Thomas Huber

Generation of the Lynn Hershman Antibody

Veröffentlicht am 10.04.2018


Could you briefly describe your work and area of research? Novartis looks for antibodies suitable for therapeutic use. Through various biotechnical methods, candidates that influence disease-relevant biological processes (targets) are selected from synthetic libraries and natural sources of antibodies. The antibodies thus found are improved until they possess the required properties and can be used to treat particular diseases. We call these therapeutic antibodies.

When and how did the collaboration with Lynn Hershman Leeson come about, and how long was your involvement? Therapeutic antibodies are a part of our portfolio. Lynn called on Novartis to find out more about the production process and application possibilities of antibodies. The idea of a new antibody came about when she visited us in October 2017. Antibodies are special proteins, and consist of amino acids. The twenty natural amino acids are typically abbreviated to a single letter, so “L,” for example, stands for leucine. The new antibody bears the name of LYNN HERSHMAN in its amino-acid sequence, thus attaining individual properties. The production and characterization of this antibody will be complete by the opening of the exhibition on May 2, 2018, in the House of Electronic Arts Basel.

In what way did your approach to the synthesis of the LYNN HERSHMAN antibody differ from your usual approach? Could you say something about the scientific method and the interaction between you and the artist? The production and characterization of the LYNN HERSHMAN antibody more or less reflects the actual process, and helps to illustrate and understand it. In this case the sequence of the antibody was determined, while in a therapeutic antibody program the so-called “target,” the protein or antigen that the antibody is intended to bind, is in the foreground. The interaction of antibody and antigen is particularly relevant, as it shows how the antibody functions. The antibody sequence is initially unknown, and is literally “found” during the process. With the LYNN HERSHMAN antibody, however, we specified the sequence, examined the functions, and looked for possible antigens. We will only evaluate the results of this decisive experiment when Lynn Hershman visits us in late April. We were in contact with Lynn during the process, and discussed how the project was going.

What, roughly speaking, is necessary for an antigen to trigger the formation of an antibody? Our body is continually producing countless new antibodies in a complex process. As soon as one of these antibodies recognize an alien antigen, it is produced in larges quantities in order to eliminate the foreign body. Our body also takes note of the blueprint of the antibodies useful to it so that they can be quickly reproduced at a later time. Antibodies recognize a wide range of different classes of antigens: parts of viruses, proteins, DNA, and even small molecules, so-called haptens. But we’ll only know whether the LYNN HERSHMAN antibody recognizes a specific antigen, whether alien or endogenous, at the end of the experiment.

What size is the antibody you created, and how many “samples” are there? Are there any pictures of it? Something like a visual portrait or a detailed description of its structure? What is its face, or should we rather speak of an inter-face? The LYNN HERSHMAN antibody consists of four protein chains with a total of 1,334 amino acids. For the exhibition we have produced around sixty quadrillion molecules. An unimaginably large number. But because antibodies are extremely small, this only amounts to about fifteen milligrams. Antibodies can’t be seen with the naked eye or an optical microscope.

The spatial structure of proteins is calculated by x-ray diffraction. The LYNN HERSHMAN antibody was also determined in this way, and the method was used to realistically integrate new LYNN HERSHMAN antigen-binding loop with corresponding programs into the structure. This loop is primarily responsible for the interaction with the antigen, and gives the antibody its binding properties. These properties will be described for the exhibition.

Visitors can find out about the structure interactively on a 3D monitor, and they can also experience the spatial flexibility of the new LYNN HERSHMAN loop in an animation. This results in a very individual “picture” or the LYNN HERSHMAN antibody. “Loops” are the spatial structure of the protein chains. They can take on various spatial formations, and you can imagine how they are able to grasp the antigen like fingers (the LYNN HERSHMAN loop is orange in the illustration below).

A small part of the amino-acid chain in an existing protein structure can be replaced using modelling software. This software calculates the energetically preferred spatial arrangement of the new amino acids while taking the protein’s whole structure into account.

How individual, meaning bound to a living individual, are antibodies? Can we speak of something like an individual signature, or in what way does an antibody distance itself from its environment, from other antibodies, from antibodies formed from the same antigens? The process of antibody-generation in our body is on the one hand exactly defined, but on the other it also permits inexactness and chance. Only in this way is it possible to obtain an adequately wide diversity of new antibody sequences that enable the body to ward off unknown pathogens. Every person generates an individual repertoire of antibodies. Every individual finds different solutions for neutralizing antigens/pathogens. If our body had to twice tackle the same illness unprepared, it would probably develop different antibodies because of the contingency of the process. So it’s unlikely that two different people would develop the same antibody sequence against the same antigen. In this sense you could describe antibodies as something individual.

Central and peripheral tolerance are terms from immunobiology. The concept of tolerance contains a certain variability in the determination of same and different, which may be relevant not least to the field of autoimmune reactions. Could you roughly describe for us, from the immunological point of view, how we should imagine this interplay, and the extent to which it differs from our cultural ideas of identity and otherness? What is the significance of an absolutely identical or foreign body from the perspective of immunobiology? Our immune system performs incredibly well every day in distinguishing between endogenous and exogenous, “good” and “bad.” It does so with enormous, almost 100% precision. Tolerance of everything endogenous is important, as otherwise our own tissue would be attacked; misperformances of this kind are called autoimmune diseases. Apart from pathogens (alien), the smallest divergences from endogenous patterns also need to be recognized (own, but “bad”), otherwise tumors could spread. So our body can recognize—though unfortunately not always—that something of itself is getting out of control. It has also come to terms with numerous foreign organisms, our “microbiome,” which it allows space on and in us in a mutually beneficial arrangement. Antibody production uses up a great deal of energy. Most of the antibodies our body produces are useless, and their production has to be discontinued as soon as possible so as to save resources.

Is the distinction between animal, human, or purely synthetic antibodies relevant, or isn’t immunobiology in particular predestined to foster ideas of trans-human future life? To what extent is today’s research operating artificially or in completely new ways in the development of therapies and immune provisions? The antibodies of other organisms are at great risk of being recognized in the human being as foreign, and even as “antigen.” Since the 1970s key technologies like Köhler and Milstein’s “hybridoma” generation have enabled the production of antibodies against specific proteins (targets). The early methods were based on the used of mouse antibodies as a therapeutic agent. But it was quickly seen that patients developed neutralizing antibodies against these agents, which diminished their therapeutic benefit. Increasing knowledge and advancing technologies (synthetic libraries, transgene mice, human sources of antibodies) enabled the creation of “human” antibodies with better properties, thus reducing the number of patients with neutralizing antibodies. But a risk remains even in the use of human antibodies, as biophysical properties, application, and target biology play a role alongside the sequence itself.

Innovative antibody formats that don’t naturally exist are also propagated in the search for improved or entirely new therapies. For example, they offer the possibility of binding different targets at the same time. Other examples: T-cells can be directed by such atibodies to attack tumor cells (redirected T-cell killing), or they can be modified in such a way that on their surface they express an antibody against a tumor, which they thus eliminate (CART therapies).

What will be the destiny of the LYNN HERSHMAN antibody? Is it supposed to have a—if at all a “first,” then, so to speak—“second life”? Together with Lynn we’re in the process of formally describing the LYNN HERSHMAN antibody and its production process, and to record its structure. This document could correspond to a scientific publication and enable anyone with access to it to portray and produce the LYNN HERSHMAN antibody. But we still have to finally discuss this with the artist. The experiment to determine how the antibody functions remains to be done. There is a (very) small chance that the antibody binds one or several antigens. At any rate we’ll discuss the data with Lynn and discuss possible ways of proceeding.

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Thomas Huber

ist Forschungsgruppenleiter, Therapeutische Antikörper, Novartis.
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