CN113968903A - TGF-β RII突变体及其融合蛋白 - Google Patents
TGF-β RII突变体及其融合蛋白 Download PDFInfo
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Abstract
本发明针对TGF‑βRII及其融合蛋白重组表达过程中易发生降解、断裂的技术问题,提供一种TGF‑βRII突变体及其融合蛋白,所述TGF‑βRII突变体与SEQ ID NO:6所述野生型TGF‑βRII胞外区相比,在选自第6位Gln、第12位Asp、第20位Gly处存在突变。TGF‑βRII突变体能够结合TGF‑β。与野生型TGF‑βRII相比,所述TGF‑βRII突变体在重组表达时具有更少的断裂和/或降解。便于大规模生产、质量更稳定的抗体/TGF‑βRII双功能蛋白。
Description
本专利申请要求于2020-07-24日提交的申请号为202010721371.4的中国专利申请的优先权益,在此将其全部内容引入作为参考。
技术领域
本发明涉及生物制药领域,特别是肿瘤治疗性蛋白药物领域,具体而言,本发明涉及一种TGF-β RII突变体、其融合蛋白及应用。
背景技术
程序性死亡因子配体1(PD-L1)又称分化簇274(CD274)或B7同源蛋白1(B7-H1),属于B7家族成员,由CD274基因编码。成熟的PD-L1蛋白大小为40kDa,是由272个氨基酸组成的一型跨膜蛋白,诱导表达于激活的T细胞、B细胞、树突细胞、巨噬细胞、间充质干细胞、骨髓来源的肥大细胞和非造血细胞的表面上,在肿瘤组织上广泛表达,如肺癌,肝癌,膀胱癌等。在干扰素及其他炎症因子刺激应答的肿瘤组织和其他组织中都可能会迅速上调。PD-L1的受体为程序性死亡蛋白1(PD-1),也被称为CD279,是T细胞受体CD28家族的成员,表达于多种免疫细胞,如激活的T细胞、B细胞及单核细胞等表面。PD-L1与其受体PD-1结合后,可诱导T细胞凋亡、失能、耗竭,进而抑制肿瘤抗原特异性T细胞的激活、增殖和抗肿瘤功能,实现肿瘤免疫逃逸。PD-1/PD-L1阻断型抗体可以解除PD-L1的免疫抑制作用,增强体内免疫细胞如T细胞等对肿瘤细胞的识别和杀伤,从而达到杀灭肿瘤的作用。目前,全球范围内已上市多个靶向PD-1/PD-L1的抗体类药物,在临床上对黑色素瘤、肺癌、肾癌、霍奇金淋巴瘤、头颈鳞癌和尿路上皮癌等多种肿瘤显示出不错的治疗效果。但是,PD-1/PD-L1治疗性抗体还存在一些问题,最主要的问题是临床上单独使用有效率偏低,对于绝大多数癌种来说,如果不加选择地单独使用,有效率平均只有10%-20%。因此需要开发更加有效的抗体类药物分子以满足临床需求。
转化生长因子-β(transforming growth factor-β,TGF-β)是TGF-β超家族的一员,主要功能是调节细胞的生长和分化。TGF-β在细胞表面有高亲和力受体(TGF-β R),分为3个亚型:TGF-β RI、TGF-β RII、TGF-β RIII。TGF-β通过与细胞膜表面具有丝氨酸/苏氨酸激酶活性的TGF-β RII结合形成复合物后,再与TGF-β RI形成复合物,进而传导信号,引起相应信号通路的激活,从而起到调节细胞增殖、分化和凋亡的功能。在肿瘤微环境中,TGF-β具有调控调节性T细胞(Tregs)发育,抑制DC细胞的成熟,抑制B细胞产生IgA,抑制NK细胞的激活等作用,进而产生免疫抑制,促进肿瘤细胞生长以及转移。通过阻断TGF-β与其主要受体TGF-β RII结合,可以抑制TGF-β的促肿瘤活性。因此开发TGF-β阻断型药物是肿瘤治疗的一个重要方向。
目前以TGF-β通路为靶点的小分子抑制剂和大分子蛋白药物多个处于临床研究阶段,并且在与PD-1/PD-L1抗体药物联用方面有多个临床试验在进行中(表1),且有文献对联用的机制进行了深入的探索。(Nature.2018 Feb 22.doi:10.1038/nature25492;Nature.2018Feb 22.doi:10.1038/nature25501)。因此开发可以阻断PD-1/PD-L1和TGF-β/TGF-β-R双通路的疗法或药物,有望进一步解决肿瘤微环境免疫抑制的难题。
在TGF-β阻断剂与PD-1/PD-L1抑制剂联用的基础上,进一步发展了同时阻断PD-1/PD-L1和TGF-β/TGF-β-R双通路的药物。Merck&GSK的PD-L1抗体与TGF-β RII形成的双功能抗体M7824的临床数据显示其对多种实体瘤具有确切的临床治疗效果(NCT02699515、NCT02517398、NCT03427411)。针对M7824的结构Merck申请了多项专利,见WO2015118175A2。陆续一些类似结构的双功能抗体,如恒瑞的SHR-1701也进入临床试验阶段(CTR20182404\CTR20181823)。目前已有抗体/TGF-βRII融合蛋白公开的专利,如WO2006074451A2、W02009152610A1、WO9309228A1、WO9409815A1、WO2015118175A2等,但一些融合蛋白存在不稳定的问题。在实际生产和应用中,仍需要开发更稳定和表达更高的抗体/TGF-β R融合蛋白。
尽管M7824具有良好的抗肿瘤效果,但在生产过程中存在TGFβ RII断裂的问题,为其在生产过程中的工艺和质量控制带来一定的难度。针对这一问题,恒瑞医药对TGFβ RII进行了截断体的设计,专利WO2018/205985 A1研究发现,将TGFβ RII的N端前26位氨基酸的截断体,尤其是14-21位氨基酸的缺失,可保持对TGFβ RII的生理学功能,且具有更好的稳定性。抗体/TGFβ RII融合蛋白中与抗体部分相比TGFβ RII部分的分子较小,在融合蛋白中TGFβ RII的功能易受到抗体分子的干扰甚至屏蔽,即使采用柔性linker也仅是一定程度上缓解该状况。将TGFβ RII的N端截短则会进一步加剧抗体/TGFβ RII融合蛋白分子中两个功能部分之间分子大小的差异程度。
发明内容
本发明要解决的技术问题是:现有技术中抗体/TGFβ RII融合蛋白在生产过程中容易发生断裂和降解、使用N端截断的TGFβ RII则会进一步加剧抗体/TGFβ RII融合蛋白两个功能部分的分子大小差异。
本发明经过研究发现抗体/TGF-β RII融合蛋白存在不稳定的问题主要原因可能在于:C末端通过连接肽连接TGF-β RII后,抗体与TGF-β RII之间会发生断裂,导致融合蛋白结构不完整,从而影响了融合蛋白的纯度和质量均一性,进而引发药物安全性和有效性方面的问题。在此基础上提供了一种对TGFβ RII进行突变改造的技术方案,既克服抗体/TGFβ RII融合蛋白易断裂和降解的缺陷、又兼顾两个功能部分的分子大小均衡,提供一种更便于大规模生产、质量更稳定的TGF-β RII融合蛋白。具体而言:
一方面,本发明提供一种TGF-β RII突变体,其特征在于与野生型TGF-β RII相比,所述TGF-β RII突变体在一个或多个选自由以下位点所组成的组中的氨基酸残基位点处存在突变:第6位、第12位、第20位;其中,所述野生型TGF-β RII的氨基酸残基编码顺序根据SEQ ID NO:6确定。
进一步,本发明所述TGF-β RII突变体,其中所述突变体相对于野生型TGF-β RII具有选自下组中的一种或几种突变:Q6N,D12T,G20T。
进一步,本发明所述TGF-β RII突变体,其能够结合TGF-β,所述TGF-β包括TGF-β1、TGF-β2、TGF-β3。
更进一步,本发明所述TGF-β RII突变体,其中与野生型TGF-β RII相比,所述TGF-β RII突变体在重组表达时具有更少的断裂和/或降解。
第二方面,本发明提供一种融合蛋白,其包括两个或更多个功能片段,其中至少一个功能片段具有如本发明第一方面所述TGF-β RII突变体的氨基酸序列。
进一步,本发明所述的融合蛋白,其中所述两个或更多个功能片段各自独立的发挥功能;
可选的,各功能片段之间通过多肽接头(Linker)连接。
进一步,本发明所述融合蛋白,其中所述功能片段还包括抗体或其抗原结合部分、受体或其配体结合部分、细胞因子或其片段、细胞毒素或其变体、标记物或示踪物等。
更进一步,本发明所述融合蛋白,其中所述功能片段特异性结合选自以下组中的靶点:肿瘤或癌症免疫治疗靶点、慢性感染性疾病免疫治疗靶点、自身免疫性疾病治疗靶点。
更进一步,本发明所述融合蛋白,其中所述靶点包括包括表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR)、布鲁顿酪氨酸激酶(BTK)、HER2、CTLA、CD20、CD52、CD30、CD33、CD133、PD-1、PD-L1、Src、Abl、磷酯酰肌醇3-激酶(PI3K)、蛋白激酶B(PKB/Akt)、雷帕霉素靶体蛋白(mTOR)、丝苏氨酸蛋白激酶Ras、丝裂原活化蛋白激酶(MAPK)、STAT1、STAT3、STAT5等。
第三方面,本发明提供一种多功能活性分子,其具有两种或更多种功能活性,其中至少一种功能活性为TGF-β结合活性,且所述TGF-β结合活性由具有如本发明第一方面所述TGF-β RII突变体的氨基酸序列的多肽片段带来。
进一步,本发明所述多功能活性分子,其中,所述功能活性还包括抗原结合活性、配体结合活性、细胞因子活性、细胞毒性、标记活性。
进一步,本发明所述多功能活性分子,其特征在于所述功能活性还包括对以下分子的结合活性,表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR)、布鲁顿酪氨酸激酶(BTK)、HER2、CTLA、CD20、CD52、CD30、CD33、CD133、PD-1、PD-L1、Src、Abl、磷酯酰肌醇3-激酶(PI3K)、蛋白激酶B(PKB/Akt)、雷帕霉素靶体蛋白(mTOR)、丝苏氨酸蛋白激酶Ras、丝裂原活化蛋白激酶(MAPK)、STAT1、STAT3、STAT5等。
第四方面,本发明提供一种抗体-TGF-β RII缀合分子,其中所述抗体靶向肿瘤治疗靶点,所述TGF-β RII具有本发明第一方面所述TGF-β RII突变体的氨基酸序列。
进一步,本发明所述抗体-TGF-β RII缀合分子,其中所述抗体特异性靶向表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR)、布鲁顿酪氨酸激酶(BTK)、HER2、CTLA、CD20、CD52、CD30、CD33、CD133、PD-1、PD-L1、Src、Abl、磷酯酰肌醇3-激酶(PI3K)、蛋白激酶B(PKB/Akt)、雷帕霉素靶体蛋白(mTOR)、丝苏氨酸蛋白激酶Ras、丝裂原活化蛋白激酶(MAPK)、STAT1、STAT3、STAT5;优选EGFR、VEGFR、PDGFR、FGFR、HER2、CTLA、CD20、CD133、PD-1、PD-L1。
进一步,本发明所述抗体-TGF-β RII缀合分子,其中所述抗体为鼠源抗体、嵌合抗体、人源化抗体、Fab、Fab'、F(ab')2、Fv、scFv、纳米抗体。本发明提供的抗体或其片段可以为单克隆抗体、单链抗体、单域抗体、双功能抗体、纳米抗体、完全或部分人源化的抗体或者嵌合抗体等任意形式;或者,所述抗体或其片段为半抗体或半抗体的抗原结合片段,例如scFv、BsFv、dsFv、(dsFv)2、Fab、Fab'、F(ab')2或Fv;关于本发明提供的抗体的片段,优选地,所述片段为抗体的能够特异性结合PD-1的任何片段。本发明所述抗体或其抗原结合片段,其为鼠源抗体、嵌合抗体、人源化抗体、Fab、Fab'、F(ab')2、Fv、scFv。
优选的,本发明的抗体为IgA、IgD、IgE、IgG或IgM,更优选为IgG1。抗体的片段选自所述抗体的scFv、Fab、F(ab')2或Fv片段。
优选地,所述抗体或其片段还包含人或鼠的恒定区,优选包含人或鼠的轻链恒定区(CL)和/或重链恒定区(CH);更优选地,所述抗体或其片段包含选自IgG、IgA、IgM、IgD或IgE的重链恒定区和/或κ或λ型轻链恒定区。根据本发明的具体实施方式,所述抗体为单克隆抗体,优选为鼠源、嵌合或人源化的单克隆抗体;更优选地,所述单克隆抗体的重链恒定区为IgG1或IgG4亚型。
进一步,本发明所述抗体-TGF-β RII缀合分子,其中所述抗体为抗人PD-L1抗体或其抗原结合片段,其中抗人PD-L1抗体或其抗原结合片段的重链具有CDR1为SEQ ID NO:25、CDR2为SEQ ID NO:26、CDR3为SEQ ID NO:27,轻链具有CDR1为SEQ ID NO:28、CDR2为SEQ IDNO:29、CDR3为SEQ ID NO:30。
进一步,本发明所述抗体-TGF-β RII缀合分子,其中所述抗体为抗人PD-L1纳米抗体,抗人PD-L1纳米抗体的氨基酸序列为SEQ ID NO:20。
进一步,本发明所述抗体-TGF-β RII缀合分子,其特征在于所述TGF-β RII通过连接肽与抗人PD-L1抗体连接,其中所述连接肽优选包括(G4S)n,其中n为1-4的整数。
第五方面,本发明提供一种组合物,包含本发明第一方面所述的TGF-β RII突变体、本发明第二方面所述所述融合蛋白、本发明第三方面所述多功能活性分子、或本发明第四方面所述所述缀合物,以及药学上可接受的辅料。
第六方面,本发明提供一种核酸,其编码本发明第一方面所述的TGF-β RII突变体、本发明第二方面所述所述融合蛋白、本发明第三方面所述多功能活性分子、或本发明第四方面所述所述缀合物。
第七方面,本发明提供一种重组载体,其包括本发明第六方面所述的核酸。
第八方面,本发明提供一种重组宿主细胞,其包括本发明第六方面所述的核酸、或本发明第七方面所述重组载体。
第九方面,本发明提供一种制备产品的方法,其特征在于利用本发明第六方面所述核酸、第七方面所述重组载体、或第八方面所述重组宿主细胞,制备TGF-β RII突变体、其融合蛋白、其多功能活性分子、或其缀合物。
第十方面,本发明提供一种降低或消除重组蛋白降解或断裂的方法,所述重组蛋白包括TGF-β RII片段,所述方法包括对重组蛋白的TGF-β RII片段的编码区进行突变,使其编码的TGF-β RII相对于野生型TGF-β RII在一个或多个选自由以下位点所组成的组中的氨基酸残基位点处引入突变:第6位、第12位、第20位;所述野生型TGF-β RII的氨基酸残基编码顺序根据SEQ ID NO:6确定。
进一步,本发明所述降低或消除重组蛋白降解或断裂的方法,其中,所述TGF-βRII片段相对于野生型TGF-β RII具有选自下组中的一种或几种突变:Q6N,D12T,G20T。
第十一方面,本发明提供一种产品在制备治疗药物中的用途,其中所述产品包括本发明第一方面所述的TGF-β RII突变体、第二方面所述所述融合蛋白、第三方面所述多功能活性分子、第四方面所述所述缀合物、第五方面所述组合物、第六方面所述核酸、第七方面所述重组载体、或第八方面所述重组细胞。
进一步,本发明所述制备治疗药物的用途,其中所述药物用于预防或治疗肿瘤或癌症、慢性感染性疾病、自身免疫性疾病。
进一步,本发明所述制备治疗药物的用途,其中其中所述肿瘤或癌症优选咽鳞癌、非小细胞肺癌、胰腺癌、肝癌、尿路上皮癌、结直肠癌、胃癌。
为更好理解本发明,首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
本文中的术语“抗体”意在包括全长抗体及其任何抗原结合片段(即,抗原结合部分)或单链。全长抗体是包含至少两条重(H)链和两条轻(L)链的糖蛋白,重链和轻链由二硫键连接。各重链由重链可变区(简称VH)和重链恒定区构成。重链恒定区由三个结构域构成,即CH1、CH2和CH3。各轻链由轻链可变区(简称VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。VH和VL区还可以划分为称作互补决定区(CDR)的高变区,其由较为保守的框架区(FR)区分隔开。各VH和VL由三个CDR以及四个FR构成,从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合,包括多种免疫系统细胞(例如,效应细胞)和传统补体系统的第一组分(C1q)。
本文所用的术语“分离的抗体”是指基本不含具有不同抗原特异性的其他抗体的抗体。
本文中的术语,抗体的“抗原结合片段”(或简称为抗体部分),是指抗体的保持有特异结合抗原能力的一个或多个片段。已证实,抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合部分”中的结合片段的例子包括(i)Fab片段,由VL、VH、CL和CH1构成的单价片段;(ii)F(ab′)2片段,包含铰链区二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1构成的Fd片段;(iv)由抗体单臂VL和VH构成的Fv片段;(v)由VH构成的dAb片段(Ward et al.,(1989)Nature 341:544-546);(vi)分离的互补决定区(CDR);以及(vii)纳米抗体,一种包含单可变结构域和两个恒定结构域的重链可变区。此外,尽管Fv片段的两个结构域VL和VH由不同的基因编码,它们可以通过重组法经由使两者成为单蛋白链的合成接头而连接,其中VL和VH区配对形成单价分子(称为单链Fc(scFv);参见例如Bird et al.,(1988)Science 242:423-426;and Huston et al.,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这些单链抗体也意在包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到,且片段可以通过与完整抗体相同的方式进行功能筛选。
本发明的抗原结合片段包括能够特异性结合抗原的那些。抗体结合片段的实例包括例如但不限于Fab、Fab'、F(ab')2、Fv片段、单链Fv(scFv)片段和单结构域片段。
Fab片段含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab'片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端处的少数残基的添加,包括来自抗体铰链区的一个或多个半胱氨酸。通过切割在F(ab')2胃蛋白酶消化产物的铰链半胱氨酸处的二硫键产生Fab'片段。抗体片段的另外化学偶联是本领域普通技术人员已知的。Fab和F(ab')2片段缺乏完整抗体的片段可结晶(Fc)区,从动物的循环中更快速地清除,并且可能具有比完整抗体更少的非特异性组织结合(参见例如,Wahl等人,1983,J.Nucl.Med.24:316)。
如本领域通常理解的,“Fc”区是不包含抗原特异性结合区的抗体的片段可结晶恒定区。在IgG、IgA和IgD抗体同种型中,Fc区由两个相同的蛋白质片段组成,衍生自抗体的两条重链的第二和第三恒定结构域(分别为CH2和CH3结构域)。IgM和IgE Fc区在每条多肽链中含有三个重链恒定结构域(CH2、CH3和CH4结构域)。
“Fv”片段是含有完整靶识别和结合位点的抗体的最小片段。该区域由以紧密的非共价结合的一个重链和一个轻链可变结构域的二聚体(VH-VL二聚体)组成。在该构型中,每个可变结构域的三个CDR相互作用,以限定在VH-VL二聚体的表面上的靶结合位点。通常,六个CDR对抗体赋予靶结合特异性。然而,在一些情况下,甚至单个可变结构域(或仅包含对于靶特异性的三个CDR的Fv的一半)可以具有识别且结合靶的能力,尽管其亲和力低于整个结合位点。
“单链Fv”或“scFv”抗体结合片段包含抗体的VH和VL结构域,其中这些结构域存在于单条多肽链中。一般地,Fv多肽进一步包含在VH和VL结构域之间的多肽接头,其致使scFv能够形成有利于靶结合的结构。
“单结构域片段”由对抗原显示出足够亲和力的单个VH或VL结构域组成。在一个具体实施方案中,单结构域片段是骆驼化的(参见例如,Riechmann,1999,JournalofImmunological Methods 231:25–38)。
本发明的抗体包括衍生化抗体。例如,衍生化抗体通常通过糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、通过已知保护/封闭基团的衍生化、蛋白酶解切割、与细胞配体或其它蛋白质的连接来修饰。可以通过已知技术进行众多化学修饰中的任一种,所述技术包括但不限于特定的化学切割、乙酰化、甲酰化、衣霉素的代谢合成等。另外,衍生物可以含有一种或多种非天然氨基酸,例如,使用ambrx技术(参见例如,Wolfson,2006,Chem.Biol.13(10):1011-2)。
多肽接头,也叫多肽连接臂、多肽Linker,是用于连接两种功能活性分子的多肽类分子。融合蛋白中两种活性成分能够分别形成正确的空间结构、更好的发挥生物学功能,与连接融合蛋白中两种成分的接头序列密切相关。重组生成的融合蛋白要求插入融合蛋白中的Linker不能印象目的蛋白各自的功能。
针对Linker序列的设计和选择已有诸多相关的研究。目前的研究主要有两种,即(1)螺旋形式的Linker如[A(EAAAK)nA];(2)低疏水、低电荷效应的接头,包括可形成螺旋状的不同长度的肽链、柔性Linker、葡萄糖球菌蛋白A等。Linker的长度是另一重要因素,Linker长度过长则使融合蛋白对蛋白酶比较敏感,导致活性融合蛋白在生产过程中产量下降;应用较短的Linker则可导致两个融合分子相距太近、影响蛋白功能。
与现有技术相比,本发明的技术方案具有以下优点:
第一、本发明通过重组抗体/TGF-β RII融合蛋白的质谱分析结果,结合生物信息学分析确定了抗体/TGF-β RII融合蛋白分子断裂、降解的位点,进一步通过设计氨基酸位点突变验证了所述断裂、降解位点,从而克服了抗体/TGF-β RII融合蛋白重组表达过程中易发生降解的技术问题。
第二、本发明通过定点突变改造TGF-β RII,不改变其氨基酸数量和长度,从而避免了与抗体等多亚基蛋白融合/缀合时分子量差异过大而导致的功能屏蔽或丧失。本发明对第6、12、20位氨基酸定点突变的TGF-β RII作为融合蛋白的组件不仅保持了对TGF-β的特异性结合活性,能够有效结合TGF-β1、TGF-β2、TGF-β3;而且还保留了TGF-β R的生物学功能,在体内也能够阻断TGF-β与TGF-β R的结合,抑制TGF-Β的促肿瘤活性,取得抗肿瘤的效应功能。
第三、本发明还对与TGF-β RII融合的抗体进行了改造和选择,采用分子量相对较小的纳米抗体通过linker与TGF-β RII融合,既降低了双功能融合蛋白中两个组件大小的差异,同时也降低了重组双功能蛋白结构的复杂性,提供一种便于大规模生产、质量稳定的抗体/TGF-β RII双功能蛋白及其制备方法。
附图说明
以下,结合附图来详细说明本发明的实施方案,其中:
图1:12%还原聚丙烯酰氨凝胶(SDS-page)电泳检测H182-MUT4-TGF-β RII融合蛋白9-14天表达细胞培养上清结果图。
图2a:12%还原聚丙烯酰氨凝胶电泳检测H182-MUT4-TGF-β RII融合蛋白突变体上清,其中:
原始:H182-MUT4-TGF-β RII细胞培养上清;
m1:H182-MUT4-TGF-β RIIm1细胞培养上清;
m2:H182-MUT4-TGF-β RIIm2细胞培养上清;
m3:H182-MUT4-TGF-β RIIm3细胞培养上清。
图2b:12%还原聚丙烯酰氨凝胶电泳检测H182-MUT4-TGF-β RII融合蛋白突变体纯化后蛋白,其中:
原始:H182-MUT4-TGF-β RII纯化蛋白;
m1:H182-MUT4-TGF-β RIIm1纯化蛋白;
m2:H182-MUT4-TGF-β RIIm2纯化蛋白;
m3:H182-MUT4-TGF-β RIIm3纯化蛋白。
图3:H182-MUT4-TGF-β RII重组蛋白SEC-HPLC分析结果图。
图4a:H182-MUT4-TGF-β RIIm1重组蛋白SEC-HPLC分析结果图。
图4b:H182-MUT4-TGF-β RIIm2重组蛋白SEC-HPLC分析结果图。
图4c:H182-MUT4-TGF-β RIIm3重组蛋白SEC-HPLC分析结果图。
图5:H182-MUT4-TGF-β RIIm2蛋白高温放置样品SEC-HPLC分析结果图。
红色线条:H182-MUT4-TGF-β RIIm2-40C,样品瓶1:A,1;进样1;通道2489ChA;
绿色线条:H182-MUT4-TGF-β RIIm2-40C-1W,样品瓶1:A,2;进样1;通道2489ChA;
蓝色线条:H182-MUT4-TGF-β RIIm2-40C-2W,样品瓶1:A,3;进样1;通道2489ChA;
灰色线条:H182-MUT4-TGF-β RIIm2-40C-3W,样品瓶1:A,4;进样1;通道2489ChA。
图6:H182-MUT4-TGF-β RIIm2蛋白反复冻融样品SEC-HPLC分析结果图。
红色线条:H182-MUT4-TGF-β RIIm2-20C,样品瓶1:A,5;进样1;通道2489ChA;
绿色线条:H182-MUT4-TGF-β RIIm2-20C-冻融1次,样品瓶1:A,6;进样1;通道2489ChA;
蓝色线条:H182-MUT4-TGF-β RIIm2-20C-冻融2次,样品瓶1:A,7;进样1;通道2489ChA;
灰色线条:H182-MUT4-TGF-β RIIm2-20C-冻融3次,样品瓶1:A,8;进样1;通道2489ChA。
图7:12%还原聚丙烯酰氨凝胶电泳检测抗人PD-L1抗体/TGF-β RII融合蛋白10、15天培养上清。
图8:M7824 15天培养上清纯化后蛋白SEC-HPLC分析结果图。
图9:hzF2-TGF-β RIIm2 15天培养上清纯化后蛋白SEC-HPLC分析结果图。
图10:hzF2-TGF-β RIIm2对人PD-L1胞外区重组蛋白亲和力分析结果图。
图11:M7824对人PD-L1胞外区重组蛋白亲和力分析结果图。
图12:hzF2-TGF-β RIIm2对人TGF-β1重组蛋白亲和力分析结果图。
图13:M7824对人TGF-β1重组蛋白亲和力分析结果图。
图14:ELISA检测hzF2-TGF-β RIIm2融合蛋白对人PD-L1胞外区重组蛋白结合活性结果图。
图15:ELISA检测hzF2-TGF-β RIIm2融合蛋白对人TGF-β1重组蛋白结合活性结果图。
图16:ELISA检测hzF2-TGF-β RIIm2融合蛋白对人TGF-β2重组蛋白结合活性结果图。
图17:ELISA检测hzF2-TGF-β RIIm2融合蛋白对人TGF-β3重组蛋白结合活性结果图。
图18:FACS检测hzF2-TGF-β RIIm2融合蛋白对细胞表面天然PD-L1蛋白结合活性结果图。
图19:ELISA检测hzF2-TGF-β RIIm2融合蛋白对人PD-L1与其受体PD-1结合的抑制作用。
图20:hzF2-TGF-β RIIm2融合蛋白的生物学活性检测。
图21:PBMC免疫重建小鼠皮下移植瘤瘤体积统计。
图22:PBMC免疫重建小鼠皮下移植瘤瘤重统计。
图23:hzF2-TGF-β RIIm2融合蛋白在人CD34+脐带血干细胞人源化小鼠皮下接种HCC827肿瘤模型上的抗肿瘤活性评价结果图。
具体实施方式
本发明针对TGF-β RII及其融合蛋白重组表达过程中易发生降解、断裂的技术问题,提供一种TGF-β RII突变体及其融合蛋白,所述TGF-β RII突变体与SEQ ID NO:6所述野生型TGF-β RII胞外区相比,在选自第6位Gln、第12位Asp、第20位Gly处存在突变。TGF-βRII突变体能够结合TGF-β。与野生型TGF-β RII相比,所述TGF-β RII突变体在重组表达时具有更少的断裂和/或降解。便于大规模生产、质量更稳定的抗体/TGF-β RII双功能蛋白及其融合蛋白。以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的药材原料、试剂材料等,如无特殊说明,均为市售购买产品。
实施例1:抗人PD-L1抗体/TGF-β RII融合蛋白及对照品样品制备
1.1抗人PD-L1抗体/TGF-β RII融合蛋白的制备
通过PCR的方法,将编码PD-L1抗体H182-MUT4(MW22,来源专利申请号:CN201911419802.5)的重链核苷酸序列(SEQ ID NO.1)C端经连接肽编码核苷酸序列(SEQID NO.3)和TGF-β RII胞外区编码核苷酸序列(SEQ ID NO.5)连接,获得含PD-L1抗体重链-TGFβ RII编码序列H182-MUT4-H-TGF-β RII,(SEQ ID NO.9),将H182-MUT4-H-TGF-β RII编码核苷酸序列和PD-L1抗体轻链(H182-MUT4-L)编码核苷酸序列(SEQ ID NO.7)通过酶切连接,克隆至含有谷氨酰氨合成酶(GS)筛选基因的稳定表达载体中,构建用于稳定转染的真核表达载体H182-MUT4-TGF-β RII,转入大肠杆菌扩增,分离获得大量H182-MUT4-TGF-βRII的真核表达质粒。将制备好的H182-MUT4-TGF-β RII真核表达质粒,电转染(Nucleofector IIb,Lonza)悬浮培养的CHO-K1细胞,通过MSX加压筛选,获得稳定表达H182-MUT4-TGF-β RII融合蛋白的细胞。将细胞进行流加培养,每天观察细胞密度和活力,并于第9天开始每天收集部分细胞培养上清,直至细胞活力<20%时,将全部细胞培养液经高速离心后收集上清,并将部分上清利用ProA亲和层析柱对表达上清进行纯化,获得抗人PD-L1抗体/TGF-β RII融合蛋白H182-MUT4-TGF-β RII。
1.2抗人PD-L1抗体/TGF-β RII融合蛋白对照品的制备
人工全合成M7824轻链和重链-TGF-β RII基因(专利WO2015/118175 A2序列),通过酶切连接,克隆至含有谷氨酰氨合成酶(GS)筛选基因的稳定表达载体中,构建完成用于稳定转染的真核表达载体,通过电转染(Nucleofector IIb,Lonza)悬浮培养的CHO-K1细胞,MSX加压筛选,获得稳定表达M7824重组蛋白的细胞。培养细胞并进行表达、纯化,可获得重组蛋白M7824作为对照样品。
实施例2:H182-MUT4-TGF-βRII断裂位点分析
2.1 H182-MUT4-TGF-βRII SDS-PAGE电泳分析
将H182-MUT4-TGF-β RII表达上清进行还原SDS-PAGE电泳分析。结果显示(图1),电泳中有三条清晰条带,其中大于70KDa的为H182-MUT4-TGFβ RII重链融合蛋白链,20-30KDa之间的为抗PD-L1抗体H182-MUT4轻链,而在50-70KDa的蛋白marker处有一明确蛋白条带,推测为脱落了TGFβ RII的H182-MUT4重链,该断裂蛋白条带的比例随着表达细胞培养时间的延长而增加。M7824分析结果和H182-MUT4-TGFβ RII分析结果相似,同样存在断裂条带的问题。
2.2 H182-MUT4-TGF-βRII断裂位点质谱分析
收集SDS-PAGE电泳中分子量在50-70KDa之间的条带,样品中加入脱色缓冲液进行充分的脱色处理,然后加入还原缓冲液进行还原处理,还原处理后加入胰酶,37℃过夜酶解。最后抽提酶解产物并脱盐处理,最后用0.1%甲酸水溶液复溶肽段,以备后续质谱分析。质谱分析时取适量样品肽段使用纳升流速Easy nLC 1200色谱系统(Thermo Scientific)进行色谱分离。肽段分离后用Q-Exactive Plus质谱仪(Thermo Scientific)进行DDA(数据依赖采集)质谱分析。最终选用MaxQuant 1.6.1.0质谱数据库检索软件进行比对分析。质谱分析结果如下表1所示,结果显示,该样品缺失478位氨基酸(含)以后片段,结合胰酶消化的可能位点在氨基酸Lys和Arg之后,综合分析认为,H182-MUT4-TGFβ RII重链可能在477/478位氨基酸位置发生了断裂。
表1.H182-MUT4-TGF-β RII质谱分析结果
实施例3:抗人PD-L1抗体/TGF-β RII融合蛋白突变体设计、表达与分析
3.1抗人PD-L1抗体/TGF-β RII融合蛋白突变体设计与表达
根据对断裂位点的推测,在TGF-β RII的N端酶切位点前后通过糖基化位点的设计实现对切割位点的保护作用,从而阻止切割的发生,突变体设计见表2。利用StarMut基因定点突变试剂盒(GenStar,Cat:T111-01),对抗人PD-L1抗体/TGF-β RII融合蛋白H182-MUT4-TGF-β RII表达载体中的TGF-β RII胞外区编码核苷酸序列进行定点突变,获得突变体表达质粒,随后表达质粒转入大肠杆菌扩增,获得抗人PD-L1抗体/TGF-β RII突变体质粒H182-MUT4-TGF-β RIIm1,H182-MUT4-TGF-β RIIm2和H182-MUT4-TGF-β RIIm3。将制备好的H182-MUT4-TGF-β RIIm1,H1 82-MUT4-TGF-β RIIm2和H182-MUT4-TGF-β RIIm3质粒,电转染(Nucleofector IIb,Lonza)悬浮培养的CHO-K1细胞,通过MSX加压筛选,获得稳定表达PD-L1抗体/TGF-β RII突变体融合蛋白的细胞。将H182-MUT4-TGF-β RII及其突变体H182-MUT4-TGF-β RIIm1,H182-MUT4-TGF-β RIIm2和H182-MUT4-TGF-β RIIm3细胞进行流加培养,每天观察细胞密度和活力,直至细胞活力<20%时,将全部细胞培养液经高速离心后收集上清,并将部分上清利用ProA亲和层析柱对表达上清进行纯化,获得H182-MUT4-TGF-βRII融合蛋白及其突变体样品。
表2.TGF-β RII胞外区序列突变设计
H182-MUT4-H-TGF-β RII | 突变位点 |
H182-MUT4-H-TGF-β RII m1 | G490T |
H182-MUT4-H-TGF-β RII m2 | Q476N |
H182-MUT4-H-TGF-β RII m3 | D482T |
3.2 H182-MUT4-TGF-β RIl及其突变体SDS-PAGE电泳检测
将H182-MUT4-TGF-β RII融合蛋白及其突变体样品表达上清及纯化后蛋白进行还原SDS-PAGE电泳。结果显示(图2),H182-MUT4-TGF-β RII突变体蛋白电泳中有两条清晰条带,其中大于70KDa的为H182-MUT4-TGF β RII重链融合蛋白链,20-30KDa之间的为抗PD-L1抗体H182-MUT4轻链,而在50-70KDa处的脱落了TGF-β RII的H182-MUT4重链条带完全消失。
3.3 H182-MUT4-TGF-β RII及其突变体SEC-HPLC检测
将H182-MUT4-TGF-β RII及其突变体H182-MUT4-TGF-β RIIm1,H182-MUT4-TGF-βRIIm2和H182-MUT4-TGF-β RIIm3蛋白样品进行SEC-HPLC分析。结果显示,H182-MUT4-TGFβRII有明显的降解片段特征峰(图3,表3),而经突变改造后,降解问题得以解决,降解片段特征峰消失,HPLC主峰纯度明显增加(图4,表3)。
表3.双功能蛋白抗人PD-L1抗体/TGF-β RII融合蛋白SEC-HPLC纯度检测
实施例4:抗人PD-L1抗体/TGF-β
RII融合蛋白突变体的稳定性检测
将双功能蛋白H182-MUT4-TGF-β RIIm2样品在40℃条件下放置三周,每周收集一管样品,分析放置稳定性;另外和-20℃反复冻融3次,每次收集一管样品,分析冻融稳定性。将处理好的样品与一直放置于4度的对照品,经过SEC-HPLC测定样品的纯度,验证样品的稳定性。结果如图5,6所示,高温放置和反复冻融样品的纯度与对照样品基本一致,产品稳定,未发生断裂。
实施例5:抗人PD-L1抗体/TGF-β
RII融合蛋白的亲和力测定
利用Fortebio公司的Octet QKe system仪器,采用抗人抗体Fc段的捕获抗体(AHC)生物探针捕获抗体Fc段的方法测定抗体亲和力。测定时将双功能蛋白H182-MUT4-TGF-β RII,H182-MUT4-TGF-β RIIm1,H182-MUT4-TGF-β RIIm2,H182-MUT4-TGF-β RIIm3,H182-MUT4,TGF-β RII-hFc(Cat:CC10,近岸科技)用PBS缓冲液稀释至5ug/mL,流经AHC探针(Cat:18-5060,PALL)表面,时间为120s。分别以人PD-L1-His重组蛋白和人TGFβ1重组蛋白(Cat:CA59,近岸科技)作为流动相,浓度为60nM。结合时间为300s,解离时间为300s。实验完毕,扣除空白对照响应值,用软件进行1:1Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。结果如表4所示,与H182-MUT4、TGF-β RII-hFc相比,双功能蛋白H182-MUT4-TGFβRII,H182-MUT4-TGF-β RIIm1,H182-MUT4-TGF-β RIIm2和H182-MUT4-TGF-β RIIm3对PD-L1、TGFβ1的亲和力无明显改变。
表4.双功能蛋白抗人PD-L1抗体/TGF-β RII融合蛋白亲和力测定结果
实施例6:抗人PD-L1纳米抗体/TGF-β
RII突变体融合蛋白的设计与表达
通过PCR的方法,将人源化抗人PD-L1纳米抗体hzF2编码核苷酸序列(来源专利申请号:CN202010324761.8)(SEQ ID NO.19)C端经由连接肽编码核苷酸序列(SEQ ID NO.2)连入TGF-β RIIm2编码核苷酸序列(SEQ ID NO.13),获得含PD-L1纳米抗体-TGF-β RIIm2编码核苷酸序列hzF2-TGF-β RIIm2(SEQ ID NO.23),并通过酶切位点,克隆至含有谷氨酰氨合成酶(GS)筛选基因的稳定表达载体中,构建完成用于稳定转染的真核表达载体hzF2m9-TGF-β RIIm2,转入大肠杆菌扩增,分离获得大量含表达hzF2-TGF-β RIIm2融合蛋白的质粒。将制备好的质粒,电转染(Nucleofector IIb,Lonza)悬浮培养的CHO-K1细胞,通过MSX加压筛选,获得稳定表达hzF2-TGF-β RIIm2融合蛋白的细胞hzF2-TGF-β RIIm2。培养细胞并进行表达、纯化,可获得hzF2-TGF-β RIIm2突变体融合蛋白hzF2-TGF-β RIIm2。
实施例7:hzF2-TGF-β
RIIm2融合蛋白的纯度检测
将M7824及hzF2-TGF-β RIIm2细胞进行流加培养,每天观察细胞密度和活力,并于培养中期第10天收集部分细胞培养液;培养后期细胞活力<20%时(15天),收集剩余细胞培养液;两次培养液分别经高速离心后收集上清,并将上清利用ProA亲和层析柱对表达上清进行纯化,定量后,并分装备用。将上述表达上清进行还原SDS-PAGE电泳及SEC-HPLC检测。SDS-PAGE结果显示(图7),M7824电泳中有三条清晰条带,其中大于70KDa的为M7824重链融合蛋白链,20-30KDa之间的为M7824轻链,在50-70KDa的蛋白marker处有一明确蛋白条带,推测为脱落了TGF-β RII的M7824重链,且该断裂随培养时间的延迟而比例增加;而hzF2-TGF-β RIIm2电泳中在50-70Kda之间有明确的主带,没有明显的其他蛋白条带。SEC-HPLC鉴定结果如图8,9和表5所示,M7824有明显的低分子量的片段峰,而hzF2-TGF-β RIIm2,降解现象得到明显改善。
表5.抗人PD-L1抗体/TGF-β RII融合蛋白SEC-HPLC纯度检测
实施例8:hzF2-TGF-β
RIIm2融合蛋白的亲和力分析
利用Fortebio公司的Octet QKe system仪器,采用抗人抗体Fc段的捕获抗体(AHC)生物探针捕获抗体Fc段的方法测定抗体亲和力。测定时将抗体(hzF2-TGF-β RIIm2和M7824)用PBS缓冲液稀释至4ug/mL,流经AHC探针(Cat:18-0015,PALL)表面,时间为120s。人PD-L1-his重组蛋白(序列号:NP_054862.1,19aa-238aa)、人TGF-β1(Cat:CA59,Novoprotein)作为流动相,结合时间为300s,解离时间为300s。实验完毕,扣除空白对照响应值,用软件进行1:1Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。
结果显示hzF2-TGF-β RIIm2及对照抗体M7824与人PD-L1重组蛋白的反应曲线如图10,11所示,与人TGF-β1重组蛋白的反应曲线如图12,13所示。拟合曲线并计算亲和力,hzF2-TGF-β RIIm2对PD-L1亲和力(KD)为1.58E-09M,对TGF-β1亲和力(KD)为2.46E-09M;M7824对PD-L1亲和力(KD)为3.21E-09M,对TGF-β1亲和力(KD)为2.81E-09M。详细动力学参数如下表,6所示。结果表明hzF2-TGF-β RIIm2与人PD-L1、TGF-β1具有高亲和力。
表6.hzF2-TGF-β RIIm2融合蛋白的亲和力测定结果
实施例9:ELISA检测hzF2-TGF-β
RIIm2融合蛋白的结合活性
将人PD-L1-his重组蛋白(序列号:NP_054862.1,19aa-238aa)、人TGF-β1(Cat:CA59,Novoprotein)、人TGF-β2(Cat:CJ79,Novoprotein)、人TGF-β3(Cat:CJ44,Novoprotein),浓度1μg/mL,4℃包被过夜,用5%BSA于37℃恒温培养箱封闭60min。将hzF2-TGF-β RIIm2和对照抗体M7824以及同型对照NC-hIgG1(起始浓度为10μg/mL,3倍连续稀释,12个梯度),37℃恒温培养箱反应60min后,PBST洗板4次;然后加入1:5000稀释的HRP-anti-human Fc(Cat:109-035-098,Jackson Immuno Research),反应45min,PBST洗板4次,加入TMB(Cat:ME142,北京泰天河生物)底物显色15min,2M HCl终止后读板。读取并记录波长450nm下孔板的吸光度值。
结果显示hzF2-TGF-β RIIm2对人PD-L1、TGF-β1、TGF-β2、TGF-β3的结合活性与M7824基本相当,半数有效结合浓度(EC50)值分别为0.261nM,0.394nM,18.045nM和1.121nM;而M7824对人PD-L1、TGF-β1、TGF-β2、TGF-β3的半数有效结合浓度(EC50)值分别为0.209nM,0.472nM,18.172nM和0.981nM(图14-17)。
实施例10:FACS检测hzF2-TGF-β
RIIm2融合蛋白的结合活性
将天然表达人PD-L1的人乳腺癌细胞MDA-MB-231,以2×104cells/样品加入至96孔细胞培养板,加入5%BSA封闭细胞,室温孵育30min,直接加入hzF2-TGF-β RIIm2和对照抗体M7824以及同型对照NC-hIgG1(起始浓度为10nM,3倍连续稀释,12个梯度),冰上孵育1h;冰冷PBS(含0.05%吐温)洗涤细胞2遍;然后加入1:200稀释的Goat Anti human IgGFc-FITC(Cat:F9512,Sigma),冰上孵育45min,冰冷PBS(含0.05%吐温)洗涤细胞2遍,重悬于200μL PBS中,流式细胞仪检测平均荧光强度(MFI)值。
结果显示hzF2-TGF-β RIIm2和M7824对细胞表面的PD-L1半数有效结合浓度(EC50)值分别为0.0717nM和0.197nM(图18)。
实施例11:ELISA检测hzF2-TGF-β
RIIm2融合蛋白的阻断活性
将人PD-1-hFc重组蛋白(序列号:NP_005009.2,21aa-167aa),浓度1μg/mL,4℃包被过夜,用5%BSA于37℃恒温培养箱封闭60min。加入50μl hzF2-TGF-β RIIm2和对照抗体M7824以及同型对照NC-hIgG1(起始浓度为60nM,1.5倍连续稀释,12个梯度),然后再加50μl浓度为1ug/ml PD-L1-mFc(序列号:NP_054862.1,19aa-238aa),37℃恒温培养箱反应60min后,PBST洗板4次;然后加入1:5000稀释的HRP-anti-mouse Fc(Cat:115-035-071,JacksonImmuno Research),反应45min,PBST洗板4次,加入TMB(Cat:ME142,北京泰天河生物)底物显色15min,2M HCl终止后读板。读取并记录波长450nm下孔板的吸光度值。
结果显示hzF2-TGF-β RIIm2可以有效阻断重组人PD-L1与其受体PD-1的结合作用。通过ELISA测定了hzF2m9-TGF-β RIIm2和M7824对人PD-L1与其受体PD-1结合的竞争抑制效应,其半数有效抑制浓度(IC50)值分别7.533nM和6.935nM(图19)。
实施例12:hzF2-TGF-β
RIIm2融合蛋白阻断PD-L1与其受体PD1结合的细胞学活性
观察
取重组表达人PD-L1和anti-CD3-ScFv的CHO细胞(CHO-PD-L1-CD3L,江苏泰康生物医药有限公司),以5000cells/孔接入96孔细胞培养板(Cat:3917,Corning),细胞培养箱中培养过夜后,弃上清,加入hzF2-TGF-β RIIm2和对照抗体M7824(起始浓度为5ug/mL,2.5倍连续稀释,8个梯度),25μl/孔,和50μl重组表达人PD-1和荧光素酶(luciferase)的Jurkat细胞(1×106cells/ml)(Jurkat-PD1-NFAT,江苏泰康生物医药有限公司)悬液,置于细胞培养箱孵育6h后。向细胞培养板中加入Bio-Turbo萤火虫荧光素酶底物(Cat:RA-GL03,江苏瑞安),125μl/孔,将细胞板置于微孔板恒温振荡器中,800rpm避光孵育5min。设置多功能酶标仪为Luminescence模式,Intergration选择500(仪器默认值),读取RLU,检测结果如图20所示。hzF2-TGF-β RIIm2和对照抗体M7824,对PD-L1/PD1通路的阻断效果EC50分别为10.122nM和8.537nM。
表7.hzF2-TGF-β RIIm2融合蛋白的生物学活性检测
实施例13:hzF2-TGF-β
RIIm2融合蛋白在PBMC免疫重建小鼠皮下移植人咽鳞癌
Fadu模型中的抗肿瘤药效
将人咽鳞癌细胞(FaDu),以5×106个/0.1mL浓度接种于5-6周龄雄性NCG小鼠的右侧胁肋部皮下,人PBMC以2×106/只接种至小鼠体内。待肿瘤生长到40-60mm3时,将肿瘤体积符合要求的小鼠随机分组,每组6只,共分为2组,分别给予hzF2-TGF-β RIIm2和同型对照hIgG1,给药方案见表8。结果如图21、图22所示,hzF2-TGF-β RIIm2明显抑制肿瘤生长,具有明确的抗肿瘤药效,瘤重抑瘤率(TGI,Tumor weight)达到53%。
表8.PBMC免疫重建小鼠皮下移植瘤模型给药方案
注:给药容积按10μl/g体重,出现体重下降15-20%时可调节给药量;
i.p.:腹腔注射;BIW×5:每周给药2次,共给药5次。
实施例14:hzF2-TGF-β
RIIm2融合蛋白在人CD34+脐带血干细胞人源化小鼠皮下
接种HCC827肿瘤模型上的抗肿瘤活性评价
复苏培养人非小细胞肺癌HCC827细胞株,用RMPI 1640培养基(添加灭活的10%FBS,)在37℃、5%CO2的培养箱中培养传代,将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。20只合格的雌性human CD34+脐带血干细胞人源化小鼠,经1周适应性饲养后,接种人非小细胞肺癌HCC827细胞,接种肿瘤细胞后,观察瘤体积及体重,选择肿瘤体积均在120-200mm3之间的小鼠,依据其肿瘤体积和体重随机分为3组,每组5只。分组当天开始给药。给药开始日期视为第0天。给药及分组信息见表9。本实验检测了在等摩尔量的情况下,受试药hzF2-TGF-β RIIm2和对照药Atezolizumab单独用药,在人CD34+脐带血干细胞人源化小鼠皮下接种HCC827肿瘤模型上的抗肿瘤药效。结果显示(图23,表10),hzF2-TGF-β RIIm28mg/kg、Atezolizumab 10mg/kg单独用药均显示出很强的药效,hzF2-TGF-β RIIm2组的瘤体积抑瘤率(TGI,Tv)可以达到80%以上,优于Atezolizumab。
表9.分组及给药信息表
组 | 动物只数 | 测试药物 | 剂量(mg/kg) | 给药途径 | 给药周期 |
1 | 6 | Isotype | 10 | i.p. | 每周两次 |
2 | 5 | Atezolizumab | 10 | i.p. | 每周两次 |
3 | 5 | hzF2-TGF-β RIIm2 | 8 | i.p. | 每周两次 |
表10.受试药在人CD34+脐带血干细胞人源化小鼠皮下HCC827模型中的抑瘤效果
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。
序列表
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gaggtgcagc tggtgcagtc cggagccgag gtgaagaagc ctggagccac cgtgaagatc 60
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cctggcaagg gcctggagtg gatgggacgg atcgaccctg ccaacgccaa caccaagtac 180
gaccccaagt tccaggaccg ggtgaccatc accgctgaca cctccaccaa caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgctgtgt actactgcgc ctctggccag 300
ctgggacctc tgggcttcga ctactgggga cagggcacca ccgtgaccgt gtcctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatctcg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtgctggt ggaggtggct ccggaggcgg aggatctgga 1380
ggaggtggca gcggcggtgg aggctctggt atccctccac acgtgcagaa gtccgtgaac 1440
aacgacatga tcgtgaccga caacaacgga gccgtgaagt tccctcagct gtgcaagttc 1500
tgcgacgtgc ggttctccac ctgcgacaac cagaagtcct gcatgtccaa ctgctccatc 1560
acctccatct gcgagaagcc tcaggaggtg tgcgtggccg tgtggcggaa gaacgacgag 1620
aacatcaccc tggagaccgt gtgccacgac cctaagctgc cctaccacga cttcatcctg 1680
gaggacgctg cctctcccaa gtgcatcatg aaggagaaga agaagcctgg cgagaccttc 1740
ttcatgtgct cctgctcctc cgacgagtgc aacgacaaca tcatcttctc cgaggagtac 1800
aacacctcca accctgac 1818
<210> 10
<211> 606
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Gln Leu Gly Pro Leu Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn
465 470 475 480
Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln
485 490 495
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
500 505 510
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
515 520 525
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
530 535 540
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
545 550 555 560
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
565 570 575
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
580 585 590
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
595 600 605
<210> 11
<211> 1818
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
gaggtgcagc tggtgcagtc cggagccgag gtgaagaagc ctggagccac cgtgaagatc 60
tcctgcaagg tgtccggctt caacatcaag gacatctaca tgcactgggt gcagcaggct 120
cctggcaagg gcctggagtg gatgggacgg atcgaccctg ccaacgccaa caccaagtac 180
gaccccaagt tccaggaccg ggtgaccatc accgctgaca cctccaccaa caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgctgtgt actactgcgc ctctggccag 300
ctgggacctc tgggcttcga ctactgggga cagggcacca ccgtgaccgt gtcctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatctcg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtgctggt ggaggtggct ccggaggcgg aggatctgga 1380
ggaggtggca gcggcggtgg aggctctggt atccctccac acgtgcagaa gtccgtgaac 1440
aacgacatga tcgtgaccga caacaacacc gccgtgaagt tccctcagct gtgcaagttc 1500
tgcgacgtgc ggttctccac ctgcgacaac cagaagtcct gcatgtccaa ctgctccatc 1560
acctccatct gcgagaagcc tcaggaggtg tgcgtggccg tgtggcggaa gaacgacgag 1620
aacatcaccc tggagaccgt gtgccacgac cctaagctgc cctaccacga cttcatcctg 1680
gaggacgctg cctctcccaa gtgcatcatg aaggagaaga agaagcctgg cgagaccttc 1740
ttcatgtgct cctgctcctc cgacgagtgc aacgacaaca tcatcttctc cgaggagtac 1800
aacacctcca accctgac 1818
<210> 12
<211> 606
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Gln Leu Gly Pro Leu Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn
465 470 475 480
Asn Asp Met Ile Val Thr Asp Asn Asn Thr Ala Val Lys Phe Pro Gln
485 490 495
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
500 505 510
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
515 520 525
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
530 535 540
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
545 550 555 560
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
565 570 575
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
580 585 590
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
595 600 605
<210> 13
<211> 1818
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gaggtgcagc tggtgcagtc cggagccgag gtgaagaagc ctggagccac cgtgaagatc 60
tcctgcaagg tgtccggctt caacatcaag gacatctaca tgcactgggt gcagcaggct 120
cctggcaagg gcctggagtg gatgggacgg atcgaccctg ccaacgccaa caccaagtac 180
gaccccaagt tccaggaccg ggtgaccatc accgctgaca cctccaccaa caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgctgtgt actactgcgc ctctggccag 300
ctgggacctc tgggcttcga ctactgggga cagggcacca ccgtgaccgt gtcctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatctcg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtgctggt ggaggtggct ccggaggcgg aggatctgga 1380
ggaggtggca gcggcggtgg aggctctggt atccctccac acgtgaacaa gtccgtgaac 1440
aacgacatga tcgtgaccga caacaacgga gccgtgaagt tccctcagct gtgcaagttc 1500
tgcgacgtgc ggttctccac ctgcgacaac cagaagtcct gcatgtccaa ctgctccatc 1560
acctccatct gcgagaagcc tcaggaggtg tgcgtggccg tgtggcggaa gaacgacgag 1620
aacatcaccc tggagaccgt gtgccacgac cctaagctgc cctaccacga cttcatcctg 1680
gaggacgctg cctctcccaa gtgcatcatg aaggagaaga agaagcctgg cgagaccttc 1740
ttcatgtgct cctgctcctc cgacgagtgc aacgacaaca tcatcttctc cgaggagtac 1800
aacacctcca accctgac 1818
<210> 14
<211> 606
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Gln Leu Gly Pro Leu Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Asn Lys Ser Val Asn
465 470 475 480
Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln
485 490 495
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
500 505 510
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
515 520 525
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
530 535 540
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
545 550 555 560
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
565 570 575
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
580 585 590
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
595 600 605
<210> 15
<211> 1818
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
gaggtgcagc tggtgcagtc cggagccgag gtgaagaagc ctggagccac cgtgaagatc 60
tcctgcaagg tgtccggctt caacatcaag gacatctaca tgcactgggt gcagcaggct 120
cctggcaagg gcctggagtg gatgggacgg atcgaccctg ccaacgccaa caccaagtac 180
gaccccaagt tccaggaccg ggtgaccatc accgctgaca cctccaccaa caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgctgtgt actactgcgc ctctggccag 300
ctgggacctc tgggcttcga ctactgggga cagggcacca ccgtgaccgt gtcctccgct 360
agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ctccatctcg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtgctggt ggaggtggct ccggaggcgg aggatctgga 1380
ggaggtggca gcggcggtgg aggctctggt atccctccac acgtgcagaa gtccgtgaac 1440
aacaccatga tcgtgaccga caacaacgga gccgtgaagt tccctcagct gtgcaagttc 1500
tgcgacgtgc ggttctccac ctgcgacaac cagaagtcct gcatgtccaa ctgctccatc 1560
acctccatct gcgagaagcc tcaggaggtg tgcgtggccg tgtggcggaa gaacgacgag 1620
aacatcaccc tggagaccgt gtgccacgac cctaagctgc cctaccacga cttcatcctg 1680
gaggacgctg cctctcccaa gtgcatcatg aaggagaaga agaagcctgg cgagaccttc 1740
ttcatgtgct cctgctcctc cgacgagtgc aacgacaaca tcatcttctc cgaggagtac 1800
aacacctcca accctgac 1818
<210> 16
<211> 606
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Gln Leu Gly Pro Leu Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val Asn
465 470 475 480
Asn Thr Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln
485 490 495
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
500 505 510
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
515 520 525
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
530 535 540
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
545 550 555 560
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
565 570 575
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
580 585 590
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
595 600 605
<210> 17
<211> 216
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 18
<211> 607
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Glu Val Gln Leu Leu 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 Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu 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 Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Gln Lys Ser Val
465 470 475 480
Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro
485 490 495
Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln
500 505 510
Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro
515 520 525
Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr
530 535 540
Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile
545 550 555 560
Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys
565 570 575
Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn
580 585 590
Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
595 600 605
<210> 19
<211> 1059
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
gaggtgcagc tggtggagtc tggaggtggc ctggtgcagc ctggaggctc cctgaggctg 60
tcctgcgctg cctctcggga ctccgacgag ggagcctcct gcatgggctg gttcaggcag 120
gctcctggca aggagagaga gggagtggcc atcatcttca acgctggcga gcggaccgac 180
tacggcgact ccgtgaaggg acggttcacc atctccaggg acaacgccaa gaacaccctg 240
tacctgcaga tgaactccct gagagccgag gacacagccg tgtactactg cgctaccgtg 300
tggtgtggct cctgggtggc tcggtcctgg ggacagggca ccctggtgac cgtgtcctcc 360
gctagcgagc ccaaatctag cgacaaaact cacacatgcc caccgtgccc agcacctgaa 420
ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 480
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 540
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 600
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 660
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 720
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgcctcca 780
tctcgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 840
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 900
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 960
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1020
aaccactaca cgcagaagag cctctccctg tccccgggt 1059
<210> 20
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
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 Arg Asp Ser Asp Glu Gly Ala
20 25 30
Ser Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly
35 40 45
Val Ala Ile Ile Phe Asn Ala Gly Glu Arg Thr Asp Tyr Gly Asp Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Thr Val Trp Cys Gly Ser Trp Val Ala Arg Ser Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
340 345 350
Gly
<210> 21
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
ggtggaggtg gctccggagg cggaggatct ggaggaggtg gcagcggcgg tggaggctct 60
ggt 63
<210> 22
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly
20
<210> 23
<211> 1530
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
gaggtgcagc tggtggagtc tggaggtggc ctggtgcagc ctggaggctc cctgaggctg 60
tcctgcgctg cctctcggga ctccgacgag ggagcctcct gcatgggctg gttcaggcag 120
gctcctggca aggagagaga gggagtggcc atcatcttca acgctggcga gcggaccgac 180
tacggcgact ccgtgaaggg acggttcacc atctccaggg acaacgccaa gaacaccctg 240
tacctgcaga tgaactccct gagagccgag gacacagccg tgtactactg cgctaccgtg 300
tggtgtggct cctgggtggc tcggtcctgg ggacagggca ccctggtgac cgtgtcctcc 360
gctagcgagc ccaaatctag cgacaaaact cacacatgcc caccgtgccc agcacctgaa 420
ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 480
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 540
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 600
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 660
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 720
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgcctcca 780
tctcgggatg agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 840
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 900
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 960
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1020
aaccactaca cgcagaagag cctctccctg tccccgggtg gtggaggtgg ctccggaggc 1080
ggaggatctg gaggaggtgg cagcggcggt ggaggctctg gtatccctcc acacgtgaac 1140
aagtccgtga acaacgacat gatcgtgacc gacaacaacg gagccgtgaa gttccctcag 1200
ctgtgcaagt tctgcgacgt gcggttctcc acctgcgaca accagaagtc ctgcatgtcc 1260
aactgctcca tcacctccat ctgcgagaag cctcaggagg tgtgcgtggc cgtgtggcgg 1320
aagaacgacg agaacatcac cctggagacc gtgtgccacg accctaagct gccctaccac 1380
gacttcatcc tggaggacgc tgcctctccc aagtgcatca tgaaggagaa gaagaagcct 1440
ggcgagacct tcttcatgtg ctcctgctcc tccgacgagt gcaacgacaa catcatcttc 1500
tccgaggagt acaacacctc caaccctgac 1530
<210> 24
<211> 510
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
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 Arg Asp Ser Asp Glu Gly Ala
20 25 30
Ser Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly
35 40 45
Val Ala Ile Ile Phe Asn Ala Gly Glu Arg Thr Asp Tyr Gly Asp Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Thr Val Trp Cys Gly Ser Trp Val Ala Arg Ser Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
340 345 350
Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
355 360 365
Gly Gly Gly Gly Ser Gly Ile Pro Pro His Val Asn Lys Ser Val Asn
370 375 380
Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln
385 390 395 400
Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys
405 410 415
Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln
420 425 430
Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu
435 440 445
Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu
450 455 460
Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro
465 470 475 480
Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp
485 490 495
Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
500 505 510
<210> 25
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Asp Ile Tyr Met His
1 5
<210> 26
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Asp
<210> 27
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gly Gln Leu Gly Pro Leu Gly Phe Asp Tyr
1 5 10
<210> 28
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 29
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Tyr Thr Ser Arg Leu His Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Gln Gln Gly Ala Gly Arg Pro Tyr Thr
1 5
<210> 31
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
1 5 10 15
<210> 32
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
1 5 10 15
His Asn His Tyr Thr Gln Lys
20
<210> 33
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Asn Gln Val Ser Leu Thr Cys Leu Val Lys
1 5 10
<210> 34
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
1 5 10
<210> 35
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Asp Thr Leu Met Ile Ser Arg
1 5
<210> 36
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10
<210> 37
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
1 5 10
<210> 38
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr Met Glu Leu
1 5 10 15
Ser Ser Leu Arg
20
<210> 39
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Asp Ile Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys
1 5 10
<210> 40
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
1 5 10
<210> 41
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Gly Leu Glu Trp Met Gly Arg
1 5
<210> 42
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Ala Leu Pro Ala Pro Ile Glu Lys
1 5
<210> 43
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
1 5 10 15
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25
<210> 44
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
1 5 10 15
Pro Glu Asn Asn Tyr Lys
20
<210> 45
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
1 5 10 15
<210> 46
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
1 5 10 15
Lys
<210> 47
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Ile Asp Pro Ala Asn Ala Asn Thr Lys
1 5
<210> 48
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Ser Leu Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ile Pro Pro
20 25 30
His Val Gln Lys
35
<210> 49
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Claims (27)
1.一种TGF-βRII突变体,其特征在于与野生型TGF-βRII相比,所述TGF-βRII突变体在一个或多个选自由以下位点所组成的组中的氨基酸残基位点处存在突变:第6位、第12位、第20位;其中,所述野生型TGF-βRII的氨基酸残基编码顺序根据SEQ ID NO:6确定。
2.如权利要求1所述TGF-βRII突变体,其特征在于所述突变体相对于野生型TGF-βRII具有选自下组中的一种或几种突变:Q6N,D12T,G20T。
3.如权利要求1所述TGF-βRII突变体,其特征在于其能够结合TGF-β,所述TGF-β包括TGF-β1、TGF-β2、TGF-β3。
4.如权利要求1所述TGF-βRII突变体,其特征在于与野生型TGF-βRII相比,所述TGF-βRII突变体在重组表达时具有更少的断裂和/或降解。
5.一种融合蛋白,其包括两个或更多个功能片段,其中至少一个功能片段具有权利要求1-4任一所述TGF-βRII突变体的氨基酸序列。
6.如权利要求5所述的融合蛋白,其特征在于所述两个或更多个功能片段各自独立的发挥功能;可选的,各功能片段之间通过多肽接头(Linker)连接。
7.如权利要求5-6任一所述融合蛋白,其特征在于所述功能片段还包括抗体或其抗原结合部分、受体或其配体结合部分、细胞因子或其片段、细胞毒素或其变体、标记物或示踪物等。
8.如权利要求5-6任一所述融合蛋白,其特征在于所述功能片段特异性结合选自以下组中的靶点:肿瘤或癌症免疫治疗靶点、慢性感染性疾病免疫治疗靶点、自身免疫性疾病治疗靶点。
9.如权利要求8所述融合蛋白,其特征在于所述靶点包括包括表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR)、布鲁顿酪氨酸激酶(BTK)、HER2、CTLA、CD20、CD52、CD30、CD33、CD133、PD-1、PD-L1、Src、Abl、磷酯酰肌醇3-激酶(PI3K)、蛋白激酶B(PKB/Akt)、雷帕霉素靶体蛋白(mTOR)、丝苏氨酸蛋白激酶Ras、丝裂原活化蛋白激酶(MAPK)、STAT1、STAT3、STAT5等。
10.一种多功能活性分子,其具有两种或更多种功能活性,其中至少一种功能活性为TGF-β结合活性,且所述TGF-β结合活性由具有权利要求1-4任一所述TGF-βRII突变体的氨基酸序列的多肽片段带来。
11.如权利要求10所述多功能活性分子,其特征在于,所述功能活性还包括抗原结合活性、配体结合活性、细胞因子活性、细胞毒性、标记活性。
12.如权利要求10-11任一所述多功能活性分子,其特征在于所述功能活性还包括对以下分子的结合活性,表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR)、布鲁顿酪氨酸激酶(BTK)、HER2、CTLA、CD20、CD52、CD30、CD33、CD133、PD-1、PD-L1、Src、Abl、磷酯酰肌醇3-激酶(PI3K)、蛋白激酶B(PKB/Akt)、雷帕霉素靶体蛋白(mTOR)、丝苏氨酸蛋白激酶Ras、丝裂原活化蛋白激酶(MAPK)、STAT1、STAT3、STAT5等。
13.一种抗体-TGF-βRII缀合分子,其中所述抗体靶向肿瘤治疗靶点,所述TGF-βRII具有权利要求1-4任一所述TGF-βRII突变体的氨基酸序列。
14.如权利要求13所述抗体-TGF-βRII缀合分子,其中所述抗体特异性靶向表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR)、布鲁顿酪氨酸激酶(BTK)、HER2、CTLA、CD20、CD52、CD30、CD33、CD133、PD-1、PD-L1、Src、Abl、磷酯酰肌醇3-激酶(PI3K)、蛋白激酶B(PKB/Akt)、雷帕霉素靶体蛋白(mTOR)、丝苏氨酸蛋白激酶Ras、丝裂原活化蛋白激酶(MAPK)、STAT1、STAT3、STAT5;优选EGFR、VEGFR、PDGFR、FGFR、HER2、CTLA、CD20、CD133、PD-1、PD-L1。
15.如权利要求13所述抗体-TGF-βRII缀合分子,其中所述抗体为鼠源抗体、嵌合抗体、人源化抗体、Fab、Fab'、F(ab')2、Fv、scFv、纳米抗体。
16.如权利要求13所述抗体-TGF-βRII缀合分子,其中所述抗体为抗人PD-L1抗体或其抗原结合片段,其中抗人PD-L1抗体或其抗原结合片段的重链具有CDR1为SEQ ID NO:25、CDR2为SEQ ID NO:26、CDR3为SEQ ID NO:27,轻链具有CDR1为SEQ ID NO:28、CDR2为SEQ IDNO:29、CDR3为SEQ ID NO:30。
17.如权利要求13所述抗体-TGF-βRII缀合分子,其中所述抗体为抗人PD-L1纳米抗体,抗人PD-L1纳米抗体的氨基酸序列为SEQ ID NO:20。
18.如权利要求16-17任一所述抗体-TGF-βRII缀合分子,其特征在于所述TGF-βRII通过连接肽与抗人PD-L1抗体连接,其中所述连接肽优选包括(G4S)n,其中n为1-4的整数。
19.一种组合物,包含权利要求1-4任一所述的TGF-βRII突变体、权利要求5-9任一所述融合蛋白、权利要求10-12任一多功能活性分子、或权利要求13-18任一所述缀合物,以及药学上可接受的辅料。
20.一种核酸,其编码权利要求1-4任一所述的TGF-βRII突变体、权利要求5-9任一所述融合蛋白、权利要求10-12任一多功能活性分子、或权利要求13-18任一所述缀合物。
21.一种重组载体或重组宿主细胞,其包括权利要求20所述核酸。
22.一种制备产品的方法,其特征在于利用权利要求20所述核酸、或权利要求21所述重组载体或重组宿主细胞,制备TGF-βRII突变体、其融合蛋白、其多功能活性分子、或其缀合物。
23.一种降低或消除重组蛋白降解或断裂的方法,所述重组蛋白包括TGF-βRII片段,所述方法包括对重组蛋白的TGF-βRII片段的编码区进行突变,使其编码的TGF-βRII相对于野生型TGF-βRII在一个或多个选自由以下位点所组成的组中的氨基酸残基位点处引入突变:第6位、第12位、第20位;所述野生型TGF-βRII的氨基酸残基编码顺序根据SEQ ID NO:6确定。
24.如权利要求23所述降低或消除重组蛋白降解或断裂的方法,其特征在于TGF-βRII片段相对于野生型TGF-βRII具有选自下组中的一种或几种突变:Q6N,D12T,G20T。
25.一种产品在制备治疗药物中的用途,所述产品包括:权利要求1-4任一所述的TGF-βRII突变体、权利要求5-9任一所述融合蛋白、权利要求10-12任一多功能活性分子、权利要求13-18任一所述缀合物、权利要求19的组合物、权利要求20的核酸、权利要求21的重组载体或重组宿主细胞。
26.如权利要求25所述的用途,其中所述药物用于预防或治疗肿瘤或癌症、慢性感染性疾病、自身免疫性疾病。
27.如权利要求25-26任一所述的用途,其中其中所述肿瘤或癌症优选咽鳞癌、非小细胞肺癌、胰腺癌、肝癌、尿路上皮癌、结直肠癌、胃癌。
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CA2122491A1 (en) | 1991-10-31 | 1993-05-13 | Herbert Y. Lin | Tgf-.beta. type receptor cdnas and uses therefor |
EP0669833B1 (en) | 1992-10-29 | 2002-06-12 | Celtrix Pharmaceuticals, Inc. | Type ii tgf-beta-binding receptor fragment as therapeutic agent |
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