JP5893037B2 - Brafv600eに特異的に結合する抗体を使用する癌の診断のための手段及び方法 - Google Patents
Brafv600eに特異的に結合する抗体を使用する癌の診断のための手段及び方法 Download PDFInfo
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Description
a)BRAFポリペプチドにおいて配列番号:1により特徴付けられるエピトープに特異的に結合する抗体に該サンプルを、該抗体のエピトープへの結合を可能にする条件下で接触させ、
b)エピトープに対する抗体の結合を決定し、それによって癌が診断される、
ことを含む方法に関する。
a)本発明の抗体を含む分析ユニットであって、該分析ユニットに適用されるサンプル中のBRAFポリペプチドにおいて配列番号:1により特徴付けられるエピトープへの抗体の特異的結合の決定を可能にする分析ユニットと;
b)分析ユニットにより決定される結合を評価し、診断を確立するための実行ルールを含む評価ユニット
を含む癌の診断装置に関する。
a)B-Rafポリペプチドにおいて配列番号:1により特徴付けられるエピトープに特異的に結合する抗体に該サンプルを、該抗体のエピトープへの結合を可能にする条件下で接触させ、
b)エピトープに対する抗体の結合を決定し、それによって癌が診断される、
ことを含む方法に関する。
a)上で言及された本発明の抗体を含む分析ユニットであって、分析ユニットに適用されるサンプル中のBRAFポリペプチドにおいて配列番号:1により特徴付けられるエピトープに対する前記抗体の特異的結合の決定を可能にする分析ユニットと;
b)分析ユニットにより決定される結合を評価し、診断を確立する実行ルールを含む評価ユニット
を含む癌診断装置にさらに関する。
596から606位のBRAFアミノ酸配列に適合し、V->E交換を抱える合成ペプチドGLATEKSRWSG(配列番号:1)を商業的に産生させた。Husarソフトウェアパッケージ(DKFZ, Heidelberg, Germany)を、適切な配列領域を選択するために使用した。ペプチドをKLH(キーホールリンペットへモシアニン)にコンジュゲートさせ、免疫原性ペプチドを形成させた。6週齢の雌のC57black sexマウス(Charles River, Sulzfeld, Germany)を使用した。常に、100μl容量を次のスケジュールに従い、マウスの後肢に注射した:
1日目:完全フロイントアジュバントを用い、1:1であることが明らかなPBSに溶解した20μgの免疫原性ペプチドを、マウスに注射した。
5日目:不完全フロイントアジュバントを用い、1:1であることが明らかなPBSに溶解した20μgの免疫原性ペプチドを、マウスに注射した。
11日目:PBSに溶解した20μgの免疫原性ペプチドを、マウスに注射した。
18日目:PBSに溶解した20μgの免疫原性ペプチドを、マウスに注射した。
ホルマリン固定されパラフィン包埋された切片を、電気冷却対物クランプ(クールカット(Cool-Cut)TM;Thermo Fisher Scientific)を具備したミクロムHM355CTMミクロトーム(Thermo Fisher Scientific,Waltham, MA, USA)を用いて4μmに切断した。その後、切片を80℃で15分乾燥させ、ベンタナベンチマーク(Ventana BenchMark)XT(登録商標)免疫染色器(Ventana Medical Systems, Tucson, AZ, USA)で抗BRAF V600E抗体(クローン263)を染色した。ベンタナ染色手順は、60分、細胞コンディショナー1(pH8)を用いた前処理を含み、ついで、37℃で32分、希釈しないBRAF V600Eハイブリドーマ上清と共にインキュベートした。抗体のインキュベートに続いて、ベンタナ増幅キット、ウルトラウォッシュ(UltraWash)を含むベンタナ標準シグナル増幅をし、1滴のヘマトキシリンで4分、1滴の青化試薬で4分、対比染色させた。発色検出のために、ウルトラビュー(ultraView)TMユニバーサルレッドv3検出キット(Ventana Medical Systems)を使用した。続いて、免疫染色器からスライドを取り除き、皿洗い用洗浄剤を用いて水で洗浄し、取り付けた。一次抗体BRAF V600E(クローン263)を取り除いても、色素原は検出されなかった。腫瘍細胞がBRAF V600Eに対して強い細胞質染色を示した場合に、免疫反応はポジティブであるとスコアリングされた。弱い拡散染色及びマクロファージの染色は、ポジティブとスコアリングされなかった。
全てのヒトの材料は、National Center for Tumor Diseases (NCT) and the Department of General Pathology, Institute for Pathology, HeidelbergのTissue Bankから得た。形質細胞腫 (n=26)、濾胞性リンパ腫(n=34)、びまん性大細胞型B細胞リンパ腫(n=41)、縦隔原発B細胞性大細胞型リンパ腫(n=25)、マントル細胞リンパ腫(n=17)、節外周辺帯B細胞リンパ腫(n=16)、ヘアリー細胞リンパ腫(n=3)及びホジキンリンパ腫(n=46)を含む成熟B細胞腫瘍の208の症例を含むパラフィン包埋組織から構築された組織マイクロアレイ(TMA)を分析した。さらなる実験のために、ヘアリー細胞白血病(全n=35)を有する骨髄(n=34)又は脾臓(n=1)、及び脾臓周辺帯リンパ腫(SMZL)(n=4)を有する骨髄からの付加的な完全切片を評価した。
Claims (11)
- 癌に罹患している疑いのある被験者のサンプルにおいて癌細胞の有無を決定する方法であって、
a)BRAFポリペプチドにおいて配列番号:1により特徴付けられるエピトープに特異的に結合する抗体に該サンプルを、該抗体のエピトープへの結合を可能にする条件下で接触させ、
b)エピトープに対する抗体の結合を決定し、それによって癌細胞の有無が決定される
ことを含み、
前記抗体が受託番号DSM ACC3091で寄託されているハイブリドーマクローンにより生成された抗体である、方法。 - 前記癌細胞が組織サンプル内に存在する請求項1に記載の方法。
- 前記組織サンプルが組織切片サンプルである請求項2に記載の方法。
- 工程b)における抗体のエピトープへの結合が、被験者が抗癌療法に応答性であることを示す、請求項1に記載の方法。
- 前記抗癌療法が、抗BRAFアンチセンスRNA、siRNA又はミクロRNA剤、抗BRAF抗体、ソラフェニブ、RAF-265、PLX-4032、セツキシマブ、及びGDC-0879からなる群から選択される請求項4に記載の方法。
- 受託番号DSM ACC3091で寄託されているハイブリドーマクローンにより生成された抗体。
- 受託番号DSM ACC3091で寄託されているハイブリドーマクローン。
- a)請求項6に記載の抗体を含む分析ユニットであって、該分析ユニットに適用されるサンプル中のBRAFポリペプチドにおいて配列番号:1により特徴付けられるエピトープへの抗体の特異的結合の決定を可能にする分析ユニットと;
b)分析ユニットにより決定される結合を評価し、診断を確立するための実行ルールを含む評価ユニット
を含む癌の診断装置。 - 前記サンプルが組織サンプルである請求項8に記載の装置。
- 前記組織サンプルが組織切片サンプルである請求項9に記載の装置。
- 請求項6に記載の抗体を含む癌診断キット。
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US61/503,950 | 2011-07-01 | ||
PCT/EP2011/067092 WO2012042009A1 (en) | 2010-09-30 | 2011-09-30 | Means and methods for diagnosing cancer using an antibody which specifically binds to braf v600e |
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