JP2006508094A - Hm1.24を応用した癌ワクチン - Google Patents
Hm1.24を応用した癌ワクチン Download PDFInfo
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- JP2006508094A JP2006508094A JP2004548092A JP2004548092A JP2006508094A JP 2006508094 A JP2006508094 A JP 2006508094A JP 2004548092 A JP2004548092 A JP 2004548092A JP 2004548092 A JP2004548092 A JP 2004548092A JP 2006508094 A JP2006508094 A JP 2006508094A
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Abstract
【解決手段】 HM1.24によりパルスされた、あるいはHM1.24をコードする遺伝子が導入された、抗原特異的樹状細胞、HM1.24蛋白質、HM1.24ペプチド、又はHM1.24蛋白質をコードするDNA又はRNAを有効成分とする癌ワクチン。
Description
本発明はまた、HM1.24蛋白質又はHM1.24ペプチドを有効成分とする癌ワクチンを提供する。このHM1.24ペプチドは、好ましくは可溶性HM1.24ペプチドである。
本発明はまた、HM1.24をコードするDNA又はRNAを有効成分とする癌ワクチンを提供する。このDNAは好ましくはcDNAである。
実験動物では、ペプチドの直接投与よりも、抗原ペプチドや遺伝子を導入した樹状細胞を投与する方が免疫効果が高い。樹状細胞に癌抗原を多量に発現させる方法として、ペプチドや蛋白質によるin vitro感作や抗原DNAやRNAの導入が行なわれる。抗原プロセスを必要とする蛋白質やRNAを取り込ませるためには、未熟樹状細胞が使用され、そしてペプチド感作には成熟樹状細胞や、CD40Lなどにより活性化した樹状細胞が使用される。
抗原蛋白質(HM1.24蛋白質)をコレステロール・多糖複合体やビーズなどの顆粒状にして投与することにより、樹状細胞などに取り込まれ、MHCクラスI抗原提示経路に効率よくペプチドを乗せてCD8+T細胞を誘導することが出来る。強いアジュバント作用をもつ細菌由来の熱ショック蛋白質との融合蛋白質として用いることにより、CD8+T細胞を強く誘導することができよう。
遺伝子は好ましくはDNA又はRNAであり、DNAは好ましくはcDNAであり、適当なベクター、好ましくは、哺乳類、特にヒトにおいて機能する発現ベクターに挿入した後動物に投与することにより、癌免疫を生じさせることが出来る。
配列番号:5に示すアミノ酸配列に対する1又は複数個のアミノ酸残基の置換、欠失及び/又は付加により修飾されたアミノ酸配列を有する可溶性HM1.24抗原蛋白質として、配列番号:7又は17、10又は18、あるいは11又は19に示されるアミノ酸配列を有する可溶性HM1.24抗原蛋白質が挙げられる。
なお、細胞膜上に発現するヒトHM1.24抗原蛋白質のアミノ酸配列を配列番号:15又は23に示す。配列番号:15又は23のアミノ酸配列を有するヒト蛋白質をコードするDNA をpUC ベクターのXbaI切断部位間に保持するプラスミドpRS38-pUC19 を含有する大腸菌はEscherichia coli DH5α(pRS38-pUC19 )と命名され、平成5(1993) 年10月5日付けで独立行政法人産業技術総合研究所特許生物寄託センター(茨城県つくば市東1 丁目1 番1 中央第6)に寄託番号FERM BP-4434として、ブダペスト条約に基づき国際寄託されている。
また例えば、ポリペプチドとしては、GST (グルタチオン・S ・トランスフェラーゼ)、HA、イムノグロブリン定常領域、b-ガラクトシダーゼ、MBP (マルトース結合蛋白質)等が挙げられる。これらは市販されているものを用いることができる。
このように作製した発現ベクターは、公知の方法により宿主に導入することができる。宿主への導入の方法としては、例えばエレクトロポレーション、リン酸カルシウム法、リポソーム法が挙げられる。
例えば、SV 40 プロモーター/エンハンサーを使用する場合、Mulliganらの方法(Nature (1979) 277, 108)、また、HEF1αプロモーター/エンハンサーを使用する場合、Mizushima らの方法(Nucleic Acids Res. (1990) 18, 5322)に従えば容易に実施することができる。
蛋白質分泌のためのシグナル配列としては、大腸菌のペリプラズムに産生させる場合、pelBシグナル配列(Lei, S. P. et al J. Bacteriol. (1987) 169, 4379 )を使用すればよい。
本発明において、蛋白質の製造のために、任意の産生系を使用することができる。蛋白質製造のための産生系は、in vitro及びin vivo の産生系がある。in vitroの産生系としては、真核細胞を使用する産生系や原核細胞を使用する産生系が挙げられる。
原核細胞を使用する場合、細菌細胞を用いる産生系がある。細菌細胞としては、大腸菌(E. coli )、枯草菌が知られている。
動物を使用する場合、哺乳類動物、昆虫を用いる産生系がある。
哺乳類動物としては、ヤギ、ブタ、ヒツジ、マウス、ウシを用いることができる(Vicki Glaser, SPECTRUM Biotechnology Applications, 1993 )。また、哺乳類動物を用いる場合、トランスジェニック動物を用いることができる。
さらに植物を使用する場合、例えばタバコを用いることができる。タバコを用いる場合、目的とするDNA を植物発現用ベクター、例えばpMON 530に挿入し、このベクターをアグロバクテリウム・ツメファシエンス(Agrobacterium tumefaciens )のようなバクテリアに導入する。このバクテリアをタバコ、例えばニコチアナ・タバクム(Nicotiana tabacum )に感染させ、本タバコの葉より所望のタンパク質を得る(Julian, K.-C. Ma et al., Eur. J. Immunol. (1994) 24, 131-138)。
実施例1. HM1.24をパルスした樹状細胞によるT細胞の刺激の有効性
末梢血単球3×108個を含むロイコアフェレシス(Leucoapheresis)画分を10%FCSを含有するRPMI培地中で2時間培養して付着せしめ、非付着細胞を除去し、10%自己血清、GM-CSF及びIL-4を含むX-vivo20培地により培地交換し、これにより樹状細胞を生成せしめ、その一部をT細胞の調製のために凍結した。こうして調製した樹状細胞にHM1.24ペプチドを加えてパルスし、次に成熟剤であるCD40−リガンド300ng/mLと共にインキュベートして成熟させた。次に、樹状細胞を採取し、HBSS中で洗浄し、そして、5%自己血清を含有するX-vivo培地中に3×106/mLの濃度で再懸濁した。これを、25Gyで照射した。
次に、このT細胞懸濁液に、前に調製した樹状細胞(HM1.24でパルスし、照射したもの)を加え、1週間の間隔で2回、T細胞を刺激した。この培養の最後の5日間にインターロイキン−2(IL-2)及びインターロイキン−15(IL-15)を添加した。
本発明者は次に、それらのHM1.24特異的T細胞の細胞溶解能力を試験した。形質細胞標的物を、PKH26によりラベルし、エフェクターT細胞と共に37℃で3時間インキュベートし、そしてTOPRO−3−ヨウ化物を添加し、死亡細胞を染色した。次に生存/死亡標的%を、フローサイトメトリー法により定量化した。
抗−クラスI mAb:W6/32クローン、Serotec, Uk.
抗−クラスII mAb: B1.12クローン、Immunotech, France.
コンカナマイシンA(100nMで使用される):Sigma Aldrich, UK.
ブレフェルジンA(10μMで使用される):Sigma Aldrich, UK.
図4及び5は、HM1.24に対して生成されたCTLの細胞毒性活性を示す。図4は、自己由来のPC及び同種異系PCに関するバックグラウンドの細胞死を示す。図5は、自己由来のPC及び同種異系PCに関して、HM1.24に対して生成される細胞障害性Tリンパ球(CTL)による特異的殺細胞を示す。
図6及び7は、対照CTLの細胞毒性活性を示す。図6は、自己由来のPC及び同種異系PCに関するバックグラウンドの細胞死を示す。図7は、自己由来のPC及び同種異系PCに関する対照CTLによる殺細胞を示す。
最終的に、HM1.24特異的CTLによる自己由来の形質細胞の溶解は、拮抗“コールド(cold)”標的物の存在下で阻止され、この標的物は、HM1.24をコードするcDNAによりトランスフェクトされた自己由来のDCであった(“コールド”標的物が3:1の比で存在する場合、43.8%の阻害率であり、10:1の比での場合、93.4%の阻害率であった)。操作されていないDCが細胞毒性アッセイに存在する場合、形質細胞の溶解の阻止は観察されなかった。HM1.24感作されたT細胞は、66±8%のCD3+CD8+T細胞を含み、そして残りはCD3+CD4+細胞であった。
プラスミドDNAを、Megaprepを用いて単離し、そして分光光度法により定量した。トランスフェクション混合物を、FuGENE6トランスフェクション試薬(Roche Diagnostics Corporation, USA)及びプラスミドDNAと共に無血清培地(X−vivo 10, Life Technologies, OK)を用いて調製した。FuGENE試薬は、100μlの合計体積で2μgのDNAに対して6μlで使用され、そして混合物は、無血清培地におけるDCへの添加の前、室温で2時間まで、静置された。6時間のインキュベーションの後、血清及び新鮮なサイトカインをDC培養物に添加した。DCを、トランスフェクションの48時間後、HM1.24の発現について分析した。
結果は、図12〜14に示される。図12は、HM1.24プラスミドによりトランスフェクトされた自己由来DCが高レベルのHM1.24抗原を発現することを示す。無血清の条件下でFugeneにより4日目にトランスフェクトされた自己由来DCを、自己由来の形質細胞と共に10:1の比でCTLアッセイにおいて6日目で使用した。
EcoRI (宝酒造社製)およびNotI(宝酒造社製)で消化することにより調製したEF1 αプロモーターを含むHEF 発現ベクター(国際特許出願公開番号WO92-19759)と、Igリーダー配列とHAタグをコードする遺伝子ペア(Amersham Pharmacia社製) を、50 mmol/L Tris-HCl、pH7.6 、10 mM MgCl2 、10 mmol/L ジチオスレイトール、1 mmol/L ATP、50 mg/mLのポリエチレングリコールおよび10ユニットT4 DNAリガーゼ(TOYOBO社製) を含有する反応混合物中で、16℃にて3時間反応させ連結した。
psHM及びpsHM164 の塩基配列決定は自動DNA シークエンサー(Applied Biosystem Inc.社製)およびTaq Dye terminator Cycle Sequencing kit (Applied Biosystem Inc.社製)を用いて、メーカー指定のプロトコールに従って行った。配列番号8及び9に示したプライマー(サワディーテクノロジー社製)を用いた。その結果、可溶性抗原にHAタグペプチドをつないだ融合タンパク(配列番号10及び11)が発現する構造になっていることを確認した。
(1)CHO 細胞へのトランスフェクション
HAタグ付加可溶性HM1.24抗原安定産生系を樹立するために、PvuI (GIBCO-BRL 社製) で消化して得た直鎖状にした前記発現ベクター (psHM及びpsHM164)をエレクトロポレーション法によりCHO 細胞DXB11 株 (Medical Research Council collaboration Center より供与) に遺伝子導入した。ベクター1μg をPBS (-) 中 1.1×107 細胞/mL の 0.8 mL アリコートに加え、Gene Pulser 装置 (Bio-Rad 社製) を用いて1.5 kV、 25 μF の容量にてパルスを与えた。
後記の可溶性ヒトHM1.24のELISA は次のようにして行った。高産生の株を選択するために可溶性抗原の産生量を抗HA抗体 (Boehringer Mannheim 社製) とヒト型化抗HM1.24抗体 (小野浩一郎ら 第20回日本分子生物学会年会 一般演題 3-501-P-478) によるサンドイッチELISA で比較し、細胞株の選択を行った。精製抗原を得ていないため抗原濃度は分からないので、濃度の比較はELISA を行った際の細胞数を考慮した。
それぞれHAタグを付加した、HM1.24抗原の膜貫通領域を欠損した可溶性HM1.24抗原 (sHM)及びsHM のC末端を欠損したsHM164の発現ベクターを導入したDXB11 細胞で、各10株ずつ (sHM 産生株:1-1, 8-2, 9-3, 11-4, 14-5, -16, -17, -22, -23, -24, sHM164産生株:164-1, -2, -3, -5, -6, -7, -8, -10, -13, -16) について、25 cm2フラスコにて10 nmol/L メトトレキセート (Methotrexate) (MTX) 含有培地 (α-MEM (GIBCO-BRL 社製) 、10% FCS (GIBCO-BRL社製、1% ペニシリン−ストレプトマイシン(GIBCO-BRL 社製) 、100 nmol/L MTX (SIGMA 社製) )で培養した。
sHM 産生株及びsHM164産生株について、10 nmol/L MTX 培地で抗原産生量の高かった各5株ずつ(sHM 産生株8-2, 9-3, 11-4, 14-16 及び14-24 並びにsHM164産生株164-1, 164-2, 164-5, 164-8及び164-13) について、100 nmol/L MTXによる遺伝子増幅を行った。
sHM 産生株8-2 並びにsHM164産生株164-2 及び164-13について、限界希釈法によるシングルクローン化を行った。
8-2, 164-2及び164-13をそれぞれ100 nmol/L MTX培地で1.7 細胞/mL に調製し、96ウェルプレート各3枚に150 μL/ウェル (0.25細胞/ ウェル)分注した。13日培養後、コロニーの形成が見られたウェル (8-2 : 13ウェル、164-2 : 36ウェル、164-13 : 23 ウェル) の培養上清 (4日培養)中の抗原産生量をELISA で測定した。
96ウェル由来164-2 から、最終的にCGM/sHM (尾嵜恭子ら 第60回日本血液学会 一般演題 690) で作製したものの約100 倍程度の産生量を示す4株(164-2-1, 164-2-13, 164-2-17 及び164-2-31) が得られた。
164-2-1, 164-2-13, 164-2-17 及び164-2-31の細胞株を25 cm2フラスコ/ 5mL培地で1日、3日、及び5日培養した培養上清についてウエスタンブロットを行った。
可溶性ヒトHM1.24抗原発現CHO 細胞培養上清より、可溶性ヒトHM1.24抗原を精製した。可溶性ヒトHM1.24抗原発現CHO 細胞を培養液 [10% FBS (MOREGATE 社製) 、1% ペニシリン−ストレプトマイシン(GIBCO-BRL 社製) 、500 nmol/L MTX (Sigma 社製) を含むαMEM 培地 (GIBCO-BRL 社製) ] 中で、37℃、5% CO2 存在下で培養した。培養上清約2 Lを遠心により、回収した。
発明の効果
従って、HM1.24蛋白質又はペプチドをパルスした、あるいはHM1.24をコードする遺伝子を導入した樹状細胞、HM1.24蛋白質又はペプチド自体、更にはHM1.24蛋白質又はペプチドをコードするDNA又はRNAは、癌ワクチンとして有用であると期待される。
Claims (12)
- HM1.24によりパルスされた抗原特異的樹状細胞を有効成分とする癌ワクチン。
- 前記HM1.24がHM1.24蛋白質又はHM1.24ペプチドである、請求項1に記載の癌ワクチン。
- 前記HM1.24ペプチドが可溶性HM1.24ペプチドである、請求項2に記載の癌ワクチン。
- HM1.24をコードする遺伝子が導入された抗原特異的樹状細胞を有効成分とする癌ワクチン。
- 前記遺伝子がDNA又はRNAである、請求項4に記載の癌ワクチン。
- 前記DNAがcDNAである、請求項5に記載の癌ワクチン。
- HM1.24蛋白質又はHM1.24ペプチドを有効成分とする癌ワクチン。
- 前記HM1.24ペプチドが可溶性HM1.24ペプチドである、請求項7に記載の癌ワクチン。
- HM1.24をコードする遺伝子を有効成分とする癌ワクチン。
- 前記遺伝子がDNA又はRNAである、請求項9に記載の癌ワクチン。
- 前記DNAがcDNAである、請求項10に記載の癌ワクチン。
- 前記癌がHM1.24を発現する器官や組織の癌である、請求項1〜11のいずれか1項に記載の癌ワクチン。
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