JP2005102701A - 抗IgEワクチン - Google Patents
抗IgEワクチン Download PDFInfo
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- JP2005102701A JP2005102701A JP2004338711A JP2004338711A JP2005102701A JP 2005102701 A JP2005102701 A JP 2005102701A JP 2004338711 A JP2004338711 A JP 2004338711A JP 2004338711 A JP2004338711 A JP 2004338711A JP 2005102701 A JP2005102701 A JP 2005102701A
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- ige
- amino acid
- antigenic
- acid sequence
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Abstract
【解決手段】本発明は、IgE分子のCH3ドメイン又はCH3/CH4ドメイン連結部から誘導される少なくとも1つの抗原性ペプチドの免疫原量を含んでなる、IgE介在性アレルギー障害の治療及び方法の組成物、方法、及びイヌにおけるIgE介在性アレルギーの評価方法を提供する。
【選択図】なし
Description
本発明はまた、IgE分子のCH3ドメインから誘導される1つ又はそれ以上の抗原性ペプチドの免疫原的に有効な量と1つ又はそれ以上の製剤的に許容される担体を含んでなる医薬組成物を提供する。1つの態様では、本発明の医薬組成物は、IgE分子のCH3ドメインから誘導される1つ又はそれ以上の抗原性ペプチドの免疫原的に有効な量と1つ又はそれ以上の製剤的に許容される担体を含む。もう1つの態様では、本発明の医薬組成物は、IgE分子のCH3及びCH4ドメインの連結部から誘導される1つ又はそれ以上の抗原性ペプチドの免疫原的に有効な量と1つ又はそれ以上の製剤的に許容される担体を含む。
遺伝子治療の方法の概説については、Goldspiel et al., 1993, Clinical Pharmacy 12: 488-505; Wu and Wu, 1991, Biotherapy 3: 87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32: 573-596; Mulligun, 1993, Science 260: 926-932 及び Morgan and Anderson, 1993, Ann. Rev. Biochem. 62: 191-217; May, 1993, TIBTECH 11 (5): 155-215 を参照のこと。使用し得る組換えDNA技術の当技術分野で一般的に知られている方法は、Ausubel et al. (eds.), 1983, Current Protocols in Molecular Biology, John Wiley & Sons, NY; 及び Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY. に説明されている。
組換え細胞が遺伝子治療において使用される態様では、本発明の抗原性ペプチド又は抗原性融合タンパク質をコードする核酸配列が、細胞又はその子孫により発現され得るように細胞へ導入され、次いでこの組換え細胞が治療効果のためにin vivo で投与される。特定の態様では、幹又は前駆細胞が使用される。in vitro で単離されて維持され得る任意の幹及び/又は前駆細胞が本発明の態様により潜在的に使用され得る(例えば、1994年4月28日付のPCT特許公開WO94/08598;Stemple and Anderson, 1992, Cell 71: 973-985; Rheinwald, 1980, Meth. Cell Bio. 21A: 229 及び Pittelkow and Scott, 1986, Mayo Clinic Proc. 61: 771を参照のこと)。
様々な特定の態様では、患者の障害に関わる細胞型の代表的な細胞を用いて、組成物がそのような細胞型に対して所望の効果を有するかどうかを決定するために、in vitro アッセイが実行され得る。本発明によれば、抗原性ペプチド又は抗原性融合タンパク質の機能活性が、ヒスタミンのような血管作用物質の放出を誘発せずに、IgEがマスト細胞又は好塩基球上のその受容体に結合することを in vitro で阻害する好IgE抗体を誘発するその能力により測定され得る。
本発明の組成物が本発明の抗原性ペプチド又は抗原性融合タンパク質をコードする核酸である特定の態様では、この核酸は、それを適切な核酸発現ベクターの一部として構築し、例えばレトロウイルスベクターの使用により(米国特許第4,980,286号)、又は直接の注射により、又は微粒子衝撃(例、遺伝子銃;Biolistic,デュポン)の使用により、又は脂質か細胞表面受容体でコーティングし、作用因子をトランスフェクトすること、又は核に入ることが知られている(例えば、Joliot et al., 1991, Proc Natl. Acad. Sci. USA 88: 1864-1868 を参照のこと)ホメオボックス様ペプチドへそれを連結して投与すること、等によって、それが細胞内になるようにそれを投与することによって、in vivo 投与され、そのコード化された抗原性ペプチド又は抗原性融合タンパク質の発現を促進することができる。他のやり方では、核酸は、細胞内に導入され、相同的組換えにより、発現用の宿主細胞DNAの内部に組込まれ得る。
イヌIgEのCH3ドメイン、並びにCH3及びCH4ドメインの連結部をペプチドワクチン候補物質の選択の基礎とした。親水性、表面確率、柔軟性、抗原性インデックス、両親媒性ヘリックス、両親媒性シート、及び二次構造を含む、適切な抗原特性の決定についてのコンピュータプログラムを使用して、様々なネスティド、重複ペプチドを選択した。このペプチドを合成し、システイン指示カップリング法を使用して、Zymed Laboratories社(サンフランシスコ、CA)でKLhへコンジュゲートした。このKLhにコンジュゲートしたペプチドを使用して、Zymed Laboratories社(サウスサンフランシスコ)でウサギを免疫化した。ペプチドはまた、KLhへコンジュゲートさせずにN末端ビオチン残基を付けて、W.M.Keck Biotechnology Resource Center(ニューヘーヴン、CT)でも合成し、KLh−ペプチドコンジュゲートで免疫化された動物において誘発される抗ペプチド抗体を検出するELISAにおいて使用するための材料を用意した。本発明の好ましいペプチドには、配列番号:1〜配列番号:14のペプチドと他のIgE種由来のその相同配列が含まれる。
実施例2.ウサギ抗ペプチド抗体のIgE由来ペプチドとの反応性
ウサギ抗血清が本発明のペプチドと反応する能力を試験するために、以下のようにELISAアッセイを開発した:ビオチニル化IgEペプチドをコーティング緩衝液(重炭酸ナトリウム:pH9.0)1mlあたり5μgへ希釈した。希釈したペプチドを、ニュートラビジンプレート(Pierce Chemical Co.ロックフォード、IL)のウェルへ100μl/ウェルで加え、4℃で一晩インキュベートした。0.05% Tween−20含有リン酸緩衝化生理食塩水(PBST)で3回プレートを洗浄した。各ウェルへ200μl/ウェルで阻止緩衝液(2%スキムミルク/PBST)を加え、室温(RT)で60分間インキュベートした。PBSTで3回プレートを洗浄した。適切なウサギ抗血清の100倍希釈液を、適切なウェルの最上列へ、各ウェルにつき100μl加え、血清サンプルを適切なプレート位置へ10倍希釈した。プレートをRTで60分間インキュベートした。プレートをPBSTで3回洗浄した。西洋ワサビペルオキシダーゼ−コンジュゲート−ヤギ抗ウサギIgG(KPL Laboratories,ゲイサースブルグ、MD)の20,000倍希釈液100μl/ウェルを各ウェルへ加え、このプレートをRTで60分インキュベートした。PBSTで3回プレートを洗浄した。TMBマイクロウェル基質(KPL;ゲイサースブルグ、MD)100μl/ウェルを各ウェルへ加え、プレートをRTで10〜20分インキュベートし、発色させた。0.18M 硫酸50μl/ウェルでこの発色反応を止めた。全ウェルの吸光度(O.D.)を、ELISAプレートリーダー(Thermo Max;Molecular Devices,サニーヴェイル、CA)を使用して、450nmの波長で定量した。図1に示すように、本発明のペプチドで免疫化した後のウサギから得られる血清は、その指定ペプチドで免疫化する前のウサギから得られる血清より、各ペプチドに対してずっと高い反応性を有していた。
実施例3.ウサギ抗−ペプチド抗体のイヌIgEとの反応性
イヌのIgEモノクローナル抗体(Bethyl laboratories;モントゴメリー;TX)を、96穴プレートのウェルにおいて、100μl量あたり1μgで分配した。プレートを4℃で一晩インキュベートした。PBSTで3回プレートを洗浄し、各ウェルへ阻止緩衝液(2%スキムミルク/PBST)を加え、室温(RT)で60分間インキュベートした。PBSTで3回プレートを洗浄し、適切なウサギ抗血清の200倍希釈液を、適切なウェルの最上列へ、各ウェルにつき100μl加えた。プレートをRTで60分間インキュベートした。プレートをPBSTで3回洗浄し、西洋ワサビペルオキシダーゼ−コンジュゲート−ヤギ抗ウサギIgG(KPL Laboratories)の10,000倍希釈液100μl/ウェルを各ウェルへ加えた。プレートをRTで60分インキュベートした。PBSTで3回プレートを洗浄し、TMB基質100μl/ウェルを各ウェルへ加えた。発色反応を10〜20分発生させた。0.18M 硫酸50μl/ウェルを加えることによって、発色反応を止めた。全ウェルの吸光度(O.D.)を、上記のようにELISAプレートリーダーを使用して、450nmで定量した。図2に示すように、本発明のペプチドで免疫化した後のウサギから得られる血清は、その指定ペプチドで免疫化する前のウサギから得られる血清より、イヌIgEに対してずっと高い反応性を有していた。
IgEワクチンの開発は、血清又は他の体液中の可溶性(フリー)IgEに結合するが、受容体結合性IgEとは架橋結合せず、マスト細胞又は好塩基球からヒスタミンを放出させない抗体(即ち、非アナフィラキシー抗体)を誘発するIgEペプチドの同定に基づく。本発明のペプチドのような、ネスティド、又は重複したIgE由来ペプチドのセットに対して産生した抗体のアナフィラキシー発現可能性を評価するために、我々は、イヌIgEに対する高アフィニティー受容体でトランスフェクトしたラット好塩基球細胞系RBL−2H3に基づいて、in vitro のイヌ特異的脱顆粒アッセイを開発した。イヌIgEをRBL2H3細胞上のその受容体に結合させて、受容体に結合したIgEを抗イヌIgE抗体とともにインキュベートすると、この受容体は(抗IgE抗体が受容体結合性IgEと結合すれば)架橋結合する可能性があり、この受容体の架橋結合によりラット細胞からヒスタミンが放出される。ヒスタミン放出の量はIgE抗体のアナフィラキシー可能性の尺度になる。逆に、ヒスタミン放出の不足は、抗イヌIgE抗体が受容体結合性IgEとは架橋結合せず、これらの抗体を誘発したペプチドが、抗ペプチド抗体がフリーIgE(例えば、血清又は他の体液中のIgE)と反応するという条件で、ワクチンとしての使用に適していることを示す。このように、本発明のペプチドに対して産生される抗体を含め、抗IgE抗体がヒスタミン放出をもたらすことの潜在可能性は、このアッセイを使用すれば容易に判定し得る。
実施例5.回虫の感作と免疫化
本発明のペプチドを用いたワクチン接種のIgE介在性反応に及ぼす効果を、回虫抽出物へ感作した後の動物で誘発されるIgE介在性の皮膚膨疹反応の試験において評価した。この試験デザインを表1にまとめ、以下の方法により試験を実施した:
1)前感作法:試験開始に先立って(第−7日)、各イヌの頚静脈から血液サンプル5mlを血清分離管(SST)へ採取した。血清を−20℃で保存した。Asc−1アレルゲン(Greer laboratories)の皮内(ID)注射により全部のイヌに対して皮膚試験を実施した。ID注射は、各イヌの腹部の剃毛サイドで実施した。各動物は、Asc−1アレルゲンの10倍系列希釈液(50μg〜0.5ng)を表す6種の注射、ヒスタミン0.1μgの注射(陽性対照)、及びリン酸緩衝化生理食塩水(PBS;陰性対照)の注射を受けた。各注射は100μlの用量である。皮膚の応答は膨疹反応の範囲のサイズに基づいた。膨疹範囲の輪郭を取り、最大の寸法(長軸)とそれに垂直な寸法(短軸)/ミリメートルを掛け合わせ、膨疹の範囲を算出する。皮膚の応答は、アレルゲンの皮内注射から15分の時点でメートル定規を使用して定量した。膨疹反応を視覚化しやすくするために、皮膚試験に先立つ約5分前に無菌の1.0%エバンスブルー溶液5mlで各イヌをI/V注射した。
実施例6.イヌの抗ペプチド抗体
本発明の特異抗原でワクチン接種したイヌにおける抗体の誘発を以下のようにELISAアッセイで評価する:コーティング緩衝液(重炭酸ナトリウム:pH9.0)1mlあたり5μgへペプチドを希釈し、ニュートラビジンプレート(Pierce)へ100μl/ウェルで加えた。プレートを4℃で一晩インキュベートした。PBSTで3回プレートを洗浄し、各ウェルへ阻止緩衝液(2%スキムミルク/PBST)200μlを加えた。プレートをRTで60分間インキュベートした。PBSTで3回プレートを洗浄し、適切なイヌ抗血清の100倍希釈液を、適切なウェルの最上列へ、各ウェルにつき100μl加えた。次いで血清サンプルを適切なプレート位置へ10倍希釈した。プレートをRTで60分間インキュベートした。プレートをPBSTで3回洗浄し、西洋ワサビペルオキシダーゼ−コンジュゲート−ヤギ抗イヌIgGの20,000倍希釈液100μl/ウェルを各ウェルへ加えた。プレートをRTで60分インキュベートした。PBSTで3回プレートを洗浄し、TMB基質100μl/ウェルを全ウェルへ加えた。発色反応をRTで10〜20分発生させた。0.18M 硫酸50μl/ウェルを加えることによって、発色反応を止め、上記のようにELISAリーダーにおいて、450nmで吸光度を定量した。表2に示すように、本発明のペプチドで免疫化した後のイヌから得られる血清は、その指定ペプチドで免疫化する前のイヌから得られる血清より、イヌIgEに対してずっと高い反応性を有していた。
実施例7.皮膚の膨疹反応性
皮膚膨疹反応の減少又は完全な消失があったワクチン接種動物の数を、ワクチン接種に先立つ同じ動物の皮膚膨疹反応に対して比較することによって、本発明のペプチドのIgE介在性皮膚膨疹反応を改善する効果を判定した。回虫抽出物を皮内注射した後のイヌの皮膚膨疹反応性は、回虫抽出物の10倍系列希釈液(50μg〜0.5ng)、並びにPBS及びヒスタミン(1μg/部位)100μlの注射により定量する。膨疹反応のサイズは、メートル定規を使用してミリメートルで測定される、膨疹の長軸及び短軸の積として定量される。表3から見られるように、CH3/CH4ドメインから誘導されるペプチド(配列番号:1〜配列番号:4)で動物をワクチン接種すると、約60%の動物で皮膚膨疹反応が完全に抑制される。
食物アレルギーモデルを開発して、本発明の抗IgEワクチンの効果を評価するために、以下のように、50頭のイヌを回虫抽出物及びリシンの注射後に回虫の抗原へ感作し、次いで回虫抽出物で経口チャレンジした。
実施例9.ノミアレルギーモデル
イヌにおけるノミアレルギー皮膚炎の発症を促進するリシンの能力を評価するために、リシンの有無でノミアレルゲンにイヌを感作させる感作プロトコールを以下のように実施する:
1.ノミを寄生させない対照としてイヌ5頭を使用する。
本明細書に引用した参項文献はすべてそのまま参照により本明細書に組込まれている。
Claims (23)
- 動物へ投与されるときにアナフィラキシー(anaphylaxis)を引き起さない抗IgE免疫応答を誘発する、配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を含んでなる、単離された抗原性ペプチド。
- 動物へ投与されるときにアナフィラキシーを引き起さない抗IgE免疫応答を誘発する、配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を含んでなる、単離された抗原性融合タンパク質。
- 配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を含んでなる抗原性ペプチドをコードする単離されたポリヌクレオチドであって、前記抗原性ペプチドが動物へ投与されるときにアナフィラキシーを引き起さない抗IgE免疫応答を誘発する、前記ポリヌクレオチド。
- 配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を含んでなる抗原性融合タンパク質をコードする単離されたポリヌクレオチドであって、前記抗原性融合タンパク質が動物へ投与されるときにアナフィラキシーを引き起さない抗IgE免疫応答を誘発する、前記ポリヌクレオチド。
- 請求項3又は4に記載のポリヌクレオチドを含有する、遺伝子工学的に処理された宿主細胞。
- 請求項3又は4に記載のポリヌクレオチドを、宿主細胞におけるポリヌクレオチドの発現を制御するヌクレオチド調節配列と機能的に関連して含有する、遺伝子工学的に処理された宿主細胞。
- IgE分子のCH3ドメイン又は少なくとも5アミノ酸残基長のそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する1つ又はそれ以上の抗原性ペプチドを含んでなる、アナフィラキシーを引き起こさない抗IgE免疫応答を誘発するための医薬組成物であって、
少なくとも1つの抗原性ペプチドが配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する、前記医薬組成物。 - IgE分子のCH3ドメイン又は少なくとも5アミノ酸残基長のそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する1つ又はそれ以上の抗原性融合タンパク質及び異種担体タンパク質を含んでなる、アナフィラキシーを引き起こさない抗IgE免疫応答を誘発するための医薬組成物であって、
少なくとも1つの抗原性融合タンパク質が配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する、前記医薬組成物。 - 異種担体タンパク質がKLh、PhoE、rmLT、TraT、及びBhV−1ウイルス由来のgDからなる群から選択される、請求項8に記載の医薬組成物。
- 抗IgE免疫応答が、血清及び他の体液中の可溶性IgEに結合し、IgEがマスト細胞及び好塩基球の上にあるその高アフィニティー受容体に結合することを防ぎ、そして受容体結合性IgEとは架橋結合しない抗IgE抗体の産生である、請求項7又は8に記載の医薬組成物。
- さらにアジュバントを含んでなる、請求項7又は8に記載の医薬組成物。
- IgE分子のCH3ドメイン又は少なくとも5アミノ酸残基長のそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する抗原性ペプチドをコードする1つ又はそれ以上のポリヌクレオチドを含んでなる、アナフィラキシーを引き起こさない抗IgE免疫応答を誘発するための医薬組成物であって、
少なくとも1つのポリヌクレオチドが配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する抗原性ペプチドをコードする、前記医薬組成物。 - IgE分子のCH3ドメイン又は少なくとも5アミノ酸残基長のそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する抗原性融合タンパク質をコードする1つ又はそれ以上のポリヌクレオチド及び異種担体タンパク質を含んでなる、アナフィラキシーを引き起こさない抗IgE免疫応答を誘発するための医薬組成物であって、
少なくとも1つのポリヌクレオチドが配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する抗原性融合タンパク質をコードする、前記医薬組成物。 - 異種担体タンパク質がKLh、PhoE、rmLT、TraT、及びBhV−1ウイルス由来のgDからなる群から選択される、請求項13に記載の医薬組成物。
- IgE介在性アレルギー障害を治療するか又は予防するための方法であって、そのような治療又は予防が所望される非ヒト動物へ、IgE分子のCH3ドメイン又はそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する1つ又はそれ以上の抗原性ペプチドの免疫原的に有効な量を投与することを含んでなり、
少なくとも1つの抗原性ペプチドが配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する、前記方法。 - IgE介在性アレルギー障害を治療又は予防するための方法であって、そのような治療又は予防が所望される非ヒト動物へ、IgE分子のCH3ドメイン又はそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する1つ又はそれ以上の抗原性融合タンパク質の免疫原的に有効な量及び異種担体タンパク質を投与することを含んでなり、
少なくとも1つの抗原性融合タンパク質が配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する、前記方法。 - IgE介在性アレルギー障害を治療するか又は予防するための方法であって、そのような治療又は予防が所望される非ヒト動物へ、IgE分子のCH3ドメイン又はそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する1つ又はそれ以上の抗原性ペプチドをコードする1つ又はそれ以上のポリヌクレオチドの免疫原的に有効な量を投与することを含んでなり、
少なくとも1つの抗原性ペプチドが配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する、前記方法。 - IgE介在性アレルギー障害を治療するか又は予防するための方法であって、そのような治療又は予防が所望される非ヒト動物へ、IgE分子のCH3ドメイン又はそのフラグメントのアミノ酸残基を含んでなるアミノ酸配列を有する1つ又はそれ以上の抗原性融合タンパク質をコードする1つ又はそれ以上のポリヌクレオチドの免疫原的に有効な量及び異種担体タンパク質を投与することを含んでなり、
少なくとも1つの抗原性融合タンパク質が配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14のアミノ酸配列を有する、前記方法。 - 動物がイヌである、請求項15、16,17又は18に記載の方法。
- IgE介在性アレルギー障害が喘息、アレルギー性鼻炎、食物アレルギーのような胃腸のアレルギー、好酸球増加症、結膜炎、又は糸球体腎炎である、請求項15、16,17、または18に記載の方法。
- 動物へ投与されるときにアナフィラキシーを引き起さない抗IgE免疫応答を誘発する、配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14又は少なくとも5アミノ酸残基長のそのフラグメントのアミノ酸配列を含んでなる、単離された抗原性ペプチド。
- 動物へ投与されるときにアナフィラキシーを引き起さない抗IgE免疫応答を誘発する、配列番号:5、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、又は配列番号:14又は少なくとも5アミノ酸残基長のそのフラグメントのアミノ酸配列を含んでなる、単離された抗原性融合タンパク質。
- 請求項7、8、12又は13に記載の医薬組成物の1つ又はそれ以上の成分で満たされた1つ又はそれ以上の容器を含んでなる、医薬キット。
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US20120321651A1 (en) | 2012-12-20 |
CA2674885A1 (en) | 2002-02-28 |
CA2674838A1 (en) | 2002-02-28 |
US6887472B2 (en) | 2005-05-03 |
CA2674837A1 (en) | 2002-02-28 |
EP1967206A3 (en) | 2009-01-07 |
EP2361635A2 (en) | 2011-08-31 |
CA2674838C (en) | 2014-02-18 |
EP1195161A3 (en) | 2002-07-24 |
EP1967205A3 (en) | 2009-01-07 |
JP2002281984A (ja) | 2002-10-02 |
CA2674885C (en) | 2013-02-26 |
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