Preparation of 212Pb-labeled monoclonal antibody using a novel 224Ra-based generator solution

Introduction: Alpha-emitting radionuclides have gained considerable attention as payloads for cancer targeting molecules due to their high cytotoxicity. One attractive radionuclide for this purpose is Pb-212, which by itself is a beta-emitter, but acts as an in vivo generator for its short-lived alpha-emitting daughters. The standard method of preparing Pb-212-labeled antibodies requires handling and evaporation of strong acids containing high radioactivity levels by the end user. An operationally easier and more rapid process could be useful since the 10.6 h half-life of Pb-212 puts time constraints on the preparation protocol. In this study, an in situ procedure for antibody labeling with Pb-212, using a solution of the generator nuclide Ra-224, is proposed as an alternative protocol for preparing Pb-212-radioimmunoconjugates. Methods: Radium-224, the generator radionuclide of Pb-212, was extracted from its parent nuclide, Th-228. Lead-212-labeling of the TCMC-chelator conjugated monoclonal antibody trastuzumab was carried out in a solution containing Ra-224 in equilibrium with progeny. Subsequently, the efficiency of separating the Pb-212-radioimmunoconjugate from Ra-224 and other unconjugated daughter nuclides in the solution using either centrifugal separation or a PD-10 desalting size exclusion column was evaluated and compared. Results: Radiolabeling with Pb-212 in Ra-224-solutions was more than 90% efficient after only 30 min reaction time at TCMC-trastuzumab concentrations from 0.15 mg/mL and higher. Separation of Pb-212-labeled trastuzumab from Ra-224 using a PD-10 column was clearly superior to centrifugal separation. This method allowed recovery of approximately 75% of the Pb-212-antibody-conjugate in the eluate, and the remaining amount of Ra-224 was only 0.9 +/- 0.8% (n = 7). Conclusions: The current work demonstrates a novel method of producing Pb-212-based radioimmunoconjugates from a Ra-224-solution, which may be simpler and less time-consuming for the end user compared with the method established for use in clinical trials of Pb-212-TCMC-trastuzumab. (C) 2017 The Authors. Published by Elsevier Inc.