Glycolipid mimetics with selective anti- or pro-inflammatory response

Novel glycolipid mimetics able to express anti-inflammatory or adjuvant activity in a context dependent manner. The compounds can be used for the treatment of immune diseases cursed with Th1/Th2 imbalance or as vaccine adjuvants.

Market need: Glycolipids play crucial roles in the regulation of immune response. There are several examples of synthetic immunoregulatory glycolipids capable of modulating Th1/Th2 cell balance by acting as agonists/antagonists of iNKT cells or the TLR4 receptor. Examples of the first category are a-Galactosylceramide (a-GalCer) and their analogues, whereas compounds acting on TLR4 are typically related to the lipopolysaccharide (LPS). However, these compounds bear limitations that hinder their therapeutics effectiveness such as complicated synthesis, chemical instability, and suboptimal Th1/Th2 modulating behaviour. Then, there is a need to identify additional glycolipid-like agents that specifically and directly can modulate the immune response by agonizing/antagonizing either iNKT cells or the TLR4.

Proposed solution: Two glycolipid mimetic families of compounds have been identified that are metabolically stable and that can be selectively modified to optimize their immunomodulatory profile in view of promoting and anti-inflammatory or and adjuvant response.
The capacity of the compounds to regulate the immune response has been shown in vitro and in vivo (mouse). They may exercise their anti-inflammatory function by binding to CD1d or TLR4, or by promoting phosphorylation of ERK, p38, and in some cases, also of STAT3. Moreover, the ability of selective compounds to function as adjuvants was assessed in a mouse model in vivo.

Competitive advantages

Selective compounds have shown suppression of a-GalCer- or LPS-induced inflammation in vitro and in vivo.
Some compounds were proficient at inducing Th1- and others Th2-biased response. The capacity of suppressing Th2 inflammation was confirmed in vivo in ovoalbumina (OVA)-induced airway hyerreactivity mouse model.
The in vivo adjuvancy capability of some compounds was also demonstrated in vivo.