title: Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737.
abstract: Immunotoxins are antibody-toxin fusion proteins directed to kill cancer cells displaying specific target antigens on their surface. Remarkably, immunotoxins directed to CD22 on hairy cell leukemia have produced complete remissions in approximately 60% of patients enrolled in phase I/II trials. For reasons that are not yet clear, 40% of patients responded less well. In addition, patients with other CD22-positive malignancies have not yet achieved complete remissions. In trying to understand 'resistance' to immunotoxin therapy, a number of challenging issues have been raised. These include insufficient dosing, the production of neutralizing anti-immunotoxin antibodies, poor access to malignant cells, and resistance to toxin killing. In designing immunotoxins, we employ truncated Pseudomonas exotoxin, which enzymatically inactivates protein synthesis and produces cell death in sensitive cells. To begin to address toxin resistance we have explored combination therapy with the BH3-only mimetic, ABT-737. Our results indicate that immunotoxin-ABT combinations often exhibit greater killing activity than either compound alone and in some instances overcome resistance. Expression of high levels of prosurvival Bcl-2 proteins may contribute to toxin resistance.
authors: Laboratory of Molecular Biology, CCR, National Cancer Institute, NIH, HHS, Bethesda, MD, USA. djpf@helix.nih.gov
authors: David J
authors: DJ
authors: Fitzgerald
authors: Elizabeth
authors: E
authors: Moskatel
authors: Gal
authors: G
authors: Ben-Josef
authors: Roberta
authors: R
authors: Traini
authors: Tara
authors: T
authors: Tendler
authors: Ashima
authors: A
authors: Sharma
authors: Antonella
authors: A
authors: Antignani
authors: Francis
authors: F
authors: Mussai
authors: Alan
authors: A
authors: Wayne
authors: Robert J
authors: RJ
authors: Kreitman
authors: Ira
authors: I
authors: Pastan
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