W135 - MRT-6160, a VAV1-Directed Molecular Glue Degrader, Inhibits Disease Progression in a Preclinical Model of T/B-cell-Mediated Experimental Autoimmune Encephalomyelitis

Abstract Text: VAV1 is a guanine nucleotide exchange factor critical for T-cell receptor (TCR) and B-cell receptor (BCR) signaling. Genetic loss of Vav1 confers diminished T/B-cell effector functions and attenuates autoimmune disease onset in preclinical models. MRT-6160 is a first-in-class MGD that specifically targets VAV1 for proteasome-mediated degradation and is currently under clinical development for immune-mediated conditions. MRT-6160 may provide therapeutic benefit across multiple T- and/or B-cell-mediated conditions including neuroinflammatory diseases.
MRT-6160-treated primary immune cells were TCR- or BCR-stimulated and assessed for various immune effector functions. MRT-6160 was then evaluated in a T/B-cell-mediated MOG protein immunization EAE mouse model. Mice were treated orally and daily from Day 9-20 with vehicle, fingolimod (3 mg/kg), or MRT-6160 (1 mg/kg); clinical scores assessed daily. At termination, spinal cords were assessed for cytokines, histopathology, and single cell RNA-sequencing.
MRT-6160 significantly inhibited EAE disease progression, consistent with inhibition of T/B-cell stimulation-induced proliferation, differentiation, and pro-inflammatory cytokine production. In vivo activity was concomitant with reduced multiple sclerosis-relevant pro-inflammatory cytokines (IL-1β, IL-12p40, IP-10/CXCL10, MIP-1⍺, and IL-17A) and spinal cord immune cell infiltration, lesion area, and demyelination. Finally, single-cell transcriptomic analyses revealed that several key activation (TCR signaling, T-cell checkpoint signaling, BCR signaling) and pro-inflammatory (Th17-mediated biology, Th1 and Th17 differentiation) pathways were reduced following treatment with MRT-6160.
MRT-6160 attenuated both T- and B-cell effector functions in vitro and demonstrated activity in a preclinical T/B-cell-mediated model of EAE. These data suggest that MRT-6160 may provide therapeutic benefit in patients with neuroinflammatory diseases among other T- and/or B-cell immune-mediated diseases.