title: Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation.
abstract: To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 ((211)At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with (211)At doses less than or equal to 405 μCi/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest (211)At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with (211)At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning.
authors: Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Ave N., Seattle, WA 98109-1024, USA.
authors: Yun
authors: Y
authors: Chen
authors: Brian
authors: B
authors: Kornblit
authors: Donald K
authors: DK
authors: Hamlin
authors: George E
authors: GE
authors: Sale
authors: Erlinda B
authors: EB
authors: Santos
authors: D Scott
authors: DS
authors: Wilbur
authors: Barry E
authors: BE
authors: Storer
authors: Rainer
authors: R
authors: Storb
authors: Brenda M
authors: BM
authors: Sandmaier
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D001246:Astatine / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001782:Blood Donors; D001896:Boron Compounds / Q000737:chemistry; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000276:immunology / Q000528:radiation effects; D019337:Hematologic Neoplasms / Q000097:blood / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D017493:Leukocyte Common Antigens / Q000276:immunology*; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D001896:Boron Compounds; C119788:dodecaborate; D017493:Leukocyte Common Antigens; D001246:Astatine