There are many clinical applications in which the exquisite specificity of a mouse monoclonal antibody would be useful. However, when mouse monoclonal antibodies are introduced into humans they are recognized as foreign and evoke an antibody response that quickly clears the mouse monoclonal antibody from the bloodstream. In addition, circulating complexes of mouse and human antibodies can cause allergic reactions. In some cases, the buildup of these complexes in organs such as the kidney can cause serious and even life-threatening reactions. Clearly, one way to avoid these undesirable reactions is to use human monoclonal antibodies for clinical applications. However, the preparation of human monoclonal antibodies has been hampered by numerous technical problems. In response to the difficulty of producing human monoclonal antibodies and the complications resulting from the use of mouse monoclonal antibodies in humans, there is now a major effort to engineer monoclonal antibodies and antibody binding sites with recombinant DNA technology.
The growing knowledge of antibody gene structure and regulation has made possible what Cesar Milstein, one of the inventors of monoclonal antibody technology, has called "man-made antibodies." It is now possible to design and construct genes that encode immunoglobulin molecules in which the variable regions come from one species and the constant regions come from another. New genes have been created that link nucleotide sequences coding nonantibody proteins with sequences that encode antibody variable regions specific for particular antigens. These molecular hybrids or chimeras may be able to deliver powerful toxins to particular antigenic targets, such as tumor cells. Finally, by replacement of the immunoglobulin loci of one species with that of another, animals of one species have been endowed with the capacity to respond to immunization by producing antibodies encoded by the donor's genetically transplanted Ig genes. By capturing a significant sample of all of the immunoglobulin heavy- and light-chain variable-region genes via incorporation into libraries of bacteriophage, it has been possible to achieve significant and useful reconstructions of the entire antibody repertoires of individuals. The next few sections describe each of these types of antibody genetic engineering.
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