Immuno-PET of the hepatocyte growth factor receptor Met using the 1-armed antibody onartuzumab.
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.


CONCLUSIONS
(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.
Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1088, USA. ejagoda@mail.nih.gov
Elaine M
EM
Jagoda
Lixin
L
Lang
Veerendra
V
Bhadrasetty
Stephanie
S
Histed
Mark
M
Williams
Gabriela
G
Kramer-Marek
Esther
E
Mena
Lauren
L
Rosenblum
Jan
J
Marik
Jeff N
JN
Tinianow
Mark
M
Merchant
Lawrence
L
Szajek
Chang
C
Paik
Fabiola
F
Cecchi
Kristen
K
Raffensperger
Joe-Marie
JM
Jose-Dizon
Donald P
DP
Bottaro
Peter
P
Choyke
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport; D001967:Bromine Radioisotopes; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D047368:Tumor Burden; D015040:Zirconium
D000911:Antibodies, Monoclonal; D001967:Bromine Radioisotopes; D015040:Zirconium; D019859:Proto-Oncogene Proteins c-met