CN116685677A - 活化免疫细胞的细胞表面抗原及其应用 - Google Patents
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Abstract
本发明涉及特异性存在于免疫细胞表面的细胞表面抗原Lrig1(富含亮氨酸重复序列和免疫球蛋白样结构域1)蛋白及其应用。
Description
技术领域
本发明涉及一种细胞表面抗原Lrig1(富含亮氨酸重复序列和免疫球蛋白样结构域1)及其应用,所述抗原是一种存在于活化免疫细胞(例如调节性T细胞和其他主动抑制其它类型的免疫细胞)表面的蛋白质。
背景技术
癌症是目前导致全球死亡人数最多的疾病之一。近年来,由于平均寿命的延长和癌症发病年龄的降低,癌症的发病率不断增加。据韩国国立癌症中心2013年的统计报告显示,2010年在癌症登记统计部门登记的癌症患者人数为202053人,而且这个数目至今仍在持续增加。
当癌症发生在实体器官中时,传统的治疗方法是手术切除。然而,在受影响区域太大或癌症发生在实体器官以外的区域时,手术切除是不切实际的,因此会采用口服或注射化疗。癌细胞利用一种蛋白质,通过过度表达内源性磷酸激活蛋白来破坏细胞信号转导系统。制造在化疗中使用的抗癌药物并投入使用,以有效结合该蛋白并抑制其活性。然而,这种抗癌化疗法是有问题的,因为它会抑制具有快速细胞周期的正常细胞(例如毛发)的生长,并且引发各种副作用,包括但不限于口干、口腔炎、恶心、呕吐、腹泻和中性粒细胞减少症。因此,人们正在努力识别与癌症相关的各种体内分子,并开发靶向这些分子的药物。也在努力通过结合上述药物来加强癌症治疗。因此,可以得出结论,努力发现和识别如癌症相关转录因子之类的靶分子至关重要,且意义重大。
所有正常个体共有的最重要特征是能够识别和消除非自身抗原,同时不会对构成自身的抗原物质产生有害反应。这种对自身抗原的无应答性被称为免疫无应答性或耐受性。自身耐受通过消除可能含有自身抗原特异性受体的淋巴细胞,或通过使响应自身抗原的自身反应功能失活而发生。当诱导或维持自身耐受方面出现问题时,针对自身抗原的免疫反应开始发生;由这种反应引起的疾病称为自身免疫性疾病。
过去,在阿尔茨海默病(Alzheimer’s Disease,AD)、帕金森病(Parkinson’sDisease,PD)和肌萎缩性侧索硬化症(Amyotrophic Lateral Sclerosis,ALS)等神经退行性疾病的病理中观察到的神经胶质细胞增殖和免疫炎症细胞与免疫介质的浸润,仅被认为是由神经细胞破坏引起的非特异性继发现象。然而,随着分子生物学的发展,识别在免疫炎症机制中发挥重要作用的细胞表皮指标成为可能。随着免疫炎症介质的识别及其功能的揭示,越来越多的证据表明免疫炎症机制不仅是神经系统损伤的非特异性继发反应,而且还可能参与神经退行性疾病的早期阶段,调节病理的严重程度,积极参与神经元的生存和死亡。
披露
技术问题
本发明的一个目的是提供一种用于免疫细胞的细胞表面抗原。
本发明的另一个目的是提供一种用于预防、改善或治疗多种疾病的组合物,所述组合物含有免疫细胞,优选的,由活化免疫细胞的细胞表面抗原Lrig1(富含亮氨酸重复序列和免疫球蛋白样结构域1)基因编码的蛋白质或其胞外结构域作为活性成分的免疫细胞。
本发明的另一个目的是提供一种诊断多种疾病的方法,所述方法包括一种检测免疫细胞(优选活化免疫细胞)的细胞表面抗原Lrig1基因,或其编码的蛋白质的表达水平的试剂。
本发明的另一个目的是提供一种含有双特异性抗体作为预防或治疗多种疾病的活性成分的药物组合物,所述双特异性抗体包括特异性结合Lrig1的抗体或其抗原结合片段,以及特异性结合免疫细胞表面标记物的抗体或其抗原结合片段。
本发明的另一个目的是提供一种药物组合物,其包含本发明的抗体或其抗原结合片段或含有抗体-药物偶联物的药物,作为预防或治疗多种疾病的活性成分。
本发明的另一个目的是提供一种分离免疫细胞(优选活化免疫细胞)的方法,所述方法通过确认Lrig1蛋白或编码该蛋白的基因的表达水平的变化来完成。
本发明的另一个目的是提供一种培养活化免疫细胞的方法。
本发明的另一目的是提供一种筛选用于预防、改善或治疗多种疾病的细胞治疗产品的方法,所述方法通过确认Lrig1蛋白或编码该蛋白的基因在免疫细胞中的表达水平的变化来完成。
然而,本发明要实现的技术问题并不限于上述问题,并且对于本领域的技术人员来说,根据本发明的主旨,将本发明的范围扩展到未明确提及的其他问题是显而易见的。
技术方案
1.细胞表面抗原
根据本发明的一个实施方式,其涉及Lrig1(富含亮氨酸重复序列和免疫球蛋白样结构域1)的免疫细胞的细胞表面抗原。
更具体地,本发明的细胞表面抗原是包含Lrig1蛋白或编码该蛋白的基因的活化免疫细胞的细胞表面抗原。
本发明的免疫细胞包括T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞,但不限于此。
本发明的T细胞可以是效应T细胞,但不限于此。
本发明的效应T细胞可以是选自Th1、Th2、Th17和Th22中的至少一种,但不限于此。
在本发明中,“Lrig1”是一种由1091个氨基酸组成的跨膜蛋白,其可以存在于活化免疫细胞(例如具有活化抑制活性的各种免疫细胞)的表面上。Lrig1由细胞外或腔侧富含亮氨酸的重复序列(leucine-rich repeats,LRR),3个免疫球蛋白样结构域,跨膜序列和细胞质尾组成。LRIG基因家族包括LRIG1、LRIG2和LRIG3,其氨基酸在家族内高度保守。LRIG1基因在正常皮肤中高度表达,通过在基底和毛囊细胞中表达来调节上皮干细胞的增殖。因此,它在维持表皮的稳态中起着至关重要的作用,缺失会发展为银屑病或皮肤癌。据报道,当Lrig1所在的染色体3p14.3被切断时,有可能会发展成癌细胞。事实上,Lrig1的表达在肾细胞癌和皮肤鳞状细胞癌中显著降低。
就本发明而言,Lrig1蛋白可以是人或小鼠蛋白,但不限于此。
本发明的Lrig1蛋白可以是人源多肽(由SEQ ID NO:1表示)或鼠源多肽(由SEQ IDNO:3表示),但不限于此。
本发明的Lrig1蛋白(由SEQ ID NO:1表示)可以由多核苷酸(由SEQ ID NO:2表示)编码,但不限于此。
本发明的Lrig1蛋白(由SEQ ID NO:3表示)可以由多核苷酸(由SEQ ID NO:4表示)编码,但不限于此。
本发明的Lrig1是一种特异性存在于免疫细胞表面上的抗原,对其它类型的免疫细胞(例如效应T细胞)具有活化的抑制功能。优选地,表达Lrig1的免疫细胞可以发挥与调节性T细胞(regulatory T cells,Treg)相同的抑制作用,但不限于此。
本文中的“Th1细胞”是一种CD4+细胞,在适应性免疫系统中起着至关重要的作用。更具体地,它通过释放改变靶细胞行为的细胞因子来帮助其他免疫细胞的活动。就本发明而言,当Lrig1在Th1细胞表面表达时,Th1细胞可以摆脱其固有功能并激活抑制功能,表现得像调节性T细胞并抑制其他效应T细胞,但不限于此。
本文中的“Th2细胞”是指由于刺激而分泌白介素(interleukin,IL)4、IL-5、IL-6、IL-13的CD4+T细胞亚群,分泌Th1辅助T细胞的干扰素γ和不分泌细胞因子如IL-2的辅助T细胞。就本发明而言,当Lrig1在Th2细胞的表面上表达时,Th2细胞可以摆脱其固有功能并激活抑制功能,表现得像调节性T细胞并抑制其他效应T细胞,但不限于此。
本文中的“Th17细胞”是指产生白介素17的促炎辅助性T细胞群。此类Th17细胞在适应性免疫中起着至关重要的作用,同时保护人体免受病原生物的侵害。这些Th17细胞可以像其他辅助性T细胞一样,通过CXCL13趋化因子信号传导等机制参与应对致病生物的B细胞强化。Th17细胞的活性有利于抗体的形成。特别是,Th17细胞具有依赖细胞因子微环境和炎症条件的可塑性,因此它们的表型和功能可以改变。
本文中的“Th17细胞”在分子水平上的特征在于产生操作因子细胞因子(operational factor cytokines),IL-17A、IL-17F、IL-26、IL-22、IL-21和TNFα的个体谱(individual profiles),并依赖IL-23进行发育、存活和增殖。这些细胞因子激活不同类型的细胞,例如角化细胞,使其过度增殖并额外产生促炎细胞因子,趋化因子和抗菌肽,这些又反过来募集并激活炎性皮肤中的其他免疫细胞,从而导致炎症反应的放大。此外,IL-17A和IL-17F引起IL-17产生的自分泌调节,这被认为可以促进和维持Th17细胞分化(Wei等人,2007,J Biol.Chem.,9月20日)。IL-17还可以诱导基质细胞中Th17细胞特异性受体的配体CCL20的上调,使进一步的细胞导致炎症组织。纯CD4 T细胞分化为Th17细胞的信号通路需要TGFb-1与IL-21、IL-1b和IL-23或IL-1b、IL-23和IL-6相结合,促进Th17细胞分化,然后诱导维甲酸相关孤儿受体(retinoid-related orphan receptor,RORC)和维甲酸相关孤儿受体α(retinoid acid-related orphan receptor alpha,RORA)的表达,这2个转录因子可以上调IL-17A和Il-17F的表达(Chung Y等人,白介素-1信号通路对早期Th17细胞分化的关键调控(Critical regulation of early Th17 cell differentiation by interleukin-1signaling),Immunity 2009;30:576-87,Veldhoen M,Hocking RJ,Akins CJ,LocksleyRM,Stockinger B.and Immunity 2006Feb;24(2):178-89)。就本发明而言,当Lrig1在Th17细胞的表面上表达时,Th17细胞可以摆脱其固有功能并激活抑制功能,表现得像调节性T细胞并抑制其他效应T细胞,但不限于此。
本文中的“Th22细胞”是指辅助性T细胞的一个亚群,其特征性功能是产生IL-22。特别地,Th22细胞具有在缺失IL-17和INF-γ情况下特异性地表达IL-22的特征。就本发明而言,当Lrig1在Th22细胞的表面上表达时,Th22细胞可以摆脱其固有功能并激活抑制功能,表现得像调节性T细胞并抑制其他效应T细胞,但不限于此。
本文中的“细胞表面抗原”是指存在于细胞表面的分子,其可以作为激活受体的分子以特异性识别细胞或表现出细胞特异性功能。这种细胞表面抗原的实例包括各种细胞表面抗原簇(cluster of differentiation,CD)。本发明的细胞表面抗原可以单独存在,或与CD组合存在,或单独存在于具有激活抑制功能的免疫细胞中,例如效应T细胞,但不限于此。
2.细胞疗法
在本发明的(2)细胞疗法中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述内容相同,因此以下省略其描述。
本文中的“细胞疗法”是指在直接注射到患者体内的治疗方法中使用的活细胞。因此,它是指通过物理、化学或生物操作制造的药物,例如体外培养、增殖或筛选活的自体细胞、同源细胞或异源细胞。
本文中的“预防”是指减少动物中病理性细胞的发生或细胞的损伤或损失程度。预防可以是完全的,也可以是部分的。在这种情况下,它可以指一种现象,即与不使用下文所述的用于预防和治疗多种疾病的组合物时相比,受试者中病理细胞或免疫功能异常的发生率降低。
本文的“治疗”是指临床上任何干预以改变待治疗靶标或细胞的自然过程的动作,可以在临床病理状态期间或预防临床病理状态期间进行。期望的治疗效果包括预防疾病的发生或复发、缓解症状、减轻疾病的任何直接或间接病理后果、预防转移、降低疾病进展速度、减轻或暂时缓解疾病状况或改善预后。因此,所述治疗可以被解释为通过组合物改善或治愈下述各种疾病症状的所有活动。
本发明的细胞可以按1x107至1x108、1x108至2x108、2x108至4x108、4x108至6x108、6x108至8x108、8x108至1x109、1x109至2x109,2x109至4x109,4x109至1x1010,2x108至6x108,6x108至1x109,1x108至2x108,2x108至2x109,1x107至1x108,1x108至1x109,1x109至1x1010,或1x107至1x109之间的任何剂量(细胞/kg)施用,但不限于此。
本发明的药物组合物可以是胶囊、片剂、颗粒剂、注射剂、软膏、粉末或饮料的形式,所述药物组合物的特征是可以用于人类。
本发明的药物组合物并不限于此,而是可以根据各自的常规方法配制成口服制剂的形式,例如粉末、颗粒、胶囊、片剂、水混悬剂,外用制剂,栓剂和无菌注射溶液。本发明的药物组合物可以包括药学上可接受的载体。药学上可接受的载体可包括用于口服给药的粘结剂、润滑剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、混悬剂、色素和香料等。在注射的情况下,可以混合使用缓冲剂、防腐剂、非转化剂、增溶剂、呈现剂(presenting agent)和稳定剂等。在局部给药的情况下,可以使用基础剂、赋形剂、润滑剂和防腐剂等。本发明的药物组合物的制剂可以通过与上述药学上可接受的载体混合而多样地制备。例如,用于口服给药时,所述组合物可以以片剂、锭剂、胶囊剂、酏剂、混悬剂、糖浆、糯米纸囊剂(wafers)等形式制备,在注射情况下,所述组合物可以以单位剂量安瓿或多剂量形式制备。此外,它可以被配制成溶液、混悬剂、片剂、胶囊和缓释制剂等。
另一方面,适用于制剂的载体、赋形剂和稀释剂的实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟苯甲酸甲酯、羟苯甲酸丙酯、滑石、硬脂酸镁或矿物油等。另外,还可以包括填充剂、抗凝剂、润滑剂、润湿剂、调味剂、乳化剂和防腐剂等。
本发明的药物组合物的给药途径可以包括但不限于口服、静脉内、肌肉内、动脉内、髓内、鞘内、心内、透皮、皮下、腹膜内、鼻内、肠内、局部、舌下或直肠给药,例如口服或肠胃外给药。
本文中的“肠胃外”包括皮下、皮内、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输液技术。就本发明而言,所述药物组合物可以通过直接注射至肾脏给药,但不限于此。
本发明的药物组合物取决于各种因素,包括所使用的特定化合物的活性、年龄、体重、总体健康状况、性别、饮食、给药时间、给药途径、排泄率、药物组合和要预防或治疗的特定疾病的严重程度。药物组合物的剂量可以根据患者的状况、体重、疾病严重程度、药物类型、给药途径和周期而变化选择,但是可以由本领域技术人员适当地选择。所述药物组合物可以以每天0.0001至50mg/kg或每天0.001至50mg/kg施用。药物组合物可以每天给药一次,或者分多次给药。上述剂量不旨在以任何方式限制本发明的范围。根据本发明的药物组合物可以配制成药丸、糖衣丸、胶囊、液体、凝胶、糖浆、浆液或混悬剂。
2-1.预防或治疗免疫相关疾病的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,其包含具有Lrig1蛋白或编码该蛋白的基因的免疫细胞作为预防或治疗免疫相关疾病的活性成分。
本发明中具有Lrig1蛋白或编码该蛋白的基因的免疫细胞可以摆脱其固有功能,并且对其他效应T细胞有良好的抑制能力,从而有效预防或治疗免疫相关疾病。
本文的“免疫相关疾病”是由多种免疫细胞和炎性细胞过度激活和表达引起的疾病。实例包括自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性或急性或慢性炎性疾病等,但不限于此。
此外,本文中的“自身免疫性疾病”可以是选自类风湿性关节炎、系统性硬皮病、系统性红斑狼疮、特应性皮炎、银屑病、斑秃、哮喘、克罗恩病、白塞病、干燥综合征、格林-巴利综合征、慢性甲状腺炎、多发性硬化、多发性肌炎、强直性脊柱炎、成纤维细胞和结节性多发动脉炎中的至少一种,但不限于此。
2-2.预防或治疗癌症的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,其包含具有Lrig1蛋白或编码该蛋白的基因的免疫细胞作为预防或治疗癌症的活性成分。
本发明中具有Lrig1蛋白或编码该蛋白的基因的免疫细胞可以摆脱其固有功能,并具有调节效应T细胞活性以有效抑制各种癌细胞的生长。
本文的“癌症”通常是指以哺乳动物体内细胞生长不受调节为特征的生理状态。本发明预防、改善或治疗的癌症可以是,例如实体器官中细胞异常生长形成的实体瘤。根据实体器官的部位,所述癌症可以选自胃癌、肝癌、胶质母细胞瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移癌、前列腺癌、胰腺癌、黑色素瘤和肺癌,优选黑色素瘤或结肠癌中的至少一种,但不限于此。
2-3.用于预防或治疗神经退行性或神经炎性疾病的药物组合物
在另一个实施例中,本发明提供了一种药物组合物,其包含具有Lrig1蛋白或编码该蛋白的基因的免疫细胞作为预防或治疗神经退行性或神经炎性疾病的活性成分。
本发明中具有Lrig1蛋白或编码该蛋白的基因的免疫细胞由于其优异的抑制其他效应T细胞的能力,可以有效地预防或治疗神经退行性或神经炎性疾病。
本文的“神经退行性或神经炎性疾病”包括但不限于中风、痴呆、阿尔茨海默氏病、帕金森氏病、亨廷顿氏病、尼曼-匹克病、朊病毒病、克雅氏病、额颞叶痴呆、路易痴呆、肌萎缩性侧索硬化症(ALS)、副肿瘤综合征、皮质基底变性、多系统萎缩性疾病、进行性核上性麻痹、神经系统自身免疫性疾病、脊髓小脑性共济失调、炎性和神经性疼痛、脑血管疾病、脊髓损伤和Tau蛋白病(tauopathy)。
3.诊断组合物
在本发明的(3)诊断组合物中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
3-1.用于诊断免疫相关疾病的组合物
在另一个实施方式中,本发明提供了一种用于免疫相关疾病的诊断组合物,所述诊断组合物包含检测免疫细胞表面的Lrig1蛋白或编码该蛋白的基因的表达水平的试剂。
用于检测Lrig1蛋白的表达水平的试剂没有明确限制,但可以包括与该蛋白特异性结合的抗体、寡肽、配体、肽核酸(peptide nucleic acids,PNA)和适体。
本文中的“抗体”是指与抗原特异性结合并引起抗原-抗体反应的物质。就本发明而言,抗体是指与Lrig1蛋白特异性结合的抗体。本发明的抗体包括多克隆抗体、单克隆抗体和重组抗体。使用本领域公知的技术可以容易地制备这种抗体。例如,可以通过本领域公知的方法制备特异性抗体,该方法包括将生物标志蛋白的抗原注射到动物中并收集其血液以获得含有抗体血清的过程。这种特异性抗体可以从任何动物中制备,如山羊、兔子、绵羊、猴子、马、猪、牛和狗等。此外,单克隆抗体可以通过本领域公知的杂交瘤方法(参见Kohler和Milstein(1976)European Journal of Immunology 6:511-519)或噬菌体抗体库技术(参见Clackson等人,Nature,352:624-628,1991;Marks等人,J.Mol.Biol.,222:58,1-597,1991)制备。通过上述方法制备的抗体可以使用如凝胶电泳,透析,盐沉淀,离子交换层析和亲和层析等方法分离和纯化。另外,本发明的抗体不仅包括具有2个轻链和2个重链的完整形式,而且还包括抗体分子的功能片段。抗体分子的功能性片段是指至少具有一个抗原结合功能的片段,包括Fab,F(ab’),F(ab’)2和Fv。
本文中的“PNA(肽核酸)”是指类似于DNA和RNA的人工合成聚合物,由丹麦哥本哈根大学的Nielsen,Egholm,Berg和Buchardt教授在1991年首次提出。DNA具有一个磷酸核糖骨架,而PNA具有一个由多肽连接的重复的N-(2-氨基乙基)-甘氨酸骨架,这大大增加了与DNA或RNA的结合力和稳定性,因此被用于分子生物学,诊断检测和反义疗法。Nielsen PE,Egholm M,Berg RH,Buchardt O在文献“胸腺嘧啶取代的聚酰胺通过链置换对DNA进行序列选择性识别(Sequence-selective recognition of DNA by strand displacement withathymine-substituted polyamide)”(1991年12月)[Science 254(5037):1497-1500]中详细描述了PNA。
本文中的“适体”是一种寡核酸或肽分子,文献[Bock LC等人,Nature355(6360):5646(1992);Hoppe-Seyler F,Butz K“肽适体:分子医学的强大新工具(Peptideaptamers:powerful new tools for molecular medicine)”.J Mol Med.78(8):42630(2000);Cohen BA,Colas P,Brent R.“一种从组合文库中分离的人工细胞周期抑制剂(anartificial cell-cycle inhibitor isolated from a combinatorial library).”ProcNatl Acad Sci USA.95(24):142727(1998)]中详细描述了适体的一般性描述。
用于检测编码Lrig1蛋白的基因(即LRIG1基因)的表达水平的试剂可以包括选自与该基因特异性结合的引物、探针和反义核苷酸中的至少一种。
本文中的“引物”是识别靶基因序列的片段。它包括正向和反向引物对,但优选地提供具有特异性和敏感性的分析结果。由于引物的核酸序列与样品中存在的非靶序列不一致,所以当引物仅扩增含有互补一级结合位点的靶基因序列而不会造成非特异性扩增时,可以赋予高特异性。
这里的“探针”是指能够与样品中要检测的靶物质特异性地结合的物质,以及能够通过结合来特异性地确认样品中靶物质存在的物质。鉴于探针在本领域中常用,探针的类型不受限制,但优选为肽核酸(peptide nucleic acid,PNA)、锁核酸(locked nucleicacid,LNA)、肽、多肽、蛋白质、RNA或DNA,其中PNA是最优选的。更具体地,所述探针是一种生物材料,包括那些来自于或类似于那些来自于生物体的或体外制造的材料。这可以包括酶、蛋白质、抗体、微生物、动植物细胞和器官、神经细胞、DNA和RNA。DNA可以包括cDNA、基因组DNA和寡核苷酸,而RNA包括基因组RNA、mRNA、寡核苷酸,而蛋白质包括抗体、抗原、酶和肽等。
本文中的“LNA(锁核酸)”是指含有2'-O,4'-C亚甲基桥的核酸类似物[JWeiler,JHunziker和J Hall Gene Therapy(2006)13,496.502]。LNA核苷含有DNA和RNA共同的核酸碱基,可以根据沃森-克里克(Watson-Crick)碱基配对规则进行碱基配对。但是,由于亚甲基桥导致分子锁定,LNA无法在沃森-克里克碱基配对中形成理想的形状。当LNA包含在DNA或RNA的寡核苷酸中时,LNA可以更迅速地与互补核苷酸链配对,以增加双螺旋的稳定性。
本文中的“反义”是指具有核苷酸碱基序列和亚基间骨架的寡聚物,其中反义寡聚物通过沃森-克里克碱基配对形式与RNA中的靶序列杂交,从而在靶序列中形成mRNA和RNA寡聚物异源双链核酸分子。寡聚物可以具有与靶序列完全互补或接近互补的序列。
关于Lrig1蛋白或编码该蛋白的LRIG1基因的信息是已知的,因此本领域技术人员可以基于这些信息容易地设计与编码该蛋白的基因特异性结合的引物、探针或反义核苷酸。
本文中的“免疫相关疾病”是由多种免疫细胞和炎性细胞过度激活和表达引起的疾病。实例包括自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性或急性或慢性炎性疾病等,但不限于此。
此外,本文中的“自身免疫性疾病”可以是选自下组的至少一种:类风湿性关节炎、系统性硬皮病、系统性红斑狼疮、特应性皮炎、银屑病、斑秃、哮喘、克罗恩病、白塞病、干燥综合征、格林-巴利综合征、慢性甲状腺炎、多发性硬化、多发性肌炎、强直性脊柱炎、成纤维细胞和结节性多发动脉炎,但不限于此。
3-2.用于诊断癌症的组合物
在另一个实施方式中,本发明提供了一种用于癌症的诊断组合物,所述组合物包含检测免疫细胞表面的Lrig1蛋白或编码该蛋白的基因的表达水平的试剂。
在本发明的(3-2)用于诊断癌症的组合物中,与检测蛋白质或编码该蛋白质的基因的表达水平的试剂有关的内容与(3-1)用于诊断免疫相关疾病的组合物中所述的内容相同,因此以下省略其描述。
本文中的“癌症”通常是指以哺乳动物体内细胞生长不受调节为特征的生理状态。本发明预防、改善或治疗的癌症可以是例如实体器官中细胞异常生长形成的实体瘤。根据实体器官的部位,所述癌症可以是选自下组的至少一种:胃癌、肝癌、胶质母细胞瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移癌、前列腺癌、胰腺癌、黑色素瘤和肺癌,优选黑色素瘤或结肠癌,但不限于此。
3-3.用于诊断神经退行性或神经炎性疾病的组合物
在另一个实施方式中,本发明提供了一种用于神经退行性或神经炎性疾病的诊断组合物,所述组合物包含检测免疫细胞表面的Lrig1蛋白或编码该蛋白的基因的表达水平的试剂。
在本发明的(3-3)用于诊断神经退行性或神经炎性疾病的组合物中,与检测蛋白质或编码该蛋白质的基因的表达水平的试剂相关的内容与(3-1)用于诊断免疫相关疾病的组合物中所述的内容相同,因此以下省略其描述。
本文的“神经退行性或神经炎性疾病”包括但不限于中风、痴呆、阿尔茨海默氏病、帕金森氏病、亨廷顿氏病、尼曼-匹克病、朊病毒病、克雅氏病、额颞叶痴呆、路易痴呆、肌萎缩性侧索硬化症(ALS)、副肿瘤综合征、皮质基底变性、多系统萎缩性疾病、进行性核上性麻痹、神经系统自身免疫性疾病、脊髓小脑性共济失调、炎性和神经性疼痛、脑血管疾病、脊髓损伤和Tau蛋白病。
4.诊断试剂盒
在本发明的(4)诊断试剂盒中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
4-1.用于免疫相关疾病的诊断试剂盒
在另一个实施方式中,本发明提供了一种用于免疫相关疾病的诊断试剂盒,所述诊断试剂盒包含用于免疫相关疾病的诊断组合物。
在本发明中,所述试剂盒可以是RT-PCR试剂盒、DNA Chip试剂盒、ELISA试剂盒、蛋白CHIP试剂盒、快速试剂盒或多反应监测(multiple reaction monitoring,MRM)试剂盒,但不限于此。
本发明的试剂盒可进一步包括一种或多种适用于分析方法的其它组分组合物、溶液或装置。
例如,本发明的试剂盒可包括进行逆转录聚合酶反应所必需的其他基本元素。逆转录聚合酶反应包含一对对编码标记蛋白基因特异的引物。引物是对给定基因的核酸序列具有特异性的核苷酸,其长度可以约在7bp至50bp之间,更优选的,在10bp至30bp之间。也可以包括对对照基因的核酸序列具有特异性的引物。其他逆转录聚合酶反应试剂盒可以包括试管或其他合适的容器、反应缓冲液(具有不同的pH值和镁浓度)、脱氧核苷酸(dNTPs)、酶(例如Taq-聚合酶和逆转录酶)、DNase和RNase抑制剂、DEPC-水以及无菌水等。
此外,本发明的诊断试剂盒可以包括进行DNA CHIP所必需的基本元素。DNA CHIP试剂盒可以包括附着有基因或其片段相对应的cDNA或寡核苷酸的底物,以及用于产生荧光标记探针的试剂、药剂和酶。另外,所述底物可以包括对照基因或其片段相对应的cDNA或寡核苷酸。
此外,本发明的诊断试剂盒可以包括进行ELISA所必需的基本元素。ELISA试剂盒包括对蛋白质有特异性的抗体。该抗体是单克隆抗体,多克隆抗体或重组抗体,其对标志物蛋白具有高特异性和亲和力,并且与其他蛋白几乎没有交叉反应性。ELISA试剂盒还可以包括对对照蛋白特异的抗体。其他ELISA试剂盒可以包括能够检测结合抗体的试剂,例如标记的二抗、发色团、酶(例如,与抗体偶联)或其底物或能够结合抗体的底物等。
4-2.用于癌症的诊断试剂盒
在另一个实施方式中,本发明提供了一种用于癌症的诊断试剂盒,所述诊断试剂盒包含用于癌症的诊断组合物。
在本发明的(4-2)用于癌症的诊断试剂盒中,与检测蛋白质或编码该蛋白质的基因的表达水平的试剂有关的内容与(3-1)用于诊断免疫相关疾病的组合物中所述的内容相同,而与试剂盒相关的内容与(4-1)用于免疫相关疾病的诊断试剂盒中所述的内容相同。因此,下面省略其描述。
4-3.用于神经退行性或神经炎性疾病的诊断试剂盒
在另一个实施方式中,本发明提供了一种用于神经退行性或神经炎性疾病的诊断试剂盒,所述诊断试剂盒包含用于神经退行性或神经炎性疾病的诊断组合物。
在本发明的(4-3)用于神经退行性或神经炎性疾病的诊断试剂盒中,与检测蛋白质或编码该蛋白质的基因的表达水平的试剂有关的内容与(3-1)用于诊断免疫相关疾病的组合物中所述的内容相同,而与试剂盒相关的内容与(4-1)用于免疫相关疾病的诊断试剂盒中所述的内容相同。因此,下面省略其描述。
5.诊断方法
在本发明的(5)诊断方法中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
5-1.为诊断免疫相关疾病提供信息的方法
在另一个实施方式中,本发明提供了一种为诊断免疫相关疾病提供信息的方法,所述方法包括检测从目标个体分离的生物样品中Lrig1蛋白或编码该蛋白的基因在免疫细胞中的表达水平。
本文中的“目标个体”是指疾病的发生是不确定的,并且发生疾病的可能性较高的个体。
本文中的“生物样品”是指从个体获得或衍生的任何物质、生物液体、组织或细胞。它可以包括全血、白细胞、外周血单核细胞、血沉棕黄层、血浆和含血清的血液、痰液、眼泪、粘液、鼻腔冲洗物、鼻腔抽吸物、呼出的气体、尿液、精液、唾液、腹膜洗液、盆腔液、囊性液、脑膜液、羊水、腺液、胰液、淋巴液、胸膜液、乳头抽吸物、支气管抽吸物、滑膜液、关节抽吸物、器官分泌物、细胞、细胞提取物或脑脊液,但不限于此。
在本发明的(5-1)为诊断免疫相关疾病提供信息的方法中,与检测Lrig1蛋白和编码该蛋白的基因的表达水平的试剂有关的内容与(3-1)用于诊断免疫相关疾病的组合物中所述的相同,因此以下省略其描述。
检测或比较Lrig1蛋白表达水平的方法包括蛋白CHIP分析、免疫分析、配体结合分析、MALDI-TOF(基质辅助激光解吸/电离飞行时间质谱)分析、SELDI-TOF(表面增强激光解吸/电离飞行时间质谱)分析、放射免疫法、放射免疫扩散法、Oukteroni免疫扩散法、火箭免疫电泳法、组织免疫染色、补体固定法、二维电泳法、液相色谱-质谱(LC-MS)、液相色谱-质谱/质谱(LC-MS)、蛋白质印迹法、或ELISA(酶联免疫吸附测定),但不限于此。
检测编码Lrig1蛋白的基因的表达水平以确认基因的存在和表达水平的分析方法包括逆转录聚合酶反应(实时;RT-PCR)、RPA(RNase保护试验)、Northern印迹和DNA CHIP,但不限于此。
与正常对照组相比,当在目标个体的生物样品中检测到免疫细胞的Lrig1蛋白或编码该蛋白的基因的表达水平增加或降低时,则可以包括预测发生免疫相关疾病的可能性很高。
更具体地说,如果与正常对照组相比,在目标个体的生物样品中检测到免疫细胞的Lrig1蛋白或编码该蛋白的基因的表达水平降低,则可以预测发生免疫相关疾病的可能性很高。
此外,通过如上所述的在目标个体的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平来预测或诊断患有免疫相关疾病的可能性很高时,可以进一步包括向目标个体施用治疗该疾病的药物这一步骤。
6.双特异性抗体
在本发明的(6)双特异性抗体中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
6-1.预防或治疗免疫相关疾病的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,所述药物组合物包含与Lrig1或免疫细胞表面标志物特异性结合的双特异性抗体作为预防或治疗免疫相关疾病的活性成分。
本发明的双特异性抗体包括与Lrig1特异性结合的抗体或其抗原结合片段,以及与免疫细胞表面标志物特异性结合的抗体或其抗原结合片段。
本发明的免疫细胞包括T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞,但不限于此。
本发明的T细胞可以是效应T细胞,但不限于此。
本发明的效应T细胞可以是选自Th1、Th2、Th17和Th22中的至少一种,但不限于此。
本发明的双特异性抗体双重靶向特异性表达在免疫细胞上的Lrig1蛋白和表面标志物,因此它特异性地与活化的效应T细胞结合,这些细胞的功能或特性会根据周围的微环境而改变。因此,它不仅可以有效地调节免疫细胞的特异性功能,而且还可以有效地调节调节性T细胞的免疫抑制功能,从而可以非常有效地预防或治疗免疫相关疾病。
本文中的“双特异性抗体”可以以任何合适的格式提供,例如文献中列出的形式,其通过引用整体并入本文中(参见Kontermann MAbs 2012,4(2):182-197)。例如,双特异性抗体或双特异性抗原结合片段可以是双特异性抗体偶联物(例如IgG2、F(ab’)2或CovX-体)、双特异性IgG或IgG样分子(例如IgG、scFv4-Ig、IgG-scFv、scFv-IgG、DVD-Ig、IgG-sVD、sVD-IgG或二合一IgG(2in 1-IgG)、mAb2或串联通用LC(Tandemab common LC)),不对称双特异性IgG或IgG样分子(例如Kih IgG、kih IgG通用LC(kih IgG common LC)、CrossMab、kih IgG-scFab、mAb-Fv、电荷对(charge pairs)或SEED-体),小型双特异性抗体分子(例如双体(Diabody,Db)、dsDb、DART、scDb、tandAbs、串联scFv(tandem scFv,taFv)、串联dAb/VHH、三体(triple body)、三头(triple head)、Fab-scFv或F(ab’)2-scFv2),双特异性Fc和CH3融合蛋白(例如taFv-Fc、di-diabody、scDb-CH3、scFv-Fc-scFv、HCAb-VHH、scFv-kih-Fc或scFv-kih-CH3),或双特异性融合蛋白(例如scFv2-白蛋白、scDb-白蛋白、taFv-毒素、DNL-Fab4-IgG、DNL-Fab4-IgG-细胞因子2)。尤其是参考文献的图2(Kontermann MAbs2012,4(2):182-19)。本领域技术人员可以根据本发明设计和制备双特异性抗体和双特异性抗原结合片段。
本发明中制备双特异性抗体的方法包括如文献中提出的,利用还原性二硫键或非还原性硫醚键将抗体或抗体片段化学交联,该文献通过引用整体并入本文中[参见:Segal和Bast,2001.双特异性抗体的生产,免疫学的最新方案(Production of BispecificAntibodies,Current Protocols in Immunology.)14:IV:2.13:2.1-2.13.16]。例如,利用N-琥珀酰亚胺基-3-(-2-吡啶基二硫基)-丙酸酯(N-succinimidyl-3-(-2-pyridyldithio)-propionate,SPDP)通过铰链区SH-基团化学交联Fab片段,以生产二硫键连接的双特异性F(ab)2异二聚体。
此外,本发明的产生双特异性抗体的另一种方法包括,如文献中提出的[参见:D.M.和Bast,B.J.2001.双特异性抗体的产生,免疫学的最新方案(Production ofBispecific Antibodies.Current Protocols in Immunology.)14:IV:2.13:1-2.13.16],例如将产生抗体的杂交体与聚乙二醇融合,以产生能够分泌双特异性抗体的四交瘤细胞(quadroma cells)。
双特异性抗体和双特异性抗体片段也可以通过,如在文献中所提出的,由表达编码抗原结合分子多肽的核酸构建体而重组产生,这2篇文献通过引用整体并入本文中[参见:《抗体工程:方法和规程》(Antibody Engineering:Methods and Protocols),第二版(Humana出版社,2012),第40章:双特异性抗体的产生:双体和串联scFv(Production ofBispecific Antibodies:Diabodies and Tandem scFv)(Hornig和Farber-Schwarz),或French,如何制造双特异性抗体(How to make bispecific antibodies),MethodsMol.Med.2000;40:333-339]。例如,可以通过分子克隆技术产生包含编码2个抗原结合结构域的轻链和重链可变结构域的序列(因此,可与PD-1结合的抗原结合结构域的轻链和重链可变结构域,以及可与其他靶蛋白结合的抗原结合结构域的轻链和重链可变结构域)并包括编码抗原结合结构域之间合适的连接子或二聚化结构域的序列的DNA构建体。然后通过在合适的宿主细胞(例如,哺乳动物宿主细胞)中表达构建体(例如,体外)来产生重组双特异性抗体。可以选择性地纯化所得到的表达的重组双特异性抗体。
本发明的抗体可以通过亲和力成熟过程产生,该过程产生的修饰抗体与未修饰的亲本抗体相比,其对抗原的亲和力有所提高。亲和力成熟的抗体可以通过本领域中详细描述的程序产生,例如文献中提出的那些[参见:Marks等人,Rio/Technology 10:779-783(1992);Barbas等人,Proc Nat.Acad.Sci.USA 91:3809-3813(1994);Schier等人,Gene169:147-155(1995);Yelton等人,J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):3310-159(1995);或Hawkins等人,J.Mol.Biol.226:889-896(1992)].
本文中的“抗体”是指通过免疫系统中的抗原刺激产生的物质。它可以包括但不限于在体内产生的那些重组体或人工合成的抗体。本发明包括所有动物抗体、嵌合抗体、人源化抗体和人抗体。本发明的抗体还包括具有抗原结合能力的抗体的抗原结合片段。
本文中的“抗原结合片段”可以选自包含一个以上互补决定区的抗体片段,例如scFv、(scFv)2、scFv-Fc、Fab、Fab’和F(ab’)2。
本发明中与Lrig1特异性结合的抗体或其抗原结合片段可包含那些选自下组的:
(a)重链可变区,包括如SEQ ID NO:5所示的重链CDR1、如SEQ ID NO:6所示的重链CDR2和如SEQ ID NO:7所示的重链CDR3;
(b)重链可变区,包括如SEQ ID NO:11所示的重链CDR1、如SEQ ID NO:12所示的重链CDR2和如SEQ ID NO:13所示的重链CDR3;
(c)重链可变区,包括如SEQ ID NO:17所示的重链CDR1、如SEQ ID NO:18所示的重链CDR2和如SEQ ID NO:19所示的重链CDR3;
(d)重链可变区,包括如SEQ ID NO:23所示的重链CDR1、如SEQ ID NO:24所示的重链CDR2和如SEQ ID NO:25所示的重链CDR3;
(e)重链可变区,包括如SEQ ID NO:29所示的重链CDR1、如SEQ ID NO:30所示的重链CDR2和如SEQ ID NO:31所示的重链CDR3;
(f)重链可变区,包括如SEQ ID NO:35所示的重链CDR1、如SEQ ID NO:36所示的重链CDR2和如SEQ ID NO:37所示的重链CDR3;
(g)重链可变区,包括如SEQ ID NO:41所示的重链CDR1、如SEQ ID NO:42所示的重链CDR2和如SEQ ID NO:43所示的重链CDR3;
(h)重链可变区,包括如SEQ ID NO:47所示的重链CDR1、如SEQ ID NO:48所示的重链CDR2和如SEQ ID NO:49所示的重链CDR3;
(i)轻链可变区,包括如SEQ ID NO:8所示的轻链CDR1、如SEQ ID NO:9所示的轻链CDR2和如SEQ ID NO:10所示的轻链CDR3;
(j)轻链可变区,包括如SEQ ID NO:14所示的轻链CDR1,如SEQ ID NO:15所示的轻链CDR2和如SEQ ID NO:16所示的轻链CDR3;
(k)轻链可变区,包括如SEQ ID NO:20所示的轻链CDR1、如SEQ ID NO:21所示的轻链CDR2和如SEQ ID NO:22所示的轻链CDR3;
(l)轻链可变区,包括如SEQ ID NO:26所示的轻链CDR1、如SEQ ID NO:27所示的轻链CDR2和如SEQ ID NO:28所示的轻链CDR3;
(m)轻链可变区,包括如SEQ ID NO:32所示的轻链CDR1、如SEQ ID NO:33所示的轻链CDR2和如SEQ ID NO:34所示的轻链CDR3;
(n)轻链可变区,包括如SEQ ID NO:38所示的轻链CDR1、如SEQ ID NO:39所示的轻链CDR2和如SEQ ID NO:40所示的轻链CDR3;
(o)轻链可变区,包含如SEQ ID NO:44所示的轻链CDR1、如SEQ ID NO:45所示的轻链CDR2和如SEQ ID NO:46所示的轻链CDR3;
(p)轻链可变区,包含如SEQ ID NO:50所示的轻链CDR1、如SEQ ID NO:51所示的轻链CDR2和如SEQ ID NO:52所示的轻链CDR3。
本发明的免疫细胞的表面标志物可以包含在单个免疫细胞的表面特异性表达的任何标志物,以使这种细胞与其他免疫细胞区分开。
本文中的“Th1细胞表面标志物”是指在Th1细胞表面特异性表达并且能够将Th1细胞与其他细胞区分开的标志物。它可以包括CD94、CD119(IFNγR1)、IFNγR2、CD183(CXCR3)、CD186(CDCR6)、CD191(CCR1)、CD195(CCR5)、CD212(IL-12Rβ1)、IL-12Rβ2、CD218a(IL-18Rα)、IL-27Rα、CD254(RANKL)或CD366(TIM3),但不限于此。
本文中的“Th2细胞表面标志物”是指在Th2细胞表面特异性表达并且能够将Th2细胞与其他细胞区分开的标志物。其可以包括CD184(CDCR4)、CD193(CCR3)、CD194(CCR4)、CD198(CCR8)、CD294(CRTH2)、CD365(TIM1)、IL-25R(IL-17RB)、IL-33R(ST2)、IL-4R或TSLPR,但不限于此。
本文中的“Th17细胞表面标志物”是指在Th17细胞的表面特异性表达并且能够将Th17细胞与其他细胞区分开的标志物。其可以包括CD121a(IL-1RI)、CD126(IL-6Rα)、CD161、CD194(CCR4)、CD196(CCR6)、IL-23R、CD360(IL-21R)、CD212(IL-12Rβ1)或TGF-βRII,但不限于此。
本文中的“Th22细胞表面标志物”是指在Th22细胞表面上特异性表达并且可以将Th22细胞与其他细胞区分开的标志物。它可以包括CD194(CCR4)、CD196(CCR6)、CCR10、IL-6Rα、TGF-βRII或TNFRI,但不限于此。
本发明中双特异性抗体除重链CDR区、轻链CDR位点、重链可变区或轻链可变区以外的其他区域可包括来源于免疫球蛋白所有亚型的那些(例如IgA、IgD、IgE、IgG、(IgG1、IgG2、IgG3、IgG4)、IgM等),如来源于免疫球蛋白所有亚型的轻链恒定区和/或重链恒定区。
本文中的“互补决定区(complementarity-determining regions,CDR)”是指抗体可变区中赋予抗原结合特异性的部分。
6-2.预防或治疗癌症的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,所述药物组合物包含与Lrig1或免疫细胞表面标志物特异性结合的双特异性抗体作为预防或治疗癌症的活性成分。
在本发明的(6-2)预防或治疗癌症的药物组合物中,与双特异性抗体、与Lrig1或免疫细胞表面标志物特异性结合的抗体或其结合片段有关的内容与(6-1)预防或治疗免疫相关疾病的药物组合物中所述的相同,因此下文省略其描述。
6-3.预防或治疗神经退行性或神经炎性疾病的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,所述药物组合物包含与Lrig1或免疫细胞表面标志物特异性结合的双特异性抗体作为预防或治疗神经退行性或神经炎性疾病活性成分。
在本发明的(6-3)预防或治疗神经退行性或神经炎性疾病的药物组合物中,与双特异性抗体、与Lrig1或免疫细胞表面标记物特异性结合的抗体或其结合片段有关的内容与(6-1)中所述的预防或治疗免疫相关疾病的药物组合物相同,因此下文省略其描述。
6-4.联合给药
本发明的药物组合物可以另外与其他治疗免疫相关疾病、癌症、神经退行性或神经炎性疾病的治疗剂联合施用。
本发明的免疫相关疾病的治疗可以是免疫调节剂,例如细胞因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(colony stimulating factors,CSF)、干扰素(interferons,IFN)、促红细胞生成素、促血小板生成素或抗炎剂,例如甾体类或非甾体类抗炎剂,但不限于此。
本发明的癌症治疗,即本发明的抗癌药物可以选自下组:氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼罗替尼、司马沙尼、博舒替尼、阿昔替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、卡铂、贝伐珠单抗、顺铂、西妥昔单抗、槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗奥唑米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿伦珠单抗、丙卡嗪、前列地尔、硝酸钬壳聚糖、吉西他滨、去氧氟尿苷、培美曲塞、替加氟、卡培他滨、吉美拉西、奥替拉西、氮胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西他赛、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春花碱、替尼泊苷、多柔比星、伊达比星、表柔比星、米托蒽醌、博来霉素、柔红霉素、更生霉素、吡柔比星、阿柔比星、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法兰、六甲蜜胺、达卡巴嗪、噻替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、亚叶酸、维甲酸、依西美坦、氨鲁米特、阿那格雷、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏氯唑、比卡鲁胺、洛莫司汀或卡莫司汀,但不限于此。
本发明的神经退行性或神经炎性疾病的治疗可包括AchE抑制剂、NMDA受体拮抗剂、多巴胺替代物、多巴胺激动剂、MAO抑制剂、小分子治疗药物如COMT抑制剂、基因疗法、单克隆抗体疗法、免疫疗法或iPSC,但不限于此。
7.双特异性抗体-药物偶联物
在本发明的(7)双特异性抗体-药物偶联物中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
另外,在本发明的(7)双特异性抗体-药物偶联物中,与联合给药有关的内容与(6-4)联合给药中所述的内容相同,因此以下省略其描述。
7-1.预防或治疗免疫相关疾病的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,所述组合物包含特异性结合Lrig1或免疫细胞表面标志物的双特异性抗体或抗原结合片段和含有抗体-药物偶联物的药物,作为预防或治疗免疫相关疾病的活性成分。
本文中的“抗体-药物偶联物(antibody-drug conjugate,ADC)”是指化学连接药物和抗体而不降低抗体和药物生物活性的一种形式。在本发明中,所述抗体-药物偶联物是指药物与抗体重链和/或轻链N末端氨基酸残基结合的形式;更具体地说,药物和抗体重链和/或轻链N末端的α-氨基结合的形式。
本文中的“药物”是一个概念,指在细胞中具有特定生物活性的任何物质,包括DNA、RNA或肽。所述药物可以包括能够与α-氨基反应和交联的反应性基团的形式,以及与含有能够与α-氨基反应和交联的反应性基团的连接子连接的形式。
能够与α-氨基反应和交联的反应性基团没有特别限制,只要它能够与抗体重链和/或轻链N末端的α-氨基交联即可。因此包括本领域公知的与氨基反应的所有类型,例如异硫氰酸酯、异氰酸酯、酰基叠氮化物、NHS酯、磺酰氯、醛、乙二醛、环氧化物、环氧乙烷、碳酸盐、芳基卤化物、亚氨酸酯、碳化二亚胺、酸酐或氟苯基酯,但不限于此。
7-2.预防或治疗癌症的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,所述药物组合物包含特异性结合Lrig1或免疫细胞表面标志物的双特异性抗体或抗原结合片段和含有抗体-药物偶联物的药物,作为预防或治疗癌症的活性成分。
在本发明的(7-2)预防或治疗癌症的药物组合物中,与特异性结合Lrig1或免疫细胞表面标志物的抗体-药物偶联物有关的内容与(7-1)预防或治疗免疫相关疾病的药物组合物中所述的相同,因此以下省略其描述。
7-3.预防或治疗神经退行性或神经炎性疾病的药物组合物
在另一个实施方式中,本发明提供了一种药物组合物,所述药物组合物包含特异性结合Lrig1或免疫细胞表面标志物的双特异性抗体或抗原结合片段和含有抗体-药物偶联物的药物,作为预防或治疗神经退行性或神经炎性疾病的活性成分。
在本发明的(7-3)预防或治疗神经退行性或神经炎性疾病的药物组合物中,与特异性结合Lrig1或免疫细胞表面标志物的抗体-药物偶联物有关的内容与(7-1)预防或治疗免疫相关疾病的药物组合物中所述的相同,因此以下省略其描述。
8.分离免疫细胞的方法
在另一个实施方式中,本发明提供了一种分离活化免疫细胞的方法。
在本发明的(8)分离免疫细胞的方法中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
本发明的分离方法包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
本文中的“分离的生物样品”可以是从健康正常对照或寻求免疫治疗的个体中分离的生物样品。更具体地说,它是指从个体获得或衍生的任何物质、生物液体、组织或细胞,例如全血、白细胞,外周血单核细胞、血沉棕黄层、血浆、血清、痰液、眼泪、粘液、鼻腔冲洗物、鼻腔抽吸物、呼出的气体、尿液、精液、唾液、腹膜洗液、盆腔液、囊性液、脑膜液、羊水、腺液、胰液、淋巴液、胸膜液、乳头抽吸物、支气管抽吸物、滑膜液、关节抽吸物、器官分泌物、细胞、细胞提取物或脑脊液,但不限于此。
本发明的分离方法可以分离表达Lrig1蛋白或编码该蛋白的基因的免疫细胞、与正常对照组相比表达水平增加的免疫细胞或与其他平均免疫细胞相比表达水平增加的免疫细胞。
根据本发明的分离方法分离得到的免疫细胞可以施用于患有或极有可能发展为免疫相关疾病、癌症或神经退行性或神经炎性疾病的个体,以预防、改善或治疗该疾病。在此,被施用免疫细胞的个体可以与生物样品所来源的个体相同或不同。
9.培养免疫细胞的方法
在另一个实施方式中,本发明提供了一种培养活化免疫细胞的方法。
在本发明的(9)培养免疫细胞的方法中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
本发明的培养方法包括通过在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平来分离活化免疫细胞,并培养所述活化免疫细胞。
在本发明的(9)培养免疫细胞的方法中,与分离活化免疫有关的内容与(8)分离免疫细胞的方法中所述的内容相同,因此以下省略其描述。
本发明的培养方法的“培养”是指任何体外细胞培养物。在本发明中,可以使用细胞培养基(指在细胞培养环境中使用的所有类型的基质),并且可以包括氨基酸、至少一种作为能量来源的碳水化合物、微量元素、维生素、盐和其他附加成分(例如,影响细胞的生长、生产力或产品质量的),但不限于此。
10.筛选细胞疗法的方法
在本发明的(10)筛选细胞疗法的方法中,与免疫细胞和Lrig1蛋白有关的内容与(1)细胞表面抗原中所述的内容相同,因此以下省略其描述。
10-1.筛选免疫相关疾病细胞疗法的方法
在另一个实施方式中,本发明提供了一种筛选免疫相关疾病细胞疗法的方法。
本发明的筛选方法包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
在本发明的筛选方法中,如果与对照组相比,分离的生物样品的免疫细胞中Lrig1蛋白或编码该蛋白的基因的表达水平升高或降低,则可以选择其作为免疫相关疾病的细胞疗法。
在本发明的细胞疗法的筛选方法中,与细胞疗法、生物样品、测定蛋白质或编码该蛋白的基因的表达水平的方法以及免疫相关疾病有关的内容与上述相同,因此以下省略其描述。
10-2.筛选癌症细胞疗法的方法
在另一个实施方式中,本发明提供了一种筛选癌症细胞疗法的方法。
本发明的筛选方法包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
在本发明的筛选方法中,如果与对照组相比,分离的生物样品的免疫细胞中Lrig1蛋白或编码该蛋白的基因的表达水平升高或降低,则可以选择其作为癌症的细胞疗法。
在本发明的筛选细胞疗法的方法中,与细胞疗法、生物样品、测定蛋白质或编码该蛋白的基因的表达水平的方法以及免疫相关疾病有关的内容与上述相同,因此以下省略其描述。
10-3.筛选神经退行性或神经炎性疾病细胞疗法的方法
在另一个实施方式中,本发明提供了一种筛选神经退行性或神经炎性疾病细胞疗法的方法。
本发明的筛选方法包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
在本发明的筛选方法中,如果与对照组相比,分离的生物样品的免疫细胞中的Lrig1蛋白或编码该蛋白的基因的表达水平增加或降低,则可以选择其作为神经退行性或神经炎性疾病的细胞疗法。
在本发明的细胞疗法的筛选方法中,与细胞疗法、生物样品、测定蛋白质或编码该蛋白的基因的表达水平的方法以及免疫相关疾病有关的内容与上述相同,因此以下省略其描述。
有益效果
本发明的免疫细胞具有活化的抑制功能,活化免疫细胞的Lrig1蛋白可作为免疫相关疾病、癌症或神经退行性或神经炎性疾病的新靶点。
附图说明
图1显示根据本发明的一个实施方式,确认Th17细胞的抑制作用的结果。
最佳实施方式
根据本发明的一个实施方式,确认Th17细胞的抑制作用的结果如图1所示。
发明实施方式
下文将通过以下实施例对本发明进行详细说明。然而,以下实施例仅说明了本发明,因此本发明的内容不受以下内容的制约或限制。
实施例
[制备例]T细胞亚群细胞培养
为了确认Th17细胞的效应T细胞抑制作用,制备了T细胞亚群Th0、Th1、Th2、Th17和iTreg。与自然分离的nTreg不同,iTreg是指在含有以下组成的培养基中人工诱导分化的细胞。
根据常规方法,首先使用MACS从小鼠脾脏中分离出初始T细胞,从而诱导T细胞亚型分化。然后将下表1的组分添加到含有10%胎牛血清(FBS;Hyclone,犹他州洛根市)的RPMI1640(Invitrogen Gibco,纽约州格兰德岛)营养培养基中,并将细胞在37℃,5%CO2培养基中孵育72小时以分化成单个细胞。
[表1]
分化细胞 | 组成 |
Th0 | 抗CD3、抗CD28 |
Th1 | IL-12、抗IL-4抗体 |
Th2 | IL-4、抗IFNβ |
Th17 | IL-6、TGFβ、抗IFNγ、抗IL-4 |
iTreg | IL-2、TGFβ |
[实施例]效应T细胞抑制作用的确认
使用荧光激活细胞分选仪(Fluorescence-Activated Cell Sorter;FACS)将来自[制备例]的分化细胞分为高表达Lrig1(Th17 L1+或iTreg L1+)的细胞和低表达Lrig1的细胞(Th17 L1-或iTreg L1-)。
然后,为了确认效应T细胞抑制作用,用PBS洗涤抗原呈递细胞(antigenpresenting cells,APC)和初始CD4+T细胞两次以完全去除血清。当用1mL PBS溶解上述细胞团以进行CFSE标记时,在2×107个细胞的情况下,将1mL5mM CFSE 0.25μl混合物加入到1mL PBS中,按1:1比例混合。然而,当细胞计数低于2×107时,将其用500mL PBS溶解,并与500mL上述CPSE+PBS混合物混合。然后,将混合物在37℃下孵育10分钟。为抑制APC分裂,当1mL PBS中有5×107个细胞时,添加100μL体积的丝裂霉素C(0.5mg/ml),在37℃下孵育20分钟。加注15mL预冷培养基并在冰上存放5分钟后,用培养基洗涤两次,并计数细胞。以与CD4+T细胞的比例为2:1,1:1和1:2添加Th17L+细胞,Th17L-细胞,iTreg L+细胞和iTreg L-细胞,同时加入蛋白质和抗CD3抗体(0.5ug/mL)。3天后,使用CFSE-FL4确认效应T细胞增殖的抑制程度,结果如图1所示。
如图1所示,与Lrig1低表达的情况相比,在Lrig1高表达的Th17细胞中,在比例为2:1,1:1和1:2的所有情况下均表现出效应T细胞抑制作用。
上文已经详细描述了本发明的具体部分,对于本领域的技术人员来说清楚的是,这些具体技术仅是优选实施方式,本发明的范围不限于此。因此,本发明的实质范围将由所附权利要求及其等同物限定。
工业实用性
本发明的免疫细胞具有活化的抑制功能,活化免疫细胞的Lrig1蛋白可作为免疫相关疾病、癌症或神经退行性或神经炎性疾病的新靶点。
<110> 古德T细胞有限公司
<120> 活化免疫细胞的细胞表面抗原及其应用
<130> P2023-0543
<150> KR 10-2020-0137432
<151> 2020-10-22
<160> 52
<170> KoPatentIn 3.0
<210> 1
<211> 759
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly Asp Ser
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Leu Asp Cys Gly Gly Arg Gly Leu Ala Ala Leu Pro Gly Asp Leu Pro
20 25 30
Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Lys Leu Ser Glu Ile
35 40 45
Asp Pro Ala Gly Phe Glu Asp Leu Pro Asn Leu Gln Glu Val Tyr Leu
50 55 60
Asn Asn Asn Glu Leu Thr Ala Val Pro Ser Leu Gly Ala Ala Ser Ser
65 70 75 80
His Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Arg Ser Val Glu
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Gly Ser Gln Leu Lys Ala Tyr Leu Ser Leu Glu Val Leu Asp Leu Ser
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Leu Asn Asn Ile Thr Glu Val Arg Asn Thr Cys Phe Pro His Gly Pro
115 120 125
Pro Ile Lys Glu Leu Asn Leu Ala Gly Asn Arg Ile Gly Thr Leu Glu
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Leu Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu Arg Leu
145 150 155 160
Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Arg Ala Phe Lys Leu Pro
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Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu Ile Glu
180 185 190
Gly Leu Thr Phe Gln Gly Leu Asn Ser Leu Glu Val Leu Lys Leu Gln
195 200 205
Arg Asn Asn Ile Ser Lys Leu Thr Asp Gly Ala Phe Trp Gly Leu Ser
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Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu Val Asn
225 230 235 240
Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His Leu Ser
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Asn Asn Ser Ile Ala Arg Ile His Arg Lys Gly Trp Ser Phe Cys Gln
260 265 270
Lys Leu His Glu Leu Val Leu Ser Phe Asn Asn Leu Thr Arg Leu Asp
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Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Val Leu Arg Leu Ser
290 295 300
His Asn Ser Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly Leu Arg
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Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly Thr Ile
325 330 335
Glu Asp Thr Ser Gly Ala Phe Ser Gly Leu Asp Ser Leu Ser Lys Leu
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Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala Phe Ser
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Gly Leu Glu Gly Leu Glu His Leu Asn Leu Gly Gly Asn Ala Ile Arg
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Ser Val Gln Phe Asp Ala Phe Val Lys Met Lys Asn Leu Lys Glu Leu
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His Ile Ser Ser Asp Ser Phe Leu Cys Asp Cys Gln Leu Lys Trp Leu
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Pro Pro Trp Leu Ile Gly Arg Met Leu Gln Ala Phe Val Thr Ala Thr
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Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser Val Pro
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Pro Glu Ser Phe Val Cys Asp Asp Phe Leu Lys Pro Gln Ile Ile Thr
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Gln Pro Glu Thr Thr Met Ala Met Val Gly Lys Asp Ile Arg Phe Thr
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Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala Trp Lys
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Val His Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile Leu His
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<210> 2
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<212> DNA
<213> 智人(Homo sapiens)
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ggcccgcggg cgccctgcgc ggccgcctgc acttgcgctg gggactcgct ggactgcggt 60
gggcgcgggc tggctgcgtt gcccggggac ctgccctcct ggacgcggag cctaaacctg 120
agttacaaca aactctctga gattgaccct gctggttttg aggacttgcc gaacctacag 180
gaagtgtacc tcaataataa tgagttgaca gcggtaccat ccctgggcgc tgcttcatca 240
catgtcgtct ctctctttct gcagcacaac aagattcgca gcgtggaggg gagccagctg 300
aaggcctacc tttccttaga agtgttagat ctgagtttga acaacatcac ggaagtgcgg 360
aacacctgct ttccacacgg accgcctata aaggagctca acctggcagg caatcggatt 420
ggcaccctgg agttgggagc atttgatggt ctgtcacggt cgctgctaac tcttcgcctg 480
agcaaaaaca ggatcaccca gcttcctgta agagcattca agctacccag gctgacacaa 540
ctggacctca atcggaacag gattcggctg atagagggcc tcaccttcca ggggctcaac 600
agcttggagg tgctgaagct tcagcgaaac aacatcagca aactgacaga tggggccttc 660
tggggactgt ccaagatgca tgtgctgcac ctggagtaca acagcctggt agaagtgaac 720
agcggctcgc tctacggcct cacggccctg catcagctcc acctcagcaa caattccatc 780
gctcgcattc accgcaaggg ctggagcttc tgccagaagc tgcatgagtt ggtcctgtcc 840
ttcaacaacc tgacacggct ggacgaggag agcctggccg agctgagcag cctgagtgtc 900
ctgcgtctca gccacaattc catcagccac attgcggagg gtgccttcaa gggactcagg 960
agcctgcgag tcttggatct ggaccataac gagatttcgg gcacaataga ggacacgagc 1020
ggcgccttct cagggctcga cagcctcagc aagctgactc tgtttggaaa caagatcaag 1080
tctgtggcta agagagcatt ctcggggctg gaaggcctgg agcacctgaa ccttggaggg 1140
aatgcgatca gatctgtcca gtttgatgcc tttgtgaaga tgaagaatct taaagagctc 1200
catatcagca gcgacagctt cctgtgtgac tgccagctga agtggctgcc cccgtggcta 1260
attggcagga tgctgcaggc ctttgtgaca gccacctgtg cccacccaga atcactgaag 1320
ggtcagagca ttttctctgt gccaccagag agtttcgtgt gcgatgactt cctgaagcca 1380
cagatcatca cccagccaga aaccaccatg gctatggtgg gcaaggacat ccggtttaca 1440
tgctcagcag ccagcagcag cagctccccc atgacctttg cctggaagaa agacaatgaa 1500
gtcctgacca atgcagacat ggagaacttt gtccacgtcc acgcgcagga cggggaagtg 1560
atggagtaca ccaccatcct gcacctccgt caggtcactt tcgggcacga gggccgctac 1620
caatgtgtca tcaccaacca ctttggctcc acctattcac ataaggccag gctcaccgtg 1680
aatgtgttgc catcattcac caaaacgccc cacgacataa ccatccggac caccaccgtg 1740
gcccgcctcg aatgtgctgc cacaggtcac ccaaaccctc agattgcctg gcagaaggat 1800
ggaggcacgg atttccccgc tgcccgtgag cgacgcatgc atgtcatgcc ggatgacgac 1860
gtgtttttca tcactgatgt gaaaatagat gacgcagggg tttacagctg tactgctcag 1920
aactcagccg gttctatttc agctaatgcc accctgactg tcctagagac cccatccttg 1980
gtggtcccct tggaagaccg tgtggtatct gtgggagaaa cagtggccct ccaatgcaaa 2040
gccacgggga accctccgcc ccgcatcacc tggttcaagg gggaccgccc gctgagcctc 2100
actgagcggc accacctgac ccctgacaac cagctcctgg tggttcagaa cgtggtggca 2160
gaggatgcgg gccgatatac ctgtgagatg tccaacaccc tgggcacgga gcgagctcac 2220
agccagctga gcgtcctgcc cgcagcaggc tgcaggaagg atgggaccac ggtaggcatc 2280
ttcaccattg ctgtcgtgag cagcatcgtc ctgacgtcac tggtctgggt gtgcatcatc 2340
taccagacca ggaagaagag tgaagagtac agtgtcacca acacagatga aaccgtc 2397
<210> 3
<211> 761
<212> PRT
<213> 小鼠(Mus musculus)
<400> 3
Gln Ala Gly Pro Arg Ala Pro Cys Ala Ala Ala Cys Thr Cys Ala Gly
1 5 10 15
Asp Ser Leu Asp Cys Ser Gly Arg Gly Leu Ala Thr Leu Pro Arg Asp
20 25 30
Leu Pro Ser Trp Thr Arg Ser Leu Asn Leu Ser Tyr Asn Arg Leu Ser
35 40 45
Glu Ile Asp Ser Ala Ala Phe Glu Asp Leu Thr Asn Leu Gln Glu Val
50 55 60
Tyr Leu Asn Ser Asn Glu Leu Thr Ala Ile Pro Ser Leu Gly Ala Ala
65 70 75 80
Ser Ile Gly Val Val Ser Leu Phe Leu Gln His Asn Lys Ile Leu Ser
85 90 95
Val Asp Gly Ser Gln Leu Lys Ser Tyr Leu Ser Leu Glu Val Leu Asp
100 105 110
Leu Ser Ser Asn Asn Ile Thr Glu Ile Arg Ser Ser Cys Phe Pro Asn
115 120 125
Gly Leu Arg Ile Arg Glu Leu Asn Leu Ala Ser Asn Arg Ile Ser Ile
130 135 140
Leu Glu Ser Gly Ala Phe Asp Gly Leu Ser Arg Ser Leu Leu Thr Leu
145 150 155 160
Arg Leu Ser Lys Asn Arg Ile Thr Gln Leu Pro Val Lys Ala Phe Lys
165 170 175
Leu Pro Arg Leu Thr Gln Leu Asp Leu Asn Arg Asn Arg Ile Arg Leu
180 185 190
Ile Glu Gly Leu Thr Phe Gln Gly Leu Asp Ser Leu Glu Val Leu Arg
195 200 205
Leu Gln Arg Asn Asn Ile Ser Arg Leu Thr Asp Gly Ala Phe Trp Gly
210 215 220
Leu Ser Lys Met His Val Leu His Leu Glu Tyr Asn Ser Leu Val Glu
225 230 235 240
Val Asn Ser Gly Ser Leu Tyr Gly Leu Thr Ala Leu His Gln Leu His
245 250 255
Leu Ser Asn Asn Ser Ile Ser Arg Ile Gln Arg Asp Gly Trp Ser Phe
260 265 270
Cys Gln Lys Leu His Glu Leu Ile Leu Ser Phe Asn Asn Leu Thr Arg
275 280 285
Leu Asp Glu Glu Ser Leu Ala Glu Leu Ser Ser Leu Ser Ile Leu Arg
290 295 300
Leu Ser His Asn Ala Ile Ser His Ile Ala Glu Gly Ala Phe Lys Gly
305 310 315 320
Leu Lys Ser Leu Arg Val Leu Asp Leu Asp His Asn Glu Ile Ser Gly
325 330 335
Thr Ile Glu Asp Thr Ser Gly Ala Phe Thr Gly Leu Asp Asn Leu Ser
340 345 350
Lys Leu Thr Leu Phe Gly Asn Lys Ile Lys Ser Val Ala Lys Arg Ala
355 360 365
Phe Ser Gly Leu Glu Ser Leu Glu His Leu Asn Leu Gly Glu Asn Ala
370 375 380
Ile Arg Ser Val Gln Phe Asp Ala Phe Ala Lys Met Lys Asn Leu Lys
385 390 395 400
Glu Leu Tyr Ile Ser Ser Glu Ser Phe Leu Cys Asp Cys Gln Leu Lys
405 410 415
Trp Leu Pro Pro Trp Leu Met Gly Arg Met Leu Gln Ala Phe Val Thr
420 425 430
Ala Thr Cys Ala His Pro Glu Ser Leu Lys Gly Gln Ser Ile Phe Ser
435 440 445
Val Leu Pro Asp Ser Phe Val Cys Asp Asp Phe Pro Lys Pro Gln Ile
450 455 460
Ile Thr Gln Pro Glu Thr Thr Met Ala Val Val Gly Lys Asp Ile Arg
465 470 475 480
Phe Thr Cys Ser Ala Ala Ser Ser Ser Ser Ser Pro Met Thr Phe Ala
485 490 495
Trp Lys Lys Asp Asn Glu Val Leu Ala Asn Ala Asp Met Glu Asn Phe
500 505 510
Ala His Val Arg Ala Gln Asp Gly Glu Val Met Glu Tyr Thr Thr Ile
515 520 525
Leu His Leu Arg His Val Thr Phe Gly His Glu Gly Arg Tyr Gln Cys
530 535 540
Ile Ile Thr Asn His Phe Gly Ser Thr Tyr Ser His Lys Ala Arg Leu
545 550 555 560
Thr Val Asn Val Leu Pro Ser Phe Thr Lys Ile Pro His Asp Ile Ala
565 570 575
Ile Arg Thr Gly Thr Thr Ala Arg Leu Glu Cys Ala Ala Thr Gly His
580 585 590
Pro Asn Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro
595 600 605
Ala Ala Arg Glu Arg Arg Met His Val Met Pro Asp Asp Asp Val Phe
610 615 620
Phe Ile Thr Asp Val Lys Ile Asp Asp Met Gly Val Tyr Ser Cys Thr
625 630 635 640
Ala Gln Asn Ser Ala Gly Ser Val Ser Ala Asn Ala Thr Leu Thr Val
645 650 655
Leu Glu Thr Pro Ser Leu Ala Val Pro Leu Glu Asp Arg Val Val Thr
660 665 670
Val Gly Glu Thr Val Ala Phe Gln Cys Lys Ala Thr Gly Ser Pro Thr
675 680 685
Pro Arg Ile Thr Trp Leu Lys Gly Gly Arg Pro Leu Ser Leu Thr Glu
690 695 700
Arg His His Phe Thr Pro Gly Asn Gln Leu Leu Val Val Gln Asn Val
705 710 715 720
Met Ile Asp Asp Ala Gly Arg Tyr Thr Cys Glu Met Ser Asn Pro Leu
725 730 735
Gly Thr Glu Arg Ala His Ser Gln Leu Ser Ile Leu Pro Thr Pro Gly
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Cys Arg Lys Asp Gly Thr Thr Val Gly
755 760
<210> 4
<211> 2283
<212> DNA
<213> 小鼠(Mus musculus)
<400> 4
caggctggcc cgcgggcccc ctgcgcggcc gcctgcactt gcgccgggga ctcgctggac 60
tgcagtgggc gcgggctggc gacgctgccc cgggacctgc cctcctggac gcgcagccta 120
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ctgcaggaag tgtacctcaa cagcaatgag ctgacagcca taccatcact gggcgctgct 240
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cagctgaagt cgtacctgtc cttggaagtg ctggatctga gttccaacaa catcacggaa 360
attcggagct cctgtttccc gaacggcctg cgtataaggg aactcaactt ggcgagcaac 420
cgcatcagca tcctggagtc tggagcattt gatggtctgt cgcggtcact gctgactctc 480
cgtctgagca aaaacaggat cacccagctt cctgtgaaag cgttcaagct acccaggctg 540
acacaactag acctgaatcg gaatcggatt cggctgattg aaggcctcac gttccagggg 600
ctcgacagct tagaggtgct gaggcttcag aggaacaaca tcagcaggct gacggacggg 660
gccttctggg ggctgtctaa gatgcacgtg ctgcacctgg agtacaacag tctggtggaa 720
gtgaacagtg gctccctcta tggcctcaca gccctgcacc agctgcacct cagcaacaac 780
tccatctctc gaattcagcg tgatggctgg agcttctgcc aaaagctgca tgagttgatt 840
ctgtccttca acaacctcac gcggctggat gaggagagtc tagcggagtt gagcagcctc 900
agtatcctgc gcctcagtca caacgccatc agtcacattg ctgaaggcgc cttcaaggga 960
ctcaagagtc tgcgggtctt ggacctggac cataacgaga tctcgggtac aatcgaggat 1020
accagtggtg cctttacggg gcttgacaac ctcagcaagc tgactctgtt tggaaacaag 1080
atcaaatctg tggctaagag agccttctcg ggcctggaaa gcctggaaca cctgaacctt 1140
ggagagaatg caatcaggtc tgtccagttt gatgcctttg caaagatgaa gaaccttaaa 1200
gagctctaca tcagcagtga gagcttcctg tgtgactgcc agctcaagtg gctgccccca 1260
tggctaatgg gtaggatgct gcaggccttt gtgacagcca cctgtgccca tccagagtcg 1320
ctgaagggcc agagcatttt ctcagtgctg ccagacagct ttgtgtgtga tgactttcca 1380
aagccacaga tcatcaccca gcctgagacg accatggctg tggtgggcaa ggacatccgt 1440
ttcacatgct ccgcagccag cagcagcagc tcaccaatga ccttcgcctg gaagaaggac 1500
aatgaggtcc tggccaatgc agacatggag aactttgccc acgtccgtgc acaggacggc 1560
gaagtgatgg agtataccac tatcctgcac ctccgtcacg tcacctttgg gcacgagggc 1620
cgctaccagt gtatcatcac aaaccacttt ggctccacat actcccacaa agccaggctc 1680
actgtgaatg tgttgccatc attcactaaa ataccccatg acattgccat ccggactggc 1740
accacagccc gcctcgagtg tgctgccacg ggccacccta accctcagat tgcctggcag 1800
aaggatggag gcaccgattt cccggcagct cgtgagcgac gcatgcatgt tatgccagac 1860
gatgatgtgt tcttcatcac tgatgtgaaa atagacgaca tgggggtcta cagctgcact 1920
gcccagaact cggcaggctc ggtttcagcc aacgctaccc tcacagtctt agaaactcca 1980
tccttggcag tgcctctgga agaccgtgtg gtaactgtgg gagaaacagt ggccttccag 2040
tgcaaagcaa ccgggagccc cacaccacgc atcacctggc ttaagggagg tcgcccattg 2100
agcctcacag agcgccacca tttcactcca ggcaaccagc tgctggttgt tcagaatgtg 2160
atgatagacg atgcagggcg gtatacctgt gagatgtcta atcccctggg cactgagcga 2220
gcacatagcc agctgagcat tttacctacc cctggctgcc ggaaggatgg gaccaccgta 2280
ggc 2283
<210> 5
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-01重链CDR1
<400> 5
Gly Phe Thr Phe Ser Asp Tyr Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-01重链CDR2
<400> 6
Trp Ile Ser His Gly Gly Gly Ser Ile
1 5
<210> 7
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-01重链CDR3
<400> 7
Ala Arg Gly Leu Gly Leu Cys Lys Thr Gly Leu Cys Tyr Tyr Tyr Asp
1 5 10 15
Ala Met Asp Val
20
<210> 8
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-01轻链CDR1
<400> 8
Ser Ser Asn Ile Gly Asn Asn Ser
1 5
<210> 9
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-01轻链CDR2
<400> 9
Ala Asp Asn
1
<210> 10
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-01轻链CDR3
<400> 10
Ala Ala Trp Asp Ser Ser Leu Ser Ala Tyr Val
1 5 10
<210> 11
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-02重链CDR1
<400> 11
Gly Phe Thr Phe Ser Asp Tyr Tyr
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-02重链CDR2
<400> 12
Gly Ile Ser His Asp Ser Gly Ser Lys
1 5
<210> 13
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-02重链CDR3
<400> 13
Ala Arg His Trp Thr Thr Phe Asp Tyr
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-02轻链CDR1
<400> 14
Ser Ser Asn Ile Gly Ser Asn Asn
1 5
<210> 15
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-02轻链CDR2
<400> 15
Ala Asn Ser
1
<210> 16
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-02轻链CDR3
<400> 16
Gly Ala Trp Asp Tyr Ser Leu Ser Ala Tyr Val
1 5 10
<210> 17
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-03重链CDR1
<400> 17
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-03重链CDR2
<400> 18
Ala Ile Tyr Pro Gly Gly Gly Ser Ile
1 5
<210> 19
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-03重链CDR3
<400> 19
Ala Arg Asp Ile Leu Pro Cys Pro Trp Gly Arg Cys Tyr Tyr Asp Tyr
1 5 10 15
Ala Met Asp Val
20
<210> 20
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-03轻链CDR1
<400> 20
Ser Ser Asn Ile Gly Ser Asn Thr
1 5
<210> 21
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-03轻链CDR2
<400> 21
Ala Asp Asn
1
<210> 22
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-03轻链CDR3
<400> 22
Gly Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 23
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-04重链CDR1
<400> 23
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 24
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-04重链CDR2
<400> 24
Val Ile Ser His Gly Gly Gly Ser Thr
1 5
<210> 25
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-04重链CDR3
<400> 25
Ala Arg Val Ile Ser Asn Cys His Leu Gly Val Cys Tyr Tyr Ser Asn
1 5 10 15
Gly Met Asp Val
20
<210> 26
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-04轻链CDR1
<400> 26
Ser Ser Asn Ile Gly Asn Asn Asp
1 5
<210> 27
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-04轻链CDR2
<400> 27
Ser Asp Ser
1
<210> 28
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC110-04轻链CDR3
<400> 28
Gly Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val
1 5 10
<210> 29
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-01重链CDR1
<400> 29
Gly Phe Thr Phe Ser Gly Tyr Asp
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-01重链CDR2
<400> 30
Leu Ile Tyr Pro Asp Ser Gly Asn Lys
1 5
<210> 31
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-01重链CDR3
<400> 31
Ala Arg Asp Ala Gly Leu Ser Trp Ala Gly Ala Phe Asp Tyr
1 5 10
<210> 32
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-01轻链CDR1
<400> 32
Ser Ser Asn Ile Gly Ser Asn Tyr
1 5
<210> 33
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-01轻链CDR2
<400> 33
Ser Asp Ser
1
<210> 34
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-01轻链CDR3
<400> 34
Gly Ser Trp Asp Tyr Ser Leu Ser Ala Tyr Val
1 5 10
<210> 35
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-02重链CDR1
<400> 35
Gly Phe Thr Phe Ser Asn Tyr Tyr
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-02重链CDR2
<400> 36
Gly Ile Ser Pro Gly Asp Ser Ser Thr
1 5
<210> 37
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-02重链CDR3
<400> 37
Ala Lys Gly Leu Tyr Ser Asn Pro Asn Glu Pro Phe Asp Tyr
1 5 10
<210> 38
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-02轻链CDR1
<400> 38
Ser Ser Asn Ile Gly Ser Asn Tyr
1 5
<210> 39
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-02轻链CDR2
<400> 39
Asp Asp Ser
1
<210> 40
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-02轻链CDR3
<400> 40
Gly Thr Trp Asp Tyr Ser Leu Asn Gly Tyr Val
1 5 10
<210> 41
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-03重链CDR1
<400> 41
Gly Phe Thr Phe Ser Ser Tyr Asp
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-03重链CDR2
<400> 42
Gly Ile Ser Pro Asp Gly Ser Asn Ile
1 5
<210> 43
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-03重链CDR3
<400> 43
Ala Lys Val Gly Leu Arg Cys Arg Tyr Glu Ala Cys Ser Tyr Ala Tyr
1 5 10 15
Gly Met Asp Val
20
<210> 44
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-03轻链CDR1
<400> 44
Ser Ser Asn Ile Gly Ser Asn Tyr
1 5
<210> 45
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-03轻链CDR2
<400> 45
Ser Asp Ser
1
<210> 46
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-03轻链CDR3
<400> 46
Ala Thr Trp Asp Ser Ser Leu Asn Gly Tyr Val
1 5 10
<210> 47
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-04重链CDR1
<400> 47
Gly Phe Thr Phe Ser Asn Tyr Asp
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-04重链CDR2
<400> 48
Ser Ile Ser Pro Ser Ser Gly Ser Ile
1 5
<210> 49
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-04重链CDR3
<400> 49
Ala Lys Asp Leu Asp Ala Phe Trp Arg Pro Ser Phe Asp Tyr
1 5 10
<210> 50
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-04轻链CDR1
<400> 50
Ser Ser Asn Ile Gly Asn Asn Asn
1 5
<210> 51
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-04轻链CDR2
<400> 51
Ser Asp Ser
1
<210> 52
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GTC210-04轻链CDR3
<400> 52
Gly Ser Trp Asp Asp Ser Leu Ser Ala Tyr Val
1 5 10
Claims (35)
1.一种由Lrig1蛋白或编码该蛋白的基因组成的活化免疫细胞的细胞表面抗原。
2.根据权利要求1所述的活化免疫细胞的细胞表面抗原,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
3.一种药物组合物,其包含具有Lrig1蛋白或编码该蛋白的基因的免疫细胞作为预防或治疗免疫相关疾病的活性成分。
4.根据权利要求3所述的药物组合物,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
5.根据权利要求3所述的药物组合物,
其中,所述免疫相关疾病是选自自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性或急性或慢性炎性疾病中的至少一种。
6.根据权利要求5所述的药物组合物,
其中,所述自身免疫性疾病是选自类风湿性关节炎、系统性硬皮病、系统性红斑狼疮、特应性皮炎、银屑病、斑秃、哮喘、克罗恩病、白塞病、干燥综合征、格林-巴利综合征、慢性甲状腺炎、多发性硬化、多发性肌炎、强直性脊柱炎、成纤维细胞和结节性多发性动脉炎中的至少一种。
7.一种药物组合物,其包含具有Lrig1蛋白或编码该蛋白的基因的免疫细胞作为预防或治疗癌症的活性成分。
8.根据权利要求7所述的药物组合物,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
9.根据权利要求7所述的药物组合物,
其中,所述癌症是选自胃癌、肝癌、胶质母细胞瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移癌、前列腺癌、胰腺癌、黑色素瘤和肺癌中的至少一种。
10.一种药物组合物,其包含具有Lrig1蛋白或编码该蛋白的基因的免疫细胞作为预防或治疗神经退行性或神经炎性疾病的活性成分。
11.根据权利要求10所述的药物组合物,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
12.根据权利要求10所述的药物组合物,
其中神经退行性或神经炎性疾病是选自中风、痴呆、阿尔茨海默氏病、帕金森氏病、亨廷顿氏病、尼曼-匹克病、朊病毒病、克雅氏病、额颞叶痴呆、路易痴呆、肌萎缩性侧索硬化症(ALS)、副肿瘤综合征、皮质基底变性、多系统萎缩性疾病、进行性核上性麻痹、神经系统自身免疫性疾病、脊髓小脑性共济失调、炎性和神经性疼痛、脑血管疾病、脊髓损伤和Tau蛋白病(tauopathy)中的至少一种。
13.一种用于免疫相关疾病的诊断组合物,其包括检测免疫细胞表面Lrig1蛋白或编码该蛋白的基因的表达水平的试剂。
14.根据权利要求13所述的诊断组合物,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
15.一种用于免疫相关疾病的诊断试剂盒,其包括根据权利要求13和14中任一项所述的诊断组合物。
16.一种为诊断免疫相关疾病提供信息的方法,其包括检测从目标个体分离的生物样品中免疫细胞中Lrig1蛋白或编码该蛋白的基因的表达水平。
17.一种用于癌症的诊断组合物,其包括检测免疫细胞表面Lrig1蛋白或编码该蛋白的基因的表达水平的试剂。
18.根据权利要求17所述的诊断组合物,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
19.一种用于癌症的诊断试剂盒,其包括根据权利要求17和18中任一项所述的诊断组合物。
20.一种为癌症诊断提供信息的方法,其包括检测从目标个体分离的生物样品中免疫细胞中Lrig1蛋白或编码该蛋白的基因的表达水平。
21.一种用于神经退行性或神经炎性疾病的诊断组合物,其包括用于检测免疫细胞表面Lrig1蛋白或编码该蛋白的基因的表达水平的试剂。
22.根据权利要求21所述的诊断组合物,
其中,所述免疫细胞是选自T细胞、B细胞、NK细胞、先天淋巴细胞、树突状细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞和肥大细胞中的至少一种。
23.一种用于神经退行性或神经炎性疾病的诊断试剂盒,其包括根据权利要求21和22中任一项所述的诊断组合物。
24.一种为诊断神经退行性疾病或神经炎性疾病提供信息的方法,其包括检测从目标个体分离的生物样品中免疫细胞中Lrig1蛋白或编码该蛋白的基因的表达水平。
25.一种药物组合物,其包含一双特异性抗体作为预防或治疗免疫相关疾病的活性成分,所述双特异性抗体包含与Lrig1特异性结合的抗体或其抗原结合片段,和与免疫细胞表面标志物特异性结合的抗体或其抗原结合片段。
26.一种药物组合物,其包含一双特异性抗体作为预防或治疗癌症的活性成分,所述双特异性抗体包含与Lrig1特异性结合的抗体或其抗原结合片段,和与免疫细胞表面标志物特异性结合的抗体或其抗原结合片段。
27.一种药物组合物,其包含一双特异性抗体作为预防或治疗免疫相关疾病的活性成分,所述双特异性抗体包含与Lrig1特异性结合的抗体或其抗原结合片段,和与免疫细胞表面标志物特异性结合的抗体或其抗原结合片段。
28.一种药物组合物,其包含与Lrig1或免疫细胞表面标志物特异性结合的双特异性抗体或抗原结合片段,和含有抗体-药物偶联物的药物,作为预防或治疗免疫相关疾病的活性成分。
29.一种药物组合物,其包含与Lrig1或免疫细胞表面标志物特异性结合的双特异性抗体或抗原结合片段,和含有抗体-药物偶联物的药物,作为预防或治疗癌症的活性成分的。
30.一种药物组合物,其包含与Lrig1或免疫细胞表面标志物特异性结合的双特异性抗体或抗原结合片段,和含有抗体-药物偶联物的药物,作为用于预防或治疗神经退行性或神经炎性疾病的活性成分。
31.一种分离活化免疫细胞的方法,其包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
32.一种培养活化免疫细胞的方法,其包括在分离的生物样品中通过检测Lrig1蛋白或编码该蛋白的基因表达水平来分离活化免疫细胞,并培养所述活化免疫细胞。
33.一种用于筛选免疫相关疾病细胞疗法的方法,其包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
34.一种用于筛选癌症细胞疗法的方法,其包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
35.一种用于筛选神经退行性疾病或神经炎性疾病细胞疗法的方法,其包括在分离的生物样品中检测Lrig1蛋白或编码该蛋白的基因的表达水平。
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PCT/KR2021/014765 WO2022086197A1 (ko) | 2020-10-22 | 2021-10-21 | 활성화된 면역 세포의 세포 표면 항원 및 이의 다양한 용도 |
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---|---|---|---|---|
KR101847523B1 (ko) * | 2011-01-24 | 2018-05-28 | 연세대학교 산학협력단 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR20180116925A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
KR102086649B1 (ko) * | 2017-04-18 | 2020-04-23 | 주식회사 굳티셀 | Lrig-1 단백질에 특이적인 결합 분자 및 이의 용도 |
CN113056485A (zh) * | 2018-10-17 | 2021-06-29 | 古德T细胞有限公司 | Lrig-1蛋白的特异性结合分子及其用途 |
BR112021018688A2 (pt) * | 2019-03-20 | 2021-11-30 | Good T Cells Inc | Composição para prevenir ou tratar doença cerebral e do sistema nervoso |
-
2020
- 2020-10-22 KR KR1020200137432A patent/KR20220053723A/ko not_active Application Discontinuation
-
2021
- 2021-10-21 WO PCT/KR2021/014765 patent/WO2022086197A1/ko active Application Filing
- 2021-10-21 JP JP2023524461A patent/JP2023549473A/ja active Pending
- 2021-10-21 CN CN202180071663.0A patent/CN116685677A/zh active Pending
- 2021-10-21 US US18/250,209 patent/US20230270787A1/en active Pending
- 2021-10-21 EP EP21883265.7A patent/EP4234575A1/en active Pending
Also Published As
Publication number | Publication date |
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JP2023549473A (ja) | 2023-11-27 |
US20230270787A1 (en) | 2023-08-31 |
KR20220053723A (ko) | 2022-05-02 |
EP4234575A1 (en) | 2023-08-30 |
WO2022086197A1 (ko) | 2022-04-28 |
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