Synergistic interaction between anti-p185(HER-2) ricin A chain immunotoxins and radionuclide conjugates for inhibiting growth of ovarian and breast cancer cells that overexpress HER-2

Radionuclide conjugates or ricin A chain (RTA) immunotoxins that target p18 5(HER-2) have partially inhibited the growth of human ovarian cancer xenogr afts in athymic mice but generally have not cured mice bearing human tumor transplants, The present study was undertaken to explore whether a combinat ion of ionizing radiation and an immunotoxin could exert additive or synerg istic cytotoxicity in culture and in vise against cancer cells that overexp ress p185(HER-2). In cell culture, treatment with 200-2000 cGy external bea m irradiation followed by incubation with TA1-anti-p185(HER-2)-RTA immunoto xin (TA1-RTA) produced synergistic inhibition of clonogenic growth of ovari an and breast cancer cells that expressed >10(6) p185(HER-2) receptors/cell . The effect on cell survival correlated with an inhibition of DNA repair. A prior study (F. J. Xu et al, Nucl. Med. Biol,, 24: 451-460, 1997) compare d the biodistribution of radionuclide conjugates prepared with monoclonal a ntibodies that bind to different epitopes on the extracellular domain of p1 85(HER-2) and found optimal tumor uptake with the 520C9 antibody, which did not compete with TA1 for binding to the receptor. In this report, the TA1- RTA immunotoxin and the I-131-labeled 520C9 radionuclide conjugate could ea ch inhibit the growth of clone-9002-18 xenografts in athymic mice but did n ot yield long-term survivors using maximally tolerated doses of each agent. When TA1-RTA and I-131-labeled 520C9 were used in combination, a greater i nhibition of tumor growth was obtained than with either single agent. Simil arly, survival with the combined treatment was significantly prolonged (P = 0.004) relative to treatment with immunotoxin or radionuclide conjugate al one. After treatment with an optimal combination of immunotoxin and radionu clide conjugate, 50% of mice survived >300 days, whereas controls succumbed with a median survival of 36 days. These results suggest that combinations of immunotoxins and radionuclide conjugates deserve further evaluation for the treatment of cancers that overexpress p185(HER-2).