Targeted myeloablation with 225-Actinium-labeled CD45-targeting antibody: An effective approach for bone marrow transplantation

Introduction: Radiolabeled anti-CD45 antibodies have shown clinical potential for targeted myeloablative conditioning prior to bone marrow (BM) transplant (BMT). CD45 is an attractive target for conditioning as it is highly expressed in all nucleated immune cells including hematopoietic stem cells, lymphoid and myeloid cells. The potent alpha-emitter 225- Actinium (²²⁵Ac) is a promising radionuclide for targeted conditioning, with high linear energy transfer (80-100 keV/μm) over a short path length, and a long 9.9-day half-life. In this study we have evaluated the tolerability and myeloablative effects of ²²⁵Ac-labelled anti-mouse pan-CD45 antibody clone 30F11 in mice for targeted conditioning prior to BMT.

Methods: The 30F11 antibody was conjugated to the bifunctional chelator DOTA and then labeled with ²²⁵Ac to generate ²²⁵Ac-30F11. CD45.2 mice were injected intravenously with 500, 250 and 100 nCi of ²²⁵Ac-30F11. Four days after conditioning, mice received BMT that was isolated from congenic CD45.1 mice and engraftment as determined by donor chimerism was evaluated over time. Blood samples were collected at regular intervals for up to 3 months and evaluated for BM engraftment and hemotoxicity. Result: 500 nCi ²²⁵Ac-30F11 was found to be a maximum tolerated dose for this myeloablation modality. Mice treated with 250 and 100 nCi of ²²⁵Ac-30F11 demonstrated effective myeloablative conditioning and donor BM engraftment in a dose-dependent manner without any long-term hematological toxicity. Conclusion: The pan-CD45-targeting antibody 30F11 armed with ²²⁵Ac appears to be a safe and potent targeted conditioning approach for BMT. This data supports the development of CD45 targeted ablation prior to BMT using ²²⁵Ac-armed antibodies.