Showing papers by "Novartis Foundation published in 2015"

A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells

Abstract: Cross-presentation is the process by which professional APCs load peptides from an extracellularly derived protein onto class I MHC molecules to trigger a CD8(+) T cell response. The ability to enhance this process is therefore relevant for the development of antitumor and antiviral vaccines. We investigated a new TLR2-based adjuvant, Small Molecule Immune Potentiator (SMIP) 2.1, for its ability to stimulate cross-presentation. Using OVA as model antigen, we demonstrated that a SMIP2.1-adjuvanted vaccine formulation induced a greater CD8(+) T cell response, in terms of proliferation, cytokine production and cytolytic activity, than a non-adjuvanted vaccine. Moreover, using an OVA-expressing tumor model, we showed that the CTLs induced by the SMIP2.1 formulated vaccine inhibits tumor growth in vivo. Using a BCR transgenic mouse model we found that B cells could cross-present the OVA antigen when stimulated with SMIP2.1. We also used a flow cytometry assay to detect activation of human CD8(+) T cells isolated from human PBMCs of cytomegalovirus-seropositive donors. Stimulation with SMIP2.1 increased the capacity of human APCs, pulsed in vitro with the pp65 CMV protein, to activate CMV-specific CD8(+) T cells. Therefore, vaccination with an exogenous antigen formulated with SMIP2.1 is a successful strategy for the induction of a cytotoxic T cell response along with antibody production.

NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

Abstract: Background and Purpose Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) by short-circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep (MCC). Key Results In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.

050: leprosy task force: a country led response for the ‘last mile’ in a neglected disease

Abstract: Background The Philippines eliminated leprosy as a public health concern when prevalence was reduced to less than 1 case per 10,000 people in 1998. However, 1,000 to 3,000 new cases continue to be identified each year and sustained commitment is essential in this last mile of disease control. Objectives Aligned with the comprehensive post-elimination strategy of the Department of Health, participants from the public and private sector have collaborated to identify innovative post-elimination approaches through a Task Force. Methods The Task Force meets on a bi-monthly basis, and is comprised of eight people collaboratively working across the public and private sectors. The Task Force aims to promote broader local engagement through convening key partners in leprosy. Result The Task Force was convened in 2012 and as its first objective recognized the need to solicit new approaches for the last mile. The “Best Practices and Innovative Ideas in Fighting Leprosy Contest” was launched, and received 35 submissions with 19 for Best Practices and 16 for Innovative Ideas. From the entries, the Task Force decided to focus its efforts on one particular “Innovative Ideas’ submission, the LEprosy Alert Response Network & Surveillance System (LEARNS) - a mobile health tool. LEARNS aims to improve communication and build capacity among remote healthcare providers and specialists to minimize the delay in diagnosis and treatment of leprosy. In addition to LEARNS, the Task Force promotes dialogue across sectors, advocates for continued commitment to leprosy and has convened an annual stakeholders9 meeting since its creation to present and disseminate key findings to move the leprosy control agenda forward. Conclusion A neglected disease such as leprosy requires continued advocacy and commitment, which the Philippines9 Department of Health has successfully led as it traverses the “last mile” against leprosy.