JP6045499B2 - 赤痢菌リポ多糖及び外膜タンパク質を含む免疫原性組成物 - Google Patents
赤痢菌リポ多糖及び外膜タンパク質を含む免疫原性組成物 Download PDFInfo
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- 150000003772 α-tocopherols Chemical class 0.000 description 1
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Description
赤痢菌株を増殖させるステップ、
赤痢菌細胞を破壊するステップ、並びに
好適には、一以上の遠心分離ステップ及び界面活性剤可溶化ステップを含むプロセスによって、外膜タンパク質及びLPSを含む画分を単離するステップ
を含むプロセスによって製造される組成物に関する。
赤痢菌株を増殖させるステップ、
赤痢菌細胞を破壊するステップ、並びに
好適には、一以上の遠心分離ステップ及び界面活性剤可溶化ステップを含むプロセスによって、外膜タンパク質及びLPSを含む画分を単離するステップ
を含む、免疫原性組成物を調製するための方法に関する。
1 前記感染性因子に対する免疫応答を惹起することができる抗原、並びに
2 赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子
を含む組成物に関する。
-Tween 80: 0.01〜1%、又は約0.1%(v/v)
-Triton X-100: 0.001〜0.1%(w/v)、又は0.005〜0.02%(w/v)である。あるいは、インフルエンザウイルスは全ウイルスワクチンの形態であってもよい。
い液滴が約5%以下であるのが望ましい。120μmを超える液滴はより小さい液滴と同様には拡散せず、従って120μmを超える液滴は約5%以下であるのが望ましい。
赤痢菌株を増殖させること、
赤痢菌細胞を破壊すること、並びに
内膜タンパク質からの外膜の分離を含むプロセスによって外膜タンパク質及びLPSを含む画分を単離すること
を含む、免疫原性組成物を調製するための方法に関する。
1 感染性因子に対する免疫応答を惹起することができる抗原、並びに
2 赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子
を含む組成物に関する。
1 抗原、並びに
2 赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子
を含む組成物に関する。
(1)原核生物、例えば、限定されるものではないが、
(a)ストレプトコッカス(Streptococcus)、スタフィロコッカス(Staphylococcus)、ボルデテラ(Bordetella)、コリネバクテリウム(Corynebacterium)、マイコバクテリウム(Mycobacterium)、ナイセリア(Neisseria)、ヘモフィルス(Haemophilus)、アクチノミセテス(Actinomycetes)、ストレプトミセテス(Streptomycetes)、ノカルジア(Nocardia)、エンテロバクター(Enterobacter)、エルシニア(Yersinia)、ファンシセラ(Fancisella)、パスツレラ(Pasturella)、モラクセラ(Moraxella)、アシネトバクター(Acinetobacter)、エリシペロトリックス(Erysipelothrix)、ブランハメラ(Branhamella)、アクチノバチルス(Actinobacillus)、ストレプトバチルス(Streptobacillus)、リステリア(Listeria)、カリマトバクテリウム(Calymmatobacterium)、ブルセラ(Brucella)、バチルス(Bacillus)、クロストリジウム(Clostridium)、トレポネマ(Treponema)、エシェリキア(Escherichia)、サルモネラ(Salmonella)、クレブシエラ(Kleibsiella)、ビブリオ(Vibrio)、プロテウス(Proteus)、エルウィニア(Erwinia)、ボレリア(Borrelia)、レプトスピラ(Leptospira)、スピリルム(Spirillum)、カンピロバクター(Campylobacter)、シゲラ(Shigella)、レジオネラ(Legionella)、シュードモナス(Pseudomonas)、エアロモナス(Aeromonas)、リケッチア(Rickettsia)、クラミジア(Chlamydia)、ボレリア(Borrelia)及びマイコプラズマ(Mycoplasma)の属のメンバー、並びにさらに、限定されるものではないが、A群連鎖球菌、B群連鎖球菌、C群連鎖球菌、D群連鎖球菌、G群連鎖球菌、肺炎球菌(Streptococcus pneumoniae)、化膿連鎖球菌(Streptococcus pyogenes)、ストレプトコッカス・アガラクチエ(Streptococcus agalactiae)、ストレプトコッカス・ファカリス(Streptococcus faecalis)、ストレプトコッカス・ファシウム(Streptococcus faecium)、ストレプトコッカス・デュランス(Streptococcus durans)、淋菌(Neisseria gonorrheae)、髄膜炎菌(Neisseria meningitidis)、黄色ブドウ球菌(Staphylococcus aureus)、表皮ブドウ球菌(Staphylococcus epidermidis)、ジフテリア菌(Corynebacterium diptheriae)、ガルドネレラ・バジナリス(Gardnerella vaginalis)、マイコバクテリウム・ツベルクロシス(Mycobacterium tuberculosis)、マイコバクテリウム・ボビス(Mycobacterium bovis)、マイコバクテリウム・ウルセランス(Mycobacterium ulcerans)、マイコバクテリウム・レプラ(Mycobacterium leprae)、アクチノミセテス・イスラエリ(Actinomyctes israelii)、リステリア・モノシトゲネス(Listeria monocytogenes)、ボルデテラ・ペルツシス(Bordetella pertusis)、ボルデテラ・パラペルツシス(Bordatella parapertusis)、ボルデテラ・ブロンキセプチカ(Bordetella bronchiseptica)、大腸菌(Escherichia coli)、シゲラ・ジセンテリア(Shigella dysenteriae)、ヘモフィルス・インフルエンザ(Haemophilus influenzae)、ヘモフィルス・エジプチウス(Haemophilus aegyptius)、ヘモフィルス・パラインフルエンザ(Haemophilus parainfluenzae)、ヘモフィルス・デュクレイ(Haemophilus ducreyi)、ボルデテラ(Bordetella)、サルモネラ・ティフィ(Salmonella typhi)、シトロバクター・フレウンジ(Citrobacter freundii)、プロテウス・ミラビリス(Proteus mirabilis)、プロテウス・バルガリス(Proteus vulgaris)、エルシニア・ペスチス(Yersinia pestis)、クレブシエラ・ニューモニア(Kleibsiella pneumoniae)、セラチア・マルセセンス(Serratia marcessens)、セラチア・リクファシエンス(Serratia liquefaciens)、ビブリオ・コレラ(Vibrio cholera)、シゲラ・ジセンテリ(Shigella dysenterii)、シゲラ・フレクスネリ(Shigella flexneri)、シュードモナス・エルギノーサ(Pseudomonas aeruginosa)、フランシセラ・ツラレンシス(Franscisella tularensis)、ブルセラ・アボルティス(Brucella abortis)、バチルス・アントラシス(Bacillus anthracis)、バチルス・セレウス(Bacillus cereus)、クロストリジウム・ペルフリンゲンス(Clostridium perfringens)、クロストリジウム・テタニ(Clostridium tetani)、クロストリジウム・ボツリナム(Clostridium botulinum)、トレポネマ・パリダム(Treponema pallidum)、リケッチア・リケッチ(Rickettsia rickettsii)及びクラミジア・トラコミティス(Chlamydia trachomitis)の種若しくは群のメンバーを意味する細菌、
(b)限定されるものではないが、アルケオバクター(Archaebacter)などの古細菌、並びに
(2)単細胞又は繊維性真核生物、例えば、限定されるものではないが、原生動物、真菌、サッカロミセス(Saccharomyces)、クルベロミセス(Kluveromyces)、若しくはカンジダ(Candida)の属のメンバー、及びサッカロミセス・セレビシア(Saccharomyces ceriviseae)、クルベロミセス・ラクティス(Kluveromyces lactis)、又はカンジダ・アルビカンス(Candida albicans)の種のメンバー、
の群より選択される。
SFOMP粒子を実施例6のプロセスに従って作製し、平均直径を散乱光の測定により経時的に評価した。図1。
実施例6に従って作製したSFOMP粒子のEMによって、抗シゲラ・フレクスネリLPS抗体結合により測定して、シゲラ・フレクスネリが粒子の外膜中にLPSを含むことが示される。図2。
SFOMP粒子は実施例6のプロセスに従って作製し、標準的な技術を用いるゲル電気泳動により、V2プロテオソーム及びプロトリン(後者は、例えば、米国特許出願公開第2003/0044425号に開示された通り、髄膜炎菌のOMP及び赤痢菌のLPSを含む)と比較した。
HEK細胞をSFOMP、プロトリン並びにV1及びV2プロテオソームで処理した。V1プロテオソームは髄膜炎菌のOMPのみを含有するが、V2プロテオソームはさらにLPSも含有する。プロトリンは髄膜炎菌のOMPとシゲラ・フレクスネリのLPSを含有する。
マウスに、RSFタンパク質F及びV2プロテオソーム又は実施例6に従って作製されたSFOMPをD0及びD21に鼻内にワクチン接種した。次いで、マウスをRSVウイルスで47日目にチャレンジし、51日目に犠牲にした。チャレンジしたマウスの肺ホモジェネートを試験して、ウイルスのLD50値を見た。
用いた細胞は、37℃で250rpで3時間振とうしながら増殖させたシゲラ・フレクスネリ2a BS103(GMP細胞バンク)であった。細胞を室温で30分間、2,770gで遠心分離し、上清を廃棄した。ペレットを10mM Hepes中に再懸濁した。細胞を5×45秒間、43AMPで超音波処理した。細胞を室温で20分間、1,700gで遠心分離し、ペレットを廃棄した。上清を4℃で60分間、100,000gで遠心分離し、上清を廃棄した。ペレットを1% N-ラウロイルサルコシン中に再懸濁した。懸濁液を4℃で60分間、100,000gで遠心分離し、上清を廃棄した。ペレットを10mM Hepes中に再懸濁し、5×45秒間、43AMPで超音波処理した。MgCl2を添加し、濾過(0.2μm)を実行した。得られた組成物を本明細書ではSFOMPと呼ぶ。図6。
樹状細胞における遺伝子発現を、ヒト樹状細胞のマイクロアレイ分析によって評価した。結果を図7に示す。SFOMPはPBS緩衝液で処理した樹状細胞と比較して、樹状細胞中の特定の遺伝子の上方調節及び下方調節を引き起こすことができる。
1μgのRSV preF抗原を3又は0.3μgのSFOMPと組合せて、マウスに鼻内送達した。中和抗体が得られた(図8)。
3mgのインフルエンザスプリット抗原及び5mgのSFOMPアジュバントの二回の鼻内免疫化後にマウスにおける免疫応答を評価した。HA並びにIgG及びIgAに対する幾何平均抗体力価を評価した。インフルエンザニューカレドニアA株を用いてスプリット抗原を作製した。幾何平均力価(GMT)を決定した。SFOMP+抗原は、PBSのみ又は抗原のみと比較した場合、有意に改善された応答を与えた(図9、10及び11)。
Claims (34)
- 赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子を含み、さらに赤痢菌以外の種に由来する抗原を含む免疫原性組成物。
- LPSがTLR4経路アゴニストである、請求項1に記載の組成物。
- OMPがTLR2経路アゴニストである、請求項1に記載の組成物。
- 赤痢菌ハウスキーピング遺伝子産物を含まない、請求項1に記載の組成物。
- 酸性のpIを有する、請求項1に記載の組成物。
- 30〜180nmの粒子直径サイズを有する、請求項1に記載の組成物。
- 粒子が4℃で3ヶ月間安定な直径を有する、請求項1に記載の組成物。
- LPSとOMPとの比率が0.6:1.3〜0.8:1.1である、請求項1に記載の組成物。
- LPSとOMPとの比率が0.9:1である、請求項1に記載の組成物。
- 赤痢菌がシゲラ・フレクスネリ(S.flexneri)である、請求項1に記載の組成物。
- さらなる抗原を含む、請求項1に記載の組成物。
- 抗原が呼吸器合胞体ウイルス(RSV)又はインフルエンザウイルスに由来する、請求項1に記載の組成物。
- 樹状細胞中の以下の遺伝子:IL6、CSF2、CSF3、CXCL10のうちの一つ以上を上方調節することができる、請求項1に記載の組成物。
- 医薬組成物を形成するための薬学的に許容し得る賦形剤をさらに含む、請求項1に記載の組成物。
- 赤痢菌株を増殖させること、
赤痢菌細胞を破壊すること、並びに
任意選択で、一以上の遠心分離ステップ及び界面活性剤可溶化ステップを含むプロセスによって、外膜タンパク質(OMP)及びLPSを含む画分を単離すること、
さらに、赤痢菌以外の種に由来する抗原を準備すること
を含む、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS並びに赤痢菌以外の種に由来する抗原を含む免疫原性組成物を調製するための方法。 - 細胞を超音波処理によって破壊するステップ、
細胞膜タンパク質をN-ラウロイルサルコシンによって可溶化するステップ
のうちの一以上をさらに含む、請求項15に記載の方法。 - 赤痢菌細胞を37℃で増殖させるステップ、
細胞を室温で30分間、2,770gで遠心分離するステップ、
上清を廃棄するステップ、
10mM Hepes中にペレットを再懸濁するステップ、
5×45秒間、43AMPで(電気)超音波処理するステップ、
室温で20分間、1,700gで遠心分離し、ペレットを廃棄するステップ、
4℃で60分間、100,000gで遠心分離し、上清を廃棄するステップ、
1% N-ラウロイルサルコシン中にペレットを再懸濁するステップ、
4℃で60分間、100,000gで遠心分離し、上清を廃棄するステップ、
10mM Hepes中にペレットを再懸濁するステップ、
5×45秒間、43AMPで超音波処理するステップ、
MgCl2を添加し、濾過する(0.2μm)ステップ
を含む、請求項15又は16に記載の方法。 - 医薬における使用のための、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子を含み、さらに赤痢菌以外の種に由来する抗原を含む組成物。
- ワクチンアジュバントとしての使用のための、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子を含み、さらに赤痢菌以外の種に由来する抗原を含む組成物。
- 粘膜ワクチンアジュバントとしての使用のための、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子を含み、さらに赤痢菌以外の種に由来する抗原を含む組成物。
- 赤痢菌感染又は疾患ではない感染又は疾患に対するワクチンとしての使用のための、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子を含み、さらに赤痢菌以外の種に由来する抗原を含む組成物。
- 赤痢菌以外の種に由来する抗原を含む免疫原性組成物のためのアジュバントの調製における、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子の使用。
- 赤痢菌以外の種に由来する抗原を含む免疫原性組成物のための粘膜アジュバントの調製における、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子の使用。
- 赤痢菌感染又は疾患ではない感染又は疾患に対するワクチンの調製における、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子の使用。
- 赤痢菌外膜タンパク質(OMP)、赤痢菌LPS分子及び赤痢菌以外の種に由来する抗原を含む、免疫応答を補助するための組成物。
- 感染性因子に対する免疫応答を惹起するための組成物であって、該感染性因子による感染又は疾患に対して免疫応答を惹起することができる、赤痢菌以外の種に由来する抗原を含み、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子をも含む組成物。
- 感染性因子による感染を治療/軽減/改善するための組成物であって、該感染性因子による感染又は疾患に対して防御的な免疫応答を惹起することができる、赤痢菌以外の種に由来する抗原を含む医薬組成物と、赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子を含む医薬組成物を含む組成物。
- 感染性因子が細菌又はウイルスである、請求項26又は27に記載の組成物。
- 請求項1から14のいずれか一項に記載の組成物を含む、赤痢菌ではない感染を治療又は軽減又は改善するための組成物。
- 組成物が鼻内経路により送達される、請求項25〜29のいずれか一項に記載の組成物。
- 同時に又は連続的に送達するための、赤痢菌外膜タンパク質(OMP)、赤痢菌LPS分子及び赤痢菌以外の種に由来する抗原を含むキット。
- 赤痢菌外膜タンパク質(OMP)及び赤痢菌LPS分子の有効量を含む、対象におけるアミロイド沈着又はアルツハイマー病を予防及び/又は軽減するための組成物。
- アミロイド沈着又はアルツハイマー病を予防及び/又は軽減するのに使用するための、請求項32に記載の組成物。
- アミロイド沈着又はアルツハイマー病を予防及び/又は軽減するための薬剤の製造における、請求項32に記載の組成物の使用。
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