Article
作者: Jhala, Manisha ; George, Mariam D. ; Mcclure, Ryan A. ; Parsons, Sydney ; Bontcheva, Velitchka ; Mali, Raghuveer Singh ; Ravanmehr, Vida ; Karunan, Sarathy ; Judge, Russell A. ; Pappano, William N. ; Plotnik, Joshua P. ; Ramathal, Cyril Y. ; Dowell, Colleen ; Will, Christine ; Rojas, Estela ; Partha ; Elsen, Nathaniel L. ; Jung, Paul ; Panchal, Sanjay C. ; Kohlhapp, Frederick J. ; Henderson, Jared ; Green, Michael R. ; Zhu, Haizhong ; Meulbroek, Jonathan A. ; Richardson, Adam E. ; Pan, Chin ; Qiu, Wei ; Mastracchio, Anthony ; Wilson, Ashley ; Yang, Haopeng
Abstract:The 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.
