BINDING CHARACTERISTICS AND ANTITUMOR PROPERTIES OF 1A10 BISPECIFIC ANTIBODY RECOGNIZING GP40 AND HUMAN TRANSFERRIN RECEPTOR

The bispecific murine monoclonal antibody (MAb) 1A10 has specificity f or the human transferrin receptor (TfR) and the human tumor-associated antigen gp40. This antibody, therefore, functions as an ''antigen for k'' by binding to two distinct antigens on the same malignant cell. Hi ghly purified 1A10 inhibits the growth of cells coexpressing high leve ls of human TfR and the tumor-associated antigen gp40 by binding to bo th target antigens. In SW948 cells, the majority of 1A10 binding is vi a its gp40 specificity, and half-maximal inhibition of cell growth by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyletrazolium bromide assay req uires 20-30-mu g/ml concentrations of 1A10. The binding of 1A10 correl ates with growth inhibition in the cell lines HT-29, SK-OV-3, OVCAR-2, and OVCAR-3. The growth of OVCAR-10 cells, which express little gp40 and TfR, is not inhibited by 1A10. However, SK-BR3 cells, which expres s abundant gp40 and extremely high levels of TfR, are insensitive to t he effects of 1A10. In some cell lines, combined exposure to 1A10 and the iron chelator deferoxamine mesylate has synergistic antiproliferat ive effects. A single i.p. dose of 600 mu g 1A10 is sufficient to achi eve an estimated tumor concentration of at least 30 mu g/ml for 7 days in C.B17/Icr-scid mice bearing SW948 human tumor xenografts. Treatmen t of scid mice bearing day 2 or day 4 SW948 xenografts with single or multiple 1A10 doses inhibits tumor growth in a dose-related fashion. A ntitumor effects are not seen with therapy using either parental antib ody of 1A10. The antiproliferative properties of 1A10 in tumor cells o verexpressing gp40 and TfR suggest avenues for the development of new bispecific antibody-promoted treatment strategies.