JP6812521B2 - クロモグラニンaを検出するための免疫アッセイ法および抗体 - Google Patents
クロモグラニンaを検出するための免疫アッセイ法および抗体 Download PDFInfo
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Description
a)クロモグラニンAを含んでいると予想される試料を、クロモグラニンAに特異的な第一の抗体または抗原結合断片もしくはその誘導体およびクロモグラニンAに特異的な第二の抗体または抗原結合断片もしくはその誘導体と、クロモグラニンAと2つの抗体または抗原結合断片もしくはそれらの誘導体との三重複合体が形成できる条件で接触させる工程、ならびに
b)2つの抗体または抗原結合断片もしくはその誘導体とクロモグラニンAとの結合を検出する工程、を含む。
a)クロモグラニンAを含んでいると予想される試料(またはその断片)を、クロモグラニンAに特異的な第一の抗体または抗原結合断片もしくはその誘導体またはその断片およびクロモグラニンAに特異的な第二の抗体または抗原結合断片もしくはその誘導体またはその断片と接触させる工程、ならびに
b)2つの抗体または抗原結合断片もしくはその誘導体とクロモグラニンAまたはその断片との結合を検出する工程、を含む。本発明の免疫アッセイ法では、前記第一の抗体は、クロモグラニンAの配列(配列番号1)に特異的、好ましくは配列番号1の124〜144番目のアミノ酸にかけての配列に含まれているエピトープに特異的であることが好ましい。第一の抗体は好ましくはモノクローナル抗体である。
a)クロモグラニンAを含んでいると予想される試料(またはその断片)を、クロモグラニンAに特異的な第一の抗体または抗原結合断片もしくはその誘導体もしくはその断片およびクロモグラニンAに特異的な第二の抗体または抗原結合断片もしくはその誘導体もしくはその断片と、クロモグラニンAまたはその断片と2つの抗体または抗原結合断片もしくはその誘導体との三重複合体が形成可能な条件で接触させる工程、および
b)2つの抗体または抗原結合断片もしくはその誘導体とクロモグラニンAまたはその断片との結合を検出する工程、を含む。本発明の免疫アッセイ法では、前記第一の抗体は、クロモグラニンAの配列(配列番号1)に特異的、好ましくは配列番号1の124〜144番目のアミノ酸にかけての配列に含まれているエピトープに特異的であることが好ましくい。第一の抗体は好ましくはモノクローナル抗体である。
a)クロモグラニンAを含んでいると予想される試料を、クロモグラニンAまたはその断片に特異的な抗体または抗原結合断片もしくはその誘導体を、クロモグラニンAと抗体または抗原結合断片もしくはその誘導体との間の免疫複合体が形成可能な条件で接触させる工程を含み、ここで前記第一の抗体は、クロモグラニンA配列(配列番号1)の124〜144番目のアミノ酸にかけてのエピトープに特異的である。クロモグラニンA配列の124〜144番目のアミノ酸にかけてのエピトープに特異的な抗体は、2014年2月20、ライプニッツ・インスティテュート−ドイツ微生物資源研究所(Deutsche Sammlungvon Mikroorganismenund Zellkulturen GmbH、DSMZ、Inhoffenstrabe7B、38124 ブラウンシュバイク、ドイツ)にDSM ACC3231として寄託されたハイブリドーマ細胞株537/H2から生産された抗体であることが好ましい。
(i)クロモグラニンAまたはその断片に特異的な第一の抗体または抗原結合断片もしくはその誘導体;および
(ii)クロモグラニンAまたはその断片に特異的な第二の抗体または抗原結合断片もしくはその誘導体、
を含む。
配列:
配列1(配列番号1):シグナルペプチドを含まないヒトクロモグラニンA(CGA)(UniProt Accession no. P10645);抗原性エピトープを下線で示す:
配列2(配列番号2):ヒトクロモグラニンA(CGA)のエピトープ1(配列番号1の124〜144番目の残基に相当):
配列3(配列番号3):ヒトクロモグラニンA(CGA)のエピトープ2(配列番号1の280〜301番目の残基の相当):
配列4(配列番号4):ヒトクロモグラニンA(CGA)の抗原性ペプチド断片(配列番号1の124〜144番目の残基のN末端にシステイン残基が負荷された配列に相当):
配列5(配列番号5):ヒトクロモグラニンA(CGA)の抗原性ペプチド断片(配列番号1の280〜301番目の残基のN末端にシステイン残基が負荷された配列に相当):
モノクローナル抗体の開発
免疫原は以下のように準備した:クロモグラニンA分子の124〜144番目のアミノ酸領域のN末端にシステインを付加した配列に相当するCSGEATDGARPQALPEPMQESK(配列番号4)ペプチドをキャリアBSAに共有結合させた。クロモグラニンA分子の280〜301番目のアミノ酸領域のN末端にシステインを付加した配列に相当するCEHSQQKEEEEEMAVVPQGLFRG(配列番号5)ペプチドをキャリアBSAに共有結合させた。
抗体の標識
クロモグラニンAの安定な断片を検出するために、時間分解増幅クリプテート発光(TRACE)技術(マチス、1993、臨床化学(Clin Chem)39(9):1953−9)を使って均一なサンドイッチ型蛍光免役測定法を開発した。
本試験では、回収した直後に−16℃以下で凍結させておいた3つの血清試料プールを使用した。
図1は、時間分解増幅クリプテート発光(TRACE)技術を使った(537/H2−クリプテート;541/E2−アレクサ・フルオロ647(登録商標))KRYPTORアッセイの反応曲線を示している。
91試料(健常人提供者由来の24試料と病理学的試料67試料)を並行して、537/H2および541/E2抗体を使い、前述した条件と先行技術であるKRYPTORクロモグラニンAアッセイ(サーモフィッシャー・サイエンティフィックB.R.A.H.M.S GmbH、ヘニッヒスドルフ、ドイツ)の条件で測定した。測定は2つ組で行い、各組の変動係数を同じグラフ上でクロモグラニンAの濃度に対してプロットした。いずれのアッセイにおいても切断プロファイルは同等であった。KRYPTORクロモグラニンAアッセイに関して公表されているアッセイの機能感度は9.04ng/mlであり;(537/H2−クリプテート;541/E2−アレクサ・フルオロ647(登録商標))KRYPTORでは、10%CVで予測されるアッセイの機能感度は13.1ng/mlである。
Claims (11)
- 対象における神経内分泌腫瘍または前立腺がんの診断、予後予測、リスク評価、リスク層別化、治療管理および/または術後管理のための方法であって、
下記の工程を含む、免疫アッセイ法を用いた、前記対象からの試料における、クロモグラニンAまたはその断片の存在および/または不存在または、そのレベルを決定することを含む方法。
a)前記試料を:
(i)クロモグラニンAに特異的な第一の抗体または抗原結合断片もしくはその誘導体(ここで、前記第一の抗体または抗原結合断片もしくはその誘導体は、配列番号1の124〜144番目のアミノ酸残基にかけての配列中にあるエピトープに特異的である。);および、
(ii)クロモグラニンAに特異的な第二の抗体または抗原結合断片もしくはその誘導体;と、
クロモグラニンAと前記2つの抗体または抗原結合断片もしくはそれらの誘導体との三重複合体が形成できる条件下で接触させる工程、ならびに
b)前記2つの抗体または抗原結合断片もしくはその誘導体とクロモグラニンAとの結合を検出する工程。 - 前記第二の抗体または抗原結合断片もしくはその誘導体が、配列番号1の280〜301番目のアミノ酸残基にかけての配列中にあるエピトープに特異的である、請求項1に記載の方法。
- 前記第一の抗体がDSM ACC3231として寄託された、537/H2ハイブリドーマ細胞株によって生産されたものである、請求項1または2のいずれか1項に記載の方法。
- 前記第二の抗体がDSM ACC3232として寄託された、541/E2ハイブリドーマ細胞株によって生産されたものである、請求項1〜3のいずれか1項に記載の方法。
- 前記試料が、前記対象の体液または組織由来のものである、請求項1〜4のいずれか1項に記載の方法。
- 前記体液が、血液、血清、血漿および尿から選択される、請求項5に記載された、方法。
- アッセイが、均一な相または不均一な相で行われる、請求項1〜6のいずれか1項に記載の方法。
- 前記抗体のうちの1つが標識されており、その他の抗体が固相に結合しているかまたは固相に選択的に結合させることができる、請求項1〜7のいずれか1項に記載の方法。
- 前記抗体第一のおよび前記第二の抗体が液体反応混合物中に分散して存在おり、
そして、蛍光−消光もしくは増幅または化学発光−消光もしくは増幅に基づく標識システムの一部である第一の標識成分が前記第一の抗体に結合しており、および前記標識システムの第二の標識成分が前記第二の抗体に結合しているため、両方の抗体が検出すべきクロモグラニンAに結合すると、測定溶液中で形成されたサンドイッチ複合体の検出を可能にする測定可能なシグナルが生成される、請求項1〜8のいずれか1項に記載の方法。 - 前記標識システムが、蛍光色素または化学発光色素、特にシアニン系色素と共に、希土類のクリプテートまたは希土類のキレートを含んでいる、請求項9に記載の方法。
- 前記蛍光色素または化学発光色素が、シアニン系色素である、請求項10の方法。
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US20190086419A1 (en) * | 2016-03-09 | 2019-03-21 | Cézanne S.A.S. | Chromogranin a as a marker for bladder cancer |
CN107090439B (zh) * | 2017-06-02 | 2020-05-05 | 福州迈新生物技术开发有限公司 | 一株分泌抗嗜铬素a单克隆抗体的杂交瘤细胞株及其应用 |
BR112020018828A2 (pt) * | 2018-03-16 | 2021-02-09 | Quest Diagnostics Investments Llc | métodos para detecção de cromogranina através de uma espectrometria de massa |
CN109507432A (zh) * | 2018-11-14 | 2019-03-22 | 嘉兴行健生物科技有限公司 | 一种嗜铬蛋白a检测试剂及检测参考区间及检测方法 |
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US4758522A (en) * | 1985-03-08 | 1988-07-19 | The Regents Of The University Of California | Immunoassay for human chromogranin A |
US6238877B1 (en) | 1997-11-05 | 2001-05-29 | Arup Institute | Method for prediction prostate cancer patients' resistance to hormonal treatment by measuring serum concentrations of chromogranin A |
FR2778744B1 (fr) * | 1998-05-14 | 2000-06-23 | Cis Bio Int | Dosage immunologique de la chromogranine a humaine (cga) anticorps, reactifs et trousses utilisables pour ce dosage |
US20050186642A1 (en) * | 2004-02-24 | 2005-08-25 | Biocare Medical, Inc. | Immunoassay reagents and methods of use thereof |
CN101377513A (zh) * | 2008-04-16 | 2009-03-04 | 北京科美东雅生物技术有限公司 | 嗜铬素a化学发光免疫分析定量测定试剂盒及其制备方法 |
WO2010146064A1 (en) * | 2009-06-16 | 2010-12-23 | B.R.A.H.M.S Gmbh | Diagnostical use of peroxiredoxin 4 |
EP2383293A1 (en) | 2010-04-28 | 2011-11-02 | Euro-diagnostica AB | Immunoassay for Chromogranin A, antibodies and kit |
US9671413B2 (en) | 2010-11-12 | 2017-06-06 | William Marsh Rice University | Prostate cancer point of care diagnostics |
JP5817838B2 (ja) * | 2011-11-02 | 2015-11-18 | ウシオ電機株式会社 | 蛍光標識抗体可変領域含有ポリペプチド複合体を用いた蛍光免疫測定方法 |
US8632971B2 (en) | 2011-11-08 | 2014-01-21 | Caldera Health Limited | Methods and materials for determining the efficacy of prostate cancer therapies |
US8658166B2 (en) | 2011-11-08 | 2014-02-25 | Caldera Health Limited | Methods and materials for the diagnosis of prostate cancers |
CN102520195B (zh) * | 2011-12-30 | 2014-07-23 | 天津市协和医药科技集团有限公司 | 一种嗜铬粒蛋白a化学发光免疫分析试剂盒及其制备方法 |
US20190086419A1 (en) * | 2016-03-09 | 2019-03-21 | Cézanne S.A.S. | Chromogranin a as a marker for bladder cancer |
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EP3132268B1 (en) | 2019-10-16 |
EA034364B1 (ru) | 2020-01-30 |
US11719697B2 (en) | 2023-08-08 |
CN106461673A (zh) | 2017-02-22 |
JP6591442B2 (ja) | 2019-10-16 |
WO2015158701A1 (en) | 2015-10-22 |
US10648984B2 (en) | 2020-05-12 |
EP3633378A1 (en) | 2020-04-08 |
CN114573692B (zh) | 2024-05-28 |
JP2017514128A (ja) | 2017-06-01 |
BR112016021714A2 (pt) | 2017-10-17 |
US20200348304A1 (en) | 2020-11-05 |
JP2020016660A (ja) | 2020-01-30 |
ES2764225T3 (es) | 2020-06-02 |
CN114573692A (zh) | 2022-06-03 |
US20170122945A1 (en) | 2017-05-04 |
DK3132268T3 (da) | 2020-01-02 |
EA201692071A1 (ru) | 2017-04-28 |
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