Graduate Program in Cancer Biology and.
Department of Surgery, Department of Cell and Developmental Biology, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
J Clin Invest. 2022 Feb 15;132(4). doi: 10.1172/JCI157168.
A challenge in cancer treatment is targeting cancer cells while sparing normal cells. Thus, identifying cancer-specific neoepitopes is an active research area. Neoepitopes are generated by the accumulation of mutations; however, deadly cancer types, including pancreatic cancer, have a low mutational burden and, consequently, a paucity of neoantigens. In this issue of the JCI, Lim, Zhou, and colleagues describe a neoepitope generated upon proteolytic cleavage of the transmembrane CUB domain containing protein 1 (CDCP1). CDCP1 is overexpressed in cancer and portends a worse prognosis; previous attempts to target CDCP1 reduced cancer growth, but adversely affected the host. Here, the authors generated an antibody that specifically targeted cleaved CDCP1 (c-CDCP1) and developed a drug conjugate, a vector for radioactive ions, and a mediator of T cell activation. The therapeutics inhibited pancreatic cancer cell growth in vitro and in vivo. Exploiting proteolytic cleavage-derived neoantigens opens an attractive way for specifically targeting cancer cells.
癌症治疗的一个挑战是靶向癌细胞而不损伤正常细胞。因此，鉴定癌症特异性的新抗原是一个活跃的研究领域。新抗原是由突变积累产生的；然而，包括胰腺癌在内的致命癌症类型突变负担较低，因此新抗原数量较少。在本期 JCI 中，Lim、Zhou 和同事描述了一种由跨膜 CUB 结构域包含蛋白 1（CDCP1）蛋白水解切割产生的新抗原。CDCP1 在癌症中过表达，并预示着预后更差；先前靶向 CDCP1 的尝试减少了癌症的生长，但对宿主产生了不利影响。在这里，作者生成了一种特异性靶向切割的 CDCP1（c-CDCP1）的抗体，并开发了一种药物偶联物、放射性离子载体和 T 细胞激活的介质。这些疗法在体外和体内抑制了胰腺癌细胞的生长。利用蛋白水解切割产生的新抗原为特异性靶向癌细胞提供了一种有吸引力的方法。
