CN1915427A - Vegf受体融合蛋白在治疗眼睛疾病中的应用 - Google Patents
Vegf受体融合蛋白在治疗眼睛疾病中的应用 Download PDFInfo
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- CN1915427A CN1915427A CNA2006100662572A CN200610066257A CN1915427A CN 1915427 A CN1915427 A CN 1915427A CN A2006100662572 A CNA2006100662572 A CN A2006100662572A CN 200610066257 A CN200610066257 A CN 200610066257A CN 1915427 A CN1915427 A CN 1915427A
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Abstract
本发明涉及VEGF受体融合蛋白在治疗眼睛疾病中的应用，所述眼睛疾病包括年龄相关性黄斑变性，糖尿病视网膜病变，糖尿病黄斑瘤腺体以及由新生血管生长而引发的治疗失败如激光凝固体，手术视网膜移植。
Description
技术领域：
本发明涉及VEGF受体融合蛋白在治疗因新生血管的生长而引发的各种眼科疾病中的应用。
背景技术：
视网膜血管系统和脉络膜(chorodial)血管系统是组成视网膜的重要组成部分。创伤或疾病而引起的血管管壁结构或功能的异常改变是导致视力下降或丧失的主要原因。例如，糖尿病视网膜病变(diabetic retinopathy)是由于糖尿病而导致视网膜血管增生，进而造成视网膜脱落。它是造成视力丧失的主要原因。在眼睛受伤后或手术后的恢复过程中也可能造成视网膜内新生血管的生长。这一类视网膜血管增生也是造成视力下降或眼睛失明的重要原因(Nature 438：932-938，2005)。
年龄相关的黄斑变性(AMD)是一种由视网膜中心区的细胞或组织退化和血管增生而引起的疾病。可分干性和湿性两种。其中湿性AMD是脉络膜新生血管形成的最常见形式，它也是引起眼睛失明的主要原因。
血管内皮生长因子(VEGF)是一种专一性调控新生血管生长的蛋白质(Am.J.Pathol.167：1451-1459，2005)。VEGF刺激内皮细胞分裂增生，进而促进新生血管生长，以提供营养和氧气给组织细胞。很多研究表明一旦眼睛视网膜的感光细胞由于营养不足而开始萎缩(称作“缺血性萎缩”)，VEGF在视网膜内的浓度便开始升高，从而促进新生血管生长。这一过程称为“新生血管的形成”(angiogenesis)。在眼内，新生的血管在形态上与正常血管不同，管腔不规则，管壁多为渗漏。这种高通透性或渗漏的血管的异常增生常导致视网膜上产生疤痕，并进一步可发生脱落从而影响到视力。
许多研究表明湿性AMD病人的脉络膜组织中有高水平的VEGF表达(Invest.Opthal.Vis.Sci 37：855-868，1996；Microvascular Res.64：162-169，2002)。由于VEGF表达水平与湿性AMD之间的相关性，VEGF可以被用作诊断AMD的一个生化指标(Br.J.Opthalmol.88：809-815，2004)。
一些VEGF抑制剂可以阻断VEGF与内皮细胞上VEGF受体(flt-1、KDR等)之间的相互作用，从而阻止由VEGF介导的信息传导，抑制由VEGF高表达而引起的新生血管的生长，以达到预防和阻止视网膜上出血的目的。这类VEGF抑制剂包括Macugen(pegaptanib sodium)，Lucentis，VEGF-Trap，Avastin(bevacizumab)和AdPEDF等。其中Macugen和Avastin已由美国国家食品和药物管理局(FDA)批准上市。
发明内容：
本发明提供一类抑制VEGF的融合蛋白，可用于治疗由于新生血管的生长而引发的各种眼科疾病。所述疾病包括(但不限于)所述眼睛疾病包括年龄相关性黄斑变性，糖尿病视网膜病变，糖尿病黄斑瘤腺体以及由新生血管生长而引发的治疗失败如激光凝固体，手术视网膜移植。在本发明中，所述融合蛋白是指大分子化合物，特别是VEGF受体的重组融合蛋白。更具体而言，本发明的VEGF抑制剂是中国专利申请“抑制血管新生的融合蛋白质及其用途”(申请号CN200510073595.4)中描述的FP1、FP2、FP3、FP4、FP5、FP6和本发明提供的FP7和FP8中的任何一种。其中FP1、FP2、FP3、FP4、FP5、FP6的融合蛋白氨基酸序列在上述专利说明书中，FP7和FP8的氨基酸序列在本发明序列表中的序列1和序列2。
本发明所述的VEGF受体融合蛋白可以通过上述专利说明书中的方法制备，其中FP1、FP2、FP3、FP4、FP5、FP6是已知物，FP7和FP8是新物质，对于新物质，本发明提供了其优选的制备方法实施例，其制备原理和上述专利说明书相同。
本发明经过重组技术制成的制品经过纯化达到药用纯度，然后根据制剂的需要再将其制备成药物制剂，这些制剂应该特别适合于静脉注射给药，玻璃体内注射给药，腹腔注射，皮下注射，局部眼内给药，其制备工艺可以采用药物制剂的常规制法完成，优选的是溶液制剂或干粉制剂，作为干粉制剂，使用时将干粉溶解使成为溶液。本发明的融合蛋白制剂，需要时可以加入药物可接受的载体，所述载体可以是任何适合本发明的制剂形式的药物载体，优选的选自：磷酸钠(sodium phosphate)、琥珀酸钠(sodium succinate)、组氨酸(histidine)、甘露醇(mannitol)、海藻糖(trehalose dihydrate)、聚山梨醇酯(polysorbate20)、氯化钠(sodium chloride)、蔗糖(sucrose)、三羟甲基氨基甲烷(trometamol)或乳糖，上述制剂缓冲液(formulation buffer)，应含有pH缓冲系统如磷酸盐(phosphate)、柠檬酸盐(citrate)、乙酸盐(acetate)、琥珀酸盐(succinate)、三羟甲基氨基甲烷(trometamol，又名Tris)或组氨酸(histidine)等中的一种，pH的范围在3至9；可含有渗透压调节剂如氯化钠(sodium chloride)、葡萄糖(dextrose)等；可含有稳定剂如氨基酸(amino acids)、甘油(glycerol)、环糊精(cyclodextrin)、蔗糖(sucrose)、海藻糖(trehalose dihydrate)等；可含有防腐剂如噻汞撒(thimerosal)、亚硫酸氢钠(sodium bisulfite)、苯基乙醇(benzylalcohol)等。对于冻干制剂，可含有赋形剂如甘露醇(mannitol)等；对于溶液制剂，可含有表面活性剂如聚山梨醇酯(polysorbate 20或80)、十二烷基磺酸钠(SDS)等。融合蛋白的浓度范围在0.01mg/ml至1000mg/ml。其用量根据临床的需要而定。另外制剂中根据需要还可加入防腐剂，稳定剂，助溶剂等辅助成分，可以选自任何适宜的药剂学常规的辅助成分。溶剂选择水或其他等渗溶液，缓冲溶液等。
本发明中，同时还介绍了VEGF抑制剂的给药方法。这些抑制剂可以通过多种不同的给药途径给予病人，其中包括(但不限于)静脉给药，玻璃体内注射，也可以通过以点眼药的方式在一定剂型下给予病人以达到治疗眼疾的目的。
本发明意外的发现本发明的融合蛋白形式的VEGF抑制剂较现有技术具有优良的眼病治疗作用，而且稳定性好，安全性高，副作用小，效果优良，本发明通过实验数据证明了本发明的有益效果，具体数据见实施例。
附图说明：
图1：本发明的8种融合蛋白的结构示意图
图2：融合蛋白与VEGF结合的亲和力的比较
图3：融合蛋白对视网膜缺血性萎缩引起的新生血管形成的影响
图4：融合蛋白对脉络膜新生血管生长的影响
具体实施方式：
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1，FP7的构建
融合蛋白FP7是由引物flt-1D2(F)、flt-1D2(R)、KDR D3(F)和KDRD3-4(R)(见专利申请书，申请号CN200510073595.4)从HUVEC细胞提取到的mRNA作为模板合成的cDNA上放大到的flt-1和KDR基因片段重组而成。具体的条件是在变性95°、30分钟，退火56°、45秒钟，延伸72°、2分钟的条件下，进行PCR扩增，30个循环，获得flt-1和KDR 1gG样结构域的PCR产物。用TA cloning试剂盒，把PCR产物克隆到PCR2.1质粒中，并转染E.coli，选取白色菌落，加入LB培养基，培养过夜。用Qiangen质粒提取试剂盒提取质粒后酶切及测序鉴定。采用拼接PCR(Sewing PCR)方法，把flt-1片段、KDR片段和IgG铰链区局部序列的核糖核酸一起连接。在两端引物中设计EcoR1酶切位点。PCR终产物在用EcoR1酶切后，经Qiangen纯化试剂盒纯化DNA片段，并插入pcDNA3.1质粒。重组质粒转染E.coli，选取阳性菌落，加入LB培养基，培养过夜。Qiangen质粒提取质粒后酶切，并测序鉴定。已获证实的质粒再转染CHO细胞就得稳定表达融合蛋白FP7的细胞系。FP7的具体核甘酸序列见序列表3。在此融合蛋白C末端保留有铰链区(hinge)的部分序列。
实施例2，FP8的构建
融合蛋白FP8是以FP7为模板直接用PCR扩增而成，PCR所用引物是flt-1D2(F)和KDR D3-hing(R)。后者的序列为：5’-aggtgctgggcacagtgggcatgtgtgagttttgtctttttcatggaccctgacaaatg。它包括与KDR第三免疫球蛋白样区相互补的序列和人IgG Fc绞链区的部分核苷酸序列。PCR扩增和基因克隆的方法与实例1相同。最终将插入了FP8的Pc DNA3.1质粒转染CHO细胞，并获得稳定细胞珠，用于蛋白质的表达。FP8的氨基酸序列见序列表2，核苷酸序列见序列表3。
实施例3 融合蛋白与VEGF结合亲和力的实验
本发明用测定VEGF的量来确定各种融合蛋白结合VEGF的能力。在这一试验中，将一定量的VEGF(10PM)加入试管中，然后将经稀释的含有不同量的各种融合蛋白加到含有VEGF的试管中，混合好后，在37°的培养箱中保存一个小时。一个小时以后，试管中游离的VEGF由R&D系统公司(R&D systems)提供的检测VEGF量的试剂盒——VEGF检测试剂盒(VEGF assay Kit)测定。测定到的结果经软件的处理而得到如图2的结果，图2表明，FP1、FP3和FP7都能有效地与VEGF亲和结合，其结合亲和能力可由IC50表示，分别是11.2PM、4.3PM和4.1PM。这个实验证明，FP3和FP7在体外与VEGF的结合能力相似，且两者都高于FP1。
这个试验结果进一步说明了KDR的第四免疫球蛋白样区域的氨基酸序列可增进融合蛋白对VEGF的结合能力。
实施例4 融合蛋白阻止由视网膜缺血性萎缩引起的新生血管的形成的实验结果
将出生七天的幼鼠放在含高氧分压(75％±2％)的培养箱内，并控制温度为23℃±2℃，日光照明。在此条件下培养几天之后，视网膜中心将无血管新生发生，五天之后，将幼鼠放回到正常氧分压的培养箱中。由于室内相对较低的氧分压浓度而对幼鼠的视网膜产生低氧条件，从而刺激产生类似于糖尿病视网膜病变和其他由于缺血性萎缩视网膜病变的新生血管反应。
利用这个模型，可以对三种融合蛋白(FP1、FP3和FP7)在缺血性萎缩视网膜病变相关的新生血管生成方面的作用做出评估。
将幼鼠放在高氧分压的培养箱中，五天之后带回到正常氧分压室内的培养箱中。幼鼠被分成五个组，每组10只，一天之后以30mg/kg的量将融合蛋白经腹腔注射幼鼠，每两天注射一次，一共注射4次。对照组的幼鼠则被注射含相同量的Fc蛋白。治疗期结束后，从各组取小鼠6只，心脏注射荧光素FAM，10分钟后，幼鼠的视网膜被摘取用来分析新生血管的生成情况。操作时将视网膜放平，在荧光显微镜下观察新生血管及荧光渗漏情况，各组其余四只小鼠的眼睛用石蜡包埋，切片后用H&E染色。镜下计数血管内皮细胞核的数目，从而判断融合蛋白对新生血管生长的影响(Investigative Ophthalomogy visual science 43，1994-2000，2002)。结果如图3所示。接受Fc蛋白注射的幼鼠视网膜都表现出严重的病变。在视网膜表面内脉膜上可观察到大量杂乱无章的血管。在经融合蛋白处理过的幼鼠其视网膜上则无明显的血管生长(如图3)。其中FP3最为有效，FP7也较有效，但其效果类似于FP1，其主要原因可能是因缺失Fc片段而影响它在体内的稳定性。FP1与FP7的效果类似。
同时，我们也试验了将这些融合蛋白在通过玻璃体内给药的情况下对新生血管的影响。试验采用同样的动物模型，在动物回到正常氧分压的培养箱内一天后，以每只眼睛0.5毫克的量进行玻璃体内注射，每只动物只接受一次治疗。给药之后第七天，动物的视网膜按上述方法收集和处理。融合蛋白对新生血管的影响如图3所示。结果表明，经玻璃体内注射，这些融合蛋白对新生血管的生长具有显著的抑制作用。玻璃体内注射的作用效果要优于腹腔注射。同时，通过这组实验，我们观察到FP7的效果类似于FP3两者都要好于FP1。在这个试验中，由于是玻璃体内注射，FP7不需经体内血液循环。因此，其血液内稳定性较低的物质不会影响它的疗效。
实施例5 融合蛋白对激光诱发的脉络膜新生血管生长的影响
根据发表的文献资料(American Journal Pathology 153，1641-1646，1998)，我们利用激光在大鼠的眼睛上建立能诱发眼底脉络膜新生血管生成的AMD模型。将150只左右的大鼠分成四组，对照组的10只大鼠通过皮下注射接受Fc蛋白(20mg/kg)，处理过的每10只大鼠分别通过皮下注射20mg/kg的FP1、FP3和FP7总共接受5次注射，分别在激光处理前一天和激光处理之后的第3、6、9和12天。在激光处理后第15天，大鼠通过静脉注射接受50mg荧光标记的右旋糖苷，然后经麻醉处理，将眼睛摘除，尽快剥离脉络膜，剖成扁平状或冷冻包埋做切片用于分析CNV病变情况。结果如图4表明，经融合蛋白处理小鼠的CNV面积都比对照(Fc)要小，其中FP3的效果要优于FP1和FP7。FP7与FP1的抑制CNV生成方面效果相当。
实施例6 融合蛋白在治疗眼疾中的应用
这些融合蛋白可以通过适当的方式，如玻璃体内注射或静脉给药，可用于治疗与病变新生血管生长相关的一系列眼科疾病，其中包括年龄相关性黄斑变性(AMD)、糖尿病视网膜病变(diabetic retinopathy)、糖尿病黄斑水肿(diabeticmacular edema)和视网膜血管阻塞(central retinal vein occlusion)。同时这些融合蛋白也可以和其他治疗方法一起结合使用，如和光敏药物(photocoagulation)或者与激光疗法结合使用，以降低在激光处理之后由新生血管生长引起的治疗失败机率。这些融合蛋白还可以和手术结合使用。如在视网膜移植之后，由于新生血管的生长而使视网膜移植的手术失败。如果在手术的同时，病人接受这些融合蛋白的治疗，就可以提高视网膜移植的成功率。AMD病人在通过正常眼科检查之后，建立基本的基准线，然后通过玻璃体注射的方法将融合蛋白(如FP3或FP7)注入体内。经处理后病人将到医院接受观察和检查，以记录这些融合蛋白对AMD的影响。一般在接受治疗之后第1、2、6、14、30和90天分别检查一次。同时，病人可能需要接受多次治疗，可以是每两到八周注射一次。每次注射的量为每只眼睛10微克至5毫克范围内。
实施例7 FP3融合蛋白冻干制剂的制备
先配制好制剂缓冲液(formulation buffer)，将合格的原液(drug substance)解冻后，用制剂缓冲液稀释到所需的蛋白浓度。进行过滤除菌后，用移液器/分装器按要求装量分装至洁净的西林瓶(规格：0.5ml/2ml)中，往瓶口加洁净的丁基橡胶塞(半压塞)。放入冷冻干燥机中，设定好合适的冻干曲线(包括预冻、冷冻、抽真空、升温各阶段的时间、温度、真空度等参数的设定)，进行冻干。当冻干过程结束后，压紧胶塞，取出西林瓶，在胶塞上加铝塑盖，用轧盖器轧紧。往西林瓶上贴标签，装入纸盒，存放于适宜的温度。
实施例8 FP3融合蛋白溶液制剂的制备
先配制好制剂缓冲液(formulation buffer)，将合格的原液(drug substance)解冻后，用制剂缓冲液稀释到所需的蛋白浓度。进行过滤除菌后，用移液器/分装器按要求装量分装至洁净的西林瓶(规格：5ml/20ml)中，往瓶口加洁净的丁基橡胶塞，塞紧。在丁基橡胶塞上加铝塑盖，用轧盖器轧紧。往西林瓶上贴标签，装入纸盒，存放于适宜的温度。
实施例9 FP3融合蛋白眼用制剂的制备
先配制好制剂缓冲液，将合格的原液(drug substance)解冻后，用制剂缓冲液稀释到所需的蛋白浓度。进行过滤除菌后，用移液器按要求装量(≤200μl)分装至洁净的西林瓶(规格：0.5ml)中，或用玻璃注射器(规格：1ml，带灰橡胶活塞、27号针头)抽吸至要求装量(≤100μl)。对于西林瓶，在瓶口端加洁净的丁基橡胶塞，塞紧，在丁基橡胶塞上加铝塑盖，用轧盖器轧紧，往西林瓶上贴标签；对于注射器，在活塞处加装橡胶塞，在针头上加装灰橡胶罩，在橡胶罩外再加装硬塑套，用铝封袋(已印好标签)封装(另配有带螺纹的塑料活塞杆、白色法兰盘接头，用不同的铝封袋封装)。装入纸盒，存放于适宜的温度。
实施例10 FP1融合蛋白眼用制剂的制备，制备方法同实施例9
实施例11 FP2融合蛋白眼用制剂的制备，制备方法同实施例9
实施例12 FP4融合蛋白眼用制剂的制备，制备方法同实施例9
实施例13 FP5融合蛋白眼用制剂的制备，制备方法同实施例9
实施例14 FP6融合蛋白眼用制剂的制备，制备方法同实施例9
实施例15 FP7融合蛋白眼用制剂的制备，制备方法同实施例9
序列表
<110>成都康弘生物科技有限公司
<120>VEGF受体融合蛋白在治疗眼睛疾病中的应用
<160>4
<210>1
<211>308
<212>PRT
<213>人工序列
<400>1
GlyArgProPheValGluMetTyrSerGluIleProGluIleIle 15
HisMetThrGIuGlyArgGluLeuValIleProCysArgValThr 30
SerProAsnIleThrValThrLeuLysLysPheProLeuAspThr 45
LeuIleProAspGlyLysArgIleIleTrpAspSerArgLysGly 60
PheIleIleSerAsnAlaThrTyrLysGluIleGlyLeuLeuThr 75
CysGluAlaThrValAsnGlyHisLeuTyrLysThrAsnTyrLeu 90
ThrHisArgGlnThrAsnThrIleIleAspValValLeuSerPro 105
SerHisGlyIleGluLeuSerValGlyGluLysLeuValLeuAsn 120
CysThrAlaArgThrGluLeuAsnValGlyIleAspPheAsnTrp 135
GluTyrProSerSerLysHisGlnHisLysLysLeuValAsnArg 150
AspLeuLysThrGlnSerGlySerGluMetLysLysPheLeuSer 165
ThrLeuThrIleAspGlyValThrArgSerAspGlnGlyLeuTyr 180
ThrCysAlaAlaSerSerGlyLeuMetThrLysLysAsnSerThr 195
PheValArgValHisGluLysProPheValAlaPheGlySerGly 210
MetGluSerLeuValGluAlaThrValGlyGluArgValArgIle 225
ProAlaLysTyrLeuGlyTyrProProProGluIleLysTrpTyr 240
LysAsnGlyIleProLeuGluSerAsnHisThrIleLysAlaGly 255
HisValLeuThrIleMetGluValSerGluArgAspThrGlyAsn 270
TyrThrValIleLeuThrAsnProIleSerLysGluLysGlnSer 285
HisValValSerLeuValValTyrValProProAspLysThrHis 300
ThrCysProLeuCysProAlaPro 308
<210>2
<211>214
<212>PRT
<213>人工序列
<400>2
GlyArgProPheValGluMetTyrSerGluIleProGluIleIle 15
HisMetThrGluGlyArgGluLeuValIleProCysArgValThr 30
SerProAsnIleThrValThrLeuLysLysPheProLeuAspThr 45
LeuIleProAspGlyLysArgIleIleTrpAspSerArgLysGly 60
PheIleIleSerAsnAlaThrTyrLysGluIleGlyLeuLeuThr 75
CysGluAlaThrValAsnGlyHisLeuTyrLysThrAsnTyrLeu 90
ThrHisArgGlnThrAsnThrIleIleAspValValLeuSerPro 105
SerHisGlyIleGluLeuSerValGlyGluLysLeuValLeuAsn 120
CysThrAlaArgThrGluLeuAsnValGlyIleAspPheAsnTrp 135
GluTyrProSerSerLysHisGlnHisLysLysLeuValAsnArg 150
AspLeuLysThrGlnSerGlySerGluMetLysLysPheLeuSer 165
ThrLeuThrIleAspGlyValThrArgSerAspGlnGlyLeuTyr 180
ThrCysAlaAlaSerSerGlyLeuMetThrLysLysAsnSerThr 195
PheValArgValHisGluLysAspLysThrHisThrCysProLeu 210
CysProAlaPro 214
<210>3
<211>924
<212>DNA
<213>人工序列
<400>3
ggtagacctt tcgtagagat gtacagtgaa atccccgaaa ttatacacat gactgaagga 60
agggagctcg tcattccctg ccgggttacg tcacctaaca tcactgttac tttaaaaaag 120
tttccacttg acactttgat ccctgatgga aaacgcataa tctgggacag tagaaagggc 180
ttcatcatat caaatgcaac gtacaaagaa atagggcttc tgacctgtga agcaacagtc 240
aatgggcatt tgtataagac aaactatctc acacatcgac aaaccaatac aatcatagat 300
gtggttctga gtccgtctca tggaattgaa ctatctgttg gagaaaagct tgtcttaaat 360
tgtacagcaa gaactgaact aaatgtgggg attgacttca actgggaata cccttcttcg 420
aagcatcagc ataagaaact tgtaaaccga gacctaaaaa cccagtctgg gagtgagatg 480
aagaaatttt tgagcacctt aactatagat ggtgtaaccc ggagtgacca aggattgtac 540
acctgtgcag catccagtgg gctgatgacc aagaagaaca gcacatttgt cagggtccat 600
gaaaaacctt ttgttgcttt tggaagtggc atggaatctc tggtggaagc cacggtgggg 660
gagcgtgtca gaatccctgc gaagtacctt ggttacccac ccccagaaat aaaatggtat 720
aaaaatggaa taccccttga gtccaatcac acaattaaag cggggcatgt actgacgatt 780
atggaagtga gtgaaagaga cacaggaaat tacactgtca tccttaccaa tcccatttca 840
aaggagaagc agagccatgt ggtctctctg gttgtgtatg tcccaccgga caaaactcac 900
acatgcccac tgtgcccagc acct 924
<210>4
<211>642
<212>DNA
<213>人工序列
<400>4
ggtagacctt tcgtagagat gtacagtgaa atccccgaaa ttatacacat gactgaagga 60
agggagctcg tcattccctg ccgggttacg tcacctaaca tcactgttac tttaaaaaag 120
tttccacttg acactttgat ccctgatgga aaacgcataa tctgggacag tagaaagggc 180
ttcatcatat caaatgcaac gtacaaagaa atagggcttc tgacctgtga agcaacagtc 240
aatgggcatt tgtataagac aaactatctc acacatcgac aaaccaatac aatcatagat 300
gtggttctga gtccgtctca tggaattgaa ctatctgttg gagaaaagct tgtcttaaat 360
tgtacagcaa gaactgaact aaatgtgggg attgacttca actgggaata cccttcttcg 420
aagcatcagc ataagaaact tgtaaaccga gacctaaaaa cccagtctgg gagtgagatg 480
aagaaatttt tgagcacctt aactatagat ggtgtaaccc ggagtgacca aggattgtac 540
acctgtgcag catccagtgg gctgatgacc aagaagaaca gcacatttgt cagggtccat 600
gaaaaagaca aaactcacaca tgcccactgt gcccagcac ct 642
Claims (10)
1.血管内皮生长因子受体融合蛋白在制备治疗由病变血管新生引起的眼睛疾病的药物中的应用。
2.权利要求1的应用，所述融合蛋白是由VEGF受体1中免疫球蛋白样区域2，第二个VEGF受体的免疫球蛋白样区域3和区域4组成。
3.权利要求2的应用，所述融合蛋白还可以是权利要求2中的融合蛋白再与另一个可以帮助蛋白分子形成二聚体的蛋白元件组成。
4.权利要求3的应用，所述帮助蛋白分子形成二聚体的蛋白元件可以是免疫球蛋白FC，包括各种免疫球蛋白类型，如IgG、IgM、IgA或亚型如IgG1、IgG2、IgG3和IgG4。这些免疫球蛋白Fc可包括Fc全长，亦可使用Fc片段，例如铰链区的部分序列。
5.权利要求2的应用，其中所述融合蛋白选自，FP1、FP2、FP3、FP4、FP5、FP6、FP7和FP8。
6.权利要求1的应用，所述眼睛疾病包括年龄相关性黄斑变性，糖尿病视网膜病变，糖尿病黄斑瘤腺体以及由新生血管生长而引发的治疗失败如激光凝固体，手术视网膜移植。
7.权利要求1的应用，所述融合蛋白可以和其他治疗方法结合应用。
8.权利要求1的应用，所述融合蛋白在制成药物制剂后应用，应用方法包括，玻璃体内注射，静脉给药，腹腔注射，皮下注射及作为眼药水滴点。
9.权利要求1的应用，所述融合蛋白可以制成任何适合的药物制剂形式
10.权利要求1的应用，所述药物制剂中含有辅助成分，所述辅助成分选自，磷酸缓冲液、琥珀酸缓冲液、组氨酸、甘露醇、海藻糖、聚山梨醇酯、氯化钠、蔗糖。
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| JP2009501824A JP2009531036A (ja) | 2006-03-31 | 2007-03-29 | Ｖｅｇｆ受容体融合タンパク質およびそれらの使用 |
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| CN101279092B (zh) * | 2007-04-02 | 2010-10-27 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗与血管生成有关的疾病中的应用 |
| CN102233132A (zh) * | 2010-04-28 | 2011-11-09 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备抑制眼表新生血管生长的药物中的应用 |
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| US7087411B2 (en) * | 1999-06-08 | 2006-08-08 | Regeneron Pharmaceuticals, Inc. | Fusion protein capable of binding VEGF |
| MEP3208A (xx) * | 1999-06-08 | 2010-02-10 | Regeneron Pharma | Modifikovani himerni polipeptidi sa poboljšanim farmakokinetičkim osobinama |
| CN1304427C (zh) * | 2004-06-08 | 2007-03-14 | 成都康弘生物科技有限公司 | 抑制血管新生的融合蛋白质及其用途 |
| US7750138B2 (en) * | 2004-06-08 | 2010-07-06 | Chengdu Kanghong Biotechnologies Co. Ltd. | Angiogenesis-inhibiting chimeric protein and the use |
-
2006
- 2006-03-31 CN CNB2006100662572A patent/CN100502945C/zh active Active
-
2007
- 2007-03-29 AU AU2007234272A patent/AU2007234272A1/en not_active Abandoned
- 2007-03-29 WO PCT/CN2007/001021 patent/WO2007112675A1/zh active Application Filing
- 2007-03-29 KR KR1020087025464A patent/KR20090010030A/ko not_active Application Discontinuation
- 2007-03-29 EP EP07720595A patent/EP2000483A4/en not_active Withdrawn
- 2007-03-29 RU RU2008136655/13A patent/RU2008136655A/ru not_active Application Discontinuation
- 2007-03-29 CA CA002647142A patent/CA2647142A1/en not_active Abandoned
- 2007-03-29 BR BRPI0710223-2A patent/BRPI0710223A2/pt not_active IP Right Cessation
- 2007-03-29 JP JP2009501824A patent/JP2009531036A/ja active Pending
-
2008
- 2008-09-29 US US12/241,017 patent/US20090264358A1/en not_active Abandoned
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101279092B (zh) * | 2007-04-02 | 2010-10-27 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗与血管生成有关的疾病中的应用 |
| CN101721699A (zh) * | 2008-10-13 | 2010-06-09 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗伴随vegf升高的炎症反应的药物中的应用 |
| CN102233132A (zh) * | 2010-04-28 | 2011-11-09 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备抑制眼表新生血管生长的药物中的应用 |
| CN102233132B (zh) * | 2010-04-28 | 2013-10-23 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备抑制眼表新生血管生长的药物中的应用 |
| CN102380096A (zh) * | 2010-08-31 | 2012-03-21 | 成都康弘生物科技有限公司 | 一种含有抑制血管增生的融合蛋白的药物组合物及用途 |
| CN102380096B (zh) * | 2010-08-31 | 2014-04-30 | 成都康弘生物科技有限公司 | 一种含有抑制血管增生的融合蛋白的药物组合物及用途 |
| WO2020114411A1 (zh) * | 2018-12-07 | 2020-06-11 | 荣昌生物制药（烟台）有限公司 | 一种双功能血管生成抑制剂及其用途 |
| CN111328336A (zh) * | 2018-12-07 | 2020-06-23 | 荣昌生物制药（烟台）有限公司 | 一种双功能血管生成抑制剂及其用途 |
| RU2760738C1 (ru) * | 2018-12-07 | 2021-11-30 | Ремеджен Ко., Лтд. | Бифункциональный ингибитор ангиогенеза и его применение |
| US11629180B2 (en) | 2018-12-07 | 2023-04-18 | Remegen Co., Ltd. | Bifunctional angiogenesis inhibitor and use thereof |
| CN111328336B (zh) * | 2018-12-07 | 2024-01-30 | 荣昌生物制药(烟台)股份有限公司 | 一种双功能血管生成抑制剂及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0710223A2 (pt) | 2011-08-02 |
| CA2647142A1 (en) | 2007-10-11 |
| AU2007234272A1 (en) | 2007-10-11 |
| CN100502945C (zh) | 2009-06-24 |
| US20090264358A1 (en) | 2009-10-22 |
| EP2000483A9 (en) | 2009-03-18 |
| EP2000483A2 (en) | 2008-12-10 |
| EP2000483A4 (en) | 2009-10-28 |
| KR20090010030A (ko) | 2009-01-28 |
| WO2007112675A8 (fr) | 2009-07-09 |
| JP2009531036A (ja) | 2009-09-03 |
| RU2008136655A (ru) | 2010-05-10 |
| WO2007112675A1 (fr) | 2007-10-11 |
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