Pharmacokinetics, Receptor Occupancy, and Pharmacodynamics of Obexelimab Following Intravenous Administration in...

Obexelimab is an investigational, bifunctional, nondepleting, humanized monoclonal antibody that binds CD19 and FcγRIIb to inhibit B-lineage cell activity. This study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of obexelimab administered intravenously in healthy volunteers (n = 48; single doses of 0.03-10.0 mg/kg) and patients with rheumatoid arthritis (n = 57; 6 doses of 0.3-10.0 mg/kg every 2 weeks). After single-dose administration, obexelimab exhibited nonlinear PK consistent with target-mediated drug disposition, with terminal elimination half-life increasing from 34.4 to 102 hours and clearance decreasing from 42.4 to 16.4 mL/day/kg across the dose range. Multiple dosing every 2 weeks demonstrated more linear PK with low accumulation (8%-22% increase in area under the concentration-time curve). Complete CD19 receptor occupancy occurred rapidly across doses, while CD20⁺ B-cell counts decreased to approximately 50% of baseline with dose-dependent recovery (15-61 days after single doses). Immunomodulatory effects included partial suppression of CD86 expression and significant reduction in antigen-specific antibody responses. Antidrug antibodies were detected in 44.4% and 17.5% of participants in single- and multiple-dose studies, respectively, with neutralizing antibodies in 0% and 2.5%. Obexelimab was generally well-tolerated, primarily mild-to-moderate gastrointestinal events occurring more frequently than with placebo. These results support further development of obexelimab for autoimmune disorders.