Hot Technologies for Developing Next-Gen Biologics

Hot Technologies for Developing Next-Gen Biologics

Tuesday, May 20, 2014

The New York Academy of Sciences

Presented By

 

The biologics field remains a flourishing drug discovery and development area currently with over 200 products on the market, among which 35 monoclonal antibody therapeutics have been approved by the FDA and hundreds of candidates are in commercial development pipeline. Technology plays a pivotal role in developing next-generation biologics. For example, molecular engineering technologies have been successfully applied to optimize the drug attributes by modifying the molecular constitution of biologics. The recent US approval of the antibody-drug conjugate Kadcyla (also called T-DM1) for the treatment of breast cancer and Japan approval of glyco-engineered antibody mogamulizumab for T cell leukemia-lymphoma are two good examples. In addition, new technologies impact other aspects of biologics discovery and development such as manufacturing and delivery of drug substances. We will start the symposium with an overview of technological advancement in the biologics field, followed by an in-depth discussion on three key areas: 1) Innovative technologies applied to the discovery of new therapeutic antibodies; 2) New technologies applied to elucidating the in vivo mechanisms of therapeutic proteins; 3) New manufacturing and delivery technologies. Our goal is to review a number of cutting-edge technologies being developed both in the biotech/ pharmaceutical industry as well as in academic institutions and address the challenges and opportunities around the application of new technologies toward the development of the next generation biologics.

*Reception to follow.

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The Biochemical Pharmacology Discussion Group is proudly supported by



  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


May 20, 2014

8:30 AM

Registration and continental breakfast

9:00 AM

Welcome and Introductory Remarks
Jennifer Henry, PhD, New York Academy of Sciences
Robert Martone, St. Jude Children’s Research Hospital
Heather Shih PhD, Pfizer External Research Solutions

Session I. An Overview: How Technologies Impact The Discovery and Development of Biologics

9:15 AM

Novel Monoclonal Antibodies for the Prevention and Treatment of Bacterial Infections
Steven J. Projan, PhD, FAAM, MedImmune/AstraZeneca

Session II. Technology Innovation and The Development of Therapeutic Antibodies

10:00 AM

Exploiting Natural Human Antibody Response
Patrick C. Wilson, PhD, The University of Chicago

10:45 AM

Coffee Break

11:15 AM

Coupling Mammalian Cell Display with Somatic Hypermutation for Development of Therapeutic Antibodies
David King, PhD, AnaptysBio Inc.

12:00 PM

Synthetic Antibodies and Proteins
Sachdev Sidhu, PhD, University of Toronto

12:45 PM

Lunch Break

Session III. Emerging Technologies to Unravel In Vivo Mechanisms of Antibody Molecules

1:45 PM

Limits of Tumor Targeting in Immunotherapy: Theory & Experiment
K. Dane Wittrup, PhD, Massachusetts Institute of Technology

2:30 PM

Targeting FcRn for Therapy and Diagnostics
E. Sally Ward, PhD, UT Southwestern

3:15 PM

Coffee Break

Session IV. New Technologies for The Making and Delivering of Biologics

3:45 PM

Accelerating Biopharmaceutical Development: Drivers and Approaches
Tim Charlebois, PhD, Pfizer

4:15 PM

Re-engineering Recombinant Proteins as Blood–Brain Barrier-Penetrating Biopharmaceuticals
William M. Pardridge, MD, Brain Research Institute, UCLA

5:00 PM

Networking reception

6:00 PM

Close

Speakers

Organizers

Robert Martone

St. Jude Children’s Research Hospital

Robert Martone recently joined the Pathology Department at St. Jude Children's Research Hospital to conduct biomarker research and development with a focus on neuro-oncology. He was previously Neuroscience Therapeutic Area Lead for the Covance Biomarker Center of Excellence. He has extensive experience in the pharmaceutical industry leading neuroscience drug discovery and technology teams through all phases of discovery from target identification through clinical trials with expertise in both small molecule and protein therapeutics. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies, and CNS tumor biomarker development. Since the year 2000, he has helped organize 12 BPDG symposia.

Heather Shih, PhD

Pfizer Centers for Therapeutic Innovation

Heather received her BS in Chemistry from the University of Massachusetts at Lowell and PhD in Biochemistry from Tufts University School of Medicine. She received her postdoctoral trainings at Harvard Medical School and Genetics Institute/Wyeth. During her 12 years of drug discovery career at Pfizer, Heather was involved in developing and applying new technologies to biotherapeutic discovery, which included recombinant protein and phage display technologies. She also co-led a number of drug discovery projects in collaboration with scientists in Neuroscience and Cardiovascular Diseases departments. Currently as a biotherapeutic sourcing lead for Pfizer's External Research Solutions (ERS) group, Heather functions as an alliance manager in several major collaborations between Pfizer's research units and global contract research organizations (CROs). Throughout her career, Heather authored 20 peer-reviewed papers, two book chapters on therapeutic antibody discovery process, and was a co-inventor on three patents. She was instrumental in initiating a new Gordon Research Conference series on Antibody Biology and Engineering in 2010, and co-chaired the 2011 NYAS symposium "Are Neurodegenerative Diseases Spreading? Disease Propagation in Protein Misfolding" and the 2012 NYAS symposium "The New Age of Antibody Therapeutics".

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Timothy Charlebois, PhD

Pfizer

Timothy Charlebois, PhD is Vice President of Technology and Innovation Strategy for BioTherapeutics Pharmaceutical Sciences at Pfizer. In this role, he is responsible for developing, integrating and maintaining strategy for process, product and analytical technologies in support of the BioTherapeutics portfolio at Pfizer. He is also responsible for supporting biologics in-licensing and out-licensing activities. He has 20 years’ experience in mammalian and microbial process development, including expression vector design, cell line selection and screening, GMP cell banking and characterization, genetic stability and viral safety testing, cell culture and purification process design and validation, as well as biochemical and microbial assay development and quality control. Dr. Charlebois began his career in 1990 at Genetics Institute and has contributed to the development and registration of drug substance manufacturing for Recombinate®, BeneFIX®, Neumega®, ReFacto®, Infuse™ Bone Graft and Enbrel®.

David J. King

Chief Scientific Officer, AnaptysBio, Inc.

David King is currently Chief Scientific Officer for AnaptysBio, where he leads a group developing antibody therapeutics using a novel technology based on somatic hypermutation and mammalian cell display. Dr. King is an established expert in antibody engineering and antibody therapeutics and has been involved in the design and development of three FDA-approved antibody therapeutics and numerous other clinical stage antibodies. At Celltech in the UK, he was involved in the design and development of Mylotarg®, an antibody-drug conjugate for therapy of acute myeloid leukemia, and was the lead inventor of Cimzia®, a PEGylated antibody fragment for therapy of autoimmune diseases. Prior to AnaptysBio, Dr. King was at Medarex where he was involved in the design and selection of therapeutic antibodies, and he led the development of a new class of antibody-drug conjugates.

William M. Pardridge, MD

Brain Research Institute, UCLA

William M. Pardridge, MD, is Distinguished Professor Emeritus, University of California. Dr. Pardridge has worked on the blood-brain barrier (BBB) since 1970, and has published over 500 publications in the field. He is the inventor of the BBB molecular Trojan horse technology, the field of Trojan horse liposomes for non-invasive, non-viral gene therapy of the brain, and the field of BBB genomics. Dr. Pardridge is Founder and Chief Scientific Officer of ArmaGen Technologies, Inc. He founded ArmaGen in 2004 to develop the BBB Trojan horse technology. At ArmaGen, biologic drugs, which normally do not cross the BBB, are re-engineered to enable BBB penetration. This is possible by re-engineering the biologic drug as a BBB-penetrating IgG fusion protein. Dr. Pardridge and colleagues developed genetically engineered monoclonal antibodies (MAb) against endogenous human BBB receptors, such as the insulin receptor or transferrin receptor. Such receptor-specific MAbs cross the BBB via receptor-mediated transport. The development of such molecular Trojan horses enabled the re-engineering of multiple classes of biologics for penetration of the human BBB, including lysosomal enzyme drugs, therapeutic antibody drugs, neurotrophins, and decoy receptor drugs for brain. First In Human clinical trials are scheduled for 2014 with an IgG-lysosomal enzyme fusion protein.

Steve Projan, PhD, FAAM

iMED Head: Infectious Diseases & Vaccines

Dr. Steve Projan is the Head of Infectious Diseases & Vaccines Innovative Medicines unit (iMED) at MedImmune, leading a cross-functional team dedicated to the therapeutic area strategy, prioritization and advancement of the company's infectious disease and vaccine portfolio.

Dr. Projan joined MedImmune in 2010 as senior vice president of research and development and head of the Infectious Diseases & Vaccines iMED.

Prior to joining MedImmune, Dr. Projan served as vice president and global head of Infectious Diseases at Novartis. He previously spent 15 years at Wyeth in roles of increasing responsibility with his last post as vice president and head of Biological Technologies. During his time at Wyeth, Dr. Projan started the Biologics Discovery Group (covering all therapeutic areas) and initiated multiple collaborations and partnerships, most notably with Cambridge Antibody Technology (now a part of MedImmune/AZ). Prior to Dr. Projan's work in the industry, he spent 14 years at the Public Health Research Institute and presently has over 110 publications to his credit.

Dr. Projan received a bachelor of science from the Massachusetts Institute of Technology and masters of arts and philosophy in biological sciences and a doctorate in molecular genetics from Columbia University.

Sachdev Siddhu, PhD

University of Toronto

Sachdev Sidhu studied chemistry at Simon Fraser University and obtained his B.Sc. with honors in 1991. He then continued his graduate work at Simon Fraser University where he investigated enzyme function, and obtained his Ph.D. in 1996. Following a postdoctoral research fellowship with James Wells at Genentech, Dr. Sidhu joined the Protein Engineering department as a principal investigator in 1998. In 2008, Dr. Sidhu moved to the University of Toronto, where he is a professor in the Banting and Best Department of Medical Research and the Department of Molecular Genetics. He has published more than 100 scientific papers and is a co-inventor on more than 30 patents filed with the US patent office. Dr. Sidhu's research interests focus on the use of combinatorial biology methods to explore protein structure and function, and his group is currently developing synthetic antibody libraries and other scaffolds as sources of potential therapeutics.

E. Sally Ward, PhD

UT Southwestern

Sally Ward received the PhD degree from the Department of Biochemistry, Cambridge University in 1985. From 1985-1988 she was a Research Fellow at Gonville and Caius College whilst working at the Department of Biochemistry at Cambridge University. She held the Stanley Elmore Senior Research Fellowship from 1988-1990, whilst carrying out research in Sir Greg Winter’s laboratory at the MRC Laboratory of Molecular Biology in Cambridge.

In 1990 she joined the University of Texas Southwestern Medical Center as an Assistant Professor. She currently holds the Paul and Betty Meek-FINA Professorship in Molecular Immunology. Her current research interests include understanding FcRn function in mouse and man, using a combination of fluorescence imaging, protein engineering and in vivo studies to understand the factors that regulate the distribution and transport of antibodies. A second area of interest is to characterize the behavior, at the subcellular level, of molecular targets in cancer. Her work includes the development of antibody-based therapies in mouse models of multiple sclerosis, arthritis and cancer. She is a member of the Board of Distinguished Advisors in the Antibody Society and serves on the editorial boards of MAbs and Protein Engineering, Design and Selection.

Patrick C. Wilson, PhD

The University of Chicago

K. Dane Wittrup, PhD

Massachusetts Institute of Technology

Professor K. Dane Wittrup is the Joseph R. Mares Professor of Chemical Engineering and Biological Engineering at the Massachusetts Institute of Technology, a position he has held since 1999. From 1989–1999 he was Assistant Professor, Associate Professor, and then J. W. Westwater Professor of Chemical Engineering, Bioengineering, and Biophysics at the University of Illinois in Champaign/Urbana.

Professor Wittrup received a BS in Chemical Engineering Summa cum Laude in 1984 from the University of New Mexico, and a PhD in Chemical Engineering from the California Institute of Technology in 1988 under the thesis direction of Professor James Bailey. Following a year of postdoctoral research at Amgen (Thousand Oaks, CA), Dr. Wittrup joined the faculty at the University of Illinois.

Wittrup's research program is focused on protein engineering of biopharmaceutical proteins by directed evolution. Areas of interest include: pretargeted radioimmunotherapy; biological response modification of EGFR; and immunotherapy of cancer via engineered cytokines and vaccines.

Professor Wittrup has received the following awards and honors recognizing his scholarship: the A. McLaren White Award, for First Prize in the National American Institute of Chemical Engineers Student Design Contest (1984); the Presidential Young Investigator Award of the National Science Foundation (1990–1995); the Allan P. Colburn Award of the American Institute of Chemical Engineers, for excellence in publications for an individual under the age of 35 (1998); the University of New Mexico College of Engineering Distinguished Young Alumnus Award (2000); the Dow Chemical Company Teaching Award (1989); the UIUC School of Chemical Sciences Award for Excellence in Teaching (1993); the UIUC College of Engineering Anderson Award for Undergraduate Advising (1991, 1994); the J.R. Mares Professorship (1999); and induction as a Fellow of the American Institute of Medical and Biological Engineers (1999).

Professor Wittrup has mentored the following PhD students and postdoctoral fellows who are now faculty members: Jennifer Cochran (Bioengineering, Stanford University); Anne Robinson (Chemical Engineering, University of Delaware); Eric Boder (Chemical Engineering, University of Pennsylvania); Eric Shusta (Chemical Engineering, University of Wisconsin, Madison); Jennifer van Antwerp (Chemical Engineering, Calvin College); Balaji Rao (Chemical Engineering, North Carolina State University); Yong-Sung Kim (Biotechnology, Ajou University, Korea); Mark Olsen (Biochemistry, Texas A&M, Amarillo).

Sponsors

Promotional Partners

The Antibody Society

Genetic Engineering & Biotechnology News

International Chemical Biology Society

Landes Bioscience

Nature

NYU Langone Medical Center


The Biochemical Pharmacology Discussion Group is proudly supported by



  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Accelerating Biopharmaceutical Development: Drivers and Approaches
Tim Charlebois, PhD, Pfizer Inc.

Biopharmaceutical development and manufacturing has historically been an expensive, complex and specialized field. However, as experience with the technology has grown and improvements have reduced the need for massive capital investments, much broader access is observed today. Is the era of biopharma innovation drawing to a close?
 
An evaluation of R&D and manufacturing drivers indicate that there continues to be significant opportunity for impactful contributions in the field. To accelerate and power the next wave of biopharmaceuticals, the pressure to improve speed and cost without compromising quality is greater than ever. And the importance of accommodating the needs of research, development and manufacturing without compromise at any stage is becoming increasingly evident. Examples of how industry is responding to these demands through scientific, technological and business process innovation will be provided.
 

Coupling Mammalian Cell Display with Somatic Hypermutation for Development of Therapeutic Antibodies
David J. King, PhD, AnaptysBio Inc.

By reproducing key features of the immune system in a controllable, in vitro system, fully-human antibodies can be selected with ideal properties for therapeutic applications. The natural mechanism of antibody maturation, known as somatic hypermutation (SHM), is coupled with a mammalian cell based display system to enable antibodies to be generated and directly selected for their functional properties as well as excellent biophysical properties for development. This is enabled through the simultaneous cell-surface display and secretion of the antibody via alternative splicing of the heavy chain mRNA. The use of high-throughput sequencing methodologies during selection and maturation allows insight into maturation pathways and can be used to rapidly identify optimized antibodies. Antibodies have been developed to novel targets for inflammatory and autoimmune diseases, as well as for numerous oncology indications, including the targeting of immune checkpoints.
 

Synthetic Antibodies and Proteins
Sachdev S. Sidhu, PhD, University of Toronto

Affinity reagents that modulate proteins are crucial for both basic research and therapeutic development. To date, antibodies derived by animal immunization have been the dominant source of affinity reagents, but recently, research in protein engineering has given rise to new technologies that promise to transform the field. "Synthetic antibodies" use man-made antigen-binding sites and circumvent the need for natural repertoires. We have developed simple synthetic antibodies that use a single human framework and limited diversity in restricted regions of the antigen-binding site. Moreover, the use of synthetically designed libraries enables the use of alternative scaffolds for applications beyond the reach of antibodies. We have designed libraries of ubiquitin variants that can be used to inhibit or activate virtually any of the hundreds of ligases and deubiquitinating enzymes in the ubiquitin system. These ubiquitin variants are adapted for intracellular function, and thus, they can be introduced into cells to probe function in a living cellular context. In addition, we have developed small, optimized scaffolds that function like antibodies but are amenable to chemical synthesis, thus enabling the incorporation of non-natural amino acids. The power of the technology has been demonstrated by the development of proteins composed entirely of D-amino acids. In sum, these advances in the design of synthetic binding proteins extend the applications for affinity reagents beyond the range of natural antibodies and this should have a transformative effect on many areas of biological research.
 

Limits of Tumor Targeting in Immunotherapy: Theory & Experiment
K. Dane Wittrup, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

Targeted agents such as immunocytokines are often developed with the intention of achieving improved therapeutic index via a compartment-specific targeting moiety. Simple PK/PD theoretical analyses of intravenously administered agents suggests that strong limits exist for this approach, and we have experimentally validated key predictions of this analysis. A critical control experiment for any targeted cytokine therapy is an untargeted extended-PK version of the cytokine, which we have found to possess identical biodistribution and efficacy in at least one case.
 

Re-Engineering Recombinant Proteins as Blood-Brain Barrier-Penetrating Biopharmaceuticals
William M. Pardridge, MD, ArmaGen Technologies, Inc.

Successful development of recombinant proteins as drugs for the brain has not been possible, because these large molecule drugs do not cross the blood-brain barrier (BBB). Bypass of the BBB with drug injection into the spinal fluid is not effective, owing to the rapid efflux of spinal fluid from brain to blood. Protein therapeutics can be re-engineered for BBB penetration as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) against an endogenous BBB receptor/transporter such as the insulin receptor or the transferrin receptor. The receptor-specific MAb binds an exofacial epitope on the BBB receptor, which triggers receptor-mediated transport across the BBB. The MAb domain acts as a molecular Trojan horse to ferry into brain the fused protein drug. The most active Trojan horse to date is a genetically engineered MAb against the human insulin receptor (HIR).
 
Bi-functional fusion proteins have been engineered with the HIRMAb and different classes of therapeutics, including lysosomal enzymes, decoy receptors, neurotrophins, and therapeutic antibodies. The HIRMAb cross reacts with the insulin receptor of Old World primates, such as the rhesus monkey. The brain uptake of the HIRMAb fusion proteins in the primate is 1–3% of injected dose, which is a level of brain uptake comparable to the brain uptake of lipid soluble small molecules. Excellent safety profiles in primates have been demonstrated with multiple 6-month chronic dosing studies. BBB-penetrating IgG fusion proteins have shown the desired therapeutic effect in mouse models of lysosomal storage disease, stroke, Parkinson's disease, and Alzheimer's disease.
 

Novel Monoclonal Antibodies for the Prevention and Treatment of Bacterial Infections
Steven J. Projan, MedImmune/AstraZeneca

The second decade of the twenty-first century marks a perfect storm of patent expirations, contracting western economies, and increasing demands from "payers" that pharmaceuticals demonstrate cost effectiveness of their drugs. The result is the shrinking of "big pharma" right before our eyes and nowhere has the impact been felt more than in infectious disease research at large pharmaceutical companies. All the while bacterial resistance to antibiotics is increasing even as the number of new drugs being developed to treat bacterial infections is at its lowest point since the drawn of the antibiotic era. This surfeit of new agents implies that the "traditional" approaches to drug discovery and development have run their course and novel (entrepreneurial, opportunistic) approaches for the treatment and prevention of microbial infections (and forestalling the emergence of resistance) are required. Against that background we are have seen an increasingly convoluted regulatory regime with indications being parsed finer and finer yet with larger numbers of patients required to reach arbitrary (but often clinically meaningless) statistical endpoints. To date there has been some modest biologics drug discovery efforts to discover novel antibacterial agents for the prevention and/or treatment of Staphylococcal, Pseudomonal and Clostridium difficile infections but these efforts now appear to be picking up speed and are progressing in the clinic. Is there hope?
 

Targeting FcRn for therapy and diagnostics
E. Sally Ward, UT Southwestern Medical Center

The MHC Class I-related receptor, FcRn, plays a pivotal role in regulating the transport and distribution of antibodies of the immunoglobulin G (IgG) class in vivo. FcRn-IgG interactions are characterized by marked pH dependence, with relatively tight binding at pH 6.0 that becomes progressively weaker as near neutral pH is approached. This pH dependence allows IgG molecules to interact with FcRn in acidic early endosomes following uptake into cells, followed by recycling/transcytosis and exocytic release at the cell surface. The engineering of IgGs with higher affinity for FcRn is of considerable interest since it can be used to produce antibodies with longer in vivo half-lives, but only if the pH dependence of the interaction is retained. Conversely, engineered IgGs with increased affinity for FcRn at both acidic and near neutral pH act as potent inhibitors of FcRn. Such engineered antibodies ('Abdegs', for antibodies that enhance IgG degradation) can lower the levels of endogenous IgG. We have analyzed the therapeutic effects of Abdegs in mouse models of autoimmunity. In addition, we have recently used Abdegs as clearing agents to reduce background and improve contrast during PET. From the point of view of using antibodies as therapeutics and from a cell biological perspective, it is important to understand how FcRn performs its function as a salvage receptor at the subcellular level. We are therefore using a combination of fluorescence imaging approaches, including localized photoactivation and multifocal plane microscopy, to analyze how FcRn and its IgG cargo traffick within live cells.
 

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