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Targeting of Liver Metastases of Colorectal Cancer with IgG, F(ab')₂, and Fab' Anti-Carcinoembryonic Antigen Antibodies Labeled with ^99mTc: The Role of Metabolism and Kinetics¹

Departments of Nuclear Medicine [T. B., W. B., F. W.] and Biochemistry [E. H.] of the Friedrich-Alexander-University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany, and Garden State Cancer Center at the Center for Molecular Medicine and Immunology [T. B., D. M. G.], Newark, New Jersey 07103

The aim of this study was to investigate targeting of the liver metastases by directly ^99mTc-labeled complete (IgG) and fragmented antibodies [F(ab')₂ and Fab'] in relation to their kinetics and metabolic fate. A total of 127 patients with metastatic colorectal cancer were examined [IgG₁, BW 431/26 (Behringwerke, Marburg, Germany) n = 50; F(ab')₂, F023C5 (Sorin Biomedica, Saluggia, Italy) n = 58; Fab', IMMU-4 (Immunomedics, Morris Plains, NJ) n = 19]. Native monoclonal antibodies (MAbs), serum samples from 10 min to 24 h postinjection (p.i.), and urine were analyzed by gel filtration chromatography. Kinetic data were deduced from whole-body and single-photon emission computed tomographic scans, performed 10 min to 24 h p.i. (region-of-interest technique). In BW 431/26, 96% of injected activity was labeled IgG₁; in F023C5, 29% was F(ab')₂, and 71% was Fab'; and in IMMU-4, 92% was Fab', and 8% was F(ab')₂. Serum half-lives were: IgG₁, 36 h (liver uptake predominant); F(ab')₂, 16 h; and Fab', 4 h (renal uptake predominant). All Mabs were metabolized, fragments more rapidly than IgG, to low-molecular-weight products and excreted into the urine (e.g., Tc-cystine). In targeting liver metastases, sensitivities were found to be higher for fragments (44.1, 72.5, and 80% for BW 431/26, F023C5, and IMMU-4, respectively) but at significantly lower tumor:background ratios than with IgG (1.78 ± 0.29 versus 1.29 ± 0.11 and 1.43 ± 0.53; P < 0.01). With IgG, there was a continuous tumor uptake over 24 h, whereas with fragments, the maximal uptake occurred mostly within 1 h, with subsequent clearance being slower for antigen-bound activity than for nonspecific background. Hence, diagnosis was possible mostly after 4 h with fragments but often not before 24 h with IgG. These results show that the higher sensitivity of fragments in liver lesion targeting at earlier p.i. times does not rely on an increased antibody uptake but on a more rapid clearance of nonspecific background activity due to faster metabolism and excretion. Intact MAbs show a slow, continuous uptake, leading to higher tumor:background ratios at later p.i. times, often beyond the imaging possibilities of ^99mTc.