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. 2012 Feb 2;119(5):1130-8.
doi: 10.1182/blood-2011-09-380436. Epub 2011 Dec 1.

Durable Donor Engraftment After Radioimmunotherapy Using α-Emitter astatine-211-labeled anti-CD45 Antibody for Conditioning in Allogeneic Hematopoietic Cell Transplantation

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Durable Donor Engraftment After Radioimmunotherapy Using α-Emitter astatine-211-labeled anti-CD45 Antibody for Conditioning in Allogeneic Hematopoietic Cell Transplantation

Yun Chen et al. Blood. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Hematologic changes after infusions of 211At–anti-CD45 mAb without bone marrow transplantation. Granulocyte, lymphocyte, and platelet counts in 6 dogs treated with 100 to 618 μCi/kg 211At-labeled anti-CD45 on day 0. The total anti-CD45 dose was 0.5 mg/kg, whereof 10% was administered as unlabeled mAb 1 hour before the radioimmunoconjugate. The solid and dashed curves represent median values from historical controls treated with 200 cGy (n = 13) or 213Bi-anti-CD45 (n = 4) without HCT rescue, respectively.
Figure 2
Figure 2
Peripheral blood granulocyte, lymphocyte, and platelet counts in dogs treated with 211At–anti-CD45 mAb-conditioned nonmyeloablative DLA identical bone marrow transplantation. Eight dogs received 155 to 625 μCi/kg 211At-labeled anti-CD45 mAb on day −3 followed by marrow grafts from a DLA- identical donor on day 0. The total anti-CD45 mAb dose was 0.5 mg/kg, whereof 10% was administered as unlabeled mAb 1 hour before the radioimmunoconjugate. Posttransplant immunosuppression consisted of cyclosporine 15 mg/kg twice daily from day −1 to day 35 and mycophenolate mofetil 10 mg/kg twice daily from day 0 to day 27. The solid and dashed curves represent median values from historical controls conditioned with 200 cGy (n = 5) or 213Bi-anti-CD45 (n = 11), before receiving bone marrow from DLA-identical donors, respectively.
Figure 3
Figure 3
Percentage of donor chimerism in granulocytes, mononuclear cells, and CD3+ in dogs treated with 211At–anti-CD45 mAb-conditioned nonmyeloablative DLA-identical bone marrow transplantation. Eight dogs received 155 to 625 μCi/kg 211At-labeled anti-CD45 mAb on day −3 followed by marrow grafts from a DLA-identical donor on day 0. The total anti-CD45 mAb dose was 0.5 mg/kg, whereof 10% was administered as unlabeled mAb 1 hour before the radioimmunoconjugate.
Figure 4
Figure 4
MLCs and NK assays from 1 dog (H388) treated with 211At–anti-CD45 mAb-conditioned nonmyeloablative DLA-identical bone marrow transplantation. In vitro lymphocyte function from 1 representative dog (H388) treated with 539 μCi/kg 211At-labeled anti-CD45 mAb on day −3 followed by a marrow graft from a DLA-identical donor on day 0. The total anti-CD45 dose was 0.5 mg/kg, whereof 10% was administered as unlabeled mAb 1 hour before the radioimmunoconjugate. Data were obtained before radiolabeled antibody infusion, day −1 before transplantation, and 33 days after transplantation. MLC data are expressed as mean counts per minute from triplicate wells of recipient response to autologous cells, donor cells, cells from an unrelated dog, and to concanavalin A as internal assay control. Error bars represent SEM from 3 wells. In the NK assay, cytotoxicity is expressed as a percentage of specific lysis of target cells (canine thyroid adenocarcinoma cells), calculated using the mean value of triplicate cultures. Effector-to-target ratios were 50:1, 25:1, 12.5:1, and 6.25:1, respectively.
Figure 5
Figure 5
Hepatic and renal function of 8 dogs treated with 211At–anti-CD45 mAb-conditioned nonmyeloablative DLA-identical bone marrow transplantation. Eight dogs received 155 to 625 μCi/kg 211At-labeled anti–CD45 mAb on day −3 followed by marrow grafts from a DLA-identical donor on day 0. Dashed lines in graphs indicate the range of values found in normal dogs.

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