First-in-man Study With Inclacumab, a Human Monoclonal Antibody Against P-selectin

Abstract

Abstract:Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered in an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, and pharmacodynamics. Fifty-six healthy subjects were enrolled in this randomized, double-blind placebo-controlled study. Each dose level (0.03–20 mg/kg) was investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo). Platelet–leukocyte aggregates, free/total soluble P-selectin concentration ratio, drug concentrations, bleeding time, platelet aggregation, antibody formation, and routine laboratory parameters were measured frequently until 32 weeks. Pharmacokinetic profiles were indicative of target-mediated drug disposition. Platelet–leukocyte aggregate inhibition and soluble P-selectin occupancy showed dose dependency and were strongly correlated to inclacumab plasma concentrations, with IC50 of 740 and 4600 ng/mL, respectively. Inclacumab was well tolerated by the majority of subjects and did neither affect bleeding time nor platelet aggregation. These findings allowed the investigation of the potential beneficial therapeutic use of inclacumab in patient study.

Role of CD40 and ADAMTS13 in von Willebrand factor-mediated endothelial cell–platelet–monocyte interaction

“…Herein we make this role tangible in patients with atherosclerosis and related cardiovascular diseases. Blocking P-selectin may represent a more feasible approach to inhibit platelet-monocyte interactions and to reduce atherosclerosis, as shown by several animal studies (60,61) and two recent clinical trials which tested the newly developed anti-P-selectin antibody inclacumab (62,63). In addition, platelet-vWF interactions can be blocked by specific antibodies targeting vWF GpIb (caplacizumab) and platelet GpIb receptor (anfibatide), which have recently been tested in phase I and phase II clinical trials with very promising results (64,65).…”

From Classical Laboratory Parameters to Novel Biomarkers for the Diagnosis of Venous Thrombosis

“…Studies on animal models demonstrated that inhibition of P-selectin can impact the development of atherosclerosis, fibrin deposition and thrombus growth [21,[57][58][59]. In humans, high levels of sP-selectin are also found in cardiovascular disease, atrial fibrillation and diabetes [60], and may be predictive of future adverse cardiovascular events [21,61,62].…”

Novel Approaches to Fine-Tune Therapeutic Targeting of Platelets in Atherosclerosis: A Critical Appraisal

“…inflammatory and antithrombotic platelet-dependent processes that are instrumental in atherogenesis, a P-selectin blocking monoclonal antibody (inclacumab) has been developed and tested in humans with NSTEMI, which resulted in decreased peri-interventional myocardial damage. 26 As a side note, P-selectin expression is enhanced in platelets and endothelial cells in patients with sickle cell disease contributing to the risk of vaso-occlusive crises. A humanized monoclonal antibody, crizanlizumab, has been shown in the SUSTAIN trial to protect patients with sickle cell disease from vaso-occlusive crises and has recently been approved by the Food and Drug Administration for this indication.…”