Targeting MALT1 for the Therapeutic Degradation in Activated B-Cell Diffuse Large B-Cell Lymphoma

The study explores a novel approach to treating ABC-DLBCL by targeting the MALT1 protein, which is crucial for NFκB activation and Treg function. A new compound, PS-II-115, has been developed to degrade MALT1 using a PROTAC mechanism, which links a MALT1-binding domain to a CRBN-binding domain, leading to the ubiquitination and degradation of MALT1.

Experiments conducted on OCI-Ly3 cells showed that PS-II-115 effectively degraded MALT1, with no significant impact on other CRBN-associated substrates. The compound also increased IκB levels, suggesting it inhibits NFκB activation pathways mediated by the MALT1 scaffold. Using the GloSensor split luciferase method, it was found that PS-II-115 inhibits MALT1 protease activity in a dose-dependent manner.

In terms of growth inhibition, PS-II-115 was more potent against ABC-DLBCL cell lines compared to GCB-DLBCL cell lines, which are not reliant on chronic NFκB activation, indicating the compound's specificity. Additionally, the compound's impact on T cells was assessed, revealing a significant reduction in Tregs and a decrease in pro-inflammatory TEMRA cells among treated cells.

The findings support the potential of MALT1 degradation via a PROTAC compound as a strategy for combating ABC-DLBCL, with possible unique effects on T-effector phenotypes. Further research is required to understand the immunological implications of MALT1 degradation and to confirm the findings in vivo.