Tracking MAPK-Dependent CD38 Upregulation by All-Trans Retinoic Acid in Human Leukemia Using ⁸⁹Zr Immuno-PET

Area of Science:

• Nuclear Medicine
• Immunotherapy
• Oncology

Background:

• Anti-CD38 antibodies (Abs) are key immunotherapeutics for hematologic malignancies.
• CD38 upregulation is often necessary for their efficacy in leukemias.
• Immuno-PET offers a noninvasive method to assess target modulation in vivo.

Purpose of the Study:

• To evaluate the use of 89Zr immuno-PET for noninvasively monitoring CD38 upregulation in leukemia models.
• To investigate the role of all-trans retinoic acid (ATRA) in modulating CD38 expression.
• To explore the underlying MAPK signaling pathway involved in CD38 induction.

Main Methods:

• Cysteine site-specific 89Zr labeling of anti-CD38 Abs (OKT10 IgG and Fc-silenced daratumumab).
• Immuno-PET imaging and biodistribution studies in murine leukemia models.
• Assessment of CD38 expression via Western blotting, flow cytometry, and immunohistochemistry.
• Pharmacologic modulation of CD38 using ATRA and MAPK inhibitor U0126.

Main Results:

• 89Zr-labeled anti-CD38 Abs specifically bound to CD38-expressing tumor cells, correlating with surface CD38 levels.
• ATRA significantly upregulated CD38 expression in all tested leukemia cell lines, including HL60 cells.
• 89Zr immuno-PET successfully visualized ATRA-induced CD38 upregulation, with 89Zr-daratumumab showing improved tumor-to-liver uptake ratios.
• ATRA-induced CD38 upregulation was mediated by ERK1/2 activation via MAPK signaling, and U0126 inhibited this process.
• U0126 treatment suppressed CD38 induction and reduced 89Zr-CD38 Ab uptake in vitro and in vivo.

Conclusions:

• 89Zr immuno-PET is a valuable tool for noninvasively monitoring CD38 expression changes in leukemia.
• ATRA-induced CD38 upregulation is dependent on MAPK signaling.
• This imaging approach can aid in optimizing combination immunotherapies for hematologic malignancies.