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

Abstract

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 [⁸⁹Zr]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 [⁸⁹Zr]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 [⁸⁹Zr]Zr-DFO-Isatuximab showed high selectivity in OPM-2 xenografts. Blocking with an excess of unlabeled Isatuximab reduced the tumor accumulation of [⁸⁹Zr]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 [⁸⁹Zr]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: [⁸⁹Zr]Zr-DFO-Isatuximab showed high specificity to CD38 positive cells, had estimated effective doses comparable to other clinically relevant ⁸⁹Zr-labeled antibodies, and can be prepared using GMP practices for clinical use.