P&S Journal: Spring 1995, Vol.15, No.2
Research & Reports
Taxol-Mimicking Antibodies Assemble Microtubules
Dr. Bernard Erlanger has isolated a novel monoclonal antibody that mimics the anti-cancer drug taxol and has the ability to assemble a large supramolecular structure, a behavior never seen in antibodies. Further research on how the unusual antibody works might lead to the development of new taxol-like tumor-killing agents.
In the October 1994 issue of the Proceedings of the National Academy of Sciences, Dr. Erlanger, professor emeritus of microbiology, reports this first example of an antibody that can build a macromolecule from its biochemical subunits. The unique antibody, which is called an anti-idiotypic antibody, is in the construction business because Dr. Erlanger generated it to imitate taxol. Like taxol, which stops tumor cell growth by irreversibly stabilizing cellular components known as microtubules that normally break down when cells divide, the antibody can assemble microtubules from tubulin components. Dr. Erlanger suggests that new taxol-like drugs could be created based on further research leading to an understanding of how the antibody, a protein, is able to do what taxol, an organic compound, does.
Antibodies normally do not assemble molecules. Antibodies are proteins made by the immune system, as part of its humoral response, to neutralize foreign antigens, such as bacteria or viruses. The immune system has evolved to be able to recognize essentially any antigen that confronts it, including biomolecules made by the organism itself. Hundreds of millions of immune cells, called B cells, continually make low levels of all the possible antibodies a person might need. Antigens, such as bacteria, for example, induce certain clones of B cells-those that make antibodies that recognize the bacteria-to grow selectively. After the antibacterial antibodies fight the infection, secondary antibodies shut off their production. The immune system maintains a balance between antibodies and these anti-antibodies, which are called anti-idiotypic antibodies.
The binding site on an anti-idiotypic antibody recognizes the antigen-binding region on the first antibody and thus has structural similarities to the original antigen. For the past 15 years, Dr. Erlanger has perfected methods to isolate these anti-idiotypic antibodies. Besides producing this latest, taxol-imitating antibody, he and his laboratory have succeeded in creating antibodies that simulate bioactive cellular receptor binding agents, such as adenosine, acetylcholine, thyroid-stimulating hormone, glucocorticoids, and aldosterone. Thus, even though anti-idiotypic antibodies are proteins, they can have biological activity similar to any type of organic molecule.
In addition to showing that the entire antibody mimics taxol, Dr. Erlanger purified a fragment of the anti-idiotypic antibody that acts like taxol. He and his colleagues also have determined the amino acid sequence of the fragment. Realizing the potential therapeutic implications of the taxol-like anti-idiotypic antibody fragment, Dr. David Langley, a scientist from Bristol-Myers Squibb, the pharmaceutical company that manufactures taxol, requested the amino acid sequence from Dr. Erlanger. Using a computer program, Dr. Langley generated a model structure of the anti-idiotypic fragment binding region based on its amino acid sequence. He found a five amino acid cluster that physically resembles the molecule taxol. Such information can be important because, if the model is correct, it could help elucidate taxol's mechanism of action and aid in the design of new anti-cancer agents.
Computer models are not necessarily reality. So Hans-Erik Aronson, a graduate student in the laboratory of Dr. Wayne Hendrickson, professor and Howard Hughes investigator, has crystallized the fragment, with the ultimate goal of clarifying its actual three-dimensional atomic structure and its similarity to taxol.
A poignant note about the paper is that Dr. Niels K. Jerne, the major reviewer and submitter of Dr. Erlanger's paper to PNAS, died last year at age 83. Dr. Jerne was one of the first scientists to suggest the clonal theory of the immune system and to assert that the antibody repertoire could recognize "all" antigens and contained anti-idiotypic antibodies that mimic them. For his insights, he shared the Nobel Prize in 1984 with Dr. Cesar Milstein and Dr. Georges J.F. Koehler who were recognized for their work on monoclonal antibodies. Dr. Jerne used the term "internal image" to describe the molecular configurations on anti-idiotypic antibodies that were similar to the original antigen. Dr. Erlanger sent his findings to Dr. Jerne, who was living in France at the time, because he felt they represented a beautiful example of his "internal image" theory.