Production, characterization and pharmacokinetic properties of antibodies with N-linked Mannose-5 glycans

Yu, Marcella; Brown, Darren M.; Reed, Chae; Chung, Shan; Lutman, Jeff; Stefanich, Eric; Wong, Anne; Stéphan, Jean-Philippe; Bayer, Robert

doi:10.4161/mabs.20737

Cited by 183 publications

(197 citation statements)

References 39 publications

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“…Many biophysical and biochemical factors have been shown to affect pharmacokinetic behavior of these proteins. These include net charge, 13 local charge clusters, hydrophobicity, 14 off-target binding, 1,9,11,16 glycosylation, 17 interactions with the antigen target, 18,19 and binding to the neonatal Fc receptor (FcRn). 8 FcRn is a membrane-associated heterodimer protein consisting of an Fc-binding a-chain and b 2 -microglobulin subunit that is widely expressed in various organs.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates

Dostálek

Prueksaritanont

Kelley³

2017

mAbs

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Pharmacokinetic studies play an important role in all stages of drug discovery and development. Recent advancements in the tools for discovery and optimization of therapeutic proteins have created an abundance of candidates that may fulfill target product profile criteria. Implementing a set of in silico, small scale in vitro and in vivo tools can help to identify a clinical lead molecule with promising properties at the early stages of drug discovery, thus reducing the labor and cost in advancing multiple candidates toward clinical development. In this review, we describe tools that should be considered during drug discovery, and discuss approaches that could be included in the pharmacokinetic screening part of the lead candidate generation process to de-risk unexpected pharmacokinetic behaviors of Fc-based therapeutic proteins, with an emphasis on monoclonal antibodies.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates

Dostálek

Prueksaritanont

Kelley³

2017

mAbs

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

Tailoring recombinant protein quality by rational media design

Brühlmann

Jordan

Hemberger³

et al. 2015

Biotechnology Progress

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Clinical efficacy and safety of recombinant proteins are closely associated with their structural characteristics. The major quality attributes comprise glycosylation, charge variants (oxidation, deamidation, and C‐ & N‐terminal modifications), aggregates, low‐molecular‐weight species (LMW), and misincorporation of amino acids in the protein backbone. Cell culture media design has a great potential to modulate these quality attributes due to the vital role of medium in mammalian cell culture. The purpose of this review is to provide an overview of the way both classical cell culture medium components and novel supplements affect the quality attributes of recombinant therapeutic proteins expressed in mammalian hosts, allowing rational and high‐throughput optimization of mammalian cell culture media. A selection of specific and/or potent inhibitors and activators of oligosaccharide processing as well as components affecting multiple quality attributes are presented. Extensive research efforts in this field show the feasibility of quality engineering through media design, allowing to significantly modulate the protein function. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:615–629, 2015

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“…The elution pool showed a decrease in CDC activity, from 103% to 83%; a larger data set would be required to confirm this effect, though the result is consistent with literature reports of HM effects on CDC. 16 The CDC activity of the FT pool was equivalent to that of the SM.…”

Section: Example Of Unknown Attribute Impact: Afucosylated Hybrid Glymentioning

confidence: 99%

“…For ADCC activity, the presence of mono-or biantennary Fc glycans without a core fucose residue can dramatically increase affinity of the antibody for FcgRIIIa [14][15][16] and increase cell killing activity. Highmannose glycans include structures with between 5 to 9 mannose residues, and represent a class of less-processed glycans lacking a core fucose residue that have been shown to affect both ADCC 16 and CDC activity. 19 Hybrid glycans (HGs) are species with one complex arm and 4 or more core mannose residues, and the afucosylated forms have the potential to affect ADCC through increased FcgRIIIa binding.…”

Section: Introductionmentioning

confidence: 99%

The criticality of high-resolution N-linked carbohydrate assays and detailed characterization of antibody effector function in the context of biosimilar development

Brady

Velayudhan

Visone

et al. 2015

mAbs

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Accurate measurement and functional characterization of antibody Fc domain N-linked glycans is critical to successful biosimilar development. Here, we describe the application of methods to accurately quantify and characterize the N-linked glycans of 2 IgG1 biosimilars with effector function activity, and show the potential pitfalls of using assays with insufficient resolution. Accurate glycan assessment was combined with glycan enrichment using lectin chromatography or production with glycosylation inhibitors to produce enriched pools of key glycan species for subsequent assessment in cell-based antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity effector function assays. This work highlights the challenges of developing high-quality biosimilar candidates and the need for modern biotechnology capabilities. These results show that high-quality analytics, combined with sensitive cell-based assays to study in vivo mechanisms of action, is an essential part of biosimilar development.

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Production, characterization and pharmacokinetic properties of antibodies with N-linked Mannose-5 glycans

Cited by 183 publications

References 39 publications

Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates

Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates

Tailoring recombinant protein quality by rational media design

The criticality of high-resolution N-linked carbohydrate assays and detailed characterization of antibody effector function in the context of biosimilar development

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