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Grad S, Farcas RA, Dumitrascu DL, Surdea-Blaga T, Ismaiel A, Popa S. Predictors of Immunogenicity and Loss of Response to ANTI-TNFα Therapy in Crohn Disease-A Systematic Review. Am J Ther 2025; 32:e262-e268. [PMID: 40338684 DOI: 10.1097/mjt.0000000000001867] [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] [Indexed: 05/10/2025]
Abstract
BACKGROUND As the use of anti-tumor necrosis factor-α (TNFα) therapies in Crohn disease (CD) is spread, the loss-of-response (LOR) to it is increasingly encountered. Discovering a pathological pathway and biomarkers that can predict LOR would assist in the management of patients with CD. In this article, we provide a comprehensive systematic review of studies assessing predictors of immunogenicity and loss-of-response to anti-TNFα drugs in patients with CD. DATA SOURCES We performed a systematic review of PubMed to identify citations pertaining to predictors of immunogenicity and loss-of-response to anti-TNFα drugs in patients with CD through April 27, 2024, using a predefined string of keywords. Data extraction and quality assessment were performed independently by 2 reviewers. RESULTS A total of 18 eligible studies were included in the review. Four major groups of studies were identified: genetic factors, factors linked with colonic inflammation, serum and anthropological markers, and prevention of LOR. Promising predictors of LOR to infliximab or adalimumab include the carriage of HLA-DQA1*05, visceral adiposity, intestinal abundant presence of CD96, IL-17, and IL-23. Substantial heterogeneity was observed, and none of the markers had undergone formal validation. Specific limitations to acceptance of these factors included failure to use a standardized definition of LOR to anti-TNFα treatment, lack of specificity, and insufficient relevance to the pathogenesis of LOR. CONCLUSIONS This review underlines the lack of well-defined studies and controlled trials investigating predictors of LOR to anti-TNFα therapies in CD. A research priority is the development of reliable and accurate biomarkers that can shed light on the pathogenesis of the implied LOR. These biomarkers, along with genetic factors, have the potential to enhance clinical management by aiding in patient stratification and monitoring.
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Affiliation(s)
- Simona Grad
- 2nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Khalil RM, Abdelhameed MF, Abou Taleb S, El-Saied MA, Shalaby ES. Preparation and characterisation of esculetin-loaded nanostructured lipid carriers gels for topical treatment of UV-induced psoriasis. Pharm Dev Technol 2024; 29:886-898. [PMID: 39315459 DOI: 10.1080/10837450.2024.2407854] [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: 07/14/2024] [Accepted: 09/19/2024] [Indexed: 09/25/2024]
Abstract
SIGNIFICANCE As an inflammatory and autoimmune skin condition, psoriasis affects 2-3% of people worldwide. Psoriasis requires prolonged treatments with immunosuppressive medications which have severe adverse effects. Esculetin (Esc) is a natural medication that has been utilised to treat psoriasis. OBJECTIVE The goal of this work is to improve Esc's solubility by developing novel Esc nanostructured lipid carriers (NLCs) for treating psoriasis and increasing the residence time on the skin which infers better skin absorption. METHODS The particle size, zeta potential and entrapment efficiency (EE) of Esc NLCs were assessed. Incorporating NLCs into gum Arabic gel preparation enhances their industrial applicability, absorption and residence time on the skin. Esc NLC gels were evaluated by in vitro release and in vivo effectiveness on a rat model of UV-induced psoriasis. RESULTS Esc NLCs showed high EE reaching more than 95% and reasonable particle size ranging between (53.86 ± 0.38 to 236.3 ± 0.11 nm) and were spherical. The release study of Esc NLCs gel demonstrated a fast release of Esc denoting enhanced bioavailability. Compared to free Esc, Esc NLCs gel (F2) could considerably lower the level of CD34 and TNF-α in the skin. The results were validated through histopathological analysis. CONCLUSION As Esc NLCs gel (F2) has strong anti-inflammatory properties, our results showed that it presented a significant potential for healing psoriasis.
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Affiliation(s)
- Rawia M Khalil
- Pharmaceutical Technology Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Cairo, Egypt
| | - Mohamed F Abdelhameed
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Sally Abou Taleb
- Pharmaceutical Technology Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Cairo, Egypt
| | - Mohamed A El-Saied
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Eman Samy Shalaby
- Pharmaceutical Technology Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Cairo, Egypt
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A Review of the Totality of Evidence for the Development and Approval of ABP 710 (AVSOLA), an Infliximab Biosimilar. Adv Ther 2022; 39:44-57. [PMID: 34757601 PMCID: PMC8799530 DOI: 10.1007/s12325-021-01944-y] [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: 08/10/2021] [Accepted: 10/01/2021] [Indexed: 11/29/2022]
Abstract
ABP 710 (AVSOLA®) is a biosimilar to infliximab reference product (RP), a monoclonal antibody targeting tumor necrosis factor alpha (TNFα). It is approved in the USA and Canada for all the same indications as infliximab RP. Approval of ABP 710 was based on the totality of evidence (TOE) generated using a stepwise approach to assess its similarity with infliximab RP with regard to analytical (structural and functional) characteristics, pharmacokinetic parameters, and clinical efficacy and safety. ABP 710 was shown to be analytically similar to infliximab RP including in amino acid sequence, primary peptide structure, and glycan mapping and purity. ABP 710 was also demonstrated to be similar to infliximab RP with regard to functional characterization including in vitro binding, effector functions, and signaling pathways important for the mechanisms of action for clinical efficacy in multiple indications of immune-mediated inflammatory disorders including inflammatory bowel disease (IBD), especially binding to both soluble and membrane-bound TNFα. Pharmacokinetic similarity of ABP 710 with infliximab RP was demonstrated in healthy volunteers following a single 5 mg/kg intravenous dose. Comparative clinical efficacy of ABP 710 with infliximab RP was demonstrated in patients with rheumatoid arthritis. Safety and immunogenicity were also demonstrated to be similar for both ABP 710 and the RP. Overall, the TOE supported the conclusion that ABP 710 is highly similar to infliximab RP and supported scientific justification for extrapolation to all approved indications of infliximab RP, including IBD.
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Mazaheri S, Talebkhan Y, Mahboudi F, Nematollahi L, Cohan RA, Mirabzadeh Ardakani E, Bayat E, Sabzalinejad M, Sardari S, Torkashvand F. Improvement of Certolizumab Fab' properties by PASylation technology. Sci Rep 2020; 10:18464. [PMID: 33116155 PMCID: PMC7595094 DOI: 10.1038/s41598-020-74549-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022] Open
Abstract
Certolizumab pegol is a Fab' antibody fragment for treatment of rheumatoid arthritis and Crohn's disease which is conjugated to a 40 kDa PEG molecule in order to increase the protein half-life. PEGylation may have disadvantages including immunogenicity, hypersensitivity, vacuolation, decreased binding affinity and biological activity of the protein. To overcome these problems, PASylation has been developed as a new approach. The nucleotide sequence encoding 400 amino acid PAS residues was genetically fused to the corresponding nucleotide sequences of both chains of certolizumab. Then, the bioactivity as well as physicochemical and pharmacokinetic properties of the recombinant PASylated expressed protein was assayed. Circular dichroism spectroscopy demonstrated that the random coil structure of PAS sequences did not change the secondary structure of the PASylated Fab' molecule. It was observed that PASylation influenced the properties of the Fab' molecule by which the hydrodynamic radius and neutralization activity were increased. Also, the antigen binding and binding kinetic parameters improved in comparison to the PEGylated Fab' antibody. Pharmacokinetic studies also showed prolonged terminal half-life and improved pharmacokinetic parameters in PASylated recombinant protein in comparison to the PEGylated and Fab' control molecules. The results reconfirmed the efficiency of PASylation approach as a potential alternative method in increasing the half-life of pharmaceutical proteins.
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Affiliation(s)
- Somayeh Mazaheri
- Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Yeganeh Talebkhan
- Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | | | - Leila Nematollahi
- Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Reza Ahangari Cohan
- Department of Nanobiotechnology, Advanced Technology Group, Pasteur Institute of Iran, Tehran, Iran
| | | | - Elham Bayat
- Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | | | - Soroush Sardari
- Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Rogers KV, Martin SW, Bhattacharya I, Singh RSP, Nayak S. A Dynamic Quantitative Systems Pharmacology Model of Inflammatory Bowel Disease: Part 2 - Application to Current Therapies in Crohn's Disease. Clin Transl Sci 2020; 14:249-259. [PMID: 32822115 PMCID: PMC7877864 DOI: 10.1111/cts.12850] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 06/14/2020] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a heterogeneic disease with a variety of treatments targeting different mechanisms. A multistate, mechanistic, mathematical model of IBD was developed in part 1 of this two-part article series. In this paper, application of the model to predict response of key clinical biomarkers following different treatment options for Crohn's disease was explored. Five therapies, representing four different mechanisms of action, were simulated in the model and longitudinal profiles of key clinical markers, C-reactive protein and fecal calprotectin were compared with clinical observations. Model simulations provided an accurate match with both central tendency and variability observed in biomarker profiles. We also applied the model to predict biomarker and clinical response in an experimental, combination therapy of existing therapeutic options and provide possible mechanistic basis for the increased response. Overall, we present a validated, modular, mechanistic model construct, which can be applied to explore key biomarkers and clinical outcomes in IBD.
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Affiliation(s)
- Katharine V Rogers
- Biologics Development Sciences, Janssen Biotherapeutics, Janssen Research and Development, LLC, Spring House, Pennsylvania, USA
| | - Steven W Martin
- Pharmacometrics, Global Clinical Pharmacology, Pfizer Inc., Cambridge, Massachusetts, USA
| | - Indranil Bhattacharya
- Clinical Pharmacology and Pharmacometrics, Takeda Pharmaceuticals, Cambridge, Massachusetts, USA
| | | | - Satyaprakash Nayak
- Pharmacometrics, Global Clinical Pharmacology, Pfizer Inc., Cambridge, Massachusetts, USA
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Gareb B, Otten AT, Frijlink HW, Dijkstra G, Kosterink JGW. Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease. Pharmaceutics 2020; 12:E539. [PMID: 32545207 PMCID: PMC7356880 DOI: 10.3390/pharmaceutics12060539] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 05/28/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.
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Affiliation(s)
- Bahez Gareb
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;
- Martini Hospital Groningen, Department of Clinical Pharmacy and Toxicology, Van Swietenplein 1, 9728 NT Groningen, The Netherlands
| | - Antonius T. Otten
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.T.O.); (G.D.)
| | - Henderik W. Frijlink
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.T.O.); (G.D.)
| | - Jos G. W. Kosterink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Department of PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
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Zhang E, Xie L, Qin P, Lu L, Xu Y, Gao W, Wang L, Xie MH, Jiang W, Liu S. Quality by Design-Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®. AAPS J 2020; 22:69. [PMID: 32385732 PMCID: PMC7210234 DOI: 10.1208/s12248-020-00454-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/07/2020] [Indexed: 12/31/2022] Open
Abstract
Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. The critical quality attributes (CQAs) were then identified through risk assessment according to impact of each quality attribute on efficacy and safety. The anticipated range for each CQA was derived from similarity acceptance range and/or the corresponding regulatory guidelines. Finally, a panel of advanced and orthogonal physicochemical and functional tests and comparison of 6 batches of HLX03 and 10 batches of the reference standard demonstrated high similarity of HLX03 to Humira®, except for slightly lower percentage of high mannosylated glycans (%HM) in HLX03 which had no effect on FcγRIII binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity in human peripheral blood mononuclear cell (PBMC). All above demonstrated the feasibility and efficiency of QbD-based similarity assessment of a biosimilar monoclonal antibody (mAb).
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Affiliation(s)
- Erhui Zhang
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Liqi Xie
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Peilan Qin
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Lihong Lu
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Yanpeng Xu
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Wenyuan Gao
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Linlin Wang
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Michael Hongwei Xie
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China.
| | - Weidong Jiang
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
| | - Scott Liu
- Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China
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Bufan B, Jančić I, Stojić-Vukanić Z. Inhibitors of tumor necrosis factor-a and mechanisms of their action. ARHIV ZA FARMACIJU 2020. [DOI: 10.5937/arhfarm2003109b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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Duivelshof BL, Jiskoot W, Beck A, Veuthey JL, Guillarme D, D’Atri V. Glycosylation of biosimilars: Recent advances in analytical characterization and clinical implications. Anal Chim Acta 2019; 1089:1-18. [DOI: 10.1016/j.aca.2019.08.044] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/15/2019] [Accepted: 08/17/2019] [Indexed: 12/14/2022]
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Wang Y, Wang J, Pekow J, Dalal S, Cohen RD, Ollech J, Israel A, Shogan BD, Micic D, Cannon L, Umanskiy K, Hurst R, Hyman N, Rubin DT, Sakuraba A. Outcome of elective switching to vedolizumab in inflammatory bowel disease patients under tumor necrosis factor antagonist-maintained clinical remission. J Gastroenterol Hepatol 2019; 34:2090-2095. [PMID: 31169926 DOI: 10.1111/jgh.14751] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/03/2019] [Accepted: 05/27/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Vedolizumab (VDZ) has been used in inflammatory bowel disease (IBD) patients who failed anti-tumor necrosis factor (TNF) therapy. This study was to examine long-term outcome of IBD patients switching to VDZ from anti-TNF agents for reasons other than failure of therapy. METHODS Inflammatory bowel disease patients at the University of Chicago IBD center who were in clinical remission with anti-TNF therapy and then electively changed to VDZ due to reasons other than loss of response were retrospectively analyzed. The primary outcome was the durability of clinical remission maintained by VDZ as assessed by Kaplan-Meier survival analysis. The proportion of patients in clinical and endoscopic remission at 6-12 months after switching to VDZ therapy was analyzed. RESULTS A total of 41 patients (36 with Crohn's disease and 5 with ulcerative colitis) met the inclusion criteria and were in clinical remission at the time of switch. The majority of patients switched therapy due to adverse effects (56.1%) or infections (14.6%). During a median duration of 30 months (range 7-52) of VDZ therapy, 34 (82.9%) were in VDZ-maintained clinical remission. One (2.4%) and four (9.8%) patients discontinued VDZ due to flare and adverse effects, respectively. Endoscopic remission was present in 25 of 30 patients (83.3%) who had a follow-up colonoscopy. CONCLUSIONS Vedolizumab was effective and safe in maintaining remission in IBD patients who switched from anti-TNF agents due to reasons other than failure of therapy. Our results suggest that switching anti-TNF remitters to VDZ treatment is a safe practice in specific patient populations.
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Affiliation(s)
- Yunwei Wang
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Jennifer Wang
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Joel Pekow
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Sushila Dalal
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Russell D Cohen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Jacob Ollech
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Amanda Israel
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Benjamin D Shogan
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Dejan Micic
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Lisa Cannon
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Konstantin Umanskiy
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Roger Hurst
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Neil Hyman
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
| | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois, USA
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Gareb B, Posthumus S, Beugeling M, Koopmans P, Touw DJ, Dijkstra G, Kosterink JGW, Frijlink HW. Towards the Oral Treatment of Ileo-Colonic Inflammatory Bowel Disease with Infliximab Tablets: Development and Validation of the Production Process. Pharmaceutics 2019; 11:pharmaceutics11090428. [PMID: 31450748 PMCID: PMC6781063 DOI: 10.3390/pharmaceutics11090428] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/15/2019] [Accepted: 08/20/2019] [Indexed: 12/13/2022] Open
Abstract
Infliximab (IFX) is an intravenously administered monoclonal antibody antagonizing the effects of tumor necrosis factor-alpha (TNF) systemically and is efficacious in the treatment of inflammatory bowel disease (IBD). However, studies suggest that the anti-inflammatory effects result from local immunomodulation in the inflamed regions. Furthermore, topical inhibition of TNF in IBD ameliorates inflammation. We therefore hypothesized that orally administered IFX targeted to the ileo-colonic region in IBD may be an efficacious new treatment option. This study describes the development and validation of the production process of ileo-colonic-targeted 5 mg IFX tablets (ColoPulse-IFX) intended for the oral treatment of IBD by means of producing three consecutive validation batches (VAL1, VAL2, and VAL3, respectively). UV-VIS spectroscopy, HPLC-SEC analysis (content, fragments, aggregates), fluorescence spectroscopy (tertiary protein structure), and ELISA (potency) showed no noticeable deviations of IFX compounded to ColoPulse-IFX compared to fresh IFX stock. The average ± SD (n = 10) IFX content of VAL1, VAL2, and VAL3 was 96 ± 2%, 97 ± 3%, and 96 ± 2%, respectively, and complied with the European Pharmacopeia (Ph. Eur.) requirements for Content Uniformity. The average ± SD (n = 3) ColoPulse-IFX potency was 105 ± 4%, 96 ± 4%, and 97 ± 5%, respectively, compared to fresh IFX stock. The IFX release profile from the tablet core was complete (≥85%) after 10 min in simulated ileum medium. The in vitro coating performance of ColoPulse-IFX showed that the formulation was targeted to the simulated ileo-colonic region. Stability data showed that ColoPulse-IFX was stable for up to 6 months stored at 25 °C/60% RH. Based on these results, the production process can be considered validated and its application is discussed in light of the rationale and available evidence for the topical treatment of IBD with IFX.
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Affiliation(s)
- Bahez Gareb
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
| | - Silke Posthumus
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Max Beugeling
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Pauline Koopmans
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Jos G W Kosterink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- Department of PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Henderik W Frijlink
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
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McClellan JE, Conlon HD, Bolt MW, Kalfayan V, Palaparthy R, Rehman MI, Kirchhoff CF. The 'totality-of-the-evidence' approach in the development of PF-06438179/GP1111, an infliximab biosimilar, and in support of its use in all indications of the reference product. Therap Adv Gastroenterol 2019; 12:1756284819852535. [PMID: 31223341 PMCID: PMC6566480 DOI: 10.1177/1756284819852535] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/25/2019] [Indexed: 02/04/2023] Open
Abstract
The 'totality-of-the-evidence' biosimilarity concept requires that sufficient structural, functional, nonclinical, and clinical data are acquired in a stepwise manner, to demonstrate that no clinically meaningful differences in quality, safety, or efficacy are observed compared with the reference product. We describe the totality of the evidence for PF-06438179/GP1111 (PF-SZ-IFX; IXIFI™ [infliximab-qbtx]/Zessly®) that supported its approval as an infliximab (IFX) biosimilar for all eligible indications of reference IFX (ref-IFX; Remicade®) in Europe and in the US. Analytical similarity involving in vitro assays capable of distinguishing structural or functional differences between PF-SZ-IFX and ref-IFX formed a foundation for the biosimilarity exercise. Differences identified in N-glycosylation and charge heterogeneity were found not to impact the results in in vitro biological assays reflective of the pharmacology underlying the mechanisms of action (tumor necrosis factor binding, reverse signaling, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) of IFX across disease indications. Similarity was assessed in a comparative clinical pharmacokinetic study and in a clinical efficacy and safety study in patients with rheumatoid arthritis, where therapeutic equivalence between PF-SZ-IFX and ref-IFX provided confirmatory evidence of biosimilarity, and, when coupled with the analytical similarity already established, supported extrapolation to all eligible disease indications of ref-IFX.
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Affiliation(s)
| | - Hugh D. Conlon
- Analytical Research and Development, Pfizer Inc., Andover, MA, USA
| | - Michael W. Bolt
- Drug Safety Research and Development, Pfizer Inc., Cambridge, MA, USA
| | | | | | | | - Carol F. Kirchhoff
- Global Technology Services, Biotechnology and Aseptic Sciences Group, Pfizer Inc., Chesterfield, MO, USA
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Sorrentino D, Nguyen VQ, Chitnavis MV. Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science. Cells 2019; 8:E548. [PMID: 31174359 PMCID: PMC6627618 DOI: 10.3390/cells8060548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 05/30/2019] [Accepted: 06/04/2019] [Indexed: 12/16/2022] Open
Abstract
While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.
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Affiliation(s)
- Dario Sorrentino
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
- Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, 33100 Udine, Italy.
| | - Vu Q Nguyen
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
| | - Maithili V Chitnavis
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
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14
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Ghersin I, Khateeb N, Katz LH, Daher S, Shamir R, Assa A. Anthropometric Measures in Adolescents With Inflammatory Bowel Disease: A Population-Based Study. Inflamm Bowel Dis 2019; 25:1061-1065. [PMID: 30358844 DOI: 10.1093/ibd/izy336] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Growth impairment is common in pediatric inflammatory bowel disease (IBD) patients. Nevertheless, a controversy exists regarding disease impact on anthropometric measures in the long term. Thus, we aimed to investigate the impact of IBD on anthropometric measures, including weight, height, and body mass index (BMI), during late adolescence in a cross-sectional, population-based study. METHODS A total of 1,144,213 Jewish Israeli adolescents who underwent a general health examination from 2002 to 2016 at a median age (interquartile range) of 17.1 (16.9-17.3) years were included. Inflammatory bowel disease cases were stratified into Crohn's disease (CD) and ulcerative colitis (UC). Patients were also subgrouped based on age at IBD diagnosis. RESULTS Overall, 2372 cases of IBD were identified out of 1,144,213 persons examined (0.2%). Crohn's disease accounted for 68% of IBD cases. Males and females with CD (but not with UC) had significantly lower weight and BMI compared with controls. Differences in height at late adolescence were not statistically significant for either disease compared with controls (females: 162 cm vs 161.7 cm vs 161.5 cm; males: 174 cm vs 173.7 cm vs 173.6 cm for controls, UC, and CD, respectively). In a subgroup analysis, patients with CD diagnosed at age <14 years were significantly shorter than controls (males: 172.7 cm vs 174 cm; P = 0.001; females: 160.6 cm vs 162; P = 0.008). This pattern was not noted in UC patients. CONCLUSIONS Adolescents with CD were leaner compared with the general population. No overall difference was noted in height at late adolescence. Younger age at diagnosis was associated with reduced height in CD patients.
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Affiliation(s)
- Itai Ghersin
- IDF Medical Corps, Israel.,Department of Internal Medicine B/H, Rambam Health Care Campus, Haifa, Israel
| | | | - Lior H Katz
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Raanan Shamir
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Amit Assa
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach Tikva, Israel
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15
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Demonstration of functional similarity of a biosimilar adalimumab SB5 to Humira®. Biologicals 2019; 58:7-15. [DOI: 10.1016/j.biologicals.2018.12.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 11/09/2018] [Accepted: 12/03/2018] [Indexed: 12/13/2022] Open
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16
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El-Hussuna A, Qvist N, Zangenberg MS, Langkilde A, Siersma V, Hjort S, Gögenur I. No effect of anti-TNF-α agents on the surgical stress response in patients with inflammatory bowel disease undergoing bowel resections: a prospective multi-center pilot study. BMC Surg 2018; 18:91. [PMID: 30390672 PMCID: PMC6215640 DOI: 10.1186/s12893-018-0425-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/18/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND TNF-α plays a role in angiogenesis and collagen synthesis, both essential in the wound healing process. There are concerns that pre-operative anti-TNF-α treatment may influence the surgical stress response and increase the risk of surgical complications. The aim of this study was to describe the surgical stress response in patients with inflammatory bowel disease (IBD) and to investigate whether the pre-operative administration of anti-tumor necrosis factor alpha (anti-TNF-α) agents modify the surgical stress response. METHODS This was a prospective, multi-center cohort pilot study. The primary outcome was the change in concentration of immunological biomarkers of the surgical stress response (TNF-α, IL-6, and IL-10). Secondary outcome measures were changes in IL-8, IL-17A, C-reactive protein, white blood cells, cortisol, transferrin, ferritin, and D-Dimer in addition to 30 days' post-operative complications and length of post-operative stay in the hospital (LOS). RESULTS Forty-six patients with IBD undergoing major abdominal surgery were included, and 18 received anti-TNF- α treatment pre-operatively. Peak increase of most of the immunological biomarkers occurred 6 hours after surgical incision. Then the concentration decreased after 24 h followed by a plateau at 48 h. After adjusting for confounders including detectable blood concentrations, no difference in the concentrations of immunological, endocrinological or haematological biomarkers of stress was found between anti-TNF-α treated and anti-TNF-α naïve patients. No increase in post-operative complications or LOS was noticed in patients who received anti-TNF-α treatment. CONCLUSIONS Anti-TNF-α did not affect surgical stress response in this pilot study. Withdrawal of anti-TNF-α drugs prior to surgical intervention in IBD patients might not be justified without measurement of drug concentration and drug antibodies. TRIAL REGISTRATION Clinicaltrails.gov.: NCT01974869 .
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Affiliation(s)
- Alaa El-Hussuna
- Department of Surgery, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark
| | - Niels Qvist
- Department of Surgery, Odense University Hospital, Odense, Denmark
| | - Marie Strøm Zangenberg
- Department of Surgery, Slagelse Hospitals, Slagelse, Denmark
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Roskilde, Denmark
| | - Anne Langkilde
- Copenhagen University Hospital Hvidovre, Optimed, Clinical Research Centre, København, Denmark
| | - Volkert Siersma
- The Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Sara Hjort
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Roskilde, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Roskilde, Denmark
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17
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Adesso S, Russo R, Quaroni A, Autore G, Marzocco S. Astragalus membranaceus Extract Attenuates Inflammation and Oxidative Stress in Intestinal Epithelial Cells via NF-κB Activation and Nrf2 Response. Int J Mol Sci 2018; 19:E800. [PMID: 29534459 PMCID: PMC5877661 DOI: 10.3390/ijms19030800] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 03/01/2018] [Accepted: 03/09/2018] [Indexed: 12/17/2022] Open
Abstract
Astragalus membranaceus, dried root extract, also known as Astragali radix, is used in traditional Chinese medicine as a tonic remedy. Moreover, it has been reported that Astragalus membranaceus could attenuate intestinal inflammation; however, the underlying mechanism for its anti-inflammatory activity in intestinal epithelial cells (IECs) remains unclear. In this study, we evaluated Astragalus membranaceus extract (5-100 µg/mL) in a model of inflammation and oxidative stress for IECs. We showed that Astragalus membranaceus extract reduced the inflammatory response induced by lipopolysaccharide from E. coli (LPS) plus interferon-γ (IFN), decreasing tumor necrosis factor-α (TNF-α) release, cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, nitrotyrosine formation, nuclear factor-κB (NF-κB) activation, and reactive oxygen species (ROS) release in the non-tumorigenic intestinal epithelial cell line (IEC-6). The antioxidant potential of Astragalus membranaceus extract was also evaluated in a model of hydrogen peroxide (H₂O₂)-induced oxidative stress in IEC-6, indicating that this extract reduced ROS release and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and the expression of antioxidant cytoprotective factors in these cells. The results contributed to clarify the mechanisms involved in Astragalus membranaceus extract-reduced inflammation and highlighted the potential use of this extract as an anti-inflammatory and antioxidant remedy for intestinal diseases.
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Affiliation(s)
- Simona Adesso
- Department of Pharmacy, University of Salerno-Via Giovanni Paolo II, 132-84084 Fisciano-Salerno, Italy.
| | - Rosario Russo
- Giellepi S.p.A. Health Science Department, Via Benvenuto Cellini 37, 20851 Lissone (Monza Brianza), Italy.
| | - Andrea Quaroni
- Department of Biomedical Sciences, Cornell University, Veterinary Research Tower, Cornell University, Ithaca, NY 14853-6401, USA.
| | - Giuseppina Autore
- Department of Pharmacy, University of Salerno-Via Giovanni Paolo II, 132-84084 Fisciano-Salerno, Italy.
| | - Stefania Marzocco
- Department of Pharmacy, University of Salerno-Via Giovanni Paolo II, 132-84084 Fisciano-Salerno, Italy.
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18
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Ding X, Li D, Li M, Tian D, Yu H, Yu Q. Tumor necrosis factor-α acts reciprocally with solute carrier family 26, member 3, (downregulated-in-adenoma) and reduces its expression, leading to intestinal inflammation. Int J Mol Med 2017; 41:1224-1232. [PMID: 29286110 PMCID: PMC5819926 DOI: 10.3892/ijmm.2017.3347] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 12/18/2017] [Indexed: 12/12/2022] Open
Abstract
Solute carrier family 26, member 3 (Slc26a3), also termed downregulated-in-adenoma (DRA) is a member of the Slc26 family of anion transporters and is mutated in congenital chloride diarrhea. Our previous study demonstrated that DRA deficiency is associated with severely reduced colonic HCO3‑ secretion, a loss of colonic fluid absorption, a lack of a firmly adherent mucus layer and a severely reduced colonic mucosal resistance to dextran sodium sulfate (DSS) damage. However, the direct effect of mediators that trigger intestinal inflammatory factors on DRA has not been fully investigated. Tumor necrosis factor (TNF)‑α is a central mediator of intestinal inflammation in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease. However, to the best of our knowledge, whether TNF‑α acts reciprocally with DRA leading to the development of gut inflammation in IBD has not been reported. The present study identified that the expression level of DRA was reduced in active UC patients and DSS‑induced colitis mice with high expression levels of TNF‑α identified in the peripheral blood serum. In addition, TNF‑α may affect the expression level of DRA in human colonic Caco2BBE cells in a dose‑dependent manner, including in DRA overexpressed Caco2BBE cells. Furthermore, knockdown of TNF‑α in Caco2BBE cells led to a higher expression level of DRA and a markedly reduced secretion of TNF‑α in the culture media. In addition, knockdown of DRA in Caco2BBE cells led to a higher secretion of TNF‑α in the culture media compared with the control cells, which could be reversed by overexpression of DRA. Overall, these results indicate that TNF‑α may act reciprocally with DRA, leading to the development of intestinal inflammation. Based on the pivotal position of TNF‑α in IBD, DRA is hypothesized to have therapeutic potential against colitis serving as an important target.
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Affiliation(s)
- Xiangming Ding
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Dongxiao Li
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Mengke Li
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Hongbing Yu
- Department of Pediatrics, BC Children's Hospital and The University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Qin Yu
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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19
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Kothari MM, Nguyen DL, Parekh NK. Strategies for overcoming anti-tumor necrosis factor drug antibodies in inflammatory bowel disease: Case series and review of literature. World J Gastrointest Pharmacol Ther 2017; 8:155-161. [PMID: 28828193 PMCID: PMC5547373 DOI: 10.4292/wjgpt.v8.i3.155] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 05/14/2017] [Accepted: 06/07/2017] [Indexed: 02/06/2023] Open
Abstract
Anti-tumor necrosis factor (TNF) biologics are currently amongst the most widely used and efficacious therapies for inflammatory bowel disease (IBD). The development of therapeutic drug monitoring for infliximab and adalimumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients (75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.
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20
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Pisupati K, Tian Y, Okbazghi S, Benet A, Ackermann R, Ford M, Saveliev S, Hosfield CM, Urh M, Carlson E, Becker C, Tolbert TJ, Schwendeman SP, Ruotolo BT, Schwendeman A. A Multidimensional Analytical Comparison of Remicade and the Biosimilar Remsima. Anal Chem 2017; 89:4838-4846. [PMID: 28365979 PMCID: PMC5599217 DOI: 10.1021/acs.analchem.6b04436] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In April 2016, the Food and Drug Administration approved the first biosimilar monoclonal antibody (mAb), Inflectra/Remsima (Celltrion), based off the original product Remicade (infliximab, Janssen). Biosimilars promise significant cost savings for patients, but the unavoidable differences between innovator and copycat biologics raise questions regarding product interchangeability. In this study, Remicade and Remsima were examined by native mass spectrometry, ion mobility, and quantitative peptide mapping. The levels of oxidation, deamidation, and mutation of individual amino acids were remarkably similar. We found different levels of C-terminal truncation, soluble protein aggregates, and glycation that all likely have a limited clinical impact. Importantly, we identified more than 25 glycoforms for each product and observed glycoform population differences, with afucosylated glycans accounting for 19.7% of Remicade and 13.2% of Remsima glycoforms, which translated into a 2-fold reduction in the level of FcγIIIa receptor binding for Remsima. While this difference was acknowledged in Remsima regulatory filings, our glycoform analysis and receptor binding results appear to be somewhat different from the published values, likely because of methodological differences between laboratories and improved glycoform identification by our laboratory using a peptide map-based method. Our mass spectrometry-based analysis provides rapid and robust analytical information vital for biosimilar development. We have demonstrated the utility of our multiple-attribute monitoring workflow using the model mAbs Remicade and Remsima and have provided a template for analysis of future mAb biosimilars.
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Affiliation(s)
- Karthik Pisupati
- Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109
| | - Yuwei Tian
- Department of Chemistry, University of Michigan, 930 North University Street, Ann Arbor, MI 48109
| | - Solomon Okbazghi
- Department of Pharmaceutical Chemistry, University of Kansas, 2010 Becker Drive, Lawrence, KS 66047
| | - Alexander Benet
- Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109
| | - Rose Ackermann
- Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109
| | - Michael Ford
- MS Bioworks, 3950 Varsity Drive, Ann Arbor, MI 48108
| | - Sergei Saveliev
- Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711
| | | | - Marjeta Urh
- Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI 53711
| | - Eric Carlson
- Protein Metrics Inc., 1622 San Carlos Avenue, San Carlos, CA 94070
| | | | - Thomas J. Tolbert
- Department of Pharmaceutical Chemistry, University of Kansas, 2010 Becker Drive, Lawrence, KS 66047
| | - Steven P. Schwendeman
- Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109
- Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109
| | - Brandon T. Ruotolo
- Department of Chemistry, University of Michigan, 930 North University Street, Ann Arbor, MI 48109
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
- Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109
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21
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Lee J, Park EJ, Kiyono H. MicroRNA-orchestrated pathophysiologic control in gut homeostasis and inflammation. BMB Rep 2017; 49:263-9. [PMID: 26923304 PMCID: PMC5070705 DOI: 10.5483/bmbrep.2016.49.5.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Indexed: 12/14/2022] Open
Abstract
The intestine represents the largest and most elaborate immune system organ, in which dynamic and reciprocal interplay among numerous immune and epithelial cells, commensal microbiota, and external antigens contributes to establishing both homeostatic and pathologic conditions. The mechanisms that sustain gut homeostasis are pivotal in maintaining gut health in the harsh environment of the gut lumen. Intestinal epithelial cells are critical players in creating the mucosal platform for interplay between host immune cells and luminal stress inducers. Thus, knowledge of the epithelial interface between immune cells and the luminal environment is a prerequisite for a better understanding of gut homeostasis and pathophysiologies such as inflammation. In this review, we explore the importance of the epithelium in limiting or promoting gut inflammation (e.g., inflammatory bowel disease). We also introduce recent findings on how small RNAs such as microRNAs orchestrate pathophysiologic gene regulation. [BMB Reports 2016; 49(5): 263-269]
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Affiliation(s)
- Juneyoung Lee
- Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561, Japan
| | - Eun Jeong Park
- Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Mie University, Mie 514-8507, Japan
| | - Hiroshi Kiyono
- Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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22
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Assas MB, Levison SE, Little M, England H, Battrick L, Bagnall J, McLaughlin JT, Paszek P, Else KJ, Pennock JL. Anti-inflammatory effects of infliximab in mice are independent of tumour necrosis factor α neutralization. Clin Exp Immunol 2016; 187:225-233. [PMID: 27669117 PMCID: PMC5217947 DOI: 10.1111/cei.12872] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/21/2016] [Accepted: 09/23/2016] [Indexed: 12/18/2022] Open
Abstract
Infliximab (IFX) has been used repeatedly in mouse preclinical models with associated claims that anti‐inflammatory effects are due to inhibition of mouse tumour necrosis factor (TNF)‐α. However, the mechanism of action in mice remains unclear. In this study, the binding specificity of IFX for mouse TNF‐α was investigated ex vivo using enzyme‐linked immunosorbent assay (ELISA), flow cytometry and Western blot. Infliximab (IFX) did not bind directly to soluble or membrane‐bound mouse TNF‐α nor did it have any effect on TNF‐α‐induced nuclear factor kappa B (NF‐κB) stimulation in mouse fibroblasts. The efficacy of IFX treatment was then investigated in vivo using a TNF‐α‐independent Trichuris muris‐induced infection model of chronic colitis. Infection provoked severe transmural colonic inflammation by day 35 post‐infection. Colonic pathology, macrophage phenotype and cell death were determined. As predicted from the in‐vitro data, in‐vivo treatment of T. muris‐infected mice with IFX had no effect on clinical outcome, nor did it affect macrophage cell phenotype or number. IFX enhanced apoptosis of colonic immune cells significantly, likely to be driven by a direct effect of the humanized antibody itself. We have demonstrated that although IFX does not bind directly to TNF‐α, observed anti‐inflammatory effects in other mouse models may be through host cell apoptosis. We suggest that more careful consideration of xenogeneic responses should be made when utilizing IFX in preclinical models.
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Affiliation(s)
- M B Assas
- Faculty of Applied Medical Sciences, King AbdulAziz University, Jeddah, Saudi Arabia.,Faculty of Biology Medicine and Health, University of Manchester, Manchester
| | | | - M Little
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - H England
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - L Battrick
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - J Bagnall
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - J T McLaughlin
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - P Paszek
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - K J Else
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
| | - J L Pennock
- School of Biological Sciences, Faculty of Medicine Biology and Health, University of Manchester, Manchester, UK
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23
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Gubernatorova EO, Tumanov AV. Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation. BIOCHEMISTRY. BIOKHIMIIA 2016; 81:1309-1325. [PMID: 27914457 DOI: 10.1134/s0006297916110092] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Ulcerative colitis and Crohn's disease are the major forms of inflammatory bowel disease. Cytokines of the tumor necrosis factor (TNF) family play an important role in the regulation of intestinal inflammation. In this review, we discuss the function of key cytokines of this family - TNF and lymphotoxin (LT) - in mucosal healing, IgA production, and in control of innate lymphoid cells (ILCs), novel regulators of mucosal homeostasis in the gut. TNF plays a central role in the pathogenesis of inflammatory bowel diseases (IBD). LT regulates group 3 of ILCs and IL-22 production and protects the epithelium against damage by chemicals and mucosal bacterial pathogens. In addition, we discuss major mouse models employed to study the mechanism of intestinal inflammation, their advantages and limitations, as well as application of TNF blockers in the therapy for IBD.
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Affiliation(s)
- E O Gubernatorova
- Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
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24
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Velayudhan J, Chen YF, Rohrbach A, Pastula C, Maher G, Thomas H, Brown R, Born TL. Demonstration of Functional Similarity of Proposed Biosimilar ABP 501 to Adalimumab. BioDrugs 2016; 30:339-51. [PMID: 27422671 PMCID: PMC4972870 DOI: 10.1007/s40259-016-0185-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Due to the complex molecular structure and proprietary manufacturing processes of monoclonal antibodies (mAbs), differences in structure and function may be expected during development of biosimilar mAbs. Important regulatory requirements for approval of biosimilar products involve comprehensive assessments of any potential differences between proposed biosimilars and reference mAbs, including differences in all known mechanisms of action, using sensitive and relevant methods. Any identified structural differences should not result in differences in biofunctional or clinical activity. OBJECTIVE A comprehensive assessment comparing the Amgen biosimilar candidate ABP 501 with FDA-licensed adalimumab (adalimumab [US]) and EU-authorized adalimumab (adalimumab [EU]) was conducted to demonstrate similarity in biofunctional activity. METHODS The functional similarity assessment included testing of binding kinetics to soluble tumor necrosis factor α (TNFα) and relative binding to transmembrane TNFα. The neutralization of TNFα-induced caspase activation, TNFα- and lymphotoxin-α (LTα)-induced chemokine production, and cytotoxicity was also tested. Binding to Fc-gamma receptors FcγRIa, FcγRIIa (131H), FcγRIIIa (158V and 158F), and neonatal Fc receptor (FcRn) was compared with the reference mAbs, as was antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. RESULTS The data demonstrate that ABP 501 is similar to both adalimumab (US) and adalimumab (EU) with respect to evaluated biofunctional activities. CONCLUSION Similarity in biofunctional activity is a critical component of the totality of evidence required for demonstration of biosimilarity. The functional similarity demonstrated for ABP 501 comprehensively assesses the known mechanisms of action of adalimumab, supporting the conclusion that ABP 501, adalimumab (US), and adalimumab (EU) are likely to be clinically similar.
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Affiliation(s)
- Jyoti Velayudhan
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA
| | - Yuh-Feng Chen
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA
| | - Amanda Rohrbach
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA
| | | | - Gwen Maher
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA
| | - Heather Thomas
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA
| | - Ryan Brown
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA
| | - Teresa L Born
- Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
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NASPGHAN Clinical Report: Surveillance, Diagnosis, and Prevention of Infectious Diseases in Pediatric Patients With Inflammatory Bowel Disease Receiving Tumor Necrosis Factor-α Inhibitors. J Pediatr Gastroenterol Nutr 2016; 63:130-55. [PMID: 27027903 DOI: 10.1097/mpg.0000000000001188] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Children and adolescents with inflammatory bowel disease (IBD) receiving therapy with tumor necrosis factor α inhibitors (anti-TNFα) pose a unique challenge to health care providers in regard to the associated risk of infection. Published experience in adult populations with distinct autoinflammatory and autoimmune diseases treated with anti-TNFα therapies demonstrates an increased risk of serious infections with intracellular bacteria, mycobacteria, fungi, and some viruses; however, there is a paucity of robust pediatric data. With a rising incidence of pediatric IBD and increasing use of biologic therapies, heightened knowledge and awareness of infections in this population is important for primary care pediatricians, pediatric gastroenterologists, and infectious disease (ID) physicians. This clinical report is the result of a consensus review performed by pediatric ID and gastroenterology physicians detailing relevant published literature regarding infections in pediatric patients with IBD receiving anti-TNFα therapies. The objective of this document is to provide comprehensive information for prevention, surveillance, and diagnosis of infections based on current knowledge, until additional pediatric data are available to inform evidence-based recommendations.
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Nguyen DX, Ehrenstein MR. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J Exp Med 2016; 213:1241-53. [PMID: 27270893 PMCID: PMC4925013 DOI: 10.1084/jem.20151255] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 04/26/2016] [Indexed: 12/11/2022] Open
Abstract
Nguyen and Ehrenstein reveal that anti-TNF antibodies paradoxically enhance membrane TNF–TNF-RII interactions to increase Foxp3 expression and confer upon T reg cells the ability to suppress Th17 cells in rheumatoid arthritis patients. The interplay between inflammatory and regulatory pathways orchestrates an effective immune response that provides protection from pathogens while limiting injury to host tissue. Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, but there is conflicting evidence as to whether it boosts or inhibits regulatory T cells (T reg cells). In this study, we show that the therapeutic anti-TNF antibody adalimumab, but not the soluble TNF receptor etanercept, paradoxically promoted the interaction between monocytes and T reg cells isolated from patients with rheumatoid arthritis (RA). Adalimumab bound to monocyte membrane TNF from RA patients and unexpectedly enhanced its expression and its binding to TNF-RII expressed on T reg cells. As a consequence, adalimumab expanded functional Foxp3+ T reg cells equipped to suppress Th17 cells through an IL-2/STAT5-dependent mechanism. Our data not only highlight the beneficial effect of membrane TNF on T reg cell numbers during chronic inflammation, but in addition reveal how a therapeutic antibody that is thought to act by simply blocking its target can enhance the regulatory properties of this proinflammatory cytokine.
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Affiliation(s)
- Dao Xuan Nguyen
- Division of Medicine, Centre for Rheumatology, University College London, WC1E 6JF London, England, UK
| | - Michael R Ehrenstein
- Division of Medicine, Centre for Rheumatology, University College London, WC1E 6JF London, England, UK
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Olesen CM, Coskun M, Peyrin-Biroulet L, Nielsen OH. Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol Ther 2016; 159:110-9. [PMID: 26808166 DOI: 10.1016/j.pharmthera.2016.01.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α but with varying efficacies in IBD. The variations in efficacy probably are caused by structural differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF inhibitors in order to identify mechanisms of importance for their efficacy in IBD. Thus, a better understanding of the mechanistic basis for clinical efficacy can lead to a more rational use of TNF inhibitors in the management of IBD.
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Affiliation(s)
- Caroline Meyer Olesen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre, France
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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Schellekens H, Lietzan E, Faccin F, Venema J. Biosimilar monoclonal antibodies: the scientific basis for extrapolation. Expert Opin Biol Ther 2015; 15:1633-46. [PMID: 26365396 DOI: 10.1517/14712598.2015.1083552] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Biosimilars are biologic products that receive authorization based on an abbreviated regulatory application containing comparative quality and nonclinical and clinical data that demonstrate similarity to a licensed biologic product. Extrapolation of safety and efficacy has emerged as an important way to simplify biosimilar development. Regulatory authorities have generally reached the consensus that extrapolation of similarity from one indication to other approved indications of the reference product can be permitted if it is scientifically justified. AREAS COVERED Recently, the first biosimilar, biosimilar infliximab (Remsima/Inflectra) to the innovator monoclonal antibody infliximab (Remicade), was approved in the European Union, Canada and South Korea; the USA subsequently approved its first biosimilar, a less complex molecule (filgrastim-sndz). Based on two clinical trials of biosimilar infliximab in patients with rheumatoid arthritis and ankylosing spondylitis, the European Medicines Agency allowed extrapolation to all eight approved indications for innovator infliximab, whereas Health Canada did not permit extrapolation to the indications for ulcerative colitis and Crohn's disease. These differing decisions on extrapolation of indications for biosimilar infliximab highlight important unanswered regulatory and scientific questions. Here, we propose substantive scientific considerations for indication extrapolation. EXPERT OPINION The preclinical and clinical criteria that are currently required to merit indication extrapolation have not been rigorously evaluated.
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Affiliation(s)
- Huub Schellekens
- a 1 Utrecht University, Departments of Pharmaceutical Sciences and Innovation Studies , Utrecht, The Netherlands
| | - Erika Lietzan
- b 2 University of Missouri School of Law , Columbia, MO, USA
| | - Freddy Faccin
- c 3 AbbVie Inc., Biotherapeutics, Global Medical Affairs , 9615 Los Romeros Avenue, Suite 700, San Juan, PR, USA +1 787 622 5454 ; +1 787 276 3016 ;
| | - Jaap Venema
- d 4 AbbVie Inc., Biotherapeutics, Global Medical Affairs, Biologics Strategic Development , North Chicago, IL, USA
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Sheth T, Pitchumoni CS, Das KM. Management of Musculoskeletal Manifestations in Inflammatory Bowel Disease. Gastroenterol Res Pract 2015; 2015:387891. [PMID: 26170832 PMCID: PMC4478299 DOI: 10.1155/2015/387891] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 04/21/2015] [Indexed: 02/08/2023] Open
Abstract
Musculoskeletal manifestations are the most common extraintestinal manifestations in inflammatory bowel diseases. Some appendicular manifestations are independent of gut inflammation and are treated with standard anti-inflammatory strategies. On the other hand, axial involvement is linked to gut inflammatory activity; hence, there is a considerable amount of treatment overlap. Biological therapies have revolutionized management of inflammatory bowel diseases as well as of associated articular manifestations. Newer mechanisms driving gut associated arthropathy have surfaced in the past decade and have enhanced our interests in novel treatment targets. Introduction of biosimilar molecules is expected in the US market in the near future and will provide an opportunity for considerable cost savings on healthcare. A multidisciplinary approach involving a gastroenterologist, rheumatologist, and physical therapist is ideal for these patients.
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Affiliation(s)
- Tejas Sheth
- Department of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - C. S. Pitchumoni
- Department of Gastroenterology, Rutgers-St. Peter's University Hospital, New Brunswick, NJ, USA
| | - Kiron M. Das
- Division of Gastroenterology and Hepatology, Crohn's and Colitis Center of NJ, Rutgers-Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, Suite 5100B, New Brunswick, NJ 08901-1962, USA
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Jiang W, Li X. Molecular Analysis of Inflammatory Bowel Disease: Clinically Useful Tools for Diagnosis, Response Prediction, and Monitoring of Targeted Therapy. Mol Diagn Ther 2015; 19:141-58. [DOI: 10.1007/s40291-015-0142-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Stein JD, Talwar N, Kang JH, Okereke OI, Wiggs JL, Pasquale LR. Bupropion use and risk of open-angle glaucoma among enrollees in a large U.S. managed care network. PLoS One 2015; 10:e0123682. [PMID: 25875446 PMCID: PMC4395241 DOI: 10.1371/journal.pone.0123682] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 02/21/2015] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Tumor Necrosis Factor (TNF) mediates retinal ganglion cell death in glaucoma. Anti-TNF drugs are neuroprotective in an animal model of glaucoma. It is unclear whether medications with anti-TNF properties such as bupropion have an impact on the risk of developing open-angle glaucoma (OAG) in humans. The purpose of this study is to determine whether bupropion use alters the risk of developing OAG. METHODS Claims data for beneficiaries age ≥35 years with no pre-existing OAG enrolled in a large nationwide U.S. managed care network continuously for ≥4 years between 2001-2011 was analyzed to identify patients who had been newly-diagnosed with OAG. The amount of bupropion use as captured from outpatient pharmacy claims over a four-year period was also quantified for each beneficiary. Multivariable Cox regression modeling assessed the impact of bupropion and other antidepressant medications on the risk of developing OAG with adjustment for sociodemographic characteristics of the enrollees along with medical and ocular comorbidities. RESULTS Of 638,481 eligible enrollees, 15,292 (2.4%) developed OAG. After adjustment for confounding factors including use of other antidepressant medication classes, each additional month of bupropion use was associated with a 0.6% reduced risk of OAG (HR = 0.994, (95% CI: 0.989-0.998), p = 0.007). Compared to nonusers, those with 24-48 months of bupropion use had a 21% reduced hazard (HR=0.79, (CI: 0.65-0.94), p = 0.0099) of OAG. This association did not differ among persons taking bupropion for depression or for other reasons (p-interaction = 0.82). There was no significant association between use of tricyclic antidepressants (HR = 1.000, (CI: 0.997-1.004), p = 0.95) or selective serotonin reuptake inhibitors (HR = 0.999, (CI: 0.997-1.001), p = 0.39) and development of OAG. CONCLUSION These findings suggest bupropion use may be beneficial in reducing the risk of OAG. If prospective studies confirm the findings of this analysis, this may identify a novel therapeutic target for OAG.
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Affiliation(s)
- Joshua D. Stein
- Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
- * E-mail:
| | - Nidhi Talwar
- Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Jae H. Kang
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Olivia I. Okereke
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Harvard School of Public Health, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Psychiatry, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Janey L. Wiggs
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Louis R. Pasquale
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America
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Infliximab preferentially induces clinical remission and mucosal healing in short course Crohn's disease with luminal lesions through balancing abnormal immune response in gut mucosa. Mediators Inflamm 2015; 2015:793764. [PMID: 25873771 PMCID: PMC4383520 DOI: 10.1155/2015/793764] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 10/10/2014] [Indexed: 01/25/2023] Open
Abstract
This study was undertaken to evaluate the efficacy of infliximab (IFX) in treatment of Crohn's disease (CD) patients. 106 CD patients were undergoing treatment with IFX from five hospitals in Shanghai, China. Clinical remission to IFX induction therapy was defined as Crohn's disease activity index (CDAI) < 150. Clinical response was assessed by a decrease in CDAI ≥ 70, and the failure as a CDAI was not significantly changed or increased. Ten weeks after therapy, 61 (57.5%) patients achieved clinical remission, 17 (16.0%) had clinical response, and the remaining 28 (26.4%) were failed. In remission group, significant changes were observed in CDAI, the Simple Endoscopic Score for Crohn's Disease (SES-CD), and serum indexes. Patients with short disease duration (22.2 ± 23.2 months) and luminal lesions showed better effects compared to those with long disease duration (71.0 ± 58.2 months) or stricturing and penetrating lesions. IFX markedly downregulated Th1/Th17-mediated immune response but promoted IL-25 production in intestinal mucosa from remission group. No serious adverse events occurred to terminate treatment. Taken together, our studies demonstrated that IFX is efficacious and safe in inducing clinical remission, promoting mucosal healing, and downregulating Th1/Th17-mediated immune response in short course CD patients with luminal lesions.
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Abstract
Objectives: To review the pharmacology, efficacy, and safety of vedolizumab in the treatment of patients with ulcerative colitis (UC) and Crohn’s disease (CD). Data Sources: A literature search through clinicialtrials.gov, EMBASE and MEDLINE was conducted (January 1966-June 2014) using the terms vedolizumab and MLN0002. References from retrieved articles were reviewed for any additional material. Additionally, the prescribing information was retrieved. Study Selection/Data Extraction: Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of vedolizumab were identified. Data Synthesis: Vedolizumab, an α4β7 integrin inhibitor, was recently approved for adult patients with moderate to severe active UC or CD who are refractory or intolerant to standard therapies or who are dependent on corticosteroids. Trial data have demonstrated that vedolizumab 300 mg at weeks 0, 2, and 6 followed by every 8 weeks is effective at inducing and maintaining clinical response and remission, improving mucosal appearance, and achieving corticosteroid-free remission in patients with UC. This regimen is also effective at achieving clinical response, remission, and corticosteroid-free remission in patients with CD. Patients treated with vedolizumab, unadjusted for exposure, reported experiencing nasopharyngitis, headache, nausea, arthralgias, pyrexia, upper-respiratory-tract infections, fatigue, and cough. Conclusions: Vedolizumab is an effective agent at inducing and maintaining remission in patients with UC or CD. Vedolizumab is generally well tolerated and has not been associated with progressive multifocal leukoencephalopathy.
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Affiliation(s)
| | - Rima A. Mohammad
- University of Michigan College of Pharmacy, University of Michigan Health Systems, Ann Arbor, MI, USA
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Yang M, Lin HB, Gong S, Chen PY, Geng LL, Zeng YM, Li DY. Effect of Astragalus polysaccharides on expression of TNF-α, IL-1β and NFATc4 in a rat model of experimental colitis. Cytokine 2014; 70:81-6. [DOI: 10.1016/j.cyto.2014.07.250] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 07/20/2014] [Accepted: 07/24/2014] [Indexed: 02/07/2023]
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Hiroz P, Vavricka SR, Fournier N, Safroneeva E, Pittet V, Rogler G, Schoepfer AM. Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort. Scand J Gastroenterol 2014; 49:1207-18. [PMID: 25120029 DOI: 10.3109/00365521.2014.946082] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. METHODS Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. RESULTS Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. CONCLUSION Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.
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Affiliation(s)
- Philippe Hiroz
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois , Lausanne , Switzerland
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Kaser A. Not all monoclonals are created equal - lessons from failed drug trials in Crohn's disease. Best Pract Res Clin Gastroenterol 2014; 28:437-49. [PMID: 24913383 DOI: 10.1016/j.bpg.2014.04.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 04/03/2014] [Accepted: 04/13/2014] [Indexed: 01/31/2023]
Abstract
The recent success of the anti-integrin antibody Vedolizumab can barely conceal the fact that the biologics armamentarium in Crohn's disease has barely evolved beyond TNF blockers so far. This contrasts with other immune-related diseases considered mechanistically and genetically closely related, such as psoriasis and rheumatoid arthritis, where approved biologics target a variety of independent biological mechanisms. Several pharmacological assets that entered clinical development have proven ineffective, or less effective than originally anticipated. While blockade of IL-17A and its receptor via Secukinumab and Brodalumab, respectively, worsened Crohn's disease, the beneficial effect of IL-12/23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn's disease patients who have previously failed on TNF blockers. Clinical development of the IFNγ blocker Fontolizumab was stopped despite demonstrating some clinical benefit, while the T cell co-stimulation blocker Abatacept did not exhibit any hint towards efficacy in Crohn's disease. Here I review results from these individual development programmes, and also reflect on the lack of efficacy of the TNF blocker Etanercept. I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years. Finally, I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn's disease.
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Affiliation(s)
- Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, United Kingdom.
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Raine T. Insights from immunology: new targets for new drugs? Best Pract Res Clin Gastroenterol 2014; 28:411-20. [PMID: 24913381 DOI: 10.1016/j.bpg.2014.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 03/27/2014] [Accepted: 04/13/2014] [Indexed: 01/31/2023]
Abstract
Rapid advances in our understanding of inflammatory bowel diseases have resulted from the synthesis of data from experimental and genetic studies. These have suggested a wide range of potential immunological targets with both local and systemic scope. Drugs to several of these targets have now reached phase I/II studies, and are discussed in the context of their scientific rationale. However, despite the advent of new classes of therapeutics targeting cellular trafficking and intracellular mediators of cytokine signalling, the armamentarium of effective therapeutics remains sparse. Only with more detailed experimental medicine studies will this imbalance be resolved.
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Affiliation(s)
- Tim Raine
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
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Abstract
The treatment of IBD with anti-TNF agents has substantially evolved since their first introduction more than a decade ago. The robust efficacy witnessed in many patients has raised new questions pertaining to the observation of subgroups of patients who fail to respond or who lose response to these otherwise very effective drugs. Conversely, the exorbitant cost of biologic agents coupled with their efficacy in inducing lasting remission has introduced new concepts addressing the possibility of therapy cessation in some patients after deep remission has been achieved. Measuring drug and anti-drug antibody (ADA) levels which develop in some patients has emerged as a valuable tool in understanding the mechanisms responsible for some of these clinical scenarios. However, knowledge on how to use these measurements to guide clinical decisions in daily practice is still in its nascency and awaits prospective validation trials. Furthermore, as described in this Review, knowledgeable interpretation of drug and ADA test results mandates understanding the interplay between the technical profile of the assay used, the timing of the measurement in the drug cycle, assessment of disease activity, and the profoundly different pharmaco-clinical scenarios that can culminate in a similar test result.
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Stopping anti-TNF agents in patients with Crohn's disease in remission: is it a feasible long-term strategy? Inflamm Bowel Dis 2014; 20:757-66. [PMID: 24572206 DOI: 10.1097/01.mib.0000442680.47427.bf] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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