IN-VITRO TUMOR-GROWTH INHIBITION BY BISPECIFIC ANTIBODIES TO HUMAN TRANSFERRIN RECEPTOR AND TUMOR-ASSOCIATED ANTIGENS IS AUGMENTED BY THE IRON CHELATOR DEFEROXAMINE

Previously, a panel of mouse monoclonal antibodies (mAbs) to several t umor-associated antigens was chemically crosslinked to an IgG1 anti-hu man transferrin receptor antibody, 454A12, We called this new class of bispecific antibodies (BmAbs) ''antigen forks'' and showed that these antigen forks inhibited but did not completely prevent tumor cell gro wth. We speculated that the conjugates acted by heterologously crossli nking two antigens in a manner that interfered with the functions of o ne or both. The most effective BmAbs all shared one specificity for th e human transferrin receptor. A monoclonal antibody to this receptor h as been shown by others to reduce tumor cell growth when used with the iron chelator deferoxamine. When we combined our antigen forks with d eferoxamine, two of five BmAbs synergized with deferoxamine to arrest tumor cell count at or below input levels, The most effective BmAbs we re 317G5/454A12 (3/4) and 520C9/454A12 (5/4). mAb 317G5 recognizes a 4 2-kDa tumor-associated glycoprotein, and mAb 520C9 recognizes the c-er bB-2 protooncogene product, BmAb 3/4 was most effective against colore ctal cancer cell line HT-29, and BmAb 5/4 was most effective against b reast cancer cell line SK-BR-3. When deferoxamine and BmAb were replac ed by fresh medium after a 6- or 7-day treatment period, no regrowth o f tumor cells was observed during the next 4 days, although regrowth w as seen if either deferoxamine or BmAb was used alone, Our results sho w that BmAbs with specificities for transferrin receptor and certain t umor-associated antigens effectively inhibit tumor growth in vitro. Wh en used in combination with deferoxamine, such BmAbs may have therapeu tic potential for the treatment of cancer. (C) 1996 Academic Press, In c.