Glycan-based site specific ADC achieves sustained tumor control through Improved payload delivery and immune activation

Antibody-drug conjugates (ADCs) achieve potent tumor killing but often limited to induce durable antitumor immunity. The Glycan conjugated platform enables site-specific glycan conjugation, enhancing pharmacokinetics (PK) and intratumoral payload delivery versus conventional cysteine-based ADCs. We hypothesized that this improved payload delivery capability by the Glycan conjugated ADC (OBI-902) would potentiate immunogenic cell death (ICD) and sustains antitumor immune activation relative to a cysteine-conjugated ADC (OBI-992). Efficacy and immune profiling were evaluated in LL2 syngeneic tumors overexpressing human Trop2. Intratumoral payload, and ICD markers (calreticulin, HSP70, HSP90) were assessed post-treatment. Tumor, lymph node, and blood immune subsets were analyzed by multiparametric flow cytometry, and serum cytokines quantified for systemic immune activation. OBI-902 demonstrated durable tumor growth inhibition and enhanced ICD in the tumor microenvironment, findings that were superior to those observed with OBI-992. Serum IFN-gamma, IL-12, and TNF-alpha elevations indicated systemic immune activation. In tumors, OBI-902 increased CD4⁺ and CD8⁺ T-cell and B-cell infiltration while reducing MDSCs. It also expanded cDC1s and upregulated their MHC-II expression, supporting improved antigen presentation. In tumor-draining lymph nodes, OBI-902 expanded progenitor-exhausted CD8⁺ T cells yet functional state while limiting terminal exhaustion. Peripheral immune profiling corroborated that OBI-902 increased T-cell proportions and reduced MDSCs. At study endpoint, OBI-902 sustained CD8⁺ T-cell functionality with higher CX3CR1 and lower CD39 expression, indicating preserved cytotoxicity and T-cell fitness. This readily accessible peripheral immune signatures may serve as pharmacodynamic biomarkers in clinical settings. The Glycan conjugated platform ADC (OBI-902), enabled by its more stable linker-payload design that delivers greater payload to the tumor, achieved sustained ICD induction and a profound reprogramming of T-cell exhaustion, driving robust innate and adaptive immune activation. These results highlight the Glycan conjugated platform as a next-generation ADC technology and strongly support its combination with immune checkpoint blockade in future clinical studies.