CD38‐Specific Gallium‐68 Labeled Peptide Radiotracer Enables Pharmacodynamic Monitoring in Multiple Myeloma with PET

Abstract The limited availability of molecularly targeted low‐molecular‐weight imaging agents for monitoring multiple myeloma (MM)‐targeted therapies has been a significant challenge in the field. In response, a first‐in‐class peptide‐based radiotracer, [68Ga]Ga‐AJ206, is developed that can be seamlessly integrated into the standard clinical workflow and is specifically designed to noninvasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). A bicyclic peptide, AJ206, is synthesized and exhibits high affinity to CD38 (KD: 19.1 ± 0.99 × 10−9 m) by surface plasmon resonance. Further, [68Ga]Ga‐AJ206‐PET shows high contrast within 60 min and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga‐AJ206 detects CD38 expression in cell line‐derived xenografts, patient‐derived xenografts (PDXs), and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga‐AJ206‐PET successfully quantifies CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following all‐trans retinoic acid (ATRA) therapy. In conclusion, [68Ga]Ga‐AJ206 exhibits the salient features required for clinical translation, providing CD38‐specific high‐contrast images in multiple models of MM. [68Ga]Ga‐AJ206‐PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement.