CN113667003A - 一种增殖调节性t细胞的突变体蛋白 - Google Patents
一种增殖调节性t细胞的突变体蛋白 Download PDFInfo
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Abstract
本发明提供了一种IL‑2突变体、包含该IL‑2突变体的融合蛋白、抗体或缀合物以及包含所述IL‑2突变体、融合蛋白、抗体或缀合物的药物组合物。与野生型IL‑2相比,该IL‑2突变体与IL‑2Rβγ二聚体的结合降低,并保留其生物学活性,优先刺激调节性T细胞增殖。本发明的IL‑2突变体可以用于自身免疫性疾病的治疗,但没有利用天然IL‑2进行免疫治疗产生的各种副作用。
Description
技术领域
本发明涉及蛋白质工程领域。具体地说,本发明涉及新颖的白介素-2(IL-2)突变体及其制备方法,与野生型IL-2相比,所述白介素-2(IL-2)突变体与其结合伴侣,IL-2受体β亚基和IL-2受体γ亚基的结合能力下降,并保持相应的生物学活性,可以更好地刺激调节性T细胞增殖。
背景技术
IL-2是由活化T细胞产生的白介素家族成员之一,可以通过与细胞表面的白介素2受体结合而刺激T细胞的增殖、发育和分化。IL-2的受体IL-2R由3种亚基构成:α、β和γ链。根据对IL-2的亲和力,IL-2R可以分为高亲和力受体(αβγ链复合物)、中亲和力受体(βγ链复合物)、低亲和力受体(只有α链或αγ链的复合物)和假性高亲和力受体(αβ链复合物)4类。IL-2只有与高亲和力受体或中亲和力受体结合后才能引发细胞内的信号转导。
不同种类的T细胞对IL-2的敏感性不同,调节性T细胞(Treg细胞)对IL-2的敏感性高于其它细胞。因为IL-2Rα可以在Treg细胞表面持续长效表达,Treg细胞在机体无外来抗原刺激情况下,对IL-2的敏感性大于NK、Teff等细胞。利用IL-2的剂量差异选择性影响Treg和Teff,可以调节免疫系统。
目前,低剂量IL-2治疗已经应用于1型糖尿病(type 1diabetes,T1D)、系统性红斑狼疮(systemic lupus erythematosus,SLE)、慢性移植物抗宿主病(chronic graft-versus-host disease,GVHD)等自身免疫性疾病中。但IL-2存在着体内半衰期短、稳定性差,注射治疗空窗期短,免疫抑制和给药部位炎症平衡的安全剂量及疗程难以把握等问题。
调节性T细胞(Treg)能胞内表达转录因子FOXP3,因此可以通过CD4+CD25+FOXP3+与效应T细胞区分。FOXP3基因缺陷和突变导致自我耐受性破坏和自身免疫疾病形成,原因在于Treg缺损或缺少功能。IL-2可以通过结合中等亲和力βγ二聚体刺激T细胞增殖,也可以通过结合高亲和力的αβγ三聚体刺激T细胞的增殖。当βγ二聚体与IL-2的亲和力减弱后,IL-2突变体会相比野生型IL-2更优先刺激存在αβγ受体的Treg细胞,而避免刺激主要表达βγ受体的其他类型T细胞的增殖。因此,降低IL-2与中亲和力受体(βγ链复合物)的结合能力,可以减少IL-2对效应T细胞的刺激作用,从而增加Treg细胞与效应T细胞的比例,改善因Treg或Treg功能的缺损导致的自身免疫反应。
因此更好地刺激调节性T细胞增殖的新型的白介素-2(IL-2)突变体是治疗不同自身免疫疾病所需要的。
发明内容
本发明的目的在于提供一种新颖的IL-2突变体。相比于野生型IL-2,本发明的IL-2突变体能够与其结合伴侣IL-2受体β亚基和IL-2受体γ亚基的结合能力下降,并保持相应的生物学活性,可以更好地刺激调节性T细胞增殖。
在第一方面,本发明提供一种IL-2突变体,与野生型IL-2相比,所述IL-2突变体的氨基酸残基发生突变,降低了所述突变体白介素2蛋白对中等亲和力IL-2受体的亲和力。
在优选的实施方式中,所述中等亲和力IL-2受体是仅包含IL-2受体β亚基和IL-2受体γ亚基而无IL-2受体α亚基。
在优选的实施方式中,所述IL-2突变体可以增加CD3+FoxP3+细胞对CD3+FoxP3-的比率。
在具体的实施方式中,所述IL-2突变体在对应于野生型IL-2的90位的氨基酸残基发生突变。
在具体的实施方式中,相比于野生型IL-2,所述IL-2突变体的氨基酸残基发生突变,从而增加人工糖基化位点。
在优选的实施方式中,所述糖基化位点是N糖位点或O糖位点;优选N糖位点。
在具体的实施方式中,相比于野生型IL-2,所述IL-2突变体的氨基酸残基发生突变。
在优选的实施方式中,所述IL-2突变体在对应于野生型IL-2蛋白的90位发生以下氨基酸残基突变:N90A、N90G、N90V、N90I、N90M、N90L、N90F、N90Y、N90W、N90H、N90R、N90K、N90Q、N90D、N90E、N90P、N90T、N90B、N90C、N90S、N90Z、N90I;
优选地,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90T、N90S、N90V、N90I、N90M、N90L;
更优选地,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90T、N90S;
最优选地,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90T。
在优选的实施方式中,所述IL-2突变体在对应于野生型IL-2蛋白的3位发生以下氨基酸残基突变:T3A、T3G、T3Q、T3E、T3N、T3D、T3R、T3K和T3P;优选T3A。
在优选的实施方式中,所述IL-2突变体突变了125位cys位点:C125L、C125S、C125A;优选C125S。
在第二方面,本发明提供一种融合蛋白或缀合物,所述融合蛋白或缀合物包含第一方面所述的IL-2突变体和非IL-2功能部分。
在优选的实施方式中,非IL-2功能部分选自下组:
Fc片段,包括但不限于:人IgG1、IgG2、IgG3、IgG4的Fc片段,及其同源性在90%以上的Fc片段突变体;
人血清白蛋白(HSA);
抗HSA抗体及片段
抗白蛋白多肽或抗体;
转铁蛋白;
人绒毛膜促性腺激素β亚基羧基末端肽(CTP);
类弹性蛋白多肽(elastin-like peptide,ELP);
抗原结合部分。
在优选的实施方式中,所述抗原结合部分是:
抗体或其活性抗体片段;
Fab分子、scFv分子和VHH分子;或
细胞受体或配体。
在优选的实施方式中,所述融合蛋白中的IL-2突变体与非IL-2功能部分可以直接连接,也可以通过连接物连接;所述连接物可以是AAA或GS的重复序列,包括但不限于G3S的重复序列或G4S的重复序列;例如(G3S)4。
在优选的实施方式中,所述IL-2突变体或融合蛋白可以进一步作以下修饰形成缀合物:
聚乙二醇修饰(PEG化);
聚唾液酸化修饰(PSA化);
饱和脂肪酸修饰;
透明质酸修饰(Hyaluronic acid,HA);
聚氨基酸修饰(proline-alamine-serine polymer,PAS化)。
在第三方面,本发明提供一种多核苷酸,所述多核苷酸编码第一方面所述的IL-2突变体或第二方面所述的融合蛋白或缀合物。
在第四方面,本发明提供一种表达载体,所述表达载体包含第三方面所述的多核苷酸。
在第五方面,本发明提供一种宿主细胞,所述宿主细胞包含第四方面所述的表达载体,或者所述宿主细胞的基因组整合有第三方面所述的多核苷酸。
在优选的实施方式中,所述宿主细胞为真核细胞;优选酵母、昆虫细胞、动物细胞;更优选动物细胞;最优选哺乳动物细胞,例如中国仓鼠卵巢细胞。
在第六方面,本发明提供一种药物组合物,所述药物组合物包含第一方面所述的IL-2突变体蛋白或第二方面所述的融合蛋白或缀合物与药学上可接受的辅料。
在第七方面,本发明提供第一方面所述的IL-2突变体或第二方面所述的融合蛋白在制备用于自身性免疫疾病的药物用途。
在优选的实施方式中,所述疾病是应用IL-2作免疫治疗的疾病。
在优选的实施方式中,所述疾病是癌症、免疫疾病、人类免疫缺陷病毒HIV感染、丙型肝炎病毒HCV感染、风湿性关节炎,特应性皮炎等。
在优选的实施方式中,所述癌症、免疫疾病、人类免疫缺陷病毒HIV感染、丙型肝炎病毒HCV感染、风湿性关节炎,特应性皮炎等通过刺激免疫系统或通过增殖免疫细胞来治疗。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了利用Biacore检测的IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc与IL-2Rα的结合力;
图2显示了利用Biacore检测的IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc与IL-2Rβγ二聚体的结合力;
图3显示了本发明的白介素-2突变体和野生型IL-2刺激NK92细胞增殖的情况;和
图4显示了本发明所用的序列SEQ ID NO:1-5。
具体实施方式
发明人经过广泛而深入的研究,出乎意料地发现对IL-2多肽作定点突变后的新型IL-2突变体能够降低与IL-2Rβγ二聚体的结合,保留其生物学活性,并优先刺激调节性T细胞增殖。因此,本发明的IL-2突变体可以用于自身免疫性疾病的治疗,但没有利用天然IL-2进行免疫治疗产生的各种副作用。在此基础上完成了本发明。
本发明的IL-2突变体
在本发明中,通过定点突变使得IL-2多肽发生氨基酸残基改变,进而改变IL-2与其受体的结合能力或亲和力,但能保留生物学活性。本发明的IL-2突变体能够刺激调节性T细胞(Treg)增殖,并且相比于野生型IL-2,其副作用还显著降低,从而能够实现更好的治疗目的。
本发明的IL-2突变体优选用真核细胞表达,通过细胞培养获得。可以选择酵母,昆虫细胞,动物细胞,也可以选择转基因动物。在具体的实施方式中,所述宿主细胞为真核细胞;优选酵母、昆虫细胞、动物细胞;动物细胞优选哺乳动物细胞,包括但不限于CHO细胞、293细胞、SP/20细胞、NS0细胞。任选地,本发明的IL-2突变体可选无细胞表达,体外合成等技术手段获得。
当采用酵母细胞或昆虫细胞作为宿主细胞时,可能得到的IL-2突变体的糖型是非人的。本领域技术人员知晓可以进一步将非人糖型改造成人糖型。
在其它实施方式中,也可以使用原核细菌表达发酵或体外无细胞合成获得IL-2突变体。
本发明的IL-2突变体是在对应于野生型IL-2的第90位发生突变。因此,在具体的实施方式中,本发明的IL-2突变体在对应于野生型IL-2蛋白的90位发生以下氨基酸残基突变:N90A、N90G、N90V、N90I、N90M、N90L、N90F、N90Y、N90W、N90H、N90R、N90K、N90Q、N90D、N90E、N90P、N90T、N90B、N90C、N90S、N90Z和N90I;优选N90T、N90S、N90V、N90I、N90M、N90L;更优选N90T、N90S;最优选N90T。
基于本领域的常规作法,也可以消除IL-2多肽中原有的O-糖位点,去除O糖不影响IL-2生物学活性,O糖结构复杂,分析困难,为了减少生产质控的复杂性,通常可以利用基因工程突变技术消除该糖基化位点。因此,本发明的IL-2突变体可以在对应于野生型IL-2蛋白的3位发生以下氨基酸残基突变:T3A、T3G、T3Q、T3E、T3N、T3D、T3R、T3K和T3P;优选T3A。在IL-2基因产物的提纯和复性过程中,如二硫键配错或分子间形成二硫键都会降低IL-2的活性。现已有应用点突变,将第125号位半胱氨酸突变为亮氨酸或丝氨基,使只能形成一种二硫键,保证了在IL-2复性过程的活性。还有报道用蛋白工程技术生产新型rIL-2,将IL-2分子第125位半胱氨酸改为丙氨酸,改构后IL-2比活性比天然IL-2明显增加。因此,本发明的IL-2突变体可以在对应于野生型IL-2蛋白的125位发生以下氨基酸残基突变:C125L、C125A、C125S;优选C125S。
“对应于”
本文所用的术语“对应于”具有本领域普通技术人员通常理解的意义。具体地说,“对应于”表示两条序列经同源性或序列相同性比对后,一条序列与另一条序列中的指定位置相对应的位置。因此,例如,“对应于野生型IL-2”表示将某条氨基酸序列与野生型IL-2的氨基酸序列进行比对,找到该氨基酸序列上与野生型IL-2相对应的位点。
本发明的融合蛋白或缀合物
基于本发明的IL-2突变体,本领域技术人员知晓可以将本发明的IL-2突变体与非IL-2的其它功能部分制成融合蛋白或缀合物。在本文中,缀合物是指一种水溶性聚合物共价连接突变体IL-2多肽的残基。在具体的实施方式中,所述非IL-2功能部分包括但不限于:Fc片段、人血清白蛋白(HSA)、抗HSA抗体及片段、转铁蛋白、人绒毛膜促性腺激素β亚基羧基末端肽(CTP)、类弹性蛋白多肽(elastin-like peptide,ELP)和抗原结合部分,还包括细胞因子,具体为白细胞介素、干扰素、肿瘤坏死因子超家族、集落刺激因子、趋化因子、生长因子等。
基于本领域的常规操作,本领域技术人员知晓如何获得包含本发明的IL-2突变体的融合蛋白或缀合物。例如,可以将本发明的IL-2突变体与其它非IL-2功能部分直接连接,也可以通过连接物连接。所述连接物可以是AAA或GS的重复序列,包括但不限于G3S的重复序列或G4S的重复序列;例如(G3S)4。
进一步地,还可以对所述IL-2突变体或融合蛋白缀合物聚乙二醇修饰(PEG化)、聚唾液酸化修饰(PSA化)、饱和脂肪酸修饰、透明质酸修饰(Hyaluronic acid,HA)或聚氨基酸修饰(proline-alamine-serine polymer,PAS化)形成缀合物。
本发明的双特异性抗体或三特异性抗体
疾病的发生通常由多种致病因素导致,对多个靶点同时进行阻断可能会实现更好的治疗效果,因此双特异性抗体(bispecific antibody,BsAb)应运而生。肿瘤免疫疗法是目前治疗肿瘤的新方向。双特异性抗体可结合两种不同的抗原,因而在肿瘤治疗领域的开发前景十分广阔。双特异性抗体最初是利用化学偶联法或杂交瘤杂交法来制备。如今,DNA重组技术的迅速发展使得双特异性抗体的结构发生了革命性变化,主要分为含有Fc区的IgG型和不含Fc区的非IgG型两大类。IgG型双特异性抗体的结构与单克隆抗体类似,蛋白相对分子质量较大,血浆半衰期长。非IgG型双特异性抗体的结构形式更加多样,蛋白相对分子质量较小,组织渗透性更强,但血浆半衰期较短。
基于本发明的IL-2突变体,本领域技术人员知晓可以将本发明的IL-2突变体与抗体结构域共价连接。在具体的实施方式中,所述抗体结构域包括但不限于:IgG型抗体和非IgG型抗体。在优选的实施方式中,所述抗体结构域可以是抗体或其活性抗体片段,Fab分子、scFv分子和VHH分子、免疫球蛋白分子、受体蛋白分子或配体蛋白分子;所述免疫球蛋白分子可以是IgG分子。
基于本领域的常规操作,本领域技术人员知晓如何获得包含本发明的IL-2突变体的双特异性抗体。例如,可以将本发明的IL-2突变体与其它非IL-2功能部分直接连接,也可以通过连接物连接。所述连接物可以是AAA或GS的重复序列,包括但不限于G3S的重复序列或G4S的重复序列;例如(G3S)4。
任选的本发明的突变体可以与T细胞表面抗原抗体进行偶连,还可以与肿瘤细胞表面抗原抗体进行偶连。优选地,本发明的突变体可以与T细胞表面抗原抗体偶连。
任选的本发明的突变体可以与T细胞表面抗原抗体进行偶连,形成双特异性抗体,还可以与肿瘤细胞表面抗原抗体进行偶连,形成双特异性抗体。任选的本发明的突变体可以与T细胞表面抗原抗体进行偶连,形成三特异性抗体,还可以与肿瘤细胞表面抗原抗体进行偶连,形成三特异性抗体。任选的本发明的突变体可以与T细胞表面抗原抗体或肿瘤细胞表面抗原抗体进行偶连,形成三特异性抗体。
本发明的药物组合物及其给药方式
在本发明的IL-2突变体的基础上,本发明还提供了药物组合物。在具体的实施方式中,本发明的药物组合物包含本发明的IL-2突变体或权利要求5所述的融合蛋白或缀合物或权利要求7所述的双特异性抗体或三特异性抗体以及任选的药学上可接受的辅料。
任选地,本发明的组合物进一步包含一种药学上可接受的赋形剂。如果希望的话,可以添加药学上可接受的赋形剂到本发明的IL-2突变体多肽、融合蛋白或缀合物、双特异性抗体或三特异性抗体中以形成一种组合物。
本发明的IL-2突变体的用途以及使用方法
如上所述,本发明的IL-2突变体能够降低突变体IL-2蛋白对中等亲和力IL-2受体的亲和力,同时保留了IL-2的生物学活性,从而更好地刺激调节性T细胞(Treg)增殖。因此,本发明的IL-2突变体、融合蛋白、缀合物、双特异性抗体或三特异性抗体、药物组合物可以制备成相应的药物。所述药物可以用于体外扩增调节性T细胞(Treg)或治疗利用IL-2作免疫治疗的疾病。在具体的实施方式中,所述疾病是系统性红斑狼疮(SLE)、自身免疫性疾病、糖尿病、人类免疫缺陷病毒HIV感染、丙型肝炎病毒HCV感染、风湿性关节炎,特应性皮炎等。
本发明的优点:
1.本发明的IL-2突变体蛋白降低了与IL-2Rβγ二聚体的结合。
2.本发明的IL-2突变体的结构与天然IL-2更接近,避免了突变对蛋白其它结构位点的影响,保留了生物学活性;
3.本发明的白介素2突变体蛋白可以用于自身免疫性疾病的治疗,但没有利用天然IL-2进行免疫治疗产生的各种副作用。
4.相比于现有技术中的其它IL-2突变体,本发明的IL-2突变体的免疫原性更低;
5.本发明的IL-2突变体便于生产和质量控制,一般不需要体外再修饰的过程,减少步骤提高生产效率;
6.本发明的IL-2突变体便于与其它分子组成双功能或多功能的融合蛋白或免疫组合物;
7.本发明的IL-2突变体可以用于免疫治疗,但不会导致天然IL-2导致的血管(或毛细管)渗漏综合征(VLS);和
8.本发明的IL-2突变体的体内半衰期显著延长。
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。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。
实施例
实施例1.突变体白介素-2(IL-2)蛋白的合成
通过分子克隆手段分别将包括人IgG4Fc编码序列的IL-2突变体IL-2-gmB2-hIgG4Fc(SEQ ID NO:1)及野生型IL2-N-hIgG4Fc(SEQ ID NO:2)的编码序列构建至真核表达载体中以制备IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc表达载体。使用Freestyle培养基培养的293E细胞进行IL-2突变体分子的瞬时转染表达。转染前24小时,在1L细胞培养瓶中接种0.5×106细胞/ml的293E细胞150ml,37℃5%CO2温箱中120rpm摇床培养。转染时先取150μl的293fectin加入到2.85ml的OptiMEM中,充分混匀后,室温孵育2分钟;同时分别将用于表达IL-2分子的质粒150μg使用OptiMEM稀释至3ml。将上述稀释后的转染试剂及质粒充分混合,室温孵育15分钟,然后将混合物全部加入细胞中,混匀,37℃5%CO2温箱中120rpm摇床培养7天。收集细胞培养上清,将上清用0.22微米的滤膜过滤,然后利用Q-HP离子交换层析柱(GE)进行纯化,利用20mM Tris 0-500mM NaCl,pH 8.0线性洗脱,按体积连续收集样品。利用4~20%梯度胶(金斯瑞公司)进行SDS-PAGE检测各收集组分,并根据电泳纯度进行合样。
突变个数 | 突变位点 | 实施例突变体名称 | 蛋白标签 | 序列 |
2 | 90 | IL-2gmB2(T3A,N90T) | IgG4Fc | SEQ ID NO:1 |
实施例2.受体蛋白的制备
为研究IL-2突变体分子与IL-2Rα受体及IL-2Rβγ异源二聚化受体的结合能力,制备了人源的IL-2Rα受体及IL-2Rβγ异源二聚化受体蛋白。
人源IL-2Rα受体的设计为将IL-2Rα胞外结构域编码序列与6×His Tag编码序列相连(SEQ ID NO:3),克隆至真核表达载体中。使用Freestyle培养基培养的293E细胞进行IL-2Rα受体的瞬时转染表达。转染前24小时,在1L细胞培养瓶中接种0.5×106细胞/ml的293E细胞150ml,37℃5%CO2温箱中120rpm摇床培养。转染时先取150μl的293fectin加入到2.85ml的OptiMEM中,充分混匀后,室温孵育2分钟;同时将用于表达IL-2Rα受体的质粒150μg使用OptiMEM稀释至3ml。将上述稀释后的转染试剂及质粒充分混合,室温孵育15分钟,然后将混合物全部加入细胞中,混匀,37℃5%CO2温箱中120rpm摇床培养7天。收集细胞培养上清,将上清用0.22微米的滤膜过滤,然后利用Ni-NTA亲和层析柱(GE)进行纯化,在20mMPB-0.5M NaCl-100mM咪唑条件下洗脱。利用4~20%梯度胶(金斯瑞公司)进行SDS-PAGE检测纯化蛋白质。
人源IL-2Rβγ异源二聚化受体的设计利用CH1和CL配对的特性完成异源配对。hIL2Rβ(SEQ ID NO:4)和hIL2Rγ(SEQ ID NO:5),分别克隆至真核表达载体中。使用Freestyle培养基培养的293E细胞进行IL-2Rβγ异源二聚化受体的瞬时转染表达。转染前24小时,在1L细胞培养瓶中接种0.5×106细胞/ml的293E细胞150ml,37℃5%CO2温箱中120rpm摇床培养。转染时先取150μl的293fectin加入到2.85ml的OptiMEM中,充分混匀后,室温孵育2分钟;同时将用于表达IL-2Rβγ异源二聚化受体(命名:hIL2Rβ,γECD-His)的质粒各75μg使用OptiMEM稀释至3ml。将上述稀释后的转染试剂及质粒充分混合,室温孵育15分钟,然后将混合物全部加入细胞中,混匀,37℃5%CO2温箱中120rpm摇床培养7天。收集细胞培养上清,将上清用0.22微米的滤膜过滤,然后利用MabSelect SuRe亲和层析柱(GE)进行纯化,在20mM枸橼酸-枸橼酸纳,pH3.0条件下洗脱,用1M Tris base调节pH至中性。利用4~20%梯度胶(金斯瑞公司)进行SDS-PAGE检测纯化蛋白质。
实施例3.利用biacore检测结合受体的亲和力实验
为研究IL-2突变体相对于野生型与受体的亲和力,在以下条件下使用重组单体IL-2Rα亚基通过Biacore 8K(GE)测定IL-2突变体分子IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc对人IL-2Rα亚基的亲和力:将人IL-2Rα亚基固定化于CM5芯片上(190RU)。在25℃在HBS-EP缓冲液中将IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc用作分析物。对于IL-2Rα,分析物浓度为200nM降至1.526nM(1:2稀释),流动为30μl/分(结合时间180秒,解离时间300秒)。对于IL-2Rα,再生用20mM NaOH,30ul/min进行10秒。对于IL-2Rα,使用1:1结合,RI≠0,R最大值=全局拟合数据。
结果如图1所示;其中IL-2-gmB2-hIgG4Fc的R最大值为25,IL2-N-hIgG4Fc的R最大值为25。因此,相对于野生型IL2-N-hIgG4Fc,IL-2-gmB2-hIgG4Fc保留了与IL-2Rα二聚体的亲和力。
在以下条件下使用重组hIL2Rβ,γECD-His异二聚体通过Biacore 8K(GE)测定IL-2突变体分子IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc对人IL-2Rβγ异二聚体的亲和力:将IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc固定化于Protein A芯片上(100RU)。25℃在HBS-EP缓冲液中将重组hIL2Rβ,γECD-His异二聚体用作分析物。对于IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc,分析物浓度为100nM降至0.78nM(1:2稀释),流动为30μl/分(结合时间180秒,解离时间300秒)。对于IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc,再生用10mM Glycine(pH 1.5),30ul/min,30秒。对于IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc,使用1:1结合,RI≠0,R最大值=局部拟合数据。
结果如图2所示;其中IL-2-gmB2-hIgG4Fc的R最大值为1.7,IL2-N-hIgG4Fc的R最大值为4.0。如图2所示,IL-2-gmB2-hIgG4Fc相对于野生型IL2-N-hIgG4Fc降低了与IL-2Rβγ二聚体的亲和力。因此,IL-2-gmB2-hIgG4Fc相对于野生型IL2-N-hIgG4Fc保留了与IL-2Rα的亲和力并降低了与IL-2Rβγ二聚体的亲和力。
实施例4.利用NK92细胞进行细胞增殖分析
NK92细胞是一株从一位患有急进性非霍奇金淋巴瘤的50岁白人男性外周血单核细胞衍生来的IL-2依赖型NK细胞株。其细胞表面表达IL-2受体α、β和γ链,该细胞表面标志物与调节性T细胞表面标志物相同。因此,本发明人利用NK92细胞在细胞增殖分析中评估IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc的活性。
收获处于对数生长期的NK92细胞,用基础培养基MEM-α清洗一遍,将其(5000个/孔)与不同浓度的IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc在实验培养基(来自Gibco(货号32561-037)的MEM-α培养基,添加12.5%胎牛血清和12.5%的马血清)中,于37℃、5%二氧化碳培养箱中共培养48h。每孔加入100μl ATP检测底物CellTiter-Glo(来自promega(货号G7571)),于酶标仪(购自Molecular Devices(型号I3x))下终点法检测全波长荧光值。
结果如图3所示;采用细胞增殖分析测量IL-2-gmB2-hIgG4Fc及野生型IL2-N-hIgG4Fc的活性,发现所有测试品均以剂量依赖性方式诱导NK92细胞生长。因此,相对于野生型IL2-N-hIgG4Fc,IL-2-gmB2-hIgG4Fc保留了生物学活性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海盖浦生物科技有限公司
<120> 一种增殖调节性T细胞的突变体蛋白
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Claims (10)
1.一种IL-2突变体,所述IL-2突变体在对应于野生型IL-2的第90位氨基酸残基发生突变。
2.如权利要求1所述的IL-2突变体,其特征在于,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90A、N90G、N90V、N90I、N90M、N90L、N90F、N90Y、N90W、N90H、N90R、N90K、N90Q、N90D、N90E、N90P、N90T、N90B、N90C、N90S、N90Z、N90I;
优选地,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90T、N90S、N90V、N90I、N90M、N90L;
更优选地,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90T、N90S;
最优选地,所述IL-2突变体在对应于野生型IL-2的90位发生以下氨基酸残基突变:N90T。
3.如权利要求1或2所述的IL-2突变体,与野生型IL-2相比,其中所述IL-2突变体优先刺激T调节性细胞。
4.一种融合蛋白或缀合物,所述融合蛋白或缀合物包含权利要求1-3中任一项所述的IL-2突变体和非IL-2功能部分。
5.如权利要求4所述的融合蛋白或缀合物,其特征在于,所述非IL-2功能部分是Fc片段。
6.一种多核苷酸,所述多核苷酸编码权利要求1-3中任一项所述的IL-2突变体或权利要求4或5所述的融合蛋白或缀合物。
7.一种表达载体,所述表达载体包含权利要求6所述的多核苷酸。
8.一种宿主细胞,所述宿主细胞包含权利要求7所述的表达载体,或者所述宿主细胞的基因组整合有权利要求6所述的多核苷酸。
9.一种药物组合物,所述药物组合物包含权利要求1-3中任一项所述的IL-2突变体或权利要求4或5所述的融合蛋白或缀合物,以及药学上可接受的辅料。
10.权利要求1-3中任一项所述的IL-2突变体或权利要求4或5所述的融合蛋白或缀合物在制备用于治疗个体的疾病中的药物的用途。
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