64Cu-labeled affibody molecules for imaging of HER2 expressing tumors.
BACKGROUND
The development of molecular probes based on novel engineered protein constructs is under active investigation due to the great potential of this generalizable strategy for imaging a variety of tumor targets.


CONCLUSIONS
In this report, human epidermal growth factor receptor type 2 (HER2)-binding Affibody molecules were radiolabeled with (64)Cu and their imaging ability was further evaluated in tumor mice models to understand the promise and limitations of such probes. The anti-HER2 Affibody molecules in monomeric (Z(HER2:477)) and dimeric [(Z(HER2:477))(2)] forms were site specifically modified with the maleimide-functionalized chelator, 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-acetate mono (N-ethylmaleimide amide) (Mal-DOTA). The resulting DOTA-Affibody conjugates were radiolabeled with (64)Cu and evaluated in nude mice bearing subcutaneous SKOV3 tumors. Biodistribution experiments showed that tumor uptake values of (64)Cu-DOTA-Z(HER2:477) and (64)Cu-DOTA-(Z(HER2:477))(2) were 6.12 +/- 1.44% and 1.46 +/- 0.50% ID/g, respectively, in nude mice (n = 3 each) at 4 h postinjection. Moreover, (64)Cu-labeled monomer exhibited significantly higher tumor/blood ratio than that of radiolabeled dimeric counterpart at all time points examined in this study. MicroPET imaging of (64)Cu-DOTA-Z(HER2:477) in SKOV3 tumor mice clearly showed good and specific tumor localization. This study demonstrates that (64)Cu-labeled Z(HER2:477) is a promising targeted molecular probe for imaging HER2 receptor expression in living mice. Further work is needed to improve the excretion properties, hence dosimetry and imaging efficacy, of the radiometal-based probe.
Molecular Imaging Program at Stanford, Departments of Radiology and Bioengineering, Bio-X Program, Stanford University, California, CA 94305-5344, USA. zcheng@stanford.edu
Zhen
Z
Cheng
Omayra Padilla
OP
De Jesus
Daniel J
DJ
Kramer
Abhijit
A
De
Jack M
JM
Webster
Olivier
O
Gheysens
Jelena
J
Levi
Mohammad
M
Namavari
Sen
S
Wang
Jinha Mark
JM
Park
Rong
R
Zhang
Hongguang
H
Liu
Brian
B
Lee
Faisal A
FA
Syud
Sanjiv Sam
SS
Gambhir
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D013194:Staining and Labeling; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human