Background/Purpose: VAV1 is a member of the VAV family of guanine nucleotide exchange factors (GEFs) and plays a critical role in mediating T- and B-cell receptor activity. VAV1 expression is primarily restricted to immune cells, positioning it as an attractive target for the treatment of inflammatory and autoimmune diseases. In knockout mice and human-based CRISPR screens, VAV1/Vav1 loss has been linked with reduced T- and/or B-cell function. Despite being a well-validated target for T- and/or B-cell mediated autoimmune disease, VAV1 has remained undruggable to date using small molecule inhibitor approaches. MRT-6160 is a highly selective first-in-class oral VAV1-targeting molecular glue degrader (MGD), which induces proteasomal degradation of VAV1 through formation of a ternary complex with the E3 ligase cereblon. We propose that targeting VAV1 will have broad therapeutic implications in a variety of autoimmune disorders driven by the underlying dysregulation of T- and B-cells, including rheumatoid arthritis.

Methods: Human cells were treated with MRT-6160 and profiled for VAV1 levels and selectivity. To determine effects of MRT-6160-mediated VAV1 degradation on lymphocyte function, pharmacodynamic and functional readouts were assayed in TCR- and BCR-stimulated purified human T- and B-cells. To test pharmaco-kinetics and -dynamics of MRT-6160 in vivo, healthy mice were treated with a single oral administration of MRT-6160 followed by assessment of compound and VAV1 levels in multiple tissues over time. The in vivo activity of MRT-6160 was evaluated in the collagen-induced arthritis (CIA) autoimmune disease setting where female DBA/1 mice were immunized on day 0 (intravenously) and boosted on day 21 (subcutaneously) using chicken type II collagen emulsified in complete or incomplete Freund’s adjuvant respectively. Following disease onset (average clinical score of ~1.5), mice were randomized into treatment groups and orally administered vehicle or 10 mg/kg MRT-6160 daily. In positive control groups, mice were administered either 1 mg/kg dexamethasone (daily via intraperitoneal injection) or 500 μg anti-TNF (three times weekly via intraperitoneal injection). Mice in all treatment groups were dosed for a duration of 20 days and assessed daily for body weight and clinical signs of arthritis in all four paws.

Results: MRT-6160-mediated selective degradation of VAV1 attenuated TCR- and BCR-mediated activation and function in primary human T- and B-cells. In vivo, oral dosing of MRT-6160 elicited Vav1 degradation across multiple tissues in a dose-dependent manner. Over the course of 20 days dosing in the CIA autoimmune disease setting, MRT-6160 significantly decreased disease progression and endpoint clinical scores (3.2±2.6) compared to vehicle (12.5±4.0) and was comparable to anti-TNF (4.4±3.7).

Conclusion: The VAV1-targeting MGD MRT-6160 attenuates disease progression in the autoimmune CIA model with a therapeutic treatment regimen. This warrants further investigation of MRT-6160 in a clinical setting.

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-vav1-directed-molecular-glue-degrader-mrt-6160-reduces-joint-inflammation-in-a-collagen-induced-arthritis-autoimmune-disease-model/