Nobel work that galvanized an industry

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    The work of the 2018 Nobel Prize Chemistry awardees is remarkable not only for its influence on modern biotech, but also for the rapidity with which it translated to commercial products.

    It is not often that Nobel awards resonate in the world of biotech. But this year's Nobels for Chemistry resonate loud and clear. Half of the prize went to Frances Arnold of Caltech, whose seminal paper on the directed evolution of enzyme activity was published in this journal's previous incarnation 27 years ago (Biotechnology (N Y) 9, 1073–1077, 1991. The directed evolution approach has since spurred a vast range of biotech products—from enzymes, bulk chemicals and biomaterials to washing detergents, oils, fragrances and biofuels. Iterative rounds of test-tube evolution are also at the heart of the phage display technique recognized in the other half of the prize, which was divided between George Smith of the University of Missouri-Columbia and Greg Winter of the MRC Laboratory of Molecular Biology in Cambridge, UK. Phage display of peptides and antibodies not only spawned a score of biopharmaceutical companies, it has also produced at least six major antibody medicines and is responsible for the majority of human antibodies and antibody fragments in industry pipelines today.

    Nobel prizes are primarily awarded for fundamental discoveries. And it is rare that work in academic labs leads so rapidly to a raft of products and medicines in the manner catalyzed by directed evolution and phage display.

    In the case of Arnold's work, it took only eight years for an industrial group at Novo Nordisk Biotech, a subsidiary of the world's largest producer of industrial enzymes, to report the creation of a heme peroxidase enzyme suitable as a dye-transfer inhibitor in laundry detergent (Nat. Biotechnol. 17, 379–384, 1999). Using Arnold's approach, the Novo Nordisk group created a bleach-stable heme peroxidase variant with 174 times the thermal stability and 100 times the oxidative stability of the wild-type enzyme.

    According to the Lens (https://www.lens.org/), companies as diverse as Hercules, Danisco, Nuevolution, Evocatal and Evonik Degussa were granted patents citing Arnold's original paper; in the nineties, Diversa, Nautilus Biotech and Maxygen were all founded as molecular evolution companies, with the last firm focusing on a new iteration: the late Pim Stemmer's DNA shuffling method, which radically improves the chances of identifying optimized variants. Today, synthetic biology companies like Amyris, Zymergen and Ginkgo Bioworks all employ directed evolution in some form. In recent years, Arnold has also cofounded two start-ups: Provivi, which started in 2013 as an NIH SBIR idea to develop environmentally friendly pesticides and pharmaceuticals; and Gevo, founded in 2005 to produce low-carbon chemicals and fuels from plant carbohydrates.

    The commercial impact of phage display is even more remarkable.

    George Smith published his breakthrough paper on phage display in 1985 (Science 228, 1315–1317). In the next three years, Smith and his PhD student Stephen Parmley refined the technique, culminating in a landmark paper (Gene 73, 305–318, 1988) that described phage display as a way of producing a library of a million or so clones from which to select a 'hit' of interest by 'biopanning' (the phage library was reacted with biotinylated antibodies against the target gene product and extracted using streptavidin). Around this time, Bill Dower of Affymax suggested to Smith and postdoc Jamie Scott that electroporation could ramp up library size—allowing >40 million instead of 1 million clones, and transforming the power of the approach to find rare functional variants.

    Although Smith had envisioned antibody fragments in phage—he had an NIH grant for work on synthetic peptides and antibodies—it was Greg Winter's group in Cambridge who successfully applied the technique to express a single-chain variable region of an antibody against hen eggwhite lysozyme on Smith's fd-tet phage (Nature 348, 552–554, 1990). The phage antibody showed the same binding profile as the original antibody. That observation—together with earlier work in Winter's lab that inserted murine variable regions into human antibody scaffolds to create a route to 'humanized' antibodies—overcame the problem of cross-species immunogenicity, which until that point had hampered therapeutic development.

    Over the subsequent decade, antibody display catalyzed a transformation in biotech. By 1993, Cambridge Antibody Technology, Greg Winter's first major industrial venture, was collaborating with the Knoll Pharmaceutical division of German chemical giant BASF on humanizing the murine anti-tumor necrosis factor antibody MAK195 to make it suitable for chronic autoimmune disease. The humanized product, D2E7, became Humira (adalimumab), which was approved in 2002 for rheumatoid arthritis and was the world's best-selling drug in 2017.

    Other antibody phage-display systems and more refined libraries were developed elsewhere, stimulating the competitive environment and leading to the formation of other humanization companies, such as Dyax and MorphoSys. The ability to move beyond natural antibodies and create constructs and antibody fragments with immune-like functions also spurred companies, like Winter's own Domantis and Bicycle Therapeutics, as well as Ablynx, MacroGenics, F-star and Micromet.

    From the point of view of the evolution of the drug business, antibody display provided a set of turnkey processes that ultimately fueled biopharmaceutical pipelines via product licensing or wholesale acquisition of the innovating companies; many of these companies were the subject of billion-dollar acquisitions. In 2018, around 60% of all therapies in development for oncology are antibody based.

    Thus, vast commercial rewards and massive improvements in healthcare have stemmed from molecular evolution and phage display. But perhaps the most exciting aspect of all is that we have just scratched the surface in terms of exploring the protein sequence space accessible through these approaches. As advances in continuous evolution and multifaceted selection continue to increase our ability to build massive libraries and explore fitness landscapes, we can expect a whole new generation of products arising from the pioneering work of these Nobel laureates.

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    Nobel work that galvanized an industry. Nat Biotechnol 36, 1023 (2018) doi:10.1038/nbt.4301

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