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CD46-Targeted Radiotheranostics for Prostate Cancer

Abstract

Radiotheranostics combines molecular imaging (especially PET and SPECT) with targeted radionuclide therapy, utilizing radionuclides emitting α-, β-, or auger-radiation. The field is emerging after FDA approval of new radiotheranostic agents like 177Lu/68Ga-DOTATATE and 177Lu/68Ga-PSMA-617. In this context, we have recently developed 134Ce/225Ac radiotheranotcis by identifying the antibody YS5, which targets the tumor-selective epitope CD46 highly expressed in prostate cancer. Targeted alpha therapy with 225Ac (~9.92 days) has gained attention due to its therapeutic potential, but challenges such as off-target toxicity, a lack of optimized chelators, and limitations in radiolabeling methods persist. To enhance tumoral uptake and reduce toxicity, we developed a radioimmunoconjugate called 225Ac-Macropa-PEG4-YS5, incorporating a stable PEGylated linker. This conjugate demonstrates greater anti-tumor efficacy while minimizing toxicity in prostate cancer 22Rv1 tumors.
A significant challenge of 225Ac is the inability to measure in vivo pharmacokinetics and dosimetric estimations due to alpha emissions, low administration activities, and a low fraction of suitable γ-emissions. We developed a PET Imaging surrogate using the 134Ce/La pair labeled with tumor-targeting agents PSMA-617 and Macropa-PEG4-YS5 to overcome this. The results show similar biodistribution and pharmacokinetics to the respective 225Ac conjugates. In summary, these studies support the future development of 134Ce-radiopharmaceuticals for cancer imaging as companions to paired α-particle radiotherapeutics.

Biography

Assistant Professor Kondapa Naidu Bobba is a decisive, analytical, and innovative professional with over 11 years of research experience in medicinal chemistry and five years of extensive experience in radiopharmaceutical development. His work primarily focuses on developing and clinically translating novel radiopharmaceuticals for cancer diagnosis and therapy. His research includes incorporating novel linker methodologies to improve imaging and therapeutic outcomes. Additionally, he is deeply interested in identifying new cancer targets and concurrently developing radiotheranostics for both imaging and therapeutic applications. He has authored more than 25 publications and has led successful funding proposals from various agencies.

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