ANTIGEN FORKS - BISPECIFIC REAGENTS THAT INHIBIT CELL-GROWTH BY BINDING SELECTED PAIRS OF TUMOR-ANTIGENS

Bispecific antibodies of a new category, termed ''antigen forks'', wer e constructed by crosslinking antibodies that recognized pairs of dist inct tumor cell surface antigens. At concentrations of 1-100 nM, sever al such forks inhibited the growth of human tumor cell lines bearing b oth relevant antigens. The same cells were not inhibited by unconjugat ed component antibodies, and the active conjugates did not inhibit the growth of human cell lines that expressed lower levels of relevant an tigens. The three most active antigen forks all contained monoclonal a ntibody 454A12, which recognizes human transferrin receptor. This anti body was conjugated respectively to antibodies 113F1 (against a tumor- associated glycoprotein complex), 317G5 (against a 42-kDa tumor-associ ated glycoprotein), or 520C9 (against the c-erbB-2 protooncogene produ ct). The 317G5-454Al2 fork strongly inhibited the HT-29 and SW948 huma n colorectal cancer cell lines, while the 113F1-454A12 and 520C9-454A1 2 forks strongly inhibited the SK-BR-3 human breast cancer cell line a nd the 113F1-454A12 fork: was also effective against SW948. By designi ng forks against antigens of incompatible function that are co-express ed at high levels on tumor cells but not on normal tissues, it may be possible to generate reagents that inhibit tumor growth with enhanced selectivity.