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Paul Ehrlich-Stiftung
Johann Wofgang Goethe Universität
Frankfurt am Main

Catalytic Antibodies Combine Properties of Antibodies and Enzymes

Immunologists Richard A. Lerner and Peter G. Schultz to receive the Paul Ehrlich and Ludwig Darmstaedter Prize 2003

Frankfurt am Main, Germany. March 10, 2003 - The Paul Ehrlich and Ludwig Darmstaedter Prize 2003 will be awarded to the immunologists Professor Richard A. Lerner, M.D. (64) and Professor Peter G. Schultz, Ph.D. (46), both of The Scripps Research Institute (TSRI), La Jolla, USA, for their achievements in connection with the development of catalytic antibodies. This was decided by the Scientific Council of the Paul Ehrlich Foundation in Frankfurt; the official statement reasons: "Richard A. Lerner and Peter G. Schultz receive the Prize for demonstrating that antibodies produced by the immune system can catalyze any chemical reaction like enzymes. A large number of enzymatic reaction mechanisms could thus be explained in detail." The prize will be awarded on March 14, 2003, in the Paul's Cathedral in Frankfurt in the presence of the President of the Federal Republic of Germany, Johannes Rau. The Paul Ehrlich and Ludwig Darmstaedter Prize belongs to the highest and internationally most renowned prizes to be awarded in the Federal Republic of Germany in the field of medicine.

Catalytic antibodies form a new group of molecules. They combine the enormous diversity of antibodies with the catalytic properties of enzymes. As a matter of fact, both types of proteins have completely different functions; enzymes facilitate the process of chemical reactions without being used up themselves. Antibodies, however, distinguish themselves through their ability to locate and bind molecules foreign to the organism. Both classes of molecules have one thing in common: They have to bind to their target molecule in order to become effective. Enzymes possess a pocket-buried binding cleft, in which the reacting partners are anchored during reaction. Antibodies, too, have a specific binding spot to bind to molecules foreign to the organism in order to mark them for immune reaction. While the immune system can dispatch a huge armada of 100 million different antibodies in order to defeat a multitude of possible intruders, the number of different biochemical reactions in the organism is rather modest; there are only a few thousand enzymes to catalyze certain reactions. This means that there are no enzymes for biologically unimportant, but otherwise possibly interesting reactions. Catalytic antibodies could fundamentally change this situation.

It was back in 1986, when Richard A. Lerner and Peter G. Schultz had the idea to combine the properties of the two classes of proteins. Both being chemists and working independently of each other - Lerner already at The Scripps Research Institute in La Jolla, Schultz at that time at the University of California at Berkeley - they were looking for ways to use the binding energy between an antibody and its target structure to catalyze chemical reactions.

Both researchers took advantage of the fact that enzymes as well as antibodies evoke structural changes in the molecules they bind to. As a result, there are more reactive conformational intermediates that possess more energy than the molecular conformations before and after a chemical reaction. However, the fundamental difference between the reactions of enzymes and antibodies lies in the fact that enzymes - contrary to antibodies - preferably stabilize high-energy activated conformations. So the hypothesis read: If an antibody could be generated that specifically recognizes and binds to a certain high-energy transition state, then this antibody could catalyze the appropriate reaction by using its binding energy.

Using immunological methods, Lerner and Schultz generated antibodies against molecules containing phosphate and phosphonate groups. They resemble the activated transition states in their three-dimensional structure, such as in ester hydrolysis. The new antibodies were specifically directed against the transition state, stabilized it and thus accelerated reaction - in some cases considerably. Using a tetrahedronically designed analogue bound to a carrier molecule and injected in a mouse, Lerner, for instance, generated an antibody against the intermediate, which was also a tetrahedron and which catalyzed the hydrolysis of esters. The reaction carried out by this catalytic antibody was at a rate of 107 to 108 faster than without antibodies. Schultz independently generated an antibody against an artificially produced porphyrin analogue - an antibody with properties very similar to those of the enzyme ferrochelarase, which is normally catalysed in this reaction.

Catalytic antibodies also accelerate Diels-Alder reactions and Claisen re-arrangements. In both ring closure reactions the conformation of the transition state was known so that antibodies against an analogue of this transition state could be generated.

The work of Schultz and Lerner shows that catalysis through antibodies only functions provided a stabilized transition state can be stabilized. The decisive key for influencing this process was found. Especially for organic chemistry, but also for molecular-biological research as well as for the medical and biotechnical fields, catalytic antibodies are of enormous significance since they play an important role in exactly controlling the direction and reactivity of chemical reactions and their efficiency. "Catalytic antibodies belong to the most important developments in immuno-chemistry," says Nobel prize winner Dr. h.c. mult. Manfred Eigen in his laudatory speech. "The work done by Lerner and Schultz has provided fundamental insight into the nature of catalysis, affords us a powerful new approach to control chemical reactivity, and has catalyzed a whole new field centered around exploiting molecular diversity, i.e. mimicry of the immune system."

Catalytic antibodies re-unite not only the properties of antibodies and enzymes, but also the chemical and biological sciences. As latest research shows, all natural antibodies are able to start the oxidative decomposition of bound substances with ozone as short-lived intermediate. "The discovery that natural antibodies - apart from their binding function - also possess reactive properties, leads to a change in paradigms with regard to their role in the immune system," says Manfred Eigen.

The Paul Ehrlich Prize

Each year on Paul Ehrlich's birthday, March 14, the Paul Ehrlich and Ludwig Darmstaedter Prize ceremony takes place in the historic Paul's Cathedral in Frankfurt. This year, the laudatory speech is held by Nobel prize winner Manfred Eigen who received the Paul Ehrlich and Ludwig Darmstaedter Prize himself in 1992. The prize will be handed over by Federal Minister of Health, Ulla Schmidt, and the Chairman of the Scientific Council of the Paul Ehrlich Foundation, Hilmar Kopper.

The Paul Ehrlich Foundation

The Foundation belongs to the Association of Friends and Supporters of Johann Wolfgang Goethe-University Frankfurt. Founded in 1929 by Hedwig Ehrlich, it is headed by the President of the Federal Republic of Germany as its honorary president and it is he who appoints the elected members of the scientific council and the board of trustees. The chairman of the Association of Friends and Supporters of Johann Wolfgang Goethe-University Frankfurt is at the same time chairman of the scientific council of the Paul Ehrlich Foundation. This body, which consists of 14 internationally renowned researchers from five countries, decides on the selection of the prize winner/s. The prize is endowed with 65,000 Euro, financed by private enterprises and the Federal Ministry of Health.

Further Information

CVs and lists of publications for both prize winners can be obtained in the press office of the Johann Wolfgang Goethe-University Frankfurt, phone: 49-69-798-23266, fax: 49-69-798-28530, e-mail Moelders@ltg.uni-frankfurt.de.


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