title: Novel immunotherapy for malignant melanoma with a monoclonal antibody that blocks CEACAM1 homophilic interactions.
abstract: 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 monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 monoclonal antibody, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (K(D) ~ 2 nmol/L). Furthermore, MRG1 is a potent inhibitor of CEACAM1 homophilic binding and does not 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 antitumor effect of adoptively transferred, melanoma-reactive human lymphocytes using human melanoma xenograft models in severe combined immunodeficient/nonobese diabetic (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, approximately 90% of melanoma specimens are CEACAM1(+), implying that the majority of patients with melanoma 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 anticancer antibodies in clinical use. Importantly, MRG1 does not directly affect CEACAM1(+) cells. CEACAM1 blockade is different from other immunomodulatory 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.
authors.affiliation: Ella Institute of Melanoma, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Rona
authors.initials: R
authors.lastname: Ortenberg
authors.forename: Yair
authors.initials: Y
authors.lastname: Sapir
authors.forename: Lee
authors.initials: L
authors.lastname: Raz
authors.forename: Liat
authors.initials: L
authors.lastname: Hershkovitz
authors.forename: Ayelet
authors.initials: A
authors.lastname: Ben Arav
authors.forename: Sivan
authors.initials: S
authors.lastname: Sapoznik
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.forename: Yackov
authors.initials: Y
authors.lastname: Berkun
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.forename: Tehila
authors.initials: T
authors.lastname: Ben-Moshe
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules