Molecular targeting of carbonic anhydrase IX in mice with hypoxic HT29 colorectal tumor xenografts.
BACKGROUND
Carbonic anhydrase IX (CAIX) is a membrane spanning protein involved in the enzymatic regulation of tumor acid-base balance. CAIX has been shown to be elevated in a number of hypoxic tumor types. The purpose of this study was to determine the efficiency of intact and IgG fragments of cG250 to target CAIX in vivo in a hypoxic tumor model.


RESULTS
Conventional biodistribution studies were performed with (111)In-DO3A-cG250, (111)In-DO3A-F(ab')(2)-cG250 and (111)In-DO3A-Fab-cG250. Additional ex vivo analysis of the tumor was performed with markers for tumor hypoxia, blood perfusion and endogenous CAIX expression. All four data sets were digitally correlated to determine the optimal agent for determining hypoxia in a HT29 colon cancer xenograft. The HT29 human colorectal tumor xenografts show strong CAIX expression in hypoxic areas of poor blood perfusion. The intact IgG had an initial high focal uptake at the periphery of these hypoxic regions and penetration into the areas of highest CAIX expression over the 7-day study period. The lower molecular weight antibody fragments had a faster uptake into areas of high CAIX expression, but had a much lower absolute uptake at the optimal imaging times.


CONCLUSIONS
For the clinical detection of hypoxia induced CAIX using cG250 antibody based agents, imaging with the intact IgG at 7 days post injection would allow for the most sensitive and accurate detection of CAIX.
Department of Radiology, Memorial Sloan Kettering Cancer Service, New York, New York, United States of America.
Sean
S
Carlin
Nahida
N
Khan
Thomas
T
Ku
Valerie A
VA
Longo
Steve M
SM
Larson
Peter M
PM
Smith-Jones
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000473:pathology*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C106533:G250 monoclonal antibody; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C492796:Car9 protein, mouse