CONJUGATES OF FOLATE AND ANTI-T-CELL-RECEPTOR ANTIBODIES SPECIFICALLYTARGET FOLATE-RECEPTOR-POSITIVE TUMOR-CELLS FOR LYSIS

High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T -cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covale ntly linked to anti-TCR antibodies are shown to be potent in mediating lysis of tumor cells that express either the alpha or beta isoform of the FR, Intact antibodies with an average of five folates per molecul e exhibited high affinity for FR(+) tumor cells but did not bind to FR (-) tumor cells, Lysis of FR(+) cell lines could be detected at concen trations as low as 1 pM (approximate to 0.1 ng/ml), which was 1/1000th the concentration required to detect binding to the FR(+) cells. Vari ous FR(+) mouse tumor cell lines could be targeted with each of three different anti-TCR antibodies that were tested as conjugates. The anti bodies included 1B2, a clonotypic antibody specific for the cytotoxic T cell clone 2C; KJ16, an anti-v beta 8 antibody; and 2C11, an anti-CD 3 antibody, These antibodies differ in affinities by up to 100-fold, y et the cytolytic capabilities of the folate/antibody conjugates differ ed by no more than 10-fold, The reduced size (in comparison with bispe cific antibodies) and high affinity of folate conjugates suggest that they may be useful as immunotherapeutic agents in targeting tumors tha t express folate receptors.