JP2016515141A - 抗egfr薬を用いた胃癌の処置のための、egfrバイオマーカーの使用 - Google Patents
抗egfr薬を用いた胃癌の処置のための、egfrバイオマーカーの使用 Download PDFInfo
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Abstract
Description
本願は、全ての目的のためにその全体において参照により本明細書に組み入れられる、2013年3月14日に出願された、国際特許出願PCT/CN2013/072638号の恩典を主張する。
本発明は、概して胃腫瘍を処置するための方法に関し、具体的には、特定の上皮成長因子受容体(EGFR)バイオマーカーを有すると以前に判定されている患者を処置するための方法に関する。
本発明は、概して抗EGFR薬を用いた胃腫瘍を処置するための方法、具体的には、特定のEGFRバイオマーカーを有すると以前に判定されている患者を処置するための方法に関する。本発明は、治療薬、つまり抗EGFR抗体を、EGFRタンパク質をコードする遺伝子の増幅またはEGFRの過剰発現(mRNA発現、タンパク質発現、または活性レベルによって測定される)を有すると見出された患者に投与することによる処置に対して応答する可能性が高い患者の処置を可能にする。本発明は、一部には、例えば蛍光インサイチューハイブリダイゼーション(FISH)によって、マイクロアレイ分析によって、または当該分野で周知の他の方法によって検出される、EGFR遺伝子増幅、またはEGFR過剰発現が、EGFR遺伝子増幅またはEGFR過剰発現が処置に対する応答に相関するために、処置する患者を選択するための基盤を提供するという発見に基づく。
本発明は、胃腫瘍を処置するための方法であって、かかる処置を必要とする患者に本明細書に記載の治療有効量の抗EGFR薬を投与することを含み、ここで患者がEGFRバイオマーカーを有すると判定されている、方法を提供する。本明細書で用いるとき、用語「有効量」は、所望の処置結果を与える一つ以上の化合物の量を指す。有効量は、一つ以上の投薬内に備えられ得る、つまり単回投薬または複数回投薬が所望の処置エンドポイントを達成するために必要とされ得る。用語「治療有効量」は、本明細書で用いるとき、場合によっては重大なマイナスのまたは有害副作用を引き起こすことなく、病状を処置する、または傷害または損傷を減らすまたは防ぐために必要な一つ以上の薬剤のレベルまたは量を指す。例えば、治療有効量は、例えば所望の治療結果(例えば疾患または病状の重症度の低減)を生成するのに十分にEGFR経路を変調することができる一つ以上の化合物を含む、医薬製剤の量を含む。一実施形態では、胃腫瘍は胃腺癌である。本明細書に記載の方法は、本明細書に記載のように患者がEGFRバイオマーカーを有すると判定されている場合の、腸型及びびまん型胃腺癌、消化管間質腫瘍(GIST)、消化管平滑筋肉腫、消化管カルチノイド及び消化管リンパ腫を含む任意のタイプの胃癌を処置するための方法を含む。ある特定の実施形態では、本方法は胃癌を処置するためのものである。具体的な実施形態では、本方法は、胃癌などのEGFR発現癌を処置するための方法を含み、ここで癌は食道胃腺癌(esophagogastric adenocarcinoma)(OGA)または転移性大腸癌でないことを特徴とする。一実施形態では、本発明は、胃腫瘍を処置するための方法であって、かかる処置を必要とする患者に治療有効量の抗EGFR薬を上述のように投与することを含み、患者がEGFRバイオマーカーを有し、HER2バイオマーカーを有さないと判定されている、方法を提供する。
この実施例は、完全に分子的に注釈付けされた(発現及び変異プロファイリング)未処置のアジア人胃腺癌(GC−ADC)患者由来の異種移植片(PDX)のコホートで、応答者及び非応答者を同定し、その後予測的バイオマーカーの発見をするために実施された無作為化セツキシマブ試験の結果を記載する。
患者由来の異種移植片(PDX)は、いかなるインビトロ操作も伴わずに、患者の組織病理学的及び遺伝子プロファイルを反映する9−14。それは前臨床癌モデルとして予測力を改善しており、真の個別化療法及び予測的バイオマーカーの発見を可能にする。モデルは、「アバターマウス」または「異種移植モデル(xenopatient)」とも呼ばれ、それらの大規模な収集は、患者における腫瘍の多様性を潜在的に反映することが可能である。癌患者集団の広範囲にわたる多様性に起因して、臨床試験の成功性は、意図された標的を発現して適切な遺伝子プロファイルを有する有望な応答者の包含と、非応答者の排除に大いに依存する。これらのモデルはゆえに、臨床試験形式をモデル化することによって治験標的薬を試験するために使用されることができる。
患者の試料、移植、セツキシマブ処置実験及びモデルの特徴付け。
外科的に取り出された新鮮なGC腫瘍組織を、外科手術の直後に、6〜8週齢の雌Balb/cヌードマウス(Beijing HFK Bioscience Co.Ltd.,中国、北京)に、以前に記載された手順10で皮下移植するために使用した。確立された腫瘍モデルは、経過及び研究実行のために連続的に再移植された。患者試料へのアクセス及びその使用は、患者からのインフォームドコンセントに加えて北京腫瘤医院の倫理委員会によって承認された。全ての手順は、Crown Bioscience社のSFP施設にて滅菌条件下で行われた。本発明者らの研究に関係する全ての実験動物は、国立衛生研究所の実験動物の管理と使用に関するガイドの推奨事項に厳密に従って行われた。プロトコルは、Crown Bioscience,Incの動物実験の倫理委員会(Crown Bioscience社のIACUC委員会)によって承認された。
腫瘍体積が100〜150mmに達したとき、マウスを類似の平均腫瘍体積を有する5匹のマウスの2群に無作為にグループ分けした。グループ分けの直後に、対照群をビヒクルで処置し(PBS、週一回の腹腔内注射(またはIP)を二週間)、処置群にセツキシマブを注射した(週一回のIP注射を二週間、50mg/kg、Merck社)。腫瘍成長を週二回モニターし、DT/DC値を処置に対する腫瘍応答を評価するために算出した(DT5 処置群における腫瘍体積変化及びDC5 対照群における腫瘍体積変化)。異種移植用のマウスの総数は200(20のPDXモデルについて10匹のマウス/モデル)である。
標準の免疫組織化学(IHC)が、PDX異種移植片モデルからの腫瘍組織を解析するために使用された。簡潔には、組織を10%中性緩衝ホルマリンで固定し、標準的な組織学的手順に従って、パラフィンに包埋した。脱パラフィン及び再水和の後、厚さ3mmの組織切片を0.01M クエン酸ナトリウム、pH6.0溶液中で95uCで30分間前処理し、その後ウサギ抗ヒトEGFR抗体(Cell Signaling、米国、ボストン)を用いて最終希釈15200で染色した。検出システム:HRPポリマーキット(Lab Vision、米国、フリーモント)を使用して陽性染色が検出された。DABを発色基質として使用し、切片をギルヘマトキシリン(Fisher Scientific、ニュージャージー州フェアローン)を用いて対比染色した。試験片を、次いで、2005年にShiaらが推奨した以下の基準に従って盲検様式で3人の研究者によって独立して採点した:スコア0は、特定の膜染色が腫瘍内になかったときであり、バックグラウンドレベルを超える任意の腫瘍細胞膜の染色があったとき正数である。正数であった場合、膜の染色強度に基づいてさらに11、21、及び31へと分類される。最強度の領域は、腫瘍切片を低倍率(1003)で走査することによって同定され、次いで画像を、DP71デジタルカメラ(オリンパス、ニューヨーク州メルヴィル)を用いて、オリンパスBX51顕微鏡システムを使用して高倍率(4003)で撮影した。
新鮮なGCPDX腫瘍組織を、腫瘍を有するマウスから採取し、遺伝子及びゲノム解析に使用される前に、瞬間凍結して280uCで保管した。遺伝子プロファイリング解析のために、全RNAを、Trizol(Invitrogen、カリフォルニア州カールスバッド)を製造業者の説明書に従って使用して凍結組織から単離し、RNeasyミニカラム(Qiagen)を使用して精製した。RNAの質をバイオアナライザー(Agilent)で評価した。高品質のRNA試料(RIN.8)のみが、標準プロトコル(GenChip(登録商標)3'IVTエクスプレスキットユーザーマニュアル、P/N 702646 Rev.8、Affymetrix)に従って、Affymetrix社のHG−U219アレイプレート上で発現プロファイリングアッセイのために使用された。全ての試料の生CELデータセットをRMAアルゴリズムによって正規化した。プローブセット強度を、log(2)変換値として表した。Affymetrix SNP6.0チップを使用するCNVアッセイのために、ゲノムDNAを、ゲノムDNA組織及び血液単離キット(Qiagen)を製造業者の説明書に従い使用して、単離及び精製した。DNAプロセシング及びチップハイブリダイゼーションを、標準的なAffymetrix社のプロトコル(ゲノムワイドsnp6_マニュアル、Affymetrix)に従って行った。生CELデータを品質チェックし(QC−ed)、フィルタリングして低コールレート試料を除去し、PICNIC及び/またはPennCNV方法によって遺伝子コピー数解析を行った。全ての試料について、相対的なEGFR遺伝子発現レベルは、定量RT−PCRによって決定された。抽出されたmRNAを、TaqMan q−PCRにより、ヒトEGFR特異的プライマーを使用して増幅に供した。ヒトGAPDH遺伝子を参照として使用した。EGFRについてのTaqManプローブ及びプライマー(アッセイID:Hs01076078_m1)、GAPDH(アッセイID:Hs99999905_m1)を、Applied Biosystemsから得た。システムによって生成された生データを、DCT相対定量を用いて処理した。DCT5(標的遺伝子のCT値)−(参照遺伝子のCT値)。DCT値を、次いで強度値(相対mRNAレベル5 2' (2DCT))に変換した。また、EGFR遺伝子コピー数を定量PCRによって決定した。簡潔には、同一のゲノムDNAをTaqMan q−PCRによって増幅に供した。EGFR(アッセイID:Hs04960197_cn)及び内因性参照としてのRNase P(部品番号4401631)についてのプライマーを、AppliedBiosystems社から購入した。生データをCopyCallerソフトウェアへと転送し、解析した。
EGFR(エクソン18;19;20;21)、KRAS(エクソン2;3;4)、BRAF(エクソン15;V600E)、c−MET(エクソン14;16;17;18;19;21)、PI3KC(エクソン1;9;20)などの、セツキシマブに対する耐性に関連する一般的な発がん遺伝子の遺伝子ホットスポット解析を、腫瘍における変異を同定するために実行した。簡潔には、ゲノムDNAを、製造業者の説明書に従って上述のキットを使用して組織から抽出した。変異解析に使用されたプライマーを表5に示す。ポリメラーゼ連鎖反応を、100ngのゲノムDNA、5mLの103PCR緩衝液、各々0.2mMのプライマー、0.2mMの43dNTP及び1mLのTaqEを含有する50mLの反応混合物において行った。反応は、40回の増幅サイクルにわたって実行された。増幅されたPCR産物をゲル精製し、サンガー自動シーケンサー(ABI)によって配列決定した。プライマーのヒト遺伝子に対する特異性は、BLAST検索によって保証されていた。シーケンスデータアライメント解析及び変異同定を、BioEditソフトウェアを使用して行った。
FISH(2色)手順を、Abbott社のPathVysion EGFR DNAプローブキットを製造業者のプロトコル(Abbott、イリノイ州ダウナーズ・グローブ)に従って使用して、実行した。スペクトラムオレンジ蛍光標識EGFR(303kb)は、染色体7p12上のEGFR遺伝子座に特異的であり、スペクトラムグリーン蛍光標識染色体エニュメレータープローブ(5.4kb)は、染色体7のセントロメア領域(CEP7;7p11.1〜q11.1)に配置されたα−サテライトDNA配列を標的とした。簡潔には、FFPE切片を脱パラフィンし、その後ペプシンで消化しハイブリダイゼーションした。処理されたスライドを変性させ、プローブでハイブリダイズし、その後15μLのDAPI/抗フェード溶液で対比染色し、DAPI、ローダミン(7p12)及びFITC(染色体7)を1000倍で検出するために単一のバンドパスフィルタセットを装備したオリンパスBX51蛍光顕微鏡(オリンパスBX51、日本)を使用して走査した。
腫瘍体積のデータを2つの比較についてスチューデントのt検定を、及び多重比較について一元配置分散分析を使用して評価した。全てのデータはSPSS16.0を使用して解析された。P<0.05は統計学的に有意であると考えられた。EGFR増幅モデルと非増幅モデル間の応答差異にアクセスするためにフィッシャーの正確確率検定を使用した(quantitativeskills.com/sisa/statistics/fisher.htmを参照)。
GC HuPrime(登録商標)モデルのサブセットはセツキシマブに応答する。
本発明者らは、GC−ADC HuPrime(登録商標)モデルの無作為に選択されたコホートを臨床試験のような研究によって潜在的なセツキシマブの活性を評価するための試験に着手した。これらのモデルはまず、GC−ADC患者から外科的に取り出された腫瘍組織を免疫低下状態のBalb/cヌードマウスに皮下接種を介して移植することによって確立された。元となる患者の診断及び説明を表2及び表3に要約した。次に、19の無作為に選択されたモデルを週一回のセツキシマブ処置に2週間供した(1mg/マウスまたは50mg/kg)。セツキシマブに対する腫瘍応答を、ΔT/ΔC 15によって定量化し、表4に要約した。モデルは、活性に応じて二つのカテゴリーに分割することができる。GC−ADC HuPrime(登録商標)の4/19または21%がセツキシマブ処置に応答した(ΔT/ΔC<0%でほぼ完全奏効);15/19または79%は応答しなかった(ΔT/ΔC>30%で部分的または完全抵抗性)。これらの二つのカテゴリーの代表的な腫瘍成長阻害曲線を図1Aに示す。ΔT/ΔC値によって測定される腫瘍応答の定量化を表1A及び表1Bに要約する。GA0152及びGA0075は、セツキシマブ感受性モデルの例であり、一方でGA0119及びGA0139は抵抗性モデルである。GC−ADCモデルにて見られるこれらのかなり明確な応答は、CRC17及びNSCLC15HuPrime(登録商標)モデルにおいて観察された応答といくらか対照的である。それにもかかわらず、本発明者らのデータはGCのサブセットにセツキシマブが潜在的に有効であり得ることを示した。移植の生着率が100%未満(本発明者らの手で通常30〜50%)であること及び応答者または非応答者間での生着率にバイアスがかかる可能性があることに起因して、このGC−ADC研究で観察された21%の応答者が、GC−ADC集団における潜在的応答者の真のパーセンテージを必ずしも反映しない可能性があることは注目に値した。
セツキシマブ応答の潜在的な予測マーカーを発見するために、それゆえ、本発明者らは、ゲノム全体のコピー数多型及びトランスクリプトームプロファイリングを含む、これらのモデルの分子特徴付けを行った。まず、本発明者らはAffymetrix社のgenome−wide human SNP6.0 array及びPICNIC(Predicting Integral Copy Numbers In Cancer;癌における全体的なコピー数の予測)アルゴリズムを使用してGC−PDXのコピー数多型を調べた。本発明者らは4応答者全てのEGFRコピー数が非応答者の大半のものよりも高いことを見出した(表1、P=0.002)。この発見をさらに確証するため、本発明者らはEGFR遺伝子コピー数をリアルタイム定量PCR(q−PCR)によって評価し、16の非応答者のうちの2(12.5%)のみが4以上のコピー数を有する一方で、全応答者が4以上のコピー数を有することを見出した。これらの二群間の差異は有意である(P=0.008)。SNP6 1 PICNIC解析による最高値である15、及びq−PCRによる最高値である1040.9は、最良の応答者でもあるGA0152からである。
観察された応答GC−ADCについての予測的バイオマーカー(複数可)を発見するために、このコホートのモデルを、いくつかの一般的な発がん遺伝子の発現及び遺伝子コピー数、ならびに遺伝子変異について全身的にプロファイルした。KRAS、BRAF(V600E)、c−MET、EGFR、AKT及びPI3KCのものを含む、活性化変異は、CRC患者におけるセツキシマブに対する耐性と関連してきた15、17−21。ゆえに、これらのモデルは、まずこれらの発がん遺伝子のホットスポット変異配列決定によって解析された。興味深いことに、検査されたモデルのほとんどが、応答者または非応答者にかかわらず、G13Dを含有するGA0139及びPIK3CAにおいて327〜329欠失を含有するGA044を除いて、いずれの変異も示さなかった(表1)。ゆえに、GC HuPrime(登録商標)のセツキシマブに対する非応答は、明らかにこれらの発がん遺伝子の変異に単に起因することができない。
しかしながら、一方で、Affymetix社のHG−U219 GeneChip解析は、4応答者全てが高レベルのEGFR(mRNAレベル)を発現したこと、及び15の不良応答者全てがより低レベルの発現と関連することを明らかにした(図2A及び2C、表1)。より高い発現を介したEGFRのより高い活性は、これらの腫瘍において発がん性形質転換を推進でき、ゆえにセツキシマブによる不活性化は腫瘍成長を阻害することができるため、この観察結果はもっともらしく思われる。
一方で、Affymetrix社のHG−U219 GeneChipを使用したトランスクリプトームプロファイリングは、16の非応答者全てよりも4応答者全てがより高いレベルのEGFR mRNA発現を発現したことを明らかにした(P=0.003)(表1)。EGFR遺伝子発現は、さらにq−RT−PCR(定量逆転写PCR)によって、ハウスキーピング遺伝子GAPDHに対して定量化された。試験された試料の中で、高いEGFR mRNAレベル(相対強度≧0.5、恣意的に定義された)を呈した4試料は、全て応答者であり、残りのモデルが中から低のEGFR mRNAレベル(相対強度≦0.1)(表1、図1C)を示したこととは対照的である。差異は有意である(P=0.002)。具体的には、最も高い値はGA0152からであり、GeneChip解析によって10.5及びq−RT−PCRによって13であり、上記のEGFR増幅に起因することができる。
次いで、本発明者らはEGFR免疫組織化学(IHC)(GCの抗HER2処置についてのHER2発現を決定するための臨床的に実用的なアッセイ)を行った。IHCは、12/20(60%)のモデルにおいて陽性なEGFR免疫染色を実証した。それらの中で、6/12は11、3/12は21、及び3/12は31の染色強度を示した。全応答者でEGFR IHC 31が見出され、一方で非応答者はより低いEGFR IHCスコア0〜21(P 5 0.002)(表1、図1C)を呈した。典型的なEGFRの強い免疫染色(GA0152及びGA0075)を図1Bに示す。これらの結果は、EGFR高発現(mRNA及びタンパク質レベルの両方において)が、セツキシマブに対する応答に相関することを実証した。関連する発がん遺伝子の変異は稀である。EGFR経路に関連するいくつかの一般的な発がん遺伝子の遺伝的変異、例えば、KRAS、BRAF(V600E)、c−MET、EGFR、AKT及びPI3KCもまた、これらのモデルにおいてホットスポット変異配列決定によって調査されている。興味深いことに、G13D KRAS変異を含有するGA0139、PIK3CAにおいて327〜329欠失を含有するGA0044、及びG545YPIK3CA変異を含有するGA0098を除く試験されたモデルのほとんどが、応答者または非応答者にかかわらず、異常を示さなかった(表1)。それゆえ、GC異種移植片のセツキシマブに対する非応答は、明らかにこれらの発がん遺伝子の変異に単に起因することができない。
この研究は、EGFR遺伝子増幅及び過剰発現を伴うGC−ADC HuPrime(登録商標)モデルのサブセットがセツキシマブに応答する(4/4)ことを明確に実証した。これと一致して、EXTRA第II相試験における4人中4人のEGFR増幅患者は、セツキシマブ及びシスプラチン/カペシタビン(NCT00477711)の併用処置に対して応答者であり16、PDXモデルの想定される予測力及びセツキシマブGC−ADC処置についてのEGFR予測的バイオマーカーの本発明者らの仮説を支持する。この仮定は、データが入手可能になったときに、最近完了された食道胃腺癌における第III相試験(EXPAND)を遡及的に調査することによってもさらに確証されることができる。EGFR遺伝子増幅についてのFISHは、医療現場にて日常的に行われることができ、したがって、これがコンパニオン診断として使用されることが可能になる。それゆえ、かかる前向き試験は容易に実現できる。最終的な承認は、HER2遺伝子増幅を有する患者へのトラスツズマブ(Herceptin(登録商標))3に加えて、GC−ADC患者のためのもう一つの標的療法選択肢を提供するだろう。
Claims (24)
- 処置を必要とする患者に有効量の抗EGFR薬を投与する工程を含む、胃腫瘍を処置するための方法であって、前記患者がEGFRバイオマーカーを有すると判定されている、前記方法。
- 前記胃腫瘍が胃腺癌である、請求項1に記載の方法。
- 前記抗EGFR薬が抗EGFR抗体である、請求項1に記載の方法。
- 前記抗EGFR薬が、セツキシマブ、パニツムマブ、ニモツズマブ、抗体806、Sym004、またはMM−151である、請求項1に記載の方法。
- 前記抗EGFR薬が、2種以上の抗EGFR薬の組み合わせである、請求項1に記載の方法。
- 胃腫瘍の標準的処置と組み合わせて前記抗EGFR薬を投与する工程をさらに含む、請求項1に記載の方法。
- 化学療法または放射線療法と組み合わせて前記抗EGFR薬を投与する工程をさらに含む、請求項1に記載の方法。
- シスプラチン及びカペシタビン、または5−フルオロウラシル、オキサリプラチン、イリノテカン、ドセタキセル、パクリタキセル、ドキソルビシンマイトマイシンC、エトポシド、ゲムシタビン、カルボプラチンと組み合わせて前記抗EGFR薬を投与する工程をさらに含む、請求項1に記載の方法。
- 前記EGFRバイオマーカーが、EGFR遺伝子増幅またはEGFR過剰発現である、請求項1に記載の方法。
- 前記EGFR遺伝子増幅が、所定の数より多いEGFR遺伝子コピー数を含む、請求項9に記載の方法。
- 前記EGFR過剰発現が、所定のレベルより高いEGFR RNA、タンパク質、または活性のレベルを含む、請求項9に記載の方法。
- 前記患者が、EGFRバイオマーカーを有し、HER2バイオマーカーを有さないと判定されている、請求項1に記載の方法。
- 前記患者が、抗HER2薬を伴わずに抗EGFR薬を投与される、請求項12に記載の方法。
- EGFRバイオマーカーの存在または非存在を患者の試料において検出する工程を含む、患者が抗EGFR処置に好適かどうか判定するための方法であって、EGFRバイオマーカーの存在が、前記患者が前記抗EGFR処置に好適であることを示す、前記方法。
- 胃腫瘍を有する患者の試料を受け取る工程、EGFRバイオマーカーの存在または非存在を前記試料において検出するための試験を行う工程、及び前記患者の医療提供者に試験結果を提供する工程を含む、ラボサービスを提供するための方法。
- 対象からの生体試料におけるEGFRバイオマーカーの存在または非存在を検出する工程を含む、胃腫瘍に罹患している対象における抗EGFR処置の応答性または有効性をモニターするための方法であって、前記EGFRバイオマーカーが、所定の基準レベルと比較してのEGFR遺伝子増幅またはEGFR過剰発現であり、前記EGFRバイオマーカーの存在が、前記抗EGFR処置を用いた処置の有効性を示す、前記方法。
- 対象からの生体試料におけるEGFRバイオマーカーの存在または非存在を検出する工程を含む、胃腫瘍に罹患している対象を処置するための処置レジメンを決定するための方法であって、前記EGFRバイオマーカーが、所定の基準レベルと比較してのEGFR遺伝子増幅またはEGFR過剰発現であり、処置レジメンが、前記生体試料における前記EGFRバイオマーカーの存在または非存在に基づいて決定される、前記方法。
- 対象からの生体試料におけるEGFRバイオマーカーの存在または非存在を検出する工程を含む、胃腫瘍に罹患している対象についての処置有効性を予測するための方法であって、前記EGFRバイオマーカーが、所定の基準レベルと比較してのEGFR遺伝子増幅またはEGFR過剰発現であり、EGFRバイオマーカーの存在が、肯定的な処置有効性を示す、前記方法。
- (a)胃腫瘍に罹患している対象からの生体試料におけるEGFRバイオマーカーの存在または非存在を検出する工程、及び(b)EGFRバイオマーカーの存在または非存在に関する情報を前記対象の診断または処置のために医療提供者に提供する工程を含む、データを提供するための方法。
- 前記検出工程の前に前記医療提供者から前記生体試料を受け取る工程をさらに含む、請求項20に記載の方法。
- (a)胃腫瘍に罹患している対象からの生体試料において、所定の基準レベルと比較してEGFRバイオマーカーの存在または非存在を検出する工程、及び(b)EGFRバイオマーカーの存在または非存在に関する情報を、前記処置有効性の予測または判定を提供する実体に提供する工程を含む、抗EGFR処置の処置有効性をモニターする、予測する、または決定するために有用な情報を提供する方法。
- EGFR活性のベースラインレベルが抗EGFR処置の前に検出され、所定の基準レベルと比較したときのEGFR活性の前記ベースラインレベルにおける増加が、EGFRバイオマーカーの存在を示す、請求項1〜21のいずれか一項に記載の方法。
- 生体試料が、血液、皮膚、毛髪、毛包、唾液、口腔粘膜、膣粘膜、汗、涙、上皮組織、尿、精液(semen)、精液(seminal fluid)、精漿、前立腺液、尿道球腺液(カウパー液)、排泄物、生検材料、腹水、脳脊髄液、リンパ液、および組織抽出試料または生検試料から選択される、請求項1〜22のいずれか一項に記載の方法。
- EGFRバイオマーカーの検出に好適な試薬と、請求項1に記載の方法に従って胃腫瘍を処置するために前記EGFRバイオマーカーを使用するための説明書とを含む、キット。
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JP7113842B2 (ja) | 2017-03-29 | 2022-08-05 | クラウン バイオサイエンス,インコーポレイテッド(タイツァン) | 胃がんのセツキシマブ感受性を決定するためのシステムおよび方法 |
JP2020522711A (ja) * | 2017-06-06 | 2020-07-30 | ユニバーシティ オブ メリーランド,カレッジ パーク | 転移検出のために単一細胞の機械的フェノタイピングを行う分析 |
JP7396902B2 (ja) | 2017-06-06 | 2023-12-12 | ユニバーシティ オブ メリーランド,カレッジ パーク | 転移検出のために単一細胞の機械的フェノタイピングを行う分析 |
WO2020100969A1 (ja) * | 2018-11-14 | 2020-05-22 | 学校法人金沢医科大学 | びまん性胃がんを治療するための医薬組成物 |
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US10442862B2 (en) | 2019-10-15 |
WO2014153018A1 (en) | 2014-09-25 |
JP2020040959A (ja) | 2020-03-19 |
WO2014139131A1 (en) | 2014-09-18 |
JP6675300B2 (ja) | 2020-04-01 |
US20160024216A1 (en) | 2016-01-28 |
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