JP2016529232A - サイトカインアンタゴニストの標的化 - Google Patents
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Abstract
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 (13)
- サイトカインアンタゴニストと、抗体または抗体様分子からなる標的部分とを含む融合タンパク質。
- 前記サイトカインアンタゴニストが変異体サイトカインである、請求項1に記載の融合タンパク質。
- 前記標的部分がナノボディである、請求項1または2に記載の融合タンパク質。
- 前記サイトカインアンタゴニストがインターフェロンアンタゴニストである、請求項1〜3のいずれか1項に記載の融合タンパク質。
- 前記インターフェロンアンタゴニストがIFNα2−R120E変異体である、請求項4に記載の融合タンパク質。
- 前記標的部分が、特に癌細胞のマーカーを標的とする、請求項1〜5のいずれか1項に記載の融合タンパク質。
- 前記標的部分が、特に免疫細胞のマーカーを標的とする、請求項1〜5のいずれか1項に記載の融合タンパク質。
- 癌の治療に使用するための、請求項1〜6のいずれか1項に記載の融合タンパク質。
- 自己免疫疾患の治療に使用するための、請求項1〜5及び7のいずれか1項に記載の融合タンパク質。
- 前記標的部分が、特に癌細胞のマーカーを標的とする、請求項8に記載の癌の治療に使用するための融合タンパク質
- 前記サイトカインアンタゴニストがIFNα2−R120E変異体である、請求項10に記載の癌の治療に使用するための融合タンパク質。
- 前記標的部分が、特に免疫細胞のマーカーを標的とする、請求項9に記載の自己免疫疾患の治療に使用するための融合タンパク質。
- 前記サイトカインアンタゴニストがIFNα2−R120E変異体である、請求項12に記載の自己免疫疾患の治療に使用するための融合タンパク質。
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Application Number | Priority Date | Filing Date | Title |
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CN109689087B (zh) | 2016-05-13 | 2023-04-04 | 奥里尼斯生物科学私人有限公司 | 靶向性突变干扰素-β及其用途 |
JP7204643B2 (ja) | 2016-10-24 | 2023-01-16 | オリオニス バイオサイエンシズ ビーブイ | 標的変異インターフェロン-ガンマおよびその使用 |
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CN110573172A (zh) | 2017-02-06 | 2019-12-13 | 奥里尼斯生物科学有限公司 | 靶向的工程化干扰素及其用途 |
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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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CN114173784B (zh) | 2019-07-18 | 2023-12-01 | 埃尼奥制药公司 | 降低干扰素的副作用的方法 |
KR20230162013A (ko) | 2021-03-26 | 2023-11-28 | 이나뜨 파르마 에스.에이. | Nk 세포 관여를 위해 사이토카인에 융합된 nkp46-결합 부위, 암 항원 결합 부위를 포함하는 다중특이적 단백질 |
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WO2024040247A1 (en) | 2022-08-18 | 2024-02-22 | Regeneron Pharmaceuticals, Inc. | Interferon proproteins and uses thereof |
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CN105658669A (zh) | 2016-06-08 |
CA2918119A1 (en) | 2015-01-22 |
IL243459B (en) | 2019-10-31 |
IL243459A0 (en) | 2016-03-31 |
US20180334488A1 (en) | 2018-11-22 |
KR102305608B1 (ko) | 2021-09-28 |
US20160159875A1 (en) | 2016-06-09 |
EP3022230B1 (en) | 2019-11-06 |
EP3022230A1 (en) | 2016-05-25 |
CA2918119C (en) | 2022-11-29 |
US20180057555A1 (en) | 2018-03-01 |
WO2015007520A1 (en) | 2015-01-22 |
KR20160108292A (ko) | 2016-09-19 |
AU2014292355B2 (en) | 2019-08-01 |
US9732135B2 (en) | 2017-08-15 |
SG10202010429YA (en) | 2020-11-27 |
US20180334489A1 (en) | 2018-11-22 |
US20210238247A1 (en) | 2021-08-05 |
US10947288B2 (en) | 2021-03-16 |
AU2014292355A1 (en) | 2016-02-04 |
MX2016000721A (es) | 2016-09-07 |
US10072059B2 (en) | 2018-09-11 |
SG11201600165WA (en) | 2016-02-26 |
JP6475712B2 (ja) | 2019-02-27 |
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