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The fucosylation of glycoproteins regulates diverse physiological processes. Inhibitors that can control cellular levels of protein fucosylation have consequently emerged as being of high interest. Anticancer antibodies primarily exert their activity using a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC). Afucosylated antibodies have potential superiority over the standard glycoforms found on antibodies; they enable targeting of low-density antigens and up to 50-fold improvement in ADCC activity as compared to their fucosylated counterparts.

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At Carbaform Biosciences, we have developed a simple platform to produce antibodies with tunable levels of fucosylation. Beta-carbafucose is a rationally-designed fucose derivative which acts as a potent metabolic inhibitor of fucosylation. Our research shows that CRB-050, when applied to the FDA-approved therapeutic antibody Herceptin, enabled the production of afucosylated antibody with no effects on cell growth nor antibody yield. Furthermore, our approach has no risk of incorporating sugar analogues into antibody glycan, which is a complication of using other leading fucosylation inhibitors.

Carbaform's proprietary compound, CRB-050, can conveniently tune the extent of protein and, more specifically, antibody fucosylation by simply adding the compound to cell media. Further, unlike with genetically engineered cell lines, CRB-050 blocks antibody fucosylation even when done at large scale in bioreactors without affecting viable cell density or protein titer. Importantly, Carbaform has developed a synthetic route to CRB-050 that allows its production at scale using an inexpensive, chromatography-free, and GMP amenable process.

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