A deimmunized bispecific ligand-directed toxin that shows an impressive anti-pancreatic cancer effect in a systemic nude mouse orthotopic model.

Abstract

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.

• Authors: Seunguk Oh, Deborah A Todhunter, Angela Panoskaltsis-Mortari, Donald J Buchsbaum, Shoko Toma, Daniel A Vallera
• Journal: Pancreas (Pancreas) Vol. 41 Issue 5 Pg. 789-96 (Jul 2012) ISSN: 1536-4828 [Electronic] United States
• PMID: 22258068 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• Antineoplastic Agents
• Exotoxins
• Immunotoxins
• Ligands
• Interleukin-4
• Epidermal Growth Factor

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Bispecific (immunology, pharmacology)
• Antineoplastic Agents (immunology, pharmacology)
• Cell Line, Tumor
• Epidermal Growth Factor (genetics, immunology)
• Exotoxins (genetics, immunology)
• Humans
• Immunotoxins (genetics, immunology, pharmacology)
• Interleukin-4 (genetics, immunology)
• Ligands
• Male
• Mice
• Mice, Nude
• Mutation
• Pancreatic Neoplasms (drug therapy, immunology, pathology)
• Pseudomonas (genetics, immunology)
• Time Factors
• Tumor Burden (drug effects, immunology)
• Xenograft Model Antitumor Assays