Identification of TIM3 2'-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy.
Identification of TIM3 2'-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy.
复制标题
DOI：
10.18632/oncotarget.6608
复制
发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Pastor F
中科院分区：
文献类型：
--
作者：
Hervas-Stubbs S;Soldevilla MM;Villanueva H;Mancheño U;Bendandi M;Pastor F
TIM3属于参与T细胞耗竭和Treg功能的受体家族。阻断这类受体的新治疗剂的开发为癌症免疫治疗开辟了一条新的途径。目前有几项临床试验正在进行中，目的是结合不同的免疫检查点阻断来改善癌症患者的预后。在这些组合中，我们应该强调PD1：PDL1轴和TIM3阻断，它们在临床前环境中已经显示出非常有希望的结果。这些类型的治疗剂大多是蛋白质细胞衍生产品，尽管在临床环境中广泛使用，但仍受到重要限制。在这项工作中，我们通过HT-SELEX TIM3鉴定了与细胞表面TIM3的胞外动机具有高亲和力和特异性的非抗原性寡核苷酸适配子(TIM3Apt)。单体形式的TIM3Apt1对表达TIM3的淋巴细胞显示出很强的拮抗能力，决定了干扰素-γ的分泌增加。在结肠癌荷瘤小鼠中，TIM3Apt1与PDL1抗体阻断联合治疗具有协同作用，具有显著的抗肿瘤作用。免疫治疗性适配子具有抗原性低、化学合成剂制造成本低、延展性好和解毒剂易得等优点，是一种很有吸引力的单抗替代品。
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.