Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model-Reference-Cited by-同舟云学术

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

Published:2024-08-26 Issue:9 Volume:16 Page:376
ISSN:2072-6651
Container-title:Toxins
language:en
Short-container-title:Toxins

Author:

Dicovitsky Rose H.¹,Schappa Jill T.¹²³,Schulte Ashley J.¹²⁴,Lang Haeree P.¹²⁵,Kuerbitz Ellen¹,Roberts Sarah¹,DePauw Taylor A.¹²⁴⁶^ORCID,Lewellen Mitzi¹²⁴,Winter Amber L.²⁷,Stuebner Kathy²⁷,Buettner Michelle²⁷,Reid Kelly²⁷,Bergsrud Kelly²⁷,Pracht Sara²⁷,Chehadeh Andrea²⁷,Feiock Caitlin¹²⁷,O’Sullivan M. Gerard²⁴⁸,Carlson Tim⁸,Armstrong Alexandra R.¹^ORCID,Meritet Danielle⁹^ORCID,Henson Michael S.¹²⁴,Weigel Brenda J.²⁴¹⁰,Modiano Jaime F.¹²⁴¹¹¹²¹³¹⁴^ORCID,Borgatti Antonella¹²⁴⁷¹²^ORCID,Vallera Daniel A.²⁴¹⁵^ORCID

Affiliation:

1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA

2. Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA

3. Experimental Surgical Services, Department of Surgery, Medical School, University of Minnesota, Minneapolis, MN 55455, USA

4. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

5. Comparative Molecular Biosciences Graduate Program and DVM-PhD Dual Degree Program, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA

6. Microbiology, Immunology, and Cancer Biology Graduate Program, Medical School, University of Minnesota, Minneapolis, MN 55455, USA

7. Clinical Investigation Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA

8. Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA

9. Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA

10. Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55455, USA

11. Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA

12. Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA

13. Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA

14. Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN 55455, USA

15. Department of Radiation Oncology, Medical School, University of Minnesota, Minneapolis, MN 55455, 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.

Publisher

MDPI AG

Link

https://www.mdpi.com/2072-6651/16/9/376/pdf

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