Murine monoclonal antibodies which bind to surface antigens of human tumor cells provide approaches to the immunotherapy of human cancers by their ability to target Fc-receptor bearing effector cells and by their indirect effect on the host's immune system in the induction of anti-idiotypes (Ab2) and anti-anti-idiotypes (Ab3) which may minimize specific tumor antigens. We intend to use recombinant DNA techniques to improve the effectiveness of murine monoclonal antibodies used for immunotherapy. For this purpose we shall clone the cDNAs and/or the genes for the light and heavy chains of hybridomas which produce antibodies with specificity towards human tumor cells. The constant regions of the cloned immunoglobulin cDNAs/genes will be replaced with the corresponding regions of human immunoglobulin genes, and the fused mouse-human genes will be inserted into animal expression vectors and introduced into mouse myeloma cells. The antibodies produced in this way will be investigated for their ability to interact with the human immune system and evaluated for use against human cancer. We have already shown that murine monoclonal antibodies tumoricidal activity depends on their isotypes. In the nude mouse system, human adenocarcinoma growth is inhibited by the IgG3 and IgG2a isotypes, while IgG1 and IgG2b are ineffective. The IgG3, IgG2a and IgG1 isotypes are effective in vitro in ADCC and ADMC, although IgG1 is not tumoricidal in vivo. Furthermore, the IgG3 and IgG2a murine isotypes bind preferentially and with high affinity to human effector cells. This binding leads to specific tumor cell destruction in ADMC. It remains unknown, however, what mechanisms will be involved in tumor cell destruction with human monoclonal antibodies of different isotypes. Since such monoclonal antibodies are at present not available, we intend to utilize recombinant monoclonal antibody (rMAb) molecules which contain murine derived V region and human derived C regions of different isotypes. To assess whether such monoclonal antibodies of a certain human isotype possess tumoricidal potential for future immunotherapeutic application in man, we will (1) identify the FcR's on the effector cell population reactive with rMAb's of different isotypes; (2) establish which isotypes are most effective in CDC and ADCC/ADMC against human target (tumor) cells and (3) to establish their tumoricidal activity in vivo in the nude mouse system.
