124I-HuCC49deltaCH2 for TAG-72 antigen-directed positron emission tomography (PET) imaging of LS174T colon adenocarcinoma tumor implants in xenograft mice: preliminary results.
BACKGROUND
18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is widely used in diagnostic cancer imaging. However, the use of 18F-FDG in PET-based imaging is limited by its specificity and sensitivity. In contrast, anti-TAG (tumor associated glycoprotein)-72 monoclonal antibodies are highly specific for binding to a variety of adenocarcinomas, including colorectal cancer. The aim of this preliminary study was to evaluate a complimentary determining region (CDR)-grafted humanized CH2-domain-deleted anti-TAG-72 monoclonal antibody (HuCC49deltaCH2), radiolabeled with iodine-124 (124I), as an antigen-directed and cancer-specific targeting agent for PET-based imaging.


METHODS
HuCC49deltaCH2 was radiolabeled with 124I. Subcutaneous tumor implants of LS174T colon adenocarcinoma cells, which express TAG-72 antigen, were grown on athymic Nu/Nu nude mice as the xenograft model. Intravascular (i.v.) and intraperitoneal (i.p.) administration of 124I-HuCC49deltaCH2 was then evaluated in this xenograft mouse model at various time points from approximately 1 hour to 24 hours after injection using microPET imaging. This was compared to i.v. injection of 18F-FDG in the same xenograft mouse model using microPET imaging at 50 minutes after injection.


RESULTS
At approximately 1 hour after i.v. injection, 124I-HuCC49deltaCH2 was distributed within the systemic circulation, while at approximately 1 hour after i.p. injection, 124I-HuCC49deltaCH2 was distributed within the peritoneal cavity. At time points from 18 hours to 24 hours after i.v. and i.p. injection, 124I-HuCC49deltaCH2 demonstrated a significantly increased level of specific localization to LS174T tumor implants (p=0.001) when compared to the 1 hour images. In contrast, approximately 50 minutes after i.v. injection, 18F-FDG failed to demonstrate any increased level of specific localization to a LS174T tumor implant, but showed the propensity toward more nonspecific uptake within the heart, Harderian glands of the bony orbits of the eyes, brown fat of the posterior neck, kidneys, and bladder.


CONCLUSIONS
On microPET imaging, 124I-HuCC49deltaCH2 demonstrates an increased level of specific localization to tumor implants of LS174T colon adenocarcinoma cells in the xenograft mouse model on delayed imaging, while 18F-FDG failed to demonstrate this. The antigen-directed and cancer-specific 124I-radiolabled anti-TAG-72 monoclonal antibody conjugate, 124I-HuCC49deltaCH2, holds future potential for use in human clinical trials for preoperative, intraoperative, and postoperative PET-based imaging strategies, including fused-modality PET-based imaging platforms.
Zou
Peng
P
Division of Pharmaceutics, College of Pharmacy, The Ohio State University,and Department of Surgery, Arthur G. James Cancer Hospital, Columbus, Ohio 43210, USA.
Povoski
Stephen P
SP
Hall
Nathan C
NC
Carlton
Michelle M
MM
Hinkle
George H
GH
Xu
Ronald X
RX
Mojzisik
Cathy M
CM
Johnson
Morgan A
MA
Knopp
Michael V
MV
Martin
Edward W
EW
Sun
Duxin
D
D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000276:immunology; D019788:Fluorodeoxyglucose F18; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D006023:Glycoproteins; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; C047052:tumor-associated antigen 72; D019788:Fluorodeoxyglucose F18