JP2021526505A - 治療用タンパク質の標的細胞に特異的な産生のための、および、標的細胞に関連する疾患、疾病、または障害の処置のための、融合性脂質ナノ粒子、および、融合性脂質ナノ粒子の製造方法と使用方法 - Google Patents
治療用タンパク質の標的細胞に特異的な産生のための、および、標的細胞に関連する疾患、疾病、または障害の処置のための、融合性脂質ナノ粒子、および、融合性脂質ナノ粒子の製造方法と使用方法 Download PDFInfo
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Abstract
Description
このPCT特許出願は2019年4月18日に出願され、2018年4月18日に出願された米国仮特許出願62/659,676号と2019年3月20日に出願された米国仮特許出願62/821,084号の利点を主張する。第62/659,676号と第62/821,084号の仮特許出願の全体は、参照により本明細書に組み込まれる。
本出願は、2019年4月18日に作成され、68,831バイトのサイズを有する、「OSIN−01−0304WO01_2019−04−18_SEQLIST_ST25」という表題のtxtファイルとしての電子フォーマットの配列表を含む。本出願はさらに、2019年4月18日に作成された「OSIN−01−0304WO01_2019−04−18_SEQLIST_ST25」という表題のPDFファイルとしての配列表を含む。「OSIN−01−0304WO01_2019−04−18_SEQLIST_ST25」という表題のtxtとPDFのファイルの内容は同一であり、参照によって本明細書に組み込まれる。
癌細胞、老化細胞、および望ましくない表現型を有する他の細胞は、人の一生の間に蓄積され得、適切な治療がなければ、こうした細胞は、人の罹患率と、最終的には死亡率に寄与するか、あるいはその原因となり得る。
1.老化、疾患、および/または他の状態に関連する細胞などの、標的細胞内の治療用タンパク質の標的化された産生のための発現構築物であって、上記発現構築物は:
a.1つ以上の因子に応答して活性化される転写プロモーターであって、その各々が標的細胞内で生産される転写プロモーターと、
b.転写プロモーターに動作可能に連結され、かつ転写プロモーターの調節制御下にある核酸であって、ここで、上記核酸は、標的細胞を含む細胞の成長および/または生存を減少させ、防ぎ、および/または排除することができる治療用タンパク質をコードする、核酸と、を含む発現構築物。
2.標的細胞内の治療用タンパク質の標的化された産生のための系であって、上記系は、標的細胞ならびに非標的細胞を含む細胞に核酸を送達するためのベクターを含み、
ここで、上記ベクターは、非標的細胞内ではなく、標的細胞(例えば、老化、癌、および/または、他の疾患および/または疾病に関連する細胞)内での治療用タンパク質の標的化された産生のための発現構築物を含み、
ここで、発現構築物は、(i)1つ以上の因子に応答して活性化される転写プロモーターであって、その各々は標的細胞内で産生される、転写プロモーターと、(ii)転写プロモーターに動作可能に連結され、かつ転写プロモーター調節制御下にある核酸であって、
ここで、核酸は、標的細胞を含む産生される細胞の成長および/または生存を減少させ、防ぎ、および/または排除する治療用タンパク質をコードする、核酸とを含む、系。
3.標的細胞の増殖を減少させ、防ぎ、および/または排除するための方法であって、ここで、上記方法は、標的細胞内の治療用タンパク質の標的化された産生のための系を、標的細胞と接触させる工程を含み、
ここで、上記系は、細胞への核酸の送達のためのベクターを含み、
ここで、上記ベクターは、非標的細胞内ではなく、標的細胞(例えば、老化、疾患、あるいは他の状態に関連する細胞)内の治療用タンパク質の標的化された産生のための発現構築物を含み、
ここで、上記発現構築物は、(i)1つ以上の因子に応答して活性化される転写プロモーターであって、その因子の各々は標的細胞内で産生される、転写プロモーターと、(ii)上記転写プロモーターに動作可能に連結され、かつ転写プロモーター調節制御下にある核酸であって、
ここで、上記核酸は、核酸の発現時に産生される治療用タンパク質をコードし、および
ここで、標的細胞(例えば、老化、疾患、あるいは他の状態に関連する細胞)中の治療用タンパク質の産生は、標的細胞の成長および/または生存を、減少し、防ぎ、および/または排除する核酸と、を含む方法。
4.ヒトの老化、疾患、あるいは他の状態の処置のための方法であって、ここで、老化、疾患、あるいは他の状態は標的細胞と関連し、上記方法は、標的細胞内の治療用タンパク質の標的化された産生のための系をヒトに投与する工程を含み、
ここで、上記系は、細胞に核酸を送達することができるベクターを含み、
ここで、上記ベクターは、非標的細胞内ではなく、標的細胞(例えば、老化、疾患、あるいは他の状態に関連する細胞)内の治療用タンパク質の標的化された産生のための発現構築物を含み、
ここで、上記発現構築物は、(i)1つ以上の因子に応答して活性化される転写プロモーターであって、その因子の各々は標的細胞内で産生される、転写プロモーターと、(ii)転写プロモーターに動作可能に連結され、かつ転写プロモーターの調節制御下にある核酸であって、
ここで、上記核酸は、核酸の発現時に治療用タンパク質をコードする、核酸と、および
ここで、標的細胞(例えば、老化、疾患、あるいは他の状態に関連する細胞)中の治療用タンパク質の産生は、標的細胞の成長および/または生存を減少させ、防ぎ、および/または排除し、それにより、ヒトの老化を遅らせ、および/または、ヒトの疾患あるいは疾病を遅らせ、回復させ、および/または排除する、方法。
本開示のこれらの態様および他の態様は、以下の非制限的な定義を参照することにより、より良く理解することができる。
ある実施形態内では、本開示は、発現構築物と、標的細胞の成長および/または生存を標的細胞に特異的に減少させ、防ぎ、および/または排除することを達成するための1つの送達ベクターおよび1つの発現構築物を含む系を提供する。
本開示の系は、(1)細胞が標的細胞あるいは非標的細胞であるかに関わらず、その細胞への核酸の非特異的な送達が可能なベクター、および(b)標的細胞に特異的な転写プロモーターと、治療用タンパク質をコードする核酸とを含む発現構築物を含み、この発現構築物は、治療用タンパク質の標的細胞に特異的な産生を達成する。本明細書に開示される系は、老化、疾患、あるいは別の状態に関連する細胞などの標的細胞の成長または生存の特性をもたらすが、同時に、正常な、老化、疾患、あるいは別の状態に関連しない非標的細胞の成長または生存の特性をもたらさないことが望ましい広範囲の治療適用に有用である。
本開示の系は、標的細胞に固有の転写機構を利用することにより、標的細胞特異性を達成する。したがって、本明細書に記載される系は、標的細胞を含むが、これに限定されない細胞への発現構築物の非特異的送達に容易に適合し得る核酸送達ベクターを利用する。
発現カセットは、例えば、リポソーム、小胞、ミセルおよび/または、マイクロスフェアなどの、脂質膜、脂質二重層、および/または脂質複合体内に取り込まれる、および/または、脂質膜、脂質二重層、および/または脂質複合体に関連し得る。本開示の発現構築物とともに利用され得る脂質ベース送達系を調製するための適切な方法は、Metselaar et al., Mini Rev. Med. Chem. 2(4):319−29(2002);O’Hagen et al., Expert Rev. Vaccines 2(2):269−83(2003);O’Hagan, Curr. Durg Targets Infect. Disord. 1(3):273−86(2001);Zho et al., Biosci Rep. 22(2):355−69(2002);Chikh et al., Biosci Rep. 22(2):339−53(2002);Bungener et al., Biosci. Rep. 22(2):323−38(2002);Park, Biosci Rep. 22(2):267−81(2002);Ulrich, Biosci. Rep. 22(2):129−50;Lofthouse, Adv. Drug Deliv. Rev. 54(6):863−70(2002);Zhou et al., J. Immunother. 25(4):289−303(2002);Singh et al., Pharm Res. 19(6):715−28(2002);Wong et al., Curr. Med. Chem. 8(9):1123−36(2001);および、Zhou et al., Immunomethods 4(3):229−35(1994)に記載されている。Midoux et al., British J. Pharmacol 157:166−178(2009)には、ポリマー、ペプチド、および脂質を含む核酸の送達のための化学的ベクターが記載されている。Sioud and Sorensen, Biochem Biophys Res Commun 312(4):1220−5(2003)には、核酸の送達のためのカチオン性リポソームが記載されている。
例えば、単純ヘルペスウイルスベクター、レンチウイルスベクター、アデノウイルスベクター、およびアデノ随伴ウイルスを含む、種々様々のウイルスベクターは、当業者に周知で、かつ容易に利用可能であり、上記ウイルスベクターは、核酸(特に、治療用タンパク質の標的細胞に特異的な発現のための発現カセットを含む核酸)の送達のために本明細書に開示される系での使用に適合し得る。
ポリプレックスはDNAとポリマーの複合体である。ポリプレックスは、カチオンポリマーからなり、それらの製作はイオン相互作用による自己組織化に基づく。ポリプレックスと、リポソームおよびリポプレックスの作用方法の間の1つの重要な違いは、ポリプレックスが、核酸カーゴを標的細胞の細胞質に直接放出することができないということである。その結果、不活性化アデノウイルスなどのエンドソーム溶解剤との同時トランスフェクションは、粒子取り込み中に作られた細胞内小胞からの逃避を容易にするために必要となる。DNAがエンドリソソームの経路(つまり、プロトンスポンジ効果)から逃れることができる機構のより良い理解は、ポリマー骨格におけるプロトン化可能な残基の取り込みなどの新規ポリマー合成方策のきっかけとなり、またポリカチオンベースの系についての研究を活性化している。例えば、Parhamifar et al., Methods e−pub (2014);Rychgak and Kilbanov, Adv Drug Deliv Rev e−pub (2014);Jafari et al.,Curr Med Chem 19(2):197−208(2012)を参照。
デンドリマーは、球形の高度に分岐したポリマーである。デンドリマー粒子の表面は、例えば、正の表面電荷(カチオン性デンドリマー)などを用いて、機能化される場合があり、それは、核酸の送達に使用され得る。デンドリマー−核酸の複合体は、エンドサイトーシスによって細胞中に取り込まれる。デンドリマーは、堅牢な共有結合構造および分子の構造およびサイズに対する極端な制御を提供する。デンドリマーは、動力学的駆動化学(kinetically driven chemistry)を使用して、デンドリマーを産生するDendritic Nanotechnologies Inc.から商業上利用可能であり、そのデンドリマーは、核酸の送達に適合することができ、低毒性、高効率で細胞をトランスフェクトすることができる。
本開示の発現構築物は、(a)標的細胞に産生される因子に反応する転写プロモーターであって、そのうち1つ以上が産生されず、実質的に低レベルで産生され、不活性であり、および/または非標的細胞中で実質的に低活性を示す、転写プロモーターと、(b)前記転写プロモーターに動作可能に連結され、かつ前記転写プロモーターの調節制御下にある核酸であって、該核酸が、標的細胞を含む細胞の成長および/または生存を減らし、妨げ、および/または排除することが可能なタンパク質をコードし、前記細胞中で前記タンパク質が産生される、核酸とを含む。
本開示は、核酸を細胞に送達するためのベクターを含む系を提供し、該核酸はプロモーターの転写制御下にあり、該プロモーターは、標的細胞中で活発化または活性化されるが、正常細胞、すなわち非標的細胞中では不活発化(reprepressed)または不活性化される。
一実施形態では、自殺遺伝子は、p16Ink4a遺伝子プロモーターなどのp16プロモーターの制御下に置くことができる。p16プロモーターは、非老化細胞ではなく老化細胞中で転写的に活性である。
治療タンパク質をコードする核酸は、老化細胞、および癌細胞または前癌細胞中で転写的に活性なことが多いp21/CDKN1A転写プロモーターの制御下に置くことができる。p53/TP53は、損傷を受けたときにp21の調節、およびこれにより細胞の成長停止において中心的な役割を果たす。p21タンパク質は、細胞周期を駆動し、かつそれらのキナーゼ活性を阻害することで細胞周期阻止を修復させる、サイクリンCDK複合体に直接結合する。p21はまた、分化に関連する成長停止、および細胞老化に関連する恒久的な成長阻止を媒介する。p21遺伝子は、p53タンパク質の直接結合を媒介する様々なp53反応要素を含んでおり、その結果、p21タンパク質をコードする遺伝子の転写活性化が生じる。細胞老化におけるp53遺伝子調節の役割は、Kelley et al.,Cancer Research 70(9):3566−75.(2010)に記載されている。
本開示の発現構築物、系、および方法に適宜利用可能な核酸は、標的細胞を含む細胞の成長および/または生存を低下し、妨げ、および/または排除することが可能なタンパク質をコードするものであり、前記細胞内ではタンパク質が産生される。ゆえに、本開示の発現構築物および系の標的細胞特異性は、治療タンパク質をコードする核酸の、非標的細胞ではなく標的細胞内での発現により達成される。
本開示は、ベクターと発現カセットとを含む系を提供し、前記発現カセットは、標的細胞中および治療タンパク質をコードする核酸中で発現される1つ以上の転写因子に反応する転写プロモーターを含む。系は、それ自体で、または、本明細書に記載されるような疾患または疾病を処置あるいは改善する投与量の適切な担体あるいは賦形剤と共に混合された医薬組成物の中で、ヒト患者に投与することができる。これら系の混合物も、単一の混合物として、または医薬組成物の中で患者に投与することができる。
本開示は、老齢化、癌、感染症、細菌感染症、および/または他の疾患あるいは疾病に関連する細胞の成長および/または生存を低下し、阻害し、および/または妨げるための方法を提供する。該方法は、本明細書に記載されるような系に標的細胞または標的細胞を含む細胞の集団を接触させる工程を含み、前記系はベクターと発現構築物とを含み、該発現構築物は転写プロモーターと核酸とを含む。
この実施例で実証されるのは、爬虫類レオウイルスのp14 FAST融合を利用するFusogenix(商標)(Innovascreen,Halifax,Nova Scotia,Canada)脂質ナノ粒子が標的腫瘍へのプラスミドDNA構築物の送達に有効であることである。
この実施例から実証されるのは、爬虫類レオウイルスのp14 FAST融合を利用するFusogenix(商標)(Innovascreen,Halifax,Nova Scotia,Canada)脂質ナノ粒子が、スプラーグドーリーラットにインビボ投与されたときに調べられる主要な哺乳動物器官系のいずれにも有害な副作用を示さないことである。このナノ粒子は標的腫瘍へのプラスミドDNA構築物の送達で有効である。
この実施例で実証されるのは、老齢化に対してマウスモデル系の例示的なp16標的化構築物のインビボ投与後のp16−陽性老化細胞負荷における標的細胞に特異的な抑制である。
この実施例で実証されるのは、ヒト前立腺腫瘍(すなわちPC−3異種移植片)を移植したNSGマウスのp53発現前立腺癌細胞の標的細胞に特異的な抑制である。
化学的二量体化誘導剤(CID)を用いる、または用いないp53−iCasp9 LNPの反復処置による転移性腫瘍増殖の抑制を、NOD−SCIDマウスモデル系で実証した。
B16マウス黒色腫細胞を移植した同質遺伝子型C57B6マウスを、マウスp53プロモーターの制御下でiCasp9およびマウスCD40Lをコードする構築物を含有するLNP、その後にAP20187二量体化剤で処置した。
この実施例で実証されるのは、肺転移マウスモデル系に移植したマウスp53+B16F10黒色腫標的細胞のインビボでのp53+標的細胞抑制である。
Claims (35)
- 標的細胞内の治療用タンパク質の標的化産生のための脂質ナノ粒子(LNP)製剤であって、
LNP製剤は:
a.両方の標的細胞または非標的細胞を含む哺乳動物細胞への核酸の非特異的な送達のための脂質ナノ粒子ベクターであって、前記脂質ナノ粒子が1つ以上の脂質と1つ以上の融合性タンパク質を含む、脂質ナノ粒子ベクターと、
b.標的細胞内での治療用タンパク質の優先的な産生のための発現構築物を含み、
前記発現構築物は:
i.前記非標的細胞と比較して、前記標的細胞内で優先的に産生される1つ以上の因子に応答して活性化される転写プロモーターと、
ii.前記転写プロモーターに動作可能に連結され、かつ、前記転写プロモーターの調節制御下にある核酸であって、前記核酸は、標的細胞と非標的細胞の両方を含む、哺乳動物細胞の成長および/または生存を減少させ、予防し、および/または排除することができる治療用タンパク質をコードし、ならびに、前記治療用タンパク質は前記標的細胞内で産生されるが、前記非標的細胞内では産生されない、核酸とを含む、
LNP製剤。 - 前記1つ以上の脂質は、1mMから100mMの範囲の濃度で前記LNP製剤中に存在する、請求項1に記載のLNP製剤。
- 前記1つ以上の脂質は、5mMから50mMの範囲の濃度で前記LNP製剤中に存在する、請求項2に記載のLNP製剤。
- 前記1つ以上の脂質は、10mMから30mMの範囲の濃度で前記LNP製剤中に存在する、請求項3に記載のLNP製剤。
- 前記1つ以上の脂質は、15mMから25mMの範囲の濃度で前記LNP製剤中に存在する、請求項4に記載のLNP製剤。
- 前記1つ以上の脂質は、約20mMの濃度で前記LNP製剤中に存在する、請求項5に記載のLNP製剤。
- 前記1つ以上の脂質は、1,2−ジオレオイル−3−ジメチルアンモニウム−プロパン(DODAP)、1,2−ジオレオイル−3−トリメチルアンモニウム−プロパン(DOTAP)、1,2−ジオレオイル−sn−グリセロ−3−ホスホエタノールアミン(DOPE)、コレステロール、および1,2−ジミリストイル−rac−グリセロ−3−メトキシポリエチレングリコール(DMG−PEG)からなる群から選択される、請求項1に記載のLNP製剤。
- 前記脂質は、DODAP、DOTAP、DOPE、コレステロール、およびDMG−PEGからなる群から選択される2以上の脂質を含む、請求項7に記載のLNP製剤。
- 前記脂質は、DODAP、DOTAP、DOPE、コレステロール、およびDMG−PEGを含む、請求項8に記載のLNP製剤。
- 前記DODAP、DOTAP、DOPE、コレステロール、およびDMG−PEGは、35−55モル%のDODAP:10−20モル%のDOTAP:22.5−37.5モル%のDOPE:4−8モル%のコレステロール:3−5モル%のDMG−PEGのモル比で前記LNP製剤中に存在する、請求項9に記載のLNP製剤。
- 前記DODAP、DOTAP、DOPE、コレステロール、およびDMG−PEGは、約45モル%のDODAP:約15モル%のDOTAP:約30モル%のDOPE:約6モル%のコレステロール:および、約4モル%のDMG−PEGのモル比で前記LNP製剤中に存在する、請求項10に記載のLNP製剤。
- 前記DODAP、DOTAP、DOPE、コレステロール、およびDMG−PEGは、45モル%のDODAP:15モル%のDOTAP:30モル%のDOPE:6モル%のコレステロール:4モル%のDMG−PEGのモル比で前記LNP製剤中に存在する、請求項11に記載のLNP製剤。
- 前記1つ以上の融合性タンパク質は、0.5μMから20μMの範囲の濃度で前記LNP製剤中に存在する、請求項1に記載のLNP製剤。
- 前記1つ以上の融合性タンパク質は、1μMから10μMの範囲の濃度で前記LNP製剤中に存在する、請求項13に記載のLNP製剤。
- 前記1つ以上の融合性タンパク質は、3μMから4μMの範囲の濃度で前記LNP製剤中に存在する、請求項14に記載のLNP製剤。
- 前記1つ以上の融合性タンパク質は、3.5μMの濃度で前記LNP製剤中に存在する、請求項15に記載のLNP製剤。
- 前記融合性タンパク質の1つ以上は、p14融合性タンパク質(SEQ ID NO:16)とp14e15融合性タンパク質(SEQ ID NO:17)からなる群から選択される、請求項1に記載のLNP製剤。
- 前記融合性タンパク質は、p14融合性タンパク質(SEQ ID NO:16)である、請求項1に記載のLNP製剤。
- 前記融合性タンパク質は、p14e15融合性タンパク質(SEQ ID NO:17)である、請求項1に記載のLNP製剤。
- 前記発現構築物は、20μg/mLから1.5mg/mLの範囲の濃度で前記LNP製剤中に存在する、請求項1に記載のLNP製剤。
- 前記発現構築物は、100μg/mLから500μg/mLの範囲の濃度で前記LNP製剤中に存在する、請求項20に記載のLNP製剤。
- 前記発現構築物は、250μg/mLの濃度で前記LNP製剤中に存在する、請求項21に記載のLNP製剤。
- 前記発現構築物は、250μg/mLの濃度で前記LNP製剤中に存在する、請求項21に記載のLNP製剤。
- 前記転写プロモーターは、p16転写プロモーター、p21転写プロモーター、およびp53転写プロモーターからなる群から選択される、請求項1に記載のLNP製剤。
- 前記転写プロモーターは、SP1、ETS1、ETS2、およびp53/TP53からなる群から選択された因子に応答する、請求項24に記載のLNP製剤。
- 前記転写プロモーターは、p16INK4a/CDKN2A転写プロモーターとp21/CDKN1A転写プロモーターから選択される、請求項24に記載のLNP製剤。
- 前記転写プロモーターは、EBF3、O/E−1、Pax−5、E2A、p53、VP16、MLL、HSF1、NF−IL6、NFAT1、AP−1、AP−2、HOX、E2F3、および/またはNF−κBの転写因子からなる群から選択された因子に応答する、請求項24に記載のLNP製剤。
- 前記転写プロモーターは、p21cip1/waf1プロモーター、p27kip1プロモーター、p57kip2プロモーター、TdTプロモーター、Rag−1プロモーター、B29プロモーター、Blkプロモーター、CD19プロモーター、BLNKプロモーター、および出るPλ5プロモーターからなる群から選択される、請求項27に記載のLNP製剤。
- 前記核酸は、カスパーゼ(Casp)、誘導性カスパーゼ(iCasp)、自己活性化カスパーゼ(saCasp)、BAX、DFF40、HSV−TK、およびシトシンデアミナーゼからなる群から選択された治療用タンパク質をコードする、請求項1に記載のLNP製剤。
- 前記核酸は、Casp3、Casp8、およびCasp9からなる群から選択されたカスパーゼをコードする、請求項29に記載のLNP製剤。
- 前記核酸はCasp9をコードする、請求項30に記載のLNP製剤。
- 前記核酸は誘導性Casp9(iCasp9)をコードする、請求項31に記載のLNP製剤。
- 前記核酸は自己活性化Casp9(saCasp9)をコードする、請求項31に記載のLNP製剤。
- 標的細胞の成長を減少させ、予防し、および/または排除するための方法であって、
前記方法は、標的細胞をLNP製剤に接触させる工程を含み、
前記LNP製剤は:
a.両方の標的細胞または非標的細胞を含む哺乳動物細胞への核酸の非特異的な送達のための脂質ナノ粒子ベクターであって、前記脂質ナノ粒子が1つ以上の脂質と1つ以上の融合性タンパク質を含む、脂質ナノ粒子ベクターと、
b.標的細胞内での治療用タンパク質の優先的な産生のための発現構築物を含み、
前記発現構築物は:
i.前記非標的細胞と比較して、前記標的細胞内で優先的に産生される1つ以上の因子に応答して活性化される転写プロモーターと、
ii.前記転写プロモーターに動作可能に連結され、かつ、前記転写プロモーターの調節制御下にある核酸であって、前記核酸は、標的細胞と非標的細胞の両方を含む、哺乳動物細胞の成長および/または生存を減少させ、予防し、および/または排除することができる治療用タンパク質をコードし、ならびに、前記治療用タンパク質は前記標的細胞内で産生されるが、前記非標的細胞内では産生されない、核酸とを含む、
方法。 - 標的細胞を有する患者の疾患または疾病の処置のための方法であって、
前記方法は:
LNP製剤を前記患者に投与する工程を含み、
前記LNP製剤は:
a.両方の標的細胞または非標的細胞を含む哺乳動物細胞への核酸の非特異的な送達のための脂質ナノ粒子ベクターであって、前記脂質ナノ粒子が1つ以上の脂質と1つ以上の融合性タンパク質を含む、脂質ナノ粒子ベクターと、
b.標的細胞内での治療用タンパク質の優先的な産生のための発現構築物を含み、
前記発現構築物は:
i.前記非標的細胞と比較して、前記標的細胞内で優先的に産生される1つ以上の因子に応答して活性化される転写プロモーターと、
ii.前記転写プロモーターに動作可能に連結され、かつ、前記転写プロモーターの調節制御下にある核酸であって、前記核酸は、標的細胞と非標的細胞の両方を含む哺乳動物細胞の成長および/または生存を減少させ、予防し、および/または排除することができる治療用タンパク質をコードし、および、前記治療用タンパク質は前記標的細胞内で産生されるが、前記非標的細胞内では産生されない、核酸とを含む、
方法。
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