CHIMERIC BISPECIFIC OC TR MONOCLONAL-ANTIBODY MEDIATES LYSIS OF TUMOR-CELLS EXPRESSING THE FOLATE-BINDING PROTEIN (MOV18) AND DISPLAYS DECREASED IMMUNOGENICITY IN PATIENTS/

The bispecific OC/TR monoclonal antibody (mAb) cross-links the CD3 mol ecule on T cells with the human folate-binding protein (FBP), which is highly expressed on nonmucinous ovarian carcinomas. Clinical trials o f patients with ovarian carcinoma with the OC/TR mAb have shown some c omplete and partial responses. Most patients developed human anti-muri ne immunoglobulin antibodies (HAMA), which can inhibit OC/TR mAb-media ted lysis. We generated a chimeric version of the OC/TR mAb to decreas e the immunogenicity of the OC/TR mAb and to allow mon extended treatm ent schedules. Sp2/0 myeloma cells were transfected with chimeric heav y-and light-chain genes encoding the anti-CD3 mAb and the MOv18 mAb, r espectively, which are reactive with FBP. The resulting cell line prod uced 80 mu g/ml of total immunoglobulin G (IgG), of which 11.5% was th e functionally active chimeric OC/TR mAb. Chimeric OC/TR F(ab')(2) fra gments mediated lysis of IGROV-1 ovarian carcinoma cells by human T ce lls at antibody concentrations of greater than or equal to 1 pg/ml, Sp ecific lysis was still detectable at an effector-to-target cell ratio as low as 0.4. Two patients with ovarian carcinoma treated with F(ab') (2) fragments of the murine OC/TR developed distinct HAMA titers, whic h were mainly anti-idiotypic and only partly directed against the muri ne antibody constant regions. However, of the two patients that were t reated with the F(ab')(2) fragments of the chimeric OC/TR mAb, only on e developed a low transient HAMA response just above background level. In conclusion, the generation of chimeric OC/TR may allow more extend ed clinical studies of bispecific mAb-mediated immunotherapy of ovaria n carcinoma.