CN102892461B - 口部粘膜电穿孔装置及其用途 - Google Patents
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Abstract
本发明涉及电穿孔(EP)装置，其能够优选以可容忍的方式产生电穿孔，从而在粘膜层处引起电场。另外，其包括使用口部EP装置连同编码免疫原序列的基因构造体来产生保护性免疫应答(细胞和/或体液)。
Description
技术领域
本发明涉及能够将治疗剂递送至受试者的电穿孔装置。
背景技术
已知大量人病原体在粘膜表面处引起感染，因此使得通过胃肠道、泌尿生殖道和呼吸道进入机体。结果，接触感染的其他首要方式是通过血液-负载的途径，例如注射、输液和叮咬。粘膜感染剂的例子包括感冒病毒、流感、食物中毒剂、结核病、性传播疾病和瘟疫。
粘膜是机体的最大器官中的一种。总体来说，它们覆盖超过400m2的表面积(等同于一个半网球场)，并且包括胃肠道、泌尿生殖道和呼吸道的内层。这些粘膜表面尽管位于体内，但是实际上是已知为″系统″环境的机体的外部和无菌内腔之间的物理屏障。关键营养物、氧气和其他分子穿过这些粘膜屏障被不断地摄取；然而，粘膜的另外重要功能是防范病原体入侵。每日这些粘膜被外部元素轰击，并且直到独特的粘膜免疫系统来决定什么是潜在有害的和什么是有益的。
粘膜免疫的重要性存在于粘膜应答和系统免疫应答之间的相互影响。一些研究已经证实，系统性刺激免疫系统(即通过注射或学院-负载的途径)导致仅在机体的无菌内部环境内产生保护性抗体和T细胞-没有产生粘膜应答。另一方面，粘膜免疫应答的刺激可以导致在粘膜和系统环境中产生保护性B和T细胞，使得在它们进入机体之前就停止感染。
粘膜产生特定类型的抗体，称为分泌型IgA或sIgA。粘膜浸在大量sIgA中，这起到防御第一线的作用以使侵入的病原体中和。试验证据表明sIgA的存在和对于各种病原体引起的感染的抗性有关，所述病原体包括细菌、病毒、寄生虫和真菌。还表明使病毒中和并防止它们粘附于粘膜内层的上皮细胞(从而防止感染)，以及介导病原体的排泄和防止成熟病毒颗粒的集合。
粘膜免疫的另外重要部分是T细胞-介导的免疫应答。特异性识别病原体的T-细胞可以帮助抗体清除感染或直接杀死入侵者本身。粘膜中产生的T细胞能够通过它们膜上的特别″导航″受体在粘膜组织内运动。这表示如果免疫应答产生于胃肠道内层，此处产生的T细胞可以运动至其他粘膜位点，例如肺腔或鼻腔，从而在较大面积内提供保护。
尽管粘膜表面具有重要的作用，但是只有少量疫苗特异性靶向该免疫系统区域，因此保持需要这样的疫苗，该疫苗导向粘膜表面以在粘膜组织处提供保护性免疫应答。
发明概述
提供能够电穿孔哺乳动物的粘膜细胞的电穿孔装置。这种装置包括：电极显微针板、反电极板、主壳体和能量源。主壳体物理相连所述显微针板和反电极板，其中主壳体流体相连注射器，所述注射器能够储存用于递送的药剂。能量源电相连显微针板，并且能够产生电势和通过所述显微针板将所述电势递送至所述细胞。
在另一方面，提供使用提供的装置将药剂施用至哺乳动物的粘膜细胞的方法。所述方法包括：使所述显微针板接触所述粘膜；将所述药物组成递送至所述粘膜；以及应用电穿孔，从而通过所述显微针板由所述能量源产生电脉冲至所述粘膜。
附图简述
图1示出待在小鼠中进行的免疫(通过标准注射)和攻击时间表。
图2显示图，该图示出趋化因子佐剂在粘膜肺部感染的小鼠模型中诱导特异性针对流感APR/8/34的细胞内免疫。
图3a显示图，该图示出流感A/PR/8/34-特异性血清长期存活的IgA和IgG预-攻击；图3b显示图，该图示出流感A/PR/8/34中和抗体预-攻击；图3c显示线图，该图示出数天内平均重量损失；以及图3d显示线图，该图示出在攻击后各种的存活率。
图4显示关于IndianRhesus猕猴免疫目录的时间表和另外的信息。
图5显示图，该图示出DNA疫苗的已知IM(肌肉)/EP(电穿孔)递送的ELISpot数据优于仅仅IM递送。
图6显示图和图像，它们示出产生强烈的免疫应答：图6a显示图，该图示出ELISpot数据；图6b显示图，该图示出T细胞增殖水平；图6c示出来自R10或SIV肽培养基的板；以及图6d示出表明CFSE增殖的图像。
图7显示图像，该图像示出在BAL中由CD4+T细胞引起的CTACKCo-免疫增强细胞因子分泌：图7a显示图，该图示出外周中的细胞应答；图7b显示图，该图示出BAL中的细胞应答。
图8显示图，该图示出CTACK在肺部引诱高水平的细胞因子分泌CD8+T细胞：图8a显示图，该图示出107a+CD8+水平；图8b显示图，该图示出IFN-γCD+水平；图8c显示图，该图示出TNF+CD8+水平；以及图8d显示图，该图示出IL-2+CD8+水平。
图9显示照片，其通过荧光的方式示出阳性GFP表达。
图10显示4x4阵列(InovioPharmaceuticals，Inc.，BlueBell，Pennsylvania)。
图11显示图，该图示出使用SynConTM流感疫苗免疫的猕猴血清中的HAI滴度水平。示出的结果为两周后的次级免疫：图11a为涉及A/H1N1/Mexico/2009株的HAI滴度；以及图11b为涉及A/H1N1/NewCaledonia的HAI滴度。
图12a显示照片，其示出浅层注射GFP质粒和电穿孔后豚鼠口部粘膜组织中的GFP表达。在3天后处理收获全部面颊顶部，并且在荧光显微镜下观察以确定阳性GFP表达。
图12b显示图，该图示出在豚鼠中3次免疫后H5-特异性IgA滴度。
图13是口部电穿孔/注射装置的3/4视图，其包括：脉冲发生器、注射和电穿孔装置。
图14是绘图，其示出口部电穿孔/注射装置的垂直剖视图A-A。
图15是电穿孔/注射装置的分解组件。
图16是电穿孔/注射装置的主电极显微针板。
图17示出涉及开口的OM-I/EP装置。
图18显示图，该图示出a)唾液；b)大便；c)血液中的IgA滴度。
发明详述
提供能够电穿孔哺乳动物的粘膜细胞的电穿孔装置。这种装置包括：电极显微针板、反电极板、主壳体和能量源。主壳体物理相连所述显微针板和反电极板，其中主壳体流体相连注射器，所述注射器能够储存用于递送的药剂。能量源电相连显微针板，并且能够产生电势和通过所述显微针板将所述电势递送至所述细胞。在实施方案中，在所述主壳体和所述显微针板之间还存在物理相连的活塞。所述活塞是可驱动的，并且通过驱动能够引起通过所述显微针板的所述药剂均匀分布。
在本发明的一个方面，提供口部电穿孔(EP)装置，其能够优选以可容忍的方式产生电穿孔，从而在粘膜层处引起电场。在该方面的一个实施方案中，存在口部粘膜注射和电穿孔装置(OM-I/EP)，其适于递送治疗剂(或预防剂)，例如DNA疫苗，并且转染到口腔内部上的粘膜组织/细胞中。在DNA免疫过程中，装置将穿过患者的面颊区域附着。具有主电极显微针板特征的主体在口腔的内部上，并且临近的返回电极板夹具特征在面颊的外部上。DNA疫苗将通过显微针板注射；然后这将进行施加至相同电极显微针板的低电压EP脉冲，该设计将DNA疫苗和电穿孔共同定位至相同区域。研究表明DNA疫苗和EP以DNA疫苗转染到周围细胞中的量共同定位是非常重要的。
在一些实施方案中，显微针板的显微针由导电材料制成，所述导电材料包括镀金和银的黄铜、镀金和银的铜、不锈钢或钛、或其他通常已知的导电金属或金属样材料。在一些实施方案中，能量源能够以至少一种电能脉冲通过所述显微针板递送至所述粘膜细胞，所述电能脉冲具有1V至30V、2mA至100mA或1mS至250mS的特性。粘膜或粘膜组织可以是颊粘膜、鼻粘膜、食道粘膜、直肠粘膜、阴道粘膜、外阴粘膜、小肠粘膜、肠粘膜、胃粘膜、膀胱粘膜、尿道粘膜或眼组织粘膜，并优选颊组织粘膜，例如口腔的内表面。
在另一方面，提供使用提供的装置将药剂施用至哺乳动物的粘膜细胞的方法。所述方法包括：使所述显微针板接触所述粘膜；将所述药物组成递送至所述粘膜；以及应用电穿孔，从而通过所述显微针板由所述能量源产生电脉冲至所述粘膜。
在体内电穿孔的过程中，电脉冲直接应用至组织以增强细胞外分子的摄取。利用非常高的伏特/厘米的电场强度来进行存在类型的体内EP，由于神经密度校对，因此在粘膜组织中使用这样大的电场强度对于患者将是痛苦的。使用当前OM-I/EP装置，它们可以装备以递送非常低场强的EP，例如使用在皮内(ID)注射位点处应用的低能量的电脉冲，这在2010年4月16日早期提交的共同拥有的PCT申请-名称“CONTACTLESSELECTROPERMEABILIZATIONELECTRODEANDMETHOD”，申请号PCT/US10/31431中有所描述，其通过引用的方式全部并入本文。这种皮内EP可以使用非常低的电压来进行，并且对于患者具有最小的痛苦。在早期试验中，在粘膜组织上，这些更低EP场强已经显示在具有类似结果(数据未示出)的情况下转染到粘膜组织中。EP参数可以包括：下列范围的电压：0.1伏特(V)至30V，0.1V至20V，0.1V至15V，0.1V至10V，0.1V至9V，0.1V至8V，0.1V至7V，0.1V至6V，0.1V至5V，0.1V至4V，0.1V至3V，0.1V至2V，0.1V至1V，2V至30V，2V至20V，2V至15V，2V至10V，2V至9V，2V至8V，2V至7V，2V至6V，2V至5V，2V至4V，2V至3V，4V至30V，4V至20V，4V至15V，4V至10V，4V至9V，4V至8V，4V至7V，4V至6V，4V至5V，6V至30V，6V至20V，6V至15V，6V至10V，6V至9V，6V至8V，8V至30V，8V至20V，8V至15V，8V至10V，8V至9V，10V至30V，10V至20V，或10V至15V；以及下列范围的电流：2mA至100mA，3mA至100mA，4mA至100mA，5mA至100mA，6mA至100mA.7mA至100mA，8mA至100mA，9mA至100mA，10mA至100mA，20mA至100mA，30mA至100mA，40mA至100mA，60mA至100mA，80mA至100mA，2mA至80mA，3mA至80mA，4mA至80mA，5mA至80mA，6mA至80mA，7mA至80mA，8mA至80mA，9mA至80mA，10mA至80mA，20mA至80mA，30mA至80mA，40mA至80mA，60mA至80mA，2mA至60mA，3mA至60mA，4mA至60mA，5mA至60mA，6mA至60mA，7mA至60mA，8mA至60mA，9mA至60mA，10mA至60mA，20mA至60mA，30mA至60mA，40mA至60mA，2mA至40mA，3mA至40mA，4mA至40mA，5mA至40mA，6mA至40mA，7mA至40mA，8mA至40mA，9mA至40mA，10mA至40mA，20mA至40mA，30mA至40mA，2mA至30mA，3mA至30mA，4mA至30mA，5mA至30mA，6mA至30mA，7mA至30mA，8mA至30mA，9mA至30mA，10mA至30mA，20mA至30mA，2mA至20mA，3mA至20mA，4mA至20mA，5mA至20mA，6mA至20mA，7mA至20mA，8mA至20mA，9mA至20mA，10mA至20mA，2mA至10mA，3mA至10mA，4mA至10mA，5mA至10mA，6mA至10mA，7mA至10mA，8mA至10mA，9mA至10mA，2mA至9mA，3mA至9mA，4mA至9mA，5mA至9mA，6mA至9mA.7mA至9mA.8mA至9mA，2mA至8mA，3mA至8mA，4mA至8mA，5mA至8mA，6mA至8mA.7mA至8mA，2mA至7mA，3mA至7mA，4mA至7mA，5mA至7mA，6mA至7mA.2mA至6mA，3mA至6mA，4mA至6mA，5mA至6mA，2mA至5mA，3mA至5mA，4mA至5mA，2mA至4mA，或3mA至4mA。在一些实施方案中，使用的EP参数范围为最高端的30伏特和100mA至2伏特和2mA。对于EP递送，期望的组织接受两次(2)脉冲，每次100ms，脉冲之间使用100ms延迟。
OM-I/EP装置具有固定至主壳体(零件#1)头部的主电极显微针板(零件#3&图15)。电压返回电极板和臂(零件#5和#6)设置在口腔的附近和外部。主壳体(零件#1)可以安装至标准1-mllure-锁注射器(零件#8)。在使用中，显微针板阵列(零件#3&图15)放置在和颊粘膜内层(面颊的内表面)紧密接触的口腔的内部上。电压返回电极(零件#5)将接触面颊的外部相邻表面。显微针板阵列(零件#3&图15)、主壳体(零件#1)和所附注射器(零件#8)形成注射/电穿孔装置。较大显微针阵列的设计允许在较大区域内注射DNA疫苗。显微针的较小尺寸和较短长度使DNA疫苗放置控制的特异性深度。活塞(零件#2)和其密封o-环(零件#9)形成通常歧管区域和驱动器，它们将确保通过显微针板(零件#3&图15)的DNA疫苗均匀分布。
主电极(零件#3&图15)的要求是它们具有拥有特异性长度和直径的多个显微针。电极也必须由导电材料(例如镀金/银的黄铜或铜、不锈钢和/或钛)制成。DNA疫苗必须放置在粘膜的上部大部分层。主电极(零件#3&图15)可以通过多种生产工艺来制造：例如化学蚀刻、放电机械加工(EDM)和在牺牲图案上的化学镀镍。主壳体和支撑部件可以由注塑材料(例如ABS、聚碳酸酯和聚烯烃)制成。
图4-8示出支持下列情况的结果：
优化的SIVDNA构建体+EP引诱的IFN-g(～12,000SFC/106)和增殖性CD8+T细胞应答(～20％)(和CTACK无差别)。在第四次免疫后这些应答最高。
通过下列方式加入优化的CTACKDNA没有在外周中进一步增强诱导的应答：
-IFN-gELISpot
-CFSE增殖
-PBMC细胞因子分泌
-血清中的IgA
加入优化的CTACKDNA改变粘膜中应答的显型，这通过下列方式来测量：
-BAL细胞因子分泌
-更多多功能CD8+T细胞
-更高频率地应答CD4+和CD8+T细胞
-粪便&BAL样品中的IgA
实施例
在下面实施例中进一步示出本发明。应该理解，尽管表明本发明的优选实施方案，但是这些实施例仅仅通过示意性方式给出。从上面讨论和这些实施例，本领域技术人员可以确认该发明的基本的特性，并且在不偏离本发明的精神和范围的情况下，可以对本发明进行多种改变和修改，以使其适应多种用途和条件。因此，除了本文示出和描述的那些，从上面的描述本领域技术人员将明白本发明的多种修改。这种修改也旨在落入所附权利要求的范围内。
进行试验以评价通过EP增强的粘膜(口部)途径使用流感HA抗原免疫的动物的血液、鼻分泌物、唾液和大便中的IgA滴度。在唾液中观察到明显的IgA滴度表明在局部粘膜区域中成功地提高粘膜免疫应答。在大便样品中检测到IgA应答表明在较远位点提高粘膜应答。在血清中检测到IgA滴度表明也提高系统应答。
H5IgAELISA
在三次粘膜EP-增强的免疫后，在使用4x4装置(InovioPharmaceuticals，Inc.，BlueBell，Pennsylvania)电穿孔的4只动物的3只和使用卡钳电穿孔装置电穿孔的4只动物的4只的唾液中观察到阳性H5特异性IgA滴度。在仅注射组中只有一只动物是阳性的。参见图18a-18c。
在使用4x4装置进行三次免疫后，两只动物在它们的血液样品中具有靶向特异性阳性IgA滴度。来自4x4装置和卡钳组的一只动物在它们的大便中具有靶向特异性IgA应答。
没有阴性对照或仅注射组动物具有阳性IgA大便或血液样品。
Claims (8)
1.一种电穿孔哺乳动物的粘膜细胞的装置，其中所述装置包括：
电极显微针板；和
能量源，其电相连所述显微针板，并且能够产生电势和通过所述显微针板将所述电势递送至所述粘膜细胞；
其特征在于所述装置还包括：
自显微针板穿过而放置的反电极板，其中所述反电极板和显微针板在粘膜的相对侧；和
与所述显微针板和反电极板物理相连的主壳体，其中所述主壳体流体相连注射器，所述注射器能够储存用于递送的药剂。
2.根据权利要求1所述的装置，其中所述显微针板的显微针由包含镀金和银的黄铜、镀金和银的铜、不锈钢或钛的导电材料制成。
3.根据权利要求1或2中任一项所述的装置，还包括：
在所述主壳体和所述显微针板之间物理相连的活塞，
其中所述活塞是可驱动的，并且能够引起通过所述显微针板的所述药剂均匀分布。
4.根据权利要求1或2中任一项所述的装置，其中所述能量源能够以至少一种电能脉冲通过所述显微针板递送至所述粘膜细胞，所述电能脉冲具有1V至30V、2mA至100mA或1mS至250mS的特性。
5.根据权利要求3所述的装置，其中所述能量源能够以至少一种电能脉冲通过所述显微针板递送至所述粘膜细胞，所述电能脉冲具有1V至30V、2mA至100mA或1mS至250mS的特性。
6.根据权利要求1或2中任一项所述的装置，其中所述粘膜包括颊粘膜、鼻粘膜、食道粘膜、直肠粘膜、阴道粘膜、外阴粘膜、小肠粘膜、肠粘膜、胃粘膜、膀胱粘膜、尿道粘膜或眼组织粘膜。
7.根据权利要求3所述的装置，其中所述粘膜包括颊粘膜、鼻粘膜、食道粘膜、直肠粘膜、阴道粘膜、外阴粘膜、小肠粘膜、肠粘膜、胃粘膜、膀胱粘膜、尿道粘膜或眼组织粘膜。
8.根据权利要求4所述的装置，其中所述粘膜包括颊粘膜、鼻粘膜、食道粘膜、直肠粘膜、阴道粘膜、外阴粘膜、小肠粘膜、肠粘膜、胃粘膜、膀胱粘膜、尿道粘膜或眼组织粘膜。
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| PCT/US2011/034277 WO2011137221A1 (en) | 2010-04-28 | 2011-04-28 | Oral mucosal electroporation device and use thereof |
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| CA3009348A1 (en) * | 2015-12-30 | 2017-07-06 | Inovio Pharmaceuticals, Inc. | Electroporation device with detachable needle array with lock-out system |
| WO2022264147A2 (en) * | 2021-06-16 | 2022-12-22 | N.M.B. Medical Applications Ltd. | Electroporation treatment |
Citations (1)
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| US6678556B1 (en) * | 1998-07-13 | 2004-01-13 | Genetronics, Inc. | Electrical field therapy with reduced histopathological change in muscle |
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|---|---|---|---|---|
| EP0398960B1 (en) * | 1988-01-21 | 1995-12-06 | Massachusetts Institute Of Technology | Transport of molecules across tissue using electroporation |
| US5318514A (en) * | 1992-08-17 | 1994-06-07 | Btx, Inc. | Applicator for the electroporation of drugs and genes into surface cells |
| AU2682795A (en) * | 1994-06-17 | 1996-01-15 | Hisamitsu Pharmaceutical Co., Inc. | Electrode for iontophoresis and device using the same |
| US5810762A (en) * | 1995-04-10 | 1998-09-22 | Genetronics, Inc. | Electroporation system with voltage control feedback for clinical applications |
| AR008242A1 (es) * | 1996-06-18 | 1999-12-29 | Alza Corp | Dispositivo para atravesar el estrato corneo de una superficie corporal |
| US6775569B2 (en) * | 1997-11-05 | 2004-08-10 | Hisamitsu Pharmaceutical Co., Inc. | Electroporation device for in vivo delivery of therapeutic agents |
| US7456012B2 (en) * | 1997-11-06 | 2008-11-25 | Cellectricon Ab | Method and apparatus for spatially confined electroporation |
| US6503231B1 (en) | 1998-06-10 | 2003-01-07 | Georgia Tech Research Corporation | Microneedle device for transport of molecules across tissue |
| US6972013B1 (en) * | 1998-07-13 | 2005-12-06 | Genetronics, Inc. | Enhanced delivery of naked DNA to skin by non-invasive in vivo electroporation |
| US6743211B1 (en) * | 1999-11-23 | 2004-06-01 | Georgia Tech Research Corporation | Devices and methods for enhanced microneedle penetration of biological barriers |
| WO2005094526A2 (en) * | 2004-03-24 | 2005-10-13 | Corium International, Inc. | Transdermal delivery device |
| US20080058706A1 (en) | 2004-06-30 | 2008-03-06 | Genetronics, Inc. | Modular electroporation device with disposable electrode and drug delivery components |
| US8696619B2 (en) * | 2004-08-10 | 2014-04-15 | Robert P. Schnall | Drug delivery devices |
| JP2011509743A (ja) | 2008-01-17 | 2011-03-31 | ジェネトロニクス，インコーポレイティド | 可変電流密度単一針電気穿孔システムおよび方法 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6678556B1 (en) * | 1998-07-13 | 2004-01-13 | Genetronics, Inc. | Electrical field therapy with reduced histopathological change in muscle |
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| KR102341551B1 (ko) | 2021-12-21 |
| KR102593818B1 (ko) | 2023-10-25 |
| KR20190020187A (ko) | 2019-02-27 |
| KR101952155B1 (ko) | 2019-02-26 |
| EP2563460A4 (en) | 2013-11-20 |
| KR101883715B1 (ko) | 2018-07-31 |
| CA2795547A1 (en) | 2011-11-03 |
| US10124159B2 (en) | 2018-11-13 |
| EP2563460B1 (en) | 2017-07-19 |
| KR102192390B1 (ko) | 2020-12-17 |
| HK1180990A1 (zh) | 2013-11-01 |
| US20210146118A1 (en) | 2021-05-20 |
| EP2563460A1 (en) | 2013-03-06 |
| US20190184153A1 (en) | 2019-06-20 |
| KR20230151558A (ko) | 2023-11-01 |
| US20130041310A1 (en) | 2013-02-14 |
| CN102892461A (zh) | 2013-01-23 |
| KR20200141542A (ko) | 2020-12-18 |
| KR20130065639A (ko) | 2013-06-19 |
| KR20210156331A (ko) | 2021-12-24 |
| WO2011137221A1 (en) | 2011-11-03 |
| US10905870B2 (en) | 2021-02-02 |
| KR20180088500A (ko) | 2018-08-03 |
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