The adhesion molecule CD146 plays a vital role in inflammation and offers a promising therapeutic target for treating inflammatory bowel disease (IBD) as well as preventing colitis-associated colorectal cancer, say scientists. Targeting CD146 with anti-CD146 antibody AA98, especially in combination with an anti-TNF-alpha antibody, showed promising results in mice. Their report is published in The American Journal of Pathology.
Enhanced CD146 expression has been reported on endothelial cells in intestinal biopsies from patients with inflammatory bowel disease. There have also been clinical observations that CD146 expression is associated with other inflammatory diseases such as rheumatoid arthritis, chronic renal failure, and diabetes. However, the mechanisms were unclear until now.
In the present study, the investigators set out to examine how CD146 functions in inflammatory diseases and, more importantly, to understand its role in chronic-inflammation-associated carcinogenesis. They found that overexpressed endothelial CD146 promoted the inflammatory responses in IBD, which further potentiated the occurrence of colitis-associated carcinogenesis (CAC). “Eliminating endothelial CD146 by conditional knockout in two different mouse models of colitis significantly reduced the severity of inflammation and decreased tumor incidence and tumor progression in a mouse model of CAC,” reports lead investigator Xiyun Yan, PhD, from the Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing.
To mimic the long-lasting and relapsing property of IBD, the team also established a chronic colitis mouse model and administrated an anti-CD146 antibody, AA98, after the onset of disease. Because IBD is a clinically heterogeneous disease with complex mechanisms, a combination of drugs targeting distinct biomarkers might be considered as a potential approach. Thus, they also tested the combined treatment of anti-CD146 antibody AA98 and anti-TNF-alpha antibody V1q in this model. Disease activity index and histological score were dramatically reduced in the AA98 treatment group and the V1q treatment group, especially the combination treatment group, compared with the mIgG treatment group.