Identification of TIM3 2’-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy
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Sandra Hervas-Stubbs1,2,*, Mario M. Soldevilla2,3, Helena Villanueva2,3, Uxua Mancheño1,2, Maurizio Bendandi4, Fernando Pastor2,3,*
1Program Immunology and Immunotherapy, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain
2Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain
3Program of Molecular Therapies, Aptamer Unit, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain
4Ross University School of Medicine, Portsmouth, Commonwealth of Dominica
*These authors have contributed equally to this work
Fernando Pastor, e-mail: [email protected]
Keywords: immunotherapy, cancer, exhaustion, aptamer, therapeutics
Received: September 16, 2015 Accepted: November 27, 2015 Published: December 14, 2015
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.
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