JP2022105531A - 遺伝学的に修飾された非ヒト動物およびその使用法 - Google Patents
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Abstract
Description
本願は、2012年9月7日出願の米国仮出願第61/698,002号および2013年3月8日出願の米国仮出願第61/775,171号に基づく優先権を主張するものであり、それらの各々の内容は、参照によってその全体が本明細書に組み入れられる。
生物医学的研究の目標は、ヒト生理学についてのよりよい理解を取得し、ヒト疾患を予防するか、処置するか、または治癒させるために、この知識を使用することである。ヒト対象における実験法に対する実務上および倫理上の障壁のため、多くの研究が、マウスのような小動物モデルにおいて実施されている。しかしながら、マウスは人間ではなく、動物実験から取得された知識は、必ずしもヒトに適用可能ではない。これに関して、ヒト血液リンパ系(HHLS)を定植されたマウスは、インビボのヒトの造血および免疫の機能の研究のために有用な小動物モデルを表す。
プロモーターに機能的に連結されたヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種をコードする少なくとも1種の核酸を含むゲノムを含み、かつヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群より選択される少なくとも1種のポリペプチドを発現する、遺伝学的に修飾された非ヒト動物。
[本発明1002]
各々プロモーターに機能的に連結されたヒトM-CSFをコードする核酸、ヒトIL-3をコードする核酸、ヒトGM-CSFをコードする核酸、ヒトSIRPAをコードする核酸、およびヒトTPOをコードする核酸を含むゲノムを含み、かつヒトM-CSFポリペプチド、ヒトIL-3ポリペプチド、ヒトGM-CSFポリペプチド、ヒトSIRPAポリペプチド、およびヒトTPOポリペプチドを発現する、本発明1001の遺伝学的に修飾された非ヒト動物。
[本発明1003]
免疫不全である、本発明1001の遺伝学的に修飾された非ヒト動物。
[本発明1004]
組換え活性化遺伝子2を発現しない(Rag-2-/-)、本発明1003の遺伝学的に修飾された免疫不全非ヒト動物。
[本発明1005]
IL2受容体γ鎖を発現しない(γ鎖-/-)、本発明1003の遺伝学的に修飾された免疫不全非ヒト動物。
[本発明1006]
Rag-2を発現せず、かつIL2受容体γ鎖を発現しない(Rag-2-/- γ鎖-/-)、本発明1003の遺伝学的に修飾された免疫不全非ヒト動物。
[本発明1007]
げっ歯類である、本発明1001の遺伝学的に修飾された非ヒト動物。
[本発明1008]
マウスである、本発明1001の遺伝学的に修飾された非ヒト動物。
[本発明1009]
ヒト造血細胞をさらに含む、本発明1001の遺伝学的に修飾された動物。
[本発明1010]
ヒト癌細胞をさらに含む、本発明1001の遺伝学的に修飾された動物。
[本発明1011]
ヒト癌細胞が白血病細胞または黒色腫細胞である、本発明1010の遺伝学的に修飾された動物。
[本発明1012]
ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種を発現する遺伝学的に修飾された動物へ少なくとも1種のHSPCを投与する工程を含む、ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種を発現する遺伝学的に修飾された非ヒト動物における造血幹細胞・前駆細胞(HSPC)生着の方法。
[本発明1013]
遺伝学的に修飾された非ヒト動物がげっ歯類である、本発明1012の方法。
[本発明1014]
遺伝学的に修飾された非ヒト動物がマウスである、本発明1012の方法。
[本発明1015]
遺伝学的に修飾された非ヒト動物が免疫不全である、本発明1012の方法。
[本発明1016]
遺伝学的に修飾された免疫不全非ヒト動物が組換え活性化遺伝子2を発現しない(Rag-2-/-)、本発明1015の方法。
[本発明1017]
遺伝学的に修飾された免疫不全非ヒト動物が内在性IL2受容体を発現しない(γ鎖-/-)、本発明1015の方法。
[本発明1018]
遺伝学的に修飾された免疫不全非ヒト動物が、内在性Rag-2を発現せず、かつ内在性γ鎖を発現しない(Rag-2-/- γ鎖-/-)、本発明1015の方法。
[本発明1019]
遺伝学的に修飾された動物がヒト癌細胞を含む、本発明1012の方法。
[本発明1020]
ヒト癌細胞が白血病細胞または黒色腫細胞である、本発明1019の方法。
[本発明1021]
少なくとも1種のプロモーターに機能的に連結されたヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種をコードする少なくとも1種の核酸を含むゲノムを有し、ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群より選択される少なくとも1種のポリペプチドを発現する、遺伝学的に修飾されたRag-2-/-γ鎖-/-マウス。
[本発明1022]
各々プロモーターに機能的に連結されたヒトM-CSFをコードする核酸、ヒトIL-3をコードする核酸、ヒトGM-CSFをコードする核酸、ヒトSIRPAをコードする核酸、およびヒトTPOをコードする核酸を含むゲノムを含み、かつヒトM-CSFポリペプチド、ヒトIL-3ポリペプチド、ヒトGM-CSFポリペプチド、ヒトSIRPAポリペプチド、およびヒトTPOポリペプチドを発現する、本発明1021の遺伝学的に修飾された非ヒト動物。
[本発明1023]
げっ歯類である、本発明1021の遺伝学的に修飾された非ヒト動物。
[本発明1024]
マウスである、本発明1021の遺伝学的に修飾された非ヒト動物。
[本発明1025]
ヒト造血細胞をさらに含む、本発明1021の遺伝学的に修飾された動物。
[本発明1026]
ヒト癌細胞をさらに含む、本発明1021の遺伝学的に修飾された動物。
[本発明1027]
ヒト癌細胞が白血病細胞または黒色腫細胞である、本発明1026の遺伝学的に修飾された動物。
本発明の好ましい態様の以下の詳細な説明は、添付の図面と共に参照された時、よりよく理解されるであろう。本発明を例示する目的のため、現在好ましい態様が図面に示される。しかしながら、本発明は、図面に示された態様の正確な配置および手段に限定されないことが、理解されるべきである。
本発明は概して、ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、またはヒトTPOのうちの少なくとも1種を発現する遺伝学的に修飾された非ヒト動物に関する。本発明は、本明細書に記載された遺伝学的に修飾された非ヒト動物を生成する方法および使用する方法にも関する。いくつかの態様において、遺伝学的に修飾された非ヒト動物はマウスである。いくつかの態様において、本明細書に記載された遺伝学的に修飾された非ヒト動物には、ヒト造血細胞が生着している。様々な態様において、本発明のヒト造血細胞が生着した、遺伝学的に修飾された非ヒト動物は、造血細胞および免疫細胞の増殖および分化のインビボ評価のため、ヒト造血系のインビボ評価のため、癌細胞のインビボ評価のため、免疫応答のインビボ査定のため、ワクチンおよび予防接種計画のインビボ評価のため、癌細胞の増殖または生存をモジュレートする薬剤の効果の試験において使用するため、癌の処置のインビボ評価のため、ヒト抗体を含む免疫メディエーターのインビボの作製および収集のため、そして造血細胞および免疫細胞の機能をモジュレートする薬剤の効果の試験において使用するため、有用である。
他に定義されない限り、本明細書において使用される技術用語および科学用語は、全て、本発明が属する技術分野の当業者によって一般的に理解されるのと同一の意味を有している。そのような用語は、J.Sambrook and D.W.Russell,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press;3rd Ed.,2001;F.M.Ausubel,Ed.,Short Protocols in Molecular Biology,Current Protocols;5th Ed.,2002;B.Alberts et al.,Molecular Biology of the Cell,4th Ed.,Garland,2002;D.L.Nelson and M.M.Cox,Lehninger Principles of Biochemistry,4th Ed.,W.H.Freeman & Company,2004;およびHerdewijn,P.(Ed.),Oligonucleotide Synthesis:Methods and Applications,Methods in Molecular Biology,Humana Press,2004を例示的に含む様々な標準的な参考書に見出され、定義され、文脈中に使用されている。本明細書に記載されたものに類似しているかまたは等価である任意の方法および材料を、本発明の実施または試行において使用することができるが、好ましい方法および材料が記載される。
本発明は、(本明細書においてMISTと呼ばれる)ヒトM-CSF、ヒトIL-3/GM-CSF、ヒトSIRPA、およびヒトTPOを発現する遺伝学的に修飾された非ヒト動物に関する。本発明は、本明細書に記載された遺伝学的に修飾された非ヒト動物を生成する方法および使用する方法にも関する。いくつかの態様において、遺伝学的に修飾された非ヒト動物はマウスである。いくつかの態様において、遺伝学的に修飾された非ヒト動物は免疫不全マウスである。具体的な態様において、免疫不全マウスはRAG2-/-γc -/-マウスである。別の具体的な態様において、本発明の遺伝学的に修飾された非ヒト動物は、ヒトM-CSF、ヒトIL-3/GM-CSF、およびヒトTPOを発現し、RAG2およびγcを発現しない(本明細書においてMITRGと呼ばれる)。別の具体的な態様において、本発明の遺伝学的に修飾された非ヒト動物は、ヒトM-CSF、ヒトIL-3/GM-CSF、ヒトSIRPA、およびヒトTPOを発現し、RAG2およびγcを発現しない(本明細書においてMISTRGと呼ばれる)。いくつかの態様において、本明細書に記載された遺伝学的に修飾された非ヒト動物には、ヒト造血細胞が生着している。
本発明は、ヒトM-CSF、ヒトIL-3/GM-CSF、ヒトSIRPA、ヒトTPO、およびそれらの任意の組み合わせのうちの少なくとも一つを発現する、遺伝学的に修飾された非ヒト動物を含む。いくつかの態様において、ヒト核酸を発現する遺伝学的に修飾された非ヒト動物は、対応する非ヒト動物核酸も発現する。他の態様において、ヒト核酸を発現する遺伝学的に修飾された非ヒト動物は、対応する非ヒト動物核酸を発現しない。いくつかの態様において、遺伝学的に修飾された動物は、本明細書中に別記されるように、動物を免疫不全動物にするため、1種または複数種の遺伝子がノックアウトされている動物である。遺伝学的に修飾された非ヒト動物を作るためには、ヒトタンパク質をコードする核酸を、非ヒト宿主細胞におけるヒトタンパク質の発現のために適当な形態で、組換え発現ベクターへ組み入れることができる。様々な態様において、組換え発現ベクターは、核酸のmRNAへの転写およびmRNAのヒトタンパク質への翻訳を可能にする様式でヒトタンパク質をコードする核酸に機能的に連結された1種または複数種の制御配列を含む。「制御配列」という用語は、当技術分野において認識されており、プロモーター、エンハンサー、およびその他の発現調節要素(例えば、ポリアデニル化シグナル)を含むものとする。そのような制御配列は、当業者に公知であり、1990,Goeddel,Gene Expression Technology:Methods in Enzymology 185,Academic Press,San Diego,Califに記載されている。発現ベクターの設計は、トランスフェクトされる宿主細胞の選択および/または発現されるヒトタンパク質の量のような要因に依り得ることが理解されるべきである。
本明細書に記載されるように、ヒト血液リンパ系(HHLS)を定植されたマウスは、予測的なヒト前臨床インビボ研究のための強力なツールを表す。現在のHHLSマウスの主要な限界は、自然免疫のために重要なヒト細胞の発達が不完全であることである。本明細書において、サイトカインをコードする複数の遺伝子が遺伝学的にヒト化されている新規のマウス系統を報告する。これらのヒト化サイトカインは、ヒト造血ならびにヒト単球/マクロファージおよびNK細胞の発達および機能を効率的に支持するために共同作用する。腫瘍微小環境において、ヒトマクロファージは、免疫抑制性の表現型を獲得し、ヒト癌の増殖を支持する。より完全な機能性のヒト自然免疫系を有するHHLSマウスのこの新規モデルは、ヒト自然免疫の生理学および病理学のインビボ研究を容易にする極めて大きい可能性を有している。
RAG2-/-γc-/-Balb/c×129遺伝的背景における、TPO、IL-3/GM-CSF、およびM-CSFをコードする遺伝子のノックイン交換、またはヒトSIRPαのBACトランスジェニック発現によるマウスの生成が報告された(Rathinam et al.,2011,Blood 118,3119;Willinger et al.,2011,Proceedings of the National Academy of Sciences 108,2390;Rongvaux et al.,2011,Proceedings of the National Academy of Sciences 108,2378;Strowig et al.,2011,Proceedings of the National Academy of Sciences 108,13218)。これらの系統を、MITRG(M-CSFh/hIL-3/GM-CSFh/hTPOh/hRAG2-/-γc-/-)マウスおよびMISTRG(M-CSFh/hIL-3/GM-CSFh/hhSIRPAtgTPOh/hRAG2-/-γc-/-)マウスを入手するため、交雑した。それらのマウスは、生存可能で、健康で、繁殖性である。マウスは、エンロフロキサシン含有飲料水(Baytril、0.27mg/ml)で継続的に処理しながら、特定病原体除去条件下で維持された。NOD Scidγc-/-(NSG)マウスは、Jackson Laboratoryから入手された。
記載されたように(Rathinam et al.,2011,Blood 118,3119;Willinger et al.,2011,Proceedings of the National Academy of Sciences 108,2390;Rongvaux et al.,2011,Proceedings of the National Academy of Sciences 108,2378;Traggiai et al.,2004,Science 304,104;Strowig et al.,2011,Proceedings of the National Academy of Sciences 108,13218)、レシピエントマウスにヒト造血幹細胞・前駆細胞を生着させた。胎児肝臓試料を、小片へ切断し、コラゲナーゼD(Roche、100ng/mL)によって37℃で45分間処理し、細胞懸濁物を調製した。密度勾配遠心(Lymphocyte Separation Medium,MP Biomedicals)後の抗ヒトCD34ミクロビーズ(Miltenyi Biotec)によるポジティブ免疫磁気選択によって、ヒトCD34+細胞を精製した。細胞を、10%DMSOを含有しているFBSにおいて凍結させ、液体窒素中に維持した。
WBCを調製するため、ヘパリン処置血液を、RBCを排除するため、ACK溶解緩衝液によって2回処理した。(大腿骨および脛骨から洗い流された)脾臓および骨髄の単細胞懸濁物を、ACK溶解緩衝液によって処理した。組織を機械的に解離させ、100U/mlコラゲナーゼIVおよび0.02mg/ml DNase I(Sigma)によって37℃で1時間消化した後の密度勾配遠心によって、肝臓および肺の白血球を単離した。
GFPを発現する大腸菌を、OD600が1.5~1.8になるまで、37℃で一晩、LB培地において増殖させ、その時点で、細菌を希釈しOD600がおよそ1.0になるまで1~2時間増殖させた。大腸菌をPBSで3回洗浄し、1×107 WBC当たり約2×108の大腸菌で、200μlの容量で、37℃で4時間、MITRGマウスに由来するWBCと共にインキュベートした。インキュベーション後、細胞をPBSによって洗浄し、フローサイトメトリーによって分析した。
ヒト単球サブセットをマウスのBMから単離した。簡単に説明すると、BM細胞を、6匹のマウスの後肢および脊椎から回収しプールした。ヒトCD33+細胞を、磁気単離(EasySep CD33選択キット、StemCell Technologies)によって濃縮した。CD14+CD16-サブセットおよびCD14+CD16+サブセットを、FACSAriaセルソーター(BD Biosciences)で精製した。200μl培地中の100,000個の細胞を、TLR4リガンドLPS(E.Coli 0111:B4、Sigma-Aldrich、100ng/ml)またはTLR7/8リガンドR848(Invivogen、10μg/ml)の存在下で一晩培養した。
RBC数はHemavet 950(Drew Scientific)で測定した。血液塗抹標本はライト-ギムザによって染色した。マウスRBC移入実験については、血液をRGマウスから入手し、CFSE(20μM、37℃で15分)によって標識し、PBSによって3回洗浄し、200μlの標識されたRBCを後眼窩静脈注射によって注射した。5分後に、フローサイトメトリーによってTer119+細胞中のCFSE陽性細胞の初期頻度(0日目、100%)を決定するため、マウスから採血した。次いで、示された時点で採血し、CFSEによって標識されたTer119+細胞の維持を、0日目の値に対する百分率として計算した。
100μlのクロドロン酸負荷リポソーム(Van Rooijen and Sanders,1994,Journal of immunological methods 174,83)の静脈内後眼窩注射によって、食細胞を枯渇させた。クロドロン酸リポソームを1日3回注射し、最後の注射の24時間後に、マウス肝臓内のヒトNK細胞を分析した。RBC食作用アッセイについては、クロドロン酸リポソームを、CFSEによって標識されたRBCの移入の3日前および1日前に注射した。
製造業者の指示に従って、TRIzol試薬(Invitrogen)によって、組織または精製された細胞から全RNAを抽出し、SuperScript First-Strand Synthesis System(Invitrogen)によるcDNA合成のために使用した。ABIから購入されたプライマー-プローブセットを用いて、7500 Fast Real-Time PCR系で、定量的RT-PCRを実施した。比較CT法(comparative threshold cycle method)を使用して発現値を計算し、示されたように、マウスHprtまたはヒトHPRTに対して標準化した。
インビボのヒトNK細胞による細胞傷害を、以前に報告されたプロトコル(Strowig et al.,2010,Blood 116,4158)に従って決定した。LCL721.221(HLAクラスI陰性)細胞およびLCL721.45(クラスI陽性)細胞を1:1比で混合し、CellTrace Violet(Invitrogen)によって標識し、生着NSGマウスまたは生着MISTRGマウスへ静脈内注射した(1×107細胞/マウス)。マウスを12時間後に屠殺し、脾臓の単細胞懸濁物を調製し、フローサイトメトリーによって分析した。青紫色細胞の中のHLAクラスI陽性および陰性の割合を測定し、(MHCクラスI陽性-MHCクラスI陰性)×100/MHCクラスI陽性として、特異的溶解を計算した。
ヒト黒色腫細胞株Me290(Valmori et al.,1998,Journal of immunology 160,1750)を、およそ90%コンフルエンシーにまで増殖させ、細胞(マウス1匹当たりおよそ700万個の細胞)を、マウスの側腹部に麻酔下で皮下注射した。いくつかの実験については、腫瘍植え込みの日から開始して、抗ヒトVEGF抗体Avastin(商標)(Roche;100μg静脈内)によってマウスを一日おきに処理した。腫瘍のサイズを11日後に測定し、以下の式を使用して体積を計算した:体積=0.5×長さ2×幅。
統計分析は、一元配置のANOVA後のチューキーの事後検定、両側独立スチューデントt検定、または反復測定ANOVAを使用して、GraphPad Prism 5ソフトウェアによって実施された。
骨髄性白血病は、骨髄系統の細胞に影響を与える癌の型である。骨髄性白血病は、急性骨髄性白血病(AML)、骨髄増殖性障害(MPD)、慢性骨髄単球性白血病(CMML)、および骨髄異形成症候群(MDS)を含む種々の型に分類される。骨髄性白血病を発症するリスクは、年齢と共に増加し、これらの疾患の罹患率は、集団の高齢化と共に増加する可能性が高い。治療アプローチおよび支持療法アプローチが、クリニックにおいて利用可能であるが、この疾患群についてのよりよい理解および新規治療が必要とされている。
Claims (27)
- プロモーターに機能的に連結されたヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種をコードする少なくとも1種の核酸を含むゲノムを含み、かつヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群より選択される少なくとも1種のポリペプチドを発現する、遺伝学的に修飾された非ヒト動物。
- 各々プロモーターに機能的に連結されたヒトM-CSFをコードする核酸、ヒトIL-3をコードする核酸、ヒトGM-CSFをコードする核酸、ヒトSIRPAをコードする核酸、およびヒトTPOをコードする核酸を含むゲノムを含み、かつヒトM-CSFポリペプチド、ヒトIL-3ポリペプチド、ヒトGM-CSFポリペプチド、ヒトSIRPAポリペプチド、およびヒトTPOポリペプチドを発現する、請求項1に記載の遺伝学的に修飾された非ヒト動物。
- 免疫不全である、請求項1に記載の遺伝学的に修飾された非ヒト動物。
- 組換え活性化遺伝子2を発現しない(Rag-2-/-)、請求項3に記載の遺伝学的に修飾された免疫不全非ヒト動物。
- IL2受容体γ鎖を発現しない(γ鎖-/-)、請求項3に記載の遺伝学的に修飾された免疫不全非ヒト動物。
- Rag-2を発現せず、かつIL2受容体γ鎖を発現しない(Rag-2-/- γ鎖-/-)、請求項3に記載の遺伝学的に修飾された免疫不全非ヒト動物。
- げっ歯類である、請求項1に記載の遺伝学的に修飾された非ヒト動物。
- マウスである、請求項1に記載の遺伝学的に修飾された非ヒト動物。
- ヒト造血細胞をさらに含む、請求項1に記載の遺伝学的に修飾された動物。
- ヒト癌細胞をさらに含む、請求項1に記載の遺伝学的に修飾された動物。
- ヒト癌細胞が白血病細胞または黒色腫細胞である、請求項10に記載の遺伝学的に修飾された動物。
- ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種を発現する遺伝学的に修飾された動物へ少なくとも1種のHSPCを投与する工程を含む、ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種を発現する遺伝学的に修飾された非ヒト動物における造血幹細胞・前駆細胞(HSPC)生着の方法。
- 遺伝学的に修飾された非ヒト動物がげっ歯類である、請求項12に記載の方法。
- 遺伝学的に修飾された非ヒト動物がマウスである、請求項12に記載の方法。
- 遺伝学的に修飾された非ヒト動物が免疫不全である、請求項12に記載の方法。
- 遺伝学的に修飾された免疫不全非ヒト動物が組換え活性化遺伝子2を発現しない(Rag-2-/-)、請求項15に記載の方法。
- 遺伝学的に修飾された免疫不全非ヒト動物が内在性IL2受容体を発現しない(γ鎖-/-)、請求項15に記載の方法。
- 遺伝学的に修飾された免疫不全非ヒト動物が、内在性Rag-2を発現せず、かつ内在性γ鎖を発現しない(Rag-2-/- γ鎖-/-)、請求項15に記載の方法。
- 遺伝学的に修飾された動物がヒト癌細胞を含む、請求項12に記載の方法。
- ヒト癌細胞が白血病細胞または黒色腫細胞である、請求項19に記載の方法。
- 少なくとも1種のプロモーターに機能的に連結されたヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群のうちの少なくとも1種をコードする少なくとも1種の核酸を含むゲノムを有し、ヒトM-CSF、ヒトIL-3、ヒトGM-CSF、ヒトSIRPA、およびヒトTPOからなる群より選択される少なくとも1種のポリペプチドを発現する、遺伝学的に修飾されたRag-2-/-γ鎖-/-マウス。
- 各々プロモーターに機能的に連結されたヒトM-CSFをコードする核酸、ヒトIL-3をコードする核酸、ヒトGM-CSFをコードする核酸、ヒトSIRPAをコードする核酸、およびヒトTPOをコードする核酸を含むゲノムを含み、かつヒトM-CSFポリペプチド、ヒトIL-3ポリペプチド、ヒトGM-CSFポリペプチド、ヒトSIRPAポリペプチド、およびヒトTPOポリペプチドを発現する、請求項21に記載の遺伝学的に修飾された非ヒト動物。
- げっ歯類である、請求項21に記載の遺伝学的に修飾された非ヒト動物。
- マウスである、請求項21に記載の遺伝学的に修飾された非ヒト動物。
- ヒト造血細胞をさらに含む、請求項21に記載の遺伝学的に修飾された動物。
- ヒト癌細胞をさらに含む、請求項21に記載の遺伝学的に修飾された動物。
- ヒト癌細胞が白血病細胞または黒色腫細胞である、請求項26に記載の遺伝学的に修飾された動物。
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