JP6605627B2 - 免疫分析用の免疫抑制剤薬物の抽出試薬 - Google Patents
免疫分析用の免疫抑制剤薬物の抽出試薬 Download PDFInfo
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- JP6605627B2 JP6605627B2 JP2017564786A JP2017564786A JP6605627B2 JP 6605627 B2 JP6605627 B2 JP 6605627B2 JP 2017564786 A JP2017564786 A JP 2017564786A JP 2017564786 A JP2017564786 A JP 2017564786A JP 6605627 B2 JP6605627 B2 JP 6605627B2
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Description
本発明によると、前記蛋白質変性剤は、尿素、塩化グアニジニウム、又は他の非有機溶剤系蛋白質変性剤から選ばれる。
1)血液サンプルを処理することであって、サンプルと抽出試薬を混合し、加熱してから室温に戻す。
2)免疫反応を行うことであって、免疫試薬を固定した固相容器に処理後のサンプルと、マーク付きの抗免疫抑制剤抗体と固定量の免疫抑制剤とを投入し、又は、処理後のサンプルと、マーク付きの固定量の免疫抑制剤と抗免疫抑制剤抗体とを投入し、固定量の免疫抑制剤とサンプル中の免疫抑制剤が競争して限定量の抗免疫抑制剤抗体に結合し、免疫複合物が同時に固相試薬に捕捉される。
3)分離することであって、分離された遊離検出試薬と結合した検出試薬とを洗浄する。
4)検出することであって、固相試薬が捕捉した免疫複合物に含まれたトレーサーから発生される信号を検出し、信号強度と免疫抑制剤の濃度との関係曲線(校正曲線)によって、免疫抑制剤の濃度を測定する。
1)有機溶剤を含有しないので、有機試薬が揮発して薬物濃度に影響を与えることを避けることができる。
2)有機溶剤を含有しないので、抽出媒体の抗体結合薬物に対する抑制作用を有効に低減し、サンプルの抽出と実験を行った後のサンプル処理とが一層簡単になる。
3)二価金属イオンを含有しないので、異なるサンプル間の、複合作用を有する抗凝固薬の濃度差による薬物抽出効果に対する影響をなくすことができる。
4)処理後の血液サンプルがいずれも均一性溶液であるので、遠心処理を行わずに直接に検出することができ、操作を簡略化し、検出時間を短縮する。
5)一層信頼性のある検出結果を得ることができる。
6)上記特性に基づいて、本発明で提供する抽出試薬の検出方法を更に簡単に全自動の検出機器に応用することができ、又は、本発明で提供する抽出試薬の検出方法に基づいて、それに適用する全自動の検出機器を更に簡単に開発することができる。
本発明における前記免疫抑制剤は、身体の免疫細胞の増生と関連機能を抑制し、身体の免疫反応を低減することのできる各種薬物を指す。本発明における前記免疫抑制剤が、タクロリムス、シロリムス、エベロリムス、タクロリムス又はシクロスポリンを指すことが好ましい。
本発明における前記抽出試薬は、蛋白質変性剤、蛋白質加水分解酵素、界面活性剤、pH緩衝液からなる混合物でる。蛋白質変性剤と、蛋白質加水分解酵素と、界面活性剤とが協同作用することで、細胞を高速に溶解し、蛋白質結合の免疫抑制剤を放出する。
本発明における前記免疫抑制剤の抽出は、上述した抽出試薬を用いて、サンプル中の結合状態の薬物を抽出し、成分を検出可能になる過程を指す。
免疫検出は、抗体−抗原(又は半抗原)間の特異的な結合反応を利用して、各種の物質を検出する分析方法を指す。本発明における前記免疫検出は、免疫抑制剤を定量的に測定する。前記免疫検出試薬キットは主に、抽出試薬と、抗体と、測定対象物と競争で抗体に結合する固定量の測定対象物と、分析緩衝液と、校正品と、を含む。検出モードの違いに応じて、抗体又は測定対象物を選択して標記することができる。
本実施例において、前記FK506−TRFIAは、固相二次抗体に基づく競争免疫分析方法で、即ち、ヤギ抗マウス二次抗体被覆の微細孔に処理後の校正品/サンプルと、抗FK506単クローン性抗体と、ビオチンマーク付きのFK506を添加し、ビオチンマーク付きのFK506と校正品又はサンプル中のFK506とが競争して限定量の抗FK506単クローン性抗体に結合し、形成された免疫複合物がヤギ抗マウス二次抗体によって微細孔の表面に捕捉される。洗浄して未結合のビオチンマーク付きのFK506を除去し、ユーロピウムイオン(Eu3+)で標記したストレプトアビジン(Streptavidin)(SA−Eu3+)を添加して、微細孔内面の免疫複合物中のビオチンと結合させる。洗浄して未結合のSA−Eu3+を除去し、免疫複合物上のEu3+は解離補強によって安定的な蛍光配合物を形成し、蛍光強度でFK506濃度の標準曲線を構築し、校正曲線によってサンプル中のFK506濃度を確定する。
TBST緩衝液で微細孔を2回洗浄する。
FK506校正品濃度をX軸とし、検出された蛍光強度信号の値をY軸とし、四つのパラメータの当てはめを行って、回帰方程式及び当てはめ曲線を得た。測定対象のサンプル信号値を回帰方程式に代入すると、サンプルの濃度を得ることができる。本発明における検出結果の分析を、例えばELISACalcソフト等の専門コンピューター演算分析ソフトウェアで行うこともでき、大量のサンプルの高速分析に方便である。
本実施例において、抽出試薬は50mM Tris−HCl緩衝液で、PHは8.0で、尿素8mol/Lと、スブチリシン5U/mlと、濃度の異なるツイーン20と、を含有する。測定対象サンプルは、健康なヒトの全血を媒体として調製した異なる濃度のFK506を含有する校正品である。操作工程は実施例1と同様である。結果は図1に示した。
本実施例において、抽出試薬は50mMのpHが8.0であるTris−HCl緩衝液であって、ツイーン20 0.05%(v/v)と、スブチリシン5U/mlと、濃度の異なる尿素又は塩化グアニジニウムと、を含有する。測定対象サンプルは、健康なヒトの全血を媒体として調製した、濃度の異なるFK506を含む校正品である。操作工程は実施例1と同様である。結果は図2に示す。
尿素、塩化グアニジニウム等の変性剤が存在する状況下、抽出試薬中のプロティナーゼの濃度は、短時間内で細胞を破裂し、蛋白質の変性を促進し、蛋白質結合薬物を放出できるものでなければならない。同時に、サンプルを処理した後に残留したプロティナーゼの活性は免疫結合反応に明確な不良影響を与えてはいけない。
本実施例において、抽出試薬は50mMのTris−HCl緩衝液で、pHは8.0であって、ツイーン20 0.05%(v/v)と、尿素8mol/Lと、スブチリシン5U/mlと、を含有し、抽出試薬とサンプルとを均一に混合した後、異なる温度で20min孵化する。
本実施例において、抽出試薬は50mMのTris−HCl緩衝液で、pHは8.0であって、ツイーン20 0.05%(v/v)と、尿素8mol/Lと、スブチリシン5U/mlと、含有し、抽出試薬とサンプルとを均一に混合した後、70℃で異なる時間孵化する。測定対象サンプルは健康なヒトの全血を媒体として調製した、濃度の異なるFK506を含有する校正品及び実施例5に記載の12個のABBOTT会社ARCHITECT i2000システム専用試薬(FK506化学発光微粒子免疫検出試薬)で測定したEDTA抗凝固全血臨床サンプル(中国人民解放軍第二軍医大学第三附属病院から取得)である。
本実施例において、ソウリン会社(PRO−Trac(商標) II Tacrolimus ELISA,Diaspora)、アボット会社(ABBOTTARCHITECT i2000 System)と本発明の前記前処理液の、本発明の前記FK506−TRFIAにおける校正曲線とサンプル測定値に対する影響を比較する。
Claims (15)
- 尿素または塩化グアニジニウムである蛋白質変性剤と、スブチリシンである蛋白質加水分解酵素と、ツイーン20である界面活性剤と、pH緩衝液と、を含み、免疫抑制剤がタクロリムスであることを特徴とする免疫分析用の血液サンプル免疫抑制剤薬物の抽出試薬。
- 前記尿素の前記抽出試薬中のモル濃度は4mol/L〜12mol/Lであって、前記塩化グアニジニウムの前記抽出試薬中のモル濃度は1mol/L〜8mol/Lであることを特徴とする請求項1に記載の抽出試薬。
- 前記尿素の前記抽出試薬中のモル濃度が6mol/L〜8mol/Lで、前記塩化グアニジニウムの前記抽出試薬中のモル濃度が2mol/L〜6mol/Lであることを特徴とする請求項2に記載の抽出試薬。
- 前記スブチリシンの前記抽出試薬中の量は2.5U/ml〜10U/mlであることを特徴とする請求項1に記載の抽出試薬。
- 前記ツイーン20の前記抽出試薬中の体積分率は0.005%〜1%(v/v)であることを特徴とする請求項1に記載の抽出試薬。
- 前記ツイーン20の前記抽出試薬中の体積分率は0.02%〜0.1%(v/v)であることを特徴とする請求項5に記載の抽出試薬。
- 前記pH緩衝液のpHが6.5〜8.5間であることを特徴とする請求項1に記載の抽出試薬。
- 請求項1乃至7の中のいずれかに記載の抽出試薬を用いて加熱方式で血液サンプルを処理し、その後、免疫分析によって、その中に含有された薬物濃度を測定することを特徴とする血液サンプル中免疫抑制剤の薬物濃度検出方法。
- 前記免疫抑制剤がタクロリムスであることを特徴とする請求項8に記載の方法。
- 前記抽出試薬と前記血液サンプルを混合する時、前記血液サンプルと前記抽出試薬の体積比は1/1〜1/10であることを特徴とする請求項8に記載の方法。
- 前記抽出試薬と前記血液サンプルを混合する時、前記血液サンプルと前記抽出試薬の体積比は1/2〜1/5であることを特徴とする請求項10に記載の方法。
- 前記加熱方式による温度は50℃〜90℃であって、前記加熱方式による時間は5min〜50minであることを特徴とする請求項8に記載の方法。
- 前記加熱方式による温度は60℃〜80℃であって、前記加熱方式による時間は10min〜30minであることを特徴とする請求項12に記載の方法。
- a)免疫抑制剤薬物と特異的に結合する抗体と、b)前記免疫抑制剤を含有する校正品と、c)請求項1乃至7の中のいずれかに記載の抽出試薬と、d)検出試薬と、を含み、前記検出試薬がトレーサーマーク付きの抗体、抗原又は半抗原であることを特徴とする血液サンプル中の免疫抑制剤の濃度を検出する試薬キット。
- 前記トレーサーが、酵素と、化学発光物質と、放射性物質と、蛍光物質と、稀土類イオンと、ビオチンと、ジゴキシンとを含み、前記稀土類イオンがEu3+、Sm3+、Tb3+、Dy3+及びそのキレートリガンドを含むことを特徴とする請求項14に記載の試薬キット。
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JP2018507422A (ja) | 2018-03-15 |
US20200232975A1 (en) | 2020-07-23 |
CN104749009B (zh) | 2018-05-04 |
US20180024124A1 (en) | 2018-01-25 |
US11573223B2 (en) | 2023-02-07 |
CN104749009A (zh) | 2015-07-01 |
KR101976964B1 (ko) | 2019-08-28 |
WO2016155111A1 (zh) | 2016-10-06 |
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