TARGETING OF LIVER METASTASES OF COLORECTAL-CANCER WITH IGG, F(AB')(2), AND FAB' ANTICARCINOEMBRYONIC ANTIGEN ANTIBODIES LABELED WITH TC-99M - THE ROLE OF METABOLISM AND KINETICS

The aim of this study was to investigate targeting of the liver metast ases by directly Tc-99m-labeled complete (IgG) and fragmented antibodi es [F(ab')(2) and Fah'] in relation to their kinetics and metabolic fa te. A total of 127 patients with metastatic colorectal cancer were exa mined [IgG(1), 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 antibodie s (MAbs), serum samples from 10 min to 24 h postinjection (p.i.), and urine were analyzed by gel filtration chromatography. Kinetic data wer e deduced from whole-body and single-photon emission computed tomograp hic scans, performed 10 min to 24 h p.i. (region-of-interest technique ). In BW 431/26, 96% of injected activity was labeled IgG(1); in F023C 5, 29% was F(ab')(2), and 71% was Fab'; and in IMMU-4 92% was Fab', an d 8% was F(ab')(2). Serum half-lives were: IgG(1), 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-cystin e). In targeting liver metastases, sensitivities were found to be high er for fragments (44.1, 72.5, and 80% for BW 431/26, F023C5, and IMMU- 4 respectively) but at significantly lower tumor:background ratios tha n 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, wherea s 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 fa ster metabolism and excretion. Intact MAbs show a slow, continuous upt ake, leading to higher tumor:background ratios at later p.i. times, of ten beyond the imaging possibilities of Tc-99m.