Afucosylated monoclonal antibodies

Afucosylated monoclonal antibodies are monoclonal antibodies engineered so that the oligosaccharides in the Fc region of the antibody do not have any fucose sugar units. When antibodies are afucosylated, antibody-dependent cellular cytotoxicity (ADCC) is increased.

Background

Most approved monoclonal antibodies are of the IgG1 isotype, where two N-linked biantennary complex-type oligosaccharides are bound to the Fc region. The Fc region exercises the effector function of ADCC through its interaction with leukocyte receptors of the FcγR family. ADCC is important in the efficacy of cancer antibodies, but with many approved cancer antibodies there is less ADCC than could be desired due to nonspecific IgG competing with the drugs for binding to FcγIIIa on natural killer cells. Afucosylated monoclonal antibodies overcome this problem through improved FcγIIIa binding.[1]

Approaches

The Swiss company GlycArt Biotechnology developed a system using CHO cells, where the cells were engineered to overexpress an enzyme called GnTIII. The effect of this overexpression is to block the formation of fucosylated oligosaccharides on the expressed antibodies. This technology was first reported in 1999 and was the basis of GlycArt Biotechnology.[2]

Roche acquired GlycArt in 2005 in order to acquire technology to afucosylate antibodies. GlycArt Biotechnology had been founded in 2000 as a spin-out company of the Swiss Federal Institute of Technology in Zurich. The first commercial product from the GlycArt acquisition was obinutuzumab, which as Gazyva gained FDA approval in November 2013 for the treatment of chronic lymphocytic leukemia.[3][4][5]

Kyowa Hakko Kirin's "Potelligent" platform uses a CHO cell line in which FUT8 has been knocked out, and which produces antibodies with little to no fucose in the Fc region. The company gained marketing approval in Japan in April 2012 for a monoclonal antibody drug called mogamulizumab which was developed using the platform.[6] The Company's technology was first reported in 2004.[7]

References
  1. Satoh M, Iida S, Shitara K (2006). "Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies". Expert Opin Biol Ther. 6 (11): 1161–73. doi:10.1517/14712598.6.11.1161. PMID 17049014. S2CID 24803037.
  2. Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE (February 17, 1999). "Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity". Nat. Biotechnol. 17 (2): 176–80. doi:10.1038/6179. PMID 10052355. S2CID 20078393.
  3. "Roche - Roche acquires Swiss based GlycArt Biotechnology to strengthen expertise in therapeutic antibody research". roche.com. Archived from the original on 2015-02-05. Retrieved 2015-04-29.
  4. Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after... by Dr. Joël Jean-Mairet. Brussels, March 31, 2011
  5. Cameron F, McCormack PL (2014). "Obinutuzumab: first global approval". Drugs. 74 (1): 147–54. doi:10.1007/s40265-013-0167-3. PMID 24338113. S2CID 40983655.
  6. Yu, X; Marshall, MJE; Cragg, MS; Crispin, M (June 2017). "Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering" (PDF). BioDrugs. 31 (3): 151–166. doi:10.1007/s40259-017-0223-8. PMID 28466278. S2CID 3722081.
  7. Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M, Kusunoki M, Iida S, Nakano R, Wakitani M, Niwa R, Sakurada M, Uchida K, Shitara K, Satoh M (September 5, 2004). "Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity". Biotechnol. Bioeng. 87 (5): 614–22. doi:10.1002/bit.20151. PMID 15352059. S2CID 40137283.
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