earticle

영어

The anti-CD20 antibody, Rituximab has been used for the treatment of B-cell non- Hodgkin's lymphoma (NHL). However, resistance or no responsiveness of some patients has evoked lots of endeavors to improve antibody efficacy through antibody engineering. The therapeutic efficacy of monoclonal antibody generally depends on the carbohydrate moiety linked to the Fc region. Especially, antibody dependent cell- mediated cytotoxicity (ADCC) has been known to be dramatically enhanced by fucose reduction. In this study we have specifically modulated the fucose residue of antibody by expressing therapeutic antibody in CHO cell that contains mutant forms of alpha- 1,6-fucosyltransferase (FUT8) and/or alpha-L-fucosidases. The modified CHO clones with these mutants were selected on the basis of FACS using LCA lectin assay. Compared to unmodified antibody therapeutics, glyco-engineered antibodies showed around 30% reduced fucose content based on the glycan analysis. As a result, these molecules had about 4-fold increase in FcrRIIIa binding activity than that of the original antibody, and up to 5-fold in ADCC using PBMC and B-lymphoma cell system with no effect on complement dependent cytotoxicity (CDC). Therapeutic efficacy of glycol- engineered antibody in B cell lymphoma mouse model could be improved at least over 2-fold when compared to Rituximab. Taken together all these results, a new strategy using FUT8 and/or fucosidase mutants could be applied to enhance therapeutic efficacy of monoclonal antibody.