Clinical development of BSCIs as anti-inflammatory medications.
Various BSCIs have now been shown to exhibit anti-inflammatory activity in a wide range of animal models of various diseases, including atherosclerosis (J Vasc Res. 2005;42:492), surgical adhesion formation (Ann Thorac Surg 2003;75:1118) and HIV replication (Retrovirology. 2005;2:23). As a result, in late 2006, Ipsen granted a worldwide exclusive license to Funxional Therapeutics Ltd (FXT) to develop drug products based on BSCIs. During 2007, FXT is completing the preclinical package necessary to begin Phase I clinical trials of FX125L in mid-2008.
Interestingly, a pattern is emerging: in all the animal models where BSCIs are proving to have anti-inflammatory efficacy, they are modulating the polarisation of T-helper (Th) cells. Th cells are CD4+ lymphocytes which play a key role in regulating the immune system, through the secretion of many different cytokines. Th cells can become polarised and produce one of several "patterns" of cytokines: for example, Th1 cells secrete IFN-gamma, while Th2 cells secrete IL-4 and IL-5. As a result, many diseases with an inflammatory component have been associated with a tendancy for the Th cell population to become polarised in one direction (towards Th1) or the other (towards Th2). In such cricumstances, it is difficult for the normal balance to be restored because IFN-gamma blocks IL-4 secretion and vice versa. In animals treated with BSCIs, however, rebalancing of the Th population has been observed in many different models. Excitingly, BSCIs seem to restore balance whether the system has become extremely Th1 polarised (as in atherosclerosis) or Th2 polarised (as in asthma). In other words, BSCIs are the first compounds with genuine "rebalancing" activity on the Th cell population (as opposed to simply being a 'Th1 driver', which could rebalance a Th2 disease, or else a 'Th2 driver' useful in Th1 diseases). The molecular mechanisms behind this rebalancing remain unknown, but it is plausible that chemokine induced cell migration is necessary for establishing and maintaining the polarised state.
Much else also remains to be learnt about BSCIs, which will likely remain an important focus for the IRTL for a number of years. For example, it has long been clear that BSCIs do not block chemokine binding to their receptors, nor indeed do BSCIs bind to chemokine receptors at all. We have recently discovered the molecular target (a cell sruface receptor) for BSCI activity, although the identity of the receptor remains confidential. Surprisingly, BSCIs are agonists at this site, and generate a series of intracellular signals which effectively "blind" the cell to the directional component of chemokine signalling. It is this unique and surprising mechanism of activity which likely confers BSCIs with such an attractive balance between efficacy and toxicity: this BSCI receptor is only expressed on certain leukocyte subsets. As a result, BSCIs block many chemokines, signalling through many chemokines, but only on a proportion of leukocytes.
After a decade of research into BSCIs (Mini Rev Med Chem. 2005;5:825-32), we are only just beginning to understand why they are such attractive candidates for development as anti-inflammatory medications.