JP5525689B2 - 過剰増殖性障害を処置するための組成物および方法 - Google Patents
過剰増殖性障害を処置するための組成物および方法 Download PDFInfo
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Description
本出願は、2004年11月2日に出願された米国仮出願番号60/624,803に関し、その全開示は参考文献に含まれる。
本発明は概して、濃縮NK細胞集団を含む組成物に関する。本発明はさらに濃縮NK細胞集団を必要とする哺乳動物被験体へ濃縮NK細胞集団を投与することによって、固形腫瘍または過剰増殖性障害の治療法に関する。
ナチュラルキラー(NK)細胞は抗原非依存性の腫瘍細胞毒性を有し、マウスモデルにおいて腫瘍の増殖及び播種性転移(dissemination)を抑制・阻止することが示されている(非特許文献1;非特許文献2)。しかし、ヒトの癌の抑制におけるNK細胞の正確な役割に関しては未だ議論の余地がある。
Morettaら、Nat.Immunol.(2002)3:6−8 Kimら、Proc.Natl.Acad.Sci.U.S.A.(2000)97:2731−2736 Morettaら、Annu.Rev.Immunol.(2001)19:197−223 Vilchesら、Annu.Rev.Immunol.(2002)20:217−251 Yokoyamaら、Semin.Immunol.(1995)7:89−101 Takeiら、Immunol.Rev.(1997)155:67−77 Lanierら、Annu.Rev.Immunol.(1998)16:359−393 Longら、Immunol.Rev.(2001)181:223−233 Morettaら、J.Exp.Med.(1995)182:875−884 Winterら、J.Immunol.(1997)158:4026−4028 Winterら、J.Immunol.(1998)161:571−577 Frohnら、J.Immunother.(2000)23:499−504 Rosenbergら、N.Engl.J.Med.(1985)313:1485−1492 Liaoら、Science,(1991)253:199−202 Giebelら、Blood,(2003)102:814−819 Childsら、N.Engl.J.Med.(2000)343:750−758 Riniら、J.Urol.(2001)165:1208−1209 Bregniら、Blood,(2002)99:4234−4236 Uenoら、J.Clin.Oncol.(1998)16:986−993 Hentschkeら、Bone Marrow Transplant,(2003)31:253−261 Strairら、J.Clin.Oncol.(2003)21:3785−3791
本発明は概して、濃縮NK細胞集団を含む組成物に関する。処置を必要とする哺乳動物被験体へ濃縮NK細胞集団を投与する工程を包含する、固形腫瘍または過剰増殖性障害を処置する方法を提供する。本発明は、濃縮同種異系NK細胞集団を含む組成物を提供する。濃縮同種異系NK細胞集団はさらにKIR/KIRリガンド−不適合性の濃縮同種異系NK細胞集団を含む。本発明はさらにKIR/KIRリガンド−不適合性の濃縮自己NK細胞集団を含む組成物を提供する。
本発明は概して、濃縮NK細胞集団を含む組成物に関する。濃縮同種異系NK細胞集団を含む組成物を提供する。濃縮同種異系NK細胞集団はさらにKIR/KIRリガンド不適合性NK細胞を含む。濃縮自己NK細胞集団を含む組成物を提供する。本発明はさらに、上記のように、固形腫瘍を治療するため、もしくはその再発を予防するための有効量で、濃縮同種異系又は自己NK細胞集団の組成物を哺乳動物被験体に投与する工程を包含する、固形腫瘍を処置する方法に関する。キラーIg様受容体(KIR)を介した細胞不活化は、潜在的に、腫瘍細胞を宿主のNK細胞媒介性免疫から回避可能にする。本発明は、KIR/KIRリガンドが不適合である同種異系NK細胞を含む組成物を利用した方法を提供し、この方法は、KIR/KIRリガンドの適合した自己および同種異系の方法よりも、in vitroで固形腫瘍に対する強い細胞傷害性を示す。本発明ではさらに、グループ1(C−G1)又はグループ2(C−G2)のいずれかのHLA−C対立遺伝子がホモ接合であり、適合したKIR−抑制性HLA−Cリガンドを欠くEBV−LCL、腎細胞癌(RCC)、黒色腫(MEL)細胞に対する細胞傷害性が上昇しており、KIR−リガンドの適合した標的に対する細胞傷害性が最小限であるような癌患者又は健常人ドナーの血液から濃縮およびクローン化された同種異系NK集団を提供する。この細胞傷害性作用は、NK細胞へのγ線照射後少なくとも48時間にわたって持続する。
“Solid tumor(固形腫瘍)”としては、肉腫、黒色腫、癌腫、他の固形腫瘍癌が挙げられるが、これらに限定されない。
哺乳動物被験体に対する固形腫瘍の処置又は固形腫瘍の再発を予防するための有効量で、増強剤(例えば、化学薬品や化学療法薬)及び濃縮同種異系NK細胞集団を含む組成物を投与する工程を包含する、固形腫瘍を処置する方法が提供される。哺乳動物被験体に対する固形腫瘍の処置又は固形腫瘍の再発を予防するための有効量で、増強剤(例えば、化学薬品や化学療法薬)及び濃縮自己NK細胞集団を含む組成物を投与する工程を包含する、固形腫瘍を処置する方法が提供される。“Potentiating agent(増強剤)”とは、NK細胞による殺傷に対して腫瘍の感作を生じさせることによって治療プロファイルを改善させるように作用する化合物をいう。一態様では、増強剤は、化学療法剤または他の腫瘍感作因子でありうる。詳細な態様では、この増強剤はプロテアソーム阻害剤(例えば、Velcade(ボルテゾミブ))、ヒストンデアセチラーゼ(例えば、デプシペプチド)であり得る。さらに詳細な態様では、この増強剤は、5−フルオロウラシルであり得る。
アッセイで使用される具体的な標識又は検出基は、分光学的、光化学的、生化学的、免疫化学的、電気的、光学的、化学的方法によって検出可能である。アッセイで使用されるNK細胞上の細胞マーカーへの抗体の特異的結合を著しく妨げない限り、標識の具体的な型は、本発明における決定的な局面ではない。検出基は、検出可能な物理的、化学的特性を有する任意の物質であり得る。このような検出可能な標識は、アッセイ又は免疫アッセイの分野において十分に開発されており、概して、このような方法において有用な標識のほとんどを本発明に適用可能である。したがって、標識は、分光学的、光化学的、生化学的、免疫化学的、電気的、光学的、化学的方法によって検出可能な任意の組成物である。本発明の有用な標識としては、磁気ビーズ(例えば、DynabeadsTM)、蛍光色素(例えば、フルオレセインイソチオシアネート、テキサスレッド、ローダミンなど)、放射性同位元素(例えば、3H、14C、35S、125I、121I、112In、99mTc)、マイクロバブルなどの他の造影剤(超音波画像診断)、18F、11C、15O(ポジトロン放射断層撮影)、99mTC、111In(単一光子放出型コンピュータ断層撮影)、酵素(例えば、ELISAで一般に使用されるホースラディッシュペルオキシダーゼ、アルカリホスファターゼなど)、コロイド金、色ガラス、プラスチック(例えば、ポリスチレン、ポリプロピレン、ラテックスなど)ビーズなどの比色測定用標識が挙げられる。このような標識の使用を記載した特許としては、米国特許第3,817,837号、同第3,850,752号、同第3,939,350号、同第3,996,345号、同第4,277,437号、同第4,275,149号、同第4,366,241号が挙げられ、それらの開示は全て、全ての目的について、本明細書中に援用される。Handbook of Fluorescent Probes and Research Chemicals(6th Ed., Molecular Probes, Inc., Eugene OR.)もまた参照のこと。
本発明は、薬学的に受容可能なキャリアとともに製剤された、疾患(例えば、転移性癌、固形腫瘍、過剰増殖性障害)の処置用の濃縮NK細胞集団を含む医薬組成物を提供する。一部の組成物は、本発明の複数(例えば、2以上)の濃縮NK細胞集団の組み合わせを含む。
(短鎖干渉RNA(RNAi))
RNA干渉(RNAi)は、二本鎖RNA(dsRNA)を介した転写後遺伝子サイレンシングの機構であり、アンチセンスやリボザイムに基づくアプローチとは異なる(RNAi及びsiRNAの概説については、Jain, K.K., 2004, Pharmacogenomics 5: 239−42を参照のこと)。RNA干渉は、ストリンジェントな条件下でキラー免疫グロブリン(Ig)様受容体(KIR)標的遺伝子にハイブリダイズして標的遺伝子の発現を弱める核酸分子(例えば、dsRNA)の哺乳動物への投与によって、腫瘍又は過剰増殖疾患の状態を治療する方法として有用である。dsRNA分子は、まずDICER(Bernstein et al., 2001, Nature 409: 363)と呼ばれるRNaseIII様酵素による、小さな2つの21ヌクレオチド鎖からなるdsRNA分子へのプロセシング後に、様々な種類の細胞におけるmRNAの配列特異的な分解を指向すると考えられている。このdsRNA分子は、それぞれ、5’リン酸および3’水酸基を有し、他方の鎖と厳密に相補的な19ヌクレオチドの領域を含み、その結果、2ヌクレオチド3’側に突出した19ヌクレオチドの二本鎖領域が存在する。このようにRNAiは、短鎖干渉RNA(siRNA)を介しており、これは通常、約19ヌクレオチド長の二本鎖領域からなり、各鎖1〜2ヌクレオチド3’側に突出しており、全長約21〜23ヌクレオチドとなっている。哺乳動物細胞では、30ヌクレオチドより長いdsRNAは通常、インターフェロン反応を介した非特異的mRNA分解を誘導する。しかし、インターフェロン反応よりもむしろ、哺乳動物細胞内でのsiRNAの存在が配列特異的な遺伝子サイレンシングをもたらす。
二本鎖RNA(dsRNA)により媒介される転写後遺伝子サイレンシングの機構であるRNA干渉(RNAi)は、ストリンジェントな条件下でキラー免疫グロブリン(Ig)様受容体(KIR)標的遺伝子にハイブリダイズして、当該標的遺伝子の発現を弱める核酸分子(例えば、dsRNA)の哺乳動物への投与による、哺乳動物における腫瘍性疾患の処置方法として有用である(RNAi及びsiRNAの概説については、Jain, K.K., 2004, Pharmacogenomics 5: 239−42を参照のこと)。本発明のRNA干渉のさらなる方法は、短鎖ヘアピンRNA(shRNA)の使用である。特定の所望のsiRNA配列をコードするDNA配列を含むプラスミドを、トランスフェクション又はウイルス媒介感染によって標的細胞内に移入させる。一度、細胞内に入れば、DNA配列は継続的にRNA分子に転写され、RNA分子は分子内の塩基対合を介してそれ自体が折れ曲がり、ヘアピン構造を形成する。これらのヘアピン構造は、細胞によってプロセシングを受けた場合、移入されたsiRNA分子と同等であり、細胞によって利用されて所望のタンパク質のRNAiを媒介する。shRNAの使用は、タンパク質発現の安定かつ長期間の抑制が可能なため、siRNAトランスフェクションよりも有利である。トランスフェクションされたsiRNAによるタンパク質発現の抑制は、数日以上の長期間にわたって起こることのない一過性の現象である。一部の例では、このことが好ましく、望まれ得る。より長期間のタンパク質の抑制が必要な場合、shRNA媒介性の抑制が好ましい。
アンチセンスRNA転写産物は同じ細胞内の他のRNA転写産物の一部又は全てと相補的な塩基配列を有する。このような転写産物は、RNAスプライシングの調節、RNA輸送の調節、mRNA翻訳の調節などの様々な機構を通じて遺伝子発現を調節することが示されている(Denhardt, 1992, Ann NY Acad. Sci. 660: 70; Nellen, 1993, Trends Biochem. Sci. 18: 419; Baker and Monia, 1999, Biochim. Biophys. Acta, 1489: 3; Xuら、2000, Gene Therapy 7: 438; French and Gerdes, 2000, Curr. Opin. Microbiol. 3: 159; Terryn and Rouze, 2000, Trends Plant Sci. 5: 1360)。
アンチセンス核酸は通常、標的核酸(例えば、mRNA転写産物)の一部分と相補的な一本鎖核酸(DNA、RNA、修飾DNA、修飾RNA)であるため、標的に結合して二本鎖を形成する。通常、これらは15〜35ヌクレオチド長のオリゴヌクレオチドであり、長さは10から約50ヌクレオチドに及び得る。通常、結合によって標的核酸の機能を低下又は抑制する。例えば、アンチセンスオリゴヌクレオチドは、ゲノムDNAに結合した場合には転写を阻害し、mRNAに結合した場合には翻訳を阻害し、そして/又は核酸の分解を導き得る。抑制性KIRポリペプチドの発現は、ポリペプチドをコードするmRNA核酸と相補的な配列からなるアンチセンス核酸又はペプチド核酸の投与によって減少され得る。アンチセンス技術及びその応用は、当業者に周知であり、Phillips, M. I. (ed.) Antisense Technology, Methods Enzymol., 2000, Volumes 313 and 314, Academic Press, San Diego及び本明細書の参考文献に記載されている。Crooke, S. (ed.), “Antisense Drug Technology: Principles, Strategies, and Applications” (1st Edition), Marcel Dekker及び本明細書で引用されている参考文献も参照のこと。
リボザイム又はデオキシリボザイムと呼ばれる特定の核酸分子が、配列特異的なRNA分子の切断を触媒することが示されている。切断部位は、RNA又はDNA酵素内のヌクレオチドと標的RNA内のヌクレオチドとの相補的な対合によって決まる。したがって、RNAおよびDNA酵素は、任意のRNA分子を切断するように設計され得、これによって分解率を高め得る(Cotten and Birnstiel, 1989, EMBO J. 8: 3861−3866; Usman et al., 1996, Nucl, Acids Mol. Biol. 10: 243; Usmanら、1996, Curr. Opin. Struct. Biol. 1: 527; Sunら、2000, Pharmacol. Rev., 52: 325;Cotten and Birnstiel, 1989, EMBO J. 8: 3861−3866も参照のこと)。
キラー免疫グロブリン(Ig)様受容体(KIR)の細胞内ドメイン又は細胞外ドメインに対するscFv抗体ライブラリーを使用して、固形腫瘍又は過剰増殖性障害の処置が可能である。KIRタンパク質へ特異的に結合する抗体組成物の同定のためのファージディスプレイライブラリーでの1つのアプローチは、scFvファージライブラリーの使用である(例えば、Huston et al., Proc. Natl. Acad. Sci U.S.A., 85: 5879−5883, 1988; Chaudhary et al., Proc. Natl. Acad. Sci U.S.A., 87: 1066−1070, 1990参照)。バクテリオファージ外殻タンパク質上にディスプレイされるscFvライブラリーの様々な実施態様が記述されてきた。例えば、WO96/06213、WO92/01047(Medical Research Council et al.)、WO97/08320(Morphosys)に記載されているような、ファージディスプレイ法の改良も知られており、これらは参考として本明細書中に援用される。例えば、WO92/01047(CAT/MRC)及びWO91/17271(Affymax)に記載されているような、Fabライブラリーのディスプレイも知られている。
本明細書に記載されている疾患(例えば、転移癌、固形腫瘍、過剰増殖性障害)の処置のための濃縮NK細胞集団の組成物の有効量は、投与方法、標的部位、患者の生理的状態、患者がヒトであるか動物であるのか、他の投薬、処置が予防的または治療的のいずれを目的としているのか、といった多くの異なる要因によって変動する。通常、患者はヒトであるが、トランスジェニックの哺乳動物を含めたヒト以外の哺乳動物も処置可能である。処置用量を漸増させて、安全性および有効性を最適化する必要がある。
疾患(例えば、転移性癌、固形腫瘍、過剰増殖性障害)の処置用の濃縮NK細胞集団の組成物は、静脈内、膀胱内、髄腔内、非経口、局所、皮下、経口、経鼻、動脈内、頭蓋内、腹腔内、筋肉内により投与可能である。予防的/アジュバントとして、もしくは疾患の処置として、濃縮NK細胞集団は過剰増殖性障害又は固形腫瘍(例えば、尿生殖器の悪性疾患)を標的とし、かつ/又は治療上の処置を目的としている。最も標準的な免疫原の投与経路は皮下であるが、他の経路も同様に効果的である。次に最も一般的な経路は筋肉注射である。この種の注射は腕又は脚の筋肉に施されるのが最も標準的である。一部の方法では、沈着物が蓄積した特定組織内に薬剤を直接注射する(例えば、頭蓋内注射)。静脈注射時の筋肉注射が、濃縮NK細胞集団の投与において好ましい。一部の方法では、特定の治療用の濃縮NK細胞を膀胱内に直接注射する。
疾患(例えば、転移性癌、固形腫瘍、過剰増殖性障害)の処置のための濃縮NK細胞集団の組成物
疾患(例えば、転移性癌、固形腫瘍、過剰増殖性障害)の処置のための濃縮NK細胞集団の組成物は、活性医薬品(即ち、他の医薬品として受容可能な様々な化合物)を含む医薬組成物として投与される場合が多い(例えば、Alfonso R Gennaro (ed.), Remington: The Science and Practice of Pharmacy, (旧Remington’s Pharmaceutical Sciences) 20th ed., Lippincott, Williams & Wilkins, 2003、その全体が本明細書において参考として援用される)。好ましい型は、目的の投与方法や治療への用途に左右される。組成物は、目的の処方に応じて、医薬品として受容可能な、毒性のないキャリア又は希釈剤を含むことも可能で、これらは動物やヒトへ投与するための医薬組成物の処方に一般的に使用される賦形剤として定義される。組み合わせの生物活性に影響を及ぼさないように、希釈剤を選択する。このような希釈剤の例は、10%不活化ヒトAB血清又は10%自己血清を含むX−vivo 20 media(Cambrex Bio Science社、メリーランド州ウォーカーズビル)である。このような希釈剤のさらなる例は、蒸留水、リン酸緩衝生理食塩水、リンガー溶液、デキストロース溶液、ハンクス液である。さらに、医薬組成物又は製剤は、他のキャリア、アジュバント、又は毒性のない非治療用の非免疫原性安定剤なども含むことができる。
好ましくは、本明細書に記載の治療に有効量の濃縮NK細胞集団の組成物が、深刻な毒性を生じることなく治療的有用性をもたらす。
本発明の組成物(例えば、濃縮NK細胞集団)を含むキット及び使用方法も本発明の範囲内である。キットは、本発明の少なくとも1種の追加試薬、もしくは1種以上の追加ヒト抗体(例えば、最初のヒト抗体とは異なる抗原中のエピトープに結合する、補体活性を有するヒト抗体)をさらに含むことができる。キットは通常、キットの内容物の目的の用途を示すラベルを含む。ラベルという用語は、キット上、キットと同梱、もしくは他の方法でキットに添付された文書又は記録を含む。
(実施例1)
同種異系KIR不適合性NK細胞の単離及び増殖
EBV形質転換B細胞株の作成:100μg/mLサイクロスポリンA(CSA, Sandoz Pharmaceuticals Inc, ワシントンDC)存在下で、B95−8細胞株(ATCC、バージニア州マナサス)から回収されたEBV上精とともに末梢血単核球(PBMC)を培養することによって、EBウイルス形質転換リンパ芽球性細胞株(EBV−LCL)を樹立した。ヒト黒色腫(MEL)細胞株St−MEL及びR−MEL、そしてヒト腎細胞癌(RCC)細胞株Wh−RCCを、転移病巣の生検及び腎腫瘍の1次試料(国立癌研究所[NCI])から樹立した。ヒトRCC細胞株SJ−RCCを、NCIから入手した腎摘出術での検体から樹立して、当研究所にて維持した。EBV−LCL、MEL、RCC株は10%ウシ胎仔血清(FCS)含有RPMI1640で維持した。MHCクラスIタイピングは、配列特異的プライマーによるPCR(PCR−SSP)を用いて、国立衛生研究所HLA研究所にて実施された。簡単に説明すると、まずゲノムDNAを、Bunceら、Tissue Antigens, 46: 355−367, 1995(その全体が本明細書において参考として援用される)に記載のプライマー及びPCR条件を利用して、末梢血リンパ球又は腫瘍サンプルから抽出した。最終PCR産物を、エチジウムブロマイド染色よって2%アガロースゲル上で可視化して、大まかなバンドサイズの有無によって結果を判定した。この試験の目的のために、単一HLA−C反応性KIR(KIR2DL2/3又はKIR2DL1;表1)への結合が予測されるHLA−C対立遺伝子がホモ接合性となるように、腫瘍株を特異的に選択した。
*SKEMは、RCC患者SJにおいてHLAが同一の同胞ドナーである。
+Wh−RCCはHLA−Cw遺伝子座を喪失していた。
EBVLCLフィーダー細胞株上でのNK細胞の増殖
EBVLCLフィーダーを含むNK細胞は、104倍以上に増殖可能であり、これはIL−2含有SCGM培地中で培養されたNK細胞集団よりも有意に高く、IL−2含有SCGM培地では約102倍の正味の増殖が通常認められる。表2を参照のこと。高率のKIR 2DL2/3陽性NK細胞を増殖させる方法を開発した。KIR 2DL2/3に結合することが判明しているHLA−C対立遺伝子の発現を欠いた、もしくはそれがヘテロ接合性であるEBVLCLフィーダーを使用して、有意に高い割合のKIR 2DL2/3陽性NK細胞を増殖可能である。
**値は2回の独立した実験での平均値を表している。
同種異系NK細胞は、KIRリガンド適合の腫瘍標的よりもKIRリガンド不適合な腫瘍標的に対して細胞傷害性がより高い
KIRリガンド適合の腫瘍標的よりもKIRリガンド不適合な腫瘍標的に対して同種異系NK細胞の細胞傷害性はより高かった。腫瘍がNK細胞エフェクター上で発現される特異的KIRに対するHLA−C対立遺伝子を欠く場合にバルク同種異系NK集団による殺傷に対する黒色腫及びRCCの感受性が高まるか否かを判断するためにin vitroでの評価をまず実施した。HLA−Cグループ1(C−G1)がホモ接合性のドナーから陰性セレクションによってPBMCから濃縮されたNK細胞を、照射済みEBV−LCLをフィーダー細胞に使用してin vitroで増殖させた。2週間後、CD158b(KIR 2DL2/3)を発現しているNK細胞をフローソーティングによって単離し、さらに2週間増殖させて、残存する結合抗体を除去した(図1A)。KIRリガンド適合(例えば、C−G1ホモ接合)又はKIRリガンド不適合(例えば、C−G2ホモ接合)である腫瘍標的のCD158b濃縮(約80%陽性)バルクNK細胞の細胞傷害作用に対する感受性における差をin vitroで試験した。
γ線照射済みNK細胞は照射後少なくとも48時間に亘って、腫瘍細胞に対する細胞傷害性を維持する
in vitroでのデータは、養子移入されたKIR不適合同種異系NK細胞はin vivoでも有益な抗腫瘍作用を持ちうることを示唆している。したがって、γ線照射がNK細胞媒介性の腫瘍細胞傷害性に及ぼす影響をさらに調べた。健常人ドナーのPBMCから増殖させたバルクNK細胞にγ線照射(50 Gy)して、照射後0、24、48、60、96時間後のNK細胞感受性K562細胞に対する細胞傷害性を試験した(図4A)。大部分のNK細胞がFACSによって速やかにアネキシンV又はヨウ化プロピジウム(PI)陽性(図4B)となったが(照射誘発性のアポトーシス及び細胞死と一致)、K562細胞に対する有意な細胞傷害性が照射後48時間まで依然として測定可能であった。健常人ドナーKR0350からのNK細胞株8−5は、照射から24時間後にKIR不適合EBV−LCL細胞に対する殺傷能力を保持しており、非照射対照と比較して細胞傷害能のわずかな低下しか認められなかった(図4C)。
自己腫瘍細胞に対する細胞傷害性の増大したサブドミナントNK細胞画分の同定及び増殖
自己HLA分子と結合できないKIR分子を発現しているサブドミナントNK細胞集団(AKI−NK細胞)をin vitroで単離および増殖させることができ、これらは未選択の“バルク”NK細胞と比較して、自己腫瘍標的に対する細胞傷害性が有意に増大する。図5を参照のこと。
抑制性KIRの発現及び機能をノックアウトするためのRNA干渉(RNAi)転写後遺伝子サイレンシング(PTGS)
これらの結果に基づき、RNA干渉(RNAi)転写後遺伝子サイレンシング(PTGS)を使用して、抑制性KIRの発現と機能をノックアウトし、これによって腫瘍細胞に対するNK細胞の細胞傷害性を増大させる。NK細胞の抑制性KIR細胞質ロングドメインを特異的にノックダウンするRNAiをコードするレンチウイルスベクターを開発中である。RNAiは抑制性のKIR 2DL2/3及び2DL1の細胞質ロングテールに特異的である。
上皮起源の腫瘍細胞に対して同様のNK細胞媒介性の効果がin vitroで生じることが実証されている。より具体的には、黒色腫及びRCC細胞では、HLA不適合に起因して、腫瘍の抑制性のHLA−C対立遺伝子が結合できないKIRを発現する同種異系NK細胞の細胞傷害作用に対する感受性がより高い。同じHLA−C対立遺伝子グループを欠く標的に対して同種反応性を有するNK細胞の頻度が高い、グループ1又はグループ2のHLA−C対立遺伝子がホモ接合であるドナー又は患者からNK細胞株を生成した。さらに、KIR不適合がNK細胞の細胞傷害性に及ぼす影響を評価し得るために、グループ1又はグループ2のHLA−C対立遺伝子がホモ接合であるEBV−LCL、黒色腫、RCC腫瘍標的を使用した。
NK細胞の殺傷に対して腫瘍細胞を感作させる方法
本発明は、腫瘍細胞をNK細胞媒介性の溶解により感受性にすることによって腫瘍疾患を治療する方法を提供する。腫瘍細胞を増強剤(例えば、化学薬品、化学療法薬)と、濃縮同種異系NK細胞集団を含む組成物又は濃縮自己NK細胞集団を含む組成物とで処置する方法を提供する。図7では、RENCA腫瘍細胞を化学薬品(例えば、デプシペプチド又はベルケード)で治療後、NK細胞の感受性アッセイを実施した。結果は、NK細胞単独での腫瘍細胞の処理と比較して、化学薬品と濃縮NK細胞集団との併用による腫瘍細胞の処理によって、腫瘍細胞をNK細胞媒介性の溶解により感受性にすることを実証している。化学薬品デプシペプチドはヒストンデアセチラーゼ阻害剤であり、ヒストンデアセチラーゼの酵素活性を阻害することで遺伝子発現調節を妨げる。デプシペプチドは、マウスモデルにおいて細胞増殖を阻害し、腫瘍形成を予防することによって抗腫瘍作用を有することが示されている。実験ではデプシペプチド処理時のMIC−A/B誘導が示された。化学薬品ベルケード(ボルテゾミブ)はプロテアソーム阻害剤である。実験では、プロテアソーム阻害剤PS−341がc−FLIPレベルの低下によってTRAIL媒介性のアポトーシスに対して腫瘍細胞を感作させることが示されている(Sayers TJ, Blood 102: 303−310, 2003)。さらなる実験では、プロテアソーム阻害剤ボルテゾミブが、薬剤の移植片対腫瘍効果を保持しながら急性移植片対宿主病を抑制することが示されている(Kai Sun, Proc. Nat. Acad. Sci. USA, 101: 8120−8125, 2004)。
Claims (27)
- 濃縮同種異系NK細胞集団を含む、固形腫瘍を処置するための組成物であって、哺乳動物被験体がボルテゾミブ又はデプシペプチドで前処置され、その後、該組成物が投与されることを特徴とする、組成物。
- 前記NK細胞集団はγ線照射済みである、請求項1に記載の組成物。
- 前記ボルテゾミブ又はデプシペプチドがNK細胞による殺傷に対して前記腫瘍の感作を起こさせる、請求項1に記載の組成物。
- 濃縮自己NK細胞集団を含む、固形腫瘍を処置するための組成物であって、哺乳動物被験体がボルテゾミブ又はデプシペプチドで前処置され、その後、該組成物が投与されることを特徴とする、組成物。
- 前記NK細胞集団はγ線照射済みである、請求項4に記載の組成物。
- 前記ボルテゾミブ又はデプシペプチドがNK細胞による殺傷に対して前記腫瘍の感作を起こさせる、請求項4に記載の組成物。
- 請求項4に記載の組成物であって、前記自己NK細胞集団がKIR/KIRリガンド不適合性である、組成物。
- 濃縮同種異系NK細胞集団を含む、哺乳動物被験体において腫瘍細胞死を誘導するか、もしくは腫瘍細胞の増殖を抑制するための組成物であって、
該哺乳動物被験体が、ボルテゾミブ又はデプシペプチドで前処置され、その後、該組成物が投与されることを特徴とする、
組成物。 - 前記ボルテゾミブ又はデプシペプチドがNK細胞による殺傷に対して前記腫瘍の感作を起こさせる、請求項8に記載の組成物。
- 濃縮自己NK細胞集団を含む、哺乳動物被験体において腫瘍細胞死を誘導するか、もしくは腫瘍細胞の増殖を抑制するための組成物であって、
該哺乳動物被験体が、ボルテゾミブ又はデプシペプチドで前処置され、その後、該組成物が投与されることを特徴とする、
組成物。 - 前記ボルテゾミブ又はデプシペプチドがNK細胞による殺傷に対して前記腫瘍細胞の感作を起こさせる、請求項10に記載の組成物。
- 請求項10に記載の組成物であって、前記自己NK細胞集団が、KIR/KIRリガンド不適合性である、組成物。
- 前記腫瘍細胞が前記哺乳動物被験体の膀胱内にある、請求項12に記載の組成物。
- 前記濃縮自己NK細胞集団がKIRグループ1内にホモ接合性のHLA−Cw遺伝子座を有する、請求項12に記載の組成物。
- 前記濃縮自己NK細胞集団がKIRグループ2内にホモ接合性のHLA−Cw遺伝子座を有する、請求項12に記載の組成物。
- 前記濃縮自己NK細胞集団がBw4又はBw6内にホモ接合性のHLA−B遺伝子座を有する、請求項12に記載の組成物。
- 前記ホモ接合性HLA−Cw遺伝子座がCw1、Cw3、Cw7、Cw8、Cw12、Cw13、Cw14、Cw1507またはCw16である、請求項14に記載の組成物。
- 前記ホモ接合性HLA−Cw遺伝子座がCw2、Cw0307、Cw0315、Cw4、Cw5、Cw6、Cw0707、Cw0709、Cw1205、Cw12041、Cw12042、Cw15、Cw1602、Cw17またはCw18である、請求項15に記載の組成物。
- 前記ホモ接合性HLA−B遺伝子座がBw−5、Bw−13、Bw−1513、Bw−1516、Bw−1517、Bw−1523、Bw−1524、Bw−17、Bw−21、Bw−27、Bw−37、Bw−38、Bw−44、Bw−47、Bw−49、Bw−51、Bw−52、Bw−53、Bw−57、Bw−58、Bw−59、Bw−63またはBw−77である、請求項16に記載の組成物。
- 前記ホモ接合性HLA−B遺伝子座がBw−7、Bw−8、Bw−12、Bw−14、Bw−18、Bw−2708、Bw−35、Bw−39、Bw−40、Bw−4005、Bw−41、Bw−42、Bw−45、Bw−46、Bw−48、Bw−50、Bw−54、Bw−55、Bw−56、Bw−60、Bw−61、Bw−62、Bw−64、Bw−65、Bw−67、Bw−71、Bw−72、Bw−73、Bw−75、Bw−76、Bw−78またはBw−81である、請求項16に記載の組成物。
- 前記被験体がホモ接合性のKIRリガンドを有し、かつNK集団が自己HLA分子と結合できないKIRを発現することを停止させることができない、請求項12に記載の組成物。
- 前記被験体がBw4又はBw6内にHLA−B遺伝子座を有する、請求項21に記載の組成物。
- 前記被験体がKIRグループ1又はKIRグループ2内にHLA−Cw遺伝子座を有する、請求項21に記載の組成物。
- 前記濃縮自己NK細胞集団がKIRグループ1又はKIRグループ2内にホモ接合性のHLA−Cw遺伝子座を有する、請求項23に記載の組成物。
- 前記濃縮自己NK細胞集団がKIRグループ1又はKIRグループ2内にヘテロ接合性のHLA−Cw遺伝子座を有する、請求項23に記載の組成物。
- KIRとKIRリガンドとの結合阻害により、NK細胞集団の細胞傷害性が強化されることを特徴とする、請求項12に記載の組成物。
- 前記KIR細胞質ドメインに対する干渉RNA(RNAi)、該KIR細胞質ドメインに対するアンチセンスRNA、該KIR細胞質ドメインに対するリボザイム、または該KIR細胞外ドメインに対する抗体もしくは該KIR細胞質ドメインに対する抗体で前記NK細胞集団が処理されることを特徴とする、請求項26に記載の組成物。
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