Faculty Collaboration Database

Anti-CD25 targeted killing of bicistronically transduced cells: a novel safety mechanism against retroviral genotoxicity. Mol Ther 2007 Jun;15(6):1174-81

Date

03/28/2007

Pubmed ID

17387334

DOI

10.1038/sj.mt.6300147

Scopus ID

2-s2.0-34249300506 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Gene therapy for Fabry disease, a deficiency in alpha-galactosidase A (alpha-gal A) activity, has the potential to provide a cure for the disorder with a single treatment. Despite modifications to existing vectors, concerns have arisen regarding the risk of genotoxicity associated with the use of retroviruses. To address safety concerns, we propose that expression of a cell surface protein, human CD25 (huCD25) in a bicistronic format, with any therapeutic gene such as alpha-gal A can provide a target that can be used to kill transduced cells selectively should transformative events occur. We show that an anti-CD25 antibody and immunotoxin can specifically target and eliminate transduced leukemia cells expressing CD25. In a murine leukemia model, antibody treatment reduced tumor burden 32-fold and increased survival compared with untreated mice. Furthermore, after a bone marrow transplant of therapeutically transduced cells into Fabry mice, antibody treatment reduced the number of retrovirally transduced huCD25-expressing cells in the peripheral blood. A systemic loss of transduced cells with functional consequences was also evident in the liver and spleen. This proof-of-principle study demonstrates that a targeted antibody can reduce tumor burden and selectively clear bicistronically transduced hematopoietic cells that express a target antigen, thus acting as a built-in safety mechanism.

Author List

Ramsubir S, Yoshimitsu M, Medin JA

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3T3 Cells
Animals
Antibodies
Cell Line, Tumor
Cell Proliferation
Cell Survival
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Fabry Disease
Genetic Therapy
Genetic Vectors
HeLa Cells
Humans
Interleukin-2 Receptor alpha Subunit
Lentivirus
Leukemia
Mice
Mice, Inbred C57BL
Retroviridae
alpha-Galactosidase