Addition of Astatine-211-Labeled Anti-CD45 Antibody to TBI as Conditioning for DLA-Identical Marrow Transplantation: A Novel Strategy to Overcome Graft Rejection in a Canine Presensitization Model: “Radioimmunotherapy to Overcome Transfusion-Induced Sensitization”

Abstract

In a canine model of presensitization using donor blood transfusions, 100% of historical control dogs receiving 9.2 Gy total body irradiation (TBI) conditioning before dog leukocyte antigen (DLA)-identical marrow grafts had graft rejection. In this presensitization model, we investigated whether the addition of monoclonal antibody (mAb)-based targeted radioimmunotherapy (RIT) with astatine-211 (211At) to TBI could overcome graft rejection. 211At is an alpha-particle-emitting isotope that has a short path length, very high energy, and a short t½ of 7.2 hours, which allowed targeting radiation to the T cells responsible for graft rejection. Normal canine recipients were given three preceding transfusions of unirradiated whole blood on days -24, -17, and -10 before transplant from their DLA-identical marrow donors. 211At-anti-CD45 mAb was administered on day -3, and TBI followed by marrow grafts on day 0. Six of the 7 dogs (86%) achieved sustained engraftment as assessed by 100% donor chimerism in mononuclear cells, granulocytes, and CD3+ T cells. One dog receiving the lowest CD34+ cell content (0.35×106 cells/kg) rejected the graft. There were no late rejections in dogs followed up to 1 year. Graft-versus-host disease was seen in one dog. 211At-anti-CD45 mAb in combination with TBI as conditioning was successful in abrogating graft rejection in 86% of dogs in this presensitization model. 211At-anti-CD45 mAb conditioning with TBI may serve as a novel promising strategy to overcome graft rejection in heavily transfused patients with red cell disorders.