Crizanlizumab and inclacumab are equally potent inhibitors of cell adhesion in the blood of patients with sickle cell disease

• Inclacumab, an anti-P-selectin Ab in clinical development has a higher affinity for P-selectin than FDA approved crizanlizumab. • The efficacy of inclacumab in inhibiting P-selectin-dependent cellular adhesion in sickle patient blood was comparable to crizanlizumab. Acute painful vaso-occlusive episodes (VOEs) are the primary reason for emergency department visit by sickle cell disease (SCD) patients and contribute to significant morbidity in SCD. Crizanlizumab, a first-in-class humanized anti-P-selectin IgG2 monoclonal antibody, is approved in more than 40 countries for prevention of VOEs in 16 years or older SCD patients. Inclacumab, a fully human anti-P-selectin IgG4 mAb in clinical development is believed to have stronger affinity to P-selectin and greater maximal inhibition of cell–cell interactions than crizanlizumab. Using in vitro blinded experiments, we investigated whether crizanlizumab and inclacumab can be differentiated in terms of P-selectin binding affinity and inhibition of P-selectin-mediated cell adhesion in blood samples from healthy volunteers or SCD patients. Surface Plasmon Resonance revealed that inclacumab had higher P-selectin binding affinity than crizanlizumab, however, the inhibition of P-selectin-mediated cell adhesion was higher or comparable with crizanlizumab than inclacumab. Crizanlizumab and inclacumab were comparable in inhibiting leukocyte and erythrocyte adhesion to P-selection under vascular mimetic flow in microfluidic channels, leukocyte-platelet aggregation, and platelet aggregation in SCD patient or control human blood. In summary, these results suggest that comparable or higher inhibition of cell adhesion with crizanlizumab vs inclacumab does not correlate with P-selectin binding affinity. Ultimately, clinical trials are required to evaluate how crizanlizumab vs inclacumab translate into treatment outcomes in SCD patients.