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High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled
1Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. awu@coh.org.
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.
Insights
Engineered antibody fragments, like the anti-CEA minibody, offer improved tumor targeting and rapid clearance for positron emission tomography (PET) imaging. This advancement enables faster and clearer visualization of tumors using copper-64 labeled agents.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Whole antibodies for tumor imaging face limitations due to slow targeting and clearance.
- Genetically engineered antibody fragments offer enhanced tumor penetration and faster blood clearance.
Purpose of the Study:
- To develop and evaluate an engineered antibody fragment for improved positron emission tomography (PET) imaging of tumors.
- To assess the in vivo targeting kinetics and biodistribution of a novel anti-CEA minibody labeled with copper-64.
Main Methods:
- Development of a bivalent single-chain variable fragment (Fv)-C(H)3 minibody targeting carcinoembryonic antigen (CEA).
- Conjugation of the macrocyclic chelator DOTA to the minibody for labeling with copper-64 (64Cu).
- In vivo microPET imaging in mice bearing CEA-positive and CEA-negative tumors.
Main Results:
- The 64Cu-labeled anti-CEA minibody demonstrated high uptake in CEA-positive tumors (17.9% ID/g) compared to CEA-negative tumors (6.0% ID/g) at 5 hours post-injection.
- Significant liver uptake was observed, with low uptake in other tissues.
- Target-to-background ratios of 3-4:1 were achieved for CEA-positive tumors relative to surrounding tissues.
Conclusions:
- Engineered antibody fragments, such as the anti-CEA minibody, are suitable for labeling with short-lived positron-emitting isotopes like 64Cu.
- These novel agents offer a promising new approach for rapid and effective PET imaging of CEA-expressing tumors.
- The rapid targeting and clearance characteristics enhance imaging efficiency and diagnostic potential.
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