![]() However, limitations of off-tissue on-target distribution of the antibody into normal tissues remain problematic, thereby limiting the potential for widespread patient benefit. ADCs have exhibited promising therapeutic results and several products have gained marketing authorization for the treatment of certain malignancies in patients. ADCs employ the exquisite specificity of mAbs for the targeted delivery of highly potent cytotoxic drugs to the tumor site. ![]() Because EDB+FN selectively accumulates in the stroma around new blood vessels in tumors and is largely absent in normal adult vasculature, EDB+FN is a promising target for drug development and tumor-specific delivery of cytotoxic payloads to the TME with an ADC. In solid tumors, EDB+FN is secreted by fibroblasts, myofibroblasts, and vascular smooth muscle cells and is associated with tumor growth, angiogenesis, and invasion ( 12). Therapies designed to target the TME, ECM, and stroma to date have had mixed results, and in some cases have been reported to promote worse outcomes ( 3–6).Įxtra domain B (EDB+FN) splice variant of fibronectin 1 consists of a 91 aa domain inserted into fibronectin 1 at the primary transcript level, is a non-internalizing, insoluble, ECM-associated protein, and is a marker of tissue remodeling and angiogenesis ( 7–11). The ECM not only serves as a structural and facilitating scaffold for tumor cell migration via the sequestration and directional concentration of cytokines, but also augments ability of the tumor to withstand harsh conditions such as hypoxia, high metabolic demand, and chemotherapeutic attack ( 2). Fibroblasts are the key TME cellular constituents responsible for laying down the ECM components, including the glycoprotein fibronectin. However, the components of the TME may limit the efficacy of these therapies by driving therapeutic resistance ( 2). Targeted cancer therapeutics, including small molecule inhibitors, monoclonal antibodies (mAbs), and antibody–drug conjugates (ADC), have been largely focused on taking advantage of the cancer cell-related molecular signatures or cell surface proteins to target cancer cells with cytotoxic and other inhibitory agents while minimally affecting normal cells. These data highlight the potential for EDB-ADC to specifically target the tumor microenvironment, provide robust therapeutic benefits against multiple tumor types, and enhance activity antitumor in combination with checkpoint blockade. In nonclinical safety studies in nonhuman primates, EDB-ADC had a well-tolerated safety profile without signs of either on-target toxicity or the off-target effects typically observed with ADCs that are conjugated through conventional conjugation methods. EDB-ADC and anti-PD-L1 combination in a syngeneic breast tumor model led to enhanced antitumor activity with sustained tumor regressions. EDB-ADC potentiated infiltration of immune cells, including CD3 + T lymphocytes into the tumor, providing rationale for the combination of EDB-ADC with immune checkpoint therapy. Increased phospho-histone H3, a pharmacodynamic biomarker of response, was observed in tumor cells distal to the target site of tumor ECM after EDB-ADC treatment. In patient-derived xenograft (PDX), cell-line xenograft (CLX), and mouse syngeneic tumor models, EDB-ADC, conjugated to auristatin Aur0101 through site-specific technology, demonstrated potent antitumor growth inhibition. EDB+FN is broadly expressed in the stroma of pancreatic, non–small cell lung (NSCLC), breast, ovarian, head and neck cancers, whereas restricted in normal tissues. We describe the generation, pharmacology, mechanism of action, and safety profile of an ADC specific for EDB+FN (EDB-ADC). We hypothesized that EDB+FN is a safe and abundant target for therapeutic intervention with an antibody–drug conjugate (ADC). Extra domain B splice variant of fibronectin (EDB+FN) is an extracellular matrix protein (ECM) deposited by tumor-associated fibroblasts, and is associated with tumor growth, angiogenesis, and invasion.
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