CN110115758B - Pik3ip1蛋白在调节t细胞反应和制备抗肿瘤药物中的应用 - Google Patents
Pik3ip1蛋白在调节t细胞反应和制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
癌症中存在一些关键的负向调控因子会破坏具有保护性的抗肿瘤免疫系统。本发明研究发现PIK3IP1蛋白在调节T细胞反应中具活性,其胞外域部分的融合蛋白在体内可促进T细胞增殖,并且和4‑1BB激活性抗体联合可抑制肿瘤生长。在此基础上,本发明提出了PIK3IP1蛋白在调节T细胞反应和用于个体癌症治疗的方法及其应用,并提出了用于调节机体免疫反应和抗肿瘤的包含PIK3IP1蛋白或其胞外域的药物组合物和试剂盒产品。
Description
技术领域
本发明属于生物医药领域,具体涉及PIK3IP1蛋白在调节T细胞增殖、调控T 细胞活化和制备抗肿瘤药物中的应用。
背景技术
T细胞是获得性免疫系统最核心的要素。根据T细胞表面的糖蛋白的不同,T 细胞可以分为CD4+T细胞和CD8+T细胞。而循环性的CD4+和CD8+T细胞在体 内巡逻时可以区分这种蛋白是异物还是自身的多肽,外源性的蛋白会释放免疫 系统处于危险的信号,导致T细胞激活,同时启动其他免疫细胞,然后杀死靶细 胞。在对抗肿瘤免疫过程中,T细胞作为核心的执行者,首先被T细胞受体介导 的抗原识别信号激活,同时众多的共刺激信号和共抑制信号精细调节T细胞反应 的强度和质量,这些抑制信号即为免疫检查点。
在生理情况下,一方面参与维持对自身抗原的免疫耐受,避免自身免疫性 疾病,另一方面避免免疫反应的过度激活对组织造成的损伤。肿瘤细胞可以通 过免疫检查点,抑制T细胞激活,从而逃避免疫损伤。因此,通过不同方法增强 T细胞的激活对肿瘤免疫治疗具有重要意义,其中针对免疫检查点的阻断是增强 T细胞激活的有效策略之一。以免疫检查点阻断为代表的肿瘤免疫治疗与其它治 疗的联合正在被日益关注。免疫系统可以识别肿瘤细胞表达的异常蛋白并将肿 瘤细胞杀灭,但是在癌症患者身上,这个过程是有缺陷的。另外,肿瘤细胞可 以调用其他多种机制逃避免疫系统的监视,也有一些肿瘤细胞会诱导调控T细胞 限制细胞毒T细胞,导致其无法攻击肿瘤细胞。
机体的免疫反应受到多种类型免疫细胞、细胞因子等的调控,以抵御危险 信号和外来抗原的攻击;T细胞在免疫应答过程中发挥了重要作用。调节机体免 疫反应并维持自身抗原引起的免疫耐受,有赖于一个由共刺激和共抑制分子组 成的复杂网络的参与。T细胞活化受协同信号网络的调控,这种调控贯穿于T细 胞反应的全程。B7/CD28为代表的Ig超家族和TNF受体超家族的一些成员构成了T细胞共刺激分子的主体。这些协同信号通路的重要性在人类多种疾病中得到了 证实,包括移植物抗宿主反应、自身免疫性疾病、感染和肿瘤。从数目众多的 临床试验中可以看出,除了大家熟知的CTLA-4,越来越多的检查点调控分子及 信号通路,如程序性死亡分子(PD)-1和B7-H4通路被发现在多种疾病的治疗中 发挥作用。近年来,新的检查点调控分子,如T细胞活化的V-区Ig抑制分子 (VISTA)和B7-H6被陆续发现和证实。
负向关键调控因子近来成为肿瘤研究的前沿。近年来,抗体药物发展的另 外一个新的方向是免疫检查点单抗,利用免疫检查点,肿瘤细胞可以抑制、削 弱机体对肿瘤的免疫反应,可以通过抑制T细胞的活化来逃避免疫系统的攻击, 而这种抗体可以激活T细胞、缩小肿瘤、提高病人生存率。这类受体包括CTLA-4 和PD-1,当用单抗来阻断CTLA-4,PD-1或PD-L1,具有保护性的抗肿瘤免疫系 统功能将会加强。2011年第一个免疫检查点抑制剂Yervoy获得FDA批准上市, 用于治疗黑色素瘤;2014年9月,FDA通过加速批准程序批准了首个PD-1抑制剂 Keytruda(pembrolizumab)上市,用于治疗不再对其他药物应答的晚期或无法 切除的黑色素瘤。免疫检查点单抗(CTLA-4单抗、PD1/PDL1单抗)是肿瘤免疫 治疗的最新成果,特别是在血液肿瘤和黑色素瘤方面,因具有良好的抗肿瘤活 性,取得了重大的进展。Ipilimumab于2011年获批,针对转移性黑色素瘤的抗 CTLA-4单抗,已被用于治疗晚期黑色素瘤,但是反应率低,抗CTLA-4治疗对患 者有免疫毒性。MDX-1106,作为抗PD-1单抗,在临床上也是极具应用潜力的。 研究表明MDX-1106的毒性比Ipilimumab低,但是在前列腺癌等癌症没有抑制肿 瘤生长的能力,因为这些肿瘤并没有PD-L1的靶点。这说明,很多癌症仍存在一 些关键的负向调控因子来破坏具有保护性的抗肿瘤免疫系统。
磷脂酰肌醇3激酶相互作用蛋白1(PI3Kinteractingprotein1,PIK3IP1)是一个新近报道的能与磷脂酰肌醇3激酶(phosphatidylinositol-3-kinase,PI3K)的p110 亚基结合的蛋白,可以下调PI3K活性,抑制丝氨酸苏氨酸激酶(AKT, RAC-alphaserine/threonine-proteinkinase)的活化。2012年,有研究报道了PIK3IP1 蛋白可在T细胞上表达。通过在人白血病细胞系Jurkat和小鼠Th2细胞系D10细胞 上过表达PIK3IP1蛋白,抑制了T细胞活化相关的转录信号分子NFAT、AP-1的活 化。相反,用SiRNA在上述细胞系沉默掉PIK3IP1基因,能够增强Akt的磷酸化、 促进T细胞的活化和IL-2的分泌。说明,新的PIK3IP1信号通路调控因子PIK3IP1 可能抑制T细胞的活化。
发明内容
本发明发明人对PIK3IP1在常见的各组织、免疫细胞、肿瘤细胞系上等的表 达进行了检测和分析。发现其在免疫细胞上表达较高,且表达强度与机体的免 疫状态相关。尤其在T细胞有相对较特异的表达。机体的免疫反应受到一系列分 子的调控,以保证机体抵御危险信号和外来抗原的攻击。其中,T细胞在维持体 内免疫内稳态和免疫防御方面发挥了重要作用。
本发明对比研究了Pik3ip1敲除小鼠和野生型小鼠在经OVA抗原特异性免疫 反应后T细胞的增殖情况,发现Pik3ip1敲除小鼠的T细胞的增殖能力强于野生型 小鼠。说明在新抗原的急性刺激下,小鼠T细胞上Pik3ip1的表达对T细胞的增殖 有抑制作用。
本发明对比研究了Pik3ip1敲除小鼠在MC38肿瘤模型中T细胞的反应和对肿 瘤生长的影响。发现Pik3ip1缺失的T细胞在肿瘤抗原刺激下其增殖能力和IFN-γ 等效应分子分泌均强于野生型小鼠。由此表明,在肿瘤抗原刺激下,小鼠T细胞 上Pik3ip1的表达对T细胞反应有明显抑制作用,Pik3ip1表达降低可有效抑制肿瘤 的生长。
本发明进一步研究了口腔鳞癌患者外周血淋巴细胞,同样发现,口腔鳞癌 患者外周血CD4+和CD8+T细胞上PIK3IP1的荧光强度与其增殖能力呈负相关, 即,CD4+和CD8+T细胞上PIK3IP1表达水平越高,相应细胞的增殖能力越弱。
此外,本发明发明人还具体研究了PIK3IP1ECD-Fc融合分子在体内可促进小 鼠CD8+T细胞的增殖,并研究了PIK3IP1ECD-Fc融合分子单独使用或与4-1BB激 活性抗体2A(Anti-m4-1BB(2A))联合应用对小鼠成瘤的免疫治疗效果。结果发 现,PIK3IP1ECD-Fc融合分子和4-1BB激活性抗体2A联合,能显著抑制肿瘤的生 长。
在此基础上,本发明提出如下技术方案:
本发明的一个方面提供,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子在 制备用于调控受试者免疫应答的药物中的用途。
根据本发明,调控受试者免疫应答包括增强受试者免疫应答,例如增强受 试者CD8+T细胞和/或CD4+T细胞的增殖。
作为本发明的一种实施方式,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分 子,和抗原一同在制备用于增强受试者对抗原的免疫应答的药物中的用途,所 述增强包括给受试者施用抗原和PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分 子,使得受试者对抗原的免疫应答得到增强。
根据本发明,所述抗原可以是癌性细胞、肿瘤抗原、病毒抗原、细菌抗原 等。可以使用的抗原非限制性实例包括黑素瘤的抗原肽,诸如肽gp100、MAGE 抗原、Trp-2、MART1和/或酪氨酸酶。在本发明的一个实施方式中,所述抗原 是gp100,更优选为hgp10025-33。在本发明的另一个实施方式中,所述抗原是OVA, 更优选为OVA257–264。在本发明的再一个实施方式中,所述抗原是癌性细胞,例 如MC38细胞,B16细胞,B16-F10细胞等。
本发明的第二个方面提供,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子 在制备免疫治疗肿瘤药物中的用途。
根据本发明,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子通过增强用药 者的免疫应答实现治疗肿瘤的效果。
根据本发明,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子可以抑制肿瘤 细胞的生长。
根据本发明,不受特殊理论的限制,发明人推测在体内,PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子可能作为PIK3IP1的竞争性抑制剂阻断了 PIK3IP1活化带来的T细胞增殖或活性的抑制作用。
PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子还可以联合其他的肿瘤标准 治疗方法,用于治疗肿瘤。
PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子可以有效联合化疗方案,并 有可能减少所施用的化疗剂的剂量。这种联合的一个例子是,PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子联合达卡巴嗪(decarbazine)来治疗黑素瘤。 另一个例子是,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子联合白介素 -2(IL-2)来治疗黑素瘤。
PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和化疗剂联合使用的科学原 理是,大多数化疗剂的细胞毒性作用使肿瘤细胞死亡,肿瘤细胞死亡导致抗原 呈递途径中肿瘤抗原水平升高。通过细胞死亡带来与PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子协同作用的其它联合疗法还可以包括放射治疗、手术等。 此外,血管发生抑制剂也可以与PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子 联合,对血管发生的抑制同样能导致肿瘤细胞死亡,使肿瘤抗原进入抗原呈递 途径。
肿瘤通过多种机制来规避宿主的免疫监视。可以通过抑制肿瘤表达的具有 免疫抑制性的蛋白质的活性来解除这些机制,所述蛋白质包括例如TGF-β和Fas 配体等。针对这些蛋白质中的每一种的抗体也可以与PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子联合使用,以抵消肿瘤的免疫抑制效果并促进宿主的肿瘤 免疫应答。
此外,能够激活宿主免疫响应性的其它抗体也可以与PIK3IP1、PIK3IP1ECD 或PIK3IP1ECD融合分子联合使用。这些抗体包括树突细胞表面上激活DC功能和 抗原呈递的分子。例如,抗CD40抗体能够有效提高T辅助细胞活性,可以与 PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子联合使用。针对T细胞共刺激性 分子诸如CTLA-4、OX-40、4-1BB和ICOS等的激活性抗体,也可以提高T细胞活 性。
因此,本发明的一个实施方式提供,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD 融合分子单独或者和另一种或多种治疗剂联合在制备治疗肿瘤药物中的用途。
根据本发明,所述另一种或多种治疗剂包括但不限于肿瘤化疗剂,能够活 化T细胞的化合物,血管生成抑制剂等。
在本发明的一个具体实施方式中,所述另一种治疗剂是4-1BB的激活性抗 体,例如4-1BB激活性抗体2A。
本发明的一个实施方式是提供,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合 分子和4-1BB的激活性抗体,例如2A,联合在制备治疗肿瘤的药物中的用途。
根据本发明,其中PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子以亚治疗 剂量施用。
根据本发明,其中4-1BB的激活性抗体,例如2A,以亚治疗剂量施用。
根据本发明,其中PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和4-1BB 的激活性抗体,例如2A,各自以亚治疗剂量施用。
在某些实施方案中,可以PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和 抗体2A的治疗性组合与药学上可接受的载体混合作为单一组合物同时施用,或 者可以将每种活性成分分别与药学上可接受的载体混合,作为分开的组合物同 时施用。在另一个实施方案中,可以序贯施用PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子和抗体2A的组合,例如,先施用PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子后施用抗体2A,或者先施用抗体2A后施用PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子。另外,如果序贯施用超过一个剂量的联合疗法,可以在每次施用时颠倒序贯施用的次序或保持相同次序,序贯施用可 以与同时施用或其任意组合联合。例如,第一次施用PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子和抗体2A的组合可以是同时的,第二次施用可以是序贯 的,先施用PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子后施用抗体2A,而第 三次施用可以是序贯的,先施用抗体2A后施用PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子等。另一种代表性的剂量给药方案可以包括第一次施用是 序贯的,先施用抗体2A后施用PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子,而后续施用可以是同时的。
任选的是,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和4-1BB的激活 性抗体,例如抗体2A的组合可以进一步联合其他免疫原剂,诸如癌性细胞、纯 化的肿瘤抗原等。可以使用的免疫原剂的非限制性实例包括黑素瘤抗原的肽, 诸如肽gp100、MAGE抗原、Trp-2、MART1和/或酪氨酸酶。
同样,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和4-1BB的激活性抗 体,例如抗体2A的组合可以进一步联合标准的肿瘤治疗方法。例如,PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子和抗体2A的组合联合达卡巴嗪 (decarbazine)治疗黑素瘤,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和抗 体2A的组合联合白介素-2(IL-2)来治疗黑素瘤。
本发明的第三个方面是提供,一种药物组合物,其包含PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子,和药学上可接受的载体。
根据本发明,该药物组合物用于调控受试者的免疫应答。所述调控受试者 免疫应答包括增强受试者免疫应答,例如增强受试者CD8+T细胞和/或CD4+T细 胞的增殖。
根据本发明,该药物组合物用于治疗肿瘤。所述治疗肿瘤通过增强用药者 的免疫应答,来实现抑制肿瘤生长的治疗效果。
根据本发明,所述药物组合物还可以以联合疗法的方式施用,即联合其他 治疗剂,例如,其他的免疫调节剂或肿瘤治疗药物。
根据本发明,所述药物组合物还可以进一步含有另一种或多种治疗剂。所 述治疗剂包括但不限于肿瘤化疗剂,能够活化T细胞的化合物,血管生成抑制剂 等。
在本发明的一个具体实施方式中,所述另一种治疗剂是4-1BB的激活性抗 体,例如抗体2A。
单剂量形式的药物组合物中活性成分的量,可以根据受试者及具体的给药 途径而变化。一般而言,在药物组合物中,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD 融合分子的重量百分比为大约0.01%到大约99%,优选大约0.1%到大约70%, 最优选大约1%到大约30%。
对于PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子,其剂量范围为大约 0.0001-100mg/kg,更通常为0.01-5mg/kg体重。例如,剂量可以是0.3mg/kg体重、 1mg/kg体重、3mg/kg体重、5mg/kg体重或10mg/kg体重或在1-10mg/kg的范围内。 例示性的治疗方案可以是每周施用一次、每两周一次、每三周一次、每四周一 次、每月一次、每3个月一次或每3-6个月一次。对于PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子而言,优选的剂量方案包括经静脉内施用1mg/kg体重或 3mg/kg体重,其利用下列剂量给药方案之一来给予:(i)每四周一剂达六个剂量, 然后每三个月一剂;(ii)每三周一剂;(iii)给予一次3mg/kg体重,随后每三周给予 1mg/kg体重。
本发明药用组合物中活性成分的实际剂量水平可以变化,从而获得对于特 定患者和给药途径能有效实现治疗性应答而对患者无毒的活性成分用量。选定 的剂量水平将取决于多种药动学因素,包括给药途径,用药时间,药物代谢情 况,所治疗患者的年龄、性别、体重、大体健康状态和既往病史等。
本发明的一个实施方式还提供,包含PIK3IP1、PIK3IP1ECD或PIK3IP1ECD 融合分子和4-1BB的激活性抗体,例如抗体2A的药物试剂盒。
该试剂盒还可以进一步包含用于治疗肿瘤的说明书。
在本发明的一个具体实施方案中,所述药物试剂盒中将PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子和4-1BB的激活性抗体,例如抗体2A以单位 剂量形式共同包装。
在本发明的另一个具体实施方案中,所述药物试剂盒中分别将PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和4-1BB的激活性抗体,例如抗体2A以各自 的单位剂量形式分别包装。
本发明的第四个方面是提供,一种调控受试者免疫应答的方法,其包括给 受试者施用PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子,使得受试者的免疫 应答得到调控。优选的是,PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子增强、 刺激或增加受试者的免疫应答。
根据本发明,所述增强、刺激或增加受试者的免疫应答包括但不限于,促 进CD4+T细胞和/或CD8+T细胞的增殖。
本发明的一个实施方式中提供,一种增强受试者对抗原的免疫应答的方法, 其包括给受试者施用抗原和PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子,使 得受试者对抗原的免疫应答得到增强。
根据本发明,所述抗原可以是癌性细胞,肿瘤抗原,病毒抗原,细菌抗原 等。可以使用的抗原非限制性实例包括黑素瘤的抗原肽,诸如肽gp100、MAGE 抗原、Trp-2、MART1和/或酪氨酸酶。在本发明的一个实施方式中,所述抗原 是gp100,更优选为hgp10025-33。在本发明的另一个实施方式中,所述抗原是OVA, 更优选为OVA257–264。在本发明的再一个实施方式中,所述抗原是癌性细胞,例 如MC38细胞,B16细胞,B16-F10细胞等。
本发明的第五个方面是提供,一种在个体中治疗肿瘤或延迟肿瘤进展的方 法,所述方法是给所述个体治疗有效量的PIK3IP1、PIK3IP1ECD或PIK3IP1ECD 融合分子。
根据本发明,所述方法还包括给予所述个体另一种或多种治疗剂。
根据本发明,所述另一种或多种治疗剂包括但不限于其他的活化T细胞的化 合物,肿瘤化疗剂,血管生成抑制剂等。
根据本发明,所述PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和另一种 或多种治疗剂各自在单独的组合物中同时施用,所述PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子和另一种治疗剂在同一个组合物中同时施用,或者,所述 PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子和另一种治疗剂各自在单独的组 合物中间隔一段时间先后施用或顺序施用。在本发明的一个实施方式中,所述 另一种治疗剂是4-1BB的激活性抗体,例如抗体2A。
根据本发明,其中施用所述PIK3IP1、PIK3IP1ECD或PIK3IP1ECD融合分子 相比于未经治疗的个体或用其他治疗剂的单一疗法治疗的个体,增加T细胞的增 殖。T细胞的增殖平均比例至少约10%、至少约20%、至少约30%、至少约40%、 至少约50%、至少约60%、至少约70%、至少约80%或至少约90%。
在本发明的一个实施方式中,施用所述PIK3IP1、PIK3IP1ECD或 PIK3IP1ECD融合分子和2A相比于未经治疗的个体或用所述PIK3IP1、 PIK3IP1ECD或PIK3IP1ECD融合分子、2A或其他治疗剂的单一疗法治疗的个体, 肿瘤体积减少。
在以上描述的技术方案的一些实施方式中,PIK3IP1包含选自SEQ ID NO.1、 2、3、4、5、6、7、8和/或17的序列;在一些实施方式中,PIK3IP1由选自SEQ ID NO.1至8之一的序列组成。
在以上描述的技术方案的一些实施方式中,PIK3IP1ECD包含选自SEQ ID NO.9和/或10的序列;在一些实施方式中,PIK3IP1ECD由选自SEQ ID NO.9或10 的序列组成。
在以上描述的技术方案的一些实施方式中,PIK3IP1ECD融合分子包含选自 SEQID NO.9和/或10的序列。在一些实施方案中,PIK3IP1ECD融合分子的至少 一个融合伴侣选自Fc、白蛋白和聚乙二醇。在一些实施方案中,PIK3IP1ECD融 合分子的至少一个融合伴侣是Fc。在一些实施方案中,PIK3IP1ECD融合分子的 至少一个融合伴侣是IgG Fc。在一些实施方案中,所述IgG Fc的碱基序列由选自 SEQ ID NO.15或16的序列组成。在一些实施方案中,PIK3IP1ECD融合分子的碱 基序列由选自SEQ ID NO.11至14之一的序列组成。
在以上描述的技术方案中,所述肿瘤包括通常对免疫疗法有响应的肿瘤, 包括但不限于黑色素瘤、白血病、肺癌、肝癌、卵巢癌、宫颈癌、皮肤癌、膀 胱癌、结肠癌、乳腺癌、神经胶质瘤、肾癌、胃癌、食道癌、口腔鳞状细胞癌、 头颈癌;优选为黑色素瘤、白血病、肺癌、肝癌、结肠癌、乳腺癌、神经胶质 瘤、胃癌、口腔鳞状细胞癌。
在一些实施方案中,所述肿瘤是转移性的。
在一些实施方案中,所述肿瘤优选为结肠癌、黑色素瘤、口腔鳞状细胞癌、 肝细胞癌。
在以上描述的技术方案中,所述肿瘤化疗剂包括但不限于:烷化剂、氮芥 类、塞替派类、亚硝脲类、甲基磺酸酯类、铂类化合物、丝裂霉素等,具体如: 氮芥、苯丁酸氮芥、环磷酰胺、异环磷酰胺、塞替派、卡莫司汀、司莫司汀、 白消安、顺铂、奥沙利铂、卡铂、草酸铂、丝裂霉素等;影响核酸合成的药物, 例如二氢叶酸还原酶抑制剂、胸腺核苷合成酶抑制剂、嘌呤核苷合成酶抑制剂、 核苷酸还原酶抑制剂、DNA多聚酶抑制剂,具体如:甲氨蝶呤、5-FU、FT-207、 卡培他滨、6-巯基嘌呤、6-TG、羟基脲、阿糖胞苷、吉西他滨、培美曲塞等; 作用于核酸转录的药物,例如放线菌素D、柔红霉素、阿霉素、表阿霉素、阿克 拉霉素、光辉霉素等;作用于DNA复制的拓扑异构酶I抑制剂,例如伊立替康、 拓扑替康、羟基喜树碱等;作用于有丝分裂M期干扰微管蛋白合成的药物,例如 紫杉醇、多西他赛、长春花碱、长春新碱、长春瑞滨、鬼臼碱类、高三尖杉酯 碱等。
在以上描述的技术方案中,所述能够活化T细胞的化合物包括但不限于T细 胞共刺激性分子的激活性抗体,例如:CTLA-4、OX-40、4-1BB或ICOS等的激 活性抗体,抗CD40抗体等。在一些实施方案中,所述能够活化T细胞的化合物 为4-1BB的激活性抗体,例如抗体2A。
在以上描述的技术方案中,所述血管生成抑制剂包括但不限于:抑制血管 内皮生长因子的作用的那些抑制剂,例如来那度胺、沙利度胺、抗血管内皮细 胞生长因子抗体例如贝伐单抗,VEGF受体酪氨酸激酶抑制剂凡德他尼 (vandetanib)(ZD6474)、瓦他拉尼(vatalanib)(PTK787)、舒尼替尼(SU11248)、阿 西替尼(AG-013736)、帕唑帕尼(GW786034)和4-(4-氟-2-甲基吲哚-5-基氧基)-6- 甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉等。
本申请中的序列和描述
术语
为了使本发明更加容易理解,首先对一些术语进行定义。如本申请中使用 的,除非在本文中有明确描述,否则下列的每一个术语应当具有下文所述的含 义。其它定义在本申请全文中给出。
本文所用的术语―PIK3IP1”是指磷脂酰肌醇3激酶相互作用蛋白1(PI3Kinteracting protein1,PIK3IP1),其能与磷脂酰肌醇3激酶 (phosphatidylinositol-3-kinase,PI3K)的p110亚基结合,可以下调PI3K活性, 抑制丝氨酸苏氨酸激酶的活化,包含其天然存在的等位基因形式和经加工的各 种同工型。术语―PIK3IP1”还指来自人物种和非人物种诸如小鼠、大鼠或灵长类 的PIK3IP1。有时通过诸如用于人PIK3IP1的h PIK3IP1、用于鼠PIK3IP1的m PIK3IP1等术语来指示来自特定物种的PIK3IP1。在本发明的一些实施例中,还 用Pik3ip1指代小鼠的PIK3IP1蛋白。
示例性的PIK3IP1包括但不限于,由选自SED ID NO.1、2、3、4、5、6、7、8和17的氨基酸序列组成。
术语―PIK3IP1胞外域”(PIK3IP1Extracellular domain―PIK3IP1ECD”)包括 全长PIK3IP1ECD、PIK3IP1ECD片段和PIK3IP1ECD变体。如本文所用的,术语 ―PIK3IP1ECD”指PIK3IP1多肽,其缺少胞内域和跨膜域,具有或没有信号肽。如 本文所用的,术语―全长PIK3IP1ECD”指延伸至胞外域的最后氨基酸的 PIK3IP1ECD,并且可以包括或不包括N-末端信号肽。在一些实施方案中, PIK3IP1ECD是人PIK3IP1ECD,由选自SEQ ID NO.9的氨基酸序列组成。在一些 实施方案中,PIK3IP1ECD是鼠PIK3IP1ECD,由选自SEQ ID NO.10的氨基酸序 列组成。
当PIK3IP1ECD―由”选自SEQ ID NO.9和10的序列―组成”时,PIK3IP1ECD可 含有或不含有多种翻译后修饰,诸如糖基化和唾液酸化。换言之,当PIK3IP1ECD 由特定的氨基酸序列组成时,其在连续的氨基酸序列中不含有另外的氨基酸, 但可能含有对氨基酸侧链、N末端氨基和/或C-末端羧基的修饰。
如本文所用的,术语―PIK3IP1ECD片段”指从全长ECD的N和/或C末端缺失 一个或多个残基并保持和全长PIK3IP1ECD相同结合能力的PIK3IP1ECD。 PIK3IP1ECD片段可以包括或不包括N-末端信号肽。
如本文所用的,术语―PIK3IP1ECD变体”指含有氨基酸添加、缺失和取代并 保持和亲代PIK3IP1ECD相同结合能力的PIK3IP1ECD。此类变体可与亲代 PIK3IP1ECD具有至少90%、92%、95%、97%、98%或99%同一性。两个多肽的 同一性可通过相似性得分来测量,所述测量方法是本领域已知的,例如使用确 定相似性的具有缺省设置的Bestfit程序来比较两个多肽的氨基酸序列的同一性 或相似性。
术语―PIK3IP1ECD融合分子”指包含PIK3IP1ECD和一个或多个―融合伴侣” 的分子。在一些实施方案中,PIK3IP1ECD和融合伴侣是共价连接的。若融合伴 侣也是多肽(―融合伴侣多肽”),则PIK3IP1ECD和融合伴侣多肽可以是连续的 氨基酸序列的部分,且融合伴侣多肽可与PIK3IP1ECD的N末端或C末端相连接。 在这样的情况下,PIK3IP1ECD和融合伴侣多肽可自编码PIK3IP1ECD和融合伴 侣多肽两者的编码序列被翻译为单一的多肽(―PIK3IP1ECD融合蛋白”)。在一 些实施方案中,PIK3IP1ECD和融合伴侣通过其他方式共价连接,诸如,除肽键 外的化学键。在另外的实施方案中,PIK3IP1ECD和融合伴侣可通过―接头”来融 合,所述接头由至少一个氨基酸或化学部分组成。
在一些实施方案中,PIK3IP1ECD多肽和融合伴侣是非共价连接的,例如使 用结合对将它们连接。示例性的结合对包括但不限于,生物素和亲和素或链霉 亲和素、抗体和其抗原等。
示例性的融合伴侣包括但不限于,免疫球蛋白Fc结构域、白蛋白和聚乙二 醇。一些示例性的Fc结构域的碱基序列示于SEQ ID NO.15和16。在一些实施方 案中,Fc结构域选自IgG1Fc、IgG2Fc、IgG3Fc和IgG4Fc。
在一些实施方式中,PIK3IP1ECD融合分子包含PIK3IP1ECD和一个融合伴 侣,所述融合伴侣为Fc。在一个具体实施方式中,PIK3IP1ECD融合分子的碱基 序列由选自SEQ IDNO.11、12、13和14的碱基序列组成。
在一些实施方案中,PIK3IP1ECD融合分子包含信号肽。在一些实施方案中,PIK3IP1ECD融合分子缺少信号肽。在一些实施方案中,PIK3IP1ECD融合分子 的PIK3IP1ECD部分包括选自SEQ ID NO:9和10的序列。在一些实施方案中, PIK3IP1ECD融合分子的PIK3IP1ECD部分由选自SEQ ID NO:9和10的序列组成。 并且,因为PIK3IP1ECD与融合分子相连接,在PIK3IP1ECD的N末端和/或C末端 可能存在另外的氨基酸,但那些氨基酸并非来自PIK3IP1序列,但可来自,例如, 接头序列或融合伴侣序列。
以下是可用于本发明的非限制性的示例性融合伴侣。
如本文所讨论的,可将PIK3IP1ECD与至少一种融合伴侣组合,产生 PIK3IP1ECD融合分子。这些融合伴侣可促进纯化,或者使PIK3IP1ECD融合分 子的体内半衰期延长。PIK3IP1ECD的合适的融合伴侣包括例如,聚合物,诸如 水溶性聚合物,免疫球蛋白的恒定结构域;人血清白蛋白(HSA)的全部或部 分;胎球蛋白A;胎球蛋白B;亮氨酸拉链结构域;四连接素三聚化结构域;甘 露糖结合蛋白(也称作甘露糖结合凝集素),例如,甘露糖结合蛋白1;和Fc区。
为了本发明的治疗目的,所述的融合伴侣不会产生中和抗原性反应或其他 不利反应。
聚合物,例如,水溶性的聚合物,作为融合伴侣使用以降低PIK3IP1ECD融 合分子在水性环境中(诸如生理环境中)的沉淀。本发明所采用的聚合物是药 学上可接受的聚合物,包括但不限于,聚乙二醇(PEG)、聚乙二醇丙醛、乙二 醇/丙二醇的共聚物、单甲氧基-聚乙二醇、羧甲基纤维素、葡聚糖、聚乙烯醇(PVA)、聚乙烯基吡咯烷酮、聚-1,3-二氧戊环、聚-1,3,6-三氧杂环己烷、乙烯 /马来酸酐共聚物、聚(β-氨基酸)(无论是均聚物或无规共聚物)、聚(正乙烯基 吡咯烷酮)聚乙二醇、聚丙二醇均聚物(PPG)和其他聚氧化烯(polyakylene oxide)、 聚环氧丙烷/环氧乙烷共聚物、聚氧乙烯化的多元醇(POG)(例如,甘油)和 其他聚氧乙烯化的多元醇、聚氧乙烯化山梨糖醇或聚氧乙烯化葡萄糖、结肠酸 或其他碳水化合物聚合物,聚蔗糖(Ficoll)或葡聚糖及其混合物。
通常,可在使蛋白质与活化的聚合物分子反应的任何合适的条件下进行化 学衍生。可用于将聚合物与活性部分连接的活化的基团包括砜、马来酰亚胺、 巯基、硫醇、三氟甲基磺酸盐、三氟乙基磺酸酯、氮丙啶(azidirine)、环氧乙烷 和5-吡啶基。通常将本发明的聚合物在氨基酸的α或ε氨基或反应性硫醇基上与 PIK3IP1ECD连接。
此外,可将本发明的PIK3IP1ECD与标记物序列融合。标记物氨基酸序列可 以是六聚组氨酸肽,六聚组氨酸为融合蛋白的纯化提供了便利。
在不同的实施方案中,寡聚化对融合蛋白提供了一些功能优点,包括但不 限于,多价、增加的结合强度和不同的结构域的组合功能。因此,在一些实施 方案中,融合伴侣包含寡聚化结构域,例如,二聚化结构域。示例性的寡聚化 结构域包括但不限于,卷曲螺旋结构域,包括α-螺旋卷曲螺旋结构域;胶原蛋白 结构域;胶原蛋白样结构域;和某些免疫球蛋白结构域。示例性的卷曲螺旋多 肽融合伴侣包括但不限于,四连接素卷曲螺旋结构域;软骨寡聚基质蛋白的卷 曲螺旋结构域;血管生成素卷曲螺旋结构域;和亮氨酸拉链结构域。
可用作融合伴侣的许多Fc结构域是本领域中已知的。在一些实施方案中, 融合伴侣是Fc免疫球蛋白结构域。Fc融合伴侣可以是在天然存在的抗体中发现 的野生型Fc、其变体或其片段。非限制性的示例性Fc融合伴侣包括包含人IgG(例 如,人IgG1、IgG2、IgG3或IgG4)的铰链结构域以及CH2和CH3恒定结构域的 Fc。另外的示例性Fc融合伴侣包括但不限于,人IgA和IgM。
在一些实施方案中,融合伴侣是白蛋白。示例性的白蛋白包括但不限于, 人血清白蛋白(HSA)和能够增加与其融合的多肽的血清半衰期或生物利用率 的HSA片段。
融合伴侣的示例性的连接
可将融合伴侣共价地或非共价地与PIK3IP1ECD的N末端或C末端连接。连接 还可发生在PIK3IP1ECD中除N末端或C末端的位置,例如,通过氨基酸侧链(例 如,半胱氨酸、赖氨酸、丝氨酸或苏氨酸的侧链)来连接。
在共价的或非共价的连接的实施方案中,接头可含于融合伴侣和 PIK3IP1ECD之间。此类接头可以由至少一个氨基酸或化学部分组成。将融合伴 侣与PIK3IP1ECD共价连接的示例性方法包括但不限于,将融合伴侣和 PIK3IP1ECD作为单一的氨基酸序列来翻译和将融合伴侣与PIK3IP1ECD化学连 接。当融合伴侣和PIK3IP1ECD作为单一的氨基酸序列来翻译时,在融合伴侣和 PIK3IP1ECD之间可包括另外的氨基酸作为接头。在一些实施方案中,基于编码 接头的多核苷酸序列来选择接头,以有利于将融合伴侣和/或PIK3IP1ECD克隆到 单个表达构建体中(例如,可将含有特定的限制位点的多核苷酸置于编码融合 伴侣的多核苷酸和编码PIK3IP1ECD的多核苷酸之间,其中含有限制位点的多核 苷酸编码短的氨基酸接头序列)。当通过化学方式将融合伴侣和PIK3IP1ECD共 价偶联时,在偶联反应过程中通常可包括不同大小的接头。
PIK3IP1ECD和PIK3IP1ECD融合分子表达和生产载体
提供了包含编码PIK3IP1ECD的多核苷酸的载体。还提供了包含编码 PIK3IP1ECD融合分子的多核苷酸的载体。此类载体包括但不限于,DNA载体、 噬菌体载体、病毒载体、逆转录病毒载体等。
在一些实施方案中,选择的载体对于多肽在CHO或CHO来源的细胞中的表 达是优化的。
宿主细胞
在不同的实施方案中,PIK3IP1ECD或PIK3IP1ECD融合分子可在原核细胞 中表达,诸如细菌细胞;或在真核细胞中表达,诸如真菌细胞、植物细胞、昆 虫细胞和哺乳动物细胞。可用于表达多肽的示例性真核细胞包括但不限于,COS 细胞,293细胞,CHO细胞和NSO细胞。
将核酸导入到期望的宿主细胞中可通过本领域中已知的任何方法来实现, 这些方法包括但不限于,磷酸钙转染、DEAE-葡聚糖介导的转染、阳离子脂质 介导的转染、电穿孔、转导、感染等。
PIK3IP1ECD多肽的纯化
可通过本领域中已知的多种方法纯化PIK3IP1ECD或PIK3IP1ECD融合分 子。此类方法包括但不限于,亲和基质或疏水作用色谱的使用。合适的亲和配 体包括PIK3IP1ECD或融合伴侣的任何配体。例如,蛋白A、蛋白G、蛋白A/G或 抗体亲和柱可用于与Fc融合伴侣结合以纯化PIK3IP1ECD融合分子。
术语―信号肽”指位于多肽的N末端的氨基酸残基的序列,其促进多肽从哺乳 动物细胞中分泌。在将多肽从哺乳动物细胞中运出之后可将信号肽裂解,形成 成熟蛋白质。信号肽可以是天然的或合成的,并且它们对于其所连接的蛋白质 可以是异源的或同源的。
―药学上可接受的载体”包括任何和全部的生理上相容的溶剂、分散介质、包 衣、防腐剂、等渗剂、缓释剂等等。优选地,载体适合于静脉内、皮下、肌内、 肠胃外、脊柱或表皮施用(例如,通过注射或输注)。本发明的药物组合物可 以包括一种或多种药学上可接受的盐、抗氧化剂、水和非水性载体,和/或佐剂, 如防腐剂、润湿剂、乳化剂和分散剂。
―免疫应答”是指脊椎动物体内针对外来作用介质的生物学应答,该应答可保 护生物体免于被这些作用介质或者由其造成的疾病的伤害。免疫应答是由免疫 系统的细胞(例如,T淋巴细胞,B淋巴细胞,自然杀伤NK细胞,巨噬细胞,嗜 酸性粒细胞,肥大细胞,树突细胞或嗜中性粒细胞)和由这些细胞的任一种或 肝脏产生的可溶性大分子(包括抗体,细胞因子和补体)的作用介导的,其导 致脊椎动物机体入侵病原体、细胞或被病原体感染的组织、癌细胞或其它异常 细胞,或者,在自身免疫性或病理性炎症中,针对正常的人细胞或组织的选择 性靶向、结合、损害、破坏,和/或消除。
―免疫疗法”是指用包括诱导、强化、抑制或者修饰免疫应答的方法对患有疾 病、具有发生疾病风险、或者疾病复发的受试者进行治疗。
―增强内源性免疫应答”意思是强化受试者体内现有的免疫应答的有效性或 强度。此类效率和潜力的强化可以通过,例如,克服抑制内源性宿主免疫应答 的机制,或者通过刺激强化内源性宿主免疫应答的机制来实现。
药物或治疗剂(例如本发明的PIK3IP1)的―治疗有效量”或―治疗有效剂量” 是药物的任何如下所述的量,当单独使用或与另一种治疗剂组合使用该量的药 物时,可促进疾病消退,疾病消退表现为疾病症状的严重度降低、无疾病症状 期的频率和持续时间增加、或者防止由患病导致的障碍或失能。药物的治疗有 效量或剂量包括―预防有效量”或―预防有效剂量”,―预防有效量”或―预防有效剂 量”是药物的任何如下所述的量,当将该量的药物单独施用或者与另一种治疗剂 组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时,可抑制疾病的 发生或复发。治疗剂促进疾病消退或抑制疾病发展或复发的能力可以用技术人 员已知的各种方法进行评估,例如在人类受试者的临床试验中,在可预测在人 类中的效力的动物模型系统中,或者通过在体外测定系统中测定试剂的活性。
―亚治疗剂量”表示治疗化合物例如,亚治疗剂量的CTLA-4抗体为少于约 3mg/kg(即抗CTLA-4抗体的已知剂量)的单剂抗体。
―癌症”是指一大类以异常细胞在体内不受控制地生长为特征的各种疾病,在 本文中可与―肿瘤”互换使用。不受控制的细胞分裂和生长分裂和生长导致形成恶 性肿瘤或细胞,它们侵入邻近组织,还可以通过淋巴系统或血流转移到身体的 远端部分。
可以使用本发明免疫疗法治疗的癌症实例包括但不限于:骨癌症、胰腺癌 症、皮肤癌症、头或颈部的癌症、乳腺癌症、肺癌症、皮肤或眼内恶性黑素瘤、 肾癌症、子宫癌症、卵巢癌症、结肠直肠癌症、结肠癌症、直肠癌症、肛门区 域的癌症、胃癌症、睾丸癌症、子宫癌症、输卵管癌、子宫内膜癌、子宫颈癌、 阴道癌、外阴癌、食道的癌症、小肠的癌症、内分泌系统的癌症、甲状腺的癌 症、甲状旁腺的癌症、肾上腺的癌症、软组织肉瘤、尿道的癌症、阴茎的癌症、 血液恶性肿瘤、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱的癌症、肾或输尿管的 癌症、肾盂癌、中枢神经系统(CNS)的肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、 脊椎轴肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌症、鳞状细 胞癌症、环境诱导的癌症包括被石棉诱导的癌症,转移性癌症,和所述癌症的 任意组合。在其它优选的实施方案中,癌症是黑色素瘤。
―受试者”是指接受本发明活性物质作用的生命体,在本申请中可与“用药者” 互换使用。受试者可以是人或者动物,例如猴、大鼠、小鼠、狗、兔等。
通过以下实施例进一步举例说明本发明,这些实施例不应当被解释为具有 限制作用。本申请明确地通过提述并入本申请全文中引用的所有图和所有参考 文献、专利和被公开专利申请的内容。
附图说明
图1PIK3IP1和Pik3ip1电泳结果。
图2a-图2d融合蛋白质谱鉴定结果。
图3Anti-PIK3IP1多克隆抗体特异性的鉴定结果,使用小鼠抗人PIK3IP1抗体;按不同比例稀释多克隆抗体后,与稳定表达人PIK3IP1的CHO细胞转染株进行染 色,流式细胞术对抗体效价鉴定结果。
图4Anti-Pik3ip1多克隆抗体特异性的鉴定结果,使用大鼠抗小鼠Pik3ip1抗体;按 不同比例稀释多克隆抗体后,与稳定表达小鼠Pik3ip1的CHO细胞转染株进行染 色,流式细胞术对抗体效价鉴定结果。
图5人外周血PIK3IP1表达的流式细胞术检测。PIK3IP1在人外周血PBMC中 CD8+T细胞、CD4+T细胞、B细胞的表达较高,在CD56+NK细胞的表达较低。 图6Pik3ip1在小鼠组织mRNA水平的表达情况检测。Pik3ip1在小鼠肌肉、PBMC、 淋巴结和脾中表达水平较高。
图7Pik3ip1在小鼠脾淋巴细胞表达的流式细胞术检测。Pik3ip1在脾CD8+T细胞、CD4+T细胞、B细胞、CD11b+细胞和CD11c+细胞上均有表达,其中,在T细胞、 B细胞和CD11b+细胞的表达较高。
图8Pik3ip1在常见小鼠细胞系中表达的流式细胞术检测,B16为小鼠黑色素瘤细胞系、P338D1为小鼠巨噬细胞系、DC2.4为小鼠树突状细胞系、CT26为小鼠结 肠癌细胞系、EL4为小鼠T细胞淋巴瘤细胞系、MB49为小鼠膀胱癌细胞系。
图9Pik3ip1在小鼠免疫激活过程中淋巴细胞上表达的流式细胞术检测。用100μghgp10025-33和CFA或单独用CFA乳化后免疫Pmel-1TCR转基因小鼠,24小时后, 检测Pik3ip1在小鼠引流淋巴结中CD8+T细胞、CD11b+单核细胞、CD11c+DC细胞、 CD19+B细胞的表达。
图10用流式细胞术检测OVA抗原特异性免疫反应中Pik3ip1敲除小鼠和野生型 小鼠的CD8+T细胞的增殖情况,经过抗原特异性免疫后,Pik3ip1敲除小鼠的 CD8+T细胞的增殖高于野生型小鼠。左图为流式细胞检测图,右图为流式细胞检 测荧光值统计图。图中KO代表Pik3ip1敲除小鼠,WT代表野生型小鼠。
图11在Pik3ip1敲除小鼠和野生型小鼠中采用MC38肿瘤细胞建立肿瘤模型,用 流式细胞术检测小鼠中CD4+和CD8+T细胞的增殖情况,24小时、48小时和72小 时,Pik3ip1敲除小鼠的CD4+和CD8+T细胞的增殖均高于野生型小鼠的,其中48 小时和72小时的差异具有显著性。图中KO代表Pik3ip1敲除小鼠,WT代表野生 型小鼠。
图12口腔鳞癌患者外周血淋巴细胞中PIK3IP1的表达与T细胞抑制状态之间的 关系,CD4+T细胞和CD8+T细胞上的PIK3IP1的荧光强度与相应T细胞的增殖能力 呈负相关,所述相关性均具有显著性。
图13Pik3ip1-Ig融合蛋白在小鼠体内发挥竞争抑制作用,促进CD8+T细胞的增殖;左图为Pik3ip1-Ig融合蛋白作用下,CD8+T细胞的增殖情况;右图为CD8+T细胞 的增殖百分比统计(*p<0.05)。
图14pik3ip1-Ig融合蛋白联合2A抑制小鼠B16-F10肿瘤的生长;A为Pik3ip1-Ig融合蛋白单独治疗,B16-F10肿瘤生长受抑制程度不明显(n.s.p>0.05);B为 Pik3ip1-Ig融合蛋白联合2A治疗,B16-F10肿瘤的生长受到明显抑制(*p<0.05)。 图15荷瘤C57BL/6小鼠大体观、肿瘤离体观;A为各组荷瘤小鼠大体观;B为各 组肿瘤离体观。
具体实施方式
下面结合具体实施例,进一步阐述本发明。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。此外,应理解,在阅读了本发明所记载 的内容之后,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 同样落于本发明所限定的范围。
在以下实施例中,PIK3IP1代表人的PIK3IP1全长碱基序列及其蛋白产物,Pik3ip1代表鼠的Pik3ip1全长碱基序列及其蛋白产物,PIK3IP1-mIg代表由人的 PIK3IP1胞外区和鼠的IgG Fc构成的融合蛋白,Pik3ip1-mIg代表由鼠的Pik3ip1胞 外区和鼠的IgGFc构成的融合蛋白,PIK3IP1-hIg代表由人的PIK3IP1胞外区和人 的IgG Fc构成的融合蛋白,Pik3ip1-hIg代表由鼠的Pik3ip1胞外区和人的IgG Fc构 成的融合蛋白,Flag-mIg为无序对照序列与鼠IgG Fc的融合蛋白,Flag-hIg为无 序对照序列与人IgG Fc的融合蛋白。
以下实施例中:
1.细胞和动物材料
正常人单个核细胞,分离自健康志愿者的外周血;
SPF级C57BL/6小鼠、BALB/c小鼠、Wistar大鼠购买自中山大学(大学城) 实验动物中心,饲养于中山大学北校区实验动物中心;
Pmel-1TCR转基因小鼠,293T细胞、小鼠黑色素瘤细胞系(B16-F10)、小 鼠结肠癌细胞系CT26细胞、小鼠膀胱癌细胞系MB49细胞、CHO细胞系、杂交 瘤2A、小鼠巨噬细胞系P338D1、小鼠树突状细胞系DC2.4、小鼠T细胞淋巴瘤细 胞系EL4、MC38细胞系、质粒pMIgV、pHIgV由中山大学中山医学院陈列平教 授课题组赠予。
hgp100特异性Pmel-1脾细胞和淋巴细胞取自Pmel-1TCR转基因小鼠脾脏和 淋巴结。
OT1小鼠购自南京大学模式动物研究所。
Pik3ip1-/-小鼠,用TALENS法于赛亚生物公司(Cyagen Biosciences Inc.)进 行敲除鼠的制备。
2.细胞培养试剂
DMEM高糖培养基,RPMI 1640培养基,Ham’s F10培养基,胰蛋白酶(0.25%Trypsin,0.02%EDTA):美国Gibco公司;2-乙酰-2-去酰胺衍生物(ADT), 盘尼西林,链霉素,L-谷氨酸盐,羟基荧光素二醋酸盐琥珀酰亚胺脂(CFSE): 美国Invitrogen公司。
hgp10025-33多肽,氨基酸序列为KVPRNQDWL,纯度大于95%:由上海英潍 捷基公司合成。
3.质粒构建、细胞转染及融合蛋白纯化试剂
RNAiso Plus(9108Q)、PrimeScriptTMRT reagent Kit试剂盒、SYBR Green qPCRMaster Mix-SYBR Advantage(638320Clontech)试剂盒:Takara公司; All-In-One一步法逆转录试剂盒:美国GeneCopoeia公司;Lipofectamine 2000 细胞转染试剂:上海英潍捷基公司;线性聚乙烯亚胺(Linear PEI):美国 Polysciences公司;NucleoBond Xtra MaxiPlus质粒提取和纯化试剂盒:德国 Macherey-Nagel公司;SDS-PAGE凝胶配制试剂盒:上海碧云天公司;琼脂糖胶 回收试剂盒:德国QIAGEN公司;蛋白质相对分子量Marker:美国Thermo Scientific。
4.细胞增殖和活化检测试剂
Cytofix/Cytoperm固定/破膜试剂盒、Anti-human CD4Percp-cy5.5、Anti- humanCD4BV421、Anti-human CD8APC:美国BD公司;Anti-human CD69 Pe-cy7、Anti-humanCD95FITC、Anti-human HLA-DR Pe-cy7、Anti-human CD3 (克隆号:OKT3):美国Biolegend公司;Anti-human CD28、Anti-human CD25 APC、Anti-human Foxp3PE、Anti-humanCD25PE:美国eBioscience公司;人CD4+T细胞磁珠阳性分选试剂盒、人CD8+T细胞磁珠阳性分选试剂盒、人CD3+T 细胞磁珠阴性分选试剂盒:德国美天旎公司;重组人TGF-beta1、重组人IL-2: 美国Peprotech公司。
5.细胞凋亡检测实验材料和试剂
FITC Annexin V细胞凋亡检测、Anti-human CD4BV421、Anti-human CD8 APC:美国BD公司。
6.其他材料和试剂
1Kb DNA ladder Marker:加拿大Fermentas公司;SYBR Green qPCR SuperMix:德国罗氏公司;弗氏完全佐剂(CFA)、弗氏不完全佐剂(IFA): 美国Sigma公司;蛋白A柱:美国GE公司;蛋白透析卡:美国Thermo Scientific; 山羊抗小鼠Alexa Fluor 647荧光二抗:北京博奥森公司;DAPI染色剂:上海英 潍捷基公司;美天妮gentleMACS组织处理M管:德国美天妮公司;中性树胶、 枸橼酸钠抗原修复液pH6.0、苏木素染色液、EDTA抗原修复液pH9.0:北京中杉 金桥公司;TO型生物制片透明剂:广州中南化工仪器公司;DAB显色剂、即用 型兔抗人CD3免疫组化单克隆抗体(克隆号SP7)、正常兔血清封闭液、免疫组 化染色检测试剂盒:中国迈新生物公司;两步法GK500705小鼠/兔通用型:丹麦 DAKO公司;Anti-mouseCD3FITC、Anti-mouse IFN-γAPC、Anti-mouse Ki67 PE:美国eBioscience公司;Anti-mouse CD8BV421:美国BD公司;佛波醇酯 (PMA):比利时Acros公司;钙离子霉素(Ionomycincalcium salt):美国Thermo Fisher公司;外周血单个核细胞(PBMC)分离试剂盒:stemcell公司。
7.主要实验仪器
Axio observer Z1倒置显微镜、激光扫描共聚焦显微镜(LSM780):德国ZEISS 公司;MACS分选器、MACS分选柱:德国美天妮公司;480全自动 荧光定量PCR仪:德国罗氏公司;BD FACSVerse流式细胞仪:美国BD公司; M205FA体视荧光显微镜:莱卡仪器有限公司;ABI 9700PCR仪:美国ABI公 司;全自动酶标仪:美国Thermo Electron公司;ScanScope病理切片扫描成像 系统:美国Apero公司。
实施例1质粒的构建
1、人外周血总RNA获取
参照stemcell公司07811号产品的试剂盒说明书进行人外周血单个核细胞的 分离,采用对应试剂盒提取鼠外周血单个核细胞。
采用Takara公司RNAiso Plus(9108Q)试剂盒,按其说明书进行细胞总RNA 提取:用约0.5-1ml RNAiso Plus将酶消化或从组织中分离的细胞进行充分破碎和 溶解;采用氯仿-异丙醇-75%乙醇提取RNA,用DEPC水将提取的RNA溶解,利 用分光光度计测定RNA浓度,调整RNA浓度为500ng/μl左右,备用。
2、RNA逆转录合成cDNA
采用Takara公司PrimeScriptTMRT reagent Kit试剂盒,按其说明书进行cDNA 合成:
(1)按如下比例配RNA-Primer Mix(总体积13μl),变性RNA:
(2)按如下比例配置逆转录反应体系,总体积25μl:
逆转录反应条件如下:37℃逆转录反应10min,然后加热至85℃反应5min使 逆转录酶失活,终止反应。
3、荧光定量PCR反应
采用Takara公司SYBR Green qPCR Master Mix-SYBR Advantage(638320Clontech)试剂盒,按照其说明书进行操作:以扩增人PIK3IP1为例,
设计并合成QPCR引物,用于扩增PIK3IP1:F:ATGCTGTTGGCCTGGGTA; R:CGGGACTCCTGGGGCCTGA;
反应体系如下:
在Roche LightCycler 480Real-Time PCR仪上进行反应,扩增条件:95℃ 5min;95℃10sec;58℃20sec;72℃30sec,40cycles;溶解曲线分析:95℃5sec; 65℃1min;97℃5min;40℃10sec至冷却。
4、质粒构建
质粒载体为pMIgV(PIK3IP1-mIg、Pik3ip1-mIg)和pHIgV(PIK3IP1-hIg、 Pik3ip1-hIg)者,酶切位点选择为BglⅡ和EcoRⅠ。质粒载体为PCDNA3.1者 (PIK3IP1和鼠Pik3ip1全长序列),酶切位点选择XholⅠ和EcorⅠ。
设计正、反向PCR引物:
分别混合之前逆转录的人的cDNA、鼠的cDNA,分别作为模板进行PCR, 扩增相应序列;
PCR反应体系如下:
PCR反应条件如下:
实验结果验证:
分别取上述3μl PCR产物,跑2%的琼脂糖凝胶电泳,观察电泳后条带大小, 是否与目的基因相同。全长碱基序列的PCR结果如图1所示,人PIK3IP1全长碱基 序列为792bp,鼠Pik3ip1全长碱基序列为795bp,证明获得了人和鼠的全长碱基 序列,经测序,结果正确。
用Qiagen胶回收试剂盒回收得到PCR产物。胶回收产物和载体质粒,选择对 应的酶切反应酶分别进行双酶切。
使用的反应体系,如下:
酶切反应条件:胶回收产物37℃,酶切40min
质粒37℃,酶切50-55min;
酶切产物经琼脂糖凝胶电泳,胶回收得到目的条带进行连接:
连接反应条件:37℃连接2小时,或16℃连接2小时,4℃过夜;
用所述方法,还分别构建了PIK3IP1-hIg,PIK3IP1-mIg,Pik3ip1-hIg,Pik3ip1-mIg(对应的碱基序列分别为SEQ ID NO.12、11、13、14)的质粒。
将构建好的质粒转化入细菌,培养获得目的克隆菌,将测序后序列正常的 阳性克隆菌进行扩大培养。
采用NucleoBond Xtra Maxi Plus质粒提取和纯化试剂盒,按照说明书的指引 进行质粒抽提和纯化。
实施例2PIK3IP1-Ig、Flag-Ig融合蛋白质粒分别转染293T细胞和CHO稳转 株的构建
1、采用线性聚乙烯亚胺(PEI)进行质粒转染。
以PIK3IP1-hIg融合蛋白质粒为例,方法如下:
培养293T细胞,以PEI(μg):DNA总量(μg)=3:1配置PEI和DNA的混合 溶液,加入细胞培养皿中转染6-8小时后,换含1%FBS和2mM丙戊酸的新鲜 DMEM培养基,继续培养细胞,5天后,收集细胞培养皿上清,融合蛋白已分泌 至上清中。
2、融合蛋白的提取、纯化和鉴定
细胞转染后5天,收集细胞培养上清离心获得上清液,采用GE公司高亲和力 蛋白A柱,按照其使用说明书进行融合蛋白的提取和纯化。之后将收集到的蛋白, 移入蛋白透析袋中,在pH7.2-7.4的1×PBS中4℃透析过夜。透析后的蛋白用于后 续实验。
融合蛋白跑SDS-PAGE凝胶,考马斯亮蓝染色后切胶,送质谱鉴定。
10%SDS-PAGE分离胶的配制(5ml)
5%SDS-PAGE浓缩胶的配制(2ml)
鉴定结果如图2所示。根据质谱鉴定结果,确定所纯化融合蛋白分别为 PIK3IP1-hIg,PIK3IP1-mIg,Pik3ip1-hIg,Pik3ip1-mIg。
3、CHO稳转株的构建和鉴定
以人PIK3IP1稳转株构建为例:培养CHO细胞系的Ham’s F10全培养基配制 方法如下:500mlHam’s F10培养基含10%FBS、1%Hepes、1%链霉素和青霉素混 合液、1×ADT。
将复苏后的CHO细胞系培养至传代2次,细胞状态良好后,取1×105细胞加 入24孔板的一个孔内,将该孔培养基调整至1ml,待孔板内细胞长至融合度约 90%,吸去培养基。加适量PBS洗一遍,后换为200μl无抗生素培养基。
用invitrogen公司LipofectaminTM 2000试剂盒,按说明书操作转染:将0.8-1μg表达PIK3IP1全长序列、载体为PCDAN3.1的质粒DNA加入50μl Opti-MEM中混合 均匀。将2μl转染试剂Lipo2000加入50μl Opti-MEM中混合均匀。将稀释后的转染 试剂逐滴加入稀释后的质粒DNA中,将DNA-Lipo2000复合物加入铺有细胞的孔 中。混匀后,将24孔板放置于5%CO2 37℃细胞培养箱;转染后6-8小时,吸去孔 内液体,换为Ham’s F10全培养基。继续将孔板放置于5%CO2 37℃细胞培养箱48 小时。
取100mm×20mm细胞培养皿9个,每个培养皿加入含1000μg/ml G418的 Ham’s F10全培养基20ml,将24孔板内用500μl培养基重悬的CHO细胞按体积比 1:100(1个细胞培养皿)、1:5000(3个细胞培养皿)、1:10000(2个细胞培养皿)、 1:20000(1个细胞培养皿),即分别加入细胞悬液200μl、4μl、2μl、1μl至细胞 培养皿中,将剩下的细胞悬液全部加入一个培养皿中,另将未做过转染正常培 养的CHO细胞加入一个细胞培养皿作为筛选对照。混匀细胞后,于5%CO2 37℃ 细胞培养箱中培养;在细胞培养皿中培养5-7天后,取出培养皿,吸去原培养基, 换含1000μg/ml G418的Ham’s F10全培养基20ml。于5%CO2 37℃细胞培养箱中继 续培养;一般转至培养皿中10天后可以观察到细胞单克隆形成。待未经转染的 筛选对照培养皿中的细胞全部死亡时,进行转染PIK3IP1质粒的CHO细胞亚克隆 挑选。
取1/3或一半细胞进行流式细胞术或WB鉴定,挑选出表达强度最高的2-3个 克隆,进行细胞培养,冻存备用。
按照如上方法还制备了Pik3ip1稳转株、PIK3IP1-hIg稳转株,PIK3IP1-mIg 稳转株,Pik3ip1-hIg稳转株,Pik3ip1-mIg稳转株。
实施例3多克隆抗体的制备
选择SPF级6-8周龄雌性Balb/c小鼠2-3只,用于人PIK3IP1多抗的制备;选择 SPF级体重200g左右雌性Wista大鼠,用于小鼠Pik3ip1多抗的制备。
初次免疫:免疫前,于免疫动物尾静脉取适量血液,提取血清,分装冻存, 作为阴性对照的血清;每只小鼠按100μl CFA和等体积的100μg人PIK3IP1-mIg融 合蛋白乳化后,注射于Balb/c小鼠双侧腋下及腹股沟,不少于4个点;每只大鼠 按500μl CFA和等体积的500μg鼠Pik3ip1-mIg融合蛋白乳化后,注射于大鼠双侧 腋下及腹股沟皮下,不少于4个点;免疫后2周,取免疫动物尾静脉血,制备血 清,用ELISA或流式细胞术检测抗体效价。
第2次和第3次免疫:每只小鼠按100μl IFA和等体积的50μg人PIK3IP1-mIg 融合蛋白,充分乳化后免疫小鼠;每只大鼠按500μl IFA和等体积的250μg鼠 Pik3ip1-mIg融合蛋白,充分乳化后免疫大鼠;每次免疫后2周,检测抗体效价。
若免疫后第2或3次血清按1:10万倍稀释后,ELISA检测OD450值约1.5,或流 式检测1:1000倍稀释有明显阳性峰。则可腹腔注射50μg人PIK3IP1-mIg融合蛋白 或250μg鼠Pik3ip1-mIg融合蛋白,增强免疫;增强免疫后3-5天,处死动物,下 腔静脉取血,制备多克隆抗体血清。
实施例4多克隆抗体特异性的检测(以小鼠抗人PIK3IP1多克隆抗体为例)
转染PIK3IP1的293T细胞接种于玻璃底培养皿,加10%FBS的DMEM培养基 培养过夜;吸去培养基,用PBS清洗2遍,4%多聚甲醛室温固定15min。吸去固 定液,PBS漂洗3min,洗2遍;10%正常山羊血清室温封闭30min;吸去封闭血清, 加入小鼠抗人PIK3IP1多克隆血清1:200稀释后4℃孵育过夜;PBS漂洗3min,洗 3遍;山羊抗小鼠Alexa Fluor 647荧光二抗1:1000稀释,常温避光孵育1小时; PBS漂洗3min,洗3遍;10μg/ml WGA常温孵育10min;PBS漂洗3min,洗3遍; DAPI染色液染核3min;PBS漂洗3min,洗3遍;培养皿滴加抗淬灭封片剂,盖玻 片封片。共聚焦显微镜观察,拍照。
采用免疫荧光和流式细胞染色对血清进行特异性和结合强度的检测。免疫荧 光结果发现anti-PIK3IP1和anti-Pik3ip1多克隆抗体能分别与瞬时转染后的293T细 胞膜上表达的PIK3IP1和Pik3ip1分子特异性结合。
流式细胞染色显示,实施例2制备的稳定表达PIK3IP1和Pik3ip1分子的CHO细 胞株,能与不同稀释比例的anti-PIK3IP1和anti-Pik3ip1多克隆抗体呈现不同强度 的结合,且多克隆抗体1:1000倍稀释后仍然能出现阳性染色(结果参见图3和图 4)。
实施例5Pik3ip1在细胞和组织中的定位表达研究
1、Pik3ip1在Pmel-1TCR转基因小鼠免疫激活过程中淋巴细胞上的表达
取hgp10025-33多肽100μg和CFA等体积乳化,另取等量CFA与等体积PBS乳 化;于雌性6-8周龄Pmel-1TCR转基因小鼠右侧皮下广泛注射100μl hgp10025-33多 肽和CFA的乳化剂。另一组小鼠则皮下注射CFA与PBS的乳化剂100μl进行免疫; 免疫24小时后,处死小鼠。取引流淋巴结,制备单细胞悬液,检测免疫过程中 CD8+T细胞、CD11b+单核细胞、CD11c+DC细胞、CD19+B细胞上Pik3ip1的表达。 2、流式细胞术检测
收集待染色的细胞,用1%FBS的流式缓冲液洗1-2遍,2000rpm离心3min; 标记好待用的流式管,若为多色染色,则每一个荧光需进行单独染色,以供调 节荧光补偿;将离心后的细胞用流式缓冲液重悬,调整细胞浓度为106-108/ml, 取100μl细胞悬液加入流式管中。按产品的说明向每个流式管中加入human-Ig或 mouse-Ig等混匀,封闭细胞上的Fc受体。向封闭后的流式管内,加入一抗。混匀 后,置于4℃冰箱,孵育30min。加入约2-3ml流式缓冲液,终止一抗染色。2000rpm 离心3min。弃去上清,使流式管中细胞悬液的总体积约100μl。加入合适剂量的 荧光二抗,混匀后,置于4℃冰箱,避光孵育30min;加入约2-3ml流式缓冲液, 终止荧光二抗染色。洗涤细胞,2000rpm离心3min,弃上清。视细胞的数量,加 入约300-400μl流式缓冲液。混匀后,流式上机检测。
3、PIK3IP1在人外周血主要淋巴细胞亚群的表达
本发明的发明人分离了健康人PBMC,采用流式细胞术对PIK3IP1在PBMC中 主要淋巴细胞亚群的表达情况进行了检测。结果如图5所示,发现PIK3IP1在人 外周血CD8+T细胞、CD4+T细胞、B细胞的表达较高。
4、Pik3ip1在小鼠组织、脾淋巴细胞亚群和常见细胞系的表达
本发明的发明人检测了小鼠Pik3ip1在PBMC、眼、脾、脑、卵巢、肺、淋巴 结、膀胱、胰腺、肾、肝、小肠、胸腺、心脏、肌肉、子宫和睾丸中mRNA水平 的表达情况,结果如图6所示,发现其在肌肉、PBMC、淋巴结和脾中表达水平 较高。
5、Pik3ip1在小鼠脾淋巴细胞表达的流式细胞术检测
本发明的发明人分离并制备了小鼠脾单细胞悬液,采用流式细胞术对Pik3ip1 在脾主要淋巴细胞亚群的表达情况进行了检测。结果如图7所示,发现Pik3ip1在 CD8+T细胞、CD4+T细胞、B细胞、CD11b+细胞和CD11c+细胞上均能检测到表达, 在T细胞、B细胞和CD11b+细胞的表达较高。
6、Pik3ip1在小鼠常见细胞系的表达
本发明的发明人检测了Pik3ip1在小鼠黑色素瘤细胞系B16、小鼠巨噬细胞系P338D1、小鼠树突状细胞系DC2.4、小鼠结肠癌细胞系CT26、小鼠T细胞淋巴瘤 细胞系EL4、小鼠膀胱癌细胞系MB49的表达,结果如图8所示,发现Pik3ip1在 P338D1、DC2.4、EL4高表达。
7、Pik3ip1在小鼠免疫激活过程中淋巴细胞上的表达
本发明的发明人用100μg hgp10025-33多肽和CFA乳化后特异性免疫,或单独用 CFA乳化后非特异性免疫Pmel-1TCR转基因小鼠。免疫激活24小时后,检测 Pik3ip1在Pmel-1TCR转基因小鼠引流淋巴结中CD8+T细胞、CD11b+单核细胞、 CD11c+DC细胞、CD19+B细胞的表达。结果如图9所示,发现Pik3ip1在上述淋巴 细胞上的表达,随免疫激活强度的不同呈现变化。
实施例6抗原特异性免疫反应中Pik3ip1缺失增强了T细胞增殖
1、day0,CFSE-标记的3×105个OT1小鼠脾细胞尾静脉转输入Pik3ip1-/-(Pik3ip1knock-out,KO)和野生型小鼠(wild-type,WT)中。
2、day1,KO和WT鼠均腹腔免疫OVA257–264(100μg),其中以CFA作为佐 剂。
3、day2,小鼠牺牲,淋巴细胞进行流式分析,观察CD8+T细胞的增殖情况。
结果如图10所示:KO鼠的CD8+T细胞增殖能力比WT鼠的强,表明Pik3ip1的 缺失有利于T细胞增殖。
实施例7肿瘤模型中Pik3ip1缺失增强了T细胞增殖
1、anti-mCD3,anti-mCD28扣板:anti-mCD3,anti-mCD28单克隆抗体,各 配成终浓度0.125μg/ml,各50μl/孔加入96孔板,封板,4℃过夜;吸去孔内未 结合的蛋白溶液,按100μl/孔加入冷的PBS,重复洗板至少3遍。
2、2×105个MC38肿瘤细胞皮下接种在KO和WT鼠的侧翼。
3、两周后,取出KO和WT鼠的脾细胞,制成单细胞悬液,用stem cell公司的EasySepTMmouseCD4+T cel isolation kit和EasySepTM mouseCD8+T cel isolation kit,按照试剂盒说明书操作,分选出CD4+和CD8+T细胞。按3.5×105细胞/孔加入 anti-mCD3,anti-mCD28扣板的孔板中。
4、在24小时、48小时和72小时检测T细胞增殖情况。
结果如图11所示:24小时、48小时和72小时,Pik3ip1敲除小鼠的CD4+和CD8+T 细胞的增殖均高于野生型小鼠的,其中48小时和72小时的差异具有显著性。
实施例8PIK3IP1与癌症患者T细胞的抑制状态有关
1、从中山大学附属口腔医院随机选取口腔鳞癌(Oral Squamous CellCarcinoma,OSCC)患者5例,抽取每个患者10ml外周血,参照stemcell公司07811 号产品的试剂盒说明书进行人外周血单个核细胞的分离,得到每个患者的 PBMC。
2、流式分析每个样品PIK3IP1的表达强度,得到平均荧光强度值(MeanFluorescence Index,MFI)值。
3、anti-hCD3,,anti-hCD28扣板:anti-hCD3,anti-hCD28单克隆抗体,各配 成终浓度0.125μg/ml,各50μl/孔加入96孔板,封板,4℃过夜;吸去孔内未结 合的蛋白溶液,按100μl/孔加入冷的PBS,重复洗板至少3遍。
4、CFSE标记每个样品,加入扣有anti-hCD3,anti-hCD28的孔板中。
5、两天后收集样品,通过流式分析OSCC和HCC患者CD4+与CD8+T细胞的 CFSE比例确定增殖强度。
结果如图12所示:OSCC患者外周血的CD4+和CD8+T细胞中PIK3IP1的荧光强 度与其增殖强度呈负相关,且所述相关性均具有显著性。表明OSCC患者外周血 的CD4+和CD8+T细胞中PIK3IP1的表达强度与相应细胞的增殖能力负相关, PIK3IP1的表达会抑制相应细胞的增殖。
实施例9Pik3ip1-mIg在体内促进gp100特异性Pmel-1CD8+T细胞的增殖
1、Pik3ip1-mIg融合蛋白对CD8+T细胞体内增殖影响的研究方法
取雌性6-8周龄Pmel-1TCR转基因小鼠2只,用CO2处死后,取脾,研磨制成 细胞悬液,用ACK裂解红细胞,0.22μm无菌滤网过滤离心,PBS重悬细胞,制 备成单细胞悬液;用CFSE标记细胞。
用PBS调整细胞浓度为1×107/毫升,每只C57BL/6小鼠尾静脉注射250-300μl 细胞悬液,共注射10只6-8周龄雌性C57小鼠;过继转输gp100特异性Pmel-1脾细 胞后第1天,按每只小鼠hgp10025-33多肽100μg,与CFA配成100μl总体积充分乳化 后,给予每只实验鼠右侧皮下注射,同时分别对3只小鼠腹腔注射Pik3ip1-mIg, 7只小鼠腹腔注射Flag-mIg融合蛋白,剂量均为200μg,300μl/只;于过继转输后 第2天开始,每天分别处死1只腹腔给予Flag-mIg融合蛋白小鼠,取引流淋巴结制 成单细胞悬液。流式抗体Anti-mouseCD90.1APC,Anti-mouse CD8BV421染色 标记细胞;流式上机检测CD90.1、CD8双阳性细胞CFSE的增殖峰比例。待检测 到明显而规则的增殖峰出现时,则处死实验组和对照组各3只小鼠,检测CD8+T 细胞的增殖水平。
2、结果
为了研究Pik3ip1-mIg融合蛋白在体内对CD8+T细胞增殖的影响,本研究检测 了gp100特异性Pmel-1脾细胞过继转输C57BL/6后,hgp10025-33多肽和CFA乳化免 疫小鼠,腹腔给予Pik3ip1-mIg融合蛋白和Flag-mIg 4天后,gp100特异性 Pmel-1CD8+T细胞体内增殖的情况。由图13可以看出:与给予Flag-mIg对照蛋白 相比,Pik3ip1-mIg融合蛋白促进了gp100特异性Pmel-1CD8+T的增殖。Pik3ip1-mIg 融合蛋白组CD8+T细胞增殖平均比例为88.32%,而Flag-mIg组CD8+T细胞的增殖 平均比例为53.34%,明显低于Pik3ip1-mIg融合蛋白组。
实施例10Pik3ip1-mIg融合蛋白增强2A对小鼠B16-F10成瘤的免疫治疗效果 ——Pik3ip1-mIg联合2A治疗抑制B16-F10肿瘤的生长
1、4-1BB激活抗体Anti-m4-1BB(2A)的提取和纯化
复苏杂交瘤2A并培养,将培养基连同细胞离心后取上清,0.45μm过滤器过 滤上清,收集滤液置于冰上或4℃保存;用亲和力蛋白G柱进行Anti-m4-1BB(2A) 的纯化,提纯后的抗体移入蛋白透析卡中,在pH7.2-7.4的1×PBS中,4℃透析24-48 小时。
2、Pik3ip1-mIg融合蛋白联合2A治疗小鼠恶性黑色素瘤实验方法
复苏DC2.4细胞并培养,用1ml含10%FBS的RPMI 1640培养基重悬细胞,按 工作浓度为5-8μM的gp10025-33多肽标记DC2.4细胞后,用适量PBS重悬细胞,配 成3.5×106细胞/毫升。
按前述方法制备Pmel-1TCR转基因小鼠脾和(或)淋巴结细胞单细胞悬液, 按每300μl细胞悬液至少1×107/细胞的比例重悬细胞;体重相近的SPF级6-8周龄 雌性C57BL/6小鼠,设置实验小鼠组别为:Flag-mIg对照组、Pik3ip1-mIg治疗组、 2A治疗组、Pik3ip1-mIg联合2A治疗组。每组至少5只小鼠,皮下广泛注射标记 了hgp10025-33多肽的DC2.4细胞悬液100μl/小鼠,同时尾静脉注射gp100特异性 Pmel-1脾细胞悬液300μl。
小鼠免疫一周后,将细胞浓度为3×106/ml的B16-F10细胞悬液按每只小鼠 100μl皮下注射成瘤;自皮下成瘤后每3天,经腹腔给予对应组300μl PBS配制的 蛋白溶液,分别含200μgFlag-mIg、200μg Pik3ip1-mIg、200μg 2A、 200μgPik3ip1-mIg+200μg2A;观察肿瘤生长情况,待可于皮下摸及肿瘤开始,每 隔一天用电子游标卡尺测量并记录肿瘤大小,直至肿瘤长至平均直径约1.5cm。 肿瘤平均直径计算方法为:(长径+宽径)/2。
3、结果
通过研究Pik3ip1-mIg融合蛋白对小鼠黑色素瘤的治疗,明确该蛋白对CD8+T 杀伤肿瘤功能的影响。本发明发明人构建了Pik3ip1-mIg融合蛋白单独和联合2A 治疗小鼠B16-F10肿瘤生长的模型。结果发现:如图14A所示,Pik3ip1-mIg融合 蛋白对B16-F10肿瘤的生长有抑制作用,但作用不显著(p=0.062)。如图14B所 示,Pik3ip1-mIg融合蛋白联合2A治疗B16-F10成瘤,能明显抑制肿瘤的生长 (p=0.029)。
于成瘤后20天,采集实验各组荷瘤小鼠的大体观、离体肿瘤的照片。由图 15A可以看出:大体看来,Pik3ip1-mIg融合蛋白联合2A治疗组,B16-F10成瘤较 Flag-mIg组、单独给予Pik3ip1-mIg融合蛋白组、单独给予2A组平均直径小;其 次为单独给予2A组;单独给予Pik3ip1-mIg融合蛋白组瘤体平均直径稍小于 Flag-mIg组。由图15B肿瘤离体后的影像也能看出相同的结果。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施 方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等, 均应包含在本发明的保护范围之内。
SEQUENCE LISTING
<110> 中山大学
<120> PIK3IP1蛋白在调节T细胞反应和制备抗肿瘤药物中的应用
<130> CPCN16110524
<160> 17
<170> PatentIn version 3.5
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Glu Asp Leu Arg Cys Pro Glu Thr Thr Ser Gln Ala Leu Pro Ala Phe
100 105 110
Thr Thr Glu Ile Gln Glu Ala Ser Glu Gly Pro Gly Ala Asp Glu Val
115 120 125
Gln Val Phe Ala Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala Ala
130 135 140
Ala Val Gln Pro Val Ile Gly Ile Ser Gln Arg Val Arg Met Asn Ser
145 150 155 160
Lys Glu Lys Lys Asp Leu Gly Thr Leu Gly Tyr Val Leu Gly Ile Thr
165 170 175
Met Met Val Ile Ile Ile Ala Ile Gly Ala Gly Ile Ile Leu Gly Tyr
180 185 190
Ser Tyr Lys Arg Gly Lys Asp Leu Lys Glu Gln His Asp Gln Lys Val
195 200 205
Cys Glu Arg Glu Met Gln Arg Ile Thr Leu Pro Leu Ser Ala Phe Thr
210 215 220
Asn Pro Thr Cys Glu Ile Val Asp Glu Lys Thr Val Val Val His Thr
225 230 235 240
Ser Gln Thr Pro Val Asp Pro Gln Glu Gly Ser Thr Pro Leu Met Gly
245 250 255
Gln Ala Gly Thr Pro Gly Ala
260
<210> 3
<211> 173
<212> PRT
<213> Homo sapiens
<400> 3
Met Leu Leu Ala Trp Val Gln Ala Phe Leu Val Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Thr Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Asp Ala Gln Ser Gly Leu Ala Ser Ala Pro Val Ser Gly Ala
50 55 60
Gly Asn His Ser Tyr Cys Arg Asn Pro Asp Glu Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Val Ser Gly Glu Ala Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Leu Arg Cys Pro Glu Thr Thr Ser Gln Ala Leu Pro Ala Phe
100 105 110
Thr Thr Glu Ile Gln Glu Ala Ser Glu Gly Pro Gly Ala Asp Glu Val
115 120 125
Gln Val Phe Ala Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala Ala
130 135 140
Ala Val Gln Pro Val Ile Gly Ile Ser Gln Arg Val Arg Met Asn Ser
145 150 155 160
Lys Glu Lys Lys Asp Leu Gly Thr Leu Gly Gly Arg Ile
165 170
<210> 4
<211> 264
<212> PRT
<213> Mus musculus
<400> 4
Met Leu Leu Ala Trp Val His Thr Phe Leu Leu Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Pro Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Ala Ala Gln Gly Ser Arg Glu Ser Leu Thr Glu Pro Ser Pro
50 55 60
Gly Asn His Asn Tyr Cys Arg Asn Pro Asp Gln Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Ile Ser Ser Glu Thr Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Val Ser Cys Pro Glu Thr Thr Ser Gln Ala Pro Pro Pro Ser
100 105 110
Ser Ala Met Glu Leu Glu Glu Lys Ser Gly Ala Pro Gly Asp Lys Glu
115 120 125
Ala Gln Val Phe Pro Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala
130 135 140
Ala Glu Val Gln Pro Val Ile Gly Ile Ser Gln Leu Val Arg Met Asn
145 150 155 160
Ser Lys Glu Lys Lys Asp Leu Gly Thr Leu Gly Tyr Val Leu Gly Ile
165 170 175
Thr Met Met Val Ile Ile Leu Ala Ile Gly Ala Gly Ile Ile Val Gly
180 185 190
Tyr Thr Tyr Lys Arg Gly Lys Asp Leu Lys Glu Gln His Glu Lys Lys
195 200 205
Ala Cys Glu Arg Glu Met Gln Arg Ile Thr Leu Pro Leu Ser Ala Phe
210 215 220
Thr Asn Pro Thr Cys Glu Thr Val Asp Glu Asn Thr Ile Ile Val His
225 230 235 240
Ser Asn Gln Thr Pro Ala Asp Val Gln Glu Gly Ser Thr Leu Leu Thr
245 250 255
Gly Gln Ala Gly Thr Pro Gly Ala
260
<210> 5
<211> 271
<212> PRT
<213> Mus musculus
<400> 5
Met Leu Leu Ala Trp Val His Thr Phe Leu Leu Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Pro Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Ala Ala Gln Gly Ser Arg Glu Ser Leu Thr Glu Pro Ser Pro
50 55 60
Gly Asn His Asn Tyr Cys Arg Asn Pro Asp Gln Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Ile Ser Ser Glu Thr Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Val Ser Cys Pro Gly Thr Arg Pro Gly Thr Thr Glu Thr Thr
100 105 110
Ser Gln Ala Pro Pro Pro Ser Ser Ala Met Glu Leu Glu Glu Lys Ser
115 120 125
Gly Ala Pro Gly Asp Lys Glu Ala Gln Val Phe Pro Pro Ala Asn Ala
130 135 140
Leu Pro Ala Arg Ser Glu Ala Ala Glu Val Gln Pro Val Ile Gly Ile
145 150 155 160
Ser Gln Leu Val Arg Met Asn Ser Lys Glu Lys Lys Asp Leu Gly Thr
165 170 175
Leu Gly Tyr Val Leu Gly Ile Thr Met Met Val Ile Ile Leu Ala Ile
180 185 190
Gly Ala Gly Ile Ile Val Gly Tyr Thr Tyr Lys Arg Gly Lys Asp Leu
195 200 205
Lys Glu Gln His Glu Lys Lys Ala Cys Glu Arg Glu Met Gln Arg Ile
210 215 220
Thr Leu Pro Leu Ser Ala Phe Thr Asn Pro Thr Cys Glu Thr Val Asp
225 230 235 240
Glu Asn Thr Ile Ile Val His Ser Asn Gln Thr Pro Ala Asp Val Gln
245 250 255
Glu Gly Ser Thr Leu Leu Thr Gly Gln Ala Gly Thr Pro Gly Ala
260 265 270
<210> 6
<211> 245
<212> PRT
<213> Mus musculus
<400> 6
Met Leu Leu Ala Trp Val His Thr Phe Leu Leu Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Pro Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Ala Ala Gln Gly Ser Arg Glu Ser Leu Thr Glu Pro Ser Pro
50 55 60
Gly Asn His Asn Tyr Cys Arg Asn Pro Asp Gln Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Ile Ser Ser Glu Thr Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Val Ser Cys Pro Gly Thr Arg Pro Gly Thr Thr Glu Thr Thr
100 105 110
Ser Gln Ala Pro Pro Pro Ser Ser Ala Met Glu Leu Glu Glu Lys Ser
115 120 125
Gly Ala Pro Gly Asp Lys Glu Ala Gln Val Phe Pro Pro Ala Asn Ala
130 135 140
Leu Pro Ala Arg Ser Glu Ala Ala Glu Val Gln Pro Val Ile Gly Ile
145 150 155 160
Ser Gln Leu Val Arg Met Asn Ser Lys Glu Lys Lys Asp Leu Gly Thr
165 170 175
Leu Gly Tyr Val Leu Gly Ile Thr Met Met Val Ile Ile Leu Ala Ile
180 185 190
Gly Ala Gly Ile Ile Val Gly Tyr Thr Tyr Lys Ser Leu Arg Thr Ala
195 200 205
Phe Gly Arg Leu Pro Ile Leu Gly Gln Phe Pro Asp Leu Gln Glu Leu
210 215 220
Asp Leu Ala Ala Leu Asn Ser Lys Leu Ser Gly Cys Pro Val Gln Lys
225 230 235 240
Pro Gly Gly Arg Thr
245
<210> 7
<211> 238
<212> PRT
<213> Mus musculus
<400> 7
Met Leu Leu Ala Trp Val His Thr Phe Leu Leu Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Pro Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Ala Ala Gln Gly Ser Arg Glu Ser Leu Thr Glu Pro Ser Pro
50 55 60
Gly Asn His Asn Tyr Cys Arg Asn Pro Asp Gln Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Ile Ser Ser Glu Thr Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Val Ser Cys Pro Glu Thr Thr Ser Gln Ala Pro Pro Pro Ser
100 105 110
Ser Ala Met Glu Leu Glu Glu Lys Ser Gly Ala Pro Gly Asp Lys Glu
115 120 125
Ala Gln Val Phe Pro Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala
130 135 140
Ala Glu Val Gln Pro Val Ile Gly Ile Ser Gln Leu Val Arg Met Asn
145 150 155 160
Ser Lys Glu Lys Lys Asp Leu Gly Thr Leu Gly Tyr Val Leu Gly Ile
165 170 175
Thr Met Met Val Ile Ile Leu Ala Ile Gly Ala Gly Ile Ile Val Gly
180 185 190
Tyr Thr Tyr Lys Ser Leu Arg Thr Ala Phe Gly Arg Leu Pro Ile Leu
195 200 205
Gly Gln Phe Pro Asp Leu Gln Glu Leu Asp Leu Ala Ala Leu Asn Ser
210 215 220
Lys Leu Ser Gly Cys Pro Val Gln Lys Pro Gly Gly Arg Thr
225 230 235
<210> 8
<211> 163
<212> PRT
<213> Mus musculus
<400> 8
Met Glu Thr Thr Ser Gln Ala Pro Pro Pro Ser Ser Ala Met Glu Leu
1 5 10 15
Glu Glu Lys Ser Gly Ala Pro Gly Asp Lys Glu Ala Gln Val Phe Pro
20 25 30
Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala Ala Glu Val Gln Pro
35 40 45
Val Ile Gly Ile Ser Gln Leu Val Arg Met Asn Ser Lys Glu Lys Lys
50 55 60
Asp Leu Gly Thr Leu Gly Tyr Val Leu Gly Ile Thr Met Met Val Ile
65 70 75 80
Ile Leu Ala Ile Gly Ala Gly Ile Ile Val Gly Tyr Thr Tyr Lys Arg
85 90 95
Gly Lys Asp Leu Lys Glu Gln His Glu Lys Lys Ala Cys Glu Arg Glu
100 105 110
Met Gln Arg Ile Thr Leu Pro Leu Ser Ala Phe Thr Asn Pro Thr Cys
115 120 125
Glu Thr Val Asp Glu Asn Thr Ile Ile Val His Ser Asn Gln Thr Pro
130 135 140
Ala Asp Val Gln Glu Gly Ser Thr Leu Leu Thr Gly Gln Ala Gly Thr
145 150 155 160
Pro Gly Ala
<210> 9
<211> 168
<212> PRT
<213> Homo sapiens
<400> 9
Met Leu Leu Ala Trp Val Gln Ala Phe Leu Val Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Thr Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Asp Ala Gln Ser Gly Leu Ala Ser Ala Pro Val Ser Gly Ala
50 55 60
Gly Asn His Ser Tyr Cys Arg Asn Pro Asp Glu Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Val Ser Gly Glu Ala Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Leu Arg Cys Pro Glu Thr Thr Ser Gln Ala Leu Pro Ala Phe
100 105 110
Thr Thr Glu Ile Gln Glu Ala Ser Glu Gly Pro Gly Ala Asp Glu Val
115 120 125
Gln Val Phe Ala Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala Ala
130 135 140
Ala Val Gln Pro Val Ile Gly Ile Ser Gln Arg Val Arg Met Asn Ser
145 150 155 160
Lys Glu Lys Lys Asp Leu Gly Thr
165
<210> 10
<211> 170
<212> PRT
<213> Mus musculus
<400> 10
Met Leu Leu Ala Trp Val His Thr Phe Leu Leu Ser Asn Met Leu Leu
1 5 10 15
Ala Glu Ala Tyr Gly Ser Gly Gly Cys Phe Trp Asp Asn Gly His Leu
20 25 30
Tyr Arg Glu Asp Gln Pro Ser Pro Ala Pro Gly Leu Arg Cys Leu Asn
35 40 45
Trp Leu Ala Ala Gln Gly Ser Arg Glu Ser Leu Thr Glu Pro Ser Pro
50 55 60
Gly Asn His Asn Tyr Cys Arg Asn Pro Asp Gln Asp Pro Arg Gly Pro
65 70 75 80
Trp Cys Tyr Ile Ser Ser Glu Thr Gly Val Pro Glu Lys Arg Pro Cys
85 90 95
Glu Asp Val Ser Cys Pro Glu Thr Thr Ser Gln Ala Pro Pro Pro Ser
100 105 110
Ser Ala Met Glu Leu Glu Glu Lys Ser Gly Ala Pro Gly Asp Lys Glu
115 120 125
Ala Gln Val Phe Pro Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala
130 135 140
Ala Glu Val Gln Pro Val Ile Gly Ile Ser Gln Leu Val Arg Met Asn
145 150 155 160
Ser Lys Glu Lys Lys Asp Leu Gly Thr Leu
165 170
<210> 11
<211> 1214
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 11
atgctgttgg cctgggtaca agcattcctc gtcagcaaca tgctcctagc agaagcctat 60
ggatctggag gctgtttctg ggacaacggc cacctgtacc gggaggacca gacctccccc 120
gcgccgggcc tccgctgcct caactggctg gacgcgcaga gcgggctggc ctcggccccc 180
gtgtcggggg ccggcaatca cagttactgc cgaaacccgg acgaggaccc gcgcgggccc 240
tggtgctacg tcagtggcga ggccggcgtc cctgagaaac ggccttgcga ggacctgcgc 300
tgtccagaga ccacctccca ggccctgcca gccttcacga cagaaatcca ggaagcgtct 360
gaagggccag gtgcagatga ggtgcaggtg ttcgctcctg ccaacgccct gcccgctcgg 420
agtgaggcgg cagctgtgca gccagtgatt gggatcagcc agcgggtgcg gatgaactcc 480
aaggagaaaa aggacctggg aactgatctg gagcccagag gggccacaat caagccctgt 540
cctccatgca aatgcccagc acctaacctc ttgggtggac catccgtctt catcttccct 600
ccaaagatca aggatgtact catgatctcc ctgagcccca tagtcacatg tgtggtggtg 660
gatgtgagcg aggatgaccc agatgtccag atcagctggt ttgtgaacaa cgtggaagta 720
cacacagctc agacacaaac ccatagagag gattacaaca gtactctccg ggtggtcagt 780
gccctcccca tccagcacca ggactggatg agtggcaagg agtgcaaatg caaggtcaac 840
aacaaagacc tcccagcgcc catcgagaga accatctcaa aacccaaagg gtcagtaaga 900
gctccacagg tatatgtctt gcctccacca gaagaagaga tgactaagaa acaggtcact 960
ctgacctgca tggtcacaga cttcatgcct gaagacattt acgtggagtg gaccaacaac 1020
gggaaaacag agctaaacta caagaacact gaaccagtcc tggactctga tggttcttac 1080
ttcatgtaca gcaagctgag agtggaaaag aagaactggg tggaaagaaa tagctactcc 1140
tgttcagtgg tccacgaggg tctgcacaat caccacacga ctaagagctt ctcccggact 1200
ccgggtaaat gatc 1214
<210> 12
<211> 1439
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 12
atgctgttgg cctgggtaca agcattcctc gtcagcaaca tgctcctagc agaagcctat 60
ggatctggag gctgtttctg ggacaacggc cacctgtacc gggaggacca gacctccccc 120
gcgccgggcc tccgctgcct caactggctg gacgcgcaga gcgggctggc ctcggccccc 180
gtgtcggggg ccggcaatca cagttactgc cgaaacccgg acgaggaccc gcgcgggccc 240
tggtgctacg tcagtggcga ggccggcgtc cctgagaaac ggccttgcga ggacctgcgc 300
tgtccagaga ccacctccca ggccctgcca gccttcacga cagaaatcca ggaagcgtct 360
gaagggccag gtgcagatga ggtgcaggtg ttcgctcctg ccaacgccct gcccgctcgg 420
agtgaggcgg cagctgtgca gccagtgatt gggatcagcc agcgggtgcg gatgaactcc 480
aaggagaaaa aggacctggg aactgatcta tcctctagag tcgacgagcc caaatcttgt 540
gacaaaactc acacatgccc accgtgccca ggtaagccag cccaggcctc gccctccagc 600
tcaaggcggg acaggtgccc tagagtagcc tgcatccagg gacaggcccc agccgggtgc 660
tgacacgtcc acctccatct cttcctcagc acctgaactc ctggggggac cgtcagtctt 720
cctcttcccc ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg 780
cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg 840
cgtggaggtg cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg 900
tgtggtcagc gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg 960
aaaggtctcc aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg 1020
tgggacccgt ggggtgcgag ggccacatgg acagaggccg gctcggccca ccctctgccc 1080
tgagagtgac cgctgtacca acctctgtcc ctacagggca gccccgagaa ccacaggtgt 1140
acaccctgcc cccatcccgg gatgagctga ccaagaacca ggtcagcctg acctgcctgg 1200
tcaaaggctt atatcccagc gacatcgccg tggagtggga gagcaatggg cagccggaga 1260
acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc ctctacagca 1320
agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc tccgtgatgc 1380
atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg ggtaaatga 1439
<210> 13
<211> 1445
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 13
atgctgttgg cttgggtaca cacatttctt ctcagcaaca tgcttctggc agaagcctat 60
ggatctggag gctgcttctg ggacaacggc cacctgtacc gggaggacca gccctcgccc 120
gcgccgggtc tccgctgcct caactggttg gccgcgcaag gcagccgcga gtcgctcacc 180
gagcccagcc cgggcaacca caactactgc cggaacccgg accaggaccc gcgcgggccc 240
tggtgctaca tcagcagcga gaccggcgtc cctgaaaagc ggccctgcga ggacgtgagt 300
tgcccagaga ccacttccca agcaccaccg ccatcctctg ccatggagct ggaagagaag 360
tctggtgcac caggtgacaa agaggcacag gtgttccctc ctgctaacgc cctaccagcc 420
aggagtgagg cagccgaggt gcagccagtg atcgggatca gtcagcttgt gaggatgaac 480
tccaaggaaa aaaaagacct aggaactctg gatctatcct ctagagtcga cgagcccaaa 540
tcttgtgaca aaactcacac atgcccaccg tgcccaggta agccagccca ggcctcgccc 600
tccagctcaa ggcgggacag gtgccctaga gtagcctgca tccagggaca ggccccagcc 660
gggtgctgac acgtccacct ccatctcttc ctcagcacct gaactcctgg ggggaccgtc 720
agtcttcctc ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt 780
cacatgcgtg gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt 840
ggacggcgtg gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac 900
gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta 960
caagtgaaag gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc 1020
caaaggtggg acccgtgggg tgcgagggcc acatggacag aggccggctc ggcccaccct 1080
ctgccctgag agtgaccgct gtaccaacct ctgtccctac agggcagccc cgagaaccac 1140
aggtgtacac cctgccccca tcccgggatg agctgaccaa gaaccaggtc agcctgacct 1200
gcctggtcaa aggcttatat cccagcgaca tcgccgtgga gtgggagagc aatgggcagc 1260
cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc ttcttcctct 1320
acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg 1380
tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg tctccgggta 1440
aatga 1445
<210> 14
<211> 1220
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 14
atgctgttgg cttgggtaca cacatttctt ctcagcaaca tgcttctggc agaagcctat 60
ggatctggag gctgcttctg ggacaacggc cacctgtacc gggaggacca gccctcgccc 120
gcgccgggtc tccgctgcct caactggttg gccgcgcaag gcagccgcga gtcgctcacc 180
gagcccagcc cgggcaacca caactactgc cggaacccgg accaggaccc gcgcgggccc 240
tggtgctaca tcagcagcga gaccggcgtc cctgaaaagc ggccctgcga ggacgtgagt 300
tgcccagaga ccacttccca agcaccaccg ccatcctctg ccatggagct ggaagagaag 360
tctggtgcac caggtgacaa agaggcacag gtgttccctc ctgctaacgc cctaccagcc 420
aggagtgagg cagccgaggt gcagccagtg atcgggatca gtcagcttgt gaggatgaac 480
tccaaggaaa aaaaagacct aggaactctg gatctggagc ccagaggggc cacaatcaag 540
ccctgtcctc catgcaaatg cccagcacct aacctcttgg gtggaccatc cgtcttcatc 600
ttccctccaa agatcaagga tgtactcatg atctccctga gccccatagt cacatgtgtg 660
gtggtggatg tgagcgagga tgacccagat gtccagatca gctggtttgt gaacaacgtg 720
gaagtacaca cagctcagac acaaacccat agagaggatt acaacagtac tctccgggtg 780
gtcagtgccc tccccatcca gcaccaggac tggatgagtg gcaaggagtg caaatgcaag 840
gtcaacaaca aagacctccc agcgcccatc gagagaacca tctcaaaacc caaagggtca 900
gtaagagctc cacaggtata tgtcttgcct ccaccagaag aagagatgac taagaaacag 960
gtcactctga cctgcatggt cacagacttc atgcctgaag acatttacgt ggagtggacc 1020
aacaacggga aaacagagct aaactacaag aacactgaac cagtcctgga ctctgatggt 1080
tcttacttca tgtacagcaa gctgagagtg gaaaagaaga actgggtgga aagaaatagc 1140
tactcctgtt cagtggtcca cgagggtctg cacaatcacc acacgactaa gagcttctcc 1200
cggactccgg gtaaatgatc 1220
<210> 15
<211> 710
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 15
gatctggagc ccagaggggc cacaatcaag ccctgtcctc catgcaaatg cccagcacct 60
aacctcttgg gtggaccatc cgtcttcatc ttccctccaa agatcaagga tgtactcatg 120
atctccctga gccccatagt cacatgtgtg gtggtggatg tgagcgagga tgacccagat 180
gtccagatca gctggtttgt gaacaacgtg gaagtacaca cagctcagac acaaacccat 240
agagaggatt acaacagtac tctccgggtg gtcagtgccc tccccatcca gcaccaggac 300
tggatgagtg gcaaggagtg caaatgcaag gtcaacaaca aagacctccc agcgcccatc 360
gagagaacca tctcaaaacc caaagggtca gtaagagctc cacaggtata tgtcttgcct 420
ccaccagaag aagagatgac taagaaacag gtcactctga cctgcatggt cacagacttc 480
atgcctgaag acatttacgt ggagtggacc aacaacggga aaacagagct aaactacaag 540
aacactgaac cagtcctgga ctctgatggt tcttacttca tgtacagcaa gctgagagtg 600
gaaaagaaga actgggtgga aagaaatagc tactcctgtt cagtggtcca cgagggtctg 660
cacaatcacc acacgactaa gagcttctcc cggactccgg gtaaatgatc 710
<210> 16
<211> 935
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 16
gatctatcct ctagagtcga cgagcccaaa tcttgtgaca aaactcacac atgcccaccg 60
tgcccaggta agccagccca ggcctcgccc tccagctcaa ggcgggacag gtgccctaga 120
gtagcctgca tccagggaca ggccccagcc gggtgctgac acgtccacct ccatctcttc 180
ctcagcacct gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga 240
caccctcatg atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga 300
agaccctgag gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac 360
aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct 420
gcaccaggac tggctgaatg gcaaggagta caagtgaaag gtctccaaca aagccctccc 480
agcccccatc gagaaaacca tctccaaagc caaaggtggg acccgtgggg tgcgagggcc 540
acatggacag aggccggctc ggcccaccct ctgccctgag agtgaccgct gtaccaacct 600
ctgtccctac agggcagccc cgagaaccac aggtgtacac cctgccccca tcccgggatg 660
agctgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttatat cccagcgaca 720
tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc acgcctcccg 780
tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac aagagcaggt 840
ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac aaccactaca 900
cgcagaagag cctctccctg tctccgggta aatga 935
<210> 17
<211> 106
<212> PRT
<213> Homo sapiens
<400> 17
Met Asn Ser Lys Glu Lys Lys Asp Leu Gly Thr Leu Gly Tyr Val Leu
1 5 10 15
Gly Ile Thr Met Met Val Ile Ile Ile Ala Ile Gly Ala Gly Ile Ile
20 25 30
Leu Gly Tyr Ser Tyr Lys Arg Gly Lys Asp Leu Lys Glu Gln His Asp
35 40 45
Gln Lys Val Cys Glu Arg Glu Met Gln Arg Ile Thr Leu Pro Leu Ser
50 55 60
Ala Phe Thr Asn Pro Thr Cys Glu Ile Val Asp Glu Lys Thr Val Val
65 70 75 80
Val His Thr Ser Gln Thr Pro Val Asp Pro Gln Glu Gly Thr Thr Pro
85 90 95
Leu Met Gly Gln Ala Gly Thr Pro Gly Ala
100 105
Claims (17)
1.PIK3IP1ECD或PIK3IP1ECD融合分子和抗原一同在制备用于增强受试者对抗原的免疫应答的药物中的用途,所述增强包括给受试者施用抗原和PIK3IP1ECD或PIK3IP1ECD融合分子,增强受试者抗原特异性CD8+T细胞的增殖;
所述PIK3IP1ECD包含选自SEQ ID NO.9和/或10的序列;PIK3IP1ECD融合分子包含选自SEQ ID NO.9和/或10的序列。
2.如权利要求1所述的用途,其特征在于,所述PIK3IP1ECD由选自SEQ ID NO.9或10的序列组成。
3.如权利要求1所述的用途,其特征在于,所述PIK3IP1ECD融合分子的融合伴侣是Fc。
4.如权利要求3所述的用途,其特征在于,所述PIK3IP1ECD融合分子的融合伴侣是IgGFc,所述IgGFc的碱基序列由选自SEQ ID NO.15或16的序列组成。
5.如权利要求1所述的用途,其特征在于,所述PIK3IP1ECD融合分子的碱基序列由选自SEQ ID NO.11、12、13或14的序列组成。
6.如权利要求1-5任一项所述的用途,其特征在于,所述抗原是癌性细胞、肿瘤抗原、病毒抗原、细菌抗原。
7.如权利要求6所述的用途,其特征在于,所述抗原为黑素瘤的抗原肽。
8.如权利要求6所述的用途,其特征在于,所述抗原为肽gp100。
9.如权利要求6所述的用途,其特征在于,所述抗原为hgp10025-33。
10.PIK3IP1ECD或PIK3IP1ECD融合分子单独或者和4-1BB的激活性抗体联合在制备治疗肿瘤药物中的用途;
所述PIK3IP1ECD包含选自SEQ ID NO.9和/或10的序列;PIK3IP1ECD融合分子包含选自SEQ ID NO.9和/或10的序列。
11.如权利要求10所述的用途,其特征在于,所述PIK3IP1ECD由选自SEQ ID NO.9或10的序列组成。
12.如权利要求10所述的用途,其特征在于,所述PIK3IP1ECD融合分子的融合伴侣是Fc。
13.如权利要求12所述的用途,其特征在于,所述PIK3IP1ECD融合分子的融合伴侣是IgGFc,所述IgGFc的碱基序列由选自SEQ ID NO.15或16的序列组成。
14.如权利要求10所述的用途,其特征在于,所述PIK3IP1ECD融合分子的碱基序列由选自SEQ ID NO.11、12、13或14的序列组成。
15.如权利要求10-14任一项所述的用途,其特征在于,所述4-1BB的激活性抗体是抗体2A。
16.如权利要求15所述的用途,其特征在于,所述肿瘤选自黑色素瘤、白血病、肺癌、肝癌、卵巢癌、宫颈癌、皮肤癌、膀胱癌、结肠癌、乳腺癌、神经胶质瘤、肾癌、胃癌、食道癌、口腔鳞状细胞癌、头颈癌。
17.如权利要求16所述的用途,其特征在于,所述肿瘤为黑色素瘤。
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Inhibition of T-Cell Activation by PIK3IP1;Marie C. DeFrances, et al.;《Eur J Immunol.》;20121031;第42卷(第10期);第2754-2759页 * |
PIK3IP1- A novel negative regulator of PI3K;Uzodinma N Uche, et al.;《The Journal of Immunology》;20160501;第196卷(第57期);第9篇第10-14行 * |
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