Comprehensive Analysis of 177Lu-lilotomab Satetraxetan in Lymphoma Cell Lines: Implications for Precision Radioimmunotherapy and Combination Schemes

177Lu-lilotomab satetraxetan (Betalutin) is an anti-CD37 radioimmunoconjugate evaluated as single administration therapy for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). 177Lu-lilotomab satetraxetan treatment is well-tolerated and shows consistent activity in most of the patients evaluated so far. Herein, we investigated the activity of 177Lu-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 negative 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 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 177Lu-lilotomab satetraxetan differed from what was achieved with a CD37-targeting antibody-drug conjugate or with R-CHOP, indicating the potential benefit of the beta-emitter payload. In conclusion, this systematic analysis of the responsiveness of lymphoma cell lines to CD37-targeting radioimmunotherapy consolidated 177Lu-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. ### Competing Interest Statement AHVR-L JD: Nordic Nanovector ASA, employment and equity ownership. KBM, RG, SP: Nordic Nanovector ASA, employment. AJA: travel grant from Floratek Pharma SA. LC: travel grant from HTG Molecular Diagnostics. FB: ADC Therapeutics, Bayer AG, BeiGene, Floratek Pharma, Helsinn, HTG Molecular Diagnostics, Ideogen AG, Idorsia Pharmaceuticals Ltd., Immagene, ImmunoGen, Menarini Ricerche, Nordic Nanovector ASA, Oncternal Therapeutics, Spexis AG; consultancy fee from BIMINI Biotech, Helsinn, Menarini; advisory board fees to institution from Novartis; expert statements provided to HTG Molecular Diagnostics; travel grants from Amgen, Astra Zeneca, Beigene, iOnctura