Summary: A new chelator significantly reduces off-target toxicity in PSMA radiopharmaceutical therapy by improving the bond between the radiometal and the PSMA-targeting antibody, making the treatment safer and more effective.

Key Takeaways:

  1. The new chelator L804 significantly reduces off-target toxicity in PSMA radiopharmaceutical therapy by improving the stability of the bond between the radiometal and the PSMA-targeting antibody.
  2. Studies showed that L804 attached to minibody conjugates resulted in lower accumulation of radioactivity in non-target tissues and prolonged survival in treated mice compared to existing chelators.
  3. L804’s ability to chelate both 89Zr and 177Lu enhances its potential for theranostic applications in PET imaging and radiopharmaceutical therapy for prostate cancer.

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A newly developed chelator can significantly reduce off-target toxicity in prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy, according to research presented at the 2024 Society of Nuclear Medicine and Molecular Imaging Annual Meeting. By improving the bond between the radioactive metal ion and the PSMA-targeting antibody, the chelator can make PSMA therapy safer and more effective for patients.

Reducing Off-Target Toxicity in PSMA Therapy

Targeted radiopharmaceutical therapy agents require a chelator to bind the radiometal to the cancer-targeting part of the molecule. This ensures that the radiometal does not leak out and cause toxicity to bone marrow, spleen, or the normal clearance organs. In PSMA radiopharmaceutical therapy, there is typically off-target localization in the salivary glands and other tissues. One of the goals of testing the new chelator was to see if toxicity is mitigated by more stably chelating the therapeutic radiometal, in this case Lu-177.

“Reducing off-target toxicity of targeted radiopharmaceutical therapy is essential, especially as PSMA radiopharmaceutical therapy continues to expand,” says Carolyn Anderson, PhD, Simón-Ellebracht Professor in Medicinal Chemistry and professor of Radiology at the University of Missouri in Columbia. “A better chelator means that the radiometal accumulates mostly in the tumor, and what does not go to the tumor rapidly clears out of the body. A weaker chelator can cause radiometal to accumulate in off-target locations, leading to slower clearance and contributing to increased toxicity.”

Promise in Prostate Cancer Treatment

In the study, a newly developed chelator (L804) was attached to the small antibody IAB2MA to create minibody conjugates and radiolabeled with 89Zr and 177Lu (177Lu-L804-IAB2MA and 89Zr-L804-IAB2MA). Similar conjugates were also created using the current gold standard chelators DOTA and DFO (177Lu-DOTA-IAB2MA and 89Zr-DFO-IAB2MA). Preclinical biodistribution, imaging, dosimetry, and efficacy studies were performed in a mouse model of prostate cancer.

Results from in vivo studies showed a significantly lower accumulation of radioactivity in tumor-bearing mice following treatment with 177Lu- and 89Zr-L804-IAB2MA compared to 177Lu-DOTA-IAB2MA and 89Zr-DFO-IAB2MA. Dosimetry analysis indicated significantly lower absorbed doses of 177Lu-L804-IAB2MA in tumor, kidney, liver, and muscle compared to 177Lu-DOTA-IAB2MA. In addition, mice treated with single doses of 177Lu-L804-IAB2MA exhibited significantly prolonged survival and reduced tumor volume compared to unlabeled minibody control.

L804-IAB2MA Enhances Imaging and Treatment

“The relative merits of stronger chelation are demonstrated here on a well-validated cancer target, using a modified version of a well-studied antibody that has been engineered to be smaller and clear more rapidly from the body,” says Anderson. “Another advantage of L804-IAB2MA is that it chelates both 89Zr and 177Lu, so only one compound is needed for both radiometals. L804-IAB2MA has strong theranostic potential for 89Zr PET imaging and 177Lu radiopharmaceutical therapy of prostate cancer.”

Featured image: Small animal SPECT/CT images comparing 177Lu-L804-IAB2MA and 177Lu-DOTA-IAB2MA, and small animal PET/CT images comparing 89Zr-L804-IAB2MA and 89Zr-DFO-IAB2MA. These images demonstrate similar tumor targeting and improved clearance of 177Lu-L804-IAB2MA compared to 177Lu-DOTA-IAB2MA, while showing comparable performance of 89Zr-L804-IAB2MA and 89Zr-DFO-IAB2MA.