Development of Antibody Chelator Conjugates for Targeted Radionuclide Therapy

/Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a very poor overall prognosis and limited treatment options. The absence of elevated expression of the three common receptors, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) that are validated targets of therapeutic drugs, poses significant challenges in treating TNBC. Better therapeutic options for efficient TNBC control and improved survival are urgently needed. In this investigation, we propose to develop antibody chelator conjugates (ACCs) for targeted radionuclide therapy of TNBC. The novel ACCs contain a monoclonal antibody with high affinity for a validated therapeutic target in TNBC and a chelating agent labeled with â..emitting therapeutic radionuclide (177Lu or 90Y). The efficacy of targeted radionuclide therapy against cancer has been demonstrated in numerous clinical trials with radiopharmaceuticals including 177Lu-based Lutathera®, 177Lu-based Pluvicto®, and 90Y-based Zevalin®. Chelation chemistry is an essential component in creating clinically viable radiotherapeutics with high therapeutic efficacy and safety profiles. The PI has invented highly effective chelators for 177Lu and 90Y in targeted radionuclide therapy. In this investigation, we aim to utilize superior chelation chemistry to create 177Lu- or 90Y-based ACCs for antibody-targeted therapy of TNBC. Promising ACCs will be identified and evaluated for radiolabeling with 177Lu or 90Y, and the corresponding 177Lu-ACCs and 90Y-ACCs will be evaluated for in vitro stability and radioimmunoassay. The top 177Lu-ACCs and 90Y-ACCs will be further evaluated for in vivo biodistribution, metabolism, radiation dosimetry, therapy, and toxicity using TNBC tumorbearing mice. The proposed in vivo studies are essential because data relevant to clinical procedures cannot be obtained using computational, invertebrate, or in vitro methods. This investigation is proposed to generate potent and safe 177Lu-ACCs and 90Y-ACCs as novel radiopharmaceuticals for TNBC Therapy. Project Number: 1R01CA303986-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: HYUN-SOON CHONG | Institution: ILLINOIS INSTITUTE OF TECHNOLOGY, CHICAGO, IL | Award Amount: $648,992 | Activity Code: R01 | Study Section: Radiation Therapeutics and Biology Study Section[RTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368027