Novel aptamer to von Willebrand factor A1 domain (TAGX-0004) shows total inhibition of thrombus formation superior to ARC1779 and comparable to caplacizumab.

• Material Type: 博士論文
• Title: Novel aptamer to von Willebrand factor A1 domain (TAGX-0004) shows total inhibition of thrombus formation superior to ARC1779 and comparable to caplacizumab.
• Author/Editor: Sakai, Kazuya; Someya, Tatsuhiko; Harada, Kaori; Yagi, Hideo; Matsui, Taei; Matsumoto, Masanori
• Author Heading: Sakai, Kazuya; Someya, Tatsuhiko; Harada, Kaori; Yagi, Hideo; Matsui, Taei; Matsumoto, Masanori
• Publication, Distribution, etc.: Ferrata Storti Foundation
• Publication Date: 2019-12-19
• Publication Date (W3CDTF): 2019-12-19
• Alternative Title: フォン・ヴィレブランド因子のA1 ドメインに対する新規アプタマー (TAGX-0004) はARC1779よりも強く、Caplacizumabと同等に血栓形成を阻害する
• Periodical title: Haematologica
• No. or year of volume/issue: 105 11
• Volume: 105
• Issue: 11
• Pages: 2631-2638
• ISSN (Periodical Title): ISSN : 0390-6078
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2020-03-16
• Dissertation Number: 甲第739号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Arterial Thrombosis; Thrombotic Thrombocytopenic Purpura; aptamer; von Willebrand factor
• Target Audience: 一般
• Note (General): type:Thesis; von Willebrand factor (VWF) is a blood glycoprotein that plays an important role in platelet thrombus formation through interaction between its A1 domain and platelet glycoprotein Ib. ARC1779, an aptamer to the VWF A1 domain, was evaluated in a clinical trial for acquired thrombotic thrombocytopenic purpura (aTTP). Subsequently, caplacizumab, an anti-VWF A1 domain nanobody, was approved for aTTP in Europe and the United States. We recently developed a novel DNA aptamer, TAGX-0004, to the VWF A1 domain; it contains an artificial base and demonstrates high affinity for VWF. To compare the effects of these three agents on VWF A1, their ability to inhibit ristocetin- or botrocetin-induced platelet aggregation under static conditions was analyzed, and the inhibition of thrombus formation under high shear stress was investigated in a microchip flow chamber system. In both assays, TAGX-0004 showed stronger inhibition than ARC1779, and had comparable inhibitory effects to caplacizumab. The binding sites of TAGX-0004 and ARC1779 were analyzed with surface plasmon resonance performed using alanine scanning mutagenesis of the VWF A1 domain. An electrophoretic mobility shift assay showed that R1395 and R1399 in the A1 domain bound to both aptamers. R1287, K1362, and R1392 contributed to ARC1779 binding, and F1366 was essential for TAGX-0004 binding. Surface plasmon resonance analysis of the binding sites of caplacizumab identified five amino acids in the VWF A1 domain (K1362, R1392, R1395, R1399, and K1406). These results suggested that TAGX-0004 possessed better pharmacological properties than caplacizumab in vitro and might be similarly promising for aTTP treatment.; 博士（医学）・甲第739号・令和2年3月16日; Copyright © 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter nal use. Sharing published material for non-commercial pur poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com mercial purposes is not allowed without permission in writing from the publisher.; identifier:Haematologica Vol.105 No.11 p.2631-2638 (2020 Nov); identifier:03906078; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3733; identifier:Haematologica, 105(11): 2631-2638
• Source: fulltext; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3733/1/01%e7%94%b2739%e6%9c%ac%e6%96%87%e3%81%ae%e8%a6%81%e6%97%a8.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3733/2/02%e7%94%b2739%e5%af%a9%e6%9f%bb%e8%a6%81%e6%97%a8.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3733/8/03%e7%94%b2739%e6%9c%ac%e6%96%87.pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.3324/haematol.2019.235549
• Periodical Title (NCID): AA00660912; https://ci.nii.ac.jp/ncid/AA00660912
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU