Targeting Sialyl-Thomsen Nouveau (Stn) Antigen With The Sgn-Stnv Antibody-Drug Conjugate Is Effective In Preclinical Studies.

Abstract Targeting glyco-epitopes with antibody-drug conjugates (ADCs) provides a unique advantage as multiple cell surface proteins expressing the same carbohydrate can be harnessed to deliver drug. Sialyl-Thomsen nouveau (STn) is a tumor associated carbohydrate antigen that has historically been difficult to target with specificity. Using glycan array screening, h2G12 was identified as a highly specific human IgG1 antibody, that exclusively binds the STn glyco-epitope independent of protein backbone. Here we introduce SGN-STNV, an investigational antibody-drug conjugate (ADC) targeting monomethyl auristatin E (MMAE) to STn expressing tumor cells with the clinically validated vedotin linker technology. STn has restricted normal tissue expression and is expressed on various solid tumors including ovarian, non-small cell lung, gastric, and endometrial carcinomas. Our work shows correlation of enzyme ST6GALNAC1 expression with STn expression on tumors. Given the frequent O-glycosylation of mucins, we also confirmed high STn expression in mucinous subtypes of ovarian, pancreatic, colorectal, and lung adenocarcinomas. Previous reports have confirmed STn is found on mucins MUC1, MUC5A, and MUC16 (CA-125), as well as cell surface receptors CD44 and integrin β1. These proteins are known to play functional roles in tumor progression and, importantly for ADC delivery, they internalize well to deliver cytotoxic payload. We sought to identify other proteins that may contribute to cytotoxic activity of SGN-STNV and determined that additional surface receptors are tagged with STn. These receptors are internalized and likely contribute to SGN-STNV activity. After binding to STn, SGN-STNV is internalized into cells and releases the microtubule inhibitor MMAE to drive mitotic arrest, apoptosis, and to induce immunogenic cell death. SGN-STNV further mediates anti-tumor response through Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In preclinical xenograft studies, SGN-STNV monotherapy treatment leveraged h2G12 specificity and ability to target STn on multiple tumor associated proteins to drive durable tumor regressions. SGN-STNV was well tolerated in non-human primates (NHP), with no concerning target-mediated toxicities and a maximum tolerated dose similar to other vedotin-platform ADCs. In summary, the antibody specificity, unique mechanism of targeting a carbohydrate, anti-tumor activity, and tolerability provide a strong rationale for initiation of a phase I study to investigate the therapeutic potential of SGN-STNV. Citation Format: Alyssa Schwartz, Hector Rincon, Nanna Hansen, Robert Lawrence, Sarah Anderson, Nicole Blesie, Kerry Klussman, Angela Epp, Shyra Gardai, William Arthur. Targeting Sialyl-Thomsen nouveau (STn) antigen with the SGN-STNV antibody-drug conjugate is effective in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 50.