Novel von willebrand factor targeting thrombolytic TGD001 is safe and well tolerated in a phase 1 first-in-human trial

作者：Marie Scully, Spero R. Cataland, Paul Coppo, Paul Knoebl, Paul T. Brinkkoetter, Javier de la Rubia, Marielle Klein Hesselink, Josefin-Beate Holz, Flora Peyvandi · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-849 · 被引用次数：1 · 研究领域：Complement system in diseases、Platelet Disorders and Treatments、Protease and Inhibitor Mechanisms

Abstract Introduction TGD001 is a novel thrombolytic fusion protein that binds with high affinity to von Willebrand factor (VWF) for targeted plasminogen activation. TGD001 is comprised of an antibody fragment that binds to VWF, fused with the catalytic domain of human urokinase-type plasminogen activator (UPA). Upon binding to VWF, the catalytic UPA domain in TGD001 is brought near plasminogen, resulting in activation to plasmin and initiation of thrombolysis at the thrombus. In contrast to standard-of-care (SoC) fibrin-targeting thrombolytics, TGD001's thrombolytic activity utilises the ubiquitous presence of VWF in all thrombi, resulting in thrombolysis independent of fibrin content, positioning TGD001 as a universal thrombolytic. TGD001's in vivo thrombolytic potential was demonstrated in animal models of thrombotic thrombocytopenic purpura (TTP) and acute ischemic stroke. In these models, TGD001 effectively degraded thrombi of varying compositions via targeted destruction of platelet-VWF complexes by plasmin, in both the macro- and microvasculature, resulting in improved outcomes. Immune-mediated TTP (iTTP) is a thrombotic microangiopathy (TMA) hallmarked by severely deficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and the formation of widespread VWF and platelet-rich thrombi in the microvasculature. The current SoC treatments aim to inhibit thrombus formation, eliminate disease triggers, and restore ADAMTS13...