Immunohistochemical and pharmacokinetic characterization of the site-specific immunoconjugate CYT-356 derived from antiprostate monoclonal antibody 7E11-C5

Abstract

In this study, a site-specific immunoconjugate, designated CYT-356, of the prostate-reactive monoclonal antibody 7E11-C5 was characterized by immunohistological methods for reactivity with normal and neoplastic human tissues. In addition, CYT-356 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 patterns of reactivity with normal human tissues. Although the majority of tissues tested were negative, weak reactivity with cardiac muscle, proximal kidney tubules, and sweat glands was observed. Positive staining of normal prostate epithelial cells and glandular lumina and strong reactivity with a subset of skeletal muscle cells were also observed. CYT-356 reacted with 100% of prostate tumors examined but was negative on a variety of other neoplasms. Following i.v. administration, CYT-356-111In rapidly localized to and imaged LNCaP human prostate adenocarcinoma xenografts in nude mice, reaching maximal levels of about 30% of injected dose/g of tumor within 3 days. No unusual localization was seen to any nontumor tissue or organ; the level of radioactivity in the normal tissues and organs was at or below that seen in the blood. The localization to xenografts was antigen specific and the accessible binding sites in 100-200-mg tumors appeared to be saturated at an antibody dose between 10 and 100 micrograms. These findings suggest that the CYT-356 immunoconjugate may be useful in the diagnosis and therapy of prostate cancer.