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Wu Q, Zeng Y, Geng K, Guo M, Teng FY, Yan PJ, Lei Y, Long Y, Jiang ZZ, Law BYK, Xu Y. The role of IL-1 family cytokines in diabetic cardiomyopathy. Metabolism 2025; 163:156083. [PMID: 39603339 DOI: 10.1016/j.metabol.2024.156083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/18/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024]
Abstract
Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.
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Affiliation(s)
- Qi Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Pathology, and Luzhou Key Laboratory of Precision Pathology Diagnosis for Serious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yan Zeng
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Kang Geng
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Department of Plastic and burns surgery, National Key Clinical Construction Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Man Guo
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Fang-Yuan Teng
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Pi-Jun Yan
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yi Lei
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yang Long
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Zong-Zhe Jiang
- Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Betty Yuen-Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China.
| | - Yong Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Endocrinology and Metabolism, and Metabolic Vascular Disease Key Laboratory of Sichuan Province, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
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Binder U, Skerra A. Strategies for extending the half-life of biotherapeutics: successes and complications. Expert Opin Biol Ther 2025; 25:93-118. [PMID: 39663567 DOI: 10.1080/14712598.2024.2436094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/26/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION Engineering of the drug half-life in vivo has become an integral part of modern biopharmaceutical development due to the fact that many proteins/peptides with therapeutic potential are quickly cleared by kidney filtration after injection and, thus, circulate only a few hours in humans (or just minutes in mice). AREAS COVERED Looking at the growing list of clinically approved biologics that have been modified for prolonged activity, and also the plethora of such drugs under preclinical and clinical development, it is evident that not one solution fits all needs, owing to the vastly different structural features and functional properties of the pharmacologically active entities. This article provides an overview of established half-life extension strategies, as well as of emerging novel concepts for extending the in vivo stability of biologicals, and their pros and cons. EXPERT OPINION Beyond the classical and still dominating technologies for improving drug pharmacokinetics and bioavailability, Fc fusion and PEGylation, various innovative approaches that offer advantages in different respects have entered the clinical stage. While the Fc fusion partner may be gradually superseded by engineered albumin-binding domains, chemical PEGylation may be replaced by biodegradable recombinant amino-acid polymers like PASylation, thus also offering a purely biotechnological manufacturing route.
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Affiliation(s)
| | - Arne Skerra
- Lehrstuhl für Biologische Chemie, Technische Universität München, Freising, Germany
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Obi ON, Saketkoo LA, Maier LA, Baughman RP. Developmental drugs for sarcoidosis. J Autoimmun 2024; 149:103179. [PMID: 38548579 DOI: 10.1016/j.jaut.2024.103179] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/04/2023] [Accepted: 02/08/2024] [Indexed: 12/15/2024]
Abstract
Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, USA; University Medical Center - Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, USA; Louisiana State University School of Medicine, Section of Pulmonary Medicine, New Orleans, LA, USA; Tulane University School of Medicine, Undergraduate Honors Department, New Orleans, LA, USA
| | - Lisa A Maier
- Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary and Critical Care Sciences, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
| | - Robert P Baughman
- Emeritus Professor of Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
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Girgis JM, Baumal CR, Witkin AJ, Vajzovic L, Goldberg RA, Kaiser P, Arevalo JF, Choudhry N, Schneider E, Tabandeh H, Wong R. Update on Retinal Drug Safety: Proceedings of the ASRS ReST Committee Webinar Part 1. JOURNAL OF VITREORETINAL DISEASES 2024; 8:500-507. [PMID: 39318987 PMCID: PMC11418662 DOI: 10.1177/24741264241261441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Purpose: To review the first Research and Safety in Therapeutics (ReST) Committee webinar and summarize the most current recommendations regarding diagnosis and management. Methods: The ReST Committee is comprised of members of the American Society of Retina Surgeons (ASRS). At regular internal meetings, safety issue reports from the website are reviewed. A webinar series was started in 2021 to update members on multiple relevant potential safety events. Results: Topics reviewed in the webinar included pentosan polysulfate sodium (Elmiron) maculopathy, intraocular pressure elevation reported with the aflibercept prefilled syringe (PFS), and brolucizumab-associated inflammation with occlusive retinal vasculitis. Retinal toxicity related to intraoperative medications was reviewed, including hemorrhagic occlusive retinal vasculitis after intraocular vancomycin, dilution errors with intravitreal aminoglycosides, inadvertent overdoses of cefuroxime after cataract surgery, and toxic posterior segment syndrome after dropless cataract surgery using compounded triamcinolone-moxifloxacin. Indocyanine green toxicity has been reported after its use as an adjuvant during macular hole surgery. Conclusions: The past decade has seen advances in retinal pharmaceuticals and drug-delivery devices. The ASRS ReST Committee collects data from its website reporting system to inform members about up-to-date pharmaceutical and device safety concerns. Recently, a webinar was used to inform members of pigmentary maculopathy associated with pentosan polysulfate sodium, safety regarding the aflibercept PFS, intraocular inflammation and occlusive retinal vasculitis secondary to brolucizumab, and retinal toxicity from intraoperative ocular medications.
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Affiliation(s)
- Jessica M. Girgis
- New England Eye Center, Tufts Medicine, Boston, MA, USA
- Tufts University School of Medicine, Boston, MA, USA
| | - Caroline R. Baumal
- New England Eye Center, Tufts Medicine, Boston, MA, USA
- Tufts University School of Medicine, Boston, MA, USA
| | - Andre J. Witkin
- New England Eye Center, Tufts Medicine, Boston, MA, USA
- Tufts University School of Medicine, Boston, MA, USA
| | | | | | - Peter Kaiser
- Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | | | - Netan Choudhry
- Vitreous Retina Macula Specialists of Toronto, ON, Canada
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Kim DH, Lee WW. IL-1 Receptor Dynamics in Immune Cells: Orchestrating Immune Precision and Balance. Immune Netw 2024; 24:e21. [PMID: 38974214 PMCID: PMC11224669 DOI: 10.4110/in.2024.24.e21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/19/2024] [Accepted: 05/20/2024] [Indexed: 07/09/2024] Open
Abstract
IL-1, a pleiotropic cytokine with profound effects on various cell types, particularly immune cells, plays a pivotal role in immune responses. The proinflammatory nature of IL-1 necessitates stringent control mechanisms of IL-1-mediated signaling at multiple levels, encompassing transcriptional and translational regulation, precursor processing, as well as the involvement of a receptor accessory protein, a decoy receptor, and a receptor antagonist. In T-cell immunity, IL-1 signaling is crucial during both the priming and effector phases of immune reactions. The fine-tuning of IL-1 signaling hinges upon two distinct receptor types; the functional IL-1 receptor (IL-1R) 1 and the decoy IL-1R2, accompanied by ancillary molecules such as the IL-1R accessory protein (IL-1R3) and IL-1R antagonist. IL-1R1 signaling by IL-1β is critical for the differentiation, expansion, and survival of Th17 cells, essential for defense against extracellular bacteria or fungi, yet implicated in autoimmune disease pathogenesis. Recent investigations emphasize the physiological importance of IL-1R2 expression, particularly in its capacity to modulate IL-1-dependent responses within Tregs. The precise regulation of IL-1R signaling is indispensable for orchestrating appropriate immune responses, as unchecked IL-1 signaling has been implicated in inflammatory disorders, including Th17-mediated autoimmunity. This review provides a thorough exploration of the IL-1R signaling complex and its pivotal roles in immune regulation. Additionally, it highlights recent advancements elucidating the mechanisms governing the expression of IL-1R1 and IL-1R2, underscoring their contributions to fine-tuning IL-1 signaling. Finally, the review briefly touches upon therapeutic strategies targeting IL-1R signaling, with potential clinical applications.
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Affiliation(s)
- Dong Hyun Kim
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Won-Woo Lee
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea
- Seoul National University Cancer Research Institute, Seoul 03080, Korea
- Institute of Endemic Diseases and Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Korea
- Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Korea
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Sanz-Cabanillas JL, Gómez-García F, Gómez-Arias PJ, Montilla-López A, Gay-Mimbrera J, Ruano J, Isla-Tejera B, Parra-Peralbo E. Efficacy and safety of anakinra and canakinumab in PSTPIP1-associated inflammatory diseases: a comprehensive scoping review. Front Immunol 2024; 14:1339337. [PMID: 38259483 PMCID: PMC10801072 DOI: 10.3389/fimmu.2023.1339337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 12/13/2023] [Indexed: 01/24/2024] Open
Abstract
Introduction This scoping review explores the effectiveness of IL-1 pathway inhibitors in managing PSTPIP1-associated inflammatory diseases (PAID). These diseases are marked by abnormal IL-1 pathway activation due to genetic mutations. Methods Our methodology adhered to a pre-published protocol and involved a thorough search of MEDLINE and EMBASE databases up to February 2022, following the Joanna Briggs Institute Reviewer's Manual and the PRISMA Extension for Scoping Reviews. The review included studies reporting on IL-1 pathway inhibitor use in PAID patients. Results From an initial pool of 5,225 articles, 36 studies involving 43 patients were selected. The studies predominantly used observational designs and exhibited diversity in patient demographics, treatment approaches, and outcomes. Anakinra and canakinumab demonstrated promise in treating sterile pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) and PSTPIP1-associated myeloid-related-proteinemia inflammatory (PAMI) syndromes, with scant data on other syndromes. Notably, there was a paucity of information on the adverse effects of these treatments, necessitating cautious interpretation of their safety profile. Conclusion Current evidence on IL-1 pathway inhibitors for PAID is primarily from observational studies and remains limited. Rigorous research with larger patient cohorts is imperative for more definitive conclusions. Collaborative efforts among specialized research centers and international health initiatives are key to advancing this field.
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Affiliation(s)
- Juan Luis Sanz-Cabanillas
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
- Department of Dermatology, Reina Sofia University Hospital, Córdoba, Spain
| | - Francisco Gómez-García
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
- Department of Dermatology, Reina Sofia University Hospital, Córdoba, Spain
| | - Pedro Jesús Gómez-Arias
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
- Department of Dermatology, Reina Sofia University Hospital, Córdoba, Spain
| | - Ana Montilla-López
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
| | - Jesús Gay-Mimbrera
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
| | - Juan Ruano
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
- Department of Dermatology, Reina Sofia University Hospital, Córdoba, Spain
- School of Medicine and Nursing, University of Cordoba, Córdoba, Spain
| | - Beatriz Isla-Tejera
- Inflammatory Immune-mediated Chronic Skin Diseases’ Laboratory, IMIBIC/Reina Sofia University Hospital/University of Cordoba, Córdoba, Spain
- Department of Pharmacology, Reina Sofia University Hospital, Córdoba, Spain
| | - Esmeralda Parra-Peralbo
- Department of Pharmacy and Nutrition, Faculty of Biomedical Science and Health, Universidad Europea, Madrid, Spain
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Peng X, Li X, Xie B, Lai Y, Sosnik A, Boucetta H, Chen Z, He W. Gout therapeutics and drug delivery. J Control Release 2023; 362:728-754. [PMID: 37690697 DOI: 10.1016/j.jconrel.2023.09.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/12/2023]
Abstract
Gout is a common inflammatory arthritis caused by persistently elevated uric acid levels. With the improvement of people's living standards, the consumption of processed food and the widespread use of drugs that induce elevated uric acid, gout rates are increasing, seriously affecting the human quality of life, and becoming a burden to health systems worldwide. Since the pathological mechanism of gout has been elucidated, there are relatively effective drug treatments in clinical practice. However, due to (bio)pharmaceutical shortcomings of these drugs, such as poor chemical stability and limited ability to target the pathophysiological pathways, traditional drug treatment strategies show low efficacy and safety. In this scenario, drug delivery systems (DDS) design that overcome these drawbacks is urgently called for. In this review, we initially describe the pathological features, the therapeutic targets, and the drugs currently in clinical use and under investigation to treat gout. We also comprehensively summarize recent research efforts utilizing lipid, polymeric and inorganic carriers to develop advanced DDS for improved gout management and therapy.
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Affiliation(s)
- Xiuju Peng
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Xiaotong Li
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Bing Xie
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Yaoyao Lai
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Alejandro Sosnik
- Department of Materials Science and Engineering, Technion - Israel Institute of Technology, Technion City, Haifa 3200003, Israel
| | - Hamza Boucetta
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China.
| | - Wei He
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 2111198, PR China; Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China.
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Zhang Y. From gene identifications to therapeutic targets for asthma: Focus on great potentials of TSLP, ORMDL3, and GSDMB. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2023; 1:139-147. [PMID: 39171126 PMCID: PMC11332877 DOI: 10.1016/j.pccm.2023.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Indexed: 08/23/2024]
Abstract
Asthma is a chronic respiratory disease, and clinically, asthma exacerbations remain difficult to treat. The disease is caused by combinations of and interactions between genetic and environmental factors. Genomic and genetic approaches identified many novel genes to treat asthma and brought new insights into the disease. The products of the genes have functional roles in regulating physiological or pathophysiological processes in airway structural cells and immune system cells. Genetic factors also interact with environmental factors such as air pollutants, and bacterial and viral infections to trigger the disease. Thymic stromal lymphopoietin (TSLP), orosomucoid-like 3 (ORMDL3), and gasdermin B (GSDMB) are three genes identified by genetic studies to have a great potential as therapeutic targets of asthma. TSLP is an important driver of type 2 inflammation. ORMDL3 mediates cell stress, sphingolipid synthesis, and viral and bacterial infections. GSDMB regulates cell pyroptosis through its N and C terminals and can bind sulfatides to influence inflammatory response. Investigating inhibitors or modulators for these pathways would bring a new landscape for therapeutics of asthma in future.
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Affiliation(s)
- Youming Zhang
- National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK
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Torices S, Daire L, Simon S, Mendoza L, Daniels D, Joseph JA, Fattakhov N, Naranjo O, Teglas T, Toborek M. The NLRP3 inflammasome and gut dysbiosis as a putative link between HIV-1 infection and ischemic stroke. Trends Neurosci 2023; 46:682-693. [PMID: 37330380 PMCID: PMC10554647 DOI: 10.1016/j.tins.2023.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/26/2023] [Accepted: 05/18/2023] [Indexed: 06/19/2023]
Abstract
HIV-associated comorbidities, such as ischemic stroke, are prevalent in people with HIV (PWH). Several studies both in animal models and humans have revealed an association between activation of the inflammasome in HIV-1 infection and stroke. The gut microbiota is an important component in controlling neuroinflammation in the CNS. It has also been proposed to be involved in the pathobiology of HIV-1 infection, and has been associated with an increase in activation of the inflammasome. In this review, we provide an overview of the microbiota-gut-inflammasome-brain axis, focusing on the NLRP3 inflammasome and dysregulation of the microbiome as risk factors that may contribute to the outcome of ischemic stroke and recovery in PWH. We also focus on the potential of targeting the NLRP3 inflammasome as a novel therapeutic approach for PWH who are at risk of developing cerebrovascular diseases.
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Affiliation(s)
- Silvia Torices
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA.
| | - Leah Daire
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Sierra Simon
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Luisa Mendoza
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Destiny Daniels
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Joelle-Ann Joseph
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Nikolai Fattakhov
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Oandy Naranjo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Timea Teglas
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Suite 528, 1011 NW 15th Street, Miami, FL 33136, USA.
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Myachikova VY, Maslyanskiy AL, Moiseeva OM, Vinogradova OV, Gleykina EV, Lavrovsky Y, Abbate A, Grishin SA, Egorova AN, Schedrova ML, Samsonov MY. Treatment of Idiopathic Recurrent Pericarditis With Goflikicept: Phase II/III Study Results. J Am Coll Cardiol 2023; 82:30-40. [PMID: 37380301 DOI: 10.1016/j.jacc.2023.04.046] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 06/30/2023]
Abstract
BACKGROUND Idiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disease. Interleukin (IL)-1α and IL-1β are the pivotal cytokines in the pathophysiology of acute pericarditis and its recurrence. We created a phase II/III study with a new IL-1 inhibitor-goflikicept in IRP. OBJECTIVES This study sought to evaluate the efficacy and safety of goflikicept treatment in patients with IRP. METHODS We conducted a 2-center open-label study of goflikicept in patients with IRP with and without recurrence at time of enrollment. The study consisted of 4 periods: screening, run-in (open-label treatment period), randomized withdrawal, and follow-up. Patients with clinical response to goflikicept in the run-in period were randomized (1:1) to a placebo-controlled withdrawal period, where the time to first pericarditis recurrence (primary endpoint) was evaluated. RESULTS We enrolled 22 patients, and 20 of these patients were randomized. Reduction of C-reactive protein level accompanied by reduction of chest pain and pericardial effusion compared to baseline was demonstrated during the run-in period. Recurrence of pericarditis occurred in 9 of 10 patients in the placebo group, and there were no recurrence events in goflikicept group within 24 weeks after randomization (P < 0.001). A total of 122 adverse events were reported in 21 patients (95.5%), with no deaths and no new safety signals identified for goflikicept. CONCLUSIONS Treatment with goflikicept prevented recurrences and maintained IRP remission with a favorable risk-benefit ratio. Goflikicept reduced the risk of recurrence compared with placebo. (Study to Evaluate the Efficacy and Safety of RPH-104 Treatment in Patients With Idiopathic Recurrent Pericarditis; NCT04692766).
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Affiliation(s)
- Valentina Yu Myachikova
- World-Class Research Center for Personalized Medicine, Rare and Genetically Determined Diseases, Research Laboratory of Autoimmune and Autoinflammatory Diseases, St Petersburg, Russia; Almazov National Medical Research Center, Rheumatology and Immunopathology Research Laboratory, St Petersburg, Russia.
| | - Alexey L Maslyanskiy
- Almazov National Medical Research Center, Rheumatology and Immunopathology Research Laboratory, St Petersburg, Russia; Saint Petersburg State University, Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, St Petersburg, Russia
| | - Olga M Moiseeva
- Almazov National Medical Research Center, Noncoronary Heart Disease Research Department, St Petersburg, Russia
| | - Oksana V Vinogradova
- State Autonomous Healthcare Institution "Orenburg Regional Clinical Hospital," Regional Vascular Center, Orenburg, Russia
| | - Ekaterina V Gleykina
- State Autonomous Healthcare Institution "Orenburg Regional Clinical Hospital," Cardiology Department No. 2, Orenburg, Russia
| | | | - Antonio Abbate
- Berne Cardiovascular Research Center and Division of Cardiology, School of Medicine, University of Virginia, Charlottesville, Virginia, USA
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Wang Y, Wang J, Zheng W, Zhang J, Wang J, Jin T, Tao P, Wang Y, Liu C, Huang J, Lee PY, Yu X, Zhou Q. Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design. Immunity 2023:S1074-7613(23)00231-5. [PMID: 37315560 DOI: 10.1016/j.immuni.2023.05.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 03/27/2023] [Accepted: 05/17/2023] [Indexed: 06/16/2023]
Abstract
The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1α or IL-1β. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1β and IL-1α, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases.
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Affiliation(s)
- Yusha Wang
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China
| | - Jun Wang
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Wenjie Zheng
- Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Jiahui Zhang
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Jinbo Wang
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Taijie Jin
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Panfeng Tao
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China
| | - Yibo Wang
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Chenlu Liu
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Jiqian Huang
- Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Pui Y Lee
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Xiaomin Yu
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China; Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University, Hangzhou 311121, Zhejiang, China; Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.
| | - Qing Zhou
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, Zhejiang, China.
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12
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Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R, Volpi S, Caorsi R, Gattorno M. An Update on Familial Mediterranean Fever. Int J Mol Sci 2023; 24:ijms24119584. [PMID: 37298536 DOI: 10.3390/ijms24119584] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/12/2023] Open
Abstract
(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself.
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Affiliation(s)
- Maddalena Lancieri
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Marta Bustaffa
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Serena Palmeri
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Ignazia Prigione
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Federica Penco
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Riccardo Papa
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Stefano Volpi
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Roberta Caorsi
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Marco Gattorno
- UOC Malattie Autoinfiammatorie e Immunodeficenze, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
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Jeon J, Lee H, Jeon MS, Kim SJ, Choi C, Kim KW, Yang DJ, Lee S, Bae YS, Choi WI, Jung J, Eyun SI, Yang S. Blockade of Activin Receptor IIB Protects Arthritis Pathogenesis by Non-Amplification of Activin A-ACVR2B-NOX4 Axis Pathway. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2205161. [PMID: 36950748 DOI: 10.1002/advs.202205161] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 02/10/2023] [Indexed: 05/18/2023]
Abstract
Although activin receptor IIB (ACVR2B) is emerging as a novel pathogenic receptor, its ligand and assembled components (or assembly) are totally unknown in the context of osteoarthritis (OA) pathogenesis. The present results suggest that upregulation of ACVR2B and its assembly could affect osteoarthritic cartilage destruction. It is shown that the ACVR2B ligand, activin A, regulates catabolic factor expression through ACVR2B in OA development. Activin A Tg mice (Col2a1-Inhba) exhibit enhanced cartilage destruction, whereas heterozygous activin A KO mice (Inhba+/- ) show protection from cartilage destruction. In silico analysis suggests that the Activin A-ACVR2B axis is involved in Nox4-dependent ROS production. Activin A Tg:Nox4 KO (Col2a1-Inhba:Nox4-/- ) mice show inhibition of experimental OA pathogenesis. NOX4 directly binds to the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction through SMAD2/3 signaling. Together, the findings reveal that the ACVR2B assembly, which comprises Activin A, ACVR2B, ACVR1B, Nox4, and AP-1-induced HIF-2α, accelerates OA development. Furthermore, it is shown that shRNA-mediated ACVR2B knockdown or trapping ligands of ACVR2B abrogate OA development by competitively disrupting the ACVR2B-Activin A interaction. These results suggest that the ACVR2B assembly is required to amplify osteoarthritic cartilage destruction and could be a potential therapeutic target in efforts to treat OA.
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Affiliation(s)
- Jimin Jeon
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea
- CIRNO, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Hyemi Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea
- CIRNO, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Min-Seung Jeon
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Seok-Jung Kim
- Department of Orthopaedic Surgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu, 11765, Republic of Korea
| | - Cham Choi
- MicroCT Applications, 3rd floor, 11, Sumyeong-ro 1-gil, Gangseo-gu, Seoul, 07644, Republic of Korea
| | - Ki Woo Kim
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
- Department of Applied Biological Science, BK21 FOUR, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Dong Joo Yang
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
- Department of Applied Biological Science, BK21 FOUR, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Sangho Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea
- CIRNO, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Yong-Soo Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea
- CIRNO, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Won Il Choi
- Center for Bio-Healthcare Materials, Bio-Convergence Materials R&D Division, Korea Institute of Ceramic Engineering and Technology, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Juyeon Jung
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Seong-Il Eyun
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Siyoung Yang
- Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea
- CIRNO, Sungkyunkwan University, Suwon, 16419, Republic of Korea
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Zhang Z, Li X, Wang Y, Wei Y, Wei X. Involvement of inflammasomes in tumor microenvironment and tumor therapies. J Hematol Oncol 2023; 16:24. [PMID: 36932407 PMCID: PMC10022228 DOI: 10.1186/s13045-023-01407-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/08/2023] [Indexed: 03/19/2023] Open
Abstract
Inflammasomes are macromolecular platforms formed in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns, whose formation would cause maturation of interleukin-1 (IL-1) family members and gasdermin D (GSDMD), leading to IL-1 secretion and pyroptosis respectively. Several kinds of inflammasomes detecting different types of dangers have been found. The activation of inflammasomes is regulated at both transcription and posttranscription levels, which is crucial in protecting the host from infections and sterile insults. Present findings have illustrated that inflammasomes are involved in not only infection but also the pathology of tumors implying an important link between inflammation and tumor development. Generally, inflammasomes participate in tumorigenesis, cell death, metastasis, immune evasion, chemotherapy, target therapy, and radiotherapy. Inflammasome components are upregulated in some tumors, and inflammasomes can be activated in cancer cells and other stromal cells by DAMPs, chemotherapy agents, and radiation. In some cases, inflammasomes inhibit tumor progression by initiating GSDMD-mediated pyroptosis in cancer cells and stimulating IL-1 signal-mediated anti-tumor immunity. However, IL-1 signal recruits immunosuppressive cell subsets in other cases. We discuss the conflicting results and propose some possible explanations. Additionally, we also summarize interventions targeting inflammasome pathways in both preclinical and clinical stages. Interventions targeting inflammasomes are promising for immunotherapy and combination therapy.
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Affiliation(s)
- Ziqi Zhang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xue Li
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yang Wang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yuquan Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xiawei Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
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Busse WW, Viswanathan R. What has been learned by cytokine targeting of asthma? J Allergy Clin Immunol 2022; 150:235-249. [DOI: 10.1016/j.jaci.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 11/24/2022]
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16
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Groza Y, Jemelkova J, Kafkova LR, Maly P, Raska M. IL-6 and its role in IgA nephropathy development. Cytokine Growth Factor Rev 2022; 66:1-14. [PMID: 35527168 DOI: 10.1016/j.cytogfr.2022.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 04/05/2022] [Indexed: 02/07/2023]
Abstract
IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes. Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria. This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.
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Affiliation(s)
- Yaroslava Groza
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Jana Jemelkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic
| | - Leona Raskova Kafkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic.
| | - Petr Maly
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic.
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Abstract
BACKGROUND Familial Mediterranean fever (FMF), a hereditary auto-inflammatory disease, mainly affects ethnic groups living in the Mediterranean region. Early studies reported colchicine may potentially prevent FMF attacks. For people who are colchicine-resistant or intolerant, drugs such as anakinra, rilonacept, canakinumab, etanercept, infliximab or adalimumab might be beneficial. This is an update of the review last published in 2018. OBJECTIVES To evaluate the efficacy and safety of interventions for reducing inflammation in people with FMF. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase and four Chinese databases on in August 2021. We searched clinical trials registries and references listed in relevant reports. The last search was 17 August 2021. SELECTION CRITERIA We included randomized controlled trials (RCTs) of people with FMF, comparing active interventions (including colchicine, anakinra, rilonacept, canakinumab, etanercept, infliximab, adalimumab, thalidomide, tocilizumab, interferon-α and ImmunoGuard (herbal dietary supplement)) with placebo or no treatment, or comparing active drugs to each other. DATA COLLECTION AND ANALYSIS We used standard Cochrane methodology. We assessed certainty of the evidence using GRADE. MAIN RESULTS We included 10 RCTs with 312 participants (aged three to 53 years), including five parallel and five cross-over designed studies. Six studies used oral colchicine, one used oral ImmunoGuard, and the remaining three used rilonacept, anakinra or canakinumab as a subcutaneous injection. The duration of each study arm ranged from one to eight months. There were inadequacies in the design of the four older colchicine studies and the two studies comparing a single to a divided dose of colchicine. However, the four studies of ImmunoGuard, rilonacept, anakinra and canakinumab were generally well-designed. We aimed to report on the number of participants experiencing an attack, the timing of attacks, the prevention of amyloid A amyloidosis, adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack; but no study reported on the prevention of amyloid A amyloidosis. Colchicine (oral) versus placebo After three months, colchicine 0.6 mg three times daily may reduce the number of people experiencing attacks (risk ratio (RR) 0.21, 95% confidence interval (CI) 0.05 to 0.95; 1 study, 10 participants; low-certainty evidence). One study (20 participants) of colchicine 0.5 mg twice daily showed there may be no difference in the number of participants experiencing attacks at two months (RR 0.78, 95% CI 0.49 to 1.23; low-certainty evidence). There may be no differences in the duration of attacks (narrative summary; very low-certainty evidence), or in the number of days between attacks: (narrative summary; very low-certainty evidence). Regarding adverse drug reactions, one study reported loose stools and frequent bowel movements and a second reported diarrhea (narrative summary; both very low-certainty evidence). There were no data on acute-phase response. Rilonacept versus placebo There is probably no difference in the number of people experiencing attacks at three months (RR 0.87, 95% CI 0.59 to 1.26; moderate-certainty evidence). There may be no differences in the duration of attacks (narrative summary; low-certainty evidence) or in the number of days between attacks (narrative summary; low-certainty evidence). Regarding adverse drug reactions, the rilonacept study reported there may be no differences in gastrointestinal symptoms, hypertension, headache, respiratory tract infections, injection site reactions and herpes, compared to placebo (narrative summary; low-certainty evidence). The study narratively reported there may be no differences in acute-phase response indicators after three months (low-certainty evidence). ImmunoGuard versus placebo The ImmunoGuard study observed there are probably no differences in adverse effects (moderate-certainty evidence) or in acute-phase response indicators after one month of treatment (moderate-certainty evidence). No data were reported for the number of people experiencing an attack, duration of attacks or days between attacks. Anakinra versus placebo A study of anakinra given to 25 colchicine-resistant participants found there is probably no difference in the number of participants experiencing an attack at four months (RR 0.76, 95% CI 0.54 to 1.07; moderate-certainty evidence). There were no data for duration of attacks or days between attacks. There are probably no differences between anakinra and placebo with regards to injection site reaction, headache, presyncope, dyspnea and itching (narrative summary; moderate-certainty evidence). For acute-phase response, anakinra probably reduced C-reactive protein (CRP) after four months (narrative summary; moderate-certainty evidence). Canakinumab versus placebo Canakinumab probably reduces the number of participants experiencing an attack at 16 weeks (RR 0.41, 95% CI 0.26 to 0.65; 1 study, 63 colchicine-resistant participants; moderate-certainty evidence). There were no data for the duration of attacks or days between attacks. The included study reported the number of serious adverse events per 100 patient-years was probably 42.7 with canakinumab versus 97.4 with placebo among people with colchicine-resistant FMF (moderate-certainty evidence). For acute-phase response, canakinumab probably caused a higher proportion of participants to have a CRP level of 10 mg/L or less compared to placebo (68% with canakinumab versus 6% with placebo; 1 study, 63 participants; moderate-certainty evidence). Colchicine single dose versus divided dose There is probably no difference in the duration of attacks at three months (MD -0.04 hours, 95% CI -10.91 to 10.83) or six months (MD 2.80 hours, 95% CI -5.39 to 10.99; moderate-certainty evidence). There were no data for the number of participants experiencing an attack or days between attacks. There is probably no difference in adverse events (including anorexia, nausea, diarrhea, abdominal pain, vomiting and elevated liver enzymes) between groups (narrative summary; moderate-certainty evidence). For acute-phase response, there may be no evidence of a difference between groups (narrative summary; low- to moderate-certainty evidence). AUTHORS' CONCLUSIONS There were limited RCTs assessing interventions for people with FMF. Based on the evidence, three times daily colchicine may reduce the number of people experiencing attacks, colchicine single dose and divided dose may not be different for children with FMF, canakinumab probably reduces the number of people experiencing attacks, and anakinra or canakinumab probably reduce CRP in colchicine-resistant participants; however, only a few RCTs contributed data for analysis. Further RCTs examining active interventions, not only colchicine, are necessary before a comprehensive conclusion regarding the efficacy and safety of interventions for reducing inflammation in FMF can be drawn.
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Affiliation(s)
- Xi Yin
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Fangyuan Tian
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Xu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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18
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Gargani S, Lourou N, Arapatzi C, Tzanos D, Saridaki M, Dushku E, Chatzimike M, Sidiropoulos ND, Andreadou M, Ntafis V, Hatzis P, Kostourou V, Kontoyiannis DL. Inactivation of AUF1 in Myeloid Cells Protects From Allergic Airway and Tumor Infiltration and Impairs the Adenosine-Induced Polarization of Pro-Angiogenic Macrophages. Front Immunol 2022; 13:752215. [PMID: 35222366 PMCID: PMC8873154 DOI: 10.3389/fimmu.2022.752215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/21/2022] [Indexed: 11/13/2022] Open
Abstract
The four isoforms of the RNA-binding protein hnRNPD/AUF1 have been proposed to limit the use of inflammatory mRNAs in innate immune cells. Mice engineered to lack AUF1s in all tissues are sensitive to acute inflammatory assaults; however, they also manifest complex degenerations obscuring assessment of AUF1s’ roles in innate immune cells. Here, we restricted a debilitating AUF1 mutation to the mouse myeloid lineage and performed disease-oriented phenotypic analyses to assess the requirement of AUF1s in variable contexts of innate immune reactivity. Contrary to the whole-body mutants, the myeloid mutants of AUF1s did not show differences in their susceptibility to cytokine storms occurring during endotoxemia; neither in type-I cell-mediated reactions driving intestinal inflammation by chemical irritants. Instead, they were resistant to allergic airway inflammation and displayed reductions in inflammatory infiltrates and an altered T-helper balance. The ex-vivo analysis of macrophages revealed that the loss of AUF1s had a minimal effect on their proinflammatory gene expression. Moreover, AUF1s were dispensable for the classical polarization of cultured macrophages by LPS & IFNγ correlating with the unchanged response of mutant mice to systemic and intestinal inflammation. Notably, AUF1s were also dispensable for the alternative polarization of macrophages by IL4, TGFβ and IL10, known to be engaged in allergic reactions. In contrast, they were required to switch proinflammatory macrophages towards a pro-angiogenic phenotype induced by adenosine receptor signals. Congruent to this, the myeloid mutants of AUF1 displayed lower levels of vascular remodeling factors in exudates from allergen exposed lungs; were unable to support the growth and inflammatory infiltration of transplanted melanoma tumors; and failed to vascularize inert grafts unless supplemented with angiogenic factors. Mechanistically, adenosine receptor signals enhanced the association of AUF1s with the Vegfa, Il12b, and Tnf mRNAs to differentially regulate and facilitate the pro-angiogenic switch. Our data collectively demonstrates that AUF1s do not act as general anti-inflammatory factors in innate immune cells but have more specialized roles in regulons allowing specific innate immune cell transitions to support tissue infiltration and remodeling processes.
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Affiliation(s)
- Sofia Gargani
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Niki Lourou
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christina Arapatzi
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Dimitris Tzanos
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Marania Saridaki
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Esmeralda Dushku
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Margarita Chatzimike
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Nikolaos D. Sidiropoulos
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Margarita Andreadou
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Vasileios Ntafis
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Pantelis Hatzis
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Vassiliki Kostourou
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
| | - Dimitris L. Kontoyiannis
- Biomedical Sciences Research Centre “Alexander Fleming”, Institute of Fundamental Biomedical Research, Vari, Greece
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
- *Correspondence: Dimitris L. Kontoyiannis, ;
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19
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Abstract
Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. Schnitzler syndrome is often underdiagnosed. Patients with Schnitzler syndrome may present to dermatologists and allergists for urticaria, hematologists for MGUS, or rheumatologists for arthritis. It is important to recognize Schnitzler syndrome for its remarkable response to interleukin (IL)-1 blockade. Besides, many cases of Schnitzler-like syndromes do not meet the diagnostic criteria of classical Schnitzler syndrome but display excellent response to IL-1 inhibitors. The overly produced IL-1 is the result of a somatic mosaic gain of function mutation of NLRP3 (nucleotide-binding oligomerization domain [NOD]-like receptor [NLR] family pyrin domain containing 3) gene in some patients with Schnitzler-like syndromes. Inflammasome activation is evident in patients with classical Schnitzler syndrome although no NLRP3 gene mutation is identified. Collectively, Schnitzler syndrome and Schnitzler-like syndromes represent a spectrum of IL-1 mediated adult-onset autoinflammatory diseases.
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20
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Dosmar E, Walsh J, Doyel M, Bussett K, Oladipupo A, Amer S, Goebel K. Targeting Ocular Drug Delivery: An Examination of Local Anatomy and Current Approaches. Bioengineering (Basel) 2022; 9:41. [PMID: 35049750 PMCID: PMC8772869 DOI: 10.3390/bioengineering9010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/03/2022] [Accepted: 01/10/2022] [Indexed: 01/23/2023] Open
Abstract
Ocular drug delivery remains the focus of much modern research. Primary routes of administration include the surface, the intravitreal space, the subretinal space, and the subconjunctival space, each with its own series of unique challenges, limitations, and advantages. Each of these approaches requires careful consideration of the local anatomy, physical barriers, and key cells as well as the interface between the anatomy and the drug or drug system being delivered. While least invasive, the topical route poses a challenge with the many physical barriers that prevent drug penetration into the eye; while injection into the intravitreal, subretinal, and subconjunctival spaces are direct and targeted but limited due to the many internal clearance mechanisms and potential for damage to the eye. Polymeric-based, sustained-release drug delivery systems have been identified as a potential solution to many of these challenges; however, the design and successful implementation of a sustained-release system that is well-tolerated, bioactive, biocompatible, and degradable remains, in many cases, only in the early stages. The drugs and biomaterials in question also require special attention as small chemical changes could result in vastly different outcomes. This paper explores the anatomy and key cells of these four primary drug delivery routes as well as the interface between drug and drug delivery systems and the anatomy, reviewing the recent developments and current state of research in each area. Finally, this paper also examines the frequently used drugs and biomaterials found in ocular drug delivery and summarizes the primary interactions observed.
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Affiliation(s)
- Emily Dosmar
- Department of Biology and Biomedical Engineering, Rose-Hulman Institute of Technology, Terre Haute, IN 47803, USA; (J.W.); (M.D.); (K.B.); (A.O.); (S.A.); (K.G.)
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21
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Atsou K, Anjuère F, Braud VM, Goudon T. A size and space structured model of tumor growth describes a key role for protumor immune cells in breaking equilibrium states in tumorigenesis. PLoS One 2021; 16:e0259291. [PMID: 34808661 PMCID: PMC8608488 DOI: 10.1371/journal.pone.0259291] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/15/2021] [Indexed: 01/29/2023] Open
Abstract
Switching from the healthy stage to the uncontrolled development of tumors relies on complicated mechanisms and the activation of antagonistic immune responses, that can ultimately favor the tumor growth. We introduce here a mathematical model intended to describe the interactions between the immune system and tumors. The model is based on partial differential equations, describing the displacement of immune cells subjected to both diffusion and chemotactic mechanisms, the strength of which is driven by the development of the tumors. The model takes into account the dual nature of the immune response, with the activation of both antitumor and protumor mechanisms. The competition between these antagonistic effects leads to either equilibrium or escape phases, which reproduces features of tumor development observed in experimental and clinical settings. Next, we consider on numerical grounds the efficacy of treatments: the numerical study brings out interesting hints on immunotherapy strategies, concerning the role of the administered dose, the role of the administration time and the interest in combining treatments acting on different aspects of the immune response. Such mathematical model can shed light on the conditions where the tumor can be maintained in a viable state and also provide useful hints for personalized, efficient, therapeutic strategies, boosting the antitumor immune response, and reducing the protumor actions.
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Affiliation(s)
- Kevin Atsou
- Université Côte d’Azur, Inria, CNRS, LJAD, Parc Valrose, Nice, France
| | - Fabienne Anjuère
- Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire UMR 7275, Valbonne, France
| | - Véronique M. Braud
- Université Côte d’Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire UMR 7275, Valbonne, France
| | - Thierry Goudon
- Université Côte d’Azur, Inria, CNRS, LJAD, Parc Valrose, Nice, France
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22
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Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily. Sci Rep 2021; 11:18341. [PMID: 34526551 PMCID: PMC8443706 DOI: 10.1038/s41598-021-97203-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/18/2021] [Indexed: 01/19/2023] Open
Abstract
Ligands of the transforming growth factor-β (TGF-β) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-β superfamily ligands with novel selectivity, we generated soluble, heterodimeric ligand traps by pairing the extracellular domain (ECD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I receptors activin receptor-like kinase 4 (ALK4), ALK7, or ALK3. Systematic analysis of these heterodimeric constructs by surface plasmon resonance, and comparison with their homodimeric counterparts, revealed that each type I receptor partner confers a distinct ligand-binding profile to the heterodimeric construct. Additional characterization in cell-based reporter gene assays confirmed that the heterodimeric constructs possessed different profiles of signaling inhibition in vitro, which translated into altered patterns of pharmacological activity when constructs were administered systemically to wild-type mice. Our results detail a versatile platform for the modular recombination of naturally occurring receptor domains, giving rise to inhibitory ligand traps that could aid in defining the physiological roles of TGF-β ligand sets or be directed therapeutically to human diseases arising from dysregulated TGF-β superfamily signaling.
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23
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Sánchez-Trasviña C, Flores-Gatica M, Enriquez-Ochoa D, Rito-Palomares M, Mayolo-Deloisa K. Purification of Modified Therapeutic Proteins Available on the Market: An Analysis of Chromatography-Based Strategies. Front Bioeng Biotechnol 2021; 9:717326. [PMID: 34490225 PMCID: PMC8417561 DOI: 10.3389/fbioe.2021.717326] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 08/09/2021] [Indexed: 02/02/2023] Open
Abstract
Proteins, which have inherent biorecognition properties, have long been used as therapeutic agents for the treatment of a wide variety of clinical indications. Protein modification through covalent attachment to different moieties improves the therapeutic's pharmacokinetic properties, affinity, stability, confers protection against proteolytic degradation, and increases circulation half-life. Nowadays, several modified therapeutic proteins, including PEGylated, Fc-fused, lipidated, albumin-fused, and glycosylated proteins have obtained regulatory approval for commercialization. During its manufacturing, the purification steps of the therapeutic agent are decisive to ensure the quality, effectiveness, potency, and safety of the final product. Due to the robustness, selectivity, and high resolution of chromatographic methods, these are recognized as the gold standard in the downstream processing of therapeutic proteins. Moreover, depending on the modification strategy, the protein will suffer different physicochemical changes, which must be considered to define a purification approach. This review aims to deeply analyze the purification methods employed for modified therapeutic proteins that are currently available on the market, to understand why the selected strategies were successful. Emphasis is placed on chromatographic methods since they govern the purification processes within the pharmaceutical industry. Furthermore, to discuss how the modification type strongly influences the purification strategy, the purification processes of three different modified versions of coagulation factor IX are contrasted.
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Affiliation(s)
- Calef Sánchez-Trasviña
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Centro de Biotecnología-FEMSA, Monterrey, Mexico
| | - Miguel Flores-Gatica
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Centro de Biotecnología-FEMSA, Monterrey, Mexico
| | - Daniela Enriquez-Ochoa
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Centro de Biotecnología-FEMSA, Monterrey, Mexico
| | - Marco Rito-Palomares
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Karla Mayolo-Deloisa
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Centro de Biotecnología-FEMSA, Monterrey, Mexico
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24
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Manrique-Suárez V, Macaya L, Contreras MA, Parra N, Maura R, González A, Toledo JR, Sánchez O. Design and characterization of a novel dimeric blood-brain barrier penetrating TNFα inhibitor. Proteins 2021; 89:1508-1521. [PMID: 34219271 DOI: 10.1002/prot.26173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/18/2021] [Accepted: 06/29/2021] [Indexed: 12/20/2022]
Abstract
Tumor necrosis factor-alpha (TNFα) inhibitors could prevent neurological disorders systemically, but their design generally relies on molecules unable to cross the blood-brain barrier (BBB). This research was aimed to design and characterize a novel TNFα inhibitor based on the angiopeptide-2 as a BBB shuttle molecule fused to the extracellular domain of human TNFα receptor 2 and a mutated vascular endothelial growth factor (VEGF) dimerization domain. This new chimeric protein (MTV) would be able to trigger receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP-1) and inhibit the cytotoxic effect of TNFα more efficiently because of its dimeric structure. Stably transformed CHO cells successfully expressed MTV, and its purification by Immobilized-Metal Affinity Chromatography (IMAC) rendered high purity degree. Mutated VEGF domain included in MTV did not show cell proliferation or angiogenic activities measured by scratch and aortic ring assays, which corroborate that the function of this domain is restricted to dimerization. The pairs MTV-TNFα (Kd 279 ± 40.9 nM) and MTV-LRP1 (Kd 399 ± 50.5 nM) showed high affinity by microscale thermophoresis, and a significant increase in cell survival was observed after blocking TNFα with MTV in a cell cytotoxicity assay. Also, the antibody staining in CHOK1 and bEnd3 cells demonstrated the adhesion of MTV to the LRP1 receptor located in the cell membrane. These results provide compelling evidence for the proper functioning of the three main domains of MTV individually, which encourage us to continue the research with this new molecule as a potential candidate for the systemic treatment of neurological disorders.
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Affiliation(s)
- Viana Manrique-Suárez
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Luis Macaya
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Maria Angélica Contreras
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Natalie Parra
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Rafael Maura
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Alaín González
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile.,Faculty of Basic Sciences, University of Medellin, Medellin, Colombia
| | - Jorge R Toledo
- Biotechnology and Biopharmaceutical Laboratory, Pathophysiology Department, School of Biological Science, Universidad de Concepción, Concepcion, Chile.,Center of Biotechnology and Biomedicine Spa, Concepción, Chile
| | - Oliberto Sánchez
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile.,Center of Biotechnology and Biomedicine Spa, Concepción, Chile
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25
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The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers (Basel) 2021; 13:cancers13133248. [PMID: 34209646 PMCID: PMC8268320 DOI: 10.3390/cancers13133248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
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26
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Intrinsic differences in the mechanisms of Tie2 binding to angiopoietins exploited by directed evolution to create an Ang2-selective ligand trap. J Biol Chem 2021; 297:100888. [PMID: 34153320 PMCID: PMC8294587 DOI: 10.1016/j.jbc.2021.100888] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Angiopoietins Ang1 and Ang2 are secreted ligands for the endothelial receptor tyrosine kinase Tie2 essential for vascular development and maintenance. Ang1 acts as an agonist to maintain normal vessel function, whereas Ang2 acts as a Tie2 antagonist. Ang2 is increased in macular edema, sepsis, and other conditions, in which it blocks Ang1-mediated signaling, causing vascular dysfunction and contributing to disease pathology. Therefore, Ang2 is an attractive therapeutic target. Previously, we reported a Tie2 ectodomain variant that selectively binds Ang2 and acts as soluble ligand trap to sequester Ang2; however, the mechanism of Ang2-binding selectivity is unknown. In the present study, we used directed protein evolution to enhance Ang2-binding affinity of this Tie2 ectodomain trap. We examined contributions of individual residues in the ligand-binding interface of Tie2 to Ang1 and Ang2 binding. Surprisingly, different combinations of Tie2 residues were found to bind each ligand, with hydrophobic residues binding both ligands and polar residues contributing selectively to either Ang1 or Ang2 binding. Our analysis also identified a single Tie2 residue, His168, with a pivotal role in both Ang1 and Ang2 binding, enabling competition between binding ligands. In summary, this study reports an enhanced-affinity Ang2-selective ligand trap with potential for therapeutic development and reveals the mechanism behind its selectivity. It also provides the first analysis of contributions of individual Tie2 residues to Ang1 and Ang2 binding and identifies selectivity-determining residues that could be targeted in the future design of small molecule and other inhibitors of Ang2 for the treatment of vascular dysfunction.
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27
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Hunter SA, McIntosh BJ, Shi Y, Sperberg RAP, Funatogawa C, Labanieh L, Soon E, Wastyk HC, Mehta N, Carter C, Hunter T, Cochran JR. An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy. Commun Biol 2021; 4:452. [PMID: 33846527 PMCID: PMC8041770 DOI: 10.1038/s42003-021-01928-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 02/26/2021] [Indexed: 02/01/2023] Open
Abstract
Leukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered 'ligand trap', fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment.
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Affiliation(s)
- Sean A Hunter
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Brianna J McIntosh
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Yu Shi
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | | | | | - Louai Labanieh
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Erin Soon
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Hannah C Wastyk
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Nishant Mehta
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Catherine Carter
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Tony Hunter
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Jennifer R Cochran
- Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Bioengineering, Stanford University, Stanford, CA, USA.
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
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28
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Griffiths JS, Camilli G, Kotowicz NK, Ho J, Richardson JP, Naglik JR. Role for IL-1 Family Cytokines in Fungal Infections. Front Microbiol 2021; 12:633047. [PMID: 33643264 PMCID: PMC7902786 DOI: 10.3389/fmicb.2021.633047] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/15/2021] [Indexed: 12/15/2022] Open
Abstract
Fungal pathogens kill approximately 1.5 million individuals per year and represent a severe disease burden worldwide. It is estimated over 150 million people have serious fungal disease such as recurrent mucosal infections or life-threatening systemic infections. Disease can ensue from commensal fungi or new infection and involves different fungal morphologies and the expression of virulence factors. Therefore, anti-fungal immunity is complex and requires coordination between multiple facets of the immune system. IL-1 family cytokines are associated with acute and chronic inflammation and are essential for the innate response to infection. Recent research indicates IL-1 cytokines play a key role mediating immunity against different fungal infections. During mucosal disease, IL-1R and IL-36R are required for neutrophil recruitment and protective Th17 responses, but function through different mechanisms. During systemic disease, IL-18 drives protective Th1 responses, while IL-33 promotes Th2 and suppresses Th1 immunity. The IL-1 family represents an attractive anti-fungal immunotherapy target. There is a need for novel anti-fungal therapeutics, as current therapies are ineffective, toxic and encounter resistance, and no anti-fungal vaccine exists. Furthering our understanding of the IL-1 family cytokines and their complex role during fungal infection may aid the development of novel therapies. As such, this review will discuss the role for IL-1 family cytokines in fungal infections.
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Affiliation(s)
- James S Griffiths
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Giorgio Camilli
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Natalia K Kotowicz
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Jemima Ho
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Jonathan P Richardson
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Julian R Naglik
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
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Intravitreal Therapy for Diabetic Macular Edema: An Update. J Ophthalmol 2021; 2021:6654168. [PMID: 33688431 PMCID: PMC7925023 DOI: 10.1155/2021/6654168] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 02/11/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic macular edema (DME) represents a prevalent and disabling eye condition. Despite that DME represents a sight-threatening condition, it is also among the most accessible to treatment. Many different treatment options including photocoagulation, intravitreal medical treatment (either vascular endothelial growth factor inhibitors or corticosteroids therapies), and surgical removal are currently available. Although laser has been considered as the gold standard for many years, over the past several years vascular endothelial growth factor inhibitors (anti-VEGFs) have become first-line therapy. However, many patients do not adequately respond to them. With the development of sustained-release corticosteroid devices, steroids have gained a presence in the management of the DME. We review and update the role of anti-VEGF and intravitreal sustained-release corticosteroid management of DME. According to the currently available scientific evidence, the choice of one anti-VEGF over another critically depends on the baseline best-corrected visual acuity (BCVA). While aflibercept may be the drug of choice in low baseline BCVA, the three anti-VEGFs (bevacizumab, ranibizumab, and aflibercept) provided similar functional outcomes when the baseline BCVA was higher. DEX implants are a valuable option for treating DME, although they are usually seen as a second choice, particularly in those eyes that have an insufficient response to anti-VEGF. The new evidence suggested that, in eyes that did not adequately respond to anti-VEGF, switching to a DEX implant at the time to 3 monthly anti-VEGF injections provided better functional outcomes.
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30
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Abstract
Thymic stromal lymphopoietin (TSLP) is an allarmin cytokine whose importance in human asthma has been repeatedly documented. Accordingly, targeting of TSLP and TSLP-mediated signalling is considered as an attractive therapeutic strategy to asthma. Tezepelumab, which is the first-in-class anti-TSLP monoclonal antibodies (mAb), is a fully human IgG2λ mAb that binds human TSLP, prevents interaction with its receptor and, consequently, inhibits multiple downstream inflammatory pathways. Because of the excellent results of Phase II trials, the Food and Drug Administration granted tezepelumab as a 'breakthrough' biological drug for the treatment of severe asthma. Several studies with this mAb are ongoing. CSJ117 is an Ab fragment that binds to TSLP and is delivered by inhalation but there is no published information on this biologic agent. Since new information suggests that targeting TSLP may be more likely to improve day-to-day asthma symptoms, in contrast to targeting mediators of the adaptive immune system, approaches that primarily act to ameliorate asthma exacerbations, novel approaches capable of blocking TSLP (for example, fully human single-chain fragment variables against TSLP, bifunctional drugs such as the one that combines an anti-IL-13 mAb with an anti-TSLP mAb, a fusion protein consisting of the ectodomains of TSLPR and IL-7Ra that extend into the extracellular space, also known as a TSLP-trap, fragments capable of disrupting the TSLP:TSLPR complex) are under preclinical investigation. However, some critical aspects remain to be clarified before being able to define this approach as the one that will probably better help patients suffering from severe asthma because of its holistic effects.
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31
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Ricci F, Bandello F, Navarra P, Staurenghi G, Stumpp M, Zarbin M. Neovascular Age-Related Macular Degeneration: Therapeutic Management and New-Upcoming Approaches. Int J Mol Sci 2020; 21:ijms21218242. [PMID: 33153227 PMCID: PMC7662479 DOI: 10.3390/ijms21218242] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/24/2020] [Accepted: 10/30/2020] [Indexed: 12/11/2022] Open
Abstract
Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.
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Affiliation(s)
- Federico Ricci
- Department of Experimental Medicine, University Tor Vergata, Viale Oxford, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-33-5663-3319
| | - Francesco Bandello
- Scientific Institute San Raffaele, University Vita Salute, 20132 Milan, Italy;
| | - Pierluigi Navarra
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
- Department of Pharmacology, Medical School, Catholic University, 00198 Rome, Italy
| | | | - Michael Stumpp
- Molecular Partners AG—Wagistrasse, 14 8952 Zurich-Schlieren, Switzerland;
| | - Marco Zarbin
- Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA;
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32
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Duivelshof BL, Murisier A, Camperi J, Fekete S, Beck A, Guillarme D, D'Atri V. Therapeutic Fc-fusion proteins: Current analytical strategies. J Sep Sci 2020; 44:35-62. [PMID: 32914936 DOI: 10.1002/jssc.202000765] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/27/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022]
Abstract
Fc-Fusion proteins represent a successful class of biopharmaceutical products, with already 13 drugs approved in the European Union and United States as well as three biosimilar versions of etanercept. Fc-Fusion products combine tailored pharmacological properties of biological ligands, together with multiple functions of the fragment crystallizable domain of immunoglobulins. There is a great diversity in terms of possible biological ligands, including the extracellular domains of natural receptors, functionally active peptides, recombinant enzymes, and genetically engineered binding constructs acting as cytokine traps. Due to their highly diverse structures, the analytical characterization of Fc-Fusion proteins is far more complex than that of monoclonal antibodies and requires the use and development of additional product-specific methods over conventional generic/platform methods. This can be explained, for example, by the presence of numerous sialic acids, leading to high diversity in terms of isoelectric points and complex glycosylation profiles including multiple N- and O-linked glycosylation sites. In this review, we highlight the wide range of analytical strategies used to fully characterize Fc-fusion proteins. We also present case studies on the structural assessment of all commercially available Fc-fusion proteins, based on the features and critical quality attributes of their ligand-binding domains.
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Affiliation(s)
- Bastiaan L Duivelshof
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland
| | - Amarande Murisier
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland
| | - Julien Camperi
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland
| | - Szabolcs Fekete
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland
| | - Alain Beck
- IRPF - Centre d'Immunologie Pierre-Fabre (CIPF), Saint-Julien-en-Genevois, France
| | - Davy Guillarme
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland
| | - Valentina D'Atri
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland
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Chadha S, Behl T, Bungau S, Kumar A, Arora R, Gupta A, Uddin MS, Zengin G, Aleya L, Setia D, Arora S. Mechanistic insights into the role of pyroptosis in rheumatoid arthritis. Curr Res Transl Med 2020; 68:151-158. [PMID: 32830085 DOI: 10.1016/j.retram.2020.07.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/09/2020] [Accepted: 07/28/2020] [Indexed: 12/30/2022]
Abstract
Cell death is ascribed as an essential biological process that is fundamental for the development of an organism along with its survival. The procedure comprises of apoptosis and pyroptosis. Pyroptosis is a programmed procedure for cell death which is inflammatory in nature and this pathway gets activated via human caspase-4, human caspase-11 and human caspase-5. The activation of this process leads to release of pro-inflammatory mediators including cytokines, alarmins, IL-18 and IL-1β. The pro-inflammatory mediators released via interaction of intracellular kinases direct the development of Rheumatoid arthritis. Rheumatoid arthritis is characterized as disorder/disease that is auto-immune and chronic in nature. It involves erosions in marginal bone along with articular cartilage which is responsible for joint destruction. The cytokine along with its complex network is responsible for inflammation. The process of pyroptosis is linked with the destruction of plasma membrane, that releases these mediators and excessive release of these mediators is linked with rheumatoid arthritis.
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Affiliation(s)
- Swati Chadha
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Rashmi Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Amit Gupta
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Gokhan Zengin
- Department of Biology, Faculty of Science, Selcuk Uniersity Campus, Konya, Turkey
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, France
| | - Dhruv Setia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sandeep Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Marković I, Savvides SN. Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer. Front Immunol 2020; 11:1557. [PMID: 32849527 PMCID: PMC7396566 DOI: 10.3389/fimmu.2020.01557] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/12/2020] [Indexed: 12/30/2022] Open
Abstract
Thymic Stromal Lymphopoietin (TSLP) and Interleukin-7 (IL-7) are widely studied cytokines within distinct branches of immunology. On one hand, TSLP is crucially important for mediating type 2 immunity at barrier surfaces and has been linked to widespread allergic and inflammatory diseases of the airways, skin, and gut. On the other hand, IL-7 operates at the foundations of T-cell and innate lymphoid cell (ILC) development and homeostasis and has been associated with cancer. Yet, TSLP and IL-7 are united by key commonalities in their structure and the structural basis of the receptor assemblies they mediate to initiate cellular signaling, in particular their cross-utilization of IL-7Rα. As therapeutic targeting of TSLP and IL-7 via diverse approaches is reaching advanced stages and in light of the plethora of mechanistic and structural data on receptor signaling mediated by the two cytokines, the time is ripe to provide integrated views of such knowledge. Here, we first discuss the major pathophysiological roles of TSLP and IL-7 in autoimmune diseases, inflammation and cancer. Subsequently, we curate structural and mechanistic knowledge about receptor assemblies mediated by the two cytokines. Finally, we review therapeutic avenues targeting TSLP and IL-7 signaling. We envision that such integrated view of the mechanism, structure, and modulation of signaling assemblies mediated by TSLP and IL-7 will enhance and fine-tune the development of more effective and selective approaches to further interrogate the role of TSLP and IL-7 in physiology and disease.
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Affiliation(s)
- Iva Marković
- VIB-UGent Center for Inflammation Research, Ghent, Belgium.,Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
| | - Savvas N Savvides
- VIB-UGent Center for Inflammation Research, Ghent, Belgium.,Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
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35
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Holgado A, Braun H, Verstraete K, Vanneste D, Callewaert N, Savvides SN, Afonina IS, Beyaert R. Single-Chain Soluble Receptor Fusion Proteins as Versatile Cytokine Inhibitors. Front Immunol 2020; 11:1422. [PMID: 32754154 PMCID: PMC7370943 DOI: 10.3389/fimmu.2020.01422] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/02/2020] [Indexed: 01/08/2023] Open
Abstract
Cytokines are small secreted proteins that among many functions also play key roles in the orchestration of inflammation in host defense and disease. Over the past years, a large number of biologics have been developed to target cytokines in disease, amongst which soluble receptor fusion proteins have shown some promise in pre-clinical studies. We have previously shown proof-of-concept for the therapeutic targeting of interleukin (IL)-33 in airway inflammation using a newly developed biologic, termed IL-33trap, comprising the ectodomains of the cognate receptor ST2 and the co-receptor IL-1RAcP fused into a single-chain recombinant fusion protein. Here we extend the biophysical and biological characterization of IL-33trap variants, and show that IL-33trap is a stable protein with a monomeric profile both at physiological temperatures and during liquid storage at 4°C. Reducing the N-glycan heterogeneity and complexity of IL-33trap via GlycoDelete engineering neither affects its stability nor its inhibitory activity against IL-33. We also report that IL-33trap specifically targets biologically active IL-33 splice variants. Finally, we document the generation and antagonistic activity of a single-chain IL-4/13trap, which inhibits both IL-4 and IL-13 signaling. Collectively, these results illustrate that single-chain soluble receptor fusion proteins against IL-4, IL-13, and IL-33 are novel biologics that might not only be of interest for research purposes and further interrogation of the role of their target cytokines in physiology and disease, but may also complement monoclonal antibodies for the treatment of allergic and other inflammatory diseases.
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Affiliation(s)
- Aurora Holgado
- Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Harald Braun
- Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kenneth Verstraete
- Center for Inflammation Research, Unit for Structural Biology, VIB, Ghent, Belgium.,Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
| | - Domien Vanneste
- Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Nico Callewaert
- Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.,Center for Medical Biotechnology, VIB, Ghent, Belgium
| | - Savvas N Savvides
- Center for Inflammation Research, Unit for Structural Biology, VIB, Ghent, Belgium.,Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
| | - Inna S Afonina
- Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Rudi Beyaert
- Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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Toms D, Al-Ani A, Sunba S, Tong QYV, Workentine M, Ungrin M. Automated Hypothesis Generation to Identify Signals Relevant in the Development of Mammalian Cell and Tissue Bioprocesses, With Validation in a Retinal Culture System. Front Bioeng Biotechnol 2020; 8:534. [PMID: 32582664 PMCID: PMC7287043 DOI: 10.3389/fbioe.2020.00534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
We have developed an accessible software tool (receptoR) to predict potentially active signaling pathways in one or more cell type(s) of interest from publicly available transcriptome data. As proof-of-concept, we applied it to mouse photoreceptors, yielding the previously untested hypothesis that activin signaling pathways are active in these cells. Expression of the type 2 activin receptor (Acvr2a) was experimentally confirmed by both RT-qPCR and immunochemistry, and activation of this signaling pathway with recombinant activin A significantly enhanced the survival of magnetically sorted photoreceptors in culture. Taken together, we demonstrate that our approach can be easily used to mine publicly available transcriptome data and generate hypotheses around receptor expression that can be used to identify novel signaling pathways in specific cell types of interest. We anticipate that receptoR (available at https://www.ucalgary.ca/ungrinlab/receptoR) will enable more efficient use of limited research resources.
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Affiliation(s)
- Derek Toms
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Abdullah Al-Ani
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada.,Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.,Leaders in Medicine Program, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Saud Sunba
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Qing Yun Victor Tong
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Matthew Workentine
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark Ungrin
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.,Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.,Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada.,Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
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Infectious Implications of Interleukin-1, Interleukin-6, and T Helper Type 2 Inhibition. Infect Dis Clin North Am 2020; 34:211-234. [PMID: 32334983 DOI: 10.1016/j.idc.2020.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Targeting interleukins that drive innate inflammation has expanded treatments of autoinflammatory and autoimmune disorders. Interleukin (IL)-1 inhibition has proven useful for monogenic autoinflammatory syndromes, and IL-6 inhibition for autoimmune arthritides. Biological therapies impeding these pathways impair detection and containment of pathogens, particularly invasive bacteria, reflecting the importance of IL-1 and IL-6 in communicating danger throughout the immune system. Biologics targeting T helper type 2 inflammation are used to treat specific allergic, atopic, and eosinophilic diseases. They may impair protections against local herpesvirus reactivations while augmenting antiviral responses to respiratory viruses. Their risks with helminth exposures have yet to be defined.
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38
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Hogg HJ, Di Simplicio S, Pearce MS. Ranibizumab and aflibercept intravitreal injection for treatment naïve and refractory macular oedema in branch retinal vein occlusion. Eur J Ophthalmol 2020; 31:548-555. [PMID: 32009462 DOI: 10.1177/1120672120904669] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Branch retinal vein occlusion complicated by macular oedema is a common disease treated with intravitreal injection of anti-vascular endothelial growth factor. Controversy exists surrounding anti-vascular endothelial growth factor selection for both treatment naïve and refractory cases. METHODS A retrospective electronic medical record review at a single UK centre generated a cohort of 259 treatment naïve eyes from 258 patients receiving ranibizumab, aflibercept or a combination (n = 83, 97 and 79, respectively) from 2013 to 2018 with ⩾6 months follow-up. Number of intravitreal injections, visual acuity and macular oedema presence were noted at 3, 6, 12, 24, 36 and 48 months. A subgroup analysis examined refractory cases switched from ranibizumab to aflibercept (n = 77) or maintained on ranibizumab (n = 35). RESULTS Eyes receiving ranibizumab or aflibercept had equivocal vision gain at 1 year, 8.0 (95% CI 5.0-11.0) and 9.6 (7.2-12.1) Early Treatment of Diabetic Retinopathy Study letters, respectively. About 35.6% had no macular oedema at 12 months with ranibizumab compared with 50.0% with aflibercept (p = 0.07) following 5.1 (4.7-5.6) and 6.0 (5.6-6.4) intravitreal injections, respectively. Visual prognosis declined significantly as treatment delay extended (p = 0.003) which was only apparent with ⩾3 months delay. Eyes with refractory macular oedema also had equivocal functional and anatomical outcomes whether they were maintained on ranibizumab or switched to aflibercept. CONCLUSION These real world data demonstrate more modest clinical improvements from anti-vascular endothelial growth factor treatment than reported in clinical trials. The functional outcomes of ranibizumab and aflibercept in both treatment naïve and refractory cases were equivocal while the anatomical outcomes of aflibercept may be superior.
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Affiliation(s)
- Hd Jeffry Hogg
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.,Newcastle Eye Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sandro Di Simplicio
- Newcastle Eye Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Mark S Pearce
- Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
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39
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Spel L, Martinon F. Inflammasomes contributing to inflammation in arthritis. Immunol Rev 2020; 294:48-62. [DOI: 10.1111/imr.12839] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Lotte Spel
- Departement of Biochemistry University of Lausanne Epalinges Switzerland
| | - Fabio Martinon
- Departement of Biochemistry University of Lausanne Epalinges Switzerland
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40
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Hu WH, Chan GKL, Duan R, Wang HY, Kong XP, Dong TTX, Tsim KWK. Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11121828. [PMID: 31757048 PMCID: PMC6966653 DOI: 10.3390/cancers11121828] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/18/2019] [Accepted: 10/21/2019] [Indexed: 12/22/2022] Open
Abstract
Ginkgetin, a biflavone from Ginkgo biloba leaf, and resveratrol, a polyphenol found in grape and wine, are two phytochemicals being identified for its binding to vascular endothelial growth factor (VEGF): the binding, therefore, resulted in the alteration of the physiological roles of VEGF-mediated angiogenesis. The bindings of ginkgetin and resveratrol were proposed on different sites of VEGF, but both of them suppressed the angiogenic properties of VEGF. The suppressive activities of ginkgetin and resveratrol in VEGF-mediated angiogenesis were supported by several lines of evidence including (i) inhibiting the formation of sub-intestinal vessel in zebrafish embryos and microvascular sprouting in rat aortic ring; and (ii) suppressing the phosphorylations of VEGFR2, Akt, eNOS, and Erk as well as expressions of matrix metalloproteinases (MMPs), MMP-2, and MMP-9 in human umbilical vein endothelial cells (HUVECs). Here, we showed the synergy of ginkgetin and resveratrol in suppressing the VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation. The synergy of ginkgetin and resveratrol was further illustrated in HT-29 colon cancer xenograft nude mice. Ginkgetin and resveratrol, when applied together, exerted a synergistic anti-tumor effect of 5-fluorouracil with decreasing microvessel density of tumors. In parallel, the combination of ginkgetin and resveratrol synergistically relieved the 5-fluorouracil-induced inflammatory response by suppressing expressions of COX-2 and inflammatory cytokines. Thus, the anti-angiogenic roles of ginkgetin and/or resveratrol could provide effective therapeutic strategy in cancer, similar to that of Avastin, in suppressing the VEGF-mediated angiogenesis during cancer development.
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Affiliation(s)
- Wei-Hui Hu
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Gallant Kar-Lun Chan
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Ran Duan
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Huai-You Wang
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Xiang-Peng Kong
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Tina Ting-Xia Dong
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
| | - Karl Wah-Keung Tsim
- Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China; (W.-H.H.); (G.K.-L.C.); (R.D.); (H.-Y.W.); (X.-P.K.); (T.T.-X.D.)
- Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 999077, China
- Correspondence: ; Tel.: +852-2358-7332; Fax: +852-2358-1552
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Kim JW, Marquez CP, Kostyrko K, Koehne AL, Marini K, Simpson DR, Lee AG, Leung SG, Sayles LC, Shrager J, Ferrer I, Paz-Ares L, Gephart MH, Vicent S, Cochran JR, Sweet-Cordero EA. Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma. Nat Med 2019; 25:1783-1795. [PMID: 31700175 PMCID: PMC7087454 DOI: 10.1038/s41591-019-0612-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 09/12/2019] [Indexed: 12/25/2022]
Abstract
Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.
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Affiliation(s)
- Jun W Kim
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Cesar P Marquez
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
- School of Medicine, Stanford University, Stanford, CA, USA
| | - Kaja Kostyrko
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - Amanda L Koehne
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
- School of Medicine, Stanford University, Stanford, CA, USA
- Department of Comparative Medicine, Stanford University, Stanford, CA, USA
| | - Kieren Marini
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - David R Simpson
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - Alex G Lee
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - Stanley G Leung
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - Leanne C Sayles
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
| | - Joseph Shrager
- Division of Thoracic Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Irene Ferrer
- H120-CNIO Lung Cancer Clinical Research Unit, i+12 Research Institute, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | - Luis Paz-Ares
- H120-CNIO Lung Cancer Clinical Research Unit, i+12 Research Institute, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | | | - Silvestre Vicent
- Program in Solid Tumors and Biomarkers, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
| | | | - E Alejandro Sweet-Cordero
- Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
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Shoval A, Markus A, Zhou Z, Liu X, Cazelles R, Willner I, Mandel Y. Anti-VEGF-Aptamer Modified C-Dots-A Hybrid Nanocomposite for Topical Treatment of Ocular Vascular Disorders. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1902776. [PMID: 31402576 DOI: 10.1002/smll.201902776] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/22/2019] [Indexed: 06/10/2023]
Abstract
The vascular endothelial growth factor (VEGF) induces pathological angiogenetic ocular diseases. It is a scientific challenge to develop carriers for the controlled release of inhibitors for VEGF present in the back of the eye domain. Carbon dots (C-dots) functionalized with the VEGF aptamer are introduced and the hybrid nanoparticles are used for ocular nanomedicine. The C-dots are applied as effective carriers of the anti-VEGF aptamer across the cornea, yielding therapeutic levels upon topical administration. The hybrids show no toxicity for both in vitro and in vivo murine animal model, and further enable noninvasive intraocular concentration monitoring through the C-dots inherent fluorescence. In addition, the hybrid C-dots effectively inhibit VEGF-stimulated angiogenesis in choroidal blood vessels. This inhibition is comparable to two commercially available anti-VEGF drugs, bevacizumab and aflibercept. The hybrid aptamer-modified C-dots provide a versatile nanomaterial to treat age-related macular degeneration and diabetic retinopathy.
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Affiliation(s)
- Asaf Shoval
- School of Optometry and Vision Science, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290009, Israel
- Bar Ilan's Institute for Nanotechnology and Advanced Materials (BINA), Bar Ilan University, Ramat-Gan, 5290009, Israel
| | - Amos Markus
- School of Optometry and Vision Science, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290009, Israel
- Bar Ilan's Institute for Nanotechnology and Advanced Materials (BINA), Bar Ilan University, Ramat-Gan, 5290009, Israel
| | - Zhixin Zhou
- Institute of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
| | - Xia Liu
- Institute of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
| | - Rémi Cazelles
- Institute of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
| | - Itamar Willner
- Institute of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
| | - Yossi Mandel
- School of Optometry and Vision Science, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290009, Israel
- Bar Ilan's Institute for Nanotechnology and Advanced Materials (BINA), Bar Ilan University, Ramat-Gan, 5290009, Israel
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Jászai J, Schmidt MHH. Trends and Challenges in Tumor Anti-Angiogenic Therapies. Cells 2019; 8:cells8091102. [PMID: 31540455 PMCID: PMC6770676 DOI: 10.3390/cells8091102] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 01/18/2023] Open
Abstract
Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of “vessel normalization” might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization.
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Affiliation(s)
- József Jászai
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.
| | - Mirko H H Schmidt
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden, 01307 Dresden, Germany.
- German Cancer Research Center (DKFZ), 61920 Heidelberg, Germany.
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Cao J, Yang R, Smith TE, Evans S, McCollum GW, Pomerantz SC, Petley T, Harris IR, Penn JS. Human Umbilical Tissue-Derived Cells Secrete Soluble VEGFR1 and Inhibit Choroidal Neovascularization. Mol Ther Methods Clin Dev 2019; 14:37-46. [PMID: 31276010 PMCID: PMC6586593 DOI: 10.1016/j.omtm.2019.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 05/10/2019] [Indexed: 01/21/2023]
Abstract
Exudative age-related macular degeneration (AMD), characterized by choroidal neovascularization (CNV), is the leading cause of irreversible blindness in developed countries. Anti-vascular endothelial growth factor (VEGF) drugs are the standard treatment for AMD, but they have limitations. Cell therapy is a promising approach for ocular diseases, and it is being developed in the clinic for the treatment of retinal degeneration, including AMD. We previously showed that subretinal injection of human umbilical tissue-derived cells (hUTCs) in a rodent model of retinal degeneration preserved photoreceptors and visual function through rescue of retinal pigment epithelial (RPE) cell phagocytosis. Here we investigated the effect of hUTCs on a rat model of laser-induced CNV and on a human RPE cell line, ARPE-19, for VEGF production. We demonstrate that subretinal injection of hUTCs significantly inhibited CNV and lowered choroidal VEGF in vivo. VEGF release from ARPE-19 decreased when co-cultured with hUTCs. Soluble VEGF receptor 1 (sVEGFR1) is identified as the only factor in hUTC conditioned medium (CM) that binds to VEGF. The level of exogenous recombinant VEGF in hUTC CM was dramatically reduced and could be recovered with sVEGFR1-neutralizing antibody. This suggests that hUTC inhibits angiogenesis through the secretion of sVEGFR1 and could serve as a novel treatment for angiogenic ocular diseases, including AMD.
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Affiliation(s)
- Jing Cao
- Janssen Research & Development, LLC, Spring House, PA 19477, USA
| | - Rong Yang
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Taylor E. Smith
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Stephanie Evans
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Gary W. McCollum
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | | | - Theodore Petley
- Janssen Research & Development, LLC, Spring House, PA 19477, USA
| | - Ian R. Harris
- Janssen Research & Development, LLC, Spring House, PA 19477, USA
| | - John S. Penn
- Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol 2019; 15:612-632. [DOI: 10.1038/s41584-019-0277-8] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2019] [Indexed: 02/07/2023]
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Barmas-Alamdari D, D’Souza HS, Kapoor KG, Wagner AL. Intravitreal Ziv-Aflibercept: A Comprehensive Review. Semin Ophthalmol 2019; 34:420-435. [DOI: 10.1080/08820538.2019.1641526] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
| | - Haley S. D’Souza
- Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, Virginia, USA
- Ophthalmology Research, Wagner Macula and Retina Center, Virginia Beach, Virginia, USA
| | - Kapil G. Kapoor
- Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, Virginia, USA
- Ophthalmology Research, Wagner Macula and Retina Center, Virginia Beach, Virginia, USA
| | - Alan L. Wagner
- Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, Virginia, USA
- Ophthalmology Research, Wagner Macula and Retina Center, Virginia Beach, Virginia, USA
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Fields JK, Günther S, Sundberg EJ. Structural Basis of IL-1 Family Cytokine Signaling. Front Immunol 2019; 10:1412. [PMID: 31281320 PMCID: PMC6596353 DOI: 10.3389/fimmu.2019.01412] [Citation(s) in RCA: 192] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 06/04/2019] [Indexed: 01/13/2023] Open
Abstract
Interleukin-1 (IL-1) family cytokines are key signaling molecules in both the innate and adaptive immune systems, mediating inflammation in response to a wide range of stimuli. The basic mechanism of signal initiation is a stepwise process in which an agonist cytokine binds its cognate receptor. Together, this cytokine-receptor complex recruits an often-common secondary receptor. Intracellularly, the Toll/IL-1 Receptor (TIR) domains of the two receptors are brought into close proximity, initiating an NF-κB signal transduction cascade. Due to the potent inflammatory response invoked by IL-1 family cytokines, several physiological mechanisms exist to inhibit IL-1 family signaling, including antagonist cytokines and decoy receptors. The numerous cytokines and receptors in the IL-1 superfamily are further classified into four subfamilies, dependent on their distinct cognate receptors—the IL-1, IL-33, and IL-36 subfamilies share IL-1RAcP as their secondary receptor, while IL-18 subfamily utilizes a distinct secondary receptor. Here, we describe how structural biology has informed our understanding of IL-1 family cytokine signaling, with a particular focus on molecular mechanisms of signaling complex formation and antagonism at the atomic level, as well as how these findings have advanced therapeutics to treat some chronic inflammatory diseases that are the result of dysregulated IL-1 signaling.
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Affiliation(s)
- James K Fields
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.,Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.,Program in Molecular Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
| | | | - Eric J Sundberg
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States.,Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.,Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
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Anti-VEGF drug interference with VEGF quantitation in the R&D systems human quantikine VEGF ELISA kit. Bioanalysis 2019; 11:381-392. [DOI: 10.4155/bio-2018-0096] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Aim: To evaluate the accuracy of the Quantikine Human VEGF Immunoassay (R&D Systems) in the presence of VEGF inhibitors. Materials & Methods: Quantikine VEGF ELISA (R&D), anti-VEGF165 mAb (R&D), VEGF165 and aflibercept (Regeneron), ranibizumab and bevacizumab (Genentech). Results: Binding affinity of anti-VEGF165 mAb for VEGF was threefold weaker than aflibercept, but 33- and 40-fold stronger than ranibizumab or bevacizumab. Extended incubation of VEGF complexed with inhibitors led to VEGF dissociation from ranibizumab and bevacizumab, but not aflibercept, and subsequent binding by the immunoassay capture antibody. The immunoassay also detected VEGF:ranibizumab and VEGF:bevacizumab complexes but not VEGF:aflibercept complexes. Conclusion: The immunoassay cannot accurately quantitate VEGF in the presence of these VEGF inhibitors as they interfere with the capture and detection of free VEGF.
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Gómez-García F, Sanz-Cabanillas JL, Viguera-Guerra I, Isla-Tejera B, Nieto AVG, Ruano J. Scoping Review on Use of Drugs Targeting Interleukin 1 Pathway in DIRA and DITRA. Dermatol Ther (Heidelb) 2018; 8:539-556. [PMID: 30392030 PMCID: PMC6261121 DOI: 10.1007/s13555-018-0269-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Deficiencies in interleukin (IL)-1 receptor (IL-R) antagonist (DIRA) and IL-36R antagonist (DITRA) are rare genetic autoinflammatory diseases related to alterations in antagonists of the IL-1 pathway. IL-1 antagonists may represent therapeutic alternatives. Here, we aim to provide a scoping review of knowledge on use of IL-1-targeting drugs in DIRA and DITRA. METHODS An a priori protocol was published, and the study was conducted using the methodology described in the Joanna Briggs Institute Reviewer's Manual and the recently published PRISMA Extension for Scoping Review statement. A three-step search using MEDLINE and EMBASE databases until March 2018 with additional hand searching was performed. Data charting was performed. The search, article selection, and data extraction were carried out by two researchers independently. RESULTS Twenty-four studies on use of anti-IL-1 drugs were included [15 studies including patients with diagnosis of DIRA (n = 19) and 9 studies including patients with diagnosis of DITRA (n = 9)]. Most studies followed a multicenter observational design. Among all patients who received treatment with anti-IL-1 drugs, nine and four mutations in IL1RN and IL36RN were found, respectively. Patients with DIRA were treated with anakinra (n = 17), canakinumab (n = 2), or rinolacept (n = 6). All patients with DITRA were treated with anakinra, and only one case was also treated with canakinumab. Time-to-response frequencies were evaluated as immediate, short, and medium-long term for DIRA (17/17, 15/17, and 9/10, respectively) and DITRA (7/9, 3/9, and 2/9, respectively). Most DITRA patients in whom anti-IL-1 treatment failed experienced good response to anti-tumor necrosis factor alpha or anti-IL-12/23 drugs. The safety profiles of treatments were similar in both diseases. CONCLUSIONS Evidence on use of anti-IL-1 drugs in DIRA and DITRA is scarce and based on observational studies. Larger studies with better methodological quality are needed to increase confidence in use of these drugs in patients with DIRA and DITRA.
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Affiliation(s)
- Francisco Gómez-García
- Immune-Mediated Inflammatory Skin Disease Research Group, IMIBIC/Reina Sofía University Hospital/University of Córdoba, Avenida Menéndez Pidal, Córdoba, 14004, Spain
- Department of Dermatology, Reina Sofía University Hospital, Avenida Menéndez Pidal, Córdoba, 14004, Spain
| | - Juan L Sanz-Cabanillas
- Immune-Mediated Inflammatory Skin Disease Research Group, IMIBIC/Reina Sofía University Hospital/University of Córdoba, Avenida Menéndez Pidal, Córdoba, 14004, Spain
- Department of Dermatology, Reina Sofía University Hospital, Avenida Menéndez Pidal, Córdoba, 14004, Spain
| | - Isabel Viguera-Guerra
- Immune-Mediated Inflammatory Skin Disease Research Group, IMIBIC/Reina Sofía University Hospital/University of Córdoba, Avenida Menéndez Pidal, Córdoba, 14004, Spain
- Agencia de Evaluación de Tecnologías Sanitarias de Andalucía (AETSA), Consejería de Salud, Avda. de la Innovación, Seville, 41020, Spain
| | - Beatriz Isla-Tejera
- Immune-Mediated Inflammatory Skin Disease Research Group, IMIBIC/Reina Sofía University Hospital/University of Córdoba, Avenida Menéndez Pidal, Córdoba, 14004, Spain
- Department of Pharmacy, Reina Sofía University Hospital, Avenida Menéndez Pidal, Córdoba, 14004, Spain
| | - Antonio Vélez-García Nieto
- Immune-Mediated Inflammatory Skin Disease Research Group, IMIBIC/Reina Sofía University Hospital/University of Córdoba, Avenida Menéndez Pidal, Córdoba, 14004, Spain
- Department of Dermatology, Reina Sofía University Hospital, Avenida Menéndez Pidal, Córdoba, 14004, Spain
| | - Juan Ruano
- Immune-Mediated Inflammatory Skin Disease Research Group, IMIBIC/Reina Sofía University Hospital/University of Córdoba, Avenida Menéndez Pidal, Córdoba, 14004, Spain.
- Department of Dermatology, Reina Sofía University Hospital, Avenida Menéndez Pidal, Córdoba, 14004, Spain.
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Abstract
BACKGROUND Familial Mediterranean fever, a hereditary auto-inflammatory disease, mainly affects ethnic groups living in the Mediterranean region. Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever. For those people who are colchicine-resistant or intolerant, drugs such as rilonacept, anakinra, canakinumab, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial. This is an updated version of the review. OBJECTIVES To evaluate the efficacy and safety of interventions for reducing inflammation in people with familial Mediterranean fever. SEARCH METHODS We used detailed search strategies to search the following databases: CENTRAL; MEDLINE; Embase; Chinese Biomedical Literature Database (CBM); China National Knowledge Infrastructure Database (CNKI); Wan Fang; and VIP. In addition, we also searched the clinical trials registries including ClinicalTrials.gov, the International Standard Randomized Controlled Trial Number Register, the WHO International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry, as well as references listed in relevant reports.Date of last search: 21 August 2018. SELECTION CRITERIA Randomized controlled studies (RCTs) of people diagnosed with familial Mediterranean fever, comparing active interventions (including colchicine, anakinra, rilonacept, canakinumab, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard™ (a herbal dietary supplement) and non-steroidal anti-inflammatory drugs) with placebo or no treatment, or comparing active drugs to each other. DATA COLLECTION AND ANALYSIS The authors independently selected studies, extracted data and assessed risk of bias. We pooled data to present the risk ratio or mean difference with their 95% confidence intervals. We assessed overall evidence quality according to the GRADE approach. MAIN RESULTS We included nine RCTs with a total of 249 participants (aged three to 53 years); five were of cross-over and four of parallel design. Six studies used oral colchicine, one used oral ImmunoGuard™ and the remaining two used rilonacept or anakinra as a subcutaneous injection. The duration of each study arm ranged from one to eight months.The three studies of ImmunoGuard™, rilonacept and anakinra were generally well-designed, except for an unclear risk of detection bias in one of these. However, some inadequacy existed in the four older studies on colchicine, which had an unclear risk of selection bias, detection bias and reporting bias, and also a high risk of attrition bias and other potential bias. Neither of the two studies comparing a single to a divided dose of colchicine were adequately blinded, furthermore one study had an unclear risk of selection bias and reporting bias, a high risk of attrition bias and other potential bias.We aimed to report on the number of participants experiencing an attack, the timing of attacks, the prevention of amyloid A amyloidosis, any adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack, but data were not available for all outcomes across all comparisons.One study (15 participants) reported a significant reduction in the number of people experiencing attacks at three months with 0.6 mg colchicine three times daily (14% versus 100%), risk ratio 0.21 (95% confidence interval 0.05 to 0.95) (low-quality evidence). A further study (22 participants) of 0.5 mg colchicine twice daily showed no significant reduction in the number of participants experiencing attacks at two months (low-quality evidence). A study of rilonacept in individuals who were colchicine-resistant or intolerant (14 participants) also showed no reduction at three months (moderate-quality evidence). Likewise, a study of anakinra given to colchicine-resistant people (25 participants) showed no reduction in the number of participants experiencing an attack at four months (moderate-quality evidence).Three studies reported no significant differences in duration of attacks: one comparing colchicine to placebo (15 participants) (very low-quality evidence); one comparing single-dose colchicine to divided-dose colchicine (90 participants) (moderate-quality evidence); and one comparing rilonacept to placebo (14 participants) (low-quality evidence). Three studies reported no significant differences in the number of days between attacks: two comparing colchicine to placebo (24 participants in total) (very low-quality evidence); and one comparing rilonacept to placebo (14 participants) (low-quality evidence).No study reported on the prevention of amyloid A amyloidosis.One study of colchicine reported loose stools and frequent bowel movements (very low-quality evidence) and a second reported diarrhoea (very low-quality evidence). The rilonacept study reported no significant differences in gastrointestinal symptoms, hypertension, headache, respiratory tract infections, injection site reactions and herpes, compared to placebo (low-quality evidence). The ImmunoGuard study observed no side effects (moderate-quality evidence). The anakinra study reported no significant differences between intervention and placebo, including injection site reaction, headache, presyncope, dyspnea and itching (moderate-quality evidence). When comparing single and divided doses of colchicine, one study reported no difference in adverse events (including anorexia, nausea, diarrhoea, abdominal pain, vomiting and elevated liver enzymes) between groups (moderate-quality evidence) and the second study reported no adverse effects were detected.The rilonacept study reported no significant reduction in acute phase response indicators after three months (low-quality evidence). In the ImmunoGuard™ study, these indicators were not reduced after one month of treatment (moderate-quality evidence). The anakinra study, reported that C-reactive protein was significantly reduced after four months (moderate-quality evidence). One of the single dose versus divided dose colchicine studies reported no significant reduction in acute phase response indicators after eight months (low-quality evidence), while the second study reported no significant reduction in serum amyloid A concentration after six months (moderate-quality evidence). AUTHORS' CONCLUSIONS There were limited RCTs assessing interventions for people with familial Mediterranean fever. Based on the evidence, three times daily colchicine appears to reduce the number of people experiencing attacks, colchicine single dose and divided dose might not be different for children with familial Mediterranean fever and anakinra might reduce C-reactive protein in colchicine-resistant participants; however, only a few RCTs contributed data for analysis. Further RCTs examining active interventions, not only colchicine, are necessary before a comprehensive conclusion regarding the efficacy and safety of interventions for reducing inflammation in familial Mediterranean fever can be drawn.
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Affiliation(s)
- Bin Wu
- West China Hospital, Sichuan UniversityDepartment of PharmacyNo.37,Guoxue LaneChengduSichuanChina610041
| | - Ting Xu
- West China Hospital, Sichuan UniversityDepartment of PharmacyNo.37,Guoxue LaneChengduSichuanChina610041
| | - Youping Li
- West China Hospital, Sichuan UniversityChinese Cochrane Centre, Chinese Evidence‐Based Medicine CentreNo. 37, Guo Xue XiangChengduSichuanChina610041
| | - Xi Yin
- West China Hospital, Sichuan UniversityDepartment of PharmacyNo.37,Guoxue LaneChengduSichuanChina610041
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