sign in sign up
<<
Home , Aaron Ciechanover, Aaron Klug, Adolf Windaus, Akira Suzuki (chemist), Albert Claude, Albrecht Kossel

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

The behind the Nobel Prizes in and is the core in Alligator’s research and development FRONTIER – A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY

The in or Medicine has been awarded to: Alligator carries on the legacy 1901 1902 1903 Niels Ryberg Finsen 1904 of the Nobel Prize winners in 1905 1906 1907 Alphonse Laveran Medicine and Chemistry . 1908 Ilja Metjnikov 1909 Theodor Kocher On Monday October 1, it was announced that James P. Allison and 1910 1911 had been awarded the 2018 Nobel Prize in Physiology or Medicine for discov- 1912 1913 eries on immune checkpoints – which according to the Nobel Assembly at the 1914 Robert Bárány 1919 “has revolutionized treatment and changed our view of how 1920 1922 Archibald V. Hill can be treated.” Otto Meyerhof 1923 Frederick G. Banting John Macleod I share the opinion of the Nobel Assembly. 1924 1926 The groundbreaking research by James 1927 Julius Wagner- Jauregg Allison and Tasuku Honjo on how the 1928 immune system can be used to fight 1929 Sir Frederick Hopkins has profoundly changed the therapeutic 1930 1931 Otto Warburg arena. Not only in terms of how we treat 1932 Sir Charles Sherrington cancer but also on the prospect of surviving the disease. 1933 Thomas H. Morgan 1934 George H. Whipple George R. Minot William P. Murphy The advancements at Alligator would not 1935 1936 Sir Henry Dale have been possible without Allison’s and 1937 Albert Szent-Györgyi Honjo’s research. Since the first immuno- 1938 therapy was approved in 2011, 1939 1943 the CTLA-4 blocker Yervoy®, scientists all Edward A. Doisy 1944 over the world have pursued the quest of Herbert S. Gasser 1945 Sir Alexander developing drugs that activate the immune Fleming system against cancer. Ernst Boris Chain Howard Walter body library ALLIGATOR-®. ATOR-1015 Florey 1946 Hermann Joseph I am proud to say that Alligator plays an is built and optimized using both phage Muller 1947 Carl Cori important part in this global effort ATOR- display and the optimization tech- 1015 is leading the way for the next gener- nology FIND. Moreover, the key mechanism Bernardo Alberto Houssay ation of CTLA-4 products, bispecific anti- of action of ATOR-1015 is to activate the 1948 Paul Müller 1949 Walter Hess bodies with tumor-localizing properties. It immune system via CTLA-4. Three Nobel Egas Moniz 1950 Edward C. Kendall is directly borne out of Allison’s research, Prize discoveries in the same . This Philip S. Hench Tadeus Reichstein is the first of its kind, and will enter clinical will be a difficult record to beat! 1951 Max Theiler phase I before the end of the year. 1952 Selman A. Waksman 1953 At Alligator, we will now make every effort to Fritz Lipmann 1954 John F. Enders What is more, , Frances H. continue to work in the spirit of the Nobel Thomas H. Weller Frederick C. Robbins Arnold, and Greg Winter were awarded the Prize. A Revolution for . 1955 on October 3. 1956 André F. Cournand Dickinson W. Arnold developed a protein tech- Per Norlén, CEO Richards nology that is related to Alligator’s FIND® 1957 1958 George Wells Beadle technology (Fragment INduced Diversity), In honor of previous prize winners in the phys- Edward Lawrie iology and medicine categories, we have listed Tatum and Smith and Winter developed phage dis- play, the technology behind our human anti- all of their names in this issue of Frontier. 1959

Frontier #2, 2018 2 FRONTIER – A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY

1960 Sir Frank Tasuku Honjo, James P. Allison and 1961 Georg von Békésy 1962 their discoveries. 1963 Sir John Eccles Alan L. Hodgkin Andrew F. Huxley This year’s Nobel Prize in Physiology or Medicine was awarded to James P. Allison 1964 Konrad Bloch USA and Tasuku Honjo for their discovery of cancer therapy through the inhibition of 1965 François Jacob negative immune regulation. Thanks to research by Allison and Honjo, it is now André Lwoff possible to release the inherent power of the immune system to fight and destroy 1966 Peyton Rous Charles B. Huggins cancer cells in a completely new and revolutionary way. 1967 1968 Robert W. Holley Marshall W. Nirenberg 1969 Max Delbrück Alfred D. Hershey Salvador E. Luria 1970 Sir 1971 Earl W Sutherland Jr. 1972 Gerald M. Edelman Rodney R. Porter 1973 1974 George E. Palade 1975 David Howard M. Temin 1976 Baruch S. Blumberg D. Carleton Gajdusek 1977 Andrew V. Schally Rosalyn Yalow 1978 Hamilton O Smith Tasuku Honjo receptors can activate or inactivate 1979 Allan M. Cormack Tasuku Honjo, born in 1942, is a Japanese the immune system’s T cells. This knowledge Godfrey N. Hounsfield immunologist. He is best known for his constitutes the core of immuno-oncology 1980 discovery and research into the mecha- and Allison’s research resulted in the first George D. Snell 1981 Roger W. Sperry nisms and that are essential in the immuno-oncology drug in 2011. Torsten N. Wiesel regulation of immune reactions. Honjo’s 1982 Sune Bergström Bengt Samuelsson research has paved the way for the develop- Allison also has very personal experiences John R. Vane Storbritannien ment of anti-PD-1 immunotherapies, which of cancer. At the age of eleven, his mother 1983 Barbara McClintock 1984 Niels K. Jerne have been approved for the treatment of died from lymphoma and his brother Georges J F Köhler César Milstein melanomas and other forms of cancer. He passed away from prostate cancer in 2005. 1985 Michael S. Brown has worked as a researcher in both the US Allison himself has undergone surgery for Joseph L. Goldstein 1986 Rita Levi-Montalcini and in . prostate cancer and skin cancer and is Stanley Cohen 1987 currently undergoing immunotherapy treat- 1988 Sir James W. Black Gertrude B. Elion James P. Allison ment for bladder cancer. George H. Hitchings James P. Allison was born in 1948 in Alice, 1989 J. Michael Bishop Harold E. Varmus , and is the youngest of three sons to Allison is a at M.D. Anderson 1990 Joseph E. Murray Edward Donnall Constance Kalula (Lynn) and Albert Murphy Cancer Center at the University of Texas. In Thomas 1991 Allison. His scientific interest was aroused his spare time, he plays the harmonica in a 1992 Edmond H. Fischer in earnest by his math teacher in the eighth blues band called Checkpoints together with Edwin G. Krebs grade, an interest that has meant Allison has colleagues from immuno-oncology. 1993 Richard J. Roberts Phillip A. Sharp spent a large share of his life studying how

Frontier #2, 2018 3 FRONTIER – A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY

1994 Alfred G. Gilman Frances H. Arnold, George P. Smith and Sir Gregory P. Winter 1995 Edward B. Lewis Eric F. Wieschaus Christiane Nüsslein- The chemistry prize winners have Volhard 1996 Rolf M. Zinkernagel Peter C. Doherty taken control over evolution. 1997 Stanley B. Prusiner 1998 Robert F. Furchgott Louis J. Ignarro The first seed of life on earth appeared some 3.7 billion years ago. Evolution has 1999 Günter Blobel since produced almost inconceivable riches on a previously deserted planet 2000 Eric R. Kandel through its modus operandi of genetic change and selection. Life now exists in 2001 locations under the most varying conditions. This year’s Nobel Prize winners in Sir Leland H. Hartwell Chemistry have been inspired by evolution and used the same principles to develop 2002 John E. Sulston proteins that solve a number of our chemical challenges, such as manufacturing H. Robert Horvitz and drugs. Using the method, we can now develop 2003 Paul C. Lauterbur Sir to treat auto-immune diseases and in some cases cure metastatic cancer. 2004 Linda B Buck 2005 2006 Andrew Z. Fire Craig C. Mello 2007 Mario R. Capecchi Sir Martin J. Evans 2008 Françoise Barré- Sinoussi 2009 Carol Greider Jack Szostak 2010 Robert Edwards 2011 Jules Hoffmann Ralph Steinman 2012 John B. Gurdon 2013 Thomas Südhof 2014 John O’Keefe May-Britt Moser The year’s Nobel Prize in Chemistry was Frances H. Arnold was born in 1956 in 2015 William C. Campbell Satoshi Ōmura awarded to three people: Frances H. , US. She received a PhD in 1985 2016 Arnold, George P. Smith and Sir Gregory from the University of , Berkeley, 2017 Jeffrey C. Hall sMichael Rosbash P. Winter. Arnold was awarded half of the US. Professor of Chemical Michael W. Young prize for performing the first directed evo- , Bioengineering and Biochemis- 2018 James P. Allison Tasuku Honjo lution of (proteins that catalyze try at the California Institute of Technology, The Nobel Prize in chemical reactions) in 1993. The second half Pasadena, US. Chemistry was awarded to: was shared between George P. Smith and 1901 Jacobus Henricus van ’t Hoff Sir Gregory P. Winter. Smith was awarded George P. Smith was born in 1941 in Nor- 1902 Hermann Emil his share of the prize for developing phage walk, US. He received a PhD in 1970 from Fischer 1903 Svante August display, a method where , , US. Cura- Arrhenius 1904 Sir ( that infect ) are used to tors’ Distinguished Professor Emeritus 1905 Johann Friedrich Wilhelm Adolf von develop new proteins. Phage display has of Biological at the University of Baeyer opened the door to the Missouri, Columbia, US. 1906 1907 of antibodies underlying much of Alligator’s 1908 Ernest 1909 research and development. Winter received Sir Gregory P. Winter was born in 1951 in 1910 1911 , född the prize for his use of phage display to Leicester, UK. He received a PhD in 1976 from Sklodowska 1912 produce new drugs against diseases such as the , UK. Research , and inflam- Leader Emeritus at MRC Laboratory of 1913 1914 Theodore William matory bowel diseases. Molecular , Cambridge, UK. Richards

Frontier #2, 2018 4 FRONTIER – A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY

1915 Richard Martin Willstätter 1918 Immuno-oncology offers 1920 Walther Hermann Nernst 1921 1922 fantastic opportunities. 1923 1924 Ej utgivet 1925 Richard Zsigmondy The body’s immune response protects us from disease by recognizing and attack- 1926 The (Theodor) Svedberg ing anything that is unfamiliar, but is also activated when the body’s own cells are 1927 Heinrich Otto changed in one way or another, such as becoming cancer cells. However, cancer Wieland 1928 cells are often highly skilled at avoiding the immune system, which allows the dis- 1929 Hans von Euler- ease to continue to grow. Immuno-oncology is based on the insight into how the Chelpin 1930 body’s own immune system can be used to fight cancer. 1931 1932 1933 Ej utgivet[E] 1934 Harold Clayton Urey 1935 Frédéric Joliot Irène Joliot-Curie 1936 Petrus (Peter) Josephus Wilhelmus Debye 1937 Walter 1938 1939 Adolf Friedrich Johann Butenandt Leopold Ruzicka The idea of activating the body’s own were 940 immuno-oncology substances in 1943 1944 immune system in the fight against cancer the clinical phase and 1,064 in the preclin- 1945 is not new. The problem has been the ability ical phase in September 2017. More than 1946 James Batcheller Sumner of cancer cells to hide from the immune 860 companies are conducting research and system, including the build-up of immuno- development in immuno-oncology. Today, Wendell Stanley suppressants that inhibit an attack by the malignant melanoma, renal 1947 Sir Robert Robinson 1948 Arne Wilhelm Kaurin immune system. Only since the approval of and lung cancer are being treated using Tiselius 1949 William Francis Yervoy (ipilimumab) has immuno-oncology immuno-oncology therapies, though there Giauque 1950 Otto Paul Hermann become a successful reality with favorable is great hope that more types of cancer may Diels treatment outcomes, for example, for malig- be treated with various immunotherapies in 1951 Edwin Mattison nant melanoma (skin cancer). This principle the future. McMillan Glenn Theodore of inhibiting the response of immune reg- Seaborg 1952 Archer John Porter ulation has formed the basis for Alligator’s Alligator – tumor-targeted therapy Martin research and development. What distinguishes Alligator is the com- Richard Laurence Millington Synge pany’s unique technology that makes it 1953 1954 Linus Carl Pauling Immuno-oncology is effective in three ways. possible to activate the immune system to 1955 1956 Sir Cyril Norman Firstly, it reinforces the immune system’s specifically attack tumors while the rest of Hinshelwood Nikolay Nikolaevich ability to fight cancer cells in an effective the body is unaffected. The main advantage Semenov manner. Secondly, the tumor’s defense of this tumor-targeted therapy is that it can 1957 Lord (Alexander R.) Todd is weakened. Thirdly, the immunological have a favorable effect on the tumor at the 1958 1959 Jaroslav Heyrovský provides longstanding protection same time as the side effects that arise if 1960 Willard Frank Libby 1961 against recurring tumor growth. This “vacci- you activate the entire immune system can 1962 Max Ferdinand nation effect” is unique to immunotherapy. be kept at as low a level as possible. Perutz John Cowdery Kendrew 1963 A dynamic field Alligator is currently conducting five promis- 1964 Dorothy Crowfoot Immuno-oncology is now one the most ing development projects. Two projects are Hodgkin in, or about to start, Phase I clinical trials, 1965 Robert Burns dynamic fields of . According Woodward to a report from the Cancer Research Insti- while the other three projects are in various 1966 Robert S. Mulliken tute (published in Annals of Oncology), there stages of preclinical development.

Frontier #2, 2018 5 FRONTIER – ETT MAGASIN OM ALLIGATOR BIOSCIENCE OCH IMMUNONKOLOGI

1967 Ronald George Wreyford Norrish ATOR-1015. Tumor-localizing 1968 1969 Derek H. R. Barton bispecific antibody with dual 1970 Luis F. Leloir 1971 1972 Christian B. Anfinsen immunostimulatory function. William H. Stein 1973 ATOR-1015 is a bispecific (CTLA-4 and OX40) antibody developed for tumor- 1974 Paul J. Flory targeted treatment of metastatic cancer. The ATOR-1015 antibody has been 1975 John Warcup Cornforth assembled and optimized using Alligator’s unique ALLIGATOR-GOLD and FIND 1976 William N. Lipscomb technologies and the bispecific fusion format. 1977 1978 Peter D. Mitchell 1979 Herbert C. Brown Project status: preclinical development, Mechanism of action 1980 Phase I clinical trial to commence in 2018 ATOR-1015 binds to two different immuno- Frederick Sanger Preclinical data presented at various confer- modulatory receptors – the CTLA-4 inhib- 1981 ences in 2018 show that ATOR-1015 localizes itory receptor, and an OX40 costimulatory 1982 to the tumor, with increased immunostim- receptor. In preclinical studies, the biospec- 1983 1984 Robert Bruce ulation in the tumor compared with normal ificity has been shown to cause a significant Merrifield 1985 Herbert A. tissue. The drug candidate ATOR-1015 is pri- increase in the immunostimulatory effect Hauptman marily designed for combination therapies and is expected be achieved mainly in envi- 1986 Dudley R. and the preclinical results presented include ronments where both of the target mole- Herschbach Yuan T. Lee data indicating an amplified anti-tumor cules are expressed at high levels, such as John C. Polanyi 1987 Donald J. Cram effect in combination therapy with a PD-1 in a tumor. This means that ATOR-1015 may Jean-Marie Lehn Charles J. Pedersen pathway-blocking antibody. have potent immunostimulatory effects in 1988 the tumor environment, but not in the rest ATOR-1015 MoA (CTLA-4 x 0X40) of the body, with the goal of reducing the 1989 Thomas R. Cech Mode of action side effects while maintaining efficacy. 1990 1991 Richard R. Ernst 1992 Rudolph A. Marcus 1993 Kary B. Mullis 1994 George A. Olah 1995 Paul J. Crutzen Mario J. Molina F. Sherwood Rowland TregTreg 1996 Robert F. Curl Jr. Sir Harold W. Kroto TregTreg Depletion Depletion T cellT cell Richard E. Smalley 1997 Paul D. Boyer John E. Walker Jens C. Skou 1998 John A. Pople 1999 Ahmed H. Zewail MacrophageMacrophage TumorTumor Killing Killing 2000 Alan J. Heeger Alan G MacDiarmid 2001 William S. Knowles Ryoji Noyori TumorTumor Cell Cell K. Barry Sharpless 2002 John B. Fenn Kurt Wüthrich 2003 Roderick MacKinnon 2004 1. ATOR-1015 binds to CTLA-4 and OX40 on the regulatory T cells, the cells which restrain the immune system. 2005 2. The macrophages are activated to kill Tregs, removing the Robert H. Grubbs ATOR-1015 CTLA-4 OX40 Richard R. Schrock inhibitory effect of Tregs on the beneficial T cells. 2006 Roger D. Kornberg 3. The effector T cells ( green) are multiplied in number 2007 and are activated to kill the tumor cells.

Frontier #2, 2018 6 FRONTIER – A MAGAZINE ABOUT ALLIGATOR BIOSCIENCE AND IMMUNO-ONCOLOGY

2008 FROM AROUND THE ALLIGATOR WORLD Roger Y. Tsien 2009 Venkatraman Ramakrishnan Thomas A. Steitz Stock exchange lunch about Nobel Ada E. Yonath Prize winners 2010 Richard F. Heck Ei-ichi Negishi Following the announcement of the Nobel Prize winners in Medicine, Alligator’s 2011 2012 CEO Per Norlén was a guest at EFNTV’s “Börslunch” web-TV program to talk about 2013 Alligator and the future of immunotherapy. www.efn.se 2014 William E. Moerner 2015 4th CRI-CIMT-EATI-AACR Paul Modrich Alligator’s researchers Karin Hägerbrand 2016 Jean-Pierre Sauvage and Eva Dahlén presented preclinical data that support good tolerability for ATOR-1017 at the 4th CRI-CIMT-EATI-AACR 2017 International Cancer lmmunotherapy Richard Henderson Conference in , US. 2018 George P. Smith Gregory P. Winter

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

About Alligator Alligator is a research-based Presentation at PEGS Europe company Anna Säll, researcher at Alligator, held developing antibody-based a presentation, ATOR-1017–An Agonistic pharmaceuticals for cancer Tumor Directed Fcγ-Receptor Cross Linking treatment. The company Dependent CD137 Antibody, at PEGS Eu- specializes in the develop- ment of tumor-directed im- rope in Lisbon, Portugal. munotherapies and is active in the early phases of drug development, from idea to clinical phase II studies.

Please visit our web: @sitcancer in Washington DC alligatorbioscience.com Alligator was kept busy at SITC (Society for Immunotherapy of Cancer) in Washington About Frontier DC, US, holding presentations of the three The aim with Frontier is to preclinical projects ATOR-1015, ATOR-1017 present Alligator’s research and ALG.APV-527. & development in brief and general terms. www.sitcancer.org/2018/home Editors Cecilia Hofvander Lotten Almén Michael Vallinder

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

Frontier #2, 2018 7