JP2009520489A - 細菌のラフ型株の製造方法およびその用途 - Google Patents
細菌のラフ型株の製造方法およびその用途 Download PDFInfo
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Abstract
Description
・安定なラフ型株はスムーズ型株へ復帰しない;
・ラフ型株は、異なる抗原提示を示し、スムーズ型株より病原毒性が低い傾向にある;
・ラフ型株から製造された皮膚試験試薬は、スムーズ型株から製造されたものよりも有効性が高い;
・ラフ型株は、in vitro細胞性免疫実験において使用された場合に非常に有効である;および
・いくつかの桿菌の小さな集団または粒子は、食細胞を刺激する上で、スムーズ型株の単一の生物より有効でありうる。
本発明は、細菌のラフ型株、例えばMycobacterium属の細菌のラフ型株が、スルホンおよび/またはスルホンアミドに対する曝露により誘導されうるという驚くべき知見に基づくものである。
1つの態様において、本発明は、細菌のラフ型株の製造方法であって、該細菌をスルホンおよび/またはスルホンアミドに曝露することを含んでなる方法に関する。
本発明のいくつかの態様は、細菌をスルホンおよび/またはスルホンアミドに曝露することによる細菌のラフ型株の製造方法、あるいはラフ型株を製造するためのスルホンおよび/またはスルホンアミドの使用に関する。
本明細書中で用いる「ヒドロカルビル基」なる語は、少なくともCおよびHを含む基を意味し、場合により、1以上の他の適当な置換基を含みうる。そのような置換基の具体例には、ハロ-、アルコキシ-、ニトロ-、アミノ基、炭化水素基、N-アシル基、環状基などが含まれうる。該置換基が環状基である可能性に加えて、置換基の組合せが環状基を形成してもよい。該ヒドロカルビル基が2以上のCを含む場合、それらの炭素は必ずしも互いに連結している必要はない。例えば、該炭素の少なくとも2つは適当な要素または基を介して連結されうる。したがって、該ヒドロカルビル基はヘテロ原子を含有しうる。適当なヘテロ原子は当業者に明らかであり、例えば硫黄、窒素および酸素を包含する。
本発明の免疫モジュレーターは治療において使用されうる。特に、そのような化合物は、Tリンパ球応答をin vivoでモジュレーションするために、および/または免疫応答に関与する他の細胞をin vivoでモジュレーションするために使用されうる。
T細胞の増殖および/または分化をモジュレーション、特に刺激(すなわち誘導または増強)することができるか、あるいはT細胞アネルギーの誘導を防止またはT細胞アネルギーを反転することができる組成物は、T細胞性免疫応答を増強または誘導するために一般に使用されうる。実質的に全ての適応免疫応答はT細胞の活性化およびサイトカイン産生細胞へのそれらの分化を要する。したがって、これらの組成物は、感染症、例えばウイルスまたは細菌感染症を予防および/または治療するために一般に使用されうる。好適には、これらの組成物は、寄生虫感染、例えばマラリア、リーシュマニア症、トキソプラズマ症およびトリパノソーマ症を予防および治療するために使用されうる。好適には、これらの組成物は、ウイルス感染、例えばウマサルコイド、性器疣贅、および子宮頸の癌に先行する子宮頸の異形成を含む、パピローマウイルスにより引き起こされる感染を予防または治療するために使用されうる。
本発明の組成物は、ウマサルコイドを予防および治療するためにも使用されうる。
離乳後多臓器消耗症候群(post-weaning multisystemic wasting syndrome)(PMWS)は4〜16週齢の離乳後の子ブタ(15〜50kg)を冒す。典型的には、PMWSは離乳の1〜2週間後に子ブタを冒し、これは離乳後に適切に飲食しない消耗/虚弱な離乳動物とは全く異なる。PMWS子ブタは、成長し始めたもののその後に急速に衰弱ししばしば抗生物質に対して極めて不良な応答を示す離乳動物である。
本発明の組成物はSIPHの予防および治療にも使用されうる。本発明の組成物は高地性肺水腫(HAPE)の治療にも使用されうる。
本発明の組成物は、アレルギー(例えば、アレルギー性喘息を含む喘息、枯草熱、アレルギー性皮膚炎(湿疹)、アナフィラキシーショック、植物接触または摂取に対するアレルギー、刺創(例えばイラクサおよび昆虫刺創)に対するアレルギー、ならびに昆虫刺咬に対するアレルギー(例えば小昆虫、例えばCulicoides(これはウマにおける夏癬を引き起こす)によるもの))を予防および治療するためにも使用されうる。
本発明の組成物は、細胞性肺気腫および/またはCOPD(慢性閉塞性肺疾患)を予防および治療するためにも使用されうる。
本発明の組成物は、T細胞調節不良および/またはT細胞調節不全にメカニズム的に関連している自己免疫疾患を治療および/または予防するために使用されうる。自己免疫疾患の具体例には、以下のうちの1以上が含まれる:望ましくない免疫反応および炎症、例えば関節炎、例えば慢性関節リウマチ、乾癬、乾癬性関節症、血管障害、特に、血管の内膜の炎症が生じる血管障害、例えばアテローム形成(またはアテローム性動脈硬化症として公知である)、前ブドウ膜炎、および血管形成術後の筋内膜過形成(myointimal hyperplasia)(MIH);甲状腺炎、アテローム性動脈硬化性心疾患、再潅流損傷、心伝導障害、心筋梗塞、習慣性流産、色素性網膜炎、変性眼底疾患(degenerative fundus disease)の免疫および炎症成分、中枢神経系(CNS)または他の任意の器官の両方において免疫および/または炎症の抑制が有益である自己免疫疾患または状態または障害に関連した炎症、パーキンソン病、パーキンソン病の治療による合併症および/または副作用、ギラン・バレー症候群、重症筋無力症、天然または人工細胞、組織および器官、例えば角膜、骨髄、臓器、レンズ、ペースメーカー、天然または人工皮膚組織の移植の場合の移植片拒絶。
ストレスは、しばしば、大きな重圧のかかる遂行性の生活様式である現代生活の症状の1つとして生じ、その影響は、胃潰瘍、高血圧、心疾患および卒中のような主要病態を招くことが広く認識されている。人生における他の大きなストレス性事象、例えば離婚、死別および転居は、心疾患の高リスク因子として理解されている。
免疫系失調(免疫系不均衡)、例えばアップレギュレーション、ダウンレギュレーションまたは不適切に調節された細胞性免疫応答は、被験体の一生の任意の時点で生じうる。好適には、該組成物は、免疫系失調をモジュレーションするために使用されうる。すなわち、本発明の組成物は、免疫系失調を治療および/または予防するために使用されうる。
好適には、該免疫モジュレーター組成物または医薬組成物は、赤ん坊、乳児および幼児を含む小児において免疫系失調をモジュレーションするために使用されうる。免疫系失調、例えばアップレギュレーション、ダウンレギュレーションまたは不適切に調節された細胞性免疫応答は、ワクチン接種後、例えば小児用ワクチン接種後の小児において生じうる。そのような免疫系失調は、アレルギー、すなわち、アレルギー性皮膚炎およびアレルギー性喘息の発症のような状態を招きうる。
免疫系失調(免疫系不均衡)、例えばアップレギュレーション、ダウンレギュレーションまたは不適切に調節された細胞性免疫応答、特に、ダウンレギュレーション、例えば免疫機能の低下は、高齢者、一般には60歳を超える高齢者において生じうる。高齢者における細胞性免疫応答のダウンレギュレーションは一般には免疫老化と称される。典型的には、免疫機能の低下は例えば感染症および新生物に対する感受性の増加を招きうる。人口に対する比率としての高齢者の数は劇的に増加しており、高齢者用医薬は臨床実施の重要な一態様となりつつある。したがって、研究が免疫老化のメカニズムおよび免疫系の健常性と寿命との関連性に焦点を合わせていることは驚くにはあたらない。Goronzy (2001)は高齢者におけるインフルエンザワクチン接種の様々な効力を検証した。この研究においては、ワクチン接種の1ヶ月後に被験体の僅か17%が全3種の赤血球凝集素に対する力価の上昇(ワクチン接種の成功)を示したに過ぎず、46%は明白な応答を全く示さなかった。インフルエンザワクチン接種に対する応答性は免疫老化の有用な生物学的マーカーであると提示された。多数の研究者が高齢者における免疫機能の種々の態様を研究している。例えば、Lio (2000)はサイトカイン応答を研究し、Solana (2000)はNKおよびNKt細胞を研究し、Ginaldi (1999)は、Th1からTh2へのサイトカイン産生移行および炎症性サイトカインの産生の増加がアテローム性動脈硬化症および骨粗鬆症のような加齢関連病的事象の多数の態様を説明しうることを示唆した。したがって、サイトカイン応答を炎症性Th2からTh1へと駆動する免疫系の非病的刺激が要求される。好ましくは、そのような免疫モジュレーターは急性感染による死亡率を減少させ、加齢関連自己免疫疾患の開始を抑制し、加齢関連自己免疫疾患の罹患率を減少させ、おそらくは、新生物疾患の割合を減少させるであろう。これらのすべては免疫老化に関連している。
本発明の組成物は、例えば被験体における成長の増進(例えば、促進)および/または飼料利用効率の向上および/または健康の全般的な増進(すなわち、被験体の全般的な健康状態の改善)をもたらしうる、動物、好ましくは哺乳動物、より好ましくは家畜および/または競争用動物における免疫系を増強するための医薬の製造において使用されうる。被験体の全般的な健康状態は以下のパラメーターの1以上により決定されうる:体重データ(体重増加は正の決定因子である)、警戒(完全な警戒は正の決定因子である)、運動性(不活発な運動性と対比した場合の活発な運動性は正の決定因子である)および疾病(疾病の量の減少は正の決定因子である)。典型的には、本発明のこの態様の免疫モジュレーター組成物または医薬組成物は免疫増強物質でありうる。
好適には、本発明の組成物は、癌を治療および/または予防するために細胞性免疫応答をモジュレーションするために使用される。特に、本発明の組成物は、癌の発生および/または進行に対して被験体を防御するために使用されうると想定される。特に、モジュレーションされた細胞性免疫応答を有する被験体は、癌の発生に対する、より低い感受性を有しうる。
いずれかの大手術の後、いくつかの状況が生じる可能性がある。
本明細書中で用いる「Th1」なる語は1型Tヘルパー細胞(Th1)を意味する。本明細書において、該用語はまた、そのような細胞型によりまたはそれを介してもたらされる応答を示すために用いられうる。そのような応答は、インターロイキン2(IL-2)の分泌、インターフェロンガンマ(IFN-γ)の分泌、マクロファージの活性化、細胞傷害性T細胞の活性化または任意の他のTh1関連事象の1以上を含みうる。したがって、「Th1」なる語は、Th1細胞、およびそのような細胞がもたらす免疫応答を含みうる。
有効成分として1以上の物質を含有するワクチンの製剤は当業者に公知である。典型的には、そのようなワクチンは液体溶液または懸濁液としての注射剤として製剤化され、注射前に液体に溶解または懸濁される固体形態も製剤化されうる。該製剤は乳化することも可能であり、あるいは有効成分はリポソーム内に封入されうる。該有効成分は、しばしば、製薬上許容され該有効成分に適合性である賦形剤と混合される。適当な賦形剤としては、例えば、水、生理食塩水、デキストロース、グリセロール、エタノールなど、またはそれらの組合せが挙げられる。あるいは、該ワクチンは、例えば、経口摂取されるよう、および/または吸入可能となるよう製剤化されうる。
典型的には、個々の被験体に最も適した、ワクチン、免疫モジュレーター組成物および医薬組成物の実際の投与量は医師により決定され、それは個々の患者の年齢、体重および応答に応じて様々となるであろう。以下の投与量は平均的な場合の典型例である。もちろん、より高いまたはより低い投与量範囲が好ましい個々の場合が存在しうる。
本明細書中で用いる「抗原」は、免疫応答性宿主内に導入されると、該抗原と結合しうる特異的抗体の産生を修飾する、ならびに/または関連Th応答、例えばTh2および/もしくはTh1を修飾する、実体を意味する。抗原は、純粋な物質、物質の混合物、または可溶性もしくは粒子状物質(細胞または細胞断片または細胞超音波処理物を含む)でありうる。この場合、該用語は、任意の適当な抗原決定基、交差反応性抗原、同種抗原、異種抗原、寛容原、アレルゲン、ハプテンおよび免疫原またはそれらの一部ならびにそれらの任意の組合せを含み、これらの用語は本明細書の全体にわたり互換的に用いられる。
本明細書中で用いる「アジュバント」なる語は、免疫応答の影響を増強しうるまたは該影響に関与しうる実体を意味する。アジュバントは、抗原に対する免疫応答を補助、増強、ダウンレギュレーション、修飾または多様化する任意の物質または物質の混合物である。
本発明はまた、Mycobacterium obuenseのラフ型株からの細菌の全細胞の治療的有効量と、場合によっては製薬上許容される担体、希釈剤または賦形剤(それらの組合せを含む)とを含んでなる医薬組成物を提供する。
本発明の物質は、1以上の他の医薬上活性な物質と共に投与されうる。例えば、本発明は、本発明の免疫モジュレーター組成物および/または医薬組成物と、1以上のステロイド、鎮痛薬、抗ウイルス薬、インターロイキン、例えばIL-2または他の医薬上活性な物質とによる同時または連続的な治療を包含する。
本明細書中で用いる「免疫増強物質」なる語は、被験体に投与された場合にその被験体の健康に利益となる分離されたまたは培養内の1以上の細菌を意味する。好ましくは、この利益は該被験体の細胞性免疫応答の修飾により達成される。
もう1つの態様においては、本発明は、(a)第1試験動物を免疫刺激物質と接触させ、(b)第2試験動物を、細菌と混合された免疫刺激物質と接触させ、(c)該試験動物のそれぞれにおいて細胞性免疫応答を測定し、(d)該試験動物のそれぞれにおける細胞性免疫応答を比較する工程を含んでなる、細胞性免疫応答をモジュレーション(例えば、修飾)するMycobacteriumのラフ型株の細菌の1以上の全細胞を同定する方法であって、該免疫刺激物質のみの場合と比べて、細菌と混合された免疫刺激物質によるより低い細胞性免疫応答が、該細菌による細胞性免疫応答の修飾を示す、方法に関する。
ツベルクリン皮膚試験
ツベルクリン皮膚試験は、免疫モジュレーター組成物、すなわち、本発明の全死菌細菌細胞を含む細菌組成物/懸濁液の、細胞性免疫応答に対する効果を評価するための適当なモデルアッセイである。
Mycobacteria属由来のラフ型株の細菌を、発酵槽中の抗原不含培地、例えばソートン(Sauton)培地内で2〜28日間増殖させることが可能である。あるいは、関心のある細菌種を固形傾斜培地(solid slope)上で増殖させることが可能である。代替方法は当業者に容易に利用可能であろう。
Mycobacterium obuense型株(ATCC 27023)の安定ラフ型変異体の誘導
Mycobacterium obuense型株ATCC 27023は、国際コレクションにおいて、この株によってのみ表される。該株は培養特性においてスムーズ型であり、ラフ型変異体に転換しないことが公知である。
Middlebrook 7H11寒天上へのMycobacterium obuense型株ATCC 27023の6回の連続的な継代培養はスムーズ型コロニーのみを生成した。
実験2、パートa
Mycobacterium obuense型株ATCC 27023を、種々の濃度のDapsone(商標)を含むMiddlebrook 7H11寒天上で増殖させた。結果を表1に示す。
M. obuenseで既に処理されている、BCGでチャレンジされたマウスにおける、ツベルクリンに対するDTH反応
実験群に、誕生時および21日後(離乳時)に107 桿菌 / 0.1mlの免疫モジュレーターを投与した。対照マウスには緩衝化ボラートを同じスケジュールで投与した。
M. obuense(ラフ型株NCTC 13365)は免疫調節効果を有する。
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Claims (33)
- 細菌のラフ型株の製造方法であって、細菌をスルホンおよび/またはスルホンアミドに曝露することを含んでなる方法。
- 前記スルホンおよび/またはスルホンアミドが4,4'-ジアミノジフェニルスルホンまたはその類似体である、請求項1記載の方法。
- 前記ラフ型株を単離する、請求項2記載の方法。
- 培地1ml当たりスルホンおよび/またはスルホンアミド5μg以上の濃度のスルホンおよび/またはスルホンアミドを含む培地で前記細菌を増殖させる、請求項1〜3のいずれか1項記載の方法。
- 前記細菌が好気性Mycobacterium属のものである、請求項1〜4のいずれか1項記載の方法。
- 前記細菌がMycobacterium obuenseである、請求項1〜5のいずれか1項記載の方法。
- 請求項1〜6のいずれか1項記載の方法により製造されたMycobacteriumのラフ型株。
- 請求項1〜6のいずれか1項記載の方法により製造可能なMycobacterium obuenseのラフ型株。
- ブダペスト条約に基づきNCTCに受託番号NCTC 13365で寄託されたMycobacterium obuenseのラフ型株。
- 請求項8または請求項9記載のMycobacterium obuenseのラフ型株の全細胞を含んでなる免疫モジュレーター組成物であって、使用した該免疫モジュレーター組成物が細胞性免疫応答を修飾する、免疫モジュレーター組成物。
- 前記組成物が抗原およびアジュバントを含み、該アジュバントがMycobacterium obuenseのラフ型株の全細胞を含む、請求項10記載の免疫モジュレーター組成物。
- Mycobacterium obuenseのラフ型株の細菌の全細胞と、場合によっては製薬上許容される担体、希釈剤または賦形剤とを含んでなる医薬組成物であって、使用した該医薬組成物が細胞性免疫応答を修飾する、医薬組成物。
- 感染(例えば、細菌、ウイルス、または寄生虫感染、例えばマラリア、トリパノソーマ症、リーシュマニア症、家禽におけるEimeria種による感染、およびトキソプラズマ症)および/または感染に伴う免疫異常、自己免疫疾患(例えば、血管障害、例えば閉塞性血管障害、ならびに筋内膜過形成および/またはアテローム形成(またはアテローム性動脈硬化症として公知である)の根底をなす免疫学的態様、関節炎および移植片拒絶)、ストレス(例えば、主外傷ストレス(major trauma stress)、社会心理学的ストレスおよび慢性ストレス)、アレルギー(例えば、アレルギー性喘息を含む喘息、枯草熱、アレルギー性皮膚炎(湿疹)、アナフィラキシーショック、植物接触または摂取に対するアレルギー、刺創(例えばイラクサおよび昆虫の刺創)に対するアレルギー、ならびに昆虫刺咬に対するアレルギー(例えば小昆虫、例えばCulicoides(これはウマにおける夏癬を引き起こす)によるもの))、細胞性肺気腫、COPDならびに癌(例えば、メラノーマまたは腺癌)ならびに免疫系失調(例えば、小児および高齢者における免疫系失調)、のうちの1以上の治療または予防のための医薬の製造における、請求項10〜12のいずれか1項記載の免疫モジュレーター組成物または医薬組成物の使用。
- 感染、自己免疫疾患、ストレス、アレルギー、細胞性肺気腫、COPD、癌および免疫系失調のうち1以上の治療または予防のための医薬の製造における、請求項10〜12のいずれか1項記載の免疫モジュレーター組成物または医薬組成物の使用。
- 小児用ワクチンに対する有害反応および/またはその影響の治療または予防のための医薬の製造における、請求項10〜12のいずれか1項記載の免疫モジュレーター組成物または医薬組成物の使用。
- 細胞性免疫応答を修飾するための医薬の製造における、請求項10〜12のいずれか1項記載の免疫モジュレーター組成物または医薬組成物の使用。
- 医薬としての使用のための、請求項10〜12のいずれか1項記載の免疫モジュレーター組成物または医薬組成物。
- ワクチン中でのまたはワクチンとしての使用のための、請求項10〜12のいずれか1項記載の免疫モジュレーター組成物または医薬組成物。
- ワクチンが予防用ワクチンまたは治療用ワクチンである、請求項18記載の免疫モジュレーター組成物。
- 前記組成物が細胞性免疫応答を修飾する、請求項18または請求項19記載の免疫モジュレーター組成物。
- 前記組成物が抗原または抗原決定基を更に含む、請求項1〜20のいずれか1項記載の免疫モジュレーター組成物および/または医薬組成物。
- 抗原または抗原決定基が、BCG(カルメット・ゲラン菌)ワクチン、ジフテリアトキソイドワクチン、ジフテリア/破傷風/百日咳ワクチン、百日咳ワクチン、破傷風トキソイドワクチン、麻疹ワクチン、おたふくかぜワクチン、風疹ワクチン、OPV(経口ポリオワクチン)およびMycobacterium vaccaeまたはその一部のうちの1以上から選ばれる抗原または抗原決定基である、請求項21記載の免疫モジュレーター組成物および/または医薬組成物。
- 前記組成物が2以上のそのような抗原または抗原決定基を含む、請求項21または請求項22記載の免疫モジュレーター組成物および/または医薬組成物。
- 前記細菌が殺菌されている、請求項10〜12および17〜23のいずれか1項記載の免疫モジュレーター組成物および/または医薬組成物。
- 請求項10〜12および17〜23のいずれか1項記載の医薬組成物および/または免疫モジュレーター組成物の有効量を被験体に投与することを含んでなり、該組成物が細胞性免疫応答をモジュレーションする、被験体における病態の治療または予防方法。
- 請求項10〜12および17〜23のいずれか1項記載の医薬組成物および/または免疫モジュレーター組成物を投与することを含んでなる、被験体を免疫化するための方法。
- 前記医薬組成物および/または免疫モジュレーター組成物を抗原または抗原決定基と共に共投与する、請求項25または請求項26記載の方法。
- 前記抗原または抗原決定基が、BCG(カルメット・ゲラン菌)ワクチン、ジフテリアトキソイドワクチン、ジフテリア/破傷風/百日咳ワクチン、百日咳ワクチン、破傷風トキソイドワクチン、麻疹ワクチン、おたふくかぜワクチン、風疹ワクチン、OPV(経口ポリオワクチン)およびMycobacterium vaccaeまたはその一部のうちの1以上から選ばれる抗原または抗原決定基である、請求項27記載の方法。
- 前記医薬組成物および/または免疫モジュレーター組成物を2以上のそのような抗原または抗原決定基と共に共投与する、請求項27または請求項28記載の方法。
- 細菌のラフ型株を製造するための、スルホンおよび/またはスルホンアミドの使用。
- 実施例に関して実質的に上述されている方法。
- 実施例に関して実質的に上述されている免疫モジュレーターまたは医薬組成物。
- 実施例に関して実質的に上述されている使用。
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JP2022512813A (ja) * | 2018-11-02 | 2022-02-07 | フォーディー ファーマ リサーチ リミテッド | 細菌株を含む組成物 |
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BRPI0620291A2 (pt) | 2011-11-08 |
CA2633127A1 (en) | 2007-06-28 |
BRPI0620291B1 (pt) | 2020-12-15 |
CN101384699B (zh) | 2012-10-10 |
PL1963484T3 (pl) | 2012-08-31 |
BRPI0620291B8 (pt) | 2021-05-25 |
CN101384699A (zh) | 2009-03-11 |
AU2006328209B2 (en) | 2012-10-11 |
JP5202330B2 (ja) | 2013-06-05 |
EP2298860A3 (en) | 2012-04-25 |
WO2007071978A1 (en) | 2007-06-28 |
DK1963484T3 (da) | 2011-09-19 |
EP1963484B1 (en) | 2011-08-10 |
EP1963484A1 (en) | 2008-09-03 |
ES2369569T8 (es) | 2012-06-26 |
US8071354B2 (en) | 2011-12-06 |
NZ568810A (en) | 2011-09-30 |
US8512694B2 (en) | 2013-08-20 |
US20090304749A1 (en) | 2009-12-10 |
EP2298860A2 (en) | 2011-03-23 |
ATE519838T1 (de) | 2011-08-15 |
GB0526033D0 (en) | 2006-02-01 |
SI1963484T1 (sl) | 2012-06-29 |
CA2633127C (en) | 2015-08-04 |
US20120082699A1 (en) | 2012-04-05 |
AU2006328209A1 (en) | 2007-06-28 |
ES2369569T3 (es) | 2011-12-02 |
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