JP2021509015A - 安全性及び抗がん効果が改善した腫瘍溶解性ウイルス - Google Patents
安全性及び抗がん効果が改善した腫瘍溶解性ウイルス Download PDFInfo
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Abstract
Description
以降、本発明は実施例を参照して詳細に記載する。しかしながら、以下の実施例は例示の目的のためだけであり、本発明の範囲を限定することを意図しない。
実施例1.1.シャトルプラスミドベクターの構築
野生型ワクシニアウイルス(NYC保健省株、VR−1536)は、アメリカ培養細胞系統保存機関(ATCC)から購入された。組換えのため、HSV1−TK遺伝子(pSE/Lプロモーター)及びホタルルシフェラーゼレポーター遺伝子(p7.5プロモーター)を含むpUC57amp+(Genewiz,USA)が、シャトルプラスミドベクターとして使用された(図1)。
組換えウイルスを確保するため、HeLa細胞(ATCC)は、4×105個の細胞/ウェルの条件、及び10%ウシ胎仔血清を含有するEMEM培地の状態で、6ウェルプレート中で調製された。次いで、細胞は0.05MOIの野生型ワクシニアウイルスによって処置された。2時間後、培地は2%ウシ胎仔血清を含有するEMEM培地で置き換えられ、次いで細胞は、Xfect(商標)ポリマー(Clontech 631317,USA)を用いることによって実施例1.1で構築されたように4μgの線状化シャトルプラスミドベクターによってトランスフェクトされた。4時間のインキュベーション後、培地は、2%ウシ胎仔血清を含有する新しいEMEM培地で置き換えられ、次いで細胞は72時間さらにインキュベートされた。HeLa細胞でのルシフェラーゼ活性が確認され、HSV1−TK遺伝子を含有する組換えワクシニアウイルスを得たことが確認された。
実施例1.2で調製されたOTS−412がHSV1−TK断片を発現することを確認するため、OTS−412をHeLa細胞に感染させ、生じる細胞は24時間後に回収され、溶解されてタンパク質を抽出された。抽出されたタンパク質は、変性され、次いでSDS−PAGEゲルにロードされた(試料当たり40μg)。電気泳動後、タンパク質のバンドはPVDF膜に移され、一次抗体、抗HSV1−TK抗体と反応させた。PBSTによる洗浄後、タンパク質のバンドは二次抗体、HRP標識抗ヤギ抗体と反応させた。PBSTによる洗浄後、タンパク質のバンドは化学発光試薬によって処置され、化学発光画像システム(Davinch K)によって検出された。結果として、HSV1−TK断片タンパク質は、ウイルスで発現されたことが確認された(図4)。
OTS−412におけるHSV1−TKmut遺伝子発現の導入を確認するため、野生型ワクシニアウイルス及びOTS−412は制限酵素マッピングによって同定された。それぞれ野生型ワクシニアウイルス及びOTS−412をヒト骨肉腫細胞に感染させた後、ウイルスが単離され、ウイルスゲノムDNAが抽出され、陰性対照(野生型−VV)及び陽性対照(OTS−412)が得られた。
実施例1.2で調製されたOTS−412のがん細胞に感染し増殖する能力は以下のように確認された。HCT−116がん細胞株は、1MOI(1pfu/細胞)のOTS−412によって処置され、それぞれ24時間及び48時間後、ウイルス力価はプラークアッセイによって測定された。
GCVによるOTS−412ウイルス複製の阻害にもかかわらず、OTS−412の細胞傷害性が維持されたかどうか決定するため、以下の群間の細胞傷害性が比較された:野生型HSV1−TK発現ワクシニアウイルスによって、単独又はGCVと組み合わせて処置された群、及びOTS−412によって、単独又はGCVと組み合わせて処置された群。特に、HCT−116がん細胞は、0.05MOI(0.05pfu/細胞)の野生型HSV1−TK発現ワクシニアウイルス又はOTS−412によって、単独又はGCV(50μg)と組み合わせて処置された。生じる細胞は、72時間培養され、CCK8を使用して細胞傷害性を分析した(Cell Counting Kit 8)。
OTS−412とGCVの組合せ投与の抗がん効果を確認するため、OTS−412とGCVの投与による細胞傷害性が、2つのヒト肺がん細胞株、A549及びNCI−H460がん細胞株、並びに2つのヒト結腸直腸がん細胞株、HT−29及びHCT−116がん細胞株で評価された。
実施例7.1.HCT−116がん細胞株移植マウスモデル(腫瘍内投与)を使用するOTC−412とGCVの組合せ投与時の抗がん効果の確認
Orient Bio(Busan)から得たBalb/cマウス(雌、8週齢)は、1週間順応させ、HCT−116ヒト結腸がん細胞株(Korean Cell Line Bank)の5×106個の細胞を異種移植した。腫瘍サイズが100mm3〜150mm3に達すると、OTS−412が、単独で又はGCVと組み合わせて腫瘍内に投与された。
Orient Bio(Busan)から得たBalb/cマウス(雌、7週齢)は、1週間順応させ、Rencaがん細胞株(Korean Cell Line Bank)の5×107個の細胞を同種移植した。腫瘍のサイズが300mm3〜500mm3に達すると、腫瘍溶解性ウイルスの投与が開始された。マウスがん細胞におけるウイルス複製は制限される事実にもかかわらず、実験が実施され、同種移植マウスモデルにおいてOTS−412とGCVの組合せの抗腫瘍効果を示した。
Orient Bio(Busan)から得たBalb/cマウス(雌、8週齢)は、1週間順応させ、HCT−116ヒト結腸がん細胞株(Korean Cell Line Bank)の2.5×106個の細胞を異種移植した。腫瘍のサイズが100mm3〜150mm3に達するまでの観察後、OTS−412が、単独で又はGCVと組み合わせて腹腔内に投与された。
様々ながん細胞株でのOTS−412の抗がん効果を確認するため、OTS−412の毒性がHeLa、PC−3、DU−145、HT−29、HCT−116、A549、NCI−H23、NCI−H460、MCF−7、MDA−MB−231、4T1、Renca、及びB16F10がん細胞株で評価された。HeLa、A549、4T1、及びB16F10がん細胞株はATCC(USA)から得て、残りの9つのがん細胞株はKorean Cell Line Bank(KCLB)から得た。
高用量のOTS−412ウイルス(1×107pfu/マウス)が、HCT−116がん細胞移植マウスに腹腔内投与され、全身に注射されたウイルスが腫瘍に標的化及び送達されるかどうか確認された。
Claims (45)
- HSV−TK(単純ヘルペスウイルスチミジンキナーゼ)断片又はそのバリアントをコードするヌクレオチド配列を含む組換えウイルスベクター。
- 前記HSV−TK断片がHSV1−TK(単純ヘルペスウイルス1型チミジンキナーゼ)断片である、請求項1に記載の組換えウイルスベクター。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から1〜195アミノ酸残基が連続的に欠失されている断片のいずれか1つである、請求項2に記載の組換えウイルスベクター。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から24〜149アミノ酸残基が連続的に欠失されている断片のいずれか1つである、請求項2に記載の組換えウイルスベクター。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から30〜46アミノ酸残基が連続的に欠失されている断片のいずれか1つである、請求項2に記載の組換えウイルスベクター。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から46アミノ酸残基が連続的に欠失されているものである、請求項2に記載の組換えウイルスベクター。
- 前記HSV1−TK断片が、配列番号2〜6からなる群から選択されるアミノ酸配列のいずれか1つを有する、請求項2に記載の組換えウイルスベクター。
- 前記HSV−TK断片のバリアントがHSV1−TK断片のバリアントである、請求項1に記載の組換えウイルスベクター。
- 前記HSV1−TK断片のバリアントが配列番号7又は8のアミノ酸配列を有する、請求項8に記載の組換えウイルスベクター。
- アデノウイルス、単純ヘルペスウイルス、レンチウイルス、レトロウイルス、アデノ随伴ウイルス、ワクシニアウイルス、又はポックスウイルスに由来する、請求項1に記載の組換えウイルスベクター。
- HSV−TK断片又はそのバリアントをコードするヌクレオチド配列を含む腫瘍溶解性ウイルス。
- 前記HSV−TK断片がHSV1−TK断片である、請求項11に記載の腫瘍溶解性ウイルス。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から1〜195アミノ酸残基が連続的に欠失されている断片のいずれか1つである、請求項12に記載の腫瘍溶解性ウイルス。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から24〜149アミノ酸残基が連続的に欠失されている断片のいずれか1つである、請求項12に記載の腫瘍溶解性ウイルス。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から30〜46アミノ酸残基が連続的に欠失されている断片のいずれか1つである、請求項12に記載の腫瘍溶解性ウイルス。
- 前記HSV1−TK断片が、配列番号1によって表されるアミノ酸配列のC末端から46アミノ酸残基が連続的に欠失されているものである、請求項12に記載の腫瘍溶解性ウイルス。
- 前記HSV1−TK断片が、配列番号2〜6からなる群から選択されるアミノ酸配列のいずれか1つを有する、請求項12に記載の腫瘍溶解性ウイルス。
- 前記HSV−TK断片のバリアントがHSV1−TK断片のバリアントである、請求項11に記載の腫瘍溶解性ウイルス。
- 前記HSV1−TK断片のバリアントが配列番号7又は8のアミノ酸配列を有する、請求項18に記載の腫瘍溶解性ウイルス。
- アデノウイルス、麻疹ウイルス、単純ヘルペスウイルス、レンチウイルス、レトロウイルス、サイトメガロウイルス、バキュロウイルス、レオウイルス、アデノ随伴ウイルス、粘液腫ウイルス、水疱性口内炎ウイルス、ポリオウイルス、ニューカッスル病ウイルス、パルボウイルス、コクサッキーウイルス、セネカウイルス、ワクシニアウイルス、又はポックスウイルスに由来する、請求項11に記載の腫瘍溶解性ウイルス。
- ワクシニアウイルスに由来する、請求項11に記載の腫瘍溶解性ウイルス。
- 有効成分として請求項11〜21のいずれか一項に記載の腫瘍溶解性ウイルスを含む、がんを予防又は治療するための医薬組成物。
- 前記腫瘍溶解性ウイルスが、1×103pfu〜1×1010pfuの用量で投与される、請求項22に記載のがんを予防又は治療するための医薬組成物。
- 前記がんが、肺がん、結腸直腸がん、前立腺がん、甲状腺がん、乳がん、脳がん、頭頚部がん、食道がん、皮膚がん、胸腺がん、胃がん、結腸がん、肝臓がん、卵巣がん、子宮がん、膀胱がん、直腸がん、胆嚢がん、胆道がん、膵臓がん、非小細胞肺がん、骨がん、眼球内黒色腫、肛門周囲がん、卵管癌、子宮内膜癌、子宮頸がん、膣癌、外陰癌、ホジキン病、小腸がん、内分泌腺癌、副甲状腺がん、副腎がん、軟部組織肉腫、尿道がん、陰茎がん、慢性白血病、急性白血病、リンパ球性リンパ腫、腎臓がん、尿管がん、腎細胞癌、腎盂癌、中枢神経系腫瘍、原発性中枢神経系リンパ腫、脊髄腫瘍、脳幹グリオーマ、下垂体腺腫、及びこれらの組合せからなる群から選択される、請求項22に記載のがんを予防又は治療するための医薬組成物。
- 請求項11〜21のいずれか一項に記載の腫瘍溶解性ウイルス、及び有効成分としてGCV(ガンシクロビル)又はACV(アシクロビル)を含む、がんを予防又は治療するための医薬組成物。
- 前記腫瘍溶解性ウイルス及びGCV又はACVが、同時に又は順次投与される、請求項25に記載のがんを予防又は治療するための医薬組成物。
- 前記腫瘍溶解性ウイルスが、1×103pfu〜1×1010pfuの用量で投与される、請求項25に記載のがんを予防又は治療するための医薬組成物。
- 前記GCV又はACVが、0.1μg/kg/日〜50mg/kg/日の用量で投与される、請求項25に記載のがんを予防又は治療するための医薬組成物。
- 前記がんが、肺がん、結腸直腸がん、前立腺がん、甲状腺がん、乳がん、脳がん、頭頚部がん、食道がん、皮膚がん、胸腺がん、胃がん、結腸がん、肝臓がん、卵巣がん、子宮がん、膀胱がん、直腸がん、胆嚢がん、胆道がん、膵臓がん、非小細胞肺がん、骨がん、眼球内黒色腫、肛門周囲がん、卵管癌、子宮内膜癌、子宮頸がん、膣癌、外陰癌、ホジキン病、小腸がん、内分泌腺癌、副甲状腺がん、副腎がん、軟部組織肉腫、尿道がん、陰茎がん、慢性白血病、急性白血病、リンパ球性リンパ腫、腎臓がん、尿管がん、腎細胞癌、腎盂癌、中枢神経系腫瘍、原発性中枢神経系リンパ腫、脊髄腫瘍、脳幹グリオーマ、下垂体腺腫、及びこれらの組合せからなる群から選択される、請求項25に記載のがんを予防又は治療するための医薬組成物。
- 請求項11〜21のいずれか一項に記載の腫瘍溶解性ウイルス及びGCV又はACVを投与するステップを含む、がんを治療する方法。
- 前記腫瘍溶解性ウイルスが、1×103pfu〜1×1010pfuの用量で投与される、請求項30に記載のがんを治療する方法。
- 前記GCV又はACVが、0.1μg/kg/日〜50mg/kg/日の用量で投与される、請求項30に記載のがんを治療する方法。
- 前記GCV又はACVが、前記腫瘍溶解性ウイルスの投与中又は後に少なくとも1回投与される、請求項30に記載のがんを治療する方法。
- 前記GCV又はACVが、前記腫瘍溶解性ウイルスの投与の24時間後から約2週間投与される、請求項30に記載のがんを治療する方法。
- 前記GCV又はACVが、5〜18日間週に2回連続的に投与される、請求項30に記載のがんを治療する方法。
- 前記がんが、肺がん、結腸直腸がん、前立腺がん、甲状腺がん、乳がん、脳がん、頭頚部がん、食道がん、皮膚がん、胸腺がん、胃がん、結腸がん、肝臓がん、卵巣がん、子宮がん、膀胱がん、直腸がん、胆嚢がん、胆道がん、膵臓がん、非小細胞肺がん、骨がん、眼球内黒色腫、肛門周囲がん、卵管癌、子宮内膜癌、子宮頸がん、膣癌、外陰癌、ホジキン病、小腸がん、内分泌腺癌、副甲状腺がん、副腎がん、軟部組織肉腫、尿道がん、陰茎がん、慢性白血病、急性白血病、リンパ球性リンパ腫、腎臓がん、尿管がん、腎細胞癌、腎盂癌、中枢神経系腫瘍、原発性中枢神経系リンパ腫、脊髄腫瘍、脳幹グリオーマ、下垂体腺腫、及びこれらの組合せからなる群から選択される、請求項30に記載のがんを治療する方法。
- 前記腫瘍溶解性ウイルスが、腫瘍内、腹腔内、又は静脈内投与によって投与される、請求項30に記載のがんを治療する方法。
- i)HSV−TK断片又はそのバリアントをコードするヌクレオチド配列を含むシャトルプラスミドを宿主細胞にトランスフェクトし、宿主細胞を野生型ワクシニアウイルスによって処置するステップ;ii)生じる宿主細胞を培養するステップ;及びiii)生じる培養物から組換えワクシニアウイルスを得るステップを含む、HSV−TK断片又はそのバリアントを発現する組換えワクシニアウイルスを調製する方法。
- 前記HSV−TK断片が、配列番号2〜6からなる群から選択されるアミノ酸配列のいずれか1つを有する、請求項38に記載のHSV−TK断片又はそのバリアントを発現する組換えワクシニアウイルスを調製する方法。
- 前記HSV−TK断片をコードする前記ヌクレオチド配列が、配列番号9のヌクレオチド配列である、請求項38に記載のHSV−TK断片又はそのバリアントを発現する組換えワクシニアウイルスを調製する方法。
- 前記HSV−TK断片のバリアントをコードする前記ヌクレオチド配列が、配列番号10又は11のヌクレオチド配列である、請求項38に記載のHSV−TK断片又はそのバリアントを発現する組換えワクシニアウイルスを調製する方法。
- がんを治療するための、請求項11〜21のいずれか一項に記載の腫瘍溶解性ウイルスの使用。
- がんを治療するための、請求項25〜29のいずれか一項に記載の医薬組成物の使用。
- がんを予防又は治療するための医薬品の製造のための、請求項11〜21のいずれか一項に記載の腫瘍溶解性ウイルスの使用。
- がんを予防又は治療するための医薬品の製造のための、請求項25〜29のいずれか一項に記載の医薬組成物の使用。
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EP3992281A4 (en) * | 2019-06-27 | 2023-07-26 | Bionoxx Inc. | ONCOLYTIC VIRUS WITH IMPROVED SAFETY AND ANTICANCER EFFECT |
AU2020337054A1 (en) * | 2019-08-29 | 2022-03-10 | Bionoxx Inc. | Pharmaceutical composition for treating cancer, comprising vaccinia virus and granulopoiesis inhibitor as active ingredients |
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JP2016519570A (ja) * | 2013-03-14 | 2016-07-07 | エペイウス バイオテクノロジーズ コーポレイション | 改善されたチミジンキナーゼ遺伝子 |
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EP1914304A1 (en) * | 1998-10-14 | 2008-04-23 | Darwin Molecular Corporation | Thymidine kinase mutants and fusion proteins having thymidine kinase and guanylate kinase activities |
KR100342382B1 (ko) * | 1999-02-18 | 2002-07-03 | 이수빈 | 간암 특이적 세포 살상 재조합 아데노바이러스 |
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IL152420A0 (en) * | 2001-02-23 | 2003-05-29 | Novartis Ag | Novel oncolytic adenoviral vectors |
GB0413702D0 (en) | 2004-06-18 | 2004-07-21 | Molmed Spa | Thymidine kinase |
EP2811023B1 (en) | 2012-02-01 | 2018-10-24 | Postech Academy-Industry Foundation | Vector simultaneously expressing dodecameric trail and hsv-tk suicide genes, and anticancer stem cell therapeutic agent using same |
ES2753259T3 (es) | 2015-04-22 | 2020-04-07 | Curevac Ag | Composición que contiene ARN para el tratamiento de enfermedades tumorales |
KR102077648B1 (ko) * | 2017-12-28 | 2020-02-14 | 주식회사 바이오녹스 | 안전성 및 항암효과가 개선된 종양 용해 바이러스 |
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CN111556899A (zh) | 2020-08-18 |
CN111556899B (zh) | 2024-05-31 |
US20240100108A1 (en) | 2024-03-28 |
AU2018395012A1 (en) | 2020-07-16 |
US20210060103A1 (en) | 2021-03-04 |
KR20200019645A (ko) | 2020-02-24 |
KR20190080806A (ko) | 2019-07-08 |
US11857585B2 (en) | 2024-01-02 |
EP3733854A4 (en) | 2021-12-01 |
CA3087175A1 (en) | 2019-07-04 |
WO2019132596A1 (ko) | 2019-07-04 |
EP3733854A1 (en) | 2020-11-04 |
KR102077648B1 (ko) | 2020-02-14 |
JP7047238B2 (ja) | 2022-04-05 |
AU2018395012B2 (en) | 2022-03-10 |
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