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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
2
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
Taiwan Antibody Association
National Research Program for Biopharmaceuticals
Biochemical Technology Education Foundation
Academia Sinica
Institute of Biological Chemistry, Academia Sinica
Institute of Biomedical Sciences, Academia Sinica
Steering Committee
Organizers
Co-Organizers
3
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
Table of Contents
4
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
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
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
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
Opening Remarks
Keynote
Session I: Perspectives on Current Trends and Future Opportunities
5
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)
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
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
Session II: Emerging Targets
Session III: Translation and Development of Antibody Therapeutics
6
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
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
Session IV: Technologies for Antibody Discovery and Engineering
7
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)
Closing Remarks
8
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).
9
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).
10
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.
11
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.
12
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.
13
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)
Session I: Perspectives on Current Trends and Future Opportunities
Lectures
14
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 Professor and Director, Institute of Toxicology College of Medicine
National Taiwan University
2005 - 2006 Professor, Institute of Toxicology College of Medicine National Taiwan
University
2006 - 2007 M.D., Department of Molecular Oncology MD Anderson Cancer Center
2007 - 2009 Distinguished Professor Associated Dean, Director of R&D, Institute of
Toxicology College of Medicine National Taiwan University
2009 - 2012 Director General, Department of Life Sciences, National Science Council
Republic of China
2010 - 2014 President, The Toxicology Society of Taiwan
2012 - Present Co-hiring Professor, Graduate Institute of Toxicology, National Taiwan
University College of Medicine
2012 - Present Professor, Institute of Biochemical Science, National Taiwan University
College of Life Science
2012 - Present 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.
15
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.
16
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.
17
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 Senior Director, Drug Metabolism and Pharmacokinetics, Biogen Idec, Inc.
(now Biogen Inc.), Cambridge, MA, USA
2005/11-2007/07 Director (German Rank), Drug Metabolism and Pharmacokinetic, Drug
Discovery Support, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield,
CT, USA
2002/02-2005/11 Senior Director, Drug Metabolism and Pharmacokinetics, Millennium
Pharmaceuticals (now Takeda Pharmaceuticals), Cambridge, MA,
USA
1996/09-2002/02 Director, Drug Metabolism and Pharmacokinetics, DuPont Merck & then
DuPont Pharmaceuticals (now Bristol-Myers Squibb Co.), Wilmington, DE,
USA
1989/03-1996/09 Principal Investigator, Drug Metabolism and Pharmacokinetics, Glaxo Inc.,
then GlaxoWellcome Inc. (now GlaxoSmithKline, GSK), Research Triangle
Park, NC, USA
1986/02- 1989/03 Post-Doc Research Fellow, Chemical Toxicology, Massachusetts Institute of
Technology, Cambridge, MA, USA
1981/08-1986/02 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.
18
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 Wang
2
1Development Center for Biotechnology, Xizhi District, New Taipei City, 22180, Taiwan, R.O.C. 2Department of Drug Metabolism and Pharmacokinetics, Biogen Inc., Cambridge, MA 02142,
USA
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.
19
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 II: Emerging Targets
20
Session II Moderator
Chia-Lin Jeff WANG President, BioGate Medical Sciences Co, Taiwan
(cljwang@aol.com)
Education
1978-1979 Research Associate, Department of Chemistry, Harvard University (Advisor:
Professor Yoshito Kishi)
1977 Ph.D., Department of Chemistry, University of Pittsburgh, Pittsburgh, PA
(Thesis Advisor: Professor Paul A. Grieco)
1971 B.S., Department of Chemistry, National Taiwan University, Taipei, Taiwan
R.O.C.
Professional Experience
2/2015 Present: President, BioGate Medical Sciences Co.
8/2014 -2/2015 Senior VP, CHO Pharma
2008-8/2014 President, Development Center for Biotechnology
2007-2008 Chief Scientific Officer, Microbio Co.
2006-2007 Vice President, Development Center for Biotechnology
2000-2005 Director, U.S. East Coast Office Development Center for Biotechnology
1997-2000 Science Advisor (Biotechnology &Pharmaceutical) Department of Industrial
Technology, Ministry of Economic Affairs (Taiwan)
1992-1996 Director, Natural Product & Medicinal Chemistry Development Center for
Biotechnology (Taiwan)
1990-1992 Principal Research Scientist, The DuPont Merck Pharmaceutical Co. (US)
1985-1990 Senior Research Chemist, Du Pont Medical Products Department (US)
1979-1985 Research Chemist, Du Pont Central Research and Development Department
(US)
Accomplishments
1. Over 50 publications and 26 patents on the synthesis of medicinally interesting compounds
2. Help Taiwan Ministry of Economic Affairs (MOEA) formulate the R&D strategies for
promotion of the Taiwan biotech and pharmaceutical industries
3. Promote international cooperation for the development of Taiwan biotech and
pharmaceutical industries
4. Help form the “Five-year Herbal Medicine Industrial R&D Plans” for Taiwan
5. Transform DCB into a new drug translational research institute working closely with
academic institutes and industries.
21
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.
22
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.
23
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.
24
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.
25
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.
26
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. Milutinovic S., et al. Dual agonist SurrobodyTM simultaneously activates death receptors
DR4 and DR5 to induce cancer cell death. Mol Cancer Ther. Submitted.
2. Ekiert D.C., et al Cross-neutralization of influenza A viruses mediated by a single antibody
loop. Nature 489:526-532, 2012.
3. 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.
4. Xu L., et al, Surrobodies with functional tails. J Mol Biol 397(1):352–360, 2010.
5. Xu L., et al, Combinatorial surrobody libraries. Proc Natl Acad Sci USA 105(31):10756–
10761, 2008.
6. 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.
7. Kashyap A.K, et al. Biochemical and genetic characterization of Yra1p function in budding
yeast. Yeast 22:43-56, 2005.
8. Wrighton N.C., et al, Increased potency of an erythropoietin peptide mimetic through
covalent dimerization. Nat Biotech 15:1261-1265, 1997.
27
9. Wrighton N.C., et al Small peptides as potent mimetics of the protein hormone
erythropoietin. Science 273(5274):458-463, 1996.
28
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.
29
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
Session III: Translation and Development of Antibody Therapeutics
30
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.
31
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. Invited speaker, Jiangsu provincial Rheumatology conference, Yangzhou, Jiangsu, China,
2013.
2. Invited seminar, Department of Rheumatology, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences, Beijing, China, 2010.
3. Invited Speaker, the 13th International Congress of Antiphospholipid Antibodies (APLA
2010), Galveston, Texas, United States, 2010.
4. Invited Speaker, The 8th International Congress on SLE, Shanghai, China, 2007.
5. 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.
6. Invited Speaker, the 9th Asian Pacific League Against Rheumatism, Beijing, China, 2000.
7. Plenary Lecturer, the Major Histocompatibility Complex in Medicine, Australasian and
South East Asian Tissue Typing Association (ASEATTA), Adelaide, Australasia, 1994.
32
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. 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.
2. 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-2GP1 antibodies from two patients
with antiphospholipid syndrome reveals three species of antibodies. Brit. J. Haematology
105:102-109, 1999.
3. 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.
4. 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.
5. 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.
6. 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.
33
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 patient’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.
34
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 BMT Fellowship, National Heart, Lung & Blood Institute, National
Institutes of Health (NIH), Bethesda, MD, USA
7/1993-7/1996 Clinical Associate and Post-doctoral Fellow, National Heart, Lung and
Blood Institute and National Cancer Institute, Bethesda, MD, USA
6/1990-5/1993 Internal Medicine Residency, University of California, Los Angeles, CA,
USA
3/1990 M.D., Univ. of Minnesota, Minneapolis-St. Paul, MN, USA
3/1986 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 Scientific Director, Oncology Research for Biologics and Immunotherapy
Translation (ORBIT), UT MD Anderson Cancer Center, Houston, TX
2011-present 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
2011-present Program Co-leader, Cancer Center Support Grant (CCSG), Basic Science
Programs, Immunology, UT MD Anderson Cancer Center, Houston, TX
2006-present Virginia H. Cockrell Distinguished Professorship in Immunology, UT MD
Anderson Cancer Center, Houston, TX
2005-present Professor (tenured), Department of Stem Cell Transplantation and Cellular
Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center,
35
Houston, TX
2003-present Co-Director, Center for Cancer Immunology Research (CCIR), Department of
Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer
Center, Houston, TX
2001-2005 Associate Professor (tenured), Department of Stem Cell Transplantation and
Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer
Center, Houston, TX
1998-present 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
1998-present Faculty (tenure track), UT Graduate School for Biomedical Sciences, Program in
Immunology, Houston, TX
1997-2001 Assistant Professor (tenure track), Department of Stem Cell Transplantation and
Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer
Center, Houston, TX
1996-1997 Attending Physician, Hematology Branch, NHLBI, NIH, Bethesda, MD
Other Experience and Professional Memberships
2012-present Scientific Advisory Board, Texas Cancer Vaccine, Dallas
2012-present Scientific Advisory Board, Baylor Institute for Immunology Research (BIIR),
Houston, TX
2010-present Scientific Advisory Board, Gabrielle's Angel Foundation for Cancer Research,
New York, NY
2004-2009 Founder and Director, Scientific Advisory Board, The Vaccine Company,
Houston, TX
2003-2014 International Scientific Advisory Committee, Jose Carreras International
Leukaemia Foundation, Barcelona, Spain
2002-2007 Medical Advisory Board, Aplastic Anemia and Myelodysplasia Foundation, Inc.
(AA&MDSIF), Annapolis, MD
Honors
2015 Robert M. Chamberlain Distinguished Mentor Award Nominee, MD Anderson
Cancer Center
2015 President's Recognition for Faculty Excellence, MD Anderson Cancer Center
2014 Fellow, American Association for the Advancement of Science
2013 Robert M. Chamberlain Distinguished Mentor Award Nominee, MD Anderson
Cancer Center
2009 American Society of Clinical Investigators
2007 Division of Cancer Medicine Mentor Award, Fellowship Program, MD Anderson
Cancer Center
2003 Julie and Ben Rogers Award for Excellence, MD Anderson Cancer Center
2001 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
36
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.
37
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 αß-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.
38
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 “Key to Life” 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.
39
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.
40
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 Children’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.
41
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
Session IV: Technologies for Antibody Discovery and Engineering
42
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.
43
Session IV Speaker
An-Suei YANG Research Fellow and Deputy Director, Genomics Research Center,
Academia Sinica, Taiwan
(yangas@gate.sinica.edu.tw)
Dr. Yang’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. Yang’s group can be found in https://scholar.google.com.tw/citations?user=YBoSfnAAAAAJ&hl=en
44
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 antibodies’ specificity and affinity to the
target antigens, the antibodies’ 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.
45
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
46
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.
47
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.
48
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.
49
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.
50
Closing Remarks
Fu-Tong LIU Distinguished Research Fellow and Director, Institute of Biomedical
Sciences, Academia Sinica, Taiwan
(ftliu@ibms.sinica.edu.tw)
51
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
List of Sponsors
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