CD37 定向抗体和基于细胞的方法已显示出临床前和有希望的早期临床活性。 Naratuximab emtansine (Debio 1562, IMGN529) 是一种抗体药物偶联物 (ADC)，其中包含与美登木素生物碱 DM1 偶联的抗 CD37 单克隆抗体作为有效负载，在淋巴瘤患者中具有作为单药和与利妥昔单抗联合使用的活性。我们在 54 个淋巴瘤模型中研究了 naratuximab emtansine 及其游离有效负载，将其活性与 CD37 表达相关联，表征了两种耐药机制，并确定了提供协同作用的组合伙伴。该活性（主要是细胞毒性）在 B 细胞淋巴瘤细胞系中比 T 细胞淋巴瘤细胞系更有效。长时间暴露于 ADC 后，一种弥漫性大 B 细胞淋巴瘤 (DLBCL) 细胞系由于 CD37 基因双等位基因缺失而对 ADC 产生耐药性。 CD37 丢失后，我们还观察到 IL6 和相关转录本的上调。重组IL6导致耐药性。抗 IL6 抗体托珠单抗改善了 ADC 在 CD37 细胞中的细胞毒活性。在第二种模型中，耐药性是通过 PIK3CD 激活突变维持的，对 PI3Kδ 抑制的敏感性增加，并且功能依赖性从 MCL1 转换为 BCL2。添加 idelalisib 或 Venetoclax 克服了耐药衍生物的耐药性，并提高了亲本细胞的细胞毒活性。总之，用 naratuximab emtansine 靶向 B 细胞淋巴瘤作为单一药物显示出强大的抗肿瘤活性，这也在具有与较差结果相关的遗传损伤的模型中观察到，例如 MYC 易位和 TP53 失活或 R-CHOP 耐药。耐药 DLBCL 模型确定了 naratuximab emtansine 与靶向 IL6、PI3Kδ 和 BCL2 的药物的活性组合。版权所有 © 2024 美国血液学会。

CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562, IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in lymphoma patients. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of IL6 and related transcripts. Recombinant IL6 led to resistance. Anti-IL6 antibody tocilizumab improved the ADC's cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved the cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous anti-tumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or R-CHOP resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3Kδ, and BCL2.Copyright © 2024 American Society of Hematology.