Thrombosis is the pathological formation of a thrombus, a blood clot, inside a blood vessel. A thrombus obstructs the blood flow and oxygen supply to organs and tissues that are downstream of the clot. An absence of oxygen for even only minutes can result in cell death and irreversible organ dysfunction. The location of the thrombus in the vasculature, the blood vessel system in the human body, determines its symptomatic outcome. For instance, a thrombus in arteries towards the heart can cause a heart attack (myocardial infarction), while one in the arteries towards the brain can result in a brain infarction (acute ischemic stroke; AIS).
Thrombosis is the leading cause of death worldwide, accounting for over 16 million deaths per year (World Health Organization, 2020).
A thrombus (blood clot) generally consists of platelets and red blood cells held together by a meshwork of two sticky proteins, von Willebrand Factor (VWF) and fibrin. In healthy situations, forming such meshwork prevents loss of blood after a blood vessel is damaged and is part of the normal wound repair mechanism in the body.
The composition of thrombi differs based on their location in the vasculature: blood clots in large blood vessels (macrovasculature) differ from those in small vessels (microvasculature). Macrovascular thrombi contain VWF, and high levels of fibrin to hold platelets and red blood cells, whereas the meshwork of microvascular thrombi generally only contain VWF, and, if any, only low levels of fibrin. TGD001’s unique ability to bind to VWF, that is present in all blood clots, and then locally degrade both fibrin and VWF-platelet complexes makes it a promising candidate for treating a wide variety of thrombotic diseases. It thus introduces the possibility to effectively treat both macrovascular (e.g. stroke and heart attacks) and microvascular (e.g. Thrombotic Thrombocytopenic Purpura) thrombotic disorders.
What is TGD001?
TGD001 is TargED’s innovative therapy in development for targeted clot breakdown: thrombolysis, localized at the site of thrombosis. TGD001 is a so-called fusion protein consisting of two parts: the catalytic domain of urokinase (also called urokinase-type plasminogen activator) which causes the clot breakdown, and a single-chain antibody (VHH) which acts as an anchor to blood clots. The single-chain antibody ‘anchor’ binds to Von Willebrand Factor (VWF), which is present in all types of blood clots and that sticks these clots together.
The targeted approach, by binding to a blood clot, makes that TGD001 acts where it needs to work, not everywhere in the blood. The activator part then locally converts plasminogen, an inactive enzyme precursor that circulates in blood, into enzymatically active plasmin. Plasmin is a naturally occurring enzyme in the body that breaks down thrombi by degrading both VWF and fibrin. Fibrin forms fibers that (with VWF) form the mesh holding the platelets and red blood cells and thus keep the blood together. When VWF and fibrin are degraded, the blood clot dissolves and blood flow is restored. Such rapid opening of blood vessels is crucial because no blood flow means that there isno oxygen supply to the downstream tissue. Restoring blood flow thus minimizes cellular and tissue damage. If untreated, such tissue damage is irreversible and may lead to life-long disabilities.
Next to the rapid clot dissolution by TGD001 as observed in animal models of thrombosis, its targeted, local action is important. Plasminogen is everywhere in the blood, but the aim is to have it only activated at the clot, and thereby avoiding unwanted bleeding side effects elsewhere in the body.