Abstract 6342: Anti-tumor in vivo efficacy of different classes of anti-CLEC-1 myeloid checkpoint antibodies in monotherapy and in combination with chemotherapeutic agents

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Abstract The c-type lectin receptor CLEC-1 is a pattern recognition receptor [1] 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 promotes anti-tumor response by increasing cross-presentation of necrotic or damaged cells by cDC1 dendritic cells and by enhancing T-cell activation [2]. To date, the identification of CLEC-1 endogenous ligand(s) and their biological activity into myeloid or endothelial cells remained to be fully investigated. We aimed to further characterize ligands that are involved into CLEC-1 activation and develop monoclonal antagonist anti CLEC-1 antibody anti-tumor therapy that are able fully counteract inhibitory signaling induced into myeloid cells. Using LC/MS campaign, we confirmed CLEC-1 specific binding to the E3 ubiquitin ligase TRIM21and to the secreted histidine rich glycoprotein (HRG) as previously described [2] and also identify several novel intra-cellular and cell surface proteins that bind to CLEC-1 receptor in protein specific-manner. To block interaction of CLEC-1 ligands, we developed different class of antagonist monoclonal antibodies and evaluated their anti-tumor efficacy in humanized CLEC-1 KI orthotopic and ectopic tumor mouse models fully resistant or partially resistant to ICI therapy. While blocking of CLEC-1 binding to its secreted ligand HRG moderately increases anti-tumor responses, inhibition of CLEC-1 binding to its cytoplasmic and membrane ligands significantly impairs MC38 tumor growth (n=12, p=0.04). Importantly, high anti-tumor efficacy was observed in combination therapy with cyclophosphamide in MC38 mouse model. Additionally, antagonist anti-CLEC-1 antibodies significantly increase overall survival of Hepa1.6-bearing mice (n=32 for each treatment, p<0.002), as compared to corresponding isotype control treatment in 3 independent experiments. Altogether, 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 anti-CLEC antagonist antibody for cancer immunotherapy. Citation Format: Aurore Morello, Mylène Deramé, Marion Drouin, Emmanuelle Wilhelm, Stéphanie Neyton, Irène Baccelli, Caroline Mary, Vanessa Gauttier, Isabelle Girault, Kévin Biteau, Cécile Batty, Géraldine Teppaz, Ariane Desselle, Marion Colonello, Marine Malloci, Elise Chiffoleau, Nicolas Poirier. Anti-tumor in vivo efficacy of different classes of anti-CLEC-1 myeloid checkpoint antibodies in monotherapy and in combination with chemotherapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6342.

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