Classical Pathway Inhibition with Anti-active C1s Antibody DNTH103 Prevents Neurotransmission Impairment in a Preclinical Model of Myasthenia Gravis
Sankalp Gokhale1, Pushpa Narayanaswami2, Tuan Vu3, John Vissing 4, Stojan Perić5, Douangsone Vadysirisack1
1Dianthus Therapeutics, 2Beth Israel Deaconess Medical Center, Harvard Medical School, 3Department of Neurology, University of South Florida Health Morsani College of Medicine, 4Department of Clinical Medicine, Neurology, University of Copenhagen, 5Neurology Clinic and Faculty of Medicine, University of Belgrade
Objective:
We describe the evaluation of DNTH103 in a functional preclinical myasthenia gravis model.
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.
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.