JP2013537422A - ヒトパピローマウイルス変形体及び免疫増強剤を含む子宮頸癌の予防または治療用組成物 - Google Patents
ヒトパピローマウイルス変形体及び免疫増強剤を含む子宮頸癌の予防または治療用組成物 Download PDFInfo
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Abstract
Description
ヒトパピローマウイルスタイプ16及び18来由の、配列リスト配列番号1に記載されたアミノ酸配列を有する、E6及びE7の3次元構造が変形された融合ポリペプチドと;
上記ポリペプチドの分泌のための信号ペプチドと;
免疫増強ペプチドと;を含む融合タンパク質を提供する。
本発明は、ヒトパピローマウイルスタイプ16及び18来由の、配列リスト配列番号1に記載されたアミノ酸配列を有するE6及びE7の3次元構造が変形された融合ポリペプチドと;
上記ポリペプチドの分泌のための信号ペプチドと;
免疫増強ペプチドと;を含む融合タンパク質に関する。
上記ポリヌクレオチドは、本発明の融合タンパク質をコーディングするもので、上記E6及びE7の融合ポリペプチドは、配列番号4に記載された塩基配列からコーディングされることができるが、これに特に限定されない。また、上記信号ペプチドは、配列番号5に記載された塩基配列からコーディングされることができるが、これに特に制限されない。上記免疫増強ペプチドは、配列番号6に記載された塩基配列からコーディングされることができるが、これに特に限定されない。
本発明において、「ベクター」というのは、ポリペプチドを暗号化するゲノム内に挿入された外部DNAを含む遺伝子作製物を言う。本発明と関連したベクターは、分泌信号配列、ヒトパピローマウイルスの3次元構造が変形されたE6とE7融合ポリペプチドをコーディングする核酸配列及び免疫増強ペプチドをコーディングする核酸配列などがゲノム内に挿入されたベクターであって、これらベクターは、プラスミドベクター、コズミドベクター、バクテリオファージベクター、酵母ベクター、またはアデノウイルスベクター、レトロウイルスベクター、アデノ−連関ウイルスベクターのようなウイルスベクターを例示することができる。
上記宿主細胞の種類は、前述した通りである。
本発明の実施例において使用された略語は、次のように定義する。最適化された核酸配列、「tPa」または「t」は、組職プラスミノゲン活性剤(tissue plasminogen activator)の分泌信号配列(secretory signal sequence)、「F」または「Flt3L」は、fms−like tyrosine kinase 3 リガンドを意味する。
GX−188Eの子宮頸癌の治療効果を確認するためにネズミC57BL/6にTC−1腫瘍細胞5×105 cellsを皮下注射し、3日目、8日目となる日に、50μg及び100μgの量で筋肉注射した後、エレクトロポレーション(electroporation)を行った。腫瘍細胞を注射した日から27日目になる日まで腫瘍細胞の体積変化を観察し、36日目となる日に、ネズミの脾臓を取り出し、5μg/mLのanti−mouse IFN−γ抗体(BD Pharmigen、Sandiego、CA)50μLでコーティングされたプレートに1×106 cellsをIL−2とHPV16 E6 CD8 T細胞抗原決定基(epitope)(E648−57;EVYDFAFRDL、Peptron、Korea)またはHPV18 E7 CD8 T細胞抗原決定基(epitope)(E749−57;RAHYNIVTF、Peptron、Korea)またはHPV18 E6 ペプチドプール(peptide pool)またはHPV18 E7ペプチドプール(peptide pool)を一緒に入れ、37℃5%CO2培養器(Froma、Minnesota、USA)で24時間培養した。プレートをPBSTで洗浄した後、ビオチンが付いているIFN−γ探知抗体(BD Pharmigen、Sandiego、CA)2μg/mLを50μLずつ入れ、約3時間程度常温で培養した。その後、PBSTで洗浄し、streptavidin−AKP(alkaline phosphate)を1:2000で希釈し、50μLずつ入れ、常温で1時間培養した。PBSTで洗浄した後、10mLのアルカリ性リン酸塩緩衝液(alkaline phosphate buffer)当たり66μLのNBT(Promega、Madison、WT)と33μLのBCIP(Promega、Madison、WT)を添加し、50μL ずつ入れて反応させた。反応による色がよく現れるように、37℃培養器で約30分間入れた後、滅菌された水(distilled water、D.W.)で洗浄し、生成された点の個数をリーダーで読み取った。
Claims (17)
- ヒトパピローマウイルスタイプ16及び18来由の、配列リスト配列番号1に記載されたアミノ酸配列を有する、E6及びE7の3次元構造が変形された融合ポリペプチドと、
上記ポリペプチドの分泌のための信号ペプチドと、
免疫増強ペプチドと、を含む融合タンパク質。 - 信号ペプチドが、tPa、HSV gDs及び成長ホルモン分泌信号ペプチドよりなる群から選択された1つ以上である、請求項1に記載の融合タンパク質。
- 信号ペプチドが、配列番号2に記載されたアミノ酸配列を有する、請求項1に記載の融合タンパク質。
- 免疫増強ペプチドが、CD40リガンド、Flt3リガンド(fms−like tyrosine kinase 3 ligand)、フラジェリン(Flagellin)及びOX40よりなる群から選択された1つ以上である、請求項1に記載の融合タンパク質。
- 免疫増強ペプチドが、配列番号3に記載されたアミノ酸配列を有する、請求項1に記載の融合タンパク質。
- 請求項1に記載の融合タンパク質をコーディングするポリヌクレオチド。
- ヒトパピローマウイルスE6及びE7の融合ポリペプチドをコーディングする配列番号4に記載された塩基配列を含む、請求項6に記載のポリヌクレオチド。
- 信号ペプチドをコーディングする配列番号5に記載された塩基配列を含む、請求項6に記載のポリヌクレオチド。
- 免疫増強ペプチドをコーディングする配列番号6に記載された塩基配列を含む、請求項6に記載のポリヌクレオチド。
- 請求項6に記載のポリヌクレオチドを含む、組換えベクター。
- 請求項10に記載の組換えベクターで形質転換された宿主細胞。
- 請求項11に記載の宿主細胞を培養し、請求項1に記載の融合タンパク質を発現する方法。
- 請求項1に記載の融合タンパク質、上記タンパク質を発現する組換えベクターで形質転換された宿主細胞及びその破砕物よりなる群から選択された1つ以上を有効成分として含む、個体でヒトパピローマウイルスによって惹起される疾患の予防または治療用組成物。
- 疾患が子宮頸癌である、請求項13に記載の組成物。
- 薬剤学的に許容可能な担体をさらに含む、請求項13に記載の組成物。
- 有効量の請求項13に記載の組成物を個体に投与する段階を含む、個体でヒトパピローマウイルスによって惹起される疾患の予防または治療する方法。
- 疾患が子宮頸癌である、請求項16に記載の方法。
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JP7385684B2 (ja) | 2022-01-18 | 2023-11-22 | パピヴァックス バイオテック インコーポレイテッド | ワクチンの組み合わせ及びその使用方法 |
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WO2012020871A1 (ko) | 2012-02-16 |
EP2604629B1 (en) | 2018-02-28 |
PL2604629T3 (pl) | 2018-08-31 |
US20130195905A1 (en) | 2013-08-01 |
ES2666720T3 (es) | 2018-05-07 |
EP2604629A4 (en) | 2014-01-15 |
US9399665B2 (en) | 2016-07-26 |
CN103180343A (zh) | 2013-06-26 |
US20150239939A1 (en) | 2015-08-27 |
JP5740473B2 (ja) | 2015-06-24 |
CN103180343B (zh) | 2016-01-20 |
US9000139B2 (en) | 2015-04-07 |
EP2604629A1 (en) | 2013-06-19 |
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