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アプタマー アフェレシス 核酸医薬の開発｜タグシクス・バイオ株式会社

Thrombotic Thrombocytopenic Purpura

Thrombotic Thrombocytopenic Purpura（aTTP)

Disease

Thrombotic thrombocytopenic purpura (TTP) is a fatal disease in which pathological thrombi form in microvessels throughout the body, resulting in death in over 90% of patients if untreated. In Japan, TTP is designated as an intractable disease. In recent years, ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13) activity, which is a von Willebrand factor (VWF) cleaving enzyme, has been significantly decreased (1). Patients with TTP may experience internal bleeding, subcutaneous bleeding, or bleeding from the surface of the skin, which can be fatal or cause sequelae such as brain damage or stroke.

Patient

TTP is a rare and intractable hematologic disease with an incidence of 4 cases per million population per year, or approximately 500 cases per year in Japan (2). There are congenital and acquired TPP, with acquired TPP accounting for more than 95% of all cases.

Current Treatment

plasma exchange therapy, (2) steroid therapy, (3) anti-CD20 antibody (rituximab), and (4) anti-VWF nanobody (caplacizumab). In recent years, progress has been made in understanding the pathogenesis of TPP, and it is hoped that drugs that enable effective and durable treatment based on these therapies can be developed.

Anti-VWF aptamer TAGX-0004

TAGX-0004 is a nucleic acid DNA aptamer targeting the human VWF A1 domain containing our proprietary artificial base Ds and shows high affinity and specificity of 61 pM for human VWF (3). The therapeutic candidate will be TAGX-0004, which is PEGylated for improved pharmacokinetics.
Binding of platelet GP1b to the VWF A1 domain causes thrombotic microvascular damage resulting in excessive aggregation of VWF multimers, which is expected to inhibit the acute phase symptoms of TTP by inhibiting the binding of platelets to VWF at an early stage.

TAGCyx has confirmed that TAGX-0004 has comparable pharmacological activity compared to caplacizumab in ex-vivo studies using human blood and animal studies in a humanized mouse thrombotic disease model (4,5).
In addition, our Xenoligo® nucleic acid aptamer can be produced by chemical synthesis, which enables stable drug production at a lower cost than existing therapies. In addition, the high stability of Xenoligo® nucleic acid aptamers will enable them to be developed as ready-to-use pre-filled syringes, which is expected to improve patient convenience. TAGCyx is moving forward with pre-clinical studies of TAGX-0004 and aims to enter clinical trials as soon as possible.

[Reference]

  1. 公益財団法人　難病医学研究財団/難病センターWeb site： https://www.nanbyou.or.jp/entry/87
  2. 血栓性血小板減少症紫斑病(TTP)の病態，診断と治療 酒井和哉、松本雅則 日本内科学会雑誌 2020; 109; 1355.
  3. High-Affinity DNA Aptamer Generation Targeting von Willebrand Factor A1-Domain by Genetic Alphabet Expansion for Systematic Evolution of Ligands by Exponential Enrichment Using Two Types of Libraries Composed of Five Different Bases Matsunaga K. et al. J Am Chem Soc. 2017; 139: 324.
  4. Novel aptamer to von Willebrand factor A1 domain (TAGX-0004) shows total inhibition of thrombus formation superior to ARC1779 and comparable to caplacizumab Sakai K. et al. Haematologica. 2020;105:2631.
  5. 動脈血栓症治療のためのVWF A1ドメインと血小板GP Ib結合を阻害する新規アプタマーの開発臨床血液　松本雅則、原田香織 2022; 63: 393.