Abstract 5675: MUC1-C-directed exatecan ADC induces genotoxic stress and transcriptional suppression of UPR-inflammatory pathways in metastatic colorectal cancer.

Abstract Background: Metastatic colorectal cancer (mCRC) remains a major cause of cancer mortality and MUC1 is overexpressed in most tumors. However, no approved therapies target the tumor-anchored MUC1 antigen. The MUC1 oncoprotein consists of MUC1-N and MUC1-C, which form a heteromeric complex on the cell surface. The MUC1-N is shed into circulation and is highly heterogeneous in its glycosylation patterns across tumor types, creating both an antigen sink and unpredictable epitope presentation. This glycosylation variability can sequester MUC1-N-directed antibodies and significantly reduce consistent target engagement. In contrast, the membrane-anchored MUC1-C remains structurally accessible and uniform, representing a more reliable target for ADC development and addressing a critical unmet need in mCRC therapy. Methods: We generated a first-in-class exatecan-based antibody-drug-conjugate (XYA02-8) recognizing the α4 helix within the extracellular domain of MUC1-C through a cleavable linker *. In vitro, cellular and patient-derived xenograft studies were perfomed to evaluate anti-tumor potency and safety of XYA02-8. Results: The anti-MUC1-C monoclonal antibody displayed high-affinity binding to the MUC1-C extracellular domain and robust, ligand-driven internalization across multiple mCRC cell lines. Conjugation to exatecan via a cleavable linker yielded XYA02-8, an optimized ADC with >98% monomeric purity and a DAR of 8. XYA02-8 induced potent cytotoxicity in vitro, achieving low-nanomolar IC50 values across a panel of MUC1-expressing mCRC models. In SW620 xenografts, QW dosing x 3 at 7.5 mg/kg generated pronounced tumor growth inhibition without measurable body-weight loss or overt systemic toxicity. Transcriptomic profiling revealed a dominant exatecan-associated DNA-damage and replication-stress signature, repression of UPR regulators (DDIT4, STC2), and attenuation of pro-inflammatory signaling, concordant with increased γH2AX induction and PARP cleavage. In a MUC1-positive mCRC PDX, XYA02-8 produced substantial tumor regression with minimal toxicity, and efficacy was recapitulated in NCG mice treated at 5 mg/kg QW ×3. High-dose escalation (10× therapeutic level) resulted in negligible changes in hematologic or serum chemistry parameters, supporting a strong preclinical safety margin. Conclusion: XYA02-8, a first-in-class MUC1-C-directed exatecan ADC, demonstrates potent and selective antitumor activity driven by efficient internalization, high DAR stability, and targeted induction of DNA-damage and replication-stress programs. Its robust efficacy across CDX and PDX models, coupled with minimal systemic toxicity at supra-therapeutic doses, positions XYA02-8 as a strong candidate for clinical translation in MUC1-positive mCRC. Citation Format: Surender Kharbanda, Deepak Raina, Rehan Ahmad, Changchuin Mao, Sourav Choudhary, Brian Lawney, Nandita Sreenivasalu, Govind Panchamoorthy, Ravi Jasuja. MUC1-C-directed exatecan ADC induces genotoxic stress and transcriptional suppression of UPR-inflammatory pathways in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5675.