PURPOSE

Abnormal CD38 expression in some hematologic malignancies, including lymphoma, has made it a biomarker for targeted therapies. Daratumumab (Dara) is the first FDA-approved CD38-specific monoclonal antibody, enabling successfully immunoPET imaging over the past years. Radiolabeled Dara however has a long blood circulation and delayed tumor uptake which can limit its applications. The focus of this study is to develop Cu-labeled Dara-F(ab') for the visualization of CD38 in lymphoma models.

METHODS

F(ab') fragment was prepared from Dara using an IdeS enzyme and purified with Protein A beads. Western blotting, flow cytometry, and surface plasmon resonance (SPR) were performed for in vitro assay. Probes were labeled with Cu after the chelation of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Small animal PET imaging and quantitative analysis were performed after injection of Cu-labeled Dara-F(ab'), IgG-F(ab'), and Dara for evaluation in lymphoma models.

RESULTS

Flow cytometry and SPR assay proved the specific binding ability of Dara-F(ab') and NOTA-Dara-F(ab') in vitro. Radiolabeling yield of [Cu]Cu-NOTA-Dara-F(ab') was over 90% and with a specific activity of 4.0 ± 0.6 × 10 MBq/μmol (n = 5). PET imaging showed [Cu]Cu-NOTA-Dara-F(ab') had a rapid and high tumor uptake as early as 2 h (6.9 ± 1.2%ID/g) and peaked (9.5 ± 0.7%ID/g) at 12 h, whereas [Cu]Cu-NOTA-Dara reached its tumor uptake peaked at 48 h (8.3 ± 1.4%ID/g, n = 4). In comparison, IgG-F(ab') and HBL-1 control groups found no noticeable tumor uptake. [Cu]Cu-NOTA-Dara-F(ab') had significantly lower uptake in blood pool, bone, and muscle than [Cu]Cu-NOTA-Dara and its tumor-to-blood and tumor-to-muscle ratios were significantly higher than controls.

CONCLUSIONS

[Cu]Cu-NOTA-Dara-F(ab') showed a rapid and high tumor uptake in CD38-positive lymphoma models with favorable imaging contrast, showing its promise as a potential PET imaging agent for future clinical applications.