Abstract Details

Title IND-Enabling Safety Studies for ART5803, a Clinical-Stage Therapeutic One-Armed Antibody to Treat Anti-NMDA Receptor Encephalitis

Topic Autoimmune Neurology

Presentation(s) S7 - Autoimmune Encephalitis (4:06 PM-4:18 PM)

Poster/Presentation
Number 004

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.

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).

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.

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 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.
Amir Razai (Arialys)	Amir Razai has received personal compensation for serving as an employee of Arialys .
Scott Snipas (Arialys)	Scott Snipas has received personal compensation for serving as an employee of Arialys Therapeutics .
Shanni Yamaki	Shanni Yamaki has received personal compensation for serving as an employee of Arialys Therapeutics Inc. .
Roghiye Kazimi (Arialys)	Roghiye Kazimi has nothing to disclose.
Vallari Eastman	Vallari Eastman has nothing to disclose.
Mari Maurer (Arialys Therapeutics)	Ms. Maurer has received personal compensation for serving as an employee of Arialys Therapeuticss, Inc.. Ms. Maurer has received personal compensation for serving as an employee of ESCAPE Bio. Ms. Maurer has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for ReCode Therapeutics. Ms. Maurer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Momentum Pharma. Ms. Maurer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ESCAPE Bio. Ms. Maurer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Arialys Therapeutics.
Mathew Mitchell (Arialys Therapeutics, Inc.)	Mr. Mitchell has received personal compensation for serving as an employee of Arialys Therapeutics.
Martin Jefson, PhD	Dr. Jefson has received personal compensation for serving as an employee of Arialys Therapeutics. Dr. Jefson has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for 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.
Peter Flynn, PhD	Dr. Flynn has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Artiva. Dr. Flynn has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Arialys.

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