Abstract Details

The current SOC for ANRE are general immunosuppressive approaches with slow onset and insufficient efficacy. Resulting long-term deficits, infection risk, and non-responsive patient populations highlight the profound unmet need in this therapeutic area.

To create and evaluate a faster acting, more efficacious and safer therapeutic than standard of care (SOC) for anti-NMDAR encephalitis (ANRE).

ANRE pathogenic autoantibodies (autoAbs) bind to limited epitopes in the N-terminal domain (NTD) of NMDA-NR1, crosslink NMDAR, and induce receptor internalization leading to hypofunction of NMDAR.  We engineered a non-pathogenic recombinant one-armed humanized IgG (ART5803) which binds to the NTD epitope of NMDAR-NR1. We tested ART5803 efficacy against pathogenic autoAbs from ANRE patients on binding, internalization and function of NMDAR expressed in HEK293 cells in vitro. We established a marmoset model where patient-derived pathogenic autoAbs were continuously ICV infused to induce and maintain mental/motor abnormalities for a month to test in vivo efficacy of ART5803.

ART5803 competes with an ANRE patient derived autoAb at a shared NTD epitope located in human NMDA-NR1 with high binding affinity (K_D= 0.69 nM). ART5803 blocked NMDAR internalization (NR1/NR2B expressed in HEK293 cells) induced by various ANRE patient-derived autoAbs. ART5803 restored NMDAR function (Ca²⁺ influx) in HEK293 cells suppressed by patient-derived autoAb. ART5803 did not show any agonist or antagonist activities on NMDAR. In vivo efficacy of ART5803 was assessed in a marmoset model. ICV infusion of ANRE-patient derived pathogenic autoAbs evoked robust mental/motor abnormalities in marmosets and simultaneous ART5803 ICV infusion reversed these behavioral abnormalities within 2 weeks.

These data indicate a therapeutic potential for ART5803 as a faster acting, more efficacious, and safer treatment option for ANRE patients. Intravenous administration is under investigation.