近日，美国约翰霍普金斯大学Shibin Zhou等研究人员合作实现对来源于常见TP53突变的新抗原靶向。该项研究成果于2021年3月1日在线发表在《科学》杂志上。

研究人员报道了一个抗体，其可高度特异性地识别最常见的TP53突变（R175H，其中第175位的精氨酸被组氨酸取代，该蛋白与细胞表面上一个常见的人类白细胞抗原-A（HLA-A）等位基因进行结合）。研究人员报道了这种特异性的结构基础及其向免疫治疗剂的转化：一种双特异性单链双抗体。尽管癌细胞表面上的p53肽-HLA复合物密度极低，但双特异性抗体能够有效激活T细胞，从而裂解在体外和小鼠体内呈递新抗原的癌细胞。

从理论上讲，该方法可用于靶向那些含有以常规方式难以靶向的突变型癌症。 

据介绍，TP53是最常见的突变的癌症驱动基因，但靶向突变的肿瘤抑制基因（如TP53）的药物尚未开发。

附：英文原文

Title: Targeting a neoantigen derived from a common TP53 mutation

Author: Emily Han-Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Qing Wang, Annika Schaefer, Michelle S. Miller, Andrew D. Skora, P. Aitana Azurmendi, Michael B. Murphy, Qiang Liu, Evangeline Watson, Yana Li, Drew M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Sandra B. Gabelli, Shibin Zhou

Issue&Volume: 2021/03/01

Abstract: TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen–A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.

DOI: 10.1126/science.abc8697

Source: https://science.sciencemag.org/content/early/2021/02/26/science.abc8697