JP2019532635A - 腫瘍溶解性ウイルスを腫瘍に標的化する方法 - Google Patents
腫瘍溶解性ウイルスを腫瘍に標的化する方法 Download PDFInfo
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Abstract
Description
本出願は、2016年9月19日出願の米国仮出願第62/396、604号の優先権を主張するものであり、図表、核酸配列表、アミノ酸配列表、図面を含む全文を参照することにより組み込まれる。
MAHAMENSWTISKEYHIDEEVGFALPNPQENLPDFYNDWMFIAKHLPDLIESGQLRERVEKLNMLSIDHLTDHKSQRLARLVLGCITMAYVWGKGHGDVRKVLPRNIAVPYCQLSKKLELPPILVYADCVLANWKKKDPNKPLTYENMDVLFSFRDGDCSKGFFLVSLLVEIAAASAIKVIPTVFKAMQMQERDTLLKALLEIASCLEKALQVFHQIHDHVNPKAFFSVLRIYLSGWKGNPQLSDGLVYEGFWEDPKEFAGGSAGQSSVFQCFDVLLGIQQTAGGGHAAQFLQDMRRYMPPAHRNFLCSLESNPSVREFVLSKGDAGLREAYDACVKALVSLRSYHLQIVTKYILIPASQQPKENKTSEDPSKLEAKGTGGTDLMNFLKTVRSTTEKSLLKEG
(UniProt寄託番号 P14902)
1 aatttctcac tgcccctgtg ataaactgtg gtcactggct gtggcagcaa ctattataag
61 atgctctgaa aactcttcag acactgaggg gcaccagagg agcagactac aagaatggca
121 cacgctatgg aaaactcctg gacaatcagt aaagagtacc atattgatga agaagtgggc
181 tttgctctgc caaatccaca ggaaaatcta cctgattttt ataatgactg gatgttcatt
241 gctaaacatc tgcctgatct catagagtct ggccagcttc gagaaagagt tgagaagtta
301 aacatgctca gcattgatca tctcacagac cacaagtcac agcgccttgc acgtctagtt
361 ctgggatgca tcaccatggc atatgtgtgg ggcaaaggtc atggagatgt ccgtaaggtc
421 ttgccaagaa atattgctgt tccttactgc caactctcca agaaactgga actgcctcct
481 attttggttt atgcagactg tgtcttggca aactggaaga aaaaggatcc taataagccc
541 ctgacttatg agaacatgga cgttttgttc tcatttcgtg atggagactg cagtaaagga
601 ttcttcctgg tctctctatt ggtggaaata gcagctgctt ctgcaatcaa agtaattcct
661 actgtattca aggcaatgca aatgcaagaa cgggacactt tgctaaaggc gctgttggaa
721 atagcttctt gcttggagaa agcccttcaa gtgtttcacc aaatccacga tcatgtgaac
781 ccaaaagcat ttttcagtgt tcttcgcata tatttgtctg gctggaaagg caacccccag
841 ctatcagacg gtctggtgta tgaagggttc tgggaagacc caaaggagtt tgcagggggc
901 agtgcaggcc aaagcagcgt ctttcagtgc tttgacgtcc tgctgggcat ccagcagact
961 gctggtggag gacatgctgc tcagttcctc caggacatga gaagatatat gccaccagct
1021 cacaggaact tcctgtgctc attagagtca aatccctcag tccgtgagtt tgtcctttca
1081 aaaggtgatg ctggcctgcg ggaagcttat gacgcctgtg tgaaagctct ggtctccctg
1141 aggagctacc atctgcaaat cgtgactaag tacatcctga ttcctgcaag ccagcagcca
1201 aaggagaata agacctctga agacccttca aaactggaag ccaaaggaac tggaggcact
1261 gatttaatga atttcctgaa gactgtaaga agtacaactg agaaatccct tttgaaggaa
1321 ggttaatgta acccaacaag agcacatttt atcatagcag agacatctgt atgcattcct
1381 gtcattaccc attgtaacag agccacaaac taatactatg caatgtttta ccaataatgc
1441 aatacaaaag acctcaaaat acctgtgcat ttcttgtagg aaaacaacaa aaggtaatta
1501 tgtgtaatta tactagaagt tttgtaatct gtatcttatc attggaataa aatgacattc
1561 aataaataaa aatgcataag atatattctg tcggctgggc gcggtggctc acgcctgtaa
1621 tcccagcact ttgggaggcc gaggcgggcg gatcacaagg tcaggagatc gagaccatct
1681 tggctaacac ggtgaaaccc cgtctctact aaaaatacaa aaaattagcc gggcgcggtg
1741 gcgggcacct gtagtcccag ctactcggga ggctgaggca ggagaatggc gtgaacctgg
1801 gaggcggagc ttgcagtgag ccaagattgt gccactgcaa tccggcctgg gctaaagagc
1861 gggactccgt ctcaaaaaaa aaaaaaaaaa gatatattct gtcataataa ataaaaatgc
1921 ataagatata aaaaaaaaaa aaaa
実施形態1 (a)自然発生又は遺伝子組換え腫瘍溶解性ウイルスにより感染した、又は(b)インドールアミン2,3−ジオキシゲナーゼ(IDO)欠損、又は(a)と(b)の両方である、間葉系幹細胞(MSC)。
「癌」及び「悪性腫瘍」という用語は、典型的に無秩序な細胞成長を特徴とする哺乳類における生理学的状態のことを指す、又は説明するのに区別なく用いられる。癌は、薬剤抵抗性又は薬剤感受性である。癌は、原発性又は転移性である。癌は、初期、中期又は後期の疾患、そして急性か慢性で表される。ある実施形態において、癌は肺癌である。ある実施形態において、癌は、肺非小細胞癌(NSCLC)又は小細胞肺癌である。
RSVは、一般的に、舌尖軌道上皮細胞に感染するが、血液及び骨髄の様々な免疫細胞にも感染する(17−19)。発明者らの実験室における細胞操作エラーにより、ヒトMSC(hMSC)はRSVに極めて罹患し易いことが分かった(図1)。72時間p.i.以内に〜90%の細胞が感染し、RSVは容易かつ攻撃的にMSC中で複製される(図1A−C)。IFN−β及びIDOの高発現レベルが、モックに比べてRSV感染MSCにおいて認められた(図1D−E)。また、これらの細胞は、IL−1β、IL−6、IL−8、プロスタグランジンD2(PGD2)及びCXCR4(図示せず)の発現を示す。
RSV感染MSCの免疫学的重要性を調べるために、本発明者らは、フレッシュヒト末梢血単核細胞(PBMC)を単離し、MSCから馴化培地(CM)で処理した。PBMSを、5,6−カルボキシフルオセイン二酢酸サクシニミジルエステル(CFSE)で染色し、IDO抑制剤、1−メチルトリプトファン(1−MT)及びビタミンK3有り又は無しで、RSVに感染したMSCから集めたCMで処理した。予測通り、MSC培養上清中で分泌されたIDOは、リンパ球増殖を抑制した(図2A)が、1−MT又はビタミンK3で処理したRSV感染MSCは、キヌレニンレベルが減少し(図2C)、フローサイトメトリーによるCFSE色素希釈により測定された、PBMC増殖に対する悪影響が取り除かれた(図2A)。しかしながら、1−MT又はビタミンK3による処理で、ウイルス力価により求められたRSV感染は減少しなかった(図2B)。本発明者らはまた、wt及びIDOノックアウトマウスのRSV感染の罹患し易さについても調べた。wt及びIDOノックアウトマウスにRSV感染させ、RSV複製をした。wt対IDOノックアウトマウスの肺で認められた、PFUs又はRSVヌクレオカプシド(RSVN)トランスクリプト(図2E)又はIFN−βトランスクリプトの数における統計的な差は認められなかった(図2F)。
オフターゲット効果を有するIDO抑制剤を使用する変形方法として、本発明者らは、CRISPR/Cas9システムを利用して、RSV感染前のhMSCからIDO遺伝子をノックアウトした。異なるIDO特異性ガイドRNA(LvA及びLvB)を発現する2つの別のプラスミドと、標的でないスクランブルガイドRNA(LvS)(GeneCopoeia)を発現するコントロールプラスミドを個別にhMSCへ形質導入した。プラスミドの発現は、細胞中のmCherry(赤)から蛍光顕微鏡検査法により明らかとなった(図3A)。同様に、rgRSVによる感染を、GFP(緑)蛍光により観察した(図3A)。IDOノックアウトとコントロールhMSCからの馴化培地を用いて、図2Aに示す通り、増殖アッセイ中、PBMCを処理した。コントロールhMSC(LvS)からの培地は、図2Aに示した通り、PBMC増殖中、同様に減少したが、2つのIDOノックアウト構造(LvA及びLvB)のそれぞれからの培地でのPBMC処理は、増殖においてRSV関連の減少を示さず(図3B)、これは、hMSCが、IDO発現しなかったことを示している。しかしながら、IDO欠損hMSCは、RSV感染の罹患のし易さを保持していた(図3C)。
1−MT のhMSCの遊走能に与える影響を調べるために、本発明者らは、ルイス肺癌由来(LLC1)細胞を下部チャンバーに入れて、栄養因子とした、ボイデンチャンバー湿潤アッセイを用いた。MSCを、8.0μmのポアのあるPET膜(BD Bioscience)上のマトリゲル層の上部で播種させ、コントロールMSC培地又は1MT含有培地で処理した。細胞を、PBS中4%パラホルムアルデヒドに固定する前、24時間、共生培養した。上部マトリゲル層をキュータップにより除去し、マイグレート細胞をギムザ染色により目視化して数えた。図4に示す結果によれば、IDO抑制剤によって、hMSCのLLC1細胞へのマイグレーションは抑制されなかったことが分かる。
LLC1細胞を、赤色蛍光マーカーmKate2(14)を発現するrA2−KL19F菌株の1及び5MOIに感染させ、蛍光顕微鏡検査法を用いて細胞を調べた。感染後48時間で、細胞の大半がRSVに感染していることが分かった(図5A)。本発明者らは、さらに、LLC1チューモロイド(Tumoroid)を感染させる、RSV感染hMSC(図2)の馴化培地の可能性について調べた。LLC1チューモロイドを、rgRSV感染MSCの馴化培地で90分間培養し、感染後72時間の細胞を、共焦点顕微鏡により調べた。結果によれば、LLC1チューモロイドは、rgRSVに容易に感染したことが分かり(図5B)、このプラットフォームの可能性は、遺伝子操作されたRSVエクス・ビボの腫瘍溶解性の可能性をスクリーンすることが分かる。hMSCは、腫瘍向性を持つことが知られている。さらに、マウス腫瘍に対するヒトMSCの腫瘍向性は、以前から示されている(20)。これと一致して、鼻腔内又はi.v.投与されるとき(図5D)、RSV負荷hMSCは、腫瘍を含む(正所性LLC1接種)C57BL/6マウスの肺に誘導された(図5C)。さらに、RSV負荷hMSCがLLC1腫瘍を含むマウスに鼻腔内投与されると、hMSCは生き残り、RSVは腫瘍細胞で複製された(図5E〜F)。
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SEQ ID NO:1−ヒトIDOアミノ酸配列(UniProt寄託番号P14902)
SEQ ID NO:2−ヒトIDO核酸配列(NCBI寄託番号NM_002164、バージョンNM_002164.5)
Claims (20)
- (a)自然発生又は遺伝子組換え腫瘍溶解性ウイルスにより感染した、又は(b)インドールアミン2,3−ジオキシゲナーゼ(IDO)欠損、又は(a)と(b)の両方である、間葉系幹細胞(MSC)。
- 前記MSCは、自然発生又は遺伝子組換え腫瘍溶解性ウイルスにより感染している、請求項1に記載のMSC。
- 前記MSCは、IDO欠損である、請求項1に記載のMSC。
- 前記MSCは、自然発生又は遺伝子組換え腫瘍溶解性ウイルスにより感染しており、前記MSCは、IDO欠損である、請求項1に記載のMSC。
- 前記腫瘍溶解性ウイルスは、RSウイルス(RSV)である、請求項1〜4のいずれか一項に記載のMSC。
- 前記MSCは、ヒトMSCである、請求項1〜4のいずれか一項に記載のMSC。
- 前記MSCには、IDOのCRISPR介在性ノックアウトによりIDO欠損が付与されている、請求項1〜4のいずれか一項に記載のMSC。
- 請求項1〜4のいずれか一項に記載の有効量のMSCを、それを必要とする、ヒトまたはヒト以外の動物対象に投与することを含む、癌の治療方法。
- 前記癌は、肺癌である、請求項8に記載の方法。
- 前記肺癌は、肺非小細胞癌(NSCLC)である、請求項9に記載の方法。
- インドールアミン2,3−ジオキシゲナーゼ(IDO阻害剤)の阻害剤の前記対象への投与をさらに含む、請求項8に記載の方法。
- MSCを提供し、前記MSCを腫瘍溶解性ウイルスで感染させることを含む、腫瘍溶解性剤を製造する方法。
- 前記MSCは、感染時、インドールアミン2,3−ジオキシゲナーゼ(IDO)欠損である、請求項12に記載の方法。
- 前記MSCインドールアミン2,3−ジオキシゲナーゼ(IDO)欠損を、前記感染の前又は後にさらに付与する、請求項12に記載の方法。
- 癌細胞を、イン・ビトロ又はイン・ビボで、請求項1〜4のいずれか一項に記載の有効量のMSCと接触又は近接させることを含む、イン・ビトロ又はイン・ビボで癌細胞の溶解又はアポトーシスを誘導する方法。
- 前記癌細胞は、肺癌細胞である、請求項15に記載の方法。
- 前記肺癌細胞は、肺非小細胞癌(NSCLC)である、請求項16に記載の方法。
- 前記イン・ビトロ又はイン・ビボで癌細胞をインドールアミン2,3−ジオキシゲナーゼ(IDO抑制剤)と接触させることをさらに含む、請求項15に記載の方法。
- 請求項1〜4のいずれか一項に記載のMSCと、医薬的に許容される担体又は希釈剤とを含む組成物。
- アジュバントをさらに含む、請求項19に記載の組成物。
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