Abstract 1518: Dose optimization and radiation dosimetry of CD45-targeting 225Actinium-armed antibody as a conditioning agent for adoptive cell therapy

Abstract

Abstract Background: Bone marrow transplantation, ex vivo gene therapies targeting hematological disorders, and other forms of adoptive cell therapies (ACT) require complete or partial removal of the host immune cells by a process called conditioning. This is usually accomplished with total body irradiation (TBI) or chemotherapy, but both modalities can result in significant toxicities, especially in elderly patients. As a result, more effective and safe alternatives to TBI and chemotherapy for conditioning prior to ACT are therefore needed. We have recently demonstrated that the murine CD45-targeting antibody 30F11 armed with the beta emitters 131Iodine or 177Lutetium successfully eliminated various cohorts of immune cells in murine models and ensured effective tumor control during adoptive T cell therapy (Dawicki W., et al. Oncotarget 2020). Here we report the results of a dose optimization study and radiation dosimetry results for 30F11 antibody labeled with the powerful alpha emitter 225Actinium (225Ac). Methods: Female C57BL/6 mice were treated with a broad dose range of 225Ac-30F11 antibody (100-500 nCi per mouse). Survival of mice was observed for 25 days post treatment, and white blood cells (WBC), red blood cells (RBC) and hematopoietic stem cells (HSC) were enumerated by flow cytometry. The cellularity of bone marrow in surviving mice was assessed histologically. Radiation dosimetry calculations were performed to yield the doses delivered to the various organs including those with significant numbers of immune cells. Results: The survival study demonstrated that all mice receiving 100 and 250 nCi doses of 225Ac-30F11 survived, 40% survived with 300 nCi, and 0% with the 400 and 500 nCi doses. While the 500 nCi group showed signs of radiation toxicity, the 100-400 nCi doses had no effect on RBC and preserved liver and kidney function. Flow cytometry and histology revealed that up to 30% of WBC and HSC were lost in the 100-250 nCi group, up to 70% in the 300 nCi group and almost complete acellularity of bone marrow was observed in 400 nCi group. Radiation dosimetry calculations determined the absorbed doses to immune organs such as bone marrow and spleen were comparable to those for beta emitters, while the doses to other organs were lower than for beta emitters. Conclusions: This study demonstrates that low doses of an 225Ac-armed CD45-targeting antibody can safely and efficiently reduce the numbers of host immune cells which would be sufficient for gene therapy or adoptive T cell therapy while high doses can completely eliminate host immune cells, thus providing the conditions for bone marrow transplant engraftment and expansion. Citation Format: Ravendra Garg, Qing Liang, Eileen M. Geoghegan, Kevin J. Allen, Wojciech Dawicki, Dale L. Ludwig, Ekaterina Dadachova. Dose optimization and radiation dosimetry of CD45-targeting 225Actinium-armed antibody as a conditioning agent for adoptive cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1518.