JP6067209B2 - 微生物細胞抑制のためのワクチンおよびワクチン構成成分 - Google Patents
微生物細胞抑制のためのワクチンおよびワクチン構成成分 Download PDFInfo
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Description
本出願は、2007年9月25日に提出した米国特許出願第60/975,104号、2007年11月22日に提出した米国特許出願第60/989,840号、および2007年11月22日に提出した米国特許出願第60/989,841号の利益を主張するものであり、これら全ての出願内容はその全体が参照によりここに取り込まれる。
特定の分子を同定することである。これは例えば、メタン生成菌を標的とする薬剤の使用により達成されてよい。一アプローチによれば、微生物細胞を標的とするためにワクチンが調製できる。従って、構成成分、特にペプチドおよびポリペプチドを含む微生物細胞由来の細胞表面構成成分、および関連ヌクレオチドならびに抗菌ワクチンとして使用できる抗体の同定が有用であろう。
02のうちのいずれか1つの細胞外ドメインを包含する最少の1アミノ酸配列を含む。
融合体または抱合体を形成すること(例えば、融合配列の発現または細胞抑制剤に対する化学的抱合により);およびc)該融合体または抱合体を回収することを含む。
またはレベルを決定することを含む。このような方法はまた、微生物細胞、特にメタン生成菌細胞のレベルを検出および/または測定するためにも使用できる。
定義
「抗体」という用語は可能な意味の最も広い範囲において理解されなければならず、かつ未変化のモノクローナル抗体およびポリクローナル抗体を含むことが意図される。抗体の断片および誘導体もまた、それらが望まれる生物学的活性を示す限りにおいて網羅されることが意図される。抗体は、免疫グロブリン分子および免疫グロブリン(Ig)分子の免疫学的活性部位、すなわち抗原に特異的に結合する(免疫反応する)抗原結合部位を含む分子を包含する。限定はされないが、これらはポリクローナル、モノクローナル、キメラ、単鎖、Fc、Fab、Fab’、およびFab2断片、ならびにFab発現ライブラリーを含む。
的に同等な配列をもたらすアミノ酸残基の欠失、挿入、または置換を含む。意図されたアミノ酸置換が、残基の極性、電荷、溶解度、疎水性、親水性、および/または両親媒性性質の類似性に基づき、生物学的活性(例えば細胞結合、膜結合)または免疫原性/免疫学的活性を保持する限りにおいて行なわれてよい。例えば陰性荷電アミノ酸はアスパラギン酸およびグルタミン酸を含んでよく;陽性荷電アミノ酸はリジンおよびアルギニンを含んでよく;類似の親水性値を有する非荷電の極性頭部基をもつアミノ酸はロイシン、イソロイシン、およびバリン、グリシンおよびアラニン、アスパラギンおよびグルタミン、セリンおよびスレオニン、ならびにフェニルアラニンおよびチロシンを含んでよい。
コードする核酸、またはそれらに相補的な核酸の化学的修飾を意味する。このような修飾は例えば、水素のアルキル、アシル、またはアミノ基による置換を含む。好ましい態様によれば核酸誘導体は、天然分子の生物学的もしくは免疫原性/免疫学的活性を保持する、ペプチド、ポリペプチド、または抗体をコードする。誘導体ペプチド、ポリペプチド、または抗体は、グリコシル化、ペグ化により、またはそれが由来する配列の生物学的機能(例えば細胞結合、膜結合)の1種以上、もしくは免疫原性/免疫学的活性を保持する同様の過程により修飾されたものである。
片、変異体、ならびに誘導体を意味する。
解されるであろう。
Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Plainview, NY, および Ausubel, F. M. et al. (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY. を参照のこと。低または高ストリンジェンシーのいずれかを含む多数の同等な条件は、配列(DNA、RNA、塩基組成物)の長さおよび性質、標的(DNA、RNA、塩基組成物)の性質、環境(溶液中または固体基質上での不動化)、塩およびその他の構成成分(例えばホルムアミド、硫酸デキストランおよび/またはポリエチレングリコール)の濃度、ならびに反応温度(例えば、プローブの融解温度より約5℃低い温度から、融解温度より約20℃から25℃低い温度の範囲内)のような因子に依存する。上に列挙した条件とは異なるが同等である、低または高ストリンジェンシーのいずれかの条件を作り出すため、1つ以上の因子が変化させられてよい。
成成分および組成物を含む。この点において特に有用なものはペプチドワクチンを含むサブユニットワクチン、ならびにベクターワクチン、核酸ワクチン、および食用ワクチンである。ワクチンは抗原、特に微生物抗原に対する免疫反応を確立または強化するために用いることができる。特定の態様によれば、ワクチンはホストの防御反応、例えば抗体形成、Tヘルパー、およびT細胞反応を惹起する抗原を含む。ワクチンはまた、例えば受動免疫のために抗体を含むこともできる。
メタンは反すう動物の前腸内で、反すう胃システムにおける炭素の最終還元作用を行うメタン生成菌により産生される。多段階メタン生成経路は、主に非反すう胃メタン生成菌の研究によって十分に解明されているが、反すう胃においてメタン生成菌の生育および存続を可能にするための適応はよく理解されていない。メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)は、ニュージーランドの反すう動物における有名なメタン生成菌である。ここに述べるように、M.ルミナンチウム(M.ruminantium)のゲノムが配列決定され、約3.0Mbのサイズにおける33.68%のGC含有量が示された。メタン生成経路の全ての構成成分が同定され、これらの遺伝子配列と、メタノバクテリウム・サーモオートトロフィクム(Methanobacterium thermoautotrophicum) および メタノスファエラ・スタッドマナエ(Methanosphaera stadtmanae)の遺伝子配列との比較は、メタノバクテリウム目内でメタン生成遺伝子機構が保存されていることを示した(図1C)。該ゲノムは、その他の反すう胃微生物との共生を仲介し得ることを示す特徴を持つ、多数の大きな表面タンパク質を含む。本発明の様々な態様によれば、同定されたポリヌクレオチドおよびポリペプチドは、反すう胃におけるメタン生成菌および/またはメタン生成を抑制し、かつメタン生成におけるM.ルミナンチウム(M.ruminantium)の役割をさらに解明するための方法として使用できる。特に有用なものは、メタン生成に関与する構成成分として(図6A〜6C)、細胞表面構成成分として(図7A〜7C)、菌体外多糖の生合成に関与する構成成分として(図8A〜8C)、膜貫通ドメインの構成成分として(図9A〜9C)同定された開示されるポリヌクレオチドおよびポリペプチド、同様に抗体産生に用いられるポリヌクレオチドおよびポリペプチド(図5A〜5B)である。
本発明は、配列番号1〜702のうち少なくとも1つ、ならびにその断片、変異体、および誘導体を含む、ペプチドおよびポリペプチドを包含する。本発明のペプチドおよびポリペプチドは、その生物学的活性を決定するため、様々なアッセイにおいて、発現され、かつ使用されてよい。該ペプチドおよびポリペプチドは大量合成および単離手順、例えば商業的産生のために使用されてよい。このようなペプチドおよびポリペプチドは、抗体を産生するため、対応するアミノ酸配列を単離するため、かつ該アミノ酸配列のレベルを定量的に決定するために使用されてよい。該ペプチドおよびポリペプチドは、微生物細胞、特にメタン生成菌細胞の標的化および抑制のためのワクチンに使用できる。該ペプチドおよびポリペプチドはまた、このような細胞の生育および複製を抑制するための抗体の調製にも使用できる。本発明のペプチドおよびポリペプチドはまた、組成物、例えば医薬組成物、特にワクチン組成物としても使用されてよい。特定の態様によれば、徐放反すう胃装置が、本発明のペプチド、ポリペプチド、抗体、および組成物(例えば医薬組成物、特にワクチン組成物)と共に使用できる。
胃装置が、本発明のポリヌクレオチド、ベクター、ホスト細胞、および組成物(例えば医薬組成物、特にワクチン組成物)と共に使用できる。
形態のいずれの実践にも使用されてよい。該方法は、DNAポリメラーゼIのクレノウ断片、SEQUENASE (U.S. Biochemical Corp、クリーブランド、オハイオ州)、Taqポリメラーゼ(Perkin Elmer)、熱安定型T7ポリメラーゼAmersham Pharmacia Biotech(ピスカタウェイ、ニュージャージー州)のような酵素、またはLife Technologies(ゲイサーズバーグ、メリーランド州)により市販されているELONGASE Amplification Systemに見出されるような、ポリメラーゼと校正エキソヌクレアーゼの組み合わせを用いてよい。好ましくは、この過程はHamilton Micro Lab 2200(ハミルトン、リノ、ネバダ州)、Peltier Thermal Cycler(PTC200; MJ Research、ウォータータウン、マサチューセッツ州)、ABI Catalyst ならびに 373 および 377 DNA Sequencers(Perkin Elmer)、またはGenome Sequencer 20(商標)(Roche Diagnostics)のような装置を用いて自動化される。
胞タンパク質と相互作用するベクターの非翻訳領域−エンハンサー、プロモーター、5’および3’非翻訳領域−である。このようなエレメントはその強度および特異性において異なり得る。ベクターシステムおよび利用するホストに依存して、恒常的および誘導的プロモーターを含む、適切な転写および翻訳エレメントが幾つでも使用されてよい。例えば細菌システムにおけるクローニングのとき、BLUESCRIPTファージミド(Stratagene、ラホヤ、カリフォルニア州)のハイブリッドlacZプロモーター、またはpSPORT1プラスミド(Life Technologies)などのような誘導性プロモーターが使用されてよい。昆虫細胞においては、バキュロウィルスのポリヘドリンプロモーターが使用されてよい。植物細胞ゲノム由来(例えば熱ショック、RUBISCO、および貯蔵タンパク質遺伝子)もしくは植物ウィルス由来(例えばウィルス性プロモーターまたはリーダー配列)のプロモーターまたはエンハンサーがベクター内へクローン化されてよい。
7417 (1987); Bothwell et al., Methods for Cloning and Analysis of Eukaryotic Genes, Eds., Jones and Bartlett Publishers Inc., Boston, Mass. (1990), Ausubel et al., Short Protocols in Molecular Biology, John Wiley and Sons, New York, NY (1992);およびFarhood, Annal. NY Acad. Sci., 716:23 34 (1994))、プロトプラスト(Bothwell、上記)または電気的パルス(Vatteroni et al., Mutn. Res., 291:163 169 (1993); Sabelnikov, Prog. Biophys. Mol. Biol., 62: 119 152 (1994); Bothwell et al.、上記;および Ausubel et al.、上記)の使用、弱毒化ウィルスの使用(Davis et al., J. Virol. 1996, 70(6), 3781 3787; Brinster et al. J. Gen. Virol. 2002, 83(Pt 2), 369 381; Moss, Dev. Biol. Stan., 82:55 63 (1994); および Bothwell et al.、上記)、同様に物理的方法(Fynan et al., lnt J Immunopharmacol. 1995 Feb;17(2):79-83; Johnston et al., Meth Cell Biol., 43(Pt A): 353 365 (1994); Bothwell et al.、上記; および Ausubel et al.、上記)を含む。
、2部位のモノクローナルに基づく免疫アッセイが使用できるが、競合的結合アッセイもまた使用できる。これらおよびその他のアッセイは、特にHampton, R. et al. (1990; Serological Methods, a laboratory Manual, APS Press, St Paul, MN) および Maddox, D. E. et al. (1983; J. Exp. Med. 158:1211-1216)に記載されている。
んでよい。例えば、ベクターは精製ドメインとペプチドまたはポリペプチドの間に1つ以上のリンカーを含んでよい。このような発現ベクターの一つは、本発明のペプチドまたはポリペプチド、およびチオレドキシンまたはエンテロキナーゼ切断部位に先立つ6ヒスチジン残基をコードする核酸を含む融合タンパク質の発現を提供する。ヒスチジン残基はIMAC(Porath, J. et al. (1992) Prot. Exp. Purif. 3: 263-281に記載される、固定化金属イオンアフィニティークロマトグラフィー)における精製を促進するが、エンテロキナーゼ切断部位は融合タンパク質からペプチドまたはポリペプチドを精製するための手段を提供する。融合タンパク質を含むベクターについての考察はKroll, D. J. et al. (1993; DNA Cell Biol. 12:441-453)により提供される。
本発明の抗体は、例えば精製または診断技術における使用のために、当該技術分野において一般に公知の方法を用いて産生されてよい。特に、公知の方法に従って抗体を産生するため、精製ペプチド、ポリペプチド、またはポリヌクレオチドが使用されてよい。このような抗体は、ポリクローナル、モノクローナル、キメラ、および単鎖抗体、Fab断片、ならびにFab発現ライブラリーにより産生された断片を含んでよいがこれらに限定されない。中和抗体(すなわち機能を抑制するもの)は、ワクチンとの併用に特に好ましい。
、関連した特異性を有するが、明確なイディオタイプ構造である抗体が作られてよい(Burton D. R. (1991) Proc. Natl. Acad. Sci. 88:11120-3)。
6ジオキソシクロヘキサ−1−イリデンが除去された後、5−および6−カルボキシフルオレセインサクシニミジルエステルを共役できる。従って、抗体への抑制分子の共役は、ポリペプチド配列へのリジン残基の包含、続いて適切に誘導体化された細胞抑制剤との反応により達成できる。
異的なモノクローナル抗体またはその断片もまた含まれる。さらに、カメリド抗体またはナノボディーも含まれる。
CR, Steward MW. Production of anti- peptide antibody in mice following immunization of mice with peptides conjugated to mannan. J Immunol Methods 1992; 142: 127-131; Ohta M, Kido N, Hasegawa T, et al. Contribution of the mannan side chains to the adjuvant action of lipopolysaccharides. Immunology 1987; 60: 503-507)。
B subunit. Proc Natl Acad Sci USA 1996;93:7196-7201)。
本発明のペプチド、ポリペプチド、ポリヌクレオチド、および抗体は健康上の効用を有すると考えられる。特定の態様によれば、メタン生成菌を標的とするワクチンが、通常はメタンとして失われるエネルギーを被験体へ還元するために使用できる。本発明は従って、上で考察されたいずれの方法の使用のための、薬理学的に許容される担体との組み合わせにおける医薬組成物(特にワクチン組成物)に関する。このような医薬組成物は、ペプチド、ポリペプチド、または抗体を細胞抑制剤と組み合わせて含んでよい。あるいは該医薬組成物は、ここに詳述されるように、ポリヌクレオチド、発現ベクター、またはホスト細胞を含んでよい。該組成物は単独で投与されてよいか、または生理食塩水、緩衝食塩水、デキストロース、および水を含むがこれらに限定されない無菌、生体適合性のいずれの薬理学的担体中で投与されてよい、安定化化合物のような少なくとも1種のその他の薬剤との組み合わせにより投与されてよい。該組成物は被験体へ単独で、またはその他の薬剤、薬物(例えば抗菌薬物)、もしくはホルモンと組み合わせて投与されてよい。
ciences (Maack Publishing Co., Easton, PA)の最新版に見出されるであろう。本発明で利用される医薬組成物は、経口、静脈内、筋肉内、動脈内、延髄内、包膜内、心室内、経皮、皮下、腹腔内、鼻内、経腸、外用、舌下、または直腸の手段を含むがこれらに限定されないいずれの数の経路により投与されてよい。
に可溶性となる傾向がある。その他の場合の好ましい製剤は、使用前に緩衝液と組み合わせた4.5ないし5.5のpH範囲において、1〜50mMヒスチジン、0.1%〜2%ショ糖、および2〜7%マンニトールのいずれかまたは全てを含んでよい、凍結乾燥粉末であってよい。医薬組成物の調製後、これらは適切な容器に配置でき、表示される状態の治療のために標識される。本発明の組成物の投与のため、このような標識は投与の量、頻度、および方法を含んでよい。
は、乾草、草、穀粒、または穀粉、例えば豆乾草、草乾草、トウモロコシサイレージ、草サイレージ、豆サイレージ、トウモロコシ粒子、カラスムギ、オオムギ、蒸留かす、ビールかす、大豆穀粉、および綿実穀粉のいずれか1を含む。特に、反すう動物の食物組成物として草サイレージが有用である。植物材料は、本発明の構成成分の1種以上、例えばポリペプチドもしくはペプチド、ポリヌクレオチド、またはベクターのうち1種以上を含むように遺伝的に改変できる。
RNAプローブ産生のためのベクターへの核酸配列のクローン化を含む。このようなベクターは当該技術分野において公知かつ市販されており、適切なRNAポリメラーゼおよび適切な標識ヌクレオチドの添加によるin vitroでのRNAプローブ合成に使用されてよい。ハイブリダイゼーションプローブは様々なレポーター群、例えば32Pもしくは35Sのような放射性核種、またはアビジン/ビオチン共役システムを通してプローブに共役されたアルカリホスファターゼのような酵素ラベルなどにより標識されてよい。ポリヌクレオチドは、サザンもしくはノーザン分析、ドットブロット、またはその他の膜に基づく技術;PCR技術;または試験紙、ピン、ELISAアッセイ、または微生物の存在もしくはレベルを検出するために、被験体生検由来の液体または組織を利用するマイクロアレイにおいて使用されてよい。このような定性または定量法は当該技術分野において公知である。
アフィニティーを有する化合物のハイスループットスクリーニングを提供する。この方法によれば、多数の異なる小さな試験化合物が、プラスチックピン、またはその他の幾つかの表面のような固体基質上で合成される。試験化合物は、ペプチドもしくはポリペプチド、またはその断片と反応し、洗浄される。結合したペプチドまたはポリペプチドは、次に当該技術分野において公知の方法により検出される。精製されたペプチドまたはポリペプチドはまた、上述の薬物スクリーニング技術における使用のため、プレート上に直接コートもできる。あるいは非中和抗体が、ペプチドの捕獲および固体支持体上への不動化のために使用できる。
メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)の種であるM1T(DSM1093)は、[g/l]NaCl(1)、KH2PO4(0.5)、(NH4)2SO4(0.25)、CaCl2.2H2O(0.13)、MgSO4.7H2O(0.2)、K2HPO4(1)、浄化した反すう胃液(300ml)dH2O(360ml)、NaHCO3(5)、レザズリン(0.2ml)L−システイン−HCl(0.5)、酵母抽出物(2)、ならびに、(g/l)ニトリロ三酢酸(1.5)、MgSO4.7H2O(3)、MnSO4.H2O(0.5)、NaCl(1)、FeSO4.7H2O(0.1)、CoCl2.6H2O(0.1)、CaCl2.2H2O(0.1)、ZnSO4.7H2O(0.1)、CuSO4.5H2O(0.01)、AlK(SO4)2.12H2O(0.01)、H3BO3(0.01)、Na2MoO4.2H2O(0.01)、NiSO4.6H2O(0.03)、Na2SeO3(0.02、およびNa2WO4.2H2O(0.02)から成るBalchの微量元素溶液(10ml)(微量元素の添加;Balch et al., 1979)、から成るBY+培地(基本培地、Joblin et al., 1990)中で生育した。細胞ペレットを液体N2下で凍結すること、および予め冷却した滅菌乳鉢および乳棒を用いて粉砕することによりゲノムDNAを抽出した。ゲノムDNAの物理的せん断を減少させるため、細胞ホモジネートをアガロースプラグ上に包埋し、続く操作をプラグ内で行った。制限酵素により消化を行い、DNA断片をパルスフィールドゲル電気泳動(PFGE)を用いて分離した。
M.ルミナンチウム(M.ruminantium)ゲノムのDNAは、Agencourt Biosciences Corporation(マサチューセッツ州、米国)によりランダムショットガンクローニングアプローチ(Fleischmann et al., 1995)を用いて、およびMacrogen Corporation(ロックビル、メリーランド州、米国)によりピロシーケンスを用いて配列決定された。簡単に述べると、M.ルミナンチウム(M.ruminantium)のDNAのライブラリーを、ゲノムDNAのランダムな物理的破壊およびゲル電気泳動による断片の分離により、大腸菌(Escherichia coli)内へ構築した。40kb範囲の大きな断片をゲルから回収し、大インサートのフォスミドライブラリーを作製するために使用した。2ないし4kb範囲のDNA断片を回収し、小インサートのプラスミドライブラリーを作製するために使用した。大および小インサートライブラリーの両方からもたらされたクローンを生育させ、それらのフォスミドまたはプラスミドDNAを回収し、ハイスループット配列決定技術を用いて配列決定した。M.ルミナンチウム(M.ruminantium)ゲノムの理論的な8倍のカバー率を生ずるために十分な数のクローンを配列決定した。さらなる配列のカバー率が、ランダムにせん断されたゲノムDNA断片のピロシーケンス(Macrogen Corporation)により得られ、約10倍の最終理論的なゲノムのカバー率となった。
配列の重複を見出すためにDNA配列を整列し、Paracel Genome Assembler(Paracel Inc、カリフォルニア州、米国)およびStadenパッケージ(Staden et al., 1998)を用い、標準および逆PCRの両方から得られた配列を組み合わせて、近接する(コンティグ)配列へ構築した。コンティグは翻訳領域(ORF)ファインダーGLIMMER(Gene Locator Interpolated Markov Model ER、Delcher et al., 1999)を用いて分析し、各ORFは、National Center for Biotechnology Information(NCBI)の非重複性ヌクレオチドおよびタンパク質データベースに対するギャップ付きBLAST(Basic Local Alignment Search Tool(Altschul et al., 1997)により分析した。
ゲノムDNAの制限酵素消化およびPFGEによる断片のサイズ決定によるM.ルミナンチウム(M.ruminantium)ゲノムのサイズ推定は、約2.5〜2.9Mbの単一染色体を示した。大および小インサートクローン(6倍ドラフトカバー率)の最初の配列決定および配列のコンティグへの構築は、ゲノムの40kb範囲が、特に小インサートライブラリー内で高度に過剰表現(>20倍)されていることを示した。これは高コピー数のプラスミド(染色体外DNAは同定されていないが)、またはDNA抽出のために使用した培養物の生育の間に複製した溶原性バクテリオファージによる可能性がある。この大きな配列バイアスのため、さらなる配列決定(2倍の理論的ゲノムカバー率)を、サンガー配列決定法により最終の8倍のカバー率をもたらす大インサートクローンのみについて行った
。8倍のドラフト段階の配列を、105のスキャフォールドを通して連結した756のコンティグへ構築した。さらなる〜10倍のカバー率に対してさらなるピロシーケンスを行い、これらの配列の構築への取り込みはコンティグの数を27に低下させた。これに続く逆および長距離PCR技術を用いるギャップ閉鎖は、コンティグの数を14に減少させた。
M.ルミナンチウム(M.ruminantium)細胞壁の調製:M.ルミナンチウム(M.ruminantium)由来の細胞壁を、細胞ペレットを液体N2下で凍結すること、および予め冷却した滅菌乳鉢および乳棒を用いて粉砕することにより調製した。微細に粉砕した細胞をトリプシンリン酸緩衝液(40mgトリプシン/200mlの0.1Mリン酸緩衝液、pH7.9)に再懸濁し、37℃において2時間インキュベートした。調製品をその後48,000gで、4℃において30分間遠心し、得られたペレットを滅菌蒸留H2Oで2回洗浄して凍結乾燥した。
(ELISA)により決定した。血清は最初に50倍希釈し、次にさらに2倍の連続希釈を行った。ELISA力価は、405nmにおいて0.2のODをもたらす推定希釈因子として算出し、これは連続希釈曲線の非線形回帰分析に由来する。検出はHRP抱合二次抗体およびABTS基質を用いて得た。
88P)を用い、1/5000希釈(2μlを10mlの希釈液へ)の50μlを各ウェルに加えた。次に3,3’,5,5’テトラメチルベンジジン(TMB)基質を加え(50μl/ウェル)、反応物を室温にて暗所で15分間インキュベートした。次に停止液(0.05M H2SO4、50μl/ウェル)を加え、450nmでプレートの読み取りを行った。
メタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)は、様々な食餌条件下でのその反すう胃内における有病率(培養および分子検出データに基づく)、培養物の有効性、実験室での日常的生育の快適性、ならびにこの生物に対する比較的多数の以前の研究および入手可能な背景文献により、ゲノム配列決定のために選択された。M.ルミナンチウム(M.ruminantium)内の著しく多数の遺伝子が機能を割り当てられ、これによってこの生物の反すう胃内での生活様式の詳細な描写が可能になる。M.ルミナンチウム(M.ruminantium)の単純な基質(H2+CO2、ギ酸塩)依存性、ならびにその表面タンパク質および菌体外多糖を通した反すう胃環境との相互作用は抑制の重要な標的である。同様にSPIDRは、M.ルミナンチウム(M.ruminantium)の特異的標的化および遺伝子機能決定補助のための将来の遺伝的操作の両方について期待される。配列データはこの生物の代謝およびそれが他の微生物とどのように相互作用するかを明らかにし、かつ反すう胃内におけるメタン生成を阻止または減少させるために不活性化できる、メタン生成菌の間で保存されたシステム、および構成成分を示している。
Claims (31)
- 以下のa)〜d)のいずれかを含む、単離されたポリペプチド:
a)配列番号641のアミノ酸配列、
b)配列番号641のアミノ酸配列と少なくとも90%の同一性を共有するアミノ酸配列、
c)配列番号641のアミノ酸配列と少なくとも95%の同一性を共有するアミノ酸配列、
d)配列番号641のアミノ酸配列と少なくとも97%の同一性を共有するアミノ酸配列。 - 配列番号641のアミノ酸配列の細胞外ドメインを含む、単離されたポリペプチドまたはペプチド。
- 以下のa)〜d)のいずれかを含む、単離されたポリヌクレオチド:
a)配列番号641のアミノ酸配列をコードする核酸配列、
b)前記a)と相補的な核酸配列、
c)配列番号1312の核酸配列、
d)前記c)と相補的な核酸配列。 - 以下のa)〜d)のいずれかを含む、単離されたポリヌクレオチド:
a)配列番号641のアミノ酸配列と少なくとも90%の同一性を共有するアミノ酸配列をコードする核酸配列、
b)配列番号641のアミノ酸配列と少なくとも95%の同一性を共有するアミノ酸配列をコードする核酸配列、
c)配列番号641のアミノ酸配列と少なくとも97%の同一性を共有するアミノ酸配列をコードする核酸配列、
d)前記a)〜c)のいずれかと相補的な核酸配列。 - 以下のa)〜c)のいずれかを含むベクター:
a)請求項1に記載のポリペプチドをコードするベクター、
b)請求項2に記載のポリペプチドまたはペプチドをコードするベクター、
c)請求項3または4に記載のポリヌクレオチドを含むベクター。 - 以下のa)〜c)のいずれかのホスト細胞:
a)請求項1に記載のポリペプチドをコードする核酸配列を含むように遺伝的に改変されたホスト細胞、
b)請求項2に記載のポリペプチドまたはペプチドをコードする核酸配列を含むように遺伝的に改変されたホスト細胞、
c)請求項3または4に記載のポリヌクレオチドを含むように遺伝的に改変されたホスト細胞、
d)請求項5に記載のベクターを含むホスト細胞。 - 原核生物またはメタン生成菌である、請求項6に記載のホスト細胞。
- 大腸菌(Escherichia coli)、またはメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)のM1T株(DSM1093)を含むメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)である、請求項7に記載のホスト細胞。
- 以下のa)またはb)に結合する、抗体または抗体断片:
a)請求項1に記載のポリペプチド、
b)請求項2に記載のポリペプチドまたはペプチド。 - モノクローナルである、請求項9に記載の抗体または抗体断片。
- 以下のa)〜d)のいずれかを含む、抱合体分子または融合体分子:
a)請求項1に記載のポリペプチド、
b)請求項2に記載のポリペプチドまたはペプチド、
c)請求項3または4に記載のポリヌクレオチド、
d)請求項9または10に記載の抗体または抗体断片。 - 以下のa)〜c)のいずれかを含む抱合体分子または融合体分子であって、抗メタン生成化合物、シグナル配列、溶解酵素、ペプチド核酸、抗菌ペプチド、または抗生剤をさらに含む、抱合体分子または融合体分子:
a)請求項1に記載のポリペプチド、
b)請求項2に記載のポリペプチドまたはペプチド、
c)請求項9または10に記載の抗体または抗体断片。 - 以下のa)またはb)を含む、医薬組成物:
a)請求項9または10に記載の抗体または抗体断片、
b)請求項11または12に記載の抱合体分子または融合体分子。 - 同定、単離、または抑制のためにメタン生成菌細胞を標的化する方法であって、
a)必要に応じて、請求項9または10に記載の抗体または抗体断片を産生または単離すること、および
b)該細胞を該抗体または抗体断片に接触させることを含む方法。 - 同定、単離、または抑制のためにメタン生成菌細胞を標的化する方法であって、
a)必要に応じて、請求項11または12に記載の抱合体分子または融合体分子を産生または単離すること、および
b)該細胞を該抱合体分子または融合体分子に接触させることを含む方法。 - 前記細胞が反すう動物のメタン生成菌細胞である、請求項14または15に記載の方法。
- 前記細胞がメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)である、請求項16に記載の方法。
- 前記細胞がメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)のM1T株(DSM1093)である、請求項17に記載の方法。
- 請求項1に記載のポリペプチドおよびアジュバントを含むワクチン組成物。
- 前記ポリペプチドが抱合体分子または融合体分子である、請求項19に記載のワクチン組成物。
- メタン生成菌に対して動物をワクチン接種するための、請求項19または20に記載のワクチン組成物。
- 前記メタン生成菌がメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)である、請求項21に記載のワクチン組成物。
- 前記動物が反すう動物である、請求項21または22に記載のワクチン組成物。
- 前記反すう動物がウシ、ヒツジ、ヤギ、バッファロー、ヘラジカ、アンテロープ、カリブー、およびシカからなる群より選択される、請求項23に記載のワクチン組成物。
- 前記反すう動物からのメタン生成を減少させるための、請求項23に記載のワクチン組成物。
- 請求項19〜25のいずれか1項に記載のワクチン組成物を含む、反すう動物におけるメタン生成菌の生育またはメタン生成を減少させるためのキット。
- 請求項19〜25のいずれか1項に記載のワクチン組成物を非ヒト動物に投与する工程を含む、メタン生成菌に対して非ヒト動物をワクチン接種するための方法。
- 前記メタン生成菌がメタノブレビバクター・ルミナンチウム(Methanobrevibacter ruminantium)である、請求項27に記載の方法。
- 前記動物が反すう動物である、請求項27または28に記載の方法。
- 前記反すう動物がウシ、ヒツジ、ヤギ、バッファロー、ヘラジカ、アンテロープ、カリブー、およびシカからなる群より選択される、請求項29に記載の方法。
- メタン生成菌に対して反すう動物をワクチン接種する工程を含む、反すう動物からのメタン生成を減少させるための、請求項27に記載の方法。
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