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
  • 1. Bayer AG, Berlin, Germany.
  • 2. Bayer AS, Oslo, Norway.
  • 3. Minerva Imaging, Oelstykke, Denmark.
PMID: 38593212 DOI: 10.1158/1078-0432.CCR-23-3746
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).

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