In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1771-1771
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-1771
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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