Studies under this project have focused on the preparation of a number of hybridoma cell lines producing monoclonal antitumor cell antibodies and the use of these reagents to study the mechanism of antibody-dependent cell cytotoxicity (ADCC). We have now prepared three panels of monoclonal antibodies that are relatively specific for small cell carcinoma of the lung (SCCL), acute myelogenous leukemia (AML), or mesothelioma tumor cells. Using these reagents, we are now obtaining new information useful in understanding ADCC and its importance and have demonstrated that SCCL cells can be killed through monoclonal antibody mediated ADCC. In particular, studies are being conducted to determine the effectiveness of various classes and subclasses of antibody and the role of various leukocyte populations in mediating ADCC. The possibility that ADCC reactions can be modulated has been explored. We have found that a number of physiological mediators including gamma-interferon are capable of dramatically enhancing ADCC by monocytes. This appears to result from induction of increased numbers of receptors for the Fc portion of immunoglobulins on these cells and perhaps on some increased activity of the monocytes' cytotoxic capabilities. These findings have considerable therapeutic significance in that they imply that in vivo serotherapy with monoclonal antibody may be made significantly more efficacious by first inducing increased cytotoxic capabilities with gamma interferon. We have also explored other mediators as potential inducers of enhanced AOCC. In particular, the active form of vitamin D3, calcitriol, was found to be a potent enhancer of ADCC by cell lines of the myeloid series. Data has also been obtained that suggests that calcitriol (plus interferon have additive effects). These studies have provided definitive information on important aspects of ADCC reactions and permit a better understanding of the role of this process in tumor immunity. Moreover, some of the information obtained may provide insights into in vivo approaches to the modulation of ADCC reactivity. (LB)
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