Preclinical efficacy of a PSMA-targeted actinium-225 conjugate (225Ac-macropa-pelgifatamab) - a targeted alpha therapy for prostate cancer.

Initially, prostate cancer responds to hormone therapy but eventually resistance develops. Beta emitter-based PSMA (prostate-specific membrane antigen)-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.

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.

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.

These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase 1 study has been initiated (NCT06052306).

Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Apr 09 [Epub ahead of print]

Christoph A Schatz, Sabine Zitzmann-Kolbe, Ingrid Moen, Monika Klotz, Shankari Nair, Stefan Stargard, Roger M Bjerke, Katrine Wickstrøm Biseth, Yuan Zeng Feng, Bård Indrevoll, Véronique Cruciani, Jenny Karlsson, Bernard Haendler, Carsten H Nielsen, Maria Z Alfsen, Stefanie Hammer, Hartwig Hennekes, Alan Cuthbertson, Urs B Hagemann, Aasmund Larsen

Bayer Pharma AG, Berlin, Germany., Bayer AG, Berlin, Germany., Bayer (Norway), Oslo, Norway., Bayer AS, Oslo, Norway., Bayer AS, Norway., Bayer AG, Berlin, Berlin, Germany., Minerva Imaging ApS, Ølstykke, Denmark., Bayer, Oslo, Norway.