CN117120088A - 佐剂活性增强剂和佐剂组合物 - Google Patents
佐剂活性增强剂和佐剂组合物 Download PDFInfo
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- CN117120088A CN117120088A CN202280026428.6A CN202280026428A CN117120088A CN 117120088 A CN117120088 A CN 117120088A CN 202280026428 A CN202280026428 A CN 202280026428A CN 117120088 A CN117120088 A CN 117120088A
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Abstract
本发明提供一种提高现有佐剂的免疫强度的佐剂活性增强剂和含有该佐剂活性增强剂的佐剂组合物。一种CpG－ODN或含有角鲨烷的乳液的佐剂活性增强剂，以结合有细胞膜穿透性肽的肽核酸作为有效成分。
Description
技术领域
本发明涉及一种佐剂活性增强剂和包含该佐剂活性增强剂的佐剂组合物。
背景技术
佐剂是为了提高疫苗的免疫原性而使用，但长期以来在人类中有实际成果的佐剂只有铝盐，其机制到近年来为止尚未被阐明。但是，现在发现了以Toll样受体(Toll－likereceptor：TLR)为代表的各种自然免疫的受体，佐剂的研究开发迅速发展。
因此，近年来，除了很早以来作为佐剂已知的有乳液型佐剂以外，还开发或上市了作为Toll样受体的配体分子的MPL(Monophosphoryl Lipid A，单磷酰脂质A)、CpG－ODN(CpG oligonucleotide，CpG寡核苷酸)、次鞭毛(Flagellin)以及PolyI：C等作为佐剂。即，能够在阐明自然免疫的机制的同时，进行以分子、机制为基础的佐剂的药物开发，因此许多新的佐剂正被实用化。另外，还开发出了将多种不同的作用机制的佐剂混合而成的混合型的佐剂，通过这些新的佐剂的开发，能够进行以往的铝盐无法诱导的Th1型免疫诱导，也能够进一步提高免疫诱导。
根据免疫诱导的类型，佐剂大致分为诱导Th1型、Th2型以及这两者的佐剂，铝盐分类为诱导Th2型，MPL、CpG－ODN和PolyI：C分类为诱导Th1型，含有角鲨烷的乳液、Flagellin分类为诱导Th1和Th2型这两者的类型。该Th1和Th2型免疫应答在生物体防御上承担不同的作用，Th1型免疫对病毒、细胞内寄生细菌显示抗性，Th2型免疫对寄生虫、细菌显示抗性。即，针对每个作为靶标的感染症，疫苗应诱导的免疫质量不同，因此需要适当地选择佐剂。
佐剂的选择点有2点，一个是如上所述进行诱导的免疫质量。另一个是免疫的强度，即能否将免疫诱导提高到防御水平。因此，必须选择佐剂以便针对每个作为靶标的感染症、疫苗抗原得到适当的免疫质量和强度。
本申请发明人等在专利文献1中报告了将细胞穿透性肽(CPP)与肽核酸结合而成的新型佐剂，但没有报告在将结合有该细胞膜穿透性肽的肽核酸与其它佐剂组合的情况下，对它们带来怎样的质量以及作用的变化。
现有技术文献
非专利文献
专利文献1：国际专利公开第2020/246584号
发明内容
本发明涉及一种提供提高现有佐剂的免疫强度的佐剂活性增强剂和含有该佐剂活性增强剂的佐剂组合物。
本发明人等进行了深入研究，结果发现在将结合有细胞膜穿透性肽的肽核酸与CpG－ODN或含有角鲨烷的乳液组合的情况下，能够在不改变CpG－ODN或含有角鲨烷的乳液的免疫质量的情况下提高免疫的强度。
即本发明涉及以下的1)～7)。
1)一种CpG－ODN或含有角鲨烷的乳液的佐剂活性增强剂，以结合有细胞膜穿透性肽的肽核酸作为有效成分。
2)一种CpG－ODN或含有角鲨烷的乳液的佐剂活性增强方法，将结合有细胞膜穿透性肽的肽核酸与CpG－ODN或含有角鲨烷的乳液组合使用。
3)一种佐剂组合物，含有结合有细胞膜穿透性肽的肽核酸和CpG－ODN或含有角鲨烷的乳液。
4)根据3)的组合物，含有药学上可允许的载体。
5)一种疫苗组合物，含有3)或4)的组合物和抗原。
6)一种结合有细胞膜穿透性肽的肽核酸的用途，用于制造CpG－ODN或含有角鲨烷的乳液的佐剂活性增强剂。
7)一种结合有细胞膜穿透性肽的肽核酸，用于增强CpG－ODN或含有角鲨烷的乳液的佐剂活性。
根据本发明，能够提高疫苗的有效性，能够创造出品质高的预防药而对医药品产业做出巨大贡献。
附图说明
图1是第21天的对A/Kansas/14/2017株(A/H3N2)的IgG抗体效价。
图2是第21天的对B/Maryland/15/2016株(B/Victoria)的IgG抗体效价。
图3A是第21天的对A/Kansas/14/2017株(A/H3N2)的IgG1子类的抗体效价。
图3B是第21天的对A/Kansas/14/2017株(A/H3N2)的IgG2a子类的抗体效价。
图3C是A/Kansas/14/2017株(A/H3N2)特异性子类比率(IgG1/IgG2a)。
图4A是第21天的对B/Maryland/15/2016株(B/Victoria)的IgG1子类的抗体效价。
图4B是第21天的对B/Maryland/15/2016株(B/Victoria)的IgG2a子类的抗体效价。
图4C是B/Maryland/15/2016株(B/Victoria)特异性的子类比率(IgG1/IgG2a)。
具体实施方式
以下，对本发明的优选的实施方式详细地进行说明。其中，本发明并不限定于以下的实施方式。
在本发明中，“结合有细胞膜穿透性肽的肽核酸”是指在细胞膜穿透性肽的N或C末端结合有肽核酸的分子，在本说明书中，也称为Mitsumata免疫刺激肽核酸(Mitsumata-Immunostimulatory Peptide nucleic acid，MIP)。
“细胞膜穿透性肽(CPP)”是指在与细胞共存的情况下通过细胞膜而转移至细胞内的肽。例如可举出表1所示的来自HIV的TAT的肽、来自果蝇的触角足的黑腹果蝇触足肽(Penetratin)、聚精氨酸、由神经肽甘丙肽衍生的转运肽(Transportan)、来自SV40的核定位信号(Nuclear LocalizationSignal，NLS)的Pep－1、抗菌肽LL37，但并不限定于它们。
优选可举出来自TAT的肽(由序列号1所示的氨基酸序列构成的肽)。
[表1]
“肽核酸(PNA)”是指具有将核酸的糖-磷酸骨架置换成N-(2-氨基乙基)甘氨酸的骨架，且通过亚甲基羰基键键合碱基而成的核酸类似物。作为本发明中使用的肽核酸中的碱基(Base)，可以为腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶中的任一者，链长理想为通常的20mer以下，从佐剂活性的方面出发，优选为3～12mer，更优选为3～10mer。
下述式(1)示出3～12mer的肽核酸的结构。
〔式中，碱基可以相同或不同，表示腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶或尿嘧啶，R表示-COOH或-CONH2，n表示1～10的整数〕
作为本发明使用的优选的肽核酸，例如可举出具有至少1个鸟嘌呤或胞嘧啶作为碱基的3mer或10mer的肽核酸、具有3个鸟嘌呤作为碱基的3mer的肽核酸(G3PNA)、具有3个胞嘧啶作为碱基的3mer的肽核酸(C3PNA)、具有10个胞嘧啶作为碱基的10mer的肽核酸(C10PNA)等。
本发明的结合有细胞膜穿透性肽的肽核酸可以通过在细胞膜穿透性肽的N或C末端利用化学的方法、例如介由两末端具有N－羟基琥珀酰亚胺酯的交联剂使细胞穿透性肽与肽核酸的N末端间共价键合来制造。
应予说明，肽核酸例如可使用Fmoc型PNA单体单元等，利用该技术领域中公知的固相肽合成法进行合成。
作为本发明中使用的优选的结合有细胞膜穿透性肽的肽核酸，可举出以下所示的来自HIV的TAT的由13个氨基酸构成的肽(序列号1)在其C末端与G3PNA共价键合而成的MIP01(式(2))、与C10PNA共价键合而成的MIP03(式(3))。
在本发明中，与结合有上述细胞膜穿透性肽的肽核酸组合使用的CpG－ODN或含有角鲨烷的乳液均为已知可作为佐剂使用的分子或组合物。
CpG－ODN(CpG oligonucleotide，CpG寡核苷酸)是包含CpG基序(由特定的6个碱基(5′－嘌呤－嘌呤－CG－嘧啶－嘧啶－3′)构成的寡聚DNA)的合成核酸，已知为介由TLR9诱导I型IFN、炎症性细胞因子、B细胞的增殖、树状细胞的成熟化、NK细胞的活化等的强力的Th1型佐剂。CpG－ODN根据结构上的特征被分类为A～C这3类，本发明的CpG－ODN的序列结构没有限定，但从诱导B细胞的增殖、树状细胞的成熟化的观点出发，优选为B类的CpG－ODN。
B类的CpG－ODN的结构的特征在于，是直线状，且具有硫代磷酸酯骨架，例如市售有ODN1668(5’-tccatgacgttcctgatgct-3’(序列号8))、ODN1826(5’-tccatgacgttcctgacgtt-3’(序列号9))、ODN2006(5’-tcgtcgttttgtcgttttgtcgtt-3’(序列号10))、CpG1018(5’-tgactgtgaacgttcgagatga-3’(序列号11)等。
含有角鲨烷的乳液是每次给药中含有角鲨烷3～15mg，优选含有5～10mg的水中包型乳浊液，除了角鲨烷以外，还可以含有表面活性剂和生育酚等抗氧化剂。作为市售品，例如可举出Addavax(商标)(InvivoGen公司；以下，称为“Addavax”)等。
在本发明的结合有细胞膜穿透性肽的肽核酸与CpG－ODN或含有角鲨烷的乳液的组合中，其使用比率相对于结合有细胞膜穿透性肽的肽核酸1质量份，CpG－ODN优选为0.06～60质量份的范围，更优选为0.6～30质量份。另外，在含有角鲨烷的乳液中，优选为30～150质量份的范围，更优选为50～100质量份。
如后所述实施例所示，在向小鼠注射将式(3)所示的MIP03与CpG－ODN(ODN1826)或含有角鲨烷的乳液(Addavax)组合，并分别添加流感抗原(分裂抗原(split antigen))而制备的疫苗组合物的情况下，对该抗原的血中的抗体效价协同地变高。另外，在IgG子类的评价中，Th1型免疫和Th2型免疫诱导的平衡分别维持CpG－ODN和含有角鲨烷的乳液的性质。即结合有细胞膜穿透性肽的肽核酸通过与CpG－ODN或含有角鲨烷的乳液组合，具有在不改变CpG－ODN或含有角鲨烷的乳液所诱导的免疫质量的情况下提高该佐剂的免疫强度的功能。
因此，结合有细胞膜穿透性肽的肽核酸成为CpG－ODN或含有角鲨烷的乳液的佐剂活性增强剂，通过与CpG－ODN或含有角鲨烷的乳液组合而使用，能够增强CpG－ODN或含有角鲨烷的乳液的佐剂活性。而且，含有结合有细胞膜穿透性肽的肽核酸和CpG－ODN或含有角鲨烷的乳液的组合物可成为发挥高免疫强度的佐剂组合物。
在本发明中，“佐剂”是指在注射或经粘膜给药抗原的情况下，使对抗原的免疫应答增加的物质。
在本发明中，“CpG－ODN或含有角鲨烷的乳液的佐剂活性增强”是指在不改变CpG－ODN或含有角鲨烷的乳液(佐剂物质)所诱导的免疫质量的情况下提高该佐剂物质的免疫强度。
本发明的佐剂组合物可以与抗原组合给药，给药可以与抗原的给药同时进行，也可以在抗原的给药之前或之后进行。
本发明的佐剂组合物的给药量可根据给药对象、给药方法、给药形态、抗原的种类而适当地确定。
本发明的佐剂组合物可以与抗原组合而制成疫苗组合物，可以进一步适当地添加药学上可允许的载体而制成适当的制剂。在本发明的疫苗组合物中，结合有细胞膜穿透性肽的肽核酸(MIP)可以与抗原或其它成分处于化学结合状态，也可以以遊离的分子状态存在。
作为抗原，符合的是由病原体纯化而得的天然产物或者通过基因重组等方法人为制作的蛋白质或肽，具体而言，可举出作为完全病毒粒子的病毒体、不完全病毒粒子、病毒结构蛋白、病毒非结构蛋白、病原菌的全菌体、来自病原菌的蛋白质或糖蛋白、感染防御抗原、中和表位等，包含具有感染性的抗原和丧失感染性的抗原(灭活抗原)。作为灭活抗原，例如可举出通过物理(X射线照射、UV照射、热、超声波)、化学(福尔马林、β-丙内酯、双乙烯亚胺、汞、醇、氯)等操作而灭活的抗原，但并不限定于这些。从安全性的观点考虑，来自病原体的抗原优选为来自上述病毒或病原菌的灭活抗原。
作为病毒，例如可举出麻疹病毒、风疹病毒、腮腺炎病毒、脊髓灰白质炎病毒、轮状病毒、诺如病毒、腺病毒、肠病毒、疱疹病毒、水痘病毒、严重急性呼吸道感染综合征(SARS)病毒、人类免疫缺陷病毒(HIV)、人类T细胞白血病病毒(HTLV-1)、人乳头状瘤病毒、日本脑炎病毒、西尼罗河病毒、黄热病毒、登革热病毒、齐卡病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒、RS病毒、流感病毒等，优选为流感病毒。
作为病原菌，可举出白喉杆菌、破伤风杆菌、百日咳杆菌、脑膜炎球菌、乙型流感菌、肺炎球菌、霍乱弧菌、结核菌、牙周病菌等。
作为疫苗组合物的剂型，例如可举出液剂、悬浮剂、冷冻干燥制剂等。作为液剂，可举出溶解于纯化水、缓冲液而成的液型等。作为悬浮剂，可举出与甲基纤维素、羟甲基纤维素、聚乙烯基吡咯烷酮、明胶、酪蛋白等一起悬浮于纯化水、缓冲液等而成的悬浮剂等。
这些制剂中，可以根据需要添加通常使用的吸收促进剂、表面活性剂、保存剂、稳定剂、防湿剂、助溶剂等。
应予说明，本发明的疫苗组合物中，只要不损害该疫苗的免疫原性和安全性，则也可以含有除结合有细胞膜穿透性肽的肽核酸、CpG－ODN和含有角鲨烷的乳液以外的佐剂物质。
本发明的疫苗组合物中所含的抗原的量只要为足以诱导特异性抗体应答的量就没有特别限定，也可考虑与所并用的佐剂组合物的比率而适当地设定。例如，在使用流感病毒的分裂抗原作为抗原的情况下，只要在1次的给药用量即1～60μgHA(HA换算)的范围内含有即可，更优选为9～15μgHA(HA换算)。上述浓度为通过利用一元放射免疫扩散试验法等按照WHO或国家的基准所确定的试验法测定HA蛋白质的浓度而得到的值。
本发明的疫苗组合物的给药路径没有特别限定，可以为利用注射的给药(皮下给药、肌肉内给药、皮内给药、静脉内给药)、口服给药、非口服给药(例如，鼻腔给药、滴眼给药、经阴道给药、舌下给药、经皮给药)中的任一者，例如通过对鼻腔内进行滴加、喷雾或喷射而进行给药。
本发明的佐剂组合物或疫苗组合物的给药对象可举出人和除人以外的哺乳动物，优选为人。作为除人以外的哺乳动物，例如可举出小鼠、大鼠、仓鼠、豚鼠、兔、猪、牛、山羊、绵羊、狗、猫、恒河猴、食蟹猴、猩猩、黑猩猩等。
实施例
以下，通过实施例对本发明进行具体说明，但本发明不受这些实施例任何限定。
＜结合有细胞膜穿透性肽的肽核酸(MIP)＞
作为MIP，委托肽研究株式会社所合成上述式(3)所示的MIP03。
实施例1DIF的流感疫苗中的佐剂活性评价
将流感HA疫苗“生研”的A/H1N1亚型(A/Kansas/14/2017株)和B/Victoria系统(B/Maryland/15/2016株)的各原液作为分裂抗原(SV)，以每0.1mL中各株的血凝素为0.6μg、MIP03为100μg以及CpG－ODN(ODN1826(InvivoGen公司)，序列号9)为6μg的方式进行添加，将其作为DIF－01制剂。另外，使用分裂抗原(SV)，以每0.05mL中各株的血凝素为0.6μg、MIP03为100μg的方式进行添加，在该制备液中混合等量的氢氧化铝(Alm(ThermoScientific公司))或含有角鲨烷的乳液(Addavax(InvivoGen公司))，分别制成DIF－02制剂和DIF－03制剂。
另外，作为对照，分别制备以每0.1mL中各株的血凝素为0.6μg的方式制备的非佐剂制剂，以每0.1mL中各株的血凝素为0.6μg和MIP03为100μg的方式制备的MIP－03制剂，以每0.1mL中各株的血凝素为0.6μg和ODN1826为6μg的方式制备的ODN1826制剂，使用分裂抗原(SV)，以每0.05mL中各株的血凝素为0.6μg的方式调整并向其中混合等量的Alm(ThermoScientific)或Addavax(InvivoGen)而成的Alm制剂和Addavax制剂。
将如上所述制备的制剂(表2)向BALB/c小鼠(雌，5周龄)的后背部皮下给药0.1mL(各组8只)，从给药起21天后进行全采血。将通过全采血而得到的血液进行离心分离而制备血清，分别测定血清的与A/Kansas/14/2017株和B/Maryland/15/2016株特异性地结合的IgG(总IgG)抗体效价、IgG1子类抗体效价以及IgG2a子类抗体效价。
[表2]
各给药组的IgG抗体效价如图1和图2所示。关于对A/Kansas/14/2017株的抗体效价，DIF－01制剂给药组相对于ODN1826制剂给药组，DIF－03制剂给药组相对于Addavax制剂给药组，均显示显著高的抗体诱导。另外，关于对B/Maryland/15/2016株的抗体效价，DIF－03制剂给药组相对于Addavax制剂给药组，显示显著高的抗体诱导，DIF－01制剂给药组虽然没有显著性差异，但为比ODN1826制剂给药组高的抗体效价。将显示统计学显著性差异的DIF－01、DIF－03和它们所包含的佐剂的单独给药组的几何平均抗体效价(GMT)和GMT相对于非佐剂组的比率汇总于表3和4。表3中总结了相对于A/Kansas/14/2017株的GMT和GMT比率，DIF－01与ODN1826、MIP－03相比，GMT的比率大，认为显示协同的效果，这在DIF－03与Addavax和MIP－03的比较中也同样。另外，对于B/Maryland/15/2016株，如表4所示，与A/Kansas/14/2017株同样地，认为DIF－01和DIF－03的GMT是协同的佐剂效果的结果。因此，对于DIF－01和DIF－03，通过佐剂的混合而显示协同的免疫激活效果。另一方面，DIF－02制剂给药组与Alm制剂给药组的抗体诱导为相同程度，可知MIP－03在与Alm混合时无法期待佐剂活性的提高。
[表3]
*相对于非佐剂组的GMT比率
[表4]
| 佐剂 | GMT | GMT比率※ |
| DTF-01 | 84733 | 5.7 |
| ODN1826 | 31152 | 2.1 |
| DIF-03 | 201740 | 13.5 |
| 佐剂 | 61167 | 4.1 |
| MIP-03 | 25802 | 1.7 |
| 非佐剂 | 14923 | 1.0 |
*相对于非佐剂组的GMT比率
接下来，评价IgG1和IgG2a子类的抗体效价与子类的比率。将A/Kansas/14/2017株的结果示于图3A～图3C，将B/Maryland/15/2016株的结果示于图4A～图4C，DIF-01制剂和DIF-03给药组的各子类的抗体效价均显示与ODN1826制剂给药组和Addavax制剂给药组相比同等或高的抗体效价，IgG1/IgG2a的子类的比率在DIF-01制剂给药组中与ODN1826制剂给药组同样地为IgG2a优势，在DIF-03制剂给药组中与Addavax制剂给药组同样地为IgG1优势。因此，认为MIP-03具有在不改变所混合的已知的佐剂所诱导的免疫质量的情况下提高免疫的强度的作用。
序列表
<110> 电化株式会社
<120> 佐剂活性增强剂和佐剂组合物
<130> DK0014
<150> JP2021-065379
<151> 2021-04-07
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Claims (7)
1.一种CpG－ODN或含有角鲨烷的乳液的佐剂活性增强剂，以结合有细胞膜穿透性肽的肽核酸作为有效成分。
2.一种CpG－ODN或含有角鲨烷的乳液的佐剂活性增强方法，将结合有细胞膜穿透性肽的肽核酸与CpG－ODN或含有角鲨烷的乳液组合使用。
3.一种佐剂组合物，含有结合有细胞膜穿透性肽的肽核酸和CpG－ODN或含有角鲨烷的乳液。
4.根据权利要求3所述的组合物，其中，含有药学上可允许的载体。
5.一种疫苗组合物，含有权利要求3或4所述的组合物和抗原。
6.一种结合有细胞膜穿透性肽的肽核酸的用途，用于制造CpG－ODN或含有角鲨烷的乳液的佐剂活性增强剂。
7.一种结合有细胞膜穿透性肽的肽核酸，用于增强CpG－ODN或含有角鲨烷的乳液的佐剂活性。
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| JP2021-065379 | 2021-04-07 | ||
| JP2021065379 | 2021-04-07 | ||
| PCT/JP2022/017302 WO2022215737A1 (ja) | 2021-04-07 | 2022-04-07 | アジュバント活性増強剤及びアジュバント組成物 |
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| JP (1) | JPWO2022215737A1 (zh) |
| KR (1) | KR20230157429A (zh) |
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| PL349347A1 (en) * | 1999-01-12 | 2002-07-15 | Smithkline Beecham Biolog | Novel treatment |
| PT2699318T (pt) * | 2011-04-18 | 2017-11-23 | Univ Georgia | Método de administração de vacina |
| JP2020002117A (ja) * | 2018-06-26 | 2020-01-09 | 日本ビーシージー製造株式会社 | スクアレン含有アジュバント組成物 |
| WO2020246584A1 (ja) | 2019-06-06 | 2020-12-10 | デンカ株式会社 | ペプチド核酸を基盤としたアジュバント |
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| JPWO2022215737A1 (zh) | 2022-10-13 |
| WO2022215737A1 (ja) | 2022-10-13 |
| KR20230157429A (ko) | 2023-11-16 |
| AU2022255844A1 (en) | 2023-11-16 |
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