1. Academic Validation
  2. Preclinical Efficacy of a PSMA-Targeted Actinium-225 Conjugate (225Ac-Macropa-Pelgifatamab): A Targeted Alpha Therapy for Prostate Cancer

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

  • Clin Cancer Res. 2024 Jun 3;30(11):2531-2544. doi: 10.1158/1078-0432.CCR-23-3746.
Christoph A Schatz 1 Sabine Zitzmann-Kolbe 1 Ingrid Moen 2 Monika Klotz 1 Shankari Nair 1 Stefan Stargard 1 Roger M Bjerke 2 Katrine Wickstrøm Biseth 2 Yuan Zeng Feng 2 Bård Indrevoll 2 Veronique Cruciani 2 Jenny Karlsson 2 Bernard Haendler 1 Carsten H Nielsen 3 Maria Z Alfsen 3 Stefanie Hammer 1 Hartwig Hennekes 1 Alan Cuthbertson 2 Urs B Hagemann 1 Åsmund Larsen 2
Affiliations

Affiliations

  • 1 Bayer AG, Berlin, Germany.
  • 2 Bayer AS, Oslo, Norway.
  • 3 Minerva Imaging, Oelstykke, Denmark.
Abstract

Purpose: 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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163608
    Actinium-225偶联物