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A Keratinocyte-Tethered Biologic Enables Location-Precise Treatment in Mouse Vitiligo

      Despite the central role of IFN-γ in vitiligo pathogenesis, systemic IFN-γ neutralization is an impractical treatment option owing to strong immunosuppression. However, most patients with vitiligo present with <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 IFN-γ signaling during vitiligo, we hypothesized that tethering an IFN-γ‒neutralizing antibody to keratinocytes would limit anti‒IFN-γ effects on the treated skin for the localized treatment. To that end, we developed a bispecific antibody capable of blocking IFN-γ signaling while binding to desmoglein expressed by keratinocytes. We characterized the effect of the bispecific antibody in vitro, ex vivo, and in a mouse model of vitiligo. Single-photon emission computed tomography/computed tomography biodistribution and serum assays after local footpad injection revealed that the bispecific antibody had improved skin retention, faster elimination from the blood, and less systemic IFN-γ inhibition than the nontethered version. Furthermore, the bispecific antibody conferred localized protection almost exclusively to the treated footpad during vitiligo, which was not possible by local injection of the nontethered anti‒IFN-γ antibody. Thus, keratinocyte tethering proved effective while significantly diminishing the off-tissue effects of IFN-γ blockade, offering a safer treatment strategy for localized skin diseases, including vitiligo.

      Graphical abstract

      Abbreviations:

      BMDC (bone marrow‒derived dendritic cell), BsAb (bispecific antibody), DSC (desmocollin), DSG (desmogleins), KC (keratinocyte), scfv (single-chain variable fragment)
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      Linked Article

      • Hitting the Bullseye in Autoimmunity: Targeting Biologics through Tethering: Examining a Therapeutic Potential for Vitiligo and Beyond
        Journal of Investigative DermatologyVol. 142Issue 12
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          Biologic therapies targeting aberrant immune responses in cutaneous and systemic autoimmune diseases have had a significant impact on reducing mortality and morbidity for conditions that could not be treated with conventional drugs. However, their systemic effects increase vulnerability to infections, malignancies, and development of secondary autoimmune complications, underscoring the need for localized, targeted delivery of biologics. The article by Ying-Chao et al. (2022) titled “A keratinocyte-tethered biologic enables location-precise treatment in mouse vitiligo” highlights the potential for using bispecific antibodies (BsAbs) as a novel method of localized drug delivery through tethering, where one of the two antibody specificities is used to target a structural surface protein to anchor the biologic within the tissue.
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