JP2017528133A - T細胞またはnk細胞を活性化および増加させるための、可溶性抗体複合体 - Google Patents
T細胞またはnk細胞を活性化および増加させるための、可溶性抗体複合体 Download PDFInfo
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Abstract
Description
本出願は、その内容の全体が参照により本明細書に組み入れられる、2014年9月4日に出願された米国特許仮出願第62/045,591号に対する優先権を主張する。
本開示は、ヒトのT細胞またはNK細胞を活性化および増加させるための、可溶性単一特異性抗体複合体の方法および組成物に関連する。
宿主の耐性および適応免疫は、複雑かつ重大な、ヒトの健康の構成要素である。Tリンパ球は、宿主の耐性の維持において主要な役割を担う制御性T細胞;環境刺激に従って免疫応答を行うCD4+ヘルパーT細胞およびCD8+細胞傷害性T細胞のようなエフェクターサブセットを含む、様々なサブセットで構成されている。
本発明者らは、インビトロにおいてヒトの初代T細胞またはNK細胞を活性化および増加させるために可溶性単一特異性四量体抗体複合体を使用する方法を開発した。特に、本発明者らは、可溶性単一特異性四量体抗体複合体を用いることで、二重特異性四量体抗体複合体を用いた場合を上回るT細胞の活性化が得られることを明らかにした。本発明者らはまた、可溶性単一特異性四量体抗体複合体を用いると、可溶性単一特異性四量体抗体複合体を含まずに培養されたNK細胞と比べて、NK細胞の活性化が促進されることも明らかにした。
本開示は、四量体抗体複合体のような単一特異性複合体を用いて、インビトロにおいてヒトのT細胞またはナチュラルキラー(NK)細胞を活性化および増加させる方法を提供する。
本開示は、可溶性単一特異性複合体がT細胞またはNK細胞上の同じ抗原に結合する連結された2つの結合タンパク質を含む、少なくとも1つの可溶性単一特異性複合体を含む組成物をも包含する。
本開示は、治療におけるその使用を含むが、それに限定されず、活性化されたT細胞またはNK細胞の全ての使用を包含する。
単一特異性CD3 TACおよびCD28 TACは、二重特異性CD3/CD28 TACの混合物と比較して、ヒトT細胞におけるより盛んな増殖を誘導する(図1)。二重特異性CD3/CD28 TACは、最初に等量の抗CD3抗体と抗CD28抗体とを混合することによって調製した。等量のラット抗マウスIgG1を添加して、二重特異性TACを形成させた。その結果生じたTAC混合物は、25%の単一特異性抗CD3 TAC、25%の単一特異性抗CD28 TAC、および50%の二重特異性抗CD3/抗CD28 TACを含有する(四量体抗体複合体およびそれを調製する方法の説明については、参照として本明細書に組み入れられる、Lansdorpの米国特許第4,868,109号を参照のこと)。
CD3およびCD28 TACと組み合わせた可溶性単一特異性CD2 TACは、ヒトT細胞の最適な活性化を誘導する(図2)。単一特異性TACは、実施例1において説明されるように調製した。抗ヒトCD3を用いて、抗CD3に対して特異的な単一特異性TACを調製した。抗ヒトCD28を用いて、単一特異性抗CD28 TACを調製した。抗ヒトCD2を用いて単一特異性抗CD2 TACを調製した。未処理のままの、または1% HSAでブロッキングした96ウェルプレートにおいて、単一特異性TACの様々な組み合わせと共に、またはDynabead(登録商標)Human T-Activator CD3/CD28ビーズと共に、CFSE標識した精製ヒトT細胞を培養した。XVIVO-15培地における培養3日後のフローサイトメトリーによって、T細胞増殖(CFSE色素希釈法)に対するi)抗CD3 TAC単独、ii)抗CD3 TACおよび抗CD28 TAC、または、iii)抗CD3 TAC、抗CD28 TAC、および抗CD2 TACの組み合わせ効果を評価した。培養第6日目にGuava ViaCountアッセイを用いて生細胞数計測を行った。
可溶性単一特異性CD3、CD28、およびCD2 TACはT細胞によるサイトカイン産生を誘導できる(図3)。可溶性単一特異性TAC構築物の様々な組み合わせ、またはDynabead(登録商標)Human T-Activator CD3/CD28ビーズの存在下において、RosetteSep(商標)で濃縮したヒトT細胞を4時間培養した(図3)。培養にブレフェルジンAを加え、細胞内におけるサイトカイン蓄積をさせ、培養後にフローサイトメトリーによって評価を行った。培養を採取し、固定および透過処理の後に、細胞表面マーカーおよび細胞内サイトカインについて染色した。
21日間の工程における、Dynabead(登録商標)Human T-Activator CD3/CD28ビーズによる刺激を受けたT細胞と比較した、単一特異性CD3、CD28、およびCD2 TAC による刺激を受けたT細胞の代表的な画像(10×および20×拡大)(図4)。EasySep(商標)によって濃縮したヒトT細胞を、30 U/mL組換えヒトIL-2の存在下において、ビーズ対細胞の比率を1:1としたDynabead(登録商標)Human T-Activator CD3/CD28ビーズ、または、最終濃度0.5ug/mLの単一特異性CD3、CD28、およびCD2 TACのいずれかと共に培養した。細胞の成長について培養をモニタリングし、細胞濃度は0.5〜2×10E6 細胞/mLに維持した。Dynabead(登録商標)Human T-Activator CD3/CD28ビーズまたは単一特異性CD3、CD28、およびCD2 TACによって、培養第7日目および第17日目にT細胞を再刺激した。
単一特異性CD3、CD28、およびCD2 TACと比較した、Dynabead(登録商標)Human T-Activator CD3/CD28ビーズを用いたヒトT細胞の長期培養および増加(図5)。30 U/mLの組換えヒトIL-2の存在下において、ビーズ対細胞の比率が1:1のDynabead(登録商標)Human T-Activator CD3/CD28ビーズ、または最終濃度0.5ug/mLの単一特異性CD3、CD28、およびCD2 TACのいずれかと共に、EasySep(商標)で濃縮した1×10E6 ヒトT細胞を培養した。細胞の成長について培養をモニタリングし、細胞濃度は0.5〜2×10E6細胞/mLに維持した。Dynabead(登録商標)Human T-Activator CD3/CD28ビーズまたは単一特異性CD3、CD28、およびCD2 TACを用いて、培養第7日目および第17日目にT細胞を再刺激し、培地を新鮮な培地に定期的に置き換えた。
EasySep Human NK Cell Isolation Kit(STEMCELL Technologies, Cat#17955)を用いたネガティブ分離によってヒトNK細胞を単離した。500 IU/mLの組換えヒトIL-2を添加し、血清を含まず、かつ異種成分を含まないImmunoCult-XF培地(STEMCELL Technologies, Cat#10981)において、単離されたNK細胞(CD45+ CD3- CD56+)を1×106細胞/mLの細胞密度で培養した。NK細胞は付加的な刺激を受けなかった(刺激なし)か、または、各抗体の最終濃度0.5ug/mLの単一特異性CD335/CD2 TAC複合体によって刺激を受けた。第3、6、8、10、および13日目に、Nucelocounterを用いて総生細胞数を計測し、フローサイトメトリーによってNK細胞の純度を評価した。培養は、500 IU/mLのIL-2を添加した新鮮なImmunoCult-XF培地を加えて〜1×10^6細胞/mLを維持した。
Claims (20)
- 少なくとも1つの可溶性単一特異性複合体を含む組成物と共に、T細胞またはNK細胞を含有するサンプルを培養する段階を含む、T細胞またはNK細胞を活性化する方法であって、各可溶性単一特異性複合体が、T細胞またはNK細胞上の同じ抗原に結合する連結された2つの結合タンパク質を含む、方法。
- 前記組成物が少なくとも2つの異なる単一特異性抗体複合体を含み、一方の単一特異性抗体複合体がT細胞またはNK細胞上の第1の抗原に結合し、他方の単一特異性抗体複合体がT細胞またはNK細胞上の第2の抗原に結合する、請求項1記載の方法。
- 前記組成物が少なくとも3つの異なる単一特異性抗体複合体を含み、T細胞またはNK細胞上で、第1の抗原に第1の単一特異性抗体複合体が結合し、第2の抗原に第2の単一特異性抗体複合体が結合し、第3の抗原に第3の単一特異性抗体複合体が結合する、請求項1または2記載の方法。
- 結合タンパク質が抗体またはそれらの断片である、請求項1〜3のいずれか一項記載の方法。
- 可溶性単一特異性複合体が四量体抗体複合体である、請求項1〜4のいずれか一項記載の方法。
- 四量体抗体複合体(TAC)が、1つの種に由来する2つの抗体に、該第1の動物種の抗体のFc部位に結合する第2の種由来の2つの抗体分子が結合したもので構成される、請求項5記載の方法。
- 一方の単一特異性抗体複合体がT細胞上の第1の抗原に結合し、他方の単一特異性抗体複合体がT細胞上の第2の抗原に結合する、T細胞を活性化するための、請求項2〜6のいずれか一項記載の方法。
- 第1の抗原がCD3である、請求項7記載の方法。
- 第2の抗原がCD28である、請求項7または8記載の方法。
- 第3の抗原がCD2である、請求項7〜9のいずれか一項記載の方法。
- T細胞の活性化が、増強されたT細胞増殖である、請求項1〜10のいずれか一項記載の方法。
- T細胞の活性化が、増強されたサイトカイン産生である、請求項1〜10のいずれか一項記載の方法。
- T細胞の活性化が、増強されたT細胞増加である、請求項1〜10のいずれか一項記載の方法。
- 一方の単一特異性抗体複合体がNK細胞上の第1の抗原に結合し、他方の単一特異性抗体複合体がNK細胞上の第2の抗原に結合する、NK細胞を活性化するための、請求項2〜6のいずれか一項記載の方法。
- 第1の抗原がCD335である、請求項14記載の方法。
- 第2の抗原がCD2である、請求項14または15記載の方法。
- NK細胞の活性化が、増強されたNK細胞増殖である、請求項1〜6または請求項14〜16のいずれか一項記載の方法。
- NK細胞の活性化が、増強されたサイトカイン産生である、請求項1〜6または請求項14〜16のいずれか一項記載の方法。
- NK細胞の活性化が、増強されたNK細胞増加である、請求項1〜10のいずれか一項記載の方法。
- T細胞またはNK細胞がヒトのものである、請求項1〜19のいずれか一項記載の方法。
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