Luiten R M, Coney L R, Fleuren G J, Warnaar S O, Litvinov S V
Department of Pathology, University of Leiden, The Netherlands.
Br J Cancer. 1996 Sep;74(5):735-44. doi: 10.1038/bjc.1996.430.
The monoclonal antibody (MAb) G250 binds to a tumour-associated antigen, expressed in renal cell carcinoma (RCC), which has been demonstrated to be a suitable target for antibody-mediated immunotherapy. A bispecific antibody having both G250 and anti-CD3 specificity can cross-link G250 antigen-expressing RCC target cells with T cells and can mediate lysis of such targets. Therapy studies with murine antibodies are limited by immune responses to the antibodies injected (HAMA response), which can be decreased by using chimeric antibodies. We generated a chimeric bispecific G250/anti CD3 MAb by transfecting chimeric genes of heavy and light chains for both the G250 MAb and the anti-CD3 MAb into a myeloma cell line. Cytotoxicity assays revealed that the chimeric bispecific MAb was capable of mediating lysis of RCC cell lines by cloned human CD8+T cells or by IL-2-stimulated peripheral blood lymphocytes (PBLs). Lysis mediated by the MAb was specific for target cells that expressed the G250 antigen and was effective at concentrations as low as 0.01 microgram ml-1. The chimeric bispecific G250/anti-CD3 MAb produced may be an effective adjuvant to the currently used IL-2-based therapy of advanced renal cell arcinoma.
单克隆抗体(MAb)G250可与一种肿瘤相关抗原结合,该抗原在肾细胞癌(RCC)中表达,已被证明是抗体介导免疫治疗的合适靶点。一种同时具有G250和抗CD3特异性的双特异性抗体可使表达G250抗原的RCC靶细胞与T细胞交联,并可介导此类靶细胞的裂解。用鼠源抗体进行的治疗研究受到对注射抗体的免疫反应(人抗鼠抗体反应)的限制,使用嵌合抗体可降低这种反应。我们通过将G250单克隆抗体和抗CD3单克隆抗体的重链和轻链嵌合基因转染到骨髓瘤细胞系中,制备了一种嵌合双特异性G250/抗CD3单克隆抗体。细胞毒性试验表明,该嵌合双特异性单克隆抗体能够介导克隆的人CD8+T细胞或经白细胞介素-2刺激的外周血淋巴细胞(PBL)对RCC细胞系的裂解。该单克隆抗体介导的裂解对表达G250抗原的靶细胞具有特异性,在低至0.01微克/毫升的浓度下也有效。所制备的嵌合双特异性G250/抗CD3单克隆抗体可能是目前用于晚期肾细胞癌的基于白细胞介素-2治疗的有效佐剂。