Oncotarget

Research Papers:

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

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Oncotarget. 2018; 9:34459-34470. https://doi.org/10.18632/oncotarget.26108

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Robbie L. McLeod _, Minilik H. Angagaw, Toya Nath Baral, Liming Liu, Raymond Joseph Moniz, Jason Laskey, SuChun Hsieh, Mike Lee, Jin-Hwan Han, Hassan Issafras, Sarah Javaid, Andrey Loboda, Svetlana Sadekova, Joann A. O'Connor, Archie Tse and Juha Punnonen

Abstract

Robbie L. McLeod1,2,3, Minilik H. Angagaw1,2,3, Toya Nath Baral1,2,3, Liming Liu1,2,3, Raymond Joseph Moniz1,2,3, Jason Laskey1,2,3, SuChun Hsieh1,2,3, Mike Lee1,2,3, Jin-Hwan Han1,2,3, Hassan Issafras1,2,3, Sarah Javaid1,2,3, Andrey Loboda1,2,3, Svetlana Sadekova1,2,3, Joann A. O'Connor1,2,3, Archie Tse1,2,3 and Juha Punnonen1,2,3

1Merck & Co., Inc., Boston, MA, USA

2Merck & Co., Inc., Kenilworth, NJ, USA

3Merck & 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.



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