JP7377679B2 - がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 - Google Patents
がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 Download PDFInfo
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Description
本出願は2019年6月24日に出願された米国仮特許出願第62/865,819号明細書、2019年年3月20日に出願された米国仮特許出願第62/821,376号明細書、及び2018年11月19日に出願された米国仮特許出願第62/769,355号明細書の優先権及び利益を主張し、これらの全ては、あらゆる目的のためにその全体が参照により本明細書に組み込まれる。
本願は、電子フォーマットの配列表と共に出願されている。配列表は、A-2326-US-NP_SeqList_102919_ST25.txt(2019年10月29日作成)という名称のファイルで提供されており、15.4kbのサイズである。電子フォーマットの配列表における情報は、その全体が参照により本明細書に組み込まれる。
a)2つのKRASG12C対立遺伝子が生成されるよう、2つのKRAS対立遺伝子両方のヌクレオチドの置換を誘発するCRISPR構築物とともに、2つのKRASG12D対立遺伝子を含む細胞株をインキュベートする工程;及び
b)2つのKRASG12C対立遺伝子を含む細胞株の単離工程、
を含む方法を含む。
a)2つのKRASG12C対立遺伝子が生成されるよう、2つのKRAS対立遺伝子両方のヌクレオチドの置換を誘発するCRISPR構築物とともに、2つのKRASG12D対立遺伝子を含む細胞株をインキュベートする工程;及び
b)2つのKRASG12C対立遺伝子を含む細胞株の単離工程を含む方法、
を含む。
A]処方、
B]販売及び販売目的の広告、
C]購入、
D]自己投与のための指導、又は
E]投与
を含む、がん治療のプロセスを含む(ただし、この併用薬は、がん治療を必要とする対象に対して、がん治療のために規制機関により認可されている)。
本開示は、細胞と、本明細書で開示される1種以上の化合物の有効量とを接触させることを含む、RAS媒介細胞シグナル伝達を阻害する方法を提供する。RAS媒介シグナル伝達の阻害は、当技術分野で周知の広範な種々の方法によって評価及び実証することができる。非限定的な例としては、(a)RASのGTPアーゼ活性の減少;(b)GTP結合親和性の減少又はGDP結合親和性の増加;(c)GTPのK offの増加又はGDPのK offの減少;(d)pMEK、pERK、又はpAKTレベルの減少などの、RAS経路の下流のシグナル伝達分子のレベルの減少;及び/又は(e)Rafを含むがこれに限定されない下流のシグナル伝達分子へのRAS複合体の結合の減少を示すことが挙げられる。上記の1つ以上を決定するために、キット及び市販のアッセイを利用することができる。
本開示はまた、他の経路を調節する、若しくは同じ経路の他の成分を調節することが知られている薬剤、又は重複する標的酵素のセットも、本開示の化合物、又はその薬学的に許容される塩と組み合わせて使用される併用治療の方法を提供する。1つの態様では、このような治療は、相乗的又は相加的な治療効果を提供するために、本開示の1つ以上の化合物と、化学療法薬、治療抗体、及び放射線治療との併用を含むが、これらに限定されない。
ブパルリシブとしても知られている、Novartis Pharmaceuticalsの治験用小分子である:
a)2つのKRASG12C対立遺伝子が生成されるよう、2つのKRAS対立遺伝子の両ヌクレオチドの置換を誘発するCRISPR構築物とともに、2つのKRASG12D対立遺伝子を含む細胞株をインキュベートする工程;及び
b)2つのKRASG12C対立遺伝子を含む細胞株の単離工程、
を含む方法を包含する。
・Illumina(Solexa)シーケンシング
・Roche 454シーケンシング
・Ion torrent:Proton/PGMシーケンシング
・SOLiD(商標)シーケンシング
を含む多くの異なる現代のシーケンシング技術を記述するために使用される、包括的な用語である。
腫瘍細胞を培養し、採取し、雌の無胸腺ヌードマウスの右の脇腹に皮下移植した。腫瘍が約200mm3に達したとき、マウスを治療群(n=10/群)に無作為化し、治療を開始した(グラフに示す日に)。腫瘍の大きさ及び体重は、週に2~3回測定した。腫瘍体積は、デジタルキャリパーによって測定し、L×W×Hとして計算し、mm3で表した。増殖曲線間で観察された差異の統計的有意性は、対数変換された腫瘍体積データの反復測定共分散分析(RMANOVA)によって評価し、ダネット調整多重比較を使用して、対照群を処置群と比較した。併用試験のために、RMANOVAを、各単剤治療群と1対1で比較した併用群で実施した。
リコンビナントHis標識ヒトKRASG12C/C118A(1-169)、GST-ヒトc-RAF(1-149)、及びHis標識ヒトKRASC118A(1-169)を大腸菌(Escherichia coli)内で発現させ、アフィニティークロマトグラフィー及びサイズ排除クロマトグラフィーを用いて精製した。リコンビナントHis標識ヒトSOS1(564-1049、昆虫コドン最適化)をトリコプルシア・ニ(Trichoplusia ni)内で発現させ、アフィニティークロマトグラフィーを用いて精製した;His標識を除去した後、サイズ排除クロマトグラフィーによってさらに精製した。Ostremら15の研究に基づき、共結晶化研究のためにシステインライト変異体構築物を使用した。リコンビナントHis標識ヒトKRASG12C/C51S/C80L/C118S(1-169)を大腸菌(E.coli)内で発現させ、アフィニティークロマトグラフィー、イオン交換クロマトグラフィー、及びサイズ排除クロマトグラフィーを用いて精製し、結晶化のためにHis標識を除去した。
ARS-1620、PD-0325901、トラメチニブ、アファチニブ、エルロチニブ、RMC-4550及びAZD5363は市販品を入手した。AMG511は自社で合成した。AMG510及びその非反応性プロピオンアミドの合成は、本明細書に記載されている。インビトロ実験に使用するAMG510及び他の全ての阻害剤のストックは、100%ジメチルスルホキシド(DMSO)の10mM溶液として調製した。インビボ研究用に、AMG510及びMEKi(PD-0325901)は、2%HPMC、1%Tween 80中に処方し、10mL/kgで毎日経口強制投与した。10mg/mLのカルボプラチンストック溶液を、1%PBS中で5mg/mL又は3mg/mLにさらに希釈し、週に1回腹腔内注射(IP)によって投与した。ラット抗マウスPD1クローン29F.1A12をキメラ化して、マウスIgG1バックボーンを含有させた。さらに、エフェクター機能を低下させるために、Fc受容体サイレンシング変異N297GをIgG重鎖領域に導入した。抗PD-1抗体、29F.1A12を1×PBS中で500μg/mLの濃度に希釈し、3日に1回、I.P.により合計3回の注射で投与した。ウェスタンブロッティングで使用した全ての抗体は、抗RAS(Abcam)、抗ホスホ-ERK1/2(ThermoFisher Scientific)、及び抗ベータ-アクチン-HRP(Sigma)を除いて、Cell Signalingから購入した。
National Cancer Instituteから入手したKM12及びNCI-H3122を除いて、すべての細胞株はAmerican Type Culture Collection(ATCC)から購入した。短いタンデム反復(STR)プロファイリングによって細胞株を認証した。インビボの増殖反応速度を改善するために、MIA PaCa-2 T2及びSW480-1AC細胞を、それぞれMIA PaCa-2及びSW480細胞をマウスに継代することによって作製した。CT-26 KRAS p.G12C細胞を、CRISPR技術を用いてマウスCT-26結腸直腸株から作製し、KRAS p.G12Dの両対立遺伝子をp.G12C(ThermoFisher Scientific)で置換した。クローンH10は、KRAS p.G12C対立遺伝子についてホモ接合と決定され、CT-26 KRASp.G12C-H10と同定され、CT-26 KRASp.G12Cと呼ばれる。全ての細胞株を、10%ウシ胎児血清及び1×ペニシリン/ストレプトマイシン/L-グルタミンで補強したRPMI1640培地により、37℃、5%CO2で、加湿インキュベーター中で培養した。
20mMのHEPES(pH7.5、150mM NaCl)中の精製無標識KRASG12C/C51S/C80L/C118S(「KRAS」)を40mg/mLに濃縮し、DMSOに溶解した2倍モル過剰の固体AMG510化合物に加えた。タンパク質-複合体試料を、RTで16時間、オービタルシェーカーに載せ、続いてスピン濾過した。共結晶化は、シッティングドロップ蒸気拡散法を用いて行った。「KRAS」-AMG510タンパク質-複合体試料及び結晶化緩衝液(1mM MgCl2、0.1M MES pH6.5、30%重量/体積のポリエチレングリコール4000)を混合した。20℃、1日で、扁平な棒状結晶が現れた。
KRASG12C/C118A又はKRASC118AのSOS1で触媒されたヌクレオチド交換活性の阻害を、Alpha(Amplified Luminescent Proximity Homogeneous Assay)技術を用いて測定した。反応緩衝液(25mMのHEPES、pH7.4;10mMのMgCl2;0.01%Triton X-100)中、室温(RT)で5分間、2倍連続希釈AMG510又はDMSOと共に、20nMのGDP結合ヒトKRASG12C/C118A又はKRASC118Aタンパク質をインキュベートした。その後の全ての工程で、1mMの最終濃度でDTTを反応緩衝液に加えた。次に、DTT反応緩衝液中に、1.25mM又は500nMの最終濃度でGTP及びSOS-1をそれぞれ加え、RTで30分間インキュベートした。最後に、c-RAF RBD(最終50nM)、αグルタチオンドナービーズ(PerkinElmer;最終20μg/mL)、及びAlphaLISA(登録商標)ニッケルキレートアクセプタービーズ(PerkinElmer;最終20μg/mL)(すべてDTT反応緩衝液で希釈した)を加えた。反応混合物をRTで5分間インキュベートし、その後、AlphaScreenプロトコルを使用して、EnVision(登録商標)Multilabel Readerでプレートを読み取った。680nmで180ms間励起した後、570nmで発光シグナルを測定した。シグナル強度はc-RAF RBDと、GTP結合KRASG12c/C118A又はKRASC118Aとの会合に対応し、DMSO対照に対して正規化した。
細胞アッセイ用に、ウェル当たり2.5E+04個の細胞を96ウェルプレートに播種し、37℃、5%CO2で終夜インキュベートした。翌日、3倍連続希釈化合物又はDMSOを細胞に加え、5%CO2、37℃でプレートを2時間インキュベートした。処理後、細胞を氷冷PBSで洗浄し、プロテアーゼ及びホスファターゼ阻害剤を含有するRIPA溶解緩衝液(50mMのTris-HCl、pH7.5;1%Igepal;0.5%デオキシコール酸ナトリウム;150mMのNaCl;0.1%ドデシル硫酸ナトリウム)中で溶解した。ホスホ-ERK1/2全細胞溶解キット(Meso Scale Discovery)を製造者のプロトコルに従って使用した処理細胞溶解物中で、基底ERK1/2リン酸化レベルを測定した。シグナル強度は、ホスホ-ERK1/2レベルに対応し、DMSO対照に対して正規化した。
接着生存アッセイ用に、ウェル当たり0.5~1.0E+03個の細胞を384ウェルプレート(又は96ウェルプレートにウェル当たり2.5~4.0E+04個の細胞)に播き、37℃、5%CO2で終夜インキュベートした。翌日、連続希釈化合物又はDMSOを細胞に加え、5%CO2、37℃でプレートを72時間インキュベートした。細胞生存率は、CellTiter-Glo(登録商標)Luminescent Cell Viability Assayキット(Promega)を製造者のプロトコルに従って使用して測定した。処理した試料の発光シグナルをDMSO対照に対して正規化した。
AMG510と他の阻害剤との相乗的相互作用をインビトロで評価するための併用実験を、以前に記載されているように実施した(Saiki,A.Y.et al.MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways.Oncotarget 5,2030-2043,doi:10.18632/oncotarget.1918(2014)).
共有結合阻害剤-KRASG12Cの付加物の形成を、先に記載したようにMSを用いて測定した44。Prism(GraphPad Software)を使用して、種々のインキュベーション時間における、種々の阻害剤濃度についての相対%結合値を指数方程式でフィッティングし、試験した各濃度についてのkobs値を生成した。次いで、得られたkobs値を阻害剤濃度に対して再プロットして、kinact及びKi値を生成した。
ヒト非小細胞肺がんNCI-H358細胞を2.0E+06細胞/10cmプレートで播種し、37℃、5%CO2で終夜インキュベートした。翌日、細胞を1μMのAMG 510又はDMSO(n=5)で処理し、37℃、5%CO2で4時間インキュベートした。処理後、プロテアーゼ阻害剤を含有する氷冷PBSで細胞を洗浄し、次いでプレートから取り出した。IQ Proteomics、LLCにおいて、Patricelliらによって記載された彼らのプロトコルに従って、質量分析(MS)によりスナップ凍結細胞ペレットを処理した。簡単に述べると、細胞ペレットを溶解し、100μMのデスチオビオチンヨードアセトアミドで処理して、溶媒に暴露されている残りの未反応のシステインを標識した。トリプシン消化後、各試料から生成されたペプチド混合物を、(商標)T-10plex(Tandem Mass Tag)同重核標識試薬(ThermoFisher Scientific)で標識した。標識後、試料を混合し、その後、高容量ストレプトアビジンアガロースを用いてデスチオビオチニル化ペプチドを濃縮した。濃縮されたペプチドを、Orbitrap Lumos質量分析計(ThermoFisher Scientific)で3時間グラジエント及び同期式前駆体選択(SPS)に基づくMS3法を使用して、ナノLC-MSによって分析した。SEQUESTを利用するHarvard Medical SchoolのGygi Labで開発された、カスタム情報パイプラインでデータベース検索を行うことにより、デスチオビオチニル化されたペプチドが同定された。変異体KRASG12Cタンパク質配列及び一般的な汚染物質を添付した、Human Uniprot(2018)タンパク質配列データベースで、すべてのスペクトルを検索した。ペプチド及びタンパク質を1%の偽発見率(FDR)にまで濾過し、最小シグナルノイズ比が200で、且つ単離純度が50%を超える基準を満たすペプチドのみを定量分析に使用した。統計分析のための全てのデータ処理は、システイン含有ペプチドの正規化ピークの存在量を用いてMicrosoft Excelにより行った。DMSO対照群とAMG510処理試料群との間に、log2-倍の変化が計算された。各ペプチドについて、等しい分散を仮定した両側t検定を行って、処理試料群とDMSO対照試料群との間の差の統計的有意性を評価した。各デスチオビオチニル化システイン含有ペプチドについて、負のlog10p-値を示すvolcano plotをlog2倍変化に対してプロットした。log2倍が2を超える存在量の減少及びp-値が0.0001未満を示すペプチドを、AMG510の共有結合標的として指定した(n=5のバイオロジカルレプリケート)。
すべての動物実験の手順は、Ammgen Animal Care and Use Committeeのガイドライン、及び実験動物ケア評価認証協会( Association for Assessment and Accreditation of Laboratory Animal Care)の標準に従って行った。全ての研究は、4~7週齢の雌無胸腺ヌード又は雌Balb/cマウス(Charles River Laboratories)を使用した。無胸腺ヌードマウスは、滅菌ハウジング中でフィルターキャップ付きケージ1個当たり5匹を飼い、Balb/cマウスは、12時間の明/暗周期で、環境制御された(温度23±2℃、相対湿度50±20%)部屋の非滅菌ハウジング中で、フィルターキャップ付きケージ1個当たり5匹を飼った。マウスには市販のげっ歯類の飼料を与えた。
RNeasy Miniキット(QIAGEN)により、ビヒクル経口、AMG510経口(100mg/kg QD)又はMEKi経口(PD-0325901、10mg/kg QD)で2日間治療(n=5/群)した、CT-26 KRAS p.G12C腫瘍からの全RNAを精製した。RNAは、DropSense 96(PerkinElmer Inc.)によって定量した。750個の標的遺伝子、20個のハウスキーピング遺伝子、8個の内部陰性対照、及び6個の内部陽性対照を含むマウス汎がん免疫プロファイリングパネルを用いて、300ngのRNAをnCounter(商標)(NanoString Technologies)により解析した。生データは、品質を整え、正規化し、nSolverソフトウェア(NanoString Technologies)により分析した。生データはlog2変換し、統計解析を行った。経路スコア(インターフェロンスコア、抗原処理スコア、MHCスコア、TLRスコア及びT細胞機能スコア)及び細胞プロファイリングスコア(NK細胞スコア、細胞毒性細胞スコア及びCD45スコア)を、nSolver Advanced Analysis(NanoString Technologies)によって生成した。
ERK1/2リン酸化に対するAMG510の影響を、MIA PaCa-2 T2、NCI-H358、及びCT-26 KRAS p.G12C腫瘍を有するマウスで評価した。MIA PaCa-2 T2又はNCI-H358腫瘍細胞(5.0E+06細胞)を、細胞対Matrigel(BD Bioscience、San Jose、CA)の2:1の比で雌無胸腺ヌードマウスの脇腹に皮下注射した。平均腫瘍サイズが約300~600mm3(n=3/群)に達したとき、マウスにビヒクル又はAMG510(0.3、1、3、10、30及び100mg/kg)のいずれかを単回経口投与し、2時間後に採取した。経時研究のために、単回経口用量(10mg/kg)のAMG510を使用した。雌Balb/cマウスは、CT-26 KRAS p.G12C腫瘍細胞(3.0E+05個の細胞)と共に皮下注射した。腫瘍体積が平均486mm3になった時点で、マウスを群(n=3/群)に無作為化し、ビヒクル又はAMG510(3、10、30、若しくは100mg/kg)、又はMEKi(PD-0325901、10mg/kg)のいずれかを単回経口投与し、2時間後に採取した。すべての試験で、血漿及び腫瘍を分析し、試験項目濃度を決定した。腫瘍試料は、また、示された時間に収集し、液体窒素中で急速冷凍し、生体分析のために処理するか、又はcryoPREP(登録商標)Dry Impactor(Covaris)を使用して粉砕した。粉砕した試料を、プロテアーゼ及びホスファターゼ阻害剤を含有するRIPA溶解緩衝液に再懸濁し、均質化した。その後、透明にした溶解物を、上記のようにしてERK1/2リン酸化レベルを分析し、またMSによりKRASG12Cの共有結合の改変を分析した。
MIA PaCa-2 T2、NCI-H358、又はSW480-1AC細胞(5.0E+06個の細胞、Matrigelと2:1の比で)を、雌の無胸腺ヌードマウス(n=10/群)の脇腹に皮下注射した。治療は、腫瘍が定着し、MIA PaCa-2 T2及びNCI-H358試験では約170mm3、SW480-1ACモデルでは約200mm3の時に開始した。用量応答試験では、マウスは、ビヒクル経口(QD)又はAMG510経口(3、10、30及び100mg/kg QD)のいずれかを受けた。AMG510及びカルボプラチンとのNCI-H358併用試験では、マウスを8群(n=10/群)に無作為化し、ビヒクル経口(QD)+PBS腹腔内(1×/週)、AMG510経口(10又は30mg/kg QD)+PBS腹腔内(1×/週)、ビヒクル経口(QD)+カルボプラチン(50又は100mg/kg)腹腔内(1×/週)、AMG510経口(10又は30mg/kg QD)+カルボプラチン(50又は100mg/kg)腹腔内(1×/週)のいずれかで投与した。AMG510とMEKiの併用試験では、マウスを4群n=10/群に無作為化し、ビヒクル経口(QD);AMG510経口(10mg/kg QD);MEKi経口(1mg/kg QD);AMG510経口(10mg/kg QD)+MEKi経口(1mg/kg QD)のいずれかで与えた。同系試験では、CT-26 KRAS p.G12C細胞(3.0E+05細胞)を、雌のBalb/cマウスの脇腹に皮下注射した。治療は、腫瘍が定着し、用量応答試験では約170mm3、併用試験では約130mm3の時にn=10/群で開始したが、MEKi用量応答試験ではn=8/群であった。用量応答試験では、マウスは、ビヒクル経口(QD)、AMG510経口(3、10、30及び100mg/kg QD)又はMEKi(PD-0325901)経口(1、3又は10mg/kg QD)のいずれかを受けた。併用試験では、マウスをn=10/群の4群に無作為化し、ビヒクル経口(QD)+PBS腹腔内(Q3D×3);AMG510経口(100mg/kg QD)+PBS腹腔内(Q3D×3);ビヒクル経口(QD)+抗PD-1抗体(29F.1A12;100μg/用量、Q3D×3)腹腔内;AMG510経口(100mg/kg QD)+抗PD-1抗体(29F.1A12;100μg/用量、Q3D×3)腹腔内のいずれかで15日目から43日目まで投与した。併用治療試験は盲検様式で実施した。Pro-Max電子デジタルキャリパー(Japan Micrometer Mfg.Co.LTD) を用いて、毎週2回腫瘍の大きさを評価し、長さ×幅×高さの式を用いて腫瘍体積を計算し、mm3として表した。KRAS p.G12C肺PDXモデルでは、約70mgの大きさの腫瘍塊をマウスの皮下に移植した。腫瘍体積が約160~200mm3になったとき、マウスを無作為化し、無作為化の翌日に、ビヒクル経口(QD)又はAMG510経口(100mg/kg QD)のいずれかを与えた。幅2×長さ×0.52の式を使用して、毎週2回腫瘍の大きさを収集し、mm3として表した。データは、平均±SEMとして表される。
抗ヒトRAS(抗RAS)抗体をAbcamから購入し、販売会社により記載されたプロトコルを用いて、EZ-Link NHS-PEG4-ビオチン(ThermoFisher Scientific)でビオチン化した。残留ビオチンを除去し、得られたビオチン-抗RASを、Dynabeads(登録商標)MyOne(商標)Streptavidin C1ビーズ(ThermoFisher Scientific)に、1:1の比で、RTで1時間、振盪しながら加えた。以前に記載した、インビトロで処理した細胞又はインビボで治療した腫瘍細胞の溶解物を、ビオチン化抗RASビーズと共に、振盪しながらRTで3時間インキュベートした。磁石を用いて、ビーズをPBST(3×)、続いてPBS(1×)、次いで水(1×)で洗浄した。試料を、2%ギ酸水溶液/10%アセトニトリル水溶液を用いてビーズから溶出させ、続いてRTで10分間振盪しながらインキュベートした。上清を96ウェルプレートに移し、乾燥させた。試料を変性緩衝液(10mMのTCEP、8M尿素)に再懸濁し、65℃で15分間振盪しながらインキュベートした。ヨードアセトアミド(40mM)を加え、37℃で30分間インキュベートし、光から保護した。50mMのNH4HCO3及びトリプシン(0.01μg/μL)を加え、試料を37℃で終夜、約16~20時間消化させ、最後にギ酸で反応を停止させ、1%(体積:体積)の最終濃度を得た。その後Acquity UPLC(Waters)に連結した6500QTRAP(AB SCIEX)を使用した陽イオンエレクトロスプレーモードでの、多重反応モニタリング(MRM)により、液体クロマトグラフィー-タンデム質量分析(LC-MS/MS)によって試料を分析した。試料を、Acquity UPLC BEH C8 1.7μm、2.1×100mmカラム(Waters)に注入した。移動相は、移動相A(水+0.1%ギ酸)及び移動相B(アセトニトリル+0.1%ギ酸)からなった。LCグラジエントは、5分で5~50%B、0.5分で50~95%B、1分で95%Bであった。以下のペプチドKRASG12CLVVVGAC(CAM)GVGK(529.8→846.3)及びAMG510改変-KRASG12CAMG510-LVVVGAC(CAM)GVGK(521.4→675.2)をモニターした。占有率は、未改変及び改変-KRASG12Cペプチドの合計に対して正規化した、AMG510改変-KRASG12Cペプチドのパーセンテージとして計算した。
MHCクラスIの抗原発現に対するAMG510の影響をインビトロで分析するために、CT-26 KRAS p.G12C細胞(5.0E+04細胞/ウェル)を96ウェルプレートに播種し、IFNγの非存在下、又は最終濃度が25又は250pg/mLのIFNγの存在下、AMG510の3倍連続希釈で処理した。プレートを37℃、5%CO2で24時間インキュベートした。細胞をウェルから非酵素的に剥がし、染色緩衝液(PBS/0.5%BSA)で洗浄し、その後、PE共役H-2Dd、H-2Kd、又はH-2Ld抗体(BioLegend)と共に氷上で30分間インキュベートした。洗浄後、SYTOX Blue Dead Cell Stain(Life Technologies)を含有する染色緩衝液に細胞を再懸濁し、その後フローサイトメトリーによって分析した。BD FACSDivaソフトウェアを使用して、BD LSRFortessaフローサイトメーターで収集及び分析を行った。
IFN-γ ELISpotアッセイ(Cellular Technology Ltd.)を用いて、抗原特異的T細胞応答を評価した。脾臓細胞を採取し(n=4~5/群)、全細胞ELISpotアッセイに使用した。簡単に述べると、2.5E+05個の脾臓細胞を2.5E+04個のCT-26、CT-26 KRAS p.G12C又は4T1腫瘍細胞と混合し、37℃で20時間インキュベートした。CTLS6フルオロスポットアナライザー(Cellular Technology Ltd.)を用いてスポットを数えた。
一元配置ANOVA、続いてDunnettの事後検定により薬力学的実験を分析した。効力試験のために、反復測定分散分析(RMANOVA)を行い、続いてGraphPad Prism7.04を用いてDunnettの事後検定を行った。回帰分析は、対応のあるt検定によって行った。生存の統計分析は、GraphPad Prism7.04を使用して、Kaplan-Meier推定量により決定し、Mantel-Coxログ-ランクにより曲線を比較した。フローサイトメトリーデータは、二元配置ANOVA多重比較、続いてテューキーの事後検定によって分析した。NanoStringデータは、一元配置ANOVA多重比較、続いてテューキーの事後検定によって分析した。ELISpotデータ比較は、GraphPad Prismを用いて対応のないt検定によって行った。
TissueLyzer(Qiagen)中で、組織に水(4:1 mL:g)を加え、タングステンカーバイドビーズを使用して、腫瘍組織の粉砕物を調製した。20μLの試料(血漿又は腫瘍組織粉砕物)に、IS(200ng/mLトルブタミド)を含有する100μLのアセトニトリルを加え、試料を10分間ボルテックスし、3500gで10分間遠心分離し、90μLの上清を収集した。回収した上清に水(0.1%ギ酸を含む)100μLを加え、得られた溶液5μLをLC-MS/MSシステムに注入した。クロマトグラフィー分離は、50℃に維持されたPhenomenex Kinetex C18 50×2.1mm、2.7μmを使用し、H2O中0.1%ギ酸(移動相A)及びアセトニトリル中0.1%ギ酸(移動相B)を使用して実施した。クロマトグラフィー勾配は、0分~0.1分は10%移動相Bの無勾配、0.1~0.85分は移動相Bの95%への直線的増加、0.85~1.10分は95%移動相Bの無勾配を保持、1.10~1.11分は移動相Bの10%への直線的減少、1.11~1.40分は10%移動相Bの無勾配保持とした。通常、API4000質量分析計を分析に使用し、561.179>134.100(AMG510)及び271.100>134.100(トルブタミド)のMS/MS転移に続いてポジティブモードESIで実施した。Analyst(登録商標)(Sciex)を用いてピーク面積を積分した。ピーク面積積分後、データをWatson LIMS(商標)(ThermoFisher Scientific)にエクスポートし、ピーク面積比(AMG510のピーク面積/ISのピーク面積)対血漿較正標準の公称濃度に対して加重(1/x2)線形回帰を行って濃度を決定した。血漿中のAMG510の較正範囲は、1.0~10,000ng/mL(LLOQ 1.0ng/mL)であった。腫瘍組織粉砕物中のAMG510の較正範囲は、5.0~50,000ng/mL(LLOQ 5.0ng/mL)であった。
軽質培地(LM)は、1Lの最終容量に以下の成分を添加することによって調製した:100mLの透析したFBS、10.4gの粉末RPMI-1640培地、2gの炭酸水素ナトリウム、200mgのL-アルギニン、48mgのL-リジン、100mgのL-ロイシン、及び1×Pen-Strep(これは0.22μmフィルターシステムで濾過された)。LMと同様に重質培地(HM)を調製したが、100mg[13C6]-L-ロイシン(Cambridge Isotope Laboratories)を非同位体濃縮L-ロイシンの代わりに使用した。MIA PaCa-2及びNCI-H358細胞を、LMを有するT75フラスコに播種した(3E+05個の細胞);LMは毎日交換した。48時間後、細胞を1×PBSで洗浄し、培地をHMに切り替えた;HMは4日間毎日交換した。6日目に、細胞を1×PBSで洗浄し、培地をLMに切り替えた;LMは毎日交換した。6日目に開始して、MIA PaCa-2試料を、0、1、3、6、9、12、15、18、21、24、30、36、48、及び72時間で収集した。6日目に開始して、NCI-H358試料を、0、3、6、9、12、24、36、48、72、及び96時間で収集した。3重に調製した別々のT75フラスコを各時点で回収し、溶解物へと処理した。
T75フラスコを1×PBSで洗浄し、トリプシンで処理し、2分間インキュベートした後、10%の透析済FBSを含有する氷冷PBSを加えた。細胞を十分に混合し、収集し、その後Vi-CELL XRを使用して細胞を計数した。残留細胞を遠心分離し、氷冷PBS(Mg+2含まず、Ca+2含まず)で洗浄した。細胞を再び遠心分離し、PBSを除去し、ホスファターゼ(PhosSTOP、Roche)及びプロテアーゼ(cOmplete EDTA-free、Roche)阻害剤を含有する少量の氷冷RIPA中で細胞を溶解した。得られた溶解物をボルテックスし、氷上に10分間置き、遠心分離して不溶性破片を除去し、その後、さらなる処理まで-80℃で保存した。
抗ヒトRAS(抗RAS)抗体をAbcamから購入し、販売会社により記載されたプロトコルを用いて、EZ-Link NHS-PEG4-ビオチン(ThermoFisher Scientific)でビオチン化した。残留ビオチンを除去し、得られたビオチン-抗RASを、Dynabeads(登録商標)MyOne(商標)Streptavidin C1ビーズ(ThermoFisher Scientific)にRTで1.5時間振盪しながら加えた。細胞溶解物(上記)を、ビオチン化抗RASビーズと共に、振盪しながら室温で2時間インキュベートした。磁石を用いて、ビーズをPBST(3×)、続いてPBS(1×)で洗浄した。3%ギ酸水溶液/30%ACN水溶液を用いて試料をビーズから溶出し、続いて振盪しながら室温で10分間インキュベートした。上清を96ウェルプレートに移し、乾燥させた。試料を変性緩衝液(10mM TCEP、8M尿素)に再懸濁させ、水浴を用いて37℃で1時間インキュベートした。ヨードアセトアミド(40mM)を加え、25℃で1時間インキュベートし、光から保護した。50mMのNH4HCO3及びトリプシン(0.1μg/μL)を加え、試料を37℃で24時間消化させ、その後ギ酸で反応を停止させ、1%(体積:体積)の最終濃度を得た。質量分析による分析の前に、試料を約80μLに濃縮した。Acquity UPLC(Waters)に連結した6500QTRAP(AB SCIEX)を使用した陽イオンエレクトロスプレーモードでの、多重反応モニタリング(MRM)により、液体クロマトグラフィー-タンデム質量分析(LC-MS/MS)によって試料を分析した。試料を、Acquity UPLC BEH C8 1.7μm、2.1×100mmカラム(Waters)に注入した。移動相は、移動相A(水+0.1%ギ酸)及び移動相B(アセトニトリル+0.1%ギ酸)からなった。LC勾配は、5分で5~50%B、0.5分で50~95%B、1分で95%Bであった。KRASG12Cについての以下のペプチド(LVVVGAC(CAM)GVGK(529.8→846.3)&13C-LVVVGAC(CAM)GVGK(532.8→846.3))及び RAS WT(LVVVGAGGVGK(478.3→743.2)&13C-LVVVGAGGVGK(481.3→743.2))を使用して、重い標識から軽い標識への移行をモニターした。相対的同位体存在量(RIA)は、以下の式を用いて決定した:
タンパク質半減期の決定に対する細胞増殖の影響を説明するために、各時点に関連する細胞数及びRIAデータを一連の式に同時に当てはめて、MIA PaCa-2及びNCI-H358細胞中のKRASG12Cの半減期を決定した。以下の式を使用した:
重いペプチドの一次方程式:
Claims (32)
- それを必要とする患者におけるKRAS G12C突然変異により媒介されるがんを治療する方法において使用するための医薬組成物であって、治療有効量の(1M)-6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オン若しくはその薬学的に許容される塩、及び/又は治療有効量の少なくとも1種の薬学的に活性な追加の薬剤を含み、前記方法が、前記患者に、前記治療有効量の(1M)-6-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)-1-(4-メチル-2-(2-プロパニル)-3-ピリジニル)-4-((2S)-2-メチル-4-(2-プロペノイル)-1-ピペラジニル)ピリド[2,3-d]ピリミジン-2(1H)-オン、又はその薬学的に許容される塩、及び前記治療有効量の少なくとも1種の薬学的に活性な追加の薬剤を投与することを含み、前記少なくとも1種の追加の薬学的に活性な薬剤が、カルボプラチン、抗PD-1抗体、MEK阻害剤、EGFR阻害剤、mTOR阻害剤、SHP2阻害剤、PI3K阻害剤又はAKT阻害剤である、医薬組成物。
- 前記がんは非小細胞肺がん、小腸がん、虫垂がん、結腸直腸がん、子宮内膜がん、膵臓がん、皮膚がん、胃がん、鼻腔がん、又は胆管がんである、請求項1に記載の医薬組成物。
- 前記がんは膵臓がんである、請求項1又は2に記載の医薬組成物。
- 前記がんは結腸直腸がんである、請求項1又は2に記載の医薬組成物。
- 前記がんは非小細胞肺がんである、請求項1又は2に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はカルボプラチンである、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤は抗PD-1抗体である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記抗PD-1抗体は、AMG404、ペムブロリズマブ、又はニボルマブである、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記抗PD-1抗体はペムブロリズマブである、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記抗PD-1抗体はニボルマブである、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記抗PD-1抗体が、配列番号1を含む重鎖(HC)相補性決定領域(CDR)1アミノ酸配列、配列番号2を含むHC CDR2アミノ酸配列、配列番号3を含むHC CDR3アミノ酸配列、配列番号4を含む軽鎖(LC)CDR1アミノ酸配列、配列番号5を含むLC CDR2アミノ酸配列、及び配列番号6を含むLC CDR3アミノ酸配列を含む、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記抗PD-1抗体が、配列番号7の重鎖可変領域配列、及び配列番号8の軽鎖可変領域を含む、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記抗PD-1抗体が、配列番号9の重鎖配列、及び配列番号10の軽鎖配列を含む、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記抗PD-1阻害剤は、AMG404である、請求項1~5及び7のいずれか一項に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はMEK阻害剤である、請求項1~5に記載の医薬組成物。
- 前記MEK阻害剤は、トラメチニブ、ピマセルチブ、PD-325901、MEK162、TAK-733、GDC-0973又はAZD8330である、請求項15に記載の医薬組成物。
- 前記MEK阻害剤はトラメチニブである、請求項16に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はEGFR阻害剤である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記EGFR阻害剤は、アファチニブ、エルロチニブ、ラパチニブ、セツキシマブ、又はパニツムマブである、請求項18に記載の医薬組成物。
- 前記EGFR阻害剤はアファチニブである、請求項19に記載の医薬組成物。
- 前記EGFR阻害剤はパニツムマブである、請求項19に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はSHP2阻害剤である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記SHP2阻害剤はRMC4550である、請求項22に記載の医薬組成物。
- 前記SHP2阻害剤はRMC4630である、請求項22に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はmTOR阻害剤である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記mTOR阻害剤は、エベロリムスである、請求項25に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はPI3K阻害剤である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記PI3K阻害剤は、AMG511又はブパルリシブである、請求項27に記載の医薬組成物。
- 前記PI3K阻害剤は、AMG511である、請求項28に記載の医薬組成物。
- 前記PI3K阻害剤は、ブパルリシブである、請求項28に記載の医薬組成物。
- 前記少なくとも1種の、薬学的に活性な追加の薬剤はAKT阻害剤である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記AKT阻害剤はAZD5363である、請求項31に記載の医薬組成物。
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TWI824990B (zh) | 2023-12-01 |
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CL2023000847A1 (es) | 2023-09-08 |
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MX2021005898A (es) | 2021-06-23 |
UY38481A (es) | 2020-05-29 |
CA3117687A1 (en) | 2020-05-28 |
US20200222407A1 (en) | 2020-07-16 |
IL282727A (en) | 2021-06-30 |
AU2019384119A1 (en) | 2021-05-27 |
US20230121955A1 (en) | 2023-04-20 |
KR20210094570A (ko) | 2021-07-29 |
JP2024001275A (ja) | 2024-01-09 |
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