JP2007532614A - 抗原デリバリベクタ及びコンストラクト - Google Patents
抗原デリバリベクタ及びコンストラクト Download PDFInfo
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- JP2007532614A JP2007532614A JP2007507833A JP2007507833A JP2007532614A JP 2007532614 A JP2007532614 A JP 2007532614A JP 2007507833 A JP2007507833 A JP 2007507833A JP 2007507833 A JP2007507833 A JP 2007507833A JP 2007532614 A JP2007532614 A JP 2007532614A
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Abstract
【解決手段】
本発明は、免疫応答性ターゲット細胞への抗原の送達用フルオロカーボンベクタに関する。更に、本発明は、フルオロカーボンベクタ抗原コンストラクト及び動物のワクチン及び免疫治療薬としての抗原に結合するこのようなベクタの使用に関する。
【選択図】図1
Description
最近のほ乳類の免疫学的応答の我々の理解の最近の進歩により、免疫療法を使用して、予防接種及び疾患の管理及び治療を通じて、ヒトのある種の疾患を予防してきた。免疫学的診療を通じて取り組まれてきたこの種の疾患は、病原菌、癌、アレルギ及び自己免疫疾患によって引き起こされる疾患を含む。これらの場合、最も一般的には、医学的治療の前提は、適切な免疫認識細胞への抗原を効果的に送達することである。例えば、予防接種は、野生株ウイルスの全抗原を有するウイルスの生きている弱毒化株の投与によって、世界中で天然痘を根絶することに成功した。同様に、インフルエンザ血清型bバクテリアによる感染症は、バクテリアの細胞壁由来のポリサッカリド抗原を基礎としたワクチンの開発後に、西側諸国では顕著に減少した。更に、ヒトメラノーマ等の癌は、腫瘍特異性抗原の源として、メラノソームタンパク質gp100から誘導された細胞アジュバント及び合成ペプチドのような自己樹木状細胞(DC)を使用する免疫療法に反応し、細胞性免疫応答を生じる。
i) これらの疾患又は症候の治療又は予防用薬剤の調製における本明細書で記載されている免疫原生コンストラクトの使用。
ii) 本明細書に記載されたコンストラクト又は製剤の投与に続く免疫応答の誘導による治療方法。
iii)フルオロカーボンベクタ及びフルオロカーボンベクタ抗原コンストラクトの薬への使用。
を提供する。
フルオロカーボン誘導ペプチド(Fluorocarbon−vectored peptides)の合成
次のフルオロカーボン誘導ペプチド(Fluorocarbon−vector peptides)を合成した:
FAVS−I−ENV:NNTRKRIRIQRGPGRAFVTIGK−C8F17(CH2)2CO−K−NH2
FAVS−2−ENV:NNTRKRIRIQRGPGRAFVTIGK−C8F17(CH2)6CO−K−NH2
FAVS−3−ENV:IRIQRGPGRAFVTIGKK−CO(CH2)2−(PEG)4−C8F17(CH2)6CO−K−NH2
ここで、標準的なアミノ酸1文字コードを使用し、PEGはCH2−CH2−Oである。NNTRKRIRIQRGPGRAFVTIGKは、ヒト免疫不全ウイルスのENV(301−322)である。
フルオロカーボン誘導ペプチド(Fluorocarbon−vectored peptides)の物理化学的分析
(i)溶解性
医薬製剤に有用な濃度の水溶液中のフルオロカーボン誘導ペプチド(Fluorocarbon−vector peptides)の安定性を確認した。乾燥凍結ペプチド粉末を、種々の濃度でPBS(0.01M、pH7.2)に溶解することによって、20℃で、ペプチドの溶液を調製した。次いで、調製した溶液を1分間ボルテックスした。アリコートを収集し、溶液の残りを12,000rpmで10分間遠心分離した。各ペプチドの25μlアリコートの連続希釈液を含有する96−ウエルの培養皿に、溶液A(水酸化ナトリウム0.1M溶液50vol,のビシンコニン酸(bicichoninic acid)、炭酸ナトリウム、酒石酸ナトリウム)及びB(4%硫酸銅溶液、1vol.)を含有するBCA常用試薬200μlを加えた。37℃で45分間インキュベートし、10分間冷却した後、この吸光度を570nmで測定した。この培養皿を、Wallac Victorマルチラベルカウンタ(Perkin Elmer)によって分析した。各ペプチドについて、較正曲線をプロットし、これを使用して、nmol/mlで表される、溶解成分のペプチド濃度を決定した。データを表1に示す。全ペプチドが、マウス免疫化研究に使用される抗原の濃度で、完全に可溶であることが分かった。
生理学的リン酸緩衝生理食塩水のフルオロカーボン誘導ペプチド(Fluorocarbon−vectored peptides)の臨界ミセル濃度を、8−アニリノ−1−ナフタレン−スルホン酸(ANS)と結合する染料によって決定した。300μgペプチド/ml溶液から出発して、連続倍数希釈のPBS(0.01M、pH7.2)のペプチド及びペプチド−ベクタ溶液を20℃で調製し、ここから200μlをマイクロプレートのウエルに加えた。次いで、PBSにすぐに溶解したANS40μlを、各ウエルに加えた。2分後、このプレートを355nmで励起し、Victorマイクロプレート蛍光光度計で460nmで走査した。比率(サンプルの蛍光強度/ブランクの蛍光強度)を線形目盛対対数目盛の濃度でプロットした。データを図3に示す。
488nmに調整したアルゴンレーザ(Uniphase Corp.,San Jose,CA)を装備したMalvern 4700C準光散乱スペクトロメータ(Malvern Ltd,UK)で、粒子サイズ分析を実施した。サンプルを温度25℃に保持した。レーザは、角度依存測定のために種々の検出形状を有する。90°及び60°の角度で測定を実施した。ろ過した0.01Mリン酸緩衝生理食塩水にペプチドを溶解して500nmol/mlの濃度にし、1分間ボルテックスすることによって、溶液を調製した。次いで、溶液をキュベット(容積1ml)に分配した。15分後に、90°の角度で測定を実施した(図4)。Kcount値出力は、検出された粒子の数に比例する;確実なサイズ分配測定を得ることを確実にするために、全ケースで、Kcountは>10であった。
(i)フルオロカーボン誘導ペプチド(Fluorocarbon−vectored peptides)の免疫原性
特定病原体未感染のマウス(6−8週 雌 Balb/c)をHarlan(UK)から購入した。ペプチドENV、FAVS−1−ENV、FAVS−2−ENV又はFAVS−3−ENVをPBS(0.01M、pH7.2)に溶解した。各投与量を、アミノ酸分析から得られた正味ペプチド含有量に基づいた1ml当たり50nmolのペプチドに標準化した。マウス(1グループ当たり3匹)を、PBSの体積100μl、pH7.2の50nmolペプチドで、肩甲骨間部分に皮下予防注射をした。3回の投与量を10日間の間隔で投与した。完全フロインドアジュバント(アジュバントの等しい容積に乳化したPBSの50nmolペプチド)と混合した起爆用量の遊離ペプチド及び追加抗原投与量の不完全フロインドアジュバントを投与されるマウスのグループは、陽性対象となった。10日後、最後の免疫化マウスが犠牲になり、脾臓を切除して、ペプチドに対する細胞性免疫応答を評価した。免疫応答の発達の進行を決定するために、1回及び2回の投与量のペプチドを投与するマウスのグループも準備した。
2.5×106/ウエルの細胞密度で、免疫化マウス由来の脾臓細胞を、1μg/mlのTヘルパENV(301−322)又はP18−I10CTLペプチドと、48−ウエルマイクロプレートに分配した。3日で、組み換えマウスIL−2、5ng/mlを各ウエルに加えた。7日で、前刺激脾臓細胞を取り、RPMI 1640で3回洗浄し、製造者の指示によりモノクローナルラット抗マウスCD8a及びCD4抗体(MACS、Microbeads Miltenyi Biotec、UK)と接合した電磁ビーズを使用する電磁細胞分類によって計数及び分離した。培養媒体(RPMI−1640、β−メルカプトエタノール5μM、グルタミン、非必須アミノ酸、5%CO2雰囲気で37℃で12時間、10%ウシ胎仔血清を追加したピルビン酸ナトリウム)のペプチド1mg/mlと、PVDFボトムウエル(96−ウエルマルチスクリーン(登録商標)−IPマイクロプレート−ミリポア)を被覆した抗体の複製で、CD4及びCD8+T細胞を、2.5×105/ウエルの細胞密度で分配した。Carl Zeiss Vision ELIspot reader unitを使用して、スポットを数えた。結果は、バックグラウンド除去後(<10スポット)、各条件で得られた平均値に相当する。1ミリオン入力脾臓細胞に対するスポット形成ユニット(SFC)として結果を示す。
合成アジュバントと共投与されるフルオロカーボン誘導ペプチド(Fluorocarbon−vectored peptides)の免疫原生
FAVS−ペプチド、FAVS−1−ENVの定量的、定性的免疫原生に対する合成免疫刺激の潜在インパクトを評価するために、単独で、或いはムラブチドと共に注入した。ムラブチド(N−アセチル−ムラミル−L−アラニル−D−グルタミン−O−n−ブチル−エステル;ムラミルジペプチドの合成誘導体及びNOD−2アゴニスト)は、先天性免疫メカニズムを活性化する合成免疫増強剤であり、免疫原(”Immune and antiviral effects of the synthetic immunomodulator murabutide: Molecular basis and clinical potential”, G.Bahr,in:”Vaccine adjuvants:Immunological and Clinical Principles”,eds Hacket and Harn(2004),Humana Press)と組み合わせる時に、細胞及び体液反応の双方を増強することが知られている。
粘膜投与されたフルオロカーボン誘導ペプチド(Fluorocarbon−vectored peptides)の免疫原性
特定病原体未感染のマウス(6−8週 雌 Balb/c)をHarlan(UK)から購入した。
標本HIVペプチド
HIV用予防薬及び治療ワクチンを生成するためのフルオロカーボンベクタに結合する候補ペプチドは、次の一又はそれ以上のペプチド又はそのフラグメント、相同体(対応するコンセンサス、限定されないが、2004年のロスアラモス国立研究所のデータベースに参照されるクレードA、B、C、D、E、F、G及びH等の異なるクレードを表すHIV−1由来の祖先又はセントラルツリーシークエンスを含む)、又はこれらの天然及び非天然変異体を含んでも良いが、排他的に必要ではない。標準1文字及び3文字アミノ酸コードを使用した。相同体は、参照シークエンスと比較して少なくとも50%同一性を有する。好ましくは、相同体は、天然産シークエンスと80、85、90、95、98又は99%同一性を有する。以下に提供されるシークエンスは、長さ35アミノ酸である。一又はそれ以上のエピトープを含有するこれらのシークエンスのフラグメントも、フルオロカーボンベクタに結合するための候補ペプチドである。
WKGEGAWIQDNSDIKWPRRKAKIIRDYGKQMAG
Trp−Lys−Gly−Glu−Gly−Ala−Val−Val−Ile−Gln−Asp−Asn−Ser−Asp−Ile−Lys−Val−Val−Pro−Arg−Arg−Lys−Ala−Lys−Ile−Ile−Arg−Asp−Tyr−Gly−Lys−GIn−Met−Ala−Gly
EIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFR
Glu−Ile−Tyr−Lys−Arg−Trp−Ile−Ile−Leu−Gly−Leu−Asn−Lys−Ile−Val−Arg−Met−Tyr−Ser−Pro−Thr−Ser−Ile−Leu−Asp−Ile−Arg−Gln−Gly−Pro−Lys−Glu−Pro−Phe−Arg
EHLKTAVQMAVFIHNFKRKGGIGGYSAGERIVDII
Glu−His−Leu−Lys−Thr−Ala−Val−Gln−Met−Ala−Val−Phe−Ile−His−Asn−Phe−Lys−Arg−Lys−Gly−Gly−Ile−Gly−Gly−Tyr−Ser−Ala−Gly−Glu−Arg−Ile−Val−Asp−Ile−Ile
WEFVNTPPLVKLWYQLEKEPIVGAETFYVDGAANR
Trp−Glu−Phe−Val−Asn−Thr−Pro−Pro−Leu−Val−Lys−Leu−Trp−Tyr−Gln−Leu−Glu−Lys−Glu−Pro−Ile−Val−Gly−Ala−Glu−Thr−Phe−Tyr−Val−Asp−Gly−Ala−Ala−Asn−Arg
GERIVDIIATDIQTKELQKQITKIQNFRVYYRDSR
Gly−Glu−Arg−Ile−Val−Asp−Ile−Ile−Ala−Thr−Asp−Ile−Gln−Thr−Lys−Glu−Leu−Gln−Lys−Gln−Ile−Thr−Lys−Ile−Gln−Asn−Phe−Arg−Val−Tyr−Tyr−Arg−Asp−Ser−Arg
FRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPA
Phe−Arg−Lys−Tyr−Thr−Ala−Phe−Thr−Ile−Pro−Ser−Ile−Asn−Asn−Glu−Thr−Pro−Gly−Ile−Arg−Tyr−Gln−Tyr−Asn−Val−Leu−Pro−Gln−Gly−Trp−Lys−Gly−Ser−Pro−Ala
NWFDITNWLWYIKIFIMIVGGLIGLRIVFAVLSIV
Asn−Trp−Phe−Asp−Ile−Thr−Asn−Trp−Leu−Trp−Tyr−Ile−Lys−Ile−Phe−Ile−Met−Ile−Val−Gly−Gly−Leu−Ile−Gly−Leu−Arg−Ile−Val−Phe−Ala−Val−Leu−Ser−Ile−Val
ENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDF
Glu−Asn−Pro−Tyr−Asn−Thr−Pro−Val−Phe−Ala−Ile−Lys−Lys−Lys−Asp−Ser−Thr−Lyo−Trp−Arg−Lys−Leu−Val−Asp−Phe−Arg−Glu−Leu−Asn−Lys−Arg−Thr−Gln−Asp−Phe
VASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTI
Val−Ala−Ser−Gly−Tyr−Ile−Glu−Ala−Glu−Val−Ile−Pro−Ala−Glu−Thr−Gly−Gln−Glu−Thr−Ala−Tyr−Phe−Leu−Leu−Lys−Leu−Ala−Gly−Arg−Trp−Pro−Val−Lys−Thr−Ile
PDKSESELVSQIIEQLIKKEKVYLAWVPAHKGIGG
Pro−Asp−Lys−Ser−Glu−Ser−Glu−Leu−Val−Ser−Gln−Ile−Ile−Glu−Gln−Leu−Ile−Lys−Lys−Glu−Lys−Val−Tyr−Leu−Ala−Trp−Val−Pro−Ala−His−Lys−Gly−Ile−Gly−Gly
NRWQVMIVWQVDRMRIRTWKSLVKHHMYISRKAKG
Asn−Arg−Trp−Gln−Val−Met−Ile−Val−Trp−Gln−Val−Asp−Arg−Met−Arg−Ile−Arg−Thr−Trp−Lys−Ser−Leu−Val−Lys−His−His−Met−Tyr−Ile−Ser−Arg−Lys−Ala−Lys−GIy
HPDKWTVQPIVLPEKDSWTVNDIQKLVGKLNWASQ
His−Pro−Asp−Lys−Trp−Thr−Val−Gln−Pro−Ile−Val−Leu−Pro−Glu−Lys−Asp−Ser−Trp−Thr−Val−Asn−Asp−Ile−Gln−Lys−Leu−Val−Gly−Lys−Leu−Asn−Trp−Ala−Ser−Gln
PAIFQSSMTKILEPFRKQNPDIVIYQYMDDLYVGS
Pro−Ala−Ile−Phe−Gln−Ser−Ser−Met−Thr−Lys−Ile−Leu−Glu−Pro−Phe−Arg−Lys−Gln−Asn−Pro−Asp−Ile−Val−Ile−Tyr−Gln−Tyr−Met−Asp−Asp−Leu−Tyr−Val−Gly−Ser
MRGAHTNDVKQLTEAVQKIATESIVIWGKTPKFKL
Met−Arg−Gly−Ala−His−Thr−Asn−Asp−Val−Lys−Gln−Leu−Thr−Glu−Ala−Val−Gln−Lys−Ile−Ala−Thr−Glu−Ser−Ile−Val−Ile−Trp−Gly−Lys−Thr−Pro−Lys−Phe−Lys−Leu
EKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQ
Glu−Lys−Ala−Phe−Ser−Pro−Glu−Val−Ile−Pro−Met−Phe−Ser−Ala−Leu−Ser−Glu−Gly−Ala−Thr−Pro−Gln−Asp−Leu−Asn−Thr−Met−Leu−Asn−Thr−Val−Gly−Gly−His−Gln
NLLRAIEAQQHLLQLTVWGIKQLQARVLAVERYLK
Asn−Leu−Leu−Arg−Ala−Ile−Glu−Ala−Gln−Gln−His−Leu−Leu−Gln−Leu−Thr−Val−Trp−Gly−Ile−Lys−Gln−Leu−Gln−Ala−Arg−Val−Leu−Ala−Val−Glu−Arg−Tyr−Leu−Lys
ASVLSGGELDRWEKIRLRPGGKKKYKLKHIVWASR
Ala−Ser−Val−Leu−Ser−Gly−Gly−Glu−Leu−Asp−Arg−Trp−Glu−Lys−Ile−Arg−Leu−Arg−Pro−Gly−Gly−Lys−Lys−Lys−Tyr−Lys−Leu−Lys−His−Ile−Val−Trp−Ala−Ser−Arg
ELYKYKWKIEPLGVAPTKAKRRWQREKRAVGIG
Glu−Leu−Tyr−Lys−Tyr−Lys−Val−Val−Lys−Ile−Glu−Pro−Leu−Gly−Val−Ala−Pro−Thr−Lys−Ala−Lys−Arg−Arg−Val−Val−Gln−Arg−Glu−Lys−Arg−Ala−Val−Gly−Ile−Gly
FPISPIETVPVKLKPGMDGPKVKQWPLTEEKIKAL
Phe−Pro−Ile−Ser−Pro−Ile−Glu−Thr−Val−Pro−Val−Lys−Leu−Lys−Pro−Gly−Met−Asp−Gly−Pro−Lys−Val−Lys−Gln−Trp−Pro−Leu−Thr−Glu−Glu−Lys−Ile−Lys−Ala−Leu
QIYQEPFKNLKTGKYARMRGAHTNDVKQLTEAVQK
Gln−Ile−Tyr−Gln−Glu−Pro−Phe−Lys−Asn−Leu−Lys−Thr−Gly−Lys−Tyr−Ala−Arg−Met−Arg−Gly−Ala−His−Thr−Asn−Asp−Val−Lys−Gln−Leu−Thr−Glu−Ala−Val−Gln−Lys
NLLRAIEAQQHLLQLTVWGIKQLQARVLAVERYLK
Asn−Leu−Leu−Arg−Ala−Ile−Glu−Ala−Gln−Gln−His−Leu−Leu−Gln−Leu−Thr−Val−Trp−Gly−Ile−Lys−Gln−Leu−Gln−Ala−Arg−Val−Leu−Ala−Val−Glu−Arg−Tyr−Leu−Lys
AGLKKKKSVTVLDVGDAYFSVPLDKDFRKYTAFTI
Ala−Gly−Leu−Lys−Lys−Lys−Lys−Ser−Val−Thr−Val−Leu−Asp−Val−Gly−Asp−Ala−Tyr−Phe−Ser−Val−Pro−Leu−Asp−Lys−Asp−Phe−Arg−Lys−Tyr−Thr−Ala−Phe−Thr−Ile
TTNQKTELQAIHLALQDSGLEVNIVTDSQYALGII
Thr−Thr−Asn−Gln−Lys−Thr−Glu−Leu−Gln−Ala−Ile−His−Leu−Ala−Leu−Gln−Asp−Ser−Gly−Leu−Glu−Val−Asn−Ile−Val−Thr−Asp−Ser−Gln−Tyr−Ala−Leu−Gly−Ile−Ile
VSQNYPIVQNLQGQMVHQAISPRTLNAWVKWEEK
Val−Ser−Gln−Asn−Tyr−Pro−Ile−Val−Gln−Asn−Leu−Gln−Gly−Gln−Met−Val−His−Gln−Ala−Ile−Ser−Pro−Arg−Thr−Leu−Asn−Ala−Trp−Val−Lys−Val−Val−Glu−Glu−Lys
EAELELAENREILKEPVHGVYYDPSKDLIAEIQKQ
Glu−Ala−Glu−Leu−Glu−Leu−Ala−Glu−Asn−Arg−Glu−Ile−Leu−Lys−Glu−Pro−Val−His−Gly−Val−Tyr−Tyr−Asp−Pro−Ser−Lys−Asp−Leu−Ile−Ala−Glu−Ile−Gln−Lys−Gln
TPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKD
Thr−Pro−Asp−Lys−Lys−His−Gln−Lys−Glu−Pro−Pro−Phe−Leu−Trp−Met−Gly−Tyr−Glu−Leu−His−Pro−Asp−Lys−Trp−Thr−Val−Gln−Pro−Ile−Val−Leu−Pro−Glu−Lys−Asp
EPFRDYVDRFYKTLRAEQASQEVKNWMTETLLVQN
Glu−Pro−Phe−Arg−Asp−Tyr−Val−Asp−Arg−Phe−Tyr−Lys−Thr−Leu−Arg−Ala−Glu−Gln−Ala−Ser−Gln−Glu−Val−Lys−Asn−Trp−Met−Thr−Glu−Thr−Leu−Leu−Val−Gln−Asn
NEWTLELLEELKSEAVRHFPRIWLHGLGQHIYETY
Asn−Glu−Trp−Thr−Leu−Glu−Leu−Leu−Glu−Glu−Leu−Lys−Ser−Glu−Ala−Val−Arg−His−Phe−Pro−Arg−Ile−Trp−Leu−His−Gly−Leu−Gly−Gln−His−Ile−Tyr−Glu−Thr−Tyr
EGLIYSQKRQDILDLWVYHTQGYFPDWQNYTPGPG
Glu−Gly−Leu−Ile−Tyr−Ser−Gln−Lys−Arg−Gln−Asp−Ile−Leu−Asp−Leu−Trp−Val−Tyr−His−Thr−Gln−Gly−Tyr−Phe−Pro−Asp−Trp−Gln−Asn−Tyr−Thr−Pro−Gly−Pro−Gly
HFLKEKGGLEGLIYSQKRQDILDLWVYHTQGYFPD
His−Phe−Leu−Lys−Glu−Lys−Gly−Gly−Leu−Glu−Gly−Leu−Ile−Tyr−Ser−Gln−Lys−Arg−Gln−Asp−Ile−Leu−Asp−Leu−Trp−Val−Tyr−His−Thr−Gln−Gly−Tyr−Phe−Pro−Asp
FPVRPQVPLRPMTYKAAVDLSHFLKEKGGLEGLIY
Phe−Pro−Val−Arg−Pro−Gln−Val−Pro−Leu−Arg−Pro−Met−Thr−Tyr−Lys−Ala−Ala−Val−Asp−Leu−Ser−His−Phe−Leu−Lys−Glu−Lys−Gly−Gly−Leu−Glu−Gly−Leu−Ile−Tyr
FPQITLWQRPLVTIKIGGQLKEALLDTGADDTVLE
Phe−Pro−Gln−Ile−Thr−Leu−Trp−Gln−Arg−Pro−Leu−Val−Thr−Ile−Lys−Ile−Gly−Gly−Gln−Leu−Lys−Glu−Ala−Leu−Leu−Asp−Thr−Gly−Ala−Asp−Asp−Thr−Val−Leu−Glu
LVITTYWGLHTGERDWHLGQGVSIEWRKKRYSTQV
Leu−Val−Ile−Thr−Thr−Tyr−Trp−Gly−Leu−His−Thr−Gly−Glu−Arg−Asp−Trp−His−Leu−Gly−Gln−Gly−Val−Ser−Ile−Glu−Trp−Arg−Lys−Lys−Arg−Tyr−Ser−Thr−Gln−Val
APPEESFRFGEETTTPSQKQEPIDKELYPLASLRS
Ala−Pro−Pro−Glu−Glu−Ser−Phe−Arg−Phe−Gly−Glu−Glu−Thr−Thr−Thr−Pro−Ser−Gln−Lys−Gln−Glu−Pro−Ile−Asp−Lys−Glu−Leu−Tyr−Pro−Leu−Ala−Ser−Leu−Arg−Ser
KRRWQREKRAVGIGAMFLGFLGAAGSTMGAASMT
Lys−Arg−Arg−Val−Val−Gln−Arg−Glu−Lys−Arg−Ala−Val−Gly−Ile−Gly−Ala−Met−Phe−Leu−Gly−Phe−Leu−Gly−Ala−Ala−Gly−Ser−Thr−Met−Gly−Ala−Ala−Ser−Met−Thr
GLGQHIYETYGDTWAGVEAIIRILQQLLFIHFRIG
Gly−Leu−Gly−Gln−His−Ile−Tyr−Glu−Thr−Tyr−Gly−Asp−Thr−Trp−Ala−Gly−Val−Glu−Ala−Ile−Ile−Arg−Ile−Leu−Gln−Gln−Leu−Leu−Phe−Ile−His−Phe−Arg−Ile−Gly
Claims (32)
- 構造CmFn−CyHx−Lのフルオロカーボンベクタ又はこれらの誘導体において、m=3から30、n<=2m+1、y=0から15、x<=2y、(m+n)=3から30であり、Lが抗原に対する共有結合を促進するためのリガンドであることを特徴とするフルオロカーボンベクタ。
- 構造CmFn−CyHx−(Sp)−Rのフルオロカーボンベクタ抗原コンストラクト又はこれらの誘導体において、m=3から30、n<=2m+1、y=0から15、x<=2y、(m+n)=3から30であり、Spが選択的化学的スペーサ部分であり、Rが抗原であることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rがウイルス、バクテリア、寄生虫、自家タンパク質、又は癌抗原由来の抗原であることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から6のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rがタンパク質、タンパク質サブユニット、ペプチド、炭水化物又は脂質、又はこれらの組み合わせであることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rが一又はそれ以上のウイルスタンパク質由来のエピトープを具えることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rが一又はそれ以上のヒト免疫不全ウイルスタンパク由来のエピトープを具えることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のコンストラクトにおいて、Rが7から70のアミノ酸から成るペプチドであることを特徴とするコンストラクト。
- 請求項2から5のいずれか1項に記載のコンストラクトにおいて、Rが少なくとも一のMHCクラスI又はII、又はB細胞エピトープを具えることを特徴とするコンストラクト。
- 請求項2から5のいずれか1項に記載のコンストラクトにおいて、Rが2以上、又は、より多くの重複エピトープを具えることを特徴とするコンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、RがHIVエピトープであることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rが2004年のロスアラモス国立研究所のデータベースから選択されたペプチド、又はフラグメント、誘導体、相同体又はこれらの組み合わせであることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、RがSEQ ID Nos1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35又は36、又はフラグメント、誘導体、相同体又はこれらの組み合わせであることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rが一又はそれ以上のHIV envエピトープであることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項13に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rがアミノ酸シークエンスNNTRKRIRIQRGPGRAFVTIGK−NH2を有するHIV envエピトープペプチドであることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 抗原と非共有結合した請求項1に記載のフルオロカーボンベクタ。
- 請求項2から5のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトにおいて、Rが多重エピトープ及び/又は融合ペプチドを具えることを特徴とするフルオロカーボンベクタ抗原コンストラクト。
- 請求項2から19に記載の一又はそれ以上のフルオロカーボンベクタ抗原コンストラクトを具える予防又は治療製剤において、一又はそれ以上の薬学上許容できる担体、賦形剤、希釈剤又はアジュバントと選択的に組み合わされることを特徴とする予防又は治療製剤。
- 請求項20に記載の予防又は治療製剤において、非経口、経口、経眼、経腸、経鼻、経皮、局所、又は経膣投与用に調合された予防又は治療製剤。
- 液体、固体、エアロゾル又はガスである請求項20に記載の予防又は治療製剤。
- 請求項20から22のいずれか1項に記載の予防又は治療製剤において、ムラミルペプチド(MDP)誘導体、CpG、モノホスホリル脂質A(monophosphoryl lipid A)、オイルインウォータアジュバント、ウォータインオイルアジュバント、アルミニウム塩、免疫刺激複合体(ISCOMs)、リポソーム、微粒子、サポニン、サイトカイン、又は細菌毒素及びトキソイドから成る群より選択されたアジュバントを含むことを特徴とする予防又は治療製剤。
- 予防ワクチン又は免疫治療医薬品の調整時の、請求項2から19のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクト、又は請求項20から23のいずれか1項に記載の製剤の使用。
- 請求項2から19のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトの調整時の、請求項1に記載のフルオロカーボンベクタの使用。
- 請求項24に記載の使用において、前記ワクチン又は製造物が、非経口、経口、経眼、経腸、経鼻、経皮、局所、又は経膣投与用であることを特徴とする使用。
- これを必要としている対象の治療又は免疫の方法が、請求項2から19のいずれか1項に記載の効果的な量のコンストラクト、又は請求項20から23のいずれか1項に記載の製剤を投与するステップを具えることを特徴とする方法。
- これを必要としている対象の免疫応答を刺激する方法が、請求項2から19のいずれか1項に記載の効果的な量のコンストラクト、又は請求項20から23のいずれか1項に記載の製剤を投与するステップを具えることを特徴とする方法。
- 請求項28に記載の方法において、前記対象が、ほ乳類、好ましくはヒトであることを特徴とする方法。
- 請求項27から29のいずれか1項に記載の方法において、前記コンストラクト又は製剤が、抗ウイルス療法と組み合わされることを特徴とする方法。
- 請求項27から29のいずれか1項に記載の方法において、前記コンストラクト又は製剤が、高活性抗レトロウイルス療法(HAART)で投与されることを特徴とする方法。
- 請求項1に記載のフルオロカーボンベクタ、又は請求項2から19のいずれか1項に記載のフルオロカーボンベクタ抗原コンストラクトの薬としての使用。
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