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.

中文翻译：

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抑制 MALT1 和 BCL2 在 B 细胞淋巴瘤模型中诱导协同抗肿瘤活性

弥漫性大 B 细胞淋巴瘤 (DLBCL) 的活化 B 细胞 (ABC) 亚群的特点是慢性 B 细胞受体信号传导，并且在使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，通过刺激 B 细胞受体或信号通路上游组件中的功能获得突变而被组成型激活，使其成为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，它可以在 ABC-DLBCL 临床前模型中选择性地有效关闭 B 细胞信号传导，从而有效抑制细胞生长和异种移植物。我们还在 BCL2 抑制剂 Venetoclax 中确定了 ABBV-MALT1 的合理组合伙伴，当组合使用时，它可以显着协同作用，在临床前模型中引发深度和持久的反应。这项工作强调了 ABBV-MALT1 单药疗法以及与 Venetoclax 联合疗法作为 ABC-DLBCL 患者有效治疗选择的潜力。