JP2017518516A - Pd−l1について染色された腫瘍組織の改善されたスコア化のための多重アッセイ - Google Patents
Pd−l1について染色された腫瘍組織の改善されたスコア化のための多重アッセイ Download PDFInfo
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Abstract
Description
[0001]本出願は、2014年5月30日出願の米国特許出願第62/005701号の利益を主張し、この出願はその全体が参照により本明細書に援用される。
[0001]本開示内容は、腫瘍組織におけるPD−L1の発現を組織化学的に検出及びスコア化するための材料及び方法に関する。
[0002]プログラム死(Programmed death)1(PD−1)は、受容体のCD28ファミリーのメンバーであり、これにはCD28、CTLA−4、ICOS、PD−1、及びBTLAが含まれる。PD−1には、PD−L1及びPD−L2という二つの細胞表面糖タンパク質リガンドが同定されており、PD−1に結合するとT細胞活性化とサイトカイン分泌を下方制御することが示されている(Freeman et al., J Exp Med 192:1027-34 (2000); Latchman et al., Nat Immunol 2:261-8 (2001); Carter et al., Eur J Immunol 32:634-43 (2002); Ohigashi et al., Clin Cancer Res 11:2947-53 (2005))。PD−L1(B7−H1)及びPD−L2(B7−DC)は共に、PD−1に結合するが、他のCD28ファミリーメンバーには結合しないB7ホモログである。
[0010]本方法は、例えば、新鮮凍結、ホルマリン固定パラフィン包埋(FFPE))試料、細胞学的スミア(子宮頚部スミア)、循環性腫瘍細胞の単離物などを含む、組織化学的又は細胞化学的分析に適した腫瘍試料と適合する。
[0012]非腫瘍細胞から腫瘍細胞を区別することのできる任意のマーカーを使用することができる。腫瘍細胞に特異的なバイオマーカーの例には、限定されないが:パンケラチン抗体で検出可能なサイトケラチン(例えば、塩基性サイトケラチン、酸性サイトケラチンの多く)、その他のサイトケラチン、例えばサイトケラチン7(CK7)及びサイトケラチン20(CK20)、クロモグラニン、シナプトフィジン、CD56、甲状腺転写因子−1(TTF−1)、p53、白血球共通抗原(LCA)、ビメンチン、平滑筋アクチンなどが含まれる(例えば、Capelozzi, V., J Bras Pneumol. 2009;35(4):375-382参照)。
[0016]組織化学及び細胞化学は、顕微鏡で可視化できる方式で、バイオマーカーに特異的に結合する分子を用いて試料を標識化することにより、無傷細胞の状況においてバイオマーカーを同定するためにしばしば使用される技術である。免疫組織化学(IHC)及び免疫細胞化学(ICC)は、バイオマーカーを標識するために抗体を用いる組織化学及び細胞化学の種類である。in situハイブリダイゼーション(ISH)は、組織又は細胞試料中の特定のヌクレオチド配列を標識するために核酸プローブを用いる組織化学又は細胞化学の種類である。組織環境又は細胞環境の状況においてバイオマーカーを同定することにより、バイオマーカーと、細胞又は組織試料の他の形態的又は分子的特徴の空間的相互関係を解明することができ、これにより他の分子的又は細胞的技術からは明らかでない情報が明らかになりうる。
[0022]先述のように、本発明のアッセイは、外因性結合要素が試料に結合した位置と相関する検出可能なシグナルを生成するための、PD−L1の染色と、腫瘍及び免疫細胞マーカーのうちの一又は複数の染色を特徴とする。試料中の外因性結合要素に由来する検出可能なシグナルを生成する組織化学的及び細胞化学的方法は、当業者に周知であり、典型的には一又は複数の標識の適用を利用する。例示的標識には、発色性標識、蛍光性標識、発光性標識、放射測定標識などが含まれ、マーカー又は標的(例えば、PD−L1、腫瘍細胞特異的マーカー、免疫細胞特異的マーカーなど)の認識のために使用される。標識は、当業者には周知であり、本明細書に記載される標識に限定されない。特定の実施態様では、検出可能なシグナルは、色素原の使用により生成される。
[0037]本発明は、実施例1に用いられるシグナル伝達コンジュゲート(例えば、酵素及び発色基質)にも、本明細書に記載される他のシグナル伝達コンジュゲートにも限定されることはない。検出方法のための代替的な酵素−発色基質の対(例えば、免疫組織化学、様々なin situハイブリダイゼーション法、例えば、シルバーin situハイブリダイゼーション法(SISH)、クロモジェニックin situハイブリダイゼーション法(CISH)、蛍光in situハイブリダイゼーション法(FISH)、mRNA in situハイブリダイゼーション法など)が、当業者には周知である。
[0041]試料は次いでスコア化される。第2の色(及び第3の色)は、腫瘍細胞又は免疫細胞におけるPD−L1のスコア化を志向する。第3の色の使用はスコア化を改善させうる。例えば、第3の色の使用は、いずれの細胞種(腫瘍対免疫)がPD−L1陽性であるかを明らかにすることを助けることができる。これは、PD−L1陽性免疫細胞、PD−L1陰性腫瘍細胞、及びPD−L1陽性腫瘍細胞の数の計算の精密化を助けうる。
[0055]画像化及び検出及び/又はスコア化は、手動で/目視により又はコンピューターシステムを介して実施することができる。スコア化のためのコンピューターベースの免疫検出の例は、当業者には既知である。例えば、その全内容が本明細書に参照により援用される、参照文献の米国仮特許出願第62/005222号、Docket Number32154 US(「Automatic Field of View Selection Systems and Methods」)には、自動細胞検出アルゴリズムを用いた病理組織画像における特定の細胞の検出が開示されている。例えば、希薄色アンミックスアルゴリズムが、生物学的に有意義な複数の異なるカラーチャネルにRGB画像を混合しないために使用される。自動免疫細胞検出アルゴリズムは、一般のニューラルネットワークを用いて免疫細胞マーカーの画像チャネル中の免疫細胞を同定するように訓練される細胞検出器を利用する。更に、自動免疫細胞検出アルゴリズムは、非最大値抑制(non−maximum suppression algorithm)アルゴリズムを利用して、CNN分類器から生成された免疫細胞存在の確率マップから免疫細胞座標を得ることを含む。
[0056]PD−L1に関する患者のスコア化は、治療的処置を決定するために使用されうる。本発明の一態様は、本明細書に記載されるスコア化が治療手法を予測するものである。一実施態様では、陽性のスコア化は、PD−L1阻害剤を用いる治療法の改善された結果を予測する。一実施態様によれば、方法は、腫瘍試料をPD−L1陽性についてスコア化し、PD−L1について陽性とスコア化された腫瘍を有する患者に対して治療剤を投与する。
[0073]本発明はPD−L1をスコア化するためのキットも特徴とする。いくつかの実施態様では、キットは、抗PD−L1抗体及び一又は二(以上)の差別化抗体、例えば、腫瘍細胞に特異的なマーカーに対する抗体、免疫細胞に特異的なマーカーに対する抗体、又は腫瘍細胞に特異的なマーカーに対する抗体と免疫細胞に特異的なマーカーに対する抗体の両方を含む。いくつかの実施態様では、キットは更に、含まれる一次抗体の検出のための二次抗体又は他の試薬を含む。例えば、キットは、検出に使用される二次抗体と基質(例えば、DAB、AEC、ファストレッドなど)を含みうる。いくつかの実施態様では、キットは更に対比染色を含む。いくつかの実施態様では、キットは更に、含まれる抗体及び/又は他の試薬との使用に適切なバッファーを含む。
[0077]実施例1は、本発明の多重IHCアッセイの非限定的実施例を記載する。NSCLC試料のスライドが、標準プロトコールに従って調製される。
[0094]以下の実施例は、国際公開第2013148498号に記載される別のシグナル伝達コンジュゲートを記載しており、この特許文献の全内容が本明細書に参照により援用される。
[00100]以下の実施例は、PD−L1陽性を決定するための様々な計算を記載する(3A−3E)。
[00101]等式:PD−L1の値=PD−L1陽性腫瘍細胞のパーセンテージ
[00102]陽性の閾値:>40%のPD−L1値がPD−L1陽性である。
[00103]病理学者は、試料3Aを調べ、PD−L1陽性腫瘍細胞のパーセンテージを48%と計算する。陽性の閾値に基づき、試料3AはPD−L1陽性と標識される。
[00104]等式:PD−L1の値=PD−L1陽性腫瘍細胞の数/細胞の総数
[00105]陽性の閾値:>0.25のPD−L1値がPD−L1陽性である。
[00106]病理学者は試料3Bを調べる。PD−L1陽性腫瘍細胞の数は68であり、細胞の総数は460である。上記計算に基づくPD−L1値は68/460=0.147である。陽性の閾値に基づき、試料3BはPD−L1陰性と標識される。
[00107]等式:PD−L1の値=PD−L1陽性腫瘍細胞の%+PD−L1陽性免疫細胞の%
[00108]陽性の閾値:>60のPD−L1値がPD−L1陽性である。
[00109]病理学者は試料3Cを調べる。PD−L1陽性腫瘍細胞のパーセントは50であり、PD−L1陽性免疫細胞のパーセントは20である。上記計算に基づくPD−L1値は50+20=70である。陽性の閾値に基づき、試料3CはPD−L1陽性と標識される。
[00110]等式:PD−L1の値=PD−L1陽性腫瘍細胞の数/(PD−L1陰性腫瘍細胞の数+PD−L1陽性免疫細胞の数)
[00111]陽性の閾値:>0.8のPD−L1値がPD−L1陽性である。
[00112]病理学者は試料3Dを調べる。PD−L1陽性腫瘍細胞の数は68であり、PD−L1陰性腫瘍細胞の数は45であり、PD−L1陽性免疫細胞の数は210である。上記計算に基づくPD−L1値は68/(45+210)=0.266である。陽性の閾値に基づき、試料3DはPD−L1陰性と標識される。
[00113]等式:Hスコア=1*(強度1+での腫瘍細胞染色のパーセンテージ)+2*(強度2+での腫瘍細胞染色のパーセンテージ)+3*(強度3+での細胞染色のパーセンテージ)
[00114]陽性の閾値:>125のHスコアがPD−L1陽性である。
[00115]病理学者は試料3Eを調べる。強度1+でのPD−L1陽性腫瘍細胞染色のパーセンテージは5%であり、強度2+でのPD−L1陽性腫瘍細胞染色のパーセンテージは35%であり、強度3+でのPD−L1陽性腫瘍細胞染色のパーセンテージは20%である。Hスコアは5(1)+2(35)+3(20)=135である。陽性の閾値に基づき、試料3EはPD−L1陽性と標識される。
[00116]以下の非特許文献及び特許文献の開示内容の全体が参照により本明細書に援用される:(1)Capelozzi, V., Role of Immunohistochemistry in the diagnosis of lung cancer, J Bras Pneumol. 2009;35(4):375−382;(2)国際公開第20131484498号/米国特許出願公開第2013/0260379号(Signaling Conjugates and Methods of Use);(3)米国仮特許出願第62/005222号 Docket Number 32154 US(Automated Field of View Selection Systems and Methods);(4)米国仮特許出願第61/875334号 Docket Number 31872 US(Scoring Method for Methothelin Protein Expression);仮特許出願第62/004572号、Docket Number 32151 US、2014年5月29日出願。
Claims (25)
- 腫瘍組織試料中のPD−L1の多重標識化方法であって:
組織試料を抗PD−L1一次抗体と接触させること;及び
同組織試料を
・腫瘍細胞に特異的なマーカーに対する一次抗体;又は
・免疫細胞に特異的なマーカーに対する一次抗体;又は
・腫瘍細胞に特異的なマーカーに対する一次抗体及び免疫細胞に特異的なマーカーに対する抗体
と接触させること;及び
組織試料中の抗体の各々を、一次抗体の各々に対応する検出可能なシグナルを生成する試薬を用いて可視化すること
を含み、ここで抗PD−L1抗体は第1の検出可能なシグナルを有し、腫瘍細胞に特異的なマーカーに対する抗体は、第1の検出可能なシグナルから区別可能な第2の検出可能なシグナルを有し、且つ免疫細胞に特異的なマーカーに対する抗体は、第1の検出可能なシグナル及び第2の検出可能なシグナルから区別可能な第3の検出可能なシグナルを有する、方法。 - 腫瘍細胞に特異的なマーカーが、サイトケラチン、クロモグラニン、シナプトフィジン、CD56、甲状腺転写因子−1(TTF−1)、p53、白血球共通抗原(LCA)、ビメンチン、及び平滑筋アクチンからなる群より選択される、請求項1に記載の方法。
- 免疫細胞に特異的なマーカーが、CD3、CD4、CD8、CD19、CD20、CD11c、CD123、CD56、CD14、CD33、又はCD66bからなる群より選択される、請求項1又は2に記載の方法。
- 免疫細胞に特異的なマーカーがT細胞マーカー又はB細胞マーカーである、請求項1から3のいずれか一項に記載の方法。
- 組織試料が、腫瘍細胞に特異的なマーカーに対する抗体及び免疫細胞に特異的なマーカーに対する抗体と接触させられ、ここで腫瘍細胞に特異的なマーカーに対する抗体がパンケラチン抗体であり、免疫細胞に特異的なマーカーに対する抗体が抗CD4抗体である、請求項1に記載の方法。
- 抗PD−L1抗体がSP263又はSP142である、請求項1から5のいずれか一項に記載の方法。
- 第1、第2及び第3の検出可能なシグナルが色素原によって生成される、請求項1から6のいずれか一項に記載の方法。
- 第1の検出可能なシグナルが、
・組織試料を、抗PD−L1一次抗体を認識するホースラディッシュペルオキシダーゼ(HRP)コンジュゲート二次抗体と接触させること;
・HRPを3,3’−ジアミノベンジジン(DAB)と反応させて褐色を生成すること
により生成され、
第2の検出可能なシグナルが、
・試料を、腫瘍細胞に特異的なマーカーに対する一次抗体を認識するアルカリホスファターゼ(AP)標識化抗体と接触させること;
・APをファストレッド色素原及びナフトールと反応させて赤色を生成すること
により生成され;且つ
第3の検出可能なシグナルが、
・試料を、免疫細胞に特異的なマーカーに対する一次抗体を認識するHRPコンジュゲート二次抗体と接触させること;
・HRPをHRP−グリーン色素原と反応させて緑色を生成すること
により生成される、
請求項7に記載の方法。 - 第1、第2及び/又は第3の検出可能なシグナルが、増幅されたシグナルである、請求項1から8のいずれか一項に記載の方法。
- 増幅されたシグナルがチラミドシグナル増幅により生成される、請求項9に記載の方法。
- 試料を一次抗体と接触させることが、同時に実施される、請求項1から10のいずれか一項に記載の方法。
- 試料を一次抗体と接触させることが、連続的に実施される、請求項1から11のいずれか一項に記載の方法。
- 組織試料を対比染色することを更に含み、対比染色が、第1、第2、及び第3の検出可能なシグナルから区別可能な第4の検出可能なシグナルを生成する、請求項1から12のいずれか一項に記載の方法。
- 対比染色がヘマトキシリンを含む、請求項13に記載の方法。
- 第5の検出可能なシグナルが、第1の検出可能なシグナルと第2の検出可能なシグナルの重複により生成される、請求項1から14のいずれか一項に記載の方法。
- 第6の検出可能なシグナルが、第1の検出可能なシグナルと第3の検出可能なシグナルの重複により生成される、請求項15に記載の方法。
- 腫瘍試料中におけるPD−L1発現をスコア化する方法であって、腫瘍組織試料を請求項1から16のいずれか一項に記載の方法に従って標識することと、腫瘍細胞、免疫細胞、若しくは両方におけるPD−L1発現をスコア化することとを含み、ここで第1及び第2の検出可能なシグナルの共局在により、PD−L1陽性腫瘍細胞の存在が示され、第1及び第3の検出可能なシグナルの共局在によりPD−L1陽性免疫細胞の存在が示される、方法。
- PD−L1陽性腫瘍細胞とPD−L1陰性腫瘍細胞の総数が定量化される、請求項17に記載の方法。
- 約10%を上回る腫瘍細胞にPD−L1の染色が検出された場合に腫瘍がPD−L1陽性とスコア化される、請求項18に記載の方法。
- 約50%を上回る腫瘍細胞にPD−L1の染色が検出された場合に腫瘍がPD−L1陽性とスコア化される、請求項18に記載の方法。
- PD−L1陽性免疫細胞とPD−L1陰性免疫細胞の総数が定量化される、請求項17に記載の方法。
- 約10%を上回る免疫細胞にPD−L1の染色が検出された場合に腫瘍がPD−L1陽性とスコア化される、請求項21に記載の方法。
- 約50%を上回る免疫細胞にPD−L1の染色が検出された場合に腫瘍がPD−L1陽性とスコア化される、請求項21に記載の方法。
- PD−L1陽性免疫細胞、PD−L1陽性腫瘍細胞、及びPD−L1陰性腫瘍細胞が定量化されてPD−L1値が生成され、ここで:
PD−L1値=PD−L1陽性腫瘍細胞/(PD−L1陰性腫瘍細胞+PD−L1陽性免疫細胞)であり、
上式中:
PD−L1陽性腫瘍細胞は、第1及び第2の検出可能なシグナルの両方について染色された細胞の数を数えることにより、又は第1の検出可能なシグナルが第2の検出可能なシグナルに関連付けられる組織試料の面積を計算することにより計算され;
PD−L1陰性腫瘍細胞は、第2の検出可能なシグナルのみについて染色された細胞の数を数えることにより、又は第2の検出可能なシグナルが第1の検出可能なシグナルに関連付けられない組織試料の面積を計算することにより計算され;且つ
PD−L1陽性免疫細胞は、第1及び第3の検出可能なシグナルの両方について染色された細胞の数を数えることにより、又は第1の検出可能なシグナルが第3の検出可能なシグナルに関連付けられる組織試料の面積を計算することにより計算される、
請求項17に記載の方法。 - PD−L1陽性腫瘍細胞中におけるPD−L1染色の強度をスコア化すること、及びHスコアを計算することを更に含み、ここで:
Hスコア=1*(強度1+でのPD−L1陽性腫瘍細胞染色のパーセンテージ)+2*(強度2+でのPD−L1陽性腫瘍細胞染色のパーセンテージ)+3*(強度3+でのPD−L1陽性腫瘍細胞染色のパーセンテージ)
である、請求項17に記載の方法。
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