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Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog
Rose H Dicovitsky1, Jill T Schappa1,2,3, Ashley J Schulte1,2,4
1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
Abstract:
EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated Pseudomonas toxin. Its purpose was to simultaneously target tumors and their vasculature in the tumor microenvironment. In prior studies on mice and dogs, the drug proved efficacious. Here, we report the safety of eBAT in normal wildtype, uPAR knockout, and immunoreplete and immunodeficient tumor-bearing mice, as well as in dogs with spontaneous sarcoma that more closely mirror human cancer onset. In immunocompetent mice, tumor-bearing mice, uPAR knockout mice, and mice receiving species-optimized eBAT, toxicities were mild and self-limiting. Likewise, in dogs with life-threatening sarcoma given dosages found to be biologically active, eBAT was well tolerated. In mice receiving higher doses, eBAT was associated with dose-dependent evidence of liver injury, including portal biliary hyperplasia, oval cell proliferation, lymphoplasmacytic inflammation, periportal hepatocellular microvesicular change, hemorrhage, necrosis, and apoptosis. The results support continuing the clinical development of eBAT as a therapeutic agent for individuals with sarcoma and other cancers.
Insights
Recombinant eBAT, a novel targeted cancer therapy, demonstrated mild, self-limiting toxicities in preclinical models and dogs. Higher doses in mice showed dose-dependent liver injury, supporting further clinical development for sarcoma and other cancers.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Epidermal growth factor receptor (EGFR)-targeted therapies show efficacy but common severe toxicities.
- Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are emerging, with unestablished efficacy and toxicity profiles.
Purpose of the Study:
- To evaluate the safety and tolerability of recombinant eBAT, a novel single-chain molecule targeting tumors and their vasculature.
- To assess eBAT's toxicity in various preclinical models and in dogs with spontaneous sarcoma.
Main Methods:
- Administered eBAT to normal wildtype, uPAR knockout, and tumor-bearing mice (immunoreplete and immunodeficient).
- Evaluated eBAT safety in dogs with spontaneous sarcoma at biologically active doses.
- Monitored for toxicities, including dose-dependent liver injury in mice.
Main Results:
- eBAT exhibited mild and self-limiting toxicities in immunocompetent, tumor-bearing, and uPAR knockout mice.
- Dogs with sarcoma tolerated eBAT well at biologically active dosages.
- Higher eBAT doses in mice induced dose-dependent liver injury, including inflammation, necrosis, and apoptosis.
Conclusions:
- The safety profile of eBAT supports its continued clinical development as a therapeutic agent.
- eBAT shows potential for treating sarcoma and other cancers.
- Further investigation into dose-dependent liver effects is warranted.
