JP5444553B2 - 微生物宿主を迅速にスクリーニングして、異種タンパク質発現の収率および/または質が改善されている特定の株を同定する方法 - Google Patents
微生物宿主を迅速にスクリーニングして、異種タンパク質発現の収率および/または質が改善されている特定の株を同定する方法 Download PDFInfo
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
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- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/74—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
- C12N15/78—Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora for Pseudomonas
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Description
宿主細胞内で適切にプロセシングされた高レベルの異種ポリペプチドを産生するのに最適な宿主株(optimal host strain)、例えば、Pseudomonas fluorescens宿主株を同定するための組成物および方法を提供する。詳細には、ライブラリー内の各株(または「宿主細胞の集団」)が、宿主細胞内の1つまたは複数の標的遺伝子の発現を調節するように遺伝子改変されている宿主株のライブラリー(または「アレイ」)を提供する。「最適な宿主株」は、アレイ内の、表現型が異なる宿主細胞の他の集団と比較した、対象とする発現タンパク質の量、質および/または位置に基づいて同定または選択できる。したがって、最適な宿主株は、対象とするポリペプチドを望ましい仕様に従って産生する株である。望ましい仕様は、産生されるポリペプチドに応じて異なるであろうが、仕様には、タンパク質の質および/または量、そのタンパク質が隔離(sequestered)されるか、または分泌されるか、ならびにタンパク質フォールディングが含まれる。
迅速にスクリーニングして、異種タンパク質の収率および/または質が改善されている(1つまたは複数の)特定の株を同定できる宿主細胞集団のアレイ(すなわち「株アレイ(strain array)」)をここに提供する。本明細書で使用される場合、「株アレイ」という用語は、アドレス特定されているか、アドレス特定可能な複数の位置を指す(例えば、ディープウェルまたはマイクロウェルなどのウェル)。通常、アレイ内のマイクロウェルまたはマイクロウェル群のそれぞれの位置は既知であり、それによって、対象とする異種タンパク質の発現に最適な宿主細胞の同定が可能となっている。
本発明の株アレイは、表現型および遺伝子型が異なる複数の宿主細胞集団を含み、アレイ内の各集団は、宿主細胞内の1つまたは複数の標的遺伝子の発現を調節するように遺伝子改変されている。「標的遺伝子」とは、宿主細胞内の異種タンパク質産生に影響を与える遺伝子を意味する。標的遺伝子は、宿主細胞プロテアーゼまたは内因性もしくは外因性タンパク質フォールディング調節因子、転写因子、翻訳因子、分泌調節因子、または対象とする異種タンパク質の適切な転写、翻訳、プロセシングおよび/または移行に関与する他の任意のタンパク質でもよい。「標的タンパク質」は、標的遺伝子の発現の結果として生じるタンパク質またはポリペプチドを指す。1つまたは複数の標的遺伝子の発現および/または活性は、標的遺伝子またはタンパク質の機能に応じて、増大または低下する。標的遺伝子は、宿主細胞で内因的に生じたものでもよく、またはアレイ内の宿主細胞集団のそれぞれで異種発現された遺伝子でもよい。
宿主細胞での異種タンパク質産生における別の重大な障害は、しばしば細胞が、可溶性または活性のタンパク質を産生するように適切に装備されていないことである。タンパク質の一次構造はアミノ酸配列によって規定(defined)されるが、二次構造はαへリックスまたはβシートの存在によって規定され、三次構造はジスルフィド結合などの隣接するタンパク質ストレッチ間の共有結合によって規定される。異種タンパク質を発現する場合、とりわけ大規模産生では、そのタンパク質それ自体の二次構造および三次構造が極めて重要である。タンパク質構造におけるいかなる有意な(significant)変化も機能的に不活性な分子または生物活性が有意に低下したタンパク質を生じ得る。多くの場合、宿主細胞は、活性な異種タンパク質の適切な産生に必要なタンパク質フォールディング調節因子(protein folding modulators)(PFMs)を発現している。しかし、使用可能かつ経済的に満足できるバイオテクノロジー製品を生産するのに通常必要な高レベルでの発現では、細胞は、しばしば、異種発現されたタンパク質をプロセシングするのに十分な天然の1つまたは複数のタンパク質フォールディング調節因子を産生できない。
異種発現されたタンパク質の好ましくない分解は、特定の発現系の効率的な使用に障害を与える。多量の標的タンパク質を産生するように細胞が改変されている場合、細胞はストレス下に置かれ、しばしば他のタンパク質を誘導または抑制することによって反応する。異種タンパク質産生中に宿主細胞が経験するストレスは、例えば、過剰発現した異種タンパク質の分解を引き起こす特定のタンパク質または補因子の発現を増大し得る。代償性の(compensatory)タンパク質の発現増大は、高レベルの活性かつ完全長の異種タンパク質を発現するという目標にとって反生産的であり得る。他のタンパク質の発現低下または適切な発現の不足は、異種発現されたタンパク質のミスフォールディングおよび凝集を引き起こし得る。ストレス下の細胞はタンパク質発現のプロファイルを変えることが知られているが、異種発現された全てのタンパク質が特定の宿主細胞内で同じタンパク質の発現を調節するわけではない。
別の実施形態では、標的遺伝子が、適切なタンパク質プロセシングおよび/または修飾に関与する遺伝子を含む。一般的な修飾には、ジスルフィド結合形成、グリコシル化、アセチル化、アシル化、リン酸化およびγ−カルボキシ化が含まれ、これらは全て、タンパク質フォールディングおよび生物活性を調節し得る。タンパク質プロセシングに関与する酵素のいくつかのクラスの網羅的ではないリストが表3に示されている。当業者ならば、アレイ用に選択された宿主細胞内で有用であるか、または対象とする異種タンパク質と併用して有用である標的遺伝子を、どのようにして表3に列挙したタンパク質修飾酵素のクラスの中から同定するか認識するであろう。標的遺伝子は、使用される宿主細胞に内因的なものでもよく、または対象とする異種タンパク質が由来する生物に内因的なものもよく、または対象とする異種発現タンパク質の適切なプロセシングを促進することが知られているものでもよい。タンパク質産生に関与するいかなる遺伝子も、対象とする異種タンパク質の望ましい仕様に従ってターゲッティングできることも認識されている。
当技術分野で知られている任意の技法によって、アレイ内の1つまたは複数の宿主細胞集団を改変でき、例えば、ゲノム内の少なくとも1つの標的遺伝子がノックアウトされる技法によって、または少なくとも1つの標的遺伝子の発現が低下するように、遺伝子に変異導入することによって、または少なくとも1つの標的遺伝子の発現が低下するように、標的遺伝子の少なくとも1つのプロモーターを改変することによって、または宿主ゲノム内の標的遺伝子または標的遺伝子の阻害因子を(対象とする異種タンパク質またはポリペプチドと共に)同時発現させることによって改変できる。上記に論じたように、標的遺伝子はアレイ内の宿主細胞集団に内因的なものでもよく、または宿主細胞集団それぞれで異種発現されるものでもよい。
宿主細胞のゲノムは、遺伝的ターゲッティング事象を介して改変することができ、それは、挿入または組換え、例えば相同組換えによるものであり得る。相同組換えは、配列相同性に基づいたDNA組換え過程を指す。相同組換えは、内因性遺伝子内における部位特異的な改変を可能にし、それゆえ、ゲノム内の新規な改変が構築できる(例えば、Radding(1982)、Ann.Rev.Genet.16:405;米国特許第4,888,274号参照)。
一実施形態では、(1つまたは複数の)標的遺伝子をコードする1または複数種のベクターを含めて、異種タンパク質またはペプチドとの標的遺伝子の同時発現を促進することによって、宿主細胞内の1つまたは複数の標的遺伝子を改変できる。別の実施形態では、宿主細胞ゲノムへの外因性プロモーターの付加を含めた、標的遺伝子のプロモーターの亢進によって、宿主細胞を改変する。
本明細書に記載の宿主細胞の細胞増殖条件には、対象とするタンパク質の発現をアレイ内の少なくとも1つの株(または少なくともそれらの細胞の一部)で促進する条件および/または発現された、対象とするタンパク質の発酵を促進する条件が含まれる。本明細書で使用される場合、「発酵」という用語には、文字通りの発酵が用いられる実施形態と、他の、非発酵性の培養モードが用いられる実施形態との両方が含まれる。アレイ内の宿主細胞集団の増殖、維持および/または発酵は、いかなるスケールで行ってもよい。しかし、宿主細胞の複数集団が同時にスクリーニングされる場合には、異なった集団の数ならびに宿主細胞の複数集団を増殖および試験する能力によってスケールが限定されるであろう。一実施形態では、発酵培地が、富栄養培地、最小培地および無機塩培地の中から選択され得る。別の実施形態では、最少培地または無機塩培地のいずれかが選択される。さらに別の実施形態では、最少培地が選択される。さらに別の実施形態では、無機塩培地が選択される。
対象とする異種タンパク質を発現するのに最適な宿主細胞集団を求めて、本明細書に記載の株アレイをスクリーニングすることができる。最適な宿主細胞集団は、発現された、対象とするタンパク質の量、質および/または局在に基づいて同定または選択できる。一実施形態では、最適な宿主細胞集団は、アレイ内の、表現型が異なる宿主細胞の他の集団と比較して、宿主細胞内における、対象とするタンパク質またはポリペプチドの収率増大をもたらすものである。
対象とする異種発現タンパク質またはポリペプチドの活性は、事前に確立されている天然タンパク質またはポリペプチドの標準的な活性と比較できる。代替として、対象のタンパク質またはポリペプチドの活性は、同時または実質的に同時に行われる、天然タンパク質またはポリペプチドを用いた比較アッセイで測定できる。例えば、発現された酵素と基質との間、発現されたホルモンとホルモン受容体との間、および発現された抗体と抗原との間の相互作用など、例えば、対象とするタンパク質またはポリペプチドと標的との間の検出可能な相互作用を測定するのに、in vitroアッセイを用いることができる。そのような検出には、熱量変化の測定、増殖変化、細胞死、細胞忌避(cell repelling)、放射能の変化、溶解性の変化、ゲル電気泳動および/またはゲル濾過法で測定した分子量の変化、リン酸化能、ELISAアッセイなどの抗体特異性アッセイなどが含まれ得る。加えて、in vivoアッセイには、天然タンパク質またはポリペプチドの生理作用と比較して、異種発現されたタンパク質またはポリペプチドの生理作用を検出するアッセイ、例えば、質量増大、電解質バランスの変化、血液凝固時間の変化、血餅融解の変化、および抗原性反応の誘導を検出するアッセイが含まれるが、これらに限定されない。通常、対象とするタンパク質またはポリペプチドの活性特性を、そのような活性がアッセイ可能である限り、天然タンパク質またはポリペプチドとの比較分析を可能にする任意のin vitroまたはin vivoアッセイを用いて決定できる。代替として、本発明のアレイ内の少なくとも1つの株で産生されたタンパク質またはポリペプチドを、そのタンパク質またはポリペプチドと、通常、そのタンパク質またはポリペプチドと相互作用する分子、例えば天然タンパク質が通常相互作用するシグナル経路の基質または構成要素との間の相互作用を刺激または抑制する能力についてアッセイできる。そのようなアッセイは、通常、タンパク質またはポリペプチドが標的分子と相互作用するのを可能にする条件下で、タンパク質を基質分子と混合し、上記タンパク質と標的分子との相互作用の生化学的帰結を検出するステップを含み得る。
対象とするタンパク質の収率、溶解性、立体配座および/または活性を測定するために、アレイ内の1つまたは複数の株からタンパク質を単離することが望ましい可能性がある。適切な測定を行うのに用いたアッセイの必要条件に応じて、単離は、粗単離でも、準粗単離でも、純粋単離でもよい。タンパク質は、細胞質で産生されるものでも、ペリプラズムにターゲッティングされるものでも、または培養もしくは発酵培地中に分泌されるものでもよい。ペリプラズムにターゲッティングされたタンパク質を遊離させるには、クロロホルム(Amesら(1984)、J.Bacteriol.、160:1181〜1183)、グアニジン−HClおよびトリトンX−100(NaglakおよびWang(1990)、Enzyme Microb.Technol.、12:603〜611)などの化学物質を用いた処置が使用されている。しかし、これらの化学物質は不活性ではなく、多くの異種タンパク質産物またはその後の精製方法に対する有害効果を有し得る。E.coliのグリシン処理は、外膜の透過化を引き起こし、ペリプラズム内容物を放出させることも報告されている(Arigaら(1989)、J.Ferm.Bioeng.68:243〜246)。異種タンパク質をペリプラズムから放出させる最も広範に使用されている方法は、浸透圧ショック(NosalおよびHeppel(1966)、J.Biol.Chem.241:3055〜3062;NeuおよびHeppel(1965)、J.Biol.Chem.240:3685〜3692)、雌鳥卵白(HEW)−リゾチーム/エチレンジアミン四酢酸(EDTA)処理(NeuおよびHeppel(1964)、J.Biol.Chem、239:3893〜3900;Witholtら(1976)、Biochim.Biophys.Acta,443:534〜544;Pierceら(1995)、ICheme Research.Event,2:995〜997)、およびHEW−リゾチーム/浸透圧ショック併用処理(Frenchら(1996)、Enzyme and Microb.Tech.19:332〜338)である。French法は、分画緩衝液中の細胞の再懸濁、およびそれに続くペリプラズム画分の回収を行ものであり、その際、浸透圧ショックはリゾチーム処理のすぐ後に行う。
異種発現されたタンパク質が変性形態で産生される場合、二次および三次タンパク質構造を生成するように、不溶性タンパク質を再生またはリフォールディングさせることができる。異種産物の立体配座を完成させるのに、タンパク質リフォールディングステップを、必要に応じて用いることができる。当技術分野で知られている、タンパク質の解離/会合を促進する薬剤を用いて、リフォールディングおよび再生を実現できる。例えば、タンパク質をジチオスレイトールと共にインキュベートし、それに続いて、酸化グルタチオン二ナトリウム塩と共にインキュベートし、それに続いて、尿素などのリフォールディング剤を含有する緩衝液と共にインキュベートすることができる。
対象とする異種タンパク質は、それぞれの菌株に対象とする異種タンパク質をコードする発現ベクターを導入することによって、本明細書に開示する1つまたは複数の宿主細胞において産生することができる。一実施形態では、ベクターは、選択した宿主細胞において働くことができるプロモーター、ならびに全ての他の必要とされる転写および翻訳調節エレメントと作用可能に連結した対象とするタンパク質をコードするポリヌクレオチド配列を含む。
対象とするタンパク質またはポリペプチドを、アレイ内の1つまたは複数の宿主細胞集団のペリプラズム、または細胞外空間に標的化することは望ましい可能性がある。一実施形態では、発現ベクターは、対象とするタンパク質またはポリペプチドをコードするヌクレオチド配列と作用可能に連結した、分泌シグナル配列ポリペプチドをコードするヌクレオチド配列をさらに含む。いくつかの実施形態では、シグナル配列と対象とするタンパク質またはポリペプチドの間に修飾を施さない。しかしながら、特定の実施形態では、追加の切断シグナルを取り込んでポリペプチドのアミノ末端の正確なプロセシングを促進する。
本発明の方法および組成物は、高レベルの適切にプロセシングされた対象とするタンパク質またはポリペプチドを産生するのに最適であるP.fluorescens菌株を同定するのに有用である。任意の種および任意の大きさの対象とするタンパク質またはポリペプチドの産生をスクリーニングするのに、アレイは有用である。しかしながら、特定の実施形態では、対象とするタンパク質またはポリペプチドは、治療上有用なタンパク質またはポリペプチドである。いくつかの実施形態では、タンパク質は哺乳動物タンパク質、例えばヒトタンパク質であってよく、かつ例えば成長因子、サイトイン、ケモカインまたは血中タンパク質であってよい。対象とするタンパク質またはポリペプチドは、天然タンパク質またはポリペプチドと同様の方法でプロセシングすることができる。特定の実施形態では、対象とするタンパク質またはポリペプチドは、100kD未満、50kD未満、または30kD未満の大きさである。特定の実施形態では、対象とするタンパク質またはポリペプチドは、少なくとも約5、10、15、20、30、40、50または100またはそれより多くのアミノ酸のポリペプチドである。
一実施形態では本発明は、そこから対象とする異種タンパク質またはペプチドを場合によっては産生するための、P.fluorescens宿主細胞のアレイを提供する。P.fluorescensは様々なタンパク質を産生するための改良された基盤であることが実証されており、いくつかの有効な分泌シグナルがこの生物から同定されている(その全容が参照によって本明細書に組み込まれる、米国出願公開第2006/0008877号を参照)。
本発明は、対象とする異種タンパク質またはポリペプチドの産生に最適な宿主菌株、例えばP.fluorescens宿主菌株を同定するのに有用なキットも提供する。キットは複数の表現型が異なる宿主細胞を含み、各集団は、タンパク質産生に関与する1つもしくは複数の標的遺伝子の発現が増大するように、タンパク質分解に関与する1つもしくは複数の標的遺伝子の発現が低下するように、またはそれらの両方となるように遺伝子改変されている。アレイは、タンパク質産生に関与する遺伝子またはタンパク質分解に関与する遺伝子のいずれかの発現を調節するように遺伝子改変されていない1つまたは複数の細胞集団をさらに含むことができる。これらのキットは、細胞集団の増殖および維持を容易にするのに十分な試薬、ならびに対象とする異種タンパク質またはポリペプチドの発現用の試薬および/またはコンストラクトも含むことができる。宿主細胞の集団は、細胞集団の保存、輸送、および再構築に適した任意の方法でキットにおいて提供することができる。細胞集団はチューブ中、プレート上、またはスラント上に生きた状態で提供することができ、あるいはチューブまたはバイアル中に凍結乾燥または乾燥のいずれかの状態で保存することができる。細胞集団は、グリセロール、スクロース、アルブミン、または他の適切な保護剤もしくは保存剤などの追加の構成要素を保存培地中に含有することができる。
概説(Overview)
異種タンパク質産生はしばしば、不溶性タンパク質または不適切にフォールディングされたタンパク質の形成をもたらし、それらは、回収が困難であり、かつ不活性であり得る。さらに、特定の宿主細胞プロテアーゼの存在によって、対象とするタンパク質が分解され、それによって最終収率が低下し得る。全ての異種タンパク質の産生を改善する単一の因子は存在しない。したがって、考えられる候補の集合由来の特定の異種タンパク質に特異的な因子を同定するための方法を探究した。
フォールディング調節因子は、新生および異種ポリペプチドのフォールディング、アンフォールディングおよび分解を助長する、全ての細胞中に存在するクラスのタンパク質である。フォールディング調節因子には、シャペロン、シャペロニン、ペプチジル−プロリルシス−トランスイソメラーゼ、およびタンパク質ジスルフィド結合形成に関与するタンパク質がある。異種タンパク質のフォールディングに助力する能力を有する新規な産生菌株を構築するための第一ステップとして、P.fluorescensのゲノムを調べて、宿主細胞のフォールディング調節因子遺伝子を同定した。
プロテアーゼは、ペプチド結合を加水分解し全ての生物の生存に必要な酵素である。しかしながら、細胞中でのそれらの役割は、Pfenex Expression Technology(商標)も含めた任意の異種タンパク質発現系中で、プロテアーゼは組換えタンパク質の収率および/または質に弊害をもたらす可能性があることを意味する。ゲノムから除去されたプロテアーゼ遺伝子を有する新規な産生菌株を構築するための第一ステップとして、P.fluorescensのゲノムを調べて、宿主細胞のプロテアーゼ遺伝子を同定した。
Pfenex Expression Technology(商標)の長所の1つは、特定の異種タンパク質を分離することができる細胞内区画(cellular compartment)を制御するその能力である。したがって、同定した宿主細胞のフォールディング調節因子およびプロテアーゼタンパク質が位置する細胞内区画を予想した。これらの予想を行うために、2つのプログラムを選択した。PsortB2.0は、所与のペプチドの細胞内位置を予想する12の別個のアルゴリズムの結果を組み合わせる。大部分のこれらのアルゴリズムは、クエリータンパク質と既知の細胞内位置のタンパク質の間の相同性の検出に依存する。PsortBは、Hidden Markov Models(HMM)を使用して膜貫通フォールディングドメインまたはI型分泌シグナル配列の存在をそれぞれ検出する、HMMTOPおよびSignalPなどのアルゴリズムも含む。PsortBの結果に加えて、SignalP HMMを使用して、I型分泌シグナル配列の存在を予想した。シグナル配列を検出するが細胞内位置を示す他の具体的情報が得られないとき、PsortBのアウトプットは曖昧である可能性があるので、これは必要であった。これらの場合、PsortBはタンパク質の細胞内局在が知られていないことを示す、何故ならそれは実際、細胞質膜、ペリプラズム、外膜または細胞外区画のいずれか1つに分離する可能性があったからである。しかしながら、タンパク質はおそらく細胞質中に位置しないことを知り、表中においてそれに注目することは十分有益である。したがって表2は、その結果が知られていない場合以外のPsortBアルゴリズムの結果を挙げる。これらの場合、SignalP HMM単独の結果は、シグナルペプチドが検出されたことを示す「シグナルペプチド(Signal Peptide)」、およびシグナルペプチドが検出されなかったことを示す「非分泌性(Non Secretory)」を用いて示す。
フォールディング調節因子遺伝子を、対象とする異種タンパク質を発現させるために通常使用される別のプラスミドと適合性がある、pCNのプラスミド誘導体(Nietoら、1990年)にクローニングした(Squiresら、2004年;Chewら、2005年)。マンニトール誘導性grpE−dnaKJ含有プラスミドの構築を例示する。他のフォールディング調節因子を、1つの遺伝子または多数の遺伝子としてオペロンで編成されるとき、以下に概説したのと同様にクローニングした。
ゲノム欠失の生成を可能にしたプラスミドは、欠失する遺伝子の5’と3’の両方の500〜1000bpのDNA断片の増幅によって構築した。生成する5’PCR産物は典型的には欠失する遺伝子の翻訳開始コドン(ATGまたはGTGまたはTGT)で終わり、一方3’PCR産物は典型的には欠失する遺伝子の停止コドン(TAAまたはTGAまたはTAG)で始まる。これら2つのPCR産物は追加の増幅ステップによって1つに融合し、次いでSOE PCR(Hortonら、1990年)を使用してpDOW1261(図1)(Chewら、2005年)にクローニングした。
プラスミドpDOW2787はモノクローナル抗体(mAb)gal2をコードし、その重鎖はPbp分泌リーダーおよびtacプロモーターの制御下で発現する。その軽鎖はOprF分泌リーダーおよびマンニトールプロモーターの制御下で発現する。プラスミドは、対象遺伝子の欠失または同時発現用のフォールディング調節因子を有するpDOW2247のいずれかを有する63菌株、および野生型菌株を含有する5つの対照菌株のコンピテント細胞にエレクトロポレーションした。300rpmで振とうすることによって、グリセロールを含む増殖培地を含有する同一の深さのウェル単位で、細胞を培養した。0.1mMのイソプロピルβ−D−チオガラクトピラノシド(IPTG)および1%マンニトールを用いて、24時間でタンパク質発現を誘導した。誘導後24時間で、アリコートを溶かし、抗原の抗原結合を測定して活性抗体の量を定量化した。その値をOD600で割って細胞特異的活性を測定した。菌株Δprc1、ΔdegP2、ΔLa2、ΔclpP、およびΔprc2、Δprc2、grpEdnaKJ同時発現菌株、Δtig、ΔclpX、およびΔlonはいずれも対照菌株より2.4倍以上高く、これは統計上有意であった(p<0.5)。可溶性細胞分画をΔprc1、ΔdegP2、ΔLa2およびgrpEdnaKJ同時発現菌株から調製し、ウエスタン分析にかけた(図2)。完全構築抗体と一致した大きさを有するバンドを4つの試験菌株において検出したが、対照においては検出しなかった。
(参考文献)
本発明は以下の態様を含み得る。
[1] Pseudomonas fluorescens(P.fluorescens)細胞の少なくとも第1および第2の集団を含むアレイであって、各集団が、
a)タンパク質分解に関与する少なくとも1つの標的遺伝子の発現が低減するように遺伝子改変されている少なくとも1つのP.fluorescens細胞集団、
b)タンパク質産生に関与する少なくとも1つの標的遺伝子の発現が増大するように遺伝子改変されている少なくとも1つのP.fluorescens細胞集団、ならびに
c)(a)および(b)に従って遺伝子改変されている少なくとも1つのP.fluorescens細胞集団
からなる群から選択され、アレイ内の各集団が同一でなく、各集団が物理的に相互に離れているアレイ。
[2] 前記タンパク質分解に関与する少なくとも1つの標的遺伝子がプロテアーゼである、上記[1]に記載のアレイ。
[3] 前記少なくとも1つのプロテアーゼが表2に記載のプロテアーゼから選択される、上記[2]に記載のアレイ。
[4] 前記タンパク質産生に関与する少なくとも1つの標的遺伝子が異種タンパク質の適切なタンパク質転写、翻訳、プロセシングまたは移行に関与する遺伝子である、上記[1]に記載のアレイ。
[5] 前記少なくとも1つの標的遺伝子がタンパク質フォールディング調節因子である、上記[4]に記載のアレイ。
[6] 前記タンパク質フォールディング調節因子が表1に記載のタンパク質フォールディング調節因子から選択される、上記[5]に記載のアレイ。
[7] 前記タンパク質産生に関与する標的遺伝子または前記タンパク質分解に関与する標的遺伝子の発現が増大するように遺伝子改変されていない少なくとも1つのP.fluorescens細胞集団をさらに含む、上記[1]から[6]のいずれか一項に記載のアレイ。
[8] 少なくとも1つの集団が、タンパク質産生に関与する2つ以上の標的遺伝子の発現が増大するように遺伝子改変されている、上記[1]から[7]のいずれか一項に記載のアレイ。
[9] 少なくとも1つの集団が、タンパク質分解に関与する2つ以上の標的遺伝子の発現が低減するように遺伝子改変されている、上記[1]から[7]のいずれか一項に記載のアレイ。
[10] 前記アレイが、前記アレイのハイスループットスクリーニングに役立つフォーマットである、上記[1]から[9]のいずれか一項に記載のアレイ。
[11] 前記フォーマットが96ウェルフォーマットである、上記[10]に記載のアレイ。
[12] 対象とする少なくとも1つの異種タンパク質をコードする少なくとも1つの遺伝子を含む発現コンストラクトで形質転換された場合、少なくとも1つの集団が、前記対象とする少なくとも1つの異種タンパク質を発現できる、上記[1]から[11]のいずれか一項に記載のアレイ。
[13] 上記[1]から[12]のいずれか一項に記載のアレイを含むキット。
[14] 対象とする少なくとも1つの異種タンパク質を発現するのに最適なPseudomonas fluorescens(P.fluorescens)宿主細胞を同定する方法であって、
a)P.fluorescens細胞の少なくとも第1および第2の集団を含むアレイであって、各集団が、
i)タンパク質分解に関与する少なくとも1つの標的遺伝子の発現が低減するように遺伝子改変されている少なくとも1つのP.fluorescens細胞集団、
ii)タンパク質産生に関与する少なくとも1つの標的遺伝子の発現が増大するように遺伝子改変されている少なくとも1つのP.fluorescens細胞集団、ならびに
iii)(i)および(ii)に従って遺伝子改変されている少なくとも1つのP.fluorescens細胞集団
からなる群から選択され、アレイ内の各集団が同一でなく、各集団が物理的に相互に離れているアレイを得るステップと、
b)対象とする少なくとも1つの異種タンパク質をコードする少なくとも1つの遺伝子を含む発現カセットを、各集団の少なくとも1つの細胞に導入するステップと、
c)少なくとも1つの細胞集団における前記対象とするタンパク質の発現に十分な条件下で前記細胞を維持するステップと、
d)前記対象とする異種タンパク質がその中で産生される最適な細胞集団を選択するステップと
を含み、前記対象とする異種タンパク質が、前記最適な細胞集団で、アレイにおける他の集団と比較して改善された発現、改善された活性、改善された溶解性、改善された移行、または低減したタンパク分解のうち1つまたは複数を示す方法。
[15] 前記タンパク質分解に関与する少なくとも1つの標的遺伝子がプロテアーゼである、上記[14]に記載の方法。
[16] 前記プロテアーゼが表2に記載のプロテアーゼから選択される、上記[15]に記載の方法。
[17] 前記タンパク質産生に関与する少なくとも1つの標的遺伝子が、異種タンパク質の適切なタンパク質転写、翻訳、プロセシングまたは移行に関与する遺伝子である、上記[14]に記載の方法。
[18] 前記少なくとも1つの標的遺伝子がタンパク質フォールディング調節因子である、上記[17]に記載の方法。
[19] 前記タンパク質フォールディング調節因子が表1に記載のタンパク質フォールディング調節因子から選択される、上記[18]に記載の方法。
[20] アレイが、前記タンパク質産生に関与する標的遺伝子または前記タンパク質分解に関与する標的遺伝子の発現が増大するように遺伝子改変されていない少なくとも1つのP.fluorescens細胞集団をさらに含む、上記[14]から[19]のいずれか一項に記載の方法。
[21] 少なくとも1つの集団が、タンパク質産生に関与する2つ以上の標的遺伝子の発現が増大するように遺伝子改変されている、上記[14]から[20]のいずれか一項に記載の方法。
[22] 少なくとも1つの集団が、タンパク質分解に関与する2つ以上の標的遺伝子の発現が低下するように遺伝子改変されている、上記[14]から[20]のいずれか一項に記載の方法。
[23] 前記アレイが、前記アレイのハイスループットスクリーニングに役立つフォーマットである、上記[14]から[22]のいずれか一項に記載の方法。
[24] 前記フォーマットが96ウェルフォーマットである、上記[23]に記載の方法。
[25] 前記発現カセットが、前記対象とする異種タンパク質に作動可能に連結したシグナリングペプチドをさらに含む、上記[14]に記載の方法。
[26] 前記シグナリングペプチドが分泌シグナルペプチドである、上記[19]に記載の方法。
[27] 前記シグナリングペプチドがPseudomonas fluorescens宿主細胞に由来する、上記[19]に記載の方法。
[28] 対象とする異種タンパク質の発現に最適なPseudomonas fluorescens(P.fluorescens)宿主細胞を同定する方法であって、
a)P.fluorescens細胞の少なくとも第1および第2の集団を含むアレイであって、各集団が、タンパク質分解に関与する少なくとも1つのタンパク質の発現が低減するように遺伝子改変されており、アレイ内の各集団が同一でなく、各集団が物理的に相互に離れているアレイを得るステップと、
b)細胞を溶解するステップと、
c)各集団の細胞の溶解物を、対象とする異種タンパク質と接触させるステップと、
d)最適な細胞集団を選択するステップと
を含み、前記最適な細胞集団が、アレイにおける他の集団と比較して、ステップ(c)において対象とする異種タンパク質の分解レベルが低下した集団である方法。
Claims (6)
- 対象とする少なくとも1つの異種タンパク質を発現するのに最適なPseudomonas fluorescens(P.fluorescens)宿主細胞集団を同定する方法であって、
a)4以上のP.fluorescens宿主細胞集団を同じアレイに提供するステップであって、前記P.fluorescens宿主細胞集団が物理的に相互に離れており、P.fluorescens宿主細胞の各集団が、
i)プロテアーゼをコードする少なくとも1つの標的遺伝子の発現が低減するように遺伝子改変されている少なくとも1つのP.fluorescens宿主細胞集団、
ii)タンパク質のプロセシング、フォールディングまたは移行を調節するタンパク質をコードする少なくとも1つの標的遺伝子の発現が増大するように遺伝子改変されている少なくとも1つのP.fluorescens宿主細胞集団、ならびに
iii)プロテアーゼをコードする少なくとも1つの標的遺伝子の発現が低減するように、かつ、タンパク質プロセシング、フォールディングまたは移行を調節するタンパク質をコードする少なくとも1つの標的遺伝子の発現が増大するように遺伝子改変されている少なくとも1つのP.fluorescens宿主細胞集団
からなる群から選択されるステップ(P.fluorescens宿主細胞の各選択された集団は同一でない)と、
b)対象とする少なくとも1つの異種タンパク質をコードする少なくとも1つの遺伝子を含む発現カセットを、前記アレイのP.fluorescens宿主細胞の各集団に導入するステップと、
c)前記対象とする少なくとも1つの異種タンパク質の発現に十分な条件下で前記アレイの前記P.fluorescens宿主細胞集団を維持するステップであって、前記細胞集団はステップ(b)で前記発現カセットを導入されたものであるステップと、
d)前記対象とする少なくとも1つの異種タンパク質を発現するための前記アレイの最適なP.fluorescens宿主細胞を選択するステップと
を含み、前記最適なP.fluorescens宿主細胞集団で発現された前記対象とする異種タンパク質が、前記アレイにおける他のP.fluorescens宿主細胞集団で発現されたものと比較して改善された発現、改善された活性、改善された溶解性、改善された移行、または低減したタンパク分解のうち1つまたは複数を示す方法。 - 前記発現カセットが、前記対象とする異種タンパク質に作動可能に連結したシグナリングペプチドをさらに含む、請求項1に記載の方法。
- 前記シグナリングペプチドが分泌シグナルペプチドである、請求項2に記載の方法。
- 前記発現カセットが、前記発現カセットが導入されるP.fluorescens宿主細胞集団に由来するシグナリングペプチドを含む、請求項2または3に記載の方法。
- 前記アレイが、前記アレイのハイスループットスクリーニングを可能にするフォーマットである、請求項1から4のいずれか一項に記載の方法。
- 前記フォーマットが96ウェルフォーマットである、請求項5に記載の方法。
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US20090062143A1 (en) | 2007-08-03 | 2009-03-05 | Dow Global Technologies Inc. | Translation initiation region sequences for optimal expression of heterologous proteins |
AU2008333985B2 (en) * | 2007-11-30 | 2015-02-05 | Kalobios Pharmaceuticals, Inc. | Antibodies to the PcrV antigen of pseudomonas aeruginosa |
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AU2008245696A1 (en) | 2008-11-06 |
EP2142651A2 (en) | 2010-01-13 |
CN101688213A (zh) | 2010-03-31 |
WO2008134461A2 (en) | 2008-11-06 |
WO2008134461A3 (en) | 2008-12-24 |
KR20100023824A (ko) | 2010-03-04 |
CA2964910C (en) | 2018-01-09 |
EP2142651B1 (en) | 2013-05-22 |
CA2964910A1 (en) | 2008-11-06 |
BRPI0810120A2 (pt) | 2014-11-11 |
US9394571B2 (en) | 2016-07-19 |
KR101530395B1 (ko) | 2015-06-19 |
JP2010524506A (ja) | 2010-07-22 |
AU2008245696B2 (en) | 2013-11-07 |
MX2009011523A (es) | 2009-11-09 |
CA2685326A1 (en) | 2008-11-06 |
EP2615172A1 (en) | 2013-07-17 |
US20080269070A1 (en) | 2008-10-30 |
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