JP2020202828A - タンパク質を産生させるために改善した宿主細胞 - Google Patents
タンパク質を産生させるために改善した宿主細胞 Download PDFInfo
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Abstract
Description
T7発現系が挿入されており、
S、R、および/またはQ遺伝子が不活性化されており、
Intおよび/またはXis遺伝子が不活性化されている
ファージとして定義されている。
本発明では、以下の用語は以下の意味を有する。
本明細書中で使用される場合、「ペプチド」は、ペプチド結合により共に結合されている50個未満のアミノ酸の直鎖状ポリマーを表し、「ポリペプチド」は、ペプチド結合により共に結合されている少なくとも50個の直鎖状のポリマーを表し、タンパク質は、具体的には、1つまたは複数のペプチドまたはポリペプチドおよび任意に非ポリペプチド補因子により形成されている、機能的な実体を表す。
本発明は、組み換えペプチド、ポリペプチド、またはタンパク質を産生する宿主細胞であって、毒性タンパク質をコードする核酸配列の少なくとも2つの複製物を含む宿主細胞に関する。一実施形態では、宿主細胞は、毒性タンパク質をコードする核酸配列の2つの複製物、またはこの核酸配列の3、4、5、もしくは6個の複製物(もしくはそれ以上)を含む。
発現系(好ましくはT7発現系)が挿入されており、
Sおよび/またはR遺伝子が不活性化されている
ファージとしてさらに定義されている。
発現系(好ましくはT7発現系)が挿入されており、
S、R、および/またはQ遺伝子が不活性化されており、
Intおよび/またはXis遺伝子が不活性化されている
ファージとしてさらに定義されている。
毒性タンパク質、好ましくはCcdBをコードする核酸配列の少なくとも2つの複製物と、
毒性タンパク質に対する解毒性タンパク質、好ましくはCcdAをコードする核酸配列の少なくとも1つの複製物と、
対象のペプチド、ポリペプチド、またはタンパク質をコードする核酸配列の少なくとも1つの複製物と
を含む、本発明の宿主細胞を培養することと、
対象のペプチド、ポリペプチド、またはタンパク質を回収することと
を含む、方法に関する。
いずれかのペプチド、ポリペプチド、またはタンパク質、さらには宿主細胞に毒性であるペプチド、ポリペプチド、またはタンパク質に使用することができる。
宿主細胞のゲノムの中のccdB遺伝子を挿入することが当業者にとって容易であるため、任意の宿主細胞に使用することができる。
以下の実施例で示されるように、対象のペプチド、ポリペプチド、またはタンパク質の産生収率が上がる。
以下の実施例で示されるように、特に対象のペプチド、ポリペプチド、またはタンパク質が宿主細胞にとって毒性である場合、対象のペプチド、ポリペプチド、またはタンパク質をコードする核酸配列を含むベクターの安定性を上げることが可能である。
一部の実施形態では、抗生物質を使用することを含まず、宿主細胞およびベクターは、両方とも抗生物質耐性遺伝子を含まない。
本発明を、さらに以下の実施例により例証する。
実施例1:ccdB遺伝子の複製は、産生の収率を上げる
Staby(登録商標)技術(宿主染色体内のccdB遺伝子の1つの複製物の挿入に基づく技術、Delphi Genetics, StabyExpress(登録商標)製品、国際特許第9958652号)によりもたらされる安定性を試験するために、本出願人は、大腸菌においても毒性の特性を有するように見える分泌タンパク質(VHH6と名付けられた可変重鎖抗体フラグメント)を生成した。W3110 E.coli株(遺伝的背景:E.coli K12、遺伝子型:F−λ−INV(rrnD−rrnE)rph−1)を、産生株の宿主として使用し、かつpBR322ベクター(pVHH6;図1)上のpTrcプロモーターを用いて発現を実現した。従来の抗生物質安定化システム(ここではカナマイシン耐性)を使用したW3110株の産生を、Staby(登録商標)技術(ccdB遺伝子が株の染色体の中に導入されている)を使用するよう改変されたW3110ccdB株の産生と比較した。この比較で使用したベクターは両方ともccdA遺伝子を含むものであり、W3110ccdBに使用したベクターを、カナマイシン耐性遺伝子(pVHH6ΔKan)に関して欠失させた。
ccdB遺伝子の2つの複製物を含む株の使用がすべてのタンパク質(ccdBの1つの複製物のみですでに良好に発現したタンパク質を含む)にとって可能であるかどうかを試験するために、本出願人は、70kDaのTraGタンパク質の産生を試験した(Szpirer et al., 2000, Mol. Microbiol. 37(6) 1283−1292)。解毒剤CcdAおよびTraG(pTraG)をコードしたプラスミドを含むW3110(DE3)ccdBおよびW3110(DE3)2ccdB株を構築した(図4)。traG遺伝子は、T7プロモーターの制御下にあった。これらの株およびプラスミドは、プラスミドを安定化させるためにStaby(登録商標)技術を使用する。第1の観察は、ccdAをコードするプラスミドの存在下でccdB遺伝子の2つの複製物の存在がW3110株の生存率および増殖に影響しない:プラスミドのccdA遺伝子の1つの複製物、完全な生存率を得るために十分である、ということであった。
大腸菌株は、K12型およびB型に分けられている。W3110株はK12株であるため、B株に対する2ccdB技術の適用性を試験した。よって、ccdBの2つの複製物を、E.coli B(BL21(DE3)型−遺伝子背景:E.coli B−遺伝子型F−ompT gal dcm lon hsdSB(rB−mB−)λ(DE3[lacI lacUV5−T7 gene1]))のゲノムに導入して、SE3株を得た。次に、灌流した培養を、いくつかの作製を終えた後にTraGタンパク質を生成するため実現させた。24時間の誘導の後のプラスミドの安定性は100%である(図7)。すべてのccdB遺伝子は、これらの発現条件下で無変化である。
上述のように、Staby(登録商標)技術は、大腸菌に関するCcdBタンパク質の毒性に基づくものである。CcdA解毒剤はccdB遺伝子の発現を阻害するため、選択圧は、この毒性遺伝子に対して適用される。よって、CcdBに対する一部の大腸菌耐性株を見出す可能性は低い。しかしながら、この種の耐性は、変異剤の存在下で数回の増殖を使用することにより、人工的に単離されている(Bernard et al., J Mol Biol. 1992, 226:735)。この耐性株は、アルギニン462をシステインに変えるgyrA遺伝子の変異(CcdBの標的)を提示する。
Fプラスミド以外の別の起源由来のccdB遺伝子の複製物が、2ccdBシステムで使用され得るかを検証するために、本出願人は、E.coli O157:H7由来のccdBの複製物を含む株を構築した。E.coli O157:H7由来のccdB遺伝子は、(1)(アミノ酸レベルで)Fプラスミド由来のccdB遺伝子と36%のみの相同性を有するため、および(2)Fプラスミド由来の同一のCcdAタンパク質により阻害されるため、選択された。
次に本出願人は、Q、S、R、およびRz遺伝子が欠失している発現系を含む遺伝的に改変したファージを含む細菌株に対する2ccdBシステムの適用性を試験した。これら遺伝子の欠失は、ファージの偶発的な再活性化が起こる場合の宿主細胞の溶解を防止する。
Claims (15)
- 毒性タンパク質をコードする核酸配列の少なくとも2つの複製物を含む宿主細胞であって、
但し、前記少なくとも2つの複製物は、前記毒性タンパク質に対する解毒性タンパク質をコードする核酸配列とは異なるレプリコンにある、
宿主細胞。 - 前記毒性タンパク質が、配列番号1、または配列番号1と少なくとも75%の同一性を有する任意の核酸配列、によりコードされるCcdBである、請求項1に記載の宿主細胞。
- 前記毒性タンパク質に対する解毒性タンパク質をコードする核酸配列の少なくとも1つの複製物をさらに含む、請求項1または2に記載の宿主細胞。
- 前記解毒性タンパク質が、配列番号13、または配列番号13と少なくとも75%の同一性を有する任意の核酸配列、によりコードされるCcdAである、請求項3に記載の宿主細胞。
- 目的の組み換えペプチド、ポリペプチドもしくはタンパク質をコードする核酸配列、または組み換え核酸、が挿入されているか挿入され得る発現系をさらに含むプラスミドによって、前記解毒性タンパク質をコードする核酸配列が担持されている、請求項3または4に記載の宿主細胞。
- 前記発現系が、T7プロモーター、Ptrc、Para、およびPlacを含む群から選択されるプロモーターを含む、請求項5に記載の宿主細胞。
- 前記発現系がT7プロモーターを含み、前記宿主細胞がT7 RNAポリメラーゼの遺伝子、好ましくは前記宿主細胞のゲノムに挿入されたT7 RNAポリメラーゼの遺伝子、より好ましくはT7発現系におけるT7 RNAポリメラーゼの遺伝子、をさらに含む、請求項5または6に記載の宿主細胞。
- 前記発現系がT7プロモーターを含み、前記宿主細胞が、そのゲノム内に挿入された遺伝的に改変したファージをさらに含み、好ましくは前記ファージが、
T7発現系が挿入されており、
S、R、および/またはQ遺伝子が不活性化されており、
Intおよび/またはXis遺伝子が不活性化されている
ファージとして定義される、
請求項5〜7のいずれか1項に記載の宿主細胞。 - 細菌、好ましくはグラム陰性細菌、より好ましくは腸内細菌科、さらにより好ましくは大腸菌である、請求項1〜8のいずれか1項に記載の宿主細胞。
- 遺伝子tonA、galK、araB、araA、lon、ompT、rcsA、hsdR、mrr、endA、およびrecAのうち少なくとも1つの不活性化をさらに含む、請求項1〜9のいずれか1項に記載の宿主細胞。
- gyrA遺伝子の少なくとも1つの追加的な複製物をさらに含む、請求項1〜10のいずれか1項に記載の宿主細胞。
- 請求項1〜11のいずれか1項に記載の宿主細胞、および
前記解毒性タンパク質をコードする核酸配列の少なくとも1つの複製物と、目的の組み換えペプチド、ポリペプチドもしくはタンパク質をコードする核酸配列、または目的の組み換え核酸、が挿入されているか挿入され得る発現系の少なくとも1つの複製物と、を含むベクター、
を含む、キット。 - 前記目的のペプチド、ポリペプチドもしくはタンパク質をコードする核酸配列が、T7プロモーター、Ptrc、Para、およびPlacを含む群から選択されるプロモーターの制御下にある、請求項12に記載のキット。
- 目的の組み換えペプチド、ポリペプチドもしくはタンパク質または目的の組み換え核酸を産生させる方法であって、請求項1〜11のいずれか1項に記載の宿主細胞を培養することと、前記目的のペプチド、ポリペプチドもしくはタンパク質または目的の組み換え核酸を回収することと、を含む方法。
- 前記組み換えタンパク質が、分泌タンパク質、膜貫通タンパク質、または前記細菌株にとって毒性であるタンパク質である、請求項14に記載の方法。
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