JP2022159552A - iNOS阻害組成物および乳がん治療薬としてのその使用 - Google Patents
iNOS阻害組成物および乳がん治療薬としてのその使用 Download PDFInfo
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Abstract
Description
関連出願への相互参照
この出願は、2014年4月8日に出願された米国仮特許出願第61/976,956号(係属中;代理人管理番号37182.170)に対する優先権を主張する;この内容は、それへの参照を表現することによってその全体が本明細書に具体的に援用される。
本発明は、国立衛生研究所(National Institutes of Health)によって授与された助成金R01-CA138197の下、政府の支援により為された。政府は、本発明に一定の権利を有する。
適用なし。
本発明は、全般的に、医学および腫瘍学の分野に関する。特に、本発明は、ヒトのがんの1種または複数の症状の処置および/または寛解のための改善された化学療法組成物を提供する。実例的な実施形態において、iNOS経路の1種または複数のエフェクターの投与を用いる、ヒトの乳がんを処置するための方法が提供される。例示的な実施形態において、例えば、単独で、またはカルシウムチャネルアンタゴニストを含む1種もしくは複数の降圧剤と組み合わせたNG-モノメチル-L-アルギニン(L-NMMA;C9H2ON4O4;MW248.28)を含むiNOS阻害剤の製剤が、哺乳動物の乳がんの処置のため、特に、従来の化学療法薬に対し抵抗性である疾患の難治性形態であり、その予後が不良である、ヒトにおけるトリプルネガティブ乳がん(TNBC)の処置のための治療用製剤として提供される。
トリプルネガティブ乳がん(TNBC)は、承認された標的化治療選択肢がない、エストロゲン(ERα)、プロゲステロン(PR)およびヒト上皮増殖因子(HER-2)受容体を欠く侵襲性かつ致死的形態のがんである。多数の進歩にもかかわらず、処置抵抗性および転移は、TNBC患者における主な死亡原因である。従来の処置に対する抵抗性および転移の発生は、腫瘍惹起能力を有する細胞の亜集団から生じ得る。化学療法後の残留腫瘍は、自己再生能力および間葉系特色を呈するCD44+/CD24-/low細胞が濃縮されている。これらのがん幹細胞(CSC)は、腫瘍成長の再惹起および転移播種に役立ち得る。よって、従来の化学療法および抗CSC化合物によるコンビナトリアル処置が、腫瘍負荷、再発および遠隔臓器への転移の低下に必要とされるであろう。残念ながら、かかる組み合わせは、診療所における日常的な使用に現在利用できない。
高血圧は、乳がんの女性における病的状態を増強する最も一般的な障害の1種である(Sarfatiら、2013年;Gampenriederら、2014年)。化学療法誘導性の高血圧症は、転移性およびTNBCにおける患者死亡率を増加させる共通効果である(Cameronら、2013年;Fanら、2014年)。よって、化学療法投与の有害な高血圧性副作用に対抗することができる1種または複数の降圧薬の同時投与は、患者の健康を改善し、生存を増加させるための重要な考察を表す。
本明細書に記す通り、本発明のiNOS阻害性化学療法製剤は、単一のがん処置モダリティとして用いることができる、あるいは、1種または複数のタンパク質、ペプチド、ポリペプチド(酵素、抗体、抗原、抗原結合性断片等を限定することなく含む);RNA分子(siRNA、iRNA、mRNA、tRNAおよびリボザイム等の触媒RNAその他を限定することなく含む)、DNA分子(オリゴヌクレオチド、ポリヌクレオチド、遺伝子、コード配列(CDS)、イントロン、エクソン、プラスミド、コスミド、ファージミド、バキュロウイルス、ベクター[ウイルスベクター、ビリオン、ウイルス粒子その他を限定することなく含む]を限定することなく含む);ペプチド核酸、検出剤、画像化剤、造影剤、検出可能ガス、放射性核種その他、および1種または複数の追加の化学療法剤、外科的介入(例えば、腫瘍切除)、放射線療法その他、または罹患患者のための多因子性もしくは多巣性処置プランの一部としてのこれらのいずれかの組み合わせを限定することなく含む、1種または複数の追加の化学療法薬、診断用試薬および/またはその他と組み合わせることができる。
本発明の別の重要な態様は、例えば、トリプルネガティブ乳がん等の処置抵抗性乳がんを含む乳がんの1種または複数の形態の症状を処置または寛解するための、開示されているiNOS阻害性化学療法製剤を使用するための方法に関係する。かかる方法は、一般に、罹患哺乳動物における乳がんの処置(あるいはその1種または複数の症状の寛解)に十分な量および時間で、開示されている抗がん組成物のうち1種または複数を哺乳動物(特に、それを必要とするヒト)に投与するステップを含む。
開示されているiNOS阻害製剤のうち1種または複数および特定のがん処置モダリティにおいてキットを使用するための説明書を含む治療用キットも、本発明の好ましい態様を表す。これらのキットは、1種もしくは複数の追加的な抗がん化合物、1種もしくは複数の診断用試薬または1種もしくは複数の追加的な治療用化合物、医薬品その他をさらに任意選択で含むことができる。
ある特定の実施形態において、本発明は、単独での、あるいは診断、予防および/または治療の1種または複数の他のモダリティと組み合わせた、動物の1個または複数の細胞または組織への送達のための薬学的に許容される製剤における1種または複数の化学療法および/または診断用化合物の製剤に関係する。種々の処置レジメンにおいて本明細書に記載されている特定の組成物を使用するための適した投薬および処置レジメンの開発と同様に、薬学的に許容される賦形剤および担体溶液の製剤は、当業者に周知である。
本明細書は、例えば、以下の項目を提供する。
(項目1)
1)化学療法において有効な量の第1のiNOS阻害剤と、
2)治療有効量の、以下:
a)第1の降圧剤、
b)第1の化学療法剤、または
c)a)およびb)の組み合わせと
を含む、医薬組成物。
(項目2)
前記第1のiNOS阻害剤が、NG-モノメチル-L-アルギニン[L-NMMA]、(N-[[3-(アミノメチル)フェニル]メチル]-エタンイミドアミド)[1400W]または(N5-[イミノ(ニトロアミノ)メチル]-L-オルニチンメチルエステル)[L-NAME]を含む、項目1に記載の医薬組成物。
(項目3)
前記第1の降圧剤が、第1のカルシウムチャネルアンタゴニストを含む、項目1または項目2に記載の医薬組成物。
(項目4)
前記第1の降圧剤が、アムロジピン、アラニジピン、アゼルニジピン、バルニジピン、ベニジピン、シルニジピン(clinidipine)、クレビジピン、ジルチアゼム、エホニジピン、フェンジリン、フェロジピン、ガロパミル、イスラジピン、ラシジピン、レルカニジピン、マニジピン、ニカルジピン、ニフェジピン、ニモジピン、ニソルジピン、ニトレンジピン、ニバルジピン、プラニジピンおよびベラパミルからなる群より選択される第1のカルシウムチャネルアンタゴニストを含む、前記項目のいずれかに記載の医薬組成物。
(項目5)
3)第2の別個のiNOS阻害剤をさらに含む、前記項目のいずれかに記載の医薬組成物。
(項目6)
d)免疫調節剤、神経活性剤、抗炎症剤、抗高脂血症剤、ホルモン、受容体アゴニスト、受容体アンタゴニスト、抗感染剤、タンパク質、ペプチド、抗体、抗原結合性断片、酵素、RNA、DNA、siRNA、mRNA、リボザイム、ホルモン、補助因子、ステロイド、アンチセンス分子、第2の別個の降圧剤、第2の別個の化学療法剤またはこれらのいずれかの組み合わせのうち1種または複数をさらに含む、前記項目のいずれかに記載の医薬組成物。
(項目7)
前記第1の化学療法剤が、1種もしくは複数の抗新生物性化合物、1種もしくは複数の細胞傷害性化合物、1種もしくは複数の細胞増殖抑制化合物またはこれらのいずれかの組み合わせを含む、前記項目のいずれかに記載の医薬組成物。
(項目8)
前記第1の化学療法剤が、シクロホスファミド、ドキソルビシン、5-フルオロウラシル、ドセタキセル、パクリタキセル、トラスツズマブ、メトトレキセート、エピルビシン、シスプラチン、カルボプラチン、ビノレルビン、カペシタビン、ゲムシタビン、ミトキサントロン、イクサベピロン(isabepilone)、エリブリン、ラパチニブ、カルムスチン、ナイトロジェンマスタード、サルファマスタード、プラチンテトラニトレート、ビンブラスチン、エトポシド、カンプトテシンおよびこれらのいずれかの組み合わせからなる群より選択される、前記項目のいずれかに記載の医薬組成物。
(項目9)
i)前記第1のiNOS阻害剤が、L-NMMAを含み、ii)前記第1の降圧剤が、アムロジピンを含む、または前記第1の化学療法剤が、ドセタキセルを含む、前記項目のいずれかに記載の医薬組成物。
(項目10)
i)前記第1のiNOS阻害剤が、L-NMMAを含み、ii)前記第1の降圧剤が、アムロジピンを含み、iii)前記第1の化学療法剤が、ドセタキセルを含む、前記項目のいずれかに記載の医薬組成物。
(項目11)
リポソーム、界面活性剤、ニオソーム、エトソーム、トランスフェロソーム、リン脂質、スフィンゴソーム、ナノ粒子、マイクロ粒子またはこれらのいずれかの組み合わせをさらに含む、前記項目のいずれかに記載の医薬組成物。
(項目12)
薬学的に許容される担体、バッファー、希釈剤、ビヒクル、賦形剤またはこれらのいずれかの組み合わせをさらに含む、前記項目のいずれかに記載の医薬組成物。
(項目13)
哺乳動物投与のため、好ましくは、ヒト投与のために製剤化されている、前記項目のいずれかに記載の医薬組成物。
(項目14)
前記組成物と、それを必要とするヒトへの前記組成物の投与のための少なくとも第1のセットの説明書とを含む治療用キットの一部として適合および構成されている、前記項目のいずれかに記載の医薬組成物。
(項目15)
哺乳動物のがんの1種または複数の症状の治療、予防または寛解における使用のための、前記項目のいずれかに記載の医薬組成物。
(項目16)
ヒトの乳がん、特に、ヒトの治療抵抗性、転移性またはトリプルネガティブ乳がんの1種または複数の症状の治療、予防または寛解における使用のための、前記項目のいずれかに記載の医薬組成物。
(項目17)
治療における使用のための、項目1~16のいずれか一項に記載の医薬組成物。
(項目18)
哺乳動物被験体におけるがんの処置における使用のための、項目1~16のいずれか一項に記載の医薬組成物。
(項目19)
哺乳動物におけるがんの1種または複数の症状を処置または寛解するための医薬の製造における、項目1~13のいずれか一項に記載の医薬組成物の使用。
(項目20)
ヒトの乳がん、特に、難治性、処置抵抗性、再燃性、転移性またはトリプルネガティブ乳がんを処置するための医薬の製造における、項目19に記載の使用。
(項目21)
処置または寛解を必要とする動物におけるがんの1種または複数の症状を処置または寛解する方法であって、前記動物における前記がんの前記1種または複数の症状の処置または寛解に十分な時間、有効量の項目1~16のいずれか一項に記載の医薬組成物を前記動物に投与するステップを含む、方法。
(項目22)
前記がんが、難治性、転移性、再燃性または処置抵抗性のがんとして診断されるか、あるいは同定される、項目21に記載の方法。
(項目23)
前記がんが、処置抵抗性または転移性のがん、特に、処置抵抗性、トリプルネガティブヒト乳がんとして診断されるか、あるいは同定される、項目21または項目22に記載の方法。
(項目24)
治療有効量の放射線を前記動物に投与するステップをさらに含む、項目21~23のいずれか一項に記載の方法。
(項目25)
前記医薬組成物が、単回投与で、あるいは1もしくは複数日間の期間にわたる、1もしくは複数週間の期間にわたる、または1もしくは複数箇月間またはそれより長い期間にわたる一連の複数回投与で、前記動物に全身的に投与される、項目19~24のいずれか一項に記載の方法。
(項目26)
前記医薬組成物が、項目1~16のいずれか一項に記載の第2の別個の化学療法剤または第2の別個のiNOS阻害剤をさらに含む、項目19~25のいずれか一項に記載の方法。
配列番号1は、本発明の一態様に従った使用のための、例示的なDNAオリゴヌクレオチドフォワードプライマーである。
本発明の実例的な実施形態を後述する。明確さのために、本明細書に実際の実施の全ての特色を記載している訳ではない。いずれかのかかる実際の実施形態の開発において、実施毎に変動するシステム関連およびビジネス関連の制約によるコンプライアンス等、開発者の特異的な目標を達成するための多数の実施特異的決定を為さなければならないことが当然ながら認められよう。さらに、かかる開発努力は、複雑かつ時間がかかり得るが、本開示の利益を有する当業者にとって日常的な試みであることが認められよう。
本発明の医薬品製剤は、ヒト患者への投与のために特に製剤化される、1種または複数の賦形剤、バッファーまたは希釈剤をさらに含むことができる。組成物は、1種または複数のマイクロスフェア、マイクロ粒子、ナノスフェアまたはナノ粒子をさらに任意選択で含むことができ、がん、特に乳がんのための処置を受けるヒトの1個または複数の細胞、組織、臓器または身体への投与のために製剤化することができる。
本発明の別の重要な態様は、脊椎動物の哺乳動物等、動物における様々な疾患、機能不全または欠乏の症状を処置または寛解するための医薬の調製において開示されている組成物(およびこれらを含む製剤)を使用するための方法に関係する。開示されている組成物の使用は、ヒトにおける1種または複数種類のがんの化学療法処置、特に、ヒトの女性におけるTNBCの処置において特に考慮される。
一酸化窒素(NO)は、濃度依存性腫瘍促進および抗腫瘍効果を有する、がん細胞および腫瘍内で多面的効果を示す生物活性分子である。NOは、3種の異なる一酸化窒素合成酵素(NOS)アイソフォームによって産生される:ニューロン性(nNOS/NOS1)、誘導性(iNOS/NOS2)および内皮(eNOS/NOS3)。iNOS発現の増加が、乳がんならびに肺、結腸、メラノーマおよび神経膠芽腫等の他の異なるがんにおいて見出された。以前の報告は、乳がん患者における高いiNOS発現、侵襲性および予後不良の間の相関を実証した。iNOS発現の増加は、最近、インターロイキン-8(IL-8)、CD44、c-Myc(7)の誘導による、また、部分的に転写因子Ets-1の活性化による、基底様(basal-like)エストロゲン受容体陰性乳がん患者における生存低下の予後因子として仮定された。本発明において、内在性iNOS発現の増強が、CSC自己再生特性および腫瘍細胞遊走のモジュレーションにより腫瘍再燃および転移を促進することにより、不十分な患者生存を駆動することが仮定された。従来の化学療法と組み合わせて、内在性iNOSの阻害が、残留TNBC細胞の侵襲性および間葉系特色および遠隔臓器への転移の数を低下させ、これにより、TNBC患者の生存を改善することがさらに仮定された。
アムロジピンは、血管平滑筋および心筋へのカルシウムイオンの膜貫通流入を阻害するジヒドロピリジンカルシウムアンタゴニストである。実験データは、アムロジピンが、ジヒドロピリジンおよび非ジヒドロピリジン結合部位の両方に結合することを示唆する。心筋および血管平滑筋の収縮過程は、特異的イオンチャネルを通ったこれらの細胞への細胞外カルシウムイオンの移動に依存する。アムロジピンは、選択的に細胞膜を横切るカルシウムイオン流入を阻害し、血管におけるより優れた効果が、治療用量でインタクトな動物において見られた。血清カルシウム濃度は、アムロジピンによって影響されない。生理的pH範囲内で、アムロジピンは、イオン化化合物(pKa=8.6)であり、それとカルシウムチャネル受容体との動態学的相互作用は、効果の漸進的な発生をもたらす、受容体結合部位との漸進的な会合および解離速度によって特徴付けられる。
本発明に従って、ポリヌクレオチド、核酸セグメント、核酸配列その他として、人の手によって全体的にまたは部分的に天然供給源から得られる、化学合成される、修飾される、または他の仕方で調製もしくは合成される、DNA(ゲノムまたはゲノム外DNAが挙げられ、これらに限定されない)、遺伝子、ペプチド核酸(PNA)、RNA(rRNA、mRNAおよびtRNAが挙げられるがこれらに限定されない)、ヌクレオシドおよび適した核酸セグメントが挙げられるがこれらに限定されない。
n~n+y(式中、nは、1から配列の最後の数までの整数であり、yは、プローブまたはプライマーの長さマイナス1であり、n+yは、配列の最後の数を超えない)。よって、25塩基対のプローブまたはプライマー(すなわち、「25-mer」)に関して、プローブまたはプライマーのコレクションは、配列の長さ全体にわたる、塩基1~25、塩基2~26、塩基3~27、塩基4~28等に対応する。同様に、35塩基対プローブまたはプライマー(すなわち、「35-mer」)に関して、例示的なプライマーまたはプローブ配列は、配列の長さ全体にわたる、塩基1~35、塩基2~36、塩基3~37、塩基4~38等に対応する配列を限定することなく含む。同様に、40-merに関して、かかるプローブまたはプライマーは、第1の塩基対~bp40、配列の第2のbp~bp41、第3のbp~bp42等のヌクレオチドに対応し得る一方、50-merに関して、かかるプローブまたはプライマーは、bp1~bp50、bp2~bp51、bp3~bp52、bp4~bp53等へと拡張するヌクレオチド配列に対応し得る。「処置すること」または「の処置」は、本明細書において、被験体へのいずれかの種類の医学的または外科的管理の提供を指す。処置することとして、被験体への治療剤を含む組成物の投与を挙げることができるがこれに限定されない。「処置すること」は、疾患、障害もしくは状態または疾患、障害もしくは状態の1種もしくは複数の症状もしくは症状発現の治癒、反転、軽減、その重症度の低下、その進行の阻害またはその見込みの低下等の目的のための、被験体への本発明の化合物または組成物のいずれかの投与または適用を含む。ある特定の態様において、本発明の組成物は、予防的に、すなわち、状態のいずれかの症状または症状発現の発症前に投与することもでき、かかる予防が保証されている。典型的には、このような場合、被験体は、その後にかかる疾患または障害を発症する傾向の指標となる、家族歴、診療記録または1種もしくは複数の診断もしくは予後検査の完了のいずれかの結果として、かかる疾患または障害を発症する「リスクがある」と診断された被験体であろう。
Basis of Therapeutics」第10版、Hardmanら編、2001年が挙げられるがこれに限定されない、いくつもの指示マニュアルを参照する。
TNBCに対する有効な標的化治療としてのiNOS阻害
XBP1-フォワード 5’-GGGTCCAAGTTGTCCAGAATGC-3’(配列番号1)
XBP1-リバース 5’-TTACGAGAGAAAACTCATGGC-3’(配列番号2)
β-アクチン-フォワード 5’-CTGGAACGGTGAAGGTGACA-3’(配列番号3)
β-アクチン-リバース 5’-AAGGGACTTCCTGTAACAATGCA-3’(配列番号4)であった。
PCR条件は、1サイクルの95℃5分間、25サイクルの30秒間95℃、1分間50℃および1分間68℃、続いて1サイクルの68℃5分間であった。2%アガロースにおいてcDNAアンプリコンを分離した。
カルシウムチャネルアンタゴニストの効果
材料と方法
Claims (1)
- 図面に記載の発明。
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EP3684375A4 (en) * | 2017-09-22 | 2021-09-22 | John Mansell | COMPOSITIONS AND METHODS OF TREATMENT OF SEPSIS-RELATED DISORDERS |
WO2019108920A1 (en) * | 2017-12-01 | 2019-06-06 | Soricimed Biopharma Inc. | Trpv6 inhibitors and combination therapies for treating cancers |
KR102217010B1 (ko) * | 2018-01-26 | 2021-02-18 | 재단법인 대구경북첨단의료산업진흥재단 | 칼슘 채널 억제제 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
KR102212699B1 (ko) | 2019-08-12 | 2021-02-05 | 한국원자력의학원 | 유방암 예방 또는 치료용 조성물 |
CN113897357A (zh) * | 2020-07-06 | 2022-01-07 | 北京大学 | Twist1基因编辑系统及其在制备治疗三阴性乳腺癌的产品中的应用 |
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US11357850B2 (en) | 2022-06-14 |
AU2015243537B2 (en) | 2020-10-22 |
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