Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA.
Department of Surgery, Surgical Sciences, Beth Israel Deaconess Medical Center, CLS 11087, 3 Blackfan Circle, Boston, MA, 02115, USA.
Sci Rep. 2023 Mar 28;13(1):5027. doi: 10.1038/s41598-023-31195-6.
The aberrant expression of the Tn antigen (CD175) on surface glycoproteins of human carcinomas is associated with tumorigenesis, metastasis, and poor survival. To target this antigen, we developed Remab6, a recombinant, human chimeric anti-Tn-specific monoclonal IgG. However, this antibody lacks antibody-dependent cell cytotoxicity (ADCC) effector activity, due to core fucosylation of its N-glycans. Here we describe the generation of an afucosylated Remab6 (Remab6-AF) in HEK293 cells in which the FX gene is deleted (FXKO). These cells cannot synthesize GDP-fucose through the de novo pathway, and lack fucosylated glycans, although they can incorporate extracellularly-supplied fucose through their intact salvage pathway. Remab6-AF has strong ADCC activity against Tn+ colorectal and breast cancer cell lines in vitro, and is effective in reducing tumor size in an in vivo xenotransplant mouse model. Thus, Remab6-AF should be considered as a potential therapeutic anti-tumor antibody against Tn+ tumors.
Tn 抗原（CD175）在人癌表面糖蛋白上的异常表达与肿瘤发生、转移和预后不良有关。为了靶向该抗原，我们开发了 Remab6，一种重组的人嵌合抗 Tn 特异性单克隆 IgG。然而，由于其 N-糖链的核心岩藻糖基化，该抗体缺乏抗体依赖的细胞毒性（ADCC）效应活性。在这里，我们描述了在 FX 基因缺失（FXKO）的 HEK293 细胞中产生无岩藻糖基化的 Remab6（Remab6-AF）。这些细胞不能通过从头途径合成 GDP-岩藻糖，并且缺乏岩藻糖基化的聚糖，尽管它们可以通过完整的补救途径从细胞外摄取岩藻糖。Remab6-AF 在体外对 Tn+结直肠癌和乳腺癌细胞系具有强烈的 ADCC 活性，并能有效减小体内异种移植小鼠模型中的肿瘤大小。因此，Remab6-AF 应被视为针对 Tn+肿瘤的潜在治疗性抗肿瘤抗体。
