Monash researchers have invented an antibody which can prevent the formation of bad clots, such as those in stroke and heart attack.
Heart attack and stroke remain the leading causes of mortality and morbidity worldwide. Current anti-thrombotic (anti-clotting) therapies can, and do, cause severe bleeding complications because they also interfere with normal blood clotting. Four out of five patients who receive antiplatelet therapy still have recurring cardiovascular events.
Existing anti-platelet drugs therefore cannot be used in higher doses. As a result, their efficacy remains disappointingly low and future therapies require a fundamental re-design from the ground up.
Dr Erik Westein and Associate Professor Christoph Hagemeyer in the Australian Centre for Blood Diseases at Monash University are senior authors on a paper in Haematologica published today which describes how they have designed a novel antibody that inhibit one particular blood-borne protein, Von Willebrand Factor (VWF), to prevent clot formation, or thrombosis, without having bleeding side effects. Their new antibody can stop pathological thrombosis without impacting normal healthy clotting.
Dr Westein said, "In this study we developed an antibody that was designed to block an important protein in the blood called Von Willebrand Factor. VWF is important in normal blood clotting but it is also involved in the development of dangerous blood clots that cause heart attacks and stroke.
“So our approach was to first identify the biological differences between normal blood clotting and pathological blood clotting, and we found that VWF changes its properties when dangerous blood clots are forming.
"Next, we engineered an antibody that only detects and blocks this pathological form of VWF and is therefore only active when a blood clot becomes pathological.”
A/Prof Hagemeyer said, "We analysed the properties of existing antibodies against VWF and identified optimal properties of each that would bind and block VWF under pathological blood clotting conditions.
"We then combined these optimal molecular structures into a new antibody to generate a first in-class drug candidate that has the potential to stop dangerous blood clots without any adverse effects such as bleeding complications.”
Dr Westein said that clinicians presently face a delicate balance of drug efficacy versus bleeding side effects. He said, “Our engineered antibody is purposely designed to not interfere with normal blood clotting so we expect that it can be used at a much higher and effective dose compared to existing therapies.”
A/Prof Hagemeyer said, “This is an in vitro study, working only with human blood samples. Our next step will be to test the efficiency of our antibody in small animal models to understand how it works in a complex living system analogous to our own.”
- Video: www.youtube.com/watch?v=OZWMkTvPZ1M
- Research group: www.monash.edu/medicine/ccs/blood-disease/research/hagemeyer
- Reference: Thomas Hoefer, Akshita Rana, Be'eri Niego, Shweta Jagdale, Hugo J Albers, Elizabeth E Gardiner, Robert K Andrews, Andries D van der Meer, Christoph E Hagemeyer, and Erik Westein. Targeting shear gradient activated von Willebrand Factor by the novel single-chain antibody A1 reduces occlusive thrombus formation in vitro. Haematologica 21 Sep 2020.