Enhanced Efficacy and Safety of 177 Lu-Anti-CD25 Radioimmunotherapy by Combination with Targeted Anticancer Agents

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell malignancy for which improved therapeutic strategies are urgently needed. CD25, the α-chain of the interleukin-2 receptor, is abundantly expressed on malignant T cells and represents a promising target for antibody (Ab)-based radiotherapeutics. We previously developed a cysteine site-specifically labeled 177 Lu-CD25 Ab that induced complete regression of SUDHL1 tumors but caused dose-limiting bone-marrow suppression at high activities. In the present study, we investigated whether combining reduced-dose 177 Lu-CD25 Ab radioimmunotherapy (RIT) with molecularly targeted inhibitors of ALK (crizotinib) or mTOR (everolimus) could enhance antitumor efficacy while minimizing systemic toxicity. In SUDHL1 cells, crizotinib markedly suppressed ALK phosphorylation, while everolimus potently inhibited phosphorylation of p70S6K, confirming effective pathway blockade. Furthermore, both agents dose-dependently suppressed SUDHL1 cell survival. In SUDHL1 xenografts, treatment with low dose (4.625 MBq) 177 Lu-CD25 Ab alone induced tumor apoptosis and reduced p70S6K activation, while combination therapy with either crizotinib or everolimus further increased cleaved PARP levels, indicating enhanced apoptosis. Longitudinal tumor-growth analysis demonstrated that low-dose 177 Lu-CD25 Ab combined with crizotinib or everolimus produced significantly greater tumor-growth suppression than monotherapies, yielding the lowest tumor burdens and smallest area-under-the-curve values. Kaplan–Meier analysis confirmed prolonged survival in all RIT groups, with the strongest benefit observed in the combination cohorts. Importantly, hematologic, hepatic, and renal parameters remained within normal ranges following combination therapy, reflecting the favorable safety profile of reduced-dose 177 Lu-CD25 Ab. These findings demonstrate that targeted inhibition of ALK or mTOR synergizes with CD25-directed 177 Lu RIT to enhance therapeutic efficacy without increasing toxicity. This combinatorial approach enables radiation-dose reduction while preserving antitumor potency, supporting further preclinical and translational development of 177 Lu-CD25-based combination RIT for ALCL and other CD25-expressing malignancies.