Radiocopper in BCMA-targeted immunotheranostics of myeloma.

Abstract

Background: The theranostic potential of copper-64 (PET imaging) and copper-67 (SPECT imaging and therapy) is increasingly recognized. This work investigates the performance of this 'true' matched pair in a preclinical radioimmunotheranostic setting that utilizes experimental monoclonal antibodies (mAbs) directed against B cell maturation antigen (BCMA), a transmembrane glycoprotein that has emerged as a critical target for the treatment of multiple myeloma (MM).

Methods: The commercially available BCMA-directed mAbs MAB193 and Vicky-1 were modified with the bispidine N₂py₄ enabling chelation of radiocopper, and their binding affinity was determined using surface plasmon resonance and flow cytometry. Pharmacokinetics and tumor uptake of the copper-64-labeled mAbs were determined in mice bearing subcutaneous myeloma xenografts, using PET. The best-performing mAb was included in a pilot study on therapeutic use with copper-67 in U266 myeloma-bearing mice, involving dose monitoring and dose predictions for humans based on quantitative SPECT.

Results: After bioconjugation, both [⁶⁴Cu]Cu-N₂py₄-MAB193 and [⁶⁴Cu]Cu-N₂py₄-Vicky-1 maintained low nanomolar BCMA binding affinity. In PET imaging, [⁶⁴Cu]Cu-N₂py₄-MAB193 showed the highest uptake in U266 myeloma xenografts and the lowest normal tissue background, e.g., achieving a tumor-to-muscle contrast of 14.9 within 48 h. [⁶⁷Cu]Cu-N₂py₄-MAB193 delivered absorbed doses up to 1.26 Gy/MBq in U266 myeloma xenografts and reduced the tumor mass at total doses above 52 Gy. Predicted human effective doses were below 35.3 µSv/MBq for immunoPET and 162 µSv/MBq for radioimmunotherapy/immunoSPECT.

Conclusion: The fundamental efficacy of copper-64 and copper-67 in BCMA-targeted immunotheranostics of MM promises both precise PET-based dose planning as well as radioimmunotherapy in combination with highly sensitive SPECT-based dose monitoring, as demonstrated by the theranostic capabilities of [⁶⁴Cu/⁶⁷Cu]Cu-N₂py₄-MAB193 in tumor-bearing mice. The results provide a strong incentive for incorporating the CopperNostics approach into the further development of BCMA-targeted radioimmunotheranostic agents, including precise tailoring of their pharmacokinetic properties to the physical half-life of copper-67.