Abstract 5657: A novel bispecific ADC to treat solid tumors by removing immunosuppression in the tumor microenvironment.

Abstract TNBC remains one of the most aggressive breast cancers, with limited success from current antibody and immuno-oncology regimens, largely due to the persistence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We developed a novel dual-action bispecific antibody drug conjugate (ADC), TRIO-525, a first-in-class Tumor Immunogenicity Enhancing Antibody Conjugate (TIE-ADC) designed for tumor-selective, dual-targeted elimination of both cancer cells (via TROP2) and MDSCs (via CD33).Mechanistically, TRIO-525 utilizes a unique antibody format engineered for higher affinity to TROP2 and, tumor-selective engagement of CD33, enabling selective depletion of immunosuppressive MDSCs within the tumor while sparing hematopoietic and other immune cells. Preclinical studies confirmed TRIO-525’s receptor-mediated cytotoxicity. It demonstrated superior potency and specificity compared to existing therapies, with effective and selective killing of both TNBC cells and MDSCs at nanomolar concentrations, restoration of T cell proliferation, and full preservation of healthy immune cells. TRIO-525 induces robust, dose-dependent tumor regression in xenograft models without any toxicity or off-target effects. TRIO-525 also displays exceptional plasma stability with no degradation species.These findings establish TRIO-525 as a ground-breaking solution to generate immunogenic tumors, directly overcoming TME-driven immunosuppression—an unmet need in TNBC and solid tumor therapy. The development of TIE-ADC drugs, as exemplified by TRIO-525, signals a paradigm shift in cancer immunotherapy through simultaneous, tumor-selective eradication of malignant and immunosuppressive cells, with broad implications for overcoming therapeutic resistance and improving patient outcomes. Citation Format: Shiva Bhowmik, William Brady. A novel bispecific ADC to treat solid tumors by removing immunosuppression in the tumor microenvironment [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 5657.