TY - JOUR
T1 - Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737
AU - Fitzgerald, David J
AU - Moskatel, Elizabeth
AU - Ben-Josef, Gal
AU - Traini, Roberta
AU - Tendler, Tara
AU - Sharma, Ashima
AU - Antignani, Antonella
AU - Mussai, Francis
AU - Wayne, Alan
AU - Kreitman, Robert J
AU - Pastan, Ira
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
U2 - 10.3109/10428194.2011.569961
DO - 10.3109/10428194.2011.569961
M3 - Article
C2 - 21599608
SN - 1029-2403
VL - 52 Suppl 2
SP - 79
EP - 81
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
ER -