TY - JOUR
T1 - Development of [89Zr]DFO-elotuzumab for immunoPET imaging of CS1 in multiple myeloma
AU - Ghai, Anchal
AU - Zheleznyak, Alexander
AU - Mixdorf, Matt
AU - O’Neal, Julie
AU - Ritchey, Julie
AU - Rettig, Michael
AU - DiPersio, John
AU - Shokeen, Monica
AU - Achilefu, Samuel
N1 - Funding Information:
We thank the Washington University isotope production team for the production of zirconium-89 and the small animal imaging facility for help with the small animal PET/CT data generation. Ms. Katie Duncan assisted with bioluminescent imaging. We thank the Washington University Biomedical Mass Spectrometry Resource facility (NIH grant 8P41GM103422) for the mass spectrometry analysis.
Funding Information:
John DiPersio received research support from Bioline, Rodger and Paula Riney Foundation (gift), and grant from NIH/NCI: U54CA199092 (PI: Achilefu, Project 3 Leader: Di Persio).
Funding Information:
This study was supported in part by grants from the National Institutes of Health (U54 CA199092, R01 EB021048, and R01 CA248493), NIH Shared Instrumentation Grants S10 OD020129, S10 OD025264, S10 OD027042 and Department of Defense CDMRP BCRP W81XWH1610286. Acknowledgments
Funding Information:
Monica Shokeen is supported by grants from NIH/NCI: R01 CA248493 and U54CA199092.
Funding Information:
Samuel Achilefu is supported by grants from the National Institutes of Health (U54 CA199092, R01 EB021048), NIH Shared Instrumentation Grants S10 OD020129, S10 OD025264, S10 OD027042 and Department of Defense CDMRP BCRP W81XWH1610286.
Funding Information:
We thank the Washington University isotope production team for the production of zirconium-89 and the small animal imaging facility for help with the small animal PET/CT data generation. Ms. Katie Duncan assisted with bioluminescent imaging. We thank the Washington University Biomedical Mass Spectrometry Resource facility (NIH grant 8P41GM103422) for the mass spectrometry analysis.
Publisher Copyright:
© 2020, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2021/5
Y1 - 2021/5
N2 - 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 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. 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.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. Conclusion: These data demonstrate the feasibility of [89Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
AB - 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 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. 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.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. Conclusion: These data demonstrate the feasibility of [89Zr]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.
KW - CS1 antigen
KW - Multiple myeloma
KW - PET imaging
KW - [Zr]DFO-elotuzumab
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U2 - 10.1007/s00259-020-05097-y
DO - 10.1007/s00259-020-05097-y
M3 - Article
C2 - 33179150
AN - SCOPUS:85095943935
VL - 48
SP - 1302
EP - 1311
JO - European Journal Of Nuclear Medicine
JF - European Journal Of Nuclear Medicine
SN - 0340-6997
IS - 5
ER -