JP7080514B2 - 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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Description
(a)次の一般式1で表示されるアミノ酸序列からなるCDRH2を含む重鎖可変領域(heavy chain variable region、VH):
一般式1
GIYYDX6X7X8X9X10X11X12X13SVKG
ここで、X6はG、A、またはSであり;X7はS、T、I、A、D、F、L、またはHであり;X8はA、T、S、Q、W、I、V、M、N、Y、またはHであり;X9はR、KS、V、A、Q、L、T、E、D、M、L、F、またはPであり;X10はY、G、S、またはTであり;X11はY、W、M、またはLであり;X12はA、S、T、またはLであり;X13はD、S、G、N、またはPである;及び
(b)次の一般式2で表示されるアミノ酸序列からなるCDRL1を含む軽鎖可変領域(light chain variable region、VL):
一般式2
X1GX3X4SNIGSX10X11X12Y
前記X1はV、A、G、S、W、N、Y、K、T、H、R、Q、E、またはDであり;X3はG、H、D、L、T、Q、K、N、S、またはMであり;X4はV、Y、I、P、V、M、A、L、F、またはSであり;X10はNまたはAであり;X11はAまたはPであり;X12はV、T、またはLである。
前記重鎖可変領域は下記の一般式1-1で表示されるアミノ酸序列からなるCDRH2を含むことを特徴とする、抗-CD19抗体またはその抗原結合断片:
一般式1-1
GIYYDX6X7X8X9YYADSVKG
ここで、X6はG、A、またはSであり;X7はS、T、I、A、D、F、L、またはHであり;X8はA、T、S、Q、W、I、V、M、N、Y、またはHであり;X9はR、KS、V、A、Q、L、T、E、D、M、L、F、またはPである。
前記軽鎖可変領域は下記の一般式2-1で表示されるアミノ酸序列からなるCDRL1を含むことを特徴とする、抗-CD19抗体またはその抗原結合断片:
一般式2-1
X1GX3X4SNIGSNAVY
前記X1はV、A、G、S、W、N、Y、K、T、H、R、Q、E、またはDであり;X3はG、H、D、L、T、Q、K、N、S、またはMであり;X4はV、Y、I、P、V、M、A、L、I、F、またはSである。
(a)第1項乃至第13項のうち、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)膜貫通ドメイン(transmembrane domain);及び
(c)細胞内信号伝達ドメイン。
FRH1(Framework region 1 of Heavy chain)-CDRH1(complementarity determining region 1 of Heavy chain)-FRH2-CDRH2-FRH3-CDRH3-FRH4;
また、HVR及びFR序列は一般的にVL(または、Vk)で次の順序で表れる:
FRL1(Framework region 1 of Light chain)-CDRL1(complementarity determining region 1 of Light chain)-FRL2-CDRL2-FRL3-CDRL3-FRL4。
(a)次の一般式1で表示されるアミノ酸序列からなるCDRH2を含む重鎖可変領域(heavy chain variable region、VH):
一般式1
GIYYDX6X7X8X9X10X11X12X13SVKG
ここで、X6はG、A、またはSであり;X7はS、T、I、A、D、F、L、またはHであり;X8はA、T、S、Q、W、I、V、M、N、Y、またはHであり;X9はR、KS、V、A、Q、L、T、E、D、M、L、F、またはPであり;X10はY、G、S、またはTであり;X11はY、W、M、またはLであり;X12はA、S、T、またはLであり;X13はD、S、G、N、またはPである;及び
(b)次の一般式2で表示されるアミノ酸序列からなるCDRL1を含む軽鎖可変領域(light chain variable region、VL):
一般式2
X1GX3X4SNIGSX10X11X12Y
前記X1はV、A、G、S、W、N、Y、K、T、H、R、Q、E、またはDであり;X3はG、H、D、L、T、Q、K、N、S、またはMであり;X4はV、Y、I、P、V、M、A、L、F、またはSであり;X10はNまたはAであり;X11はAまたはPであり;X12はV、T、またはLである。
一般式1-1
GIYYDX6X7X8X9YYADSVKG
ここで、X6はG、A、またはSであり;X7はS、T、I、A、D、F、L、またはHであり;X8はA、T、S、Q、W、I、V、M、N、Y、またはHであり;X9はR、KS、V、A、Q、L、T、E、D、M、L、F、またはPである。
一般式2-1
X1GX3X4SNIGSNAVY
前記X1はV、A、G、S、W、N、Y、K、T、H、R、Q、E、またはDであり;X3はG、H、D、L、T、Q、K、N、S、またはMであり;X4はV、Y、I、P、V、M、A、L、I、F、またはSである。
(a)前記の抗-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)膜貫通ドメイン(transmembrane domain);及び
(c)細胞内信号伝達ドメイン。
本発明のキメラ抗原受容体の膜貫通ドメイン及び細胞内信号伝達ドメインは、前述した具体的な膜貫通ドメイン及び細胞内信号伝達ドメインのうち、1以上選択された組合せで含まれることができる。例えば、本発明のキメラ抗原受容体はCD8α膜貫通ドメイン及びCD28及びCD3ζの細胞内信号伝達ドメインを含むことができる。
実施例1:CD19に対する抗体開発
抗体開発のためにヒトCD19タンパク質の細胞外部ドメイン(Extracellular domain、ECD)を動物細胞を用いて生産した後、抗原に用いた。ECDのC-末端にヒトIgG1のヒンジ及びFc部位(CH2-CH3)が結合された形態のDNAをpCEP4ベクター(Invitrogen、米国)にクローニングした。次に、FreeStyleTM293F(Invitrogen、米国)細胞に前記クローニングされたベクターを一時的に形質転換させて、CD19-ECD Fc融合タンパク質を確保した。前記CD19-ECD Fc融合タンパク質とオパールライブラリを用いてファージバイオ-パンニング(bio-panning)を実施した。抗体ライブラリはVCSM13ヘルパーファージ(helper phage)を用いてファージ形態に収得してパンニングに用いた。初めて抗原と結合させるライブラリファージの数は1013を用いた。パンニングラウンド(panning round)は4ラウンドまで実施したものであり、親和度の高いファージが選択的によく選別できるパンニング戦略でパンニングラウンド回数が増えるにつれて抗原の量を減らし、洗浄回数は増やす方法を適用した。ターゲット抗原に結合したファージの数はER2537E.coliを用いて下記のように適正した。バイオ-パンニング各ラウンドで得たバインダーファージ(binder phage)をpH2.2グリシン緩衝液に湧出した。SB培養液で一夜間培養したER2537を新たなSB培養液を用いて1/200で希薄して継代した。次に、3時間の間37℃で追加培養してログファージ(log phage)に到達するようにした。100μlの新鮮なER2537と10μlの希釈されたファージを1.5mlチューブで混合した後、30分間培養した後、アンピシリン(ampicillin)LBプレートに塗抹した。次に、37℃で一夜間培養して生成されたコロニー(colony)数と希釈因子を適用してファージ数を測定した。バイオ-パンニング各ラウンドで得たバインダーファージはER2537に感染させてコロニー形態に維持した状態でELISA方法により各抗原に対する結合有無を確認した。バインダーファージを感染させて得たコロニーをSB培養液に接種した後、OD600で0.5になるまで培養した。次に、0.5mMのIPTGを入れて30℃でシェーキング(shaking)培養して抗体断片タンパク質が過発現されるようにした。BBS緩衝液を用いてscFvタンパク質を精製した。精製された抗体断片をCD19-ECD Fcタンパク質がコーティングされたプレートとCD19過発現細胞株であるRaJiに処理した。2次抗体を処理した後、TMBで発色反応を発生させてELISAリーダ器(Victor X3 PerkinElmer)を用いてOD450値を測定した。CD19に特異的に結合するものとして選別された抗体クローンはファージミド(phagemid)プラスミドと公知されたプライマセット(Phage display: a laboratory manual, Carlos Barbas III, et al., Cold Spring Harbor Laboratory Press)を用いてシーケンシング(sequencing)分析を通じて可変部位の塩基序列を確認した。選別された抗体のうち、CD19に対する結合能に優れるCD19_8.1を選別したものであり、選別されたCD19_8.1抗体の可変部位の塩基序列は表1の通りである。
CD19に対してCD19_8.1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を組合せて新たなサブライブラリを製作した。サブライブラリを生成するために、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た。CD19_8.1抗体断片はtemplate DNAに使われた。無作為コドンはPCRによりHCDR3のみを除いて5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、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を製作した。製作されたファージライブラリに基づいて実施例1と同一な方法により抗体を選別した。
開発された抗体CD19_8.1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、scFv形態のCD19_8.1、CD8ヒンジ領域、CD137膜貫通領域及び細胞質領域、及びCD3ゼー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181序列)は塩基序列分析を通じて確認した。
実施例3で製造されたウイルスを用いて、CD19_8.1抗体断片が連結されたキメラ抗原受容体が表面に提示された細胞毒性T細胞を製造した。
実施例3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細胞を使用して、前記T細胞が細胞の表面の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。具体的に、実験はCD19陽性細胞株であるRaJiとCD19陰性細胞株であるJurkat E61細胞株を10%ウシ胎児血清及び1%ペニシリン-ストレプトマイシンが添加されたRPMI-1640培地に培養して使用した。まず、CD19陽性または陰性細胞株を底の丸い形態の96-ウェルプレートにウェル当たり3x104個になるように株分けした。培養上等液を除去した後、ウェル当たり処理割合に合うように製造したキメラ抗原受容体T細胞を添加し、5%のCO2及び37℃の条件で24時間の間培養した。その結果、培地に分泌されたインターフェロンガンマの量をELISAキットを使用して製造社のプロトコルの通り測定し、その結果を図6に示した。この際、対照群として細胞を培養しないプレートにキメラ抗原受容体T細胞を添加した群(Effector T cell only)、細胞を培養したプレートに何も添加しない群(Target cell only)を使用した。
CD19_8.1_2F1に基づいて第2、3重鎖と第1軽鎖ライブラリを組合せて新たなサブライブラリを製作した。サブライブラリを生成するために、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_8.1_2F1の序列が70%以上維持されるようにした。CD19_8.1_2F1抗体断片をtemplate DNAに使用した。同意コドンを用いた多様性はPCRにより3個のCDRに導入された。増幅した抗体断片は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を製作した。製作されたファージライブラリに基づいて実施例1と同一な方法により抗体を選別した。開発された抗体の重鎖可変領域及び軽鎖可変領域のアミノ酸序列は表5の通りである。
開発された抗体のうち、親和度が向上したCD19_8.1_3C12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、scFv形態の開発された抗体、CD8ヒンジ及び膜貫通領域、CD137細胞質領域、及びCD3ゼータの細胞質領域をGeneOptimizer(Invitrogen)アルゴリズムを用いてコドン最適化した後、プロモーターがEF-1 alphaに変更されたpLenti6.3/V5-TOPO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7で製造されたレンチウイルスを用いて、CD19_8.1_3C12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。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。
Claims (3)
- 次を含むCD19特異的キメラ抗原受容体:
(a)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);
ここで、前記抗-CD19抗体またはその抗原結合断片は、以下を含む:
(i)配列番号1のアミノ酸配列からなるCDRH1、配列番号2のアミノ酸配列からなるCDRH2、及び配列番号3のアミノ酸配列からなるCDRH3を含む重鎖可変領域(heavy chain variable region、VH)、並びに、配列番号4のアミノ酸配列からなるCDRL1、配列番号5のアミノ酸配列からなるCDRL2、及び配列番号6のアミノ酸配列からなるCDRL3を含む軽鎖可変領域(light chain variable region、VL);又は
(ii)配列番号1のアミノ酸配列からなるCDRH1、配列番号190のアミノ酸配列からなるCDRH2、及び配列番号191のアミノ酸配列からなるCDRH3を含む重鎖可変領域(VH)、並びに、配列番号199のアミノ酸配列からなるCDRL1、配列番号5のアミノ酸配列からなるCDRL2、及び配列番号6のアミノ酸配列からなるCDRL3を含む軽鎖可変領域(VL);
(b)CD8のヒンジドメインを含む、膜貫通ドメイン(transmembrane domain);及び
(c)4-1BBの細胞ドメイン及びCD3ζ(CD3ゼータ)の細胞ドメインを含む、細胞内信号伝達ドメイン。 - 請求項1のキメラ抗原受容体を発現するエフェクター細胞。
- 請求項2のエフェクター細胞を含む薬剤学的組成物。
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