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    Physical stability comparisons of IgG1-Fc variants: effects of N-glycosylation site occupancy and Asp/Gln residues at site Asn 297

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    joshi_physical.pdf (3.271Mb)
    Issue Date
    2014-04-16
    Author
    Alsenaidy, Mohammad A.
    Okbazghi, Solomon Zeray
    Kim, Jae Hyun
    Joshi, Sangeeta B.
    Middaugh, C. Russell
    Tolbert, Thomas J.
    Volkin, David B.
    Publisher
    Wiley
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
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    Abstract
    The structural integrity and conformational stability of various IgG1-Fc proteins produced from the yeast Pichia pastoris with different glycosylation site occupancy (di-, mono-, and non- glycosylated) was determined. In addition, the physical stability profiles of three different forms of non-glycosylated Fc molecules (varying amino acid residues at site 297 in the CH2 domain due to point mutations and enzymatic digestion of the Fc glycoforms) were also examined. The physical stability of these IgG1-Fc glycoproteins was examined as a function of pH and temperature by high throughput biophysical analysis using multiple techniques combined with data visualization tools (three index empirical phase diagrams and radar charts). Across the pH range of 4.0 to 6.0, the di- and mono- glycosylated forms of the IgG1-Fc showed the highest and lowest levels of physical stability respectively, with the non-glycosylated forms showing intermediate stability depending on solution pH. In the aglycosylated Fc proteins, the introduction of Asp (D) residues at site 297 (QQ vs. DN vs. DD forms) resulted in more subtle changes in structural integrity and physical stability depending on solution pH. The utility of evaluating the conformational stability profile differences between the various IgG1-Fc glycoproteins is discussed in the context of analytical comparability studies.
    Description
    This is the author's accepted manuscript. Made available by the permission of the publisher.
    URI
    http://hdl.handle.net/1808/20054
    DOI
    https://doi.org/10.1002/jps.23975
    Collections
    • Pharmaceutical Chemistry Scholarly Works [288]
    Citation
    Alsenaidy, Mohammad A., Solomon Z. Okbazghi, Jae Hyun Kim, Sangeeta B. Joshi, C. Russell Middaugh, Thomas J. Tolbert, and David B. Volkin. "Physical Stability Comparisons of IgG1-Fc Variants: Effects of N-Glycosylation Site Occupancy and Asp/Gln Residues at Site Asn 297." Journal of Pharmaceutical Sciences 103.6 (2014): 1613-627. doi:10.1002/jps.23975.

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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