Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
Tri-Institutional MD-PhD Program (Memorial Sloan Kettering Cancer Center, Rockefeller University, Weill Cornell Medical College), New York, New York.
Cancer Immunol Res. 2020 May;8(5):672-684. doi: 10.1158/2326-6066.CIR-19-0745. Epub 2020 Mar 17.
T-cell receptor (TCR)-based therapeutic cells and agents have emerged as a new class of effective cancer therapies. These therapies work on cells that express intracellular cancer-associated proteins by targeting peptides displayed on MHC receptors. However, cross-reactivities of these agents to off-target cells and tissues have resulted in serious, sometimes fatal, adverse events. We have developed a high-throughput genetic platform (termed "PresentER") that encodes MHC-I peptide minigenes for functional immunologic assays and determines the reactivities of TCR-like therapeutic agents against large libraries of MHC-I ligands. In this article, we demonstrated that PresentER could be used to identify the on-and-off targets of T cells and TCR-mimic (TCRm) antibodies using coculture assays or binding assays. We found dozens of MHC-I ligands that were cross-reactive with two TCRm antibodies and two native TCRs and that were not easily predictable by other methods.
基于 T 细胞受体 (TCR) 的治疗性细胞和药物已成为一类新的有效癌症治疗方法。这些治疗方法针对表达 MHC 受体上呈现的细胞内癌症相关蛋白的细胞起作用。然而，这些药物对靶外细胞和组织的交叉反应导致了严重的、有时甚至致命的不良事件。我们开发了一种高通量遗传平台（称为“PresentER”），该平台可对 MHC-I 肽迷你基因进行编码，以进行功能免疫测定，并确定 TCR 样治疗性药物对 MHC-I 配体文库的反应性。在本文中，我们证明了 PresentER 可用于通过共培养测定或结合测定来识别 T 细胞和 TCR 模拟 (TCRm) 抗体的靶内和靶外目标。我们发现了数十种与两种 TCRm 抗体和两种天然 TCR 交叉反应的 MHC-I 配体，而其他方法则不易预测。
