Radioimmunotherapy with bismuth-213 as conditioning for nonmyeloablative allogeneic hematopoietic cell transplantation in dogs: a dose deescalation study.
BACKGROUND
Using a canine model of nonmyeloablative hematopoietic cell transplantation (HCT), the authors demonstrated that pretransplant radioimmunotherapy with the alpha-emitter bismuth-213 (Bi) coupled to anti-CD45 or anti-T-cell receptor alphabeta (TCRalphabeta) monoclonal antibodies (mAb), together with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine A (CsA), achieved stable engraftment of dog leukocyte antigen (DLA)-identical marrow. Engraftment was achieved with doses of 3.6 to 8.8 mCi/kg Bi, but signs of liver toxicity were noted in all dogs. To find a safe and effective dose for further trials, the authors performed a dose deescalation study in 15 dogs with 2.7 to 0.8 mCi/kg Bi.


METHODS
Bi was linked to the mAb using the metal-binding chelate CHX-A"-DTPA. All dogs received three to six injections of Bi linked to anti-CD45 or anti-TCRalphabeta mAb followed by marrow grafts from DLA-identical littermates and postgrafting MMF and CsA.


RESULTS
During follow-up of greater than 30 weeks, engraftment remained stable in all evaluable dogs conditioned with 1.4 to 2.1 mCi/kg Bi-anti-CD45 or 2.0 to 2.7 mCi/kg Bi-anti-TCRalphabeta. Only one dog conditioned with 1.5 mCi/kg Bi-anti-TCRalphabeta had stable engraftment, whereas two rejected their grafts. In both groups, all dogs conditioned with less than 1.3 mCi/kg Bi rejected their grafts. No signs of graft-versus-host disease or other toxicities were noted. Only mild and transient elevation of liver function tests occurred in 4 of 15 dogs.


CONCLUSIONS
This study demonstrates that dose deescalation of radioimmunotherapy with Bi labeled to anti-CD45 or anti-TCRalphabeta as conditioning for nonmyeloablative HCT minimizes toxicity without compromising engraftment. With a dose of 2 mCi/kg Bi, further trials using radioimmunotherapy with Bi for nonmyeloablative HCT seem feasible.
Bethge
Wolfgang A
WA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Wilbur
D Scott
DS
Storb
Rainer
R
Hamlin
Donald K
DK
Santos
Erlinda B
EB
Brechbiel
Martin W
MW
Sandmaier
Brenda M
BM
D000818:Animals; D001729:Bismuth / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods; D017493:Leukocyte Common Antigens / Q000276:immunology; D023421:Models, Animal; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D033581:Stem Cell Transplantation / Q000379:methods*; D014184:Transplantation, Homologous / Q000276:immunology*
D011868:Radioisotopes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017493:Leukocyte Common Antigens; D001729:Bismuth