Preclinical development of first-in-class antibodies targeting Siglec-9 immune checkpoint for cancer immunotherapy

Siglec-9 is a MHC class I-independent inhibitory receptor expressed on NK and myeloid cells (including dendritic cells, monocytes and neutrophils). Its ligands are sialic acid-containing carbohydrates which are over-expressed on various tumor types compared to normal tissues (1). Sialylation of tumor cells is involved in tumor cell malignancy and is reported for decades as a mechanism of escape from immune surveillance (2). The loss of beta-2-microglobulin, an essential component of MHC class I antigen presentation, was recently described as a common mechanism of resistance to checkpoint blockade in clinical trials and revealed the need for MHC class I-independent therapies (3-4). Thus, Siglec-9-sialic acid interaction disruption may promote anti-tumor immunity independently of MHC class I expression by tumors. Here, we describe the discovery and characterization of first-in class anti-human Siglec-9 antibodies as new checkpoint blockade therapy in a wide range of cancers. Antibodies were discovered that efficiently block the interaction between Siglec-9 and its ligands. Epitope mapping revealed that antibodies bind to distinct epitopes on Siglec-9 near the sialic acid binding site. In vitro assays showed that they potently reverse inhibitory functions of Siglec-9 on NK cells leading to subsequent sialic acid-expressing tumor cell killing. Interestingly, Siglec-9 is enhanced on both CD4+ and CD8+ T cells from RCC, melanoma and NSCLC PBMC patients suggesting a putative additional role on adaptive immunity. Siglec-9 was also co-expressed with other inhibitory receptors on NK cells and combination with other immune checkpoint blockers in in vitro assays is ongoing. The antibodies displaying the most interesting features were successfully humanized. (1) Pathol Oncol Res. 2016 Jul;22(3):443-7 (2) Nature. 1968 Jun 29;218(5148):1254-5 (3) Nat Commun. 2017 Oct 26;8(1):1136 (4) N Engl J Med. 2016 Sep 1;375(9):819-29 Citation Format: Olivier Benac, Marion Gaudin, Melody Ors, Aude Le Roy, Helene Rispaud Blanc, Caroline Soulas, Stephanie Chanteux, Benjamin Rossi, Laurent Gauthier, Carine Paturel, Yannis Morel, Ivan Perrot, Stephanie Cornen. Preclinical development of first-in-class antibodies targeting Siglec-9 immune checkpoint for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2713.