Science ( IF 56.9 ) Pub Date : 2021-03-05 , DOI: 10.1126/science.abc8697 Emily Han-Chung Hsiue 1, 2, 3 , Katharine M Wright 2, 4, 5 , Jacqueline Douglass 1, 2, 3 , Michael S Hwang 1, 2, 3 , Brian J Mog 1, 2, 3, 6 , Alexander H Pearlman 1, 2, 3 , Suman Paul 1, 2, 3, 7 , Sarah R DiNapoli 1, 2, 3 , Maximilian F Konig 1, 2, 3, 8 , Qing Wang 1, 2, 9 , Annika Schaefer 1, 2, 3 , Michelle S Miller 2, 4, 5 , Andrew D Skora 1, 2 , P Aitana Azurmendi 2, 4, 5 , Michael B Murphy 10 , Qiang Liu 1, 2, 3 , Evangeline Watson 1, 2, 3 , Yana Li 4 , Drew M Pardoll 5, 7 , Chetan Bettegowda 1, 3, 11 , Nickolas Papadopoulos 1, 3, 5, 12 , Kenneth W Kinzler 1, 3, 5 , Bert Vogelstein 1, 2, 3, 5, 12 , Sandra B Gabelli 4, 7, 13 , Shibin Zhou 1, 3, 5
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.
中文翻译:
靶向源自常见 TP53 突变的新抗原
TP53(肿瘤蛋白p53)是最常见的突变癌症驱动基因,但靶向突变肿瘤抑制基因的药物,如TP53,目前还没有。在这里,我们描述了对最常见的TP53具有高度特异性的抗体的鉴定突变(R175H,其中 175 位的精氨酸被组氨酸取代)与细胞表面上常见的人类白细胞抗原-A (HLA-A) 等位基因复合。我们描述了这种特异性的结构基础及其转化为免疫治疗剂:双特异性单链双抗体。尽管癌细胞表面的 p53 肽-HLA 复合物密度极低,但双特异性抗体有效地激活 T 细胞以裂解在体外和小鼠体内呈递新抗原的癌细胞。这种方法理论上可以用于靶向含有以传统方式难以靶向的突变的癌症。