JP2021509669A - 免疫療法を強化するためのベータ−カテニン及びidoの発現の低減 - Google Patents
免疫療法を強化するためのベータ−カテニン及びidoの発現の低減 Download PDFInfo
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Abstract
Description
本出願は、2018年1月5日に出願された米国仮特許出願第62/614,206号の優先権を主張する。本段落で参照される各関連出願の全内容は、参照することにより全体として本明細書に組み込まれる。
本出願は、ASCII形式にて電子出願され、その全体が参照することにより本明細書に組み込まれる配列表を含む。2018年12月18日に作成された当該ASCIIコピーの名称は0243_0028−PCT_SL.txtであり、サイズは2キロバイトである。
治療有効量のβ−カテニン核酸阻害剤分子であって、該β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに該センス鎖及びアンチセンス鎖間の18〜34ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、該センス鎖が19〜36ヌクレオチド長であり、該アンチセンス鎖が、18〜38ヌクレオチド長であり、その3’末端に一本鎖の1〜5ヌクレオチドを含むもの、
治療有効量のIDO阻害剤であって、該IDO阻害剤が、エパカドスタット、インドキシモド、BMS−986205、NLG802、HTI−1090、ナボキシモド、PF−06840003、IOM2983、RG−70099、フェニルベンゼンスルホニルヒドラジド、β−(3−ベンゾフラニル)−アラニン、β−[3−ベンゾ(b)チエニル]−アラニン、または6−ニトロ−D−トリプトファンを含むもの、及び
治療有効量の免疫療法薬であって、該免疫療法薬が、抗CTLA−4モノクローナル抗体、抗PD−1モノクローナル抗体、抗PD−L1モノクローナル抗体、または抗CTLA−4モノクローナル抗体と抗PD−1モノクローナル抗体の組み合わせであるもの。1つの実施形態では、該IDO阻害剤は、エパカドスタットを含む。ある特定の実施形態では、該がんは、Wnt活性化がんである。ある特定の実施形態では、該がんは、IDO1を過剰発現するWnt活性化がんである。
本開示をより容易に理解するため、ある特定の用語を最初に以下に定義する。以下の用語及び他の用語のさらなる定義は、本明細書を通して記載され得る。以下に記載される用語の定義が、参照することにより組み込まれる出願または特許における定義と矛盾する場合、本出願に記載の定義を使用して該用語の意味を理解されたい。
a)4’−CH2−O−N(R)−2’及び4’−CH2−N(R)−O−2’、ここで、Rは、H、C1−C12アルキル、または、例えば、4’−CH2−NH−O−2’(別名BNANC)、4’−CH2−N(CH3)−O−2’(別名BNANC[NMe])を含めた保護基(参照することにより全体として本明細書に組み込まれる米国特許第7,427,672号に記載の通り)、
b)4’−CH2−2’、4’−(CH2)2−2’、4’−(CH2)3−2’、4’−(CH2)−O−2’(別名LNA)、4’−(CH2)−S−2’、4’−(CH2)2−O−2’(別名ENA)、4’−CH(CH3)−O−2’(別名cEt)、及び4’−CH(CH2OCH3)−O−2’(別名cMOE)、ならびにそれらのアナログ(参照することにより全体として本明細書に組み込まれる米国特許第7,399,845号に記載の通り)、
c)4’−C(CH3)(CH3)−O−2’及びそのアナログ(参照することにより全体として本明細書に組み込まれる米国特許第8,278,283号に記載の通り)、
d)4’−CH2−N(OCH3)−2’及びそのアナログ(参照することにより全体として本明細書に組み込まれる米国特許第8,278,425号に記載の通り)、
e)4’−CH2−O−N(CH3)−2’及びそのアナログ(参照することにより全体として本明細書に組み込まれる米国特許公開第2004/0171570号に記載の通り)、
f)4’−CH2−C(H)(CH3)−2’及びそのアナログ(参照することにより全体として本明細書に組み込まれるChattopadhyaya et al.,J.Org.Chem.,2009, 74, 118−34に記載の通り)、ならびに
g)4’−CH2−C(=CH2)−2’及びそのアナログ(参照することにより全体として本明細書に組み込まれる米国特許第8,278,426号に記載の通り)が挙げられるがこれらに限定されない。
Claims (53)
- 対象におけるがんの治療方法であって、前記対象に対して、
治療有効量のβ−カテニン核酸阻害剤分子、
治療有効量のインドールアミン2,3−ジオキシゲナーゼ(「IDO」)阻害剤、及び
治療有効量の免疫療法薬を投与することを含む、前記方法。 - がんの治療用のβ−カテニン核酸阻害剤分子を含む医薬組成物であって、免疫療法薬及びIDO阻害剤と組み合わせて投与される、前記組成物。
- 前記対象がヒトである、請求項1に記載の方法。
- 前記がんが、Wnt活性化がんである、先行請求項のいずれか1項に記載の方法または組成物。
- 前記がんがIDO1を過剰発現する、請求項4に記載の方法または組成物。
- 前記IDO阻害剤が、エパカドスタット、インドキシモド、BMS−986205、NLG802、HTI−1090、ナボキシモド、PF−06840003、IOM2983、RG−70099、フェニルベンゼンスルホニルヒドラジド、β−(3−ベンゾフラニル)−アラニン、β−[3−ベンゾ(b)チエニル]−アラニン、または6−ニトロ−D−トリプトファンを含む、先行請求項のいずれか1項に記載の方法または組成物。
- 前記IDO阻害剤がエパカドスタットである、先行請求項のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、二本鎖RNAi阻害剤分子である、先行請求項のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の約15〜45ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子である、先行請求項のいずれか1項に記載の方法または組成物。
- 請求項9に記載の方法または組成物であって、
a)前記センス鎖が、15〜45、18〜26、もしくは19〜21ヌクレオチドであり、前記アンチセンス鎖が、15〜45、18〜26、もしくは19〜21ヌクレオチドであるか、
b)前記センス鎖が、15〜66ヌクレオチドであり、前記アンチセンス鎖が、15〜66ヌクレオチドであるか、
c)前記センス鎖が、25〜40ヌクレオチドもしくは19〜25ヌクレオチドであるか、
d)前記アンチセンス鎖が、25〜40ヌクレオチドもしくは19〜25ヌクレオチドであるか、
e)前記センス鎖が、19〜25ヌクレオチドであり、前記アンチセンス鎖が、19〜25ヌクレオチドであるか、
f)前記センス鎖が、26〜30もしくは34〜40ヌクレオチドであり、ステム及びテトラループを含み、前記アンチセンス鎖が、18〜24ヌクレオチドであり、前記センス鎖及びアンチセンス鎖が、18〜24ヌクレオチドの二本鎖領域を形成するか、または
g)前記センス鎖が、27〜29もしくは33〜39ヌクレオチドであり、ステム及びトリループを含み、前記アンチセンス鎖が、18〜24ヌクレオチドであり、前記センス鎖及びアンチセンス鎖が、18〜24ヌクレオチドの二本鎖領域を形成する、前記方法または組成物。 - 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の18〜34ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、前記センス鎖が25〜36ヌクレオチド長であり、前記アンチセンス鎖が、26〜38ヌクレオチド長であり、その3’末端に1〜5ヌクレオチドの一本鎖オーバーハングを含む、先行請求項のいずれか1項に記載の方法または組成物。
- 前記二本鎖RNAi阻害剤分子の前記アンチセンス鎖が、さらに、その5’末端に1〜10ヌクレオチドの一本鎖オーバーハングを含む、請求項11に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の20〜30、21〜26、19〜24、または19〜21ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子である、先行請求項のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の19ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、前記センス鎖が21ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含み、前記アンチセンス鎖が、21ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含む、先行請求項のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の21ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、前記センス鎖が21ヌクレオチド長であり、前記アンチセンス鎖が、23ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含む、先行請求項のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の26ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、前記センス鎖が26ヌクレオチド長であり、前記アンチセンス鎖が、38ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含み、その5’末端に10ヌクレオチドの一本鎖オーバーハングを含む、請求項のいずれか1項に記載の方法または組成物。
- 前記センス鎖が、配列番号1の配列を含むか、または配列番号1の配列からなる、請求項9〜13または16のいずれか1項に記載の方法または組成物。
- 前記アンチセンス鎖が、配列番号2の配列を含むか、または配列番号2の配列からなる、請求項9〜13、16、または17のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、テトラループまたはトリループを含む、先行請求項のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、従来のアンチセンスオリゴヌクレオチドであり、ヒトβ−カテニン遺伝子のセグメントの逆相補体を含む、12〜30、12〜25、12〜22、14〜20、または18〜22ヌクレオチド長のヌクレオチド配列を5’から3’の方向に有する、請求項1〜7のいずれか1項に記載の方法または組成物。
- 前記従来のアンチセンスオリゴヌクレオチドが、16〜18または18〜20ヌクレオチド長である、請求項20に記載の方法または組成物。
- 前記免疫療法薬が、抑制性免疫チェックポイント分子のアンタゴニストであるか、または、共刺激チェックポイント分子のアゴニストである、先行請求項のいずれか1項に記載の方法または組成物。
- 前記免疫療法薬が、抑制性チェックポイントのアンタゴニストであり、前記抑制性チェックポイントが、PD−1またはPD−L1である、請求項22に記載の方法または組成物。
- 前記抑制性免疫チェックポイント分子の前記アンタゴニストまたは前記共刺激チェックポイント分子の前記アゴニストが、モノクローナル抗体である、請求項22または23に記載の方法または組成物。
- 前記モノクローナル抗体が、抗CTLA−4モノクローナル抗体、抗PD−1モノクローナル抗体、抗PD−L1モノクローナル抗体、または抗CTLA−4モノクローナル抗体と抗PD−1モノクローナル抗体の組み合わせである、請求項24に記載の方法または組成物。
- ヒト対象におけるがんの治療方法であって、前記ヒト対象に対して、以下を投与することを含む、前記方法:
治療有効量のβ−カテニン核酸阻害剤分子であって、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の18〜34ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子である前記β−カテニン核酸阻害剤分子であり、前記センス鎖が19〜36ヌクレオチド長であり、前記アンチセンス鎖が、18〜38ヌクレオチド長であり、その3’末端に一本鎖の1〜5ヌクレオチドを含む、前記β−カテニン核酸阻害剤分子、
治療有効量のIDO阻害剤であって、エパカドスタット、インドキシモド、BMS−986205、NLG802、HTI−1090、ナボキシモド、PF−06840003、IOM2983、RG−70099、フェニルベンゼンスルホニルヒドラジド、β−(3−ベンゾフラニル)−アラニン、β−[3−ベンゾ(b)チエニル]−アラニン、または6−ニトロ−D−トリプトファンを含む前記IDO阻害剤、及び
治療有効量の免疫療法薬であって、抗CTLA−4モノクローナル抗体、抗PD−1モノクローナル抗体、抗PD−L1モノクローナル抗体、または抗CTLA−4モノクローナル抗体と抗PD−1モノクローナル抗体の組み合わせである、前記免疫療法薬。 - がんの治療用のβ−カテニン核酸阻害剤分子を含む医薬組成物であって、免疫療法薬及びIDO阻害剤と組み合わせて投与される前記組成物であり、
前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の18〜34ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、前記センス鎖が19〜36ヌクレオチド長であり、前記アンチセンス鎖が、18〜38ヌクレオチド長であり、その3’末端に一本鎖の1〜5ヌクレオチドを含み、
前記免疫療法薬が、抗CTLA−4モノクローナル抗体、抗PD−1モノクローナル抗体、抗PD−L1モノクローナル抗体、または抗CTLA−4モノクローナル抗体と抗PD−1モノクローナル抗体の組み合わせであり、
前記IDO阻害剤が、エパカドスタット、インドキシモド、BMS−986205、NLG802、HTI−1090、ナボキシモド、PF−06840003、IOM2983、RG−70099、フェニルベンゼンスルホニルヒドラジド、β−(3−ベンゾフラニル)−アラニン、β−[3−ベンゾ(b)チエニル]−アラニン、または6−ニトロ−D−トリプトファンを含む、前記組成物。 - 前記IDO阻害剤がエパカドスタットである、請求項26または27に記載の方法または組成物。
- 前記がんが、Wnt活性化腫瘍である、請求項26〜28のいずれか1項に記載の方法または組成物。
- 前記がんがIDO1を過剰発現する、請求項29に記載の方法または組成物。
- 前記センス鎖及び前記アンチセンス鎖間の相補性領域が21〜26ヌクレオチドであり、前記センス鎖が21〜26ヌクレオチド長であり、前記アンチセンス鎖が、23〜38ヌクレオチド長であり、その3’末端に1〜2ヌクレオチドの一本鎖オーバーハングを含む、請求項26〜30のいずれか1項に記載の方法または組成物。
- 前記アンチセンス鎖が、さらに、その5’末端に1〜10ヌクレオチドの一本鎖オーバーハングを含む、請求項31に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、センス鎖及びアンチセンス鎖ならびに前記センス鎖及び前記アンチセンス鎖間の26ヌクレオチドの相補性領域を含む二本鎖RNAi阻害剤分子であり、前記センス鎖が26ヌクレオチド長であり、前記アンチセンス鎖が、38ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含み、その5’末端に10ヌクレオチドの一本鎖オーバーハングを含む、請求項26〜30のいずれか1項に記載の方法または組成物。
- 前記センス鎖が、配列番号1の配列を含むか、または配列番号1の配列からなり、前記アンチセンス鎖が、配列番号2の配列を含むか、または配列番号2の配列からなる、請求項26〜30のいずれか1項に記載の方法または組成物。
- 請求項26〜30のいずれか1項に記載の方法であって、
a)前記センス鎖が、34〜36ヌクレオチドであり、ステム及びテトラループを含み、前記アンチセンス鎖が、18〜24ヌクレオチドであり、前記センス鎖及びアンチセンス鎖が、18〜24ヌクレオチドの二本鎖領域を形成するか、または
b)前記センス鎖が、33〜35ヌクレオチドであり、ステム及びトリループを含み、前記アンチセンス鎖が、18〜24ヌクレオチドであり、前記センス鎖及びアンチセンス鎖が、18〜24ヌクレオチドの二本鎖領域を形成する、前記方法。 - 前記センス鎖及び前記アンチセンス鎖間の前記相補性領域が19ヌクレオチドであり、前記センス鎖が21ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含み、前記アンチセンス鎖が、21ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含む、請求項26〜30のいずれか1項に記載の方法または組成物。
- 前記センス鎖及び前記アンチセンス鎖間の前記相補性領域が21ヌクレオチドであり、前記センス鎖が21ヌクレオチド長であり、前記アンチセンス鎖が、23ヌクレオチド長であり、その3’末端に2ヌクレオチドの一本鎖オーバーハングを含む、請求項26〜30のいずれか1項に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子が、脂質ナノ粒子とともに製剤化される、先行請求項のいずれか1項に記載の方法または組成物。
- 前記脂質ナノ粒子が、カチオン性脂質及びペグ化脂質を含む、請求項38に記載の方法または組成物。
- 前記β−カテニン核酸阻害剤分子、前記IDO阻害剤、及び前記免疫療法薬の投与が、前記対象のがんの量を低減する、先行請求項のいずれか1項に記載の方法。
- 前記対象が、前記投与ステップの前に、Wnt活性化がんを有する、及び/またはIDO1を過剰発現するがんを有すると特定されている、先行請求項のいずれか1項に記載の方法。
- さらに、前記投与ステップの前に、前記対象がWnt活性化がんを有するかどうか、またはIDO1を過剰発現するがんを有するかどうかを特定するため、前記対象の腫瘍サンプルを分析するステップを含む、先行請求項のいずれかに記載の方法。
- 前記Wnt活性化がんが、前記免疫療法薬が前記β−カテニン核酸阻害剤分子及び前記IDO阻害剤と組み合わせて投与されない場合に、前記免疫療法薬での治療に対して耐性を示す、先行請求項のいずれかに記載の方法または組成物。
- がんに対する免疫療法薬の治療効果を高める方法であって、前記がんを有する対象に対して、β−カテニン核酸阻害剤分子及びIDO阻害剤を、前記がんに対する前記免疫療法薬の治療効果を高めるのに十分な量で投与することを含む、前記方法。
- 前記がんが、Wnt活性化がんである、請求項44に記載の方法。
- 前記がんが、IDO1を過剰発現する、請求項45に記載の方法。
- 前記β−カテニン核酸阻害剤分子及び前記IDO阻害剤の投与の前は、前記がんは、免疫療法に対して耐性を示す非T細胞炎症性表現型と関連しており、前記β−カテニン核酸阻害剤分子及びIDO阻害剤の投与が、前記非T細胞炎症性表現型を、免疫療法薬に反応するT細胞炎症性表現型に変換する、請求項44〜46のいずれか1項に記載の方法。
- 前記IDO阻害剤が、エパカドスタット、インドキシモド、BMS−986205、NLG802、HTI−1090、ナボキシモド、PF−06840003、IOM2983、RG−70099、フェニルベンゼンスルホニルヒドラジド、β−(3−ベンゾフラニル)−アラニン、β−[3−ベンゾ(b)チエニル]−アラニン、または6−ニトロ−D−トリプトファンを含む、請求項44〜47のいずれか1項に記載の方法。
- 前記IDO阻害剤がエパカドスタットである、請求項48に記載の方法。
- 前記免疫療法薬が、抑制性免疫チェックポイント分子のアンタゴニストであるか、または、共刺激チェックポイント分子のアゴニストである、請求項44〜49のいずれか1項に記載の方法。
- 前記免疫療法薬が、抑制性チェックポイントのアンタゴニストであり、前記抑制性チェックポイントが、PD−1またはPD−L1である、請求項50に記載の方法または組成物。
- 前記抑制性免疫チェックポイント分子の前記アンタゴニストまたは前記共刺激チェックポイント分子の前記アゴニストが、モノクローナル抗体である、請求項50または51に記載の方法。
- 前記モノクローナル抗体が、抗CTLA−4モノクローナル抗体、抗PD−1モノクローナル抗体、抗PD−L1モノクローナル抗体、または抗CTLA−4モノクローナル抗体と抗PD−1モノクローナル抗体の組み合わせである、請求項52に記載の方法。
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WO2019136157A2 (en) | 2019-07-11 |
CA3084829A1 (en) | 2019-07-11 |
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