ABBV-MALT1 is a potent, selective, allosteric inhibitor of the MALT1 paracaspase with binding KD of 37 nM, exhibits potent biochemical inhibition of MALT1 protease activity with IC50 of 349 nM.
Displays no meaningful off-target activity against a panel of 177 kinases representing each branch of the kinome, 55 pharmacological receptor binding assays and four caspase activity assays.
ABBV-MALT1 effectively inhibits immune cell activation as measured by secreted IL-2 with EC50 of 300 nM in human PBMCs.
ABBV-MALT1 treatment completely inhibits the ability of T cells to express IFNy after co-stimulation with 10 ug/mL anti-PD1, with no effect on T cell viability.
ABBV-MALT1 selectively inhibitsthe growth of ABC subtype diffuse large B cell lymphoma (ABC-DLBCL) models (OCI-LY3 tumor cell line, EC50=300 nM) to varying maxima and shows no activity in GCBDLBCL cells, upregulates MALT1 substrates BCL10, RELB and ZC3H12D protein levelsin a dose-dependent manner in OCI-LY3 cells.
ABBV-MALT1 (30 mg/kg, twice daily for 14 days, oral) is efficacious in the OCILY10 CDX model (TGI of 73%), which harbors an activating CD79A mutation, combination of MALT1 and BCL2 inhibition is highly efficacious in vivo.