Cell Line Engineering

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.

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PEOPLE

dr_song

Dr. Song Zhiwei

song_zhiwei@bti.a-star.edu.sg
Senior Principal Scientist

PhD in Biochemistry (1993) University of Michigan, Ann Arbor, USA

Research Focus/Interests

  • Glycosylation of recombinant protein drugs
  • Apoptosis in cultured mammalian cells
  • Developing cell lines to produce follow-on biologics such as therapeutic antibodies
Chan Kah Fai

Dr. Chan Kah Fai

chan_kah_fai@bti.a-star.edu.sg 
Associate Staff Scientist

PhD in Biochemistry (2017), Yong Loo Lin School of Medicine, National University of Singapore

Research Focus/Interests

  • Genetic engineering of novel CHO cell lines for industrial manufacturing of biologics
  • Applications of BTI CHO glycosylation mutant cell lines for production of alternative biomolecules
  • Recombinant fusion proteins and antibodies for therapeutic application
Wang Huashan

Dr. Wang Huashan

wang_huashan@bti.a-star.edu.sg
Associate Staff Scientist

PhD in Molecular genetics (2006), Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Research Focus/Interests

  • Expression of anticancer antibodies in cell lines
  • Development of cell lines for the production of therapeutic antibodies