Abstract Details

Title Classical Pathway Inhibition with Anti-active C1s Antibody DNTH103 Prevents Neurotransmission Impairment in a Preclinical Model of Myasthenia Gravis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S15 - Autoimmune Neuromuscular Diseases: New Observations and Therapeutic Approaches (1:00 PM-1:12 PM)

Poster/Presentation
Number 001

Background While complement C5 therapies have been approved for acetylcholine receptor antibody (AChR) positive myasthenia gravis (MG), there remains significant need for therapies with a lower treatment burden on patients, including lower risk of encapsulated bacterial infections, improved dosing, and convenience with less frequent, low-volume, subcutaneous self-administration. Dianthus Therapeutics has developed DNTH103, a monoclonal antibody engineered to selectively target the classical pathway by inhibiting only the active form of the C1s protein with every two-week subcutaneous dosing of 300 mg/2 mL.

Objective

We describe the evaluation of DNTH103 in a functional preclinical myasthenia gravis model.

Design/Methods Human induced pluripotent stem cell (iPSC)-derived motor neuron and muscle cells were co-cultured in a two-chamber compartmentalized microfluidic device. Sera from 3 healthy individuals and 3 AChR+ MG patients, supplemented with complement-preserved pooled normal human sera were added to the muscle cell reservoir in the absence or presence of DNTH103 or anti-C5 antibody. The motor neuron chamber received electrical stimulation at 2 Hz for 2 minutes and muscle contraction was recorded. Muscle contraction fatigue index score was calculated based on the area under the curve of the region of interest divided by tetanic response from individual myotubes.

Results Treatment with DNTH103 at 0.1 and 1 μM reduced muscle contraction fatigue in AChR+ MG samples relative to baseline by 24.8% and 27.8% respectively, indicating improved neurotransmission and muscle contraction. Treatment with the anti-C5 antibody at 1 μM reduced muscle contraction fatigue in AChR+ MG samples relative to baseline by 14.8%. No significant effect of DNTH103 or anti-C5 antibody was observed in healthy volunteer samples.

Conclusions DNTH103 improved neurotransmission impairment in a physiologically relevant preclinical MG model, providing additional scientific rationale for DNTH103 in this disease. DNTH103 is being investigated in Phase II trial in MG.

Authors/Disclosures
Sam Gokhale PRESENTER	No disclosure on file
Pushpa Narayanaswami, MD, MBBS, FAAN (Beth Israel Deaconess Medical Center)	Dr. Narayanaswami has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. Dr. Narayanaswami has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Narayanaswami has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Narayanaswami has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Narayanaswami has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx USA. Dr. Narayanaswami has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Narayanaswami has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Muscle and Nerve, Wiley. Dr. Narayanaswami has stock in Moderna. Dr. Narayanaswami has stock in Dr. Reddys laboratories. Dr. Narayanaswami has stock in Pfizer. Dr. Narayanaswami has stock in Viatris. Dr. Narayanaswami has stock in Doximity. The institution of Dr. Narayanaswami has received research support from Alexion. Dr. Narayanaswami has a non-compensated relationship as a Member, Medical and Scientific Advisory Board with Myasthenia Gravis Foundation of America that is relevant to AAN interests or activities. Dr. Narayanaswami has a non-compensated relationship as a Member, Board of Directors with AANEM that is relevant to AAN interests or activities.
Tuan H. Vu, MD (University of South Florida)	Dr. Vu has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Dianthus. Dr. Vu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ImmunAbs. Dr. Vu has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ARGENX. Dr. Vu has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Vu has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Vu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amgen (Horizon). Dr. Vu has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Johnson & Johnson. Dr. Vu has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Vu has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for CSL Behring. Dr. Vu has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Argenx. The institution of Dr. Vu has received research support from CSL Behring. The institution of Dr. Vu has received research support from Alexion. The institution of Dr. Vu has received research support from RA Pharma/UCB. The institution of Dr. Vu has received research support from Mass Gen Hospital/Healy Platform Study. The institution of Dr. Vu has received research support from ARGENX. The institution of Dr. Vu has received research support from Horizon/Amgen. The institution of Dr. Vu has received research support from Woolsey Pharma. The institution of Dr. Vu has received research support from CSL Behring. The institution of Dr. Vu has received research support from Cartesian Therapeutics. The institution of Dr. Vu has received research support from Janssen/Johnson & Johnson. The institution of Dr. Vu has received research support from Immunovant. The institution of Dr. Vu has received research support from Regeneron. The institution of Dr. Vu has received research support from Dianthus. The institution of Dr. Vu has received research support from COUR.
John Vissing, MD (Rigshospitalet)	Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dyne Therapeutics. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Solid Biosciences. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus therapeutics. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AskBio. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity Therapeutics. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Italfarmaco. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Biopharma. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Argenx. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion Pharmaceuticals. Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Johnson & Johnson (Janssen). Prof. Vissing has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Edgewise Therapeutics. The institution of Prof. Vissing has received research support from Rigshospitalet. The institution of Prof. Vissing has received research support from UCB Pharma. The institution of Prof. Vissing has received research support from Sanofi. The institution of Prof. Vissing has received research support from Roche. The institution of Prof. Vissing has received research support from AnJii.
Stojan Peric, MD, PhD	Dr. Peric has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Dr. Peric has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Dianthus. Dr. Peric has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Peric has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for argenx.
Douangsone Vadysirisack (Dianthus Therapeutics)	No disclosure on file