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Xu X, Wang L, Sun Y, Yang C, Wang X, Guo P, Mei D. Unveiling the differences: infection disorders associated with tumor necrosis factor α inhibitors in pediatric patients-a pharmacovigilance study (2004-2023). Eur J Pediatr 2025; 184:324. [PMID: 40317305 DOI: 10.1007/s00431-025-06152-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/15/2025] [Accepted: 04/23/2025] [Indexed: 05/07/2025]
Abstract
The increasing use of tumor necrosis factor inhibitors (TNFi) in pediatric patients has raised concerns about their potential impact on the immune system and related adverse events. Infection-related adverse events (AEs) caused by TNFi have already raised widespread concerns in real-world settings. This study aims to comprehensively analyze and summarize the infection-related AEs associated with TNFi in pediatric patients. A retrospective pharmacovigilance study was conducted to identify cases of TNFi-related infections reported to the FDA Adverse Event Reporting System (FAERS) database between Q1 2004 and Q1 2023. TNFi reports were carefully reviewed to exclude confounding factors like other AEs, concomitant medications, and prescription indications. Proportionality analysis was conducted by comparing TNFi reports to the entire FAERS database to identify infection-related AEs significantly associated with TNFi use. Infection-related AEs accounted for 8.36% of all TNFi-related adverse event reports in the FAERS database. A total of 8050 cases of TNFi-associated infections were identified in the pediatric population, with 2.57% of reports resulting in fatalities. Infliximab and golimumab showed a stronger association with infection-related AEs compared to other TNFi. Notably, only adalimumab shows a lower risk of viral infections, while it exhibits an increased risk of bacterial and mycobacterial infections, similar to other TNFi. CONCLUSIONS This study identified a significant association between TNFi use and infection-related AEs in pediatric patients, providing the foothold for further research. However, due to its retrospective nature, further investigations are warranted to confirm these findings and identify potential risk factors in a controlled, prospective study setting. WHAT IS KNOWN • There is sufficient evidence to demonstrate the infection risk associated with TNFi in adult patients. • Pediatric patients, whose immune systems are still developing, are more vulnerable to certain infections. WHAT IS NEW • There is a significant association between TNFi use and infection-related adverse events in pediatric patients, and different TNFi have distinct infection profiles.
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Affiliation(s)
- Xiaolin Xu
- Department of Pharmacy, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China
| | - Luquan Wang
- Department of Pharmacy, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yixin Sun
- Department of Pharmacy, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China
| | - Changqing Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xiaoling Wang
- Department of Pharmacy, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China
| | - Peng Guo
- Department of Pharmacy, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China.
| | - Dong Mei
- Department of Pharmacy, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China.
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Wysocki T, Wajda A, Kmiołek T, Wroński J, Roszkowska M, Olesińska M, Paradowska-Gorycka A. NADPH oxidase expression profile and PBMC immunophenotypic changes in anti-TNF-treated rheumatoid arthritis patients. Clin Immunol 2025; 271:110414. [PMID: 39643026 DOI: 10.1016/j.clim.2024.110414] [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: 09/29/2024] [Revised: 11/27/2024] [Accepted: 11/29/2024] [Indexed: 12/09/2024]
Abstract
The aim of this research was to prospectively evaluate the impact of NOX2 gene expression profile (including NCF1, NCF2 and NCF4 genes) in peripheral blood mononuclear cells (PBMCs) on immune signatures, clinical characteristics and responsiveness to anti-TNF treatment in RA patients. Blood specimens were collected from 31 rheumatoid arthritis (RA) patients and 25 healthy controls, and 16 RA patients were followed at two timepoints during anti-TNF treatment. mRNA expression levels of selected genes and immunoregulatory cytokines concentrations were determined. We observed the significant upregulation of NCF4 and CD14 expression in RA group. The mRNA levels of NCF1 and CD14 positively correlated both in groups of RA patients and healthy controls. NOX2 gene expression profile was not associated with anti-TNF responsiveness, nor with RA clinical features. TNFα inhibition has not influenced NOX2 expression either. Notably, this study indicate the novel links between expression levels of NCF1 and monocyte differentiation antigen CD14.
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Affiliation(s)
- Tomasz Wysocki
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland.
| | - Anna Wajda
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Tomasz Kmiołek
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Jakub Wroński
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Magdalena Roszkowska
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Marzena Olesińska
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
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Wang D, Zhao J, Zhang J, Lv C, Bao S, Gao P, He M, Li L, Zhao H, Zhang C. Targeting TNF-α: The therapeutic potential of certolizumab pegol in the early period of cerebral ischemia reperfusion injury in mice. Int Immunopharmacol 2024; 137:112498. [PMID: 38908079 DOI: 10.1016/j.intimp.2024.112498] [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: 02/20/2024] [Revised: 06/05/2024] [Accepted: 06/13/2024] [Indexed: 06/24/2024]
Abstract
The neuroinflammatory response triggered by cerebral ischemia-reperfusion injury (CIRI) is characterized by the upsurge of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, which promote leukocyte infiltration and subsequent accumulation in the ischemic zone. This accumulation further intensifies inflammation and aggravates ischemic damage. Certolizumab pegol (CZP), a monoclonal antibody targeting TNF-α, is widely used in treating various inflammatory diseases. This study explored the therapeutic potential of CZP in a mouse model of CIRI, induced by middle cerebral artery occlusion (MCAO), focusing on its influence on the microglial inflammatory response. In vitro analyses revealed that CZP markedly inhibits TNF-α-stimulated inflammation in primary microglia with an EC50 of 1.743 ng/mL. In vivo, MCAO mice treated with CZP (10 μg/mouse, i.p.) for 3 days showed reduced infarct volume, partially improved neurological function, and diminished blood-brain barrierdisruption. Additionally, CZP treatment curtailed microglial activation and the release of pro-inflammatory mediators in the early stages of stroke. It also favorably modulated microglial M1/M2 polarization, rebalanced Th17/Treg cells dynamics, and inhibited Caspase-8-mediated GSDMD cleavage, preventing microglial pyroptosis. Collectively, this study described that the treatment with CZP reversed damaging process caused by CIRI, offering a promising therapeutic strategy for the treatment of ischemic stroke.
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Affiliation(s)
- Dexiao Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Jie Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Jingyu Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Changling Lv
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Shuangyan Bao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Pengfei Gao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Miao He
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China
| | - Lijuan Li
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; School of Public Health, Dali University, Dali, PR China.
| | - Hairong Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
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Jiang Z, Zou Y, Li G, Zhao S, Zhang W. Comparisons of infection events associated with tumor necrosis factor inhibitors in patients with inflammatory arthritis: A systematic review and network meta-analysis. Front Pharmacol 2024; 15:1376262. [PMID: 39070789 PMCID: PMC11273365 DOI: 10.3389/fphar.2024.1376262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 06/10/2024] [Indexed: 07/30/2024] Open
Abstract
Objective: To compare the risk of infection in inflammatory arthritis patients treated with tumor necrosis factor (TNF) inhibitors. Methods: PubMed, Embase, and the Cochrane Library were systematically searched from inception to 28 December 2023 for randomized controlled trials (RCTs) assessing TNF inhibitors and reporting infections. Subsequently, pairwise and network meta-analyses were conducted to determine odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Results: A total of 61 RCTs involving 20,458 patients were included. Pairwise meta-analysis revealed that certolizumab pegol was significantly associated with an increased risk of serious infection compared to placebo (OR:2.28, 95% CI: 1.13-4.62). Both adalimumab and certolizumab pegol were also significantly associated with an increased risk of any infection compared to placebo (OR:1.18, 95% CI: 1.06 to 1.30 and OR:1.40, 95% CI: 1.11 to 1.76, respectively). Moreover, a network meta-analysis indicated that certolizumab pegol and infliximab were associated with a higher risk of serious infection compared to other TNF inhibitors. In the cumulative ranking of any infection risk, certolizumab pegol had the highest risk compared with others. TNF inhibitors increased the risk of tuberculosis but not that of herpes zoster. Conclusion: Available evidence indicates etanercept and golimumab are likely associated with a lower risk of infection compared to other TNF inhibitors in inflammatory arthritis. For patients at a heightened risk of infection, prioritizing the use of etanercept and golimumab may be advisable to minimize patient risk. Systematic Review Registration: identifier CRD42022316577.
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Affiliation(s)
- Ziwei Jiang
- Department of Pharmacy, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yue Zou
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Guangyao Li
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Sixuan Zhao
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- Department of Pharmacy, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
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Siegmund D, Wajant H. TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond. Nat Rev Rheumatol 2023; 19:576-591. [PMID: 37542139 DOI: 10.1038/s41584-023-01002-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2023] [Indexed: 08/06/2023]
Abstract
The cytokine TNF signals via two distinct receptors, TNF receptor 1 (TNFR1) and TNFR2, and is a central mediator of various immune-mediated diseases. Indeed, TNF-neutralizing biologic drugs have been in clinical use for the treatment of many inflammatory pathological conditions, including various rheumatic diseases, for decades. TNF has pleiotropic effects and can both promote and inhibit pro-inflammatory processes. The integrated net effect of TNF in vivo is a result of cytotoxic TNFR1 signalling and the stimulation of pro-inflammatory processes mediated by TNFR1 and TNFR2 and also TNFR2-mediated anti-inflammatory and tissue-protective activities. Inhibition of the beneficial activities of TNFR2 might explain why TNF-neutralizing drugs, although highly effective in some diseases, have limited benefit in the treatment of other TNF-associated pathological conditions (such as graft-versus-host disease) or even worsen the pathological condition (such as multiple sclerosis). Receptor-specific biologic drugs have the potential to tip the balance from TNFR1-mediated activities to TNFR2-mediated activities and enable the treatment of diseases that do not respond to current TNF inhibitors. Accordingly, a variety of reagents have been developed that either selectively inhibit TNFR1 or selectively activate TNFR2. Several of these reagents have shown promise in preclinical studies and are now in, or approaching, clinical trials.
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Affiliation(s)
- Daniela Siegmund
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
| | - Harald Wajant
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
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Chua JV, Baddley JW. Anti-tumor Necrosis Factor-Alpha Agents. INFECTIOUS COMPLICATIONS IN BIOLOGIC AND TARGETED THERAPIES 2022:69-87. [DOI: 10.1007/978-3-031-11363-5_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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7
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Biological Treatments in Inflammatory Bowel Disease: A Complex Mix of Mechanisms and Actions. BIOLOGICS 2021. [DOI: 10.3390/biologics1020012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires lifelong medication and whose incidence is increasing over the world. There is currently no cure for IBD, and the current therapeutic objective is to control the inflammatory process. Approximately one third of treated patients do not respond to treatment and refractoriness to treatment is common. Therefore, pharmacological treatments, such as monoclonal antibodies, are urgently needed, and new treatment guidelines are regularly published. Due to the extremely important current role of biologics in the therapy of IBD, herein we have briefly reviewed the main biological treatments currently available. In addition, we have focused on the mechanisms of action of the most relevant groups of biological agents in IBD therapy, which are not completely clear but are undoubtfully important for understanding both their therapeutic efficacy and the adverse side effects they may have. Further studies are necessary to better understand the action mechanism of these drugs, which will in turn help us to understand how to improve their efficacy and safety. These studies will hopefully pave the path for a personalized medicine.
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Ho CH, Silva AA, Tomita B, Weng HY, Ho IC. Differential impacts of TNFα inhibitors on the transcriptome of Th cells. Arthritis Res Ther 2021; 23:199. [PMID: 34301319 PMCID: PMC8299604 DOI: 10.1186/s13075-021-02558-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/18/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. METHODS Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. RESULTS Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. CONCLUSIONS TNFis can have drug-specific effects on the transcriptional profile of Th cells.
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Affiliation(s)
- Ching-Huang Ho
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA
- Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA
| | - Andrea A Silva
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA
- Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA
| | - Beverly Tomita
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA
- Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA
| | - Hui-Ying Weng
- Biomedical Industry PhD Program, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan
| | - I-Cheng Ho
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA.
- Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA.
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Kwon JC, Kwon OH, Jeong RU, Kim N, Song S, Choi I, Lee J, Horiuchi T. Physicochemical and biological similarity assessment of LBAL, a biosimilar to adalimumab reference product (Humira®). Anim Cells Syst (Seoul) 2021; 25:182-194. [PMID: 34262661 PMCID: PMC8253209 DOI: 10.1080/19768354.2021.1943709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
LBAL was developed as an adalimumab (Humira®) biosimilar using Chinese hamster ovary cell lines. Comparable quality, safety, and efficacy between a biosimilar and its reference product should be ensured for regulatory approval. Here, we present the results of a comprehensive physicochemical and biological characterization between LBAL and Humira®. As physicochemical attributes, primary and higher-order structure, N-glycan profile, and disulfide linkage were investigated. Biological attributes were evaluated by target/receptor binding analysis and in vitro/ex vivo cell-based assays, which are linked to mechanisms of action. As a result, LBAL had the identical amino acid sequence, similar post-translational modifications and N-/C-terminal variants, and comparable primary, secondary, and tertiary structures and disulfide linkage profile. However, some differences in N-glycan profiles were observed. Biological activities, including tumor necrosis factor (TNF) binding, TNF-neutralization, apoptosis, Fc receptor binding, and complement-dependent cytotoxicity, were largely consistent. Despite a slightly lower antibody-dependent cellular cytotoxicity activity in LBAL, this difference was not significant under physiological conditions. As indicated, this extensive analytical characterization and functional comparison assessment showed that LBAL was similar to Humira®, with minor differences of no clinical relevance. Taken together, our comparative assessment of physicochemical and biological attributes demonstrated that LBAL is structurally and functionally very similar to Humira®, supporting the biosimilarity of clinical efficacy and safety.
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Affiliation(s)
- Joon-Cheol Kwon
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.,Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - O Hwan Kwon
- Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - Rae Ung Jeong
- Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - Nayoun Kim
- Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - Seonah Song
- Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - Ilsub Choi
- Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - Juneok Lee
- Life Science R&D campus, LG Science Park, LG Chem, Ltd., Seoul, Republic of Korea
| | - Takahiko Horiuchi
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan
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Wang Q, Oryoji D, Mitoma H, Kimoto Y, Koyanagi M, Yokoyama K, Ayano M, Akahoshi M, Arinobu Y, Niiro H, Akashi K, Horiuchi T. Methotrexate Enhances Apoptosis of Transmembrane TNF-Expressing Cells Treated With Anti-TNF Agents. Front Immunol 2020; 11:2042. [PMID: 32922407 PMCID: PMC7456895 DOI: 10.3389/fimmu.2020.02042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 07/27/2020] [Indexed: 11/13/2022] Open
Abstract
Background Concomitant use of methotrexate (MTX) improves the clinical efficacy of anti-TNF agents in the treatment of rheumatoid arthritis (RA). We aimed to clarify the cytotoxic effect of MTX on transmembrane TNF (tmTNF)-expressing cells treated with anti-TNF agents. Methods Jurkat T cells stably expressing tmTNF were used for the following experiments. Cytotoxicity induced by an anti-TNF agent (infliximab, adalimumab, or certolizumab pegol) with concomitant MTX were compared with that by MTX alone or by an anti-TNF agent alone using flow cytometry. Apoptosis-induction mediated by reverse signal through tmTNF, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) were evaluated. Folic acid and Y-27632, a Rho kinase inhibitor, were used as inhibitors to study intracellular signaling pathway in apoptosis induced by MTX and anti-TNF agents. Results Apoptosis of tmTNF-expressing cells was significantly increased by the concomitant administration of MTX and an anti-TNF agent, compared with MTX alone or an anti-TNF agent alone. The apoptosis induction by concomitant MTX was most pronounced in infliximab-treatment. Reverse signal transduction, but not CDC or ADCC/ADCP, was responsible for the coordinate effect of MTX and an anti-TNF agent on tmTNF-expressing cells. Folic acid inhibited MTX-mediated apoptosis, while Y-27632 suppressed JNK activation and infliximab-induced apoptosis via revere signal through tmTNF. Conclusion The apoptotic effect was enhanced by combination of MTX and an anti-TNF agent in tmTNF-expressing cells. The intracellular pathways induced by MTX and anti-TNF agents seem to be independent. These findings might explain at least in part improved the clinical response upon co-therapy of MTX and an anti-TNF agent in RA.
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Affiliation(s)
- Qiaolei Wang
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan.,Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Daisuke Oryoji
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan
| | - Hiroki Mitoma
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasutaka Kimoto
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan
| | - Masamichi Koyanagi
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan
| | - Kana Yokoyama
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masahiro Ayano
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitsuteru Akahoshi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yojiro Arinobu
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroaki Niiro
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiko Horiuchi
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan
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Attwood MM, Jonsson J, Rask-Andersen M, Schiöth HB. Soluble ligands as drug targets. Nat Rev Drug Discov 2020; 19:695-710. [PMID: 32873970 DOI: 10.1038/s41573-020-0078-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases.
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Affiliation(s)
- Misty M Attwood
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Jörgen Jonsson
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Mathias Rask-Andersen
- Medical Genetics and Genomics, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Helgi B Schiöth
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden. .,Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
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12
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Durmaz Engin C, Cilaker Miçili S, Yilmaz O, Bağriyanik HA, Ergür BU, Önen F, Saatci AO. Ocular toxicity of intravitreal golimumab in a rabbit model. Turk J Med Sci 2020; 50:1111-1122. [PMID: 32151118 PMCID: PMC7379407 DOI: 10.3906/sag-1911-11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/05/2020] [Indexed: 01/13/2023] Open
Abstract
Background/aim To investigate the effect of intravitreal golimumab on rabbit retina histopathology. Materials and methods Sixteen albino New Zealand rabbits were divided into three groups. The right eye of each rabbit in groups I, II, and III received a single intravitreal injection of 5 mg/0.05 mL (6 eyes), 10 mg/0.1 mL (6 eyes), or 20 mg/0.2 mL (4 eyes) golimumab, while left eyes served as controls with the same volume of a balanced salt solution injection. All animals were examined using slit-lamp biomicroscopy and indirect ophthalmoscopy before and after intravitreal injection and at days 1 and 7. Animals were euthanized on day 7 and the eyes were enucleated for immunohistochemistry evaluation and electron microscopic examination of the retinas. Results For groups I, II, and III, the number of cells in the outer nuclear layer and the inner nuclear layer was decreased compared to those in the control groups. In group I, the percentage of caspase-3 staining of the outer nuclear layer was significantly higher than that in the control. For groups II and III, TUNEL and caspase-3 staining percentages in the outer and inner nuclear layers were found to be significantly higher than those for the control groups. In the ganglion cell layer, for groups I, II, and III, neither TUNEL nor caspase-3 staining percentages showed any significant difference between two groups. No significant dose-dependent relationship was found for increasing doses of golimumab in all layers. Myelin figures and karyorrhexis in the photoreceptor cells were prominent in electron microscopy of the golimumab-injected eyes. Conclusion Golimumab caused apoptosis in both photoreceptors and bipolar cells of the rabbit retina. Potential retinal toxicity of intravitreal golimumab should be considered if an intravitreal administration is planned.
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Affiliation(s)
- Ceren Durmaz Engin
- Department of Ophthalmology, Karadeniz Ereğli State Hospital, Zonguldak, Turkey
| | - Serap Cilaker Miçili
- Department of Histology and Embryology, School of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Osman Yilmaz
- Department of Laboratory Animals Science, School of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Hüsnü Alper Bağriyanik
- Department of Histology and Embryology, School of Medicine, Dokuz Eylül University, İzmir, Turkey,İzmir Biomedicine and Genome Center (iBG), İzmir, Turkey
| | - Bekir Uğur Ergür
- Department of Histology and Embryology, School of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Fatoş Önen
- Department of Internal Medicine, Division of Rheumatology, School of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Ali Osman Saatci
- Department of Ophthalmology, School of Medicine, Dokuz Eylül University, İzmir, Turkey
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13
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Giuffrida P, Di Sabatino A. Targeting T cells in inflammatory bowel disease. Pharmacol Res 2020; 159:105040. [PMID: 32585338 DOI: 10.1016/j.phrs.2020.105040] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022]
Abstract
T cells play a pivotal role in the immune response underlying inflammatory bowel disease (IBD) pathogenesis. On this basis, over the past 25 years several drugs have assessed to target T cells in IBD patients. Amongst anti-CD3 antibodies, visilizumab and foralumab did not show clinical efficacy in ulcerative colitis (UC) and Crohn's disease (CD) patients, respectively, whereas otelixizumab has been tested in vitro only. The anti-CD4 BF-5 and cM-T412, and the anti-CD25 basiliximab and daclizumab were not effective in CD and UC patients, respectively. The anti-NKG2D antibody NNC0142-0002 showed clinical benefit in CD patients, in particular in biologic naïve ones, in a randomized, double-blind, parallel-group, placebo-controlled trial. The anti-CD40L M90 and the GSK1349571A blocking calcium release-activated calcium (CRAC) channels, which are involved in the T cell activation and proliferation, were tested only in ex vivo/in vitro experiments. Apart from ustekinumab, all the other drugs targeting T cell-derived cytokines failed. The reinduction of lamina propria T cell apoptosis is a mechanism to modulate T cell survival exploited by cyclosporin A, azathioprine and anti-tumor necrosis factor-α agents, such as infliximab, adalimumab and golimumab. In this article, we review the drugs targeting T cells via surface receptors, via T cell-derived cytokines, via CRAC channels or by inducing apoptosis.
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Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
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14
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Convertino I, Tuccori M, Ferraro S, Valdiserra G, Cappello E, Focosi D, Blandizzi C. Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2020; 24:331. [PMID: 32527304 PMCID: PMC7289228 DOI: 10.1186/s13054-020-03020-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
Sars-CoV-2 complications include pneumonia and acute respiratory distress syndrome (ARDS), which require intensive care unit admission. These conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. Social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. Among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. Particularly, since pneumonia and ARDS are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-IL-6, anti-TNF, and JAK inhibitors are currently studied. In this article, we discuss the potential advantages of the most promising pharmacological approaches.
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Affiliation(s)
- Irma Convertino
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Marco Tuccori
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. .,Unit of Adverse Drug Reactions Monitoring, Pisa University Hospital, Pisa, Italy.
| | - Sara Ferraro
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giulia Valdiserra
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Emiliano Cappello
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Daniele Focosi
- North-Western Tuscany Blood Bank, Pisa University Hospital, Pisa, Italy
| | - Corrado Blandizzi
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Unit of Adverse Drug Reactions Monitoring, Pisa University Hospital, Pisa, Italy
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15
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Zhang E, Xie L, Qin P, Lu L, Xu Y, Gao W, Wang L, Xie MH, Jiang W, Liu S. Quality by Design-Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®. AAPS J 2020; 22:69. [PMID: 32385732 PMCID: PMC7210234 DOI: 10.1208/s12248-020-00454-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/07/2020] [Indexed: 12/31/2022] Open
Abstract
Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. The critical quality attributes (CQAs) were then identified through risk assessment according to impact of each quality attribute on efficacy and safety. The anticipated range for each CQA was derived from similarity acceptance range and/or the corresponding regulatory guidelines. Finally, a panel of advanced and orthogonal physicochemical and functional tests and comparison of 6 batches of HLX03 and 10 batches of the reference standard demonstrated high similarity of HLX03 to Humira®, except for slightly lower percentage of high mannosylated glycans (%HM) in HLX03 which had no effect on FcγRIII binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity in human peripheral blood mononuclear cell (PBMC). All above demonstrated the feasibility and efficiency of QbD-based similarity assessment of a biosimilar monoclonal antibody (mAb).
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Affiliation(s)
- Erhui Zhang
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Liqi Xie
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Peilan Qin
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Lihong Lu
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Yanpeng Xu
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Wenyuan Gao
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Linlin Wang
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Michael Hongwei Xie
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China.
| | - Weidong Jiang
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Scott Liu
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
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16
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Abstract
Biologic therapies including monoclonal antibodies, tyrosine kinase inhibitors, and other agents represent a notable expansion in the pharmacotherapy armamentarium in treatment of a variety of diseases. Many of these therapies possess direct or indirect immunosuppressive and immunomodulatory effects, which have been associated with bacterial, viral, and fungal opportunistic infections. Careful screening of baseline risk factors before initiation, targeted preventive measures, and vigilant monitoring while on active biologic therapy mitigate these risks as use of biologics becomes more commonplace. This review compiles reported evidence of fungal infections associated with these agents with a focus on the tumor necrosis factor-α inhibitor class.
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Affiliation(s)
- Matthew R Davis
- Department of Pharmacy, University of California, Los Angeles Ronald Reagan Medical Center, 757 Westwood Plaza, Los Angeles, CA 90095, USA.
| | - George R Thompson
- Division of Infectious Diseases, Department of Internal Medicine, University of California Davis Health, 4150 V Street, Sacramento, CA 95817, USA; Department of Medical Microbiology and Immunology, University of California Davis Health, 4150 V Street, Sacramento, CA 95817, USA
| | - Thomas F Patterson
- Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, South Texas Veterans Health Care System, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
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17
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Cimaz R, Maioli G, Calabrese G. Current and emerging biologics for the treatment of juvenile idiopathic arthritis. Expert Opin Biol Ther 2020; 20:725-740. [PMID: 32116038 DOI: 10.1080/14712598.2020.1733524] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION The management of a child with juvenile idiopathic arthritis (JIA) requires a combination of pharmacological, physical, and psychosocial therapies in order to induce disease remission, by controlling articular and systemic inflammation. This review aims to provide a comprehensive discussion on the biological therapies currently in use in the treatment of JIA referring to existing recommendations and clinical evidence. We also discuss on the emerging biological drugs actually under consideration. AREAS COVERED Recent findings on immunological mechanisms involved in the pathogenesis of the disease allowed us to identify several specific targets for biologic therapies. A systematic literature review was conducted between January 1997 and January 2020 on PubMed including national and international guidelines and recommendations, trials and case-control studies. EXPERT OPINION There is now a plethora of therapies that are directed against variable targets, and the physician has to choose the most appropriate available medication in order to achieve early and sustained remission with as few side effects as possible. Research is advancing very fast in order to be more and more specific in suppressing inflammatory pathways without harming natural defenses. Finally, pharmacoeconomic considerations will also be very important to deal with, considering the high cost of most of these molecules.
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Affiliation(s)
- Rolando Cimaz
- Pediatric Rheumatology Department, ASST-Gaetano Pini-CTO, Department of Clinical Sciences and Community Health, University of Milan , Milan, Italy.,Pediatric Rheumatology Department, ASST-Gaetano Pini-CTO, University of Milan , Milan, Italy
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18
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Bufan B, Jančić I, Stojić-Vukanić Z. Inhibitors of tumor necrosis factor-a and mechanisms of their action. ARHIV ZA FARMACIJU 2020. [DOI: 10.5937/arhfarm2003109b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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19
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Fernández-Ruiz M, Aguado JM. Risk of infection associated with anti-TNF-α therapy. Expert Rev Anti Infect Ther 2018; 16:939-956. [PMID: 30388900 DOI: 10.1080/14787210.2018.1544490] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The advent, more than two decades ago, of monoclonal antibodies and soluble receptors targeting tumor necrosis factor (TNF)-α has revolutionized the therapeutic approach to otherwise difficult-to-treat autoimmune and inflammatory diseases. However, due to the pleiotropic functions played by this pro-inflammatory cytokine (with particular relevance in granuloma maintenance), TNF-α blockade may increase the incidence of serious infections. Areas covered: The present review summarizes the biological rationale supporting the impact of anti-TNF-α therapy on the host's susceptibility to infection. The structure, mode of action, and indications of available agents are reviewed, as well as the clinical evidence coming from clinical trials and observational registries. We discuss the impact of patient- and disease-related factors influencing the occurrence of infection. Finally, strategies for risk minimization are also covered, with particular attention to recommendations for screening of latent tuberculosis infection and management of chronic hepatitis B infection. Expert commentary: Methodological limitations (confounding by indication bias, patient dropout, or switching therapies) should be considered when interpreting observational data. Clinicians must individualize the infection risk assessment not only on the basis of the specific anti-TNF-α agent used or the expected duration of therapy, but also by taking into account the baseline susceptibility of a given patient.
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Affiliation(s)
- Mario Fernández-Ruiz
- a Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), School of Medicine , Universidad Complutense , Madrid , Spain.,b Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0002) , Instituto de Salud Carlos III , Madrid , Spain
| | - José María Aguado
- a Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), School of Medicine , Universidad Complutense , Madrid , Spain.,b Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0002) , Instituto de Salud Carlos III , Madrid , Spain
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20
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Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF. The current state of the art for biological therapies and new small molecules in inflammatory bowel disease. Mucosal Immunol 2018; 11:1558-1570. [PMID: 29907872 PMCID: PMC6279599 DOI: 10.1038/s41385-018-0050-3] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/15/2018] [Accepted: 05/21/2018] [Indexed: 02/06/2023]
Abstract
The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.
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Affiliation(s)
- Sudarshan Paramsothy
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adam K. Rosenstein
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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21
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Davignon JL, Rauwel B, Degboé Y, Constantin A, Boyer JF, Kruglov A, Cantagrel A. Modulation of T-cell responses by anti-tumor necrosis factor treatments in rheumatoid arthritis: a review. Arthritis Res Ther 2018; 20:229. [PMID: 30314507 PMCID: PMC6235207 DOI: 10.1186/s13075-018-1725-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in many aspects of immune regulation. Anti-TNF biological therapy has been considered a breakthrough in the treatment of chronic autoimmune diseases, such as rheumatoid arthritis (RA). In this review, because of the major involvement of T cells in RA pathogenesis, we discuss the effects of anti-TNF biotherapy on T-cell responses in RA patients. We also outline the potential fields for future research in the area of anti-TNF therapy in RA.This could be useful to better understand the therapeutic efficiency and the side effects that are encountered in RA patients. Better targeting of T cells in RA could help set more specific anti-TNF strategies and develop prediction tools for response.
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Affiliation(s)
- Jean-Luc Davignon
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France. .,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.
| | - Benjamin Rauwel
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France
| | - Yannick Degboé
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, 31062, Toulouse, France
| | - Arnaud Constantin
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, 31062, Toulouse, France
| | - Jean-Fredéric Boyer
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France
| | - Andrey Kruglov
- Lomonosov Moscow State University, 119991, Moscow, Russia.,German Rheumatism Research Center (DRFZ), 10117, Berlin, Germany
| | - Alain Cantagrel
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, 31062, Toulouse, France
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22
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ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents). Clin Microbiol Infect 2018; 24 Suppl 2:S10-S20. [DOI: 10.1016/j.cmi.2017.12.025] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 12/25/2017] [Accepted: 12/30/2017] [Indexed: 12/14/2022]
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23
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Romano S, Moura V, Simões S, Moreira JN, Gonçalves J. Anticancer activity and antibody-dependent cell-mediated cytotoxicity of novel anti-nucleolin antibodies. Sci Rep 2018; 8:7450. [PMID: 29748553 PMCID: PMC5945777 DOI: 10.1038/s41598-018-25816-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 04/09/2018] [Indexed: 01/09/2023] Open
Abstract
Nucleolin arises as a relevant target for cancer therapy, as it is overexpressed at the surface of cancer and angiogenic endothelial cells thus enabling a dual cellular targeting strategy. Immunotherapeutic strategies, albeit of proven therapeutic relevance, have been scarcely explored against this target. Therefore, this work aimed at engineering an anti-nucleolin VHH-based antibody capable of triggering anticancer immune responses. Herein, anti-nucleolin VHHs have been generated upon grafting F3 peptide-derived nucleolin-binding sequences onto a VHH CDR1 or CDR3. One of these nucleolin-binding CDR3-grafted VHH was subsequently fused to a human IgG1 Fc region, enabling a significant antibody-dependent cell-mediated cytotoxicity (ADCC). The generated anti-nucleolin VHH revealed increased binding and antiproliferative effects against cancer cells, relative to the parental VHH, while the VHH-Fc counterpart presented increased cytotoxicity relative to the corresponding VHH. This VHH-Fc also triggered an ADCC effect, in the nanomolar range, against a nucleolin-overexpressing cancer cell line. This effect was evidenced by a 2 or 1.7-fold increase of cell death, in the presence of PBMCs, relative to the parental VHH-Fc or the VHH counterpart, respectively. Overall, these formats represent the first anti-nucleolin VHHs and the first anti-nucleolin antibody with ADCC activity that have been successfully developed.
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Affiliation(s)
- Sofia Romano
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I), University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal
- IIIUC - Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789, Coimbra, Portugal
| | - Vera Moura
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I), University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal
- TREAT U, SA, Parque Industrial de Taveiro, Lote 44, 3045-508, Coimbra, Portugal
| | - Sérgio Simões
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I), University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal
- FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal
| | - João Nuno Moreira
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I), University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal.
- FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
| | - João Gonçalves
- iMed.ULisboa - Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Avenida Prof. Gama Pinto, 1649-003, Lisbon, Portugal.
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Kaifu T, Nakamura A. Polymorphisms of immunoglobulin receptors and the effects on clinical outcome in cancer immunotherapy and other immune diseases: a general review. Int Immunol 2018; 29:319-325. [PMID: 28910969 DOI: 10.1093/intimm/dxx041] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 07/10/2017] [Indexed: 12/15/2022] Open
Abstract
Receptors for the Fc domain of immunoglobulins [Fc receptors (FcRs)] are essential for the maintenance of antibody-mediated immune responses. FcRs consist of activating- and inhibitory-type receptors that regulate adequate thresholds for various immune cells. In particular, polymorphisms and/or gene copy-number variations of FcRs for IgG (FcγRs) are closely associated with the development of inflammatory disorders, including autoimmune diseases. Recent evidence has implicated polymorphisms of FcRs in the efficacy of monoclonal antibody (mAb)-mediated therapy. This review provides an overview of genetic variations in human FcγRs and the clinical contribution of FcγR polymorphisms in mAb treatments for cancer, autoimmune diseases and allergies.
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Affiliation(s)
- Tomonori Kaifu
- Division of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan
| | - Akira Nakamura
- Division of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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25
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Lim H, Lee SH, Lee HT, Lee JU, Son JY, Shin W, Heo YS. Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis. Int J Mol Sci 2018. [PMID: 29518978 PMCID: PMC5877629 DOI: 10.3390/ijms19030768] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα-TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis.
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Affiliation(s)
- Heejin Lim
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Sang Hyung Lee
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Hyun Tae Lee
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Jee Un Lee
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Ji Young Son
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Woori Shin
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Yong-Seok Heo
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
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Certolizumab pegol administration devices: a profile of their use and usability. DRUGS & THERAPY PERSPECTIVES 2017. [DOI: 10.1007/s40267-017-0446-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Hoshiyama T, Matsueda Y, Tono T, Arinuma Y, Nagai T, Hirohata S. Differential influences of Fc gamma receptor blocking on the effects of certolizumab pegol and infliximab on human monocytes. Mod Rheumatol 2017; 28:506-512. [PMID: 28805137 DOI: 10.1080/14397595.2017.1354796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To compare the effects of certolizumab pegol (CZP) and infliximab (IFX) on human monocytes. METHODS Highly purified monocytes from healthy donors were cultured with CZP, IFX, control IgG1, or polyethylene glycol (PEG) at pharmacological attainable concentrations in culture medium with 10% autologous normal human serum (NHS) or with fetal bovine serum (FBS) for 24 h, after which the supernatants were replaced by fresh culture medium containing LPS. After additional 24 h of incubation, the supernatants were assayed for TNF-α and IL-6. In some experiments, the cells were harvested after 1 h of stimulation with LPS for analysis of mRNA for TNF-α by quantitative PCR. RESULTS Pre-incubation of monocytes with CZP or IFX reduced the production of TNF-α in subsequent cultures stimulated by LPS in a dose-dependent manner. The suppressive effects of IFX on the TNF-α production were significantly diminished, but those of CZP were rather enhanced, in cultures with autologous NHS compared with in cultures with FBS. Addition of IgG, but not IgG F(ab')2 fragments, significantly inhibited the suppressive effects of IFX on the production of TNF-α and IL-6, whereas either IgG or IgG F(ab')2 fragments had no significant influences on the suppressive effects of CZP. Furthermore, pre-incubation with CZP or IFX significantly inhibited the expression of mRNA for TNF-α and IL-6 in monocytes compared with PEG or IgG. CONCLUSION These results indicate that the mechanism of action of CZP is different from that of IFX. Thus, CZP suppresses the production of proinflammatory cytokines independently of Fc receptors, whereas the suppressive effects of IFX on human monocytes are almost totally dependent on the interaction with Fc receptors.
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Affiliation(s)
- Takayuki Hoshiyama
- a Department of Rheumatology and Infectious Diseases , Kitasato University School of Medicine , Sagamihara , Kanagawa , Japan
| | - Yu Matsueda
- a Department of Rheumatology and Infectious Diseases , Kitasato University School of Medicine , Sagamihara , Kanagawa , Japan
| | - Toshihiro Tono
- b Department of Internal Medicine , Kawasaki Municipal Hospital , Kawasaki , Kanagawa , Japan
| | - Yoshiyuki Arinuma
- c Center for Autoimmune and Musculoskeletal Disease , The Feinstein Institute for Medical Research , Manhasset , NY , USA
| | - Tatsuo Nagai
- a Department of Rheumatology and Infectious Diseases , Kitasato University School of Medicine , Sagamihara , Kanagawa , Japan
| | - Shunsei Hirohata
- a Department of Rheumatology and Infectious Diseases , Kitasato University School of Medicine , Sagamihara , Kanagawa , Japan
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Desmarais J, Beier S, Deodhar A. Certolizumab pegol for treating axial spondyloarthritis. Expert Opin Biol Ther 2017; 16:1059-64. [PMID: 27366922 DOI: 10.1080/14712598.2016.1205581] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the spine and sacroiliac (SI) joints. The spectrum of axSpA includes ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). Evidence has supported the use of TNF alpha inhibitors (TNFi) in treating these diseases, with good efficacy and tolerable safety profiles. Certolizumab pegol (CZP) is an anti-TNF alpha (TNFa) agent with data to support its use in both AS and nr-axSpA. AREAS COVERED The pharmacologic properties of CZP were reviewed. Data regarding the use and efficacy of CZP in axSpA were reviewed. Quality of life outcomes and safety profiles of CZP in axSpA patients were discussed as well. EXPERT OPINION While there are several biologics with evidence for improved outcomes in AS, there is less evidence for biologic medications that have good efficacy in nr-axSpA. CZP has good evidence of improved outcomes in terms of clinical efficacy, patient reported outcomes and imaging outcomes in both conditions, with a tolerable safety profile.
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Affiliation(s)
- Julianna Desmarais
- a Division of Arthritis & Rheumatic Diseases , Oregon Health & Sciences University , Portland , OR , USA
| | - Secia Beier
- a Division of Arthritis & Rheumatic Diseases , Oregon Health & Sciences University , Portland , OR , USA.,b Department of Pharmacy , Oregon Health & Sciences University , Portland , OR , USA
| | - Atul Deodhar
- a Division of Arthritis & Rheumatic Diseases , Oregon Health & Sciences University , Portland , OR , USA
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Salinas-Jazmín N, González-González E, Vásquez-Bochm LX, Pérez-Tapia SM, Velasco-Velázquez MA. In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis. J Vis Exp 2017:55542. [PMID: 28518088 PMCID: PMC5607884 DOI: 10.3791/55542] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Therapeutic monoclonal antibodies (mAbs) are relevant to the treatment of different pathologies, including cancers. The development of biosimilar mAbs by pharmaceutical companies is a market opportunity, but it is also a strategy to increase drug accessibility and reduce therapy-associated costs. The protocols detailed here describe the evaluation of target binding and CDC induction by rituximab in Daudi cells. These two functions require different structural regions of the antibody and are relevant to the clinical effect induced by rituximab. The protocols allow the side-to-side comparison of a reference rituximab and a marketed rituximab biosimilar. The evaluated products showed differences both in target binding and CDC induction, suggesting that there are underlying physicochemical differences and highlighting the need to analyze the impact of those differences in the clinical setting. The methods reported here constitute simple and inexpensive in vitro models for the evaluation of the activity of rituximab biosimilars. Thus, they can be useful during biosimilar development, as well as for quality control in biosimilar production. Furthermore, the presented methods can be extrapolated to other therapeutic mAbs.
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Affiliation(s)
- Nohemi Salinas-Jazmín
- Unit for Development and Research in Bioprocesses Unit (UDIBI), National School of Biological Sciences, National Polytechnic Institute (IPN), University of Mexico (UNAM); School of Chemistry, National Autonomous University of Mexico (UNAM)
| | - Edith González-González
- Unit for Development and Research in Bioprocesses Unit (UDIBI), National School of Biological Sciences, National Polytechnic Institute (IPN), University of Mexico (UNAM)
| | - Luz X Vásquez-Bochm
- Graduate Program in Chemical Sciences, National Autonomous University of Mexico (UNAM)
| | - Sonia M Pérez-Tapia
- Unit for Development Research and Medical Innovation in Biotechnology (UDIMEB), National School of Biological Sciences, National Polytechnic Institute (IPN); Department of Immunology, National Scool of Biological Sciences, National Polytechnic Institute (IPN)
| | - Marco A Velasco-Velázquez
- Department of Pharmacology and Unit of Translational Biomedicine (CMN 20 de noviembre), School of Medicine, National Autonomous University of Mexico (UNAM);
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Ota S, Sakuraba H, Hiraga H, Hasui K, Satake M, Hanabata N, Akemoto Y, Watanabe R, Tanaka N, Ishiguro Y, Tanaka M, Fukuda S. Successful adalimumab treatment and usefulness of capsule endoscopy for gut inflammation concomitant with ankylosing spondylitis. Mod Rheumatol 2017; 29:708-713. [PMID: 28271948 DOI: 10.1080/14397595.2017.1295785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Here we describe a 20-year-old man with ankylosing spondylitis and gut inflammation, who was successfully treated with adalimumab. Capsule endoscopy and ileocolonoscopy showed multiple erosions and aphthoid ulcers in the ileum and the ileocecal valve. Immunohistochemical analysis of the terminal ileum demonstrated that the number of IL-23p19 expressing macrophages was increased. Adalimumab was administered, and his back pain and abdominal symptoms improved. Adalimumab might be an effective treatment for gut inflammation related to ankylosing spondylitis.
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Affiliation(s)
- Shinji Ota
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Hirotake Sakuraba
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan.,b Department of Community Medicine , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Hiroto Hiraga
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan.,c Department of Community Healthcare Development in Odate and North Akita , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Keisuke Hasui
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Miwa Satake
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Norihiro Hanabata
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Yui Akemoto
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Rina Watanabe
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Nahoko Tanaka
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
| | - Yoh Ishiguro
- d Division of Clinical Research , Hirosaki National Hospital, National Hospital Organization , Hirosaki , Japan
| | - Masanori Tanaka
- e Department of Pathology and Laboratory Medicine , Hirosaki Municipal Hospital , Hirosaki , Japan
| | - Shinsaku Fukuda
- a Department of Gastroenterology and Hematology , Hirosaki University Graduate School of Medicine , Hirosaki , Japan.,b Department of Community Medicine , Hirosaki University Graduate School of Medicine , Hirosaki , Japan
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Campanati A, Benfaremo D, Luchetti MM, Ganzetti G, Gabrielli A, Offidani A. Certolizumab pegol for the treatment of psoriasis. Expert Opin Biol Ther 2017; 17:387-394. [DOI: 10.1080/14712598.2017.1283401] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- A. Campanati
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy
| | - D. Benfaremo
- Internal Medicine Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy
| | - M. M. Luchetti
- Internal Medicine Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy
| | - G. Ganzetti
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy
| | - A. Gabrielli
- Internal Medicine Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy
| | - A. Offidani
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy
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Lee JU, Shin W, Son JY, Yoo KY, Heo YS. Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases. Int J Mol Sci 2017; 18:ijms18010228. [PMID: 28124979 PMCID: PMC5297857 DOI: 10.3390/ijms18010228] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 01/17/2017] [Accepted: 01/17/2017] [Indexed: 12/20/2022] Open
Abstract
Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.
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Affiliation(s)
- Jee Un Lee
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Woori Shin
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Ji Young Son
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Ki-Young Yoo
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
| | - Yong-Seok Heo
- Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.
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Abstract
Certolizumab pegol (Cimzia®) is a subcutaneously administered polyethylene glycolylated (PEGylated) antigen-binding fragment of a recombinant human monoclonal antibody that selectively neutralizes TNFα. The drug is indicated for a variety of inflammatory autoimmune diseases, including Crohn's disease (CD), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), based on its benefit in these settings in well-designed clinical trials. In these studies, certolizumab pegol (as first- or subsequent-line therapy) reduced the severity of CD when used as an induction or maintenance therapy, and improved the signs/symptoms and slowed the radiographic progression of RA (with or without concomitant methotrexate), PsA and axSpA. Certolizumab pegol is generally well tolerated, with upper respiratory tract infections, rash and urinary tract infections being among the most frequent adverse reactions. Thus, certolizumab pegol is an effective option for the management of these autoimmune diseases.
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Affiliation(s)
- Emma D Deeks
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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34
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Szondy Z, Pallai A. Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications. Pharmacol Res 2017; 115:124-132. [DOI: 10.1016/j.phrs.2016.11.025] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 11/21/2016] [Indexed: 12/25/2022]
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Billmeier U, Dieterich W, Neurath MF, Atreya R. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 2016; 22:9300-9313. [PMID: 27895418 PMCID: PMC5107694 DOI: 10.3748/wjg.v22.i42.9300] [Citation(s) in RCA: 161] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 09/15/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn’s disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.
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36
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Gubernatorova EO, Tumanov AV. Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation. BIOCHEMISTRY. BIOKHIMIIA 2016; 81:1309-1325. [PMID: 27914457 DOI: 10.1134/s0006297916110092] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Ulcerative colitis and Crohn's disease are the major forms of inflammatory bowel disease. Cytokines of the tumor necrosis factor (TNF) family play an important role in the regulation of intestinal inflammation. In this review, we discuss the function of key cytokines of this family - TNF and lymphotoxin (LT) - in mucosal healing, IgA production, and in control of innate lymphoid cells (ILCs), novel regulators of mucosal homeostasis in the gut. TNF plays a central role in the pathogenesis of inflammatory bowel diseases (IBD). LT regulates group 3 of ILCs and IL-22 production and protects the epithelium against damage by chemicals and mucosal bacterial pathogens. In addition, we discuss major mouse models employed to study the mechanism of intestinal inflammation, their advantages and limitations, as well as application of TNF blockers in the therapy for IBD.
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Affiliation(s)
- E O Gubernatorova
- Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
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37
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Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists. Cytokine 2016; 101:56-63. [PMID: 27567553 DOI: 10.1016/j.cyto.2016.08.014] [Citation(s) in RCA: 190] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 08/16/2016] [Accepted: 08/16/2016] [Indexed: 12/13/2022]
Abstract
Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.
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Levin AD, Wildenberg ME, van den Brink GR. Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2016; 10:989-97. [PMID: 26896086 DOI: 10.1093/ecco-jcc/jjw053] [Citation(s) in RCA: 242] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/16/2016] [Indexed: 12/12/2022]
Abstract
Several anti-tumour necrosis factor [TNF] blocking strategies have been evaluated in patients with Crohn's disease. Compounds that have been tested included the full monoclonal IgG1 antibodies infliximab and adalimumab, the pegylated anti-TNF F[ab']2 fragment certolizumab, an IgG4 anti-TNF CDP571 with reduced affinity for the Fc receptor, the soluble TNF receptor I onercept, and the TNF receptor II-Fc fusion protein etanercept. The endpoints of these studies suggest that not all methods of blocking TNF are equal. Here we will review the differences in the clinical, biochemical, and endoscopic endpoints of the major clinical studies. Collectively the data suggest that only IgG1 monoclonal antibodies have the ability to induce complete clinical, biochemical, and endoscopic remission. We discuss the potential multiple modes of action that may contribute to the response to full IgG1 anti-TNFs, focusing on the rapid induction of lamina propria T cell apoptosis and Fc receptor-dependent induction of M2-type wound-healing macrophages. We discuss how novel insights into the mechanism of action of anti-TNFs in Crohn's disease may contribute to the development of novel anti-TNFs with improved efficacy.
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Affiliation(s)
- Alon D Levin
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Manon E Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Gijs R van den Brink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands
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Pierri CL, Bossis F, Punzi G, De Grassi A, Cetrone M, Parisi G, Tricarico D. Molecular modeling of antibodies for the treatment of TNFα-related immunological diseases. Pharmacol Res Perspect 2016; 4:e00197. [PMID: 26977294 PMCID: PMC4777268 DOI: 10.1002/prp2.197] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/20/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α-related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor-mediated effector functions such as the complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand-binding interaction of these mAbs used in TNF α-related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen-binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab-TNF α interactions, we found that in the absence of fucosylation the Fc-mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.
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Affiliation(s)
- Ciro Leonardo Pierri
- Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
| | - Fabrizio Bossis
- Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
| | - Giuseppe Punzi
- Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
| | - Anna De Grassi
- Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
| | | | - Giovanni Parisi
- Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
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Olesen CM, Coskun M, Peyrin-Biroulet L, Nielsen OH. Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol Ther 2016; 159:110-9. [PMID: 26808166 DOI: 10.1016/j.pharmthera.2016.01.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α but with varying efficacies in IBD. The variations in efficacy probably are caused by structural differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF inhibitors in order to identify mechanisms of importance for their efficacy in IBD. Thus, a better understanding of the mechanistic basis for clinical efficacy can lead to a more rational use of TNF inhibitors in the management of IBD.
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Affiliation(s)
- Caroline Meyer Olesen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre, France
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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Isaacs JD, Cutolo M, Keystone EC, Park W, Braun J. Biosimilars in immune-mediated inflammatory diseases: initial lessons from the first approved biosimilar anti-tumour necrosis factor monoclonal antibody. J Intern Med 2016; 279:41-59. [PMID: 26403380 DOI: 10.1111/joim.12432] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The introduction of targeted biological therapies has revolutionised the management of immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and inflammatory bowel disease. Following treatment with these therapies, many patients experience significant improvements in different aspects of their disease, including symptoms, work productivity and other outcomes relevant for individuals and society. However, due to the complexity of biological drug development and manufacturing processes, the costs of these therapies are relatively high. Indeed, the financial burden on healthcare systems due to biological therapies is considerable and lack of patient access to effective treatment remains a concern in many parts of the world. As many reference biological therapies have now reached or are near to patent expiry, a number of 'biosimilar' drugs have been developed for use in various clinical settings, and some of these drugs are already in use in several countries. While the potential pharmacoeconomic benefits of cost-effective biosimilars seem clear, several issues have been raised regarding, for example, the definition of biosimilarity and the validity of indication extrapolation, as well as the 'switchability' and relative immunogenicity of biosimilars and their reference drugs. In this review, these issues will be discussed with reference to CT-P13, a biosimilar of the anti-tumour necrosis factor monoclonal antibody infliximab, which is approved in Europe and elsewhere for the treatment of various IMIDs. Other important issues, including those related to data collection during nonclinical and clinical development of biosimilars, are also discussed.
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Affiliation(s)
- J D Isaacs
- Institute of Cellular Medicine, NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UK
| | - M Cutolo
- Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - E C Keystone
- Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - W Park
- Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea
| | - J Braun
- Rheumazentrum Ruhrgebiet, Herne, Germany
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Cessak G, Kuzawińska O, Burda A, Lis K, Wojnar M, Mirowska-Guzel D, Bałkowiec-Iskra E. TNF inhibitors – Mechanisms of action, approved and off-label indications. Pharmacol Rep 2014; 66:836-44. [DOI: 10.1016/j.pharep.2014.05.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 04/13/2014] [Accepted: 05/07/2014] [Indexed: 12/13/2022]
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King J, Alexander M, Byrne J, MacMillan K, Mollo A, Kirsa S, Green M. A review of the evidence for occupational exposure risks to novel anticancer agents – A focus on monoclonal antibodies. J Oncol Pharm Pract 2014; 22:121-34. [DOI: 10.1177/1078155214550729] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Introduction Evidence of occupational exposure risks to novel anticancer agents is limited and yet to be formally evaluated from the Australian healthcare perspective. Methods From March to September 2013 medical databases, organizational policies, drug monographs, and the World Wide Web were searched for evidence relating to occupational exposure to monoclonal antibodies, fusion proteins, gene therapies, and other unclassified novel anticancer agents. Results Australian legislation, national and international guidelines, and drug company information excluded novel agents or provided inconsistent risk assessments and safe handling recommendations. Monoclonal antibody guidelines reported conflicting information and were often divergent with available evidence and pharmacologic rationale demonstrating minimal internalisation ability and occupational exposure risk. Despite similar physiochemical, pharmacologic, and internalisation properties to monoclonal antibodies, fusion proteins were included in only a minority of guidelines. Clinical directives for the safe handling of gene therapies and live vaccines were limited, where available focusing on prevention against exposure and cross-contamination. Although mechanistically different, novel small molecule agents (proteasome inhibitors), possess similar physiochemical and internalisation properties to traditional cytotoxic agents warranting cytotoxic classification and handling. Conclusion Novel agents are rapidly emerging into clinical practice, and healthcare personnel have few resources to evaluate risk and provide safety recommendations. Novel agents possess differing physical, molecular and pharmacological profiles compared to traditional cytotoxic anticancer agents. Evaluation of occupational exposure risk should consider both toxicity and internalisation. Evidence-based guidance able to direct safe handling practices for novel anticancer agents across a variety of clinical settings is urgently required.
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Affiliation(s)
- Julie King
- Pharmacy Department, Western Health, Melbourne, Australia
| | - Marliese Alexander
- Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Jenny Byrne
- Western and Central Melbourne Integrated Cancer Service, Melbourne, Australia
| | - Kent MacMillan
- Pharmacy Department, Western Health, Melbourne, Australia
| | | | - Sue Kirsa
- Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Michael Green
- Department of Cancer Services, Western Health, Melbourne, Australia
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Certolizumab Pegol: A Review of Its Use in Patients with Axial Spondyloarthritis or Psoriatic Arthritis. Drugs 2014; 74:999-1016. [DOI: 10.1007/s40265-014-0239-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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45
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Novedades sobre los tratamientos para la enfermedad inflamatoria intestinal. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36 Suppl 2:21-9. [DOI: 10.1016/s0210-5705(13)70050-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Chimenti MS, Saraceno R, Chiricozzi A, Giunta A, Chimenti S, Perricone R. Profile of certolizumab and its potential in the treatment of psoriatic arthritis. Drug Des Devel Ther 2013; 7:339-48. [PMID: 23620660 PMCID: PMC3633576 DOI: 10.2147/dddt.s31658] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab' fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn's disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.
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Affiliation(s)
- Maria Sole Chimenti
- Unit of Rheumatology, Allergology, and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy.
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