title: Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab--preclinical and clinical studies.
abstract: 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.
  
  
  METHODS
  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 μg/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 μg/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.
  
  
  CONCLUSIONS
  By inhibiting platelet-leukocyte interactions, demonstrated in multiple preclinical and clinical studies, inclacumab may provide an effective treatment for cardiovascular diseases.
authors.affiliation: F. Hoffmann-La Roche, AG, Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kling
authors.forename: Corinne
authors.initials: C
authors.lastname: Stucki
authors.forename: Sven
authors.initials: S
authors.lastname: Kronenberg
authors.forename: Dietrich
authors.initials: D
authors.lastname: Tuerck
authors.forename: Eric
authors.initials: E
authors.lastname: Rhéaume
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Jacques
authors.initials: J
authors.lastname: Gaudreault
authors.forename: Christophe
authors.initials: C
authors.lastname: Schmitt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000276:immunology; D015539:Platelet Activation; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D019007:P-Selectin