PMID- 22917884
OWN - NLM
STAT- MEDLINE
DCOM- 20121210
LR  - 20211021
IS  - 1535-5667 (Electronic)
IS  - 0161-5505 (Print)
IS  - 0161-5505 (Linking)
VI  - 53
IP  - 10
DP  - 2012 Oct
TI  - Immuno-PET of the hepatocyte growth factor receptor Met using the 1-armed 
      antibody onartuzumab.
PG  - 1592-600
LID - 10.2967/jnumed.111.102293 [doi]
AB  - The overexpression and overactivation of hepatocyte growth factor receptor (Met) 
      in various cancers has been linked to increased proliferation, progression to 
      metastatic disease, and drug resistance. Developing a PET agent to assess Met 
      expression would aid in the diagnosis and monitoring of responses to Met-targeted 
      therapies. In these studies, onartuzumab, the experimental therapeutic 1-armed 
      monoclonal antibody, was radiolabeled with (76)Br or (89)Zr and evaluated as an 
      imaging agent in Met-expressing cell lines and mouse xenografts. METHODS: 
      (89)Zr-desferrioxamine (df)-onartuzumab was synthesized using a df-conjugate; 
      (76)Br-onartuzumab was labeled directly. Met-binding studies were performed using 
      the human tumor-derived cell lines MKN-45, SNU-16, and U87-MG, which have 
      relatively high, moderate, and low levels of Met, respectively. Biodistribution 
      and small-animal PET studies were performed in MKN-45 and U87-MG xenografts. 
      RESULTS: (76)Br-onartuzumab and (89)Zr-df-onartuzumab exhibited specific, 
      high-affinity Met binding (in the nanomolar range) that was concordant with 
      established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both 
      tracers cleared slowly from nontarget tissues, with the highest uptake in tumor, 
      blood, kidneys, and lungs. (76)Br-onartuzumab MKN-45 tumor uptake remained 
      relatively constant from 18 h (5 percentage injected dose per gram of tissue 
      [%ID/g]) to 48 h (3 %ID/g) and exhibited tumor-to-muscle ratios ranging from 4:1 
      to 6:1. In contrast, (89)Zr-df-onartuzumab MKN-45 tumor uptake continued to 
      accumulate from 18 h (10 %ID/g) to 120 h (23 %ID/g), attaining tumor-to-muscle 
      ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging 
      studies with both tracers at 18 h, but after 48 h (89)Zr-df-onartuzumab image 
      quality improved, with at least 2-fold-greater tumor uptake than nontarget 
      tissues. MKN-45 tumor uptake for both tracers correlated significantly with tumor 
      mass and Met expression and was not affected by the presence of plasma shed Met. 
      CONCLUSION: (89)Zr-df-onartuzumab and (76)Br-onartuzumab specifically targeted 
      Met in vitro and in vivo; (89)Zr-df-onartuzumab achieved higher tumor uptake and 
      tumor-to-muscle ratios than (76)Br-onartuzumab at later times, suggesting that 
      (89)Zr-df-onartuzumab would be better suited to image Met for diagnostic and 
      prognostic purposes.
FAU - Jagoda, Elaine M
AU  - Jagoda EM
AD  - Molecular Imaging Program, National Cancer Institute, National Institutes of 
      Health, Bethesda, Maryland 20892-1088, USA. ejagoda@mail.nih.gov
FAU - Lang, Lixin
AU  - Lang L
FAU - Bhadrasetty, Veerendra
AU  - Bhadrasetty V
FAU - Histed, Stephanie
AU  - Histed S
FAU - Williams, Mark
AU  - Williams M
FAU - Kramer-Marek, Gabriela
AU  - Kramer-Marek G
FAU - Mena, Esther
AU  - Mena E
FAU - Rosenblum, Lauren
AU  - Rosenblum L
FAU - Marik, Jan
AU  - Marik J
FAU - Tinianow, Jeff N
AU  - Tinianow JN
FAU - Merchant, Mark
AU  - Merchant M
FAU - Szajek, Lawrence
AU  - Szajek L
FAU - Paik, Chang
AU  - Paik C
FAU - Cecchi, Fabiola
AU  - Cecchi F
FAU - Raffensperger, Kristen
AU  - Raffensperger K
FAU - Jose-Dizon, Joe-Marie
AU  - Jose-Dizon JM
FAU - Bottaro, Donald P
AU  - Bottaro DP
FAU - Choyke, Peter
AU  - Choyke P
LA  - eng
GR  - ZIA BC010656-09/Intramural NIH HHS/United States
GR  - ZIA BC011124-06/Intramural NIH HHS/United States
PT  - Journal Article
DEP - 20120823
PL  - United States
TA  - J Nucl Med
JT  - Journal of nuclear medicine : official publication, Society of Nuclear Medicine
JID - 0217410
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Bromine Radioisotopes)
RN  - C6V6S92N3C (Zirconium)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - *Antibodies, Monoclonal/metabolism/pharmacokinetics
MH  - Biological Transport
MH  - Bromine Radioisotopes
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Isotope Labeling
MH  - Mice
MH  - Positron-Emission Tomography/*methods
MH  - Proto-Oncogene Proteins c-met/*metabolism
MH  - Tumor Burden
MH  - Zirconium
PMC - PMC3982858
MID - NIHMS517340
EDAT- 2012/08/25 06:00
MHDA- 2012/12/12 06:00
PMCR- 2014/04/10
CRDT- 2012/08/25 06:00
PHST- 2012/08/25 06:00 [entrez]
PHST- 2012/08/25 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
PHST- 2014/04/10 00:00 [pmc-release]
AID - jnumed.111.102293 [pii]
AID - 10.2967/jnumed.111.102293 [doi]
PST - ppublish
SO  - J Nucl Med. 2012 Oct;53(10):1592-600. doi: 10.2967/jnumed.111.102293. Epub 2012 
      Aug 23.