TY - JOUR T1 - Molecular Imaging of Multiple Myeloma Targeting CD46 Using ImmunoPET JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 62 LP - 62 VL - 62 IS - supplement 1 AU - Sinan Wang AU - Yang Su AU - Bonell Patino Escobar AU - Veronica Steri AU - Byron Hann AU - Ryan Tang AU - Youngho Seo AU - Bin Liu AU - Arun Wiita AU - Robert Flavell Y1 - 2021/05/01 UR - http://jnm.snmjournals.org/content/62/supplement_1/62.abstract N2 - 62Introduction: The extensive heterogeneity in multiple myeloma (MM) emphasizes the need for accurate prognostic tools. 18F-FDG PET/CT imaging has been used for MM detection but false-negative 18F-FDG PET/CT in MM may be seen in some cases [1]. Therefore, there is an unmet clinical need for improved imaging biomarkers for the detection of MM. CD46 has been identified as a novel and underexplored therapeutic target in multiple myeloma. We have developed an antibody drug conjugate against CD46, which is now in phase 1 clinical trials [2]. In principle, a CD46-directed molecular imaging agent could be used as a companion biomarker for this ADC and other CD46-targeted therapies. Recently, we have developed an anti-CD46 positron emission tomography radiopharmaceutical, [89Zr]DFO-YS5, and demonstrated its sensitivity for the detection of prostate cancer [3]. In the present study, we evaluated [89Zr]DFO-YS5 for immunoPET imaging in murine MM models. Methods: [89Zr]DFO-YS5 was prepared based on our previous method [3], and a control, nonspecific [89Zr]DFO-IgG was prepared using similar methods. NSG mice bearing subcutaneous MM1.S-luc (luciferase expressing) xenograft tumor were prepared. Additionally, an orthometastatic model of myeloma was prepared by administration of the MM1.S-luc cell via tail vein in NSG mice. ImmunoPET imaging was performed at 6 days post injection for the subcutaneous model, and 4 days post injection in the orthometastatic model on a Siemens Inveon micro PET/CT, at which time the mice were sacrificed and biodistribution analysis was performed. For the orthometastatic model, uptake in the organs was compared against bioluminescence imaging after dissection. Results: [89Zr]DFO-YS5 binds specifically to the CD46 positive human MM1s subcutaneous xenografts. In biodistribution studies using the subcutaneous xenograft model, the tumor uptake of [89Zr]DFO-YS5 was 17.4 ± 3.6 % ID/g at 6 days post injection, significantly higher than the uptake of the blocked group (5.3 ± 1.4 % ID/g) and the nonspecific [89Zr]DFO-IgG group (3.7 ± 0.3 % ID/g) (Figure A-D). In the orthometastastic model, [89Zr]DFO-YS5 also demonstrated specific uptake in the bone marrow (16.7 ± 6.6% ID/g at 4 days post injection), higher than the uptake of the blocked group (4.2 ± 0.6 % ID/g) (Figure E-G). Analysis of ex-vivo bioluminescence data indicated heterogeneous osseous tumor involvement, with matching areas of [89Zr]DFO-YS5 tracer uptake (Figure H). Conclusion: Our results demonstrate successful CD46-targeted immunoPET imaging of multiple myeloma in a murine model. CD46-targeted imaging shows great potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in multiple myeloma. Acknowledgements: We would like to acknowledge pilot funding from the Stephen and Nancy Grand Multiple Myeloma Translational Initiative. References1. Spinnato, P., et al., Contrast enhanced MRI and 18F-FDG PET-CT in the assessment of multiple myeloma: A comparison of results in different phases of the disease. European Journal of Radiology, 2012. 81(12): p. 4013-4018.2. Sherbenou, D.W., et al., Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. The Journal of clinical investigation, 2016. 126(12): p. 4640-4653.3. Wang, S., et al., Molecular imaging of prostate cancer targeting CD46 using immunoPET. Clinical Cancer Research, 2020. ER -