title: Factors influencing the pharmacokinetics, dosimetry, and diagnostic accuracy of radioimmunodetection and radioimmunotherapy of carcinoembryonic antigen-expressing tumors.
abstract: 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-protein-dose therapy injection (4.0-27.5 mg of protein; 29.8-238.9 mCi). The anti-CEA antibodies NP-4 (Ka=10(8)M-1) and MN-14 (ka=10(9)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 (T1/2=17.6+/-12.6 versus 44.2 +/- 23.7 h) and whole body (t1/2= 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 131 I-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.
authors.affiliation: Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Newark, New Jersey 07103, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Behr
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: M I
authors.initials: MI
authors.lastname: Juweid
authors.forename: R M
authors.initials: RM
authors.lastname: Dunn
authors.forename: Z
authors.initials: Z
authors.lastname: Ying
authors.forename: C H
authors.initials: CH
authors.lastname: Zhang
authors.forename: J A
authors.initials: JA
authors.lastname: Siegel
authors.forename: D V
authors.initials: DV
authors.lastname: Gold
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D001853:Bone Marrow / Q000000981:diagnostic imaging; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy; D005260:Female; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D018579:Patient Selection; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D015203:Reproducibility of Results; D012189:Retrospective Studies; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes