CN108484774B - 一种SIRPα融合蛋白及其制备方法和用途 - Google Patents
一种SIRPα融合蛋白及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种SIRPα融合蛋白及其制备方法和用途，该融合蛋白包含：SIRPα的V结构域，以及具有效应子功能的Fc段；所述的V结构域包含：氨基酸序列SEQ ID No.1；所述的Fc段包含：人体IgG1或IgG4抗体的恒定区。本发明的融合蛋白增强了SIRPα与CD47的亲和力、体内半衰期、以及Fc段介导的效应子功能，能够强烈地诱导巨噬细胞针对多种肿瘤细胞的吞噬作用。
Description
技术领域
本发明涉及一种融合蛋白，具体涉及一种SIRPα融合蛋白及其制备方法和用途。
背景技术
逃避免疫系统的杀伤作用是肿瘤的特征之一。近年来，利用机体原有的免疫反应对抗肿瘤逐渐成为新的治疗策略，根据不同机理疗法应用的时间先后排序，主要包括非特异性免疫刺激、免疫检验点单抗、过继细胞回输、单克隆T细胞受体疗法、CD47单抗、肿瘤疫苗等，无论在试验阶段还是在临床应用中都是最具前景的疗法之一。通常情况下，巨噬细胞可渗透到肿瘤体中，其抗肿瘤的效果可以被利用而使病人受益。
CD47也被称为整合素相关蛋白（Integrin Associated Protein，IAP），是免疫球蛋白超家族成员。CD47广泛的表达于细胞的表面，可与信号调节蛋白α（Signal RegulatoryProtein α, SIRPα）、血小板反应蛋白（Thrombospondin-1, TSP1），以及整合素（integrins）相互作用，介导凋亡、增殖、免疫等一系列的反应。
已有研究显示，CD47作为抗吞噬效应的“别吃我”信号分子，几乎所有的肿瘤细胞和组织都高表达CD47，且是对应正常细胞和组织的3倍，其可避免细胞被巨噬细胞识别与杀伤。另外，当采用抗体进行治疗时，CD47的表达也限制了Fc段受体介导的吞噬作用。
研究发现CD47直接与巨噬细胞表面调节性糖蛋白SIRPα结合而发挥对肿瘤的保护功能。SIRPα作为抑制性受体，与CD47交互作用时，负向调节巨噬细胞的骨架强度，减弱其吞噬能力。SIRP α胞外结构域与CD47结合，通过胞内区域传递信号，其NH2端V型结构参与CD47结合的调控。
目前，抗CD47治疗的临床前研究涵盖了非霍奇金淋巴瘤（Anti-CD47 antibodysynergizes with rituximab to promote phagocytosis and eradicate non-Hodgkinlymphoma[J]. Cell, 2010, 142(5): 699-713）、乳腺癌（The CD47-signal regulatoryprotein alpha (SIRPα) interaction is a therapeutic target for human solidtumors[J]. Proc Nat Acad Sci U S A, 2012, 109(17): 6662-6667）、卵巢癌（In vitroapplication of anti-CD47 monoclonal antibody for targeted therapy of ovariancancer[J]. Chinese Journal of Clinical Oncology, 2013, 40(8): 440-443）、非小细胞肺癌（CD47-blocking immunotherapies stimulate macrophage-mediateddestruction of small-cell lung cancer[J]. J Clin Invest, 2016, 126(7): 2610-2620）等多种肿瘤。
目前，已经有相关的抗-CD47抗体药物进入临床Ⅰ期研究，Hu5F9-G4是Forty Seven公司研发的一种抗-CD47的单克隆抗体，其对CD47具有较好的亲和力(nM级别)。
而且，美国斯坦福大学医学院的研究人员临床前试验中发现在接受儿童脑癌细胞移植的模式小鼠体内，一种导致巨噬细胞吞噬和吃掉肿瘤细胞同时不伤害健康脑细胞的抗体能够安全地和有效地治疗5种儿童脑癌类型，相关研究结果发表在ScienceTranslational Medicine期刊上（Disrupting the CD47-SIRPα anti-phagocytic axisby a humanized anti-CD47 antibody is an efficacious treatment for malignantpediatric brain tumors, Science Translational Medicine 15 Mar 2017, Vol. 9,Issue 381）。令人鼓舞地，Hu5F9-G4对正常的人脑细胞没有毒性，但是具有非常非常有效的肿瘤杀伤性。
大量研究显示，采用抗体或通过基因工程修饰SIRPα，都可以阻断CD47-SIRPα的结合，从而极大地提高对肿瘤细胞的吞噬作用。然而，由于抗体在组织间的分布有限，并且Fc段也会介导脱靶效应，SIRPα作为靶点将更具吸引力。
但是，目前的SIRPα分子设计尚存在有效性、安全性与生产成本等局限性。
发明内容
本发明的目的是提供一种SIRPα融合蛋白及其制备方法和用途，该融合蛋白增强了SIRPα与CD47的亲和力、体内半衰期、以及Fc段介导的效应子功能，能够强烈地诱导巨噬细胞针对多种肿瘤细胞的吞噬作用，同时降低了生产成本。
为了达到上述目的，本发明提供了一种SIRPα融合蛋白，该融合蛋白包含：SIRPα的V结构域，以及具有效应子功能的Fc段；所述的V结构域包含：氨基酸序列SEQ ID No.1；所述的Fc段包含：人体IgG1或IgG4抗体的恒定区。
所述的人体IgG1抗体的恒定区包含：氨基酸序列SEQ ID No.2。
所述的人体IgG4抗体的恒定区包含：氨基酸序列SEQ ID No.3。
该融合蛋白包含：氨基酸序列SEQ ID No.4。
该融合蛋白包含：氨基酸序列SEQ ID No.5。
该融合蛋白包含：两个IgG1串联或两个IgG4 Fc串联的结构域。
该融合蛋白包含：氨基酸序列SEQ ID No.6。
该融合蛋白包含：氨基酸序列SEQ ID No.7。
所述的Fc段含有Ser228Pro突变。Ser228Pro突变能够抑制抗体链交换。 IgG4抗体是能够经历称为Fab臂交换（FAE）的过程的动态分子，这导致功能性单价双特异性抗体（bsAb）具有未知特异性，因此潜在地降低治疗功效，S228P突变可以阻止IgG4 FAE。
本发明还提供了一种根据所述的SIRPα融合蛋白的制备方法，该方法包含：将表达SIRPα融合蛋白的核苷酸序列克隆到表达载体中，该表达载体包含一个Leader序列，通过PCR技术合成所述的SIRPα融合蛋白。其中，在哺乳动物表达结构的N端设计了一个leader序列，以确保适当的与分泌相关的信号转导与加工。
所述的表达载体包含：表达CMVa-intron启动子的哺乳动物表达载体，或在T7启动子和Lac Operator下的细菌表达载体。
本发明还提供了一种表达载体，该表达载体包含如所述的SIRPα融合蛋白的核苷酸序列。
本发明还提供了一种宿主细胞，该宿主细胞含有如所述的表达载体；该宿主细胞为哺乳动物或细菌来源的细胞。
优选地，哺乳动物宿主细胞为能糖基化表达蛋白的细胞。
优选地，所述的细菌包含：大肠杆菌。当该重组SIRPα-Fc融合蛋白由大肠杆菌表达时，仍保留其与CD47较强的亲和力与诱导肿瘤细胞的吞噬作用，同时显著降低生产费用。
本发明还提供了一种免疫治疗药物组合物，该药物组合物包含：如所述的SIRPα融合蛋白，以及其药学上可接受的载体；该药物能够抑制癌细胞生长或增殖。本发明的“药学上可接受的载体”是指使适用于与人和动物组织接触且不造成过度毒性、刺激、过敏反应或其它问题或并发症的载体和赋形剂，其具有合理的益处/风险比。
所述的癌细胞包含：胃癌细胞。
本发明的SIRPα融合蛋白及其制备方法和用途，具有以下优点：
本发明的SIRPα融合蛋白由SIRPα蛋白成分与抗体恒定区（Fc）融合组成，其增强了SIRPα与CD47的亲和力、体内半衰期、以及Fc段介导的效应子功能，能够强烈地诱导巨噬细胞针对多种肿瘤细胞的吞噬作用，尤其对胃癌具有很好的吞噬作用，同时本发明的制备方法降低了生产成本。
附图说明
图1为本发明的SIRPα融合蛋白的结构示意图。
图2为本发明的SIRPα-lgG4-Fc融合蛋白进行IP-WB实验的蛋白印迹图。
图3为使用直接结合测定法比较三种SIRPα融合蛋白与CD47结合的亲合力结果图。
图4为巨噬细胞在10nM对照IgG4 Fc蛋白存在下与Raji细胞共孵育2小时后镜下图像。
图5为巨噬细胞在10nM SIRPα-lgG4-Fc融合蛋白存在下与Raji细胞共孵育2小时后镜下图像。
图6为本发明的SIRPα-lgG4-Fc融合蛋白诱导Raji细胞吞噬效应的剂量关系图。
图7为巨噬细胞在10nM SIRPα-lgG4-Fc融合蛋白存在下与癌细胞共培养2小时的吞噬效应统计图。
图8为比较三种SIRPα融合蛋白诱导Raji细胞吞噬效应的剂量关系图。
具体实施方式
以下结合附图和实验例对本发明的技术方案做进一步的说明，下述对融合蛋白的制备方法为示例性方法，并不为限制性的，其它现有技术也可实现其制备，这样的方法在本领域技术人员的知识范围内。
实验例1 本发明的SIRPα融合蛋白制备
如图1所示，为本发明的SIRPα融合蛋白的结构示意图，SIRPα-Fc和SIRPα-Fc-Fc融合蛋白是由人IgG1 Fc区（SEQ ID NO. 2）、人IgG4 Fc区（SEQ ID NO. 3）、人IgG1 Fc-Fc或人IgG4 Fc-Fc融合人SIRPα（SEQ ID NO. 1）的N端V结构域（可变区结构域）组成，获得融合蛋白。
其中，相同的人SIRPα结构域与含有阻止链内二硫键形成的铰链稳定S288P突变的人IgG4Fc区连接，获得含S288P突变的SIRPα-Fc（Fc为人IgG4 Fc）和SIRPα-Fc-Fc（Fc为人IgG4 Fc-Fc）融合蛋白，其序列分别见SEQ ID NO. 8和SEQ ID NO. 9。
上述所有的融合蛋白均通过使用标准分子生物学技术的重叠PCR产生合成DNA片段，然后将DNA片段克隆到表达载体中。而后，在稳定转染的CHO-S细胞（中国仓鼠卵巢悬浮细胞）中表达融合蛋白，或CHO-S细胞和细菌细胞中表达融合蛋白。最后，采用蛋白质A亲和色谱和疏水相互作用色谱以纯化融合蛋白，浓缩并除去残留的内毒素。
转染表达SIRPα融合蛋白的具体方法如下：
（1）在哺乳动物细胞中表达SIRPα融合蛋白
采用CHO-S细胞株（购自Invitrogen）生成稳定的转染子。用QIAGEN蛋白纯化柱对分离的质粒DNA进行线性化和纯化。
具体地，CHO-S细胞培养于8mM L -谷氨酰胺和lxht-补剂的无血清化学定义培养基（CD-CHO, Invitrogen），用Lipofectamine 2000试剂（购自Invitrogen）转入质粒DNA。在48小时后，这些细胞被转移到包含600μg /毫升的潮霉素B（表达载体）的介质中。经过2-3周的药物选择，使用ELISA检测耐药克隆的融合蛋白在上层清液中的Fc表达量，方法具体如下：
浓度0.1的捕捉抗体（山羊抗IgGFc）包被于96孔板，并在4°C孵育过夜。洗脱并用200μL 2% BSA PBST封闭和置于室温1小时。洗后，100μL样本用1% BSA在PBST中稀释，加至样品孔, 孵化1小时，洗净，然后用HRP-conjugated孵育检测Ab（HRP-耦合山羊抗人IgGFc），置于室温下1小时。于室温下清洗样品孔，加入TMB底物（3,3’,5,5’-四甲基联苯胺二盐酸，购自Moss Inc.），在室温下孵育3-5分钟。采用iMark微平板阅读器（Biorad）测量了450纳米/655纳米波长的吸光度，并利用已知的纯化融合蛋白构建了标准曲线。表达最高的克隆被用于上清批量生产。
蛋白纯化的具体步骤如下：
为了从CHO-S细胞中纯化融合蛋白，需要在滚瓶式生物反应器系统中从稳定转染的高表达细胞克隆体产生 5到10升的培养物上清液。
简言之，首先将CHO-S转染子在完全生长培养基（补充有8mM L-谷氨酰胺，1HT补充物和600xglmL潮霉素B的CD-CHO）在37℃下生长以产生足够的细胞数目到达0.5×106个细胞/ mL容量为1L或2L，然后分别放至生物反应器瓶，在37℃，10％CO2，摇摆速度15-20rpm，角度7°和空气流量0.2-0.4Lpm下孵育。当培养物达到2~2.5×106细胞/ mL（通常在接种2-3天内）的密度时，将生物反应器进一步放大至5L或10L，并在37℃，10％CO2下进一步温育，摇动速度15-20rpm，角度7°，气流量0.2-0.4Lpm。当细胞达到1至1.5×106个细胞/mL的密度时，将温度降至30℃，并在上述条件下再培养培养7至10天。从第0天开始，在30℃下，每两天向培养物中加入1％CHO饲料生物反应器补充物（Sigma），当细胞活力下降约90％时收获。收集上清液，在4℃以3000×g离心40分钟并在-20℃冷冻直至纯化。
蛋白质纯化需要通过两步程序：
首先，使用蛋白质A色谱法。先用结合缓冲液（20mM Na3PO4，1M NaCl，pH7.8）将缓冲液交换的上清液稀释9倍，并以2-3mL/分钟的流速加载到rProtein A柱子（GE Healthcare）上（取决于加样体积和加载时间），在4℃过夜。
然后，用结合缓冲液（3体积/分钟20体积）洗涤柱子，并以3mL /分钟用0.1M柠檬酸pH 4.0和pH 2.2洗脱蛋白质。用1M Tris-HCl（pH8.5）将洗脱物质pH调节至中性，然后用HiTrap Phenyl HP色谱纯化。简单讲，先用0.2M硫酸铵（pH 7.5）将蛋白质稀释至至少4倍，然后以2-3mL / min（取决于柱子大小和上样时间）加载到HiTrap Phenyl HP柱子（GEHealthcare）上。非聚集的SIRPaFc蛋白质可在流通部分收集。
最后，使用BioMax 10膜（Millipore）将SIRPα融合蛋白质浓缩并将溶液转换成pH7.4的PBS。通过SDS-PAGE，每种蛋白质的质量由 Western blots及HPLC分析确定。所有蛋白质的身份通过N末端测序和质谱确认。
（2）在细菌细胞中表达SIRPα融合蛋白
具体地，将细菌表达质粒转入BL21细胞（购自Novagen），稳定的克隆通过含有卡那霉素（50μg/mL）的选择性琼脂培养皿产生。将每个克隆生长在2ml LB培养基中，OD 0.6-0.8，37ºC，重组蛋白通过添加终浓度100μM 的IPTG（异丙基硫代半乳糖苷，Isopropyl β-D-Thiogalactoside）诱导生成。培养物于25ºC继续培养 4小时。菌团在1×Ranish缓冲液（30mM Tris-HCl，pH 7.5，10%的甘油，50 mm KCl，EDTA 1mM，2mM的 DTT；其中，EDTA为乙二胺四乙酸，DTT为二硫苏糖醇）于4ºC采用声波溶解。用可结合人Fc的抗体进行蛋白印迹法来检测融合蛋白的表达量。高表达克隆被用于大规模的蛋白质生产。
实验例2 本发明的SIRPα-lgG4-Fc融合蛋白与CD47结合作用
（1）本发明的SIRPα-lgG4-Fc融合蛋白与CD47结合的蛋白印迹实验
将不同浓度（等比升高，浓度为0.1nM、1nM、10nM、100nM）的上述纯化得到的融合蛋白与纯化CD47 蛋白（10ng，Abcam）和蛋白A琼脂糖珠在PBS溶液中混合，4度过夜，免疫复合物经离心沉淀后跑SDS-PAGE凝胶电泳。最后，用蛋白质印迹试验定量检测CD47 蛋白水平。其中，加入CD47的量直接作为对照。
如图2所示，为本发明的SIRPα-lgG4-Fc融合蛋白进行IP-WB实验的蛋白印迹图（IP，Immunoprecipitation，免疫沉淀实验；WB，Western Blotting，免疫印迹实验），可以看出随着本发明的SIRPα-lgG4-Fc融合蛋白的浓度增加，其与CD47结合的量越多。通过与CD47结合，肿瘤细胞不能通过CD47逃避吞噬细胞的吞噬作用，从而在吞噬细胞的吞噬下而消除。
（2）本发明的SIRPα融合蛋白与CD47结合的定量及对比实验
比较三种SIRPα Fc融合蛋白，包括：在哺乳动物细胞中产生的SIRPα-lgG4-Fc融合蛋白和SIRPα-lgG4-Fc-Fc融合蛋白，以及在细菌中产生的SIRPα-lgG4-Fc融合蛋白（图3中以SIRPα-lgG4-Fc-Bac表示），分别与纯化的CD47蛋白的亲合力，具体实验如下：
将与镍珠(Nickel beads)复合的纯化的CD47蛋白与不同浓度的SIRPα融合蛋白在冰上孵育1小时。 然后洗涤镍珠以去除任何未结合的蛋白质，并通过Western印迹分析定量结合的SIRPα融合蛋白。结合曲线和Kd值（Dissociation Constant，解离常数，反映了与蛋白质结合的小分子的解离速率，也直接决定蛋白质与小分子的亲合力）由Prism（Graphpad）使用非线性回归拟合数据到一个位点结合模型产生。
如图3所示，为使用直接结合测定法比较三种SIRPα融合蛋白与CD47结合的亲合力结果图，SIRPα-lgG4-Fc-Fc融合蛋白的Kd值（19.9±1.3nM）较SIRPα-lgG4-Fc融合蛋白的Kd值（37.4±4.0nM）小近2倍，结果证明SIRPα-lgG4-Fc-Fc融合蛋白与CD47的亲合力最强。
比较在哺乳动物细胞中产生的SIRPα-lgG4-Fc融合蛋白及在细菌中产生的SIRPα-lgG4-Fc融合蛋白分别与纯化的CD47蛋白的亲合力，如图3所示，在哺乳动物细胞中产生的SIRPα-lgG4-Fc 的Kd值为37.4nM, 在细菌中产生的SIRPα-lgG4-Fc的Kd值为46.9nM，结果表明两种融合蛋白与CD47的亲合力相当。
实验例3 本发明的SIRPα-lgG4-Fc融合蛋白对吞噬效应的体外诱导
（1）制备M1巨噬细胞
人M1巨噬细胞从正常健康人供体获得的单核细胞（人外周血单核细胞由StemCelltechnologies提供）制备。通过在补充有M-CSF（Macrophage Colony-Stimulating Factor，巨噬细胞集落刺激因子）（20ng/mL）的特殊分化培养基（由StemCell technologies提供）中培养，将单核细胞分化成巨噬细胞，具体步骤如下：
单核细胞经基于RPMI 1640的分化培养液培养6-10天分化为巨噬细胞。培养液添加成分如下：10% 热灭活的人AB 血清，1% GlutaMax，1% 青链霉素（购自GIBCO LifeTechnologies）。
在吞噬作用测定前一天，用IFN-γ（Interferon-γ，γ-干扰素）(100ng/mL)引发上述巨噬细胞全部极化为M1型巨噬细胞，具体吞噬作用检测方法如下：
取u型底96孔板超低密度培养的肿瘤细胞，活体染料CFSE（羟基荧光素二醋酸盐琥珀酰亚胺脂，Carboxyfluorescein Succinimidyl Amino Ester）标记。对照组每孔加入50微升IgG1（4微克/毫升），实验组加入 50微升SIRPα-lgG4-Fc融合蛋白（4微克/毫升），室温作用30分钟后，每孔加入50微升（50000个）巨噬细胞。96孔板置37度培养箱培养2个小时后，细胞固定，染色后，经荧光显微镜分析。原代人巨噬细胞用抗CD14、CD45，或CD206抗体（购自BioLegend）标记鉴定，死亡细胞用DAPI （购自Sigma，为4',6-二脒基-2-苯基吲哚，4',6-diamidino-2-phenylindole）检测鉴定。
吞噬功能评估：用荧光标记阳性的巨噬细胞比例作为吞噬作用功能的评估指标。
M1型巨噬细胞表现出很强的促炎及抗原提呈能力，对病原体和肿瘤细胞发挥宿主免疫清除功能，其可分泌大量促炎因子，如肿瘤坏死因子-α（tumornecrosis factor-α，TNF-α）。而且，M1型巨噬细胞通常通过分泌活性氧和氮中间体来杀死癌细胞，以及分泌TNF-α和IL-1β招募细胞毒性T淋巴细胞（cytotoxiclymphocyte，CTL）来攻击癌细胞。
（2）对Raji细胞的吞噬效应
用CellTrace CFSE（购自Invitrogen，是一种细胞增殖试剂盒）标记Raji细胞（淋巴瘤细胞），并以1:5的巨噬细胞：标记Raji细胞的比例将其加入到24孔板中的上述被引发极化的巨噬细胞中。将被引发极化的巨噬细胞和Raji细胞在SIRPα-lgG4-Fc融合蛋白或对照IgG4 Fc蛋白存在下于37℃在5％CO2中共培养2小时，随后用抗-CD45抗体染色。通过荧光显微镜观察吞噬作用，吞噬百分比计算如下：（M1巨噬细胞内的肿瘤细胞数量/ M1巨噬细胞数量）；每个样本（24孔板中的每个孔中的样本）计数至少200个M1巨噬细胞。
如图4所示，为巨噬细胞在10nM对照IgG4 Fc蛋白存在下与Raji细胞共孵育2小时后镜下图像，从图中可以看出并无吞噬效应。如图5所示，为巨噬细胞在10nM SIRPα-lgG4-Fc融合蛋白存在下与Raji细胞共孵育2小时后镜下图像，从图中可以看出巨噬细胞对Raji细胞的吞噬作用，表明本发明的SIRPα融合蛋白对吞噬作用有影响。如图6所示，为本发明的SIRPα-lgG4
-Fc融合蛋白诱导Raji细胞吞噬效应的剂量关系图，从图中可以看出，随着SIRPα-lgG4-Fc融合蛋白的剂量的不断增大，其不断诱导促进Raji细胞吞噬效应。
（3）不同癌细胞对吞噬作用的影响
来自不同癌症类型的癌细胞，如肺癌（H460细胞ATCC® HTB-177™、A549细胞ATCC®CCL-185™、H1299细胞ATCC® CRL-5803™）、结直肠癌（HCT116细胞ATCC® CCL-247™、SW480细胞ATCC® CCL-228™、Caco-2细胞ATCC® HTB-37™）、胃癌（ASG细胞ATCC® CRL-1739™、MKN1细胞CVCL_1415、N87细胞ATCC® CRL-5822™）、肝癌（HepG2细胞ATCC® HB-8065™、Hep3B细胞ATCC® HB-8064™、Huh7细胞CVCL_0336）、B细胞淋巴瘤（Raji细胞ATCC® CCL-86™），这些细胞均获自ATCC（美国菌种保藏中心），在10nM的SIRPa-Fc蛋白存在下与巨噬细胞于37℃在5％CO2中共培养2小时，随后用抗-CD45抗体染色。通过荧光显微镜观察吞噬作用，吞噬百分比由在荧光显微镜下计数而得。
如图7所示，为巨噬细胞在10nM SIRPα-lgG4-Fc融合蛋白存在下与癌细胞共培养2小时的吞噬效应统计图（Lung肺癌、Colorectal直肠癌、Gastric胃癌、Liver肝癌、Lym淋巴瘤），从图中可以看出，胃癌细胞对SIRPa-Fc蛋白介导的吞噬作用更敏感。
（4）比较三种SIRPα融合蛋白对Raji细胞的吞噬效应
比较三种SIRPα融合蛋白，包括：在哺乳动物细胞中产生的SIRPα-lgG4-Fc融合蛋白和SIRPα-lgG4-Fc-Fc融合蛋白，以及在细菌中产生的SIRPα-lgG4-Fc融合蛋白，分别对癌细胞的吞噬效应。
如图8所示，为比较三种SIRPα融合蛋白诱导Raji细胞吞噬效应的剂量关系图，巨噬细胞在不同浓度的三种SIRPα融合蛋白存在下与Raji细胞共孵育2小时后对Raji细胞的吞噬效应的结果表明，SIRPα-lgG4-Fc-Fc融合蛋白比SIRPα-lgG4-Fc的吞噬作用大近一倍，哺乳动物细胞中产生的SIRPα-lgG4-Fc融合蛋白和在细菌中产生的SIRPα-lgG4-Fc融合蛋白对癌细胞的吞噬效应相当。
一般情况下，本发明的SIRPα融合蛋白在使用时其有效剂量为0.05mg/kg至5mg/kg，其使用量需根据具体情况确定，如待治疗的肿瘤的类型、患者的总体健康状况、抗体的体内效力、药物制剂和给药途径等。本发明的“有效剂量”是指可对受试者产生功能或活性的且可被受试者所接受的量。
综上所述，本发明的SIRPα融合蛋白及其制备方法和用途，该融合蛋白增强了SIRPα与CD47的亲和力、体内半衰期、以及Fc段介导的效应子功能，能够强烈地诱导巨噬细胞针对多种肿瘤细胞的吞噬作用。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。
序列表
<110> 上海高菲生物科技有限公司
<120> 一种SIRPα融合蛋白及其制备方法和用途
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Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala
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Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
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Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
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Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
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Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
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Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
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Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
565 570 575
Leu Ser Leu Ser Pro Gly Lys
580
<210> 7
<211> 577
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala
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Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Ile Pro
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Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu
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Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly
115 120 125
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
130 135 140
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
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Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
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Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
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Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
195 200 205
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
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Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
225 230 235 240
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
245 250 255
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
260 265 270
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
275 280 285
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
290 295 300
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
305 310 315 320
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
325 330 335
Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
340 345 350
Ser Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
355 360 365
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
370 375 380
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
385 390 395 400
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
405 410 415
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
420 425 430
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
435 440 445
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
450 455 460
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
465 470 475 480
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
485 490 495
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
500 505 510
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
515 520 525
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
530 535 540
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
545 550 555 560
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570 575
Lys
<210> 8
<211> 338
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ala Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
115 120 125
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
130 135 140
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
145 150 155 160
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
165 170 175
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
180 185 190
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
195 200 205
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
210 215 220
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
225 230 235 240
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
245 250 255
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
260 265 270
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
275 280 285
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
290 295 300
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
305 310 315 320
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
325 330 335
Gly Lys
<210> 9
<211> 577
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
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20 25 30
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50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
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115 120 125
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130 135 140
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
145 150 155 160
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165 170 175
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180 185 190
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195 200 205
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225 230 235 240
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
245 250 255
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
260 265 270
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
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290 295 300
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
305 310 315 320
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325 330 335
Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
340 345 350
Ser Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
355 360 365
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
370 375 380
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
385 390 395 400
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
405 410 415
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
420 425 430
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
435 440 445
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
450 455 460
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
465 470 475 480
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
485 490 495
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
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Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
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Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
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Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
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Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
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Lys
Claims (4)
1.一种SIRPα融合蛋白，其特征在于，该融合蛋白包含：SIRPα的V结构域，以及具有效应子功能的Fc段；
所述的V结构域包含：氨基酸序列SEQ ID No.1；
所述的Fc段包含：人体IgG4抗体的恒定区，且该Fc段含有Ser228Pro突变；
该融合蛋白包含：两个IgG4 Fc串联的结构域；
其中，该融合蛋白包含：氨基酸序列SEQ ID No.7。
2.一种根据权利要求1所述的SIRPα融合蛋白的制备方法，其特征在于，该方法包含：将表达SIRPα融合蛋白的核苷酸序列克隆到表达载体中，该表达载体包含一个Leader序列，通过PCR技术合成所述的SIRPα融合蛋白；所述的表达载体包含：表达CMVa-intron启动子的哺乳动物表达载体，或在T7启动子和Lac Operator下的细菌表达载体。
3.一种宿主细胞，其特征在于，该宿主细胞含有：具有如权利要求1所述的SIRPα融合蛋白的核苷酸序列的表达载体；该宿主细胞为哺乳动物或细菌来源的细胞；所述的细菌包含：大肠杆菌。
4.一种免疫治疗药物组合物，其特征在于，该药物组合物包含：如权利要求1所述的SIRPα融合蛋白，以及其药学上可接受的载体；该药物能够抑制癌细胞生长或增殖；所述的癌细胞包含：胃癌细胞。
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| CN109517054B (zh) * | 2018-12-04 | 2022-04-08 | 江苏东抗生物医药科技有限公司 | SIRPα变体或其融合蛋白及其应用 |
| CN109535263B (zh) * | 2018-12-04 | 2022-06-17 | 江苏东抗生物医药科技有限公司 | SIRPα突变体及其融合蛋白 |
| CN111484558B (zh) * | 2019-01-28 | 2023-02-17 | 上海交通大学 | 信号调节蛋白α片段-抗FcRn单链抗体融合蛋白及其制备与应用 |
| CN111909276A (zh) * | 2019-05-10 | 2020-11-10 | 复旦大学 | 一种融合蛋白及其用途 |
| CN111087473B (zh) * | 2019-12-11 | 2022-06-14 | 上海百英生物科技有限公司 | 一种SIRPa-Fc-IL21融合蛋白及其应用 |
| CN111253482B (zh) * | 2020-02-18 | 2021-11-30 | 中国人民解放军军事科学院军事医学研究院 | SIRPa变体、融合蛋白、及其应用 |
| EP4434999A1 (en) * | 2021-11-19 | 2024-09-25 | Hangzhou Sumgen Biotech Co., Ltd. | Sirp? variant and use thereof |
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| CN107252476A (zh) * | 2009-05-15 | 2017-10-17 | 大学健康网络 | 化合物用于治疗患者体内的cd47+癌细胞或肿瘤的用途 |
| RS60606B1 (sr) * | 2012-01-17 | 2020-08-31 | Univ Leland Stanford Junior | Reagensi sirp-alfa visokog affiniteta |
| EP4116331A1 (en) * | 2012-12-17 | 2023-01-11 | PF Argentum IP Holdings LLC | Treatment of cd47+ disease cells with sirp alpha-fc fusions |
| WO2018026600A1 (en) * | 2016-08-03 | 2018-02-08 | The Board Of Trustees Of The Leland Stanford Junior University | Disrupting fc receptor engagement on macrophages enhances efficacy of anti-sirpalpha antibody therapy |
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| WO2016169261A1 (zh) * | 2015-04-24 | 2016-10-27 | 宜明昂科生物医药技术（上海）有限公司 | 一种新的重组双功能融合蛋白及其制备和应用 |
| WO2018014067A1 (en) * | 2016-07-19 | 2018-01-25 | Teva Pharmaceuticals Australia Pty Ltd | Anti-cd47 combination therapy |
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