JP6538707B2 - 免疫応答を調節するための方法及び組成物 - Google Patents
免疫応答を調節するための方法及び組成物 Download PDFInfo
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Description
本出願は、その内容が全体としてすべての目的のために参照により本明細書に明確に組み込まれる2014年3月7日出願の米国仮出願第61/949,927号に対する優先権の利益を請求する。
本発明は、免疫系経路、特にTosoタンパク質(本明細書では「Toso」または「Toso受容体」または「Faim3」または「FCMR」とも相互交換可能に呼ぶ)を包含する任意の経路を調節するための方法及び組成物に向けられる。「免疫系経路」及び「免疫経路」という用語は本明細書で使用する場合、病原体、不活性材料による損傷及び癌を撲滅する組織及び循環系のネットワークにおける細胞性及び可溶性構成要素による協調した作用を指す。免疫系経路の調節は、当該経路の1つ以上の構成要素における発現または機能的活性を変化させて、それにより免疫系による応答(「免疫応答」)を調節することを包含してもよい。本発明は、これらの免疫系経路の構成要素の活性または発現を調整して当該免疫応答に減弱または亢進のいずれかをなすための方法及び組成物を提供する。ある例示的な実施形態において、免疫応答を減弱させることは、自己免疫疾患の症状を治療または寛解させるよう機能する。他の例示的な実施形態において、免疫応答を亢進させることは、癌を治療、寛解または予防するよう機能する。
本明細書でさらに詳細に論議するであろうように、本発明は、Toso、B7H3、PAMP及びDAMP、スクランブラーゼ、ならびにPD−1及びCTLA−4のような免疫確認箇所阻害薬を含む、免疫応答に関与するタンパク質の活性を調節するための方法及び組成物を提供する。
本発明のある態様において、免疫応答に関与する1つ以上のタンパク質の発現が阻害される。このようなタンパク質には、Toso、IgM、B7H3、PAMP、DAMP、スクランブラーゼ、ならびにPD−1及びCTLA−4のような免疫確認箇所阻害薬を含んでもよいが、これらに限定しない。
一態様において、本発明は、Toso、IgM、B7H3、PAMP、DAMP、スクランブラーゼ、ならびにPD−1及びCTLA−4のような免疫確認箇所阻害薬を含むがこれらに限定しない、免疫応答に関与する1つ以上のタンパク質へ結合する抗体を提供する。いくつかの実施形態において、本発明の抗体は、これらのタンパク質の活性を亢進させる。他の実施形態において、本発明の抗体は、当該タンパク質の活性を低下させる。
本発明の可溶性Tosoタンパク質(本明細書では相互交換可能に「可溶性Toso受容体」、「Toso−Fc」、及び「可溶性Tosoポリペプチド」とも呼ぶ)には、Toso受容体の細胞外ドメインの全部または部分を含む。本発明の可溶性Tosoタンパク質には、さらなる実施形態において、シグナルドメイン及び/またはFcドメインを含む。本明細書でさらに詳細に論議するように、可溶性Tosoタンパク質のこれらの構成要素は、追加の構成要素及び/または修飾を有するまたは有さない任意の方法で組み合わされて、本発明の可溶性Tosoタンパク質を提供してもよい。
先のいずれかにしたがって、本発明の方法には、癌または自己免疫疾患を治療することを必要とする対象を、免疫系経路の構成要素を調節する分子の組み合わせで治療することによる、癌または自己免疫疾患の治療方法を含む。概して、これらの併用療法には、可溶性Tosoタンパク質を免疫系経路の1つ以上の他の調節因子とともに投与することを含む。可溶性Tosoタンパク質は、免疫系経路の1つ以上の他の調節因子の投与の前に、当該投与と同時に、または当該投与の後に投与してもよい。ある態様において、免疫系経路の1つ以上の他の調節因子には、IgM、B7H3、PAMP、DAMP、スクランブラーゼ、及び免疫確認箇所阻害薬を含むが、これらに限定しない。
図3は、B細胞増殖のアッセイの結果を示す。標的細胞は、精製された野生型B細胞とした。刺激は、抗マウスIgMとのBCR架橋またはLPSによるTLR刺激とした。本アッセイは、ヒトまたはマウス可溶性Tosoタンパク質によって増殖が修飾されるかどうかを判定することとした。図3に示すように、hToso−Fc及びmToso−Fcの両方は、培養物中のマウスB細胞の増殖を阻害する。Fcタンパク質単独(対照)は、増殖に影響しない。
図6は、IgM結合アッセイの結果を示す。本アッセイについて、可溶性TOSOタンパク質は、96ウエルプレート(Nunc Maxisorb)において固定した。洗浄及びブロッキング後、マウスIgMはプレート上でインキュベートした。洗浄後、結合IgMを、抗マウスIgM−HRPを用いたインキュベーション、次いで、洗浄及びHRP基質の添加によって検出した。図6に示すように、固定した全長のhTosoは、用量依存的様式でマウスIgMを結合する。
図8は、4つの独立した患者の試料からのCLL活性化のインビトロでの試験の結果を示す。本アッセイは、CLLリンパ系器官において認められる増殖中心のインビトロモデルを提供する。末梢血CD19+細胞は、CLL患者から精製し、無血清系においてResinquimod(TLR7/8アゴニストであるR−848)+IL−2を用いてインビトロで活性化した。これらの細胞は、「2S」と命名した。増殖に及ぼす可溶性hTOSO及び外来性ヒトIgMの効果を評価した。hTOSO及びhIgMはより少ない程度まで、3H Thy組み込みによって概算されるように、CLL増殖に及ぼす阻害効果を有するように見える。
C57Bl/6マウスは、The Jackson Laboratoryから得た。B16F10ネズミ黒色腫細胞株は、10%FBS、2mMのL−グルタミン、及び抗生物質(50U/mlのペニシリン及び50μg/mlのストレプトマイシン)を補充したイスコフ変法ダルベッコ培地中で増殖させた。
図11は、Toso−Fc治療が、腫瘍浸潤リンパ球を含有する腫瘍の割合を増大させることを示す。マウスに先に説明した通りB16F10を摂取した。B16F10黒色腫接種の15日後、マウスを屠殺氏、腫瘍浸潤リンパ球(TIL)分析を実施した。皮下黒色腫腫瘍は、外科的に摘出して秤量した。腫瘍は次に、メスで1mm3片へと切り出し、消化培地(10%FBS、2mM L−グルタミン、抗生物質(50U/mlペニシリン及び50μg/mlストレプトマイシン)、1mg/mlコラゲナーゼIV型、及び20μg/ml DNアーゼI)を補充したRPMI)中に置いた。消化培地中の腫瘍試料はその後、37℃における30分間のインキュベーション中に10分ごとにボルテックスした。単細胞懸濁液を得るために、腫瘍は次に、70μmナイロンフィルターを通過し、1%FBSを補充したRPMIを用いて3回洗浄した。全腫瘍単細胞懸濁液を計数し、6×106個をT細胞マーカー(CD3、CD8、CD4)についてのMAbで染色し、フローサイトメトリーによって分析した。
C57Bl/6マウスは、The Jackson Laboratoryから得た。B16F10ネズミ黒色腫細胞株は、10%FBS、2mM L−グルタミン、及び酷性物質(50U/mlペニシリン及び50μg/mlストレプトマイシン)を補充したイスコフ変法ダルベッコ培地中で増殖させた。
Claims (10)
- 癌の治療のための医薬組成物であって、医薬有効量の可溶性Tosoタンパク質、並びに抗PD−1抗体及び抗CTLA−4抗体からなる群から選択される少なくとも1つの免疫確認箇所阻害薬を含む、医薬組成物。
- 前記少なくとも1つの免疫確認箇所阻害薬は、抗PD−1抗体を含む、請求項1に記載の医薬組成物。
- 前記少なくとも1つの免疫確認箇所阻害薬は、抗CTLA−4抗体を含む、請求項1に記載の医薬組成物。
- 前記少なくとも1つの免疫確認箇所阻害薬は、抗PD−1抗体と抗CTLA−4抗体とを含む、請求項1に記載の医薬組成物。
- 腫瘍における浸潤リンパ球のレベルを亢進させることにより腫瘍を治療するための医薬組成物であって、可溶性Tosoタンパク質を含み、前記治療から結果として生じる浸潤リンパ球のレベルは、治療を有さないレベルよりも高い、医薬組成物。
- 前記浸潤リンパ球は、CD3+細胞、CD8+細胞、またはCD3+細胞及びCD8+細胞の組み合わせを含む、請求項5に記載の医薬組成物。
- さらに、抗PD−1抗体及び抗CTLA−4抗体からなる群から選択される少なくとも1つの免疫確認箇所阻害薬を含む、請求項5または6に記載の医薬組成物。
- 前記少なくとも1つの免疫確認箇所阻害薬は、抗PD−1抗体を含む、請求項7に記載の医薬組成物。
- 前記少なくとも1つの免疫確認箇所阻害薬は、抗CTLA−4抗体を含む、請求項7に記載の医薬組成物。
- 前記少なくとも1つの免疫確認箇所阻害薬は、抗PD−1抗体と抗CTLA−4抗体とを含む、請求項7に記載の医薬組成物。
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