AbbVie Inc., North Chicago, Illinois.
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Ther. 2024 Jul 2;23(7):949-960. doi: 10.1158/1535-7163.MCT-23-0518.
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.
生发中心 B 细胞（ABC）亚群是弥漫性大 B 细胞淋巴瘤（DLBCL）的一个亚型，其特征为慢性 B 细胞受体信号转导，并且当采用标准疗法治疗时，与不良预后相关。在 ABC-DLBCL 中，MALT1 是一种核心酶，可被 B 细胞受体的刺激或信号通路上游成分的功能获得性突变持续激活，使其成为一个有吸引力的治疗靶点。我们发现了一种新型小分子抑制剂 ABBV-MALT1，它能够在 ABC-DLBCL 临床前模型中选择性地抑制 B 细胞信号，导致强烈的细胞生长抑制和异种移植物抑制。我们还确定了 ABBV-MALT1 的一种合理的联合治疗伙伴，即 BCL2 抑制剂 venetoclax，当联合使用时，在临床前模型中能显著协同作用，产生深入且持久的反应。这项工作突出了 ABBV-MALT1 单药治疗和与 venetoclax 联合治疗作为 ABC-DLBCL 患者有效治疗选择的潜力。
