JP7401161B2 - 慢性リンパ球性白血病のb細胞受容体を標的とする抗体およびその使用 - Google Patents
慢性リンパ球性白血病のb細胞受容体を標的とする抗体およびその使用 Download PDFInfo
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Description
抗体療法は、B系列細胞の悪性形質転換由来の白血病およびリンパ腫の処置のための非常に有効な試薬であることが証明されている。リツキシマブなどのモノクローナル抗体の承認以来、CLLを有する患者の奏効率、長期転帰、および生活の質は著しく改善した。
本発明は上記の問題を、第1の態様において、抗体であって、配列番号1の重鎖アミノ酸配列および配列番号2の軽鎖アミノ酸配列、もしくは配列番号11の重鎖アミノ酸配列および配列番号12の軽鎖アミノ酸配列を有するか、または配列番号16、配列番号17、配列番号18、および配列番号19のリストから選択される配列を有する可変軽鎖との任意の組合せで配列番号15および配列番号20からなるリストから選択される配列を有する可変重鎖を含む、抗体を提供することにより解決する。
特に定義されない限り、本明細書で使用される全ての技術用語および科学用語は、本発明が属する技術分野の当業者に一般に理解される意味を有する。しかし、以下の参考文献は、本発明が属する技術分野の当業者に本発明において使用される用語のうちの多くの一般的な定義を提供することができ、このような定義が当技術分野において一般に理解される意味と一致している限り参照および使用することができる。このような参考文献には、これらに限定されないが、Singleton et ah, Dictionary of Microbiology and Molecular Biology (2d ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988);Hale & Marham, The Harper Collins Dictionary of Biology (1991);およびLackie et al., The Dictionary of Cell & Molecular Biology (3d ed. 1999);およびCellular and Molecular Immunology, Eds. Abbas, Lichtman and Pober, 2nd Edition, W.B. Saunders Companyが含まれる。当技術分野において一般に理解される意味を有する、本明細書で使用される用語の定義を提供する当業者に利用可能な任意の追加の技術資源を参照することができる。本発明のために、以下の用語がさらに定義される。
本発明の第1の態様-抗体
本発明の抗体は、IGLV3-21R110を持つBCRに対する特異的親和性を有し、かつ治療利益を対象にもたらすことができる新規なマウス抗体の発見に基づく。治療活性を可能にする抗体およびそれらの有益な特性を以下でより詳しく説明する。
本発明の第2の態様は、IGLV3-21R110陽性患者におけるCLLの処置における使用のための本発明の第1の態様の抗体の提供に関する。同じく本発明のこの第2の態様は、本発明の第1の態様の治療活性量の抗体を投与することによる、IGLV3-21R110陽性患者におけるCLLの処置の方法に関する。
本発明は、本発明の第1の態様の抗体をコードするDNA分子にも関する。
本発明の第2の態様において使用される本発明の第1の態様の抗体は、既知の医薬と共投与されてよい。例えば、抗体は、任意の一般的な抗B細胞抗体と共投与され得る。
配列番号1の重鎖アミノ酸配列および配列番号2の軽鎖アミノ酸配列、もしくは
配列番号11の重鎖アミノ酸配列および配列番号12の軽鎖アミノ酸配列を有するか、または
配列番号16、配列番号17、配列番号18、および配列番号19のリストから選択される配列を有する可変軽鎖との任意の組合せで配列番号15および配列番号20からなるリストから選択される配列を有する可変重鎖を含む、
使用のための抗体。
実施例1
マウス抗体の生成
ハイブリドーマ細胞株の免疫化および生成
可溶型のBCRとのマウスの免疫化の組合せ、および完全かつ機能的なBCRに膜結合が提示される細胞系を使用した適した抗体の選択により、IGLV3-21R110を持つBCRに対するマウス抗体を発生させた。
陽性クローンのスクリーニングは、通常通りの酵素結合免疫吸着検定法(ELISA)によって実施しなかった。標的構造体は膜結合受容体であるため、すなわち、この細胞型に固有の細胞生理的状態をおおむね維持しながら、細胞系における潜在的な抗体の結合を検証することが中心的な重要性を持つ。まず、蛍光活性化セルソーティング(FACS)解析を使用して、プールした上清の群を結合事象に関して調べた。この目的のために、異なるBCR変異体をトリプルノックアウト(TKO)細胞株の表面で発現させた。これは、BCR自体を発現できない。
選別による好ましい抗体の同定後、個々のハイブリドーマクローンからmRNAを単離し、cDNAを作成し、アンカーPCRにより増幅した(Rapid expression cloning of human immunoglobulin Fab fragments for the analysis of antigen specificity of B cell lymphomas and anti-idiotype lymphoma vaccination; Osterroth F, Alkan O, Mackensen A, Lindemann A, Fisch P, Skerra A, Veelken H. J Immunol Methods 1999 Oct 29; 229(1-2):141-53)。モノクローナル抗体mAb01-01をコードするcDNAの配列をサンガー配列決定により確認し(HCヌクレオチドについては配列番号25、LCヌクレオチドについては配列番号26)、CHO細胞における発現に適したベクター内に配置した。
キメラ抗体の生成
マウスモノクローナル抗体mAb01-01VHおよびVLヌクレオチド配列(VHヌクレオチドについては配列番号27、およびVLヌクレオチドについては配列番号28)を使用してキメラ抗体を合成した。この目的のために、PCRによりVH配列をヒトIgG1アイソタイプ定常ドメイン配列(IgG1定常ヌクレオチドについては配列番号31)と融合させ、VL配列をヒトIgKアイソタイプ定常ドメイン(IgK定常ヌクレオチドについては配列番号32)と融合させ、CHOベースの一過性発現系を使用して発現させた。生じた抗体を含む細胞培養上清を遠心分離および濾過により清澄化した。キメラ抗体をアフィニティークロマトグラフィーによって細胞培養上清から精製した。還元および変性ドデシル硫酸ナトリウムポリアクリルアミドゲル電気泳動(SDS-PAGE)で判断して、抗体の純度を95%超と決定した。抗体をPBS緩衝液中のサイズ排除クロマトグラフィー(SEC)によってタンパク質含量および濃度に関して分析した。全てのステップを最先端の設備および技法を用いて実施した。
ヒト化抗体の生成
Fusion Antibodies Plc、Belfast、N.Irelandによる標準的なCDR移植技術を使用してマウスCDRを成熟ヒト抗体フレームワークにインシリコ移植することによりmAb01-01のヒト化を行った。VH/VL界面および古典的ループ構造にとって重要な鍵となる残基は、CDRxプラットホーム(Fusion Antibodies Plc、Belfast、N.Ireland)を使用してヒト化変異体内にできるだけ維持された。続いて、融合抗体により生成されたヒト化変異体のアミノ酸配列を、Geneiouseソフトウェア(Geneious Prime 2、Auckland、New Zealand)を使用してヌクレオチド配列に変換した。PCRによりVH配列をヒトIgG1アイソタイプ定常ドメイン配列(IgG1定常ヌクレオチドについては配列番号31)と、およびVL配列をヒトIgKアイソタイプ定常ドメイン(IgK定常ヌクレオチドについては配列番号32)と融合することにより、16対のヒト化重鎖および軽鎖を産生し、抗体遺伝子配列がチャイニーズハムスター卵巣細胞(CHO)において一過性に発現した。バッチ培養後、発現したヒト化抗体を細胞培養上清から精製し、HC0-LC0について実施例2に記載されているように分析した。表2に示されるよう8種のヒト化抗体が首尾よく得られた。
IGLV3-21 R110 -BCRおよびIGLV3-21 G110 -BCR発現TKO細胞へのmAb01-01の結合
蛍光マーカーに結合された抗体を使用したFACSアッセイにおいて、選択において観察された抗体mAb01-01の特異性(実施例1)を検証した。
IGLV3-21 R110 B細胞受容体に対する抗体の親和性
IGLV3-21R110を持つB細胞受容体に対する抗体の結合親和性を定義するために、可溶性組換えバージョンのBCR(170.5kDa;HCについては配列番号51およびLCについては配列番号52による配列)を、実施例1に記載されたプロトコールを使用した一過性発現により単量体ヒトIgMとして293-HEK細胞株において作製し、固定化抗IGLV3-21R110抗体への結合をFortebio Octet装置(Satorius)でBio-Layer Interferometry(BLI)によりモニターした。
IGLV3-21 R110 -BCR陽性ヒトB-CLL細胞の細胞表面へのマウス抗体mAb01-01の結合
IGLV3-21R110-B細胞受容体陽性ヒトCLL細胞対非IGLV3-21R110ヒトB細胞上のmAb01-01の結合特性を決定するために、結合をフローサイトメトリーにより試験した。
IGLV3-21 R110 -BCR陽性マウスTKO細胞の細胞表面へのキメラ抗体およびヒト化抗体の結合特性
キメラ抗体および2種のヒト化バージョンの特異的IGLV3-21R110-BCR結合を比較するために、IGLV3-21R110-BCRマウスTKO細胞(実施例1参照)を異なる濃度の抗体HC0-LC0、HC6-LC6およびHC7-LC6とインキュベートし、フローサイトメトリーおよびサンドイッチアッセイセットアップにより分析した。TKO-空ベクター細胞株(表面BCRなし)を用いて制御を実施した。
mAb01-01の組織交差反応性プロファイル
免疫組織化学(IHC)実験においてヒトCLLおよび健常組織に対するmAB01-01の結合特性を決定するために、IGLV3-21R110-BCRを発現する脾臓組織ならびに健常な脾臓、皮膚、腎臓、心臓、および脳組織の切片に対して免疫染色を実施した。
患者由来の異種移植モデルにおける抗IGLV3-21 R110 -BCR抗体の試験
抗IGLV3-21R110抗体の効果を決定するために、患者由来の異種移植モデルを選んだ。用量設定実験のために、4匹のNOD-scid IL2rgヌル(NSG)-マウス(Jackson ImmunoResearch、Qi J et al.: An IgG1-like bispecific antibody targeting CD52 and CD20 for the treatment of B-cell malignancies, Methods 2019, 154:70-76に記載されているように用意された)を含む4群を使用した:
群A:抗体処置なしの対照群
群B:用量0.3mg/kg体重
群C:用量5mg/kg体重
群D:用量10mg/kg体重
IGLV3-21R110-BCR患者からのPMBSを解凍し、PBSに再懸濁させた。T細胞は、製造業者により提供された使用説明書に従ってMiltenyi CD3ビーズ(Miltenyi Biotec)を使用することにより分離した。前述のようにCD3/CD28ダイナビーズ(Dynabeads(商標)Human T-Activator CD3/CD28 for T Cell Expansion and Activation、カタログ番号11161D、GIBCO)を使用してT細胞を7日間培養および増殖した(Qi J et al. Methods, 2019も参照)。
Claims (14)
- IGLV3-21R110陽性患者におけるCLLの処置における使用のための抗体であって、
配列番号1の重鎖アミノ酸配列および配列番号2の軽鎖アミノ酸配列、もしくは
配列番号11の重鎖アミノ酸配列および配列番号12の軽鎖アミノ酸配列を有するか、または
配列番号16、配列番号17、配列番号18、および配列番号19のリストから選択される配列を有する可変軽鎖との任意の組合せで配列番号15および配列番号20からなるリストから選択される配列を有する可変重鎖を含む、
抗体。 - 配列番号1に対応する重鎖および配列番号2に対応する軽鎖によって特徴付けられる、請求項1記載の抗体。
- 配列番号11の重鎖アミノ酸配列および配列番号12の軽鎖アミノ酸配列によって特徴付けられる、請求項1記載の抗体。
- 配列番号13に対応する重鎖および配列番号14に対応する軽鎖によって特徴付けられる、請求項1記載の抗体。
- 配列番号21に対応する重鎖および配列番号14に対応する軽鎖によって特徴付けられる、請求項1記載の抗体。
- キメラ抗体である、請求項1または3記載の抗体。
- ヒト化抗体である、請求項4または5記載の抗体。
- 0.25~25mg/kg(体重)の用量で適用される、請求項1記載の抗体。
- 1~20mg/kg(体重)の用量で適用される、請求項8記載の抗体。
- 7~15mg/kg(体重)の用量で適用される、請求項8記載の抗体。
- 8~12mg/kg(体重)の用量で適用される、請求項8記載の抗体。
- 請求項1記載の抗体と、薬学的に許容される担体または賦形剤とを含む、IGLV3-21R110陽性患者におけるCLLの処置における使用のための医薬組成物。
- 請求項12記載の医薬組成物を含む、IGLV3-21R110陽性患者におけるCLLの処置における使用のためのキット。
- IGLV3-21 R110 陽性B細胞を枯渇させる活性を有する、請求項1記載の抗体。
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