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Factors Influencing the Pharmacokinetics, Dosimetry, and Diagnostic Accuracy of Radioimmunodetection and Radioimmunotherapy of Carcinoembryonic Antigen-expressing Tumors¹

Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Newark, New Jersey 07103 [T. M. B., R. M. S., M. E. J., R. M. D., D. V. G., D. M. G.]; Department of Statistics, Rutgers University, Piscataway, New Jersey 08855 [Z. Y., C-H. Z.]; and Department of Radiation Oncology, Cooper Hospital/University Medical Center, Camden, New Jersey 08103 [J. A. S.]

The aim of this study was to examine factors that may influence the pharmacokinetics, diagnostic accuracy, and dosimetry in radioimmunodetection and radioimmunotherapy with anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs). Data from 275 patients with CEA-expressing tumors were analyzed retrospectively. Of these, 69 patients devoid of human antimouse antibody (i.e., 31 colorectal, 9 lung, 7 breast, 4 ovarian, 6 pancreatic, 9 medullary thyroid, 1 gallbladder, and 1 salivary gland cancer, and 1 primary tumor of unknown origin) underwent a low-protein-dose diagnostic study (0.3–2.6 mg of protein; 6.8–28.8 mCi ¹³¹I-labeled IgG or fragments), followed within 4 weeks by a high-proteindose therapy injection (4.0–27.5 mg of protein; 29.8–238.9 mCi). The anti-CEA antibodies NP-4 (K_a = 10⁸ M^-1) and MN-14 (K_a = 10⁹ M^-1) were used. Plasma clearance, the molecular composition of radioactivity in the plasma, and the cumulated activity in organs and tumors were determined. Radiation doses were derived from the Medical Internal Radiation Dose scheme. At a low-protein dose and over a similar range of plasma CEA, a significantly higher percentage of MN-14 than of NP-4 was complexed with circulating CEA, consistent with its higher affinity. Complexation was reduced with increasing protein doses. However, the targeting sensitivity was not affected. Profound differences were 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 whole body (t_1/2 = 53.2 ± 30.1 versus 114.6 ± 59.7 h) than all other tumor types (P < 0.001). Consequently, significantly lower red marrow (2.1 ± 1.0 cGy/mCi versus 4.3 ± 1.6 cGy/mCi) and whole-body doses (0.5 ± 0.3 cGy/mCi versus 1.0 ± 0.4 cGy/mCi) were seen in colorectal cancer patients as compared with other tumor types (P < 0.001). This clearance is probably due to hepatic metabolism of the immune complexes. Clearance rates were especially high in patients with colorectal cancer having large liver metastases and elevated liver enzymes (rapid hepatic clearance with liberation of free I^-). In contrast, a disease-stage and plasma CEA-matched cohort of colorectal cancer patients, examined with the ¹³¹I-labeled anti-colon-specific antigen p mAb Mu-9, showed normal murine IgG pharmacokinetics (n = 22; 3 of them compared intraindividually to MN-14). Only in colorectal cancer patients did complexes between mAb and CEA tend to clear rapidly, whereas Mu-9 had normal kinetics in these patients. This suggests that different CEA-expressing cancer types may produce heterogeneous CEA molecules and that the variability in mAb clearance is due to varying clearance rates of these different circulating CEA subspecies. Disease-related alterations in antibody metabolism are unlikely, given that only anti-CEA antibodies exhibit this phenomenon.

¹ Supported in part by Grant DFG Be 1689/1-1/2 from the Deutsche Forschungsgemeinschaft and NIH Grants CA54425 and CA39841.

² To whom requests for reprints should be addressed, at Garden State Cancer Center at the Center for Molecular Medicine and Immunology, 1 Bruce Street, Newark, NJ 07103-2763. Phone: (201) 982-4600; Fax: (201) 982-7047.

Received 10/20/95. Accepted 2/ 8/96.

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