# Phase I dose-escalation study of 225Ac-J591, a PSMA-targeting alpha-emitting antibody, in mCRPC

Source: https://nuclide.cc/key-papers/paper-tagawa-ac225-j591-jco-2024/  
Nuclide record `paper-tagawa-ac225-j591-jco-2024` (Key paper). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

The first human test of an alpha-emitting radioactive drug attached to an antibody (rather than a small molecule) against PSMA found a safe dose in men with advanced prostate cancer who had exhausted other treatments, and shrank the PSA marker in nearly half of them - including those whose cancer had already stopped responding to the more common lutetium-177 PSMA treatment.

## Summary

This first-in-human phase 1 dose-escalation trial tested 225Ac-J591 - the anti-PSMA monoclonal antibody J591 labelled with the alpha emitter actinium-225 - as a single intravenous dose in 32 men with progressive metastatic castration-resistant prostate cancer who had received or were ineligible for taxane chemotherapy and an androgen receptor pathway inhibitor. Unlike PSMA-617 or PSMA-I&T, J591 is a full antibody rather than a small peptidomimetic ligand, giving different pharmacokinetics (slower clearance, longer tumour residence). Patients were treated across seven dose levels (13.3 to 93.3 kBq/kg) without pre-selection by PSMA PET.

One dose-limiting toxicity (grade 4 anaemia and thrombocytopenia) occurred at 80 kBq/kg; none occurred at the highest dose level tested (93.3 kBq/kg), so a maximum tolerated dose was not reached and the recommended phase 2 dose was set at the top studied level. Most high-grade adverse events were haematological and dose-related; non-haematological toxicity was generally low grade - a different pattern from PSMA-617-based alpha agents, where xerostomia (dry mouth) from salivary gland uptake dominates, since antibodies clear the salivary glands less than small-molecule ligands. Efficacy signals were encouraging for a phase 1, dose-finding, unselected population: 46.9% of patients had a PSA decline of 50% or more at some point, 34.4% had a confirmed PSA50 response, and 59.1% had control of circulating tumour cells, with responses seen regardless of prior 177Lu-PSMA exposure.

As one of the first published clinical results for an antibody-based (rather than small-molecule) PSMA alpha-emitter, this trial supports antibody-delivered alpha therapy as a second route to targeted alpha therapy in prostate cancer, potentially with a different toxicity trade-off (more marrow suppression, less xerostomia) than PSMA-617-based agents, and without requiring PSMA PET pre-selection.

## Fields

- Kind: Key paper
- Last checked: 2026-09-22
- Tags: alpha therapy; prostate cancer; phase 1
- Journal: JCO
- Year: 2024
- DOI: 10.1200/JCO.23.00573
- Authors: Tagawa ST, Thomas C, Sartor AO, Sun M, Stangl-Kremser J, et al.
- Findings: Recommended phase 2 dose was the highest studied level, 93.3 kBq/kg; maximum tolerated dose was not reached across seven dose levels.; One dose-limiting toxicity (grade 4 anaemia and thrombocytopenia) occurred, at 80 kBq/kg; none at the highest dose level.; 46.9% of patients had a PSA decline of 50% or more at any time; 34.4% had a confirmed PSA50 response.; Circulating tumour cell count control occurred in 13 of 22 evaluable patients (59.1%); responses were seen regardless of prior 177Lu-PSMA treatment.; High-grade adverse events were predominantly haematological and radioactivity-dose related; non-haematological toxicity was generally low grade.
- What it means: An alpha-emitting radioactive drug built on a PSMA-targeting antibody, rather than the small-molecule ligands used in existing PSMA therapies, was safe enough to move into further testing and shrank PSA in roughly a third to a half of heavily pre-treated men, including some whose cancer had already stopped responding to lutetium-177 PSMA therapy.
- Caveats: Small, single-arm, phase 1 dose-escalation trial (32 patients) - not designed or powered to show a survival or definitive efficacy benefit.; No PSMA PET pre-selection was used, unlike VISION and TheraP, so response rates are not directly comparable to those trials.; Blood toxicity (anaemia, thrombocytopenia) tracked with dose, which will need careful management as the drug moves into larger trials.

## Sources

- PubMed record: https://pubmed.ncbi.nlm.nih.gov/37922438/
- ASCO Publications: full text: https://ascopubs.org/doi/10.1200/JCO.23.00573

## Connected records

- drugs: [Actinium-225 PSMA agents](https://nuclide.cc/drugs/ac225-psma/)
- technologies: [Targeted alpha therapy](https://nuclide.cc/technologies/targeted-alpha-therapy/)
- targets: [PSMA](https://nuclide.cc/targets/psma/)
- indications: [Metastatic castration-resistant prostate cancer](https://nuclide.cc/indications/prostate-mcrpc/)
- people: [A. Oliver Sartor](https://nuclide.cc/people/oliver-sartor/)
- pairings: [Beta radioligand → alpha radioligand](https://nuclide.cc/pairings/beta-then-alpha/)
- isotopes: [Actinium-225](https://nuclide.cc/isotopes/ac-225/), [Lutetium-177](https://nuclide.cc/isotopes/lu-177/)

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