title: Bismuth 213-labeled anti-CD45 radioimmunoconjugate to condition dogs for nonmyeloablative allogeneic marrow grafts.
abstract: To lower treatment-related mortality and toxicity of conventional marrow transplantation, a nonmyeloablative regimen using 200 cGy total-body irradiation (TBI) and mycophenolate mofetil (MMF) combined with cyclosporine (CSP) for postgrafting immunosuppression was developed. To circumvent possible toxic effects of external-beam gamma irradiation, strategies for targeted radiation therapy were investigated. We tested whether the short-lived (half-life, 46 minutes) alpha-emitter bismuth 213 ((213)Bi) conjugated to an anti-CD45 monoclonal antibody (mAb) could replace 200 cGy TBI and selectively target hematopoietic tissues in a canine model of nonmyeloablative DLA-identical marrow transplantation. Biodistribution studies using iodine 123-labeled anti-CD45 mAb showed uptake in blood, marrow, lymph nodes, spleen, and liver. In a dose-escalation study, 7 dogs treated with the (213)Bi-anti-CD45 conjugate ((213)Bi dose, 0.1-5.9 mCi/kg [3.7-218 MBq/kg]) without marrow grafts had no toxic effects other than a mild, reversible suppression of blood counts. On the basis of these studies, 3 dogs were treated with 0.5 mg/kg (213)Bi-labeled anti-CD45 mAb ((213)Bi doses, 3.6, 4.6, and 8.8 mCi/kg [133, 170, and 326 MBq/kg]) given in 6 injections 3 and 2 days before grafting of marrow from DLA-identical littermates. The dogs also received MMF (10 mg/kg subcutaneously twice daily the day of transplantation until day 27 afterward) and CSP (15 mg/kg orally twice daily the day before transplantation until 35 days afterward). The therapy was well tolerated except for transient elevations in levels of transaminases in 3 dogs, followed by, in one dog, ascites. All dogs had prompt engraftment and achieved stable mixed hematopoietic chimerism, with donor contributions ranging from 30% to 70% after more than 27 weeks of follow-up. These results will form the basis for additional studies in animals and later the design of clinical trials using (213)Bi as a nonmyeloablative conditioning regimen with minimal toxicity.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. bsandmai@fhcrc.org
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Bethge
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: Erlinda B
authors.initials: EB
authors.lastname: Santos
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D001729:Bismuth / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000379:methods*; D004285:Dogs; D004307:Dose-Response Relationship, Radiation; D006085:Graft Survival; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D017493:Leukocyte Common Antigens / Q000276:immunology*; D023421:Models, Animal; D004369:Pentetic Acid; D011868:Radioisotopes; D014018:Tissue Distribution; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011868:Radioisotopes; D004369:Pentetic Acid; D017493:Leukocyte Common Antigens; D001729:Bismuth