PHARMACOKINETICS, TISSUE DISTRIBUTION, AND IN-VIVO ANTITUMOR EFFECTS OF THE ANTIMELANOMA IMMUNOTOXIN ZME-GELONIN

Antibody ZME-018 is directed against the gp240 glycoprotein on the sur face of more than 80% of human melanoma cell lines and fresh biopsy sp ecimens. Previous studies in our laboratory described the in vitro cyt otoxicity and specificity of an immunoconjugate composed of mAb ZME-01 8 and the plant toxin gelonin. The present study describes the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xeno graft/nude mouse models. Pharmacokinetic studies of I-125-labeled ZME- 018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half- life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h ). The initial volume of distribution of the ZME-gelonin was also high er compared to that of ZME alone (2.85 ml compared to 1.91 ml) suggest ing an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME -gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 mu Ci . ml(-1) x min), In nude mice bearing well-developed h uman tumor A375 melanoma xenografts, administration of I-125-labeled Z ME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9 +/- 0.5 an d 1.5 +/- 0.6 respectively by 72 h. Compared with ZME, ZME-gelonin con jugate caused an increase in the content of radiolabel in kidney, sple en and liver. Treatment of nude mice bearing well-developed (150 mm(3) ) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelon in, or saline resulted in suppression of tumor growth in the immunotox in group but virtually no retardation of tumor growth in