Recombinant immunotoxins directed against the c-erb-2/HER2/neu oncogene product: In vitro cytotoxicity, pharmacokinetics, and in vivo efficacy studies in xenograft models

TAB-250 and BACH-250 are murine and human chimeric antibodies directed at t he extracellular domain of the gp185(c-erb-2) (HER2/neu) growth factor rece ptor overexpressed in a variety of tumor types, including ovarian and breas t carcinoma. The ribosome-inhibiting plant toxin gelonin (rGel) was chemica lly coupled to both antibodies, and the resulting immunotoxins were purifie d and tested in vitro against human tumor cells expressing various levels o f HER2/neu and in vivo against human tumor xenograft models. The binding of both BACH-250 and BACH-250/rGel conjugate to target cells was essentially equivalent, Against SKOV-3 cells, the IC50 of BACH-250/rGel was 97 pM (17 n g/ml), whereas BACH-250 and rGel alone showed no cytotoxic effects, There w as a clear correlation between expression levels of HER-2/neu and cytoimmun otoxin. Tissue distribution studies showed that the antibody and immunotoxi n both concentrate 2-10-fold higher in tumors than in normal tissues, with optimal tumor uptake occurring 48-96 h after administration, Plasma clearan ce curves for BACH-250 and BACH-250/rGel showed terminal-phase half-lives o f 26 and 72 h, respectively. In athymic mice bearing s.c. or i.p. SKOV-3 tu mors, immunotoxin treatment slowed tumor growth by 99 and 94% at days 35 an d 49 after implantation, respectively, and lengthened the median survival b y 40% (from 30 to 50 days) in mice bearing lethal i.p. tumors. We conclude that clinical development of BACH-250/rGel may be warranted in patients wit h HER2/neu-expressing malignancies.