JP7013387B2 - Hdac阻害剤とpd-1阻害剤との組み合わせ療法 - Google Patents
Hdac阻害剤とpd-1阻害剤との組み合わせ療法 Download PDFInfo
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Description
本発明は、2016年5月11日に出願された米国仮特許出願第62/335,044号および2016年12月19日に出願された米国仮特許出願第62/436,361号の優先権を主張するものであり、これらは、全ての表、図、および特許請求の範囲を含めて、参照によりそれらの全体が本明細書に組み込まれる。
本発明は、HDACiおよびPD-1阻害剤の組み合わせ、ならびにがんの治療におけるこのような組み合わせの使用に関する。
がんは、世界的に罹患率および死亡率の重要な原因である。多くの異なるがん型の治療基準が長年にわたって大幅に改善されているが、現行の治療基準は、がんの治療を改善するための有効な治療の必要性を依然として満たしていない。細胞傷害性Tリンパ球関連タンパク質4(CTLA-4)、ならびにプログラム細胞死受容体-1(PD-1)およびそのリガンドPD-L1を標的とする免疫腫瘍剤の臨床使用は、多くのがん型の治療における治療基準にわたって改善をもたらしている。これらのチェックポイント阻害剤は、このようなある特定のがんにおいて改善された臨床応答を生成しているが、持続的な臨床応答は、約10~45%の患者においてのみ起こる。さらに、かなりの数の腫瘍は、耐性であるか、または不応性になる。ヒストンデアセチラーゼ阻害剤(HDACi)などのエピジェネティック修飾因子は、いくつかの血液悪性腫瘍の治療に成功しているが、固形腫瘍に対する活性を示す前臨床データにもかかわらず、この結果は単独療法として臨床には移行していない。したがって、当該技術分野において、例えば、がんの治療のための組み合わせ療法を含む、新しい療法が必要とされている。本明細書に提供されるものは、当該技術分野におけるこれらおよび他の問題に対する解決策である。
本明細書において、とりわけ、HDAC阻害剤(HDACi)およびPD-1阻害剤を含む組み合わせが提供される。この組み合わせには、式Iの化合物およびPD-1阻害剤が含まれる。場合によっては、PD-1阻害剤は、PD-1抗体である。
Aは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、C1-C4アルコキシカルボニル、フェニル、および複素環基からなる群から選択される1~4個の置換基で任意に置換される、フェニルまたは複素環基である。Bは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキルチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、C1-C4アルコキシカルボニル、およびフェニルからなる群から選択される1~3個の置換基で任意に置換される、フェニルである。Yは、直鎖である-CO-を含む部分であり、環Bの重心(W1)と、環Aの重心(W2)と、当該部分Yにおける水素結合受容体としての酸素原子(W3)との間の距離は、それぞれ、W1-W2=約6.0Å、W1-W3=約3.0Å~約6.0Å、およびW2-W3=約4.0Å~約8.0Åである。Zは、結合またはC1-C4アルキレン、-O-、-S-、-NH-、-CO-、-CS-、-SO-、または-SO2-である。R1およびR2は、独立して、水素またはC1-C4アルキルである。R3は、水素またはC1-C4アルキルである。R4は、水素または-NH2である。X1、X2、X3、またはX4のうちの1つは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキルチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、またはハロゲンまたはC1-C4アルキルで任意に置換されたC1-C4アルコキシカルボニルであるが、X1、X2、X3、またはX4の他のものは、独立して、水素であるが、ただし、R4が水素である場合に、X1、X2、X3、またはX4のうちの1つは、-NH2、アミノアルキル基、またはアルキルアミノ基である。
定義
全ての特許、出願、公開された出願、および他の刊行物は、その全体が参照により組み込まれる。他に定義されない限り、本明細書で使用される全ての技術用語および科学用語は、本発明が属する技術分野の当業者によって一般的に理解されるのと同じ意味を有する。本明細書に記載される化学構造および式は、化学技術において知られている化学原子価の標準規則に従って構築される。描写された構造とその構造に与えられた名前との間に相違がある場合、描写された構造はより重視されるべきである。構造または構造の一部の立体化学が、示された構造または図示された構造の一部に示されていない場合、示された構造は、その可能な立体異性体の全てを包含するものとして解釈されるべきである。
組成物
Aは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、C1-C4アルコキシカルボニル、フェニル、および複素環式基からなる群から選択される1~4個の置換基で任意に置換される、フェニルまたは複素環基であり、
Bは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキルチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、C1-C4アルコキシカルボニル、およびフェニルから選択される1~3個の置換基で任意に置換される、フェニルであり、
Yは、直鎖である-CO-を含む部分であり、環Bの重心(W1)と、環Aの重心(W2)と、当該部分Yにおける水素結合受容体としての酸素原子(W3)との間の距離は、それぞれ、W1-W2=約6.0Å、W1-W3=約3.0Å~約6.0Å、およびW2-W3=約4.0Å~約8.0Åであり、
Zは、結合またはC1-C4アルキレン、-O-、-S-、-NH-、-CO-、-CS-、-SO-、または-SO2-であり、
R1およびR2は、独立して、水素またはC1-C4アルキルであり、
R3は、水素またはC1-C4アルキルであり、
R4は、水素または-NH2であり、
X1、X2、X3またはX4のうちの1つは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキルチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、またはハロゲンもしくはC1-C4アルキルで任意に置換されるC1-C4アルコキシカルボニルであるが、X1、X2、X3、またはX4の他のものは、独立して、水素であり、
ただし、R4が水素である場合、X1、X2、X3、またはX4の1つは、-NH2、アミノアルキル基、またはアルキルアミノ基である。
本明細書に記載される組み合わせは、経口、粘膜(例えば、鼻、吸入、肺、舌下、膣、頬、または直腸)、非経口(例えば、皮下、静脈内、ボーラス注射、筋肉内、または動脈内)、局所(例えば、点眼剤または他の眼科用調製物)、患者への経皮または経皮投与が含まれるが、これらに限定されない、患者への本明細書に記載される任意の経路による投与に好適な薬学的組成物として提供され得る。
本明細書に記載される組み合わせおよび薬学的組成物は、キットの一部として提供することができる。そのようなキットは、例えば、患者のコンプライアンスを改善するか、または組み合わせを投与するための正確性または調製の容易性を改善することができる。キットは、式Iの化合物を含み、ここで、化合物は、本明細書に記載される製剤中に供給される。このキットはまた、本明細書に記載されるPD-1阻害剤も含む。このキットには、AMP-224が含まれ得る。いくつかの実施形態において、キットは、例えば、ニボルマブ、ペンブロリズマブ、ピジリズマブ、REGN2810(SAR-439684としても知られている)、PDR001、SHR-1210、またはMEDI0680などの本明細書に記載されるPD-1抗体を含む。キットは、本明細書に記載されるがん患者などの、それを必要とする患者への組み合わせの投与に有用な添付文書または他の情報(例えば、処方情報)を含むことができる。
本明細書に記載される組み合わせ、薬学的組成物、およびキットは、疾患、障害の治療、または例えばがんなどの疾患および障害の症状の緩和または除去に有用である。本明細書に記載される方法は、本明細書に記載される組み合わせおよび薬学的組成物の投与に関するものであり、そのような組み合わせおよび薬学的組成物は、本明細書に記載されるキットの形態で提供することができることを理解されたい。治療有効量の本明細書に記載される組み合わせを、それを必要とする患者に投与することによって、がんを治療する方法が本明細書に提供される。また、治療有効量の本明細書に記載される組み合わせを、それを必要とする患者に投与することによって、がんを管理する方法も本明細書に提供される。
Aは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、C1-C4アルコキシカルボニル、フェニル、および複素環式基からなる群から選択される1~4個の置換基で任意に置換される、フェニルまたは複素環基であり、
Bは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキルチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、C1-C4アルコキシカルボニル、およびフェニルから選択される1~3個の置換基で任意に置換される、フェニルであり、
Yは、直鎖である-CO-を含む部分であり、環Bの重心(W1)と、環Aの重心(W2)と、当該部分Yにおける水素結合受容体としての酸素原子(W3)との間の距離は、それぞれ、W1-W2=約6.0Å、W1-W3=約3.0Å~約6.0Å、およびW2-W3=約4.0Å~約8.0Åであり、
Zは、結合またはC1-C4アルキレン、-O-、-S-、-NH-、-CO-、-CS-、-SO-、または-SO2-であり、
R1およびR2は、独立して、水素またはC1-C4アルキルであり、
R3は、水素またはC1-C4アルキルであり、
R4は、水素または-NH2であり、
X1、X2、X3またはX4のうちの1つは、ハロゲン、-OH、-NH2、-NO2、-CN、-COOH、C1-C4アルキル、C1-C4アルコキシ、C1-C4アミノアルキル、C1-C4アルキルアミノ、C2-C4アシル、C2-C4アシルアミノ、C1-C4アルキルチオ、C1-C4ペルフルオロアルキル、C1-C4ペルフルオロアルキルオキシ、またはハロゲンもしくはC1-C4アルキルで任意に置換されるC1-C4アルコキシカルボニルであるが、X1、X2、X3、またはX4の他のものは、独立して、水素であり、
ただし、R4が水素である場合、X1、X2、X3、またはX4の1つは、-NH2、アミノアルキル基、またはアルキルアミノ基である。
t(9;22)(q34;q11.2)、BCR-ABL1を伴うBリンパ芽球性白血病/リンパ腫、
t(v;11q23)MLL再構成を伴うBリンパ芽球性白血病/リンパ腫、
t(12;21)(p13;q22)TEL-AML1(ETV6-RUNX1)を伴うBリンパ芽球性白血病/リンパ腫、
高2倍体性Bリンパ芽球性白血病/リンパ腫、
低2倍体性Bリンパ芽球性白血病/リンパ腫、
t(5;14)(q31;q32)IL3-IGHを伴うBリンパ芽球性白血病/リンパ腫、または
t(1;19)(q23;p13.3)TCF3-PBX1を伴うBリンパ芽球性白血病/リンパ腫。
染色体8と21との間の転座を伴うAML、
染色体16における転座または逆位を伴うAML、
染色体9と11との間の転座を伴うAML、
染色体15と17との間の転座を伴うAPL(M3)、
染色体6と9との間の転座を伴うAML、
染色体3における転座または逆位を伴うAML、または
染色体1と22との間の転座を伴うAML(巨核芽球)。
最小分化を伴うAML(M0)、
成熟を伴わないAML(M1)、
成熟を伴うAML(M2)、
急性骨髄単球性白血病(M4)、
急性単球性白血病(M5)、
急性赤血球性白血病(M6)、
急性巨核芽球性白血病(M7)、
急性好塩基球性白血病、または
線維症を伴う急性汎髄症。
ド;バリオリンB;ベラレソール;ベラミン;ベルテポルフィン;ビノレルビン;ビンキサルチン;ビタキシン;ビンブラスチン;硫酸ビンブラスチン;硫酸ビンクリスチン;ビンデシン;硫酸ビンデシン;硫酸ビネピジン;硫酸ビングリシネート;硫酸ビンロイロシン;酒石酸ビノレルビン;硫酸ビンロシジン;硫酸ビンゾリジン;ボロゾール;ウォルトマンニン;XL518;ザノテロン;ゼニプラチン;ジラスコルブ;ジノスタチンスチマラマー;ジノスタチン;塩酸ゾルビシンが含まれるが、これらに限定されない。
実施例1:
群1には、有効性対照の役割を果たし、ビヒクルを毎日13日間(1日1回×13)経口投与した。
群2には、50mg/kgでHBI-8000を1日1回13日間経口投与した。
群3には、5mg/kgで抗PD-1を週2回2週間(週2回×2)腹腔内投与した。
群4には、50mg/kgでHBI-8000を1日1回13日間経口投与し、5mg/kgで抗PD-1を週2回2週間腹腔内投与した。
本件出願は、以下の態様の発明を提供する。
(態様1)
治療有効量のPD-1阻害剤および治療有効量の式Iの化合物を含む組み合わせであって、
(化1)
式中、
Aは、ハロゲン、-OH、-NH 2 、-NO 2 、-CN、-COOH、C 1 -C 4 アルキル、C 1 -C 4 アルコキシ、C 1 -C 4 アミノアルキル、C 1 -C 4 アルキルアミノ、C 2 -C 4 アシル、C 2 -C 4 アシルアミノ、C 1 -C 4 アルキチオ、C 1 -C 4 ペルフルオロアルキル、C 1 -C 4 ペルフルオロアルキルオキシ、C 1 -C 4 アルコキシカルボニル、フェニル、および複素環式基からなる群から選択される1~4個の置換基で任意に置換される、フェニルまたは複素環式基であり、
Bは、ハロゲン、-OH、-NH 2 、-NO 2 、-CN、-COOH、C 1 -C 4 アルキル、C 1 -C 4 アルコキシ、C 1 -C 4 アミノアルキル、C 1 -C 4 アルキルアミノ、C 2 -C 4 アシル、C 2 -C 4 アシルアミノ、C 1 -C 4 アルキルチオ、C 1 -C 4 ペルフルオロアルキル、C 1 -C 4 ペルフルオロアルキルオキシ、C 1 -C 4 アルコキシカルボニル、およびフェニルから選択される1~3個の置換基で任意に置換される、フェニルであり、
Yは、直鎖である-CO-を含む部分であり、環Bの重心(W1)と、環Aの重心(W2)と、当該部分Yにおける水素結合受容体としての酸素原子(W3)との間の距離は、それぞれ、W1-W2=約6.0Å、W1-W3=約3.0Å~約6.0Å、およびW2-W3=約4.0Å~約8.0Åであり、
Zは、結合またはC 1 -C 4 アルキレン、-O-、-S-、-NH-、-CO-、-CS-、-SO-、または-SO 2 -であり、
R 1 およびR 2 は、独立して、水素またはC 1 -C 4 アルキルであり、
R 3 は、水素またはC 1 -C 4 アルキルであり、
R 4 は、水素または-NH 2 であり、
X 1 、X 2 、X 3 またはX 4 のうちの1つは、ハロゲン、-OH、-NH 2 、-NO 2 、-CN、-COOH、C 1 -C 4 アルキル、C 1 -C 4 アルコキシ、C 1 -C 4 アミノアルキル、C 1 -C 4 アルキルアミノ、C 2 -C 4 アシル、C 2 -C 4 アシルアミノ、C 1 -C 4 アルキルチオ、C 1 -C 4 ペルフルオロアルキル、C 1 -C 4 ペルフルオロアルキルオキシ、またはハロゲンもしくはC 1 -C 4 アルキルで任意に置換されるC 1 -C 4 アルコキシカルボニルであるが、X 1 、X 2 、X 3 、またはX 4 の他のものは、独立して、水素であり、
ただし、R 4 が水素である場合、X 1 、X 2 、X 3 、またはX 4 の1つは、-NH 2 、アミノアルキル基、またはアルキルアミノ基である、組み合わせ。
(態様2)
Zは結合である、態様1に記載の組み合わせ。
(態様3)
R 3 は水素である、態様1または2に記載の組み合わせ。
(態様4)
Aはピリジニルである、態様1~3のいずれか1項に記載の組み合わせ。
(態様5)
X 2 はハロゲンである、態様1~4のいずれか1項に記載の組み合わせ。
(態様6)
X 2 は-Fである、態様1~5のいずれか1項に記載の組み合わせ。
(態様7)
R 1 及びR 2 は、独立して、水素である、態様1~6のいずれか1項に記載の組み合わせ。
(態様8)
R 3 は水素である、態様1~7のいずれか1項に記載の組み合わせ。
(態様9)
R 4 は-NH 2 である、態様1~8のいずれか1項に記載の組み合わせ。
(態様10)
Yは-C(O)NH-CH 2 である、態様1~9のいずれか1項に記載の組み合わせ。
(態様11)
前記式Iの化合物が、以下の式を有する、態様1に記載の組み合わせ
(化2)
。
(態様12)
前記式Iの化合物は、N-(2-アミノ-4-フルオロフェニル)-4-[[[(2E)-1-オキソ-3-(3-ピリジニル)-2-プロペン-1-イル]アミノ]メチル]ベンズアミドである、態様1に記載の組み合わせ。
(態様13)
前記式Iの化合物は、約5mgを超える量で存在する、態様1~12のいずれか1項に記載の組み合わせ。
(態様14)
前記式Iの化合物は、約5~約50mgの量で存在する、態様1~12のいずれか1項に記載の組み合わせ。
(態様15)
前記PD-1阻害剤は、小分子化合物、核酸、ペプチド、タンパク質、抗体、ペプチボディ、ダイアボディ、ミニボディ、一本鎖可変断片(ScFv)、またはその断片もしくはバリアントである、態様1に記載の組み合わせ。
(態様16)
前記PD-1阻害剤は、AMP-224である、態様15に記載の組み合わせ。
(態様17)
前記PD-1阻害剤は、抗体である、態様15に記載の組み合わせ。
(態様18)
前記PD-1抗体は、モノクローナル抗体である、態様17に記載の組み合わせ。
(態様19)
前記PD-1抗体は、ヒト抗体、マウス抗体、キメラ抗体、ヒト化抗体、またはキメラヒト化抗体を含む、態様17に記載の組み合わせ。
(態様20)
前記PD-1抗体は、ヒト抗体またはヒト化抗体である、態様19に記載の組み合わせ。
(態様21)
前記PD-1抗体は、ニボルマブ、ペンブロリズマブ、ピジリズマブ、REGN2810(SAR-439684としても知られている)、PDR001、SHR-1210、またはMEDI0680を含む、態様15、18、または20のいずれか1項に記載の組み合わせ。
(態様22)
前記PD-1抗体は、約0.1mg/kg~約10mg/kgの量で存在する、態様15~21のいずれか1項に記載の組み合わせ。
(態様23)
前記PD-1抗体は、約0.5mg/kg~約5mg/kgの量で存在する、態様15~21のいずれか1項に記載の組み合わせ。
(態様24)
前記PD-1抗体は、約1mg/kg、2mg/kg、3mg/kg、または5mg/kgの量で存在する、態様15~21のいずれか1項に記載の組み合わせ。
(態様25)
前記組み合わせは、がん患者への投与に好適である、態様1~24のいずれか1項に記載の組み合わせ。
(態様26)
態様1~25のいずれか1項に記載の組み合わせと、薬学的に許容可能な賦形剤と、を含む、薬学的組成物。
(態様27)
態様1~25のいずれか1項に記載の組み合わせまたは態様26に記載の薬学的組成物を含む、キット。
(態様28)
前記組み合わせの前記式Iの化合物および前記PD-1阻害剤は、前記キット中の個々の容器に供給される、態様27に記載のキット。
(態様29)
前記組み合わせの前記式Iの化合物および前記PD-1阻害剤は、異なる製剤を含む、態様27または28に記載のキット。
(態様30)
前記組み合わせの前記式Iの化合物は、経口投与のために製剤化される、態様27~29のいずれか1項に記載のキット。
(態様31)
前記PD-1阻害剤前記組み合わせは、非経口投与のために製剤化される、態様27~30のいずれか1項に記載のキット。
(態様32)
前記非経口投与は、静脈内(IV)投与を含む、態様31に記載の方法。
(態様33)
少なくとも1つの投与デバイスをさらに含む、態様27~32のいずれか1項に記載のキット。
(態様34)
前記キット中の構成要素は、滅菌されている、態様27~33のいずれか1項に記載のキット。
(態様35)
がんを治療するための方法であって、治療有効量の態様1~25のいずれか1項に記載の組み合わせまたは態様26に記載の薬学的組成物を、それを必要とする患者に投与することを含む、方法。
(態様36)
前記がんは、扁平上皮癌、非扁平上皮癌、非小細胞肺癌(NSCLC)、小細胞肺癌、メラノーマ、肝細胞癌、腎細胞癌、卵巣癌、頭頸部癌、尿路上皮癌、乳癌、前立腺癌、膠芽細胞腫、結腸直腸癌、膵臓癌、リンパ腫、平滑筋肉腫、脂肪肉腫、滑膜肉腫、または悪性末梢鞘腫瘍(MPNST)からなる群から選択される固形腫瘍がんである、態様35に記載の方法。
(態様37)
前記がんは、非小細胞肺癌(NSCLC)、肝細胞癌、メラノーマ、卵巣癌、乳癌、膵臓癌、腎細胞癌、または結腸直腸癌である、態様0に記載の方法。
(態様38)
前記がんは、リンパ腫、非ホジキンリンパ腫(NHL)、ホジキンリンパ腫、リードステルベルグ病、多発性骨髄腫(MM)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)、または慢性リンパ性白血病(CLL)である、態様35に記載の方法。
(態様39)
前記がん患者は、治療未経験である、態様35~38のいずれか1項に記載の方法。
(態様40)
前記がん患者は、非小細胞肺癌(NSCLC)、肝細胞癌、メラノーマ、卵巣癌、乳癌、膵臓癌、腎細胞癌、または結腸直腸癌に対して治療未経験である、態様39に記載の方法。
(態様41)
前記組み合わせは、一次治療として前記がん患者に投与される、態様35~40のいずれか1項に記載の方法。
(態様42)
前記組み合わせは、二次、三次、四次、五次、または六次治療として前記がん患者に投与される、態様35~40のいずれか1項に記載の方法。
(態様43)
前記組み合わせは、少なくとも1つの抗癌治療による治療後に前記がん患者に投与される、態様35~38のいずれか1項に記載の方法。
(態様44)
前記抗癌治療は、化学療法、放射線療法、外科手術、標的療法、免疫療法、またはこれらの組み合わせを含む、態様43に記載の方法。
(態様45)
前記がんは、少なくとも1つの抗癌剤に耐性がある、態様35~44のいずれか1項に記載の方法。
(態様46)
前記組み合わせの前記式Iの化合物および前記PD-1阻害剤は、同時にまたは連続的に投与される、態様35~44のいずれか1項に記載の方法。
(態様47)
前記式Iの化合物は、1週間に2~3回投与される、態様35~46のいずれか1項に記載の方法。
(態様48)
前記式Iの化合物は、毎日投与される、態様35~46のいずれか1項に記載の方法。
(態様49)
PD-1阻害剤および前記式Iの化合物は、投与レジメンの1日目に併用投与される、態様35~47のいずれか1項に記載の方法。
(態様50)
前記PD-1阻害剤は、小分子化合物、核酸、ペプチド、タンパク質、抗体、ペプチボディ、ダイアボディ、ミニボディ、一本鎖可変断片(ScFv)、またはそのバリアントである、態様35~48に記載の組み合わせ。
(態様51)
前記PD-1阻害剤は、AMP-224である、態様50に記載の方法。
(態様52)
前記PD-1阻害剤は、PD-1抗体である、態様50に記載の方法。
(態様53)
前記PD-1抗体は、ニボルマブ、ペンブロリズマブ、ピジリズマブ、REGN2810(また、SAR-439684としても知られている)、PDR001、SHR-1210、またはMEDI0680を含む、態様51に記載の方法。
(態様54)
前記組み合わせは、レジメンとして前記患者に投与される、態様35に記載の方法。
(態様55)
前記レジメンは、疾患の進行または許容不可能な毒性まで繰り返される、態様54に記載の方法。
(態様56)
前記レジメンは、連続投与期間の間に少なくとも1日の休息期間を含む、態様54に記載の方法。
(態様57)
前記組み合わせの前記式Iの化合物は、前記レジメンにおいて1週間に2~3回投与され、前記PD-1抗体は、2~3週間毎に投与される、態様54に記載の方法。
(態様58)
前記組み合わせの前記式Iの化合物は、前記レジメンにおいて21日間1日1回投与され、前記PD-1抗体は、2~3週間毎に投与される、態様54に記載の方法。
(態様59)
前記がんを治療する方法は、前記患者の前記がんの転移を阻害する、態様35~57のいずれか1項に記載の方法。
(態様60)
前記がんを治療する方法は、前記患者の腫瘍または腫瘍負荷を減少させる、態様35~57のいずれか1項に記載の方法。
(態様61)
前記がんを治療する方法は、前記患者の前記がんの既存の転移を阻害する、態様35~57のいずれか1項に記載の方法。
(態様62)
前記がんを治療する方法は、前記患者の前記がんの疾患の進行までの時間を延長する、態様35~57のいずれか1項に記載の方法。
(態様63)
前記がんを治療する方法は、前記患者の生存を延長させる、態様35~57のいずれか1項に記載の方法。
(態様64)
前記がんを治療する方法は、前記患者の無増悪生存期間を増加させる、態様35~57のいずれか1項に記載の方法。
(態様65)
骨髄由来サプレッサー細胞(MDSC)のレベルの低下を必要とする患者におけるそのレベルを低下させるための方法であって、治療有効量の態様1~25のいずれか1項に記載の組み合わせまたは態様26に記載の薬学的組成物をそれを必要とする患者に投与することと、前記投与後のMDSCのレベルを判定することと、を含む、方法。
(態様66)
調節性T細胞(Treg細胞)のレベルの低下を必要とする患者におけるそのレベルを低下させる方法であって、治療有効量の態様1~25のいずれか1項に記載の組み合わせまたは態様26に記載の薬学的組成物をそれを必要とする患者に投与することと、前記投与後のTreg細胞のレベルを判定することと、を含む、方法。
(態様67)
がん患者におけるインビボでのナチュラルキラー(NK)の活性または細胞傷害性T細胞活性を増強するための方法であって、治療有効量の態様1~25のいずれか1項に記載の組み合わせまたは態様26に記載の薬学的組成物を、前記患者に投与することを含み、前記組み合わせは、前記組み合わせの非存在と比較して前記NKまたは細胞傷害性T細胞の活性を増加させる、方法。
(態様68)
がん患者における抗体依存性細胞媒介性細胞傷害性を増強するための方法であって、治療有効量の態様1~25のいずれか1項に記載の組み合わせまたは態様26に記載の薬学的組成物を、それを必要とする患者に投与することを含む、方法。
(態様69)
がんを治療するための方法であって、治療有効量の、ヒストンデアセチラーゼ阻害剤(HDAC阻害剤)およびPD-1阻害剤の組み合わせを、治療を必要とし、かつそのがんがPD-L1阻害剤でこれまでに治療されたことがある対象に投与することを含む、方法。
(態様70)
PD-L1阻害剤による治療後の前記がんは、部分的応答をもたらしたが、後に疾患の進行に伴ってPD-L1に対する耐性を生じる、態様69に記載の方法。
(態様71)
PD-L1阻害剤による治療後のがんは、安定した疾患をもたらしたが、後に疾患の進行に伴ってPD-L1に対する耐性を生じる、態様69に記載の方法。
(態様72)
PD-L1阻害剤による治療後のがんは、完全な応答をもたらしたが、後に疾患の進行に伴ってPD-L1に対する耐性を生じる、態様69に記載の方法。
(態様73)
PD-L1阻害剤による治療後のがんは、治療に応答しない、態様69に記載の方法。
(態様74)
前記PD-1阻害剤は、小分子化合物、核酸、ペプチド、タンパク質、抗体、ペプチボディ、ダイアボディ、ミニボディ、一本鎖可変断片(例えば、ScFv)、またはその断片もしくはバリアントである、態様69~73に記載の方法。
(態様75)
前記PD-1阻害剤は、抗体を含む、態様69~74に記載の方法。
(態様76)
前記抗体は、ニボルマブ、ペンブロリズマブ、ピジリズマブ、REGN2810(SAR-439684としても知られている)、PDR001、SHR-1210、またはMEDI0680のうちの1つ以上を含む、態様75に記載の方法。
(態様77)
前記HDAC阻害剤は、以下の式Iの化合物を含み、
(化3)
式中、
Aは、ハロゲン、-OH、-NH 2 、-NO 2 、-CN、-COOH、C 1 -C 4 アルキル、C 1 -C 4 アルコキシ、C 1 -C 4 アミノアルキル、C 1 -C 4 アルキルアミノ、C 2 -C 4 アシル、C 2 -C 4 アシルアミノ、C 1 -C 4 アルキチオ(alkythio)、C 1 -C 4 ペルフルオロアルキル、C 1 -C 4 ペルフルオロアルキルオキシ、C 1 -C 4 アルコキシカルボニル、フェニル、および複素環基からなる群から選択される1~4個の置換基で任意に置換される、フェニルまたは複素環式基であり、
Bは、ハロゲン、-OH、-NH 2 、-NO 2 、-CN、-COOH、C 1 -C 4 アルキル、C 1 -C 4 アルコキシ、C 1 -C 4 アミノアルキル、C 1 -C 4 アルキルアミノ、C 2 -C 4 アシル、C 2 -C 4 アシルアミノ、C 1 -C 4 アルキルチオ、C 1 -C 4 ペルフルオロアルキル、C 1 -C 4 ペルフルオロアルキルオキシ、C 1 -C 4 アルコキシカルボニル、およびフェニルからなる群から選択される1~3個の置換基で任意に置換される、フェニルであり、
Yは、直鎖である-CO-を含む部分であり、環Bの重心(W1)と、環Aの重心(W2)と、当該部分Yにおける水素結合受容体としての酸素原子(W3)との間の距離は、それぞれ、W1-W2=約6.0Å、W1-W3=約3.0Å~約6.0Å、およびW2-W3=約4.0Å~約8.0Åであり、
Zは、結合またはC 1 -C 4 アルキレン、-O-、-S-、-NH-、-CO-、-CS-、-SO-、または-SO 2 -であり、
R 1 およびR 2 は、独立して、水素またはC 1 -C 4 アルキルであり、
R 3 は、水素またはC 1 -C 4 アルキルであり、
R 4 は、水素または-NH 2 であり、
X 1 、X 2 、X 3 またはX 4 のうちの1つは、ハロゲン、-OH、-NH 2 、-NO 2 、-CN、-COOH、C 1 -C 4 アルキル、C 1 -C 4 アルコキシ、C 1 -C 4 アミノアルキル、C 1 -C 4 アルキルアミノ、C 2 -C 4 アシル、C 2 -C 4 アシルアミノ、C 1 -C 4 アルキルチオ、C 1 -C 4 ペルフルオロアルキル、C 1 -C 4 ペルフルオロアルキルオキシ、またはハロゲンもしくはC 1 -C 4 アルキルで任意に置換されるC 1 -C 4 アルコキシカルボニルであるが、X 1 、X 2 、X 3 、またはX 4 の他のものは、独立して、水素であり、
ただし、R 4 が水素である場合、X 1 、X 2 、X 3 、またはX 4 の1つは、-NH 2 、アミノアルキル基、またはアルキルアミノ基である、態様69~76に記載の方法。
(態様78)
前記HDAC阻害剤は、N-(2-アミノ-4-フルオロフェニル)-4-[[[(2E)-1-オキソ-3-(3-ピリジニル)-2-プロペン-1-イル]アミノ]メチル]ベンズアミドである、態様77に記載の方法。
(態様79)
前記HDAC阻害剤は、以下の式を有する、態様77に記載の方法
(化4)
。
(態様80)
前記HDAC阻害剤は、ボリノスタット、ロミデプシン、パノビノスタット、ベリノスタット、エンチノスタット、モセチノスタット、ジビノスタット、プラクチノスタット、キシノスタット、アベキシノスタット、chr-3996、およびAR-42からなる群のうちの1つ以上から選択される、態様69~76に記載の方法。
(態様81)
治療される前記がんは、前立腺、皮膚、卵巣癌;心臓、胎盤、骨格筋、および肺を含む非リンパ様実質性臓器の癌;乳癌;マントル細胞リンパ腫、非ホジキンB細胞リンパ腫、PTCL、腺腫、扁平上皮癌、喉頭癌、唾液腺癌、胸腺腫、および胸腺癌などの種々のリンパ腫を含む頭頸部癌;白血病;網膜の癌;食道の癌;多発性骨髄腫;メラノーマ;結腸直腸癌;肺癌;子宮頸癌;子宮内膜癌;胆嚢癌;肝臓癌;甲状腺濾胞癌;胃癌;非小細胞肺癌;神経膠腫;尿路上皮癌;膀胱癌;前立腺癌;腎細胞癌;浸潤性腺管癌;ならびに多形性膠芽腫のうちの1つ以上である、態様69~80に記載の方法。
(態様82)
対象における原発性腫瘍の転移を低減するための方法であって、前記治療が治療有効量の、ヒストンデアセチラーゼ阻害剤およびPD-1阻害剤の組み合わせを投与することを含む、方法。
(態様83)
対象における原発性腫瘍の転移を低減するための方法であって、前記治療が治療を必要とする前記対象に、治療有効量の態様1~26のいずれか1項に記載の組み合わせを投与することを含む、方法。
(態様84)
前記原発性腫瘍の前記治療が、放射線、外科手術、化学療法、免疫療法、標的療法、ホルモン療法、幹細胞移植、凍結療法、レーザー療法、および精密医療からなる群の1つ以上を含む、態様82または83に記載の方法。
(態様85)
前記組み合わせは、前記原発性腫瘍の治療前に、同時に、その後に、または3つ全ての組み合わせで投与される、態様84に記載の方法。
(態様86)
前記組み合わせの投与前に、前記HDAC阻害剤は、ある期間中単独で投与される、態様82~85のいずれか1項に記載の方法。
(態様87)
減少した転移が、副腎、脳、脊髄、骨、肺、肝臓、および/または胸膜、胃腸管、腹膜、筋肉、リンパ節、および皮膚のうちの1つ以上への転移である、態様82~86のいずれか1項に記載の方法。
(態様88)
前記原発性腫瘍は、乳房、肺、肝臓、膀胱、皮膚、脳、腸、結腸、腎臓、卵巣、膵臓、前立腺、胃、甲状腺、頭頸部、胃食道管、結合組織または他の非上皮性組織、骨髄性細胞、リンパ細胞、または子宮のがんである、態様82~87のいずれか1項に記載の方法。
(態様89)
前記原発性腫瘍は、進行性転移性乳癌である乳癌である、態様88に記載の方法。
(態様90)
前記乳癌は、三重陰性である、態様89に記載の方法。
(態様91)
治療は、E-セレクチン阻害剤、またはプレリキサホル、またはE-セレクチン阻害剤とプレリキサホルの組み合わせで前記対象を治療することをさらに含む、態様89または90に記載の方法。
(態様92)
前記E-セレクチン阻害剤、または前記プレリキサホル、またはE-セレクチン阻害剤とプレリキサホルの前記組み合わせは、前記HDACiおよびPD-1の組み合わせより前に、同時に、またはその後に、または3つ全ての組み合わせで与えられる、態様91に記載の方法。
(態様93)
治療は、αvインターグリン阻害剤、またはエタラシズマブ、インテツムマブ、もしくはアビツズマブを含む群からの抗体、またはαvインターグリン阻害剤と、エタラシズマブ、エタラシズマブ、インテツムマブ、もしくはアビツズマブを含む群からの抗体との組み合わせで前記対象を治療することをさらに含む、態様89または90に記載の方法。
(態様94)
前記αvインターグリン阻害剤、またはエタラシズマブ、エタラシズマブ、インテツムマブ、もしくはアビツズマブを含む群からの前記抗体、またはE-セレクチン阻害剤と、エタラシズマブ、エタラシズマブ、インテツムマブ、もしくはアビツズマブを含む群からの抗体の前記組み合わせは、HDACiおよびPD-1の組み合わせより前、同時に、またはその後に、または3つ全ての組み合わせで与えられる、態様93に記載の方法。
(態様95)
治療は、前記対象をマトリックスメタロプロテイナーゼ阻害剤で治療することをさらに含む、態様89または90に記載の方法。
(態様96)
前記マトリックスメタロプロテイナーゼ阻害剤は、HDACiおよびPD-1の組み合わせより前に、同時に、またはその後に、または3つ全ての組み合わせで与えられる、態様92に記載の方法。
(態様97)
前記HDAC阻害剤は、ボリノスタット、ロミデプシン、パノビノスタット、ベリノスタット、エンチノスタット、モセチノスタット、ジビノスタット、プラクチノスタット、キシノスタット、アベキシノスタット、chr-3996、およびAR-42を含む群のうちの1つ以上から選択される、態様82に記載の方法。
(態様98)
対象における原発性または二次性のがんを治療するための方法であって、前記治療により(i)がん細胞の数の減少、(ii)腫瘍体積の減少、(iii)腫瘍退行率の増加、(iv)末梢器官へのがん細胞の浸潤の減少または減速、(v)腫瘍転移の減少または減速、(vi)腫瘍増殖の減少または阻害、(vii)がんの発生および/もしくは再発の予防または遅延、ならびに/または疾患もしくは腫瘍がない生存期間の延長、(viii)全生存期間の増加、(ix)治療頻度の減少、(x)がん負荷の軽減、ならびに(XI)前記がんに関連する症状のうちの1つ以上の軽減、のうちの1つ以上の結果が生じ、前記治療が治療有効量の態様1~24のいずれか1項に記載の組み合わせを、治療を必要とする前記対象に投与することを含む、方法。
(態様99)
前記組み合わせは、前記原発性腫瘍の治療より前、同時に、その後に、または前記原発性腫瘍の治療より前、同時、およびその後の組み合わせで投与される、態様98に記載の方法。
(態様100)
前記原発性腫瘍の治療は、放射線、外科手術、化学療法、免疫療法、標的療法、ホルモン療法、幹細胞移植、凍結療法、レーザー療法、および精密医療からなる群のうちの1つ以上を含む、態様98に記載の方法。
(態様101)
前記組み合わせの投与前に、前記HDAC阻害剤は、単一の薬剤として一定期間投与される、態様98~100のいずれか1項に記載の方法。
(態様102)
前記原発性腫瘍は、乳房、肺、膀胱、皮膚、腸、結腸、腎臓、肝臓、脳、卵巣、膵臓、前立腺、胃、甲状腺、頭頸部、胃食道管、結合組織または他の非上皮性組織、骨髄性細胞、リンパ細胞、および子宮のがんである、態様98~101のいずれか1項に記載の方法。
Claims (14)
- 前記式Iの化合物が、約5mgを超える量で、又は約5mg~約50mgの量で存在する、請求項1に記載の薬学的組成物。
- 前記PD-1阻害剤が、小分子化合物、核酸、ペプチド、タンパク質、抗体、ペプチボディ、ダイアボディ、ミニボディ、一本鎖可変断片(ScFv)、もしくはその断片もしくはバリアント;AMP-224;抗体;モノクローナル抗体;ヒト抗体、マウス抗体、キメラ抗体、ヒト化抗体、もしくはキメラヒト化抗体、又はニボルマブ、ペンブロリズマブ、ピジリズマブ、REGN2810(SAR-439684としても知られている)、PDR001、SHR-1210、もしくはMEDI0680である、請求項1に記載の薬学的組成物。
- 前記PD-1阻害剤が、約0.1mg/kg~約10mg/kgの量;約0.5mg/kg~約5mg/kgの量;又は、約1mg/kg、約2mg/kg、約3mg/kg、もしくは約5mg/kgの量で存在する、請求項1に記載の薬学的組成物。
- 前記薬学的組成物が、がん患者への投与に好適である、請求項1~4のいずれか1項に記載の薬学的組成物。
- 請求項1~5のいずれか1項に記載の薬学的組成物を含む、キット。
- 前記式Iの化合物及び前記PD-1阻害剤が、前記キット中の個々の容器に供給され;
前記式Iの化合物及び前記PD-1阻害剤が、異なる製剤を含み;
前記式Iの化合物が、経口投与用に製剤化され;
前記PD-1阻害剤が、非経口投与、静脈内(IV)投与用に製剤化され;
前記キットが、少なくとも1つの投与デバイスをさらに含み;
ここで、前記キット中の構成要素が、滅菌されている、請求項6に記載のキット。 - 前記がんが、扁平上皮癌、非扁平上皮癌、非小細胞肺癌(NSCLC)、小細胞肺癌、メラノーマ、肝細胞癌、腎細胞癌、卵巣癌、頭頸部癌、尿路上皮癌、乳癌、前立腺癌、膠芽細胞腫、結腸直腸癌、膵臓癌、リンパ腫、平滑筋肉腫、脂肪肉腫、滑膜肉腫、もしくは悪性末梢鞘腫瘍(MPNST);非小細胞肺癌(NSCLC)、肝細胞癌、メラノーマ、卵巣癌、乳癌、膵臓癌、腎細胞癌、もしくは結腸直腸癌であるか;又は
前記がんが、リンパ腫、非ホジキンリンパ腫(NHL)、ホジキンリンパ腫、リードステルベルグ病、多発性骨髄腫(MM)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)、又は慢性リンパ性白血病(CLL)である、請求項5に記載の薬学的組成物。 - 前記がん患者が、非小細胞肺癌(NSCLC)、肝細胞癌、メラノーマ、卵巣癌、乳癌、膵臓癌、腎細胞癌、又は結腸直腸癌に対して治療未経験である、請求項5に記載の薬学的組成物。
- 前記薬学的組成物が、
前記化合物を前記PD-1阻害剤と組み合わせて、一次治療として前記がん患者に投与するように;又は
前記化合物を前記PD-1阻害剤と組み合わせて、二次、三次、四次、五次、又は六次治療として前記がん患者に投与するように;又は
前記化合物を前記PD-1阻害剤と組み合わせて、少なくとも1つの抗癌治療による治療後に前記がん患者に投与するように使用され;
ここで、該抗癌治療が、化学療法、放射線療法、外科手術、標的療法、免疫療法、又はこれらの組み合わせであり、かつ
前記がんが、少なくとも1つの抗癌剤に耐性があり;又は
前記化合物及び前記PD-1阻害剤が、同時に又は連続的に投与される、請求項1~5、8及び9のいずれか1項に記載の薬学的組成物。 - 前記化合物が、1週間に2~3回投与される;又は
前記化合物が、毎日投与される;又は
前記PD-1阻害剤及び前記化合物が、投与レジメンの1日目に併用投与される、請求項1~5及び8~10のいずれか1項に記載の薬学的組成物。 - 前記薬学的組成物が、前記化合物を前記PD-1阻害剤と組み合わせて、レジメンとして前記患者に投与するように使用され;
ここで、該レジメンが、疾患の進行又は許容不可能な毒性まで繰り返されるか;又は
該レジメンが、連続投与期間の間に少なくとも1日の休止期間を含むか;又は
前記化合物が、該レジメンにおいて1週間に2~3回投与され、かつ前記PD-1阻害剤が、2~3週間毎に投与されるか;又は
前記化合物が、前記レジメンにおいて21日間1日1回投与され、かつ前記PD-1阻害剤が、2~3週間毎に投与される、請求項11に記載の薬学的組成物。 - 前記がんの治療が、
前記患者の前記がんの転移を阻害する;
前記患者の腫瘍又は腫瘍負荷を減少させる;
前記患者における前記がんの既存の転移を阻害する;
前記患者の前記がんの疾患の進行までの時間を延長する;
前記患者の生存を延長させる;又は
前記患者の無増悪生存期間を増加させる、請求項1~5及び8~12のいずれか1項に記載の薬学的組成物。 - 前記薬学的組成物が、
(i)それを必要とする患者において骨髄由来サプレッサー細胞(MDSC)のレベルを低下させる;
(ii)それを必要とする患者において調節性T細胞(Treg細胞)のレベルを低下させる;
(iii)がん患者におけるインビボでのナチュラルキラー(NK)の活性又は細胞傷害性T細胞活性を増強する;又は
(iv)がん患者における抗体依存性細胞媒介性細胞傷害性を増強するためものであり;かつ
該薬学的組成物が、前記化合物をPD-1阻害剤と組み合わせて該患者に投与するように使用される、請求項5に記載の薬学的組成物。
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