JPWO2015129790A1 - Wt1抗原性ポリペプチド、及び該ポリペプチドを含む抗腫瘍剤 - Google Patents
Wt1抗原性ポリペプチド、及び該ポリペプチドを含む抗腫瘍剤 Download PDFInfo
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Abstract
Description
<2> 前記融合ポリペプチド1分子あたり1個の前記ヘルパーエピトープと2個の前記キラーエピトープとを含む、<1>に記載のポリペプチド。
<3> 前記ヘルパーエピトープの両側に前記キラーエピトープが結合している、<2>に記載のポリペプチド。
<4> 前記ヘルパーエピトープのアミノ酸配列は、配列番号:2〜39に記載のアミノ酸配列から選択される少なくとも一のアミノ酸配列であり、かつ前記キラーエピトープのアミノ酸配列は、配列番号:40〜45に記載のアミノ酸配列から選択される少なくとも一のアミノ酸配列である、<1>〜<3>のうちのいずれか一に記載のポリペプチド。
<5> 前記ヘルパーエピトープのアミノ酸配列が、配列番号:5に記載のアミノ酸配列であり、かつ前記キラーエピトープのアミノ酸配列が、配列番号:40及び/又は44に記載のアミノ酸配列である、<2>に記載のポリペプチド。
<6> 前記ヘルパーエピトープのアミノ酸配列が、配列番号:5に記載のアミノ酸配列であり、前記ヘルパーエピトープのアミノ末端側に結合している前記キラーエピトープのアミノ酸配列が、配列番号:40に記載のアミノ酸配列であり、かつ前記ヘルパーエピトープのカルボキシル末端側に結合している前記キラーエピトープのアミノ酸配列が、配列番号:44に記載のアミノ酸配列である、<3>に記載のポリペプチド。
<7> <1>〜<6>のうちのいずれか一に記載のポリペプチドを有効成分として含有する抗腫瘍剤。
<8> <1>〜<6>のうちのいずれか一に記載のポリペプチドと単核球とをインキュベーションする工程、及び前記インキュベーションした単核球と抗原提示細胞とをインキュベーションする工程を含む、WT1タンパク質を発現している腫瘍細胞に対してサイトカインを産生するT細胞をインビトロで製造する方法。
<9> <8>に記載の製造方法により製造されたT細胞を有効成分として含有する抗腫瘍剤。
<10> <1>〜<6>のうちのいずれか一に記載のポリペプチドをさらに含む、<9>に記載の抗腫瘍剤。
<11> <1>〜<6>のうちのいずれか一に記載のポリペプチド及び抗原提示細胞を有効成分とする抗腫瘍剤。
<12> <1>〜<6>のうちのいずれか一に記載のポリペプチドによってパルスされた抗原提示細胞を有効成分とする抗腫瘍剤。
後述の実施例において示す通り、WT1タンパク質由来のヘルパーエピトープとキラーエピトープとを合わせて3個以上結合して長鎖ポリペプチドとすることで、これらエピトープを混合してT細胞を刺激する場合と比較し、由来の異なる多くのCD4+T細胞及びCD8+T細胞を刺激し、サイトカインを産生するTh1細胞及びCTLを多く誘導することができる。一方、WT1タンパク質由来のヘルパーエピトープとキラーエピトープとを1個ずつ結合して長鎖ポリペプチドとしても、かかるTh1細胞又はCTLの誘導は亢進されなかった。
後述の実施例において示す通り、前述の融合ポリペプチドによって、由来の異なる多くのT細胞を刺激し、それらの免疫応答を強く誘導することができる。したがって、本発明の融合ポリペプチドを有効成分として含有する抗腫瘍剤を提供することもできる。
前記インキュベーションした単核球と抗原提示細胞とをインキュベーションする工程を含む方法。
健常人ボランティア6名より供与された血液から、Ficoll−Paque(Amersham Bioscience社製)を用い、ヒト末梢血単核細胞(PBMC)を分離した。分離したPBMCを、無血清のAIM−Vを用い、細胞培養フラスコ(BD Biosciences社製)にて37℃、CO2インキュベータ内で1時間培養した後、非付着性細胞を除去した。そして、フラスコ上に残った付着性細胞を、リコンビナントGM−CSF(10ng/ml、Wako社製)及びリコンビナントIL−4(10ng/ml、Wako社製)存在下、AIM−V培地にて培養を開始した。培養を開始してから3日後、GM−CSFとIL−4とを添加したAIM−V培地に交換し、培養を開始してから7日後トリプシンを用いて樹状細胞(DC)を回収した。このDCを抗原特異的T細胞の誘導、又はT細胞からの抗原特異的サイトカイン(IFN−γ)産生解析の際の抗原提示細胞(APC:antigen−presenting cells)として用いた。
表6に示す6種類のWT1タンパク質に由来するポリペプチドを設計し、株式会社ペプチド研究所にて化学合成し、95%以上の純度にてポリペプチドを得た。
ミックス(比較例1):HE4、KE1及びKE5を各5μM混合したものを培地に添加
H/K−HELP1(比較例2):5μMのH/K−HELP1を培地に添加
H/K−HELP2(実施例1):5μMのH/K−HELP2を培地に添加
H/K−HELP3(実施例2):5μMのH/K−HELP3を培地に添加。
健常人ボランティアから分離した前述のPBMCを、24穴プレート(BD Biosciences社製)に2×106細胞/穴になるよう播種した。そして、前述のWT1タンパク質に由来する、抗原特異的T細胞を誘導するための各ポリペプチド(5μM)及び血清を添加したAIM−V培地1ml/穴にて、37℃、CO2インキュベータ内で培養を開始した。
前述の通り誘導したT細胞(前記共培養21日目のT細胞)を5×104細胞/穴になるよう、また自己DCを5×103細胞/穴となるように、96穴プレート(BD Biosciences社製)の同一の穴に播種した。そして、抗原特異的な反応性を解析するための各ポリペプチド(HE4、KE1、KE5、H/K−HELP1、H/K−HELP2又はH/K−HELP3)5μMの存在下、培養を行った。また、対照群としてポリペプチドを加えない群を用意した。
<223> ヒトWT1タンパク質
配列番号:2
<223> ヘルパーエピトープ1(HE1)
配列番号:3
<223> ヘルパーエピトープ2(HE2)
配列番号:4
<223> ヘルパーエピトープ3(HE3)
配列番号:5
<223> ヘルパーエピトープ4(HE4)
配列番号:6
<223> ヘルパーエピトープ5(HE5)
配列番号:7
<223> ヘルパーエピトープ6(HE6)
配列番号:8
<223> ヘルパーエピトープ7(HE7)
配列番号:9
<223> WT1タンパク質の180〜208位において194位のアルギニンがチロシンに置換されているアミノ酸配列からなる、ヘルパーエピトープ8(HE8)
配列番号:10
<223> ヘルパーエピトープ9(HE9)
配列番号:11
<223> ヘルパーエピトープ10(HE10)
配列番号:12
<223> ヘルパーエピトープ11(HE11)
配列番号:13
<223> ヘルパーエピトープ12(HE12)
配列番号:14
<223> ヘルパーエピトープ13(HE13)
配列番号:15
<223> ヘルパーエピトープ14(HE14)
配列番号:16
<223> ヘルパーエピトープ15(HE15)
配列番号:17
<223> ヘルパーエピトープ16(HE16)
配列番号:18
<223> ヘルパーエピトープ17(HE17)
配列番号:19
<223> ヘルパーエピトープ18(HE18)
配列番号:20
<223> ヘルパーエピトープ19(HE19)
配列番号:21
<223> ヘルパーエピトープ20(HE20)
配列番号:22
<223> ヘルパーエピトープ21(HE21)
配列番号:23
<223> ヘルパーエピトープ22(HE22)
配列番号:24
<223> ヘルパーエピトープ23(HE23)
配列番号:25
<223> ヘルパーエピトープ24(HE24)
配列番号:26
<223> ヘルパーエピトープ25(HE25)
配列番号:27
<223> ヘルパーエピトープ26(HE26)
配列番号:28
<223> ヘルパーエピトープ27(HE27)
配列番号:29
<223> ヘルパーエピトープ28(HE28)
配列番号:30
<223> ヘルパーエピトープ29(HE29)
配列番号:31
<223> ヘルパーエピトープ30(HE30)
配列番号:32
<223> ヘルパーエピトープ31(HE31)
配列番号:33
<223> ヘルパーエピトープ32(HE32)
配列番号:34
<223> ヘルパーエピトープ33(HE33)
配列番号:35
<223> ヘルパーエピトープ34(HE34)
配列番号:36
<223> ヘルパーエピトープ35(HE35)
配列番号:37
<223> ヘルパーエピトープ36(HE36)
配列番号:38
<223> ヘルパーエピトープ37(HE37)
配列番号:39
<223> ヘルパーエピトープ38(HE38)
配列番号:40
<223> キラーエピトープ1(KE1)
配列番号:41
<223> キラーエピトープ2(KE2)
配列番号:42
<223> WT1タンパク質の194〜202位において194位のアルギニンがチロシンに置換されているアミノ酸配列からなる、キラーエピトープ3(KE3)
配列番号:43
<223> キラーエピトープ4(KE4)
配列番号:44
<223> WT1タンパク質の303〜311位において304位のメチオニンがチロシンに置換されているアミノ酸配列からなる、キラーエピトープ5(KE5)
配列番号:45
<223> キラーエピトープ6(KE6)
配列番号:46
<223> N末端から順に、HE4と、5つのグリシンからなるリンカーと、KE1とが結合している、融合ポリペプチド
配列番号:47
<223> N末端から順に、HE4と、5つのグリシンからなるリンカーと、KE1と、5つのグリシンからなるリンカーポリペプチドと、KE5とが結合している、融合ポリペプチド
配列番号:48
<223> N末端から順に、KE1と、5つのグリシンからなるリンカーと、HE4と、5つのグリシンからなるリンカーポリペプチドと、KE5とが結合している、融合ポリペプチド
Claims (12)
- WT1タンパク質に由来するヘルパーエピトープ及びWT1タンパク質に由来するキラーエピトープを含む融合ポリペプチドであって、該融合ポリペプチド1分子あたり前記ヘルパーエピトープと前記キラーエピトープとを合わせて3〜6個含むポリペプチド。
- 前記融合ポリペプチド1分子あたり1個の前記ヘルパーエピトープと2個の前記キラーエピトープとを含む、請求項1に記載のポリペプチド。
- 前記ヘルパーエピトープの両側に前記キラーエピトープが結合している、請求項2に記載のポリペプチド。
- 前記ヘルパーエピトープのアミノ酸配列は、配列番号:2〜39に記載のアミノ酸配列から選択される少なくとも一のアミノ酸配列であり、かつ前記キラーエピトープのアミノ酸配列は、配列番号:40〜45に記載のアミノ酸配列から選択される少なくとも一のアミノ酸配列である、請求項1〜3のうちのいずれか一項に記載のポリペプチド。
- 前記ヘルパーエピトープのアミノ酸配列が、配列番号:5に記載のアミノ酸配列であり、かつ前記キラーエピトープのアミノ酸配列が、配列番号:40及び/又は44に記載のアミノ酸配列である、請求項2に記載のポリペプチド。
- 前記ヘルパーエピトープのアミノ酸配列が、配列番号:5に記載のアミノ酸配列であり、前記ヘルパーエピトープのアミノ末端側に結合している前記キラーエピトープのアミノ酸配列が、配列番号:40に記載のアミノ酸配列であり、かつ前記ヘルパーエピトープのカルボキシル末端側に結合している前記キラーエピトープのアミノ酸配列が、配列番号:44に記載のアミノ酸配列である、請求項3に記載のポリペプチド。
- 請求項1〜6のうちのいずれか一項に記載のポリペプチドを有効成分として含有する抗腫瘍剤。
- 請求項1〜6のうちのいずれか一項に記載のポリペプチドと単核球とをインキュベーションする工程、及び前記インキュベーションした単核球と抗原提示細胞とをインキュベーションする工程を含む、WT1タンパク質を発現している腫瘍細胞に対してサイトカインを産生するT細胞をインビトロで製造する方法。
- 請求項8に記載の製造方法により製造されたT細胞を有効成分として含有する抗腫瘍剤。
- 請求項1〜6のうちのいずれか一項に記載のポリペプチドをさらに含む、請求項9に記載の抗腫瘍剤。
- 請求項1〜6のうちのいずれか一項に記載のポリペプチド及び抗原提示細胞を有効成分とする抗腫瘍剤。
- 請求項1〜6のうちのいずれか一項に記載のポリペプチドによってパルスされた抗原提示細胞を有効成分とする抗腫瘍剤。
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EP2565201B1 (en) | 2005-10-17 | 2014-11-26 | Sloan-Kettering Institute For Cancer Research | WT1 HLA class II-binding peptides and compositions and methods comprising same |
CA2645766A1 (en) | 2006-04-10 | 2007-10-25 | Sloan Kettering Institute For Cancer Research | Immunogenic wt-1 peptides and methods of use thereof |
CN104684577B (zh) | 2012-01-13 | 2018-05-08 | 纪念斯隆凯特林癌症中心 | 免疫原性wt-1肽及其使用方法 |
BR112015013557B1 (pt) | 2012-12-11 | 2021-12-14 | Albert Einstein College Of Medicine | Sistema, método, método para determinar o efeito de um resíduo de aminoácido predeterminado de uma primeira proteína sobre a ligação da primeira proteína a uma segunda proteína e polipeptídeo pd-l1 mutante |
US10815273B2 (en) | 2013-01-15 | 2020-10-27 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
PT2945647T (pt) | 2013-01-15 | 2020-11-26 | Memorial Sloan Kettering Cancer Center | Péptidos imunogénicos wt-1 e métodos de uso dos mesmos |
JPWO2017150698A1 (ja) * | 2016-03-04 | 2019-01-31 | 国立大学法人旭川医科大学 | がん免疫療法に利用可能な抗原性ポリペプチド及び当該ポリペプチドを含む抗腫瘍剤 |
IL262606B2 (en) | 2016-05-18 | 2023-04-01 | Albert Einstein College Medicine Inc | pd-l1 variant polypeptides, T-cell modulatory multimeric polypeptides, and methods of using them |
KR20190019068A (ko) | 2016-05-18 | 2019-02-26 | 큐 바이오파마, 인크. | T-세포 조절 다량체 폴리펩타이드 및 이의 사용 방법 |
JP2019122261A (ja) * | 2016-05-19 | 2019-07-25 | 東洋製罐グループホールディングス株式会社 | 細胞調製方法、及び細胞培養容器 |
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US20200010528A1 (en) | 2017-03-15 | 2020-01-09 | Cue Biopharma, Inc. | Methods for modulating an immune response |
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JP4719876B2 (ja) | 2005-04-04 | 2011-07-06 | 国立大学法人愛媛大学 | Hlaクラスii拘束性wt1抗原ペプチド |
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