CN115716875A - 一种多功能融合蛋白及其用途 - Google Patents
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Abstract
本发明提供了一种多功能融合蛋白,具体提供了一种靶向B7H3与CD3,同时具有IL‑15/IL‑15Rα复合物的生物学效应的多功能融合蛋白。所述多功能融合蛋白可解决单靶点抗体药物的耐药和复发问题,降低起效剂量,更加有效地杀伤肿瘤细胞,延长IL‑15/IL‑15Rα血清半衰期并提高肿瘤靶向性,降低其毒副作用。利用CD3抗体与肿瘤靶向抗体的组合,可定向肿瘤并招募T细胞接近肿瘤细胞,起到介导T细胞杀伤肿瘤细胞的作用。通过免疫突触的形成,抗体功能位点与抗原之间的相对距离等结构设计,使该融合蛋白结构更加稳定。IL‑15/IL‑15Rα复合物促进了对T细胞和NK细胞持久的招募和激活作用。
Description
技术领域
本发明属于抗体药物领域,具体涉及一种多功能融合蛋白,尤其涉及靶向B7H3与CD3,同时具有IL-15/IL-15Rα复合物的生物学效应的多功能融合蛋白。
背景技术
肿瘤的发生和发展都伴随着对免疫系统的入侵,免疫功能不全的个体常常有较高的癌症发生率和较差的预后。细胞因子(cytokine,CK)属于免疫调节分子,根据其性质、给药浓度和活性发挥部位的不同,对免疫系统具有一定的激活或者抑制作用。因此给予免疫刺激性的细胞因子治疗的这种方式,可以达到提高癌症患者免疫功能的作用。
细胞因子作为免疫疗法,虽然有一定益处,但在临床上的使用存在着单药给药靶向性差的缺点,只有高浓度给药才可以达到抗肿瘤作用,而高浓度给药会产生免疫抑制作用和高毒性。并且,非靶向性细胞因子对于免疫系统的激活是系统性的,免疫系统被广泛的激活,具有致命的副作用。此外,由于细胞因子属于小分子量蛋白,不具备抗体的体内循环保护机制,单纯的细胞因子往往半衰期较短,需要短时间重复高剂量给药。目前临床研究药物多采用PEG化或者Fc融合来提高细胞因子的半衰期,虽然半衰期得以延长,但仍无法解决细胞因子的靶向性差的问题。目前已在多种小鼠肿瘤模型中验证了NK细胞和T细胞,尤其是细胞毒性T细胞在肿瘤免疫过程中的作用。多个临床试验正在评估某些细胞因子单用,或者与多种化疗药物和肿瘤靶向的单克隆抗体和其他细胞因子联用的抗癌疗效。但是,诸如IL-15等细胞因子存在的高剂量用药下的毒性以及半衰期短而导致的短时间重复给药问题仍然存在,成为联用策略的一大制约因素。
CD3是由肽链以非共价键组成的复合分子,在成熟T细胞表面表达,对阻断急性同种异体排斥反应起主要作用,且具有稳定TCR结构和传递活化信号的作用。针对CD3分子的单克隆抗体能够激活T细胞增殖及活化,在其他细胞因子IL-15、IL-15Rα等共同作用下,产生具有增殖速度快、杀瘤活性高、杀瘤谱广及非MHC限制性杀瘤特点的CIK细胞,对癌症、慢性白血病、肝病及神经性疾病等多种疾病治疗具有显著疗效。因此利用CD3抗体与肿瘤靶向抗体进行组合,所构建的双特异性抗体可招募T细胞接近肿瘤细胞,起到介导T细胞杀伤肿瘤细胞的作用。
双特异性抗体在临床上有望成为针对癌症、自身免疫和传染病的下一代生物疗法,具有单一靶点抗体无法达到的功能。双特性抗体为细化抗体药物作用机制、探索多机制协同效应提供了很好的途径。
专利CN110023336A公开了包含至少三个结合结构域的结合剂,其中第一结合结构域与T细胞特异性抗原结合,并且第二结合结构域和第三结合结构域与密蛋白(Claudin6或Claudin18.2)结合。其首次报道了包含密蛋白的两个结合结构域和靶向T细胞特异性抗原(例如CD3)的另一个结合结构域的结合剂可诱导强效的T细胞介导的裂解并且在治疗肿瘤疾病中有效。而此抗体结构没有细胞因子的加入,对T细胞和NK细胞的的激活作用不能达到很好的效果。
而随着抗体工程技术的发展和治疗机制研究的深入,三特异性抗体和多特异性抗体也在大量涌现。这些多功能抗体常常以细胞因子或CD3等靶点作为辅助抗肿瘤抗原的免疫刺激或抑制剂,达到单抗或联合用药不具备的机理或超过其疗效。
专利CN109496217A公开了一种包含至少两种可溶性融合蛋白的可溶性融合蛋白复合体,例如,第一融合蛋白是共价连接至白介素-15(IL-15)多肽或其功能性片段的抗CD3抗体。第二融合蛋白包含识别疾病抗原的结合域,其中,这一域共价链接至可溶性白介素-15受体α(IL-15Rα)多肽或其功能性片段。虽然此结构抗体能够激活效应T细胞和NK细胞并引导其活性以对抗疾病细胞为目标,从而导致疾病特异性的细胞毒性。但是,由于IL-15和IL-15Ra很容易被体内酶降解,且在体外难表达,因此,此抗体在稳定性方面不尽人意。
因此靶点设计组合达到良好的多机制协同作用是优选的一种策略,然而多靶点设计同样带来结构设计上的难题。在行业经验中,不同的架构设计,对抗体的成药性乃至机制发挥有莫大的关系。免疫突触的形成,抗体功能位点与抗原之间的相对距离等等都与架构设计息息相关。
发明内容
为了克服现有技术的不足,解决现有技术中存在的上述问题,满足多功能融合蛋白架构设计需求,提高多功能融合蛋白的稳定性,改善肿瘤患者的预后生活,兼具良好的成药性。本发明设计了一种结构,主要由抗B7H3/CD3及IL-15/IL-15Rα复合物组成。本文叙述以多功能融合蛋白(抗B7H3与CD3,外加IL-15/IL-15Rα的多功能融合蛋白)作为示例,使用该种架构设计与靶点组合,公开了通过基因工程技术获得的靶向B7H3与CD3,同时具有IL-15/IL-15Rα复合物的生物学效应的多功能融合蛋白,并公开了编码所述多功能融合蛋白的氨基酸序列、架构设计、以及包含所述重组载体的重组细胞以及所述多功能融合蛋白的制备方法及其医药用途。
本发明涉及一种多功能融合蛋白,由第一重链、第二重链、第一轻链和第二轻链组成,所述多功能融合蛋白包含特异性结合B7H3的第一抗原结合部分,特异性结合CD3的第二抗原结合部分,和细胞因子和/或细胞因子受体。
在可选的实施方案中,所述多功能融合蛋白的第一轻链和第二轻链相同。
在可选的实施方案中,所述多功能融合蛋白的第一抗原结合部分为Fab或scFv。
在可选的实施方案中,所述多功能融合蛋白的第一抗原结合部分为Fab。
在可选的实施方案中,所述多功能融合蛋白的第二抗原结合部分为Fab或scFv。
在可选的实施方案中,所述多功能融合蛋白的第二抗原结合部分为scFv。
在可选的实施方案中,所述多功能融合蛋白的细胞因子和/或细胞因子受体为IL-15和/或IL-15受体。
在可选的实施方案中,所述多功能融合蛋白还包含Fc部分。
在可选的实施方案中,所述多功能融合蛋白的Fc部分选自IgG1、IgG2、IgG3、IgG4的恒定区氨基酸序列,优选选自IgG1或IgG4的恒定区氨基酸序列。
在可选的实施方案中,所述多功能融合蛋白的Fc部分还包含一个或多个选自由以下组成的组的氨基酸替换:S228P、L234F、L235E、P331S、D356K、T366W、K392D、D399K、Y407A、和K409D,优选S228P、T366W和/或Y407A。
在可选的实施方案中,所述多功能融合蛋白的IL-15和IL-15受体可以在同一条重链上,也可以在不同重链上。在可选的实施方案中,所述多功能融合蛋白第一重链中的IL-15片段和第二重链中的IL-15受体片段分别嵌合于所述重链的Fc部分内部,或存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。
在可选的实施方案中,所述多功能融合蛋白第一重链中的IL-15和/或IL-15受体和第二重链中的第二抗原结合部分可以分别嵌合于所述第一重链和所述第二重链的Fc部分内部,也可以存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。在可选的实施方案中,所述多功能融合蛋白第一重链中的IL-15和/或IL-15受体、第二重链中的第二抗原结合部分单独或与额外的连接肽一起共价结合于所述链中;所述连接肽包含甘氨酸(G)和丝氨酸(S)残基,优选包含氨基酸为GGGGS的重复,更优选包含1-2个GGGGS重复。
在可选的实施方案中,所述多功能融合蛋白的IL-15选自天然的IL-15或其变体,所述变体包含选自N1D、N4D、D30N、E64Q、N65D、N72D、N79A、Q108E和N112A的组的一个或多个氨基酸突变,优选包含选自N4D、N65D、N72D、N79A和N112A的组的一个或多个氨基酸突变;所述IL-15受体选自IL-15Rα或其变体。
在可选的实施方案中,所述多功能融合蛋白的第一重链氨基酸序列选自SEQ IDNO:1;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:2;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:3。
本发明还涉及一种编码上述任一多功能融合蛋白的核酸分子,其包含编码第一轻链和第二轻链的核苷酸序列,或者包含编码第一重链的核苷酸序列,或者包含编码第二重链的核苷酸序列。
在可选的实施方案中,所述编码第一重链的核苷酸序列选自SEQ ID NO:4;所述编码第二重链的核苷酸序列选自SEQ ID NO:5;所述编码第一轻链和第二轻链的核苷酸序列选自SEQ ID NO:6。
本发明还涉及一种重组载体,其包含编码上述任一所述多功能融合蛋白的第一重链、和/或第二重链、和/或第一轻链、和/或第二轻链的核苷酸序列。
本发明还涉及一种重组细胞,其含有上述任一所述的重组载体,优选地,所述细胞包括人胚肾细胞HEK293或HEK293T、HEK293E、HEK293修饰的HEK293F、中国仓鼠卵巢细胞(CHO)、CHO-S、CHO-dhfr-、CHO/DG44、ExpiCHO、CHO修饰的ExpiCHO,和其组合。
本发明还涉及一种制备上述任一所述多功能融合蛋白的方法,其具体包括:
在足以表达上述任一所述多功能融合蛋白的条件下,培养上述所述的重组细胞,表达并纯化所述的多功能融合蛋白。
本发明还涉及上述任一所述多功能融合蛋白作为活性成分的药物,所述药物任选含有药学上可接受的载体或赋形剂。
本发明还涉及上述任一所述多功能融合蛋白在制备预防或治疗与TAA有关的疾病或病症如肿瘤的药物中的用途。
在可选的实施方案中,所述肿瘤为对B7H3单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗B7H3抗体单独治疗产生抗性或无效的肿瘤;进一步优选为胃癌、食道癌、胰腺癌等。
因此,本发明涉及以下实施方案:
1、一种多功能融合蛋白,由第一重链、第二重链、第一轻链和第二轻链组成,其特征在于:所述多功能融合蛋白包含特异性结合B7H3的第一抗原结合部分,特异性结合CD3的第二抗原结合部分,和细胞因子和/或细胞因子受体。
2、如方案1所述的多功能融合蛋白,其中所述第一轻链和第二轻链相同。
3、如方案1或2所述的多功能融合蛋白,其中所述第一抗原结合部分为Fab或scFv。
4、如方案3所述的多功能融合蛋白,其中所述第一抗原结合部分为Fab。
5、如方案1或2所述的多功能融合蛋白,其中所述第二抗原结合部分为Fab或scFv。
6、如方案5所述的多功能融合蛋白,其中所述第二抗原结合部分为scFv。
7、如方案1或2所述的多功能融合蛋白,其中所述细胞因子和/或细胞因子受体为IL-15和/或IL-15受体。
8、如方案1-7任一所述的多功能融合蛋白,其还包含Fc部分。
9、如方案8所述的多功能融合蛋白,其Fc部分选自IgG1、IgG2、IgG3、IgG4的恒定区氨基酸序列,优选选自IgG1或IgG4的恒定区氨基酸序列。
10、如方案8或9所述的多功能融合蛋白,其中所述Fc部分还包含一个或多个选自由以下组成的组的氨基酸替换:S228P、L234F、L235E、P331S、D356K、T366W、K392D、D399K、Y407A、和K409D,优选S228P、T366W和/或Y407A。
11、如方案7-10任一所述的多功能融合蛋白,其中所述IL-15和IL-15受体可以在同一条重链上,也可以在不同重链上。
12、如方案11所述的多功能融合蛋白,其中所述第一重链中的IL-15片段和第二重链中的IL-15受体片段分别嵌合于所述重链的Fc部分内部,或存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。
13、如方案11所述的多功能融合蛋白,其中所述第一重链中的IL-15和/或IL-15受体和第二重链中的第二抗原结合部分可以分别嵌合于所述第一重链和所述第二重链的Fc部分内部,也可以存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。
14、如方案13所述的多功能融合蛋白,其中所述第一重链中的IL-15和/或IL-15受体、第二重链中的第二抗原结合部分单独或与额外的连接肽一起共价结合于所述链中;所述连接肽包含甘氨酸(G)和丝氨酸(S)残基,优选包含氨基酸为GGGGS的重复,更优选包含1-2个GGGGS重复。
15、如方案7-14任一所述的多功能融合蛋白,其中所述IL-15选自天然的IL-15或其变体,所述变体包含选自N1D、N4D、D30N、E64Q、N65D、N72D、N79A、Q108E和N112A的组的一个或多个氨基酸突变,优选包含选自N4D、N65D、N72D、N79A和N112A的组的一个或多个氨基酸突变;所述IL-15受体选自IL-15Rα或其变体。
16、如方案1-15任一所述的多功能融合蛋白,其中所述第一重链氨基酸序列选自SEQ ID NO:1;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:2;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:3。
17、一种编码如方案1-16任一所述多功能融合蛋白的核酸分子,其特征在于包含编码第一轻链和第二轻链的核苷酸序列,或者包含编码第一重链的核苷酸序列,或者包含编码第二重链的核苷酸序列。
18、如方案17所述的核酸分子,其中所述编码第一重链的核苷酸序列选自SEQ IDNO:4;所述编码第二重链的核苷酸序列选自SEQ ID NO:5;所述编码第一轻链和第二轻链的核苷酸序列选自SEQ ID NO:6。
19、一种重组载体,其包含编码方案1-16任一所述多功能融合蛋白的第一重链、和/或第二重链、和/或第一轻链、和/或第二轻链的核苷酸序列。
20、一种重组细胞,其含有方案19所述的重组载体,优选地,所述细胞包括人胚肾细胞HEK293、HEK293T、HEK293E、HEK293修饰的HEK293F、中国仓鼠卵巢细胞(CHO)、CHO-S、CHO-dhfr-、CHO/DG44、ExpiCHO或CHO修饰的ExpiCHO中的一种或几种。
21、一种制备如方案1-16任一所述多功能融合蛋白的方法,其具体包括:
在足以表达方案1-16任一所述多功能融合蛋白的条件下,培养方案20所述的重组细胞,表达并纯化所述的多功能融合蛋白。
22、如方案1-16任一所述多功能融合蛋白作为活性成分的药物,所述药物任选含有药学上可接受的载体或赋形剂。
23、如方案1-16任一所述多功能融合蛋白在制备预防或治疗与TAA有关的疾病或病症如肿瘤的药物中的用途。
24、如方案23所述的用途,所述肿瘤为对B7H3单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗B7H3抗体单独治疗产生抗性或无效的肿瘤;进一步优选为胃癌、食道癌、胰腺癌等。
有益效果
本发明在已有的异源二聚体开发经验的基础上通过基因重组、密码子优化和分子生物学等技术,设计获得了一种靶向肿瘤相关抗原B7H3与CD3,同时具有IL-15/IL-15Rα复合物的生物学效应的多功能融合蛋白。该多功能融合蛋白在靶向肿瘤相关抗原的基础上,利用IL-15/IL-15Rα复合物可以有效地扩增和活化PMBC中的T细胞及NK细胞,并使得免疫细胞数目以及杀伤性细胞因子的释放增加,从而解决单靶点抗体药物的耐药和复发问题,同时也可降低有效剂量,更加有效地杀伤肿瘤细胞,且较IL-15或IL-15/IL-15受体复合物而言,延长了血清半衰期并提高了肿瘤靶向性,降低其毒副作用。同时利用CD3抗体与肿瘤靶向抗体的组合,可定向肿瘤并招募T细胞接近肿瘤细胞,起到介导T细胞杀伤肿瘤细胞的作用。
由于IL-15和IL-15Ra很容易被体内酶降解,且在体外难表达,因此,本发明人利用天然抗体在体内的稳定性,将IL-15和IL-15Ra的融合蛋白设计在多功能融合蛋白结构内部,将其被保护在多功能融合蛋白内部,免于暴露而被体内酶降解,同时降低了表达难度。此种设计的多功能融合蛋白经实验证明具有极高的表达能力和稳定性。
同时,通过将IL-15和IL-15Ra通过连接子连接,即IL-15的受体IL-15Rα内含一个sushi结构域,能与IL-15结合,使得多功能融合蛋白结构更稳定。
另外,本发明合理设计B7H3、CD3和IL-15融合蛋白的相对距离,理论上为最佳接触距离,既保留了识别B7H3抗体的识别位点,又保证识别特异性抗体端与IL-15融合蛋白功能发挥,此种设计的多功能融合蛋白可以全方位接触抗原,并保持其他协同功能活性。
经所述示例试验验证,本发明所获得的多功能融合蛋白具有高效的B7H3抗原亲和力和IL-15亲和力,以及与CD3较好的结合效果,此外还具有较好的纯度、稳定性以及生物活性,在常用的抗体表达宿主细胞CHO上,也可得到较好的表达量。
因此使用该靶点组合或结构设计,不影响功能域的功能发挥,增加了多功能融合蛋白结构的稳定性,且有良好协同作用机制,可应用于免疫或肿瘤治疗。
为了更容易理解本发明,以下具体定义了某些技术和科学术语。除显而易见在本文件的它处另有明确定义,否则本文中使用的所有其他技术和科学术语都具有本发明所属技术领域的一般技术人员通常理解的含义。
术语
在本专利中,术语“抗体”是指天然的免疫球蛋白或者通过部分或完全合成而制备的免疫球蛋白。抗体可从天然存在该抗体的血浆或血清等的天然资源、或者产生抗体的杂交瘤细胞的培养上清中、动物免疫血清中、噬菌体文库筛选进行重建得到分离。备选地,可通过使用基因重组等的技术部分或完全地合成。优选的抗体包括,例如,免疫球蛋白的同种型或这些同种型的亚类的抗体。已知人免疫球蛋白包括IgGl、IgG2、IgG3、IgG4、IgAl、IgA2、IgD、IgE、IgM这9种类别(同种型)。在这些同种型中,本发明的抗体可以包括IgGl、IgG2、IgG3、IgG4。
术语“多功能融合蛋白”是指包含两个或更多个抗原结合结构域,能够结合两个或更多个不同的表位(例如,两个、三个或更多个不同的表位),表位可以在相同或不同的抗原上的融合蛋白,多功能融合蛋白还可以包含细胞因子和/或受体(例如IL-15和/或IL-15受体、IL-15变体和/或IL-15变体的受体等)等。
抗体的“可变区”指抗体重链或轻链的氨基末端结构域。重链和轻链的可变区可以分别称为“VH”和“VL”。这些结构域一般是抗体的最可变部分(相对于其他同类抗体)并含有抗原结合位点。
术语“scFv”指单个多肽链的抗体片段,其含有源自重链和轻链的可变区,但没有恒定区。通常,scFv还在VH和VL结构域之间含有多肽接头,这使得能够形成被认为允许抗原结合的所需结构。
术语“多肽”是指任何长度的氨基酸链,而与修饰(例如磷酸化或糖基化)无关。术语多肽包括蛋白质及其片段。本文将多肽公开为氨基酸残基序列。那些序列按氨基末端到羧基末端的方向从左到右书写。根据标准命名法,氨基酸残基序列以三字母或单字母代码命名,如下所示:丙氨酸(Ala,A)、精氨酸(Arg,R)、天冬酰胺(Asn,N)、天冬氨酸(Asp,D)、半胱氨酸(Cys,C)、谷氨酰胺(Gln,Q)、谷氨酸(Glu,E)、甘氨酸(Gly,G)、组氨酸(His,H)、异亮氨酸(Ile,I)、亮氨酸(Leu,L)、赖氨酸(Lys,K)、甲硫氨酸(Met,M)、苯丙氨酸(Phe,F)、脯氨酸(Pro,P)、丝氨酸(Ser,S)、苏氨酸(Thr,T)、色氨酸(Trp,W)、酪氨酸(Tyr,Y)和缬氨酸(Val,V)。
术语“变体”是指与参与多肽或多核苷酸不同但保持基本特性的多肽或多核苷酸。多肽的典型变体在氨基酸序列方面与另一参考多肽不同。通常,差异是有限的,使得参与多肽和变体的序列总体上非常相似,并且在许多区域中是相同的。变体和参考多肽可以在氨基酸序列方面因一个或多个修饰(例如,取代、添加和/或缺失)而不同。取代或插入的氨基酸残基可以是或可以不是由遗传密码编码的氨基酸残基。多肽的变体可以是天然存在的,诸如等位基因变体,或者可以是不知道会天然存在的变体。
术语“肿瘤相关抗原”或“TAA”优选涉及在正常条件下在有限数目的组织和/或器官中或在特定发育阶段中特异性表达以及在一个或更多个肿瘤或癌症组织中表达或异常表达的蛋白质。在本发明的上下文中,肿瘤相关抗原优选与癌细胞的细胞表面缔合,并且优选不在或仅很少在正常组织中表达。本发明中“肿瘤相关抗原”或“TAA”可互换使用。
本发明中第一重链的Fc或其变体和第二重链的Fc或其变体之间的“相互作用”指的是Fc间作用或Fc变体间作用。“Fc变体”指通过在Fc的合适位点处存在一个或多个氨基酸替换、插入或缺失突变引起Fc结构或功能的变化。“Fc变体间作用”指经突变设计的Fc变体之间可以形成空间填充效应、静电转向、氢键作用、疏水作用等。Fc变体间相互作用有助于形成稳定的异源二聚体。优选的突变设计为“Knob-in-hole”形式的突变设计。此外,本发明所述Fc上还可以存在其他导致其功能变化的突变,例如糖基化改造突变、FcγR结合区域突变(以调整ADCC活性)和改善抗体稳定性的氨基酸突变等。
术语“IL-15”或“IL-15片段”可以是任何IL-15或其突变体,如人IL-15或非人哺乳动物或非哺乳动物的IL-15。示例性非人哺乳动物如猪、兔、猴、猩猩、鼠等,非哺乳动物如鸡等;优选人的白介素15成熟分子(见数据库UniProtKB,登录号P40933,49-162aa)。术语“IL-15变体”指通过一个或多个氨基酸替换、增加或者缺失突变获得的对IL-15与其受体间亲和力提高或者降低,或其刺激T细胞或者NK细胞活性增加或者降低的突变体分子。本发明中“IL-15”和“IL-15片段”可互换使用。
术语“IL-15Rα”可以是任何物种的IL-15Rα或者其功能性片段,如人IL-15Rα或非人哺乳动物IL-15Rα或非哺乳动物IL-15Rα。示例性非人哺乳动物如猪、兔、猴、猩猩、鼠等,非哺乳动物如鸡等。优选人的IL-15Rα,更优选人IL-15Rα胞外域片段,简称IL-15RαECD(见数据库UniProtKB,登录号Q13261,31-205aa)。术语“IL-15Rα变体”指在IL-15Rα上通过一个或者多个氨基酸缺失、插入或替换突变形成的具有与其配体分子如IL-15结合能力的功能性突变体,优选人的IL-15Rα分子更优选人的IL-15Rα胞外域片段的缩短形式,即从胞外域片段C端开始通过一个或多个氨基酸缺失突变所得的具有人IL-15受体α活性的分子,优选保留65-120个氨基酸的缺失突变形式,更优选保留65-102个氨基酸的缺失突变缩短形式,比如IL-15RαSushi(65)或IL-15RαSushi(77)。
本发明中“与额外的连接肽一起共价结合”是指两个或多个基因的编码区之间可由编码连接肽的序列于一个或数个位置发生共价结合。
术语“免疫球蛋白”指具有抗体活性或化学结构与抗体分子相似的球蛋白,存在五种主要类别的免疫球蛋白:IgA、IgD、IgE、IgG和IgM,这些中的几种可以进一步划分为亚类(同种型),例如IgG1、IgG2、IgG3和IgG4、IgA1和IgA2。对应于不同类别免疫球蛋白的重链恒定结构域分别称为α、δ、ε、γ和μ。
术语“免疫球蛋白Fc部分”指免疫球蛋白的C端区域,无抗原结合活性,是抗体分子与效应分子和细胞相互作用的部位,是包含两个二硫化物连接的抗体重链Fc区多肽的二聚体分子。Fc区可以通过木瓜蛋白酶消化或IdeS消化成胰蛋白酶消化完整(全长)抗体来产生或可以重组产生。“Fc部分”优选包括至少一个免疫球蛋白铰链区,以及IgG的CH2和CH3区。
术语“连接肽”在本发明中用于将IL-15与IL-15Rα、CD3的VH与VL连接至相应的重链中,以保证蛋白的正确折叠和肽稳定性。本发明的“连接肽”优选为(GGGGS)n,其中n可以为0、1、2、3、4、5或者更多,优选n为1-2。如果连接肽序列太短,可能影响两蛋白高级结构的折叠,从而相互干扰;如果连接肽序列太长,又涉及免疫原性的问题,因为连接肽序列本身就是新的抗原。
术语的“异源二聚体”优选为基因共表达的产物。如在原核细胞在大肠杆菌中共表达;或在真核细胞,如293、CHO中共表达。所述“共表达”指在一个细胞中多个基因一起表达,同时出现它们的产物。这些基因可以是同时存在而分别或共同地受控表达。在本发明中,优选在一个真核细胞中共表达三种基因。共表达得到的基因表达产物有利于高效、简单地形成复合物;在本发明中,有利于形成异源二聚体。
术语“核酸”旨在包括DNA和RNA,例如基因组DNA、cDNA、mRNA、重组产生和化学合成的分子。核酸可是单链或双链。RNA包括体外转录的RNA(IVT RNA)或合成的RNA。
术语“载体”包括技术人员已知的任何载体,其包括质粒载体、黏粒载体、噬菌体载体(例如λ噬菌体)、病毒载体(例如腺病毒或杆状病毒载体),或人工染色体载体(例如细菌人工染色体(BAC)、酵母人工染色体(YAC)或P1人工染色体(PAC))。所述载体包括表达载体以及克隆载体。表达载体包括质粒和病毒载体且一般含有用于在特定宿主生物体(例如,细菌、酵母、植物、昆虫或哺乳动物)或者在体外表达系统中可操作地连接的编码序列之表达所必需的期望编码序列和合适的DNA序列。克隆载体一般用于改造和扩增某期望DNA片段,并可缺乏表达所期望DNA片段所需要的功能性序列。
本发明所述“肿瘤”可选自B细胞淋巴瘤、肺癌、支气管癌、结肠直肠癌、前列腺癌、乳腺癌、胰腺癌、胃癌、卵巢癌、膀胱癌、脑或中枢神经系统癌症、外周神经系统癌症、食道癌、宫颈癌、黑色素瘤、子宫或子宫内膜癌、口腔癌或喉癌、肝癌、肾癌、胆管癌、小肠癌或阑尾癌、唾液腺癌、胸腺癌、肾上腺癌、骨肉瘤、软骨肉瘤、脂肪瘤、睾丸癌以及恶性纤维组织细胞瘤等。
附图说明
图1为多功能融合蛋白与B7H3的结合活性。
图2为多功能融合蛋白与CD3的结合活性。
图3为多功能融合蛋白与受体IL-2Rβ的结合活性。
图4为多功能融合蛋白的抗肿瘤活性。
具体实施方式
以下结合附图与具体实施例对本发明做进一步的描述,本发明的保护内容不局限于以下实施例。还应该理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求及其任何等同物为本发明的保护范围。在本发明的说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域技术人员的普遍知识和公知常识,本发明没有特别限制内容。
本发明实施例中B7H3嵌合抗体的重链氨基酸序列为SEQ ID NO:7,轻链氨基酸序列为SEQ ID NO:8。
实施例1核苷酸序列的获得与优化
本发明的多功能融合蛋白的轻链和重链氨基酸序列信息选自公开的或自研B7H3靶点单抗序列信息,分析获得该序列的可变区和恒定区信息。将天然IL-15与IL-15Rα复合物变体序列插入一条重链的氨基酸序列中,并在另一条重链的相应位置插入CD3抗体的scFv序列。根据需要,调整所述多功能融合蛋白氨基酸序列的Fc为其他IgG类型,如IgG4等,并进一步在各重链中设计所需形式的氨基酸突变,由此得到目标多功能融合蛋白的氨基酸序列,为:
本发明多功能融合蛋白—第一重链为SEQ ID NO:1,第二重链为SEQ ID NO:2,第一轻链和第二轻链为SEQ ID NO:3。
将上述各目标氨基酸序列转化为核苷酸序列,并针对可能影响多功能融合蛋白在哺乳动物细胞中表达的一系列参数:密码子偏好性、GC含量(即DNA的4种碱基中鸟嘌呤G和胞嘧啶C所占的比率)、CpG岛(即CpG双核苷酸在基因组中密度较高的区域)、mRNA的二级结构、拼接位点、前成熟PolyA位点、内部Chi位点(基因组中一段短的DNA片段,在该位点附近发生同源重组的几率增加)或者核糖体结合位点、RNA不稳定序列、反向重复序列及可能干扰克隆的限制性酶切位点等进行优化;同时增加了可能会提高翻译效率的相关序列,例如Kozak序列、SD序列,以及终止密码子。设计得到分别编码上述多功能融合蛋白的重链基因和轻链基因,另外在重链和轻链的5’端分别设计上根据氨基酸序列优化而得的编码信号肽的核苷酸序列;此外,还对轻链和重链核苷酸序列的3’端分别加上终止密码子。
最终优化获得抗体核苷酸序列为:
本发明多功能融合蛋白—第一重链为SEQ ID NO:4,第二重链为SEQ ID NO:5,第一轻链和第二轻链为SEQ ID NO:6。
实施例2基因合成与表达载体的构建
采用pcDNA3.1-G418载体作为表达所述多功能抗体的轻链和重链的专用载体。pcDNA3.1-G418载体含有重链所使用的启动子CMVPromoter、真核筛选标记G418标签和原核筛选标签Ampicilline。基因合成得到多功能融合蛋白表达轻链和重链的核苷酸序列,用HindIII和XhoI对载体和目的片段进行双酶切,回收后通过DNA连接酶进行酶连,并转化大肠杆菌感受态细胞DH5α,挑选出阳性克隆并进行质粒提取和酶切验证,获得含所述多功能融合蛋白的全长第一重链、第二重链和轻链的重组质粒。
实施例3质粒抽提
根据《分子克隆实验指南》(2002年,科学出版社)所述方法将含有上述各目的基因的重组质粒转化至大肠杆菌感受态细胞DH5α中,将转化细菌涂布在含100μg/mL氨苄青霉素的LB平板上培养,挑选质粒克隆至液体LB培养基中培养,260rpm摇菌14小时,由无内毒素质粒大抽试剂盒抽提质粒,用无菌水溶解并用核酸蛋白定量仪进行浓度测定。
实施例4质粒转染、瞬转表达与抗体纯化
在37℃、8%CO2、100rpm下培养ExpiCHO至细胞密度6×106个/mL。使用脂质体分别将构建的载体(多功能融合蛋白的全长第一重链、第二重链和轻链的重组质粒)转染到上述细胞中,转染质粒浓度为1mg/mL,脂质体浓度参照ExpiCHOTMExpressionSystem试剂盒确定,在32℃、5%CO2,100rpm下培养7-10天。转染18-22h之后和第5天之间分别补料一次。4000g离心上述培养产物,0.22μm滤膜过滤并收集培养基上清液,采用ProteinA、离子柱纯化所得的抗体6蛋白并收集洗脱液。
ProteinA、离子柱纯化的具体操作步骤为:细胞培养液经过高速离心后取上清,利用GE的ProteinA层析柱进行亲和层析。层析使用平衡缓冲液为1×PBS(pH7.4),细胞上清上样结合后利用PBS洗涤至紫外线回到基线,然后利用洗脱缓冲液0.1M甘氨酸(pH3.0)洗脱目的蛋白,利用Tris调节pH至中性保存。将亲和层析所得产物调节pH至低于或者高于pI1-2个pH单位,适当稀释以控制样本电导在5ms/cm以下。利用合适的对应pH缓冲液如磷酸缓冲液、醋酸缓冲液等条件,利用本领域内常规的离子交换层析方法如阴离子交换或者阳离子交换进行对应pH条件下NaCl梯度洗脱,根据SDS-PAGE选择目的蛋白所在的收集管合并保存。
将纯化后所得的洗脱液超滤换液至缓冲液中,通过SDS-聚丙烯酰胺凝胶电泳测定检测蛋白质。
实施例5多功能融合蛋白与B7H3的结合活性
采用pH7.4的PBS缓冲液将huB7H3-his受体稀释至0.5μg/mL,每孔100μL加入到96孔ELISA板中,4度包被过夜。用1%BSA封闭液封闭1小时后。PBST洗板3次后,将多功能融合蛋白用0.5%BSA样品稀释液稀释至10μg/mL,以此为起始浓度,进行3倍梯度稀释,共11个梯度,并设无关抗体阴性对照与阳性对照B7H3嵌合抗体,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的山羊抗人IgG Fc用样品稀释液按1:20000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μL TMB底物,室温避光孵育10分钟,每孔加入100μL1M HCL液终止显色反应。在多功能酶标仪上选择波长450nm,参比波长570nm测定96孔板中各孔的吸光值,每孔吸光值(OD)=OD450nm-OD570nm。将抗体的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(VariableSlope)方式(GraphPadPrism软件,GraphPadSoftware,SanDiego,California)进行非线性回归,得到目标抗体与B7H3蛋白的结合曲线。本发明的多功能融合蛋白的结合活性由图1所示。
由图1可知,本发明的多功能融合蛋白在各浓度下均与B7H3有很好的结合能力。
实施例6多功能融合蛋白与CD3的结合活性
采用pH7.4的PBS缓冲液将huCD3-his受体稀释至1μg/mL,每孔100μL加入到96孔ELISA板中,4度包被过夜。用1%BSA封闭液封闭1小时后。PBST洗板3次后,将BCI、CD3抗体、无关抗体IgG样品稀释液稀释至10μg/mL,以此为起始浓度,进行3倍梯度稀释,共11个梯度,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的山羊抗人IgG Fc用样品稀释液按1:10000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μLTMB底物,室温避光孵育10分钟,每孔加入100μL 1MHCL液终止显色反应。在多功能酶标仪上选择波长450nm,参比波长570nm测定96孔板中各孔的吸光值,每孔吸光值(OD)=OD450nm-OD570nm。将抗体的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidal dose-response(Variable Slope)方式(GraphPadPrism软件,GraphPadSoftware,SanDiego,California)进行非线性回归,得到本发明的多功能融合蛋白与CD3的结合曲线。
由图2可知,本发明的多功能融合蛋白在各浓度下均与CD3有很好的结合能力。
实施例7多功能融合蛋白与IL-2Rβ的结合活性
采用pH7.4的PBS缓冲液将IL-2Rβ受体稀释至4μg/mL,每孔100μL加入到96孔ELISA板中,4度包被过夜。用1%BSA封闭液封闭1小时后。PBST洗板3次后,将多功能融合蛋白用0.5%BSA样品稀释液稀释至4μg/mL,以此为起始浓度,进行3倍梯度稀释,共7个梯度,并设阴性对照,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的山羊抗人IgG Fc用样品稀释液按1:10000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μLTMB底物,室温避光孵育10分钟,每孔加入100μL 1M HCl液终止显色反应。在多功能酶标仪上选择波长450nm,参比波长570nm测定96孔板中各孔的吸光值,每孔吸光值(OD)=OD450nm-OD570nm。将多功能融合蛋白的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(Variable Slope)方式(GraphPad Prism软件,GraphPadSoftware,SanDiego,California)进行非线性回归,得到多功能融合蛋白与IL-2Rβ的结合曲线。
多功能融合蛋白的ELISA结果如图3所示,所述多功能融合蛋白在各浓度下均可与IL-2Rβ结合,表明所述多功能融合蛋白与IL-2Rβ有较好的结合能力。
实施例8多功能融合蛋白的抗肿瘤活性
使用B7H3阳性的乳腺癌细胞MCF-7以2×104/孔铺于96孔板,培养24h后,加入多功能融合蛋白BCI和无关抗体20μg/mL起始,5倍稀释,共10个浓度梯度,同时加入CIK(CD3+CD56+细胞)效应细胞4×104/孔,并设置空白对照(稀释液)、阴性对照(MCF-7+CIK,无抗体)、无关抗体组,于细胞培养箱孵育24h后,PBS润洗次,洗去效应细胞。加入含10%CCK-8(Cat:CK04)培养基100μL,于培养箱孵育3h后,于酶标仪OD值450nm进行检测。计算细胞杀伤率,公式为细胞杀伤率(%)=(样品孔OD值-空白OD值)/(阴性孔OD值-空白OD值)×100%。
由图4可知,本发明的多功能融合蛋白可杀伤B7H3阳性的乳腺癌细胞MCF-7,而无关抗体不具有杀伤作用,说明本发明的多功能融合蛋白介导CIK细胞特异性杀伤B7H3阳性的MCF-7细胞。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求为保护范围。
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Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
485 490 495
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
500 505 510
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
515 520 525
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
530 535 540
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
545 550 555 560
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
565 570 575
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
580 585 590
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
595 600 605
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
610 615 620
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
625 630 635 640
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
645 650 655
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
660 665 670
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
675 680 685
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
690 695 700
Lys
705
<210> 3
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 4
<211> 2067
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
caggtccagc tgcaacagtc tggagcagaa ttggtcaaac ctggtgccag cgtgaagctc 60
tcctgcaaag cctcaggtta tacattcacc aactatgata tcaactgggt ccgccagcga 120
cctgaacagg gcttggagtg gatcggctgg atctttcctg gagatggatc tacccagtac 180
aacgaaaaat ttaaaggaaa ggccacgctg acaaccgaca cgagctccag caccgcttac 240
atgcaattga gtcggctgac ctccgaggac agtgctgtgt atttctgtgc acgccagact 300
accgccacat ggttcgctta ctggggtcag ggaacccttg tcaccgtttc tgccgcttca 360
actaaaggcc caagtgtgtt tcccctggct ccaagctcta aaagcacatc cggggggaca 420
gctgcactgg gttgtctggt gaaggattat ttccccgagc ctgtcaccgt gagctggaac 480
tcaggagcac tgacctccgg agtccacacc ttccctgccg tgctgcagtc atccggattg 540
tattccctga gcagcgtggt gacagtcccg agctcttcac tcggcacgca gacctacata 600
tgcaacgtca accacaaacc gagcaatact aaggtggata agcgagttgg tggcggcgga 660
tctggaggtg gaggatcaat cacctgtcct ccacctatgt ccgttgaaca cgctgatatc 720
tgggtgaaga gctactcact gtacagtcga gaacggtaca tttgtaattc agggtttaag 780
agaaaggccg gaacatcatc cctcactgag tgcgtcttga acaaagccac taacgtggct 840
cattggacta ctccttcact gaaatgcata agaggtggtg gaggcagtgg aggtggggga 900
tctggtggtg gaggttctgg tggaggtgga agtggaggtg gaggatcagg gggaggtggt 960
tctaattggg taaacgtcat tagcgatttg aaaaaaatcg aggatcttat tcagagcatg 1020
catattgacg ccaccctgta caccgagagc gatgtgcatc ctagctgcaa agtcacggca 1080
atgaagtgct tccttctcga attgcaggtg atatcactgg aatcaggcga cgcatctatt 1140
catgacacag tggaaaacct gataatcctc gccaatgact ctctttcctc aaacggaaac 1200
gtgacagaga gcggttgtaa agagtgcgag gagctggagg aaaagaatat caaggagttc 1260
ctgcagagct tcgtccacat cgtgcagatg tttatcaaca catctggagg tggcggatca 1320
ggaggtggtg gaagcggtgg aggaggtagt ggaggaggcg gaagtggcgg aggaggaagt 1380
gaaagtaagt acggcccacc ttgtcctccc tgtccagctc cagagttcct gggaggcccc 1440
agtgtgttcc ttttcccacc gaagccaaag gacacactca tgatatctag gacacccgag 1500
gtgacctgtg tcgtagttga cgtctcccaa gaggacccag aagtacaatt taactggtat 1560
gtagacggag tggaagtcca taacgccaag accaaaccaa gagaggaaca gtttaattct 1620
acgtaccgcg ttgtgagcgt gttgacagtc ctgcatcagg actggctcaa cggcaaggag 1680
tacaaatgca aggttagcaa taaaggactg ccatcatcca ttgaaaaaac catctctaag 1740
gccaagggac agcctaggga acctcaggtt tacacactcc ccccctctca agaggaaatg 1800
actaagaacc aagtgagcct tacttgcctt gtaaagggct tttacccatc cgacatcgct 1860
gttgagtggg agagcaacgg ccagcccgaa aacaactata agaccactcc tcctgtgttg 1920
gactctgatg gttccttttt tctggccagc aggctgaccg tagataagag ccggtggcag 1980
gaaggaaacg tgttttcttg ctctgtaatg catgaggcac ttcataatca ctatactcag 2040
aagagtctgt cactgtcttt gggtaag 2067
<210> 5
<211> 2115
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
caagtccagc tgcaacaaag cggtgctgag ctggttaaac ctggagcttc agttaagctc 60
agttgtaagg ccagcgggta caccttcact aactatgata ttaattgggt gaggcagagg 120
ccagaacagg ggctggaatg gattggttgg atcttccccg gagacgggtc aacccagtat 180
aacgagaagt ttaagggaaa agccaccctg accacagata cctcctcttc cacagcttat 240
atgcagctgt caagattgac tagcgaggat tctgccgtgt atttttgcgc ccgccagacc 300
actgccacct ggtttgctta ttggggacaa gggacattgg taacagtttc cgcagcctcc 360
accaagggcc cttcagtgtt tccattggct cccagctcta agtcaaccag tgggggcact 420
gccgctttgg gttgtctggt caaagattat ttccccgaac ccgtgactgt gagctggaac 480
agtggcgcac tcacttcagg agttcacacc tttcccgcag ttcttcaaag ttccggcctc 540
tatagtcttt ctagcgtcgt tacagtgccc agcagttctc tggggactca gacctatatc 600
tgtaacgtca atcacaaacc cagcaacact aaagttgata agagggttga agtgcagctg 660
gttgagtctg gaggaggcct ggtgcagcca ggaaggagtc tcagattgtc ctgtgctgcc 720
agtggcttca cattcgatga ttacaccatg cactgggtga ggcaggctcc tggaaaagga 780
cttgagtggg tgtctggtat cagttggaat tccggctcca ttggatacgc agattcagtg 840
aagggtcggt tcacaatctc cagggataac gctaagaagt cactgtactt gcagatgaat 900
tcactgagag ctgaggacac agccctgtat tattgtgcca aagataacag cggatacggg 960
cactattact atgggatgga cgtgtggggc cagggaacaa ctgtcacggt ggcttctgga 1020
ggtggagggt ctggtggtgg aggcagtgga ggaggtgggt ctgagatcgt gatgactcag 1080
agccccgcca ccttgagtgt gtcaccaggc gaaagagcaa ccctctcatg cagggccagc 1140
cagtcagtgt cctccaacct cgcttggtac cagcagaaac ctggtcaagc cccccgcctc 1200
ctgatatacg gagcaagcac cagagccact ggaatccctg ctaggttctc tggaagcggc 1260
tccggcacag agtttaccct gacgatctcc tctctccagt ccgaggattt cgccgtctac 1320
tactgccagc actacattaa ttggcccctc acctttggag gcggtactaa ggttgaaatc 1380
aaaggtggag gtggatctgg tggaggagga tctggggggg gaggatcaga gagcaaatat 1440
ggacctccat gtccaccctg tcccgctcct gagttcctgg gtggtccatc agtcttcttg 1500
tttcccccaa agcctaaaga caccttgatg atttcccgga cgccagaggt tacgtgcgta 1560
gttgtagacg tttcccaaga ggaccccgag gtgcagttta actggtacgt cgacggggtc 1620
gaagtgcaca acgctaagac taaacctcgg gaggaacagt tcaattccac gtaccgggtg 1680
gtgtctgtcc ttaccgtcct tcatcaggat tggctgaacg gtaaagaata taagtgcaaa 1740
gtgtctaata aggggctccc tagctctata gagaagacaa tctccaaagc taagggccag 1800
cctagggagc cgcaggttta tactctgcct ccatctcagg aagagatgac caagaatcag 1860
gtctccttgt ggtgtctggt caagggcttc tacccaagcg atatcgctgt ggagtgggaa 1920
agcaacggcc aaccagagaa caactataag acaacgccac ccgtgctcga tagtgacggt 1980
agctttttcc tgtattcacg gcttaccgtg gacaagagcc ggtggcaaga gggcaatgtg 2040
tttagttgct ctgtcatgca cgaagccttg cacaaccact acacacaaaa gtcactgtct 2100
ttgagcctgg gtaag 2115
<210> 6
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
gatattgtca tgactcagag ccccgccaca ttgtccgtga ctcctggaga tcgagtctct 60
ttgtcctgcc gggccagcca gtccattagc gattatctcc attggtacca gcagaagagt 120
cacgagagtc caagattgct cattaagtac gctagtcaga gtattagtgg aattcccagt 180
agattttccg gtagcggatc cggcagtgat ttcactctgt ctatcaacag cgttgagcca 240
gaggacgtcg gcgtgtatta ctgccagaat gggcatagct ttcccctgac ttttggggct 300
ggaacaaagc tggaactgaa aagaactgtg gctgccccct ctgtcttcat cttccccccc 360
agcgatgagc agctgaagag tggaactgcc agcgtagtgt gtctgctgaa caatttttac 420
cccagggagg ctaaggtcca gtggaaagtc gataatgctc tgcaatctgg aaacagtcag 480
gaaagtgtaa ctgagcagga ctctaaagac tccacatatt cactgtcatc caccctcacc 540
ctctctaagg ccgactatga aaaacacaag gtgtacgcct gcgaagtaac acaccaagga 600
ctgtcttccc ctgtcacaaa gagctttaac cggggggaat gc 642
<210> 7
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Phe Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gln Thr Thr Ala Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 8
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (10)
1.一种多功能融合蛋白,由第一重链、第二重链、第一轻链和第二轻链组成,其特征在于:所述多功能融合蛋白包含特异性结合B7H3的第一抗原结合部分,特异性结合CD3的第二抗原结合部分,和细胞因子和/或细胞因子受体。
2.如权利要求1所述的多功能融合蛋白,其中所述第一轻链和第二轻链相同。
3.如权利要求1或2所述的多功能融合蛋白,其中所述第一抗原结合部分为Fab或scFv。
4.如权利要求3所述的多功能融合蛋白,其中所述第一抗原结合部分为Fab。
5.如权利要求1或2所述的多功能融合蛋白,其中所述第二抗原结合部分为Fab或scFv。
6.如权利要求5所述的多功能融合蛋白,其中所述第二抗原结合部分为scFv。
7.如权利要求1或2所述的多功能融合蛋白,其中所述细胞因子和/或细胞因子受体为IL-15和/或IL-15受体。
8.如权利要求1-7任一所述的多功能融合蛋白,其还包含Fc部分。
9.如权利要求8所述的多功能融合蛋白,其Fc部分选自IgG1、IgG2、IgG3、IgG4的恒定区氨基酸序列,优选选自IgG1或IgG4的恒定区氨基酸序列。
10.如权利要求8或9所述的多功能融合蛋白,其中所述Fc部分还包含一个或多个选自由以下组成的组的氨基酸替换:S228P、L234F、L235E、P331S、D356K、T366W、K392D、D399K、Y407A、和K409D,优选S228P、T366W和/或Y407A。
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