JP2019502753A - ナンセンス変異依存mRNA分解機構の抑制による免疫応答の誘導法 - Google Patents
ナンセンス変異依存mRNA分解機構の抑制による免疫応答の誘導法 Download PDFInfo
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Abstract
Description
本出願は、2015年12月23日に提出された米国仮特許出願第62/387,565号明細書の優先権を請求するものであり、この参照によりその全体が本明細書に組み込まれる。
本発明の実施では、他に示されていない限り、分子生物学、微生物学、細胞生物学、生化学、核酸化学、および免疫学の従来の技術を利用し、これらは当業者に周知である。そのような技術は、Molecular Cloning: A Laboratory Manual, fourth edition (Sambrook et al., 2012)およびMolecular Cloning: A Laboratory Manual, third edition (Sambrook and Russel, 2001)(本明細書では、「Sambrook」と連帯で表す);Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987, including supplements through 2014); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Antibodies: A Laboratory Manual, Second edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (Greenfield, ed., 2014), Beaucage et al. eds., Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, Inc., New York, 2000(2014年までの補遺を含む), Gene Transfer and Expression in Mammalian Cells (Makrides, ed., Elsevier Sciences B.V., Amsterdam, 2003)、およびCurrent Protocols in Immunology (Horgan K and S. Shaw (1994)(2014年までの補遺を含む)などの文献で十分に説明されている。
本明細書に用いるとおり、「未成熟終止コドン」(PTC)または「未成熟停止コドン」は、変異の結果として、(内因性停止コドンの前に)mRNAへ停止コドンを誘導することを指す。
未成熟終止コドン(PTC)の変異は、塩基置換またはフレームシフト変異がセンスコドンを3種類の停止コドン(UAA、UAG、またはUGA)のいずれか1つに変化させる変異である。酵母、ヒト遺伝疾患、および免疫グロブリンファミリー遺伝子の発現に関する研究から、翻訳を最小限とし、そのような鎖停止変異を含むナンセンスRNAsのRNA安定性を制御するRNAサーベイランス機序が同定された。このサーベイランス機序は「ナンセンス変異依存mRNA分解機構(NMD)」と呼ばれ、例えばHentze & Kulozik, Cell 96:307−310 (1999); Culbertson, Trends in Genetics 15:74−80 (1999);およびLi & Wilkinson, Immunity 8:135−141 (1998)を参照。NMDは、正常細胞(例えば、BおよびT細胞)および遺伝子が変異した細胞(すなわち、細胞増殖をコントロールする遺伝子が変異した細胞)のいずれにおいても使用できる、転写後の機序である。
さらなる態様では、前記化合物が、前記NMD分解複合体と関連した1若しくはそれ以上のタンパク質のナンセンス変異依存mRNA分解機構に関与する1若しくはそれ以上の分子の発現および機能を調節する。本明細書に用いるとおり、「NMD分解複合体」の表現は、PTCを有するmRNAのNMDに関与する細胞内タンパク質のいずれか1つ(これに限定されるものではないが、UPF1、UPF2、UPF3、UPF3BI、RNPS1、eIF4AIII、MLN51、Y14/MAGOHヘテロダイマー、RENT1、RENT2、SMG−1、SMG−5、SMG−6、および/またはSMG−7の1若しくはそれ以上など)を指す。それ自体、前記化合物は1若しくはそれ以上のNMD分解複合体タンパク質の機能を阻害することで、PTCを有するmRNAがポリペプチドに翻訳されるようにすることができる。
一部の態様では、前記化合物が1若しくはそれ以上のNMD分解複合体タンパク質(これに限定されるものではないが、UPF1、UPF2、UPF3、UPF3BI、RNPS1、eIF4AIII、MLN51、Y14/MAGOHヘテロダイマー、RENT1、RENT2、SMG−1、SMG−5、SMG−6、および/またはSMG−7)およびその抗体に(選択的に結合するなど)結合する。一部の実施形態では、前記抗体がNMD分解複合体タンパク質拮抗薬であり、NMDを阻害することができる。
一部の態様では、前記化合物が1若しくはそれ以上のNMD分解複合体タンパク質(これに限定されるものではないが、UPF1、UPF2、UPF3、UPF3BI、RNPS1、eIF4AIII、MLN51、Y14/MAGOHヘテロダイマー、RENT1、RENT2、SMG−1、SMG−5、SMG−6、および/またはSMG−7)に(選択的に結合するなど)結合し、非抗体結合ポリペプチドである。一部の実施形態では、前記非抗体結合ポリペプチドがNMD分解複合体タンパク質拮抗薬であり、NMDを阻害することができる。
本明細書では、本明細書で開示されるNMD複合体を阻害する化合物を有する薬学的組成物も提供される。本発明の薬学的組成物には、錠剤、カプセル、顆粒、粉末、ペレット、カプレット、ミニ錠剤、トローチ剤、ミニ錠剤および/またはペレットを充填したカプセル、多層錠剤、懸濁用顆粒、顆粒、または小袋に充填した粉末の1若しくはそれ以上を含んでもよい。他の実施形態では、本発明の組成物がコーティングされ、フィルムコーティング錠を与えることもできる。
一部の態様では、本明細書で、それを必要とする個体に免疫応答を発生させる方法、および/または異常細胞表面に1若しくはそれ以上のネオアンチゲンの発現を誘導する方法が提供される。NMDは真核細胞で進化的に保存されたmRNAサーベイランス経路であり、未成熟終止コドン(PTCs)を内包するmRNAsを検出し、排除する。理論に縛られることは望まないが、NMDが腫瘍細胞で抑制される場合の遺伝子発現のアップレギュレーションは、治療上有用な腫瘍抗原性の増大に変換され、つまり、新製剤が効果的な腫瘍抗原として機能し、腫瘍拒絶に関与する免疫応答を誘発することができる。抑制は、上述のNMD分解複合体の抑制を促すため、それを必要とする個体に有効量の1若しくはそれ以上の化合物を投与することで達成される。一実施形態では、前記NMD分解複合体の抑制後に前記mRNAから翻訳されたタンパク質が非機能性タンパク質である。有効量では、以下および本明細書に説明するとおり、機能性が得られる。
本明細書に説明される方法で誘発される免疫応答は、免疫細胞によりPTC含有mRNAの翻訳から作成された処理タンパク質を認識することで媒介される。一部の実施形態では、前記免疫細胞が、骨髄造血幹細胞由来の主なリンパ球タイプであるT細胞またはB細胞である。B細胞は体液性免疫応答に関与し、T細胞は細胞性免疫応答に関与する。B細胞およびT細胞は、いずれも特異的標的を認識する受容体分子を保有する。T細胞は「非自己」標的を認識し、そのようなタンパク質は、抗原が主要組織適合複合体(MHC)分子と一緒に処理、提示された後、ナンセンスまたはフレームシフト変異により生じたPTC含有mRNAから翻訳される。T細胞には、キラーT細胞とヘルパーT細胞の2つの主要サブタイプがある。キラーT細胞はクラスI MHC分子と結合した抗原のみを認識するが、ヘルパーT細胞はクラスII MHC分子と結合した抗原のみを認識する。これらの2種類の抗原提示メカニズムはこの2種類のT細胞の役割が異なることを反映している。第3の少量存在するサブタイプはy5 T細胞であり、MHC受容体に結合していないそのままの抗原を認識する(Holtmeier & Kabelitz, (2005), Chemical Immunology and Allergy, 86:151−83)。
本明細書に開示される方法の一部の態様では、1若しくはそれ以上の新規抗原の発現が異常細胞表面に誘導される。特定の実施形態では、前記異常細胞が癌などの過剰増殖性細胞である。
本明細書で開示される方法の一部の実施形態では、前記方法が、さらに、1若しくはそれ以上の免疫チェックポイント分子を阻害する、1若しくはそれ以上の化合物を投与する工程を有する。免疫チェックポイントは、シグナル(同時刺激分子)を発生またはシグナルを停止する免疫系の分子である。チェックポイント阻害剤は、癌細胞が免疫系の検出を逃れる主な方法の1つを克服するようにデザインされている。Tリンパ球は、定期的に疾患の徴候となる細胞をモニターする。細胞表面の抗原がその細胞が異常であることを示していた場合、前記T細胞は、前記免疫応答が身体の正常細胞を損傷しないように、追加分子の発現増加を含む免疫応答を開始する。これらの分子は免疫チェックポイントとして知られている。
本明細書で開示される方法の一部の実施形態では、前記方法が、さらに、1若しくはそれ以上のエピジェネティック調節化合物を投与する工程を有する。本明細書に用いるとおり、「エピジェネティック」は染色体および遺伝子で細胞に生じ、前記変化が前記染色体で前記DNAおよび遺伝子の機能に影響するが、前記遺伝子DNAのヌクレオチド配列は変化させない物理的変化を指す。エピジェネティック調節の代表例には、これに限定されるものではないが、メチル化およびアセチル化などのDNAの共有結合化学的修飾、また、DNA−DNAスーパーコイルの非共有結合、非化学的修飾およびヒストンなどの染色体タンパク質の結合を含む。限定されない、エピジェネティック変化の結果の代表例には、RNAs、これによって特定遺伝子から生じたタンパク質産物レベルの増減、および/または転写因子が遺伝子プロモーターで結合する様式の変化が含まれる。
本発明の方法は、アジュバントの条件で実施してもよい。「アジュバントの条件」は、個体に増殖性疾患、特に癌の既往があり、一般には(ただし、これに限らない)、これに限定されるものではないが、外科手術、放射線療法、および/または化学療法を含む治療に反応した臨床条件を指す。ただし、増殖性疾患の既往があるため、これらの個体はその疾患を発症するリスクがあると考えられる。前記「アジュバントの条件」での治療または投与は、その後の治療様式を指す。
本明細書で開示される方法の一部の実施形態では、前記方法が、さらに、1若しくはそれ以上のT細胞を活性化する化合物を投与する工程を有する。これらのポリペプチドはしばしば「刺激性チェックポイント分子」と呼ばれ、腫瘍壊死因子(TNF)受容体スーパーファミリーおよびB7−CD28スーパーファミリーの一種である。本発明での使用に適したT細胞作用薬の限定されない例は、これに限定されるものではないが、CD27アクチベーター(例えば、CDX−1127(Celldex Therapeutics))、GITR、B7−H3、CD28(例えば、TGN1412)、CD40、インターロイキン−2受容体サブユニットβ(ILR2P、別名CD122、例えば、NKTR−214)、CD137(別名TNFRSF9、4−1BB、およびinduced by lymphocyte activation(ILA))、ICOS、および/またはOX40(別名CD134およびTNFRSF4、例えば、MEDI0562、MEDI6469、およびMEDI6383(AstraZeneca))を含む。
本明細書で開示される方法の一部の実施形態では、前記方法が、さらに、1若しくはそれ以上の分子アジュバントを投与する工程を有する。本明細書に用いるとおり、「分子アジュバント」は、これに限定されるものではないが、樹状細胞を活性化する薬剤など、免疫応答を向上させる分子を指す。分子アジュバントには、これに限定されるものではないが、樹状細胞が受容体を有し、その受容体が使用されることで細胞内シグナルおよび前記樹状細胞表現型の変化が伝達されるタンパク質、脂質、核酸、炭水化物、または化学化合物を含み、これにより続く免疫応答の質および量が改善する。分子アジュバントの制限されない例には、TNF受容体スーパーファミリー(TNFRSF)作用薬、Toll様受容体(TLR)リガンド、細胞内DNAセンサー作用薬を含む。
前記TNFRSFには、樹状細胞、マクロファージ、およびT細胞の重要な受容体を数多く含む。例えば、cluster of differentiation 40(CD40)は、抗原提示細胞にみられる共刺激タンパク質であり、その活性化に必要である。CD40細胞へのTH細胞CD 154(CD40L)の結合は抗原提示細胞を活性化し、様々な下流の作用を誘導する。CD40LはDCsのCD80およびCD86の発現を強力にアップレギュレートし、CD4+ T細胞をTh1細胞に分化させる。
本明細書で使用される「トール様受容体」(または「TLR」)の用語は、微生物生産物を感知する、および/または適応的免疫応答を開始する、そのタンパク質またはフラグメントのトール様受容体ファミリーを指す。一実施形態では、TLRが樹状細胞(DC)を活性化する。トール様受容体(TLRs)はパターン認識受容体ファミリーであり、微生物病原体を認識する先天性免疫応答のセンサーとして最初に同定された。TLRsは、ロイシンに富んだ受容体の外部ドメイン、膜貫通ドメイン、および細胞内TIR(Toll/IL−IR)ドメインを含む保存された膜貫通分子ファミリーを有する。TLRsは、「PAMPs」(病原体関連分子パターン)と呼ばれることが多い、微生物の明確に異なる構造を認識する。TLRsへのリガンドの結合は細胞内シグナル伝達経路のカスケードを誘発し、これが炎症および免疫に関与する因子の生産を誘導する。
cGAS−STING経路は、細胞質DNAの有無を検出し、それに応じて炎症性遺伝子の発現を誘発するように機能する先天性の免疫系コンポーネントである。DNAは通常、細胞の核に認められる。前記細胞質へのDNAの局在化は、腫瘍形成またはウイルス感染と関連する。cGAS−STING経路は、細胞質DNAを検出し、免疫応答を誘発するように作用する。
本明細書で開示される方法の他の実施形態では、前記方法が、さらに、1若しくはそれ以上の微小環境調節因子を投与する工程を有する。「微小環境修調節因子」は、腫瘍増殖を支援する、免疫抑制性腫瘍微小環境を作ることができる因子を指す(Ino et al., 2013, J Cancer Sci Ther., S13)。そのような調節因子の1つは、チェックポイントタンパク質としても同定されたインドールアミン(2,3)−ジオキシゲナーゼ(IDO)である(上記参照)。IDOは、2つのイソ型(IDO1およびIDO2)を持ち、必須アミノ酸のトリプトファンを分解する代謝経路の最初の段階に作用する酵素である。IDOは、免疫系のエフェクターT細胞を停止させることで、免疫調節作用を示す(Smith et al., Cancer Discov.2012;2(8):772−735)。IDOの発現も、その主な機能が免疫応答の最後にT細胞性免疫を停止することである、制御性T細胞を直接活性化する。
本明細書で開示される方法の他の実施形態では、前記方法が、さらに、1若しくはそれ以上のケモカイン受容体拮抗薬を投与する工程を有する。ケモカイン受容体は、主に白血球表面に認められる7回膜貫通ドメインを含むGタンパク質共役受容体である。ケモカイン受容体は異なるファミリーに分かれ、受容体が結合するケモカインのサブファミリー4種類に対応し、CXCケモカイン受容体、CCケモカイン受容体、CX3Cケモカイン受容体、およびXCケモカイン受容体がある。
本明細書で開示される方法の他の実施形態では、前記方法が、さらに、1若しくはそれ以上のサイトカイン療法を実施する工程を有する。サイトカインは、腫瘍内に存在する多数の細胞タイプから産生される広範なタンパク質群であり、免疫応答を調節することができる。これらの免疫調節作用により、薬物を免疫応答の誘発に使用することができる。多く使用されるサイトカイン群はインターフェロンとインターロイキンの2種類である。
本明細書で開示された方法に使用するために適した他の免疫療法には、これに限定されるものではないが、免疫原性化学療法、XRT、腫瘍溶解性ウイルス、寒冷療法、TACE、免疫調節薬の腫瘍内注入、発癌経路の標的療法(MAPK、βカテニン、PI3K/PTEN、FGFR3など)、エピジェネティック治療、CSF1/CSFR1欠乏抗体および抗CCR4抗体(例えば、モガムリズマブ、Kyowa)、抗IL−8/IL−8R抗体、抗CCR2抗体、抗CCR5抗体、抗CXCRl/CXCR2抗体、抗CTLA4抗体、抗CCR4抗体、抗CCR8抗体、抗CD25抗体、抗KIR抗体、抗NKG2a抗体、抗NKG2DL抗体(MICA)、アルギナーゼ、IDO/TDO、アデノシン、A2AR、CD39、CD73、PI3Kγ、抗NKG2D抗体、CD94、およびCD47/SIRPa、Mer/Axl/Tyro3、TIM3、MFG−E8/GAS6、および/またはDD1αの1若しくはそれ以上を活性化または阻害する治療を含む。免疫療法に関するさらなる情報は、Adams et al., 2015, Nature Rev. Drug. Disc, 14:603−22; Weinmann, 2016, ChemMedChem, 11:450−66; and Zhan et al., 2016, Drug Disc. Today, 21(6): 1027−36に見ることができ、その開示はこの参照により本明細書に組み込まれる。
本実施例は、ナンセンス変異依存mRNA分解機構阻害剤(NMDI)によるナンセンス変異依存mRNA分解機構(NMD)経路の阻害により免疫応答が発生し、腫瘍が縮小することを証明する。
同種免疫適格腫瘍モデルはマウス癌細胞株から作られ、その例には、特に、膵臓癌(PanO2)、前立腺癌(RM1)、結腸癌(CT−26、Colon−26、MC38−26)、腎臓癌(Renca)、膀胱癌(MBT−2)、肺癌(LL/2、KLN205)、黒色腫(B16BL6、B16F10、S91)、乳癌(4T1、EMT6、JC)、線維肉腫(WEHI−164)、白血病(C1498、L1210)、肝臓癌(H22、Hepal−6)、リンパ腫(A20、EL−4、E.G&−OVA、L5178−R、P388D1)、肥満細胞腫(P815)、骨髄腫(MPC−11)、神経芽腫(Neuro−2a)を含む(world wide web.crownbio.com/oncology/in−vivo−services/syngeneic−tumour−models/)。マウスには腫瘍細胞懸濁液を皮下注射し、これが注射後約4〜6週間で腫瘍を発症する。
本実施例は、NMDIsと免疫療法剤との併用による同種免疫適格マウスの腫瘍治療効果を示す。これらの(局所的または全身的)アプローチをチェックポイントの遮断などの免疫療法剤と併用することで、in vivoにおいて強力な腫瘍ネオアンチゲンが生成するため、癌免疫療法の有効性が大きく上昇する可能性がある。これらのこれまで隠れていた強力な内因性腫瘍抗原に気付いたことで、他のアプローチ(チェックポイント遮断、免疫アジュバント)を併用することでさらに増強し、各個体の腫瘍に内在するこれらの変異に免疫性を誘導することができる新たなステージの免疫サーベイランスが導入される可能性がある。
使用したマウス癌モデルについては上述している。
本実施例は、NMDIsとエピジェネティック調節薬との併用による同種免疫適格マウスの腫瘍治療効果を示す。1若しくはそれ以上のエピジェネティック調節薬の追加は、ネオアンチゲンの免疫認識を強化する可能性を有する。
使用したマウス癌モデルについては上述している。
本実施例は、NMDIsと放射線療法との併用による同種免疫適格マウスの腫瘍治療効果を示す。放射線療法(RT)前にNMDI薬を投与することで、免疫刺激による細胞死前に腫瘍のネオアンチゲンの発現が増加し、ネオアンチゲンの提示が強化されるだろう。
使用したマウス癌モデルについては上述している。
本実施例は、NMDIsと化学療法との併用による同種免疫適格マウスの腫瘍治療効果を示す。化学療法前にNMDI薬を投与することで、免疫刺激による細胞死前に腫瘍のネオアンチゲンの発現が増加し、ネオアンチゲンの提示が強化されるだろう。
使用したマウス癌モデルについては上述している。
本実施例は、NMDIsと腫瘍溶解性ウイルスとの併用による同種免疫適格マウスの腫瘍治療効果を示す。
使用したマウス癌モデルについては上述している。
本実施例は、NMDIsとワクチン療法との併用による同種免疫適格マウスの腫瘍治療効果を示す。
使用したマウス癌モデルについては上述している。
本実施例は、NMDIsとCAR−T細胞または患者由来の腫瘍浸潤リンパ球との併用による同種免疫適格マウスの腫瘍治療効果を示す。
使用したマウス癌モデルについては上述している。
本実施例では、腫瘍を有するC57BL/6マウスの治療について、NMDI単独および1若しくはそれ以上の免疫療法薬との併用の有効性を評価した。
動物:6〜8週齢(接種時の推定年齢)の雌C57BL/6マウスをShanghai Lingchang Bio−Technology Co. Ltd(LC、中国、上海)から入手した。動物は20〜26°C、12時間/12時間の明暗サイクルで飼育した。
腫瘍細胞を播種後、前記動物の罹患率および死亡率、また腫瘍増殖および投与が移動性などの正常な行動、食餌および水分摂取の目測、体重増減、眼/体毛の一致、他の異常作用に与える効果を毎日確認した。腫瘍容積はカリパスを用いて少なくとも2次元で週2回測定し、前記容積は式V=0.5axb2を用いてmm3で表し、式中、aおよびbはそれぞれ腫瘍の最大および最小直径である。
本実施例では、腫瘍を有するC57BL/6マウスの治療について、NMDIと2つの免疫療法薬(抗PD−1抗体および抗CTLA−4抗体)との併用の効果を評価する。
動物の管理、細胞培養、播種、群の割り付け、およびNMDI14、抗PD−1抗体、および抗CTLA−4抗体の製剤化は、実施例9に考察したとおりに行った。
腫瘍細胞を播種後、動物の罹患率および死亡率、また腫瘍増殖および投与が移動性などの正常な行動、食餌および水分摂取の目測、体重増減、眼/体毛の一致、他の異常作用に与える効果を毎日確認する。腫瘍容積はカリパスを用いて少なくとも2次元で週2回測定し、前記容積は式V=0.5axb2を用いてmm3で表し、式中、aおよびbはそれぞれ腫瘍の最大および最小直径である。
Claims (45)
- それを必要とする個体に免疫応答を発生させる方法であって、未成熟終止コドン(PTC)をもたらすフレームシフト変異を有するmRNAのナンセンス変異依存分解機構(NMD)を阻害する一定量の化合物を前記個体に投与する工程を有し、前記量は前記mRNAのタンパク質への翻訳をもたらすために十分であり、前記化合物は抑制性核酸ではない、方法。
- 異常細胞の表面で1またはそれ以上のネオアンチゲンの発現を誘導する方法であって、未成熟終止コドン(PTC)をもたらすフレームシフト変異を有するmRNAのナンセンス変異依存分解機構(NMD)を阻害する化合物を前記細胞に接触させる工程を有し、前記mRNAのNMDの阻害は、前記mRNAのタンパク質への翻訳及び前記細胞の表面での1またはそれ以上のネオアンチゲンの発現をもたらし、前記化合物は抑制性核酸ではない、方法。
- 請求項1または請求項2記載の方法において、前記化合物が小分子化学化合物、抗体、または非抗体結合ポリペプチドである、方法。
- 請求項1〜3のいずれか1つに記載の方法において、ナンセンス変異依存分解機構(NMD)を阻害する前記化合物は、UPF3A、UPF3B、UPF1、UPF2、UPF3、eIF4AIII、MLN51、Y14/MAGOHヘテロダイマー、SMG−1、SMG−5、SMG−6、および/またはSMG−7ポリペプチドの機能を阻害する、方法。
- 請求項1〜4のいずれか1つに記載の方法において、前記フレームシフト変異をもつmRNAから翻訳されたタンパク質は非機能性である、方法。
- 請求項1または3〜5のいずれか1つに記載の方法において、前記免疫応答は、免疫細胞による前記mRNAの翻訳から処理されたタンパク質の認識によって媒介される、方法。
- 請求項6記載の方法において、前記免疫細胞はT細胞またはB細胞である、方法。
- 請求項6記載の方法において、前記免疫応答はクラスIまたはクラスII主要組織適合複合体(MHC)分子によって媒介される、方法。
- 請求項1または3〜5のいずれか1つに記載の方法において、前記免疫応答はT細胞によって媒介される、方法。
- 請求項1または3〜5のいずれか1つに記載の方法において、前記免疫応答はB細胞によって媒介される、方法。
- 請求項7または請求項9に記載の方法において、前記T細胞は、γδT細胞、αβT細胞、またはナチュラルキラーT細胞である、方法。
- 請求項1または3〜5のいずれか1つに記載の方法において、前記免疫応答は炎症反応である、方法。
- 請求項1〜12のいずれか1つに記載の方法において、前記mRNAは増殖細胞において発現される、方法。
- 請求項1〜13のいずれか1つに記載の方法において、前記増殖細胞または異常細胞は癌細胞である、方法。
- 請求項14記載の方法において、前記癌は、結腸癌、乳癌、膵癌、卵巣癌、前立腺癌、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、滑液腫瘍、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、扁平上皮細胞癌、基底細胞癌、腺癌、汗腺癌、脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、髄様癌、気管支原性肺癌、腎細胞癌、肝癌、胆管癌、絨毛癌、精上皮腫、胚性癌腫、ウィルムス腫瘍、子宮頚癌、精巣腫瘍、肺癌、小細胞肺癌、膀胱癌、上皮癌、神経膠腫、星細胞腫、髄芽腫、メルケル細胞癌、頭蓋咽頭腫、脳室上衣細胞腫、松果体腫、血管芽細胞腫、聴神経腫、乏突起細胞腫、髄膜腫、黒色腫、神経芽細胞腫、網膜芽細胞腫;白血病、例えば、急性リンパ性白血病および急性骨髄性白血病、慢性白血病;真性赤血球増加症、リンパ腫、多発性骨髄腫、ルデンシュトレーム型マクログロブリン血症、および重鎖病から成る群から選択される、方法。
- 請求項1〜15のいずれか1つに記載の方法において、前記方法は、さらに、1またはそれ以上の免疫チェックポイント分子を阻害する化合物を投与する工程を有する、方法。
- 請求項16記載の方法において、前記免疫チェックポイント分子は、CTLA4、PD−L1、PD−1、A2AR、B7−H3、B7−H4、またはTIM3のうちの1つまたはそれ以上である、方法。
- 請求項17記載の方法において、1またはそれ以上の免疫チェックポイント分子を阻害する前記化合物がアンタゴニスト抗体である、方法。
- 請求項18記載の方法において、前記アンタゴニスト抗体は、イピリムマブ、ニボルマブ、ペムブロリズマブ、デュルバルマブ、アテゾリズマブ、トレメリムマブ、またはアベルマブである、方法。
- 請求項1〜19のいずれか1つに記載の方法において、前記方法は、さらに、1またはそれ以上のエピジェネティック調節化合物を投与する工程を有する、方法。
- 請求項20記載の方法において、前記エピジェネティック調節化合物は、ボリノスタット、ロミデプシン、デシタビン、5−アザシチジン、パノビノスタット、および/またはベリノスタットのうちの1つまたはそれ以上である、方法。
- 請求項1〜21のいずれか1つに記載の方法において、前記化合物は小分子化学化合物である、方法。
- 請求項1〜22のいずれか1つに記載の方法において、前記個体は哺乳類である、方法。
- 請求項23記載の方法において、前記哺乳類はヒトである、方法。
- それを必要とする個体に免疫応答を発生させる方法であって、ノンストップ変異を有するmRNAのナンセンス変異依存分解機構(NMD)を阻害する一定量の化合物を前記個体に投与する工程を有し、前記量は前記mRNAのタンパク質への翻訳をもたらすために十分であり、前記化合物は抑制性核酸ではない、方法。
- 異常細胞の表面で1またはそれ以上のネオアンチゲンの発現を誘導する方法であって、ノンストップ変異を有するmRNAのナンセンス変異依存分解機構(NMD)を阻害する化合物を前記細胞に接触させる工程を有し、前記mRNAのNMDの阻害は、前記mRNAのタンパク質への翻訳及び前記細胞の表面での1またはそれ以上のネオアンチゲンの発現をもたらし、前記化合物は抑制性核酸ではない、方法。
- 請求項25または請求項26記載の方法において、前記化合物は小分子化学化合物、抗体、または非抗体結合ポリペプチドである、方法。
- 請求項76〜78のいずれか1つに記載の方法において、ナンセンス変異依存分解機構(NMD)を阻害する前記化合物は、UPF3A、UPF3B、UPF1、UPF2、UPF3、eIF4AIII、MLN51、Y14/MAGOHヘテロダイマー、SMG−1、SMG−5、SMG−6、および/またはSMG−7ポリペプチドの機能を阻害する、方法。
- 請求項25〜28のいずれか1つに記載の方法において、前記フレームシフト変異をもつmRNAから翻訳されたタンパク質は非機能性である、方法。
- 請求項25または27〜29のいずれか1つに記載の方法において、前記免疫応答は、免疫細胞による前記mRNAの翻訳から処理されたタンパク質の認識によって媒介される、方法。
- 請求項30記載の方法において、前記免疫細胞はT細胞またはB細胞である、方法。
- 請求項30記載の方法において、前記免疫応答はクラスIまたはクラスII主要組織適合複合体(MHC)分子によって媒介される、方法。
- 請求項25または27〜29のいずれか1つに記載の方法において、前記免疫応答はT細胞によって媒介される、方法。
- 請求項25または27〜29のいずれか1つに記載の方法において、前記免疫応答はB細胞によって媒介される、方法。
- 請求項31または請求項33に記載の方法において、前記T細胞は、γδT細胞、αβT細胞、またはナチュラルキラーT細胞である、方法。
- 請求項25または27〜29のいずれか1つに記載の方法において、前記免疫応答は炎症反応である、方法。
- 請求項25〜36のいずれか1つに記載の方法において、前記mRNAは増殖細胞において発現される、方法。
- 請求項25〜37のいずれか1つに記載の方法において、前記増殖細胞または異常細胞は癌細胞である、方法。
- 請求項38記載の方法において、前記癌は、結腸癌、乳癌、膵癌、卵巣癌、前立腺癌、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、滑液腫瘍、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、扁平上皮細胞癌、基底細胞癌、腺癌、汗腺癌、脂腺癌、乳頭癌、乳頭腺癌、嚢胞腺癌、髄様癌、気管支原性肺癌、腎細胞癌、肝癌、胆管癌、絨毛癌、精上皮腫、胚性癌腫、ウィルムス腫瘍、子宮頚癌、精巣腫瘍、肺癌、小細胞肺癌、膀胱癌、上皮癌、神経膠腫、星細胞腫、髄芽腫、メルケル細胞癌、頭蓋咽頭腫、脳室上衣細胞腫、松果体腫、血管芽細胞腫、聴神経腫、乏突起細胞腫、髄膜腫、黒色腫、神経芽細胞腫、網膜芽細胞腫;白血病、例えば、急性リンパ性白血病および急性骨髄性白血病、慢性白血病;真性赤血球増加症、リンパ腫、多発性骨髄腫、ルデンシュトレーム型マクログロブリン血症、および重鎖病から成る群から選択される、方法。
- 請求項25〜39のいずれか1つに記載の方法において、前記方法は、さらに、1またはそれ以上の免疫チェックポイント分子を阻害する化合物を投与する工程を有する、方法。
- 請求項40記載の方法において、前記免疫チェックポイント分子は、CTLA4、PD−L1、PD−1、A2AR、B7−H3、B7−H4、またはTIM3のうちの1つまたはそれ以上である、方法。
- 請求項41記載の方法において、1またはそれ以上の免疫チェックポイント分子を阻害する前記化合物がアンタゴニスト抗体である、方法。
- 請求項42記載の方法において、前記アンタゴニスト抗体は、イピリムマブ、ニボルマブ、ペムブロリズマブ、デュルバルマブ、アテゾリズマブ、トレメリムマブ、またはアベルマブである、方法。
- 請求項25〜43のいずれか1つに記載の方法において、前記方法は、さらに、1またはそれ以上のエピジェネティック調節化合物を投与する工程を有する、方法。
- 請求項44記載の方法において、前記エピジェネティック調節化合物は、ボリノスタット、ロミデプシン、デシタビン、5−アザシチジン、パノビノスタット、および/またはベリノスタットのうちの1つまたはそれ以上である、方法。
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EP3405587A1 (en) | 2018-11-28 |
CA3048204A1 (en) | 2017-06-29 |
US10898483B2 (en) | 2021-01-26 |
WO2017112956A1 (en) | 2017-06-29 |
US20190083489A1 (en) | 2019-03-21 |
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