A Patient-Derived Antibody Ameliorates Disease Severity in a Relapsing Remitting Murine Model of Multiple Sclerosis.

Abstract

OBJECTIVE: Naturally occurring autoantibodies are commonly considered to be causative of autoimmune diseases or epiphenomena with no known biological impact. Although clinically beneficial autoantibodies have been described, there have been no naturally occurring anti-neuronal antibodies that have been found to be neuroprotective. Here, we identify a recombinant human antibody (TGM-010) derived from a patient with multiple sclerosis (MS) that binds human and mouse neurons, leading to beneficial effects. METHODS: TGM-010 was examined for its ability to be internalized by human and mouse neurons and protect neurons from death in vitro following a stress event. TGM-010 was also injected systemically into a relapsing-remitting model of experimental autoimmune encephalomyelitis (EAE) to examine its ability to impact disease score, extent of demyelination, and neuron frequency. RESULTS: TGM-010 demonstrates many novel characteristics including crossing the blood-brain barrier (BBB) and internalizing into neurons. TGM-010 also protects primary mouse neurons from death in vitro. In a mouse model of MS, TGM-010 ameliorates disease severity and is associated with improved neuronal survival. INTERPRETATION: This study identified a patient-derived neuron-binding autoantibody that crosses the BBB in mice and reduces neuron loss in a mouse model of MS. These data suggest that the human derived anti-neuronal antibody, TGM-010, may potentially be used to ameliorate neurodegeneration that underlies disability in neurodegenerative conditions. ANN NEUROL 2026;99:1152-1165.