title: A genetic fiber modification to achieve matrix-metalloprotease-activated infectivity of oncolytic adenovirus.
abstract: Selective tumor targeting of oncolytic adenovirus at the level of cell entry remains a major challenge to improve efficacy and safety. Matrix metalloproteases (MMPs) are overexpressed in a variety of tumors and in particular in pancreatic cancer. In the current work, we have exploited the expression of MMPs together with the penetration capabilities of a TAT-like peptide to engineer tumor selective adenoviruses. We have generated adenoviruses containing CAR-binding ablated fibers further modified with a C-terminus TAT-like peptide linked to a blocking domain by an MMP-cleavable sequence. This linker resulted in a MMP-dependent cell transduction of the reporter MMP-activatable virus AdTATMMP and in efficient transduction of neoplastic cells and cancer-associated fibroblasts. Intravenous and intraductal administration of AdTATMMP into mice showed very low AdTATMMP activity in the normal pancreas, whereas increased transduction was observed in pancreatic tumors of transgenic Ela-myc mice. Intraductal administration of AdTATMMP into mice bearing orthotopic tumors led to a 25-fold increase in tumor targeting compared to the wild type fiber control. A replication competent adenovirus, Ad(RC)MMP, with the MMP-activatable fiber showed oncolytic efficacy and increased antitumor activity compared to Adwt in a pancreatic orthotopic model. Reduced local and distant metastases were observed in Ad(RC)MMP treated-mice. Moreover, no signs of pancreatic toxicity were detected. We conclude that MMP-activatable adenovirus may be beneficial for pancreatic cancer treatment.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: José
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Rovira-Rigau
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Jeroni
authors.initials: J
authors.lastname: Luna
authors.affiliation: Laboratori de Recerca Traslacional IDIBELL, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Giménez-Alejandre
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain; Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Vaquero
authors.affiliation: Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: García de la Torre
authors.affiliation: Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Andreu
authors.affiliation: Laboratori de Recerca Traslacional IDIBELL, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Alemany
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. Electronic address: cfillat@clinic.ub.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014161:Transduction, Genetic
chemical_list: D020782:Matrix Metalloproteinases
keywords: Cancer-associated fibroblasts; Metalloproteases; Oncolytic adenovirus; Pancreatic cancer; Tumor targeting