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. 2024 Aug 26;16(9):376.
doi: 10.3390/toxins16090376.

Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model

Rose H Dicovitsky  1 , Jill T Schappa  1   2   3 , Ashley J Schulte  1   2   4 , Haeree P Lang  1   2   5 , Ellen Kuerbitz  1 , Sarah Roberts  1 , Taylor A DePauw  1   2   4   6 , Mitzi Lewellen  1   2   4 , Amber L Winter  2   7 , Kathy Stuebner  2   7 , Michelle Buettner  2   7 , Kelly Reid  2   7 , Kelly Bergsrud  2   7 , Sara Pracht  2   7 , Andrea Chehadeh  2   7 , Caitlin Feiock  1   2   7 , M Gerard O'Sullivan  2   4   8 , Tim Carlson  8 , Alexandra R Armstrong  1 , Danielle Meritet  9 , Michael S Henson  1   2   4 , Brenda J Weigel  2   4   10 , Jaime F Modiano  1   2   4   11   12   13   14 , Antonella Borgatti  1   2   4   7   12 , Daniel A Vallera  2   4   15
Affiliations

Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model

Rose H Dicovitsky et al. Toxins (Basel). .

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.

Keywords: immunotoxin; pharmacology; sarcoma; targeted therapy; toxicity.

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Conflict of interest statement

eBAT is licensed to Anivive Lifesciences, Inc. for therapeutic use in non-human animals.

Figures

Figure 1
Figure 1
Weight in grams plotted over time in days for groups of male (A) and female (B) mice receiving increasing dosages of eBAT. Statistical analysis revealed no differences among any of the groups.
Figure 2
Figure 2
Dose-dependent changes in liver-specific enzymes in mice receiving eBAT. MALT: male ALT; MAST: male AST; FALT: female ALT; FAST: female AST.
Figure 3
Figure 3
(A) Image of mouse liver histopathology from the 200 µg/kg (high dose) group, revealing extensive leukocyte infiltration, inflammation, and tissue damage. (B) Image of normal liver (100×).
Figure 4
Figure 4
C57BL/6 mouse weight in female (A) and male (B) mice when given meBAT shows no differences compared to vehicle control. Statistical analysis revealed no significant differences.
See this image and copyright information in PMC

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References

    1. Leshem Y., Pastan I. Pseudomonas Exotoxin Immunotoxins and Anti-Tumor Immunity: From Observations at the Patient’s Bedside to Evaluation in Preclinical Models. Toxins. 2019;11:20. doi: 10.3390/toxins11010020. - DOI - PMC - PubMed
    1. Tsai A.K., Oh S., Chen H., Shu Y., Ohlfest J.R., Vallera D.A. A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature. J. Neurooncol. 2011;103:255–266. doi: 10.1007/s11060-010-0392-5. - DOI - PMC - PubMed
    1. Oh F., Modiano J.F., Bachanova V., Vallera D.A. Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors. Biomolecules. 2020;10:956. doi: 10.3390/biom10060956. - DOI - PMC - PubMed
    1. Borgatti A., Koopmeiners J.S., Sarver A.L., Winter A.L., Stuebner K., Todhunter D., Rizzardi A.E., Henriksen J.C., Schmechel S., Forster C.L., et al. Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR. Mol. Cancer Ther. 2017;16:956–965. doi: 10.1158/1535-7163.MCT-16-0637. - DOI - PMC - PubMed
    1. Zdanovsky A.G., Chiron M., Pastan I., FitzGerald D.J. Mechanism of action of Pseudomonas exotoxin. Identification of a rate-limiting step. J. Biol. Chem. 1993;268:21791–21799. doi: 10.1016/S0021-9258(20)80612-7. - DOI - PubMed

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