Annotating STEAP1 Regulation in Prostate Cancer with Zr-89 Immuno-PET

Antibodies and antibody-drug conjugates targeting the cell surface protein 6 transmembrane epithelial antigen of prostate 1 (STEAP1) are in early clinical development for the treatment of castration-resistant prostate cancer (PCa). In general, antigen expression directly affects the bioactivity of therapeutic antibodies, and the biologic regulation of STEAP1 is unusually complicated in PCa. Paradoxically, STEAP1 can be induced or repressed by the androgen receptor (AR) in different human PCa models, while also expressed in AR-null PCa. Consequently, there is an urgent need to translate diagnostic strategies to establish which regulatory mechanism predominates in patients to situate the appropriate therapy within standard of care therapies inhibiting AR. Methods: To this end, we prepared and evaluated Zr-89-labeled MSTP2109A (Zr-89-2109A), a radiotracer for PET derived from a fully humanized monoclonal antibody to STEAP1 in preclinical PCa models. Results: Zr-89-2109A specifically localized to the STEAP1-positive human PCa models CWR22Pc, 22Rv1, and PC3. Moreover, Zr-89-2109A sensitively measured treatment-induced changes (similar to 66% decline) in STEAP1 expression in CWR22PC in vitro and in vivo, a model we showed to express STEAP1 in an AR-dependent manner. Conclusion: These findings highlight the ability of immuno-PET with Zr-89-2109A to detect acute changes in STEAP1 expression and argue for an expansion of ongoing efforts to image PCa patients with Zr-89-2109A to maximize the clinical benefit associated with antibodies or antibody-drug conjugates to STEAP1.