CN110691613B - 增强免疫反应的组合物及方法 - Google Patents
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Abstract
本发明提供一种医药组合物,包含一抗原融合蛋白,该抗原融合蛋白包含一抗原及一Fcγ受体拮抗分子。本发明亦提供一种增强抗原的免疫原性的方法,包含将该抗原与一Fcγ受体拮抗分子相连接以形成一抗原融合蛋白。本发明亦提供一种增强个体对一抗原的免疫反应的方法,包含施予该个体有效量的一包含抗原及Fcγ受体拮抗分子的抗原融合蛋白。本发明可应用于开发强效疫苗,此基于通过与Fcγ受体结合而将疫苗抗原靶向至抗原呈献细胞。
Description
相关专利申请的交叉引用
本发明申请案主张2017年1月3日所提交的临时申请案No.62/441,682之优先权,其全部内容皆可引用并合併于此。
技术领域
本发明关于一种增强免疫反应的组合物及方法。具体而言,本发明关于利用含有抗原和Fcγ受体拮抗分子的抗原融合蛋白来增强免疫反应的一种医药组合物及方法。
背景技术
疫苗抗原的免疫原性(immunogenicity)是疫苗开发的主要关注点,因为疫苗预防或治疗疾病的潜力高度依赖疫苗抗原有效诱发免疫反应的能力。增加疫苗免疫原性的一种常用策略是将佐剂(adjuvant)加入疫苗制剂。佐剂是种类多样的免疫增强物质,其作用经由多种机制,包含延长抗原由注射部位释放的时间,为抗原穿越淋巴系统的运输提供载体,及作为免疫刺激物。尽管佐剂能有效增强免疫反应,许多佐剂可能造成不欲意的过敏反应(hypersensitivity)。
有效诱发免疫反应的替代方案是直接刺激抗原呈献细胞(antigen-presentingcells)。周边组织中的专职抗原呈献细胞会捕获及处理抗原、表现淋巴细胞的共刺激分子(co-stimulatory molecules)、迁移至淋巴器官、并分泌细胞激素以启动免疫反应。树突细胞(dendritic cells)是最有效的抗原呈献细胞,其在后天性免疫反应(adaptive immuneresponse)的起始过程中发挥关键作用,导致初生细胞(CD4+或CD8+T细胞)分化为作用(effector)细胞(辅助性或细胞毒杀性T细胞),且进一步调节体液性免疫反应(humoral immune response)。这些特征使得树突细胞成为免疫调节策略的主要目标。
抗原呈献细胞表现多种Fcγ受体(FcγR),其调节抗原-抗体复合物(也称为免疫复合物)的内化并且调控免疫反应。FcγR依据其功能分为如FcγRI、FcγRIIA、FcγRIII、FcγRIV的活化性受体,以及如FcγRIIB的抑制性受体。先前报导显示免疫复合物通过与树突细胞的FcγR接合而有效诱发免疫反应。然而,在疫苗开发过程中使用免疫复合物花费甚巨,因为抗体及相关免疫复合物的制备既昂贵又复杂。
因此,开发一种不使用免疫复合物而将抗原靶向抗原呈献细胞以增强抗原专一性免疫反应的新策略,实有其必要。
发明内容
有鉴于此,本发明提供一种医药组合物,包含一抗原融合蛋白,该抗原融合蛋白包含一抗原及一Fcγ受体(Fc gamma receptor,FcγR)的拮抗分子。
本发明的另一目的在提供一种增强一抗原的免疫原性的方法,包含将该抗原与一Fcγ受体的拮抗分子相连接以形成一抗原融合蛋白。
本发明的又一目的在提供一种增强一个体对一抗原的免疫反应的方法,包含施予该个体有效量的一抗原融合蛋白,其中该抗原融合蛋白包含该抗原及一Fcγ受体的拮抗分子。
在本发明的一实施例中,该Fcγ受体的拮抗分子为一类甲酰化胜肽受体1抑制蛋白(formyl peptide receptor-like 1inhibitory protein,FLIPr)或一类FLIPr蛋白(FLIPr-like protein)。
在本发明的另一实施例中,该抗原为一源自癌细胞或病毒的多胜肽。该抗原可选自由生存素(survivin)、间皮素(mesothelin)、及兹卡病毒套膜蛋白第三结构域(Zikavirus envelope protein domain III)所组成的群组。
在本发明的又一实施例中,所谓被增强的免疫反应包含CD4+T细胞、CD8+T细胞、或其组合的增加,一选自于由干扰素-γ(interferon gamma,IFN-γ)、介白素-2(interleukin-2,IL-2)、介白素-5(interleukin-5,IL-5)、介白素-17A(interleukin-17A,IL-17A)、及其组合所组成群组的细胞激素的分泌,以及抗原专一性免疫球蛋白G(IgG)抗体的生成。
本发明的医药组合物利用通过与FcγR结合而将抗原靶向至抗原呈献细胞的抗原融合蛋白来增强个体的抗原专一性免疫反应,因此导致抗原专一性CD4+或CD8+T细胞的数目增加,以及促发炎细胞激素与抗原专一性抗体的含量升高。本文所提供增强抗原的免疫原性和增强个体对抗原的免疫反应的方法是简单,并且可以在不使用额外的佐剂或免疫复合物的情况下用于开发强效疫苗,例如抗肿瘤及抗病毒疫苗。本发明提高了疫苗抗原的效力,因此提供了在如老年患者的免疫力低下个体中引发有效免疫反应的策略。
本发明将以下方图式及实施例进一步解说。可以理解的是,以下举出的实施例并非限制本发明的范围,并且在不脱离所附申请专利范围的范畴的情况下,本技术领域熟习技艺者当可进行修饰。
附图说明
图1A展示了经纯化的重组蛋白的聚丙烯酰胺(polyacrylamide)胶体影像,该重组蛋白包括卵清蛋白(ovalbumin,OVA)及二种OVA融合蛋白,其将OVA分别与类甲酰化胜肽受体1抑制蛋白(OVA-FLIPr)或类FLIPr蛋白(OVA-FLIPr-like)融合。
图1B显示了使用抗组胺酸标签抗体(anti-His-tag antibody)依西方墨点法(western blotting)侦测该经纯化的重组蛋白,包括该卵清蛋白、该OVA-FLIPr融合蛋白、及该OVA-类FLIPr融合蛋白。
图2A显示了重组蛋白与FcγRI的结合,该重组蛋白包括该卵清蛋白、该OVA-FLIPr融合蛋白、及该OVA-类FLIPr融合蛋白。
图2B显示了重组蛋白与FcγRIIa-H131的结合,该重组蛋白包括该卵清蛋白、该OVA-FLIPr融合蛋白、及该OVA-类FLIPr融合蛋白。
图2C显示了重组蛋白与FcγRIIb的结合,该重组蛋白包括该卵清蛋白、该OVA-FLIPr融合蛋白、及该OVA-类FLIPr融合蛋白。
图2D显示了重组蛋白与FcγRIIIa-V158的结合,该重组蛋白包括该卵清蛋白、该OVA-FLIPr融合蛋白、及该OVA-类FLIPr融合蛋白。
图2E显示了重组蛋白与FcγRIIIa-F158的结合,该重组蛋白包括该卵清蛋白、该OVA-FLIPr融合蛋白、及该OVA-类FLIPr融合蛋白。
图3A显示了予以该卵清蛋白、该OVA-FLIPr融合蛋白、该OVA-类FLIPr融合蛋白、或磷酸缓冲盐溶液(phosphate buffered saline,PBS)二次免疫注射的小鼠的脾脏细胞以胜肽刺激后,其中分泌IFN-γ的CD4+T细胞的频率。
图3B显示了予以该卵清蛋白、该OVA-FLIPr融合蛋白、该OVA-类FLIPr融合蛋白、或PBS二次免疫注射的小鼠的脾脏细胞以胜肽刺激后,其中分泌IFN-γ的CD8+T细胞的频率。
图4A显示了予以该卵清蛋白、该OVA-FLIPr融合蛋白、该OVA-类FLIPr融合蛋白、或PBS二次免疫注射的小鼠中经高浓度羧基荧光素琥珀酰亚胺酯(carboxyfluoresceinsuccinimidyl ester,CFSE)标记且受OT-1胜肽刺激的脾脏细胞的CFSE图谱;各图所示百分比表示一实验中的专一性杀伤百分比。
图4B显示了予以该卵清蛋白、该OVA-FLIPr融合蛋白、该OVA-类FLIPr融合蛋白、或PBS二次免疫注射的小鼠中受OT-1胜肽刺激的脾脏细胞的专一性灭杀百分比。
图5显示了予以该卵清蛋白、该OVA-FLIPr融合蛋白、该OVA-类FLIPr融合蛋白、或PBS二次免疫注射而后接种EG7肿瘤细胞的小鼠的肿瘤体积估计值。
图6A展示了经纯化的重组生存素的聚丙烯酰胺胶体影像。
图6B展示了经纯化的重组生存素-FLIPr(Sur-FLIPr)融合蛋白的聚丙烯酰胺胶体影像。
图6C显示了使用抗组胺酸标签抗体依西方墨点法侦测该经纯化的重组生存素。
图6D显示了使用抗组胺酸标签抗体依西方墨点法侦测该经纯化的重组Sur-FLIPr融合蛋白。
图7A显示了予以该生存素、该Sur-FLIPr融合蛋白、或PBS二次免疫注射的小鼠的脾脏细胞以培养基处理后,其中分泌IFN-γ的CD8+T细胞的频率。
图7B显示了予以该生存素、该Sur-FLIPr融合蛋白、或PBS二次免疫注射的小鼠的脾脏细胞以RAH胜肽刺激后,其中分泌IFN-γ的CD8+T细胞的频率。
图7C显示了予以该生存素、该Sur-FLIPr融合蛋白、或PBS二次免疫注射的小鼠的脾脏细胞以生存素21-29胜肽刺激后,其中分泌IFN-γ的CD8+T细胞的频率。
图7D显示了予以该生存素、该Sur-FLIPr融合蛋白、或PBS二次免疫注射的小鼠的脾脏细胞以生存素57-64胜肽刺激后,其中分泌IFN-γ的CD8+T细胞的频率。
图8显示了接种EG7肿瘤细胞而后以该生存素、该Sur-FLIPr融合蛋白、或PBS二次免疫注射的小鼠的肿瘤体积估计值。
图9显示了予以一重组间皮素、一重组间皮素-FLIPr融合蛋白、或PBS二次免疫注射的小鼠的脾脏细胞以间皮素刺激后,其中辅助性T细胞的促发炎细胞激素分泌量;该细胞激素包括IFN-γ、IL-2、IL-5、及IL-17A。
图10A展示了兹卡病毒套膜蛋白第三结构域(ZE3)的纯化重组蛋白的聚丙烯酰胺胶体影像。
图10B展示了经纯化的重组ZE3-FLIPr融合蛋白的聚丙烯酰胺胶体影像。
图10C显示了使用抗组胺酸标签抗体依西方墨点法侦测该经纯化的重组ZE3。
图10D显示了使用抗组胺酸标签抗体依西方墨点法侦测该经纯化的重组ZE3-FLIPr融合蛋白。
图11显示了重组蛋白与FcγRIIA的结合,该重组蛋白包括该ZE3及该ZE3-FLIPr融合蛋白。
图12显示了小鼠经过该ZE3或该ZE3-FLIPr融合蛋白二次免疫注射后,其血清中ZE3专一性IgG抗体的效价(titer)。
具体实施方式
定义
本文中所使用数值为近似的、实验性数值,其值可在20%的范围内,较佳为在10%的范围内,最佳为在5%的范围内变化。因此,用语“约”和“近似于”是指在一给定值或范围的20%以内,较佳为在10%以内,最佳为在5%以内。
本文中所谓“免疫原性”的用语是指一抗原引起或诱发免疫反应的能力。造成较强免疫反应的抗原具有较高的免疫原性。
用语“有效量”是指一活性物质赋予受治疗个体治疗效果所需要的量。如本技术领域熟习技艺者所认知,有效剂量将依给药途径、赋形剂的使用、以及与其它治疗方法共享的可能而变化。
本发明关于一种医药组合物,其含有一包含一抗原及一Fcγ受体拮抗分子的抗原融合蛋白,以及关于一种增强个体对一抗原的免疫反应的方法,其包含对该个体施予有效量的该抗原融合蛋白以供免疫。在以下实施例中,以卵清蛋白(OVA)、生存素(Sur)、间皮素、及兹卡病毒套膜蛋白第三结构域(ZE3)作为例示性抗原以研究本发明的抗原融合蛋白的免疫增强作用。类甲酰化胜肽受体1抑制蛋白(FLIPr;SEQ ID NO:1)及其同源物的类FLIPr蛋白(SEQ ID NO:2)是金黄色葡萄球菌(Staphylococcus aureus)为躲避Fcγ受体调节的宿主免疫力而分泌的强效Fcγ受体拮抗分子,其作为例示性Fcγ受体拮抗分子以制备含有FLIPr或类FLIPr的融合蛋白。
材料及方法
抗原融合蛋白的选殖(cloning)及表现
抗原融合蛋白的FLIPr或类FLIPr片段较佳为通过由三重复的四个甘氨酸(glycine)残基与一个丝氨酸(serine)残基组成的胜肽连接物(linker)连接至如OVA、生存素、及ZE3等抗原的羧基端。重组抗原或抗原融合蛋白可进一步包含一由组氨酸(histidine)残基构成的短胜肽(His-tag)以便于利用金属螯合亲和层析法(metal-chelating affinity chromatography)进行纯化。根据重组OVA(SEQ ID NO:3)、OVA-FLIPr融合蛋白(SEQ ID NO:4)、OVA-类FLIPr融合蛋白(SEQ ID NO:5)、生存素(SEQ ID NO:6)、生存素-FLIPr(Sur-FLIPr)融合蛋白(SEQ ID NO:7)、间皮素(SEQ ID NO:8)、间皮素-FLIPr融合蛋白(SEQ ID NO:9)、ZE3(SEQ ID NO:10)、及ZE3-FLIPr融合蛋白(SEQ ID NO:11)的氨基酸序列,其相应的核苷酸序列依大肠杆菌(Escherichia coli)密码子的使用而决定,并且将具有各该核苷酸序列的脱氧核醣核酸(DNA)全部合成。其后,该合成的DNA以聚合酶链锁反应(polymerase chain reaction,PCR)扩增。该PCR产物选殖至表现载体pET-22b(+)(Novagen)的NdeI和XhoI位点以产生抗原或抗原融合蛋白的表现质体。该些质体用于生产重组抗原及抗原融合蛋白。
为制备重组蛋白,利用上述各表现质体转型大肠杆菌BL21(DE3)。该转型细胞在37℃隔夜培养,并通过添加1mM异丙基β-D-1-硫代吡喃半乳糖苷(isopropylβ-D-1-thiogalactopyranoside,IPTG)诱导蛋白质表现,接着在37℃培养3小时。其后,利用高压破碎机French Press(Constant Systems,Daventry,UK)在27Kpsi将转型细胞裂解于均质缓冲液(20mM Tris(pH8.0),50mM蔗糖,500mM NaCl,10%甘油)。然后,该细胞裂解物以80,000×g离心40分钟以获得含有包涵体的细胞沉淀。大部分重组蛋白存在于包涵体且以萃取缓冲液(50mM NaH2PO4,5mM乙二胺四乙酸(ethylenediaminetetraacetic acid,EDTA),200mMNaCl,0.5M尿素,1wt%Triton X-100,pH 6.0)将其溶解。重组蛋白通过将萃取分划加载固定化金属亲和层析管柱(QIagen,Hilden,德国)而纯化。
FcγR结合的酵素结合免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)
为检测重组抗原或抗原融合蛋白与FcγR次类的结合,在4℃的磷酸缓冲盐溶液(PBS;137mM氯化钠,2.7mM氯化钾,10mM磷酸氢二钠,1.8mM磷酸二氢钾,pH7.4)中以0.1mL的1μg/mL重组蛋白涂覆96孔盘隔夜。该盘以添加0.05%(v/v)吐温20(Tween 20)的PBS清洗三次,并与连结生物素(biotin)的多种重组FcγR蛋白的连续稀释液培养。该重组FcγR蛋白包括FcγRI、FcγRIIa-H131、FcγRIIb、FcγRIIIa-V158、FcγRIIIa-F158、及FcγRIIA。在室温下培养2小时后,该盘经清洗再与连结山葵过氧化酶(horseradish peroxidase,HRP)的链霉亲合素(streptavidin)培养30分钟。为检测与Fcγ受体的结合,将3,3’,5,5’-四甲基联苯胺(3,3’,5,5’-tetramethylbenzidine,TMB)加入盘中,并使用ELISA测读仪测量在450nm的吸光值。
动物研究
雌性C57BL/6小鼠购自财团法人实验动物中心。所有小鼠饲养于财团法人卫生研究院的实验动物中心。所有动物研究皆获得许可并依照财团法人卫生研究院动物委员会的方针进行。为进行免疫接种,将小鼠随机分组并由皮下(subcutaneously)二次施予重组抗原或抗原融合蛋白,间隔为二周。
酵素连结免疫斑点试验(Enzyme-linkedimmunospot(ELISPOT)assay)
使用小鼠IFN-γELISPOT试剂组(eBioscience)测定产生IFN-γ的细胞的数目。简言之,先以捕捉抗体(capture antibody)涂覆附带聚偏二氟乙烯(polyvinylidenedifluoride,PVDF)膜的96孔盘,并在4℃培养18小时。该盘经二次清洗以添加10wt%胎牛血清(fetal bovine serum,FBS)的RPMI培养基阻断1小时以防止后续步骤中的非专一性结合。将来自免疫小鼠的脾脏细胞依5x105个细胞/孔的密度接种,并施加所指示的胜肽刺激。
予以OVA或OVA融合蛋白免疫注射的小鼠的脾脏细胞被施加10μg/mL的一称为OT-1(SIINFEKL;SEQ ID NO:12)的OVA胜肽、另一称为OT-2(ISQAVHAAHAEINEAGR;SEQ ID NO:13)的OVA胜肽、一OT-1胜肽的对照胜肽(RAHYNIVTF;SEQ ID NO:14)、或一OT-2胜肽的对照胜肽(GRLITVNPIVTEKDS;SEQ ID NO:15)的刺激,并且培养2天。
予以生存素或生存素融合蛋白免疫注射的小鼠的脾脏细胞被施加10μg/mL的一称为生存素21-29(TFKNWPFLE;SEQ ID NO:16)的生存素胜肽、另一称为生存素57-64(CFFCFKEL;SEQ ID NO:17)的生存素胜肽、或一RAH对照胜肽(SEQ ID NO:14)的刺激,并且培养2天。
经过培养后,该些脾脏细胞以含0.05%(w/v)Tween20的PBS清洗三次而自该盘上移除。将100μL生物素化检测抗体的等分试样加入各孔中,使该盘在37℃培养2小时。如上重复清洗步骤,并在室温下以亲合素(avidin)-HRP复合物试剂培养45分钟后,该盘以含0.05%(w/v)Tween 20的PBS清洗三次,而后以PBS单独清洗三次。在各孔中加入100μL3-氨基-9-乙基咔唑(3-amine-9-ethyl carbazole;Sigma-Aldrich)染色溶液的等分试样以显现斑点。该盘于1小时后置于自来水下以停止反应。使用ELISPOT测读仪(CellularTechnology Ltd.)计算斑点数。
体内(in vivo)细胞毒性试验
来自C57BL/6初生(naive)小鼠的脾脏细胞被分为二群。一群以10μMOT-1胜肽在37℃下刺激90分钟。这些细胞以羧基荧光素琥珀酰亚胺酯(CFSE)在最终浓度为10μM(CFSEhigh)时在37℃下标记15分钟。同时,另一群以OT-1的对照胜肽(SEQ ID NO:14)刺激并以1μMCFSE(CFSElow)标记。将该二群细胞等量混合,并将2×107个细胞经由静脉注射至免疫小鼠。24小时后,分离来自脾脏的单个细胞,并使用FACSCalibur流式细胞仪及CellQuestPro软件分析CFSE强度。专一性灭杀百分比计算如下:专一性灭杀%=[1-(%CFSEhigh/注射前的%CFSEhigh)/(%CFSElow/注射前的%CFSElow)]。
EG7肿瘤模型
肿瘤携带小鼠的建立在抗原融合蛋白免疫注射之前或之后通过皮下注射将EG7细胞接种至小鼠。该EG7肿瘤细胞来源于EL4细胞,其一种小鼠淋巴瘤细胞株。肿瘤有无的评估以视觉检查和触诊进行。用量尺每周测量肿瘤大小三次,当肿瘤体积达到3000mm3时牺牲小鼠。肿瘤体积估计如下:肿瘤体积=肿瘤宽度×肿瘤长度×(肿瘤宽度+肿瘤长度)/2。
实施例1
OVA融合蛋白的制备及FcγR结合
编码OVA、OVA-FLIPr融合蛋白、或OVA-类FLIPr融合蛋白的DNA被合成、通过PCR扩增、并选殖至基于pET-22b的载体中以产生pOVA、pOVA-FLIPr、或pOVA-类FLIPr表现质体。其后,利用各该质体转型大肠杆菌以表现蛋白质。经固定化金属亲和层析纯化后,用十二烷基硫酸钠聚丙烯酰胺胶体电泳(polyacrylamide gel electrophoresis,SDS-PAGE)和西方墨点法验证重组蛋白的成功制备。
如图1A所示,重组OVA、OVA-FLIPr融合蛋白、及OVA-类FLIPr融合蛋白可见于考马斯亮蓝(Coomassie brilliant blue)染色的聚丙烯酰胺胶体。如图1B所示,使用抗组胺酸标签抗体(BioRad CatNo:MCA1396P)依西方墨点法检测到重组OVA、OVA-FLIPr融合蛋白、及OVA-类FLIPr融合蛋白。
为分析重组OVA-FLIPr融合蛋白及OVA-类FLIPr融合蛋白的功能活性,进行捕捉ELISA以验证该二种OVA融合蛋白皆直接与FcγR的同型异构体交互作用。如图2A-2E所示,重组OVA-FLIPr融合蛋白及OVA-类FLIPr融合蛋白可与所有受试的FcγR同型异构体结合,包括FcγRI(图2A)、FcγRIIa-H131(图2B)、FcγRIIb(图2C)、FcγRIIIa-V158(图2D)、及FcγRIIIa-F158(图2E)。相对地,重组OVA与该些FcγR同型异构体之间没有交互作用。此结果为二重复孔的平均值±标准误差(SEM)。这些结果说明本发明的抗原融合蛋白可以直接结合不同的FcγR同型异构体。
实施例2
OVA融合蛋白的免疫注射增强OVA专一性T细胞反应
为确认本发明的抗原融合蛋白的FcγR结合活性是否与体内的免疫反应相关,将C57BL/6小鼠随机分组(每组6只小鼠),并且由皮下二次施予10μg的OVA、OVA-FLIPr融合蛋白、或OVA-类FLIPr融合蛋白,间隔为二周。单独施予PBS的小鼠作为负控制组。第二次免疫注射一周后采集该免疫小鼠的脾脏细胞并以ELISPOT试验检视分泌IFN-γ的CD4+及CD8+T细胞的数量。
如图3A-3B所示,在未受刺激(仅培养基)或以对照胜肽刺激的所有脾脏细胞中检测到IFN-γ分泌细胞的背景值。当以OT-2胜肽(一种CD4+T细胞抗原决定位(epitope);图3A)或OT-1胜肽(一种CD8+T细胞抗原决定位;图3B)刺激后,在OVA免疫小鼠的脾脏细胞中观察到低频率的IFN-γ分泌细胞。相对地,予以OVA-FLIPr融合蛋白或OVA-类FLIPr融合蛋白免疫注射的小鼠被诱发高频率的IFN-γ分泌细胞。这些结果说明使用本发明的抗原融合蛋白进行免疫注射能有效诱发抗原专一性T细胞反应。
实施例3
OVA融合蛋白的免疫注射刺激细胞毒杀性免疫力
为探讨本发明的抗原融合蛋白是否刺激细胞毒杀性免疫力而进行体内细胞毒性试验。将C57BL/6小鼠随机分组(每组7-8只小鼠),并且由皮下二次施予30μg的OVA、OVA-FLIPr融合蛋白、或OVA-类FLIPr融合蛋白,间隔为二周。单独施予PBS的小鼠作为负控制组。其后,通过静脉内途径将经高浓度CFSE(CFSEhigh)标记且以OT-1胜肽刺激的脾脏细胞及经较低浓度CFSE(CFSElow)标记且以对照胜肽刺激的脾脏细胞的等量混合物注射至该免疫小鼠。24小时后牺牲该免疫小鼠并以流式细胞技术(flow cytometry)分析细胞毒杀性T淋巴细胞对脾脏中受胜肽刺激脾脏细胞的灭杀。
图4A显示来自各组免疫小鼠的受胜肽刺激脾脏细胞的CFSE图谱。图4B显示来自各组免疫小鼠的受胜肽刺激脾脏细胞的专一性灭杀百分比。如图4A-4B所示,在OVA免疫小鼠观察到较少量受胜肽刺激脾脏细胞的专一性灭杀。相对地,予以OVA-FLIPr融合蛋白或OVA-类FLIPr融合蛋白免疫注射的小鼠对于受胜肽刺激的脾脏细胞表现出明显较多的灭杀作用。这些结果说明使用本发明的抗原融合蛋白进行免疫注射能有效刺激抗原专一性细胞毒杀性免疫力。
实施例4
OVA融合蛋白的免疫注射诱发抗肿瘤反应
为检视本发明的抗原融合蛋白是否在体内诱发抗肿瘤反应,将C57BL/6小鼠随机分组(每组6只小鼠),并且二次施予10μg的OVA、OVA-FLIPr融合蛋白、或OVA-类FLIPr融合蛋白,间隔为二周。单独施予PBS的小鼠作为负控制组。第二次免疫注射一周后,在小鼠左腹皮下接种经转染OVA基因且持续产生OVA的5×105个EG7肿瘤细胞,随后测量肿瘤体积。
如图5所示,在予以OVA-FLIPr融合蛋白或OVA-类FLIPr融合蛋白免疫注射的小鼠中肿瘤生长受到抑制。相对地,以OVA免疫的小鼠相比以PBS免疫的小鼠并未表现出肿瘤体积显著减少。这些结果说明使用本发明的抗原融合蛋白进行免疫注射能有效诱发肿瘤携带个体中的抗原专一性抗肿瘤反应。
实施例5
生存素融合蛋白的制备
依据类似于实施例1所述步骤制备一细胞凋亡(apoptosis)抑制蛋白的生存素(Sur)以及Sur-FLIPr融合蛋白的重组蛋白,并且以SDS-PAGE及西方墨点法进行分析。
如图6A-6B所示,重组生存素及Sur-FLIPr融合蛋白可见于考马斯亮蓝染色的聚丙烯酰胺胶体。如图6C-6D所示,使用抗组胺酸标签抗体依西方墨点法检测到重组生存素及Sur-FLIPr融合蛋白。
实施例6
生存素融合蛋白的免疫注射增强生存素专一性T细胞反应
将C57BL/6小鼠随机分组(每组6只小鼠),并且由皮下二次施予30μg的生存素或Sur-FLIPr融合蛋白,间隔为二周。单独施予PBS的小鼠作为负控制组。第二次免疫注射一周后采集该免疫小鼠的脾脏细胞并以ELISPOT试验检视分泌IFN-γ的CD8+T细胞的数量。
如图7A-7D所示,在未受刺激(仅培养基)或以RAH对照胜肽刺激的所有脾脏细胞中检测到IFN-γ分泌细胞的背景值。当以生存素21-29胜肽或生存素57-64胜肽(皆CD8+T细胞抗原决定位)刺激后,在生存素免疫小鼠的脾脏细胞中观察到低频率的IFN-γ分泌细胞。相对地,生存素-FLIPr融合蛋白免疫小鼠被诱发高频率的IFN-γ分泌CD8+T细胞。这些结果说明使用本发明的抗原融合蛋白进行免疫注射能有效诱发抗原专一性T细胞反应。
实施例7
生存素融合蛋白的免疫注射诱发抗肿瘤反应
将经过皮下接种5×104个EG7肿瘤细胞的C57BL/6小鼠随机分组(每组9-11只小鼠),并且在肿瘤接种后第3天及第10天二次施予30μg的生存素或Sur-FLIPr融合蛋白。单独施予PBS的小鼠作为负控制组。测量肿瘤体积以评估Sur-FLIPr融合蛋白的抗肿瘤活性。
如图8所示,在予以Sur-FLIPr融合蛋白免疫注射的小鼠中肿瘤生长受到抑制。相对地,以生存素免疫的小鼠相比以PBS免疫的小鼠并未表现出肿瘤体积显著减少。这些结果说明使用本发明的抗原融合蛋白进行免疫注射能有效诱发抗原专一性抗肿瘤反应。
实施例8
间皮素融合蛋白的免疫注射增强间皮素专一性T细胞反应
依据类似于实施例1所述步骤制备间皮素以及间皮素-FLIPr融合蛋白的重组蛋白(数据未显示),该间皮素据报导是一种在如间皮瘤(mesothelioma)及卵巢与胰脏腺癌(adenocarcinoma)的肿瘤中过度表现的蛋白质。将C57BL/6小鼠随机分组(每组3只小鼠),并且由皮下二次施予10μg之间皮素或间皮素-FLIPr融合蛋白,间隔为一周。单独施予PBS的小鼠作为负控制组。第二次免疫注射一周后分离该免疫小鼠的脾脏细胞并施以10μg/mL间皮素刺激五天,其后依厂商说明书利用ELISA套组(eBioscience)测量分泌至细胞培养基中的IFN-γ、IL-2、IL-5、及IL-17A的含量。
如图9所示,在以间皮素-FLIPr融合蛋白免疫的小鼠的受刺激脾脏细胞中,辅助性T细胞分泌高含量的促发炎细胞激素,包括IFN-γ、IL-2、IL-5、及IL-17。相对地,在间皮素或PBS免疫小鼠的脾脏细胞中检测到少量的该些细胞激素。这些结果说明使用本发明的抗原融合蛋白进行免疫注射能有效诱发抗原专一性辅助性T细胞反应。
实施例9
ZE3融合蛋白的制备及FcγR结合
依据类似于实施例1所述步骤制备ZE3以及ZE3-FLIPr融合蛋白的重组蛋白,并且以SDS-PAGE及西方墨点法进行分析。
如图10A-10B所示,重组ZE3及ZE3-FLIPr融合蛋白可见于考马斯亮蓝染色的聚丙烯酰胺胶体。如图10C-10D所示,使用抗组胺酸标签抗体依西方墨点法检测到重组ZE3及ZE3-FLIPr融合蛋白。
为分析重组ZE3-FLIPr融合蛋白的功能活性,进行捕捉ELISA以验证FcγRIIA与该ZE3-FLIPr融合蛋白间的交互作用。如图11所示,FcγRIIA与重组ZE3-FLIPr融合蛋白的结合可检测。相对地,重组ZE3与FcγRIIA之间有微弱交互作用。此结果证明本发明的抗原融合蛋白能直接与FcγR结合。
实施例10
ZE3融合蛋白的免疫注射增强抗体生成
将C57BL/6小鼠随机分组(每组4只小鼠),并且由皮下二次施予10μg的该ZE3或ZE3-FLIPr融合蛋白,间隔为二周。第一次免疫注射四周后采集该免疫小鼠的血清以便利用ELISA测定抗ZE3的IgG抗体的效价。简言之,制备血清样品的3倍连续稀释液(始于1:33)。将重组ZE3涂覆于96孔盘。使用连结HRP的山羊抗小鼠IgG Fc抗体(ICN Cappel)检测被结合的IgG。清洗后,加入TMB以进行呈色。使用ELISA测读仪测量在450nm的吸光值。ELISA终点效价(end-point titer)定义为产生OD450值为0.2的血清稀释倍数。除非开始稀释时(1:33)的OD值小于0.2,否则所有效价均以内插法由滴定曲线获得。
如图12所示,在予以ZE3-FLIPr融合蛋白免疫注射的小鼠中观察到ZE3专一性IgG抗体的优势生成。相比之下,ZE3免疫小鼠产生较少量的ZE3专一性IgG。此结果说明使用本发明的抗原融合蛋白进行免疫注射能有效诱导抗原专一性抗体的生成。
综上所述,本发明的抗原融合蛋白相比抗原本身能在一个体引发更强的抗原专一性免疫反应。因此,含有此种抗原融合蛋白的医药组合物可应用于开发强效疫苗,例如例如抗肿瘤及抗病毒疫苗。本发明的实施例亦示范一种简单而直接的增强抗原免疫原性的方法及一种增强个体对抗原的免疫反应的方法。这些方法可以增加疫苗抗原的效力,并且在免疫力低下个体中引起有效的免疫反应。
SEQUENCE LISTING
<110> 财团法人卫生研究院
<120>增强免疫反应的组合物及方法
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<212> PRT
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<212> PRT
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<210> 7
<211> 258
<212> PRT
<213> Artificial sequence(人工序列)
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<221> UNSURE
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<400> 7
Met Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys
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His His
<210> 8
<211> 312
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Recombinant mesothelin(重组间皮素)
<400> 8
Met Asp Ala Glu Gln Lys Ala Cys Pro Pro Gly Lys Glu Pro Tyr Lys
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Asp Ile Ala Thr Phe Lys Arg Leu Gln Val Asp Ser Leu Val Gly Leu
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Ser Val Ala Glu Val Gln Lys Leu Leu Gly Pro Asn Ile Val Asp Leu
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His Gln Lys Asp Leu Asp Arg Leu Gly Leu Gly Leu Gln Gly Gly Ile
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Pro Asn Gly Tyr Leu Val Leu Asp Phe Asn Val Arg Glu Ala Phe Ser
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Leu Glu His His His His His His
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<210> 9
<211> 436
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Recombinant mesothelin-FLIPr fusion protein(重组间皮素-FLIPr融合蛋白)
<400> 9
Met Asp Ala Glu Gln Lys Ala Cys Pro Pro Gly Lys Glu Pro Tyr Lys
1 5 10 15
Val Asp Glu Asp Leu Ile Phe Tyr Gln Asn Trp Glu Leu Glu Ala Cys
20 25 30
Val Asp Gly Thr Met Leu Ala Arg Gln Met Asp Leu Val Asn Glu Ile
35 40 45
Pro Phe Thr Tyr Glu Gln Leu Ser Ile Phe Lys His Lys Leu Asp Lys
50 55 60
Thr Tyr Pro Gln Gly Tyr Pro Glu Ser Leu Ile Gln Gln Leu Gly His
65 70 75 80
Phe Phe Arg Tyr Val Ser Pro Glu Asp Ile His Gln Trp Asn Val Thr
85 90 95
Ser Pro Asp Thr Val Lys Thr Leu Leu Lys Val Ser Lys Gly Gln Lys
100 105 110
Met Asn Ala Gln Ala Ile Ala Leu Val Ala Cys Tyr Leu Arg Gly Gly
115 120 125
Gly Gln Leu Asp Glu Asp Met Val Lys Ala Leu Gly Asp Ile Pro Leu
130 135 140
Ser Tyr Leu Cys Asp Phe Ser Pro Gln Asp Leu His Ser Val Pro Ser
145 150 155 160
Ser Val Met Trp Leu Val Gly Pro Gln Asp Leu Asp Lys Cys Ser Gln
165 170 175
Arg His Leu Gly Leu Leu Tyr Gln Lys Ala Cys Ser Ala Phe Gln Asn
180 185 190
Val Ser Gly Leu Glu Tyr Phe Glu Lys Ile Lys Thr Phe Leu Gly Gly
195 200 205
Ala Ser Val Lys Asp Leu Arg Ala Leu Ser Gln His Asn Val Ser Met
210 215 220
Asp Ile Ala Thr Phe Lys Arg Leu Gln Val Asp Ser Leu Val Gly Leu
225 230 235 240
Ser Val Ala Glu Val Gln Lys Leu Leu Gly Pro Asn Ile Val Asp Leu
245 250 255
Lys Thr Glu Glu Asp Lys Ser Pro Val Arg Asp Trp Leu Phe Arg Gln
260 265 270
His Gln Lys Asp Leu Asp Arg Leu Gly Leu Gly Leu Gln Gly Gly Ile
275 280 285
Pro Asn Gly Tyr Leu Val Leu Asp Phe Asn Val Arg Glu Ala Phe Ser
290 295 300
Lys Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Glu Phe Phe Phe Ser Tyr Glu Trp Lys Gly Leu Glu Ile Ala Lys
325 330 335
Asn Leu Ala Asp Gln Ala Lys Lys Asp Asp Glu Arg Ile Asp Lys Leu
340 345 350
Met Lys Glu Ser Asp Lys Asn Leu Thr Pro Tyr Lys Ala Glu Thr Val
355 360 365
Asn Asp Leu Tyr Leu Ile Val Lys Lys Leu Ser Gln Gly Asp Val Lys
370 375 380
Lys Ala Val Val Arg Ile Lys Asp Gly Gly Pro Arg Asp Tyr Tyr Thr
385 390 395 400
Phe Asp Leu Thr Arg Pro Leu Glu Glu Asn Arg Lys Asn Ile Lys Val
405 410 415
Val Lys Asn Gly Glu Ile Asp Ser Ile Tyr Trp Asp Leu Glu His His
420 425 430
His His His His
435
<210> 10
<211> 115
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Recombinant ZE3(重组ZE3)
<400> 10
Met Lys Gly Val Ser Tyr Ser Leu Cys Thr Ala Ala Phe Thr Phe Thr
1 5 10 15
Lys Ile Pro Ala Glu Thr Leu His Gly Thr Val Thr Val Glu Val Gln
20 25 30
Tyr Ala Gly Thr Asp Gly Pro Cys Lys Val Pro Ala Gln Met Ala Val
35 40 45
Asp Met Gln Thr Leu Thr Pro Val Gly Arg Leu Ile Thr Ala Asn Pro
50 55 60
Val Ile Thr Glu Ser Thr Glu Asn Ser Lys Met Met Leu Glu Leu Asp
65 70 75 80
Pro Pro Phe Gly Asp Ser Tyr Ile Val Ile Gly Val Gly Glu Lys Lys
85 90 95
Ile Thr His His Trp His Arg Ser Gly Ser Thr Leu Glu His His His
100 105 110
His His His
115
<210> 11
<211> 239
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Recombinant ZE3-FLIPr fusion protein(重组ZE3-FLIPr融合蛋白)
<400> 11
Met Lys Gly Val Ser Tyr Ser Leu Cys Thr Ala Ala Phe Thr Phe Thr
1 5 10 15
Lys Ile Pro Ala Glu Thr Leu His Gly Thr Val Thr Val Glu Val Gln
20 25 30
Tyr Ala Gly Thr Asp Gly Pro Cys Lys Val Pro Ala Gln Met Ala Val
35 40 45
Asp Met Gln Thr Leu Thr Pro Val Gly Arg Leu Ile Thr Ala Asn Pro
50 55 60
Val Ile Thr Glu Ser Thr Glu Asn Ser Lys Met Met Leu Glu Leu Asp
65 70 75 80
Pro Pro Phe Gly Asp Ser Tyr Ile Val Ile Gly Val Gly Glu Lys Lys
85 90 95
Ile Thr His His Trp His Arg Ser Gly Ser Thr Lys Leu Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Phe Phe Phe
115 120 125
Ser Tyr Glu Trp Lys Gly Leu Glu Ile Ala Lys Asn Leu Ala Asp Gln
130 135 140
Ala Lys Lys Asp Asp Glu Arg Ile Asp Lys Leu Met Lys Glu Ser Asp
145 150 155 160
Lys Asn Leu Thr Pro Tyr Lys Ala Glu Thr Val Asn Asp Leu Tyr Leu
165 170 175
Ile Val Lys Lys Leu Ser Gln Gly Asp Val Lys Lys Ala Val Val Arg
180 185 190
Ile Lys Asp Gly Gly Pro Arg Asp Tyr Tyr Thr Phe Asp Leu Thr Arg
195 200 205
Pro Leu Glu Glu Asn Arg Lys Asn Ile Lys Val Val Lys Asn Gly Glu
210 215 220
Ile Asp Ser Ile Tyr Trp Asp Leu Glu His His His His His His
225 230 235
<210> 12
<211> 8
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> OT-1 peptide(OT-1胜肽)
<400> 12
Ser Ile Ile Asn Phe Glu Lys Leu
1 5
<210> 13
<211> 17
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> OT-2 peptide(OT-2胜肽)
<400> 13
Ile Ser Gln Ala Val His Ala Ala His Ala Glu Ile Asn Glu Ala Gly
1 5 10 15
Arg
<210> 14
<211> 9
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> RAH peptide(RAH胜肽)
<400> 14
Arg Ala His Tyr Asn Ile Val Thr Phe
1 5
<210> 15
<211> 15
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Control peptide for OT-2 peptide(OT-2胜肽的对照胜肽)
<400> 15
Gly Arg Leu Ile Thr Val Asn Pro Ile Val Thr Glu Lys Asp Ser
1 5 10 15
<210> 16
<211> 9
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Survivin21-29(生存素21-29)
<400> 16
Thr Phe Lys Asn Trp Pro Phe Leu Glu
1 5
<210> 17
<211> 8
<212> PRT
<213> Artificial sequence(人工序列)
<220>
<221> UNSURE
<223> Survivin57-64(生存素57-64)
<400> 17
Cys Phe Phe Cys Phe Lys Glu Leu
1 5
Claims (6)
1.一种医药组合物,其特征在于,包含一种抗原融合蛋白,所述抗原融合蛋白包含一种抗原及一种Fcγ受体的拮抗分子;所述抗原融合蛋白的氨基酸序列如SEQ ID NO:4、SEQ ID
NO:5、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:11之一所示。
2.一种增强抗原的免疫原性的方法,其特征在于,包含将所述抗原与一种Fcγ受体的拮抗分子相连接以形成一种抗原融合蛋白;所述抗原融合蛋白的氨基酸序列如SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:11之一所示。
3.一种抗原融合蛋白用于制备增强个体对抗原的免疫反应的药物的应用,其特征在于,包含施予所述个体有效量的所述抗原融合蛋白;其中所述抗原融合蛋白包含抗原及一种Fcγ受体的拮抗分子;所述抗原融合蛋白的氨基酸序列如SEQ ID NO:4、SEQ ID NO:5、SEQ ID
NO:7、SEQ ID NO:9、SEQ ID NO:11之一所示。
4.如权利要求3所述的应用,其特征在于,所述免疫反应包含CD4+T细胞、CD8+T细胞、或其组合的增加。
5.如权利要求3所述的应用,其特征在于,所述免疫反应包含选自由干扰素-γ、介白素-2、介白素-5、介白素-17A、及其组合所组成群组的细胞激素的分泌。
6.如权利要求3所述的应用,其特征在于,所述免疫反应包含抗原专一性免疫球蛋白G抗体的生成。
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US20190321456A1 (en) | 2019-10-24 |
TW201834693A (zh) | 2018-10-01 |
CN110691613A (zh) | 2020-01-14 |
TWI660742B (zh) | 2019-06-01 |
US11266728B2 (en) | 2022-03-08 |
EP3565606A1 (en) | 2019-11-13 |
WO2018128931A1 (en) | 2018-07-12 |
EP3565606A4 (en) | 2020-08-12 |
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