Current Issue : April-June Volume : 2024 Issue Number : 2 Articles : 5 Articles
Adalimumab biosimilar experience is still recent. Interchangeability differences could reduce persistence times. Our goal was to compare biosimilar persistence differences with a reference. A retrospective observational study was performed in three groups divided according to the adalimumab received. The primary outcome measure was persistence, represented with Kaplan–Meier analysis, and we secondarily evaluated security, efficacy, and biomarkers. We obtained approval from the regional ethical committee, and the study was conducted following the Helsinki Declaration as revised in 2013. Data from 104 patients were collected: 50 received the biosimilar, 29 received the reference, and 25 switched from the original to the biosimilar. After a follow-up of 12 months, the biosimilar’s persistence was higher, without differences in mild adverse events per group. In contrast, there were differences in severe events, with the switched group’s frequency being higher. Biomarkers were reduced at similar proportions in all groups, and 43% had a clinical response at week 20 without differences. Adalimumab biosimilars are a valuable option for IBD based on clinical equivalence that are less expensive than the original drug. Their use does not have a detrimental influence on disease, although there are a few nuances in terms of interchangeability. These results support increasing confidence in using biosimilars, thus promoting the better sustainability of health systems....
Melioidosis, a severe tropical illness caused by Burkholderia pseudomallei, poses significant treatment challenges due to limited therapeutic options and the absence of effective vaccines. The pathogen’s intrinsic resistance to numerous antibiotics and propensity to induce sepsis during acute infections further complicate management strategies. Thus, exploring alternative methods for prevention and treatment is crucial. Monoclonal antibodies (mAbs) have emerged as a promising strategy for the prevention and treatment of infectious diseases. This study focused on generating three mAbs (13F1, 14G11, and 15D9) targeting hemolysin-coregulated protein 1 (Hcp1), a protein involved in the type VI secretion system cluster 1 (T6SS1) of B. pseudomallei. Notably, pretreatment with 13F1 mAb significantly reduced the intracellular survival of B. pseudomallei and inhibited the formation of macrophage-derived multinucleated giant cells (MNGCs). This protective effect was also observed in vivo. We identified a sequence of amino acids (Asp95-Leu114) within Hcp1 as the likely binding site for 13F1 mAb. In summary, our findings reveal that 13F1 mAb counteracts infection by targeting Hcp1, offering potential new targets and insights for melioidosis prevention....
Purpose: This analysis aimed to characterize the exposure–response relationship of bevacizumab in non-small-cell lung cancer (NSCLC) and evaluate the efficacy of SB8, a bevacizumab biosimilar, and Avastin®, the reference bevacizumab sourced from the European Union (EU), based on the exposure reported in a comparative phase III efficacy and safety study (EudraCT, 2015-004026-34; NCT 02754882). Materials and methods: The overall survival (OS) and progression-free survival (PFS) data from 224 patients with steady-state trough concentrations (Css,trough) were analyzed. A parametric time-to-event (TTE) model was developed using NONMEM®, and the effects of treatments (SB8 and bevacizumab-EU) and patient demographic and clinical covariates on OS and PFS were evaluated. Simulations of median OS and PFS by bevacizumab Css,trough were conducted, and concentrations required to achieve 50% and 90% of the maximum median TTE were computed. Results: A log-logistics model with Css,trough best described the OS and PFS data. Treatment was not a predictor of the hazard for OS or PFS. Simulations revealed steep exposure–response curves with a phase of rapid rise before saturating to a plateau. The median Css,trough values of SB8 and bevacizumab-EU reported from the clinical study were on the plateaus of the exposure–response curves. The concentrations required to achieve 50% and 90% of the maximum effect were 82.4 and 92.2 μg/mL, respectively, for OS and 79.7 and 89.1 μg/mL, respectively, for PFS. Conclusion: Simulations based on the constructed TTE models for OS and PFS have well described the exposure–response relationship of bevacizumab in advanced NSCLC. The analysis demonstrated comparable efficacy between SB8 and bevacizumab-EU in terms of OS and PFS based on their exposure levels....
Dengue virus is an enveloped virus with an icosahedral assembly of envelope proteins (E). The E proteins are arranged as a head-to-tail homodimer, and domain III (EDIII) is placed at the edge of the dimer, converging to a pentamer interface. For a structure-based approach, cholera toxin B (CTB) was harnessed as a structural scaffold for the five-fold symmetry of EDIII. Pivoted by an RNAmediated chaperone for the protein folding and assembly, CTB-EDIII of dengue serotype 1 (DV1) was successfully produced as soluble pentamers in an E. coli host with a high yield of about 28 mg/L. Immunization of mice with CTB-DV1EDIII elicited increased levels of neutralizing antibodies against infectious viruses compared to the control group immunized with DV1EDIII without CTB fusion. IgG isotype switching into a balanced Th1/Th2 response was also observed, probably triggered by the intrinsic adjuvant activity of CTB. Confirming the immune-enhancing potential of CTB in stabilizing the pentamer assembly of EDIII, this study introduces a low-cost bacterial production platform designed to augment the soluble production of subunit vaccine candidates, particularly those targeting flaviviruses....
Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection; however, no clinical trial data are available, and combined use of direct-acting antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the B.1 and BQ.1.1 variants were comparable. In the post hoc analysis weighting synergy by concentrations, several cases of highly synergistic scores were detected at specific drug concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro confirmation experiments showing a more than a linear shift of a drug-effective concentration (IC50) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results support the cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic....
Loading....