二聚体 IgA (dIgA) 可以通过 IgA/IgM 聚合免疫球蛋白受体 (PIGR) 在细胞中移动，PIGR 主要表达于粘膜上皮细胞。在这里，我们研究了 dIgA 靶向常见突变的细胞质致癌驱动因素的能力。突变特异性 dIgA（而非 IgG）中和了卵巢癌细胞内的 KRASG12D，并将该致癌驱动因子从肿瘤细胞中排出。 dIgA 结合改变了 KRASG12D 的内体运输，从循环内体中的积累转变为早期/晚期内体中的聚集，通过 dIgA 转胞吞。在细胞培养测定中，KRASG12D 的 dIgA 靶向消除了肿瘤细胞增殖。在体内，KRASG12D 特异性 dIgA1 以依赖 CD8 T 细胞的方式限制 KRASG12D 突变的卵巢癌和肺癌的生长。 IDH1R132H 特异的 dIgA 可减少结肠癌的生长，证明其能有效靶向与表面受体无关的细胞质致癌驱动剂。 KRASG12D 的 dIgA 靶向比小分子 KRASG12D 抑制剂更有效地限制肿瘤生长，支持了这种方法治疗人类癌症的潜力。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.