ALX-0081 Nanobody™, an Engineered Bivalent Anti-Thrombotic Drug Candidate with Improved Efficacy and Safety as Compared to the Marketed Drugs

Autor: Peter Casteels, J. P. Roodt, Bob van der Jeugt, Flip G. de Groot, Karen Silence, Torsten Dreier, Muriel Meiring, M. J. W. Ijsseldijk, Kristi de Smet, Seb Lamprecht, Heidi Maria Florence Jonckheere
Rok vydání: 2006
Předmět:
Zdroj: Blood. 108:896-896
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v108.11.896.896
Popis: In patients with plaque rupture, platelets adhere, aggregate and form a thrombus. Current strategies to prevent thrombus formation consist of the use of Aspirin®, Plavix® and integrin αIIbβ3 blockers (e.g. Reopro®) in combination with Heparin®. These drugs are associated with high bleeding risk. Several in vivo experiments have shown that neutralizing the collagen von Willebrand Factor (vWF) platelet glycoprotein (GP)Ib-IX-V axis strongly inhibits arterial thrombosis without bleeding complications, therefore, these targets are of high interest to develop new anti-thrombotic drugs. Nanobodies are antibody-derived therapeutic proteins with the structural and functional properties of naturally occurring single-chain antibodies derived from camelids. ALX-0081 is a bivalent humanized Nanobody targeting the GPIb-IX-V binding site at the A1 domain of vWF. The precursor molecule was isolated from a llama immunized with the recombinant A1 domain of vWF and then humanized and engineered into a bivalent format to maximally benefit from the avid binding to vWF. In vitro, ALX-0081 can completely inhibit platelet adhesion to collagen at nanomolar concentrations. This inhibition is specific for the high shear rates relevant for coronary and carotid arteries whilst platelet adhesion and aggregation under low shear conditions is unaltered. The Nanobody also inhibits platelet adhesion to ultra large vWF (ULvWF) whilst it does not inhibit cleavage of ULvWF by ADAMTS-13. In a modified Folt’s model in baboons ALX-0081 inhibits thrombus formation more efficiently than a combination of Aspirin, Heparin and Plavix. Inhibition of thrombus formation is sustained in the presence of epinephrine and upon a new injury confirming the strong anti-thrombotic effect of ALX-0081. The Nanobody is effective at doses approximately 10–20 times lower than the dose required for Reopro. Ex vivo analysis of plasma samples after ALX-0081 administration in baboons in the ristocetin induced platelet aggregation (RIPA) assay reflects the efficacy seen in the Folt’s model. Therefore, this assay seems to be suited to predict effective ALX-0081 concentrations in vitro. In comparison to Reopro and Plavix, ALX-0081 is associated with less bleeding complications, even at doses exceeding the effective dose by a factor of 10 probably because of its selective inhibition of platelet aggregation under high shear but not under low shear conditions. After treatment with ALX-0081 no effect on other hematological parameters such as PT, aPTT, platelet count, VWF concentration and FVIII levels is seen and no immunogenicity is detected in baboons after repeated administration of ALX-0081. The terminal half-life of ALX-0081 in baboons is 8 hours, indicating that the molecule adopts the half-life of vWF. This high efficacy combined with an improved safety compared to the currently marketed drugs suggests that Ablynx’ drug development candidate ALX-0081 can become a powerful drug to treat acute thrombotic events in indications such as ACS, stroke, and TTP.
Databáze: OpenAIRE
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