Tb Radioimmunotherapy as a Treatment for CD30-Positive Lymphomas.

in Journal of nuclear medicine : official publication, Society of Nuclear Medicine by Elisa Rioja-Blanco, Yara Banz, Christoph Schlapbach, Urban Novak, Tanja Chiorazzo, Nicole L Bertschi, Peter Bernhardt, Pascal V Grundler, Nicholas P van der Meulen, Michal Grzmil, Roger Schibli, Martin Behe

TLDR

  • The study evaluates the effectiveness of two radioimmunotherapy agents, Tb and Lu, in targeting CD30-positive T-cell lymphoma cells and finds superior cytotoxicity and biodistribution for Tb.
  • Tb's unique emission characteristics may enhance its therapeutic potential, and further studies are needed to optimize its use and combination with other therapies.

Abstract

Lymphoma remains a significant health concern, necessitating innovative treatment approaches.Tb'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 comparedTb radioimmunotherapy targeting CD30-a receptor overexpressed in lymphomas-withLu-radiolabeled therapy to evaluate the effect ofTb's additional emission of conversion and Auger electrons.The ability ofTb- andLu-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 [Tb]Tb-cAC10 and [Lu]Lu-cAC10 were submitted for quantitative proteomics and phosphoproteomics analyses, followed by bioinformatics analysis.[Tb]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 forTb. Importantly, a single administration of theTb-radiolabeled compound significantly prolonged survival time compared with an equal injected activity of [Lu]Lu-cAC10 (median survival, 41 d vs. 21 d). Phosphoproteomic analysis revealed that both [Lu]Lu-cAC10 and [Tb]Tb-cAC10 induced alterations in pathways regulating DNA damage response and cell cycle, among others, withTb inducing more pronounced changes than didLu.Tb 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 ofTb overLu.

Overview

  • The study compares the effectiveness of two radioimmunotherapy agents, Tb and Lu, in targeting CD30-positive T-cell lymphoma cells.
  • Tb emits ultra-short-range conversion and Auger electrons, as well as medium-energy β-particles, which may enhance its ability to eliminate single cells and small clusters.
  • The primary objective of the study is to evaluate the cytotoxicity, biodistribution, and therapeutic effect of Tb and Lu radiolabeled anti-CD30 antibodies in a xenograft mouse model.

Comparative Analysis & Findings

  • Tb demonstrated superior and CD30-specific cytotoxicity across a panel of T-cell lymphoma cell lines compared to Lu.
  • In vivo studies showed a favorable biodistribution for Tb, with high tumor uptake and a higher tumor-absorbed dose.
  • Phosphoproteomic analysis revealed that both agents induced alterations in pathways regulating DNA damage response and cell cycle, with Tb inducing more pronounced changes than Lu.

Implications and Future Directions

  • The study suggests that Tb radioimmunotherapy may be an effective therapy for CD30-positive T-cell lymphomas, and its unique emission characteristics may enhance its therapeutic potential.
  • Future studies should investigate the optimal dosing and administration schedule of Tb, as well as its combination with other therapies.
  • Invasive phosphoproteomics analysis may provide valuable insights into the biologic processes and pathways regulated by radioimmunotherapy administration, facilitating the development of more effective therapies.
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