0009: MRT-6160, a VAV1-Directed Molecular Glue Degrader, Attenuates T and B Cell Effector Functions and Inhibits Disease Progression in a Spontaneous MRL-Fas^lpr Mouse Model

Background/Purpose: VAV1, an immune cell restricted guanine nucleotide exchange factor (GEF) and scaffolding protein, plays a critical role in mediating T- and B-cell receptor activity. Genetic loss of hVAV1 in CRISPR-based screens confers reduced T-cell effector function and murine (m)VAV1 knockout mice are resistant to T- and T/B-cell mediated autoimmune disease models. MRT-6160 is a highly selective, first-in-class oral VAV1-targeting molecular glue degrader currently being evaluated in healthy subjects [NCT06597799]. Given the role of VAV1 in T- and B-cells, MRT-6160-mediated degradation of VAV1 could have broad therapeutic implications in lymphocyte-driven autoimmune and rheumatic disorders, including primary Sjögren’s Syndrome (pSS) and systemic lupus erythematosus (SLE).

Methods: PBMCs from pSS and SLE patients were pre-treated with MRT-6160 prior to TCR or T cell-dependent-like BCR stimulation and assessed for VAV1 levels, IL-2 secretion, and IgG production. Primary human T follicular helper cells and B cells were enriched from allogenic healthy patient PBMCs, treated with or without MRT-6160, co-cultured for 6 days, then assessed for IgG secretion and plasmablast differentiation. MRL-Fas^lpr mice were treated with vehicle, prednisone (10 mg/kg, PO QD), anti-CD40L (5 mg/kg, IP Q3D), or MRT-6160 (1 mg/kg, PO QD) from 11 to 18 weeks of age following onset of disease at around 9 weeks of age. Mice were assessed in-life from 9 weeks of age for body weight, lymphadenopathy, skin lesions, proteinurea and autoantibody levels. At the end of the study, organomegaly and kidney histopathological assessments were performed.

Results: MRT-6160 degraded VAV1 in healthy and pSS patient PBMCs, concomitant with an attenuation of TCR stimulation-induced IL-2 and T cell-dependent-like BCR stimulation-induced IgG secretion. Treatment of Tfh and B cell co-cultures with MRT-6160 reduced plasmablast differentiation (CD38⁺CD27⁺CD20^– cells) of both naïve and memory B cells and concurrently reduced in IgM and IgG respectively. In MRL-Fas^lpr mice, whilst blockade of the CD40/CD40L axis had no effect, MRT-6160 inhibited lymphadenopathy and skin lesion formation comparable to prednisone and levels of proteinuria and anti-dsDNA levels were inhibited to a greater extent than prednisone. At study termination, MRT-6160 reduced organomegaly of lymph nodes, spleen and kidneys. In histopathological assessment of the kidneys, MRT-6160 significantly reduced glomerulonephritis and vascular nephritis comparable to prednisone.

Conclusion: MRT-6160-mediated degradation of VAV1 attenuates TCR- and BCR-mediated activation in vitro diminishing activation and effector functions of pSS/SLE patient PBMCs and Tfh-mediated differentiation and immunoglobulin production. In vivo, MRT-6160 inhibited disease progression and kidney histopathological organ damage in an MRL-Fas^lpr mouse model of rheumatic disease. These data demonstrate the therapeutic potential of MRT-6160 in various lymphocyte-driven autoimmune and rheumatic diseases.