CN102905728B - 具有不偶合的佐剂的纳米载体组合物 - Google Patents
具有不偶合的佐剂的纳米载体组合物 Download PDFInfo
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Abstract
披露了多种具有分开的佐剂组合物的合成纳米载体组合物以及相关方法。
Description
相关申请
本申请根据35U.S.C.§119要求了2010年5月26日提交的美国临时申请61/348713、2010年5月26日提交的61/348717号、2010年5月26日提交的61/348728以及2010年6月25日提交的61/358635的权益,各自的全文内容通过引用结合在此。
发明领域
本发明涉及如用于治疗希望产生免疫应答的疾病的合成纳米载体和分开的佐剂组合物以及相关方法。
发明背景
佐剂总体上是用于大多数当前使用的疫苗接种方案的重要组分。但是,在多种情况下,尚未知晓用于用佐剂增强免疫应答的最佳方法。因此,需要改进的组合物和治疗方法来提供用于希望产生免疫应答和/或增强免疫应答的疾病的改进疗法。
发明内容
一个方面,提供一种组合物,包含一个剂型,该剂型包含(1)一群合成纳米载体,(2)一种不偶合到任何合成纳米载体上的第一佐剂,以及(3)一种药物学上可接受的赋形剂。另一个方面,提供一种方法,包括给予一位受试者该组合物。
在一个实施方案中,在此提供的这些组合物(包括所提供的这些方法的组合物)包含一次全身剂量的该第一佐剂。在另一个实施方案中,所述组合物进一步包含一种第二佐剂。在再另一个实施方案中,该第一佐剂与该第二佐剂不同。在又另一个实施方案中,该第一佐剂与该第二佐剂相同。在再另一个实施方案中,在此提供的这些组合物(包括所提供的这些方法的组合物)包含一次全身剂量的该第一佐剂和/或该第二佐剂。在一个实施方案中,该全身剂量引起全身释放TNF-α、IL-6和/或IL-12。在另一个实施方案中,该全身剂量引起全身释放IFN-γ、IL-12和/或IL-18。
在一个实施方案中,所提供的这些组合物(包括所提供的这些方法的组合物)的第二佐剂被偶合到这些合成纳米载体上。在另一个实施方案中,这些第二佐剂不偶合到任何合成纳米载体上。在又另一个实施方案中,该第二佐剂被偶合到另一群合成纳米载体上。
在另一个实施方案中,在此提供的这些组合物(包括所提供的这些方法的组合物)包含一种或多种抗原。在另一个实施方案中,该一种或多种抗原被偶合到这些合成纳米载体上。在又另一个实施方案中,该一种或多种抗原被偶合到另一群合成纳米载体上。在另一个实施方案中,该一种或多种抗原不偶合到任何合成纳米载体上。
在一个实施方案中,所提供的这些组合物(包括所提供的这些方法的组合物)的该一种或多种抗原包含一种B细胞抗原和/或一种T细胞抗原。在另一个实施方案中,这些T细胞抗原是一种通用T细胞抗原或T辅助细胞抗原。在另一个实施方案中,该一种或多种抗原包含一种B细胞抗原和/或一种T细胞抗原以及一种通用T细胞抗原或T辅助细胞抗原。在一个实施方案中,该B细胞抗原是烟碱。在又另一个实施方案中,所提供的这些组合物(包括所提供的这些方法的组合物)不包含一种抗原。
在所提供的这些组合物(包括所提供的这些方法的组合物)的一个实施方案中,该第一佐剂和/或该第二佐剂包含一种矿物盐、凝胶型佐剂、一种微生物佐剂、一种基于油-乳液或乳化剂的佐剂、一种微粒佐剂、一种合成佐剂、一种磷酸盐佐剂、一种聚合物、一种脂质体、一种微载体、一种免疫刺激核酸、明矾、一种皂甙、一种白细胞介素、一种干扰素、一种细胞因子、一种toll样受体(TLR)激动剂、一种咪唑并喹啉、一种细胞因子受体激动剂、一种CD40激动剂、一种Fc受体激动剂、一种补体受体激动剂、QS21、维生素E、角鲨烯、生育酚、QuilA、多种ISCOM、ISCOMATRIX、RibiDetox、CRL-1005、L-121、四氯十氧化物(tetrachlorodecaoxide)、明矾、MF59、AS02、AS15、霍乱毒素、单磷酰脂质A、不完全弗氏佐剂、完全弗氏佐剂、胞壁酰二肽或莫泰立德(montanide)。在一个实施方案中,该免疫刺激核酸包含一种包含CpG的核酸。在另一个实施方案中,该咪唑并喹啉包含瑞喹莫德或咪喹莫特。在再另一个实施方案中,该第一和/或该第二佐剂包含明矾。在一个实施方案中,当该第一佐剂包含一种包含CpG的核酸时,该第二佐剂包含一种咪唑并喹啉或明矾。在另一个实施方案中,该咪唑并喹啉是瑞喹莫德。在再另一个实施方案中,当该第一佐剂包含一种咪唑并喹啉时,该第二佐剂包含一种包含CpG的核酸或明矾。在另一个实施方案中,该咪唑并喹啉是瑞喹莫德。在一个实施方案中,当该第一佐剂包含明矾时,该第二佐剂包含一种咪唑并喹啉或一种包含CpG的核酸。在另一个实施方案中,该咪唑并喹啉是瑞喹莫德。在另一个实施方案中,该TLR激动剂包含一种TLR-1、TLR-2、TLR-3、TLR-4、TLR-5、TLR-6、TLR-7、TLR-8、TLR-9、TLR-10、TLR-11激动剂或其一种组合。在另一个实施方案中,该第一佐剂和/或该第二佐剂不包含一种TLR激动剂。在又另一个实施方案中,该第一佐剂和/或该第二佐剂不包含一种TLR-3、TLR-7、TLR-8或TLR-9激动剂。在一个实施方案中,该第二佐剂被偶合到该合成纳米载体上并且包含瑞喹莫德。
在一个实施方案中,在此提供的这些组合物(包括所提供的这些方法的组合物)的这些合成纳米载体包含脂质纳米颗粒、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳液、树枝状聚合物、巴克球、纳米线、病毒样颗粒、肽或蛋白质颗粒、包含纳米材料的一种组合的纳米颗粒、球形纳米颗粒、立方形纳米颗粒、金字塔形纳米颗粒、长方形纳米颗粒、圆柱形纳米颗粒或环形纳米颗粒。
在一个实施方案中,这些合成纳米载体包含一种或多种聚合物。在另一个实施方案中,该一种或多种聚合物包含一种聚酯。在又另一个实施方案中,该一种或多种聚合物包含或进一步包含一种偶合到一种亲水性聚合物上的聚酯。在另一个实施方案中,该聚酯包含一种聚(乳酸)、聚(乙醇酸)、聚(乳酸-共-乙醇酸)或聚己内酯。在再另一个实施方案中,该亲水性聚合物包含一种聚醚。在另一个实施方案中,该聚醚包含聚乙二醇。
在另一个实施方案中,在此提供的这些组合物(包括所提供的这些方法的组合物)的该一种或多种抗原包含烟碱和一种通用T细胞抗原或T辅助细胞抗原,这些物质各自被偶合到这些合成纳米载体上。
在另一个实施方案中,在此提供的这些组合物(包括所提供的这些方法的组合物)的该通用T细胞抗原或T辅助细胞抗原通过封装来偶合。在再另一个实施方案中,该T辅助细胞抗原包含一种从卵白蛋白获得或衍生的肽。在另一个实施方案中,该从卵白蛋白获得或衍生的肽包含如SEQIDNO:1中所阐明的序列。
另一个方面,提供一种方法,包括给予一位受试者在此提供的任何这些组合物。在一个实施方案中,该受试者是一个人。
另一个方面,提供一种方法,包括给予一位受试者任何所提供的这些组合物和一种第二佐剂,其中在不同于给予该组合物的时间给予该第二佐剂。在一个实施方案中,该受试者是一个人。在另一个实施方案中,共给予该组合物与该第二佐剂。在又另一个实施方案中,不共给予该组合物与该第二佐剂。在再另一个实施方案中,在该组合物之前给予该第二佐剂。
在一个实施方案中,所提供的任何这些方法进一步包括给予一种或多种抗原。在另一个实施方案中,所提供的任何这些组合物(包括所提供的这些方法的组合物)进一步包含一种或多种抗原。在一个实施方案中,共给予该一种或多种抗原。
在一个实施方案中,所提供的任何这些方法的该受试者或被给予所提供的任何这些组合物的该受试者需要一种发炎应答。在另一个实施方案中,该受试者需要一种Th1免疫应答。在又另一个实施方案中,该受试者需要一种体液免疫应答。在再另一个实施方案中,该受试者需要一种特异性局部细胞毒性T淋巴细胞应答。在另一个实施方案中,该受试者罹患或有风险罹患癌症。在再另一个实施方案中,该受试者罹患或有风险罹患感染或感染性疾病。在又另一个实施方案中,该受试者罹患或有风险罹患一种特应性病状、哮喘、COPD或一种慢性感染。
在一个实施方案中,任何这些组合物可以用于治疗或预防中。在另一个实施方案中,任何这些组合物可以用于所提供的任何这些方法中。在又另一个实施方案中,任何这些组合物可以用于一种在一位受试者中诱导一种发炎应答的方法中。在再另一个实施方案中,任何这些组合物可以用于一种在一位受试者中诱导一种Th1免疫应答的方法中。在又另一个实施方案中,任何这些组合物可以用于一种在一位受试者中诱导一种体液免疫应答的方法中。在另一个实施方案中,任何这些组合物可以用于一种在一位受试者中诱导一种特异性局部细胞毒性T淋巴细胞应答的方法中。在再另一个实施方案中,任何这些组合物可以用于一种治疗或预防癌症的方法中。在又另一个实施方案中,任何这些组合物可以用于一种治疗或预防感染或感染性疾病的方法中。在另一个实施方案中,任何这些组合物可以用于一种治疗或预防一种特应性病状、哮喘、COPD或一种慢性感染的方法中。
另一个方面,在此提供一种所提供的任何这些组合物的用途,用于制造一种供所提供的任何这些方法中使用的药剂。
图式简要说明
图1示出了纳米载体(NC)接种后小鼠中的全身细胞因子产生。图1A、图1B以及图1C-分别示出了实验组中的TNF-α、m-6以及IL-12产生。汇集来自具有三只小鼠的组的血清并且通过ELISA分析。
图2展现了NC接种后小鼠中的全身IFN-γ产生。汇集来自具有三只小鼠的组的血清并且通过ELISA分析。
图3展现了利用包埋在NC内的R848产生免疫应答,它优于由不具有R848的NC诱导的免疫应答。
图4示出了用包含表面烟碱和T辅助性卵白蛋白衍生的肽OP-II的NC(NC-Nic)(不具有佐剂)或用混合有20雕的游离R848的相同NC-Nic免疫的小鼠中的抗烟碱抗体滴度(5只动物/组;皮下,每次注射100雌的NC,以4周为间隔,3次)。示出了第一次免疫后第26天和第40天的滴度(ELISA,针对聚赖氨酸-烟碱)(组1:用(即无佐剂),OP-II](2.2%的OP-II)免疫;组2:用混合有20雌的游离R848的免疫)。
图5示出了用包含表面烟碱和T辅助性卵白蛋白衍生的肽OP-II的NC(NC-Nic)(具有R848佐剂)或用混合有80雌的游离明矾或25啡的游离CpG-1826的相同NC-Nic免疫的小鼠中的抗烟碱抗体滴度(5只动物/组;皮下,每次注射100雌的NC,以4周为间隔,3次)。示出了第一次免疫后第26天和第40天的滴度(ELISA,针对聚赖氨酸-烟碱)(所有组:用NC[Nic,R848,OP-II]免疫;组2:混合有80啡的游离明矾的NC;组3:混合有25雌的游离CpG-1826)。
图6示出了用包含表面烟碱、R848以及T辅助性卵白蛋白衍生的肽OP-II的NC(NC[Nic,R848,OP-II])或用混合有80雕的游离明矾的相同NC-Nic免疫的小鼠中的抗烟碱抗体滴度(5只动物/组;皮下,每次注射100雌的NC,以4周为间隔,3次)。示出了第一次免疫后第40天和70天的滴度(ELISA,针对聚赖氨酸-烟碱X组1:用NC[Nic,R848,OP-II](3.1%的R848,1.5%的OP-II)免疫;组2:用混合有80啡的游离明矾的NC[Nic,R848,OP-II]免疫)。
图7示出了用包含卵白蛋白或游离卵白蛋白的NC免疫的小鼠中的特异性局部CTL应答。使小鼠免疫一次(皮下,100啡包含2.8%的OVA的NC,或用2.5雌的OVA;两种免疫原都混合有10雌的游离1826-CpG)。
图8示出了用包含表面烟碱和T辅助性卵白蛋白衍生的肽OP-II的NC(NC-Nic)(NC内无佐剂)(混合有20啡的游离CpG(PS)或20啡的游离CpG(PO))免疫的小鼠中的抗烟碱抗体滴度(5只动物/组;皮下,每次注射100雕的NC,以2周为间隔,3次)。对照小鼠仅接受PBS。示出了第26天和第40天的滴度(ELISA,针对聚赖氨酸-烟碱)(组1:用NC-Nic(无佐剂)+游离CpG(PS)免疫;组2:用NC-Nic(无佐剂)+游离CpG(PO)免疫;组3:仅用PBS免疫)。
图9示出了用包含表面OVA的NC(NC-OVA)(NC内无佐剂)(混合有20啡的游离R848或CpG(PS))免疫的小鼠中的抗卵白蛋白(OVA)抗体滴度(5只动物/组;皮下,每次注射100啡的NC,以2周为间隔,3次)。对照小鼠用2.5雌混合有20啡的CpG(PS)的可溶性OVA免疫。示出了第26天和44天的滴度(ELISA,针对OVA蛋白)(组1:用NC-OVA(无佐剂)+游离R848免疫;组2:用NC-OVA(无佐剂)+游离CpG(PS)免疫;组3:用可溶性OVA+CpG(PS)免疫)。
图10示出了用CpG注射(每次注射20雌,以2周为间隔,2次)接着在第35天用包含表面烟碱和T辅助性卵白蛋白衍生的肽OP-II的NC(NC-Nic)(具有或不具有NC所包含的R848)免疫的小鼠中的抗烟碱抗体滴度(5只动物/组;皮下,每次注射100雌的NC,以2周为间隔,2次)。示出了用NC免疫后第12、26以及40天的滴度(ELISA,针对聚赖氨酸-烟碱)(组1:用CpG接着NC-Nic(R848+OP-II)免疫;组2:用CpG接着NC-Nic(仅OP-II)免疫)。
发明的详细说明
在详细地描述本发明之前,应了解,本发明不限于特别例证的材料或工艺参数,因为这些材料和工艺参数当然可以变化。还应理解,在此使用的术语仅出于描述本发明的特定实施方案的目的,并且不打算对使用替代性术语描述本发明进行限制。
在此引用的所有公布、专利以及专利申请,无论上文还是下文,都出于所有目的特此通过引用以其全文结合。
除非发明内容另外明确规定,否则如本说明书和随附权利要求书中所使用,单数形式“一个/一种(a/an)”和“该”包括复数指示物。举例来说,提及“一种聚合物”包括两种或更多种这些分子的混合物,提及“一种溶剂”包括两种或更多种这些溶剂的混合物,提及“一种粘合剂”包括两种或更多种这些物质的混合物,等等。
引言
诸位发明人已出乎意料并且出人意料地发现上文指出的问题和限制可以通过实施在此披露的发明来克服。诸位发明人已出乎意料并且出人意料地发现给予一群合成纳米载体和一种不偶合到任何合成纳米载体上的佐剂提供较强并且较快速的免疫应答。具体来说,诸位发明人已出乎意料地发现,有可能提供组合物和方法,这些组合物和方法涉及一种包含一个剂型的组合物,该剂型包含(1)一群合成纳米载体,(2)一种不偶合到任何合成纳米载体上的第一佐剂,以及(3)一种药物学上可接受的赋形剂。
在实施方案中,给予与合成纳米载体分开的佐剂使得快速并且强烈地全身诱导促炎性细胞因子,如TNF-α、IL-6和/或IL-12。在一些实施方案中,组合物中佐剂或多种佐剂的剂量是全身剂量。在实施方案中,全身剂量引起释放TNF-α、IL-6或IL-12。在其他实施方案中,全身剂量引起全身释放TNF-α、IL-6以及IL-12。因为这些细胞因子具有促炎性,所以给予在此提供的组合物可以有益于希望发炎应答的受试者。因此,在一些实施方案中,给予这些受试者所提供的组合物。在实施方案中,这些受试者罹患或有风险罹患癌症。在其他实施方案中,这些受试者罹患或有风险罹患感染或感染性疾病。还提供用于给予这些受试者组合物的方法。
在其他实施方案中,给予与合成纳米载体分开的佐剂使得快速并且强烈地全身诱导对Th1免疫应答重要的细胞因子,如IFN-γ、IL-12和/或IL-18。因此,在一些实施方案中,组合物中佐剂或多种佐剂的剂量是引起全身释放IFN-γ、IL-12和/或IL-18的全身剂量。因为这些细胞因子对于Th1免疫应答重要,所以给予在此提供的组合物可以有益于需要Th1免疫应答的受试者。在一些实施方案中,给予这些受试者所提供的组合物。在实施方案中,这些受试者罹患或有风险罹患特应性病状、哮喘、慢性阻塞性肺部疾病(COPD)或慢性感染。还提供用于给予这些受试者组合物的方法。
诸位发明人还出乎意料地发现有可能与以上提到的组合物一起给予一种第二佐剂来提供强烈体液应答。因此,以上提到的组合物可以进一步包含一种第二佐剂。在一些实施方案中,第二佐剂偶合到合成纳米载体上。在其他实施方案中,第二佐剂不偶合到任何合成纳米载体上。在再其他实施方案中,第二佐剂被偶合到另一群合成纳米载体上。但是,在一些实施方案中,在不同于给予包含一群合成纳米载体和一种不偶合到任何合成纳米载体上的第一佐剂的组合物的时间给予受试者第二佐剂。在一些实施方案中,在不同时间给予但共给予第二佐剂。在其他实施方案中,不共给予第二佐剂。在再其他实施方案中,在给予包含一群合成纳米载体和一种不偶合到任何合成纳米载体上的第一佐剂的组合物之前或之后给予第二佐剂。在一些实施方案中,第二佐剂也不偶合到任何合成纳米载体上。在其他实施方案中,第二佐剂被偶合到另一群合成纳米载体上。因此,在此提供的组合物可以有益于希望体液免疫应答的受试者。在一些实施方案中,给予这些受试者所提供的组合物。在实施方案中,这些受试者罹患或有风险罹患癌症、感染或感染性疾病。还提供用于给予这些受试者组合物的方法。
在其他实施方案中,证明与上文所提供的组合物一起给予一种或多种抗原提供强烈的特异性局部细胞毒性T淋巴细胞(CTL)应答。在实施方案中,该一种或多种抗原与所提供的组合物一起共给予。在一些实施方案中,该一种或多种抗原被偶合到合成纳米载体上。在其他实施方案中,该一种或多种抗原不偶合到这些合成纳米载体上但偶合到另一群合成纳米载体上。该一种或多种抗原可以包含B细胞或T细胞抗原。在一些实施方案中,T细胞抗原是T辅助细胞抗原。在其他实施方案中,该一种或多种抗原包含B细胞或T细胞抗原以及T辅助细胞抗原。因此,所提供的组合物可以有益于希望特异性局部CTL应答的受试者。在一些实施方案中,给予这些受试者所提供的组合物。还提供用于给予这些受试者组合物的方法。
现在将更详细地描述本发明。
定义
“佐剂”意指一种不构成特异性抗原但加强对伴随给予的抗原产生的免疫应答的强度和寿命的试剂。这些佐剂可以包括但不限于:模式识别受体(如Toll样受体、RIG-1和NOD样受体(NLR))的刺激剂、矿物盐(如明矾,与肠道细菌(如大肠埃希氏杆菌、明尼苏达沙门菌、鼠伤寒沙门菌、或弗氏志贺菌)的单磷酰脂质(monphosphoryllipid,MPL)A组合的明矾或分别与(AS04)、以上提到的细菌的MPLA特异性组合的明矾)、皂甙(如QS-21、Quil-A、ISCOM、ISCOMATRIXTM)、乳液(如MF59TM、ISA51以及ISA720)、AS02(QS21+角鲨烯+)、AS15、脂质体和脂质体配制品(如AS01)、合成的或特别制备的微粒和微载体(如淋病奈瑟菌(N.gonorrheae)、沙眼衣原体和其他细菌的衍生自细菌的外膜泡(OMV))、或壳聚糖颗粒、贮存形成剂(depot-formingagent)(如嵌段共聚物)、特异性修饰或制备的肽(如胞壁酰二肽)、氨基烷基氨基葡糖苷4麟酸酯(如RC529)、或蛋白质(如细菌类毒素或毒素片段)。
在实施方案中,佐剂包含模式识别受体(PRR)(包括但不限于Toll样受体(TLR),特别是TLR2、3、4、5、7、8、9和/或其组合)的激动剂。在其他实施方案中,佐剂包含Toll样受体3的激动剂、Toll样受体7和8的激动剂或Toll样受体9的激动剂;优选地,这些佐剂包含咪唑并喹啉;如R848;腺嘌呤衍生物,如美国专利6,329,381(住友医药公司(SumitomoPharmaceuticalCompany))、比格戴克(Biggadike)等人的美国已公布专利申请2010/0075995或坎普斯(Campos)等人的WO2010/018132中披露的腺嘌呤衍生物;免疫刺激DNA;或免疫刺激RNA。在具体的实施方案中,合成纳米载体合并了化合物作为佐剂,它们是toll样受体(TLR)7&8的激动剂(“TLR7/8激动剂”)托马伊(Tomai)等人的美国专利6,696,076中披露的TLR7/8激动剂化合物具有效用,包括但不限于咪唑并喹啉胺、咪唑并吡啶胺、6,7-稠合环烷基咪唑并吡啶胺、以及1,2-桥接咪唑并喹啉胺。优选的佐剂包含咪喹莫特和瑞喹莫德(也称为R848)。在具体的实施方案中,佐剂可以是DC表面分子CD40的激动剂。在某些实施方案中,为了刺激免疫性而不是耐受性,合成的纳米载体合并了促进DC成熟(对于引发初始T细胞是需要的)和细胞因子(如促进抗体免疫应答的类型I干扰素)产生的佐剂。在实施方案中,佐剂还可以包含免疫刺激RNA分子,如但不限于dsRNA、聚I:C或聚I:聚C12U(以获得,聚I:C与聚I:聚C12U都称为TLR3刺激剂)、和/或在E海尔(EHeil)等人,“经由Toll样受体7和8种属特异性识别单链RNA(Species-SpecificRecognitionofSingle-StrandedRNAviaToll-likeReceptor7and8)”,科学(Science),303(5663),1526-1529(2004);J.福尔默(J.Vollmer)等人,“通过化学修饰的核糖核苷和寡核糖核苷酸进行的免疫调节(Immunemodulationbychemicallymodifiedribonucleosidesandoligoribonucleotides)”,WO2008033432A2;A.福尔斯巴赫(A.Forsbach)等人,“含有特异性序列基元并且靶向Toll样受体8通路的免疫刺激性寡核糖核苷酸(Immunostimulatoryoligoribonucleotidescontainingspecificsequencemotif(s)andtargetingtheToll-likereceptor8pathway”,WO2007062107A2;E.乌尔曼(E.Uhlmann)等人,“具有增强的免疫疫刺激性活性的修饰的寡核糖核苷酸类似物(Modifiedoligoribonucleotideanalogswithenhancedimmunostimulatoryactivity)”,美国专利申请公布US2006241076;G利甫福德(GLipford)等人,“免疫刺激性病毒性RNA寡核糖核苷酸和其用于治疗癌症和感染的用途(ImmunostimulatoryviralRNAoligonucleotidesandusefortreatingcancerandin托ctions)”,WO2005097993A2;G利普福德(GLipford)等人,“包含GU的免疫刺激性寡核糖核苷酸、组合物以及筛选方法(ImmunostimulatoryG,U-containingoligoribonucleotides,compositions,andscreeningmethods)”,WO2003086280A2中披露的那些。在一些实施方案中,佐剂可以是TLR-4激动剂,如细菌脂多糖(LPS)、VS矿G和/或HMGB-L在一些实施方案中,佐剂可以包含TLR-5激动剂(如鞭毛蛋白)或其部分或衍生物,包括但不限于美国专利6,130,082、6,585,980以及7,192,725中所披露的那些。在具体的实施方案中,合成纳米载体合并了Toll样受体(TLR)-9的配体,如包含CpG的免疫刺激DNA分子,这些分子诱导类型I干扰素分泌并且刺激T和B细胞活化,从而使抗体产生和细胞毒性T细胞应答增加(科瑞格(Krieg)等人,细菌DNA中的CpG基元触发直接B细胞活化(CpGmotifsinbacterialDNAtriggerdirectBcellactivation),自然(Nature),1995.374:546-549;朱(Chu)等人,CpG寡脱氧核苷酸充当接通T辅助细胞1型(Th1)免疫性的佐剂(CpGoligodeoxynucleotidesactasadjuvantsthatswitchonThelper1(Th1)immunity),实验医学杂志(J.Exp.Med.),1997.186:1623-1631;利普福德(Lipford)等人,包含CpG的合成寡核苷酸促进对蛋白质抗原产生的B细胞和细胞毒性T细胞应答:一种新型疫苗佐剂(CpG-containingsyntheticoligonucleotidespromoteBandcytotoxicTce"responsestoproteinantigen:anewclassofvaccineadjuvants),欧洲免疫学杂志(EunJ.Immunol.),1997.27:2340-2344;罗曼(Roman)等人,免疫刺激DNA序列充当促进T辅助细胞1型的佐剂(ImmunostimulatoryDNAsequencesfunctionasThelper-1-promotingadjuvants),自然医学(Nat.Med.),1997.3:849-854;载维斯(Davis)等人,CpGDNA是用重组B型肝炎表面抗原免疫的小鼠中特异性免疫的有效增强剂(CpGDNAisapotentenhancerofspecificimmunityinmiceimmunizedwithrecombinanthepatitisBsurfaceantigen),免疫学杂志(J.Immunol.),1998.160:870-876;利普福德(利普福德)等人,作为免疫细胞活化剂的细菌DNA(BacterialDNAasimmunecellactivator),微生物学趋势(TrendsMicrobiol),1998.6:496-500;科瑞格(Krieg)等人的美国专利6,207,646;塔克(Tuck)等人的美国专利7,223,398;凡涅斯特(VanNest)等人的美国专利7,250,403;或科瑞格(Krieg)等人的美国专利7,566,703)。
在一些实施方案中,佐剂可以是从坏死细胞释放的促炎性刺激剂(例如尿酸盐结晶)。在一些实施方案中,佐剂可以是补体级联的活化组分(例如CD21、CD35等)。在一些实施方案中,佐剂可以是免疫复合物的活化组分。佐剂还包括补体受体激动剂(如结合到CD21或CD35上的分子)。在一些实施方案中,补体受体激动剂诱导合成纳米载体的内生补体调理作用。在一些实施方案中,佐剂是细胞因子,它们是由细胞释放并且对细胞-细胞相互作用、通讯以及其他细胞的行为具有特异性作用的小蛋白质或生物因子(在5kD-20kD的范围内)。在一些实施方案中,细胞因子受体激动剂是小分子、抗体、融合蛋白或适体。
在实施方案中,至少一部分剂量的佐剂不偶合到任何合成纳米载体上,优选地,全部剂量的佐剂都不偶合到任何合成纳米载体上。在实施方案中,该剂量的佐剂包含两种或更多种类型的佐剂,并且这些类型的佐剂中至少一种的至少一部分不偶合到任何合成纳米载体上。举例来说,而没有限制,可以组合作用于不同受体(如不同TLR受体)的佐剂。作为一个实例,在一个实施方案中,可以将TLR7/8激动剂与TLR9激动剂组合。在另一个实施方案中,可以将TLR7/8激动剂与TLR4激动剂组合。在又另一个实施方案中,可以将TLR9激动剂与TLR3激动剂组合。
“给予”或“给药”意指以药理学上有用的方式提供一种物质(例如药物)给受试者。
“过敏”(在此还称为“过敏性病状”)是存在对过敏原产生的所不希望的免疫应答(即过敏反应)的任何病状。过敏或过敏性病状包括但不限于过敏性哮喘、枯草热、麻疹、湿疹、植物过敏、蜂螫伤过敏、宠物过敏、乳胶过敏、霉菌过敏、化妆品过敏、食物过敏、过敏性鼻炎或鼻伤风、局部过敏反应、全身性过敏反应、特应性皮肤炎、过敏反应以及其他过敏性病状。过敏反应可以是对任何过敏原产生的免疫反应的结果。
“有效量”是在此提供的组合物产生一种或多种所希望的免疫应答的任何量。这个量可以用于体外或体内目的。出于体内目的,该量可以是临床医生认为可能对需要发炎、Th1、体液或特异性局部CTL免疫应答的受试者具有临床益处的量。这些受试者包括罹患或有风险罹患癌症、感染或感染性疾病、特应性病状、哮喘、慢性阻塞性肺部疾病(COPD)或慢性感染的受试者。
有效量包括涉及全身释放一种或多种细胞因子的量。在实施方案中,有效量包括涉及产生全身细胞因子释放特征曲线(profile)的量。在一些实施方案中,一种或多种细胞因子或细胞因子释放特征曲线包含全身释放TNF-α、IL-6和/或IL-12。在其他实施方案中,一种或多种细胞因子或细胞因子释放特征曲线包含全身释放IFN-γ、IL-12和/或IL-18。这可以通过常规方法监测。有效产生一种或多种所希望的免疫应答的量还可以是在此提供的组合物产生所希望的治疗终点或所希望的治疗结果的量。
有效量当然应取决于正进行治疗的特定受试者;病状、疾病或病症的严重性;个体患者的参数,包括年龄、身体情况、体型以及体重;治疗的持续时间;并行治疗(如果有)的性质;具体的给药途径以及健康开业医师的知识和专门技术范围内的类似因素。这些因素为本领域的普通技术人员熟知,并且可以通过仅仅用常规实验方法来解决。总体上优选的是使用最大剂量,即根据正确医学判断的最高安全剂量。但是,本领域的普通技术人员应了解,出于医学原因、心理原因或出于实际上任何其他原因,患者可以坚持较低剂量或耐受剂量。
总体而言,本发明的组合物的剂量可以在从约10μ批吵约100,000μ批g的范围内。在一些实施方案中,剂量可以在从约0.1m妙kg到约100mg/kg的范围内。在再其他实施方案中,剂量可以在从约0.1mg/kg到约25mg/kg、约25m田kg到约50mg/kg、约50m妙kg到约75m妙kg或约75mg/kg到约100mg/kg的范围内。作为替代方案,剂量可以基于合成纳米载体的数目给予。举例来说,有用的剂量包括每次剂量大于106、107、108、109或1010个合成纳米载体。有用的剂量的其他实例包括每次剂量从约1x106到约1x1010、约1x107到约1x109或约1x108到约1x109个合成纳米载体。在一些实施方案中,所提供的组合物的剂量是全身剂量。
“抗原”意指B细胞抗原或T细胞抗原。在实施方案中,抗原被偶合到合成纳米载体上。在其他实施方案中,抗原未偶合到合成纳米载体上。在实施方案中,抗原与合成纳米载体一起共给予。在其他实施方案中,抗原不与合成纳米载体一起共给予。“一种或多种类型的抗原”意指共享相同或实质上相同的抗原特征的分子。在实施方案中,所提供的组合物的抗原与正治疗的疾病或病状有关。举例来说,抗原可以是过敏原(用于治疗过敏或过敏性病状)、与癌症有关的抗原(用于治疗癌症或肿瘤)、感染因子抗原(用于治疗感染、感染性疾病或慢性感染性疾病),等等。
“至少一部分剂量”意指剂量的至少某一部分,范围高达包括所有剂量。
“有风险”的受试者是健康开业医师认为有机会罹患在此提供的疾病或病状的受试者。
“B细胞抗原”意指由B细胞识别并且在B细胞中触发免疫应答的任何抗原(例如由B细胞上的B细胞受体特异性识别的抗原)。在一些实施方案中,作为T细胞抗原的抗原也是B细胞抗原。在其他实施方案中,T细胞抗原并不也是B细胞抗原。B细胞抗原包括但不限于蛋白质、肽、小分子以及碳水化合物。在一些实施方案中,B细胞抗原包含非蛋白质抗原(即不是蛋白质或肽抗原)。在一些实施方案中,B细胞抗原包含与感染因子缔合的碳水化合物。在一些实施方案中,B细胞抗原包含与感染因子缔合的糖蛋白或糖肽。感染因子可以是细菌、病毒、真菌、原生动物、寄生虫或朊病毒。在一些实施方案中,B细胞抗原包含免疫原性差的抗原。在一些实施方案中,B细胞抗原包含滥用的物质或其一部分。在一些实施方案中,B细胞抗原包含上瘾的物质或其一部分。上瘾的物质包括但不限于烟碱、麻醉药、咳嗽抑制剂、安神剂以及镇静剂。在一些实施方案中,B细胞抗原包含毒素(如来自化学武器或天然来源的毒素)或污染物。B细胞抗原还可以包含危险的环境因素。在其他实施方案中,B细胞抗原包含异体抗原、过敏原、接触性致敏原、退化性疾病抗原、半抗原、感染性疾病抗原、癌症抗原、特应性疾病抗原、自体免疫疾病抗原、上瘾的物质、异种抗原或代谢性疾病酶或其酶促产物。
“共给予”意指以时间上关联、优选时间上充分关联的方式给予受试者两种或更多种物质,从而提供对免疫应答的调节。在实施方案中,共给予可以通过在同一剂型中给予两种或更多种物质进行。在其他实施方案中,共给予可以涵盖以不同剂型但在指定时间段内、优选在1个月内、更优选在1周内、再更优选在1天内并且甚至更优选在1小时内给予两种或更多种物质。
“偶合”或“偶合的”或“偶合了”(等等)意指使一个实体(例如部分)与另一个实体在化学上缔合。在一些实施方案中,偶合是共价偶合,意指偶合在两个实体之间存在共价键的情况下发生。在非共价的实施方案中,非共价偶合通过非共价相互作用介导,这些非共价相互作用包括但不限于电荷相互作用、亲和相互作用、金属配位、物理吸附、主客体相互作用、疏水性相互作用、TT堆积相互作用、氢键结相互作用、范德华相互作用、磁相互作用、静电相互作用、偶极-偶极相互作用、和/或其组合。在实施方案中,封装是一种偶合形式。在实施方案中,至少一部分剂量的一种或多种佐剂不偶合到任何合成纳米载体上,优选地,并不是全部剂量的该一种或多种佐剂都偶合到任何合成纳米载体上。
“衍生”意指从一个来源获得并且进行实质性修饰。举例来说,序列与天然肽或核酸(优选天然共同肽或核酸)具有仅50%的一致性的肽或核酸将被称为衍生自天然肽或核酸。实质性修饰是显著影响所讨论物质的化学或免疫学特性的修饰。如果所述衍生的肽和核酸相比于天然肽或核酸具有改变的化学或免疫学特性,那么衍生的肽和核酸还可以包括序列与天然肽或核酸序列具有大于50%的一致性的肽和核酸。这些化学或免疫学特性包含亲水性、稳定性、亲和性以及与载体(如合成纳米载体)偶合的能力。
“剂型”意指在培养基、载体、媒剂或器件中的适用于给予受试者的药理学和/或免疫学活性物质。
“封装”意指密封在合成纳米载体内,优选完全密封在合成纳米载体内。被封装的大部分或所有物质不暴露于合成纳米载体外的局部环境。封装与吸附不同,吸附将大部分或所有物质放置在合成纳米载体的表面上,并且使物质暴露于合成纳米载体外的局部环境。
“体液应答”意指引起B细胞产生或刺激和/或抗体产生的任何免疫应答。优选地,体液免疫应答对本发明的组合物内所包含或在实施本发明的方法期间所给予的抗原具有特异性。评定是否诱发体液应答的方法为本领域的普通技术人员已知。下文在实例中提供这些方法的实例。
“感染”或“感染性疾病”是由微生物、病原体或其他因子(如细菌、真菌、朊病毒或病毒)引起的任何病状或疾病。感染性疾病的实例包括但不限于病毒性感染性疾病,如AIDS、禽痘(水痘)、普通感冒、细胞肥大病毒感染、科罗拉多蜱传热、登革热、埃博拉出血热、手足口病、肝炎、单纯疱疹、带状疱疹、HPV、流感(Flu)、拉沙热、麻疹、马尔堡出血热、感染性单核细胞增多症、腮腺炎、诺如病毒、脊髓灰质炎、进行性多灶性脑白质病、狂犬病、风疹、SARS、天痘(天花)、病毒性脑炎、病毒性胃肠炎、病毒性脑膜炎、病毒性肺炎、西尼罗病以及黄热病;细菌性感染性疾病,如炭疽、细菌性脑膜炎、肉毒中毒、布鲁氏菌病、弯曲菌病、猫抓病、霍乱、白喉、流行性斑疹伤寒、淋病、脓疱病、军团病、麻风病(汉森病)、钩端螺旋体病、李斯特菌病、莱姆病、类鼻疽、风湿热、MRSA感染、诺卡氏菌病、百日咳(Pertussis/WhoopingCough)、瘟疫、肺炎球菌肺炎、鹦鹉热、Q热、落矶山斑疹热(RMSF)、沙门菌病、猩红热、志贺氏菌病、梅毒、破伤风、沙眼、结核病、土拉菌病、伤寒、斑疹伤寒以及尿路感染;寄生虫感染性疾病,如非洲锥虫病、阿米巴病、蛔虫病、巴贝虫病、恰加斯氏病、华支睾吸虫病、隐孢子虫病、囊虫病、裂头绦虫病、麦地那龙线虫病、棘球蚴病、蛲虫病、片吸虫病、姜片虫病、丝虫病、自由生活阿米巴感染、贾第鞭毛虫病、颚口线虫病、膜壳绦虫病、等孢子球虫病、黑热病、利什曼病、疟疾、后殖吸虫病、蝇蛆病、盘尾丝虫病、虱病、蛲虫感染、疥疮、血吸虫病、绦虫病、弓蛔虫病、弓形虫病、旋毛虫病(Trichinellosis/Trichinosis)、鞭虫病、滴虫病以及锥虫病;真菌感染性疾病,如曲霉菌病、芽生菌病、念珠菌病、球孢子菌病、隐球菌病、组织胞浆菌病、香港脚(脚癣)以及股癣;朊病毒感染性疾病,如阿尔珀斯病、致命性家族性失眠症、杰茨曼-斯脱司勒-史茵综合症、库鲁症以及变异的克罗伊茨费尔特-雅各布病。
“发炎应答”意指参与身体的先天免疫防御系统的任何免疫应答,该免疫应答对暴露于例如感染因子、细胞损伤等作出应答而操作。在实施方案中,发炎应答包括全身释放细胞因子,如TNF-α、IL-6和/或IL-12。评定是否诱发发炎应答(如评定促炎性细胞因子的产生)的方法为本领域的普通技术人员已知。下文在实例中提供这些方法的实例。
“分离的核酸”意指从核酸的天然环境中分离并且以足以允许鉴别或使用的数量存在的核酸。分离的核酸可以是“)在体外通过例如聚合酶链反应(PCR)扩增;“i)通过克隆重组产生;(iii)如通过裂解和凝胶分离进行纯化;或“v)通过例如化学合成而合成的核酸。分离的核酸是可以通过本领域中熟知的重组DNA技术容易地操作的核酸。因此,认为已知5′和3′限制位点或已披露聚合酶链反应(PCR)引物序列的载体中包含的核苷酸序列是分离的核苷酸序列,但以天然状态存在于天然宿主中的核酸序列不是分离的核酸序列。分离的核酸可以实质上被纯化,但并非必需。举例来说,在克隆或表达载体内分离的核酸是不纯的,因为它可能包含仅微小百分比的它所存在的细胞中的物质。但是,如同在此使用该术语,该核酸为分离的核酸,因为它可以通过本领域的普通技术人员已知的标准技术容易地操作。在此提供的任何核酸可以是分离的。在一些实施方案中,在此提供的组合物中的抗原以分离的核酸的形式存在,如编码抗原肽、多肽或蛋白质的分离的核酸。
“分离的肽、多肽或蛋白质”意指多肽(或肽或蛋白质)从它的天然环境分离并且以足以允许其鉴别或使用的数量存在。这意指例如这些多肽(或肽或蛋白质)可以(i)通过表达克隆选择性地产生或(ii)如通过色谱或电泳进行纯化。分离的肽、蛋白质或多肽可以是(但不必是)实质上纯的。因为分离的肽、多肽或蛋白质可以与药物制剂中的药物学上可接受的载体混合,所以多肽(或肽或蛋白质)可以包含仅占该制剂的小重量百分比。但是,该多肽(或肽或蛋白质)是分离的多肽(或肽或蛋白质),因为它与生命系统中它可能缔合的物质分开,即与其他蛋白质(或肽或多肽)分离。在此提供的任何肽、多肽或蛋白质可以是分离的。在一些实施方案中,在此提供的组合物中的抗原呈分离的肽、多肽或蛋白质的形式。
“合成纳米载体的最大尺寸”意指沿合成纳米载体的任何轴测量的纳米载体的最大尺寸。“合成纳米载体的最小尺寸”意指沿合成纳米载体的任何轴测量的纳米载体的最小尺寸。举例来说,对于球形合成纳米载体,合成纳米载体的最大和最小尺寸应该是实质上一致的,并且应该是它的直径的大小。类似地,对于立方形合成纳米载体,合成纳米载体的最小尺寸应该是它的高度、宽度或长度中最小的那个,而合成纳米载体的最大尺寸应该是它的高度、宽度或长度中最大的那个。在一个实施方案中,基于样品中合成纳米载体的总数,样品中至少75%、优选至少80%、更优选至少90%的合成纳米载体的最小尺寸是大于100nm。在一个实施方案中,基于样品中合成纳米载体的总数,样品中至少75%、优选至少80%、更优选至少90%的合成纳米载体的最大尺寸是等于或小于5μm。优选地,基于样品中合成纳米载体的总数,样品中至少75%、优选至少80%、更优选至少90%的合成纳米载体的最小尺寸是大于110nm,更优选大于120nm,更优选大于130nm,并且再更优选大于150nm。本发明的合成纳米载体的最大尺寸与最小尺寸的纵横比可以取决于实施方案而变化。举例来说,合成纳米载体的最大尺寸与最小尺寸的纵横比可以从1∶1到1,000,000∶1、优选从1∶1到100,000∶1、更优选从1∶1到1000∶1、再优选从1∶1到100∶1、并且又更优选从1∶1到10∶1变化。优选地,基于样品中合成纳米载体的总数,样品中至少75%、优选至少80%、更优选至少90%的合成纳米载体的最大尺寸是等于或小于3μm、更优选等于或小于2μm、更优选等于或小于1μm、更优选等于或小于800nm、更优选等于或小于600nm、并且再更优选等于或小于500nm。在优选的实施方案中,基于样品中合成纳米载体的总数,样品中至少75%、优选至少80%、更优选至少90%的合成纳米载体的最大尺寸是等于或大于100nm、更优选等于或大于120nm、更优选等于或大于130nm、更优选等于或大于140nm、并且再更优选等于或大于150nm。通过将合成纳米载体悬浮于一种液体(通常是水溶液)介质中,并且使用动态光散射(例如使用一台BrookhavenZetaPALS仪器)获得合成纳米载体大小的测量值。
“获得”意指从一个来源获得不进行实质性修饰。实质性修饰是显著影响所讨论物质的化学或免疫学特性的修饰。举例来说,作为一个非限制性实例,序列与天然肽或核苷酸序列(优选天然共同肽或核苷酸序列)具有大于90%、优选大于95%、优选大于97%、优选大于98%、优选大于99%、优选100%的一致性,并且具有不显著不同于天然肽或核酸的化学和/或免疫学特性的肽或核酸将被称为是获自天然肽或核苷酸序列。这些化学或免疫学特性包含亲水性、稳定性、亲和性以及与载体(如合成纳米载体)偶合的能力。
“药物学上可接受的载体或赋形剂”意指与所述合成纳米载体一起用来配制本发明的组合物的药理学上无活性的物质。药物学上可接受的载体或赋形剂包含本领域中已知的多种物质,包括但不限于糖(如葡萄糖、乳糖等)、防腐剂(如抗微生物剂)、相互作用、着色剂、生理盐水(如磷酸盐缓冲的生理盐水)以及缓冲剂。在一些实施方案中,药物学上可接受的载体或赋形剂包含碳酸钙、磷酸钙、不同的稀释剂、不同的糖以及各种淀粉、纤维素衍生物、明胶、植物油以及聚乙二醇。
“特异性局部细胞毒性T淋巴细胞(CTL)应答”意指对细胞毒性T细胞、优选对抗原具有特异性的细胞毒性T细胞的任何刺激、诱导或增殖。在实施方案中,该抗原与在此提供的任何疾病或病状有关。在一些实施方案中,抗原包含在本发明的组合物内或在在此提供的本发明的方法中给予。评定CTL应答的方法为本领域的普通技术人员已知。实例中提供该方法的一个实例。
“受试者”意指动物,包括温血哺乳动物,如人和灵长类动物;禽类;家庭驯养动物或农用动物,如猫、狗、绵羊、山羊、牛、马以及猪;实验动物,如小鼠、大鼠以及天竺鼠;鱼;爬行动物;动物园动物和野生动物;等等。
“一种或多种合成纳米载体”意指未见于自然界中并且拥有至少一个小于或等于5微米大小的尺寸的离散物体。总体上包括白蛋白纳米颗粒作为合成纳米载体,但是,在某些实施方案中,合成纳米载体不包含白蛋白纳米颗粒。在实施方案中,本发明的合成纳米载体不包含壳聚糖。
合成纳米载体可以是但不限于一个或多个基于脂质的纳米颗粒(例如脂质体)(在此还称为脂质纳米颗粒,即构成其结构的大多数物质是脂质的纳米颗粒)、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳液、树枝状聚合物、巴克球、纳米线、病毒样颗粒(即主要由病毒结构蛋白构成但不具有感染性或具有低感染性的颗粒)、基于肽或蛋白质的颗粒(在此还称为蛋白质颗粒,即构成其结构的大多数物质是肽或蛋白质的颗粒)(如白蛋白纳米颗粒)和/或使用纳米材料的组合产生的纳米颗粒(如脂质-聚合物纳米颗粒)。合成纳米载体可以具有多种不同的形状,包括但不限于球形、立方形、金字塔形、长方形、圆柱形、环形,等等。根据本发明的合成纳米载体包含一个或多个表面,包括但不限于内表面(总体上面对合成纳米载体的内部的表面)和外表面(总体上面对合成纳米载体的外部环境的表面)。可以适用于本发明的惯例中的实例性合成纳米载体包含:(1)格里夫(Gref)等人的美国专利5,543,158中披露的生物可降解纳米颗粒,(2)索尔兹曼(Saltzman)等人的已公布美国专利申请20060002852的聚合物纳米颗粒,(3)德西蒙(DeSimone)等人的已公布美国专利申请20090028910的用平版印刷法建构的纳米颗粒,(4)冯安德里安(vonAndrian)等人的WO2009/051837的披露,(5)佩纳德斯(Penades)等人的已公布美国专利申请2008/0145441中披露的纳米颗粒,(6)德洛斯里奥斯(delosRios)等人的已公布美国专利申请20090226525中披露的蛋白质纳米颗粒,(7)西贝(Sebbel)等人的已公布的美国专利申请20060222652中披露的病毒样颗粒,(8)巴赫曼(Bachmann)等人的已公布的美国专利申请20060251677中披露的与核酸偶合的病毒样颗粒,(9)WO2010047839A1或WO2009106999A2中披露的病毒样颗粒,或(10)E保利赛利(EPaolicelli)等人,“可以有效缔合并且递送病毒样颗粒的经过表面修饰的基于PLGA的纳米颗粒(Surface-modifiedPLGA-basedNanoparticlesthatcanEfficientlyAssociateandDeliverVims-likeParticles)”,纳米医学(Nanomedicine),5(6):843-853(2010)中披露的纳米沉淀的纳米颗粒。在实施方案中,合成纳米载体可以拥有大于1∶1、1∶1.2、1∶1.5、1∶2、1∶3、1∶5、1∶7或大于1∶10的纵横比。
最小尺寸等于或小于约100nm、优选等于或小于100nm的根据本发明的合成纳米载体不包含具有活化补体的羟基的表面,或可替代地包含主要由不是活化补体的羟基的部分组成的表面。在一个优选的实施方案中,最小尺寸等于或小于约100nm、优选等于或小于100nm的根据本发明的合成纳米载体不包含实质上活化补体的表面,或可替代地包含主要由不实质上活化补体的部分组成的表面。在一个更优选的实施方案中,最小尺寸等于或小于约100nm、优选等于或小于100nm的根据本发明的合成纳米载体不包含活化补体的表面,或可替代地包含主要由不活化补体的部分组成的表面。在实施方案中,合成纳米载体可以拥有大于1∶1、1∶1.2、1∶1.5、1∶2、1∶3、1∶5、1∶7或大于1∶10的纵横比。
“全身剂量”意指提供特定全身细胞因子释放、优选特定全身细胞因子释放特征曲线的佐剂的剂量。在一些实施方案中,特定全身细胞因子释放、优选特定全身细胞因子释放特征曲线在人体内进行。在实施方案中,在此提供的组合物和方法(其中至少一部分剂量的佐剂不偶合到任何纳米载体上)引起受试者中特定全身细胞因子释放特征曲线。术语“分开”还用于意指不偶合到任何合成纳米载体上的佐剂。另外,“全身细胞因子释放特征曲线”意指一种全身细胞因子释放的模式,其中该模式包含针对数种不同全身细胞因子测量的细胞因子水平。在一些实施方案中,特定全身细胞因子释放特征曲线包含全身释放TNF-α、IL-6和/或H-12。在其他实施方案中,特定全身细胞因子释放特征曲线包含全身释放IFN-γ、IL12和/或IL-18。
“T细胞抗原”意指由T细胞识别并且触发T细胞中的免疫应答的任何抗原(例如,由T细胞或NKT细胞上的T细胞受体经由呈现结合到I类或II类主要组织相容性复合分子(MHC)上或结合到CD1复合物上的抗原或它的一部分特异性识别的抗原)。在一些实施方案中,是T细胞抗原的抗原也是B细胞抗原。在其他实施方案中,T细胞抗原并不也是B细胞抗原。T细胞抗原总体上是蛋白质、多肽或肽。T细胞抗原可以是刺激CD8+T细胞应答、CD4+T细胞应答或两者的抗原。因此,在一些实施方案中,纳米载体可以有效地刺激两种类型的应答。
在一些实施方案中,T细胞抗原是‘通用’T细胞抗原或T细胞记忆抗原(即受试者具有原有记忆并且可以用于加强T细胞对不相关抗原(例如不相关的B细胞抗原)的辅助的T细胞抗原)。通用T细胞抗原包括破伤风类毒素以及一种或多种衍生自破伤风类毒素、埃-巴二氏病毒或流感病毒的肽。通用T细胞抗原还包括流感病毒的组分,如血球凝集素、神经氨酸酶或核蛋白或一种或多种从它们衍生的肽。在一些实施方案中,通用T细胞抗原不是存在于与MHC分子的复合物中的抗原。在一些实施方案中,通用T细胞抗原不与用于呈现到T辅助细胞上的MHC分子复合。因此,在一些实施方案中,通用T细胞抗原不是T辅助细胞抗原。但是,在其他实施方案中,通用T细胞抗原是T辅助细胞抗原。
在实施方案中,T辅助细胞抗原可以包含一种或多种获自或衍生自以下物质的肽:破伤风类毒素、埃-巴二氏病毒、流感病毒、呼吸道合胞体病毒、麻疹病毒、腮腺炎病毒、风疹病毒、细胞肥大病毒、腺病毒、白喉类毒素或PADRE肽(从赛特(Sette)等人的美国专利7,202,351的工作中知晓)。在其他实施方案中,T辅助细胞抗原可以包含卵白蛋白或从它获得或衍生的肽。优选地,卵白蛋白包含如登录号AAB59956、NP990483.1、AAA48998或CAA2371中所述的氨基酸序列。在其他实施方案中,获自或衍生自卵白蛋白的肽包含以下氨基酸序列:H-Ile-Ser-Gln-Ala-Val-His-Ala-Ala-His-Ala-Glu-Ile-Asn-Glu-Ala-Gly-Arg-OH(SEQIDNO:1)。在其他实施方案中,T辅助细胞抗原可以包含一种或多种脂质或糖脂,包括但不限于:α-半乳糖苷神经酰胺(α-GalCer)、α-键联的鞘糖脂(来自鞘氨醇单胞菌属)、半乳糖苷二酰基甘油(来自伯氏疏螺旋体)、脂磷酸聚糖(来自杜氏利什曼虫)以及磷脂酰肌醇四甘露糖苷(PIM4)(来自麻风分枝杆菌)。对于用作T辅助细胞抗原的另外的脂质和/或糖脂,参看v塞昂多罗(vCerundolo)等人,“开发疫苗接种策略中的不变NKT细胞(HarnessinginvariantNKTcellsinvaccinationstrategies.)”,自然免疫学评论(NatureRevImmun),9:28-38(2009)。
在实施方案中,CD4+T细胞抗原可以是获自一个来源(如天然来源)的CD4+T细胞抗原的衍生物。在此类实施方案中,CD4+T细胞抗原序列(如结合到MHCII上的那些肽)可以与获自该来源的抗原具有至少70%、80%、90%或95%的一致性。在实施方案中,T细胞抗原、优选通用T细胞抗原或T辅助细胞抗原可以偶合到合成纳米载体上或与合成纳米载体去偶合。在一些实施方案中,通用T细胞抗原或T辅助细胞抗原封装在本发明的组合物的合成纳米载体中。
“Th1免疫应答”意指引起Th1细胞和Th1相关细胞因子(IFN吖、IL-12和/或IL-18)的产生或对抗Th2细胞分化和Th2细胞因子的作用的任何免疫应答。评定是否诱发Th1免疫应答的方法为本领域的普通技术人员已知。下文在实例中提供这些方法的实例。
“不同给予时间”或“不同于给予组合物的时间的时间”意指如下时间,该时间在给予之前或之后超过约30秒、优选在给予之前或之后超过约1分钟、更优选在给予之前或之后超过5分钟、再更优选在给予之前或之后超过1天、再更优选在给予之前或之后超过2天、再更优选在给予之前或之后超过1周、再更优选在给予之前或之后超过2周、再更优选在给予之前或之后超过3周、再更优选在给予之前或之后超过1个月并且再更优选在给予之前或之后超过2个月。
“疫苗”意指改进对特定病原体或疾病产生的免疫应答的物质组合物。疫苗典型地包含刺激受试者的免疫系统的因子以将特异性抗原识别为外来的并且将它从受试者的体内去除。疫苗还建立免疫学‘记忆’,使得在一个人再受到攻击时,抗原将被快速识别并且产生应答。疫苗可以是预防性的(例如预防未来感染任何病原体)或治疗性的(例如针对肿瘤特异性抗原以治疗癌症或针对衍生自感染因子的抗原以治疗感染或感染性疾病的疫苗)。在实施方案中,疫苗可以包含根据本发明的剂型。优选地,在一些实施方案中,这些疫苗包含不偶合到任何合成纳米载体上的佐剂。
在具体的实施方案中,本发明的组合物合并包含toll样受体(TLR)7及8的激动剂(“TLR7/8激动剂”)的佐剂。托马伊(Tomai)等人的美国专利6,696,076中披露的TLR7/8激动剂化合物具有效用,包括但不限于咪唑并喹啉胺、咪唑并吡啶胺、6,7-稠合环烷基咪唑并吡啶胺、以及1,2-桥接咪唑并喹啉胺。优选的佐剂包含咪喹莫特和R848。
在具体的实施方案中,本发明的组成物合并包含Toll样受体(TLR)-9的配体的佐剂,该配体如包含CpG的免疫刺激DNA分子,这些分子诱导类型I干扰素分泌并且刺激T细胞和B细胞活化,从而使抗体产生和细胞毒性T细胞应答增加(科瑞格(Krieg)等人,细菌DNA中的CpG基元触发直接B细胞活化(CpGmotifsinbacterialDNAtriggerdirectBcellactivation),自然(Nature),1995.374:546-549;朱(Chu)等人,CpG寡脱氧核苷酸充当接通T辅助细胞1型(Th1)免疫性的佐剂(CpGoligodeoxynucleotidesactasadjuvantsthatswitchonThelper1(Th1)immunity),实验医学杂志(J.Exp.Med.),1997.186:1623-1631;利普福德(Lipford)等人,包含CpG的合成寡核苷酸促进对蛋白质抗原产生的B细胞和细胞毒性T细胞应答:一种新型疫苗佐剂(CpG-containingsyntheticoligonucleotidespromoteBandcytotoxicTcellresponsestoproteinantigen:anewclassofvaccineadjuvants),欧洲免疫学杂志(EunJ.Immunol.),1997.27:2340-2344;罗曼(Roman)等人,免疫刺激DNA序列充当促进T辅助细胞1型的佐剂(ImmunostimulatoryDNAsequencesfunctionasThelper-1-promotingadjuvants),自然医学(Nat.Med.),1997.3:849-854;戴维斯(Davis)等人,CpGDNA是用重组B型肝炎表面抗原免疫的小鼠中特异性免疫的有效增强剂(CpGDNAisapotentenhancerofspecificimmunityinmiceimmunizedwithrecombinanthepatitisBsurfaceantigen),免疫学杂志(J.Immunol.),1998.160:870-876;利普福德(Lipford)等人,作为免疫细胞活化剂的细菌DNA(BacterialDNAasimmunecellactivator),微生物学趋势(TrendsMicrobiol),1998.6:496-500)。在实施方案中,CpG可以包含打算增强稳定性的修饰(如硫代磷酸酯键)或其他修饰(如已修饰的碱基)。参看例如美国专利5,663,153、6,194,388、7,262,286或7,276,489。在某些实施方案中,为了刺激免疫性而不是耐受性,在此提供的组合物合并促进DC成熟(对于引发初始T细胞是需要的)和细胞因子(如促进抗体应答和抗病毒免疫性的类型I干扰素)产生的佐剂。在一些实施方案中,佐剂包含TLR-4激动剂,如细菌脂多糖(LPS)、VS矿G和/或HMGB-L在一些实施方案中,佐剂包含细胞因子,它们是由细胞释放并且对细胞-细胞相互作用、通讯以及其他细胞的行为具有特异性作用的小蛋白质或生物因子(在5kD-20kD的范围内)。在一些实施方案中,佐剂包含从坏死细胞释放的促炎性刺激剂(例如尿酸盐结晶)。在一些实施方案中,佐剂包含补体级联的活化组分(例如CD21、CD35等)。在一些实施方案中,佐剂包含免疫复合物的活化组分。佐剂还包括包含补体受体激动剂(如结合到CD21或CD35上的分子)的佐剂。在一些实施方案中,补体受体激动剂诱导纳米载体的内生补体调理作用。佐剂还包括包含细胞因子受体激动剂(如细胞因子)的佐剂。
在一些实施方案中,细胞因子受体激动剂是小分子、抗体、融合蛋白或适体。在实施方案中,佐剂还可以包含免疫刺激RNA分子,如但不限于dsRNA或聚I:C(TLR3刺激剂)、和/或在E海尔(EHeil)等人,“经由Toll样受体7和8种属特异性识别单链RNA(Species-SpecificRecognitionofSingle-StrandedRNAviaToll-likeReceptor7and8)”,科学(Science),303(5663),1526-1529(2004);J.福尔默(J.Vollmer)等人,“通过化学修饰的核糖核苷和寡核糖核苷酸进行的免疫调节(Immunemodulationbychemicallymodifiedribonucleosidesandoligoribonucleotides)”,WO2008033432A2;九福尔斯巴赫(A.Forsbach)等人,“含有特异性序列基元并且靶向Toll样受体8通路的免疫刺激性寡核糖核苷酸(Immunostimulatoryoligoribonucleotidescontainingspecificsequencemotif(s)andtargetingtheToll-likereceptor8pathway”,WO2007062107A2;E.乌尔曼(E.Uhlmann)等人,“具有增强的免疫疫刺激性活性的修饰的寡核糖核苷酸类似物(Modifiedoligoribonucleotideanalogswithenhancedimmunostimulatoryactivity)”,美国专利申请公布US2006241076;G利甫福德(GLipford)等人,“免疫刺激性病毒性RNA寡核糖核苷酸和其用于治疗癌症和感染的用途(ImmunostimulatoryviralRNAoligonucleotidesandusefortreatingcancerandinfections)”,WO2005097993A2;G利普福德(GLipford)等人,“包含GU的免疫刺激性寡核糖核苷酸、组合物以及筛选方法(ImmunostimulatoryGU-containingoligoribonucleotides,compositions,andscreeningmethods)”,WO2003086280A2中披露的那些。
在一些实施方案中,佐剂包含凝胶型佐剂(例如氢氧化铝、磷酸铝、磷酸钙等)、微生物佐剂(例如包括CpG基元的免疫调节DNA序列;免疫刺激RNA分子;内毒素,如单磷酰脂质A;外毒素,如霍乱毒素、大肠埃希氏杆菌的不耐热毒素以及百日咳毒素;胞壁酰二肽等);基于油-乳液和乳化剂的佐剂(例如弗氏佐剂、MF59[Novartis]、SAF等);微粒佐剂(例如脂质体、生物可降解微球体、皂甙等);合成佐剂(例如非离子嵌段共聚物、胞壁酰肽类似物、聚磷腈、合成聚核苷酸等)和/或其组合。
合成纳米载体组合物
根据本发明,可使用多种合成纳米载体。在一些实施方案中,合成纳米载体是球形或球状体。在一些实施方案中,合成纳米载体是平坦的或板状的。在一些实施方案中,合成纳米载体是立方体或立方形(cuboidal/cubic)。在一些实施方案中,合成纳米载体是卵形体或椭圆体。在一些实施方案中,合成纳米载体是圆柱体、圆锥或金字塔。
在一些实施方案中,希望使用一群在大小、形状、和/或组成方面相对均匀的合成纳米载体,使得各合成纳米载体具有类似特性。举例来说,基于合成纳米载体的总数,至少80%、至少90%或至少95%的合成纳米载体可以具有落在合成纳米载体的平均直径或平均尺寸的5%、10%或20%内的最小尺寸或最大尺寸。在一些实施方案中,一群合成纳米载体就大小、形状、和/或组成而论可以是不均匀的。
合成纳米载体可以是实心或空心的,并且可以包含一个或多个层。在一些实施方案中,每一层相对于其他一个或多个层都具有独特的组成和独特的特性。为了给出但是一个实例,合成纳米载体可以具有核/壳结构,其中核是一个层(例如聚合物核)并且壳是一个第二层(例如一个脂质双层或单层)。合成纳米载体可以包含多个不同的层。
在一些实施方案中,合成纳米载体可以任选包含一种或多种脂质。在一些实施方案中,合成纳米载体可以包含脂质体。在一些实施方案中,合成纳米载体可以包含脂质双层。在一些实施方案中,合成纳米载体可以包含一个脂质单层。在一些实施方案中,合成纳米载体可以包含胶束。在一些实施方案中,合成纳米载体可以包含核,该核包含由脂质层(例如脂质双层、脂质单层等)环绕的聚合物基质。在一些实施方案中,合成纳米载体可以包含由脂质层(例如脂质双层、脂质单层等)环绕的非聚合物核(例如金属颗粒、量子点、陶瓷颗粒、骨颗粒、病毒性颗粒、蛋白质、核酸、碳水化合物等)。
在一些实施方案中,合成纳米载体可以包含一种或多种聚合物或聚合物基质。在一些实施方案中,此类聚合物或聚合物基质可以由涂层(例如脂质体、脂质单层、胶束等)环绕。在一些实施方案中,合成纳米载体的不同的要素可以与聚合物或聚合物基质偶合。
在一些实施方案中,要素(如靶向部分、寡核苷酸、抗原、佐剂等)可以与聚合物基质共价缔合。在一些实施方案中,共价缔合由连接物介导。在一些实施方案中,要素可以与聚合物基质非共价缔合。举例来说,在一些实施方案中,要素可以封装在聚合物基质内、由聚合物基质环绕和/或分散在整个聚合物基质内。可替代地或另外地,要素可以通过疏水性相互作用、电荷相互作用、范德华力等与聚合物基质缔合。
常规地,已知多种聚合物和从这些聚合物形成聚合物基质的方法。总体而言,聚合物基质包含一种或多种聚合物。聚合物可以是天然或非天然(合成)聚合物。聚合物可以是均聚物或包含两种或更多种单体的共聚物。在序列方面,共聚物可以是无规共聚物、嵌段共聚物,或包含无规与嵌段序列的组合。典型地,根据本发明的聚合物是有机聚合物。
适用于本发明中的聚合物的实例包括但不限于聚乙烯、聚碳酸酯(例如聚(1,3-二噁烷-2-酮))、聚酸酐(例如聚(癸二酸酐))、聚富马酸丙酯、聚酰胺(例如聚己内酰胺)、聚缩醛、聚醚、聚酯(例如聚丙交酯、聚乙交酯、聚丙交酯-共-乙交酯、聚己内酯、聚羟基酸(例如聚(β-羟基烷酸酯))、聚(原酸酯)、聚氰基丙烯酸酯、聚乙烯醇、聚氨酯、聚磷腈、聚丙烯酸酯、聚甲基丙烯酸酯、聚脲、聚苯乙烯、聚胺、聚赖氨酸、聚赖氨酸-PEG共聚物以及聚(乙亚胺)、聚(乙亚胺)-PEG共聚物。
在一些实施方案中,根据本发明的聚合物包括根据21C.ER.§177.2600已经由美国食品与药品管理局(FDA)批准用于人类的聚合物,包括但不限于聚酯(例如聚乳酸、聚(乳酸-共-乙醇酸)、聚己内酯、聚戊内酯、聚(1,3-二噁烷-2-酮));聚酸酐(例如聚(癸二酸酐));聚醚(例如聚乙二醇);聚氨酯;聚甲基丙烯酸酯;聚丙烯酸酯;以及聚氰基丙烯酸酯。
在一些实施方案中,聚合物可以具有亲水性。举例来说,聚合物可以包含阴离子基团(例如磷酸酯基、硫酸酯基、羧酸酯基);阳离子基团(例如季胺基);或极性基团(例如羟基、硫醇基、胺基)。在一些实施方案中,包含亲水性聚合物基质的合成纳米载体在合成纳米载体内产生亲水性环境。在一些实施方案中,聚合物可以是疏水的。在一些实施方案中,包含疏水性聚合物基质的合成纳米载体在合成纳米载体内产生疏水性环境。聚合物的亲水性或疏水性的选择可能对合并(例如偶合)在合成纳米载体内的物质的性质具有影响。
在一些实施方案中,聚合物可以用一个或多个部分和/或官能团修饰。根据本发明,可以使用多种部分或官能团。在一些实施方案中,可以用聚乙二醇(PEG)、用碳水化合物、和/或用衍生自多糖的非环状聚缩醛修饰聚合物(巴比索夫(Papisov),2001,ACS研讨会系列(ACSSymposiumSeries),786:301)。可以使用格里夫(Gref)等人的美国专利号5543158或冯安德里安(VonAndrian)等人的WO公布WO2009/051837中的全部传授内容进行某些实施方案。
在一些实施方案中,聚合物可以用脂质或脂肪酸基团修饰。在一些实施方案中,脂肪酸基团可以是丁酸、己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸或二十四烷酸中的一种或多种。在一些实施方案中,脂肪酸基团可以是棕榈油酸、油酸、异油酸、亚油酸、α-亚油酸、γ-亚油酸、花生四烯酸、二十碳烯酸、花生四烯酸、二十碳五烯酸、二十二碳六烯酸或芥酸中的一种或多种。
在一些实施方案中,聚合物可以是聚酯,包括包含乳酸和乙醇酸单元的共聚物(例如聚(乳酸-共-乙醇酸)和聚(丙交酯-共-乙交酯)(在此统称为“PLGA”);和包含乙醇酸单元的均聚物(在此称为“PGA”)和包含乳酸单元的均聚物(如聚-L-乳酸、聚-D-乳酸、聚-D,L-乳酸、聚-L-丙交酯、聚-D-丙交酯和聚-D,L-丙交酯,在此统称为“PLA”)。在一些实施方案中,示例性聚酯包括例如聚羟基酸;PEG共聚物和丙交酯与乙交酯的共聚物(例如PLA-PEG共聚物、PGA-PEG共聚物、PLGA-PEG共聚物)以及其衍生物)。在一些实施方案中,聚酯包括例如聚(己内酯)、聚(己内酯)-PEG共聚物、聚(L-丙交酯-共-L-赖氨酸)、聚(丝氨酸酯)、聚(4-羟基-L-脯氨酸酯)、聚怔(4-氨基丁基)-L-乙醇酸]以及它们的衍生物。
在一些实施方案中,聚合物可以是PLGA。PLGA是一种生物相容的并且生物可降解的乳酸与乙醇酸的共聚物,并且不同形式的PLGA的特征在于乳酸∶乙醇酸的比率。乳酸可以是L-乳酸、D-乳酸或D,L-乳酸。可以通过改变乳酸∶乙醇酸的比率调整PLGA的降解速率。在一些实施方案中,根据本发明,将使用的PLGA的特征在于乳酸∶乙醇酸比率是约85∶15、约75∶25、约60∶40、约50∶50、约40∶60、约25∶75或约15∶85。
在一些实施方案中,聚合物可以是一种或多种丙烯酸聚合物。在某些实施方案中,丙烯酸聚合物包括例如丙烯酸与甲基丙烯酸的共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、甲基丙烯酸氰基乙酯、甲基丙烯酸氨基烷酯共聚物、聚(丙烯酸)、聚(甲基丙烯酸)、甲基丙烯酸烷基酰胺共聚物、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸酐)、甲基丙烯酸甲酯、聚甲基丙烯酸酯、聚(甲基丙烯酸甲酯)共聚物、聚丙烯酰胺、甲基丙烯酸氨基烷酯共聚物、甲基丙烯酸缩水甘油酯共聚物、聚氰基丙烯酸酯以及包含一种或多种以上聚合物的组合。丙烯酸聚合物可以包含丙烯酸和甲基丙烯酸酯与低含量季铵基团的全聚合共聚物。
在一些实施方案中,聚合物可以是阳离子型聚合物。总体而言,阳离子型聚合物能够缩合和/或保护核酸(例如DNA或其衍生物)的带负电的链。包含胺的聚合物(如聚(赖氨酸)(泽纳(Zauner)等人,1998,先进药物递送评论(Adv.DrugDel.耻轧),30:97;和卡巴诺夫(Kabanov)等人,1995,生物结合化学(BioconjugateChem.),6:7)、聚(乙亚胺)(PEI;博塞夫(Boussif)等人,1995,美国国家科学院院刊(Proc.Natl.Acad.Sci.),美国(USA),1995,92:7297)和聚(酰胺基胺)树枝状聚合物(库沃斯卡-拉塔罗(Kukowska-Latallo)等人,1996,美国国家科学院院刊(Proc.Natl.Acad.Sci.),美国(USA),93:4897;唐(Tang)等人,1996,生物结合化学(BioconjugateChem.),7:703;和汉斯勒(Haensler)等人,1993,生物结合化学(BioconjugateChem.),4:372))在生理pH下带正电,与核酸形成离子对,并且在多种细胞系中介导转染。在实施方案中,本发明的合成纳米载体可以不包含(或可以排除)阳离子型聚合物。
在一些实施方案中,聚合物可以是带有阳离子侧链的可降解聚酯(普特南(Putnam)等人,1999,大分子(Macromolecules),32:3658;巴雷拉(Barrera)等人,1993,美国化学会志(J.Am.Chem.Soc.),115:11010;权(Kwon)等人,1989,大分子(Macromolecules),22:3250;林(Lim)等人,1999,美国化学会志(J.Am.Chem.Soc.),121:5633;以及Zhou(周)等人,1990,大分子(Macromolecules),23:3399)。这些聚合物的实例包括聚(L-丙交酯-共-L-赖氨酸)(巴雷拉(Barrera)等人,1993,美国化学会志(J.Am.Chem.Soc.),115:11010)、聚(丝氨酸酯)(周(Zhou)等人,1990,大分子(Macromolecules),23:3399)、聚(4-羟基-L-脯氨酸酯)(普特南(Putnam)等人,1999,大分子(Macromolecules),32:3658;以及林(Lim)等人,1999,美国化学会志(J.Am.Chem.Soc.),121:5633)以及聚(4-羟基-L-脯氨酸酯)(普特南(Putnam)等人,1999,大分子(Macromolecules),32:3658;以及林(Lim)等人,1999,美国化学会志(J.Am.Chem.Soc.),121:5633)。
这些和其他聚合物的特性以及用于制备它们的方法在本领域中是熟知的(参看例如美国专利6,123,727;5,804,178;5,770,417;5,736,372;5,716,404;6,095,148;5,837,752;5,902,599;5,696,175;5,514,378;5,512,600;5,399,665;5,019,379;5,010,167;4,806,621;4,638,045;以及4,946,929;王(Wang)等人,2001,美国化学会志(J.Am.Chem.Soc.),123:9480;林(Lim)等人,200L美国化学会志(J.Am.Chem.Soc.),123:2460;朗格尔(Langer),2000,化学研究评述(Acc.Chem.Res.),33:94;朗格尔(Langer),1999,控释杂志(王Control.Release),62:7;以及乌利希(Uhrich)等人,1999,化学评论(Chem.Rev.),99:3181)。更总体而言,聚合物科学以及聚合物胺和铵盐的简明百科全书(ConciseEncyclopediaofPolymerScienceandPolymericAminesandAmmoniumSalts),由戈萨尔斯(Goethals)编,培格曼出版社(PergamonPress),1980;聚合原理(PrinciplesofPolymerization),奥迪安(Odian),约翰威利父子出版公司(JohnWiley&Sons),第四版,2004;当代聚合物化学(ContemporaryPolymerChemistry),奥科克(Allcock)等人,普伦蒂斯霍尔出版社(Prentice-Hall),1981;载明(Deming)等人,1997,自然(Nature),390:386;以及美国专利6,506,577、6,632,922、6,686,446以及6,818,732中描述用于合成某些适合聚合物的多种方法。
在一些实施方案中,聚合物可以是直链或分支链聚合物。在一些实施方案中,聚合物可以是树枝状聚合物。在一些实施方案中,聚合物可以彼此实质上交联。在一些实施方案中,聚合物可以实质上不交联。在一些实施方案中,聚合物可根据本发明使用而不进行交联步骤。进一步应了解,本发明的合成纳米载体可以包含嵌段共聚物、接枝共聚物、掺合物、混合物和/或任何以上和其他聚合物的加合物。本领域普通技术人员应认识到在此列出的聚合物代表可根据本发明使用的聚合物的示例性不详尽清单。
在一些实施方案中,合成纳米载体包含一种或多种聚合物。因此,聚合的合成纳米载体还可以包括冯安德里安(VonAndrian)等人的WO公布WO2009/051837中描述的聚合的合成纳米载体,包括但不限于具有一种或多种亲水性组分的那些。优选地,一种或多种聚合物包含聚酯,如聚(乳酸)、聚(乙醇酸)、聚(乳酸-共-乙醇酸)或聚己内酯。更优选地,一种或多种聚合物包含或进一步包含偶合到亲水性聚合物(如聚醚)上的聚酯。在实施方案中,该聚醚包含聚乙二醇。再更优选地,一种或多种聚合物包含聚酯和偶合到亲水性聚合物(如聚醚)上的聚酯。在其他实施方案中,一种或多种聚合物被偶合到一种或多种抗原和/或一种或多种佐剂上。在实施方案中,至少一些聚合物被偶合到这一种或多种抗原上,和/或至少一些聚合物被偶合到这一种或多种佐剂上。优选地,当存在大于一种类型的聚合物时,一种类型的聚合物被偶合到这一种或多种抗原上。在实施方案中,一种其他类型的聚合物被偶合到这一种或多种佐剂上。举例来说,在实施方案中,当纳米载体包含聚酯和偶合到亲水性聚合物(如聚醚)上的聚酯时,该聚酯被偶合到佐剂上,而该偶合到亲水性聚合物(如聚醚)上的聚酯被偶合到这一种或多种抗原上。在实施方案中,如果纳米载体包含T辅助细胞抗原,那么T辅助细胞抗原可以封装在纳米载体中。
在一些实施方案中,合成纳米载体可以不包含聚合组分。在一些实施方案中,合成纳米载体可以包含金属颗粒、量子点、陶瓷颗粒等等。在一些实施方案中,非聚合的合成纳米载体是非聚合组分的聚集体,如金属原子(例如金原子)的聚集体。
在一些实施方案中,合成纳米载体可以任选包含一种或多种两亲实体。在一些实施方案中,两亲实体可以促进具有增加的稳定性、改进的均匀性或增加的黏性的合成纳米载体的制造。在一些实施方案中,两亲实体可以与脂质膜(例如脂质双层、脂质单层等)的内表面缔合。本领域中已知的多种两亲实体适用于制备根据本发明的合成纳米载体。这些两亲实体包括但不限于磷酸甘油酯;磷脂酰胆碱;二棕榈酰磷脂酰胆碱(DPPC);二油烯基磷脂酰基乙醇胺(DOPE);二油烯氧基丙基三乙基铵(DOTMA);二油酰基磷脂酰胆碱;胆固醇;胆固醇酯;二酰基甘油;二酰基甘油丁二酸酯;二磷脂酰基甘油(DPPG);十六烷醇;脂肪醇(如聚乙二醇(PEG));聚氧乙烯-9-月桂醚;表面活性脂肪酸,如棕榈酸或油酸;脂肪酸;脂肪酸单甘油酯;脂肪酸二甘油酯;脂肪酸酰胺;脱水山梨糖醇三油酸酯甘氨胆酸酯;脱水山梨糖醇单月桂酸酯聚山梨醇酯20聚山梨醇酯60聚山梨醇酯65聚山梨醇酯80聚山梨醇酯85聚氧乙烯单硬脂酸酯;表面活性素;泊洛沙姆;脱水山梨糖醇脂肪酸酯,如脱水山梨糖醇三油酸酯;卵磷脂;溶血卵磷脂;磷脂酰丝氨酸;磷脂酰肌醇;鞘磷脂;磷脂酰乙醇胺(脑磷脂);心磷脂;磷脂酸;脑苷脂;双十六烷基磷酸酯;二棕榈酰磷脂酰甘油;硬脂胺;十二烷胺;十六烷胺;棕榈酸乙酰酯;蓖麻油酸甘油酯;硬脂酸十六烷酯;肉豆蔻酸异丙酯;泰洛沙泊;聚(乙二醇)5000-磷脂酰乙醇胺;聚(乙二醇)400-单硬脂酸酯;磷脂;具有高表面活性剂特性的合成和/或天然洗涤剂;脱氧胆酸酯;环糊精;离液序列高的盐;离子对试剂;以及它们的组合。两亲实体组分可以是不同两亲实体的混合物。本领域普通技术人员应认识到这是具有表面活性剂活性的物质的示例性的不详尽清单。任何两亲实体可用于制造根据本发明使用的合成纳米载体中。
在一些实施方案中,合成纳米载体可以任选包含一种或多种碳水化合物。碳水化合物可以是天然或合成的。碳水化合物可以是衍生的天然碳水化合物。在某些实施方案中,碳水化合物包含单糖或二糖,包括但不限于葡萄糖、果糖、半乳糖、核糖、乳糖、蔗糖、麦芽糖、海藻糖、纤维二糖、甘露糖、木糖、阿拉伯糖、葡糖醛酸、半乳糖醛酸、甘露糖醛酸、葡糖胺、半乳糖胺以及神经氨酸。在某些实施方案中,碳水化合物是一种多糖,包括但不限于:支链淀粉、纤维素、微晶纤维素、羟丙基甲基纤维素(HPMC)、羟基纤维素(HC)、甲基纤维素(MC)、右旋糖酐、环葡聚糖、糖原、淀粉、羟基乙基淀粉、卡拉胶、多聚糖(glycon)、直链淀粉、壳聚糖、N,O-羧基甲基壳聚糖、褐藻胶和褐藻酸、淀粉、甲壳质、肝素、菊糖、魔芋、葡萄甘露聚糖(glucommannan)、石耳素、肝素、透明质酸、凝胶多糖以及黄原胶。在实施方案中,本发明的合成纳米载体不包含(或特别排除)碳水化合物,如多糖。在某些实施方案中,碳水化合物可以包含碳水化合物衍生物,如糖醇,包括但不限于甘露糖醇、山梨糖醇、木糖醇、赤藻糖醇、麦芽糖醇和乳糖醇。
根据本发明的组合物包含本发明的合成纳米载体与药物学上可接受的赋形剂(如防腐剂、缓冲剂、生理盐水或磷酸盐缓冲生理盐水)的组合。组合物可以使用常规医药制造和配合技术获得有用剂型来制备。在一个实施方案中,将本发明的合成纳米载体与防腐剂一起悬浮于无菌的供注射生理盐水溶液中。
在实施方案中,在制备作为试剂(例如抗原或佐剂)的载体的合成纳米载体以用于疫苗中时,用于将试剂偶合到合成纳米载体上的方法可以是有用的。如果试剂是小分子,那么在组装合成纳米载体之前将试剂连接到聚合物上可能具有优势。在实施方案中,制备具有用于将试剂偶合到合成纳米载体上的表面基团的合成纳米载体也可能是一个优势,该制备通过使用这些表面基团而不是将试剂连接到聚合物上随后在建构合成纳米载体时使用聚合物结合物来进行。多种反应可以用于将试剂连接到合成纳米载体上的目的。
在某些实施方案中,偶合物可以是共价连接物。在实施方案中,根据本发明的肽可以经由1,2,3-三唑连接物共价偶合到外表面上,该连接物通过纳米载体表面上的叠氮基与包含炔基的抗原或佐剂进行1,3-偶极环加成反应或通过纳米载体表面上的炔与包含叠氮基的抗原或佐剂进行1,3-偶极环加成反应形成。这些环加成反应优选在铜(I)催化剂以及适合的Cu(I)-配体和将Cu(II)化合物还原成催化活性的Cu(I)化合物的还原剂存在下执行。这种Cu(I)催化的叠氮-炔环加成反应(CuAAC)还可以称为点击反应。
另外,共价偶合物可以包含共价连接物,它包含酰胺连接物、二硫基连接物、硫醚连接物、腙连接物、酰肼连接物、亚胺或肟连接物、脲或硫脲连接物、脒连接物、胺连接物以及磺酰胺连接物。
酰胺连接物经由一种组分(如抗原或佐剂)上的胺与第二组分(如纳米载体)的羧酸基团之间的酰胺键形成。连接物中的酰胺键可以用被适当保护的氨基酸或抗原或佐剂以及被活化的羧酸(如被N-羟基丁二酰亚胺活化的酯)使用任何常规酰胺键形成反应制备。
二硫基连接物经由在例如R1-S-S-R2的形式的两个硫原子之间形成二硫(S-S)键制备。二硫键可以通过包含硫醇基/巯基(-SH)的抗原或佐剂与聚合物或纳米载体上另一被活化的硫醇基或包含硫醇基/巯基的纳米载体与包含被活化的硫醇基的抗原或佐剂进行硫醇交换形成。三唑连接物(特别是R1和R2可以是任何化学实体的形式的1,2,3-三唑)通过连接到第一组分(如纳米载体)上的叠氮基与连接到第二组分(如肽)上的炔的1,3-偶极环加成反应制备。1,3-偶极环加成反应在具有或不具有催化剂的情况下、优选在有经由1,2,3-三唑官能团连接两个组分的Cu(I)催化剂的情况下执行。这种化学方法详细地描述在夏普勒斯(Sharpless)等人,德国应用化学(An掌mChem.Int.Ed.),41(14),2596,(2002)和梅尔达尔(Meldal)等人,化学评论(Chem.Rev.),2008,108(8),2952-3015中,并且经常称为“点击”反应或CuAAC。
在实施方案中,制备一种聚合物,它在聚合物链末端包含叠氮基或炔基。随后使用这种聚合物制备合成纳米载体,其方式为使得多个炔或叠氮基安置在纳米载体的表面上。可替代地,合成纳米载体可以通过另一个途径制备,并且随后用炔或叠氮基官能化。抗原或佐剂在炔(如果聚合物包含叠氮基)或叠氮基(如果聚合物包含炔)存在下制备。随后在具有或不具有催化剂下允许抗原或佐剂与纳米载体经由1,3-偶极环加成反应进行反应,该催化剂将抗原或佐剂经由1,4-二取代的1,2,3-三唑连接物共价偶合到颗粒上。
硫醚连接物通过以例如R1-S-R2的形式形成硫碳(硫醚)键制备。硫醚可以通过用第二组分(如纳米载体)上的烷基化基团(如卤基或环氧基)烷基化一种组分(如抗原或佐剂)上的硫醇基/巯基(-SH)制备。硫醚连接物还可以通过将一种组分(如抗原或佐剂)上的硫醇基/巯基与作为迈克尔受体的第二组分(如包含顺丁烯二酰亚胺基或乙烯砜基的聚合物)上的缺电子烯基进行迈克尔加成来形成。以另一种方式,硫醚连接物可以通过一种组分(如抗原或佐剂)上的硫醇基/巯基与第二组分(如聚合物或纳米载体)上的烯基进行自由基硫醇-烯反应来制备。
腙连接物通过一种组分(如抗原或佐剂)上的酰肼基与第二组分(如纳米载体)上的醛/酮基进行反应来制备。
酰肼连接物通过一种组分(如抗原或佐剂)上的肼基与第二组分(如纳米载体)上的羧酸基团进行反应来形成。此类反应总体上使用类似于形成酰胺键的化学方法(其中羧酸用活化试剂活化)执行。
亚胺或肟连接物通过一种组分(如抗原或佐剂)上的胺或N-烷氧基胺基(或氨氧基)与第二组分(如纳米载体)上的醛或酮基进行反应来形成。
脲或硫脲连接物通过一种组分(如抗原或佐剂)上的胺基与第二组分(如纳米载体)上的异氰酸酯或异硫氰酸酯基进行反应来形成。
脒连接物通过一种组分(如抗原或佐剂)上的胺基与第二组分(如纳米载体)上的酰亚胺酯基进行反应来制备。
胺连接物通过一种组分(如抗原或佐剂)上的胺基与第二组分(如纳米载体)上的烷基化基团(如卤基、环氧基或磺酸酯基)进行烷基化反应来制备。可替代地,胺连接物还可以通过一种组分(如抗原或佐剂)上的胺基与第二组分(如纳米载体)上的醛或酮基在适合的还原试剂(如氰基硼氢化钠或三乙酰氧基硼氢化钠)存在下进行还原胺基化反应来制备。
磺酰胺连接物通过一种组分(如抗原或佐剂)上的胺基与第二组分(如纳米载体)上的磺酰基卤化物(如磺酰氯)基团进行反应来制备。
砜连接物通过亲核试剂与乙烯砜进行迈克尔加成反应来制备。乙烯砜或亲核试剂可以位于纳米颗粒的表面上或连接到抗原或佐剂上。
抗原或佐剂还可以与纳米载体经由非共价结合方法结合。举例来说,带负电的抗原或佐剂可以与带正电的纳米载体通过静电吸附结合。包含金属配体的抗原或佐剂还可以与包含金属复合物的纳米载体经由金属-配体复合物结合。
在实施方案中,抗原或佐剂可以在组装合成纳米载体之前连接到聚合物(例如聚乳酸-嵌段-聚乙二醇)上,或可以形成合成纳米载体而使得反应性或可活化基团在它的表面上。在后一情况下,制备抗原或佐剂以使其具有与由合成纳米载体的表面呈现的连接化学结构相容的基团。在其他实施方案中,可以使用适合的连接物将试剂(如肽抗原)连接到VLP或脂质体上。连接物是能够将两个分子偶合在一起的化合物或试剂。在一个实施方案中,连接物可以是同双官能或杂双官能试剂,如海尔曼森(Hermanson)2008中所述。举例来说,可以在EDC存在下用同双官能连接物己二酸二酰肼(ADH)处理表面上包含羧基的VLP或脂质体合成纳米载体,形成具有ADH连接物的相应合成纳米载体。随后使所得被ADH连接的合成纳米载体与包含酸基的试剂经由NC上的ADH连接物的另一端结合,产生相应的VLP或脂质体肽结合物。
对于可用的结合方法的详细描述,参看海尔曼森GT(HermansonGT),生物结合技术“(Bioconjugate配chniques)”,第2版,由学术出版公司(AcademicPress,Inc.)出版,2008。除共价连接以外,抗原或佐剂还可以通过吸附于预成型的合成纳米载体上来偶合,或它还可以通过在形成合成纳米载体期间进行封装来偶合。制备和使用组合物的方法和相关方法
合成纳米载体可以使用本领域中已知的多种方法来制备。举例来说,合成纳米载体可以通过以下方法形成:纳米沉淀、使用射流通道的流动聚焦、喷雾干燥、单一和双重乳液溶剂蒸发、溶剂萃取、相分离、研磨、微乳液程序、微制造、纳米制造、牺牲层、简单和复杂的凝聚以及为本领域的普通技术人员熟知的其他方法。可替代地或另外,已经描述了用于单分散半导体、传导性、磁性、有机以及其他纳米材料的水性和有机溶剂合成(普莱伊亚瓢Pellegrino)等人,2005,微小(Small),1:48;默瑞(Murray)等人,2000,材料科学综述年报(Ann.Rev.Mat.Sci.),30:545;以及特林达迪(Trindade)等人,2001,化学材料(Chem.Mat.),13:3843)。文献中已经描述了另外的方法(参看例如达保罗(Doubrow)编,“医学和药学中的微胶囊和纳米颗粒(MicrocapsulesandNanoparticlesinMedicineandPharmacy)”,CRC出版社(CRCPress),博卡拉顿(BocaRaton),1992;马西威兹(Mathiowitz)等人,1987,控释杂志(J.Control.Release),5:13;马西威兹(Mathiowitz)等人,1987,反应性聚合物(ReactivePolymers),6:275;以及马西威兹(Mathiowitz)等人,1988,应用聚合物科学杂志(J.Appl.PolymerSci.),35:755,美国专利5578325和6007845;E保利赛利(EPaolicelli)等人,“可以高效缔合并且递送病毒样颗粒的经过表面修饰的基于PLGA的纳米颗粒(Surface-modifiedPLGA-basedNanoparticlesthatcanEfficientlyAssociateandDeliverVirus-likeParticles)”,纳米医学(Nanomedicine),5(6):843-853(2010))。
希望时,可以使用多种方法将不同的物质封装于合成纳米载体中,这些方法包括但不限于阿斯特提(C.Astete)等人,“PLGA纳米颗粒的合成和表征(SynthesisandcharacterizationofPLGAnanoparticles)”,生物材料科学杂志聚合物版(J.Biomater.Sci.PolymerEdn),第17卷,第3期,第247-289页(2006);K阿沟司达奇斯(KAvgoustakis),“被聚乙二醇化的聚(丙交酯)与聚(丙交酯-共-乙交酯)纳米颗粒:制备、特性以及在药物递送中的可能应用(PegylatedPoly(Lactide)andPoly(Lactide-Co-aycolide)Nanoparticles:Preparation,PropertiesandPossibleApplicationsinDrugDelivery)”,当前药物递送(CurrentDrugDelivery),1:321-333(2004);C.瑞斯(C.Reis)等人,“纳米封装L用于制备负载药物的聚合物纳米颗粒的方法(NanoencapsulationI.Methodsforpreparationofdrug-loadedpolymericnanoparticles)”,纳米医学(Nanomedicine),2:8-21(2006);E保利赛利(EPaolicelli)等人,“可以高效缔合并且递送病毒样颗粒的经过表面修饰的基于PLGA的纳米颗粒(Surface-modifiedPLGA-basedNanoparticlesthatcanEfficientlyAssociateandDeliverVirus-likeParticles)”,纳米医学(Nanomedicine),5(6):843-853(2010)。可以使用适用于将物质(例如寡核苷酸)封装在合成纳米载体中的其他方法,包括但不限于在安格(Unger)的美国专利6,632,671(2003年10月14日)中披露的方法。
在某些实施方案中,合成纳米载体通过纳米沉淀工艺或喷雾干燥来制备。可以改变在制备合成纳米载体中使用的条件以产生具有所希望的大小或特性(例如疏水性、亲水性、外部形态、“粘性”、形状等)的颗粒。制备合成纳米载体的方法和使用的条件(例如溶剂、温度、浓度、空气流速等)可以取决于有待偶合到合成纳米载体上的物质和/或该聚合物基质的组成。
如果通过任何上述方法制备的颗粒具有所希望范围以外的大小范围时,可以例如使用筛网来定颗粒尺寸。
本发明的合成纳米载体的要素(如靶向部分、聚合物基质、抗原、佐剂等)可以例如通过一个或多个共价键偶合到合成纳米载体上,或可以借助一种或多种连接物偶合。使合成纳米载体官能化的另外的方法可以由以下文献改编而来:索尔兹曼(Saltzman)等人的已公布美国专利申请2006/0002852、德西蒙(DeSimone)等人的已公布美国专利申请2009/0028910或默蒂(Murthy)等人的已公布国际专利申请WO/2008/127532A1。
可替代地或另外,合成纳米载体可以直接或间接地经由非共价相互作用被偶合到如靶向部分、佐剂、不同抗原等的要素上。在非共价实施方案中,非共价偶合通过非共价相互作用介导,这些非共价相互作用包括但不限于:电荷相互作用、亲和相互作用、金属配位、物理吸附、主客体相互作用、疏水性相互作用、TT堆积相互作用、氢键结相互作用、范德华相互作用、磁相互作用、静电相互作用、偶极-偶极相互作用、和/或它们的组合。这些偶合可以安排在本发明的合成纳米载体的外表面或内表面上。在实施方案中,封装和/或吸附是一种偶合形式。
在实施方案中,本发明的合成纳米载体可以与其他佐剂通过在同一媒剂或递送系统中混合而组合。这些佐剂可以包括但不限于矿物盐(如明矾,与肠道细菌(如大肠埃希氏杆菌、明尼苏达沙门菌、鼠伤寒沙门菌、或弗氏志贺菌)的单磷酰脂质(MPL)A组合的明矾或分别与(AS04)、以上提到的细菌的MPLA特异性组合的明矾)、皂甙(如QS-21、Quil-A、ISCOM、ISCOMATRIXTM)、乳液(如MF59TM、ISA51以及ISA720)、AS02(QS21+角鲨烯+)、AS15、脂质体和脂质体配制品(如AS01)、合成的或特别制备的微粒和微载体(如淋病奈瑟菌、沙眼衣原体和其他细菌的衍生自细菌的外膜泡(OMV))、或壳聚糖颗粒、贮存形成剂(如嵌段共聚物)、特异性修饰或制备的肽(如胞壁酰二肽)、氨基烷基氨基葡糖苷4麟酸酯(如RC529)、或蛋白质(如细菌类毒素或毒素片段)。另外的有用佐剂可见于WO2002/032450;US7,357,936,“佐剂系统和疫苗(AdjuvantSystemsandVaccines)”;US7,147,862,“包含佐剂的疫苗组合物(Vaccinecompositioncontainingadjuvants)”;US6,544,518,“疫苗(Vaccines)”;US5,750,110,“包含佐剂的疫苗组合物(Vaccinecompositioncontainingadjuvants)”中。这些其他佐剂的剂量可以使用常规剂量范围研究来确定。在实施方案中,不偶合到所述合成纳米载体上的佐剂可以与偶合到合成纳米载体上的佐剂(如果存在)相同或不同。在其他实施方案中,这些佐剂的剂量也可以相同或不同。
在实施方案中,偶合到本发明的合成纳米载体上的任何佐剂可以与不偶合到任何纳米载体上的佐剂不同、类似或一致。这些佐剂(偶合和不偶合)可以在不同时间点和/或在不同身体部位和/或通过不同免疫途径分别给予。另外,分开的佐剂和纳米载体群可以在不同时间点和/或在不同身体部位和/或通过不同免疫途径分别给予。
合成纳米载体群可以使用传统的药物混合方法组合以形成根据本发明的药物剂型。这些方法包括液体-液体混合,其中两种或更多种各包含一个或多个纳米载体子组的悬浮液直接组合或经由一个或多个包含稀释剂的容器集合在一起。因为合成纳米载体还可以用粉末形式制造或储存,所以可以执行干燥的粉末-粉末混合,因为可以将两种或更多种粉末再悬浮于共同的介质中。取决于纳米载体的特性和它们的相互作用势,使用一种或另一种混合途径可能也有优势。
包含合成纳米载体的典型的发明的组合物可以包含无机或有机缓冲剂(例如磷酸、碳酸、乙酸或柠檬酸的钠盐或钾盐)和pH调节剂(例如盐酸、氢氧化钠或氢氧化钾、柠檬酸或乙酸的盐、氨基酸和它们的盐)、抗氧化剂(例如抗坏血酸、α-生育酚)、表面活性剂(例如聚山梨醇20、聚山梨酯80、聚氧乙烯9-10壬基酚、去氧胆酸钠)、溶液和/或低温/冻干稳定剂(例如蔗糖、乳糖、甘露糖醇、海藻糖)、渗透调节剂(例如盐类或糖类)、抗细菌剂(例如苯甲酸、苯酚、庆大霉素)、消泡剂(例如聚二甲基硅酮)、防腐剂(例如硫柳汞、2-苯氧乙醇、EDTA)、聚合物稳定剂和粘度调节剂(例如聚乙烯吡咯烷酮、泊洛沙姆488、羧甲基纤维素)以及共溶剂(例如甘油、聚乙二醇、乙醇)。
根据本发明的组合物包含本发明的合成纳米载体与药物学上可接受的赋形剂的组合。组合物可以使用常规的药物制造和配合技术获得有用的剂型来制备。适用于实施本发明的技术可以在工业混合手册:科学和惯例(HandbookofIndustrialMixing:ScienceandPractice),由爱德华L保罗(EdwardL.Paul)、维克多九阿蒂莫-奥本格(Victor九Atiemo-Obeng)以及苏珊妮M.克里斯塔(SuzanneM.Kresta)编、2004、约翰威利父子出版公司(JohnWiley&Sons,Inc.);和制药学:剂型设计科学(Pharmaceutics:TheScienceofDosageFormDesign),第2版,由M.E.奥顿(M.E.Auten)编,2001,邱吉尔利文斯通公司(ChurchillLivingstone)中找到。在一个实施方案中,将本发明的合成纳米载体与防腐剂一起悬浮于无菌的供注射生理盐水溶液中。
应了解,本发明的组合物可以用任何适合方式制备,并且本发明决不限于可以使用在此描述的方法产生的组合物。适当方法的选择可能要求注意特定缔合部分的特性。
在一些实施方案中,本发明的合成纳米载体在无菌条件下制造或最后进行灭菌。这可以确保所得组合物是无菌的并且无感染性的,从而在与非无菌组合物比较时改进安全性。这提供了有价值的安全措施,尤其在接受合成纳米载体的受试者具有免疫缺陷、正在遭受感染和/或对感染敏感时。在一些实施方案中,取决于配制策略,本发明的合成纳米载体可以进行冻干并且储存在悬浮液中或呈冻干粉末形式较长时间而不会丧失活性。
本发明的组合物可以通过多种给药途径来给予,包括但不限于皮下、肌肉内、皮内、经口、鼻内、经粘膜、舌下、经直肠、经眼、透皮、经皮或通过这些途径的组合。
根据本发明,剂型的剂量包含不同量的合成纳米载体群和/或不同量的佐剂和/或抗原。本发明的剂型中存在的合成纳米载体和/或佐剂和/或抗原的量可以根据佐剂和/或抗原的性质、打算实现的治疗益处以及其他这些参数变化。在一些实施方案中,剂型的剂量是全身剂量。在实施方案中,可以进行剂量范围研究以建立剂型中存在的合成纳米载体群的最佳治疗量和/或佐剂和/或抗原的量。在实施方案中,合成纳米载体和/或佐剂和/或抗原以在给予受试者后有效产生免疫应答的量存在于剂型中。有可能可以使用常规剂量范围研究和技术确定在受试者中有效产生免疫应答的佐剂和/或抗原的量。本发明的剂型可以用多种频率给予。在一个优选的实施方案中,剂型的至少一次给予足以产生药理学上相关的应答。在更优选的实施方案中,利用剂型的至少两次给予、至少三次给予或至少四次给予来确保药理学上相关的应答。
在此描述的组合物和方法可以用于诱导、增强、刺激、调节、引导或再引导免疫应答。在此说明的组合物和方法可以用于诊断、预防和/或治疗以下病状,如癌症、感染性疾病、代谢性疾病、退化性疾病、自体免疫疾病、发炎疾病、免疫疾病或其他病症和/或病状。在此说明的组合物和方法还可以用于预防或治疗成瘾,如对烟碱或麻醉药成瘾。在此说明的组合物和方法还可以用于预防和/或治疗由于暴露于毒素、有害物质、环境毒素或其他有害试剂而导致的病状。
在实施方案中,可使用所提供的组合物诱导快速并且强烈地全身诱导促炎性细胞因子,如TNF-α、IL-6和/或IL-12。因此,所提供的组合物可以给予需要发炎应答、优选全身发炎应答的受试者。在其他实施方案中,所提供的组合物可以用于快速并且强烈地全身诱导对于Th1免疫应答重要的细胞因子,如IFN-γ、IL-12和/或IL-18。因此,所提供的组合物可以给予需要Th1应答、优选全身Th1应答的受试者。在再其他实施方案中,可以使用所提供的组合物诱导强烈的体液应答。因此,所提供的组合物可以给予需要体液应答的受试者。在再另一个实施方案中,可以使用所提供的组合物诱导强烈的特异性局部CTL应答。因此,所提供的组合物可以给予需要特异性局部CTL应答的受试者。该应答可以对在此提供的任何抗原、优选对本发明的组合物中的或根据在此提供的本发明的方法给予的一种或多种抗原具有特异性。
在此提供的受试者可能罹患或有风险罹患癌症。癌症包括但不限于乳癌;胆道癌;膀胱癌;脑癌,包括成胶质母细胞瘤和神经管母细胞瘤;子宫颈癌;绒膜癌;结肠癌;子宫内膜癌;食道癌;胃癌;血液赘瘤,包括急性淋巴细胞性和骨髓性白血病,例如B细胞CLL;T细胞急性淋巴母细胞性白血病僻巴瘤;毛细胞白血病;慢性骨髓性白血病、多发性骨髓瘤;AIDS相关白血病和成人T细胞白血病/淋巴瘤;上皮内赘瘤,包括博文氏病和佩吉特氏病;肝癌;肺癌;淋巴瘤,包括霍奇金氏病和淋巴细胞性淋巴瘤;神经母细胞瘤;口腔癌,包括鳞状细胞癌;卵巢癌,包括从上皮细胞、基质细胞、生殖细胞以及间叶细胞产生的卵巢癌;胰腺癌;前列腺癌;直肠癌;肉瘤,包括平滑肌肉瘤、横纹肌肉瘤、脂肪肉瘤、纤维肉瘤以及骨肉瘤;皮肤癌,包括黑色素瘤、梅克尔细胞癌、卡波西氏肉瘤、基底细胞癌以及鳞状细胞癌;睾丸癌,包括生殖瘤,如精原细胞瘤、非精原细胞瘤(畸胎瘤、绒膜癌)、基质肿瘤以及生殖细胞肿瘤;甲状腺癌,包括甲状腺腺癌和髓样癌;以及肾癌,包括腺癌和维尔姆斯氏瘤。
在此提供的受试者可能罹患或有风险罹患感染或感染性疾病。感染或感染性疾病包括但不限于病毒性感染性疾病,如AIDS、禽痘(水痘)、普通感冒、细胞肥大病毒感染、科罗拉多蜱传热、登革热、埃博拉出血热、手足口病、肝炎、单纯疱疹、带状疱疹、HPV、流感(Flu)、拉沙热、麻疹、马尔堡出血热、感染性单核细胞增多症、腮腺炎、诺如病毒、脊髓灰质炎、进行性多灶性脑白质病、狂犬病、风疹、SARS、天痘(天花)、病毒性脑炎、病毒性胃肠炎、病毒性脑膜炎、病毒性肺炎、西尼罗病以及黄热病;细菌性感染性疾病,如炭疽、细菌性脑膜炎、肉毒中毒、布鲁氏菌病、弯曲菌病、猫抓病、霍乱、白喉、流行性斑疹伤寒、淋病、脓疱病、军团病、麻风病(汉森病)、钩端螺旋体病、李斯特菌病、莱姆病、类鼻疽、风湿热、MRSA感染、诺卡氏菌病、百日咳(Pertussis/WhoopingCough)、瘟疫、肺炎球菌肺炎、鹦鹉热、Q热、落矶山斑疹热(RMSF)、沙门菌病、猩红热、志贺氏菌病、梅毒、破伤风、沙眼、结核病、土拉菌病、伤寒、斑疹伤寒以及尿路感染;寄生虫感染性疾病,如非洲锥虫病、阿米巴病、蛔虫病、巴贝虫病、恰加斯氏病、华支睾吸虫病、隐孢子虫病、囊虫病、裂头绦虫病、麦地那龙线虫病、棘球蚴病、蛲虫病、片吸虫病、姜片虫病、丝虫病、自由生活阿米巴感染、贾第鞭毛虫病、颚口线虫病、膜壳绦虫病、等孢子球虫病、黑热病、利什曼病、疟疾、后殖吸虫病、蝇蛆病、盘尾丝虫病、虱病、蛲虫感染、疥疮、血吸虫病、绦虫病、弓蛔虫病、弓形虫病、旋毛虫病(Trichinellosis/Trichinosis)、鞭虫病、滴虫病以及锥虫病;真菌感染性疾病,如曲霉菌病、芽生菌病、念珠菌病、球孢子菌病、隐球菌病、组织胞浆菌病、香港脚(脚癣)以及股癣;朊病毒感染性疾病,如阿尔珀斯病、致命性家族性失眠症、杰茨曼-斯脱司勒-史茵克综合症、库鲁症以及变异的克罗伊茨费尔特-雅各布病。
在此提供的受试者还包括罹患或有风险罹患以下疾病的受试者:特应性病状,如但不限于过敏、过敏性哮喘或特应性皮肤炎;哮喘;慢性阻塞性肺部疾病(COPD,例如气肿或慢性支气管炎);和由于慢性感染因子所产生的慢性感染,如慢性利什曼病、念珠菌病或血吸虫病以及由疟原虫、刚地弓形虫、分枝杆菌、HIV、HBV、HCVEBV或CMV或任一种以上感染因子或以上感染因子的任何子组引起的感染。可以使用本发明的组合物治疗的其他适应症包括但不限于受试者的Th1应答是次最佳和/或无效的适应症。可以使用本发明利用可以刺激Th1免疫应答的佐剂增强受试者的Th1免疫应答。因此,受试者还包括罹患或有风险罹患癌症的受试者、具有受损或次最佳免疫性的受试者,如婴儿、老人、癌症患者、接受免疫抑制药物或照射的个体、血液透析患者以及具有遗传或特发性免疫功能障碍的受试者。
实例
实例1:给予纳米载体和混合的R848佐剂引起强烈地全身产生发炎性细胞因子
用于NC-R848-1纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号(Part#)4065609)。合成了组成是75/25丙交酯/乙交酯单体并且分子量是约4100Da的PLGA-R848结合物,它具有5.2%w/wR848含量。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.丑Baker)(件号U232-08)。用于产生NC-R848-1纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA-R848和25mg/mL的PLA-PEG-烟碱通过将PLGA-R848以100mg/mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA-R848溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生一种初级初级(W1/O)乳液。将溶液1(0.1mL)与溶液2(1.0mL)组合于一个小玻璃压力管中,并且使用一个必能信数字式声波仪(BransonDi蜘alSonifier)250在50%的振幅下进行声处理40秒。随后通过向初级乳液中添加溶液3(2.0mL)并且使用一个必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。将二级乳液添加到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将颗粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10mg/mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表1:根据上文产生的纳米载体的表征
用于NC-R848-2配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。合成了组成是75/25丙交酯/乙交酯单体并且分子量是约4100Da的PLGA-R848结合物,它具有5.2%w/wR848含量。合成了PLA-PEG-烟碱,它具有约5,000Da的由烟碱封端的PEG嵌段和约17,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生NC-R848-2纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA-R848和25mg/mL的PLA-PEG-烟碱通过将PLGA-R848以100mg/mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA-R848溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m/mL的纳米载体悬浮液。将悬浮液冷冻储存于-2℃下直到使用。
表2:根据上文产生的纳米载体的表征
用于仅NC配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。具有73%丙交酯和27%乙交酯含量并且固有黏度是0.12dL/g的PLGA购自塞莫迪克斯制药(SurModicsPharmaceuticals)(汤姆马丁路(TomMartinDrive)756号,伯明翰市(Birmingham),AL35211,产品代码7525DLG1A)。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.LBaker)(件号U232-08)。用于产生仅NC的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA和25mg/mL的PLA-PEG-烟碱通过将PLGA以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m田mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表3:根据上文产生的纳米载体的表征
结果
向小鼠组的后肢皮下注射100雌偶合有、不偶合有或混合有小分子核苷类似物和已知的TLR7/8激动剂以及佐剂R848的纳米载体(NC)。纳米载体中的R848量是2%-3%,使得每次注射有2-3雌偶合的R848;所使用的游离R848的量是每次注射20啡。通过末梢取血获得小鼠血清,并且在不同时间点通过ELISA(BD生物科学公司(BDBiosciences))测量血清中的全身细胞因子产生。如图1A-1C中所示,在使用混合的R848(NC+R848)时观察到强烈地全身产生主要促炎性细胞因子TNF-α、IL-6以及IL-12,而在使用含有与R848偶合的NC(NC-R848-1和NC-R848-2)的两种分开的制剂时未检测到表达TNF-α、IL-6以及IL-12。峰值细胞因子表达水平的差异是:对于TNF-α和IL-6,>100倍,并且对于IL-12,>50倍。不偶合到R848上的NC(标记为仅NC)在不具有混合的R848下使用时不诱导任何全身细胞因子。
实例2:纳米载体偶合到R848佐剂上不抑制免疫细胞因子IFN-γ的全身产生。
用于NC-R848纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。合成了组成是75/25丙交酯/乙交酯单体并且分子量是约4100Da的PLGA-R848结合物,它具有5.2%w/wR848含量。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生NC-R848纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70mg/mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA-R848和25mg/mL的PLA-PEG-烟碱通过将PLGA-R848以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA-R848溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妒mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表4:根据上文产生的纳米载体的表征
用于仅NC纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。具有73%丙交酯和27%乙交酯含量并且固有黏度是0.12dL/g的PLGA购自塞莫迪克斯制药(SurModicsPharmaceuticals)(汤姆马丁路(TomMartinDrive)756号,伯明翰市(Birmingham),AL35211,产品代码7525DLG1A)。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.LBaker)(件号U232-08)。
用于产生仅NC纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA和25mg/mL的PLA-PEG-烟碱通过将PLGA以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表5:根据上文产生的纳米载体的表征
结果
尽管早期的促炎性细胞因子主要与免疫期间的副作用有关,但已知其他细胞因子(如免疫IFN-γ)的产生参与有效免疫应答的诱导。因此,在接种后0-24小时测量注射NC后免疫细胞因子IFN-γ的全身产生。简单来说,向小鼠组的后肢皮下注射100雕偶合有或混合有小分子核苷类似物和已知的TLR7/8激动剂以及佐剂R848的NC。纳米载体中的R848量是2%,使得每次注射有2雕偶合的R848;所使用的游离R848的量是每次注射20雌。通过末梢取血获得小鼠血清,并且在不同时间点通过ELISA(BD生物科学公司(BDBiosciences))测量血清中的全身细胞因子产生。使用NC-R848(包含2啡的R848)与混合有R848的NC(20雕)都看到对于Th1免疫应答重要的IFN-γ(图2)。此外,之前出现过由混合有R848的NC产生较高水平的IFN吖。
实例3:添加游离佐剂增强免疫应答
用于NC-Nicw/oR848纳米载体配制品的材料
卵白蛋白肽323-339酰胺TFA盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4064565)。固有黏度是0.19dL/g的PLA购自勃林格殷格翰公司(BoehringerIngelheim)(德国殷格翰公司(IngelheimGermany),产品代码R202H)。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生NC-Nicw/oR848纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备69m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLA和25mg/mL的PLA-PEG-烟碱通过将PLA以100mg/mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLA溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的去离子水中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250以35%的振幅进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到离心管中,以5300rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表6:根据上文产生的纳米载体的表征
用于NC-Nicw/包埋的R848纳米载体配制品的材料
卵白蛋白肽323-339酰胺TFA盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4064565)。合成约98%-99%纯度的R848(瑞喹莫德)并且纯化。固有黏度是0.19dUg的PLA购自勃林格殷格翰公司(BoehringerIngelheim)(德国殷格翰公司(IngelheimGermany),产品代码R202H)。合成了PLA-PEG烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87-89%水解的)购自杰帝贝柯公司(J.里Baker)(件号U232-08)。
用于产生NC-Nicw/包埋的R848纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备69m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLA、7.5mg/mL的R848和25m妙mL的PLA-PEG-烟碱通过将PLA以100mg/mL溶解于二氯甲烷中并且添加10mg/mL的R848,还将PLA-PEG-烟碱以100mg/mL溶解于二氯甲烷中,随后组合3份PLA/R848溶液与1份PLA-PEG-烟碱来制备。
溶液3:于100mM的去离子水中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250以35%的振幅进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到离心管中,以5300rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表7:根据上文产生的纳米载体的表征
结果
在具有或不具有第二佐剂的情况下用携带包埋(非结合)的R848的NC-Nic(在外表面上展现烟碱的纳米载体)使小鼠免疫。以2周为间隔(第0天、14天以及28天)用100雕的NC-Nic使具有五只小鼠的组免疫三次(皮下,后肢)。随后在第26天和第40天测量血清抗烟碱抗体。通过标准ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的EC50(图3X组1:NC-Nicw/o包埋的R848;组2:NC-Nic僦1.5%的包埋的R848;组3:NC-Nic靴1.5%的包埋的R848+80啡的明矾;组4:NC-Nic僦1.5%的包埋的R84+25雌的Cp心1826)。这说明了在纳米载体(NC)内利用包埋的R848(Th1佐剂,TLR7/8激动剂)产生免疫应答,它优于由不具有R848的NC诱导的免疫应答(组2>组1)。此外,添加游离Th2佐剂(明矾)到具有R848的NC-Nic增强体液免疫应答(组3>组2)。同时,添加另一游离Th1佐剂(CpG,TLR9激动剂;组4)也增强免疫应答,但这个组合不如明矾有效(组4>组2并且4<组3)。实例4:向不具有佐剂的NC中添加游离佐剂增强免疫应答
用于NC-Nic纳米载体配制品的材料
卵白蛋白肽323-339酰胺TFA盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4064565)。固有黏度是0.19dL/g的PLA购自勃林格殷格翰公司(BoehringerIngelheim)(德国殷格翰公司(IngelheimGermany),产品代码R202H)。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生NC-Nic纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备69m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLA和25mg/mL的PLA-PEG-烟碱通过将PLA以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100mg/mL溶解于二氯甲烷中,随后组合3份PLA溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的去离子水中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250以35%的振幅进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到离心管中,以5300rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表8:根据上文产生的纳米载体的表征
用于NC-Nic-R848纳米载体配制品的材料
卵白蛋白肽323-339酰胺TFA盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4064565)。合成约98%-99%纯度的R848(瑞喹莫德)并且纯化。固有黏度是0.19dL/g的PLA购自勃林格殷格翰公司(BoehringerIngelheim)(德国殷格翰公司(IngelheimGermany),产品代码R202H)。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.吼Baker)(件号U232-08)。
用于产生NC-Nic-R848纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备69m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75m妒mL的PLA、7.5m妒mL的R848和25mg/mL的PLA-PEG-烟碱通过将PLG以100mg/mL溶解于二氯甲烷中并且添加10mg/mL的R848,还将PLA-PEG-烟碱以100mg/mL溶解于二氯甲烷中,随后组合3份PLA/R848溶液与1份PLA-PEG-烟碱来制备。
溶液3:于100mM的去离子水中的50m妙mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250以35%的振幅进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。
通过将纳米载体悬浮液转移到离心管中,以5300rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表9:根据上文产生的纳米载体的表征
结果
用具有或不具有混合的R848的NC中不具有佐剂的NC-Nic(在外表面上展现烟碱的纳米载体)使小鼠免疫。以2周为间隔(第0天、14以及28天)用100雌的NC-Nic使具有五只小鼠的组免疫三次(皮下,后肢)。随后在第26和40天测量血清抗烟碱抗体。通过标准ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的EC50(图4)(组1:NC-Nicw/o包埋的R848;组2:NC-Nicw/o包埋的R848+20雌的游离R848)。这说明了混合游离R848(Th1佐剂,TLR7/8激动剂)与携带抗原的NC产生免疫应答,它优于由不具有混合的R848的NC诱导的免疫应答(组2>组1)。
类似地,增强了用携带封装的R848佐剂的NC-Nic(NC-Nic-R848)与游离Th1佐剂CpG-1826(恩佐公司(Enzo))或Th2佐剂明矾(皮亚斯公司(Pierce))的混合物免疫的小鼠中对NC携带的抗原产生的免疫应答。以2周为间隔(第0、14以及28天)用100μg的NC-Nic-R848使具有五只小鼠的组免疫三次(皮下,后肢)。随后在第26和40天测量血清抗烟碱抗体。通过标准ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的EC50(图5)(组1:NC-Nic-R848;组2:NC-NicR848+80啡的游离明矾;组3:NC-NicR848+25鸭的游离CpG-1826)。这说明了混合游离佐剂与携带抗原/佐剂的NC产生免疫应答,它优于由不具有混合的佐剂的相同NC诱导的免疫应答(组2>组1;组3>组1)。
实例5:向包含封装的佐剂的NC中添加游离佐剂增强免疫应答
用于纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。合成约98%-99%纯度的R848(瑞喹莫德)并且纯化。通过开环工艺合成了分子量是约1300Da并且R848含量是约9重量%的PLA-R848结合物。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。.
用于产生纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLA-R848、25mg/mL的PLA-PEG-烟碱以及1.9m田mL的R848通过以100mg/mL溶解聚合物,添加R848到PLA-PEG-烟碱溶液中,随后组合3份PLA-R848溶液与1份PLA-PEG-烟励R848溶液来制备。
溶液3:于100mM的去离子水中的50m妙mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过向初级乳液中添加溶液3(2.0mL)并且使用必能信数字式声波仪250以35%的振幅进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到离心管中,以13,800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表10:根据上文产生的纳米载体的表征
结果
在具有或不具有混合的明矾的情况下用携带R848和OP-II辅助肽的纳米载体NC-Nic(在外表面上展现烟碱的纳米载体)使小鼠免疫。以2周为间隔(第0、14以及28天)用100μg的NC晒ic,R848,OP-II]+/-80啡的混合的明矾(皮亚斯公司(Pierce))使具有五只小鼠的组免疫三次(皮下,后肢)。随后在第40和70天测量血清抗烟碱抗体。通过标准ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的EC50(图6)(组1:NC[Nic,R848,OP-II];组2:NC[Nic,R848,OP-II]+80雌的混合的明矾)。这说明了混合游离明矾(Th2佐剂)与携带抗原并且包含佐剂的NC产生免疫应答,它优于由不具有混合的明矾的相同NC诱导的免疫应答(组2>组1)。
实例6:相较于游离抗原(混合有游离佐剂),NC封装的抗原产生较强的细胞免疫应答
用于纳米载体配制品的材料
卵白蛋白购自沃辛顿生物化学公司(Worthin蚺onBiochemicalCorporation)(瓦萨大道(VassarAvenue)730号,湖木市(Lakewood),NJ08701,产品代码3048)。固有黏度是0.21dL/g的PLA购自塞莫迪克斯制药(SurModicsPharmaceuticals)(汤姆马丁路(TomMartinDrive)756号,伯明翰市(Birmingham),AL35211,产品代码100DL2A)。合成了PLA-PEG-OMe嵌段共聚物,它具有约2,000Da的由甲醚封端的PEG嵌段和约19,000Da的PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.丑Baker)(件号U232-08)。用于产生纳米载体的方法
溶液如下制备:
溶液1:在室温下在磷酸盐缓冲生理盐水中制备20mg/mL的卵白蛋白。
溶液2:于二氯甲烷中的75m妙mL的PLA和25m妒mL的PLA-PEG-OMe通过将PLA以100mg/mL溶解于二氯甲烷中并且将PLA-PEG-OMe以100m妙mL溶解于二氯甲烷中,随后组合3份PLA溶液与1份PLA-PEG-OMe溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50m妒mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.2mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(3.0mL)到初级乳液中,涡旋以产生一种过程分散体,并且然后使用必能信数字式声波仪250在30%的振幅下进行声处理60秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以21,000rcf旋转45分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表11:根据上文产生的纳米载体的表征
结果
用纳米载体NC-OVA(携带封装的卵白蛋白的纳米载体)或用混合有游离佐剂的游离卵白蛋白(OVA)使小鼠免疫。用100啡的NC-OVA(2.8%OVA)或用2.5啡的混合有10啡的游离1826-CpG(TLR9激动剂)的游离OVA使具有3只小鼠的组免疫一次(皮下,后肢)。在免疫后第4天取出引流腿窝淋巴结,过筛,在体外在每毫升补充有10单位IL-2的完全RPMI培养基中孵育4天,并且在不同的效应子/标靶(E∶T)比率下测定特异性CTL(表示为细胞毒性T细胞)活性(表达卵白蛋白的细胞系EG.7-OVA的溶解%-该细胞系的亲本细胞系EL-4的溶解%X图7)。这说明了相较于用游离抗原免疫,利用NC封装的抗原引起较强的局部细胞免疫应答的产生。
实例7:向不具有佐剂的NC中添加游离佐剂增强免疫应答
用于纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。固有黏度是0.19dL仅的PLA购自勃林格殷格翰公司(BoehringerIngelheim)(德国殷格翰公司(IngelheimGermany),产品代码R202H)。合成了PLA-PEG-烟碱,它具有约5,000Da的由烟碱封端的PEG嵌段和约17,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生纳米载体的方法
溶液如下制备:
溶液1:于稀盐酸水溶液中的17.5m妙mL卵白蛋白肽323-339。该溶液通过在室温下将卵白蛋白肽溶解于0.13N盐酸溶液中来制备。
溶液2:于二氯甲烷中的75mg/mL的0.19-IVPLA和25mg/mL的PLA-PEG-烟碱。该溶液通过分别将PLA以100mg/mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m田mL溶解于二氯甲烷中,随后通过对于每份PLA-PEG-烟碱溶液添加3份PLA溶液混合这些溶液来制备。
溶液3:于100mMpH8磷酸盐缓冲液中的50m田mL的聚乙烯醇。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且然后使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。随后添加二级乳液到包含70mMpH8磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以蒸发二氯甲烷并且形成纳米载体于水性悬浮液中。通过将悬浮液转移到一个离心管中并且以13,800g旋转一小时,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分纳米载体。重复该洗涤程序,并且将球粒再悬浮于磷酸盐缓冲生理盐水中,最终得到约10m妙mL的纳米载体分散液。通过HPLC分析测定纳米载体中寡核苷酸和肽的量。通过重量分析法测定每毫升悬浮液的总干燥纳米载体质量并且调节到5m妙mL。
表12:根据上文产生的纳米载体的表征
结果
用混合有磷酸二酯(PO)或硫代磷酸酯(PS)形式的CpG的NC-Nic(在在外表面上展现烟碱并且包含OP-II辅助肽的纳米载体,该NC中无佐剂)使小鼠免疫。PO形式被核酸酶降解,并且因此在注射到小鼠中后并不稳定。PS形式抗核酸酶,并且因此在注射到小鼠中后是稳定的。作为阴性对照,仅用PBS使小鼠免疫。以2周为间隔(第0、14以及28天)用100鸭的NC-Nic+20雌的CpG(PS或PO)或PBS使具有五只小鼠的组免疫三次(皮下,后肢)。在第26和40天测量血清抗烟碱抗体滴度。通过ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的滴度(EC50)(图8)(组1:NC-Nic(无佐剂)+游离CpG(PS);组2:NC-Nic(无佐剂)+游离CpG(PO);组3:仅PBS)。这说明了混合游离CpG(PS)(Th1佐剂,TLR9激动剂)与携带抗原的NC产生免疫应答,它优于由具有混合的CpG(PO)的NC或用PBS诱导的免疫应答(组1>组2>组3)。
实例8:向不具有佐剂的NC中添加游离佐剂增强免疫应答
用于纳米载体配制品的材料
卵白蛋白购自沃辛顿生物化学公司(Worthin蚺onBiochemicalCorporation)(瓦萨大道(VassarAvenue)730号,湖木市(Lakewood),NJ08701,产品代码3048)。固有黏度是0.21dL/g的PLA购自塞莫迪克斯制药(SurModicsPharmaceuticals)(汤姆马丁路(TomMartinDrive)756号,伯明翰市(Birmingham),AL35211,产品代码100DL2A)。合成了PLA-PEG-OMe嵌段共聚物,它具有约2,000Da的由甲醚封端的PEG嵌段和约19,000Da的PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.丑Baker)(件号U232-08)。
用于产生纳米载体的方法
溶液如下制备:
溶液1:在室温下在磷酸盐缓冲生理盐水中制备20mg/mL的卵白蛋白。
溶液2:于二氯甲烷中的75mg/mL的PLA和25mg/mL的PLA-PEG-OMe通过将PLA以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-OMe以100m妙mL溶解于二氯甲烷中,随后组合3份PLA溶液与1份PLA-PEG-OMe溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.2mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(3.0mL)到初级乳液中,涡旋以产生一种过程分散体,并且然后使用必能信数字式声波仪250在30%的振幅下进行声处理60秒,从而形成二级(W1/O/W2)乳液。将二级乳液添加到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以21,000rcf旋转45分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m妙mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表13:根据上文产生的纳米载体的表征
结果
用混合有20鸭的R848或CpG(PS;抗核酸酶)的NC-OVA(在外表面上展现卵白蛋白(OVA)的纳米载体,该NC中无佐剂)使小鼠免疫。对照小鼠接受2.5鸭的混合有20雌的CpG(PS)的可溶性抗原(OVA)。以2周为间隔(第0、14以及28天)用100μg的NC-OVA+20鸭的R848或CpG(PS)或2.5μg的可溶性OVA+20鸭的CpG(PS)使具有五只小鼠的组免疫三次(皮下,后肢)。在第26和44天测量血清抗OVA抗体滴度。通过ELISA测量抗OVA抗体针对OVA蛋白的滴度(EC50)(图9)(组1:NC-OVA(无佐剂)+游离R848;组2:NC-OVA(无佐剂)+游离CpG(PS);组3:可溶性OVA+CpG(PS))。这说明了混合游离R848(Th1佐剂,TLR7/8激动剂)或CpG(PS)(Th1佐剂,TLR9激动剂)与携带抗原的NC产生免疫应答,它优于由混合有佐剂(CpG(PS))的可溶性抗原诱导的免疫应答(组1和组2>组3)。
实例9:向具有佐剂的NC中添加游离佐剂增强免疫应答
用于组1纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。合成了组成是75/25丙交酯/乙交酯单体并且分子量是约4100Da的PLGA-R848结合物,它具有5.2%w/wR848含量。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生组1纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70mg/mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA-R848和25mg/mL的PLA-PEG-烟碱通过将PLGA-R848以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA-R848溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。将二级乳液添加到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10mg/mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表14:根据上文产生的纳米载体的表征
用于组2纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4065609)。具有73%丙交酯和27%乙交酯含量并且固有黏度是0.12dL佃的PLGA购自塞莫迪克斯制药(SurModicsPharmaceuticals)(汤姆马丁路(TomMartinDrive)756号,伯明翰市(Birmingham),AL35211,产品代码7525DLG1A)。合成了PLA-PEG-烟碱,它具有约3,500Da的由烟碱封端的PEG嵌段和约15,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生组2纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备70m妙mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLGA和25mg/mL的PLA-PEG-烟碱通过将PLGA以100m妙mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLGA溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的磷酸盐缓冲液(pH8)中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.1mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。添加二级乳液到包含70mM磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到一个离心管中,以13800rcf旋转60分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10m田mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表15:根据上文产生的纳米载体的表征
以2周为间隔(第0和14天)用20μgCpG注射小鼠两次(皮下,后肢)。在第35和49天,用100雕的NC-Nic(包含2.6%的R848和0.9%的OP-II肽)或100啡的NC-Nic(仅包含1.1%的OP-II肽)使小鼠免疫。在用NC免疫后第12、26以及40天测量血清抗烟碱抗体滴度。通过ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的滴度(EC50)(图10)(组1:NC-Nic(R848+OP-II);组2:NC-Nic(仅OP-II))。这说明了相较于用CpG接着在稍后的日子用不包含R848的NC-Nic免疫的小鼠,用CpG接着在稍后的日子用包含R848的NC-Nic的组合免疫的小鼠对烟碱产生较高的抗体滴度(组1>组2)。
实例10:向NC-Nic添加两种游离佐剂增强免疫应答(预示的)
用于NC-Nic纳米载体配制品的材料
卵白蛋白肽323-339酰胺乙酸盐购自巴亨美国公司(BachemAmericasInc.)(柏市街(KashiwaStreet)3132号,托兰斯市(Torrance),CA90505,件号4064565)。固有黏度是0.19dL/g的PLA购自塞莫迪克斯制药(SurModicsPharmaceuticals)(汤姆马丁路(TomMartinDrive)756号,伯明翰市(Birmingham),AL35211,产品代码100DL2A)。合成了PLA-PEG-烟碱,它具有约5,000Da的由烟碱封端的PEG嵌段和约20,000Da的DL-PLA嵌段。聚乙烯醇(Mw=11,000-31,000,87%-89%水解的)购自杰帝贝柯公司(J.工Baker)(件号U232-08)。
用于产生NC-Nic纳米载体的方法
溶液如下制备:
溶液1:在室温下在0.13N盐酸中制备20mg/mL的卵白蛋白肽323-339。
溶液2:于二氯甲烷中的75mg/mL的PLA和25mg/mL的PLA-PEG-烟碱通过将PLA以100mg/mL溶解于二氯甲烷中并且将PLA-PEG-烟碱以100m妙mL溶解于二氯甲烷中,随后组合3份PLA溶液与1份PLA-PEG-烟碱溶液来制备。
溶液3:于100mM的去离子水中的50mg/mL的聚乙烯醇。
溶液4:70mM的磷酸盐缓冲液,pH8。
首先,使用溶液1和溶液2产生初级(W1/O)乳液。在小玻璃压力管中组合溶液1(0.2mL)与溶液2(1.0mL),并且使用必能信数字式声波仪250在50%的振幅下进行声处理40秒。随后通过添加溶液3(2.0mL)到初级乳液中并且使用必能信数字式声波仪250在30%的振幅下进行声处理40秒,从而形成二级(W1/O/W2)乳液。将二级乳液添加到包含70mM的磷酸盐缓冲溶液(30mL)的一个50mL开口烧杯中,并且在室温下搅拌2小时以允许二氯甲烷蒸发并且纳米载体形成于悬浮液中。通过将纳米载体悬浮液转移到离心管中,以21,000rcf旋转45分钟,去除上清液并且将球粒再悬浮于磷酸盐缓冲生理盐水中,借此洗涤一部分悬浮的纳米载体。重复此洗涤程序,随后将球粒再悬浮于磷酸盐缓冲生理盐水中,得到以聚合物计标称浓度是10mg/mL的纳米载体悬浮液。将悬浮液冷冻储存于-20℃下直到使用。
表16:根据上文产生的纳米载体的表征
结果
用混合有第一(R848)和第二佐剂(明矾)的NC-Nic(在外表面上展现烟碱的纳米载体)使小鼠免疫。用100啡的NC-Nic以2周间隔以2周为间隔(第0、14以及28天)使具有五只小鼠的组免疫三次(皮下,后肢)。随后在第26和40天测量血清抗烟碱抗体。通过标准ELISA测量抗烟碱抗体针对聚赖氨酸-烟碱的EC。50
Claims (66)
1.一种组合物,包含:
一个剂型,包含
(1)一群合成纳米载体,
(2)一种不偶合到任何合成纳米载体上的第一佐剂,
(3)一种偶合到所述合成纳米载体的第二佐剂,以及
(4)一种药物学上可接受的赋形剂。
2.如权利要求1所述的组合物,其中该组合物包含一次全身剂量的该第一佐剂。
3.如权利要求1所述的组合物,其中该第一佐剂与该第二佐剂不同。
4.如权利要求1或3所述的组合物,其中该组合物包含一次全身剂量的该第一佐剂和/或该第二佐剂。
5.如权利要求2所述的组合物,其中该全身剂量引起全身释放TNF-α、IL-6和/或IL-12。
6.如权利要求2所述的组合物,其中该全身剂量引起全身释放IFN-γ、IL-12和/或IL-18。
7.如权利要求1到3中任何一项所述的组合物,进一步包含一种或多种抗原。
8.如权利要求7所述的组合物,其中该一种或多种抗原被偶合到这些合成纳米载体上。
9.如权利要求7所述的组合物,其中该一种或多种抗原被偶合到另一群合成纳米载体上。
10.如权利要求7所述的组合物,其中该一种或多种抗原不偶合到任何合成纳米载体上。
11.如权利要求7所述的组合物,其中该一种或多种抗原包含一种B细胞抗原和/或一种T细胞抗原。
12.如权利要求11所述的组合物,其中该T细胞抗原是一种T辅助细胞抗原。
13.如权利要求7所述的组合物,其中该一种或多种抗原包含一种B细胞抗原和/或一种T细胞抗原以及一种T辅助细胞抗原。
14.如权利要求1到3中任何一项所述的组合物,其中该组合物不包含一种抗原。
15.如权利要求1到3中任何一项所述的组合物,其中该第一佐剂和/或该第二佐剂包含一种矿物盐、凝胶型佐剂、一种微生物佐剂、一种基于油-乳液或乳化剂的佐剂、一种微粒佐剂、一种合成佐剂、一种磷酸盐佐剂、一种聚合物、一种脂质体、一种微载体、一种免疫刺激核酸、一种皂甙、一种白细胞介素、一种干扰素、一种细胞因子、一种toll样受体(TLR)激动剂、一种咪唑并喹啉、一种细胞因子受体激动剂、一种CD40激动剂、一种Fc受体激动剂或一种补体受体激动剂。
16.如权利要求1到3中任何一项所述的组合物,其中该第一佐剂和/或该第二佐剂包含QS21、维生素E、角鲨烯、QuilA、多种ISCOM、ISCOMATRIX、RibiDetox、CRL-1005、L-121、四氯十氧化物、明矾、MF59、AS02、AS15、霍乱毒素、单磷酰脂质A、不完全弗氏佐剂、完全弗氏佐剂、胞壁酰二肽或莫泰立德(montanide)。
17.如权利要求15所述的组合物,其中该免疫刺激核酸包含一种包含CpG的核酸。
18.如权利要求15所述的组合物,其中该咪唑并喹啉包含瑞喹莫德或咪喹莫特。
19.如权利要求15所述的组合物,其中该第一和/或该第二佐剂包含明矾。
20.如权利要求17所述的组合物,其中当该第一佐剂包含一种包含CpG的核酸时,该第二佐剂包含一种咪唑并喹啉或明矾。
21.如权利要求20所述的组合物,其中该咪唑并喹啉是瑞喹莫德。
22.如权利要求15所述的组合物,其中当该第一佐剂包含一种咪唑并喹啉时,该第二佐剂包含一种包含CpG的核酸或明矾。
23.如权利要求22所述的组合物,其中该咪唑并喹啉是瑞喹莫德。
24.如权利要求19所述的组合物,其中当该第一佐剂包含明矾时,该第二佐剂包含一种咪唑并喹啉或一种包含CpG的核酸。
25.如权利要求24所述的组合物,其中该咪唑并喹啉是瑞喹莫德。
26.如权利要求15所述的组合物,其中该TLR激动剂包含一种TLR-1、TLR-2、TLR-3、TLR-4、TLR-5、TLR-6、TLR-7、TLR-8、TLR-9、TLR-10、TLR-11激动剂或其一种组合。
27.如权利要求1到3中任何一项所述的组合物,其中该第一佐剂和/或该第二佐剂不包含一种TLR激动剂。
28.如权利要求1到3中任何一项所述的组合物,其中该第一佐剂和/或该第二佐剂不包含一种TLR-3、TLR-7、TLR-8或TLR-9激动剂。
29.如权利要求1到3中任何一项所述的组合物,其中这些合成纳米载体包含脂质纳米颗粒、聚合物纳米颗粒、金属纳米颗粒、基于表面活性剂的乳液、树枝状聚合物、巴克球、纳米线、病毒样颗粒、肽或蛋白质颗粒、包含纳米材料的一种组合的纳米颗粒、球形纳米颗粒、立方形纳米颗粒、金字塔形纳米颗粒、长方形纳米颗粒、圆柱形纳米颗粒或环形纳米颗粒。
30.如权利要求29所述的组合物,其中该第二佐剂被偶合到这些合成纳米载体上并且包含瑞喹莫德。
31.如权利要求30所述的组合物,其中该一种或多种抗原包含烟碱和一种T辅助细胞抗原,这些物质各自被偶合到这些合成纳米载体上。
32.如权利要求31所述的组合物,其中该T辅助细胞抗原包含SEQIDNO:1中所阐明的序列。
33.如权利要求12所述的组合物,其中该T辅助细胞抗原通过封装来偶合。
34.如权利要求29所述的组合物,其中这些合成纳米载体包含一种或多种聚合物。
35.如权利要求34所述的组合物,其中该一种或多种聚合物包含一种聚酯。
36.如权利要求34所述的组合物,其中该一种或多种聚合物包含一种偶合到一种亲水性聚合物上的聚酯。
37.如权利要求35所述的组合物,其中该聚酯包含一种聚(乳酸)、聚(乙醇酸)、聚(乳酸-共-乙醇酸)或聚己内酯。
38.如权利要求36所述的组合物,其中该亲水性聚合物包含一种聚醚。
39.如权利要求38所述的组合物,其中该聚醚包含聚乙二醇。
40.如权利要求1到39中任何一项所述的组合物在制备药物中的用途,其中给予受试者所述药物。
41.如权利要求40所述的用途,其中该受试者是一个人。
42.如权利要求40到41中任何一项所述的用途,其中该用途进一步包括给予一种或多种抗原。
43.如权利要求42所述的用途,其中共给予该一种或多种抗原。
44.如权利要求42所述的用途,其中该一种或多种抗原包含一种B细胞抗原和/或一种T细胞抗原。
45.如权利要求44所述的用途,其中该T细胞抗原是一种T辅助细胞抗原。
46.如权利要求42所述的用途,其中该一种或多种抗原包含一种B细胞抗原和/或一种T细胞抗原以及一种T辅助细胞抗原。
47.如权利要求44所述的用途,其中该B细胞抗原是烟碱。
48.如权利要求45所述的用途,其中该T辅助细胞抗原包含SEQIDNO:1中所阐明的序列。
49.如权利要求45所述的用途,其中该T辅助细胞抗原通过封装来偶合。
50.如权利要求40所述的用途,其中该受试者需要一种发炎应答。
51.如权利要求40所述的用途,其中该受试者需要一种Th1免疫应答。
52.如权利要求40所述的用途,其中该受试者需要一种体液免疫应答。
53.如权利要求40所述的用途,其中该受试者需要一种特异性局部细胞毒性T淋巴细胞应答。
54.如权利要求40所述的用途,其中该受试者罹患或有风险罹患癌症。
55.如权利要求40所述的用途,其中该受试者罹患或有风险罹患感染或感染性疾病。
56.如权利要求40所述的用途,该受试者罹患或有风险罹患一种特应性病状、哮喘、COPD或一种慢性感染。
57.如权利要求1到3中任何一项所述的组合物在制备用于治疗或预防的药物中的用途。
58.如权利要求1到3中任何一项所述的组合物,用于如权利要求40到56中任何一项所述的用途中。
59.如权利要求1到3中任何一项所述的组合物,用于一种在一位受试者中诱导一种发炎应答的方法中。
60.如权利要求1到3中任何一项所述的组合物,用于一种在一位受试者中诱导一种Th1免疫应答的方法中。
61.如权利要求1到3中任何一项所述的组合物,用于一种在一位受试者中诱导一种体液免疫应答的方法中。
62.如权利要求1到3中任何一项所述的组合物,用于一种在一位受试者中诱导一种特异性局部细胞毒性T淋巴细胞应答的方法中。
63.如权利要求1到3中任何一项所述的组合物,用于一种治疗或预防癌症的方法中。
64.如权利要求1到3中任何一项所述的组合物,用于一种治疗或预防感染或感染性疾病的方法中。
65.如权利要求1到3中任何一项所述的组合物,用于一种治疗或预防一种特应性病状、哮喘、COPD或一种慢性感染的方法中。
66.一种如权利要求1到3中任何一项所述的组合物的用途,用于制造一种供如权利要求40所述的用途中使用的药剂。
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CN201611150052.2A Pending CN107080839A (zh) | 2010-05-26 | 2011-05-26 | 多价的合成纳米载体疫苗 |
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