Serotherapy provides an appealing approach to eliminate tumor cells that remain after conventional treatment, particularly in the case of ovarian carcinoma where monoclonal antibodies or their conjugates can be administered intraperitoneally to contact residual tumor cells. Due to heterogeneity in antigen expression, more than one antibody will be required to eliminate different subpopulations. Coordinate expression of two or more antigens by tumor cells, but not by normal cells should permit effective serotherapy, provided that coordinate expression is associated with 'additive or synergistic antitumor activity. During the last grant period antigenic targets have been defined on tumor cells that permit additive or synergistic interactions between different immunotoxins which contain monoclonal antibodies linked to ricin A chain (RTA). Among the targets that permit log additive antitumor activity is the c-erbB-2 (HER-2/neu) gene product pl85 that is expressed in 87% of ovarian cancers and overexpressed in 32%. Using a panel of monoclonal antibodies, multiple immunochemically and functionally distinct epitopes have been identified in a linear array on the extracellular domain of pl85. Unconjugated antibodies inhibit anchorage independent and dependent growth of tumor cells that overexpress pl85, an effect that may relate to modulation of tyrosine kinase activity in the intracellular domain. Interestingly, most of the intracellular domain is not required for pl85 to serve as a target for immunotoxin. Log additive antitumor activity has been observed with immunotoxins that bind to different epitopes of pl85. Antitumor activity has also been produced by a combination of immunotoxins directed against pl85 and the epidermal growth factor receptor (EGFR). In continued studies we propose to map epitopes associated with the extracellular domain of pl85 to determine whether epitopes closest to the cell membrane are the most effective targets for immunotoxin. Mechanisms for additive interactions between unconjugated antibodies will be compared and contrasted with those for immunotoxins. Interactions of immunotoxins and ligands reactive with pl85 and EGFR will be evaluated in clonogenic assays and nude mouse heterografts. Synergistic interactions will be sought with an immunotoxin against a third target p55. The feasibility of this approach to serotherapy will be further tested by measuring coexpression of these antigens on normal and malignant human tissues.
Showing the most recent 10 out of 82 publications
