JP2019521312A - Clever−1、tnf−アルファおよびhla−dr結合剤を用いた免疫活性化の診断 - Google Patents
Clever−1、tnf−アルファおよびhla−dr結合剤を用いた免疫活性化の診断 Download PDFInfo
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Abstract
Description
(a)上記患者から採取された血液試料から末梢血単球(PBLs)を得る工程、
(b)上記PBLsのTNF−アルファ分泌を測定する工程、および/または
(c)CD14陽性PBLs上のHLA−DR発現を測定する工程、および
(e)工程(b)および(c)で測定されたTNF−アルファ分泌および/またはHLA−DR発現の値を、抗−CLEVER−1治療の有効性を評価するために対照値と比較する工程であって、対照値が、患者においてCLEVER−1に結合することのできる薬剤を投与する前に測定された値、または同じ患者において異なる時点で行われた1つ以上の先の測定値であり、TNF−アルファ分泌またはHLA−DR発現の増加がM2マクロファージのM1マクロファージへの変化を示す工程
を含む方法に関する。
PFTVLVPSVSSFSSR(配列番号1)および
QEITVTFNQFTK(配列番号2)
を含む。
感染症の治療に好適であり、感染性抗原に対する免疫抑制が、M2マクロファージをM1マクロファージに変化させることにより除去される。
用語「CLEVER−1」は、特許文献1に開示されたタンパク質、共通リンパ内皮および血管内皮受容体−1を示すために使用される。
PFTVLVPSVSSFSSR(配列番号1)および
QEITVTFNQFTK(配列番号2)
を含む。
ATQTGRVFLQ(配列番号:3)、
DSLRDGRLIYLF(配列番号:4)、
SKGRILTMANQVL(配列番号:5)、および
LCVYQKPGQAFCTCR(配列番号:6)
からなる群より選択される1つ以上の配列を含む。
(a)該患者から採取した血液試料から末梢血単球(PBLs)を得る工程、
(b)該PBLsのTNF−α分泌を測定する工程、および/または
(c)CD14陽性PBLs上のHLA−DR発現を測定する工程、および
(e)工程(b)および(c)で測定されるTNF−α分泌および/またはHLA−DR発現の値を、抗CLEVER−1治療の有効性を評価するために対照値と比較する工程であって、対照値が、CLEVER−1に結合することのできる薬剤を患者に投与する前に測定された値、または同じ患者における異なる時点で行われた1つ以上の先の測定の値であり、TNF−アルファ分泌またはHLA−DR発現の増加はM2マクロファージのM1マクロファージへの変化を示す工程
を含む。
健常ドナー由来のヒト末梢血単球を集め、それらを約9mlの末梢血からFicoll−グラジエント遠心分離により富化した。その後、それらを低接着96ウェルプレートに、1%ヒトAB血清を補足したIMDM培地中、1.2×106細胞/ウェルの密度で蒔いた。細胞を1μg/mlまたは10μg/mlの抗−CLEVER−1抗体3−372(2001年8月21日にDSMZ−ドイチェ・ザンルング・フォン・ミクロオルガニズメン・ウント・ツェルクルツレン・ゲーエムベーハーに寄託されたDSM ACC2520)またはVH3/VK5(上記特定のCLEVER−エピトープを認識するヒト化抗−CLEVER−1抗体、その抗体の詳細は以下に示す。)で48時間処理した。HLA−DR発現は、48時間後、CD14陽性細胞からLSR Fortessaフローサイトメトリーを用いて測定した。死んだ細胞は、7−AAD細胞生存染色に関する陽性シグナルに基づき解析から除外した。
ヒト化抗−CLEVER−1抗体VH3/VK5は、3−372マウスモノクローナル抗体(2001年8月21日にDSMZ−ドイチェ・ザンルング・フォン・ミクロオルガニズメン・ウント・ツェルクルツレン・ゲーエムベーハーに寄託されたDSM ACC2520)から、フィンランド特許出願第20165335号により詳細に開示されているComposite Human Antibody(商標)技術を用いて作製された。ヒト化抗−CLEVER−1抗体VH3/VK5は、本願に定義されるヒトCLEVER−1のエピトープ配列を認識する。
健常ドナー由来のヒト末梢血単球を集め、実施例1に記載したように富化した。赤血球溶解緩衝液で処理した血液3mlからの単球は、6ウェルプレートに一晩接着させ、PBSで一回洗浄し、3日間、10μg/mlの抗−CLEVER−1抗体3−372またはAK−1と共に培養した。
樹立したE0771マウス乳癌を、5mg/kgの抗−CLEVER−1(mStab1)または同位体対照で3〜4日毎に腫瘍が1mm3の大きさに達するまで処置した。フローサイトメトリーを用いて、TAMs、別の単球亜群、および腫瘍浸潤白血球の補充および亜型に対する抗−CLEVER−1処置の効果を評価した。
Claims (5)
- CLEVER−1に結合することのできる薬剤を患者に投与した場合に、M2マクロファージのM1マクロファージへの変化をモニタリングすることによる抗−CLEVER−1治療の有効性の評価方法であって、
(a)前記患者から採取された血液試料から末梢血単球(PBLs)を得る工程、
(b)前記PBLsのTNF−アルファ分泌を測定する工程、および/または
(c)CD14陽性PBLs上のHLA−DR発現を測定する工程、および
(e)工程(b)および(c)で測定されたTNF−アルファ分泌および/またはHLA−DR発現の値を、CLEVER−1治療の有効性を評価するために対照値と比較する工程であって、対照値が、患者においてCLEVER−1に結合することのできる薬剤を投与する前に測定された値、または同じ患者において異なる時点で行われた1つ以上の先の測定値であり、TNF−アルファ分泌またはHLA−DR発現の増加がM2マクロファージのM1マクロファージへの変化を示す工程
を含む方法。 - CLEVER−1に結合することのできる薬剤がCLEVER−1のエピトープに結合し、該エピトープが、不連続であり、かつ配列:
PFTVLVPSVSSFSSR(配列番号1)および
QEITVTFNQFTK(配列番号2)
を含む請求項1記載の方法。 - 不連続エピトープが、さらに
ATQTGRVFLQ(配列番号:3)、
DSLRDGRLIYLF(配列番号:4)、
SKGRILTMANQVL(配列番号:5)、および
LCVYQKPGQAFCTCR(配列番号:6)
からなる群より選択される1つ以上の配列を含む
請求項1または2記載の方法。 - CLEVER−1に結合することのできる薬剤が、前記エピトープに結合するのに十分な親和性を有する抗体、その断片、ペプチドまたはマクロ分子からなる群より選択される請求項1〜3のいずれか1項に記載の方法。
- 対照値と比較した測定されたTNF−アルファ分泌の少なくとも2倍の増加が、M2マクロファージのM1マクロファージへの変化を示す請求項1〜4のいずれか1項に記載の方法。
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EP4058805A1 (en) * | 2019-11-11 | 2022-09-21 | Faron Pharmaceuticals OY | Anti-clever-1 agents for controlling the expression of cell surface markers on leucocytes, and using these to guide anti-clever-1 based cancer treatment |
CA3174858A1 (en) * | 2020-04-20 | 2021-10-28 | Juho JALKANEN | Treatment of diseases with clever-1 inhibition in combination with an interleukin inhibitor |
US20220227858A1 (en) | 2021-01-18 | 2022-07-21 | Faron Pharmaceuticals Oy | Controlling of immune activation by soluble clever-1 |
WO2023105118A1 (en) * | 2021-12-07 | 2023-06-15 | Faron Pharmaceuticals Oy | Method for using inflammatory markers to guide anti-clever-1 cancer treatment |
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JP2012524536A (ja) * | 2009-04-22 | 2012-10-18 | ファロン ファーマシューティカルズ オサケ ユキチュア | 新規細胞ならびに該細胞にもとづく治療および診断方法 |
WO2014209802A1 (en) * | 2013-06-25 | 2014-12-31 | Vaccinex, Inc. | Use of semaphorin-4d inhibitory molecules in combination with an immune modulating therapy to inhibit tumor growth and metastases |
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JP2005523247A (ja) * | 2002-01-09 | 2005-08-04 | ファロン ファーマシュティカルズ オサケ ユキチュア | 共通リンパ管内皮および血管内皮受容体−1(clever−1)およびその用途 |
JP2012524536A (ja) * | 2009-04-22 | 2012-10-18 | ファロン ファーマシューティカルズ オサケ ユキチュア | 新規細胞ならびに該細胞にもとづく治療および診断方法 |
WO2014209802A1 (en) * | 2013-06-25 | 2014-12-31 | Vaccinex, Inc. | Use of semaphorin-4d inhibitory molecules in combination with an immune modulating therapy to inhibit tumor growth and metastases |
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EP3445786C0 (en) | 2023-10-04 |
CN109153720A (zh) | 2019-01-04 |
JP2022065088A (ja) | 2022-04-26 |
EP3445786B1 (en) | 2023-10-04 |
US20190064180A1 (en) | 2019-02-28 |
CA3020418A1 (en) | 2017-10-26 |
CN109153720B (zh) | 2022-10-21 |
JP7100588B2 (ja) | 2022-07-13 |
KR102403660B1 (ko) | 2022-05-30 |
BR112018070350A2 (pt) | 2019-01-29 |
EP3445786A1 (en) | 2019-02-27 |
KR20180133854A (ko) | 2018-12-17 |
EA201892313A1 (ru) | 2019-03-29 |
AU2017252344B2 (en) | 2023-12-21 |
WO2017182706A1 (en) | 2017-10-26 |
US10884000B2 (en) | 2021-01-05 |
AU2017252344A1 (en) | 2018-10-11 |
JP7302049B2 (ja) | 2023-07-03 |
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