JPWO2017078049A1 - ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 - Google Patents
ジアミノヘテロ環カルボキサミド化合物を有効成分とするがん免疫治療用、及び/又は、免疫活性化用医薬組成物 Download PDFInfo
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Abstract
Description
PD-1とPD-L1との結合を阻害する抗体としては、現在までに抗PD-1抗体であるニボルマブ(nivolumab)が悪性黒色腫、非小細胞肺癌の治療剤として、またペンブロリズマブ(pembrolizumab)が悪性黒色腫の治療薬として、それぞれ上市されており、その他いくつかの抗PD-1抗体又は抗PD-L1抗体についても、悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療薬として臨床開発が進められている。ニボルマブを悪性黒色腫に対する第1選択薬として用いた二重盲検の無作為化フェーズ3試験CheckMate-066において、ニボルマブ群の72.9%において全生存期間の延長を示すことが報告されたが、奏功しない患者の存在も認められている。
(17)PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて投与されることを特徴とする、(2)又は(13)の使用。
(18)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(17)の使用。
(19)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(17)又は(18)の使用。
(20)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(17)〜(19)の使用。
(21)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(17)〜(20)の使用。
(22)PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて併用投与されることを特徴とする、(3)又は(14)の使用。
(23)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(22)の使用。
(24)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(22)又は(23)の使用。
(25)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(22)〜(24)の使用。
(26)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(22)〜(25)の使用。
(27)PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて併用投与されることを特徴とする、(4)又は(15)の化合物又はその塩。
(28)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(27)の化合物又はその塩。
(29)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(27)又は(28)の化合物又はその塩。
(30)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(27)〜(29)の化合物又はその塩。
(31)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(27)〜(30)の化合物又はその塩。
(32)PD-1とPD-L1との結合を阻害するモノクローナル抗体の併用治療に用いる場合の治療有効用量、並びに化合物A又はその製薬学的に許容される塩を併用治療に用いる場合の治療有効用量とを組み合わせて、対象に投与することを特徴とするがん免疫治療方法。
(33)化合物A又はその製薬学的に許容される塩が化合物A ヘミフマル酸塩である(32)のがん免疫治療方法。
(34)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(32)又は(33)の治療方法。
(35)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(32)〜(34)の治療方法。
(36)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(32)〜(35)の治療方法。
(37)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(32)〜(36)の治療方法。
(38)化合物A又はその製薬学的に許容される塩を含有する免疫活性化によるがん治療剤。
(39)(38)の治療剤であって、PD-1とPD-L1との結合を阻害するモノクローナル抗体と併用されることを特徴とする剤。
(40)PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、(39)の剤。
(41)PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、(39)又は(40)の剤。
(42)PD-1とPD-L1との結合を阻害するモノクローナル抗体の投与を受けている対象におけるがんの治療用である(39)〜(41)の剤。
(43)悪性黒色腫、非小細胞肺癌、腎細胞癌、再発性膠芽腫、頭頚部癌、胃癌、食道癌、結腸直腸癌、膀胱癌、尿路上皮癌、肝細胞癌、前立腺癌、メルケル細胞癌、非ホジキンリンパ腫、ホジキンリンパ腫、B細胞リンパ腫、急性骨髄性白血病、又はC型慢性肝炎の治療用である(39)〜(42)の剤。
上述の通り、化合物Aの化学名は6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミドであり、その化学構造は以下に示すとおりである。
なお、「化合物A又はその製薬学的に許容される塩」のある態様としては、化合物Aが挙げられ、またある態様としては、化合物Aのフマル酸との酸付加塩が挙げられる。またある態様としては、化合物A ヘミフマル酸塩が挙げられる。
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
大腸癌細胞株MC38細胞(National Cancer Institute)を10% Fetal Bovine Serum(FBS)を添加したダルベッコ・フォークト変法イーグル最小必須培地(DMEM)にて培養した。その後、C57BL/6Jマウス(雌、日本チャ−ルスリバー)の背部にMC38細胞を皮下移植することでMC38皮下担癌マウスを作製した。腫瘍の生着を確認した後、0.5% メチルセルロースにて溶解した被験化合物である化合物A ヘミフマル酸塩をフリー体換算で30 mg/kgの用量で1日2回、17日間経口投与した群(COMPOUND A 30 mg/kg bid)、及び化合物A ヘミフマル酸塩をフリー体換算で60 mg/kgの用量で1日1回、17日間経口投与した群(COMPOUND A 60 mg/kg qd)、及び対照として化合物Aを投与していない群(control)について、それぞれの、腫瘍体積の変化を週2回の頻度で測定した。
C57BL/6Jマウス(雌、日本チャ−ルスリバー)の背部にMC38細胞を皮下移植することでMC38皮下担癌マウスを作製した。腫瘍の生着を確認した後、被験化合物である化合物A ヘミフマル酸塩をフリー体換算で100 mg/kgの用量で1日1回、7日間、7例のマウスそれぞれへ経口投与した。また対照として0.5% メチルセルロースも100 mg/kg投与と同様の用法で1日1回、7日間、7例のマウスそれぞれへ経口投与した。投与後4日目、7日目の腫瘍体積の変化を測定した後、対照群から抽出した3例(control-1、control-2及びcontrol-3)および化合物A投与群から抽出した3例(COMPOUND A 100mg/kg qd-1、同qd-2、及び同qd-3)の計6例のマウスから脾臓及び腫瘍を回収し、抗CD3抗体(eBioscience)、抗CD4抗体(Biolegend)、抗CD8抗体(eBioscience)、抗CD45抗体(Biolegend)にて染色を実施し、フローサイトメーター(BD FACSVerse)を用いて各抗原の陽性細胞の数を測定した。
本発明の被験化合物である化合物A ヘミフマル酸塩と抗PD-1抗体、又は被験化合物である化合物A ヘミフマル酸塩と抗PD-L1抗体との併用による効果は、マウス同系担癌モデルに投与した際の抗腫瘍作用と延命作用を評価することにより確認することができる。マウスの腫瘍由来の細胞としては、例えばCT26、A20、 J558、4T1、MC38が挙げられる。
Claims (10)
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩を有効成分として含有するがん免疫治療用医薬組成物。
- がん免疫治療用医薬組成物が、AXL及び/又はMERの発現により免疫逃避機構を獲得したがんに対するがん免疫治療用医薬組成物である、請求項1に記載の医薬組成物。
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩を有効成分として含有する、免疫活性化用医薬組成物。
- 免疫活性化用医薬組成物が、AXL及び/又はMERの発現により免疫逃避機構を獲得したがんに対する免疫活性化用医薬組成物である、請求項3に記載の医薬組成物。
- 免疫活性化が、CD8陽性細胞数の増加作用を介した免疫活性化である、請求項4に記載の医薬組成物。
- PD-1とPD-L1との結合を阻害するモノクローナル抗体と組み合わせて投与されることを特徴とする、請求項1乃至5に記載の医薬組成物。
- PD-1とPD-L1との結合を阻害するモノクローナル抗体が、ニボルマブ、ペンブロリズマブ、アテロリズマブ、ピディリズマブ、アヴェルマブ及びデュルバルマブから選択される抗体である、請求項6に記載の医薬組成物。
- PD-1とPD-L1との結合を阻害するモノクローナル抗体と同時に、別々に、連続して、或いは、間隔をあけて投与されることを特徴とする、請求項7に記載の医薬組成物。
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩、及び製薬学的に許容される賦形剤を含有する、請求項1乃至8に記載の医薬組成物。
- 6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩が、6-エチル-3-({3-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)-5-(テトラヒドロ-2H-ピラン-4-イルアミノ)ピラジン-2-カルボキサミド ヘミフマル酸塩である、請求項1乃至9に記載の医薬組成物。
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