The University of Birmingham researchers have discovered antibody fragments known as nanobodies, designed to shed light on platelet disorders, specifically those related to bleeding or thrombosis.
The research team developed nanobodies and then crosslinked them to create ligands targeting four distinct platelet receptors: GPVI, CLEC-2, FcɣRIIA, and PEAR1.
Nanobodies serve a crucial role in the development of validated clinical assays for diagnosing patients with platelet disorders, as well as functioning as invaluable research tools for studying platelet activation.
Nanobodies share many properties with conventional antibodies, but they offer distinct advantages to platelet researchers. Their smaller size makes them particularly well-suited for cross-linking, and their stability, coupled with their high affinity for platelet receptors, makes them excellent reagents for receptor imaging.
Scientists already recognise that when these four receptors cluster on the surface of platelets, it leads to the generation of signalling molecules that, in turn, trigger platelet activation and blood clot formation. However, the relationship between cluster size, signal generation, and how this pertains to platelet activation remains incompletely understood.
The current limitations of the ligands in use have hindered further research in this area. Some exhibit undefined valency (binding power), while others, like the snake venom toxin rhodocytin, display significant batch-to-batch variation and uncertain specificity for the receptors.
The researchers in Birmingham have engineered nanobodies with one, two, three, and four binding sites and then tested their ability to generate signalling molecules and stimulate platelet activation. These nanobody-based reagents are expected to significantly enhance the understanding of platelet activation in the laboratory.
Although nanobodies have a relatively short half-life when used in vivo, this limitation can potentially be overcome by linking them to larger inert molecules, thus opening the door to the development of novel therapeutics for blood and thrombotic disorders.