The specificity of antibodies is astonishing -- they can distinguish between proteins that differ by only a single amino acid, and between the cells of different individual members of the same species.
All vertebrates produce large variety of antibodies. The immune system can even produce antibodies that can bind to chemically synthesized molecules that do not exist in nature. Exposure to an antibody-producing agent -- called an antigen or immunogen -- causes an organism to produce a wide spectrum of antibody proteins, each of which may bind to a slightly different antigen. These constellations of antibodies may differ from one member of a species to another for a given antigen.
Antibodies serve as markers, seeking out and binding to antigens, or foreign proteins including bacteria and viruses, so that other immune system cells called phagocytes can find and destroy them, ridding the body of the intruders. The antibodies do their work by binding themselves to the part of the antigen known as the epitope, and it proves to be significant for monoclonal antibody therapies that the binding takes place even when the entire antigen molecule is not present. (Cancer is exempt from this immunological defense, because the immune cells do their job by differentiating between the self and the non-self, and tumors count as home-grown cells.)
Another critical fact is that each antibody, like the B cell that produced it, is specific to one particular antigen—it only binds to the epitope it was meant to find. That means that our bodies are populated by vast numbers of B cells and the highly specialized antibodies they produce in response to the various antigens we have been exposed to.
For science, that understanding was both an opportunity and an obstacle until Kohler and Milstein made their breakthrough. If a specific antibody could be aimed at its intended epitope through clinical means, it could perform several key functions in diagnosis and treatment, including helping to deliver toxins to cancer cells without attacking normal cells.
The rub, however, was that to turn that knowledge into a useful tool required significant amounts of a single antibody from a single ancestor cell. Several factors combine to make that impossible in the normal course of cell development. First, a single B cell must be cultured to produce a population of identical B cells, each of which would spawn the desired antibodies—monoclonal antibodies. The quest for that ancestor cell from a human, or other organism, was stymied by the immune system’s response to any antigen, because the system invariably manufactures a wide range of antibodies with different structures, resulting in polyclonal antibodies.
Beyond that, the B cell’s own life cycle means that, even if a single antibody-producing cell is isolated and cultured, the population of antibodies it will produce is too limited for use in human therapy, because it would die out after a few generations in the lab.
To overcome these obstacles Kohler and Milstein immunized mice with specific antigens to trigger B cells to produce specific antibodies. They next harvested the antibody-secreting cells from the spleens of the mice, and fused them with myeloma cells, producing what are known as hybridoma.
The process built on the fact that the rapidly proliferating myeloma cells are, in scientific terms, immortal—and therefore would overcome the self-limiting life span of normal B cells—and the fact that the spleen cells contain a critical enzyme called HGPRT that the myeloma cells lacked, but need for growth. That meant that the hybridoma cells could grow indefinitely and produce an infinite number of monoclonal antibodies, because the spleen cell provides the HGPRT and the myeloma cell supplies the immortality.
For the first time, monoclonal antibodies could be created in unlimited supplies and put to work fighting an array of diseases. More on production of monoclonal antibodies.