Welcome Message Dear Friends and Colleagues, On behalf of the Organizing Committee, I would like to welcome you to “the fourth Antibody Therapeutic Conference: Infectious Diseases, Oncology, and Immunology being held in Academia Sinica on November 6, 2015 Looking at the application of antibody therapeutics, it remains a growing field today, especially in the treatment of some cancer, many immune-mediated and infectious diseases, such as breast cancer, leukemia, asthma, arthritis, psoriasis, Crohn's disease and transplant rejection, all highlighting the critical pharmaceutical importance of antibody therapeutics. This meeting covers a broad spectrum of topics on the new advances, as well as emerging methods for effective discovery, production and application in antibody therapeutics; it aims to provide young scientists an opportunity to face-to-face discuss the comprehensive scientific knowledge and experiences on how to develop a therapeutic antibody from discovery, development to commercialization. Last but not least, we hope the meeting stimulates cross talks between senior experts and young scientists working on antibody therapeutics. This meeting not only provides a forum for sharing your insightful research but also a great opportunity to network with your fellow professionals. We look forward to welcoming you to Taiwan’s dynamic city, Taipei and hope that you will find this meeting an informative, constructive and inspiring experience.
Andrew H.-J. Wang Ph. D Chairman, Organizing Committee Distinguished Research Fellow Institute of Biological Chemistry Academia Sinica
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Steering Committee Chairman Dr. Andrew H.-J. Wang
Academia Sinica
Committee Dr. Fu-Tong Liu
Academia Sinica
Dr. An-Suei Yang
Academia Sinica
Dr. Zhiqiang An
University of Texas Health Science Center at Houston, USA
Dr. Wei-Kuan Chi
Development Center for Biotechnology
Organizers
Taiwan Antibody Association
National Research Program for Biopharmaceuticals
Co-Organizers Biochemical Technology Education Foundation
Academia Sinica
Institute of Biological Chemistry, Academia Sinica
Institute of Biomedical Sciences, Academia Sinica
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Table of Contents Welcome Message
P.1
Table of Contents
P.3
Agenda
P.4
Opening Remarks Dr. Chien-Jen Chen
P.8
Dr. Andrew H.-J. Wang
P.10
Lectures Keynote: Moderator: Dr. Andrew H.-J. Wang
P.10
Speaker: Dr. David Ho
P.11
Session I: Perspectives on Current Trends and Future Opportunities Moderator: Dr. Min-Liang Kuo
P.14
Speaker: Dr. Zhiqiang An
P.15
Speaker: Dr. Lawrence L. Gan
P.17
Session II: Emerging Targets Moderator: Dr. Chia-Lin Jeff Wang
P.20
Speaker: Dr. Peter Kwong
P.21
Speaker: Dr. Michael Jennings
P.24
Speaker: Dr. Arun Kashyap
P.26
Session III: Translation and Development of Antibody Therapeutics Moderator: Dr. Fu-Tong Liu
P.30
Speaker: Dr. Po-Jen Chen
P.31
Speaker: Dr. Jeffrey J. Molldrem
P.34
Speaker: Dr Alice Yu
P.38
Session IV: Technologies for Antibody Discovery and Engineering Moderator: Dr. Han-Chung Wu
P.42
Speaker: Dr. An-Suei Yang
P.43
Speaker: Dr. Tien-Lu Cheng
P.45
Speaker: Dr. Hao-Chen
P.48
Closing Remarks Dr. Fu-Tong Liu
P.50
Sponsors
P.51
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Antibody Therapeutics Conference 2015 Infectious Diseases, Oncology, and Immunology Friday, November 6 Venue: The First Conference Room, 2F, Center for Academic Activities, Academia Sinica
08:30 - 09:00
Registration
Opening Remarks 09:00 - 09:05
Dr. Chien-Jen Chen Vice President, Academia Sinica, Taiwan
09:05 - 09:10
Dr. Andrew H.-J. Wang Distinguished Research Fellow, Institute of Biological Chemistry, Academia Sinica, Taiwan President, Taiwan Antibody Association, Taiwan
Keynote Moderator:
Dr. Andrew H.-J. Wang Distinguished Research Fellow, Institute of Biological Chemistry, Academia Sinica, Taiwan President, Taiwan Antibody Association, Taiwan
09:10 - 09:55
Dr. David Ho Scientific Director and CEO, Aaron Diamond AIDS Research Center Irene Diamond Professor, the Rockefeller University, New York, NY, USA Engineering Bispecific Antibodies to Treat and Prevent HIV Infection
Session I: Perspectives on Current Trends and Future Opportunities Moderator:
Dr. Min-Liang Kuo Dean and Professor, College of Life Science, National Taiwan University, Taiwan
10:00 - 10:35
Dr. Zhiqiang An Director and Professor, Robert A. Welch Distinguished University Chair in Chemistry Director, Texas Therapeutics Institute, the University of Texas Health Science Center at Houston, USA The Current Landscape of Monoclonal Antibody Drug Discovery
10:35 - 10:55
Tea break
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10:55 - 11:20
Dr. Lawrence L. Gan President, Development Center for Biotechnology, Taiwan Drug Delivery into the Brain – the Role of Transporters at the Blood Brain Barrier and Convective Flows of Brain Interstitial Fluid (ISF) and Cerebrospinal Fluid (CSF)
Session II: Emerging Targets Moderator:
Dr. Chia-Lin Jeff Wang CEO, BioGate Medical Science Corp. Taiwan
11:25 – 12:00
Dr. Peter Kwong Chief, Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, NIAID, National Institutes of Health, USA HIV-1 Env as a Target of Neutralizing Antibodies
12:00 - 12:35
Dr. Michael Jennings Deputy Director & Principal Research Leader, Institute for Glycomics, Griffith University, Australia Discovery and Exploitation of Host - Pathogen Interactions as New Opportunities for Antibody Therapy
12:35 - 14:00
Lunch (Taiwan Antibody Association Members Meeting)
14:00 - 14:35
Dr. Arun Kashyap Head of Research, Sea Lane Biotechnologies, USA Surrobodies: A Novel Immune Scaffold for Immunotherapeutic Applications
Session III: Translation and Development of Antibody Therapeutics Moderator:
Dr. Fu-Tong Liu Director and Distinguished Research Fellow, Institute of Biomedical Sciences, Academia Sinica, Taiwan
14:40 - 15:15
Dr. Po-Jen Chen Professor, Department of Medicine, Rheumatology Division, UCLA, USA From Autoantibodies to Potentially Therapeutic Antibodies against HIV
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15:15 - 15:50
Dr. Jeffrey J Molldrem Professor and Chief, Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, USA T Cell Receptor-Like Antibody 8F4 Targets Leukemia and Non-Hematopoietic Cancer
15:50 - 16:10
Tea break
16:10 - 16:35
Dr. Alice Yu Distinguished Chair Professor and Co-Director, Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital & Chang Gung University, Taiwan Development of Antibodies Directed against Cancer Associated Glycans
Session IV: Technologies for Antibody Discovery and Engineering Moderator:
Dr. Han-Chung Wu Research Fellow and Deputy Director, Institute of Cellular and Organismic Biology, Academia Sinica, Taiwan
16:40 - 17:05
Dr. An-Suei Yang Research Fellow and Deputy Director, Genomics Research Center, Academia Sinica, Taiwan A High Throughput Antibody Engineering Platform for Discovering and Optimizing Antibodies in Antibody-Guided Drug Delivery Systems
17:05 - 17:30
Dr. Tien-Lu Cheng Director of Graduate Institute of Medicine and Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan Proteases (MMP2/9) Enhance the Affinity and Therapeutic Efficacy of Targeted Antibody
17:30 - 18:05
Dr. Hao Chen Director, BioProcess Development, Merck Research Laboratories, Kenilworth, NJ, USA Accelerated FIH (First-In-Human) for Mabs Enabled by Innovative Bioprocess Strategy and Technologies
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Closing Remarks 18:05 - 18:10
Dr. Fu-Tong Liu Director and Distinguished Research Fellow, Institute of Biomedical Sciences, Academia Sinica, Taiwan
18:10
Dinner & Taiwan Antibody Association Council Meeting (By Invitation)
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Opening Remarks Chien-Jen CHEN Vice President, Academia Sinica, Taiwan (chencj@gate.sinica.edu.tw)
Professor Chien-Jen Chen received his B.Sc. (1973) and M.P.H. (1977) from National Taiwan University, and Sc.D. (1982) in epidemiology and human genetics from the Johns Hopkins University. He then worked as a lecturer (1982-1983), associate professor (1983-1986), and professor (since 1986) of National Taiwan University. He was appointed as the director of Graduate Institute of Public Health (1993-1994), founding director of Graduate Institute of Epidemiology (1994-1997), and dean of College of Public Health (1999-2002) in National Taiwan University. He is now a distinguished research fellow of Genomics Research Center (since 2006) and a Vice President (since 2011) of Academia Sinica. Professor Chen has dedicated himself to molecular and genomic epidemiological researches on chronic arsenic poisoning and virus-induced cancers for 30 years. His discoveries of multiple health hazards of arsenic in drinking water has led to the global awareness and prevention of the largest environmental calamity, and his researches on end-stage liver disease risk prediction of chronic hepatitis B has pioneered the viral load paradigm in its clinical management. He has published 12 books, 22 book chapters, 35 conference full articles, and over 640 original, review and editorial articles in international journals, which have been cited for more than 27,000 times in the SCI (Science Citation Index) journals with an h-index over 85. He has received Outstanding Research Award (1986-1996) and Outstanding Research Fellow Award (2003) from National Science Council; as well as Outstanding Teaching Award (1992), Academic Award (1997) and National Chair Professor (1999-2002) from Ministry of Education in Taiwan. He was elected as an academician of the Academia Sinica in 1998. He received the Presidential Science Prize, the most prestigious science award in Taiwan, in 2005. Professor Chen was elected as a fellow of American College of Epidemiology (1993), a member of the World Academy of Sciences (2005), an honorary member of Mongolian Academy of Science (2007), and a member of the Delta Omega Honorary Society in Public Health, Johns Hopkins University (2010). He was elected as the Dr. D.V. Datta Memorial Orator by the Indian National Association for Study of the Liver (2008), the Cutter Lecturer on Preventive Medicine by Harvard University (2008) and Professor Vikit Viranuvatti Lecturer by the Gastroenterological Association of Thailand (2011). He received the Science and Engineering Achievement Award from Taiwanese- America Foundation in the USA (2009), the Outstanding Academic Award from Wang Ming-Ning Memorial Foundation in Taiwan (2010), the Knowledge for World Award from Johns Hopkins University (2012), the Outstanding Contribution in Science and Technology Award from Executive Yuan in Taiwan (2013), Professor Juei-Low Sung Award from Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014).
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Professor Chen has served in several government positions including the Director General of Division of Life Sciences (1997-1999) and Deputy Minister (2002-2003) of National Science Council, Minister of Department of Health (2003-2005), and Minister of National Science Council (2006-2008). After his outstanding leadership to control the outbreak of severe acute respiratory syndrome successfully in 2003, he has made fundamental reforms of the organization of Department of Health and Center for Disease Control, the Medical Care System for Infectious Diseases and the Act of Infectious Disease Control in Taiwan. Under his significant leadership to promote scientific research and technology development in Taiwan, he has successfully made the reform of National Science Council and the promotion of international R&D collaboration. He has won widespread praise as a successful academic administrator and government leader. He received the Health Medal from Department of Health (2005), the Achievement Medal from Executive Yuan (2005) and the Science Professional Medal from National Science Council (2012) in Taiwan, the Officier dans l'Ordre des Palmes Academiques from the Ministry of Education, France (2009), and the Knight of Pontifical Equestrian Order of St. Gregory the Great, Vatican (2013).
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Opening Remarks & Keynote Moderator Andrew H.-J. WANG Distinguished Research Fellow, Institute of Biological Chemistry, Academia Sinica, Taiwan President, Taiwan Antibody Association, Taiwan (ahjwang@gate.sinica.edu.tw)
Professor Andrew H.-J. Wang was educated in Taiwan with B.S. (1967) and M.S. (1970) degrees, both from the Department of Chemistry, National Taiwan University. He obtained the Ph.D. degree from the Department of Chemistry, University of Illinois in 1974. He was Professor of Biochemistry, Biophysics and Chemistry at the University of Illinois (Urbana), during 1988-2000. Dr. Wang served as Vice President of Academia Sinica and is currently Distinguished Research Fellow of the Institute of Biological Chemistry, Academia Sinica, Taipei. He is an outstanding research scholar, as evidenced by over 440 of his scientific papers in top international journals of the field. He has made many seminal scientific contributions including the discovery of Z-DNA. Dr. Wang has also actively been involved in the advancement of sciences. He served as Editor for European J. Biochem., on Advisory Board of Nucleic Acids Research. He has been Council Member of Human Proteomics Organization (HUPO). As the President of three societies (Taiwan Society of Biochemistry and Molecular Biology (a member of IUBMB), Biophysical Society of ROC (a member of IUPAB) and Taiwan Proteomics Society (a member of AOHUPO)), he has successfully organized several major international conferences in Taipei, most recently the 2014_IUBMB/FAOBMB Joint Conference. Dr. Wang’s numerous achievements were recognized by his election as Academician of Academia Sinica (Taiwan), Fellow of American Association for the Advancement of Science, Fellow of Third World Academy of Sciences and President of FAOBMB, President Elect of IUBMB, etc. His research interests include structural proteomics, drug discovery including therapeutic antibody development, synchrotron crystallography, structure-function relationship of enzymes, membrane proteins and DNA-interacting proteins.
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Keynote Speaker David HO Scientific Director and CEO, Aaron Diamond AIDS Research Center Irene Diamond Professor, the Rockefeller University, New York, NY, USA (dho@adarc.org)
David D. Ho, M.D. is the founding Scientific Director and Chief Executive Officer of the Aaron Diamond AIDS Research Center, a world-renowned biomedical research institute. He is also the Irene Diamond Professor at The Rockefeller University. Dr. Ho received his degrees from California Institute of Technology (1974) and Harvard Medical School (1978). Subsequently, he did his clinical training in internal medicine and infectious diseases at Cedars-Sinai Medical Center/UCLA School of Medicine (1978-1982) and Massachusetts General Hospital/Harvard Medical School (1982-1985), respectively. Dr. David Ho has been at the forefront of AIDS research for 34 years, publishing over 350 papers. His elegant studies, beginning in 1994, unveiled the dynamic nature of HIV replication in vivo and revolutionized our basic understanding of this horrific disease (Nature 1995; Science 1996). This knowledge led Dr. Ho to champion combination antiretroviral therapy (N. Engl. J. Med. 1995; Science 1996) that resulted in unprecedented control of HIV in patients (Nature 1997). AIDS mortality in richer nations has declined 6-fold since 1996, and a massive international effort is now underway to bring such life-saving treatment to millions in the developing world. Dr. Ho has been the major driving force behind this major medical breakthrough in what is arguably the worst plague in human history. Dr. Ho’s research team is now devoting considerable efforts to develop vaccines to halt the spread of the AIDS epidemic. Furthermore, he is now heading up a consortium of Chinese and American organizations to help address the crisis of HIV/AIDS in China. Dr. Ho has received numerous honors and awards for his scientific accomplishments. He is the recipient of 12 honorary doctorates (including from Swarthmore, Tufts, Columbia, Tulane, University of Natal, Tsinghua University and University of Hong Kong). He has been chosen as the commencement speaker at Caltech, MIT, and Harvard School of Public Health. Additional accolades include the Ernst Jung Prize in Medicine, Mayor’s Award for Excellence in Science & Technology, the Squibb Award, and the Hoechst Marion Roussel Award. Dr. Ho has been elected as a member of the American Academy of Arts and Sciences, Academia Sinica (Republic of China), Chinese Academy of Engineering, and the Institute of Medicine, National Academy of Science in the United States. He was inducted into the California Hall of Fame in 2006. Dr. Ho is also an honorary professor at Peking Union Medical College, Chinese Academy of Medical Sciences, Chinese Academy of Sciences, University of Hong Kong, Wuhan University, and Fudan University. He was a member of the Board of Overseers of Harvard University and is a board member of the Massachusetts Institute of Technology Corporation. Dr. Ho was named Time Magazine’s Man of the Year in 1996, and was the recipient of a Presidential Medal in 2001.
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Engineering Bispecific Antibodies to Treat and Prevent HIV Infection David Ho There is no effective vaccine to protect against HIV infection today, and none will be available for the foreseeable future. The lack of an effective HIV vaccine is in part due to the structural properties of the viral envelope glycoprotein, which possesses highly variable amino-acid sequences along with extensive glycosylation that shield the virus from many anti-envelope antibodies. As an alternative strategy, our group is pursuing the use of antibodies as agents for passive administration to prevent HIV infection. We have engineered a number of bi-specific monoclonal antibodies that have remarkable potency and breadth against the virus in vitro. We have in hand a number of constructs with 100% breadth against a large panel of HIV strains with potency in the nM range. Modifications to improve the pharmacokinetic properties of the antibodies have also been made and evaluated. Several of the best antibody constructs are now being assessed for their “developability� and two are now being advanced as candidates for clinical development.
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Lectures
Session I: Perspectives on Current Trends and Future Opportunities Moderator:
Dr. Min-Liang KUO
10:00 - 10:35
Dr. Zhiqiang AN Director and Professor, Robert A. Welch Distinguished University Chair in Chemistry Director, Texas Therapeutics Institute, the University of Texas Health Science Center at Houston, USA The Current Landscape of Monoclonal Antibody Drug Discovery
10:35 - 10:55
Tea break
10:55 - 11:20
Dr. Lawrence L. GAN President, Development Center for Biotechnology, Taiwan Drug Delivery into the Brain – the Role of Transporters at the Blood Brain Barrier and Convective Flows of Brain Interstitial Fluid (ISF) and Cerebrospinal Fluid (CSF)
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Session I Moderator Min-Liang KUO Dean, National Taiwan University College of Life Science Professor, Institute of Biochemical Science, National Taiwan University College of Life Science Co-hiring Professor, Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taiwan (kuominliang@ntu.edu.tw)
Professional Experiences 1999 - 2005 2005 - 2006 2006 - 2007 2007 - 2009 2009 - 2012 2010 - 2014 2012 - Present 2012 - Present 2012 - Present
Professor and Director, Institute of Toxicology College of Medicine National Taiwan University Professor, Institute of Toxicology College of Medicine National Taiwan University M.D., Department of Molecular Oncology MD Anderson Cancer Center Distinguished Professor Associated Dean, Director of R&D, Institute of Toxicology College of Medicine National Taiwan University Director General, Department of Life Sciences, National Science Council Republic of China President, The Toxicology Society of Taiwan Co-hiring Professor, Graduate Institute of Toxicology, National Taiwan University College of Medicine Professor, Institute of Biochemical Science, National Taiwan University College of Life Science Dean, National Taiwan University College of Life Science
Research Interests Professor Kuo dedicate to the research of tumor progression and translational medicine for more than 20 years in Taiwan. His works including discovery the molecular mechanism of cancer malignance progression by epigenetic regulation and growth factor/cytokine response of cancer cells. His mechanistical studies about epigenetic regulation, microRNA synthesis, protein post-translational modification, growth factors and cytokines also give rise to serial discoveries of novel tumor suppressors and oncogenes involve in tumor growth, invasiveness, metastasis, and angiogenesis. These outstanding researches of Professor Kuo not only provide novel insights into the underlying mechanisms but also translated into development of novel therapeutic strategies for clinical application.
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Session I Speaker Zhiqiang AN Director and Professor, Robert A. Welch Distinguished University Chair in Chemistry Director, Texas Therapeutics Institute, the University of Texas Health Science Center at Houston, USA (Zhiqiang.An@uth.tmc.edu)
Dr. Zhiqiang An is Professor of Molecular Medicine, the Robert A. Welch Distinguished University Chair in Chemistry, and Director of the Texas Therapeutics Institute at the University of Texas Health Science Center at Houston. His laboratory focuses on cancer antibody drug resistance mechanisms, biomarkers for cancer therapeutic antibodies, and antibody drug discovery targeting cancer and infectious diseases. Dr. An also directs the Therapeutic Monoclonal Antibody Lead Optimization and Development Core Facility funded by the Cancer Prevention and Research Institute of Texas (CPRIT). Previously, he served as Chief Scientific Officer at Epitomics, Inc. and was Director of Biologics Research at Merck Research Laboratories. He started his biotech career at Millennium Pharmaceuticals. Dr. An received his Ph.D. degree from the University of Kentucky and his postdoctoral training at the University of Wisconsin-Madison.
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The Current Landscape of Monoclonal Antibody Drug Discovery Zhiqiang An Antibody therapeutics represents a major breakthrough in combating human diseases and the improvement of human health. At least 40 antibody therapies have been approved for the treatment of cancer, immune disorders, and infectious diseases. A record six antibody therapies were granted first marketing approval in 2014. Among the top 10 bestselling prescription medicines in 2014, seven are recombinant proteins and antibodies. This trend will continue as about 50% of the new drugs in various stages of clinical development are antibodies. Despite the remarkable progress, many scientific, technological, and clinical challenges remain and opportunities for innovation exist at every level: accessing difficult antibody targets, small molecule and antibody combination therapies, immune check point therapies, antibody-drug conjugation, novel antibody sources and formats, crossing the brain-blood-barrier and cell membranes, modified effector functions, bispecific and poly-monoclonals, improved formulation and delivery methods, and lower manufacturing cost, to name a few. This presentation will review the current trend in therapeutic antibody discovery to fulfill the dream of personalized medicine through basic scientific discovery and technological innovation.
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Session I Speaker Lawrence L. GAN President, Development Center for Biotechnology, Taiwan (lawrence.gan@mail.dcb.org.tw)
Accomplishments 1. Involved in four NDA and two BLA filings. 2. Participated in >25 IND filings. Experience/Education 2007/07-2015/2/28 2005/11-2007/07
2002/02-2005/11
1996/09-2002/02
1989/03-1996/09
1986/02- 1989/03 1981/08-1986/02
Senior Director, Drug Metabolism and Pharmacokinetics, Biogen Idec, Inc. (now Biogen Inc.), Cambridge, MA, USA Director (German Rank), Drug Metabolism and Pharmacokinetic, Drug Discovery Support, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA Senior Director, Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals (now Takeda Pharmaceuticals), Cambridge, MA, USA Director, Drug Metabolism and Pharmacokinetics, DuPont Merck & then DuPont Pharmaceuticals (now Bristol-Myers Squibb Co.), Wilmington, DE, USA Principal Investigator, Drug Metabolism and Pharmacokinetics, Glaxo Inc., then GlaxoWellcome Inc. (now GlaxoSmithKline, GSK), Research Triangle Park, NC, USA Post-Doc Research Fellow, Chemical Toxicology, Massachusetts Institute of Technology, Cambridge, MA, USA Doctoral Research (Ph.D.), Department of Chemistry, Tulane Univ., New Orleans, LA, USA
Adjunct Professorship UNC, Chapel Hill, Northeastern Univ., West Virginia University, Massachusetts College of Pharmacy. Supervised twelve doctoral and M.S. candidates. Industry Representatives Board of Director, International Consortium for Innovation and Quality (IQ) in Pharmaceutical Development. IQ Drug Metabolism Leadership Group Representative. New England Drug Metabolism Discussion Group Committee Member. Editorial Roles Editorial Advisory Board, Editor, and referee for more than 10 peer-reviewed journals. Publications >80 peer-reviewed journal publications, 128 meeting abstracts, 6 book chapters, Associate Editor for Drug Metabolism Handbooks, 32 invited presentations.
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Drug Delivery into the Brain – the Role of Transporters at the Blood Brain Barrier and Convective Flows of Brain Interstitial Fluid (ISF) and Cerebrospinal Fluid (CSF) Lawrence L.-S. Gan1, and Qin Wang2 1
Development Center for Biotechnology, Xizhi District, New Taipei City, 22180, Taiwan, R.O.C. Department of Drug Metabolism and Pharmacokinetics, Biogen Inc., Cambridge, MA 02142, USA 2
The brain is a privileged organ, sequestered from the general systemic circulation by the blood brain barrier (BBB). BBB eliminates toxic substances from the endothelial compartment and supplies the brain with nutrients and other endogenous compounds. It can be considered as an organ protecting the brain and regulating its homeostasis. To date, many transport systems have been discovered that play an important role in maintaining BBB integrity, brain homeostasis, and drug uptake into the brain. The role of carrier-mediated transport systems (CMT, e.g. Pgp, BCRP, MRPs, OATPs) and receptor-mediated transport systems (RMT, e.g. transferrin 1&2) at the BBB will be reviewed first. The role that convective flows of brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) play in clearing wastes out of the central nervous system (CNS) and its implications including the onset of β-amyloid accumulation in the brain will also be discussed. The phenomenon that acetazolamide, a carbonic anhydrase inhibitor, reduces ISF and CSF production and decreases the clearance of acetaminophen out of brain has been demonstrated via microdialysis studies.
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Session II: Emerging Targets Moderator:
Dr. Chia-Lin Jeff WANG CEO, BioGate Medical Science Corp. Taiwan
11:25 – 12:00
Dr. Peter KWONG Chief, Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, NIAID, National Institutes of Health, USA HIV-1 Env as a Target of Neutralizing Antibodies
12:00 - 12:35
Dr. Michael JENNINGS Deputy Director & Principal Research Leader, Institute for Glycomics, Griffith University, Australia Discovery and Exploitation of Host - Pathogen Interactions as New Opportunities for Antibody Therapy
12:35 - 14:00
Lunch (Taiwan Antibody Association Members Meeting)
14:00 - 14:35
Dr. Arun KASHYAP Head of Research, Sea Lane Biotechnologies, USA Surrobodies: A Novel Immune Scaffold for Immunotherapeutic Applications
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Session II Moderator Chia-Lin Jeff WANG President, BioGate Medical Sciences Co, Taiwan (cljwang@aol.com)
Education 1978-1979 1977 1971
Research Associate, Department of Chemistry, Harvard University (Advisor: Professor Yoshito Kishi) Ph.D., Department of Chemistry, University of Pittsburgh, Pittsburgh, PA (Thesis Advisor: Professor Paul A. Grieco) B.S., Department of Chemistry, National Taiwan University, Taipei, Taiwan R.O.C.
Professional Experience 2/2015 8/2014 -2/2015 2008-8/2014 2007-2008 2006-2007 2000-2005 1997-2000 1992-1996 1990-1992 1985-1990 1979-1985
Present: President, BioGate Medical Sciences Co. Senior VP, CHO Pharma President, Development Center for Biotechnology Chief Scientific Officer, Microbio Co. Vice President, Development Center for Biotechnology Director, U.S. East Coast Office Development Center for Biotechnology Science Advisor (Biotechnology &Pharmaceutical) Department of Industrial Technology, Ministry of Economic Affairs (Taiwan) Director, Natural Product & Medicinal Chemistry Development Center for Biotechnology (Taiwan) Principal Research Scientist, The DuPont Merck Pharmaceutical Co. (US) Senior Research Chemist, Du Pont Medical Products Department (US) Research Chemist, Du Pont Central Research and Development Department (US)
Accomplishments 1. 2. 3. 4. 5.
Over 50 publications and 26 patents on the synthesis of medicinally interesting compounds Help Taiwan Ministry of Economic Affairs (MOEA) formulate the R&D strategies for promotion of the Taiwan biotech and pharmaceutical industries Promote international cooperation for the development of Taiwan biotech and pharmaceutical industries Help form the “Five-year Herbal Medicine Industrial R&D Plans� for Taiwan Transform DCB into a new drug translational research institute working closely with academic institutes and industries.
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Session II Speaker Peter D. KWONG Chief, Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, NIAID, National Institutes of Health, USA (peter.kwong@nih.gov)
Dr. Peter Kwong joined the Dale and Betty Bumpers Vaccine Research Center as chief of the Structural Biology Section in the Laboratory of Virology. Dr. Kwong comes to the Washington area from New York City, where he conducted research in the Department of Biochemistry and Molecular Biophysics at Columbia University. Dr. Kwong's research specialty is structural biology. Specifically, he has studied the atomic-level structures of both the HIV protein, gp120, which resides on the outer surface of the virus as well as the structure of the primary HIV receptor, CD4. HIV uses gp120 to find and latch onto special CD4-containing immune cells in the first step of infection. Because of its exposed position on the outer surface of the virus, gp120 is the primary target of antibodies, the body's first line of defense against the invading virus. But, by mechanisms still not fully understood, gp120 is able to evade most of these antibodies. Because of its central role in evading the immune system, many investigators had previously attempted to analyze the gp120 structure. However, these attempts were not successful due to masking of the gp120 molecule. Dr. Kwong and his research collaborators constructed altered forms of the gp120 protein until they found one that was suitable for analysis. By using X-ray crystallography, Dr. Kwong elucidated the atomic-level structure of gp120 in complex with the CD4 receptor and a neutralizing human antibody. The results of this seminal experiment and discovery were published in the journals Nature and Science in 1998. Although structural information has not played a large role in vaccine development thus far, Dr. Kwong's research may change this. Since arriving at the VRC in 2001, Dr. Kwong and his research team have focused on three areas of investigation: 1) Unveiling mechanisms used by the HIV-1 envelope to evade the humoral immune response; 2) The characterization of antibodies that neutralize HIV-1, including their precise epitopes and mechanisms of neutralization; and 3) The design of envelope-based vaccine immunogens that elicit an effective antibody immune response against HIV-1. The most dramatic advances have been in understanding mechanisms used by HIV-1 to disguise its surface, thereby evading the immune system's attack of neutralizing antibodies. These involve novel mechanisms of conformational masking and glycan shielding (published in the journal Nature in 2002 and 2003). The investigations of antibodies have also revealed novel mechanisms of binding, involving membrane interactions with the broadly neutralizing anti-HIV-1 antibody, 2F5, and of mimicry, involving antibody sulfation with the CD4i-class of gp120-reactive antibodies.
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By studying the mechanisms gp120 uses to evade the immune system, Dr. Kwong and his team hope to find how to disable them and construct a modified HIV-1 envelope that will elicit an immune response against HIV. Conversely, by understanding how the rare select antibodies from HIV-1 infected individuals can neutralize HIV-1, Dr. Kwong and his team hope to understand how they might be efficiently re-elicited. The success of this research may lead to new strategies for developing vaccines against HIV as well as against other disease-causing viruses. Dr. Kwong entered the University of Chicago at age 16 and earned a bachelor's degree in chemistry and physics and a master's degree in biochemistry by age 20. He earned his second master's degree and his doctoral degree in biochemistry and molecular biophysics from Columbia University in New York.
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HIV-1 Env as a Target of Neutralizing Antibodies Peter D. Kwong Vaccine Research Center, NIAID, National Institutes of Health, USA Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified (1). One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region of HIV-1 and neutralizes over 95% of circulating HIV-1 strains (2). Antibody 10E8, however, suffers from issues of solubility and, if dosed at 30 mg/kg, would require over ~2 g of antibody per dose for a typical adult. Here, we describe the use of structural biology, somatic variation and surface-matrix screening to identify optimized versions of 10E8 with substantially increased solubility and potency. First we used both structural biology and somatic variants obtained by next generation sequencing to identify 10E8-v4, with 26 amino acid changes, similar neutralization potency, but more than 10-fold improved solubility relative to the parent 10E8. Second we used a matrix-screening approach to analyze the surface of 10E8 with Arg, Phe/Trp, N-linked glycan and poly-glycine alterations coupled to assessment of neutralization potency and solubility. By using clues glean from this surface-matrix analysis, we developed modified versions of 10E8-v4 with neutralization potency increased by over 30-fold. Delivery of these more potent versions of 10E8-v4, along with an extended half-life alteration (a “LS� change in the constant region), may reduce dosing to ~0.1 g of optimized 10E8 every 3 months, a more practical target. The impact of such optimized antibodies on treatment and prevention of HIV-1 will be discussed. References 1. Kwong P.D. and Mascola J.R. Human antibodies that neutralize HIV-1: Identification, structures and B cell ontogenies. Immunity 37, 412-425, 2012. 2. Huang J., Ofek G., Laub L., Louder M.K., Doria-Rose N.A., Longo N.S., Imamichi H., Bailer R.T., Chakrabarti B., Sharma S.K., Alam S.M., Wang T., Yang Y., Zhang B., Migueles S.A., Wyatt R., Haynes B.F., Kwong P.D., Mascola J.R., Connors M. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406-412, 2012.
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Session II Speaker Michael JENNINGS Deputy Director & Principal Research Leader, Institute for Glycomics, Griffith University, Australia (m.jennings@griffith.edu.au)
Professor Michael Jennings works in the fields of glycobiology, bacterial genetics and bacterial pathogenesis. His work has focused on bacterial pathogens, in particular the pathogenic Neisseria (meningitis) and Haemophilus influenzae. He was awarded his PhD (1990) from Griffith University. His post-doctoral training was in the laboratory of Professor Richard Moxon at the University of Oxford 1992-1996 funded by the Beit Memorial Fellowship for Medical Research. In 1997 he took up a faculty position at the University of Queensland. He remained at University of Queensland until 2009, until he returned to Griffith University to take up the position of Deputy Director at the Institute for Glycomics. His current research program is investigating the molecular basis for interactions between a wide range of pathogens and the human host and the application of this data to develop novel strategies for diagnostics, prevention and treatment of disease.
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Discovery and Exploitation of Host - Pathogen Interactions as New Opportunities for Antibody Therapy Michael Jennings Glycans are important structures in many host - pathogen interactions. Bacterial lectins such as adhesins and toxins exploit host glycans as targets. Host lectins recognize bacterial glycans in innate immune processes. The molecular details of many bacterial - host interactions remain to be discovered. Understanding these processes is key for the development of novel strategies for prevention and therapeutics. We have applied glycan array to discover novel interactions between bacterial and human cells. Interfering with these processes may for the basis of therapeutic approaches using antibody therapeutics.
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Session II Speaker Arun KASHYAP Head of Research, Sea Lane Biotechnologies, Atherton, CA, USA (Arun.Kashyap@sealanebio.com)
Experience Head of Research, Sea Lane Biotechnologies, 12/2014-present Director of Biology, Sea Lane Biotechnologies, 2/2008 to 9/2012 Principal Scientist, Sea Lane Biotechnologies, 2/2006 to 2/2008 Bioprocess Engineer, BD Biosciences, 5/2004-2/2006 Scientist, Pharmagenesis, 9/2001-7/2003 Research Associate, Affymax Research Institute, 11/1992-10/1995 Scientist, Sandoz Agro, 4/1990-11/1992 Education PhD, University of California, Santa Cruz, 2001 AB, University of California, Berkeley, 1989 Awards and Associations University of California Regents Fellowship (1995) Newcomb Cleveland Prize- AAAS (1997) Member, American Society for Cell Biology (2003-present) Qualifying Therapeutic Discovery Program- Awards for two programs (2011) Publications 1. 2. 3. 4. 5. 6.
7. 8.
Milutinovic S., et al. Dual agonist SurrobodyTM simultaneously activates death receptors DR4 and DR5 to induce cancer cell death. Mol Cancer Ther. Submitted. Ekiert D.C., et al Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489:526-532, 2012. Kashyap A.K., et al. Protection from the 2009 H1N1 Pandemic Influenza by an Antibody from Combinatorial Survivor-based Libraries PLoS Pathog 6(7):e1000990, 2010. Xu L., et al, Surrobodies with functional tails. J Mol Biol 397(1):352–360, 2010. Xu L., et al, Combinatorial surrobody libraries. Proc Natl Acad Sci USA 105(31):10756– 10761, 2008. Kashyap A.K, et al. Combinatorial Antibody Libraries from Survivors of the Turkish H5N1 Avian Influenza Outbreak Reveal Virus Neutralization Strategies. Proc Natl Acad Sci USA 105(16):5986-91, 2008. Kashyap A.K, et al. Biochemical and genetic characterization of Yra1p function in budding yeast. Yeast 22:43-56, 2005. Wrighton N.C., et al, Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat Biotech 15:1261-1265, 1997.
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9.
Wrighton N.C., et al Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273(5274):458-463, 1996.
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Surrobodies: A Novel Immune Scaffold for Immunotherapeutic Applications Arun Kashyap Surrobodies are heterotetrameric proteins that contain the surrogate light chain and a full antibody heavy chain. The surrogate light chain is the fusion of two human immune proteins that form the pre-B-cell receptor, namely VpreB and Lambda 5. Normally expressed during B-cell development just after heavy chainV-DJ joining, the complex of VpreB and Lambda 5 pair with all heavy chains in what is thought to be a quality control step to eliminate self reactive combinations. We have adapted the surrogate light chain to the development of the Surrobody scaffold that has highly desirable characteristics; high affinity and specificity, long serum half-life, excellent stability, and developed manufacturing processes. In addition, since the surrogate light chain is an undiversified and fixed component of all Surrobodies, it is uniquely suited to the creation of bispecific molecules and drug conjugate applications. Sea Lane has created a full discovery package including a 2.8 X1010 member phagemid library based on proprietary ConCIRT diversity and transient production methods. Application of Surrobody libraries to oncology targets ErbB3 and the death receptors DR4 and DR5 has produced highly potent molecules with unique activity profiles in pre-clinical proof of concept studies.
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Session III: Translation and Development of Antibody Therapeutics Moderator:
Dr. Fu-Tong LIU Director and Distinguished Research Fellow, Institute for Biomedical Sciences, Academia Sinica, Taiwan
14:40 - 15:15
Dr. Po-Jen CHEN Professor, Department of Medicine, Rheumatology Division, UCLA, USA From Autoantibodies to Potentially Therapeutic Antibodies against HIV
15:15 - 15:50
Dr. Jeffrey J MOLLDREM Professor and Chief, Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, USA T Cell Receptor-Like Antibody 8F4 Targets Leukemia and Non-Hematopoietic Cancer
15:50 - 16:10
Tea break
16:10 - 16:35
Dr. Alice YU Distinguished Chair Professor and Co-Director, Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital & Chang Gung University, Taiwan Development of Antibodies Directed against Cancer Associated Glycans
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Session III Moderator Fu-Tong LIU Distinguished Research Fellow and Director, Institute of Biomedical Sciences, Academia Sinica, Taiwan (ftliu@ibms.sinica.edu.tw)
Dr. Fu-Tong Liu is currently Distinguished Research Fellow and Director at Institute of Biomedical Sciences, Academia Sinica and was previously Distinguished Professor and Chair at Department of Dermatology, University of California-Davis. He is currently Associate Director for the Academia Sinica Translational Medicine Degree Program, Co-Director for the International Collaboration Program under the National Research Program for Biopharmaceuticals (NRPB), Director for the National Glycoscience Program of the Ministry of Science and Technology, and Principle Investigator of the Taiwan Biobank. He received his BS in Chemistry from National Taiwan University, PhD in Chemistry from University of Chicago, and MD from University of Miami. He has served as Head of the Allergy Research Section at the Scripps Research Institute and Head of the Division of Allergy at La Jolla Institute for Allergy and Immunology. Dr. Liu is a pioneer and leading investigator in the studies of a family of animal lectins, galectins, and his research is focused on the roles of these proteins in inflammation and immunity, as well as cancer progression and adiposity. He has published over 310 original scientific papers and review articles. He has served as an Associate Editor of Journal of Clinical Investigation and is currently a member of the Editorial Boards of a number of scientific journals in dermatology and allergy. He is a Fellow of American Association for the Advancement of Science (AAAS) and an Academician of Academia Sinica. He was the Laureate of the 2015 Khwarizmi International Award.
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Session III Speaker Po-Jen CHEN Professor, Department of Medicine, Rheumatology Division, UCLA, USA (ppchen@g.ucla.edu)
Experience Professor Emeritus, Department of Medicine, Division of Rheumatology, UCLA, 2014-date Member, International Advisory Committee for the International Congress of Antiphospholipid Antibodies, 2010-2012 Scientific Consultant, PEREGRINE PHARMACEUTICALS, INC., Tustin, California, United States, 2007-2009 Professor, Department of Medicine, Division of Rheumatology, University of California Los Angeles (UCLA), Los Angeles, California, United States, 1997-2014 Member, General Medicine A Study Section, NIH, 1996-2000 Professor, Departments of Medicine and Pathology, UCSD, 1995-1997 Member, General Medicine A Study Section, National Institutes of Health (NIH), USA, 1991-1995 Scientific Consultant, CIBA-GEIGY Corp., Summit, New Jersey, 1990-1996 Associate Professor, Departments of Medicine and Pathology, University of California San Diego (UCSD), 1990-1995 Assistant and Associate Professor, Department of Basic and Clinical Research, the Scripps Research Institute, La Jolla, California, USA, 1985-1990 PhD, University of California, San Francisco, 1980 BS, Tunghai University, Taiwan, 1973 Selected Invited Lectures 1. 2. 3. 4. 5.
6. 7.
Invited speaker, Jiangsu provincial Rheumatology conference, Yangzhou, Jiangsu, China, 2013. Invited seminar, Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China, 2010. Invited Speaker, the 13th International Congress of Antiphospholipid Antibodies (APLA 2010), Galveston, Texas, United States, 2010. Invited Speaker, The 8th International Congress on SLE, Shanghai, China, 2007. Invited keynote speaker, the joint annual meeting of the Taiwanese society of Immunology and the Taiwanese Rheumatology Association, November 22-23, 2003, Taichung, Taiwan, 2003. Invited Speaker, the 9th Asian Pacific League Against Rheumatism, Beijing, China, 2000. Plenary Lecturer, the Major Histocompatibility Complex in Medicine, Australasian and South East Asian Tissue Typing Association (ASEATTA), Adelaide, Australasia, 1994.
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8.
Plenary Lecturer, First International Workshop on: "Platelets, Endothelial Cells: from Autoimmunity to Immunomodulation", Annecy, France, 1993. 9. Plenary Lecturer, XXIst Annual Meeting of the Society of Immunology, Aachen, Germany, 1990. 10. Invited Speaker, XVIIth International Congress of Rheumatology-ILAR '89, Rio de Janeiro, Brazil, 1989. 11. Plenary Lecturer, the Third Mediterranean Congress of Rheumatology, Tunis, Tunisia, 1986. Selected Publications 1.
2.
3.
4.
5.
6.
Moody M.A., Liao H.X., Alam S.M., Scearce R.M., Plonk M.K., Kozink D.M., Drinker M.S., Zhang R., Xia S.M., Sutherland L.L., Tomaras G.D., Giles I.P., Kappes J.C., Ochsenbauer-Jambor C., Edmonds T.G., Soares M., Barbero G., Forthal D.N., Landucci G., Chang C., King S.W., Kavlie A., Denny T.N., Hwang K.K., Chen P.P, Thorpe P.E., Montefiori D.C., Haynes B.F. Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce beta-chemokines. J Exp Med 207:763-776, 2010. Zhu M., Olee T., Le D.T., Roubey R.A.S., Hahn B.H., Woods Jr. V.L., Chen P.P. Characterization of IgG monoclonal anti-cardiolipn/anti-ď ˘2GP1 antibodies from two patients with antiphospholipid syndrome reveals three species of antibodies. Brit. J. Haematology 105:102-109, 1999. Olee T., Pierangeli S.S., Handley H.H., Le D.T., Wei X., Lai C.J., En J., Novotny W., Harris E.N., Woods V.L., Chen P.P. A monoclonal IgG anticardiolipin antibody from a patient with the antiphospholipid syndrome is thrombogenic in mice. Proc Natl Acad Sci USA 93:8606-8611, 1996. Lu E.W., Deftos M., Tighe H., Carson D.A., Chen P.P.. Generation and characterization of two monoclonal self-associating IgG rheumatoid factors from a rheumatoid synovium. Arthritis Rheum 35:101-105, 1992. Chen P.P., Houghten R.A., Fong S., Rhodes G.H., Gilbertson T.A., Vaughan J.H., Lerner R.A., Carson D.A. Anti-hypervariable region antibody induced by a defined peptide. A new approach for studying the structural correlates of idiotypes. Proc Natl Acad Sci USA 81:1784-1788, 1984. Chen P.P., Nitecki D.E., Lewis G.K., Goodman J.W. Antigen structural requirements for immunoglobulin isotype switching in mice. J Exp Med 152:1670-1683, 1980.
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From Autoantibodies to Potentially Therapeutic Antibodies against HIV Po-Jen Chen In 2005, Haynes et al. showed that two broadly neutralizing human monoclonal antibodies (mAbs) against HIV-1 envelope glycoprotein 41 (gp41; 2F5 and 4E10) were polyspecific autoantibodies. In particular, both reacted with the phospholipid cardiolipin [1]. Subsequently, it was found that four human anti-phospholipid mAbs (PGN632, P1, IS4, and CL1, including three from patients with the antiphodpholipid syndrome) inhibited HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to approximately 10 microgram/ml [2]. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1alpha and MIP-1beta. Recently, a patient with systemic lupus erythematosus (SLE) and HIV-1-infection was found to have controlled viral load (<5,000 copies/ml). Serological analysis revealed that this patientâ&#x20AC;&#x2122;s plasma neutralized 41/42 (97.6%) HIV-1 strains tested [3]. When the memory B cells from this individual were used to generate mAbs, a broadly neutralizing mAb (bnmAb), CH98, was obtained. The mAb targeted the CD4 binding site (CD4bs) of HIV-1 envelope gp120. CH98 also bound to human antigens including double-stranded DNA (dsDNA), a hallmark autoantibody of SLE. Taken together, these findings show that broadly neutralizing anti-HIV mAb may be more readily obtained from HIV-1-infected individuals with autoimmune diseases. 1. Bonsignori et al. An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1. J Clin Invest 124:1835, 2014. 2. Moddy et al. Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce beta-chemokines. J Exp Med 207:763, 2010. 3. Haynes et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308:1906, 2005.
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Session III Speaker Jeffrey J MOLLDREM Professor and Chief, Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, USA (jmolldre@mdanderson.org)
Experience 7/1993-7/1997 7/1993-7/1996 6/1990-5/1993 3/1990 3/1986
BMT Fellowship, National Heart, Lung & Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA Clinical Associate and Post-doctoral Fellow, National Heart, Lung and Blood Institute and National Cancer Institute, Bethesda, MD, USA Internal Medicine Residency, University of California, Los Angeles, CA, USA M.D., Univ. of Minnesota, Minneapolis-St. Paul, MN, USA B.A., Moorhead State University, Moorhead, MN, USA
Personal Statement The long-term goals of my lab are to understand how immunity to hematopoietic cells is mediated and regulated, and to develop novel immunotherapies that target hematological malignancies. We found T cells suppress effective hematopoiesis in patients with myelodysplastic syndrome, and showed ATG restored cytopenia in patients by reducing autoreactive T cells. We identified PR1 as an HLA-A2-restricted leukemia-associated self-antigen and determined that self-renewing PR1-specific CD8+ memory T cells contribute to long-term cytogenetic remission of CML. Conversely, high PR1-expressing leukemia shapes host immunity by deleting high avidity PR1-specific T cells, enabling leukemia outgrowth. Recently, peptide vaccine-induced immunity to PR1 with objective clinical response was observed in low leukemia burden patients. To treat high leukemia burden, we developed a T cell receptor-like monoclonal antibody that binds a conformational epitope of PR1/HLA-A2 on the cell surface, which mediates specific lysis of AML blasts and leukemia stem cells. Positions and Employment 2014-present 2011-present
2011-present 2006-present 2005-present
Scientific Director, Oncology Research for Biologics and Immunotherapy Translation (ORBIT), UT MD Anderson Cancer Center, Houston, TX Program Co-Leader, Cancer Center Support Grant (CCSG), Clinical/Translational Thematic Programs, Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX Program Co-leader, Cancer Center Support Grant (CCSG), Basic Science Programs, Immunology, UT MD Anderson Cancer Center, Houston, TX Virginia H. Cockrell Distinguished Professorship in Immunology, UT MD Anderson Cancer Center, Houston, TX Professor (tenured), Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center,
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2003-present
2001-2005
1998-present
1998-present 1997-2001
1996-1997
Houston, TX Co-Director, Center for Cancer Immunology Research (CCIR), Department of Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX Associate Professor (tenured), Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX Associate Medical Director, Bone Marrow Transplant Lab, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX Faculty (tenure track), UT Graduate School for Biomedical Sciences, Program in Immunology, Houston, TX Assistant Professor (tenure track), Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX Attending Physician, Hematology Branch, NHLBI, NIH, Bethesda, MD
Other Experience and Professional Memberships 2012-present 2012-present 2010-present 2004-2009 2003-2014 2002-2007
Scientific Advisory Board, Texas Cancer Vaccine, Dallas Scientific Advisory Board, Baylor Institute for Immunology Research (BIIR), Houston, TX Scientific Advisory Board, Gabrielle's Angel Foundation for Cancer Research, New York, NY Founder and Director, Scientific Advisory Board, The Vaccine Company, Houston, TX International Scientific Advisory Committee, Jose Carreras International Leukaemia Foundation, Barcelona, Spain Medical Advisory Board, Aplastic Anemia and Myelodysplasia Foundation, Inc. (AA&MDSIF), Annapolis, MD
Honors 2015 2015 2014 2013 2009 2007 2003 2001
Robert M. Chamberlain Distinguished Mentor Award Nominee, MD Anderson Cancer Center President's Recognition for Faculty Excellence, MD Anderson Cancer Center Fellow, American Association for the Advancement of Science Robert M. Chamberlain Distinguished Mentor Award Nominee, MD Anderson Cancer Center American Society of Clinical Investigators Division of Cancer Medicine Mentor Award, Fellowship Program, MD Anderson Cancer Center Julie and Ben Rogers Award for Excellence, MD Anderson Cancer Center Faculty Scholar Award, The University of Texas MD Anderson Cancer Center
Contribution to Science 1. Reported the discovery of PR1 as the first leukemia-associated antigen, which is targeted by CD8+ T lymphocytes that preferentially kill leukemia, but not normal bone marrow cells. Established biological and clinical validation of the PR1 leukemia-associated antigen by showing that CD8+ T lymphocyte immunity to PR1 induces complete cytogenetic remission by chronic myelogenous leukemia. Determined an important mechanism of how leukemia
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escapes immune surveillance through the deletion of high-avidity leukemia-reactive CD8+ T lymphocytes by leukemia that over-expresses leukemia-associated antigens, which results in unchecked growth of leukemia. Blood 88(7):2450-7, 1996; PubMed PMID:8839835; Nat Med. 6(9):1018-23, 2000; PubMed PMID:10973322; J Clin Invest. 111(5):639-47, 2003; PubMed PMID:12618518; PubMed Central PMCID:PMC151894. 2. Demonstrated that adoptive cell transfer of a limited number of PR1-specific CD8+ T lymphocytes reduces or eliminates human AML cells in xenograft models. Further, a small, circulating population of memory leukemia-specific T lymphocytes that self-renew mediate long-term cytogenetic and molecular remission of CML after treatment. This study showed the critical role of a long-lived specific anti-leukemia immune response in maintaining sustained molecular remission of leukemia. PLoS One 5(7):e11770, 2010; PubMed PMID:20668669; PubMed Central PMCID:PMC2909896; Cytotherapy 12(8):1056-62, 2010; PubMed PMID:20735170; PubMed Central PMCID:PMC3365857. 3. Initial report of our development of a T cell receptor-like monoclonal antibody (8F4) recognizes PR1 in the context of HLA-A2 and is highly active against Acute Myeloid Leukemia (AML) and leukemia-initiating cells. 8F4 is currently in development as a first-in-class antibody for clinical use. Blood 117(16):4262-72, 2011; PubMed PMID:21296998; PubMed Central PMCID:PMC3087478. 4. Established that hematopoietic antigens derived from tumor-associated neutrophils are cross-presented on non-hematopoietic solid tumors as novel target antigens that induce susceptibility to antigen-specific immunotherapies. Cancer Res. 72(13):3153-62, 2012; PubMed PMID:22564522; PubMed Central PMCID:PMC3397251; J Immunol. 189(11):5476-84, 2012; PubMed PMID:23105141; PubMed Central PMCID:PMC3504175.
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T Cell Receptor-Like Antibody 8F4 Targets Leukemia and Non-Hematopoietic Cancer Jeffrey Molldrem, Anna Sergeeva, Helen He, Amanda Herrmann, Tian-Hui Yang, Celine Kerros, Haley Peters, Jin Im, Sapna Parshottam, Sijie Lu, Qing Ma, Karen Dwyer, Elizabeth Mittendorf, and Gheath Alatrash. Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Adaptive anti-tumor immune surveillance of leukemia, called the graft-versus-leukemia (GVL) effect in the setting of allogeneic stem cell transplantation (alloSCT), is responsible for inducing and maintaining long term remission. However, although donor T cells mediate GVL, they also mediate graft-versus-host disease (GVHD), which results in significant morbidity and can be fatal, and is thus a substantial barrier to the more widespread application of alloSCT for many patients with hematological malignancies. CD8 T cells are activated by cognate peptide/MHC-I target cell antigens through binding of clonally unique ÎąĂ&#x;-heterodimer T cell receptors (TCRs) on the cell surface. Thus, because GVL and GVHD target antigens can be unique, immunotherapy strategies that target GVL antigens such as adoptively transferred T cells could be developed to mediate GVL without GVHD. Likewise, TCR-like monoclonal antibodies (mAbs) that similarly bind to peptide/MHC-I also could be useful as novel immunotherapeutic agents to mediate GVL in the absence of cellular therapies. Moreover, if potent anti-tumor activity was mediated by such TCR-like mAbs, they could have advantages over adoptively transferred donor T cells, including easier standardized manufacturing, ease of dose and scheduled administration, and they could be given to patients in the absence of an alloSCT. We identified PR1, an HLA-A2-restricted 9-mer peptide a peptide derived from aberrantly expressed proteinase 3 (P3) and neutrophil elastase (NE) in myeloid leukemia, as a leukemia-associated target antigen for CD8 T cells that mediate GVL. PR1-specific CD8 T cells target HLA-A2+ AML, CML and MDS but not normal hematopoietic cells and they contribute to cytogenetic and molecular remission of myeloid leukemia. We developed a murine TCR-like mAb that binds to PR1/HLA-A2 (8F4) and showed that 8F4 mediated complement-dependent cytotoxicity (CDC) of AML, CML and MDS progenitor cells and blasts, but not normal bone marrow cells. Because 8F4 did not eliminate normal human hematopoietic cells in a xenograft model, we humanized 8F4 to an IgG1 isotype (h8F4). In AML PDX models, 8F4 and h8F4 eliminated HLA-A2+ AML and leukemia stem cells (LSCs). In preclinical safety models, only mild reversible blood cytopenia was observed after multiple-dose IV administration of high-dose 8F4. Based on these findings, h8F4 is being developed for a first-in-human phase I safety study in HLA-A2+ patients with high-risk AML. In addition, 8F4 also mediated lysis of many non-hematopoietic cancers due to PR1 cross-presentation on surface HLA-A2, which increased cancer cells susceptibility to 8F4-mediated lysis. Therefore, 8F4 also could be tested for the treatment of non-hematopoietic HLA-A2+ cancers such as breast cancer, non-small cell lung cancer, and colon cancer.
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Session III Speaker Alice YU Distinguished Chair Professor and Co-Director, Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital & Chang Gung University, Taiwan (aliceyu@ucsd.edu)
Dr. Alice Yu is a Distinguished Professor & Co-Director of the Institute of Stem Cell & Cancer Translational Research in Chang Gung Memorial Hospital at Linko, Taiwan, and a Professor Emeritus at the University of California in San Diego. Formerly she was the Chief of Pediatric Hematology/Oncology at the University of California in San Diego, and Distinguished Research Fellow and Deputy Director of the Genomics Research Center of Academia Sinica in Taiwan. Dr. Yu received her MD at the National Taiwan University Medical College, and a PhD in microbiology/ immunology at University of Chicago. She had received â&#x20AC;&#x153;Key to Lifeâ&#x20AC;? Award from the Leukemia & Lymphoma Society, the 19th Wang Min-Ning Memorial Award for Outstanding Contribution to the Development Mediccal Sciene and Technology, National Health and Society, and the 55th Academic Award from the Ministry of Education, Taiwan. She is a pioneer in GD2-targeted immunotherapy of neuroblastoma who led the development of a monoclonal anti-GD2 antibody, ch14.18, from preclinical studies to IND, phase I through phase III studies. It culminated in a remarkable improvement in the event free survival leading to approval by FDA and European Commission. This is the first antibody targeting a glycolipid shown to be effective for cancer immunotherapy. Her recent research focused on other glycan-targeted cancer immunotherapy in breast cancer, the biology of breast cancer stem cells and identification new markers for breast cancer. Relevant publications in past 5 years 1. Lin H.H, Lee H.W, Lin R.J., Huang C.W., Liao Y.C., Chen Y.T., Fang J.M., Lee T.C., Yu A. L., and Chang H.C. Tracking and finding slow-proliferating/quiescent cancer stem cells with fluorescent nanodiamonds. Small 2015, (In press). 2. Cheng J.Y., Wang S.H., Lin J., Tsai Y.C., Yu J., Wu J.C., Hung J.T., Lin J.J., Wu Y.Y., Yeh K.T., and Yu A.L.* Globo-H ceramide shed from cancer cells triggers translin-associated factor X-dependent angiogenesis. Cancer Research 74:6856-66, 2014. 3. Lin J.J., Huang C.S., Yu J., Liao G.S., Lien H.C., Hung J.T., Lin R.J., Chou F.P., Yeh K.T., Yu A.L.* Malignant phyllodes tumors display mesenchymal stem cell features and aldehyde dehydrogenase/disialoganglioside identify their tumor stem cells. Breast Cancer Research 16(2): R29, 2014. 4. Huang J.R., Tsai Y.C., Chang Y.J., Wu J.C., Hung J.T., Lin K.H., Wong C.H., Yu A.L.* alpha-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3. J Immunol 192(4): 1972-1981, 2014. 5. Tsai Y.C., Huang J.R., Cheng J.Y., Lin J.J., Hung J.T., Wu Y.Y., Yeh K.T., Yu A.L. A Prevalent Cancer Associated Glycan, Globo H Ceramide, Induces Immunosuppression by Reducing Notch1 Signaling. Journal of Cancer Science & Therapy 5:264-270, 2013.
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6. Huang Y.L., Hung J.T., Cheung S.K., Lee H.Y., Chu K.C., Li S.T., Lin Y.C., Ren C.T., Cheng T.J., Hsu T.L., Yu A.L.*, Wu C.Y.*, Wong C.H.* Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer. Proc Natl Acad Sci USA 110(7):2517-2522, 2013. 7. Matthay K.K.*, George R.E., Yu A.L. Promising therapeutic targets in neuroblastoma. Clin Cancer Res 18(10):2740-2753, 2012. 8. Wu T.N., Lin K.H., Chang Y.J., Huang J.R., Cheng J.Y., Yu A.L.*, Wong C.H.* Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy. Proc Natl Acad Sci USA 108(42):17275-17280, 2011. 9. Yu A.L.*, Gilman A.L., Ozkaynak M.F., London W.B., Kreissman S.G., Chen H.X., Smith M., Anderson B., Villablanca J.G., Matthay K.K., Shimada H., Grupp S.A., Seeger R., Reynolds C.P., Buxton A., Reisfeld R.A., Gillies S.D., Cohn S.L., Maris J.M., Sondel P.M. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363(14) :1324-1334, 2010.
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Development of Antibodies Directed against Cancer Associated Glycans Alice Yu Although aberrant glycosylation is a feature of cancer cells, all approved cancer immunotherapeutics target proteins but not glycans, until recently. The approval of Unituxin (dinutuximab), a chimeric monoclonal antibody targeting GD2, ch14.18, for the treatment of patients with high-risk neuroblastoma by US FDA on March 10, 2015 and European Commission on August 17, 2015, marks the first new agent targeting a non-protein glycolipid molecule, thereby widening the net of potential pharmaceutical targets. It is also the first agent approved for therapy aimed specifically for neuroblastoma. In fact, there had been only two initial FDA approvals for drugs to treat any pediatric cancer - Erwinase and clofarabine. The remaining new drugs were first approved for adult cancers and then trickled down to children. The development history of Unituxin is also quite unique. Usually, after the initial discovery of a new drug, it is steered by pharmaceutical companies, which drive the development and execution of clinical trials. In the case of Unituxin, Dr. Yu had to take it from the initial investigational new drug (IND) application all the way through the final randomized phase III clinical trial. It started out as collaboration between Dr. Ralph Reisfeld at the Scripps Research and Dr. Yu at UC San Diego, in the mid-1980s. The initial investigational new drug (IND) for ch14.18 was submitted in 1989, 3 years before rituxan and Herceptin. In spite of promising results in phase I and II clinical trials, no pharmaceutical company was willing to manufacture the anti-GD2 antibody for the pivotal phase III clinical trial, because of the rarity of neuroblastoma. NCI began producing the antibody for a randomized national phase III clinical trial, led by Dr. Yu under the auspice of the NCI sponsored multicenter Childrenâ&#x20AC;&#x2122;s Oncology Group. This trial showed an event-free survival at two years of 66% with Unituxin plus isotretinoin compared with 46% in patients treated with isotretinoin alone (NEJM 2010). Overall survival was improved from 75% to 86% with the immunotherapy. After the announcement of the impressive phase III results, many biotech companies competed and United Therapeutics Corporation obtained the rights and was awarded a Rare Pediatric Priority Review Voucher. This was the second time such a voucher was awarded, under the Creating Hope Act which was included in the FDA Reform Bill in 2011. These vouchers allow the companies to expedite the review process for their more profitable drugs if researching and developing drugs for rare diseases, such as childhood cancers. The strategies to improve the efficacy and reduce the side effects of Unituxin and development of other immunotherapeutics targeting potentially promising glycans, such as O-acetyl GD2 and Globo H will be discussed.
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Session IV: Technologies for Antibody Discovery and Engineering Moderator:
Dr. Han-Chung WU Research Fellow and Deputy Director, Institute of Cellular and Organismic Biology, Academia Sinica, Taiwan
16:40 - 17:05
Dr. An-Suei YANG Research Fellow and Deputy Director, Genomics Research Center, Academia Sinica, Taiwan A High Throughput Antibody Engineering Platform for Discovering and Optimizing Antibodies in Antibody-Guided Drug Delivery Systems
17:05 - 17:30
Dr. Tien-Lu CHENG Director of Graduate Institute of Medicine and Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan Proteases (MMP2/9) Enhance the Affinity and Therapeutic Efficacy of Targeted Antibody
17:30 - 18:05
Dr. Hao CHEN Director, BioProcess Development, Merck Research Laboratories, Kenilworth, NJ, USA Accelerated FIH (First-In-Human) for Mabs Enabled by Innovative Bioprocess Strategy and Technologies
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Session IV Moderator Han-Chung WU Research Fellows and Vice Director Institute of Cellular and Organismic Biology, Academia Sinica, Taiwan (hcw0928@gate.sinica.edu.tw)
Dr. Wu is currently a Professor and the Vice Director of the Institute of Cellular and Organismic Biology at Academia Sinica, Taiwan. He is also a Professor at the College of Medicine of the National Taiwan University. His research interest focuses on the development of targeting drug delivery systems for cancer therapy and targeting imaging. He has developed phage display methods for the generation of fully human monoclonal antibodies and the identification of peptides for a variety of target molecules; including neutralizing epitopes of dengue viruses, disease-specific antigens from serum samples of dengue or SARS patients, surface markers for cancer stem cells and stem cells, as well as liver, lung, breast and colon cancer cell-specific peptide ligands for the development of ligand-targeted cancer therapy. His lab has also leveraged this technology platform to select tumor homing peptide ligands for the development of anti-angiogenic therapy. Dr. Wu has published over 72 original articles, 45 patents, 8 Invited review articles or books, and over 130 plenary, invited or conference contributions. He frequently serves as the reviewer for the international journals and has received numerous awards; including Academia Sinica Young Investigator award (中央研究院年輕學者研究著作獎) in 2008, Yung-Shing Investigator Award (永信李天德醫藥科技獎) in 2010, Outstanding Research Award, National Science Council (國 科會傑出研究獎) in 2011, three times of National Innovation Awards (國家新創獎) in 2011, 2012 and 2013, and Taiwan Healthcare and Agricultural Biotech Industries Innovation and Excellence Awards (生醫暨生農產業選秀大賽生醫組潛力新秀獎) in 2013. He is also the editor for a number of journals; such as PLoS ONE, International Journal of Oncology, Clinical Cancer Drugs, and The Open Breast Cancer Journal. Dr. Wu is actively involved in basic and translational research in the areas of lung cancer, breast cancer, colon cancer and hepatocellular carcinoma. During the course of his research, forty-five patents have been filed as the results of our research. Twenty-three patents were successfully granted and 8 of them were licensed out to the biotech/pharmaceutical companies for drug development.
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Session IV Speaker An-Suei YANG Research Fellow and Deputy Director, Genomics Research Center, Academia Sinica, Taiwan (yangas@gate.sinica.edu.tw)
Dr. Yangâ&#x20AC;&#x2122;s lab has implemented phage-based protein display systems in connection with computational and bioinformatics methodologies harnessing the power of rapidly expanding computing capabilities and high throughput experimental technologies for antibody/protein engineering and antibody/protein design. The research directions are aiming at innovating antibody/protein design and engineering technologies and understanding the biological function of natural antibody repertoires with synthetic phage-displayed antibody libraries and bioinformatics; the goal is to develop antibody-based molecules for important biomedical applications. The works from Dr. Yangâ&#x20AC;&#x2122;s group can be found in https://scholar.google.com.tw/citations?user=YBoSfnAAAAAJ&hl=en
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A High Throughput Antibody Engineering Platform for Discovering and Optimizing Antibodies in Antibody-Guided Drug Delivery Systems An-Suei Yang Medicinal payloads effective in treating human diseases are frequently guided to specific sites with antibodies conjugated to the payloads, but engineering antibodies with optimal capability in guiding drug delivery is not trivial. In addition to the antibodiesâ&#x20AC;&#x2122; specificity and affinity to the target antigens, the antibodiesâ&#x20AC;&#x2122; epitopes on the antigens are critical to the capability of the antibodies in guiding the payloads to the desired sites. Attaining a wide variety of antibody candidates targeting diverse epitopes on a target antigen has been difficult with conventional monoclonal antibody technologies. Moreover, each of the antibody candidates has to be evaluated at low throughput rate on the efficiency to deliver a medicinal payload. Consequently, engineering optimal antibodies for the antibody-guided drug delivery systems has been resource-intensive. Synthetic antibody repertoires can be advantageous over natural antibody repertoires in generating antibodies suitable for antibody-guided drug delivery systems. We used HER2 as a model antigen, for which antibodies selected in vitro from a phage-displayed synthetic antibody library bound to the model antigen on diverse epitopes with high affinity and specificity. To select the most effective antibody candidates to deliver a biological toxin to cells with over-expressed HER2 on the cell surfaces, we have established adaptor systems specifically coupled with the synthetic antibody repertoires; antibody candidates suitable for delivering the biological toxin to the HER2-positive cancer cells can be readily screened with cell-based assay in high throughput format. The results demonstrate that the synthetic antibody libraries and the coupled adaptor systems constitute an effective technological platform capable of engineering optimal antibodies for medicinal payload delivery.
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Session IV Speaker Tien-Lu CHENG Director of Graduate Institute of Medicine and Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan (tlcheng@kmu.edu.tw)
Job Titles
Distinguished Professor Vice Dean, College of Medicine Director of Graduate Institute of Medicine and Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
Education
1995/8-1999/7 Ph.D. Graduate Institute of Life Science, Academia Sinica and National Defense Medical Center, Taiwan 1991/8-1993/7 M.S. Institute of Microbiology and Immunology, National Defense Medical Center, Taiwan 1987/9-1991/6 B.S. Department of Medical Technology, Kaohsiung Medical College, Taiwan
Professional Experience
2013/03~2014/7, Chairman, Office for Operation of Industry-University Cooperation, Kaohsiung Medical University 2011/08~2013/2, Chairman, Center for Promotion of Industry-University Cooperation, Kaohsiung Medical University 2009/08~2011/07, Chairman, Department of Biomedical Science and Environmental Biology , Kaohsiung Medical University 2008/08~, Professor, Department of Biomedical Science and Environmental Biology , Kaohsiung Medical University
Honors 2013 annual excellent research project funding, Kaohsiung Medical University, 2013 Award of Excellent Paper, Kaohsiung Medical University, 2013 annual excellent technique transfer award, Kaohsiung Medical University, 2013 annual excellent patent award, Kaohsiung Medical University, the Second Prize of the 10th National Innovation Award- Student Research Contest by the Institute for Biotechnology and Medicine Industry, the third Prize of the 10th National Innovation Award- Student Research Contest by the Institute for Biotechnology and Medicine Industry, the Third Prize of 9th 戰國策 Entrepreneurial Competition. The award of the 11th National Innovation Award in the Academic Research Category by the Institute for
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Biotechnology and Medicine Industry. 2014 Ministry of Science and Technology, Outstanding Research Award Selective publications in past 5 years 1. Kao C.H., Wang J.Y., Chuang K.H., Chuang C.H., Cheng T.C., Hsieh Y.C., Tseng Y.L., Chen B.M., Roffler S.R. *, Cheng T.L.* One-step mixing with humanized antimPEG bispecific antibody enhances tumor accumulatio n andtherapeutic efficacy of mPEGylated nanoparticles. Biomaterials 35(37):9930-40, 2014. 2. Chuang K.H., Kao C.H., Roffler S.R., Lu S.J., Cheng T.C., Wang Y.M., Chuang C.H., Hsieh Y.C., Wang Y.T., Wang J.Y., Weng K.Y., Cheng T.L. Development of an Anti-Methoxy Poly(ethylene glycol) (α-mPEG) Cell-Based Capture System to Measure mPEG and mPEGylated Molecules. Macromolecules 47:6880-6888, 2014. 3. Su Y.C., Cheng T.C., Leu Y.L., Roffler S.R., Wang J.Y., Chuang C.H., Kao C.H., Chen K.C., Wang H.E., Cheng T.L.* PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy. Mol Cancer Ther. 13(12):2852-63, 2014. 4. Cheng T.C., Roffler S.R., Tzou S.C., Chuang K.H., Su Y.C., Chuang, C.H., Kao C.H., Chen C.S., Harn I.H., Liu K.Yi., Cheng T.L.*, Leu Y.L.* An Activity-Based Infrared Glucuronide Trapping Probe for Imaging b-Glucuronidase Expression in Deep Tissues. J. Am. Chem. Soc. 134:3103−3110, 2012. 5. Chuang C.H., Chuang K.H., Wang H.E., Roffler S.R., Tzou S.C., Cheng T.C., Kao C.H., Wu S.Y., Tseng W.L., Shiea J., Wang J.M.*, Cheng T.L.* In vivo PET Imaging of protease activity by hydrophilic-to-hydrophobic conversion of a protease substrate. Clin Cancer Res. 18(1):238-247, 2012. 6. Chuang C.H., Wang W.J., Li C.F., Ko C.Y., Chou Y.H., Chuu C.P., Cheng T.L.*, Wang J.M.*. The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer. Cell Death Dis. 5:e1220, 2014. 7. Chuang K.H., Wang H.E., Cheng T.C., Tzou S.C., Cheng C.M., Kao C.H., Chuang C.H., Tseng W.L., Hung W.C., Tai M.H., Chang T.K., Chen B.M., Roffler S.R., Cheng T.L.* Development of an Universal Anti-Polyethylene Glycol Reporter Gene for Noninvasive Imaging of PEGylated Probes. Journal of Nuclear Medicine 51:933-941, 2010. 8. Chuang K.H., Tzou S.C., Chang Y.C, Kao C.H., Liao K.W., Cheng T.C., Huang B.J., Wu C.J., Tseng W.L., Shiea J., Chu P.Y., Roffler S.R., Cheng T.L.* Measurement of Free Polyethylene Glycolby a Novel Cell-Based Anti-Polyethylene Glycol ELISA. Anal Chem. 82(6):2355-62, 2010. 9. Cheng T.L., Chuang K.H., Chen B.M., Roffler S.R. Analytical Measurement of PEGylated Molecules. Bioconjug Chem. 23:81-899, 2012. 10. Chuang K.H., Wang H.E., Chen F.M., Tzou S.C., Cheng C.M., Chang Y.C., Tseng W.L., Shiea J., Lin S.R., Wang J.Y., Chen B.M., Roffler S.R., Cheng T.L.* Endocytosis of PEGylated agents enhances cancer imaging and anti-cancer efficacy. Molecular cancer therapeutics 9(6):1903-1912, 2010.
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Proteases (MMP2/9) Enhance the Affinity and Therapeutic Efficacy of Targeted Antibody Tien-Lu Cheng Monoclonal antibody therapies apply to cancer, autoimmune diseases, inflammation and many infectious diseases, etc. Based on monoclonal antibodies market statistics show that in 2010 the global antibody labeled drugs total sales up to $ 43 billion, and the antibody will become most potential biotech drugs. Its therapeutic mechanism of many anti-cancer antibody drugs for the clinical use of high affinity antibody antigen, thereby blocking the growth of cancer cells metabolic pathways. Therefore, we can improve antibody affinity binding force, the monoclonal antibody drug treatment to achieve a breakthrough. Here, we provide the novel invention to enhance the affinity of antibody to antigens, which improves the therapeutic effects and lower the dosage used. Protease was used to cleavage the antibody for the enhancement its affinity, which is attributed to the conformational changes at antibody-antigen interacting site. The methods we used to enhance the antibody affinity included: 1. Antibody was treated with soluble protease. 2. Antibody was digested by using protease conjugated column. 3. Recombinant antibody was produced by genetic engineering. These methods not only enhance the binding affinity of tested antibodies, improve the therapeutic efficacy, but also lower the dosage use. Based on the highly conserve sequence among antibodies, we suggest that this invention is applicable to all of the antibodies (antibody drugs) in markets for the affinity enhancement. This protease activation technology could be applied to many clinical antibodies to enhance the affinity of antibodies to antigens via ELIAS, for example: Erbitux, Herceptin, Humira, Remicade, Prolia, Yervoy, Rituxan and Ilaris antibody. Based on a database included one thousand more sequence of antibody, we calculated the specific substrate of protease almost 90% on antibody, and has high conservation of sequence. We use MALDI-TOF MS to detect the substrate of protease cleavage on antibody. So we initially found that protease enhanced antibody affinity and binding force due to the cleavage on the antibody. Importantly, we also proved that the protease treatment can enhance the in vitro and in vivo anti-tumor efficacy of Erbitux. In addition, this novel invention has advanced global patent deployment and has applied for US provisional patent application and through the Defense by Ministry of Science and Technology, committee of the bridge plan in addition to promotes global Patent Cooperation Treaty (PCT).This innovative invention can apply in enhancing mAb affinity of nowadays therapeutic antibodies, and provide more effective treatment for patients. The novel method will not increase excessive pharmaceutical costs, and only one simple step for treatment. This invention is most significantly applied in enhancing mAb affinity of nowadays therapeutic antibodies, and is believed to possess immense commercial value.
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Session IV Speaker Hao CHEN Director, BioProcess Development, Merck Research Laboratories, Kenilworth, NJ, USA (hao.chen12@merck.com)
Dr. Hao Chen is a Director in BioProcess Development at Merck Research Laboratories (Kenilworth, NJ, USA). He currently manages the Upstream & Recovery Process Development group, responsible for process development and scale-up, tech transfer, and initial process characterization. His group supports both mammalian cell culture and microbial fermentation projects from preclinical to commercial stage, including regulatory filings. Prior to Merck, he worked on upstream process development and tech transfer for cell culture and fermentation in various companies including Becton Dickinson (BD) and Amylin Pharmaceuticals. Dr. Chen received his Ph.D. degree in Chemical Engineering from Purdue University. He also holds an MS in Biochemical Engineering and a BS in Fine Chemical Engineering, from Zhejiang University.
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Accelerated First-In-Human for Mabs Enabled by Innovative Bioprocess Strategy and Technologies Hao Chen Biologics including monoclonal antibodies is becoming the fastest growing area in pharmaceutical industry due to their efficacy and safety profiles for unmet medical needs such as oncology and autoimmune disease. Along with more competition, the new biologics development is under more pressure to accelerate First in Human (FIH) trials. Traditionally, it takes 2 years or even longer for CMC development from final cDNA to FIH. This timeline is reduced significantly with recent progress in innovative technologies, such as high throughput automation, single use technology, new medium, and perfusion based processes. Thoughtfully crafted strategy to integrate these technologies and different functional areas can further reduce the development timeline.
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Closing Remarks Fu-Tong LIU Distinguished Research Fellow and Director, Institute of Biomedical Sciences, Academia Sinica, Taiwan (ftliu@ibms.sinica.edu.tw)
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List of Sponsors
香港分子儀器公司 Molecular Devices (Hong Kong) Limited
進階生物科技股份有限公司 Level Biotechnology Inc.
PALL Corporation
GE Healthcare Life Sciences
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