GENETICALLY-ENGINEERED ANTIBODIES AND THEIR APPLICATION TO BRAIN DELIVERY

Techniques of genetic engineering and expression have been applied to the production of antibodies in a variety of expression systems. Combi natorial libraries produced in bacteriophage may present an alternativ e to animal immunization as a source of antigen-binding specificities. Transfectomas which express genetically engineered antibody genes pro vide one approach to overcoming some of the limitations inherent in cl assical monoclonal antibodies. Novel antibodies have been produced wit h a variety of modifications: as chimeric antibodies, as 'humanized' a ntibodies, with catalytic groups, as bifunctional or fusion proteins a nd as functional fragments such as Fabs or Fvs. The domain structure o f the antibody is favorable to such manipulation; the novel proteins o ften retain their antibody-derived activity and acquire new properties as well. Chimeric and CDR-grafted antibodies have been effective in i mmunotherapy, but problems of immunogenicity remain. Careful analysis and comparison of effector functions among immunoglobulin isotypes may be applied to the design of effective therapeutic antibodies. In addi tion, antibody combining specificities can be joined with non-immunogl obulin sequences thereby providing properties not usually found in ant ibodies. In particular, antibodies fused with the growth factors insul in-like growth factor(IGF)-1, IGF-2 and transferrin have shown increas ed uptake into the brain parenchyma. These fusion proteins provide a f amily of reagents with many potential applications.