Session: 113. Hemoglobinopathies, Excluding Thalassemia—Basic and Translational Science: Poster II
Hematology Disease Topics & Pathways:
Anemias, sickle cell disease, Biological, antibodies, Diseases, Therapies, red blood cells, Hemoglobinopathies, Cell Lineage, Clinically relevant
A crystal structure of inclacumab and P-selectin reveals that inclacumab directly binds to an epitope in the PSGL-1 binding region on P-selectin and thus competitively inhibits P-selectin and its ligand interaction. In contrast, crizanlizumab binds to a more distant epitope to the PSGL-1 binding site on P-selectin. To further elucidate differences between the two antibodies, we characterized inclacumab and crizanlizumab in a series of in vitro functional assays including ligand binding affinity, competitive ligand binding by surface plasmon resonance (SPR), P-selectin mediated cell-based adhesion assay and cell-cell interaction with human whole blood samples. In vitro, inclacumab binds to human P-selectin with high affinity and potently suppresses the interaction of P-selectin with its main ligand PSGL-1. Both antibodies exhibited similar binding affinities to P-selectin (KD of 9.9 and 9.1 nM for inclacumab and crizanlizumab, respectively) and comparable potencies at preventing a PSGL-1 mimetic peptide from binding P-selectin (IC50 of 1.9 and 2.2 µg/mL for inclacumab and crizanlizumab, respectively) or blocking the adhesion of PSGL-1 expressing cells to an immobilized P-selectin (IC50 = 430 ng/mL for inclacumab and IC50 = 453 ng/mL for crizanlizumab). However, inclacumab demonstrated greater maximal platelet-leukocyte cell adhesion inhibition in response to thrombin receptor activating peptide (TRAP) in blood samples from both healthy volunteers and subjects with SCD in an in vitro efficacy assay (see figure).
Inclacumab is differentiated from crizanlizumab as a fully human monoclonal antibody that directly blocks the PSGL-1 binding region of P-selectin and shows greater maximal inhibition of cell-cell interactions in vitro. At doses up to 20 mg/kg Q4W, which previous clinical trials have shown to be safe and well-tolerated, inclacumab has much greater drug exposure than the approved dose of crizanlizumab (5 mg/kg W0/W2/Q4W) (Ataga KI et al., N Engl J Med, 2017; Schmitt C et al., J Cardiovasc Pharmacol. 2015; Tardif JC et al., J Am Coll Cardiol, 2013). A single dose of inclacumab 20 mg/kg demonstrated full PLA inhibition for ≥84 days in healthy volunteers (Morrison M et al., Eur J Clin Pharmacol, 2015; Kling D et al., Thromb Res, 2013). Inclacumab may allow for a substantially longer and therefore more convenient dosing interval as compared with crizanlizumab. In aggregate, these data suggest that inclacumab has the potential to be a best-in-class P-selectin inhibitor to reduce VOCs in sickle cell disease. Clinical studies of inclacumab in patients with SCD are planned for the 1st half of 2021.
Disclosures: Geng: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mihaila: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yuan: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Strutt: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Benz: Roche Pharmaceuticals: Current Employment. Tang: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayer: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Oksenberg: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company.