Lohmueller Jason J, Ham James D, Kvorjak Michael, Finn Olivera J
University of Pittsburgh School of Medicine, Department of Immunology, Pittsburgh, PA USA.
Carnegie Mellon University, Department of Biomedical Engineering, Pittsburgh, PA USA.
Oncoimmunology. 2017 Oct 26;7(1):e1368604. doi: 10.1080/2162402X.2017.1368604. eCollection 2017.
Chimeric antigen receptor T cells (CAR-Ts) are promising cancer therapeutics. However, since cancer cells can lose the CAR-targeted antigen and avoid destruction, targeting multiple antigens with multiple CARs has been proposed. We illustrate here a less cumbersome alternative, anti-tag CARs (AT-CARs) that bind to tags on tumor-targeting antibodies. We have created novel AT-CARs, using the affinity-enhanced monomeric streptavidin 2 (mSA2) biotin-binding domain that when expressed on T cells can target cancer cells coated with biotinylated antibodies. Human T cells expressing mSA2 CARs with CD28-CD3ζ and 4-1BB-CD3ζ signaling domains were activated by plate-immobilized biotin and by tumor cells coated with biotinylated antibodies against the tumor-associated antigens CD19 and CD20. Furthermore, mSA2 CAR T cells were capable of mediating cancer cell lysis and IFNγ production in an antibody dose-dependent manner. The mSA2 CAR is a universal AT-CAR that can be combined with biotinylated tumor-specific antibodies to potentially target many different tumor types.
嵌合抗原受体T细胞（CAR-T细胞）是很有前景的癌症治疗手段。然而，由于癌细胞可能会丢失CAR靶向的抗原并避免被破坏，因此有人提出用多种CAR靶向多种抗原。我们在此展示了一种不那么繁琐的替代方法，即抗标签CAR（AT-CAR），它能与肿瘤靶向抗体上的标签结合。我们利用亲和力增强的单体抗生物素蛋白链菌素2（mSA2）生物素结合结构域创建了新型AT-CAR，当在T细胞上表达时，它可以靶向包被有生物素化抗体的癌细胞。表达带有CD28-CD3ζ和4-1BB-CD3ζ信号结构域的mSA2 CAR的人T细胞，可被平板固定的生物素以及包被有针对肿瘤相关抗原CD19和CD20的生物素化抗体的肿瘤细胞激活。此外，mSA2 CAR T细胞能够以抗体剂量依赖的方式介导癌细胞裂解和产生IFNγ。mSA2 CAR是一种通用的AT-CAR，可与生物素化的肿瘤特异性抗体结合，有可能靶向许多不同的肿瘤类型。
