Development of [ 89 Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma
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ORIGINAL ARTICLE
Development of [89Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma Anchal Ghai 1 & Alexander Zheleznyak 1 & Matt Mixdorf 1 & Julie O’Neal 2 & Julie Ritchey 2 & Michael Rettig 2 & John DiPersio 2 & Monica Shokeen 1,3 & Samuel Achilefu 1,2,3,4 Received: 19 August 2020 / Accepted: 26 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [89Zr]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models. Methods Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [89Zr]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [89Zr]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [18F]FDG (7–8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [89Zr]DFO-elotuzumab postimaging at 7 days was also done. In vivo specificity of [89Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography. Results [89Zr]DFO-elotuzumab was produced with high specific activity (56 ± 0.75 MBq/nmol), radiochemical purity (99% ± 0.5), and yield (93.3% ± 1.5). Dissociation constant of 40.4 nM and receptor density of 126 fmol/mg was determined in MM.1SCG cells. Compared to [89Zr]DFO-IgG, [89Zr]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [89Zr]DFO-elotuzumab in the bones. Importantly, while [18F]FDG demonstrated similar uptake in the bone and muscle, [89Zr]DFO-elotuzumab showed > 3-fold enhanced uptake in bones. Conclusion These data demonstrate the feasibility of [89Zr]DFO-elotuzumab as a companion diagnostic for CS1targeted therapies. Keywords PET imaging . CS1 antigen . [89Zr]DFO-elotuzumab . Multiple myeloma
This article is part of the Topical Collection on Preclinical Imaging.
Introduction
* Samuel Achilefu [email protected]
Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by abnormal proliferation of plasma cells in the bone marrow, monoclonal protein spike, anemia, and renal failure [1, 2]. The use of proteasome inhibitors, immunomodulatory drugs, and transplantation has increased the 5-year relative survival of patients with MM to ~ 53.4% [3, 4]. Nevertheless, patients showing an initial response to these therapies almost certainly relapse and become refractory over time [5]. To improve treatment outcomes, a number of monoclonal antibod
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