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Abstract Details

Peripherally Administered Therapeutic One-armed Antibody Reversed Behavioral Abnormalities in a Marmoset Model of Anti-NMDAR Encephalitis
Autoimmune Neurology
S4 - Autoimmune Neurology: Autoimmune Encephalitis and Neuronal Autoantibodies (1:36 PM-1:48 PM)
004

ANRE pathogenic autoantibodies (autoAbs) bind to limited epitopes in the N-terminal domain (NTD) of NMDAR NR1 subunit, crosslink NMDARs, induce receptor internalization and associated neurological symptoms. We engineered a one-armed IgG (ART5803) to bind with high affinity to the NTD of NMDAR-NR1 without impacting receptor function. Further we demonstrate ART5803 blocks the pathogenicity of anti-NMDAR autoAbs. We established a marmoset model of ANRE by ICV infusion of pathogenic autoAbs and demonstrated ART5803 ICV infusion reversed behavioral abnormalities. In this study, we tested if ART5803 could reach therapeutic CNS levels with IP peripheral dosing and reverse behavioral abnormalities in the marmoset model.

To invent and evaluate a precision medicine with fast onset and improved safety for anti-NMDAR encephalitis (ANRE). 

Pathogenic autoAbs (10 μg/hr) were continuously ICV infused for 21 days to evoke mental and motor abnormalities in marmosets. The concentration of autoAbs in the CSF (10 – 20 ug/ml) was used to predict that 1 – 2 ug/ml of ART5803 in the CSF would be necessary to block autoAbs. The IP dose to achieve this target CSF concentration was determined by PK studies in marmosets. Six days after ICV infusion of pathogenic autoAbs (Day 6), marmosets were equally divided into two cohorts (n=7-8 each) and dosed with either 400 mg/kg ART5803 or vehicle via IP twice a week for 2 weeks starting on Day 7. 

ICV infusion of ANRE-patient derived pathogenic autoAbs evoked robust behavioral and motor abnormalities in marmosets. IP dosing of 400 mg/kg ART5803 reversed these abnormalities within 1 week and was well tolerated.

These data indicate a therapeutic potential for ART5803 as a faster acting, more efficacious, and safer treatment option for ANRE patients. PK and GLP toxicology studies in monkeys and rats are underway to support studies in humans.

Authors/Disclosures
Mitsuyuki Matsumoto (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 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.
No disclosure on file
No disclosure on file
No disclosure on file
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No disclosure on file
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No disclosure on file
Mathew Mitchell (Arialys Therapeutics, Inc.) Mr. Mitchell has received personal compensation for serving as an employee of Arialys Therapeutics.
Carrolee Barlow (Arialys) No disclosure on file
Jay Lichter (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.