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Bertin D, Aghzadi J, Balandraud N, Roman C, Serrero M, Desplat-Jégo S. Detection of antibodies to infliximab in routine care: a 4-year French retrospective study. Clin Exp Immunol 2025; 219:uxae122. [PMID: 39714327 PMCID: PMC11747995 DOI: 10.1093/cei/uxae122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 11/25/2024] [Accepted: 12/20/2024] [Indexed: 12/24/2024] Open
Abstract
Despite its wide use to treat various inflammatory diseases, infliximab becomes ineffective in some patients due to inadequate drug levels and production of anti-drug antibodies (ADA). The aim of this study was to compare the prevalence and ADA levels in a large cohort of patients. ADA and infliximab (IFX) through levels measured by enzyme-linked immunosorbent assay were collected from 505 patients within a period of 4 years. The results indicate that (i) 13.5% of patients produce ADA, (ii) male patients were more likely to produce ADA at levels above 10 000 ng/ml than female patients, (iii) ADA levels were lower when associated with immunosuppressant drugs, (iv) there was an inverse relationship between ADA presence and IFX detection, and (v) no correlation was observed between ADA levels and number of injections or brand of IFX administered. This study improves our understanding of the factors promoting IFX immunogenicity and highlights the need to develop personalized treatment strategies.
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Affiliation(s)
- Daniel Bertin
- Immunology Laboratory, Biogenopôle, Hôpital de la Timone, APHM, Marseille, France
- CNRS, INP, Institute of Neurophysiopathology, Aix-Marseille University, Marseille, France
| | - Jehanne Aghzadi
- CNRS, INP, Institute of Neurophysiopathology, Aix-Marseille University, Marseille, France
| | | | - Céline Roman
- Multidisciplinary Pediatrics Department, Hôpital de la Timone, APHM, Marseille, France
| | - Mélanie Serrero
- Gastroenterology Department, Hôpital Nord, APHM, Marseille, France
| | - Sophie Desplat-Jégo
- Immunology Laboratory, Biogenopôle, Hôpital de la Timone, APHM, Marseille, France
- CNRS, INP, Institute of Neurophysiopathology, Aix-Marseille University, Marseille, France
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Mansouri P, Mansouri P, Behmard E, Najafipour S, Kouhpayeh A, Farjadfar A. Novel targets for mucosal healing in inflammatory bowel disease therapy. Int Immunopharmacol 2025; 144:113544. [PMID: 39571265 DOI: 10.1016/j.intimp.2024.113544] [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: 06/01/2024] [Revised: 10/13/2024] [Accepted: 10/28/2024] [Indexed: 12/15/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic condition affecting the gastrointestinal tract, primarily manifesting as ulcerative colitis (UC) or Crohn's disease (CD). Both inflammation and disruption of the intestinal epithelial barrier are key factors in IBD pathogenesis. Substantial evidence has revealed a significant association between aberrant immune responses and impairment of the intestinal epithelial barrier in IBD pathogenesis. The components of the intestinal epithelium, particularly goblet cells and Paneth cells, are crucial to gut homeostasis, as they secrete mucin, antimicrobial peptides (AMPs), and cytokines. Furthermore, impairment of epithelial integrity, which is regulated by tight junctions, is a hallmark of IBD pathology. While common treatments for IBD, such as anti-inflammatory drugs, target various signaling pathways with varying efficacies, therapeutic approaches focused on mucosal and epithelial barrier healing have been largely neglected. Moreover, high costs, side effects, and insufficient or inconsistent therapeutic outcomes remain major drawbacks of conventional anti-IBD drugs. Recent studies on epithelial barrier regeneration and permeability reduction have introduced promising therapeutic targets, including farnesoid X receptor (FXR), urokinase-type plasminogen activator (uPA)-urokinase-type plasminogen activator receptor (uPAR) interaction, fecal microbiota transplantation (FMT), and insulin receptor (INSR). Notably, the simultaneous targeting of intestinal inflammation and promotion of epithelial barrier healing shows promise for efficient IBD treatment. Future research should explore targeted therapies and combination treatments, including natural remedies, microbiota colonization, stem cell approaches, and computer-aided drug design. It is also crucial to focus on accurate prognosis and developing a thorough understanding of IBD development mechanisms.
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Affiliation(s)
- Pardis Mansouri
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran; Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Pegah Mansouri
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran; Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Esmaeil Behmard
- School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran
| | - Sohrab Najafipour
- School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran
| | - Amin Kouhpayeh
- Department of Pharmacology, Faculty of Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran.
| | - Akbar Farjadfar
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran.
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3
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Su H, Xiao S, Liang Z, Xun T, Zhang J, Yang X. Systematic review and bayesian network meta-analysis: comparative efficacy and safety of six commonly used biologic therapies for moderate-to-severe Crohn's disease. Front Pharmacol 2025; 15:1475222. [PMID: 39911832 PMCID: PMC11794990 DOI: 10.3389/fphar.2024.1475222] [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: 10/09/2024] [Accepted: 12/10/2024] [Indexed: 02/07/2025] Open
Abstract
Background In contrast to previous network meta-analysis using classical frequentist methods, we evaluated the efficacy and safety of six frequently-used biologics through a Bayesian method. Methods Web of Science, Scopus, CENTRAL, ClinicalTrials.gov and ICTRP were searched to collect randomized controlled trials (RCTs) in adults with moderate-to-severe Crohn's disease, comparing Infliximab, Adalimumab, Certolizumab pegol, Ustekinumab, Risankizumab, or Vedolizumab, relative to placebo or an active comparator for induction of clinical response (two different definitions) and maintenance of clinical remission. A random-effects model was performed with rankings according to the surface under cumulative ranking curve (SUCRA) probability. Finally, we completed sensitivity and consistency analyses, and evaluated the certainty of evidence through GRADE working group guidance. Results We identified 22 and 20 RCTs for induction and maintenance therapy, respectively. Infliximab combined with azathioprine was most effective for inducing clinical response in TNF (tumor necrosis factor) antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab (SUCRA 86.19) and Risankizumab (SUCRA 62.56) have the largest SUCRA in induction of clinical response. Risankizumab has the lowest risk of adverse events (SUCRA 84.81), serious adverse events (SUCRA 94.23), and serious infections (SUCRA 79.73) in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab rank highest for maintaining clinical remission. Conclusion This analysis suggests that Infliximab in combination with azathioprine may be preferred biologic agents for induction therapy in TNF antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab and Risankizumab may be preferred biologic agents for induction therapy. Risankizumab potentially has the lowest safety risk worth exploring in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab have maintenance efficacy benefits for responders to induction therapy. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=458609, Identifier CRD42023458609.
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Affiliation(s)
- Haohang Su
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Shengwei Xiao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhiqing Liang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Tianrong Xun
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jinfang Zhang
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China
- Shenzhen Traditional Chinese Medicine Oncology Medical Center, Shenzhen, China
| | - Xixiao Yang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- Shenzhen Clinical Research Center for Digestive Disease, Shenzhen, China
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Yeung AWK. Tracing the historical foundations of infliximab in Crohn's disease treatment: a cited reference analysis. Front Pharmacol 2024; 15:1498464. [PMID: 39605921 PMCID: PMC11598417 DOI: 10.3389/fphar.2024.1498464] [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: 09/19/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024] Open
Abstract
Introduction The use of infliximab to treat Crohn's disease patients has been evaluated for decades. The current work aimed to identify the historical roots of this research topic. Methods The literature database Web of Science Core Collection was searched to identify relevant papers. Cited reference analysis on the identified literature set was performed using CRExplorer, a dedicated bibliometric software. The disruption index was computed with an automated routine described by Leydesdorff and Bornmann, which is freely available online. Based on data from citation count and reference list, the disruption index can range from -1 to +1, with -1 meaning a continuity from existing research and +1 meaning a disruption. Results This analysis successfully identified key references dealing with infliximab use on Crohn's disease patients, such as the original report that introduced the Crohn's Disease Activity Index (CDAI) in 1976, the first case series reporting a favourable outcome of infliximab infusion on 10 patients published in 1995, the first randomized controlled trial published in 1997, the ACCENT I and ACCENT II trials published in 1999 and 2002, and a couple of European consensus guidelines on the diagnosis and management of Crohn's disease. Conclusion Cited reference analysis could reveal the historical origins of the use of infliximab in treating Crohn's disease. Highly cited references included CDAI, important early clinical studies, and European consensus guidelines. The important cited references identified by the analysis provided solid foundation to support subsequent research.
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Affiliation(s)
- Andy Wai Kan Yeung
- Oral and Maxillofacial Radiology, Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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Bhol NK, Bhanjadeo MM, Singh AK, Dash UC, Ojha RR, Majhi S, Duttaroy AK, Jena AB. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother 2024; 178:117177. [PMID: 39053423 DOI: 10.1016/j.biopha.2024.117177] [Citation(s) in RCA: 80] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/03/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024] Open
Abstract
Cytokines regulate immune responses essential for maintaining immune homeostasis, as deregulated cytokine signaling can lead to detrimental outcomes, including inflammatory disorders. The antioxidants emerge as promising therapeutic agents because they mitigate oxidative stress and modulate inflammatory pathways. Antioxidants can potentially ameliorate inflammation-related disorders by counteracting excessive cytokine-mediated inflammatory responses. A comprehensive understanding of cytokine-mediated inflammatory pathways and the interplay with antioxidants is paramount for developing natural therapeutic agents targeting inflammation-related disorders and helping to improve clinical outcomes and enhance the quality of life for patients. Among these antioxidants, curcumin, vitamin C, vitamin D, propolis, allicin, and cinnamaldehyde have garnered attention for their anti-inflammatory properties and potential therapeutic benefits. This review highlights the interrelationship between cytokines-mediated disorders in various diseases and therapeutic approaches involving antioxidants.
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Affiliation(s)
- Nitish Kumar Bhol
- Post Graduate Department of Biotechnology, Utkal University, Bhubaneswar, Odisha 751004, India
| | | | - Anup Kumar Singh
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India
| | - Umesh Chandra Dash
- Environmental Biotechnology Laboratory, KIIT School of Biotechnology, KIIT Deemed to be University, Bhubaneswar, Odisha, India
| | - Rakesh Ranjan Ojha
- Department of Bioinformatics, BJB (A) College, Bhubaneswar, Odisha-751014, India
| | - Sanatan Majhi
- Post Graduate Department of Biotechnology, Utkal University, Bhubaneswar, Odisha 751004, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
| | - Atala Bihari Jena
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
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Zeng Z, Lin H, Jiang M, Yuan J, Li X, Jia Y, Yang L, Zhang H. Anti-TNFα in inflammatory bowel disease: from originators to biosimilars. Front Pharmacol 2024; 15:1424606. [PMID: 39114362 PMCID: PMC11303209 DOI: 10.3389/fphar.2024.1424606] [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: 04/28/2024] [Accepted: 07/12/2024] [Indexed: 08/10/2024] Open
Abstract
The introduction of anti-tumor necrosis factor α (TNFα) biologics significantly innovated inflammatory bowel disease (IBD) treatment and increased medical costs. The recent expiration of patents of some anti-TNFα biologics (such as infliximab and adalimumab) facilitated the development of biosimilars. Comparable pharmacokinetic, efficacy, safety, and immunogenicity profiles between anti-TNFα originators and biosimilars were demonstrated in different studies. Anti-TNFα biosimilars hold promise for reducing the high cost of biologics and increasing patient access to biologics. In this review, we outline the current data on the use of anti-TNFα originators and biosimilars in patients with IBD, with a focus on the efficacy, safety, and immunogenicity profiles of infliximab and adalimumab biosimilars. The potential benefits, challenges, and future directions of anti-TNFα biosimilars are also discussed in the review.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Lin
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Yuan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Li
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yongbin Jia
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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Kruckow KL, Murray E, Shayhidin E, Rosenberg AF, Bowdish DME, Orihuela CJ. Chronic TNF exposure induces glucocorticoid-like immunosuppression in the alveolar macrophages of aged mice that enhances their susceptibility to pneumonia. Aging Cell 2024; 23:e14133. [PMID: 38459711 PMCID: PMC11296116 DOI: 10.1111/acel.14133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 01/22/2024] [Accepted: 02/12/2024] [Indexed: 03/10/2024] Open
Abstract
Chronic low-grade inflammation, particularly elevated tumor necrosis factor (TNF) levels, occurs due to advanced age and is associated with greater susceptibility to infection. One reason for this is age-dependent macrophage dysfunction (ADMD). Herein, we use the adoptive transfer of alveolar macrophages (AM) from aged mice into the airway of young mice to show that inherent age-related defects in AM were sufficient to increase the susceptibility to Streptococcus pneumoniae, a Gram-positive bacterium and the leading cause of community-acquired pneumonia. MAPK phosphorylation arrays using AM lysates from young and aged wild-type (WT) and TNF knockout (KO) mice revealed multilevel TNF-mediated suppression of kinase activity in aged mice. RNAseq analyses of AM validated the suppression of MAPK signaling as a consequence of TNF during aging. Two regulatory phosphatases that suppress MAPK signaling, Dusp1 and Ptprs, were confirmed to be upregulated with age and as a result of TNF exposure both ex vivo and in vitro. Dusp1 is known to be responsible for glucocorticoid-mediated immune suppression, and dexamethasone treatment increased Dusp1 and Ptprs expression in cells and recapitulated the ADMD phenotype. In young mice, treatment with dexamethasone increased the levels of Dusp1 and Ptprs and their susceptibility to infection. TNF-neutralizing antibody reduced Dusp1 and Ptprs levels in AM from aged mice and reduced pneumonia severity following bacterial challenge. We conclude that chronic exposure to TNF increases the expression of the glucocorticoid-associated MAPK signaling suppressors, Dusp1 and Ptprs, which inhibits AM activation and increases susceptibility to bacterial pneumonia in older adults.
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Affiliation(s)
- Katherine L. Kruckow
- Department of MicrobiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Elizabeth Murray
- Department of MicrobiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Elnur Shayhidin
- Firestone Institute for Respiratory HealthSt. Joseph's Healthcare HamiltonHamiltonOntarioCanada
- The M.G. DeGroote Institute for Infectious Disease ResearchMcMaster UniversityHamiltonOntarioCanada
| | - Alexander F. Rosenberg
- Department of MicrobiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
- Informatics InstituteUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Dawn M. E. Bowdish
- Firestone Institute for Respiratory HealthSt. Joseph's Healthcare HamiltonHamiltonOntarioCanada
- The M.G. DeGroote Institute for Infectious Disease ResearchMcMaster UniversityHamiltonOntarioCanada
| | - Carlos J. Orihuela
- Department of MicrobiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
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Gordon M, Sinopoulou V, Akobeng AK, Sarian A, Moran GW. Infliximab for maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst Rev 2024; 2:CD012609. [PMID: 38372447 PMCID: PMC10875719 DOI: 10.1002/14651858.cd012609.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
BACKGROUND Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α) which is present in high levels in the blood serum, mucosa and stool of patients with Crohn's disease. OBJECTIVES To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn's disease. SEARCH METHODS On 31 August, 2021 and 23 June, 2023, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP. SELECTION CRITERIA Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn's disease. DATA COLLECTION AND ANALYSIS Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE. Our primary outcome was clinical relapse. Secondary outcomes were loss of clinical response, endoscopic relapse, and withdrawal due to serious and adverse events. MAIN RESULTS Nine RCTs with 1257 participants were included. They were conducted between 1999 and 2022; seven RCTs included biologically-naive patients, and the remaining two included a mix of naive/not naive patients. Three studies included patients in clinical remission, five included patients with a mix of activity scores, and one study included biologic responders with active disease at baseline. All studies allowed some form of concomitant medication during their duration. One study exclusively included patients with fistulating disease. The age of the participants ranged from 18 to 69 years old. All but one single-centre RCT were multicentre RCTs. Four studies were funded by pharmaceutical companies, two had a mix of commercial and public funding, and two had public funding. Infliximab is probably superior to placebo in preventing clinical relapse in patients who have mixed levels of clinical disease activity at baseline, and are not naive to biologics (56% vs 75%, RR 0.73, 95% CI 0.63 to 0.84, NNTB = 5, moderate-certainty evidence). We cannot draw any conclusions on loss of clinical response (RR 0.59, 95% CI 0.37 to 0.96), withdrawals due to adverse events (RR 0.66, 95% CI 0.37 to 1.19), or serious adverse events (RR 0.60, 95% CI 0.36 to 1.00) because the evidence is very low certainty. Infliximab combined with purine analogues is probably superior to purine analogues for clinical relapse (12% vs 59%, RR 0.20, 95% CI 0.10 to 0.42, NNTB = 2, moderate-certainty evidence), for patients in remission, and who are not naive to biologics. We cannot draw any conclusions on withdrawals due to adverse events (RR 0.47, 95% CI 0.15 to 1.49), and serious adverse events (RR 1.19, 95% CI 0.54 to 2.64) because the evidence is very low certainty. We cannot draw any conclusions about the effects of infliximab on serious adverse events compared to purine analogues (RR 0.79, 95% CI 0.37 to 1.68) for a population in remission at baseline because the evidence is very low certainty. There was no evidence available for the outcomes of clinical relapse, loss of clinical response, and withdrawal due to adverse events. Infliximab may be equivalent to biosimilar for clinical relapse (47% vs 40% RR 1.18, 95% CI 0.82 to 1.69), and it may be slightly less effective in averting loss of clinical response (49% vs 32%, RR 1.50, 95% CI 1.01 to 2.23, low-certainty evidence), for a population with mixed/low disease activity at baseline. Infliximab may be less effective than biosimilar in averting withdrawals due to adverse events (27% vs 0%, RR 20.73, 95% CI 2.86 to 150.33, low-certainty evidence). Infliximab may be equivalent to biosimilar for serious adverse events (10% vs 10%, RR 0.99, 95% CI 0.39 to 2.50, low-certainty evidence). We cannot draw any conclusions on the effects of subcutaneous biosimilar compared with intravenous biosimilar on clinical relapse (RR 1.01, 95% CI 0.65 to 1.57), loss of clinical response (RR 0.94, 95% CI 0.70 to 1.25), and withdrawals due to adverse events (RR 0.77, 95% CI 0.30 to 1.97) for an active disease population with clinical response at baseline because the evidence is of very low certainty. We cannot draw any conclusions on the effects of infliximab compared to adalimumab on loss of clinical response (RR 0.68, 95% CI 0.29 to 1.59), withdrawals due to adverse events (RR 0.10, 95% CI 0.01 to 0.72), serious adverse events (RR 0.09, 95% CI 0.01 to 1.54) for an active disease population with clinical response at baseline because the evidence is of very low certainty. There was no evidence available for the outcome of clinical relapse. AUTHORS' CONCLUSIONS Infliximab is probably more effective in preventing clinical relapse than placebo (moderate-certainty evidence). Infliximab in combination with purine analogues is probably more effective in preventing clinical and endoscopic relapse than purine analogues alone (moderate-certainty evidence). No conclusions can be drawn regarding prevention of loss of clinical response, occurrence of withdrawals due to adverse events, or total adverse events due to very low-certainty evidence for both of these comparisons. There may be little or no difference in prevention of clinical relapse, withdrawal due to adverse events or total adverse events between infliximab and a biosimilar (low-certainty evidence). Infliximab may lead to more loss of clinical response than a biosimilar (low-certainty evidence). We were unable to draw meaningful conclusions about other comparisons and outcomes related to missing data or very low-certainty evidence due to serious concerns about imprecision and risk of bias. Further research should focus on comparisons with other active therapies for maintaining remission, as well as ensuring adequate power calculations and reporting of methods.
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Affiliation(s)
- Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | | | - Anthony K Akobeng
- Pediatric Gastroenterology, Sidra Medicine, Doha, Qatar
- Weill Cornell Medicine, Cornell University, Doha, Qatar
| | - Arni Sarian
- School of Medicine, University of Central Lancashire, Preston, UK
| | - Gordon William Moran
- National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK
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Kuwahara A, Nazuka M, Kuroki Y, Ito K, Watanabe S, Kumagai I, Asano R. Functional integration of protein A binding ability to antibody fragments for convenient and tag-free purification. Bioengineered 2023; 14:2259093. [PMID: 37732741 PMCID: PMC10515673 DOI: 10.1080/21655979.2023.2259093] [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: 10/11/2022] [Accepted: 09/07/2023] [Indexed: 09/22/2023] Open
Abstract
Although the development of small therapeutic antibodies is important, the affinity tags used for their purification often result in heterogeneous production and immunogenicity. In this study, we integrated Staphylococcus aureus protein A (SpA) binding ability into antibody fragments for convenient and tag-free purification. SpA affinity chromatography is used as a global standard purification method for conventional antibodies owing to its high binding affinity to the Fc region. SpA also has a binding affinity for some variable heavy domains (VH) classified in the VH3 subfamily. Through mutagenesis based on alignment and structural modeling results using the SpA-VH3 cocrystal structure, we integrated the SpA-binding ability into the anti-CD3 single-chain Fv. Furthermore, we applied this mutagenesis approach to more complicated small bispecific antibodies and successfully purified the antibodies using SpA affinity chromatography. The antibodies retained their biological function after purification. Integration of SpA-binding ability into conventional antibody fragments simplifies the purification and monitoring of the production processes and, thus, is an ideal strategy for accelerating the development of small therapeutic antibodies. Furthermore, because of its immunoactivity, the anti-CD3 variable region with SpA-binding ability is an effective building block for developing engineered cancer therapeutic antibodies without the Fc region.
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Affiliation(s)
- Atsushi Kuwahara
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Misae Nazuka
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Yuri Kuroki
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Kohei Ito
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | | | - Izumi Kumagai
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Ryutaro Asano
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
- Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Tokyo, Japan
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10
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Gordon M, Sinopoulou V, Akobeng AK, Radford SJ, Eldragini MEAA, Darie AM, Moran GW. Infliximab for medical induction of remission in Crohn's disease. Cochrane Database Syst Rev 2023; 11:CD012623. [PMID: 37982428 PMCID: PMC10658649 DOI: 10.1002/14651858.cd012623.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
BACKGROUND Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α), which is present in high levels in the blood serum, mucosa and stool of people with Crohn's disease. OBJECTIVES To evaluate the benefits and harms of infliximab alone or in combination with another agent for induction of remission in Crohn's disease compared to placebo or active medical therapies. SEARCH METHODS On 31 August 2021 and 4 March 2023, we searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and World Health Organization ICTRP. SELECTION CRITERIA Randomised control trials (RCTs) comparing infliximab alone or in combination with another agent to placebo or another active comparator in adults with active Crohn's disease. DATA COLLECTION AND ANALYSIS Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were clinical remission, clinical response and withdrawals due to adverse events. Our secondary outcomes were endoscopic remission, histological remission, endoscopic response, and serious and total adverse events. MAIN RESULTS The search identified 10 RCTs with 1101 participants. They were conducted between 1999 and 2019, and 7/10 RCTs included biologically naive participants. All but one RCT, which did not provide information, were multicentre and funded by pharmaceutical companies, and their authors declared conflicts. The age of the participants ranged from 26 to 65 years. Results were based on one study unless otherwise stated. Infliximab 5 mg/kg to 10 mg/kg may be more effective than placebo at week four for clinical remission (30/55 versus 3/25; RR 4.55, 95% CI 1.53 to 13.50; number needed to treat for an additional beneficial outcome (NNTB) 3) and response (36/55 versus 4/25; RR 4.09, 95% CI 1.63 to 10.25, NNTB 3). The evidence was low certainty. The study did not report withdrawals due to adverse events. We could not draw conclusions on the effects of infliximab 5 mg/kg to 10 mg/kg compared to placebo for fistulating participants for clinical remission (29/63 versus 4/31; RR 3.57, 95% CI 1.38 to 9.25; NNTB 4), response (48/106 versus 15/75; RR 1.94, 95% CI 1.10 to 3.41; NNTB 6; 2 studies) or withdrawals due to adverse events (2/63 versus 0/31; RR 2.50, 95% CI 0.12 to 50.54). The evidence was very low certainty. Infliximab used in combination with purine analogues is probably more effective than purine analogues alone for clinical remission at weeks 24 to 26 (182/301 versus 95/302; RR 1.92, 95% CI 1.59 to 2.32, NNTB 4; 4 studies; moderate-certainty evidence) and clinical response at week 26 (107/177 versus 66/178; RR 1.64, 95% CI 1.31 to 2.05; NNTB 5; 2 studies; moderate-certainty evidence). There may be little or no difference in withdrawals due to adverse events at week 26 (62/302 versus 53/301; RR 0.87, 95% CI 0.63 to 1.21; 4 studies; low-certainty evidence). Infliximab alone may be more effective than purine analogues alone at week 26 for clinical remission (85/177 versus 57/178; RR 1.50, 95% CI 1.15 to 1.95; NNTB 7; 2 studies) and response (94/177 versus 66/178; RR 1.44, 95% CI 1.13 to 1.82; NNTB 7; 2 studies). There may be little or no difference in withdrawals due to adverse events (30/177 versus 43/178; RR 0.70, 95% CI 0.46 to 1.06; 4 studies). The evidence was low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) and response (22/27 versus 24/28; RR 1.63, 95% CI 1.08 to 2.46). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg in an exclusively fistulating population for clinical remission (17/31 versus 12/32; RR 1.46, 95% CI 0.84 to 2.53), response (21/31 versus 18/32; RR 1.20, 95% CI 0.82 to 1.78), or withdrawals due to adverse events (1/31 versus 1/32; RR 1.03, 95% CI 0.07 to 15.79). The evidence was very low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 20 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) or response (22/27 versus 18/28; RR 1.27, 95% CI 0.91 to 1.76). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 10 mg/kg compared to 20 mg/kg for clinical remission (11/28 versus 11/28; RR 1.00, 95% CI 0.52 to 1.92) or response (14/28 versus 18/28; RR 0.78, 95% CI 0.49 to 1.23). The evidence was very low certainty. Withdrawals due to adverse events were not reported. There may be little or no difference between infliximab and a CT-P13 biosimilar at week six for clinical remission (47/109 versus 49/111; RR 0.98, 95% CI 0.72 to 1.32), response (67/109 versus 70/111; RR 0.97, 95% CI 0.79 to 1.20) and withdrawals due to adverse events (21/109 versus 17/111; RR 1.26, 95% CI 0.70 to 2.25). The evidence was low certainty. AUTHORS' CONCLUSIONS Infliximab in combination with purine analogues is probably more effective than purine analogues alone in inducing clinical remission and clinical response. Infliximab alone may be more effective in inducing clinical remission and response than purine analogues alone or placebo. Infliximab may be similar in efficacy to a CT-P13 biosimilar and there may be little or no difference in withdrawals due to adverse events. We were unable to draw meaningful conclusions as to whether infliximab alone is effective when used for exclusively fistulating populations. There was evidence that there may be little or no difference in withdrawal due to adverse events between infliximab plus purines compared with purines alone, as well as infliximab alone compared with purines alone. Meaningful conclusions cannot be drawn on all other outcomes related to adverse events due to very low certainty evidence.
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Affiliation(s)
- Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | | | | | - Shellie J Radford
- NIHR Nottingham Biomedical Research Centre - Gastrointestinal and Liver disorders theme, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | | | - Ana-Maria Darie
- NIHR Nottingham Biomedical Research Centre - Gastrointestinal and Liver disorders theme, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Gordon William Moran
- National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK
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11
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Yamashita M, Takayasu M, Maruyama H, Hirayama K. The Immunobiological Agents for Treatment of Antiglomerular Basement Membrane Disease. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2014. [PMID: 38004064 PMCID: PMC10673378 DOI: 10.3390/medicina59112014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 10/30/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023]
Abstract
Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.
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Affiliation(s)
| | | | | | - Kouichi Hirayama
- Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ami 300-0395, Ibaraki, Japan; (M.Y.); (M.T.); (H.M.)
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12
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Gottardi F, Leardini D, Muratore E, Baccelli F, Cerasi S, Venturelli F, Zanaroli A, Belotti T, Prete A, Masetti R. Treatment of steroid-refractory graft versus host disease in children. FRONTIERS IN TRANSPLANTATION 2023; 2:1251112. [PMID: 38993897 PMCID: PMC11235274 DOI: 10.3389/frtra.2023.1251112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/17/2023] [Indexed: 07/13/2024]
Abstract
Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients.
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Affiliation(s)
- Francesca Gottardi
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Davide Leardini
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Edoardo Muratore
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesco Baccelli
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Sara Cerasi
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesco Venturelli
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Andrea Zanaroli
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Tamara Belotti
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Arcangelo Prete
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Riccardo Masetti
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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Sharma P, Joshi RV, Pritchard R, Xu K, Eicher MA. Therapeutic Antibodies in Medicine. Molecules 2023; 28:6438. [PMID: 37764213 PMCID: PMC10535987 DOI: 10.3390/molecules28186438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/05/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.
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Affiliation(s)
- Prerna Sharma
- Geisinger Commonwealth School of Medicine, Scranton, PA 18509, USA
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14
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Sensi M, de Oliveira RF, Berto M, Palmieri M, Ruini E, Livio PA, Conti A, Pinti M, Salvarani C, Cossarizza A, Cabot JM, Ricart J, Casalini S, González-García MB, Fanjul-Bolado P, Bortolotti CA, Samorì P, Biscarini F. Reduced Graphene Oxide Electrolyte-Gated Transistor Immunosensor with Highly Selective Multiparametric Detection of Anti-Drug Antibodies. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2211352. [PMID: 37435994 DOI: 10.1002/adma.202211352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 06/29/2023] [Accepted: 07/10/2023] [Indexed: 07/13/2023]
Abstract
The advent of immunotherapies with biological drugs has revolutionized the treatment of cancers and auto-immune diseases. However, in some patients, the production of anti-drug antibodies (ADAs) hampers the drug efficacy. The concentration of ADAs is typically in the range of 1-10 pm; hence their immunodetection is challenging. ADAs toward Infliximab (IFX), a drug used to treat rheumatoid arthritis and other auto-immune diseases, are focussed. An ambipolar electrolyte-gated transistor (EGT) immunosensor is reported based on a reduced graphene oxide (rGO) channel and IFX bound to the gate electrode as the specific probe. The rGO-EGTs are easy to fabricate and exhibit low voltage operations (≤ 0.3 V), a robust response within 15 min, and ultra-high sensitivity (10 am limit of detection). A multiparametric analysis of the whole rGO-EGT transfer curves based on the type-I generalized extreme value distribution is proposed. It is demonstrated that it allows to selectively quantify ADAs also in the co-presence of its antagonist tumor necrosis factor alpha (TNF-α), the natural circulating target of IFX.
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Affiliation(s)
- Matteo Sensi
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
| | - Rafael Furlan de Oliveira
- Université de Strasbourg, CNRS, ISIS, 8 allée Gaspard Monge, Strasbourg, 67000, France
- Brazilian Nanotechnology National Laboratory (LNNano), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, 13083-970, Brazil
| | - Marcello Berto
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
| | - Marina Palmieri
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
| | - Emilio Ruini
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
| | - Pietro Antonio Livio
- Université de Strasbourg, CNRS, ISIS, 8 allée Gaspard Monge, Strasbourg, 67000, France
| | - Andrea Conti
- Dermatology Unit, Surgical, Medical, and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, via del Pozzo 71, Modena, 41125, Italy
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
| | - Carlo Salvarani
- Rheumatology Unit, University of Modena and Reggio Emilia, Medical School Azienda Ospedaliero-Universitaria Policlinico di Modena, via del Pozzo 71, Modena, 41125, Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Via Campi 287, Modena, 41125, Italy
| | - Joan M Cabot
- Leitat Technology Center, Innovació 2, Barcelona, 08225, Spain
| | - Jordi Ricart
- Leitat Technology Center, Innovació 2, Barcelona, 08225, Spain
| | - Stefano Casalini
- Université de Strasbourg, CNRS, ISIS, 8 allée Gaspard Monge, Strasbourg, 67000, France
- Dipartimento di Scienze Chimiche University of Padova, via Marzolo 1, Padova, 35131, Italy
| | | | - Pablo Fanjul-Bolado
- Metrohm DropSens, S.L. Vivero Ciencias de la Salud, C/Colegio Santo Domingo de Guzmán s/n, Oviedo, 33010, Spain
| | - Carlo Augusto Bortolotti
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
| | - Paolo Samorì
- Université de Strasbourg, CNRS, ISIS, 8 allée Gaspard Monge, Strasbourg, 67000, France
| | - Fabio Biscarini
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena, 41125, Italy
- Center for Translational Neurophysiology, Istituto Italiano di Tecnologia, Via Fossato di Mortara 17-19, Ferrara, 44121, Italy
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15
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Grasmeier MK, Weber S, Treiber M, Thaler MA, Luppa PB. Surface plasmon resonance assays for the therapeutic drug monitoring of infliximab indicate clinical relevance of anti-infliximab antibody binding properties. Clin Chem Lab Med 2023; 61:1255-1265. [PMID: 36753693 DOI: 10.1515/cclm-2022-0949] [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: 09/23/2022] [Accepted: 01/27/2023] [Indexed: 02/10/2023]
Abstract
OBJECTIVES The therapeutic antibody infliximab (IFX) has improved the life quality of numerous autoinflammatory disease patients. However, IFX can trigger the generation of anti-drug antibodies (ADA), whose optimal evaluation and management are currently subject of controversial discussions. We present two novel surface plasmon resonance (SPR) biosensor assays for therapeutic drug monitoring of IFX and characterization of ADA and investigated the diagnostic value of ADA binding properties. METHODS IFX and ADA were quantified via developed SPR biosensor assays (IFXmon and ADAmon, respectively) and diagnostics-approved ELISA in sera from inflammatory bowel disease patients. Pre-analytic ADA enrichment with magnetic beads enabled analytical drug tolerance of the ADAmon assay. The dissociation ratio (DissR) as an index for ADA:IFX binding stability was calculated from the SPR sensorgrams of ADA quantification runs. RESULTS IFX levels determined by IFXmon assay and ELISA showed high agreement, whereas ADA quantification concordance between ADAmon assay and ELISA was poor. In patients, DissR was predominantly constant over time and differed significantly between therapy outcomes. A DissR cut-off of 1.524 indicated undetectable IFX levels with 71.4% sensitivity and 88.9% specificity. Additionally, the SPR reference surface was exploited as serum-individual negative control to check result plausibility within multi-sample run sequences. CONCLUSIONS Overall, both SPR biosensor assays exhibited reliable quantitative performance with accuracies superior to their ELISA counterparts and precision inferior to ELISA only for ADAmon. DissR presented itself as promising ADA binding parameter and could contribute to both earlier and more tailored therapeutic decisions.
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Affiliation(s)
- Melina K Grasmeier
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Susanne Weber
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Matthias Treiber
- Clinic and Polyclinic for Internal Medicine II (Gastroenterology), Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Markus A Thaler
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Peter B Luppa
- Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
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Blais A, Lan A, Blachier F, Benamouzig R, Jouet P, Couvineau A. Efficiency of Orexin-A for Inflammatory Flare and Mucosal Healing in Experimental Colitis: Comparison with the Anti-TNF Alpha Infliximab. Int J Mol Sci 2023; 24:9554. [PMID: 37298505 PMCID: PMC10253642 DOI: 10.3390/ijms24119554] [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: 04/23/2023] [Revised: 05/25/2023] [Accepted: 05/29/2023] [Indexed: 06/12/2023] Open
Abstract
Inflammatory bowel diseases are chronic inflammation of the intestinal mucosa characterized by relapsing-remitting cycle periods of variable duration. Infliximab (IFX) was the first monoclonal antibody used for the treatment of Crohn's disease and ulcerative colitis (UC). High variability between treated patients and loss of IFX efficiency over time support the further development of drug therapy. An innovative approach has been suggested based on the presence of orexin receptor (OX1R) in the inflamed human epithelium of UC patients. In that context, the aim of this study was to compare, in a mouse model of chemically induced colitis, the efficacy of IFX compared to the hypothalamic peptide orexin-A (OxA). C57BL/6 mice received 3.5% dextran sodium sulfate (DSS) in drinking water for 5 days. Since the inflammatory flare was maximal at day 7, IFX or OxA was administered based on a curative perspective at that time for 4 days using intraperitoneal injection. Treatment with OxA promoted mucosal healing and decreased colonic myeloperoxidase activity, circulating concentrations of lipopolysaccharide-binding protein, IL-6 and tumor necrosis factor alpha (TNFα) and decreased expression of genes encoding cytokines in colonic tissues with better efficacy than IFX allowing for more rapid re-epithelization. This study demonstrates the comparable anti-inflammatory properties of OxA and IFX and shows that OxA is efficient in promoting mucosal healing, suggesting that OxA treatment is a promising new biotherapy.
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Affiliation(s)
- Anne Blais
- UMR-PNCA, Université Paris-Saclay, AgroParisTech, INRAE, 91120 Palaiseau, France; (A.L.); (F.B.); (R.B.)
| | - Annaïg Lan
- UMR-PNCA, Université Paris-Saclay, AgroParisTech, INRAE, 91120 Palaiseau, France; (A.L.); (F.B.); (R.B.)
| | - François Blachier
- UMR-PNCA, Université Paris-Saclay, AgroParisTech, INRAE, 91120 Palaiseau, France; (A.L.); (F.B.); (R.B.)
| | - Robert Benamouzig
- UMR-PNCA, Université Paris-Saclay, AgroParisTech, INRAE, 91120 Palaiseau, France; (A.L.); (F.B.); (R.B.)
- Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, 93000 Bobigny, France;
| | - Pauline Jouet
- Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, 93000 Bobigny, France;
| | - Alain Couvineau
- INSERM UMR 1149/Centre de Recherche sur l’Inflammation (CRI), Faculté de Médecine X. Bichat, Université Paris Cité, 75018 Paris, France
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Reinert T, Gahoual R, Mignet N, Kulus A, Allez M, Houzé P, François YN. Simultaneous quantification and structural characterization of monoclonal antibodies after administration using capillary zone electrophoresis-tandem mass spectrometry. J Pharm Biomed Anal 2023; 233:115446. [PMID: 37209497 DOI: 10.1016/j.jpba.2023.115446] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/27/2023] [Accepted: 05/06/2023] [Indexed: 05/22/2023]
Abstract
Monoclonal antibodies (mAbs) are demonstrating major success in various therapeutic areas such as oncology and the treatment of immune disorders. Over the past two decades, novel analytical methodologies allowed to address the challenges of mAbs characterization in the context of their production. However, after administration only their quantification is performed and insights regarding their structural evolution remain limited. For instance, clinical practice has recently highlighted significant inter-patient differences in mAb clearance and unexpected clinical responses, without providing alternative interpretations. Here, we report the development of a novel analytical strategy based on capillary zone electrophoresis coupled to tandem mass spectrometry (CE-MS/MS) for the simultaneous absolute quantification and structural characterization of infliximab (IFX) in human serum. CE-MS/MS quantification was validated over the range 0.4-25 µg·mL-1 corresponding to the IFX therapeutic window and achieved a LOQ of 0.22 µg·mL-1 (1.5 nM) while demonstrating outstanding specificity compared to the ELISA assay. CE-MS/MS allowed structural characterization and estimation of the relative abundance of the six major N-glycosylations expressed by IFX. In addition, the results allowed characterization and determination of the level of modification of post-translational modifications (PTMs) hotspots including deamidation of 4 asparagine and isomerization of 2 aspartate. Concerning N-glycosylation and PTMs, a new normalization strategy was developed to measure the variation of modification levels that occur strictly during the residence time of IFX in the patient's system, overcoming artefactual modifications induced by sample treatment and/or storage. The CE-MS/MS methodology was applied to the analysis of samples from patients with Crohn's disease. The data identified a gradual deamidation of a particular asparagine residue located in the complementary determining region that correlated with IFX residence time, while the evolution of IFX concentration showed significant variability among patients.
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Affiliation(s)
- Tessa Reinert
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS) UMR 7140 (Unistra-CNRS), Université de Strasbourg, France; Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France
| | - Rabah Gahoual
- Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France.
| | - Nathalie Mignet
- Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France
| | - Alexandre Kulus
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS) UMR 7140 (Unistra-CNRS), Université de Strasbourg, France
| | - Matthieu Allez
- Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), Inserm, U1160 Paris, France
| | - Pascal Houzé
- Université Paris Cité, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), CNRS, Inserm, Faculté de sciences pharmaceutiques et biologiques, Paris, France; Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - Yannis-Nicolas François
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS) UMR 7140 (Unistra-CNRS), Université de Strasbourg, France
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Awad A, Goyanes A, Orlu M, Gaisford S, Basit AW. 3D printed infliximab suppositories for rectal biologic delivery. Int J Pharm X 2023. [DOI: 10.1016/j.ijpx.2023.100176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
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19
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Supratherapeutic Infliximab Levels Do Not Predict Risk of Short-term Complications in Adults With Crohn's Disease. J Clin Gastroenterol 2023; 57:66-73. [PMID: 34907922 DOI: 10.1097/mcg.0000000000001637] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 10/10/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND It is uncertain if higher infliximab trough levels (TLs) confer a greater risk of infectious/noninfectious complications (IC/NIC). We aimed to assess the risk of IC and NIC in patients with different TLs. METHODS We retrospectively evaluated a cohort of Crohn's disease (CD) patients treated with infliximab who underwent therapeutic drug monitoring (TDM), at a tertiary inflammatory bowel disease center, between January 1, 2010, and December 1, 2019. TDM was defined as checking of infliximab trough and antibody levels within a 48-hour period before administration. Patients with a minimum of 3-month assessment pre-TDM and post-TDM were included. In the case of multiple TDMs, the highest TL was considered, and patients were distributed across 4 predefined TL groups (A: <5 µg/mL, B: 5 to 10 µg/mL, C: 10 to 15 µg/mL, and D: ≥15 µg/mL). Rates of IC and NIC during the 3-month prior and following TDM were compared across the groups. In addition, duration of exposure, in terms of months up to TDM, was collected to analyze differences in rates of IC and NIC. RESULTS Our study included 341 CD patients (median age: 35 y, 58% men). IC and NIC occurred in 52 (15%) and 30 (9%) patients, respectively. Rates of IC and NIC were similar across the 4 TL groups ( P =0.9 and 0.7, respectively for IC and NIC). On multivariable analysis, exposure to infliximab >40 months (as determined by receiver operating characteristic curve analysis) was associated with decreased odds for IC (adjusted odds ratio=0.51, P =0.04), but not NIC (adjusted odds ratio=0.72, P =0.46). CONCLUSIONS In this large CD cohort, there was no association between infliximab TL and risk of short-term IC or NIC. Interestingly, a shorter duration of exposure predicted higher rates of IC. This supports the safety of targeting higher infliximab TLs when necessary and greater vigilance during the early stages of treatment.
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20
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Aslam N, Lo SW, Sikafi R, Barnes T, Segal J, Smith PJ, Limdi JK. A review of the therapeutic management of ulcerative colitis. Therap Adv Gastroenterol 2022; 15:17562848221138160. [PMID: 36478780 PMCID: PMC9720837 DOI: 10.1177/17562848221138160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 10/26/2022] [Indexed: 12/03/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic relapsing and remitting gastrointestinal disorder of uncertain aetiology. The last two decades have seen an expansion in the therapeutic arsenal used to treat UC. This has resulted in improved clinical remission and response rates. Nonetheless, staples in our current medical management originate from trials conducted in the early 20th century. In this review article, we aim to outline the key milestones in the history of the medical management of UC in addition to highlighting promising therapeutic developments for the future.
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Affiliation(s)
| | | | - Rafid Sikafi
- St Mark’s Hospital, London North West University Healthcare NHS Trust, London, UK
| | - Tom Barnes
- Section of IBD – Division of Gastroenterology, Northern Care Alliance NHS Foundation Trust, Salford, UK
| | - Jonathan Segal
- Northern Hospital, Epping, Melbourne, VIC, Australia,Department of Medicine, University of Melbourne, Parkville, VIC, Australia
| | - Philip J Smith
- Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals Foundation NHS Trust, Liverpool, UK
| | - Jimmy K Limdi
- Section of IBD – Division of Gastroenterology, Northern Care Alliance NHS Foundation Trust, Manchester, UK,Manchester Academic Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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21
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Wang X, Yang C, Körner H, Ge C. Tumor Necrosis Factor: What Is in a Name? Cancers (Basel) 2022; 14:5270. [PMID: 36358688 PMCID: PMC9656125 DOI: 10.3390/cancers14215270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 12/18/2024] Open
Abstract
Tumor Necrosis Factor was one of the first cytokines described in the literature as a soluble mediator of cytotoxicity to tumors. Over the years, more extensive research that tried to employ Tumor Necrosis Factor in cancer treatments showed nevertheless that it mainly functioned as a proinflammatory cytokine. However, this did not stop the search for the holy grail of cancer research: A cytokine that could act as a one-stop treatment for solid tumors and lymphomas. This review will summarize the long experimental history of Tumor Necrosis Factor that caused the initial observations of a tumor necrotizing cytokine that could serve as a potential cancer treatment and discuss the current state of research into this side of the activities of Tumor Necrosis Factor.
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Affiliation(s)
- Xinming Wang
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Chunlan Yang
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Heinrich Körner
- Menzies Institute for Medical Research, Liverpool Street, Hobart, TAS 7000, Australia
| | - Chaoliang Ge
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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22
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Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review. Pharmaceutics 2022; 14:pharmaceutics14102095. [PMID: 36297530 PMCID: PMC9610912 DOI: 10.3390/pharmaceutics14102095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/07/2022] [Accepted: 09/15/2022] [Indexed: 11/18/2022] Open
Abstract
Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis α monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.
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Zhou X, Yu M, Ma L, Fu J, Guo J, Lei J, Fu Z, Fu Y, Zhang Q, Zhang CY, Chen X. In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis. Nat Commun 2022; 13:5700. [PMID: 36171212 PMCID: PMC9519883 DOI: 10.1038/s41467-022-33436-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/12/2022] [Indexed: 11/08/2022] Open
Abstract
Given the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.
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Affiliation(s)
- Xinyan Zhou
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Mengchao Yu
- Central Laboratories, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, 266061, Qingdao, China
| | - Luzhen Ma
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Jinyu Fu
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Jingwei Guo
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Jieqiong Lei
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Zheng Fu
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
- Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Yong Fu
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China
| | - Qipeng Zhang
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China.
| | - Chen-Yu Zhang
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China.
- Research Unit of Extracellular RNA, Chinese Academy of Medical Sciences, Jiangsu, 210023, Nanjing, China.
- Institute of Artificial Intelligence Biomedicine, Nanjing University, Jiangsu, 210023, Nanjing, China.
- Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, 518055, Shenzhen, Guangdong, China.
| | - Xi Chen
- Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, 210023, Nanjing, Jiangsu, China.
- Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, 210023, Nanjing, Jiangsu, China.
- Institute of Artificial Intelligence Biomedicine, Nanjing University, Jiangsu, 210023, Nanjing, China.
- Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, 518055, Shenzhen, Guangdong, China.
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Efficacy and Safety of Infliximab Retreatment in Crohn's Disease: A Multicentre, Prospective, Observational Cohort (REGAIN) Study from the GETAID. Am J Gastroenterol 2022; 117:1482-1490. [PMID: 35973142 DOI: 10.14309/ajg.0000000000001842] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 05/06/2022] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance. METHODS We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic. RESULTS At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26. DISCUSSION In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.
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25
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Camela E, Potestio L, Ruggiero A, Ocampo-Garza SS, Fabbrocini G, Megna M. Towards Personalized Medicine in Psoriasis: Current Progress. Psoriasis (Auckl) 2022; 12:231-250. [PMID: 36071793 PMCID: PMC9444142 DOI: 10.2147/ptt.s328460] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/13/2022] [Indexed: 12/14/2022] Open
Abstract
Although innovative targeted therapies have positively revolutionized psoriasis treatment shifting treatment goals to complete or almost complete skin clearance, primary or secondary lack of efficacy is still possible. Hence, identifying robust biomarkers that reflect the various clinical psoriasis phenotypes would allow stratify patients in subgroups or endotypes, and tailor treatments according to the characteristics of each individual (precision medicine). To sum up the current progress in personalized medicine for psoriasis, we performed a review on the available evidence on biomarkers predictive of response to psoriasis treatments, with focus on phototherapy and systemic agents. Relevant literature published in English was searched for using the following databases from the last five years up to March 20, 2022: PubMed, Embase, Google Scholar, EBSCO, MEDLINE, and the Cochrane library. Currently, more evidence exists towards biologicals, as justified by the huge health care costs as compared to phototherapy or conventional systemic drugs. Among them, most of the studies focused on anti-TNF and IL12/23, with still few on IL17 (mainly secukinumab). The most discussed biomarker gene is the HLA-C*02:06 status that has been shown to be associated with psoriasis, and also differential response to biologicals. Although its positivity is associated with great response to MTX, debatable results were retrieved concerning both anti-TNF and IL12/23 while it seems not to affect secukinumab response. Personalized treatment in psoriasis would provide excellent outcome minimizing the risk of side effects. To date, although several candidates were proposed and assessed, the scarcity and heterogeneity of the results do not allow the identification of the gold-standard biomarker per each treatment. Anyway, the creation of a more comprehensive panel would be more reliable for the treatment decision process.
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Affiliation(s)
- Elisa Camela
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Correspondence: Elisa Camela, Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy, Tel +39 - 081 - 7462457, Fax +39 - 081 - 7462442, Email
| | - Luca Potestio
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Angelo Ruggiero
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Sonia Sofia Ocampo-Garza
- Dermatology Department, Universidad Autónoma de Nuevo León, University Hospital ¨Dr. José Eleuterio González¨, Monterrey, Nuevo León, México
| | - Gabriella Fabbrocini
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Matteo Megna
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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26
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Tackling Inflammatory Bowel Diseases: Targeting Proinflammatory Cytokines and Lymphocyte Homing. Pharmaceuticals (Basel) 2022; 15:ph15091080. [PMID: 36145301 PMCID: PMC9502105 DOI: 10.3390/ph15091080] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 11/21/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are characterized by chronic inflammatory disorders that are a result of an abnormal immune response mediated by a cytokine storm and immune cell infiltration. Proinflammatory cytokine therapeutic agents, represented by TNF inhibitors, have developed rapidly over recent years and are promising options for treating IBD. Antagonizing interleukins, interferons, and Janus kinases have demonstrated their respective advantages in clinical trials and are candidates for anti-TNF therapeutic failure. Furthermore, the blockade of lymphocyte homing contributes to the excessive immune response in colitis and ameliorates inflammation and tissue damage. Factors such as integrins, selectins, and chemokines jointly coordinate the accumulation of immune cells in inflammatory regions. This review assembles the major targets and agents currently targeting proinflammatory cytokines and lymphatic trafficking to facilitate subsequent drug development.
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27
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Bueno-Soler A, Palacios-Oliva J, Dorvignit-Pedroso D, Quintana-Cantillo A, Ramirez-Roque Y, Santo Tomas-Pompa J, Solazabal-Armstrong JA, Ruiz-Ramirez I, Mateo-de Acosta C, Boggiano-Ayo T, Lao-Gonzalez T. Production of an anti-TNFα antibody in murine myeloma cells by perfusion culture. Appl Microbiol Biotechnol 2022; 106:5007-5021. [PMID: 35835964 DOI: 10.1007/s00253-022-12052-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 06/16/2022] [Accepted: 06/25/2022] [Indexed: 11/26/2022]
Abstract
Infliximab is a mouse/human chimeric IgG1 monoclonal antibody which recognizes the proinflammatory cytokine, tumor necrosis factor α (TNFα), and inhibits receptor interactions, thereby decreasing inflammation and autoimmune response in patients. This monoclonal antibody has been successfully used to treat rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the high treatment cost limits patient access to this biotherapy. One alternative to this problem is the use of biosimilars. In this work, we describe the stable expression and physicochemical characterization of an anti-TNFα antibody. While infliximab is produced in recombinant murine SP2/0 cells, our anti-TNFα IgG antibody was expressed in recombinant murine NS0 myeloma cells. The best anti-TNFα antibody-expressing clone was selected from three clone candidates based on the stability of IgG expression levels, specific productivity as well as TNFα-binding activity compared to commercial infliximab. Our results indicate that the selected cell clone, culture medium, and fermentation mode allowed for the production of an anti-TNFα antibody with similar characteristics to the reference commercially available product. An optimization of the selected culture medium by metabolomics may increase the volumetric productivity of the process to satisfy the demand for this product. Further experiments should be performed to evaluate the biological properties of this anti-TNFα antibody. KEY POINTS: • An anti-TNFα antibody was produced in NS0 cells using perfusion culture. • A proprietary chemically defined culture medium was used to replace commercially available protein-free medium. • The purified anti-TNFα antibody was comparable to the reference marketed product.
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Affiliation(s)
- Alexi Bueno-Soler
- Process Development Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
| | - Julio Palacios-Oliva
- Process Development Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
| | - Denise Dorvignit-Pedroso
- Immunobiology Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
- Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland
| | | | - Yaima Ramirez-Roque
- Process Development Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
| | | | | | - Ingrid Ruiz-Ramirez
- Quality Control Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
| | - Cristina Mateo-de Acosta
- Immunobiology Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
- CIMAB S. A, 11600, Playa, Havana, Cuba
| | - Tammy Boggiano-Ayo
- Process Development Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba
| | - Thailin Lao-Gonzalez
- Process Development Direction, Center of Molecular Immunology, 11600, Playa, Havana, Cuba.
- Animal Biotechnology Division, Center for Genetic Engineering and Biotechnology, 10600, Playa, Havana, Cuba.
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Rani T, Behl T, Sharma N, Makeen HA, Albratty M, Alhazmi HA, Meraya AM, Bhatia S, Bungau SG. Exploring the role of biologics in depression. Cell Signal 2022; 98:110409. [PMID: 35843573 DOI: 10.1016/j.cellsig.2022.110409] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 11/03/2022]
Abstract
Depression is a chronic and prevalent neuropsychiatric disorder; clinical symptoms include excessive sad mood, anhedonia, increased anxiety, disturbed sleep, and cognitive deficits. The exact etiopathogenesis of depression is not well understood. Studies have suggested that tumor necrosis factor-alpha (TNF-α) and interleukins (ILs) perform vital roles in the pathogenesis and treatment of depression. Increasing evidence suggests the upregulation of TNF-α and ILs expression in patients with depression. Therefore, biologics like TNF inhibitors (etanercept, infliximab, adalimumab) and IL inhibitors (ustekinumab) have become key compounds in the treatment of depression. Interestingly, treatment with an antidepressant has been found to decrease the TNF-α level and improve depression-like behaviors in several preclinical and clinical studies. In the current article, we have reviewed the recent findings linking TNF-α and the pathogenesis of depression proving TNF-α inhibitors as potential new therapeutic agents. Animal models and clinical studies further support that TNF-α inhibitors are effective in ameliorating depression-like behaviors. Moreover, studies showed that peripheral injection of TNF-α exhibits depressive symptoms. These symptoms have been improved by treatment with TNF-α inhibitors. Hence suggesting TNF-α inhibitors as potential new antidepressants for the management of depressive disorder.
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Affiliation(s)
- Tarapati Rani
- Chitkara College of Pharmacy, Chitkara University, Punjab, India; Government Pharmacy College, Seraj, Mandi, Himachal Pradesh, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Hafiz A Makeen
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Hassan A Alhazmi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, Saudi Arabia; Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, Saudi Arabia
| | - Abdulkarim M Meraya
- Pharmacy Parctice Research Unit, Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman; School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania; Doctoral School of Biomedical Sciences, University of Oradea, Oradea, Romania
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Abstract
Rheumatoid arthritis is a common chronic inflammatory disease with substantial economic, social, and personal costs. Its pathogenesis is multifactorial and complex. The ultimate goal of rheumatoid arthritis treatment is stopping or slowing down the disease progression. In the past two decades, invention of new medicines, especially biologic agents, revolutionized the management of this disease. These agents have been associated with an improved prognosis and clinical remission, especially in patients who did not respond to traditional disease-modifying anti-rheumatic drugs (DMARDs). Improvement in the understanding of the rheumatoid arthritis pathogenesis leads to the development of novel biologic therapeutic approaches. In the present paper, we summarized the current therapeutics, especially biologic agents, available for the treatment of rheumatoid arthritis.
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30
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Rommasi F, Nasiri MJ, Mirsaeidi M. Immunomodulatory agents for COVID-19 treatment: possible mechanism of action and immunopathology features. Mol Cell Biochem 2022; 477:711-726. [PMID: 35013850 PMCID: PMC8747854 DOI: 10.1007/s11010-021-04325-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/01/2021] [Indexed: 02/06/2023]
Abstract
The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.
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Affiliation(s)
- Foad Rommasi
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mirsaeidi
- Department of Pulmonary and Critical Care, Miller School of Medicine, University of Miami, Miami, FL, USA
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Mohd Noor AA, Azlan M, Mohd Redzwan N. Orchestrated Cytokines Mediated by Biologics in Psoriasis and Its Mechanisms of Action. Biomedicines 2022; 10:biomedicines10020498. [PMID: 35203707 PMCID: PMC8962336 DOI: 10.3390/biomedicines10020498] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 12/27/2022] Open
Abstract
Psoriasis is an autoimmune disease mediated by disturbed T cells and other immune cells, and is defined by deep-red, well-demarcated skin lesions. Due to its varied etiologies and indefinite standard pathogenesis, it is challenging to consider the right treatment exclusively for each psoriasis patient; thus, researchers yearn to seek even more precise treatments other than topical treatment and systemic therapy. Using biologics to target specific immune components, such as upregulated cytokines secreted by activated immune cells, is the most advanced therapy for psoriasis to date. By inhibiting the appropriate pro-inflammatory cytokines, cellular signaling can be altered and, thus, can inhibit further downstream inflammatory pathways. Herein, the roles of cytokines with their mechanisms of action in progressing psoriasis and how the usage of biologics alleviates cellular inflammation are discussed. In addition, other potential pro-inflammatory cytokines, with their mechanism of action, are presented herein. The authors hope that this gathered information may benefit future research in expanding the discovery of targeted psoriasis therapy.
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Affiliation(s)
- Aina Akmal Mohd Noor
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Maryam Azlan
- School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Norhanani Mohd Redzwan
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
- Correspondence: ; Tel.: +60-9767-6130
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Signore A, Lauri C, Micheli F, Baccini F. Gamma camera imaging of inflammatory bowel diseases. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00164-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Garcia-Montoya L, Emery P. Disease modification in ankylosing spondylitis with TNF inhibitors: spotlight on early phase clinical trials. Expert Opin Investig Drugs 2021; 30:1109-1124. [PMID: 34842481 DOI: 10.1080/13543784.2021.2010187] [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: 10/19/2022]
Abstract
INTRODUCTION Ankylosing spondylitis (AS) is a chronic inflammatory disease whose main hallmark is involvement of the axial skeleton. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line treatment; however, their use is limited because of side effects. Tumor necrosis factor inhibitors (TNFi) are a safe and effective therapy, and they have been approved for the management of AS. AREAS COVERED This is a review of the efficacy of TNFi in disease modification in AS. It is focused on results from early-phase clinical trials; however, it also discusses the most relevant findings in order to optimize anti-TNF treatment. A literature search was done using PubMed, Medline, Embase, Google Scholar, and Cochrane library, looking for scientific publications from inception to August 2021. Further information was retrieved from ClinicalTrial.gov and Clinicaltrialsregister.eu. EXPERT OPINION TNFi have demonstrated short- and long-term improvements in all aspects of disease activity, as well as physical function in patients with AS. They have drastically revolutionized the management of the disease; and even though new drugs have become available in the market, TNFi has not been displaced for the treatment of AS, and still constitute the best alternative when NSAIDs are no-longer an option.
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Affiliation(s)
- Leticia Garcia-Montoya
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,National Institute for Health Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Paul Emery
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,National Institute for Health Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Yang S, Yang S, Kwon Jo Y, Kim S, Jung Chang M, Choi J, Hee Cheon J, Yu YM. Efficacy and tolerability of infliximab retreatment in patients with inflammatory bowel disease: a systematic review and meta-analysis. Ther Adv Chronic Dis 2021; 12:20406223211041927. [PMID: 34729142 PMCID: PMC8438941 DOI: 10.1177/20406223211041927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 08/03/2021] [Indexed: 11/30/2022] Open
Abstract
Background: A large proportion of patients with inflammatory bowel disease (IBD) relapse after drug discontinuation despite achieving a stable state of infliximab-induced clinical remission. Resuming the use of the same tumor necrosis factor-alpha (TNF-α) inhibitors in patients who relapse following TNF-α inhibitor discontinuation was suggested as a treatment strategy. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of infliximab retreatment in patients with IBD. Methods: A systematic literature search to shortlist relevant studies was conducted using the MEDLINE, Embase, CINAHL, and SCOPUS databases for studies published from inception to August 2020. Results: Nine studies were included in the meta-analysis. The pooled clinical remission rate of infliximab retreatment in patients with IBD was 85% (95% confidence interval (CI), 81–89%) for induction treatment and 73% (95% CI, 66–80%) for maintenance treatment. A clinical remission rate following infliximab reintroduction was achieved in a greater proportion of patients with Crohn’s disease (87%; 95% CI, 83–91%) than in those with ulcerative colitis (78%; 95% CI, 61–91%) for induction treatment, but the difference was not statistically significant. Infusion-related reactions after infliximab retreatment occurred in 9% of patients with IBD (95% CI, 3–16%). Conclusion: Infliximab retreatment showed high clinical remission rates with tolerable infusion-related reactions in patients with IBD who achieved remission with initial infliximab treatment but relapsed after its discontinuation. We suggest infliximab as a viable alternative in patients with IBD who previously responded well to infliximab treatment.
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Affiliation(s)
- Seungwon Yang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Siyoung Yang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Young Kwon Jo
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Seungyeon Kim
- College of Pharmacy & Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Min Jung Chang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Junjeong Choi
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yun Mi Yu
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
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Auranofin: Past to Present, and repurposing. Int Immunopharmacol 2021; 101:108272. [PMID: 34731781 DOI: 10.1016/j.intimp.2021.108272] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 01/15/2023]
Abstract
Auranofin (AF), a gold compound, has been used to treat rheumatoid arthritis (RA) for more than 40 years; however, its mechanism of action remains unknown. We revealed that AF inhibited the induction of proinflammatory proteins and their mRNAs by the inflammatory stimulants, cyclooxygenase-2 and inducible nitric oxide synthase, and their upstream regulator, NF-κB. AF also activated the proteins peroxyredoxin-1, Kelch-like ECH-associated protein 1, and NF-E2-related factor 2, and inhibited thioredoxin reductase, all of which are involved in oxidative or electrophilic stress under physiological conditions. Although the cell membrane was previously considered to be permeable to AF because of its hydrophobicity, the mechanisms responsible for transporting AF into and out of cells as well as its effects on the uptake and excretion of other drugs have not yet been elucidated. Antibodies for cytokines have recently been employed in the treatment of RA, which has had an impact on the use of AF. Trials to repurpose AF as a risk-controlled agent to treat cancers or infectious diseases, including severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019, are ongoing. Novel gold compounds are also under development as anti-cancer and anti-infection agents.
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Sain A, Sen P, Venkataraman K, Vijayalakshmi MA. Expression of a Tagless Single-Chain Variable Fragment (scFv) of Anti-TNF-α by a Salt Inducible System and its Purification and Characterization. Protein Pept Lett 2021; 28:1272-1280. [PMID: 34551688 DOI: 10.2174/0929866528666210922141402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/31/2021] [Accepted: 08/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Anti-TNF-α scFv is gaining acceptance as an effective drug for various diseases, such as rheumatoid arthritis and Crohn's disease that involve elevated levels of TNF-α. The single-chain variable fragment (scFv) consists of variable regions of heavy and light chains of monoclonal antibodies (mAb). Due to its smaller size, it curbs the mAb's auto-antibody effects and their limitation of penetration into the tissues during the neutralization of TNF-α. OBJECTIVE In this work, a cDNA coding for anti-TNF-α scFv was successfully cloned into a pRSET-B vector and efficiently expressed in an E. coli strain GJ1158, a salt inducible system that uses sodium chloride instead of IPTG as an inducer. METHODS The protein was expressed in the form of inclusion bodies (IB), solubilized using urea, and refolded by pulse dilution. Further, the amino acid sequence coverage of scFv was confirmed by ESI-Q-TOF MS/MS and MALDI-TOF. Further studies on scaling up the production of scFv and its application of scFv are being carried out. RESULTS The soluble fraction of anti-TNF-α scFv was then purified in a single chromatographic step using CM-Sephadex chromatography, a weak cation exchanger with a yield of 10.3 mg/L. The molecular weight of the scFv was found to be ~ 28 kDa by SDS PAGE, and its presence was confirmed by western blot analysis and mass spectrometry. CONCLUSION Anti-TNF-α scFv has been successfully purified in a salt inducible system GJ1158. As per the best of our knowledge, this is the first report of purification of Anti-TNF-α scFv in a salt inducible system from soluble fractions as well as inclusion bodies.
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Affiliation(s)
- Avtar Sain
- Centre for Bio-Separation Technology, Vellore Institute of Technology, Vellore 632014, Tamilnadu,India
| | - Priyankar Sen
- Centre for Bio-Separation Technology, Vellore Institute of Technology, Vellore 632014, Tamilnadu,India
| | - Krishnan Venkataraman
- Centre for Bio-Separation Technology, Vellore Institute of Technology, Vellore 632014, Tamilnadu,India
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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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Sturm L, Schwemberger B, Menzel U, Häckel S, Albers CE, Plank C, Rip J, Alini M, Traweger A, Grad S, Basoli V. In Vitro Evaluation of a Nanoparticle-Based mRNA Delivery System for Cells in the Joint. Biomedicines 2021; 9:biomedicines9070794. [PMID: 34356857 PMCID: PMC8301349 DOI: 10.3390/biomedicines9070794] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/30/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Biodegradable and bioresponsive polymer-based nanoparticles (NPs) can be used for oligonucleotide delivery, making them a promising candidate for mRNA-based therapeutics. In this study, we evaluated and optimized the efficiency of a cationic, hyperbranched poly(amidoamine)s-based nanoparticle system to deliver tdTomato mRNA to primary human bone marrow stromal cells (hBMSC), human synovial derived stem cells (hSDSC), bovine chondrocytes (bCH), and rat tendon derived stem/progenitor cells (rTDSPC). Transfection efficiencies varied among the cell types tested (bCH 28.4% ± 22.87, rTDSPC 18.13% ± 12.07, hBMSC 18.23% ± 14.80, hSDSC 26.63% ± 8.81) and while an increase of NPs with a constant amount of mRNA generally improved the transfection efficiency, an increase of the mRNA loading ratio (2:50, 4:50, or 6:50 w/w mRNA:NPs) had no impact. However, metabolic activity of bCHs and rTDSPCs was significantly reduced when using higher amounts of NPs, indicating a dose-dependent cytotoxic response. Finally, we demonstrate the feasibility of transfecting extracellular matrix-rich 3D cell culture constructs using the nanoparticle system, making it a promising transfection strategy for musculoskeletal tissues that exhibit a complex, dense extracellular matrix.
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Affiliation(s)
- Lisa Sturm
- Institute of Tendon and Bone Regeneration, Spinal Cord Injury & Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; (L.S.); (B.S.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Bettina Schwemberger
- Institute of Tendon and Bone Regeneration, Spinal Cord Injury & Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; (L.S.); (B.S.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Ursula Menzel
- AO Research Institute Davos, 7270 Davos Platz, Switzerland; (U.M.); (M.A.); (V.B.)
| | - Sonja Häckel
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (S.H.); (C.E.A.)
| | - Christoph E. Albers
- Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (S.H.); (C.E.A.)
| | | | - Jaap Rip
- 20Med Therapeutics B.V., Galileiweg 8, 2333BD Leiden, The Netherlands;
| | - Mauro Alini
- AO Research Institute Davos, 7270 Davos Platz, Switzerland; (U.M.); (M.A.); (V.B.)
| | - Andreas Traweger
- Institute of Tendon and Bone Regeneration, Spinal Cord Injury & Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; (L.S.); (B.S.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Correspondence: (A.T.); or (S.G.)
| | - Sibylle Grad
- AO Research Institute Davos, 7270 Davos Platz, Switzerland; (U.M.); (M.A.); (V.B.)
- Department of Health Sciences and Technology, ETH Zurich, 8092 Zurich, Switzerland
- Correspondence: (A.T.); or (S.G.)
| | - Valentina Basoli
- AO Research Institute Davos, 7270 Davos Platz, Switzerland; (U.M.); (M.A.); (V.B.)
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D'Haens GR, van Deventer S. 25 years of anti-TNF treatment for inflammatory bowel disease: lessons from the past and a look to the future. Gut 2021; 70:1396-1405. [PMID: 33431575 DOI: 10.1136/gutjnl-2019-320022] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023]
Abstract
Anti-tumour necrosis factor (TNF) antibodies have been widely used for approximately 25 years now. The first clinical observations in patients with refractory Crohn's disease rapidly responding to infliximab prompted accelerated clinical development and approval for this indication. However, many questions remained unanswered when this treatment came to market related to maintenance schedules, pharmacokinetics, toxicity and positioning. Many of these open questions were addressed by investigators and sponsors during more than two decades of clinical use. The authors were among the first to use infliximab in Crohn's disease and felt that now is a good time to look back and draw lessons from the remarkable anti-TNF story. Even today, new insights continue to appear. But more importantly, what was learnt in the past 25 years has created a platform for future development of even stronger and safer therapies. We should not forget to learn from the past.
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Affiliation(s)
- Geert R D'Haens
- Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
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Ventin-Holmberg R, Eberl A, Saqib S, Korpela K, Virtanen S, Sipponen T, Salonen A, Saavalainen P, Nissilä E. Bacterial and Fungal Profiles as Markers of Infliximab Drug Response in Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1019-1031. [PMID: 33300552 DOI: 10.1093/ecco-jcc/jjaa252] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases [IBDs], Crohn's disease [CD] and ulcerative colitis [UC], are globally increasing chronic gastro-intestinal inflammatory disorders associated with altered gut microbiota. Infliximab [IFX], a tumour necrosis factor [TNF]-alpha blocker, is used to treat IBD patients successfully, though one-third of the patients do not respond to therapy. No reliable biomarkers are available for prediction of IFX response. Our aims were to investigate the faecal bacterial and fungal communities during IFX therapy and find predictors for IFX treatment response in IBD patients. METHODS A total of 72 IBD patients [25 CD and 47 UC] started IFX therapy and were followed for 1 year or until IFX treatment was discontinued. An amplicon sequencing approach, targeting the bacterial 16S rRNA gene and fungal ITS 1 region separately, was used to determine the microbiota profiles in faecal samples collected before IFX therapy and 2, 6, and 12 weeks and 1 year after initiation of therapy. The response to IFX was evaluated by colonoscopy and clinically at 12 weeks after initiation. RESULTS Both faecal bacterial and fungal profiles differed significantly between response groups before start of IFX treatment. Non-responders had lower abundances of short chain fatty acid producers, particularly of the class Clostridia, and higher abundances of pro-inflammatory bacteria and fungi, such as the genus Candida, compared with responders. This was further indicated by bacterial taxa predicting the response in both CD and UC patients [area under the curve >0.8]. CONCLUSIONS Faecal bacterial and fungal microbiota composition could provide a predictive tool to estimate IFX response in IBD patients.
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Affiliation(s)
| | - Anja Eberl
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Schahzad Saqib
- Human Microbiome Research Program, University of Helsinki, Helsinki, Finland
| | - Katri Korpela
- Human Microbiome Research Program, University of Helsinki, Helsinki, Finland
| | - Seppo Virtanen
- Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Taina Sipponen
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anne Salonen
- Human Microbiome Research Program, University of Helsinki, Helsinki, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Eija Nissilä
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
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Telegin GB, Chernov AS, Kazakov VA, Romanova EA, Sharapova TN, Yashin DV, Gabibov AG, Sashchenko LP. A 8-mer Peptide of PGLYRP1/Tag7 Innate Immunity Protein Binds to TNFR1 Receptor and Inhibits TNFα-Induced Cytotoxic Effect and Inflammation. Front Immunol 2021; 12:622471. [PMID: 34163464 PMCID: PMC8215708 DOI: 10.3389/fimmu.2021.622471] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
Search for novel regulatory protein fragments with potential functional roles is required both for understanding the immune response mechanisms and the development of targeted immunotherapy. Earlier we demonstrated that the PGLYRP1/Tag7 innate immunity protein can be regarded as an inhibitor of TNFα cytotoxic activity via the interaction with its TNF receptor 1 (TNFR1). A C-terminal peptide fragment 17.1 of the molecule is responsible for this function. In this study we have identified a minimal 8-mer region of this peptide (hereinafter – 17.1A) capable to bind to TNFR1. As a result of such interaction, the cytotoxic signals induced by this receptor are blocked. Also, this peptide demonstrates an anti-inflammatory activity in vivo in the complete Freund’s adjuvant (CFA)-induced arthritis model in laboratory mice. Peptide 17.1A is capable to reduce periarticular inflammation, inhibit the development of synovitis and exhibit a protective effect on cartilage and bone tissues. This peptide can turn out to be a promising medicinal agent for autoimmune arthritis and other diseases.
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Affiliation(s)
- Georgii B Telegin
- Animal Breeding Facility, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Pushchino, Russia
| | - Aleksandr S Chernov
- Animal Breeding Facility, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Pushchino, Russia
| | - Vitaly A Kazakov
- Animal Breeding Facility, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Pushchino, Russia
| | - Elena A Romanova
- Laboratory of Molecular Immunogenetics of Cancer, Institute of Gene Biology Russian Academy of Science, Moscow, Russia
| | - Tatiana N Sharapova
- Laboratory of Molecular Immunogenetics of Cancer, Institute of Gene Biology Russian Academy of Science, Moscow, Russia
| | - Denis V Yashin
- Laboratory of Molecular Immunogenetics of Cancer, Institute of Gene Biology Russian Academy of Science, Moscow, Russia
| | - Alexander G Gabibov
- Laboratory of Biocatalysis, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - Lidia P Sashchenko
- Laboratory of Molecular Immunogenetics of Cancer, Institute of Gene Biology Russian Academy of Science, Moscow, Russia
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Melo AT, Campanilho-Marques R, Fonseca JE. Golimumab (anti-TNF monoclonal antibody): where we stand today. Hum Vaccin Immunother 2021; 17:1586-1598. [PMID: 33369527 PMCID: PMC8115761 DOI: 10.1080/21645515.2020.1836919] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/17/2020] [Accepted: 10/09/2020] [Indexed: 01/07/2023] Open
Abstract
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine and its overexpression has been implicated in the pathophysiology of several chronic immune-mediated inflammatory diseases. Biological therapies, like TNF inhibitors, have been revolutionizing the course of these disorders. Golimumab is a transgenic anti-TNF monoclonal antibody that acts primarily by targeting and neutralizing TNF, thus preventing inflammation. It is approved for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Nonradiographic axial Spondyloarthritis, Juvenile Idiopathic Arthritis, and Ulcerative Colitis. Clinical trials are also being conducted in other conditions. This review charts the clinical development of golimumab and outlines the data that support its potential use across several Immune-mediated inflammatory diseases.
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Affiliation(s)
- Ana Teresa Melo
- Rheumatology Department, Hospital De Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
- Rheumatology Research Unit, Instituto De Medicina Molecular João Lobo Antunes, Faculdade De Medicina, Universidade De Lisboa, Lisbon, Portugal
| | - Raquel Campanilho-Marques
- Rheumatology Department, Hospital De Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
- Rheumatology Research Unit, Instituto De Medicina Molecular João Lobo Antunes, Faculdade De Medicina, Universidade De Lisboa, Lisbon, Portugal
| | - João Eurico Fonseca
- Rheumatology Department, Hospital De Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
- Rheumatology Research Unit, Instituto De Medicina Molecular João Lobo Antunes, Faculdade De Medicina, Universidade De Lisboa, Lisbon, Portugal
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Kettler B, Trauzold A, Röder C, Egberts JH, Kalthoff H. Topology impacts TRAIL therapy: Differences in primary cancer growth and liver metastasis between orthotopic and subcutaneous xenotransplants of pancreatic ductal adenocarcinoma cells. Hepatobiliary Pancreat Dis Int 2021; 20:279-284. [PMID: 33947634 DOI: 10.1016/j.hbpd.2021.04.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/13/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND To study novel treatment modalities for pancreatic ductal adenocarcinoma (PDAC), we need to transfer the knowledge from in vitro to in vivo. It is important to mirror the clinical characteristics of the typically local invasive growth of pancreatic cancer and the distant spread resulting in liver metastasis. Notably, for xenotransplant studies using human specimen, two models, i.e. subcutaneous (s.c.) and orthotopic (o.t.) transplantation are widely used. METHODS The subcutaneously and orthotopically inoculated Colo357 Bcl-xL cell-derived tumors were directly compared with and without TNF-related apoptosis inducing ligand (TRAIL) treatment. The size of primary tumors, number of liver metastasis and the histologic markers Ki67, M30, TNF-α and CD31 were assessed. RESULTS Upon TRAIL treatment, the primary tumors did not change their size, neither in the s.c. nor in the o.t. approaches. But when s.c. was compared to o.t., the size of the s.c. tumors was more than two-fold bigger than that of the o.t. tumors (P < 0.01). However, mice with orthotopically inoculated PDAC cells developed liver metastasis upon TRAIL treatment much more frequently (n = 13/17) than mice with subcutaneously inoculated PDAC cells (n = 1/11) (P < 0.01). As a likely driving force for this increased metastasis, a higher TNF-α staining intensity in the o.t. tumors was observed by immunohistochemistry. CONCLUSIONS These data from a direct side-by-side comparison underline the importance of the proper inoculation site of the PDAC cells. Local invasion and liver metastases are a hallmark of PDAC in the clinic; the o.t. model is clearly superior in reflecting this setting. Moreover, a serious side-effect of a possible new therapeutic compound became obvious only in the o.t. MODEL
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Affiliation(s)
- Bastian Kettler
- Clinic for General-, Abdominal- and Transplant-Surgery, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Anna Trauzold
- Institute for Experimental Cancer Research, University of Kiel and University Clinic of Schleswig-Holstein, Campus Kiel, Hs. U30, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Christian Röder
- Institute for Experimental Cancer Research, University of Kiel and University Clinic of Schleswig-Holstein, Campus Kiel, Hs. U30, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Jan-Hendrik Egberts
- Clinic for General, Visceral, Thoracic, Transplantation- and Pediatric Surgery, University Clinic of Schleswig-Holstein, Campus Kiel, Hs. C, Arnold-Heller-Str.3, 24105 Kiel, Germany
| | - Holger Kalthoff
- Institute for Experimental Cancer Research, University of Kiel and University Clinic of Schleswig-Holstein, Campus Kiel, Hs. U30, Arnold-Heller-Str. 3, 24105 Kiel, Germany.
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Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study. Pediatr Rheumatol Online J 2021; 19:62. [PMID: 33933127 PMCID: PMC8088679 DOI: 10.1186/s12969-021-00548-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 04/14/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. METHODS In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. RESULTS IFX trough concentrations ranged from 0 to > 40 μg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. CONCLUSIONS Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.
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Tong X, Zheng Y, Li Y, Xiong Y, Chen D. Soluble ligands as drug targets for treatment of inflammatory bowel disease. Pharmacol Ther 2021; 226:107859. [PMID: 33895184 DOI: 10.1016/j.pharmthera.2021.107859] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by persistent inflammation in a hereditarily susceptible host. In addition to gastrointestinal symptoms, patients with IBD frequently suffer from extra-intestinal complications such as fibrosis, stenosis or cancer. Mounting evidence supports the targeting of cytokines for effective treatment of IBD. Cytokines can be included in a newly proposed classification "soluble ligands" that has become the third major target of human protein therapeutic drugs after enzymes and receptors. Soluble ligands have potential significance for research and development of anti-IBD drugs. Compared with traditional drug targets for IBD treatment, such as receptors, at least three factors contribute to the increasing importance of soluble ligands as drug targets. Firstly, cytokines are the main soluble ligands and targeting of them has demonstrated efficacy in patients with IBD. Secondly, soluble ligands are more accessible than receptors, which are embedded in the cell membrane and have complex tertiary membrane structures. Lastly, certain potential target proteins that are present in membrane-bound forms can become soluble following cleavage, providing further opportunities for intervention in the treatment of IBD. In this review, 49 drugs targeting 25 distinct ligands have been evaluated, including consideration of the characteristics of the ligands and drugs in respect of IBD treatment. In addition to approved drugs targeting soluble ligands, we have also assessed drugs that are in preclinical research and drugs inhibiting ligand-receptor binding. Some new types of targetable soluble ligands/proteins, such as epoxide hydrolase and p-selectin glycoprotein ligand-1, are also introduced. Targeting soluble ligands not only opens a new field of anti-IBD drug development, but the circulating soluble ligands also provide diagnostic insights for early prediction of treatment response. In conclusion, soluble ligands serve as the third-largest protein target class in medicine, with much potential for the drugs targeting them.
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Affiliation(s)
- Xuhui Tong
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China
| | - Yuanyuan Zheng
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China
| | - Yu Li
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China
| | - Yongjian Xiong
- Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dapeng Chen
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China.
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Molecular Imaging of Autoimmune Diseases. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00055-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Abstract
Five biologics are approved for the treatment of ulcerative colitis (UC): infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab. These drugs have varying levels of efficacy and are recommended as first-line treatment of moderate to severe UC. There has been only 1 head-to-head trial comparing the efficacy of the biologics, adalimumab and vedolizumab, which has important implications for management. Therapeutic drug monitoring of biologics, especially anti-TNF alpha agents, may improve the long-term efficacy of these agents. The future of treatment may include personalization of medications, based on patient-specific and disease-specific characteristics as well as biomarkers, along with appropriate therapeutic drug monitoring.
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Kuwahara A, Nagai K, Nakanishi T, Kumagai I, Asano R. Functional Domain Order of an Anti-EGFR × Anti-CD16 Bispecific Diabody Involving NK Cell Activation. Int J Mol Sci 2020; 21:ijms21238914. [PMID: 33255436 PMCID: PMC7727810 DOI: 10.3390/ijms21238914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/19/2020] [Accepted: 11/22/2020] [Indexed: 12/12/2022] Open
Abstract
Bispecific antibodies (bsAbs) have emerged as promising therapeutics. A bispecific diabody (bsDb) is a small bsAb consisting of two distinct chimeric single-chain components, with two possible arrangements of the domains. We previously reported the effect of domain order on the function of a humanized bsDb targeting the epidermal growth factor receptor (EGFR) on cancer cells, and CD3 on T cells. Notably, the co-localization of a T-cell receptor (TCR) with CD3 is bulky, potentially affecting the cross-linking ability of bsDbs, due to steric hindrance. Here, we constructed and evaluated humanized bsDbs, with different domain orders, targeting EGFR and CD16 on natural killer (NK) cells (hEx16-Dbs). We predicted minimal effects due to steric hindrance, as CD16 lacks accessory molecules. Interestingly, one domain arrangement displayed superior cytotoxicity in growth inhibition assays, despite similar cross-linking abilities for both domain orders tested. In hEx16-Dbs specifically, domain order might affect the agonistic activity of the anti-CD16 portion, which was supported by a cytokine production test, and likely contributed to the superiority of one of the hEx16-Dbs. Our results indicate that both the target antigen and mode of action of an antibody must be considered in the construction of highly functional bsAbs.
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Affiliation(s)
- Atsushi Kuwahara
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan; (A.K.); (I.K.)
| | - Keisuke Nagai
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan;
| | - Takeshi Nakanishi
- Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University, Osaka 558-8585, Japan;
| | - Izumi Kumagai
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan; (A.K.); (I.K.)
| | - Ryutaro Asano
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan; (A.K.); (I.K.)
- Correspondence: ; Tel.: +81-42-388-7512
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Abstract
The U.S. government has sought to restrict immigration under the “America First” doctrine. These policies severely harm American science by stripping it of talent and eliminating a major driver of its innovation engine. We urge scientists to work to reverse these policies and forcefully condemn anti-immigrant sentiments.
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Affiliation(s)
- Brian D Brown
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
| | - Andrew M Leader
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Jan Vilcek
- Department of Microbiology, NYU Grossman School of Medicine, NYU Langone Health, New York, New York 10016, USA
| | - Miriam Merad
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
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Del Duca E, Morelli P, Bennardo L, Di Raimondo C, Nisticò SP. Cytokine Pathways and Investigational Target Therapies in Hidradenitis Suppurativa. Int J Mol Sci 2020; 21:ijms21228436. [PMID: 33182701 PMCID: PMC7696820 DOI: 10.3390/ijms21228436] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting areas with a high density of apocrine glands and characterized by subcutaneous nodules that may evolve into fistulas with pus secretion. Methods: The aim of this review is to investigate all current knowledge on cytokine regulation in the pathogenesis of HS. A systematic literature research using the words “cytokine”, “interleukin”, “pathway”, and “hidradenitis suppurativa” was performed in PubMed/Medline and Scopus/Embase databases. A search of the clinicaltrials.gov website for interventional recruiting and completed trials including the term “hidradenitis suppurativa” was also performed up to August 2020. We will discuss the pathogenetic role of various cytokines in HS and potential therapeutic targets for this debilitating disease. Results: The pathophysiology underlying this complex condition has not been clearly defined. An upregulation of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-17, IL-23, and other molecules seems to be related to this inflammatory condition. Various cells, such as lymphocytes T Helper 1 and 17 and keratinocytes seem to be involved in the genesis of this condition. Conclusions: Several future studies and clinical trials are necessary in order to have new knowledge about HS and to properly treat this complex condition.
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Affiliation(s)
- Ester Del Duca
- Department of Health Science, University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy; (P.M.); (L.B.); (S.P.N.)
- Correspondence: ; Tel.: +39-917-9694-386; Fax: +39-0961-369-6150
| | - Paola Morelli
- Department of Health Science, University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy; (P.M.); (L.B.); (S.P.N.)
| | - Luigi Bennardo
- Department of Health Science, University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy; (P.M.); (L.B.); (S.P.N.)
| | - Cosimo Di Raimondo
- Department of Dermatology, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Steven Paul Nisticò
- Department of Health Science, University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy; (P.M.); (L.B.); (S.P.N.)
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