State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
ACS Synth Biol. 2021 May 21;10(5):1176-1183. doi: 10.1021/acssynbio.1c00007. Epub 2021 Apr 15.
Various antibody-redirected immunotherapeutic approaches, including antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor-T (CAR-T) cells, have been devised to produce specific activity against various cancer types. Using genetically encoded unnatural amino acids, we generated a homogeneous Her2-targeted ADC, a T cell-redirected bsAb, and a FITC-modified antibody capable of redirecting anti-FITC CAR-T (switchable CAR-T; sCAR-T) cells to target different Her2-expressing breast cancers. sCAR-T cells showed activity against Her2-expressing tumor cells comparable to that of conventional anti-Her2 CAR-T cells and superior to that of ADC- and bsAb-based approaches. To prevent antigen escape, we designed bispecific sCAR-T cells targeting both the Her2 receptor and IGF1R, which showed an overall improved activity against cancer cells with low Her2 expression. This study increases our understanding of various explored cancer therapeutics and underscores the efficient application of sCAR-T cells as a promising therapeutic option for breast cancer patients with low or heterogeneous antigen expression.
已经设计了各种抗体导向的免疫治疗方法，包括抗体药物偶联物（ADCs）、双特异性抗体（bsAbs）和嵌合抗原受体-T（CAR-T）细胞，以针对各种癌症类型产生特异性活性。我们使用遗传编码的非天然氨基酸生成了一种均质的 Her2 靶向 ADC、一种 T 细胞重定向 bsAb 和一种可重定向抗 FITC CAR-T（可切换 CAR-T；sCAR-T）细胞以靶向不同 Her2 表达乳腺癌的 FITC 修饰抗体。sCAR-T 细胞对表达 Her2 的肿瘤细胞的活性与传统的抗 Her2 CAR-T 细胞相当，优于 ADC 和 bsAb 方法。为了防止抗原逃逸，我们设计了针对 Her2 受体和 IGF1R 的双特异性 sCAR-T 细胞，显示出对低 Her2 表达癌细胞的整体改善活性。这项研究增加了我们对各种探索性癌症治疗方法的理解，并强调了 sCAR-T 细胞作为低或异质性抗原表达乳腺癌患者有前途的治疗选择的有效应用。
