Abstract 1064P
Background
CEACAM1, a novel target for cancer immunotherapy, is a member of the CEA family; it contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in the intra-cytoplasmic domain. The ITIM motif appears to function in immune tolerance and immune exhaustion. Consequently, it plays a crucial role in inhibitory signals to immune cells. CEACAM1 is expressed on the membrane of T cells, NK cells, TILs, and tumor cells, and is known for the homophilic interaction with CEACAM1 expressed on tumor cells or immunocytes. We developed MG1124, a fully human monoclonal antibody against CEACAM1.
Methods
TILs were isolated from tumor tissues of various types of cancer patients and expanded in media supplemented with IL-2. We performed FACS analysis using HEK 293T cells that transiently expressed the CEA family members. The Jurkat-CEACAM1 stable cell lines were stimulated with anti-CD3 antibody in the presence or absence of MG1124 and then luciferase activity and IL-2 secretion were measured. NK cell or T cell-mediated cytotoxicity were also measured using calcein-AM. We evaluated the in vivo antitumor activity of MG1124 in patient-derived xenograft (PDX) models of NSCLC.
Results
CEACAM1 was expressed on patient-derived TILs rather than PBMCs. MG1124 bound specifically to CEACAM1, but not to other CEA family proteins. MG1124 prevented CEACAM1 homophilic interactions as assessed by NFAT-mediated luciferase activity and IL-2 secretion. Furthermore, MG1124 induced NK cell and T cell-mediated elimination of CEACAM1-expressing cancer cell lines. MG1124 significantly attenuated the tumor growth in an NSCLC PDX-huNSG mouse model. In addition, combination therapy with anti-PD-1 antibody exerted synergistic anticancer effects. These results suggest that MG1124 could improve the therapeutic efficacy in cancer patients.
Conclusions
We generated a fully human monoclonal antibody MG1124 that targets human CEACAM1 and blocks the biological activities of CEACAM1. It enhanced the efficacy of antitumor activity in an NSCLC PDX-huNSG mouse model. Collectively, MG1124 could be a novel therapeutic approach for immune checkpoint blockade in cancer therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.