JP2018528439A - 抗体に基づく薬物のコンパニオン診断としての細胞結合補体活性化産物アッセイ - Google Patents
抗体に基づく薬物のコンパニオン診断としての細胞結合補体活性化産物アッセイ Download PDFInfo
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Abstract
【選択図】図2
Description
本願は、2015年7月31日出願の「Cell‐Bound Complement Activation Products Assays as Companion Diagnostics for Antibody‐Based Drugs」と題する米国仮特許出願第62/199,713号の利益を主張し、その開示内容全体を参照によって本明細書に援用する。
C4d標識Bリンパ球を、事前に規定されたプロトコルを用いてインビトロで生成した。Bリンパ球に結合しているC4dのレベルを、マルチカラーフローサイトメトリアッセイを用いて測定した。簡潔に述べると、抹消血白血球(PBL)を、Ficoll Plus(GE ヘルスケア)を用いた勾配遠心分離によって調製した。低張性溶解によって混入赤血球を除去した後、PBLをリン酸緩衝食塩水(PBS)で洗浄し、1%のウシ血清を含むPBSに再懸濁し、抗体染色のために小分けした。リンパ球を、特徴的な表面分子の発現及び前方(サイズ)/側方(粒度)散乱のそれら独自の特徴に基づいて、単球及び顆粒球から区別した。Zenon抗体標識キット(Invitrogen社、カリフォルニア、カールスバッド)を用いてAlexa Fluor 488により標識された抗ヒトC4d(マウスIgG1;C4のC4d含有分画と反応;Quidel社、カリフォルニア、サンディエゴ)と併用して、系統特異的細胞表面マーカ(Bリンパ球用CD19;BD Biosciences社、カリフォルニア、サンディエゴ)と反応するフィコエリトリン‐又はフィコエリトリンCy5‐結合マウスモノクローナル抗体(mAb)を使用した。
Claims (20)
- 被検者に抗体による療法から利益を得る可能性があるか否かを判定する方法において、前記被検者からの白血球細胞を含む血液試料について、
前記試料中のBリンパ球の表面に付けられた少なくとも1つのバイオマーカのレベルを定量化する工程であって、前記バイオマーカは、C4d、C3d、C4b、iC4b、C3b、iC3b、及びC3dgからなる群から選択される、工程と、
前記被検者の前記バイオマーカのレベルを対照試料のBリンパ球の表面に付けられたバイオマーカのレベルと比較して、前記被検者のレベルが前記対照レベルに比べて上昇しているバイオマーカの数を判定する工程と、
を含んでおり、
前記対照のレベルに比べて前記被検者からの前記血液試料中の前記バイオマーカのレベルが増加している場合、特定の抗体による治療に有利に反応する可能性が低いものとして、前記被検者を同定する、方法。 - 前記バイオマーカはC4dである、請求項1に記載の方法。
- 前記抗体は、Bリンパ球抗原に対するものである、請求項1に記載の方法。
- 前記抗原は、CD5、CD19、CD20、CD21、CD22、CD23、CD25、CD40、CD69、CD70、CD79、CD80、CD85、CD86、CD137、CD138、CD252、及びCD268からなる群から選択される、請求項1に記載の方法。
- 患者に治療用抗体による治療から利益を得る可能性があるか否かを判定する方法において、処理装置を用いて、
患者の1組の血液試料データを受け取る工程であって、前記1組の血液試料データが、前記患者のBリンパ球に関連付けられる少なくとも1つの細胞結合補体活性化産物(CB‐CAP)のレベルを含んでいる、工程と、
対照データセットにアクセスする工程であって、前記対照データセットが、前記CB‐CAPの各々に対する対照レベルを含んでいる、工程と、
前記患者のCB‐CAPレベルを前記対照レベルと比較して、前記患者のレベルが前記対照レベルに比較して上昇しているCB‐CAPの数を判定する工程と、
前記決定された数が閾値を超える場合、抗体療法から利益を得られる可能性が無いとして前記患者を分類する工程と、
前記患者が抗体療法から利益を得られる可能性が低いものと分類されるか否かの指標を含む報告を生成する工程と、
を含む方法。 - 前記CB‐CAPは、B‐C4d、B‐C3d、B‐C3b、B‐C4b、B‐iC3b、B‐iC4b、及びB‐C3dgからなる群から選択される、請求項5に記載の方法。
- 前記CB‐CAPはB‐C4dである、請求項6に記載の方法。
- 前記抗体はBリンパ球抗原に対するものである、請求項5に記載の方法。
- 前記抗原は、CD5、CD19、CD20、CD21、CD22、CD23、CD25、CD40、CD69、CD70、CD79、CD80、CD85、CD86、CD137、CD138、CD252、及びCD268からなる群から選択される、請求項8に記載の方法。
- 前記抗体は、リツキシマブ、エプラツズマブ、オファツムマブ、ベルツズマブ、及びオクレリズマブからなる群から選択される、請求項8に記載の方法。
- 患者に抗体療法から利益を得る可能性があるか否かを判定するためのシステムにおいて、
前記システムは、
処理装置と、コンピュータ可読媒体と、対照被検者集団の血液試料データの対照データセットを保持するデータ格納設備とを備えており、前記血液試料データは、前記患者の1つ以上の細胞結合補体活性化産物(CB‐CAP)のレベルを含んでおり、前記コンピュータ可読媒体は、実行されると
(i)前記患者の1組の血液試料データを受け取る工程であって、前記患者の1組の血液試料データは、前記患者に関するCB‐CAPレベルを含んでおり、前記CB‐CAPレベルは、B‐C4d、B‐C3d、B‐C3b、B‐C4b、B‐iC3b、B‐iC4b、又はB‐C3dgの少なくとも1つについてのものである、工程と、
(ii)前記患者の前記CB‐CAPのレベルを前記対照レベルと比較して、前記患者のレベルが前記対照レベルに比べて上昇しているCB‐CAPを判定する工程と、
(iii)前記患者のCB‐CAPの前記決定されたレベルが閾値を超えて上昇している場合、抗体療法から利益を得る可能性が低いものとして前記患者を分類する工程と、
(iv)前記患者が前記抗体療法から利益を得る可能性があるか否かの指標を含む報告を生成する工程と、
を前記処理装置に対し命令するように構成されたプログラミング命令を含んでいる、システム。 - 前記CB‐CAPはB‐C4dである、請求項11に記載のシステム。
- 前記抗体は、Bリンパ球抗原に対するものである、請求項11に記載のシステム。
- 前記抗原は、CD5、CD19、CD20、CD21、CD22、CD23、CD25、CD40、CD69、CD70、CD79、CD80、CD85、CD86、CD137、CD138、CD252、及びCD268からなる群から選択される、請求項13に記載のシステム。
- 前記抗体は、リツキシマブ、エプラツズマブ、オファツムマブ、ベルツズマブ、及びオクレリズマブからなる群から選択される、請求項13に記載のシステム。
- (a)Bリンパ球の細胞表面マーカと反応する蛍光標識された抗体と、
(b)少なくとも1つのCB‐CAPと反応する蛍光標識された抗体と、
を含むキット。 - 前記(a)の抗体は、CD5、CD19、CD20、CD21、CD22、CD23、CD25、CD40、CD69、CD70、CD79、CD80、CD85、CD86、CD137、CD138、CD252、及びCD268からなる群から選択されたB細胞抗原と反応するモノクローナル抗体である、請求項16に記載のキット。
- 前記CB‐CAPは、B‐C4d、B‐C3d、B‐C3b、B‐C4b、B‐iC3b、B‐iC4b、及びB‐C3dgからなる群から選択される、請求項16に記載のキット。
- 1つ以上の生化学試薬を更に含む、請求項16に記載のキット。
- 1つ以上のバイオマーカを同定する際に前記キット及びキット構成要素を使用するための説明書を更に含む、請求項16に記載のキット。
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