Data from Preclinical Efficacy of a PSMA-Targeted Actinium-225 Conjugate (²²⁵Ac-Macropa-Pelgifatamab): A Targeted Alpha Therapy for Prostate Cancer

AbstractPurpose: Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs. Experimental Design: The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of ²²⁵Ac-macropa-pelgifatamab (²²⁵Ac-pelgi) and other TATs were investigated in cell line– and patient-derived prostate cancer xenograft models. The antitumor efficacy of ²²⁵Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide. Results: Actinium-225-labeling of ²²⁵Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both ²²⁵Ac-pelgi and ²²⁵Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, ²²⁵Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with ²²⁵Ac-DOTA-pelgi, ²²⁵Ac-DOTA-J591, and ²²⁷Th-HOPO-pelgifatamab (²²⁷Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. ²²⁵Ac-pelgi was less myelosuppressive than ²²⁷Th-pelgi. ²²⁵Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line– (22Rv1) and patient-derived (ST1273) xenograft models. Conclusions: These results provide a strong rationale to investigate ²²⁵Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306).