EFFICACY & SAFETY
Glycosylation is the most common post-translational modification of proteins. Many recombinant protein drugs require proper glycosylation in order to be fully functional. The glycans attached to the biotherapeutics can have a dramatic impact on the efficacy and safety of glycoprotein drugs. Proteins such as EPO require high levels of sialylation on their N-glycans as the lack of sialylation results in their rapid removal from the circulation by liver cells.
Alternatively, the lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fc receptor and consequently enhances antibody-dependent cellular toxicity (ADCC). Recombinant glucocerebrosidase (Cerezyme) can enter its target cells, macrophages, only if it carries mannose-terminated N-glycans. These observations highlighted the need for engineering the glycosylation pathways in the host cells in order to produce recombinant protein drugs with optimal and consistent glycans. In the Cell Line Engineering Group 1, our goal is to improve the efficacy and safety of recombinant therapeutics by manipulating the glycosylation pathways in mammalian cells.
Specifically, we aim to generate host cells for the production of therapeutic biologics with enhanced efficacy. Using cytotoxic lectins and zinc-finger nuclease (ZFN) technologies (see figure), our group has isolated/generated novel CHO glycosylation mutants that can produce fucose-free antibodies, recombinant proteins with highly sialylated N-glycans and proteins with mannose-terminated N-glycans.
The number of recombinant monoclonal antibodies approved for the treatment of cancer and inflammatory diseases has dramatically increased in recent years. The biotech industry faces a major challenge in meeting this demand due to the inability to produce recombinant antibodies at high levels. To address these problems, we have developed a technology to optimize the signal peptides for 5 best-selling antibody drugs to permit their efficient secretion and/or production in CHO cells. In collaboration with other groups in BTI, we are currently developing technologies to produce these antibodies as biosimilar therapeutics.
Our group also directs efforts towards investigating the molecular mechanisms that underlies the function, regulation and localization of glycosyltransferases and nucleotide sugar transporters in mammalian cells. Novel techniques have been developed to study the structure-functional relationships of these proteins.