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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most devastating and lethal cancer. PDAC patients with the current standard of care produce dismal overall survival benefits with high toxicities. Thus, there is an unmet clinical need to develop targeted therapeutics against PDAC. Approximately 50 to 70% of PDAC patients overexpress MUC16, which is associated with disease progression, metastasis, drug resistance, and poor patient survival. We demonstrated that MUC16 enhances PDAC tumor growth via binding and activating epidermal growth factor (EGF) receptor family members and its downstream target PI3K/AKT signaling pathways. Here, we show the efficacy of humanized anti-MUC16 antibody (huAR9. 6) against MUC16-positive PDAC. Methods: We tested the in vitro efficacy of humanized anti-MUC16 antibody (huAR9. 6) against MUC16+ PDAC cells, patient-derived xenografts (PDXs), and patient-derived organoids (PDOs). We evaluated the in vivo therapeutic efficacy of the huAR9. 6 antibody in MUC16+ PDAC cells implanted in subcutaneous and orthotopic tumor models. Fucosylated and afucosylated huAR9. 6 induced direct tumor-killing activity was evaluated by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with MUC16 positive PDAC cells. Results: Treatment with huAR9. 6 reduced the in vitro growth, migration, invasion, and clonogenicity of MUC16+ PDAC cells and patient-derived organoids (PDOs). HuAR9. 6 blocked MUC16-mediated ErbB and AKT activation in PDAC, PDOs, and PDX-derived cells. HuAR9. 6 treatment induces ADCC and CDC against MUC16+ cells. Removing fucose residue on the N-glycans of the huAR9. 6-IgG substantially increased huAR9. 6’s ADCC activity. More importantly, huAR9. 6 treatment caused PDAC regression in subcutaneous and orthotopic tumor models. Conclusion: The results of this study validate the translational therapeutic potential of huAR9. 6 against MUC16-positive PDACs (detected in ∼ 50-70% of patients). Citation Format: Cory L Brooks, Prakash Radhakrishnan. MUC16 - Potential Target for Antibody-based Immunotherapy in Pancreatic Cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr B033.
Brooks et al. (Sun,) studied this question.