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Specific racemization of heavy-chain cysteine-220 in the hinge region of immunoglobulin gamma 1 as a possible cause of degradation during storage. | LitMetric

Specific racemization of heavy-chain cysteine-220 in the hinge region of immunoglobulin gamma 1 as a possible cause of degradation during storage.

Anal Chem

Analytical & Quality Evaluation Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.

Published: May 2011

AI Article Synopsis

Article Abstract

Therapeutic antibodies often suffer from degradation due to various modifications during storage. We detected a degradation of immunoglobulin gamma 1 (IgG1) stored for 6 month at 40 °C, and identified the modification as the racemization of Cys220 in the hinge sequence S(219)CDKTHT(225) of the heavy chain by tryptic peptide mapping and tandem mass spectrometry. The rate of racemization at Cys220 was enhanced deliberately by incubating the protein at 50 °C and pH 9.0, while all the other cysteine residues were not affected. The racemization of Cys220 was confirmed by mass spectrometry in conjunction with extracted ion chromatography of the tryptic digest of IgG1 forced to degrade in D(2)O and a series of synthetic hinge fragments containing D-amino acid, as well as the detection of D-cysteine in the acid hydrolysate. To rationalize the possible relationship between the racemization of Cys220 and isopeptide formation at the neighboring residue of Asp221, we suggest a new reaction mechanism that assumes a base catalyst to initiate these reactions by activating the amide nitrogen of Lys222. Due to the highly flexible nature of the hinge region, Lys222 can participate in either the formation of a cyclic imidazoline intermediate involving the α-carbonyl carbon of Cys220 to facilitate the racemization of Cys220 or that of a succinimide structure leading to the isomerization of Asp221.

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Source
http://dx.doi.org/10.1021/ac200321vDOI Listing

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