Preclinical studies combining bispecific antibodies with cytokine-stimulated effector cells for immunotherapy of renal cell carcinoma

Background: Bispecific antibodies - consisting of a F(ab')- fragment derive d from a monoclonal antibody against a tumor epitope as well as of another antibody against a cytotoxic trigger molecule on immune effector cells-can improve the effectiveness of antibody- based tumor therapy. Materials and M ethods: We used bispecific antibodies with one specifity against the EGF-re ceptor; which is overexpressed on the majority of renal cell carcinomas, an d another specifity against Fe receptors on human leukocytes (FcyRI/CD64; F cyRIII/CD16 and FcaRI/CD89). As source of effector cells, whole blood fi om patients treated with G-CSF, GM-CSF or IL2/IFN-a was used Cu-51- release a ssays using various renal cancer cell fines as in tumor targets. Further ex periments with Percoll- isolated granulocytes or mononuclear cells from the same donors were performed in order to identify the active effector cell p opulations. Results: Compared with conventional monoclonal EGF-R directed a ntibodies (murine IgG2a, humanized IgG1), bispecific antibodies induced sig nificantly enhanced cytotoxicity. Highest amounts of tumor cell killing wer e observed using whole blood from patients treated with G-CSF or GM-CSF in combination with an [FcaRI x EGF-R] bispecific antibody. Under these condit ions guanulocytes constituted the most active effector. cell population. Co nclusion: The combination of myeloid growth factors and bispecific antibodi es offer a promising new approach for the treatment of advanced renal cell carcinoma.