JP2019516711A - 癌を処置するためのリルゾール、リルゾールプロドラッグまたはリルゾール類似体と免疫療法との併用 - Google Patents
癌を処置するためのリルゾール、リルゾールプロドラッグまたはリルゾール類似体と免疫療法との併用 Download PDFInfo
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Abstract
Description
本願は、2016年5月20日に出願された米国仮出願番号第62/339,433号の利益を主張する。
本発明は、腫瘍学的疾患または癌を処置するために免疫治療剤の治療効果を増強するためのリルゾール、リルゾールの類似体、リルゾールのプロドラッグおよび他の関連リルゾール化合物の使用に関する。
以下の詳細な説明は、当業者が本発明を実施するのを助けるために提供される。当業者は、本開示の趣旨または範囲から逸脱せずに、本明細書に記載の実施態様に改変および変更を加えることができる。別段の定義がない限り、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、本開示が属する技術分野の当業者によって一般に理解されるのと同じ意味を有する。本明細書で使用される用語は、特定の実施態様を説明するためだけのものであって、限定することを意図するものではない。本明細書に記載の全ての刊行物、特許出願、特許、図面および他の参考文献は、明示的に出典明示によりその全体として本明細書の一部を構成する。
を有する。
GL261−Luc細胞は、5%COおよび5%O2に維持した湿式インキュベーター(Gibco)において、ダルベッコ変法イーグル培地(DMEM)+10%ウシ胎仔血清+1%ペニシリンストレプトマイシン中にて37℃で増殖させる。
4〜6週齢または6〜8週齢の雌性C57BL/6Jマウス(Harlan)を、Sonabend AM, Velicu S, Ulasov IV, et al. A safety and efficacy study of local delivery of インターロイキン12 transgene by PPC polymer in a model of experimental glioma. Anticancer Drugs. 2008;19:133-142に記載の同所性神経膠腫実験に使用する。同系神経膠腫を確立するために、130,000個のGL261−Luc細胞を1分間にわたって左線条体に1μLの体積で定位的に以下の座標に注射する:前方1mm、ブレグマから側方1mm、および皮質表面から深さ3mm。移植から7日目、21日目および35日目にルシフェラーゼイメージングにより腫瘍負荷をモニターし、各群の平均腫瘍放射輝度がほぼ同等になるようにマウスを腫瘍放射輝度に基づいて無作為に処置アームに割り当てる。動物が予め決定された神経脱落の兆候(歩行不能(failure to ambulate)、体重減少>20%体重、嗜眠、猫背の姿勢)を示した時に、該動物を安楽死させる。腫瘍の発生率は100%である。生存実験において、各アームは、マウス6〜10匹を有する。全ての実験は少なくとも3回繰り返される。
ハムスター抗マウスPD−1モノクローナル抗体産生ハイブリドーマG4は、Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65:1089-1096に記載されているように抗体を産生するために使用される。
4〜6週齢の雌性C57BL/6Jマウスの左線条体に各々130,000個のGL261細胞を頭蓋内移植した。マウスは、Johns Hopkins University Animal FacilityのInstitutional Animal Care and Use Committeeプロトコルに従って収容および維持した。腫瘍負荷を評価するために7日目、21日目および35日目にマウスを生物発光IVIS(登録商標)イメージング(Perkin Elmer)によって画像化し、以下のように、1アーム当たり10匹のマウスの群に無作為に割り当てた:
1. 対照
2. 抗PD−1
3. トリグリルゾール15mg/kg
4. トリグリルゾール30mg/kg
5. トリグリルゾール45mg/kg
6. 抗PD−1+トリグリルゾール15mg/kg
7. 抗PD−1+トリグリルゾール30mg/kg
8. 抗PD−1+トリグリルゾール45mg/kg
Claims (13)
- 癌の処置方法であって、該処置を必要とする対象体に有効量のリルゾールおよびチェックポイント阻害剤からなる併用療法を投与することによる、方法。
- リルゾールおよびチェックポイント阻害剤が、同時にまたは逐次的に投与される、請求項1記載の方法。
- チェックポイント阻害剤が、PD−1、PD−L1またはCTLA−4を標的とする、請求項1記載の方法。
- チェックポイント阻害剤が、ニボルマブ、ペンブロリズマブ、ピディリズマブ、イピリムマブ、PDR001、MEDI0680、アテゾリズマブ、デュルバルマブおよび「それらの組み合わせからなる群から選択される、請求項1記載の方法。
- リルゾールが、リルゾールの類似体もしくはプロドラッグ、またはその薬学的に許容される塩、溶媒和物、アノマー、エナンチオマーもしくは水和物の形態である、請求項1記載の方法。
- リルゾールおよびチェックポイント阻害剤の組合せが、他の抗癌標準治療療法と併せてまたは逐次的に投与される、請求項1記載の方法。
- 組合せが、リルゾールおよび抗PD1または抗PD−L1であり、処置される癌が神経膠芽腫である、請求項1記載の方法。
- 組合せが、リルゾールおよび抗PD1または抗PD−L1であり、処置される癌が黒色腫である、請求項1記載の方法。
- プロドラッグが、下記式:
- リルゾールおよびチェックポイント阻害剤が、少なくとも2.0の60日目のマウス生存比(MSR60)を提供する能力を有する、請求項1記載の方法。
- リルゾールおよびチェックポイント阻害剤が、少なくとも2.0の60日目のマウス生存比(MSR60)を提供する能力を有する、請求項4記載の方法。
- リルゾールのプロドラッグおよびチェックポイント阻害剤が、少なくとも2.0の60日目のマウス生存比(MSR60)を提供する能力を有する、請求項5記載の方法。
- リルゾールのプロドラッグおよびチェックポイント阻害剤が、少なくとも2.0の60日目のマウス生存比(MSR60)を提供する能力を有する、請求項9記載の方法。
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