PB0855 - TGD001, a VWF-targeted thrombolytic, is safe and effective in animal models for the treatment of thrombotic thrombocytopenic purpura

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

CT

Claudia Tersteeg

Professor, Dr.
Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
SM

Sarah Mc Fie

Scientific/Medial Writer
TargED Biopharmaceuticals
Utrecht, Utrecht, Netherlands
DV

Danielle Versluis

Research Analist
TargED Biopharmaceuticals
Utrecht, Utrecht, Netherlands
AD

Anne-Sophie Delmote

Research Analist
Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium
KV

Kristof Vercruysse

CEO
TargED Biopharmaceuticals
Utrecht, Utrecht, Netherlands
KW

Katja Wosikowski

VP Nonclinical Development
TargED Biopharmaceuticals
Utrecht, Utrecht, Netherlands
Gv

Gerben van 't Klooster

CDO
TargED Biopharmaceuticals
Utrecht, Utrecht, Netherlands
Karen Vanhoorelbeke

Full professor
Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium
Kortrijk, West-Vlaanderen, Belgium

Presenting Author(s)

Sd

Steven de Maat, PhD

CSO
TargED Biopharmaceuticals
Utrecht, Utrecht, Netherlands

Background: Thrombi have heterogenous compositions, which can limit the efficacy of available thrombosis treatments. To overcome this, the published “Microlyse”, an anti-von Willebrand factor (VWF) VHH antibody coupled to the protease domain of urokinase, was created for localized thrombolysis . Microlyse was superior to available products in in vivo models with various thrombi compositions. For clinical application, TGD001 (a humanized Microlyse with an updated urokinase protease domain) was created.

Aims: First, demonstrate TGD001’s efficacy in a murine model of thrombotic thrombocytopenic purpura (TTP), which is a VWF-driven thrombotic microangiopathy caused by ADAMTS13 deficiency. Secondly, determine the safety profile of TGD001 in rats.

Methods: Adamts13-/- mice were triggered into a TTP attack by the administration of recombinant human VWF. After 15 minutes, vehicle or TGD001 was administrated intravenously. For the pharmacokinetic and first toxicology studies, healthy wild-type rats (3 males & 3 females) received intravenous bolus(es) of TGD001.

Results: When TTP was triggered, vehicle-treated mice showed thrombocytopenia and tissue damage (elevated lactate dehydrogenase) within 15 minutes, which progressed and remained stable for up to 24 hours. Treatment with TGD001 rapidly reduced thrombocytopenia and tissue damage after 1 hour and reached statistical significance from 4 hours onwards. A dose-dependent effect was found with maximum efficacy achieved at 1 mg/kg.
TGD001 was quantifiable in rats up to 8 hours post-dose with a plasma half-life of 2 hours. The elimination profile of TGD001 in plasma was marked to be biphasic.
In the first toxicology study, TGD001 was successively administered intravenously on days 1, 3, 5 and 8, up to 12 mg/kg. No TGD001-related changes in clinical phenotype, body weight, or clinical pathology were observed, indicating that TGD001 is well tolerated.

Conclusion(s): TGD001 rapidly attenuates thrombocytopenia and tissue damage compared to vehicle-treated mice in a model of TTP. Moreover, TGD001 is well-tolerated and causes no treatment-related adverse effects in rats.