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

Author:

Schatz Christoph A.1ORCID,Zitzmann-Kolbe Sabine1ORCID,Moen Ingrid2ORCID,Klotz Monika1ORCID,Nair Shankari1ORCID,Stargard Stefan1ORCID,Bjerke Roger M.2ORCID,Wickstrøm Biseth Katrine2ORCID,Feng Yuan Zeng2ORCID,Indrevoll Bård2ORCID,Cruciani Veronique2ORCID,Karlsson Jenny2ORCID,Haendler Bernard1ORCID,Nielsen Carsten H.3ORCID,Alfsen Maria Z.3ORCID,Hammer Stefanie1ORCID,Hennekes Hartwig1ORCID,Cuthbertson Alan2ORCID,Hagemann Urs B.1ORCID,Larsen Åsmund2ORCID

Affiliation:

1. 1Bayer AG, Berlin, Germany.

2. 2Bayer AS, Oslo, Norway.

3. 3Minerva Imaging, Oelstykke, Denmark.

Abstract

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).

Funder

Bayer AG

Publisher

American Association for Cancer Research (AACR)

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