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FRONTIERA MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY #2, 2018

The science behind the Nobel Prizes in Medicine and Chemistry

is the core in Alligator’s research and development

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FRONTIER – A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY

Alligator carries on the legacy of the Nobel Prize winners in Medicine and Chemistry .On Monday October 1, it was announced that James P. Allison and Tasuku Honjo had been awarded the 2018 Nobel Prize in Physiology or Medicine for discov-eries on immune checkpoints – which according to the Nobel Assembly at the Karolinska Institute “has revolutionized treatment and changed our view of how cancers can be treated.”

I share the opinion of the Nobel Assembly. The groundbreaking research by James Allison and Tasuku Honjo on how the immune system can be used to fight cancer has profoundly changed the therapeutic arena. Not only in terms of how we treat cancer but also on the prospect of surviving the disease.

The advancements at Alligator would not have been possible without Allison’s and Honjo’s research. Since the first immuno-therapy antibody was approved in 2011, the CTLA-4 blocker Yervoy®, scientists all over the world have pursued the quest of developing drugs that activate the immune system against cancer.

I am proud to say that Alligator plays an important part in this global effort ATOR-1015 is leading the way for the next gener-ation of CTLA-4 products, bispecific anti-bodies with tumor-localizing properties. It is directly borne out of Allison’s research, is the first of its kind, and will enter clinical phase I before the end of the year.

What is more, George Smith, Frances H. Arnold, and Greg Winter were awarded the Nobel Prize in Chemistry on October 3. Arnold developed a protein evolution tech-nology that is related to Alligator’s FIND® technology (Fragment INduced Diversity), and Smith and Winter developed phage dis-play, the technology behind our human anti-

body library ALLIGATOR-GOLD®. ATOR-1015 is built and optimized using both phage display and the protein optimization tech-nology FIND. Moreover, the key mechanism of action of ATOR-1015 is to activate the immune system via CTLA-4. Three Nobel Prize discoveries in the same molecule. This will be a difficult record to beat!

At Alligator, we will now make every effort to continue to work in the spirit of the Nobel Prize. A Revolution for Life.

Per Norlén, CEO

In honor of previous prize winners in the phys-iology and medicine categories, we have listed all of their names in this issue of Frontier.

The Nobel Prize in Physiology or Medicine has been awarded to:1901 Emil von Behring 1902 Ronald Ross 1903 Niels Ryberg Finsen1904 Ivan Pavlov 1905 Robert Koch 1906 Camillo Golgi 1907 Alphonse Laveran 1908 Ilja Metjnikov Paul Ehrlich 1909 Theodor Kocher 1910 Albrecht Kossel 1911 Allvar Gullstrand 1912 Alexis Carrel 1913 Charles Richet 1914 Robert Bárány 1919 Jules Bordet 1920 August Krogh1922 Archibald V. Hill Otto Meyerhof 1923 Frederick G. Banting John Macleod 1924 Willem Einthoven 1926 Johannes Fibiger 1927 Julius Wagner-

Jauregg 1928 Charles Nicolle 1929 Christiaan Eijkman Sir Frederick Hopkins 1930 Karl Landsteiner 1931 Otto Warburg 1932 Sir Charles

Sherrington Edgar Adrian 1933 Thomas H. Morgan 1934 George H. Whipple George R. Minot William P. Murphy1935 Hans Spemann 1936 Sir Henry Dale Otto Loewi 1937 Albert Szent-Györgyi 1938 Corneille Heymans 1939 Gerhard Domagk 1943 Henrik Dam Edward A. Doisy 1944 Joseph Erlanger Herbert S. Gasser1945 Sir Alexander

Fleming Ernst Boris Chain Howard Walter

Florey1946 Hermann Joseph

Muller1947 Carl Cori Gerty Cori Bernardo Alberto

Houssay1948 Paul Müller1949 Walter Hess Egas Moniz1950 Edward C. Kendall Philip S. Hench Tadeus Reichstein1951 Max Theiler1952 Selman A. Waksman1953 Hans Krebs Fritz Lipmann1954 John F. Enders Thomas H. Weller Frederick C. Robbins1955 Hugo Theorell1956 André F. Cournand Dickinson W.

Richards Werner Forssmann1957 Daniel Bovet 1958 George Wells Beadle Edward Lawrie

Tatum Joshua Lederberg1959 Severo Ochoa Arthur Kornberg

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Tasuku Honjo, James P. Allison and their discoveries.This year’s Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their discovery of cancer therapy through the inhibition of negative immune regulation. Thanks to research by Allison and Honjo, it is now possible to release the inherent power of the immune system to fight and destroy cancer cells in a completely new and revolutionary way.

Tasuku HonjoTasuku Honjo, born in 1942, is a Japanese immunologist. He is best known for his discovery and research into the mecha-nisms and proteins that are essential in the regulation of immune reactions. Honjo’s research has paved the way for the develop-ment of anti-PD-1 immunotherapies, which have been approved for the treatment of melanomas and other forms of cancer. He has worked as a researcher in both the US and in Japan.

James P. AllisonJames P. Allison was born in 1948 in Alice, Texas, and is the youngest of three sons to Constance Kalula (Lynn) and Albert Murphy Allison. His scientific interest was aroused in earnest by his math teacher in the eighth grade, an interest that has meant Allison has spent a large share of his life studying how

antigen receptors can activate or inactivate the immune system’s T cells. This knowledge constitutes the core of immuno-oncology and Allison’s research resulted in the first immuno-oncology drug in 2011.

Allison also has very personal experiences of cancer. At the age of eleven, his mother died from lymphoma and his brother passed away from prostate cancer in 2005. Allison himself has undergone surgery for prostate cancer and skin cancer and is currently undergoing immunotherapy treat-ment for bladder cancer.

Allison is a professor at M.D. Anderson Cancer Center at the University of Texas. In his spare time, he plays the harmonica in a blues band called Checkpoints together with colleagues from immuno-oncology.

1960 Sir Frank Macfarlane Burnet

Peter Medawar1961 Georg von Békésy1962 Francis Crick James Watson Maurice Wilkins1963 Sir John Eccles Alan L. Hodgkin Andrew F. Huxley1964 Konrad Bloch USA Feodor Lynen1965 François Jacob André Lwoff Jacques Monod1966 Peyton Rous Charles B. Huggins1967 Ragnar Granit Haldan Keffer

Hartline George Wald1968 Robert W. Holley Har Gobind Khorana Marshall W.

Nirenberg1969 Max Delbrück Alfred D. Hershey Salvador E. Luria1970 Sir Bernard Katz Ulf von Euler Julius Axelrod1971 Earl W Sutherland Jr.1972 Gerald M. Edelman Rodney R. Porter1973 Karl von Frisch Konrad Lorenz Nikolaas Tinbergen1974 Christian de Duve Albert Claude George E. Palade1975 David Baltimore Renato Dulbecco Howard M. Temin1976 Baruch S. Blumberg D. Carleton Gajdusek1977 Andrew V. Schally Roger Guillemin Rosalyn Yalow1978 Werner Arber Daniel Nathans Hamilton O Smith1979 Allan M. Cormack Godfrey N.

Hounsfield1980 Jean Dausset Baruj Benacerraf George D. Snell1981 Roger W. Sperry Torsten N. Wiesel1982 Sune Bergström Bengt Samuelsson John R. Vane

Storbritannien1983 Barbara McClintock1984 Niels K. Jerne Georges J F Köhler César Milstein1985 Michael S. Brown Joseph L. Goldstein1986 Rita Levi-Montalcini Stanley Cohen1987 Susumu Tonegawa1988 Sir James W. Black Gertrude B. Elion George H. Hitchings1989 J. Michael Bishop Harold E. Varmus1990 Joseph E. Murray Edward Donnall

Thomas1991 Erwin Neher Bert Sakmann1992 Edmond H. Fischer Edwin G. Krebs1993 Richard J. Roberts Phillip A. Sharp

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1994 Alfred G. Gilman Martin Rodbell1995 Edward B. Lewis Eric F. Wieschaus Christiane Nüsslein-

Volhard1996 Rolf M. Zinkernagel Peter C. Doherty1997 Stanley B. Prusiner1998 Robert F. Furchgott Louis J. Ignarro Ferid Murad1999 Günter Blobel2000 Paul Greengard Eric R. Kandel Arvid Carlsson2001 Tim Hunt Sir Paul Nurse Leland H. Hartwell2002 Sydney Brenner John E. Sulston H. Robert Horvitz2003 Paul C. Lauterbur Sir Peter Mansfield2004 Richard Axel Linda B Buck2005 Barry Marshall Robin Warren2006 Andrew Z. Fire Craig C. Mello2007 Mario R. Capecchi Oliver Smithies Sir Martin J. Evans2008 Harald zur Hausen Françoise Barré-

Sinoussi Luc Montagnier2009 Elizabeth Blackburn Carol Greider Jack Szostak2010 Robert Edwards2011 Bruce Beutler Jules Hoffmann Ralph Steinman2012 John B. Gurdon Shinya Yamanaka2013 James Rothman Randy Schekman Thomas Südhof2014 John O’Keefe Edvard Moser May-Britt Moser2015 William C. Campbell Satoshi Ōmura Tu Youyou2016 Yoshinori Ohsumi2017 Jeffrey C. Hall sMichael Rosbash Michael W. Young2018 James P. Allison Tasuku Honjo

The Nobel Prize in Chemistry was awarded to:1901 Jacobus Henricus

van ’t Hoff1902 Hermann Emil

Fischer1903 Svante August

Arrhenius1904 Sir William Ramsay1905 Johann Friedrich

Wilhelm Adolf von Baeyer

1906 Henri Moissan1907 Eduard Buchner1908 Ernest Rutherford1909 Wilhelm Ostwald1910 Otto Wallach1911 Marie Curie, född

Sklodowska1912 Victor Grignard Paul Sabatier1913 Alfred Werner1914 Theodore William

Richards

Frances H. Arnold, George P. Smith and Sir Gregory P. Winter

The chemistry prize winners have taken control over evolution.The first seed of life on earth appeared some 3.7 billion years ago. Evolution has since produced almost inconceivable riches on a previously deserted planet through its modus operandi of genetic change and selection. Life now exists in locations under the most varying conditions. This year’s Nobel Prize winners in Chemistry have been inspired by evolution and used the same principles to develop proteins that solve a number of our chemical challenges, such as manufacturing biofuel and drugs. Using the phage display method, we can now develop antibodies to treat auto-immune diseases and in some cases cure metastatic cancer.

The year’s Nobel Prize in Chemistry was awarded to three people: Frances H. Arnold, George P. Smith and Sir Gregory P. Winter. Arnold was awarded half of the prize for performing the first directed evo-lution of enzymes (proteins that catalyze chemical reactions) in 1993. The second half was shared between George P. Smith and Sir Gregory P. Winter. Smith was awarded his share of the prize for developing phage display, a method where bacteriophages (viruses that infect bacteria) are used to develop new proteins. Phage display has opened the door to the directed evolution of antibodies underlying much of Alligator’s research and development. Winter received the prize for his use of phage display to produce new drugs against diseases such as rheumatoid arthritis, psoriasis and inflam-matory bowel diseases.

Frances H. Arnold was born in 1956 in Pittsburgh, US. She received a PhD in 1985 from the University of California, Berkeley, US. Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemis-try at the California Institute of Technology, Pasadena, US.

George P. Smith was born in 1941 in Nor-walk, US. He received a PhD in 1970 from Harvard University, Cambridge, US. Cura-tors’ Distinguished Professor Emeritus of Biological Sciences at the University of Missouri, Columbia, US.

Sir Gregory P. Winter was born in 1951 in Leicester, UK. He received a PhD in 1976 from the University of Cambridge, UK. Research Leader Emeritus at MRC Laboratory of Molecular Biology, Cambridge, UK.


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1915 Richard Martin Willstätter

1918 Fritz Haber1920 Walther Hermann

Nernst1921 Frederick Soddy1922 Francis William Aston1923 Fritz Pregl1924 Ej utgivet1925 Richard Zsigmondy1926 The (Theodor)

Svedberg1927 Heinrich Otto

Wieland1928 Adolf Windaus1929 Arthur Harden Hans von Euler-

Chelpin1930 Hans Fischer1931 Carl Bosch Friedrich Bergius1932 Irving Langmuir1933 Ej utgivet[E]1934 Harold Clayton Urey1935 Frédéric Joliot Irène Joliot-Curie1936 Petrus (Peter)

Josephus Wilhelmus Debye

1937 Walter Norman Haworth

Paul Karrer1938 Richard Kuhn1939 Adolf Friedrich

Johann Butenandt Leopold Ruzicka1943 George de Hevesy1944 Otto Hahn1945 Artturi Ilmari

Virtanen1946 James Batcheller

Sumner John Howard

Northrop Wendell Stanley1947 Sir Robert Robinson1948 Arne Wilhelm Kaurin

Tiselius1949 William Francis

Giauque1950 Otto Paul Hermann

Diels Kurt Alder1951 Edwin Mattison

McMillan Glenn Theodore

Seaborg1952 Archer John Porter

Martin Richard Laurence

Millington Synge1953 Hermann Staudinger1954 Linus Carl Pauling1955 Vincent du Vigneaud1956 Sir Cyril Norman

Hinshelwood Nikolay Nikolaevich

Semenov1957 Lord (Alexander R.)

Todd1958 Frederick Sanger1959 Jaroslav Heyrovský1960 Willard Frank Libby1961 Melvin Calvin1962 Max Ferdinand

Perutz John Cowdery

Kendrew1963 Karl Ziegler Giulio Natta1964 Dorothy Crowfoot

Hodgkin1965 Robert Burns

Woodward1966 Robert S. Mulliken

Immuno-oncology offers fantastic opportunities.The body’s immune response protects us from disease by recognizing and attack-ing anything that is unfamiliar, but is also activated when the body’s own cells are changed in one way or another, such as becoming cancer cells. However, cancer cells are often highly skilled at avoiding the immune system, which allows the dis-ease to continue to grow. Immuno-oncology is based on the insight into how the body’s own immune system can be used to fight cancer.

The idea of activating the body’s own immune system in the fight against cancer is not new. The problem has been the ability of cancer cells to hide from the immune system, including the build-up of immuno-suppressants that inhibit an attack by the immune system. Only since the approval of Yervoy (ipilimumab) has immuno-oncology become a successful reality with favorable treatment outcomes, for example, for malig-nant melanoma (skin cancer). This principle of inhibiting the response of immune reg-ulation has formed the basis for Alligator’s research and development.

Immuno-oncology is effective in three ways. Firstly, it reinforces the immune system’s ability to fight cancer cells in an effective manner. Secondly, the tumor’s defense is weakened. Thirdly, the immunological memory provides longstanding protection against recurring tumor growth. This “vacci-nation effect” is unique to immunotherapy.

A dynamic fieldImmuno-oncology is now one the most dynamic fields of cancer research. According to a report from the Cancer Research Insti-tute (published in Annals of Oncology), there

were 940 immuno-oncology substances in the clinical phase and 1,064 in the preclin-ical phase in September 2017. More than 860 companies are conducting research and development in immuno-oncology. Today, malignant melanoma, renal cell carcinoma and lung cancer are being treated using immuno-oncology therapies, though there is great hope that more types of cancer may be treated with various immunotherapies in the future.

Alligator – tumor-targeted therapyWhat distinguishes Alligator is the com-pany’s unique technology that makes it possible to activate the immune system to specifically attack tumors while the rest of the body is unaffected. The main advantage of this tumor-targeted therapy is that it can have a favorable effect on the tumor at the same time as the side effects that arise if you activate the entire immune system can be kept at as low a level as possible.

Alligator is currently conducting five promis-ing development projects. Two projects are in, or about to start, Phase I clinical trials, while the other three projects are in various stages of preclinical development.

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FRONTIER – ETT MAGASIN OM ALLIGATOR BIOSCIENCE OCH IMMUNONKOLOGI

1967 Manfred Eigen Ronald George

Wreyford Norrish George Porter1968 Lars Onsager1969 Derek H. R. Barton Odd Hassel1970 Luis F. Leloir1971 Gerhard Herzberg1972 Christian B. Anfinsen Stanford Moore William H. Stein1973 Ernst Otto Fischer Geoffrey Wilkinson1974 Paul J. Flory1975 John Warcup

Cornforth Vladimir Prelog1976 William N. Lipscomb1977 Ilya Prigogine1978 Peter D. Mitchell1979 Herbert C. Brown Georg Wittig1980 Paul Berg Walter Gilbert Frederick Sanger1981 Kenichi Fukui Roald Hoffmann1982 Aaron Klug1983 Henry Taube1984 Robert Bruce

Merrifield1985 Herbert A.

Hauptman Jerome Karle1986 Dudley R.

Herschbach Yuan T. Lee John C. Polanyi1987 Donald J. Cram Jean-Marie Lehn Charles J. Pedersen1988 Johann Deisenhofer Robert Huber Hartmut Michel1989 Sidney Altman Thomas R. Cech1990 Elias James Corey1991 Richard R. Ernst1992 Rudolph A. Marcus1993 Kary B. Mullis Michael Smith1994 George A. Olah1995 Paul J. Crutzen Mario J. Molina F. Sherwood

Rowland1996 Robert F. Curl Jr. Sir Harold W. Kroto Richard E. Smalley1997 Paul D. Boyer John E. Walker Jens C. Skou1998 Walter Kohn John A. Pople1999 Ahmed H. Zewail2000 Alan J. Heeger Alan G MacDiarmid Hideki Shirakawa2001 William S. Knowles Ryoji Noyori K. Barry Sharpless2002 John B. Fenn Koichi Tanaka Kurt Wüthrich2003 Peter Agre Roderick MacKinnon2004 Aaron Ciechanover Avram Hershko Irwin Rose2005 Yves Chauvin Robert H. Grubbs Richard R. Schrock2006 Roger D. Kornberg2007 Gerhard Ertl

ATOR-1015. Tumor-localizing bispecific antibody with dual immunostimulatory function. ATOR-1015 is a bispecific (CTLA-4 and OX40) antibody developed for tumor- targeted treatment of metastatic cancer. The ATOR-1015 antibody has been assembled and optimized using Alligator’s unique ALLIGATOR-GOLD and FIND technologies and the bispecific fusion format.

Project status: preclinical development, Phase I clinical trial to commence in 2018Preclinical data presented at various confer-ences in 2018 show that ATOR-1015 localizes to the tumor, with increased immunostim-ulation in the tumor compared with normal tissue. The drug candidate ATOR-1015 is pri-marily designed for combination therapies and the preclinical results presented include data indicating an amplified anti-tumor effect in combination therapy with a PD-1 pathway-blocking antibody.

Mechanism of actionATOR-1015 binds to two different immuno-modulatory receptors – the CTLA-4 inhib-itory receptor, and an OX40 costimulatory receptor. In preclinical studies, the biospec-ificity has been shown to cause a significant increase in the immunostimulatory effect and is expected be achieved mainly in envi-ronments where both of the target mole-cules are expressed at high levels, such as in a tumor. This means that ATOR-1015 may have potent immunostimulatory effects in the tumor environment, but not in the rest of the body, with the goal of reducing the side effects while maintaining efficacy.

1. ATOR-1015 binds to CTLA-4 and OX40 on the regulatory T cells, the cells which restrain the immune system.

2. The macrophages are activated to kill Tregs, removing the inhibitory effect of Tregs on the beneficial T cells.

3. The effector T cells (light green) are multiplied in number and are activated to kill the tumor cells.

ATOR-1015 MoA (CTLA-4 x 0X40)

Mode of action

Macrophage

Tumor Cell

Tumor Killing

Treg Depletion

Treg

T cell

ATOR-1015 CTLA-4 OX40

Macrophage

Tumor Cell

Tumor Killing

Treg Depletion

Treg

T cell


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2008 Osamu Shimomura Martin Chalfie Roger Y. Tsien2009 Venkatraman

Ramakrishnan Thomas A. Steitz Ada E. Yonath2010 Richard F. Heck Ei-ichi Negishi Akira Suzuki2011 Dan Shechtman2012 Brian Kobilka Robert Lefkowitz2013 Martin Karplus Michael Levitt Arieh Warshel2014 William E. Moerner Eric Betzig Stefan Hell2015 Tomas Lindahl Paul Modrich Aziz Sancar2016 Jean-Pierre Sauvage Fraser Stoddart Ben Feringa2017 Jacques Dubochet Joachim Frank Richard Henderson2018 Frances Arnold George P. Smith Gregory P. Winter

About Alligator Alligator is a research-based biotechnology company developing antibody-based pharmaceuticals for cancer treatment. The company specializes in the develop-ment of tumor-directed im-munotherapies and is active in the early phases of drug development, from idea to clinical phase II studies.

Please visit our web: alligatorbioscience.com

About Frontier The aim with Frontier is to present Alligator’s research & development in brief and general terms.

EditorsCecilia HofvanderLotten AlménMichael Vallinder

DistributionFrontier is distributed to subscribers and also available on the Alligator web site.

Stock exchange lunch about Nobel Prize winnersFollowing the announcement of the Nobel Prize winners in Medicine, Alligator’s CEO Per Norlén was a guest at EFNTV’s “Börslunch” web-TV program to talk about Alligator and the future of immunotherapy. www.efn.se

4th CRI-CIMT-EATI-AACRAlligator’s researchers Karin Hägerbrand and Eva Dahlén presented preclinical data that support good tolerability for ATOR-1017 at the 4th CRI-CIMT-EATI-AACR International Cancer lmmunotherapy Conference in New York, US.

BIO-Europe 2018Alligator’s CEO Per Norlén discusses the challenges and opportunities of immuno-oncology from a business development perspective at BIO-Europe 2018.

Presentation at PEGS EuropeAnna Säll, researcher at Alligator, held a presentation, ATOR-1017–An Agonistic Tumor Directed Fcγ-Receptor Cross Linking Dependent CD137 Antibody, at PEGS Eu-rope in Lisbon, Portugal.

@sitcancer in Washington DCAlligator was kept busy at SITC (Society for Immunotherapy of Cancer) in Washington DC, US, holding presentations of the three preclinical projects ATOR-1015, ATOR-1017 and ALG.APV-527.

www.sitcancer.org/2018/home

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