Pinkert et al. studied the immunosuppressive activity of CEACAM6, expressed on epithelial cancer cells, with CEACAM1, shown to be its binding partner on activated tumor-specific T cells. A humanized CEACAM6-blocking antibody, BAY 183492, was developed and compared with other checkpoint inhibitors in human T cell co-cultures with solid tumor cells. Blocking CEACAM6 with BAY 1834942 increased T cell IFNγ secretion and T cell cytotoxicity, and correlated with CEACAM6 expression. BAY 1834942 was equally or more effective than PD-L1 inhibition, and was additive with anti-PD-1 or anti-TIM-3 mAbs, suggesting clinical potential.
Contributed by Katherine Turner
ABSTRACT: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells. The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3). The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis. In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation.
Author Info: (1) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (2) Joint Immunotherapeutics Laboratory of
Author Info: (1) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (2) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (3) Pharmaceutical Division, Bayer AG, Wuppertal, Germany. (4) Pharmaceutical Division, Bayer AG, Berlin, Germany. (5) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (6) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (7) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (8) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. (9) Pharmaceutical Division, Bayer AG, Wuppertal, Germany. (10) Pharmaceutical Division, Bayer AG, Cologne, Germany. (11) Pharmaceutical Division, Bayer AG, Berlin, Germany. (12) Pharmaceutical Division, Bayer AG, Berlin, Germany. (13) Pharmaceutical Division, Bayer AG, Berlin, Germany. (14) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (15) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (16) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (17) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (18) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. Institute of Theoretical Physics, University of Regensburg, Regensburg, Germany. (19) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (20) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (21) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (22) Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. (23) Pharmaceutical Division, Bayer AG, Berlin, Germany. (24) Pharmaceutical Division, Bayer AG, Wuppertal, Germany. (25) Pharmaceutical Division, Bayer AG, Wuppertal, Germany. (26) Pharmaceutical Division, Bayer AG, Berlin, Germany. (27) Pharmaceutical Division, Bayer AG, Berlin, Germany. (28) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. (29) Pharmaceutical Division, Bayer AG, Berlin, Germany. (30) Joint Immunotherapeutics Laboratory of the DKFZ-Bayer Innovation Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Interventional Immunology, RCI Regensburg Center for Interventional Immunology, Regensburg, Germany. Hematology and Oncology Department, University Hospital Regensburg, Regensburg, Germany. (31) Pharmaceutical Division, Bayer AG, Berlin, Germany.
