The lympho-epithelial Kazal-type inhibitors (LEKTI) are key to control skin turnover, and their absence causes Netherton syndrome. For clinical sample testing of LEKTI-based therapies, a robust analytical method to measure LEKTI-like activity in skin is required. This work reports on the development of a back-titration method to determine incremental LEKTI-like activity in skin samples. The method meets the analytical requirements for study sample testing, and reliable quantification can be achieved with negligible skin matrix interference. This assay does not provide analyte identity, but it can be used to measure treatment-driven increments of LEKTI-like activity within the skin epidermis.

2023-01-17·Biochemistry

Identification of Kazal Inhibitor Scaffolds with Identical Canonical Binding Loops and Their Effects on Binding Properties

Article

作者: Delcea, Mihaela ; Susemihl, Anne ; Eulberg, Tobias ; Nagel, Felix

Kazal inhibitors hold high potential as scaffolds for therapeutic molecules, taking advantage of the easily exchangeable canonical binding loop. Different Kazal inhibitor backbones have been suggested to be therapeutically useful, but the impact of different Kazal-like scaffolds on binding properties is still largely unknown. Here, we identified trypsin-targeting human serine protease inhibitor Kazal type 1 (SPINK1) homologues in different mammalian species that cluster in two P2-P1 combinations, implying the coevolution of these residues. We generated loop exchange variants of human SPINK1 for comparison with Kazal inhibitors from related species. Using comprehensive biophysical characterization of the inhibitor-enzyme interactions, we found not only affinity but also pH resistance to be highly backbone-dependent. Differences are mostly observed in complex stability, which varies by over one order of magnitude. We provide clear evidence for high backbone dependency within the Kazal family. Hence, when designing Kazal inhibitor-based therapeutic molecules, testing different backbones after optimizing the canonical binding loop can be beneficial and may result in increased affinity, complex stability, specificity, and pH resistance.

2023-01-01·Molecular Biology Reports

Cloning and functional identification of pmKPI cDNA in Poecilobdella manillensis

Article

作者: Li, Wen-Bo ; Wang, Su-Yan ; Tian, Qing-Qing ; Shao, Gui-Yan ; Liu, Fei ; Cheng, Bo-Xing ; Lu, Yu-Xi

BACKGROUNDKazal-type serine protease inhibitors play a role in physiological processes such as blood coagulation and fibrinolysis. The amino acid residues at the P1 site are different, and they inhibit different types of proteases. The inhibitory mechanism of the protease in the salivary glands of Poecilobdella manillensis is still unclear.METHODS AND RESULTSBased on cloning, prokaryotic expression and bioinformatics analysis, we studied the role of Kazal-type serine protease inhibitors in P. manillensis and analyzed their expression by quantitative real-time PCR. The results suggested that the recombinant protein was successfully expressed in the supernatant when a prokaryotic expression vector was constructed and induced with 0.2 mmol/L IPTG at 37 °C for 4 h, and the enzymatic activity was determined. The mature protein encodes 91 amino acids and has a relative molecular weight of 9929.32 Da, and after removing the signal peptide, the theoretical isoelectric point was 8.79. It is an unstable protein without a transmembrane domain. The mature protein contains two Kazal-type domains, in which all P1 residues are Lys, consisting of an α helix and three antiparallel β sheets. The upregulated expression of the mRNA was induced after a meal was provided, and the results showed an increasing and then decreasing trend.CONCLUSIONSTaken together, the results indicate that mature proteins from P. manillensis inhibit thrombin activity, laying the foundation for the subsequent in-depth study of the function of genes encoding Kazal-type serine protease inhibitors.

项与 Lympho-Epithelial Kazal-Type Inhibitor (PHARIS Biotec) 相关的新闻（医药）

2024-08-28

·Business Wire

Azitra Announces First Patient Dosed in Phase 1b Trial of ATR-12 for Netherton Syndrome

BRANFORD, Conn.--( BUSINESS WIRE )--Azitra, Inc. (NYSE American: AZTR), a precision dermatology company, announced that it has initiated dosing the first patient in its Phase 1b clinical trial evaluating ATR-12 for the treatment of Netherton syndrome. The study is designed to enroll approximately 12 adult patients with twice-daily treatment for 14 days, with primary endpoints focusing on safety and tolerability, and secondary and exploratory endpoints assessing efficacy signals and biomarkers. Azitra expects to report interim safety data from the Phase 1b trial in early 2025 with full results anticipated in the second half of 2025. ATR-12 is Azitra's lead candidate, a proprietary strain of Staphylococcus epidermidis engineered to express therapeutic levels of an active subunit of the LEKTI protein to treat Netherton syndrome, a chronic genetic skin disease that can be life threatening. "Dosing the first patient in our Phase 1b trial of ATR-12 marks a vital milestone for Azitra and for patients suffering from Netherton syndrome," said Francisco Salva, CEO of Azitra. "We are exhilarated to start dosing patients and look forward to executing this trial and delivering clinical data." Mary Spellman, MD, Azitra’s acting CMO, added, “We are thrilled to begin this clinical trial of ATR-12 in patients with Netherton syndrome. These patients often suffer from poor quality of life due to debilitating disease. This first-in-human study will inform future studies for the treatment of Netherton syndrome, including in pediatric patients and for longer treatment durations.” The Phase 1b trial (NCT06137157) is a multicenter, randomized, double-blind, vehicle-controlled study in approximately 12 adult patients with Netherton syndrome. Patients will be treated with 10 9 CFU / g twice daily with ATR-12 or its vehicle control on the contralateral side of the body twice daily for 14 days. The primary objective is to assess the safety and tolerability of topical ATR-12 application. Secondary objectives include evaluating efficacy signals (e.g., investigator and patient global assessments) and skin pharmacokinetics of the LEKTI subunit. Additional exploratory objectives include evaluating pharmacodynamic parameters, biomarkers, anti-LEKTI response, and cytokine responses. About ATR-12 ATR-12 (also known as ATR12-351) is an engineered strain of S. epidermidis that expresses an active subunit of human lympho-epithelial Kazal-type-related inhibitor (LEKTI) protein, which is missing in patients with Netherton syndrome, a chronic and sometimes fatal disease of the skin estimated to affect approximately one to nine in every 100,000. ATR-12 has been engineered to deliver the missing LEKTI protein when applied topically. Azitra has initiated a 12-patient, Phase 1b clinical trial, which will assess safety, tolerability, and efficacy endpoints (NCT06137157). Azitra expects to announce initial safety data in early 2025. About Azitra, Inc. Azitra, Inc. is an early-stage clinical biopharmaceutical company focused on developing innovative therapies for precision dermatology using engineered proteins and topical live biotherapeutic products. The Company has built a proprietary platform that includes a microbial library comprised of approximately 1,500 unique bacterial strains that can be screened for unique therapeutic characteristics. The platform is augmented by artificial intelligence and machine learning technology that analyzes, predicts, and helps screen the Company's library of strains for drug like molecules. The Company's initial focus is on the development of genetically engineered strains of Staphylococcus epidermidis , or S. epidermidis , which the Company considers to be an optimal therapeutic candidate species for engineering of dermatologic therapies. For more information, please visit https://azitrainc.com/ . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by words such as "aims," "anticipates," "believes," "could," "estimates," "expects," "forecasts," "goal," "intends," "may," "plans," "possible," "potential," "seeks," "will," and variations of these words or similar expressions that are intended to identify forward-looking statements. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. These forward-looking statements include, without limitation, statements regarding the expected timing of the presentation of data from the Phase 1b study of ATR-12 and statements about our clinical and preclinical programs, and corporate and clinical/preclinical strategies. Any forward-looking statements in this press release are based on current expectations, estimates and projections only as of the date of this release and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to that we may fail to successfully complete our Phase 1b trial for ATR-12 and preclinical studies of other product candidates and obtain required approval before commercialization; our product candidates may not be effective; there may be delays in regulatory approval or changes in regulatory framework that are out of our control; our estimation of addressable markets of our product candidates may be inaccurate; we may fail to timely raise additional required funding; more efficient competitors or more effective competing treatment may emerge; we may be involved in disputes surrounding the use of our intellectual property crucial to our success; we may not be able to attract and retain key employees and qualified personnel; earlier study results may not be predictive of later stage study outcomes; and we are dependent on third-parties for some or all aspects of our product manufacturing, research and preclinical and clinical testing. Additional risks are described in our Form 10-Q filed with the SEC on August 12, 2024. Azitra explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

临床1期临床2期微生物疗法

2024-08-21

·PipelineReview

Azitra Announces First Patient Screened and Scheduled to Enroll in Phase 1b Trial of ATR-12 for Netherton Syndrome

BRANFORD, CT, USA I August 20, 2024 I Azitra, Inc. (NYSE American: AZTR), a precision dermatology company announced that it has successfully screened the first patient in its Phase 1b clinical trial evaluating ATR-12 for the treatment of Netherton syndrome. The patient is scheduled to initiate treatment by the end of the month. The study is designed to enroll approximately 12 adult patients with twice-daily treatment for 14 days, with primary endpoints focusing on safety and tolerability, and secondary and exploratory endpoints assessing efficacy signals and biomarkers. Azitra expects to report interim safety data from the Phase 1b trial in early 2025 with full results anticipated in the second half of 2025. ATR-12 is Azitra’s lead candidate, a proprietary strain of Staphylococcus epidermidis engineered to express therapeutic levels of an active subunit of the LEKTI protein to treat Netherton syndrome, a chronic genetic skin disease that can be life threatening. “Enrolling the first patient in our Phase 1b trial of ATR-12 will mark a significant milestone for Azitra and, more importantly, for patients suffering from Netherton syndrome, who currently have limited treatment options,” said Travis Whitfill, founder and COO of Azitra. “Our recent preclinical data demonstrate ATR-12’s potential to effectively deliver an active LEKTI subunit into the skin and address the underlying mechanisms of Netherton syndrome.” Mary Spellman MD, Azitra’s acting CMO, added, “We are thrilled to begin this clinical trial of ATR-12 in Netherton syndrome patients. These patients suffer from poor quality of life and often debilitating disease, and this trial will inform future studies for the treatment of Netherton syndrome in pediatric patients and for longer treatment durations.” The Phase 1b trial (NCT06137157) is a multicenter, randomized, double-blind, vehicle-controlled study in approximately 12 adult patients with Netherton syndrome. Patients will be treated with 10 9 CFU / g twice daily with ATR-12 or its vehicle control on the contralateral side of the body twice daily for 14 days. The primary objective is to assess the safety and tolerability of topical ATR-12 application. Secondary objectives include evaluating efficacy signals (e.g., investigator and patient global assessments) and skin pharmacokinetics of the LEKTI subunit. Additional exploratory objectives include evaluating pharmacodynamic parameters, biomarkers, anti-LEKTI response, and cytokine responses. The trial design is supported by compelling preclinical data recently presented at the American Society of Gene and Cell Therapy (ASGCT) 2024 Annual Meeting. Key findings included: About ATR-12 ATR-12 (also known as ATR12-351) is an engineered strain of S. epidermidis that expresses an active subunit of human lympho-epithelial Kazal-type-related inhibitor (LEKTI) protein, which is missing in patients with Netherton syndrome, a chronic and sometimes fatal disease of the skin estimated to affect approximately one to nine in every 100,000. ATR-12 has been engineered to deliver missing LEKTI protein when applied topically to Netherton syndrome patients. Azitra has an open IND for a Phase 1b clinical trial in adult patients (NCT06137157). Azitra has secured clinical sites and identified Netherton syndrome patients for enrollment in its 12-patient, Phase 1b clinical trial, which will assess safety, tolerability, and efficacy endpoints. Azitra expects to announce initial safety data before year end. About Azitra, Inc. Azitra, Inc. is an early-stage clinical biopharmaceutical company focused on developing innovative therapies for precision dermatology using engineered proteins and topical live biotherapeutic products. The Company has built a proprietary platform that includes a microbial library comprised of approximately 1,500 unique bacterial strains that can be screened for unique therapeutic characteristics. The platform is augmented by artificial intelligence and machine learning technology that analyzes, predicts, and helps screen the Company’s library of strains for drug like molecules. The Company’s initial focus is on the development of genetically engineered strains of Staphylococcus epidermidis , or S. epidermidis , which the Company considers to be an optimal therapeutic candidate species for engineering of dermatologic therapies. For more information, please visit https://azitrainc.com/ . SOURCE: Azitra

临床1期基因疗法

2024-08-06

·GlobeNewswire-Health Care

Quoin Pharmaceuticals to Initiate Clinical Study for Peeling Skin Syndrome

Peeling Skin Syndrome is a rare autosomal disease with no approved treatment or cure Initial clinical site and pediatric patient identified in New Zealand Company actively evaluating opening additional clinical sites in other countries ASHBURN, Va., Aug. 06, 2024 (GLOBE NEWSWIRE) -- Quoin Pharmaceuticals Ltd. (NASDAQ: QNRX) (the “Company” or “Quoin”) a clinical stage, specialty pharmaceutical company focused on developing and commercializing novel treatments for rare and orphan diseases, today announced the planned initiation of an investigator-led clinical study in New Zealand to evaluate the safety and efficacy of QRX003 in a pediatric patient with Peeling Skin Syndrome (PSS). QRX003 is Quoin’s most advanced pipeline product and is currently being evaluated in two late stage clinical trials in the United States as a potential treatment for Netherton Syndrome (NS). Both studies are being conducted under an open Investigational New Drug (IND) application with the Food and Drug Administration (FDA). “We are excited to expand QRX003’s development into this second indication, peeling skin syndrome, where it is believed the mechanism of action of our product could also provide a benefit for this devastating disease. Given the overlapping nature of how PSS presents, patients with the disease are known to have been previously misdiagnosed as having NS. Currently there are no clinical studies listed for peeling skin syndrome on clinicaltrials.gov as actively recruiting and dosing subjects and there is no approved treatment or cure, presenting a further opportunity for Quoin to achieve the first regulatory approval for another rare genetic disease,” stated Michael Myers, CEO, Quoin Pharmaceuticals. “The planned initiation of this study represents the execution of a key pillar of Quoin’s strategy to expand the clinical testing of QRX003 into other rare and orphan disease indications and we are actively assessing additional opportunities beyond this one.” QRX003 is a unique “whole body, whole life” topical lotion that targets the vicious circle of skin inflammation and barrier disruption. Quoin is conducting two ongoing clinical trials evaluating QRX003 for the treatment of Netherton Syndrome. For more information about the trials, please visit: https://www.nethertonsyndromeclinicaltrials.com/. About Peeling Skin Syndrome (PSS) Generalized inflammatory peeling skin syndrome (PSS) is a rare autosomal recessive genodermatosis caused by loss-of-function disease-causing variants of the corneodesmosin gene (CDSN), resulting in excessive shedding of the superficial layers of the epidermis. Patients generally suffer from a variety of conditions including severe pain and chronic pruritis (itch). There is currently no approved treatment for PSS, and patients manage symptoms using over-the-counter emollients. About QRX003 QRX003 is a topical lotion, formulated with a proprietary delivery technology, and contains a broad- spectrum serine protease inhibitor, whose mechanism of action is intended to perform the function of a specific protein, called LEKTI. The absence of LEKTI in Netherton patients leads to excessive skin shedding resulting in a highly porous and compromised skin barrier. QRX003 is designed to lead to a more normalized skin shedding process and the formation of a stronger and more effective skin barrier. About Quoin Pharmaceuticals Ltd. Quoin Pharmaceuticals Ltd. is an emerging specialty pharmaceutical company focused on developing and commercializing therapeutic products that treat rare and orphan diseases. We are committed to addressing unmet medical needs for patients, their families, communities and care teams. Quoin’s innovative pipeline comprises three products in development that collectively have the potential to target a broad number of rare and orphan indications, including Netherton Syndrome, Peeling Skin Syndrome, Palmoplantar Keratoderma, Epidermolysis Bullosa and others. For more information, go to: www.quoinpharma.com. Cautionary Note Regarding Forward Looking Statements The Company cautions that statements in this press release that are not a description of historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words referencing future events or circumstances such as “expect,” “intend,” “plan,” “anticipate,” “believe,” and “will,” among others. All statements that reflect the Company’s expectations, assumptions, projections, beliefs, or opinions about the future, other than statements of historical fact, are forward-looking statements, including, without limitation, statements relating to the Company’s expected cash runway, the belief that the data set from both clinical studies could potentially be sufficiently robust and comprehensive to support an NDA filing, without the need for any additional clinical studies in Netherton subjects, and the belief that certain protocol changes has enhanced the potential for a successful outcome and Quoin’s products in development collectively have the potential to target a broad number of rare and orphan indications, including Netherton Syndrome, Peeling Skin Syndrome, Palmoplantar Keratoderma, Scleroderma, Epidermolysis Bullosa and others. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon the Company’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties including, but not limited to, the Company may need to raise additional funds sooner than planned, the clinical studies may not generate data which is sufficiently robust and comprehensive to support an NDA filing and the Company’s ability to obtain regulatory approvals. More detailed information about the risks and uncertainties affecting the Company is summarized in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023 and in other filings the Company has made and may make with the SEC in the future. One should not place undue reliance on these forward-looking statements, which speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as may be required by law. For further information, contact: Quoin Pharmaceuticals Ltd.Michael Myers, Ph.D., CEOmmyers@quoinpharma.com Investor RelationsPCG AdvisoryJeff Ramsonjramson@pcgadvisory.com(646) 863-6341

临床研究

100 项与 Lympho-Epithelial Kazal-Type Inhibitor (PHARIS Biotec) 相关的药物交易

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