P4.04Inhibition of the novel immune checkpoint CEACAM1 enhances anti-tumor activity

ABSTRACT Blockade of co-inhibitory immune receptors has become a promising approach for the activation of anti-tumor immunity. CEACAM1, a recently characterized immune checkpoint, is a member of the Ig superfamily expressed by activated effector lymphocytes and cancer cells. Expression of CEACAM1 on cancer cells induces a co-inhibitory signal to T and NK cells through homophilic CEACAM1 interactions. CEACAM1 is expressed across multiple tumor types. CM-24 is a humanized anti-CEACAM1 IgG4 antibody with high affinity and selectivity for CEACAM1. We investigated the activity of CM-24 and its ability to reverse CEACAM1-induced immune evasion. CM-24 was demonstrated to be a potent blocker of intercellular CEACAM1-CEACAM1 interactions and reversed inhibition of activated lymphocytes by restoring the phosphorylation signal of ZAP70. CM-24 enhanced the cytotoxic activity of cytotoxic T cell and NK cells against various cancer types, which was accompanied by higher secretion of Granzyme B and IFNγ. Various in vivo tumor xenograft models demonstrated that CM-24 has clear anti-tumor activity accompanied by an increase in immunological activity of T cells within the tumor. Collectively, preclinical data show that CM-24 has effective anti-tumor activity in various in vitro and in vivo models and demonstrate that CM-24 has the potential to enhance the cytotoxic activity of lymphocytes against malignant cells. CM-24 is now moving towards phase 1 clinical study.