JP2022537628A - 生物学的結合分子 - Google Patents
生物学的結合分子 Download PDFInfo
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Abstract
Description
・急性骨髄性白血病(AML)
・慢性骨髄性白血病(CML)
・急性リンパ性白血病(ALL)
・慢性リンパ性白血病(CLL)
- RAG2のノックアウトは、免疫グロブリンの固有の重鎖と軽鎖の体細胞組換えを妨げることから、BCRの内因性形成は排除される。これは、この発生期で、対応して処理されたB細胞の停止、遮断または「凍結」につながる。RAG1とRAG2は、最初に通常のVDJ再編成を可能にする複合体を形成することが知られていることから、RAG1のノックアウトが同じ効果を持つ手段であり、ひいてはRAG2のノックアウトに代わるものであり、本発明による教示に含まれる。
トリプルノックアウト細胞(TKO)の産生の出発点は、遺伝子Lambda5、RAG2およびSLP65のそれぞれのノックアウトを有するトランスジェニックマウスによって形成される(Duehren von Minden et al.,2012,Nature 489,p.309-313)。そのようなマウスの作成は当業者に知られており、先行技術に含まれる。細胞を取得するために、マウスの犠牲後に大腿骨の骨髄を抽出した。このようにして取得した細胞を、続いてプロ/プレB細胞の生存を促進する条件下で培養した(37℃、7.5%CO2、イスコベス培地、10%FCS、P/S、マウスIL7)。数回継代した後、対照のためにFACSソーティングを実施し、プロ/プレB細胞をソーティングし、続いて培養に戻した。このために使用したマーカーは当業者に知られている。
・対照(BCRを持たないトランスフェクションベクター)(図1のAを参照)
・CLLサブセット2に典型的なHC/LCを持つベクター(VL3-21)(図1のBを参照)
・非CLLサブセット2HC/CLLサブセット2に典型的なLCを持つベクター(VL3-21;標的モチーフR110Gを持たない)(図1のCを参照)
・CLLサブセット2に典型的なHC/非CLLサブセット2LCを持つベクター(図1のDを参照)
・1つの非CLLサブセット2HC/1つの非CLLサブセット2LCを持つベクター(図1のEを参照)
・CLLサブセット2に典型的なHC/LCを持つベクター(VL3-21;変異R110G(標的モチーフ)を含む)(図1のFを参照)。
GFSLTSYG
配列番号12(AVA mAB01 CDR2 HC)
IWRGGGT
配列番号13(AVA mAB01 CDR3 HC)
ARSRYDEEESMNY
配列番号14(AVA mAB01 CDR1 LC)
GNIHSY
配列番号15(AVA mAB01 CDR2 LC)
NAKT
配列番号16(AVA mAB01 CDR3 LC)
QHFWNTPPT
GYTFTDYA
配列番号20(AVA-mAB02 CDR2 HC)
ISTYYGDS
配列番号21(AVA-mAB02 CDR3 HC)
SRDTSNFDY
配列番号22(AVA-mAB02 CDR1 LC)
QDINSH
配列番号23(AVA-mAB02 CDR2 LC)
RANR
配列番号24(AVA-mAB02 CDR3 LC)
LQYDEFPRT
例2
本発明による教示を用いて、患者から少量の末梢血を採取した。解析のために、100μlの血液を反応容器に移し、2mlのPBS-BSA緩衝液を入れた。続いてサンプルをエッペンドルフ5804遠心機で1500rpmにて5分間遠心分離した。上清を廃棄し、沈殿物をよく混ぜた。続いて抗体を加えた。暗所で室温にて15分間インキュベートする前に、以下の表面パラメーターに対して染色を行った:1)CD19-FITC、2)CD5-PE、および3)VL3-21に特異的な抗体(APC)。その後、溶解を開始し、赤血球を溶解した。既述のとおり、細胞をPBS-BSA緩衝液で2回洗浄し、500μlの0.1%PBS-BSA緩衝液に取り込んで再懸濁した。フローサイトメーターで測定するまで、細胞を2~8℃の暗所で保管した。
VL3-21を持つBCRに特異性を持つ本発明による抗体を、患者の血液サンプルから白血病細胞を分離するためのアフェレシスシステムに使用した。
Claims (10)
- 生物学的結合分子であって、配列番号18による配列を有する軽鎖の存在を特徴とするB細胞受容体に選択的に結合し、配列番号18による軽鎖を持たないB細胞受容体には結合しない、生物学的結合分子。
- 抗体またはその機能的断片である、請求項1記載の生物学的結合分子。
- T細胞特異的活性化ドメインとの融合タンパク質の形態である、請求項1または2記載の生物学的結合分子。
- B細胞新生物を単離または殺滅する少なくとも1つの追加の領域を含む、請求項1から3までのいずれか1項記載の生物学的結合分子。
- 請求項1から4までのいずれか1項記載の定義による生物学的結合分子を、予防および/または治療目的で含む、物質組成物。
- 前記B細胞受容体の軽鎖および/または重鎖に対する抗体またはその機能的断片をさらに含む、請求項5記載の物質組成物。
- 診断、予防および/または治療目的での、請求項1から4までのいずれか1項記載の定義による生物学的結合分子、または請求項5もしくは6記載の定義による物質組成物の使用。
- 悪性B細胞新生物の診断、予防および/または治療のための、請求項7記載の使用。
- アフェレシスまたはCAR-T細胞免疫療法における、請求項7または8記載の使用。
- 前記診断目的が、配列番号18による軽鎖の存在を特徴とするB細胞受容体を有するB細胞の検出に関する、請求項7または8記載の使用。
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