A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNOONCOLOGY2 2018 - PDF document

FRONTIER A 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 2 FRONTIERA 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 discoveries 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 �ght 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 �rst immunotherapy 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 e�ort ATOR-1015 is leading the way for the next generation of CTLA-4 products, bispeci�c antibodies with tumor-localizing properties. It is directly borne out of Allison’s research, is the �rst 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 technology that is related to Alligator’s FINDtechnology (Fragment INduced Diversity), and Smith and Winter developed phage display, the technology behind our human antibody library ALLIGATOR-GOLD. ATOR-1015 is built and optimized using both phage display and the protein optimization technology 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 di�cult record to beat!At Alligator, we will now make every e�ort to continue to work in the spirit of the Nobel Prize. A Revolution for Life.Per Norlén, CEOIn honor of previous prize winners in the physiology 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:1901Emil von Behring 1902Ronald Ross 1903Niels Ryberg Finsen1904Ivan Pavlov 1905Robert Koch 1906Camillo Golgi1907Alphonse Laveran 1908Ilja MetjnikovPaul Ehrlich 1909Theodor Kocher 1910Albrecht Kossel 1911Allvar Gullstrand 1912Alexis Carrel 1913Charles Richet 1914Robert Bárány 1919Jules Bordet 1920August Krogh1922Archibald V. Hill Otto Meyerhof 1923Frederick G. Ba

nting John Macleod 1924Willem Einthoven 1926Johannes Fibiger 1927Julius Wagner-Jauregg 1928Charles Nicolle 1929Christiaan Eijkman Sir Frederick Hopkins 1930Karl Landsteiner 1931Otto Warburg 1932Sir Charles Sherrington Edgar Adrian 1933Thomas H. Morgan 1934George H. Whipple George R. Minot William P. Murphy1935Hans Spemann 1936Sir Henry Dale Otto Loewi 1937Albert Szent-Györgyi 1938Corneille Heymans 1939Gerhard Domagk 1943Henrik Dam Edward A. Doisy 1944Joseph Erlanger Herbert S. Gasser1945Sir Alexander FlemingErnst Boris ChainHoward Walter Florey1946Hermann Joseph Muller1947Carl CoriGerty CoriBernardo Alberto Houssay1948Paul Müller1949Walter HessEgas Moniz1950Edward C. KendallPhilip S. HenchTadeus Reichstein1951Max Theiler1952Selman A. Waksman1953Hans KrebsFritz Lipmann1954John F. EndersThomas H. WellerFrederick C. Robbins1955Hugo Theorell1956André F. CournandDickinson W. RichardsWerner Forssmann1957Daniel Bovet1958George Wells BeadleEdward Lawrie TatumJoshua Lederberg1959Severo OchoaArthur Kornberg 3 FRONTIERA MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY 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 �ght 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 mechanisms and proteins that are essential in the regulation of immune reactions. Honjo’s research has paved the way for the development 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 scienti�c 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 �rst 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 treatment 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. 1960Sir Frank Macfarlane BurnetPe

ter Medawar1961Georg von Békésy1962Francis CrickJames WatsonMaurice Wilkins1963Sir John EcclesAlan L. HodgkinAndrew F. Huxley1964Konrad BlochUSAFeodor Lynen1965François JacobAndré Lwo�Jacques Monod1966Peyton RousCharles B. Huggins1967Ragnar GranitHaldan Ke�er HartlineGeorge Wald1968Robert W. HolleyHar Gobind KhoranaMarshall W. Nirenberg1969Max DelbrückAlfred D. HersheySalvador E. Luria1970Sir Bernard KatzUlf von EulerJulius Axelrod1971Earl W Sutherland Jr.1972Gerald M. EdelmanRodney R. Porter1973Karl von FrischKonrad LorenzNikolaas Tinbergen1974Christian de DuveAlbert ClaudeGeorge E. Palade1975David BaltimoreRenato DulbeccoHoward M. Temin1976Baruch S. BlumbergD. Carleton Gajdusek1977Andrew V. SchallyRoger GuilleminRosalyn Yalow1978Werner ArberDaniel NathansHamilton O Smith1979Allan M. CormackGodfrey N. Houns�eld1980Jean DaussetBaruj BenacerrafGeorge D. Snell1981Roger W. SperryTorsten N. Wiesel1982Sune BergströmBengt SamuelssonJohn R. VaneStorbritannien1983Barbara McClintock1984Niels K. JerneGeorges J F KöhlerCésar Milstein1985Michael S. BrownJoseph L. Goldstein1986Rita Levi-MontalciniStanley Cohen1987Susumu Tonegawa1988Sir James W. BlackGertrude B. ElionGeorge H. Hitchings1989J. Michael BishopHarold E. Varmus1990Joseph E. MurrayEdward Donnall Thomas1991Erwin NeherBert Sakmann1992Edmond H. FischerEdwin G. Krebs1993Richard J. RobertsPhillip A. Sharp 4 FRONTIERA MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY 1994Alfred G. GilmanMartin Rodbell1995Edward B. LewisEric F. WieschausChristiane Nüsslein-Volhard1996Rolf M. ZinkernagelPeter C. Doherty1997Stanley B. Prusiner1998Robert F. FurchgottLouis J. IgnarroFerid Murad1999Günter Blobel2000Paul GreengardEric R. KandelArvid Carlsson2001Tim HuntSir Paul NurseLeland H. Hartwell2002Sydney BrennerJohn E. SulstonH. Robert Horvitz2003Paul C. LauterburSir Peter Mans�eld2004Richard AxelLinda B Buck2005Barry MarshallRobin Warren2006Andrew Z. FireCraig C. Mello2007Mario R. CapecchiOliver SmithiesSir Martin J. Evans2008Harald zur HausenFrançoise Barré-SinoussiLuc Montagnier2009Elizabeth BlackburnCarol GreiderJack Szostak2010Robert Edwards2011Bruce BeutlerJules Ho�mannRalph Steinman2012John B. Gurdon Shinya Yamanaka2013James RothmanRandy SchekmanThomas Südhof2014John O’KeefeEdvard MoserMay-Britt Moser2015William C. CampbellSatoshi ŌmuraTu Youyou2016Yoshinori Ohsumi2017Je�rey C. HallsMichael RosbashMichael W. Young2018James P. AllisonTasuku HonjoThe Nobel Prize in Chemistry was awarded to:1901Jacobus Henricus van ’t Ho�1902Hermann Emil Fischer1903Svante August Arrhenius1904Sir William Ramsay1905Johann Friedrich Wilhelm Adolf von Baeyer1906Henri Moissan1907Eduard Buchner1908Ernest Rutherford1909Wilhelm Ostwald1910Otto Wallach1911Marie Curie, född Sklodowska1912Victor GrignardPaul Sabatier1913Alfred Werner1914Theodore William RichardsFrances H. Arnold, George P. Smith and Sir Gregory P. Winter The chemistry prize winners have taken control over evolution.The �rst 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 �rst directed evolution 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 in�ammatory 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 Biochemistry at the California Institute of Technology, Pasadena, US.George P. Smith was born in 1941 in Norwalk, US. He received a PhD in 1970 from Harvard University, Cambridge, US. Curators’ 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. 5 1915Richard Martin Willstätter1918Fritz Haber1920Walther Hermann Nernst1921Frederick Soddy1922Francis William Aston1923Fritz Pregl1924Ej utgivet1925Richard Zsigmondy1926The (Theodor) Svedberg1927Heinrich Otto Wieland1928Adolf Windaus1929Arthur HardenHans von Euler-Chelpin1930Hans Fischer1931Carl BoschFriedrich Bergius1932Irving Langmuir1933Ej utgivet[E]1934Harold Clayton Urey1935Frédéric JoliotIrène Joliot-Curie1936Petrus (Peter) Josephus Wilhelmus Debye1937Walter Norman HaworthPaul Karrer1938Richard Kuhn1939Adolf Friedrich Johann ButenandtLeopold Ruzicka1943George de Hevesy1944Otto Hahn1945Artturi Ilmari Virtanen1946James Batcheller SumnerJohn Howard NorthropWendell Stanley1947Sir Robert Robinson1948Arne Wilhelm Kaurin Tiselius1949William Francis Giauque1950Otto Paul Hermann DielsKurt Alder1951Edwin Mattison McMillanGlenn Theodore Seaborg1952Archer John Porter MartinRichard Laurence Millington Synge195

3Hermann Staudinger1954Linus Carl Pauling1955Vincent du Vigneaud1956Sir Cyril Norman HinshelwoodNikolay Nikolaevich Semenov1957Lord (Alexander R.) Todd1958Frederick Sanger1959Jaroslav Heyrovský1960Willard Frank Libby1961Melvin Calvin1962Max Ferdinand PerutzJohn Cowdery Kendrew1963Karl ZieglerGiulio Natta1964Dorothy Crowfoot Hodgkin1965Robert Burns Woodward1966Robert S. MullikenImmuno-oncology o�ers fantastic opportunities.The body’s immune response protects us from disease by recognizing and attacking 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 disease to continue to grow. Immuno-oncology is based on the insight into how the body’s own immune system can be used to �ght cancer.The idea of activating the body’s own immune system in the �ght 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 immunosuppressants 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 malignant melanoma (skin cancer). This principle of inhibiting the response of immune regulation has formed the basis for Alligator’s research and development. Immuno-oncology is e�ective in three ways. Firstly, it reinforces the immune system’s ability to �ght cancer cells in an e�ective manner. Secondly, the tumor’s defense is weakened. Thirdly, the immunological memory provides longstanding protection against recurring tumor growth. This “vaccination e�ect” is unique to immunotherapy.A dynamic �eldImmuno-oncology is now one the most dynamic �elds of cancer research. According to a report from the Cancer Research Institute (published in Annals of Oncology), there were 940 immuno-oncology substances in the clinical phase and 1,064 in the preclinical 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 company’s unique technology that makes it possible to activate the immune system to speci�cally attack tumors while the rest of the body is una�ected. The main advantage of this tumor-targeted therapy is that it can have a favorable e�ect on the tumor at the same time as the side e�ects that arise if you activate the entire immune system can be kept at as low a level as possible. Alligator is currently conducting �

;ve promising 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. 6 FRONTIERETT MAGASIN OM ALLIGATOR BIOSCIENCE OCH IMMUNONKOLOGI 1967Manfred EigenRonald George Wreyford NorrishGeorge Porter1968Lars Onsager1969Derek H. R. BartonOdd Hassel1970Luis F. Leloir1971Gerhard Herzberg1972Christian B. An�nsenStanford MooreWilliam H. Stein1973Ernst Otto FischerGeo�rey Wilkinson1974Paul J. Flory1975John Warcup CornforthVladimir Prelog1976William N. Lipscomb1977Ilya Prigogine1978Peter D. Mitchell1979Herbert C. BrownGeorg Wittig1980Paul BergWalter GilbertFrederick Sanger1981Kenichi FukuiRoald Ho�mann1982Aaron Klug1983Henry Taube1984Robert Bruce Merri�eld1985Herbert A. HauptmanJerome Karle1986Dudley R. HerschbachYuan T. LeeJohn C. Polanyi1987Donald J. CramJean-Marie LehnCharles J. Pedersen1988Johann DeisenhoferRobert HuberHartmut Michel1989Sidney AltmanThomas R. Cech1990Elias James Corey1991Richard R. Ernst1992Rudolph A. Marcus1993Kary B. MullisMichael Smith1994George A. Olah1995Paul J. CrutzenMario J. MolinaF. Sherwood Rowland1996Robert F. Curl Jr.Sir Harold W. KrotoRichard E. Smalley1997Paul D. BoyerJohn E. WalkerJens C. Skou1998Walter KohnJohn A. Pople1999Ahmed H. Zewail2000Alan J. HeegerAlan G MacDiarmidHideki Shirakawa2001William S. KnowlesRyoji NoyoriK. Barry Sharpless2002John B. FennKoichi TanakaKurt Wüthrich2003Peter AgreRoderick MacKinnon2004Aaron CiechanoverAvram HershkoIrwin Rose2005Yves ChauvinRobert H. GrubbsRichard R. Schrock2006Roger D. Kornberg2007Gerhard ErtlATOR-1015. Tumor-localizing bispeci�c antibody with dual immunostimulatory function. ATOR-1015 is a bispeci�c (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 bispeci�c fusion format. Project status: preclinical development, Phase I clinical trial to commence in 2018Preclinical data presented at various conferences in 2018 show that ATOR-1015 localizes to the tumor, with increased immunostimulation in the tumor compared with normal tissue. The drug candidate ATOR-1015 is primarily designed for combination therapies and the preclinical results presented include data indicating an ampli�ed anti-tumor e�ect in combination therapy with a PD-1 pathway-blocking antibody.Mechanism of actionATOR-1015 binds to two di�erent immunomodulatory receptors – the CTLA-4 inhibitory receptor, and an OX40 costimulatory receptor. In preclinical studies, the biospeci�city has been shown to cause a signi�cant increase in the immunostimulatory e�ect and is expected be achieved mainly in environments where both of the target molecules are expressed at high levels, such as in a tumor. This means that ATOR-1015 may have potent immunostimulatory e�ects

in the tumor environment, but not in the rest of the body, with the goal of reducing the side e�ects while maintaining e�cacy. 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 e�ect of Tregs on the bene�cial T cells.3.The e�ector 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 actionMacrophageTumor CellTumor KillingTreg Depletion TregT cell ATOR-1015 CTLA-4 OX40 MacrophageTumor Cell Tumor Killing Treg Depletion TregT cell 2008Osamu ShimomuraMartin Chal�eRoger Y. Tsien2009Venkatraman RamakrishnanThomas A. SteitzAda E. Yonath2010Richard F. HeckEi-ichi NegishiAkira Suzuki2011Dan Shechtman2012Brian KobilkaRobert Lefkowitz2013Martin KarplusMichael LevittArieh Warshel2014William E. MoernerEric BetzigStefan Hell2015Tomas LindahlPaul ModrichAziz Sancar2016Jean-Pierre SauvageFraser StoddartBen Feringa2017Jacques DubochetJoachim FrankRichard Henderson2018Frances ArnoldGeorge P. SmithGregory P. Winter About Alligator Alligator is a research-based biotechnology company developing antibody-based pharmaceuticals for cancer treatment. The company specializes in the development of tumor-directed immunotherapies and is active in the early phases of drug development, from idea to clinical phase II studies.Please visit our web: alligatorbioscience.comAbout Frontier The aim with Frontier is to present Alligator’s research & development in brief and general terms. EditorsCecilia HofvanderLotten AlménMichael VallinderDistributionFrontier 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.se4th 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 Europe 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 FROM AROUND THE ALLIGATOR WORLD Frontier #2, 2018 FRONTIERA MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY Frontier #2