Human hepatocellular carcinoma (HCC) represents a major worldwide disease and is often associated with chronic hepatitis B virus (HBV) infection. In this proposal we will focus on three major aspects of HCC: 1) viral pathogenesis, 2) techniques for immunodiagnosis, and 3) development of antibody-conjugates for immunotherapy. In this regard we have developed a library of high affinity monoclonal antibodies directed toward distinct and separate determinants on hepatitis B surface antigen (HBsAg). Such reagents have been used to develop highly sensitive and specific radioimmunoassays (RIAs) for HBsAg-associated determinants. Attempts will be made to determine if there are fundamental differences in the antigenic composition of HBsAg in HBV infected patients with HCC compared to HBsAg carriers who have not developed HCC; the antigenic characteristics of HBsAg may be related in part to the oncogenicity of HBV. In addition we have produced monoclonal antibodies to HCC cell surface antigens. Likewise these antibodies have been used to establish specific and sensitive RIA's and they detect soluble antigen released from four HCC cell lines into the culture medium. More importantly, preliminary studies suggest that these monoclonal RIA's identify similar antigens in the serum of patients with HCC. Therefore it is our goal to provide immunodiagnostic techniques which will detect HCC at an early stage when the tumors may be surgically resectable. Finally, recent in vitro and in vivo investigations suggest that monoclonal antibodies may have value in the treatment of HCC. We will extend and consolidate these findings and covalently link the monoclonal antibodies to cytotoxic and complement-activating agents. Such antibody-conjugates will be screened in vitro as potential immunotherapeutic reagents from the destruction of HCC cells. In vivo studies will be performed in nude mice with the eventual goal of developing treatment regimens for an otherwise lethal disease in man.
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