JP2019517995A - 膜受容体への結合による抗ウイルス免疫療法 - Google Patents
膜受容体への結合による抗ウイルス免疫療法 Download PDFInfo
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Abstract
Description
CD4+Tリンパ球を、健康なドナーの末梢血から単離した。単離したCD4+Tリンパ球を、フィトヘマグルチニン(PHA)で3日間刺激した。続いて、刺激した細胞を、内部リボソーム進入部位(IRES)を介してnef読取枠とCFP(「シアン蛍光タンパク質」)を発現させたHIV−1に感染させた。感染の後、感染したCD4+Tリンパ球の表面を、4枚の96ウェルマイクロタイタープレート内において332PE標識抗体を用いて48〜72時間かけて染色した。自家蛍光を除去するために、アロフィコシアニン(APC)の波長域で感染細胞および非感染細胞のフィルタリングを行った。感染したCFP陽性細胞および非感染のCFP陰性細胞のPEの平均値を使用して、これらの細胞を分析した。HIV−1感染CD4+Tリンパ球における受容体表面スクリーニングの確立の概略を、図1に示す。
CD4+Tリンパ球の感染後48〜72時間の間、CD45RO、CD25、CD150およびCD279のようなHIV感染症に関して先行技術で既に記載のある膜受容体の過剰発現が、予想通りに示される。この結果は、今回開発したスクリーニング方法のロバスト性および信頼性を裏付けるものである。
現在の最先端技術において、ヒトCD134に対するいくつかの抗体が、既に利用可能となっている。この一例として、MedImmune社の開発した、MEDI6469または9B12と称される抗体が挙げられる。このアゴニスト抗体は、現在固形腫瘍の治療のみに使用されている。ヒトにおける安全性および抗腫瘍活性については、既に試験されている(前記Curti et al.,2013)。この9B12抗体については、現在、がん療法への適用を判定するための臨床試験が行われている。発明者らの知見によれば、この抗体は、ウイルスに感染したCD4+Tリンパ球を除去し、それによって感染宿主から病原性ウイルスを除去することに適している可能性もある。
Claims (16)
- ウイルス感染症の予防および/または治療のための細胞傷害薬であって、ウイルスに感染したTリンパ球の膜受容体に選択的に結合するよう構成され、該膜受容体がCD134、CD132、CD71、CD70、CD54、CD39、BTLA、CD97、CD2、CD63、CD50、CD161、CD218、CD226、CD7、CD49dおよびCD29からなる群から選択される、細胞傷害薬。
- 前記膜受容体に選択的に結合する分子に連結されている、請求項1に記載の細胞傷害薬。
- 前記結合分子が、免疫グロブリン、免疫グロブリンフラグメント、アプタマー、低分子量化合物、受容体、受容体フラグメントおよびサイトカインからなる群から選択される、請求項2に記載の細胞傷害薬。
- 前記免疫グロブリンがアゴニスト抗体である、請求項3に記載の細胞傷害薬。
- 前記免疫グロブリンが、MEDI6469(9B12)、MEDI6383、MEDI0562およびHu106−222/Hu119−122(UTMDACC)からなる群から選択される、請求項3または4に記載の細胞傷害薬。
- 前記ウイルスに感染したTリンパ球が、ウイルスに感染したCD4+Tリンパ球である、先行する請求項のいずれか1項に記載の細胞傷害薬。
- 前記ウイルス感染症が、HIV感染症である、先行する請求項のいずれか1項に記載の細胞傷害薬。
- 細胞増殖抑制薬を含む、先行する請求項のいずれか1項に記載の細胞傷害薬。
- 前記細胞増殖抑制薬が、アルキル化剤、白金アナログ、インターカラント、抗生物質、有糸分裂阻害薬およびタキサン類からなる群から選択される、請求項8に記載の細胞傷害薬。
- ウイルス増殖抑制薬を含む、先行する請求項のいずれか1項に記載の細胞傷害薬。
- 請求項1〜10のいずれか1項に記載の細胞傷害薬と、薬学的に許容される担体とを含む、医薬組成物。
- ウイルス感染症の予防および/または治療のための、細胞傷害薬の使用であって、該細胞傷害薬が、ウイルスに感染したTリンパ球の膜受容体に選択的に結合するよう構成され、該膜受容体が、CD134、CD132、CD71、CD70、CD54、CD39、BTLA、CD97、CD2、CD63、CD50、CD161、CD218、CD226、CD7、CD49dおよびCD29からなる群から選択される、使用。
- 細胞傷害薬を見出すための方法であって、ウイルスに感染したTリンパ球の膜受容体に選択的に結合できる化合物を選択することを含み、該膜受容体がCD134、CD132、CD71、CD70、CD54、CD39、BTLA、CD97、CD2、CD63、CD50、CD161、CD218、CD226、CD7、CD49dおよびCD29からなる群から選択される、方法。
- ウイルス非感染Tリンパ球と比較してウイルス感染Tリンパ球で過剰発現している膜受容体の、ウイルス感染症を診断するための使用であって、該膜受容体がCD134、CD132、CD71、CD70、CD54、CD39、BTLA、CD97、CD2、CD63、CD50、CD161、CD218、CD226、CD7、CD49dおよびCD29からなる群から選択される、使用。
- ウイルス感染症を診断するための方法であって、ウイルス非感染Tリンパ球と比較してウイルスに感染したTリンパ球で過剰発現している膜受容体を特定することを含み、該膜受容体がCD134、CD132、CD71、CD70、CD54、CD39、BTLA、CD97、CD2、CD63、CD50、CD161、CD218、CD226、CD7、CD49dおよびCD29からなる群から選択される、方法。
- 細胞増殖抑制薬の標的として適した、ウイルスに感染したTリンパ球の表面構造、好ましくはウイルスに感染したTリンパ球の膜受容体を特定するための方法であって、Tリンパ球をウイルスに感染させること、および非感染のTリンパ球と比較して該ウイルス感染Tリンパ球上で過剰発現している表面構造を特定することを含む方法。
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---|
AIDS RESEARCH AND HUMAN RETROVIRUSES, vol. 26, no. 10, JPN6020026470, 2010, pages 1147 - 1154, ISSN: 0004310046 * |
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, vol. 11, no. 6, JPN6021004880, 2004, pages 1040 - 1044, ISSN: 0004445052 * |
HUMAN IMMUNOLOGY, vol. 72, JPN6020026471, 2011, pages 295 - 304, ISSN: 0004310047 * |
JOURNAL OF IMMUNOASSAY AND IMMUNOCHEMISTRY, vol. 33, JPN6019039282, 2012, pages 195 - 202, ISSN: 0004132446 * |
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