Background: VAV1 is an immune cell restricted guanine nucleotide exchange factor (GEF) and scaffolding protein that plays a critical role in mediating T- and B-cell receptor (TCR and BCR respectively) activity and signaling. The role of human (h)VAV1 has been demonstrated in CRISPR-based screens ^[1] and in murine (m)VAV1 knockout mice ^[2] that exhibited resistance to experimentally induced autoimmune disease ^[3,4] . GEFs lack binding pockets for targeting with small molecule inhibitors and, as such, VAV1 has remained undruggable by conventional means. MRT-6160 is a highly selective first-in-class oral VAV1-targeting molecular glue degrader. Given the role of VAV1 in T- and B-cells, MRT-6160-mediated proteasomal degradation of VAV1 could have broad therapeutic implications in autoimmune disorders, including rheumatoid arthritis.

Objectives: This study aimed to assess the impact of MRT-6160-mediated degradation of VAV1 on immune cell effector functions and preclinical activity in a collagen-induced arthritis (CIA) model.

Methods: Primary human T- and B-cells were treated with MRT-6160 prior to antigen receptor stimulation and assessed for activation and effector functions. MRT-6160 was administered to naïve mice followed by analysis of in vivo (m)VAV1 degradation. In a CIA disease model, activity of MRT-6160-mediated mVAV1 degradation was assessed. Female DBA/1 mice were immunized with bovine type II collagen emulsified in complete Freund’s adjuvant. Following disease onset (clinical score of 1–2), mice were randomized into treatment groups: vehicle; anti-TNF (20 mg/kg); or MRT-6160 (10 mg/kg) and treated for 21 days with daily assessment for clinical signs of arthritis. At study termination, serum pro-inflammatory cytokines and anti-collagen II antibody levels were assessed.

Results: MRT-6160-mediated degradation of hVAV1 dose-dependently attenuated TCR- and BCR-mediated activation (CD69 expression), proliferation, and function in T- and B-cells, including cytokine and IgG secretion. Oral dosing of mice with MRT-6160 elicited mVAV1 degradation in a dose-dependent manner. In the CIA disease setting, MRT-6160-mediated mVAV1 degradation significantly reduced clinical scores and inhibited disease progression compared to vehicle and anti-TNF treated mice. Analysis of serum samples showed that degradation of mVAV1 significantly reduced the production of key pro-inflammatory cytokines (IL-1β, IL-6, TNF⍺, and IL-17A) and anti-collagen II IgG1.

Conclusion: MRT-6160 is a highly selective and orally bioavailable molecular glue degrader targeting VAV1, a key signaling protein in lymphocytes. MRT-6160-mediated degradation of VAV1 attenuates TCR- and BCR-mediated activation in vitro and inhibits disease progression and autoimmune proinflammatory effector functions in vivo warranting clinical investigation.

REFERENCES: [1] Schmidt et al . Science . (2022) 375(6580): eabj4008

[2] Fujikawa et al . J Exp Med . (2003) 189(10): 1595-1608

[3] Korn et al . J Neuroinmmunol. (2003) 139(1-2): 17–26

[4] Conde et al . Biomedicines . (2021) 9(6): 695

Acknowledgements: NIL.

Disclosure of Interests: Adam Cartwright Monte Rosa Therapeutics, Foram Desai Monte Rosa Therapeutics, Shailee Vora Monte Rosa Therapeutics, Lucas Gyger Monte Rosa Therapeutics, Laura Roditi Monte Rosa Therapeutics, Sophia Nguyen Monte Rosa Therapeutics, Alexandra Trouilloud Monte Rosa Therapeutics, Daniel Lam Monte Rosa Therapeutics, Peter Trenh Monte Rosa Therapeutics, Xavi Lucas Monte Rosa Therapeutics, Mary Zlotosch Monte Rosa Therapeutics, Elisa Liardo Monte Rosa Therapeutics, Daric Wible Monte Rosa Therapeutics, Vladas Oleinikovas Monte Rosa Therapeutics, Ilaria Lamberto Monte Rosa Therapeutics, Bradley Demarco Monte Rosa Therapeutics, Chris King Monte Rosa Therapeutics, Debora Bonenfant Monte Rosa Therapeutics, Eswar Krishnan Monte Rosa Therapeutics, Steven De Beukelaer Monte Rosa Therapeutics, Sharon Townson Monte Rosa Therapeutics, Owen Wallace Monte Rosa Therapeutics, Filip Janku Monte Rosa Therapeutics, Laura McAllister Monte Rosa Therapeutics, Alison Paterson Monte Rosa Therapeutics, Marisa Peluso Monte Rosa Therapeutics