CN116675777A - 包含补体抑制结构域的多特异性配体结合分子及其用途 - Google Patents
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Abstract
本发明涉及一种包含补体抑制结构域和生长因子结合结构域的配体结合分子,包含这类配体结合分子的药物组合物,以及产生该配体结合分子的方法和用途。
Description
技术领域
本发明涉及蛋白质领域,具体地,本发明涉及一种能与多种生长因子结合的配体结合分子,以及此类配体结合分子的药物组合物,编码这类分子的核酸序列,以及其产生方法和用途。
背景技术
年龄相关湿性黄斑病变(wAMD)与糖尿病黄斑水肿(DME)病患广,病程进展快,发病后果严重(视力丧失),是导致失明的最大诱因。地图样萎缩(GA)是wAMD的最终发展形式之一。目前wAMD、DME的主要治疗方式是靶向VEGF-A,其比传统治疗手段(激光光凝等)具有明显进步的疗效,相应的靶向药(如雷珠单抗、阿柏西普等)也取得了巨大的市场成功。但单一靶向VEGF-A仍无法彻底攻克这些疾病,例如在AMD治疗后,仅三分之一的病人能够受益,其余病人的视力无明显增加,三分之一的病人仍发展为地图样萎缩,视力接近失明(RofaghaS.等人,Seven-Year Outcomes in Ranibizumab-Treated Patients in ANCHOR,MARINA,and HORIZON:A multicenter cohort study(SEVEN UP).J.Ophthalmology.2013,120(11):2292-2299)。
此外,在治疗随访研究中发现,持续的靶向VEGF-A治疗还会增加地图样萎缩的发病风险,是地图样萎缩的一个风险因素(Grunwald J.E.等人,Risk of GeographicAtrophy in the Comparison of Age-related Macular Degeneration TreatmentsTrials.J.Ophthalmology.2014,121(1):150-161)(Mitchell P.等人,Ranibizumab(Lucentis)in neovascular age-related macular degeneration:evidence fromclinical trial.Br.J.Ophthalmol.2010,94:2-13)。
在另一方面,补体系统的激活及膜攻击复合物(MAC)的产生被认为是AMD与DME的发病起始病因,早期研究发现在患者血液中可检测到补体激活的产物,若干补体相关的基因突变也被列为发病的风险因素。
补体系统的激活为一种级联反应,受到多种调节分子的控制,其活化的程度和单一成分的活性都是在生物反馈机制下进行的,从而限制了活化的扩大化,以维持补体水平的平衡。调节作用包括两个方面,即自身失活及一些抑制物的灭活作用。前者指已活化的补体分子结构不稳定,如不及时与靶细胞膜结合会衰变失活,抑制物的作用是指某些分子可与补体活性成分结合,使其失活或阻断其与其他成分的结合,进而抑制膜攻击复合物的组装。其中CD59(又称为保护素)是补体抑制物的一种。
本发明提供了一种重组的配体结合分子,其同时包含生长因子结合结构域和补体抑制结构域,从而既能够结合包括VEGF-A、VEGF-B和PlGF家族分子在内的一种或多种生长因子,又能够阻止在细胞表面形成膜攻击复合物(MAC)的产生,对于治疗新生血管相关的疾病有重要的临床意义。
发明内容
广义而言,本公开涉及提供多特异性的配体结合分子(例如融合蛋白分子)的化合物、方法、组合物和制品。这种配体结合分子能在膜表面中和阻断血管内皮生长因子等多种生长因子与受体的结合,从而在病灶微环境发挥协同作用,既有利于控制血管新生、渗漏等病状,又可以在病因上干预过度活化的补体系统,从而克服了单一靶向生长因子治疗的局限性及不良反应。本公开提供的益处广泛地适用于治疗和诊断领域,并且可以与能够与其他各种药物联合使用。
在一些方面,本公开提供一种配体结合分子,其包含至少一个生长因子结合结构域和至少一个补体抑制结构域,其中所述生长因子结合结构域能够识别、结合、靶向和/或拮抗包括VEGF-A、VEGF-B、和PlGF在内的一种或多种生长因子(优选为人的生长因子)。在一些实施方案中,所述补体抑制结构域包含来源于CD59蛋白(优选为人CD59蛋白)的氨基酸序列。
在一些实施方案中,所述生长因子结合结构域包含来源于选自VEGFR1、VEGFR2和VEGFR3蛋白的任意一种或多种的氨基酸序列。
在一些具体的实施方案中,所述生长因子结合结构域包含与选自以下的任一种氨基酸序列具有至少90%同一性(例如至少95%同一性,例如100%同一性即相同)的氨基酸序列:
(a)SEQ ID NO:1的位置132-230限定的氨基酸序列;
(b)SEQ ID NO:2的位置117-218、117-327、123-327、117-421、23-327、225-327、23-421限定的氨基酸序列;
(c)SEQ ID NO:3的位置47-210限定的氨基酸序列;和
(d)上述至少两种氨基酸序列的任意组合(又称为嵌合氨基酸序列),其中氨基酸序列彼此之间可操作地连接,例如SEQ ID NO:1的位置132-230限定的氨基酸序列可操作地连接于SEQ ID NO:2的位置225-327限定的氨基酸序列。
在一些实施方案中,所述生长因子结合结构域包含与SEQ ID NO:1的位置132-230限定的氨基酸序列(即SEQ ID NO:9)具有至少90%同一性的氨基酸序列。例如,所述生长因子结合结构域包含与SEQ ID NO:1的位置132-230所示的氨基酸序列相比具有不超过10个氨基酸、不超过5个氨基酸、不超过4个氨基酸、不超过3个氨基酸、不超过2个氨基酸、不超过1个氨基酸的突变的氨基酸序列。所述突变可选自插入、取代和缺失。在一个实施方案中,所述生长因子结合结构域包含如SEQ ID NO:9所示的序列。
在一些实施方案中,所述生长因子结合结构域包含与SEQ ID NO:2的位置225-327所限定的氨基酸序列具有至少90%同一性的氨基酸序列可操作地连接于与SEQ ID NO:1的位置132-230所限定的氨基酸序列具有至少90%同一性的氨基酸序列。在一些具体的实施方案中,所述生长因子结合结构域包含如SEQ ID NO:10所示的序列。在一些其他实施方案中,所述生长因子结合结构域包含与SEQ ID NO:10所示的氨基酸序列具有至少80%同一性的氨基酸序列。
在一些实施方案中,所述补体抑制结构域包含与SEQ ID NO:4的位置26-102限定的氨基酸序列具有至少90%同一性的氨基酸序列。例如,所述生长因子结合结构域包含与SEQ ID NO:4的位置26-102所示的氨基酸序列相比具有不超过10个氨基酸、不超过5个氨基酸、不超过4个氨基酸、不超过3个氨基酸、不超过2个氨基酸、不超过1个氨基酸的突变的氨基酸序列。所述突变可选自插入、取代和缺失。
在一些实施方案中,所述补体抑制结构域包含与SEQ ID NO:11限定的氨基酸序列具有至少90%同一性的氨基酸序列。例如,所述生长因子结合结构域包含与SEQ ID NO:11所示的氨基酸序列相比具有不超过10个氨基酸、不超过5个氨基酸、不超过4个氨基酸、不超过3个氨基酸、不超过2个氨基酸、不超过1个氨基酸的突变的氨基酸序列。所述突变可选自插入、取代和缺失。
在一些实施方案中,所述配体结合分子包含一个或多个补体抑制结构域可操作地连接于一个或多个生长因子结合结构域的N末端。或者,所述配体结合分子包含一个或多个补体抑制结构域可操作地连接于一个或多个生长因子结合结构域的C末端。所述可操作地连接可以是直接连接或经由接头连接,例如肽接头包含(G4S)n肽接头,其中n=1-5。在一个具体的实施方案中,所述配体结合分子包含或组成为一个补体抑制结构域可操作地连接于一个生长因子结合结构域的N末端。
在一些实施方案中,所述配体结合分子包含或组成为SEQ ID NO:6或7或8所示的序列。
在一些实施方案中,所述配体结合分子还包含免疫球蛋白的Fc区,所述免疫球蛋白选自IgA、IgM、IgE、IgD和IgG,包括IgG1、IgG2、IgG3、IgG4。Fc区可以是人IgG1的Fc区或其变体。
在一些实施方案中,所述配体结合分子包含:
(a)补体抑制结构域可操作地连接于生长因子结合结构域的N末端,且生长因子结合结构域的C末端可操作地连接于Fc区;
(b)生长因子结合结构域可操作地连接于补体抑制结构域的N末端,且补体抑制结构域的C末端可操作地连接于Fc区;
(c)补体抑制结构域可操作地连接于Fc区的N末端,且Fc区的C末端可操作地连接于生长因子结合结构域;或
(d)生长因子结合结构域可操作地连接于Fc区的N末端,且Fc区的C末端可操作地连接于补体抑制结构域。
所述可操作地连接可以是直接连接或通过接头(例如肽接头可包含或组成为G4S系列或GPG肽)连接。
在一些实施方案中,包含Fc的配体结合分子为二聚体,根据Fc两条链是否不同(例如当包含把手-孔(knob into hole)结构时,Fc的两条链不同),其包含两条相同的链或不同的链。在一些实施方案中,所述配体结合分子包含如SEQ ID NO:12、13或14所示的氨基酸序列。
在一些实施方案中,所述配体结合分子能抑制或阻断VEGF-A、VEGF-B、PlGF中的至少一种与其相应受体的结合。
在一些具体的实施方案中,所述配体结合分子能以低于3.5nM、低于3nM、或低于2.5nM的EC50阻断VEGF-A与VEGFR2的结合,如通过ELISA测定的。
在一些实施方案中,所述配体结合分子还包含信号肽。
在一些实施方案中,所述配体结合分子还包含聚乙二醇部分,任选地,所述聚乙二醇部分附接于所述分子的氨基末端。
在一些方面,本发明还提供了一种融合蛋白,其包含上文公开的配体结合分子可操作地连接于异源性肽。
在一些另外的实施方案中,所述异源性肽选自以下:另外的配体结合分子,如常见的人源受体蛋白胞外结构域(ECD)或其截短及重组等形成的Trap;抗体可变区片段及其组合,如抗体Fab、单链抗体(scFv)、纳米抗体(nanobody)、人重链可变区单域抗体(VH)、活性多肽及蛋白适配体。
在一些实施方案中,所述异源性肽为靶向人VEGF-A、VEGF-B、VEGF-C、VEGF-D、PDGF-AA、PDGF-AB、PDGF-BB、PDGF-CC、PDGF-DD、Ang-2、TGF-β、FGF(成纤维细胞生长因子)、CTGF(结缔组织生长因子)、EGF(表皮生长因子)、S1P、Galectin、或Decorin的异源性肽。
在一些实施方案中,所述异源性肽可以为靶向人VEGF-A的抗体或其抗原结合片段(例如Fab),如贝伐单抗(Avastin)或雷珠单抗(Lucentis)。
在一些实施方案中,所述配体结合分子在C末端通过肽键直接连接于异源性肽的N末端,或在N末端通过肽键直接连接于异源性肽的C末端。在一些实施方案中,所述连接子为多肽或化学基团。
在一些方面,本发明还提供了一种缀合物,其包含如上文所述的配体结合分子缀合于至少一个选自以下的模块:修饰模块、毒素(例如化学治疗剂)、可检测标记(例如放射性同位素、镧系元素、发光标记、荧光标记或酶-底物标记)或纯化模块。
在一些方面,本发明还提供了一种分离的核酸分子,其包含编码所述配体结合分子或融合蛋白的多核苷酸序列。所述核酸分子可以进一步包含连接至所述多核苷酸序列的启动子序列。
在一些方面,本发明还提供了一种载体,其包含所述核酸分子。所述载体可以包括但不限于,慢病毒载体、腺相关病毒载体、腺病毒载体、脂质体载体及其任意组合。
在一些实施方案中,所述载体为复制缺陷型腺病毒载体,其中所述核酸分子可操作地连接至启动子并且两侧具有腺病毒多核苷酸序列。
在一些方面,本发明还提供了一种宿主细胞,其经过上文所述的多核苷酸或体转化或转染。所述宿主细胞优选为真核细胞,例如中国仓鼠卵巢(CHO)细胞或人细胞。
在一些方面,本发明还提供了一种制备如本文公开的配体结合分子的方法,其包括以下步骤:
在适宜的条件下培养所述的宿主细胞以表达所述配体结合分子;并
从宿主细胞分离所述配体结合分子。
在一些方面,本发明还提供了一种药物组合物,其包含如上文公开的所述配体结合分子或融合蛋白或编码所述配体结合分子的核酸分子,以及药学上可接受的佐剂或载剂,例如稀释剂或赋形剂。所述药物组合物可以被制成用于局部施用或玻璃体内注射或植入施用。所述组合物可以为固体、糊剂、软膏、凝胶、液体、气雾剂、喷雾剂、聚合物、薄膜、乳液或混悬液形式。
在一些方面,本发明还提供了一种抑制受试者中的补体过度活化以及由补体过度活化引起的疾病或病况的方法,所述方法包括以有效抑制所述受试者中的补体过度活化的量向所述受试者施用如本文公开的配体结合分子或药物组合物。所述受试者可以是人或除人以外的哺乳动物,例如小鼠、大鼠、兔、猴等。
在一些方面,本发明还提供了一种抑制受试者中的新生血管形成以及由新生血管形成引起的疾病或病况的方法,所述方法包括以有效抑制所述受试者中的新生血管形成的量向所述受试者施用如本文公开的配体结合分子或药物组合物。
在一些实施方案中,所述新生血管形成为视网膜新生血管形成和/或脉络膜新生血管形成。
在一些实施方案中,所述疾病或病况包括脉络膜血管病变及新生、视网膜新生血管形成、与眼底渗漏有关的眼部病症。所述疾病可以选自,包括但不限于,眼底地图样萎缩、老年黄斑变性、糖尿病性眼部病症(例如糖尿病性黄斑水肿)、息肉状脉络膜血管病变、眼底纤维化病变、视网膜静脉阻塞相关病变、早产儿视网膜病变和黄斑毛细血管扩张。
在一些实施方案中,所述药物组合物被局部施用于所述受试者的眼睛,或者通过玻璃体内注射施用、通过玻璃体内植入物施用、或通过局部施用来施用所述组合物。
在一些方面,本发明还提供了所述的配体结合分子或融合蛋白在制备用于治疗受试者中新生血管形成以及由新生血管形成引起的疾病或病况的药物中的用途。
在一些方面,本发明还提供了所述的配体结合分子或融合蛋白在制备用于治疗受试者中新生血管形成并同时抑制受试者中的补体过度活化的药物中的用途。
在一些方面,本发明提供了一种试剂盒,其包含如本文所述的配体结合分子或融合蛋白或药物组合物。
以上内容是一个概述,因此必要时包含细节的简化、概括和省略;因此,本领域技术人员将认识到,该概述仅是举例说明性的,并不意图以任何方式进行限制。本文所述的方法、组合物和用途和/或其他主题的其它方面、特征和优势将在本文所示的教导中变得明显。
附图说明
图1显示各个分子的蛋白结构组成。
图2显示各个分子的一步蛋白A纯化后的SEC检测图谱。
图3显示LFV-035、LFV-036、LFV-050和对照分子对于VEGF-A165与VEGFR2之间结合的阻断作用,如通过ELISA测定的。
图4显示各分子对VEGF-B的结合作用,如通过ELISA测定的。
图5显示各分子对PlGF的结合作用,如通过ELISA测定的。
图6A显示大鼠眼底激光造模实验中,各药物组在给药14天、27天后的眼底四级荧光光斑平均所占的百分比。*P≤0.05:模型对照组vs.Eylea组(D14)、Eylea+LFV-038混合物组(D14)、LFV-036组(D27);**P≤0.01:模型对照组vs.LFV-050组(D14);***P≤0.001:模型对照组vs.Eylea+LFV-038混合物组(D27)、LFV-050组(D27);■P≤0.05:LFV-036组vs.LFV-050组(D27)。
图6B显示大鼠眼底激光造模实验中,各药物组在给药14天、27天后的眼底荧光光斑的平均荧光渗漏面积。**P≤0.01:模型对照组vs.Eylea组(D14、D27);***P≤0.001:模型对照组vs.Eylea+LFV-038混合物组(D14、D27)、LFV-050组(D14、D27);▲P≤0.05:Eyleavs.LFV-050组(D27);●P≤0.05:Eylea+LFV-038混合物组vs.LFV-050组(D14、D27)。
发明详述
除非另有定义,否则本文使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常所理解的相同含义。本文引用的所有专利、专利申请和其他出版物均通过引用全文并入。如果本文中提出的定义与通过引用并入本文的专利、专利申请和其他出版物中提出的定义相冲突,则以本文中提出的定义为准。
如本文所用的,术语“生长因子结合结构域”是指包含在配体结合分子中的能够识别、结合、靶向和/或拮抗一种或多种生长因子(优选为人的生长因子)的结构域。所述生长因子一般包括VEGF-A、VEGF-B、VEGF-C、VEGF-D、PlGF、和PDGF家族分子(例如PDGF-A、PDGF-B、PDGF-C)。
在一些实施方案中,所述生长因子结合结构域包含来源于VEGF受体(例如SEQ IDNO:1所示的VEGFR1全长氨基酸序列、SEQ ID NO:2所示的VEGFR2氨基酸序列和SEQ ID NO:3所示的VEGFR3全长氨基酸序列)的氨基酸序列。如本文公开的,所述来源于VEGF受体的氨基酸序列包括VEGF受体的片段或其变体,且基本上保留了与相应的VEGF生长因子结合的能力。在一些实施方案中,所述生长因子结合结构域是包含来源于两种或更多种VEGFR的氨基酸序列的嵌合体。术语“嵌合体”或“嵌合氨基酸序列”指来源于两种或更多种VEGFR的氨基酸序列可操作性地连接(直接连接或通过接头间接连接)在一起。例如,嵌合体可以是SEQID NO:1(VEGFR1)的132-230的片段可操作地连接于SEQ ID NO:2(VEGFR2)的225-327的片段的N末端或C末端。
如本文所用的,术语“补体抑制结构域”在本文中又称为“CD59结构域”或“保护素结构域”,是指来源于补体抑制蛋白(具体地为CD59)的结构域,或者具有抑制补体的过度活化的功能的结构域。在一些实施方案中,所述补体抑制结构域包含来源于CD59蛋白(例如SEQ ID NO:4所示的全长CD59蛋白)的氨基酸序列。如本文公开的,所述来源于CD59蛋白的氨基酸序列是CD59蛋白的片段或其变体,且基本上保留了全长CD59蛋白抑制补体活化或破坏膜攻击复合体组装的功能。在一些具体的实施方案中,所述来源于CD59蛋白的氨基酸序列如SEQ ID NO:11所示。本领域技术人员将理解,虽然本文中具体公开的是涉及CD59的补体抑制结构域,但其可包含来源于多种其他补体抑制蛋白的氨基酸序列,包括但不限于,CR1、CR2、CR3、CD55、CD46等补体调节分子及其功能性片段。因此,本发明的配体结合分子可以包含一个来源于CD59蛋白的补体抑制结构域和一个来源于其他补体抑制蛋白的补体抑制结构域。
如本文所用的,术语“CD59(又称为保护素)”是指分化因子59,是一个12KD的膜结合的糖基化蛋白,其可以结合在补体的C8与C9成分相互作用的部位,阻断C8与C9的结合,抑制C9成分最终在膜上排列形成渗漏孔,因而是一个有效的膜攻击复合体的抑制因子。在小鼠内,保护素有两个同源序列,保护素a和保护素b,其中保护素b仅在局部器官表达,保护素a被认为是主要发挥作用的功能序列。在人、猴、大鼠内,均只有一条保护素序列。人保护素与鼠保护素a的序列相似度为34%。
如本文所用的,术语“VEGF”是指VEGF家族,其由VEGF糖蛋白(VEGF-A、VEGF-B、VEGF-C、VEGF-D和VEGF-E)和血小板源性生长因子(PDGF)组成。VEGF-A涵盖VEGF-A的任何形式,包括VEGF-A的天然蛋白(加工或未加工形式)、全长VEGF-A、其片段(例如截短形式、胞外/跨膜结构域)或变体(例如剪接变体、等位变体或人工改造的变体)以及其修饰形式(例如糖基化)。人体中根据不同的剪切方式存在5种VEGF-A同等型,即VEGF-A121、VEGF-A145、VEGF-A165、VEGF-A189、VEGF-A206,其中VEGF-A165是VEGF-A最重要的同源单体。类似地,VEGF-B、VEGF-C、VEGF-D也涵盖其天然蛋白(包括加工或未加工形式)、全长或片段(例如截短形式、胞外/跨膜结构域)或变体(例如剪接变体、等位变体或人工改造的变体)以及其修饰形式(例如糖基化)。
如本文所用的,术语“血管内皮生长因子受体”或“VEGF受体”包括VEGFR1、VEGFR2和VEGFR3,它们是受体酪氨酸激酶家族的成员。这三种受体的蛋白质包含由6或7个免疫球蛋白(Ig)样结构域(分别称为D1-D7)组成的大的细胞外区域、单一的跨膜(TM)螺旋和具有酪氨酸激酶活性的胞质区域以及另外的调控序列。人VEGFR1和VEGFR2的全长天然蛋白的氨基酸序列的示例分别是SEQ ID NO:1和SEQ ID NO:2。
如本文所用的,“Fc”是指源自抗体的以下部分,其包含第一重链的第二(CH2)和第三(CH3)恒定区经由二硫键联合第二重链的第二和第三恒定区。Fc区还可以包含全部或部分的铰链区。抗体的Fc部分负责多种效应器功能例如ADCC和CDC,但并不在抗原结合中发挥功能。抗体经由其Fc域启动和调节效应器功能的能力是其体内保护性活性的关键部分。越来越多的证据表明抗体的体内活性还高度依赖于IgG Fc域与其相关受体Fcγ受体(FcγR)和FcRn受体之间的相互作用。
如本文所用的,术语“可操作地连接”是指两个或更多个感兴趣的生物序列的并置(带有或不带有间隔区或接头或插入序列)以使得它们处于允许以意图方式起作用的关系。当就多肽使用时,是指以允许连接的产物具有意图的生物学功能的方式连接多肽序列。例如,配体结合分子可以可操作地连接于免疫球蛋白恒定区,以便提供具有配体结合活性的稳定产物。又例如,配体结合分子可以与免疫球蛋白恒定区通过其间的插入序列可操作地连接,并且该类插入序列可以是间隔区或可以包含更长的序列。在本发明的实施方案中,生长因子结合结构域与补体抑制结构域之间是可操作地连接的,例如通过接头连接,从而不干扰彼此的功能。
如本文所用的,当就氨基酸序列(例如肽、多肽或蛋白质)使用时,术语“融合”或“融合的”是指两个或更多个氨基酸序列的组合,例如通过化学键合或重组的方式,形成天然不存在的单个氨基酸序列。融合氨基酸序列可以通过两个编码多核苷酸序列的遗传重组产生,并且可以通过将包含重组多核苷酸的构建体引入宿主细胞的方法来表达。术语“融合蛋白”在本文中指具有两个(或更多个)共价连接在一起的部分的多肽,其中每个部分是具有不同特性的肽。该性质可以是生物学性质,例如体外或体内活性。该性质也可以是简单的化学或物理性质,例如与靶抗原的结合,反应的催化等。这两个部分可以通过单个肽键直接连接或通过包含一个或多个氨基酸残基的肽接头连接。通常,这两个部分和接头将以符合阅读框的方式连接。
如本文所用的,术语“来源于”与“衍生自”可交换使用,指的是亲本(parental)序列通过缺失、添加、和/或取代一个或多个氨基酸残基所获得的变体。在一些实施方案中,“来源于”亲本氨基酸序列的氨基酸序列是该亲本氨基酸序列的片段,例如以VEGFR1的全长氨基酸序列(如SEQ ID NO:1所示)作为亲本氨基酸序列时,来源于SEQ ID NO:1的氨基酸序列可以指包含SEQ ID NO:1的位置132-230所示的片段或由其组成的氨基酸序列;以VEGFR2的全长氨基酸序列(如SEQ ID NO:2所示)作为亲本氨基酸序列时,来源于SEQ ID NO:2的氨基酸序列可以指包含SEQ ID NO:2的位置225-327所示的片段或由其组成的氨基酸序列。在一些其他的实施方案中,“来源于”亲本氨基酸序列的氨基酸序列是该亲本氨基酸序列或其片段的变体,例如在一个或多个氨基酸位点处进行突变。所述突变可以是在糖基化位点处的突变以消除糖基化位点。例如,以CD59全长氨基酸序列(如SEQ ID NO:4所示)作为亲本氨基酸序列时,来源于SEQ ID NO:4的氨基酸序列可以指包含SEQ ID NO:11所示片段或由其组成的氨基酸序列。
如本文所用,术语“同一性”是指通过比对和比较序列确定的两个或更多个多肽分子或两个或更多个核酸分子的序列之间的关系。“百分比同一性”是指比较分子中氨基酸或核苷酸之间相同残基的百分比,并基于被比较的最小分子的大小计算。对于这些计算,比对中的缺口(如果有的话)优选通过特定的数学模型或计算机程序(即“算法”)来寻址。可以用于计算比对的核酸或多肽的同一性的方法包括在Computational Molecular Biology,(Lesk,A.M.编),1988,New York:Oxford University Press;Biocomputing Informaticsand Genome Projects,(Smith,D.W.编),1993,New York:Academic Press;ComputerAnalysis of Sequence Data,Part I,(Griffin,A.M.和Griffin,H.G.编),1994,NewJersey:Humana Press;von Heinje,G.,1987,Sequence Analysis in MolecularBiology,New York:Academic Press;Sequence Analysis Primer,(Gribskov,M.和Devereux,J.编),1991,New York:M.Stockton Press;和Carillo等人,1988,SIAMJ.Applied Math.48:1073中描述的那些。
如本文所用,术语“特异性结合”或“特异性地结合”是指两个分子之间,例如配体和配体结合分子之间的非随机结合反应。在某些实施方案中,本文提供的配体结合分子以≤10-6M(例如,≤5x10-7M、≤2x10-7M、≤10-7M、≤5x10-8M、≤2x10-8M、≤10-8M、≤5x10-9M、≤4x10-9M、≤3x10-9M、≤2x10-9 M、或≤10-9M)的结合亲和力(KD)特异性结合人VEGF-A。本文中使用的KD是指解离速率与缔合速率的比率(koff/kon),其可通过使用本领域已知的任何常规方法来确定,包括但不限于表面等离子体共振方法、微量热泳动法、LC-MS方法和流式细胞术(例如FACS)方法。在某些实施方案中,可以通过使用流式细胞术适当地确定KD值。
如本文所用,“阻断结合”的能力是指本发明的配体结合分子抑制两个分子(例如VEGF-A和VEGFR2)之间的结合相互作用至任何可检测程度的能力。在某些实施方案中,阻断两个分子之间的结合的配体结合分子抑制两个分子之间的结合相互作用至少85%或至少90%。在某些实施方案中,抑制可以大于85%,或大于90%。在某些实施方案中,通过IC50(半数抑制浓度)或EC50(半数效用浓度)来衡量配体结合分子阻断结合的能力。
如本文所用,术语“有效量”涉及活性化合物的量或包含活性化合物的材料、组合物或剂量的量,其在按照所需的治疗方案施用时有效用于产生与合理的益处/风险比相称的某些所需的治疗效果,例如,有效量在本文中可以指有效抑制受试者中的新生血管形成的量,有效抑制受试者中的补体过度活化的量,有效抑制受试者中(例如眼部)VEGF-A、VEGF-B、PlGF中的至少一种所需的量,或刺激在眼部细胞或眼睛血管中表达的VEGFR-1、VEGFR-2受体家族的至少一种的量。根据受试者的具体情况,本领域技术人员可以容易地确定针对特定受试者的有效量和治疗方案。
包含生长因子结合结构域和补体抑制结构域的配体结合分子
本发明中的配体结合分子同时包含生长因子结合结构域和补体抑制结构域,从而在有效结合阻断一种或多种生长因子的同时,还能作用于补体的下游途径,阻断补体介导的攻膜复合体的形成。本申请发明人意外地发现,这两种结构域的组合产生了协同作用,克服单一使用靶向生长因子治疗的局限性,有利于从发病根源上对血管新生相关病症进行有效治疗,达到最终治愈的目的。
优选地,生长因子结合结构域与补体抑制结构域之间通过接头进行连接,从而使得两种结构域之间在空间上有一定的距离,在发挥功能时不会互相干扰。所述接头通常可采用本领域中熟知的用于蛋白质工程的各种接头,优选肽接头,且长度可以从2个氨基酸到几十个氨基酸,例如20、30、40或更多个氨基酸。在一些实施方案中,连接两种结构域所采用的肽接头包含G4S系列接头,例如(G4S)1、(G4S)2、(G4S)3等。
生长因子结合结构域
本文中公开的生长因子结合结构域能够特异性地结合VEGF-A、VEGF-B、PlGF中的至少一种,更优选至少两种。最优选地,所述配体结合分子对VEGF-A、VEGF-B、PlGF都具有特异性结合亲和力。
如本文所用,表述“特异性结合…”或“对…具有特异性结合亲和力”在指生长因子时,不仅包括特异性结合该生长因子的游离、活性形式,还包括结合该生长因子的其他形式。例如,VEGF-A有多种同工型,其中一些处于循环中而另一些与细胞表面上的肝素硫酸蛋白聚糖缔合。特异性结合VEGF-A的配体结合分子结合至少一种循环中的同工型,优选所有循环中的同工型,更优选结合其他的同工型。因此,在提到配体结合分子特异性结合VEGF-A时,涵盖其能够特异性结合VEGF-A121、VEGF-A145、VEGF-A165、VEGF-A189和VEGF-A206。
在一些实施方案中,所述生长因子结合结构域包含衍生于VEGFR1、VEGFR2、和VEGFR3蛋白的一种或多种的氨基酸序列。
在一些实施方案中,所述配体结合分子的至少一个生长因子结合结构域包含衍生于天然VEGFR1,特别是天然VEGFR1的胞外区的氨基酸序列。
在一些实施方案中,所述配体结合分子的至少一个生长因子结合结构域包含衍生于天然VEGFR2,特别是天然VEGFR2的胞外区的氨基酸序列。
在一些实施方案中,所述配体结合分子的至少一个生长因子结合结构域包含衍生于天然VEGFR3,特别是天然VEGFR3的胞外区的氨基酸序列。
优选地,相比于天然VEGFR2胞外区或对照配体结合分子,所述配体结合分子对VEGF-A、VEGF-B、PlGF中一种或多种的结合亲和力显著提高。
优选地,所述VEGF-A、VEGF-B、PlGF是来自或衍生自哺乳动物例如人、鼠、猴的,更优选地,分别是人的天然VEGF-A、VEGF-B、PlGF,包括其各种同工型、部分加工或未加工的前体形式。
在一些实施方案中,所述VEGF-A、VEGF-B、PlGF中的一种或多种呈现为游离的可溶性蛋白质,或者是在细胞表面表达的锚定形式。
本发明还涵盖所述配体结合分子能够结合VEGF-A、VEGF-B、PlGF的异常高表达形式,从而可经由结合这些异常高表达的生长因子而促进机体恢复正常机能。如本领域已知的,部分在病理状态中VEGF/PlGF生长因子过量表达,使这些生长因子在机体组织中呈现异常功能。
在一些实施方案中,所述配体结合分子的至少一个生长因子结合结构域包含衍生于VEGFR1(特别是VEGFR1的胞外区)的氨基酸序列,所述衍生于VEGFR1的氨基酸序列是VEGFR1的片段或与其具有至少80%同一性的氨基酸序列。具体地,所述VEGFR1的片段可选自SEQ ID NO:1的位置132-230限定的氨基酸序列以及其N末端或C末端截短或延长片段(例如截短或延长不超过20、15、10、9、8、7、6、5、4、3、2或1个氨基酸)。
在一些实施方案中,所述配体结合分子的至少一个生长因子结合结构域包含衍生于VEGFR3(特别是VEGFR3的胞外区)的氨基酸序列,所述衍生于VEGFR3的氨基酸序列是VEGFR3的片段或与其具有至少80%同一性的氨基酸序列。具体地,所述VEGFR3的片段可选自以下:
(a)SEQ ID NO:3的位置47-115或25-115限定的氨基酸序列;
(b)SEQ ID NO:3的位置154-210或116-153限定的氨基酸序列;
(c)SEQ ID NO:3的位置248-314或211-247限定的氨基酸序列;和
(d)(a)、(b)、或(c)的N末端或C末端截短或延长片段(例如截短或延长不超过20、15、10、9、8、7、6、5、4、3、2或1个氨基酸)。
在一些实施方案中,所述至少一个生长因子结合结构域包含衍生于VEGFR1的氨基酸序列可操作地连接于衍生于VEGFR2的氨基酸序列。具体地,包含SEQ ID NO:1的位置132-230限定的氨基酸序列可操作地连接于SEQ ID NO:2的位置225-327限定的氨基酸序列。
所述可操作地连接可以是彼此直接连接或经由接头相连接。用于蛋白质工程领域的接头是本领域技术人员熟知的且均可以用于本发明的配体结合分子中。在一些实施方案中,所述接头包含G4S系列接头,也可以是AAA或其他天然短肽序列。如本领域技术人员将理解的,接头可以具有较广范围的氨基酸序列,只要其能实现两个氨基酸序列之间的可操作连接。
补体抑制结构域
如上文所述,本公开提供一种配体结合分子,其包含至少一个生长因子结合结构域和至少一个补体抑制结构域,所述补体抑制结构域包含来源于CD59蛋白(优选为人CD59蛋白)的氨基酸序列。
研究发现,在地图样萎缩患者中,补体过度反应并破坏黄斑区的细胞,黄斑是视网膜的中央部分,负责处理中央视觉和视力细节,这种过度反应会导致患者逐渐发展为失明。
人CD59蛋白是一种终末补体途径的抑制剂,由128个氨基酸残基组成(如SEQ IDNO:4所示),分布甚广泛,已证明皮肤、肝、肾、胰、肺、唾腺、神经系统、胎盘以及各种血细胞(红细胞、淋巴细胞、中性粒细胞及血小板)均有表达。C59蛋白的主要生理功能是,防止MAC对同种或自身细胞的溶解破坏,即同种限制作用,通过其与C7、C8或C9的结合而阻止MAC组装。当其与C5b~7复合物结合后,可阻止其再与C8结合;当其与C8结合后,则可阻碍结合至MAC上的第1个C9分子的铺展,从而阻止后继C9的结合;而当其与MAC中的C9结合后,又可阻止C9进一步聚合。这样,在有CD59存在的情况下,在同种或自身细胞的表面便不能顺利地完成MAC的全部组装,或不能组装成C5b~(9)n复合物,从而限制了对同种或自身细胞的溶解作用。而且,CD59蛋白通过在下游对补体系统进行抑制,相比于在上游作用的补体调节分子更具优势。
本文中的配体结合分子包含补体抑制结构域。所述补体抑制结构域可包含来源于多种补体抑制蛋白的氨基酸序列,包括但不限于,CR1、CR2、CR3、CD55、CD59、CD46等补体调节分子及其功能性片段。优选地,所述补体抑制结构域包含来源于CD59蛋白或其功能性片段的氨基酸序列。
如本文所用,术语“功能性片段”指多肽分子(例如人CD59蛋白)的一部分,其含有多肽(例如SEQ ID NO:4)全长的至少60%、70%、80%、90%、95%、或更多,且保留了全长多肽的功能。即,在本发明中所述的功能性片段能够抑制补体过度活化,破坏膜攻击复合物的组装。在一些实施方案中,所述功能性片段是SEQ ID NO:4的第26-102位或SEQ ID NO:11所示的氨基酸。
在一些实施方案中,所述补体抑制结构域包含与SEQ ID NO:4的位置26-102限定的氨基酸序列具有至少90%同一性的氨基酸序列。例如,所述生长因子结合结构域包含与SEQ ID NO:4的位置26-102所示的氨基酸序列相比具有不超过10个氨基酸、不超过5个氨基酸、不超过4个氨基酸、不超过3个氨基酸、不超过2个氨基酸、不超过1个氨基酸的突变的氨基酸序列。所述突变可选自插入、取代和缺失。
在一些实施方案中,所述补体抑制结构域包含与SEQ ID NO:11所限定的氨基酸序列具有至少90%同一性的氨基酸序列。例如,所述生长因子结合结构域包含与SEQ ID NO:11所示的氨基酸序列相比具有不超过10个氨基酸、不超过5个氨基酸、不超过4个氨基酸、不超过3个氨基酸、不超过2个氨基酸、不超过1个氨基酸的突变的氨基酸序列。所述突变可选自插入、取代和缺失。
包含Fc区以及任选地信号肽的配体结合分子
本发明的配体结合分子可以是单体(即单链),也可以是二聚体(即双链)或多聚体。在二聚体或多聚体结构中,配体结合分子的各个链彼此共价或非共价连接。在一些实施方案中,连接发生在配体结合分子的VEGFR2衍生的序列之间和/或Fc的两条链之间。例如,所述连接可以是通过二硫键连接。
在一些实施方案中,本发明提供的配体结合分子还包含免疫球蛋白恒定结构域序列,例如人IgG的恒定结构域序列,更具体地是IgG1、IgG2、IgG3、IgG4的Fc区序列。所述配体结合分子可以是同二聚体或异二聚体。例如,当所述配体结合分子为同二聚体时,包含两条相同的链,每条链分别包含补体结合结构域可操作地连接于生长因子结合结构域,生长因子结合结构域可操作地连接于单链Fc。或者,每条链分别包含生长因子结合结构域可操作地连接于补体结合结构域,补体结合结构域可操作地连接于单链Fc。在某些实施方案中,Fc区经由铰链区可操作地连接于生长因子结合结构域和/或补体抑制结构域。任选地,该铰链区可以源自人IgG1、IgG2或IgG4。在某些实施方案中,该铰链区源自人IgG1。
所述免疫球蛋白恒定结构域序列可以通过接头(例如GPG)连接至衍生自VEGFR1和/或VEGFR2和/或VEGFR3的序列。如本领域已知的,Fc是指由抗体的第一重链的第二和第三恒定区经由二硫键合结合至第二重链的第二和第三恒定区组成的抗体的部分,任选地Fc区还包含全部或部分的铰链区。本文中的Fc区既包括野生型Fc区还包括其变体,具有用于多种目的的不同突变。所述变体可在Fc区中包含一个或多个氨基酸残基修饰,例如取代。
在某些实施方案中,Fc区变体包含一个或多个氨基酸取代,其改善对新生儿Fc受体(FcRn)的pH依赖性结合。这样的变体可以具有延长的药代动力学半衰期,因为它在酸性pH结合FcRn从而使其能够逃离溶酶体中的降解并然后被转运并释放出细胞。工程化抗体分子以改善与FcRn的结合亲和力的方法在本领域中是众所周知的,参见,例如,Vaughn,D.等人,Structure,6(1):63-73,1998;Kontermann,R.等人,Antibody Engineering,Volume 1,Chapter 27:Engineering of the Fc region for improved PK,published bySpringer,2010;Yeung,Y.等人,Cancer Research,70:3269-3277(2010);和Hinton,P.等人,J.Immunology,176:346-356(2006)。
在某些实施方案中,Fc区变体包含一个或多个改变抗体依赖性细胞毒性(ADCC),或者通过改善或减少C1q结合和/或CDC来改变补体依赖性细胞毒性(CDC)的氨基酸取代。
在某些实施方案中,本发明提供的配体结合分子包含人IgG4恒定区,其中第228个氨基酸残基被改变,例如Ser228Pro(S228P,其可以防止或减少链交换),和/或第235个氨基酸残基被改变,例如Leu235Glu(L235E,其可以改变Fc受体相互作用)。
在某些实施方案中,本发明提供的配体结合分子在Fc区的界面中包含一个或多个氨基酸取代,以协助和/或促进异二聚化。这些修饰包括将突起引入第一Fc多肽中和将腔引入第二Fc多肽中,其中突起可以位于腔中以促进第一和第二Fc多肽的相互作用而形成异二聚体或复合物。生成具有这些修饰的蛋白分子的方法在本领域中是已知的,例如,如在美国专利号5,731,168中所述。
在某些实施方案中,本发明提供的配体结合分子包含人IgG1的天然Fc序列,如SEQID NO:5的Asp104-Lys330所示。在一些实施方案中,本发明提供的配体结合分子包含与SEQID NO:5的位置104-330的氨基酸序列具有至少80%、或至少85%、或至少90%、或至少92%、或至少95%、或至少96%、或至少97%、或至少98%、或至少99%同一性或具有100%同一性的氨基酸序列。
在一些实施方案中,所述配体结合分子还在氨基末端包含信号肽,以便于在细胞中分泌和纯化。
配体结合分子的性质
在本发明中,发现了同时包含生长因子结合结构域和补体抑制结构域的配体结合分子能够定向地将补体抑制靶向到期望的位点,即生长因子结合结构域发挥作用的位点。通过两者组合得到的配体结合分子既能保护视网膜免受人体补体免疫反应损伤,又能在膜表面中和阻断血管内皮生长因子等多种生长因子与受体的结合。因此,所述配体结合分子在病灶微环境发挥协同作用,既有利于控制血管新生、渗漏等病状,又可以在病因上干预过度活化的补体系统,从而克服了单一靶向生长因子治疗的局限性及不良反应。
本发明发现所述配体结合分子可阻断VEGF-A与VEGFR受体的结合,并且还可结合或中和VEGF-B、PlGF分子。如实施例中通过ELISA所验证的:所述配体结合分子能以低于3.5nM、低于3nM、或低于2.5nM的IC50阻断VEGF-A与VEGFR2的结合;能以低于2nM、低于1.5nM、或低于1nM的EC50结合PlGF;能以低于3.5nM、低于3nM、低于2.5nM、或低于2nM的EC50结合VEGF-B。
多核苷酸、载体和宿主细胞
在一些方面,本发明还提供编码此类配体结合分子的多核苷酸。所述多核苷酸可用于表达配体结合分子。在一些实施方案中,所述多核苷酸还可以用作用于实现多肽配体结合分子的体内表达的呈活性形式的治疗剂。
在某些实施方案中,分离的多核苷酸包含编码以下氨基酸序列中至少一种的核苷酸序列和/或与其具有至少80%(例如,至少85%、88%、90%、92%、93%、94%、95%、96%、97%、98%或99%)序列同一性的核苷酸序列,和/或其仅具有简并取代的变体:
(a)SEQ ID NO:6、9或12所示的氨基酸序列;
(b)SEQ ID NO:7、10或13所示的氨基酸序列;和
(c)SEQ ID NO:8、11或14所示的氨基酸序列。
编码所述配体结合分子的多核苷酸易于使用本领域已知的常规程序进行分离和测序。所述多核苷酸也可以通过合成方法获得。优选地,所述多核苷酸经过密码子优化以便在真核宿主细胞,特别是哺乳动物细胞中表达。
使用已知的重组技术,可以将编码配体结合分子的多核苷酸插入载体中以进一步克隆(DNA的扩增)或表达。载体组分通常包括但不限于以下一种或多种:信号序列、复制起点、一个或多个标志物基因、增强子元件、启动子(例如SV40、CMV、EF-1α)以及转录终止序列。
在一些实施方案中,本公开提供了包含本文提供的编码配体结合分子的多核苷酸的载体(例如表达载体),与所述多核苷酸可操作地连接的至少一个启动子(例如SV40、CMV、EF-1α),和至少一个选择标志物。载体的实例包括但不限于逆转录病毒(包括慢病毒),腺病毒,腺伴随病毒,疱疹病毒(例如单纯疱疹病毒),痘病毒,杆状病毒,乳头瘤病毒,乳多空病毒(例如SV40),λ噬菌体,和M13噬菌体,脂质体,质粒pcDNA3.3,pMD18-T,pOptivec,pCMV,pEGFP,pIRES,pQD-Hyg-GSeu,pALTER,pBAD,pcDNA,pCal,pL,pET,pGEMEX,pGEX,pCI,pEGFT,pSV2,pFUSE,pVITRO,pVIVO,pMAL,pMONO,pSELECT,pUNO,pDUO,Psg5L,pBABE,pWPXL,pBI,p15TV-L,pPro18,pTD,pRS10,pLexA,pACT2.2,pCMV-SCRIPT.RTM,pCDM8,pCDNA1.1/amp,pcDNA3.1,pRc/RSV,PCR 2.1,pEF-1,pFB,pSG5,pXT1,pCDEF3,pSVSPORT,pEF-Bos等。
可以将包含编码配体结合分子的多核苷酸序列的载体导入宿主细胞用于进行克隆或基因表达。用于在本文的载体中克隆或表达DNA的合适宿主细胞是原核生物、酵母或更高等的真核细胞。为此目的合适的原核生物包括真细菌,例如革兰氏阴性或革兰氏阳性细菌,如大肠杆菌。除了原核生物外,真核微生物如丝状真菌或酵母是用于提供的载体的合适克隆或表达宿主。酿酒酵母或普通的面包酵母是低等真核宿主微生物中最常用的。然而,许多其他属、种和菌株在本文中是普遍可获得的和有用的。
用于表达本文提供的配体结合分子的合适宿主细胞也可以衍生自多细胞生物。无脊椎动物细胞的实例包括植物和昆虫细胞。已经鉴定出来自寄主的许多杆状病毒株和变体以及相应的允许的昆虫寄主细胞。然而,对脊椎动物细胞的兴趣最大,并且在培养(组织培养)中脊椎动物细胞的繁殖已成为常规程序。有用的哺乳动物宿主细胞系的实例是用SV40转化的猴肾CV1系(COS-7,ATCC CRL 1651);人胚胎肾细胞系(在悬浮培养中亚克隆生长的293或293细胞,Graham等人,J.Gen Virol.36:59(1977));幼仓鼠肾细胞(BHK,ATCC CCL10);中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub等人,Proc.Natl.Acad.Sci.USA77:4216(1980));猴肾细胞(CV1 ATCC CCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL 2);犬肾细胞(MDCK,ATCC CCL 34);水牛大鼠肝细胞(BRL 3A,ATCC CRL 1442);人肺细胞(W138,ATCC CCL 75);人肝细胞(Hep G2,HB 8065);小鼠乳腺肿瘤(MMT 060562,ATCC CCL51);TRI细胞(Mather等人,Annals N.Y.Acad.Sci.383:44-68(1982));MRC 5细胞;FS4细胞;和人类肝癌细胞系(Hep G2)。在一些优选的实施方案中,宿主细胞是中国仓鼠卵巢(CHO)细胞。在一些另外的优选的实施方案中,宿主细胞是其他哺乳动物细胞系,例如人细胞系。
用上述表达或克隆载体转化宿主细胞用于产生配体结合分子并在经适当修饰的常规营养培养基中培养用于诱导启动子,选择转化子或扩增编码所需序列的基因。
用于产生本文提供的配体结合分子的宿主细胞可以在多种培养基中培养。诸如Ham的F10(Sigma),基本必需培养基(MEM),(Sigma),RPMI-1640(Sigma)和Dulbecco改良的Eagle's培养基(DMEM),Sigma)的可商购获得的培养基都适合于培养宿主细胞。另外,Ham等人,Meth.Enz.58:44(1979),Barnes等人,Anal.Biochem.102:255(1980),美国专利号4,767,704;4,657,866;4,927,762;4,560,655;或5,122,469;WO 90/03430;WO 87/00195;或U.S.Pat.Re.30,985中描述的任何培养基可以用作宿主细胞的培养基。这些培养基中的任何一种可以根据需要补充激素和/或其他生长因子(例如胰岛素、转铁蛋白或表皮生长因子),盐(例如氯化钠、钙、镁和磷酸盐),缓冲液(例如HEPES),核苷酸(例如腺苷和胸苷),抗生素(例如GENTAMYCINTM药物),微量元素(定义为通常以微摩尔范围的最终浓度存在的无机化合物),和葡萄糖或等效能量来源。也可以以本领域技术人员已知的适当浓度包括任何其他必要的补充剂。培养条件,例如温度、pH等是先前与选择用于表达的宿主细胞一起使用的那些条件,并且对于普通技术人员而言是显而易见的。
当使用重组技术时,配体结合分子可以在细胞内、在周质空间中产生,或直接分泌到培养基中。如果配体结合分子在细胞内产生,则第一步,例如通过离心或超滤除去宿主细胞或裂解片段的颗粒碎片。可以通过离心去除细胞碎片。在配体结合分子分泌到培养基中的情况下,通常首先使用可商购获得的蛋白质浓缩过滤器,例如Amicon或MilliporePellicon超滤单元,浓缩来自这种表达系统的上清液。蛋白酶抑制剂例如PMSF可以包括在上述任何步骤中以抑制蛋白水解,并且可以包括抗生素以防止不定污染物的生长。
由细胞制备的配体结合分子可以使用例如羟磷灰石色谱、凝胶电泳、透析、DEAE-纤维素离子交换色谱、硫酸铵沉淀、盐析和亲和色谱来纯化,其中亲和色谱是优选的纯化技术。
在某些实施方案中,固定化在固相上的蛋白A用于配体结合分子的免疫亲和纯化。蛋白A作为亲和配体的适用性取决于在配体结合分子中存在的任何免疫球蛋白Fc结构域的种类和同种型。蛋白A可以用于纯化基于人γ1、γ2或γ4重链的抗体(Lindmark等人,J.Immunol.Meth.62:1-13(1983))。亲和配体所附着的基质最通常是琼脂糖,但也可以使用其他基质。机械稳定的基质(例如受控孔玻璃或聚(苯乙烯二乙烯基)苯)允许比琼脂糖所实现的更快的流速和更短的处理时间。其他蛋白质纯化技术,例如在离子交换柱上的分馏,乙醇沉淀,反相HPLC,在硅胶上的色谱,在肝素SEPHAROSETM色谱上在阴离子或阳离子交换树脂上的色谱(例如聚天冬氨酸柱),色谱聚焦,SDS-PAGE和硫酸铵沉淀也可用,取决于要回收的抗体。
缀合物
在一些方面,本发明还提供包含配体结合分子和与其缀合的缀合物模块的缀合物。缀合物模块是可以附着至配体结合分子的部分。涵盖多种缀合物模块可以与本文提供的配体结合分子连接(参见,例如,“Conjugate Vaccines”,Contributions toMicrobiology and Immunology,J.M.Cruse和R.E.Lewis,Jr.(编),Carger Press,NewYork,(1989))。这些缀合物模块可以通过共价结合、亲和力结合、插入(intercalation)、配位结合、络合、缔合、掺合或加入等方法与配体结合分子连接。
在某些实施方案中,可以将本文公开的配体结合分子工程化为在配体结合部分之外包含可以用于结合一种或多种缀合物模块的特异性位点。例如,这样的位点可以包括一个或多个反应性氨基酸残基,例如半胱氨酸或组氨酸残基,以协助与缀合物模块的共价连接。
在某些实施方案中,所述缀合物包含将缀合物模块连接至所述配体结合分子的连接子。在一些其他实施方案中,本文所述的配体结合分子在C末端通过肽键直接附接到缀合物模块的N末端氨基酸,或在N末端通过肽键直接附接到缀合物模块的C末端氨基酸。亦可以通过化学键,包括但不限于酰胺键与缀合物模块连接形成多肽链。在某些实施方案中,配体结合分子可以间接地或通过第二缀合物模块与第一缀合物模块连接。例如,可以将配体结合分子与生物素缀合,然后间接地缀合至与抗生物素蛋白缀合的第二缀合物模块。缀合物模块可以是清除修饰(clearance modifying)模块、毒素(例如化学治疗剂)、可检测标记(例如放射性同位素、镧系元素、发光标记、荧光标记或酶-底物标记)或纯化模块。
“毒素”可以是对细胞有害或可以损害或杀死细胞的任何试剂。毒素的实例包括但不限于紫杉醇,细胞松弛素B,短杆菌肽D,溴化乙锭,依米丁,丝裂霉素,依托泊苷,替诺泊苷,长春新碱,MMAE,MMAF,DM1,长春碱,秋水仙碱,阿霉素,柔红霉素,二羟基蒽醌二酮,米托蒽醌,光辉霉素,放线菌素D,1-去氢睾酮,糖皮质激素,普鲁卡因,丁卡因,利多卡因,普萘洛尔,嘌呤霉素及其类似物,抗代谢物(例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶脱羧嗪),烷基化剂(例如甲乙胺、噻菌灵苯丁酸氮芥、美法仑、卡莫司汀(BSNU)和洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、丝裂霉素C和顺式二氯二胺铂(II)(DDP)顺铂),蒽环类药物(例如柔红霉素(以前称为道诺霉素)和阿霉素),抗生素(例如放线菌素(以前称为更生霉素)、博来霉素、光神霉素和蒽霉素(AMC)),抗有丝分裂剂(例如长春新碱和长春花碱),拓扑异构酶抑制剂和微管蛋白结合剂。
可检测标记的实例可以包括荧光标记(例如荧光素、罗丹明、丹酰、藻红蛋白或德克萨斯红),酶-底物标记(例如辣根过氧化物酶、碱性磷酸酶、萤光素酶、葡糖淀粉酶、溶菌酶、糖氧化酶或β-D-半乳糖苷酶),放射性同位素(例如123I、124I、125I、131I、35S、3H、111In、112In、14C、64Cu、67Cu、86Y、88Y、90Y、177Lu、211At、186Re、188Re、153Sm、212Bi和32P、其他镧系元素),发光标记,发色团部分,洋地黄毒苷,生物素/亲和素,DNA分子或用于检测的金。
在某些实施方案中,缀合物模块可以是清除修饰剂,其帮助增加配体结合分子的半衰期。示例说明性实例包括水溶性聚合物,例如PEG、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、乙二醇/丙二醇的共聚物等。聚合物可以具有任何分子量,并且可以是支链的或非支链的。附着至配体结合分子的聚合物的数量可以变化,并且如果附着多于一个聚合物,则它们可以是相同或不同的分子。在一些具体的实施方案中,本发明提供的配体结合分子缀合于至少一个聚乙二醇模块,所述聚乙二醇模块可以附接于配体结合分子的氨基末端。
在某些实施方案中,缀合物模块可以是纯化模块,例如磁珠。
药物组合物
在一些方面,本发明提供包含与药学上可接受的载体一起配制的本发明的配体结合分子的组合物,例如药物组合物。这类组合物包含至少一种本发明的配体结合分子、融合蛋白或缀合物。在一些实施方案中,所述药物组合物为适合于玻璃体内注射的制剂。
如本文所使用的,“药学上可接受的载体”包括生理上相容的任何和所有药学上可接受的液体、凝胶或固体载体、水性媒介物、非水媒介物、抗微生物剂、等渗剂、缓冲剂、抗氧化剂、麻醉剂、悬浮液/分散剂、隔绝剂或螯合剂、稀释剂、佐剂、赋形剂或无毒的辅助物质,本领域已知的其他组分或其各种组合等等。所述载体可以适于静脉内、肌内、皮下、胃肠外、脊髓、经表皮、玻璃体内注射或植入施用等。取决于给药途径,活性化合物,即本发明的成分,可以包被在材料中以防止所述化合物免受酸和其它可能灭活所述化合物的自然条件的作用。
本发明的药物组合物还可包括药学上可接受的抗氧化剂。药学上可接受的抗氧化剂的实例包括:(1)水溶性抗氧化剂,例如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等等;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等等;和(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等等。
可用于本发明的药物组合物中的适当的水性载体和非水性载体的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等等)和其适当的混合物、植物油如橄榄油及可注射的有机酯如油酸乙酯。例如,可以通过利用包衣材料(如卵磷脂)、在分散剂的情况下通过维持所需要的颗粒大小和通过利用表面活性剂维持适当的流动性。
这些组合物还可包含辅助剂如防腐剂、润湿剂、乳化剂和分散剂。通过灭菌方法和通过包含各种抗菌剂和抗真菌剂(例如对羟苯甲酸酯、氯代丁醇、苯酚、山梨酸等等)可以确保防止微生物的存在。将等渗剂如糖、氯化钠等等包括入所述组合物也可能是期望的。此外,通过包含延迟吸收的物质如单硬脂酸铝和明胶,可以引起注射药物形式的吸收延长。
药物组合物可以是固体、糊剂、软膏、凝胶、液体、气雾剂、喷雾剂、聚合物、薄膜、乳液或混悬液形式。
在某些实施方案中,药物组合物配制成可注射的组合物。可以以任何常规形式制备可注射药物组合物,例如液体溶液,悬浮剂,乳剂或适于产生液体溶液、悬浮剂或乳剂的固体形式。用于注射的制备物可以包括准备注射的无菌和/或非热解溶液,无菌干燥可溶产品,如冻干粉,准备在使用前与溶剂混合,包括皮下注射片剂,准备注射的无菌悬浮液,准备在使用前与媒介物组合的无菌干燥的不溶性产品,以及无菌和/或非热解乳液。溶液可以是水性或非水性的。
药学上可接受的载体包括无菌水溶液或分散液和用于临时制备无菌注射溶液或分散液的无菌粉末。用于药学上活性物质的这类介质和试剂在本领域中是已知的。除非任何常规介质或试剂与活性化合物不相容,可以考虑任何常规介质或试剂在本发明的药物组合物中的使用。补充活性化合物也可以被加入所述组合物中。
药物组合物通常必须是无菌的并且在制造和储存的条件下是稳定的。所述组合物可以被配制为溶液、微乳剂、脂质体或其它适于高药物浓度的有序结构。所述载体可以是溶剂或分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等等)及其适当的混合物。例如,通过利用包衣(如卵磷脂)、在分散剂的情况下通过维持所需要的颗粒大小和通过利用表面活性剂可以维持适当的流动性。在很多情况下,优选在所述组合物中包括等渗剂例如糖、多元醇(如甘露糖醇、山梨醇)或氯化钠。通过将延迟吸收的物质(例如单硬脂酸盐和明胶)包括在所述组合物内可以引起可注射组合物的吸收延长。
可以通过将活性化合物以需要的量与按照需要的上文列举的组分之一或其组合一起加入适当的溶剂中,然后无菌微过滤制备无菌注射溶液。通常,可以通过将所述活性化合物加入包含基本分散介质和来自上文列举的物质的其它需要的组分的无菌载体中制备分散液。在用于制备无菌注射液的无菌粉末的情况中,优选的制备方法是真空干燥和冷冻干燥(冻干),其从先前无菌过滤的溶液产生活性成分加任何附加的需要成分的粉末。
可以与载体物质结合以产生单一剂型的活性成分的量取决于所治疗的对象和特定施用模式。可以与载体结合以产生单一剂型的活性成分的量一般是产生治疗效应的组合物的量。通常,以100%算,该量的范围为约0.01%至约99%的活性成分,优选从约0.1%至约70%,最优选约1%至约30%的活性成分与药学上可接受的载体组合。
调节给药方案以提供最佳的期望反应(例如治疗反应)。例如,可以施用单一大丸剂,可以随着时间施用几个分开的剂量,或者可以根
据治疗情况的紧迫性而按比例减少或增加所述剂量。由于便于施用和剂量的均匀性,将药物组合物配制成单位剂型是特别有利的。如本文所使用,单位剂型是指适合作为用于待治疗对象的单一剂量的物理上分散的单位;各单元包含与需要的药物载体结合的适于产生期望治疗效应的预定量的活性化合物。本发明的单位剂型的规格由以下因素规定并直接取决于以下因素:(a)活性化合物的独特性质和待实现的特定治疗效应,和(b)在配制这类活性化合物用于治疗个体敏感性的领域中固有的限制。
对于所述配体结合分子的施用,剂量范围为宿主体重的约0.0001至100mg/kg,并更通常是0.01至5mg/kg。例如,剂量可以是0.3mg/kg体重、1mg/kg体重、3mg/kg体重、5mg/kg体重或10mg/kg体重或在1-10mg/kg的范围内。示例性的治疗方案包括每周施用一次、每两周一次、每三周一次、每四周一次、一月一次、每3个月一次或每三至6个月一次。
可选地,所述配体结合分子可以作为缓释制剂进行施用,在这种情况下需要较低频度的施用。剂量和频率随所施用的物质在患者中的半衰期而变化。施用的剂量和频率可以取决于治疗是预防性或者是治疗性的。在预防性应用中,以相对不频繁的间隔在长时间内施用以相对低的剂量施用。一些患者在他们的余生中持续接受治疗。在治疗性应用中,有时要求相对短的时间间隔和相对高的剂量,直到疾病的进展被减缓或终止,并优选直到患者显示出疾病症状的部分或完全改善。其后,可以给予患者预防性方案。
活性成分在本发明的药物组合物中的实际剂量水平可以有所变化,以便获得对特定患者、组成和施用模式有效实现期望治疗响应而对所述患者无毒性的活性成分的量。所选择的剂量水平取决于各种药代动力学因素,包括所使用的本发明的特定组合、或者其酯、盐或酰胺的活性、给药途径、施用时间、使用的特定化合物的排泄速率、治疗持续时间、与所使用的特定组合联合使用的其它药物、化合物和/或材料、待治疗患者的年龄、性别、体重、病症、总体健康状况和在先病史、以及医学领域内熟知的类似因素。
配体结合分子的应用
在一些方面,本发明提供一种抑制、预防或治疗受试者中的新生血管形成以及由新生血管形成引起的疾病或病况的方法,该方法包括向受试者施用如本文所述的配体结合分子、其缀合物或药物组合物。所述新生血管形成包括视网膜新生血管形成和/或脉络膜新生血管形成;所述疾病或病况包括息肉状脉络膜血管病变、视网膜新生血管形成、与眼底渗漏有关的眼部病症。
在一些实施方案中,所述眼部病症选自老年黄斑变性、糖尿病性眼部病症、地图样萎缩、糖尿病性黄斑水肿(DME)、息肉状脉络膜血管病变、眼底纤维化病变、视网膜静脉阻塞相关病变、早产儿视网膜病变和黄斑毛细血管扩张。优选地,本文所述的包含配体结合分子的药物组合物通过滴眼、通过玻璃体注射、通过玻璃体内植入物从而被局部施用于受试者的眼睛。
在一些实施方案中,本文公开的配体结合分子、其缀合物或药物组合物可以以单次施用或多次施用的方式施用。优选地,通过单次施用即能实现期望的治疗效果,而无需与其他靶向治疗药物一起施用。
在一些实施方案中,本文公开的配体结合分子、其缀合物或药物组合物可以单独施用或者与一种或多种另外的治疗手段或试剂组合施用。例如,本文公开的配体结合分子、其缀合物或药物组合物可以与另外的治疗剂,例如化学治疗剂或抗癌药,或其他治疗方法联用实施。例如,在眼部疾病的治疗实施中,其他治疗方法包括激光光凝术、玻璃体切除术等。
在本文所述的配体结合分子用于治疗癌症的实施方案中,所述的另外的治疗剂包括抗体、双特异性抗体、多特异性抗体、化疗剂、细胞因子,也包括各种化学治疗剂,以及放射性治疗。
在这些实施方案的某些中,与一种或多种另外的治疗剂组合施用的本文公开的配体结合分子、其缀合物或药物组合物可以与一种或多种另外的治疗剂同时或顺序地或交替地施用。与另一种治疗剂“组合”施用的配体结合分子不必与该试剂同时或在相同的组合物中施用。即使在配体结合分子和第二种试剂经由不同途径施用的情况下,在本文中使用的短语也认为在另一种试剂之前或之后施用的配体结合分子与该试剂“组合”施用。在可能的情况下,根据另外的治疗剂产品信息表中列出的时间表或根据Physicians'DeskReference 2003(《Physicians'Desk Reference,57th Ed;Medical Economics Company;ISBN:1563634457;57th edition(November 2002))或本领域众所周知的方案施用与本文公开的配体结合组合施用的另外的治疗剂。
在一些方面,本发明还提供试剂盒,其包含所述配体结合分子、其缀合物或药物组合物。
本发明的有益效果
年龄相关黄斑病变(AMD)与糖尿病黄斑水肿(DME)可能与黄斑长期慢性光损伤、遗传、代谢等因素有关。炎症免疫、VEGF表达上调、氧化应激等因素,以及补体系统失调在AMD的发生发展中都产生影响。地图样萎缩是湿性AMD的最终发展形式之一。补体系统的激活及膜攻击复合物(MAC)的产生对AMD与DME的发病有重要影响。在本发明中,发明人通过将具有特定组成的生长因子结合结构域和补体抑制结构域组合,产生了具有协同技术效果的配体结合分子。在对生长因子结合和阻断方面,本发明的配体结合分子除了可以阻断VEGF-A,同时还能结合或中和VEGF-B、PlGF。在对补体抑制方面,本发明的配体结合分子直接将补体抑制物定位至补体相关疾病位点(需要VEGF拮抗的位点,例如黄斑病变部位)的策略可以提高对补体的抑制效率,同时可以避免由于系统性和长期性补体抑制带来的副作用。
具体如激光造模大鼠实验所验证的,采用本发明的组合分子,同时阻断生长因子以及补体激活途径,相比单用生长因子拮抗剂(Eylea)、单用补体拮抗剂以及二者联用,对四级光斑比例、光斑荧光渗漏面积均具有明显更优的疗效。
采用本发明的配体结合分子或包含其的药物组合物,比单用VEGF-A拮抗剂具有更加优异的疗效,从而一方面可以满足目前对VEGF-A单靶向无明显应答的治疗方法空缺,另一方面可以藉由更优的疗效从而减少注射次数,在得到最优疗效的同时明显降低患者负担,减少治疗不便,提高依从性,以及减少注射带来的眼内感染等危险。
序列汇总:
下表和随说明书一同提供的序列表中提供了本申请所涉及的蛋白和配体结合分子。
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实施例
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分比和份数按重量计。
实验材料和试剂:
Eylea:按照WO0075319公开的序列由泰州百英生物表达提供
实施例1-配体结合分子及其Fc融合蛋白的设计与表达
将CD59蛋白的片段(如SEQ ID NO:4的位置26-102所示)分别与VEGFR1的片段(如SEQ ID NO:1的位置132-230所示)、衍生自VEGFR2与VEGFR1的氨基酸序列(如SEQ ID NO:1的位置132-230与SEQ ID NO:2的位置225-327所示)构建在一起,使用单G4S连接子(AGGGGSG)进行连接,从而得到2种配体结合分子。进一步地,对CD59蛋白序列进行合理化设计(如SEQ ID NO:11所示),将其与衍生自VEGFR2与VEGFR1的氨基酸序列(如SEQ ID NO:1的位置132-230与SEQ ID NO:2的位置225-327所示)构建在一起,得到新的配体结合分子。
将所得配体结合分子均经由短的人造连接序列Gly-Pro-Gly(GPG)与人免疫球蛋白恒定结构域序列(Fc,如SEQ ID NO:5的Asp104-Lys330所示)连接构建在一起,得到配体结合分子的与Fc融合的蛋白序列,名称分别为LFV-036、LFV-035、LFV-050,它们的氨基酸序列分别如SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14所示,它们的蛋白结构组成如图1所示。
此外,在将CD59蛋白片段连接于衍生自VEGFR2与VEGFR1的氨基酸序列时,还分别尝试使用了不同长度的连接子,以对生产表达情况进行比较和选择。如上所述,LFV-035、LFV-036和LFV-050采用了单G4S连接子(AGGGGSG),除此外,还分别构建了无G4S连接子(AAA)、2×G4S连接子和3×G4S连接子,所得到的蛋白分别为LFV-048、LFV-049、LFV-041(具体见下面表1)。
上述Fc融合蛋白经基因合成、载体构建与抽提后瞬转CHO细胞(购自Gibco Life),先经过蛋白A亲和洗脱,再依SEC纯度情况选择是否使用分子筛进行二次精纯(全部过程由泰州百英生物完成),各个分子的信息及其表达情况如下面表1所示:
表1.
由上可见,使用单G4S连接子(AGGGGSG)为较优的选择,使用其他连接子的序列(LFV-048、LFV-049、LFV-041),蛋白A一步纯化后,目的主峰纯度占比均未达到30%以上,可开发性较差,具体各个分子的蛋白A一步纯化的SEC结果如图2所示。
此外,作为下面实施例5的大鼠脉络膜新生血管模型实验内的对照组分子,还将CD59蛋白片段(如SEQ ID NO:4的位置26-102所示)与Fc序列融合在一起并同样进行表达纯化,所构建的分子名称为LFV-038,其序列如SEQ ID NO:15所示。
实施例2-Fc融合蛋白对VEGF-A的VEGFR2结合阻断实验
500ng/孔的VEGFR2-Fc(购自Sinobio)分子4℃过夜包被,第二天用PBS洗板,加入BSA液室温封闭2小时,封闭期间,将各个融合蛋白分子(以Eylea作为对照)从高浓度到低浓度梯度稀释,然后与60ng/孔的VEGF-A165(购自Sinobio,带His标签)混匀,室温孵育30分钟,将VEGFR2-Fc板洗板,将孵育液加入其中,室温孵育结合1小时,PBST洗板,加入偶联辣根过氧化物酶的抗多组氨酸二抗,室温孵育结合1小时,PBST洗板,加入TMB显色,5%盐酸液终止,使用酶标仪读取450nm下的OD值。
结果如图3所示,可见各个Fc融合蛋白均具有显著的对VEGF A-VEGFR2结合的阻断能力,其中LFV-035、LFV-050较强,接近对照分子Eylea。
实施例3-Fc融合蛋白对VEGF-B的结合实验
200ng/孔的VEGF-B(购自ACROBiosystems公司)配制在PBS中,4°过夜包被,第二天用PBS洗板,加入1%BSA液室温封闭2小时,PBS洗板,将重组受体分子从高浓度到低浓度梯度稀释后加入各孔,室温、300rpm孵育1.5小时,使用PBST液洗板三次,加入偶联辣根过氧化物酶的羊抗人Fc二抗,室温、300rpm孵育1h,PBST液洗板三次,加入TMB进行显色,5%盐酸液终止,使用酶标仪读取450nm下的OD值。
结果如图4所示,可见LFV-035、LFV-036、LFV-050均展现出一定的对VEGF-B的结合能力,与对照分子Eylea基本一致。
实施例4-Fc融合蛋白对PlGF的结合实验
200ng/孔的PlGF(购自ACROBiosystems公司)配制在PBS中,4°过夜包被,第二天用PBS洗板,加入1%BSA液室温封闭2小时,PBS洗板,将重组受体分子从高浓度到低浓度梯度稀释后加入各孔,室温、300rpm孵育1.5小时,使用PBST液洗板三次,加入偶联辣根过氧化物酶的羊抗人Fc二抗,室温、300rpm孵育1h,PBST液洗板三次,加入TMB进行显色,5%盐酸液终止,使用酶标仪读取450nm下的OD值。
结果如图5所示,可见LFV-035、LFV-036、LFV-050均展现出一定的对PlGF的结合能力,其中LFV-035、LFV-050结合能力较优,与对照分子Eylea基本一致。
实施例5-激光诱导大鼠脉络膜新生血管及纤维化的治疗实验
49只Brown Norway大鼠,根据体重随机分为7个组,除模型对照组和Avastin组各为13只动物外,其余组各11只动物,雌雄兼有,分别为模型对照组(0.9%氯化钠)、Eylea组、LFV-038(CD59)单用组、组合治疗组(Eylea+LVF-038混合物)、LVF-036治疗组、Avastin治疗组和LVF-050治疗组。双眼玻璃体单次注射给药,给药体积4μL/眼,药物组浓度均为10mg/mL,即给药剂量40μg/眼。给药后24小时后,使用激光损伤大鼠视网膜外层Bruch膜进行脉络膜新生血管模型建模,可见到有气泡产生即提示Bruch膜被击破。首次给药当天定义为试验第1天。
试验期间,每天观察各组存活大鼠一般状态。在给药前,给药后第14、27天进行荧光造影和眼底照相,统计各组的四级荧光光斑个数,使用Heidelberg Eye explorer软件计算各个渗漏荧光或新生血管的面积,从而比较各组药效。
数据使用Stata/IC 15.0(Windows版)进行统计分析。四级荧光斑所占百分比、荧光素渗漏面积均采用均数±标准差(X±SD)进行描述。四级荧光斑所占百分比和荧光素渗漏面积越低,则表明候选药物的治疗效果越好。所有数据采用ANOVA或K-W法进行统计,当K-W法显示差异有统计学意义时(P≤0.05),则采用M-W法对组间差异进行两两比较。
结果如图6A-6B所示,可见LFV-038(CD59)单用疗效与模型对照组相比无显著差别,LFV-036在四级荧光占比统计结果中相比模型对照组具有一定治疗效果,在荧光渗漏面积结果统计中则差别不明显。Eylea与LFV-038组合使用时,大多呈现出比Eylea单用更好的治疗效果,且均呈现出比LFV-038更好的治疗效果。LFV-050组则具有所有组中最优的治疗效果,其不仅优于Eylea组和其他单药物治疗组,甚至还优于组合治疗组。
本领域技术人员将进一步认识到,在不脱离其精神或中心特征的情况下,本发明可以以其他具体形式来实施。由于本发明的前述描述仅公开了其示例性实施方案,应该理解的是,其他变化被认为是在本发明的范围内。因此,本发明不限于在此详细描述的特定实施方案。相反,应当参考所附权利要求来指示本发明的范围和内容。
序列表
<110> 苏州光度生物科技有限公司
香港光度生物有限公司
<120> 包含补体抑制结构域的多特异性配体结合分子及其用途
<130> IDC226007
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Asp Ser Gly Leu Ser Leu Pro Thr Ser Pro Val Ser Cys Met Glu
1190 1195 1200
Glu Glu Glu Val Cys Asp Pro Lys Phe His Tyr Asp Asn Thr Ala
1205 1210 1215
Gly Ile Ser Gln Tyr Leu Gln Asn Ser Lys Arg Lys Ser Arg Pro
1220 1225 1230
Val Ser Val Lys Thr Phe Glu Asp Ile Pro Leu Glu Glu Pro Glu
1235 1240 1245
Val Lys Val Ile Pro Asp Asp Asn Gln Thr Asp Ser Gly Met Val
1250 1255 1260
Leu Ala Ser Glu Glu Leu Lys Thr Leu Glu Asp Arg Thr Lys Leu
1265 1270 1275
Ser Pro Ser Phe Gly Gly Met Val Pro Ser Lys Ser Arg Glu Ser
1280 1285 1290
Val Ala Ser Glu Gly Ser Asn Gln Thr Ser Gly Tyr Gln Ser Gly
1295 1300 1305
Tyr His Ser Asp Asp Thr Asp Thr Thr Val Tyr Ser Ser Glu Glu
1310 1315 1320
Ala Glu Leu Leu Lys Leu Ile Glu Ile Gly Val Gln Thr Gly Ser
1325 1330 1335
Thr Ala Gln Ile Leu Gln Pro Asp Ser Gly Thr Thr Leu Ser Ser
1340 1345 1350
Pro Pro Val
1355
<210> 3
<211> 1363
<212> PRT
<213> 人
<400> 3
Met Gln Arg Gly Ala Ala Leu Cys Leu Arg Leu Trp Leu Cys Leu Gly
1 5 10 15
Leu Leu Asp Gly Leu Val Ser Gly Tyr Ser Met Thr Pro Pro Thr Leu
20 25 30
Asn Ile Thr Glu Glu Ser His Val Ile Asp Thr Gly Asp Ser Leu Ser
35 40 45
Ile Ser Cys Arg Gly Gln His Pro Leu Glu Trp Ala Trp Pro Gly Ala
50 55 60
Gln Glu Ala Pro Ala Thr Gly Asp Lys Asp Ser Glu Asp Thr Gly Val
65 70 75 80
Val Arg Asp Cys Glu Gly Thr Asp Ala Arg Pro Tyr Cys Lys Val Leu
85 90 95
Leu Leu His Glu Val His Ala Asn Asp Thr Gly Ser Tyr Val Cys Tyr
100 105 110
Tyr Lys Tyr Ile Lys Ala Arg Ile Glu Gly Thr Thr Ala Ala Ser Ser
115 120 125
Tyr Val Phe Val Arg Asp Phe Glu Gln Pro Phe Ile Asn Lys Pro Asp
130 135 140
Thr Leu Leu Val Asn Arg Lys Asp Ala Met Trp Val Pro Cys Leu Val
145 150 155 160
Ser Ile Pro Gly Leu Asn Val Thr Leu Arg Ser Gln Ser Ser Val Leu
165 170 175
Trp Pro Asp Gly Gln Glu Val Val Trp Asp Asp Arg Arg Gly Met Leu
180 185 190
Val Ser Thr Pro Leu Leu His Asp Ala Leu Tyr Leu Gln Cys Glu Thr
195 200 205
Thr Trp Gly Asp Gln Asp Phe Leu Ser Asn Pro Phe Leu Val His Ile
210 215 220
Thr Gly Asn Glu Leu Tyr Asp Ile Gln Leu Leu Pro Arg Lys Ser Leu
225 230 235 240
Glu Leu Leu Val Gly Glu Lys Leu Val Leu Asn Cys Thr Val Trp Ala
245 250 255
Glu Phe Asn Ser Gly Val Thr Phe Asp Trp Asp Tyr Pro Gly Lys Gln
260 265 270
Ala Glu Arg Gly Lys Trp Val Pro Glu Arg Arg Ser Gln Gln Thr His
275 280 285
Thr Glu Leu Ser Ser Ile Leu Thr Ile His Asn Val Ser Gln His Asp
290 295 300
Leu Gly Ser Tyr Val Cys Lys Ala Asn Asn Gly Ile Gln Arg Phe Arg
305 310 315 320
Glu Ser Thr Glu Val Ile Val His Glu Asn Pro Phe Ile Ser Val Glu
325 330 335
Trp Leu Lys Gly Pro Ile Leu Glu Ala Thr Ala Gly Asp Glu Leu Val
340 345 350
Lys Leu Pro Val Lys Leu Ala Ala Tyr Pro Pro Pro Glu Phe Gln Trp
355 360 365
Tyr Lys Asp Gly Lys Ala Leu Ser Gly Arg His Ser Pro His Ala Leu
370 375 380
Val Leu Lys Glu Val Thr Glu Ala Ser Thr Gly Thr Tyr Thr Leu Ala
385 390 395 400
Leu Trp Asn Ser Ala Ala Gly Leu Arg Arg Asn Ile Ser Leu Glu Leu
405 410 415
Val Val Asn Val Pro Pro Gln Ile His Glu Lys Glu Ala Ser Ser Pro
420 425 430
Ser Ile Tyr Ser Arg His Ser Arg Gln Ala Leu Thr Cys Thr Ala Tyr
435 440 445
Gly Val Pro Leu Pro Leu Ser Ile Gln Trp His Trp Arg Pro Trp Thr
450 455 460
Pro Cys Lys Met Phe Ala Gln Arg Ser Leu Arg Arg Arg Gln Gln Gln
465 470 475 480
Asp Leu Met Pro Gln Cys Arg Asp Trp Arg Ala Val Thr Thr Gln Asp
485 490 495
Ala Val Asn Pro Ile Glu Ser Leu Asp Thr Trp Thr Glu Phe Val Glu
500 505 510
Gly Lys Asn Lys Thr Val Ser Lys Leu Val Ile Gln Asn Ala Asn Val
515 520 525
Ser Ala Met Tyr Lys Cys Val Val Ser Asn Lys Val Gly Gln Asp Glu
530 535 540
Arg Leu Ile Tyr Phe Tyr Val Thr Thr Ile Pro Asp Gly Phe Thr Ile
545 550 555 560
Glu Ser Lys Pro Ser Glu Glu Leu Leu Glu Gly Gln Pro Val Leu Leu
565 570 575
Ser Cys Gln Ala Asp Ser Tyr Lys Tyr Glu His Leu Arg Trp Tyr Arg
580 585 590
Leu Asn Leu Ser Thr Leu His Asp Ala His Gly Asn Pro Leu Leu Leu
595 600 605
Asp Cys Lys Asn Val His Leu Phe Ala Thr Pro Leu Ala Ala Ser Leu
610 615 620
Glu Glu Val Ala Pro Gly Ala Arg His Ala Thr Leu Ser Leu Ser Ile
625 630 635 640
Pro Arg Val Ala Pro Glu His Glu Gly His Tyr Val Cys Glu Val Gln
645 650 655
Asp Arg Arg Ser His Asp Lys His Cys His Lys Lys Tyr Leu Ser Val
660 665 670
Gln Ala Leu Glu Ala Pro Arg Leu Thr Gln Asn Leu Thr Asp Leu Leu
675 680 685
Val Asn Val Ser Asp Ser Leu Glu Met Gln Cys Leu Val Ala Gly Ala
690 695 700
His Ala Pro Ser Ile Val Trp Tyr Lys Asp Glu Arg Leu Leu Glu Glu
705 710 715 720
Lys Ser Gly Val Asp Leu Ala Asp Ser Asn Gln Lys Leu Ser Ile Gln
725 730 735
Arg Val Arg Glu Glu Asp Ala Gly Arg Tyr Leu Cys Ser Val Cys Asn
740 745 750
Ala Lys Gly Cys Val Asn Ser Ser Ala Ser Val Ala Val Glu Gly Ser
755 760 765
Glu Asp Lys Gly Ser Met Glu Ile Val Ile Leu Val Gly Thr Gly Val
770 775 780
Ile Ala Val Phe Phe Trp Val Leu Leu Leu Leu Ile Phe Cys Asn Met
785 790 795 800
Arg Arg Pro Ala His Ala Asp Ile Lys Thr Gly Tyr Leu Ser Ile Ile
805 810 815
Met Asp Pro Gly Glu Val Pro Leu Glu Glu Gln Cys Glu Tyr Leu Ser
820 825 830
Tyr Asp Ala Ser Gln Trp Glu Phe Pro Arg Glu Arg Leu His Leu Gly
835 840 845
Arg Val Leu Gly Tyr Gly Ala Phe Gly Lys Val Val Glu Ala Ser Ala
850 855 860
Phe Gly Ile His Lys Gly Ser Ser Cys Asp Thr Val Ala Val Lys Met
865 870 875 880
Leu Lys Glu Gly Ala Thr Ala Ser Glu His Arg Ala Leu Met Ser Glu
885 890 895
Leu Lys Ile Leu Ile His Ile Gly Asn His Leu Asn Val Val Asn Leu
900 905 910
Leu Gly Ala Cys Thr Lys Pro Gln Gly Pro Leu Met Val Ile Val Glu
915 920 925
Phe Cys Lys Tyr Gly Asn Leu Ser Asn Phe Leu Arg Ala Lys Arg Asp
930 935 940
Ala Phe Ser Pro Cys Ala Glu Lys Ser Pro Glu Gln Arg Gly Arg Phe
945 950 955 960
Arg Ala Met Val Glu Leu Ala Arg Leu Asp Arg Arg Arg Pro Gly Ser
965 970 975
Ser Asp Arg Val Leu Phe Ala Arg Phe Ser Lys Thr Glu Gly Gly Ala
980 985 990
Arg Arg Ala Ser Pro Asp Gln Glu Ala Glu Asp Leu Trp Leu Ser Pro
995 1000 1005
Leu Thr Met Glu Asp Leu Val Cys Tyr Ser Phe Gln Val Ala Arg
1010 1015 1020
Gly Met Glu Phe Leu Ala Ser Arg Lys Cys Ile His Arg Asp Leu
1025 1030 1035
Ala Ala Arg Asn Ile Leu Leu Ser Glu Ser Asp Val Val Lys Ile
1040 1045 1050
Cys Asp Phe Gly Leu Ala Arg Asp Ile Tyr Lys Asp Pro Asp Tyr
1055 1060 1065
Val Arg Lys Gly Ser Ala Arg Leu Pro Leu Lys Trp Met Ala Pro
1070 1075 1080
Glu Ser Ile Phe Asp Lys Val Tyr Thr Thr Gln Ser Asp Val Trp
1085 1090 1095
Ser Phe Gly Val Leu Leu Trp Glu Ile Phe Ser Leu Gly Ala Ser
1100 1105 1110
Pro Tyr Pro Gly Val Gln Ile Asn Glu Glu Phe Cys Gln Arg Leu
1115 1120 1125
Arg Asp Gly Thr Arg Met Arg Ala Pro Glu Leu Ala Thr Pro Ala
1130 1135 1140
Ile Arg Arg Ile Met Leu Asn Cys Trp Ser Gly Asp Pro Lys Ala
1145 1150 1155
Arg Pro Ala Phe Ser Glu Leu Val Glu Ile Leu Gly Asp Leu Leu
1160 1165 1170
Gln Gly Arg Gly Leu Gln Glu Glu Glu Glu Val Cys Met Ala Pro
1175 1180 1185
Arg Ser Ser Gln Ser Ser Glu Glu Gly Ser Phe Ser Gln Val Ser
1190 1195 1200
Thr Met Ala Leu His Ile Ala Gln Ala Asp Ala Glu Asp Ser Pro
1205 1210 1215
Pro Ser Leu Gln Arg His Ser Leu Ala Ala Arg Tyr Tyr Asn Trp
1220 1225 1230
Val Ser Phe Pro Gly Cys Leu Ala Arg Gly Ala Glu Thr Arg Gly
1235 1240 1245
Ser Ser Arg Met Lys Thr Phe Glu Glu Phe Pro Met Thr Pro Thr
1250 1255 1260
Thr Tyr Lys Gly Ser Val Asp Asn Gln Thr Asp Ser Gly Met Val
1265 1270 1275
Leu Ala Ser Glu Glu Phe Glu Gln Ile Glu Ser Arg His Arg Gln
1280 1285 1290
Glu Ser Gly Phe Ser Cys Lys Gly Pro Gly Gln Asn Val Ala Val
1295 1300 1305
Thr Arg Ala His Pro Asp Ser Gln Gly Arg Arg Arg Arg Pro Glu
1310 1315 1320
Arg Gly Ala Arg Gly Gly Gln Val Phe Tyr Asn Ser Glu Tyr Gly
1325 1330 1335
Glu Leu Ser Glu Pro Ser Glu Glu Asp His Cys Ser Pro Ser Ala
1340 1345 1350
Arg Val Thr Phe Phe Thr Asp Asn Ser Tyr
1355 1360
<210> 4
<211> 128
<212> PRT
<213> 人
<400> 4
Met Gly Ile Gln Gly Gly Ser Val Leu Phe Gly Leu Leu Leu Val Leu
1 5 10 15
Ala Val Phe Cys His Ser Gly His Ser Leu Gln Cys Tyr Asn Cys Pro
20 25 30
Asn Pro Thr Ala Asp Cys Lys Thr Ala Val Asn Cys Ser Ser Asp Phe
35 40 45
Asp Ala Cys Leu Ile Thr Lys Ala Gly Leu Gln Val Tyr Asn Lys Cys
50 55 60
Trp Lys Phe Glu His Cys Asn Phe Asn Asp Val Thr Thr Arg Leu Arg
65 70 75 80
Glu Asn Glu Leu Thr Tyr Tyr Cys Cys Lys Lys Asp Leu Cys Asn Phe
85 90 95
Asn Glu Gln Leu Glu Asn Gly Gly Thr Ser Leu Ser Glu Lys Thr Val
100 105 110
Leu Leu Leu Val Thr Pro Phe Leu Ala Ala Ala Trp Ser Leu His Pro
115 120 125
<210> 5
<211> 330
<212> PRT
<213> 人
<400> 5
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 6
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> LFV-036
<400> 6
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Phe Asn
35 40 45
Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Ala Gly Gly
65 70 75 80
Gly Gly Ser Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
85 90 95
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
100 105 110
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
115 120 125
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
130 135 140
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
145 150 155 160
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
165 170 175
Gln Thr Asn Thr Ile Ile
180
<210> 7
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> LFV-035
<400> 7
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Phe Asn
35 40 45
Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Ala Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
85 90 95
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
100 105 110
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
115 120 125
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
130 135 140
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
145 150 155 160
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
165 170 175
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
180 185 190
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
195 200 205
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
210 215 220
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
225 230 235 240
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
245 250 255
Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu
260 265 270
Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
275 280 285
<210> 8
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> LFV-050
<400> 8
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Ala Asn
35 40 45
Asp Val Leu Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Ala Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
85 90 95
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
100 105 110
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
115 120 125
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
130 135 140
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
145 150 155 160
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
165 170 175
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
180 185 190
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
195 200 205
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
210 215 220
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
225 230 235 240
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
245 250 255
Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu
260 265 270
Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys
275 280 285
<210> 9
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> LFV-036
<400> 9
Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met
1 5 10 15
Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn
20 25 30
Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp
35 40 45
Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn
50 55 60
Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn
65 70 75 80
Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr
85 90 95
Ile Ile
<210> 10
<211> 202
<212> PRT
<213> 人工序列
<220>
<223> LFV-035
<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> 77
<212> PRT
<213> 人工序列
<220>
<223> LFV-050
<400> 11
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Ala Asn
35 40 45
Asp Val Leu Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn
65 70 75
<210> 12
<211> 412
<212> PRT
<213> 人工序列
<220>
<223> LFV-036
<400> 12
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Phe Asn
35 40 45
Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Ala Gly Gly
65 70 75 80
Gly Gly Ser Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
85 90 95
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
100 105 110
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
115 120 125
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
130 135 140
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
145 150 155 160
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
165 170 175
Gln Thr Asn Thr Ile Ile Gly Pro Gly Asp Lys Thr His Thr Cys Pro
180 185 190
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
195 200 205
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
210 215 220
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
225 230 235 240
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
245 250 255
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
260 265 270
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
275 280 285
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
290 295 300
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
305 310 315 320
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
325 330 335
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
340 345 350
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
355 360 365
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
370 375 380
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
385 390 395 400
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
405 410
<210> 13
<211> 516
<212> PRT
<213> 人工序列
<220>
<223> LFV-035
<400> 13
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Phe Asn
35 40 45
Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Ala Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
85 90 95
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
100 105 110
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
115 120 125
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
130 135 140
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
145 150 155 160
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
165 170 175
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
180 185 190
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
195 200 205
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
210 215 220
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
225 230 235 240
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
245 250 255
Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu
260 265 270
Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly Pro
275 280 285
Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
290 295 300
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
305 310 315 320
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
325 330 335
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
340 345 350
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
355 360 365
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
370 375 380
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
385 390 395 400
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
405 410 415
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
420 425 430
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
435 440 445
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
450 455 460
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
465 470 475 480
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
485 490 495
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
500 505 510
Ser Pro Gly Lys
515
<210> 14
<211> 516
<212> PRT
<213> 人工序列
<220>
<223> LFV-050
<400> 14
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Ala Asn
35 40 45
Asp Val Leu Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Ala Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
85 90 95
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
100 105 110
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
115 120 125
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
130 135 140
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
145 150 155 160
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
165 170 175
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
180 185 190
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
195 200 205
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
210 215 220
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
225 230 235 240
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
245 250 255
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Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Gly Pro
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Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
290 295 300
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
305 310 315 320
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
325 330 335
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
340 345 350
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
355 360 365
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
370 375 380
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
385 390 395 400
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
405 410 415
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
420 425 430
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
435 440 445
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
450 455 460
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
465 470 475 480
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
485 490 495
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
500 505 510
Ser Pro Gly Lys
515
<210> 15
<211> 309
<212> PRT
<213> 人工序列
<220>
<223> LFV-038
<400> 15
Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala
1 5 10 15
Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly
20 25 30
Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Phe Asn
35 40 45
Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys
50 55 60
Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Glu Pro Lys
65 70 75 80
Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
85 90 95
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
100 105 110
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
115 120 125
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
130 135 140
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
145 150 155 160
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
165 170 175
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
180 185 190
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
195 200 205
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
210 215 220
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
225 230 235 240
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
245 250 255
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
260 265 270
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
275 280 285
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
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Leu Ser Pro Gly Lys
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<210> 16
<211> 7
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<213> 人工序列
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Ala Gly Gly Gly Gly Ser Gly
1 5
Claims (39)
1.一种配体结合分子,其包含至少一个生长因子结合结构域和至少一个补体抑制结构域,所述生长因子结合结构域包含来源于VEGFR1、VEGFR2和VEGFR3蛋白中的任意一种或多种的氨基酸序列,所述补体抑制结构域包含来源于CD59蛋白的氨基酸序列。
2.权利要求1所述的配体结合分子,其中所述生长因子结合结构域包含与选自以下的任一种氨基酸序列具有至少95%同一性的氨基酸序列:
(a)如SEQ ID NO:9所示的氨基酸序列;
(b)嵌合氨基酸序列,所述嵌合氨基酸序列包含SEQ ID NO:1的位置132-230限定的氨基酸序列可操作地连接于SEQ ID NO:2的位置225-327限定的氨基酸序列。
3.权利要求1所述的配体结合分子,其中所述嵌合氨基酸序列包含如SEQ ID NO:10所示的氨基酸序列。
4.前述权利要求中任一项所述的配体结合分子,其中所述补体抑制结构域包含与SEQID NO:4的位置26-102所限定的氨基酸序列具有至少95%同一性的氨基酸序列。
5.权利要求4所述的配体结合分子,其中所述补体抑制结构域包含如SEQ ID NO:11所示的氨基酸序列。
6.前述权利要求中任一项的配体结合分子,其包含:
(a)SEQ ID NO:6所示的氨基酸序列或与SEQ ID NO:6所示的氨基酸序列相比具有不超过10个氨基酸的添加、缺失或取代的氨基酸序列;
(b)SEQ ID NO:7所示的氨基酸序列或与SEQ ID NO:7所示的氨基酸序列相比具有不超过10个氨基酸的添加、缺失或取代的氨基酸序列;
(c)SEQ ID NO:8所示的氨基酸序列或与SEQ ID NO:8所示的氨基酸序列相比具有不超过10个氨基酸的添加、缺失或取代的氨基酸序列。
7.前述权利要求中任一项的配体结合分子,其还包含免疫球蛋白的Fc区,所述免疫球蛋白选自IgA、IgM、IgE、IgD和IgG,包括IgG1、IgG2、IgG3、IgG4。
8.权利要求7所述的配体结合分子,其中所述Fc区为人IgG1的Fc区或其变体。
9.权利要求7-8中任一项的配体结合分子,其包含:
(a)补体抑制结构域可操作地连接于生长因子结合结构域的N末端,且生长因子结合结构域的C末端可操作地连接于Fc区;
(b)生长因子结合结构域可操作地连接于补体抑制结构域的N末端,且补体抑制结构域的C末端可操作地连接于Fc区;
(c)补体抑制结构域可操作地连接于Fc区的N末端,且Fc区的C末端可操作地连接于生长因子结合结构域;或
(d)生长因子结合结构域可操作地连接于Fc区的N末端,且Fc区的C末端可操作地连接于补体抑制结构域。
10.权利要求9所述的配体结合分子,其中所述可操作地连接为直接连接或通过接头(例如肽接头包含G4S系列或GPG肽)连接。
11.权利要求10所述的配体结合分子,其中所述接头长度为5-8个氨基酸残基,且包含1个G4S连接子,例如所使用的接头序列为SEQ ID NO:16所示的序列。
12.权利要求7-11中任一项的配体结合分子,其包含如SEQ ID NO:12、13或14所示的氨基酸序列。
13.前述权利要求中任一项的配体结合分子,其中所述配体结合分子能抑制或阻断VEGF-A、VEGF-B和PlGF中的至少一种与其相应受体的结合。
14.权利要求13所述的配体结合分子,其中所述VEGF-A、VEGF-B和PlGF来自或衍生自人、小鼠、大鼠或食蟹猴。
15.前述权利要求中任一项所述的配体结合分子,其还包含信号肽。
16.一种融合蛋白,其包含前述权利要求中任一项所述的配体结合分子可操作地连接于异源性肽。
17.权利要求16所述的融合蛋白,其中所述异源性肽选自以下:人源受体蛋白胞外结构域(ECD)或其截短及重组多肽;抗体可变区片段及其组合,如抗体Fab、单链抗体(scFv)、纳米抗体(nanobody)、人重链可变区单域抗体(VH)、活性多肽及蛋白适配体。
18.权利要求17所述的融合蛋白,其中所述异源性肽为靶向VEGF-A、VEGF-B、VEGF-C、VEGF-D、PDGF-AA、PDGF-AB、PDGF-BB、PDGF-CC、PDGF-DD、Ang-2、TGF-β、FGF(成纤维细胞生长因子)、CTGF(结缔组织生长因子)、EGF(表皮生长因子)、S1P、Galectin、或Decorin的异源性肽。
19.权利要求16-18中任一项所述的融合蛋白,其中所述配体结合分子直接连接或通过接头连接于所述异源性肽的N末端或C末端。
20.一种缀合物,其包含权利要求1-15中任一项所述的配体结合分子或权利要求16-19中任一项所述的融合蛋白缀合于至少一个选自以下的模块:修饰模块、毒素(例如化学治疗剂)、可检测标记(例如放射性同位素、镧系元素、发光标记、荧光标记或酶-底物标记)或纯化模块。
21.权利要求20所述的缀合物,其中所述修饰模块是聚乙二醇模块,任选地所述聚乙二醇模块附接于所述配体结合分子的氨基末端。
22.一种分离的核酸分子,其包含编码权利要求1-15中任一项所述的配体结合分子或权利要求16-19中任一项所述的融合蛋白的多核苷酸序列。
23.一种载体,其包含权利要求22所述的核酸分子。
24.权利要求23所述的载体,其中所述载体选自慢病毒载体、腺相关病毒载体、腺病毒载体、脂质体载体及其任意组合。
25.权利要求24所述的载体,其中所述载体为复制缺陷型腺病毒载体,其中所述核酸分子可操作地连接至启动子并且两侧具有腺病毒多核苷酸序列。
26.一种宿主细胞,其经过权利要求22所述的核酸分子或权利要求23-25中任一项所述的载体转化或转染。
27.权利要求26所述的宿主细胞,其为真核细胞,例如中国仓鼠卵巢(CHO)细胞或人细胞。
28.一种制备配体结合分子的方法,其包括以下步骤:
-在适宜的条件下培养权利要求26或27所述的宿主细胞以表达所述配体结合分子;并
-从宿主细胞分离所述配体结合分子。
29.一种药物组合物,其包含权利要求1-15中任一项所述的配体结合分子或权利要求16-19中任一项所述的融合蛋白或权利要求22所述的核酸分子,以及药学上可接受的载剂。
30.权利要求29所述的药物组合物,其为固体、糊剂、软膏、凝胶、液体、气雾剂、喷雾剂、聚合物、薄膜、乳液或混悬液形式。
31.权利要求29或30所述的药物组合物,其被配制成用于局部施用、玻璃体内注射或玻璃体内植入施用。
32.权利要求1-15中任一项所述的配体结合分子或权利要求16-19中任一项所述的融合蛋白在制备用于治疗受试者中新生血管形成以及由新生血管形成引起的疾病或病况的药物中的用途。
33.权利要求32的用途,其中所述新生血管形成为视网膜新生血管形成和/或脉络膜新生血管形成。
34.权利要求32或33的用途,其中所述药物还用于抑制受试者中的补体过度活化以及由补体过度活化引起的疾病或病况。
35.权利要求32-34中任一项的用途,其中所述疾病或病况选自脉络膜血管病变或新生、视网膜血管新生、和与眼底渗漏有关的眼部病症。
36.权利要求35的用途,其中所述疾病选自地图样萎缩、老年黄斑变性、糖尿病性眼部病症(例如糖尿病性黄斑水肿)、息肉状脉络膜血管病变、眼底纤维化病变、视网膜静脉阻塞相关病变、早产儿视网膜病变和黄斑毛细血管扩张。
37.根据权利要求32-36中任一项所述的用途,其中所述药物被局部施用于所述受试者的眼睛。
38.根据权利要求37所述的用途,其中通过玻璃体内注射或通过玻璃体内植入物施用来施用所述药物。
39.一种试剂盒,其包含权利要求1-15中任一项所述的配体结合分子或权利要求16-19中任一项所述的融合蛋白或权利要求29-31中任一项所述的药物组合物。
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CN117467025B (zh) * | 2023-12-28 | 2024-04-16 | 上海鼎新基因科技有限公司 | 一种抗vegf和补体双功能融合蛋白及其应用 |
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