A novel chelator may significantly reduce off-target toxicity in prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy, according to new findings presented by Ho et al at the 2024 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting (Abstract 242340).
Background
Targeted radiopharmaceutical therapy agents require a chelator to bind the radiometal to the cancer-targeting part of the molecule. This often ensures that the radiometal doesn’t cause toxicity to the bone marrow, spleen, or normal clearance organs. In PSMA radiopharmaceutical therapy, there is typically off-target localization in the salivary glands and other tissues.
“Reducing off-target toxicity of targeted radiopharmaceutical therapy is essential, especially as PSMA radiopharmaceutical therapy continues to expand,” stressed senior study author Carolyn Anderson, PhD, the Simón-Ellebracht Professor in Medicinal Chemistry and Professor of Radiology at the University of Missouri. “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 [the] radiometal to accumulate in off-target locations, leading to slower clearance and contributing to increased toxicity,” she added.
Study Methods and Results
In the new study, researchers attached a novel chelator (L804) to the small antibody IAB2MA to create minibody conjugates. The chelator was radiolabeled with lutetium Lu-177 and zirconium Zr-89 (Lu-177–L804-IAB2MA and Zr-89–L804-IAB2MA). They also created similar conjugates using the current standard chelators DOTA and DFO (Lu-177–DOTA-IAB2MA and Zr-89–DFO-IAB2MA). The researchers then performed preclinical biodistribution, imaging, dosimetry, and efficacy studies in a mouse model of prostate cancer—with the goal of determining whether toxicity may be mitigated with higher stability chelating of the therapeutic radiometal.
The researchers found that tumor-bearing mice that received Lu-177–L804-IAB2MA and Zr-89–L804-IAB2MA demonstrated a significantly lower accumulation of radioactivity following treatment compared with the mice that received Lu-177–DOTA-IAB2MA and Zr-89–DFO-IAB2MA. Additionally, dosimetry analysis indicated lower absorbed doses of Lu-177–L804-IAB2MA in the tumors, kidneys, livers, and muscles compared with Lu-177–DOTA-IAB2MA. The researchers noted that the mice treated with single doses of Lu-177–L804-IAB2MA exhibited prolonged survival and reduced tumor volume compared with unlabeled minibody control.
Conclusions
The researchers suggested that by improving the bond between the radioactive metal ion and the PSMA-targeting antibody, the novel chelator could improve the safety and efficacy of PSMA radiopharmaceutical therapy in this patient population.
“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,” underscored Dr. Anderson. “Another advantage of L804-IAB2MA is that it chelates both Zr-89 and Lu-177, so only one compound is needed for both radiometals. L804-IAB2MA has strong theranostic potential for Zr-89 PET imaging and Lu-177 radiopharmaceutical therapy of prostate cancer,” she concluded.
Disclosure: For full disclosures of the study authors, visit xcdsystem.com.
