JP6664323B2 - 神経膠芽腫を治療するための診断方法及び組成物 - Google Patents
神経膠芽腫を治療するための診断方法及び組成物 Download PDFInfo
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Description
本発明は、VEGFアンタゴニスト、例えば、抗VEGF抗体での治療に感受性または応答性のある、神経膠芽腫を有する患者をモニタリングおよび/または同定するための方法及び組成物を提供する。本発明は、VEGFアンタゴニスト(抗VEGF抗体など)で治療する前の、表1、表2、または表3に記載される少なくとも1、2、3、4、5、6、7、8、9、10、11またはそれ以上の遺伝子の発現レベルの決定が、VEGFアンタゴニスト、例えば、抗VEGF抗体での治療に感受性または応答性の患者を同定するのに有用であるという発見に基づく。場合によっては、次いで、VEGFアンタゴニスト療法を患者のために選択することができ、さらに、VEGFアンタゴニスト療法を場合によっては患者に施すことができる。
「抗血管形成剤」または「血管新生(血管形成)インヒビター」は、直接的または間接的に、血管新生、脈管形成または望ましくない血管透過を阻害する、小分子量の物質、ポリヌクレオチド、ポリペプチド、単離したタンパク質、組み換えタンパク質、抗体、またはそれらのコンジュゲートまたは融合タンパク質のことを言う。抗血管形成剤には、結合して、血管形成因子またはそのレセプターの血管形成活性を遮断する作用剤が含まれることが理解されるであろう。例えば、抗血管形成剤は、明細書全体を通じて定義されまたは当該技術分野で公知の血管形成剤に対する抗体または他のアンタゴニスト、例えば、限定されないが、VEGF-Aに対する、または、VEGF―Aレセプター(例えば、KDRレセプターまたはFlt−1レセプター)に対する抗体、VEGF−trap、Gleevec(商標)(メシル酸イマチニブ)などの抗PDGFRインヒビターである。また、抗血管形成剤には、天然の血管形成インヒビター、例えば、アンジオスタチン、エンドスタチンなどが含まれる。Klagsbrun及びD’Amore, Annu.Rev.Physiol.,53:217−39(1991);Streit及びDetmar,Oncogene,22:3172−3179(2003)(例えば、悪性黒色腫の抗血管形成治療を記載している表3);Ferrara & Alitalo,Nature Medicine 5(12):1359−1364(1999);Toniniら.,Oncogene,22:6549−6556(2003)(例えば、公知の抗血管新生因子を記載している表2);及び、Sato Int.J.Clin.Oncol.,8:200−206(2003)(例えば、臨床試験で用いられる抗血管形成剤を記載している表1)を参照されたい。
L1 L24−L34 L24−L34 L26−L32 L30−L36
L2 L50−L56 L50−L56 L50−L52 L46−L55
L3 L89−L97 L89−L97 L91−L96 L89−L96
H1 H31−H35B H26−H35B H26−H32 H30−H35B(カバット番号付け)
H1 H31−H35 H26−H35 H26−H32 H30−H35(Chothia番号付け)
H2 H50−H65 H50−H58 H53−H55 H47−H58
H3 H95−H102 H95−H102 H96−H101 H93−H101
本発明は、VEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)療法に応答する可能性が高い患者を同定および/またはモニタリングするための方法を提供する。本方法は、特に、VEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)の患者への投与が有効である確度を高めるのに有用である。本方法は、患者由来の生体試料中の1つ以上の遺伝子バイオマーカーの発現の検出であって、1つ以上のそうしたバイオマーカーの発現は、患者が抗VEGF抗体などのVEGFアンタゴニストに感受性であるか、または応答性であるかの指標となる発現の検出を含む。
本明細書に記載の遺伝子バイオマーカーは、当該技術分野で公知の任意の方法を使用して検出することができる。例えば、哺乳動物由来の組織または細胞試料は、ノーザン、ドットブロットまたはポリメラーゼ連鎖反応(PCR)解析、アレイハイブリダイゼーション、RNaseプロテクションアッセイを使用して、またはDNAマイクロアレイスナップショットを含めた、市販品として入手可能なDNA SNPチップマイクロアレイを使用して、例えば、目的の遺伝子バイオマーカー由来のmRNAまたはDNAについて簡便にアッセイすることができる。例えば、定量的PCRアッセイなどのリアルタイムPCR(RT−PCR)アッセイが当該技術分野でよく知られている。本発明の例示的実施形態では、腫瘍試料(例えば、神経膠芽腫瘍試料)などの生体試料中の目的の遺伝子バイオマーカー由来のmRNAを検出するための方法は、少なくとも1つのプライマーを使用して逆転写によって試料からcDNAを生成すること、そのようにして生成されたcDNAを増幅すること、及び増幅cDNAの存在を検出することを含む。加えて、そうした方法は、(例えば、アクチンファミリーメンバーなどの「ハウスキーピング」遺伝子の比較対照mRNA配列のレベルを同時に調査することによって)生体試料中のmRNAレベルを決定することを可能にする1つ以上の工程を含むことができる。場合によっては、増幅cDNAの配列を決定することができる。
特定の一実施形態では、本明細書に記載のバイオマーカー遺伝子の発現は、RT−PCR技術によって行うことができる。PCRに使用されるプローブは、検出可能なマーカー、例えば、放射性同位元素、蛍光化合物、生物発光化合物、化学発光化合物、金属キレーター、または酵素などで標識することができる。そうしたプローブ及びプライマーを使用して、試料中の、表1、表2、または表3に記載される発現遺伝子の存在を検出することができる。当業者なら理解するように、非常に多くの異なるプライマー及びプローブを調製し、表1、表2、及び表3に記載される1つ以上の発現遺伝子の増幅、クローニング、及び/または存在及び/またはレベルを決定するために効果的に使用することができる。
表1、表2、または表3に記載される遺伝子の少なくとも1つ(例えば、表3に記載の遺伝子の1、2、3、4、5、6、7、8、9、または10個、及び/または、表2に記載の少なくとも1つの異なる遺伝子(例えば、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、50、または60個もしくはそれ以上の異なる遺伝子)、及び/または、表1に記載の少なくとも1つの異なる遺伝子(例えば、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、50、60、70、80、90、または100個もしくはそれ以上の異なる遺伝子))に対応するタンパク質バイオマーカーなどのタンパク質バイオマーカーの検出については、例えば、抗体ベースの方法、並びに質量分析法、及び当該技術分野で公知の他の同様の手段を含む、様々なタンパク質アッセイが利用できる。抗体ベースの方法の場合では、例えば、試料を、抗体−バイオマーカー複合体を生成するのに十分な条件下で、そのバイオマーカーに特異的な抗体と接触させてよく、次いで該複合体が検出される。タンパク質バイオマーカーの存在の検出は、血漿や血清を含む広範な種類の組織や試料をアッセイするウェスターンブロット法(免疫沈降の有無にかかわらず)、2次元SDS−PAGE、免疫沈降、蛍光活性化細胞分取(FACS)、フローサイトメトリー、及びELISA手順をなど複数の方法で達成できる。このようなアッセイフォーマットを使用する広範な免疫アッセイ技術が入手可能であり、例えば、米国特許法第4,016,043号、同第4,424,279号、及び同第4,018,653号などを参照されたい。これらには、非競合タイプのシングルサイト及び2サイトまたは「サンドイッチ」アッセイと、従来の競合結合アッセイの両方が包含される。これらのアッセイは、標識抗体と標的バイオマーカーの直接的な結合も含む。
バイオマーカーの検出に使用するため、キットまたは製造品も本発明により提供される。このようなキットは、患者がVEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)での治療から恩恵を得るかどうかを決定するために使用することができる。これらのキットは、表1、表2、または表3に記載される遺伝子の少なくとも1つ(例えば、表3に記載の遺伝子の1、2、3、4、5、6、7、8、9、または10個、及び/または、表2に記載の少なくとも1つの異なる遺伝子(例えば、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、50、または60個もしくはそれ以上の異なる遺伝子)、及び/または、表1に記載の少なくとも1つの異なる遺伝子(例えば、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、50、60、70、80、90、または100個もしくはそれ以上の異なる遺伝子))の発現レベルを決定することができるポリペプチドまたはポリヌクレオチドと、表1、表2、または表3に記載される遺伝子の少なくとも1つの発現レベルを決定するためのポリペプチドまたはポリヌクレオチドの使用説明書とを含み得る。表1、表2、または表3に記載される遺伝子の少なくとも1つの発現が、基準レベル(例えば、上記を参照のこと)に対して変化(即ち、増大または低下)するかまたは基準レベルと異なる場合、患者がVEGFアンタゴニスト、例えば、抗VEGF抗体(例えば、ベバシズマブ)での治療から恩恵を得る。次に、患者には、VEGFアンタゴニストでの治療に感受性または応答性がある可能性が高いことを知らせてもよく、及び/または、抗癌治療がVEGFアンタゴニストを含む提案を提供してもよい。
本明細書で使用する場合、予測ルールの一般的形態は、応答性または非応答性を予測し、またはより一般的には、適切に定められた臨床エンドポイントによる有益性または有益性の欠如を予測するための臨床的共変量を潜在的に含む1つ以上のバイオマーカーの関数の仕様からなる。
バイオマーカーXについて、高発現レベルが悪い臨床応答に関与していることが、臨床試験集団において見出される(一変量分析)。詳細な分析が、集団には2種類の臨床応答が存在し、その第一の群が第二の群よりも悪い応答を有し、同時に第一の群に対するバイオマーカー発現が少なくとも1つの用量のVEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)の投与後に一般により高いことを示す。調整共変量分析は、各群について、臨床有益性と臨床応答との間の関係が逆転し、即ち、群内で、より低い発現レベルは良好な臨床応答に関連していることを明らかにする。全体的な反対効果は共変量タイプによりマスクされ、予測ルールの一部としての共変量調整分析は方向を逆転させた。
バイオマーカーXについて、高発現レベルが悪い臨床応答に僅かに関与していることが、臨床試験集団において見出される(一変量分析)。第2のバイオマーカーYについては、同様な観察が一変量分析によってなされた。XとYの組み合わせはでは、双方のバイオマーカーが低い場合に、良好な臨床応答が見られることが明らかになった。これにより、双方のバイオマーカーが所定のカットオフよりも低いならば、有益であると予測されるという規則が作成される(ヘビサイド予測関数のAND−−接続)。組み合わせ規則については、一変量の意味における単純なルールはもはや通用しない;例えば、Xにおいて低い発現レベルを有していても、より良好な臨床応答を自動的には予測しないであろう。
A.用量及び投与
本明細書に記載のVEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)での治療に応答性または感受性のある患者がひとたび同定されれば、VEGFアンタゴニスト単独での治療または他の薬剤との組み合わせでの治療を行うことができる。例えば、そのような治療は、腫瘍サイズ(例えば、神経膠芽腫腫瘍サイズ)の減少、または無増悪生存期間(PFS)及び/または全生存期間(OS)の増加を生じ得る。さらに、VEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)と少なくとも1つの第2の薬剤(単数または複数)の組み合わせでの治療は、好ましくは患者に対して相加的な、より好ましくは相乗的な(または相加的よりも大なる)治療的恩恵を生じる。好ましくは、この併用方法において、第2の薬剤の少なくとも一回の投与と本明細書におけるアンタゴニストの少なくとも一回の投与の間のタイミングは、約1ヶ月以下、より好ましくは約2週間以下である。
VEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)は、非経口、局所、皮下、腹腔内、肺内、鼻腔内、及び/または病巣内投与を含む、任意の適切な手段により投与される。非経口注入には、筋肉内、静脈内、動脈内、腹腔内、または皮下投与が含まれる。くも膜下腔内投与もまた考えられる。加えて、VEGFアンタゴニストは、例えば、減少用量のVEGFアンタゴニストでのパルス注入により適切に投与されてもよい。最も好ましくは、投薬は、静脈内注射により投与される。
いくつかの実施形態では、VEGFアンタゴニスト(例えば、抗VEGF抗体、例えば、ベバシズマブ)は、1つ以上のさらなる抗癌剤または療法と併用してもよい。抗癌療法の例としては、限定されないが、手術、放射線療法(放射線治療)、生物療法、免疫療法、化学療法(例えば、テモゾロミド(TMZ))、またはこれらの療法の組み合わせが挙げられる。加えて、細胞傷害性剤、抗血管形成剤、及び抗増殖剤を抗VEGF抗体と併用してもよい。1つ以上のさらなる抗癌剤または療法は、好ましくは、それらが互いに悪影響を及ぼさないようにVEGFアンタゴニストに対して相補的な活性を有している。併用投与には、別々の製剤または単一の薬学的製剤を使用しての同時投与と、何れかの順序での連続投与が含まれ、ここで、両方(または全て)の活性剤が同時にその生物学的活性を作用させる時間があるのが好ましい。
本明細書に記載の全ての方法では、VEGFアンタゴニストは、抗VEGF抗体である。
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKR(配列番号1)を含む軽鎖可変領域と、以下のアミノ酸配列:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS(配列番号2)を含む重鎖可変領域を有する。
本発明に従って使用されるアンタゴニストの治療製剤は、所望の程度の純度を有するアンタゴニストと任意の薬学的に許容される担体、賦形剤または安定剤とを、凍結乾燥製剤または水性溶液の形態で混合することによって保存用に調製される。製剤に関する一般的な情報については、例えば、Gilmanら、(eds.) (1990), The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press; A.Gennaro (ed.), Remington’s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Eastori, Pennsylvania.; Avisら、(eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications Dekker, New York; Liebermanら、(eds.) (1990) Pharmaceutical Dosage Forms: Tablets Dekker, New York;及びLiebermanら、(eds.) (1990), Pharmaceutical Dosage Forms: Disperse Systems Dekker, New York, Kenneth A.Walters (ed.) (2002) Dermatological and Transdermal Formulations (Drugs and the Pharmaceutical Sciences), Vol 119, Marcel Dekkerを参照されたい。
次の実施例は、現在請求している発明を、限定しないで例証するために提供される。
統計的方法
一般に、統計的タスクは次の工程を含み得る:
・ 1.候補バイオマーカーの事前選択
・ 2.関連性のある臨床効果の応答性予測共変量の事前選択
・ 3.一変量レベルでのバイオマーカー予測関数の選択
・ 4.一変量レベルでの臨床的共変量を含むバイオマーカー予測関数の選択
・ 5.多変量レベルでのバイオマーカー予測関数の選択
・ 6.多変量レベルでの臨床的共変量を含むバイオマーカー予測関数の選択
次のテキストは、異なる工程を詳細に説明する:
候補バイオマーカーの統計的事前選択は、臨床的有益性の尺度関連性の強度に向けられている。この目的のために、異なる臨床エンドポイントは、誘導されたサロゲートスコア、例えば、観測打ち切りを回避するTTPに関する臨床的有益性スコアの度合いの順序割り当てに変換され得る。これらのサロゲート変換指標は、例えば、ノンパラメトリックスピアマン順位相関アプローチにより、簡単な相関関係分析に容易に使用することができる。代替法は、例えば、コックス比例ハザード回帰のように、事象発生までの時間の回帰モデル(time−to−event regression models)における計量的共変量として、バイオマーカー測定値を使用する。バイオマーカー値の統計的分布に応じて、この工程は、いくつかの事前加工、例えば、分散安定化変換、適切な尺度の使用、または未加工測定値の代わりにパーセンタイルを使用するなどの標準化工程が必要となり得る。さらなるアプローチは、例えば、一人の患者を基準に、(x軸=バイオマーカー値、y軸=臨床的有益性の尺度)の散布を示すことによる、二変量散布プロットの検査である。例えば、平滑化スプラインにより達成されるいくつかのノンパラメトリック回帰線は、バイオマーカーと臨床的有益性との関連性を視覚化するのに有用であり得る。
本明細書で定義された臨床的共変量の統計的事前選択は、バイオマーカーの事前選択についてのアプローチと類似しており、臨床的有益性の尺度との関連性の強度を指向している。よって、原則的には、上の1で検討したものと同じ方法が適用される。統計的基準に加え、臨床経験からの基準及び理論的知識が、関連する臨床的共変量を事前選択するのに適用され得る。
「予測関数」という用語は、一般的に標的予測を暗示するためにスケーリングされた数をもたらすバイオマーカー測定値の数的関数を意味するのに使用される。
一変量は、1つのバイオマーカーのみを使用することを言い、臨床的共変量に関して、これは多変量モデルであり得る。このアプローチは、該方法が関連する共変量情報の導入を可能にすべきことを除けば、臨床的共変量を用いない探索と類似している。カットオフを選択する散布図法は、共変量の限られた使用のみを可能にし、例えば、二値共変量は、プロット内でカラーコード化され得る。分析が、いくつかの回帰手法に依存しているならば、共変量(また一回でのそれらの多く)を使用することは通常は容易である。上の3に記載されたコックスモデルに基づくカットオフ探索により、共変量を容易に導入することが可能となり、それによって、共変量調整された一変量カットオフ探索に至る。共変量による調節は、モデルにおける共変量として、または層別解析における包含物を介してなされ得る。
異なる一変量予測関数の選択内で、それらの予測可能性を維持するいくつかのバイオマーカー候補が存在している場合、バイオマーカーの組み合わせにより、即ち、多変量予測関数を考慮することにより、さらなる改善が達成され得る。
関連する臨床的共変量が存在する場合、複数の臨床的共変量と複数のバイオマーカーを組み合わせることにより、さらなる改善が達成され得る。異なる予測関数の選択は、臨床的共変量を含む可能性に関して評価されるであろう。
全ての解析工程は、オープンソースプログラミング言語R(R Core Team (2013) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria)を用いて行った。全てのAffymetrixマイクロアレイからの未加工データをRefPlus Rパッケージを用いて共通基準分布に正規化した(Harbronら、Bioinformatics。23(18): 2493−2494、2007)。
AvaGlio試験は、新たに診断された神経膠芽腫ための、テモゾロミドと放射線治療とを組み合わせたベバシズマブの有効性と安全性を評価した。この試験は、ベバシズマブ+化学療法対化学療法単独の前向き、無作為化、二重盲検、プラセボを対照第III相評価として設計された。適格であるためには、外科的切除または生検の何れかの後に確定された組織診断で患者は新たに神経膠芽腫と診断されていなければならない。化学療法や放射線治療にベバシズマブを追加することにより、AvaGlio試験は、治療の選択肢が限られ、特に不良な予後に直面している患者のこの群に対する全生存期間(OS)及び無増悪生存期間(PFS)を改善することを目的とした。主な目的は、テモゾロミド(TMZ)及び放射線治療にのみに対して、またはテモゾロミド及び放射線治療+ベバシズマブに対して無作為化された患者のOSとPFSを比較することであった。
この試験は、3相(同時、維持、及び単剤療法)、及び2つ(2)の治療群:TMZ及び放射線治療(治療群1)とTMZ及び放射線治療+ベバシズマブ(治療群2)から構成された。患者は無作為にどちらかの治療群に割り当てられた(1:1)。
18歳以上で、外科的切除または生検のいずれかの後に確定された組織診断で新たにテント上神経膠芽腫(GBM)と診断された患者が含まれた。これは、組織学的に検証されたGBMにアップグレードされた低悪性度星細胞腫の診断を以前に受けた未治療の化学療法及び放射線治療患者を含む。患者のWHOのパフォーマンスステータスは、≦2でなければならない。
脳の手術後のMRIにおける最近の出血の証拠は、候補患者から排除した。しかしながら、手術に関連した出血性変化が消散した、臨床的に無症状のヘモジデリンの存在、腫瘍において点状出血の存在を有する患者は、試験への参加を許可された。臨床試験への登録のためMGMTステータスについての事前の集中スクリーニング;神経膠芽腫及び低悪性度星細胞腫に対する任意の事前の化学療法(カルムスチン含有ウエハー(Gliadel(登録商標)を含む)または免疫療法(ワクチン療法を含む);脳への任意の事前の放射線治療または放射線場に潜在的な重複が生じる任意の事前の放射線治療;高血圧性クリーゼまたは高血圧性脳症の既往歴;無作為化前の1ヶ月以内にNCI−CTCの基準に従って≧グレード2の喀血の既往歴;(治療的抗凝血がない場合)出血性素因または凝固障害の証拠;無作為化前の28日以内の、大手術、直視下生検、頭蓋内生検、脳室腹腔短絡術、または重大な外傷性損傷;無作為化前の7日以内のコア生検(頭蓋内生検を除く)または他の軽微な外科的処置も患者から排除した。ベバシズマブ/プラセボ投与の前の2日以内に行われる場合、中心血管アクセスデバイス(CVAD)の配置;無作為化前の6ヶ月以内に腹瘻または消化管穿孔の既往歴;無作為化前の6ヶ月以内に頭蓋内膿瘍の既往歴;深刻な非治癒傷、活動性潰瘍または未治療骨折も患者から排除した。妊娠中または授乳中の女性に対して、試験治療開始前の7日以内または14日以内(試験治療開始前の7日以内に確認の尿妊娠検査を伴う)に血清妊娠検査を評価した。非常に効果の高い、ホルモン性避妊手段または非ホルモン性の避妊手段(即ち、子宮内避妊具)を使用しない(最後の月経後2年未満または外科的に不妊ではないと定義される)繁殖性の女性及び男性;無作為化前6ヶ月以内の脳卒中または一過性脳虚血発作(TIA)の既往歴;無作為化前6ヶ月以内に、制御が不十分な高血圧(持続的収縮期血圧>150mmHg及び/または拡張期圧>100mmHg)、または外科的修復を必要とする大動脈瘤または最近の末梢動脈血栓症を含む重大な血管疾患を持つ患者も排除した。無作為化前6ヶ月以内に心筋梗塞または不安定狭心症またはニューヨーク心臓協会(NYHA)グレードII以上のうっ血性心不全(CHF);試験薬物または賦形剤のいずれかに対する既知の過敏症を有する患者も排除した。
Phillipsら(Cancer Cell. 9(3): 157−173、2006)に最初に記載された遺伝子発現サブタイプをAvaGlio試験から得た試料に割り当てようとする代替のアプローチでは、Nanostring遺伝子発現データの教師なし分析を行った。35個のプローブシグネチャに加えて、Phillipsらは、667個のEntrez遺伝子識別子にマッピングした書き込み時に、556個の固有注釈付き遺伝子記号に対応するより広範な一連の725個のAffymetrixマイクロアレイプローブも同定した。上の表1に列挙した、これらの遺伝子の108個をNanostringプラットフォーム上にアッセイした。
収縮セントロイドは、新規の試料の分類において、競合する方法よりも正確であることが多いことが示されている(Tibshiraniら、PNAS. 99(10): 6567−6572, 2002)。各クラスのセントロイドを(各遺伝子の級内標準偏差によって正規化後の)全セントロイドへ収縮させることで、同じクラスの試料内で発現が安定な遺伝子により重い重量を割り当てる。同時に、例えば、ユーザ定義した閾値を下回って重量が収縮する遺伝子を除去することで、減少した一連の分類子特徴を得ることができる。ここで、PNをAvaGlioトライアル由来の非PN試料から区別する収縮セントロイド分類子を得るためにPAMRアルゴリズムを使用している。
以前の実施例では、患者を遺伝子発現サブタイプに分類することができ、前神経(PN)サブタイプへの割り当ては、この亜群中のOSにおいて、RT及び化学療法と併用した抗VEGF治療(例えば、抗VEGF抗体療法、例えば、ベバシズマブ療法)の予測となることを実証した。ここで、収縮セントロイド分類子(実施例4)からトップテンの最も高く重み付けた予測遺伝子を用いて、各患者の定量的PNスコアを算出した。
Claims (28)
- 神経膠芽腫を有する患者がVEGFアンタゴニストでの治療に応答する可能性が高いかどうか決定することを補助する方法であって、
(a)VEGFアンタゴニストの前記患者への投与の前に、前記患者から得られた生体試料中のNCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択される遺伝子の少なくとも1つの発現を検出することと、
(b)前記少なくとも1つの遺伝子の発現レベルと前記少なくとも1つの遺伝子の基準発現レベルを比較することを含み、
ここで、決定することは、前記基準レベルに対する前記患者試料中の前記少なくとも1つの遺伝子の発現レベルの増加により、患者を、前神経(PN)亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療に応答する可能性が高い患者として同定することを含む、前記方法。 - 神経膠芽腫を有する患者に対する抗癌治療の治療効果を最適化することを補助する方法であって、
(a)VEGFアンタゴニストの前記患者への投与の前に、前記患者から得られた生体試料中のNCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択される遺伝子の少なくとも1つの発現を検出することと、
(b)前記少なくとも1つの遺伝子の発現レベルと前記少なくとも1つの遺伝子の基準発現レベルを比較することを含み、
ここで、最適化することは、前記基準レベルに対する前記患者試料中の前記少なくとも1つの遺伝子の発現レベルの増加により、患者を、PN亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療に応答する可能性が高い患者として同定することを含む、前記方法。 - 前記患者が、神経膠芽腫を有しかつVEGFアンタゴニストへの応答性を試験されている患者の集団であり、前記基準レベルが、前記患者集団における前記少なくとも1つの遺伝子の発現の中央値レベルである、請求項1または2に記載の方法。
- 前記基準レベルが、神経膠芽腫を有しかつVEGFアンタゴニスト治療に応答しないと同定された患者における前記少なくとも1つの遺伝子の発現の中央値レベルである、請求項1または2に記載の方法。
- 前記患者から得られた前記生体試料中の前記少なくとも1つの遺伝子の発現が、mRNAを測定することで検出される、請求項1〜4のいずれか1項に記載の方法。
- 前記患者から得られた前記生体試料中の前記少なくとも1つの遺伝子の発現が、血漿タンパク質レベルを測定することで検出される、請求項1〜5のいずれか1項に記載の方法。
- 前記生体試料が、腫瘍組織である、請求項1〜6のいずれか1項に記載の方法。
- 前記患者由来の前記生体試料中の前記遺伝子の少なくとも2つの発現を検出することをさらに含む、請求項1〜7のいずれか1項に記載の方法。
- 前記患者由来の前記生体試料中の前記遺伝子の少なくとも3つの発現を検出することをさらに含む、請求項8に記載の方法。
- 前記患者由来の前記生体試料中の前記遺伝子の少なくとも4つの発現を検出することをさらに含む、請求項9に記載の方法。
- 前記VEGFアンタゴニストが、抗VEGF抗体である請求項1〜10のいずれか1項に記載の方法。
- 抗VEGF抗体が、A4.6.1エピトープに結合する、請求項11に記載の方法。
- 抗VEGF抗体が、ベバシズマブである、請求項11に記載の方法。
- 抗VEGF抗体が、可変重鎖(VH)及び可変軽鎖(VL)を含み、前記VHが、配列番号2のアミノ酸配列を含み、前記VLが、配列番号1のアミノ酸配列を含む、請求項11に記載の方法。
- VEGFアンタゴニストでの治療への応答性が、全生存期間の増加である、請求項1〜14のいずれか1項に記載の方法。
- 神経膠芽腫を有する患者に対する治療を選択することを補助する方法であって、
(a)VEGFアンタゴニストの前記患者への投与の前に、前記患者から得られた生体試料中のNCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択される遺伝子の少なくとも1つの発現を検出することと、
(b)前記少なくとも1つの遺伝子の発現レベルと前記少なくとも1つの遺伝子の基準発現レベルを比較することを含み、
ここで、選択することは、前記基準レベルに対する前記患者試料中の前記少なくとも1つの遺伝子の発現レベルの増加により、患者を、PN亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療に応答する可能性が高い患者として同定することを含む、前記方法。 - 前記基準レベルが、神経膠芽腫を有する患者の集合における前記少なくとも1つの遺伝子の発現の中央値レベルである、請求項16に記載の方法。
- 前記基準レベルが、神経膠芽腫を有しかつVEGFアンタゴニスト治療に応答しないと同定された患者における前記少なくとも1つの遺伝子の発現の中央値レベルである、請求項16に記載の方法。
- 前記患者由来の前記生体試料中の前記遺伝子の少なくとも2つの発現を検出することをさらに含む、請求項16〜18のいずれか1項に記載の方法。
- 前記患者由来の前記生体試料中の前記遺伝子の少なくとも3つの発現を検出することをさらに含む、請求項19に記載の方法。
- 前記患者由来の前記生体試料中の前記遺伝子の少なくとも4つの発現を検出することをさらに含む、請求項20に記載の方法。
- 選択される治療が、VEGFアンタゴニスト並びに抗腫瘍剤、化学療法剤、増殖阻害剤、及び細胞傷害性剤からなる群から選択される薬剤、放射線治療、またはその組み合わせを含む、請求項16に記載の方法。
- 選択される治療が、VEGFアンタゴニスト及びテモゾロミド(TMZ)を含む、請求項16に記載の方法。
- VEGFアンタゴニストでの治療への応答性が、全生存期間の増加である、請求項16〜23のいずれか1項に記載の方法。
- 神経膠芽腫を有する患者がVEGFアンタゴニストでの治療から恩恵を得る可能性があるかどうかを決定するためのキットであって、
(a)NCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択される遺伝子の少なくとも1つの発現レベルを決定することができるポリペプチドまたはポリヌクレオチドと、
(b)NCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択される前記遺伝子の少なくとも1つの発現レベルを決定するための前記ポリペプチドまたはポリヌクレオチドの使用説明書であって、ここで、基準レベルに対する前記少なくとも1つの遺伝子発現レベルの増加は、前記患者がPN亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療から恩恵を得る可能性があることを示す、使用説明書
を含む、前記キット。 - 神経膠芽腫を有する患者がVEGFアンタゴニストでの治療に応答する可能性が高いかどうかを決定するためのキットであって、
VEGFアンタゴニストの前記患者への投与の前に、前記患者から得られた生体試料中の少なくとも1つの遺伝子の発現を検出するための手段を含み、ここで、前記少なくとも1つの遺伝子は、NCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択され、
前記少なくとも1つの遺伝子の発現レベルと前記少なくとも1つの遺伝子の基準発現レベルが比較され、ここで、前記基準レベルに対する前記患者試料中のNCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及び/またはPFN2の発現レベルの増加により、患者を、PN亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療に応答する可能性が高い患者として同定する、
キット。 - 神経膠芽腫を有する患者に対する抗癌治療の治療効果を最適化するためのキットであって、
VEGFアンタゴニストの前記患者への投与の前に、前記患者から得られた生体試料中の少なくとも1つの遺伝子の発現を検出するための手段を含み、ここで、前記少なくとも1つの遺伝子は、NCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択され、
前記少なくとも1つの遺伝子の発現レベルと前記少なくとも1つの遺伝子の基準発現レベルが比較され、ここで、前記基準レベルに対する前記患者試料中のNCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及び/またはPFN2の発現レベルの増加により、患者を、PN亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療に応答する可能性が高い患者として同定する、
キット。 - 神経膠芽腫を有する患者に対する治療を選択するためのキットであって、
VEGFアンタゴニストの前記患者への投与の前に、前記患者から得られた生体試料中の少なくとも1つの遺伝子の発現を検出するための手段を含み、ここで、前記少なくとも1つの遺伝子は、NCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及びPFN2からなる群から選択され、
前記少なくとも1つの遺伝子の発現レベルと前記少なくとも1つの遺伝子の基準発現レベルが比較され、ここで、前記基準レベルに対する前記患者試料中のNCAM1、OMG、PRKCZ、GALNT13、GPR17、DNM3、FERMT1、SNAP91、ABHD6、及び/またはPFN2の発現レベルの増加により、患者を、PN亜型の神経膠芽腫を有しVEGFアンタゴニストでの治療に応答する可能性が高い患者として同定する、
キット。
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