Targeting tumor-specific Tn-glycoforms of MUC1 and MUC4 with first-in-class antibody-drug conjugates: Preclinical efficacy and translational potential of GO-M100B and GO-M400

Aberrant O-glycosylation in epithelial cancers generates tumor-specific neoepitopes absent from normal tissues. GO Therapeutics has developed monoclonal antibodies that selectively recognize these Tn-glycoforms on mucins, including GO-M100B, targeting Tn-MUC1, and GO-M400, targeting Tn-MUC4. These antibodies bind aberrantly truncated O-glycans presented on mucin backbones with sub- to low-nanomolar affinity and exceptional site-specificity. These programs exemplify our “clean target” approach that exploits cancer-restricted glycoepitopes to enhance selectivity and therapeutic index. Structural and biochemical characterization revealed that M100B and M400 recognize proprietary glycopeptide neoepitopes unique to malignant epithelial cells, enabling precise tumor targeting. Immunohistochemistry confirmed broad reactivity across epithelial cancers. This includes breast, lung, ovarian, pancreatic, and gastrointestinal tumors. Negligible binding was seen to normal tissues. Both antibodies were engineered as site-specific antibody-drug conjugates (ADCs) using an mc-vc-PAB-MMAE linker to generate homogeneous DAR2 conjugates. These ADCs exhibited potent, selective cytotoxicity against Tn-positive cell lines, achieving sub-nanomolar IC₅₀ values, while showing no measurable activity in Tn-negative or primary normal cell models. In vivo, M100B-vedotin and M400-vedotin induced marked tumor regression in both cell-derived (CDX) and patient-derived xenograft (PDX) models, with favorable pharmacokinetics and clean toxicology profiles in cynomolgus monkeys and mice. By targeting cancer-specific glycosylation patterns on mucins, M100B and M400 expand the therapeutic frontier of “clean target” oncology. These next-generation ADCs demonstrate exceptional tumor selectivity, strong preclinical efficacy, and favorable safety, supporting advancement into IND-enabling studies and clinical development for multiple epithelial malignancies.