The goal of this work is to understand 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 have been demonstrated to have protective efficacy in a model of neonatal sepsis. We are now examining the pharmacologic characteristics of these antibodies in neonatal animals including: body distribution, long-term persistence, dose and appropriate mixtures of different monoclonals to project against all serotypes of group-B streptococci. 2. The in vitro efficacy of anti-HIV envelope (gp 120) monoclonal antibodies has been tested. Combinations of antibody, complement, and leukocyte populations are only marginally effective in inducing lysis of HIV- infected targets. Antibody coupled to ricin A-chain is highly lethal to infected targets while sparing uninfected cells. This immunoloxin also blocks infectivity of the targeted cell. We are beginning in vivo studies to test the efficacy of antibody based therapies of AIDS. B. Genetically Engineered Antibodies. Vectors have been prepared carrying human mu, gamma-l, and gamma-4 constant region genes in an enhancer containing expression vector. Variable region genes from anti-(T,G)-A--L antibodies have been inserted. DNA has been transfected into cell lines by electroporation and expressed as functional antibody. Variant hinge region genes are being constructed. These will be used to study the role of the antibody hinge in Fc-mediated effector function. C. Idiotypy. The idiotypic network induced in CS7BL10 mice by immunizalion with the synthetic polypeplide (Tyr, Glu-Ala--Lys is being explored. Monoclonal antibodies representing antibody 1 (ab 1), ab 2, and ab 3 have been made and sequences obtained. Transgenic mice that over-express the ab 1 heavy chain have been bred. The effect of this over-expression on the network is being studied.
