A new class of anti-platelet therapy has been developed by researchers from Monash University that provides selective blockade of thrombus formation while maintaining normal haemostasis.
Researchers from the Australian Centre for Blood Diseases have described how they engineered a novel single-chain antibody (scFv) that exclusively recognises and blocks the pathological form of the Von Willebrand Factor (VWF) blood protein.
“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,” explained study investigator Dr Erik Westein
They noted that shear rate gradients (SRG) are known to be pro-thrombotic engineered the antibody to target a shear gradient specific conformation of VWF to specifically inhibit platelet adhesion at sites of SRGs but not in areas of constant shear.
In findings published in Haematologica, they show that scFv-A1 specifically reduced VWF-GPIbα binding and thrombus formation at sites of SRGs but did not block platelet deposition and aggregation under constant shear rate in upstream sections of the channels.
“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,” said co-investigator Associate Professor Christoph Hagemeyer .
“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 says clinicians currently face a delicate balance of antithrombotic drug efficacy versus bleeding side effects. “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,” he said.
After success in an in vitro study with human blood samples, the next step will be to test the efficiency of the antibody in small animal models, they said.
“The lack of VWF inhibition in non-stenosed vessel segments places scFV-A1 in an entirely new class of anti-platelet therapy for selective blockade of pathological thrombus formation while maintaining normal haemostasis,” they concluded.