Product pipeline: Toll-like receptor based adjuvants (TLR)

Toll-Like Receptors (TLRs) are an evolutionary old protein family. TLRs are the sentinels of the innate immune system and play a crucial role in host defence against infection. The TLR family consists of 11 members, although new members are likely to be identified in coming years. TRLs have a common structure consisting of a large extracellular, one transmembrane domain and a TLR/IL-1 receptor (TIR) intracellular domain. Some TLRs reside on the plasma membrane, others are primarily located on intracellular membranes (endosomes). TLRs recognize a variety of complex ligands. They signal through intracellular adaptors such as MyD88, TRIF and kinase cascades, leading to activation of NF-KB and the MAP kinases.

Over the last years it has become clear that the innate and adaptive immune system are closely linked. As a result TLRs turn out to be important not only in infectious diseases but in fact in all diseases where the immune system is deregulated, including inflammation, autoimmune disease, atherosclerosis and oncology. For some TLRs, their agonists and their mode of action are fairly well understood. These can e.g. be exploited to develop tumor- and infection vaccination strategies.

In 2007, the 17 million euro funded Project "Exploitation of Toll-like Receptors in Drug discovery" of the Dutch Top Institute Pharma commenced in which ISA is collaborating with the pharmaceutical companies Schering-Plough (Organon) and Numico Research, The Netherlands Organisation for Applied Scientific Research (TNO) and 6 Dutch Universities / University Medical Centers.

The overall focus of the consortium is the identification of new and improved Toll-like receptor modulators and their potential therapeutic applications.

Within the consortium three clusters are defined that work together in a concerted way:

• Generation of a TLR tool box, including biological and chemical leads
• Tumor immunology and infectious disease: novel immune intervention strategies
• Exploration of the role of TLRs in inflammatory diseases

ISA Pharmaceuticals has obtained the exclusive rights on all compounds coming forth from the program for the use as adjuvant in combination with peptide based vaccines. At present, several promising compounds are being evaluated for their potential use as clinical adjuvant for ISA's SLP® technology.