JP6475712B2 - サイトカインアンタゴニストの標的化 - Google Patents
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Description
ナノボディ−IFNアンタゴニスト融合物の構築
QuickChange II−E部位特異的突然変異誘発キット(Agilent)を使用し、IFN−IFNAR1結合を抑制し、ヒトIFNα2の拮抗的挙動を付与する変異体R120E(Panら、2008)(PCT/US2009/056366)を、マウスレプチン受容体に対するナノボディとヒトIFNα2との融合物である、pMET7 SIgK−HA−4.11−His−PAS−ybbr−IFNα2構築物(PCT/EP2013/050787)に導入した。
Hek293T細胞に、標準的なリポフェクタミン法(Invitrogen)を用いて、タンパク質融合構築物をトランスフェクトした。トランスフェクションの48時間後、培養培地を収集し、−20℃で保存した。
Hek293T細胞を、10%FCSを補充したDMEM中で増殖させた。HL116クローン(Uzeら、1994)は、ヒトHT1080株化細胞に由来する。これは、IFN誘導性6−16プロモーターによって制御されるホタルルシフェラーゼ遺伝子を含む。マウスレプチン受容体を発現する、得られたHL116−mLR10クローンが記載されている(PCT/EP2013/050787)。
拮抗的IFN活性を、HL116細胞内及びmLRを発現するHL116−mLR10でIFNα2またはIFNβにより誘導されるルシフェラーゼ活性の阻害を定量することにより測定した。IC50値は、Prismソフトウェア(GraphPad)での非線形データ回帰を用いて算出した。ルシフェラーゼ活性を、ルシフェラーゼ基質緩衝液(20mMトリシン、1.07mM (MgCO3)4Mg(OH)2・5H2O、2.67mM MgSO4・7H2O、0.1mM EDTA、33.3mMジチオスレイトール、270μM補酵素A、470μMルシフェリン、530μM ATP、最終pH 7.8)を使用し、Berthold Centro LB960ルミノメーターで、IFN刺激の6時間後に測定した。
マウスレプチン受容体に対するナノボディ4−11を、材料及び方法に記載したようにしてIFNα2変異体R120Eと融合した。図1は、マウスレプチン受容体に対するナノボディ4−11及びヒトIFNα2−R120E(Piehlerら、2000におけるように番号付け)を用いて構築したナノボディ−IFNアンタゴニスト融合タンパク質の模式図を示す。
親のHL116細胞、及びマウスレプチン受容体を発現する誘導されたHL116−mLR10細胞を、4−11−IFNα2−R120E融合タンパク質を発現するHek 293T細胞による培養上清のいくつかの希釈物の存在下、10pMのIFNα2で6時間処理した。両方の株化細胞で、10pMがIFNα2のEC50に相当するので、10pMのIFNα2の量を選択した。次いで、細胞を溶解し、IFNが誘発したルシフェラーゼ活性を定量した。試験を行った最も高い濃度で、4−11−IFNα2−R120E融合タンパク質は、非標的のHL116細胞のIFNα2作用を阻害することができなかった(図2A)。これに対し、4−11ナノボディの標的を発現するHL116−mLR10細胞では、用量依存的阻害効果が明白である(図2B)。
ヒトI型IFNを構成するサブタイプの中で、IFNβが、IFNα/β受容体に対し最も高い親和力を示す。したがって、本発明者らは、4−11−IFNα2−R120E融合タンパク質もIFNβの作用に対して拮抗的活性を発揮するかどうかの試験を行った。
I型IFNアンタゴニストIFNα2−R120Eを、GGSモチーフの20リピートからなるリンカー配列を介して抗ヒトCD20ナノボディ2HCD25と融合した。融合タンパク質を大腸菌内で産生させ、固定化金属アフィニティクロマトグラフィー(IMAC)により精製した。ヒト末梢血単核球細胞(PBMC)は、CD19の細胞表面発現を特徴とし得るB細胞の約4%を含むと予想される。循環するB細胞の大多数はCD20発現についても陽性である。フィコール勾配(histopaque−1077、Sigma−Aldrich)により、健常人ドナーの血液試料からPBMCを単離した。細胞を未処理のままにするか、10μg/mlの2HCD25ナノボディ−IFNα2−R120E融合タンパク質の非存在下または存在下に、50pMのヒトIFNα2と15分間インキュベートした。次いで、細胞を固定し(BD Fix Buffer I)、透過処理し(BD Perm Buffer III)、PE標識した抗pSTAT1(BD#612564)、及びAPC標識した抗ヒトCD19(BD #555415)で標識化した。BD FACS Cantoを用いてFACSデータを得、CD19陽性及び陰性細胞集団におけるpSTAT1と関連する蛍光について、Diva(BD Biosciences)ソフトウェアを用いて解析した。図4は、B細胞集団の大部分において、CD20に対する特異的ナノボディに連結したIFNアンタゴニストがIFN作用を特異的に阻害し、CD19陰性細胞集団においてはIFN応答がそのままであることを示す。
2HCD25ナノボディ及びIFNα2−R120Eの融合タンパク質が、B細胞内で、IFNが誘導するSTAT1リン酸化を特異的に阻害することが証明されたので、本発明者らは、それがI型IFNの抗増殖性活性を阻害し得るかどうかの試験を行った。更に、変異体R120Eの阻害と合わせ、IFNAR2についてIFNα2の親和力をそれぞれ10倍及び100倍低下させる、IFN変異体L153A及びR149Aの効果を評価した。Daudi細胞は、CD20を発現する、ヒトリンパ芽球様のB細胞である。Daudi細胞を、2.0×105細胞/mlに播種し、未処理のままにするか、2pMのIFNα2のみの存在下、またはCD20標的IFNアンタゴニストとの組合せの存在下、72時間培養した。次いで、それらの細胞を数え、IFNα2により誘導される増殖の阻害効果を評価した。図5は、CD20標的IFNアンタゴニストが、IFNα2の抗増殖性活性を完全に阻害することを示す。また、IFN−IFNAR2の親和力を低下させると拮抗的活性が低下することも示され、これは、阻害効果が実際に標的アンタゴニストの結合のためであることを示している。
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Claims (9)
- インターフェロンアンタゴニストと、標的部分とを含む融合タンパク質を含む組成物であって、
前記インターフェロンアンタゴニストは、R120Eからなる変異を含むヒトIFNα2であり、
前記標的部分は、拮抗的活性の細胞特異的標的化を提供する抗体または抗体様分子からなる、組成物。 - 前記標的部分は、ラクダ重鎖抗体の可変ドメイン(VHH)を含む、請求項1に記載の組成物。
- 前記標的部分は、免疫細胞のマーカーを特異的に標的とする、請求項1または2に記載の組成物。
- 前記標的部分は、レプチン受容体を特異的に標的とする、請求項1に記載の組成物。
- 前記標的部分は、CD20を特異的に標的とする、請求項1に記載の組成物。
- 前記ヒトIFNα2は、インターフェロンアンタゴニストの結合活性を低下させる第二の変異を含む、請求項1に記載の組成物。
- サイトカインアンタゴニストと標的部分を含む融合タンパク質を含む組成物であって、
前記サイトカインアンタゴニストは、R120Eからなる変異を含むヒトIFNα2を含み、
前記標的部分は、CD20に特異的に標的化されたラクダ重鎖抗体の可変ドメイン(VHH)を含む、組成物。 - 自己免疫疾患の治療に使用するための、請求項1〜7のいずれか1項に記載の組成物。
- 前記インターフェロンアンタゴニストと前記標的部分を連結するためのリンカーをさらに含む、請求項1〜8のいずれか1項に記載の組成物。
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EP13306045.9 | 2013-07-19 | ||
EP13306045 | 2013-07-19 | ||
PCT/EP2014/063976 WO2015007520A1 (en) | 2013-07-19 | 2014-07-01 | Targeting of cytokine antagonists |
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JP2016529232A JP2016529232A (ja) | 2016-09-23 |
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EP3426278B1 (en) * | 2016-03-07 | 2024-01-03 | Vib Vzw | Cd20 binding single domain antibodies |
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EP3455245A2 (en) * | 2016-05-13 | 2019-03-20 | Orionis Biosciences NV | Therapeutic targeting of non-cellular structures |
WO2017194783A1 (en) | 2016-05-13 | 2017-11-16 | Orionis Biosciences Nv | Targeted mutant interferon-beta and uses thereof |
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CA3050601A1 (en) | 2017-02-07 | 2018-08-16 | Vib Vzm | Immune-cell targeted bispecific chimeric proteins and uses thereof |
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EP3665201A4 (en) * | 2017-08-09 | 2021-06-02 | Orionis Biosciences, Inc. | CD8 BINDERS |
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CN111499718B (zh) * | 2019-01-30 | 2022-06-14 | 复旦大学 | 人α干扰素受体结合相关位点突变体及其用途 |
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WO2022258691A1 (en) | 2021-06-09 | 2022-12-15 | Innate Pharma | Multispecific proteins binding to nkg2d, a cytokine receptor, a tumour antigen and cd16a |
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WO2024040247A1 (en) | 2022-08-18 | 2024-02-22 | Regeneron Pharmaceuticals, Inc. | Interferon proproteins and uses thereof |
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US20160159875A1 (en) | 2016-06-09 |
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US10947288B2 (en) | 2021-03-16 |
CN105658669A (zh) | 2016-06-08 |
CA2918119C (en) | 2022-11-29 |
CA2918119A1 (en) | 2015-01-22 |
US10072059B2 (en) | 2018-09-11 |
MX2016000721A (es) | 2016-09-07 |
JP2016529232A (ja) | 2016-09-23 |
SG10202010429YA (en) | 2020-11-27 |
EP3022230B1 (en) | 2019-11-06 |
IL243459B (en) | 2019-10-31 |
IL243459A0 (en) | 2016-03-31 |
US20180334488A1 (en) | 2018-11-22 |
US9732135B2 (en) | 2017-08-15 |
US20180057555A1 (en) | 2018-03-01 |
WO2015007520A1 (en) | 2015-01-22 |
KR20160108292A (ko) | 2016-09-19 |
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