Targeting Tn-positive tumors with an afucosylated recombinant anti-Tn IgG.
Yasuyuki MatsumotoNan JiaJamie Heimburg-MolinaroRichard D CummingsPublished in: Scientific reports (2023)
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.
Keyphrases
- induced apoptosis
- atrial fibrillation
- cell cycle arrest
- cell therapy
- recombinant human
- endothelial cells
- poor prognosis
- endoplasmic reticulum stress
- single cell
- immune response
- dendritic cells
- gene expression
- cell death
- regulatory t cells
- stem cells
- mesenchymal stem cells
- signaling pathway
- free survival
- dna methylation
- transcription factor
- cell surface
- multiple myeloma
- drug delivery
- genome wide identification
- nk cells
- pi k akt