PSMA and Beyond 2025: 212Pb-PSMA vs 225Ac-PSMA: from Biology to Supply

(UroToday.com) The 2025 PSMA and Beyond annual meeting featured an alpha and other radionuclides session and a presentation by Dr. Alfred Morgenstern discussing ²¹²Pb-PSMA versus ²²⁵Ac-PSMA. Dr. Morgenstern started his presentation by emphasizing that ²¹²Pb versus ²²⁵Ac are two promising alpha emitters:

The supply of ²¹²Pb comes from ²²⁸Th via extraction from natural ore and from neutron irradiation of ²²⁶Ra:

There are several generator principles for ²¹²Pb:

• Extraction from ²²⁸Th solutions requires an industrial environment
• ²²⁸Th/²¹²Pb generators via emanation of ²²⁰Rn are potentially useful in hospital settings
• ²²⁴Ra (3.6 days)/ ²¹²Pb generators is easier for distribution, but only for short use
• The 10.6 hour half-life of ²¹²Pb allows for centralized GMP production and distribution of ²¹²Pb radiopharmaceuticals

Dr. Morgenstern emphasized that alpha emitters induce a strong immune response but with a 22.5 times shorter half-life of ²¹²Pb compared to ²²⁵Ac. Thus, it is a good match for pharmacokinetics of many ligands. ²¹²Pb has a more rapid deposition of dose and production of radicals, but what are the differential effects on immune response activation?

Pathway analysis has identified biological pathways modulated after ²¹²Pb-ADVC001 treatment, with (i) early response – DNA damage repair, and cell cycle, growth and metabolism; (ii) intermediate response – DNA damage repair, and cell cycle, growth and metabolism, immune response regulation, and cell senescence and death; and (iii) late response – other signaling (resistance?):

Additionally, pathway analysis reveals very similar pathways dysregulated in ¹⁷⁷Lu- and ²¹²Pb-PSMA treated tumors. ²¹²Pb-PSMA affects pathways unaffected by ¹⁷⁷Lu-PSMA, including several related to cell cycle regulation. Dr. Morgenstern then discussed the following table of clinical studies using ²¹²Pb in prostate cancer:

Published on March 13, 2025, Berner and colleagues¹ reported a first-in-human phase 0 study of AB001, a PSMA-targeted ²¹²Pb radioligand among patients with mCRCP. The primary objective was the feasibility of gamma-camera imaging to assess biodistribution and uptake in metastatic lesions. A low dose of 9.4 +/- 0.3 MBq of AB001 was administered to 3 patients and found to be safe, and stable in vivo, and imaging was feasible but needs further investigation. Phase I studies are in preparation with a higher dose:

A phase I/II trial of ²¹²Pb-ADVC001 is currently enrolling at 60 MBq, 120 MBq, and 200 MBq, with no signs of myelosuppression and no grade 3 symptomatic adverse events. There has been low salivary gland uptake, with only grade 1 xerostomia, and no treatment discontinuation. The trial design is as follows:

²¹²Pb-ADVC001 at 60 MBq was initially reported in April 2024 [2], showing low salivary gland uptake and rapid kidney clearance:

Even at 160 MBq, ²¹²Pb-ADVC001 shows favorable biodistribution with low salivary gland uptake:

Dr. Morgenstern concluded his presentation discussing ²¹²Pb-PSMA versus ²²⁵Ac-PSMA with the following take-home points:

• ²²⁵Ac-PSMA and ²¹²Pb-PSMA are promising compounds for therapy of prostate cancer
• The therapeutic efficacy of ²¹²Pb-PSMA is still under investigation
• Half-lives of ²¹²Pb (10.6 hours) and ²²⁵Ac (9.9 days) allow for combination with ligands of different pharmacokinetics
• Securing a supply of ²¹²Pb and ²²⁵Ac is crucial for further development

Presented by: Alfred Morgenstern, PhD, Joint Research Centre, Karlsruhe, Germany

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 PSMA and Beyond Annual Meeting, Los Angeles, CA, Fri, Mar 28 – Sat, Mar 29, 2025. 

References:

1. Berner K, Hemes E, Kvassheim M, et al. First-in-human phase 0 study of AB001, a prostate-specific membrane antigen-targeted ²¹²Pb radioligand, in patients with metastatic castration-resistant prostate cancer. J Nucl Med. 2025 Mar 13 [Epub ahead of print].
2. Griffiths MR, Pattison DA, Latter M, et al. First-in-human ²¹²Pb-PSMA-Targeted alpha-therapy SPECT/CT imaging in a patient with metastatic castration-resistant prostate cancer. J Nucl Med. 2024;65(4):664.