Comparative Evaluation of Disodium Edetate and Diethylenetriaminepentaacetic Acid as Iron Chelators to Prevent Metal -Catalyzed Destabilization of a Therapeutic Monoclonal Antibody

Zhou, Shu; Zhang, Bo; Sturm, Emily C.; Teagarden, Dirk L.; Schöneich, Christian; Kolhe, Parag; Lewis, Lavinia M.; Muralidhara, B. K.; Singh, Satish K.

doi:10.1002/jps.22141

Cited by 56 publications

(31 citation statements)

References 38 publications

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“…From a pharmaceutical viewpoint, the fact that the addition of EDTA cannot prevent the hydrolysis is important, as EDTA is frequently used as a chelator to prevent metal-catalyzed reactions in formulations. 54 We did not observe the hydrolysis of the peptide bond between Met[8] and His[9] in the presence of phosphate buffer. We did not investigate in detail the reason why the hydrolysis did not occur in the presence of phosphate.…”

Section: Discussionmentioning

confidence: 77%

Metal-Catalyzed Oxidation of Protein Methionine Residues in Human Parathyroid Hormone (1-34): Formation of Homocysteine and a Novel Methionine-Dependent Hydrolysis Reaction

Mozziconacci

Ji²,

Wang³

et al. 2013

Mol. Pharmaceutics

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The oxidation of PTH(1-34) catalyzed by ferrous ethylenediaminetetraacetic acid (EDTA) is site-specific. The oxidation of PTH(1-34) is localized primarily to the residues Met[8] and His[9]. Beyond the transformation of Met[8] and His[9] into methionine sulfoxide and 2-oxo-histidine, respectively, we observed a hydrolytic cleavage between Met[8] and His[9]. This hydrolysis requires the presence of FeII and oxygen and can be prevented by diethylenetriaminepentaacetic acid (DTPA) and phosphate buffer. Conditions leading to this site-specific hydrolysis also promote the transformation of Met[8] into homocysteine, indicating that the hydrolysis and transformation of homocysteine may proceed through a common intermediate.

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Section: Discussionmentioning

confidence: 77%

Metal-Catalyzed Oxidation of Protein Methionine Residues in Human Parathyroid Hormone (1-34): Formation of Homocysteine and a Novel Methionine-Dependent Hydrolysis Reaction

Mozziconacci

Ji²,

Wang³

et al. 2013

Mol. Pharmaceutics

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“…Furthermore, it resulted in greater sialylation and higher harvest titer 54 . Iron plays a major role in inhibiting the formation of aggregate forms, as shown in long-term drug substance stability studies, where the abundance of high-molecularweight species was significantly lower at low iron concentrations (0-4 ppm) in the presence of a chelator 174 . Surfactant containing culture media were reported to stabilize the expressed protein and thus reduce aggregation 175,176 .…”

Section: Aggregatesmentioning

confidence: 98%

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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“…However, metal ion leaching from IV bags can occur, and it has been shown that IgG2 mAb not stored in IV bags can undergo subtle changes in tertiary structure when exposed to Fe (III) ions (Zhou et al, 2010). The ions may promote oxidation reactions, which in turn impacts the physical stability of the antibody.…”

Section: Extractables and Leachables From IV Bags And Impact On Protementioning

confidence: 98%

Challenges in the intravenous (IV) administration of monoclonal antibodies (mAbs)

Shire¹

2015

Monoclonal Antibodies

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Comparative Evaluation of Disodium Edetate and Diethylenetriaminepentaacetic Acid as Iron Chelators to Prevent Metal -Catalyzed Destabilization of a Therapeutic Monoclonal Antibody

Cited by 56 publications

References 38 publications

Metal-Catalyzed Oxidation of Protein Methionine Residues in Human Parathyroid Hormone (1-34): Formation of Homocysteine and a Novel Methionine-Dependent Hydrolysis Reaction

Metal-Catalyzed Oxidation of Protein Methionine Residues in Human Parathyroid Hormone (1-34): Formation of Homocysteine and a Novel Methionine-Dependent Hydrolysis Reaction

Tailoring recombinant protein quality by rational media design

Challenges in the intravenous (IV) administration of monoclonal antibodies (mAbs)

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