JP6193120B2 - 組換え腫瘍ワクチンおよびこのようなワクチンを生産する方法 - Google Patents
組換え腫瘍ワクチンおよびこのようなワクチンを生産する方法 Download PDFInfo
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Description
本開示は、抗原提示ポリペプチドをコードする第1のポリヌクレオチド、サイトカインをコードする第2のポリヌクレオチド、ならびに第1のポリヌクレオチドおよび第2のポリヌクレオチドの少なくとも1つに機能可能に連結している少なくとも1つのプロモーターを含有する組成物を有する組換え腫瘍ワクチンに関する。
上記のポリヌクレオチドは、1つまたは複数の発現ベクター内に挿入することができる。本開示は、抗原提示ポリペプチドをコードする第1のポリヌクレオチドセグメント、サイトカインをコードする第2のポリヌクレオチドセグメント、および少なくとも1つのプロモーターを含有する発現ベクターであって、少なくとも1つのプロモーターが第1のポリヌクレオチドセグメントおよび第2のポリヌクレオチドセグメントの少なくとも1つに機能可能に連結している発現ベクターを提供する。
本開示において記載されている核酸組成物、発現ベクター、および宿主細胞は、腫瘍および/または癌を予防および/または治療するための腫瘍ワクチンとして用いることができる。別の態様において、本開示は、薬学的に許容可能な担体と、本明細書において提供される核酸組成物、発現ベクター、および/または宿主細胞とを含む医薬組成物を提供する。核酸、発現ベクター、および宿主細胞は、当技術分野において周知の方法を用いて、構築、単離、および精製することができる。本明細書において用いられる用語「薬学的に許容可能な担体」は、本開示の核酸、発現ベクター、および/または宿主細胞の保管および対象への投与を容易にし得る、任意のおよび全ての溶媒、分散媒質、被覆剤、抗菌剤および抗真菌剤、等張剤および吸収遅延剤などを言う。薬学的に許容可能な担体には、任意の適切な構成要素、例えば、限定はしないが、生理食塩水、リポソーム、ポリマー性賦形剤、コロイド、または担体粒子が含まれ得る。
別の態様において、本開示は、薬学的に許容可能な担体と本開示の腫瘍ワクチンとを含有する医薬組成物を対象に投与することを含む、腫瘍を治療する方法を提供する。
アデノウイルスベクターAd−HSP−hGM−CSFを、以下に記載されるように構築する。
アデノウイルスベクターAd−HSP−mGM−CSFを、以下に記載されるように構築する。
アデノウイルスベクターAd−HSP−mGM−CSFを用いて、Hela細胞およびHepB細胞をそれぞれ含めたヒト細胞系、ならびにマウスB16細胞を感染させる。
ウイルスベクターを、T型フラスコ内のHEK293細胞において増幅し、CsCl勾配遠心分離によって精製する。ウイルス収量を、ウイルス滴定アッセイおよび分光光度計法によって決定する。ウイルスを、その後の使用のために−70℃で保管する。
アデノウイルスベクターAd−HSP−hGM−CSFの細胞傷害性を、A549(Fudan University、Shanghai、Chinaから購入した、腺癌ヒト歯槽基底上皮細胞)、Hepal−6(China Centre for Type Culture Collection(CCTCC)、Wuhan、Chinaから購入した、マウス肝臓癌細胞)、MCF−7(Fudan University、Shanghai、Chinaから購入した、ヒト乳癌細胞)、TCa8113(Chinese Academy of Science、Shanghaiから購入した、ヒト舌癌細胞)、ACC−M(CCTCC、Wuhan、Chinaから購入した、肺に高度に転移性である腺様嚢胞癌細胞クローン)、HeLa(Fudan University、Shanghai、Chinaから購入した、ヒト子宮頸癌細胞)、Hep3B(Fudan University、Shanghai、Chinaから購入した、ヒト肝臓癌細胞)、およびLncap(Chinese Academy of Science、Shanghaiから購入した、アンドロゲン感受性のヒト前立腺腺癌細胞)を含めた異なる腫瘍細胞系において、他のウイルスベクターと比較する。Ad−GM−CSF(プラスミドpORF9−hGM−CSFとpAdEasy−1ウイルスDNAプラスミドとの間の相同組換えによって構築された)、ONYX015(p53欠損癌細胞において選択的に複製するE1B−55k欠失アデノウイルス)(千葉大学から譲り受けた)、およびAd−CMV−HSP(Shanghai Sunway Biotechから譲り受けた)を、細胞傷害効果の比較のために並行して試験する。
組換え腫瘍溶解性アデノウイルスAd−HSP−mGM−CSFの細胞傷害性を、HEK293、Hep3B、A549、7402(Fudan University、Shanghai、Chinaの肝癌研究所から購入した、肝細胞癌細胞系)、7721(liver cancer institute、Fudan University、Shanghai、Chinaから購入した、肝細胞癌細胞系)、およびHelaを含めた異なるヒト腫瘍細胞系において試験し、これらの細胞系の全てを、RPMI1640完全培地において維持する。正常細胞系(2BS)を対照として用いる。HEK293細胞系は、アデノウイルスのE1遺伝子で形質転換されており、したがって任意のタイプのアデノウイルスの成長を支え得るため、この細胞系を陽性対照として用いる。特異的殺腫瘍効果を比較する。
Ad−HSP−mGM−CSFの治療効果を、C57マウスB16腫瘍モデルにおいて研究する。高用量群、中用量群、および低用量群を含めた3つの実験群を設定する。ブランク対照群(10%グリセリンPBS)および陽性対照群(2mg/kgのシスプラチン)もまた含める。投与群を表3に示す。
Claims (7)
- 抗原提示ポリペプチドをコードする第1のポリヌクレオチドセグメント、
サイトカインをコードする第2のポリヌクレオチドセグメント、ならびに
構成的プロモーターおよび腫瘍特異的なプロモーター
を含み、
第1のポリヌクレオチドが構成的プロモーターに機能可能に連結しており、第2のポリヌクレオチドが腫瘍特異的なプロモーターに機能可能に連結しており、
抗原提示ポリペプチドは、Hsp60、Hsp70、Hsp71、Hsp72、Hsp90、Hsp104、Hsp110、およびグルコース調節型のタンパク質からなる群から選択される熱ショックタンパク質であり、グルコース調節型のタンパク質はGrp75、Grp78、Grp94およびGrp170からなる群から選択され、サイトカインが、マクロファージ/顆粒球コロニー刺激因子であり、発現ベクターが、E1a遺伝子を含有する、複製可能アデノウイルスベクターであり、E1a遺伝子が、腫瘍特異的なプロモーターに機能可能に連結している、
癌および腫瘍を治療するための発現ベクター。 - 熱ショックタンパク質がHsp70である、請求項1に記載の発現ベクター。
- プロモーターに機能可能に連結している、サイトカインをコードする第3のポリヌクレオチドをさらに含む、請求項1に記載の発現ベクター。
- 少なくとも1つのプロモーターが真核生物プロモーターである、請求項1に記載の発現ベクター。
- 請求項1に記載の発現ベクターを含有する、単離された宿主細胞。
- 薬学的に許容可能な担体と、請求項1に記載の発現ベクター、および請求項5に記載の単離された宿主細胞のいずれか1つとを含む医薬組成物。
- 癌を治療するための医薬組成物である、請求項6に記載の医薬組成物。
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PCT/CN2010/074823 WO2012000188A1 (en) | 2010-06-30 | 2010-06-30 | Recombinant tumor vaccine and method of producing such |
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PCT/CN2011/076668 WO2012000443A1 (en) | 2010-06-30 | 2011-06-30 | Recombinant tumor vaccine and method of producing such vaccine |
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TWI531652B (zh) | 2005-12-02 | 2016-05-01 | 美國紐約大學西奈山醫學院 | 表現非原生表面蛋白質之嵌合病毒及其用途 |
EP2313097B1 (en) | 2008-07-24 | 2013-03-27 | Nerviano Medical Sciences S.r.l. | Therapeutic combination comprising an aurora kinase inhibitor and antiproliferative agents |
EP2393921B1 (en) | 2009-02-05 | 2015-07-15 | Icahn School of Medicine at Mount Sinai | Chimeric newcastle disease viruses and uses thereof |
JP6596411B2 (ja) | 2013-03-14 | 2019-10-23 | アイカーン スクール オブ メディシン アット マウント サイナイ | ニューカッスル病ウイルス及びその使用 |
CN103159859B (zh) * | 2013-03-22 | 2014-03-12 | 中国医学科学院医学实验动物研究所 | 一种仙台病毒抗原肽组合物及其在仙台病毒感染检测中的应用 |
CN103193865B (zh) * | 2013-03-22 | 2014-09-17 | 中国医学科学院医学实验动物研究所 | 一种仙台病毒抗原肽及其在仙台病毒感染检测中的应用 |
AU2015222685A1 (en) | 2014-02-27 | 2016-09-08 | Viralytics Limited | Combination method for treatment of cancer |
CN106794208B (zh) | 2014-07-17 | 2021-06-01 | 西密歇根大学信托董事会 | 用于处理癌细胞的组合物及其方法 |
EP3388522B1 (en) * | 2015-12-08 | 2020-08-12 | University-Industry Foundation, Yonsei University | Antitumor composition comprising gm-csf gene, flt3l-trail fusion gene, shrna inhibiting tgf- expression, and shrna inhibiting hsp expression |
JOP20190256A1 (ar) | 2017-05-12 | 2019-10-28 | Icahn School Med Mount Sinai | فيروسات داء نيوكاسل واستخداماتها |
WO2019093435A1 (ja) * | 2017-11-08 | 2019-05-16 | 国立大学法人 鹿児島大学 | 安全を確保しながら転移性がんまで効果的に治療可能な、搭載する免疫誘導遺伝子の最適発現レベルを与える発現制御システムを有する腫瘍溶解性ウイルス(腫瘍溶解性免疫治療) |
KR102184377B1 (ko) | 2018-02-19 | 2020-11-30 | 고려대학교 산학협력단 | 열충격단백질의 에피토프를 포함하는 백신 및 이의 용도 |
CN116555191B (zh) * | 2023-05-26 | 2024-09-17 | 东北农业大学 | 编码白细胞介素24和粒细胞-巨噬细胞集落刺激因子的新城疫病毒在肿瘤治疗中的应用 |
CN116814688B (zh) * | 2023-06-30 | 2024-06-07 | 呈诺再生医学科技(北京)有限公司 | 一种携带双特异性启动子的载体、构建方法及其应用 |
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EP2329846B1 (en) * | 2000-09-08 | 2014-11-12 | University Of Maryland, Baltimore | Genetically engineered co-expression DNA vaccines, construction methods and uses thereof |
IL152420A0 (en) * | 2001-02-23 | 2003-05-29 | Novartis Ag | Novel oncolytic adenoviral vectors |
CN1304559C (zh) * | 2001-10-09 | 2007-03-14 | 杭州康科生物技术有限公司 | 表达热休克蛋白的溶瘤微生物及其应用 |
US20030108524A1 (en) * | 2001-10-18 | 2003-06-12 | Melissa Diagana | Vectors for expressing multiple transgenes |
US6984389B2 (en) * | 2002-04-25 | 2006-01-10 | University Of Connecticut Health Center | Using heat shock proteins to improve the therapeutic benefit of a non-vaccine treatment modality |
AU2003278695A1 (en) * | 2002-05-28 | 2004-02-02 | Maxygen, Inc. | Nucleic acid vectors |
CN100381460C (zh) * | 2004-11-30 | 2008-04-16 | 北京市肿瘤防治研究所 | Her-2模拟抗原表位及含有该表位的肽 |
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CN101563104A (zh) * | 2006-02-01 | 2009-10-21 | 约翰霍普金斯大学 | 用于肿瘤或传染性疾病免疫预防或免疫治疗的多肽-核酸结合物 |
CN101461942B (zh) * | 2008-08-27 | 2010-07-21 | 时宏珍 | 负载重组人hsp70多肽复合物的树突状细胞疫苗、制备方法与应用 |
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EP2603223A4 (en) | 2014-03-05 |
US20130108665A1 (en) | 2013-05-02 |
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