JP7164598B2 - トランスジェニックマクロファージ、キメラ抗原受容体、及び関連する方法 - Google Patents
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腫瘍微小環境は、マクロファージの分極に影響を及ばすことができる。分極の過程は、IL-10、グルココルチコイドホルモン、アポトーシス細胞、及び自然免疫細胞機能を妨げることができる免疫複合体の不利な環境により、多様及び複雑であり得る[11、19]。分極の機構は、依然として明確ではないが、転写調節を伴うことは知られている。例えば、LPS又はIFNγに曝露されたマクロファージは、M1表現型に向かって分極するが、IL-4又はIL-13に曝露されたマクロファージは、M2表現型に向かって分極する。LPS又はIFNγは、Trif及びMyD88経路を誘導するマクロファージの表面上のToll様受容体4(TLR4)と相互作用し、転写因子IRF3、AP-1、及びNFκBの活性化を誘導し、したがって、炎症性M1マクロファージ応答に必要なTNF遺伝子、インターフェロン遺伝子、CXCL10、NOS2、IL-12などを活性化させることができる[20]。同様に、IL-4及びIL-13は、IL-4Rと結合し、抗炎症応答(M2応答)に関連する遺伝子であるCCL17、ARG1、IRF4、IL-10、SOCS3などの発現を調節するJak/Stat6経路を活性化する。
M1炎症誘発性マクロファージ又は古典的に活性化されたマクロファージは、活動的で貪食性が高く、大量の反応性酸素及び窒素種を生成し、それによってTh1応答を促進する[11]。M1マクロファージは、2つの重要な炎症性サイトカインであるIL-12及びIL-23を高レベルで分泌する。IL-12は、炎症に寄与する大量のIL-17を分泌する、Th17細胞の活性化及びクローン増殖を誘導する[23]。これらの特徴により、M1マクロファージは、転移を制御し、腫瘍成長を抑制し、微生物感染を制御することができる[24]。更に、M1マクロファージの腫瘍部位への浸潤及び補充は、固形腫瘍を有する患者におけるより良好な予後及びより高い全体生存率と相関する[17、18、25~28]。
M2マクロファージは、抗炎症性であり、血管形成及び組織修復の過程において助成する。それらはスカベンジャー受容体を発現し、大量のIL-10及び他の抗炎症性サイトカインを産生する[33、36]。M2マクロファージによるIL-10の発現は、Th2応答を促進する。結果として、Th2細胞は、IL-3及びIL-4の産生を上方制御する。IL-3は、ミエロイド系(顆粒球、単球、及び樹状細胞)における全ての細胞の増殖を、他のサイトカイン、例えば、エリスロポエチン(EPO)、顆粒球マクロファージコロニー刺激因子(GM-CSF)、及びIL-6と併せて刺激する。IL-4は、細胞外マトリックスの産生に寄与するため、治癒の過程において重要なサイトカインである[23]。M2マクロファージは、血管が悪性細胞に栄養を与えることを可能にし、したがって増殖を促進することによって腫瘍の進行を助け得る機能を示す。固形腫瘍の大部分におけるマクロファージ(M2と考えられる)の存在は、治療の成功及びより長い生存率と負に相関する[37]。更に、M2マクロファージの存在は、乳癌における転移能に連鎖されている。Lin及び同僚らは、マウスにおける乳房腫瘍部位へのマクロファージの早期の補充が血管形成及び悪性腫瘍の発生率を増加することが見出された[38]。腫瘍微小環境は、マクロファージがM2表現型を維持するのを助けると考えられる[23、39]。アディポネクチン及びIL-10などの腫瘍微小環境中に存在する抗炎症シグナルは、M2応答を増強できる[41]。
腫瘍微小環境に曝露された細胞は、異なる挙動である。例えば、固形腫瘍の周辺部に見られる腫瘍関連マクロファージは、腫瘍の増殖及び転移を促進するのを助け、M2様表現型を有すると考えられる[42]。腫瘍関連マクロファージは、組織に存在するマクロファージ、又は骨髄由来の補充されたマクロファージ(単球からマクロファージに分化して組織に移行するマクロファージ)のいずれかであり得る。Cortez-Retamozoによる研究では、脾臓中のTAM前駆体の多数が腫瘍間質に移行し、更にTAMの貯蔵所としてこの器官を示唆することが見出された[43]。脾臓に見られるTAM前駆体は、CCR2ケモカイン受容体を通して移動を開始することが見出された[43]。最近の研究では、がん細胞によるCSF-1産生が生存率の低下を予測し、全体的な予後不良を示す、マクロファージを腫瘍周辺に誘引する主要な因子としてCSF-1が見出されている[44~46]。TNF-α及びIL-6などの他のサイトカインもまた、マクロファージの腫瘍周辺部への蓄積/補充に連鎖されている[45]。
腫瘍細胞中に存在する代謝性異常は、がんを産生する同一の遺伝子変異によって制御される[53]。これらの代謝性異常の結果として、がん細胞は、マクロファージの分極を改変し、腫瘍の増殖を促進することができるシグナルを生成できる[54、55]。
がん免疫療法の役割は、免疫系を刺激してがん細胞を認識、拒絶、及び破壊することである。単球/マクロファージを用いたがん免疫療法は、マクロファージを炎症促進応答(M1)に向かって分極することを目的とし、したがって、マクロファージ及び他の免疫細胞が腫瘍を破壊することを可能にする。多数のサイトカイン及び細菌化合物は、生体外でこれを達成できるが、典型的には、副反応が生体内で非常に深刻である。重要なのは、患者の副反応が最小限又は簡単に管理される化合物を見つけることである。単球/マクロファージを使用する免疫療法は過去数十年に使用されており、新しいアプローチは毎年開発されている[64、65]。早期免疫療法は、より良好ながん療法のための良好な基盤が確立されており、免疫療法を用いて治療された患者における生存率が増加された[66]。
Toll様受容体4は、TLR4遺伝子によりコードされるヒトのタンパク質である。TLR4は、グラム陰性細菌上でリポ多糖(LPS)を検出し、したがって、危険の認識及び自然免疫系の活性化に根本的な役割を果たす(図7)。それは、マクロファージがLPSによって誘導される際に、シグナル伝達を媒介するために、LY96(MD-2)及びCD14と協働する。TLR4の細胞質ドメインは、LPSの存在を検出する際に、M1マクロファージの活性化に関与する。これは、CARが標的タンパク質に結合する際に、単球/マクロファージの活性化を誘導するために、MOTO-CAR(すなわち、キメラ受容体)と結合される受容体の機能部分である。
ヒトチミジンキナーゼ1(TK1)は、腫瘍での過剰発現の状況下において大部分が研究されている、周知のヌクレオチドサルベージ経路の酵素である。当初TK1は、がん患者の血清(sTK)での発現により最初に一般化されたため、その診断及び予後の可能性は広範に研究されてきた。例えば、いくつかの研究では、多くの異なるがん患者におけるsTK1が、より進行した腫瘍を示す、より高いレベルのTK1を有するステージ上様式で上昇されることが実証されている[81]。
実施例1:特定のリガンドに対するScFv断片の単離
cDNAは、ヒトTK1と特異的な抗体を発現する、モノクローナル抗体ハイブリドーマ細胞(CB1)から精製した。単離されたcDNAを使用して、ポリメラーゼ連鎖反応(PCR)を介してCB1可変領域の重鎖及び軽鎖を増幅させた。その重鎖及び軽鎖からの配列を、NCBI Blastを使用して確認した。CB1重鎖及び軽鎖を、部位重複伸長(SOE)PCRを介して一緒に融合させ、G4Sリンカーを使用して一本鎖断片可変(scFv)を形成させた。G4Sリンカーを、タンパク質発現を最大化するために、IDT(https://www.idtdna.com/CodonOpt)により提供されるコドン最適化ツールを使用して、酵母及びヒトに対してコドン最適化した。CB1 scFvを、制限酵素を用いて切断し、pMP71 CARベクターに挿入した。
図26を参照すると、105の酵母は、蛍光タグAPCを用いて標識化された2.5ugの目的タンパク質と培養された。左のより高いピーク(赤色)は、目的のタンパク質と結合されていない酵母集団を示す(陰性対照)。左の左下のピーク(青色)は、その表面タンパク質を発現しない酵母を示し、一方で右側の高いピーク(青色)は、発現された抗体断片の目的のタンパク質との結合を示す。
キメラ受容体ベクターの構築:
過程における第1のステップは、合成キメラ受容体遺伝子のヌクレオチド配列の設計、及び好適なレンチウイルスベクターの選択である。全てのベクターの設計は、高度なソフトウェアバージョン9.1.6で実行される。配列は、Uniprot及びHuman Protein Reference Data base及びNCBIからも取得する。
a)TK1、HPRT、ROR1、MUC-16、EGFRvIII、メソセリン、HER2、CEA、BCMA、GPC3、FAP、EphA2、NKG2Dリガンド、GD2、CD19、CD20、CD30、CD33、CD123、CD133、CD138、及びCD171に対して特異的なScFv、
b)GSリンカー又はGSリンカー無し、
c)LRRの5アミノ酸の短いヒンジ、LRRの長いヒンジ、IgG4の短いヒンジ、IgGの119アミノ酸媒介ヒンジ、及びIgG4の長いヒンジ、CD8のヒンジ、システインがセリンに変換されたCD8ヒンジから選択されるヒンジ領域、並びにヒンジ無し、
d)MYD88、TLR3、TLR4、TLR7、TLR8、TLR9、MAL、IRAK1、FCGR2A、FCGR3A、及びFCER1Gの膜貫通ドメインから選択される膜貫通ドメイン
e)Myd88、TLR3、TLR4、TLR7、TLR8、TLR9、MAL、IRAK1、FCGR2A、FCGR3A、及びFCER1Gのサイトゾルドメインから選択されるサイトゾルドメインである。
実施例2において調製した形質導入されたマクロファージは、TK1、HPRT、ROR1、MUC-16、EGFRvIII,メソセリン、HER2、CEA、BCMA、GPC3、FAP、EphA2、NKG2D共役リガンド、GD2、CD19、CD20、CD30、CD33、CD123、CD133、CD138、及びCD171に別個で曝露され、標準的なサイトカインアッセイを使用してIL-12及びIL-23の分泌をモニタリングするか、又はRNA産生を測定することによって、M1表現型への分極について試験された。キメラ受容体を有するマクロファージは、特定のキメラ受容体に対して特異的なリガンドに曝露され、IL-12及び/又はIL-23の分泌が増加されることによって決定されると、M1表現型に分極される。特定のキメラ受容体に対する特異的リガンド以外のリガンドは、IL-12及び/又はIL-21の増加を示さない。
分化の7日後の単球由来マクロファージは、表現型の変化を受けていた。これらの変化は、形質導入細胞と非形質導入細胞とが比較されたものである。図27で観察できるように、形質導入された細胞は、M1又は古典的に活性化されたマクロファージと同様のより活動的な表現型を有する。図27は、分化の8日目での非形質導入及び形質導入された単球由来マクロファージの画像を示す。この時点では、インターフェロンガンマ及びLPSは追加されていない。キメラ受容体を用いて形質導入されたマクロファージの表現型は、非形質導入マクロファージとは異なることが観察できる。形質導入された細胞は、マクロファージ活性化を示す古典的に活性化された又はM1様表現型を表示した。改変された表現型は、形質導入過程及び新たな合成受容体の発現の組み合された効果であり得る。
分化の10日後の形質導入効率が評価され、キメラ受容体を発現するマクロファージが細胞選別された。レンチウイルス形質導入は、マクロファージにおいて困難である。しかしながら、EF1-αプロモーターを有するHIV-1系システムを使用して、ほぼ30%のマクロファージ形質導入が達成された。マクロファージ分化の初期段階における細胞の形質導入は、異なる形質導入効率を表示した。分化の早期段階における単球又はマクロファージは、形質導入がより容易である。キメラアデノウイルスAD5/F35を用いたアデノウイルス形質導入は、マクロファージ形質導入の別の選択肢として現れている。図29は、形質導入されたマクロファージの結果を、FACSAriaシステムを使用して細胞選別した結果を示す。マクロファージ形質導入の約30%は、レンチウイルスアプローチを使用して達成された。左端のプロットは、細胞の0.58%のみが、dTomatoの発現を表すであろう蛍光を示す対照を示す。右2つのプロットは、形質導入後に27.1パーセントの形質導入効率を示す。
キメラ受容体の発現のためのベクターを用いて形質導入されたマクロファージの免疫表現型検査を行い、形質導入された細胞の活性化状態を特定した。TLR-4の細胞外ドメインの修飾により、そのシグナル伝達ドメインの定常的な活性化が誘導され得ることが報告されている(Gay et al.,2014)。TLR-4シグナル伝達の定常的な活性化は、マクロファージ活性化又はM1表現型をもたらし得る。TLR-4に基づいて使用された構築物が、TLR-4から取得されたTIRドメインを介したシグナル伝達の定常的な活性化を誘因できるかどうかは知られていない。しかしながら、形質導入の過程の後に、表現型の変化が観察され、マクロファージ内の細胞表面マーカーの発現が変化した。これは、レンチウイルス形質導入とキメラ受容体タンパク質の発現との組み合わせに起因する可能性が高い。CD14、CD80、D206の発現及びCD163の発現が低いことは、M1表現型に向かうマクロファージの分極の指標であった。これらの細胞表面マーカーの発現は、形質導入された細胞において観察された。図30は、キメラ受容体を用いて形質導入されたマクロファージにおける色素(Alexa 647)の保持、並びにCD80、CD163、CD206、及びCD14の発現を実証する蛍光活性化セルソーティングの6つの散布図を提示する。
キメラ受容体が形質導入されたマクロファージを標的とするTK1の腫瘍活性を、NCI-H460-GFP細胞に対して試験した。使用されたE:T比は、1:10であった。分析は、共焦点顕微鏡検査を用いて実行した。蛍光の検出は、12時間の間、5分毎に実行した。タイムラプス中に、キメラ受容体を形質導入したマクロファージを標的とするTK1がH460-GFP細胞に向かって移行し、それらを攻撃することが観察された。シナプスの後に、標的細胞に特異的な細胞死が誘導される。図32において画像によって実証されるように、TK1標的化キメラ受容体で形質導入されたマクロファージは、TK1を発現する肺癌細胞株において検出、攻撃、及び細胞死を誘導することができる。NCI-H460細胞は、改変されてGFPを発現させた。キメラ受容体が形質導入されたマクロファージを標的とするTK1の殺腫瘍活性は、標的細胞における蛍光の喪失として共焦点顕微鏡を用いて検出された。
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Claims (13)
- マクロファージをM2マクロファージに分極する方法における使用のための、キメラ受容体を含むマクロファージを含む、組成物であって、前記方法が、
キメラ受容体を含む前記マクロファージを、前記キメラ受容体の細胞外ドメインのリガンドと接触させることと、
前記リガンドを、前記キメラ受容体の前記細胞外ドメインと結合させることと、を含み、
前記キメラ受容体の前記細胞外ドメインに対する前記リガンドの前記結合が、前記キメラ受容体の細胞質部分を活性化させ、
前記キメラ受容体の細胞質部分の活性化が、前記マクロファージをM2マクロファージに分極し、
前記キメラ受容体が、
細胞質ドメインと、
膜貫通ドメインと、
細胞外ドメインと、を含み、
前記細胞質ドメインが、活性化された際にマクロファージをM2マクロファージに分極する受容体の細胞質部分を含み、
前記細胞質部分を含む野生型タンパク質が、前記細胞外ドメインを含まない、組成物。 - 前記細胞外ドメインとのリガンドの結合が、前記細胞質部分を活性化する、請求項1に記載の組成物。
- 前記細胞外ドメインが、ScFv断片である、請求項1に記載の組成物。
- 前記キメラ受容体が、前記膜貫通ドメインと前記細胞外ドメインとの間にリンカーを更に含む、請求項1に記載の組成物。
- 前記リンカーが、GSリンカーである、請求項4に記載の組成物。
- 前記キメラ受容体が、前記膜貫通ドメインと前記細胞外ドメインとの間にヒンジ領域を更に含む、請求項1に記載の組成物。
- 前記キメラ受容体が、前記膜貫通ドメインと前記リンカーとの間にヒンジ領域を更に含む、請求項4に記載の組成物。
- 前記キメラ受容体が、ポリヌクレオチドを含む核酸によってコードされる、請求項1に記載の組成物。
- 前記核酸が、前記ポリヌクレオチドと作動可能に連結されたプロモーターを更に含む、請求項8に記載の組成物。
- 前記核酸が、ベクターに含まれる、請求項8に記載の組成物。
- 前記ベクターが、レンチウイルスベクターである、請求項10に記載の組成物。
- キメラ受容体が、マクロファージである細胞に含まれる、請求項1に記載の組成物。
- 前記核酸が、マクロファージである細胞に含まれる、請求項8に記載の組成物。
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WO2017019848A1 (en) | 2015-07-28 | 2017-02-02 | The Trustees Of The University Of Pennsylvania | Modified monocytes/macrophage expressing chimeric antigen receptors and uses thereof |
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