JP6054745B2 - 非競合的免疫アッセイにおける白血球の干渉の低減 - Google Patents
非競合的免疫アッセイにおける白血球の干渉の低減 Download PDFInfo
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
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Description
表面−Ab1−分析物−Ab2−酵素;酵素+S→P (1)
表面−Ab2−酵素;酵素+S→P (2)
表面−分析物−Ab2−酵素;酵素+S→P (3)
補正シグナル=IS−IRS (4)
図7は、トロポニンI(TnI)、心臓壊死のマーカーの存在及び量を決定するための、関連する係属中の米国出願第12/411,325号の特定の実施形態による電流測定免疫アッセイの原理を示す。血液サンプルを、カートリッジのサンプル保持チャンバに導入し、サンプル保持チャンバ内にコーティングされた乾燥試薬を溶解することによって修正した。乾燥試薬はIgM 77を含み、これがサンプル中に溶解すると、サンプル中に含有される可能性がある相補的異好性抗体78に選択的に結合する。図示されるように、乾燥試薬は、やはりサンプル中に溶解した後に相補的抗体78に選択的に結合するIgG 79も含む。
カートリッジを使用する方法に関しては、計量されていない流体サンプルを、サンプル進入ポート4を通してカートリッジのサンプル保持チャンバ34に導入する。キャピラリーストップ25は、この段階でサンプルがコンジット15を通過するのを防止し、保持チャンバ34にサンプルが充填される。蓋2又は要素200を閉じて、サンプルがカートリッジから漏れないようにする。次いでカートリッジを、参照により本明細書に組み込まれるZelinの米国特許第5,821,399号に開示されるように、読取り装置に挿入する。読取り装置へのカートリッジの挿入は、パッケージがスパイク38に対して押圧されたときに42に位置付けられた流体含有パッケージを穿孔するメカニズムを活性化する。それによって流体は第2のコンジットに排出され、39、20、12、及び11の順序で到達する。狭窄部12は、流体がさらに移動するのを防止するが、それは第2のコンジット部分11を介して廃棄物チャンバ44に至る流体の流れによって、残留静水圧が消失するからである。第2のステップでは、ポンプ手段の動作によって空気ブラダ43に圧力が加えられ、空気が切欠き部17及び18を通してコンジット40内に押し遣られ、所定位置27にあるコンジット34に至る。キャピラリーストップ25及び位置27は、当初のサンプルの計量部分の限界を定める。サンプルはサンプル保持チャンバ34内にあるが、犠牲ビーズ及びその他の材料をチャンバの内面上に含む乾燥試薬コーティングで修正される。次いでサンプルの計量部分を、空気ブラダ43内で生成された空気圧によりキャピラリーストップ内に通して排出する。サンプルはコンジット15内に入り、分析物センサ又は切欠き部35内に位置付けられたセンサに接触する。
図15を参照すると、免疫センサカートリッジの上面図が示されている。カートリッジ150は、好ましくはプラスチックで構成されたベース及び上部を含む。これら2つの部分は、薄い接着ガスケット又は薄い可撓性フィルムにより接続される。先の実施形態でのように、組み立てられたカートリッジは、サンプル保持チャンバ151を含み、そこには問題となっている分析物を含有するサンプルが、サンプル入口167を介して導入される。サンプルの計量部分は、好ましくはカートリッジの2つの部分を接続するガスケット又はフィルムの0.012インチ(0.3mm)のレーザカットホールにより形成されたキャピラリーストップ152と、サンプル保持チャンバ内の所定の点に位置付けられた進入点155との組み合わされた動作によって、以前のようにサンプルコンジット154(第1のコンジット)を介してセンサチップ153に送達され、この場合空気は、サンプルダイヤフラム156を押圧するパドルなどのポンプ手段の動作により導入されるものである。センサを接触させて結合を引き起こした後、サンプルを吸収する吸上げ材料を含有するベント157にサンプルを移動させ、それによって、液体又は空気のさらなる通路に近接してベントを密閉する。吸上げ材料は、好ましくは木綿繊維材料、セルロース材料、又はその他の細孔を有する親水性材料である。本出願では、以下に記述される、後で行われるサンプルダイヤフラム作動手段の引出しに相応した時間内で弁が閉じるように、材料が十分に吸収性である(即ち、十分な吸上げ速度を有する)ことが重要であり、したがってサンプルはその後、センサチップの領域に引き戻されない。
流体工学及び分析物測定の調整に関し、分析の連続事象中は、使用者はサンプルをカートリッジ内に置き、このカートリッジをアナライザ内に1から20分間置き、1種又は複数の分析物の定量測定を行う。本明細書には、分析中に生じる一連の事象の非限定的な例を示す:
いくつかの実施形態では、デバイスは、アッセイ中に生じる非特異的結合の程度を評価する目的で、免疫参照センサを用いる。免疫参照センサは、免疫試薬が抗分析物抗体ではなく抗−HSA(ヒト血清アルブミン)抗体であること以外、分析物免疫センサとして、大部分が同じ方法で製作される。ヒト全血又は血漿サンプルに曝されると、参照センサは、特異的に結合したHSAでコーティングされるようになり、豊富な内因性タンパク質が全てのヒト血液サンプル中に存在し、したがって本発明の免疫アッセイフォーマットを使用した全ての個々の試験操作に対して、共通参照を提供する。不適切な洗浄により又は干渉の存在により生じるNSBは、この第2のセンサを用いてモニタすることができる。
Claims (16)
- 血液サンプル中に存在することが疑われる分析物に関してサンドイッチ免疫アッセイを行うためのキットであって、白血球に対してオプソニン化された犠牲ビーズと、前記分析物に対する固定化された第1の抗体と、前記分析物に対する標識された第2の抗体とを含み、
固定化された第1の抗体がセンサに結合しているか、電流測定電極に結合しているアッセイビーズに結合している、
上記キット。 - 前記分析物が、BNP、proBNP、NTproBNP、cTnI、TnT、HCG、TSH、PSA、Dダイマー、CRP、ミオグロビン、NGAL、CKMB、及びミエロペルオキシダーゼからなる群から選択される、請求項1に記載のキット。
- 前記犠牲ビーズが、
非ヒトIgG又はその断片;又は
タンパク質、細菌、ウイルス、及び生体異物からなる群から選択される材料又はその断片;
でコーティングされた基材ビーズを含むか、あるいは
前記犠牲ビーズが、安定化した細菌又は細菌性胞子である、
請求項1に記載のキット。 - 前記基材ビーズが、
非ヒトIgG又はその断片でコーティングされ;
ポリスチレン、ポリアクリル酸、及びデキストランからなる群から選択される材料で形成される、
請求項3に記載のキット。 - 前記犠牲ビーズが、0.01μmから20μmの平均粒度を有し、
サンプル1マイクロリットル当たり少なくとも10 4 ビーズである、溶解した犠牲ビーズの濃度を提供するのに十分な量で存在する、
請求項1に記載のキット。 - 前記固定化された第1の抗体が、電流測定電極、電位差測定電極、伝導度測定電極、光導波路、表面プラズモン共鳴センサ、音波センサ、及び圧電センサからなる群から選択されるセンサに結合している、請求項1に記載のキット。
- 前記犠牲ビーズ及び前記第2の標識された抗体が、1つ又は複数の溶解可能な乾燥試薬コーティング内にある、請求項1に記載のキット。
- 前記標識された第2の抗体が、放射標識;アルカリホスファターゼ、グルコシダーゼ、ジアホラーゼ、ホースラディッシュペルオキシダーゼ、及びグルコースオキシダーゼからなる群から選択される酵素;発色団;蛍光体;及び化学発光種からなる群から選択される標識で標識されている、請求項1に記載のキット。
- 血液サンプル中に存在することが疑われる分析物に関してサンドイッチ免疫アッセイを行うためのカートリッジであって、
(a)血液サンプルを受容するためのサンプル入口と、
(b)血液サンプルを計量して計量サンプルを形成するための計量チャンバと、
(c)白血球に対してオプソニン化された犠牲ビーズ、及び分析物に対する標識された抗体を含む、1つ又は複数の乾燥試薬コーティング層と、
(d)分析物に対する固定化された抗体を含む電極と、
(e)計量されたサンプル、流動化した犠牲ビーズ、及び標識された抗体を電極に移動させるための、1つ又は複数のポンピング要素と
を含む上記カートリッジ。 - 前記分析物が、BNP、proBNP、NTproBNP、cTnI、TnT、HCG、TSH、PSA、Dダイマー、CRP、ミオグロビン、NGAL、CKMB、及びミエロペルオキシダーゼからなる群から選択される、請求項9に記載のカートリッジ。
- 前記犠牲ビーズが、非ヒトIgG又はその断片でコーティングされた基材ビーズを含む、請求項9に記載のカートリッジ。
- 前記基材ビーズが、ポリスチレン、ポリアクリル酸、及びデキストランからなる群から選択される材料で形成される、請求項11に記載のカートリッジ。
- 前記犠牲ビーズが、0.01μmから20μmの平均粒度を有する、請求項9に記載のカートリッジ。
- 前記犠牲ビーズが、サンプル1マイクロリットル当たり少なくとも104ビーズである、溶解した犠牲ビーズの濃度を提供するのに十分な量で存在する、請求項9に記載のカートリッジ。
- 前記1つ又は複数の乾燥試薬コーティング層が、前記計量チャンバ内に配置される、請求項9に記載のカートリッジ。
- 血液サンプル中に存在することが疑われる分析物に関して免疫アッセイを行う方法であって、
(a)分析物を含有することが疑われる血液サンプルを過剰量の犠牲ビーズと混合して、修正されたサンプルを形成するステップであって、サンプル中の白血球が犠牲ビーズを優先的に貪食しようとする上記ステップと、
(b)修正されたサンプルを、電極に固定化された、分析物に対する抗体コーティングビーズを含む免疫センサと接触させて、前記抗体コーティングビーズ、前記分析物、及び第2の標識された抗体の間でサンドイッチを形成するステップと、
(c)前記免疫センサから前記血液サンプルを洗浄するステップと、
(d)前記免疫センサとの前記サンドイッチ状態の標識の量を決定し、前記標識の量をサンプル中の分析物の濃度と関連付けるステップと
を含む上記方法。
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