JP5709396B2 - がんワクチン - Google Patents
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Description
snailタンパク質の有するアミノ酸配列の一部である配列番号1または2からなるペプチドを抗原提示細胞である樹状細胞に添加したとき、HLAクラスI分子に結合することにより、細胞表面に提示され、細胞傷害性T細胞に認識されることで、snailを認識する細胞傷害性T細胞を誘導できる。また、各ペプチドの刺激により樹立された細胞傷害性T細胞がsnailタンパク質を発現するがん細胞を効率よく認識することから、配列番号1および2の両方又はいずれか一つのペプチド、そのペプチドを細胞表面に提示した抗原提示細胞、および、抗原提示細胞によって誘導され、snail抗原を発現しているがん細胞を認識する細胞傷害性T細胞は、がんワクチンとして、がんの治療・予防に利用することができる。
現在、がんワクチンとして、腫瘍特異的がん抗原、がん抗原提示抗原提示細胞、または、がん抗原反応性細胞傷害性T細胞をがん患者に投与する方法が開発されている。snailタンパク質の部分ペプチドを用いたがんワクチンの、治療または予防対象となるがんは、snailタンパク質を発現しているがんであれば特に限定されず、神経腫、腎癌、肝癌、膵臓癌、肉腫、大腸癌、メラノーマ、肺癌、食道癌、子宮癌、精巣癌、卵巣癌、白血病、リンパ腫、骨髄腫など、固形がんでも血液のがんでも構わないが、膵臓癌、メラノーマ、白血病、大腸癌であることが好ましい。
本発明のがんワクチンは、配列番号1および2のペプチドの両方またはいずれか一つを含有してもよい。この場合、あらかじめ患者のHLAクラスIのタイプを調べるのが好ましい。ここでは、患者のHLAクラスIタイプがA24である場合に、配列番号1および2のペプチドの両方又はいずれか一つを投与することが好ましい。一方、HLAクラスIタイプがA02である場合には、配列番号1のペプチドを投与することが好ましい。このがんワクチンは、配列番号1および配列番号2のペプチド以外に、治療対象であるがん細胞の発現している他種のがん抗原ペプチドを含有していてもよい。また、投与する際には、免疫誘導能を高めるアジュバンドなどと共にペプチドを投与してもよい。また、投与されるペプチドは、生体内で分解されにくくするような修飾が施されていてもよい。さらには、ペプチドそのものではなく、これらのペプチドをコードするDNAを組み込んだ発現ベクターなどを用い、DNAワクチンとして投与してもよい。
配列番号1または2からなるペプチドを提示した抗原提示細胞も、がんワクチンとして使用することができる。ここで、細胞表面に提示されているペプチドは、無修飾であっても、糖やリン酸などで修飾されてもよい。抗原提示細胞としては、樹状細胞、マクロファージ、B細胞、B7や4−1BBLなどのT細胞刺激因子などを遺伝子導入等で強制的に発現させた腫瘍細胞(偽抗原提示細胞)等が例示できるが、抗原提示能の高さなどを考慮すると、樹状細胞が好ましい。以下、樹状細胞の単離方法の例を記載するが、他の細胞も公知の方法で容易に取得できる。
また、配列番号1または2からなるペプチドを提示した抗原提示細胞の刺激によって樹立されたT細胞もまた、がんワクチンとして使用できる。このT細胞は、配列番号1または2からなるペプチドを提示した抗原提示細胞と共に、血清の存在下でナイーブT細胞を共培養し、CD8陽性細胞障害性T細胞(CTL)またはCD4陽性のヘルパーT細胞などへと分化させることによって得られる。このようにして樹立されたT細胞をがんに罹患する個体に投与してもよい。
本実施例では、snail遺伝子が正常組織にほとんど発現していないが、がん細胞株およびがん組織では発現が高いことを示す。
RNeasykit(Qiagen 社)を用いて、健常人正常組織、大腸癌患者の癌組織と肉眼的に判定して得られた大腸正常部位、および種々のヒト腫瘍細胞株(膵臓癌、メラノーマ、白血病、大腸癌)(図1、2参照)からRNAを抽出し、AMVで逆転写してcDNAを得た。次に、下記のプライマーを用いてiCycler(Biorad 社)で遺伝子を増幅し、電気泳動にて遺伝子発現を検出した。なお、内部標準として、GAPDH遺伝子の発現を用いた。
Snail用プライマー:
Forward 5'-CAGATGAGGACAGTGGGAAAGG -3'(配列番号5)
Reverse 5'-ACTCTTGGTGCTTGTGGAGCAG -3'(配列番号6)
GAPDH用プライマー:
Forward 5'- GTCAACGGATTTGGTCGTATT -3'(配列番号7)
Reverse 5'- ATCACTGCCACCCAGAAGACT -3'(配列番号8)
本実施例では、snail 1及びsnail 3ペプチドを用いることにより、健常人のHLA−A24陽性PBMCから、各ペプチドを認識して活性化するCTLの誘導が可能であることを示す。
snail 1:KMHIRSHTL(配列番号1)
snail 2:KAFSRPWLL(配列番号9)
snail 3:RTFSRMSLL(配列番号2)
HERV−H env:SYLHHTINL(配列番号10)
NY−ESO−1:LLMWITQCF(配列番号11)
本実施例では、snail 3ペプチドを用いてPMBCを刺激培養することにより得られたCTLが、HLA依存的にsnail抗原陽性の腫瘍細胞に対する傷害活性を有することを示す。
本実施例では、snail 1ペプチドを用いて分化誘導されたCTLは、HLA−A02依存的にsnail 1ペプチドを提示している細胞を認識することができることを示す。
Claims (8)
- 配列番号1(KMHIRSHTL)または配列番号2(RTFSRMSLL)の配列からなるペプチド。
- 配列番号1または2の配列からなるペプチドを細胞表面に提示した抗原提示細胞。
- 請求項2に記載の抗原提示細胞によって誘導され、snail抗原を発現しているがん細胞を認識するT細胞。
- 細胞傷害性T細胞であることを特徴とする請求項3に記載のT細胞。
- 前記がん細胞が、膵臓癌細胞、メラノーマ細胞、白血病細胞、あるいは大腸癌細胞であることを特徴とする、請求項3または4に記載のT細胞。
- 配列番号1、2から選択される一つ以上のペプチド、前記ペプチドを発現する発現ベクター、請求項2に記載の抗原提示細胞、または、請求項3〜5のいずれかに記載のT細胞を含有するがんワクチン。
- Snailタンパク質を発現するがん細胞に対するがんワクチンであることを特徴とする請求項6に記載のがんワクチン。
- 前記がんが、膵臓癌、メラノーマ、白血病、または大腸癌であることを特徴とする、請求項6または7に記載のがんワクチン。
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