IL-15 and Refractory Celiac Disease
Refractory celiac disease
Celiac disease is caused by an immune reaction to gluten present in wheat, in genetically predisposed individuals. Peptides derived from gluten trigger inflammation in the small intestine, leading to atrophy of intestinal villi and malabsorption of nutrients.
Marsh classification (0 to 4) of small bowel pathology in Celiac disease. Source: http://en.wikipedia.org/wiki/Coeliac_disease#/media/File:Coeliac_Disease.png (under CC BY-SA 3.0 via Wikimedia Commons)
The main symptoms of celiac disease are gastrointestinal pain, bloating and diarrhea, as well as problems related to malabsorption including weight loss, anemia and vitamin deficiencies. There may be subsequent development of dermatitis herpetiformis, infertility, osteoporosis and other auto-immune diseases. It is estimated that about 1% of the population has celiac disease in Western countries, often without knowing it.
A life-long gluten-free diet is currently the only option for those suffering from celiac disease. Although some patients experience relief under gluten-free diet, others do not respond and belong to the refractory celiac disease (RCD) group of patients. Among the RCD group of patients, some present a more severe form (RCDII), which is a life-threatening condition characterized by a high risk of progressing to deadly intestinal lymphoma.
There are no treatments approved for RCDII and existing remedies are not effective: there is therefore a clear need to bring new efficient and safe therapeutic options for those patients.
IL-15 is a cytokine mainly expressed by monocytes, dendritic cells and epithelial cells and induced by infection or antigenic stimulation. IL-15 plays multiple roles in the immune system, especially in the gastro-intestinal tract, by controlling the homeostasis and activation of T, B, and NK cells and the immune response to tissue damage. IL-15 can bind to three receptor chains and its signaling is complex, which is a challenge for the discovery of efficient neutralizing antibodies. CALY-002 is an optimized anti-IL-15 antibody able to fully neutralize all signaling modes of IL-15.
Calypso Biotech has demonstrated that its CALY-002 anti-IL-15 development candidate antibody was efficient in a mouse model of refractory celiac disease.
Blocking IL-15 in Refractory Celiac Disease
Enterocytes from celiac disease patients express and secrete IL-15, unless on an effective gluten-free diet. IL-15 is believed to play its pathogenic role by increasing T and B cell responses and favoring cytotoxic responses against the gut epithelium. In RCDII, IL-15 has been further incriminated in supporting the expansion of the abnormal intraepithelial lymphocyte population that can transform into deadly lymphoma cells in those patients. Neutralizing IL-15 could therefore correct the expansion of abnormal cells and mitigate intestinal inflammation in RCDII.
Biological events leading to refractory celiac disease