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.
Bhowmik et al. (Fri,) studied this question.