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Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors

1
School of Medicine, Department of Radiation Oncology, University of Minnesota, Minneapolis, MN 55455 USA
2
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
3
College of Veterinary Medicine, Department of Veterinary Clinical Sciences, University of Minnesota, St Paul, MN 55108, USA
4
School of Medicine, Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 956; https://doi.org/10.3390/biom10060956
Received: 29 May 2020 / Revised: 20 June 2020 / Accepted: 22 June 2020 / Published: 25 June 2020
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target. We discuss the development and testing of a bispecific LTT targeting EGFR and urokinase-type plasminogen activator receptor (uPAR) as two attractive targets implicated in tumor growth and in the regulation of the tumor microvasculature in solid tumors. In vitro and mouse xenograft studies have shown that EGFR-targeted bispecific angiotoxin (eBAT) is effective against human solid tumors. Canine studies have shown that eBAT is both safe and effective against canine hemangiosarcoma, which is physiologically similar to human angiosarcoma. Finding the appropriate dosing strategy and sequencing of eBAT administration, in combination with other therapeutics, are among important factors for future directions. Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may have a role in reducing toxicity in comparative oncologic trials in dogs. View Full-Text
Keywords: EGFR (epidermal growth factor receptor); uPAR (urokinase-type plasminogen activator receptor); bispecific; angiogenesis; immunotoxin; LTT (ligand-targeted toxin); KDEL EGFR (epidermal growth factor receptor); uPAR (urokinase-type plasminogen activator receptor); bispecific; angiogenesis; immunotoxin; LTT (ligand-targeted toxin); KDEL
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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.

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