CD38 as a PET Imaging Target in Lung Cancer

Emily B Ehlerding, Christopher G England, Dawei Jiang, Stephen A Graves, Lei Kang, Saige Lacognata, Todd E Barnhart, Weibo Cai
Molecular Pharmaceutics 2017 July 3, 14 (7): 2400-2406
Daratumumab (Darzalex, Janssen Biotech) is a clinically approved antibody targeting CD38 for the treatment of multiple myeloma. However, CD38 is also expressed by other cancer cell types, including lung cancer, where its expression or absence may offer prognostic value. We therefore developed a PET tracer based upon daratumumab for tracking CD38 expression, utilizing murine models of non-small cell lung cancer to verify its specificity. Daratumumab was prepared for radiolabeling with 89 Zr (t1/2 = 78.4 h) through conjugation with desferrioxamine (Df). Western blot, flow cytometry, and saturation binding assays were utilized to characterize CD38 expression and binding of daratumumab to three non-small cell lung cancer cell lines: A549, H460, and H358. Murine xenograft models of the cell lines were also generated for further in vivo studies. Longitudinal PET imaging was performed following injection of 89 Zr-Df-daratumumab out to 120 h postinjection, and nonspecific uptake was also evaluated through the injection of a radiolabeled control IgG antibody in A549 mice, 89 Zr-Df-IgG. Ex vivo biodistribution and histological analyses were also performed after the terminal imaging time point at 120 h postinjection. Through cellular studies, A549 cells were found to express higher levels of CD38 than the H460 or H358 cell lines. PET imaging and ex vivo biodistribution studies verified in vitro trends, with A549 tumor uptake peaking at 8.1 ± 1.2%ID/g at 120 h postinjection according to PET analysis, and H460 and H358 at lower levels at the same time point (6.7 ± 0.7%ID/g and 5.1 ± 0.4%ID/g, respectively; n = 3 or 4). Injection of a nonspecific radiolabeled IgG into A549 tumor-bearing mice also demonstrated lower tracer uptake of 4.4 ± 1.3%ID/g at 120 h. Immunofluorescent staining of tumor tissues showed higher staining levels present in A549 tissues over H460 and H358. Thus, 89 Zr-Df-daratumumab is able to image CD38-expressing tissues in vivo using PET, as verified through the exploration of non-small cell lung cancer models in this study. This agent therefore holds potential to image CD38 in other malignancies and aid in patient stratification and elucidation of the biodistribution of CD38.


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