title: Cetuximab retargeting of adenovirus via the epidermal growth factor receptor for treatment of intraperitoneal ovarian cancer.
abstract: Gene and virotherapy of ovarian cancer, using type 5 adenovirus (Ad5), has demonstrated good activity in preclinical animal studies, particularly after intraperitoneal administration of virus; however, success in clinical trials has been limited by poor infectivity of ovarian cancer cells and inflammatory responses to Ad5. We previously demonstrated that covalent modification of Ad5 with reactive copolymers on the basis of poly(hydroxypropylmethacrylamide) can shield the virus, offering protection from neutralizing antibodies and enabling retargeting to cancer-upregulated receptors with peptide ligands (basic fibroblast growth factor [bFGF] and murine epidermal growth factor [EGF]). These ligands may be less than ideal for clinical use, however, because they are potential mitogens. Accordingly, in this study we investigated the use of an anti-EGF receptor (EGFR) antibody, cetuximab, to retarget adenoviral transduction of EGFR-positives in vitro and in vivo. Cetuximab retargeting altered the physicochemical characteristics of Ad5, although it did not cause particle aggregation. Although cetuximab stimulated internalization of EGFR, similarly to EGF, it inhibited EGFR phosphorylation. Adenoviral transduction was inhibited after polymer coating, but was rescued in EGFR-positive cells (and not in EGFR-negative cells) by cetuximab retargeting. Cetuximab retargeting of wild-type adenovirus serotype 5 (Ad5WT) prolonged survival in an animal model of human ovarian cancer, similar to unmodified Ad5WT, but polymer coating ameliorated stimulation of adhesion formation. We conclude that polymer coating and covalent attachment of cetuximab successfully retargeted adenovirus to EGFR-positive cells, retained in vivo efficacy of an oncolytic adenovirus, and ameliorated side effects caused by unmodified adenovirus.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford, United Kingdom. jo.morrison@obs-gyn.ox.ac.uk
authors.forename: Joanne
authors.initials: J
authors.lastname: Morrison
authors.forename: Simon S
authors.initials: SS
authors.lastname: Briggs
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Green
authors.forename: Clemens
authors.initials: C
authors.lastname: Thoma
authors.forename: Kerry D
authors.initials: KD
authors.lastname: Fisher
authors.forename: Sean
authors.initials: S
authors.lastname: Kehoe
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Seymour
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007274:Injections, Intraperitoneal; D008689:Methacrylates / Q000737:chemistry; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014161:Transduction, Genetic; D053586:Virus Internalization
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008689:Methacrylates; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000068818:Cetuximab; C032802:hydroxypropyl methacrylate