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    Instability of Immunoglobulin G (IgG) Monoclonal Antibodies Induced by Redox-Active Metal Ions adn Photo-Irradiation

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    Issue Date
    2012-08-31
    Author
    Zhou, Shuxia
    Publisher
    University of Kansas
    Format
    286 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmaceutical Chemistry
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Since the approval of the first monoclonal antibody (mAb) drug in 1986, mAbs have developed into a major class of therapeutic agents due to their unique properties. Compared to traditional small molecule drug products, the actions of the antibodies are more specific leading to generally fewer off-target related side effects. Also antibodies may be conjugated to another therapeutic entity for efficient delivery of this entity to a target site, thus reducing potential side effects. On the other hand, due to the structural complexity and the dependence of stability of the antibodies on the conformation and structure, antibodies are subject to multiple degradation pathways induced by a variety of factors encountered during antibody production, purification, development, manufacturing, storage, shipping and delivery to the patients. The exposure of antibodies to redox-active metal ions and/or light during processing and use is inevitable, and may result in antibody degradation. Although abundant information on metal-catalyzed oxidation (MCO) and photo-degradation of peptides and small proteins is documented in the literature, very limited research has been performed on IgG oxidative modifications and physical instability. The research covered in this dissertation focused on two major degradation mechanisms for IgG therapeutic mAbs: chemical and physical instability induced by redox-active metal ions and photo-degradation. Redox-active metal ion-induced instability was first examined by a comprehensive study of IgG oxidation induced by MCO. The oxidation of the amino acids, especially Phe and Tyr in IgG1 was first identified, and subsequently a fluorogenic derivatization methodology was developed for their detection. Secondly, a systematic study of the conformational change and intrinsic thermal stability of IgG revealed that metal ions perturbed IgG tertiary structure resulting in decreased intrinsic thermal stability. Lastly, metal chelators were examined to protect the IgG from MCO-induced degradation. This dissertation also documents the formation of carbon-centered radicals due to homolytic cleavage of disulfide bonds upon photo-irradiation and an UPLC-MS method was developed to simultaneously separate and characterize IgG1 photo-degradants. The ultimate goal of this research is to gain better understanding of IgG degradation mechanism, thereof, providing guidance to develop a therapeutic mAb drug product with desired attributes for unmet medical needs.
    URI
    http://hdl.handle.net/1808/11458
    Collections
    • Dissertations [2939]
    • Pharmaceutical Chemistry Dissertations and Theses [90]

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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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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