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dc.contributor.advisorTolbert, Thomas
dc.contributor.authorAl-Kinani, Khalid Kadhem Abed
dc.date.accessioned2017-11-16T03:56:59Z
dc.date.available2017-11-16T03:56:59Z
dc.date.issued2017-08-31
dc.date.submitted2017
dc.identifier.otherhttp://dissertations.umi.com/ku:15473
dc.identifier.urihttp://hdl.handle.net/1808/25383
dc.description.abstractImmunoglobulin G (IgG) is a complex glycoprotein that is largely being used in the development of antibody-based therapeutics to treat a variety of diseases such as cancers, autoimmune diseases, and infectious diseases. A major challenge in developing such therapeutics originates from the heterogeneity of the Asn297 glycan of IgG. This sugar part (Asn297 glycan) of IgG has been shown to play an important role in the antibody properties such as antibody stability, effector functions, solubility, pharmacokinetics, and immunogenicity. To study the effect of Asn297 glycan composition on the properties of the human IgG2 (a preferred IgG subclass for developing antibody-based therapeutics when the antibody effector functions are not required), we developed an approach to produces homogeneous IgG2 Fc glycoforms. Studying these homogeneous IgG2 Fc glycoforms suggested that enriching the core fucose within IgG2 Asn297 glycan could add more advantages to developing IgG2-based therapeutics by providing more reduction in any possible undesirable effector functions of these therapeutics. The in vitro enzymatic synthesis developed here also enabled studies of different glycosylation sites accessibility to glycosyltransferase and expanded our understanding of the glycosylation heterogeneity. The Asn297 glycan also offers a great opportunity in developing antibody drug conjugates (ADCs), a therapeutic modality where a toxic payload is conjugated to IgG. The early ADC development relied on conjugating the payload non-specifically through either the lysine or cysteine residues of IgG using conventional chemistries. Producing ADCs in this way, results in heterogeneous products. ADC heterogeneity usually translates into poor pharmacokinetics, stability, and efficacy. In this work, we developed a chemoenzymatic synthesis platform to functionalize the Asn297 glycan in a novel way and use it as a specific site for conjugation. The work involved using and optimizing click chemistry reactions for conjugating different linkers on IgG2 Fc. This approach enabled us to produce conjugates with excellent homogeneity. Subsequent studies of these conjugates showed the utility of the approach followed here in making of site-specific conjugates with good properties and the possibility of following this approach in designing and testing site-specific ADCs during the process of developing next generation ADCs.
dc.format.extent199 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmaceutical sciences
dc.subjectAntibody
dc.subjectChemoenzymatic synthesis
dc.subjectFucosylation
dc.subjectFUT8
dc.subjectGlycosylation
dc.subjectSite-Specific ADC
dc.titleModifying the Fc Asn297 Glycan of Human IgG2 Subclass for Improved Antibody Therapeutics and Design of Site-Specific Antibody Drug Conjugates
dc.typeDissertation
dc.contributor.cmtememberMiddaugh, C.Russel
dc.contributor.cmtememberSiahaan, Teruna
dc.contributor.cmtememberWang, Michael
dc.contributor.cmtememberSaint Onge, Jarron
dc.thesis.degreeDisciplinePharmaceutical Chemistry
dc.thesis.degreeLevelPh.D.
dc.identifier.orcid
dc.rights.accessrightsopenAccess


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