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

TL;DR

This study shows that [89Zr]Zr-DFO-Isatuximab can be used as a PET imaging agent to detect CD38-positive multiple myeloma tumors in mice and is suitable for clinical trials.

Contribution

The paper demonstrates the clinical viability of [89Zr]Zr-DFO-Isatuximab for PET imaging of CD38 in multiple myeloma using GMP practices.

Findings

[89Zr]Zr-DFO-Isatuximab showed high specificity for CD38-positive cells in vitro and in vivo.

Blocking experiments confirmed the in vivo specificity of the radiotracer with a 45.5–48.5% reduction in tumor accumulation.

The radiotracer had an estimated effective dose comparable to other 89Zr-labeled antibodies and was stable for clinical use.

Abstract

CD38 is an excellent biomarker and therapeutic target for multiple myeloma due to its high expression on cancerous cells in comparison to healthy cells.

We aimed to adapt Isatuximab as a PET imaging agent to detect CD38 positive multiple myeloma.

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.

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.

[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.

The online version contains supplementary material available at 10.1007/s11307-025-02062-9.

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