biostudies-literatureArribas AJSwiss National Science FoundationNCI NIH HHS6268-6281https://www.ebi.ac.uk/biostudies/studies/S-EPMC11699082biostudies-literatureUnknown8(24)<h4>Abstract</h4>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 devBlood advancesPI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas.PMC11699082P01 CA206978182880205601Aresu LKwee IRossi DCascione LCavalli ADavids MSArribas AJNapoli SBertoni FCannas EBordone-Pittau RMunz NStathis ATarantelli CZucca ERinaldi AStussi GSloss CSgrignani JGaudio EHerbaux CfalsePI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas.<h4>Abstract</h4>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 dev2024-01-01T00:00:00Z2024 Dec2026-04-08T19:52:34.254Z2026-04-08T14:31:18.43ZS-EPMC116990823937458310.1182/bloodadvances.2023012291