Preclinical development and First-in-human imaging of 89Zr-Daratumumab for CD38 targeted imaging of myeloma

Objectives: CD38 is an established therapeutic target in multiple myeloma that is expressed at high density by almost all myeloma cells. Daratumumab is an FDA-approved therapeutic antibody that binds directly to CD38. Our objective was preclinical development and clinical translation of ⁸⁹Zr-radiolabeled daratumumab for CD38-targeted imaging of myeloma. Methods: Daratumumab was radiolabeled with ⁸⁹Zr via desferrioxamine conjugation, producing ⁸⁹Zr-DFO-daratumumab. Western blot, flow cytometry, saturation binding assays, and internalization assays characterized CD38 expression and binding of ⁸⁹Zr-DFO-daratumumab in an OPM2 myeloma cell line. A murine xenograft model of the OPM2 cell line was generated for in vivo studies. Mice with OPM2 xenographs and healthy mice were administered 200 microCi of ⁸⁹Zr-DFO-daratumumab and PET/CT imaging was performed. Following successful preclinically imaging, an IRB protocol and IND from the FDA were obtained for first-in-human phase I imaging. Six myeloma patients received 2 mCi of intravenous ⁸⁹Zr-DFO-daratumumab in 20 or 50 mg of total antibody mass. Each patient underwent 4 PET/CT scans over the next 8 days, as well as blood draws and whole-body counts, to determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Results: ⁸⁹Zr-DFO-daratumumab was produced with 100% radiochemical purity and high stability. Flow cytometry demonstrated >90% antibody immunoreactivity in OPM2 cells. PET/CT of murine xenograft models demonstrated background ⁸⁹Zr-DFO-daratumumab distribution in the blood pool, liver and spleen. Substantial bone marrow uptake was seen in OPM2 mice, but not in healthy mice, consistent with targeted imaging of OPM2 myeloma cells engrafted in this cancer model. Phase I first-in-human ⁸⁹Zr-DFO-daratumumab PET/CT imaging demonstrated distribution in the blood pool, liver and spleen. Focal ⁸⁹Zr-DFO-daratumumab uptake was visualized in previously known as well as unknown sites of osseous myeloma, consistent with successful CD38-targeted immunoPET imaging of myeloma in human patients. Conclusion: ⁸⁹Zr-DFO-daratumumab provides successful whole-body PET visualization of myeloma in both a murine myeloma xenograft model and in a first-in-human phase I trial of myeloma patients. This novel PET antibody will be tested for its potential to provide sensitive detection of myeloma, predict the effectiveness of daratumumab therapy, and serve as the basis of theranostic constructs for patients with myeloma. Research support: Leukemia and Lymphoma Society, NIH/NCI Cancer Center Support Grant (P30 CA008748).

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