Abstract 4180: Evaluation of CD38 pharmacodynamics in multiple myeloma using PET with a Ga-68 labelled peptide

Abstract Introduction: Multiple myeloma (MM) is a disease of plasma cells that primarily arises in the bone marrow. CD38 is a receptor expressed uniformly and with high density in MM. Several CD38 targeted therapeutics are in clinic for MM. However, how those therapeutics engage or modulate CD38 is poorly understood particularly in lesions that cannot be assessed with routine blood testing. CD38 specific radiotracers for positron emission tomography (PET) could be helpful for detection of MM and for assessing therapy response early by measuring CD38 pharmacodynamics non-invasively. Here, we report the development of a first-in-class peptide-based PET radiotracer, [68Ga]AJ206, evaluation of its pharmacokinetics (PK), specificity for non-invasive CD38 detection, and its potential to evaluate therapy induced CD38 pharmacodynamics in mouse models of MM. Methods: A bicyclic peptide, AJ206, was synthesized and its binding affinity for CD38 was determined by surface plasmon resonance. AJ206 was labelled with Gallium-68 in high radiochemical yields and purity. In vitro uptake of [68Ga]AJ206 was carried out in four MM cell lines with variable CD38 expression (MOLP8, MM1S, RPMI8226, and U266). PK and biodistribution of [68Ga]AJ206 were evaluated by PET in cell line derived xenografts, in patient derived xenografts (PDXs) and in a disseminated disease model. PET data was corroborated by ex vivo biodistribution studies. [68Ga]AJ206 in vivo specificity for CD38 was confirmed by co-injection of non-radioactive AJ206 (1 mg/kg) and cross-correlative immunohistochemistry (IHC) of matched xenografts. Furthermore, ability of [68Ga]AJ206 to quantify CD38 pharmacodynamics was established by treating PDX models with all-trans retinoic acid (ATRA) and cross validating PET imaging observations with IHC. Results: AJ206 exhibits high affinity (KD,19 nM) for human CD38. In vitro binding assays showed variable [68Ga]AJ206 uptake in MM cells that correlated with receptor density measured by flow cytometry. Dynamic PET-MR imaging revealed high and specific uptake of [68Ga]AJ206 in MOLP8 tumor within 5 min that retained for at least 90 min. In contrast, [68Ga]AJ206 exhibited rapid clearance from normal tissues providing high contrast images at 60 minutes and a high tumor-to-muscle ratio of 27.1±2.7. Tumor uptake was reduced by > 80 % in mice receiving blocking dose, confirming the specificity of the radiotracer. Also, [68Ga]AJ206 could detect CD38 expression in different MM xenografts, PDXs and disseminated disease models which was corroborated by flow cytometry and IHC findings. Moreover, [68Ga]AJ206 successfully quantified the increased CD38 expression in PDXs following ATRA treatment. Conclusion: [68Ga]AJ206 is a CD38 specific high affinity peptide-based PET imaging agent that can be used to non-invasively quantify CD38 pharmacodynamics in MM, with potential applications in other diseases with CD38 involvement. Citation Format: Ajay Kumar Sharma, Kuldeep Gupta, Akhilesh Mishra, Gabriela Lofland, Ian Marsh, Dhiraj Kumar, Gabriel Ghiaur, Philip Imus, Steven P. Rowe, Robert Hobbs, Christian B. Gocke, Sridhar Nimmagadda. Evaluation of CD38 pharmacodynamics in multiple myeloma using PET with a Ga-68 labelled peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4180.