JP2009523722A - ポリイノシン酸−ポリシチジル酸を基礎としたアジュバントを含む粘膜免疫原性物質 - Google Patents
ポリイノシン酸−ポリシチジル酸を基礎としたアジュバントを含む粘膜免疫原性物質 Download PDFInfo
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Abstract
Description
本発明は、概して、免疫原性組成物およびその利用方法に関する。より詳細には、本発明は、一つ以上の抗原性物質と共にポリヌクレオチドアジュバントを含み、宿主における疾患特異的粘膜免疫応答を引き起こすために用いられる、免疫原性組成物に関する。
免疫システムは、特異免疫および非特異免疫の何れをも示す。非特異免疫は、いろいろある中で、例えば、マクロファージまたは顆粒球によるファゴサイトーシス(外来微粒子または抗原の取り込み)、およびナチュラルキラー(NK)細胞活性など、様々な細胞およびメカニズムを含んでいる。非特異免疫は、進化があまり進んでいないメカニズムに依存しており、特異免疫応答の典型的な特徴である、特異性および記憶の獲得性質を示さない。特異免疫と非特異免疫との主要な違いは、B細胞およびT細胞特異性に基づくものである。これらの細胞は、主に、特定の抗原による活性化の後にそれらに対する応答性を獲得し、将来この特定の抗原にさらされることがあったときに、記憶を提示するメカニズムを有している。その結果、ワクチン接種(特異性および記憶を含む)は、有害な病原体に対する防御のための有効な手順となる。
以下の参考文献が着目される。
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主に、本発明は、ポリイノシン酸−ポリシチジル酸と、カナマイシンと、カルシウムとの複合アジュバントを含む免疫原性組成物、ならびに疾患特異的粘膜免疫応答を引き起こすための、それらの使用方法に関する。
図1−PIKAおよび/または不活化全SARS抗原を含むワクチンによる免疫化後の、肺の上清における特異的S−IgAの力価のELISA検出。
図2−PIKAおよび/または不活化全SARS抗原を含むワクチンによる免疫化後の、血清における特異的IgAの力価のELISA検出。
図3−PIKAおよび/または不活化全SARS抗原を含むワクチンによる免疫化後の、血清における特異的IgGの力価のELISA検出。
図4−PIKAおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、肺の上清における特異的S−IgAの力価のELISA検出。
図5−PIKAおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、腸の上清における特異的S−IgAの力価のELISA検出。
図6−PIKAおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、血清における特異的IgGの力価のELISA検出。
図7−PIKAおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、血清における特異的IgAの力価のELISA検出。
図8−PIKAおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、IL−2を産生しているマウス脾細胞のELISPOT検出。
図9:PIKAもしくはAl(OH)3および/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、肺の上清(32×希釈)における特異的S−IgAのELISA検出。
図10:PIKAもしくはAl(OH)3および/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、腸の上清(32×希釈)における特異的S−IgAのELISA検出。
図11:PIKAもしくはミョウバンおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、IFN−ガンマを産生しているマウス脾細胞のELISPOT検出。
図12:PIKAもしくはミョウバンおよび/または不活化され分割されたインフルエンザ抗原を含むワクチンによる免疫化後の、IL−2を産生しているマウス脾細胞のELISPOT検出。
本発明は、以下の本発明の特定の実施形態の詳細な説明および本明細書に記載の実施例を参照することにより、より容易に理解されるだろう。
本発明の詳細について記載する前に、本明細書に用いられるいくつかの用語の定義を記載することは、本発明を理解するために有用であろう。
特に:
1.用語「PICKCa」は、特定の物理的特性および免疫原性特性に関わりなく、概して、ポリI:C、カナマイシンおよびカルシウムを含む組成物を指す。
2.「Av−PICKCa」は、抗ウイルス剤として商業的に用いられているPICKCaの形態を指す。
3.「PIKA」は、ポリI:C、抗生物質(例えば、カナマイシン)、陽イオン(例えば、カルシウム)を含む本発明の組成物を指し、PIKAは投与におけるような物質特性(例えば、分子量、サイズなど)により特徴付けられ、PIKAは、意に沿わない副作用が例えばPICKCaよりも低減しており(例えば、毒性の低下)、また例えばAv−PICKCaよりも有効性が優れている(例えば、亢進した免疫応答を刺激する)というアジュバントの特徴を示す。
本発明は、免疫原性組成物、免疫応答の誘導および/または亢進に有効な方法に関する。ここで免疫応答とは、ヒト、非ヒト動物、または細胞培養系における、粘膜性および/または全身性のものであってよく、液性および/または細胞性のものであってよい。概して、本発明にかかる免疫原性組成物は、抗原(抗原性組成物)とアジュバントとを含んでなる。アジュバントの存在は抗原に対する免疫応答を亢進させるまたは修飾する。アジュバントは、産生される免疫グロブリンのサブクラス(アイソタイプ)および/またはケモカイン類および/またはサイトカイン類に影響を与えることによって、免疫応答の質を変化させうる。結果として、先天性免疫、液性および/または細胞性免疫応答は、アジュバントの存在により、より一層効率化される。
対象となる免疫原性組成物はPICを含んでなるポリヌクレオチドアジュバントを含んでなり、例えばPIKA組成物等である。当該免疫原性組成物は、概して、ポリイノシン酸、ポリシチジル酸、少なくとも一種の抗生物質(例えばカナマイシン)、および二価の陽イオン(例えばカルシウム)を含み構成される。ここでは、PIKAへの言及は、PICを含んでなるアジュバントの具体例として理解される。
特に着目される実施形態においては、ポリヌクレオチドアジュバントはPIKAである。PIKAはさまざまな方法で製造することができる。PICKCaから製造することがとりわけ利益が大きい。PIKAは、特定の分子サイズおよび/または分子量を有する分子を単離および/または濃縮することを含む追加的な製造工程をへてPICKCaから製造することができる。特定の特徴を有するポリヌクレオチド分子を、ろ過、クロマトグラフィー、熱的処理、遠心分離、電気泳動、または類似の方法により分離し濃縮することは、通常のプロセスであり、かつ当業者に公知である。
例えば、PIKAと或る抗原とを含んでなるもののような免疫原性組成物は、一般に少なくとも二種類の方法により抗原特異的な免疫応答を誘導することができる。i)は液性免疫によるもので、例えばB細胞の刺激と、抗体または免疫グロブリンの産生とが含まれる(他の細胞、例えば、マクロファージやヘルパーT細胞(Th1およびTh2)等を含む抗原提示細胞も抗体反応の発生に関与している)。ii)は細胞性免疫によるもので、一般的には細胞傷害性Tリンパ球などを含むT細胞が関与するものであるが、しかしながら他の細胞もまた細胞傷害性Tリンパ球応答の発生に関与している(例えば、Th1および/またはTh2細胞、並びに抗原提示細胞等)。
さらに別の実施形態では、対象となる免疫原性組成物は、PIKAアジュバントと抗原(複数種であってよい)との相対的な存在比にて定義付けられる。ここで存在比は、量的、濃度、体積、分子の数、または他の知られた計量単位の一つまたは複数の性質にて数量的に表しうる。
特に着目される実施形態では、本発明はポリヌクレオチドアジュバント組成物と抗原またはワクチンとを含んでなる免疫原性組成物であって、当該抗原がヒト由来のもの、非ヒト動物由来のもの、植物由来のもの、ウイルス、マイコバクテリアを含む細菌、真菌または寄生生物等の感染性病原体から選択される一またはそれ以上の病原体、がん抗原、アレルギー抗原、または自己免疫疾患を引き起こす抗原等のその他の抗原であるものを提供する。
幾つかの具体例では、本発明の免疫原性組成物は、ポリヌクレオチドアジュバントと抗原とに加えて、例えば免疫調節剤(immunomodulatory agent)や担体その他の剤等の一またはそれ以上の追加の剤を含んでなる。
或る具体例では、本発明は、対象となる免疫原性組成物を含んでなるキットを提供する。或る具体例では、本発明は、ポリヌクレオチドアジュバントと抗原とを別々の調剤として含んでなるキットを提供する。
対象となる免疫原性組成物は、様々な如何なる形式の調剤でも提供される。例えば、対象となる免疫原性組成物は、注射可能なもの、乾燥粉末、または溶液として調製されてもよい。例えば、水性溶液または生理的食塩水溶液、懸濁液、クリーム、乳化剤、錠剤、丸薬、糖衣錠、カプセル剤、ゲル、シロップ、スラリーが例示される。幾つかの具体例では、対象となる免疫原性組成物は、例えば、吸入器を介した送達、人工呼吸装置の管を介した送達、経口送達、経直腸送達、経膣送達等の粘膜投与用として調製される。所望する免疫原性組成物の調剤方法は、その概要がVaccine 4th Edition (Stanley A Plotkin等、W.B. Saunders Company、4th edition 2003)に記載されている。好適な調剤法は、例えばまた、A. Gennaro(2000) “Remington: The Science and Practice of Pharmacy”, 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery System(1999) H.C. Ansel et al., eds.,7th ed., Lippincott, Williams, & Wilkins; Handbook of Pharmaceutical Excipients(2000) A.H. Kibbe et al.,eds.,3rded. Amer.Pharmaceutical Assoc.にも記載されている。
特に着目される側面として、本発明は、抗原化合物に対する免疫応答を顕在化させるおよび/または亢進させる方法であって、対象となる免疫原性組成物を宿主に投与することを含んでなる方法を提供する。幾つかの具体例では、宿主はヒトである。他の具体例では、宿主は、例えば、非ヒト哺乳動物および鳥類の種等の非ヒト動物である。
微生物性の病原体に対する免疫応答を誘導する本発明の方法、並びに微生物性の病原体の感染を治療または予防する本発明の方法が適用される好適な被験体には、病原性の微生物に感染している個体、病原性の微生物に感染しやすいが未感染の個体、病原性の微生物に感染する危険にさらされているが未感染の個体、が挙げられる。好適な被験体としては、幼子(infant)、子、青年期の個体(adolescent)、大人、が挙げられる。
[実施例1:SARS抗原と組み合わせてPIKAを腹膜および粘膜に投与することによって誘起される全身性免疫応答]
この実施例は、PIKAおよびSARS抗原を含む免疫原性物質が、腹膜注射により投与すると、投与位置の近くおよび遠くのいずれの部位においても強い免疫応答を示すことを実証している。例えば、粘膜に投与すると、粘膜性免疫応答および全身性免疫応答の両方が引き起こされる。
この実施例は、PIKAおよびインフルエンザ抗原を含む免疫原性物質が、投与位置の近くおよび遠くのいずれの部位においても強い粘膜性免疫応答を誘起することを実証している。すなわち、粘膜に投与すると、全身性免疫応答だけでなく、呼吸器官および腸の粘膜のいずれにおいても粘膜性免疫応答が誘起される。
この実施例は、PIKAおよびインフルエンザ抗原を含む免疫原性物質が、粘膜表面に投与された後に、強い抗原特異的な粘膜性および全身性の体液性免疫応答並びにT細胞免疫応答を誘起することを実証している。
Claims (23)
- (a)ポリリボイノシン酸−ポリリボシチジル酸(PIC)、少なくとも1種類の抗生物質および少なくとも1種類の陽イオンを含むポリヌクレオチドアジュバントと、
(b)少なくとも1種類の抗原とを含む免疫原性組成物であって、
粘膜への投与用に調剤されていることを特徴とする免疫原性組成物。 - 分子量が不均一なポリヌクレオチドアジュバント組成物分子を含んでおり、該分子量は少なくとも66,000ダルトンであることを特徴とする請求項1に記載の免疫原性組成物。
- 分子量が不均一なポリヌクレオチドアジュバント組成物分子を含んでおり、該分子量は約66,000から1,200,000ダルトンであることを特徴とする請求項1または2に記載の免疫原性組成物。
- 分子量が不均一なポリヌクレオチドアジュバント組成物分子を含んでおり、該分子量は少なくとも150,000ダルトンであることを特徴とする請求項1から3の何れか1項に記載の免疫原性組成物。
- 少なくとも1種類の免疫賦活剤をさらに含んでいることを特徴とする請求項1から4の何れか1項に記載の免疫原性組成物。
- 粘膜吸収を亢進させる少なくとも1種類の剤をさらに含んでいることを特徴とする請求項1から5の何れか1項に記載の免疫原性組成物。
- 請求項1から6の何れか1項に記載の免疫原性組成物であって、該免疫原性組成物または該免疫原性組成物に含まれる上記アジュバントが、液体、溶液、液滴、固形物、カプセル、乳液、懸濁物、エリキシル剤、クリーム、坐薬、ゲル、ソフトカプセル、スプレー、吸入薬、エアロゾル、錠剤、被覆錠剤、丸薬、糖衣錠、粉末、シロップ剤、スラリー、マイクロカプセル、浣腸剤、顆粒またはトローチ剤の形態であることを特徴とする免疫原性組成物。
- 請求項1から7の何れか1項に記載の免疫原性組成物であって、上記アジュバント組成物の少なくとも1種または該免疫原性組成物が凍結乾燥されていることを特徴とする免疫原性組成物。
- 吸入、経直腸送達、経膣送達、経鼻送達、経口送達、経肺送達、経目送達、局所送達、経眼送達または経皮送達により投与されることを特徴とする請求項1から8の何れか1項に記載の免疫原性組成物。
- 宿主の粘膜免疫原性応答を亢進させるために使用される請求項1から9の何れか1項に記載の免疫原性組成物。
- 宿主の粘膜免疫原性応答を亢進させるための薬剤を調製するための、請求項1から10の何れか1項に記載の免疫原性組成物または該免疫原性組成物に含まれるアジュバントの利用。
- 上記薬剤は、局部および遠隔部における粘膜免疫応答を亢進させるためのものであることを特徴とする請求項11に記載の利用。
- 宿主のT細胞依存性免疫応答を誘導するための薬剤を調製するための、請求項1から10の何れか1項に記載の免疫原性組成物または該免疫原性組成物に含まれるアジュバントの利用。
- 上記薬剤が、吸入、経直腸送達、経膣送達、経鼻送達、経口送達、経肺送達、経目送達、局所送達、経眼送達または経皮送達により投与されることを特徴とする請求項11から13の何れか1項に記載の利用。
- 上記宿主は感染症に罹患しており、抗原性化合物の投与により、該感染症の原因となっている病原体に対する免疫応答を引き起こすことを特徴とする請求項11から14の何れか1項に記載の利用。
- 請求項1から10の何れか1項に記載の免疫原性組成物を備えているキット。
- 請求項1から10の何れか1項に記載の免疫原性組成物を含む送達システムであって、粘膜面への上記免疫原性組成物の送達を亢進させることを特徴とする送達システム。
- 請求項1から10の何れか1項に記載の免疫原性組成物を宿主に投与する工程を含む、粘膜免疫応答を亢進させる方法。
- 上記宿主は感染症に罹患しており、抗原性化合物の投与により、該感染症の原因となっている病原体に対する免疫応答を引き起こすことを特徴とする請求項18に記載の方法。
- 請求項1から10の何れか1項に記載の免疫原性組成物を宿主に投与する工程を含む、局部および遠隔部における粘膜免疫応答を亢進させる方法。
- 請求項1から10の何れか1項に記載の免疫原性組成物を宿主に投与する工程を含む、T細胞依存性免疫応答を誘導する方法。
- 上記宿主がヒトであることを特徴とする請求項11から15の何れか1項に記載の利用または請求項18から21の何れか1項に記載の方法。
- 上記宿主が非ヒト動物であることを特徴とする請求項11から15の何れか1項に記載の利用または請求項18から21の何れか1項に記載の方法。
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US11/331,839 US20070166239A1 (en) | 2006-01-13 | 2006-01-13 | Mucosal immunogenic substances comprising a polyinosinic acid - polycytidilic acid based adjuvant |
PCT/SG2006/000177 WO2007081288A1 (en) | 2006-01-13 | 2006-06-27 | Mucosal immunogenic substances comprising a polyinosinic acid - polycytidilic acid based adjuvant |
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EP (1) | EP1971403A4 (ja) |
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EP3518938A4 (en) * | 2016-09-30 | 2020-07-08 | BioSyngen Pte. Ltd. | USE OF POLYINOSINIC-POLYCYTIDYLIC ACID COMPOSITIONS IN THE TREATMENT OF MALIGNANT SPUR |
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CN114432436B (zh) * | 2020-11-05 | 2023-06-02 | 北京快乐星生物科技有限公司 | 佐剂组合物及其制备方法 |
CN112972673B (zh) * | 2021-02-02 | 2023-04-11 | 兰州大学 | PLGA-PEG-Poly I:C纳米颗粒的制备及其在结核亚单位疫苗中的应用 |
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WO2007081288A1 (en) | 2007-07-19 |
NZ570380A (en) | 2012-01-12 |
RU2008133216A (ru) | 2010-02-20 |
AU2006335368A1 (en) | 2007-07-19 |
CA2632418A1 (en) | 2007-07-19 |
KR101312308B1 (ko) | 2013-09-30 |
IL192747A0 (en) | 2009-02-11 |
TWI421091B (zh) | 2014-01-01 |
HK1112864A1 (en) | 2008-09-19 |
ZA200806340B (en) | 2010-05-26 |
CN101124014B (zh) | 2013-05-22 |
CA2632418C (en) | 2015-12-08 |
CN101124014A (zh) | 2008-02-13 |
KR20080091124A (ko) | 2008-10-09 |
TW200803891A (en) | 2008-01-16 |
US20070166239A1 (en) | 2007-07-19 |
EP1971403A1 (en) | 2008-09-24 |
US20090311334A1 (en) | 2009-12-17 |
BRPI0621185A2 (pt) | 2011-12-06 |
CU23819A3 (es) | 2012-06-21 |
MY143347A (en) | 2011-04-29 |
WO2007081288A9 (en) | 2007-12-21 |
AU2006335368B2 (en) | 2013-02-28 |
EP1971403A4 (en) | 2010-06-09 |
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