CN115073607A - Tnfr2与baff受体的融合蛋白 - Google Patents
Tnfr2与baff受体的融合蛋白 Download PDFInfo
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Abstract
本发明提供了一类TNFR2与BAFF受体蛋白融合的制法和应用。具体地,本发明提供了一类融合蛋白,所述融合蛋白包括TNFR2胞外段和BAFFR或BCMA或TACI的胞外段。本发明的融合蛋白在抑制TNFα诱导的炎症的同时,通过结合BAFF或APRIL,抑制B细胞的激活,起到与TNFR2协同作用,增强对各类自身免疫性疾病治疗的效果。
Description
技术领域
本发明涉及生物技术领域。具体地,涉及一种TNFR2与BAFF受体的融合蛋白。
背景技术
自身免疫性疾病是自身细胞和体液对自身机体产生反应的一类疾病,目前全球范围内自身免疫性疾病的发病率和患病率都呈逐年上升状态。常见的自身免疫疾病包括类风湿关节炎(RA)、强直性脊柱炎(AS)、银屑病(PS)、系统性红斑狼疮(SLE)等,给患者的工作能力和生活质量带来了很大的影响。近年来,TNFα靶向抑制剂通过拮抗TNFα,并抑制其下游IL-2、IL-6、IFN-γ等细胞因子的上调,同时抑制被过度激活的T细胞,有效的控制了疾病的进程,被广泛应用于多种自身免疫性疾病。虽然TNFα抑制剂取得了不错的疗效,但是仍有50%患者治疗效果不甚理想,因此亟需新的组合来实现对自身免疫性疾病更有效的控制。
本发明提供了一种更安全、有效、精准用于自身免疫性疾病的治疗性融合蛋白。
发明内容
本发明的目的在于提供一种更安全、有效、精准用于自身免疫性疾病的治疗性融合蛋白。
在本发明的第一方面,提供了一种融合蛋白,所述融合蛋白包括融合在一起的以下元件:
(a)TNF受体或其活性片段;
(b)BAFF受体或其活性片段,其中所述的BAFF受体包括TACI,BCMA,BAFFR或其组合;
和任选的(c)抗体Fc区域;
其中,所述的融合蛋白保留了上述元件(a)和(b)的生物活性。
在另一优选例中,所述TNF受体选自下组:TNFR2、TNFR1、或其组合。
在另一优选例中,所述TNF受体来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述TNF受体包括野生型和突变型。
在另一优选例中,所述TNF受体包括全长的、成熟形式的TNF受体,或其活性片段。
在另一优选例中,所述TNF受体还包括TNF受体的衍生物。
在另一优选例中,所述TNF受体的衍生物包括经修饰的TNF受体、氨基酸序列与天然TNF受体同源且具有天然TNF受体活性的蛋白分子、TNF受体的二聚体或多聚体、含有TNF受体氨基酸序列的融合蛋白。
在另一优选例中,所述经修饰的TNF受体是PEG化的TNF受体。
在另一优选例中,所述“氨基酸序列与天然TNF受体同源且具有天然TNF受体活性的蛋白分子”是指其氨基酸序列与TNF受体相比具有≥85%的同源性,较佳地≥90%的同源性,更佳地≥95%的同源性,最佳地≥98%同源性;并且具有TNF受体活性的蛋白分子。
在另一优选例中,所述TNF受体包括第一结构域、第二结构域、第三结构域、和/或第四结构域。
在另一优选例中,所述第一结构域、第二结构域、第三结构域、和/或第四结构域各自独立地为半胱氨酸富集区(CRD)。
在另一优选例中,所述的TNF受体为含有或具有TNFR2氨基酸序列(SEQ ID NO.:13)的第1-235位,或第17-179位,或第17-140位,或第55-179位,或第55-140位。
在另一优选例中,所述BAFF受体来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述BAFF受体包括野生型和突变型。
在另一优选例中,所述BAFF受体还包括BAFF受体的衍生物。
在另一优选例中,所述BAFF受体的衍生物包括经修饰的BAFF受体、氨基酸序列与天然BAFF受体同源且具有天然BAFF受体活性的蛋白分子、BAFF受体的二聚体或多聚体、含有BAFF受体氨基酸序列的融合蛋白。
在另一优选例中,所述“氨基酸序列与天然BAFF受体同源且具有天然BAFF受体活性的蛋白分子”是指其氨基酸序列与BAFF受体相比具有≥85%的同源性,较佳地≥90%的同源性,更佳地≥95%的同源性,最佳地≥98%同源性;并且具有BAFF受体活性的蛋白分子。
在另一优选例中,所述BAFF受体选自下组:TACI、BCMA、BAFFR,或其组合。
在另一优选例中,所述TACI含有或具有TACI氨基酸序列(SEQ ID NO.:14)的第1-109位,或第33-109位,或第68-109位。
在另一优选例中,所述BCMA含有或具有BCMA氨基酸序列(SEQ ID NO.:15)的第1-54位,或第6-54位。
在另一优选例中,所述BAFFR含有或具有BAFFR氨基酸序列(SEQ ID NO.:16)的第1-78位,或第12-78位,或第12-46位。
在另一优选例中,所述Fc片段来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述Fc片段为免疫球蛋白IgG的Fc片段,较佳地为IgG1的Fc部分。
在另一优选例中,所述Fc片段包括天然的Fc片段及Fc突变体。
在另一优选例中,所述的Fc片段含有或具有人IgG1氨基酸序列(登录号为UniProtKB-P01857)的第99-329位。
在另一优选例中,所述Fc片段的氨基酸序列如SEQ ID NO.:17所示。
在另一优选例中,所述的融合蛋白还具有以下一种或多种功能:
(a)结合TNFα的活性;
(b)抑制TNFα诱导的炎症;
(c)结合BAFF或APRIL的活性;
(d)抑制或封闭BAFF/APPRIL途径;
(e)降低体内B细胞的数量。
在另一优选例中,所述融合蛋白具有下式I或II所示的二聚体结构:
X-Y-Z (I)
Y-X-Z (II);
式中,
X为TNF受体的胞外段;
Y为TACI,BCMA或BAFFR的胞外段;
Z为无、或任选的人抗体的Fc区域;
-表示肽键或肽接头。
在另一优选例中,所述融合蛋白为同源二聚体。
在另一优选例中,所述融合蛋白的氨基酸序列如SEQ ID NO.:18或19或20所示。
在另一优选例中,所述的X、Y、Z中的任何两者以头-头、头-尾、或尾-尾方式相连。
在另一优选例中,所述的“头部”指多肽或其片段的N端,尤其是野生型多肽的或其片段的N端。
在另一优选例中,所述的“尾部”指多肽或其片段的C端,尤其是野生型多肽的或其片段的C端。
在另一优选例中,所述的肽接头是1-20个长度的肽接头,较佳地,1-10个氨基酸。
在另一优选例中,所述的X含有或具有TNFR2氨基酸序列(SEQ ID NO.:13)的第1-235位,或第17-179位,或第17-140位,或第55-179位,或第55-140位;和/或
所述的Y含有或具有:
(a)TACI氨基酸序列(SEQ ID NO.:14)的第1-109位,或第33-109位,或第68-109位;
(b)BCMA氨基酸序列(SEQ ID NO.:15)的第1-54位,或第6-54位;或
(c)BAFFR氨基酸序列(SEQ ID NO.:16)的第1-78位,或第12-78位,或第12-46位。
在另一优选例中,所述的Z含有或具有人IgG1氨基酸序列(登录号为UniProtKB-P01857)的第99-329位。
在本发明的第二方面,提供了一种核酸分子,所述的核酸分子编码本发明的第一方面所述的融合蛋白。
在另一优选例中,所述的核酸分子在所述突变蛋白或融合蛋白的ORF的侧翼还额外含有选自下组的辅助元件:信号肽、分泌肽、标签序列(如6His)、或其组合。
在另一优选例中,所述的核酸分子选自下组:DNA序列、RNA序列、或其组合。
在本发明的第三方面,提供了一种载体,它含有在本发明的第二方面所述的核酸分子。
在另一优选例中,所述载体包含一个或多个启动子,所述启动子可操作地与所述核酸序列、增强子、转录终止信号、多腺苷酸化序列、复制起点、选择性标记、核酸限制性位点、和/或同源重组位点连接。
在另一优选例中,所述载体包括质粒、病毒载体。
在另一优选例中,所述的病毒载体选自下组:腺相关病毒(AAV)、腺病毒、慢病毒、逆转录病毒、疱疹病毒、SV40、痘病毒、或其组合。
在另一优选例中,所述载体包括表达载体、穿梭载体、整合载体。
在本发明的第四方面,提供了一种基因工程化的细胞,所述的细胞含有本发明的第三方面所述的载体;或所述的细胞基因组中整合有本发明的第二方面所述的核酸分子。
在另一优选例中,所述基因工程化的细胞为真核细胞,如酵母细胞、植物细胞或哺乳动物细胞(包括人和非人哺乳动物)。
在另一优选例中,所述基因工程化的细胞为原核细胞,如大肠杆菌。
在另一优选例中,所述基因工程化的细胞选自下组:大肠杆菌、麦胚细胞,昆虫细胞,SF9、SP2/0、Hela、HEK293、CHO(比如CHOKS)、酵母细胞、或其组合。
在本发明的第五方面,提供了一种产生本发明第一方面所述的融合蛋白的方法,所述的方法包括步骤:
在适合表达所述融合蛋白的条件下,培养本发明的第四方面所述的基因工程化的细胞,从而表达所述的融合蛋白;和
分离或纯化所述的融合蛋白。
在本发明的第六方面,提供了一种药物组合物,所述的药物组合物含有本发明第一方面所述的融合蛋白及其药物学上可接受的载体。
在另一优选例中,所述药物组合物还包括其他用于治疗免疫性疾病的药物。
在另一优选例中,其他用于治疗免疫性疾病的药物选自下组:激素类药物、免疫抑制药物、小分子靶向药物、生物制剂、或其组合。
在另一优选例中,所述激素类药物选自下组:可的松、氢化可的松、强的松、波尼松、波尼松龙、地塞米松、倍他米松、或其组合。
在另一优选例中,所述免疫抑制药物选自下组:甲氨蝶呤、环磷酰胺、咪唑硫嘌呤、环孢素、霉酚酸酯、他克莫司、西罗莫司、来氟米特、柳氮磺砒啶、羟氯喹、或其组合。
在另一优选例中,所述小分子靶向药物选自下组:托法替布、巴瑞替尼、或其组合。
在另一优选例中,所述生物制剂选自下组:依那西普、赛妥珠单抗、阿达木单抗、戈利木单抗、英夫利昔单抗、托珠单抗、苏金单抗、优特克单抗、卡纳单抗、阿那白滞素、利纳西普、阿巴西普、利妥昔单抗、贝利尤单抗、或其组合。
在本发明的第七方面,提供了一种如本发明第一方面所述的融合蛋白、本发明第二方面所述的核酸分子、本发明第三方面所述的载体、本发明第四方面所述的基因工程化的细胞的用途,用于制备选自下组的一种或多种组合物:
(a)抑制BAFF/APPRIL信号通路组合物;
(b)治疗免疫疾病的组合物;和/或
(c)治疗B细胞增多相关疾病的组合物。
在另一优选例中,所述的组合物为药物组合物。
在另一优选例中,所述免疫性疾病选自下组:类风湿关节炎(RA)、强直性脊柱炎(AS)、银屑病(PS)、银屑病关节炎(PsA)、幼年特发性关节炎(JIA)、系统性红斑狼疮(SLE)、白塞病(behcet’s disease,BD)、多发性硬化症(MS)、干燥综合征(SS)、Graves病、克罗恩病(CD)、溃疡性结肠炎(UC)、原发性肾小球肾炎、自身免疫性血管炎、多发性肌炎(PM)、非感染性葡萄膜炎、自身免疫性溶血性贫血(AIHA)、自身免疫性紫癜(ATTP)、N-甲基-d-天冬氨酸受体(NMDAR)脑炎、重症肌无力、化脓性汗腺炎(HS)、髓鞘-少突胶质细胞糖蛋白谱紊乱(MOGSD)和视神经脊髓炎频谱障碍(NMOSD)、或其组合。
在另一优选例中,所述免疫性疾病包括自身免疫性疾病,例如类风湿关节炎(RA)、强直性脊柱炎(AS)、银屑病(PS)、银屑病关节炎(PsA)、幼年特发性关节炎(JIA)、系统性红斑狼疮(SLE)、自身免疫性紫癜(ATTP)。
在另一优选例中,所述的B细胞增多相关疾病包括多发性骨髓瘤、慢性淋巴细胞白血病、巨球蛋白血症和浆细胞性白血病。
在本发明的第八方面,提供了一种治疗免疫性疾病的方法,向有需要的患者施用如本发明第一方面所述的融合蛋白。
在另一优选例中,所述的融合蛋白以单体和/或二聚体形式施用。
在另一优选例中,所述免疫性疾病包括类风湿关节炎(RA)、强直性脊柱炎(AS)、银屑病(PS)、银屑病关节炎(PsA)、幼年特发性关节炎(JIA)、系统性红斑狼疮(SLE)、白塞病(BD)、多发性硬化症(MS)、干燥综合征(SS)、Graves病、克罗恩病(CD)溃疡性结肠炎(UC)、原发性肾小球肾炎、自身免疫性血管炎、多发性肌炎(PM)、非感染性葡萄膜炎、自身免疫性溶血性贫血(AIHA)、自身免疫性紫癜(ATTP)、N-甲基-d-天冬氨酸受体(NMDAR)脑炎、重症肌无力、化脓性汗腺炎(HS)、髓鞘-少突胶质细胞糖蛋白谱紊乱(MOGSD)和视神经脊髓炎频谱障碍(NMOSD)。
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显示了融合蛋白的结构示意图(1A和1B),图1C显示了TNFR2-BCMA-Fc融合蛋白的氨基酸序列(SEQ ID NO.:19),第1-235位为TNFR2活性片段,加粗标记(第236-284位)的是BCMA活性片段,下划线标记(第285-515位)的是IgG Fc片段;图1D显示了TNFR2-BAFFR-Fc融合蛋白的氨基酸序列(SEQ ID NO.:20),第1-235位为TNFR2活性片段,加粗标记(第236-270位)的是BAFFR活性片段,下划线标记(第271-501位)的是IgG Fc片段;图1E显示了TNFR2-TACI-Fc融合蛋白的氨基酸序列(SEQ ID NO.:18),第1-235位为TNFR2活性片段,其中加粗标记(第236-277位)的是TACI活性片段,下划线标记(第278-508位)的是IgG Fc片段。
图2显示了融合蛋白(TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc)的还原和非还原SDS-PAGE电泳分析结果
图3显示了TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc融合蛋白体外结合人TNFα的活性。
图4显示了TNFR2-BCMA-Fc、TNFR2-TACI-Fc融合蛋白体外结合人BAFF的活性。
图5显示了TNFR2-BCMA-Fc、TNFR2-TACI-Fc融合蛋白体外结合APRIL的活性。
图6显示了TNFR2-BCMA-Fc与TNFa的体外结合不被BAFF(6A)或APRIL(6B)影响。
图7显示了TNFR2-BCMA-Fc(7A)、TNFR2-TACI-Fc(7B)融合蛋白抑制TNFα诱导L929细胞凋亡的活性。
图8显示了TNFR2-BCMA-Fc融合蛋白抑制BAFF(图8A)或APRIL(8B)保护RPMI8226细胞被DEX杀伤的功能,其中control为对照。
图9显示了TNFR2-BCMA-Fc融合蛋白抑制LPS诱导的小鼠感染性休克死亡的功能。
图10显示了TNFR2-BCMA-Fc显著降低小鼠血液(10A)和脾脏(10B)中B细胞的数量,其中etanercept为依那西普。
具体实施方式
本发明人经过广泛而深入地研究,首次意外发现,将(a)TNF受体或其活性片段、(b)TACI,BCMA,BAFFR或其活性片段、和(c)抗体Fc区域相融合,获得的融合蛋白具有优异的生物活性。本发明的融合蛋白在抑制TNFα诱导的炎症的同时,能够高效识别免疫反应中关键分子(如BAFF或APRIL),抑制B细胞的激活,起到与TNFR2协同作用,有助于治疗某些自身免疫性疾病。在此基础上完成了本发明。
具体地,本发明人制备了优化的融合蛋白TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc,研究表明,融合蛋白生物活性强,能够阻断BAFF或APRIL与其细胞膜受体结合。此外,本发明的融合蛋白能够明显降低C57小鼠脾脏B淋巴细胞的含量,抑制TNFa诱导细胞凋亡,保护LPS诱导小鼠休克死亡,缓解CIA和AIA大鼠模型骨关节炎症。
本发明构建的BAFF相关受体与TNFR2的全新组合的融合蛋白,该融合蛋白具有精确识别、协同作用、毒性可控的优势。在抑制TNFα及其下游通路引起自身免疫反应的同时,通过欺骗受体阻断B细胞上BAFF-R、BCMA、TACI与配体BAFF和APRIL的结合。该融合蛋白将通过对B细胞、T细胞以及一系列细胞因子有效的调控,进一步提高对自身免疫性疾病的疗效。
如本文所用,除非另外说明,Fc是指人免疫球蛋白的Fc片段。术语“免疫球蛋白Fc区”指免疫球蛋白链恒定区,特别是免疫球蛋白重链恒定区的羧基端或其中的一部分,例如免疫球蛋白Fc区可包括重链CH1、CH2、CH3的两个或更多结构域与免疫球蛋白铰链区的组合,在优选例中,所用的免疫球蛋白的Fc区包括至少一个免疫球蛋白绞链区,一个CH2结构域和一个CH3结构域,优选缺少CH1结构域。
已知人免疫球蛋白有多种类别,如IgA、IgD、IgE、IgM及IgG(包括IgG1、IgG2、IgG3、IgG4四个亚类),从特定的免疫球蛋白类别和亚类中选择特定的免疫球蛋白Fc区是在本领域技术人员所掌握的范围之内的,在一个优选的实例中,免疫球蛋白Fc区可选择包含有人免疫球蛋白IgG4亚类Fc区的编码序列,其中缺失一个免疫球蛋白重链1结构域(CH1),但包括了铰链区以及CH2、CH3、二个结构域的编码序列。
如本文所用,所述的“含有”,“具有”或“包括”包括了“包含”、“主要由……构成”、“基本上由……构成”、和“由……构成”;“主要由……构成”、“基本上由……构成”和“由……构成”属于“含有”、“具有”或“包括”的下位概念。
B细胞活化因子(B lymphocyte stimulator factor,BAFF)
BAFF是TNF家族的配体,其结构是一种II型膜结合蛋白。BAFF是B细胞存活与成熟的必需因子。BAFF主要通过与其受体BAFF-R、BCMA和TACI结合发挥生理作用。在狼疮小鼠模型中发现,血清中可溶性BAFF蛋白含量与疾病严重程度间呈显著正相关,主要与外周血自身反应性B细胞增加、B细胞异常活化以及自身抗体产生有关。另外,研究发现BAFF过表达的转基因小鼠易自发SLE。
BAFF-R(BAFF receptor)是BAFF的受体,可特异性与其结合,其结构是一种III型跨膜蛋白。BAFF-R在B细胞成熟阶段起到至关重要的作用,其通过与可溶性BAFF结合后促进B细胞增殖,并使B细胞向浆细胞分化,是B细胞发育早期阶段的重要受体。BAFF与BAFF-R结合后激活了一系列蛋白质合成和能量代谢的下游途径,进而延长了未成熟B细胞、过渡B细胞以及成熟B细胞的半衰期。BAFF与BAFF-R结合后,还可以通过NF-κB途径以及PI3K途径持续诱导B细胞的活化。研究显示,在系统性红斑狼疮患者中同样存在着BAFF的异常表达增高,而给予抗BAFF抗体后可有效的抑制体内可溶性的BAFF与其三种受体(BAFF-R、BCMA、TACI)的结合,进而抑制B细胞的分化和存活,达到治疗效果。
B细胞成熟抗原(B Cell Maturation Antigen,BCMA)
BCMA是肿瘤坏死因子受体超家族的成员,BCMA及其配体在调节免疫系统,尤其是调控B细胞增殖、分化和凋亡中起着重要的作用。BCMA主要在成熟的B细胞上表达,与维持B细胞的稳态、耐受性和终末分化中起着重要的作用,BCMA主要功能是介导浆细胞的长期存活并维持长效的体液免疫。BCMA已知与多发性骨髓瘤以及自身免疫性疾病的发生发展都有着紧密的联系。增殖诱导配体(A proliferation-inducing ligand,APRIL,或称TALL-2、TRDL-1及TNFSF-13)是TNF配体超家族的成员,与B淋巴细胞的发育、T细胞活化及体液免疫直接相关。
既往研究表明,B细胞上表达的BCMA的调控作用与其配体BAFF和APRIL有着紧密的联系。BAFF与BCMA结合在体内和体外都被证明是B细胞激活和抗体产生的共刺激分子。在狼疮模型小鼠中进行干预阻断BAFF和APRIL后,可以发现外周血B细胞和浆细胞数量都显著降低。研究显示,BCMA与其配体BAFF或APRIL的结合会启动浆细胞抗凋亡基因的转录,延长细胞的存活时间。一项研究显示,在类风湿关节炎患者中发现了APRIL显著增加并加剧了疾病的进展,而在使用BCMA-Fc融合蛋白进行干预后,发现BCMA-Fc融合蛋白在体内可以作为欺骗受体高亲和力的结合APRIL,进而抑制APRIL的生物活性,控制自身免疫性疾病的进展。
钙调亲环素配体相互作用分子(transmembrane activator and calmodulinligand interactor,TACI)
TACI是除BAFF-R和BCMA外,BAFF的第三种受体。目前认为TACI在B细胞成熟的过程中产生负性调节作用。除了与BAFF结合外,TACI同BCMA一样,还可与APRIL高亲和力的结合。BCMA/TACI与APRIL或BAFF结合后诱导NF-κB激活,并启动下游多个信号转导途径,导致过度激活的免疫反应进而造成自身免疫性疾病。TACI融合蛋白在体内和体外都被证实可以高亲和力的结合游离BAFF和APRIL,并竞争性抑制其与淋巴细胞上受体(TACI、BCMA、BAFF-R)结合,从而降低循环中成熟B细胞和免疫球蛋白的量。
融合蛋白
如本文所用,“本发明的融合蛋白”、或“多肽”均指本发明第一方面所述的融合蛋白。
如本文所用,除非另外说明,所述的融合蛋白是一种分离的蛋白,与其它蛋白、多肽或分子无联系,是重组宿主细胞培养的纯化产物或作为一种纯化的提取物。
本发明提供了一种融合蛋白,包含以下元件:(a)TNF受体或其活性片段、(b)BAFF受体(如TACI,BCMA和BAFFR)或其活性片段、和(c)抗体Fc区域。本发明所述的融合蛋白中,所述的各元件之间(如元件a与元件b、元件b或元件c之间),可以含有或不含有连接序列。所述的连接序列通常是对两个蛋白不产生影响作用的序列。
本发明的融合蛋白,不仅具有更长的体内半衰期,可以更有效地抑制血清中免疫疾病相关的抗体(尤其是IgE)的浓度。
根据本发明提供的氨基酸序列,本技术领域人员可方便地用各种已知方法制得本发明的融合蛋白。这些方法例如但不限于:重组DNA法,人工合成,等[参见Murray KM,DahlSLAnn;Pharmacother 1997Nov;31(11):1335-8]。
在得知了本发明的融合蛋白的氨基酸序列后,本领域人员可以方便地根据所述的氨基酸序列获得编码本发明的融合蛋白的基因序列。
作为本发明的优选方式,特别适合于在真核细胞(优选CHO细胞)中高表达本发明的融合蛋白,其中包括其氨基酸序列如SEQ ID NO.:19所示的TNFR2-BCMA-Fc融合蛋白的全长(即第1-515位)或其活性片段,例如第55-515位所示的多肽(融合蛋白)。
在一优选实施方式中,本发明的融合蛋白包含以下元件:
(a)TNF受体或其活性片段;(b)BAFF受体或其活性片段,其中所述的BAFF受体包括TACI,BCMA,BAFFR或其组合;和任选的(c)抗体Fc区域;本发明所述的融合蛋白中,所述的各元件之间(如元件a与元件b、元件b或元件c之间),可以含有或不含有连接序列。所述的连接序列通常是对两个蛋白不产生影响作用的序列。
如本文所用,术语“融合蛋白”还包括具有上述活性的融合蛋白(例如TNFR2-TACI-Fc(氨基酸序列如SEQ ID NO.:18所示)、TNFR2-BCMA-Fc(氨基酸序列如SEQ ID NO.:19所示)、TNFR2-BAFFR-Fc(氨基酸序列如SEQ ID NO.:20所示))的变异形式。这些变异形式包括(但并不限于):1-3个(通常为1-2个,更佳地1个)氨基酸的缺失、插入和/或取代,以及在C末端和/或N末端添加或缺失一个或数个(通常为3个以内,较佳地为2个以内,更佳地为1个以内)氨基酸。例如,在本领域中,用性能相近或相似的氨基酸进行取代时,通常不会改变蛋白质的功能。又比如,在C末端和/或N末端添加或缺失一个或数个氨基酸通常也不会改变蛋白质的结构和功能。此外,所述术语还包括单体和多聚体形式的本发明多肽。该术语还包括线性以及非线性的多肽(如环肽)。
本发明还包括上述融合蛋白的活性片段、衍生物和类似物。如本文所用,术语“片段”、“衍生物”和“类似物”是指基本上保持本发明融合蛋白的功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是(i)有一个或几个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽,或(ii)在一个或多个氨基酸残基中具有取代基团的多肽,或(iii)抗原肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iv)附加的氨基酸序列融合于此多肽序列而形成的多肽(与前导序列、分泌序列或6×His等标签序列融合而形成的融合蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。
一类优选的活性衍生物指与式I或式II的氨基酸序列相比,有至多3个,较佳地至多2个,更佳地至多1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
本发明还提供本发明融合蛋白的类似物。这些类似物与SEQ ID NO.:18、19或SEQID NO.:20所示的多肽的差别可以是氨基酸序列上的差异,也可以是不影响序列的修饰形式上的差异,或者兼而有之。类似物还包括具有不同于天然L-氨基酸的残基(如D-氨基酸)的类似物,以及具有非天然存在的或合成的氨基酸(如β、γ-氨基酸)的类似物。应理解,本发明的多肽并不限于上述例举的代表性的多肽。
修饰(通常不改变一级结构)形式包括:体内或体外的多肽的化学衍生形式如乙酰化或羧基化。修饰还包括糖基化,如那些在多肽的合成和加工中或进一步加工步骤中进行糖基化修饰而产生的多肽。这种修饰可以通过将多肽暴露于进行糖基化的酶(如哺乳动物的糖基化酶或去糖基化酶)而完成。修饰形式还包括具有磷酸化氨基酸残基(如磷酸酪氨酸,磷酸丝氨酸,磷酸苏氨酸)的序列。还包括被修饰从而提高了其抗蛋白水解性能或优化了溶解性能的多肽。
表达载体和宿主细胞、制备方法
本发明还提供了一种表达载体,包含编码本发明的融合蛋白的序列以及与之操作性相连的表达调控序列。所述的“操作性相连”或“可操作地连于”指这样一种状况,即线性DNA序列的某些部分能够调节或控制同一线性DNA序列其它部分的活性。例如,如果启动子控制序列的转录,那么它就是可操作地连于编码序列。
表达和克隆载体可含有一个或多个筛选基因,也称作可筛选标记。典型的筛选基因编码蛋白可以(a)抵抗抗菌素等;(b)补偿营养缺陷或(c)提供关键的在培养基中没有的营养物质。例如,DHFR(二氢叶酸还原酶缺陷细胞)缺陷的DG44细胞不能生长在不含次黄嘌呤-胸腺嘧啶的培养基里生长,在细胞被可表达DHFR的载体转染后,转染的细胞不仅可生长在不含含次黄嘌呤-胸腺嘧啶的培养基里生长,还可生长在含有一定量的MTX(氨甲喋呤)培养基里生长。
表达载体和克隆载体通常都会含有一个或多个基因转录启动子,或者被原核细胞转录机制识别,或者被真核细胞转录机制识别。用于真核细胞转录的启动子有但不限于巨细胞病毒(CMV)启动子,反转录病毒启动子,猴病毒40(SV40)前期启动子等。
表达载体可采用市售的例如但不限于:pIRES、pDR,pUC18等可用于真核细胞系统表达的载体。本领域技术人员可以根据宿主细胞来选择合适的表达载体。
根据已知空载表达载体的酶切图谱,本领域技术人员可按照常规方法通过限制性酶剪切与拼接,将本发明的融合蛋白的编码序列插入合适的限制性位点,制得本发明的重组表达载体。
本发明还提供了表达本发明融合蛋白的宿主细胞,其中含有本发明的融合蛋白的编码序列。所述的宿主细胞优选的是真核细胞,例如但不限于CHO,COS细胞,293细胞,RSF细胞等。作为本发明的优选方式,所述的细胞是CHO细胞,其可良好地表达本发明的融合蛋白,可获得结合活性良好,稳定性良好的融合蛋白。
本发明还提供一种用重组DNA制备本发明融合蛋白的方法,其步骤包括:
1)提供编码融合蛋白的核酸序列;
2)将1)的核酸序列插入到合适的表达载体,获得重组表达载体;
3)将2)的重组表达载体导入合适的宿主细胞;
4)在适合表达的条件下培养转化宿主细胞;
5)收集上清液,并纯化融合蛋白产物。
将所述编码序列导入宿主细胞可采用本领域的多种已知技术,例如但不限于:磷酸钙沉淀,原生质体融合,脂质体转染,电穿孔,微注射,反转录法,噬菌体转导法,碱金属离子法。
有关宿主细胞的培养和表达可参见Olander RM Dev Biol Stand 1996;86:338。可通过离心去除悬浮液中的细胞和残渣,收集清液。可通过聚丙烯酰胺凝胶电泳技术进行鉴定。
可将上述制备获得的融合蛋白纯化为基本均一的性质,例如在SDS-PAGE电泳上呈单一条带。例如,当重组蛋白为分泌表达时,可以采用商品化的超滤膜来分离所述蛋白,例如Millipore、Pellicon等公司产品,首先将表达上清浓缩。浓缩液可采用凝胶层析的方法进一步加以纯化,或采用离子交换层析的方法纯化。例如阴离子交换层析(DEAE等)或阳离子交换层析。凝胶基质可为聚丙烯酰胺、葡聚糖、聚酰胺等常用于蛋白纯化的基质。Q-或SP-基团是较为理想的离子交换基团。最后,还可用羟基磷灰石吸附层析,金属螯合层析,疏水相互作用层析和反相高效液相色谱(RP-HPLC)等方法对上述纯化产物进一步精制纯化。上述所有纯化步骤可利用不同的组合,最终使蛋白纯度达到基本均一。
可利用含有所述融合蛋白的特异性抗体、受体或配体的亲和层析柱对表达的融合蛋白进行纯化。根据所使用的亲和柱的特性,可利用常规的方法,如高盐缓冲液、改变pH等方法洗脱结合在亲和柱上的融合性多肽。可选择地,所述的融合蛋白的氨基端或羧基端还可含有一个或多个多肽片段,作为蛋白标签。任何合适的标签都可以用于本发明。例如,所述的标签可以是FLAG,HA,HA1,c-Myc,6-His或8-His等。这些标签可用于对融合蛋白进行纯化。
肽接头
本发明提供了一种融合蛋白,它可任选地含有肽接头。肽接头大小和复杂性可能会影响蛋白的活性。通常,肽接头应当具有足够的长度和柔韧性,以保证连接的两个蛋白在空间上有足够的自由度以发挥其功能。同时避免肽接头中形成α螺旋或β折叠等对融合蛋白的稳定性的影响。
连接肽的长度一般为0-20个氨基酸,较佳地0-10个氨基酸。
药物组合物
本发明还提供了一种药物组合物,它含有有效量(如0.000001-90wt%;较佳的0.1-50wt%;更佳的,5-40wt%)的本发明的融合蛋白,以及药学上可接受的载体。
通常,可将本发明的融合蛋白配制于无毒的、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5-8,较佳地,pH约为6-8。
如本文所用,术语“有效量”或“有效剂量”是指可对人和/或动物产生功能或活性的且可被人和/或动物所接受的量。
如本文所用,“药学上可接受的”的成分是适用于人和/或哺乳动物而无过度不良副反应(如毒性、刺激和变态反应)的,即具有合理的效益/风险比的物质。术语“药学上可接受的载体”指用于治疗剂给药的载体,包括各种赋形剂和稀释剂。
本发明的药物组合物含有安全有效量的本发明的融合蛋白以及药学上可接受的载体。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。通常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。所述的药物组合物宜在无菌条件下制造。活性成分的给药量是治疗有效量。本发明的药物制剂还可制成缓释制剂。
本发明所述的融合蛋白的有效量可随给药的模式和待治疗的疾病的严重程度等而变化。优选的有效量的选择可以由本领域普通技术人员根据各种因素来确定(例如通过临床试验)。所述的因素包括但不限于:所述的融合蛋白的药代动力学参数例如生物利用率、代谢、半衰期等;患者所要治疗的疾病的严重程度、患者的体重、患者的免疫状况、给药的途径等。通常,当本发明的融合蛋白每天以约0.00001mg-50mg/kg动物体重(较佳的0.0001mg-10mg/kg动物体重)的剂量给予,能得到令人满意的效果。例如,由治疗状况的迫切要求,可每天给予若干次分开的剂量,或将剂量按比例地减少。
本发明的主要优点包括
(1)本发明融合蛋白具有精确识别、协同作用、毒性可控的优势。
(2)本发明融合蛋白能够高效识别免疫反应中关键分子(如TNFa、BAFF或APRIL)。
(3)本发明融合蛋白能同时结合TNFa和BAFF或APRIL,同时抑制TNFa和BAFF或APRIL的生物学功能。
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。
引物
本发明涉及的引物如下表1所示:
表1引物序列
实施例1.TNFR2-BCMA-Fc融合蛋白表达质粒的构建
编码人TNFR2氨基酸序列(Met1-Asp257)的核糖核苷酸序列和编码人IgG Fc氨基酸序列的核糖核苷酸序列均由GenScript(USA)公司合成,编码人BCMA氨基酸序列(Gly6-Ala54)的核糖核苷酸序列由Genewiz(中国)公司合成。
编码TNFR2-BCMA-Fc融合蛋白的重组基因用两步聚合酶链式反应技术(PCR)方法连接起来。第一步,用PCR方法(高保真聚合酶Pfx,Invitrogen)扩增人TNFR2(Met1-Asp257)基因:
5’端引物KDP068(SEQ ID NO:1):5'-CTTTGGCAAAGAATTGGG-3',位于基因5’的载体上。
3’端引物KDP422(SEQ ID NO:2):5'-GTCGCCAGTGCTCCCTTCAG-3',是TNFR2基因专一引物。
同样,用PCR方法扩增BCMA(Gly6-Ala54)的基因:
5’端引物KDP410(SEQ ID NO:3):
5'-CTGAAGGGAGCACTGGCGACGGGCAGTGCTCCCAAAATG-3';
3’端引物KDP411(SEQ ID NO:4):
5'-TATCACAGCTCTTGGGCTCCGCATTCGTTCCTTTCACTG-3'。
同样,用PCR方法扩增人IgG1 Fc(Glu99-Gly329)的基因:
5’端引物KDP134(SEQ ID NO:5):
5'-GAGCCCAAGAGCTGTGATA-3';
3’端引物BGHR(SEQ ID NO:6):
5'-AACTAGAAGGCACAGTCGAGGC-3',位于基因3’端的载体上。
其中引物KDP410的头20个核苷酸序列与引物KDP422的核苷酸序列互补,引物KDP411的头19个核苷酸序列与引物KDP134的核苷酸序列互补,这样在第二步的重叠延伸PCR过程中,可以把这3个PCR片段连接起来。
上面3个PCR片段经DNA胶纯化后(天根生化科技有限公司,北京),进行第二步重叠PCR。
5’端引物KDP066(SEQ ID NO:7),5'-CGAACATCGATTGAATTCC-3'。
3’端引物KDP093(SEQ ID NO:8),5'-TCTAGCATTTAGGTGACAC-3'。
TNFR2基因转录起始位点前有Not I的酶切位点,IgG1 Fc终止密码子的3’端有XbaI酶切位点,在胶纯化重叠延伸PCR反应获得到的DNA片段后,进行Not I/Xba I双酶切(Takara)。然后把酶切的PCR片段克隆到同样酶切的哺乳动物细胞表达载体上。此哺乳动物细胞表达载体是改进的pcDNA3.1(Invitrogen),pcDNA3.1里的抗neomycin(新霉素)基因被DHFR(二氢叶酸还原酶)基因取代,改进后的载体适用于筛选稳定转染蛋白高表达的哺乳动物细胞。将重组质粒转染进DH5a感受态细菌,用菌落PCR方法鉴定含有正确重组质粒的阳性菌落,提纯重组质粒。
TNFR2-BCMA-Fc融合蛋白的氨基酸序列(SEQ ID NO.:19)如图1C所示,具体氨基酸如下:
片段1.TNFR2氨基酸序列(SEQ ID NO.:13)的第1-235位;
片段2.BCMA氨基酸序列(SEQ ID NO.:16)的第6-54位;
片段3.人IgG1氨基酸序列(登录号为UniProtKB-P01857)的第99-329位(SEQ IDNO.:17)。
实施例2.TNFR2-BAFFR-Fc融合蛋白表达质粒的构建
用实施例1的方法构建TNFR2-BAFFR-Fc融合蛋白基因。编码人BAFFR氨基酸序列(Asp12-Ala46)的核糖核苷酸序列由Genewiz(中国)公司合成。
第一步,用PCR方法(高保真聚合酶Pfx,Invitrogen)扩增人TNFR2(Met1-Asp257)基因和人IgG1 Fc(Glu99-Gly329)的基因(方法同实施例1)。
同样,用PCR方法扩增BAFFR(Asp12-Ala46)的基因:
5’端引物KDP408(SEQ ID NO:9):
5'-CTGAAGGGAGCACTGGCGACGACGCGCCAGCCCCCACGC-3';
3’端引物KDP409(SEQ ID NO:10):
5'-TATCACAGCTCTTGGGCTCGGCCGGTTTCGGCCGCGG-3'。
其中引物KDP408的头20个核苷酸序列与引物KDP422的核苷酸序列互补,引物KDP409的头19个核苷酸序列与引物KDP134的核苷酸序列互补,这样在第二步的重叠延伸PCR过程中,可以把这3个PCR片段连接起来。
上面3个PCR片段经DNA胶纯化后(天根生化科技有限公司,北京),进行第二步重叠PCR(方法同实施例1),把上述3个PCR片段按照相应的顺序连接,构建成TNFR2-BAFFR-Fc融合蛋白编码基因。再用与实施例1中相同的方法把构建好的重组基因克隆到哺乳细胞表达载体中。
TNFR2-BAFFR-Fc融合蛋白的氨基酸序列(SEQ ID NO.:20)如图1D所示,具体氨基酸如下:
片段1.TNFR2氨基酸序列(SEQ ID NO.:13)的第1-235位;
片段2.BAFFR氨基酸序列(SEQ ID NO.:16)的第12-46位;
片段3.人IgG1氨基酸序列(登录号为UniProtKB-P01857)的第99-329位(SEQ IDNO.:17)。
实施例3.TNFR2-TACI-Fc融合蛋白表达质粒的构建
用实施例1的方法构建TNFR2-TACI-Fc融合蛋白基因。编码人TACI氨基酸序列(Ser68-Arg109)的核糖核苷酸序列由Genewiz(中国)公司合成。
第一步,用PCR方法(高保真聚合酶Pfx,Invitrogen)扩增人TNFR2(Met1-Asp257)基因和人IgG1 Fc(Glu99-Gly329)的基因(方法同实施例1)。
同样,用PCR方法扩增TACI(Ser70-Arg109)的基因:
5’端引物KDP412(SEQ ID NO:11):
5'-CTGAAGGGAGCACTGGCGACTCACTCAGCTGCCGCAAGGAG-3';
3’端引物KDP413(SEQ ID NO:12):
5'-TATCACAGCTCTTGGGCTCCCTGAGCTTGTTCTCACAGAAG-3'。
其中引物KDP412的头20个核苷酸序列与引物KDP422的核苷酸序列互补,引物KDP412的头19个核苷酸序列与引物KDP134的核苷酸序列互补,这样在第二步的重叠延伸PCR过程中,可以把这3个PCR片段连接起来。
上面3个PCR片段经DNA胶纯化后(天根生化科技有限公司,北京),进行第二步重叠PCR(方法同实施例1),把上述3个PCR片段按照相应的顺序连接,构建成TNFR2-TACI-Fc融合蛋白编码基因。再用与实施例1中相同的方法把构建好的重组基因克隆到哺乳细胞表达载体中。
TNFR2-TACI-Fc融合蛋白的氨基酸序列(SEQ ID NO.:18)如图1E所示,具体氨基酸如下:
片段1.TNFR2氨基酸序列(SEQ ID NO.:13)的第1-235位;
片段2.TACI氨基酸序列(SEQ ID NO.:16)的第68-109位;
片段3.人IgG1氨基酸序列(登录号为UniProtKB-P01857)的第99-329位(SEQ IDNO.:17)。
实施例4.建立融合蛋白稳定表达细胞株
用于稳定表达这些融合蛋白的宿主细胞为中国仓鼠卵巢细胞CHO-KS。CHO-KS是生长在含胎牛血清(FBS)培养基里的CHO-K1细胞经过逐渐降低培养基中FBS含量的培养直至无FBS培养基培养,最终驯化成在不含FBS的OptiCHO培养基(Invitrogen)中悬浮生长的细胞。含有融合蛋白基因的pcDNA3.1载体中的抗新霉素基因用大鼠谷氨酰胺合成酶基因取代,采用电转染(Bio-Rad,Gene Pulser Xcell)的方法把融合蛋白表达表达质粒转染进CHO-KS细胞,转染的细胞在培养24-48个小时后,用有限稀释法在96孔培养板上对转染的细胞进行筛选培养。筛选培养基是OptiCHO,5μg/ml重组人胰岛素和10μM氨基亚砜蛋氨酸(MSX)。在37℃,8%CO2的培养箱里培养细胞。3个星期后,用ELISA方法(碱性磷酸酶偶联的羊抗人IgG Fc抗体,Jackson ImmunoResearch Lab)对每个长有细胞群的孔的细胞培养液进行分析,把融合蛋白表达阳性的细胞群进一步扩增,再ELISA检测,再扩增,最后得到融合蛋白表达稳定细胞株。
实施例5.融合蛋白的制备、纯化和鉴定
将实施例4所得的各融合蛋白稳定表达细胞株,培养扩增细胞。离心细胞培养液,收集上清,用Protein-A亲和层析柱从上清中纯化融合蛋白。
结果与分析
本发明的融合蛋白为同源共价二聚体,TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc的分子量差别不大,二聚体约为112kDa(图2,泳道1、3、7,非还原SDS-PAGE),单体约为56kDa(图2,泳道2、4、8,还原SDS-PAGE),都略为大于TNFR2-Fc(依那西普),其二聚体和单体的分子量分别为102kDa和51kDa(图2,泳道5、6)。
实施例6.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc与重组人TNFa体外结合研究
用ELISA方法研究融合蛋白与重组人TNFa的体外结合活性。
用PBS(pH7.4)溶解重组人TNFa(Novoprotein)至终浓度0.8μg/mL,并加入50μL/孔重组蛋白于96-孔ELISA板,4℃冰箱里过夜。第二天,用PBST(PBS含0.05%Tween-20)洗ELISA板3次,加入100μL/孔PBST含3%BSA的封闭溶液。ELISA板于37℃恒温箱里放置1小时。分别将融合蛋白稀释在PBST含1%BSA的结合溶液里,制备3倍系列稀释的溶液。倒掉封闭液,分别加入稀释的蛋白,50μL/孔,在37℃恒温箱里反应1小时。倒掉溶液,ELISA板用PBST清洗3次,加入50μL/孔的二抗(碱性磷酸酶偶联的羊抗人IgG Fc抗体,JacksonImmunoResearch Lab),在37℃恒温箱里反应1小时。倒掉显色抗体,向ELISA板上加200μL/孔PBST清洗溶液,ELISA板于水平摇床上放置5分钟,转速100转/分钟,倒掉清洗溶液,再重复清洗4次。加50μL/孔抗体显色液(PNPP)后ELISA板置于37℃恒温箱里进行显色。用酶标仪在波长405nm/490nm下读板。
结果与分析
图3显示了融合蛋白TNFR2-BAFFR-Fc和TNFR2-BCMA-Fc均能特异性结合人TNFα。TNFR2-BAFFR-Fc和TNFR2-BCMA-Fc与TNFa结合的亲和力EC50分别为189ng/mL和46ng/mL(图3A和3B)。
实施例7.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc与重组人BAFF结合研究
用ELISA方法研究融合蛋白与重组人BAFF的结合活性。
用50mM NaHCO3(pH9.6)溶解重组人BAFF至终浓度1.0μg/mL,并加入50μL/孔重组蛋白于96-孔ELISA板,4℃冰箱里过夜。第二天,用PBST(PBS含0.05%Tween-20)洗ELISA板3次,加入100μL/孔PBST含3%BSA的封闭溶液。ELISA板于37℃恒温箱里放置1小时。分别将各融合蛋白稀释在PBST含1%BSA的结合溶液里,制备3倍系列稀释的溶液。倒掉封闭液,分别加入稀释的蛋白,50μL/孔,在37℃恒温箱里反应1小时。倒掉溶液,ELISA板用PBST清洗3次,加入50μL/孔的二抗(碱性磷酸酶偶联的羊抗人IgG Fc抗体,Jackson ImmunoResearchLab),在37℃恒温箱里反应1小时。倒掉显色抗体,向ELISA板上加200μL/孔PBST清洗溶液,ELISA板于水平摇床上放置5分钟,转速100转/分钟,倒掉清洗溶液,再重复清洗4次。加50μL/孔抗体显色液(PNPP)后ELISA板置于37℃恒温箱里进行显色。用酶标仪在波长405nm/655nm下读板。
结果与分析
图4显示了融合蛋白TNFR2-BCMA-Fc和TNFR2-TACI-Fc均能特异性体外结合重组人BAFF。TNFR2-BCMA-Fc和TNFR2-TACI-Fc融合蛋白与BAFF结合的亲和力分别为71ng/mL和50ng/mL(图4A和4B)。
实施例8.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc与重组人APRIL结合研究
用ELISA方法研究融合蛋白与重组人APRIL的结合活性。
用50mM NaHCO3(pH9.6)溶解重组人APRIL至终浓度1.0μg/mL,并加入50μL/孔重组蛋白于96-孔ELISA板,4℃冰箱里过夜。第二天,用PBST(PBS含0.05%Tween-20)洗ELISA板3次,加入100μL/孔PBST含3%BSA的封闭溶液。ELISA板于37℃恒温箱里放置1小时。分别将各融合蛋白稀释在PBST含1%BSA的结合溶液里,制备3倍系列稀释的溶液。倒掉封闭液,分别加入稀释的蛋白,50μL/孔,在37℃恒温箱里反应1小时。倒掉溶液,ELISA板用PBST清洗3次,加入50μL/孔的二抗(碱性磷酸酶偶联的羊抗人IgG Fc抗体,Jackson ImmunoResearchLab),在37℃恒温箱里反应1小时。倒掉显色抗体,向ELISA板上加200μL/孔PBST清洗溶液,ELISA板于水平摇床上放置5分钟,转速100转/分钟,倒掉清洗溶液,再重复清洗4次。加50μL/孔抗体显色液(PNPP)后ELISA板置于37℃恒温箱里进行显色。用酶标仪在波长405nm/655nm下读板。
结果与分析
图5显示了融合蛋白TNFR2-BCMA-Fc和TNFR2-TACI-Fc均能特异性体外结合重组人APRIL。TNFR2-BCMA-Fc和TNFR2-TACI-Fc与APRIL结合的亲和力分别为23ng/mL和104ng/mL(图5A和5B)。
实施例9.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc融合蛋白同时结合TNFa和BAFF或APRIL且互不影响
本发明的融合蛋白高亲和力结合TNFa和BAFF或APRIL,重组人TNFa(Novoprotein)溶解于PBS(pH7.4)至终浓度0.8μg/mL,加入rhTNFa 50μL/孔于96-孔ELISA板,4℃冰箱里过夜。第二天,用PBST(PBS含0.05%Tween-20)洗ELISA板3次,加入100μL/孔PBST含3%BSA的封闭溶液。ELISA板于37℃恒温箱里放置1小时。融合蛋白用结合溶液(PBST含1%BSA)含或不含1μg/mL的BAFF或APRIL进行3倍系列稀释。倒掉封闭液,分别加入系列稀释的融合蛋白,50μL/孔,在37℃恒温箱里反应1小时。倒掉溶液,ELISA板用PBST清洗3次,加入50μL/孔的二抗(碱性磷酸酶偶联的羊抗人IgG Fc抗体,Jackson ImmunoResearch Lab),在37℃恒温箱里反应1小时。倒掉显色抗体,向ELISA板上加200μL/孔PBST清洗溶液,ELISA板于水平摇床上放置5分钟,转速100转/分钟,倒掉清洗溶液,再重复清洗4次。加50μL/孔抗体显色液(PNPP)后ELISA板置于37℃恒温箱里进行显色。用酶标仪在波长405nm/490nm下读板。
结果与分析
TNFR2-BCMA-Fc在含BAFF溶液里和不含BAFF溶液里与TNFa的结合完全一致(图6A),在含APRIL溶液里和不含APRIL溶液里与TNFa的结合没有显著差别(图6B)。
实验结果证明BAFF或APRIL不影响TNFR2-BCMA-Fc与TNFa的结合,TNFR2-BCMA-Fc能同时并互不影响的结合TNFa和BAFF或APRIL。
实施例10.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc融合蛋白抑制TNFa诱导细胞凋亡的生物学活性研究
融合蛋白的TNFR2生物学活性研究方法采用在体外中和TNFa的生物学活性。TNFa生物活性用小鼠成纤维细胞L929细胞毒性检测。5ng/mL的rhTNFa与系列稀释不同浓度的各融合蛋白混合,然后加入到培养在96-well培养板里的L929细胞中,培养液中加入Actinomycin D(终浓度20μg/mL),在细胞培养箱里培养20小时后用结晶子染色方法检测L929细胞活率。
结果与分析
图7显示了融合蛋白抑制TNFa诱导细胞凋亡的研究结果。TNFR2-BCMA-Fc和TNFR2-TACI-Fc抑制TNFa诱导L929细胞凋亡的活性EC50分别为27ng/mL和23ng/mL(图7A和7B)。
实施例11.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc融合蛋白抑制BAFF和APRIL体外刺激RPMI8226细胞的生长
RPMI8226是人多发性骨髓瘤细胞,地塞米松(DEX)能诱导RPMI8226细胞死亡,BAFF或APRIL能抑制DEX诱导RPMI8226细胞死亡的作用。我们对本发明的融合蛋白对BAFF和APRIL的上述抑制作用的影响进行了研究。
RPMI8226细胞培养在96-well板RPMI1660培养基中(含10%FBS),加入图8中所示的各试剂,在细胞培养箱中培养5天,然后用CCK-8检测活细胞数量。
结果与分析
与阴性对照细胞相比(只培养在RPMI1660+10%FBS培养基中),RPMI8226细胞在0.1μM浓度的DEX中细胞存活率为37%,0.1μg/mL的BAFF抑制DEX诱导的细胞死亡,增加RPMI8226细胞的活率达到55%,10μg/mL的TNFR2-BCMA-Fc抑制BAFF的功能,使RPMI8226的细胞存活率降到42%,具有显著的抑制BAFF活性的效果(p<0.0001)(图8A)。TNFR2-BCMA-Fc同样能抑制APRIL保护RPMI8226细胞的功能,使RPMI8226细胞存活率从63%降低到46%(p<0.0001)(图8B)。
本实验的结果证明了本发明的融合蛋白具有抑制BAFF或APRIL保护RPMI8226细胞存活的功能。
实施例12.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc融合蛋白降低LPS诱导的小鼠感染性休克死亡率
研究融合蛋白对LPS诱导的小鼠感染性休克死亡的影响,评估融合蛋白体内中和TNFa的生物学活性。16只7-8周龄Balb/c雄鼠分成2组,每组8只。每只小鼠腹腔注射1mg的LPS,随即给2组小鼠分别静脉注射PBS和6mg/kg的TNFR2-BCMA-Fc,在随后的80小时内观察小鼠状态,记录小鼠死亡的时间。
结果与分析
图9显示,在给予LPS后24小时内,PBS组有2只小鼠死亡,而TNFR2-BCMA-Fc组没有小鼠死亡。在41小时内,PBS组又有5只小鼠死亡,死亡率88%,在48小时内PBS组小鼠全部死亡。而TNFR2-BCMA-Fc组在41小时内死亡5只小鼠,死亡率63%,在72小时内又死亡1只,在80小时内共死亡6只,死亡率75%。
实验结果表明,TNFR2-BCMA-Fc能降低LPS诱导的小鼠休克死亡率。
实施例13.TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc融合蛋白降低小鼠B淋巴细胞含量的研究
给小鼠注射融合蛋白2次,检测小鼠脾脏B淋巴细胞的含量,评估融合蛋白对B淋巴细胞的影响。
6-7周龄的雄性C57BL/6小鼠按体重随机分组,每组5只,在D1、D5尾静脉给予相应的药物。D9分别采集小鼠眼底血100μL,各加入100μL含抗凝剂的PBS,加入anti-mouse B220(CD45R)-APC 1μL和anti-mouse CD3-FITC,冰上染色30min后,再加入6倍体积的流式溶血素裂解,震荡后并静置10分钟,再800G离心15分钟,加入FACS工作液200μL重悬。用流式细胞仪检测样本中B220+细胞群和CD3+细胞群所占比例。D10脱颈处死全部小鼠,取血、解剖取脾脏,分离脾脏淋巴细胞。用上述同样的方法检测脾脏淋巴细胞中B220+细胞群和CD3+细胞群所占比例。
结果与分析
膜蛋白B220是小鼠B淋巴细胞的生物标志物,所有B细胞都表达B220。图10显示了TNFR2-BCMA-Fc能显著降低小鼠血液中(图10A)和脾脏中(图10B)B淋巴细胞的含量,7.5mg/kg和15mg/kg剂量的TNFR2-BCMA-Fc分别降低血液中B淋巴细胞的含量37%和43%,降低脾脏中B淋巴细胞的含量44%和56%。依那西普(etanercept)对血液中B淋巴细胞的含量没有任何影响,对脾脏中B淋巴细胞的含量有降低的作用(降低23%),但显著弱于同等剂量的TNFR2-BCMA-Fc的作用(降低44%)
实施例14.融合蛋白对CIA和AIA小鼠鼠模型关节炎症的影响
AIA和CIA小鼠模型建立方法分别参考文献Feige e等,Cell Mol Life Sci,57:1457-1470,2000和Schett等,Arthritis Rheum.52:1604-1611,2005。AIA和CIA模型小鼠分别随机分成1~3个依那西普剂量组、1~3个TNFR2-BAFFR-Fc剂量组、1~3个TNFR2-BCMA-Fc和1~3个TNFR2-TACI-Fc剂量组,每个模型含1个对照组(PBS),每组含8~10只小鼠。在每个小鼠模型的临床症状出现后几天之内开始皮下注射药物或PBS,每天或每隔几天给药,共持续1~4周。
大鼠临床症状检测如下:
评估局部关节炎的炎症程度。测量大鼠前或后足肿胀程度,包括前后足的体积和直径,计算前后足肿胀程度。
评估各组大鼠踝和椎骨被炎症细胞浸润程度。进行大鼠踝和椎骨的组织学和免疫组织化学研究。在试验结束后,取下大鼠的足踝和腰椎骨,制备组织切片。用常规光学显微镜观察组织切片,对组织的炎症细胞浸润程度进行打分。
讨论:
后续将进行本发明融合蛋白(TNFR2-BAFFR-Fc、TNFR2-BCMA-Fc和TNFR2-TACI-Fc)抑制BAFF体内刺激小鼠B淋巴细胞的增殖,以及融合蛋白对小鼠红斑狼疮模型的疾病抑制作用和对小鼠白塞病模型的疾病抑制作用的研究,以说明本发明融合蛋白的优异的生物活性。
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> 上海康岱生物医药技术股份有限公司
<120> TNFR2与BAFF受体的融合蛋白
<130> P2020-2430
<160> 20
<170> SIPOSequenceListing 1.0
<210> 1
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Cys Thr Thr Thr Gly Gly Cys Ala Ala Ala Gly Ala Ala Thr Thr Gly
1 5 10 15
Gly Gly
<210> 2
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gly Thr Cys Gly Cys Cys Ala Gly Thr Gly Cys Thr Cys Cys Cys Thr
1 5 10 15
Thr Cys Ala Gly
20
<210> 3
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Cys Thr Gly Ala Ala Gly Gly Gly Ala Gly Cys Ala Cys Thr Gly Gly
1 5 10 15
Cys Gly Ala Cys Gly Gly Gly Cys Ala Gly Thr Gly Cys Thr Cys Cys
20 25 30
Cys Ala Ala Ala Ala Thr Gly
35
<210> 4
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Thr Ala Thr Cys Ala Cys Ala Gly Cys Thr Cys Thr Thr Gly Gly Gly
1 5 10 15
Cys Thr Cys Cys Gly Cys Ala Thr Thr Cys Gly Thr Thr Cys Cys Thr
20 25 30
Thr Thr Cys Ala Cys Thr Gly
35
<210> 5
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gly Ala Gly Cys Cys Cys Ala Ala Gly Ala Gly Cys Thr Gly Thr Gly
1 5 10 15
Ala Thr Ala
<210> 6
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Ala Ala Cys Thr Ala Gly Ala Ala Gly Gly Cys Ala Cys Ala Gly Thr
1 5 10 15
Cys Gly Ala Gly Gly Cys
20
<210> 7
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Cys Gly Ala Ala Cys Ala Thr Cys Gly Ala Thr Thr Gly Ala Ala Thr
1 5 10 15
Thr Cys Cys
<210> 8
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Thr Cys Thr Ala Gly Cys Ala Thr Thr Thr Ala Gly Gly Thr Gly Ala
1 5 10 15
Cys Ala Cys
<210> 9
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Cys Thr Gly Ala Ala Gly Gly Gly Ala Gly Cys Ala Cys Thr Gly Gly
1 5 10 15
Cys Gly Ala Cys Gly Ala Cys Gly Cys Gly Cys Cys Ala Gly Cys Cys
20 25 30
Cys Cys Cys Ala Cys Gly Cys
35
<210> 10
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Thr Ala Thr Cys Ala Cys Ala Gly Cys Thr Cys Thr Thr Gly Gly Gly
1 5 10 15
Cys Thr Cys Gly Gly Cys Cys Gly Gly Thr Thr Thr Cys Gly Gly Cys
20 25 30
Cys Gly Cys Gly Gly
35
<210> 11
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Cys Thr Gly Ala Ala Gly Gly Gly Ala Gly Cys Ala Cys Thr Gly Gly
1 5 10 15
Cys Gly Ala Cys Thr Cys Ala Cys Thr Cys Ala Gly Cys Thr Gly Cys
20 25 30
Cys Gly Cys Ala Ala Gly Gly Ala Gly
35 40
<210> 12
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Thr Ala Thr Cys Ala Cys Ala Gly Cys Thr Cys Thr Thr Gly Gly Gly
1 5 10 15
Cys Thr Cys Cys Cys Thr Gly Ala Gly Cys Thr Thr Gly Thr Thr Cys
20 25 30
Thr Cys Ala Cys Ala Gly Ala Ala Gly
35 40
<210> 13
<211> 235
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser
1 5 10 15
Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys
20 25 30
Ser Lys Cys Ser Pro Gly Gln His Ala Lys Val Phe Cys Thr Lys Thr
35 40 45
Ser Asp Thr Val Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu
50 55 60
Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser
65 70 75 80
Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys
85 90 95
Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys
100 105 110
Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
115 120 125
Arg Pro Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala Pro
130 135 140
Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
145 150 155 160
Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala
165 170 175
Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val
180 185 190
His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr
195 200 205
Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly
210 215 220
Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp
225 230 235
<210> 14
<211> 293
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Met Ser Gly Leu Gly Arg Ser Arg Arg Gly Gly Arg Ser Arg Val Asp
1 5 10 15
Gln Glu Glu Arg Phe Pro Gln Gly Leu Trp Thr Gly Val Ala Met Arg
20 25 30
Ser Cys Pro Glu Glu Gln Tyr Trp Asp Pro Leu Leu Gly Thr Cys Met
35 40 45
Ser Cys Lys Thr Ile Cys Asn His Gln Ser Gln Arg Thr Cys Ala Ala
50 55 60
Phe Cys Arg Ser Leu Ser Cys Arg Lys Glu Gln Gly Lys Phe Tyr Asp
65 70 75 80
His Leu Leu Arg Asp Cys Ile Ser Cys Ala Ser Ile Cys Gly Gln His
85 90 95
Pro Lys Gln Cys Ala Tyr Phe Cys Glu Asn Lys Leu Arg Ser Pro Val
100 105 110
Asn Leu Pro Pro Glu Leu Arg Arg Gln Arg Ser Gly Glu Val Glu Asn
115 120 125
Asn Ser Asp Asn Ser Gly Arg Tyr Gln Gly Leu Glu His Arg Gly Ser
130 135 140
Glu Ala Ser Pro Ala Leu Pro Gly Leu Lys Leu Ser Ala Asp Gln Val
145 150 155 160
Ala Leu Val Tyr Ser Thr Leu Gly Leu Cys Leu Cys Ala Val Leu Cys
165 170 175
Cys Phe Leu Val Ala Val Ala Cys Phe Leu Lys Lys Arg Gly Asp Pro
180 185 190
Cys Ser Cys Gln Pro Arg Ser Arg Pro Arg Gln Ser Pro Ala Lys Ser
195 200 205
Ser Gln Asp His Ala Met Glu Ala Gly Ser Pro Val Ser Thr Ser Pro
210 215 220
Glu Pro Val Glu Thr Cys Ser Phe Cys Phe Pro Glu Cys Arg Ala Pro
225 230 235 240
Thr Gln Glu Ser Ala Val Thr Pro Gly Thr Pro Asp Pro Thr Cys Ala
245 250 255
Gly Arg Trp Gly Cys His Thr Arg Thr Thr Val Leu Gln Pro Cys Pro
260 265 270
His Ile Pro Asp Ser Gly Leu Gly Ile Val Cys Val Pro Ala Gln Glu
275 280 285
Gly Gly Pro Gly Ala
290
<210> 15
<211> 184
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr
20 25 30
Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser
35 40 45
Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu
50 55 60
Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile
65 70 75 80
Ser Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu
85 90 95
Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu
100 105 110
Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys
115 120 125
Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe
130 135 140
Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys
145 150 155 160
Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu
165 170 175
Ile Glu Lys Ser Ile Ser Ala Arg
180
<210> 16
<211> 184
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Met Arg Arg Gly Pro Arg Ser Leu Arg Gly Arg Asp Ala Pro Ala Pro
1 5 10 15
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
20 25 30
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Gly Ala
35 40 45
Ser Ser Pro Ala Pro Arg Thr Ala Leu Gln Pro Gln Glu Ser Val Gly
50 55 60
Ala Gly Ala Gly Glu Ala Ala Leu Pro Leu Pro Gly Leu Leu Phe Gly
65 70 75 80
Ala Pro Ala Leu Leu Gly Leu Ala Leu Val Leu Ala Leu Val Leu Val
85 90 95
Gly Leu Val Ser Trp Arg Arg Arg Gln Arg Arg Leu Arg Gly Ala Ser
100 105 110
Ser Ala Glu Ala Pro Asp Gly Asp Lys Asp Ala Pro Glu Pro Leu Asp
115 120 125
Lys Val Ile Ile Leu Ser Pro Gly Ile Ser Asp Ala Thr Ala Pro Ala
130 135 140
Trp Pro Pro Pro Gly Glu Asp Pro Gly Thr Thr Pro Pro Gly His Ser
145 150 155 160
Val Pro Val Pro Ala Thr Glu Leu Gly Ser Thr Glu Leu Val Thr Thr
165 170 175
Lys Thr Ala Gly Pro Glu Gln Gln
180
<210> 17
<211> 231
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly
225 230
<210> 18
<211> 508
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser
1 5 10 15
Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys
20 25 30
Ser Lys Cys Ser Pro Gly Gln His Ala Lys Val Phe Cys Thr Lys Thr
35 40 45
Ser Asp Thr Val Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu
50 55 60
Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser
65 70 75 80
Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys
85 90 95
Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys
100 105 110
Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
115 120 125
Arg Pro Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala Pro
130 135 140
Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
145 150 155 160
Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala
165 170 175
Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val
180 185 190
His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr
195 200 205
Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly
210 215 220
Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp Ser Leu Ser Cys Arg
225 230 235 240
Lys Glu Gln Gly Lys Phe Tyr Asp His Leu Leu Arg Asp Cys Ile Ser
245 250 255
Cys Ala Ser Ile Cys Gly Gln His Pro Lys Gln Cys Ala Tyr Phe Cys
260 265 270
Glu Asn Lys Leu Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
275 280 285
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
290 295 300
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
305 310 315 320
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
325 330 335
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
340 345 350
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
355 360 365
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
370 375 380
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
385 390 395 400
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
405 410 415
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
420 425 430
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
435 440 445
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
450 455 460
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
465 470 475 480
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
485 490 495
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
500 505
<210> 19
<211> 515
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser
1 5 10 15
Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys
20 25 30
Ser Lys Cys Ser Pro Gly Gln His Ala Lys Val Phe Cys Thr Lys Thr
35 40 45
Ser Asp Thr Val Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu
50 55 60
Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser
65 70 75 80
Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys
85 90 95
Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys
100 105 110
Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
115 120 125
Arg Pro Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala Pro
130 135 140
Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
145 150 155 160
Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala
165 170 175
Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val
180 185 190
His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr
195 200 205
Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly
210 215 220
Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp Gly Gln Cys Ser Gln
225 230 235 240
Asn Glu Tyr Phe Asp Ser Leu Leu His Ala Cys Ile Pro Cys Gln Leu
245 250 255
Arg Cys Ser Ser Asn Thr Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn
260 265 270
Ala Ser Val Thr Asn Ser Val Lys Gly Thr Asn Ala Glu Pro Lys Ser
275 280 285
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
290 295 300
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
305 310 315 320
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
325 330 335
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
340 345 350
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
355 360 365
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
370 375 380
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
385 390 395 400
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
405 410 415
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
420 425 430
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
435 440 445
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
450 455 460
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
465 470 475 480
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
485 490 495
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
500 505 510
Ser Pro Gly
515
<210> 20
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser
1 5 10 15
Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys
20 25 30
Ser Lys Cys Ser Pro Gly Gln His Ala Lys Val Phe Cys Thr Lys Thr
35 40 45
Ser Asp Thr Val Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu
50 55 60
Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser
65 70 75 80
Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys
85 90 95
Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys
100 105 110
Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
115 120 125
Arg Pro Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala Pro
130 135 140
Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
145 150 155 160
Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala
165 170 175
Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val
180 185 190
His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr
195 200 205
Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly
210 215 220
Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp Asp Ala Pro Ala Pro
225 230 235 240
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
245 250 255
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Glu Pro
260 265 270
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly
500
Claims (10)
1.一种融合蛋白,其特征在于,所述融合蛋白包括融合在一起的以下元件:
(a)TNF受体或其活性片段;
(b)BAFF受体或其活性片段,其中所述的BAFF受体包括TACI,BCMA,BAFFR或其组合;
和任选的(c)抗体Fc区域;
其中,所述的融合蛋白保留了上述元件(a)和(b)的生物活性。
2.如权利要求1所述的融合蛋白,其特征在于,所述的融合蛋白还具有以下一种或多种功能:
(a)结合TNFα的活性;
(b)抑制TNFα诱导的炎症;
(c)结合BAFF或APRIL的活性;
(d)抑制或封闭BAFF/APPRIL途径;
(e)降低体内B细胞的数量。
3.如权利要求1所述的融合蛋白,其特征在于,所述融合蛋白具有下式I或II所示的二聚体结构:
X-Y-Z(I)
Y-X-Z(II);
式中,
X为TNF受体的胞外段;
Y为TACI,BCMA或BAFFR的胞外段;
Z为无、或任选的人抗体的Fc区域;
-表示肽键或肽接头。
4.如权利要求1所述的融合蛋白,其特征在于,所述融合蛋白的氨基酸序列如SEQ IDNO.:18或19或20所示。
5.如权利要求3所述的融合蛋白,其特征在于,所述的X含有或具有TNFR2氨基酸序列(SEQ ID NO.:13)的第1-235位,或第17-179位,或第17-140位,或第55-179位,或第55-140位;和/或
所述的Y含有或具有:
(a)TACI氨基酸序列(SEQ ID NO.:14)的第1-109位,或第33-109位,或第68-109位;
(b)BCMA氨基酸序列(SEQ ID NO.:15)的第1-54位,或第6-54位;或
(c)BAFFR氨基酸序列(SEQ ID NO.:16)的第1-78位,或第12-78位,或第12-46位;和/或
所述的Z含有或具有人IgG1氨基酸序列(登录号为UniProtKB-P01857)的第99-329位。
6.一种核酸分子,其特征在于,所述的核酸分子编码权利要求1所述的融合蛋白。
7.一种载体,其特征在于,它含有权利要求6所述的核酸分子。
8.一种基因工程化的细胞,其特征在于,所述的细胞含有权利要求7所述的载体;或所述的细胞基因组中整合有权利要求6所述的核酸分子。
9.一种产生权利要求1所述的融合蛋白的方法,其特征在于,所述的方法包括步骤:
在适合表达所述融合蛋白的条件下,培养权利要求8所述的基因工程化的细胞,从而表达所述的融合蛋白;和
分离或纯化所述的融合蛋白。
10.一种药物组合物,其特征在于,所述的药物组合物含有权利要求1所述的融合蛋白及其药物学上可接受的载体。
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PCT/CN2022/080467 WO2022188883A1 (zh) | 2021-03-12 | 2022-03-11 | Tnfr2与april/baff受体的融合蛋白 |
CN202280007564.0A CN116802301A (zh) | 2021-03-12 | 2022-03-11 | Tnfr2与april/baff受体的融合蛋白 |
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US6541610B1 (en) * | 1989-09-05 | 2003-04-01 | Immunex Corporation | Fusion proteins comprising tumor necrosis factor receptor |
AU671116B2 (en) * | 1992-03-30 | 1996-08-15 | Immunex Corporation | Fusion proteins comprising tumor necrosis factor receptor |
US7300773B2 (en) * | 2004-08-27 | 2007-11-27 | Wyeth Research Ireland Limited | Production of TNFR-Ig |
CN1309740C (zh) * | 2005-10-20 | 2007-04-11 | 高基民 | 可溶性肿瘤坏死因子受体ⅱ-“脂联素”球部融合蛋白 |
BRPI0716382B8 (pt) * | 2006-08-28 | 2021-05-25 | Ares Trading Sa | método para reduzir o teor de porções de fc livres em um fluido compreendendo uma proteína contendo fc, e uso de cromatografia de troca catiônica |
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BRPI0914005A2 (pt) * | 2008-07-02 | 2015-11-17 | Emergent Product Dev Seattle | proteínas antagonistas tnf-alfa de ligação a alvos múltiplos |
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