Abstract 4254: Development of DEM201, a blocking antibody against SMAGP, a novel “Don′t Eat Me” signal overexpressed in cancer

Abstract Small Cell Adhesion Glycoprotein (SMAGP), a poorly characterized glycoprotein thought to function in cell adhesion, is highly expressed in gastrointestinal (GI) cancers and overexpressed in bladder cancer, hepatocellular carcinoma, kidney papillary cell carcinoma, pancreatic adenocarcinoma, thyroid carcinoma, and endometrial carcinoma. SMAGP was recently identified as a novel “Don’t Eat Me” (DEM) signal, and overexpression of human SMAGP suppresses tumor cell phagocytosis by primary human macrophages. Unlike the canonical DEM signal CD47, SMAGP is not detected in platelets or erythrocytes. Two cellular receptors for SMAGP have been identified, PILRα, an ITIM-containing transmembrane receptor broadly expressed in the myeloid lineage, and CD177, a GPI-anchored neutrophil marker also expressed in some epithelial cells and tumor-associated regulatory T cells (Tregs). To investigate the role of SMAGP in regulating anti-tumor responses, monoclonal antibodies were raised against SMAGP and humanized. DEM201 was selected as a clinical candidate and is specific for human SMAGP with sub-nanomolar (nM) affinity. DEM201 binds cell-associated SMAGP on cancer cell lines derived from GI, pancreatic and lung cancer and elicits potent ADCP and ADCC with sub-nM EC50. In vivo, DEM201 significantly inhibited the growth of SMAGP-expressing RKO tumor xenografts. To assess the potential of SMAGP inhibition in regulating both innate and adaptive immunity in vivo, we tested mAb255-mIgG2a, a SMAGP mAb with sub-nanomolar affinity to mouse SMAGP, in immunocompetent syngeneic tumor models. mAb255-mIgG2a potently inhibited the growth of H22 and Hepa1-6 liver cancer. A significant increase in CD8 T cells and macrophages was observed in H22 tumors after treatment with mAb255-mIgG2a. All SMAGP mAb treatments were well-tolerated, clearing the way for DEM201 IND-enabling activities. Citation Format: Sarah E. Carden, Agnieszka Denslow, Mary Baumel, Jing Zhu, Lissette Garcia, Sarah Nesti, Kayla Belanger, Meghan Davis, Carmen Adriaens, Sandeep Kumar, Christophe Quéva, Loise Francisco. Development of DEM201, a blocking antibody against SMAGP, a novel “Don′t Eat Me” signal overexpressed in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4254.