reducing intraocular pressure |
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AU (1) | AU2021227958A1 (zh) |
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FR2736916B1 (fr) * | 1995-07-21 | 1997-09-19 | Univ Paris Curie | Proteines hetero-multimeriques recombinantes du type alpha-beta c4bp |
US6054485A (en) * | 1996-08-20 | 2000-04-25 | Regents Of The University Of California | Eye treatments using synthetic thyroid hormone compositions |
US7081443B2 (en) * | 2002-05-21 | 2006-07-25 | Korea Advanced Institutes Of Science And Technology (Kaist) | Chimeric comp-ang1 molecule |
EP1529109A2 (en) * | 2002-08-14 | 2005-05-11 | Avidis SA | Production of multimeric fusion proteins using a c4bp scaffold |
PL3062811T3 (pl) * | 2013-11-01 | 2019-10-31 | Regeneron Pharma | Interwencje oparte na angiopoetynie do leczenia malarii mózgowej |
WO2019018350A1 (en) * | 2017-07-17 | 2019-01-24 | Keith Roizman | TOPICAL ADMINISTRATION OF THERAPEUTIC AGENTS COMPRISING CELL PENETRATION PEPTIDES, FOR USE IN THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION AND OTHER OCULAR DISEASES |
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US20230103583A1 (en) | 2023-04-06 |
JP2023515827A (ja) | 2023-04-14 |
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WO2021173999A1 (en) | 2021-09-02 |
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