JP2022051775A - がんを処置するための組み合わせベクターおよび方法 - Google Patents
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Abstract
Description
この出願は、2016年3月9日に出願され、「Combination Vectors and Uses Thereof」との表題の米国仮特許出願第62/305,944号(これは、参考として本明細書に援用される)への優先権を主張する。
GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAGGACTTTTT(配列番号1);
GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCCTGCTTTTT(配列番号2);
GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACATGGCTTTTT(配列番号3);または
GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTCTGCTTTTT(配列番号4)
を含むFDPSのスモールRNA配列と少なくとも80%、または少なくとも85%、または少なくとも90%、または少なくとも95%の同一性パーセントを有する配列を含む。実施形態では、スモールRNA配列は、配列番号1、2、3、または4から選択される。
GGTGAAACGATCATCGAGCCTCGAGGCTCGATGATCGTTTCACCTTTTT(配列番号5);
GCTACTGGCCTTGGTTTAACTCGAGTTAAACCAAGGCCAGTAGCTTTTT(配列番号6);
CCTCCTTCGTCATTGCCATCTCGAGATGGCAATGACGAAGGAGGTTTTT(配列番号7);
GCATGGCCCTCTTCTGATTCTCGAGAATCAGAAGAGGGCCATGCTTTTT(配列番号8);またはGGTGAAACGATCATCGAGCTACTCGAGTAGCTCGATGATCGTTTCACCTTTTT(配列番号9)を含むCD47のスモールRNA配列または
GCTTCACCAACAGGAACTATGCTCGAGCATAGTTCCTGTTGGTGAAGCTTTT(配列番号10);
GCGAACACACAACGTCTTGGACTCGAGTCCAAGACGTTGTGTGTTCGCTTTT(配列番号11);
GACATGGTGAACCAGAGTTTCCTCGAGGAAACTCTGGTTCACCATGTCTTTTT(配列番号12);
GAGAATGTCAAGAGGCGAACACTCGAGTGTTCGCCTCTTGACATTCTCTTTTT(配列番号13);または
GCTCATTTCTGAAGAGGACTTCTCGAGAAGTCCTCTTCAGAAATGAGCTTTTT(配列番号14)
を含むcMycのスモールRNA配列と少なくとも80%、または少なくとも85%、または少なくとも90%、または少なくとも95%の同一性パーセントを有する配列を含む。実施形態では、第2のスモールRNA配列は、配列番号5、6、7、8、9、10、11、12、13、または14から選択される。
本開示は、治療ベクター、および細胞へのその送達に関する。実施形態では、治療ベクターは、1つより多くのmRNA標的を標的化する。実施形態では、治療ベクターは、FDPSを標的化することによりこの酵素の発現レベルを低下させる、短鎖相同RNA(shRNA)またはマイクロRNA(miRNA)などのスモールRNAを備えている。治療ベクターとしては、レンチウイルスベクターが挙げられる。本開示は、アミノビスホスホネート薬物での処置と組み合わせたFDPSの標的化により、がんを効果的に処置し得ることを実証する。
本明細書中で別様に定義しない限り、本開示との関連で使用する科学技術用語は、当業者によって一般に理解される意味を有する。さらに、文脈上別様に要求されない限り、単数の語は複数を包含し、複数の語は単数を包含する。一般に、本明細書中に記載する細胞および組織の培養、分子生物学、免疫学、微生物学、遺伝学、ならびにタンパク質および核酸の化学およびハイブリダイゼーションとの関連で使用する学術用語およびそれらの技術は周知であり、当該技術分野において一般に使用されている。本開示の方法および技術は、別段の記載がなければ、当該技術分野において周知の、本明細書全体で引用し議論する様々な一般的およびより具体的な参考文献に記載される従来の方法にしたがって一般に行われる。例えば、Sambrook J.およびRussell D.、Molecular Cloning: A Laboratory Manual、第3版、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、N.Y.(2000年);Ausubelら、Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in
Molecular Biology、Wiley, John&Sons, Inc.(2002年);HarlowおよびLane、Using Antibodies:
A Laboratory Manual;Cold Spring Harbor Laboratory Press、Cold Spring Harbor、N.Y.(1998年);およびColiganら、Short Protocols in Protein Science、Wiley, John&Sons, Inc.(2003年)を参照。あらゆる酵素反応または精製技術は、当該技術分野において一般に遂行されるように、または本明細書中に記載するように、製造業者の仕様にしたがって行われる。本明細書中に記載する分析化学、合成有機化学、医薬品化学、および製薬化学との関連で使用する学術用語、ならびに実験の手順および技術は、当該技術分野において周知であり一般に使用されるものである。
BLASTを利用することができる。BLASTプログラムおよびGapped BLASTプログラムを利用する場合、各プログラム(例えば、XBLASTおよびNBLAST)のデフォルトのパラメーターを使用することができる。http://www.ncbi.nlm.nih.gov.を参照。
本開示の一態様では、治療カーゴ部分を含むウイルスベクターが開示される。治療カーゴ部分は、少なくとも1つの予め定められた相補的mRNA配列に結合することができる少なくとも1つのスモールRNA配列を含み、少なくとも1つの相補的mRNA配列は、FDPSのmRNA配列を含む。実施形態では、治療カーゴ部分は、第2の予め定められた相補的mRNA配列に結合することができる第2のスモールRNA配列をさらに含み得、第2の予め定められた相補的mRNA配列は、CD47のmRNA配列またはcMycのmRNA配列を含む。実施形態では、治療カーゴ部分は、第3の予め定められた相補的mRNA配列に結合することができる第3のスモールRNA配列をさらに含み得、第3の予め定められた相補的mRNA配列は、CD47のmRNA配列またはcMycのmRNA配列を含む。スモールRNA配列は、マイクロRNA(miRNA)または短鎖ヘアピンRNA(shRNA)であり得る。
FDPS配列#3(配列番号55)、miR155 FDPS配列#1(配列番号56)、miR21 FDPS配列#1(配列番号57)、miR185 FDPS配列#1(配列番号58)、miR155 CD47配列#1(配列番号82;miR155 CD47標的配列#2(配列番号66)、miR155 CD47標的配列#3(配列番号67)、miR155 CD47標的配列#4(配列番号68)、miR21 cMyc配列(配列番号83)、またはmiR155 cMyc配列(配列番号70)などの本明細書中で詳述されるmiRNA配列のいずれかと少なくとも80%、または少なくとも81%、または少なくとも82%、または少なくとも83%、または少なくとも84%、または少なくとも85%、または少なくとも86%、または少なくとも87%、または少なくとも88%、または少なくとも89%、または少なくとも90%、または少なくとも91%、または少なくとも92%、または少なくとも93%、または少なくとも94%、または少なくとも95%、またはそれより高い同一性を有する配列を含み得る。
CD47標的配列#4(配列番号68)、miR21 cMyc配列(配列番号83)、またはmiR155 cMyc配列(配列番号70)などの本明細書中で詳述するmiRNA配列のいずれかを含み得る。
本明細書中に提供する組成物および方法は、がんを処置するために使用される。細胞、組織、または標的は、がん細胞であり得、がん性組織であり得、がん性組織を有し得、あるいは疾患または状態を発症していると診断されたまたはそのリスクがある被験体または患者であり得る。ある特定の態様では、細胞は、上皮細胞、内皮細胞、中皮細胞、グリア細胞、間質細胞、または粘膜細胞であり得る。がん細胞集団は、脳細胞、神経細胞、血液細胞、子宮内膜細胞、髄膜細胞、食道細胞、肺細胞、心臓血管細胞、肝細胞、リンパ細胞、乳房細胞、骨細胞、結合組織細胞、脂肪細胞、網膜細胞、甲状腺細胞、腺細胞、副腎細胞、膵臓細胞、胃細胞、腸細胞、腎臓細胞、膀胱細胞、結腸細胞、前立腺細胞、子宮細胞、卵巣細胞、子宮頸部細胞、精巣細胞、脾臓細胞、皮膚細胞、平滑筋細胞、心筋細胞、または横紋筋細胞を含み得るが、これらに限定されない。他のさらなる態様では、がんとしては、星状細胞腫、急性骨髄性白血病、未分化大細胞リンパ腫、急性リンパ芽球性白血病、血管肉腫、B細胞リンパ腫、バーキットリンパ腫、乳癌、膀胱癌、頭頸部癌、子宮頸癌、慢性リンパ芽球性白血病、慢性骨髄性白血病、結腸直腸癌、子宮内膜癌、食道扁平上皮癌、ユーイング肉腫、線維肉腫、神経膠腫、膠芽腫、ガストリノーマ、胃癌、胚芽腫、肝細胞癌、カポジ肉腫、ホジキンリンパ腫、喉頭扁平上皮癌、喉頭癌、白血病、平滑筋肉腫、脂肪腫、脂肪肉腫、黒色腫、マントル細胞リンパ腫、髄芽腫、中皮腫、粘液線維肉腫、骨髄性白血病、粘膜関連リンパ組織B細胞リンパ腫、多発性骨髄腫、高リスク骨髄異形成症候群、鼻咽腔癌、神経芽腫、神経線維腫、高悪性度非ホジキンリンパ腫、非ホジキンリンパ腫、肺癌、非小細胞肺癌、卵巣癌、食道癌、骨肉腫、膵臓癌、褐色細胞腫、前立腺癌、腎細胞癌、網膜芽腫、横紋筋肉腫、唾液腺腫瘍、シュワン細胞腫(Schwanomma)、小細胞肺がん、頭頸部の扁平上皮癌、精巣腫瘍、甲状腺癌、尿路上皮癌、およびウィルムス腫瘍が挙げられるが、これらに限定されない。
治療ベクターは、以下に限定されないが、レンチウイルスベクター、アデノ随伴ウイルスベクター、ポックスウイルスベクター、ヘルペスウイルスベクターなどの公知のトランスフェクションベクターおよび/または形質導入ベクター、タンパク質および/または脂質複合体、リポソーム、ミセルなどを介して送達され得る。
レンチウイルスのビリオン(粒子)は、ビリオン(ウイルス粒子)を産生するために必要なウイルスタンパク質をコードするベクター系によって発現される。プロモーターに作動可能に連結された、逆転写および組込みに必要なレンチウイルスのpolタンパク質をコードする核酸配列を含有する少なくとも1つのベクターがある。別の実施形態では、polタンパク質は、複数のベクターによって発現される。プロモーターに作動可能に連結された、ウイルスカプシドを形成するために必要なレンチウイルスのgagタンパク質をコードする核酸配列を含有するベクターもある。一実施形態では、このgagの核酸配列は、polの核酸配列の少なくとも一部とは別のベクター上にある。別の実施形態では、gagの核酸は、polタンパク質をコードする全てのpolの核酸配列とは別のベクター上にある。
本開示のベクター組成物は、目的の遺伝子または配列の短期、中期、または長期の発現、ならびに本開示のベクターのエピソームの維持を可能とする。したがって、投薬レジメンは、処置されている状態および投与方法に基づいて変化し得る。
図1に要約するように、レンチウイルスベクター系を開発した(環状形態)。治療ベクター、エンベローププラスミド、およびヘルパープラスミドのトランスフェクション後に、293T/17 HEK細胞(American Type Culture Collection、Manassas、VAより購入)中でレンチウイルス粒子を生産した。293T/17 HEK細胞のトランスフェクションにより、機能的なウイルス粒子が生産された。このトランスフェクションには、プラスミドDNAの取込み効率を増加させるために試薬ポリ(エチレンイミン)(PEI)を用いた。最初に、血清を含まない培養培地中にプラスミドおよびDNAを3:1の比(DNAに対するPEIの質量比)で別々に加えた。2~3日後、細胞培地を回収し、高速遠心分離および/または濾過とその後の陰イオン交換クロマトグラフィーによってレンチウイルス粒子を精製した。レンチウイルス粒子の濃度は、形質導入単位/ml(TU/ml)で表すことができる。TUの決定は、培養液中のHIV p24レベルの測定(p24タンパク質はレンチウイルス粒子中に組み込まれる)、定量PCRによる形質導入された細胞あたりのウイルスDNAコピー数の測定、または細胞の感染および光の使用(ベクターがルシフェラーゼまたは蛍光タンパク質マーカーをコードする場合)によって達成した。
ヘルパープラスミドの構築:Gag、Pol、およびインテグラーゼ遺伝子を含有するpNL4-3 HIVプラスミド(NIH Aids Reagent Program)由来のDNA断片の初期PCR増幅によってヘルパープラスミドを構築した。pCDNA3プラスミド(Invitrogen)中の同じ部位に挿入するために使用され得るEcoRIおよびNotI制限部位を有する断片を増幅するためのプライマーを設計した。フォワードプライマーは(5’-TAAGCAGAATTCATGAATTTGCCAGGAAGAT-3’)(配列番号31)であり、リバースプライマーは(5’-CCATACAATGAATGGACACTAGGCGGCCGCACGAAT-3’)(配列番号32)であった。
水疱性口内炎インディアナウイルス糖タンパク質(VSV-G)配列は、隣接EcoRI制限部位を用いてMWG Operonによって合成された。次いで、EcoRI制限部位においてDNA断片をpCDNA3.1プラスミド(Invitrogen)に挿入し、CMV特異的プライマーを使用するシークエンシングによって正しい配向であることを決定した。DNA配列は以下の通りであった:
Revを含まないヘルパープラスミドの構築:
RREおよびウサギベータグロビンポリA配列を含有するDNA断片を挿入することによって、Revを含まないヘルパープラスミドを構築した。この配列は、隣接XbaIおよびXmaI制限部位を用いてMWG Operonによって合成された。次いで、XbaIおよびXmaI制限部位においてRRE/ウサギポリAベータグロビン配列をヘルパープラスミドに挿入した。DNA配列は以下の通りである:
RSVプロモーターおよびHIV Rev配列は、隣接MfeIおよびXbaI制限部位を用いて、MWG Operonによって単一のDNA断片として合成された。次いで、CMVプロモーターがRSVプロモーターで置換されたMfeIおよびXbaI制限部位において、DNA断片をpCDNA3.1プラスミド(Invitrogen)に挿入した。DNA配列は以下の通りであった:
例えば図3に示すように、例示的な治療ベクターを設計し、開発した。
miRNA配列を含むFDPS miR(miRNA)、ウッドチャック転写後調節エレメント(WPRE)、およびU3領域に欠失を有するLTR。
GTCCTGGAGTACAATGCCATT(FDPS標的配列;配列番号49);
GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAGGACTTTTT(FDPS shRNA配列#1;配列番号1);
GCAGGATTTCGTTCAGCACTT(FDPS標的配列#2;配列番号50);
GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCCTGCTTTTT(FDPS shRNA配列#2;配列番号2);
GCCATGTACATGGCAGGAATT(FDPS標的配列#3;配列番号51);
GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACATGGCTTTTT(FDPS shRNA配列#3;配列番号3);
GCAGAAGGAGGCTGAGAAAGT(FDPS標的配列#4;配列番号52);および
GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTCTGCTTTTT(FDPS shRNA配列#4;配列番号4)。
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTGCCTACTGCCTCGGACTTCAAGGGGCT(miR30 FDPS配列#1;配列番号53)
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGTGCTGCCTACTGCCTCGGACTTCAAGGGGCT(miR30
FDPS配列#2;配列番号54)
TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTGCCTCGGA(miR30 FDPS配列#3;配列番号55)
CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCTCCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAAGTCAGGACACAAGGCCTGTTACTAGCACTCA(miR155 FDPS配列#1;配列番号56)
CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCTCCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAGTCTGACATTTTGGTATCTTTCATCTGACCA(miR21
FDPS配列#1;配列番号57)
GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCTCCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGTCCTTCCCTCCCAATGACCGCGTCTTCGTCG(miR185 FDPS配列#1;配列番号58)
miR30 FDPS配列#1:
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTGCCTACTGCCTCGGACTTCAAGGGGCT(配列番号53)
miR155 CD47標的配列#1:
CCTGGAGGCTTGCTGAAGGCTGTATGCTGTTATCCATCTTCAAAGAGGCAGTTTTGGCCACTGACTGACTGCCTCTTAAGATGGATAACAGGACACAAGGCCTGTTACTAGCACTCA(配列番号82)
miR21 cMyc配列:
CATCTCCATGGCTGTACCACCTTGTCGGGTGTTCGCCTCTTGACATTCTCCTGTTGAATCTCATGGAGAATGTCAAGGGCGAACACTGACATTTTGGTATCTTTCATCTGACCA(配列番号83)
阻害性RNAの設計:ホモサピエンスファルネシル二リン酸合成酵素(FDPS)転写物バリアント1のmRNA配列(NM_002004.3)を使用して、ヒト細胞においてFDPSレベルをノックダウンするための潜在的なsiRNAまたはshRNA候補を検索した。Broad Instituteのもの、またはThermo ScientificのBLOCK-iT(商標)RNAi DesignerなどのsiRNAまたはshRNA設計プログラムによって選択された候補から潜在的なRNA干渉配列を選択した。shRNA発現を調節するために、H1、U6、または7SKなどのRNAポリメラーゼIIIプロモーターの後ろにおいて、shRNA配列をレンチウイルスベクターに挿入し得る。また、RNA配列をマイクロRNA骨格内に埋め込んで、CMVまたはEF-1アルファなどのRNAポリメラーゼIIプロモーターによる発現を可能とし得る。RNA配列をsiRNAオリゴヌクレオチドとしても合成し、レンチウイルスベクターとは独立して利用してもよい。
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTGCCTACTGCCTCGGACTTCAAGGGGCT(配列番号53)
miR30 FDPS配列#2:
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGTGCTGCCTACTGCCTCGGACTTCAAGGGGCT(配列番号54)
阻害性RNAの選択:ホモサピエンスCD47分子(CD47)mRNAの配列(NM_001777)を使用して、ヒト細胞においてCD47レベルを低下させることができる潜在的なsiRNAまたはshRNA候補を検索した。Broad Instituteのもの、またはThermo ScientificのBLOCK-iT(商標)RNAi DesignerなどのsiRNAまたはshRNA設計プログラムによって選択された候補から潜在的なRNA干渉配列を選択した。最初に、shRNAの発現を調節するために、H1、U6、または7SKなどのRNAポリメラーゼIIIプロモーターのすぐ3’側において、個々の選択したshRNA配列をレンチウイルスベクターに挿入した。これらのレンチウイルスshRNA構築物を使用して細胞への形質導入を行い、特定のmRNAレベルの変化を測定した。mRNAレベルの低下のために最も強力なshRNAをマイクロRNA骨格内に個々に埋め込むことで、CMVまたはEF-1アルファRNAポリメラーゼIIプロモーターのいずれかによる発現を可能とした。RNA配列を合成siRNAオリゴヌクレオチドとしても合成し、レンチウイルスベクターを使用せずに細胞内に直接導入した。
表3に示すCD47 shRNA標的配列の非限定的な例を本明細書中に記載する実験において利用した。さらに、表3に詳述する配列は、本明細書中で詳述する治療ベクターにおいて使用することができる。
miR155 CD47標的配列#1:
CCTGGAGGCTTGCTGAAGGCTGTATGCTGTTATCCATCTTCAAAGAGGCAGTTTTGGCCACTGACTGACTGCCTCTTAAGATGGATAACAGGACACAAGGCCTGTTACTAGCACTCA(配列番号82)
miR155 CD47標的配列#2:
CCTGGAGGCTTGCTGAAGGCTGTATGCTGTTAGCTCGATGATCGTTTCACGTTTTGGCCACTGACTGACGTGAAACGCATCGAGCTAACAGGACACAAGGCCTGTTACTAGCACTCA(配列番号66)
miR155 CD47標的配列#3:
CCTGGAGGCTTGCTGAAGGCTGTATGCTGAAGAATGGCTCCAACAATGACGTTTTGGCCACTGACTGACGTCATTGTGAGCCATTCTTCAGGACACAAGGCCTGTTACTAGCACTCA(配列番号67)
miR155 CD47標的配列#4:
CCTGGAGGCTTGCTGAAGGCTGTATGCTGTATACACGCCGCAATACAGAGGTTTTGGCCACTGACTGACCTCTGTATCGGCGTGTATACAGGACACAAGGCCTGTTACTAGCACTCA(配列番号68)
阻害性RNAの設計:v-myc鳥類骨髄球腫症ウイルス性がん遺伝子のホモサピエンスホモログ(MYC)のmRNA配列(NM_002467.4)を使用して、肝細胞の細胞株においてMYCの発現をノックダウンするための潜在的なshRNA候補をスクリーニングした。MYCの発現を低下させることができる5つのMYC shRNA配列を得た。Broad Instituteのもの、またはThermo ScientificのBLOCK-iT(商標)RNAi DesignerなどのsiRNAまたはshRNA設計プログラムによって選択された候補から潜在的なRNA干渉配列を選択した。shRNA発現を調節するために、H1、U6、または7SKなどのRNAポリメラーゼIIIプロモーターの後ろにおいて、shRNA配列をレンチウイルスベクターに挿入し得る。また、RNA配列をマイクロRNA骨格内に埋め込んで、CMVまたはEF-1アルファなどのRNAポリメラーゼIIプロモーターによる発現を可能とし得る。RNA配列をsiRNAオリゴヌクレオチドとしても合成し、レンチウイルスベクターとは独立して利用してもよい。
miR155 cMyc配列:
CCTGGAGGCTTGCTGAAGGCTGTATGCTGTGTTCGCCTCTTGACATTCTCTTTTGGCCACTGACTGAGAGAATGTAGAGGCGAACACAGGACACAAGGCCTGTTACTAGCACTCA(配列番号70)
miR21 cMyc配列:
CATCTCCATGGCTGTACCACCTTGTCGGGTGTTCGCCTCTTGACATTCTCCTGTTGAATCTCATGGAGAATGTCAAGGGCGAACACTGACATTTTGGTATCTTTCATCTGACCA(配列番号83)
cMyc標的配列:
GAGAATGTCAAGAGGCGAACA(配列番号71)
cMyc shRNA配列:
GAGAATGTCAAGAGGCGAACACTCGAGTGTTCGCCTCTTGACATTCTCTTTTT
(配列番号13)
ヒト前立腺がん細胞株PC3を移植したマウスにおける、ゾレドロン酸ありまたはなしでのLV-shRNA-FDPS(ファルネシル二リン酸合成酵素)の共投与のプロトコールの概要。腫瘍細胞をin vitroで培養後、スクランブル配列の(機能しない)shRNA挿入物およびホタルルシフェラーゼ用発現カセットを有するレンチウイルスベクター対照、またはFDPS mRNAの発現を低下させることができるshRNAおよびホタルルシフェラーゼ用発現カセットを有するLV-FDPSを用いて形質導入した。形質導入された腫瘍細胞を皮下注射により免疫欠損マウスの脇腹に移植した。腫瘍が約200mm3の体積に達したら、全てのマウスに食塩水中の単回用量のゾレドロン酸(キログラム体重あたり100マイクログラム;これは標準的なヒトでの用量に類似する)を与える。ゾレドロン酸注射の7日後、画像検査を繰り返して、個々の腫瘍の体積および光子強度を測定した。
CMV GFP T2Aルシフェラーゼ配列を含有するpGF-1プラスミド(System Biosciences)をClaIおよびKPN1を用いて消化し、LV-H1-shFDPSプラスミドをBstBIおよびKpnI制限酵素(NEB)を用いて消化した。DNAを1%アガロースゲル上の電気泳動にかけ、DNAゲル抽出キット(Thermo Scientific)を用いてDNA断片を抽出した。T4 DNAリガーゼ(NEB)を用いて2つの断片をライゲートし、STBL3細菌(Thermo Scientific)の形質転換を行った。プラスミドDNAミニプレップキット(Thermo Scientific)を用いてプラスミドDNAを細菌から抽出し、DNAシークエンシング(Eurofins Genomics)によって配列を検証した。
詳細な実験プロトコール:
-19日目:175mlのフラスコでのコンフルエントな生育は1.87×107mlのPC3細胞を生じ、75mlのフラスコでのコンフルエントな生育は7.5×106mlのPC3細胞を生じる。
-7日目:PC3細胞を解凍し、生育する。
-4日目:材料の調製および送達。レンチベクター対照およびレンチ-shRNA-FDPSで形質導入したPC3細胞を調製する。
1. 75mlのフラスコ中、50%コンフルエントのPC3細胞に12μlのレンチ対照+8μlのポリブレンを加え、5分間インキュベートした後、4mlのRPMI-10と混合し、PC3細胞の表面を覆う。
2. 75mlのフラスコ中、50%コンフルエントのPC3細胞に20μlのレンチ-FDPS+8μlのポリブレンを加え、5分間インキュベートした後、4mlのRPMI-10と混合し、PC3細胞の表面を覆う。
3. 形質導入した細胞を37℃で8時間インキュベートする。終夜培養のために6mlのRPMI-10を加える。
-2日目:75mlの形質導入したPC3細胞(コンフルエントの7.5×106細胞)をトリプシン処理し、175mlのフラスコに移す。
0日目:材料の調製および送達
1. 80%コンフルエントのレンチベクターで形質導入したPC3細胞およびレンチ-FDPSで形質導入したPC3細胞を別々にトリプシン処理し、細胞をカウントする。
レンチベクター:1.5×108細胞(50×3×106/5ml)15フラスコ
レンチ-FDPS:1.5×108細胞(50×3×106/5ml)20フラスコ
2. FBSを含まないRPMI中に、レンチベクターで形質導入したPC3細胞およびレンチ-FDPSで形質導入したPC3細胞を再懸濁し、3×106細胞/100μlの最終濃度とする。
本発明の実施形態の例として、以下の項目が挙げられる。
(項目1)
治療カーゴ部分を含むウイルスベクターであって、前記治療カーゴ部分が、少なくとも1つの予め定められた相補的mRNA配列に結合することができる少なくとも1つのスモールRNA配列を含み、前記少なくとも1つの相補的mRNA配列が、FDPSのmRNA配列を含む、ウイルスベクター。
(項目2)
前記治療カーゴ部分が、第2の予め定められた相補的mRNA配列に結合することができる第2のスモールRNA配列をさらに含み、前記第2の予め定められた相補的mRNA配列が、CD47のmRNA配列またはcMycのmRNA配列を含む、項目1に記載のウイルスベクター。
(項目3)
前記少なくとも1つのスモールRNAが、第1のプロモーターの制御下にあり、前記第2のスモールRNA配列が、第2のプロモーターの制御下にある、項目2に記載のウイルスベクター。
(項目4)
前記治療カーゴ部分が、第3の予め定められた相補的mRNA配列に結合することができる第3のスモールRNA配列をさらに含み、前記第3の予め定められた相補的mRNA配列が、CD47のmRNA配列またはcMycのmRNA配列を含む、項目2に記載のウイルスベクター。
(項目5)
前記第3のスモールRNA配列が、第3のプロモーターの制御下にある、項目4に記載のウイルスベクター。
(項目6)
前記スモールRNA配列が、単一のプロモーターの制御下にある、項目4に記載のウイルスベクター。
(項目7)
前記スモールRNA配列が、miRNAまたはshRNAを含む、項目1に記載のウイルスベクター。
(項目8)
前記スモールRNA配列が、
GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAGGACTTTTT(配列番号1);
GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCCTGCTTTTT(配列番号2);
GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACATGGCTTTTT(配列番号3);または
GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTCTGCTTTTT(配列番号4)
を含むFDPSのスモールRNA配列と少なくとも80%、または少なくとも85%、または少なくとも90%、または少なくとも95%の同一性パーセントを有する配列を含む、項目1に記載のウイルスベクター。
(項目9)
前記スモールRNA配列が、配列番号1、2、3、または4から選択される、項目8に記載のウイルスベクター。
(項目10)
前記第2のスモールRNA配列が、
GGTGAAACGATCATCGAGCCTCGAGGCTCGATGATCGTTTCACCTTTTT(配列番号5);
GCTACTGGCCTTGGTTTAACTCGAGTTAAACCAAGGCCAGTAGCTTTTT(配列番号6);
CCTCCTTCGTCATTGCCATCTCGAGATGGCAATGACGAAGGAGGTTTTT(配列番号7);
GCATGGCCCTCTTCTGATTCTCGAGAATCAGAAGAGGGCCATGCTTTTT(配列番号8);または
GGTGAAACGATCATCGAGCTACTCGAGTAGCTCGATGATCGTTTCACCTTTTT(配列番号9)を含むCD47のスモールRNA配列、あるいは
GCTTCACCAACAGGAACTATGCTCGAGCATAGTTCCTGTTGGTGAAGCTTTT(配列番号10);
GCGAACACACAACGTCTTGGACTCGAGTCCAAGACGTTGTGTGTTCGCTTTT(配列番号11);
GACATGGTGAACCAGAGTTTCCTCGAGGAAACTCTGGTTCACCATGTCTTTTT(配列番号12);
GAGAATGTCAAGAGGCGAACACTCGAGTGTTCGCCTCTTGACATTCTCTTTTT(配列番号13);または
GCTCATTTCTGAAGAGGACTTCTCGAGAAGTCCTCTTCAGAAATGAGCTTTTT(配列番号14)
を含むcMycのスモールRNA配列と少なくとも80%、または少なくとも85%、または少なくとも90%、または少なくとも95%の同一性パーセントを有する配列を含む、項目2に記載のウイルスベクター。
(項目11)
前記第2のスモールRNA配列が、配列番号5、6、7、8、9、10、11、12、13、または14から選択される、項目10に記載のウイルスベクター。
(項目12)
前記第3のスモールRNA配列が、配列番号5、6、7、8、もしくは9を含むCD47のスモールRNA配列または配列番号10、11、12、13、もしくは14を含むcMycのスモールRNA配列と少なくとも80%、または少なくとも85%、または少なくとも90%、または少なくとも95%の同一性パーセントを有する配列を含む、項目4に記載のウイルスベクター。
(項目13)
前記第3のスモールRNA配列が、配列番号5、6、7、8、9、10、11、12、13、または14から選択される、項目12に記載のウイルスベクター。
(項目14)
レンチウイルスベクターである、項目1から13のいずれか一項に記載のウイルスベクター。
(項目15)
標的細胞に感染することができるレンチウイルス粒子であって、
a.前記標的細胞に感染するために最適化されたエンベロープタンパク質、および
b.項目1から14のいずれか一項に記載のウイルスベクター
を含む、レンチウイルス粒子。
(項目16)
a.項目15に記載のレンチウイルス粒子、および
b.アミノビスホスホネート薬物
を含む組成物。
(項目17)
前記アミノビスホスホネート薬物が、ゾレドロン酸である、項目16に記載の組成物。
(項目18)
治療有効量の項目16または17に記載の組成物を被験体に投与することを含む、前記被験体におけるがんを処置する方法。
(項目19)
a.治療有効量の項目15に記載のレンチウイルス粒子、および
b.治療有効量のアミノビスホスホネート薬物
を被験体に投与することを含む、前記被験体におけるがんを処置する方法。
(項目20)
a.有効量の項目15に記載のレンチウイルス粒子、および
b.有効量のアミノビスホスホネート薬物
を被験体に投与することを含む、前記被験体におけるがんを予防する方法。
(項目21)
前記アミノビスホスホネート薬物が、ゾレドロン酸である、項目19または20に記載の方法。
(項目22)
ステップ(a)およびステップ(b)が同時に実行される、項目19または20に記載の方法。
(項目23)
規定された長さの期間が、ステップ(a)とステップ(b)との間に経過する、項目19または20に記載の方法。
(項目24)
治療有効量の前記レンチウイルス粒子が、複数の単回用量の前記レンチウイルス粒子を含む、項目19または20に記載の方法。
(項目25)
治療有効量の前記アミノビスホスホネート薬物が、単回用量の前記アミノビスホスホネート薬物を含む、項目19または20に記載の方法。
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