Long Term Outcome of Ulcerative Colitis Patients Responders to Cyclosporine in the Biological era (original) (raw)
Related papers
Annals of Gastroenterology, 2004
SUMMARY We attempt to summarize the current aspects concerning the role of the chimeric antibody against tumor necrosis factor-alpha (Infliximab n Remicade) in patients with active ulcerative colitis. Experimental and clinical data suggest that, apart from Crohnis disease, tumor necrosis factor also plays quite an important role in the pathogenesis of ulcerative colitis as well. So far, there are limited data on the use of infliximab in animal models of ulcerative colitis and in patients with ulcerative and indeterminate colitis and pouchitis. Although the existing clinical, endoscopic and laboratory evidence for the efficacy of infliximab in the treatment of ulcerative colitis are controversial, we can support the assumption that a proportion of patients may benefit from this treatment. In addition, treatment with infliximab appeared to be well-tolerated at the doses studied. Further, ongoing, controlled studies are investigating the potential efficacy and safety of infliximab in p...
BioDrugs, 2019
Background There are two products in which infliximab is the active pharmaceutical ingredient. These are Remicade ® (INF; reference product) and Remsima™/Inflectra™ (CT-P13; infliximab biosimilar). Remsima™/Inflectra™ are bioidentical products. Different recommendations have been made for the clinical solutions of each brand (Remicade ® or Remsima™/ Inflectra™) despite the manufacturer of the biosimilar claiming high levels of similarity to the innovator. Objective The objective of this study was to assess and compare stability against degradation and over time of different clinical infliximab solutions prepared from Remicade ® and from Remsima™/Inflectra™ using a suitable set of characterization methods in line with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) recommendations. Methods Reconstituted solutions of INF and CT-P13 and dilutions as used in hospital were stored in glass vials (10 and 2 mg/ mL) or in polyolefin infusion bags (0.4 mg/mL) refrigerated between 2 and 8 °C for 2 weeks. Regarding the physicochemical properties, the distribution of the particulates were studied over a range of 0.001-1 µm by dynamic light scattering (DLS) and oligomers up to 8 monomer were analyzed by native size-exclusion ultra-high-performance liquid chromatography with ultraviolet (UV)-visible detection coupled to (native) mass spectrometry (SE/UHPLC-UV-(native) MS); mass spectrometry was also used to evaluate natural aggregates and isoform profile; DLS was also employed to detect gross conformational changes by tracking the hydrodynamic radius (HR). The secondary structure of the proteins was studied by far UV circular dichroism (CD). The tertiary structure was investigated by intrinsic tryptophan fluorescence (IT-F). Reverse-phase ultra-high-performance liquid chromatography with UV detection (RP/UHPLC-UV) was used to analyze intact INF and CT-P13 for quantification purposes. Functionality was evaluated via the biological activity measured by the extension of the immunological reaction of the INF and the CT-P13 with its antigen, i.e., the tumor necrosis factor-α by enzyme-linked immunosorbent assay (ELISA). Results The stress applied to INF and CT-P13 solutions showed similar levels of aggregate formation, structural variation, and chemical modifications. The only noteworthy difference between INF and CT-P13 was detected in their behavior to freeze-thaw cycles, in which CT-P13 showed slightly more robustness. INF and CT-P13 showed identical CD spectra, similar to those reported for IgG1 in which there is dominance in β sheet secondary structures; this typical conformation remained unmodified over time in INF and CT-P13. No significant changes were detected in the tertiary structure and no aggregates process was noticed over the time studied. Polydispersity slightly increased for the most concentrated solutions, while there were no meaningful differences in the HR in the solutions over time. The concentration of INF and CT-P13 also remained constant. Differences in the native isoform MS profile were detected, as expected by the different glycosylation pattern, with Electronic supplementary material The online version of this article (
PLOS ONE
Introduction TNF-α-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-α antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues. Aim To determine the neutralizing capacity of first-and second generation anti-TNF-α antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra). Methods TNF-α neutralization was measured using a quantitative TNF-α sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF-кB response element. All available anti-TNF-α drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-α-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab 2-fragment, biosimilar CT-P13 (Inflectra) and ADA. Results TNF-α strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of firstgeneration anti-TNF-α drugs were required to neutralize TNF-α compared to the secondgeneration anti-TNF-α drugs. Serum of IBD patients with proven ATI blocked TNF-α
Extensive preclinical evaluation of an infliximab biosimilar candidate
Infliximab is therapeutic monoclonal antibody (mAb) against TNF-α employed in the treatment of immunoin-flammatory diseases. The development of biosimilar mAbs is a global strategy to increase drug accessibility and reduce therapy-associated costs. Herein we compared key physicochemical characteristics and biological activities produced by infliximab and infliximab-Probiomed in order to identify functionally relevant differences between the mAbs. Binding of infliximab-Probiomed to TNF-α was specific and had kinetics comparable to that of the reference product. Both mAbs had highly similar neutralizing efficacy in HUVEC cell cultures stimulated with TNF-α. In vitro induction of CDC and ADCC were also similar between the evaluated products. In vivo comparability was assessed using a transgenic mouse model of arthritis that expresses human TNF-α in a 13-week multiple-administration study. Infliximab and infliximab-Probiomed showed comparable efficacy, safety, and pharmacokinetic profiles. Our results indicate that infliximab-Probiomed has highly similar activities to infliximab in preclinical models, warranting a clinical evaluation of its biosimilarity.
Drug Design, Development and Therapy, 2019
Background: Infliximab (Remicade), a chimeric monoclonal antibody against human TNFα, will inevitably face competition from biosimilar products, because of its effectiveness in autoimmune diseases and rapidly increasing market demand. According to guidelines for biosimilar development, the "biosimilar-expression system" may differ from that of the innovator, but more appropriate studies should be carried out to demonstrate the comparability between biosimilar and innovator. CMAB008 is an infliximab biosimilar candidate developed by the State Key Laboratory of Antibody Medicine and Targeted Therapy of China. Infliximab was expressed in SP2/0 cells, while CMAB008 was produced in a CHO-expression system. Methods: In this study, infliximab and CMAB008 were compared on physicochemical and biological characterizations, including protein content, activity, physiochemical integrity, impurities, additives, and immunogenicity. Results: The results showed that they were highly similar and comparable, except some differences in glycosylation. As glycosylation profiles can influence immunogenicity and occurrence of allergy or other adverse reactions of antibody therapeutics, primary tolerability and pharmacokinetics of CMAB008 were evaluated. In the phase I clinical trial, plasma concentration of CMAB008 and antidrug antibodies were also measured using ELISA and bridging ELISA, respectively. CMAB008 exhibited favorable clinical tolerability, no adverse events in the 3 mg/kg single-dose group (recommended therapeutic dosage), and no serious adverse events in the multiple-dose group. Also, no injection-site reactions were observed in the experiment. Conclusion: In summary, CMAB008 might have the potential to be an effective drug compared with infliximab.
Infliximab induces clinical, endoscopic and histological responses in refractory ulcerative colitis
Revista Espanola De Enfermedades Digestivas, 2004
infliximab is a monoclonal antiTNF-ct antibody that has repeatedly shown to be effective in the management of Crohn's disease. However, data are scarce about its efficacy in ulcerative colitis. to describe the joint experience of three Spanish hospitals in the use of infliximab in patients with active refractory ulcerative colitis. we present seven cases of ulcerative colitis (6 with chronic active disease despite immunosuppressive therapy, and one with acute steroid-refractory ulcerative colitis) treated with infliximab 5 mg/kg of body weight. Clinical response was evaluated by means of the Clinical Activity Index at 2, 4 and 8 weeks after initial infusion. Biochemical (erythrocyte sedimentation rate and C-reactive protein), endoscopic, and histological changes were also assessed. mean age of patients was 45.8 +/- 17 years (range 23-77); 4 were female. No adverse effects were recorded. Inflammatory activity diminished significantly in 6 of 7 patients (85.7%; CI 95%: 42-99%) bot...
P524 Efficacy of infliximab treatment in acute severe ulcerative colitis
Journal of Crohn's and Colitis, 2013
Poster presentations reaction (47%). At the ADA start the mean age was 14.6 y, 70.2% pts had moderate-severe disease (30.2% PCDAI >30). 46% CRP value was positive. The mean time from diagnosis was 3 y (range 3 11 y). Nobody needed steroids. At 6 months, 35/37 pts were evaluable. 63% in complete clinical remission, 12% in partial clinical remission and 25% had active disease. 39% had CRP positive values. Mean follow up time after ADA start was 13.2 m. At the last follow up, 62% pts were in clinical complete remission, 6% in partial clinical remission and 32% pts had active disease. The mean PCDAI value at the ADA start was 20.8 (median 22.5), at 6 m was 11.4 (median 10) and at the last follow up 10.9 (median 10). PCDAI decrements were statistically significant (p < 0.01). In 29% of pts CRP values were positive. At the last follow up endoscopic evaluation was available in 54% pts and documented mucosal healing in 65%, mild-moderate lesions in 10% and severe disease in 25%. In univariate analysis no prognostic factors were found (disease duration and extension, reasons for IFX stop) except for the combined therapy IFX+ IM that was negatively correlated with the PCDAI values (p < 0.01). At last follow up the growth parameters were not significantly different. Adverse events were one case of meningitis and one of medulloblastoma in a boy treated with IFX (12 m) and ADA (6m) without IM. Conclusions: According to our data ADA is an effective therapy for pediatric CD who failed IFX. Despite the severity of disease, more than 60% of pts showed clinical and endoscopic remission. Treatment efficacy with anti-TNF alfa agents should be balanced against infection risk and possible onset of cancer.
EBioMedicine, 2017
Although infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics among clinically-asymptomatic UC patients. This was a multicentric and prospective study involving 65 UC patients in the maintenance phase of IFX therapy. There were no significant differences between patients with positive and negative clinical, endoscopic and histological outcomes concerning their IFX trough levels (TLs), area under the IFX concentration vs. time curve (AUC), clearance and antibodies to infliximab (ATI) levels. However, the need to undergo therapeutic escalation later in disease development was significantly associated with higher ATI levels (2.62μg/mL vs. 1.15μg/mL, p=0.028). Moreover, and after adjusting for disease severity, the HR (hazard ratio) for therapeutic escalation was significantly decreased for patients with an ATI c...
Journal of Crohn's & colitis, 2015
The cellular mechanisms leading to infliximab therapy response in patients with ulcerative colitis (UC) are incompletely known. We therefore investigated early effects of infliximab therapy on monocytes and associated chemokines linked to clinical therapy response in UC patients. Blood and biopsies were obtained from anti-TNF therapy-naïve UC patients (n = 43) before (baseline) and during induction therapy with infliximab. Therapy response was evaluated at Week 14. Expression of monocyte activation markers and levels of chemokines in serum and biopsies were determined. Quantitative proteomic analysis was performed in cultured mucosal biopsies, and obtained data was validated in serum. In therapy responders, but not in non-responders, infliximab reduced blood monocyte expression of CD14 and CD86, 2 weeks after therapy commenced, relative to baseline. Serum CCL2 levels were decreased only among therapy responders at Week 2 and Week 14, relative to baseline. These data corresponded wit...
mAbs
Due to the increase in the number of infliximab products, the need for global harmonization of the bioactivity of this monoclonal antibody was recognized by the World Health Organization (WHO). In response, the National Institute for Biological Standards and Control (NIBSC) developed the first international standard (IS) for infliximab, which targets tumour necrosis factor (TNF). Each ampoule is assigned values of 500 IU of TNF neutralizing activity and 500 IU of binding activity. Two preparations of infliximab were formulated and lyophilized at NIBSC prior to evaluation in a collaborative study for their suitability to serve as an IS for the in vitro biological activity of infliximab. The study involved participants using in vitro cell-based bioassays (TNF neutralization, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) and binding assays. The results of this study showed that the candidate preparation, coded 16/170, is suitable as an IS for infliximab bioactivity. This infliximab IS from NIBSC, is intended to support in vitro bioassay calibration and validation by defining international units of bioactivity. The proposed unitages, however, are not intended to revise product labelling or dosing requirements, as any decisions regarding this relies solely with the regulatory authorities. Furthermore, the infliximab IS is not intended for determining the specific activity of products, nor to serve any regulatory role in defining biosimilarity. We briefly discuss the future use of WHO international standards in supporting the global harmonisation of biosimilar infliximab products.