JP2009534027A - 子宮頸癌の予防及び治療のためのヒトパピローマウイルスポリペプチドと免疫増強剤を含む組成物 - Google Patents
子宮頸癌の予防及び治療のためのヒトパピローマウイルスポリペプチドと免疫増強剤を含む組成物 Download PDFInfo
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Abstract
Description
本発明のさらに別の目的は、上記ポリヌクレオチドを含む組換えベクトルを提供することにある。
本発明のさらに別の目的は上記融合タンパク質及び組換えベクトルを含む薬剤学的組成物を提供することにある。
本発明の実施例で使われた略語は次ぎの通り定義する。
“Co”はコドン最適化された核酸配列、“tPa”または“t”は組織プラスミノーゲン活性剤の分泌シグナル配列、“F”はFlt3リガンド、“L”はCD40リガンドを意味する。
配列番号1の核酸配列を有するコドン最適化されたtPa分泌シグナル配列は化学的に合成した。末端にECORI−KpnI(5’)とEco47III−NheI(3’)サイトを添加した。配列番号7の核酸配列を有するコドン最適化されたHPV16E6E7は化学的に合成しており、ベクトルに挿入しやすくするため末端に、Eco47III−NheI(5’)、AscI−XhoI(3')サイトを添加した。E6とE7の接合部分にBamHIサイトを添加した。腫瘍原性を引き起こす性質をなくすために、E6の63位コドン(システイン)をグリシンに、106位コドン(システイン)を、グリシンを指令するコドンに変えており(配列番号3)、E7は24位コドン(システイン)をグリシンに、26にコドン(グルタミン)を、グリシンを指令するコドンに変えた(配列番号5)。DNAワクチン製造用ベクトルであるpGX10(大韓民国特許出願公開第2003−0047667号)をEcoRIとNheI酵素(エンザイム)で処理した後、合成した分泌シグナル配列であるtPaをリガーゼ(ligase)で連結した、これを再度NheIとXhoI酵素で切り裂いて合成したHPV16E6E7をリガーゼで連結してpGX10/tE67Coを製作した。
配列番号1の核酸配列を有するコドン最適化されたtPa分泌シグナル配列と配列番号15の核酸配列を有するコドン最適化されたFlt3Lは連結された形態で化学的に合成した。ベクトルに挿入しやすくするために末端にKpnI(5')、EcoRV(3')サイトを添加した。実施例1で製造したpGX10/tE67CoをKpnIとEco47III酵素で処理し、分泌シグナル配列であるtPaのみを除去した後、tFCoを、リガーゼで連結してpGX10/tFCoE67Coを製作した。
配列番号17の核酸配列を有するコドン最適化されたCD40L化学的に合成した。ベクトルに挿入しやすくするために末端にAscI(5')、XhoI(3')サイトを添加した。実施例1で製造したpGX10/tE67CoをAscIとXhoI酵素で処理した後、CD40LCoをリガーゼで連結してpGX10/tE67CoLCoを製作した。
pGX10/tE67Co、pGX10/tFCoE67Co、pGX10/tE67CoLCoの子宮頸癌予防効果を確認するために、マウスC57BL/6に4週間隔で2度にわたって50μgずつ筋肉注射しており、対照群としてpGX10、pGX10.E6Co、pGX10/E7Co、pGX10/E67Co、pGX10/E67を同じ投与量と間隔で筋肉注射した。最初筋肉注射した日より、6.5週後、マウスの脾臓を摘出し、3μg/mLのanti−mouse IFN−γ抗体(BD Pharmingen, Sandiego, CA)50μLでコートされたプレートに、1×106細胞をIL−2とE6またはE7 CD8 T細胞抗原決定基(epitope)(E648-57; EVYDFAFRDL, E749−57; RAHYNIVTF, Peptron, Korea.)を共に入れ、37℃、5%CO2培養器(Forma, Minnesota, USA)で24時間培養した。プレートをPBSTで洗浄後、垂れ下がったビオチンを有するIFN−γ探知(detecting)抗体(BD Pharmingen, 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、ストレプトアビジン−AKP(アルカリ性リン酸)を1:2000に希釈し、50μLずつ入れ、常温で1時間培養した。PBSTで洗浄後、10mLのアルカリ性リン酸緩衝液当たり66μLのNBT(Promega, Madison, WT)と33μLのBCIP(Promega, Madison, WT)の混合液の50μLを入れて反応させた。反応による色がよく現れるように、37℃培養器で約30分、放置した後、滅菌された水(distilled water, D.W)で洗浄し、生成された点の個数を読取機で読み取った(図1及び図2参照)。
pGX10/tE67Co、pGX10/tFCoE67Co、pGX10/tE67CoLCoの子宮頸癌治療効果を確認するために、マウスC57BL/6にTC−1腫瘍細胞5×105細胞を皮下注射し、3日目、8日目になる日、50μgの量で筋肉注射した。腫瘍細胞を注射した日から、21日目になる日まで腫瘍細胞の体積変化を観察し、22日目になる日、マウスの脾臓を摘出し、実施例4で説明した方法(ELISPOT)でE6及びE7に対する抗原特異的CD8 T細胞免疫反応の誘導程度を測定した。対照群のpGX10に比べて、pGX10/tE67Co、pGX10/tFCoE67Co、pGX10/tE67CoLCoで治療したマウスで、高い抗原特異的免疫反応が誘導され、特に、pGX10/tFCoE67Coで治療したマウスでの免疫反応が最も高く測定され、抗癌免疫反応を誘導するのに卓越した効能があることを確認した(図4及び図5参照)。
Claims (41)
- ヒトパピローマウイルスE6及びE7の融合ポリペプチド、これを細胞外へ分泌させるためのシグナルペプチド及び個体内免疫増強ペプチドを含む融合タンパク質。
- E6及びE7の融合ポリペプチドが、ヒトパピローマウイルスタイプ16(HPV16)または18(HPV18)から由来されたものである請求項1に記載の融合タンパク質。
- E6及びE7の融合ポリペプチドが、配列番号8に示される請求項2に記載の融合タンパク質。
- E6及びE7の融合ポリペプチドが、配列番号14に示される融合タンパク質。
- シグナルペプチドがtPa、HSV gDsまたは成長ホルモン分泌シグナルペプチドである請求項1に記載の融合タンパク質。
- tPaが、配列番号2に示される請求項5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、フラジェリンまたはOX40である請求項1に記載の融合タンパク質。
- Flt3リガンドが、配列番号16に示される請求項7に記載の融合タンパク質。
- CD40リガンドが、配列番号18に示される請求項7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ドするポリヌクレオチド。
- E6及びE7の融合ポリペプチドをコードする配列が、ヒトパピローマウイルスタイプ16(HPV16)または18(HPV18)から由来されたものである請求項10に記載のポリヌクレオチド。
- E6及びE7の融合ポリペプチドをコードする配列が、遺伝子の発現率を高めるために哺乳類に最適化されたコドンで改変されたものである請求項11に記載のポリヌクレオチド。
- E6及びE7の融合ポリペプチドが、配列番号8のアミノ酸配列を有するものである請求項12に記載のポリヌクレオチド。
- E6及びE7の融合ポリペプチドが、配列番号14のアミノ酸配列を有するものである請求項12に記載のポリヌクレオチド。
- シグナルペプチドが、tPa、HSV gDsまたは成長ホルモン分泌シグナルペプチドである請求項10に記載のポリヌクレオチド。
- シグナルペプチドをコードする配列が、遺伝子の発現率を高めるために哺乳類に最適化されたコドンで改変されたものである請求項15に記載のポリヌクレオチド。
- tPaが、配列番号2のアミノ酸配列を有するものである請求項16に記載のポリヌクレオチド。
- 免疫増強ペプチドが、CD40リガンド、Flt3リガンド、フラジェリンまたはOX40である請求項10に記載のポリヌクレオチド。
- 免疫増強ペプチドをコードする配列が、遺伝子の発現率を高めるために哺乳類に最適化されたコドンで改変されたものである請求項18に記載のポリヌクレオチド。
- Flt3リガンドが、配列番号16のアミノ酸配列を有するものである請求項19に記載のポリヌクレオチド。
- CD40リガンドが、配列番号18のアミノ酸配列を有するものである請求項19に記載のポリヌクレオチド。
- 請求項20または21に記載のポリヌクレオチドを含む組換えベクトル。
- 配列番号7または配列番号13の核酸配列を含む組換えベクトル。
- 分泌シグナル配列及び免疫増強ペプチドをコードする配列を、さらに含む請求項23に記載のベクトル。
- 分泌シグナル配列が、tPa、HSV gDsまたは成長ホルモン分泌シグナル配列である請求項24に記載のベクトル。
- 分泌シグナル配列が、コドン最適化された請求項25に記載のベクトル。
- tPaが、配列番号1に示される請求項26に記載のベクトル。
- 免疫増強ペプチドが、CD40リガンド、Flt3リガンド、フラジェリンまたはOX40から1つ以上選択されるものである請求項24に記載のベクトル。
- 配列がコドン最適化された請求項28に記載のベクトル。
- Flt3リガンドが、配列番号15に示される請求項29に記載のベクトル。
- CD40リガンドが、配列番号17に示される請求項29に記載のベクトル。
- 請求項22に記載のベクトルで形質転換された宿主細胞。
- 請求項23に記載のベクトルで形質転換された宿主細胞。
- 請求項1に記載の融合タンパク質及び薬剤学的に許容しうる担体を含む、個体でヒトパピローマウイルスによって引き起こされる疾患の治療または予防用薬剤学的組成物。
- 疾患が子宮頸癌である請求項34に記載の組成物。
- 第22項に記載のベクトル及び薬剤学的に許容しうる担体を含む、個体で、ヒトパピローマウイルスによって引き起こされる疾患の治療または予防用薬剤学的組成物。
- 疾患が子宮頸癌である請求項36に記載の組成物。
- 第23項に記載のベクトル及び薬剤学的に許容しうる担体を含む、個体で、ヒトパピローマウイルスによって引き起こされる疾患の治療または予防用薬剤学的組成物。
- 疾患が子宮頸癌性急行38に記載の組成物。
- 治療学的な量の請求項34、36または38のいずれかに記載の薬剤学的組成物を個体に投与する工程を含む、個体で、ヒトパピローマウイルスによって引き起こされる疾患の治療または予防する方法。
- 疾患が、子宮頸癌である請求項40に記載の方法。
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JP2013537422A (ja) * | 2010-08-13 | 2013-10-03 | ジェネクサイン・インコーポレーテッド | 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 |
JP2015091874A (ja) * | 2015-01-30 | 2015-05-14 | ジェネクサイン・インコーポレーテッド | 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 |
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JP2019505567A (ja) * | 2015-12-09 | 2019-02-28 | アドメダス バクシーンズ プロプライアタリー リミティド | 治療用免疫調節組成物 |
WO2020251014A1 (ja) * | 2019-06-14 | 2020-12-17 | 国立研究開発法人理化学研究所 | 免疫系を賦活化する細胞および当該細胞を含む医薬組成物 |
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JP7110108B2 (ja) | 2015-12-09 | 2022-08-01 | ジンガン メディスン(オーストラリア) プロプライアタリー リミティド | 治療用免疫調節組成物 |
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Also Published As
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EP2010572A4 (en) | 2010-08-25 |
KR20090007333A (ko) | 2009-01-16 |
ES2443216T3 (es) | 2014-02-18 |
JP5345053B2 (ja) | 2013-11-20 |
USRE46453E1 (en) | 2017-06-27 |
CN101421306B (zh) | 2013-09-18 |
US20090305979A1 (en) | 2009-12-10 |
WO2007119896A1 (en) | 2007-10-25 |
EP2010572B1 (en) | 2013-10-23 |
EP2010572A1 (en) | 2009-01-07 |
KR101180885B1 (ko) | 2012-09-10 |
PL2010572T3 (pl) | 2014-05-30 |
US8137674B2 (en) | 2012-03-20 |
CN101421306A (zh) | 2009-04-29 |
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