CN115707716A - 一种TGF-β/VEGF双功能抗体融合蛋白 - Google Patents
一种TGF-β/VEGF双功能抗体融合蛋白 Download PDFInfo
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Abstract
本发明提供了一种TGF‑β/VEGF双功能抗体融合蛋白。本发明的双功能抗体融合蛋白为两个单体形成的二聚体,每个单体包含:第一结合结构域Z1;和第二结合结构域Z2;其中,所述第一结合结构域特异性结合靶分子TGF‑β;所述第二结合结构域特异性结合靶分子VEGF。本发明的双功能抗体融合蛋白能同时阻断VEGF和TGF‑β信号通路,对有效地治疗CNV,PVR和AMD等眼科疾病,以及对于肿瘤的治疗具有重要的临床意义。
Description
技术领域
本发明涉及融合蛋白技术领域,更具体地,涉及一种TGF-β/VEGF双功能抗体融合蛋白。
背景技术
起因于脉络膜新生血管形成(CNV)的渗出型老化相关性黄斑变性(AMD),在发达国家中是导致高度视力障碍的主要原因之一。目前已得到的证据显示,血管内皮生长因子(VEGFs)在CNV的发生中扮演中心角色,抑制VEGF产生的化合物或抑制VEGF信号传导途径的化合物可以抑制CNV。近年来,与包含光线力学疗法在内的传统治疗方法相比,抗VEGF抗体显示出更高的治疗有效性。抗VEGF药物已经成为针对CNV、AMD等药物疗法的主要选择。目前,已上市的主要抗VEGF药物给药频次为2-4周,多次反复进行玻璃体注射,给患者带来极大的心理与生理负担。因此,本领域迫切需要开发一种能更为长效的针对VEGF、并且能够用于治疗CNV,AMD等眼科疾病的药物。除此之外,VEGFs也在角膜新生血管形成中起着重要作用,一种治疗角膜新生血管性疾病(如角膜碱烧伤)的策略是抑制VEGF活性。
血管内皮生长因子(VEGFs)家族中,VEGF-A165(以下简称VEGF)是最丰富活跃的亚型。VEGF通过与II型受体VEGFR2结合,激活信号通路发生一系列级联反应,促进新生血管形成并维持其完整性。但I型受体VEGFR1与VEGF结合的能力远大于VEGFR2,发生作用部位主要是VEGFR1的胞外区D2结构域。VEGFR1-D2通过竞争结合VEGF,阻断VEGFR2与VEGF结合,从而阻断信号通路,抑制内皮细胞增殖与血管生成。
转化生长因子-β(transforming growth factor-β,TGF-β)属于调节细胞生长和分化的TGF-β超家族,是一种多功能细胞因子。高水平的TGF-β对视网膜色素上皮(RPE)的影响广泛,在增殖性玻璃体视网膜病变(PVR)和AMD等眼科疾病的发病机制中发挥重要作用。TGF-β通过与其受体复合物结合传递信号,诱导了SMAD2和SMAD3的磷酸化,激活下游效应基因,其中包括血管内皮生长因子A(VEGFA),从而起到促进血管新生的作用。此外,TGF-β促进上皮细胞向间充质转化,减弱视网膜屏障细胞连接的紧密性,增加平滑肌肌动蛋白表达,增强纤维性RPE细胞的收缩特性,导致视网膜脱离风险增强。
另一方面,VEGF信号通路与肿瘤新生内皮细胞的迁移、增殖、生存有关,在肿瘤周围血管新生过程中具有重要的作用,与机体多种常见肿瘤的发病及肿瘤的转移有着密切的关系。TGF-β信号可作用于肿瘤微环境中的免疫细胞。一方面,分泌的TGF-β会抑制效应性T细胞和天然杀伤细胞(NK)的细胞毒性,这就减弱了肿瘤微环境中固有免疫细胞的抗肿瘤能力;另外,TGF-β表达上调,也会促进VEGF-A等因子的分泌,刺激新生血管生成,从而为癌细胞的生长和转移提供助力。近期的研究还表明,TGF-β信号通路还与肿瘤细胞的耐药性相关。
因此,一种同时阻断VEGF和TGF-β信号通路的药物,在治疗CNV,PVR和AMD等眼科疾病,以及***上具有临床潜力。亟待开发一种同时靶向VEGF和TGF-β的双功能药物。
发明内容
本发明的目的在于提供一种TGF-β/VEGF双功能抗体融合蛋白。
在本发明的第一方面,提供了一种双功能融合蛋白,所述双功能融合蛋白为两个单体形成的二聚体,每个单体包含:
第一结合结构域Z1;和
第二结合结构域Z2;
其中,所述第一结合结构域特异性结合靶分子TGF-β;
所述第二结合结构域特异性结合靶分子VEGF。
在另一优选例中,所述Z1为特异性结合TGF-β的抗体或抗体片段。
在另一优选例中,所述的抗体包括:动物源抗体(如鼠源抗体)、嵌合抗体、人源化抗体。
在另一优选例中,所述的抗体片段包含重链可变区和轻链可变区。
在另一优选例中,所述的抗体片段包含单链可变区片段(scFv)、双链可变区片段(dcFv)。
在另一优选例中,所述Z2为特异性结合VEGF的多肽片段。
在另一优选例中,所述VEGF的多肽片段衍生自VEGF受体。
在另一优选例中,所述Z2为I型VEGF受体(VEGFR1)的胞外区。
在另一优选例中,所述Z1和所述Z2通过接头或肽键相连。
在另一优选例中,所述接头为柔性接头。
在另一优选例中,所述的柔性接头包括5-30个氨基酸,较佳地10-25个氨基酸。
在另一优选例中,所述的柔性肽接头包括1-6个G4S。
在另一优选例中,Z1为抗体,且所述的接头为(G4S)n,其中,n为正整数(例如1、2、3、4、5或6),较佳地,n=2或4。
在另一优选例中,Z1为抗TGF-β单克隆抗体,并且Z2通过接头连接在Z1的选自下组的位置:重链的N端、重链的C端、轻链的N端、轻链的C端或其组合。
在另一优选例中,Z1为抗TGF-β单克隆抗体,并且Z2通过接头连接在Z1的重链恒定区末端。
在另一优选例中,Z1为抗TGF-β单克隆抗体,并且Z2通过接头连接在Z1的重链可变区末端。
在另一优选例中,Z1为抗TGF-β单克隆抗体,并且Z2通过接头连接在Z1的轻链恒定区末端。
在另一优选例中,所述的双功能融合蛋白中的每个单体从N端到C端具有如式I所示的结构:
其中,
T1、T2、T3各自独立地为无或I型VEGF受体(VEGFR1)的胞外区,且至少一个不为无;
L1、L2、L3各自独立地为无或键或接头元件;
VL代表抗TGF-β抗体的轻链可变区;
CL代表抗TGF-β抗体的轻链恒定区;
VH代表抗TGF-β抗体的重链可变区;
CH代表抗TGF-β抗体的重链恒定区;
“~”代表二硫键或共价键;
“-”代表肽键;
其中,所述双功能融合蛋白具有同时结合VEGF以及结合TGF-β的活性。
在另一优选例中,所述的“~”为重链或轻链间的一个或多个链间二硫键。
在另一优选例中,所述的L1、L2、L3各自独立地为(G4S)2、(G4S)3、或(G4S)4。
在另一优选例中,所述的T2、T3、L2和L3为无。
在另一优选例中,T1为I型VEGF受体的胞外区。
在另一优选例中,所述的抗TGF-β抗体为单克隆抗体。
在另一优选例中,所述的抗TGF-β抗体为人源化抗体。
在另一优选例中,所述的抗TGF-β抗体为IgG类抗体。
在另一优选例中,所述抗TGF-β抗体的重链氨基酸序列如SEQ ID NO:13所示,所述抗TGF-β抗体的轻链氨基酸序列如SEQ ID NO:9所示。
在另一优选例中,所述的融合蛋白选自下组:
(1)所述融合蛋白的重链氨基酸序列如SEQ ID NO:1所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:3所示;
(2)所述融合蛋白的重链氨基酸序列如SEQ ID NO:5所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:3所示;
(3)所述融合蛋白的重链氨基酸序列如SEQ ID NO:7所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:9所示;
(4)所述融合蛋白的重链氨基酸序列如SEQ ID NO:11所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:9所示;
(5)所述融合蛋白的重链氨基酸序列如SEQ ID NO:13所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:14所示;或
(6)将(1)至(5)中的氨基酸序列经过一个或多个氨基酸残基的取代、缺失或添加而形成的,且具有同时结合VEGF以及结合TGF-β的活性的由(1)至(5)衍生的多肽。
在本发明的第二方面,提供了一种多核苷酸分子,所述多核苷酸分子编码根据在本发明的第一方面所述的融合蛋白。
在本发明的第三方面,提供了一种表达载体,所述表达载体含有根据本发明的第二方面所述的多核苷酸分子。
在本发明的第四方面,提供了一种宿主细胞,所述宿主细胞含有根据本发明的第三方面所述的表达载体。
在本发明的第五方面,提供了一种根据本发明的第一方面所述的融合蛋白的制备方法,其特征在于,所述制备方法包括以下步骤:
a)在表达条件下,培养根据本发明的第四方面所述的宿主细胞,从而表达双功能融合蛋白;
b)分离并纯化步骤a)所述的融合蛋白。
在本发明的第六方面,提供了一种药物组合物,其特征在于,所述药物组合物包含有效量的根据本发明的第一方面所述的融合蛋白和一种或多种药学上可接受的载体、稀释剂或赋形剂。
在另一优选例中,所述药物组合物为单元剂型。
在另一优选例中,所述药物组合物还包括其他治疗眼科疾病的药物。
在另一优选例中,所述药物组合物的剂型包括胃肠给药剂型或胃肠外给药剂型。
在另一优选例中,所述的胃肠外给药剂型包括玻璃体注射、静脉注射、静脉滴注、皮下注射、局部注射、肌肉注射、瘤内注射、腹腔内注射、颅内注射、或腔内注射。
在本发明的第七方面,提供了一种根据本发明的第一方面所述的融合蛋白、或根据本发明的第六方面所述的药物组合物在制备治疗眼科疾病的药物中的用途。
在另一优选例中,所述眼科疾病选自:渗出型老化相关性黄斑变性(AMD)、脉络膜新生血管形成(CNV)、增殖性玻璃体视网膜病变(PVR)、角膜新生血管性疾病。
在另一优选例中,所述眼科疾病为角膜碱烧伤。
在本发明的第八方面,提供了一种根据本发明的第一方面所述的融合蛋白、或根据本发明的第六方面所述的药物组合物在制备***的药物中的用途。
在另一优选例中,所述肿瘤为胰腺癌。
在本发明的第九方面,提供了一种治疗眼科疾病或肿瘤的方法,所述方法包括向有需要的受试者施用根据本发明的第一方面所述的融合蛋白、或其免疫偶联物、或根据本发明的第六方面所述的药物组合物。
在本发明的第十方面,提供了一种免疫偶联物,所述免疫偶联物包括:
(a)如本发明第一方面所述的融合蛋白;和
(b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶。
在另一优选例中,所述偶联物部分选自:荧光或发光标记物、放射性标记物、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶、放射性核素、生物毒素、细胞因子(如IL-2等)。
在另一优选例中,所述的免疫偶联物包括抗体-药物偶联物(ADC)。
在另一优选例中,所述的免疫偶联物用于制备治疗眼科疾病的药物组合物。
在本发明的第十一方面,提供了一种如本发明的第十方面所述的免疫偶联物的用途,用于制备治疗眼科疾病或肿瘤的药物组合物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了抗体融合蛋白TV01,TV03结构示意图如图1A,抗体融合蛋白TV02,TV04结构示意图如图1B,抗体融合蛋白TV05结构示意图如图1C。
图2显示了HPLC检测纯化后的蛋白。
图3显示了ELISA检测抗TGF-β/VEGF双功能融合蛋白与TGF-β1的亲和力。
图4显示了SMAD3报告基因抑制实验。
图5显示了TGF-β/VEGF双功能融合蛋白阻断VEGF与受体KDR结合的细胞实验。
图6显示了抗TGF-β/VEGF双功能融合蛋白在碱烧伤角膜新生血管模型中的抗血管生成作用。
图7显示了抗TGF-β/VEGF双功能融合蛋白在基质胶血管生成模型中的抗血管生成作用。
图8显示了抗TGF-β/VEGF双功能融合蛋白在人胰腺癌BxPC-3裸小鼠移植瘤模型上的抗肿瘤作用。
具体实施方式
本发明人经过广泛而深入地研究,首次构建了一种抗TGF-β/VEGF的双功能融合蛋白,其包括抗TGF-β抗体部分以及I型VEGF受体(VEGFR1)的胞外区。实验结果表明,本发明的双功能融合蛋白具有良好的物理稳定性,能够有效阻断VEGF与受体KDR结合,在小鼠碱烧伤角膜新生血管模型中能显著抑制角膜新生血管的形成,在小鼠基质胶血管生成模型中能显著抑制新生血管的形成。此外,在人胰腺癌的小鼠肿瘤模型上,本发明的双功能融合蛋白能够显著地抑制肿瘤生长,具有重要的临床应用前景。在此基础上完成了本发明。
术语
本发明中,术语“融合蛋白”是指由两个或多个相同或不同的多肽序列融合得到的新的多肽序列。术语“融合”是指由肽键直接连接或借助一个或多个接头有效连接。术语“接头”是指可以连接两个多肽序列的短肽,一般是长度为2-30个氨基酸的肽。
本发明中,术语“抗体(Antibody,缩写Ab)”是有相同结构特征的约150000道尔顿的异四聚糖蛋白,其由两条相同的轻链(L)和两条相同的重链(H)组成。每条重链的一端有可变区(VH),其后是恒定区,重链恒定区由三个结构域CH1、CH2、以及CH3构成。每条轻链的一端有可变区(VL),另一端有恒定区,轻链恒定区包括一个结构域CL;轻链的恒定区与重链恒定区的CH1结构域配对,轻链的可变区与重链的可变区配对。恒定区不直接参与抗体与抗原的结合,但是它们表现出不同的效应功能,例如参与抗体依赖的细胞介导的细胞毒性作用(ADCC,antibody-dependent cell-mediated cytotoxicity)等。重链恒定区包括IgG1、IgG2、IgG3、IgG4亚型;轻链恒定区包括κ(Kappa)或λ(Lambda)。抗体的重链和轻链通过重链的CH1结构域和轻链的CL结构域之间的二硫键共价连接在一起,抗体的两条重链通过铰链区之间形成的多肽间二硫键共价连接在一起。
本发明中,术语“单克隆抗体(单抗)”指从一类基本均一的群体获得的抗体,即该群体中包含的单个抗体是相同的,除少数可能存在的天然发生的突变外。单克隆抗体高特异性地针对单个抗原位点。而且,与常规多克隆抗体制剂(通常是具有针对不同抗原决定簇的不同抗体的混合物)不同,各单克隆抗体是针对抗原上的单个决定簇。除了它们的特异性外,单克隆抗体的好处还在于它们可以通过杂交瘤培养来合成,不会被其它免疫球蛋白污染。
本发明中,术语“人源化”是指其CDR来源于非人物种(优选小鼠)抗体,抗体分子中残余的部分(包括框架区和恒定区)来源于人抗体。此外,框架区残基可被改变以维持结合亲和性。
如本文所用,术语“框架区”(FR)指免疫球蛋白可变区内超变区之外的氨基酸组成和排列顺序变化相对较小的部分。免疫球蛋白的轻链和重链各具有四个FR,分别称为FR1-L、FR2-L、FR3-L、FR4-L和FR1-H、FR2-H、FR3-H、FR4-H。相应地,轻链可变结构域可因此称作(FR1-L)-(CDR1-L)-(FR2-L)-(CDR2-L)-(FR3-L)-(CDR3-L)-(FR4-L)且重链可变结构域可因此表示为(FR1-H)-(CDR1-H)-(FR2-H)-(CDR2-H)-(FR3-H)-(CDR3-H)-(FR4-H)。优选地,本发明的FR是人抗体FR或其衍生物,所述人抗体FR的衍生物与天然存在的人抗体FR基本相同,即序列同一性达到85%、90%、95%、96%、97%、98%或99%。
获知CDR的氨基酸序列,本领域的技术人员可轻易确定框架区FR1-L、FR2-L、FR3-L、FR4-L和/或FR1-H、FR2-H、FR3-H、FR4-H。
如本文所用,术语“人框架区”是与天然存在的人抗体的框架区基本相同的(约85%或更多,具体地90%、95%、97%、99%或100%)框架区。
如本文所用,术语“接头”或是指***免疫球蛋白结构域中为轻链和重链的结构域提供足够的可动性以折叠成交换双重可变区免疫球蛋白的一个或多个氨基酸残基。在本发明中,优选的接头是指接头L1、L2和L3,其中,L1连接VEGFR1的胞外区与抗TGF-β抗体的重链的N端,L2连接VEGFR1的胞外区与抗TGF-β抗体的重链的C端,L3连接VEGFR1的胞外区与抗TGF-β抗体的轻链的C端。
合适的接头为柔性接头,其实例包括单甘氨酸(Gly)、或丝氨酸(Ser)残基,连接子中氨基酸残基的标识和序列可随着接头中需要实现的次级结构要素的类型而变化。在本发明中,所述接头为(G4S)n,较佳地为(G4S)2、(G4S)3、或(G4S)4。
双功能融合蛋白
本发明的双功能融合蛋白是一种抗VEGF和TGF-β的双功能融合蛋白,包括抗TGF-β抗体部分以及I型VEGF受体(VEGFR1)的胞外区。
如本文所用,“双功能融合蛋白”、“本发明的双功能抗体融合蛋白”、“TGF-β/VEGF双功能抗体融合蛋白”、“抗VEGF和TGF-β的双功能融合蛋白”可以互换使用,皆指本发明第一方面所述的包含抗TGF-β抗体部分以及I型VEGF受体(VEGFR1)的胞外区的双功能融合蛋白。
优选地,本发明中的抗TGF-β抗体的重链氨基酸序列如SEQ ID NO:13所示,所述抗TGF-β抗体的轻链氨基酸序列如SEQ ID NO:9所示。本领域技术人员也可以通过本领域熟知的技术对本发明抗TGF-β抗体进行修饰或改造,例如添加、缺失和/或取代一个或几个氨基酸残基,从而进一步增加抗TGF-β的亲和力或结构稳定性,并通过常规的测定方法获得修饰或改造后的结果。
在本发明中,本发明双功能融合蛋白还包括其保守性变异体,指与本发明双功能融合蛋白的氨基酸序列相比,有至多10个,较佳地至多8个,更佳地至多5个,最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
本发明中,术语“抗”和“结合”是指两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。通常,抗体以小于大约10-7M,例如小于大约10-8M、10-9M、10-10M、10-11M或更小的平衡解离常数(KD)结合该抗原。术语“KD”是指特定抗体-抗原相互作用的平衡解离常数,其用于描述抗体与抗原之间的结合亲和力。平衡解离常数越小,抗体-抗原结合越紧密,抗体与抗原之间的亲和力越高。例如,使用表面等离子体共振术(Surface PlasmonResonance,缩写SPR)在BIACORE仪中测定抗体与抗原的结合亲和力或使用ELISA测定抗体与抗原结合的相对亲和力。
本发明的双功能融合蛋白可以单独使用,也可与可检测标记物(为诊断目的)、治疗剂、或任何以上这些物质的组合结合或偶联。
编码核酸和表达载体
本发明还提供了编码上述抗体或其片段或其融合蛋白的多核苷酸分子。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。本发明中,术语“表达载体”是指携带表达盒用于表达特定目的蛋白或其他物质的载体,如质粒、病毒载体(如腺病毒、逆转录病毒)、噬菌体、酵母质粒或其他载体。例如包含适当的调控序列,例如启动子、终止子、增强子等的本领域的常规表达载体,所述表达载体包括但并不限于:病毒载体(如腺病毒、逆转录病毒)、质粒、噬菌体、酵母质粒或其他载体。所述表达载体较佳地包括pDR1、pcDNA3.4(+)、pDHFR或pTT5。
一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。
本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的载体。这些载体可以用于转化适当的宿主细胞,以使其能够表达蛋白质。
本发明中,术语“宿主细胞”为本领域常规的各种宿主细胞,只要能使载体稳定地自行复制,且所携带的多核苷酸分子可被有效表达即可。其中所述宿主细胞包括原核表达细胞和真核表达细胞,所述宿主细胞较佳地包括:COS、CHO、NS0、sf9、sf21、DH5α、BL21(DE3)、TG1、BL21(DE3)、293F或293E细胞。
药物组合物和应用
本发明还提供了一种组合物。优选地,所述的组合物是药物组合物,它含有上述的抗体或其活性片段或其融合蛋白,以及药学上可接受的载体。通常,可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中,其中pH通常约为4-8,较佳地pH约为5-7,尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药,其中包括(但并不限于):静脉注射、静脉滴注、皮下注射、局部注射、肌肉注射、瘤内注射、腹腔内注射(如腹膜内)、颅内注射、或腔内注射。
本发明中,术语“药物组合物”是指本发明的双功能融合蛋白可以和药学上可以接受的载体一起组成药物制剂组合物从而更稳定地发挥疗效,这些制剂可以保证本发明公开的双功能融合蛋白的氨基酸核心序列的构象完整性,同时还保护蛋白质的多官能团防止其降解(包括但不限于凝聚、脱氨或氧化)。
本发明的药物组合物含有安全有效量(如0.001-99wt%,较佳地0.01-90wt%,更佳地0.1-80wt%)的本发明上述的双功能融合蛋白(或其偶联物)以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。药物组合物如针剂、溶液宜在无菌条件下制造。活性成分的给药量是治疗有效量,例如每天约10微克/千克体重-约50毫克/千克体重。此外,本发明的双功能融合蛋白还可与其他治疗剂一起使用。
使用药物组合物时,是将安全有效量的双功能融合蛋白或其免疫偶联物施用于哺乳动物,其中该安全有效量通常至少约10微克/千克体重,而且在大多数情况下不超过约50毫克/千克体重,较佳地该剂量是约10微克/千克体重-约10毫克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明中,术语“有效量”是指本发明的药物组合物施用受试者后,在治疗的个体中产生预期效果的量或剂量,该预期效果包括个体病症的改善。术语“受试者”包括但不限于哺乳动物,例如人、非人灵长类动物、大鼠和小鼠等。
本发明的主要优点包括:
(1)本发明的双功能融合蛋白与VEGF和TGF-β高亲和力结合。
(2)本发明的双功能融合蛋白具有良好的物理稳定性。
(3)本发明的双功能融合蛋白能有效抑制TGF-β1诱导的Smad3活化。
(4)本发明的双功能融合蛋白能有效阻断VEGF与受体KDR结合,并且其阻断功能比阳性对照Bevacizumab更优。
(5)本发明的双功能融合蛋白在碱烧伤角膜新生血管模型中能够显著抑制角膜新生血管的形成,在基质胶血管生成模型中能显著抑制新生血管的形成。
(6)本发明的双功能融合蛋白能够显著地抑制肿瘤生长。
(7)本发明的双功能融合蛋白具有有效治疗CNV,PVR和AMD等眼科疾病和肿瘤的潜力。特别是在眼科疾病领域,一方面可以迅速抑制由VEGF诱发的眼部血管新生及渗漏,另一方面阻断TGF-β信号通路抑制VEGF诱导表达,使眼部较长时间内维持低VEGF水平,可更有效地治疗CNV,PVR和AMD等眼科疾病。
下面结合具体实施例,进一步陈述本发明。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详细条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
以下实施例涉及的序列信息总结在表1中。
表1.本发明抗体的序列信息
其中,TV02轻链氨基酸序列与TV01轻链相同;
TV04轻链、TV03轻链和12.7单抗轻链相同;
TV05重链氨基酸序列与12.7单抗重链相同。
实施例1.抗体融合蛋白分子构建
本发明采用了分别在抗TGF-β单克隆抗体IgG重链的C端(图1A)或N端(图1B),以及轻链的C端(图1C),与VEGFR1的D2结构域串联的方式,构建了抗体融合蛋白。本发明的融合蛋白的氨基酸序列如下表2所示:
表2.
抗体融合蛋白TV01,TV03结构示意图如图1A,抗体融合蛋白TV02,TV04结构示意图如图1B,抗体融合蛋白TV05结构示意图如图1C所示。具体连接方式如表3所示。
其中,TV02中的抗TGF-β单克隆抗体序列来源于PCT专利申请PCT/CN2021/088153中构建的人源化抗体1D11-Hu(将US20180244763A1中鼠源1D11经人源化构建而成),重链和轻链分别为实施例2.1中的1D11-Hu-HC和1D11-Hu-LC。TV01中的抗TGF-β单克隆抗体的重链相对TV02在448位将氨基酸K突变为A。TV04和TV05中的抗TGF-β单克隆抗体序列来源于PCT专利申请PCTCN2021088153中构建的另一个抗体mAb127(即本申请中的12.7单抗,其重链可变区和轻链可变区来源自US20100136021A1),重链和轻链分别为实施例2.1中的mAb127-HC和mAb127-LC。TV03中的抗TGF-β单克隆抗体的重链相对TV04在448位将氨基酸K突变为A。
表3.
融合蛋白 | 连接方式 | 抗体来源 |
TV01 | 抗TGF-β抗体重链C末端连接VEGFR-D2 | 1D11-Hu |
TV02 | 抗TGF-β抗体重链N末端连接VEGFR-D2 | 1D11-Hu |
TV03 | 抗TGF-β抗体重链C末端连接VEGFR-D2 | mAb127 |
TV04 | 抗TGF-β抗体重链N末端连接VEGFR-D2 | mAb127 |
TV05 | 抗TGF-β抗体轻链C末端连接VEGFR-D2 | mAb127 |
实施例2.TGF-β/VEGF双功能融合蛋白制备
将抗TGF-β/VEGF双功能融合蛋白重链和轻链的DNA片段分别亚克隆到pcDNA3.4载体(购自thermofisher,A14697)中,提取重组质粒共转染CHO细胞和/或293F细胞。细胞培养7天后,将培养液通过高速离心、微孔滤膜抽真空过滤后上样至HiTrap MabSelect SuRe柱,用100mM柠檬酸,pH3.5的洗脱液一步洗脱蛋白,回收目标样品并透析换液至PBS。将纯化后的蛋白用HPLC检测,图2A-图2E,检测结果表明融合蛋白分子状态均一,单体纯度达到97%以上。
实施例3.酶联免疫吸附法(ELISA)测定抗TGF-β/VEGF双功能融合蛋白对抗原的亲和力
3.1 ELISA检测抗TGF-β/VEGF双功能融合蛋白与TGF-β1的亲和力
将TGF-β1蛋白(购自acrobiosystems,Cat.#TG1-H4212),以100ng/孔包板,4℃过夜。PBST洗板3次,加入200μl/孔封闭液,37℃放置1小时后PBST洗板1次待用。用稀释液稀释抗体至100nM,4倍比稀释形成12个浓度梯度,依次加入封闭后的酶标板,100μl/孔,37℃放置1小时。PBST洗板3次,加入HRP标记的羊抗人Fab抗体(购自abcam,Cat.#ab87422),37℃放置30分钟。PBST洗板3次后,在吸水纸上尽量拍干残留液滴,每孔加入100μl的TMB,室温(20±5℃)避光放置5分钟;每孔加入终止液终止底物反应,酶标仪450nm处读取OD值,GraphPadPrism6进行数据分析,作图并计算EC50。
实验结果如图3A所示,抗TGF-β/VEGF双功能融合蛋白TV01,TV02,TV03,TV04,TV05和阳性对照12.7单抗均能有效结合TGF-β1,EC50(nM)值分别为0.188,0.213,0.174,0.221,0.187和0.202,亲和力相当。
3.2 ELISA检测抗TGF-β/VEGF双功能融合蛋白与VEGF的亲和力
为了检测抗TGF-β/VEGF双功能融合蛋白与VEGF的结合能力,将VEGF蛋白(购自acrobiosystems,Cat.#VE5-H4210)以100ng/孔包板,4℃过夜。PBST洗板3次,加入200μl/孔封闭液,37℃放置1小时后PBST洗板1次待用。用稀释液稀释抗体至200nM,4倍比稀释形成12个浓度梯度,依次加入封闭后的酶标板,100μl/孔,37℃放置1小时。PBST洗板3次,加入HRP标记的羊抗人Fab抗体(购自abcam,Cat.#ab87422),37℃放置30分钟。PBST洗板3次后,在吸水纸上尽量拍干残留液滴,每孔加入100μl的TMB,室温(20±5℃)避光放置5分钟;每孔加入终止液终止底物反应,酶标仪450nm处读取OD值,GraphPad Prism6进行数据分析,作图并计算EC50。
实验结果如图3B所示,抗TGF-β/VEGF双功能融合蛋白TV01,TV02,TV03,TV04,TV05均能有效结合VEGF,EC50(nM)值分别为0.478,0.394,0.340,0.381,和0.393,亲和力相当。抗TGF-β单抗12.7不能有效结合VEGF。
3.3 ELISA检测抗TGF-β/VEGF双功能融合蛋白同时结合TGF-β1和VEGF的能力
空间位阻可能会影响抗TGF-β/VEGF双功能融合蛋白同时结合两种抗原的能力。为了检测抗TGF-β/VEGF双功能融合蛋白同时结合TGF-β1和VEGF的能力,将TGF-β1以100ng/孔包板,4℃过夜。PBST洗板3次,加入200μl/孔封闭液,37℃放置1小时后PBST洗板1次待用。用稀释液稀释抗TGF-β/VEGF双功能融合蛋白至起始浓度为200nM,2倍比稀释形成12个浓度梯度,依次加入封闭后的酶标板,100μl/孔,37℃放置1小时。PBST洗板3次,按150ng/孔加入Biotinylated VEGF(义翘神州,Cat.#11066-H27H-B)抗原,37℃放置1小时。PBST洗板3次后加入HRP标记的Streptavidin,37℃放置30分钟。PBST洗板3次后,在吸水纸上尽量拍干残留液滴,每孔加入100μl的TMB,室温(20±5℃)避光放置5分钟;每孔加入50μl 2M H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,GraphPad Prism6进行数据分析,作图并计算EC50。
实验结果如图3C所示,TV03能同时结合TGF-β1和VEGF,EC50(nM)值为5.855。
实施例4.抗TGF-β/VEGF双功能融合蛋白对抗原TGF-β1,TGF-β2的亲和解离常数KD的测定
利用octet分子相互作用分析仪,使用捕获法测定抗TGF-β/VEGF双功能融合蛋白和抗原TGF-β1/TGF-β2结合解离的动力学参数,用20mM EDC和10mM s-NHS将AR2G探针活化,分别将抗原TGF-β1/TGF-β2用10mM Sodium Acetate(乙酸钠,pH6.0)稀释至5μg/ml,结合在活化过的AR2G探针上,再用1M Ethanolamine(乙醇胺,pH8.5)溶液封闭探针。将融合蛋白用1*Kinetic Buffer工作液稀释,设最高浓度分别为3.13nM/6.25nM的5个浓度梯度,于1*Kinetic Buffer工作液中解离。
实验结果如表4所示,抗TGF-β/VEGF双功能融合蛋白TV01、TV03与阳性对照抗TGF-β1单抗12.7,对于TGF-β1的亲和解离常数相当;而对于TGF-β2,TV03与12.7的亲和力相当,TV01的亲和力略弱。
表4亲和解离常数
注:KD为亲和力常数;kon为结合速率常数;kdis为解离速率常数。
实施例5.抗TGF-β/VEGF双功能融合蛋白对抗原VEGF的亲和解离常数KD的测定
利用octet分子相互作用分析仪,使用捕获法测定抗TGF-β/VEGF双功能融合蛋白和抗原VEGF-A165结合解离的动力学参数,用20mM EDC和10mM s-NHS将AR2G探针活化,将抗原VEGF-A165用10mM Sodium Acetate(乙酸钠,pH6.0)稀释至5μg/ml,结合在活化过的AR2G探针上,再用1M Ethanolamine(乙醇胺,pH8.5)溶液封闭探针。将融合蛋白用1*KineticBuffer工作液稀释,设最高浓度为12.5nM的5个浓度梯度,于1*Kinetic Buffer工作液中解离。
实验结果如表5所示,抗TGF-β/VEGF双功能融合蛋白TV03对于VEGF-A165的亲和力略优于阳性对照抗VEGF单抗Bevacizumab。
表5亲和解离常数
注:KD为亲和力常数;kon为结合速率常数;kdis为解离速率常数。
实施例6.SMAD3报告基因抑制实验
SBE Reporter HEK293 Cell(购自BPS bioscience,Cat.#60653)表达带荧光素酶报告基因的Smad3结合原件(SEB),通过研究抗体蛋白对该细胞中TGF-β1诱导的Smad3活化的抑制作用,可评价抗体的体外活性。取贴壁培养的对数期生长的SBE293细胞,用DPBS洗一次后,用胰酶消化,中和胰酶。Trypan蓝细胞计数,300g离心5分钟。用MEM(10%FBS、1%非必需氨基酸、1mM丙酮酸钠)培养基(均购自Gibico公司,Cat.#10095-098,10091-148,11140-050,11360-070)重悬后计数铺板,调整密度为35000个/孔,100μl/孔,置于37℃,5%CO2,孵育过夜,约24小时。用MEM(0.5%FBS、1%非必需氨基酸、1mM丙酮酸钠)培养基稀释TGF-β1(10ng/ml),以及稀释融合蛋白至200nM,4倍稀释,10个梯度,室温放置1小时后,置换细胞板原来的培养基,37℃温箱过夜。加入100μl/孔检测试剂Bio-Glo(提前30分钟放25℃水浴锅解冻平衡温度)。室温孵育10分钟后,用SpectraMax i3读取luminescence。
实验结果如图4所示,融合蛋白以剂量依赖性形式抑制TGF-β诱导的pSMAD3报告物活性,融合蛋白TV01,TV02,TV03,TV04,TV05及阳性对照12.7单抗的IC50(nM)值分别为0.388,0.177,0.255,0.221,0.341及0.337,抑制活性相当。
实施例7.TGF-β/VEGF双功能融合蛋白阻断VEGF与受体KDR结合的细胞实验
取贴壁培养的对数期生长的密度约在80%-90%的KDR细胞(购自promega,Cat.#GA1082),弃掉生长培养基。用DPBS洗一次后,用solution(Sigma,Cat.#A6964)消化,中和胰酶后,200g离心5分钟,用含10%FBS的DMEM培养基(购自Gibco,Cat.#11995)将细胞重悬后,台盼蓝细胞计数,调整细胞密度以40000个/孔铺板,50μl/孔,置于37℃,5%CO2。用含10%FBS的DMEM培养基稀释VEGF至30ng/ml,用含VEGF的培养基倍比稀释抗体,3倍稀释,10个梯度。将稀释好的抗体加入细胞孔每孔25μl(最终VEGF浓度为10ng/ml,抗体起始浓度为100nM),37℃孵育6小时后,每孔加入75μl检测试剂Bio-Glo(购自promega,Cat.#G7940)。室温孵育10分钟后,用SpectraMax i3x读取luminescence。所有数据均为双复孔,所得信号值取平均值后用4-parameter法拟合,用GraphPad Prism6进行数据分析。
实验结果如图5所示:TGF-β/VEGF双功能融合蛋白与阳性对照Bevacizumab均能够有效阻断VEGF与其受体KDR之间的相互作用,并且双功能融合蛋白的阻断能力更优。TV03,TV04和Bevacizumab的IC50(nM)值分别为0.096,0.092和0.305。
实施例8.抗TGF-β/VEGF双功能融合蛋白在碱烧伤角膜新生血管模型中的抗血管生成作用
采用碱烧伤角膜新生血管模型验证TGF-β/VEGF双功能融合蛋白抑制血管新生的作用。首先用0.7%戊巴比妥钠腹腔注射,麻醉8周雌性Balb/c小鼠(购自斯莱克公司),待小鼠麻醉后,将直径2mm滤纸浸泡入1M NaOH,然后将滤纸放在小鼠角膜上进行灼烧,持续30秒;取走滤纸,用大量生理盐水冲洗被灼烧的眼睛,以免NaOH损伤眼睑,然后将动物随机分组,分组当天(第1天)进行首次给药,连续给药6天,每天给药5次,给药组每次滴入TV03(1mg/ml)5μl,正常组和对照组滴PBS(0.01M)5μl;前三天的第一次给药30分钟前,先滴入左氧氟沙星3μl;第7天将老鼠进行安乐死,摘取角膜制备石蜡切片,进行CD31免疫组织化学染色评估新生血管的形成;新生血管面积(Neovascular Area%)=CD31(+)area/corneaarea。
实验结果如图6显示,在此模型中,TV03能显著抑制角膜新生血管的形成。
实施例9.抗TGF-β/VEGF双功能融合蛋白在基质胶血管生成模型中的抗血管生成作用
将含有肝素,VEGF、TGF-β1因子的基质胶注入小鼠皮下,则会诱发小鼠皮下的血管向基质胶内生长,导致部分血液滞留在基质胶当中。因此,测量基质胶中的血红素含量可用于表征基质胶中新生的血管含量。我们用此模型来验证TGF-β/VEGF双功能融合蛋白对血管新生的抑制作用。
首先分装基质胶(Matrigel Matrix,购自Corning公司,货号356231),提前一晚将基质胶放置于4℃冰箱中解冻,将无菌1.5mlEP管、200μl枪头至于-80℃冰箱冷冻备用。隔天在超净台内分装基质胶,然后将肝素(终浓度40U)、VEGF(终浓度800ng/ml)、TGF-β1(终浓度800ng/ml)以及TV03(终浓度1000μg/ml)、单抗12.7(终浓度860μg/ml)、融合蛋白FC-D2(IgG1的Fc片段与VEGFR1的D2结构域融合构建的同源二聚体形式的融合蛋白,其单体氨基酸序列如SEQ ID NO:17所示,终浓度443.3μg/ml)加入到基质胶中,然后混匀备用,全程置于冰上操作。其中TV03、12.7、FC-D2的摩尔量相等。
将8周雄性C57BL/6小鼠(购自斯莱克公司)随机分为5组:Blank正常组,n=10只;VEGF+TGF-β1造模组,n=15只;VEGF+TGF-β1+TV03给药组,n=10只;VEGF+TGF-β1+12.7给药组,n=10只;VEGF+TGF-β1+FC-D2给药组,n=10只。用0.7%戊巴比妥钠腹腔注射麻醉,待小鼠麻醉后,将小鼠腹外侧大腿根部内侧处毛发剃除,然后将基质胶混合物使用胰岛素针(提前置于-20℃冷冻)在此处进行皮下注射。2周之后取出小鼠皮下基质胶,使用Drabkin试剂盒(购自sigma,货号D5941)进行血红素(hemoglobin)的测定。
实验结果如图7和表6所示,在此模型中,TV03、12.7单抗以及FC-D2均能显著抑制VEGF和TGF-β1诱导的血管形成,其中TV03的药效最优。
表6
实施例10抗TGF-β/VEGF双功能融合蛋白在人胰腺癌BxPC-3裸小鼠移植瘤模型上的抗肿瘤作用
收集体外培养的BxPC-3细胞,将细胞悬液浓度调整为1×108/ml,与等体积的基质胶混合。在无菌条件下,接种100μl细胞悬液于BALB/C-nude裸小鼠(购自北京维通利华实验动物技术有限公司上海分公司)右侧肋部皮下。移植瘤用游标卡尺测量移植瘤直径,待平均肿瘤体积生长至100mm3-150mm3左右后将动物随机分组。受试样品TV03的剂量为46.4mg/kg,对照单抗12.7的剂量设置为40mg/kg。空白对照组给以相同体积的生理盐水。每周腹腔注射给药2次并同时测量移植瘤直径及小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2。其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relativetumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分组给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(%),计算公式如下:T/C(%)=(TRTV/CRTV)×100(TRTV:治疗组RTV;CRTV:阴性对照组RTV)。抑瘤率TGI(%)=1-T/C(%)
实验结果如图8所示,在人胰腺癌BxPC-3裸小鼠移植瘤模型上,第32天时TV03抑瘤率TGI为83.66%。结果表明,在此移植瘤模型上,TV03能够显著抑制肿瘤生长。
实施例11.抗TGF-β/VEGF双功能融合蛋白的物理稳定性
利用DSC(Differential scanning calorimetry,差示扫描量热法)检测TV03样品在PBS缓冲体系下的热稳定性。将样品置换到PBS缓冲液中,控制样品浓度在1mg/ml,利用MicroCal*Vp-Capillary DSC(Malvern)进行检测。检测前,将样品及空白缓冲液用0.22μm滤膜过滤。样品板每个孔加入400μl样品或空白缓冲液(设置6组空白缓冲对),最后三对孔板加入ddH2O,以备清洗用。样品板加样完毕后,套上塑料软盖板。扫描温度从25℃开始到100℃结束,扫描速率150℃/h。
具体结果如表7所示,样品TV03蛋白表现出良好的热稳定性。
表7TV03热稳定性检测数据
讨论
与单用VEGF受体以及TGF-β抗体相比,本发明的TGF-β/VEGF双功能抗体融合蛋白能够高效地同时阻断VEGF和TGF-β信号通路。更佳地,本发明的双功能抗体可以协同地、显著地治疗CNV,PVR和AMD等眼科疾病以及肿瘤,具有重要的临床应用前景。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 三生国健药业(上海)股份有限公司
<120> 一种TGF-β/VEGF双功能抗体融合蛋白
<130> P2021-1643
<160> 17
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465 470 475 480
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
515 520 525
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Leu Gly Lys
565
<210> 6
<211> 1758
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atgggcgtga aggtgctgtt cgccctgatc tgcatcgccg tggccgaggc cgatactgga 60
aggccatttg tggagatgta cagcgagatc ccagagatca ttcacatgac agaaggaagg 120
gagctcgtca tcccatgcag agtgacaagc cctaacatca ctgtcactct caagaagttc 180
ccactcgaca cactcatccc agatggcaag agaatcattt gggacagcag aaagggcttc 240
atcatctcca acgccacata taaggagatc ggactgctca cttgcgaagc tacagtcaac 300
ggccacctct ataagactaa ctatctgact cataggcaaa caaacactat cggtggaggc 360
ggttcaggcg gaggtggcag cggcggtggc gggtcgggag ggggtggctc tcaggtgcag 420
ctggtgcagt ctggagctga ggtgaagaag cctggcgctt ctgtgaaggt gtcttgtaag 480
gcttctggat atatctttat tacctattgg atgaattggg tgagacaggc tcctggccag 540
ggcctggagt ggatcggaca gatttttcca gcttctggct ccacaaatta taatgagatg 600
tttgagggca gagctacact gacagtggat acatctacat ctaccgccta catggaactg 660
tcttctctga gatctgagga tacagctgtg tactattgtg ctagaggcga tggcaattat 720
gctctggatg ctatggatta ttggggccag ggaacactgg tgaccgtgtc ttctgcaagt 780
accaagggac ctagtgtttt ccctcttgca ccttgctcca ggtcaacatc agagtccaca 840
gctgctcttg gatgtctcgt taaggactac ttcccagagc cagttaccgt atcctggaac 900
tccggagctt tgacaagcgg cgttcataca ttcccagctg tgttgcagag ttctgggttg 960
tacagtttga gctcagtggt gaccgtgcct tcatcttctt tgggcactaa gacctacacc 1020
tgcaacgtgg atcacaagcc aagcaacacc aaggtggata agagggtgga gtccaagtac 1080
ggcccaccat gtcctccatg tccagcccct gaatttttgg gcgggccttc tgtctttctg 1140
tttcctccta aacctaaaga taccctgatg atcagccgca cacccgaagt cacttgtgtg 1200
gtcgtggatg tgtctcagga agatcccgaa gtgcagttta actggtatgt cgatggcgtg 1260
gaagtgcata atgccaaaac taagccccgc gaagaacagt tcaacagcac ttatcgggtc 1320
gtgtctgtgc tcacagtcct ccatcaggat tggctgaatg ggaaagaata taagtgcaag 1380
gtgagcaata agggcctccc cagcagcatc gagaagacta ttagcaaagc caaagggcag 1440
ccacgggaac cccaggtgta cactctgccc ccctctcagg aggagatgac taaaaatcag 1500
gtctctctga cttgtctggt gaaagggttt tatcccagcg acattgccgt ggagtgggag 1560
tctaatggcc agcccgagaa taattataag acaactcccc ccgtcctgga ctctgacggc 1620
agctttttcc tgtattctcg gctgacagtg gacaaaagtc gctggcagga gggcaatgtc 1680
tttagttgca gtgtcatgca tgaggccctg cacaatcact atacacagaa aagcctgtct 1740
ctgagtctgg gcaaatga 1758
<210> 7
<211> 556
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Glu
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gln Ile Phe Pro Ala Leu Gly Ser Thr Asn Tyr Asn Glu Met Tyr
50 55 60
Glu Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Gly Asn Tyr Ala Leu Asp Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Ala
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Gly Arg Pro Phe
450 455 460
Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly
465 470 475 480
Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val
485 490 495
Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg
500 505 510
Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr
515 520 525
Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu
530 535 540
Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
545 550 555
<210> 8
<211> 1731
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atggagactg gactcagatg gctgctgctg gtcgctgtgc tgaagggcgt ccaatgccaa 60
gtgcagctgg tgcagagcgg cgccgaggtg aagaagcctg gcgctagcgt gaaggtgagc 120
tgcaaggcta gcggctacac cttcacaagc gagtggatga actgggtgag acaagcccct 180
ggccaaggcc tggagtggat gggacagatc ttccctgccc tgggcagcac caactacaac 240
gagatgtacg agggtagagt caccatgacg accgacacaa gcacaagcac cgcctacatg 300
gagctgagaa gcctgagaag cgacgacacc gccgtgtact actgcgctag aggcatcggc 360
aactacgccc tggacgccat ggactactgg ggccaaggca ccctggtgac agtcagcagc 420
gctagcacca agggccctag cgtgttccct ctggcccctt gcagcagaag cacaagcgag 480
agcaccgccg ccctgggctg tttggtgaag gactacttcc ctgagcctgt gaccgtaagc 540
tggaacagcg gcgccctgac aagcggcgtg cacaccttcc ctgccgtgct gcagagcagc 600
ggcctgtaca gcctgagcag cgtggtgacc gttcctagca gcagcctggg caccaagacc 660
tacacctgca acgtggacca caagcctagc aacaccaagg tggacaagag agtggagagc 720
aagtacggcc cgccatgccc tccttgtcct gccccggagt tcctgggcgg ccctagcgtt 780
ttcctcttcc ctcctaagcc taaggatacg ctaatgatta gcagaacccc tgaggtgacc 840
tgcgtggtgg tggacgtgag ccaagaggac cctgaggtgc agttcaactg gtacgtggac 900
ggcgtggagg tgcacaacgc caagaccaag cctagagagg agcagttcaa cagcacctac 960
agagtggtga gcgtgctgac cgtgctgcac caagactggc tgaacggcaa ggagtacaag 1020
tgcaaggtga gcaacaaggg cctgccgtcc tccatcgaga agaccatcag caaggccaag 1080
ggacagccta gagagcctca agtgtacacc ctgcctccta gccaagagga gatgaccaag 1140
aaccaagtga gcctgacctg tcttgtgaag ggcttttacc ctagcgacat cgccgtggag 1200
tgggagagca acggacagcc tgagaacaac tacaagacca cccctcctgt gctggacagc 1260
gacggcagct tcttcctgta cagcagactg accgtggaca agagcagatg gcaagagggc 1320
aacgtgttca gctgcagcgt gatgcacgag gccctgcaca accactacac tcagaaatct 1380
ctgagcctgt cgttaggagc cggcggaggc ggctccggcg gaggcggcag cgacacgggc 1440
agacctttcg tggagatgta cagcgagatc cctgagatca tccacatgac cgagggcaga 1500
gagctggtga tcccttgcag agtaactagc cctaacatca ccgtgaccct gaagaagttc 1560
cctctggaca ccctgatccc tgacggcaag agaatcatct gggacagcag aaagggcttc 1620
atcatcagca acgccaccta caaggagatc ggcctgctga cctgcgaggc caccgtgaac 1680
ggccacctgt acaagaccaa ctacctgacc cacagacaga ccaactgata a 1731
<210> 9
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Ile
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 10
<211> 726
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atggatacta gggctcctac acagctgctg ggactgctgc tgctgtggct gcccggcgct 60
agatgtgaca ttcagatgac acagagccct agcagcctga gcgctagcgt gggcgacaga 120
gtgaccatca cctgcagagc tagcgagagc gtggacttct acggcaacag cttcatgcac 180
tggtatcagc agaagcctgg caaggcccct aagctgctga tctacctggc tagcaacctg 240
gagagcggcg tgcctagcag attcagcggc agcggcagcg gcaccgactt caccctgacc 300
atcagcagcc tgcagcctga ggacttcgcc acctactact gtcagcagaa catcgaggac 360
cctctgacct tcggcggcgg caccaaggtg gagatcaaga gaaccgtggc cgcccctagc 420
gtgttcatct tccctcctag cgacgagcag ctgaagagcg gcaccgctag cgtggtgtgc 480
ctgctgaaca acttctaccc tagagaggcc aaggtgcagt ggaaggtgga caacgccctg 540
cagagcggca acagccaaga gagcgtgacc gagcaagaca gcaaggacag cacctacagc 600
ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcacaaggt gtacgcctgc 660
gaggtgaccc accaaggcct gagcagccct gtgaccaaga gcttcaacag aggcgagtgc 720
tgataa 726
<210> 11
<211> 568
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile
1 5 10 15
Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr
20 25 30
Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu
35 40 45
Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile
50 55 60
Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala
65 70 75 80
Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln
85 90 95
Thr Asn Thr Ile Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly
115 120 125
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala
130 135 140
Ser Gly Tyr Thr Phe Thr Ser Glu Trp Met Asn Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Gln Gly Leu Glu Trp Met Gly Gln Ile Phe Pro Ala Leu Gly
165 170 175
Ser Thr Asn Tyr Asn Glu Met Tyr Glu Gly Arg Val Thr Met Thr Thr
180 185 190
Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser
195 200 205
Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Ile Gly Asn Tyr Ala
210 215 220
Leu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
245 250 255
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
305 310 315 320
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
435 440 445
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
515 520 525
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Leu Gly Lys
565
<210> 12
<211> 1758
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgggcgtga aggtgctgtt cgccctgatc tgcatcgccg tggccgaggc cgatactgga 60
aggccatttg tggagatgta cagcgagatc ccagagatca ttcacatgac agaaggaagg 120
gagctcgtca tcccatgcag agtgacaagc cctaacatca ctgtcactct caagaagttc 180
ccactcgaca cactcatccc agatggcaag agaatcattt gggacagcag aaagggcttc 240
atcatctcca acgccacata taaggagatc ggactgctca cttgcgaagc tacagtcaac 300
ggccacctct ataagactaa ctatctgact cataggcaaa caaacactat cggtggaggc 360
ggttcaggcg gaggtggcag cggcggtggc gggtcgggag ggggtggctc tcaagtgcag 420
ctggtgcaga gcggcgctga ggtcaaaaag cccggcgcct ccgtgaaggt gagctgtaag 480
gccagcggct acacattcac tagcgagtgg atgaactggg tgagacaagc ccccggccaa 540
ggactggaat ggatgggcca gatcttccca gctctgggct ccactaacta caacgagatg 600
tacgagggaa gggtcactat gactacagac actagcacta gcactgccta catggaactg 660
aggtctctga gaagcgacga tacagccgtg tactactgcg ccagaggcat cggcaactat 720
gctctggatg ccatggacta ctggggccaa ggcactctcg tgactgtgag ctccgcaagt 780
accaagggac ctagtgtttt ccctcttgca ccttgctcca ggtcaacatc agagtccaca 840
gctgctcttg gatgtctcgt taaggactac ttcccagagc cagttaccgt atcctggaac 900
tccggagctt tgacaagcgg cgttcataca ttcccagctg tgttgcagag ttctgggttg 960
tacagtttga gctcagtggt gaccgtgcct tcatcttctt tgggcactaa gacctacacc 1020
tgcaacgtgg atcacaagcc aagcaacacc aaggtggata agagggtgga gtccaagtac 1080
ggcccaccat gtcctccatg tccagcccct gaatttttgg gcgggccttc tgtctttctg 1140
tttcctccta aacctaaaga taccctgatg atcagccgca cacccgaagt cacttgtgtg 1200
gtcgtggatg tgtctcagga agatcccgaa gtgcagttta actggtatgt cgatggcgtg 1260
gaagtgcata atgccaaaac taagccccgc gaagaacagt tcaacagcac ttatcgggtc 1320
gtgtctgtgc tcacagtcct ccatcaggat tggctgaatg ggaaagaata taagtgcaag 1380
gtgagcaata agggcctccc cagcagcatc gagaagacta ttagcaaagc caaagggcag 1440
ccacgggaac cccaggtgta cactctgccc ccctctcagg aggagatgac taaaaatcag 1500
gtctctctga cttgtctggt gaaagggttt tatcccagcg acattgccgt ggagtgggag 1560
tctaatggcc agcccgagaa taattataag acaactcccc ccgtcctgga ctctgacggc 1620
agctttttcc tgtattctcg gctgacagtg gacaaaagtc gctggcagga gggcaatgtc 1680
tttagttgca gtgtcatgca tgaggccctg cacaatcact atacacagaa aagcctgtct 1740
ctgagtctgg gcaaatga 1758
<210> 13
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Glu
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gln Ile Phe Pro Ala Leu Gly Ser Thr Asn Tyr Asn Glu Met Tyr
50 55 60
Glu Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Gly Asn Tyr Ala Leu Asp Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 14
<211> 336
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Phe Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Ile
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly
210 215 220
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr
225 230 235 240
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
245 250 255
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
260 265 270
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
275 280 285
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
290 295 300
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
305 310 315 320
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
325 330 335
<210> 15
<211> 453
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 16
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 17
<211> 337
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Gly
225 230 235 240
Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met
245 250 255
Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn
260 265 270
Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp
275 280 285
Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn
290 295 300
Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn
305 310 315 320
Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr
325 330 335
Ile
Claims (12)
1.一种双功能融合蛋白,其特征在于,所述双功能融合蛋白为两个单体形成的二聚体,每个单体包含:
第一结合结构域Z1;和
第二结合结构域Z2;
其中,所述第一结合结构域特异性结合靶分子TGF-β;
所述第二结合结构域特异性结合靶分子VEGF。
3.如权利要求1或2所述的双功能融合蛋白,其特征在于,所述的融合蛋白选自下组:
(1)所述融合蛋白的重链氨基酸序列如SEQ ID NO:1所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:3所示;
(2)所述融合蛋白的重链氨基酸序列如SEQ ID NO:5所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:3所示;
(3)所述融合蛋白的重链氨基酸序列如SEQ ID NO:7所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:9所示;
(4)所述融合蛋白的重链氨基酸序列如SEQ ID NO:11所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:9所示;
(5)所述融合蛋白的重链氨基酸序列如SEQ ID NO:13所示,所述融合蛋白的轻链氨基酸序列如SEQ ID NO:14所示;或
(6)将(1)至(5)中的氨基酸序列经过一个或多个氨基酸残基的取代、缺失或添加而形成的,且具有同时结合VEGF以及结合TGF-β的活性的由(1)至(5)衍生的多肽。
4.一种多核苷酸分子,其特征在于,所述多核苷酸分子编码根据权利要求1至3任一项所述的融合蛋白。
5.一种表达载体,其特征在于,所述表达载体含有根据权利要求4所述的多核苷酸分子。
6.一种宿主细胞,其特征在于,所述宿主细胞含有根据权利要求5所述的表达载体。
7.一种根据权利要求1所述的融合蛋白的制备方法,其特征在于,所述制备方法包括以下步骤:
a)在表达条件下,培养根据权利要求6所述的宿主细胞,从而表达双功能融合蛋白;
b)分离并纯化步骤a)所述的融合蛋白。
8.一种药物组合物,其特征在于,所述药物组合物包含有效量的根据权利要求1至3任一项所述的融合蛋白和一种或多种药学上可接受的载体、稀释剂或赋形剂。
9.根据权利要求1至3任一项所述的融合蛋白、或根据权利要求8所述的药物组合物在制备治疗眼科疾病的药物中的用途。
10.如权利要求9所述的用途,其特征在于,所述眼科疾病选自:渗出型老化相关性黄斑变性(AMD)、脉络膜新生血管形成(CNV)、增殖性玻璃体视网膜病变(PVR)或角膜新生血管性疾病。
11.根据权利要求1至3任一项所述的融合蛋白、或根据权利要求8所述的药物组合物在制备***的药物中的用途。
12.一种免疫偶联物,其特征在于,所述免疫偶联物包括:
(a)如权利要求1至3任一项所述的融合蛋白;和
(b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶。
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PCT/CN2022/113411 WO2023020592A1 (zh) | 2021-08-18 | 2022-08-18 | 一种TGF-β/VEGF双功能抗体融合蛋白 |
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