Development of a STEAP1-Targeted Prostate Cancer Specific Antibody Drug Conjugate Platform with Immunostimulatory...

Patients with prostate cancer who develop androgen pathway modulation resistant (APMR) disease face lethal outcomes despite advances in androgen receptor-pathway inhibitors, chemotherapy, and PSMA-directed radioligands. Antibody-drug conjugates (ADCs) have demonstrated transformative efficacy in multiple malignancies, yet ADCs evaluated in patients with metastatic APMR have largely focused on direct tumor cytotoxicity without assessing immune mechanisms that may underpin durable therapeutic responses. Whether immune activation contributes to ADC efficacy in prostate cancer remains unexplored.

We applied immune-centric design principles to ADC development targeting six transmembrane epithelial antigen of the prostate 1 (STEAP1), a prostate-lineage restricted, androgen receptor-regulated surface antigen. vandortuzumab-based ADCs were generated using multiple clinically validated linker-payload platforms. Constructs were evaluated using in vitro assays of Fcγ receptor engagement, antigen presentation, and T-cell activation, followed by in vivo testing in bone-metastatic and syngeneic immunocompetent APMR models.

STEAP1 specific Fcγ receptor engagement was required for optimal antigen presentation and downstream T-cell activation. Among tested payloads, exatecan-based ADCs demonstrated the strongest immunostimulatory activity. In bone-metastatic and immunocompetent APMR models, vandortuzumab-exatecan mediated durable tumor control and induced adaptive immune memory capable of preventing tumor rechallenge.

These findings identify immune activation as an important determinant of ADC efficacy in APMR and demonstrate that vandortuzumab-exatecan functions as an immune-engaging ADC capable of inducing durable anti-tumor responses. Incorporating immune activation into ADC design may improve the therapeutic potential of ADCs for patients with advanced prostate cancer.