CN113660948A - 调节黏膜免疫原性的方法 - Google Patents
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Abstract
本公开提供一种用于调节黏膜免疫反应的新颖方法,其包含向有需要的个体的黏膜部位投与抗原,和向所述个体的不同解剖学黏膜部位投与免疫调节剂。所述抗原可投与至舌下黏膜且所述免疫调节剂可投与至鼻内黏膜。可引发涉及针对所述抗原产生IgG和IgA的免疫反应。
Description
交叉引用
本申请要求于2019年3月20日提交的美国临时申请第62/820,966号的优先权,其以全文引用的方式并入本文中。
技术领域
本发明系关于黏膜免疫接种的领域,并且确切地说,将抗原和免疫调节剂递送至不同黏膜部位以用于免疫接种。
背景技术
增强疫苗的免疫原性的常见实践涉及将一或多种抗原与免疫调节剂(诸如佐剂)共投与。非活疫苗的大多数抗原,诸如重组、经纯化或***抗原,通常免疫原性较小,且依赖于佐剂以增强免疫原性。疫苗接种的佐剂属于免疫调节剂,且其机制涉及但不限于注射部位处的积存形成、细胞介素和趋化因子的诱发、驻留兰格汉氏细胞(Langerhans's cell)的活化、抗原呈递吞噬细胞(APC)的募集,和促进抗原呈递细胞回归至引流***等。在当前含佐剂的疫苗中,将佐剂与抗原预混合且同时投与。视佐剂的分子特征和反应性APC的性质而定,佐剂调节免疫性的质量和数量。然而,单独和/或在不同时间点投与的免疫调节剂不被认为是佐剂(EMEA/CHMP/VWP/244894/2006)。佐剂经设计以增强针对抗原的免疫反应。免疫调节剂以更全身性方式调整抗原的免疫性。
黏膜表面为最容易受到病原体侵袭的部位。黏膜疫苗接种为对于有效疫苗接种的集中研究的疫苗接种途径,且为了提供抗经由黏膜途径的感染的第一道防线建议疫苗接种。与肌内(IM)或皮下(SC)免疫接种相比,黏膜免疫提供显著的公众健康优势,其包括但不限于非侵袭性、对病原体的交叉反应性IgA、低成本和降低的血源性疾病的传播风险。
黏膜上皮保护身体免受环境侵袭,但其为黏膜疫苗接种的障碍。为设计有效黏膜免疫调节剂或佐剂(针对疫苗),进入或绕过上皮障壁、促进抗原摄取和活化抗原呈递树突状细胞(DC)的能力必不可少。兰格汉氏细胞(不成熟DC)为上皮中的常见驻留物。DC产生树突样伪足,其在分层鳞状上皮之间延伸且一直到黏膜表面以经由表面受体对环境取样。此取样机制为黏膜免疫调节剂和抗原提供高效通道,以促进随后兰格汉氏细胞的摄取。当今,仅少数黏膜疫苗可用于人类,其主要归因于安全和有效黏膜佐剂的缺乏。
细菌组分、毒素和类毒素调节免疫反应且适合作为佐剂。大肠杆菌(Escherichiacoli)不稳定毒素(LT)由于其增强免疫原性的出色的有效性而为经研究最多的黏膜佐剂中的一者。
在一般的疫苗接种实践中,抗原经预混合且与佐剂共投与。抗原介导的淋巴细胞活化的过程涉及短暂地将抗原暴露于不成熟APC,将抗原吞噬至APC中至成熟APC,诱发APC分泌细胞介素,募集免疫细胞,成熟APC回归至近端***(LN),在淋巴细胞与APC之间交叉对话,和活化淋巴细胞。将佐剂与抗原预混合的基本原理系基于如下假设:仅抗原不足以使APC优化以完成淋巴细胞活化,其亦表明同时用佐剂刺激抗原可调节APC且定义其在后续淋巴细胞活化中的作用。
流感疫苗接种系用于预防流感病毒感染和其潜在严重并发症的最有效方法。此类感染需要血球凝集素(HA)和神经胺糖酸苷酶(NA)蛋白,且所述蛋白质代表流感病毒粒子的主表面醣蛋白。因为流感病毒在HA和NA上经历频繁抗原改变(亦即,抗原漂移),所以经推荐用于疫苗接种的个人必须接受每年抗当前在传播的流感病毒的疫苗接种。
尽管缺乏对黏膜IgA的扩增,当前流感疫苗接种增强了抗病毒特异性IgG。在1938年研发出第一流感疫苗。此后,肌内或皮下投药已成为疫苗接种的主要途径。然而,两者均不提供黏膜保护。现可用经由鼻用喷雾的减毒季节性流感疫苗接种且所述疫苗接种提供增强的黏膜保护,但其伴随一些局限性和安全问题。对于老年接受者的低功效为当前流感疫苗接种的另一公众健康问题。为满足未满足的医学需求,国际上已审批通过高剂量抗原或添加佐剂的疫苗。
过敏为免疫***的病症且其特征在于对通常无害环境物质发生过敏性反应,所述环境物质可存在于广泛多种来源中,包括但不限于:螨、花粉或其他植物组分、尘、霉菌或真菌、食品、添加剂、乳胶、输液反应、动物或鸟类皮屑、昆虫毒液、放射性造影剂、药物或化学物质。
室内尘螨提取物(HDM)为来自室内尘螨的提取物且用于HDM特异性呼吸道过敏的过敏原免疫疗法(AIT)中。HDM可藉由肌内(IM)或舌下(SL)途径投与。然而,HDM的免疫原性不良。对于SL途径,通常需要每年3至5个月每日给药持续3年或更多年,以完全缓解过敏性症状。当前,治疗功效的最高准则为过敏原特异性IgG4的效价。许多研究已证明,过敏原特异性IgG4的效价与呼吸道过敏呈负相关。啮齿动物不具有IgG4且其作用经其他IgG亚型替代。
在本发明中,发现递送至抗原所递送至的不同解剖学黏膜部位的免疫调节剂,诸如LTh(αK),对抗原特异性免疫反应提供显著增强。本发明拓宽免疫调节剂(诸如LTh(αK))在黏膜免疫性中作为免疫调节剂的用途和其在研发用于呼吸道过敏症的黏膜疫苗和疗法中的应用。
发明内容
本发明系关于藉由向不同黏膜部位投与抗原和免疫调节剂,可调节抗原的免疫原性且可引发所需免疫反应的发现。因此,本发明提供一种用于调节黏膜免疫反应的新颖方法,其包含向有需要的个体的黏膜部位投与抗原,和向所述个体的不同解剖学黏膜部位投与免疫调节剂。
在一优选实施例中,抗原为哺乳动物(诸如人类)的外来蛋白。特定言之,抗原对临床需求展现不令人满意的免疫原性。在一优选实施例中,抗原诱发黏膜免疫反应;更优选地,抗原参与病原反应。在一优选实施例中,抗原由病毒蛋白、花粉、霉菌、昆虫蛋白(HDM、蜂毒、蟑螂等)、动物皮屑、尘、化学物质、植物等组成。在一优选实施例中,抗原为生物制剂。
在一个实施例中,免疫调节剂可经由黏膜上皮传导信号。优选地,免疫调节剂为毒素或类毒素,且更优选地,免疫调节剂为细菌来源的毒素或类毒素。在一优选实施例中,免疫调节剂为经解毒的LT、LTh(αK)、铎样受体(TLR)促效剂或拮抗剂、Vaxfectin或模式识别受体(PRR)促效剂或拮抗剂。在另一优选实施例中,免疫调节剂为LTh(αK)。LTh(K)对应于如US 2008102078中所揭示的LTS61K,其为如US 2008102078中所揭示的在对应于SEQ ID NO:5的位置61的位置处具有离胺酸取代的经解毒的大肠杆菌(E.coli)LT全毒素。在另一优选实施例中,免疫调节剂不诱发与其接触的细胞中产生细胞介素IL6,所述细胞包括上皮细胞、兰格汉氏细胞、驻留单核细胞和神经元细胞。
在一个实施例中,黏膜部位可为任何解剖学黏膜。在一优选实施例中,黏膜部位为舌下黏膜、鼻内黏膜、呼吸道黏膜、口腔黏膜、***黏膜、直肠黏膜或其他解剖学黏膜。在另一优选实施例中,向舌下黏膜投与抗原。在另一优选实施例中,向可延伸至咽的鼻内黏膜投与免疫调节剂。
在一优选实施例中,免疫反应涉及产生抗原特异性IgG和其亚类、抗原特异性IgA和其亚类、抗原特异性IgM和其亚类,或细胞介导的免疫性。更优选地,免疫反应提供治疗效益。在另一优选实施例中,免疫反应涉及免疫组分的上调。在另一优选实施例中,免疫反应涉及免疫组分的下调。在另一优选实施例中,免疫反应涉及产生针对抗原的免疫球蛋白。
在一优选实施例中,抗原经依序投与或与免疫调节剂结合投与,但投与至不同黏膜部位。在另一优选实施例中,同时投与抗原和免疫调节剂。在另一优选实施例中,分别投与抗原和免疫调节剂。更优选地,投与抗原与投与免疫调节剂之间的时间间隔在1分钟、2分钟、3分钟、5分钟、10分钟、20分钟、30分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、1天、2天、3天、4天或5天内。
在以下部分中详细描述本发明。本发明的其他特征、目的和优点可以在本发明的实施方式和权利要求书中容易地找到。
附图说明
图1A-F说明来自与鼻内递送LTh(αK)结合或不结合之舌下疫苗接种的***B型流感疫苗(B/Brisbane/60/2008样病毒)的抗原特异性免疫原性效应。在免疫接种后14天收集来自小鼠的血清(A-D)和洗鼻液(E、F);且分析B型流感IgG(A、B)和IgA(C-F)的效价。X轴指示各免疫接种中Flu B和LTh(αK)的HA抗原的剂量。对C57BL/6(A、C和E)和Balb/c(B、D和F)两种品系均进行此研究。所有动物均接受每周三次投药。在与鼻内投与LTh(αK)结合的舌下投与B型流感抗原之后,血清抗B型流感免疫球蛋白G和洗鼻液抗B型流感免疫球蛋白A得到增强。
图2A-F说明来自与鼻内递送LTh(αK)结合或不结合的舌下疫苗接种A型流感(H3N2)疫苗(A/Hong Kong/4801/2014(H3N2)样病毒)的抗原特异性免疫原性效应。在免疫接种后14天收集血清(A-D)和洗鼻液(E、F);且分析流感-H3N2 IgG(A、B)和IgA(C-F)的效价。X轴指示各免疫接种中H3N2和LTh(αK)的HA抗原的剂量。对C57BL/6(A、C和E)和Balb/c(B、D和F)两种品系均进行此研究。所有动物均接受每周三次投药。在与鼻内投与LTh(αK)结合的舌下投与Flu抗原之后,血清抗Flu(A/H3N2)免疫球蛋白G、血清抗Flu(A/H3N2)免疫球蛋白A和洗鼻液抗Flu(A/H3N2)免疫球蛋白A得到增强。
图3A和3B说明在额外HDM攻击之后,来自与鼻内投与LTh(αK)结合或不结合的舌下投与过敏原(HDM,购自Greer实验室,目录号:XPB70D3A2.5)的抗原特异性免疫原性效应。收集血清(A)和洗鼻液(B);且分析HDM的IgG(A)和IgA(B)效价。处理持续两周。X轴指示HDM和LTh(αK)的剂量,和总处理数。对Balb/c小鼠进行此研究。
图4A和4B说明来自与鼻内递送LTh(αK)结合或不结合的两轮舌下递送过敏原(猪草,购自Greer实验室,目录号:XP56D3A25)处理,和另一仅猪草处理随后经由鼻内途径进行猪草攻击的抗原特异性免疫原性效应。在研究结束时收集小鼠血清且分析猪草特异性IgG效价。每轮处理持续两周。X轴指示猪草和LTh(αK)的剂量,和总处理数。在每次处理中,投与猪草或LTh(αK)6次。在攻击阶段中,每日投与5次猪草。对C57BL/6(A)和Balb/c(B)小鼠进行此研究。
具体实施方式
除非本文另外定义,否则结合本发明使用的科学和技术术语应当具有所属领域的一般技术人员通常理解的含义。术语的含义和范围应该明确;然而在具有任何潜在不明确性的事件中,本文提供的定义优先于任何词典或外来定义。
如根据本公开所用,除非另外指示,否则以下术语应理解为具有以下含义。
本文所用的术语「调节(modulating/modulation)」系指条件、水平或量的调节。所述调节可为上调或下调。
本文所用的术语「黏膜免疫反应」系指在黏膜处诱发的免疫反应。例如,黏膜免疫反应包括但不限于抗原特异性免疫球蛋白G和其亚类、免疫球蛋白A和其亚类、免疫球蛋白M和其亚类和针对经免疫抗原的细胞介导的免疫性。
如本文所用,术语「黏膜部位」系指覆盖有黏膜上皮的任何解剖学黏膜。例如,黏膜部位可为舌下黏膜、鼻内黏膜、呼吸道黏膜、口腔黏膜、***黏膜、直肠黏膜或其他解剖学黏膜。
本文所用的术语「佐剂」可与「免疫调节剂」互换且系指调整对于特异性抗原的免疫反应的药理学或免疫试剂。例如,佐剂可为经解毒的LT、LTh(αK)、铎样受体(TLR)促效剂或拮抗剂、Vaxfectin或模式识别受体(PRR)促效剂或拮抗剂。
如本文所用的术语「免疫调节剂」系指调整免疫性且最终改变特异性抗原/过敏原的免疫原性结果的药理学或免疫试剂。例如,免疫调节剂可为经解毒的LT或铎样受体(TLR)促效剂。
如本文所用的术语「个体」表示动物,尤其哺乳动物。在一个优选实施例中,术语「个体」表示人类。
除非上下文另外需要,否则单数术语应包括复数,且复数术语应包括单数。
本发明的发明人意外地发现,与将佐剂与抗原混合以增强特异性免疫反应的传统方式相反,将免疫调节剂和抗原分别投与至不同黏膜部位可显著增强所需黏膜免疫反应。另外,不需要同时投与免疫调节剂和抗原。抗原和免疫调节剂可如本文所述在数分钟至数天内依序投与。本发明提供一种免疫调节剂在黏膜免疫性中的新颖作用且可促进除传统手段以外的新颖黏膜疫苗投与的研发。
现已大体描述本发明,参考以下实例可以更容易理解本发明,所述实例提供用于执行本发明的方法调节黏膜免疫反应的例示性方案。所述实例仅出于说明性目的提供,且不意欲以任何方式限制本发明的范畴。已作出努力以确保关于所用数字(例如,量、温度等)的精确性,但一些实验性误差和偏差当然应为允许的。
实例
后续实例中所用的小鼠为雌性,购自BioLASCO Taiwan Co.,Ltd.且在无特异性病原体(SPF)的条件下圈养。在8周龄开始研究。对于舌下投药,藉由吸入异氟醚轻度麻醉小鼠,且接着在固定卧位中以单次12μL处理25秒舌下投药。对于鼻内投药,小鼠各鼻孔接受单体积2.5μL的处理。在实例1至4中使用Balb/c和C57BL/6小鼠两者。
实例1:评估针对B型流感疫苗的黏膜免疫调节剂LTh(αK)的免疫原性效应
在图1中,小鼠接受舌下投与的Flu B且一些接受经由鼻内途径作为共同处理的鼻内投与LTh(αK)(图1)。在第一组中,各小鼠舌下接受20μg的Flu B。在第2、3和4组中,小鼠与5μg鼻内LTh(αK)结合经由舌下途径分别接受20、10和5μg的Flu B。在所有组中,间隔一周提供处理,总共三次处理。
在处理后14天收集来自所研究小鼠的血液和洗鼻液。藉由ELISA分析抗Flu B IgG和IgA。结果展示于图1中。
经由鼻内途径投与的LTh(αK)增强针对舌下投与的Flu B疫苗的体液和黏膜免疫性(图1A-D)。Flu B为不良黏膜免疫原,因为其在舌下投药的后诱发低效价的血清Flu B特异性IgG和最低IgA(第1组,图1A-D)。经由鼻内途径的额外LTh(αK)增强血清Flu B特异性IgG和IgA效价。对于两种小鼠品系揭示Flu B特异性IgG和IgA的增强(图1A-D)。已知Balb/c和C57BL/6小鼠分别展现对Th2和Th1的偏向免疫反应。免疫学相异小鼠的以上结果表明具有不同免疫基因背景的动物在本发明中可适用。
黏膜特异性抗Flu B IgA仅在用LTh(αK)共同处理的组中揭示(图1C-F)。IgA为黏膜免疫性的标志和抵抗大多数感染的一线。当仅藉由舌下途径投与Flu B时,Flu B特异性IgA未增强(第1组,图1C-E)。
总之,藉由鼻内途径投与LTh(αK)显著增强由SL投与诱发的Flu B特异性IgG和IgA效价。对Balb/c与C57BL/6两种小鼠揭示相同结果。
实例2:评估针对A型流感疫苗的黏膜免疫调节剂LTh(αK)的免疫原性效应
在图2中,小鼠接受舌下投与的Flu A/Hong Kong/4801/2014(H3N2)样病毒疫苗(Flu A)且一些接受鼻内投与LTh(αK)的共同处理(图2)。在第一组中,各小鼠舌下接受20μg的Flu A。在第2、3和4组中,小鼠分别接受与鼻内5μg LTh(αK)结合的经由舌下途径的20、10和5μg的Flu A。在所有组中,分开地一周提供处理,总共三次处理。
在所有小鼠免疫接种后14天收集来自所研究动物的血液和洗鼻液。藉由ELISA分析抗Flu AIgG和IgA。结果展示于图2中。
经由鼻内途径投与的LTh(αK)增强针对舌下投与的Flu A疫苗的体液和黏膜免疫性(图2A-D)。Flu A为不良黏膜免疫原,因为其在舌下投药的后诱发低效价的血清Flu A特异性IgG和最低IgA(第1组,图2A-D)。经由鼻内途径的额外LTh(αK)增强血清Flu A特异性IgG和IgA效价。对两种小鼠品系揭示Flu A特异性IgG和IgA的增强(图2A-D)。已知Balb/c和C57BL/6小鼠分别展现对Th2和Th1的偏向免疫反应。免疫学相异小鼠的以上结果表明具有不同免疫基因背景的动物在本发明中可适用。
黏膜特异性抗Flu AIgA仅在用LTh(αK)共同处理的组中揭示(图2C-F)。IgA为黏膜免疫性的标志和抵抗大多数感染的一线。当仅藉由舌下途径投与Flu A时,Flu A特异性IgA未增强(第1组,图2C-E)。
总之,藉由鼻内途径投与LTh(αK)显著增强由SL投与诱发的Flu A特异性IgG和IgA效价。对Balb/c和C57BL/6两种小鼠揭示相同结果。
实例3:评估针对室内尘螨提取物的黏膜免疫调节剂LTh(αK)的免疫原性效应
小鼠经由舌下途径用HDM提取物预处理,所述提取物购自Stallergenes Greer(XPB70D3A2.5),具有或不具有藉由鼻内途径的免疫调节剂(LTh(αK))共同处理共同处理。为模拟过敏性反应,在预处理之后,使小鼠气管内致敏一次且用HDM提取物鼻内攻击五次。最终攻击后4天时收集血液样品和支气管肺泡灌洗液(BALF)且藉由ELISA分析HDM特异性IgG和IgA。
结果展示,鼻内投与LTh(αK)增强舌下和鼻内投与HDM提取物的体液和黏膜免疫性(图3A和3B)。第1组为阳性对照组。此组小鼠在无先前HDM提取物处理的情况下接受用于致敏和攻击的鼻内HDM提取物。第2组为健康对照组。此组小鼠既不接受处理亦不接受攻击。第3组为过敏原免疫疗法(AIT)组。此组小鼠在鼻内HDM提取物致敏和攻击之前两周接受10次剂量的舌下HDM提取物处理。第4组为LTh(αK)对照组。此组小鼠在两周内经由鼻内途径接受6次剂量的LTh(αK)处理,随后鼻内HDM提取物致敏和攻击。第5组至第8组为共同处理组。此等组小鼠分别经由舌下和鼻内途径以各种量接受HDM提取物和LTh(αK)的共同处理,随后鼻内HDM提取物致敏和攻击。结果证明在具有鼻内共同处理的LTh(αK)的组中,血清中的抗HDMIgG和BALF中的IgA显著升高。
实例4:评估针对猪草花粉提取物的黏膜免疫调节剂LTh(αK)的免疫原性效应
为了证明LTh(αK)在增强抗花粉IgG方面的有效性,在具有或不具有鼻内LTh(αK)的共同处理的情况下给与四组小鼠三轮舌下猪草花粉提取物(猪草),随后由猪草进行呼吸道攻击(图4)。在第一轮处理中,第1组接受6次舌下剂量的猪草,每剂量40μg不含LTh(αK)。第2组、第3组和第4组分别接受与鼻内5μg的LTh(αK)结合的40、20和10μg的舌下猪草。在第二轮中,其在第一轮处理结束后9天开始,第1组的小鼠在两周内具有额外6次剂量各10μg的鼻内猪草。第2组、第3组和第4组接受10μg猪草的舌下给药和鼻内5μg LTh(αK)的共同处理。第2次处理后11天开始第三轮。此为类似AIT的处理,且动物仅用猪草舌下给药6次。如图4A和4B中所示,第1组和第2组接受40μg,且第3组和第4组分别具有20和10μg的猪草。最终攻击在第三轮处理后第11天开始。在所述攻击中,动物接受五次重复各15μg的鼻内猪草,随后进行试样收集。已知Balb/c和C57BL/6小鼠分别展现对Th2和Th1的偏向免疫反应。免疫学相异小鼠的以上结果表明具有不同免疫基因背景的动物在本发明中可适用。基于此类结果得出结论,Balb/c与C57BL/6两种小鼠中的抗猪草IgG的量藉由LTh(αK)的共同处理而升高。另外,针对过敏原的IgG增强在LTh(αK)的处理之后持续数周。
此研究中的猪草购自Stallergenes Greer(XPB56D3A25)。自免疫前和处理后一周和最终攻击收集血液样品。藉由ELISA分析猪草特异性IgG。
Claims (22)
1.一种调节黏膜免疫反应的方法,其包含向有需要的个体的黏膜部位投与抗原,和向所述个体的不同解剖学黏膜部位投与免疫调节剂。
2.根据权利要求1所述的方法,其中所述抗原为免疫原。
3.根据权利要求2所述的方法,其中所述抗原为疫苗。
4.根据权利要求2所述的方法,其中所述抗原为过敏原。
5.根据权利要求2所述的方法,其中所述抗原为生物制剂。
6.根据权利要求1所述的方法,其中所述黏膜部位系选自舌下黏膜、鼻内黏膜、呼吸道黏膜、口腔黏膜、***黏膜、直肠黏膜或任何其他解剖学黏膜。
7.根据权利要求1所述的方法,其中所述免疫调节剂不诱发与其接触之细胞中产生IL6。
8.根据权利要求1所述的方法,其中所述免疫反应包括产生抗原特异性IgG和其亚类。
9.根据权利要求1所述的方法,其中所述免疫反应包括产生抗原特异性Ig M和其亚类。
10.根据权利要求1所述的方法,其中所述免疫反应包括产生抗原特异性IgA和其亚类。
11.根据权利要求1所述的方法,其中所述免疫反应包括产生抗原特异性细胞介导之免疫性。
12.根据权利要求1所述的方法,其中所述免疫反应为治疗有效的。
13.根据权利要求1所述的方法,其中所述免疫反应涉及免疫组分之上调。
14.根据权利要求1所述的方法,其中所述免疫反应涉及免疫组分之下调。
15.根据权利要求6所述的方法,其中向舌下黏膜投与所述抗原且向鼻内黏膜投与所述免疫调节剂。
16.根据权利要求3所述的方法,其中所述疫苗为季节性流感疫苗。
17.根据权利要求16所述的方法,其中所述季节性流感疫苗为A型流感病毒样疫苗或B型流感病毒样疫苗。
18.根据权利要求4所述的方法,其中所述过敏原为尘螨提取物或花粉提取物。
19.根据权利要求18所述的方法,其中所述花粉系猪草花粉。
20.根据权利要求1所述的方法,其中所述免疫调节剂为经解毒之大肠杆菌(Escherichia coli)不稳定毒素(LT)、LTh(αK)、铎样受体(TLR)促效剂或拮抗剂、Vaxfectin或模式识别受体(PRR)促效剂或拮抗剂。
21.根据权利要求20所述的方法,其中所述免疫调节剂为LTh(αK)。
22.根据权利要求1所述的方法,其中依序投与所述抗原和所述免疫调节剂。
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