Data from Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma

• DOI: 10.1158/1535-7163.c.7311485.v1
• Publication Date: 2024-07-02T10:55:36Z
• Authors: Joshua P. Plotnik; Adam E. Richardson; Haopeng Yang; Estela Rojas; Velitchka Bontcheva; Colleen Dowell; Sydney Parsons; Ashley Wilson; Vida Ravanmehr; Christine Will; Paul Jung; Haizhong Zhu; Sarathy Karunan P...; Sanjay C. Panchal; Raghuveer Singh Mali; Frederick J. Kohl...; Ryan A. McClure; Cyril Y. Ramathal; Mariam D. George; Manisha Jhala; Nathaniel L. Elsen; Wei Qiu; Russell A. Judge; Chin Pan; Anthony Mastracchio; Jared Henderson; Jonathan A. Meulb...; Michael R. Green; William N. Pappano

<div>Abstract<p>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.</p></div>