JPWO2016143816A1 - Gpc3由来のペプチド、これを用いた癌の治療又は予防のための医薬組成物、免疫誘導剤、及び抗原提示細胞の製造方法 - Google Patents
Gpc3由来のペプチド、これを用いた癌の治療又は予防のための医薬組成物、免疫誘導剤、及び抗原提示細胞の製造方法 Download PDFInfo
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
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Abstract
Description
(1)配列番号1〜11のいずれかで表されるアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ11以下のアミノ酸残基から成るペプチド。
(2)前記アミノ酸配列中、1又は数個のアミノ酸が置換、挿入、欠失又は付加しており、且つ免疫原性を有する、(1)に記載のペプチド。
(3)前記アミノ酸配列中、第2位のアミノ酸がチロシン、フェニルアラニン、メチオニン、トリプトファン、バリン、ロイシン又はグルタミンで、そして/あるいはC末端のアミノ酸がフェニルアラニン、ロイシン、イソロイシン、トリプトファン、メチオニン又はバリンで置換されている、(2)に記載のペプチド。
(4)(1)〜(3)のいずれかに記載のペプチドを含む、癌の治療又は予防のための医薬組成物。
(5)ワクチンの形態である、(4)に記載の医薬組成物。
(6)前記ペプチドが1又は複数の型のHLA分子と結合することができる、(4)又は(5)に記載の医薬組成物。
(7)(1)〜(3)のいずれかに記載のペプチドを含む免疫誘導剤。
(8)細胞傷害性T細胞を誘導するための、(7)に記載の免疫誘導剤。
(9)前記ペプチドが1又は複数の型のHLA分子と結合することができる、(7)又は(8)に記載の免疫誘導剤。
(10)(1)〜(3)のいずれかに記載のペプチドと抗原提示細胞とをin vitroで接触させる工程を含む、CTL誘導活性を有する抗原提示細胞の製造方法。
1."Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma." Jorge Filmus and Mariana Capurro, FEBS J., 280: 2471-2476, 2013.
2."Glypican-3: a new target for cancer immunotherapy." Mitchell Ho and Heungnam Kim, Eur. J. Cancer, 47, 333-338, 2011.
3."Peptide vaccines for hepatocellular carcinoma." Daisuke Nobuoka, Toshiaki Yoshikawa, Yu Sawada, Toshiyoshi Fujiwara and Tetsuya Nakatsura, Human Vaccines & Immunotherapeutics, 9, 210-212, 2013.
4. "Phase I Trial of a Glypican-3-Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential fo Improving Overall Survival." Yu Sawada, et.al., Clin. Cancer. Res., 18, 3636-3696, 2012.
本発明に係るペプチドは配列番号1〜11のいずれかで表されるアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ合計11以下、好ましくは10以下、より好ましくは9以下のアミノ酸残基から成るペプチドである。本発明のペプチドは配列番号1〜11のいずれかで表されるアミノ酸配列から成るものであってもよい。本発明のペプチドはGlypicanの一つであるGPC3に由来する。GPC3を構成するアミノ酸配列に基づき、能動学習実験法(特開平8−151396号)を用いて得られる仮説により予測された、HLA分子との結合性が−logKd値に換算して3以上であるアミノ酸配列が選択された。
本発明に係る癌の治療又は予防のための医薬組成物は、有効成分として、例えば、配列番号1〜11から成る群から選択される1種以上のアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ、合計11以下、好ましくは10以下、より好ましくは9以下のアミノ酸残基からなるペプチドを含む。医薬組成物に含まれるペプチドは配列番号1〜11のいずれかで表されるアミノ酸配列から成るものであってもよい。当該ペプチドは上文で定義したとおりである。
本発明に係る免疫誘導剤は、有効成分として、例えば、配列番号1〜11から成る群から選択される1種以上のアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ11以下、好ましくは10以下、より好ましくは9以下のアミノ酸残基からなるペプチドを含む。免疫誘導剤に含まれるペプチドは配列番号1〜11のいずれかで表されるアミノ酸配列から成るものであってもよい。当該ペプチドは上文で定義したとおりである。
本発明に係る抗原提示細胞の製造方法は、例えば、配列番号1〜11から成る群から選択される1種以上のアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ合計11以下、好ましくは10以下、より好ましくは9以下のアミノ酸残基からなるペプチドと抗原提示細胞とをin vitroで接触させる工程を含む。本発明の製造方法で使用されるペプチドは配列番号1〜11のいずれかで表されるアミノ酸配列から成るものであってもよい。当該ペプチドは上文で定義したとおりである。
配列番号1〜11のアミノ酸配列を有するペプチドは、Fmocアミノ酸を用い、Merrifieldの固相法にて、マニュアル合成をした。脱保護の後、C18カラムを用いて逆相HPLC精製をし、95%以上の純度にした。ペプチドの同定と純度の確認は、MALDI−TOF質量分析にて行った(AB SCIEX MALDI−TOF/TOF5800)。ペプチドの定量は、BSAを標準蛋白質としてMicro BCAアッセイ(Thermo Scientific社)にて行った。
HLA−A*24:02遺伝子の産物であるHLA−A*24:02分子へのペプチドの結合能の測定は、HLA−A*24:02分子を発現するC1R−A24細胞(熊本大学、滝口雅文教授作成のものを、許可を得て愛媛大学、安川正貴助教授から供与いただいた。)を用いて行った。
HLA−A*02:01遺伝子の産物であるHLA−A*02:01分子へのペプチドの結合能の測定は、HLA−A*02:01分子を発現する細胞株T2(ATCCより購入)を用いて行った。
HLA−A*02:06遺伝子の産物であるHLA−A*02:06分子へのペプチドの結合能の測定は、マウスのTAP(transporter associated with antigen processing)欠損細胞株であるRMASに、HLA−A*02:06遺伝子のcDNAを導入したRA2.6細胞(高知大学にて新たに作成した細胞株)を用いて行った。
その結果、以下の表に示すような各HLA分子に対する本発明のペプチドの結合実験データが得られた。
(1)ペプチド刺激樹状細胞の調製
・Day0〜9(樹状細胞の誘導)
HSP70に対する樹状細胞療法を受けた患者[0]からフェレーシスにより得られた末梢血単球のうち、培養フラスコに接着した細胞画分をAIM−CM培地(Gibco社製)中で10日間、37℃で培養した。培養期間中、培地に対し0日目及び3日目にIL−4を15μl、顆粒球単球コロニー刺激因子(GM−CSF)を30μlそれぞれ添加し、5日目にIL−4を15μl、GM−CSFを30μl、腫瘍壊死因子(TNF)-αを75μl添加した。
誘導した樹状細胞を新たにAIM−CM培地中に回収し、本発明のペプチド(配列番号1〜11)が20μg/mlとなるよう添加した。その後、樹状細胞を含む培地を2時間37℃で培養した。ポジティブコントロール及びネガティブコントロールとして以下のペプチドを使用した。
HLA−A*24:02用ポジティブコントロール(EBV LMP2, 419-427:TYGPVFMCL(配列番号13))
HLA−A*24:02用ネガティブコントロール(HIV env gp160, 584-592:RYLRDQQLL(配列番号14))
HLA−A*02:01用ポジティブコントロール(Flu A MP, 58-66:GILGFVFTL(配列番号15))
HLA−A*02:01用ネガティブコントロール(HIV gap p17, 77-85:SLYNTVATL(配列番号16))
HLA−A*02:06用ポジティブコントロール(EBV LMP2 453-461:LTAGFLIFL(配列番号17))
HLA−A*02:06用ネガティブコントロール(HIV gap p24 341-349:ATLEEMMTA(配列番号18))
・Day0〜9
上記ワクチンで2回以上治療された後の患者からフェレーシスにより得られた末梢血単球のうち、培養フラスコに接着しない浮遊細胞画分(リンパ球を含む)をAIM−CM培地(Gibco社製)中で10日間、37℃で培養した。培養期間中、培地に対し4日目及び6日目にそれぞれIL−2を40μl添加した。
CD8ネガティブセレクションキット(Miltenyi社製)を用いて培地からCD8T細胞を分離しセルカウントした。
上記(1)及び(2)で得られた樹状細胞とCD8T細胞を以下の条件にてAIM培地中で37℃で共培養した。
・CD8T細胞:5×105cells/well
・樹状細胞 :2×105cells/well
上記培地にIL−2 20U/ml を含んだAIM−CM培地0.4ml/wellを添加した。
・Day17
抗TFN-γモノクローナル抗体(MABTECH社製)をコートしたELISPOT用96穴プレート(Millipore社製)に、上記CD8T細胞を1穴あたり2×104cells/wellになるように加えた。各サンプルにつき、3ウェル以上使用した。各ウェルにはAIM−V(Gibco社製)を100μl添加した。ELISPOT用96穴プレートを37℃で培養した。
抗TFN-γ抗体を各ウェルに加え、さらにHRP酵素標識した2次抗体を反応させて、呈色反応により、IFN-γ産生細胞の数を測定した。代表的なELISPOTアッセイの結果として、HLA型が24:02/24:02の患者についてのものを図1に、02:01/24:02の患者についてのものを図2に、また、02:01/33:03の患者についてのものを図3に示す。各図において、3回ずつのアッセイ結果の平均値を表示する。
・Day17
T細胞と上記ペプチドでパルスした樹状細胞の共培養7日目の培養上清を、x1, x5, x25, x125の4段階に希釈し、Human IFN-γ ELISA MAX Deluxe Set (BioLegend社製)を用いて、測定限度内に収まる希釈段階を同定した。その後、同定した希釈段階にて、各サンプルにつき3回ずつ測定を行った。代表的なELISAアッセイの結果として、HLA型が24:02/26:01の患者、24:02/24:02の患者、11:01/24:02の患者、02:01/24:02の患者、02:01/33:03の患者、についてのものを順に図4〜8に示す。
Claims (10)
- 配列番号1〜11のいずれかで表されるアミノ酸配列における連続した8以上のアミノ酸残基を含み、且つ11以下のアミノ酸残基から成るペプチド。
- 前記アミノ酸配列中、1又は数個のアミノ酸が置換、挿入、欠失又は付加しており、且つ免疫原性を有する、請求項1に記載のペプチド。
- 前記アミノ酸配列中、第2位のアミノ酸がチロシン、フェニルアラニン、メチオニン、トリプトファン、バリン、ロイシン又はグルタミンで、そして/あるいはC末端のアミノ酸がフェニルアラニン、ロイシン、イソロイシン、トリプトファン、メチオニン又はバリンで置換されている、請求項2に記載のペプチド。
- 請求項1〜3のいずれか1項に記載のペプチドを含む、癌の治療又は予防のための医薬組成物。
- ワクチンの形態である、請求項4に記載の医薬組成物。
- 前記ペプチドが1又は複数の型のHLA分子と結合することができる、請求項4又は5に記載の医薬組成物。
- 請求項1〜3のいずれか1項に記載のペプチドを含む免疫誘導剤。
- 細胞傷害性T細胞を誘導するための、請求項7に記載の免疫誘導剤。
- 前記ペプチドが1又は複数の型のHLA分子と結合することができる、請求項7又は8に記載の免疫誘導剤。
- 請求項1〜3のいずれか1項に記載のペプチドと抗原提示細胞とをin vitroで接触させる工程を含む、CTL誘導活性を有する抗原提示細胞の製造方法。
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BR112017018703A2 (ja) | 2018-04-17 |
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US10590179B2 (en) | 2020-03-17 |
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TWI714558B (zh) | 2021-01-01 |
RU2714117C2 (ru) | 2020-02-11 |
DK3269733T3 (da) | 2020-07-27 |
US10526388B2 (en) | 2020-01-07 |
AU2016230125A1 (en) | 2017-09-21 |
EP3269733B1 (en) | 2020-06-17 |
CN107428815B (zh) | 2021-07-09 |
EP3269733A4 (en) | 2018-08-01 |
RU2017135038A (ru) | 2019-04-08 |
RU2017135038A3 (ja) | 2019-08-30 |
EP3269733A1 (en) | 2018-01-17 |
AU2016230125B2 (en) | 2020-07-16 |
ES2805829T3 (es) | 2021-02-15 |
US10875900B2 (en) | 2020-12-29 |
CN113388021A (zh) | 2021-09-14 |
CN107428815A (zh) | 2017-12-01 |
TW202115102A (zh) | 2021-04-16 |
US20200157163A1 (en) | 2020-05-21 |
US20180105567A1 (en) | 2018-04-19 |
WO2016143816A1 (ja) | 2016-09-15 |
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