Arribas Alberto J, Napoli Sara, Gaudio Eugenio, Herbaux Charles, Cannas Eleonora, Tarantelli Chiara, Bordone-Pittau Roberta, Cascione Luciano, Munz Nicolas, Aresu Luca, Sgrignani Jacopo, Rinaldi Andrea, Kwee Ivo, Rossi Davide, Cavalli Andrea, Zucca Emanuele, Stussi Georg, Stathis Anastasios, Sloss Callum, Davids Matthew S, Bertoni Francesco
Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Blood Adv. 2024 Dec 24;8(24):6268-6281. doi: 10.1182/bloodadvances.2023012291.
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 patients with lymphoma. 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 interleukin-6 (IL-6) and related transcripts. Recombinant IL-6 led to resistance. Anti-IL-6 antibody tocilizumab improved the ADC's cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by a 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 cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous antitumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as Myc Proto-Oncogene (MYC) translocations and TP53 inactivation or R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL-6, PI3Kδ, and BCL2.
靶向CD37的抗体及基于细胞的治疗方法已显示出临床前及早期临床的良好活性。那拉妥昔单抗（Naratuximab emtansine，Debio 1562；IMGN529）是一种抗体药物偶联物（ADC），其包含一种抗CD37单克隆抗体，该抗体与作为有效载荷的美登素（maytansinoid）DM1偶联，在淋巴瘤患者中作为单药及与利妥昔单抗联合使用时均具有活性。我们在54种淋巴瘤模型中研究了那拉妥昔单抗及其游离有效载荷，将其活性与CD37表达相关联，鉴定了两种耐药机制，并确定了具有协同作用的联合用药伙伴。其活性主要为细胞毒性，在B细胞淋巴瘤细胞系中比在T细胞淋巴瘤细胞系中更有效。在长时间暴露于该ADC后，一株弥漫性大B细胞淋巴瘤（DLBCL）细胞系因CD37基因双等位基因缺失而对该ADC产生耐药性。在CD37缺失后，我们还观察到白细胞介素-6（IL-6）及相关转录本的上调。重组IL-6导致耐药。抗IL-6抗体托珠单抗提高了该ADC在CD37+细胞中的细胞毒性活性。在第二个模型中，耐药性由PIK3CD激活突变维持，对PI3Kδ抑制的敏感性增加，且功能依赖性从MCL1转变为BCL2。添加idelalisib或维奈克拉可克服耐药衍生物中的耐药性，并提高亲代细胞中的细胞毒性活性。总之，那拉妥昔单抗靶向B细胞淋巴瘤作为单药显示出强大的抗肿瘤活性，在携带与不良预后相关的基因损伤（如Myc原癌基因（MYC）易位、TP53失活或R-CHOP（利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松）耐药）的模型中也观察到了这种活性。耐药的DLBCL模型确定了那拉妥昔单抗与靶向IL-6、PI3Kδ和BCL2的药物的有效联合用药方案。
