7u5b
Structure of Human KLK5 bound to anti-KLK5 Fab
Structural highlights
Publication Abstract from PubMedThe 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. Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis.,Chavarria-Smith J, Chiu CPC, Jackman JK, Yin J, Zhang J, Hackney JA, Lin WY, Tyagi T, Sun Y, Tao J, Dunlap D, Morton WD, Ghodge SV, Maun HR, Li H, Hernandez-Barry H, Loyet KM, Chen E, Liu J, Tam C, Yaspan BL, Cai H, Balazs M, Arron JR, Li J, Wittwer AJ, Pappu R, Austin CD, Lee WP, Lazarus RA, Sudhamsu J, Koerber JT, Yi T Sci Transl Med. 2022 Dec 14;14(675):eabp9159. doi: 10.1126/scitranslmed.abp9159. , Epub 2022 Dec 14. PMID:36516271[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
