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 the effect is to increase antibody-dependent cellular cytotoxicity (ADCC).
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 FcgammaR family. ADCC is important in the efficacy of cancer antibodies, but with many approved cancer antibodies there is less ADCC that 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]
History
The use of afucosylated monoclonal antibodies in therapy was pioneered by two major pharma companies - Kyowa Hakko Kirin and Roche.
- Kyowa Hakko Kirin's POTELLIGENT platform is based on technologies to produce such antibodies.[2] Kyowa Hakko Kirin gained marketing approval in Japan in April 2012 for a monoclonal antibody drug called mogamulizumab which was developed using POTELLIGENT technology.[3]
- Roche acquired the Swiss company GlycArt Biotechnology 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.[4][5][6]
Manufacture
Roche manufactures afucosylated monoclonal antibodies in CHO cells lines, where the cell has been 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.[7]
Kyowa Hakko Kirin manufactures afucosylated monoclonal antibodies in CHO cells in which the endogenous FUT8 gene has been knocked out. Except for the complete depletion of FUT8 expression, Kyowa Hakko Kirin's cell lines are the same as regular CHO cells in terms of morphology, growth kinetics, and productivity. The Company's technology was first reported in 2004.[8]
The US biotechnology company Seattle Genetics developed a technology in 2008 called SEA, short for 'Sugar-Engineered Antibody', in which fucose analogs are added to antibody-expressing CHO cells, resulting in a significant reduction in fucosylation.[9]
Examples
- Obinutuzumab, approved in 2013 by the FDA as a treatment for chronic lymphocytic leukemia[10]
- AstraZeneca's MEDI-551 antibody is an afucosylated antibody that targets CD19
- GlaxoSmithKline's GSK2831781 monoclonal antibody for autoimmune diseases is afucosylated. It entered its first clinical trial in early 2015.
- Seattle Genetics is working on SEA-CD40, an afucosylated antibody that targets CD40.
- KaloBios Pharmaceuticals' KB004 product is an afucosylated antibody for hematologic malignancies.
References
- ↑ "Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. - PubMed - NCBI". ncbi.nlm.nih.gov. Retrieved 2015-04-29.
- ↑ "Enhanced Antibody Activity Technology". Kyowa Hakko Kirin. Kyowa_Hakko_Kirin Research and Development.
- ↑ "New Drug Application Approval for POTELIGEO (Mogamulizumab) Injection in Japan, a Therapeutic Antibody for Adult T-cell Leukemia-Lymphoma (ATL)" (Press release). March 30, 2012.
- ↑ "Roche - Roche acquires Swiss based GlycArt Biotechnology to strengthen expertise in therapeutic antibody research". roche.com. Retrieved 2015-04-29.
- ↑ Presentation: GlycArt Biotechnology AG From Inception to trade sale – and what happened after... by Dr. Joël Jean-Mairet. Brussels, March 31, 2011
- ↑ Cameron F, McCormack PL. Obinutuzumab: first global approval. Drugs. 2014 Jan;74(1):147-54. PMID 24338113
- ↑ 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.
- ↑ 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.
- ↑ WO application 2009135181, Stephen C. Alley, "Methods and compositions for making antibodies and antibody derivatives with reduced core fucosylation", published November 5, 2009, assigned to Seattle Genetics
- ↑ FDA approves Gazyva for chronic lymphocytic leukemia: Drug is first with breakthrough therapy designation to receive FDA approval, FDA NEWS RELEASE, FDA, November 13, 2013, retrieved July 20, 2015