161Tb Radioimmunotherapy as a Treatment for CD30-Positive Lymphomas

Abstract

Lymphoma remains a significant health concern, necessitating innovative treatment approaches. ¹⁶¹Tb’s coemission of ultra-short-range conversion and Auger electrons, with its medium-energy β^–-particles, may enable the elimination of single cells and small clusters present in circulation, improving therapeutic outcomes. In this study, we compared ¹⁶¹Tb radioimmunotherapy targeting CD30—a receptor overexpressed in lymphomas—with ¹⁷⁷Lu-radiolabeled therapy to evaluate the effect of ¹⁶¹Tb’s additional emission of conversion and Auger electrons. Methods: The ability of ¹⁶¹Tb- and ¹⁷⁷Lu-radiolabeled anti-CD30 antibody (cAC10) to reduce cell viability and survival and induce DNA damage was evaluated in vitro in CD30-positive T-cell lymphoma cell lines. The biodistribution, dosimetry, and therapeutic effect of both radioimmunoconjugates were studied in a xenograft mouse model. Xenografts treated with [¹⁶¹Tb]Tb-cAC10 and [¹⁷⁷Lu]Lu-cAC10 were submitted for quantitative proteomics and phosphoproteomics analyses, followed by bioinformatics analysis. Results: [¹⁶¹Tb]Tb-cAC10 demonstrated superior and CD30-specific cytotoxicity across a panel of T-cell lymphoma cell lines. In vivo studies showed a favorable biodistribution, with high tumor uptake (31.0 ± 7.4 percentage of injected activity per mass of tissue after 48 h) and a higher tumor-absorbed dose for ¹⁶¹Tb. Importantly, a single administration of the ¹⁶¹Tb-radiolabeled compound significantly prolonged survival time compared with an equal injected activity of [¹⁷⁷Lu]Lu-cAC10 (median survival, 41 d vs. 21 d). Phosphoproteomic analysis revealed that both [¹⁷⁷Lu]Lu-cAC10 and [¹⁶¹Tb]Tb-cAC10 induced alterations in pathways regulating DNA damage response and cell cycle, among others, with ¹⁶¹Tb inducing more pronounced changes than did ¹⁷⁷Lu. Conclusion: ¹⁶¹Tb radioimmunotherapy was an effective therapy for CD30-positive T-cell lymphomas. To our knowledge, this is the first evaluation of this therapeutic radionuclide for the treatment of hematologic malignancies. Additionally, in vivo phosphoproteomics provided insights into the biologic processes and pathways regulated by radioimmunotherapy administration, further supporting the superior efficacy of ¹⁶¹Tb over ¹⁷⁷Lu.