title: 2-fluoro-RNA oligonucleotide CD40 targeted aptamers for the control of B lymphoma and bone-marrow aplasia.
abstract: Recent studies have underscored the importance of immunomodulatory antibodies in the treatment of solid and hematological tumors. ODN-Aptamers are rising as a novel class of drugs that can rival therapeutic antibodies. The success of some of the current cancer immunotherapy approaches in oncological patients depends on the intrinsic antigenicity of each tumor as has recently been disclosed, and it is hampered in those patients that are treated with myeloablative chemotherapy or radiotherapy, which induce profound immunosuppression. CD40 agonist and antagonist molecules offer a new therapeutic alternative which has the potential to generate anticancer effects by different mechanisms. HS-SELEX was performed to identify high-affinity aptamers against CD40, and three therapeutic CD40 constructs were engineered as: CD40 agonist aptamer, CD40 antagonist aptamer and CD40 agonistic aptamer-shRNA chimera. It is shown that CD40 agonist aptamers can be used to promote bone-marrow aplasia recovery. CD40 antagonist aptamers are revealed to have a direct antitumor effect on CD40-expressing B-cell lymphoma in vitro and in vivo. Further, in order to identify a therapeutic reagent that will generate the optimal conditions for cancer immunotherapy (antigen-presenting cell activation, tumor antigenicity enhancement and bone-marrow aplasia recovery), CD40 agonist aptamer-shRNA chimera was generated to target the inhibition of the Nonsense mRNA Mediated Decay (NMD) to tumor cells.
authors.affiliation: CIMA, Program of Molecular Therapies, Aptamer Unit, Universidad de Navarra, Avenida Pio XII 55, 31008, Pamplona, Spain.
authors.forename: Mario Martinez
authors.initials: MM
authors.lastname: Soldevilla
authors.affiliation: CIMA, Program of Molecular Therapies, Aptamer Unit, Universidad de Navarra, Avenida Pio XII 55, 31008, Pamplona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Villanueva
authors.affiliation: Ross University School of Medicine, PO Box 266 Roseau, Portsmouth, Dominica.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bendandi
authors.affiliation: Clínica Universidad de Navarra, Avenida Pío XII, 36, 31008, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Inoges
authors.affiliation: Clínica Universidad de Navarra, Avenida Pío XII, 36, 31008, Pamplona, Spain.
authors.forename: Ascensión
authors.initials: A
authors.lastname: López-Díaz de Cerio
authors.affiliation: CIMA, Program of Molecular Therapies, Aptamer Unit, Universidad de Navarra, Avenida Pio XII 55, 31008, Pamplona, Spain. Electronic address: fpasordri@unav.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pastor
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology*; D019013:CD40 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000378:metabolism; D005453:Fluorescence; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D059365:Nonsense Mediated mRNA Decay; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D052156:SELEX Aptamer Technique; D016019:Survival Analysis
chemical_list: D052157:Aptamers, Nucleotide; D019013:CD40 Antigens; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases; C551743:Smg1 protein, mouse
keywords: Aptamer; Immunology; Lymphoma; Therapeutics