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 have studied the efficacy of the interleukin GM-CSF both in vivo and in vitro when applied in combination with the antibody. 2. The in vitro efficacy of anti-HIV envelope antibodies coupled to ricin A chain has been studied. Monoclonal and polyclonal antibodies directed against different epitopes have been tested. Biological variants of HIV that escape immunotoxin action have been characterized and the mechanism of immunotoxin escape has been studied. B. Genetically engineered antibodies. Vectors have been prepared carrying human mu, gamma-1 and gamma-4 genes. Mutant constructs have been created with altered constant regions. These constructs have been ligated to variable region genes from antibodies to the synthetic peptide (Tyr,Glu)-Ala--Lys. Antibodies were expressed and the function of the engineered antibodies has been studied in immune complexes. We are currently cloning variable region genes from anti-group B streptococcal antibodies which will be ligated into the constant region vectors and expressed. C. Idiotypy. The idiotypic network induced in mice by immunization with (Tyr,Glu)-Ala--Lys has been explored. The immune response of transgenic mice that overexpress the heavy chain of antibody 1 has been explored. An anti-idiotypic antibody has been coupled to ricin A chain. The in vivo effect of this anti-idiotypic immunotoxin is being explored.
