JP6317824B2 - メラトニンの高感度検出 - Google Patents
メラトニンの高感度検出 Download PDFInfo
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- JP6317824B2 JP6317824B2 JP2016560584A JP2016560584A JP6317824B2 JP 6317824 B2 JP6317824 B2 JP 6317824B2 JP 2016560584 A JP2016560584 A JP 2016560584A JP 2016560584 A JP2016560584 A JP 2016560584A JP 6317824 B2 JP6317824 B2 JP 6317824B2
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- melatonin
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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Description
(a)本明細書において先に記載したメラトニンの誘導体を含む所定の量の化合物と共に試料をインキュベートするステップ、
(b)メラトニン及び/又は上記のメラトニンの誘導体を含む化合物を、メラトニン結合分子と結合させるステップであり、上記のメラトニン結合分子は表面上に固定化される、ステップ、
(c)上記のメラトニン結合分子に結合した上記のメラトニンの誘導体を含む化合物の量を測定するステップ、並びに、
(d)試料内のメラトニンの存在を検出する、及び/又は、測定された上記のメラトニンの誘導体を含む化合物の量の反比例に基づき、試料内のメラトニンの量を推定するステップ、
を含む。
(a)表面上に固体化された形、又は、固定化可能な形で、本明細書において先に記載したメラトニンの誘導体を含む化合物を提供するステップ、
(b)所定の量のメラトニン結合分子と共に上記の表面上で試料をインキュベートし、その結果、メラトニン及び/又は固定化された若しくは固定化可能な上記のメラトニンの誘導体を含む化合物に対するメラトニン結合分子の結合を可能にするステップ、
(c)上記の固定化されたメラトニンの誘導体を含む化合物に結合した上記のメラトニン結合分子の量を測定するステップ、並びに、
(d)測定されたメラトニン結合分子の量の反比例に基づき、試料内のメラトニンの量を推定するステップ、
を含む。
を含む。
(外1)
)におおよそ線形従属である。信号は、
(外2)
として表すことができ、式中、Sは、%における測定された信号変化であり、さらに、βは、表面密度から信号変化への換算係数である。
最終的なアッセイフォーマットにおいて、デキストランメラトニンと結合されたビーズは、カートリッジの積層上で乾燥させられ、さらに、試料の添加後、磁力を使用して、表面まで引っ張られる。被覆された磁性粒子が、被覆された抗メラトニン抗体を介して基底部分の表面上で捕獲される(図3を参照)。試料内のメラトニンの存在が、被覆されたビーズの結合を阻止して、被覆されたスポットの黒さを減らし、従って、より少ない信号の読取りをもたらす。
メラトニンを、EDCを使用してアミノ−デキストランに結合させた。要するに、19μlのEDC(水中10mg/ml)を、5μlのメラトニン−COOH(DNSO中20mg/ml)及び130μlのアミノデキストラン40(50mMのMES pH=6.2中10mg/ml)と混ぜ合わせ、さらに、1時間インキュベートし、ローラーベンチに流し続けた。非結合のメラトニンをPD10によって除去し、MESを脱塩した。結合の効率を、分光光度分析によって、及び、脱塩後のデキストランの100%回復を仮定することによって決定した。
デキストラン−メラトニンビーズコーティング
ビーズを反応小瓶に移し、さらに、磁性粒子濃縮装置を使用して50mMのMES pH=6.2で3回洗浄した。磁気ビーズを回収し、さらに、20mg/mlの最終濃度まで懸濁させた。カルボキシル化されたビーズを、50mMのMES pH6.2中21mMのNHS及び12.5mMのEDCを用いて30分間活性化した。活性化の後で、ビーズを、50mM MES pH6.2で洗浄し、さらに、1又は10μg/mlのデキストランの最終濃度まで、等しい量のデキストラン−メラトニン複合体と混ぜ合わせ(50mMのMES pH6.2まで脱塩させ)た(メラトニン−1−プロピオン酸又はGUS)。ローラーベンチ上での30分のインキュベーションの後で、反応を、0.4%の最終濃度までの2%ブロックマスターCE510(JSR社)の添加によって停止させた。ビーズを、ローラーベンチ上で一晩インキュベートした。そのビーズを、凝集されたビーズ(のクラスター)の存在に対して検査した。非結合のデキストラン複合体を、10mMのHEPES pH=7.4/250mMのKCl/250mMのKBr/20%スクロース/0.05%プルロニック−F127/0.09%NaN3で3回洗浄することによって除去し、さらに、必要となるまで5.33g/lの濃度のこの緩衝液において4℃にて保管した。
ビーズを反応小瓶に移し、さらに、磁性粒子濃縮装置を使用して回収した。次に、回収したビーズを、乾燥緩衝液(10mMのHEPES pH=7.4/10%FCS/50mMのKCl/50mMのKBr/20%スクロース/0.05%プルロニック−F127/0.09%NaN3)において再懸濁させ、さらに、150nlを、Nanodrop(商標)(Innovadyne(商標)−IDEX(登録商標)Health&Science)を使用して、各積層上に分けた。分けられたビーズ溶液を、37℃にて30分間乾燥させ、さらに、必要となるまでTotech cabinet(Totech Europe B.V,Netherlands)において保管した。
抗体のプリント
抗体1−76−4(Salimetrics,USA)を、80μg/mlのBSAを追加した50mMのBTP pH=6.8において0.5又は1μg/mlまで希釈した(メラトニン−1−プロピオン酸又はGUS)。抗体を、sciFLEXARRAYER(SCIENION AG)を使用してプリントし、各チャンバにおいて
(外3)
のスポット2つをプリントした。プリントの後で、部品を、37℃にて一晩保管し、さらに、緩衝液(10mMのホスフェート pH=7.4、2%スクロース、0.1%ヤギIgG、0.1%サポニン、0.09%NaN3)で満たして親水化させた。
33%EtOHにおいて溶解したメラトニン(Sigma社)を使用して、0から1000pg/mlに及ぶ血漿における標準系列を調製した。標準系列を、−20℃にて100μlのアリコートで保管した。
完全な用量反応曲線を、参照複合体及びGUS複合体、20℃及び30℃(GUS複合体に対して)のアッセイ温度、並びに、血漿におけるメラトニン希釈系列を用いて作成した。30℃にてGUS複合体を測定した場合も、20℃にて参照複合体を測定した場合も構築物に対する類似の阻害を発見し、改善された阻害を、どちらの複合体も20℃にて試験した場合に観察した(図4を参照)。
Claims (18)
- 免疫生物学的アッセイにおけるメラトニンの誘導体の使用であって、前記誘導体は、メラトニンのインドール環の位置3での複合体であり、前記複合体はポリペプチド又はタンパク質の抗原を含まないという条件付きで、前記複合体は少なくとも2つの炭素原子のリンカーを含み、
前記誘導体は、キャリアに結合し、前記キャリアは、粒子にさらに結合する、又は、表面を覆っている、使用。 - 前記誘導体は、3−(2−グルタル酸エチルアミド)−5−メトキシインドールである、又は、3−(2−グルタル酸エチルアミド)−5−メトキシインドールを含む、請求項1に記載の使用。
- 前記キャリアはデキストランである、請求項1に記載の使用。
- 前記メラトニンの誘導体及びキャリアを含む化合物は標識されている、請求項1乃至3のいずれか一項に記載の使用。
- 前記アッセイは、10pgメラトニン/ml未満の感度を有した免疫生物学的メラトニンアッセイである、請求項1に記載の使用。
- 前記アッセイは、20℃以上の温度にて行われ、且つ/又は、前記アッセイは、16時間未満行われる、請求項1に記載の使用。
- 試料内のメラトニンを検出及び/又は定量化するための方法又は免疫生物学的アッセイであって、
(a)請求項1乃至6のいずれか一項に記載のメラトニンの誘導体を含む所定の量の化合物と共に試料をインキュベートするステップ、
(b)メラトニン及び/又は前記メラトニンの誘導体を含む化合物を、メラトニン結合分子と結合させるステップであり、前記メラトニン結合分子は表面上に固定化される、ステップ、
(c)前記メラトニン結合分子に結合した前記メラトニンの誘導体を含む化合物の量を測定するステップ、並びに、
(d)前記試料内のメラトニンの存在を検出する、及び/又は、測定された前記メラトニンの誘導体を含む化合物の量の反比例に基づき、前記試料内のメラトニンの量を推定するステップ、
を含む方法又は免疫生物学的アッセイ。 - 試料内のメラトニンを検出及び/又は定量化するための方法又は免疫生物学的アッセイであって、
(a)表面上に固定化された形、又は、固定化可能な形で、請求項1乃至6のいずれか一項に記載のメラトニンの誘導体を含む化合物を提供するステップ、
(b)所定の量のメラトニン結合分子と共に前記表面上で試料をインキュベートし、その結果、メラトニン及び/又は固定化された若しくは固定化可能な前記メラトニンの誘導体を含む化合物に対する前記メラトニン結合分子の結合を可能にするステップ、
(c)前記固定化されたメラトニンの誘導体を含む化合物に結合した前記メラトニン結合分子の量を測定するステップ、並びに、
(d)測定された前記メラトニン結合分子の量の反比例に基づき、前記試料内のメラトニンの量を推定するステップ、
を含む方法又は免疫生物学的アッセイ。 - 前記結合分子は、メラトニン特異的抗体である、請求項7又は8に記載の方法又はアッセイ。
- 10pgメラトニン/ml未満の感度を有し、さらに、20℃以上の温度にて行われ、且つ/又は、16時間未満行われる、請求項7又は8に記載の方法又はアッセイ。
- 粒子の磁気作動を可能にする装置内で行われる、請求項7又は8に記載の方法又はアッセイ。
- 前記試料は、唾液、血液、血清、血漿、尿又は汗の試料である、請求項7又は8に記載の方法又はアッセイ。
- 請求項1乃至6のいずれか一項に記載のメラトニンの誘導体、及び、メラトニン特異的抗体を含む、メラトニンを検出及び/又は定量化するためのキット。
- 前記免疫生物学的メラトニンアッセイは、免疫生物学的メラトニン定量化アッセイである、請求項5に記載の使用。
- 前記アッセイは、0.5時間行われる、請求項6に記載の使用。
- 前記アッセイは、20℃から25℃の温度にて行われる、請求項6又は15に記載の使用。
- 0.5時間行われる、請求項10に記載の方法又はアッセイ。
- 20℃から25℃の温度にて行われる、請求項10又は17に記載の方法又はアッセイ。
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