JP5753783B2 - 神経膠芽細胞腫(gbm)およびその他の癌の治療に用いる腫瘍関連ペプチド組成物と関連抗癌ワクチン - Google Patents
神経膠芽細胞腫(gbm)およびその他の癌の治療に用いる腫瘍関連ペプチド組成物と関連抗癌ワクチン Download PDFInfo
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Description
米国癌協会(ACS)によると、大腸癌(CRC)は米国で3番目に多い癌であり、175,000例を超える患者が毎年新たに罹患している。米国、日本、フランス、ドイツ、イタリア、スペイン、英国では480,000例を超える患者が罹患している。先進国での癌による死亡の最も一般的な原因の1つである。大腸癌の発症は遺伝的要因と環境的要因の相互作用の結果であることを調査が示唆している。殆どの場合、腺腫性ポリープが大腸癌の前駆状態として現れるが、癌への移行には多年を要することもある。大腸癌の主なリスク要因は年齢であり、大腸癌と診断される症例の90%が50歳を超えている。米国癌協会によると大腸癌の他のリスク要因には、アルコール消費量、脂肪および/または赤身肉の多い食事、および果物野菜の不十分な摂取などが含まれる。大腸癌の発症増加は、特に日本などの地域で続いており、脂肪や肉の過剰摂取と、食物線維摂取の低下につながる西洋化された食事を取り入れたことが原因と思われる。しかしながら、スクリーニングの増加やポリープの除去が、ポリープの癌への進行を防いでいると考えられ、発症率の増加は以前ほど速くはない。
前立腺癌による死亡は2007年に27,050例と推定され、男性の癌において主要な死因となっている。白人とアフリカ系米国人男性では1990年初頭より、その死亡率は減少しているが、アフリカ系米国人男性の死亡率はなおも白人男性の2倍を超えている。前立腺癌は男性で最も頻繁に診断される癌である。理由は未だ不明であるが、アフリカ系米国人男性の発症率は白人男性よりも有意に高い。前立腺癌の発症率はここ20年でかなり変化している。つまり、1988〜1992年では急増し、1992〜1995年では急減し、1995年以降は徐々に増えている。この傾向は、前立腺特異抗原(PSA)血液検査による前立腺癌スクリーニングの増加によるところが大きい。過去10年間で発症率が徐々に上昇していることの大部分は、65歳未満の男性の間でPSAスクリーニングが広まったことに帰する可能性が最も高い。男性前立腺癌の発症率は65歳以上では横ばいとなる。白人男性での発症率のピークは1992年(10万人中237.6例)に、アフリカ系米国人男性では1993年(10万人中342.8例)にある。
2007年、米国では、癌診断症例の約15%にあたる、推定210,000例が新たに肺癌になることが予想されている。男性の発症率は、1984年の10,000人当たり102例から2003年の78.5例に有意に減少している。女性では、発症率は長期間にわたり上昇が続いた後、ほぼ横ばい状態となっている。肺癌は治療目的から、臨床的に小細胞癌(13%)または非小細胞癌(87%)に分類される。
同一性パーセント=100[I−(C/R)]
Cは、参照配列と比較配列間でアラインメントした長さにおいて、参照配列と比較配列間とで異なる残基数を示し、ここで、
(i)比較配列上で相当するアラインメントした塩基やアミノ酸を持たない参照配列の各塩基またはアミノ酸、および
(ii)参照配列の各欠落部、および
(iii)比較配列のアラインメントした塩基あるいはアミノ酸とは異なる、参照配列のアラインメントした各塩基あるいはアミノ酸が差の構成要素となっており、
Rは、塩基またはアミノ酸としても数えられ、参照配列に作られた任意の欠落部を伴い、比較配列とアラインメントした長さにおいて、参照配列の塩基またはアミノ酸の数である。
免疫応答の刺激は、宿主の免疫系により異物であると認識された抗原が存在するかに依存する。腫瘍関連坑原が存在することが発見され、現在、腫瘍の発育に介入するため、宿主の免疫系を利用する可能性が浮上している。体液性免疫系と細胞性免疫系の両方を結びつける様々なメカニズムが、現在、癌の免疫療法において研究されつつある。
CSPG4(コンドロイチン硫酸プロテオグリカン)は、内在性膜コンドロイチン硫酸プロテオグリカンを意味する。これは、腫瘍細胞の増殖、遊走、浸潤の刺激に関係する、初期の細胞表面メラノーマ進行マーカーとしても知られている。CSPG4は、ヒトメラノーマ病変の90%超で強く発現される。CSPG4は厳密には腫瘍に特異的なものではないが、メラノーマ患者および健常者の腫瘍反応性CD4+T細胞応答は、自己免疫を伴わずに、HLA-DR11発現メラノーマ細胞のCSPG4693-709を認識する (Erfurt et al.,2007)。
脂肪酸結合タンパク質(FABP)は14〜15kDaの細胞質タンパク質であり、脂肪酸(FA)の取り込み、輸送、標的化に関与していると想定されている。FABPは、膜分画間でFAを輸送する際にFAの溶解性を上昇させると考えられ、FAを核内の標的に輸送する(Glatz et al., 2002)。FABPはFA濃度を調節すると考えられ、このようにして、酵素活性、遺伝子発現、細胞の増殖と分化など、様々な細胞機能に影響する(Glatz and Storch, 2001)。
X染色体ニューログリン4は、神経細胞シナプスの成熟と機能に関与していると考えられる、細胞接着タンパク質ファミリーの一員である。ニューログリンファミリーには関連する構造的構成があり、N末端シグナルペプチド、2箇所の選択的スプライシングがあるエステラーゼ様ドメイン、膜貫通ドメイン前の配列同一性の低い小さなリンカー領域、C末端が非常に保存された短い細胞質部分がある。相対的にニューログリン4 mRNAレベルが最も高いのは心臓であることが分かった。肝臓、骨格筋、および膵臓で検出された発現は少なく、脳、胎盤、肺、腎臓ではニューログリン4 mRNAは殆ど検出できなかった(Bolliger et al., 2001)。
腫瘍細胞を囲む細胞外基質は、正常組織の細胞外基質とは異なる。テネイシン−C(TNC)は、胚発生(Bartsch et al., 1992)、創傷治癒 (Mackie et al., 1988)、腫瘍過程 (Chiquet-Ehrismann,1993; Chiquet-Ehrismann and Chiquet, 2003)など、遊走能の上昇と密接な関連性があるプロセスで非常にアップレギュレートされる、細胞外基質タンパク質である。さらに、TNCは増殖指数が高い腫瘍血管で過剰発現されるが、増殖指数はTNCが腫瘍の血管形成に関係していることを示している(Kim et al., 2000)。正常なヒト脳では、TNCの発現が検出されることはまれにしかないが、悪性神経膠腫では高レベルで発現される (Bourdonet al., 1983)。TNCの発現は、低酸素症 (Lal et al., 2001)、高悪性度神経膠腫の正常な実質への浸潤メカニズムを形成するTGF-β1(Hau et al., 2006)、またはヒトGBM細胞遊走の調節に重要な意味を持つガストリン (Kucharczak et al., 2001)によって誘導されうる。TNCはトロポミオシン−1をダウンレギュレートするため、アクチンストレス線維を不安定化する。さらに、TNCはWnt阻害因子Dickkopf1をダウンレギュレートさせる。トロポミオシン−1の発現低下とWntシグナル伝達の亢進は形質転換および腫瘍形成と密接な関連性があるため、TNCはこれらのシグナル伝達経路を特異的に調節し、神経膠腫細胞の増殖を増進する(Ruiz et al., 2004)。
NRCAM(神経細胞接着分子)は、免疫グロブリン様のC2型ドメインおよびフィブロネクチンIII型ドメインを複数持つ、神経細胞の膜貫通細胞接着分子である。NRCAMは、他のIgCAMと同種親和性、および異好性の相互作用を形成することにより(Volkmer et al., 1996; Sakurai et al., 1997; Zacharias et al., 1999)、神経細胞の誘導、成長、線維束性収縮に関与する(Grumet et al., 1991; Morales et al., 1993; Stoeckli and Landmesser, 1995;Perrin et al., 2001; Sakurai et al., 2001)。アンキリン結合NRCAM (Davis and Bennett,1994)は管形成を行う内皮細胞でアップレギュレートされているため、管形成および血管形成に関与している可能性が示唆される (Aitkenhead etal., 2002)。
IGF2BP3はインスリン様成長因子II mRNA結合タンパク質ファミリーの一員であり、mRNAの局在化、代謝回転、翻訳調節に関係があるとされている。このタンパク質にはいくつかのKH(K−相同性)ドメインが含まれ、RNA結合において重要であり、RNAの合成および代謝に関与していることが知られている。発現は主に胚発生時に起こり、いくつかの腫瘍で報告されてきた。そのため、IGF2BP3は癌胎児性タンパク質であると考えられている(Liao et al., 2005)。対照組織と比較し、多数の癌組織でIGF2BP3の転写レベルが高くなっていることは、IGF2BP3タンパク質が形質転換細胞の増殖に機能的役割を果たしていることを示している。この仮説はIGF2BP3転写産物を発現した、唯一の非悪性ヒト組織はヒト胎盤であり、この組織は細胞成長と増殖を特徴としているという所見によって裏付けられる(Mueller-Pillasch et al., 1997)。
IGF2BP3発現は高悪性度の尿路上皮腫瘍で有意に増加することも分かったが、良性の尿路上皮または低悪性度の尿路上皮腫瘍では一般に発現されない。さらに、IGF2BP3陽性腫瘍の患者はIGF2BP3陰性腫瘍の患者よりも、無進行生存率および無病生存率がはるかに低い(Li et al., 2008; Sitnikova et al., 2008; Zheng et al., 2008)。
ブレビカン(BCAN)は、コンドロイチン硫酸プロテオグリカンのレクチンファミリーの脳特異的な構成要素である。2種類のBCANアイソフォームが報告されており、細胞外基質に分泌される全長のアイソフォームと、グリコフォスファチジル(GPI)アンカーを予測する配列を持つ、短いアイソフォームである。分泌されたアイソフォームは出生時から8歳までは高く発現され、20歳までに低レベルにダウンレギュレートされ、正常成人の大脳皮質ではこのレベルが維持される。GPIアイソフォームは、発達中、一様に低レベルで発現される(Gary et al., 2000)。BCANは通常、成人の神経系で細胞および神経突起の運動を妨げるバリア分子として説明される、プロテオグリカンファミリーに属する(Viapiano and Matthews, 2006)。in vivoでは、BCANは吻側細胞移動経路の境界あたりで発現され(Jaworski and Fager, 2000)、神経損傷後のグリア性瘢痕で主にアップレギュレートされる成分である (Jaworski et al.,1999)。
METプロトオンコジーンのc-Metは、細胞の増殖、分化、運動性、接着、浸潤の調節能を有する膜貫通チロシンキナーゼ受容体をコードする。c-Metは肝細胞成長因子(HGF)によって活性化される(Giordano et al., 1989; Trusolino and Comoglio, 2002)。
PTPRZ1は、受容体型タンパク質チロシンホスファターゼファミリーの一員であり、細胞質側に2つのチロシンタンパク質ホスファターゼドメイン、α−炭酸脱水酵素ドメイン、フィブロネクチンIII型ドメインを持つ、1回膜貫通型I型膜タンパク質をコードしている。この遺伝子の発現は、胃癌細胞(Wu et al., 2006)、乳癌 (Perez-Pinera et al., 2007)、複数の硬化病変の稀突起膠細胞による再ミエリン化(Harroch et al., 2002)、低酸素条件下でのヒト胎児腎臓細胞 (Wang et al., 2005)で誘導される。
タンパク質と転写産物は共に神経膠芽細胞腫の細胞で過剰発現され、走触性の遊走(Lu et al., 2005)、および神経膠芽細胞腫でのゲノムDNAの増幅 (Mulholland et al., 2006)を促す。
CHI3L2は最初に軟骨細胞から同定され、変形性関節症などでアップレギュレートされる(Steck et al., 2002)。このタンパク質はまだ十分に特徴が決定されていないが、細胞外間隙に分泌される可能性が最も高い。しばしば、関節リウマチの標的抗原として説明されてきた。ヒト神経膠腫細胞株のsiRNA形質移入により、実験的に抗血管形成作用を誘導すると(VEGF-A)、CHI3L2がアップレギュレートされた。
アポトーシス阻害タンパク質(IAP)ファミリーの一員であるBIRC5(サービビン)の発現は、胎生組織および様々なヒト癌で上昇している。サービビンは、細胞増殖とアポトーシス細胞死の両方の調節が可能であると思われる。特に神経膠芽細胞腫では、非常に高レベルのサービビンの発現が検知できる(Angileri et al., 2008)。脳神経膠腫中のサービビン過剰発現が悪性増殖、抗アポトーシスおよび血管形成に重要な役割を果たしている可能性があることが指摘されている(Zhen et al., 2005; Liu et al., 2006)。特に神経膠芽細胞腫では、ただし他の腫瘍にも当てはまるが、サービビン陰性腫瘍患者と比較し、サービビンの発現が悪性度(神経膠芽細胞腫においてサービビンの発現が最も高い)および全体的な生存期間が短いことと有意に関連していた(Kajiwara et al., 2003; Saito et al., 2007; Uematsu et al., 2005; Mellai et al., 2008; Grunda et al., 2006; Xie et al., 2006; Sasaki et al., 2002;Chakravarti et al., 2002)。
B型肝炎ウイルス(HBV)コアタンパク質HBcでは、免疫原性ペプチドがよく知られている(Bertoletti et al., 1993; Livingston et al., 1997)。HBcの10アミノ酸ペプチドは、本発明に基づき、患者の免疫能および癌ワクチンへの免疫付与成功の陽性コントロールに含めることができる。
ペプチドはFmoc法を利用し、標準的で十分確立された固相合成により合成した。分取用HPLCによる精製後、イオン交換法を行い、生理的に適合可能な対イオン(例えば、酢酸、アンモニウム、または塩化物イオン)を組み込んだ。最終的に、凍結乾燥後、白色から黄色がかった白色の固体が得られた。全てのTUMAPは好ましくは酢酸塩として投与され、他の塩の形態も可能である。
IMA950は、大部分が原発性大腸癌細胞で同定された合成腫瘍関連ペプチド(TUMAP)の混合物からなる。TUMAPには、細胞傷害性T細胞(CD8+T細胞)活性化能を持つ10個のHLAクラスI結合ペプチド、ヘルパーT細胞(CD4+ T細胞)活性化能を持つ1個のHLAクラスII結合ペプチド、および両方の活性化能を持つ1個の伸長HLAクラスI結合ペプチドが含まれる。ヘルパーT細胞は、CD8+T細胞の殺傷機能を高めるサイトカインを放出することで、細胞傷害性T細胞の機能を助ける重要な役割を果たし、腫瘍細胞に直接作用することもある (Knutsonand Disis, 2005)。上記12個のTUMAPに加え、IMA950はウイルスのコントロールペプチドも1つ含む。
典型的IMA950は、10個のHLA-A*02結合ペプチド(クラスI)、1個のHLA-DR結合ペプチド(クラスII)、および1個の伸長HLA-A*02ペプチドを含む。さらに、ウイルスマーカーペプチドHBV-001が含まれるが、ここに記載されていない。
組織サンプル
患者の腫瘍組織は、HopitalCantonal Universitaire de Geneve(腫瘍免疫学癌治療研究室)とNeurochirurgische Universitaets-Klinik Heidelberg(分子生物学研究室)から提供された。手術前に全ての患者から書面でインフォームドコンセントを得た。組織は、術後直ちに液体窒素で衝撃冷凍し、TUMAPを単離するまで−80℃で保存した。
衝撃冷凍した組織サンプルのHLAペプチドプールは、わずかに変更したプロトコール(Falk,K. et al 1991;Seeger, F.H. et al.T 1999)に従い、HLA-A*02特異的抗体BB7.2またはHLA-A、-B、-C特異的抗体W6/32、CNBr活性化セファロース、酸処理、および限外ろ過により、固形組織から免疫沈降によって得た。
方法1:
得られたHLAペプチドプールをその疎水性に従い逆相クロマトグラフィー(CapLC、Waters)により分離し、溶出したペプチドは、ESI源付きハイブリッド四重極直交加速飛行時間型タンデム質量分析計(Q-TOFUltima、Waters)を用いて分析した。ペプチドプールは、濃縮と脱塩のためC18プレカラムに装填された。装填後、5μmの逆相C18充填剤(Dionex)が詰まった溶融石英マイクロキャピラリーカラム(75μmi.d. x 250mm)により分離するため、プレカラムをラインにセットした。溶媒Aは、4mM酢酸アンモニウム水溶液とした。溶媒Bは、2mM酢酸アンモニウムの80%アセトニトリル水溶液とした。両溶媒とも蟻酸でpH3.0に調整した。スプリットシステムで流速を5μl/分から約200nl/分まで減少させながら、90分以内に15%から60%のバイナリー勾配をかけた。金被覆ガラスキャピラリー(PicoTip、NewObjective)をマイクロESI源への導入に使った。TOF分析計の積分時間は内部スキャン遅延時間0.1秒で1.9秒であった。その後、ペプチド配列を衝突誘起解離(CID)質量分析計(ESI-LCMS/MS)で明らかにした。同定したTUMAP配列は、作製された天然TUMAPの断片化パターンを、合成配列の同一参照ペプチドの断片化パターンと比較して確認した。
得られたHLAペプチドプールをその疎水性に従い逆相クロマトグラフィー(AcquityUPLC system、Waters)により分離し、溶出したペプチドは、ESI源付きLTQオービトラップ型ハイブリッド質量分析計(ThermoElectron)で分析した。ペプチドプールを1.7μmの逆相C18充填剤(Waters)が詰まった分析用溶融石英マイクロキャピラリーカラム(75μm i.d. x 250 mm)に、流速400nL/分とし、直接装填した。その後前記ペプチドは、流速300nL/分で10%から33%に、2段階の180分バイナリー勾配をかけて分離した。勾配は、溶媒A(0.1%蟻酸水溶液)と溶媒B(0.1%蟻酸アセトニトリル溶液)からなる。金被覆ガラスキャピラリー(PicoTip、NewObjective)をマイクロESI源への導入に使った。LTQオービトラップ型質量分析計をTOP5戦略により、データ依存モードで操作した。手短に言えば、オービトラップで(R=30.000)、高い質量精度の全スキャンからスキャンサイクルを開始し、続いて、以前に選択したイオンを動的排除した5つの最も多量に存在する前駆イオンについて、オービトラップ内で(R=7.500)MS/MSスキャンを実施した。タンデム質量スペクトルは、SEQUESTおよび別の手動コントロールにより解釈した。同定したTUMAP配列は、作製された天然TUMAPの断片化パターンを、合成配列の同一参照ペプチドの断片化パターンと比較して確認した。図1aおよびbは、腫瘍組織から得たMHCクラスI関連TUMAPの典型的スペクトルを示している。
クラスIリガンドについて分析した腫瘍サンプルのみを含めた(「-」=IMA950クラスI TUMAP非検出、「+」=IMA950クラスITUMAP検出)
IMA950に含まれるペプチドの免疫原性について情報を得るため、すでに(Walter,S, Herrgen, L, Schoor, O, Jung, G, Wernet, D, Buhring, HJ, Rammensee, HG, and Stevanovic, S; 2003, Cutting edge: predetermined avidity of human CD8 T cellsexpanded on calibrated MHC/anti-CD28-coated microspheres, J.Immunol., 171,4974-4978)により報告され、十分確立されたin vitro刺激プラットフォームを用いて検討を行った。このように、IMA950に含まれ、検討されたHLA-A*0201拘束性ペプチド10個中10個について、陽性の免疫原性データを示すことができ、これらのペプチドはT細胞エピトープであり、ヒトではこれに対するCD8+前駆T細胞が存在することを証明している。MET-005は伸長型ではHLA-A*02に結合しなかったため、MET-005の免疫原性はこの方法では検討できなかった。従って、in vitroにおける刺激に不可欠なMET-005との四量体は形成することができなかった。しかし、含まれるHLA-A*02エピトープMET-001(YVDPVITSI、EP1507795B1参照)については、in vitroで免疫原性が示された。APCによる適切で自然に発生するプロセシングの後、MET-005はMET-001特異的CTLを刺激すると考えられている。MET-001の免疫原性は健常ドナーにMET-001特異的CTLが存在することを示しており、癌ワクチンの一部としてのMET-005の有効性には必要不可欠な条件でもある。そのため、MET-001の免疫原性はMET-005の免疫原性の強力な指標である。
ペプチド−MHC複合体(pMHC)と抗CD28抗体を載せた人工抗原提示細胞(aAPC)によるin vitro刺激を実行するために、発明者はまず、標準的な密度勾配分離用溶媒(PAA、Coelbe、ドイツ)を使って、新しいHLA-A*02+バフィーコートからPBMC(末梢血単核細胞)を単離した。バフィーコートは血液バンクのTuebingenまたはKatharinenhospitalStuttgartから入手した。単離されたPBMCは、10%熱不活性化ヒトAB血清(PAA、Coelbe、ドイツ)が補充されたRPMI−グルタマックス(Invitrogen、Karlsruhe、ドイツ)、100U/mlペニシリン/100μg/mlストレプトマイシン(Cambrex、Verviers、ベルギー)、1mMピルビン酸ナトリウム(CCPro、Neustadt、ドイツ)、および20μgml/ゲンタマイシン(Cambrex)で構成される、ヒトin vitroプライミング用T細胞培地(TCM)で一晩インキュベートした。CD8+リンパ球は、製造業者の指示に従い、CD8+MACS陽性分離キット(Miltenyi、Bergisch Gladbach、ドイツ)を用いて単離した。得られたCD8+細胞は、2.5ng/ml IL-7(PromoCell、Heidelberg、ドイツ)および10U/mlIL-2(Chiron、Munich、ドイツ)が補充されたTCM中で使用するまで、インキュベートした。pMHC/抗CD28被覆ビーズの作製、T細胞刺激および読み出しなどは、わずかな変更を行い、すでに報告の通り(Walteret al., 2003)に実施した。簡単に言うと、膜貫通型ドメインを欠き重鎖のカルボキ末端でビオチン化された、ビオチン化組み換えHLA-A*0201分子は、(Altmanet al., 1996)が報告した方法に従い生成した。精製した共刺激マウスIgG2a抗ヒトCD28 Ab 9.3(Jung et al., 1987)は、製造業者が推奨するように、スルホ−N−ヒドロキシスクシンイミドビオチンで化学的にビオチン化した。使用したビーズは、5.60μmの大きいサイズのストレプタビジン被覆ポリスチレン粒子(BangsLaboratories、米国イリノイ州)である。陽性および陰性コントロールとして使用したpMHCは、それぞれ、A*0201/MLA-001(修飾Melan-A/MART-1から得たペプチドELAGIGILTV)とA*0201/DDX5-001(DDX5から得たYLLPAIVHI)である。
検討したHLAクラスIペプチドについて、in vitro免疫原性はペプチド特異的T細胞株を生成させることにより証明できた。特異的T細胞株が生成したことを示す代表的な染色を図1に示す。結果は表8にまとめる。
配列番号:12ペプチドの免疫原性を確認するために、臨床試験を実施した。
この第I/II相試験の一部として、根治的前立腺切除術後に生化学的に再発したHLA-A*02+患者において、前立腺特異的ペプチドパネルのワクチン接種による腫瘍発育停止の指標として、PSAレベルを軽減させる試みが行われた。前立腺特異的ペプチドの組み合わせが皮下投与され、抗原構造の様々な投与形態に照らし、各免疫応答の程度が評価された。
事前の根治的前立腺切除術後にPSA再発が検出された(14日以上の間隔で2回測定し、PSAが50%上昇した)患者に、CTと骨シンチグラフィーにより顕性転移病変を除外した後、前立腺特異的ペプチドワクチンを異なる投与形態で皮下投与した。ワクチンは0、7、14、28、42、56日目に8倍投与した(1ペプチド、注射1回につき約100mg)。各ワクチン接種後と70日目に再度、PSAを測定し、治療の奏効を評価した。
要約すると、ワクチンの投与形態には以下の方法が含まれる。
- モンタニド中で乳化されたペプチドワクチンの皮下投与
- 増殖因子の同時投与によりより強力な免疫応答を得る目的で、GM-CSF225μlの局所投与を併用した、モンタニド500μl中に乳化したペプチドワクチンの皮下投与
- 熱で誘導されるより強力な免疫応答を得る目的で行われる局所温熱療法と併用した、モンタニド500μl中に乳化したペプチドワクチンの皮下投与
- TLR 7を介して樹状細胞を活性化するためにイミキモド経皮投与を併用した、モンタニド500μl中に乳化したペプチドワクチンの皮下投与
- TLR7/8によって樹状細胞を活性化するため、ムチン−1のmRNA/プロタミン55μlと共に、モンタニド500μl中に乳化したペプチドワクチンの皮下投与
前立腺特異的ペプチドワクチンは0、7、14、28、42、56日目に患者に投与した。病態安定または目的とする腫瘍応答(PSA-CRまたはPSA-PR)が見られる患者では、検出可能な進行が起こるまで毎月1回i.d.でワクチン接種を行った。これまで得られた経験に基づき、ペプチド注射は忍容性があり、重大な有害反応はない。ワクチン接種療法への奏効は、PSA測定に基づき血清学的にのみに評価されたため、検査は試験の開始時に実施し、in vitroのPSA測定を投与ワクチンが妨害するか否かを決定したが、これにより臨床奏効をシミュレートできる。0、7、14、28、42、56、70日目に、臨床検査、PSAレベル、白血球百分率数、FACS分析およびサイトカイン測定用に血液サンプルを採取した。70日目を過ぎて治療が継続される場合、時宜、治療失敗を検出するために、6週間のPSAのモニタリングが実施された。
患者2例に継続的なデジタル直腸検査によって局所腫瘍が検出された後、PET-CTスキャンで局所再発を発見できた。残る17例の患者では、疾患活動部位を試験終了時に確認できなかった。
完全奏功とは、PSA値の初期上昇後、共同研究している検査室の検出可能最小値に従い、PSA値が検出不能の場合とみなした。測定は4週間以上の間隔後に確認する必要があった。従って、80%超および50%超のPRは、4週間後に再評価する必要があった。少なくとも4週間後にPSAが50%未満の低下または10%未満の上昇の範囲内と確認されれば、病態安定を示した。病態進行は、治療開始時にPSAの上昇が10%を超えた場合と考えた。
患者2例(10.2%)のPSA値は上述した生化学的奏効基準に従う病態安定を示し、これは、治療開始時に10%を超えていたPSA値は、試験終了時に上昇していなかったことを示している(図6、表10、11、12)。最後のワクチンを投与後、これらの2症例の追跡調査は14ヶ月間および16ヶ月間実施された。病態安定の平均期間は、データのカットオフ時点で24ヶ月(28ヶ月および31ヶ月)であり、平均ワクチン接種回数は18回(14回および20回)であった。
患者11のPSADTは6ヶ月の試験期間中に1.5ヶ月から10.1ヶ月に延びた。この患者は、PSAが最初に10.8ng/mlであり、17.8ng/mlまで進行したため試験を中止し、PET-CTでは視覚的に悪性病変はなく、抗アンドロゲン単剤療法を受けた。アジュバントとしてAldaraが投与された。
患者5は、ワクチン接種前の推定PSA倍加時間から判断して試験中に進行した。しかし、この患者はPSA低下を経験し、治療終了後半減期が20.2ヶ月であり、データカットオフ時点で10ヶ月間継続していた。この患者はワクチン接種終了後2回目の治療を受けなかった。この患者には、唯一のアジュバントとしてモンタニドをワクチン接種した。
目的および概要
本分析の目的は、IMA950の作用機序の重要なパラメータであるため、HLA-A*0201対立遺伝子によってコードされるMHC分子へのHLAクラスIペプチドの親和性を評価することであった。HLA-A*0201への親和性は、IMA950およびMET-001では、10個のHLAクラスI拘束性ペプチド全てにおいて中等度から高度であり、解離定数(KD)は0.14(MET-001)から2.05nM(CSP-001)であった。全ての値が、強力な結合因子HBV-001の0.1から中等度の結合因子MUC-001の4.4までの範囲内にあった。これらの結果から、ワクチン候補のIMA950およびMET-005由来MET-001からHLA-A*02のHLAクラスIペプチド全てにおいて強い結合親和性が確認された。
安定なHLA/ペプチド複合体は、HLA重鎖、β2ミクログロブリン(b2m)、およびペプチド性リガンドの3つの分子からなる。変性組み換えHLA-A*0201重鎖分子単独の活性は、その重鎖分子に「空のHLA-A*0201分子」と同等な機能を与えながら保存することができる。これらの分子は、b2mと適切なペプチドを含む水性緩衝剤に希釈すると、完全にペプチド依存的に迅速に効率よく折り畳まれる。これらの分子の有用性は、ペプチドとHLAクラスI分子間の相互作用の親和性を測定する、ELISAに基づくアッセイで利用されている(Sylvester-Hvidet al., 2002)。
結果は、図2に示している。KD値が低いほどHLA-A*0201への親和性は高い。殆どのIMA950ペプチドは、0.1nM(HBV-001、強力な結合因子)から44.4nM(MUC-001、中等度の結合因子)の範囲でHLA-A*0201に対して同様の強い親和性を示した。従って、全てのIMA950クラスITUMAPはMHC分子A*02に対して中等度から強度の結合親和性を持つ。
目的および概要
クラスII TUMAPは、クラスI拘束性TUMAPにより誘導されるCTLの機能を補助する上で重要な役割を果たすヘルパーT細胞を活性化する。IMA950クラスIIペプチドが数種類の異なるHLAクラスII分子に結合することは(無差別な結合)、ワクチン候補IMA950を投与した患者の大部分が補助的なヘルパーT細胞応答の利益を得ることができる、ということを確認するために重要である。例えば、最も優位に発現されるヒトHLAクラスII分子のHLA-DRは、非常に多様な形を持ち、数百種類の対立遺伝子が知られている。HLA-DRB1ハプロタイプの既知の対立遺伝子頻度および十分確立された結合アルゴリズムに基づき、IMA950のいずれのHLAクラスIIリガンド、IMA-BIR-002およびIMA-MET-005とも、無差別なHLA-DR結合ペプチドであると予測できる。詳細には、HLA-A*02陽性白人が少なくとも1つ適切なHLA-DR対立遺伝子を発現している可能性は、いずれのIMA950クラスIITUMAPとも90%を超える。頻度データあるいは結合予測アルゴリズムがないという理由から、残りのヒトクラスII対立遺伝子HLA-DQおよび-DPはこの計算から除外したため、実際の無差別性はさらに高くなる可能性が最も高い。2つのIMA950クラスIITUMAPについて計算された無差別性は、既知のpan-DRエピトープ(PADRE、遺伝子型頻度Fprojected=93.1%)と同じ範囲である。さらに、これらのペプチドの無差別な結合は、invitro結合アッセイにより実験的に確認された。また、IMA-BIR-002では、高いin vivo免疫原性を証明することができた(上記参照)。要約すると、これらの結果から、MET-005およびBIR-002は無差別なHLA-DR結合ペプチドがあることが確認される。
University of Tuebingenで開発されたSYFPEITHIアルゴリズムにより(Rammensee et al., 1997; Rammensee et al., 1999)、IMA950クラスII TUMAPのいくつかの共通HLA-DR対立遺伝子への結合をランク付けした。このアルゴリズムは、例えばヒト腫瘍関連抗原TRP2(クラスI)(Sun et al., 2000)およびSSX2(クラスII) (Neumann et al., 2004)など、広範な抗原からクラスIおよびクラスIIエピトープを同定するため、すでに使用され、成功している。結合閾値は、開示された既知の無差別HLA-DRリガンドの結合スコア分析に基づき、スコア18に定義した。
IMA-BIR-002およびIMA-MET-005を広範なHLA-DR抗原(HLA-DR1からDR7、分割された抗原HLA-DR11から-DR15も含む(Mori et al., 1997))と会合させ、REVEAL(商標) MHC:ペプチド結合アッセイ(ProImmune、英国オックスフォード)により分析し、MHC分子に組み込まれたレベルを決定した。このアッセイでは、結合を合否判定用のコントロール結合因子、および各HLA-DR抗原の陽性コントロールペプチドと比較した。
SYFPEITHIアルゴリズムの予測に基づき、IMA-BIR-002およびIMA-MET-005は、それぞれ既知の結合モチーフを持つHLA-DR対立遺伝子7/8個および8/8個と結合する可能性がある(表11)。HLA-A*02陽性白人がIMA-BIR-002またはIMA-MET-005に対して少なくとも1つ適切なHLA-DRB1対立遺伝子を発現する確率は、それぞれ92.6%および100%近くである。従って、いずれのIMA950クラスIIペプチドも無差別なHLA-DR結合因子と予想される。
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Claims (10)
- a)ペプチドの全長が9〜30アミノ酸長である、配列番号1に示されるアミノ酸配列を含むペプチドおよび配列番号2に示されるアミノ酸配列を含むペプチドの少なくとも2つのペプチド、および/または
b)a)に記載のペプチドをコードする核酸を含むポリヌクレオチド、ならびに薬学的に許容される担体
を含む、神経膠腫の予防または治療のための医薬組成物。 - 配列番号3〜20からなる群から1つ選択されるアミノ酸配列を含む少なくとも1つの付加的なペプチド、または配列番号3〜20からなる群から1つ選択されるアミノ酸配列をコードする核酸を含むポリヌクレオチドをさらに含む、請求項1に記載の医薬組成物。
- ペプチドの全長は、9〜17アミノ酸長である、請求項1または2に記載の医薬組成物。
- 少なくとも1つのペプチドは非ペプチド結合を含む、請求項1〜3のいずれか1項に記載の医薬組成物。
- 配列番号1に示されるアミノ酸配列からなるペプチドおよび配列番号2に示されるアミノ酸配列からなるペプチドの少なくとも2つのペプチドを含む、または前記少なくとも2つのペプチドと共に配列番号3〜20からなる群から1つ選択されるアミノ酸配列からなる少なくとも1つの付加的なペプチドを含む、請求項1〜4のいずれか1項に記載の医薬組成物。
- 神経膠腫の患者に有効なペプチドが選択され、および/または有効なペプチドの数量が含まれる、請求項1〜5のいずれか1項に記載の医薬組成物。
- 1018 ISS、アルミニウム塩、Amplivax、AS15、BCG、CP-870,893、CpG7909、CyaA、dSLIM、GM-CSF、IC30、IC31、イミキモド、ImuFactIMP321、IS Patch、ISCOMATRIX、JuvImmune、LipoVac、MF59、モノホスホリルリピドA、モンタニドIMS 1312、モンタニドISA206、モンタニドISA 50V、モンタニドISA-51、OK-432、OM-174、OM-197-MP-EC、ONTAK、PepTelベクター系、PLG微粒子、レシキモド、SRL172、ビロソームおよび他のウイルス様粒子、YF-17DBCG、Aquila'sQS21 stimulon、Ribi's Detox. Quil、Superfos、フロイントアジュバント、GM-CSF、コレラ毒素、免疫学的アジュバント、MF59、およびサイトカインからなる群から選択される、少なくとも1つの適切なアジュバントをさらに含む、請求項1〜6のいずれか1項に記載の医薬組成物。
- さらに少なくとも1つの抗原提示細胞または樹状細胞を含む、請求項1〜7のいずれか1項に記載の医薬組成物。
- 少なくとも1つの抗原提示細胞または樹状細胞が、
a)ペプチドでパルスされているか、もしくは前記ペプチドを提示している、または
b)ペプチドをコードする発現構成物を含む、
請求項8に記載の医薬組成物。 - 医薬組成物がワクチンとして、静脈内投与、動脈内投与、腹腔内投与、筋肉内投与、経皮投与、腫瘍内投与、経口投与、経皮投与、経鼻投与、頬側投与、直腸投与、経膣投与、吸入、または局所投与される、請求項1〜9のいずれか1項に記載の医薬組成物。
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