Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T Cell-Mediated Antitumor Responses and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression

Ozgun Kilic, Marcos R.Matos De Souza, Abdulaziz A. Almotlak, Yiao Wang, Jill M. Siegfried, Mark D. Distefano, Carston R. Wagner

Research output: Contribution to journalArticlepeer-review

Abstract

Overexpression of the epidermal growth factor receptor (EGFR) on various cancers makes it an important target for cancer immunotherapy. We recently demonstrated that single-chain variable fragment-based bispecific chemically self-assembled nanorings (CSANs) can successfully modify T cell surfaces and function as prosthetic antigen receptors (PARs) allowing selective targeting of tumor antigens while incorporating a dissociation mechanism of the rings. Here, we report the generation of anti-EGFR fibronectin (FN3)-based PARs with high yield, rapid protein production, predicted low immunogenicity, and increased protein stability. We demonstrated the cytotoxicity of FN3-PARs successfully while evaluating FN3 affinities, CSAN valencies, and antigen expression levels. Using an orthotopic breast cancer model, we showed that FN3-PARs can suppress tumor growth with no adverse effects and FN3-PARs reduced immunosuppressive programmed cell death ligand-1 (PD-L1) expression by downregulating EGFR signaling. These results demonstrate the potential of FN3-PARs to direct selective T cell-targeted tumor killing and to enhance antitumor T cell efficacy by modulating the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)10235-10245
Number of pages11
JournalJournal of medicinal chemistry
Volume63
Issue number18
DOIs
StatePublished - Sep 24 2020

Bibliographical note

Funding Information:
This work was supported by Tychon Bioscience, LLC, the National Cancer Institute CA185627 (CRW), CA247681 (CRW), GM084152 (MDD) and NSF Grant ECCS-2025124 to the Minnesota Nano Center. We thank Mark Sanders and the University of Minnesota University Imaging Centers for experimental and technical support.

PubMed: MeSH publication types

  • Journal Article

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