CELL-SURFACE DENSITY OF P185(C-ERBB-2) DETERMINES SUSCEPTIBILITY TO ANTI-P185(C-ERBB-2)-RICIN-A CHAIN (RTA) IMMUNOTOXIN THERAPY ALONE AND IN COMBINATION WITH ANTI-P170(EGFR)-RTA IN OVARIAN-CANCER CELLS

Approximately 30% of ovarian and breast cancers overexpress p185(c-erb B-2) With as many as 10(6) receptors/cell, Normal cells have as few as 10(4) receptors/cell, We have examined the susceptibility of SKOv3 hu man ovarian cancer cells to anti-c-erbB2 antibodies and immunotoxins a s a function of c-erbB-2 density on the cell surface. A panel of SKOv3 clones that expressed different densities of p185(c-erbB-2) receptor were generated through transfection with the c-er6B-2 gene. A signific ant correlation was found between p185(c-erbB-2) density and susceptib ility to killing by anti-p185(c-erbB-2)-ricin A chain (anti-p185(c-erb B-2)-RTA) immunotoxins. With 10(5) copies/cell of p185(c-erbB-2), <10% of clonogenic ovarian cancer cells could be eliminated, whereas in cl ones that expressed 10(6) copies/cell of p185(c-erbB-2), 99.9% of clon ogenic tumor cells were killed. In cell lines that overexpressed p185( c-erbB-2) also expressed p170(EGFR), anti-p185(c-erbB-2)-RTA and anti- p170EGFR-RTA immunotoxins exerted synergistic cytotoxicity. Treatment with the two immunotoxins could eliminate 99.99% of clonogenic cells. Importantly, tumor cells that had survived first treatment with anti-p 185(c-cerbB-2)-RTA alone still retained sensitivity to repeat treatmen t with the same immunotoxin and also proved susceptible to the synergi stic cytotoxicity of anti-p185(c-cerB-2) RTA in combination with anti- p170(EGFR)-RTA. Growth characteristics of the clones expressing variou s levels of p185(c-erbB-2) were also studied. No correlation was found between p185(c-erbB-2) expression levels and the rate of anchorage-de pendent growth, anchorage-independent growth, or in vivo growth in nud e mice.