title: Identification of TIM3 2'-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy.
abstract: TIM3 belongs to a family of receptors that are involved in T-cell exhaustion and Treg functions. The development of new therapeutic agents to block this type of receptors is opening a new avenue in cancer immunotherapy. There are currently several clinical trials ongoing to combine different immune-checkpoint blockades to improve the outcome of cancer patients. Among these combinations we should underline PD1:PDL1 axis and TIM3 blockade, which have shown very promising results in preclinical settings. Most of these types of therapeutic agents are protein cell-derived products, which, although broadly used in clinical settings, are still subject to important limitations. In this work we identify by HT-SELEX TIM3 non-antigenic oligonucleotide aptamers (TIM3Apt) that bind with high affinity and specificity to the extracellular motives of TIM3 on the cell surface. The TIM3Apt1 in its monomeric form displays a potent antagonist capacity on TIM3-expressing lymphocytes, determining the increase of IFN-γ secretion. In colon carcinoma tumor-bearing mice, the combinatorial treatment of TIM3Apt1 and PDL1-antibody blockade is synergistic with a remarkable antitumor effect. Immunotherapeutic aptamers could represent an attractive alternative to monoclonal antibodies, as they exhibit important advantages; namely, lower antigenicity, being chemically synthesized agents with a lower price of manufacture, providing higher malleability, and antidote availability.
authors.affiliation: Program Immunology and Immunotherapy, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.|Program of Molecular Therapies, Aptamer Unit, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Soldevilla
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.|Program of Molecular Therapies, Aptamer Unit, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Villanueva
authors.affiliation: Program Immunology and Immunotherapy, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Uxua
authors.initials: U
authors.lastname: Mancheño
authors.affiliation: Ross University School of Medicine, Portsmouth, Commonwealth of Dominica.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bendandi
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.|Program of Molecular Therapies, Aptamer Unit, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pastor
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011494:Protein Kinases; D052156:SELEX Aptamer Technique / Q000379:methods*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D052157:Aptamers, Nucleotide; D016376:Oligonucleotides, Antisense; D019717:Tissue Inhibitor of Metalloproteinase-3; D011494:Protein Kinases; C403405:Smok1 protein, mouse
keywords: aptamer; cancer; exhaustion; immunotherapy; therapeutics