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Abstract Details

Monoclonal Humanized One-Armed Antibody Blocking Therapy for Anti-NMDAR Encephalitis
Autoimmune Neurology
S22 - Autoimmune Neurology: Autoimmune Encephalitis and Other Antibody-associated Syndromes (4:18 PM-4:30 PM)
005

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 (KD= 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.

Authors/Disclosures
Mitsuyuki Matsumoto, PhD (Arialys Therapeutics, Inc.)
PRESENTER
Dr. Matsumoto has received personal compensation for serving as an employee of Arialys Therapeutics, Inc.. Dr. Matsumoto has received personal compensation for serving as an employee of Astellas Pharma Inc.. Dr. Matsumoto has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Arialys Therapeutics, Inc.. Dr. Matsumoto has stock in Arialys Therapeutics, Inc.. Dr. Matsumoto has received intellectual property interests from a discovery or technology relating to health care. Dr. Matsumoto has received intellectual property interests from a discovery or technology relating to health care.
Shanni Tsuyako Yamaki, PhD Dr. Yamaki has received personal compensation for serving as an employee of Arialys. Dr. Yamaki has received personal compensation for serving as an employee of Astellas. Dr. Yamaki has received intellectual property interests from a discovery or technology relating to health care.
Roghiye Kazimi, Other (Arialys) Mrs. Kazimi has received personal compensation for serving as an employee of Arialys Therapeutics. Mrs. Kazimi has received personal compensation for serving as an employee of BPS Bioscience.
Atsuo Kanno, PhD Mr. Kanno has received personal compensation for serving as an employee of Astellas Pharma Inc,. Mr. Kanno has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arialys. Mr. Kanno has received intellectual property interests from a discovery or technology relating to health care.
Masashi Maeda, PhD Dr. Maeda has received personal compensation for serving as an employee of Astellas Pharma Inc.. Dr. Maeda has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Arialys Therapeytic Inc.. Dr. Maeda has received intellectual property interests from a discovery or technology relating to health care.
Satoshi Kubo, PhD (Arialys Therapeutics Inc.) Dr. Kubo has received personal compensation for serving as an employee of Astellas Pharma Inc.. Dr. Kubo has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arialys Therapeutics Inc.. Dr. Kubo has received intellectual property interests from a discovery or technology relating to health care.
Mathew Mitchell (Arialys Therapeutics, Inc.) Mr. Mitchell has received personal compensation for serving as an employee of Arialys Therapeutics.
Jay Lichter, PhD (Arialys Therapeutics, Inc.) Dr. Lichter has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Janux.