Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin

Abstract

Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study described the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of 125I-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 higher compared to that of ZME alone (2.85 ml compared to 1.94 ml) suggesting 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 microCi.ml-1 x min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of 125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9 +/- 0.5 and 1.5 +/- 0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, 213% increase in mean survival time compared with the saline treatment (14.2 +/- 2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.