To assess the safety and pharmacokinetic profile of ART5803, a therapeutic one-armed antibody designed to block the pathogenicity of anti-NMDA receptor (NMDAR) autoantibodies in patients with anti-NMDAR encephalitis (ANRE), in healthy volunteers.

ANRE is a severe rare disease for which there are currently no approved therapeutic options. We engineered a one-armed IgG with a silent Fc (ART5803) that binds the N-terminal domain of the NMDAR GluN1 subunit with high affinity without impacting receptor function. We further demonstrated that ART5803 blocks the pathogenicity of anti-NMDAR autoantibodies. In a marmoset model of ANRE, peripherally dosed ART5803 (intraperitoneal injection) rapidly reversed behavioral abnormalities. GLP toxicology studies in rats and cynomolgus monkeys resulted in a No-Observed-Adverse-Effect-Level (NOAEL) for ART5803 at dose 1000 mg/kg.

The safety, tolerability, and pharmacokinetics of ART5803 are being evaluated in an ongoing Phase 1 trial (NCT06575153). Forty healthy adult volunteers were enrolled in a randomized, double-blind, placebo-controlled study with single ascending intravenous (IV) doses ranging from 3 to 100 mg/kg. An additional 24 healthy adult volunteers were enrolled in a multiple ascending dose study with IV doses ranging from 30 to 100 mg/kg. Clinical and laboratory safety parameters were extensively monitored.

ART5803 was generally well tolerated.  Pharmacokinetic analysis demonstrated that a single IV administration of ART5803 at 30, 60, and 100 mg/kg achieved therapeutic Cerebro Spinal Fluid (CSF) concentrations (>0.5 μg/mL) as early as 48 hours post-infusion. Multiple IV doses of 30, 60, and 100 mg/kg (once weekly for 4 weeks) resulted in expected accumulation, achieving therapeutic CSF concentrations (>1 μg/mL).

Safety and pharmacokinetic assessments from this Phase 1 trial support continued clinical development. Pharmacokinetic analysis suggests that IV doses above 30 mg/kg achieve therapeutic concentrations in ANRE patients allowing for dose and regimen selection for future studies. Phase 2 clinical assessments in ANRE and autoimmune psychosis patients are planned.