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bioRxiv · 10.1101/2025.10.01.679886

EGFR-targeted affibody-polyIC polyplex kills EGFR-overexpressing cancer cells without activating the EGFR

Pettikiriarachchi, A.·Ugolev, Y.·Birkinshaw, R.·Wardak, A.·Faux, M.·Adams, T.·Joubran, S.·Shir, A.·Edinger, N.·Zigler, M.·Burgess, A. W.·Levitzki, A.
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Abstract

The epidermal growth factor receptor (EGFR) is aberrantly activated in many human epithelial cancers. This report presents the preparation, purification, and the anti-cancer potency of an anti-EGFR affibody (ZEGFR 1907)-polyethylenimine (PEI)-polyIC complex (PPEA-polyplex). Surface plasmon resonance analysis showed that the ZEGFR 1907 affibody binds tightly to full-length sEGFR with an average equilibrium dissociation constant, KD, value of 6.74 nM. The PPEA-polyplex does not activate the EGFR kinase, but kills tumor cells expressing medium to high levels of EGFR. The PPEA-polyplex stimulates the release of chemotactic cytokines (e.g., GRO-, IFN-{gamma}-inducible protein-10) and promoted PBMC-mediated bystander killing of non-transfected tumor cells. The PPEA-polyplex inhibited the growth of human epidermoid vulval carcinoma (A431) xenografts growing in immunocompromised nude mice. PPEA-polyplexes have the potential to inhibit the growth of tumors in Triple-negative breast cancer (TNBC) patients and other cancers which over-express the EGFR.

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Pettikiriarachchi, A., Ugolev, Y., Birkinshaw, R., Wardak, A., Faux, M., Adams, T., Joubran, S., Shir, A., Edinger, N., Zigler, M., Burgess, A. W., Levitzki, A.. 2025-10-03. EGFR-targeted affibody-polyIC polyplex kills EGFR-overexpressing cancer cells without activating the EGFR. https://doi.org/10.1101/2025.10.01.679886

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