Murine monoclonal antibodies against carcinoembryonic antigen: immunological, pharmacokinetic, and targeting properties in humans.
We have examined three 131I-labeled murine monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA), NP-2, NP-3, and NP-4, after i.v. injection in patients with diverse cancers. Although the MAbs had a similar tumor-targeting ability, several important features were discovered that have led us to the selection of one of these MAbs for further clinical evaluation. We found that it is important to evaluate MAbs with a high immunoreactivity. For example, the MAb NP-2 was used initially in patients with an immunoreactivity between 35 and 50%. Although the tumor-imaging properties of this MAb compared favorably with the affinity-purified, goat anti-CEA antibody that we used previously, further purification of NP-2 to an immunoreactivity greater than 70% uncovered a previously unknown cross-reactivity with human granulocytes. It was also discovered that the MAbs differed in their ability to complex with CEA in the blood. Plasma samples were analyzed by gel filtration at 1 or 24 h after injection. The formation of complexes with circulating CEA was dependent on the CEA:MAb ratio in the blood. NP-3 complexed to a greater degree with CEA than NP-4, but NP-2 did not complex with CEA even at CEA:NP-2 ratios of 55 to 1. NP-3 commonly showed enhanced uptake in the colon by external scintigraphy, and examination of the radioactivity in the stool showed that most of the radioactivity was associated with whole IgG and large-sized fragments of NP-3. We also compared the rate of elimination of radioactivity from the blood for all of the MAbs and compared the clearance of NP-3 to NP-4 at three different ranges of MAb protein doses (less than 1.0 mg, 1 to 5 mg, and 5 to 20 mg). The blood clearance rate for NP-3 was fastest among the other MAbs at protein doses exceeding 1.0 mg. Patients given less than 1.0 mg of NP-4 had a significantly (P less than 0.005) shorter elimination half-life than patients given more than 1.0 mg of NP-4. By virtue of NP-4's good targeting properties in patients and its limited complexation with circulating CEA, it was selected as the MAb of choice for CEA tumor imaging.
Sharkey
R M
RM
Center for Molecular Medicine and Immunology, University of Medicine and Dentistry of New Jersey, Newark 07103.
Goldenberg
D M
DM
Goldenberg
H
H
Lee
R E
RE
Ballance
C
C
Pawlyk
D
D
Varga
D
D
Hansen
H J
HJ
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000032:analysis; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003429:Cross Reactions; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007457:Iodine Radioisotopes; D008657:Metabolic Clearance Rate; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging; D011877:Radionuclide Imaging
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D002272:Carcinoembryonic Antigen; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes