Novel immunotherapy for malignant melanoma with a monoclonal antibody that blocks CEACAM1 homophilic interactions
Menée in vitro et in vivo, cette étude évalue l'intérêt d'un anticorps bloquant l'action d'une glycoprotéine biliaire, CEACAM1, pour l'immunothérapie du mélanome
CEACAM1 (Biliary glycoprotein-1, CD66a) was reported as a strong clinical predictor of poor prognosis in melanoma. We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here we present substantial evidence in-vitro and in-vivo that blocking of CEACAM1 function with a novel mAb (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 mAb, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (KD~2nM). Further, MRG1 is a potent inhibitor of CEACAM1 homophilic binding, and doesn't induce any agonistic effect. We show using cytotoxicity assays that MRG1 renders multiple melanoma cell lines more vulnerable to T-cells in a dose-dependent manner, only following antigen-restricted recognition. Accordingly, MRG1 significantly enhances the anti-tumor effect of adoptively transferred melanoma-reactive human lymphocytes using human melanoma xenograft models in SCID-NOD mice. A significant antibody-dependent cell-cytotoxicity response was excluded. It is shown that MRG1 reaches the tumor and is cleared within a week. Importantly, ~90% of melanoma specimens are CEACAM1+, implying that the majority of melanoma patients could be amenable to MRG1-based therapy. Normal human tissue microarray displays limited binding to luminal epithelial cells on some secretory ducts, which was weaker than the broad normal cell binding of other anti-cancer antibodies in clinical use. Importantly, MRG1 doesn't directly affect CEACAM1+ cells. CEACAM1-blockade is different from other immune-modulatory approaches, as MRG1 targets inhibitory interactions between tumor cells and late effector lymphocytes, which is thus a more specific and compartmentalized immune stimulation with potentially superior safety profile.
http://mct.aacrjournals.org/content/early/2012/03/30/1535-7163.MCT-11-0526.abstract