CN103533922A - 抗原制剂 - Google Patents
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Abstract
本发明涉及一种包含生物抗原的抗原制剂,其中该制剂包含含有桐酸的脂肪酸酯作为主要成分的油。本发明同样涉及所述油用于制备抗原制剂的用途。
Description
本发明涉及抗原制剂,其包含至少一种生物抗原。
包含生物抗原的制剂在本技术领域中是已知的,其例如可用于诊断目的或作为疫苗,以用于预防、减轻或治疗由(微)生物如细菌、病毒、立克次氏体和寄生虫引起的疾病。这种制剂含有至少一种生物来源的抗原(即具有与免疫应答的最终产物(即抗体和/或T细胞上的表面受体)特异结合的能力的物质)。生物抗原例如可以是活的(任选减活的)微生物、死的微生物、生物的毒素(任选的呈灭活形式,即所谓的类毒素)或生物的任何其它代谢物,所述生物的亚单元(如例如所述生物的DNA)或所述生物的表面分子(如外表面蛋白质、外膜蛋白、脂多糖、碳水化合物)等。在任何情况下,术语“生物抗原”涵盖了活的或死的微生物,以及来自生物,如细菌、病毒、动物、原生生物、真菌等的生物分子(优选为蛋白质或多糖)。术语“来自”包括生物分子本身或由生物产生的前体。
抗原制剂中存在的抗原和抗体或T细胞之间的相互作用的量,不仅取决于抗原与相应的抗体或T细胞受体的内在结合特性,还取决于在制剂中的抗原的有关结合位点(一个或多个)(也称为表位(一个或多个))的可用性。该可用性取决于在制剂中的抗原对呈递的开启,以及保持(preservation)。理想的制剂提供了最佳的抗原的呈递并优选地,保护抗原防御降解。在本领域中,包含惰性油如轻质烃油(如Marcol52TM)和角鲨烷的制剂最常用于抗原呈递。对于人类应用,维生素E醋酸酯被广泛地使用。
仍然存在对提供良好抗原呈递的可替换的制剂的需要。为此,已经设计出根据前文所述的抗原制剂,其中该制剂包含含有桐酸的脂肪酸酯作为主要成分(按油本身的重量计一般超过50%)的油。令人惊讶的是,已经发现,本制剂中各种不同类型的抗原与抗体结合的可用性与现有技术的制剂相比得到了改善,并且,所述呈递可以通过使制剂经受紫外线辐射而甚至进一步的改善。当将含有抗原的制剂经受紫外线辐射时,后者与预测是完全矛盾的。众所周知,紫外线辐射对于许多抗原,特别是蛋白质的结构是有害的。所发现的抗原的改善的呈递的原因不明。当与例如非可生物降解的油如轻质烃油和角鲨烷相比时,桐酸的脂肪酸的使用所伴随的优点是它的可生物降解性(由于该油在体内可以留下较少的痕迹)。本发明还涉及含有桐酸的脂肪酸酯作为主要成分的油在制造包含至少一种生物抗原的抗原制剂中的用途。
注意到,该油也可以用于与水相结合构成乳剂。众所周知,乳剂是分散体系,其含有至少两种互不相混溶的液相。不变地,两种互不相混溶的相中的一种是水相,而另一种是油相(其简单地表示为与水不相混溶的液体)。水或油相是否成为分散相,这尤其取决于两液相存在的量。乳剂(其中油以液滴形式分散在整个水相中)称为水包油(O/W)型乳剂。当水是分散相,并且油是分散介质(也称为连续介质)时,乳剂为油包水(W/O)型。此外,特别是为了延缓活性成分的释放,已经研制了多重乳剂(multiple emulsions)。在这些类型的乳剂中存在三(或更多)相。这样的乳剂为例如W/O/W或O/W/O型。已知,当乳化而不是简单地悬浮在水性制剂中时,生物抗原可以引起更快且更好的免疫应答。
该脂肪酸酯可以是桐酸的甘油三酯,其是一种桐酸的天然存在的酯的常见形式。这样的油优选含有60至90%之间的桐酸的脂肪酸酯。本发明中可以使用的一种典型的油来自于油桐种子油(也称为“桐油”或“中国木油”)。该种子油可常规获得且价廉。通过除去来自实际的种子油的杂质,或通过添加成分(如粘度调节剂、稳定剂、去污剂等),可以例如从这种天然存在的油制造一种改良的衍生油(来满足特定需求)。在一个实施方案中,该油是实际的桐油,即从油桐树得到的油。桐油含有超过50%(W/W)(一般在73至82%(W/W)之间)的桐酸的酯,这使得它理想地适合于在根据本发明的制剂中使用。
在一个实施方案中,该制剂是一种该油在水性液体中的乳剂。优选地,抗原存在于水性液体中。合适的抗原的例子是APX III毒素、牛呼吸道合胞病毒的抗原(例如该病毒的一个亚单元或作为整体的病毒)以及副流感3病毒的抗原(例如该病毒的一个亚单元或作为整体的病毒)。
在再一个实施方案中,将该制剂暴露于紫外线辐射。完全令人惊奇地,发现通过使制剂经受紫外线辐射可以甚至进一步改善抗原呈递。
本发明将在下列实施例中作进一步的说明。
实施例1配制在水包油乳剂中的RTX毒素APXIII。
实施例2配制在水包油乳剂中的灭活的BRS病毒。
实施例3配制在水包油乳剂中的灭活的PI-3病毒。
实施例4配制在另一种水包油乳剂中的RTX毒素APXIII。
实施例1
作为第一个实施例制剂,其用细菌重复序列毒素APX III制成,所述细菌重复序列毒素APX III是由猪病原体胸膜肺炎放线杆菌(Actinobacilluspleurpneumoniae)(也称为APP)产生的。该抗原作为一种疫苗成分用于市售的疫苗Porcilis APPTM(可从Intervet Schering-Plough Animal Health,Boxmeer,TheNetherlands获得)中,并可用于诊断测试中以验证猪是否已经被APP血清型2、3、4、6或8(此血清型生产AxpIII)中的任意种感染。
通过在159.21克的PBS缓冲液(50℃)中磁力混合40.79克的吐温80,直至获得澄清的溶液,制备吐温80(Uniqema Nederland BV,Gouda,TheNetherlands)在0.01M磷酸盐缓冲液(PBS)中的溶液。将该溶液冷却至约8℃。向53.07g的该溶液中,缓慢加入50g温度约20℃的桐油(Vliegenthart BV,Tiel,The Netherlands),并在氮气氛下,用14N转子/定子ultra turrax混合器(IKA,Staufen,Germany)混合。在约每分钟11000转的混合速度下,在3分12秒内完成油的加入。此后,在约每分钟22000转下,将乳剂另外搅拌10分钟。在此过程中,乳剂的温度从16℃升至32℃。发现80%的油滴具有低于2μm的直径(在显微镜下测定)。
向9.25克乳剂中加入50.58克的APXIII抗原的水性(0.01M PBS)混悬液,以获得最终的APXIII制剂。在该最终制剂中意图达到的抗原浓度为25U/ml。
为构建对照制剂,将50.58克相同的APXIII抗原混悬液加入到9.25克的0.01M PBS中(因此也意图达到25U/ml的APXIII的浓度)。
使用对抗APX III的抗体,通过抗原质量ELISA(antigenic mass ELISA)来测定制剂的滴度。为了验证制剂是否可以使毒素抵御降解,进行了一项测试,其中将该制剂暴露于紫外线辐射。在该测试中,使用Mirasol PRT系统(5.1版Illuminator,可得自CaridianBCT,Lakewood,Colorado,USA)。将待暴露的约57ml样品转移到一个塑料袋中(用Mirasol设备来使其标准化)。在此之后,同样加入120毫升的氧气。按照制造商的说明书,将包含其内容物的袋子置于Mirasol设备上,并进行(标准)紫外线照射程序。总的照射时间为15分钟。紫外线处理后通过用氮气冲洗除去氧气。
表1描述了在制剂中确定的滴度。滴度为两次测量的平均值。
显而易见,在de ELISA测试中,该油对抗原的呈递具有积极效果:凭借该油的存在,滴度增加了13单位/ml。似乎APXIII的相关结合位点的可用性由于桐油的存在而增加了。引人注目的是,由于用紫外线辐射暴露,滴度从43U/m1增加至69U/ml。
表1有或无紫外线暴露的各种制剂的APXIII滴度
测试序号 | 样品说明 | 紫外线 | 滴度[U/ml] |
l | APXIII水溶液,对照 | 无 | 30 |
2 | APXIII水包油乳剂 | 无 | 43 |
3 | APXIII水溶液,对照 | 有 | 30 |
4 | APXIII水包油乳剂 | 有 | 69 |
实施例2
在第二个实施例中,用灭活的BRS病毒来制备制剂。此抗原作为一种疫苗成分用于市售的疫苗Bovilis BovipastTM(可从Intervet Schering-Plough AnimalHealth,Boxmeer,The Netherlands获得)中,并可用于诊断测试,以验证牛是否已经被牛呼吸道合胞病毒感染。
通过在159.21克的PBS缓冲液(50℃)中磁力混合40.79克的吐温80,直至获得澄清的溶液,制备吐温80(ICI Americas,Wilmington Delaware)在0.01M磷酸盐缓冲液(PBS)中的溶液。将该溶液冷却至约20℃。向53.07g的该溶液中,缓慢加入50g温度约20℃的桐油(Vliegenthart BV, Tiel,The Netherlands),并在氮气氛下,用18N转子/定子ultra turrax混合器(IKA,Staufen,Germany)混合。在每分钟17000转的混合速度下,在3分13秒内完成油的加入。此后,将乳剂在每分钟20200转下搅拌5分30秒,并在每分钟24000转下另外搅拌3分30秒。在此过程中,乳剂的温度从22℃升至35℃。发现大约80-90%的油滴具有低于5μm的直径(在显微镜下测定)。
向9.25克乳剂中加入50.58克的灭活的BRS病毒的水性(0.01M PBS)混悬液,以获得最终的制剂。在该最终制剂中意图达到的抗原浓度为125U/ml。
为构建对照制剂,将50.58克相同的BRS病毒混悬液加入到9.25克的0.01MPBS中(因此也意图达到125U/ml的BRSV浓度)。
使用对抗BRS病毒的抗体,通过抗原质量ELISA(antigenic mass ELISA)来测定制剂的滴度。并且,进行了一项测试,其中将该制剂暴露于紫外线辐射。在该测试中,使用Mirasol PRT系统(5.1版Illuminator,可得自CaridianBCT,Lakewood,Colorado,USA)。将待暴露的约57ml样品转移到一个塑料袋中(用Mirasol设备来使其标准化)。在此之后,同样加入120毫升的氧气。按照制造商的说明书,将包含其内容物的袋子置于Mirasol设备上,并进行(标准)紫外线照射程序。总的照射时间为15分钟。紫外线处理后通过用氮气冲洗除去氧气。
表2描述了在制剂中确定的滴度。滴度为两种制剂(每种测量两次)的平均值。
表2有或无紫外线暴露的各种制剂的BRSV滴度
测试序号 | 样品说明 | 紫外线 | 滴度[U/ml] |
1 | BRSVI水溶液,对照 | 无 | 125 |
2 | BRSV水包油乳剂 | 无 | 147 |
3 | BRSV水溶液,对照 | 有 | 0 |
4 | BRSV水包油乳剂 | 有 | 147 |
显而易见,在de ELISA测试中,该油对抗原的呈递具有积极效果:凭借该油的存在,滴度增加了22单位/ml。似乎BRSV的相关结合位点的可用性由于桐油的存在而增加了。同样引人注目的是防御紫外线辐射暴露的明显的完全保护。在没有桐油的存在下,紫外线辐射导致了滴度的完全丧失。凭借桐油的存在,滴度保持不变。
实施例3
在第三个实施例中,用灭活的副流感3病毒来制备制剂。此抗原作为一种疫苗成分用于市售的疫苗Bovilis BovipastTM(可从Intervet Schering-PloughAnimalHealth,Boxmeer,The Netherlands获得)中,并可用于诊断测试,以验证牛是否已经被该副流感病毒感染。
使用为BRSV制剂的制备而制造的相同的油乳剂。向9.25克的乳剂中加入50.58克灭活的PI-3病毒的水性(0.01M PBS)混悬液,以获得最终的制剂。在该最终制剂中意图达到的抗原浓度为25U/ml。
为构建对照制剂,将50.58克相同的PI-3混悬液加入到9.25克的0.01MPBS中(因此也意图达到25U/ml的PI-3浓度)。
使用对抗PI-3病毒的抗体,通过抗原质量ELISA(antigenic mass ELISA)来测定制剂的滴度。并且,进行了一项测试,其中将该制剂暴露于紫外线辐射。在该测试中,使用Mirasol PRT系统(5.1版Illuminator,可得自CaridianBCT,Lakewood,Colorado,USA)。将待暴露的约57ml样品转移到一个塑料袋中(用Mirasol设备来使其标准化)。在此之后,同样加入120毫升的氧气。按照制造商的说明书,将包含其内容物的袋子置于Mirasol设备上,并进行(标准)紫外线照射程序。总的照射时间为15分钟。紫外线处理后通过用氮气冲洗除去氧气。
表3描述了在制剂中确定的滴度。滴度为两种制剂(每种测量两次)的平均值。
表3有或无紫外线暴露的各种制剂的PI-3滴度
测试序号 | 样品说明 | 紫外线 | 滴度[U/ml] |
1 | PI-3水溶液,对照 | 无 | 26 |
2 | PI-3水包油乳剂 | 无 | 28 |
3 | PI-3水溶液,对照 | 有 | 0 |
4 | PI-3水包油乳剂 | 有 | 34 |
在de ELISA测试中,似乎该油对抗原的呈递具有积极效果:凭借油的存在,滴度增加了2单位/ml(尽管在测试1和2中结果的标准偏差(即分别为0.9和1.1)使得该增加在统计上可能是不相关的)。非常引人注目的是紫外线辐射暴露后滴度的增加甚至更多,因为在没有桐油的存在下,紫外线辐射导致了滴度的完全丧失。凭借桐油(具有作为主要成分的桐酸的脂肪酸酯)的存在,滴度增加了。
实施例4
在该实施例中,用—种可替换的桐酸的脂肪酯,即桐酸的甲酯,重复实施例1的实验。该酯以纯的形式而不是实施例1中所述的桐油的形式使用。
将所得的制剂进行如实施例1中所述的相同的滴度测定,包括所述的UV处理。不同之处在于,考虑到对250μl(而不是实施例1中所述的57ml)的所得的制剂进行紫外线处理的事实,仅应用1分钟的紫外线处理。结果显示在下面表4中。
表4有或无紫外线暴露的各种制剂的APXIII滴度
测试序号 | 样品说明 | 紫外线 | 滴度[U/ml] |
1 | APXIII水溶液,对照 | 无 | 24 |
2 | APXIII水包油乳剂 | 无 | 32 |
3 | APXIII水包油乳剂 | 有 | 42 |
显而易见,在de ELISA测试中,桐酸的甲酯对抗原的呈递具有积极效果:凭借该油的存在,滴度增加了8单位/ml。似乎APXIII的相关结合位点的可用性由于该油的存在而增加了。由于用紫外线辐射暴露,同样提供了滴度的显著增加(从32U/ml增加至42U/ml)。
Claims (10)
1.一种包含生物抗原的抗原制剂,其特征在于,该制剂包含含有桐酸的脂肪酸酯作为主要成分的油。
2.根据权利要求1所述的制剂,其特征在于,该酯是桐酸的甘油三酯。
3.根据前述权利要求中的任一项所述的制剂,其特征在于,该油包含60%至90%(W/W)的桐酸的脂肪酸酯。
4.根据前述权利要求中的任一项所述的制剂,其特征在于,该油来自于油桐种子油。
5.根据权利要求4所述的制剂,其特征在于,该油是桐油。
6.根据前述权利要求中的任一项所述的制剂,其特征在于,该制剂是一种该油在水性液体中的乳剂。
7.根据权利要求6所述的制剂,其特征在于,该抗原存在于水性液体中。
8.根据权利要求7所述的制剂,其特征在于,该抗原选自APX III毒素、牛呼吸道合胞病毒抗原和副流感3病毒抗原。
9.根据前述权利要求中的任一项所述的制剂,其特征在于,将该制剂暴露于紫外线辐射。
10.含有桐酸的脂肪酸酯作为主要成分的油在制造包含至少一种生物抗原的抗原制剂中的用途。
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US61/479007 | 2011-04-26 | ||
PCT/EP2012/057231 WO2012143486A1 (en) | 2011-04-22 | 2012-04-20 | Antigenic formulation |
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EP (1) | EP2699234A1 (zh) |
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AU2007333225B2 (en) * | 2006-12-08 | 2014-06-12 | Massachusetts Institute Of Technology | Delivery of nanoparticles and/or agents to cells |
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- 2012-04-20 RU RU2013151905/15A patent/RU2013151905A/ru not_active Application Discontinuation
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WO1996024374A1 (en) * | 1995-02-06 | 1996-08-15 | The United States Of America, As Represented By The Secretary, Department Of Agriculture | Oil emulsion vaccines prepared with animal, vegetable, and synthetic oils using a mixture of nonionic surfactants |
US6861410B1 (en) * | 2002-03-21 | 2005-03-01 | Chiron Corporation | Immunological adjuvant compositions |
US7279163B1 (en) * | 2002-03-21 | 2007-10-09 | The United States Of America, As Represented By The Secretary Of Agriculture | Water-in-oil emulsion vaccines |
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EP2699234A1 (en) | 2014-02-26 |
MX2013012309A (es) | 2014-01-31 |
ZA201307648B (en) | 2014-08-27 |
JP2014512374A (ja) | 2014-05-22 |
US20140056941A1 (en) | 2014-02-27 |
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