The goal of this work is to study the structure and function of the immunoglobulin molecule. The work is being performed so that this understanding will be applied to the development of antibodies for human therapy. A. Therapeutic systems. 1. Antibodies to surface antigens of group B streptococci (GBS) have been demonstrated to have protective efficacy in a model of neonatal sepsis. We have identified colony opacity variants of GBS and studied their interactions with antibodies and other components of the immune system. 2. The efficacy of anti-HIV antibodies coupled to ricin A-chain has been studied in vitro. Monoclonal and polyclonal antibodies directed against different epitopes have been tested. Biological variants of HIV that escape killing with these immunotoxins an CD4-PE40 have been identified. The phenotype of the cells carrying these HIV has been studied, and the molecular mechanisms of immunotoxin escape have been evaluated. Immunotoxins are being tested in vivo in well- studied animal systems. 3. Evaluation of the anti-HIV antibody response in subjects exposed to the IIIB/LAV isolate of HIV. Subjects include humans and chimpanzees infected with the virus or immunized with envelope subunits. B. Antibody Engineering. We are using both genetic and chemical approaches to alter the antibody molecule and then study the effect. Using genetic approaches, we have studied the ability of immune complexes containing chimeric antibodies to interact with antigen and with effector functions. Chemical engineering of antibodies includes the conjugation of anti-HIV drugs to antibodies and the design of cross-linkers that are specifically cleaved by HIV protease.
