Comprehensive analysis of ¹⁷⁷Lu‐lilotomab satetraxetan in lymphoma cell lines: Implications for precision radioimmunotherapy and combination schemes

Summary 177 Lu‐lilotomab satetraxetan (Betalutin) is an anti‐CD37 radioimmunoconjugate evaluated as a single administration therapy for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B‐cell lymphoma (DLBCL). 177 Lu‐lilotomab satetraxetan treatment is well tolerated and shows consistent activity in most of the patients evaluated so far. Herein, we investigated the activity of 177 Lu‐lilotomab satetraxetan in a panel of 55 lymphoma cell lines of B‐ and T‐cell origin. CD37‐targeted radioimmunotherapy was more effective in CD37‐positive B‐cell lymphomas ( n = 46) than in CD37‐negative T‐cell lymphomas ( n = 9). Focusing on DLBCL cell lines, mutations such as BCL2 or MYC translocations were not correlated to sensitivity. However, BCL2 expression was higher in resistant than in sensitive GCB‐DLBCL cell lines, and the addition of the BCL2 inhibitor venetoclax showed synergism when added to the radioimmunoconjugate. Finally, the pattern of activity of 177 Lu‐lilotomab satetraxetan differed from what was achieved with a CD37‐targeting antibody–drug conjugate or with Rituximab cyclophosphamide hydroxydaunorubicin (doxorubicin) oncovin prednisone (R‐CHOP), indicating the potential benefit of the beta‐emitter payload. This systematic analysis of the responsiveness of lymphoma cell lines to CD37‐targeting radioimmunotherapy consolidated 177 Lu‐lilotomab satetraxetan as a promising compound for the treatment of CD37‐positive malignancies and identified candidate biomarkers and co‐targets to detect and overcome cancer cell‐intrinsic resistance mechanisms.