Biomarker Development for TLR4 Agonists

In DARPA-supported studies, we have shown that a family of novel synthetic glycolipids known as the aminoalkyl glucosaminide phosphates (AGPs) act as potent agonists of Toll-like receptor 4 (TLR4), and that administration of AGPs to the airways results in protection against lethal challenge with virulent bacterial and viral agents. Preliminary toxicological studies indicate that intranasal delivery of the compounds is safe, and human clinical trials with aerosolized TLR4 agonists are now anticipated. To monitor the effectiveness of immunoprophylaxis in human trials, it may become necessary to develop surrogate biomarkers of protection since experimental challenge endpoints are not readily available. Under the current contract, we have completed a series of in vitro and in vivo studies to identify candidate biomarkers via microarray-based-based transcriptional profiling, conventional multiplex cytokine and flow cytometric analyses. Through these studies we have identified biomarkers suitable for clinical monitoring of AGP mediated protection. Synthesis and scale- up requirements have been established and carried out for a single lead AGP candidate, CRX-527, for production of OMP grade material suitable for clinical trials. Formal GLP toxicology studies with CRX-527 will be initiated in early 2005 with a Phase I Clinical trial planned for the first quarter of 2006. Pre-IND documents for this phase I clinical trial are currently being assembled and will be submitted to the FDA for approval in mid-October.