JP2008063342A - ワクチン - Google Patents
ワクチン Download PDFInfo
- Publication number
- JP2008063342A JP2008063342A JP2007291459A JP2007291459A JP2008063342A JP 2008063342 A JP2008063342 A JP 2008063342A JP 2007291459 A JP2007291459 A JP 2007291459A JP 2007291459 A JP2007291459 A JP 2007291459A JP 2008063342 A JP2008063342 A JP 2008063342A
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- JP
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- Prior art keywords
- vaccine
- antigen
- virus
- cpg
- adjuvant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
【解決手段】特に、本発明のアジュバント組成物は、場合により、担体とともに、サポニンと免疫刺激性オリゴヌクレオチドを含む。本発明により、本発明のアジュバントと抗原を含むワクチンも提供される。さらに、本発明のアジュバントとワクチンの製法、並びに医薬としてのそれらの使用も提供する。疾患にかかり易い又はかかった個体の治療方法であって、本発明のワクチンの投与を含むものも提供される。
【選択図】なし
Description
362 279 B1中に記載されている。
109 942 B1;WO96/11711)。
TT(CpG1826)
オリゴ2(配列番号2):TCT CCC AGC GTG CGC CAT
(CpG1758)
オリゴ3(配列番号3):ACC GAT GAC GTC GCC GGT
GAC GGC ACC ACG
オリゴ4(配列番号4):TCG TCG TTT TGT CGT TTT
GTC GTT(CpG2006)
オリゴ5(配列番号5):TCC ATG ACG TTC CTG ATG
CT(CpG1668)
他のCpGオリゴヌクレオチドは、それらがそれに対する取るに足りない欠失又は付加をもつ点で、上記好ましい配列を含みうる。
E6/E7融合タンパク質の形態で含むことができる。
本実施例において、我々は、溶解性サポニン、例えば、QS21と免疫刺激剤、例えば、CpGが、シナルジスティックなやり方で、マウスの鼻腔内ブースティング・ワクチン接種に対する全身的免疫学的応答を高めることができたかどうかを調べた。8週齢の雌Balb/cマウス(群当り5動物)を、アルム(alum)(50μg)上に配合されたリポ−OspA(1μg)で筋中免疫化した。3ヶ月後、このマウスを、A:PBS;B:20μg CpG1001(TCC ATG AGC TTC CTG ACG TT,Krieg 1826);C:5μg QS21(Cambridge Biotech, USAから得たもの);D:20μg CpG1001+5μg QS21のいずれかの中に5μgリポ−OspAを含む10μlの溶液(鼻孔当り5μl、ピペットにより滴としてデリバリーされる)を(麻酔下で)鼻腔内で;又はE;アルム(50μg)上に吸着された1μgのリポ−OspAの筋肉内注射により、ブーストした。
マウスにおけるOspA−特異的血清IgGの計測のためのELISA
Maxisorp Nuncイムノプレートを、PBS中に希釈した1μg/ml OspA 50μl/ウェル(プレートのB〜H列内)で、又はPBS中5μg/ml精製ヤギ抗−マウスIg(Boerhinger)50μl(A列)で、一夜コートする。上記プレートの空いた場所を、飽和バッファー:1%BSA、0.1%ポリオキシエチレン・ソルビタン・モノラウレート(TWEEN20)、及び4%正常ウシ血清(NBS)を含むPBSを用いて、ブロックする(1時間、37℃)。次に、飽和バッファー(ウェル当り50μl)中で希釈され、そして標準曲線として添加されたIgGアイソタイプ混合物の逐次的2倍希釈物(200ng/mlから出発し、そしてA列内に入れられたSigmaからのマウス・モノクローナル抗体IgG1,IgG2a、及びIgG2bの混合物)、及び(1/100希釈から出発し、そしてB〜H列内に入れられた)血清サンプルを、37℃で1時間30分の間インキュベートする。次に、上記プレートを、洗浄バッファー(PBS、0.1%ポリオキシエチレン・ソルビタン・モノラウレート(TWEEN20))で(3回)洗浄する。次に、飽和バッファー中で1/5000希釈されたビオチニル化ヤギ抗−マウスIgG(Amersham)を、37℃で、1時間30分の間インキュベートする(50μl/ウェル)。3回の洗浄、その後のストレプトアビジン−ホースラディシュ・ペルオキシダーゼ・コンジュゲート(Amersham)の添加の後、プレートを5回洗浄し、そして顕色バッファー(50mM pH4.5クエン酸バッファー中OPDA 0.4mg/ml(Sigma)及びH2 O2 0.03%)50μl/ウェルとともに、室温で20分間インキュベートする。顕色を、50μl/ウェルH2 SO4 2Nの添加により停止する。光学密度を、Biorad 3550イムノリーダーを用いて492nmと630nmで読む。抗体力価を、SoftMaxProソフトウェアを用いて4変数計算法により計算する。
ワクチン受容者における抗体力価を、彼(女)らのLA2−様特異性に関して試験した。LA2は、バクテリアの表面にあるコンホメーショナルなOspAエピトープを認識し、そしてインビトロにおいてB.burgdorferiを殺すことができ、そして実験室で培養されたスピロヘータによる感染に対してマウスを保護することができることが示されているネズミのモノクローナル抗体である(Schaible UE et al. 1990. Proc Natl Acad Sci USA 87 : 3768-3772)。さらに、LA−2 mabは、殺バクテリア抗体と相関することが示されており、そしてヒト血清についての研究は、(ELISAにより計測されるとき)合計抗−OspA IgG力価とLA2力価との間の良い相関をも示している。Maxisorp Nuncイムノプレートを、PBS水で希釈した0.5μg/mlリポOspA 50μl/ウェルで4℃において一夜コートする。空いた場所を、飽和バッファー(100μl/ウェルの飽和バッファー:PBS/BSA 1%/Tween20
0.1%/NBS 4%)で、37℃において1時間ブロックした。4μg/mlから開始するLA2モノクローナルAb(mAb)の逐次的2倍希釈物を、標準曲線を作るために、飽和バッファー中で希釈した(ウェル当り50μl)。(1/10希釈から開始する)ワクチン受容者からの血清サンプルの希釈物も添加し、そして上記プレートを37℃で2時間インキュベートした。上記プレートを、PBS/TWEEN20(0.1%)で3回のインキュベーションの後に洗浄した。飽和バッファー中で希釈したLA2 mAb−ペルオキシダーゼ・コンジュゲート(1/10,000)を、各ウェルに添加し(50μl/ウェル)、そして37℃で1時間インキュベートした。5回の洗浄後、プレートを、50μl/ウェルの顕色バッファー(50mM pH4.5クエン酸バッファー中OPDA 0.4mg/ml及びH2 O2 0.03%)で、(暗所で)室温において20分間インキュベートする。上記反応及び色の形成を、H2 SO4 2Nで停止した。光学密度を、Biorad 3550イムノリーダーを用いて、492nmと630nmで読む。LA2−様Ab力価を、SoftMaxProソフトウェアを用いて4変数計算方法により計算する。LA2−様抗体力価を、上記標準曲線との比較により測定した。
CpGとQS21は、リポ−OspAに対する全身的抗体の鼻腔内ブースティングを有意に改善する。さらに、両アジュバントが併合されるとき、特に、LA2抗体に関して、上記応答に対するシナルジスティックな効果が明らかに証明される。QS21とCpGの存在下で顕出される体液性応答は、非経口的ブースターにより誘導されたものよりも有意に高い。これらの結果を総合すると、上記結果は、溶解性サポニンと免疫刺激剤を併合する鼻腔内配合物の能力をはっきりと示している。
本実施例において、我々は、溶血性サポニン、例えば、QS21(実施例を参照のこと)、及び免疫刺激剤、例えば、CpGが、失活全インフルエンザ・ウイルスで鼻腔内プライムされたマウスにおける全身的抗体の鼻腔内ブーストをシナルジスティックなやり方で高めることができたかどうかを調べた。
マウスにおける抗−インフルエンザIgG力価の計測のためのELISA
Maxisorp Nuncイムノプレートを、PBS中に希釈した50μl/ウェルの、1μg/mlの全インフルエンザ・ウイルス抗原(プレートのB〜H列内)で、又はPBS中5μg/ml精製ヤギ抗−マウスIg(Boerhinger)50μl(A列)で、一夜コートする。上記プレートの空いた場所を、飽和バッファー:1%BSA、0.1%ポリオキシエチレン・ソルビタン・モノラウレート(TWEEN20)、及び4%正常ウシ血清(NBS)を含むPBSを用いて、ブロックする(1時間、37℃)。次に、飽和バッファー(ウェル当り50μl)中で希釈され、そして標準曲線として添加されたIgGアイソタイプ混合物の逐次的2倍希釈物(200ng/mlから出発し、そしてA列内に入れられたSigmaからのマウス・モノクローナル抗体IgG1,IgG2a、及びIgG2bの混合物)、及び(1/100希釈から出発し、そしてB〜H列内に入れられた)血清サンプルを、37℃で1時間30分の間インキュベートする。次に、上記プレートを、洗浄バッファー(PBS、0.1%ポリオキシエチレン・ソルビタン・モノラウレート(TWEEN20))で(3回)洗浄する。次に、飽和バッファー中で1/5000希釈されたビオチニル化ヤギ抗−マウスIgG(Amersham)を、37℃で、1時間30分の間インキュベートする(50μl/ウェル)。3回の洗浄、その後のストレプトアビジン−ホースラディシュ・ペルオキシダーゼ・コンジュゲート(Amersham)の添加の後、プレートを5回洗浄し、そして顕色バッファー(50mM pH4.5クエン酸バッファー中OPDA 0.4mg/ml(Sigma)及びH2 O2 0.03%)50μl/ウェルとともに、室温で20分間インキュベートする。顕色を、50μl/ウェルH2 SO4 2Nの添加により停止する。光学密度を、Biorad 3550イムノリーダーを用いて492nmと630nmで読む。抗体力価を、SoftMaxProソフトウェアを用いて4変数計算法により計算する。β−プロピオラクトン(BPL)で失活させた、上記コーティングのために使用された全インフルエンザ・ウイルス(株A/北京/262/95)は、SSD GmBH製造者(Dresden,Germany)により供給される。
血清(25μl)を、室温(RT)で20分間、100μlのボレート0.5Mバッファー(pH9)及び125μl Dade Behring−購入カオリン(kaolin)でまず処理する。遠心分離(30分間、3000RPM又は860g)の後、(上記血清の1/10希釈物に対応する)100μl上清を取り、そして0.5%ニワトリ赤血球とともに4℃で1時間インキュベートする。上清を、3200RPMで10分間の遠心分離の後に集める(970g)。両操作を、上記血清中に含まれる天然の血液凝集性因子を除去するために行う。次に、25μlの処理された血清を、96ウェルGreinerプレート内の25μl PBS中で希釈する(1/20から出発する逐次的2倍希釈物)。BPL失活全ウイルスを、撹乱下RTにおいて30分間、4血清凝集ユニットの濃度において(すなわち、赤血球の凝集を引き起こす最後のものよりも4倍低い希釈において)添加する(25μl/ウェル)。次にニワトリの赤血球をRTで1時間添加する(25μl/ウェル)。最後に、プレートを、読む前に4℃で一夜保つ。HAI力価は、上記ウイルス誘導血液凝集を阻害する最後の血清希釈に対応する。
CpGとQS21は、Flu株に対するIgG又はHAI抗体の鼻腔内ブースティングを改善しない。しかしながら、両アジュバントが併合されるとき、上記応答に対するシナルジスティックな効果が明らかに証明される。QS21とCpGの存在下で顕出されるHAI応答は、非経口ブースターにより誘導されるものよりもさらに類似する。これらの結果は、溶血性サポニン及び免疫刺激剤を併合する鼻腔内配合物の能力を確認する。それらは、また、いくつかのCpG配列がこの文脈において効率的であることができるということをも示す(本実施例におけるKrieg 2006、及び実施例3と5におけるKrieg 1826)。
我々は本実施例において、QS21とCpGの間に観察されるものよりも類似するシナジーが、他の溶血性サポニン(実施例参照)、例えば、β−エスシンとともに観察されることができる可能性を評価する。非溶血性サポニン、グリチルリジン酸(glycyrrhizic acid)もテストする。
本方法は、実施例1に詳述したものと同じである。
β−エスシンとCpGは、全身的LA2 Absの鼻腔内ブースティングを高めるためにシナルジスティックに作用する。この併合は、非経口ブースターよりも高められたAb応答を顕出する。他方において、このようなシナジーは、グリチルリジン酸とCpGの併合によっては得られない。
1.実験概要
2つのマウス免疫原性試験を、CpGオリゴヌクレオチド(CpG)及びQS21の潜在的な付加的又はシナルジスティックな効果を評価するために行った。マウスの群を、CpGとQS21を単独で又は併合して配合されたRTS,Sとgp120で免疫化した。これらのアジュバント併合物を、担体Al(OH)3 又は油/水(o/w)エマルジョンの存在下でもテストした。
2.1.実験1
配合方法:
配合物を、各注射の3日前に調製した。必要なとき、RTS,S(10μg)とgp120(10μg)を、100μgのAL(OH)3 上に吸着させた。必要なとき、MPL(5μg)を添加し、そして10倍濃縮PBS pH7.4とH2 Oのミックスとして、バッファー添加の30分前にインキュベートした。但し、それに関してそのバッファーがPO4 ,NaCl 10/150 pH6.8であるところのDQを含まない群を除く。30分後、必要な場合、1/5のQS21/コレステロールの重量比においてリポソームと混合されたQS21(5μg)(DQという)を、上記配合物に添加した。30分後、上記オリゴとの配合のために、100μgのCpGを、保存料として50μg/mlのチオメルサールの添加の30分前に添加した。
配合方法:
配合を、両注射と同時に行う。1のマウスのための注射の容量は100μlである。50μg/mlのチオメルサールを保存料として添加する。
群当り9匹の(Balb/c×C57B1/6)F1マウスが、後肢に、2週間の間隔をあけて2回、2×50μlのワクチンを受容した。2週間後、抗体応答を評価するために血清を得、そして脾臓細胞を収獲して、細胞−仲介免疫応答を測定した。
実験1
リンパ球増殖応答の分析は、上記群間でRTS,Sに関して有意差を示さなかった。これに反し、両CpGとDQS21を含む群1と3は、CpG又はDQ21単独を含む群よりも良好なgp120−特異的リンパ球増殖応答を示した(図6)。
RTS,Sとgp120に特異的なリンパ球増殖応答は、本実験において酷似していた。このデータは、(単独又はo/wエマルジョンとともにある)DQS21の添加が、両抗原に対するリンパ球増殖応答を高めるということを示している(図9)。
CpGとDQS21の組合せにより配合されたRTS,Sとgp120による免疫化は、強い抗原特異的免疫応答をもたらす。アジュバント成分CpGとDQS21の組合せは、その単一成分に比較して、
−リンパ球増殖応答を高め、
−CTL活性を高め、
−抗体力価及びTH1アイソタイプ・パターンを強化する。
1.実験デザイン
4群の、10匹のマウスC57b1/6は、脇腹に0日目に皮下に、10e6(200μl)TCI細胞(E7発現腫瘍細胞)を受容した。
1.ワクチンなし
2.PD1/3E7+CPG(10μg ODN2006)
3.PD1/3E7+DQS21(0.5μg)
4.PD1/3E7+CPG+DQS21
上記腫瘍増殖を、1周間に2回、個々の腫瘍を計測することによりモニターした。
配合を、注射の日に行った。1匹のマウスについての注射の容量は100μlであった。必要な場合、PD1/3E7(5μg)を、等張性のためにH2 OとPBS pH7.4で希釈した。5分後、必要な場合、1/5のQS21/コレステロール重量比でリポソームと混合されたQS21(0.5μg)(DQという)を、上記配合物に添加した。30分後、上記オリゴとの配合のために、保存料としての1μg/mlのチオメルサールの添加の30分前に、10μgのCpG(ODN2006)を添加した。
時間にわたる10動物の群当りの平均腫瘍成長の評価を図12に示す。10e6 TCI細胞の腫瘍接種を受容した動物の100%が、増殖性の腫瘍を進行性に顕出した。
Claims (14)
- QS21,3D−MPL、及び免疫刺激性オリゴヌクレオチドであってプリン、プリン、C,G、ピリミジン、ピリミジンの配列を含むものを含むアジュバント組成物。
- 前記免疫刺激性オリゴヌクレオチドが、TCC ATG ACG TTC CTG ACG TT(配列番号1);TCT CCC AGC GTG CGC CAT(配列番号2);ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG(配列番号3);TCG TCG TTT TGT CGT TTT GTC GTT(配列番号4);TCC ATG ACG TTC CTG ATG CT(配列番号5)から成る群から選ばれる、請求項1に記載のアジュバント組成物。
- 前記免疫刺激性オリゴヌクレオチドが、少なくとも3つのヌクレオチドにより分離された少なくとも2つのメチル化されていないCGリピートを含む、請求項1又は2に記載のアジュバント組成物。
- 前記免疫刺激性オリゴヌクレオチドが、少なくとも2つのメチル化されていないCGリピートであって6つのヌクレオチドにより分離されているものを含む、請求項3に記載のアジュバント組成物。
- 担体をさらに含む、請求項1〜4のいずれか1項に記載のアジュバント組成物。
- 前記担体が、無機塩、エマルジョン、ポリマー、リポソーム、ISCOMsから選ばれる粒子状担体である、請求項5に記載のアジュバント組成物。
- 抗原をさらに含む、請求項1〜6のいずれか1項に記載のアジュバント組成物を含むワクチン組成物。
- 前記抗原が、ヒト免疫不全ウイルス、水疱瘡ウイルス、単純ヘルペスウイルス1型、単純ヘルペスウイルス2型、ヒト・サイトメガロウイルス、デング病(Dengue)ウイルス、A型、B型、C型又はE型肝炎ウイルス、呼吸器合胞体ウイルス、ヒト乳頭腫ウイルス、インフルエンザ・ウイルス、Hib、髄膜炎ウイルス、サルモネラ、ナイセリア、ボレリア、クラミジア、ボルデテラ、ストレプトコッカス、マイコプラズマ、マイコバクテリア、ヘモフィラス、プラスモディウム又はトキソプラズマ、スタンワース(stanworth)デカペプチドから成る群から選ばれる生物由来;又は腫瘍関連抗原(TAA)、MAGE,BAGE,GAGE,MUC−1,Her−2−neu,CEA,PSA,KSA、又はPRAME;又は自己ペプチド・ホルモン、GnRHである、請求項7に記載のワクチン組成物。
- 前記抗原が、(a)腫瘍関連抗原PSMA,PSCA、チロシナーゼ、スルビビン(survivin)、NY−ESO1、プロスターゼ(prostase)、PS108,RAGE,LAGE,HAGE;(b)ミエロイド前駆タンパク質のN末端39〜43アミノ酸断片(Aβ);又は(c)アテローム性動脈硬化症に関連する抗原、から成る群に由来する、請求項7に記載のワクチン組成物。
- 前記ワクチンが全身的に投与される、請求項7〜9のいずれか1項に記載のワクチン組成物。
- 前記ワクチンが粘膜に投与される、請求項7〜9のいずれか1項に記載のワクチン組成物。
- 請求項7〜9のいずれか1項に記載のワクチン組成物を予め充填されたデリバリー・デバイスであって、当該ワクチン組成物を全身的に投与するように設計されているもの。
- 医薬として使用される、請求項7〜9のいずれか1項に記載のワクチン。
- ウイルス、バクテリア、寄生生物感染、アレルギー、癌又は他の慢性失調の予防又は治療のためのワクチンの製造における、QS21と、3D−MPLと、免疫刺激性オリゴヌクレオチドであってプリン、プリン、C,G、ピリミジン、ピリミジンの配列を含むものとの組合せ使用。
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JP2019142911A (ja) * | 2013-03-01 | 2019-08-29 | アステックス ファーマシューティカルズ インコーポレイテッド | 薬物組み合わせ |
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