OSE Immunotherapeutics has announced the publication in the peer-reviewed journal Science Advances of data from a first-in-class preclinical program with CLEC-1, a novel myeloid immune checkpoint target in cancer immunotherapy.
The academic collaboration carried out with the team of Dr Elise Chiffoleau at the Nantes Transplantation and Immunology Research Center (1) has made it possible to identify CLEC-1 as a checkpoint. CLEC-1 is a receptor expressed by myeloid cells inhibiting key pro-phagocytic and cross-activating functions of T cells, thereby limiting the antitumor immune response.
The article, titled “CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy” (2), reports fundamental findings and preclinical results showing that CLEC-1 is a new myeloid checkpoint that interacts with a newly identified ligand, TRIM-21, and confirming the therapeutic potential of CLEC-1 antagonist antibodies as an innovative cancer immunotherapy.
Nicolas Poirier, CEO of OSE Immunotherapeutics, comments: “We are very pleased with the publication of these data on CLEC-1 in the journal ‘Science Advances’. This confirms both the potential therapeutic value of the research program of our innovative ‘Myeloids’ platform in immuno-oncology, and the quality of our strategic academic collaboration with Dr. Elise Chiffoleau’s team on CLEC-1. The set of results on the first ligand of CLEC-1, overexpressed by several types of tumor in humans, such as pancreatic, liver or colon cancers associated with a strong medical need, and the new data from preclinical efficacy generated by our patented antagonist antibodies, pave the way for future clinical development in the continuity of the SIRPα/CD47 axis, whose anti-SIRPα antibody is already in clinical development at OSE. »
Elise Chiffoleau, researcher at INSERM, explains: “We are honored by the publication of our research carried out jointly with OSE Immunotherapeutics in a journal of very high scientific level. Our teams worked closely on the CLEC-1 target and identified for the first time TRIM-21 as an endogenous ligand induced during stress and/or cell death. CLEC-1 is a cell death receptor and binds to dead cells induced secondary necrosis. We discovered that CLEC-1 represents a new type of myeloid checkpoint within the Type-C lectin family that controls the ability of type-1 dendritic cells to activate the T cell response against tumor antigens. In addition, we have selected human anti-CLEC-1 monoclonal antibodies capable of prolonging survival in preclinical models of colon carcinoma and hepatocarcinoma. The action of these antibodies recapitulates the changes in the tumor microenvironment observed in these same models by genetic deletion of CLEC-1A, with more CD8 positive T cells, and also a change in myeloid cell composition with fewer immunosuppressive myeloid cells ( MDSCs – Myeloid Derived Suppressor Cells – and macrophages) and more mature dendritic cells”.
The results described in the scientific article show that:
– Overall, genetic deletion of CLEC-1 results in profound invigoration of the tumor immune microenvironment by increasing dendritic cell (antigen presenting cells) infiltrates, increasing activated and memory T cell infiltrates, decreasing lymphocyte infiltrates T expressing the depletion marker PD1 and limiting the recruitment of immunosuppressive cells such as MDSCs.
– Importantly, blocking CLEC-1 using monoclonal antibody treatment demonstrates robust antitumor activity, also by invigorating the tumor immune microenvironment in several preclinical oncology models, thus recapitulating the effect of the genetic deletion of CLEC-1 in the context of mice expressing human CLEC-1. Patented anti-CLEC-1 monoclonal antibodies increase survival as monotherapy in an orthotopic model of hepatocellular carcinoma, while combination with chemotherapy increases tumor eradication in a preclinical model of colon carcinoma.
(1) Collaborative program led by the research teams of OSE Immunotherapeutics and Dr Elise Chiffoleau (https://cr2ti.univ-nantes.fr/research/team-1) of the Center for Research in Transplantation and Translational Immunology (CR2TI ), UMR1064, INSERM, Nantes University, at Nantes University Hospital.
(2) “CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy.”
Marion Drouin, Javier Saenz, Vanessa Gauttier, Bérangère Evrard, Géraldine Teppaz, Sabrina Pengam, Caroline Mary, Ariane Desselle, Virginie Thepenier, Emmanuelle Wilhelm, Emmanuel Merieau, Camille Ligeron, Isabelle Girault, Maria-Dolores Lopez, Cynthia Fourgeux, Debajyoti Sinha, Irène Baccelli, Aurélie Moreau, Cedric Louvet, Régis Josien, Jérémie Poschmann, Nicolas Poirier, Elise Chiffoleau.
Source and visual: OSE Immunotherapeutics