Anti‐tumor effects of antibodies to L‐type amino‐acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes

Abstract

L‐type amino‐acid transporter 1 (LAT1) disulfide‐linked to the CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In this study, we developed novel anti‐LAT1 mAbs, and demonstrated the internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody‐dependent cellular cytotoxicity, as well as in vivo anti‐tumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side effects of anti‐human LAT1 mAbs in clinical trials. Anti‐human LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney‐derived cells, and this reactivity was significantly decreased by small interfering RNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino‐acid difference between human and macaca LAT1 was shown. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and anti‐human LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and K_A values were increased by anti‐CD98hc mAb, suggesting anti‐LAT1 mAbs detect an epitope on LAT1‐CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anti‐cancer target and that Macaca fascicularis can be used in pre‐clinical studies with anti‐human LAT1 mAbs.

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