(211)Astatine-Conjugated Monoclonal CD45 Antibody-Based Nonmyeloablative Conditioning for Stem Cell Gene Therapy.
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.
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.
Christopher R
CR
Burtner
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.
Devikha
D
Chandrasekaran
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.
Erlinda B
EB
Santos
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.|2 Division of Oncology, Department of Medicine, University of Washington , Seattle, WA 98195.
Brian C
BC
Beard
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.|2 Division of Oncology, Department of Medicine, University of Washington , Seattle, WA 98195.
Jennifer E
JE
Adair
3 Radiation Oncology Department, University of Washington , Seattle, WA 98195.
Donald K
DK
Hamlin
3 Radiation Oncology Department, University of Washington , Seattle, WA 98195.
D Scott
DS
Wilbur
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.|2 Division of Oncology, Department of Medicine, University of Washington , Seattle, WA 98195.
Brenda M
BM
Sandmaier
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.|2 Division of Oncology, Department of Medicine, University of Washington , Seattle, WA 98195.
Hans-Peter
HP
Kiem
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000633:toxicity; D001246:Astatine / Q000737:chemistry*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D017493:Leukocyte Common Antigens / Q000276:immunology*; D019076:Transgenes; D019172:Transplantation Conditioning / Q000379:methods*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D017493:Leukocyte Common Antigens; D045643:DNA Repair Enzymes; D001246:Astatine