ORCID ID

0000-0003-2600-5718

Publication Date

2022-06-06

Document Type

Doctoral Dissertation

Academic Program

Immunology and Microbiology

Department

Department of Dermatology

First Thesis Advisor

John Harris

Keywords

vitiligo, bispecific antibody, IFN-γ, tissue targeted drug delivery, skin-tethered BsAb, autoimmune disease

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

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Wednesday, December 07, 2022

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