ANTI-RENAL-CELL CARCINOMA CHIMERIC ANTIBODY G250 FACILITATES ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY WITH IN-VITRO AND IN-VIVO INTERLEUKIN-2-ACTIVATED EFFECTORS

Renal cell carcinoma (RCC) is relatively resistant to chemotherapy and radiotherapy, whereas treatment with biologics has achieved limited s uccess. Although monoclonal antibodies able to recognize human RCC hav e been identified, most induce little complement-dependent cytotoxicit y or antibody-dependent cellular cytotoxicity (ADCC), and thus are of limited potential as therapeutic modalities in their natural conformat ion. We evaluated a human/ mouse chimeric derivative of the previously described G250 murine monoclonal antibody (mAb), reactive with RCC, t o identify a reagent for potential immunotherapy. This chimeric antibo dy (ch-G250) is composed of the murine variable region from the G250 m Ab, which recognizes a tumor-associated antigen expressed on 95% of pr imary and 86% of metastatic renal cell carcinomas. The constant region of the ch-G250 is comprised of the human IgG, isotype domains. This c himeric antibody does not bind to normal renal tissue or other normal human tissues, with the exception of gastric mucosal cells and large b ile-duct epithelium. Clinical radiolocalization studies have demonstra ted the relative tumor-targeting potential of this radiolabeled antibo dy. This ch-G250 antibody facilitated potent ADCC against several RCC lines when using in vitro and in vivo interleukin-2 (IL-2)-activated p eripheral blood mononuclear cells obtained from healthy control donors and patients with cancer, respectively. This lymphocyte-mediated ADCC was specific for RCC cells recognized by the ch-G250 antibody. Using flow cytometry, we found that the level of ADCC was directly related t o the degree of binding of ch-G250 to the renal cell target. These in vitro data suggest that this antibody may improve efficacy of IL-2 the rapy by targeting cytokine-activated effector cells directly to the tu mor and facilitating in vivo ADCC. Clinical studies combining this chi meric antibody with IL-2 treatment will be needed to test the antitumo r effects of this ADCC effect in vivo.