Glycan engineering reveals interrelated effects of terminal galactose and core fucose on antibody-dependent cell-mediated cytotoxicity.

Autor: Zhang Q; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Joubert MK; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Polozova A; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., De Guzman R; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Lakamsani K; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Kinderman F; Drug Product Technologies, Amgen Inc., Thousand Oaks, California, USA., Xiang D; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Shami A; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Miscalichi N; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Flynn GC; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA., Kuhns S; Attribute Sciences, Amgen Inc., Thousand Oaks, California, USA.
Jazyk: angličtina
Zdroj: Biotechnology progress [Biotechnol Prog] 2020 Nov; Vol. 36 (6), pp. e3045. Date of Electronic Publication: 2020 Aug 04.
DOI: 10.1002/btpr.3045
Abstrakt: Antibody-dependent cell-mediated cytotoxicity (ADCC) has been identified as one of the potentially critical effector functions underlying the clinical efficacy of some therapeutic immunoglobin G1 (IgG1) antibodies. It has been well established that higher levels of afucosylated N-linked glycan structures on the Fc region enhance the IgG binding affinity to the FcγIIIa receptor and lead to increased ADCC activity. However, whether terminal galactosylation of an IgG1 impacts its ADCC activity is less understood. Here, we used a new strategy for glycan enrichment and remodeling to study the impact of terminal galactose on ADCC activity for therapeutic IgG1s. Our results indicate that the degree of influence of terminal galactose on in vitro ADCC activity depends on the presence or absence of the core fucose, which is typically linked to the first N-acetyl glucosamine residue of an N-linked glycosylation core structure. Specifically, terminal galactose on afucosylated IgG1 mAbs enhanced ADCC activity with impact coefficients (ADCC%/Gal%) more than 20, but had minimal influence on ADCC activity on fucosylated structures with impact coefficient in the range of 0.1-0.2. Knowledge gained here can be used to guide product and process development activities for biotherapeutic antibodies that require effector function for efficacy, and also highlight the complexity in modulating the immune response through N-linked glycosylation of antibodies.
(© 2020 American Institute of Chemical Engineers.)
Databáze: MEDLINE
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