JP2018119966A - 肝細胞がん患者の再発リスク予測を補助する方法、装置、コンピュータプログラム製品及びキット - Google Patents
肝細胞がん患者の再発リスク予測を補助する方法、装置、コンピュータプログラム製品及びキット Download PDFInfo
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Abstract
Description
非特異反応抑制剤としては、測定で使用する抗体が目的抗原以外の物質に結合することを抑制するものであれば特に制限されない。具体的には、マウス血清、ヒツジ血清、ヤギ血清、マウス抗体及びヒツジ抗体、ヤギ抗体などが挙げられる。非特異反応抑制剤は市販されており、例えば、TRUBlock(Meridian Life Science社)、ASSAY DEVELOPMENT BLOCKING KIT(SCANTIBODIS LABORATOR社)、THBR2(株式会社特殊免疫研究所)等が知られている。
1)まず、無再発患者群から術前に得た血液試料と、再発患者群から術前に得た血液試料のそれぞれについて、GPC3濃度を測定する。
2)測定結果に基づいて、無再発の患者のGPC3濃度の値よりも高く、且つ、再発した患者のGPC3濃度の値よりも低い範囲から閾値を設定する。
好ましくは、無再発の患者とがんが再発した患者とを高精度に区別し得る値を、閾値として設定する。なお、後述の実施例では、GPC3濃度の閾値を15 pg/mLに設定している。本実施形態では、肝細胞がん患者の血液試料中のGPC3ペプチドの濃度を、上記のようにして予め設定された閾値と比較し、無再発患者群および再発患者群の何れに分類されるかが予測される。検査の結果として、たとえば、無再発患者群に分類される場合は再発リスクが低いという判定結果が出力され、再発患者群に分類される場合は再発リスクが高いという判定結果が出力される。
B型肝炎ウイルスの遺伝子型は特に限定されず、本願の出願日において既知のジェノタイプA〜J及びこれらのサブタイプ(例えばAa/1等)のいずれであってもよいし、将来発見され得る、本願の出願日において未知のジェノタイプであってもよい。
HCC患者血液サンプル39例は、患者からの同意を得て、国立がん研究センター東病院(千葉県柏市)にて肝切除治療前に採取し、遠心分離により血漿を取得した。このうち28例は肝切除治療後4年以内にHCCの再発が確認されており、11例は無再発であった。
健常人血漿サンプル50例はサンフコ社より購入した。いずれのサンプルも使用直前まで-80℃で凍結保存した。
さらに、実施例1で得られた測定結果で判定したGPC3陽性/陰性群について、再発リスク予測の有意差があるか検定した。再発の有無についてKaplan -Meier曲線を作成し、ログランク検定を行なったところ、図7に示す通りP値は0.0002となり、GPC3陽性群は有意に再発しやすい傾向が見られることが示された。なお、統計解析ソフトにはStatFlex ver.6(アーテック社)を用いた。
実施例1及び2で使用した抗体のエピトープを解析し、HCCの再発リスク判定精度が飛躍的に向上した理由が全長型GPC3を正しく捉えることであるかについて検証した。
検出用に用いたC末端認識型モノクローナル抗体のエピトープ解析は、図8のようなオーバーラッピングペプチド(表2)を用いた競合ELISAによって行なった。
捕捉用に用いたN末端認識型モノクローナル抗体のエピトープ解析は、図12のような部分リコンビナント蛋白質を用いたウェスタンブロット解析によって行なった。
GPC3の301番目から358番目のペプチドを認識する第一のN末端認識型モノクローナル抗体(ビオチン標識)と、GPC3の543番目から552番目のペプチドを認識する第二のC末端認識型モノクローナル抗体(アルカリフォスファターゼ標識)を用いて、自動免疫測定装置HISCL-800(シスメックス社)によって市販血漿10種(Proteogenex社)の測定を行った。なお、抗体のビオチン標識はBiotin Labeling Kit - SH(同仁化学研究所)を添付プロトコール通りに用いて行なった。
HCC患者血液サンプル39例のうち、4年以内に再発が見られた28例について、ウイルス感染の有無に基づく解析を実施した。再発群は年齢中央値68歳(63-72)であり、このうちHCV陽性は18例、HBV陽性は7例、ウイルス感染なしは3例であった。また、無再発期間は中央値10ヶ月(3-21)であった。
22 測定装置
33 判定装置
33a コンピュータ本体
33b 入力部
33c 表示部
301 受信部
302 記憶部
303 算出部
304 判定部
305 出力部
330 CPU
331 ROM
332 RAM
333 ハードディスク
334 入出力インターフェイス
335 読出装置
336 通信インターフェイス
337 画像出力インターフェイス
338 バス
340 記録媒体
500 箱
501 第1試薬容器
502 第2試薬容器
503 添付文書
Claims (8)
- グリピカン3(GPC3)の1〜358番目のアミノ酸配列を有するペプチドを認識する第1モノクローナル抗体と、アミノ酸配列TPKDNEISTFを認識する第2モノクローナル抗体と、血液試料とを混合する工程と、
前記第1モノクローナル抗体及び前記第2モノクローナル抗体の両方に認識されるGPC3ペプチドを測定する工程と
を含む、血液試料中のGPC3の測定値の取得方法。 - 前記血液試料が、肝細胞がん患者、肝細胞がんの発症が疑われる患者、又は肝細胞がんの再発が疑われる患者から採取した血液試料である請求項1に記載の方法。
- 前記測定値が、肝細胞がんの再発リスク診断を補助するための指標となる請求項1又は2に記載の方法
- 前記第1モノクローナル抗体又は前記第2モノクローナル抗体が、固相に固定化されている請求項1〜3のいずれか1項に記載の方法。
- 前記固相が、粒子である請求項4に記載の方法。
- 前記第1モノクローナル抗体又は前記第2モノクローナル抗体が、標識物質で標識されている請求項1〜5のいずれか1項に記載の方法。
- 測定工程が、非特異反応抑制剤の存在下で行われる、請求項1〜6のいずれか1項に記載の方法。
- プロセッサ及び前記プロセッサの制御下にあるメモリを含むコンピュータを備え、前記メモリには、血液試料中のグリピカン3(GPC3)ペプチドの測定値を取得するステップを前記コンピュータに実行させるためのコンピュータプログラムが記録されており、
前記GPC3ペプチドが、GPC3の1〜358番目のアミノ酸配列を有するペプチドを認識する第1モノクローナル抗体と、アミノ酸配列TPKDNEISTFを認識する第2モノクローナル抗体との両方に認識されるペプチドであり、
前記測定値が、肝細胞がんの再発リスク診断を補助するための指標となる、
血液試料中のGPC3の測定値を取得するための装置。
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