Abstract Number: PB0002
Meeting: ISTH 2020 Congress
Background: The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass.
Aims: To produce a pharmaceutically modified disintegrin derivative with improved physicochemical, pharmacokinetic, and antithrombotic properties.
Methods: We utilized NH2-terminal-specific PEGylation technique to modify the disintegrin derivative KGDRR. We compared the antithrombotic activities of intact KGDRR (RR) and PEGylated KGDRR (P-RR) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated.
Results: P-RR exhibited optimal potency in inhibiting platelet aggregation of human and mouse platelet-rich plasma induced by collagen or ADP in vitro with a lower IC50 than the intact derivative RR. In illumination-induced mesenteric venous thrombosis model, RR and P-RR efficaciously prevented occlusive thrombosis in dose-dependent manner. In rotational thromboelastometry assay, P-RR did not induce hypocoagulation in human whole blood even given at a higher concentration (30 µg/mL), while RR slightly prolonged clotting time. However, at equally efficacious antithrombotic dosages, both RR and P-RR caused neither severe thrombocytopenia nor bleeding in FcγRIIa-transgenic mice. The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of RR (RR: 15.65 hrs vs. P-RR: 20.45 hrs).
Conclusions: P-RR exhibits higher antithrombotic potency and longer half-life in vivo as compared with native RR on a molar basis. In addition, P-RR exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.
To cite this abstract in AMA style:Kuo Y-, Chuang W-, Huang T-. Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/improved-antithrombotic-activity-and-diminished-bleeding-side-effect-of-a-pegylated-%ce%b1iib%ce%b23-antagonist-disintegrin/. Accessed February 27, 2024.
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