FACTORS INFLUENCING THE PHARMACOKINETICS, DOSIMETRY, AND DIAGNOSTIC-ACCURACY OF RADIOIMMUNODETECTION AND RADIOIMMUNOTHERAPY OF CARCINOEMBRYONIC ANTIGEN-EXPRESSING TUMORS

The aim of this study was to examine factors that may influence the ph armacokinetics, diagnostic accuracy, and dosimetry in radioimmunodetec tion and radioimmunotherapy with anti-carcinoembryonic antigen (CEA) m onoclonal antibodies (mAbs), Data from 275 patients with CEA-expressin g tumors were analyzed retrospectively. Of these, 69 patients devoid o f human antimouse antibody (i.e., 31 colorectal, 9 lung, 7 breast, 4 o varian, 6 pancreatic, 9 medullary thyroid, 1 gallbladder, and 1 saliva ry gland cancer, and 1 primary tumor of unknown origin) underwent a lo w-protein-dose diagnostic study (0.3-2.6 mg of protein; 6.8-28.8 mCi I -131-labeled IgG or fragments), followed within 4 weeks by a high-prot ein-dose therapy injection (4,0-27,5 mg of protein; 29.8-238.9 mCi). T he anti-CEA antibodies NP-4 (K-a = 10(8) M(-1)) and MN-14 (K-a = 10(9) M(-1)) were used. Plasma clearance, the molecular composition of radi oactivity in the plasma, and the cumulated activity in organs and tumo rs were determined, Radiation doses were derived from the Medical Inte rnal Radiation Dose scheme. At a low-protein dose and over a similar r ange of plasma CEA, a significantly higher percentage of MN-14 than of NP-4 was complexed with circulating CEA, consistent with its higher a ffinity, Complexation was reduced with increasing protein doses. Howev er, the targeting sensitivity was not affected. Profound differences w ere found in the clearance of the antibody between different types of cancer. Colorectal cancer patients cleared the antibody significantly faster from blood (T-1/2 = 17.6 +/- 12.6 versus 44.2 +/- 23.7 h) and w hole body (t(1/2) = 53.2 +/- 30.1 versus 114.6 +/- 59.7 h) than all ot her tumor types (P < 0.001). Consequently, significantly loser red mar row (2.1 +/- 1.0 cGy/mCi versus 4.3 +/- 1.6 cGy/mCi) and whole-body do ses (0.5 +/- 0.3 cGy/mCi versus 1.0 +/- 0.4 cGy/mCi) were seen in colo rectal cancer patients as compared with other tumor types (P < 0.001), This clearance is probably due to hepatic metabolism of the immune co mplexes. Clearance rates were especially high in patients with colorec tal cancer having large liver metastases and elevated liver enzymes (r apid hepatic clearance with liberation of free I-). In contrast, a dis ease-stage and plasma CEA-matched cohort of colorectal cancer patients , examined with the I-131-labeled anti-colon-specific antigen p mAb Mu -9, showed normal murine IgG pharmacokinetics (It = 22; 3 of them comp ared intraindividually to MN-14). Only in colorectal cancer patients d id complexes between mAb and CEA tend to clear rapidly, whereas Mu-9 h ad normal kinetics in these patients. This suggests that different CEA -expressing cancer types may produce heterogeneous CEA molecules and t hat the variability in mAb clearance is due to varying clearance rates of these different circulating CEA subspecies. Disease-related altera tions in antibody metabolism are unlikely, given that only anti-CEA an tibodies exhibit this phenomenon.