کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2487440 | 1114417 | 2008 | 16 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Removal of Cysteinylation from an Unpaired Sulfhydryl in the Variable Region of a Recombinant Monoclonal IgG1 Antibody Improves Homogeneity, Stability, and Biological Activity
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Removal of Cysteinylation from an Unpaired Sulfhydryl in the Variable Region of a Recombinant Monoclonal IgG1 Antibody Improves Homogeneity, Stability, and Biological Activity Removal of Cysteinylation from an Unpaired Sulfhydryl in the Variable Region of a Recombinant Monoclonal IgG1 Antibody Improves Homogeneity, Stability, and Biological Activity](/preview/png/2487440.png)
چکیده انگلیسی
The antibody MAB007 was recently shown to be cysteinylated on an unpaired cysteine residue in the CDR3 Variable region. Cysteinylation at this position was not complete and resulted in heterogeneous lots of MAB007 with respect to this posttranslational modification. In this report, a mild redox step was used that effectively removed cysteinylation while keeping native inter and intra-molecular disulfide bonds intact. Biophysical methods were employed to determine what consequences cysteinylation of the variable region had by directly comparing cysteinylated and de-cysteinylated MAB007 antibodies. No differences were detected in secondary structure; however, several pieces of evidence indicated that cysteinylation may result in tertiary or quaternary structural perturbations. These included differences in the cation-exchange chromatography and fluorescence-emission spectra of the cysteinylated and de-cysteinylated antibodies as well as differences in the solvent accessibility of the unpaired cysteine residue determined by labeling experiments. Such structural changes induced by cysteinylation were shown to increase the rate of MAB007 aggregation and to decrease the melting temperature of the Fab region by as much as 6 °C. The bioactivity of MAB007 was also shown to be adversely affected by cysteinylation and a direct correlation was made between the percent cysteinylation and biological activity. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 764-779, 2008
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 97, Issue 2, February 2008, Pages 775-790
Journal: Journal of Pharmaceutical Sciences - Volume 97, Issue 2, February 2008, Pages 775-790
نویسندگان
Douglas D. Banks, Himanshu S. Gadgil, Gary D. Pipes, Pavel V. Bondarenko, Vipa Hobbs, Joanna L. Scavezze, Jun Kim, Xu-Rong Jiang, Venkat Mukku, Thomas M. Dillon,