CN107108757B - 包含vegf及pdgf的配体结合域的融合蛋白 - Google Patents
包含vegf及pdgf的配体结合域的融合蛋白 Download PDFInfo
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Abstract
本发明关于融合蛋白,其含有PDGF结合部分(binding portion)、VEGF结合部分、及Fc抗体区。本发明也关于编码该融合蛋白的核酸、包含该融合蛋白的组合物、及使用该融合蛋白以治疗或预防临床症状的方法,该临床症状的特征在于异常的血管生成,例如血管渗透性、水肿、或发炎。
Description
本申请依美国专利法35U.S.C.§119(e)主张于2015年3月11日提出申请的美国临时专利申请第62/131,261号的优先权权益,该美国临时专利申请的全文并于此处以供参考。
本申请包括通过EFS-Web电子送件的序列表,该序列表为ASCII格式,文件名为“688947-3WO_ST25”,建文件日期为2016年3月3日,文件大小为88.9千字节。该通过EFS-Web电子送件的序列表是本说明书的一部分,且全文并于此处以供参考。
技术领域
本发明关于融合蛋白(其包含PDGF结合部分(binding portion)、VEGF结合部分、及Fc抗体区)、编码该融合蛋白的核酸及表现载体(expression vector)、其重组细胞、及包含该融合蛋白的组合物。也提供使用该融合蛋白以抑制PDGF及VEGF功能的方法。
背景技术
血管生成(自既存血管形成新血管)在胎儿发育及组织修复中是正常且重要的程序。血管生成受血管生成及抗血管生成两种因子高度调控,且其参与内皮细胞的迁移及增生、血管成熟及重塑、及胞外基质的分解。不仅其在正常生长及发育中是一重要的程序,血管生成也在肿瘤生长、局部缺血、及发炎中扮演关键的角色。
在快速的未受控眼部血管生成过程中,血管渗透性增加,导致血管脆弱及漏泄,因而造成出血及液体与蛋白质渗出物的累积,最终造成血管功能不全或血管过度生长。眼部血管生成可发生在一系列的眼部病症中,例如老年性黄斑退化(age-related maculardegeneration,AMD)、增生性糖尿病神经病变(proliferative diabetic neuropathy,PDR)、及角膜血管新生(corneal neovascularization)。AMD及PDR两者皆可造成视网膜神经结构及功能的损伤,最终造成视力丧失。如果不处理,该不正常的血管可导致纤维性结疤,对视网膜功能造成不可逆损伤,其最后可造成失明(Zhang及Ma,Prog Retin EyeRes.2007Jan;26(1):1-37)。角膜血管新生可类似地导致角膜透明度降低及视力丧失。
血管内皮生长因子(vascular endothelial growth factor,VEGF)在血管生成中扮演一个重要的角色。人类VEGF家族含有6种成员:VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E、及胎盘生长因子(placental growth factor,PlGF)。另外,VEGF-A、VEGF-B、及PlGF的多种同功体通过选择性RNA剪接来产生(Sullivan及Brekken,MAbs.2010Mar-Apr;2(2):165-75)。VEGF-A是该家族中的原型成员且定性最为清楚。已显示VEGF-A作为内皮细胞的细胞分裂因子,可以促进内皮细胞生存及增生,诱导细胞迁移及增加微血管渗透性。VEGF家族的蛋白是通过结合至细胞表面VEGF受体(VEGFR)的胞外区来活化VEGF讯息路径。
有三种型态的VEGFR蛋白:VEGFR1、VEGFR2、及VEGFR3,且其各含有包含七个类免疫球蛋白(Ig)结构域的胞外区。该VEGFR的胞外区结合至不同的VEGF蛋白。举例而言,VEGFR-1(Flt-1)结合至VEGF-A、VEGF-B、及PlGF,且可作为用于VEGF的诱饵受体(decoy receptor),或作为VEGFR-2的调节子。VEGFR-2(KDR/Flt-1)与所有VEGF同功体结合,且是VEGF诱导的血管生成讯息的主要介质。VEGFR-3(Flt-4)与VEGF-C及VEGF-D结合,但不与VEGF-A结合,且是作为淋巴管生成(lymphangiogenesis)的介质。
高分子量变异体VEGF206及VEGF189K紧密地结合至胞外膜,且不与VEGF受体交互作用。而VEGF165是主要的可溶性变异体,VEGF121及VEGF145也是结合至VEGFR1及VEGFR2受体的可溶性变异体,和分解产物VEGF110一样(Bhisitkuk,Br J Ophthalmol.2006 Dec;90(12):1542-7)。
以抗体、可溶性VEGF受体、或VEGF酪胺酸激酶活性的抑制剂来阻断VEGF活性,是已被用于治疗血管生成型病症(angiogenic-type disorder)(例如AMD)的策略。虽然抗VEGF疗法一般可稳定或改善视觉功能,其已被报告在抗VEGF治疗两年内,在所有经治疗的眼睛中大约半数产生次视网膜结疤或纤维化(Daniel等人,Ophthalmology.2014 Mar;121(3):656-66)。另外,仅靶向VEGF虽可避免新生血管的形成,但其对已建立的血管没有效果。
最近的数据暗示周细胞(pericyte)可在抗VEGF抗性、新血管的稳定、及结疤中扮演一角色。周细胞与内皮细胞交互作用,并帮助血液-视网膜屏障的建立。重要的是,周细胞提供存活讯息至新生血管内皮细胞,使其抵抗VEGF耗竭疗法(Benjamin等人,Development.1998 May;125(9):1591-8;Patel,Retina.2009 Jun;29(6Suppl):S45-8)。血小板衍生生长因子(platelet-derived growth factor,PDGF)控制周细胞,驱使其补充、增生、存活及调控新血管的成熟。
人类PDGF家族含有四种成员:PDGF-A、PDGF-B、PDGF-C、及PDGF-D。该四种PDGF蛋白形成同二聚体或异二聚体(例如,PDGF-AA、PDGF-AB、PDGF-BB、PDGF-CC、及PDGF-DD),且其在单体型时是无活性的。该二聚蛋白结合至细胞表面PDGF受体(PDGFR)的胞外区,以活化PDGF讯息路径。
有两种型态的PDGF受体,PDGFR-α及PDGFR-β,其形成同二聚体或异二聚体(例如,PDGFR-αα、PDGFR-ββ、及PDGFR-αβ)且含有包含五个类免疫球蛋白结构域的胞外区。该受体的配体结合位位在前三个类免疫球蛋白结构域(D1至D3)。
该PDGFR二聚体的胞外区结合至不同的PDGF蛋白。举例而言,PDGFR-αα专一性地与PDGF-AA、PDGF-AB、PDGF-BB、及PDGF-CC交互作用。PDGFR-αβ专一性地与PDGF-AB、PDGF-BB、PDGF-CC、及PDGF-DD交互作用。PDGFR-ββ专一性地与PDGF-BB及PDGF-DD交互作用。PDGF-BB是唯一可以高亲合力结合至所有三种受体二聚体型的PDGF,其在体外及体内两者皆已被显示可以诱导周细胞增生及迁移。先前已显示由PDGFR-β的所有五个类免疫球蛋白结构域(D1至D5)组成的胞外区,拮抗通过PDGF-B所刺激的反应(Duan等人,J Biol Chem.1991 Jan 5;266(1):413-8;Ueno等人,Science.1991 May 10;252(5007):844-8)。使用PDGFRβ-Fc嵌合蛋白(chimeric protein)的研究,证明人类PDGFR-β的D1至D3对高亲合力PDGF-BB配体结合是足够的(Heidaran等人,FASEB J.1995 Jan;9(1):140-5;Lokker等人,J Biol Chem.1997Dec 26;272(52):33037-44)。另外,融合至麸胱甘肽S-转移酶(glutathione S-transferase,GST)的PDGFR-β D1至D3蛋白的预二聚化(pre-dimerization),相较于重组PDGFR-β D1至D3,其改善至PDGF-BB配体的结合亲合力(Leppanen等人,Biochemistry.2000Mar 7;39(9):2370-5)。
虽现行的抗VEGF疗法是高度有效的,然而为达成最佳的结果仍需要加强患者监测及频繁地治疗。另外,因为这些药剂是靶向疾病的症状而非根本的病因,因而须无限期地持续治疗。进行次最佳(suboptimal)治疗,现存的脉络膜血管新生病变(choroidalneovascular lesions,CNVs)将继续生长且最后成熟成为纤维性疤痕,其导致不可逆的视觉丧失(Martin等人,Ophthalmology 2012;119:1388-1398;Bloch等人,Am JOphthalmol.2013 Jul;156(1):116-124;Daniel等人Ophthalmology.2014 Mar;121(3):656-66)。可以阻断血管新生及造成脉络膜血管新生病变中未成熟血管退化的药剂,具有排除血管漏泄及纤维化的来源的潜力,降低或排除患者密集性监测及持续性治疗的需要。
最近,包含(从N端至C端)PDGF受体的胞外部分、VEGF受体的胞外部分、及多聚化域的融合蛋白被描述(美国专利申请公开号2014/0315804)。该融合蛋白与PDGF及VEGF两者结合,并抑制彼等的活性。
尽管在本技术领域中述及对PDGF及VEGF的双重抑制剂的进展,在本技术领域中,针对血管生成型病症仍有改善调配物(formulation)及治疗的需求。
发明内容
本发明通过提供新颖的融合蛋白来满足此需求,该融合蛋白同时结合至VEGF及PDGF两者,同时靶向该两者的讯息路径。该融合蛋白以通过融合衍生自VEGF受体及PDGF受体的胞外配体结合域,至来自IgG1的半衰期延长Fc域来产生。在本发明特定实施方案中,所有该融合蛋白组分源自人类,且因此预期其对于人类为有用的非免疫性疗法。该融合蛋白可以在体外抑制VEGF依赖及PDGF依赖的两种细胞生长,且在动物模式中其可以降低VEGF诱导的视网膜漏泄。
有增加的证据显示在不存在VEGF讯息下血管生成可发生,且周细胞供应VEGF及其他细胞存活因子至增生的内皮细胞,给予其抗VEGF抗性(Reinmuth等人,FASEB J.2001May;15(7):1239-41)。周细胞源也使人联想到在结疤组织及肿瘤中的纤维母细胞。PDGF讯息路径负责周细胞补充、存活、及成熟(Andrae等人,Genes Dev.2008 May 15;22(10):1276-312)。在多种眼部血管新生的小鼠模式中,通过抗体来抑制PDGF受体讯息,显示增强抗VEGF治疗的治疗效果(Jo等人,Am J Pathol.2006 Jun;168(6):2036-53)。抗PDGF药剂E10030与抗VEGF药剂的组合的大型第2期临床试验,显示比抗VEGF单一药物治疗为优的结果(Dugel,Retina Today,March 2013,65-71)。因此,本发明融合蛋白可有效地治疗血管生成型病症(例如,AMD及癌症)。该融合蛋白的额外的好处是不需要注射两种分开的组合物,即,一种抗PDGF药剂及一种抗VEGF药剂。取而代之,允许单一注射包含两种药剂的融合蛋白的单一组合物,因此降低患者感染的风险及因注射所造成的外伤。
在一个普遍方面中,本发明是关于一种融合蛋白,其包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域(binding domain),(b)抗体的Fc区(Fc region),以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a);以及其中,该融合蛋白可以结合至VEGF-A分子及PDGF-BB分子,并抑制VEGFR1、VEGFR2的活性及PDGFR的活性。
在本发明的一个实施方案中,VEGF受体的胞外配体结合域可以结合至VEGF配体,并包含一种或多种VEGF受体的一个或多个类免疫球蛋白结构域D1至D7。较佳地,VEGF受体的胞外配体结合域包含第一VEGF受体的类免疫球蛋白结构域D2、及第二VEGF受体的类免疫球蛋白结构域D3,其中该第一及第二VEGF受体是相同或不同的VEGF受体。在一个实施方案中,VEGF受体的胞外配体结合域包含VEGFR1的类免疫球蛋白结构域D2、及VEGFR2的类免疫球蛋白结构域D3。在另一实施方案中,VEGF受体的胞外配体结合域包含与SEQ ID NO:7具有至少90%同一性的胺基酸序列。更佳地,VEGF受体的胞外配体结合域包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:7及SEQ ID NO:10。
在本发明的一个实施方案中,PDGF受体的胞外配体结合域可以结合至PDGF配体,并包含一种或多种PDGF受体的一个或多个类免疫球蛋白结构域D1至D5。较佳地,PDGF受体的胞外配体结合域包含一种或多种PDGF受体的类免疫球蛋白结构域D1至D3。在一个实施方案中,PDGF受体的胞外配体结合域包含与SEQ ID NO:2具有至少90%同一性的胺基酸序列。更佳地,PDGF受体的胞外配体结合域呈现包含选自由以下所组成的群组的胺基酸序列:SEQID NO:2及SEQ ID NO:5。
在本发明的一个实施方案中,抗体的Fc区包含IgG1的CH2及CH3区。较佳地,抗体的Fc区包含一与SEQ ID NO:12具有至少90%同一性的胺基酸序列。更佳地,抗体的Fc区包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:12及SEQ ID NO:15。
在本发明的一较佳实施方案中,融合蛋白包含(a)VEGFR1的类免疫球蛋白结构域D2、及VEGFR2的类免疫球蛋白结构域D3,(b)抗体的Fc区,其包含IgG1的CH2及CH3区,以及(c)PDGFRβ的类免疫球蛋白结构域D1至D3,其中该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a),更佳是依照(c)-(b)-(a)的次序。
在本发明的一个实施方案中,融合蛋白还包含连接胜肽(linker peptide),其位于该融合蛋白的C端处的第一或第二胜肽与该Fc区之间,以及根据需要包含第二连接胜肽,其位于该融合蛋白的N端处的第二或第一胜肽与该Fc区之间。
在本发明的一个实施方案中,融合蛋白还包含讯息胜肽,其可行地连接至融合蛋白的N端。
在另一普遍方面中,本发明关于一种分离核酸分子(isolated nucleic acidmolecule),其编码本发明的融合蛋白。
在另一普遍方面中,本发明关于一种表现载体,其包含编码本发明融合蛋白的核酸分子。
在另一普遍方面中,本发明关于一种重组宿主细胞,该重组细胞包含编码本发明融合蛋白的核酸分子。
在另一普遍方面中,本发明关于一种获得本发明融合蛋白的方法。该方法包含:(1)在制造该融合蛋白的条件下培养宿主细胞,其包含编码该融合蛋白的核酸分子;以及(2)回收该宿主细胞所制造的融合蛋白。
在另一普遍方面中,本发明关于一种医药组合物,其包含本发明融合蛋白、及医药上可接受的载体(carrier)。
在另一普遍方面中,本发明关于一种医药组合物,其包含编码本发明融合蛋白的核酸分子、及医药上可接受的载体。
在另一普遍方面中,本发明关于一种降低VEGFR的活性及PDGFR的活性的方法,该方法包含对有需要的个体投予有效量的本发明融合蛋白。
在另一普遍方面中,本发明关于一种治疗或预防临床症状(clinical condition)的方法,该临床症状是选自由以下所组成的群组:组织血管形成、血管渗透性、水肿、及发炎,该方法包含对有需要的个体投予有效量的根据本发明实施方案的融合蛋白。
在另一普遍方面中,本发明关于一种治疗或预防临床症状的方法,该临床症状是选自由以下所组成的群组:脉络膜血管新生(choroidal neovascularization,CNV)、湿性老年性黄斑退化(AMD)、及地图样萎缩(geographic atrophy),该方法包含对有需要的个体投予有效量的根据本发明实施方案的融合蛋白。
在本发明的一个实施方案中,融合蛋白是作为分离蛋白或作为表现载体来投予。
在本发明的一个实施方案中,临床症状是选自由以下所组成的群组:脑水肿、中风、癌症、牛皮癣、关节炎、气喘、烧伤相关的全身性水肿、肿瘤相关的腹水及胸膜积水、发炎或创伤、慢性呼吸道发炎、微血管漏泄症候群(capillary leak syndrome)、败血症、蛋白质漏泄增加相关的肾脏疾病、类风湿性关节炎(rheumatoid arthritis)、炎症性关节炎(inflammatory arthritis)、骨关节炎、动脉粥样硬化、牛皮癣、眼部发炎及/或眼部血管生成(其包括老年性黄斑退化、增生性及非增生性糖尿病视网膜病变(proliferative andnonproliferative diabetic retinopathy)、角膜血管新生、虹膜发红(rubeosisiridis)、及血管新生性青光眼(neovascular glaucoma))。
在另一普遍方面中,本发明关于一用于PDGF及VEGF的二聚体拮抗剂,其包含本发明融合蛋白。
在另一普遍方面中,本发明关于一种蛋白共轭体,其包含结合至选自由以下所组成的群组中至少一配体的本发明融合蛋白:PDGF-BB及VEGF-A。
本发明的其他方面、特征及优点,将因下列公开内容而变得明显,包括本发明实施方式及其较佳实施方案、及权利要求书。
附图说明
上述发明内容及以下本发明实施方式应搭配附图阅读以获得更清楚的理解。应了解,本发明不限于附图所示的明确实施方案。
图1显示根据本发明实施方案的例示性双功能融合蛋白的结构设计,融合蛋白2(上方)及融合蛋白1(下方)被设计来同时抑制PDGF及VEGF两者的路径:其中,是讯息胜肽;是PDGFR胞外类免疫球蛋白结构域(PID),代表PDGFRβ的胞外类免疫球蛋白结构域D1至D3;是Fc,代表IgG1的CH2及CH3区;-是GS,代表甘胺酸-丝胺酸连接子;是VEGFR胞外类免疫球蛋白结构域(VID),代表VEGFR1的类免疫球蛋白结构域D2及VEGFR2的类免疫球蛋白结构域D3
图2A及图2B分别显示经纯化的双功能Fc融合蛋白1及2的SDS-PAGE胶体分析;图2C显示非还原性及还原性经纯化的双功能Fc融合蛋白的分别的SDS-PAGE胶体分析:泳道M=标准液(marker),泳道1(非还原性)及泳道2(还原性)=正对照组2;泳道3(非还原性)及泳道4(还原性)=融合蛋白5;泳道5(非还原性)及泳道6(还原性)=融合蛋白3;
图3显示三种测试样品针对VEGF165的直接配体结合检定(direct ligand bindingassay)结果:纯化的正对照组1(●)、融合蛋白3(▲)、及融合蛋白5(■)。孔以VEGF165预涂布且与多种浓度的测试样品一同培养;使用HRP共轭的山羊抗人IgG1 Fc专一性抗体来监测结合的测试样品的量,及将OD450读数对测试样品浓度作图;
图4显示三种测试样品针对PDGF-BB的直接配体结合检定结果:纯化的正对照组2(●)、融合蛋白3(▲)、及融合蛋白5(■)。孔以PDGF-BB预涂布且与多种浓度的测试样品一同培养;使用HRP共轭的山羊抗人IgG1Fc专一性抗体来监测测试样品的量,及将OD450读数对测试样品浓度作图;
图5A及图5B分别显示在竞争性结合检定(competitive binding assay)中,融合蛋白1分别对VEGF165及PDGF-BB在溶液中的亲合力评估。多种浓度的融合蛋白1与固定浓度的VEGF165或PDGF-BB在溶液中过夜培养;使用定量三明治酵素免疫检定法(quantitativesandwich enzyme-linked immunoassay(ELISA)assay)测定游离的VEGF165或PDGF-BB的浓度,并对融合蛋白1的浓度作图;
图6A及图6B分别显示在竞争性结合检定中,融合蛋白2分别对VEGF165及PDGF-BB在溶液中的亲合力评估。多种浓度的融合蛋白2与固定浓度的VEGF165或PDGF-BB在溶液中过夜培养;使用定量三明治酵素免疫检定法测定游离的VEGF165或PDGF-BB的浓度,并对融合蛋白2的浓度作图;
图7显示正对照组1(●)、融合蛋白3(▲)、及融合蛋白5(■)在HUVEC细胞的VEGF依赖性生长上的抑制效果。OD490读数对测试样品浓度作图;以及
图8显示正对照组2(●)、融合蛋白3(▲)、及融合蛋白5(■)在BALB/3T3细胞的PDGF依赖性生长上的抑制效果。OD490读数对测试样品浓度作图。
具体实施方式
在先前技术及整篇说明书中引用或阐述了许多出版品、文章、及专利;这些文献的全文各自并于此处以供参考。包括在本发明说明书中的文件、技术、材料、装置、文章或诸如此类的讨论是为了提供本发明的内容。这些讨论并非承认任意或所有这些材料成为任何公开或请求的发明的先前技术。
除非另外定义,此处所用的所有技术及科学术语具有与本发明所属技术领域中普通技术人员通常所了解的相同意义。否则,此处所用的这些术语具有如本发明说明书所定的意义。本文所引用的所有专利、已公开专利申请、及出版品并于此处以供参考如全文阐述于此。须注意除非内文另外明确指出,否则本申请说明书及权利要求书所用的单数型式的“一”、“该”包括复数形式。
本发明关于一种融合蛋白,其包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a);以及其中,该融合蛋白可以结合至VEGF-A及PDGF-BB以及抑制VEGFR1、VEGFR2的活性及PDGFR的活性。
在本发明过程中惊讶地发现,VEGF及PDGF受体的胞外配体结合域相对于在融合蛋白中其他组分(例如,抗体Fc区)的定位(orientation),会影响融合蛋白对VEGF及PDGF配体的结合亲合力。根据本发明一实施方案的融合蛋白,该融合蛋白对该两种配体皆具有最适亲合力,且可增加该融合蛋白的效果。
如本文所用,词语“融合蛋白”意指具有两个或更多共价连接在一起的部分的蛋白,其中该各部分衍生自不同蛋白。
如本文所用,术语“VEGF”意指调控VEGF讯息路径的任意血管内皮生长因子蛋白。因此术语VEGF可意指VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E、PIGF、或其同功体。
如本文所用,术语“VEGF受体”及“VEGFR”意指结合至VEGF配体的任意受体。因此,术语VEGF受体可意指VEGFR1、VEGFR2、或VEGFR3。
如本文所用,词语“胞外配体结合域”意指位于细胞外侧且可结合至其配体的受体蛋白的任意区。
因此,存在本发明融合蛋白中的VEGF受体的胞外配体结合域可来自任意VEGFR,包括,但不限于,VEGFR1、VEGFR2、及VEGFR3。VEGFR蛋白的七个胞外类免疫球蛋白结构域从胞外区的N端至C端编号为1、2、3、4、5、6、及7,且作为另一选择可称为D1、D2、D3、D4、D5、D6、及D7。存在本发明融合蛋白中的VEGFR的胞外配体结合域,可包含来自一种或多种任意VEGFR蛋白的胞外配体结合域的七个类免疫球蛋白结构域中的任意一个或多个。举例而言,存在本发明融合蛋白中的VEGF受体的胞外配体结合域可来自VEGFR1、VEGFR2、或VEGFR3中的一种或多种的一个或多个D1、D2、D3、D4、D5、D6、或D7。
在一个较佳实施方案中,存在本发明融合蛋白中的VEGF受体的胞外配体结合域包含VEGFR1的类免疫球蛋白结构域D2、及VEGFR2的类免疫球蛋白结构域D3。较佳地,VEGFR的胞外配体结合域包含可增加其结合至VEGF的一个或多个突变。在一个更佳实施方案中,存在本发明融合蛋白中的VEGF受体的胞外配体结合域包含与SEQ ID NO:7具有至少90%同一性的胺基酸序列。在一甚至更佳的实施方案中,存在本发明融合蛋白中的VEGF受体的胞外配体结合域包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:7及SEQ ID NO:10。
存在本发明融合蛋白中的VEGF受体的胞外配体结合域可来自任意动物,例如人类或其他适合的哺乳类(例如小鼠、兔子、大鼠、猪、狗、或灵长动物)。在一个较佳实施方案中,VEGFR来自人类。
如本文所用,术语“PDGF”意指调控PDGF讯息路径的任意血浆衍生(plasma-derived)生长因子蛋白。因此,术语PDGF可意指PDGF-A、PDGF-B、PDGF-C、或PDGF-D。
如本文所用,术语“PDGF受体”及“PDGFR”意指结合至PDGF配体的任意受体。
存在本发明融合蛋白中的PDGF受体的胞外配体结合域可来自任意PDGFR,包括,但不限于,PDGFR-α及PDGFR-β。PDGFR蛋白的五个胞外类免疫球蛋白结构域从胞外区的N端至C端编号为1、2、3、4、及5,且作为另一选择可称为D1、D2、D3、D4、及D5。存在本发明融合蛋白中的PDGFR的胞外配体结合域,可包含来自一种或多种任意PDGFR蛋白的胞外配体结合域的五个类免疫球蛋白结构域中的任意一个或多个。举例而言,存在本发明融合蛋白中的PDGF受体的胞外配体结合域可来自PDGFR-α或PDGFR-β中的一种或多种的一个或多个D1、D2、D3、D4、或D5。
在一个较佳实施方案中,存在该融合蛋白中的PDGF受体的胞外配体结合域包含PDGFRβ的类免疫球蛋白结构域D1至D3。较佳地,PDGFR的胞外配体结合域包含增加其结合至PDGF的一个或多个突变。在一个更佳实施方案中,存在该融合蛋白中的PDGF受体的胞外配体结合域包含与SEQ ID NO:2具有至少90%同一性的胺基酸序列。在一甚至更佳的实施方案中,存在该融合蛋白中的PDGF受体的胞外配体结合域包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:2及SEQ ID NO:5。
存在本发明融合蛋白中的PDGF受体的胞外配体结合域可来自任意动物,例如人类或其他适合的哺乳类(例如小鼠、兔子、大鼠、猪、狗、或灵长动物)。在一个较佳实施方案中,PDGFR来自人类。
如本文所用,术语抗体的“Fc区”,根据抗体分类意指由两条包含两个或三个不变域(constant domain)的重链所组成的抗体的“可结晶片段(fragment,crystallizable)”区。该术语用以定义含有至少一部分的不变区的免疫球重链的C端区。该术语包括天然及变异Fc区两个。抗体的Fc区可作为多聚域,其是促进次单元结合成多聚体(例如,二聚体、三聚体、四聚体等)的域。较佳地,Fc区包含促进次单元结合成多聚体的一个或多个突变。
存在本发明融合蛋白中的抗体的Fc区可来自任意同功体(例如,IgG、IgM、IgA、IgD、或IgE)、任意次型(例如,IgG1、IgG2、IgG3、IgG4、IgA1、IgA2等)、任意异型、或任意工程突变型(例如,凸凹(knob and hole)Fc片段)。在一个较佳实施方案中,存在本发明融合蛋白中的抗体的Fc区包含IgG1的CH2及CH3区。在一个更佳实施方案中,存在本发明融合蛋白中的抗体的Fc区包含与SEQ ID NO:12具有至少90%同一性的胺基酸序列。在一甚至更佳实施方案中,存在本发明融合蛋白中的抗体的Fc区包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:12及SEQ ID NO:15。
存在本发明融合蛋白中的抗体的Fc区可来自任意动物,例如人类或其他适合的哺乳类(例如小鼠、兔子、大鼠、猪、狗、或灵长动物)。在一个较佳实施方案中,Fc区来自人类抗体。
根据本发明的实施方案,融合蛋白的组分可通过连接部分(linking moiety)连接,例如胜肽连接子(peptide linker)。较佳地,连接子增加融合蛋白组分的挠性,帮助确保正确地折迭,最小化立体阻碍及不会显著地干扰融合蛋白内各功能性组分的结构。在一些实施方案中,胜肽连接子包含2至20个胺基酸。在一些实施方案中,胜肽连接子包含2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、或20个胺基酸。较佳地,融合蛋白包含第一连接胜肽,其位于该融合蛋白的C端处的第一或第二胜肽与该Fc区之间,以及根据需要包含第二连接胜肽,其位于该融合蛋白的N端处的第二或第一胜肽与该Fc区之间。在本发明的较佳实施方案中,该第一连接胜肽包含一种或多种选自由以下所组成的群组的胺基酸序列:SEQ ID NO:20、SEQ ID NO:22、SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28、SEQ IDNO:30、及SEQ ID NO:32,以及该第二连接胜肽包含SEQ ID NO:18的胺基酸序列。
根据本发明的实施方案,融合蛋白还包含连接至该融合蛋白的N端的讯息胜肽,以确保融合蛋白自细胞中分泌。可以使用任意被宿主细胞所辨识及处理的讯息胜肽。在较佳实施方案中,该讯息胜肽包括,但不限于,SEQ ID NO:34或SEQ ID NO:36的胺基酸序列。
在一个较佳实施方案中,本发明融合蛋白包含与SEQ ID NO:38具有至少90%同一性、或与SEQ ID NO:40具有至少90%同一性的胺基酸序列,较佳地,与SEQ ID NO:42的胺基酸20至766、SEQ ID NO:44的胺基酸21至769、或SEQ ID NO:50的胺基酸20至768具有至少90%同一性。融合蛋白在VEGF受体域及/或PDGF受体域中,可包括一个或多个突变或单核苷酸多型性(single nucleotide polymorphism,SNP)。根据本发明实施方案,其也可包括发生在抗体的Fc区的一个或多个突变或SNP。
在一个更佳实施方案中,本发明融合蛋白包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42的胺基酸20-766、SEQ ID NO:44的胺基酸21-769、及SEQ ID NO:50的胺基酸20-768。
在一普遍方面中,本发明融合蛋白结合至VEGF及PDGF并抑制VEGF受体及PDGF受体的活性。如本文所用,术语“结合至”意指受体蛋白的胞外域结合至配体,其造成配体活性的抑制、阻断、中和、降低、废除或干扰中的一种或多种。在某些实施方案中,VEGF受体蛋白或PDGF受体蛋白的胞外域通过分别结合至配体(即,VEGF或PDGF)来抑制配体活性,并将配体隔离使其不能结合至其他分子,例如其他VEGF受体及PDGF受体。在某些其他实施方案中,VEGF受体蛋白或PDGF受体蛋白的胞外域通过分别结合至配体(即,VEGF或PDGF)来抑制配体活性,并预防该配体在细胞中诱发下游讯息事件。
如本文所用,术语“抑制”在如本文所用的配体活性的上下文中,意指受体蛋白的胞外域降低配体活性的性质,如通过多种功能性检定所分析,包括,但不限于,结合检定、细胞生长检定、竞争性结合检定、及体内检定。
本文所公开的融合蛋白或融合蛋白的组分可以生物活性加以表征(characterized)或评估,该生物活性包括,但不限于,对目标结合伴侣(例如,PDGF及/或VEGF家族蛋白)的亲合力、竞争性结合(例如,阻断PDGF或VEGF结合至PDGFR或VEGFR)、抑制性活性(例如,抑制PDGF或VEGF讯息路径的活化)、抑制细胞增生、抑制肿瘤生长、及抑制血管生成(例如,抑制脉络膜血管新生)。在一些实施方案中,本文所公开的融合蛋白或融合蛋白的组分可以体内或体外生物活性评估。
本发明也提供编码融合蛋白的分离核酸分子,该融合蛋白包含:(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a)。根据本发明的实施方案,编码融合蛋白的核酸分子可为一优化的密码子,其可在特定型态的宿主细胞(例如,中国仓鼠卵巢细胞(Chinese hamster ovary cell))中表现。根据本发明的较佳实施方案,编码融合蛋白的核酸分子包含选自由以下所组成的群组的核苷酸序列:SEQ ID NO:37、SEQ ID NO:39、SEQ IDNO:41、SEQ ID NO:43、及SEQ ID NO:49。
根据本发明的其他实施方案,编码融合蛋白的核酸分子可在表现载体中。表现载体包括,但不限于,用于重组蛋白表现的载体、及用于递送核酸进入个体以在该个体的组织内表现的载体(例如,病毒载体)。适合用于本发明的病毒载体的例子包括,但不限于,腺病毒载体、腺相关病毒载体、慢病毒载体等。载体也可是非病毒载体,非病毒载体的例子包括,但不限于,质体、细菌人工染色体、酵母菌人工染色体、噬菌体等。载体可包括任意组件以建立表现载体的现有功能,例如,启动子、核醣体结合组件、终止子、强化子、选择标记、或复制起点。
根据本发明的其他实施方案,鉴于现呈公开内容,可使用本技术领域已知的方法,对编码融合蛋白的核酸分子进行密码子优化,以改善所需宿主细胞中重组体的表现。
本发明也提供一种宿主细胞,其包含编码融合蛋白的核酸分子,该融合蛋白包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a)。宿主细胞包括,但不限于,用于重组蛋白表现的宿主细胞、及用于递送核酸进入个体以在该个体的组织内表现的宿主细胞。适合用于本发明的宿主细胞的例子包括,但不限于,中国仓鼠卵巢(Chinesehamster ovary,CHO)细胞、人类胚胎肾293(Human Embryonic Kidney 293,HEK-293)等。
本发明也提供一种用于制造融合蛋白的方法,该融合蛋白包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a)。在一普遍方面中,该方法包含(1)在制造该融合蛋白的条件下培养宿主细胞,其包含编码该融合蛋白的核酸分子;以及(2)回收该宿主细胞所制造的融合蛋白。还可使用本技术领域已知的方法纯化该融合蛋白。
在一些实施方案中,融合蛋白在宿主细胞中表现,并使用一种或多种标准纯化技术的组合自其中纯化,该标准纯化技术包括,但不限于,蛋白A亲合性层析、蛋白G亲合性层析、缓冲液置换、尺寸排除层析、超过滤、及透析。
本发明也提供一种包含融合蛋白的医药组合物,该融合蛋白包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a)。本发明组合物包含治疗有效量的融合蛋白。
术语“治疗有效量”意指治疗活性化合物引出所需的生物或临床效果所需要的量。根据本发明的实施方案,“治疗有效量”是对有利影响或所需结果(包括临床结果)而言足够的量。治疗有效量可在一次或多次投予中投予。依照疾病状态,有效量是足够改善、稳定、或推迟疾病发展的量。根据本发明的特定实施方案,治疗有效量是治疗或预防特征是不正常血管生成的病症(例如特征是血管渗透性、水肿、发炎、视网膜病变、纤维化或癌症的疾病)所需的融合蛋白量。
在一些实施方案中,包含融合蛋白的医药组合物包含在缓冲液中调配的融合蛋白,其蛋白质浓度自约0.5至约100毫克/毫升,较佳约40至约80毫克/毫升,例如约40、50、60、70或80毫克/毫升,最佳约40±约5毫克/毫升。在其他较佳实施方案中,融合蛋白以高于约40毫克/毫升的蛋白浓度在缓冲液中调配,较佳约80±约10毫克/毫升。
在具体实施方案中,缓冲液具有约6.5至8、更佳约7至7.5、甚至更佳约7.2的pH值的磷酸盐缓冲液。该磷酸盐缓冲液包含约5至20mM的磷酸钠,例如5、10、15、或20mM的磷酸钠,更佳约10mM的磷酸钠;约20至60mM的氯化钠,更佳约40mM的氯化钠;约1至10%重量/体积的蔗糖,更佳约5%重量/体积的蔗糖;以及约0.01至0.05%重量/体积的界面活性剂,更佳约0.03%重量/体积的聚山梨醇酯20。
在其他具体实施方案中,缓冲液具有约5至8、更佳约6至7、最佳约6.8的pH值的组胺酸缓冲液。该组胺酸缓冲液包含约10至50mM的组胺酸,例如10、20、30、40、或50mM的组胺酸,更佳约25mM的组胺酸;约10至30mM的氯化钠,例如10、20、或30mM的氯化纳,更佳约20mM的氯化钠;约1至10%重量/体积的蔗糖,例如1、2、4、6、8、或10%重量/体积的蔗糖,更佳约6%重量/体积的蔗糖;以及约0.01至0.05%重量/体积的界面活性剂,更佳约0.03%重量/体积的聚山梨醇酯20。
本发明也提供包含一种编码融合蛋白的核酸分子的组合物,该融合蛋白包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a),较佳依(c)-(b)-(a)的次序。
包含编码本发明融合蛋白的核酸分子的组合物,可包含用于引导核酸分子进入细胞以表现该融合蛋白的递送媒介物(delivery vehicle)。核酸递送媒介物的例子包括脂质体、生物可相容聚合物(包括天然聚合物及合成聚合物)、脂蛋白、多胜肽、多醣、脂多醣、人工病毒套膜、金属颗粒、及细菌、病毒(例如,杆状病毒、腺病毒、及反转录病毒)、噬菌体、黏质体(cosmid)、质体、真菌载体、及其他常用于本技术领域的重组媒介物,这些媒介物已被描述用于在多种真核宿主中表现。
本发明也关于本文所述的医药组合物在治疗或预防特征是不正常血管生成的症状、疾病或病症(例如特征是血管新生、血管渗透性、水肿、发炎、视网膜病变、纤维化或癌症的疾病)中的用途。根据本发明的实施方案,用于在一个体中治疗特征是不正常血管生成的症状、疾病或病症的方法包含,对该有需要治疗的个体投予本发明医药组合物。本文所述的任意医药组合物可使用在本发明的方法中,包括包含融合蛋白的医药组合物、或包含编码该融合蛋白的核酸的医药组合物。较佳地,本发明医药组合物通过玻璃体、结膜、坦诺囊(tenon)、眼后、或巩膜(用于眼科相关疾病)及进入血液或组织(用于系统性疾病)来投予至个体。
如本文所用,“个体”意指将被或已被根据本发明施实方案的方法治疗的任意动物,较佳是哺乳类,最佳是人类。如本文所用,术语“哺乳类”包括任意哺乳类。哺乳类的例子包括,但不限于,牛、马、羊、猪、猫、狗、小鼠、大鼠、兔子、天竺鼠、非人类灵长类(non-humanprimates,NHP)(例如猴子或人猿)、人类等,更佳是人类。
如本文所用,“特征是不正常血管生成的症状、疾病或病症”或“血管生成型病症”应具有相同意义,并意指任意有关不正常血管制造的病症,包括过量、不足、或不正常血管生成。可根据本发明方法治疗的血管生成型病症的例子包括,但不限于,特征是血管新生、血管渗透性、水肿、或发炎的疾病。这些包括,但不限于,眼部发炎及/或眼部血管生成,其包括老年性黄斑退化(例如湿性AMD、干性AMD、或地图样萎缩)、增生性及非增生性糖尿病视网膜病变、特征是血管新生的眼部疾病(例如,角膜血管新生、或脉络膜血管新生)、眼色素层炎(例如前眼色素层炎或后眼色素层炎)、色素性视网膜炎、糖尿病视网膜病变、虹膜发红、血管新生性青光眼、发炎性疾病、类风湿性关节炎、炎症性关节炎、骨关节炎、自体免疫性疾病、及癌症。在本发明的较佳实施方案中,欲治疗的血管生成型病症是视网膜病变、纤维化、或癌症。
在其他实施方案中,可根据本发明方法治疗的血管生成型病症包括,但不限于,脑水肿、中风、牛皮癣、气喘、烧伤相关的全身性水肿、肿瘤相关的腹水及胸膜积水、发炎或创伤、慢性呼吸道发炎、微血管漏泄症候群、败血症、蛋白质漏泄增加相关的肾脏疾病。
如本文所用,术语“治疗”意指对个体投予组合物,以在该个体内达到所需治疗或临床结果。在一实施方案中,术语“治疗”意指投予本发明医药组合物以降低、缓和或减慢血管生成型病症(例如血管渗透性、水肿、或发炎)的进程或发展。在另一实施方案中,术语“治疗”意指投予本发明医药组合物以抑制或降低角膜血管新生及/或眼中漏泄性血管分布。在又一实施方案中,术语“治疗”意指投予本发明医药组合物以减缓角膜或有兴趣的点中新血管的进程或发展(即,角膜血管新生)。在本发明的具体实施方案中,当有关AMD的使用时,术语“治疗”意指预防或降低VEGF所诱导的视网膜漏泄,及预防或降低与血管生成有关的眼部结疤及纤维化。在本发明的具体实施方案中,当有关癌症的使用时,术语“治疗”意指降低癌细胞的增生、去分化、或散布。根据本发明治疗肿瘤包括降低肿瘤尺寸、降低肿瘤生长、及降低肿瘤迁移。如本文所用,术语“肿瘤”意指不正常组织团块,并包括良性及恶性团块两者。
根据本发明实施方案,鉴于现呈公开内容,医药组合物可通过本领域技术人员所知的任意方法投予,例如通过局部投予、玻璃体内注射、脉络膜上或结膜下注射。在一较佳实施方案中,该眼部调配物经玻璃体内投予。医药组合物可投予至眼睛的任何部位,且对治疗血管生成型病症而言较佳是投予至眼睛的玻璃体。医药组合物可投予至身体的任意部位,且对治疗血管生成型病症而言较佳是投予至血液或组织/器官。
根据本发明实施方案投予医药组合物至个体的参数,例如剂量、投予频率、及投予长度,并不被任意具体方式所限制。这些参数的最适值可依据多种因子,例如欲治疗的个体、欲治疗的具体血管生成型疾病、疾病的严重性等,且本技术领域中普通技术人员可决定这些参数的最适值,以达到所需的治疗或临床结果。举例而言,医药组合物可一天投予一次、或一天投予多次(例如,两次、三次、四次等)。一例示性及非限制性给药方案包含在一个月的期间中经玻璃体内投予一次医药组合物。
在其他实施方案中,本发明可与其他抗血管生成药剂(例如抗肝细胞生长因子(hepatocyte growth factor,HGF)、抗HGF受体(HGFR)、抗纤维母细胞生长因子(fibroblast growth factor,FGF)、抗FGF受体(FGFR)、抗发炎(皮质类固醇、非类固醇抗发炎药物)、免疫调节剂、抗生素、及抗癌药剂)共同投予。
在一普遍方面,本发明提供对PDGF及VEGF的二聚体拮抗剂,其包含本发明融合蛋白。在二聚体中的各融合蛋白包含本文所公开的任意融合蛋白。在一实施方案中,该二聚体融合蛋白包含两种相同的本发明融合蛋白。在另一实施方案中,该二聚体融合蛋白包含两种不同的本发明融合蛋白。在另一实施方案中,该二聚体融合蛋白包含至少一种融合蛋白,该融合蛋白包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42的胺基酸20-766、SEQ ID NO:44的胺基酸21-769、及SEQ ID NO:50的胺基酸20-768,或包含与选自由以下所组成的群组的胺基酸序列具有至少90%序列同一性的胺基酸序列:SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42的胺基酸20-766、SEQ ID NO:44的胺基酸21-769、或SEQ ID NO:50的胺基酸20-768。
在另一普遍方面中,本发明提供一种蛋白共轭体,其包含结合至选自由以下所组成的群组中的至少一配体的本发明融合蛋白:PDGF及VEGF。
实施方案
实施方案1是一种融合蛋白,其包含(a)第一胜肽,该第一胜肽包含VEGF受体的胞外配体结合域,(b)抗体的Fc区,以及(c)第二胜肽,该第二胜肽包含PDGF受体的胞外配体结合域;其中,该融合蛋白从N端至C端是依照选自由以下所组成的群组的次序排列:(a)-(b)-(c)及(c)-(b)-(a);以及其中,该融合蛋白可以结合至VEGF及PDGF以及抑制VEGF的活性及PDGF的活性。
实施方案2是一种根据实施方案1的融合蛋白,其中该VEGF受体的胞外配体结合域可以结合至VEGF配体,及包含一个或多个选自由以下所组成的群组的类免疫球蛋白结构域:VEGF受体的类免疫球蛋白结构域D1至D7。
实施方案3是一种根据实施方案1的融合蛋白,其中该PDGF受体的胞外配体结合域可以结合至PDGF配体,及包含一个或多个选自由以下所组成的群组的类免疫球蛋白结构域:PDGF受体的类免疫球蛋白结构域D1至D5。
实施方案4是一种根据实施方案1的融合蛋白,其中(a)VEGF受体的胞外配体结合域包含第一VEGFR(较佳是VEGFR1)的类免疫球蛋白结构域D2、及第二VEGFR(较佳是VEGFR2)的类免疫球蛋白结构域D3;(b)抗体的Fc区包含IgG1的CH2及CH3区;及(c)PDGF受体的胞外配体结合域包含PDGFR(较佳是PDGFRβ)的类免疫球蛋白结构域D1至D3。
实施方案5是一种根据实施方案4的融合蛋白,其中(a)VEGF受体的胞外配体结合域包含与SEQ ID NO:7具有至少90%同一性的胺基酸序列;(b)抗体的Fc区包含与SEQ IDNO:12具有至少90%同一性的胺基酸序列;以及(c)PDGF受体的胞外配体结合域包含与SEQID NO:2具有至少90%同一性的胺基酸序列。
实施方案6是一种根据实施方案5的融合蛋白,其中(a)VEGF受体的胞外配体结合域包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:7及SEQ ID NO:10;(b)抗体的Fc区包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:12及SEQ ID NO:15;以及(c)PDGF受体的胞外配体结合域包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:2及SEQ ID NO:5。
实施方案7是一种根据实施方案1至6中任一种的融合蛋白,其还包含第一连接胜肽,其位于该融合蛋白的C端处的第一或第二胜肽与该Fc区之间,以及根据需要包含第二连接胜肽,其位于该融合蛋白的N端处的第二或第一胜肽与该Fc区之间。
实施方案8是一种根据实施方案7的融合蛋白,其中该第一连接胜肽包含一种或多种选自由以下所组成的群组的胺基酸序列:SEQ ID NO:20、SEQ ID NO:22、SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28、SEQ ID NO:30、及SEQ ID NO:32,以及该第二连接胜肽包含SEQ ID NO:18的胺基酸序列。
实施方案9是一种根据实施方案1至8的融合蛋白,其中该融合蛋白还包含连接至该融合蛋白的N端的讯息胜肽。
实施方案10是一种根据实施方案9的融合蛋白,其中该讯息胜肽包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:34及SEQ ID NO:36。
实施方案11是一种根据实施方案1至10中任一种的融合蛋白,其中该融合蛋白从N端至C端是依照(c)-(b)-(a)的次序排列。
实施方案12是一种融合蛋白,其包含与SEQ ID NO:38或SEQ ID NO:40具有至少90%同一性的胺基酸序列,或与SEQ ID NO:42的胺基酸20-766、SEQ ID NO:44的胺基酸21-769、或SEQ ID NO:50的胺基酸20-768具有至少90%同一性的胺基酸序列。
实施方案13是一种根据实施方案12的融合蛋白,其包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42的胺基酸20-766、SEQ ID NO:44的胺基酸21-769、及SEQ ID NO:50的胺基酸20-768。
实施方案14是一种编码如实施方案1至13中任一种的融合蛋白的分离核酸分子。
实施方案15是一种根据实施方案14的分离核酸分子,其中该融合蛋白还包含连接至该融合蛋白的N端的讯息胜肽。
实施方案16是一种根据实施方案15的分离核酸分子,其中该讯息胜肽包含选自由以下所组成的群组的胺基酸序列:SEQ ID NO:34及SEQ ID NO:36。
实施方案17是一种根据实施方案14至16中任一种的分离核酸分子,其中该核酸分子包含选自由以下所组成的群组的核苷酸序列:SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:41、SEQ ID NO:43、及SEQ ID NO:49。
实施方案18是一种表现载体,其包含编码如实施方案1至13中任一种的融合蛋白的核酸分子。
实施方案19是一种根据实施方案18的表现载体,其中该核酸分子包含选自由以下所组成的群组的核苷酸序列:SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:41、SEQ ID NO:43、及SEQ ID NO:49。
实施方案20是一种宿主细胞,其包含编码如实施方案1至13中任一种的融合蛋白的核酸分子。
实施方案21是一种用于制造如实施方案1至13中任一种的融合蛋白的方法,其包含:(1)在制造该融合蛋白的条件下培养宿主细胞,其包含编码如实施方案1至13中任一种的融合蛋白的核酸分子;以及(2)回收该宿主细胞所制造的融合蛋白。
实施方案22是一种医药组合物,其包含如实施方案1至13中任一种的融合蛋白、及医药上可接受的载体。
实施方案23是一种根据实施方案22的医药组合物,其中该组合物包含40至80毫克/毫升的在缓冲液中调配的融合蛋白,该缓冲液包含5至100mM的组胺酸、约1至10%重量/体积的蔗糖、及约0.005至0.1%重量/体积的聚山梨醇酯20,pH值约6.3至7.3。
实施方案24是一种医药组合物,其包含编码如实施方案1至13中任一种的融合蛋白的核酸分子、及医药上可接受的载体,例如脂质载体(例如,Lipofectamine)、化学物质(例如,聚乙烯亚胺)、或电穿孔缓冲液。
实施方案25是一种根据实施方案24的医药组合物,其中该组合物包含具有表现卡匣(expression cassette)的质体、及医药上可接受的载体,例如脂质载体(例如,Lipofectamine)、化学物质(例如,聚乙烯亚胺)、或电穿孔缓冲液。
实施方案26是一种治疗或预防临床症状的方法,该临床症状是选自由以下所组成的群组:血管新生、血管渗透性、水肿、及发炎,该方法包含对有需要的个体投予有效量的如实施方案1至13中任一种的融合蛋白、或如实施方案22至25中任一种的医药组合物。
实施方案27是实施方案26的方法,其中在实施方案22至23中任一种的医药组合物中,该融合蛋白是作为分离蛋白来投予。
实施方案28是实施方案26的方法,其中该融合蛋白在实施方案24及25中任一种的医药组合物中投予。
实施方案29是实施方案26至28中任一种的方法,其中该临床症状是选自由以下所组成的群组:脑水肿、中风、癌症、牛皮癣、关节炎、气喘、烧伤相关的全身性水肿、肿瘤相关的腹水及胸膜积水、发炎或创伤、慢性呼吸道发炎、微血管漏泄症候群、败血症、蛋白质漏泄增加相关的肾脏疾病、眼部发炎及/或眼部血管生成,其包括老年性黄斑退化、糖尿病视网膜病变、眼色素层炎、及角膜血管新生。
实施方案30是一种治疗或预防临床症状的方法,该临床症状是选自由以下所组成的群组:脉络膜血管新生(CNV)、湿性老年性黄斑退化(AMD)、及地图样萎缩,该方法包含对有需要的个体投予有效量的如实施方案1至13中任一种的融合蛋白、或如实施方案22至25中任一种的医药组合物。
实施方案31是实施方案30的方法,其中在实施方案22至23中任一种的医药组合物中,该融合蛋白是作为分离蛋白来投予。
实施方案32是实施方案30的方法,其中该融合蛋白在实施方案24及25中任一种的医药组合物中投予。
实施方案33是一种对PDGF及VEGF的二聚体拮抗剂,其包含如实施方案1至13中任一种的融合蛋白。
实施方案34是一种蛋白共轭体,其包含如实施方案1至13中任一种的结合至选自由以下所组成的群组中的至少一配体的融合蛋白:PDGF及VEGF。
实施例
以下本发明的实施例是为了进一步说明本发明的本质。应了解以下实施例并非用以限制本发明,且本发明的保护范围由权利要求书范围来界定。
实施例1-融合蛋白的产生、表现、纯化及分析
PDGFR胞外类免疫球蛋白结构域(PID)(SEQ ID NO:2)(Heidaran等人,FASEBJ.1995 Jan;9(1):140-5;Lokker等人,J Biol Chem.1997 Dec 26;272(52):33037-44)及VEGFR胞外类免疫球蛋白结构域(VID)(SEQ ID NO:7),并入融合蛋白中,其中该PDGFR胞外类免疫球蛋白结构域具有PDGFRβ的类免疫球蛋白结构域D1至D3,该VEGFR胞外类免疫球蛋白结构域具有VEGFR-1的类免疫球蛋白结构域D2(VEGFR-1_D2)及VEGFR-2的类免疫球蛋白结构域D3(VEGFR-2_D3)(Holash,J.等人,PNAS,2002,99(17):11393–98)。短的挠性胜肽连接子GGGGGS(SEQ ID NO:20)是放置在Fc区(SEQ ID NO:12)的C端及N端模组(PID或VID)之间,以确保正确地折迭及最小化立体阻碍。讯息胜肽(例如,SEQ ID NO:34或SEQ ID NO:36)被包括在内以确保所制造的融合蛋白2或融合蛋白1被分泌。将人类IgG1的Fc区并入以使融合蛋白二聚化,模仿体内受体二聚化,并使该表现的融合蛋白可轻易纯化。
融合蛋白1及2的编码序列分别具有SEQ ID NO:38及SEQ ID NO:40的胺基酸序列,其被转染进人类胚胎肾细胞株(HEK293F)中,并在其中表现。使用一步骤蛋白G层析(one-step Protein G chromatography)自细胞培养上清液中纯化分泌的融合蛋白。该蛋白通过蛋白G亲合性管柱(赛默飞世尔科技)捕捉,以低pH值(3.5)缓冲液洗提,并以三(羟甲基)胺基甲烷-盐酸(Tris-HCl)中和。如图2A至2C所示,使用单一步骤纯化方法可达到大于90%的纯度。图2A至2C也显示,经纯化融合蛋白1、2、3、及5具有预测的重量(分子量~180千道尔顿),及当在哺乳类细胞中表现时恰当地二聚化。
在发展的过程中,融合蛋白1的编码序列SEQ ID NO:37被并入表现载体中。经纯化融合蛋白1对PDGF的竞争性结合检定、及融合蛋白1的PDGF依赖型BALB/3T3细胞生长抑制检定的结果表示,在融合蛋白1的结合能力上具有位置效应,例如其以较低的亲合力结合PDGF-BB(见,例如,表4及6)。
因此,融合蛋白2通过重新安排VID及PID的定位来建构。融合蛋白2的编码序列SEQID NO:39被并入表现载体中。使用合适量的表现载体DNA,以表现载体转染HEK293F宿主细胞。依据抗Fc ELISA评估的蛋白表现程度来选取一稳定细胞株,且研究细胞库(researchcell bank,RCB)是自具有最适的融合蛋白表现程度的细胞株中产生。融合蛋白2的RCB是用于摇瓶蛋白制造,及使用蛋白A亲合性树脂自培养物上清液中纯化该蛋白。该蛋白使用赋形剂而将缓冲液更换成磷酸盐缓冲液。经纯化融合蛋白2的最终浓度大约20毫克/毫升。
对融合蛋白2进行突变诱发以产生融合蛋白2的变异体,即,融合蛋白3,其包含位于IgG1 Fc的C端的经删除离胺酸的残基(K528)、及位在融合蛋白2的PID的苯丙胺酸至丝胺酸(F150S)突变。2步骤的PCR突变诱发方法为,首先删除离胺酸,然后将苯丙胺酸变为丝胺酸。最终结构是包含SEQ ID NO:43的编码序列。使用合适量的表现载体DNA,以表现载体转染CHO-S宿主细胞。依据抗Fc ELISA评估的蛋白表现程度来选取一第一稳定细胞株。此用于制造具有SEQ ID NO:44的21-769胺基酸的胺基酸序列的融合蛋白3(SEQ ID NO:44的1-20胺基酸讯息胜肽序列,其在蛋白合成过程中被切掉)。通过FACS监测单株性(monoclonality),以进行一轮的重新选殖(re-cloning)。依据表现程度选取一第二稳定细胞株,且该细胞株是用以产生融合蛋白4的RCB。该融合蛋白4的RCB是用于摇瓶研究及生物反应器制造两者。解冻一小瓶的融合蛋白4的RCB,并在1升摇瓶中扩充以制造融合蛋白4,其具有与融合蛋白3一样的胺基酸序列。使用蛋白A亲合性树脂(一步骤纯化)制备六批次经纯化蛋白。该蛋白使用赋形剂而将缓冲液更换成组胺酸缓冲液。融合蛋白4的最终浓度大约20毫克/毫升。
为获得足够量的融合蛋白4,7升的生物反应器(bioreactor,BR)以约5升的最终工作体积运转。使用平台操作程序、参数设定、及控制策略,接续使用基质种类及进料列表。最终产物滴定浓度是0.21克/升。
该经纯化融合蛋白样品通过净化作用、蛋白A亲合力层析、第一超过滤步骤、尺寸排除层析、第二超过滤步骤、透析及第三超过滤步骤来进一步加工,以获得最终产物。
为产生具有SEQ ID NO:50的20-768胺基酸(SEQ ID NO:50的1-19胺基酸是讯息胜肽序列,其在蛋白合成过程中被切掉)的胺基酸序列的融合蛋白5,编码融合蛋白5的DNA序列为优化的密码子,其在CHO细胞中表现。经密码子优化的合成DNA具有SEQ ID NO:49的核酸序列,其被选殖入表现载体中。在转染前72小时,CHO K1宿主细胞以2x105个细胞/毫升接种于CD CHO(Gibco 12490-003)中,该CD CHO含有4mM麸酰胺酸(J.T贝克2078-06)及1%HT补充液(Gibco 11067-030)。宿主细胞培养于Infors震荡培养箱中(36.5℃、75%湿度、6%CO2、110RPM),并在使用前计数细胞密度。添加适合量的表现质体DNA至宿主细胞内(1升或5升工作体积),并添加聚合物基底(polymer-based)的转染剂。转染的培养物培养于Infors震荡培养箱中(36.5℃、75%湿度、6%CO2、110RPM)4小时,并添加专用料液。然后将转染的培养物培养于Infors震荡培养箱中(32℃、75%湿度、6%CO2、110RPM)。在转染后第10天收获转染的培养物。纯化上清液以产生研究材料。纯化程序包括:净化、蛋白A亲合力层析、通过Amicon Ultracel浓缩、尺寸排除层析、通过Slide-A-Lyzer透析及通过Amicon Ultracel在调配物缓冲液中获致最终浓缩物。
具有SEQ ID NO:42的20-766胺基酸的融合蛋白6,其衍生自删除首两个胺基酸(QG)的融合蛋白5,其中SEQ ID NO:42的1-19胺基酸是讯息胜肽序列,其在蛋白合成过程中被切掉。DNA插入片段是使用融合蛋白5表现载体作为模板通过PCR产生,及具有SEQ ID NO:41的胺基酸序列的编码融合蛋白6的DNA序列,其被选殖入表现载体中。培养及纯化程序与融合蛋白5一样。在指定的调配物缓冲液中,融合蛋白6的最终浓度是大约80毫克/毫升(依据280奈米的吸光值)。
综合地,这些数据表示具有同时抗VEGF及抗PDGF活性的融合蛋白已被建构、表现、纯化及表征。
实施例2:融合蛋白对VEGF165的结合亲合力
使用直接结合酵素免疫检定法(ELISA)以测量本发明融合蛋白对VEGF165(VEGF-A的接合变异体)的结合亲合力。合成的VEGF诱捕剂(VEGF Trap)用来作为正对照组1。
VEGF诱捕剂是可溶的VEGF受体,其被设计用于治疗用途,最近被FDA批准用来治疗AMD。VEGF诱捕剂含有VEGFR1的第二类免疫球蛋白结构域(D2)融合至VEGFR2的第三类免疫球蛋白结构域(D3)融合至人类IgG1的Fc区(Holash,J.,等人Proc Natl Acad Sci U SA.2002Aug 20;99(17):11393-8)。VEGF诱捕剂靶向VEGF-A、VEGF-B及PIGF。
添加100微升的涂布溶液(1微克/毫升VEGF165在1倍磷酸盐缓冲生理食盐水(PBS)中、pH 7.2)至96-孔ELISA盘的各孔中,且将该盘于4℃下过夜培养。以400微升的1倍PBS缓冲液清洗这些孔两次,并以纸巾小心地移除过量液体。
添加400微升的阻断液(5克脱脂乳在100毫升1倍PBS中)至各孔中,并将该盘于室温下培养1小时。这些孔以1倍PBS缓冲液清洗两次。
融合蛋白及对照组样品以阻断液依序稀释三倍,最高蛋白浓度是10mM。添加100微升的系列稀释样品至各孔中。将该盘加盖并于室温下在盘震荡器(~100rmp)上培养1小时。以清洗缓冲液(1倍PBS、0.05%聚山梨醇酯20)清洗这些孔三次。
添加100微升的山葵过氧化酶共轭的山羊抗人类IgG Fc专一性抗体至各孔中,该抗体以阻断液以1:2500稀释。密封该盘并于室温下在盘震荡器上培养1小时。以清洗缓冲液清洗该盘三次。
添加100微升的3,5,3’,5’-四甲基联苯胺(tetramethylbenzidine,TMB)至各孔中,将该盘培养3至5分钟以使反应进行。为停止反应,添加100微升的停止液(1N HCl)至各孔中。
各孔的光学密度(optical density,OD),是使用ELISA盘读取器在吸收波长450奈米下测定。该吸光值对融合蛋白或对照组的蛋白浓度作图,且该浓度是以半最大有效浓度(half the maximal effective concentration,EC50)的讯号决定。
经测试的本发明融合蛋白的结合亲合力,以EC50值表现,在0.22nM及0.93nM之间。ELISA的结果显示于表1中。
表1
测试材料 | EC<sub>50</sub>(nM) |
正对照组1 | 0.087 |
融合蛋白1(SEQ ID NO:38) | 0.220 |
融合蛋白2(SEQ ID NO:40) | 0.928 |
融合蛋白3(胺基酸21-769SEQ ID NO:44) | 0.477 |
融合蛋白4(胺基酸21-769SEQ ID NO:44) | 0.384 |
融合蛋白5(胺基酸20-768SEQ ID NO:50) | 0.388 |
来自本实施例的结果显示根据本发明实施方案的融合蛋白,例如融合蛋白1至5,以高亲合力与VEGF165结合。也可见于图3。
实施例3-融合蛋白对PDGF的结合亲合力
使用直接结合ELISA以测量本发明融合蛋白对PDFG的结合亲合力。合成的PDGF诱捕剂(PDGF Trap)用来作为正对照组2。
PDGF诱捕剂是可溶的PDGF受体,其被设计用于当作正对照组。PDGF诱捕剂含有PDGFRβ的第二类免疫球蛋白结构域(D1至D3)融合至人类IgG1的Fc区(Lu等人,Am J ObstetGynecol.,2008,198(4):477.e1-e10)。PDGF诱捕剂靶向PDGF-BB、PDGF-DD及PDGF-AB。
添加100微升的涂布溶液(1微克/毫升PDGF-BB在1倍磷酸盐缓冲生理食盐水(PBS)中、pH 7.2)至96-孔ELISA盘的各孔中,并将该盘于4℃下过夜培养。以400微升的1倍PBS缓冲液清洗这些孔两次,并以纸巾小心地移除过量液体。
添加400微升的阻断液(1克牛血清白蛋白在100毫升1倍PBS中)至各孔中,并将该盘于室温下培养1小时。这些孔以1倍PBS缓冲液清洗两次。
融合蛋白及对照组样品以阻断液依序稀释三倍,最高蛋白浓度是10mM。添加100微升的系列稀释样品至各孔中。将该盘加盖并于室温下在盘震荡器(~100rmp)上培养1小时。以清洗缓冲液(1倍PBS、0.05%聚山梨醇酯20)清洗这些孔三次。
添加100微升山葵过氧化酶共轭的山羊抗人类IgG Fc专一性抗体至各孔中,该抗体以阻断液以1:2500稀释。密封该盘并于室温下在盘震荡器上培养1小时。以清洗缓冲液清洗该盘三次。
添加100微升的3,5,3’,5’-四甲基联苯胺(TMB)至各孔中,将该盘培养3至5分钟以使反应进行。为停止反应,添加100微升的停止液(1N HCl)至各孔中。
各孔的光学密度(OD),是使用ELISA盘读取器在吸收波长450奈米下测定。该吸光值对融合蛋白或对照组的蛋白浓度作图,且该浓度是以半最大有效浓度(EC50)的讯号决定。
经测试的本发明融合蛋白的结合亲合力,以EC50值表现,是大约0.16nM至2.5nM。ELISA的结果显示于表2中。
表2
测试材料 | EC<sub>50</sub>(nM) |
正对照组2 | 1.354 |
融合蛋白1 | 0.160 |
融合蛋白2 | 0.939 |
融合蛋白3 | 2.285 |
融合蛋白4 | 2.538 |
融合蛋白5 | 2.286 |
来自本实施例的结果显示根据本发明实施方案的融合蛋白,例如融合蛋白1至5,以高亲合力与PDGF结合。也可见于图4。
实施例4-融合蛋白对VEGF165的竞争性结合
使用竞争性结合检定以评估本发明融合蛋白对VEGF165的结合亲合力。合成的VEGF诱捕剂用来作为正对照组1。
融合蛋白及对照组样品以阻断液依序稀释三倍,最高蛋白浓度是10mM。为了最终浓度是5pM的VEGF-A(R&D系统),将等量的稀释样品与10pM的VEGF165在室温下过夜培养。
添加Quantikine ELISA人类VEGF套组(R&D系统,有限公司)的50微升检定稀释剂至96-孔盘的各孔中。添加200微升的标准品、对照组、或融合蛋白至相应的孔中,每份两个平行样。密封该盘并于室温下培养2小时,然后以清洗缓冲液清洗三次。
添加套组中所提供的200微升VEGF165共轭体至各孔中,密封该盘并于室温下培养2小时。清洗该盘三次。
添加套组中所提供的200微升受质溶液至各孔中,密封该盘并于室温下培养20分钟。为停止反应,添加套组中所提供的50微升停止液至各孔中。
各孔的OD值,是使用ELISA盘读取器在吸收波长450奈米及540奈米(或570奈米)下测定。未结合的VEGF165(游离VEGF165)的浓度对融合蛋白或对照组的蛋白浓度作图,且该融合蛋白浓度是以游离VEGF165的半抑制浓度(IC50)讯号决定。
本发明融合蛋白的IC50值测得约3.78pM至4.67pM。竞争性结合检定的结果显示于表3中。
表3
测试材料 | IC<sub>50</sub>(pM) |
正对照组1 | 5.173 |
融合蛋白1 | 4.670 |
融合蛋白2 | 3.780 |
融合蛋白3 | 3.775 |
本实施例的结果证实本发明融合蛋白,例如融合蛋白1、2及3,以高亲合力与VEGF165结合。也可见于图5A及6A。
实施例5-融合蛋白对PDGF-BB的竞争性结合
使用竞争性结合检定以评估本发明融合蛋白对PDGF-BB的结合亲合力。合成的PDGF诱捕剂用来作为正对照组2。
融合蛋白及对照组样品以阻断液依序稀释三倍,最高蛋白浓度是10mM。等体积的稀释样品与20pM的PDGF-BB在室温下过夜培养,使其最终浓度是10pM。
添加来自Quantikine ELISA人类PDGF-BB套组的100微升检定稀释剂至96-孔盘的各孔中。将100微升的标准品、对照组、或融合蛋白添加至相应的孔中,每份两个平行样。密封该盘并于室温下培养2小时,然后以清洗缓冲液清洗四次。
添加在套组中所提供的200微升PDGF-BB共轭体至各孔中,密封该盘并于室温下培养1.5小时。清洗该盘四次。
添加在套组中所提供的200微升受质溶液至各孔中,密封该盘并于室温下培养20分钟。为停止反应,添加套组中所提供的50微升停止液至各孔中。
各孔的OD值,是使用ELISA盘读取器在吸收波长450奈米及540奈米(或570奈米)下测定。未结合的PDGF-BB的浓度对融合蛋白或对照组的蛋白浓度作图,且该融合蛋白浓度是以游离PDGF-BB的半抑制浓度(IC50)讯号决定。
本发明融合蛋白的IC50值测得约为0.125nM至200nM。竞争性结合检定的结果显示于表4中。
表4
测试材料 | IC<sub>50</sub>(nM) |
正对照组2 | 1.015 |
融合蛋白1 | 200 |
融合蛋白2 | 0.125 |
融合蛋白3 | 1.371 |
本实施例的结果证实本发明融合蛋白,例如融合蛋白2及3,以高亲合力与PDGF结合。也可见于图5B及6B。
实施例6-通过融合蛋白抑制HUVEC增生
实施人类脐静脉内皮细胞(HUVEC)增生检定以测试本发明融合蛋白的功能。合成的VEGF诱捕剂用来作为正对照组1。
添加100微升的涂布溶液(1%明胶在二次蒸馏水中)至96-孔ELISA盘的各孔中,该盘于37℃下培养2小时或过夜。孔以1倍PBS缓冲液清洗两次。
添加3500计数的在内皮细胞生长基中的人类脐静脉内皮细胞至各孔中,并将该盘于37℃下过夜培养。
融合蛋白样品以检定缓冲液(培养基-199 1倍厄尔盐(Earle’s Salts)、10%胎牛血清、10mM HEPES、1倍抗生素/抗霉剂)稀释,其最高蛋白浓度是300nM。融合蛋白样品与VEGF165(8奈克/毫升)混合,且该混合物在室温下过夜培养。然后该些孔以200微升的1倍PBS清洗。
添加100微升的VEGF165/样品混合物至各孔中,且该盘在37℃下与5%的CO2培养72小时。在培养后,添加10微升的MTS监测试剂(3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲氧苯基)-2-(4-磺苯基)-2H-四唑)+吩嗪硫酸甲酯在蒸馏的PBS中)至各孔中,并将该盘于37℃下培养2.5小时。
各孔的OD,是使用ELISA盘读取器在吸收波长490奈米下测定。吸光值对融合蛋白或对照组的蛋白浓度作图,且确定细胞增生被抑制50%时的浓度(IC50)。
对经测试的本发明融合蛋白而言,细胞增生的抑制(IC50)测得于0.058nM及0.285nM之间。增生检定的结果显示于表5中。
表5
本实施例的结果显示本发明融合蛋白,例如融合蛋白1至5,抑制HUVEC细胞的VEGF依赖性生长。也可见于图7。
实施例7-通过融合蛋白抑制BALB/3T3增生
使用衍生自BALB小鼠的3T3纤维母细胞来实施细胞增生检定,以测试本发明融合蛋白的功能。合成的PDGF诱捕剂用来作为正对照组2。
添加4000计数的在DMEM(1mM丙酮酸钠、4mM L-麸酰胺酸、10%牛血清白蛋白、1倍抗生素/抗霉剂)中的小鼠3T3纤维母细胞至各孔中,且将该盘于37℃下过夜培养。
融合蛋白样品以检定缓冲液(1mM丙酮酸钠、4mM L-麸酰胺酸、0.5%牛血清白蛋白、1倍抗生素/抗霉剂)稀释,其最高蛋白浓度是300nM。融合蛋白样品与PDGF(8奈克/毫升)混合,且将该混合物于室温下过夜培养。然后以200微升的1倍PBS清洗。
细胞以检定缓冲液在37℃与5%的CO2下挨饿4小时。添加100微升的PDGF/样品混合物至各孔中,并将该盘于37℃下与5%的CO2培养72小时。在培养后,添加10微升的MTS监测试剂至各孔中,并将该盘于37℃下培养2.5小时。
各孔的OD,是使用ELISA盘读取器在吸收波长490奈米下测定。吸光值对融合蛋白或对照组的蛋白浓度作图,且确定细胞增生被抑制50%时的浓度(IC50)。
对测试的本发明融合蛋白而言,IC50经计算确定在0.45nM及1000nM之间。增生检定的结果显示于表6中。
表6
测试材料 | IC<sub>50</sub>(nM) |
正对照组2 | 0.260 |
融合蛋白1 | 1000 |
融合蛋白2 | 0.669 |
融合蛋白3 | 0.1992 |
融合蛋白4 | 0.708 |
融合蛋白5 | 0.275 |
本实施例的结果显示本发明融合蛋白,例如融合蛋白1至5,抑制BALB/3T3细胞的PDGF依赖性生长。也可见于图8。
实施例8-通过融合蛋白在荷兰黑带兔中抑制VEGF诱导的漏泄
本发明融合蛋白是在视网膜血管新生的体内模式中测试,以测定其在预防血管漏泄中的功效。在此模式中,将VEGF以玻璃体内注射的方式,注射至兔眼的玻璃体中,以诱导不受控的视网膜血管新生及随后的漏泄。癌思停是一重组人化单株抗体,其通过抑制VEGF-A来阻断血管生成;及采视明(Eylea),其是一由人类VEGFR1及VEGFR2的部分融合至人类IgG1的Fc部分所组成的重组融合蛋白,这两者用来作为正对照组3及4。
使用活宁液(isoflurane)(3至5%)麻醉荷兰黑带兔,且以眼用必达净(betadine)溶液处理其眼睛。然后以灭菌生理食盐水清洗兔眼,施用盐酸利多卡因(Lidocainehydrochloride)(2%注射液)或丙对卡因(proparacaine)至眼睛表面。
第1天,荷兰黑带兔使用BD 300微升胰岛素注射器(31线规x 5/16英吋),经玻璃体内注射预决定剂量的本发明融合蛋白、媒介物(负)对照组、或参考(正)对照组。该针穿过眼的背颞象限(dorsotemporal quadrant),大约在缘后3至4毫米及上直肌侧3至4毫米,递送50微升的液体。第3天,对相同眼睛注射VEGF165。
经VEGF诱导3天后(第6天),对所有给药的组别进行荧光血管摄影(fluoresceinangiogram,FA),并使用从0(正常)至4(严重)的量尺评估其漏泄及曲折度。
在以融合蛋白给药之前、VEGF诱导之前及FA评估之前,使用德莱兹(Draize)评分系统来评分眼部刺激的征象。根据德莱兹分析,在开始给药之前所有兔子的眼睛皆是正常的,且在研究过程中并未发现明显的药物相关结果。使用德莱兹系统进行评分,发现其在所有给药组别中皆观察到短暂地评分结果,因此有可能是玻璃体内投药相关的程序所造成。
媒介物对照组相关的FA具有最高的视网膜血管分布漏泄及曲折度相关的平均分数(2.58)。两个参考正对照组具有0.25及0的平均分数,显示视网膜血管分布漏泄及曲折度显着降低。经测试的本发明融合蛋白具有0.167的平均分数,显示其比得上正对照组的降低VEGF所诱导视网膜漏泄及曲折度的效果。体内检定的结果显示于表7中。
表7
实施例9-通过融合蛋白在荷兰黑带兔中对于VEGF诱导的漏泄的剂量-反应抑制
本发明融合蛋白以多种剂量在视网膜血管新生的体内模式中测试,以测定其在预防血管漏泄中的剂量反应功效。在此模式中,将VEGF165以玻璃体内注射的方式,注射至兔眼的玻璃体中,以诱导不受控的视网膜血管新生及随后的漏泄。
第1天,荷兰黑带兔经玻璃体内注射多种浓度的根据本发明实施方案的融合蛋白5、媒介物(负)对照组、或参考(正)对照组。在第3天进行VEGF诱导。
经VEGF诱导3天后(第6天),对所有给药的组别进行FA,并使用从0(正常)至4(严重)的量尺评估其漏泄及曲折度。
在以融合蛋白给药之前、VEGF诱导之前、及FA评估之前,使用德莱兹评分系统来记录眼部刺激的征象。根据德莱兹分析,在开始给药之前所有兔子的眼睛皆是正常的,且在研究过程中并未发现明显的药物相关结果。使用德莱兹系统进行评分,发现其在所有给药组别中皆观察到短暂地评分结果,因此有可能是玻璃体内投药相关的程序所造成。
对第一次的VEGF诱导而言,媒介物对照组相关的FA具有最高的视网膜血管分布漏泄及曲折度相关的平均分数(3.4)。两个参考正对照组具有0的平均分数,显示视网膜血管分布漏泄及曲折度显着降低。经测试的本发明融合蛋白(融合蛋白5)在100微克、500微克、及1000微克的剂量下分别具有0.08、0.42、及0.17的分数,显示其比得上正对照组的降低VEGF所诱导视网膜漏泄及曲折度的效果。
体内检定的剂量反应结果显示于表8中。
表8
实施例10-通过融合蛋白在大鼠中降低雷射诱导的脉络膜血管新生(CNV)的损伤尺寸
棕色挪威大鼠的眼睛以睫体痹露(Cyclogyl,1%)溶液放大,并避光。在放大后,使用K他命及甲苯噻嗪(xylazine)的混合物来麻醉大鼠。在第1天,各眼的视网膜利用532奈米的雷射产生三处烧伤。
第3天以K他命及甲苯噻嗪的混合物麻醉动物,放大其眼,并以汉弥尔顿注射器(Hamilton syringe)配合33线规针头,经玻璃体内注射预决定剂量的5微升根据本发明实施方案的融合蛋白、媒介物(负)对照组、或参考(正)对照组至动物的两眼中。
第22天,动物接受1微升/克体重的10%荧光素钠的IP注射。眼底影像(fundusimage)在引入损伤前、烧伤后拍摄以确认成功损伤、及在第22天使用Micron III小动物眼底镜(Phoenix Research)拍摄。测定损伤尺寸,并交叉比对给药组别。
实施例11-通过融合蛋白在猴子中降低雷射诱导的CNV的损伤尺寸
在猴子中建立雷射诱导的CNV模式。在各眼的黄斑部周围使用532奈米二极管雷射光凝来产生6至9处烧伤,并在同一天经玻璃体内注射0.5毫克的本发明融合蛋白。
20天后,以静脉注射2.5%可溶性戊巴比妥(pentobarbitone,1毫升/公斤)来镇静动物。固定眼皮使眼睛保持打开,并使用眼底相机拍摄彩色照片。
然后注射荧光染剂(20%的荧光素钠;0.05毫升/公斤)至下肢静脉中。在注射染剂后多个时间点拍摄照片,包括动脉阶段、动静脉阶段早期、及多个动静脉阶段晚期,以监测与CNV损伤相关的荧光素漏泄。
实施例12-通过融合蛋白在异种移植小鼠中抑制人类肿瘤生长
多种人类癌症细胞,例如人类肝细胞癌Hep3B细胞(ATCC#HB-8064)及人类大肠直肠癌LoVo细胞(ATCC#CCL-229),可用来在裸鼠中建立异种移植模式。
为了评估本发明融合蛋白对肿瘤生长的抑制效果,将肿瘤细胞移植入裸鼠内,且将多种浓度的根据本发明实施方案的融合蛋白(范围从0.1至10毫克/公斤)每周两次经静脉内投予至小鼠。每周测量肿瘤的生长,达7周。
实施例13-融合蛋白在大鼠及猴子中的药物动力学评估
本发明融合蛋白的药物动力学是在动物体中评估。通过皮下注射或静脉注射投予根据本发明实施方案的融合蛋白至大鼠或猴子,该融合蛋白的范围从10毫克/公斤至300毫克/公斤。在注射后至达第15天的中的不同时间点获取血液样品。使用ELISA方法测定血液样品中融合蛋白的浓度,并计算药物动力学参数。
实施例14-融合蛋白在兔子及猴子中的眼部药物动力学评估
本发明融合蛋白的药物动力学是在动物体中评估。通过玻璃体内注射投予根据本发明实施方案的融合蛋白至兔子或猴子,该融合蛋白的范围从每眼0.1毫克至4毫克。在注射后至达第28天的中的不同时间点获取眼部组织及血液样品。使用ELISA方法测定眼部组织及血液样品中融合蛋白的浓度,并计算药物动力学参数。
虽然已详述本发明细节,且参照其特定实施方案,然而对本技术领域中具通常知识者而言,在不背离其精神与范围下可在其中作多种变化及修饰。
【序列表】
<110> 新源生物科技股份有限公司
圆祥生命科技股份有限公司
<120> 多靶向融合蛋白及其应用
<130> 688947.3WO
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Val Arg Gln Gly Glu Asn Ile Thr Leu Met Cys Ile Val Ile Gly Asn
195 200 205
Glu Val Val Asn Phe Glu Trp Thr Tyr Pro Arg Lys Glu Ser Gly Arg
210 215 220
Leu Val Glu Pro Val Thr Asp Phe Leu Leu Asp Met Pro Tyr His Ile
225 230 235 240
Arg Ser Ile Leu His Ile Pro Ser Ala Glu Leu Glu Asp Ser Gly Thr
245 250 255
Tyr Thr Cys Asn Val Thr Glu Ser Val Asn Asp His Gln Asp Glu Lys
260 265 270
Ala Ile Asn Ile Thr Val Val Glu Ser Gly Tyr Val Arg Leu Leu Gly
275 280 285
Glu Val Gly Thr Leu Gln Phe Ala Glu
290 295
<210> 6
<211> 612
<212> DNA
<213> 人工序列
<220>
<223> VID的编码序列
<400> 6
gacactggta gaccttttgt tgaaatgtat tctgaaattc ctgaaattat tcatatgact 60
gaaggaagag aacttgttat tccttgtaga gttacttctc ctaatattac tgttactctt 120
aagaagtttc ctcttgatac tcttattcct gatggaaaga gaattatttg ggattctaga 180
aagggattta ttatttctaa tgctacttat aaggaaattg gacttcttac ttgtgaagct 240
actgttaatg gacatcttta taagactaat tatcttactc atagacaaac taataccatc 300
atcgacgtgg ttctgagtcc gtctcatgga attgaactat ctgttggaga aaagcttgtc 360
ttaaattgta cagcaagaac tgaactaaat gtggggattg acttcaactg ggaataccct 420
tcttcgaagc atcagcataa gaaacttgta aaccgagacc taaaaaccca gtctgggagt 480
gagatgaaga aattcttgag caccctgact atagatggtg taacccggag tgaccaagga 540
ttgtacacct gtgcagcatc cagtgggctg atgaccaaga agaacagcac atttgtcagg 600
gtccatgaaa aa 612
<210> 7
<211> 204
<212> PRT
<213> 人工序列
<220>
<223> VID序列
<400> 7
Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile
1 5 10 15
Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr
20 25 30
Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu
35 40 45
Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile
50 55 60
Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala
65 70 75 80
Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln
85 90 95
Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu
100 105 110
Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu
115 120 125
Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His
130 135 140
Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser
145 150 155 160
Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg
165 170 175
Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr
180 185 190
Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
195 200
<210> 8
<211> 609
<212> DNA
<213> 人工序列
<220>
<223> 经修饰VID的编码序列
<400> 8
ggaaggccct tcgtggagat gtacagcgag attcctgaga ttatccacat gaccgaggga 60
cgggaactgg tgattccctg ccgggtcacc agccccaaca tcaccgtgac cctcaagaag 120
ttccccctgg acaccctgat ccctgacggc aaaaggatta tctgggacag ccggaagggc 180
tttatcatca gcaatgccac atacaaggag attggactcc tgacctgcga ggctacagtc 240
aacggacacc tgtacaagac caactacctg acccaccggc agaccaatac catcatcgac 300
gtggtgctga gccccagcca cggaattgag ctgagcgtgg gagaaaaact cgtgctcaac 360
tgcacagccc ggaccgaact caatgtcgga atcgacttca actgggaata ccccagctcc 420
aagcaccagc acaagaagct ggtcaaccgg gatctcaaga cccagtccgg cagcgaaatg 480
aagaagttcc tcagcaccct gaccatcgat ggcgtcacaa ggagcgatca gggactctac 540
acctgcgccg ctagctccgg actcatgacc aagaagaact ccacatttgt ccgggtgcac 600
gaaaagtga 609
<210> 9
<211> 606
<212> DNA
<213> 人工序列
<220>
<223> 经修饰VID的编码序列
<400> 9
ggtagacctt ttgttgaaat gtattctgaa attcctgaaa ttattcatat gactgaagga 60
agagaacttg ttattccttg tagagttact tctcctaata ttactgttac tcttaagaag 120
tttcctcttg atactcttat tcctgatgga aagagaatta tttgggattc tagaaaggga 180
tttattattt ctaatgctac ttataaggaa attggacttc ttacttgtga agctactgtt 240
aatggacatc tttataagac taattatctt actcatagac aaactaatac catcatcgac 300
gtggttctga gtccgtctca tggaattgaa ctatctgttg gagaaaagct tgtcttaaat 360
tgtacagcaa gaactgaact aaatgtgggg attgacttca actgggaata cccttcttcg 420
aagcatcagc ataagaaact tgtaaaccga gacctaaaaa cccagtctgg gagtgagatg 480
aagaaattct tgagcaccct gactatagat ggtgtaaccc ggagtgacca aggattgtac 540
acctgtgcag catccagtgg gctgatgacc aagaagaaca gcacatttgt cagggtccat 600
gaaaa a 606
<210> 10
<211> 202
<212> PRT
<213> 人工序列
<220>
<223> 经修饰VID序列
<400> 10
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
1 5 10 15
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
20 25 30
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
35 40 45
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
50 55 60
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
65 70 75 80
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
85 90 95
Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser
100 105 110
Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn
115 120 125
Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His
130 135 140
Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met
145 150 155 160
Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp
165 170 175
Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys
180 185 190
Asn Ser Thr Phe Val Arg Val His Glu Lys
195 200
<210> 11
<211> 681
<212> DNA
<213> 智人
<400> 11
gacaaaactc acacatgtcc accgtgtcca gcacctgaac tcctgggtgg accgtcagtc 60
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 420
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660
ctctccctgt ctccgggtaa a 681
<210> 12
<211> 227
<212> PRT
<213> 智人
<400> 12
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 13
<211> 678
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白6的Fc序列的编码序列
<400> 13
gataagaccc acacctgtcc tccttgtcct gctcctgagc tcctcggcgg acctagcgtg 60
ttcctgtttc cccctaagcc taaagacacc ctcatgatca gccggacccc cgaggtcaca 120
tgcgtggtgg tcgacgtctc ccatgaggat cccgaggtga agttcaattg gtacgtcgac 180
ggcgtcgagg tccacaatgc caaaaccaaa ccccgggagg agcagtacaa cagcacctat 240
agggtggtca gcgtcctgac cgtgctgcac caagactggc tgaacggcaa ggagtacaaa 300
tgcaaagtca gcaataaggc cctccccgcc cccattgaga agaccatctc caaggctaag 360
ggccaaccta gggagcccca ggtgtacacc ctgcctccca gccgggatga gctgacaaag 420
aaccaggtga gcctcacctg tctggtgaag ggcttttacc cctccgatat tgccgtggag 480
tgggaaagca acggacagcc tgagaacaac tacaagacaa ccccccctgt cctggacagc 540
gatggctcct tcttcctgta cagcaagctg acagtggata agagccggtg gcagcaggga 600
aacgtcttta gctgcagcgt gatgcatgag gccctgcaca atcactacac ccagaagtcc 660
ctgtccctga gccctggc 678
<210> 14
<211> 678
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白4的Fc序列的编码序列
<400> 14
gacaaaactc acacatgtcc accgtgtcca gcacctgaac tcctgggtgg accgtcagtc 60
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 420
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660
ctctccctgt ctccgggt 678
<210> 15
<211> 226
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白的经修饰Fc序列
<400> 15
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly
225
<210> 16
<211> 6
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 16
gccagc 6
<210> 17
<211> 6
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 17
gctagc 6
<210> 18
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 18
Ala Ser
1
<210> 19
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 19
ggaggaggcg gtggatct 18
<210> 20
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 20
Gly Gly Gly Gly Gly Ser
1 5
<210> 21
<211> 6
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 21
ggaggc 6
<210> 22
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 22
Gly Gly
1
<210> 23
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 23
ggcggcggcg gcagcggcgg aggcggatcc ggcggaggcg gctcc 45
<210> 24
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 24
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 25
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 25
ggagacacc 9
<210> 26
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 26
Gly Asp Thr
1
<210> 27
<211> 6
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 27
ggtgga 6
<210> 28
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 28
Gly Gly
1
<210> 29
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 29
ggaggcggtg gatctggtgg cggtggaagc ggaggtggag gttcc 45
<210> 30
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 30
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 31
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 连接子序列的编码序列
<400> 31
ggagacact 9
<210> 32
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 连接子序列
<400> 32
Gly Asp Thr
1
<210> 33
<211> 60
<212> DNA
<213> 人工序列
<220>
<223> 讯息胜肽序列的编码序列
<400> 33
atggagacag acacactcct gctatgggta ctgcttcttt gggttcccgg atccactggc 60
<210> 34
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 讯息胜肽序列
<400> 34
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly
20
<210> 35
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 讯息胜肽序列的编码序列
<400> 35
atggagtttg gcctgtcctg gctcttcctc gtggctatcc tgaagggcgt gcagtgt 57
<210> 36
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 讯息胜肽序列
<400> 36
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys
<210> 37
<211> 2217
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白1序列的编码序列
<400> 37
gacactggaa gaccttttgt tgaaatgtat tctgaaattc ctgaaattat tcatatgact 60
gaaggaagag aacttgttat tccttgtaga gttacttctc ctaatattac tgttactctt 120
aagaagtttc ctcttgatac tcttattcct gatggaaaga gaattatttg ggattctaga 180
aagggattta ttatttctaa tgctacttat aaggaaattg gacttcttac ttgtgaagct 240
actgttaatg gacatcttta taagactaat tatcttactc atagacaaac taataccatc 300
atcgacgtgg ttctgagtcc gtctcatgga attgaactat ctgttggaga aaagcttgtc 360
ttaaattgta cagcaagaac tgaactaaat gtggggattg acttcaactg ggaataccct 420
tcttcgaagc atcagcataa gaaacttgta aaccgagacc taaaaaccca gtctgggagt 480
gagatgaaga aattcttgag caccctgact atagatggtg taacccggag tgaccaagga 540
ttgtacacct gtgcagcatc cagtgggctg atgaccaaga agaacagcac atttgtcagg 600
gtccatgaaa aagacaaaac tcacacatgt ccaccgtgtc cagcacctga actcctgggt 660
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 720
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 780
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 840
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 900
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 960
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1020
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1080
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1140
gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1200
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1260
acgcagaaga gcctctccct gtctccgggt aaaggtggag gaggcggtgg atccggatct 1320
cagggcctgg tcgtcacacc cccggggcca gagcttgtcc tcaatgtctc cagcaccttc 1380
gttctgacct gctcgggttc agctccggtg gtgtgggaac ggatgtccca ggagccccca 1440
caggaaatgg ccaaggccca ggatggcacc ttctccagcg tgctcacact gaccaacctc 1500
actgggctag acacgggaga atacttttgc acccacaatg actcccgtgg actggagacc 1560
gatgagcgga aacggctcta catctttgtg ccagatccca ccgtgggctt cctccctaat 1620
gatgccgagg aactattcat ctttctcacg gaaataactg agatcaccat tccatgccga 1680
gtaacagacc cacagctggt ggtgacactg cacgagaaga aaggggacgt tgcactgcct 1740
gtcccctatg atcaccaacg tggctttttt ggtatctttg aggacagaag ctacatctgc 1800
aaaaccacca ttggggacag ggaggtggat tctgatgcct actatgtcta cagactccag 1860
gtgtcatcca tcaacgtctc tgtgaacgca gtgcagactg tggtccgcca gggtgagaac 1920
atcaccctca tgtgcattgt gatcgggaat gaggtggtca acttcgagtg gacatacccc 1980
cgcaaagaaa gtgggcggct ggtggagccg gtgactgact tcctcttgga tatgccttac 2040
cacatccgct ccatcctgca catccccagt gccgagttag aagactcggg gacctacacc 2100
tgcaatgtga cggagagtgt gaatgaccat caggatgaaa aggccatcaa catcaccgtg 2160
gttgagagcg gctacgtgcg gctcctggga gaggtgggca cactacaatt tgctgag 2217
<210> 38
<211> 739
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白1序列
<400> 38
Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile
1 5 10 15
Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr
20 25 30
Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu
35 40 45
Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile
50 55 60
Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala
65 70 75 80
Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln
85 90 95
Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu
100 105 110
Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu
115 120 125
Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His
130 135 140
Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser
145 150 155 160
Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg
165 170 175
Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr
180 185 190
Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr His
195 200 205
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
210 215 220
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
225 230 235 240
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
245 250 255
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
260 265 270
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
275 280 285
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
290 295 300
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
305 310 315 320
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
325 330 335
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
340 345 350
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
355 360 365
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
370 375 380
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
385 390 395 400
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
405 410 415
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
420 425 430
Gly Gly Gly Gly Gly Ser Gly Ser Gln Gly Leu Val Val Thr Pro Pro
435 440 445
Gly Pro Glu Leu Val Leu Asn Val Ser Ser Thr Phe Val Leu Thr Cys
450 455 460
Ser Gly Ser Ala Pro Val Val Trp Glu Arg Met Ser Gln Glu Pro Pro
465 470 475 480
Gln Glu Met Ala Lys Ala Gln Asp Gly Thr Phe Ser Ser Val Leu Thr
485 490 495
Leu Thr Asn Leu Thr Gly Leu Asp Thr Gly Glu Tyr Phe Cys Thr His
500 505 510
Asn Asp Ser Arg Gly Leu Glu Thr Asp Glu Arg Lys Arg Leu Tyr Ile
515 520 525
Phe Val Pro Asp Pro Thr Val Gly Phe Leu Pro Asn Asp Ala Glu Glu
530 535 540
Leu Phe Ile Phe Leu Thr Glu Ile Thr Glu Ile Thr Ile Pro Cys Arg
545 550 555 560
Val Thr Asp Pro Gln Leu Val Val Thr Leu His Glu Lys Lys Gly Asp
565 570 575
Val Ala Leu Pro Val Pro Tyr Asp His Gln Arg Gly Phe Phe Gly Ile
580 585 590
Phe Glu Asp Arg Ser Tyr Ile Cys Lys Thr Thr Ile Gly Asp Arg Glu
595 600 605
Val Asp Ser Asp Ala Tyr Tyr Val Tyr Arg Leu Gln Val Ser Ser Ile
610 615 620
Asn Val Ser Val Asn Ala Val Gln Thr Val Val Arg Gln Gly Glu Asn
625 630 635 640
Ile Thr Leu Met Cys Ile Val Ile Gly Asn Glu Val Val Asn Phe Glu
645 650 655
Trp Thr Tyr Pro Arg Lys Glu Ser Gly Arg Leu Val Glu Pro Val Thr
660 665 670
Asp Phe Leu Leu Asp Met Pro Tyr His Ile Arg Ser Ile Leu His Ile
675 680 685
Pro Ser Ala Glu Leu Glu Asp Ser Gly Thr Tyr Thr Cys Asn Val Thr
690 695 700
Glu Ser Val Asn Asp His Gln Asp Glu Lys Ala Ile Asn Ile Thr Val
705 710 715 720
Val Glu Ser Gly Tyr Val Arg Leu Leu Gly Glu Val Gly Thr Leu Gln
725 730 735
Phe Ala Glu
<210> 39
<211> 2250
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白2序列的编码序列
<400> 39
cagggcctgg tcgtcacacc cccggggcca gagcttgtcc tcaatgtctc cagcaccttc 60
gttctgacct gctcgggttc agctccggtg gtgtgggaac ggatgtccca ggagccccca 120
caggaaatgg ccaaggccca ggatggcacc ttctccagcg tgctcacact gaccaacctc 180
actgggctag acacgggaga atacttttgc acccacaatg actcccgtgg actggagacc 240
gatgagcgga aacggctcta catctttgtg ccagatccca ccgtgggctt cctccctaat 300
gatgccgagg aactattcat ctttctcacg gaaataactg agatcaccat tccatgccga 360
gtaacagacc cacagctggt ggtgacactg cacgagaaga aaggggacgt tgcactgcct 420
gtcccctatg atcaccaacg tggctttttt ggtatctttg aggacagaag ctacatctgc 480
aaaaccacca ttggggacag ggaggtggat tctgatgcct actatgtcta cagactccag 540
gtgtcatcca tcaacgtctc tgtgaacgca gtgcagactg tggtccgcca gggtgagaac 600
atcaccctca tgtgcattgt gatcgggaat gaggtggtca acttcgagtg gacatacccc 660
cgcaaagaaa gtgggcggct ggtggagccg gtgactgact tcctcttgga tatgccttac 720
cacatccgct ccatcctgca catccccagt gccgagttag aagactcggg gacctacacc 780
tgcaatgtga cggagagtgt gaatgaccat caggatgaaa aggccatcaa catcaccgtg 840
gttgagagcg gctacgtgcg gctcctggga gaggtgggca cactacaatt tgctgaggct 900
agcgacaaaa ctcacacatg tccaccgtgt ccagcacctg aactcctggg tggaccgtca 960
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1020
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1080
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1140
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1200
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1260
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1320
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1380
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1440
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1500
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1560
agcctctccc tgtctccggg taaaggtgga ggaggcggtg gatctggtgg cggtggaagc 1620
ggaggtggag gttccggaga cactggtaga ccttttgttg aaatgtattc tgaaattcct 1680
gaaattattc atatgactga aggaagagaa cttgttattc cttgtagagt tacttctcct 1740
aatattactg ttactcttaa gaagtttcct cttgatactc ttattcctga tggaaagaga 1800
attatttggg attctagaaa gggatttatt atttctaatg ctacttataa ggaaattgga 1860
cttcttactt gtgaagctac tgttaatgga catctttata agactaatta tcttactcat 1920
agacaaacta ataccatcat cgacgtggtt ctgagtccgt ctcatggaat tgaactatct 1980
gttggagaaa agcttgtctt aaattgtaca gcaagaactg aactaaatgt ggggattgac 2040
ttcaactggg aatacccttc ttcgaagcat cagcataaga aacttgtaaa ccgagaccta 2100
aaaacccagt ctgggagtga gatgaagaaa ttcttgagca ccctgactat agatggtgta 2160
acccggagtg accaaggatt gtacacctgt gcagcatcca gtgggctgat gaccaagaag 2220
aacagcacat ttgtcagggt ccatgaaaaa 2250
<210> 40
<211> 750
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白2序列
<400> 40
Gln Gly Leu Val Val Thr Pro Pro Gly Pro Glu Leu Val Leu Asn Val
1 5 10 15
Ser Ser Thr Phe Val Leu Thr Cys Ser Gly Ser Ala Pro Val Val Trp
20 25 30
Glu Arg Met Ser Gln Glu Pro Pro Gln Glu Met Ala Lys Ala Gln Asp
35 40 45
Gly Thr Phe Ser Ser Val Leu Thr Leu Thr Asn Leu Thr Gly Leu Asp
50 55 60
Thr Gly Glu Tyr Phe Cys Thr His Asn Asp Ser Arg Gly Leu Glu Thr
65 70 75 80
Asp Glu Arg Lys Arg Leu Tyr Ile Phe Val Pro Asp Pro Thr Val Gly
85 90 95
Phe Leu Pro Asn Asp Ala Glu Glu Leu Phe Ile Phe Leu Thr Glu Ile
100 105 110
Thr Glu Ile Thr Ile Pro Cys Arg Val Thr Asp Pro Gln Leu Val Val
115 120 125
Thr Leu His Glu Lys Lys Gly Asp Val Ala Leu Pro Val Pro Tyr Asp
130 135 140
His Gln Arg Gly Phe Phe Gly Ile Phe Glu Asp Arg Ser Tyr Ile Cys
145 150 155 160
Lys Thr Thr Ile Gly Asp Arg Glu Val Asp Ser Asp Ala Tyr Tyr Val
165 170 175
Tyr Arg Leu Gln Val Ser Ser Ile Asn Val Ser Val Asn Ala Val Gln
180 185 190
Thr Val Val Arg Gln Gly Glu Asn Ile Thr Leu Met Cys Ile Val Ile
195 200 205
Gly Asn Glu Val Val Asn Phe Glu Trp Thr Tyr Pro Arg Lys Glu Ser
210 215 220
Gly Arg Leu Val Glu Pro Val Thr Asp Phe Leu Leu Asp Met Pro Tyr
225 230 235 240
His Ile Arg Ser Ile Leu His Ile Pro Ser Ala Glu Leu Glu Asp Ser
245 250 255
Gly Thr Tyr Thr Cys Asn Val Thr Glu Ser Val Asn Asp His Gln Asp
260 265 270
Glu Lys Ala Ile Asn Ile Thr Val Val Glu Ser Gly Tyr Val Arg Leu
275 280 285
Leu Gly Glu Val Gly Thr Leu Gln Phe Ala Glu Ala Ser Asp Lys Thr
290 295 300
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
305 310 315 320
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
325 330 335
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
340 345 350
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
355 360 365
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
370 375 380
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
385 390 395 400
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
405 410 415
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
420 425 430
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
435 440 445
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
450 455 460
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
465 470 475 480
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
485 490 495
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
500 505 510
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
515 520 525
Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
530 535 540
Ser Gly Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
545 550 555 560
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
565 570 575
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
580 585 590
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
595 600 605
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
610 615 620
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
625 630 635 640
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
645 650 655
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
660 665 670
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
675 680 685
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
690 695 700
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
705 710 715 720
Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu
725 730 735
Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
740 745 750
<210> 41
<211> 2301
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白6序列的编码序列
<400> 41
atggagtttg gcctgtcctg gctcttcctc gtggctatcc tgaagggcgt gcagtgtctg 60
gtcgtgacac ctcccggacc cgagctggtg ctcaacgtct cctccacctt tgtgctgaca 120
tgcagcggca gcgctcctgt ggtctgggaa cggatgtccc aggagcctcc ccaggaaatg 180
gccaaggccc aggacggcac cttttccagc gtcctcacac tcaccaacct gacaggcctg 240
gacaccggcg agtacttttg cacccacaat gactccaggg gactggaaac cgatgagcgg 300
aagcggctct acattttcgt ccccgacccc accgtcggat ttctgcctaa tgacgctgaa 360
gagctgttta tcttcctgac agagatcacc gaaatcacca tcccctgtcg ggtcaccgat 420
ccccagctgg tggtcacact gcacgagaag aagggagatg tcgccctgcc tgtgccttat 480
gaccatcaga ggggcttttc cggcattttc gaggacagga gctacatctg caaaaccacc 540
atcggagacc gggaggtcga cagcgatgcc tattacgtct accggctcca ggtctcctcc 600
atcaatgtga gcgtgaatgc tgtccagaca gtggtccggc agggcgagaa tatcacactg 660
atgtgcattg tcattggcaa cgaggtggtc aacttcgagt ggacctatcc taggaaggag 720
agcggccggc tcgtcgaacc tgtgaccgac ttcctcctgg acatgcctta ccacattcgg 780
tccatcctgc acattcctag cgccgagctg gaggacagcg gaacctacac ctgcaacgtg 840
accgagtccg tgaatgacca ccaggatgag aaggccatca acatcacagt cgtggagagc 900
ggatacgtca ggctgctcgg agaagtcggc acactgcagt tcgccgaggc cagcgataag 960
acccacacct gtcctccttg tcctgctcct gagctcctcg gcggacctag cgtgttcctg 1020
tttcccccta agcctaaaga caccctcatg atcagccgga cccccgaggt cacatgcgtg 1080
gtggtcgacg tctcccatga ggatcccgag gtgaagttca attggtacgt cgacggcgtc 1140
gaggtccaca atgccaaaac caaaccccgg gaggagcagt acaacagcac ctatagggtg 1200
gtcagcgtcc tgaccgtgct gcaccaagac tggctgaacg gcaaggagta caaatgcaaa 1260
gtcagcaata aggccctccc cgcccccatt gagaagacca tctccaaggc taagggccaa 1320
cctagggagc cccaggtgta caccctgcct cccagccggg atgagctgac aaagaaccag 1380
gtgagcctca cctgtctggt gaagggcttt tacccctccg atattgccgt ggagtgggaa 1440
agcaacggac agcctgagaa caactacaag acaacccccc ctgtcctgga cagcgatggc 1500
tccttcttcc tgtacagcaa gctgacagtg gataagagcc ggtggcagca gggaaacgtc 1560
tttagctgca gcgtgatgca tgaggccctg cacaatcact acacccagaa gtccctgtcc 1620
ctgagccctg gcggaggcgg cggcggcggc agcggcggag gcggatccgg cggaggcggc 1680
tccggagaca ccggaaggcc cttcgtggag atgtacagcg agattcctga gattatccac 1740
atgaccgagg gacgggaact ggtgattccc tgccgggtca ccagccccaa catcaccgtg 1800
accctcaaga agttccccct ggacaccctg atccctgacg gcaaaaggat tatctgggac 1860
agccggaagg gctttatcat cagcaatgcc acatacaagg agattggact cctgacctgc 1920
gaggctacag tcaacggaca cctgtacaag accaactacc tgacccaccg gcagaccaat 1980
accatcatcg acgtggtgct gagccccagc cacggaattg agctgagcgt gggagaaaaa 2040
ctcgtgctca actgcacagc ccggaccgaa ctcaatgtcg gaatcgactt caactgggaa 2100
taccccagct ccaagcacca gcacaagaag ctggtcaacc gggatctcaa gacccagtcc 2160
ggcagcgaaa tgaagaagtt cctcagcacc ctgaccatcg atggcgtcac aaggagcgat 2220
cagggactct acacctgcgc cgctagctcc ggactcatga ccaagaagaa ctccacattt 2280
gtccgggtgc acgaaaagtg a 2301
<210> 42
<211> 766
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白6序列
<400> 42
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Leu Val Val Thr Pro Pro Gly Pro Glu Leu Val Leu Asn
20 25 30
Val Ser Ser Thr Phe Val Leu Thr Cys Ser Gly Ser Ala Pro Val Val
35 40 45
Trp Glu Arg Met Ser Gln Glu Pro Pro Gln Glu Met Ala Lys Ala Gln
50 55 60
Asp Gly Thr Phe Ser Ser Val Leu Thr Leu Thr Asn Leu Thr Gly Leu
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Thr His Asn Asp Ser Arg Gly Leu Glu
85 90 95
Thr Asp Glu Arg Lys Arg Leu Tyr Ile Phe Val Pro Asp Pro Thr Val
100 105 110
Gly Phe Leu Pro Asn Asp Ala Glu Glu Leu Phe Ile Phe Leu Thr Glu
115 120 125
Ile Thr Glu Ile Thr Ile Pro Cys Arg Val Thr Asp Pro Gln Leu Val
130 135 140
Val Thr Leu His Glu Lys Lys Gly Asp Val Ala Leu Pro Val Pro Tyr
145 150 155 160
Asp His Gln Arg Gly Phe Ser Gly Ile Phe Glu Asp Arg Ser Tyr Ile
165 170 175
Cys Lys Thr Thr Ile Gly Asp Arg Glu Val Asp Ser Asp Ala Tyr Tyr
180 185 190
Val Tyr Arg Leu Gln Val Ser Ser Ile Asn Val Ser Val Asn Ala Val
195 200 205
Gln Thr Val Val Arg Gln Gly Glu Asn Ile Thr Leu Met Cys Ile Val
210 215 220
Ile Gly Asn Glu Val Val Asn Phe Glu Trp Thr Tyr Pro Arg Lys Glu
225 230 235 240
Ser Gly Arg Leu Val Glu Pro Val Thr Asp Phe Leu Leu Asp Met Pro
245 250 255
Tyr His Ile Arg Ser Ile Leu His Ile Pro Ser Ala Glu Leu Glu Asp
260 265 270
Ser Gly Thr Tyr Thr Cys Asn Val Thr Glu Ser Val Asn Asp His Gln
275 280 285
Asp Glu Lys Ala Ile Asn Ile Thr Val Val Glu Ser Gly Tyr Val Arg
290 295 300
Leu Leu Gly Glu Val Gly Thr Leu Gln Phe Ala Glu Ala Ser Asp Lys
305 310 315 320
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
325 330 335
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
340 345 350
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
355 360 365
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
370 375 380
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
385 390 395 400
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
405 410 415
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
420 425 430
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
435 440 445
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
450 455 460
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
465 470 475 480
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
485 490 495
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
500 505 510
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
515 520 525
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
530 535 540
Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Gly Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
565 570 575
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
580 585 590
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
595 600 605
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
610 615 620
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
625 630 635 640
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
645 650 655
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
660 665 670
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
675 680 685
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
690 695 700
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
705 710 715 720
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
725 730 735
Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu
740 745 750
Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
755 760 765
<210> 43
<211> 2307
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白3及4序列的编码序列
<400> 43
atggagacag acacactcct gctatgggta ctgcttcttt gggttcccgg atccactggc 60
cagggcctgg tcgtcacacc cccggggcca gagcttgtcc tcaatgtctc cagcaccttc 120
gttctgacct gctcgggttc agctccggtg gtgtgggaac ggatgtccca ggagccccca 180
caggaaatgg ccaaggccca ggatggcacc ttctccagcg tgctcacact gaccaacctc 240
actgggctag acacgggaga atacttttgc acccacaatg actcccgtgg actggagacc 300
gatgagcgga aacggctcta catctttgtg ccagatccca ccgtgggctt cctccctaat 360
gatgccgagg aactattcat ctttctcacg gaaataactg agatcaccat tccatgccga 420
gtaacagacc cacagctggt ggtgacactg cacgagaaga aaggggacgt tgcactgcct 480
gtcccctatg atcaccaacg tggcttttcc ggtatctttg aggacagaag ctacatctgc 540
aaaaccacca ttggggacag ggaggtggat tctgatgcct actatgtcta cagactccag 600
gtgtcatcca tcaacgtctc tgtgaacgca gtgcagactg tggtccgcca gggtgagaac 660
atcaccctca tgtgcattgt gatcgggaat gaggtggtca acttcgagtg gacatacccc 720
cgcaaagaaa gtgggcggct ggtggagccg gtgactgact tcctcttgga tatgccttac 780
cacatccgct ccatcctgca catccccagt gccgagttag aagactcggg gacctacacc 840
tgcaatgtga cggagagtgt gaatgaccat caggatgaaa aggccatcaa catcaccgtg 900
gttgagagcg gctacgtgcg gctcctggga gaggtgggca cactacaatt tgctgaggct 960
agcgacaaaa ctcacacatg tccaccgtgt ccagcacctg aactcctggg tggaccgtca 1020
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1080
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1140
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1200
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1260
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1320
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1380
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1440
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1500
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1560
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1620
agcctctccc tgtctccggg tggtggagga ggcggtggat ctggtggcgg tggaagcgga 1680
ggtggaggtt ccggagacac tggtagacct tttgttgaaa tgtattctga aattcctgaa 1740
attattcata tgactgaagg aagagaactt gttattcctt gtagagttac ttctcctaat 1800
attactgtta ctcttaagaa gtttcctctt gatactctta ttcctgatgg aaagagaatt 1860
atttgggatt ctagaaaggg atttattatt tctaatgcta cttataagga aattggactt 1920
cttacttgtg aagctactgt taatggacat ctttataaga ctaattatct tactcataga 1980
caaactaata ccatcatcga cgtggttctg agtccgtctc atggaattga actatctgtt 2040
ggagaaaagc ttgtcttaaa ttgtacagca agaactgaac taaatgtggg gattgacttc 2100
aactgggaat acccttcttc gaagcatcag cataagaaac ttgtaaaccg agacctaaaa 2160
acccagtctg ggagtgagat gaagaaattc ttgagcaccc tgactataga tggtgtaacc 2220
cggagtgacc aaggattgta cacctgtgca gcatccagtg ggctgatgac caagaagaac 2280
agcacatttg tcagggtcca tgaaaaa 2307
<210> 44
<211> 769
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白3或4加上一讯息胜肽序列
<400> 44
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Gln Gly Leu Val Val Thr Pro Pro Gly Pro Glu Leu
20 25 30
Val Leu Asn Val Ser Ser Thr Phe Val Leu Thr Cys Ser Gly Ser Ala
35 40 45
Pro Val Val Trp Glu Arg Met Ser Gln Glu Pro Pro Gln Glu Met Ala
50 55 60
Lys Ala Gln Asp Gly Thr Phe Ser Ser Val Leu Thr Leu Thr Asn Leu
65 70 75 80
Thr Gly Leu Asp Thr Gly Glu Tyr Phe Cys Thr His Asn Asp Ser Arg
85 90 95
Gly Leu Glu Thr Asp Glu Arg Lys Arg Leu Tyr Ile Phe Val Pro Asp
100 105 110
Pro Thr Val Gly Phe Leu Pro Asn Asp Ala Glu Glu Leu Phe Ile Phe
115 120 125
Leu Thr Glu Ile Thr Glu Ile Thr Ile Pro Cys Arg Val Thr Asp Pro
130 135 140
Gln Leu Val Val Thr Leu His Glu Lys Lys Gly Asp Val Ala Leu Pro
145 150 155 160
Val Pro Tyr Asp His Gln Arg Gly Phe Ser Gly Ile Phe Glu Asp Arg
165 170 175
Ser Tyr Ile Cys Lys Thr Thr Ile Gly Asp Arg Glu Val Asp Ser Asp
180 185 190
Ala Tyr Tyr Val Tyr Arg Leu Gln Val Ser Ser Ile Asn Val Ser Val
195 200 205
Asn Ala Val Gln Thr Val Val Arg Gln Gly Glu Asn Ile Thr Leu Met
210 215 220
Cys Ile Val Ile Gly Asn Glu Val Val Asn Phe Glu Trp Thr Tyr Pro
225 230 235 240
Arg Lys Glu Ser Gly Arg Leu Val Glu Pro Val Thr Asp Phe Leu Leu
245 250 255
Asp Met Pro Tyr His Ile Arg Ser Ile Leu His Ile Pro Ser Ala Glu
260 265 270
Leu Glu Asp Ser Gly Thr Tyr Thr Cys Asn Val Thr Glu Ser Val Asn
275 280 285
Asp His Gln Asp Glu Lys Ala Ile Asn Ile Thr Val Val Glu Ser Gly
290 295 300
Tyr Val Arg Leu Leu Gly Glu Val Gly Thr Leu Gln Phe Ala Glu Ala
305 310 315 320
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
325 330 335
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
340 345 350
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
355 360 365
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
370 375 380
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
385 390 395 400
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
405 410 415
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
420 425 430
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
435 440 445
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
450 455 460
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
465 470 475 480
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
485 490 495
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
500 505 510
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
515 520 525
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
530 535 540
Ser Pro Gly Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
545 550 555 560
Gly Gly Gly Ser Gly Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser
565 570 575
Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile
580 585 590
Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe
595 600 605
Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser
610 615 620
Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu
625 630 635 640
Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr
645 650 655
Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro
660 665 670
Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys
675 680 685
Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr
690 695 700
Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys
705 710 715 720
Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile
725 730 735
Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser
740 745 750
Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu
755 760 765
Lys
<210> 45
<211> 1353
<212> DNA
<213> 人工序列
<220>
<223> VEGF诱捕剂序列的编码序列
<400> 45
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg gtcgactggc 60
gacactggaa gaccttttgt tgaaatgtat tctgaaattc ctgaaattat tcatatgact 120
gaaggaagag aacttgttat tccttgtaga gttacttctc ctaatattac tgttactctt 180
aagaagtttc ctcttgatac tcttattcct gatggaaaga gaattatttg ggattctaga 240
aagggattta ttatttctaa tgctacttat aaggaaattg gacttcttac ttgtgaagct 300
actgttaatg gacatcttta taagactaat tatcttactc atagacaaac taataccatc 360
atcgacgtgg ttctgagtcc gtctcatgga attgaactat ctgttggaga aaagcttgtc 420
ttaaattgta cagcaagaac tgaactaaat gtggggattg acttcaactg ggaataccct 480
tcttcgaagc atcagcataa gaaacttgta aaccgagacc taaaaaccca gtctgggagt 540
gagatgaaga aattcttgag caccctgact atagatggtg taacccggag tgaccaagga 600
ttgtacacct gtgcagcatc cagtgggctg atgaccaaga agaacagcac atttgtcagg 660
gtccatgaaa aagacaaaac tcacacatgt ccaccgtgtc cagcacctga actcctgggt 720
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1080
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320
acgcagaaga gcctctccct gtctccgggt aaa 1353
<210> 46
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> VEGF诱捕剂序列加上一讯息序列
<400> 46
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
20 25 30
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
35 40 45
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
50 55 60
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
65 70 75 80
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
85 90 95
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
100 105 110
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
115 120 125
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
130 135 140
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
145 150 155 160
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
165 170 175
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
180 185 190
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
195 200 205
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 47
<211> 1644
<212> DNA
<213> 人工序列
<220>
<223> PDGF诱捕剂序列的编码序列
<400> 47
atggagacag acacactcct gctatgggta ctgcttcttt gggttcccgg atccactggc 60
cagggcctgg tcgtcacacc cccggggcca gagcttgtcc tcaatgtctc cagcaccttc 120
gttctgacct gctcgggttc agctccggtg gtgtgggaac ggatgtccca ggagccccca 180
caggaaatgg ccaaggccca ggatggcacc ttctccagcg tgctcacact gaccaacctc 240
actgggctag acacgggaga atacttttgc acccacaatg actcccgtgg actggagacc 300
gatgagcgga aacggctcta catctttgtg ccagatccca ccgtgggctt cctccctaat 360
gatgccgagg aactattcat ctttctcacg gaaataactg agatcaccat tccatgccga 420
gtaacagacc cacagctggt ggtgacactg cacgagaaga aaggggacgt tgcactgcct 480
gtcccctatg atcaccaacg tggctttttt ggtatctttg aggacagaag ctacatctgc 540
aaaaccacca ttggggacag ggaggtggat tctgatgcct actatgtcta cagactccag 600
gtgtcatcca tcaacgtctc tgtgaacgca gtgcagactg tggtccgcca gggtgagaac 660
atcaccctca tgtgcattgt gatcgggaat gaggtggtca acttcgagtg gacatacccc 720
cgcaaagaaa gtgggcggct ggtggagccg gtgactgact tcctcttgga tatgccttac 780
cacatccgct ccatcctgca catccccagt gccgagttag aagactcggg gacctacacc 840
tgcaatgtga cggagagtgt gaatgaccat caggatgaaa aggccatcaa catcaccgtg 900
gttgagagcg gctacgtgcg gctcctggga gaggtgggca cactacaatt tgctgaggct 960
agcgacaaaa ctcacacatg tccaccgtgt ccagcacctg aactcctggg tggaccgtca 1020
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1080
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 1140
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 1200
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 1260
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1320
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1380
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1440
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1500
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1560
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1620
agcctctccc tgtctccggg taaa 1644
<210> 48
<211> 548
<212> PRT
<213> 人工序列
<220>
<223> PDGF诱捕剂序列加上一讯息序列
<400> 48
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Gln Gly Leu Val Val Thr Pro Pro Gly Pro Glu Leu
20 25 30
Val Leu Asn Val Ser Ser Thr Phe Val Leu Thr Cys Ser Gly Ser Ala
35 40 45
Pro Val Val Trp Glu Arg Met Ser Gln Glu Pro Pro Gln Glu Met Ala
50 55 60
Lys Ala Gln Asp Gly Thr Phe Ser Ser Val Leu Thr Leu Thr Asn Leu
65 70 75 80
Thr Gly Leu Asp Thr Gly Glu Tyr Phe Cys Thr His Asn Asp Ser Arg
85 90 95
Gly Leu Glu Thr Asp Glu Arg Lys Arg Leu Tyr Ile Phe Val Pro Asp
100 105 110
Pro Thr Val Gly Phe Leu Pro Asn Asp Ala Glu Glu Leu Phe Ile Phe
115 120 125
Leu Thr Glu Ile Thr Glu Ile Thr Ile Pro Cys Arg Val Thr Asp Pro
130 135 140
Gln Leu Val Val Thr Leu His Glu Lys Lys Gly Asp Val Ala Leu Pro
145 150 155 160
Val Pro Tyr Asp His Gln Arg Gly Phe Phe Gly Ile Phe Glu Asp Arg
165 170 175
Ser Tyr Ile Cys Lys Thr Thr Ile Gly Asp Arg Glu Val Asp Ser Asp
180 185 190
Ala Tyr Tyr Val Tyr Arg Leu Gln Val Ser Ser Ile Asn Val Ser Val
195 200 205
Asn Ala Val Gln Thr Val Val Arg Gln Gly Glu Asn Ile Thr Leu Met
210 215 220
Cys Ile Val Ile Gly Asn Glu Val Val Asn Phe Glu Trp Thr Tyr Pro
225 230 235 240
Arg Lys Glu Ser Gly Arg Leu Val Glu Pro Val Thr Asp Phe Leu Leu
245 250 255
Asp Met Pro Tyr His Ile Arg Ser Ile Leu His Ile Pro Ser Ala Glu
260 265 270
Leu Glu Asp Ser Gly Thr Tyr Thr Cys Asn Val Thr Glu Ser Val Asn
275 280 285
Asp His Gln Asp Glu Lys Ala Ile Asn Ile Thr Val Val Glu Ser Gly
290 295 300
Tyr Val Arg Leu Leu Gly Glu Val Gly Thr Leu Gln Phe Ala Glu Ala
305 310 315 320
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
325 330 335
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
340 345 350
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
355 360 365
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
370 375 380
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
385 390 395 400
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
405 410 415
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
420 425 430
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
435 440 445
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
450 455 460
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
465 470 475 480
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
485 490 495
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
500 505 510
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
515 520 525
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
530 535 540
Ser Pro Gly Lys
545
<210> 49
<211> 2250
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白5序列的编码序列
<400> 49
cagggcctgg tcgtgacacc tcccggaccc gagctggtgc tcaacgtctc ctccaccttt 60
gtgctgacat gcagcggcag cgctcctgtg gtctgggaac ggatgtccca ggagcctccc 120
caggaaatgg ccaaggccca ggacggcacc ttttccagcg tcctcacact caccaacctg 180
acaggcctgg acaccggcga gtacttttgc acccacaatg actccagggg actggaaacc 240
gatgagcgga agcggctcta cattttcgtc cccgacccca ccgtcggatt tctgcctaat 300
gacgctgaag agctgtttat cttcctgaca gagatcaccg aaatcaccat cccctgtcgg 360
gtcaccgatc cccagctggt ggtcacactg cacgagaaga agggagatgt cgccctgcct 420
gtgccttatg accatcagag gggcttttcc ggcattttcg aggacaggag ctacatctgc 480
aaaaccacca tcggagaccg ggaggtcgac agcgatgcct attacgtcta ccggctccag 540
gtctcctcca tcaatgtgag cgtgaatgct gtccagacag tggtccggca gggcgagaat 600
atcacactga tgtgcattgt cattggcaac gaggtggtca acttcgagtg gacctatcct 660
aggaaggaga gcggccggct cgtcgaacct gtgaccgact tcctcctgga catgccttac 720
cacattcggt ccatcctgca cattcctagc gccgagctgg aggacagcgg aacctacacc 780
tgcaacgtga ccgagtccgt gaatgaccac caggatgaga aggccatcaa catcacagtc 840
gtggagagcg gatacgtcag gctgctcgga gaagtcggca cactgcagtt cgccgaggcc 900
agcgataaga cccacacctg tcctccttgt cctgctcctg agctcctcgg cggacctagc 960
gtgttcctgt ttccccctaa gcctaaagac accctcatga tcagccggac ccccgaggtc 1020
acatgcgtgg tggtcgacgt ctcccatgag gatcccgagg tgaagttcaa ttggtacgtc 1080
gacggcgtcg aggtccacaa tgccaaaacc aaaccccggg aggagcagta caacagcacc 1140
tatagggtgg tcagcgtcct gaccgtgctg caccaagact ggctgaacgg caaggagtac 1200
aaatgcaaag tcagcaataa ggccctcccc gcccccattg agaagaccat ctccaaggct 1260
aagggccaac ctagggagcc ccaggtgtac accctgcctc ccagccggga tgagctgaca 1320
aagaaccagg tgagcctcac ctgtctggtg aagggctttt acccctccga tattgccgtg 1380
gagtgggaaa gcaacggaca gcctgagaac aactacaaga caaccccccc tgtcctggac 1440
agcgatggct ccttcttcct gtacagcaag ctgacagtgg ataagagccg gtggcagcag 1500
ggaaacgtct ttagctgcag cgtgatgcat gaggccctgc acaatcacta cacccagaag 1560
tccctgtccc tgagccctgg cggaggcggc ggcggcggca gcggcggagg cggatccggc 1620
ggaggcggct ccggagacac cggaaggccc ttcgtggaga tgtacagcga gattcctgag 1680
attatccaca tgaccgaggg acgggaactg gtgattccct gccgggtcac cagccccaac 1740
atcaccgtga ccctcaagaa gttccccctg gacaccctga tccctgacgg caaaaggatt 1800
atctgggaca gccggaaggg ctttatcatc agcaatgcca catacaagga gattggactc 1860
ctgacctgcg aggctacagt caacggacac ctgtacaaga ccaactacct gacccaccgg 1920
cagaccaata ccatcatcga cgtggtgctg agccccagcc acggaattga gctgagcgtg 1980
ggagaaaaac tcgtgctcaa ctgcacagcc cggaccgaac tcaatgtcgg aatcgacttc 2040
aactgggaat accccagctc caagcaccag cacaagaagc tggtcaaccg ggatctcaag 2100
acccagtccg gcagcgaaat gaagaagttc ctcagcaccc tgaccatcga tggcgtcaca 2160
aggagcgatc agggactcta cacctgcgcc gctagctccg gactcatgac caagaagaac 2220
tccacatttg tccgggtgca cgaaaagtga 2250
<210> 50
<211> 768
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白5加上一讯息胜肽序列
<400> 50
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Gln Gly Leu Val Val Thr Pro Pro Gly Pro Glu Leu Val
20 25 30
Leu Asn Val Ser Ser Thr Phe Val Leu Thr Cys Ser Gly Ser Ala Pro
35 40 45
Val Val Trp Glu Arg Met Ser Gln Glu Pro Pro Gln Glu Met Ala Lys
50 55 60
Ala Gln Asp Gly Thr Phe Ser Ser Val Leu Thr Leu Thr Asn Leu Thr
65 70 75 80
Gly Leu Asp Thr Gly Glu Tyr Phe Cys Thr His Asn Asp Ser Arg Gly
85 90 95
Leu Glu Thr Asp Glu Arg Lys Arg Leu Tyr Ile Phe Val Pro Asp Pro
100 105 110
Thr Val Gly Phe Leu Pro Asn Asp Ala Glu Glu Leu Phe Ile Phe Leu
115 120 125
Thr Glu Ile Thr Glu Ile Thr Ile Pro Cys Arg Val Thr Asp Pro Gln
130 135 140
Leu Val Val Thr Leu His Glu Lys Lys Gly Asp Val Ala Leu Pro Val
145 150 155 160
Pro Tyr Asp His Gln Arg Gly Phe Ser Gly Ile Phe Glu Asp Arg Ser
165 170 175
Tyr Ile Cys Lys Thr Thr Ile Gly Asp Arg Glu Val Asp Ser Asp Ala
180 185 190
Tyr Tyr Val Tyr Arg Leu Gln Val Ser Ser Ile Asn Val Ser Val Asn
195 200 205
Ala Val Gln Thr Val Val Arg Gln Gly Glu Asn Ile Thr Leu Met Cys
210 215 220
Ile Val Ile Gly Asn Glu Val Val Asn Phe Glu Trp Thr Tyr Pro Arg
225 230 235 240
Lys Glu Ser Gly Arg Leu Val Glu Pro Val Thr Asp Phe Leu Leu Asp
245 250 255
Met Pro Tyr His Ile Arg Ser Ile Leu His Ile Pro Ser Ala Glu Leu
260 265 270
Glu Asp Ser Gly Thr Tyr Thr Cys Asn Val Thr Glu Ser Val Asn Asp
275 280 285
His Gln Asp Glu Lys Ala Ile Asn Ile Thr Val Val Glu Ser Gly Tyr
290 295 300
Val Arg Leu Leu Gly Glu Val Gly Thr Leu Gln Phe Ala Glu Ala Ser
305 310 315 320
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
325 330 335
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
340 345 350
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
355 360 365
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
370 375 380
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
385 390 395 400
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
405 410 415
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
420 425 430
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
435 440 445
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
450 455 460
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
465 470 475 480
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
485 490 495
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
500 505 510
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
515 520 525
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
530 535 540
Pro Gly Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
545 550 555 560
Gly Gly Ser Gly Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
565 570 575
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
580 585 590
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
595 600 605
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
610 615 620
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
625 630 635 640
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
645 650 655
Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser
660 665 670
His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr
675 680 685
Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro
690 695 700
Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr
705 710 715 720
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp
725 730 735
Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser
740 745 750
Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
755 760 765
Claims (14)
1.一种融合蛋白,其特征在于,其由以下部分组成:
a.第一多肽,其为VEGF受体的胞外配体结合域,该VEGF受体的胞外配体结合域由VEGFR1的类免疫球蛋白结构域D2、及VEGFR2的类免疫球蛋白结构域D3所组成;
b.抗体的Fc区(Fc region),其由IgG1的CH2及CH3区组成;以及
c.第二多肽,其为PDGF受体的胞外配体结合域,该PDGF受体的胞外配体结合域是由PDGFRβ的类免疫球蛋白结构域D1至D3所组成;
其中,该融合蛋白从N端至C端是依照以下次序排列:(a)-(b)-(c)或(c)-(b)-(a);(a)、(b)、(c)之间可以通过连接肽连接或直接连接;
其中,该融合蛋白结合至VEGF及PDGF以抑制该VEGF的活性及该PDGF的活性;
其中,a.该VEGF受体的胞外配体结合域选自以下氨基酸序列:SEQ ID NO: 7或SEQ IDNO:10;
b.该抗体的Fc区选自以下氨基酸序列:SEQ ID NO: 12或SEQ ID NO:15;以及
c.该PDGF受体的胞外配体结合域选自以下氨基酸序列:SEQ ID NO: 2或SEQ ID NO:5。
2.如权利要求1所述的融合蛋白,其特征在于,其还包含第一连接肽,其位于该融合蛋白的C端处的第一或第二多肽与该Fc区之间,以及任选地包含第二连接肽,其位于该融合蛋白的N端处的第二或第一多肽与该Fc区之间。
3.如权利要求2所述的融合蛋白,其特征在于,该第一连接肽选自由以下所组成的群组的一个或多个氨基酸序列:SEQ ID NO: 20、SEQ ID NO: 22、SEQ ID NO: 24、SEQ ID NO:26、SEQ ID NO: 28、SEQ ID NO: 30、及SEQ ID NO: 32,以及该第二连接肽为SEQ ID NO:18的氨基酸序列。
4.如权利要求1所述的融合蛋白,其特征在于,该融合蛋白还包含连接至该融合蛋白的N端的信号肽。
5.如权利要求2所述的融合蛋白,其特征在于,该融合蛋白还包含连接至该融合蛋白的N端的信号肽。
6.如权利要求3所述的融合蛋白,其特征在于,该融合蛋白还包含连接至该融合蛋白的N端的信号肽。
7.一种融合蛋白,其特征在于,其选自以下氨基酸序列:SEQ ID NO: 38、SEQ ID NO:40、SEQ ID NO: 42的第20-766位氨基酸、SEQ ID NO: 44的第21-769位氨基酸、或SEQ IDNO: 50的第20-768位氨基酸。
8.一种分离核酸分子,其特征在于,其编码如权利要求1至7中任一项所述的融合蛋白。
9.一种宿主细胞,其特征在于,其包含编码如权利要求1至7中任一项所述的融合蛋白的核酸分子。
10.一种用于制造如权利要求1至7中任一项所述的融合蛋白的方法,其特征在于,其包含:
(1)在制造该融合蛋白的条件下培养宿主细胞,其包含编码如权利要求1至7中任一项所述的融合蛋白的核酸分子;以及
(2)回收该宿主细胞所制造的融合蛋白。
11.一种医药组合物,其特征在于,其包含如权利要求1至7中任一项所述的融合蛋白、及医药上可接受的载体。
12.一种医药组合物,其特征在于,其包含编码如权利要求1至7中任一项的融合蛋白的核酸分子、及医药上可接受的载体。
13.一种使用如权利要求1至7中任一项所述的融合蛋白在制备治疗或预防一种临床症状的药剂的用途,其特征在于,该临床症状是选自由以下所组成的群组:血管新生、血管渗透性、水肿、及发炎。
14.一种使用如权利要求1至7中任一项所述的融合蛋白在制备治疗或预防一种临床症状的药剂的用途,其特征在于,该临床症状是选自由以下所组成的群组:脉络膜血管新生(choroidal neovascularization,CNV)、湿性老年性黄斑退化(age-related maculardegeneration,AMD)、及地图样萎缩(geographic atrophy)。
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US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
KR102155875B1 (ko) | 2015-06-28 | 2020-09-16 | 올제네시스 바이오테라퓨틱스 아이엔씨. | 혈관신생 억제용 융합 단백질 |
RU2744860C2 (ru) | 2015-12-30 | 2021-03-16 | Кодиак Сайенсиз Инк. | Антитела и их конъюгаты |
TWI723247B (zh) * | 2017-02-06 | 2021-04-01 | 中央研究院 | 重組蛋白及其用途 |
EP3710483A4 (en) * | 2017-11-16 | 2021-10-20 | XL-protein GmbH | PASYLATED VEGFR / PDGFR FUSION PROTEINS AND THEIR USE IN THERAPY |
CN111406071B (zh) * | 2017-11-16 | 2024-01-16 | 成都硕德药业有限公司 | Pas化的vegfr/pdgfr融合蛋白及其在治疗中的用途 |
CA3085467A1 (en) * | 2018-02-28 | 2019-09-06 | Ap Biosciences, Inc. | Bifunctional proteins combining checkpoint blockade for targeted therapy |
TW202021988A (zh) * | 2018-08-17 | 2020-06-16 | 三鈺生物科技股份有限公司 | 抗血管新生融合蛋白及其用途 |
CN112552410A (zh) * | 2019-09-26 | 2021-03-26 | 三生国健药业(上海)股份有限公司 | 一种抗体融合蛋白及其制法和在抗肿瘤中的应用 |
CA3157509A1 (en) | 2019-10-10 | 2021-04-15 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
CN112834753A (zh) * | 2019-11-22 | 2021-05-25 | 北京泰德制药股份有限公司 | 一种融合蛋白体外生物学活性的检测方法 |
US20230137756A1 (en) * | 2020-03-30 | 2023-05-04 | The Wistar Institute Of Anatomy And Biology | Synthetic Soluble Receptor Mimics and Methods of Use for Treatment of COVID-19 |
CN116836281A (zh) * | 2022-03-25 | 2023-10-03 | 英诺湖医药(杭州)有限公司 | B7h3抗体及包含其的双功能抗体 |
US11723955B1 (en) * | 2022-05-13 | 2023-08-15 | Allgenesis Biotherapeutics Inc. | VEGFR fusion protein pharmaceutical composition |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060234347A1 (en) * | 2005-04-13 | 2006-10-19 | Harding Thomas C | Targeting multiple angiogenic pathways for cancer therapy using soluble tyrosine kinase receptors |
CN102311502A (zh) * | 2010-07-10 | 2012-01-11 | 成都康弘生物科技有限公司 | 一种抑制血管新生或生长的融合蛋白及其医疗应用 |
WO2014160507A1 (en) * | 2013-03-13 | 2014-10-02 | Genzyme Corporation | Fusion proteins comprising pdgf and vegf binding portions and methods of using thereof |
CN105026433A (zh) * | 2014-01-24 | 2015-11-04 | 上海恒瑞医药有限公司 | VEGF与PDGFRβ双特异性融合蛋白及其用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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AU2003900481A0 (en) * | 2003-02-05 | 2003-02-20 | Queensland University Of Technology | Synthetic modulators of cell migration and growth |
KR102155875B1 (ko) * | 2015-06-28 | 2020-09-16 | 올제네시스 바이오테라퓨틱스 아이엔씨. | 혈관신생 억제용 융합 단백질 |
-
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- 2016-03-10 WO PCT/US2016/021762 patent/WO2016145189A1/en active Application Filing
- 2016-03-10 ES ES16713194T patent/ES2873379T3/es active Active
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- 2016-03-10 CA CA2970384A patent/CA2970384A1/en not_active Abandoned
- 2016-03-10 KR KR1020177024998A patent/KR20170117107A/ko not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060234347A1 (en) * | 2005-04-13 | 2006-10-19 | Harding Thomas C | Targeting multiple angiogenic pathways for cancer therapy using soluble tyrosine kinase receptors |
CN102311502A (zh) * | 2010-07-10 | 2012-01-11 | 成都康弘生物科技有限公司 | 一种抑制血管新生或生长的融合蛋白及其医疗应用 |
WO2014160507A1 (en) * | 2013-03-13 | 2014-10-02 | Genzyme Corporation | Fusion proteins comprising pdgf and vegf binding portions and methods of using thereof |
CN105026433A (zh) * | 2014-01-24 | 2015-11-04 | 上海恒瑞医药有限公司 | VEGF与PDGFRβ双特异性融合蛋白及其用途 |
Non-Patent Citations (2)
Title |
---|
"Chain A, Ig Gamma-1 Chain C Region;PDB: 3S7G_A;《GenBank》;20121010;氨基酸序列 * |
Beta PDGFR-IgG chimera demonstrates that human beta PDGFR Ig-like domains 1 to 3 are sufficient for high affinity PDGF BB binding;M A Heidaran;《FASEB》;19950101;第9卷(第1期);第140-145页 * |
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CN107108757A (zh) | 2017-08-29 |
US11299531B2 (en) | 2022-04-12 |
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CA2970384A1 (en) | 2016-09-15 |
WO2016145189A8 (en) | 2017-09-08 |
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