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.
CEACAM6 (CD66c) is a novel immune checkpoint regulator suppressing the activity of effector T cells against tumors. CEACAM6 is expressed on tumor cells of multiple malignancies e.g.adenocarcinomas of the lung, colon, pancreas and stomach. In these tumor types higher CEACAM6 expression is associated with advanced stages and a poor prognosis. In immunohistochemistry analyses on primary tumor tissue slides and tissue microarrays the tumor cell expression of CEACAM6 was found to be independent from that of programmed death ligand 1 (PD-L1). BAY 1834942 is a humanized monoclonal antibody selectively blocking CEACAM6-mediated suppression of human T cells. Because there is no rodent orthologue of CEACAM6, BAY 1834942 was fully characterized in in vitro studies as reported earlier (AACR 2018, abstract nr. 1771). Benchmarking and combination studies showed that CEACAM6-mediated inhibition of T cell activation is apparently non-redundant with the programmed death-receptor 1 (PD-1)/ PD-L1 axis. Combination experiments were performed in co-cultures of PD-1, T cell immunoglobulin and mucin domain 3 (TIM3) and CEACAM1 (CD66a) positive virus antigen-specific T cells and virus peptide-loaded CEACAM6-expressing tumor cells (HCC2935, HCT116-C6 cells). When BAY 1834942 was combined with antibody inhibitors of either PD-1 or PD-L1, we consistently observed enhanced secretion of proinflammatory cytokines by T cells in the presence of PD-L1 positive tumor cells (HCC2935). Unexpectedly, combination of BAY 1834942 with an anti-TIM3 antibody resulted in an even more pronounced, synergistic increase of cytokine secretion. The combined effect of CEACAM6 and TIM-3 blockade was confirmed using survivin peptide-specific T cells as alternative T cell source. In contrast, combination of BAY 1834942 with an anti-CEACAM1 function blocking antibody was not superior to anti-CEACAM1 treatment alone, which is in line with our hypothesis that CEACAM1 is the main T cell receptor for CEACAM6 in our functional assays. In summary, BAY 1834942 is a novel immune checkpoint inhibitor with monotherapy potential for the treatment of patients with CEACAM6-expressing cancers. The data shown here provide a rationale for examining its combination potential with immune checkpoint inhibitors targeting either PD-1, PD-L1 or TIM-3. BAY 1834942 is currently under investigation in Ph1 clinical trials (NCT03596372). Citation Format: Joerg Willuda, Hans-Henning Boehm, Jessica Pinkert, Mark Trautwein, Wolf-Dietrich Doecke, Oliver von Ahsen, Karl Ziegelbauer, Rienk Offringa, Bertolt Kreft, Philipp Beckhove. Increased T cell- activation resulting from the combination of the anti-CEACAM6 function-blocking antibody BAY 1834942 with checkpoint inhibitors targeting either PD-1/PD-L1 or TIM-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-075.
CEACAM6 (CD66c) was previously shown to act as a novel immune checkpoint regulator suppressing the activity of effector T cells against tumors (Witzens-Harig et al., Blood 2013). CEACAM6 is a GPI-linked protein that is strongly expressed at the tumor cell surface in multiple cancer indications such as non-small cell lung adenocarcinoma (NSCLC), colorectal carcinoma (CRC), gastric adenocarcinoma and pancreatic cancer. In general, elevated CEACAM6 expression is associated with advanced tumor stages and poor prognosis. In vitro experiments showed that engagement of T-cells with CEACAM6, either expressed on tumor cells or presented on beads, resulted in suppression of TCR-mediated T-cell activation and ZAP70 phosphorylation. Based on these findings, we hypothesized that antibodies targeting CEACAM6 may be employed to enhance T-cell responses against CEACAM6-expressing cancers. Here we report the generation and characterization of BAY 1834942, a humanized monoclonal antibody selectively blocking the inhibitory impact of CEACAM6 on human T cells. There is no rodent ortholog of CEACAM6 precluding in vivo efficacy studies. In tumor cell / T cell co-culture systems, BAY 1834942 increased secretion of T-cell cytokines and effector molecules (e.g. IFNγ, TNFα, IL-2, granzyme B) and resulted in improved tumor cell killing. The effects of BAY 1834942 were dose-dependent, only observed in the context of CEACAM6-expressing tumor cells and could be reproduced in experiments using tumor cell lines and T-cell preparations from different sources, including T cells derived from tumor infiltrating lymphocytes from pancreatic cancer. BAY 1834942 is cross-reactive with the cynomolgus CEACAM6 ortholog and was well-tolerated in monkey toxicology studies. In summary, BAY 1834942 is a novel checkpoint inhibitor with potential for the treatment of patients with CEACAM6 expressing cancers, both as single agent and in combination with other checkpoint inhibitors. First-in-man trials are expected to commence in 2018. Citation Format: Joerg Willuda, Mark Trautwein, Jessica Pinkert, Wolf-Dietrich Doecke, Hans-Henning Boehm, Florian Wessel, Yingzi Ge, Eva Maria Gutierrez, Joerg Weiske, Christoph Freiberg, Uwe Gritzan, Julian Glueck, Dieter Zopf, Sven Golfier, Oliver von Ahsen, Ruprecht Zierz, Sabine Wittemer-Rump, Heiner Apeler, Ziegelbauer Karl, Rienk Offringa, Bertolt Kreft, Beckhove Philipp. BAY 1834942 is an immunotherapeutic antibody blocking the novel immune checkpoint regulator CEACAM6 (CD66c) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1771.
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