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Incorporation of peptides targeting EGFR and FGFR1 into the adenoviral fibre knob domain, and their evaluation as targeted cancer therapies

Uusi-Kerttula, Hanni, Legut, Mateusz, Davies, James Anthony, Jones, Rachel, Hudson, Emma, Hanna, Louise, Stanton, Richard James, Chester, John D. and Parker, Alan L. 2015. Incorporation of peptides targeting EGFR and FGFR1 into the adenoviral fibre knob domain, and their evaluation as targeted cancer therapies. Human Gene Therapy 26 (5) , pp. 320-329. 10.1089/hum.2015.015

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Abstract

Oncolytic virotherapies based on Adenovirus 5 (Ad5) hold promise as adjunctive cancer therapies; however their efficacy when delivered systemically is hampered by poor target cell specificity and pre-existing anti-Ad5 immunity. Ovarian cancer represents a promising target for virotherapy, since the virus can be delivered locally into the peritoneal cavity. Both Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor Receptor 1 (FGFR1) are over-expressed in the majority of human tumours, including ovarian cancer. To generate adenoviral vectors with improved tumour specificity, we generated a panel of Ad5 vectors with altered tropism for EGFR and FGFR, rather than the natural Ad5 receptor, hCAR. We have included mutations within AB loop the viral fibre knob (KO1 mutation) to preclude interaction with, hCAR, combined with insertions in the HI loop to incorporate peptides that bind either EGFR (peptide YHWYGYTPQNVI, GE11) or FGFR1 (peptides MQLPLAT, M* and LSPPRYP, LS). Viruses were produced to high titres, and the integrity of the fibre protein was validated by Western blotting. The KO1 mutation efficiently ablated hCAR interactions, and significantly increased transduction was observed in hCARlow/EGFRhigh cell lines using Ad5.GE11, whilst transduction levels using Ad5.M* or Ad5.LS were not increased. In the presence of physiological concentrations of human blood clotting factor X (hFX), significantly increased levels of transduction via the hFX-mediated pathway were observed in cell lines, but not in primary tumour cells derived from epithelial ovarian cancer (EOC) ascites samples. Ad5 mediated transduction of EOC cells were completely abolished by the presence of 2.5% serum from patients, whilst surprisingly, incorporation of the GE11 peptide resulted in significant evasion of neutralisation in the same samples. We thus speculate that incorporation of the YHWYGYTPQNVI dodecapeptide within the fibre knob domain may provide a novel means of circumventing pre-existing Ad5 immunity that warrants further investigation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: Mary Ann Liebert
ISSN: 1043-0342
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Jun 2019 19:50
URI: http://orca.cf.ac.uk/id/eprint/72757

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