JP2016514957A - 宿主細胞および使用方法 - Google Patents
宿主細胞および使用方法 Download PDFInfo
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- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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Abstract
Description
本発明の一態様では、キラーエクスプレッションプロテアーゼ(Kex2p)または少なくとも1つのKex2pの機能活性を有するその断片および/もしくは変異体をコードする少なくとも1つの単離されたポリヌクレオチドと、タンパク質ジスルフィドイソメラーゼ(Pdi1)または少なくとも1つのPdiの機能活性を有するその断片および/もしくは変異体をコードする少なくとも1つの単離されたポリヌクレオチドとを含んでなる、遺伝子改変宿主細胞が提供される。また、本明細書では、キラーエクスプレッションプロテアーゼ(Kex2p)または少なくとも1つのKex2pの機能活性を有するその断片および/もしくは変異体をコードすると、少なくとも1つの単離されたポリヌクレオチドと、タンパク質ジスルフィドイソメラーゼ(Pdi1)または少なくとも1つのPdi1の機能活性を有するその断片および/もしくは変異体をコードする少なくとも1つの単離されたポリヌクレオチドと、小胞体オキシドレダクチン(Ero1)または少なくとも1つのEro1の機能活性を有するその断片および/もしくは変異体をコードする少なくとも1つの単離されたポリヌクレオチドを含んでなる遺伝子改変宿主細胞も提供される。
「宿主細胞」は、本明細書で使用する場合、単離したポリヌクレオチド配列により導入された(例えば、形質転換、感染、もしくはトランスフェクトされた)、または導入(例えば、形質転換、感染、もしくはトランスフェクション)可能な細胞を意味する。本発明の宿主細胞としては、限定されるものではないが、細菌細胞、真菌細胞、酵母細胞、微生物細胞、昆虫細胞、および哺乳動物細胞を含み得る。酵母および/または糸状真菌起源の本発明の宿主細胞としては、限定されるものではないが、以下の科、属、および種を含み得る:ピキア・パストリス(Pichia pastoris)、ピキア・フィンランディカ(Pichia finlandica)、ピキア・トレハロフィア(Pichia trehalophila)、ピキア・コクラメ(Pichia koclamae)、ピキア・メンブラナエファシエンス(Pichia membranaefaciens)、ピキア・メタノリカ(Pichia methanolica)、ピキア・ミヌタ(Pichia minuta)(オガタ・エミヌタ(Ogataea minuta)、ピキア・リンドネリ(Pichia lindneri))、ピキア・オプティアエ(Pichia opuntiae)、ピキア・サーモトレランス(Pichia thermotolerans)、ピキア・サリクタリア(Pichia alictaria)、ピキア・ゲルカム(Pichia guercum)、ピキア・ピジュペリ(Pichia pijperi)、ピキア・スティプティス(Pichia stiptis)、ピキア属種(Pichia sp.)、サッカロミセス・カステリ(Saccharomyces castelii)、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)、サッカロミセス・クルイベリ(Saccharomyces kluyveri)、サッカロミセス属種(Saccharomyces sp.)、シゾサッカロミセス・ポンベ(Schizosaccharomyces pombe)、シゾサッカロミセス・ジャポニカス(Schizosaccharomyces japonicus)、シゾサッカロミセス・オクトスポラス(Schizosaccharomyces octosporus)、シゾサッカロミセス・クリオフィルス(Schizosaccharomyces cryophilus)、シゾサッカロミセス属種(Schizosaccharomyces sp.)、ハンセヌラ・ポリモルファ(Hansenula polymorpha)、クリベロマイセス属種(Kluyveromyces sp.)、クリベロマイセス・ラクティス(Kluyveromyces lactis)、カンジダ・アルビカンス(Candida albicans)、カンジダ属種(Candida sp.)、アスペルギルス・フミガツス(Aspergillus fumigatus)、アスペルギルス・ニデュランス(Aspergillus nidulans)、アスペルギルス・ニガー(Aspergillus niger)、アスペルギルス・オリゼ(Aspergillus oryzae)、トリコデルマ・リーセイ(Trichoderma reesei)、クリソスポリウム・ラクノウェンス(Chrysosporium lucknowense)、フザリウム属種(Fusarium sp.)、フザリウム・グラミネアラム(Fusariumu gramineum)、フザリウム・ベネナタム(Fusariumu venenatum)、フィスコミトレラ・パテンス(Physcomitrella patens)、ヤルロウィア・リポリチカ(Yarrowia lipolytica)、アークスラ・アデニニボランス(Arxula adeninivorans)、シュワンニオミセス・オシデンタリス(Schwanniomyces occidentalis)、およびアカパンカビ(Neurospora crassa)が挙げられる。
アルゴリズム:Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970)
比較マトリックス:BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA. 89:10915-10919 (1992)
ギャップペナルティー:12
ギャップ長ペナルティー:4
これらのパラメーターを用いる有用なプログラムは、「ギャップ」プログラムとしてGenetics Computer Group, Madison WIから公開されている。上述のパラメーターは、ペプチド比較(終端ギャップについてはペナルティーなし)のためのデフォルトパラメーターである。
アルゴリズム:Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970)
比較マトリックス:一致=+10、不一致=0
ギャップペナルティー:50
ギャップ長ペナルティー:3
入手先:Genetics Computer Group, Madison WI.からの「ギャップ」プログラム。これらは、核酸比較のためのデフォルトパラメーターである。
nn≦xn−(xn・y)
(式中、nnはヌクレオチド変異の数であり、xnは配列番号3のヌクレオチドの総数であり、yは95%では0.95、97%では0.97または100%では1.00であり、・は乗算演算子を表す記号であり、xnとyの非整数の積は最も近い整数に切り捨てた後に、それをxnから差し引く。ポリペプチドをコードするポリヌクレオチド配列の変異は、そのコード配列にナンセンス、ミスセンスまたはフレームシフト突然変異を作り出し、それにより、このような変異の後にポリヌクレオチドによりコードされるポリペプチドを変化させる)
により求められる。
割ったものを掛け、次に、その結果を前記アミノ酸総数から差し引くこと、すなわち、
na≦xa−(xa・y)
(式中、naはアミノ酸変異の数であり、xaは配列中のアミノ酸の総数であり、yは95%では0.95、97%では0.97または100%では1.00であり、・は乗算演算子を表す記号であり、xaとyの非整数の積は最も近い整数へ切り捨てた後、それをxaから差し引く)
により求められる。
KEX2、PDI1およびERO1を過剰発現するS.セレビシエ(S. ceresiviae)株を、ノッティンガム、UKのDelta Biotechnology Ltd.(Delta)社で開発された酵母宿主発現系(S.セレビシエBXP10)を用いて構築した。BXP10は、ATCCから入手したs288c由来S.セレビシエAH22株に起源するものであった。BXP10の構築は、組換えヒト血清アルブミン(rHSA)分泌能を高め、かつ、望まない翻訳後修飾を低減するための、一連のランダム突然変異誘発と標的化された特異的遺伝子破壊を含んだ。
Claims (40)
- キラーエクスプレッションプロテアーゼ(Kex2p)またはその断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列と、タンパク質ジスルフィドイソメラーゼ(Pdi1)またはその断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列とを含んでなる宿主細胞。
- 小胞体オキシドレダクチン(Ero1)またはその断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列をさらに含んでなる、請求項1に記載の宿主細胞。
- 前記宿主細胞が培養系で増殖される際に、前記宿主細胞がKex2p、Pdi1およびEro1から選択されるタンパク質またはその断片および/もしくは変異体をコードする前記少なくとも1つの異種核酸配列の少なくとも1つの遺伝子産物を発現または過剰発現する、請求項1または2に記載の宿主細胞。
- 前記宿主細胞が真菌細胞である、請求項1〜3のいずれか一項に記載の宿主細胞。
- 前記真菌細胞が酵母細胞である、請求項4に記載の宿主細胞。
- 前記酵母細胞の属がサッカロミセス、クルイベロミセス、カンジダ、ピキア、シゾサッカロミセス、ハンセヌラ、クロエケラ、シュワンニオミセス、およびヤロウイアからなる群から選択される、請求項5に記載の宿主細胞。
- 前記宿主細胞がS.セレビシエである、請求項1〜6のいずれか一項に記載の宿主細胞。
- 前記宿主細胞が哺乳動物細胞である、請求項1〜3のいずれか一項に記載の宿主細胞。
- Kex2pまたはその断片および/もしくは変異体をコードする前記少なくとも1つの異種核酸配列が、TEF1、PRB1 ADH1、ADH2、PYK1、PGK1、ENO、GAL1.10.7、GALS、MET25、CUP1、PHO5、tetO−CYC1、CaMV、HXT6、HXT7およびAREの群から選択される少なくとも1つのプロモーターに作動可能に連結されている、請求項1〜8のいずれか一項に記載の宿主細胞。
- Pdi1をコードする前記少なくとも1つの異種核酸配列が、TEF1、PRB1 ADH1、ADH2、PYK1、PGK1、ENO、GAL1.10.7、GALS、MET25、CUP1、PHO5、tetO−CYC1、CaMV、HXT6、HXT7およびAREの群から選択される少なくとも1つのプロモーターに作動可能に連結されている、請求項1〜8のいずれか一項に記載の宿主細胞。
- Ero1をコードする前記少なくとも1つの異種核酸配列が、TEF1、PRB1 ADH1、ADH2、PYK1、PGK1、ENO、GAL1.10.7、GALS、MET25、CUP1、PHO5、tetO−CYC1、CaMV、HXT6、HXT7およびAREの群から選択される少なくとも1つのプロモーターに作動可能に連結されている、請求項2〜8のいずれか一項に記載の宿主細胞。
- 前記宿主細胞が下記遺伝子改変:pep4プロテアーゼノックアウト、野生型宿主細胞に比べて低いubc4および/またはubc5活性、yps1ノックアウト、hsp150ノックアウト、ならびにpmt1ノックアウトのうち少なくとも1つをさらに含んでなる、請求項1〜11のいずれか一項に記載の宿主細胞。
- 組換えポリペプチドをコードする少なくとも1つの核酸を含んでなる、請求項1〜12のいずれか一項に記載の宿主細胞。
- 組換えポリペプチドをコードする前記少なくとも1つの核酸がプラスミド中に含まれている、請求項13に記載の宿主細胞。
- 組換えポリペプチドをコードする前記少なくとも1つの核酸が前記宿主細胞のゲノムに組み込まれている、請求項13に記載の宿主細胞。
- 前記組換えポリペプチドが少なくとも1つのジスルフィド結合を有する、請求項13〜15のいずれか一項に記載の宿主細胞。
- 前記組換えポリペプチドがアルブミン融合タンパク質である、請求項13〜16のいずれか一項に記載の宿主細胞。
- 前記組換えポリペプチドが、アルブミンに遺伝子学的に融合された、GLP−1活性を有する少なくとも1つの治療用ポリペプチドを含んでなる、請求項13〜17のいずれか一項に記載の宿主細胞。
- 前記組換えポリペプチドが、配列番号1に示されるアミノ酸配列と少なくとも95%の配列同一性を有するポリペプチドを有する、請求項13〜18のいずれか一項に記載の宿主細胞。
- 前記組換えポリペプチドが、配列番号1に示されるアミノ酸配列を含んでなる、請求項13〜19のいずれか一項に記載の宿主細胞。
- 前記組換えポリペプチドがリーダー配列を含んでなる、請求項13〜20のいずれか一項に記載の宿主細胞。
- 前記リーダー配列がKEX2リーダー配列または改変KEX2リーダー配列である、請求項21に記載の宿主細胞。
- 前記組換えタンパク質が配列番号10に示されるような改変リーダー配列を含んでなる、請求項13〜22のいずれか一項に記載の宿主細胞。
- 請求項13〜23のいずれか一項に記載の宿主細胞を培養することを含んでなる、組換えポリペプチドを生産する方法。
- 培養培地から前記組換えポリペプチドを回収することをさらに含んでなる、請求項24に記載の方法。
- 請求項24または25に記載の方法により作製された組換えポリペプチド。
- 前記組換えポリペプチドが配列番号1と99%の配列同一性を有するアミノ酸配列を含んでなる、請求項26に記載の組換えポリペプチド。
- 前記組換えポリペプチドが配列番号1のアミノ酸配列からなる、請求項27に記載の組換えポリペプチド。
- 請求項27または28に記載の組換えポリペプチドを含んでなる、医薬組成物。
- 治療上有効な量の請求項29に記載の医薬組成物を投与することを含んでなる、それを必要とする患者を治療する方法。
- 前記患者がI型糖尿病、II型糖尿病、グルコース不耐性、高血糖症、アルツハイマー病、肥満、心血管障害、うっ血性心不全、および網膜症から選択される疾患または病態を有する、請求項30に記載の方法。
- キラーエクスプレッションプロテアーゼ(Kex2p)またはその機能的断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列と、タンパク質ジスルフィドイソメラーゼ(Pdi1)またはその機能的断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列と、小胞体オキシドレダクチン(Ero1)またはその機能的断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列とを含んでなる、宿主細胞。
- 前記Kex2pまたはその機能的断片および/もしくは変異体が配列番号3の機能的遺伝子産物である、請求項32に記載の宿主細胞。
- 前記Pdi1またはその機能的断片および/もしくは変異体が配列番号5の機能的遺伝子産物である、請求項32に記載の宿主細胞。
- 前記Ero1または機能的断片および/もしくは変異体が配列番号7の機能的遺伝子産物である、請求項32に記載の宿主細胞。
- 前記宿主細胞がS.セレビシエである、請求項32〜35のいずれか一項に記載の宿主細胞。
- 組換えポリペプチドをコードする少なくとも1つの核酸をさらに含んでなる、請求項32または36に記載の宿主細胞。
- 前記組換えポリペプチドが、配列番号1に示されるアミノ酸と少なくとも99%の配列同一性を有するポリペプチドを含んでなる、請求項37に記載の宿主細胞。
- 前記宿主細胞が、培養系で増殖される際に、同種であるが、キラーエクスプレッションプロテアーゼ(Kex2p)またはその機能的断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列と、タンパク質ジスルフィドイソメラーゼ(Pdi1)またはその機能的断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列と、小胞体オキシドレダクチン(Ero1)またはその機能的断片および/もしくは変異体をコードする少なくとも1つの異種核酸配列とを含まない遺伝子改変の宿主細胞に比べて、前記組換えポリペプチドの力価収率を増大する、請求項37または38に記載の宿主細胞。
- 前記宿主細胞が培養系で増殖される際に、同種であって、Kex2p、Pdi1、およびEro1から選択される少なくとも2つの遺伝子産物を過剰発現しないこと以外は同じ培養条件で増殖された野生型宿主細胞に比べて、Kex2p、Pdi1、およびEro1から選択される少なくとも2つのタンパク質またはその断片および/もしくは変異体を過剰発現する、宿主細胞。
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US11135276B2 (en) | 2019-05-17 | 2021-10-05 | Imam Abdulrahman Bin Faisal University | Method of making PDIA2 and compositions containing PDIA2 |
US20220380508A1 (en) | 2019-06-28 | 2022-12-01 | Mitsubishi Gas Chemical Company, Inc. | Resin composition, resin sheet, laminate, semiconductor wafer with resin composition layer, substrate for mounting semiconductor with resin composition layer, and semiconductor device |
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