JP2015187143A - プログラム細胞死1(pd−1)経路を阻害することによる持続感染および癌の処置のための方法および組成物 - Google Patents
プログラム細胞死1(pd−1)経路を阻害することによる持続感染および癌の処置のための方法および組成物 Download PDFInfo
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Abstract
【解決手段】プログラム細胞死−1(PD−1)ポリペプチドの活性または発現を減少させる化合物を投与する。該化合物は、抗PD−1抗体、抗PD−L1抗体、抗PD−L2抗体、抗PD−1 RNAi、抗PD−L1 RNAi、抗PD−L2 RNAi、抗PD−1アンチセンスRNA、抗PD−L1アンチセンスRNA、抗PD−L2アンチセンスRNA、ドミナントネガティブPD−1タンパク質、ドミナントネガティブPD−L1タンパク質、またはドミナントネガティブPD−L2タンパク質、または低分子である。
【選択図】なし
Description
本発明は、NIH助成金AI39671およびNIH助成金CA84500の下での米国政府支援によってなされた。米国政府は、本発明において特定の権利を有する。
一般に、本発明は、持続感染および癌の処置のための方法および組成物に関する。
予防ワクチンの開発はウイルス感染の死亡率を顕著に減少させたが、持続感染を引き起こすウイルス(例えば、C型肝炎ウイルス)に対するこのようなワクチンの使用は、限られた成果しか上げていない。急性感染および自己限定型の感染を引き起こすウイルスとは対照的に、持続感染を引き起こす微生物に対して惹起される免疫応答は、しばしば、一過性であり、そしてその感染を除去するには不十分である。結果として、その感染性微生物は、必ずしも宿主に一定の損傷を引き起こすことなく、感染した被験体内に長期間にわたって残存する。
本発明は、持続感染または癌の処置、予防、または減少のための方法および組成物、あるいは持続感染または癌の1種以上の症状の軽減のための方法および組成物を提供する。本発明は、抗原特異的CD8+ T細胞が、プログラム細胞死(Programmed Death)−1ポリペプチド(PD−1)の誘導後に感染因子に対して機能的に寛容性になる(「疲弊する(exhausted)」)という知見に基づく。したがって、PD−1、PD−L1またはPDL2の発現または活性を減少させることによって、機能的に寛容性のCD8+ T細胞の増殖、サイトカインの産生、および感染因子(例えば、ウイルス、細菌、真菌、寄生虫、マイコプラズマまたは癌)クリアランスの速度は、増大され、その結果、その感染因子に特異的な免疫応答が、増強される。
最近数十年間における抗生物質およびワクチンの使用は、微生物感染に起因する死亡率を顕著に減少させている。しかし、抗微生物治療様式の成功は、宿主生物体の免疫系を回避し、次に持続感染を確立する特定の感染因子の能力によって制限されている。例えば、肝炎およびHIVなどのウイルスに対して惹起される免疫応答は、感染因子を除去するのに十分ではなく、その感染因子は、感染した被験体に残存する。このような感染において、抗原特異的CD8+ T細胞は、感染因子に対して機能的に寛容性(「アネルギー」または「疲弊(exhaustion)」として公知である)になる。アネルギー性T細胞は、それらの細胞傷害活性(すなわち、それらのサイトカインを産生する能力、増殖する能力、および感染因子を除去する能力)を失う。
本明細書中で使用される場合、「持続感染」によって、感染因子(例えば、ウイルス、細菌、寄生虫、マイコプラズマ、または真菌)が免疫応答の誘導後でさえも、感染した宿主から除去または排除されていない感染が意味される。持続感染は、慢性感染、潜在性感染、または遅発性感染であり得る。急性感染は、比較的短期間(数日間〜数週間持続する)であり、そして免疫系によって身体から消散され、一方で、持続感染は、数ヶ月間、数年間、または一生にわたってでさえ持続し得る。これらの感染はまた、長期間の間に頻繁に再発し得、細胞の殺傷または宿主細胞に対する過剰な損傷さえも伴わない無症候性かつ増殖性の感染の段階を含む。原因である感染因子はまた、免疫応答が解消した後でさえ、標準的な技術を使用して宿主(例えば、感染した個体の内部の特定の細胞)において検出され得る。哺乳動物は、当該分野において公知である任意の標準的な方法および例えば、米国特許第6,368,832号、同第6,579,854号、および同第6,808,710号ならびに米国特許出願第20040137577号、同第20030232323号、同第20030166531号、同第20030064380号、同第20030044768号、同第20030039653号、同第20020164600号、同第20020160000号、同第20020110836号、同第20020107363号、および同第20020106730号(これらの全ては、本明細書によって参考として援用される)に記載される任意の標準的な方法に従って、持続感染を有すると診断される。例えば、被験体は、PCR分析を使用したこの個体からの生物学的サンプルにおけるクラミジア種の検出後に、持続性クラミジア感染を有すると診断され得る。哺乳動物は、本発明によって処置されるべき持続感染と診断されていない必要がない。持続感染を確立し得る微生物因子としては、ウイルス(例えば、パピローマウイルス、肝炎ウイルス、ヒト免疫不全ウイルス、およびヘルペスウイルス)、細菌(例えば、Escherichia coliおよびクラミジア属の種)、寄生虫(例えば、プラスモディウム属、リーシュマニア属の種、住血吸虫属の種、トリパノソーマ属の種、トキソプラスマ属の種)および真菌が挙げられる。
Publishing Co.、Easton、Pa.、2000を参照のこと。
T細胞の細胞傷害は、T細胞とPD−1の発現または活性を減少させる化合物とを接触させることによって増大する。上記T細胞は、ナイーブT細胞、記憶T細胞または活性化T細胞である。あるいは、上記T細胞は、抗原特異的T細胞である。上記抗原特異的T細胞は、感染因子に対してアネルギー性または寛容性である。T細胞の細胞傷害は、細胞増殖およびサイトカイン放出の増加によって特徴付けられる。
本発明は、被験体に、PD−1の発現または活性を減少させる化合物(本明細書中で「PD−1インヒビター」または「治療用化合物」と称される)を含む組成物を投与することを包含する。
本発明による処置後に免疫応答を測定するための方法は、当該分野において周知である。T細胞の活性は、例えば、サイトカイン産生を検出するアッセイ、T細胞増殖を測定するアッセイ、微生物因子のクリアランスを測定するアッセイ、およびCD8+ T細胞の細胞傷害を測定するアッセイによって評価され得る。これらのアッセイは、例えば、米国特許第6,808,710号ならびに米国特許出願第20040137577号、同第20030232323号、同第20030166531号、同第20030064380号、同第20030044768号、同第20030039653号、同第20020164600号、同第20020160000号、同第20020110836号、同第20020107363号、および同第20020106730号(これらの全ては、本明細書によって参考として援用される)に記載される。
本発明は、PD−1の発現または活性を阻害し得る化合物を同定するためのスクリーニング方法を提供する。有用な化合物は、PD−1の生物学的活性を阻害するか、またはPD−1の細胞レベルを低下させる任意の薬剤を含む。例えば、候補化合物は、PD−L1、PD−L2、またはその両方に対するPD−1の結合を減少させ得る。リード化合物としてこのような薬剤を使用することにより、例えば、本発明のスクリーニング方法はまた、持続感染を処置するか、減少させるか、または予防するように機能するか、あるいはこのような感染に関連した1種以上の症状を軽減するPD−1のさらなる新規であり特異的なインヒビターの同定を、可能にする。上記スクリーニングの方法は、ハイスループット技術を含み得る。
癌(例えば、血管免疫芽球性T細胞リンパ腫または結節性リンパ球優勢型ホジキンリンパ腫)は、試験サンプル(すなわち、患者由来サンプル)中のPD−1ポリペプチドの量を調べることによって検出される。上記PD−1ポリペプチドをコントロールサンプル比較した場合、そのレベルの変化は、被験体における癌を示す。上記変化は、コントロールサンプルに対する上記PD−1ポリペプチドの増加または減少であり得る。上記コントロールサンプルは、試験サンプルと同様の様式で調製(すなわち、分画)される。
Of Laboratory Procedures」、第14章、Teitz、Fundamentals of Clinical Chemistry、Burtis and Ashwood(編)、第4版、1996、W.B.Saunders Company、192〜199ページ;およびZweigら、「ROC Curve Analysis:An Example Showing The Relationships Among Serum Lipid And Apolipoprotein Concentrations In Identifying Patients With Coronory Artery Disease」、Clin.Chem.、1992、38(8):1425−1428を参照のこと。
種々の株のリンパ球脈絡髄膜炎ウイルス(LCMV)に感染したマウスを、CD8+ T細胞機能に対する慢性ウイルス感染の影響を研究するために使用した。LCMV Armstrong株は、8日以内に除去される急性感染を引き起こし、非常に機能的な休止記憶(resting memory)CD8+ T細胞の長寿命の集団を残す。LCMV Cl−13株は、対照的に、宿主において持続感染を確立し、最長で3ヶ月間まで持続するウイルス血症によって特徴付けられる。上記ウイルスは、いくつかの組織においていつまでも残存し、そして抗原特異的CD8+ T細胞は、機能的に損なわれるようになる。DbNP396−404 CD8+ T細胞が、身体から消失する一方で、DbGP33−41 CD8+ T細胞およびDbGP276−286 CD8+ T細胞は、存続するが、抗ウイルスサイトカイン(例えば、IFN−γおよびTNF−α)を増殖または分泌する能力を失う。
IAbGP61−80のCD4+ T細胞)であったからである。
T細胞は、IFN−γおよびTNF−αを分泌する能力を完全に失う。
持続感染中にT細胞応答をブーストするための1つのアプローチは、治療用ワクチン接種である。このアプローチについての理論的根拠は、内因性抗原が慢性ウイルス感染中に最適かまたは免疫原性の様式で与えられる可能性がないこと、およびワクチンの形態で抗原を提供することがウイルス特異的T細胞およびウイルス特異的B細胞に対するより有効な刺激を提供し得ることである。上記慢性LCMVモデルを使用して、マウスに、治療用ワクチン(VVGP33)としてLCMV GP33エピトープを発現する組換えワクシニアウイルスを投与した。その治療用ワクチンは、いくつかの慢性的に感染したマウスにおいてCD8+ T細胞応答の適切な増強をもたらした。上記治療用ワクチンを受容した9匹の慢性的に感染したマウスのうちの4匹は、陽性の応答を示したが、コントロールマウスは、GP33に対する免疫応答の有意な増大を有さなかった。この治療用ワクチン接種をPD−L1インヒビターと組み合せた場合、LCMV特異的T細胞応答は、単独のどの処置と比較してもより大きいレベルまでブーストされ、そして組み合せた処置の効果は、相加的なものよりも大きかった。
RNA干渉(RNAi)は、哺乳動物細胞において遺伝子発現をサイレンシングし得る。長い二本鎖RNA(dsRNA)が、細胞に導入され、そして次に、特異的mRNA分子または小さい群のmRNAを標的とするより小さいサイレンシングRNA(siRNA)へとプロセシングされる。この技術は、抗体が機能的ではない状況において特に有用である。例えば、RNAiは、特有のスプライス改変体がPD−1およびCTLA−4の可溶性形態を産生する状況において使用され得る。
ウイルス特異的な疲弊したCD8+ T細胞を、磁性ビーズまたは密度勾配遠心分離(density centrifugation)を使用してLCMV−Cl−13に慢性的に感染したマウスから単離する。トランスフェクトしたCD8 T細胞を、PD−L1、PD−L2またはPD−1を標的とするモノクローナル抗体と接触させる。実施例1に記載する通り、PD−1経路の阻害は、CD8 T細胞の若返りを生じる。したがって、例えば、CD8+ T細胞増殖およびサイトカイン産生の増大が、存在する。これらの若返ったCD8+ T細胞を、上記感染したマウスに再度導入し、そしてウイルス量を、実施例1において記載するように測定する。
PD−1経路を調節する化合物は、慢性ウイルス感染によるCD8+ T細胞の疲弊を逆転するそれらの能力に基づくインビボスクリーニングアッセイおよびエキソビボスクリーニングアッセイにおいて同定され得る。
疲弊したCD8+ T細胞を、LCMV−Cl−13に慢性的に感染したマウスから得る。試験化合物を、上記感染したマウスに対して静脈内に投与する。処置マウスおよび未処置マウスの血清中に放出される抗ウイルスサイトカイン(例えば、IFN−γまたはTNF−α)の量を、例えば、ELISAまたは他の定量方法によって測定し、そしてその量を、比較する。未処置マウスにおける量と比較した処置マウスの血清において見出される抗ウイルスサイトカインの量の増加により、上記試験化合物はPD−1インヒビターと同定される。あるいは、ウイルス力価(例えば、血清ウイルス力価)が、上記試験化合物による処置の前後に決定され得る。
チンパンジーは、ヒトにおけるHCV持続のモデルを提供する。長寿命のウイルス持続を生じるT細胞免疫の欠損は、HCV特異的CD4+ Tヘルパー細胞および損なわれたかまたは変化したCD8+ Tエフェクター細胞活性の欠損の両方を誘導する。持続的に感染したチンパンジーを、CTLA−4、PD−1、またはその2つの組み合せに対する抗体によって処置する。組換え構造的HCVタンパク質および組換え非構造的HCVタンパク質を使用してワクチン接種と組み合わせた上記阻害性経路の遮断の効力、ならびにこのようなストラテジーがウイルス特異的記憶T細胞の頻度および寿命を向上させ得るか否かを、決定する。T細胞免疫の欠損は、持続的に感染したヒトおよびチンパンジーにおいて専らHCV特異的である。感染したチンパンジーの血液および肝臓を、CTLA−4、PD−1、BTLAおよびそれらのリガンドの発現ならびにTreg細胞の存在について調べる。次いで、抗ウイルス活性は、これらの分子によってシグナリングを遮断するヒト化モノクローナル抗体をチンパンジーに送達することによって回復され得る。
(材料)
症例の材料を、施設の方針に従ってBrigham & Women's Hospital、Boston、MAから得た。全ての診断は、World Health Organization Lymphoma Classificationシステム(Jaffe ESら、2001)に記載される組織学的特徴および免疫表現型の特徴に基づき、そして全ての場合において、診断材料は、血液病理学者によって再評価された。
PD−1の免疫染色を、ホルマリン固定したパラフィン包埋組織切片に対して、マイクロ波抗原賦活後に先に記載される(Jones Dら、1999;Dorfman DMら、2003)ような標準的な間接アビジン−ビオチン西洋ワサビペルオキシダーゼ法およびジアミノベンジジン発色を使用し、10mMクエン酸緩衝液(pH6.0)において先に記載した抗ヒトPD−1モノクローナル抗体(2H7;5)を用いて行った。症例を、少なくとも25%の腫瘍性細胞が陽性の染色を示した場合、PD−1に対して免疫反応性と見なした。PD−1染色を、研究した全ての症例について同一のタンパク質濃度まで希釈したマウスIgGアイソタイプコントロール抗体の染色と比較して、染色の特異性を確かめた。
PD−1発現についてさまざまなB細胞リンパ増殖性障害およびT細胞リンパ増殖性障害を、研究した;その結果を、表1にまとめる。前駆Bリンパ芽球性白血病/リンパ芽球性リンパ腫の代表的な症例、ならびに多くの濾胞起源のB細胞非ホジキンリンパ腫(6症例の濾胞性リンパ腫および7症例のバーキットリンパ腫を含む)を含むさまざまな成熟B細胞のリンパ増殖性障害を含む42症例のB細胞リンパ増殖性障害を、PD−1発現について調べた。B細胞リンパ増殖性障害は、PD−1についての染色を示さなかった。いくつかの症例において、非腫瘍性の反応性リンパ組織が、存在し、そして扁桃腺および上に記載した他の反応性リンパ組織において見られるようなPD−1染色パターンを示した。
*免疫反応性の症例の数/症例の総数
**PD−1陽性細胞は、14/14症例において腫瘍性L&H細胞の周りにロゼットを形成する。
以下の方法を、実施例11〜14で詳述する実験を行うために使用した。
慢性のクレード(clade)C HIV−I感染を有する研究参加者を、McCord Hospital、Durban、South Africa、およびSt.Mary's Hospital、Mariannhill、South Africaにおける外来診療所から募った。末梢血を、このコホートの65人の被験体の全員が分析時に抗レトロウイルス治療ナイーブであったから得た。被験体を、構築された10種のクラスIテトラマーに適合するそれらの発現したHLA対立遺伝子に基づいて加入に関して選択した(下を参照のこと)。上記コホートのウイルス量の中央値は、血漿1mlあたり42,800のHIV−I RNAコピー(163〜750,000の範囲)であり、そして絶対的CD4数の中央値は、362(129〜1179の範囲)であった。感染の持続期間に関する情報は、入手可能ではなかった。全ての被験体は、その施設の施設内審査委員会によって承認された上記研究についてのインフォームドコンセントに署名した。
ヒトPD−L1に対するモノクローナル抗体(29E.2A3、マウスIgG2b)およびPD−1に対する抗体(EH12、マウスIgG1)を、先に記載したように調製し、そしてそれらの抗体は、PD−1:PD−L1相互作用を遮断することが示された。
先に記載される(Airman JDら、1996)ように合成した10種のHIV MHCクラスIテトラマーを、この研究のために使用した:A*0205 GL9(p24、GAFDLSFFL;配列番号1)、A*3002 KIY9(インテグラーゼ、KIQNFRVYY;配列番号2)、B*0801 DI8(p24、DIYKRWII;配列番号3)、B*0801 FL8(Nef、FLKEKGGL;配列番号4)、B*4201 RM9(Nef、RPQVPLRPM;配列番号5)、B*4201 TL9(p24、TPQDLNTML;配列番号6)、B*4201 TL10(Nef、TPGPGVRYPL;配列番号7)、B*4201 YL9(RT、YPGIKVKQL;配列番号8)、B*8101 TL9(p24、TPQDLNTML;配列番号9)、およびCw0304 YL9(p24、YVDRFFKTL;配列番号10)。A*0205を発現するプラスミド構築物、A*3002を発現するプラスミド構築物、およびCw*0304を発現するプラスミド構築物は、寛大にもDr.Eugene RavkovおよびDr.John Airman、NIH Tetramer Core Facility、Atlanta、Georgiaによって提供された。
新鮮に単離した末梢血単核細胞(PBMC、50万個)を、テトラマーによって37℃にて20分間染色した。次いで、その細胞を、リン酸緩衝化生理食塩水(PBS)によって1回洗浄し、ペレットにし、そしてフルオレセインイソチオシアネート(FITC)結合体化抗CD8(Becton Dickinson)、フィコエリトリン結合体化抗PD−1(クローンEH12)、およびViaProbe(Becton Dickinson)によって直接染色した。細胞を、室温にて20分間インキュベートし、PBSにおいて1回洗浄し、そして1%パラホルムアルデヒドを含む200μl PBSに懸濁し、そして蛍光活性化セルソーター(FACSCalibur、Becton Dickinson)において取得した。最低で100,000イベントを、FACSCaliburにおいて獲得した。
100万個の新鮮に単離したPBMCを、PBSにおいて2回洗浄し、ペレットにし、そして1mlの0.5μMカルボキシ−フルオレセインジアセテート,スクシンイミジルエステル(CFSE、Molecular Probes)に37℃にて7分間懸濁した。その細胞を、PBSにおいて2回洗浄し、1ml R10培地(グルタチオン、ペニシリン、ストレプトマイシン、および10%ウシ胎仔血清[FCS]を補充したRPMI 1640)に懸濁し、そして24ウェルプレートのうちの1つのウェルに蒔いた。最初の研究は、0.2μg/mlの最終濃度のペプチドが最適な増殖性応答をもたらしたことを示し、したがってこれは、各アッセイに使用したウェルにおける最終ペプチド濃度であった。ネガティブコントロールウェルは、培地単独中のPBMC、または精製した抗PD−L1(10μg/ml)を含む培地中のPBMCからなり、そしてポジティブコントロールウェルを、10μg/mlのフィトヘマグルチニン(phytohemagluttinin)(PHA)によって刺激した。37℃のインキュベーターにおいて6日間インキュベートした後、その細胞を、2ml PBSによって洗浄し、そしてPE結合体化MHCクラスIテトラマー、ViaProbe(Becton Dickinson)、および抗CD8−APC抗体によって染色した。細胞を、FACSCaliburにおいて獲得し、そしてCellQuest(登録商標)ソフトウェア(Becton Dickinson)によって分析した。細胞を、ViaProbe− CD8+リンパ球についてゲート選別(gate)した。テトラマー+細胞の増加倍率(fold increase)を、ペプチドの存在下におけるCD8+テトラマー+細胞の%をペプチド刺激の非存在下におけるCD8テトラマー細胞の%で除算することによって算出した。
スピアマン相関、マン−ホイットニー検定、および対t検定(paired t−test)分析を、GraphPad Prism Version 4.0aを使用して行った。全ての検定は、両側であり、そしてp<0.05のp値を、有意であると見なした。
優性のHIV−1クレードCウイルスCD8 T細胞エピトープに特異的な10のMHCクラスIテトラマーのパネルを、一般的なHLA対立遺伝子、ならびに、Gag、Nef、インテグラーゼ、およびRTにおける頻繁に標的される、エピトープ(Kiepiela Pら、2004)に基づいて合成、これらの細胞上の表面PD−1発現の直接的な可視化を可能にした。高分解能HLA分類を、コホート全体に対して行い、そして65人の抗レトロウイルス治療ナイーブの者のサブセットを、関連するHLA対立遺伝子の発現に基づいて研究のために選択した。合計で120の個々のエピトープを調べた。HIVテトラマー+細胞上のPD−1の代表的なエキソビボ染色を、図5Aに示す。PD−1発現は、これらのテトラマー+細胞上に迅速に出現し、そして同じ個体由来の全CD8 T細胞集団におけるPD−1発現よりも有意に高い(p<0.0001);次に、テトラマー+ CD8 T細胞および全CD8 T細胞集団の両方におけるPD−1発現は、HIV血清反応陰性コントロールにおけるPD−1発現よりも有意に高かった(図5B)。試験した10個のテトラマーのうちの8個に関して、抗原特異的CD8細胞上の発現のレベルが100%である少なくとも1人の者を、同定した(図5C)。3〜25人の個体由来のPBMCを各HIVテトラマー応答について染色し、PD−1発現レベルの中央値は、テトラマー+細胞の68%〜94%の範囲であった。(図5C)。これらの知見を、テトラマー+細胞および全CD8 T細胞集団の両方におけるPD−1の平均蛍光強度(MFI)の分析によってさらに確かめた(図5B、図5C)。
相関を、HIV特異的CD8 T細胞上のPD−1発現と、血漿ウイルス量およびCD4数(その両方は、HIV疾患の進行の指標である)との間において決定した。先の研究と一致して、テトラマー陽性細胞の数とウイルス量またはCD4数との間の相関は、何の有意な相関をも示さなかった(図6A、図6B)。対照的に、ウイルス量と、HIVテトラマー陽性細胞上のPD−1発現の%およびMFIの両方との有意にポジティブな相関(それぞれ、p=0.0013およびp<0.0001;図6A)が存在した。CD4数と、HIVテトラマー陽性細胞上のPD−1の%およびMFIとの間に、逆相関(それぞれ、p=0.0046およびp=0.0150;図6B)がまた存在する。試験したテトラマーは、これらの被験体におけるHIV特異的CD8 T細胞集団の画分のみを示すようであるので、全てのCD8細胞上のPD−1発現とこれらのパラメータとの間の相関をまた、調べた。ウイルス量と、全CD8 T細胞集団上のPD−1発現の%およびMFIとの間の有意にポジティブな相関(それぞれ、p=0.0021およびp<0.0001;図6C)が存在し、そして逆相関がまた、CD4数と、全CD8 T細胞集団上のPD−1発現の%およびMFIとの間において観察された(それぞれ、p=0.0049およびp=0.0006;図6D)。この同じ群において、CMV特異的CD8 T細胞上のPD−1発現を、5人の被験体において試験し、そして有意に少ないPD−1が、HIV特異的CD8 T細胞と比較してこれらの細胞上に発現され(CMVテトラマー+ PD−1+の23%という中央値、p=0.0036、データ示さず)、そしてその発現は、それらの同一の個体における大部分のCD8 T細胞とは異ならなかった。このことは、高いPD−1発現が全てのウイルス特異的CD8 T細胞の一様な特徴ではないことを示す。これらのデータは、慢性HIV感染における抗原の量の増加がCD8 T細胞上のPD−1の増大した発現を生じることを示唆し、そしてそのデータは、PD−1発現がCD8
T細胞の機能的な疲弊に関連する慢性LCMV感染におけるマウスのデータ(Barber DLら、2005)と一致する。さらに、それらは、複数のエピトープの分析を含む大規模研究における、HIV特異的CD8 T細胞とウイルス量またはCD4数のいずれかとの間の最初の明確な関連を提供する。
次に、PD−1発現を、CD8 T細胞の記憶状態および機能に関連する多くのさらなる表現型マーカー(CD27、CD28、CD45RA、CD57、CD62L、CD127、CCR7、パーフォリン、グランザイムB、およびKi67を含む)の構成において分析した(図7)。1人の個体由来のB*4201 TL9テトラマー+細胞におけるこれらのマーカーに対する代表的な染色を、図7Aに示し、そして13人の被験体について集められたデータを、図7Bに示す。4色よりも多いマルチパラメータフローサイトメトリーはKwaZulu Natalにおいて利用可能ではなかったので、これらの研究は、95%よりも大きいPD−1陽性であったテトラマー応答に限られた。上記HIVテトラマー+ PD−1+細胞は、高レベルのCD27およびグランザイムB、非常に低レベルのCD28、CCR7、および細胞内Ki67、低レベルのCD45RAおよびパーフォリン、ならびに中程度のレベルのCD57およびCD62Lを発現する(図7B)。これらのデータは、HIV特異的PD−1+ T細胞がエフェクター/エフェクター記憶表現型を提示することを示し、そしてそれは、先の報告のHIV特異的CD8 T細胞の歪んだ成熟(Champagne Pら、2001;Appay Vら、2002;Hess Cら、2004)と一致する。さらに、ウイルスの配列決定を、これらの細胞が免疫回避(Brown JAら、2003)を駆動していたか否かを決定するために行った。45個の評価したこれらのテトラマー陽性応答のうち、5個のみにおけるウイルスエピトープが、South AfricanクレードC共通配列と異なっており(データ示さず)、これは、これらの細胞が、インビボでほとんど選択圧を発揮しなかったこと示す。
HIV特異的CD8 T細胞はまた、損なわれた増殖能力を示す(Migueles SAら、2002;Lichterfeld Mら、2004)ので、PD−1/PD−L1の遮断がインビトロでこの機能を増強し得るか否かを、決定した。B*4201陽性個体からの代表的なデータを、図8Aに示す。培地単独、または抗PD−L1抗体を含む培地を伴う新鮮に単離したCFSE標識PBMCのインキュベーションは、培養の6日後にCFSEhiを保持したB*4201−TL9特異的CD8 T細胞の集団(1.2%のCD8 T細胞)の維持をもたらした。TL9ペプチド単独による6日間にわたるCFSE標識PBMCの刺激が、CFSElo B*4201 TL9テトラマー+細胞の4.8倍の拡大をもたらしたのに対し、抗PD−L1遮断抗体の存在下でのTL9ペプチドによるCFSE標識PBMCの刺激は、10.3倍のテトラマー+細胞の増加を生じる、TL9特異的細胞の増殖をさらに増強した。CFSE増殖アッセイを、精製した抗ヒトPD−L1遮断抗体の存在下および非存在下で28個のサンプルに対して行った。HIV特異的CD8+ T細胞の増殖の有意な増大が、ペプチド単独による刺激後における増殖の量と比較して、抗PD−L1遮断抗体を加えたペプチドの存在下で観察された(図8B;p=0.0006、対t検定)。抗PD−L1遮断抗体の存在下におけるテトラマー+細胞の増加倍率は、個体および所定の個体内のエピトープによって変化し(図8C)、それはまた、これらの応答の機能的疲弊の程度におけるエピトープ特異的な差を示唆する。
本発明は、その詳細な説明と組み合せて記載されているが、上記の説明は、例示することを意図し、そして添付の特許請求の範囲によって規定される本発明の範囲を限定しない。他の局面、利点、および改変は、添付の特許請求の範囲の範囲内である。
Claims (50)
- 持続感染または癌の症状を軽減または予防する方法であって、その必要がある被験体に、該被験体におけるプログラム細胞死−1(PD−1)ポリペプチドの活性または発現を減少させる化合物を投与する工程を包含する、方法。
- 前記持続感染は、ウイルス感染、細菌感染、真菌感染、マイコプラズマ感染、または寄生虫感染である、請求項1に記載の方法。
- 前記ウイルス感染は、肝炎ウイルス、ヒト免疫不全ウイルス(HIV)、ヒトTリンパ球向性ウイルス(HTLV)、ヘルペスウイルス、エプスタイン−バーウイルス、またはヒトパピローマウイルスによる感染である、請求項2に記載の方法。
- 前記寄生虫感染は、マラリアである、請求項2に記載の方法。
- 前記細菌感染は、結核である、請求項2に記載の方法。
- 前記癌は、血管免疫芽球性リンパ腫または結節性リンパ球優勢型ホジキンリンパ腫である、請求項1に記載の方法。
- 前記化合物は、PD−1リガンド(PD−L1)またはPD−1リガンド2(PD−L2)の発現または活性を減少させる、請求項1に記載の方法。
- 前記化合物は、PD−1とPD−L1との間の相互作用またはPD−1とPD−L2との間の相互作用を減少させる、請求項1に記載の方法。
- 前記化合物は、前記被験体における細胞傷害性T細胞の活性を増大させる、請求項1に記載の方法。
- 前記細胞傷害性T細胞活性は、サイトカイン産生、T細胞増殖、または感染因子クリアランスである、請求項9に記載の方法。
- 前記感染因子は、ウイルス、細菌、真菌、マイコプラズマ、または寄生虫である、請求項10に記載の方法。
- 前記T細胞は、癌特異的T細胞である、請求項9に記載の方法。
- 前記サイトカインは、IFNγ、TNFα、またはIL−2である、請求項10に記載の方法。
- 前記化合物は、抗PD−1抗体、抗PD−L1抗体、抗PD−L2抗体、抗PD−1 RNAi、抗PD−L1 RNAi、抗PD−L2 RNAi、抗PD−1アンチセンスRNA、抗PD−L1アンチセンスRNA、抗PD−L2アンチセンスRNA、ドミナントネガティブPD−1タンパク質、ドミナントネガティブPD−L1タンパク質、またはドミナントネガティブPD−L2タンパク質である、請求項1に記載の方法。
- 前記抗体は、モノクローナル抗体、ヒト化抗体、脱免疫抗体、またはIg融合タンパク質である、請求項12に記載の方法。
- 前記化合物は、低分子である、請求項1に記載の方法。
- 前記被験体にワクチンを投与する工程をさらに包含する、請求項1に記載の方法。
- 前記ワクチンは、アジュバントまたはプライムブースト注射を含む、請求項17に記載の方法。
- 前記被験体に第2の化合物を投与する工程をさらに包含する、請求項1に記載の方法。
- 前記第2の化合物は、抗ウイルス化合物、抗細菌化合物、抗真菌化合物、抗寄生虫化合物、抗炎症性化合物、抗腫瘍性化合物または鎮痛剤である、請求項19に記載の方法。
- 前記第2の化合物は、細胞傷害性Tリンパ球抗原4(CTLA−4)またはBリンパ球およびTリンパ球のアテニュエーター(BTLA)の発現または活性を減少させる、請求項19に記載の方法。
- 前記第2の化合物は、癌細胞量を減少させる、請求項19に記載の方法。
- 前記第2の化合物は、抗CTLA−4抗体、抗BTLA抗体、抗CD28抗体、抗ICOS抗体、抗ICOS−L抗体、抗B7−1抗体、抗B7−2抗体、抗B7−H3抗体、または抗B7−H4抗体である、請求項19に記載の方法。
- 前記被験体は、ヒトである、請求項1に記載の方法。
- 持続感染または癌の症状を軽減または予防する方法であって、その必要がある被験体にCD28様ファミリーのメンバーの活性または発現を減少させる化合物を投与する工程を包含し、該CD28ファミリーメンバーが、PD−1、CTLA−4、BTLA、およびそれらの機能性フラグメントまたは改変体からなる群より選択される、方法。
- 前記持続感染は、ウイルス感染である、請求項25に記載の方法。
- 前記ウイルス感染は、肝炎ウイルス、ヒト免疫不全ウイルス(HIV)、ヒトTリンパ球向性ウイルス(HTLV)、ヘルペスウイルス、エプスタイン−バーウイルス、またはヒトパピローマウイルスのよる感染である、請求項26に記載の方法。
- 前記化合物は、前記被験体における細胞傷害性T細胞活性を増大させる、請求項25に記載の方法。
- 前記細胞傷害性T細胞活性は、サイトカイン産生、T細胞増殖、または感染因子クリアランスである、請求項28に記載の方法。
- 前記化合物は、抗PD−1抗体、抗PD−L1抗体、抗PD−L2抗体、抗CTLA−4抗体、抗BTLA抗体、抗CD28抗体、抗ICOS抗体、抗ICOS−L抗体、抗B7−1抗体、抗B7−2抗体、抗B7−H3抗体、または抗B7−H4抗体である、請求項25に記載の方法。
- 前記被験体にワクチンを投与する工程をさらに包含する、請求項25に記載の方法。
- 前記被験体に第2の化合物を投与する工程をさらに包含する、請求項25に記載の方法。
- 被験体において持続感染または癌の症状を軽減または予防する方法であって、該被験体に、抗原特異的T細胞におけるPD−1ポリペプチドの発現または活性を減少させる化合物と接触させた抗原特異的T細胞を投与する工程を包含する、方法。
- 前記被験体は、抗原特異的B細胞におけるPD−1ポリペプチドの発現または活性を減少させる化合物と接触させた抗原特異的B細胞をさらに投与される、請求項33に記載の方法。
- 前記T細胞は、自系供給源に由来する、請求項33に記載の方法。
- 前記T細胞は、前記被験体と同じ種の被験体に由来する、請求項33に記載の方法。
- 前記T細胞は、前記処置される被験体とは異なる種の被験体に由来する、請求項33に記載の方法。
- 前記抗原特異的T細胞は、ウイルス抗原、細菌抗原、真菌抗原または寄生虫抗原または癌抗原に特異的である、請求項33に記載の方法。
- 前記ウイルス抗原は、肝炎ウイルス、ヒト免疫不全ウイルス(HIV)、ヒトTリンパ球向性ウイルス(HTLV)、ヘルペスウイルス、エプスタイン−バーウイルス、またはヒトパピローマウイルスの抗原である、請求項38に記載の方法。
- T細胞の細胞傷害活性を増大させる方法であって、該T細胞と、PD−1ポリペプチドの活性または発現を減少させる化合物とを接触させる工程を包含する、方法。
- 前記生物学的活性は、PD−1リガンド(PD−L1)またはPD−1リガンド2(PD−2L)の発現または活性を減少させることによって減少する、請求項40に記載の方法。
- 前記化合物は、PD−1とPD−L1との間の相互作用またはPD−1とPD−L2との間の相互作用を減少させる、請求項40に記載の方法。
- 前記細胞傷害活性は、サイトカイン産生、T細胞増殖、または感染因子クリアランスである、請求項40に記載の方法。
- 前記化合物は、抗PD−1抗体、抗PD−L1抗体、抗PD−L2抗体、抗PD−1 RNAi、抗PD−L1 RNAi、抗PD−L2 RNAi、抗PD−1アンチセンスRNA、抗PD−L1アンチセンスRNA、抗PD−L2アンチセンスRNA、ドミナントネガティブPD−1タンパク質、ドミナントネガティブPD−L1タンパク質、またはドミナントネガティブPD−L2タンパク質である、請求項40に記載の方法。
- 前記細胞と、抗PD−1抗体、抗PD−L1抗体、抗PD−L2抗体、抗CTLA−4抗体、抗BTLA抗体、抗CD28抗体、抗ICOS抗体、抗ICOS−L抗体、抗B7−1抗体、抗B7−2抗体、抗B7−H3抗体、または抗B7−H4抗体とを接触させる工程をさらに包含する、請求項40に記載の方法。
- 持続感染または癌を有するか、あるいは持続感染または癌を有する危険性があると被験体を診断する方法であって、
(a)該被験体由来のサンプルを提供する工程であって、該サンプルが、免疫細胞を含む、工程;および
(b)該被験体由来の該サンプルにおけるPD−1の発現または活性を測定する工程であって、コントロールサンプルにおけるPD−1の発現または活性と比較したPD−1の発現または活性の増大により、持続感染または癌を有するか、あるいは持続感染または癌を有する危険性があると該被験体が同定される、工程;
を包含する、方法。 - 持続感染または癌を有するか、あるいは持続感染または癌を有する危険性がある被験体の処置を選択する方法であって、
(a)免疫細胞を含む該被験体由来のサンプルを提供する工程;
(b)該免疫細胞におけるPD−1の発現または活性を測定する工程であって、コントロールサンプルにおけるPD−1の発現または活性と比較したPD−1の発現または活性における増大により、持続感染または癌を有するか、あるいは持続感染または癌を有する危険性があると該被験体が同定される、工程;
(c)持続感染または癌を有するか、あるいは持続感染または癌を有する危険性があると診断された該被験体に対する処置を選択する工程であって、該処置が、PD−1の発現または活性を減少させる化合物を含む、工程;
を包含する、方法。 - 前記工程(b)は、抗原特異的免疫細胞を同定する工程をさらに包含し、該抗原は、ウイルス抗原、細菌抗原、寄生虫抗原、または真菌抗原である、請求項46または47に記載の方法。
- 前記サンプルは、血液サンプル、組織生検、または骨髄サンプルである、請求項46または47に記載の方法。
- 前記コントロール細胞は、持続感染または癌のいずれかを有することも、あるいは持続感染または癌のいずれかを有する危険性もない被験体に由来する、請求項46または47に記載の方法。
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