2-fluoro-RNA oligonucleotide CD40 targeted aptamers for the control of B lymphoma and bone-marrow aplasia

• Published in: Biomaterials Vol. 67; pp. 274 - 285
• Main Authors: Soldevilla, Mario Martinez, Villanueva, Helena, Bendandi, Maurizio, Inoges, Susana, López-Díaz de Cerio, Ascensión, Pastor, Fernando
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-10-2015
• Subjects: Advanced Basic Science; Animals; Antibodies; Anticancer properties; Aptamer; Aptamers, Nucleotide - genetics; Aptamers, Nucleotide - metabolism; Base Sequence; Biomedical materials; Bone Marrow - pathology; Cancer; CD40 Antigens - metabolism; Cell Line, Tumor; Cell Proliferation; Dendritic Cells - metabolism; Dentistry; Fluorescence; Immunology; Lymphocyte Activation; Lymphoma; Lymphoma, B-Cell - pathology; Mice; Molecular Sequence Data; Nonsense Mediated mRNA Decay; Patients; Protein-Serine-Threonine Kinases - metabolism; Recovery; RNA, Small Interfering - metabolism; SELEX Aptamer Technique; Surgical implants; Survival Analysis; Therapeutics; Tumors; Aptamer; Immunology; Lymphoma; Therapeutics
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.07.020

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.