The primary treatment for asthma is inhaled steroids which is not uniformly effective and has the potential for long-term side effects. Based on the activity of IL-16 in asthmatic inflammation, we have identified a novel immunotherapeutic approach. Asthmatic inflammation is absolutely dependent on the recruitment and activation of CD4+ T cells into the lung following allergen provocation. IL-16 stimulation of CD4+ T cells, by virtue of its direct interaction with CD4 and disruption of CD4 aggregation, results in significant inhibition of CD4+ T cell activation and Th2 cytokine production. Administration of IL-16 in a murine model of allergic asthma is immunomodulatory with a 90-95% decrease in airway hyperreactivity (AHR) and inflammation. We investigated whether a peptide derived from the bioactive site of IL-16 could mimic the immunomodulatory effect and serve as a new therapeutic modality. ? Our Preliminary Data show that a 16 residue peptide (ST-P1) disrupts CD4 aggregation in vitro. Moreover, aerosolized administration of ST-P1 peptide to mice results in a 75% reduction in AHR and inflammation, which is similar to treatment with IL-16 (whole protein). We hypothesize that additional CD4-binding peptides can be generated that bind to the same IL-16 binding site on CD4, with equal or greater avidity. These peptides will inhibit the asthma model with greater efficacy than the ST-P1 peptide. The goal of this proposal is to identity a peptide that can inhibit asthmatic inflammation as well as, or better, than IL-16 protein. The advantage of peptide therapy versus whole IL-16 protein is three fold: 1) a peptide would not have the potential agonistic effect of IL-16 on CD4+T cell recruitment; 2) a peptide would likely have better airway distribution due to its smaller size; and 3) a peptide would be less expensive to produce than the whole molecule. ? The aims for this Phase I application are to 1) screen and synthesize peptides derived from a phage displayed combinatorial peptide library, as well as logically derived peptides based on the IL-16 sequence; 2) test the peptides for their ability to bind to CD4 and disrupt T cell activation; 3) screen the best peptides from Aim 2 in the murine asthma model to identify maximal inhibition and identification of a lead compound. This peptide will then represent a novel, steroid independent, modality for asthma therapy which will be used for further development and GMP production as part of a Phase II application. ?
These studies will identify a new generation of drug candidates for treating asthma. The drug, a peptide, would be inexpensive to produce, easily administered to the lungs and have potentially no side-effects. This immune-based strategy represents a novel approach to asthma therapy which would potentially replace the use of inhaled steroids. ? ?
