bioRxiv2023
PurposeThe 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, we developed [68Ga]Ga-AJ206, a peptide-based radiotracer that can be seamlessly integrated into the standard clinical workflow and is specifically designed to non-invasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). Experimental designWe synthesized a high-affinity binder for quantification of CD38 levels. Affinity was tested using surface plasmon resonance, and In vitro specificity was evaluated using a gallium-68-labeled analog. Distribution, pharmacokinetics, and CD38 specificity of the radiotracer were assessed in MM cell lines and in primary patient-derived myeloma cells and xenografts (PDX) with cross-validation by flow cytometry and immunohistochemistry. Furthermore, we investigated the radiotracers potential to quantify CD38 pharmacodynamics induced by all-trans retinoic acid therapy (ATRA). Results[68Ga]Ga-AJ206 exhibited high CD38 binding specificity (KD: 19.1{+/-}0.99 nM) and CD38-dependent In vitro binding. [68Ga]Ga-AJ206-PET showed high contrast within 60 minutes and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detected CD38 expression in xenografts, PDXs and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantified CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following ATRA therapy. Conclusions[68Ga]Ga-AJ206 exhibited 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. STATEMENT OF TRANSLATIONAL RELEVANCEThere is an unmet need for functional imaging agents to monitor the pharmacodynamic effects of new therapeutics targeting multiple myeloma (MM). MM is a challenging bone marrow plasma cell cancer that is associated with heterogenous responses and universal recurrence. While minimal residual disease monitoring by blood and invasive bone marrow samples have improved prognostication of disease recurrence, molecularly targeted, non-invasive imaging options that can assess therapy response early remain limited. To address this gap, we report the development of a high affinity, first-in-class gallium-68 labeled peptide radiotracer, [68Ga]Ga-AJ206, for CD38 protein, which is highly expressed on MM cells. [68Ga]Ga-AJ206 provides high-contrast CD38-specific images by PET within the standard clinical workflow of 60 minutes. Furthermore, the potential of [68Ga]Ga-AJ206 PET to measure pharmacodynamics of CD38 was demonstrated. Further development of this new radiotracer may complement existing technologies and improve prognostication and monitoring of therapy response in patients with MM.