JP4233458B2 - アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 - Google Patents
アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 Download PDFInfo
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- JP4233458B2 JP4233458B2 JP2003586182A JP2003586182A JP4233458B2 JP 4233458 B2 JP4233458 B2 JP 4233458B2 JP 2003586182 A JP2003586182 A JP 2003586182A JP 2003586182 A JP2003586182 A JP 2003586182A JP 4233458 B2 JP4233458 B2 JP 4233458B2
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Description
本発明は、BCG株が有する増殖の窒素源として天然に存在するアミノ酸を使用する能力に対する限定を乗り越えるワクチンを提供する。さらにまた、L−アラニン、D−アラニンまたはL−セリンは、アンモニウムが存在しているときでさえBCG株の増殖を阻害する。機能的アラニンデヒドロゲナーゼ(配列番号1;配列番号2)のBCG株での発現はアラニンによるBCGの増殖阻害を軽減する。同様に、機能的L−セリンデヒドラターゼ(配列番号5;配列番号6)のBCG株での発現はL−セリンによるBCGの増殖阻害を軽減する。そのような阻害のメカニズムはグルタミンシンテターゼの阻害から生じる。グルタミンシンテターゼ(配列番号7から配列番号14)のBCGでの過剰発現はアラニンおよびL−セリンによるBCGの増殖阻害を軽減する。機能的アラニンデヒドロゲナーゼ(配列番号1;配列番号2)、L−セリンデヒドラターゼ(配列番号5;配列番号6)および/またはグルタミンシンテターゼ(配列番号7から配列番号14)を発現(または過剰発現)するリコンビナントBCG株はホストの体内でより長期間生存し続けて結果として長期の防御免疫を誘導する。そのような持続的リコンビナントBCG株は、結核および他のマイコバクテリア感染の予防のためのより有効なワクチンを提供する。
BCGワクチン株は増殖のための窒素源としてアミノ酸を利用する能力が限られている。さらにまた、天然に存在するアミノ酸L−アラニンおよびL−セリンはBCG株の増殖を阻害することを我々は発見した。BCGでの機能的L−アラニンデヒドロゲナーゼ(配列番号1;配列番号2)の発現はアラニンによる増殖阻害を軽減する。BCGでの機能的L−セリンデヒドラターゼ(配列番号5;配列番号6)の発現はL−セリンによる増殖阻害を軽減する。同様に、グルタミンシンテターゼ(配列番号7から配列番号14)の過剰発現は、アラニンおよびセリンによる増殖阻害を軽減させる。これらの新規な発見は重要である。なぜならば、機能的なアラニンデヒドロゲナーゼ(配列番号1;配列番号2)、L−セリンデヒドラターゼ(配列番号5;配列番号6)および/またはグルタミンシンテターゼ(配列番号7から配列番号14)を発現(または過剰発現)するリコンビナントBCG株はヒトホストの体内でより良好に生存し、長期の記憶免疫を誘導し、結核予防のためのより有効なワクチンを提供し、特に成人の肺結核を防ぐからである。
改変
本明細書に開示した核酸分子のDNA配列に多くの改変を加えることができる。そのような改変は当業者には明白であろう。本発明は、細菌または哺乳類細胞で発現を指令可能な、本明細書に開示した配列(またはそのフラグメント)のヌクレオチド改変を含む。改変にはヌクレオチドの置換、挿入もしくは欠失、またはヌクレオチドの相対的位置もしくは順序の変更が含まれる。
本発明の核酸分子はまた、本発明の核酸分子に対して少なくとも約60%の同一性、少なくとも70%の同一性、少なくとも80%の同一性、少なくとも90%の同一性、少なくとも95%の同一性、少なくとも96%の同一性、少なくとも97%の同一性、少なくとも98%の同一性、またはもっとも好ましくは少なくとも99%または99.5%の同一性を有し、細菌または哺乳類細胞で核酸分子発現可能な核酸分子(またはそのフラグメント)を含む。同一性とは、最高の順序適合が得られるようにアラインメントを実施した2つのヌクレオチド配列の類似性を指す。同一性は当業界で公知の方法にしたがって計算される。例えば、あるヌクレオチド配列(“配列A”と呼ぶ)が配列番号1の一部分と90%同一性を有する場合、配列Aは配列番号1の照合された部分の各100ヌクレオチドにつき10個までの点変異(例えば他のヌクレオチドをもつ置換)を含みうることを除けば配列Aは配列番号1の照合された部分と同一である。
本発明は、本明細書に記載された核酸とストリンジェントな条件下でハイブリダイズするために十分な同一性を有する配列をもつDNAを含む(ハイブリダイゼーション技術は当業界では周知である)。本発明はまた配列番号1から配列番号14の配列またはその相補性配列の1つまたは2つ以上とハイブリダイズする核酸分子を含む。そのような核酸分子は、好ましくは高度にストリンジェントな条件下でハイブリダイズする(以下を参照されたい:Sambrook et al. Molecular Cloning: A Laboratory Manual, Most Recent Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY)。高度にストリンジェントな洗浄は好ましくは低塩濃度(好ましくは約0.2%のSSC)および約50−65℃の温度を有する。
当業者には生リコンビナントワクチンの製造は公知である。典型的にはそのようなワクチンは注射可能な溶液または懸濁液として製造される。注射前に液体となる溶液または懸濁液に適した固体形態に製造してもよい。前記調製物はまた乳化されてもよく、またはタンパク質をリポソームに被包化してもよい。生の免疫原性成分は、医薬的に許容され活性成分と適合する賦形剤としばしば混合される。適切な賦形剤は、例えば、水、食塩水、デキストロース、グリセロール、エタノールなど、またはその組み合わせなどである。さらにまた、所望の場合には、本ワクチンは微量の補助物質、例えば湿潤剤、乳化剤、pH緩衝剤および/またはワクチンの有効性を高めるアジュバントを含むことができる。有効でありうるアジュバントの例には以下が含まれるがこれらに限定されるものではない:水酸化アルミニウム、N−アセチル−ムラミル−L−スレオニル−D−イソグルタミン(thr−MDP)、N−アセチル−ノル−ムラミル−L−アラニル−D−イソグルタミン(CGP11637、nor−MDPと称される)、N−アセチルムラミル−L−アラニル−D−イソグルタミニル−L−アラニン−2−(1'−2'−ジパルミトイル−sn−グリセロ−3−ヒドロキシホスホリルオキシ)−エチルアミン(CGP19835A、MTE−PEと称される)およびRIBI(細菌から抽出された3つの成分(モノホスホリル脂質A、トレハロースジミコレートおよび細胞壁骨格(MPL+TDM+CWS))を2%スクォレン/トゥイーン80(登録商標)乳液中に含む)。
簡便には、前記ワクチンは非経口的に、例えば注射(皮下または筋肉内)によって投与される。他の投与態様に適したさらに別の製剤には座薬および、いくつかの事例では経口製剤が含まれる。座薬のためには、伝統的な結合剤および担体には例えばポリアルキレングリコールまたはトリグリセリドが含まれるであろう。そのような座薬は、0.5%から10%、好ましくは1%から2%の範囲の活性成分を含む混合物から成形されるであろう。経口製剤には通常用いられる賦形剤、例えば医薬グレードのマンニトール、ラクトース、澱粉、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース炭酸マグネシウムなどが含まれる。これらの製剤は、溶液、懸濁液、錠剤、ピル、カプセル、徐放性製剤または散剤の形態をもち、10%から95%、好ましくは25%から70%の活性成分を含む。
本発明の医薬組成物は、Mycobacterium tuberculosisまたはMycobacterium bovisによる攻撃に対して哺乳類を治療または予防するために用いられる。本発明の医薬組成物はまた、変性疾患、障害または異常な身体状態(例えば癌)をもつ患者の治療に用いられる。
Mycobacterium bovis−BCGの増殖を阻害する本発明の培地組成物は唯一の窒素源としてアラニンまたはセリンを含む。アラニンが唯一の窒素源であるときアラニンは0.03mM以上の量で存在し、セリンが唯一の窒素源であるときセリンは0.03mM以上の量で存在する。
免疫診断に適し、適切な標識試薬を含むキットは、本発明の生リコンビナントMycobacterium bovisBCG株を含む適切な材料を適切な容器に残りの試薬およびアッセイの実施に必要な材料並びに適切なアッセイ使用説明書セットとともに包装することによって構築される。いかなる免疫学的検査様式も意図され(例えばELISA、ウェスタンブロット、サンドイッチアッセイなど)、それらは当業者に周知である。
細菌株および培養条件:12のMycobacterium bovisBCG株:BCG−Japan、BCG−Russia、BCG−Moreau、BCG−Sweden、BCG−Birkhaug、BCG−Frappier、BCG−Pasteur、BCG−Glaxo、BCG−Phipps、BCG−Tice、BCG−Denmark、およびBCG−Pragueを本実験に用い、それらはマーセル=ベーア博士(Dr. Macel Behr, McGill University)から入手した。前記の株の特性については以前に詳細に記載された(Behr et al. 1999)。ミドルブルック7H9培地(Midlebrook 7H9, Difco)は1リットル当たり以下を含む:硫酸アンモニウム、0.5g;L−グルタメート、0.5g;クエン酸ナトリウム、0.1g;ピリドキシン、1mg;ビオチン、0.5mg;リン酸二ナトリウム、2.5g;リン酸一カリウム、1g;クエン酸第二鉄アンモニウム、40mg;硫酸マグネシウム、50mg;塩化カルシウム、0.5mg;硫酸亜鉛、1mg;硫酸銅、1mg;およびグリセロール2mL(前記の他に5gのアルブミン(ウシ、V分画)、デキストロース2gおよび0.05%トゥイーン80を滅菌後に添加)。Sauton培地は1リットル当たり以下を含む:L−アスパラギン、4g;硫酸一カリウム、0.5g;硫酸マグネシウム、0.5g;クエン酸第二鉄アンモニウム、50mg;クエン酸、2g;硫酸亜鉛、1mg;およびグリセロール、60mL(0.05%トゥイーン80を滅菌後に添加)。グリセロール−アラニン−塩類(GAS)培地は1リットル当たり以下を含む:塩化アンモニウム、2g;L−アラニン、1g;バクトカシトーン(Bacto Casitone, Difco)、0.3g;二塩基性リン酸カリウム、4g;クエン酸、2g;クエン酸第二鉄アンモニウム、50mg;塩化マグネシウム6水和物、1.2g;硫酸カリウム、0.6g;10Mの水酸化ナトリウム、1.8mL;および10mLのグリセロール。トゥイーン80を滅菌後に0.05%添加した。BCG培養は37℃で定常的に振盪しながら3−4週間増殖させた。
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Claims (20)
- アラニンデヒドロゲナーゼ活性またはL−セリンデヒドラターゼ活性を示す少なくとも1つのタンパク質またはポリペプチドを発現し、アラニンおよび/またはL−セリンによる増殖の阻害を軽減することができる生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、アラニンデヒドロゲナーゼ(配列番号1から配列番号2)およびL−セリンデヒドラターゼ(配列番号5から配列番号6)から成る群から選択される請求項1の生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、配列番号1および配列番号5から成る群から選択される少なくとも1つの核酸分子と少なくとも90%の配列同一性を有する配列を含む核酸によりコードされる請求項1または2の生リコンビナントMycobacterium bovis−BCG株。
- グルタミンシンテターゼ活性を示す少なくとも1つのタンパク質またはポリペプチドを過剰発現し、アラニンおよび/またはL−セリンによる増殖の阻害を軽減することができる生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、グルタミンシンテターゼ(配列番号7から配列番号14)から成る群から選択される請求項4の生リコンビナントMycobacterium bovis−BCG株。
- 前記少なくとも1つのタンパク質またはポリペプチドが、配列番号7、配列番号9、配列番号11および配列番号13から成る群から選択される少なくとも1つの核酸分子と少なくとも90%の配列同一性を有する配列を含む核酸によりコードされる請求項4または5の生リコンビナントMycobacterium bovis−BCG株。
- 前記Mycobacterium bovis−BCG株が、Mycobacterium bovis−BCG−Russia、Mycobacterium bovis−BCG−Moreau、Mycobacterium bovis−BCG−Japan、Mycobacterium bovis−BCG−Sweden、Mycobacterium bovis−BCG−Birkhaug、Mycobacterium bovis−BCG−Prague、Mycobacterium bovis−BCG−Glaxo、Mycobacterium bovis−BCG−Denmark、Mycobacterium bovis−BCG−Tice、Mycobacterium bovis−BCG−Frappier、Mycobacterium bovis−BCG−Connaught、Mycobacterium bovis−BCG−Phipps、およびMycobacterium bovis−BCG−Pasteurから成る群から選択される請求項1、2、3、4、5または6の生リコンビナントMycobacterium bovis−BCG株。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株を含む医薬組成物。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株を含む、マイコバクテリアによる攻撃に対し哺乳類を治療または予防するワクチンまたは免疫原性組成物。
- 前記マイコバクテリアがMycobacterium tuberculosisである請求項9のワクチンまたは免疫原性組成物。
- 医薬的に許容できる担体をさらに含む請求項9または10のワクチンまたは免疫原性組成物。
- さらにアジュバントを含む請求項9、10または11のワクチンまたは免疫原性組成物。
- 1つ以上の他の病源体に由来する免疫原性物質をさらに含む請求項9、10、11または12のワクチンまたは免疫原性組成物。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株をヒトを除く哺乳類に投与することを含む、Mycobacterium tuberculosisまたはMycobacterium bovisによる攻撃に対し前記哺乳類を治療または予防する方法。
- 前記哺乳類が牛である請求項14の方法。
- 前記ワクチンまたは免疫原性組成物がアジュバントの存在下で投与される請求項14の方法。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株をヒトを除く哺乳類に投与することを含む、癌に対して前記哺乳類を治療または予防する方法。
- 前記ワクチンまたは免疫原性組成物がアジュバントの存在下で投与される請求項17の方法。
- 前記癌が膀胱癌である請求項17または18の方法。
- 請求項1、2、3、4、5、6または7の生リコンビナントMycobacterium bovis−BCG株を含む検査キット。
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JP2003586182A Expired - Fee Related JP4233458B2 (ja) | 2002-04-16 | 2003-04-16 | アラニンデヒドロゲナーゼ、セリンデヒドラターゼおよび/またはグルタミンシンテターゼを発現する結核ワクチンとしてのリコンビナントbcg株 |
Country Status (9)
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US (1) | US7611720B2 (ja) |
JP (1) | JP4233458B2 (ja) |
CN (1) | CN100572540C (ja) |
AU (1) | AU2003218838A1 (ja) |
CA (1) | CA2481108C (ja) |
GB (1) | GB2403477B (ja) |
RU (1) | RU2339692C2 (ja) |
WO (1) | WO2003089462A2 (ja) |
ZA (1) | ZA200408344B (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006000045A1 (en) * | 2004-06-25 | 2006-01-05 | Proteome Systems Intellectual Property Pty Ltd | Novel methods of diagnosis and treatment of m. tuberculosis infection and reagents therefor i |
US7919285B2 (en) * | 2004-10-13 | 2011-04-05 | Mitsui Chemicals, Inc. | DNA encoding novel enzyme having D-serine synthase activity, method of producing the enzyme and method of producing D-serine by using the same |
US8647641B2 (en) * | 2008-10-20 | 2014-02-11 | University Of Zurich | Mycobacterium tuberculosis vaccine |
PL2663318T3 (pl) * | 2011-01-11 | 2015-08-31 | Cadila Pharmaceuticals Ltd | Kompozycja farmaceutyczna do leczenia raka |
US20140127251A1 (en) * | 2011-04-11 | 2014-05-08 | Alarum Development Ltd. | Vaccines for prevention and treatment of tuberculosis |
CN114748615A (zh) * | 2022-04-29 | 2022-07-15 | 成都安永鼎业生物技术有限公司 | 一种治疗用重组卡介苗的冻干制剂及其制备方法和用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998032862A2 (de) * | 1997-01-29 | 1998-07-30 | Leopold Flohe | L-alanin dehydrogenase von mycobacterium marinum |
US6291190B1 (en) * | 1998-08-25 | 2001-09-18 | The Board Of Trustees Of The Leland Stanford Junior University | Molecular differences between species of the M. tuberculosis complex |
US6471967B1 (en) * | 2000-04-17 | 2002-10-29 | The Regents Of The University Of California | Recombinant intracellular pathogen vaccines and methods for use |
-
2003
- 2003-04-16 CA CA2481108A patent/CA2481108C/en not_active Expired - Fee Related
- 2003-04-16 CN CNB038022761A patent/CN100572540C/zh not_active Expired - Lifetime
- 2003-04-16 AU AU2003218838A patent/AU2003218838A1/en not_active Abandoned
- 2003-04-16 JP JP2003586182A patent/JP4233458B2/ja not_active Expired - Fee Related
- 2003-04-16 US US10/511,718 patent/US7611720B2/en not_active Expired - Fee Related
- 2003-04-16 GB GB0425165A patent/GB2403477B/en not_active Expired - Lifetime
- 2003-04-16 RU RU2004133751/13A patent/RU2339692C2/ru not_active IP Right Cessation
- 2003-04-16 WO PCT/CA2003/000566 patent/WO2003089462A2/en active Application Filing
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2004
- 2004-10-14 ZA ZA2004/08344A patent/ZA200408344B/en unknown
Also Published As
Publication number | Publication date |
---|---|
AU2003218838A8 (en) | 2003-11-03 |
US7611720B2 (en) | 2009-11-03 |
ZA200408344B (en) | 2005-11-30 |
WO2003089462A3 (en) | 2004-05-21 |
CA2481108A1 (en) | 2003-10-30 |
AU2003218838A1 (en) | 2003-11-03 |
RU2339692C2 (ru) | 2008-11-27 |
CN100572540C (zh) | 2009-12-23 |
GB2403477A (en) | 2005-01-05 |
RU2004133751A (ru) | 2005-08-10 |
GB0425165D0 (en) | 2004-12-15 |
US20070264286A1 (en) | 2007-11-15 |
JP2006508633A (ja) | 2006-03-16 |
CN1703513A (zh) | 2005-11-30 |
GB2403477B (en) | 2006-08-23 |
WO2003089462A2 (en) | 2003-10-30 |
CA2481108C (en) | 2013-05-28 |
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