Project description:Interventions: The study will consist of 3 dosing cohorts. In each cohort, 3 participants will be treated with once weekly subcutaneous injections of INB03 at a dose of 0.3 (no more than 30 mg), 1.0 (no more than 100 mg) or 3.0 mg/kg (no more than 220 mg or 2 vials of INB03), respectively. INB03 will be administered weekly for 9 months or until disease progression as determined by the PI and/or participant intolerance as determined by the Principal Investigator (PI). However, participants may continue INB03 therapy at any time, including after study end at Month 9, on a compassionate use basis if the attending physician believes the subject is benefiting from the therapy in any way. INB03 will be administered by a study nurse at clinical investigation site from Day 1 till Day 85 visits. At the discretion of the investigator patients may be allowed to self-administer INB03 at home from Month 4 visit onwards. Subjects who undergo home-administration of INB03 will be asked to bring all used, partially used, or unused contains to study staff at each study visit for completion of drug accountability and monitor adherence. All subjects will receive their assigned INB03 dose through Month 3. After all subjects have completed 3 months of therapy, an interim analysis will be conducted and an optimal dose for the Phase 2 trial will be determined by the Data Safety Monitoring Board (DSMB). Further dosing of INB03 after Month 3 may be adjusted to the selected dosage for Phase 2. Primary outcome(s): Safety and tolerability of INB03 given by sub-cutaneous injection once a week. This outcome is incidence of grade 3 or greater AEs and SAEs as graded by NCI CTCAE criteria v 5.0. [Day 1, 3, 5, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78 & 85];Evaluate the pharmacokinetics (PK) of single dose and multiple doses of INB03. Due to the cross-reactivity of INB03 and serum soluble TNF in assay systems, the FDA recommended the Sponsor use serum soluble TNF levels as a measure of drug level during the clinical trials. An abbreviated PK study format will be used.[Four time points will be studied for the first dose PK and trough levels will be monitored for the multi-dose PK. Specifically measurements of human TNF-Alpha levels will be tested in blood samples collected at time 0, 1, 4 and 8 hours after the first INB03 dosing on Day 1. Trough levels will continue to be collected on Day 3 and prior to successive doses on Day 8, 15, 22, 29, 43, 57, 85, and Month 4-9.];The study will examine the following efficacy parameters throughout the study: - change in hsCRP serum levels[Screening, Days 1, 8, 29, 43, 57, 71, 85, Months 4, 5, 6, 7, 8 and 9] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Type of endpoint: Safety

Project description:Homeostatic perturbation caused by infection fosters two major defense strategies, resistance and tolerance, which promote the host's survival. Resistance relates to the ability of the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without directly affecting pathogen fitness. These concepts have been explored mechanistically in murine models of malaria but only superficially in human disease. Indeed, individuals infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms, or be severely ill. We and others have reported a diverse repertoire of immunopathological events that potentially underly susceptibility to disease severity in vivax malaria. Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features associated with defining the disease outcomes are still not fully understood. In the present study, we perform an extensive outlining of cytokines and inflammatory proteins in plasma samples from a cohort of individuals from the Brazilian Amazon infected with P. vivax and presenting with asymptomatic (n = 108) or symptomatic (n = 134) disease (106 with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls (n = 128) to elucidate these gaps further. We employ highly multidimensional Systems Immunology analyses using the molecular degree of perturbation to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity as well as with other clinical and epidemiologic characteristics. Additionally, our findings reveal that the main factor associated with severe cases of P. vivax infection was the number of symptoms, despite of a lower global inflammatory perturbation and parasitemia. In these participants, the number of symptoms directly correlated with perturbation of markers of inflammation and tissue damage. On the other hand, the main factor associated with non-severe infections was the parasitemia values, that correlated only with perturbation of inflammatory markers, such as IL-4 and IL-1β, with a relatively lower number of symptoms. These observations suggest that some persons present severe vivax regardless of pathogen burden and global inflammatory perturbation. Such patients are thus little tolerant to P. vivax infection and show higher susceptibility to disrupt homeostasis and consequently exhibit more clinical manifestations. Other persons are capable to tolerate higher parasitemia with lower inflammatory perturbation and fewer symptoms, developing non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria.

Project description:In the present study, we studied chronic HCV patients who responded to IFN-based therapy as evidenced by absence of HCV RNA at the end of treatment, and focused on two issues that have not received much attention. Firstly, we evaluated whether specific genes or gene expression patterns in blood were able to distinguish responder patients with a viral relapse from responder patients who remained virus-negative after cessation of treatment. We found that chronic HCV patients who were sustained responders and relapsers to IFN-based therapy showed comparable baseline clinical parameters and immune composition in blood. However, at baseline, the gene expression profiles of a set of 18 genes predicted treatment outcome with an accuracy of 94%. Secondly, we examined whether patients with successful therapy-induced clearance of HCV still exhibited gene expression patterns characteristic for HCV, or whether normalization of their transcriptome was observed. We observed that the relatively high expression of IFN-stimulated genes (ISG) in chronic HCV patients prior to therapy was reduced after successful IFN-based antiviral therapy (at 24 weeks follow-up). These ISG included CXCL10, OAS1, IFI6, DDX60, TRIM5 and STAT1. In addition, 1428 differentially expressed non-ISG genes were identified in paired pre- and post-treatment samples from sustained responders, which included genes involved in TGF-β signaling, apoptosis, autophagy, and nucleic acid and protein metabolism. Interestingly, 1424 genes were identified with altered expression in responder patients after viral eradication in comparison to normal expression levels in healthy individuals. Additionally, aberrant expression of a subset of these genes, including IL-32, IL-16, CCND3 and RASSF1, was also observed at baseline. Our findings indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of their blood transcriptional signature. The altered transcriptional activity may reflect HCV-induced liver damage in previously infected individuals.

Project description:In the present study, we studied chronic HCV patients who responded to IFN-based therapy as evidenced by absence of HCV RNA at the end of treatment, and focused on two issues that have not received much attention. Firstly, we evaluated whether specific genes or gene expression patterns in blood were able to distinguish responder patients with a viral relapse from responder patients who remained virus-negative after cessation of treatment. We found that chronic HCV patients who were sustained responders and relapsers to IFN-based therapy showed comparable baseline clinical parameters and immune composition in blood. However, at baseline, the gene expression profiles of a set of 18 genes predicted treatment outcome with an accuracy of 94%. Secondly, we examined whether patients with successful therapy-induced clearance of HCV still exhibited gene expression patterns characteristic for HCV, or whether normalization of their transcriptome was observed. We observed that the relatively high expression of IFN-stimulated genes (ISG) in chronic HCV patients prior to therapy was reduced after successful IFN-based antiviral therapy (at 24 weeks follow-up). These ISG included CXCL10, OAS1, IFI6, DDX60, TRIM5 and STAT1. In addition, 1428 differentially expressed non-ISG genes were identified in paired pre- and post-treatment samples from sustained responders, which included genes involved in TGF-β signaling, apoptosis, autophagy, and nucleic acid and protein metabolism. Interestingly, 1424 genes were identified with altered expression in responder patients after viral eradication in comparison to normal expression levels in healthy individuals. Additionally, aberrant expression of a subset of these genes, including IL-32, IL-16, CCND3 and RASSF1, was also observed at baseline. Our findings indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of their blood transcriptional signature. The altered transcriptional activity may reflect HCV-induced liver damage in previously infected individuals. A genome-wide gene expression analysis was performed on a blood cohort of 59 chronic HCV patients and 20 healthy controls. The expression profiles of patients who responded to IFN-based therapy, who developed a viral relapse were compared respectively to the profiles of healthy controls. Pre- and post-treatment expression profiles of same responders were compared as well.

Dataset Information

Chronic Hepatitis B Infection Is Associated with Increased Molecular Degree of Inflammatory Perturbation in Peripheral Blood.

Publications

Chronic Hepatitis B Infection Is Associated with Increased Molecular Degree of Inflammatory Perturbation in Peripheral Blood.

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