Pharmacokinetics, Receptor Occupancy, and Pharmacodynamics of Obexelimab Following Intravenous Administration in Adult Healthy Volunteers and in Patients With Rheumatoid Arthritis.

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.