JPWO2009025196A1 - Foxm1ペプチドおよびこれを含む薬剤 - Google Patents
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Abstract
Description
〔1〕 以下の(A)または(B)に記載のペプチド、
(A)配列番号:1から3のいずれかに記載のアミノ酸配列を含むペプチド
(B)配列番号:1から3のいずれかに記載のアミノ酸配列を含むペプチドにおいて、1個、2個または数個のアミノ酸が置換、欠失、挿入、および/または付加されており、細胞傷害性(キラー)T細胞の誘導活性を示すペプチド
〔2〕 N末端から2番目のアミノ酸がロイシンまたはメチオニンである、〔1〕に記載のペプチド、
〔3〕 C末端アミノ酸がバリンまたはロイシンである、〔1〕に記載のペプチド、
〔4〕 〔1〕に記載のペプチドを有効成分として1種類以上含有する、癌に対する免疫誘導剤、
〔5〕 〔1〕に記載のペプチドを有効成分として1種類以上含有する、癌の治療および/または予防のための薬剤、
〔6〕 〔1〕に記載のペプチドを有効成分として1種類以上含有する、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導するための薬剤、
〔7〕 〔1〕に記載のペプチドをコードするポリヌクレオチドを有効成分として1種類以上含有する、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導するための薬剤、
〔8〕 〔1〕に記載のペプチドを有効成分として1種類以上含有する、細胞傷害性(キラー)T細胞を誘導するための薬剤、
〔9〕 〔1〕に記載のペプチドに対する抗体、
〔10〕 〔1〕に記載のペプチドを用いて誘導される、細胞傷害性(キラー)T細胞、ヘルパーT細胞、またはこれらを含む免疫細胞集団、
〔11〕 〔1〕に記載のペプチドおよびHLA抗原を含む複合体を提示する抗原提示細胞、
〔12〕 〔6〕または〔7〕に記載の薬剤によって誘導される、〔11〕に記載の抗原提示細胞、
〔13〕 〔1〕に記載のペプチドおよびHLA抗原を含む複合体を提示するエキソソーム、
〔14〕 HLA抗原がHLA-A2 (HLA-A*0201)である、〔13〕に記載のエキソソーム、
〔15〕 抗原提示細胞と〔1〕に記載のペプチドとを接触させる工程を含む、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導する方法、
〔16〕 〔1〕に記載のペプチドをコードするポリヌクレオチドを抗原提示細胞へ導入する工程を含む、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導する方法、
〔17〕 T細胞と〔1〕に記載のペプチドとを接触させる工程を含む、細胞傷害性(キラー)T細胞を誘導する方法、
を提供する。
〔18〕 〔1〕に記載のペプチドを対象に投与する工程を含む、癌に対する免疫を誘導する方法、
〔19〕 〔1〕に記載のペプチドを対象に投与する工程を含む、癌を治療および/または予防する方法、
〔20〕 癌に対する免疫誘導剤の製造における〔1〕に記載のペプチドの使用、
〔21〕 癌の治療および/または予防のための薬剤の製造における〔1〕に記載のペプチドの使用、
〔22〕 癌に対する免疫を誘導するための〔1〕に記載のペプチド、
〔23〕 癌の治療および/または予防のための〔1〕に記載のペプチド、
を提供する。
他に定義がない限り、本明細書において用いられるすべての技術用語および科学用語は、本発明が属する技術分野の当業者に一般的に理解されているものと同じ意味をもつ。
本発明のペプチドは、以下の(A)から(D)のいずれかに記載のペプチドである。
(A)配列番号:1から3のいずれかに記載のアミノ酸配列を含むペプチド。
(B)配列番号:1から3のいずれかに記載のアミノ酸配列を含むペプチドにおいて、1個、2個または数個のアミノ酸が置換、欠失、挿入、および/または付加されており、細胞傷害性(キラー)T細胞の誘導活性を示すペプチド。
(C)N末端から2番目のアミノ酸がロイシンまたはメチオニンである(B)に記載のペプチド。
(D)C末端アミノ酸がバリンまたはロイシンである(B)に記載のペプチド。
実施例において、本発明のペプチドが、生体内における癌細胞特異的キラーT細胞を誘導することができることが示された。さらに、先の発明では、FOXM1は、肺癌、胆管細胞癌、膀胱癌、腎細胞癌、前立腺癌、慢性骨髄性白血病、悪性リンパ腫、子宮頸癌、骨肉腫、乳癌、軟部肉腫、大腸癌等の大部分の症例で高発現していることが示された。したがって本発明のペプチドを有効成分として1種類以上含有する免疫誘導剤には、癌の治療および/または予防のための薬剤としての効果が期待できる。つまり、本発明のペプチドを適当なアジュバントと共に、あるいはペプチドを樹状細胞などの抗原提示細胞に負荷した後に体内に注入することにより、腫瘍攻撃性キラーT細胞を誘導ならびに活性化することが期待できる。さらにその結果として抗腫瘍効果も期待できる。また発明のペプチドをコードする遺伝子を適当なベクターに組み込み、この組換えDNAで形質転換されたヒトの抗原提示細胞(樹状細胞など)、BCG結核菌などの細菌、または本発明のペプチドをコードするDNAをゲノムに組み込まれたワクシニアウイルス等のウイルスは、ヒト癌の治療および/または予防用生ワクチンとして有効に利用できる。なお、癌ワクチンの投与量および投与法は通常の種痘やBCGワクチンと同様である。
(1)FOXM1を発現する細胞を含む腫瘍に対するキラーT細胞の誘導、
(2)FOXM1を発現する細胞を含む腫瘍を認識する抗体の誘導、および
(3)抗腫瘍性サイトカイン産生の誘導。
本発明は、上記した本発明のペプチドの一部もしくは全部をエピトープ(抗原)として認識する抗体、ならびに当該蛋白質またはペプチドを用いてインビトロ刺激により誘導されたキラーT細胞にも関する。一般的には、キラーT細胞は抗体よりも強い抗腫瘍活性を示す。
本発明はまた、本発明のペプチドを用いてインビトロ刺激により誘導されたキラーT細胞、ヘルパーT細胞、またはこれらを含む免疫細胞集団に関する。例えば、末梢血リンパ球や腫瘍浸潤リンパ球を本発明のペプチドを用いて、インビトロで刺激すると腫瘍反応性活性化T細胞が誘導され、この活性化されたT細胞を癌患者の血管内、あるいは腫瘍局所などに投与する養子免疫療法に有効に用いることができる。また本発明のペプチドを強力な抗原提示細胞である樹状細胞に負荷、あるいは遺伝子導入により発現させて、これらを用いてT細胞をインビボあるいはインビトロで刺激することにより、抗腫瘍免疫応答を誘導することができる。
本発明はさらに、本発明のペプチドとHLA抗原の間で形成された複合体をその表面上に提示するエキソソームと呼ばれる細胞内小胞を提供する。エキソソームは、例えば、第平11-510507号および第2000-512161号の公開された日本語翻訳文に詳細に記載された方法を用いることにより調製することができ、好ましくは、治療および/または予防の標的である被検体から得られた抗原提示細胞を用いて調製される。本発明のエキソソームは、本発明のペプチドと同様に、癌ワクチンとして接種することができる。
本発明は、本発明の1つまたは複数のペプチドを用いて抗原提示細胞を誘導する方法を提供する。末梢血単球から誘導した樹状細胞に本発明の1つまたは複数のペプチドを接触させ、刺激することにより抗原提示細胞を誘導することができる。本発明のペプチドを被検体へ投与する場合、本発明のペプチドを細胞表面に提示している抗原提示細胞を、被検体の生体内において誘導することができる。あるいは、本発明のペプチドと抗原提示細胞とを接触させた後(あるいは本発明のペプチドを抗原提示細胞へ負荷した後)、該細胞をワクチンとして被検体に投与するエクスビボ法を用いることができる。例えば、エクスビボ投与は以下の工程を含みうる:
(1) 被検体から抗原提示細胞を収集する工程、および
(2) 工程(1)の抗原提示細胞と本発明のペプチドとを接触させる(あるいは工程(1)の抗原提示細胞に本発明のペプチドを負荷する)工程。
(1)被検体から抗原提示細胞を収集する工程、
(2)工程(1)の抗原提示細胞と本発明のペプチドとを接触させる工程(あるいは工程(1)の抗原提示細胞に本発明のペプチドを負荷する工程)、
(3)細胞傷害性T細胞を誘導するために、工程(2)の抗原提示細胞をCD8+ T細胞と混合し共培養する工程、および
(4)工程(3)の共培養物からCD8+ T細胞を収集する工程。
なお本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
(1)HLA-A2に結合性を示すFOXM1ペプチドの選択
ヒトFOXM1のアミノ酸配列をBIMAS system により解析して、推定されたHLA-A2との結合親和性(binding affinity) が20以上のものを23種類選択した。
HLA-A2結合性FOXM1ペプチドによるヒト・キラーT細胞の誘導
(1)採血
健常人および熊本大学医学部付属病院にて治療中の、HLA-A2が陽性の乳癌患者からインフォームドコンセントを得た後、血液サンプル50 mlを得て、先に報告した方法により(Nakatsura, Tら、Eur.J.Immunol.32,826-836,2002)、Ficoll-Conray密度勾配遠心法を利用して末梢血単核細胞を単離した。
単離した末梢血単核細胞から、FOXM1ペプチド特異的キラーT細胞を誘導した。キラーT細胞の誘導はKomori, Hらの報告 (Komori, Hら、Clin.Cancer.Res.12: 2689-2697, 2006) に準じて行った。まずMACSを用いて末梢血単核細胞中のCD8陽性細胞を分離し、CD8陰性細胞をGM-CSF (100 ng/ml)とIL-4 (20 ng/ml) 存在下に4日間培養して樹状細胞を分化誘導した。その後、OK-432 (0.1 KE/ml)を添加して樹状細胞を成熟させ、7日目に各FOXM1ペプチドを添加 (10μM)して、IL-7 (10 ng/ml) 存在下にCD8陽性細胞と共に培養した。CD8陽性細胞と共培養して2日後にIL-2を添加(20 IU/ml)した。この自己CD8陰性細胞由来の樹状細胞による抗原刺激を1週毎に3回繰り返し、ペプチド特異的キラーT細胞を誘導した。
これらのFOXM1ペプチドで誘導したキラーT細胞が、確かにこれらのFOXM1由来のペプチドに特異的に反応して、IFN-γを産生するか否かをELISPOT法にて検討した。ELISPOT法は、先に報告した方法 (Komori, Hら、Clin.Cancer.Res.12: 2689-2697, 2006) により行った。その結果、FOXM1 362-370、373-382、640-649ペプチドで誘導したキラーT細胞において、FOXM1ペプチド特異的なキラーT細胞の活性化が観察された (図1)。FOXM1ペプチドで誘導したキラーT細胞の解析結果の、代表的なものを図1に示す。
誘導したFOXM1ペプチド特異的キラーT細胞の細胞傷害活性を、HLA-A2陽性でFOXM1を発現するpanc-1細胞株と、HLA-A2陰性でFOXM1を発現する膵臓癌細胞株であるPK-8細胞を刺激細胞として、細胞傷害性試験により検討した。キラーT細胞の細胞傷害活性は、クロミウム遊離試験による細胞傷害性試験により評価した。クロミウム遊離試験は先に報告した方法 (Monji, Mら、Clin. Cancer. Res. 10: 6047-6057, 2004)を用いて実施した。この結果、FOXM1 362-370、373-382、640-649ペプチドで誘導したキラーT細胞において、HLA-A2拘束性でFOXM1特異的な細胞傷害活性が認められた (図1)。
Claims (23)
- 以下の(A)または(B)に記載のペプチド。
(A)配列番号:1から3のいずれかに記載のアミノ酸配列を含むペプチド
(B)配列番号:1から3のいずれかに記載のアミノ酸配列を含むペプチドにおいて、1個、2個または数個のアミノ酸が置換、欠失、挿入、および/または付加されており、細胞傷害性(キラー)T細胞の誘導活性を示すペプチド - N末端から2番目のアミノ酸がロイシンまたはメチオニンである、請求項1に記載のペプチド。
- C末端アミノ酸がバリンまたはロイシンである、請求項1に記載のペプチド。
- 請求項1に記載のペプチドを有効成分として1種類以上含有する、癌に対する免疫誘導剤。
- 請求項1に記載のペプチドを有効成分として1種類以上含有する、癌の治療および/または予防のための薬剤。
- 請求項1に記載のペプチドを有効成分として1種類以上含有する、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導するための薬剤。
- 請求項1に記載のペプチドをコードするポリヌクレオチドを有効成分として1種類以上含有する、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導するための薬剤。
- 請求項1に記載のペプチドを有効成分として1種類以上含有する、細胞傷害性(キラー)T細胞を誘導するための薬剤。
- 請求項1に記載のペプチドに対する抗体。
- 請求項1に記載のペプチドを用いて誘導される、細胞傷害性(キラー)T細胞、ヘルパーT細胞、またはこれらを含む免疫細胞集団。
- 請求項1に記載のペプチドおよびHLA抗原を含む複合体を提示する抗原提示細胞。
- 請求項6または7に記載の薬剤によって誘導される、請求項11に記載の抗原提示細胞。
- 請求項1に記載のペプチドおよびHLA抗原を含む複合体を提示するエキソソーム。
- HLA抗原がHLA-A2 (HLA-A*0201)である、請求項13に記載のエキソソーム。
- 抗原提示細胞と請求項1に記載のペプチドとを接触させる工程を含む、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導する方法。
- 請求項1に記載のペプチドをコードするポリヌクレオチドを抗原提示細胞へ導入する工程を含む、細胞傷害性(キラー)T細胞の誘導活性を示す抗原提示細胞を誘導する方法。
- T細胞と請求項1に記載のペプチドとを接触させる工程を含む、細胞傷害性(キラー)T細胞を誘導する方法。
- 請求項1に記載のペプチドを対象に投与する工程を含む、癌に対する免疫を誘導する方法。
- 請求項1に記載のペプチドを対象に投与する工程を含む、癌を治療および/または予防する方法。
- 癌に対する免疫誘導剤の製造における請求項1に記載のペプチドの使用。
- 癌の治療および/または予防のための薬剤の製造における請求項1に記載のペプチドの使用。
- 癌に対する免疫を誘導するための請求項1に記載のペプチド。
- 癌の治療および/または予防のための請求項1に記載のペプチド。
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