JP2019522796A - 免疫グロブリン単一可変ドメインについての改善された薬物動態アッセイ - Google Patents
免疫グロブリン単一可変ドメインについての改善された薬物動態アッセイ Download PDFInfo
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Abstract
Description
a)試料を補足剤と接触させ、これにより、ISVD、タンパク質、ポリペプチド、化合物又は構築物を、該補足剤によって捕捉する工程;
b)補足剤によって捕捉されたISVD、タンパク質、ポリペプチド、化合物、又は構築物を、検出剤と接触させ、これにより、該検出剤は、該補足剤によって捕捉されたISVD、タンパク質、ポリペプチド、化合物、又は構築物に結合する工程;
c)該捕捉剤によって捕捉されたISVD、タンパク質、ポリペプチド、化合物、又は構築物に結合した検出剤の量に対応するシグナルが発生する工程
を含み、該方法は、消光剤の存在下で実施され、該消光剤は、既存抗体は結合(すなわち特異的に結合)することができるが、捕捉剤及び検出剤は(実質的に)結合(すなわち、非特異的結合以外は結合)することができない、タンパク質又はポリペプチドである。この目的のために、消光剤は好ましくは、さらに本明細書に記載されている通りである。
この実施例は、ヒト血清試料中のナノボディに基づいた(融合)タンパク質の総濃度を決定するために使用された薬物動態アッセイにおける消光剤の使用を示す。この実施例では、メソスケールディスカバリープラットフォームを使用して、様々な濃度のALX−0171の添加されたヒト血清試料中のALX−0171(ヒト呼吸器合胞体ウイルスに対する三価ナノボディ構築物;国際公開公報第2010/139808号参照)の濃度を決定する。アッセイの構成は実質的に、図1に図示されている通りである(ALX−0171は、図1に説明のために示されている二価ナノボディ構築物の代わりに三価ナノボディ構築物であるが)。
この実施例は、ヒト血清試料中のナノボディに基づいた(融合)タンパク質の総活性濃度を決定するために使用された、ELISAに基づいた薬物動態アッセイにおける消光剤の使用を示す。
この実施例は、ヒト血清試料中のナノボディに基づいた(融合)タンパク質の総活性濃度を決定するために使用された薬物動態アッセイにおける消光剤の使用を示す。この実施例では、メソスケールディスカバリープラットフォームを使用して、様々な濃度のALX−0761の添加されたヒト血清試料中のALX−0761(インターロイキン17A及びFに対する三価ナノボディ構築物)の濃度を決定する。
この実施例は、マウス血漿試料中のナノボディに基づいた(融合)タンパク質の濃度を決定するために使用された、ELISAに基づいた薬物動態アッセイにおける消光剤の使用を示す。
結合測定を、ビアコアT100を使用して、CM5センサーチップを使用して、ランニング緩衝液HBS−EP+を用いて、25℃で実施した。21−4を、固定されたウサギ抗マウスIgGを介して捕捉した。なぜなら、直接固定されたmAb21−4表面は、効率的に再生されることができないことが判明したからであった。使用される抗マウスIgG抗体は、全てのIgGサブクラス、IgA及びIgMと反応する、ポリクローナルウサギ抗マウスIgG抗体であった(GEヘルスケア社;製造番号BR−1008−38;ロット番号10111487)。抗マウスIgG抗体の固定は、活性化のためのEDC/NHSの7分間かけての注入、及び失活のための1Mエタノールアミン塩酸塩(pH8.5)の7分間かけての注入を使用した、手作業によるアミンカップリング(ビアコア社、アミンカップリングキット)を使用して実施された。結合条件は表Iに列挙されている。タンパク質の固定化レベル及び分子量に基づいて、固定された抗マウスIgG抗体に結合しているmAb21−4の理論的Rmaxは約13000RUであった(1分子のmAb21−4が、1分子の抗マウスIgG抗体に結合している)。
Claims (8)
- 試料中の少なくとも1つのISVD、又は少なくとも1つのISVDを含むタンパク質若しくはポリペプチドの量及び/又は濃度を決定するための方法であって、該方法は、
a)試料を捕捉剤と接触させ、これにより、ISVD、タンパク質又はポリペプチドは該捕捉剤によって捕捉される工程;
b)該補足剤によって捕捉されたISVD、タンパク質又はポリペプチドを検出剤と接触させ、これにより、該検出剤は、捕捉剤によって捕捉されたISVD、タンパク質又はポリペプチドと結合する工程;
c)該補足剤によって捕捉されたISVD、タンパク質又はポリペプチドに結合した検出剤の量に対応するシグナルを発生させる工程
を含み、該方法は、消光剤の存在下で実施され、該消光剤は、既存の抗体は結合することができるが、捕捉剤も検出剤も結合することができないタンパク質又はポリペプチドである、前記方法。 - 消光剤として使用されるタンパク質又はポリペプチドが、モノクローナル抗体21−4と、1マイクロモル(μM)より良好な親和性、例えば1000〜1nMの親和性で結合するタンパク質又はポリペプチドである、請求項1記載の方法。
- 消光剤として使用されるタンパク質又はポリペプチドが、目的とする補足剤及び目的とする検出剤と、3μM未満/3μMより悪い、好ましくは10μM未満、より好ましくは50μM未満、例えば100μMより悪い親和性で結合するタンパク質又はポリペプチドである、請求項1又は2記載の方法、
- 消光剤が、一価免疫グロブリン単一可変ドメイン、又は5個以下、例えば4個、3個、2個、又は1個の免疫グロブリン単一可変ドメイン(群)を含む融合タンパク質又は構築物である、請求項1〜3のいずれか記載の方法。
- 消光剤に存在する免疫グロブリン単一可変ドメインの少なくとも1つが、露出したC末端を有する、請求項4記載の方法。
- 露出したC末端を有する免疫グロブリン単一可変ドメインの少なくとも1つが、配列VTVSS(配列番号1)をそのC末端に有する、請求項5記載の方法。
- 少なくとも消光剤が、そのC末端に免疫グロブリン単一可変ドメインを有する、請求項4又は5記載の方法。
- 消光剤のC末端における免疫グロブリン単一可変ドメイン(及びひいては完全な消光剤)が、配列VTVSS(配列番号1)をそのC末端に有する、請求項7記載の方法。
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