LIFETHE LEADING LIFE SCIENCE BUSINESSSC MAG 169 SEK / 20 EUR / 25 USD NO RDIC

BUSINESS IN FOCUS LIFE SCIENCE THE LEADING NORDIC LIFE SCIENCE NEWS CHANNEL

IMMUNE ONCOLOGY

NOVO NORDISK FOUNDATION

CONTENTS NORDIC LIFE SCIENCE BUSINESS NEWS | PROFILES | FINANCE | LEGAL ADVICE | CAREERS

“I believe this is the beginning of a new era in cancer treatment. I believe cancer immunotherapy will be the Number One choice in the future.” TASUKU HONJO

JENNY ÖHMAN JENNY

NORDICLIFESCIENCE.ORG

6 PHOTO The Nobel Laureates in Chemistry The 2018 Nobel Prize in Physiology or The Nobel Prize in Physics 2018 was 2018, Francis H. Arnold (1/2), George Medicine was awarded to James P. Allison awarded to Arthur Ashkin (1/2), Smith (1/4) and Sir Gregory Winter and Tasuku Honjo for their pioneering Gérard Mourou (1/4) and Donna (1/4) employed genetic change and work in cancer immunotherapy. Immune Strickland (1/4) “for groundbreaking selection – the same principles checkpoint therapy has fundamentally inventions in the field of laser physics,” as evolution – to create molecules changed the outcome for certain patient providing us with optical tweezers for the common good. groups with advanced cancer. and corrective eye surgeries.

NIKLAS ELMEHED. COPYRIGHT: NOBEL MEDIA AB 2018 read more on page 42 read more on page 58 read more on page 78

ILUSTRATION NORDICLIFESCIENCE.ORG 41

42 NORDICLIFESCIENCE.ORG ENZYME EVOLUTION

RANDOM MUTATIONS ARE INTRODUCED IN THE GENE FOR THE ENZYME THAT WILL BE CHANGED.

THE GENES ARE INSERTED IN BACTERIA, DNA WHICH USE THEM AS TEMPLETES AND mutation PRODUCE RANDOMLY MUTATED ENZYMES.

enzymes

mutation

THE CHANGED ENZYMES ARE TESTED. THOSE THAT ARE MOST EFFICIENT AT CATALYSING THE DESIRED CHEMICAL REACTION ARE SELECTED.

test plate

discarded enzyme

NEW RANDOM MUTATIONS ARE INTRODUCED IN THE GENES FOR THE SELECTED ENZYMES. THE CYCLE BEGINS AGAIN. JOHAN JARNESTAD/THE ROYAL SWEDISH ACADEMY OF SCIENCES ILUSTRATION PHAGE DISPLAY

PEPTIDE (A PART OF A PROTEIN) CAPSULE- PROTEIN A GENE PHAGE

ANTIBODY DNA

PEPTIDE

The peptide produced from the Smith introduced a gene into the gene for mith s l t sh ut th hg using introduced gene ended up as part a protein in the phage’s capsule. The phage an antibody designed to attach to the of the capsule protein on the surface DNA was then inserted into bacteria that peptide. As a bonus, he got the gene for of the phage. produced phages. the peptide.

JOHAN JARNESTAD/THE ROYAL SWEDISH ACADEMY OF SCIENCES ILUSTRATION catalyze reactions that are not catalyzed by naturally occurring enzymes, such as carbon-silicon bonds. I many cases, the enzymes that Arnold has developed offer a more effective and environmen- tally friendly alternative to the current metallic catalyzed reactions.”

Following the Nobel announcement, Arnold explained to Adam Smith of Nobel Media that what she actually does is “copies nature’s design process”: “All this tremendous beauty and complexity of the biological world all comes about through this one simple, beautiful design algorithm, and what I do is use that algorithm to build new biological things. And to me it’s not … it’s obvious, it’s totally obvious that this is the way it should be done.” In her Nobel lecture entitled “Bring- ing new chemistry to life”, she described how her discovery is a versatile tool to make this planet a better place. She further emphasized in her speech at the Nobel Banquet that it is all too easy to apply the evolution incorrectly: both in practice and in theory. Therefore, we APELÖGA Carl Borrebaeck must use the term wisely. PHOTO

George Smith, currently Professor Emeritus at the University of Missouri, HE CHEMISTRY Pasadena. Arnold carried out pioneering is someone who has used the term well. LAUREATES’ work in the 1990s on the directed evolu- Smith shares the other half of the Chem- groundbreaking tion of enzymes: proteins that catalyze istry Prize with Sir Gregory Winter. In work harnesses chemical reaction. She developed meth- 1985 Smith developed a method where the process of ods for inducing mutations in enzyme- a bacteriophage – that is to say, a virus evolution for producing bacteria and then screening that infects bacteria – is used to evolve the generation and selecting the bacteria to speed up new proteins. He coined his method of novel bio- and direct enzyme evolution. phage display, which can be used to logical compounds. “Nowadays, her methods are rou- quickly select new binding proteins. Enzymes produced through directed evo- tinely used in the chemical industry, Gregory Winter, currently Researcher lution are used to manufacture everything for example in the manufacturing of Emeritus at MRC Laboratory of Molecular from biofuels to pharmaceuticals, and chemical substances, such as pharma- Biology in the U.K., used phage display antibodies evolved using phage display can ceuticals, and in the manufacturing of for directed evolution of antibodies. combat autoimmune diseases and in some renewable fuels for a greener transpor- His goal was to produce new pharma- cases cure metastatic cancer. tation sector,” says Claes Gustafsson, ceuticals. Adalimumab (Humira) was Professor of Medical Biochemistry at the the first produced with this method. University of Gothenburg and Chairman Approved by the FDA in 2002, it has Half of the Prize was awarded to Frances of the Nobel Committee for Chemistry become a blockbuster drug used to treat H. Arnold, who is a chemical engineer at 2018. “I am very impressed by Arnold’s illnesses such as rheumatoid arthritis the California Institute of Technology in ability to develop new enzymes that and inflammatory bowel disease.

NORDICLIFESCIENCE.ORG 45 evolved to the field of immuno-oncology where the aim is to kick-start the body’s own immune defense to eliminate tumors. ”Although there are pharmaceuticals on the market, this therapy is only in its infancy, which means that over the next few years there will be a revolution on how we look upon cancer therapy,” says Borrebaeck. “We are probably only at the beginning of this development because many new therapeutic antibodies, produced through phage display or other techniques, are cur- rently in different stages of clinical trials,” adds Gustafsson. The Laureates have now laid the foun- dation and have developed techniques that, in one way or the other are used by the majority of biopharma companies that develop biological drugs. Göran Forsberg, CEO of the Swedish company Cantargia, which specializes in antibody-based can- cer treatments, agrees: “These technolo- gies have been a part of our toolbox and will continue to be important in the future to further develop and broaden our pro- ject portfolio. Their contribution today is JOHAN WINGBORG JOHAN Claes Gustafsson a pillar for the development of biophar-

PHOTO maceuticals.”

Carl Borrebaeck founded the Swedish company Alligator Biosciences in 2001, which is currently developing antibody- based pharmaceuticals for cancer treat- ment. The corporation has probably been the most successful in this field in all of Nordic Europe. In 2017, Johnson & Johnson licensed the company’s immune- oncology agonistic CD40 antibody for ince then, phage society and patients can hardly be overes- more than $700 million. display has become timated; the entire industry of antibody- The company started a clinical phase I a powerful tool in based pharmaceuticals had a turnover of study in December with ATOR-1015: drug discovery; it more than $50–60 billion in 2018,” says a drug candidate developed for tumor- has been used to Professor Carl Borrebaeck of the Depart- directed immunotherapy. The phase I produce antibodies ment of Immunotechnology at Lund study is a first-in-human dose-escalation that may help to cure University and one of the world’s leading study of up to 53 patients with advanced metastatic cancer, researchers in the field of antibody design. solid tumor disease at five different clinics counteract toxins, across Sweden and Denmark. The primary and treat autoimmune diseases. aim will be to investigate the safety and “This Nobel Prize has opened up The Nobel Prize in Chemistry has also in- tolerability of the drug and to identify the entirely new ways of producing biologi- dicated new possibilities within antibody- recommended dose for subsequent Phase cal pharmaceuticals. The importance for based immunotherapy, which now has II studies. NLS

46 NORDICLIFESCIENCE.ORG

Chemistry Laureate George P. Smith at a press confer- ence in Stockholm during the Nobel week 2018 Chemistry Laureate Sir Gregory Winter at the 2018 Nobel Prize Award Ceremony in Stockholm ALEXANDER MAHMOUD PHOTO © NOBEL MEDIA AB 2018. AB MEDIA NOBEL ©

ALEXANDER MAHMOUD PHOTO © NOBEL MEDIA AB 2018. AB MEDIA NOBEL ©

Chemistry Laureate George P. Smith at the 2018 Nobel Prize Award Ceremony in Stockholm

HE 2018 CHEMISTRY NOBEL PRIZE Chemistry Department chair at Missouri University of honors three scientists for evolving, Science and Technology. He worked with Smith on the screening, and optimizing proteins: initiative and says, “He was committed to increasing George P. Smith, Curators’ Distinguished quantitative methods in science and especially to helping Professor Emeritus of Biological Sciences, underprivileged students join the program.” Smith devel- University of Missouri, and Sir Gregory oped a microbial evolution lab class that pushes students Winter, Master of Trinity College, to do rigorous experiments and quantitative analysis. University of Cambridge, UK, were This type of lab is usually for upper-level classes, Glaser awarded half the prize, with half to Frances Arnold, Califor- says, “But George has high standards and developed it for nia Institute of Technology. first-year students.” After “a brief period of having to un-retire” for Nobel Prize activities, Smith will write papers from the education The theme of this year’s award is directed evolution, exem- initiative. He’ll return to community activities and progres- plified by the phage-display method that Smith developed sive politics that have always been been a priority for him and Winter extended. To use the method, researchers put and his wife Margie Sable. a library of DNA sequences into bacteriophages – viruses that infect bacteria. As the phages replicate, they express the sequences as peptide amino acid chains on their surface. Winter’s current scientific work is advising investment and Selecting phages with a trait such as binding to an com- life science companies. He cofounded Bicycle Therapeutics, pound yields the DNA that confers that property. Mutagen- which chemically crosslinks phage-displayed peptides to esis and more selection optimizes the product. increase their stability and binding. Daniel Barton, Director of Business Development for Bio-sceptre, a cancer therapy company where Winter is on Smith says that not patenting phage display was critical to the Scientific Advisory board, says Winter advances both its spread as a research and development tool. “I could talk science and business, with “intellectual rigor and commercial about it and give samples to anyone in industry or acade- experience.” Biosceptre’s drug target presents a new challenge mia,” he says. “I doubt I’d have received a Nobel Prize if I’d to the antibody discovery and engineering technology that been pursuing intellectual property protection instead.” Winter helped pioneer, and he has great energy and enthusiasm He understands the reasons for patents but warns they for that type of work, Barton says. “He is a scientist to his can restrict creativity. “Ideas are not your property,” he says. core and remains curious and fascinated by the problems of “They infect you from other people like viruses. They recom- biology.” bine in your body with other ideas and come out and infect other people. That’s how science – and culture – flourish.” inter advises entrepreneurs Winter moved phage display beyond small peptides. to think about their com- “We wondered about using this powerful technique to look mercialization goals and at folded proteins, in particular to screen our repertoire of identify if industry partner- antibodies,” he says, “and it proved to be a great technology.” ships, licensing agreements, Phage-display methods are now standard for developing or a startup is the best way antibody therapy, thanks in part to Winter’s work as a to achieve them. founder of Cambridge Antibody Technology, developer of “Is the goal to get adalimumab (Humira). resources for the lab, validation of techniques developed in the lab, or doing public good?” Earning money is also a motivator, he says, “although I tend to think if you get the Both Smith and Winter have moved on from the lab. The other things right, that will take care of itself.” day of the Nobel Prize news, Smith visited an undergraduate genetics class, reflecting his work before he retired in 2015. MANAGING DRUG DEVELOPMENT requires different skills “The last six years of my time at university,” he says, “my than leading a research group, Winter says, so get help from major focus was an education initiative.” Funded by the US experienced advisors. That said, reflecting on his first startup, National Science Foundation, the project increased student he recalls that funds were scarce because using antibody reper- diversity and use of mathematics in science, which Smith toires and phage display to make human antibodies “seemed says was an integral part of his own research. pretty harebrained.” He adds, “Sometimes you have to just Smith was “a fabulous collaborator and one of most learn drug development on the job and get on with it your- engaged people in the project,” says Rainer Glaser, now self. In startups, you have to do a lot of that.” NLS