Preclinical development of CD38-Targeted [ 89 Zr]Zr-DFO-Daratumumab for Imaging Multiple Myeloma

Anchal Ghai, Dolonchampa Maji, Nicholas Cho, Chantiya Chanswangphuwana, Michael Rettig, Duanwen Shen, John DiPersio, Walter Akers, Farrokh Dehdashti, Samuel Achilefu, Ravi Vij, Monica Shokeen

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Multiple myeloma (MM) is a plasma B-cell hematologic cancer that causes significant skeletal morbidity. Despite improvements in survival, heterogeneity in response remains a major challenge in MM. Cluster of differentiation 38 (CD38) is a type II transmembrane glycoprotein overexpressed in myeloma cells and is implicated in MM cell signaling. Daratumumab is a U.S. Food and Drug Administration–approved high-affinity monoclonal antibody targeting CD38 that is clinically benefiting refractory MM patients. Here, we evaluated [ 89 Zr]Zr-desferrioxamine (DFO)-daratumumab PET/CT imaging in MM tumor models. Methods: Daratumumab was conjugated to DFO-p-benzyl-isothiocyanate (DFO-Bz-NCS) for radiolabeling with 89 Zr. Chelator conjugation was confirmed by electrospray ionization-mass spectrometry, and radiolabeling was monitored by instant thin-layer chromatography. Daratumumab was conjugated to Cyanine5 (Cy5) dye for cell microscopy. In vitro and in vivo evaluation of [ 89 Zr]Zr-DFO-daratumumab was performed using CD38 1 human myeloma MM1.S-luciferase (MM1.S) cells. Cellular studies determined the affinity, immunoreactivity, and specificity of [ 89 Zr]Zr-DFO-daratumumab. A 5TGM1-luciferase (5TGM1)/KaLwRij MM mouse model served as control for imaging background noise. [ 89 Zr]Zr-DFO-daratumumab PET/CT small-animal imaging was performed in severe combined immunodeficient mice bearing solid and disseminated MM tumors. Tissue biodistribution (7 d after tracer administration, 1.11 MBq/animal, n 5 4–6/group) was performed in wild-type and MM1.S tumor–bearing mice. Results: A specific activity of 55.5 MBq/nmol (0.37 MBq/mg) was reproducibly obtained with [ 89 Zr]Zr-daratumumab-DFO. Flow cytometry confirmed CD38 expression (.99%) on the surface of MM1.S cells. Confocal microscopy with daratumumab-Cy5 demonstrated specific cell binding. Dissociation constant, 3.3 nM (60.58), and receptor density, 10.1 fmol/mg (60.64), was obtained with a saturation binding assay. [ 89 Zr]Zr-DFO-daratumumab/PET demonstrated specificity and sensitivity for detecting CD38 1 myeloma tumors of variable sizes (8.5–128 mm 3 ) with standardized uptake values ranging from 2.1 to 9.3. Discrete medullar lesions, confirmed by bioluminescence images, were efficiently imaged with [ 89 Zr]Zr-DFO-daratumumab/PET. Biodistribution at 7 d after administration of [ 89 Zr]Zr-DFO-daratumumab showed prominent tumor uptake (27.7 6 7.6 percentage injected dose per gram). In vivo blocking was achieved with a 200-fold excess of unlabeled daratumumab. Conclusion: [ 89 Zr]Zr-DFO- and Cy5-daratumumab demonstrated superb binding to CD38 1 human MM cells and significantly low binding to CD38 low cells. Daratumumab bioconjugates are being evaluated for image-guided delivery of therapeutic radionuclides.

Original languageEnglish
Pages (from-to)216-222
Number of pages7
JournalJournal of Nuclear Medicine
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2018

Keywords

  • Cluster of differentiation 38 (CD38)
  • Molecular imaging
  • Multiple myeloma (MM)
  • [ Zr]Zr-DFO-daratumumab

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