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Life sciences · Journal article
Journal of Nuclear Medicine · October 22, 2026
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Trastuzumab deruxtecan (T-DXd) has clinical activity in human epidermal growth factor receptor 2 (HER2)-low and -ultralow tumors in addition to HER2-positive tumors. However, no consistent correlation has been observed between traditional HER2 scoring criteria and response to T-DXd in HER2-low and HER2-ultralow tumors. There is a need for complementary approaches to monitor T-DXd delivery in vivo and potentially improve understanding of which tumors may benefit from T-DXd therapy. This study evaluated tumor uptake of radiolabeled T-DXd in tumors with varying HER2 protein levels using PET in treatment-naïve tumors and during T-DXd therapy. Methods: Chelator-conjugated T-DXd or trastuzumab was prepared via conventional lysine conjugation and radiolabeled with 64Cu. The binding and in vitro cytotoxicity of the conjugates were determined in cancer cell lines. PET/CT was performed across 11 tumor models (representing 5 tumor types), including cell xenografts, patient-derived xenografts, and syngeneic models in both subcutaneous and orthotopic models. Image-based tumor uptake of the radiolabeled antibodies was quantified in all models. In the treatment studies, mice bearing CT26-hHER2 tumors that express heterogeneous HER2 with an immunohistochemistry score of 2+ levels received weekly coinjections of therapeutic T-DXd (6 mg/kg) together with imaging-dose [64Cu]Cu-NOTA-T-DXd (4 mg/kg), corresponding to a total T-DXd administered dose of 10 mg/kg. Results: [64Cu]Cu-NOTA-T-DXd was obtained at a radiochemical purity of at least 98%. Purified [64Cu]Cu-NOTA-T-DXd bound to cells in a concentration-dependent manner and had a positive correlation between HER2 protein levels and bound T-DXd. Conjugation of T-DXd to NOTA did not affect T-DXd binding or cytotoxicity in cancer cells. [64Cu]Cu-NOTA-T-DXd mean tumor uptake varied across models (7.45 ± 1.28 to 19.10 ± 2.50 %ID/mL), and the mean uptake was similar to that of the parental antibody 64Cu-labeled trastuzumab. Preimaging doses of either trastuzumab or pertuzumab did not affect [64Cu]Cu-NOTA-T-DXd uptake in tumors. There was a positive correlation between the change in [64Cu]Cu-NOTA-T-DXd uptake and the change in tumor volume between weeks 1 and 2 of T-DXd treatment (P < 0.01) in CT26.hHER2 tumors grown in immunocompetent mice. Conclusion: [64Cu]Cu-NOTA-T-DXd PET detects antibody–drug accumulation in tumors with low HER2 protein levels and may provide an early imaging biomarker associated with response. These studies show the potential of using HER2-targeted imaging in preclinical models to noninvasively assess antibody–drug conjugate delivery and explore imaging-based biomarkers associated with T-DXd response.