title: High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment.
abstract: Rapid imaging by antitumor antibodies has been limited by the prolonged targeting kinetics and clearance of labeled whole antibodies. Genetically engineered fragments with rapid access and high retention in tumor tissue combined with rapid blood clearance are suitable for labeling with short-lived radionuclides, including positron-emitting isotopes for positron-emission tomography (PET). An engineered fragment was developed from the high-affinity anticarcinoembryonic antigen (CEA) monoclonal antibody T84.66. This single-chain variable fragment (Fv)-C(H)3, or minibody, was produced as a bivalent 80 kDa dimer. The macrocyclic chelating agent 1,4,7, 10-tetraazacyclododecane-N,N',N", N"'-tetraacetic acid (DOTA) was conjugated to the anti-CEA minibody for labeling with copper-64, a positron-emitting radionuclide (t(1/2) = 12.7 h). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA positive) and C6 rat glioma (CEA negative) xenografts. Five hours after injection with (64)Cu-DOTA-minibody, microPET imaging showed high uptake in CEA-positive tumor (17.9% injected dose per gram +/- 3.79) compared with control tumor (6.0% injected dose per gram +/- 1.0). In addition, significant uptake was seen in liver, with low uptake in other tissues. Average target/background ratios relative to neighboring tissue were 3-4:1. Engineered antibody fragments labeled with positron-emitting isotopes such as copper-64 provide a new class of agents for PET imaging of tumors.
authors.affiliation: Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. awu@coh.org.
authors.forename: A M
authors.initials: AM
authors.lastname: Wu
authors.forename: P J
authors.initials: PJ
authors.lastname: Yazaki
authors.forename: S w
authors.initials: Sw
authors.lastname: Tsai
authors.forename: K
authors.initials: K
authors.lastname: Nguyen
authors.forename: A L
authors.initials: AL
authors.lastname: Anderson
authors.forename: D W
authors.initials: DW
authors.lastname: McCarthy
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
authors.forename: J E
authors.initials: JE
authors.lastname: Shively
authors.forename: L E
authors.initials: LE
authors.lastname: Williams
authors.forename: A A
authors.initials: AA
authors.lastname: Raubitschek
authors.forename: J Y
authors.initials: JY
authors.lastname: Wong
authors.forename: T
authors.initials: T
authors.lastname: Toyokuni
authors.forename: M E
authors.initials: ME
authors.lastname: Phelps
authors.forename: S S
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003301:Copper Radioisotopes; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007553:Isotope Labeling; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D014055:Tomography, Emission-Computed / Q000379:methods; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D002272:Carcinoembryonic Antigen; D003301:Copper Radioisotopes; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins; C055966:immunoglobulin Fv