Development of [⁸⁹Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma.

Abstract

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. 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 post-imaging at 7 days was also done. In vivo specificity of [⁸⁹Zr]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography. [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.1S-CG 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. These data demonstrate the feasibility of [⁸⁹Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.