Novel ‘nanobody’ shows antithrombotic potential
MedWire News: ALX-0081, a novel nanobody that targets the von Willebrand factor (VWF) glycoprotein (gp)Ib platelet binding site, may be an effective alternative to current antithrombotic drugs for patients undergoing percutaneous coronary intervention (PCI), preclinical study data show.
Han Ulrichts (Ablynx NV, Zwijnaarde, Belgium) and colleagues report in the journal Blood that ALX-0081 "combines a high efficacy with an improved safety profile compared with currently marketed antithrombotics."
They explain that nanobodies are therapeutic proteins derived from naturally occurring heavy-chain-only antibodies, and combine a small molecular size with a high inherent stability.
The team developed ALX-0081 to neutralize the interaction between the platelet receptor gpIb and VWF, which is involved in the early stages of thrombus formation under high shear conditions - such as those observed in normal arterioles and stenotic arteries.
They tested its antithrombotic activity in a series of in vitro and in vivo experiments.
Firstly, the researchers used a perfusion chamber to examine the capacity of ALX-0081 to inhibit in vitro platelet aggregation in blood samples from patients with acute coronary syndrome undergoing a planned PCI procedure.
They found that addition of ALX-0081 0.8 µg/ml to the patients' blood samples resulted in complete inhibition of platelet adhesion (0.4% surface coverage) under high shear conditions (> 1500 s-1).
However, in the absence of ALX-0081, residual adhesion (22.5% surface coverage) was observed, even though the patients were receiving treatment with aspirin, clopidogrel, and/or heparin.
In a baboon model of acute thrombosis, only ALX-0081 and abciximab completely abolished cyclic flow reductions (CFR), even after infusion of epinephrine, a potent stimulator of platelet activation.
Of note, 10-fold lower doses of ALX-0081 were needed to obtain the same effect as abciximab, while aspirin, heparin, and clopidogrel did not abolish CFR in this model.
Furthermore, blood loss following surgical injury in animals receiving ALX-0081 was 1.5- and 6.0-fold lower than in those treated with clopidogrel and abciximab, respectively.
"Together, the lower effective dose and the lower bleeding risk clearly indicate that ALX-0081 has a broader therapeutic window than the currently marketed antithrombotic drugs clopidogrel and abciximab," Ulricht and co-authors remark.
They conclude: "Building on this extensive and convincing preclinical data package and subsequent toxicology studies, two phase 1 clinical trials have been successfully completed and a phase 2 trial in high-risk PCI patients comparing the efficacy and safety of ALX-0081 to abciximab is currently ongoing."
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By Laura Dean