Protein tyrosine phosphatase conjugated with a novel transdermal delivery peptide, astrotactin 1–derived peptide recombinant protein tyrosine phosphatase (AP-rPTP), alleviates both atopic dermatitis–like and psoriasis-like dermatitis

Abstract

Atopic dermatitis (AD) and psoriasis are the 2 most common chronic inflammatory skin diseases. There is an unmet medical need to overcome limitations for transcutaneous drug development posed by the skin barrier. We aimed to identify a novel transdermal delivery peptide and to develop a transcutaneously applicable immunomodulatory protein for treating AD and psoriasis. We identified and generated reporter proteins conjugated to astrotactin 1-derived peptide (AP), a novel transdermal delivery peptide of human origin, and analyzed the intracellular delivery efficiency of these proteins in mouse and human skin cells and tissues using multiphoton confocal microscopy. We also generated a recombinant therapeutic protein, AP-recombinant protein tyrosine phosphatase (rPTP), consisting of the phosphatase domain of the T-cell protein tyrosine phosphatase conjugated to AP. The immunomodulatory function of AP-rPTP was confirmed in splenocytes on cytokine stimulation and T-cell receptor stimulation. Finally, we confirmed the invivo efficacy of AP-rPTP transdermal delivery in patients with oxazolone-induced contact hypersensitivity, ovalbumin-induced AD-like, and imiquimod-induced psoriasis-like skin inflammation models. AP-conjugated reporter proteins exhibited significant intracellular transduction efficacy in keratinocytes, fibroblasts, and immune cells. In addition, transcutaneous administration of AP-dTomato resulted in significant localization into the dermis and epidermis in both mouse and human skin. AP-rPTP inhibited phosphorylated signal transducer and activator of transcription (STAT) 1, STAT3, and STAT6 in splenocytes and also regulated T-cell activation and proliferation. Transcutaneous administration of AP-rPTP through the paper-patch technique significantly ameliorated skin tissue thickening, inflammation, and cytokine expression in both AD-like and psoriasis-like dermatitis models. We identified a 9-amino-acid novel transdermal delivery peptide, AP, and demonstrated its feasibility for transcutaneous biologic drug development. Moreover, AP-rPTP is a novel immunomodulatory drug candidate for human dermatitis.