The coupling of tumor-reactive antibodies to toxic agents as a way of directing

The coupling of tumor-reactive antibodies to toxic agents as a way of directing such agents to tumor cells in vivo offers the promise of highly selective therapy. During the past several years, there have been numerous reports describing the use of antibody coupled to drugs (reviewed in 1) and toxic peptides (immunotoxins) (2-18) to kill tumor cells in vitro. The tumoricidal effect of these immunotoxins is highly specific and requires only minute doses. To explore further the therapeutic potential of immunotoxins, we chose a welldefined mouse tumor model (BCLx) (19). The tumor is a B cell leukemia ofmonoclonal origin, bearing surface IgM and IgD molecules (20, 21) that express a unique idiotype (22). The tumor can be transferred with 1-10 cells (17, 23), and its growth pattern can be accurately measured by indirect immunofluorescence using an anti-idiotypic (anti-Id) a antibody (24). Animals bearing the tumor survive for several months, despite massive tumor burdens (5 X 109-1 × 101° cells/mouse). We have demonstrated that immunotoxins directed against the immunoglobulin (Ig) on the surface of BCL1 cells can kill virtually all tumor cells in a suspension of bone marrow or spleen (7, 17). In the present study, we treated mice bearing advanced BCL1 tumors by intravenous administration of tumor reactive immunotoxin. The approach was to eliminate the vast majority of the tumor burden by nonspecific cytoreductive therapy. The residual tumor cells were then killed by intravenous administration of an immunotoxin reactive with the idiotype or isotype of the surface Ig of the tumor cells. The results of these studies indicate that such immunotoxins are highly effective at inducing prolonged remissions in tumor-bearing mice provided that sufficient prior cytoreduction has been achieved.