JP2019516733A - Notch阻害剤とPD−1またはPD−L1阻害剤との併用療法 - Google Patents
Notch阻害剤とPD−1またはPD−L1阻害剤との併用療法 Download PDFInfo
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Abstract
Description
医薬の製造のための、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブおよびアベルマブから選択される、PD−1またはPD−L1阻害剤の使用であって、
大腸がんを同時に、個別に、または逐次に治療するための、これらの使用を提供する。
in−vivo試験
in−vivo試験では、ハンクス平衡塩類溶液(HBSS)0.2mL中、1×106個のCT26細胞(ATCC(登録商標)CRL2639(商標))大腸がん細胞株を、6〜8週齢のBALB/C雌マウス(Harlan Laboratories)の後肢に、皮下注射によって移植する。マウスは、通常の固形飼料を適宜与えられる。1%カルボキシメチルセルロースナトリウム(Na−CMC)の0.25%Tween(登録商標)80溶液中に溶解した化合物Aの経口投与(胃管栄養)、またはリン酸緩衝生理食塩水(PBS)中のマウス抗PD−L1抗体(10F.9G2、Bio X Cell、カタログ#BE0101)の腹腔内注射もしくはPBS中のマウス抗PD−1(CD279)抗体(クローン:RMP1−14、Bio X Cell#BP0146−R)の腹腔内注射、または、これらそれぞれの媒体0.2mL量の投与により、腫瘍移植から6日目に治療を開始する。8mg/kgの化合物Aを月、水、金曜日のスケジュールで2週間投与し、250μg/回/動物の10F.9G2およびRMP−14を月、木曜日のスケジュールで2週間投与する。
1 1%CMC/0.25%Tween(登録商標)80/0.05%消泡剤、月−水−金×2、PO/PBS、月−木×2、IP
2 化合物A、8mg/kg、月−水−金×2、PO
3 化合物B(PD−L1)、250μg/回、月−木×2、IP
4 化合物C(PD−1)、250μg/回、月−木×2、IP
5 化合物A、8mg/kg、月−水−金−×2、PO/化合物B(PD−L1)、250μg/回、月−木×2、IP
6 化合物A、8mg/kg、月−水−金−×2、PO/化合物C(PD−1)、250μg/回、月−木×2、IP
前述の反復測定分析を用いて、試験20日目に相互作用効果を試験するのにCONTRASTステートメントを使用し、ここでは、2つの特定の治療(化合物AおよびPD−L1)を併用した。この試験は、p=0.008により統計学的に有意であり、併用群の推定平均腫瘍体積(298mm3)が、Bliss独立法による推定相加腫瘍体積(1134×1069/1448=837mm3)未満であるため、相加活性よりも優れ、または相乗活性を実証している。
機序分析では、20日目、化合物Aの最後の投与から1時間後にCT−26腫瘍を切除する。約30mgの小片を切り出し、遺伝子発現分析用にRNALater中に保存した。この腫瘍の残りは、フローサイトメトリー分析用に処理する。
腫瘍を秤量し、次いで4℃で5mLの完全培地(CM;RPMI−1640/10%ウシ胎仔血清(FBS))中で100μmストレーナに通してホモジナイズして、単一細胞の懸濁液を生成する。細胞を466×g、4℃で5分間遠心分離し、ペレットを新たなCM(ペレットの量に応じて0.5〜3mL)に再懸濁し、Vi−CellXR(Beckman Coulter)を使用して細胞を計数する。1腫瘍あたり等数の総細胞(10×106)を96ウェルでV字底のマイクロプレート(Fisher Scientific)に移す。細胞を遠心分離し(700×g、3分間、4℃)、CM中の100μL、1μg/mLのFc block(抗CD16/32(クローン2.4G2)、Tonbo Biosciences)に氷冷下で30分間再懸濁する。細胞を遠心分離し(700×g、3分間、4℃)、固定可能な生体染色色素(eBioscience)を含有する、100μLの蛍光色素結合表面マーカー抗体混合物のいくつかのうちの1つ[抗CD3(クローン145−2C11)、抗Ly−6G(クローン1A8)、抗CD11c(クローンHL3)、抗CD45(クローン30−F11)(BD Biosciences)、抗CD8(クローン53−6.7)(Biolegend)、抗CD11b(クローンM1/70)、抗CD3(クローン145−2C11)、抗F4/80(クローンBM8)、抗CD4(クローンRM4−5)(eBioscience)]に再懸濁し、氷冷下で遮光して30分間培養する。細胞を200μLのCMで2回洗浄し、遠心分離する(700×g、3分間、4℃)。2回目の洗浄後、細胞を固定し、透過処理し、記載された改変を有するメーカーの指示に従って、Foxp3/Transcription Factor Staining Buffer Set(eBioscience)を使用してKi67(クローンSolA15)(eBioscience)について細胞内染色する。簡潔に言えば、細胞を100μL/ウェルで30分間固定し、次いで、100μL/ウェルの透過処理バッファで、細胞内染色ありまたはなしで(使用する染色パネルに応じて)30分間固定する。細胞を200μL、1Xの透過処理バッファで2回洗浄し、遠心分離し(700×g、3分間、4℃)、次いで、2%のFBSを添加したPBSに再懸濁する。デブリを除く1×106のイベントを、各試料について、10チャンネルのLSR IIサイトメーター(BD Biosciences)を使用して収集し、FlowJo V.10.0.8ソフトウェアを使用して分析する。データは、腫瘍細胞に対するパーセントとして表されるが、記載された例外は母集団に対するパーセントとして表される。ANOVAによる事後t検定を媒体および治療群の間の統計分析に使用する。結果を表3にまとめる。
腫瘍からのRNAの単離では、約30mgの組織を切り出す。RNAをRNeasyプロトコル(2002年1月版)によって、RNeasy96ウェルカラムプレート(Qiagen、Valencia、CA;Cat#74182)およびQiaVac96真空マニホールドを15psiの真空で使用して抽出する。簡潔に言えば、2mLのLysing Matrix−D(登録商標)チューブ(MP Biomedicals、Solon、OH;Cat#6913−500、Lot#6913−500−120156)中、1%のβ−メルカプトエタノールを含有する800μLのバッファ−RLTで、FP120(Thermo Fisher Scientific、Waltham、MA;Cat#6001−120)またはFastPrep−24(MPBiomedicals;Cat#116003500)を使用して、2回の混合について速度6.0で各30秒、組織をホモジナイズする。チューブを毎分14,000回転(RPM)で30分間遠心分離にかける。400〜600μLの上清を取り出し、等量の70%エタノール(Decon Labs、King of Prussia、PA;Cat#2401)と混合し、96ウェルのRNeasyプレート上に移す。供給元のプロトコルに従ってDNase−I消化酵素(Qiagen、Cat#79254)をカラム上へ添加することにより、潜在的に混入しているDNAをすべて除去する。全RNAを、DNase/RNaseを含まない水の40μLアリコート2つに抽出する。全RNA濃度を、Nanodrop ND−1000分光光度計(Thermo Scientific)を使用して、260nMの吸光度により推定する。全RNAを、cDNA合成に必要とするまで−80℃で保存する。
Claims (8)
- 患者におけるT細胞急性リンパ芽球性白血病、急性リンパ芽球性白血病、慢性リンパ芽球性白血病、急性骨髄性白血病、慢性骨髄性白血病、赤白血病、トリプルネガティブ乳がん、乳がん、卵巣がん、黒色腫、肺がん、非小細胞肺がん、膵がん、膠芽腫、大腸がん、頭頸部がん、子宮頸がん、前立腺がん、肝がん、口腔扁平上皮癌、皮膚がん、髄芽腫、肝細胞癌、肝内および肝外胆管癌、類腱腫、軟部組織肉腫または腺様嚢胞癌である、がんを治療する方法であって、有効量の4,4,4−トリフルオロ−N−[(1S)−2−[[(7S)−5−(2−ヒドロキシエチル)−6−オキソ−7H−ピリド[2,3−d][3]ベンゾアゼピン−7−イル]アミノ]−1−メチル−2−オキソ−エチル]ブタンアミドまたはその薬学的に許容される塩もしくは水和物と、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブおよびアベルマブから選択される、有効量のPD−1またはPD−L1阻害剤とを、治療を必要とする患者に投与するステップを含む、方法。
- 前記がんが大腸がんである、請求項1に記載の方法。
- がんの治療を必要とする患者におけるT細胞急性リンパ芽球性白血病、急性リンパ芽球性白血病、慢性リンパ芽球性白血病、急性骨髄性白血病、慢性骨髄性白血病、赤白血病、トリプルネガティブ乳がん、乳がん、卵巣がん、黒色腫、肺がん、非小細胞肺がん、膵がん、膠芽腫、大腸がん、頭頸部がん、子宮頸がん、前立腺がん、肝がん、口腔扁平上皮癌、皮膚がん、髄芽腫、肝細胞癌、肝内および肝外胆管癌、類腱腫、軟部組織肉腫または腺様嚢胞癌である、がんを治療する方法であって、有効量の4,4,4−トリフルオロ−N−[(1S)−2−[[(7S)−5−(2−ヒドロキシエチル)−6−オキソ−7H−ピリド[2,3−d][3]ベンゾアゼピン−7−イル]アミノ]−1−メチル−2−オキソ−エチル]ブタンアミドまたはその薬学的に許容される塩もしくは水和物と、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブおよびアベルマブから選択される、有効量のPD−1またはPD−L1阻害剤とを同時に、個別に、または逐次に投与するステップを含む、方法。
- 前記がんが大腸がんである、請求項3に記載の方法。
- T細胞急性リンパ芽球性白血病、急性リンパ芽球性白血病、慢性リンパ芽球性白血病、急性骨髄性白血病、慢性骨髄性白血病、赤白血病、トリプルネガティブ乳がん、乳がん、卵巣がん、黒色腫、肺がん、非小細胞肺がん、膵がん、膠芽腫、大腸がん、頭頸部がん、子宮頸がん、前立腺がん、肝がん、口腔扁平上皮癌、皮膚がん、髄芽腫、肝細胞癌、肝内および肝外胆管癌、類腱腫、軟部組織肉腫または腺様嚢胞癌の治療に同時に、個別に、または逐次に使用するための、化合物、4,4,4−トリフルオロ−N−[(1S)−2−[[(7S)−5−(2−ヒドロキシエチル)−6−オキソ−7H−ピリド[2,3−d][3]ベンゾアゼピン−7−イル]アミノ]−1−メチル−2−オキソ−エチル]ブタンアミドまたはその薬学的に許容される塩もしくは水和物、ならびにペンブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブおよびアベルマブから選択される、PD−1またはPD−L1阻害剤。
- 前記がんが大腸がんである、請求項5に記載の使用。
- 医薬の製造のための、4,4,4−トリフルオロ−N−[(1S)−2−[[(7S)−5−(2−ヒドロキシエチル)−6−オキソ−7H−ピリド[2,3−d][3]ベンゾアゼピン−7−イル]アミノ]−1−メチル−2−オキソ−エチル]ブタンアミドまたはその薬学的に許容される塩もしくは水和物の使用、ならびに医薬の独立した製造のための、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、デュルバルマブおよびアベルマブから選択される、PD−1またはPD−L1阻害剤の使用であって、T細胞急性リンパ芽球性白血病、急性リンパ芽球性白血病、慢性リンパ芽球性白血病、急性骨髄性白血病、慢性骨髄性白血病、赤白血病、トリプルネガティブ乳がん、乳がん、卵巣がん、黒色腫、肺がん、非小細胞肺がん、膵がん、膠芽腫、大腸がん、頭頸部がん、子宮頸がん、前立腺がん、肝がん、口腔扁平上皮癌、皮膚がん、髄芽腫、肝細胞癌、肝内および肝外胆管癌、類腱腫、軟部組織肉腫または腺様嚢胞癌を同時に、個別に、または逐次に治療するための、これらの使用。
- 前記がんが大腸がんである、請求項7に記載の使用。
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JP7194022B2 (ja) | 2022-12-21 |
KR20190008913A (ko) | 2019-01-25 |
US20220008432A1 (en) | 2022-01-13 |
AU2017268187A1 (en) | 2018-11-29 |
WO2017200969A1 (en) | 2017-11-23 |
SG11201810268YA (en) | 2018-12-28 |
MA45025A (fr) | 2019-03-27 |
CN115845070A (zh) | 2023-03-28 |
IL263110B (en) | 2022-07-01 |
KR102463617B1 (ko) | 2022-11-03 |
CA3025024A1 (en) | 2017-11-23 |
IL263110A (en) | 2018-12-31 |
ES2904880T3 (es) | 2022-04-06 |
US20190192531A1 (en) | 2019-06-27 |
US10688104B2 (en) | 2020-06-23 |
EP3458091B1 (en) | 2021-11-17 |
CN109475629A (zh) | 2019-03-15 |
MX2018013941A (es) | 2019-03-21 |
EP3458091A1 (en) | 2019-03-27 |
US11826317B2 (en) | 2023-11-28 |
BR112018073673A2 (pt) | 2019-02-26 |
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