Radioimmunotherapy with bismuth-213 as nonmyeloablative conditioning for marrow transplantation


Wolfgang A. Bethge1, D. Scott Wilbur2, Donald K. Hamlin2, Erlinda B. Santos1, Martin W. Brechbiel3, Rainer Storb1, and Brenda M. Sandmaier1. (1) Transplantation Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. Box 19024, D1-100, Seattle, WA 98102, (2) Department of Radiation Oncology, University of Washington, 2121 N. 35th Street, Seattle, WA 98103, (3) Radiation Oncology Branch, National Cancer Institute, NIH, Bldg 10 Room B3B69, Bethesda, MD 20892
To lower treatment-related toxicity and mortality of conventional marrow transplantation, a nonmyeloablative conditioning regimen using 2 Gy total body irradiation (TBI) and mycophenolate mofetil (MMF) combined with cyclosporine (CSP) for postgrafting immunosuppression was developed in a canine model. To specifically target cells responsible for graft rejection and to circumvent potential toxic effects of external beam irradiation, we investigated replacing TBI by radioimmunotherapy with the alpha-emitting radionuclide bismuth-213 (213Bi). 213Bi was coupled to monoclonal antibodies, either to the panhematopoietic antigen CD45 or the T-cell receptor ab, using the metal binding chelate CHX-A-DTPA. The radioimmunoconjugates were administered in 6 injections on days -3 and -2 followed by transplant of DLA-identical marrow on day 0 and postgrafting immunosuppression with MMF and CSP. Targeting either CD45 or TCRab with the radioimmunoconjugates in combination with postgrafting immunosuppression allowed stable marrow engraftment in a canine model, thus replacing TBI.