2025 American Academy of Neurology Abstract Website

Objective:

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

Background:

ANRE pathogenic autoAbs bind to limited epitopes in the N-terminal domain (NTD) of NMDAR NR1 subunit and crosslink NMDARs inducing receptor internalization and associated neurological symptoms. We engineered a one-armed IgG with a silent Fc (ART5803) binding to the NTD of NMDAR-NR1 with high affinity without impacting receptor function. Further we demonstrated ART5803 blocks the pathogenicity of anti-NMDAR autoAbs. We established a marmoset model of ANRE by ICV infusion of pathogenic autoAbs and demonstrated that peripherally dosed ART5803 (IP injection) reversed marmoset behavioral abnormalities.

Design/Methods:

IV infusion toxicity and toxicokinetic study with ART5803 (100, 300 and 1000 mg/kg) in rats for 4 weeks and in Cynomolgus monkeys for 13-weeks, and ART5803 tissue cross reactivity study in human, Cynomolgus monkey and rat tissues were conducted under Good Laboratory Practice (GLP) conditions. Complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) activities of ART5803 were assessed using HEK293 cells expressing NMDAR NR1 proteins.

Results:

No adverse events attributable to ART5803 were observed in both GLP-toxicology studies in rats and Cynomolgus monkeys at doses tested. The no observed adverse effect level (NOAEL) is 1000 mg/kg. Expected NMDAR binding of ART5803 in the brain, spinal cord and retina was observed in human, monkey, and rat tissues. There was no off-target binding of ART5803 observed in any human, monkey, or rat tissues. ART5803 did not induce CDC, ADCC or ADCP activity in the experimental system.

Conclusions:

The data support clinical development of ART5803. After establishment of safety in Phase 1 clinical studies we plan on proof-of-concept clinical evaluation in human ANRE. Further, we are assessing the potential clinical development of ART5803 in a broader set of disease indications.