Keratinocyte-tethering modification for biologics enables location-precise treatment in mouse vitiligo

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, we 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, we developed a bispecific antibody (BsAb) capable of blocking IFNγ signaling while binding to desmoglein expressed by keratinocytes. We 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. ### Competing Interest Statement J.E.H. is a scientific founder of Villaris Therapeutics and Vimela Therapeutics, which develop treatments for vitiligo, as well as Aldena Therapeutics and NIRA Biosciences focused on treating inflammatory diseases of the skin. J.E.H. and J.M.R. are inventors on patent #62489191, Diagnosis and Treatment of Vitiligo, which covers targeting IL-15 and Trm for treatment of vitiligo. J.R.S. and D.L.S. have a patent (US 8,470,323 B2) for targeted drug delivery with anti-desmoglein scFv. The remaining authors state no conflict of interest.