Abstract 338: Innovative strategy for enhancing the reach of HER3 antibody-drug conjugates: A novel drug combination approach
Authors: Kathryn E. Vanderlaag, Anukriti Dhar, Arisa Paul, Molly I. Volkman, Erik M. Werner, Transon V. Nguyen, Kamran A. Ali
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADC) and radioligand therapies (RLT) have emerged as promising treatment modalities for various cancers. In recent years, there have been numerous approvals of ADCs and RLTs by regulatory agencies, highlighting their clinical success. Despite their success, they still suffer from a common challenge: tumor heterogeneity. Tumor heterogeneity limits not only the patient response, but also the eligible patient population for these therapies. To address this challenge, we have developed a high throughput screening platform to identify small molecule “priming” agents that selectively upregulate tumor antigens in cancer, but not in normal cells. We have demonstrated that by increasing expression of target antigens on cancer cells, priming agents sensitize tumors to ADCs and can thus improve their efficacy and therapeutic window. Our priming screens thus far included evaluating priming agents for HER3, B7-H4, FR-A, TROP2, HER2, NECTIN-4, and CD123. Additionally, DLL3, c-MET, and SSTR2 are scheduled for early next year. Our lead program focuses on HER3, where we have utilized our library to identify priming agents that upregulate HER3 cell surface expression by 2-3 fold across breast and ovarian cancer cell lines, demonstrating potential for indication-agnostic applications. Mechanistic validation has been achieved through the use of multiple inhibitors within the same pathway, which exhibit similar priming effects. Notably, HER3 upregulation is cancer-selective, with expression levels remaining low in normal cells. Ongoing experiments aim to further elucidate the underlying mechanism, and we have initiated medicinal chemistry efforts to advance this program. Utilizing a priming approach in conjunction with an ADC or radiopharmaceutical offers three distinct advantages that lead to best-in-class or first-in-class therapies: Patient Population Expansion: The priming approach enables the treatment of a broader range of cancer patients by overcoming tumor heterogeneity. Reduced Toxicity: The ability to lower the dose of the ADC or radiopharmaceutical while maintaining efficacy reduces the risk of adverse effects and enhances patient safety. Improved Durability of Responses: By addressing tumor heterogeneity, the priming approach enhances the durability of patient responses, leading to longer-lasting remissions. By leveraging the potential of ADC and RLT (radioligand therapy), the priming approach opens up new avenues for more effective and personalized cancer treatments. Citation Format: Kathryn E. Vanderlaag, Anukriti Dhar, Arisa Paul, Molly I. Volkman, Erik M. Werner, Transon V. Nguyen, Kamran A. Ali. Innovative strategy for enhancing the reach of HER3 antibody-drug conjugates: A novel drug combination approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 338.