OBJECTIVE: The objective was to test a bispecific ligand-directed toxin (BLT), with reduced immunogenicity for enhanced efficacy in targeting orthotopic pancreatic cancer in vivo. METHOD: A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single chain molecule with deimmunized pseudomonas exotoxin (dEGF4KDEL). Key amino acids dictating B-cell generation of neutralizing antitoxin antibodies were mutated. Bioassays were used to determine whether mutation reduced potency, and enzyme-linked immunosorbent assay studies were performed to determine whether antitoxin antibodies were reduced. A genetically altered luciferase MIA PaCa-2 xenograft model was used to image in real time and determine effects on systemic malignant human cancer. Bispecific ligand-directed toxins targeting B cells were used as specificity controls. RESULTS: Deimmunized EGF4KDEL was significantly effective after systemic injection against established orthotopic MIA PaCa-2 pancreatic cancer and selectively prevented metastasis. Mutagenesis significantly reduced antitoxin levels in vivo with no apparent activity loss in vitro. The drug was effective against 3 human pancreatic cancer lines in vitro, MIA PaCa-2, SW1990, and S2VP10. CONCLUSIONS: Despite the metastatic nature of the MIA PaCa-2 orthotopic tumor xenografted in nude mice, high percentages of tumors responded to extended dEGFKDEL treatment resulting in significant anticancer effects and disease-free survivors.
OBJECTIVE: The objective was to test a bispecific ligand-directed toxin (BLT), with reduced immunogenicity for enhanced efficacy in targeting orthotopic pancreatic cancer in vivo. METHOD: A new BLT was created in which both humanepidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single chain molecule with deimmunized pseudomonas exotoxin (dEGF4KDEL). Key amino acids dictating B-cell generation of neutralizing antitoxin antibodies were mutated. Bioassays were used to determine whether mutation reduced potency, and enzyme-linked immunosorbent assay studies were performed to determine whether antitoxin antibodies were reduced. A genetically altered luciferase MIA PaCa-2 xenograft model was used to image in real time and determine effects on systemic malignant humancancer. Bispecific ligand-directed toxins targeting B cells were used as specificity controls. RESULTS: Deimmunized EGF4KDEL was significantly effective after systemic injection against established orthotopic MIA PaCa-2 pancreatic cancer and selectively prevented metastasis. Mutagenesis significantly reduced antitoxin levels in vivo with no apparent activity loss in vitro. The drug was effective against 3 humanpancreatic cancer lines in vitro, MIA PaCa-2, SW1990, and S2VP10. CONCLUSIONS: Despite the metastatic nature of the MIA PaCa-2 orthotopic tumor xenografted in nude mice, high percentages of tumors responded to extended dEGFKDEL treatment resulting in significant anticancer effects and disease-free survivors.
Authors: Ching-Wei D Tzeng; Andrey Frolov; Natalya Frolova; Nirag C Jhala; J Harrison Howard; Donald J Buchsbaum; Selwyn M Vickers; Martin J Heslin; J Pablo Arnoletti Journal: Surgery Date: 2007-01-22 Impact factor: 3.982
Authors: Seunguk Oh; Brad J Stish; Deepali Sachdev; Hua Chen; Arkadiusz Z Dudek; Daniel A Vallera Journal: Clin Cancer Res Date: 2009-09-29 Impact factor: 12.531
Authors: Yu Cao; Khalid A Mohamedali; John W Marks; Lawrence H Cheung; Walter N Hittelman; Michael G Rosenblum Journal: Mol Cancer Ther Date: 2013-03-14 Impact factor: 6.261