Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

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.