A study in glycation of a therapeutic recombinant humanized monoclonal antibody: Where it is, how it got there, and how it affects charge-based behavior

Quan, Cynthia; Alcala, Emily; Petkovska, Irena; Matthews, Domenic; Canova-Davis, Eleanor; Taticek, Ron; Ma, Stacey

doi:10.1016/j.ab.2007.09.027

Cited by 192 publications

(223 citation statements)

References 29 publications

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“…A linear correlation was observed between the sugar concentration and the level of glycation in the tested range between 11.5 and 31 g/L of sugar. Furthermore, glucose-only cultures exhibited about 0.3% glycation increase for each glucose g/L addition, in contrast to a glycation increase in galactose-containing cultures by about 0.6 to 0.9% 75 . Diabetes testing in both healthy subjects and patients revealed an association of trace element plasma concentrations (Cu, Zn, Mg) with glycated hemoglobin levels, which increased at higher levels of Cu (16. 144 .…”

Section: Glycationmentioning

confidence: 71%

“…Subsequent spontaneous oxidation or rearrangement leads to the more stable Amadori products, which are eventually transformed through a series of intermediates into advanced glycation end products (AGE) 74 . Even though one has not observed a specific sequence of the positively charged primary amines located on the protein structure's surface, which increases the likelyhood of glycation, local environments that contain histidine residues or basic residues seem to favor glycation in structurally known proteins 75 . This posttranslational chemical reaction will also be discussed, as it is reported to potentially affect the biological activity (increased or decreased) as well as PK 76 .…”

Section: Glycosylationmentioning

confidence: 99%

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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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Section: Glycationmentioning

confidence: 71%

Section: Glycosylationmentioning

confidence: 99%

Tailoring recombinant protein quality by rational media design

Brühlmann

Jordan

Hemberger³

et al. 2015

Biotechnology Progress

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“…[1][2][3][4] It occurs when protein is incubated with reducing sugars, including glucose, galactose 5 and fructose. 6 The reaction between the amino acid and reducing sugar was first described by Maillard in 1912.…”

Section: Introductionmentioning

confidence: 99%

“…1a). 5 However, the ketoamine Amadori product can be reversibly driven to lose the sugar adduct under certain conditions. For a highly glycated recombinant monoclonal antibody, the total glycation level decreased from 42% to 20% when it was incubated at 37 C for 100 hours in a pH 7 phosphate buffer without glucose, which confirmed the reversible nature of the glycation.…”

Section: Introductionmentioning

confidence: 99%

“…12,13 ). 5 The reactivity of the amine group depends on the localized conditions that influence both initial amine deprotonation and stabilization of the intermediate before the ketoamine Amadori product is formed. Modeling of the antigen-binding fragment of a recombinant humanized monoclonal antibody (rhuMAb) has shown that the unusually high level of glycation of lysine (K) residue 49 (near complementarity-determining region (CDR) 2 was catalyzed by an aspartic acid residue in CDR1 on the light chain.…”

Section: Introductionmentioning

confidence: 99%

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Glycation of antibodies: Modification, methods and potential effects on biological functions

Wei¹,

Berning²,

Quan³

et al. 2017

mAbs

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Glycation is an important protein modification that could potentially affect bioactivity and molecular stability, and glycation of therapeutic proteins such as monoclonal antibodies should be well characterized. Glycated protein could undergo further degradation into advance glycation end (AGE) products. Here, we review the root cause of glycation during the manufacturing, storage and in vivo circulation of therapeutic antibodies, and the current analytical methods used to detect and characterize glycation and AGEs, including boronate affinity chromatography, charge-based methods, liquid chromatography-mass spectrometry and colorimetric assay. The biological effects of therapeutic protein glycation and AGEs, which ranged from no affect to loss of activity, are also discussed.

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Process Development of Protein Therapeutics

Thomas

Guhan

Pettit

2010

Burger's Medicinal Chemistry and Drug Discovery

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The application of recombinant DNA technology to the production of protein therapeutics has undergone considerable progress since first introduced 30 years ago. Considerable scientific effort has been devoted to developing robust processes that produce large amounts of complex proteins with the desired product quality attributes. An overview of the contributions from the four major disciplines working in concert to deliver these processes and methods will be covered. This chapter will discuss some of the tools, methods, and approaches used to produce, purify, formulate, and analyze the drugs of modern biotechnology. Future trends in each of the disciplines will also be presented.

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A study in glycation of a therapeutic recombinant humanized monoclonal antibody: Where it is, how it got there, and how it affects charge-based behavior

Cited by 192 publications

References 29 publications

Tailoring recombinant protein quality by rational media design

Tailoring recombinant protein quality by rational media design

Glycation of antibodies: Modification, methods and potential effects on biological functions

Process Development of Protein Therapeutics

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