JP2022058778A - 試料中の非結合c5の定量化方法 - Google Patents
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Abstract
Description
本出願は配列表を含んでおり、該配列表はASCIIフォーマットで電子的に提出されたものであり、かつその全体が参照により本明細書に援用される。このASCIIコピーは2017年10月18日に作成され、1900-426PCT_SL.txtという名称であり、サイズは54,331バイトである。
a.ストレパビジン(strepavidin)被覆粒子に対して、ビオチン化抗C5捕捉抗体を結合させることであって、前記ビオチン化抗C5捕捉抗体が、ストレパビジン被覆粒子を含むカラムを備えるGyros Bioaffy 200 CDに毛細管作用によって付着して、該CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、ビオチン化抗C5捕捉抗体が、カラム中のストレパビジン被覆粒子へと動かされることと、
b.試料中の遊離(非結合)C5を捕捉することであって、該試料が毛細管作用によってCDに付着して、前記CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、試料が、カラム中のストレパビジン被覆粒子に結合した前記ビオチン化抗C5捕捉抗体へと動かされることと、
c.捕捉された遊離C5を検出することであって、アレクサフルオール(AlexaFluor)標識抗C5検出抗体が、毛細管作用によってCDに付着して、該抗C5検出抗体が、捕捉抗体によって結合されるエピトープとは異なるエピトープにおいてC5に結合し、前記CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、該検出抗体が、前記カラム中のストレパビジン被覆粒子に結合された捕捉抗体に結合された遊離C5へと動かされることと、
d.レーザー誘導蛍光検出を使用して、捕捉された遊離C5を定量化することと、を含む。
(項目1)
試料からの遊離(非結合)ヒトC5補体タンパク質(C5)を定量化する方法であって、前記方法が、
a.ストレパビジン(strepavidin)被覆されたメソスケールディスカバリー(Meso Scale Discovery((登録商標)))(MSD(登録商標))96ウェルアッセイプレートに対して、ビオチン化抗C5捕捉抗体を結合させることと、
b.前記試料を前記プレートに添加することによって、前記試料中の前記遊離(非結合)C5を捕捉することと、
c.sulfo-tag標識した抗C5検出抗体を前記プレートに添加することにより前記捕捉された遊離C5を検出することと、
d.電気化学発光を使用して、捕捉された遊離C5を定量化することと、を含むものであって、
前記試料が約1:2で希釈され、前記試料が氷上に保持され、工程b~cは約15~30分であり、前記ビオチン化抗C5捕捉抗体は、約5μg/mLの濃度で添加される、方法。
(項目2)
試料からの遊離(非結合)ヒトC5補体タンパク質(C5)を定量化する方法であって、前記方法が、
a.ストレパビジン(strepavidin)被覆粒子に対して、ビオチン化抗C5捕捉抗体を結合させることであって、前記ビオチン化抗C5捕捉抗体が、ストレパビジン被覆粒子を含むカラムを備えるGyros Bioaffy 200 CDに毛細管作用によって添加されて、前記CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、前記ビオチン化抗C5捕捉抗体が、前記カラム中の前記ストレパビジン被覆粒子へと動かされることと、
b.前記試料中の前記遊離(非結合)C5を捕捉することであって、前記試料が毛細管作用によって前記CDに添加されて、前記CDが前記Gyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、前記試料が、前記カラム中の前記ストレパビジン被覆粒子に結合した前記ビオチン化抗C5捕捉抗体へと動かされることと、
c.捕捉された遊離C5を検出することであって、アレクサフルオール(AlexaFluor)標識抗C5検出抗体が、毛細管作用によって前記CDに添加されて、前記抗C5検出抗体が、前記捕捉抗体によって結合されるエピトープとは異なるエピトープにおいてC5に結合し、
前記CDが前記Gyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、前記検出抗体が、前記カラム中の前記ストレパビジン被覆粒子に結合された前記捕捉抗体に結合された前記遊離C5へと動かされることと、
d.レーザー誘導蛍光検出を使用して、前記捕捉された遊離C5を定量化することと、を含む方法。
(項目3)
工程dから得たデータを、項目1記載の方法を使用してC5枯渇試料に添加した既知の量のC5から作成した標準曲線と比較することによって、遊離C5抗体の濃度または量を計算することをさらに含む、項目1記載の方法。
(項目4)
工程dから得たデータを、項目2記載の方法を使用してC5枯渇試料に添加した既知の量のC5から作成した標準曲線と比較することによって、遊離C5抗体の濃度または量を計算することをさらに含む、項目2記載の方法。
(項目5)
Gyros Evaluatorソフトウェアを用いて遊離C5抗体の濃度を計算することをさらに含む、項目3記載の方法。
(項目6)
前記試料がヒト患者から得られる、項目1から5のいずれか一項に記載の方法。
(項目7)
前記試料が血清試料または血漿試料である、項目6記載の方法。
(項目8)
患者が抗C5抗体で治療されている、項目1から7のいずれか一項に記載の方法。
(項目9)
前記患者がエクリズマブで治療されている、項目8記載の方法。
(項目10)
前記患者がALXN1210で治療されている、項目8記載の方法。
(項目11)
前記ビオチン化捕捉抗体がエクリズマブまたはALXN1210である、項目1から10のいずれか一項に記載の方法。
(項目12)
検出抗C5抗体がN19-8(マウス抗ヒトC5抗体)である、項目1から11のいずれか一項に記載の方法。
(項目13)
試料の希釈に、Rexxip A緩衝液が使用され、前記検出抗体の希釈に、Rexxip F緩衝液が使用される、項目2記載の方法。
(項目14)
前記Gyros機器を、Bioaffy wash 1およびpH11緩衝液を用いて別個に二回プライミングすることをさらに含む、項目2記載の方法。
(項目15)
前記試料が患者からのヒト血清試料であり、抗C5抗体を用いた前記患者の治療前および治療後の血清試料の前記遊離C5が定量化され、前記治療前および治療後の試料の両方が同じ希釈で希釈される、項目2記載の方法。
(項目16)
前記治療前および治療後の試料の両方が1:20~1:30の希釈で希釈される、項目15記載の方法。
本発明のこれらおよびその他の態様に従って、多数のその他の態様が提供される。本発明のその他の特徴および態様は、以下の発明を実施するための形態および添付の特許請求の範囲からより完全に明らかになる。
a.ストレパビジン(strepavidin)被覆粒子に対して、ビオチン化抗C5捕捉抗体を結合させることであって、前記ビオチン化抗C5捕捉抗体が、ストレパビジン被覆粒子を含むカラムを備えるGyros Bioaffy 200 CDに毛細管作用によって付着して、該CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、ビオチン化抗C5捕捉抗体が、カラム中のストレパビジン被覆粒子へと動かされることと、
b.試料中の遊離(非結合)C5を捕捉することであって、試料が毛細管作用によってCDに付着して、前記CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、該試料が、カラム中のストレパビジン被覆粒子上に結合したビオチン化抗C5捕捉抗体へと動かされることと、
c.捕捉された遊離C5を検出することであって、アレクサフルオール(AlexaFluor)標識抗C5検出抗体が、毛細管作用によってCDに付着して、該抗C5検出抗体が、捕捉抗体によって結合されるエピトープとは異なるエピトープにおいてC5に結合し、前記CDがGyrolab xPloreまたはGyrolab XP機器内で遠心力を受けることによって、該検出抗体が、カラム中のストレパビジン被覆粒子上に結合された捕捉抗体に結合された遊離C5へと動かされることと、
d.レーザー誘導蛍光検出を使用して、捕捉された遊離C5を定量化することと、を含む。
BPM:バイオ分析プロジェクトマネージャー(Bioanalytical Project Manager)
CV:変動係数
C5a:補体因子5a
低VS:低検証試料
中VS:中検証試料
高VS:高検証試料
LLOQ:定量下限
ULOQ:定量上限
BLQ:定量限界より下
ALQ:定量限界より上
MRD:Minimum Required Dilution(最小必要希釈率)
PBST:リン酸緩衝生理食塩水、0.01% Tween
・ ULOQ=40ng/mL
・ 高VS=20ng/mL
・ 中VS=2.5ng/mL
・ 低VS=0.625ng/mL
・ LLOQ-1=0.200ng/mL
・ LLOQ-2=0.156ng/mL
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