Diseased and infected cells can be recognized through peptide antigens presented on the surface of the cell by major histocompatibility complex (MHC) proteins. Whereas the T cell receptor is nature’s solution for recognizing peptide antigen–loaded MHCs, smaller proteins synthesized for this purpose could be transformative for diagnostic tools and immunotherapies. Liu et al., Johansen et al., and Householder et al. developed computational and experimental pipelines to facilitate the rapid design and validation of proteins that could recognize peptides from viral proteins, tumor-associated proteins, or neoantigens when presented by MHC molecules, with high specificity and low off-target recognition (see the Perspective by Hickok and Stromnes). When incorporated as the recognition domain for a chimeric antigen receptor and expressed in T cells, these de novo–designed peptide-MHC binders could induce signaling and on-target cell killing. —Sarah H. Ross
The recognition of intracellular antigens by CD8+ T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from patient material remains complex. We present a rapid de novo minibinder (miBd) design platform leveraging state-of-the-art generative models to engineer miBds targeting the cancer-associated peptide-bound major histocompatibility complex (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1). Incorporating in silico cross-panning enabled computational prescreening of specificity, and molecular dynamics simulations allowed for improved predictability of in vitro success. We identified a high-affinity NY-ESO-1 binder and confirmed its structure using cryo–electron microscopy, which, when incorporated in a chimeric antigen receptor, induced killing of NY-ESO-1+ melanoma cells. We further designed and validated binders to a neoantigen pMHC complex, RVTDESILSY/HLA-A*01:01, with unknown structure, demonstrating the potential for precision immunotherapy.
患病和感染细胞可以通过主要组织相容性复合体 (MHC) 蛋白在细胞表面呈现的肽抗原被识别。虽然T细胞受体是自然界识别负载肽抗原的MHC的解决方案，但为此目的合成的较小蛋白质可能对诊断工具和免疫疗法具有变革性意义。Liu等人、Johansen等人和Householder等人开发了计算和实验流程，以促进快速设计和验证能够识别来自病毒蛋白、肿瘤相关蛋白或新抗原的肽（当由MHC分子呈现时）的蛋白质，具有高特异性和低脱靶识别（参见Hickok和Stromnes的展望）。当将这些从头设计的肽-MHC结合剂作为识别域整合到嵌合抗原受体中并在T细胞中表达时，它们可以诱导信号传导和靶向细胞杀伤。——Sarah H. Ross
CD8+ T细胞通过T细胞受体 (TCRs) 识别细胞内抗原对于对抗感染和癌症的适应性免疫至关重要。然而，从患者材料中鉴定TCRs仍然复杂。我们提出了一个快速从头设计迷你结合剂 (miBd) 的平台，利用最先进的生成模型来设计靶向癌症相关肽结合主要组织相容性复合体 (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1) 的miBds。结合计算机交叉筛选实现了特异性的计算预筛选，分子动力学模拟提高了体外成功率的可预测性。我们鉴定了一个高亲和力的NY-ESO-1结合剂，并使用冷冻电镜确认了其结构，当将其整合到嵌合抗原受体中时，诱导了NY-ESO-1+黑色素瘤细胞的杀伤。我们进一步设计并验证了针对新抗原pMHC复合物RVTDESILSY/HLA-A*01:01的结合剂，该复合物结构未知，展示了精准免疫疗法的潜力。
De novo-designed pMHC binders facilitate T cell–mediated cytotoxicity toward cancer cells
肿瘤(癌症)患者之家