Newest radiopharmaceutical: thorium-227 PSMA antibody

Bayer has announced a new clinical trial of the latest entry in the race for radiopharmaceuticals to treat prostate cancer, joining 177Lu PSMA-617, 225Ac PSMA-617, and 131I MIP-1095. They are trying thorium-227 attached to a PSMA antibody.

Thorium-227, like actinium-225, is an α-particle emitter. Alpha-emitters are very powerful, but very short range, only killing cells that are two to 10 cells away from the cancer cell it attaches to. This may limit its toxicity, but may require higher doses for larger, more widespread tumors.  By contrast, beta-emitters, like lutetium-177, are less powerful, but the β-particle penetrates to a much greater depth, affecting about 125 cells. Researchers at the University of Heidelberg are experimenting with mixtures of the two.

The other part of the equation is the ligand that the radioactive atom is attached to and that attaches to the PSMA protein on the prostate cancer cell. Ligands include PSMA-617, PSMA-I&T, MIP-1095, and J591. Ligands may be small molecules, antibodies, or “minibodies.” Bayer is using a proprietary antibody-type ligand that they developed for the purpose. Ligands that are more specific for PSMA have less toxicity.

On the other side of the ligand molecule, it must bind very tightly to the radioactive element. If it doesn’t, the radioactive element might be released into systemic circulation where it can damage healthy cells. Heavy metals, like thorium, are attached relatively weakly by a process called “chelation,” but some chelators are stronger than others. Researchers have so far been unsuccessful in developing a stable chelate for radium-223 (the main therapeutic ingredient in Xofigo, which is also manufactured by Bayer) to a PSMA ligand.

Thorium-227 decays into radium-223, so it is unknown if the thorium chelate will continue to hold as it decays. However, Bayer has already initiated two clinical trials for thorium-227 chelated to an antibody for non-Hodgkin’s lymphoma (since 2015), and for ovarian cancer and mesothelioma (since April this year), which have not been terminated for excess toxicity. There is every reason to hope that the chelation complex they devised for the PSMA antibody ligand holds up in biological systems.

This is a dose-finding (Phase I) clinical trial among 108 patients with metastatic castration-resistant prostate cancer (mCRPC). They list four locations that will be recruiting patients: at Memorial Sloan-Kettering Cancer Center in New York City, as well as at locations in the UK, Finland, and Sweden.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

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