JP2021513370A - 目的タンパク質を産生するための宿主細胞 - Google Patents
目的タンパク質を産生するための宿主細胞 Download PDFInfo
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Abstract
Description
a)HCP1は、宿主細胞がコマガタエラ・ファフィである場合、配列番号1で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含み、
b)HCP2は、宿主細胞がコマガタエラ・ファフィである場合、配列番号3で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含み、
c)HCP3は、宿主細胞がコマガタエラ・ファフィである場合、配列番号5で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含む、真核宿主細胞が提供される。
d)HCP4は、宿主細胞がコマガタエラ・ファフィである場合、配列番号7で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含む、真核宿主細胞が提供される。
a)ピキア属、ハンセヌラ属(Hansenula)、コマガタエラ属、サッカロマイセス属、クルイウェロマイセス属(Kluyveromyces)、カンジダ属(Candida)、オガタエア属(Ogataea)、ヤロウィア属(Yarrowia)及びゲオトリクム属(Geotrichum)からなる群より選択される属の酵母細胞、例えば、ピキア・パストリス、コマガタエラ・ファフィ、コマガタエラ・パストリス、コマガタエラ・シュードパストリス、サッカロマイセス・セレビシエ(Saccharomyces cerevisiae)、オガタエア・ミヌタ(Ogataea minuta)、クルイウェロマイセス・ラクチス(Kluyveromces lactis)、クルイウェロマイセス・マルキシアヌス(Kluyveromes marxianus)、ヤロウィア・リポリティカ(Yarrowia lipolytica)若しくはハンセヌラ・ポリモルファ(Hansenula polymorpha)、又は、
b)糸状菌類の細胞、例えば、アスペルギルス・アワモリ(Aspergillus awamori)若しくはトリコデルマ・リーセイ(Trichoderma reesei)である。
− 第1の内因性ポリヌクレオチドはHCP1をコードし、
− 第2の内因性ポリヌクレオチドはHCP2をコードし、
− 第3の内因性ポリヌクレオチドはHCP3をコードする。
− 当該更なる内因性ポリヌクレオチドはHCP4をコードする。
(i)1つ以上の内因性ポリヌクレオチド若しくはその一部の、又は
(ii)好ましくは、プロモーター、リボソーム結合部位、転写若しくは翻訳の開始及び停止配列、エンハンサー及びアクティベータ配列からなる群より選択される、当該1つ以上の内因性ポリヌクレオチドの発現制御配列の、破壊、置換、欠失又はノックアウトを含む1以上の遺伝子改変によって、遺伝子改変される。
CAP-232、パシレオチド、huN901-DMI、卵巣がん免疫療法ワクチン、SB-249553、Oncovax-CL、OncoVax-P、BLP-25、CerVax-16、マルチエピトープペプチドメラノーマワクチン(MART-1、gp100、チロシナーゼ)、ネミフィチド、rAAT(吸入用)、rAAT(皮膚科用)、CGRP(吸入用、喘息)、ペグスネルセプト、チモシンβ4、プリチデプシン、GTP-200、ラモプラニン、GRASPA、OBI-1、AC-100、サーモンカルシトニン(経口、eligen)、カルシトニン(経口、骨多孔症)、エキサモレリン、カプロモレリン、Cardeva、ベラフェルミン、131I-TM-601、KK-220、T-10、ウラリチド、デペレスタット、ヘマタイド、Chrysalin(局所用)、rNAPc2、遺伝子組換え第V因子111(PEG化リポソーム)、bFGF、PEG化遺伝子組換えスタフィロキナーゼ変異体、V-10153、SonLysis Prolyse、NeuroVax、CZEN-002、膵島細胞新生療法、rGLP-1、BIM-51077、LY-548806、エクセナチド(制御放出、メディソーブ)、AVE-0010、GA-GCB、アボレリン、ACM-9604、リナクロチド アセタート、CETi-1、ヘモスパン、VAL(注射可)、速効型インスリン(注射可、Viadel)、鼻腔内用インスリン、インスリン(吸入用)、インスリン(経口、eligen)、遺伝子組換えメチオニルヒトレプチン、ピトラキンラ皮下注射薬、湿疹)、ピトラキンラ(吸入用乾燥粉末、喘息)、Multikine、RG-1068、MM-093、NBI-6024、AT-001、PI-0824、Org-39141、Cpn10(自己免疫疾患/炎症)、talactoferrin(局所用)、rEV-131(眼用)、rEV-131(呼吸器疾患)、経口遺伝子組換えヒトインスリン(糖尿病)、RPI-78M、オプレルベキン(経口)、CYT-99007CTLA4-Ig、DTY-001、バラテグラスト、インターフェロンα-n3(局所用)、IRX-3、RDP-58、タウフェロン、胆汁酸塩刺激リパーゼ、Merispase、アラリンホスファターゼ、EP-2104R、メラノタン-II、ブレメラノチド、ATL-104、遺伝子組換えヒトマイクロプラスミン、AX-200、セマックス、ACV-1、Xen-2174、CJC-1008、ダイノルフィンA、SI-6603、LAB GHRH、AER-002、BGC-728、マラリアワクチン(ビロソーム、PeviPRO)、ALTU-135、パルボウイルスB19ワクチン、インフルエンザワクチン(遺伝子組換えニューラミニダーゼ)、マラリア/HBVワクチン、炭疽菌ワクチン、Vacc-5q、Vacc-4x、HIVワクチン(経口)、HPVワクチン、Tatトキソイド、YSPSL、CHS-13340、PTH(1−34)リポソームクリーム(Novasome)、Ostabolin-C、PTH類似体(局所用、乾癬)、MBRI-93.02、MTB72Fワクチン(結核)、MVA-Ag85Aワクチン(結核)、FARA04、BA-210、遺伝子組換えペストFIVワクチン、AG-702、OxSODrol、rBetV1、Der-p1/Der-p2/Der-p7アレルゲン標的ワクチン(チリダニアレルギー)、PR1ペプチド抗原(白血病)、変異rasワクチン、HPV-16E7リポペプチドワクチン、迷路ワクチン(腺がん)、CMLワクチン、WT1-ペプチドワクチン(がん)、IDD-5、CDX-110、Pentrys、Norelin、CytoFab、P-9808、VT-111、イクロカプチド、テルベルミン(皮膚潰瘍、糖尿病性足部潰瘍)、ルピントリビル、レチクロース、rGRF、HA、α-ガラクトシダーゼA、ACE-011、ALTU-140、CGX-1160、アンジオテンシン治療ワクチン、D-4F、ETC-642、APP-018、rhMBL、SCV-07(経口、結核)、DRF-7295、ABT-828、ErbB2特異的免疫毒素(抗がん)、DT3SSIL-3、TST-10088、PRO-1762、Combotox、コレシストキニン-B/ガストリン受容体結合ペプチド、111In-hEGF、AE-37、トラスツズマブ(trasnizumab)−DM1、アンタゴニストG、IL-12(遺伝子組換え)、PM-02734、IMP-321、rhIGF-BP3、BLX-883、CUV-1647(局所用)、L-19系放射免疫療法薬(がん)、Re-188-P-2045、AMG-386、DC/1540/KLHワクチン(がん)、VX-001、AVE-9633、AC-9301、NY-ESO-1ワクチン(ペプチド)、NA17.A2ペプチド、メラノーマワクチン(パルス抗原治療薬)、前立腺がんワクチン、CBP-501、遺伝子組換えヒトラクトフェリン(ドライアイ)、FX-06、AP-214、WAP-8294A(注射可)、ACP-HIP、SUN-11031、ペプチドYY[3−36](肥満、鼻腔用)、FGLL、アタシセプト、BR3-Fc、BN-003、BA-058、ヒト副甲状腺ホルモン1−34(鼻用、骨多孔症)、F-18-CCR1、AT-1100(セリアック病/糖尿病)、JPD-003、PTH(7−34)リポソームクリーム(Novasome)、デュラマイシン(眼用、ドライアイ)、CAB-2、CTCE-0214、GlycoPEGylatedエリスロポエチン、EPO-Fc、CNTO-528、AMG-114、JR-013、第XIII因子、アミノカンジン、PN-951、716155、SUN-E7001、TH-0318、BAY-73-7977、テベレリックス(即時放出)、EP-51216、hGH(制御放出、Biosphere)、OGP-I、シフビルチド、TV4710、ALG-889、Org-41259、rhCC10、F-991、チモペンチン(肺疾患)、r(m)CRP、肝選択的インスリン、subalin、L19−IL-2融合タンパク質、エラフィン、NMK-150、ALTU-139、EN-122004、rhTPO、トロンボポエチン受容体アゴニスト(血小板低減症)、AL-108、AL-208、神経成長因子アンタゴニスト(疼痛)、SLV-317、CGX-1007、INNO-105、経口テリパラチド(eligen)、GEM-OS1、AC-162352、PRX-302、LFn-p24融合ワクチン(Therapore)、EP-1043、肺炎連鎖球菌小児用ワクチン、マラリアワクチン、髄膜炎菌B群ワクチン、新生児B群連鎖球菌ワクチン、炭疽菌ワクチン、HCVワクチン(gpE1+gpE2+MF-59)、中耳炎治療薬、HCVワクチン(コア抗原+ISCOMATRIX)、hPTH(1−34)(経皮、ViaDerm)、768974、SYN-101、PGN-0052、aviscumnine、BIM-23190、結核ワクチン、マルチエピトープチロシナーゼペプチド、がんワクチン、enkastim、APC-8024、GI-5005、ACC-001、TTS-CD3、血管標的TNF(固形腫瘍)、デスモプレシン(口腔制御放出)、オナセプト、又はTP-9201、アダリムマブ(ヒューミラ)、インフリキシマブ(レミケイド(登録商標)、リツキシマブ(リツキサン(登録商標)/MAB THERA(登録商標))、エタナーセプト(エンブレル(登録商標))、ベバシズマブ(アバスチン(登録商標))、トラスツズマブ(ハーセプチン(登録商標))、ペグリルグラスチム(ニューラスタ(登録商標))、又はバイオシミラー及びバイオベターを含む任意の他の好適なPOIである。
i)第1の宿主細胞タンパク質(HCP1)、第2の宿主細胞タンパク質(HCP2)及び第3の宿主細胞タンパク質(HCP3)からなる群より選択される少なくとも1つの内因性の宿主細胞タンパク質(HCP)の産生を低減するように宿主細胞を遺伝子改変する工程、
a)HCP1は、宿主細胞がコマガタエラ・ファフィである場合、配列番号1で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含み、
b)HCP2は、宿主細胞がコマガタエラ・ファフィである場合、配列番号3で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含み、
c)HCP3は、宿主細胞がコマガタエラ・ファフィである場合、配列番号5で示されるアミノ酸配列を含み、又は宿主細胞が別の種である場合、宿主細胞に対して内因性である当該配列の相同配列を含み、
ii)POIをコードするヌクレオチド配列に操作可能に連結された1つ以上の調節核酸配列を含む発現カセットを宿主細胞に導入する工程、
iii)当該POIを産生する条件下で当該宿主細胞を培養する工程、及び任意に、
iv)当該POIを細胞培養物から、特に細胞培養上清から、単離する工程、及び任意に、
v)当該POIを精製する工程を含む方法を提供する。
・ 宿主細胞によって産生される当該少なくとも1つのHCPの量が、全HCPの10%、5%、又は3%(mol/mol)未満に低減され;
・ 宿主細胞によって産生される当該少なくとも1つのHCPの量が、50%、60%、70%、80%、90%、95%、(mol/mol)の少なくともいずれかだけ、又は100%までも低減され、これによりそれぞれのHCPの産生を止め;
・ 宿主細胞によって産生される当該少なくとも1つのHCPのそれぞれの量、特にHCP1及びHCP2、HCP3、又はHCP4のいずれか1つ、2つ、又は3つのそれぞれの量が、50%、60%、70%、80%、90%、95%、又は100%(mol/mol)のうちの少なくともいずれかだけ低減され;
・ 宿主細胞によって産生される当該少なくとも1つのHCPのそれぞれの量、特にHCP1及びHCP2、HCP3、又はHCP4のいずれか1つ、2つ、又は3つのそれぞれの量が、全HCPの1%(mol/mol)未満に低減され;
・ 細胞培養上清における全HCPの量が、5%、又は10%、又は15%(mol/mol)の少なくともいずれかだけ低減されている。
POIとして組換えタンパク質を産生するピキア・パストリス細胞(CBS2612株)に由来する宿主細胞タンパク質(HCP)不純物を同定するために、細胞培養上清試料を、以下に記載されるように、HCP組成、含量及び同一性について分析した。異なるシグナルペプチド(POI1:国際公開第2014/067926号の配列番号12、POI2及びPOI3:α交配因子のシグナルペプチド(例えば、米国特許第9534039号明細書の配列番号1))を含む、2つの異なる発現システム:pG1-3(国際公開第2017/021541号の配列番号38)及びpAOX1(例えばStrattonら、1998(High Cell-Density Fermentation. In: Higgins D.R., Cregg J.M. (eds) Pichia Protocols. Methods in Molecular Biology, vol 103. Humana Press))を使用して、毎回、表1に示す様々なpH及び温度の発酵条件で、3つの異なるPOIを流加培養により発現させた。各試料を、HCP組成、含量及び同一性について、3回試験した。
試料を6.6M グアニジンHCl中で変性させ、TCEPで還元し、分析前にトリプシンで消化した。各試料について3つの複製物を調製した。体積18.5μlの各試料を96ウェルプレートに移した。90μlの0.5M 2-(N-モルフォリノ)エタンスルホン酸(MES)pH5.5、6.6M グアニジンHCl、10mM トリス(2-カルボキシエチル)ホスフィン(TCEP)を各複製物に添加した。インキュベーションを50℃で30分間行った。その後、全ての試料を、ZebaSpin脱塩プレート(Thermo)を使用して、製造者の説明書にしたがって、0.1M 3-(N-モルフォリノ)プロパンスルホン酸(MOPS)、4-モルフォリンプロパンスルホン酸 pH7.3、2M 尿素、2mM CaCl2、1mM TCEPに緩衝液交換した。質量分析グレードのトリプシン(Promega)で消化を行った。緩衝液交換後の各試料のアリコート75μlに、25μlのトリプシン消化溶液(4mg/mlトリプシン、0.1M MOPS pH7.3、2M 尿素、2mM CaCl2、1mM TCEPを添加及び混合した。試料を30±2℃で一晩インキュベートした。2%(最終)トリフルオロ酢酸(TFA)の添加によって消化をクエンチした。
Thermo Fusion Tribrid Q-OT-qIT(Quadrupole-Orbitrap-Linear Ion Trap)質量分析器に連結されたDionex RSSLnano nanoLCシステムを使用してデータを収集した。各試料について体積1μlのトリプシンペプチドを、水:アセトニトリル(98:2)及び0.05%TFAからなるローディングバッファーで12μl/分で3分間、Acclaim PepMap100C18 5μm、100Å、内径300μm×5mm Nano-Trapカラム(Thermo)に注入した。3分後、nanoLCフローを、トラップカラムを通して分析カラム(EasySpray PepMap C18 2μm、100Å、75μm×25cm(Thermo))上に逆方向に向けた。水中の0.1%ギ酸とアセトニトリル:水(80:20)中の0.08%ギ酸との間に直線勾配を適用した。
MS2フラグメンテーションに基づくタンパク質同定を、PEAKS Studioソフトウェアを使用して行った。清澄化細胞培養上清(CCCS)についてのみタンパク質同定を行った。ペプチドレベルでの偽発見率は、デコイ融合法(Zhang, J, et al., "PEAKS DB: de novo sequencing assisted database search for sensitive and accurate peptide identification", Mol. Cell Proteomics 4(11), 111 (2012))を用いて、<0.5%に制御した。少なくとも2つの特異的ペプチドが各タンパク質の割り当てに必要であった。質量許容差は、親イオンについては<5ppmで、フラグメントイオンについては<0.3Daで特定した。
pAOX1発現系を用いた試料は、メタノール代謝に特異的なタンパク質(アルコールオキシダーゼ、ギ酸デヒドロゲナーゼ、アルコールデヒドロゲナーゼ)、並びにメタノール代謝中に生成される活性酸素種の代謝(スーパーオキシドジスムターゼ、ペルオキシレドキシンPMP、タンパク質ジスルフィドイソメラーゼ、チオレドキシン)の有意な増加を示した。試料7、8及び10と比較して、試料9及び11の高力価と相関する更なる変化がこの実験内で観察された。これらの変化には、タンパク質、例えば、タンパク質フォールディングに関与するATPase、GPIアンカー細胞表面糖タンパク質、ペプチジル-プロピルシストランスイソメラーゼ及び翻訳伸長因子EF-1γ(コマガタエラ・ファフィ)(C4R6E8)と相同性を示す特徴付けられていないタンパク質F2QUJ0が含まれていた。pG1−3発現系を使用した試料は、炭水化物のプロセシングに関与する酵素(グルカナーゼ、グルコシダーゼ)及び構造タンパク質の発現の増加を呈した。様々な発酵条件(温度、pH)は、HCP発現プロファイルの変化をもたらすことが示され、例えば、高い温度及びpHで発酵を行った場合にシャペロンタンパク質HSP90の量の増加が観察された。
HCP1(F2QXM5:配列番号1及び2により示される)は、実施例1の宿主細胞タンパク質同定分析において同定され、異なる発現系及び発酵条件を用いて3つの異なるPOIを発現する異なるピキア・パストリス株における全HCP負荷の26〜64%、平均して約50%を占めた(実施例1)。
HCP1をノックアウトする際のHCPの総量の強い低減を更に示すために、更なる株を作製した。実施例2とは対照的に、先ず、ノックアウト株を作製し、次いで、この株を、目的タンパク質を発現する3つのプラスミドのうちの1つで形質転換した。
8つの選択された株(実施例3)に由来するHCP不純物を特徴付けるために、株を、実施例1に記載されるような流加発酵で培養した。発酵終了試料をHCP同定に使用した。
試料を6.6M グアニジンHCl中で変性させ、TCEPで還元し、分析前にトリプシンで消化した。各試料について3つの複製物を調製した。体積60μlの各試料を96ウェルプレートに移した。90μlの0.5M 2-(N-モルフォリノ)エタンスルホン酸(MES)pH5.5、6.6M グアニジンHCl、10mM トリス(2-カルボキシエチル)ホスフィン(TCEP)を各複製物に添加した。インキュベーションを50℃で30分間行った。その後、全ての試料を、ZebaSpin脱塩プレート(Thermo)を使用して、製造者の説明書にしたがって、0.1M 3-(N-モルフォリノ)プロパンスルホン酸(MOPS)、4-モルフォリンプロパンスルホン酸)pH7.3、2M 尿素、2mM CaCl2、1mM TCEPに緩衝液交換した。質量分析グレードのトリプシン(Promega)で消化を行った。緩衝液交換後の各試料のアリコート50μlに、16.6μlのトリプシン消化溶液(4mg/mlトリプシン、0.1M MOPS pH7.3、2M 尿素、2mM CaCl2、1mM TCEPを添加及び混合した。試料を30±2℃で一晩インキュベートした。2%(最終)トリフルオロ酢酸(TFA)の添加によって消化をクエンチした。試料を消化緩衝液で1:10に希釈した。
Thermo Fusion Tribrid Q-OT-qIT(Quadrupole-Orbitrap-Linear Ion Trap)質量分析器に連結されたDionex RSSLnano nanoLCシステムを使用してデータを収集した。各試料について体積1μlのトリプシンペプチドを、水:アセトニトリル(98:2)及び0.05%TFAからなるローディングバッファーで12μl/分で3分間、Acclaim PepMap100C18 5μm、100Å、内径300μm×5mm Nano-Trapカラム(Thermo)に注入した。3分後、nanoLCフローを、トラップカラムを通して分析カラム(EasySpray PepMap C18 2μm、100Å、75μm×25cm(Thermo))上に逆方向に向けた。水中の0.1%ギ酸とアセトニトリル:水(80:20)中の0.08%ギ酸との間に直線勾配を適用した。ソースイオン化設定は、2500Vのスプレー電圧及び275℃のトランスファーチューブ温度での収集の間、静的であった。質量分析器を、350〜1500m/zの走査範囲、5.0e5のAGCターゲット及び150msの最大注入時間で、120,000FWHMの公称分解能におけるオービトラップでMS1データを収集するためにポジティブイオン化モードに構成した。別のイオン源から生成されたフルオランテンイオンロックマスに基づく内部標準を使用して、データを質量補正した。z=2〜z=8の電荷状態のみをMS2フラグメンテーションのために選択した。HCD法を用いたTopNの最も強いデータ依存性モードを使用して、リニアイオントラップでMS2フラグメンテーションを行った。HCDは、28%の衝突エネルギー、1.0e4のAGCターゲット、及び「高速」トラップ走査速度で100msの最大走査時間で行った。
MS2フラグメンテーションに基づくタンパク質同定を、PEAKS Studioソフトウェアを使用して行った。清澄化細胞培養上清(CCCS)についてのみタンパク質同定を行った。ペプチドレベルでの偽発見率は、デコイ融合法(Zhang, J, et al., "PEAKS DB: de novo sequencing assisted database search for sensitive and accurate peptide identification", Mol. Cell Proteomics 4(11), 111 (2012))を用いて、<0.1%に制御した。少なくとも2つの特異的ペプチドが各タンパク質の割り当てに必要であった。質量許容差は、親イオンについては<5ppmで、フラグメントイオンについては<0.3Daで特定した。作成されたLC−MS/MSデータを、3つのPOIのそれぞれについて別々に分析して、処理中のデータのより良好なアラインメントを可能にした。UniProtデータベースからのコマガタエラ・ファフィ(ATCC76273/CBS7435/CECT11047/NRRL Y−11430/Wegner21−1)(酵母)(ピキア・パストリス)のプロテオームに対してデータベース検索を行い、PEAKS studio7を用いて存在するタンパク質を同定した。Progenesis QI for Proteomicsを使用して、全ての試料を処理した。PEAKSからの同定は、定量化のために実験の間ずっとProgenesisにインポートした。各POIのデータを別個に処理した。Hi3法を用いて定量化を行った。発現プロファイルの有意な変化(p値<0.05)及び倍率変化>2を呈するタンパク質を、発現プロファイルの類似性について評価した。全HCPは以下のように決定される。同定された各タンパク質について、そのタンパク質に由来する3つの最も強いペプチドシグナルのピーク面積を決定し、次いでまとめて加算する。得られた数により、モルベースでのタンパク質の存在量の比較が可能となる(Silva et al., 2006: "Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition."
Mol Cell Proteomics 5(1): 144-56)。試験試料中の個々のHCPの全てについてこのようにして得られた値を合計した。得られた合計値は、試験試料中の全HCPの量(mol)に正比例する。したがって、HCPにおける百分率又は倍率変化の差に関して試料間で比較を行うことができる。
実施例1に見られるように、非設計株の全HCPプールにおけるHCP1の驚くほど高い存在量が、この実験で確認された(図4)。HCP1は、組換えタンパク質の発現を伴う又は伴わない野生型株の上清中の全HCPの43〜70%を構成する。
Claims (15)
- 異種目的タンパク質(POI)を産生するように設計された真核宿主細胞であって、前記細胞は、第1の宿主細胞タンパク質(HCP1)、第2の宿主細胞タンパク質(HCP2)及び第3の宿主細胞タンパク質(HCP3)からなる群より選択される少なくとも1つの内因性の宿主細胞タンパク質(HCP)の産生を低減するように遺伝子改変され、
a)HCP1は、前記宿主細胞がコマガタエラ・ファフィ(Komagataella phaffii)である場合、配列番号1で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、前記宿主細胞に対して内因性である前記配列の相同配列を含み、
b)HCP2は、前記宿主細胞がコマガタエラ・ファフィである場合、配列番号3で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、前記宿主細胞に対して内因性である前記配列の相同配列を含み、
c)HCP3は、前記宿主細胞がコマガタエラ・ファフィである場合、配列番号5で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、前記宿主細胞に対して内因性である前記配列の相同配列を含む、
真核宿主細胞。 - 前記少なくとも1つのHCPはHCP1であり、任意にHCP2及び/又はHCP3である、請求項1に記載の宿主細胞。
- 前記細胞は、更なるHCPであるHCP4の産生を低減するように更に遺伝子改変され、
a)HCP4は、前記宿主細胞がコマガタエラ・ファフィ(Komagataella phaffii)である場合、配列番号7で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、宿主細胞に対して内因性である前記配列の相同配列を含む、請求項1又は2に記載の宿主細胞。 - 前記相同配列は、それぞれのアミノ酸配列に対する少なくとも50%の配列同一性により特徴付けられる、請求項1〜3のいずれか1項に記載の宿主細胞。
- 前記宿主細胞は、前記宿主細胞ゲノムの、
(i)1つ以上の内因性ポリヌクレオチド若しくはその一部の、又は
(ii)好ましくは、プロモーター、リボソーム結合部位、転写若しくは翻訳の開始及び停止配列、エンハンサー及びアクティベータ配列からなる群より選択される発現制御配列の、
破壊、置換、欠失又はノックアウトを含む1以上の遺伝子改変によって、遺伝子改変された、請求項1〜4のいずれか1項に記載の宿主細胞。 - 前記少なくとも1つのHCPのいずれかをコードする遺伝子が、前記1以上の遺伝子改変によってノックアウトされている、請求項5に記載の宿主細胞。
- 前記少なくとも1つのHCPの量を、好ましくは、前記少なくとも1つのHCPをコードする遺伝子のノックアウトによって、改変を伴わない前記宿主細胞と比較して少なくとも50%(mol/mol)低減するように遺伝子改変された、請求項1〜6のいずれか1項に記載の宿主細胞。
- 前記POIをコードするヌクレオチド配列に操作可能に連結された1つ以上の調節核酸配列を含む発現カセットを含み、前記操作可能に連結された1つ以上の配列は前記POIをコードする配列と天然には関連付けられていない、請求項1〜7のいずれか1項に記載の宿主細胞。
- 前記POIは、抗原結合タンパク質、治療タンパク質、酵素、ペプチド、タンパク質抗生物質、毒素融合タンパク質、炭水化物−タンパク質コンジュゲート、構造タンパク質、調節タンパク質、ワクチン抗原、成長因子、ホルモン、サイトカイン、プロセス酵素及び代謝酵素からなる群より選択されるペプチド又はタンパク質である、請求項1〜8のいずれか1項に記載の宿主細胞。
- 動物細胞、脊椎動物細胞、哺乳動物細胞、ヒト細胞、植物細胞、線虫細胞、無脊椎動物細胞、昆虫細胞、軟体動物細胞、前述のいずれかに由来する幹細胞、又は酵母若しくは真菌細胞のいずれか1つである、請求項1〜9のいずれか1項に記載の宿主細胞。
- a)ピキア属(Pichia)、ハンセヌラ属(Hansenula)、コマガタエラ属(Komagataella)、サッカロマイセス属(Saccharomyces)、クルイウェロマイセス属(Kluyveromyces)、カンジダ属(Candida)、オガタエア属(Ogataea)、ヤロウィア属(Yarrowia)及びゲオトリクム属(Geotrichum)からなる群より選択される属の酵母細胞、例えば、ピキア・パストリス(Pichia pastoris)、コマガタエラ・ファフィ(Komagataella phaffii)、コマガタエラ・パストリス(Komagataella pastoris)、コマガタエラ・シュードパストリス(Komagataella pseudopastoris)、サッカロマイセス・セレビシエ(Saccharomyces cerevisiae)、オガタエア・ミヌタ(Ogataea minuta)、クルイウェロマイセス・ラクチス(Kluyveromces lactis)、クルイウェロマイセス・マルキシアヌス(Kluyveromes marxianus)、ヤロウィア・リポリティカ(Yarrowia lipolytica)若しくはハンセヌラ・ポリモルファ(Hansenula polymorpha)、又は
b)糸状菌類の細胞、例えば、アスペルギルス・アワモリ(Aspergillus awamori)若しくはトリコデルマ・リーセイ(Trichoderma reesei)である、請求項1〜10のいずれか1項に記載の宿主細胞。 - 真核宿主細胞において目的タンパク質(POI)を産生する方法であって、
i)第1の宿主細胞タンパク質(HCP1)、第2の宿主細胞タンパク質(HCP2)及び第3の宿主細胞タンパク質(HCP3)からなる群より選択される少なくとも1つの内因性の宿主細胞タンパク質(HCP)の産生を低減するように前記宿主細胞を遺伝子改変する工程、
a)HCP1は、前記宿主細胞がコマガタエラ・ファフィ(Komagataella phaffii)である場合、配列番号1で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、前記宿主細胞に対して内因性である前記配列の相同配列を含み、
b)HCP2は、前記宿主細胞がコマガタエラ・ファフィである場合、配列番号3で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、前記宿主細胞に対して内因性である前記配列の相同配列を含み、
c)HCP3は、前記宿主細胞がコマガタエラ・ファフィである場合、配列番号5で示されるアミノ酸配列を含み、又は前記宿主細胞が別の種である場合、前記宿主細胞に対して内因性である前記配列の相同配列を含む、
ii)前記POIをコードするヌクレオチド配列に操作可能に連結された1つ以上の調節核酸配列を含む発現カセットを前記宿主細胞に導入する工程、
iii)前記POIを産生する条件下で前記宿主細胞を培養する工程、及び任意に、
iv)前記POIを前記細胞培養物から単離する工程、及び任意に
v)前記POIを精製する工程
を含む方法。 - 前記目的タンパク質(POI)を産生する条件下で請求項1〜11のいずれか1項に記載の宿主細胞を培養することによる、POIを産生する方法。
- 前記少なくとも1つのHCPの量が、好ましくは、前記少なくとも1つのHCPをコードする遺伝子のノックアウトによって、改変を伴わない前記宿主細胞と比較して少なくとも50%(mol/mol)低減されている、請求項12又は13に記載の方法。
- 前記目的タンパク質(POI)を産生する条件下で請求項1〜10のいずれか1項に記載の宿主細胞を培養すること、及び、前記POIを前記細胞培養物から単離することによる、宿主細胞培養物中に産生されたPOIの内因性の宿主細胞タンパク質(HCP)による汚染のリスクを低減する方法。
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CA3089682A1 (en) | 2019-08-15 |
WO2019154686A8 (en) | 2020-03-05 |
IL276625A (en) | 2020-09-30 |
AU2019218931A1 (en) | 2020-07-23 |
CN112105737B (zh) | 2024-06-14 |
EP3752617A1 (en) | 2020-12-23 |
JP2023156329A (ja) | 2023-10-24 |
CN112105737A (zh) | 2020-12-18 |
WO2019154686A1 (en) | 2019-08-15 |
KR20200120908A (ko) | 2020-10-22 |
BR112020016258A2 (pt) | 2020-12-15 |
SG11202006449RA (en) | 2020-08-28 |
US20200399325A1 (en) | 2020-12-24 |
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