The Impact of the New Regulatory Guidance Landscape on the Validation of the Manufacturing Process and the Characterization of Starting Materials, Drug Substance and Drug Product
Steffen Gross, Ph.D., Head, Monoclonal and Polyclonal Antibodies, Paul-Ehrlich-Institut - Biography
The regulatory guidance landscape regarding biological products changes rapidly. Documents overseeing process validation is currently facing major overhauls. New guidelines are published defining the requirements for starting materials and excipients. This might have a deep impact not only on the process development of traditional monoclonal antibody type products but also on new antibody formats such as conjugates as well as on new developed formulations.
Current Progress with Armed Antibody Products
Dario Neri, Ph.D., Professor, Chemistry and Applied Biosciences, ETH Zurich - Biography
There is an emerging trend in Pharmaceutical Biotechnology to "arm" antibodies, capable of selective localization at the site of disease, with suitable therapeutic payloads (e.g., drugs, cytokines, radionuclides, a second antibody moiety, hence producing a bispecific product). This strategy aims at concentrating therapeutic agents in diseased part of the body, while sparing normal tissues. In this lecture, I will present a comparative evaluation of different classes of armed antibody products, developed in my laboratory in collaboration with Philogen. In particular, I will present preclinical and clinical data of armed antibodies in the field of cancer, of chronic inflammation and of endometriosis.
Playing Catch-Up with Escherichia coli: Using Yeast to Increase Success Rates in Recombinant Protein Production Experiments
Roslyn M. Bill, Ph.D., Professor, School of Life and Health Sciences, Aston University Birmingham - Biography
This presentation highlights the benefits of using yeast for more challenging targets such as membrane proteins. We’ve seen advances in understanding how a yeast cell responds to the stress of producing a recombinant protein and how this information can be used to identify improved host strains in order to increase functional yields. I argue that S. cerevisiae and P. pastoris should be considered at an early stage in any serious strategy to produce proteins.
Next-Generation Cancer Treatment using Multi-Specific Darpins
H. Kaspar Binz, Ph.D., V.P. & Co-founder, Molecular Partners AG - Biography
Precision oncology is an emerging treatment paradigm by which well-chosen targeted therapeutics will inhibit the specific tumor drivers of each patient. Such an approach will require the combination of several targeted therapeutics, which may be hampered by overlapping off-target toxicities and economic reasons, or ideally the availability of multi-specific therapeutics - a natural setting for DARPins given their high specificity and modular architecture. We have generated multi-specific DARPin drug candidates against various tumor drivers, which compare favorably in preclinical models to available standards of care. Insights on the rationale for target choice, drug format, mechanism of action and differentiation will be provided.
RG7787 - A Cytolytic Fusion Protein Based on a De-Immunised Variant of Pseudomonas Exotoxin (PE)
Klaus Bosslet, Ph.D., Head, Discovery Oncology, Roche Pharmaceuticals, Penzberg - Biography
Development of immunotoxins into actual drugs has been hampered by their immunogenicity and off-target toxicity, particularly vascular leak syndrome. Together with Ira Pastan’s lab at NCI we have developed a new cytolytic fusion protein format that is de-immunized and has much reduced off-target toxicity. Cell viability assays show that RG7787 has similar cytotoxic potency in a variety of cell lines as well as similarly strong efficacy as the immunogenic Mesothelin targeted PE38 from NCI (SS1P) even in slow growing tumor xenograft systems.
Safety Challenges and Risk Mitigation Strategies to Develop Immune Activating Biologics
Rakesh Dixit, Ph.D., Vice President, Research and Development, Safety Assessment, MedImmune LLC - Biography
This presentation will cover: how immunotherapy may result in autoimmune and off-target toxicities to self versus tumours; combining immunotherapy with other agents; how to maximize the efficacy and balance safety vs. efficacy; measures to streamline the combined approach and reducing toxicity to self; and strategies to risk mitigate safety concerns with the immune activating biologics and their combination.
Protein Inactivation in vivo in Intrabody Expressing Mice
Stefan Dübel, Ph.D., Director, Biotechnology, Technische Universität Braunschweig - Biography
We demonstrate for the first time that endoplasmatic reticulum retained antibodies ("intrabodies") can induce a knock down phenotype in transgenic mice. The phenotype found in adult mice expressing VCAM1 intrabodies included aberrant distribution of immature B-cells in blood and bone marrow. The availability of our technology and the rapidly growing number of available antibody genes will spark a new level for the functional study of membrane and plasma proteins in vivo.
High-Throughput Construct Screening Approaches and Rational Strategies for Kinase Structural Platform Establishment: Case Studies of Difficult Kinases
Jacques Dumas, Ph.D., Head, Protein Production, Vitry Biologics SCP, Vitry Research Center, sanofi - Biography
sanofi has a long experience in kinases for medicinal chemistry projects, with more than 90% success in crystallization. However several kinases are still very difficult to obtain. Recently we started a collaboration with EMBL Grenoble which established a platform called ESPRIT (Expression of Soluble Proteins by Random Incremental Truncation) allowing the selection of tracks of soluble constructs in E. coli. We further pursue within sanofi our efforts in expression and purification optimizations.
Cell and Process Engineering Strategies to Cure Cellular Aggregation of a Difficult-to-Express Fusion Protein
David C. James, Ph.D., Professor, Chemical & Biological Engineering, University of Sheffield - Biography
Based on kinetic modeling of the cellular synthetic process, we compared different strategies (cell engineering, modulation of culture environment) to alleviate cellular aggregation and the associated poor expression of a recombinant Fc-fusion protein by CHO cells. Our analysis serves as a paradigm for multivariate optimization of DTE protein production.
Characterizing and Release Testing of Protein Aggregates in Biologics
Ewa Marszal, Ph.D., CMC Reviewer, Division of Hematology, Center for Biologics Evaluation and Research, U.S. Food & Drug Administration - Biography
Protein aggregates in biologics present a quality issue and raise safety concerns. Thus, their content should be minimized and controlled. This presentation will cover recent guidelines for particulate matter control and the advancements in particulate matter detection and metrology.
New Applications of Phage Display
John McCafferty, Ph.D., Co-Founder, Director and CEO, IONTAS Ltd. - Biography
Construction of libraries of binders displayed on the surface of mammalian cells will allow the screening of millions of clones by flow sorting while providing information on both the level of expression and the extent of binding within individual clones. The main limitation to achieving this has been the inability to construct large libraries containing 1-2 antibody genes/cell. We have solved this problem by directing the integration of antibody genes into a single genomic locus through the use of site-specific nucleases. The presentation will describe construction of libraries of millions of clones and selection of binders including antibodies formatted as IgGs.
Development of High-Throughput Selection and Screening Methods
Jonas V. Schaefer, Ph.D., Head of High-Throughput Laboratory, Department of Biochemistry, University of Zurich - Biography
With the help of technology developments, a robust pipeline could be established that already generated valuable DARP in binders (Designed Ankyrin Repeat Proteins, an alternative scaffold), not just covering a variety of different targets but also meeting the high quality criteria important for most scientific projects: monomeric binders that specifically recognize different, non-overlapping epitopes at their targets with high affinities and which can be expressed at high levels in bacterial systems.
Philosophy and Principal Dogma behind Modern Discovery & Development of Biologics
Ralf Schumacher, Ph.D., Site Head, Large Molecule Research, Roche Penzberg & pRED - Biography
This talk will examine challenges facing the industry today, e.g. recognition of redundancy of pathways; the understanding of the signalling and interaction between cells and organs, e.g. what is responsible for suppression of immune response to a cancer and how it can be overcome; the importance of linking together deep biological understanding, disease understanding, and MOA for targeted therapies, companion diagnostics for stratification of patients and clinical study design. Examples will be provided.
The Mechanism of Complement Activation by IgG Antibodies
Janine Schuurman, Ph.D., VP, Research, Genmab - Biography
Complement activation by antibodies is an important mechanism in immune defense and immunotherapy. Using x-ray crystallography, mutagenesis studies and cryo-EM tomography, we revealed that IgG antibodies form hexamers on the cell surface following antigen binding. Enhancing hexamerisation on the cell surface by using the HexaBody platform potentiated the intrinsic killing capability of antibodies in in vitro, in vivo and ex vivo models.
CHO Cells and Processes for Antibody Manufacturing: Convoluted History and Insights
Florian Wurm, Ph.D., Dr. rer. nat., Professor of Biotechnology, Swiss Federal Institute of Technology Lausanne (EPFL) - Biography
“Superstar” CHO are THE production system for therapeutic rec-proteins. Sequencing of one CHO cell genome (2013) has extended our knowledge established in the 1960s and 70s. What made CHO cells so popular? The talk will cover the “prehistory” of CHOs as well as key insights and key opportunities that have emerged during the 30 + year biotech history of these cells.