Immuno-PET quantitation of de2-7 epidermal growth factor receptor expression in glioma using 124I-IMP-R4-labeled antibody ch806.
Overexpression, activation, and mutations of the epidermal growth factor receptor (EGFR) are commonly found in solid tumors. The aim of this study was to develop a PET-based method for detecting the constitutively active mutant de2-7 EGFR, which is associated with disease progression and resistance to chemotherapy and radiotherapy in glioma.


METHODS
The chimeric antibody ch806, which selectively binds an epitope of the EGFR that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor, was conjugated to the radiohalogen (124)I via the residualizing ligand IMP-R4, and in vitro properties were characterized. In vivo biodistribution and small-animal PET studies were performed in BALB/c nude mice bearing U87MG.de2-7 glioma xenografts. Imaging results were correlated with measured tumor uptake of the radioconjugate.


RESULTS
(124)I-IMP-R4-ch806 had an immunoreactivity of 78.3% and was stable for 7 d when incubated in serum in vitro. The biodistribution analysis of (124)I-IMP-R4-ch806 demonstrated a maximal uptake of 30.95 +/- 6.01 percentage injected dose per gram (%ID/g) in U87MG.de2-7 xenografts at 48 h after injection, with prolonged tumor retention (6.07 +/- 0.80 %ID/g at 216 h after injection). The tumor-to-blood ratio increased from 0.44 at 4 h after injection to a maximum of 4.70 at 168 h after injection. PET of (124)I-IMP-R4-ch806 biodistribution was able to clearly detect the U87MG.de2-7 tumors at 24 h after injection and for at least 168 h after injection. Correlation between tumor PET image quantitation of (124)I-IMP-R4-ch806 and %ID/g determined from resected tissues (r = 0.9350) was excellent.


CONCLUSIONS
These results show that immuno-PET with (124)I-IMP-R4-ch806 is feasible and allows noninvasive quantitation of de2-7 EGFR expression in vivo.
Lee
Fook T
FT
Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia.
O'Keefe
Graeme J
GJ
Gan
Hui K
HK
Mountain
Angela J
AJ
Jones
Gareth R
GR
Saunder
Timothy H
TH
Sagona
Jessica
J
Rigopoulos
Angela
A
Smyth
Fiona E
FE
Johns
Terrance G
TG
Govindan
Serengulam V
SV
Goldenberg
David M
DM
Old
Lloyd J
LJ
Scott
Andrew M
AM
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D014057:Tomography, X-Ray Computed
D000911:Antibodies, Monoclonal; C550249:IMP-R4 peptide; D007457:Iodine Radioisotopes; D009842:Oligopeptides; C518939:monoclonal antibody 806; D004369:Pentetic Acid; D066246:ErbB Receptors