Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab - preclinical and clinical studies

作者：Kling Dorothee; Stucki Corinne; Kronenberg Sven; Tuerck Dietrich; Rheaume Eric; Tardif Jean Claude; Gaudreault Jacques; Schmitt Christophe^*

来源：Thrombosis Research, 2013, 131(5): 401-410.

DOI：10.1016/j.thromres.2013.02.020

• Human anti-P-selectin
• platelet-leukocyte aggregates
• leukocyte activation
• leukocyte adhesion
• single and multiple ascending dose studies
• peripheral arterial disease

Background and Objective: Elevated levels of platelet-leukocyte aggregates (PLAs) have been reported in several cardiovascular diseases and suggested to contribute to disease pathology. Our aim was to characterize the effects of inclacumab, a novel human anti-P-selectin antibody, on the interactions between leukocytes and platelets in preclinical and clinical studies.
Experimental Approaches: Dual-label flow cytometry was used to detect the effect of inclacumab on agonist-induced platelet-leukocyte/platelet-monocyte aggregates in cynomolgus monkeys and humans, following ex vivo and in vivo administration. Platelet-dependent leukocyte activation and leukocyte adhesion to a platelet monolayer were also investigated after ex vivo administration of inclacumab to human blood.
Results: Treatment of cynomolgus monkeys with inclacumab profoundly inhibited thrombin receptor-activating peptide (TRAP) or adenosine diphosphate (ADP)-induced PLAs with an IC50 (<2 mu g/mL) similar to the in vitro spiking experiments. Maximal inhibition of PLAs persisted for >= 28 days following single dose of inclacumab. In human blood, inclacumab was about 2-fold more potent in inhibiting TRAP-induced PLAs (IC50: 0.7 mu g/mL) compared to monkeys. PLA formation was suppressed independently of the inducing platelet agonist. Inclacumab also inhibited the activation of the leukocyte integrin Mac-1 and leukocyte adhesion to a platelet monolayer under flow conditions.
In clinical studies, inclacumab inhibited TRAP-induced PLA formation in a dose-dependent manner following single and multiple dose administration to healthy volunteers. It also reduced elevated circulating PLA levels in patients with peripheral arterial disease.
Conclusion: By inhibiting platelet-leukocyte interactions, demonstrated in multiple preclinical and clinical studies, inclacumab may provide an effective treatment for cardiovascular diseases.

• 出版日期2013-5