PMID- 28573863
OWN - NLM
STAT- MEDLINE
DCOM- 20180409
LR  - 20181113
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Print)
IS  - 1543-8384 (Linking)
VI  - 14
IP  - 7
DP  - 2017 Jul 3
TI  - CD38 as a PET Imaging Target in Lung Cancer.
PG  - 2400-2406
LID - 10.1021/acs.molpharmaceut.7b00298 [doi]
AB  - Daratumumab (Darzalex, Janssen Biotech) is a clinically approved antibody 
      targeting CD38 for the treatment of multiple myeloma. However, CD38 is also 
      expressed by other cancer cell types, including lung cancer, where its expression 
      or absence may offer prognostic value. We therefore developed a PET tracer based 
      upon daratumumab for tracking CD38 expression, utilizing murine models of 
      non-small cell lung cancer to verify its specificity. Daratumumab was prepared 
      for radiolabeling with (89)Zr (t(1/2) = 78.4 h) through conjugation with 
      desferrioxamine (Df). Western blot, flow cytometry, and saturation binding assays 
      were utilized to characterize CD38 expression and binding of daratumumab to three 
      non-small cell lung cancer cell lines: A549, H460, and H358. Murine xenograft 
      models of the cell lines were also generated for further in vivo studies. 
      Longitudinal PET imaging was performed following injection of 
      (89)Zr-Df-daratumumab out to 120 h postinjection, and nonspecific uptake was also 
      evaluated through the injection of a radiolabeled control IgG antibody in A549 
      mice, (89)Zr-Df-IgG. Ex vivo biodistribution and histological analyses were also 
      performed after the terminal imaging time point at 120 h postinjection. Through 
      cellular studies, A549 cells were found to express higher levels of CD38 than the 
      H460 or H358 cell lines. PET imaging and ex vivo biodistribution studies verified 
      in vitro trends, with A549 tumor uptake peaking at 8.1 +/- 1.2%ID/g at 120 h 
      postinjection according to PET analysis, and H460 and H358 at lower levels at the 
      same time point (6.7 +/- 0.7%ID/g and 5.1 +/- 0.4%ID/g, respectively; n = 3 or 4). 
      Injection of a nonspecific radiolabeled IgG into A549 tumor-bearing mice also 
      demonstrated lower tracer uptake of 4.4 +/- 1.3%ID/g at 120 h. Immunofluorescent 
      staining of tumor tissues showed higher staining levels present in A549 tissues 
      over H460 and H358. Thus, (89)Zr-Df-daratumumab is able to image CD38-expressing 
      tissues in vivo using PET, as verified through the exploration of non-small cell 
      lung cancer models in this study. This agent therefore holds potential to image 
      CD38 in other malignancies and aid in patient stratification and elucidation of 
      the biodistribution of CD38.
FAU - Ehlerding, Emily B
AU  - Ehlerding EB
AD  - Department of Medical Physics, University of Wisconsin-Madison , Madison, 
      Wisconsin 53705, United States.
FAU - England, Christopher G
AU  - England CG
AD  - Department of Medical Physics, University of Wisconsin-Madison , Madison, 
      Wisconsin 53705, United States.
FAU - Jiang, Dawei
AU  - Jiang D
AD  - Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 
      53705, United States.
FAU - Graves, Stephen A
AU  - Graves SA
AD  - Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 
      53705, United States.
FAU - Kang, Lei
AU  - Kang L
AD  - Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 
      53705, United States.
FAU - Lacognata, Saige
AU  - Lacognata S
AD  - Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 
      53705, United States.
FAU - Barnhart, Todd E
AU  - Barnhart TE
AD  - Department of Medical Physics, University of Wisconsin-Madison , Madison, 
      Wisconsin 53705, United States.
FAU - Cai, Weibo
AU  - Cai W
AUID- ORCID: 0000-0003-4641-0833
AD  - Department of Medical Physics, University of Wisconsin-Madison , Madison, 
      Wisconsin 53705, United States.
AD  - Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 
      53705, United States.
AD  - Carbone Cancer Center, University of Wisconsin School of Medicine and Public 
      Health , Madison, Wisconsin 53705, United States.
LA  - eng
GR  - T32 GM008505/GM/NIGMS NIH HHS/United States
GR  - R01 CA205101/CA/NCI NIH HHS/United States
GR  - P30 CA014520/CA/NCI NIH HHS/United States
GR  - T32 CA009206/CA/NCI NIH HHS/United States
GR  - R01 CA169365/CA/NCI NIH HHS/United States
GR  - R01 EB021336/EB/NIBIB NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170608
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Antibodies, Monoclonal)
RN  - 4Z63YK6E0E (daratumumab)
RN  - C6V6S92N3C (Zirconium)
RN  - EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
RN  - J06Y7MXW4D (Deferoxamine)
SB  - IM
MH  - A549 Cells
MH  - ADP-ribosyl Cyclase 1/*metabolism
MH  - Animals
MH  - Antibodies, Monoclonal/therapeutic use
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Deferoxamine/therapeutic use
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Lung Neoplasms/*diagnostic imaging
MH  - Mice
MH  - Mice, Nude
MH  - Positron-Emission Tomography/*methods
MH  - Zirconium/therapeutic use
PMC - PMC5552967
MID - NIHMS886510
OTO - NOTNLM
OT  - CD38
OT  - daratumumab
OT  - lung cancer
OT  - positron emission tomography (PET)
OT  - zirconium-89 (89Zr)
COIS- Notes The authors declare no competing financial interest.
EDAT- 2017/06/03 06:00
MHDA- 2018/04/10 06:00
PMCR- 2018/07/03
CRDT- 2017/06/03 06:00
PHST- 2017/06/03 06:00 [pubmed]
PHST- 2018/04/10 06:00 [medline]
PHST- 2017/06/03 06:00 [entrez]
PHST- 2018/07/03 00:00 [pmc-release]
AID - 10.1021/acs.molpharmaceut.7b00298 [doi]
PST - ppublish
SO  - Mol Pharm. 2017 Jul 3;14(7):2400-2406. doi: 10.1021/acs.molpharmaceut.7b00298. 
      Epub 2017 Jun 8.