Engineering Antibodies May 2-3
Therapeutic and diagnostic antibodies continue to make inroads in biomedicine, but the successful application of these products requires smart discovery and development. This conference will explore the latest methods to overcome challenges and open new opportunities for making these valuable proteins viable.
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WEDNESDAY, MAY 2
7:00 am Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
» 8:40 FEATURED PRESENTATION
Whole-Molecule Antibody Engineering: Generation of a High-Affinity Anti-IL-6 Antibody with Extended Pharmacokinetics
David G. Lowe, Ph.D., Fellow, Research and Development, MedImmune Ltd.
We describe here the generation of MEDI5117, a human anti-interleukin (IL)-6 antibody generated by variable domain engineering, to achieve subpicomolar affinity for IL-6, combined with Fc (fragment crystallizable) engineering to enhance pharmacokinetic half-life. MEDI5117 was shown to be highly potent in disease-relevant cellular assays. The half-life of MEDI5117 was extended by approximately 3-fold, and clearance was reduced by approximately 4-fold when compared to CAT6001. MEDI5117 therefore represents a potential ‘next-generation’ antibody.
9:10 Homogeneous Time Resolved Fluorescence - Multiple Applications in the Generation of Protein Therapeutics
Paula Harrison, Ph.D., Associate Director, Research, MedImmune (biography)
Often with protein therapeutics, use of unpurified sample material is beneficial to the cost and throughput of early campaigns but this brings associated challenges when designing assay cascades. The application of Homogeneous Time Resolved Fluorescence technology to enable 384 well throughput at multiple stages of an antibody drug discovery project will be presented. This includes biochemical and cell based assays to measure antibody function, specificity, mechanism of action and epitope.
9:40 Engineered VH and CH2 Antibody Domains as Candidate Therapeutics
Dimiter S. Dimitrov, Ph.D., Protein Interactions Group, Center for Cancer Research Nanobiology Program, National Institutes of Health (biography)
Isolated single engineered antibody domains are small and can access targets and epitopes that are not accessible by larger molecules. We have constructed libraries based on soluble VH and stabilized CH2 from which binders against HIV and cancer-related proteins were identified and characterized with potential use as therapeutics. An update on further engineering to confer additional functions will be discussed.
10:10 Coffee Break in the Exhibit Hall with Poster Viewing
11:10 In silico Antibody Design and Affinity Maturation
Samuel Flores, Ph.D., Assistant Professor, Cell and Molecular Biology, Uppsala University (biography)
MMB addresses issues by allowing full flexibility in tightly restricted regions of the antibody, thus obtaining accurate sampling at low cost. The package also permits modeling of large scale domain motions, allowing the structure and dynamics of interaction to be probed well beyond the binding interface. The results demonstrate an effective and practical paradigm for biological therapy development.
11:40 Developing the Next Generation Designer Cell Lines as a Customized Approach for Optimized Therapeutic Protein Production
Armelle Gaussin, Ph.D., Chief Technology Officer, Selexis SA
The Chinese Hamster Ovary cell line is the predominant host for the production of therapeutic proteins. However, its capacity to provide high levels of certain classes of products such as fusion proteins remains limited. In order to overcome the specific expression bottlenecks associated with these difficult-to-express proteins, we have developed new designer CHO cell lines.
These next generation cell lines have been metabolically engineered to over-express key components of the cell secretion network.
12:10 Protein Aggregation and Stability: A Case Study for the use of Computational Algorithms for Biotherapeutics Design
Francisco G. Hernandez-Guzman, Ph.D., Sr. Product Manager, Life Sciences, Accelrys, Inc.Over the past decade we have seen a significant rebalancing in the pharmaceutical drug portfolio towards the development of new biologics based therapies. Though small molecule development remains a critical area of interest, biotherapeutics based therapies continue to gain acceptance and importance as more biologics drugs gain FDA approval. Given that the development of biotherapeutics has been classically driven by in-vitro and in-vivo studies, there is a great opportunity for computational algorithms to support this effort. Undeniably, the use of in-silico tools has the potential for reducing the experimental burden by providing speed and insight into the drug development process. In this presentation, we will show case well validated computational algorithms used in the areas of Protein Aggregation and Stability that are being used in the industry for hypothesis generation and validation, as well as workflow improvements.
12:25 pm Luncheon Presentation (Sponsorship Opportunities Available) or Lunch on Your Own
1:30 Chairperson’s Remarks
1:35 NHLBI-AbDesigner: An Online Tool for Design of Peptide-Directed Antibodies
Mark Knepper, Ph.D., Cell Biology and Physiology, National Institutes of Health (biography)
Here we describe a new, web-based software tool called NHLBI-AbDesigner that allows the user to visualize the information needed to choose optimal peptide sequences for peptide-directed antibody production (http://helixweb.nih.gov/AbDesigner/). Several examples of the use of AbDesigner for the display of such trade-offs are presented, including production of a new antibody to Slc9a3.
2:05 A Screening Tool for Therapeutic Monoclonal Antibodies: Identifying the Most Stable Protein and its Best Formulation based on Thioflavin T Binding
Veysel Kayser, Ph.D., Research Engineer, Chemical Engineering, Massachusetts Institute of Technology (biography)
We present an alternative method for initial screening of aggregation propensity of proteins, using monoclonal antibodies (mAb) as an example, with Thioflavin T binding. The major advantage of ThT binding is the short duration of testing compared with SEC measurements that can take 6 months or more even under accelerated conditions. ThT binding can determine the propensity of proteins to aggregate in a few days, illustrating that ThT binding would be a valuable screening tool.
2:35 The Use of DNA Immunization Technology to Create Antibodies against Targeted Conformational Epitopes
Ross Chambers, Ph.D., Senior Scientist, SDIX
DNA immunization-based approaches provide efficient access to conformational epitopes for antibody development. Our Genomic Antibody Technology™ represents a highly optimized form of DNA immunization. Antigen design is key to the success of the process and allows specific regions to be targeted, overcome expression problems, and avoid immune dominance from undesired epitopes.
3:05 Refreshment Break in the Exhibit Hall with Poster Viewing
3:50 Problem Solving Breakout Discussions
Concurrent problem solving breakout discussions, open to all attendees, speakers, sponsors, and exhibitors, provide a forum for discussing key issues and meeting potential collaborators. Plan to take part and explore these topics in-depth. Please pick a topic of your choice, find your table and join in.
Engineered Antibody Domains (eAds) as Candidate Therapeutics
Moderator: Dimiter Dimitrov, Ph.D., Head, Protein Interaction Group, Membrane Structure & Function, NIH-NCI
• eAds vs full antibodies vs peptides - advantages and disadvantages
• Stability - increased by additional S-S bonds or other mutations
• Immunogenicity - could be a problem for some Penetration into tissues - excellent but short half-life Pharmacokinetics - the short half-life can be increased in various ways
• Aggregation - a major challenge for eAds
Optimization of the Pharmacokinetics of Therapeutic Proteins
Moderator: David G. Lowe, Ph.D., Fellow, Research & Development, MedImmune Ltd.
• Methods for modification and optimization of antibody pharmacokinetics
• Modification of pharmacokinetics of non-antibody therapeutic proteins and peptides
• Key challenges in engineering therapeutic proteins for optimal pharmacokinetic properties
Challenges with Antibody Screening Assays
Moderator: Paula Harrison, Ph.D., Head, High Throughput Screen, MedImmune Ltd.
• The right screening cascade
• Choice of assay format/technology
• Sample tolerance
• Assay sensitivity
• Disease relevance
Targeting Amyloid and Other Protein Misfolding Diseases
Moderator: Robin Barbour, Director, Antibody Technology, NeoTope Biosciences
• Target selection
• Approaches for antibody development
• Difficulties encountered along the path to the clinic
Emerging Analytical Tools for Screening Stability and Aggregation of mAbs
Moderator: Veysel Kayser, Ph.D., Research Engineer, Chemical Engineering, MIT
• Currently available screening tools and their shortcomings
• New emerging analytical tools for candidate and formulation screening
• Why do we need new screening methods?
• Optimizing biotherapeutic formulation development
Protein Purification from Transgenic Algae
Moderator: Zivko Nikolov, Ph.D., Professor, Biological & Agricultural Engineering, Texas A & M University
4:50-6:00 Networking Reception in the Exhibit Hall with Poster Viewing
Poster Awards Sponsored by
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