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Identification of TIM3 2′-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy

2015; Impact Journals LLC; Volume: 7; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.6608

1949-2553

Sandra Hervás‐Stubbs, Mario Martínez Soldevilla, Helena Villanueva, Uxua Mancheño, Maurizio Bendandi, Fernando Pastor,

Bacteriophages and microbial interactions

// Sandra Hervas-Stubbs 1, 2, * , Mario M. Soldevilla 2, 3 , Helena Villanueva 2, 3 , Uxua Mancheño 1, 2 , Maurizio Bendandi 4 , Fernando Pastor 2, 3, * 1 Program Immunology and Immunotherapy, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain 2 Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain 3 Program of Molecular Therapies, Aptamer Unit, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain 4 Ross University School of Medicine, Portsmouth, Commonwealth of Dominica * These authors have contributed equally to this work Correspondence to: Fernando Pastor, e-mail: fpasrodri@unav.es Keywords: immunotherapy, cancer, exhaustion, aptamer, therapeutics Received: September 16, 2015 Accepted: November 27, 2015 Published: December 14, 2015 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.