Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model
Abstract
:1. Introduction
2. Results
2.1. The Effect of eBAT on Immunocompetent CD-1 Mice
2.2. The Effect of Mouse eBAT (meBAT) on Immunocompetent Mice
2.3. The Effect of eBAT and meBAT on Tumor-Bearing BNX Mice
2.4. The Effect of eBAT and meBAT on uPAR Knockout Tumor-Bearing B6 Mice
2.5. The Effect of eBAT on Dogs with Hemangiosarcoma
3. Discussion
4. Materials and Methods
4.1. eBAT and meBAT
4.2. Cell Lines
4.3. Mice
4.4. Dogs
4.5. Non-GLP eBAT Toxicology Study in Healthy Mice
4.6. meBAT Toxicology Study in Healthy Mice
4.7. eBAT and meBAT Toxicology Study in Mice Harboring Canine Hemangiosarcoma Xenografts
4.8. eBAT and meBAT Toxicology Study in Wildtype Mice and uPAR KO Mice Harboring Syngeneic Sarcomas
4.9. Statistical Analysis
4.10. Canine Experimental Clinical Study 1 (SRCBST-1)
4.11. Canine Experimental Clinical Study 2 (SRCBST-2)
4.12. Canine Study 3 (eBAT-CC)
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Group | |||
---|---|---|---|
µg/kg | Biochemical | Anatomic Liver | Anatomic GI |
Saline | None | None | None |
40 | None | (Periportal hepatocellular microvesicular vacuolar change and hepatocellular regeneration) | None |
80 | None | None | |
140 | Dose-dependent increase in hepatocellular enzymes | (Dose-dependent portal biliary hyperplasia, lymphoplasmacytic inflammation, periportal microvesicular change, hemorrhage, coagulation, necrosis, and apoptosis) | None |
200 | dose dependent changes in several parameters of liver function (hypoglycemia, hypoalbuminemia, and hyperbilirubinemia) | (Villous atrophy and submucosal edema) |
Grade | ALT | ALP | AST |
---|---|---|---|
1 | 4 | 2 | 0 |
2 | 3 | 0 | 3 |
3 | 3 | 0 | 2 |
4 | 0 | 0 | 0 |
Group | Mouse Strain | Subcutaneous Injection | Drug/Dose |
---|---|---|---|
1 | Wildtype | MC-17 fibrosarcoma cells | eBAT (50 µg/kg) |
2 | Wildtype | MC-17 fibrosarcoma cells | meBAT (50 µg/kg) |
3 | Wildtype | MC-17 fibrosarcoma cells | Saline |
4 | uPAR-KO | D10 uPAR-KO cells | eBAT (50 µg/kg) |
5 | uPAR-KO | D10 uPAR-KO cells | meBAT (50 µg/kg) |
6 | uPAR-KO | D10 uPAR-KO cells | Saline |
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Dicovitsky, R.H.; Schappa, J.T.; Schulte, A.J.; Lang, H.P.; Kuerbitz, E.; Roberts, S.; DePauw, T.A.; Lewellen, M.; Winter, A.L.; Stuebner, K.; et al. Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model. Toxins 2024, 16, 376. https://doi.org/10.3390/toxins16090376
Dicovitsky RH, Schappa JT, Schulte AJ, Lang HP, Kuerbitz E, Roberts S, DePauw TA, Lewellen M, Winter AL, Stuebner K, et al. Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model. Toxins. 2024; 16(9):376. https://doi.org/10.3390/toxins16090376
Chicago/Turabian StyleDicovitsky, Rose H., Jill T. Schappa, Ashley J. Schulte, Haeree P. Lang, Ellen Kuerbitz, Sarah Roberts, Taylor A. DePauw, Mitzi Lewellen, Amber L. Winter, Kathy Stuebner, and et al. 2024. "Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model" Toxins 16, no. 9: 376. https://doi.org/10.3390/toxins16090376