Glycoengineering in cancer therapeutics:  a review with fucose-depleted trastuzumab as the model.
Experimentally modified trastuzumab antibodies show increased cytotoxic potency when used with human effector cells against HER2-overexpressing human breast cancer cells in vitro and ex vivo. Furthermore, the superior efficacy of 'glycoengineered' trastuzumab has been confirmed in vivo utilizing a preclinical xenograft model of human HER2-amplified, trastuzumab-resistant human breast cancer. The increased cytotoxic potency coupled with other improvements are achieved by a seemingly modest change in trastuzumab's structure, that is, depletion of two α-L-fucose residues from trastuzumab's heavy chains. Fucose-free trastuzumab binds with much greater affinity to human natural killer cells. This improved binding induces much greater antibody-dependent cellular cytotoxicity against HER2-overexpressing cells. The pharmaceutical industry has recognized the advantages of fucose-free therapeutic antibodies and has developed technologies that aim to mass produce such antibodies for human use. Here, we summarize data from multiple academic and pharmaceutical laboratories highlighting fucose depletion of antibodies as a key strategy of glycoengineering in cancer therapeutics. We use fucose-depleted trastuzumab as a model to show the advantages of this new class of anticancer agents. We predict that these advantages will translate clinically into improved therapeutics for many patients including those with HER2-overexpressing neoplasms.
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35249 6823, USA.
Jay J
JJ
Listinsky
Gene P
GP
Siegal
Catherine M
CM
Listinsky
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D005643:Fucose / Q000737:chemistry*; D006801:Humans; D007121:Immunocompetence / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005643:Fucose; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D000068878:Trastuzumab; C508053:ERBB2 protein, human