Article
作者: Green, Michael R ; Meulbroek, Jonathan A ; Panchal, Sanjay C ; Judge, Russell A ; Jung, Paul ; Dowell, Colleen ; Plotnik, Joshua P ; Yang, Haopeng ; Rojas, Estela ; Wilson, Ashley ; George, Mariam D ; Bontcheva, Velitchka ; Jhala, Manisha ; Pan, Chin ; Zhu, Haizhong ; Kohlhapp, Frederick J ; Qiu, Wei ; McClure, Ryan A ; Partha, Sarathy Karunan ; Will, Christine ; Parsons, Sydney ; Richardson, Adam E ; Ramathal, Cyril Y ; Pappano, William N ; Mali, Raghuveer Singh ; Ravanmehr, Vida ; Henderson, Jared ; Mastracchio, Anthony ; Elsen, Nathaniel L
AbstractThe activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.
