Richard Alan Lerner is a worldwide recognized american scientist with outstanding contributions to immunochemisty.

The discovery of combinatorial antibody libraries has revolutionized immunochemistry. It allows construction of immunological repertoires that are many orders of magnitude larger than those of nature. They solve the problems of the generation of fully human antibodies as well as the immune tolerance problem. The solution to the tolerance problem is particularly important because nowadays most therapeutic antibodies are antibodies to self. Thus, antibody libraries have profound implications for human therapy. Indeed, the first dramatic example of this is Humira that is an antibody used in thousands of patients worldwide with rheumatoid arthritis. Other antibodies made by these methods are in advanced stage of development. While the impact of these methods for global human health is already evident and established, there are many more extensions already being developed. Finally, after two hundred years there is no longer any need to use immunization to produce antibodies.

While this citation focuses on combinatorial antibody libraries that Lerner developed simultaneously with Winter, it should be remembered that these developments on Lerner’s part are the result of a sustained effort in immunochemistry over decades. He is widely regarded as the world’s leading immunochemist and rightly carries the position previously afforded to the great figures in this field such as Porter and Kabat. In the late 1970’s and early 1980’s he pioneered the use of anti-peptide antibodies to generate sequence specific antibodies. In this way one could go from a nucleic acid sequence of a protein to an antibody of defined specificity by simply making an antibody to a peptide predicted from the sequence. This method is in wide use today and is, in fact, the genesis of the tagging of proteins with defined peptide sequences to which one has an antibody such as the “flag tag” to aid in their identification and purification. Indeed, the original description of this method was Lerner’s.  In collaboration with the Wigler laboratory at Cold Spring Harbor, he used a C-terminal peptide of the influenza virus hemaglutinin  to tag proteins which could now react with a monoclonal antibody he had made to the peptide  (Field et. al. Mol. Cell Biol. 5,2159-2165, 1988). The observation that one had sequence specific antibodies led to the concept that if these antibodies could be converted to proteases one could generate site-specific reagents that could cleave any protein sequence which would be the equivalent of restriction enzymes for proteins. While this difficult goal is still a work in progress, Lerner approached the problem according to the first principles of catalysis such as transition state stabilization and today scientists have generated more than 100 catalytic antibodies that catalyze a wide range of reactions including disfavored process for which there are no natural enzymes. We have learned much about the evolution of protein catalysis from these studies including the general capability of proteins to do unusual things such as generate intense blue fluorescence on binding to the stillbene molecule. Remarkably, it is now known that this antibody functions like an LED where, in the first step, an electron is transferred from a tryptophane residue that is part of an aromatic triad of the antibody to an excited state diradical of stillbene to form a radical anion-radical cation complex that upon relaxation generates intense blue light with high quantum yield. These studies were carried out in collaboration with Harry Gray. In some sense this kind of study carries the unique signature of Lerner where the programmable binding energy of antibodies is used to do unusual things. These studies are more than “cute-tricks” because they illustrate the general capacity of proteins to accomplish chemistry beyond that which evolution afforded. The central idea is that one can generate protein binding energy to almost any substance whether it be a protein, metal ion, or small organic molecule and, if the system is chosen according to first chemical principles, chemical reaction coordinates can be perturbed in remarkable ways. This is indeed the incarnation of modern immunochemistry in that it amalgamates immunology and chemistry in ways that would have not been deemed possible a decade ago.  While it is always possible to ask   “of what use is all this” one never knows and the innovative use of technology in ways that are not immediately transparent often flows from creative insight and the sustained effort that derives its energy from belief. (This was, of course, true of the combinatorial antibody libraries that now generate many products that alleviate human suffering and because of the Lerner-Winter patents return very significant revenues to British science.)

In the case of other immunochemical efforts by Lerner, the most remarkable example of creativity and sustained effort that ultimately had a practical outcome is the aldolase antibody. I will give some detail here because it illustrates Lerner’s thinking. From the point of view of pure basic science, Lerner and his colleagues wanted to generate a catalytic antibody that was an aldolase. They knew that the centerpiece of all the class 1 aldolase enzymes of nature is an active site lysine that has a highly perturbed pKa so that it can function as a un-protonated amine nucleophile . This lysine attacks the incoming carbonyl to form a Schiff base that collapses into the nascent enamine aldol donor. But, how could one select for the very rare antibodies that have evolved such a lysine in their combining site?  They reasoned that during affinity maturation of an immune response there is a competition amongst B-cell clones to achieve the highest binding energy. Thus, if the possibility of covalency is offered it might be a selectable parameter. To select for such antibodies they synthesized a 1,3-diketone antigen that would react with a un-protonated lysine to form an enaminone that has a unique 315 nanometer spectroscopic signal. Thus, one simply screened for evolved antibodies that when offered acetyl acetone gave the 315 nanometer signal. This, approach was highly successful and many efficient aldolase antibodies were generated.   When the crystal structure of such antibodies were solved the mechanism by which function was revealed in that the lysine residues that evolved during the immune response appeared in otherwise hydrophobic areas in the combining site such that the positive charge of the protonated amine is highly disfavored. The pKa’s of these nucleophilic lysines were perturbed by three orders of magnitude! The matter might have rested here. But, drawing on his knowledge of immunochemistry, Lerner realized something else of much practicality. It was that the overall nature of the antibody combining site depended on when the lysine appeared during the evolution of the immune response. The basic concept is that once the nucleophilic lysine appears, further “refinement” of that antibody molecule is no longer selectable because one cannot beat the binding energy achieved by a covalent interaction.  Thus, if the lysine appears late in the evolution of the immune response it will be contained in an otherwise highly refined antibody pocket whose main feature is specificity for the particular haptenic construct that contains the 1,3-diketone. This is simply because increased binding energy is accompanied by increased specificity. However, if the lysine appears early, the pocket will remain undifferentiated because further refinement is no longer selectable.  Such “early adaptor” antibodies are remarkable because they basically have a highly reactive lysine at the base of an otherwise unrefined antibody. This means that such an antibody will catalyze its own attachment to virtually any organic compound or peptide to which a diketone or alternative aldol substrate is appended.  Thus, antibody half-life can be given to compounds that do not circulate and/or antibody effector function is afforded to otherwise inert functions. Importantly, these studies break the “one antibody one target” axiom in that the specificity comes from what the antibody carries rather than the antibody itself. In the best sense it allows a merger between the best aspects of organic chemistry and immunochemistry. The antibody can gain surrogate specificity from the unlimited repertoire of organic compounds selected and refined for binding to a target while the organic compound can enjoy antibody-like properties.

Such antibodies are now the first catalytic antibodies in the clinic. There are 4 clinical trials underway and 16 more planed where a single antibody carries a different compound in each of the trials depending on the clinical situation under study. Thus, what began simply as exploratory immunochemistry has become the basis of a powerful new therapeutic antibody platform.

In addition to these scientific efforts, Richard Lerner has a long record of excellence and discovery in research. Importantly, he has led The Scripps Research Institute with distinction (1987-). Perhaps, most importantly this stresses for the scientific community that scientific leadership is a prerequisite for institutional leadership. Indeed, under his innovative and inspiring leadership, Scripps has become a world leader in the marriage of biological and chemical sciences.