Article Text

Download PDFPDF

493 Identification of different classes of antagonist monoclonal antibodies targeting the myeloid checkpoint CLEC-1 and their associated anti-tumoral in vivo efficacies in humanized preclinical models
  1. Irène Baccelli1,
  2. Caroline Mary1,
  3. Stéphanie Neyton1,
  4. Mylène Deramé1,
  5. Marion Drouin1,
  6. Geraldine Teppaz1,
  7. Emmanuelle Wilhelm1,
  8. Isabelle Girault1,
  9. Vanessa Gauttier1,
  10. Virginie Thepenier1,
  11. Cecile Batty1,
  12. Kevin Biteau1,
  13. Ariane Desselle1,
  14. Marion Colonello1,
  15. Julien Taurelle1,
  16. Marine Malloci1,
  17. Elise Chiffoleau2 and
  18. Nicolas Poirier1
  1. 1OSE Immunotherapeutics, Nantes, Loire-Atlantique, France
  2. 2Nantes Université, Inserm, Centre de Recherche en Transplantation et Immunologie Translationnelle, UMR 1064, ITUN, Nantes, Loire Atlantique, France
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background The c-type lectin receptor CLEC-1 is a pattern recognition receptor1 expressed by endothelial and myeloid cells in mice, non-human primates, and humans. While genetic deletion of CLEC-1 in mice does not lead to any developmental defect, CLEC-1 deletion or CLEC-1 targeting using monoclonal antibodies increases damaged or necrotic cell antigen cross-presentation by cDC1 dendritic cells, as well as subsequent T-cell activation and anti-tumor response.2 However, the identification of CLEC-1 endogenous ligands and their relative involvement in the immune checkpoint activity of CLEC-1 remained to be fully investigated.

Methods Endogenous CLEC-1 ligand candidates were identified by affinity capture assays followed by LC/MS analysis. Ligand candidates were validated through protein-protein binding assays and Biacore affinity measurements. Through an immunization campaign, a library of anti-CLEC-1 monoclonal antibodies was generated and screened for CLEC-1 protein binding. Monoclonal antibodies were also assessed for their abilities to inhibit the binding of CLEC-1 to its newly identified endogenous ligands. Different classes of antagonist anti-CLEC-1 antibodies were thereby identified and subsequently evaluated for their anti-tumor efficacies in hepatocellular carcinoma (Hepa1.6) and colorectal cancer (MC38) preclinical models, using human CLEC-1 knock-in mice.

Results While we confirm CLEC-1 specific binding to the E3 ubiquitin ligase TRIM212 and to the secreted histidine rich glycoprotein (HRG),3 we also identify several novel intra-cellular and cell surface CLEC-1 ligands. We show that the binding of CLEC-1 to these newly identified ligands is protein-specific, as deglycosylation does not impair CLEC-1 binding to its ligands. Finally, we document the antitumoral activities of several classes of antagonist anti-CLEC-1 monoclonal antibodies: while blocking of CLEC-1 binding to its secreted ligand HRG moderately increases anti-tumor responses, inhibition of CLEC-1 binding to its cytoplasmic membrane ligands significantly impairs MC38 tumor growth (n=12, p=0.04) and increases the overall survival of Hepa1.6-bearing mice (n=12, p=0.002), as compared to corresponding isotype control treatment.

Conclusions Altogether, by shedding new light on the role of CLEC-1/CLEC-1 ligand interactions, our results further dissect the mechanism of action of the myeloid checkpoint CLEC-1 in its ability to impair anti-tumor immunity and support its use as a novel and highly promising target for cancer immunotherapy.


  1. Drouin M, Saenz J, Chiffoleau E. C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity. Front Immunol. 2020;11:251.

  2. Drouin M, Saenz J, Gauttier V, et al. CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy. Sci Adv. 2022;8(46):eabo7621.

  3. Gao S, Wake H, Sakaguchi M, et al. Histidine-Rich Glycoprotein Inhibits High-Mobility Group Box-1-Mediated Pathways in Vascular Endothelial Cells through CLEC-1A. iScience. 2020;23(6):101180.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.