Characterization of murine CEACAM1 in vivo reveals low expression on CD8+ T cells and no tumor growth modulating activity by anti-CEACAM1 mAb CC1

Abstract

// Robbie L. McLeod 1, 2, 3 , Minilik H. Angagaw 1, 2, 3 , Toya Nath Baral 1, 2, 3 , Liming Liu 1, 2, 3 , Raymond Joseph Moniz 1, 2, 3 , Jason Laskey 1, 2, 3 , SuChun Hsieh 1, 2, 3 , Mike Lee 1, 2, 3 , Jin-Hwan Han 1, 2, 3 , Hassan Issafras 1, 2, 3 , Sarah Javaid 1, 2, 3 , Andrey Loboda 1, 2, 3 , Svetlana Sadekova 1, 2, 3 , Joann A. O'Connor 1, 2, 3 , Archie Tse 1, 2, 3 and Juha Punnonen 1, 2, 3 1 Merck & Co., Inc., Boston, MA, USA 2 Merck & Co., Inc., Kenilworth, NJ, USA 3 Merck & Co., Inc., Palo Alto, CA, USA Correspondence to: Robbie L. McLeod, email: robbie.mcleod@merck.com Keywords: CEACAM1; CC1; CD8+ T cells; syngeneic mouse model; pharmacokinetic Received: June 21, 2018      Accepted: August 27, 2018      Published: October 02, 2018 ABSTRACT Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been reported to mediate both tumorigenic and anti-tumor effects in vivo . Blockade of the CEACAM1 signaling pathway has recently been implicated as a novel mechanism for cancer immunotherapy. CC1, a mouse anti-CEACAM1 monoclonal antibody (mAb), has been widely used as a pharmacological tool in preclinical studies to inform on CEACAM1 pathway biology although limited data are available on its CEACAM1 blocking characteristics or pharmacodynamic-pharmacokinetic profiles. We sought to investigate CEACAM1 expression on mouse tumor and immune cells, characterize CC1 mAb binding, and evaluate CC1 in syngeneic mouse oncology models as a monotherapy and in combination with an anti-PD-1 mAb. CEACAM1 expression was observed at high levels on neutrophils, NK cells and myeloid-derived suppressor cells (MDSCs), while the expression on tumor-infiltrating CD8+ T cells was low. Unexpectedly, rather than blocking, CC1 facilitated binding of soluble CEACAM1 to CEACAM1 expressing cells. No anti-tumor effects were observed in CT26, MBT2 or A20 models when tested up to 30 mg/kg dose, a dose that was estimated to achieve >90% target engagement in vivo . Taken together, tumor infiltrating CD8+ T cells express low levels of CEACAM1 and CC1 Ab mediates no or minimal anti-tumor effects in vivo , as a monotherapy or in combination with anti-PD-1 treatment.