Manufacturing immunity to disease in a test tube: the magic bullet realized.

Although it took over one hundred years, Ehrlich's concept of the magic bullet is now a reality. Today, therapeutic antibodies are, arguably, the most important class of new drugs for the treatment of illnesses ranging from Alzheimer's disease to cancer. The emergence of therapeutic antibodies had to wait for advances in immunochemistry that allowed construction of antibodies in vitro. The centerpiece of the new technology is the combinatorial antibody library, which essentially allows one to synthesize an artificial immune system with a diversity that exceeds that of the natural repertoire. The construction of such libraries was perceived to be difficult because, if the natural immune system was to be used as the starting material, construction of the libraries would entail protocols that are the opposite of usual cloning. In gene cloning one starts with complexity and reduces it to a singularity. In the generation of diversity by construction of combinatorial antibody libraries, one starts with a collection of clones, randomly expands their complexity, and then returns them to recoverable singularities. The methods developed to accomplish this seemingly formidable task now allow construction of antibodies in a test tube to any antigen. These synthetic antibodies may be qualitatively and quantitatively superior to those of nature.