Abstract
Despite recent progress, an unmet clinical need remains for novel treatments to improve cancer outcomes. Compared to chemotherapy, targeted radiopharmaceuticals coupled with diagnostic or therapeutic radionuclides are highly promising to improve therapeutic efficacy with less toxicity. The CD70-CD27 axis is aberrantly activated in many tumors (e.g., renal cell carcinoma) and facilitates immune evasion and tumor progression. Its limited expression in normal tissues makes CD70 an attractive target for monoclonal antibody-based (mAb) therapies, yet confirmation of target expression is essential for personalized treatment success. Currently available treatments targeting CD70 have shown insufficient tumor-killing potential, and we hypothesize that radioimmunotherapy can bridge this gap using a theranostic approach. Under the theranostic paradigm "what you see is what you treat", we will develop CD70-targeted radiopharmaceuticals using the potent theranostic pair 64Cu/67Cu for diagnosis using positron emission tomography (PET) and radionuclide therapy. This pair allows the creation of diagnostic (i.e., for patient selection and treatment planning) and therapeutic (i.e., for cancer treatment and post-treatment dosimetry) constructs that differ only in the isotope of the same element, guaranteeing identical biochemical behavior and pharmacokinetics, in contrast to many currently used theranostic agents. For this, we will investigate a novel intracellular pretargeted radioimmunotherapy (PRIT) approach using radiolabeled transcyclooctenes (TCO) and mAb-tetrazine (Tz) conjugates. This strategy aims to improve CD70 targeting by creating stable and reactive mAb-Tz conjugates and novel cell-permeable radiolabeled TCO structures with high stability and reactivity. Next, we will optimize the dosing, regimen, and radiation dosimetry of the anti-CD70-mAb-Tz and 64Cu/67Cu-NOTA-TCO for in vivo tumor pretargeting. Finally, we will perform an initial proof-of-concept in vivo preclinical study to detect a therapeutic signal using our PRIT approach.
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