JP2021505137A - 悪性b細胞を特異的に認知する抗体またはその抗原結合断片、これを含むキメラ抗原受容体及びその用途 - Google Patents
悪性b細胞を特異的に認知する抗体またはその抗原結合断片、これを含むキメラ抗原受容体及びその用途 Download PDFInfo
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Abstract
Description
(a)次の重鎖にCDR(Complementarity determining region)アミノ酸序列を含む重鎖に可変領域:序列番号1のCDRH1及び序列番号2のCDRH2;及び
(b)次の軽鎖にCDRアミノ酸序列を含む軽鎖可変領域:序列目録第4序列のCDRL1。
(a)第1項の抗−CD19抗体またはその抗原結合断片を含む細胞外ドメイン(Extracellular domain);
(b)膜横断ドメイン(transmembrane domain);及び
(c)細胞内信号伝達ドメイン。
(a)次の重鎖CDR(Complementarity determining region)アミノ酸序列を含む重鎖可変領域:序列番号1のCDRH1及び序列番号2のCDRH2;及び
(b)次の軽鎖CDRアミノ酸序列を含む軽鎖可変領域:序列目録第4序列のCDRL1。
本発明で、前記抗体または抗原結合断片はヒト抗体であるか、またはヒト化されたものでありうる。また、本発明で前記抗体または抗原結合断片はscFvであろうるが、これに限定されるのではない。
FRH1(Framework region 1 of Heavy chain)-CDRH1 (complementarity determining region 1 of Heavy chain)-FRH2-CDRH2-FRH3-CDRH3-FRH4;
FRL1(Framework region 1 of Light chain)-CDRL1(complementarity determining region 1 of Light chain)-FRL2-CDRL2-FRL3-CDRL3-FRL4.
本明細書で、用語、“キメラ(chimeric)抗体”は重鎖及び/又は軽鎖の一部が特定根源(source)または種(species)から由来し、重鎖及び/又は軽鎖の残りが相異する根源または種から由来した抗体を意味する。
(a)上記の抗−CD19抗体またはその抗原結合断片を含む細胞外ドメイン(Extracellular domain);
(b)膜横断ドメイン(transmembrane domain);及び
(c)細胞内信号伝達ドメイン。
実施例1:CD19に対する抗体開発
抗体開発のためにヒトCD19蛋白質の細胞外部ドメイン(extracellular domain、ECD)部位を動物細胞を用いて生産した。ECDのC−末端にヒトIgG1のヒンジ及びFc部位(CH2−CH3)が結合された形態(CD19−ECD−Fc)とHis tagが結合された形態(CD19−ECD−His)のDNAをpCEP4 (Invitrogen、Cat. No. V044-50)にHind−IIIとBamH−I制限酵素を用いてクローニングした。次に、Freestyle 293F(Invitrogen、Cat. No. R790-07)細胞にポリエチレンイミン(Polyscience Inc., Cat. No. 23966)を用いて前記クローニングされたベクターを一時形質転換(transient transfection)させ、細胞培養液からprotein-A Ceramic HyperD Fレジン(PALL、Cat No. 20078-028)またはNi-NTA Superflow(Qiagen、Cat No. 30410) を用いて精製した。精製された蛋白質をProtein assay dye(Bio-Rad、Cat. No. 500-0006)を用いて定量し、SDS−PAGE後、クマシブルー染色を通じて濃度及び純度を確認した。確保したCD19−ECD−His蛋白質を鶏の皮下に注射し、免疫が完了した鶏から脾臓及び滑液嚢を得た。採取した脾臓及び滑液嚢試料からTRI試薬(Invitrogen、米国)を使用してtotal RNAを抽出し、これからcDNAを合成した。免疫グロブリンの重鎖可変領域と軽鎖可変領域に特異的な公知のプライマーを用いて抗体断片ライブラリーを製作した(表1、Phage display: a laboratory manual、Carlos Barbas III、et al., Cold Spring Harbor Laboratory Press参照)。
開発された抗体がB細胞由来血液癌治療のためのキメラ抗原受容体(chimeric antigen receptor、CAR)に使われるマウス由来CD19抗体であるFMC63とエピトープが重複するかを確認するためにOctet(Pall ForteBio)機器を用いてエピトープビニング(epitope binning)を進行した。AR2Gセンサーチップ(Fortebio、Cat. No. 18-5092(tray)、18-5093(pack)、18-5094(case))にFMC63−Fcを10μg/mLの濃度でEDC/NHSを用いたアミンカップリング方法により固定させた。FMC63が固定されたセンサーチップにCD19−ECDカッパ軽鎖融合蛋白質(CD19−ECD−Ck)を10μg/mLの濃度で10分間結合させ、以後、5分間FMC63とCD19−ECDとの間の結合を安定化させた。以後、本発明の抗体であるCD19_12.18またはFMC63を10μg/mLの濃度で10分間結合させ、10分間抗原と抗体との間の結合を安定化させた。FMC63を固定した以後に、全ての抗体抗原は kinetics buffer (Fortebio、 cat No. 18-1092)を用いて希釈し、安定化させる段階でも同一なbufferを使用した。仮に、2次に結合させた抗体がFMC63と結合されたCD19−ECD蛋白質に追加結合すれば、これはFMC63とエピトープを共有しない抗体と解析することができる。図3に示すように、FMC63は追加で結合しない一方、本発明者らにより開発された抗体であるCD19_12.18はFMC63に結合されたCD19−ECDに追加結合することを確認した。したがって、本発明のCD19_12.18抗体は既存のFMC63抗体と結合するエピトープが相異することが分かった。
開発された抗体断片のエピトープを確認するための方法で、多様なmutant CD19を構築した後、開発された抗体断片の結合を流細胞分析器を用いて確認した。より具体的に、CD19蛋白質の発現を確認するためにpLenti6−V5/DESTレンチウイルスベクター(Invitrogen、米国)にT2A systemを用いてGFP蛋白質を同時に発現するbi-cistronic expression system(mutant CD19-T2A-GFP)をClaI/XhoIに切断及び結紮させた。製造されたコンストラクトは塩基序列分析を通じて確認した。抗体の結合有無は full length CD19 蛋白質をtransient transfectionを通じて発現した293細胞に精製された抗体断片(Anti-CD19 scFv-Fc)を結合して流細胞分析器で分析する方法を使用した。
開発された抗体CD19_12.18を用いてキメラ抗原受容体を開発した。キメラ抗原受容体はCD8リーダー、scFv形態のCD19_12.18、CD8ヒンジ及び膜横断領域、CD137細胞質領域、及びCD3ゼタの細胞質領域をコドン最適化した後、pLenti6−V5/DESTレンチウイルスベクター(Invitrogen、米国)にSpeI/XhoIに切断及び結紮させた。製造されたコンストラクト(序列目録第23序列)は塩基序列分析を通じて確認した。
実施例3で製造されたレンチウイルスを用いて、CD19_12.18抗体断片(scFv)を含むキメラ抗原受容体が表面に提示された細胞毒性T細胞を製造した。
実施例4で製造したキメラ抗原受容体が表面に提示された細胞毒性T細胞(CD19_12.18 CAR−T cell)を使用して、前記T細胞が細胞表面のCD19を認識することによって、キメラ抗原受容体細胞の活性化を誘導するか否かを確認した。
CD19に対してCD19_12.18対比優れる結合力を有する抗体断片を確保するために重鎖と軽鎖ライブラリーを組み合わせて新たなサブライブラリーを製作した。サブライブラリーを生成するために、NNK同意コドン(degenerate codons)を含有するオリゴヌクレオチドが使われており、この際、CD19_12.18の序列が70%以上維持されるようにした。CD19_12.18抗体断片はtemplate DNAに使われた。ランダムコドンはPCRにより6個のCDRに導入された。増幅された抗体断片は QIAquick Gel Extraction Kit (QIAGEN、米国)により精製された。抗体断片及びpComb3XSSベクターはsfiI制限酵素に切断されており、ライゲーション後、ER2537に形質注入してファージライブラリーを製作した。製作されたファージライブラリーに基づいて実施例1と同一な方法により抗体を選別した。
開発された抗体のうち、親和度が異なる3種(hzCD19_1218.81、hzCD19_1218.82、hzCD19_1218.81.79)を用いてキメラ抗原受容体を開発した。キメラ抗原受容体はCD8リーダー、scFv形態の開発された抗体、CD8ヒンジ及び膜横断(transmembrane)領域、CD137細胞質領域、及びCD3ゼタの細胞質領域をGeneOptimizer(Invitrogen)アルゴリズムを用いてコドン最適化した後、プロモータがEF−1 alphaに変更されたpLenti6.3/V5TOPOレンチウイルスベクター(Invitrogen、米国)にSpeI/PacIに切断及び結紮させた。製造されたコンストラクトは塩基序列分析を通じて確認した。
実施例8で製造されたレンチウイルスを用いて、CD19_12.18抗体断片(scFv)を含むキメラ抗原受容体が表面に提示された細胞毒性T細胞を実施例5の方法を用いて製造した。これを通じてキメラ抗原受容体が表面に提示された細胞毒性T細胞を使用して、前記T細胞が細胞表面のCD19を認識することによって、キメラ抗原受容体細胞の活性化を誘導するか否かを確認した。
開発された抗体断片を用いたキメラ抗原受容体活性を最適化するためにキメラ抗原受容体を構成するヒンジ領域(CD8、CD28、Fc)、膜横断ドメイン(CD8、CD28、ICOS)及び補助刺激ドメイン(CD137、CD28、ICOS、CS3)の変更を通じて新たなキメラ抗原受容体(CAR2乃至CAR7)を開発しており、活性を確認するためにCD19抗原に結合する抗体断片部位はhzCD19_1218.81を用いた(図9)。CAR1乃至CAR7の各々のキメラ抗原受容体は実施例8と同一な方法によりプロモータがEF−1 alphaに変更されたpLenti6.3/V5TOPOレンチウイルスベクター(Invitrogen、米国)に切断及び結紮させており、製造されたコンストラクトは塩基序列分析を通じて確認した。前記開発されたCAR1乃至CAR7のコンストラクトのアミノ酸及びヌクレオチド序列は序列番号74乃至87の序列で序列目録に添付された。開発された各々のコンストラクトは実施例8のプロトコルの通りレンチウイルスを製造及び濃縮して保管した。
本発明で開発されたCD19_1218抗体及びこれから親和度増進及びヒト化がなされた抗体がCD19_1218抗体と同一な結合部位を有するかを分析するためにepitope binningとcompetitition ELISAを進行した。実施例2のように、FMC63抗体をimmobilizationsしたsensor chipにCD19−ECD蛋白質を結合させた後、FMC63、CD19_1218、hzCD19_1218.81、hzCD19_1218.81.79、及びhzCD19_1218.82抗体を各々追加で結合させた(図12a)。その結果、FMC63抗体は追加結合できなかったが、CD19_1218を含んだ4種の抗体は追加で結合することを確認した。Competition ELISAはCD19_1218.81−Fc抗体をELISA plateに2μg/mLの濃度でコーティングし、CD19−ECD−Ck(3μg/mL)単独、あるいはCD19−ECD−Ck(3μg/mL)とCD19_1218−Fc抗体(300μg/mL)の混合液を加えて結合させた。以後、CD19_1218.81−Fc抗体に結合したCD19−ECD−Ck蛋白質をanti−Ck−HRP抗体を用いて測定した。その結果、CD19_1218抗体がある場合にCD19_1218.81−FcとCD19−ECD−Ck蛋白質の結合が抑制されることを確認した(図12b)。以上の結果に基づいて開発された抗体がCD19_1218抗体と同一な結合部位を有することを確認した。
Claims (18)
- 以下を含む抗−CD19抗体またはその抗原結合断片:
(a)次の重鎖CDR(Complementarity determining region)アミノ酸序列を含む重鎖可変領域:序列番号1のCDRH1及び序列番号2のCDRH2;及び
(b)次の軽鎖CDRアミノ酸序列を含む軽鎖可変領域:序列目録第4序列のCDRL1。 - 前記重鎖可変領域は、序列番号3、30乃至35のうち、いずれか1つのアミノ酸序列を含むCDRH3を追加的には含むことを特徴とする、請求項1に記載の抗−CD19抗体またはその抗原結合断片。
- 前記軽鎖可変領域は、序列番号5、36乃至39のうち、いずれか1つのアミノ酸序列を含むCDRL2を追加的に含むことを特徴とする、請求項1に記載の抗−CD19抗体またはその抗原結合断片。
- 前記軽鎖可変領域は、序列番号6、40、及び41のうち、いずれか1つのアミノ酸序列を含むCDRL3を追加的に含むことを特徴とする、請求項1に記載の抗−CD19抗体またはその抗原結合断片。
- 前記重鎖可変領域は、序列番号7、42、46、50、54、58、62、66、及び70のうち、いずれか1つのアミノ酸序列を含むことを特徴とする、請求項1に記載の抗−CD19抗体またはその抗原結合断片。
- 前記軽鎖可変領域は、序列番号8、43、47、51、55、59、63、67、及び71のうち、いずれか1つのアミノ酸序列を含むことを特徴とする、請求項1に記載の抗−CD19抗体またはその抗原結合断片。
- CD19に特異的に結合し、序列番号92のアミノ酸序列のT51、S53、E55、L58、K59、及びK63からなる群より選択される少なくとも1つのアミノ酸残基に結合する抗体または抗原結合断片のCD19に対する結合を遮断する抗−CD19抗体またはその抗原結合断片。
- 前記抗体または抗原結合断片はCD19に特異的に結合し、序列番号92のアミノ酸序列のL58、K59、及びK63からなる群より選択される少なくとも1つ以上のアミノ酸残基に結合する抗体または抗原結合断片のCD19に対する結合を遮断することを特徴とする、請求項7に記載の抗−CD19抗体またはその抗原結合断片。
- 前記抗体または抗原結合断片はFMC63抗体が結合するエピトープに結合しないものであることを特徴とする、請求項7に記載の抗−CD19抗体またはその抗原結合断片。
- 請求項1乃至9のうち、いずれか一項の抗−CD19抗体またはその抗原結合断片をエンコーディングする核酸分子。
- 請求項10の核酸分子を含む再組合せベクター。
- 請求項11の再組合せベクターに形質転換された宿主細胞。
- 以下を含むCD19特異的キメラ抗原受容体:
(a)請求項1乃至9のうち、いずれか一項の抗−CD19抗体またはその抗原結合断片を含む細胞外ドメイン(Extracellular domain);
(b)膜横断ドメイン(transmembrane domain);及び
(c)細胞内信号伝達ドメイン。 - 請求項13のキメラ抗原受容体を発現する効果器細胞。
- 請求項14の効果器細胞を含むCD19を発現する細胞と関連した疾患、自己免疫疾患または炎症疾患の予防または治療用薬剤学的組成物。
- 請求項13のキメラ抗原受容体をエンコーディングする核酸分子。
- 請求項16の核酸分子を含む再組合せベクター。
- 請求項17の再組合せベクターに形質転換された宿主細胞。
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KR102136063B1 (ko) | 2020-07-22 |
CA3083936A1 (en) | 2019-06-13 |
JP7089806B2 (ja) | 2022-06-23 |
KR20190067125A (ko) | 2019-06-14 |
CA3083936C (en) | 2022-08-23 |
EP3722313A2 (en) | 2020-10-14 |
AU2018379502A1 (en) | 2020-06-18 |
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