Generation of recombinant antibodies against human tissue kallikrein 7 to treat skin diseases

Laureano, Ana Flávia S.; Zani, Marcelo B.; Sant'Ana, Aquiles M.; Tognato, Rafael C.; Lombello, Christiane Bertachini; Nascimento, Mônica Helena Monteiro do; Helmsing, Saskia; Fühner, Viola; Hust, Michael; Puzer, Luciano

doi:10.1016/j.bmcl.2020.127626

Cited by 5 publications

(10 citation statements)

References 43 publications

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“…More promising in principle, though not in practice, are small-molecule inhibitors, which have been described for both KLK5 and KLK7 ( 12 , 52 ). Another approach that uses antibodies, which have advantageous pharmacological properties, has been recently described for KLK7 ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

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

Chavarría-Smith

Chiu²,

Jackman

et al. 2022

Sci. Transl. Med.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Chavarría-Smith

Chiu²,

Jackman

et al. 2022

Sci. Transl. Med.

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“…KLK7 without any inhibition was set as the positive control for 100% activity, and the scFv-Fcs released from the hydrogels (after 24 h) were added to the assay. The IC 50 values for the antibodies, previously assessed by our research group, were 0.90 (A10), 6.2 (B10), 0.5 (C11), and 0.8 nM (D11) . The residual activity results are listed in Figure .…”

Section: Resultsmentioning

confidence: 88%

“…The theoretical amount retained in porcine skin for the A10, C11, and D11 antibodies was around 20–30% below their IC 50 . These quantities should be enough to show a partial inhibition of KLK7, which can control its activity but not completely inhibit the enzyme (according to previously calculated IC 50 values) …”

Section: Resultsmentioning

confidence: 99%

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Recombinant scFv-Fc Anti-kallikrein 7 Antibody-Loaded Thermosensitive Hydrogels Against Skin Desquamation Disorders

Laureano,

Vigato,

Puzer

et al. 2024

ACS Appl. Bio Mater.

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Human tissue kallikrein-related peptidase 7 (KLK7) is a serine protease implicated in the physiology of skin desquamation, and its uncontrolled activity can lead to chronic diseases such as psoriasis, atopic dermatitis, and Netherton syndrome. For this reason, kallikrein 7 has been identified as a potential therapeutic target. This work aimed to evaluate Pluronic (PL) hydrogels as topical carriers of four specific scFv-Fc antibodies to inhibit KLK7. The hydrogels comprised PL F127 (30% w/v) alone and a binary F127/P123 (28−2% w/v) system. Each formulation was loaded with 1 μg/mL of each antibody and characterized by physicochemical and pharmaceutical techniques, considering antibody−micelle interactions and hydrogel behavior as smart delivery systems. Results showed that the antibodies were successfully loaded into the PL-based systems, and the sol− gel transition temperature was shifted to high values after the P123 addition. The antibodies released from the gels preserved their rheological properties (G′ > G′′, 35-to 41-fold) and inhibitory activity against KLK7, even after 24 h. This work presented potential agents targeting KLK7 that may provide strategies for treating skin abnormalities.

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“…Chen et al ( 94 ) have been developing inhibitors based on the scaffold of the SFTI, a small Bowman-Birk inhibitor characterized for its bifunctional inhibition of trypsin and chymotrypsin. Laureano et al ( 95 ) used phage display to generate recombinant antibody fragments with inhibitory potential against hKLK7, presenting IC 50 of the order of nM.…”

Section: Therapeutic Approaches Focused On Human Tissue Kallikreins-r...mentioning

confidence: 99%

Human Tissue Kallikreins-Related Peptidases Are Targets for the Treatment of Skin Desquamation Diseases

et al. 2022

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Human tissue Kallikrein-related peptidases (hKLKs) are serine proteases distributed in several tissues that are involved in several biological processes. In skin, many are responsible for skin desquamation in the Stratum Corneum (SC) of the epidermis, specially hKLK5, hKLK7, hKLK6, hKLK8, and hKLK14. In SC, hKLKs cleave proteins of corneodesmosomes, an important structure responsible to maintain corneocytes attached. As part of skin desquamation, hKLKs are also involved in skin diseases with abnormal desquamation and inflammation, such as Atopic Dermatitis (AD), psoriasis, and the rare disease Netherton Syndrome (NS). Many studies point to hKLK overexpression or overactive in skin diseases, and they are also part of the natural skin inflammation process, through the PAR2 cleavage pathway. Therefore, the control of hKLK activity may offer successful treatments for skin diseases, improving the quality of life in patients. Diseases like AD, Psoriasis, and NS have an impact on social life, causing pain, itchy and mental disorders. In this review, we address the molecular mechanisms of skin desquamation, emphasizing the roles of human tissue Kallikrein-related peptidases, and the promising therapies targeting the inhibition of hKLKs.

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Generation of recombinant antibodies against human tissue kallikrein 7 to treat skin diseases

Cited by 5 publications

References 43 publications

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

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

Recombinant scFv-Fc Anti-kallikrein 7 Antibody-Loaded Thermosensitive Hydrogels Against Skin Desquamation Disorders

Human Tissue Kallikreins-Related Peptidases Are Targets for the Treatment of Skin Desquamation Diseases

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