title: Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs.
abstract: Neutralizing the interaction of the platelet receptor gpIb with VWF is an attractive strategy to treat and prevent thrombotic complications. ALX-0081 is a bivalent Nanobody which specifically targets the gpIb-binding site of VWF and interacts avidly with VWF. Nanobodies are therapeutic proteins derived from naturally occurring heavy-chain-only Abs and combine a small molecular size with a high inherent stability. ALX-0081 exerts potent activity in vitro and in vivo. Perfusion experiments with blood from patients with acute coronary syndrome on standard antithrombotics demonstrated complete inhibition of platelet adhesion after addition of ALX-0081, while in the absence of ALX-0081 residual adhesion was observed. In a baboon efficacy and safety model measuring acute thrombosis and surgical bleeding, ALX-0081 showed a superior therapeutic window compared with marketed antithrombotics. Pharmacokinetic and biodistribution experiments demonstrated target-mediated clearance of ALX-0081, which leads to a self-regulating disposition behavior. In conclusion, these preclinical data demonstrate that ALX-0081 combines a high efficacy with an improved safety profile compared with currently marketed antithrombotics. ALX-0081 has entered clinical development.
authors.affiliation: Pharmacology Department, Ablynx NV, Zwijnaarde, Belgium. Hans.Ulrichts@ablynx.com
authors.forename: Hans
authors.initials: H
authors.lastname: Ulrichts
authors.forename: Karen
authors.initials: K
authors.lastname: Silence
authors.forename: Anne
authors.initials: A
authors.lastname: Schoolmeester
authors.forename: Peter
authors.initials: P
authors.lastname: de Jaegere
authors.forename: Stefaan
authors.initials: S
authors.lastname: Rossenu
authors.forename: Jan
authors.initials: J
authors.lastname: Roodt
authors.forename: Sofie
authors.initials: S
authors.lastname: Priem
authors.forename: Marc
authors.initials: M
authors.lastname: Lauwereys
authors.forename: Peter
authors.initials: P
authors.lastname: Casteels
authors.forename: Femke
authors.initials: F
authors.lastname: Van Bockstaele
authors.forename: Katrien
authors.initials: K
authors.lastname: Verschueren
authors.forename: Patrick
authors.initials: P
authors.lastname: Stanssens
authors.forename: Judith
authors.initials: J
authors.lastname: Baumeister
authors.forename: Josefin-Beate
authors.initials: JB
authors.lastname: Holz
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D001665:Binding Sites / Q000276:immunology; D005343:Fibrinolytic Agents / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000494:pharmacology*; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D010215:Papio; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000276:immunology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology / Q000378:metabolism; D011673:Pulsatile Flow / Q000502:physiology; D057127:Single-Chain Antibodies / Q000493:pharmacokinetics*; D013927:Thrombosis / Q000188:drug therapy* / Q000276:immunology; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism
chemical_list: C561581:ALZ 0081; D018033:Antibodies, Bispecific; D005343:Fibrinolytic Agents; D007143:Immunoglobulin Heavy Chains; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D057127:Single-Chain Antibodies; D014841:von Willebrand Factor