PET Imaging of CD38 and IND enabling studies of [89Zr]Zr-DFO-Isatuximab

Background CD38 is an excellent biomarker and therapeutic target for multiple myeloma due to its high expression on cancerous cells in comparison to healthy cells. Purpose We aimed to adapt Isatuximab as a PET imaging agent to detect CD38 positive multiple myeloma. Methods In vitro studies confirmed the specificity of [ 89 Zr]Zr-DFO-Isatuximab in CD38 + OPM-2 and MM.1S cells. Upregulation of CD38 was performed using pomalidomide and ricolinostat. Athymic nude mice were implanted with OPM-2 tumors and PET/CT images were collected 24 h, 3d, and 7d post-injection. Dosimetry data was collected from male and female mice and calculated using OLINDA. Three productions of [ 89 Zr]Zr-DFO-Isatuximab were produced using GMP techniques and validated for use in the clinic. Results Upregulation of CD38 was observed in vitro in CD38 + cells when treated with either pomalidomide or ricolinostat. In vivo evaluation of [ 89 Zr]Zr-DFO-Isatuximab showed high selectivity in OPM-2 xenografts. Blocking with an excess of unlabeled Isatuximab reduced the tumor accumulation of [ 89 Zr]Zr-DFO-Isatuximab by 45.5–48.5% confirming the in vivo specificity of this radiotracer. Dosimetry calculations were performed and showed an estimated effective dose of 0.359 mSv/MBq in females and 0.327 mSv/MBq in males. Three clinical grade [ 89 Zr]Zr-DFO-Isatuximab doses using good manufacturing practices were synthesized which passed all quality control requirements and were stable up to 6 h, thus validating this compound for use in future clinical trials. Conclusion [ 89 Zr]Zr-DFO-Isatuximab showed high specificity to CD38 positive cells, had estimated effective doses comparable to other clinically relevant 89 Zr-labeled antibodies, and can be prepared using GMP practices for clinical use.