CN111741761B - 用于使用抗vegf剂治疗血管生成病症的方法和组合物 - Google Patents
用于使用抗vegf剂治疗血管生成病症的方法和组合物 Download PDFInfo
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Abstract
提供用于使用抗VEGF剂治疗血管生成病症的方法和组合物。所述抗VEGF剂包含VEGF结合结构域并且具有结合玻璃体的能力。提供具有VEGF结合结构域的Fc‑IgG融合蛋白的示例性实施例,所述VEGF结合结构域具有强肝素结合特性、对VEGF有丝分裂活性的强抑制和改善的药代动力学,即所述抗VEGF剂的半衰期更长,并且因此投配频率更低。
Description
相关申请的交叉引用
本申请要求2018年1月26日提交的美国临时申请第62/622,382号的优先权权益,所述申请以引用的方式并入本文中。
序列表
本申请含有序列表,所述序列表以ASCII格式以电子方式提交,并且以全文引用的方式并入本文。所述ASCII副本创建于2019年1月25日,被命名为24978-0470_SL.txt并且大小为50,960字节。
背景技术
新生血管供应或血管生成的发展起至关重要的动态平衡作用,因为血管将营养物输送到组织和器官并且移出分解代谢产物1。然而,不受控制的血管生长可能促进或有助于多种疾病进程,包括肿瘤和眼内血管病症1。尽管最初鉴定并表征了几种血管生成因子(例如EGF、TGF-α、TGF-β、aFGF、bFGF、血管生成素)2,但是在过去的三十年中进行的工作已确定了VEGF-A(下文VEGF)在正常和病理性血管生成中的关键作用3 4。VEGF为以下基因家族的成员,所述家族还包括PlGF、VEGF-B、VEGF-C和VEGF-D。据报道,三种相关的受体酪氨酸激酶(RTK)结合VEGF配体:VEGFR-1、VEGFR-2和VEGFR-35。PlGF和VEGF-B与VEGFR-1选择性地相互作用,VEGF结合VEGFR-1和VEGFR-2。此RTK家族的第三个成员VEGFR-36结合VEGF-C和VEGF-D,这与淋巴管生成有关。此RTK类的每个成员在胞外部分中均具有七个免疫球蛋白(Ig)样结构域7。人们普遍认为VEGFR-2为VEGF的主要信号传导受体5。然而,VEGFR-1结合VEGF的结合亲和力显著高于VEGFR-27。
VEGF抑制剂已成为多种肿瘤的疗法标准,并且彻底改变了眼内新生血管病症的治疗,如年龄相关性黄斑变性(AMD)的新生血管形式、增生性糖尿病性视网膜病变和视网膜静脉闭塞,这些都是视力丧失和法定盲的主要原因8 4。目前,在美国,三种抗VEGF药物被广泛用于眼科适应症:贝伐单抗、兰尼单抗和阿柏西普4。贝伐单抗为靶向VEGF的全长IgG抗体9。即使贝伐单抗尚未开发用于眼科适应症,但由于其低成本而被广泛超药品说明书使用。雷尼单抗为亲和力成熟的抗VEGF Fab10。阿柏西普一种IgG-Fc融合蛋白11 12,具有来自结合VEGF、PIGF和VEGF-B的VEGFR-1和VEGFR-2的成员13。康柏西普为结构上与阿柏西普相关的可溶VEGF受体,广泛在中国用于治疗眼内新血管生成14。在世界范围内已有数百万患者用这些药物治疗。重要的是,在使用兰尼单抗或贝伐单抗治疗五年后,约有一半的新生血管AMD患者视力良好,即视敏度为20/40或更高,在获得抗VEG剂之前无法达到的结果15。
然而,在现实临床环境中,许多患者接受比在临床试验中少的抗VEGF注射剂,并且已假设,这可与差的视力结果相关16。确实,需要进行相对频繁的玻璃体内注射已经阻碍了患者的依从性并最终阻碍疗法的益处,尤其是在某些国家16。因此,需要开发在眼内注射时具有更长持续时间的药剂,因此降低注射频率,并且为此目的已经尝试了许多方法17,18。阿柏西普(艾力雅(EYLEA))是基于临床试验批准的,所述临床试验示出,每8周施用2mg剂量可匹配每月兰尼单抗(0.5mg)的功效。然而,尽管预测改用阿柏西普将减少玻璃体内注射的次数,但是最近的研究表明事实并非如此19。因此,对于具有改善半衰期的玻璃体内抗VEGF仍然剂存在未满足的医学需求。
在1996年,Davis-Smyth等人20(参也见美国专利第5,952,199号)报道VEGFR-1的结构域(D)2为VEGF和PIGF的关键结合元件。缺失D2完全消除结合。用VEGFR-1D2代替VEGFR-3的D2将VEGFR-1的配体特异性授予VEGFR-320。随后的工作通过X射线晶体学证明D2和VEGF(或PlGF)之间的相互作用21-23。
最初的研究导致设计了具有完整VEGF结合特性的构建体,所述构建体包含与Fc-lgG(Flt-1-3-IgG)融合的VEGFR-1的前三个Ig样Ds20。Flt-1-3-lgG在体外和体内均显示出强有力的中和VEGF的能力24-27。然而,此分子的全身半衰期受存在D3的阻碍,D3由于存在碱性残基簇而具有显著的肝素亲和力,导致结合到各种组织中的HSPG。在2002年,Holash等人13(美国专利第7,070,959号)描述了包含VEGFR-1D2(结合元件)和VEGFR2的D3的IgG融合构建体,与VEGFR-1D3相比,其具有弱的多的肝素亲和力。据报道,此分子在全身施用后与Flt(1-3-lgG)相比具有更长的半衰期(今天称为阿柏西普(以EYLEA出售))13,显然,例如针对肿瘤适应症的治疗优势。
发明内容
本发明提供用于抑制血管生成和用于治疗VEGF相关的病状如眼部疾病的组合物和方法,所述眼部疾病包括但不限于年龄相关性黄斑变性、增生性糖尿病性视网膜病变、视网膜静脉闭塞、继发于近视的脉络膜新生血管生成、早产儿视网膜病、糖尿病黄斑水肿、息肉状脉络膜血管病变,所述方法包含施用抑制VEGF活性并且同时具有强肝素结合特性的抗VEGF剂,由此提供优异的药代动力学,即在玻璃体内施用后具有更长的治疗剂半衰期。
在实施例中,本发明提供治疗其中局部直接施用抗VEGF剂为有益的病状的组合物和方法,例如治疗和预防内皮细胞增殖性病状或血管生成,例如在治疗实体瘤中,如但不限于在胶质母细胞瘤中的颅内施用。
在实施例中,本发明提供抗VEGF剂,其中抗VEGF剂为融合具有VEGF结合特性的结构域和结合肝素蛋白多糖的结构域的Fc-IgG构建体。在实施例中,本发明提供抗VEGF剂,其中抗VEGF剂为具有结合肝素的能力的Fc-IgG构建体并且含有具有VEGF结合特性的一个或多个结构域。在实施例中,本发明提供抗VEGF剂,其中抗VEGF剂为具有改善的结合到VEGF和肝素的功效的融合蛋白。在实施例中,本发明提供抗VEGF剂,其中抗VEGF剂为具有极低内毒素水平的融合蛋白。
在实施例中,本发明提供抗VEGF剂,其中抗VEGF剂为包含VEGF受体元件的IgG嵌合蛋白。在实施例中,本发明提供IgG嵌合蛋白,其中IgG嵌合蛋白在VEGF酪氨酸激酶受体的胞外部分中包含七个免疫球蛋白(Ig)样结构域的一个或多个片段。在实施例中,本发明提供IgG嵌合蛋白,其中IgG嵌合蛋白包含与Fc-IgG融合的VEGFR-1的一个或多个胞外结构域片段。在实施例中,本发明提供IgG嵌合蛋白,其包含至少一个VEGF结合结构域VEGFR-1结构域2和至少一个额外的VEGFR-1结构域1或3,并且不包括结构域4。在实施例中,本发明提供IgG嵌合蛋白,其中IgG嵌合蛋白包含与Fc-IgG融合的VEGFR-2的一个或多个胞外结构域片段。在实施例中,本发明提供IgG嵌合蛋白,其中IgG嵌合蛋白包含与Fc-IgG融合的VEGFR-1和VEGFR-2的一个或多个胞外结构域片段。
在实施例中,本发明提供包含可操作地连接到Fc-IgG的VEGF结合部分的抗VEGF剂,其中VEGF结合部分包含至少一个VEGF结合结构域,所述VEGF结合结构域为VEGFR-1的IgG样结构域2,并且其中抗VEGF剂的抑制VEGF刺激的有丝分裂的能力比阿柏西普更大。在实施例中,本发明提供抗VEGF剂具有比阿柏西普大的玻璃体结合能力。在实施例中,本发明提供抗VEGF剂的抑制玻璃体结合VEGF刺激的内皮细胞增殖的能力比阿柏西普更大。在实施例中,本发明提供与阿柏西普相比,药剂在体内具有增加的半衰期。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域1、2和3(V1-2-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:1中定义的氨基酸序列。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域2和3(V2-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:3中定义的氨基酸序列。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域1、2、3和3(V1-2-3-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:5中定义的氨基酸序列。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域2、3和3(V2-3-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:7中定义的氨基酸序列。
在实施例中,本发明提供包含治疗有效量的如权利要求所定义的抗VEGF剂和药学上可接受的赋形剂的药物组合物。在实施例中,本发明提供治疗有需要的受试者的VEGF相关病症的方法,所述方法包含向受试者施用治疗有效量的如所定义的抗VEGF剂。可将抗VEGF剂直接注射到受影响的组织或器官如眼睛中。
在实施例中,本发明提供用于治疗眼部疾病的方法,其中以对应于与VEGF相比2:1的摩尔比的剂量向眼睛局部施用。在实施例中,本发明提供用于治疗眼部疾病的方法,其中通过玻璃体内注射施用抗VEGF剂。在实施例中,本发明提供用于治疗眼部疾病的方法,其中每4-6周施用一次抗VEGF剂,并且在其它实施例中,治疗继续至少一年的时间。
根据一个实施例,本发明提供用于治疗眼部疾病的方法,所述方法包含将治疗有效量的抗VEGF剂局部施用到眼睛中,其中治疗有效治疗隐性最小典型和主要典型形式的湿性黄斑变性,其中药剂为融合蛋白。
在实施例中,本发明可用于治疗各种VEGF相关病症,其包括新生血管年龄相关性黄斑变性、继发于近视的脉络膜新生血管生成、增生性糖尿病性视网膜病变、糖尿病黄斑水肿、如视网膜静脉闭塞的视网膜血管阻塞、眼部肿瘤、希佩尔林道综合症、早产儿视网膜病、息肉样脉络膜血管病变、结肠直肠癌、肺癌、宫颈癌、子宫内膜癌、卵巢癌、肾癌、神经鞘瘤、神经胶质瘤、室管膜瘤和受益于抗VEGF疗法的肿瘤或非肿瘤病症。
根据另一个方面,本发明提供药物配制物,所述药物配制物包含在用于局部施用(如到眼睛中)的药学上可接受的载剂配制物中的抗VEGF剂。
在实施例中,本发明公开新颖的构建体,其中构建体强有力地中和VEGF活性而同时具有强肝素结合特性。
附图说明
将通过参考以下详细描述(其阐述其中利用本公开的原理的说明性实施例)和附图获得对本公开的特征和优点的更好理解,其中:
图1描绘具有与Fc-IgG(Fc)融合的VEGFR-1(V)的各种Ig样胞外结构域的示例性构建的融合蛋白的示意图。示出以下构建体:V1-2-3-Fc;V2-3-Fc;V1-2-3-3-Fc;V2-3-3-Fc;V1-2-3-4-Fc;V2-3-4-Fc;V1-2-4-Fc和V2-4-Fc。
图2描绘质粒构建和表达的策略。
图3描绘构建体V1-2-3的氨基酸序列和核酸序列。分别为SEQ ID NO:1和SEQ ID NO:2。
图4描绘构建体V2-3的氨基酸序列和核酸序列。分别为SEQ ID NO:3和SEQ ID NO:4。
图5描绘构建体V1-2-3-3的氨基酸序列和核酸序列。分别为SEQ ID NO:5和SEQ IDNO:6。
图6描绘构建体V2-3-3的氨基酸序列和核酸序列。分别为SEQ ID NO:7和SEQ ID NO:8。
图7描绘构建体V1-2-3-3-4的氨基酸序列和核酸序列。分别为SEQ ID NO:9和SEQ IDNO:10。
图8描绘构建体V2-3-4的氨基酸序列和核酸序列。分别为SEQ ID NO:11和SEQ IDNO:12。
图9描绘构建体V2-4的氨基酸序列和核酸序列。分别为SEQ ID NO:13和SEQ ID NO:14。
图10描绘VEGFR-1构建体在293细胞中的表达。
图11描绘与EYLEA相比,200ng的每种VEGFR-1Fc融合蛋白在还原和非还原条件下的银染色PAGE凝胶。
图12描绘VEGF受体嵌合蛋白对VEGF刺激的内皮细胞增殖的抑制性作用。
图13描绘用于结合到VEGFR1可溶受体的生物素化VEGF(在100ng/ml下)的VEGF的竞争。
图14描绘结合到生物素化VEGF和牛玻璃体的VEGFR-1可溶受体。
图15描绘牛玻璃体结合V1-2-3-3具有生物活性。
图16示出对照IgG、EYLEA或VEGFR-1Fc融合蛋白对脉络膜新生血管生成(CNV)区域的影响。激光治疗前一天,将每种蛋白以2.5mg的剂量玻璃体内注射入小鼠。EYLEA也在25mg下检验。星号表示与适当IgG对照组相比显著差异(学生t检验)(**p<0.01,*p<0.05)。
图17A和17B示出在激光治疗前1天、7天或14天单玻璃体内施用(2.5mg)后EYLEA、V1,2,3,3或对照IgG对CNV区域的影响。星号表示与IgG对照组相比显著差异(p<0.05,学生t检验)。图17B示出在图17A中各组的代表性CD31免疫荧光图像。
具体实施方式
本说明书中提到的所有出版物、专利以及专利申请都以引用的方式并入本文中,其引用程度就如同每个单独的出版物、专利或专利申请特定地并且单独地指示以引用的方式并入一般。
应理解,本文所描述的本发明的各方面和实施例包括“由…组成”和“主要由…组成”的各方面和实施例。在结合附图阅读以下说明书后,本发明的其它目的、优点和特征从结合附图作出的以下说明书将变得显而易见。
当介绍本发明或其(一个或多个)优选的实施例的要素时,冠词“一(a/an)”、“所述(the)”和“所述(said)”旨在表示存在一个或多个元素。术语“包含”、“包括”和“具有”旨在包括性的并且意指可存在除所列要素外的附加要素。
如本文所用,术语“包含(comprises/comprising)”、“包括(includes/including)”、“具有(has/having)”、“含有(contains/containing)”、“其特征在于”或其任何其它变型旨在在不进行另外明确指示的任何限制的情况下涵盖所述组分的非排他性包括。举例来说,“包含”要素(例如组分、特征或步骤)的列表的融合蛋白、药物组合物和/或方法不必仅限于那些要素(或组分或步骤),但是可包括未明确列出的或固有的融合蛋白、药物组合物和/或方法的其它要素(或组分或步骤)。
如本文所用,过渡短语“由…组成(consists of和consisting of)”不包括未指定的任何要素、步骤或组分。举例来说,在权利要求中使用的“由…组成(consists of或consisting of)”将权利要求限制为除了通常与其相关联的杂质(即,在给定组分内的杂质)以外的在权利要求中特别叙述的组分、材料或步骤。当在权利要求书正文条款中出现短语“由...组成(consists of或consisting of)”而不是紧接在前言后时,短语“由组成”仅限制在所述条款中阐述的要素(或组分或步骤);其它要素不整体上排除在从权利要求外。
如本文所用,过渡短语“主要由...组成(consists essentially of和consistingessentially of)”用于定义融合蛋白、药物组合物和/或方法包括除了字面上公开那些之外的材料、步骤、特征、组分或要素,其条件是这些额外的材料、步骤、特征、组分或要素不实质上影响所要求的发明的(一个或多个)基本和新颖特性。术语“主要由…组成”在“包含”和“由…组成”之间占据中间地带。
如本文所用,术语“药物组合物”涵盖包含如下文所描述的一种或多种治疗剂或药物和一种或多种药学上可接受的赋形剂、载剂或媒剂的组合物。
如本文所用,术语“药学上可接受的赋形剂、载剂或媒剂”包含所属领域中已知的任何可接受的材料和/或任何一种或多种添加剂。如本文所用,术语“赋形剂”、“载剂”或“媒剂”是指适于通过所属领域中已知的各种常规施用路线进行药物施用的材料。本文适用的赋形剂、载剂和媒剂包括所属领域中已知的任何这类材料,其为无毒的并且不以有害的方式与组合物的其它组分相互作用,并且通常是指与活性剂或药物一起施用的赋形剂、稀释剂、防腐剂、增溶剂、乳化剂、佐剂和/或媒剂。这类载剂可为无菌液体,如水和油,包括石油、动物、植物或合成来源的那些,如花生油、大豆油、矿物油、芝麻油等;聚乙二醇;丙三醇;丙二醇或其它合成溶剂。抗菌剂,如苯甲醇或对羟苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;和用于调整张力的试剂,如氯化钠或右旋糖也可为载剂。用于生产组合物与载剂的组合的方法是所属领域的普通技术人员已知的。在一些实施例中,措辞“药学上可接受的载剂”旨在包括任何和所有的与药物施用相容的溶剂、分散介质、包衣、等渗剂以及吸收延迟剂等。这类介质和药剂用于药学上活性物质的使用是在所属领域中众所周知的。
如本文所使用,术语“治疗有效量”是指当鉴于受试者的病状的性质和严重程度向特定受试者施用时将具有所期望治疗效果的那些量,例如将治愈、预防、抑制或至少部分遏制或部分预防目标病状的量。在一些实施例中,术语“治疗有效量”或“有效量”是指当单独或与额外治疗剂或药物组合向细胞、组织、器官或受试者施用时有效地预防或改善眼部疾病和癌症的治疗剂或药物的量,所述眼部疾病和癌症包括但不限于年龄相关性黄斑变性、增生性糖尿病性视网膜病变、视网膜静脉闭塞、继发于近视的脉络膜新生血管生成;早产儿视网膜病、糖尿病黄斑水肿、息肉状脉络膜血管病变、结肠直肠癌、肺癌、乳癌、胰腺癌和前列腺癌。治疗有效剂量另外指足以引起症状改善,例如治疗、治愈、预防或改善相关医学病状,或提高治疗、治愈、预防或改善这类病状的速率的治疗剂或药物的量。当应用于单独施用的个别活性成分时,治疗有效剂量仅指所述成分。当应用于组合时,治疗有效剂量指产生治疗效果的活性成分的组合量,无论是组合施用、依次施用还是同时施用。
如本文所用,术语“治疗(Treating/treatment)"或"缓解"是指其中目标是减缓(减轻)(如果没有治愈)目标病理性病状或病症或预防病状复发的治疗性治疗。在接受治疗量的治疗剂或药物之后,如果受试者示出特定病状的一种或多种病征和症状可观测和/或可测量的降低或不存在,那么受试者被成功“治疗”。病状的病征或症状的减轻还可被受试者感觉到。如果受试者经历稳定病状,那么也认为受试者被治疗。在一些实施例中,用治疗剂或药物进行的治疗有效地导致受试者在治疗后3个月,优选地6个月,更优选地一年,甚至更优选地在治疗后2年或更多年无症状。用于评定病状的成功治疗和改善的这些参数可容易通过具有所属领域的适当技能的医生熟悉的常规程序测量。
如本文所用,“预防性”治疗意指指示延缓病状或病状的症状的发展、抑制可能出现的症状或降低发展或复发病状或症状的风险。“治愈性”治疗包括减轻现有症状或病状的严重程度或抑制现有症状或病状恶化。
如本文所用,术语“治疗剂”、“抗VEGF剂”、“融合蛋白”、“嵌合蛋白”或“重组蛋白”包含可操作地连接到第二多肽的第一多肽,其中“治疗剂”、“抗VEGF剂”、“融合蛋白”、“嵌合蛋白”或“重组蛋白”抑制VEGF的活性。嵌合蛋白可任选地包含可操作地连接到第一或第二多肽的第三、第四或第五或其它多肽。嵌合蛋白可包含两种或更多种不同的多肽。嵌合蛋白可包含相同多肽的多个拷贝。嵌合蛋白还可在一种或多种多肽中包含一种或多种突变。用于制备嵌合蛋白的方法在所属领域中是众所周知的。在一些实施例中,术语“治疗剂”、“融合蛋白”、“嵌合蛋白”或“重组蛋白”是指表达或合成的任何构建体,其包括但不限于将VEGFR-1和/或VEGFR-2的一个或多个Ig样结构域或结构域片段与Fc-IgG可操作地连接的肽或蛋白。
术语“Ig样结构域”是指VEGFR-1和VEGFR-2的Ig样结构域1-7。术语“Ig样结构域片段”包含全长结构域的一部分,通常是肝素和/或VEGF结合或其可变区。结构域片段的实例包括氨基酸序列,其包含具有100%序列一致性和其变化的全长结构域的至少75%,更优选地至少80%、90%、95%,并且最优选地99%的片段。设想本公开包涵融合蛋白的氨基酸序列的变化,其条件是氨基酸序列的变化维持至少75%,更优选地至少80%、90%、95%,并且最优选地99%。包括在中间的某些百分比,如75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、和99%序列一致性。具体地,包涵保守性氨基酸替代。保守性替代为在其侧链相关的氨基酸家族内进行的那些。遗传编码的氨基酸通常分为以下家族:(1)酸性氨基酸为天冬氨酸、谷氨酸;(2)碱性氨基酸为赖氨酸、精氨酸、组氨酸;(3)非极性氨基酸为丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙胺酸、甲硫氨酸、色氨酸,和(4)不带电荷的极性氨基酸为甘氨酸、天冬酰胺、谷氨酰胺、半胱氨酸、丝氨酸、苏氨酸、酪氨酸。亲水性氨基酸包括精氨酸、天冬酰胺、天冬氨酸、谷氨酰胺、谷氨酸、组氨酸、赖氨酸、丝氨酸和苏氨酸。疏水性氨基酸包括丙氨酸、半胱氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苯丙胺酸、脯氨酸、色氨酸、酪氨酸和缬氨酸。氨基酸的其它家族包括(i)丝氨酸和苏氨酸,其为脂肪族羟基家族;(ii)天冬酰胺和谷氨酰胺,其为含有酰胺的家族;(iii)丙氨酸、缬氨酸、亮氨酸和异亮氨酸,其为脂肪族家族;和(iv)苯丙胺酸、色氨酸和酪氨酸,其为芳香族家族。举例来说,合理期望用异亮氨酸或缬氨酸独立代替亮氨酸,用谷氨酸独立代替天冬氨酸、用丝氨酸独立代替苏氨酸,或用结构相关氨基酸类似代替氨基酸将对所得分子的结合或特性没有重大影响,尤其如果代替不涉及构架位点内的氨基酸。通过测定融合蛋白衍生物的比活性,可容易地确定氨基酸改变是否导致功能性融合蛋白。融合蛋白的片段或类似物可由所属领域普通技术人员容易地制备。片段或类似物的优选的氨基和羧基末端出现在功能性结构域的边界附近。
如本文所用,“分离的”或“纯化的”融合蛋白意指融合蛋白为存在的主要物种(即,以摩尔计,它比在组合物中的任何其它单个物种更丰富),并且优选地基本上纯化的级分为其中融合蛋白包含所有存在的大分子物种的至少约50%(以摩尔计)的组合物。一般来说,纯化的组合物将包含存在于组合物中的所有大分子的物种的大于约80%,更优选地大于约85%、90%、95%和99%。最优选地,将融合蛋白纯化到基本均质(通过常规检测方法不能在组合物中检测到污染物物种),其中组合物主要由单个大分子物种组成。
值或范围在本文中可表达为“约”或从“约”一个特定值和/或到“约”另一个特定值。当表达这类值或范围时,公开的其它实施例包括叙述的具体值,从一个具体值和/或到其它具体值。类似地,当通过使用先行词“约”将值表达为近似值时,应当理解,特定值形成另一个实施例。还将理解,其中存在公开的多个值,并且每个值在本文还被公开为除所述值本身之外的“约”特定值。在实施例中,“约”可用于意指例如在所叙述值的10%内,在所叙述值的5%内或在所叙述值的2%内。
在一个方面,本发明公开包含治疗剂的组合物,其中治疗剂包含VEGFR-1或VEGFR-2的一个或多个肝素结合结构域,和一个或多个VEGF结合结构域,由此抑制VEGF结合到其同源受体。
在实施例中,本发明提供包含可操作地连接到Fc-IgG的VEGF结合部分的抗VEGF剂,其中VEGF结合部分包含至少一个VEGF结合结构域,所述VEGF结合结构域为VEGFR-1的IgG样结构域2,并且其中抗VEGF剂的抑制VEGF刺激的有丝分裂的能力比阿柏西普更大。在实施例中,本发明提供抗VEGF剂具有比阿柏西普大的玻璃体结合能力。在实施例中,本发明提供抗VEGF剂的抑制玻璃体结合VEGF刺激的内皮细胞增殖的能力比阿柏西普更大。在实施例中,本发明提供与阿柏西普相比,药剂在体内具有增加的半衰期。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域1、2和3(V1-2-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:1中定义的氨基酸序列。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域2和3(V2-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:3中定义的氨基酸序列。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域1、2、3和3(V1-2-3-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:5中定义的氨基酸序列。
在实施例中,本发明提供VEGF结合部分主要由VEGFR-1的IgG样结构域2、3和3(V2-3-3)组成。在实施例中,抗VEGF剂包含如SEQ ID NO:7中定义的氨基酸序列。
在实施例中,本发明提供包含治疗有效量的如权利要求所定义的抗VEGF剂和药学上可接受的赋形剂的药物组合物。在实施例中,本发明提供治疗有需要的受试者的VEGF相关病症的方法,所述方法包含向受试者施用治疗有效量的如所定义的抗VEGF剂。可将抗VEGF剂直接注射到受影响的组织或器官如眼睛中。
在实施例中,本发明可用于治疗各种VEGF相关病症,其包括新生血管年龄相关性黄斑变性、继发于近视的脉络膜新生血管生成、增生性糖尿病性视网膜病变、糖尿病黄斑水肿、如视网膜静脉闭塞的视网膜血管阻塞、眼部肿瘤、希佩尔林道综合症、早产儿视网膜病、息肉样脉络膜血管病变、结肠直肠癌、肺癌、宫颈癌、子宫内膜癌、卵巢癌、肾癌、神经鞘瘤、神经胶质瘤、室管膜瘤和受益于抗VEGF疗法的肿瘤或非肿瘤病症。
在一些实施例中,治疗剂为可施用的剂型,其包含治疗剂和额外的赋形剂、载剂、佐剂、溶剂或稀释剂。
在一些实施例中,本发明公开适于治疗和/或预防性治疗受试者的药物组合物,其中以有效地实现其预期目的的量含有治疗剂。
在一些实施例中,本文公开的治疗剂或组合物通过注射施用。在某些实施例中,组合物或治疗剂直接注射到患病的器官或组织中。在一些实施例中,治疗剂可局部施用,例如通过贴剂或直接施用到患病器官或组织,或通过电离子透入疗法。治疗剂可以持续释放组合物提供,如在例如美国专利第5,672,659号和第5,595,760号中描述的那些。立即或持续释放组合物的使用取决于所治疗的病状的性质。如果病状由急性或过度急性病症组成,那么与延长释放组合物相比,优选立即释放形式的治疗。替代地,对于某些预防或长期治疗,持续释放组合物可为适当的。
还可使用植入物,如但不限于眼内植入物来递送治疗剂。这类植入物可为可生物降解的和/或生物相容的植入物,或可为不可生物降解的植入物。植入物对于活性剂可为可渗透的或不可渗透的。用于递送治疗剂的具体植入物取决于受影响的组织或器官以及所治疗的病状的性质。这类植入物的使用在所属领域中为众所周知的。
在本发明中描述的抑制剂可以纳米粒子或其它药物配制物配制以便提供向具体组织的递送并且还提供控制释放疗法。
在本申请中描述的抑制剂不仅可作为纯化的重组蛋白递送并且还通过基因治疗方法递送。重组腺相关载体(rAAV)或其它合适的载体可用于通过视网膜下或玻璃体内递送43,44来递送VEGF抑制剂。
在相关方面,本发明提供用于治疗受试者的VEGF相关或新生血管病症的方法,其中方法涉及向受试者施用:(a)有效量的能够结合肝素并且减少或预防不希望的新生血管发展的融合蛋白。融合蛋白可与其它抗VEGF剂组合,其包括但不限于:对VEGF特异性的抗体或抗体片段;对VEGF受体特异性的抗体;抑制、调节和/或调整酪氨酸激酶信号转导的化合物;VEGF多肽;在核酸水平下抑制VEGF表达的寡核苷酸,例如反义RNA;和具有血管生成抑制活性的各种有机化合物和其它药剂。
本发明提供由VEGFR1的D3(或其它Ig样结构域)介导的肝素结合28,虽然对于全身施用不利,但是可为玻璃体内(或其它局部)施用带来重要的优势。确实,结合胞外基质关键成分HGPSG的能力29促进玻璃体积聚以及视网膜渗透30。本发明提供具有与HSPG相互作用的能力不同的一系列的VEGFR-1Fc融合构建体。这使得能够选择具有在眼睛中不同持续时间/半衰期的VEGF抑制剂9,这在不同的临床病状下有用。
现在将在以下描述优选的技术和实验结果的实施例中更具体地描述和指出本发明的特征和其它细节。实例出于说明本发明的目的提供,并且不应被理解为限制。
实例
在实施例中,本发明因此公开抗VEGF剂,其为新颖的并且由于高的生物效力与强的肝素结合特性组合而对包括阿柏西普的现有抗VEGF剂进行了改善。肝素结合预测更长的半衰期并因此降低施用频率。
本发明提供由VEGFR1的D3(或其它Ig样结构域)介导的肝素结合28,虽然对于全身施用不利,但是可为玻璃体内(或其它局部)施用带来重要的优势。确实,结合胞外基质关键成分HGPSG的能力29可促进玻璃体积聚以及视网膜渗透30。本发明提供具有与HSPG相互作用的能力不同的一系列的VEGFR-1Fc融合构建体。
图1提供这里采用的构建体的示意图。图2说明采用的载体和克隆策略。图3-9示出产生的构建体的核酸和氨基酸序列。
实例示出大部分构建体的表达水平低;V1-2-3-4、V1-2-3-3、V2-3-4和V1-2-4在条件培养基中几乎完全不可检测。先前的研究已示出,具有肝素高亲和力的VEGF同工型(VEGF189或VEGF206)在经转染的细胞的条件培养基中不可检测,其紧密结合到细胞表面或胞外基质31 32。然而,它们可通过添加肝素或肝素酶以可溶形式释放,指示结合位点由HSPG组成31 32。此实例寻求确定添加肝素是否还可影响重组VEGFR-1融合蛋白的水平。确实,肝素添加到在6孔板中的经转染的细胞的培养基导致在培养基中重组蛋白的浓度的剂量依赖性增加(图10)。
在寻求纯化重组蛋白时,常规的蛋白A(PA)亲和色谱单独产生了预期质量的主谱带,但是具有许多次谱带,这很可能反映重组蛋白与宿主细胞衍生的HSPG和其它分子的相互作用。如方法中所描述,已开发去除这类杂质的方案。当蛋白结合到PA时,在1.2M NaCl存在下于高pH(例如9.2)下洗涤,导致释放许多污染物。下一步,用Hi-Trap Q进行阴离子交换色谱,在纯化的蛋白处于流通中时,对去除大量污染物和聚集体非常有效。最终纯化制剂中的LPS水平<0.1EU/mg(范围0.02-0.08),非常低的水平与临床前研究相容33。如图11所示,重组蛋白的纯度为>>95%,如通过银染色的SDS/PAGE凝胶评估,并且与FDA批准的药物EYLEA相似。
检验重组蛋白其在牛脉络膜内皮细胞中抑制通过VEGF(10ng/ml)刺激的有丝分裂的能力。重组蛋白具有抑制作用,其中除了效力较低的V1-2-4和V2-4以外,IC50值在~1nM的范围内(图12)。有趣的是,即使在最高浓度下检验,EYLEA抑制不多于~80%的VEGF刺激的增殖(图12)。相比之下,本发明VEGFR-1构建体(除了V1-2-4和V2-4以外)完全阻断VEGF诱发的增殖(图12)。结合测定证明可溶性VEGF受体和生物素化VEGF之间的相互作用以及VEGF置换结合的能力(图13、14)。
为了进一步定义治疗相关的相互作用,我们寻求评估重组蛋白是否在体外结合牛玻璃体。如图14所示,虽然EYLEA或对照IgG几乎没有结合或没有结合,但是本发明的蛋白示出显著的结合。最强的结合剂为V1-2-3-3、V2-3-3和V1-2-3-4随后为V1-2-3。V2-3具有在EYLEA(或对照IgG)和V1-2-3-3之间的中间结合特性。通常用于治疗眼内新血管生成的单克隆抗体9安维汀(AVASTIN)也几乎没有或没有结合。
为了确定玻璃体结合VEGFR-1FC融合蛋白是否可具有生物活性,板涂有牛玻璃体。添加V1-2-3-3但是不增加EYLEA或对照IgG抑制外源添加的VEGF刺激内皮细胞增殖的能力(图15)。
重组蛋白在小鼠CNV测定中进行检验,并与对照IgG或EYLEA进行比较。激光治疗前一天,将每种蛋白以2.5μg的剂量玻璃体内注射入。EYLEA也在25μg进行检验。在2.5μg的剂量下的V1-2-3、V2-3、V1-2-3-3和V2-3-3展示与用25μg EYLEA实现的类似或更高的抑制程度。然而,在检验的情况下,没有含有D4的构建体展示显著的抑制(图16)。
为了确定肝素结合是否可在单次施用后转化为持久的治疗效果,在激光诱发的损伤前1天、7天或14天玻璃体内注射(2.5μg)V1-2-3-3EYLEA或对照IgG。如图17所示,仅当在损伤前1第天施用时,EYLEA导致显著抑制。然而,当在损伤前7天或14天施用时,V1-2-3-3也导致显著抑制。
公开在各种体外和体内测定中评估的若干新颖VEGFR-1-Fc构建体。为了纯化重组蛋白,使用多步骤方案。这在很大程度上是由瞬时表达的293细胞中相对低的表达水平决定的,需要向培养基添加肝素以改善释放。然而,使用肝素的需求可通过不同的宿主细胞(例如,具有不同的HSPG组成或其突变)或通过更高的表达水平(如在扩增的稳定细胞系中)部分或全部避免。
除了V2-4以外的所有构建体强有力地中和VEGF的活性,并且同时具有强肝素结合特性,这可预测在玻璃体内施用后的半衰期长。实例证明这些蛋白结合到牛玻璃体。最强的结合剂为V1-2-3-3、V2-3-3、V1-2-3-4随后为V1-2-3。V2-3具有显著但是较低的玻璃体结合。相反,对照IgG、EYLEA或AVASTIN具有最小结合。选择最强玻璃体结合剂中的一个V1-2-3-3检验玻璃体基质结合VEGFR1 Fc构建体可具有生物活性的假定。如图15所示,在涂有牛玻璃体板中,添加V1-2-3-3,但是不增加EYLEA或对照IgG,抑制外源添加的VEGF刺激内皮细胞增殖的能力。
接下来,在小鼠CNV模型中检验重组蛋白其抑制激光诱发的新血管生成的能力。EYLEA用作阳性对照,并且人IgG1用作阴性对照。选择相对低剂量用于体内检验,最适合于揭示各种构建体之间的效力差异。另外,已报道,当玻璃体内注射时,玻璃体内施用相对高剂量的IgG1同型的抗体可具有由FcgRI(CD64)和c-Cbl介导的脱靶抑制作用34。使用的剂量应避免这类脱靶作用,并且检测真正的特异性作用。
如图16所示,在2.5μg的剂量下,EYLEA导致大约30%抑制,并且在25μg下导致~50%抑制。这些发现与已公布的文献基本一致。Saishin等人报道玻璃体内注射~5μg阿柏西普导致小鼠的CNV区域~30%抑制35。确实,40μg的剂量通常用于在小鼠CNV模型中实现最大作用36。我们的研究出乎意料发现我们的构建体:V1-2-3、V2-3、V1-2-3-3和V2-3-3中的一些的效力更高。在损伤之前一天施用2.5μg的这些构建体匹配或甚至超过用25μg的EYLEA实现的抑制水平。发现当在损伤之前7天或14天施用时(图17),V1-2-3-3但不是EYLEA对预防CNV具有显著作用,证明作用的持久性和治疗价值。
出乎意料的发现是,含有D4(V1-2-3-4、V2-3-4、V1-2-4、V2-4)的构建体均不导致明显的体内抑制(至少在检验的剂量下),尽管事实上这些分子(除V2-4外)展示在体外阻断VEGF刺激的有丝分裂的能力。然而,所有这些构建体展示形成多聚体或聚集体的倾向,如通过在非还原条件下(图11)的SDS/PAGE凝胶或尺寸排阻色谱法(未示出)评估。尽管较早的工作37将D4(与D7一起)鉴定为VEGFR-1二聚化的要求,但是已经知道这类作用为配体依赖性的。晶体结构研究显示,在D4中的一个环负责这类同型相互作用23。可想象,高浓度和/或通过Fc构建体施加的强制二聚化可导致配体非依赖性相互作用,导致聚集。在任何情况下,鉴于炎症和免疫原性的可能性,聚集体不为理想的药品38,39。因此,本发明的方面为在实施例中鉴定具有VEGFR-1D2/D3但不是D4的构建体。
值得注意的是,降低效应子功能的所属领域的技术人员众所周知的充分表征的Fc突变可为本发明的有用的补充,以便最小化抗体依赖性细胞毒性(ADCC)以及与C1q的相互作用和引发补体级联40。
总之,阿柏西普被设计成消除肝素结合肝素结构域,以便改善肿瘤适应症的全身半衰期。相反,本研究中描述的构建体被设计为促进在玻璃体中的结合和保留,以确保更持续和治疗相关的相互作用。
方法
对于VEGFR-1ECD-Fc表达质粒的构建,编码信号肽和VEGRF-1的各种胞外Ig样结构域一到四20(基因ID:2321)的核酸片段由金斯瑞美国公司(GenScript USA Inc)合成。各种胞外Ig样结构域构建体如下:V123含有D1、2和3;V23含有D1和D2、V1234含有D1、2、3和4;V1233含有D1、2、3和3;V234含有D2、3和4;V124含有D1、2和4;V24含有D2和4;F7为ECD2、2和3,并且F8为ECD2和3。将合成的片段插入到pFUSE-hIgG1-Fc载体(InvivoGen,#pfuse-hgifc1)中的EcoRI和BgIII位点处,生成含有各种Flt1 ECD的质粒。然后,使用PrineSTAR诱变基础试剂盒(Takara,R046A),去除在ECD和Fc片段之间的间隔氨基酸R和S(BgIII位点),生成表达具有227个氨基酸的人IgG1-Fc的Flt1 ECD的融合蛋白的质粒(F1-F8)。
转染和条件培养基制备
根据制造商的说明,使用Expi293表达系统(生命技术(Life technologies),A14524)生成用于纯化的条件培养基。简单来说Expi293FTM细胞(赛默飞世尔(ThermoFisher))在具有8%CO2的潮湿气氛中在37℃下Expi293TM表达培养基中悬浮培养。当细胞密度达到250万/ml时,将质粒DNA和ExpiFectamineTM 293试剂混合,孵育5min,并且然后添加到细胞。DNA和转染试剂的终浓度分别为1μg和2.7μl每毫升。在转染五小时后,将100μg/ml肝素(西格玛(Sigma),H3149)和蛋白酶抑制剂混合液1:400(西格玛,P1860)添加到细胞。在转染后16小时,添加增强剂1和2。在转染后九十六小时,收获条件培养基。根据制造商的说明书,使用人Fc ELISA Kit(Syd Labs,EK000095-HUFC-2)测试等分试样的Fc融合蛋白浓度。将蛋白酶抑制剂(1:500)添加到大量溶液中,并在-80℃下存储直至进一步使用。
重组蛋白的纯化
采用无热原试剂。使用前,将色谱柱和设备(Akta Explorer System)暴露于0.5NNaOH大约45分钟进行消毒。将经转染的细胞的条件培养基调节到PBS,0.01%聚山梨酯(PS)20。PS20在所有步骤添加缓冲剂。在20,000xg离心30分钟后,使用Hi-Trap MabSelect SuRe((5ml,通用电气医疗集团(GE Healthcare))将上清液进行蛋白A(PA)亲和色谱法。上样后,用20mM二乙醇胺(pH 9.2)、1.2M NaCl洗涤色谱柱,然后用0.1M柠檬酸(pH 3.0)洗脱,其立即被中和。然后将PA洗脱合并物在20mM二乙醇胺(pH 9.2)中稀释,并且应用到Hi-Trap Q(5ml,通用电气医疗集团)阴离子交换色谱柱。结合材料用NaCl梯度洗脱。立即将含有纯化的重组蛋白的流通液调节到20mM Tris,pH 6.8,并且然后通过结合到肝素-琼脂糖(Hi-TrapTM-HS)浓缩。在用0.2-0.45M NaCl(取决于构建体)洗涤之后,用1M NaCl洗脱重组VEGFR1融合蛋白。最终精制步骤由使用例如通用电气医疗集团的Superdex 200Increase、10/300GL或Hi-Load 16/600Superdex 200pg组成尺寸排阻色谱(SEC)。最后,通过透析将蛋白缓冲液交换为10mM Tris,pH 6.8、10mM组氨酸、1%海藻糖、40mM的NaCl、0.01%PS20。为了确定内毒素水平,根据制造商的方案使用了ToxinSensor显色LAL内毒素测定试剂盒(金斯瑞,L00350)。
细胞增殖测定
基本上如先前所述进行牛内皮细胞增殖测定41。胰蛋白酶化对数期生长的牛脉络膜内皮细胞(BCEC)(代<10),重新悬浮并以200μl体积每孔1000个细胞的密度接种在补充有10%牛犊血清、2mM谷氨酰胺和抗生素的低葡萄糖DMEM中的96孔板中(无涂覆)。以10ng/ml的浓度添加rhVEGF165(派普泰克)。阿柏西普(EYLEA)购自药店。在如图所示的各种浓度下抑制剂添加到细胞,然后添加配体。在5或6天后,将细胞与Alamar Blue一起孵育4小时。在530nm激发波长和590nm发射波长下测量荧光。
固相VEGFR-1变体结合测定
将Costar 96孔EIA/RIA带孔(#2592,缅因州肯纳邦克的康宁有线公司(CorningIncorporated,Kennebunk,ME))在涂覆缓冲液(加利福尼亚州圣地亚哥的Biolegend(Biolegend,San Diego,CA),#421701)中于4℃用纯化的VEGF受体蛋白(250ng/孔)涂覆过夜。在用ELISA洗涤缓冲液(安迪生物公司(R&D systems)895003)进行单次洗涤后,在室温(RT)下,将试纸条与2%BSA(西格玛,A6003)在PBS中孵育1小时,从而阻断非特异性结合位点。然后将条洗涤3次,随后在37℃下在测定稀释剂(Biolegend,#421203)中单独或与各种浓度的非生物素化人VEGF165(安迪生物公司)组合添加生物素化人VEGF165(加利福尼亚州圣克拉拉的G&P Biosciences(G&P Biosciences,Santa Clara,CA))2小时。在洗涤三次后,通过与HRP抗生蛋白链菌素(1:1000,Biolegend,#405210)在室温下孵育1小时,检测到生物素化人VEGF165结合到VEGFR1。将条洗涤5次,然后与TMB高灵敏度底物溶液(Biolegend,#421501)一起孵育30分钟,并且在添加等量的终止溶液(Biolegend,#77316)后测量在450nm处的吸光度。一式两份地进行孔的所有实验并且重复至少两次。
体外结合牛玻璃体
牛玻璃体(华盛顿州西雅图的InVision BioResource)在4℃下融化。首先将材料用PBS 1:1稀释,通过0.22μm过滤器过滤,等分并且存储在-80℃下。牛玻璃体材料的总蛋白浓度通过Pierce BCA蛋白测定来测量。在室温下将Costar 96孔EIA RIA带孔涂覆牛玻璃体(1μg/孔)4小时,随后用ELISA洗涤缓冲液洗涤一次。通过在室温下在PBS中添加2%BSA1小时阻断非特异性结合位点,随后用0.01%PBS-T洗涤三次。向每个孔中,于4℃过夜添加50ulVEGFR1或对照蛋白。第二天,将板用0.01%PBS-T洗涤三次,随后与100ul AP-缀合的山羊抗人Fc(1:2000,英杰(Invitrogen),#A18832)一起在室温下孵育1小时。将板用0.01%PBS-T再洗涤五次,然后在室温下添加50ul 1步骤PNPP底物(伊利诺斯州罗克福德的赛默科技(Thermo Scientific,Rockford,IL),#37621)维持15-30min。OD在405nm处测量。
玻璃体结合的VEGFR1对Costar 96孔EIA/RIA带孔中VEGF刺激的内皮细胞增殖的影响首先进行UV灭菌1小时,随后涂覆1μg/孔牛玻璃体,在室温下于PBS中稀释4小时。将板用PBS洗涤一次,在4℃下用2%BSA,并且在生物安全罩中用PBS洗涤两次。将等量的可溶受体或对照IgG添加到板,在4℃下于PBS中稀释(50μl/孔)。然后将板用PBS洗涤一次,随后用含有10%BCS的测定培养基洗涤一次。将100μl培养基添加到每个孔,随后以5ng/ml添加VEGF或仅PBS作为无VEGF对照。将板与VEGF或PBS一起孵育1小时,随后添加100μl BCEC细胞悬浮液(最终2500个细胞/孔)。48小时后,通过添加Alamar Blue测量增殖。
激光诱发的脉络膜新生血管(CNV)
在激光治疗之前,用氯胺酮/甲苯噻嗪混合液麻醉雄性C57BL/6J小鼠(6-8周)。CNV病变是通过使用二极管激光器(IRIDEX,Oculight GL)和裂隙灯(Zeiss)进行激光光凝诱发,其中斑点尺寸为50um,功率为180mW,暴露持续时间为100ms。36,42。通常在每只眼睛的视神经盘周围的3点、6点、9点和12点位置诱发四次激光烧伤。以1μl体积,在每只眼睛2.5μg的剂量下,玻璃体内注射不同的构建体或IgG同型对照。EYLEA用作2.5或25μg的阳性对照。在注射后一天,进行激光治疗,并且在激光治疗后7天将眼睛摘除并固定在4%多聚甲醛(PFA)中15分钟。在另一组研究中,在激光治疗前1天、7天或14天注射一次选择的构建体。分离脉络膜-巩膜络合物和视网膜,并且进行抗CD31免疫荧光(IF),以通过对视网膜和脉络膜组织进行全胚胎染色来证明脉管系统。对于CD31 IF,将大鼠抗小鼠抗体BD 550274稀释1:100,并且在4℃下孵育过夜。在与继发性抗大鼠抗体(生命技术A11006)一起孵育4小时后,将全胚胎在488nm处成像。通过Image J对病灶区域的新血管生成和视网膜中的血管密度进行定量。通过学生t检验评估P值(显著变化,p<0.05)。
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<120> 用于使用抗VEGF剂治疗血管生成病症的方法和组合物
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atgcagaaca aagacaaagg actttatact tgtcgtgtaa ggagtggacc atcattcaaa 960
tctgttaaca cctcagtgca tatatatgat aaagacaaaa ctcacacatg cccaccgtgc 1020
ccagcacctg aactcctggg gggaccgtca gtcttcctct tccccccaaa acccaaggac 1080
accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 1140
gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1200
aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1260
caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa agccctccca 1320
gcccccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1380
accctgcccc catcccggga ggagatgacc aagaaccagg tcagcctgac ctgcctggtc 1440
aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1500
aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctacagcaag 1560
ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcac 1620
gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaa 1674
<210> 3
<211> 459
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 3
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ile Phe Ile Ser Asp Thr
20 25 30
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
35 40 45
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
50 55 60
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
65 70 75 80
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
85 90 95
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
100 105 110
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
115 120 125
Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val Lys Leu Leu
130 135 140
Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr Pro Leu Asn
145 150 155 160
Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys Asn Lys Arg
165 170 175
Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His Ala Asn Ile
180 185 190
Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys Asp Lys Gly
195 200 205
Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys Ser Val Asn
210 215 220
Thr Ser Val His Ile Tyr Asp Lys Asp Lys Thr His Thr Cys Pro Pro
225 230 235 240
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
355 360 365
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 4
<211> 1377
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成多核苷酸
<400> 4
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggtat atttattagt gatacaggta gacctttcgt agagatgtac 120
agtgaaatcc ccgaaattat acacatgact gaaggaaggg agctcgtcat tccctgccgg 180
gttacgtcac ctaacatcac tgttacttta aaaaagtttc cacttgacac tttgatccct 240
gatggaaaac gcataatctg ggacagtaga aagggcttca tcatatcaaa tgcaacgtac 300
aaagaaatag ggcttctgac ctgtgaagca acagtcaatg ggcatttgta taagacaaac 360
tatctcacac atcgacaaac caatacaatc atagatgtcc aaataagcac accacgccca 420
gtcaaattac ttagaggcca tactcttgtc ctcaattgta ctgctaccac tcccttgaac 480
acgagagttc aaatgacctg gagttaccct gatgaaaaaa ataagagagc ttccgtaagg 540
cgacgaattg accaaagcaa ttcccatgcc aacatattct acagtgttct tactattgac 600
aaaatgcaga acaaagacaa aggactttat acttgtcgtg taaggagtgg accatcattc 660
aaatctgtta acacctcagt gcatatatat gataaagaca aaactcacac atgcccaccg 720
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 780
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 840
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 900
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 960
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1020
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1080
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1140
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1200
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1260
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1320
cacgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1377
<210> 5
<211> 659
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 5
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro
20 25 30
Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln Thr
35 40 45
Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp Ser Leu Pro
50 55 60
Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Ala
65 70 75 80
Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu Thr Leu Asn Thr
85 90 95
Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val
100 105 110
Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile
115 120 125
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
130 135 140
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
145 150 155 160
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
165 170 175
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
180 185 190
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
195 200 205
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
210 215 220
Gln Thr Asn Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val
225 230 235 240
Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr
245 250 255
Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys
260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His
275 280 285
Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys
290 295 300
Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
305 310 315 320
Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Val Gln Ile Ser
325 330 335
Thr Pro Arg Pro Val Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn
340 345 350
Cys Thr Ala Thr Thr Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser
355 360 365
Tyr Pro Asp Glu Lys Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp
370 375 380
Gln Ser Asn Ser His Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp
385 390 395 400
Lys Met Gln Asn Lys Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser
405 410 415
Gly Pro Ser Phe Lys Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys
420 425 430
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
435 440 445
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
450 455 460
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
465 470 475 480
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
485 490 495
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
500 505 510
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
515 520 525
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
530 535 540
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
545 550 555 560
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
565 570 575
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
580 585 590
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
595 600 605
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
610 615 620
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
625 630 635 640
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
645 650 655
Pro Gly Lys
<210> 6
<211> 1977
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成多核苷酸
<400> 6
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggttc aaaattaaaa gatcctgaac tgagtttaaa aggcacccag 120
cacatcatgc aagcaggcca gacactgcat ctccaatgca ggggggaagc agcccataaa 180
tggtctttgc ctgaaatggt gagtaaggaa agcgaaaggc tgagcataac taaatctgcc 240
tgtggaagaa atggcaaaca attctgcagt actttaacct tgaacacagc tcaagcaaac 300
cacactggct tctacagctg caaatatcta gctgtaccta cttcaaagaa gaaggaaaca 360
gaatctgcaa tctatatatt tattagtgat acaggtagac ctttcgtaga gatgtacagt 420
gaaatccccg aaattataca catgactgaa ggaagggagc tcgtcattcc ctgccgggtt 480
acgtcaccta acatcactgt tactttaaaa aagtttccac ttgacacttt gatccctgat 540
ggaaaacgca taatctggga cagtagaaag ggcttcatca tatcaaatgc aacgtacaaa 600
gaaatagggc ttctgacctg tgaagcaaca gtcaatgggc atttgtataa gacaaactat 660
ctcacacatc gacaaaccaa tacaatcata gatgtccaaa taagcacacc acgcccagtc 720
aaattactta gaggccatac tcttgtcctc aattgtactg ctaccactcc cttgaacacg 780
agagttcaaa tgacctggag ttaccctgat gaaaaaaata agagagcttc cgtaaggcga 840
cgaattgacc aaagcaattc ccatgccaac atattctaca gtgttcttac tattgacaaa 900
atgcagaaca aagacaaagg actttatact tgtcgtgtaa ggagtggacc atcattcaaa 960
tctgttaaca cctcagtgca tatatatgat aaagcagtcc aaataagcac accacgccca 1020
gtcaaattac ttagaggcca tactcttgtc ctcaattgta ctgctaccac tcccttgaac 1080
acgagagttc aaatgacctg gagttaccct gatgaaaaaa ataagagagc ttccgtaagg 1140
cgacgaattg accaaagcaa ttcccatgcc aacatattct acagtgttct tactattgac 1200
aaaatgcaga acaaagacaa aggactttat acttgtcgtg taaggagtgg accatcattc 1260
aaatctgtta acacctcagt gcatatatat gataaagaca aaactcacac atgcccaccg 1320
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 1380
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 1440
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 1500
acaaagccgc gggaggagca gtacaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1560
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1620
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1680
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1740
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1800
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1860
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1920
cacgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1977
<210> 7
<211> 560
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 7
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ile Phe Ile Ser Asp Thr
20 25 30
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
35 40 45
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
50 55 60
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
65 70 75 80
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
85 90 95
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
100 105 110
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
115 120 125
Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val Lys Leu Leu
130 135 140
Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr Pro Leu Asn
145 150 155 160
Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys Asn Lys Arg
165 170 175
Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His Ala Asn Ile
180 185 190
Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys Asp Lys Gly
195 200 205
Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys Ser Val Asn
210 215 220
Thr Ser Val His Ile Tyr Asp Lys Ala Val Gln Ile Ser Thr Pro Arg
225 230 235 240
Pro Val Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala
245 250 255
Thr Thr Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp
260 265 270
Glu Lys Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn
275 280 285
Ser His Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln
290 295 300
Asn Lys Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser
305 310 315 320
Phe Lys Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Asp Lys Thr
325 330 335
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
340 345 350
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
355 360 365
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
370 375 380
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
385 390 395 400
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
405 410 415
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
420 425 430
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
435 440 445
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
450 455 460
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
465 470 475 480
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
485 490 495
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
500 505 510
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
515 520 525
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
530 535 540
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
545 550 555 560
<210> 8
<211> 1680
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成多核苷酸
<400> 8
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggtat atttattagt gatacaggta gacctttcgt agagatgtac 120
agtgaaatcc ccgaaattat acacatgact gaaggaaggg agctcgtcat tccctgccgg 180
gttacgtcac ctaacatcac tgttacttta aaaaagtttc cacttgacac tttgatccct 240
gatggaaaac gcataatctg ggacagtaga aagggcttca tcatatcaaa tgcaacgtac 300
aaagaaatag ggcttctgac ctgtgaagca acagtcaatg ggcatttgta taagacaaac 360
tatctcacac atcgacaaac caatacaatc atagatgtcc aaataagcac accacgccca 420
gtcaaattac ttagaggcca tactcttgtc ctcaattgta ctgctaccac tcccttgaac 480
acgagagttc aaatgacctg gagttaccct gatgaaaaaa ataagagagc ttccgtaagg 540
cgacgaattg accaaagcaa ttcccatgcc aacatattct acagtgttct tactattgac 600
aaaatgcaga acaaagacaa aggactttat acttgtcgtg taaggagtgg accatcattc 660
aaatctgtta acacctcagt gcatatatat gataaagcag tccaaataag cacaccacgc 720
ccagtcaaat tacttagagg ccatactctt gtcctcaatt gtactgctac cactcccttg 780
aacacgagag ttcaaatgac ctggagttac cctgatgaaa aaaataagag agcttccgta 840
aggcgacgaa ttgaccaaag caattcccat gccaacatat tctacagtgt tcttactatt 900
gacaaaatgc agaacaaaga caaaggactt tatacttgtc gtgtaaggag tggaccatca 960
ttcaaatctg ttaacacctc agtgcatata tatgataaag acaaaactca cacatgccca 1020
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 1080
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 1140
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1200
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1260
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1320
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1380
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 1440
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1500
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1560
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1620
atgcacgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1680
<210> 9
<211> 655
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 9
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro
20 25 30
Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln Thr
35 40 45
Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp Ser Leu Pro
50 55 60
Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Ala
65 70 75 80
Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu Thr Leu Asn Thr
85 90 95
Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val
100 105 110
Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile
115 120 125
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
130 135 140
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
145 150 155 160
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
165 170 175
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
180 185 190
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
195 200 205
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
210 215 220
Gln Thr Asn Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val
225 230 235 240
Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr
245 250 255
Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys
260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His
275 280 285
Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys
290 295 300
Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
305 310 315 320
Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Phe Ile Thr Val
325 330 335
Lys His Arg Lys Gln Gln Val Leu Glu Thr Val Ala Gly Lys Arg Ser
340 345 350
Tyr Arg Leu Ser Met Lys Val Lys Ala Phe Pro Ser Pro Glu Val Val
355 360 365
Trp Leu Lys Asp Gly Leu Pro Ala Thr Glu Lys Ser Ala Arg Tyr Leu
370 375 380
Thr Arg Gly Tyr Ser Leu Ile Ile Lys Asp Val Thr Glu Glu Asp Ala
385 390 395 400
Gly Asn Tyr Thr Ile Leu Leu Ser Ile Lys Gln Ser Asn Val Phe Lys
405 410 415
Asn Leu Thr Ala Thr Leu Ile Val Asn Val Lys Pro Asp Lys Thr His
420 425 430
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
435 440 445
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
450 455 460
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
465 470 475 480
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
485 490 495
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
500 505 510
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
515 520 525
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
530 535 540
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
545 550 555 560
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
565 570 575
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
580 585 590
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
595 600 605
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
610 615 620
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
625 630 635 640
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
645 650 655
<210> 10
<211> 1965
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成多核苷酸
<400> 10
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggttc aaaattaaaa gatcctgaac tgagtttaaa aggcacccag 120
cacatcatgc aagcaggcca gacactgcat ctccaatgca ggggggaagc agcccataaa 180
tggtctttgc ctgaaatggt gagtaaggaa agcgaaaggc tgagcataac taaatctgcc 240
tgtggaagaa atggcaaaca attctgcagt actttaacct tgaacacagc tcaagcaaac 300
cacactggct tctacagctg caaatatcta gctgtaccta cttcaaagaa gaaggaaaca 360
gaatctgcaa tctatatatt tattagtgat acaggtagac ctttcgtaga gatgtacagt 420
gaaatccccg aaattataca catgactgaa ggaagggagc tcgtcattcc ctgccgggtt 480
acgtcaccta acatcactgt tactttaaaa aagtttccac ttgacacttt gatccctgat 540
ggaaaacgca taatctggga cagtagaaag ggcttcatca tatcaaatgc aacgtacaaa 600
gaaatagggc ttctgacctg tgaagcaaca gtcaatgggc atttgtataa gacaaactat 660
ctcacacatc gacaaaccaa tacaatcata gatgtccaaa taagcacacc acgcccagtc 720
aaattactta gaggccatac tcttgtcctc aattgtactg ctaccactcc cttgaacacg 780
agagttcaaa tgacctggag ttaccctgat gaaaaaaata agagagcttc cgtaaggcga 840
cgaattgacc aaagcaattc ccatgccaac atattctaca gtgttcttac tattgacaaa 900
atgcagaaca aagacaaagg actttatact tgtcgtgtaa ggagtggacc atcattcaaa 960
tctgttaaca cctcagtgca tatatatgat aaagcattca tcactgtgaa acatcgaaaa 1020
cagcaggtgc ttgaaaccgt agctggcaag cggtcttacc ggctctctat gaaagtgaag 1080
gcatttccct cgccggaagt tgtatggtta aaagatgggt tacctgcgac tgagaaatct 1140
gctcgctatt tgactcgtgg ctactcgtta attatcaagg acgtaactga agaggatgca 1200
gggaattata caatcttgct gagcataaaa cagtcaaatg tgtttaaaaa cctcactgcc 1260
actctaattg tcaatgtgaa acccgacaaa actcacacat gcccaccgtg cccagcacct 1320
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1380
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1440
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1500
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1560
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1620
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1680
ccatcccggg aggagatgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1740
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1800
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1860
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca cgaggctctg 1920
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1965
<210> 11
<211> 556
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 11
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ile Phe Ile Ser Asp Thr
20 25 30
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
35 40 45
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
50 55 60
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
65 70 75 80
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
85 90 95
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
100 105 110
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
115 120 125
Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val Lys Leu Leu
130 135 140
Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr Pro Leu Asn
145 150 155 160
Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys Asn Lys Arg
165 170 175
Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His Ala Asn Ile
180 185 190
Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys Asp Lys Gly
195 200 205
Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys Ser Val Asn
210 215 220
Thr Ser Val His Ile Tyr Asp Lys Ala Phe Ile Thr Val Lys His Arg
225 230 235 240
Lys Gln Gln Val Leu Glu Thr Val Ala Gly Lys Arg Ser Tyr Arg Leu
245 250 255
Ser Met Lys Val Lys Ala Phe Pro Ser Pro Glu Val Val Trp Leu Lys
260 265 270
Asp Gly Leu Pro Ala Thr Glu Lys Ser Ala Arg Tyr Leu Thr Arg Gly
275 280 285
Tyr Ser Leu Ile Ile Lys Asp Val Thr Glu Glu Asp Ala Gly Asn Tyr
290 295 300
Thr Ile Leu Leu Ser Ile Lys Gln Ser Asn Val Phe Lys Asn Leu Thr
305 310 315 320
Ala Thr Leu Ile Val Asn Val Lys Pro Asp Lys Thr His Thr Cys Pro
325 330 335
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
340 345 350
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
355 360 365
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
370 375 380
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
385 390 395 400
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
405 410 415
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
420 425 430
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
435 440 445
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
450 455 460
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
465 470 475 480
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
485 490 495
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
500 505 510
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
515 520 525
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
530 535 540
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
545 550 555
<210> 12
<211> 1668
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成多核苷酸
<400> 12
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggtat atttattagt gatacaggta gacctttcgt agagatgtac 120
agtgaaatcc ccgaaattat acacatgact gaaggaaggg agctcgtcat tccctgccgg 180
gttacgtcac ctaacatcac tgttacttta aaaaagtttc cacttgacac tttgatccct 240
gatggaaaac gcataatctg ggacagtaga aagggcttca tcatatcaaa tgcaacgtac 300
aaagaaatag ggcttctgac ctgtgaagca acagtcaatg ggcatttgta taagacaaac 360
tatctcacac atcgacaaac caatacaatc atagatgtcc aaataagcac accacgccca 420
gtcaaattac ttagaggcca tactcttgtc ctcaattgta ctgctaccac tcccttgaac 480
acgagagttc aaatgacctg gagttaccct gatgaaaaaa ataagagagc ttccgtaagg 540
cgacgaattg accaaagcaa ttcccatgcc aacatattct acagtgttct tactattgac 600
aaaatgcaga acaaagacaa aggactttat acttgtcgtg taaggagtgg accatcattc 660
aaatctgtta acacctcagt gcatatatat gataaagcat tcatcactgt gaaacatcga 720
aaacagcagg tgcttgaaac cgtagctggc aagcggtctt accggctctc tatgaaagtg 780
aaggcatttc cctcgccgga agttgtatgg ttaaaagatg ggttacctgc gactgagaaa 840
tctgctcgct atttgactcg tggctactcg ttaattatca aggacgtaac tgaagaggat 900
gcagggaatt atacaatctt gctgagcata aaacagtcaa atgtgtttaa aaacctcact 960
gccactctaa ttgtcaatgt gaaacccgac aaaactcaca catgcccacc gtgcccagca 1020
cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1080
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1140
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1200
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1260
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1320
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1380
cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1440
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1500
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1560
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcacgaggct 1620
ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1668
<210> 13
<211> 456
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 13
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ile Phe Ile Ser Asp Thr
20 25 30
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
35 40 45
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
50 55 60
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
65 70 75 80
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
85 90 95
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
100 105 110
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
115 120 125
Thr Ile Ile Asp Val Phe Ile Thr Val Lys His Arg Lys Gln Gln Val
130 135 140
Leu Glu Thr Val Ala Gly Lys Arg Ser Tyr Arg Leu Ser Met Lys Val
145 150 155 160
Lys Ala Phe Pro Ser Pro Glu Val Val Trp Leu Lys Asp Gly Leu Pro
165 170 175
Ala Thr Glu Lys Ser Ala Arg Tyr Leu Thr Arg Gly Tyr Ser Leu Ile
180 185 190
Ile Lys Asp Val Thr Glu Glu Asp Ala Gly Asn Tyr Thr Ile Leu Leu
195 200 205
Ser Ile Lys Gln Ser Asn Val Phe Lys Asn Leu Thr Ala Thr Leu Ile
210 215 220
Val Asn Val Lys Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 14
<211> 1368
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成多核苷酸
<400> 14
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggtat atttattagt gatacaggta gacctttcgt agagatgtac 120
agtgaaatcc ccgaaattat acacatgact gaaggaaggg agctcgtcat tccctgccgg 180
gttacgtcac ctaacatcac tgttacttta aaaaagtttc cacttgacac tttgatccct 240
gatggaaaac gcataatctg ggacagtaga aagggcttca tcatatcaaa tgcaacgtac 300
aaagaaatag ggcttctgac ctgtgaagca acagtcaatg ggcatttgta taagacaaac 360
tatctcacac atcgacaaac caatacaatc atagatgtct tcatcactgt gaaacatcga 420
aaacagcagg tgcttgaaac cgtagctggc aagcggtctt accggctctc tatgaaagtg 480
aaggcatttc cctcgccgga agttgtatgg ttaaaagatg ggttacctgc gactgagaaa 540
tctgctcgct atttgactcg tggctactcg ttaattatca aggacgtaac tgaagaggat 600
gcagggaatt atacaatctt gctgagcata aaacagtcaa atgtgtttaa aaacctcact 660
gccactctaa ttgtcaatgt gaaacccgac aaaactcaca catgcccacc gtgcccagca 720
cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 780
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 840
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 960
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1020
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1080
cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 1140
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1200
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1260
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcacgaggct 1320
ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1368
Claims (11)
1.一种抗VEGF剂,其包含可操作地连接到Fc-IgG的VEGF结合部分,其中所述抗VEGF剂为SEQ ID NO: 3的氨基酸27至459。
2.根据权利要求1所述的抗VEGF剂,其中所述抗VEGF剂具有比阿柏西普大的玻璃体结合能力。
3.根据权利要求2所述的抗VEGF剂,其中所述抗VEGF剂的抑制玻璃体结合VEGF刺激的内皮细胞增殖的能力比阿柏西普更大。
4.根据权利要求3所述的抗VEGF剂,其中与阿柏西普相比,所述抗VEGF剂在玻璃体内给药后具有增加的持续时间。
5.一种药物组合物,其包含治疗有效量的根据前述权利要求中任一项所述的抗VEGF剂和药学上可接受的赋形剂。
6.根据权利要求1到4中任一项所述的抗VEGF剂在制备用于治疗有需要的受试者眼睛的VEGF相关病症的药物中的用途,其中在使用时,治疗有效量的所述抗VEGF剂被施用给所述受试者。
7.根据权利要求6所述的用途,其中所述抗VEGF剂被直接注射到眼睛中。
8.根据权利要求6所述的用途,其中所述眼睛的VEGF相关病症选自以下的组:新生血管年龄相关性黄斑变性、继发于近视的脉络膜新生血管生成、增生性糖尿病性视网膜病变、糖尿病黄斑水肿、视网膜血管阻塞、眼部肿瘤、希佩尔林道综合症、早产儿视网膜病和息肉样脉络膜血管病变。
9.根据权利要求5所述的药物组合物在制备用于治疗有需要的受试者眼睛的VEGF相关病症的药物中的用途,其中在使用时,治疗有效量的所述药物组合物被施用给所述受试者。
10.根据权利要求9所述的用途,其中所述抗VEGF剂被直接注射到眼睛中。
11.根据权利要求9所述的用途,其中所述VEGF相关病症选自以下的组:新生血管年龄相关性黄斑变性、继发于近视的脉络膜新生血管生成、增生性糖尿病性视网膜病变、糖尿病黄斑水肿、视网膜血管阻塞、眼部肿瘤、息肉样脉络膜血管病变、希佩尔林道综合症、和早产儿视网膜病。
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AU2016381964B2 (en) | 2015-12-30 | 2024-02-15 | Kodiak Sciences Inc. | Antibodies and conjugates thereof |
KR20200112893A (ko) | 2018-01-26 | 2020-10-05 | 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 | 항-vegf 제제를 사용한 혈관신생 장애의 치료 방법 및 조성물 |
MX2020011848A (es) | 2018-05-10 | 2021-03-29 | Regeneron Pharma | Formulaciones que contienen proteína de fusión del receptor de vegf a alta concentración. |
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SG11202007130RA (en) | 2020-08-28 |
IL276158B1 (en) | 2024-03-01 |
CN111741761A (zh) | 2020-10-02 |
JP2021511061A (ja) | 2021-05-06 |
WO2019147944A8 (en) | 2020-08-20 |
EP3743091A4 (en) | 2021-12-15 |
MX2021001424A (es) | 2021-06-23 |
IL276158A (en) | 2020-09-30 |
CN116059318A (zh) | 2023-05-05 |
US11524053B2 (en) | 2022-12-13 |
CA3089481A1 (en) | 2019-08-01 |
BR112020015074A2 (pt) | 2020-12-08 |
US20200353041A1 (en) | 2020-11-12 |
EA202091786A1 (ru) | 2020-10-20 |
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CO2020010384A2 (es) | 2020-12-10 |
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