Immunohistochemical and pharmacokinetic characterization of site-specific immunoconjugate 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine derived from anti-breast carcinoma monoclonal antibody 15A8.
In this study, the breast carcinoma-reactive monoclonal antibody 15A8 and a site-specific immunoconjugate of the antibody, 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine (15A8-GYK-DTPA), were characterized by immunohistological methods for reactivity with normal and neoplastic human tissues and normal cynomolgus monkey tissues. In addition, 15A8-GYK-DTPA labeled with 111In was assessed by in vivo imaging and pharmacokinetic studies for localization to human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar limited reactivity with normal human tissues. Specifically, epithelial structures, including normal breast epithelium, lung alveoli, bronchial epithelium and glands, liver bile ducts, pancreatic ducts, kidney distal and collecting tubules, epidermal and esophageal epithelium, endometrial glands, and thymic Hassall's corpuscles, were reactive. Normal monkey tissues stained with 15A8 exhibited a similar pattern of reactivities. Antibody 15A8 reacted broadly with epithelium-derived tumors; more than 60% of the cells in all of the breast, colon, non-small cell lung, ovarian, prostate, bladder, and renal carcinomas tested expressed the antigen. In contrast, a variety of nonepithelial neoplasms, including lymphomas, melanomas, sarcomas, and small cell lung carcinomas, were nonreactive. 15A8-GYK-DTPA-111In administered i.v. rapidly localized to and imaged both MX-1 and MCF-7 human breast carcinoma xenografts in nude mice, reaching maximal levels of about 20% of injected dose/g of tumor within 4 days. No unusual localization to any nontumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that seen in the blood. Furthermore, the immunoconjugate did not accumulate in xenografts of the antigen-negative breast carcinoma ZR-75-1, which indicates that tumor localization was antigen specific. Pharmacokinetic studies in cynomolgus monkeys suggested that significant amounts of 15A8-GYK-DTPA-111In did not localize to normal epithelia and demonstrated that the immunoconjugate was not toxic. These findings suggest that antibody 15A8 may be useful in the diagnosis and therapy of breast cancer and possibly other carcinomas.
Rosenstraus
M J
MJ
Department of Biological Research, Cytogen Corporation, Princeton, New Jersey 08540.
Davis
W L
WL
Lopes
A D
AD
D'Aleo
C J
CJ
Gilman
S C
SC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D000922:Immunotoxins / Q000378:metabolism*; D007205:Indium Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000276:immunology*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000276:immunology; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D007074:Immunoglobulin G; D000922:Immunotoxins; D007205:Indium Radioisotopes; D009842:Oligopeptides; C062250:glycyl-tyrosyl-lysine-DTPA; D004369:Pentetic Acid