Pharmacokinetics, biodistribution, and gamma camera imaging of 111In-KC-4G3 murine monoclonal antibody in athymic nude mice with or without human tumor xenografts.
The pharmacokinetics and tissue distribution of the monoclonal antibody radioconjugate 111In-diethylenetriaminepentaacetic acid-KC-4G3, which is directed against a high molecular weight mucin(s) antigen expressed on the human milk fat globule and many epithelial cell membranes, were examined in BALB/c nude mice with and without xenografts of the human tumor lines ZR-75 (mammary adenocarcinoma, KC-4G3 antigen positive) and BALL-1 (B-cell lymphoma, KC-4G3 antigen negative). Plasma of ZR-75 and BALL-1 tumor-bearing nude mice inoculated with 111In-KC-4G3 had a higher initial volume of distribution (V1), steady state volume of distribution (Vss), and plasma clearance and a lower initial half-life (t1/2 alpha) than non-tumor-bearing nude mice. There were no significant differences in biological half-life (t1/2 beta) in tumor- and non-tumor-bearing nude mice. Urinary and fecal excretion of radioactivity by ZR-75 tumor-bearing mice was greater than that of BALL-1 and non-tumor-bearing mice. Localization of 111In-KC-4G3 in mice bearing xenografts of ZR-75 was significantly greater than in mice with BALL-1 tumors. Uptake of 111In-KC-4G3 by ZR-75 tumors averaged 14% of injected dose/g at 72 h after inoculation and was unaffected by antibody dose. Significantly, the radioconjugate concentration in ZR-75 tumors remained relatively constant from 72 to 336 h post-inoculation, while that in normal tissues declined considerably over this period. Nonspecific reticuloendothelial tissue uptake of 111In-KC-4G3 was only moderately affected by pretreatment with a large excess of unlabeled normal mouse immunoglobulin and was not changed by treatment with asialofetuin. Further enhancement of specific localization of 111In-KC-4G3 was obtained by subtraction of the blood pool identified by co-inoculation of 131I-labeled, isotype-identical, normal mouse immunoglobulin. Gamma camera images of 111In-KC-4G3-inoculated ZR-75 tumor-bearing mice showed enhanced tumor localization compared to mice with BALL-1 tumors. The results of this study suggest that 111In-KC-4G3 may prove useful for imaging and possibly therapy of human malignancies expressing the high molecular weight epithelial mucin(s).
Longley
C
C
Laboratory of Cell Biology, AMC Cancer Research Center, Denver, Colorado.
Furmanski
P
P
Dienhart
D G
DG
Lear
J
J
Bloedow
D
D
Kasliwal
R
R
Bunn
P A
PA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000276:immunology; D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009077:Mucins / Q000032:analysis* / Q000276:immunology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000276:immunology*; D011877:Radionuclide Imaging; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007205:Indium Radioisotopes; D009077:Mucins