Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis

The epidermis is a barrier that prevents water loss while keeping harmful substances from penetrating the host. The impermeable cornified layer of the stratum corneum is maintained by balancing continuous turnover driven by epidermal basal cell proliferation, suprabasal cell differentiation, and corneal shedding. The epidermal desquamation process is tightly regulated by balance of the activities of serine proteases of the Kallikrein-related peptidases (KLK) family and their cognate inhibitor lymphoepithelial Kazal type–related inhibitor (LEKTI), which is encoded by the serine peptidase inhibitor Kazal type 5 gene. Imbalance of proteolytic activity caused by a deficiency of LEKTI leads to excessive desquamation due to increased activities of KLK5, KLK7, and KLK14 and results in Netherton syndrome (NS), a debilitating condition with an unmet clinical need. Increased activity of KLKs may also be pathological in other dermatoses such as atopic dermatitis (AD). Here, we describe the discovery of inhibitory antibodies against murine KLK5 and KLK7 that could compensate for the deficiency of LEKTI in NS. These antibodies are protective in mouse models of NS and AD and, when combined, promote improved skin barrier integrity and reduced inflammation. To translate these findings, we engineered a humanized bispecific antibody capable of potent inhibition of human KLK5 and KLK7. A crystal structure of KLK5 bound to the inhibitory Fab revealed that the antibody binds distal to its active site and uses a relatively unappreciated allosteric inhibition mechanism. Treatment with the bispecific anti-KLK5/7 antibody represents a promising therapy for clinical development in NS and other inflammatory dermatoses. Description We develop a bispecific inhibitory antibody against KLK5 and KLK7 for treatment of Netherton Syndrome and atopic dermatitis. Subduing skin inflammation Subduing skin inflammationThe integrity of the epidermis is maintained through a continuous turnover process and involves members of the Kallikrein-related peptidase (KLK) family and their cognate inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). Netherton Syndrome (NS) is a debilitating skin condition caused by a LEKTI deficiency that results in unregulated activity of KLK5, KLK7 and KLK14. Chavarria-Smith et al. characterized two monoclonal antibodies that inhibited murine KLK5 and KLK7, which improved skin barrier function and reduced inflammation in a mouse model of NS as well as a mouse model of atopic dermatitis. They engineered a bispecific human anti-KLK5/KLK7 that displayed inhibitory activity by targeting an allosteric site in KLK5 distal from the active site. These findings suggest anti-KLK5/7 antibodies may be a potential strategy for treating NS and other inflammatory skin disorders.