Radioimmunoscintigraphy and radioimmunotherapy in nude mouse models. Studies with site-specifically modified monoclonal antibodies.
Site-specific covalent modification of monoclonal antibodies at the oligosaccharide offers advantages over more conventional modification processes that involve direct attachment at tyrosine, lysine or glutamic/aspartic acid side chains. Using the site-specific modification process, attachment sites on the antibody are distal to the antigen-binding region. Thus, homogeneity of antigen-binding properties and affinity for the unmodified protein are preserved. Furthermore, higher derivatization ratios with no resultant loss of immunoreactivity can be achieved for monoclonal antibodies modified at the oligosaccharide. In vivo biodistribution and tumor localization studies in nude mouse models suggest that antibodies radiolabeled at their oligosaccharide might represent improved immunoscintigraphic reagents. In a variety of tumor xenograft models, site-specific modified 111In-labeled antibody conjugates localized to the tumor site with little non-specific localization in other tissues or organs. The degree of localization at the target site was substantially greater than that of 111In-labeled antibodies directly modified at the tyrosine side chain. Preliminary studies with 212Bi- and 90Y-labeled antibodies modified at the oligosaccharide indicate that both of these radioisotopes have immunotherapeutic potential. Because of its preferential uptake by the kidney, the use of 212Bi may be best suited for tumors localized within the peritoneal cavity, such as ovarian and colorectal carcinomas. The toxicity of 90Y at high specific activities suggests that a regimen of repeated smaller doses of this radioisotope is best suited for therapeutic use. Studies in tumor-bearing mouse models are currently underway to better define the optimal dosage and administration regimens for both of these radioisotopes when attached to site-specific modified antibodies.
Alvarez
V L
VL
CYTOGEN Corporation, Princeton, New Jersey.
Lopes
A D
AD
Rodwell
J D
JD
McKearn
T J
TJ
Stuart
F P
FP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001666:Binding Sites, Antibody; D004195:Disease Models, Animal; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D016719:Radioimmunodetection; D016499:Radioimmunotherapy
D000911:Antibodies, Monoclonal