Characterization of TAG-72, a glycan-based ADC target and its pan-tumor expression profile

Background: Tumor-Associated Glycoprotein 72 (TAG-72) is a cancer-specific glycoepitope displayed on mucins and expressed across epithelial cancers, predominantly adenocarcinomas. Initially studied using the B72.3 and CC49 antibodies, TAG-72-expressing cancers lack optimal therapeutic approaches. TGW101, a novel antibody-drug conjugate (ADC) targeting non-internalizing TAG-72, incorporates a CC49-derived diabody and a DAR4 MMAE payload linked via a trans-cyclooctene-based linker that enables controlled cleavage following administration of a tetrazine small-molecule trigger. This ADC-trigger system is currently in phase I clinical development (NCT06959706) for select solid tumors that frequently express TAG-72. Here we present characterization of the TAG-72 glycoepitope, the development of fit-for-purpose TAG-72 IHC assays for patient selection, estimates of its prevalence across solid tumors, and its overlap with established predictive biomarkers used in standard-of-care settings for populations with unmet need. Methods: Glycan arrays were set up by GlycoDisplay, using engineered cells transfected with a range of probes containing mucin-like repeats. TAG-72 IHC assays were developed at NeoGenomics. Results: A cell-based glycan array analysis revealed that the CC49-diabody binding requires clustered Thomsen-nouvelle (Tn) and/or sialylated-Tn (STn) glycans on the tandem repeat domain of specific cancer-associated mucins, including MUC1, 2, 5AC, 6, 13, and 17, suggesting it is co-dependent on macrostructural glycan conformation. Optimized IHC using both B72.3 and CC49 anti-TAG-72 clones revealed highly specific staining, with positive staining of the duodenum luminal mucosa (known to be moderate or low positive) and absent staining in the duodenum submucosa, muscularis, and other normal tissues including kidney. Both B72.3 and CC49 IHC clones demonstrated highly similar staining patterns. Additionally, TAG-72 staining was observed in CDX and PDX xenograft models where tumor regressions occurred following treatment with TGW101. Initial screening of tumor microarrays indicated expression across a wide range of solid tumors, with highest expression in adenocarcinomas and mucinous tumors. Scoring criteria, biomarker overlap, and estimated prevalence for both B72.3 and CC49 clones by indication will be presented. Conclusions: TAG-72 is a tumor-associated glycoepitope consisting of STn and Tn glycans present on multiple mucin proteins. It is widely expressed in epithelial cancers, while almost entirely absent in normal tissues, making it an attractive therapeutic target. Current commercially available antibodies show excellent specificity using modern IHC techniques and could facilitate biomarker-driven clinical development for TAG-72-targeted therapies.