Journal
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Volume 48, Issue 5, Pages 1302-1311Publisher
SPRINGER
DOI: 10.1007/s00259-020-05097-y
Keywords
PET imaging; CS1 antigen; [Zr-89]DFO-elotuzumab; Multiple myeloma
Funding
- National Institutes of Health [U54 CA199092, R01 EB021048, R01 CA248493]
- Department of Defense [CDMRP BCRP W81XWH1610286]
- NIH Shared Instrumentation Grants [S10 OD020129, S10 OD025264, S10 OD027042]
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This study demonstrates the feasibility of [Zr-89]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
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 [Zr-89]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 [Zr-89]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [Zr-89]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [F-18]FDG (7-8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [Zr-89]DFO-elotuzumab post-imaging at 7 days was also done. In vivo specificity of [Zr-89]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography. Results [Zr-89]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 [Zr-89]DFO-IgG, [Zr-89]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 [Zr-89]DFO-elotuzumab in the bones. Importantly, while [F-18]FDG demonstrated similar uptake in the bone and muscle, [Zr-89]DFO-elotuzumab showed > 3-fold enhanced uptake in bones. Conclusion These data demonstrate the feasibility of [Zr-89]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
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