Believe it or not, every human body with a healthy immune systemcan generate antibodies that target any and every antigen in theworld.One of the first to believe, and assert, this apparently absurd truthwas immunologist Niels Jerne. For his insights into how antibodiesfunction, this British-Danish scientist shared the 1984 Nobel prize inPhysiology or Medicine with Cesar Milstein and Georges Koehler,the fathers of monoclonal antibodies.Jerne's best-known contribution to antibody formation is the clonalselection theory. Another of his concepts predicted the latentantibodies poised to multiply and confront every antigen on earth.What's more, the immune system's machinery for recruiting an armyof precisely matching antibodies to take on every antigen _microbe, alien protein or whatever _ that invaded the body alsoprovided for a second, back-up phalanx of anti-antibodies to shutdown the operation when the immune-defense engagement was over.To pull those first-string antibodies off the battlefield after theirusefulness had ended, the second-response antibodies had to "see"the name, rank and serial number of the front-line troops _ that is,their unique, active combining sites, or idiotopes. These of coursewere mirror images of the invading antigen's epitopes ordeterminants, which made them visible and bindable to thedefending antibodies in the first place.Internal Images Of Every External ThreatPut another way, the idiotopes on the defending antibodies were seenas antigenic by the mop-up antibodies, called auto-idiotypicantibodies, which carried mirror-images of the original antigens'active sites. Jerne called these matching, twice-removed molecularconfigurations "internal images."That is, the cells of the immune system that raise antibodies to meetany antigenic challenge should contain antibodies that act like atemplate or model, anticipating and mimicking the original antigen.Jerne described this intricate, Nobel-winning feedback system as anetwork.In theory, it implied that every drug or bug out there in the world hasa matching mold or die inside every immune system, capable ofassembling and reproducing it precisely.Jerne died very recently. One of his last acts as a member of the U.S.National Academy of Sciences was to see that theory turned intopractice. He sponsored an article published yesterday in theAcademy's Proceedings of the National Academy of Sciences(PNAS). Its title tells how: "Idiotypic mimicry and the assembly of asupramolecular structure: An anti-idiotypic antibody that mimicstaxol in its tubulin-microtubule interactions."That paper's senior author is chemist and immunologist BernardErlanger, professor of microbiology at Columbia University Schoolof Medicine. "We are interested in receptors," he told BioWorldToday. "What we've done is look for antibodies that mimic receptorligands, usually drugs _ in this case, taxol."Taxol stymies tumor-cell growth by irreversibly stabilizingmicrotubule assembly. This imparted rigidity prevents the cell frommultiplying.Anti-Antibody Anticipates Taxol ActivityAs his PNAS paper reports, Erlanger tracked down and sequencedthe mouse anti-taxol auto-idiotypic antibody that mimics the taxolmolecule. So much so, that it actually causes tubulin to assemble intomicrotubules."This is important," Erlanger said, "as taxol is really the first of anew family of anti-cancer drugs. Because its mode of action isdifferent, the possibility of synergism exists between taxol and otheranti-cancer drugs, which act on different sites of a tumor cell."He explained that "Other drugs inhibit cell multiplication by entirelydifferent mechanisms, usually having to do with DNA replication.All of them affect rapidly growing cells, which of course is what acancer is," he said, "but they do it by mechanisms entirely differentfrom taxol's action on microtubule assembly."Erlanger has sent its active-site fragment for X-ray crystallographicanalysis, to get its three-dimensional structure. Once this is in hand,and with its sequence now known, "we will attempt to design,probably in collaboration with some biotech company, anti-cancercompounds that may very well have taxol-like activity, withoutbeing taxol."Preliminary scientific collaboration is already in progress, with amolecular biologist at Affymax Research Institute, of Palo Alto,Calif., that company's vice-president, director of receptorpharmacology, Ron Barrett, told BioWorld Today. "It is endeavoringto identify peptides that binds to the anti-taxol auto-idiotypicantibody fragment," he said. n
-- David N. Leff Science Editor
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