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Antibodies in the lab: Higher quality through DNA technology

University of Zurich

Antibodies are now established as therapeutics and indispensable in the research lab. In con-trast to high-quality therapeutics, commercial antibodies used in research often do not proper-ly function, as an international group of authors around Andreas Plückthun of UZH have warned. They demand that antibodies used in research should be made by recombinant DNA technology -- just like therapeutic antibodies.

Antibodies can recognize foreign invaders (bacteria and viruses) and fight against them in the body. Antibodies have found their place as therapeutics and have become completely indispensable in bio-logical and biomedical research -- they are essential lab tools. Now Andrew Bradbury of the Los Alamos National Labs, USA, and Andreas Plückthun of the Department of Biochemistry of the Uni-versity of Zürich write that the quality of routinely used commercial antibodies is insufficient for re-search. "Of 6000 tested antibodies only 3000 recognize their target molecule", explains the biochem-ist of the University of Zurich. With over 100 co-signatories, they elaborate the enormous problems that arise from "irreproducible experiments and waste of time and resources". The authors calculated that in the US every year about 350 Mio $ are wasted on useless antibody reagents, and presume similar numbers for Europe. They are confident that antibodies made with recombinant DNA technol-ogy as well as other recombinant binding proteins would be the solution for this problem.

Many monoclonal antibodies have deficits

Monoclonal antibodies are usually made by immunization of a mouse and subsequent fusion of an antibody-producing B-cell with a tumor cell. This creates so-called hybridomas, which produce mono-clonal antibodies. Many researchers believed that by this invention the problem of lack of specificity was finally solved. But quite the opposite: Genuine monoclonal antibodies have often several specific-ities, hybridomas can secrete more than one antibody, and they can die, leading to an irreversible loss of an antibody, forever. Inadequate characterization by the manufacturer, lack of documentation by the manufacturer, but also by the researchers about which antibody they exactly used compound the problem -- with the consequences that many antibodies do not recognize their presumed target molecule, that experiments fail or are not reproducible.

DNA technology can solve the problems

Bradbury, Plückthun and colleagues advocate to produce antibodies with recombinant DNA technolo-gy, i.e., on the basis of artificially assembled DNA. This has a key advantage: "Once you know the DNA of an antibody, anybody in the world, at any time, can regenerate the antibody", explains Plück-thun, a pioneer of recombinant antibody research. "Therapeutic antibodies are all made from recom-binant DNA, extremely well characterized and are thus of very high quality". Unfortunately, these technologies have not yet entered the reagent business, simply, because the companies with the relevant know-how have all entered the lucrative therapeutics business because of its much greater margins.

Research must be reproducible

What should be done? "In the long run, the DNA sequences of the reagents used in research would have to be publically available" explains Plückthun. Thereby, some companies who now produce classical reagent antibodies would have to adapt their business models, but the reproducibility of bio-logical science must have priority. "There is no real alternative to recombinant DNA technology."

In a first step it is important to invest in research towards the efficient generation of recombinant bind-ing reagents, this can be antibodies or alternative reagents. Currently, they are not yet cheaper to produce than classical monoclonal antibodies, but they contain an enormous potential through new technologies and automation, as the UZH biochemist explains. "Perhaps in 10 years, the problems caused by poorly characterized monoclonal antibodies will be a thing of the past".

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