Householder Karsten D, Xiang Xinyu, Jude Kevin M, Deng Arthur, Obenaus Matthias, Wilson Steven C, Chen Xiaojing, Wang Nan, Garcia K Christopher
Department of Molecular and Cellular Physiology, Stanford University School of Medicine; Stanford, CA 94305 USA.
Program in Immunology, Stanford University School of Medicine; Stanford, CA 94305 USA.
bioRxiv. 2024 Dec 20:2024.12.16.628822. doi: 10.1101/2024.12.16.628822.
T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-MHC in cancer immunotherapy. Here, we designed a α-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by HLA-A02, achieving high on-target specificity with nanomolar affinity (K = 9.5 nM). The structure of the TCRm/pMHC complex at 2.05 Å resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informed screen of 14,363 HLA-A02 peptides correctly predicted two off-target peptides, yet our TCRm maintained a wide therapeutic window as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused α-helical TCR mimics.
T细胞受体（TCR）模拟物为癌症免疫治疗中肿瘤特异性靶向肽-MHC提供了一个很有前景的平台。在此，我们设计了一种针对由HLA-A02呈递的NY-ESO-1肽的α-螺旋TCR模拟物（TCRm），以纳摩尔亲和力（K = 9.5 nM）实现了高靶向特异性。TCRm/pMHC复合物在2.05 Å分辨率下的结构揭示了一种类似TCR的刚性对接模式，对向上的NY-ESO-1侧链有着不同寻常程度的聚焦，这表明降低脱靶反应性的潜力。事实上，对14363种HLA-A02肽进行的基于结构的筛选正确预测了两种脱靶肽，但我们的TCRm作为T细胞衔接子仍保持着较宽的治疗窗口。这些结果为利用聚焦肽的α-螺旋TCR模拟物精确靶向肿瘤抗原开辟了一条道路。
