CN108623689A - 新型重组双功能融合蛋白及其制备方法和用途 - Google Patents
新型重组双功能融合蛋白及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了一种新型重组双功能融合蛋白及其制备方法和用途;具体地,本发明提供的重组双功能融合蛋白(CD20mAb‑SD1)由抗人CD20单克隆抗体与人SIRPα膜外端第一个功能区(SIRPα‑Domain 1,SD1)串联而成。体外实验证实,该蛋白可同时与人CD20及人CD47结合,可通过抗体依赖、细胞介导的细胞毒及补体依赖的细胞毒活性而发挥对CD20阳性肿瘤细胞的治疗作用,同时可阻断CD47与SIRPα的结合,从而激活巨噬细胞对肿瘤细胞进行攻击,具有显著地抗肿瘤活性。
Description
技术领域
本发明属于是生物医药领域,具体地本发明涉及新型重组双功能融合蛋白及其制备方法和用途。
背景技术
CD20是表达在B淋巴细胞膜表面的穿膜蛋白,生物学功能至今未明,有可能作为钙离子通道,促进B细胞免疫反应。CD20表达在除了早前细胞及浆细胞以外所有发育阶段的B细胞膜上。同时CD20也在B淋巴瘤、慢性B淋巴细胞白血病、毛细胞白血病、以及黑色素瘤干细胞上表达。已经批准上市的、针对CD20的单克隆抗体药物有利妥昔单抗(Rituximab)、阿托珠单抗(Obinutuzumab)、奥法木单抗(Ofatumumab)。这些抗体药物的作用机制均通过ADCC及CDC。然而在临床治疗过程中发现,有些患者经过一定时间治疗以后,可诱导CD20从细胞上脱落,从而失去对抗体药物的敏感性。有些患者则表达低亲和性基因型(158F)的Fcgamma受体(FcγRIIIA-158F),对美罗华也具有一定的耐受性。所以如何克服患者对美罗华的耐受性,已成为抗体药物研发领域比较热门的话题。
CD47也是一种穿膜糖蛋白,属于免疫球蛋白超家族成员,在包括红细胞在内的几乎所有细胞表面表达。CD47的配体包括黏附因子(integrins)、凝血酶敏感蛋白1(thrombospondin-1)、以及信号调节蛋白(SIRPs)。CD47具有多种生物学功能,包括细胞迁移、T细胞、树突状细胞活化、轴突发育等。除此之外,CD47通过与SIRPα相互作用可抑制巨噬细胞的吞噬作用。CD47以这种方式传递一种所谓的“不要吃我”("Don't eat me")信号,可以保护血细胞等正常细胞不被巨噬细胞吞噬。
研究发现,除正常组织细胞表达CD47以外,许多肿瘤细胞过度表达CD47,并通过与巨噬细胞表面的SIRPα相结合而阻止巨噬细胞对肿瘤细胞的吞噬,这被视为肿瘤逃避机体免疫监视的一种机制。高表达CD47的肿瘤包括急性髓样白血病细胞(AML)、慢性髓样白血病细胞(CML)、急性淋巴细胞白血病细胞(ALL)、非何杰金氏淋巴瘤(NHL)、多发性骨髓瘤(MM)、膀胱癌、卵巢癌、前列腺癌、肺癌、大肠癌、乳腺癌、胰腺癌等等。
研究表明,用具有阻断CD47-SIRPα结合活性的CD47-特异性抗体给荷瘤小鼠注射,可以显著抑制肿瘤在小鼠体内的生长。
发明内容
本发明的目的在于提供一种新型重组双功能融合蛋白及其制备方法和用途。
本发明的第一方面,提供了一种重组双功能融合蛋白,所述重组双功能融合蛋白包含:
第一结合结构域(D1);和
第二结合结构域(D2);
其中,所述第一结合结构域特异性结合靶分子CD20蛋白;
所述第二结合结构域特异性结合靶分子CD47蛋白。
在另一优选例中,所述D1为特异性结合CD20蛋白的抗体或抗体片段。
在另一优选例中,所述D2为特异性结合CD47蛋白的多肽片段,并且所述多肽片段衍生自SIRPα。
在另一优选例中,所述D1和所述D2通过连接肽相连;优选地,所述连接肽包括抗体恒定区序列。
在另一优选例中,D1为抗CD20单克隆抗体,D2为人SIRPα膜外端第一个功能区(SIRPα-Domain 1,SD1),D2连接在D1的重链恒定区末端。
在另一优选例中,所述抗CD20单克隆抗体包括SEQ ID NO.5所示的重链可变区和SEQ ID NO.7所示的轻链可变区。
在另一优选例中,D2的氨基酸序列如SEQ ID NO.9所示。
在另一优选例中,所述重组双功能融合蛋白为同源二聚体。
在另一优选例中,所述抗CD20单克隆抗体包括通过二硫键连接的四条多肽链(两条重链及两条轻链),并且D2连接在所述抗CD20单克隆抗体的重链C端或N端。
本发明的第二方面,提供了一种多核苷酸,它编码如本发明第一方面所述的重组双功能融合蛋白。
本发明的第三方面,提供了一种载体,它含有本发明第二方面所述的多核苷酸。
在另一优选例中,所述的载体包括:细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒、或其他载体。
本发明的第四方面,提供了一种遗传工程化的宿主细胞,它含有本发明第三方面所述的载体或基因组中整合有本发明第二方面所述的多核苷酸。
本发明第五方面,提供了一种免疫偶联物,该免疫偶联物含有:
(a)如如本发明第一方面所述的重组双功能融合蛋白;和
(b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶。
在另一优选例中,所述偶联物部分选自:荧光或发光标记物、放射性标记物、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶、放射性核素、生物毒素、细胞因子(如IL-2等)、抗体、抗体Fc片段、抗体scFv片段、金纳米颗粒/纳米棒、病毒颗粒、脂质体、纳米磁粒、前药激活酶(例如,DT-心肌黄酶(DTD)或联苯基水解酶-样蛋白质(BPHL))、化疗剂(例如,顺铂)或任何形式的纳米颗粒等。
本发明的第六方面,提供了一种药物组合物,它含有:
(i)如本发明第一方面所述的重组双功能融合蛋白、或如本发明第五方面所述的免疫偶联物;以及
(ii)药学上可接受的载体。
在另一优选例中,所述的药物组合物为注射剂型。
在另一优选例中,所述的药物组合物用于制备治疗肿瘤的药物,优选地,所述的肿瘤选自下组:胃癌、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、前列腺癌、宫颈癌、肾上腺肿瘤、或膀胱肿瘤。
本发明的第七方面,提供了如本发明第一方面所述的重组双功能融合蛋白、或如本发明第五方面所述的免疫偶联物的用途,用于制备药物;所述药物用于治疗或预防表达CD20蛋白的肿瘤。
在另一优选例中,所述肿瘤包括:胃癌、淋巴瘤、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、前列腺癌、或肾上腺肿瘤。
本发明的第八方面,提供了一种重组双功能融合蛋白的制备方法,该方法包含:
(a)在适合表达的条件下,培养本发明第四方面所述的宿主细胞;
(b)从培养物中分离出如本发明第一方面所述的重组双功能融合蛋白。
本发明的第九方面,提供了一种治疗肿瘤的方法,所述方法包括步骤给需要的对象施用本发明本发明第一方面所述的重组双功能融合蛋白或本发明第五方面所述的免疫偶联物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了CD20mAb-SD1蛋白结构及工作模式。
图2A和图2B显示了CD20mAb-SD1核苷酸序列,图2A为重链核苷酸序列,图2B为轻链核苷酸序列
图3A和图3B显示了CD20mAb-SD1氨基酸序列,图3A为重链氨基酸序列,图3B为轻链氨基酸序列。
图4A、图4B和图4C显示了HPLC和CE-SDS分析,图4A显示了SEC-HPLC分析结果;图4B显示了非还原的(Non-reduced)CE-SDS分析结果,图4C显示而来还原的CE-SDS分析结果。
图5A和图5B显示了靶点亲和活性,图5A显示了与CD20靶点的亲和活性,图5B与CD47靶点的亲和活性。
图6显示了CD47靶点阻断活性。
图7A和图7B显示了ADCC和CDC活性分析,图7A显示了ADCC活性,图7B显示了CDC活性。
图8显示了体内抗肿瘤活性。
具体实施方式
本发明人通过广泛而深入的研究,意外地获得一种基因重组双功能融合蛋白(CD20mAb-SD1),由抗人CD20单克隆抗体与人SIRPα膜外端第一个功能区(SIRPα-Domain 1,SD1)串联而成。CD20mAb-SD1属于同源二聚体,分子量为180kDa。经过细胞株筛选,利用中国仓鼠卵巢细胞(CHO)制备了该蛋白的稳定表达细胞株,并经过发酵培养制备了500毫克该蛋白。体外实验证实,该蛋白可同时与人CD20及人CD47结合,可通过抗体依赖、细胞介导的细胞毒(Antibody-Dependent Cell Cytotoxicity,ADCC)及补体依赖的细胞毒(Complement-Dependent Cytotoxicity,CDC)活性而发挥对CD20阳性肿瘤细胞的治疗作用,同时可阻断CD47与SIRPα的结合,从而激活巨噬细胞对肿瘤细胞进行攻击。经人淋巴瘤模型体内药效实验证实,CD20Ab-SD1具有显著地抗肿瘤活性,经过CD20mAb-SD1治疗的小鼠存活率为100%,而单一美罗华治疗的小鼠,存活率只有67%。因此,本发明的CD20mAb-SD1可以被开发为一种疗效优越的抗肿瘤药物,用来治疗对美罗华无效或出现耐受的B细报淋巴瘤及B淋巴细胞白血病患者。
在具体描述本发明之前,应当理解本发明不限于所述的具体方法和实验条件,因为这类方法和条件可以变动。还应当理解本文所用的术语其目的仅在于描述具体实施方案,并且不意图是限制性的,本发明的范围将仅由所附的权利要求书限制。
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料,本文在此处例举优选的方法和材料。
SIRPα
信号调节蛋白α(signal regulatory proteinα,SIRPα)也称为SH2结构域的蛋白酪氨酸磷酸酶底物1,属于免疫球蛋白超家族的跨膜蛋白。SIRPα是CD47的一种重要的表面受体,CD47-SIRPα信号通路在免疫系统中存在负性调节作用。
在一优选的实施方式中,所述SIRPα膜外端第一个功能区(SIRPα-Domain1,SD1)的氨基酸序列如下:
EEELQVIQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISAITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSAPVVSGPAARATPQH(SEQ ID NO.9)。
抗CD20抗体
CD20是表达在B淋巴细胞膜表面的穿膜蛋白。CD20表达在除了早前细胞及浆细胞以外所有发育阶段的B细胞膜上。同时CD20也在B淋巴瘤、慢性B淋巴细胞白血病、毛细胞白血病、以及黑色素瘤干细胞上表达。已经批准上市的、针对CD20的单克隆抗体药物有利妥昔单抗(Rituximab)、阿托珠单抗(Obinutuzumab)、奥法木单抗(Ofatumumab)。因此,在本发明的一个优选地实施方式中,用于制备本发明基因重组双功能融合蛋白的抗CD20抗体选自下组:利妥昔单抗(Rituximab)、阿托珠单抗(Obinutuzumab)、奥法木单抗(Ofatumumab)。
在本发明的另一个优选地实施方式中,所述抗CD20抗体的重链可变区的氨基酸序列如下:
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA(SEQ ID NO.5);
其编码核苷酸序列为:
CAGGTCCAGCTGCAGCAGCCGGGCGCGGAGCTCGTGAAGCCGGGGGCCTCGGTCAAGATGAGCTGCAAGGCCAGCGGCTACACCTTCACGAGCTACAACATGCACTGGGTGAAGCAGACCCCGGGCCGGGGGCTGGAGTGGATCGGCGCCATCTACCCCGGGAACGGCGACACCAGCTACAACCAGAAGTTCAAGGGCAAGGCGACCCTGACGGCGGACAAGTCGAGCAGCACCGCCTACATGCAGCTCAGCAGCCTGACCTCGGAGGACAGCGCCGTCTACTACTGCGCCCGGTCCACGTACTACGGCGGCGACTGGTACTTCAACGTCTGGGGGGCCGGCACGACCGTGACCGTGAGCGCG(SEQ ID NO.6)。
在本发明的一个优选地实施方式中,所述抗CD20抗体的轻链可变区的氨基酸序列如下:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK(SEQ ID NO.7);
其编码核苷酸序列为:
CAGATCGTGCTGAGCCAGTCGCCGGCCATCCTCAGCGCGAGCCCCGGCGAGAAGGTCACCATGACGTGCCGGGCCAGCAGCTCGGTGAGCTACATCCACTGGTTCCAGCAGAAGCCCGGGAGCAGCCCCAAGCCGTGGATCTACGCCACCAGCAACCTGGCCTCGGGCGTGCCCGTGCGCTTCAGCGGGAGCGGCAGCGGGACCAGCTACAGCCTGACCATCTCGCGGGTCGAGGCCGAGGACGCCGCCACCTACTACTGCCAGCAGTGGACCTCCAACCCGCCCACGTTCGGCGGCGGCACCAAGCTCGAGATCAAG(SEQ ID NO.8)。
在本发明的一个优选地实施方式中,所述抗CD20抗体为单链抗体,其重链可变区和轻链可变区之间任选地具有连接肽,所述连接肽长度优选为1-15个氨基酸,更优地为3-10个氨基酸。
双功能融合蛋白CD20mAb-SD1
本发明人令人惊讶地发现,本发明构建的双功能融合蛋白(包含特异性结合靶分子CD20蛋白结合结构域和特异性结合靶分子CD47蛋白的结合结构域),对于CD20阳性的肿瘤具有显著的抑制作用,而且能够增强美罗华对CD20阳性的肿瘤的疗效,以及治疗对美罗华单抗起抗性的CD20阳性肿瘤,能够用作美罗华单抗的增敏剂。
因此,本发明提供包含第一结合结构域(在本文中也称作“D1”)和第二结合结构域(在本文中也称作“D2”)的重组双功能融合蛋白,其中D1特异性结合靶分子CD20蛋白;D2特异性结合靶分子CD47蛋白。
根据本发明,重组双功能融合蛋白可以是单个多功能多肽,或它可以是彼此共价或非共价结合的两个或更多个多肽的多聚体复合物。如将因本公开而变得明显,将具有同时结合CD20和CD47分子的能力的任何结合性构建体视为重组双功能融合蛋白。
本发明的任何重组双功能融合蛋白或其变体可以使用标准分子生物学技术(例如,重组DNA和蛋白质表达技术)构建,如本领域普通技术人员将知晓。
在本发明的一个优选地实施方式中,所述特异性结合靶分子CD20蛋白结合结构域为抗CD20抗体,其包含SEQ ID NO.5所示的重链可变区和SEQ ID NO.7所示的轻链可变区。
在本发明的一个优选地实施方式中,所述特异性结合靶分子CD47蛋白结合结构域衍生自上述SIRPα,优选为SIRPα膜外端第一个功能区。
在本发明的另一个优选地实施方式中,所述重组双功能融合蛋白中,D2连接于D1的C端或N端。
在本发明的一个优选地实施方式中,所述抗CD20单克隆抗体包括通过二硫键连接的四条多肽链(两条重链及两条轻链),并且D2连接在所述抗CD20单克隆抗体的重链C端,优选地,重链和D2连接形成的多肽的氨基选序列如SEQ ID NO.3所示,其编码多核苷酸序列如SEQ ID NO.1;轻链的氨基选序列如SEQ ID NO.4所示,其编码多核苷酸序列如SEQ IDNO.2。
结合结构域
本发明的重组双功能融合蛋白包含至少两个独立的结合结构域(D1和D2)。如本文所用,表述“结合结构域”意指能够特异性结合特定目的蛋白的任何肽、多肽、核酸分子、支架型分子、肽展示分子或含多肽的构建体。
如本文所用,术语“特异性结合”等意指抗原结合结构域与以500pM或更小的解离常数(KD)为特征的特定抗原形成复合物,并且在普通测试条件下不结合其他不相关的蛋白。优选地,“不相关的蛋白”是彼此具有小于95%氨基酸同一性的蛋白质、肽或多肽。
可以在本发明上下文中使用的抗原结合结构域的示例性分类包括抗体、抗体的抗原结合部分、与特定抗原特异性相互作用的肽(例如,肽体(peptibody))、与特定抗原特异性相互作用的受体分子,包含特异性结合特定抗原的受体的配体结合部分的蛋白质、抗原结合支架(例如,DARPin,HEAT重复序列蛋白、ARM重复序列蛋白、三角形四肽重复序列蛋白和基于天然存在性重复序列蛋白的其他支架等[见,例如,Boersma和Pluckthun,2011,Curr.Opin.Biotechnol.22:849-857,和其中引用的参考文献])和适配体或其部分。
用于确定两个分子彼此是否特异性结合的方法是本领域熟知的并且例如包括平衡透析法、表面等离子体共振法等。例如,如本发明上下文中所用,抗原结合结构域包括如在表面等离子体共振测定法中所述测量,以小于约500pM、小于约400pM、小于约300pM、小于约200pM、小于约100pM、小于约90pM、小于约80pM、小于约70pM、小于约60pM、小于约50pM、小于约40pM、小于约30pM、小于约20pM、小于约10pM、小于约5pM、小于约4pM、小于约2pM、小于约1pM、小于约0.5pM、小于约0.2pM、小于约0.1pM,或小于约0.05pM的KD结合特定抗原或其部分的多肽。
如本文所用,术语“表面等离子体共振”指允许例如使用BIAcoreTM系统(GEHealthcare的BiacoreLifeSciences部门,Piscataway,NJ),通过检测生物传感器基质内部蛋白质浓度的改变来分析实时相互作用的光学现象。
如本文所用,术语“KD”意指特定蛋白质-蛋白质相互作用(例如,抗体-抗原相互作用)的平衡解离常数。除非另外指明,否则本文中公开的KD值指通过表面等离子体共振测定法在25℃确定的KD值。
抗体和抗体的抗原结合片段
如上文所示,“抗原结合结构域”(D1和/或D2)可以包含抗体或抗体的抗原结合片段或由其组成。如本文所用,术语“抗体”意指包含与特定抗原(例如,CD20蛋白或CD47蛋白)特异性结合或与之相互作用的至少一个互补决定区(CDR)的任何抗原结合分子或分子复合物。术语“抗体”包括包含4条多肽链(由二硫键相互连接的两条重链(H)和两条轻链(L))的免疫球蛋白分子以及其多聚体(例如,IgM)。每条重链包含重链可变区(本文中缩写为HCVR或VH)和重链恒定区。重链恒定区包含3个结构域:CH1、CH2和CH3。每条轻链包含轻链可变域(本文中缩写为LCVR或VL)和轻链恒定区。轻链恒定域包含一个结构域(CL1)。VH区和VL区可以进一步再划分为超变区,名为互补性决定区(CDR),其间插有更保守的区域,名为框架区(FR)。每个VH和VL由从氨基端至羧基端按以下顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4排列的3个CDR和4个FR的组成。在本发明的不同实施方案中,本发明抗体的(或其抗原结合部分)的FR可以与人种系序列相同,或可以经天然或人工修饰。可以基于并排分析两个或更多个CDR限定氨基酸共有序列。
本发明的重组双功能融合蛋白的D1和/或D2组分可以包含完整抗体分子的抗原结合片段或由其组成。如本文所用,术语抗体的“抗原结合部分”、抗体的“抗原结合片段”等包括特异性结合抗原以形成复合物的任何天然存在的、酶促可获得的、合成性或基因修饰的多肽或糖蛋白。可以使用任何合适的标准技术如蛋白酶解消化或涉及操作并表达编码抗体可变域和任选地抗体恒定域的DNA的重组基因工程技术,例如,从完整抗体分子衍生抗体的抗原结合片段。这类DNA是已知的和/或从例如商业来源、DNA文库(包括例如,噬菌体抗体文库)轻易可获得或可以合成。可以对所述DNA测序并化学地或通过使用分子生物学技术操作,例如以将一个或多个可变域和/或恒定域排列成合适布局,或以引入密码子、产生半胱氨酸残基、修饰、添加或缺失氨基酸等。抗原结合片段的非限制性例子包括:(i)Fab片段;(ii)F(ab')2片段;(iii)Fd片段;(iv)Fv片段;(v)单链Fv(scFv)分子;(vi)dAb片段;和(vii)由模拟抗体高变区的氨基酸残基组成的最小识别单位(例如,独立的互补性决定区(CDR)如CDR3肽)或受约束的FR3-CDR3-FR4肽。如本文所用,表述“抗原结合片段”内部也涵盖其他工程化分子,如结构域特异性抗体,单结构域抗体,结构域缺失抗体,嵌合抗体,CDR移植抗体、双体抗体、三体抗体、四体抗体、微型抗体、纳米体(例如单价纳米体、双价纳米体等)、小模块免疫药物(SMIP)和鲨鱼可变IgNAR域。
抗体的抗原结合片段一般将包含至少一个可变域。可变域可以具有任何尺寸或氨基酸组成并且通常将包含与一个或多个框架序列毗邻或符合可读框的至少一个CDR。在具有与VL结构域缔合的VH结构域的抗原结合片段中,VH和VL结构域可以按任何合适的排列彼此相对设置。例如,可变区可以是二聚体并含有VH-VH、VH-VL或VL-VL二聚体。可选地,抗体的抗原结合片段可以含有单体性VH或VL结构域。
在某些实施方案中,抗体的抗原结合片段可以含有与至少一个恒定域共价连接的至少一个可变域。可以在本发明抗体的抗原结合片段内部存的可变域和恒定域的非限制、示例性布局包括:(i)VH-CH1;(ii)VH-CH2;(iii)VH-CH3;(iv)VH-CH1-CH2;(v)VH-CH1-CH2-CH3;(vi)VH-CH2-CH3;(vii)VH-CL;(viii);)VL-CH1;(ix)VL-CH2;(x)VL-CH3;(xi)VL-CH1-CH2;(xii)VL-CH1-CH2-CH3;(xiii)VL-CH2-CH3;和(xiv)VL-CL。在可变域和恒定域的任何布局中,包括上文所列的任何示例性布局,可变域和恒定域可以彼此直接连接或可以由完整或部分的铰链区或接头区连接。铰链区可以由在单个多肽分子中相邻可变域和/或恒定域之间产生柔性连接或半柔性连接的至少2个(例如,5个、10个、15个、20个、40个、60个或更多个)氨基酸组成。另外,抗原结合片段可以包含具有上文所列的任何可变域和恒定域布局的彼此和/或与一个或多个单体性VH或VL结构域(例如,通过二硫键))处于非共价缔合的同型二聚体或异二聚体(或其他多聚体)。
本发明的重组双功能融合蛋白可以包含人抗体和/或重组人抗体或其片段或由其组成。如本文所用,术语“人抗体”包括具有源自人种系免疫球蛋白序列的可变区和恒定区的抗体。然而,人抗体可以包括不由人种系免疫球蛋白序列编码的(例如在CDR和尤其CDR3中)的氨基酸残基(例如,通过体外随机诱变或位点特异性诱变或通过体内体细胞突变引入的突变)。然而,如本文所用,术语“人抗体”不意在包括其中已经将从另一个哺乳动物物种(如小鼠)的种系衍生的CDR序列移植到人框架序列上的抗体。
本发明的重组双功能融合蛋白可以包含重组人抗体或其抗原结合片段或由其组成。如本文所用,术语“重组人抗体”意在包括通过重组手段所制备、表达、产生或分离的全部人抗体,如使用转染至宿主细胞(在下文进一步描述)中的重组表达载体表达的抗体、从重组人抗体组合文库(在下文进一步描述)分离的抗体、从相对于人免疫球蛋白基因而言转基因的动物(例如,小鼠)分离的抗体(见例如,Taylor等人,(1992)Nucl.AcidsRes.20:6287-6295)或通过涉及将人免疫球蛋白基因序列剪接至其他DNA序列的任何其他手段所制备、表达、产生或分离的抗体。此类重组人抗体具有源自人种系免疫球蛋白序列的可变区和恒定区。然而,在某些实施方案中,此类重组人抗体经历体外诱变(或,使用就人Ig序列而言为转基因的动物时,经历体内体细胞诱变)并且因此重组抗体的VH和VL区的氨基酸序列是尽管衍生自人种系VH和VL序列并且与之相关,但可能在体内人抗体种系库内部不天然存在的序列。
肿瘤靶向作用
在本发明的另一个方面,重组双功能融合蛋白可用于靶向肿瘤细胞。
本发明的重组双功能融合蛋白可以与药物、毒素、放射性同位素或有损细胞生存力的其他物质缀合(偶联)。可选地,药物或毒素可以是不直接杀伤细胞,但使细胞更易遭其他外部物质杀伤的物质。在涉及肿瘤靶向作用的另外的其他实施方案中,本发明的重组双功能融合蛋白本身不与药物、毒素或放射性同位素缀合,但是与其它抗原结合分子(本文中称作“协从分子”)组合施用,如其它的抗肿瘤抗体。
根据本发明的肿瘤靶向方面的某些实施方案,重组双功能融合蛋白(或协从抗体)可以与选自以下的一种或多种细胞毒药物缀合:刺孢霉素、埃斯波霉素、甲氨蝶呤、多柔比星、美法仓、苯丁酸氮芥、ARA-C、长春地辛、丝裂霉素C、顺铂、依托泊苷、博来霉素、5-氟尿嘧啶、雌氮芥、长春新碱、依托泊苷、多柔比星、紫杉醇、拉罗他赛、替司他赛、奥他赛(orataxel)、多西紫杉醇、多拉司他汀10、澳瑞司他汀E、澳瑞司他汀PHE和基于美坦辛的化合物(例如,DM1、DM4等)。重组双功能融合蛋白(或协从抗体)还可以或可选地与毒素缀合,如白喉毒素、铜绿假单胞菌(Pseudomonasaeruginosa)外毒素A、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒蛋白A链、α-帚曲菌素、油桐(Aleuritesfordii)蛋白、香石竹毒蛋白、垂序商陆(Phytolacaamericana)蛋白等。重组双功能融合蛋白(或协从抗体)还可以或可选地与选自以下的一种或多种放射性同位素缀合:225Ac、211At、212Bi、213Bi、186Rh、188Rh、177Lu、90Y、131I、67Cu、125I、123I、77Br、153Sm、166Ho、64Cu、121Pb、224Ra和223Ra。因此,本发明的这个方面包括作为抗体-药物缀合物(ADC)或抗体-放射性同位素缀合物(ARC)的重组双功能融合蛋白。
药物组合物和施用方法
本发明还提供了一种组合物。在优选例中,所述的组合物是药物组合物,它含有上述的抗体或其活性片段或其融合蛋白,或者上述的重组双功能融合蛋白,以及药学上可接受的载体。通常,可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中,其中pH通常约为5-8,较佳地pH约为6-8,尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药,其中包括(但并不限于):瘤内、腹膜内、静脉内、或局部给药。
本发明的药物组合物可用于预防和治疗肿瘤。此外,还可同时使用其他治疗剂。
本发明的药物组合物含有安全有效量(如0.001-99wt%,较佳地0.01-90wt%,更佳地0.1-80wt%)的本发明上述的特异性结合分子(或其偶联物)以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。药物组合物如针剂、溶液宜在无菌条件下制造。活性成分的给药量是治疗有效量,例如每天约1微克/千克体重-约5毫克/千克体重。此外,本发明的多肽还可与其他治疗剂一起使用。
使用药物组合物时,是将安全有效量的免疫偶联物施用于哺乳动物,其中该安全有效量通常至少约10微克/千克体重,而且在大多数情况下不超过约8毫克/千克体重,较佳地该剂量是约10微克/千克体重-约1毫克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
材料和方法
1、CD20mAb-SD1表达载体构建及蛋白生产
在美罗华(Rituximab)重链编码序列的羧基端与人SIRPα膜外端第一个功能区(SIRPα-Domain 1,SD1)的基因编码序列链接在一起,并在序列的两端加上了两个克隆位点(氨基端为HindIII、羧基端为SalI),从而构成CD20mAb-H-SD1基因编码序列。然后将CD20mAb-H-SD1的基因序列及美罗华轻链基因编码序列(CD20mAb-L)一起委托苏州省心生物技术有限公司予以合成,合成好的序列分别克隆至pMac-H及pMac-L表达载体(购自Macroimmune Inc公司),从而形成pMac-CD20mAb-H-SD1及pMac-CD20mAb-L表达载体。
将pMac-CD20mAb-H-SD1及pMac-CD20mAb-L表达载体构共转染CHO细胞(购自ATCC),并经过一系列加压筛选,制备能稳定表达CD20mAb-SD1蛋白的CHO细胞株。经过放大培养,制备出了500毫克CD20mAb-SD1蛋白。
2、SEC-HPLC/rCE-SDS/nrCE-SDS分析
将1mg CD20mAb-SD1蛋白进行SEC-HPLC及CE-SDS分析。
3、靶点结合活性(FACS):
我们利用两种肿瘤细胞分别鉴定了CD20mAb-SD1蛋白与CD20及CD47的结合活性。用Jurkat细胞(CD20-CD47+)分析CD47的靶点结合活性,用Raji-CD47KO细胞(CD20+CD47-)分析CD20的靶点结合活性。
4、CD47靶点阻断活性(FACS)
将不同浓度的CD20mAb-SD1蛋白及美罗华分别与25nM生物素标记的SIRPα-Fc(Biotin-SIRP α-Fc)混合在一起,室温孵育30分钟,然后将混合物与Jurkat细胞室温孵育1小时,经洗涤后,再与荧光标记的Streptavidin(FITC-Strep)一起室温孵育1小时,经洗涤后,将细胞混悬于100l冷的磷酸缓冲液(PBS)中,最后用流式细胞分析仪(FACS)分析SIRPα-Fc与细胞的结合情况。
5、ADCC
将106/ml Raji细胞(靶细胞)与1mM CFSE(1:500)混合,37度孵育30min,每10分钟混匀一次。将NK92MI-CD16a细胞(效应细胞)密度调整为6x105/ml。将效应细胞与靶细胞按照2:1比例混合在一起,然后加入不同浓度的美罗华、CD20mAb-SD1、及赫赛汀(Herceptin),37℃,5%CO2培养箱孵育4小时。孵育结束后,将细胞培养板于室温放置10min,平衡至室温,然后每孔中加入20l PI(Propodium Iodide)染料(终浓度5ug/ml),排枪吹打混匀后用FACS分析技术分析不同蛋白浓度下细胞PI染色阳性率,并按照以下公式计算ADCC活性:
%Lysis=(Sample%PI Positive Cell-No Antibody%PI Positive Cell)/(100-No Antibody%PI Positive Cell)*100。
最后利用GraphPad Prism软件绘制Lysis%与浓度的关系图。
6、CDC
将Raji细胞(靶细胞)与不同浓度的美罗华、CD20mAb-SD1、及赫赛汀(Herceptin)混合在一起,然后加入一定浓度的兔补体,将细胞放置37℃,5%CO2培养箱孵育4小时。孵育结束后,将细胞培养板于室温放置10min,平衡至室温,然后每孔中加入20ul PI(PropodiumIodide)染料(终浓度5ug/ml),排枪吹打混匀后用FACS分析技术分析不同蛋白浓度下细胞PI染色阳性率,并按照以下公式计算CDC活性:
Lysis%=Experimental Sample Lysis%-No Antibody Lysis%
最后利用GraphPad Prism软件绘制Lysis%与浓度的关系图。
7、体内抗肿瘤药效实验
利用Raji细胞原位肿瘤模型,对CD20mAb-SD1的体内抗肿瘤活性进行了研究。给30只免疫缺陷小鼠尾静脉注射Raji细胞,每只小鼠注射5x106个细胞,注射后第二天随机分为五组,第一组腹腔注射PBS,第二组腹腔注射CD20mAb-SD1(5mg/kg),第三组腹腔注射SD1-Fc(2.5mg/kg),第四组腹腔注射美罗华(2.5mg/kg),第五组腹腔注射SD1-Fc及美罗华(2.5+2.5mg/kg)。每周1次,连续5次给药。每天观察小鼠状况及测量体重。
本发明的主要优点在于:
(1)本发明设计的基因重组双功能融合蛋白具有显著地抗肿瘤活性,其肿瘤抑制效果明显高于单一美罗华治疗;
(2)本发明的基因重组双功能融合蛋白CD20mAb-SD1可以用来治疗对美罗华无效或出现耐受的肿瘤患者。
下面结合具体实施例,进一步详陈本发明。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(NewYork:ColdSpringHarborLaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1 CD20mAb-SD1表达载体构建
CD20mAb-SD1蛋白结构如图1所示,是由一条重链基因及一条轻链基因所编码的四条多肽链(两条重链及两条轻链)通过相应的二流键连接所组成。其中重链基因编码序列由1749个核苷酸组成(图2A),其中CD20mAb重链有1350个核苷酸,编码450个氨基酸(1-450),SD1序列有399个核苷酸,编码133个氨基酸(451-583)。相应的氨基酸序列如图3A所示。CD20mAb轻链有639个核苷酸(图2B),编码213个氨基酸(1-213)(图3B)。
实施例2 SEC-HPLC/rCE-SDS/nrCE-SDS分析
通过SEC-HPLC分析,证实CD20mAb-SD1蛋白聚体含量小于3%,低分子量成分(断裂)小于1%,表明蛋白的完整性非常好(图4A)。非还原条件下SDS结果表明,蛋白呈现一个主峰,比例大于95%(图4B)。还原条件下蛋白呈现两个主峰,分别代表重链(~70%)和轻链(~30%)(图4C)。
实施例3双靶点结合活性
我们利用流式细胞分析仪分别分析了CD20mAb-SD1蛋白与CD20及CD47的结合活性,结果显示,CD20mAb-SD1与两个靶点的结合活性都很高,其中与CD20的结合活性与美罗华类似,ED50分别为0.28nM(CD20mAb-SD1)及0.24nM(美罗华)。与CD47的亲和活性为EC50=5.28nM。
实施例4 CD47靶点阻断活性
利用Jurkat细胞,我们分析了CD20mAb-SD1对CD47与其配体SIRPα结合的阻断活性。如图6所示,CD20mAb-SD1可显著抑制SIRPα与Jurkat细胞的结合,并且抑制效应呈剂量依赖性。
实施例5 ADCC及CDC活性
CD20mAb-SD1蛋白同时具有ADCC(图7A)及CDC(图7B)活性,其中ADCC活性显著优于美罗华(EC50:CD20mAb-SD1=0.31ng/ml;美罗华=2.24ng/ml)。
实施例6体内抗肿瘤活性
利用Raji细胞原位肿瘤模型,我们研究了CD20mAb-SD1蛋白的体内抗肿瘤活性。如图8所示,未经治疗组的小鼠,在治疗开始后的38天之内全部死亡,经美罗华及SD1-Fc等单一靶点治疗的小组,小鼠的生存率得到大幅度延缓,至实验结束时,生存率分别为67%及83%。然而经过双靶点重组蛋白CD20mAb-SD1治疗的小组,生存率为100%,显著优于只作用于单一靶点的药物。
本发明的研究表明基因重组双功能融合蛋白CD20mAb-SD1是一种新型融合蛋白,具有良好的双靶点结合活性。生物学研究表明该蛋白同时具有ADCC、CDC、及CD47靶点阻断等活性,可以用于CD20、CD47靶点阳性的癌症治疗。
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> 宜明昂科生物医药技术(上海)有限公司
<120> 新型重组双功能融合蛋白及其制备方法和用途
<130> P2017-0149
<160> 9
<170> PatentIn version 3.5
<210> 1
<211> 1752
<212> DNA
<213> 人工序列
<400> 1
caggtccagc tgcagcagcc gggcgcggag ctcgtgaagc cgggggcctc ggtcaagatg 60
agctgcaagg ccagcggcta caccttcacg agctacaaca tgcactgggt gaagcagacc 120
ccgggccggg ggctggagtg gatcggcgcc atctaccccg ggaacggcga caccagctac 180
aaccagaagt tcaagggcaa ggcgaccctg acggcggaca agtcgagcag caccgcctac 240
atgcagctca gcagcctgac ctcggaggac agcgccgtct actactgcgc ccggtccacg 300
tactacggcg gcgactggta cttcaacgtc tggggggccg gcacgaccgt gaccgtgagc 360
gcggctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 660
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtatgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacgccacgt accgtgtggt cagcgtcctc accgtcctgc accaagactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcgc cgcaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080
gagatgacca agaaccaagt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgctggact ccgacggctc cttcttcctc tattccaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320
acgcagaaga gcctctccct gtctccgggc gaggaggagc tgcaggtgat tcagcctgac 1380
aagtccgtat cagttgcagc tggagagtcg gccattctgc actgcactgt gacctccctg 1440
atccctgtgg ggcccatcca gtggttcaga ggagctggac cagcccggga attaatctac 1500
aatcaaaaag aaggccactt cccccgggta acaactgttt cagagtccac aaagagagaa 1560
aacatggact tttccatcag catcagtgcc atcaccccag cagatgccgg cacctactac 1620
tgtgtgaagt tccggaaagg gagccctgac acggagttta agtctggagc aggcactgag 1680
ctgtctgtgc gtgccaaacc ctctgccccc gtggtatcgg gccctgcggc gagggccaca 1740
cctcagcact ga 1752
<210> 2
<211> 642
<212> DNA
<213> 人工序列
<400> 2
cagatcgtgc tgagccagtc gccggccatc ctcagcgcga gccccggcga gaaggtcacc 60
atgacgtgcc gggccagcag ctcggtgagc tacatccact ggttccagca gaagcccggg 120
agcagcccca agccgtggat ctacgccacc agcaacctgg cctcgggcgt gcccgtgcgc 180
ttcagcggga gcggcagcgg gaccagctac agcctgacca tctcgcgggt cgaggccgag 240
gacgccgcca cctactactg ccagcagtgg acctccaacc cgcccacgtt cggcggcggc 300
accaagcacg agctgaagcg aactgtggct gcaccatctg tcttcatctt cccgccatct 360
gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420
agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480
agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540
agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600
agctcgcccg tcacaaagag cttcaacagg ggagagtgtt ag 642
<210> 3
<211> 583
<212> PRT
<213> 人工序列
<400> 3
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ala Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Ala Ala Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser
450 455 460
Val Ala Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu
465 470 475 480
Ile Pro Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg
485 490 495
Glu Leu Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr
500 505 510
Val Ser Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile
515 520 525
Ser Ala Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe
530 535 540
Arg Lys Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu
545 550 555 560
Leu Ser Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala
565 570 575
Ala Arg Ala Thr Pro Gln His
580
<210> 4
<211> 213
<212> PRT
<213> 人工序列
<400> 4
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys His Glu Leu Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 5
<211> 121
<212> PRT
<213> 人工序列
<400> 5
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala
115 120
<210> 6
<211> 363
<212> DNA
<213> 人工序列
<400> 6
caggtccagc tgcagcagcc gggcgcggag ctcgtgaagc cgggggcctc ggtcaagatg 60
agctgcaagg ccagcggcta caccttcacg agctacaaca tgcactgggt gaagcagacc 120
ccgggccggg ggctggagtg gatcggcgcc atctaccccg ggaacggcga caccagctac 180
aaccagaagt tcaagggcaa ggcgaccctg acggcggaca agtcgagcag caccgcctac 240
atgcagctca gcagcctgac ctcggaggac agcgccgtct actactgcgc ccggtccacg 300
tactacggcg gcgactggta cttcaacgtc tggggggccg gcacgaccgt gaccgtgagc 360
gcg 363
<210> 7
<211> 106
<212> PRT
<213> 人工序列
<400> 7
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 8
<211> 318
<212> DNA
<213> 人工序列
<400> 8
cagatcgtgc tgagccagtc gccggccatc ctcagcgcga gccccggcga gaaggtcacc 60
atgacgtgcc gggccagcag ctcggtgagc tacatccact ggttccagca gaagcccggg 120
agcagcccca agccgtggat ctacgccacc agcaacctgg cctcgggcgt gcccgtgcgc 180
ttcagcggga gcggcagcgg gaccagctac agcctgacca tctcgcgggt cgaggccgag 240
gacgccgcca cctactactg ccagcagtgg acctccaacc cgcccacgtt cggcggcggc 300
accaagctcg agatcaag 318
<210> 9
<211> 133
<212> PRT
<213> 人工序列
<400> 9
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Ala
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg
115 120 125
Ala Thr Pro Gln His
130
Claims (10)
1.一种重组双功能融合蛋白,其特征在于,所述重组双功能融合蛋白包含:
第一结合结构域(D1);和
第二结合结构域(D2);
其中,所述第一结合结构域特异性结合靶分子CD20蛋白;
所述第二结合结构域特异性结合靶分子CD47蛋白。
2.如权利要求1所述的重组双功能融合蛋白,其特征在于,所述D1为特异性结合CD20蛋白的抗体或抗体片段。
3.如权利要求1所述的重组双功能融合蛋白,其特征在于,所述D2为特异性结合CD47蛋白的多肽片段,并且所述多肽片段衍生自SIRPα。
4.一种多核苷酸,其特征在于,它编码如权利要求1所述的重组双功能融合蛋白。
5.一种载体,其特征在于,它含有权利要求2所述的多核苷酸。
6.一种遗传工程化的宿主细胞,其特征在于,它含有权利要求5所述的载体或基因组中整合有权利要求4所述的多核苷酸。
7.一种免疫偶联物,其特征在于,该免疫偶联物含有:
(a)如如权利要求1所述的重组双功能融合蛋白;和
(b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶。
8.一种药物组合物,其特征在于,它含有:
(i)如权利要求1所述的重组双功能融合蛋白、或如权利要求7所述的免疫偶联物;以及
(ii)药学上可接受的载体。
9.如权利要求1所述的重组双功能融合蛋白、或如权利要求7所述的免疫偶联物的用途,其特征在于,用于制备药物;所述药物用于治疗或预防表达CD20蛋白的肿瘤。
10.一种重组双功能融合蛋白的制备方法,其特征在于,该方法包含:
(a)在适合表达的条件下,培养权利要求6所述的宿主细胞;
(b)从培养物中分离出如权利要求1所述的重组双功能融合蛋白。
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CN201880011334.5A CN110300766B (zh) | 2017-03-15 | 2018-03-15 | 新型重组双功能融合蛋白及其制备方法和用途 |
JP2019542396A JP7056858B2 (ja) | 2017-03-15 | 2018-03-15 | 新規な組換え型二機能性融合タンパク質、その調製方法および用途 |
EP18768501.1A EP3626747B1 (en) | 2017-03-15 | 2018-03-15 | Novel recombinant bifunctional fusion protein, preparation method therefor and use thereof |
ES18768501T ES2960311T3 (es) | 2017-03-15 | 2018-03-15 | Nueva proteína de fusión bifuncional recombinante, procedimiento de preparación y uso de la misma |
US16/489,360 US11407841B2 (en) | 2017-03-15 | 2018-03-15 | Recombinant bi-functional fusion protein and use thereof |
PCT/CN2018/079187 WO2018166507A1 (zh) | 2017-03-15 | 2018-03-15 | 新型重组双功能融合蛋白及其制备方法和用途 |
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WO2020088437A1 (zh) * | 2018-11-01 | 2020-05-07 | 安源医药科技(上海)有限公司 | 针对cd20和cd3的双特异性抗体及其用途 |
CN111484558A (zh) * | 2019-01-28 | 2020-08-04 | 上海交通大学 | 信号调节蛋白α片段-抗FcRn单链抗体融合蛋白及其制备与应用 |
CN113896802A (zh) * | 2021-10-09 | 2022-01-07 | 宜明昂科生物医药技术(上海)有限公司 | 靶向cd47和cd38的重组融合蛋白及其制备和用途 |
WO2023061084A1 (zh) * | 2021-10-13 | 2023-04-20 | 宜明昂科生物医药技术(上海)股份有限公司 | 靶向cd47和cd24的重组融合蛋白及其制备和用途 |
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JP7193058B2 (ja) * | 2018-08-08 | 2022-12-20 | イミューンオンコ バイオファーマシューティカルズ (シャンハイ) インコーポレイテッド | Cd47およびher2を標的とする組換え二機能性タンパク質 |
WO2020127373A1 (en) * | 2018-12-21 | 2020-06-25 | Ose Immunotherapeutics | Bifunctional anti-pd-1/sirpa molecule |
CN111423515A (zh) * | 2020-03-23 | 2020-07-17 | 倍而达药业(苏州)有限公司 | 一种cd20/cd47双特异性抗体及应用 |
WO2023072217A1 (en) * | 2021-10-28 | 2023-05-04 | Guangzhou Lintonpharm Co., Ltd. | Fusion proteins targeting cd3 and cd47 |
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WO2016024021A1 (en) * | 2014-08-15 | 2016-02-18 | Merck Patent Gmbh | Sirp-alpha immunoglobulin fusion proteins |
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EP2970485A1 (en) | 2013-03-15 | 2016-01-20 | Merck Patent GmbH | Tetravalent bispecific antibodies |
CA2957531A1 (en) | 2014-08-08 | 2016-02-11 | The Board Of Trustees Of The Leland Stanford Junior University | Sirp alpha-antibody fusion proteins |
CN107849143B (zh) * | 2015-05-18 | 2021-12-10 | 起源生物医药公司 | Sirp多肽组合物和使用方法 |
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WO2016024021A1 (en) * | 2014-08-15 | 2016-02-18 | Merck Patent Gmbh | Sirp-alpha immunoglobulin fusion proteins |
Cited By (6)
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WO2020088437A1 (zh) * | 2018-11-01 | 2020-05-07 | 安源医药科技(上海)有限公司 | 针对cd20和cd3的双特异性抗体及其用途 |
CN111484558A (zh) * | 2019-01-28 | 2020-08-04 | 上海交通大学 | 信号调节蛋白α片段-抗FcRn单链抗体融合蛋白及其制备与应用 |
CN111484558B (zh) * | 2019-01-28 | 2023-02-17 | 上海交通大学 | 信号调节蛋白α片段-抗FcRn单链抗体融合蛋白及其制备与应用 |
CN113896802A (zh) * | 2021-10-09 | 2022-01-07 | 宜明昂科生物医药技术(上海)有限公司 | 靶向cd47和cd38的重组融合蛋白及其制备和用途 |
WO2023061084A1 (zh) * | 2021-10-13 | 2023-04-20 | 宜明昂科生物医药技术(上海)股份有限公司 | 靶向cd47和cd24的重组融合蛋白及其制备和用途 |
US11891449B2 (en) | 2021-10-13 | 2024-02-06 | Immuneonco Biopharmaceuticals (Shanghai) Inc. | Recombinant fusion proteins targeting CD47 and CD24, preparation and use thereof |
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US11407841B2 (en) | 2022-08-09 |
CN110300766A (zh) | 2019-10-01 |
US20220010031A1 (en) | 2022-01-13 |
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