UPDATE: TD001 a New Potent ADC for Prostate Cancer Expressing PSMA Enters Phase 1/2

TD001, is an investigational antibody-drug conjugate directed against prostate-specific membrane antigen (PSMA), developed for the treatment of men with metastatic castration-resistant prostate cancer whose tumors express PSMA will start recruiting patients for its phase 1/2 clinical trial.

Mechanistically, TD001 combines a monoclonal antibody directed against PSMA with a topoisomerase I inhibitor payload, exatecan, linked through a cleavable linker engineered to be stable in circulation yet efficiently release the drug after internalization into PSMA-expressing tumor cells. This design leverages the high and relatively selective expression of PSMA on prostate cancer cells to deliver a potent DNA-damaging agent directly into malignant tissue, aiming to improve the therapeutic index compared with systemic chemotherapy. Preclinical work in xenograft and patient-derived models has shown robust tumor uptake of TD001, high tumor-to-plasma exposure ratios, and sustained tumor growth inhibition after single or intermittent dosing, including in models with heterogeneous or intermediate PSMA expression where some other PSMA-directed modalities perform less consistently. The bystander effect of the exatecan payload, enabled by the membrane-permeable nature of the released drug, may allow killing of adjacent tumor cells with lower antigen density, which is particularly attractive in the context of heterogeneous PSMA expression typical of advanced disease.​

An important conceptual aspect of this program is its positioning relative to other PSMA-directed agents. Radioligand therapies require sufficient and homogeneous PSMA expression and are constrained by radiation logistics and cumulative dose limits, while bispecific T cell engagers can be limited by cytokine release and immune-mediated toxicities. In contrast, TD001 seeks to exploit the validated PSMA target while using a cytotoxic payload class that has already shown success in other tumor types when deployed via antibody-drug conjugates, potentially allowing broader use in patients with lower or heterogeneous PSMA expression as long as target presence remains adequate for internalization.

Clinical trial.