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Hum Gene Ther. 2015 Jun;26(6):399-406. doi: 10.1089/hum.2015.021.

(211)Astatine-Conjugated Monoclonal CD45 Antibody-Based Nonmyeloablative Conditioning for Stem Cell Gene Therapy.

Author information

1
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.
2
2 Division of Oncology, Department of Medicine, University of Washington , Seattle, WA 98195.
3
3 Radiation Oncology Department, University of Washington , Seattle, WA 98195.

Abstract

Most hematopoietic stem cell gene therapy studies require host conditioning to allow for efficient engraftment of gene-modified cells. Conditioning regimens with lower treatment-related toxicities are especially relevant for the treatment of nonmalignant blood disorders, such as hemoglobinopathies and immunodeficiencies, and for patients who are otherwise ineligible for conventional high-dose conditioning. Radioimmunotherapy, which employs an α- or a β-emitting radionuclide conjugated to a targeting antibody, is effective for delivering cytotoxic doses of radiation to a cell type of interest while minimizing off-target toxicity. Here, we demonstrate the feasibility of using a nonmyeloablative dose of a monoclonal anti-CD45 antibody conjugated to the α-emitter Astatine-211 ((211)At) to promote engraftment of an autologous gene-modified stem cell graft in the canine model. The doses used provided myelosuppression with rapid autologous recovery and minimal off-target toxicity. Engraftment levels were low in all dogs and reflected the low numbers of gene-modified cells infused. Our data suggest that a cell dose exceeding 1×10(6) cells/kg be used with nonmyeloablative doses of (211)At-anti-CD45 monoclonal antibodies for sustained engraftment in the dog model.

PMID:
25919226
PMCID:
PMC4492596
DOI:
10.1089/hum.2015.021
[Indexed for MEDLINE]
Free PMC Article

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