Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®

PURPOSE: The chimeric monoclonal antibody (mAb) chDAB4 (APOMAB®) targets the Lupus associated (La)/Sjögren Syndrome-B (SSB) antigen, which is over-expressed in tumors but only becomes available for antibody binding in dead tumor cells. Hence, chDAB4 may be used as a novel theranostic tool to distinguish between responders and nonresponders early after chemotherapy. Here, we aimed to ascertain which positron emitter, Zirconium-89 ([(89)Zr]Zr(IV)) or Iodine-124 ([(124)I]I), was best suited to label chDAB4 for post-chemotherapy PET imaging of tumor-bearing mice and to determine which of two different bifunctional chelators provided optimal tumor imaging by PET using [(89)Zr]Zr(IV)-labeled chDAB4. METHODS: C57BL/6 J mice bearing subcutaneous syngeneic tumors of EL4 lymphoma were either untreated or given chemotherapy, then administered radiolabeled chDAB4 after 24 h with its biodistribution examined using PET and organ assay. We compared chDAB4 radiolabeled with [(89)Zr] Zr(IV) or [(124)I] I, or [(89)Zr]Zr-chDAB4 using either DFO-NCS or DFOSq as a chelator. RESULTS: After chemotherapy, [(89)Zr]Zr-chDAB4 showed higher and prolonged mean (± SD) tumor uptake of 29.5 ± 5.9 compared to 7.8 ± 1.2 for [(124)I] I -chDAB4. In contrast, antibody uptake in healthy tissues was not affected. Compared to DFO-NCS, DFOSq did not result in significant differences in tumor uptake of [(89)Zr]Zr-chDAB4 but did alter the tumor:liver ratio in treated mice 3 days after injection in favour of DFOSq (8.0 ± 1.1) compared to DFO-NCS (4.2 ± 0.7). CONCLUSION: ImmunoPET using chDAB4 radiolabeled with residualizing [(89)Zr] Zr(IV) rather than [(124)I] I optimized post-chemotherapy tumor uptake. Further, PET imaging characteristics were improved by DFOSq rather than DFO-NCS. Therefore, the radionuclide/chelator combination of [(89)Zr] Zr(IV) and DFOSq is preferred for the imminent clinical evaluation of chDAB4 as a selective tumor cell death radioligand. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s41181-020-00109-6.