The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular…

By T. Shinkawa, K. Nakamura, N. Yamane, Emi Shoji-Hosaka, Y. Kanda, Mikiko Sakurada, Kazuhisa Uchida, H. Anazawa, M. Satoh, M. Yamasaki and 2 more. Journal of Biological Chemistry, 2003

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An anti-human interleukin 5 receptor (hIL-5R) humanized immunoglobulin G1 (IgG1) and an anti-CD20 chimeric IgG1 produced by rat hybridoma YB2/0 cell lines showed more than 50-fold higher antibody-dependent cellular cytotoxicity (ADCC) using purified human peripheral blood mononuclear cells as effector than those produced by Chinese hamster ovary (CHO) cell lines. Monosaccharide composition and oligosaccharide profiling analysis showed that low fucose (Fuc) content of complex-type oligosaccharides was characteristic in YB2/0-produced IgG1s compared with high Fuc content of CHO-produced IgG1s. YB2/0-produced anti-hIL-5R IgG1 was subjected to Lens culinaris aggulutin affinity column and fractionated based on the contents of Fuc. The lower Fuc IgG1 had higher ADCC than the IgG1 before separation. In contrast, the content of bisecting GlcNAc of the IgG1 affected ADCC much less than that of Fuc. In addition, the correlation between Gal and ADCC was not observed. When the combined effect of Fuc and bisecting GlcNAc was examined in anti-CD20 IgG1, only a severalfold increase of ADCC was observed by the addition of GlcNAc to highly fucosylated IgG1. Quantitative PCR analysis indicated that YB2/0 cells had lower expression level of FUT8 mRNA, which codes α1,6-fucosyltransferase, than CHO cells. Overexpression of FUT8 mRNA in YB2/0 cells led to an increase of fucosylated oligosaccharides and decrease of ADCC of the IgG1. These results indicate that the lack of fucosylation of IgG1 has the most critical role in enhancement of ADCC, although several reports have suggested the importance of Gal or bisecting GlcNAc and provide important information to produce the effective therapeutic antibody.

Subfields: Immunology, Molecular Biology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/075dff5a60b0f4bec21415c91fd9a40f51f280ec

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Citations in the corpus

Antibody Structure and Function: The Basis for Engineering Therapeutics (2019, background): “Such mAbs may be produced using different methods reported to lead to the successful expression of relatively low level fucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides, such as the control of culture osmolality [411], application of a variant CHO line Lec13 as the ”
Crystal structure of mammalian α1,6-fucosyltransferase, FUT8 (2007, background): “Moreover, the core fucosylation of N-glycans in human immunoglobulin (Ig) G1 was found to regulate antibody-dependent cellular cytotoxicity (ADCC) (Shields et al. 2002; Shinkawa et al. 2003).”
Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose (2011, background): “In particular, a next generation of anticancer antibodies carrying afucosylated glycoforms (13, 14) is currently in clinical development; the most advanced among these is the glycoengineered CD20 antibody obinutuzumab (GA101), currently in phase II/III clinical trials for treatment of non-Hodgkin’s ”
Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate (2004, background): “For example several approaches have been shown to enhance the ability of an antibody to mediate antibody-dependent cell-mediated cytotoxicity by optimizing the structure of the Fc-associated N-linked oligosaccharide (2, 3).”
Treatment of HER2-positive breast cancer: current status and future perspectives (2012, background): “Recombinant antibodies lacking fucose show enhanced FcγR binding and ADCC”
Therapeutic antibodies: successes, limitations and hopes for the future (2009, neutral): “This difference was attributed to the elevated expression of FUT8, the gene coding for a1,6-fucosyltransferase, in the CHO line (Shinkawa et al., 2003).”
Potent antibody therapeutics by design (2006, background): “Reducing the fucose content increases ADCC activity to a greater extent than does increasing the presence of bisecting N -acetylglucosamin”
Therapeutic antibodies for autoimmunity and inflammation (2010, background): “Decreasing the fucose content of the carbohydrates in the Fc region can also enhance ADC”