EGF‑IL2 bispecific and bivalent EGF fusion toxin efficacy against syngeneic head and neck cancer mouse models

Qiu,Yue; Qi,Zeng; Wang,Zhaohui; Cao,Yu; Lu,Ling; Zhang,Huiping; Mathes,David; Pomfret,Elizabeth A.; Lu,Shi-Long; Wang,Zhirui

doi:10.3892/or.2022.8474

EGF‑IL2 bispecific and bivalent EGF fusion toxin efficacy against syngeneic head and neck cancer mouse models

Authors:
- Yue Qiu
- Zeng Qi
- Zhaohui Wang
- Yu Cao
- Ling Lu
- Huiping Zhang
- David Mathes
- Elizabeth A. Pomfret
- Shi-Long Lu
- Zhirui Wang
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Affiliations: Department of Otolaryngology‑Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA, Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA, Division of Transplant Surgery, Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Published online on: December 27, 2022 https://doi.org/10.3892/or.2022.8474
Article Number: 37
Copyright: © Qiu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The epidermal growth factor receptor (EGFR) remains one of the best molecules for developing targeted therapy for multiple human malignancies, including head and neck squamous cell carcinoma (HNSCC). Small molecule inhibitors or antibodies targeting EGFR have been extensively developed in recent decades. Immunotoxin (IT)‑based therapy, which combines cell surface binding ligands or antibodies with a peptide toxin, represents another cancer treatment option. A total of 3 diphtheria toxin (DT)‑based fusion toxins that target human EGFR‑monovalent EGFR IT (mono‑EGF‑IT), bivalent EGFR IT (bi‑EGF‑IT), and a bispecific IT targeting both EGFR and interleukin‑2 receptor (bis‑EGF/IL2‑IT) were recently generated by the authors. Improved efficacy and reduced toxicity of bi‑EGF‑IT compared with mono‑EGF‑IT in immunocompromised HNSCC mouse models was reported. In the present study, bis‑EGF/IL2‑IT were generated using a unique DT‑resistant yeast expression system and evaluated the in vitro and in vivo efficacy and toxicity of the 3 EGF‑ITs in immunocompetent mice. The results demonstrated that while the three EGF‑ITs had different efficacies in vitro and in vivo against HNSCC, bi‑EGF‑IT and bis‑EGF/IL2‑IT had significantly improved in vivo efficacy and remarkably less off‑target toxicity compared with mono‑EGF‑IT. In addition, bis‑EGF/IL2‑IT was superior to bi‑EGF‑IT in reducing tumor size and prolonging survival in the metastatic model. These data suggested that targeting either the tumor immune microenvironment or enhancing the binding affinity could improve the efficacy of IT‑based therapy. Bi‑EGF‑IT and bis‑EGF/IL2‑IT represent improved candidates for IT‑based therapy for future clinical development.

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