Objective: To investigate the regulatory effect and mechanism of interleukin-22 (IL-22) on the gingival epithelial barrier in the context of periodontal inflammation. Methods: IL-22 knockout (IL-22 KO) mice were constructed, and periodontitis mice models were established through oral gavage with polymicrobial inoculation. DNAs were extracted from the oral plaques of IL-22 KO periodontitis mice group (n=7) and their wild-type littermates periodontitis group (n=7) to establish a periodontitis-related oral microbiota database"PD-RiskMicroDB", determining the relationship between changes in oral microbiota and microbial function in two groups using 16S rRNA sequencing results. Gingival epithelial cells (GEC) were cultured by modified trypsinization method, and were stimulated with 100 μg/L IL-22, Porphyromonas gingivalis (Pg) (multiplicity of infection:100), separately or together for 3 and 12 hours. The experimental groups were as follows: control group (no stimulation), IL-22 group, Pg group and Pg+IL-22 group. The expression of barrier protein E-cadherin in each group at 3 h was detected by immunofluorescence, real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Fluorescein isothiocyanate-dextran-mediated epithelial cell permeability experiment was conducted to clarify the changes in permeability of GEC in each group at 3 and 12 h. The mRNA expressions of E-cadherin in the gingival epithelium of wild-type littermates periodontitis group and IL-22 KO periodontitis group were detected by RT-qPCR. Fifteen C57BL/6 wild-type mice were randomly divided into control group (n=5), periodontitis group (n=5) and periodontitis+IL-22 treatment group (n=5). RT-qPCR and immunohistochemistry (IHC) staining were used to detect the expression level of E-cadherin in the gingival epithelium of each group. Results: 16S rRNA sequencing results showed that the composition of oral microbiota changed in IL-22 KO periodontitis group, of which the abundance of bacterial genera related to periodontal tissue invasion was significantly increased (linear discriminant analysis score: 2.22, P=0.009), compared with wild-type littermates periodontitis group. In vitro cell experiments showed that after Pg infection for 3 hours, the cell connections of GEC in Pg group were interrupted, and the fluorescence intensity of E-cadherin was reduced in Pg group compared with the control group. Meanwhile, the mRNA and protein expression levels of E-cadherin (mRNA: 0.69±0.12; protein: 0.60±0.12) were downregulated compared with the control group [mRNA: 1.00±0.00 (P=0.043); protein: 1.04±0.08 (P=0.003)], respectively. The fluorescence intensity of E-cadherin in the Pg+IL-22 group was enhanced compared with Pg group, and expression levels of E-cadherin mRNA (1.16±0.10) and protein (0.98±0.07) in Pg+IL-22 group showed a significant increase compared with Pg group [mRNA: 0.69±0.12 (P=0.005); protein: 0.60±0.12 (P=0.007)]. The result of epithelial permeability test showed that there was no statistical difference in epithelial permeability among control group, Pg group, IL-22 group and Pg+IL-22 group with treatment for 3 hours (F=0.20, P=0.893). While when the treatment time turned to be 12 hours, the epithelial barrier permeability showed a significant increase in Pg group (1.39±0.15) compared with control group (1.00±0.00, P=0.027), and a decrease in Pg+IL-22 group (1.02±0.18) compared with Pg group (1.39±0.15, P=0.034). In vivo, the mRNA expression of E-cadherin in the gingival epithelium of IL-22 KO periodontitis group decreased significantly (0.32±0.21) compared with wild-type littermates periodontitis group (1.01±0.01) (t=5.70, P=0.005). Moreover, RT-qPCR and IHC staining results showed that the mRNA expression level of E-cadherin (0.40±0.07) and absorbance value of E-cadherin positive expression (0.02±0.00) in gingival epithelial tissue of periodontitis group were both significantly down-regulated compared with control group [mRNA: 1.00±0.00 (P=0.005); absorbance value of E-cadherin positive expression: 0.04±0.01 (P=0.006)]. Meanwhile, the mRNA expression level of E-cadherin (1.06±0.24) and the absorbance value of E-cadherin positive expression (0.03±0.01) were both observed increase in periodontitis+IL-22 treatment group compared with periodontitis group (P=0.003, P=0.039). Conclusions: IL-22 may exert a protective effect on the gingival epithelial barrier in an inflammatory environment by regulating the invasiveness of oral microbiota and the expression of host barrier protein.

2024-01-01·Bio-protocol

Fluorescent Labeling and Imaging of IL-22 mRNA-Loaded Lipid Nanoparticles

Article

作者: Bolay, Eunice ; Merlin, Didier ; Yang, Chunhua ; Mow, Rabeya Jafrin ; Srinivasan, Anand

Lipid nanoparticle (LNP)-based drug delivery systems (DDSs) are widely recognized for their ability to enhance efficient and precise delivery of therapeutic agents, including nucleic acids like DNA and mRNA. Despite this acknowledgment, there is a notable knowledge gap regarding the systemic biodistribution and organ accumulation of these nanoparticles. The ability to track LNPs in vivo is crucial for understanding their fate within biological systems. Fluorescent labeling of LNPs facilitates real-time tracking, quantification, and visualization of their behavior within biological systems, providing valuable insights into biodistribution, cellular uptake, and the optimization of drug delivery strategies. Our prior research established reversely engineered LNPs as an exceptional mRNA delivery platform for treating ulcerative colitis. This study presents a detailed protocol for labeling interleukin-22 (IL-22) mRNA-loaded LNPs, their oral administration to mice, and visualization of DiR-labeled LNPs biodistribution in the gastrointestinal tract using IVIS spectrum. This fluorescence-based approach will assist researchers in gaining a dynamic understanding of nanoparticle fate in other models of interest. Key features • This protocol is developed to assess the delivery of IL-22 mRNA to ulcerative colitis sites using lipid nanoparticles. • This protocol uses fluorescent DiR dye for imaging of IL-22 mRNA-loaded lipid nanoparticles in the gastrointestinal tract of mice. • This protocol employs the IVIS spectrum for imaging.

2019-02-06·ACS applied materials & interfaces

Targeted Interleukin-22 Gene Delivery in the Liver by Polymetformin and Penetratin-Based Hybrid Nanoparticles to Treat Nonalcoholic Fatty Liver Disease

Article

作者: Chen, Wei ; Tang, Shijie ; Ju, Dianwen ; Zhang, Xuyao ; Wu, Zimei ; Fan, Jiajun ; Liu, Hongrui ; Hao, Qiang ; Jin, Xin ; Mei, Xiaobin ; Luan, Jingyun ; Zai, Wenjing

Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan-metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient cellular internalization. Furthermore, CDPIA also demonstrated a unique superiority in endosomal escape capacity and satisfactory biocompatibility as well as predominant liver accumulation. Most importantly, CDPIA distinctly alleviated hepatic steatosis, restored insulin sensitivity, and improved metabolic syndrome in high-fat-diet-fed mice model. This liver-targeted delivery of IL-22 activated STAT3/Erk1/2 and Nrf2/SOD1 signaling transductions as well as modulated lipid-metabolism-related gene expression. These findings altogether demonstrated that the polymetformin and penetratin-based hybrid nanoparticles could be exploited as a novel safe and efficient strategy for the improvement of NAFLD.

项与 IL-22(Synthekine) 相关的新闻（医药）

2024-07-23

·Firstwordpharma

Cytoki’s IL-22 analogue shows early promise for obesity and diabetes

Cytoki Pharma on Tuesday reported promising early data for its investigational lipidated IL-22 analogue CK-0045 in a Phase I study of 76 healthy participants and otherwise healthy participants with obesity, highlighting improvements on key cardiometabolic parameters."We believe CK-0045 offers a differentiated opportunity to address obesity and type 2 diabetes, either as monotherapy or in combination,” said Rasmus Jørgensen, chief executive of Cytoki. The company noted the data were adequate to support the drug’s advancement into mid-stage testing, which is likely to commence in the second half of the year.CK-0045 is an analogue of a non-immunomodulatory cytokine IL-22, selectively targeting epithelial cells in the gut and liver. According to the biotech, the drug’s “unique mechanism of action” mimicking endogenous IL-22 could potentially help treat various metabolic and inflammatory conditions. Preclinical data from mice studies have earlier shown weight loss and improved glucose homeostasis.Phase I findings established target engagement through liver and gut-derived biomarkers, while the pharmacokinetic data indicated the feasibility of once-weekly subcutaneous dosing. Additionally, exposure-dependent reductions in body mass and improvements on low-density lipoprotein cholesterol, insulin levels, and insulin resistance were observed, especially in participants with reduced insulin sensitivity. Moreover, CK-0045 had a favourable safety and tolerability profile, with no significant gastrointestinal side effects.Cytoki was founded in 2019 by Jørgensen, who previously headed research at Novo Nordisk. CK-0045 was subsequently in-licensed from Novo and positioned as the company’s lead asset.

临床1期临床结果

2024-07-23

·PRNewswire

Cytoki Pharma Announces Positive Phase 1 Data Showing Potential of CK-0045 to Improve Cardiometabolic Risk Factors

CK-0045 induced exposure-dependent reductions in body weight and improvement of key metabolic parameters in participants with obesity Data support advancement of CK-0045 into Phase 2 proof-of-concept studies in individuals with type 2 diabetes and/or obesity COPENHAGEN, Denmark, July 23, 2024 /PRNewswire/ -- Cytoki Pharma, ApS (Cytoki), a clinical-stage biotechnology company pioneering a new class of medicines that harness IL-22 biology to drive improved outcomes for metabolic disease, today announced positive data from a Phase 1 study evaluating the safety, tolerability, and pharmacokinetics of CK-0045, its lead lipidated IL-22 candidate, in healthy participants and otherwise healthy participants with obesity. The data signal the effect of CK-0045 across several key metabolic parameters including body weight, cholesterol, blood glucose levels, and insulin sensitivity. "As the obesity treatment landscape continues to evolve, there remains a need for approaches that drive lasting disease modification through healthy weight loss and broader, deeper weight loss-independent metabolic effects," said Rasmus Jorgensen, Ph.D., Founder and CEO of Cytoki Pharma. "We believe CK-0045 offers a differentiated opportunity to address obesity and type 2 diabetes, either as monotherapy or in combination with other clinical approaches and are encouraged by these first data supporting CK-0045's unique mechanism of action." IL-22 is a non-immunomodulatory cytokine that selectively targets epithelial tissues such as the gut and liver. Previously reported preclinical data demonstrate the potential of lipidated IL-22 to reduce body weight and improve glucose homeostasis in mice through a novel mode-of-action. Results from the Phase 1 study signal successful translation of the preclinical findings to humans, with confirmed target engagement based on liver and gut-derived biomarkers. Pharmacokinetic data confirm feasibility of once weekly subcutaneous dosing. CK-0045 induced exposure-dependent reductions in body mass that were complemented by beneficial reductions in low-density lipoprotein cholesterol, blood insulin concentration, and insulin resistance—particularly in participants with reduced insulin sensitivity. CK-0045 was safe and tolerated across the multiple ascending dose portion of the study, with all but one participant having completed dosing. The most commonly occurring side effects were mild skin reactions and a notable absence of substantial gastrointestinal effects was observed. The available clinical data support advancement of CK-0045 into Phase 2 proof-of-concept studies in individuals with obesity and type 2 diabetes to further assess the clinical relevance of observed effects. Initiation of the Phase 2 is anticipated in the second half of 2024. About CK-0045 CK-0045 is a long-acting analogue of interleukin-22 (IL-22), an atypical, non-immunomodulatory cytokine that selectively targets epithelial cells. In-licensed from Novo Nordisk A/S, CK-0045 incorporates validated technology to optimize the pharmacologic properties of the endogenous IL-22 protein to create a differentiated, first-in-class therapy with potential to address a broad range of metabolic diseases, including obesity and type 2 diabetes, and conditions characterized by epithelial injury, such as inflammatory bowel disease. CK-0045 has been evaluated in a randomized, double-blind, placebo-controlled Phase 1 study designed to investigate its safety, tolerability, and pharmacokinetics in healthy individuals with and without obesity (NCT05712876). CK-0045 is expected to enter Phase 2 studies in the second half of 2024. About Cytoki Pharma Cytoki Pharma is a clinical-stage biotechnology company pioneering a new class of medicines that harness IL-22 biology to drive improved outcomes for cardiometabolic disease. Cytoki's lead program, CK-0045, is a lipidated IL-22 analogue that has been evaluated in a Phase 1 clinical study and is expected to enter Phase 2 clinical studies in the second half of 2024. The lead compound is selected from a full program of therapeutic IL-22 variants based on an exclusive license from Novo Nordisk A/S. The company is also advancing a broader portfolio of preclinical IL-22-based assets for the treatment of metabolic disease and inflammatory bowel disease. Cytoki was founded in 2019 and is led by a team of pharma industry veterans with deep expertise in the discovery and clinical development of novel drugs. Please visit or follow us on LinkedIn for additional details. SOURCE Cytoki Pharma

临床1期引进/卖出临床结果临床2期

2024-05-16

·BioSpace

J&J Buys Proteologix for $850M, Bispecific Antibodies for Atopic Dermatitis

Pictured: Johnson & Johnson Business Center in Switzerland/iStock, yuelan Johnson & Johnson is expanding its dermatology portfolio with an $850 million cash deal. The pharma giant announced Thursday its acquisition of privately-held biotech Proteologix, adding bispecific antibody assets for atopic dermatitis to its pipeline. Proteologix’s PX128 is a bispecific antibody targeting interleukin 13 plus TSLP. The antibody is Phase I-ready for severe atopic dermatitis (AD) and moderate to severe asthma. Another preclinical antibody, PX130, targets IL-13 plus IL-22 for moderate to severe AD. Targeting dual pathways is expected to increase efficacy, according to J&J, and both candidates are designed for convenient, infrequent dosing intervals. “Together, these pipeline additions demonstrate a strategic approach to build a portfolio of differentiated and complementary bispecifics,” J&J said in its announcement of the deal. In addition to the $850 million in cash, California-based Proteologix will also be eligible for an additional milestone payment. J&J will also scoop up other bispecific antibody programs in the acquisition. Subject to antitrust clearance and other customary closing conditions, the deal is expected to close in mid-2024. “Atopic dermatitis is the most common inflammatory skin disease, impacting more than 100 million adults worldwide,” David Lee, global immunology therapeutic area head at J&J, said in a statement, noting that roughly 70% of patients on standard-of-care medicines do not achieve remission. “We see an opportunity for best-in-disease efficacy for both PX128 and PX130 as each bispecific antibody targets two different combinations of disease driving pathways that are mediating the skin inflammation in heterogenous subpopulations of AD patients.” In March 2024, Eli Lilly reported Phase IIIb results of its IL-13 targeting monoclonal antibody in moderate-to-severe AD. The trial was specifically designed for people of color, a group which is disproportionately affected by the condition. Initial 16-week data showed over two-thirds of participants on lebrikizumab experienced improvement of at least 75% in disease extent and severity. After an FDA rejection in October 2023 due to on-site issues with its third-party contract manufacturer, Lilly resubmitted its BLA for lebrikizumab in April 2024. A decision is expected later this year. In June 2023, MilliporeSigma announced that Proteologix was selected as the North American winner of its 12th Advance Biotech Grant program, noting that the startup was “selected for its robust pipeline targeting autoimmune/inflammatory diseases and oncology indications that affect a large patient population.” Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

临床结果并购免疫疗法临床3期临床1期

100 项与 IL-22(Synthekine) 相关的药物交易

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