Non-fucosylated therapeutic antibodies: the next generation of therapeutic antibodies

Abstract

Therapeutic antibody IgG1 has two N-linked oligosaccharide chains bound to the Fc region. The oligosaccharides are of the complex biantennary type, composed of a trimannosyl core structure with the presence or absence of core fucose, bisecting N-acetylglucosamine (GlcNAc), galactose, and terminal sialic acid, which gives rise to structural heterogeneity. Both human serum IgG and therapeutic antibodies are well known to be heavily fucosylated. Recently, antibody-dependent cellular cytotoxicity (ADCC), a lytic attack on antibody-targeted cells, has been found to be one of the critical effector functions responsible for the clinical efficacy of therapeutic antibodies such as anti-CD20 IgG1 rituximab (Rituxan((R))) and anti-Her2/neu IgG1 trastuzumab (Herceptin((R))). ADCC is triggered upon the binding of lymphocyte receptors (FcgammaRs) to the antibody Fc region. The activity is dependent on the amount of fucose attached to the innermost GlcNAc of N-linked Fc oligosaccharide via an alpha-1,6-linkage, and is dramatically enhanced by a reduction in fucose. Non-fucosylated therapeutic antibodies show more potent efficacy than their fucosylated counterparts both in vitro and in vivo, and are not likely to be immunogenic because their carbohydrate structures are a normal component of natural human serum IgG. Thus, the application of non-fucosylated antibodies is expected to be a powerful and elegant approach to the design of the next generation therapeutic antibodies with improved efficacy. In this review, we discuss the importance of the oligosaccharides attached to the Fc region of therapeutic antibodies, especially regarding the inhibitory effect of fucosylated therapeutic antibodies on the efficacy of non-fucosylated counterparts in one medical agent. The impact of completely non-fucosylated therapeutic antibodies on therapeutic fields will be also discussed.

Advantages of AlaGln as an additive to cell culture medium: use with anti-CD20 chimeric antibody-producing POTELLIGENT™ CHO cell lines

“…However, these methods can be expensive, and to reduce the overall cost of therapeutic MAbs, several approaches have been tried to upgrade the efficacy per unit dose. For example, antibodies lacking fucose can be produced in a-1, 6-fucosyltransferase (FUT8) knockout Chinese hamster ovary (CHO) cell lines (POTELLIGENT TM technology) and have been reported to show higher antibodydependent cellular cytotoxicity (ADCC) (Mori et al 2007;Shields et al 2002;Shinkawa et al 2003). In addition, use of larger scale production facilities can reduce the cost per unit weight, and tanks are now available that contain more than 10,000 L of culture medium (Birch and Racher 2006;Brian 2009).…”

Glycoengineered Yeast as an Alternative Monoclonal Antibody Discovery and Production Platform

“…In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent (Ferrara et al, 2011). Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies with enhanced ADCC activity is currently being developed for better efficacy (Mori et al, 2007;Ysebaert et al, 2010;Robak and Robak, 2011).…”

“…Preclinical studies have shown that antibody dependant cell-mediated cytotoxicity (ADCC) is an important part of mechanism of action of therapeutic monoclonal antibodies, especially anti-cancer antibodies, such as Trastumab and Rituximab against tumors (Mori et al, 2007). Some clinical evidence based on genetic analysis of leukocyte receptor (Fc R) polymorphisms of cancer patients treated with anti-CD20 IgG1 Rituximab and anti-HER2 IgG1 Trastuzumab therapies has revealed that ADCC is one of the critical mechanisms responsible for the clinical efficacy of these therapeutic antibodies (Musolino et al, 2008;Kim et al, 2006;Cartron et al, 2002).…”

Tailoring recombinant protein quality by rational media design

“…It is not surprising that increasing effector functions by means of Fc-glycosylation engineering has gained considerable interest 196 . As a consequence, the pharmaceutical industry has allocated remarkable research efforts to glycan engineering, aiming to increase ADCC of mAbs, in particular by limiting core fucosylation 48,65,91,[308][309][310][311][312][313] . Many reports have described the significant increase of ADCC whenever the fucose attachment to the glycan backbone was precluded 42,196,308,312 .…”