Skip to main navigationSkip to main content
The University of Southampton
Institute for Life Sciences

Research project: Linclau: The synthesis of glycosylceramide analogues

Currently Active: 
Yes

The a-galactosylceramide KRN7000, is currently in phase I clinical trials for cancer immunotherapy. Extensive exploration of the biological effects of KRN7000 has unveiled its remarkable activity against diverse diseases, such as several types of cancer, as well as malaria, juvenile diabetes, hepatitis B, and autoimmune encephalomyelitis.

The unifying mechanism of action of KRN7000 is its remarkable ability to induce a potent expansion of NKT cells, involving the following sequence of events:

  • the galactosyl ceramide binds to the CD1d receptor of antigen-presenting cells, then
  • the ceramide receptor complex binds to NKT cells, which stimulate a cascade of cytokine signals that result in the suppression of disease.
Image 1`

Nevertheless, the widespread use of a-GalCer as a therapeutic agent is hampered by the fact that it induces the simultaneous production of both Th1 and Th2 cytokines that antagonise each other's effects. However, there is now proof of principle that synthetic modifications of a-GalCer may significantly modify the Vai NKT cell mediated responses. A synthetic C-glycoside analogue was described that resulted in a prolonged secretion of IFN-g and proved to be highly efficacious in the protection against metastatic tumours and malaria. Conversely, an analogue of a-GalCer with a truncated sphingosine tail (OCH) was reported to preferentially promote IL-4 secretion and to be more potent in preventing collagen-induced arthritis than a-GalCer. Therefore, inducing a polarization in the cytokine response induced by Vai NKT cells by altered glycolipid CD1d antigens is an attractive strategy to treat either malignant or autoimmune disease.

In collaboration with Prof T. Elliott, Dr. C. Ottensmeyer, and Dr Al-Shamkani from the Southampton Somers Cancer Research Institute, Dr Werner from the Southampton School of Biological Sciences, Prof Van Calenbergh from the Faculty of Pharmaceutical Sciences at Ghent University, and Prof Elewaut from the Ghent University Hospital, and funded by CR-UK, an research programme is set up for the synthesis and biological evaluation of KRN7000 analogues.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
Share this research project Share this on Facebook Share this on Twitter Share this on Weibo

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×