Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY/ABSTRACT Over the last fifteen years, radioimmunotherapy (RIT) using antibodies labeled with a-emitting radionuclides has shown significant promise for the treatment of cancer. Yet the the multi-day circulation time of monoclonal antibodies means that they must be labeled with an a-emitting radionuclide with a multi-day physical half-life: 225Ac (t1/2 ~ 9.9 d). This unavoidable combination of long biological and physical half-lives can create high radiation dose rates to healthy tissues, a complication that has hampered the clinical proliferation of 225Ac-labeled radioimmunoconjugates. One approach to circumventing this issue lies in pretargeted radioimmunotherapy (PRIT). PRIT is predicated on decoupling the immunoglobulin and radionuclide, injecting the former prior to the latter, and empowering them to recombine at target sites within the body. Labeling the antibody with a fast- moving, small molecule radioligand after it has reached an optimal biodistribution in vivo limits the circulation time of the assembled radioimmunoconjugate in the blood and enables the use of radionuclides with half-lives that are normally incompatible with full-length IgGs. As a result, this approach can produce high activity concentrations in target tissues at only a fraction of the radiation dose to healthy organs produced by traditional, directly-labeled radioimmunoconjugates. This F31 proposal is focused upon creating a novel approach to PRIT that leverages the short-lived, a- emitting radiohalogen astatine-211 (211At; t1/2 ~ 7.2 h) and the in vivo bioorthogonal click ligation between tetrazine (Tz) and trans-cylooctene (TCO). To this end, we will employ a proof-of-concept model system based on the A33 antigen-targeting huA33 antibody as well as murine models of colorectal carcinoma. Specific Aim 1 (SA1) will be focused on the synthesis, characterization, and in vivo evaluation of a library of Tz radioligands labeled with iodine-131 (t1/2 ~ 8.0 d), an inexpensive surrogate for 211At. In Specific Aim 2 (SA2), we will create 211At-labeled variants of the four most promising radioligands identified in SA1. We will then use these 211At- labeled tetrazines and huA33-TCO to perform pretargeted biodistribution studies in a subcutaneous xenograft model of colorectal carcinoma. These biodistribution data will be used to assess the performance of in vivo pretargeting with each 211At-Tz and enable dosimetry calculations designed to elucidate the radiation dose of each strategy to tumor tissue and healthy organs. Finally, Specific Aim 3 (SA3) will be centered on validating the therapeutic efficacy of this approach to 211At-PRIT in subcutaneous, orthotopic, and patient-derived xenograft models of human colorectal carcinoma. Longitudinal PRIT studies will performed with the two most promising 211At-Tz radioligands from SA2 in order to identify a single construct suitable for clinical translation. In the near term, this investigation could lead to the creation of a safer and more effective treatment modality for patients with colorectal cancer. And in the long term, this work could help usher in an era in which 211At-based radiopharmaceuticals play a vital role in the endoradiotherapy of patients with a wide variety of malignancies.
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