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    The Development of a Skin-Targeted Interferon-Gamma-Neutralizing Bispecific Antibody for Vitiligo Treatment

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    Authors
    Hsueh, Ying-Chao
    Faculty Advisor
    John Harris
    Academic Program
    Immunology and Microbiology
    UMass Chan Affiliations
    Department of Dermatology
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-06-06
    Keywords
    vitiligo
    bispecific antibody
    IFN-γ
    tissue targeted drug delivery
    skin-tethered BsAb
    autoimmune disease
    Biotechnology
    Dermatology
    Immunotherapy
    Skin and Connective Tissue Diseases
    
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    Abstract
    Despite the central role of IFNγ in vitiligo pathogenesis, systemic IFNγ neutralization is an impractical treatment option due to strong immunosuppression. However, most vitiligo patients present with less than 20% affected body surface area, which provides an opportunity for localized treatments that avoid systemic side effects. After identifying keratinocytes as key cells that amplify IFNγ signaling during vitiligo, I hypothesized that tethering an IFNγ neutralizing antibody to keratinocytes would limit anti-IFNγ effects to the treated skin for the localized treatment. To that end, I developed a bispecific antibody (BsAb) capable of blocking IFNγ signaling while binding to desmoglein expressed by keratinocytes. I characterized the effect of the BsAb in vitro, ex vivo, and in a mouse model of vitiligo. SPECT/CT biodistribution and serum assays after local footpad injection revealed that the BsAb had improved skin retention, faster elimination from the blood, and less systemic IFNγ inhibition than the non-tethered version. Furthermore, the BsAb conferred localized protection almost exclusively to the treated footpad during vitiligo that was not possible by local injection of the non-tethered anti-IFNγ antibody. Thus, keratinocyte-tethering proved effective while significantly diminishing off-tissue effects of IFNγ blockade, offering a new treatment strategy for localized skin diseases, including vitiligo.
    DOI
    10.13028/0zsa-gj08
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32402
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/0zsa-gj08
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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