Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
Department of Surgery and the Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, IL, USA.
Mol Ther. 2019 Feb 6;27(2):300-313. doi: 10.1016/j.ymthe.2018.12.010. Epub 2018 Dec 14.
T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.
T 细胞受体 (TCRs) 已成为一类新的免疫治疗药物。然而，尽管抗原特异性是适应性免疫的标志，但 TCR 本身并不具备单克隆抗体的高度特异性。尽管这是 T 细胞生物学的必要功能，但由此产生的交叉反应性对 TCR 为基础的治疗开发构成了重大挑战，因为它有可能导致非靶识别和免疫毒性。通过模拟抗体成熟过程和增强亲和力来提高 TCR 特异性的努力可能会无意中加剧 TCR 的交叉反应性。在这里，我们通过展示即使 TCR 中的肽靶向突变也会引入针对与原始靶标具有相似性的肽的新反应性来证明这一点。为了抵消这一点，我们探索了一种新的基于结构的方法，用于在不依赖亲和力的情况下增强 TCR 特异性。用 MART-1 特异性 TCR DMF5 进行测试，我们的方法对 MART-1 同源物的交叉反应性有很小但可辨别的影响，但能够消除 DMF5 对更多不同、不相关表位的交叉识别。我们的研究为使用先进的基于结构的设计技术来提高 TCR 特异性提供了一个原理证明，并为增强 TCR 用于治疗提供了新的途径。
